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'55:?“ .9." «r 43;“. - .11."! .‘A 'niaws IIIIHIll”lllHlllllllllltlHtlllllllllllllllllllllllllllll 3 1293 01019 7618 This is to certify that the dissertation entitled STUDIES OF THE 3—AZA-COPE REARRANGEMENT AND AZA-ANNULATION FOR THE CONSTRUCTION OF NITROGEN HETEROCYCLES presented by Gregory Richard Cook has been accepted towards fulfillment of the requirements for Ph.D. Chemistry degree in fags/M Major professor Date December 14, 1993 MS U is an Affirmative Action/Equal Opportunity Institution 0- 12771 LIBRARY 1 Michigan State Unlverslty 30X to man this Momma your record. PLACED! RETURN m on or bdorodato duo. TO AVOID FINES Mu 7 MSUIoAnNflnthAwm/Equdowomnnylmnmon 7 W 7 Wan-p.17 STUDIES OF THE 3-AZA-COPE REARRANGEMENT AND AZA-ANNULATION FOR THE CONSTRUCTION OF NITROGEN HETEROCYCLES By Gregory Richard Cook A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY College of Natural Science Department of Chemistry 1993 ABSTRACT STUDIES OF THE 3-AZA-COPE REARRANGEMENT AND AZA- ANNULATION FOR THE CONSTRUCTION OF NITROGEN HETEROCYCLES By Gregory Richard Cook General routes for the synthesis of alkaloids utilizing the charge-promoted 3-aza- Cope rearrangement and aza-annulation methodologies were explored. An efficient and general synthesis of N -alkyl-N -allyl enamines has been established through the condensation of allylamine with a carbonyl compound, followed by acylation with an acid chloride. Enamines of isobutyraldehyde, n-butanal, 2-phenylpropanal, cyclohexanone, and cyclopentanone were prepared in high yields. The E olefin selectivity of this process was high, giving only the E isomer with n-butanal, and a 86:14 E :2 ratio with 2- phenylpropanal. Acceleration of the aliphatic 3-aza-Cope rearrangement with a variety of electrophiles has been accomplished, and reduction of the imine products in situ provided high yields of figs-unsaturated amines. Of the elecu'ophiles examined, organoaluminum reagents afforded the broadest range of utility for this [3,3] rearrangement. Examination of the degree of asymmetric induction in the charge-promoted 3-aza- Cope rearrangement was carried out. Relative asymmetric induction transferred from amino acid derived chiral auxiliaries was found to be very low (8-20% de). Internal asymmetric induction was determined to be highly dependent on the promoting reagent as well as the substitution of the enamine olefin. Diastereomer ratios ranged from 52:48 to 95:5. Selectivity was found to be very high with concomitant relative and internal asymmetric induction for some cases (>95z5). The [3,3] rearrangement of the enamine derived from 2-phenylpropanal, with a variety of starting enamine olefin ratios, provided modest selectivity (54:37:9 - 89:8:2). Ring expansion reactions were accomplished, and yielded a nine-membered ring with complete stereoselectivity. The ring expansion process provided evidence of a reversible [3,3] rearrangement. Aza-annulation quickly afforded six-membered nitrogen heterocyles, and methods for the modification of this 8-lactam template were investigated. This methodology was applied to the synthesis of hydroxylated alkaloids, and the first total synthesis of (i)- prosopinine was accomplished. To my wife Lisa and my parents Clayton and Lucille iv ACKNOWLEDGEMENTS First and foremost, I would like to extend my deepest appreciation to Dr. John Stille. You have instilled in me an excitement and enthusiasm for research that I never knew was possible. I have learned many valuable things from working with you that will stay with me always. Though I'm sure you won't need it, I'd like to wish you the best of luck in your career. Second, I'd like to say "thanks" to my wife Lisa. You kept me sane and stuck it out through all the delays. I couldn't have asked for anyone better to accompany me on this trip through life, and, well, I'll tell you the rest in private! As for my fellow group members, I owe you a lot. Nancy, it's been a lot of fun working with you. I appreciate all you've done for me. You're the best spell/grammar checker anyone could ask for. Keep the country playing! Lars, I couldn't have finished Chapter V without you. You and Elizabeth have been wonderful friends. Good luck in whatever career you decide to pursue. Petr, you're the funniest Czech I've ever met! Keep up the good work and don't forget to email me. Carol, my thio-sister, thanks for being a friend. Brian, good luck at Rutgers. Subramani, thanks for all the interesting debates, discussions, arguments, and for being a great friend. (Let's go down!) Paulvannan, I don't know what I would have done without your encyclopedia brain. I want to thank you and Susila for your friendship. Art, save me a bench, I'm on my way! I would like to thank all the students at MSU who have made my stay here very enjoyable. Thanks to Dr. Jackson for all his encouragement and advice. I would also like to extend my appreciation to the staff who have helped me tremendously; Evy, Long, Kermit, Lisa, Beth, and everyone else who have made my work easier. TABLE OF CONTENTS LIST OF TABLES ............................................................................... viii LIST OF FIGURES ............................................................................. ix LIST OF SCHEMES ............................................................................ x LIST OF ABBREVIATIONS ................................................................... xi CHAPTER I. AN INTRODUCTION TO STRATEGIES FOR ALKALOID SYNTHESIS Biological Importance of Alkaloids ................................................... 1 3-Aza-Cope Strategy .................................................................... 3 Aza-Annulation Strategy ............................................................... 4 References ............................................................................... 7 CHAPTER II. ENAMINE SYNTHESIS Background: Enamine Synthesis ..................................................... 10 Preparation of Enamines in the Presence of AlMe2C1 .............................. 11 Preparation of N-Allyl-N-Isobutyl Enamines ........................................ 14 Summary ................................................................................. 18 Experimental ............................................................................. 20 References ............................................................................... 32 CHAPTER HI. CHARGE-PROMOTED 3-AZA-COPE REARRANGEMENT Background: Charge-Promoted 3-Aza-Cope Rearrangement ..................... 33 Charge-Promoted 3-Aza-Cope Rearrangement of N—Allyl-N-Isobutyl Enamines ................................................................................. 34 Summary ................................................................................. 38 Experimental ............................................................................. 39 References ............................................................................... 44 CHAPTER IV. ASYMMETRIC INDUCTION IN THE CHARGE- PROMOTED 3-AZA-COPE REARRANGEMENT Background: Asymmetric Induction in 3-Aza—Cope Rearrangements ............ 45 Amino Acid Derived Chiral Auxiliaries in the Charge-Promoted 3-Aza-Cope Rearrangement .......................................................................... 51 Internal Asymmetric Induction ........................................................ 56 Concomitant Relau've and Internal Asymmetric Induction ......................... 61 Asymmetric Ring Expansion Reactions .............................................. 67 Summary ................................................................................. 70 Experimental ............................................................................. 71 References ................................................................................ 96 CHAPTER V. , AZA-ANNULATION AS A ROUTE TO- HYDROXYLATED ALKALOIDS. THE TOTAL SYNTHESIS OF (i)-PROSOPININE Background: Isolation and Synthesis of Prosopis Africana Alkaloids ........... 98 Model Studies for Alkaloid Synthesis ................................................ 103 Total Synthesis of (:t)-Prosopinine ................................................... 209 Summary ................................................................................. 1 16 Experimental ............................................................................. 1 17 References ............................................................................. g. .. 134 REPRINTS OF PUBLICATIONS Table 11-1. Table 11-2. Table III- 1. Table IV-l. Table IV-2. Table IV-3. Table IV -4. Table IV-S. Table IV-6. Table IV -7. LIST OF TABLES Preparation of Enamines in the Presence of AlMezCl ....................... 13 Isolated Yields for N-Allyl-N-Isobutyl Enamine Formation ................ 17 Proton and Lewis Acid Promoted 3-Aza-Cope Rearrangements ........... 36 Asymmetric 3-Aza—Cope Rearrangements Catalyzed by TiCl4 .............. 47 Diastereoselective 3-Aza-Cope Rearrangement of Ketene N,0-Acetals. . . . 50 Asymmetric Induction with Chiral Auxiliaries ................................ 54 Yields of N-(E)-2-Hepten- 1-y1 Enamides and Enamines .................... 58 Internal Asymmetric Induction ................................................. 59 Yields of N-(E)-3-penten-2-y1 Enamides and Enamines .................... 62 Concomitant Relative and Internal Asymmetric Induction .................. 63 LIST OF FIGURES Figure I-l. Alkaloids Containing Six-Membered Nitrogen Heterocycles .............. 2 Figure I-2. Aza-Annulation: Convergent Synthesis of 8—Lactams ...................... 5 Figure I-3. Modification of the 5-Lactam Template ....................................... 6 Figure TV-l. 3-Aza-C0pe Transition States .................................................. 45 Figure IV -2. Expected Coordination of Electrophiles with Amino Acid Derived Chiral Auxiliaries ................................................................ 52 Figure IV -3. Possible Imine-Enamine Tautomerization .................................... 59 Figure IV-4. Reversible Ring Expansion Reaction ......................................... 70 Figure V-l. Structures of Some Prosopis Alkaloids ...................................... 98 Figure V—2. Compounds with Structural Features Similar to those of Prosopis Alkaloids .............................................................. 99 Figure v-3. NOE for V-42a and V-42b ................................................... 109 Figure V-4. NOE for V-Sl ................................................................... 112 Figure v-5. 1H and 13c NMR of Prosopinine v.1 ........................................ V115 Scheme I-l. Scheme 11- 1. Scheme II-2. Scheme II—3. Scheme III-l. Scheme IV- 1. Scheme IV-2. Scheme IV-3. Scheme IV-4. Scheme IV-5. Scheme IV-6. Scheme IV-7. Scheme IV-8. Scheme V-l. Scheme V-2. Scheme V-3. Scheme V-4. Scheme V—5. Scheme V-6. Scheme V-7. Scheme V-8. LIST OF SCHEMES 3-Aza—Cope Strategy for the Preparation of 8,8-Unsaturated Amines ... 4 Preparation of Methoxymethyl Pyrrolidine II-4 ........................... 14 Different Synthetic Routes to Enamine II-lSa ............................ 16 Synthesis of N-Allyl-N-Isobutyl Enamine Substrates ..................... 17 Proton and Lewis Acid Promoted 3-Aza-C0pe Rearrangements ......... 36 Asymmetric 3-Aza-Cope Rearrangement of N—Allylamide Enolates ..... 49 Asymmetric Induction in the 3-Aza-Cope Rearrangement of Ketene N,0-Acetals ..................................................................... 50 Methylation of Amino Alcohols .............. y ................................ 53 Preparation of a-Methoxy Acid IV -23 ..................................... 55 Preparation of Enamine IV-25 .............................................. 56 Synthesis of (B-Z-Hepten-l-ylamine ........................... , ............ 57 Synthesis of N-(E)-3-Penten-2-yl Enamines ............................... 62 Transition States for the 3-Aza-Cope Rearrangement of IV-3Sb ........ 65 Synthetic Route to Prosophylline ............................................. 100 Route to (-)-Desoxoprosopinine and (-)-Desoxoprosophylline ........... 101 Route to (:t)-Desoxoprosopinine .................... 102 B—Amino Acid Rearrangement ................................................ 107 Introduction of the C—3 Hydroxyl Substituent of Prosopinine ............ 110 Homologation of the Lactam Carbonyl ...................................... 111 Preparation of the Aliphatic Witti g Reagent ................................. 113 Wittig Homologation and Deprotection to Give (i)-Prosopinine (V -l).. 114 E? Boc i—Bu n-Bu t-Bu n-BuLi Bz Cbm de DIBAH DMF DMSO DPPA 5+ LIST OF ABBREVIATIONS Aoetyl 2,6-Diphenylphenoxy Benzyl t-Butylcarboxy Isobutyl Normal Butyl Tertiarybutyl n-Butyllithium Benzoyl Carbomethoxy Carbobenzoxy Diastereomeric Excess Diisobutyl Aluminum Hydride NJV-Dimethylformamide Dirnethylsulfoxide Diphenylphosphorylazide Electrophile Enantiomeric Excess Ethyl Lithum Aluminum Hydride Methyl NOE Ts stOH Methoxymethyl Nuclear Overhauser Effect Phenyl Isopropyl Phthalimide Tetrahydrofuran Trimethylsilyl p—Toluenesulfonyl p-Toluenesulfonic Acid CHAPTER I. AN INTRODUCTION TO STRATEGIES FOR ALKALOID SYNTHESIS Biological Importance of Alkaloids Alkaloids, compounds which possess a nitrogen heteroatom, are prevalent in nature, and many that contain six-membered nitrogen heterocycles display a wide range of biological activity.1 The piperidine alkaloids can have simple structures such as pinidine (I-l), or more complex features like the hydroxylated piperidines I-2 and L3 (Figure I-l). These hydroxylated alkaloids display a broad range of physiological effects due to their ability to mimic carbohydrates and peptides in biological systems.2 Alkaloids with the general structure of 14, which bear along aliphatic chain, also show interesting biological properties ranging from anesthetic and antibiotic to antitumor activity. These compounds include the Prosopis alkaloids (R2 = CH20H)3 as well as several others in which R2 = Me.4 Bicyclic alkaloids often show intriguing biological properties. The decahydroquinoline, pumiliotoxin C (I-S), isolated from Dendrobates pumilio, a Panamanian frog, displays toxicity at high concentrations.5 Derivatives of lupinine (I-6) possess local anesthetic characteristics,6 and swainsonine 0-7), which belongs to the indolizidine class of alkaloids, is another potent carbohydrate mimic.l The indolizidine, ipalbine (I-8), isolated from the seeds of Ipomoea alba, is structurally very similar to septicine (I-9), which was extracted from Ficus septica. These were the first simple, unfused, indolizidine alkaloids isolated from natural sources. Several reports of their total synthesis have appeared in the literature.7 Clearly, piperidine alkaloids, especially those that are polyhydroxylated, will have a great impact on the treatment of many physiological anomalies. The development of facile and efficient new routes to these alkaloid skeletons, for the rational design of new drugs, has been a focus of synthetic efforts in our group. Piperidine Alkaloids OH OH , ,, on on II Me‘“ N ” %\Me N N R1 N R2 H H . H H Pinidine Deoxynorjirimycin Deoxymannojirimycin R1 = lipid long chain R2 = Me, 01on I- I I-2 L3 L4 Hydroquinoline and Quinolizidine Alkaloids OH Me _/ t 1,, N N I /\Me 0:) H Pumiliotoxin C Lupinine I-S I-6 Indolizidine Alkaloids Ipalbine (R = B-D-glucose) Ipalbidine (R = H) I-8 Swainsonine I-7 FIGURE I-l. Alkaloids Containing Six-Membered Nitrogen Heterocycles 3-Aza-Cope Strategy The cyclization of 5,8-unsaturated amines (I-10) has been studied and several reports have appeared in the literature (eq I-1).8 Electrophilic reagents utilized for this cyclization include Hg(II) salts, 12, Brz, Pd(II) catalysts, as well as transition metal hydrides. In most cases the predominant product of this cyclization was the five-membered ring, I-12. The pyrrolidine, I-12, could be further elaborated, by extending the alkyl substituent containing E, to afford compounds which could be further cyclized to indolizidine skeletons. A more direct approach to indolizidines is the transannular cyclization9 of I-l3, which would afford the bicyclic I-l4 (eq I-2). Therefore, methods for the preparation of the requisite unsaturated amines would provide easy access to these nitrogen heterocycles. H , H R\ R—N E R-N lizati N R-N 3— m M» Q QM \ ‘\ +0, 1. 1 o ‘B' E I - l 2 1.11 E H N F.“ N C3 cyclization : (1'2) E I - 1 3 I- l 4 Our approach to 8,6-unsaturated amines (I-lO) involved the use of the 3-aza-Cope rearrangement (Scheme I-l). Beginning with an N-allylenamine (I-lS), [3,3] sigmatropic rearrangement would afford imine I-l6. In most reported cases of 3-aza-Cope rearrangements, the imine products were hydrolyzed to give the corresponding aldehydes. Our approach was to reduce the imine functionality to provide the secondary amine, I-10. The cyclic amine, I-l3, could be obtained by analogous rearrangement of enamines with 4 the general structure of I-17 (eq I-3). To increase the diversity of substitution on the amines, a general and efficient route to the N-allylenamine substrates needed to be developed (Chapter II). As the thermal 3-aza-Cope rearrangement occurs at relatively high temperatures, methods for promoting the reaction to a synthetically useful range was required (Chapter III). In order to exploit the well-defined transition state of [3,3] rearrangements for stereochemical control, a detailed investigation of the factors that influence asymmetric induction was essential (Chapter IV). SCHEME I-l. 3-Aza-Cope Strategy for the Preparation of 8,e-Unsaturated Amines 1%ch RxN,/.-..\.. [3:51 “\N/ tH'] H13 I-15 I-16 1.10 1) [3.3] H /\ 2 ' N \ )[H] : N (1-3) / \ I-17 I-13 Aza-Annulation Strategy Aza-annulation methodology, systematically investigated in our group, involved the convergent, one—pot synthesis of 8—lactams (1-18) from three common starting compounds (Figure I-2). The process entailed the addition of a primary amine to a carbonyl compound or alkyne (conjugated with an electron withdrawing group) to give an imine or enamine which was subsequently reacted with an a,B-unsaturated acid derivative. The reaction of imines derived from carbonyl compounds where R3 = alkyl with acrylic acid derivatives has been explored, and a mixture of lactam and uncyclized enamides was obtained.10 This 5 reaction has been investigated by our group, and evidence for an initial Michael addition followed by N-acylation mechanism has been obtained.11a If R3 was an electron withdrawing group (ketone, ester, -CN), only lactam products were obtained.12 This annulation methodology has been applied to the synthesis of (i)-lupinine (I-6),11b (i)-5- epipumiliomxin.1 1° and (i)-tashiromine.11d 2 3 R R‘ R3 R3 R R1 3 4s / <== . .I = a II 1 o N R4 o R‘ o x I R‘ I-18 J! NH, 1!, FIGURE 1-2. Aza-Annulation: Convergent Synthesis of 8—Lactams With an efficient and facile route to I-18, the preparation of a variety of alkaloids could be achieved. The &1actam template offers a wide range of possibilities for further modification (Figure I-3). If R3 is an electron withdrawing group, the possibility for conjugate addition to C-6 exists. The double bond could be selectively reduced giving a cis disubstituted heterocycle.ll The substituents that were in place during the annulation process could be further manipulated by functional group conversions. Enolate chemistry would provide the ability to functionalize the 03 position, and oxidation could provide (LB-unsaturated lactams, which would allow modification of the C-4 position as well. The lactam carbonyl could be reduced to afford C—2 unsubstituted piperidines, or homologated 6 by a number of methods to allow the inclusion of a variety of groups found in natural piperidine alkaloids. 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(i) Hofle, G.; Steglixh, W.; Vorberggen, H. Angew. Chem. Int. Ed. Engl. 1978, 17, 569. (k) Ninomiya, I.; Kiguchi, T. J. Chem. Soc., Chem. Commun. 1976, 624. (l) Ninomiya, 1.; Naito, T.; Higuchi, S.; Mori, T. J. Chem. Soc., Chem Commun. 1971, 457. (m) Ninomiya, 1.; Naito, T.; Higuchi, S. J. Chem. Soc., Chem. Commun. 1970, 1662. (a) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1992, 57, 5319. (b) Paulvannan, K.; Schwarz, J. B.; Stille, J. R. Tetrahedron Lett. 1993, 34, 215. (c) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34 , 6673. (d) Paulvannan, K. PhD Dissertation 1993. (a) Huang, Z. T.; Zhang, P. C. J. Chem. Soc. Perkin Trans. 1 1993, 1085. (b) Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J. Org. Chem. 1993, 58, 611. (0) Coco, M. T.; Congiu, C.; Maccioni, A.; Onnis, V. Synthesis 1992, 371. (d) Capps, N. K.; Davies, G. M.; Loakes, D.; McCabe, R. W.; Young, D. W. J. Chem. Soc. Perkin Trans. 1 1991, 3077. (e) Singh, B.; Lesher, G. Y.; Brundage, R. P.; Synthesis 1991, 894. (f) Huang, 2. T.; Zhang, P. C. Chem. Ber. 1989, 122, 2011. (g) Fang, G. F.; Danishefsky, S. J. Tetrahedron Lett. 1989, 28, 3621. (h) Brunerie, P.; Celerier, J. P.; Huche, M.; Lhommet, G. Synthesis 1985, 735. (i) Nagasaka, T.; Inoue, H.; Ichimura, M. Synthesis 1982, 848. (i) Danishefsky, S. J.; Etheredge, S. J. J. Org. Chem. 1974, 39, 3430. (k) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. (C) 1971, 2112. CHAPTER II: ENAMINE SYNTHESIS Background: Enamine Synthesis In order to fully utilize the 3—aza-Cope rearrangement in organic synthesis, efficient and facile methods for the preparation of a wide variety of enamines needed to be studied. A variety of methods for the synthesis of enamines have appeared.1 The vast majority involve the condensation of a secondary amine with an aldehyde or ketone with various methods used for removal of the water formed in the reaction (eq II-1). R2 R‘ O 1.1+ \NH + /U\ 4 Rknjfi/Ra (II-1) Rn’ R2 CHR3R‘ ’H20 | R1 R‘ Mannich and Davidsen first reported that secondary amines and aldehydes condensed in the presence of potassium carbonate to give enamines,2 and reactions proceeded at temperatures as low as 5 °C. Ketones required calcium oxide, higher temperatures and resulted in poor yields. Almost two decades later, Herr and Hey] reported that enamines of ketones and aldehydes could be more easily prepared in benzene with azeotropic removal of water.3 In some cases, the addition of a catalytic amount of p-toluenesulfonic acid was required, and yields were generally good (60-90%). This procedure worked well with a,a-disubstituted aldehydes while straight chain aldehydes often reacted through aldol condensation pathways and gave only oligomeric products. Further, the preparation of enamines from ketones and acyclic secondary amines by this method was very sluggish. Other drying agents have been employed as well. Ketones and amines could be condensed over magnesium sulfate in the absence of any solvent and provided good yields (77-84%) of enamines at room temperature.4 10 l 1 In 1967, White and Weingarten reported that enamines could be obtained from secondary amines and carbonyl compounds in the presence of TiCl4.5 The Lewis acid acted both as a catalyst for the reaction and as a water scavenger (eq. II-2). This method has since been studied by Carlson and others, and has been optimized to provide good yields of enamines with short reaction times.6 1 R\ o 6 NH + 2 2 + Tic14 : R1, R \/U\R3 (11-2) While the TiCl4 procedure worked well for the two most commonly studied amines (morpholine and pyrrolidine), as Hill demonstrated, the use of an allylic amine gave rearranged products rather than the pure enamines.7 Furthermore, a large excess of the amine was required, and this method would not be efficient if a costly chiral amine were used. This method failed to produce good yields of enamines derived from aldehydes that have more than one a-hydrogen (straight chain aldehydes) and ketones. Preparation of Enamines in the Presence of AIMeZCl The studies described above for the preparation of enamines in the presence of TiCl4 prompted us to explore the use of other Lewis acids in this condensation process. For this reaction, a secondary amine was first complexed with AlMezCl and then condensed with a carbonyl compound at room temperature (eq II-3). The reaction of amine-aluminum complexes with esters has been reported.8 It was hoped that the use of an organoaluminum Lewis acid/water scavenger would allow for the use of stochiometric 12 amounts of amines due to the fact that methane would be produced as a byproduct rather than HCl. To probe the applicability of this condensation process, three amines were chosen to be condensed with a variety of carbonyl compounds. Table II-l summarizes the results of this study. Reactions were carried out at ambient temperature for 1 hour, and enamine II-S was prepared from N -methylaniline and isobutyraldehyde in 75% yield. Condensation with 2-phenylpropionaldehyde provided enamine II-6 in 85% yield as a mixture of isomers (E:Z 83:17). Unfortunately, attempts to prepare the enamine of butyraldehyde led to the formation of aldol products. It was hoped that the reaction would proceed with the acetal of butyraldehyde, but product formation was not observed. Two other amines were tested with isobutyraldehyde and 2- phenylpropionaldehyde. Methoxyamine II-4, prepared as shown in Scheme II-l, and pyrrolidine gave similar results as N-methylaniline. Enamine II-7 was prepared in 72% yield. Likewise, enamine II-8 was obtained in 76% as a mixture of isomers (E:Z 90:10). The condensation of pyrrolidine with isobutyraldehyde gave enamine II-9 in only 49% yield, perhaps due to its high volatility. However, enamine II-10, being less volatile, was prepared in respectable yield (76%, El 84:16). Attempts to condense these amine- aluminum complexes with ketones gave no condensation products. The use of AlMe2Cl in the condensation of secondary amines and carbonyl compounds was an efficient and facile process. Short reaction times (1 hour) and mild conditions (ambient temperature) have been employed and high yields of enamines were obtained. Unfortunately, this process, as in the TiCl4 catalyzed process, was limited to the preparation of enamines derived from a,a—disubstituted aldehydes only. However, only one equivalent of amine was required eliminating the waste of costly amines. . .. AIM l(0.5 . .. RzNH + RR CHCHO 62C “9 = RZNCH=CRR (II-3) Toluene, RT TABLE II-l: Preparation of Enamines in the Presence of AlMe2Cl Amine Aldehyde Enamine Yield (E :Z) _ Me O pk~ Me P“ ‘1‘“ >—(/ 15 \ 75% M" Me 11 Me Me II-S P11 0 Ph H ““er 85% (83:17) Me H Me Me 0 11.6 CE, OMe II-4 ONH Me 0 Me H Ph 0 Me H Me 0 Me H Ph 0 Me H Oligomers 72% 76% (90:10) 49%“ 78% (84:16) "This product was difficult to isolate due to its volatility. l4 SCHEME II-l. Preparation of Methoxymethly Pyrrolidine II-4 @ LiAlH4 _ Chi, EtOCHO A d0 , OH , c0211 (85%) on aq. KOH CHO cu - N’ W" (85%) CK/OMe ”'4 II-3 Preparation of N-Allyl-N-Isobutyl Enamines In order to study the scope and utility of the charge-promoted 3-aza-Cope rearrangement (Chapter 111), an efficient and selective synthesis of a wide variety of N- alkyl-N-allyl enamines was required. Methods of forming enamines derived from ketones and aldehydes possessing a range of substitution variation was needed. Further, any methods developed should selectively produce a major isomer in the case where E :Z enamines could arise. As shown in Scheme II-2, four different routes to the N-alkyl-N-allyl enamine 11- 15a were explored. Starting from allylamine, condensation with isobutyraldehyde resulted in the formation of II-lla in 74% isolated yield. Reduction of this imine with LiAlH4 gave allylisobutylamine (II- 12) in 84% yield. Condensation with isobutyraldehyde, catalyzed by p-toluenesulfonic acid (stOl-I), provided enamine II- 15a in 80% distilled yield. The secondary amine II-12 could also be prepared in high yield by acylation of allylamine with isobutyryl chloride (II-l3, 95% yield) followed by reduction with LiAlH4 (88% yield). It was thought that II-15a could be obtained by the reduction of enamide II-l4a. The allylamide II-13 could be condensed with 15 isobutyraldehyde to give the enamide in high yield, however long reaction times were required (66 hours for completion). Acylation of imine II-lla with isobutyryl chloride resulted in nearly quantitative yields of the desired enamide (99% yield). These enamide compounds were much more stable to hydrolysis than the corresponding enamines and could be purified by silica gel chromatography. This synthetic sequence provided for high yields of pure enamines upon reduction. Reduction of II-l4a resulted in a 98% yield of the N—alkyl-N-allyl enamine. The efficiency of this route was improved by direct acylation of imine II-lla, prepared from allylamine without isolation, providing a 94% yield (for two steps) of enamine II-l4a. Thus, the synthesis of enamine II-lSa was achieved from allylamine in 92% overall yield. With an optimal route for enamine synthesis, N—allyl-N-isobutyl enamines derived from butanal, 2-phenylpropanal, cyclohexanone, and cyclopentanone were prepared (Scheme II-3, Table II-2). In order to study the selectivity in the formation of the enamine-olefin geometry, n-butanal was employed inthis sequence. As mentioned earlier, the use of linear aldehydes in the traditional condensation methods with a secondary amine gave aldol products. Similar products were observed while preparing the imine of allylamine and n-butanal in refluxing benzene. Therefore, it was necessary to prepare the imine II-llb at room temperature and isolate it by distillation. Since this compound was quite volatile, only a modest yield of 68% was obtained. Acylation with isobutyryl chloride provided a 90% yield of enamide II-l4b as a 63:37 mixture of E2 isomers, respectively. Employing pyridine as the base, this ratio increased slightly to 71:29. Reduction of this mixture of enamides gave a 95% yield of a single compound which was determined by 1H NMR to be the E isomer. The mechanism by which this isomerization occurred is not fully understood, and probably resulted from the ability of the rt-electrons to delocalize during the reduction process. This resonance would allow rotation around the enamine double bond, and lead to the more thermodynamically stable product. l6 SCHEME II-2. Different Synthetic Routes to Enamine II-lSa II-lla l) LiAlH4 2) aq. NaOH (34%) l7 SCHEME II-3. Synthesis of N -Allyl-N-Isobutyl Enamine Substrates II-ll II-l4 1)LiAlH4 2)aq.NaOH R‘ R2 R3 a H Me 11 b H Et R1 C Me 11 H Ph D46 Me R2 (1 (cm),- H WAN \ H II-lS TABLE II-2. Isolated Yields for N-Allyl-N—Isobutyl Enamine Formation yield, % II-ll II-l4 II-lS a a 94 98 b 68 90b 7 95 c a 790 96d d a 82 98 e a 68 90 “Carried on to II-l4 without isolation. bMixture of isomers E:Z (63:37). CMixture of isomers E :Z (57:43). dMixture of isomers E:Z (86: 14). 18 Similar results were observed in the formation of the enamine derived from 2- phenylpropanal. In situ imine formation in benzene, followed by acylation with isobutyryl chloride gave enamide II-l4c in 79% overall yield. A 57:43 mixture of enamine geometric isomers was obtained. The major isomer was determined by 1H NMR Nuclear Overhauser Enhancement techniques to have the E enamine geometry, while the minor isomer had Z geometry. As was observed for the reduction of II-l4b, this ratio changed upon treatment with LiA1H4. Reduction provided a 96% yield of 11- 15c in a 86:14 (E:Z) ratio. Enamines derived from cyclic ketones, cyclohexanone and cyclopentanone, were also prepared by this method. Reaction of allylamine with cyclohexanone gave imine II- lld, which was acylated without isolation to provide II-14d in 82% overall yield. Reduction with LiAlH4 resulted in formation of II- 15d in 98% yield. Cyclopentanone was more sluggish during the imine formation and II-lle showed a greater sensitivity towards hydrolysis than cyclohexanone. Nevertheless, in situ acylation with isobutyryl chloride gave enamide II-l4e in 68% yield. The desired enamine II-lSe was obtained in 90% yield after reduction. Summary A new method for the synthesis of enamines from secondary amines and aldehydes was developed employing AlMezCl as a water scavenger. Good yields of enamines were obtained, cleanly, without the loss of amine as by-products. This method appeared to be limited to a,a-disubstituted aldehydes, as linear aldehydes lead to aldol products and ketones did not react. An efficient and general synthesis of N-alkyl-N-allyl enamines has been established through the condensation of allylamine with the appropriate carbonyl compound, followed by acylation with acid chlorides. Enamines of isobutyraldehyde, n-butanal, 2-phenylpropanal, cyclohexanone, and cyclopentanone have 19 been prepared in high yields. Most notable was the fact that enamines of ketones and linear aldehydes could be prepared. The E olefin selectivity of this process was high, giving only the E isomer with n-butanal, and a 86:14 E .2 ratio with 2-phenylpropanal. EXPERIMENTAL General Methods All reactions were carried out performing standard inert atmosphere techniques to exclude moisture and oxygen, and reactions were performed under an atmosphere of either nitrogen or argon. Benzene, toluene, tetrahydrofuran (THF), and EtzO were distilled from sodium/benzophenone immediately prior to use. Triethylamine, methylene chloride, dioxane, and pyridine were heated at reflux over calcium hydride for a minimum of 12 hours and then distilled immediately prior to use. Solutions of HCl (1.0 M in Et20) and LiAlH4 (1.0 M in THF) were obtained from Aldrich Chemical Company. Solutions of A1Me3 (2 M in toluene), MezAlCl (1 M in toluene), and DIBAL-H (1 M in THF) were prepared from neat organoaluminum compounds obtained from Aldrich Chemical Company. TiCl4 were distilled prior to use. All other organic reagents were used as provided by the vender or purified by distillation. Additions were made with gas tight syringes, or via cannula transfer under nitrogen or argon. Unless specified, concentration of solutions after workup was performed on a Biichi rotary evaporator. Oven temperature ranges are reported for bulb to bulb (Kugelrohr) distillations. Gas chromatographic (GLC) analyses were carried out on a Perkin-Elmer 8500 instrument with a 50 m RSL-200 capillary column (5% methyl phenyl silicone) and an FID detector at a 220 °C injector temperature, and a 300 °C detector temperature. Helium gas pressure was set at 15 psi with a flow rate of 2 mIJmin. NMR spectra were obtained on Varian Gemini 300, VXR-300, or VXR-SOO spectrometers with CDCl3 as solvent. 1H NMR data are reported as follows: chemical shift relative to residual CHC13 (7.24 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet, m = multiplet), coupling, and integration. 13C NMR data are reported as chemical shift relative to CDC13 (77.0 ppm). 20 21 Preparation of Prolinol (II-l): To a suspension of LiAlH4 (7.6 g, 200 mmol) in THF (400 mL) was added proline (11.51 g, 100 mmol), and the mixture was heated at reflux overnight. The reaction was quenched with 7.6 mL H20, 7.6 mL 15% aq. NaOH, followed by 22.8 mL H20, stirred for 15 minutes and then filtered. After concentration by rotary evaporation, the oil was dissolved in benzene and heated at reflux overnight with a Dean-Stark trap to collect water. The solution was concentrated, and the oil was distilled (Kugelrohr) to give 7 (8.608 g, 85 mmol) in 85% yield (oven temp 55-65 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.37 (m, 1H), 1.73 (m, 3H), 2.86 (m, 2H), 2.93 (bs, 2H), 3.24 (m, 1H), 3.28 (dd, J = 7.3, 10.1 Hz, 1H), 3.49 (dd, J = 3.4, 10.1 Hz, 1H); 13c NMR (75.5 MHz) (CDCl3) 8 25.9, 27.5, 46.4, 59.6, 64.8. Preparation of Formate Protected Methylmethoxy pyrrolidine 11-3: To prolinol (8.092 g, 80 mol) at 0 °C was added ethyl formate (6.519 g, 88 mmol), and the mixture was stirred at room temperature for one hour. The volatile materials were removed by rotary evaporation and the crude formamide (II-2) was dissolved in THF (100 mL). MeI (11.355 g, 80 mmol) was added, the solution was cooled to 0 °C, and NaH (2.112 g, 88 mmol) was added. After heating at reflux for 30 minutes, 100 mL of H20 were added, and the methoxy formamide was extracted with 3 x 200 mL CH2C12, dried over MgSO4, and concentrated. Kugelrohr distillation provided II-3 (9.636 g, 67 mmol) in 84% yield (oven temp 75-85 °C, <1 mmHg). Hydrolysis of IV-3 to Methylmethoxy Pyrrolidine II-4: Formarnide II-3 (9.60 g, 67 mmol) was placed in 6 M aq. KOH (200 mL), and heated at reflux overnight. The amine was extracted with 3 x 200 mL of EtzO, dried over Na2804, and concentrated. Distillation (Kugelrohr) gave II-4 (6.553 g, 57 mmol) in 85% yield (oven temp 50-55 °C, 34 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.28 (m, 1H), 22 1.64 (m, 3H), 2.21 (bs, 1H), 2.75 (m, 1H), 2.84 (m, 1H), 3.16 (m, 2H), 3.24 (m, 1H), 3.26 (s, 3H); 13C NMR (75.5 MHz) (CDCl3) 8 25.1, 27.7, 46.3, 57.5, 58.8, 76.1. General Procedure for AlMezCl Promoted Enamine Preparation: To a solution of secondary amine (0.5 eq.) in toluene (0.2 M) was added AlMezCl (0.5 eq., 2 M in toluene) and the mixture was stirred at room temperature for one hour. The amine-Lewis acid complex was transferred via cannula to a solution of secondary amine (0.5 eq.) and aldehyde (1.0 eq.) in toluene (0.2 M). After stirring for one hour, solid K2C03 was added and the mixture was stirred for 10 minutes. Filtration, rotary evaporation, and Kugelrohr distillation provided the pure enamine. II-S: (1.202 g, 7.5 mmol) in 75% yield (oven temp 60-70 °C, <1 mmHg): 1H NMR (300 MHz) (CDC13) 8 1.69 (d, J = 0.8 Hz, 3H), 1.81 (d, J = 1.4 Hz, 3H), 3.07 (s, 3H), 5.84 (qq, J = 0.8, 1.4 Hz, 1H), 6.78 (m, 3H), 7.28 (m, 2H); 13C NMR (75.5 MHz) (CDC13) 8 17.8, 21.8, 38.5, 112.7, 117.0, 125.3, 128.2, 128.9, 129.2. II-6: (1.903 g, 8.5 mmol) in 85% yield as a mixture of isomers (E :2 83:17) (oven temp 100-120 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 2.07 (d, J = 1.3 Hz, 3H), 3.26 (s, 3H), 6.57 (q, J = 1.3 Hz, 1H), 6.81 (m, 3H), 7.39 (m, 5H), 7.55 (m, 2H), (Z isomer) 2.20 (d,J = 1.3 Hz, 3H), 2.84 (s, 3H), 6.35 (q, J = 1.3 Hz, 1H), 6.81 (m, 3H), 7.39 (m, 5H), 7.55 (m, 2H); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 16.0, 38.9, 113.7, 118.2, 125.5, 126.6, 127.3, 128.3, 129.0, 132.5, 141.4, 148.0, (Z isomer) 14.6, 37.9, 113.1, 118.0, 125.5, 126.5, 127.3, 128.1, 129.0, 132.5, 140.5. II-7: (1.223 g, 7.2 mmol) in 72% yield (oven temp 60-70 °C, 10 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.59 (s, 3 H), 1.65 (s, 3 H), 1.66-1.95 (m, 4 H), 2.62 (q, I = 7.1 Hz, 2 H), 2.80-2.98 (m, 2 H), 3.14 (dd, J = 7.8, 9.5 Hz, 1 H), 3.20-3.38 (m, 1 H), 3.30 (s, 3 H), 5.52 (s, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.9, 24.0, 28.8, 54.0, 57.7, 58.1, 64.1, 76.6, 116.6, 134.1. 23 II-8: (1.768 g, 7.6 mmol) in 76% yield as a mixture of isomers (E :2 90:10) (oven temp >100 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.50-2.0 (m, 4 H), 2.12 (s, 3 H), 3.23 (m, l H), 3.28 (m, 1 H), 3.35-3.50 (m, 2 H), 3.36 (S, 3 H), 3.61 (q, I = 7.1 Hz, 1 H), 6.47 (S, l H), 7.07-7.40 (m, 5 H), (Z isomer) 1.50-2.00 (m, 4 H), 2.01 (S, 3 H), 3.00 (m, 1 H), 3.28 (m, 1 H), 3.35-3.50 (m, 2 H), 3.40 (S, 3 H), 3.61 (q, J = 7.1 Hz, 1 H), 6.15 (S, l H), 7.07-7.40 (m, 5 H); 13C NMR (75.5 NIHZ) (CDCl3) 8 (E isomer) 15.7, 24.8, 28.8, 53.1, 59.2, 63.9, 76.8, 111.5, 124.5, 128.1, 128.2, 137.3, 143.9, (Z isomer) 14.6, 22.4, 18.0, 52.9, 57.6, 63.6, 77.2, 107.5, 124.5, 128.3, 129.0, 134.9, 142.4. II-9: (0.616 g, 4.9 mmol) in 49% yield (oven temp 50-60 °C, 30 mmHg): 1H NMR (300 NIHz) (CDCl3) 8 1.59 (d, J = 0.8 Hz, 3 H), 1.66 (d, J = 1.3 Hz, 3 H), 1.74 (m, 4 H), 2.90 (m, 4 H), 5.57 (qq. J = 0.8, 1.3 Hz, 1 H); 13C NMR (75.5 MHZ) (CDCl3) 5 17.9, 23.0, 24.9, 53.7, 114.0, 134.6. II-10: (1.456 g, 7.8 mmol) in 78% yield as a mixture of isomers (E :Z 84:16) (oven temp 80-100 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.85 (m, 4H), 2.14 (d, J = 1.1 Hz, 3H), 3.28 (m, 4H), 6.45 (q, I = 1.1 Hz, 1H), 7.10 (m, 2H), 7.28 (m, 3H), (Z isomer) 1.70 (m, 4H), 2.02 (d, J = 1.1 Hz, 3H), 2.89 (m, 4H), 6.14 (q, I = 1.1 Hz, 1H), 7.10 (m, 2H), 7.28 (m, 3H); 13C NMR (75.5 MHz) (CDC13) 5 (E isomer) 15.6, 25.6, 53.1, 110.4, 124.4, 127.3, 128.1, 137.6, 144.1, (Z isomer) 14.7, 22.9, 52.8, 106.3, 124.4, 127.5, 128.3, 137.6, 144.1. N-Allyl-N-isobutylideneamine (II-11a): A mixture of allylamine (3.54 g, 62 mmol), isobutyraldehyde (4.47 g, 62 mmol), and 4-A molecular sieves in 100 mL of Et20 was stirred for 2 hours at ambient temperature. The solution was then removed from the insoluble material via cannula and distilled at atmospheric pressure to give II-lla (5.11 g, 50.0 mmol) in 74% yield (bp 112-114 °C): 1H NMR (300 MHz) (CDCl3) 81.05 (d, J = 6.9 Hz, 6 H), 2.42 (dsept, J = 24 4.9, 6.9 Hz, 1 H), 3.95 (d, J = 5.6 Hz, 2 H), 5.05 (dd, J = 1.8, 10.3 Hz, 1H), 5.10 (dd, J = , 1.8, 17.2 Hz, 1H), 5.93 (ddt, J = 10.3, 17.2, 5.6 Hz, 1 H), 7.51 (d, J: 4.9 Hz, 1H); 13C NMR (75.5 MHz) (CDCl3) 8 19.3, 34.1, 63.2, 115.5, 136.1, 170.9; IR (neat) 3083, 3013, 2967, 2932, 2874, 2824, 1466, 1456, 1437, 1366, 1103, 1019, 995, 916 cm'l. N-Allylisobutyramide (II-13): To a mixture of allylamine (9.02 g, 158 mmol) and pyridine (12.48 g, 158 mmol) in 600 mL of dry THF at 0 °C was added isobutyryl chloride (16.84 g, 158 mmol). After the addition was complete, the mixture was heated at reflux for 5 hours, cooled to ambient temperature, and washed with 50 mL of 15% aq. NaOH. The aqueous layer was extracted with 4 x 20 mL of 320 and the organic fractions were dried over MgSO4. The solvents were removed by rotary evaporation, and the oil was distilled to give II-13 (18.99 g, 149 mmol) in 95% yield (bp 78 °C, <1 mmHg): 1H NMR (300 MHz) (CDC13) 8 1.13 (d, J = 6.9 Hz, 6 H), 2.37 (sept, J = 6.9 Hz, 1 H), 3.84 (ddd, J = 1.6, 1.6, 6.6 Hz, 2H), 5.09 (ddt, J: 1.4, 10.2, 1.6 Hz, 1 H), 5.14 (ddt,J= 1.4, 17.1, 1.6 Hz, 1 H), 5.81 (ddt, J = 10.2, 17.1, 6.6 Hz, 1 H), 5.85 (br s, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 19.3, 35.3, 41.5, 116.2, 134.5, 177.3; IR (neat) 3293, 2085, 3015, 2971, 1934, 1876, 1645, 1545, 1470, 1422, 1387, 1242, 1098, 988, 918 cm'l. Anal. Calc'd for C7H13NO C, 66.11; H, 10.30; N, 11.01; obsd C, 66.04, H, 9.91; N, 11.85. Reduction of II-lla to N-Allyl-N-isobutylamine (II-12): To a suspension of LiAlH4 (1.37 g, 36 mmol) in 150 mL of Et20 at 0 °C was slowly added II-lla (3.34 g, 30 mmol). After stirring for 2 hours at ambient temperature, the solution was cooled to 0 °C, and quenched by addition of 1.4 mL of H20, followed by 1.4 mL of 15% aq NaOH, and finally 4.1 mL of H20. The mixture was stirred for 1 hour and then filtered through Na2804. The solvent was removed, and the allylic amine was distilled at atmospheric pressure to give H-12 (2.84 g, 25.1 mmol) in 84% yield (bp 122- 25 124 °C): 1H NMR (300 MHz) (CDCl3) a 0.87 (d, J = 6.7 Hz, 6 H), 1.00 (br s, 1 H), 1.70 (tsept, J = 6.8, 6.7 Hz, 1 H), 2.38 (d, J = 6.8, 2 H), 3.20 (ddd, J = 1.4, 1.4, 6.0 Hz, 2 H), 5.04 (ddt, J = 1.7, 10.2, 1.4 Hz, 1 H), 5.13 (ddt, J = 1.7, 17.2, 1.4 Hz, 1 H), 5.88 (ddt, J = 10.2, 17.2, 6.0 Hz, 1 H); 13c NMR (75.5 MHz) (CDC13) 8 20.7, 28.3, 52.6, 57.5, 115.5, 137.2; IR (neat) 3407, 3081, 2959, 2934, 2874, 2811, 1646, 1466, 1385, 1368, 1129, 918 cm-1. Anal. calcd for C7H15N c, 74.27; H, 13.36; N, 12.37; obsd c, 74.43; H, 13.69; N, 12.21. Reduction of II-13 to N -Allyl-N-isobutylamine (II-12): To a suspension of LiA1H4(1.85 g, 48.6 mmol) in 200 mL of EtzO at 0 °C was slowly added II-13 (5.62 g, 44.2 mmol). The mixture was heated at reflux for 3 hours, after which time the solution was cooled to 0 °C, and quenced by addition of 2 mL of water, followed by 2 mL of 15% aq NaOH, and again with 6 mL of water. After being stirred for 2 hours, the mixture was filtered through NaZSO4 and the solvents removed by rotary evaporation at 0 °C. The oil was distilled at atmospheric pressure to give II-12 (4.38 g, 38.7 mmol) in 88% yield (bp 125 °C). Spectroscopic data were identical with that reported for the product obtained by reduction of II-lla. Preparation of II-l4a by Acylation of II-lla: To 100 mL of dry THF were added II-lla (2.00 g, 18 mmol) and Et3N (1.82 g, 18 mmol). Isobutyryl chloride (1.92 g, 18 mmol) was added dropwise. After being heated at reflux for 2 hours, the solution was cooled to ambient temperature and washed with 30 mL of 15% aq NaOH. The aqueous layer was exu'acted with 2 x 75 mL of Et20 and then dried over Na2804. After removal of the solvent by rotary evaporation, the oil was distilled via Kugelrohr distillation under vacuum to give II-l4a (3.24 g, 17.9 mmol) in 99% yield (oven temp 55-65 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.02 (d, J = 6.8 Hz, 6 H), 1.57 (s, 3 H), 1.70 (s, 3 H), 2.65 (sept, J = 6.8 Hz, 1 H), 3.89 (d,J = 6.2 26 Hz, 2 H), 5.04 (dd, J = 1.6, 11.3 Hz, 1 H), 5.06 (dd, J = 1.6, 16.0 Hz, 1 H), 5.74 (ddt,J = 11.3, 16.0, 6.2 Hz, 1 H), 5.85 (s, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.3, 18.8, 21.5, 30.9, 50.0, 116.9, 123.5, 133.4, 135.9, 177.7; IR (neat) 3083, 2975, 2936, 2876, 1653, 1472, 1404, 1242, 1208, 1092, 993, 920 cm'l. Anal. calcd for C11H19NO C, 72.88; H, 10.56; N, 7.73; obsd C, 72.84; H, 10.78; N, 7.72. Formation of II-l4a from II-13: To 300 mL of benzene were added 11-13 (3.51 g, 27.6 mmol), isobutyraldehyde (2.38 g, 33.1 mmol), and stOH (0.48 g, 2.8 mmol). The reaction flask was fitted with a Dean-Stark trap containing 4-A molecular sieves, and the solution was heated at reflux for 66 hours. After cooling, the solvents were removed and the oil was distilled under vacuum to give II-14a (4.24 g, 23.4 mmol) in 85% yield (oven temp 60-70 °C, <1 mmHg). Spectroscopic data were identical with that reported for the product obtained by acylation of II-ll. Preparation of II-lSa by Condensation of Isobutyraldehyde with 11-12: A flask containing II-12 (1.70 g, 15 mmol), isobutyraldehyde (1.08 g, 15 mmol), and stOH (0.007 g, 0.04 mmol) in 754 mL of benzene was fitted with a Dean-Stark trap containing 4-A molecular sieves. The solution was heated at reflux for 28 hours and then cooled to ambient temperature. After removal of the solvent, the oil was distilled via Kugelrohr distillation to give II-lSa (2.00 g, 12.0 mmol) in 80% yield (oven temp 45-50 °C, 8 mmHg): 1H NMR (300 MHz) (CDC13) 8 0.83 (d, J = 6.6 Hz, 6 H), 1.58 (d, J = 1.3 Hz, 3 H), 1.58 (tsept, J = 7.3, 6.6 Hz, 1 H), 1.65 (d, J = 1.3 Hz, 3 H), 2.25 (d, J = 7.3 Hz, 2 H), 3.15 (ddd, J = 1.6, 1.6, 6.2 Hz, 2 H), 5.02 (ddt, J = 2.0, 10.2, 1.6 Hz, 1 H), 5.08 (ddt, J = 2.0, 17.2, 1.6 Hz, 1 H), 5.22 (qq, J = 1.3, 1.3 Hz, 1 H), 5.81 (ddt, J = 2.0, 17.2, 9 1.6 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.4, 20.4, 22.0, 27.4, 59.6, 63.1, 115.9, 122.8, 135.8, 136.9; IR (neat) 3081, 3009, 2955, 2926, 2870, 2803, 1676, 1644, 1468, 27 1377, 1337, 1194, 1117, 1101, 995, 916 cm ‘1. Anal. calcd for C11H21N C, 78.98; H, 12.65; N, 8.37; obsd C, 79.18; H, 12.83; N, 8.48. General Method for the Two-Step Synthesis of II-14 from Allylamine: Allylamine (1.0 equiv), and the necessary aldehyde or ketone (1.0 equiv) were taken up in benzene (0.35 M). A Dean-Stark trap was fitted on the apparatus and the solution was heated at reflux to remove the water. After heating for 20 hours, the water was drained, the Dean-Stark trap was filled with 4-A molecular sieves and reflux was continued for 2 hours. The solution was cooled to ambient temperature and Et3N (1.0 equiv) and isobutyryl chloride (1.0 equiv) were added, sequentially. The mixture was heated at reflux for 3 hours, cooled, filtered to remove the Et3N-HC1 salts, and the solvent was evaporated. The crude oil was purified by flash column chromatography (silica, 230- 400 mesh; eluent 70:30 EtzOzpetroleum ether). The solvents were evaporated, and the enamide was distilled under vacuum to give I1-l4. . II-l4a: 42.68 g, (23.5 mmol, 94% yield), (bp 50-54 °C, <1 mmHg). Spectroscopic data were identical with that reported for the product obtained by acylation of II-lla. II-l4c: 9.56 g (E:Z 57:43), (39.3 mmol, 79% yield), (bp 112-115 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.10 (d, J = 6.7 Hz, 6 H), 2.02 (d, J = 1.4 Hz, 3 H), 2.80 (sept, J = 6.7 Hz, 1 H), 4.15 (ddd, J = 1.3, 1.3, 6.2 Hz, 2 H), 5.14 (ddt,J =1.1, 10.4, 1.3 Hz, 1 H), 5.17 (ddt,J= 1.1, 17.0, 1.3 Hz, 1 H), 5.85(ddt,J=10.4, 17.0, 6.2 Hz, 1 H), 6.43 (q, J = 1.4 Hz, 1 H), 7.33 (m, 5 H), (Z isomer) 1.00 (d, J = 6.8 Hz, 6 H), 2.10 (d, J = 1.4 Hz, 3 H), 2.91 (sept, J = 6.8 Hz, 1 H), 3.84 (ddd, J = 1.3, 1.3, 6.0 Hz, 2 H), 4.99 (ddt, J = 1.2, 17.0, 1.3 Hz, 1 H), 5.06 (ddt, J = 1.2, 10.4, 1.3 Hz, 1 H), 5.70 (ddt, J = 10.4, 17.0, 6.0 Hz, 1 H), 6.26 (q, J = 1.4 Hz, 1 H), 7.33 (m, 5 H); 13C NMR (75.5 MHz) (CDCl3) 8 (both isomers) 15.6, 18.8, 18.9, 21.7, 31.3, 31.5, 49.2, 50.0, 116.7, 117.5, 124.2, 125.9, 126.2, 127.3, 127.9, 128.3, 128.7, 128.8, 133.2, 133.5, 134.2, 138.3, 28 138.8, 140.0, 177.5, 177.6; IR (neat) 3083, 3059, 2971, 2874, 1663, 1401, 1231, 995, 909 cm'l. Anal. calcd for C16H21NO C, 78.97; H, 8.70; N, 5.76; obsd (C, 78.96; H, 8.80; N, 5.70. II-14d: 47.84 g, (247 mmol, 77% yield), (oven temp 80-120 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.03 (d, J = 6.8 Hz, 6 H), 1.52 (m, 2 H), 1.64 (m, 2 H), 2.02 (m, 4 H), 2.66 (sept, J = 6.8 Hz, 1 H), 3.87 (d, J = 6.3 Hz, 2 H), 5.04 (m, 2 H), 5.55 (t, J = 3.8, 1 H), 5.74 (ddt, J = 10.2, 17.0, 6.3 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 19.9, 21.2, 22.5, 24.4, 28.7, 31.0, 48.9, 117.0, 127.1, 134.3, 139.0, 176.9; IR (neat) 3081, 2967, 2936, 2863, 1649, 1480, 1400, 1360, 1245, 909 cm'l. Anal. calcd for C13H21NO C, 75.32; H, 10.21; N, 6.75; obsd C, 74.98; H, 9.85; N, 6.60. II-14e: 39.55 g, (205 mmol, 68% yield), (oven temp 100-130 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.05 (d, J = 6.7 Hz, 6 H), 1.91 (m, 2 H), 2.33 (m, 4 H), 2.79 (sept, J = 6.7 Hz, 1 H), 3.99 (d, J = 5.9 Hz, 2 H), 5.06 (m, 2 H), 5.50 (s, l H), 5.74 (ddt, J = 10.2, 17.0, 5.9 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 19.8, 22.1, 30.1, 31.0, 33.1, 48.7, 116.8, 126.9, 134.1, 177.0; IR (neat) 3081, 2967, 2934, 2872, 2851, 1649, 1480, 1400, 1370, 1225, 995, 909 cm'l. Anal. calcd for C12H19NO C, 74.57; H, 9.91; N, 7.24; obsd C, 74.70; H, 10.07; N, 7.55. General Method for Reduction of 11-14 to N-Allyl-N-Isobutyl Enamines 11-15: To a suspension of LiA1H4 (1.1 equiv) in Et20 (0.2 M) was added II-l4 (1.0 equiv) slowly via syringe. After addition was complete, the reaction was stirred at ambient temperature for 3-4 hours, cooled to 0 °C, and quenched by addition of water (1 leg LiAlH4), 15% aq NaOH (1 leg LiAlI-I4), and finally water (3 mL/g LiAlH4). The mixture was stirred for 2 hours, then filtered. The solvent was evaporated and the enamines II-lS were distilled via short-path or Kugelrohr distillation. 29 II-lSa: 9.84 g, (58.8 mmol, 98% yield), (bp 54-55 °C, 8 mmHg). Spectroscopic data were consistent with that reported for the preparation of II-lSa by condensation of 11-13 with isobutyraldehyde. II-15b: 3.64 g, (21.8 mmol,i95% yield), (bp 63-64 °C, 8 mmHg): 1H NMR (300 MHZ) (CDCl3) 5 0.83 (d, 6 H, J = 6.7 Hz), 0.92 (t, 3 H, J = 7.4 Hz), 1.82 (tsept, l H,J = 7.3, 6.7 Hz), 1.94 (ddq, 2 H, J = 1.2, 6.7, 6.7 Hz), 2.62 (d, 2 H, J = 7.3 Hz), 3.49 (ddd, 2 H, J = 1.5, 1.5, 5.8 Hz), 4.12 (dt, 1 H, J= 13.8, 6.7 Hz), 5.07 (ddt, l H, J = 1.4, 10.2, 1.5 Hz), 5.09 (ddt, l H, J = 1.4, 17.1, 1.5 HZ), 5.77 (ddt, l H, J = 10.2, 17.1, 5.8 HZ), 5.89 (dt, 1 H, J = 13.8, 1.2 Hz); 13C NMR (75.5 MHZ) (CDCl3) 5 16.1, 20.2, 23.7, 27.0, 54.2, 59.8, 98.9, 116.2, 135.3, 137.7; IR (neat) 3079, 3052, 3009, 2957, 2930, 2070, 2847, 1653, 1468, 1389, 1368, 1223, 1203, 1175, 1117, 934, 918 cm'l. II-lSc: 4.77 g (E:Z 86:14), (20.6 mmol, 95% yield), (bp 105 °C, <1 mmHg): 1H NMR (300 MHZ) (CDCl3) 5 (E isomer) 0.91 (d, 6 H, J = 6.6 Hz), 1.76 (tsept., l H, J = 7.4, 6.6 Hz), 2.09 (d, 3 H, J = 1.2 Hz), 2.63 (d, 2 H, J = 7.4 HZ), 3.53 (ddd, 2 H, J = 1.5, 1.5, 5.9 Hz), 5.13 (ddt, l H, J = 1.9, 10.2, 1.5 HZ), 5.20 (ddt, l H, J = 1.9, 17.2, 1.5 Hz), 5.91 (ddt, l H, J = 10.2, 17.2, 5.9 HZ), 6.15 (q, l H, J = 1.2 Hz), 7.30 (m, 5 H), (Z isomer) 0.86 (d, 6 H, J = 6.6 Hz), 1.75 (tsept., l H, J = 7.4, 6.6 Hz), 1.98 (d, 3 H, J = 1.2 HZ), 2.51 (d, 2 H, J = 7.4 HZ), 3.26 (ddd, 2 H, J = 1.4, 1.4, 5.9 HZ), 5.02 (m, l H), 5.68 (m, l H), 5.84 (q, l H, J = 1.2 HZ), 7.30 (m, 5 H); 13C NMR (7 5.5 MHZ) (CDCl3) 5 (E isomer) 15.4, 20.2, 58.3, 62.4, 116.4, 125.2, 125.5, 128.2, 128.3, 136.4, 139.3, 143.5; IR (neat) 3079, 3059, 3029, 2955, 2936, 2870, 2813, 1632, 1597, 1495, 1480, 1445, 1204, 1121, 918 cm'l. { II-15d: 1.52 g (7.8 mmol, 98% yield), (oven temp 50-60 °C, <1 mmHg): 1H NMR (300 MHZ) (CDCl3) 5 0.82 (d, 6 H, J = 6.7 HZ), 1.49 (m, 2 H), 1.63 (m, 2 H), 1.84 (tsept., 1 H, J = 7.1, 6.7 Hz), 2.06 (m, 4 H), 2.66 (d, 2 H, J= 7.1 Hz), 3.57 (ddd, 2 H, J = 1.5, 1.5, 5.7 Hz), 4.41 (dd, 1 H, J = 3.4, 3.4 HZ), 5.04 (ddt, l H, J = 1.7, 10.3, 1.5 Hz), 5.06 (ddt, 1 H, J = 1.7, 17.3, 1.5 Hz), 5.75 (ddt, l H, J= 10.3, 17.3, 5.7); 13C NMR (75.5 30 MHz) (CDCl3) 5 20.4, 22.7, 23.4, 24.5, 26.5, 27.1, 52.6, 56.8, 96.7, 115.6, 136.1, 143.5; IR (neat) 3079, 2953, 2869, 1714, 1644, 1607, 1564, 1468, 1420, 1387, 1339, 1223, 1119, 993, 916 cm'l. II-lSe: 1.29 g, (7.1 mmol, 90% yield), (oven temp 50—60 °C, <1 mmHg): 1H NMR (300 MHZ) (CDCl3) 5 0.83 (d, 6 H, J = 6.7 HZ), 1.86 (br. m, 3 H), 2.34 (br. m, 4 H), 2.74 (d, 2 H, J = 7.4 Hz), 3.61 (ddd, 2 H, J = 1.4, 1.4, 5.5 Hz), 4.08 (bs, l H), 5.05 (ddt, l H, J = 1.6, 10.5, 1.4 Hz), 5.07 (ddt, l H, J = 1.6, 17.0, 1.4 Hz), 5.77 (ddt, 1 H, J = 10.5, 17.0, 5.5 Hz); 13C NMR (75.5 MHZ) (CDCl3) 5 20.2, 26.9, 30.5, 32.3, 38.2, 53.8. 58.4, 92.3, 115.7, 135.6, 137.3; IR (neat) 3087, 2964, 2915, 2874, 1670, 1634, 1607, 1561, 1468, 1418, 1391, 1341, 1238, 1096, 991, 909 cm'l. Preparation of N-Allylbutylideneamine (II-11b): To 20.70 g (150 mmol) of potassium carbonate and 2.855 g (50 mmol) of allylamine in 50 mL of dry diethyl ether were added dropwise 2.904 g (40 mmol) of n- butanal in 25 mL of dry diethyl ether over one half hour. The mixture was stirred for an additional 1.5 hours at ambient temperature. The solution was filtered, and the ether was removed by rotary evaporation at 0 °C. The imine was distilled via Kugelrohr under vacuum to give II-llb (3.02 g, 27.2 mmol) in 68% yield (oven temp 30—40 °C, 25 mmHg): 1H NMR (300 MHz) (CDC13) 8 0.89 (t, 3 H, J = 7.4 Hz), 1.51, (tq, 2 H, J = 7.3, 7.4 Hz), 2.19 (dt, 2 H, J = 4.9, 7.3 Hz), 3.94 (ddd, 2 H, J = 1.3, 1.3, 5.7 Hz), 5.03 (ddt, 1 H, J = 1.7, 10.3, 1.3 Hz), 5.08 (ddt, 1 H, J = 1.7, 17.2, 1.3 Hz), 5.91 (ddt, 1 H,J = 1.03, 17.2, 5.7 Hz), 7.61 (t, 1 H, J = 4.9 Hz); 13C NMR (75.5 MHz) (CDCl3) 5 12.9, 18.5, 37.1, 62.8, 115.1, 135.7, 165.8; IR (neat) 3081, 3013, 2963, 2938, 2874, 2832, 1673, 1644, 1470, 1440, 1375, 1305, 990, 905 cm'l. 3 1 Acylation of Imine II-llb to Give Enamide II-l4b: To a solution of imine II-llb (12.52 g, 100 mmol) and pyridine (7.910 g, 100 mmol) in 500 mL of dry diethyl ether was slowly added isobutyryl chloride (10.660 g, 100 mmol). The solution was heated at reflux for six hours, then filtered and washed with 100 mL aqueous saturated sodium bicarbonate and 100 mL of water. The organic layer was dried over MgSO4 and filtered. The ether was removed by rotary evaporation, and the enamide was distilled under vacuum to give II-l4b (15.57 g, 85.9 mmol) in 86% yield as a 63:37 (E:Z) mixture of isomers (b.p. 57-62 °C/<1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 0.96 (t, 3 H, J = 7.4 Hz), 1.13 (d, 6 H, J = 6.7 Hz), 2.03 (ddq, 2 H, J = 1.3, 6.9, 7.4 Hz), 2.91 (sept., 1 H, J = 6.7 Hz), 4.20 (d, 2 H, J = 5.1 Hz), 5.08 (m, 3 H), 5.73 (m, 1 H), 6.78 (d, 1 H, J = 14.0 Hz), (Z isomer) 0.95 (t, 3 H, J = 7.4 Hz), 1.12 (d, 6 H, J = 6.7 Hz), 2.03 (ddq 2 H, J = 1.3, 6.9, 7.4 Hz), 2.70 (sept., 1 H, J = 6.7 Hz), 4.12 (d, 2 H, J = 5.1 Hz), 5.08 (m, 3 H), 5.73 (m, 1 H), 7.21 (d, 1 H, J: 12.8 Hz); 13C NMR (75.5 MHz) (CDCl3) 5 14.3, 19.0, 19.4, 20.5, 23.3, 23.4, 30.7, 30.9, 46.0, 47.2, 113.9, 115.9, 116.0, 116.1, 125.7, 126.5, 132.8, 133.1, 175.5; IR (neat) 3347, 3085, 2967, 2934, 2874, 1673, 1647, 1480, 1405, 1315, 1205, 945 cm'l. Anal. calcd for C11H19NO C, 72.88; H, 10.56; N, 7.73; obsd C, 72.59; H, 10.93; N, 7.84. 1) 2) 3) 4) 5) 6) 7) 3) REFERENCES Haynes, L. W.; Cook, A. G. in "Enamines: Synthesis, Structure, and Reactions", Cook, A. 0., Ed.; Marcel Dekker: New York, 1988, p. 103-163. Mannich, C.; Davidsen, H. Ber. 1936, 69, 2106. (a) Herr, M. B.; Heyl, F. W. J. Am. Chem. Soc. 1952, 74, 3627. (b) Heyl, F. W.; Herr, M. E. J. Am. Chem. Soc. 1953, 75, 1918. (c) Herr, M. B.; Heyl, F. W. J. Am. Chem. Soc. 1953, 75 , 5927. (d) Heyl, F. W.; Herr, M. E. J. Am. Chem. Soc. 1955, 77, 488. (e) Johnson, J. L.; Herr, M. B.; Babcock, J. C.; Fonken, A. B.; Stafford, J. B.; Heyl, F. W. J. Am. Chem. Soc. 1956, 78, 430. Zoretic, P. A.; Barcelos, F.; Branchaud, B. Org. Prep. Proced. Int. 1976, 8, 211. White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213. (a) Carlson, R.; Phan-Tan-Luu, R.; Mathieu, D.; Ahouande, F. S.; Babadjamian, A.; Metzger, J. Acta. Chem. Scand. B 1978,32, 335. (b) Carlson, R.; Nilsson, A, Strfimqvist, M. Acta. Chem. Scand. B 1983,37, 7. (c) Carlson, R.; Nilsson, A. Acta. Chem. Scand. B 1984, 38, 49. (d) Nilsson, A.; Carlson, R. Acta. Chem. Scand. B 1984, 38, 523. (e) Chou, S.-S. P.; Chu, C.-W. J. Chin. Chem. Soc. 1984, 31 , 351. (f) Pocar, D.; Stradi, R.; Bianchetti, G. Gazz. Chim. Ital. 1970, 100, 1135. Hill, R. K.; Khatri, H. N. Tetrahedron Lett. 1978, 4337. (a) Bassha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4717. For recent references see: (b) Solladié-Cavallo, A.; Bencheqroun, M. J. Org. Chem. 1992, 5 7, 5831. (c) Bigg, D. C. H.; Lesimple, P. Synthesis 1992, 277. (d) Lesimple, P.; Bigg, D. C. H. Synthesis 1991, 306. 32 CHAPTER III: CHARGE-PROMOTED 3-AZA-COPE REARRANGEMENTS Background: Acceleration of the 3-Aza-Cope Rearrangement The N-allyl-N-methyl enamine III-l has been reported to undergo [3,3] sigmatropic rearrangement thermally at 250 °C, followed by hydrolysis of imine III-2 to produce the 7,5-unsaturated aldehyde III-3 (eq III-1).l Because many sensitive functional groups cannot tolerate such harsh temperatures, promotion of this rearrangement at lower temperatures would lead to greater utility of this transformation in organic synthesis. 2 1 M M ““19“? ° 250°C M6\N/ Me 1130‘“ o/ 6 Me ’ Me Me (III-1) 4 /6 [3.3] \ \ 1115-1 III-2 III-3 Modification of the electronic environment of the enamine has led to lower reaction temperatures. Increasing the electron density by placing an oxygen substituent on the C-2 position, as in the case of ketene N,O-acetals allowed for [3,3] rearrangement at 180-190 °C.2 The [3,3] sigmatropic rearrangement of the enolate of an N-allyl amide proceeded at 135 °C.3 Acceleration of the 3-aza-Cope rearrangment could be accomplished through reduction of the electron density around the enamine as well. The addition of alkyl electrophiles resulted in the formation of a quaternary ammonium salt, which was reported to undergo [3,3] rearrangment at 80 °C (eq III-2).4 In most cases where 3-aza- Cope rearrangment has been carried out on cationic quaternary enamines, the imine products were hydrolyzed to the corresponding aldehydes for isolation. 33 34 Me\ Me M /N NM Brm Me e e \ 1) [3,3] 80 °C Me Me \+ M“ 2 H o+ o/ Mc’N/N L 3M6 (III-2) Me \ v Me MeOTs Me Me\N/|\>Me / Me Me The use of Lewis acids for the promotion of [3,3] sigmatropic rearrangements has been extensively explored.5 Although, aluminum complexes have been employed in the Claisen rearrangement of allyl vinyl ethers, the only Lewis acid reported to promote the 3-aza-Cope rearrangement, aside from the findings of this group,6 was TiCl4. During the TiCl4 catalyzed formation of an N—allyl enamine, Hill discovered that [3,3] sigmatropic rearrangment occurred in refluxing benzene, and even slowly at room temperature.51 Bailey has used TiC14 catalysis in the stereoselective 3-aza-Cope rearrangement of chiral enamines at 55 °C.5m Again, in these cases, the imine products were hydrolyzed in situ to the corresponding aldehydes, and overall yields for the condensation, [3,3] rearrangement, and subsequent hydrolysis were low to moderate (IS-68%). Further, the use of straight-chain aldehydes in this procedure resulted in low yields (20-30%), and condensation and rearrangement with ketones was unsuccessful. This methodology, condensation and in situ 3-aza-Cope rearrangment, was limited to a,a-disubstitued aldehydes, thus its utility for practical synthesis was low. Charge-Promoted 3-Am-Cope Rearrangments of N-Allyl-N-Isobutyl Enamines Several features were required for our study of the charge-promoted 3-aza-Cope rearrangement. First, electrophilic reagents were needed which would promote the reaction at temperatures that would be synthetically useful. Second, this charge- 35 promoted [3,3] sigmatropic rearrangement should be applicable to enamines derived from straight-chain aldehydes and ketones. And finally, the imine products should be reduced efficiently to 8,6-unsaturated amines in order to preserve the nitrogen functionality for further manipulation. Initial studies were focused on the use of methyl electrophiles (Mel and MeOTs) in refluxing acetonitrile or dioxane.5a’7 While the [3,3] rearrangement proceeded well, clean reduction with LiAlH4 or NaBH4 could not be obtained, and further investigation was not carried out. Acceleration of the [3,3] rearrangement of II-lS by protic and Lewis Acids (HCl, TiCl4, AlMe3) was investigated (Scheme III-l, Table III-1). Treatment of II-15a with 1.0 eq. of HCl in dioxane at reflux, and subsequent reduction, provided III-5a in 81% isolated yield. Rearrangement promoted by catalytic TiCl4 and stoichiometric AlMe3 produced similar results. High yields were also obtained for the rearrangement and reduction of the geminally disubstituted enamine II-lSc derived from 2-phenylpropanal. Substrate II-le, monosubstituted on the nucleophilic enamine carbon, was found to be sensitive to the reaction conditions. Treatment with HCl and TiCl4 gave only oligomeric products derived from aldol-type reactions, which indicated that the electrophilic reagent has a preference for the nucleophilic carbon over the nitrogen. In contrast, the organoaluminum electrophile produced clean rearrangement and III-Sc was obtained in 84% yield. 36 SCHEME III-l. Proton and Lewis Acid Promoted 3-Aza-Cope Rearrangements R1 R1 Me /k R2 \ R4 3 R1\N/ R ——> It2 \ R‘ FIGURE IV -1. 3-Aza-Cope Transition States In order to achieve asymmetric induction in the [3,3] sigmatropic rearrangement, two requirements must be met. First, there must be a preference for either a chair-like or boat-like conformation in the transition state. Secondly, the geometry of the olefins must 45 46 be fixed. The example of the 3-aza-Cope rearrangement in Figure IV-l shows the stereochemical outcome of the rearrangement of a N-allylenamine which contains only E olefin geometry. Assuming the allylic substituent, R2, would occupy an equatorial position in both transition states, the effect of the olefin geometries is clearly seen in the products obtained from each conformation. The 3-aza-Cope rearrangement offers an advantage over the Claisen rearrangement in that a chiral auxiliary can be attached to the nitrogen. Hill first reported asymmetric induction in the thermal rearrangement of IV-la (eq. IV--1).2 Two aldehydes were obtained after hydrolysis of the reaction mixture which had opposite double bond geometries and opposite configurations at the newly formed stereogenic center. Asymmetric induction from the chiral auxiliary to the new center of chirality was determined to be 69%. A similar substrate (IV-lb), prepared in situ and rearranged with TiCl4, was also studied by Hill, and asymmetric induction was found to be 67%.3 This substrate did not contain a chiral auxiliary and asymmetry was imparted solely from the allylic stereocenter in the 3-aza-Cope framework. Hill conCluded that the aliphatic 3-aza- Cope rearrangement, both thermal and TiCl4 catalyzed, proceeded in a concerted fashion that favored a chair-like transition state. There is some doubt as to whether the catalyst for this rearrangement was TiCl4 since the condensation process would produce water which would hydrolyze the Lewis acid. It is reasonable to conclude that the TiC14 was consumed, and that HCl was truly the catalyst in these studies. 1) 175 °C 911 Ph R P11 2)H30+ 0/ it / ... ‘N/\< : M, + 0 Me (IV-1) /I\/ Me \ Me * / Me '— Me 9:1 (69% ee) IV-l a: R = (R)-pheny1ethyl b: R = phenyl 47 Bailey has extended the study of Hill's TiC14 catalyzed 3-aza-Cope rearrangement of N-alkyl-N—allylenamines (eq. IV-2) and the results are summarized in Table IV-1.4 In probing 1,4- and 1.5-asymmetric induction (entries 1 and 2, respectively), very little stereoselection was observed. In contrast, simultaneous 1,4- and 1,5-asymmetric induction was relatively high (entries 3 and 4), although diastereoselectivity was only moderate (IV-4c/IV-4d 40-72% de). Temperature affected the asymmetric induction slightly, which provided greater selectivity at 55 °C than at 110 °C. A dramatic solvent effect was observed when the reaction was performed in benzene rather than toluene (entry 5), and asymmetric induction was reduced to almost zero. The authors provided no explanation for this phenomenon. Me Me ;) Elite, reflux / R2 / ph P“ N" + 2:11:61: ‘ U“ :1” (IV-2) V R1 OHC R1 0th Me IV-2 IV-3 IV-4 IV-4d a: R1=H,R2=Ph ‘ b: R1=Me, R2=Me c: R1=Me,R2=Ph Table IV-l: Asymmetric 3-Aza-Cope Rearrangements Catalyzed by TiCl4 %ee Entry Amine Aldehyde Solvent Temp. %de N4 7 IV-4d %Yield 1 IV-2a IV-3a PhMe 1 10 —--- 30 ---- 16 2 IV -2b IV-3b PhMe 1 10 ---- 18 ---- 48 3 IV-2b IV-3a PhMe 1 10 72 81 76 56 4 IV-2b IV-3a PhMe 55 70 90 98 46 5 IV-2b IV-3a PhH 55 4O 1 12 18 48 One example of an asymmetric 3-aza-Cope rearrangement, charge-promoted via a cationic quaternary amine, has appeared in the literature.5 Alkylation of IV-S with allyl bromide in acetonitrile at reflux, followed by hydrolysis and subsequent oxidation, gave IV-6 in 63% yield with 45% optical purity (eq IV-3). Me 3 _ i - 9“ If N 3) A820 ' J (IV 3) Me (45% ee) rv-s (63%) IV-6 Although not a true concerted 3-aza-Cope rearrangement, the intramolecular allylation of an enamine which contained a chiral auxiliary, catalyzed by palladium (0), has been explored. Amine IV -7 was condensed with 2-phenylpropanal in the presence of catalytic Pd(PPh3)4 and protic acid, and heated in benzene with azeotropic removal of water. After hydrolysis, IV-8 was obtained in excellent yield with low asymmetric induction (eq. IV--4).6 A similar Pd(0) catalyzed allylatiOn of chiral proline allyl ester enamines provided an enantiomeric excess which ranged from 5-16%, and chiral pyrrolidine enamines gave higher selectivity (6-88% ee).7 1) PdCPPh3)4 (5 mol %) 19¢ CFgCOzH (2.5 mol %) Ph A M" 80 °C 0/ * (Iv 4) + = - P“ N" Duck“! 2) 1130* M“ K/ \ / (34%) (12% ee) IV-7 IV-8 Much greater internal and relative asymmetric induction was observed in the thermal rearrangement of N-allyl amide enolates. Internal asymmetric induction from the reaction of the enolate derived from N- (2E )-buteny1-N-butylpropanamide was found to be as high as 199:1 (syn:anti).83’b The utilization of chiral auxiliaries on the nitrogen 49 provided for high relative asymmetric induction (77:21 - 92:8) (Scheme IV-l).8c The high syn:anti ratios observed reflect the high Z selectivity in the formation of amide enolates.9 It should be noted that longer reaction times (>6 hours) resulted in lower and even reversed syn:anti ratios due to base catalyzed isomerization of the amide products. SCHEME IV-l. Asymmetric 3-Aza-Cope Rearrangements of N-Allylamide Enolates. (R5) + 0 R" M ‘.N ° H 0 - L10 " \ 0 Me R*\NJk/Me Bax R*\NJ\/Me Heat (SR) —-—-’ ——. \ v”, _ v1“, R*=(S)-phenylethyl, (S)-p-Me0-phenylethyl, (S)-2,6-dimethylphenylethyl, (S)-naphthylethyl, (S)-phenylpropy1, (S)-phenylisobutyl (syn:anti >98:2) (RS:SR 77:21 - 92:8) 50 SCHEME IV-2. Asymmetric Induction in the 3-Aza-Cope Rearrangement of Ketene N,O-Acetals o o / R11 )\/ R2 Rl4/X/ R2 TsO/\/ y + N / IV-9 o RII R2 150 °C. 3h IV-10 N \ = + v 0 R11}; R2 \ IV-ll TABLE IV-2. Diastereoselective 3-Aza-Cope Rearrangement of Ketene N,O-Acetals IV-lO/IV-ll % Yield Entry Substrate R1 R2 Ratio from IV-9 1 IV-9a Et Bn 92/ 8 67 2 IV-9b Bn Bn 94/ 6 53 3 IV -9c i-Pr Bn 97/3 8 1 4 IV-9d t—Bu Bn 98/2 ‘ 58 5 IV-9e Ph Bn 78/22 34 6 IV-9f t-Bu Me 97/3 79 7 IV-9g t-Bu CMezPh 98/2 81 8 IV-9h i-Pr Me 97/3 80 51 The chemistry of chiral auxiliary-mediated 3-aza-Cope rearrangements has been elegantly extended by Kurth with the utilization of oxazolines derived from a-amino acids.lo As shown in Scheme IV-2 and summarized in Table IV-2, the covalent tethering of the auxiliary to the [3,3] rearrangement framework provided for excellent diastereoselection. A number of features made this a desirable process for C-C bond formation. The starting oxazolines (IV-9) were easily prepared from the appropriate carboxylic acid and amino alcohol. N-Alkylation with allyl tosylates provided high yields of the oxazolinium salt, and the oxazoline enamines required lower temperatures to affect [3,3] rearrangement in comparison to simple aliphatic enamines. Finally, the chiral auxiliary was readily recovered by hydrolysis of the rearrangement products. The high degree of asymmetric induction implied the selective formation of enamine olefin geometry. As demonstrated by entries 6-8, variation of the R2 substituent had little effect on enamine olefin selectivity. The rearrangement appeared to be the controlled by the steric influence of the R1 substituent, although both relatively small (Et) and relatively large (t-Bu) groups gave high selectivity (entries 1 and 4). This selectivity, concurrent with E or Z substituted allylic groups, afforded [3,3] rearrangement products ((1,0- disubstituted) with 79-92% diastereoselectivity and 97-98% enantioselectivity from optically pure oxazolines.10c This methodology has been applied to the synthesis of (+)- dihydropallescensin-Z.l 1 Amino Acid Derived Chiral Auxiliaries in the Charge-Promoted 3-Aza-Cope Rearrangement Inspired by the work of Kurth, investigations were fust directed toward the use of amino acid derived chiral auxiliaries. The possibility that auxiliaries bearing a methoxy substituent would allow for coordination of the promoting reagent (Lewis acid) with both the nitrogen and the oxygen (Figure IV-2) and effect a diastereofacial bias was explored. 52 Me — Me _ Me .3 (I)... 3 r. r ——» R -——. r 111* NW: .. éM’>RZR4 R‘ N/ * 1,: K/w ,. N \ . R. b d FIGURE IV-2. Expected Coordination of Electrophiles with Amino Acid Derived Chiral Auxiliaries Two N-crotyl enamines were prepared from the requisite amino alcohols, which were obtained from commercial sources or from the amino acids (eq. IV-5). The amino acid alanine (IV-12) was converted into its ester hydrochloride salt upon treatment with thionyl chloride in methanol (100% yield). 12 Reduction with LiA1H4 gave good yield of IV - 148. The amino alcohol IV-l4b was obtained commercially. Methyl protection of the alcohol was carried out as shown in Scheme IV-3. The amine functionality was protected as the phthalimide by reaction with phthalic anhydride to provide IV-lS in excellent yields. Methylation by treatment with NaH, followed by Mel, gave the methoxy phthalimides IV-l6 in good yield, and deprotection with hydrazine afforded IV- 17 in moderate yields. With the methoxy amines in hand, preparation of the N-crotyl enamines was straightforward (eq. IV-6). Condensation with crotonaldehyde followed by reduction with NaBH4 gave IV-18a and 1V18b in 47% and 70% yield respectively. Reaction with isobutyraldehyde afforded enamines IV -l9a and IV-l9b in excellent yield, which were obtained as a mixture of E:Z double bond isomers (85:15). 53 0 0H 0 OMe R‘ on 8002, MeOH ”All-14,1111? = I : (IV'S) (100%) (95%) Me N82 Me NH3C1 R2 N812 IV-l2 IV-l3 IV-l4 a: R1=H, R2=Me b: R‘=Me, R2=H I SCHEME IV-3. Methylation of Amino Alcohols 0 R1 011 IV 14 + Toluene reflux y ' 0 (a: 98%) ' (b: 100%) R2 NPth ° IV-15 1)NaH,THF 2) Mel (a: 78%) (b: 82%) v R1 OMe HzNNHz'Hzo, EIOH R1 OMe j: 1 (a: 54%) I R2 NH, (b: 53%) R2 NPth IV- 17 IV- 16 1) Crotonaldehyde RI OMe Isobutyraldehyde R1 OMe TOIuene team I W reflux 2) NaBH4, MeOH ca,” T803 1v - 17 e P e Me (IV-6) 1?.2 NH 2 (a: 47%) (a: 94%) R “N Me (b: 70%) / M60” 32%) v1“: IV-18 IV-l9 54 The charge-promoted 3-aza-Cope rearrangement of IV-l9a and IV-l9b promoted by protic and Lewis acids is summarized in eq. IV-7 and Table IV-3. Treatment of IV- l9a with catalytic TiCl4 in toluene at reflux and subsequent LiAlH4 reduction afforded IV-ZOa in good yield, however, asymmetric induction was very low (15% de). This was surprising in light of the fact that the placement of a center of chirality or to the nitrogen has shown greater selectivity in the TiCl4 promoted [3,3] rearrangement};4 Rearrangement of IV-19b, bearing a center of chirality B to the nitrogen, showed improved selectivity (20% de) with TiCl4 catalysis but lower selectivity when the reaction was promoted with protic acid (8% de). It was interesting that 1,6-asymmetric induction was greater than 1,5-asymmetric induction. These results hinted that some complexation of both heteroatoms had occurred with TiCl4 since selectivity would be expected to be lowered by locating the stereogenic center further from the 3-aza-Cope framework. R1 OMe 1) ML“, Toluene reflux 2) LiAlHn H R2 N3 M6 (IV-7) Me \ IV-20 Me IV-l9 17 TABLE IV-3. Asymmetric Induction with Chiral Auxiliaries Substrate R1 R2 MLn Product %Yield %de IV- 198 H Me TiCl4 IV-20a 77 15 IV-l9b Me H HCl IV-20b 86 8 IV-l9c Me H TiC14 IV -20c 72 20 55 SCHEME IV-4. Preparation of a-Methoxy Acid IV-23 OIOH NaN02, H2504 CID“ . NH; (59%) 1 r-Pr r Pr OH IV - 2 l 1) NaH (2 eq) 2) Mel (2 eq) (93%) V i-Pr OMe (94%) i-Pr OMe IV-23 1v. 22 Since greater selectivity was observed by placing a substituent on the chiral auxiliary B to the nitrogen, enamine IV-25 was studied in which the B-substituent was larger (i -Pr) and the newly formed stereogenic center was closer. The preparation of IV - 25 is described in Schemes N4 and IV-5. Starting with valine, conversion of the amino group to a hydroxyl group was carried out in 59% yield with NaN02/ H2804. Methylation of IV -21 gave methoxy ester IV-22 in 93% yield and hydrolysis afforded the (rt-methoxy acid IV-23 in 94% yield. Using a literature procedure for converting 0t- hydroxyl acids to a-hydroxyl amides,l3 IV-24 was obtained in 71% yield as a 72:28 mixture of E:Z isomers. Reduction with LiAlH4 gave IV-25 in nearly quantitative yield as a single enamine olefin isomer having E geometry. Since enamines derived from linear aldehydes were observed to react through pathways other than [3,3] rearrangement when promoted by HCl or TiCl4 (Chapter III), the rearrangement of IV-25 was studied with an organoaluminum reagent. Treatment with Me2AlCl followed by reduction gave IV-26 in 56% yield. Asymmetric induction was very low giving only a 10% diastereomeric excess. 56 SCHEME IV-S. Preparation of Enamine IV-25 1) TMSCI, Pyr. CH2C12 ' 0 1 2) (coc1)2. cat. DMF B IV-23 = ”60 C, NW - '2” . K/II-llb (71%) pyridine o MeO Et - L1A1H4 Iii/V : (987) ij/[LN/VEt PPT / 0 1"“ v E l IV-25 ( °" Y) {v.24 (E:Z 72:28) 1) Me2A1C1(l.l eq) Toluene reflux H Me0 N N Br 2) LiA1H4 ‘ MeO N Et 7 (IV ~8) hp, v (56%) i-Pr \ IV-25 IV-26 (10% dc) Internal Asymmetric Induction In order to study diastereoselectivity arising from chair- or boat-like conformations of the transition state, enamines containing an n-butyl group pendant on the allyl moiety (N-(E)-2-hepten-l-ylenamines) combined with a variety of substitution patterns on the enamine olefin were prepared. The preparations of these substrates were carried out from the primary allylic amine IV-29 obtained as shown in Scheme IV-6. Addition of vinyl magnesium bromide to valeraldehyde gave the allyl alcohol IV-27 in 57 95% yield. Treatment of IV -27 with trichloroacetonitrile and catalytic NaH followed by thermal rearrangement in xylenes provided the trichloroacetamide IV-2814 which was determined by 1H NMR and IR to be only the E olefin isomer. Hydrolysis with NaOH cleaved the amide to give IV-29 in 84% yield. SCHEME IV-6. Synthesis of (E)-2-Hepten-1-ylamine O CHZCHMgBr, THF 0” Jl\/\/M° : \/l\ H (95%) n-Bu I V - 2 7 1) cat. NaH, CC13CN 2) 140 °C (95%) 0 NH, NaOH, H20 Jk v 1 an eel3 / ".13.. (84%) v B n- u IV-29 IV-28 The synthesis of enamines IV-3l is outlined and eq. IV-9 and summarized in Table IV-4. Condensation of IV-29 with .n-butanal followed by acylation with isobutyryl chloride gave the enamide IV-30a in 66% purified yield (enamine olefin E:Z 65:35). Reduction to IV-3la was carried out to give a single compound (E only). IV-3lb was synthesized in a similar fashion. Condensation of 2-phenylpropanal with IV-29 in benzene at reflux was followed by acylation with isobutyryl chloride to give the purified IV -30b in 56% yield as a mixture of E :Z isomers (66:34 respectively). Reduction provided IV-31b with a good selectivity of 90:10 (E :2). Likewise, IV -30c was obtained from the condensation of IV-29 and cyclohexanone in toluene at reflux followed by acylation with isobutyryl chloride. Reduction to IV-31c was accomplished in excellent yield (97%). 58 l) Aldehyde or Ketone 2) Isbutyryl Chloride i R‘ R1 El N R2 ' '-B R2 IV-29 3 esp, n’l\98:2). Although the exact configuration was not rigorously determined, the syn product was assumed based on the most favorable chair-like transition state (Figure IV-l). Use of the more bulky bis-2,6-diphenylphenoxy methyl aluminum reagent resulted in decreased selectivity (70:30). Likewise, asymmetric induction in the AlMe3 promoted rearrangement of IV-3Sc was very high (>95:5) and IV-36c was obtained in almost quantitative yield. Products of the [3,3] rearrangement of IV-35a were not obtained under HCl or TiCl4 catalyzed reaction conditions, thus asymmetric induction with these reagents could not be ascertained. 62 SCHEME IV-7. Synthesis of N—(E)-3-Penten-2-yl Enamines 1) cat. NaH 0 OH CC13CN JL MeMgBr 2) 140 °C M e/V CH0 M t HN C03 Me \ M (81%) M Me Me I V - 3 3 1) NaOH/I120 2) Carbonyl ll R1 o R‘ ' ' TABLE IV-6. Yields of N—(E)-3-penten-2-yl Enamides and Enamines %Yield of %Yield of Carbonyl R1 R2 R3 IV-34 rv-35 a M,/\/CH0 H Et H 75a 88b Me b ,k H Ph Me 64c 96d PH CHO c 0:0 -(CH2)4- H 56 95 “Ratio of E:Z 100:0. bRatio of E:Z 100:0. CRatio of E :2 55:45. dRatio of E:Z 55:45. 63 Rl 1)MI-n. [3.3] i-Bu\NJ\98:2 IV-3Sa 100:0 Me2AlCl LiAlH4 81 IV-36a >98:2 IV-35a 100:0 (Ar0)2AlMea LiAlI-I4 60 IV-36a 70:30 IV-35b 55:45 HClb LiA1H4 75 IV-36bf 79:13:8 IV-35b 70:30 HClb LiA1H4 78 IV-36bf 54:37 :9 won: 58:42 HClc LiA1H4 85 Iv-36btr 70:20: 10 IV-3Sb 52:48 HCld LiAlH4 92 IV-36bf 78:14:8 IV -35b 52:48 HCle LiAlH4 91 IV ~36bf 79:13:8 IV-3Sb 83:17 HCld LiA1H4 94 IV-36bf 81:10:9 IV-35b 83:17 HCl‘ LiAlI-I4 98 IV-36bf 89:8:3 IV-35b 52:48 TiCl4 LiAlH4 38 IV-36bf 65:24:1 1 IV-35b 55:45 AlMe3 LiAlH4 97 IV-36bf 71:21:8 IV-35b 70:30 AlMe3 LiAlH4 98 IV-36bf 73:20:7 IV-35b 58:42 (ArOhAlMea LiAlH4 84 IV-36bf 80:14:6 IV-35c ----- AlMe3 DIBAH 95 IV-36c >95:5 “ArO = 2,6-diphenylphenoxy. b1.0 eq. 01.1 eq. d0.6 eq. 91.2 eq. Products have been assigned as IV-36b(E), IV-36b'(E), and IV-36b(Z), respectively based on transition state analysis (Scheme IV-8). 64 The variety of E:Z ratios obtained in the preparation of IV-35b, afforded an opportunity for in depth examination of the factors that influence selectivity in the charge-promoted [3,3] sigmatropic rearrangement. With a nearly equal mixture of isomers (E:Z 55:45), promotion with 1.0 equivalent HCl provided a 79:13:8 mixture of three rearrangement products. If one transition state conformation dominated in the course of this reaction, the highest selectivity expected would have been equal to the starting isomer ratio. Since IV-35b could not undergo imine-enamine tautomerization, it was clear that another factor must have been involved. It was possible that one isomer could have been reacting predominantly through a chair-like conformation while the other reacted through a boat-like conformation. However, with IV-35b as an E .2 mixture of 70:30 lower selectivity was obtained (54:37:9). If a chair-boat preference was the only controlling feature, this selectivity should have been at least as high as that obtained in the first case. Another possible explanation for the results obtained was that isomerization of the olefin by HCl had occurred. To probe this iheory, low (52:48) and high (83:17) starting ratios of IV -35b were reacted with either 0.6 or 1.2 equivalents of HCl. The use of less than one equivalent of protic acid would allow for intermolecular proton transfer from one protonated enamine to the carbon of another enamine, which would facilitate proton catalyzed isomerization. By the addition of excess HCl, all enamines would have been protonated and proton transfer would not occur, thus reducing the possibility of acid catalyzed isomerization.15 The results of this study indicated that the probability of proton catalyzed olefin isomerization as the feature controlling asymmetric induction was low. In all cases, almost the same ratio of diastereomers of IV-36b was obtained (78:14:8 to 89:8:2). Analogous results were found for the TiCl4 promoted rearrangement of IV-3Sb. A slightly lower 65:24:11 ratio of diastereomers of IV-36b was obtained from the treatment of IV-35b (E:Z 58:42) with TiCl4 followed by reduction. Reaction of IV-35b, having either a 55:45 or 70:30 mixture of E:Z isomers, with AlMe3 gave consistent product mixtures, and moderate selectivity was obtained (71:21:8 and 73:20:7). A higher selectivity (80:14:6) resulted from use of the more bulky aluminum reagent. 65 SCHEME IV-8. Transition States for the 3-Aza-Cope Rearrangement of IV ~35b. i-Bu IV-35b(E) IV-35b(Z) l) [3,3] 2) LiAlH4 1) [3.3] 2) LiAlH4 1) [3.31 2) LiAlH4 -s ‘l n r- u e fl ’1»: \ Me Me IV-36b(E) . H r~Bu\qu ” Me Me _ I,’n1 Me IV-36b'(Z) _ H r—Bu\1!I ” Ph Me _ 1,34: Me IV-36b(Z) H B \lll ,’ Ph \ Me Me Me IV-36b'(E) 66 While protic acid isomerization of enamines IV-35b remained a possibility with HCl, and even with TiCl4 by hydrolysis to produce protic acid, the results of the organoaluminum promoted rearrangement clearly indicated that an additional factor was involved. The most probable explanation was that olefin isomerization occurred via a reversible [3,3] sigmatropic rearrangement. The reverse of the 3-aza-Cope rearrangement, the l-aza-Cope has been shown to occur in some cases.16 This would have been more likely to be the case with IV-35b than the other two enamines examined due to the stabilization of the enamine olefin by conjugation with the phenyl group. Also, with substrate IV-3Sb, the presence of a third product was observed, which was not detected in the rearrangement products from IV-35a and IV-35c. The products have been assigned the structures IV-36b(E) (major isomer), IV-36b'(E) (intermediate isomer), and IV-36b(Z) (minor isomer) based on the possible transition states shown in Scheme IV-8. IV-36b(E) was derived from the most favored transition state in which a chair-like conformation was adopted with the allylic methyl group in an equatorial position. The minor product was assigned as described for two reasons. First, the chair-like conformation with the allylic methyl group axial would have predominated over the boat- ' like conformation. Secondly, hydrogenation of the product mixture increased the amount of the major product over the minor product. Reduction of the 79:13:8 mixture derived from BC] rearrangement, gave approximately a 90:10 mixture of two diastereomers, and reduction of the 71:21:8 mixture from AlMe3-promoted rearrangement afforded a 80:20 mixture. These results indicated that the minor isomer possessed the same relative stereochemistry at the two asymmetric centers as the major product, and reduction of the double bond would have made these two compounds identical. The intermediate isomer resulted from the chair-like conformation with an equatorial allylic methyl substituent, and had opposite relative stereochemmistry as the major isomer. The fourth possible isomer, IV-36b'(Z), was not detectable by NMR. 67 Asymmetric Ring Expansion Reactions As a possible route to indolizidine alkaloids, the charge-promoted 3-aza-Cope rearrangement with concurrent ring expansion was examined.17 Treatment of the amino acid proline with thionyl chloride in methanol, followed by N—protection gave IV-37 in 99% yield (eq. IV -12). DIBAH reduction afforded aldehyde IV-38. Two enamines were I prepared as shown in eq. IV -13. IV-38 was olefinated with benzylidenetriphenyl- phosphine and deprotected with HCl in methanol to afford IV-39a as a 65:35 ratio of E:Z isomers. Condensation with phenylacetaldehyde gave IV -40a in quantitative yield with complete E selectivity of the enamine olefin. Enamine IV-40b was obtained by same sequence with ethylidenetriphenylphosphine. Due to its volatility, IV-39b was not isolated, and IV-40b was prepared in 79% overall yield from IV-38. Again, complete enamine selectivity was achieved, while the allylic olefin was procured as a 27:73 mixture of E :Z isomers. I H 1) SOCIz, MCOH [Boc Boc N 2 , N ’ Q )(Boc)20 Et3N : DIBAH CI: (IV-12) c0211 (99%) C02Me (90%) C110 IV-37 IV-38 1) Ph3P=CHR PhCH2CH0 I 2) HCl, MeOH N’ H K2003 N/V Ph - CV. - CV (IV-13> / / R R IV-39 IV-40 a: R = Ph (69%) a: R = Ph (100%) (E:Z 65:35) (E:Z (enamine) 100:0) b: R = Me (E:Z (allylic) 65:35) b: R: Me (79% from IV-38) (E:Z (enamine) 100:0) (E:Z (allylic) 27:73) 68 Success in the charge-promoted 3-aza-Cope rearrangement/ring expansion of the pyrrolidine enamines (eq. IV-l4) was found to be very dependent on the electronic demands of the substituents. Treatment of IV-40a, where R was a phenyl group, with organoaluminum reagents and subsequent reaction with LiAlH4 did not provide the ring- expanded product. Instead, IV-40a was recovered quantitatively, and the allylic olefin had been isomerized to a single isomer (E) (Figure IV-4). This result provided further evidence that olefin isomerization through reversible sigmatmpic rearrangement had occurred under the charge-promoted reaction conditions. Only two possibilities could be formulated to explain the isomerization. Either the aluminum species had added to the allylic olefin, which would have allowed for single bond rotation, or the proposed reversible reaction had occurred. Since addition of aluminum to the double bond was highly unlikely, the reversible [3,3] rearrangement was assumed to have taken place. The quantitative recovery of starting material indicated that the equilibrium lay far on the side of IV-408 in which both olefins were in conjugation with the phenyl groups. In contrast, replacing one of the phenyl groups with a methyl group allowed for complete rearrangement with MezAlCI, and reduction afforded IV-4lb in 85% yield. A 27:73 mixture of isomers was produced, and the double bond geometry was determined by 1H NMR to have Z geometry. To determine that the product ratio was due to the cis/trans relationship of the phenyl and methyl substituents rather than possible E :Z isomers of the olefin, IV-4lb was hydrogenated over 10% palladium on carbon, and a 27:73 mixture of isomers was obtained. This result demonstrated that the 3-aza-Cope rearrangement/ring expansion reaction promoted by Me2AlCl was completely stereoselective. Thus, the product ratio was solely dependent on the starting olefin geometries. 1) MLn H NW Ph 2) LiAlI-L; N Pb / $ \ (IV- 14) R a: - R 69 AlMe3. MegAlCl, pn Git: an or (ArO)2AlMe t Cg / Ph / Ph IV-40a IV-40a E:Z 65:35 E:Z 100:0 Ph N/ \ Ph FIGURE IV-4. Reversible Ring Expansion Reaction Summary Studies of the stereoselectivity of the charge-promoted 3-aza-Cope rearrangement were carried out by examining diastereomer ratios of the resulting products. Relative asymmetric induction transferred from amino acid derived chiral auxiliaries was found to be very low (8-20% de). Internal asymmetric induction was determined to be highly dependent on the promoting reagent as well as the substitution of the enamine olefin. The enamine derived from n-butanal provided low selectivity when promoted with organoaluminum reagents (52:48 - 62:38). With the disubstituted enamine (IV-31b) asymmetric induction was very high with protic acids yielding a 95:5 ratio of isomers. Organoaluminum reagents gave lower selectivity, and the more bulky bis-phenoxy methyl aluminum reagent gave the opposite ratio of the same magnitude as AlMe3. The rearrangement of IV-3lc provided contrasting results, giving the highest selectivity upon reaction with organoaluminum reagents, and lower selectivity with HCl and TiCl4. A 70 more thorough investigation of the features which control selectivity was carried out by the study of concurrent relative and internal asymmetric induction. Selectivity was found to be very high with enamines derived from n-butanal and cyclohexanone (>98:2 and >95:5 respectively). [3,3] rearrangement of the enamine derived from 2-phenylpropanal, with a variety of starting enamine olefin ratios, provided evidence that the 3-aza-Cope rearrangement was a reversible process. This substrate provided modest selectivity in all cases (54:37:9 - 89:8:2). Ring expansion reactions were accomplished with IV-40b yielding a nine-membered ring with complete stereoselectivity. The ring expansion process was also found to be reversible with IV-40a, and the degree of the reverse reaction was dependent on the electronic demands of the enamine. EXPERIMENTAL General Methods For general experimental methods see General Methods in Chapter H. Preparation of IV-l3: L-Alanine (17.819 g, 200 mmol) was placed in anhydrous methanol (200 mL) and cooled to 0 °C. Thionyl chloride (59.584 g, 500 mmol) was added dropwise over 30 min. The solution was warmed to room temperature and allowed to stir for 12 hours. The mixture was concentrated by rotary evaporation under reduced pressure and the crystals were triturated with ether. The solid was filtered and allowed to dry in the air to afford IV-l3 (27.90 g, 200 mmol) in 100% yield: 1H NMR (300 MHz) (D20) 8 1.41 (d,J = 7.3 Hz, 3 H), 3.68 (s, 3 H), 4.06 (q, J = 7.3 Hz, 1 H); 13C NMR (75.5 MHz) (D20) 8 21.1 54.8, 59.6, 177.3. Preparation of Amino Alcohol IV-14a: IV-l3 (27.90 g, 200 mmol) was slowly added to a cooled suspension of LiA1H4 (19.0 g, 500 mmol) in THF (750 mL). After addition, the mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched at 0 °C by the addition of H20 (19 mL), then 15% NaOH (19 mL), and finally H20 (57 mL). After 2 hours, the mixture was filtered, concentrated and the resulting oil was distilled (Kugelrohr) under vacuum to afford IV-14a (14.30 g, 190 mmol) in 95% yield (oven temp 60-80 °C, 10 mmHg): 1H NMR (300 MHz) (CDC13) 8 0.93 (d, J = 6.5 Hz, 3 H), 2.75 (bs, 3 H), 2.89 (ddq, J = 3.9, 7.8, 6.5 Hz, 1 H), 3.13 (dd, J = 7.8, 10.7 Hz, 1 H), 3.42 (dd, J = 3.9, 10.7 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 19.4, 48.2, 67.8. 71 72 General Method for the Phthalimide Protection of Amino Alcohols: The amino alcohol (1 eq.) and phthalic anhydride (1 eq.) were placed in toluene (0.3 M). The solution was heated at reflux for 48 hours with azeotropic removal of water. The mixture was concentrated by rotary evaporation under reduced pressure. The crystals were washed with petroleum ether and dried under vacuum. IV-lSa: (15.69 g, 76 mmol) in 98% yield, (yellow crystals): 1H NMR (300 MHz) (CDCl3) 8 1.41 (d, J = 7.0 Hz, 3 H), 3.08 (bs, 1 H), 3.86 (dd, J = 3.8, 11.8 Hz, 1 H), 4.01 (dd, J = 7.5, 11.8 Hz, 1 H), 4.48 (ddq, J = 3.8, 7.5, 7.0 Hz, 1 H), 7.68 (m, 2 H), 7.80 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 14.8, 49.3, 64.2, 123.3, 131.9, 134.1, 168.9. IV-le: (40.86 g, 199 mmol) in 100% yield (yellow crystals, mp 87-89 °C): 1H NMR (300 MHz) (CDCl3) 8 1.24 (d, J = 6.3 Hz, 3 H), 2.28 (bs, 1 H), 3.70 (dd, J = 7.1, 14.2 Hz, 1 H), 3.76 (dd, J = 4.0, 14.2 Hz, 1 H), 4.09 (ddq, J = 4.0, 7.1, 6.3 Hz, 1 H), 7.71 (m, 2 H), 7.83 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 821.1, 45.5, 66.8, 123.4, 131.9, 134.1, 168.9. General Method for the Methylation of the IV-IS: The phthalimide (1 eq.) was slowly added to a 1.2 M suspension of NaH (1.2 eq.) in THF. The mixture was allowed to stir for one hour, and then was heated at reflux for one hour. The solution was cooled, Mel (1.2 eq.) was added, and the solution was stirred for one hour and then heated at reflux for an additional hour. The mixture was concentrated and washed with water. The methylated phthalimide was extracted with ether and the organic layer was dried over potassium carbonate. Concentration by rotary evaporation afforded yellow crystals which were washed with petroleum ether and dried under vacuum. IV-l6a: (13.703 g, 62.4 mmol) in 78% yield (yellow wax): 1H NMR (300 MHz) (CDCl3) 8 1.40 (d, J = 7.0 Hz, 3 H), 3.28 (s, 3 H), 3.49 (dd, J = 5.3, 9.8 Hz, 1 H), 73 3.93 (dd, J = 9.8, 9.8 Hz, 1 H), 4.56 (ddq, J = 5.3, 9.8, 7.0 Hz, 1 H), 7.66 (m, 2 H), 7.77 (m, 2 H); 13C NMR (75.5 MHZ) (CDCl3) 5 15.0, 46.2, 58.6, 72.8, 123.0, 132.0, 133.7. 168.4. IV-l6b: (62.76 g, 286 mmol) in 82% yield (yellow crystals, mp 72-74 °C): 1H NMR (300 MHZ) (CDCl3) 5 1.16 (d, J = 6.0 Hz, 3 H), 3.30 (s, 3 H), 3.61 (dd, J = 4.5, 12.6 HZ, 1 H), 3.67 (ddq, J = 4.5, 6.2, 6.0 HZ, 1 H), 3.78 (dd,J = 6.2, 12.6 Hz, 1 H), 7.68 (m, 2 H), 7.82 (m, 2 H); 13C NMR (75.5 NIHZ) (CDCl3) 5 17.2, 42.4, 56.4, 74.3, 123.2, 132.0, 133.9, 168.4. General Method for the Deprotection of Phthalimides IV-l6: 7 Phthalimide IV- 16 (1 eq.) and hydrazine hydrate (2 eq.) were placed in 100% ethanol (0.1-0.2 M). The solution was heated at reflux for a minimum of 6 hours. The mixture was then filtered to remove the phthalhydrazide and treated with excess conc. HCl. The solution was concentrated, and the amine-hydrochloride salt was dissolved in a minimum amount of water. Additional insoluble phthalhydrazide was filtered and the water solution was treated with NaOH pellets until the pH reached 14. The amine was extracted with ether and the combined organic layers were dried over potassium carbonate. The ether was removed by distillation and the amine was distilled at normal pressure. IB-l7a: (2.872 g, 32 mmol) in 54% yield (bp 95-97 °C, 760 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.98 (d, J = 6.2 Hz, 3 H), 3.05 (d, J = 5.3 Hz, 1 H), 3.07 (ddq, J = 5.0, 5.3, 6.2 Hz, 1 H), 3.25 (d, J = 5.0 Hz, 1 H), 3.32 (s, 3 H); 13C NMR (75.5 MHz) (CDC13) 8 19.8, 46.3, 58.8, 79.7. IV-l7b: (1.812 g, 20 mmol) in 68% yield (bp 102-105 °C, 760 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.03 (d, J = 6.1 Hz, 3 H), 2.56 (dd, J = 6.8, 13.2 Hz, 1 H), 2.65 (dd, J = 4.0, 13.2 Hz, 1 H), 3.21 (ddq, J = 4.0, 6.8, 6.1 Hz, 1 H), 3.28 (s, 3 H); 13C NMR (75.5 MHz) (CDCl3) 8 16.4, 47.2, 56.1, 78.3. 74 General Method for the Synthesis of IV-18: IV -17 (1 eq.) and crotonaldehyde (1 eq.) were placed in toluene (0.2-0.4 M) and heated at reflux for 1-2 hours with azeotropic removal of water. The solution was cooled, and NaBH4 (1-2 eq.) was added. The mixture was cooled to 0 °C and MeOH (half the volume of toluene) was added dropwise. The solution was allowed to stir for 16-24 hours. Solvents were removed by rotary evaporation, and the white solids were treated with 15% NaOH. The amine was extracted with ether, and the organic layer was dried over potassium carbonate. Ether was removed by rotary evaporation at 0 °C and the amines were distilled. IV-lSa: (1.663 g, 12 mmol) in 47% yield (bp 45-55 °C, 16 mmHg): 1H NMR (300 MHz) (CD03) 8 (major isomer) 0.96 (d, J = 6.4 Hz, 3 H), 1.55 (bs, 1 H), 1.62 (m, 3 H), 2.84 (ddq, J = 4.2, 7.5, 6.4 Hz, 1 H), 3.06 (m, 1 H), 3.17 (dd, J = 7.5, 9.2 Hz, 1 H), 3.20 (m, 1 H), 3.26 (dd, J = 4.2, 9.2 Hz, 1 H), 3.30 (s, 3 H), 5.43-5.62 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 16.9, 17.7, 49.1, 51.8, 58.8, 77.3, 127.1, 129.6; IR (neat) 3330, 3020, 2969, 2926, 2880, 2828, 1673, 1453, 1375, 1109, 966 cm'l; HRMS calcd for C3H17N0 m/e 143.1310, obsd m/e 143.1308. IV-18b: (5.013 g, 35 mmol) in 70% yield (bp 165-167 °C, 760 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 1.09 (d, J = 6.2 Hz, 3 H), 1.39 (bs, 1 H), 1.64 (bd, J = 4.8 Hz, 3 H), 2.49-2.62 (m, 2 H), 3.10-3.15 (m, 2 H), 3.32 (s, 3 H), 3.42 (ddq, J = 4.7, 7.6, 6.2 Hz, 1 H), 5.42-5.64 (m, 2 H); 13C NMR (755 MHz) (CDCl3) 8 (major isomer) 17.0, 17.7, 51.7, 54.9, 56.2, 76.2, 127 .1, 129.5; IR (neat) 3332, 3020, 2973, 2930, 2880, 2822, 1672, 1453, 1374, 1090, 968 cm'l; HRMS calcd for C3H17N0 m/e 143.1310, obsd m/e 143.1372. General Method for the Preparation of IV-19: The crotyl amine IV-18 (1 eq.), isobutyraldehyde (1 eq.), and p-toluenesulfonic acid (0.0025 eq.) were placed in benzene and heated at reflux 24-48 hours with azeotropic 75 removal of water. The benzene was removed by rotary evaporation under reduced pressure and the enamine was distilled (Kugelrohr) under vacuum. IV-l9a: (1.850 g, 9.4 mmol) in 94% yield (oven temp 60-80 °C, 5 mmHg): This enamine was extremely sensitive to hydrolysis and full spectral characterization could not be obtained. 1H NMR (500 MHz) (CDCl3) 8 (major isomer) 0.98 (d, J = 6.7 Hz, 3 H), 1.59 (bs, 3 H), 1.63 (bs, 3 H), 1.64 (d, J = 4.7 Hz, 3 H), 3.01 (sext, J = 6.8 Hz, 1 H), 3.12 (dd, J = 7.2, 9.3 Hz, 1 H), 3.16-3.25 (m, 2 H), 3.29 (s, 3 H), 3.40 (dd, J = 5.8, 9.3 Hz, 1 H), 5.36-5.62 (m, 3 H). * IV-l9b: (4.843 g, 25 mmol) in 82% yield (oven temp 75-80 °C, 6 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 1.08 (d, J = 6.2 Hz, 3 H), 1.58 (bs, 3 H), 1.64 (bs, 3 H), 1.65 (d, J = 4.6 Hz, 3 H), 2.39 (dd, J = 6.6, 12.8 Hz, 1 H), 2.64 (dd, J = 5.9, 12.8 Hz, 1 H), 3.10-3.16 (m, 2 H), 3.25 (q, J = 6.2 Hz, 1 H), 3.31 (s, 3 H), 5.25 (m, 1 H), 5.38-5.62 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 17.6, 17.8, 17.9, 22.2, 56.5, 59.1, 60.0, 76.1, 122.7, 127.5, 128.7, 135.2; IR (neat) 3077, 2971, 2932, 2865, 2822, 1682, 1451, 1377, 1098, 966 cm'l. ’ Synthesis of 2-Hydroxy-3-methylbutanoic Acid (IV -21): L-valine (19.916 g, 170.0 mmol) was dissolved in a solution of 10 mL conc. sulfuric acid in 250 ml water and cooled to 0 °C. A solution of NaN02 (17.595 g, 255.0 mmol) in 40 mL water was slowly added over 0.5 hours. The mixture was stirred at 0 °C for 4 hours and then allowed to warm to room temperature. The acid was extracted with 5 x 150 mL Et20 and dried over MgSO4. The solution was concentrated and then placed under high vacuum to give IV-21 (11.74 g, 99.4 mmol) as white crystals in 59% yield: 1H NMR (300 MHz) (CDCl3) 8 0.89 (d, J = 6.7 Hz, 3 H), 1.02 (d, J = 7.0 Hz, 3 H), 2.13 (ddq, J = 3.4, 6.7, 7.0 Hz, 1 H), 4.12 (d, J = 3.4 Hz, 1 H), 6.00-8.00 (bs, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 15.9, 18.7, 32.0, 74.9, 179.2. 76 Synthesis of Methyl 2-Methoxy-3-methylbutyrate (IV-22): To a suspension of NaH (5.952 g, 248.0 mmol) in 200 mL DMSO cooled in an ice bath was added dropwise a solution of IV-21 (11.74 g, 99.0 mmol) in 150 mL DMSO. The mixture was stirred at room temperature for 2 hours, then cooled again and Mel (35.201 g, 248 mmol) was added over a 0.5 hour period. The mixture was allowed to stir at room temperature for 12 hours. Water (300 mL) was carefully added and the methoxy ester was extracted with 4 x 300 mL pentane. The organic layers were combined and washed with 100 mL sat. NaCl, dried over MgSO4, and concentrated to give IV-22 (13.53 g, 92.6 mmol) in 93% yield as a yellow oil. The ester was hydrolyzed without further purification: 1H NMR (300 MHz) (CDCl3) 8 0.89 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 1.99 (ddq, J = 5.5, 6.8, 6.9 Hz, 1 H), 3.3 (s, 3 H), 3.47 (d, J = 5.5 Hz, 1 H), 3.72 (s, 3 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.6, 18.5, 31.5, 51.6, 58.5, 85.9, 172.8. Hydrolysis of IV-22 to 2-Methoxy-3-methylbutanoic Acid (IV-23): The 2—methoxy ester (IV-22) was placed in 100 mL 6 N NaOH and heated at reflux for 24 hours. The heterogeneous mixture was brought to a pH < 2 by careful addition of conc. HCl with external cooling in an ice bath. The acid was extracted with 3 x 100 mL Et20 and dried over MgSO4. Solvents were evaporated and the oil was distilled to give IV-23 (5.191 g, 39.3 mmol) in 96% yield (bp 92-94 °C, 8 mmHg): 1H NMR (300 MHz) (CDC13) 8 0.95 (d, J = 6.9 Hz, 3 H), 1.00 (d, J = 6.9 Hz, 3 H), 2.10 (ddq,] = 4.7, 6.9, 6.9 Hz, 1 H), 3.42 (s, 3 H), 3.56 (d, J = 4.7 Hz, 1 H), 6.60-7.90 (bs, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.2, 18.6, 31.4, 59.1, 85.4, 176.7. Preparation of IV-24: To 60 mL of CH2C12 was added the methoxy acid IV-23 (5.286 g, 40.0 mmol) and pyridine (3.322 g, 42.0 mmol). Trimethylsilyl chloride (4.563 g, 42.0 mmol) was 77 slowly added and the mixture was allowed to stir for 3.5 hours. DMF (5 drops) was added and the solution was cooled to 0 °C. 0xalyl chloride (5.331 g, 42.0 mmol) was added dropwise, and the mixture was stirred at 0 °C for 1 hour, then at room temperature for 30 minutes. The mixture was again cooled to 0 °C and pyridine (4.746 g, 60.0 mmol) followed by a solution of imine II-llb (5.259 g, 42.0 mmol) in 40 mL CH2C12 were added. After stirring 5 hours the reaction mixture was filtered through a pad of silica gel/alumina and concentrated. The enamide was purified by flash column chromatography (silica gel, 70:30 Et20:petroleum ether) and concentrated. Kugelrohr distillation gave IV-24 (6.389 g, 28.4 mmol) in 71% yield as a mixture of isomers (E:Z 72:28) (oven temp 60-70 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3)J8 (E isomer) 0.87 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (t, J = 7.4 Hz, 3 H), 2.02 (m, 3 H), 3.23 (s, 3 H), 3.62 (d, J = 7.7 Hz, 1 H), 4.23 (m, 2 H), 5.09 (m, 3 H), 5.72 (m, 1 H), 6.88 (d, J = 13.9 Hz, 1 H), (Z isomer) 0.87 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (t, J = 7.4 Hz, 3 H), 2.02 (m, 3 H), 3.28 (s, 3 H), 3.72 (d, J = 7.9 Hz, 1 H), 4.23 (m, 2 H), 5.09 (m, 3 H), 5.72 (m, 1 H), 7.20 (d, J = 14.6 Hz, 1 H); 3C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 14.4, 18.6, 18.9, 23.4, 30.6, 46.3, 57.4, 87.9, 115.6, 116.3, 125.9, 132.7, 169.6, (Z isomer) 14.4, 18.2, 19.1, 23.5, 30.4, 46.6, 57.3, 86.4, 114.8, 116.2, 125.3, 132.8, 169.7; IR (neat) 3080, 3020, 2967, 2934, 2876, 2828, 2645, 1520, 1464, 1408, 1368, 1318, 1200, 1136, 1102, 988, 949 cm'l; HRMS calcd for C13H23N02 m/e 225.1728, obsd m/e 225.1770. Reduction of IV -24 to Enamine IV-25: To a suspension of LiAlH4 (0.920 g, 24.2 mmol) in 100 mL Et20 was added enamide IV-24 (4.957 g, 22.0 mmol). The mixture was stirred at room temperature for 3 hours, and then quenched by addition of 0.92 mL H20, then 0.92 mL 15% aq. NaOH, and finally 2.76 mL H20. After filtration, the solution was concentrated and distilled (Kugelrohr) to give IV-25 (4.534 g, 21.5 mmol) in 98% yield as a single isomer (oven 78 temp 45-60 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 5 0.87 (d, J = 6.9 Hz, 3 H), 0.88 (d, J = 6.9 Hz, 3 H), 0.91 (t, J = 7.4 Hz, 3 H), 1.76 (dqq, J = 4.6, 6.9, 6.9 Hz, 1 H), 1.94 (ddq, J = 1.2, 6.8, 7.4 Hz, 2 H), 2.85 (dd, J = 7.7, 14.4 Hz, 1 H), 2.95 (dd, J= 3.8, 14.5 Hz, 1 H), 3.06 (ddd, J = 3.8, 7.4, 7.7 Hz, 1 H), 3.35 (s, 3 H), 3.54 (ddd, J = 1.4, 1.7, 5.7 Hz, 2 H), 4.14 (dt, J = 13.8, 6.8 Hz, 1 H), 5.07 (ddt, J = 3.5, 10.4, 1.4 Hz, 1 H), 5.10 (ddt, J = 3.5, 17.1, 1.7 Hz, 1 H), 5.77 (ddt, J = 10.4, 17.1.5.7 Hz, 1 H), 5.89 (dt, J = 13.8, 1.2 Hz, 1 H); 3C NMR (75.5 MHz) (CDCl3) 8 16.3, 17.5, 18.5, 23.8, 30.1, 52.9, 54.6, 58.8, 84.1, 99.2, 116.2, 135.1, 137.0; IR (neat) 3081, 2965, 2875, 2828, 1676, 1606. 1389, 1285, 1186, 1094, 995, 970, 924 em-l. Synthesis of 3-Hydroxy-l-heptene (IV -27): To a flask containing 100 mL THF was added vinyl magnesium bromide (220 mL, 1 M in THF), and the solution was cooled in an ice bath. Valeraldehyde (17.227 g, 810.0 mmol) was slowly added, and the mixture was stirred for 30 min at 0 °C then 30 min at room temperature. The mixture was quenched with 50 g sat. aq. NH4C1 and then dried with K2C03. Filtration and concentration provided an oil which was distilled to give IV-27 (21.56 g, 188.8 mmol) in 95% yield (bp 61 °C, 15 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.87 (t, J = 7.0 Hz, 3 H), 1.30 (m, 4 H), 1.50 (m, 2 H), 1.75 (s, 1 H), 4.05 (dddt, J = 1.2, 1.2, 6.5, 6.3 Hz, 1 H), 5.06 (ddd, J = 1.2, 1.5, 10.2 Hz, 1 H), 5.17 (ddd, J = 1.2, 1.5, 17.2 Hz, 1 H), 5.84 (ddd,] = 6.5, 10.2, 17.2 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 14.0, 22.6, 27.5, 36.7, 73.2, 114.4, 141.3; IR (neat) 3357 (br), 3081, 2960, 2933, 2874, 2862, 1646, 1468, 1425, 1380, 1319, 1276, 1146, 1089, 1052, 992, 920 cm'l. Synthesis of Trichloroacetamide IV-28: To a suspension of NaH (0.571 g, 23.8 mmol) in 200 mL THF was added IV-27 (18.10 g, 158.5 mmol). After stirring for 1 hour at room temperature the alkoxide/alcohol 79 mixture was transfered to a cooled solution of CCl3CN (22.886 g, 158.5 mmol) in 200 mL Et20. The mixture was stirred for 1.5 hours at 0 °C and then concentrated. Methanol (2 mL) in 100 mL pentane was added to the thick oil and shaken for 1 min. The solution was filtered and concentrated. The dark oil was dissolved in 600 mL xylenes and heated at reflux for 20 hours. The amide solution was filtered through a pad of silica gel and eluted with toluene and then concentrated. Kugelrohr distillation provided IV-28 (39.05 g, 151.0 mmol) in 95% yield (oven temp 85-100 °C, >1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.87 (t, J = 7.2 Hz, 3 H), 1.32 (m, 4 H), 2.03 (m, 2 H), 3.89 (dd, J = 1.2, 6.5 Hz, 2 H), 5.45 (m, 1 H), 5.70 (m, 1 H), 6.60-6.80 (bs, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 13.9,_22.1, 31.1, 31.9, 43.3, 123.5, 135.7, 161.5; IR (neat) 3411 (br), 3022, 2959, 2930, 2873, 1718, 1495, 1457, 1263, 1050, 972, 839, 728, 671 cm'l. Hydrolysis of IV-28 to 2-Heptenylamine (IV -29): The trichloroacetamide IV-28 was placed in 6 N aq. NaOH (300 mL) and heated at reflux for 36 hours. The amine was extracted from the aqueous mixture with 4 x 150 mL Et20 and dried over K2C03. The oil was concentrated and distilled (Kugelrohr) to give IV-29 (14.268 g, 126.0 mmol) in 84% yield (oven temp 60-70 °C, 22 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.84 (t, J = 7.4 Hz, 3 H), 1.25 (m, 6 H), 1.97 (m, 2 H), 3.19 (m, 2 H), 5.50 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 13.9, 22.1, 31.5, 31.9, 44.1, 130.7, 131.2; IR (neat) 3371, 3300, 2959, 2928, 2858, 1467, 1379, 969 cm'l. General Method for the Synthesis of Enamides IV -30: The amine IV-29 and an equimolar amount of the appropriate carbonyl compound were condensed in either Et20 with K2C03 at room temperature (for n-butanal) or in benzene (for 2-phenylpropanal) or toluene (for cyclohexanone) at reflux to prepare the corresponding imines which were used without isolation. After imine formation the solution was treated with Et3N (1 eq.), and isobutyryl chloride (1 eq.) was slowly added. 80 The mixture was stirred for a minimum of 4 hours at room temperature and then filtered through a pad of silica gel/alumina. The enamide was concentrated and purified by flash chromatography (silica gel, 70:30 Et20/petroleum ether) and then distilled (Kugelrohr). IV-30a: (2.63 g, 11.1 mmol) in 66% yield as a mixture of E:Z enamine olefin isomers (65:35 respectively) (oven temp 60-90 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (mixture of isomers) 0.84 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.11 (d, J = 6.6 Hz, 6 H), 1.19-1.35 (m, 4 H), 1.92-2.05 (m, 2 H), 2.04 (ddq, J = 1.3, 6.7, 7.5 Hz, 2 H), 2.75 (sept, J = 6.6 Hz, 1 H, Z isomer), 2.89 (sept, J = 6.6 Hz, 1 H, E isomer), 4.05 (bd, J = 2.9 Hz, 2 H, Z isomer), 4.14 (bd, J = 5.3 Hz, 2 H), 5.02 (dt, J = 13.8, 7.4 Hz, 1 H, z isomer), 5.12 (dt, J = 13.8, 6.7 Hz, 1 H, E isomer), 5.34 (m, 1 H), 5.46 (m, 1 H), 6.52 (d, J = 13.8 Hz, 1 H, E isomer), 7.19 (d,J = 14.8 Hz, 1 H, Z isomer); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 13.8, 14.6, 19.2, 22.0, 23.7, 30.8, 31.3, 31.8, 45.5, 116.0, 124.4, 126.4, 133.0, 175.2, (Z isomer) 13.8, 14.6, 19.7, 22.1, 23.6, 31.0, 31.3, 31.8, 46.7, 113.7, 124.1, 125.6, 132.7, 175.9; IR (neat) 3081, 2965, 2874, 1734, 1651, 1545, 1468, 1379, 1240, 1099, 970 cm‘l; HRMS cald for C15H27N0 m/e 237.2092, obsd m/e 237.2100. IV -30b: (8.937 g, 29.8 mmol) in 56% yield as a mixture of E :Z enamine olefin isomers (66:34 respectively) (oven temp 80-140 °C, 0.05 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 0.86 (t, J = 6.9 Hz, 3 H), 1.07 (d, J = 6.6 Hz, 6 H), 1.20-1.34 (m, 4 H), 1.91-2.04 (m, 2 H), 1.97 (d, J = 1.4 Hz, 3 H), 2.75 (sept, J = 6.6 Hz, 1 H), 4.06 (d, J = 6.0 Hz, 2 H), 5.24-5.62 (m, 2 H), 6.36 (bq, J = 1.4 Hz, 1 H), 7.18-7.58 (m, 5 H), (Z isomer) 0.83 (t, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 6 H), 1.20-1.34 (m, 4 H), 1.91-2.04 (m, 2 H), 2.07 (d, J = 1.4 Hz, 3 H), 2.85 (sept, J = 6.9 Hz, 1 H), 3.78 (d, J = 5.8 Hz, 2 H), 5.24-5.62 (m, 2 H), 6.17 (bq, J = 1.4 Hz, 1 H), 7.18-7.58 (m, 5 H); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 13.8, 19.1, 22.1, 31.2, 31.4, 31.7, 31.9, 49.4, 124.4, 126.0, 127.1, 128.0, 128.5, 134.7, 138.0, 139.9, 177.1, (2 isomer) 15.8, 19.0, 21.8, 31.2, 31.4, 31.7, 31.8, 48.6, 124.1, 125.8, 127.1, 127.7, 128.5, 134.0, 138.6, 139.9, 177.0; IR (neat) 3083, 81 3058, 3029, 2965, 2930, 2874, 1734, 1663, 1470, 1445, 1406, 1227, 1090, 970, 758, 698 cm'l; HRMS calcd for C20H29N0 m/e 299.2249, obsd m/e 299.2239. IV-30c: (3.755 g, 14.3 mmol) in 89% yield (oven temp 90-100 °C, <1 mmHg): 1H NMR (300 MHZ) (CDCl3) 5 0.82 (t, J = 7.2 Hz, 3 H), 1.03 (d, J = 6.7 Hz, 6 H), 1.25 (m, 4 H), 1.54 (m, 2 H), 1.64 (m, 2 H), 1.98 (m, 4 H), 2.06 (m, 2 H), 2.71 (sept, J = 6.7 HZ, 1 H), 3.90 (bs, 2 H), 5.40 (m, 2 H), 5.52 (m, 1 H); 13C NMR (75.5 MHZ) (CDCl3) 5 13.8, 20.1, 21.5, 22.0, 22.7, 24.7, 29.0, 31.2, 31.3, 31.8, 48.1, 125.5, 127.0, 134.0, 138.5, 176.4; IR (neat) 3027, 2960, 2931, 2873, 1651, 1469, 1438, 1400, 1361, 1246, 1234, 1139, 1092, 970, 922 cm‘l; HRMS calcd for C17H29N0 m/e 263.2249, obsd m/e 263.2248. Preparation of Trichloroacetamide IV-33: To a solution of crotonaldehyde (14.018 g, 200 mmol) in Et20 (250 mL) at -78 °C was added methyl magnesium bromide (66.67 mL, 3 M in Et20). The solution was allowed to warm to room temperature overnight, and quenched with saturated aq. NH4Cl (100 mL) and water (100 mL). The alcohol was extracted with 3 x 100 mL B20, and dried over MgSO4. The solution was filtered and concentrated to half its volume by distillation. To the alcohol solution was added NaH (0.72 g, 30 mmol), and the mixture was stirred for 30 minutes. The alkoxide solution was added to a 0 °C solution of CC13CN in THF (400 mL). The mixture was stirred at ambient temperature overnight, concentrated. The residue was taken up in pentane/MeOH (200 mL/20 mL) and filtered. The solvents were evaporated, and the oil was placed in xylenes (400 mL). The solution was heated at reflux for 20 hours, filtered through silica with toluene as eluant, and concentrated. The trichloroacetamide was distilled via Kugelrhor to give IV-33 (37.10 g, 162 mmol) in 81% yield (oven temp 80-120 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.27 (d, J = 6.8 hz, 3 H), 1.67 (dd, J = 1.6, 6.4 Hz, 3 H), 4.42 (ddq, J = 1.3, 5.8, 6.8 Hz, 1 H), 5.43 (ddq, J = 5.8, 15.4, 1.6 Hz, 1 H), 5.66 (ddq, J = 1.3, 15.4, 6.4 Hz, 1 SLAB" 82 H), 6.58 (s, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.6, 20.1, 48.8, 92.7, 127.2, 130.5, 160.7; IR (neat) 3333, 3035, 2978, 2938, 2921, 2830, 1696, 1518, 1453, 1379, 1240, 1167, 1130, 1078, 966, 823, 740, 683 cm'l. General Method for the Preparation of Enamides IV-34: Amide IV-33 was heated at reflux for at least 12 hours in 6 M NaOH, extracted with either Et20 or benzene, and dried‘with K2C 03. The amine solution and an equimolar amount of the appropriate carbonyl compound were condensed in either Et20 with K2C03 at room temperature (for n-butanal) or in benzene (for 2-phenylpropanal and cyclohexanone) at reflux to prepare the corresponding imines which were used without isolation. After imine formation the solution was treated with Et3N (1 eq.), and isobutyryl chloride (1 eq.) was slowly added. The mixture was stirred for a minimum of 4 hours at room temperature and then filtered through a pad of silica gel/alumina. The enamide was concentrated and purified by flash chromatography (silica gel, 70:30 Et20/petroleum ether) and then distilled. IV-34a: (25.44 g, 121.2 mmol) in 75% yield (bp 83-95 °C, <1 mmHg): 1H NMR (300 MHz)(CDC13)81.01 (t, J = 7.4 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 6 H), 1.15 (d,J = 6.6 Hz, 3 H), 1.64 (d, J = 5.2 Hz, 3 H), 2.07 (quint, J = 7.4 Hz, 2 H), 2.86 (sept, J = 6.6 Hz, 1 H), 5.13 (m, 1 H), 5.35-5.57 (m, 3 H), 5.95 (d, J = 13.7 Hz, 1 H); 13C NMR (75.5 MHz) (CDC13) 8 13.8, 17.5, 17.7, 19.2, 23.3, 31.4, 50.4, 124.5, 126.1, 131.5, 132.4, 176.3; IR (neat) 3030, 2969, 2936, 2876, 1645, 1458, 1395, 1237, 968 cm'l; HRMS calcd for C13H23N0 m/e 209.1779, obsd m/e 209.1781. IV-34b: (6.101 g, 22.4 mmol) in 64% yield as a mixture of isomers (E :2 55:45) (oven temp 95-110 °C, <1 mmHg): 1H NMR: (300 MHz) (CDC13) 8 (E isomer) 0.75 (d, J = 6.7 Hz, 3 H), 1.07 (d, J= 6.7 Hz, 3 H), 1.16 (d, J: 6.9 Hz, 3 H), 1.61 (d, J: 6.1 Hz, 3 H), 2.11 (d, J = 1.3 Hz, 3 H), 2.75 (sept, J = 6.7 Hz, 1 H), 5.05 (quint, J = 6.9 Hz, 1 H), 5.35-5.61 (m, 2 H), 6.00 (d, J = 1.3 Hz, 1 H), 7.16-7.42 (m, 5 H), (Z isomer) 0.72 (d, J = 83 6.7 Hz, 3 H), 1.05 (d, J = 6.7 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.65 (d,J= 6.4 Hz, 3 H), 1.96 (d, J = 1.3 Hz, 3 H), 2.73 (sept,J = 6.7 Hz, 1 H), 5.29 (quint, J = 6.9 Hz, 1 H), 5.40-5.67 (m, 2 H), 6.23 (d, J = 1.3 Hz, 1 H), 7.16-7.42 (m, 5 H); 13C NMR: (75.5 MHz) (CDC13) 8 (E isomer) 17.2, 17.8, 18.6, 19.0, 22.2, 31.4, 52.2, 121.5, 126.0, 126.9, 127.3, 128.3, 131.0, 135.5, 140.0, 177.1, (Z isomer) 16.0, 17.6, 18.8, 19.3, 22.2, 31.5, 51.4, 122.8, 126.0, 127.0, 127.6, 128.5, 130.7, 135.5, 138.6, 176.8; IR (neat) 3083, 3058, 3029, 2971, 2934, 2874, 1655, 1447, 1402, 1246, 1192, 1090, 970, 864, 764, 698 cm'l; HRMS calcd for C13H25N0 m/e 271.1936, obsd m/e 271.1936. IV-34c: (3.317 g, 14.0 mmol) in 56% yield (oven temp 80-90 C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.02 (m, 6 H), 1.14, (m, 3 H), 1.43-1.72 (m, 4 H), 1.62 (d, J = 5.8 Hz, 3 H), 1.80-2.18 (m, 4 H), 2.62 (sept, J = 6.5 Hz, 1 H), 4.93 (m, 1 H), 5.35- 5.60 (m, 3 H); 13C NMR (75.5 MHz) (CDCl3) 8 17.8, 18.6, 19.9, 20.4, 21.5, 22.9, 24.9, 32.0, 51.0, 126.4, 128.2, 131.9, 136.7, 176.1; IR (neat) 3031, 2967, 2934, 2874, 2842, 1647, 1393, 125, 972 cm'l; HRMS calcd for C15H25N0 m/e 235.1936, obsd m/e 235.1917. General Method for the Reduction of Enamides to Enamines IV-31 and IV-35: Enamide IV-31 or IV-35 was slowly added to a suspension of LiA1H4 (1.2 eq.) in Et20 (0.2 M) and stirred at room temperature for a minimum of 2 hours. The mixture was quenched by careful addition of H20 (1 mL/g LiAlH4), then 15% aq. NaOH (1 mL/g LiAlH4), and finally H20 (3 mL/g LiAlH4), stirred for 1 hours, and filtered. The was concentrated, and the enamine was distilled (Kugelrohr). IV-3la: (1.94 g, 8.7 mmol) in 99% yield as a single enamine olefin isomer (oven temp 60-70 °C, <1 mmHg): This enamine was extremely sensitive to hydrolysis and full spectral characterization could not be obtained. Characteristic enamine olefin resonances; 1H NMR (300 MHz) (CDCl3) 8 4.11 (dt, J = 6.7, 13.9 Hz, 1 H), 5.88 (bd, J = 13.9 Hz, 1 H). 84 IV -3lb: (7.129 g, 25.0 mmol) in 99% yield as a mixture of E :Z enamine olefin isomers (90le respectively) (oven temp 95-120 °C, <1 mmHg): 1H NMR (300 MHz) (CDC13) 8 (mixture of isomers) 0.89 (d, J = 6.6 Hz, 6 H), 0.91 (t, J = 6.4 Hz, 3 H), 1.25- 1.40 (m, 4 H), 1.76 (non, J = 6.6 Hz, 1 H), 1.97 (d, J = 1.1 Hz, 3 H, z isomer), 2.00-2.10 (m, 2 H), 2.09 (d, J = 1.1 Hz, 3 H, E isomer), 2.49 (d, J = 7.2 Hz, 2 H, Z isomer), 2.61 (d, J = 7.4 Hz, 2 H, E isomer), 3.46 (d, J = 5.1 Hz, 2 H), 5.44-5.64 (m, 2 H), 5.82 (d, J = 1.1 Hz, 1 H, z isomer), 6.14 (d, J = 1.1 Hz, 1 H, E isomer); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 13.9, 15.6, 20.4, 22.2, 28.3, 31.5, 32.0, 57.5, 62.1, 117.7, 124.9, 125.1, 127.4, 128.0, 133.1, 139.3, 143.4, (2 isomer) 13.9, 15.6, 20.7, 22.7, 28.3, 31.4, 31.9, 56.1, 61.5, 117.7, 124.9, 125.1, 127.6, 127.9, 133.0, 136.7, 142.0; IR (neat) 3085, 3050, 3028, 2957, 2928, 2870, 1632, 1495, 1466, 1120, 970, 756, 696 em-l. IV-31c: (2.901 g, 11.6 mmol) in 97% yield (bp 75% °C, <1 mmHg): 1H NMR (300 MHz) (CDC13) 8 0.82 (d, J = 6.6 Hz, 6 H), 0.86 (t, J = 7.2 Hz, 3 H), 1.29 (m, 4 H), 1.49 (m, 2 H), 1.65 (m, 2 H), 1.84 (dsept, J = 7.1, 6.6 Hz, 1 H), 1.98 (m, 2 H), 2.06 (m, 4 H), 2.63 (d, J = 7.1 Hz, 2 H), 3.49 (d, J= 5.5 Hz, 2 H), 4.41 (dd, J = 1.2, 3.6 Hz, 1 H), 5.40 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 13.9, 20.6, 22.1, 22.9, 23.6, 24.7, 26.6, 27.3, 31.6, 32.0, 51.8, 56.3, 96.5, 126.9, 132.3, 143.5; IR (neat) 3022, 2958, 2929, 2872, 1685, 1653, 1646, 1466, 1437, 1367, 1120, 970 em-l. IV-3Sa: (4.277 g, 22.0 mmol) in 88% yield (bp 75-85 °C, 8 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.83 (d, J = 6.7 Hz, 6 H), 0.92 (t, J = 7.4 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H), 1.65 (m, 3 H), 1.84 (non, J = 6.7 Hz, 1 H), 1.95 (ddq, J =1.1,6.6,7.4 Hz, 2 H), 2.49 (d, J = 7.1 Hz, 2 H), 3.5 (m, 1 H), 4.11 (dt, J = 13.9, 6.6 Hz, 1 H), 5.42-553 (m, 2 H), 5.92 (dt, J= 13.9, 1.1 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 16.3, 17.3, 17.8, 20.6, 24.2, 26.6, 56.0. 58.7, 100.1, 125.2, 133.4, 135.0; IR (neat) 3020, 2959,2932, 2870, 1649, 1453, 1379, 1080, 972, 938 em-l. IV-35b: (2.949 g, 11.52 mmol) in 96% yield as a mixture of isomers (E :2 55:45) (bp 80-90 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) (mixture of isomers) 8 0.86 (d, 85 J = 6.7 Hz, 3 H), 0.87 (d, J= 6.7 Hz, 3 H), 1.15 (d, J: 6.8 Hz, 3 H), 1.63 (m, 1 H), 1.64 (dd, J = 1.3, 4.7 Hz, 3 H, z isomer), 1.69 (dd, J = 1.1, 4.8 Hz, 3 H, E isomer), 1.97 (d, J = 1.2 Hz, 3 H, z isomer), 2.08 (d, J = 1.2 Hz, 3 H, E isomer), 2.41 (dd, J = 7.3, 12.7 Hz, 1 H), 2.44 (dd, J = 7.3, 12.7 Hz, 1 H), 3.48 (m, 1 H), 5.25-5.60 (m, 2 H), 5.77 (bq, J = 1.2 Hz, 1 H, z isomer), 6.08 (bq, J = 1.2 Hz, 1 H, E isomer), 7.08-7.55 (m, 5 H); 13C NMR (75.5 MHz) (CDCl3) (E isomer) 8 15.8, 17.6, 17.9, 20.5, 28.6, 57.0, 57.7, 60.0, 113.9, 125.1,127.7, 128.1, 1291,1335, 138.8, 143.0, (2 isomer) 16.6, 17.6, 17.9, 22.6, 28.7, 55.9, 57.8, 60.0, 111.4, 125.6, 127.6, 128.3, 129.1, 133.3, 136.8, 141.9; IR (neat) 3028, 2965,2870, 1686, 1450, 1360, 1285, 972, 760, 698 em-l. IV-35c: (2.532 g, 11.4 mmol) in 95% yield (oven temp 60-70 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.78 (d, J = 6.6 Hz, 6 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.46- 1.56 (m, 2 H), 1.57-1.68 (m, 2 H), 1.66 (dd, J = 1.5, 4.7 Hz, 3 H), 1.80 (non, J = 6.6 Hz, 1 H), 1.99-2.11 (m, 4 H), 2.35 (dd, J = 6.8, 10.7 Hz, 1 H), 2.42 (dd, J = 6.8, 10.7 Hz, 1 H), 3.87 (m, 1 H), 4.48 (t, J = 3.8 Hz, 1 H), 5.34-5.50 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 16.2, 17.9, 20.8, 20.9, 23.1, 23.7, 24.9, 25.2, 27.9, 51.4, 53.0, 101.7, 124.5, 134.4, 142.2; IR (neat) 3027,2957, 2938, 2868, 1717, 1450, 1119, 970 em-l. Preparation of IV-37: Proline (8.635 g, 75.0 mmol) was dissolved in MeOH (75 mL), cooled to 0 °C and S002 (22.307 g, 187.5 mmol) was slowly added. The solution was allowed to stir at room temperature overnight and was then concentrated. The crude ester hydrochloride was dissolved in THF (150 mL) and Et3N (16.665 g, 165.0 mmol) was added followed bydi-tert-butyldicarboxylate (17.242 g, 79.0 mmol). After stirring 4 hours, the mixture was filtered, concentrated, and distilled (Kugelrhor) under vacuum to give IV-37 (17.10 g, 74.6 mmol) in 99% yield as a mixture of two amide isomers (oven temp 90-100 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 1.38 (s, 9 H), 1.90 (m, 3 H), 2.17 (m, 1 H), 3.46 (m, 2 H), 3.69 (s, 3 H), 4.19 (dd, J = 4.0, 8.5 Hz, 1 H), (minor isomer) 86 1.43 (s, 9 H), 1.85 (m, 3 H), 2.17 (m, 1 H), 3.40 (m, 2 H), 3.70 (s, 3 H), 4.29 (dd, J = 4.0, 8.5 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 23.6, 28.2, 30.8, 46.2, 51.8, 59.0, 79.7, 152.7, 173.7, (minor isomer) 24.2, 28.3, 29.8, 46.5, 52.0, 58.6, 79.6. 154.3, 173.4; IR (neat) 2978, 2882, 1752, 1701, 1455, 1397, 1367, 1258, 1202, 1161, 1122, 1088, 1001, 889, 774 cm'l. DIBAH Reduction of IV-37 to Aldehyde IV-38: IV -38 (8.025 g, 35.0 mmol) was placed in toluene (100 mL) and cooled to -78 °C. DIBAH (36 mL, 2 M in hexane) was added. The mixture was stirred at -78 °C for 2 hours, and quenched by addition of Na2SO4(10 H20). The solution was filtered, concentrated, and the oil was distilled under vacuum to give IV-38 6.30 g, 31.6 mmol) in 90% yield as a mixture of amide resonance isomers (bp 88-90 °C <1 mmHg): .1H NMR (300 MHz) (CDCl3) 8 (major isomer) 1.40 (s, 9 H), 1.8-2.2 (m, 4 H), 3.42 (m, 2 H), 4.0 (m, 1 H), 9.42 (d, J = 2.8 Hz, 1 H); 13C NMR (75.5 MHz) (CDC13) 8 (major isomer) 23.9, 28.2, 28.3, 46.7, 65.0, 80.6, 153.9, 200.4, (minor isomer) 24.6, 28.0, 28.4, 46.8, 64.8, 80.2, 154.7, 200.6; IR (neat) 2978, 2930, 2882, 2813, 1738, 1698, 1480, 1456, 1397, 1256, 1167, 1123, 984, 912, 858, 774 cm'l. Wittig Reaction and Deprotection of IV-38 to give IV -39: To a solution of benzyltriphenylphosphonium or ethyltriphenylphosphonium bromide (1 eq.) in DMSO (0.5 M), was added NaH (1.1 eq.), and the mixture was stirred for 15 minutes. A solution of IV-38 (1 eq.) in DMSO (2 M) was added. The mixture was stirred for 30 minutes, and washed with water. The mixture was extracted with pentane and dried over K2C03. The organic layer was concentrated and the crude olefin was dissolved in MeOH (1 M). Excess concentrated HCl was added and the solution was allowed to stir overnight. The mixture was brought to pH 14 by addition of NaOH pellets, extracted with ether, dried over K2C03, concentrated and distilled (Kugehohr). 87 IV-39a: (1.401 g, 8.11 mmol) in 69% yield as a mixture of isomers (E :2 65:35) (oven temp 85-95 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.50 (m, 1 H), 1.65 (bs, l H), 1.70-1.90 (m, 2 H), 1.98 (m, 1 H), 2.90 (m, 1 H), 3.07 (m, l H), 3.68 (bq, J = 7.1 Hz, 1 H), 6.20 (dd, J: 7.2, 15.7 Hz, 1 H), 6.49 (d, J = 15.7 Hz, 1 H), 7.15- 7.40 (m, 5 H), (Z isomer) 1.50 (m, 1 H), 1.65 (bs, 1 H), 1.70-1.90 (m, 2 H), 2.85 (m, 1 H), 1.98 (m, 1 H), 3.07 (m, 1 H), 3.96 (dt, J = 9.3, 7.1 Hz, 1 H), 5.62 (dd, J: 9.3, 11.4 Hz, 1 H), 6.46 (d, J = 11.4 Hz, 1 H), 7.15-7.40 (m, 5 H); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 25.1, 32.2, 46.3, 60.7, 126.1, 127.0, 128.3, 129.3, 132.7, 137.0, (Z isomer) 25.7, 33.0, 46.6, 55.6, 126.7, 128.0, 128.5, 129.4, 135.4, 136.9; IR (neat) 3275, 3080, 3058, 3025, 2961, 2870, 1493, 1449, 1399, 1073, 965, 748, 694 cm'l. IV-39b: carried on to IV-40b without isolation. Condensation of IV-39 with Phenylacetaldehyde to give IV-40: Amine IV-39 (1 eq.) and phenylacetaldehyde (1 eq.) were dissolved in Et20 (0.3 M). Potassium carbonate or magnesium sulfate was added and the mixture was stirred for 1-6 hours, filtered, and concentrated. If necessary the enamine was distilled under vacuum. IV-408: (0.826 g, 3.0 mmol) in 100% yield as a mixture of isomers at the allylic double bond (E:Z 65:35): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.87-2.36 (m, 4 H), 3.34 (m, 1 H), 3.47 (m, 1 H), 4.15 (q, J = 6.8 Hz, 1 H), 5.28 (d, J = 14.0 Hz, 1 H), 6.22 (dd, J = 7.4, 15.7 Hz, 1 H), 6.65 (d, J = 15.7 Hz, 1 H), 6.99-7.07 (m, 2 H), 7.12 (d, J = 14.0 Hz, 1 H), 7.21-7.26 (m, 2 H), 7.30-7.70 (m, 6 H), (Z isomer) 1.87-2.36 (m, 4 H), 3.34 (m, 1 H), 3.47 (m, 1 H), 4.49 (dt, J = 6.9, 9.5 Hz, 1 H), 5.16 (d, J = 13.9 Hz, 1 H), 5.70 (dd, J = 9.5, 11.5 Hz, 1 H), 6.78 (d, J = 11.5 Hz, 1 H), 6.99-7.07 (m, 2 H), 7.04 (d, J = 13.9 Hz, 1 H), 7.21-7.26 (m, 2 H), 7.30-7.70 (m, 6 H); 13C NMR (75.5 MHz) (CDCl3) 8 (E isomer) 23.5, 32.9, 47.7, 63.6, 98.2, 122.9, 123.3, 126.4, 127.5, 128.4, 128.5, 131.3, 131.4, 134.5, 136.6, 139.9, (Z isomer) 23.9, 33.3, 47.7, 58.1, 98.2, 122.8, 123.2, 126.4, 88 127.1, 128.2, 128.6, 131.3, 134.1, 134.3, 136.6, 139.9; IR (neat) 3080, 3056, 3025, 2969, 2872, 1636, 1597, 1495, 1370, 1142, 968, 936, 747, 693 cm'l. IV-40b: (3.19 g, 14.93 mmol) in 79% yield (from IV-38) (oven temp 100-110 °C, <1 mmHg) as a mixture of isomers at the allylic double bond (E :2 27:73): 1H NMR (300 MHz) (CDCl3) 8 (E isomer) 1.53-1.68 (m, 1 H), 1.72 (dd,J = 1.7, 6.9 Hz, 3 H), 1.81-2.12 (m, 3 H), 3.16 (m, 1 H), 3.28 (m, 1 H), 3.80 (q, J = 7.2 Hz, 1 H), 5.11 (d, J = 13.8 Hz, 1 H), 5.32 (m, 1 H), 5.68 (m, 1 H), 6.92 (m, 1 H), 6.93 (d, J = 13.8 Hz, 1 H), 7.11-7.23 (m, 4 H), (Z isomer) 1.53-1.68 (m, 1 H), 1.75 (dd, J = 1.8, 6.9 Hz, 3 H), 1.81- 2.12 (m, 3 H), 3.16 (m, 1 H), 3.28 (m, 1 H), 4.20 (bq, J = 7.1 Hz, 1 H), 5.11 (d,J = 13.8 Hz, 1 H), 5.32 (ddq, J = 9.0, 10.8, 1.8 Hz, 1 H), 5.66 (ddq, J = 1.1, 10.8, 6.9 Hz, 1 H), 6.92 (m, 1 H), 6.93 (d, J= 13.8 Hz, 1 H), 7.11-7.23 (m, 4 H); 13c NMR (75.5 MHz) (CDCl3) 8 (E isomer) 23.4, 32.9, 46.7, 56.7, 63.8, 97.5, 122.8, 123.3, 127.7, 128.1, 132.9, 135.0, 140.2, (Z isomer) 23.8, 32.9, 46.7, 56.7, 63.6, 97.8, 122.8, 123.3, 126.8, 128.1, 132.3, 134.5, 140.1; IR (neat) 3080, 3061, 3029, 2975, 2924, 2875, 1690, 1634, 1601, 1495, 1453, 1121, 1030, 970, 752, 700 cm'l. General Procedure for BC! Promoted Rearrangement and Reduction: The procedure was identical to the the general HCl promoted rearrangement procedure in Chapter III with the exception that toluene was used as the solvent and reduction of the cyclohexanone derived substrate was carried out with DIBAH (3 eq.). IV-20b: 0.687 g (3.4 mmol, 86% yield, 8% de), (oven temp 60-70 °C, 5 mmHg): 1H NMR (500 MHz) (CDCl3) (major isomer) 8 0.81 (s, 3 H), 0.83 (s, 3 H), 0.91 (d, J = 7.0 Hz, 3 H), 1.10 (d, J= 6.2 Hz, 3 H), 2.14 (quint, J = 7.4 Hz, 1 H), 2.31 (d, J =11.5 Hz, 1 H), 2.37 (d,J = 11.5 Hz, 1 H), 2.51 (dd, J = 4.1, 10.7 Hz, 1 H), 2.58 (dd,J = 7.6, 10.7 Hz, 1 H), 3.32 (s, 3 H), 3.44 (m, 1 H), 4.89-4.98 (m, 2 H), 5.76 (ddd, J = 8.6, 10.3, 18.9 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) (major isomer) 8 14.7, 17.1, 22.9, 23.0, 36.2, 44.4, 56.1, 56.5, 59.6, 76.0, 114.0, 141.7; (minor isomer) 14.7, 17.0, 23.0, 22.9, 36.2, 89 44.5, 56.2, 56.4, 59.5, 75.9, 114.0, 141.8; IR (neat) 3343, 3075, 2973, 2878, 2822, 1636, 1458, 1373, 1128, 1088, 999, 912, 812 cm4; HRMS calcd for C12H25N0 m/e 199.1936, obsd m/e 199.1922. IV-32b: (0.465 g, 1.6 mmol) in 54% yield as a mixture of diastereomers (95:5) (oven temp 85-100 °C, <1 mmHg): 1H NMR (500 MHz) (CDCl3) 8 (major isomer) 0.71 (d, J = 6.6 Hz, 6 H), 0.81 (t, J = 6.6 Hz, 3 H), 0.86-1.32 (m, 7 H), 1.34 (s, 3 H), 1.59 (non, J = 6.6 Hz, 1 H), 2.19-2.30 (m, 2 H), 2.60 (d, J = 11.5 Hz, 1 H), 2.83 (d, J = 11.5 Hz, 1 H), 5.07 (dd, J = 2.3, 16.9 Hz, 1 H), 5.11 (dd,J = 2.3, 9.9 Hz, 1 H), 5.63 (dt, J = 16.9, 9.9 Hz, 1 H), 7.15-7.36 (m, 5 H); (minor isomer) 0.73 (d, J = 6.6 Hz, 6 H), 0.83 (t, J = 6.6 Hz, 3 H), 0.86-1.32 (m, 7 H), 1.39 (s, 3 H), 1.66 (non, J = 6.6 Hz, 1 H), 2.27-2.43 (m, 2 H), 2.72 (d, J=11.5 Hz, 1 H), 3.01(d,J=11.5 Hz, 1 H), 4.78 (dd,J: 2.1, 17.1 Hz, 1 H), 4.92 (dd, J = 2.1, 10.3 Hz, 1 H), 5.42 (dt, J = 17.1, 10.3 Hz, 1 H), 7.15-7.36 (m, 5 H); 13C NMR (75.5 MHz) (CDC13) 8 (major isomer) 13.9, 17.7, 20.4, 20.5, 22.3, 27.5, 28.3, 29.9, 44.8, 53.2, 58.6, 60.6, 116.8, 125.7, 126.8, 128.1, 139.6, 146.0; (minor isomer) 14.0, 17.7, 20.6, 21.1, 22.6, 27.7, 28.2, 30.3, 44.7, 53.8, 58.1, 58.9, 116.3, 125.6, 127.1, 127.8, 139.3, 145.4; IR (neat) (neat) 3341, 3061, 3025, 2957, 2932, 2872, 2809, 1684, 1466, 1379, 1121, 912, 700 cm'l; HRMS calcd for C20H33N m/e 287.2613, obsd m/e 287.2614. IV-32c: (0.692 g, 2.8 mmol) in 69% yield as a mixture of diastereomers (54:46) (oven temp 75-85 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 0.85 (t, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 6 H), 1.0-1.74 (m, 16 H), 1.79-2.00 (m, 2 H), 2.14 (dd, J= 6.7, 11.2 Hz, 1 H) 2.47 (dd, J = 6.4, 11.2 Hz, 1 H), 2.82 (q, J = 2.5 Hz, 1 H), 4.91 (dd, J = 2.2, 17.0 Hz, 1 H) 4.93 (dd, J = 2.2, 10.1 Hz, 1 H), 5.47 (ddd, J = 9.8, 10.1, 17.0 Hz, 1 H); (minor isomer) 0.83 (t, J = 6.7 Hz, 3 H), 0.86 (d, J = 6.7 Hz, 6 H), 1.0-1.74 (m, 16 H), 1.79-2.00 (m, 2 H), 2.06 (dd, J = 6.7, 11.2 Hz, 1 H) 2.38 (dd, J = 6.4, 11.2 Hz, 1 H), 2.67 (q, J = 2.8 Hz, 1 H), 4.94 (dd, J = 2.2, 17.0 Hz, 1 H) 4.96 (dd, J = 2.2, 10.1 Hz, 1 H), 5.53 (ddd, J = 9.8, 10.1, 17.0 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major 90 isomer) 14.1, 19.9, 20.9, 21.0, 22.8, 25.4, 26.7, 28.7, 29.3, 31.1, 45.1, 46.7, 53.7, 55.9, 114.9, 143.0; (minor isomer) 14.0, 20.0, 20.8, 21.0, 22.8, 24.8, 26.7, 28.8, 29.4, 31.8, 45.6, 46.4, 54.1, 55.7, 114.4, 142.3; IR (neat) 3360, 3074, 2955, 2930, 2857, 1640, 1469, 1377, 1105, 998, 909 cm'l; HRMS calcd for C17H33N m/e 251.2613, obsd m/e 251.2606. IV-36b: (0.778 g, 3.0 mmol) in 75% yield as a mixture of diastereomers (90:10) (oven temp 80-100 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (mixture of isomers) 0.40 (bs, 1 H), 0.63 (d, J = 6.7 Hz, 3 H), 0.69 (d, J = 6.7 Hz, 3 H), 0.72 (d, J = 6.7 Hz, 3 H), 1.29 (s, 3 H), 1.57 (m, 1 H), 1.67 (d, J = 5.3 Hz, 3 H), 2.16-2.34 (m, 2 H), 2.47 (quint, J = 7.8 Hz, 1 H), 2.59 (d, J = 11.4 Hz, 1 H), 2.83 (d,J = 11.4 Hz, 1 H, major isomer), 2.96 (d, J = 11.4 Hz, 1 H, minor isomer), 5.09-5.29 (m, 2 H, minor isomer), 5.30—5.58 (m, 2 H, major isomer), 7.11-7.21 (m, 2 H), 7.24-7.37 (m, 3 H); 13C NMR (75.5 MHz) (CDC13) 8 (major isomer) 15.9, 17.4, 18.1, 20.4, 20.5, 27.6, 45.0, 45.7, 58.8. 60.4, 125.4, 125.6, 126.8, 128.1, 133.6, 146.2, (minor isomer) 15.1, 17.2, 18.0, 20.1, 20.6, 27.7, 44.8, 45.4, 58.3, 59.8, 124.7, 125.7, 127.1, 127.8, 133.5, 145.6; IR (neat) 3375, 3090, 3059, 3025, 2959, 2925, 2876, 2809, 1497, 1464, 1379, 1121, 1030, 970, 764, 700 cm'l; HRMS calcd for C13H29N m/e 259.2300, obsd m/e 259.2286. General Procedure for the TiCl4 Promoted Rearrangement and Reduction: The procedure was identical 'to the the general TiCl4 promoted rearrangement procedure in Chapter III with the exception that reduction of the cyclohexanone derived substrate was carried out with DIBAH (3 eq.). IV-20a: (0.923 g, 4.6 mmol) in 77% yield (15% de) (oven temp 60-70 °C, 5 mmHg): 1H NMR (500 MHz) (CDCl3) 8 0.82 (s, 3 H), 0.83 (s, 3 PD, 0.92 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H), 1.40 (bs, 1 H), 2.14 (dq, J = 8.5, 7.0 Hz, 1 H), 2.31 (d, J = 11.3 Hz, 1 H), 2.42 (d, J = 11.3 Hz, 1 H), 2.73 (m', 1 H), 3.22-3.25 (m, 2 H), 3.32 (s, 3 H), 4.92-4.99 (m, 2 H), 5.76 (ddd, J = 8.5, 10.3, 17.1 Hz, 1 H), (minor isomer) 0.81 (s, 3 H), 0.83 (s, 3 H), 0.91 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 6.4 Hz, 3 H), 1.40 (bs, 1 H), 2.14 (dq, 91 J = 8.6, 7.0 Hz, 1 H), 2.28 (d, J = 11.5 Hz, 1 H), 2.41 (d, J: 11.5 Hz, 1 H), 2.73 (m, l H), 3.22-3.25 (m, 2 H), 3.32 (s, 3 H), 4.92-4.99 (m, 2 H), 5.77 (ddd, J = 8.5, 10.3, 17.1 Hz, 1 H); 13C NMR (75.5 MHz) (CDC13)8 (major isomer) 14.7, 17.2, 22.9, 35.9, 44.2, 53.3, 56.9, 58.6, 77.2, 114.0, 141.5; (minor isomer) 14.6, 17.3, 22.8, 35.9, 44.2, 53.3, 56.7. 58.7, 77.1, 114.0, 141.6; IR 3341, 3075, 2967, 2874, 2826, 1635, 1474, 1458, 1370, 1111, 912 cm‘l; HRMS calcd for C12H25N0 m/e 199. 1936, obsd m/e 199.1940. IV-20b: (0.854 g, 4.3 mmol) 72% yield (20% de) (oven temp 60-70 °C, 5 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-32b: (0.411 g, 1.4 mmol) in 48% yield as a mixture of diastereomers (80:20) (oven temp 85-100 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-32c: (0.635 g, 2.5 mmol) in 72% yield as a mixture of diastereomers (55:45) (oven temp 75-85 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-36b: (0.65 g, 2.52 mmol) in 84% yield as a mixture of diastereomers (90:10) (oven temp 80-90 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. General Procedure for the AlMe3 Promoted Rearrangement and Reduction: The procedure was identical to the the general AlMe3 promoted rearrangement procedure in Chapter III with the exception that reduction of the cyclohexanone derived substrate was carried out with DIBAH (3 eq.). IV -32a: (0.693 g, 3.1 mmol) in 88% yield as a mixture of diastereomers (62:38) (oven temp 55-65 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 0.84- 0.89 (m, 12 H), 1.05-1.47 (m, 3 H), 1.51 (sept, J = 6.3 Hz, 2 H), 1.89 (dsept, J = 6.8, 5.6 Hz, 1 H), 2.06 (t, J = 7.2 Hz, 2 H), 2.42-2.62 (m, 4 H), 3.06 (m, 1 H), 3.38 (s, 3 H), 4.95- 92 5.04 (m, 2 H), 5.73-5.82 (m, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 10.7, 17.5, 18.2, 24.3, 29.2, 36.1, 39.3, 49.9, 53.1, 57.8, 85.2, 115.5, 138.8, (minor isomer) 10.8, 17.5, 18.2, 24.1, 29.2, 36.0, 39.2, 49.8, 53.0, 57.8, 85.2, 115.5, 138.8; IR (neat) cm'l; HRMS calcd for C15H31N m/e 225.2456, obsd m/e 225.2439. IV-32b: (0.740 g, 2.6 mmol) in 86% yield as a mixture of diastereomers (68:32) (oven temp 85-100 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-32c: (0.940 g, 3.7 mmol) in 94% yield as a mixture of diastereomers (67:33) (oven temp 75-85 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-36a: (0.771 g, 3.9 mmol) in 78% yield as a single diastereomer (>98:2) (oven temp 65-75 °C, 5 mmHg): 1H NMR (300 MHz) (CDCl3) 8 0.83 (bs, 1 H), 0.84 (t, J = 7.0 Hz, 3 H), 0.86 (d, J = 6.4 Hz, 6 H), 0.91 (d, J = 7.0 Hz, 3 H), 1.20-1.40 (m, 3 H), 1.61 (d, J= 4.5 Hz, 3 H), 1.70 (non, J = 6.7 Hz, 1 H), 2.18 (m, 1 H), 2.36 (d, J= 6.7 Hz, 2 H), 2.39 (dd, J = 6.0, 11.7 Hz, 1 H), 2.50 (dd, J = 5.5, 11.7 Hz, 1 H), 5.25-5.42 (m, 2 H); 13C NMR (75.5 MHz) (CDC13) 811.6, 17.3, 18.0, 20.6, 22.1, 28.1, 37.5, 45.1, 50.9, 58.4, 123.6, 135.8; IR (neat) 3360, 3025, 2981, 2934, 2874, 2815, 1464, 1379, 1125, 968. 742 cm-1; HRMS calcd for C13H27N mle 197.2143, obsd m/e 197.2147. IV-36b: (1.002 g, 3.88 mmol) in 97% yield as a mixture of diastereomers (80:20) (oven temp 80-90 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV-36c: (0.847 g, 3.8 mmol) in 95% yield as a mixture of diastereomers (>95:5) (oven temp 55-65 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 0.81 (d, J = 7.0 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 6 H), 0.90-1.25 (m, 7 H), 1.50-1.68 (m, 3 H), 1.60 (d, J = 4.5 Hz, 3 H), 1.95 (m, 1 H), 2.14-2.25 (m, 2 H), 2.47 (dd, J = 6.7, 11.2 Hz, 1 H), 2.56 (m, 1 H), 5.25-5.43 (m, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 13.5, 18.0, 20.7, 20.8, 25.0, 25.4, 25.9, 28.7, 32.6, 34.8, 47.5, 54.9, 57.9, 122.9, 137.0. 93 (minor isomer) 13.5, 18.0, 20.7, 20.9, 25.2, 25.7, 26.1, 28.7, 32.4, 36.0, 47.9, 54.8, 58.4, 124.1, 134.0; IR (neat) 3380, 3025, 2955, 2928, 2870, 2859, 1470, 1458, 1377, 1105, 968, 702 cm'l. HRMS calcd for C15H29N m/e 223.2300, obsd m/e 223.2300. General Procedure for the MezAlCl Promoted Rearrangement and Reduction: The procedure was identical to the the general AlMe3 promoted rearrangement procedure in Chapter III with the exception that AlMe2Cl was used instead of AlMe3, and reduction of the cyclohexanone derived substrate was carried out with DIBAH (3 eq.). IV-26: (0.955 g, 4.5 mmol) in 56% yield as a mixture of diastereomers (55:45) (oven temp 65-75 °C, 4 mmHg): 1H NMR (500 MHz) (CDCl3) 8 (major isomer) 0.86 (d, J = 7.6 Hz, 3 H), 0.87 (t,J = 8.2 Hz, 3 H), 0.91(d,J = 7.0 Hz, 3 H), 1.33 (m, 4 H), 1.51 (sept, J = 6.3 Hz, 2 H), 1.89 (dsept, J = 6.8, 5.6 Hz, 1 H), 2.06 (t, J = 7.2 Hz, 2 H), 2.42- 2.62 (m, 4 H), 3.06 (m, 1 H), 3.38 (s, 3 H), 4.95-5.04 (m, 2 H), 5.73-5.82 (m, l H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 10.7, 17.5, 18.2, 24.3, 29.2, 36.1, 39.3, 49.9, 53.1, 57.8, 85.2, 115.5, 138.8, (minor isomer) 10.8, 17.5, 18.2, 24.1, 29.2, 36.0, 39.2, 49.8, 53.0, 57.8, 85.2, 115.5, 138.8; IR (neat) 3345, 3077, 2961, 2932, 2876, 2822, 1640, 1464, 1385, 1094, 995, 910, 771 cm'l; HRMS calcd for C13H27N0 m/e 213.2092, obsd m/e 213.2084. IV -32a: (0.724 g, 3.2 mmol) in 94% yield as a mixture of diastereomers (52:48) (oven temp 55-65 °C, <1 mmHg): Spectral data were consistent with that reported for the AlMe3 promoted rearrangement. IV-36a: (1.284 g, 6.48 mmol) in 81% yield as a single diastereomer (>98:2) (oven temp 65-75 °C, 5 mmHg): Spectral data were consistent with that reported for the AlMe3 promoted rearrangement. IV-41b: (0.712 g, 3.32 mmol) in 85% yield as a mixture of diastereomers (73:27) (oven temp 95-100 °C, <1 mmHg): 1H NMR (500 MHz) (CDCl3) 8 (mixture of isomers) 0.79 (d, J = 7.9 Hz, 3 H, minor isomer), 0.82 (d, J = 6.6, 3 H, major isomer), 94 0.93 (bs, 1 H), 1.53 (m, 1 H, major isomer), 1.65 (m, 1 H, minor isomer), 1.77 (m, 1 H), 1.93 (m, 1 H), 2.24 (ddd, J = 2.2, 4.3, 10.8 Hz, 1 H), 2.56-2.72 (m, 2 H), 2.75-2.98 (m, 2 H), 3.02 (dd, J = 6.5, 13.1 Hz, 1 H), 3.51 (m, 1 H, major isomer), 3.63 (m, 1 H, minor isomer), 5.09 (t, J = 10.7 Hz, 1 H, minor isomer), 5.26 (t, J = 10.6 Hz, 1 H, major isomer), 5.56 (ddd, J = 6.0, 10.6, 17.0 Hz, 1 H, major isomer), 5.70 (ddd, J = 6.8, 10.7, 17.3 Hz, 1 H, minor isomer), 7.16-7.35 (m, 5 H); 13C NMR (75.5 MHz) (CDCl3) 8 (major isomer) 19.7, 22.6, 28.0, 32.3, 47.1, 48.2, 51.2, 52.5, 53.5, 126.0, 128.1, 128.4, 131.3, 135.4, 145.6, (minor isomer) 19.0, 21.9, 26.8, 30.4, 47.1, 49.0, 51.2, 52.5, 53.5. 126.1, 127.7, 129.1, 131.5, 135.4, 141.7; IR (neat) 3380, 3061, 3027, 2996, 2926, 2870, 1603, 1493, 1453, 1372, 1354, 1142, 763, 739, 702 cm'l; HRMS calcd for C15H21N m/e 215.1674, obsd m/e 215.1689. General Procedure for the (Ar0)2AlMe Promoted Rearrangement and Reduction: To 2,6-diphenylphenol (2.2 eq.) in toluene was added a solution of AlMe3 (1.1 eq, 2 M in toluene). The mixture was stirred for a minimum of 5 hours at room temperature and the enamine (1 eq.) was added The mixture was heated at reflux for 24 hours, then cooled to room temperature and LiA1H4 (1.2 eq, 1 M in THF) or DIBAH (3 eq., 2 M in hexane) was added. The mixture was stirred for 2 hours (for LiAlH4) or 24 hours (for DIBAH) and then quenched by careful addition of H20 (1 mL/g LiA1H4 or 3.7 g DIBAH), then 15% aq. NaOH (1 mL/g LiAlH4 or 3.7 g DIBAH), and finally H20 (3 mL/g LiAlH4 or 3.7 g DIBAH), stirred for 1 hours, and filtered. The amines were purified by flash column chromatography where necessary (silica gel washed with Et3N/Et20 then washed with Et20, 50:50 Et20/petroleum ether) and distilled. IV -32b: (1.003 g, 3.5 mmol) in 58% yield as a mixture of diastereomers (37:63) (oven temp 85-100 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. 95 IV-32c: (0.547 g, 2.2 mmol) in 73% yield as a mixture of diastereomers (77:23) (oven temp 75-85 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. IV -363: (0.592 g, 3.0 mmol) in 60% yield as a mixture of diastereomers (70:30) (oven temp 65-75 °C, 5 mmHg): Spectral data were consistent with that reported for the AlMe3 promoted rearrangement. IV-36b: (0.65 g, 2.52 mmol) in 84% yield as a mixture of diastereomers (90:10) (oven temp 80-90 °C, <1 mmHg): Spectral data were consistent with that reported for the HCl promoted rearrangement. 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) REFERENCES For reviews on [3,3] sigmatropic rearrangements see: (a) Rhoads, S. J .; Raulins, N. R. Org. React. (N. Y.) 1975, 22, 1. (b) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227. (c) Bennett, 0. B. Synthesis 1977, 589. (d) Bartlett, P. A. Tetrahedron 1980, 36, 3. (e) Hill, R. K. Chirality Transfer via Sigmatropic Rearrangements. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984; Vol. 3, p. 503. (t) Lutz, R. P. Chem. Rev. 1984, 84, 205. (g) 0verman, L. E. Angew. Chem. Int. Ed. Engl. 1984, 23, 579. (h) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (i) Blechert, S. Synthesis 1989, 71. Hill, R. K.; Gilman, N. W. Tetrahedron Lett. 1967, 1421. Hill, R. K.; Khatri, H. N. Tetrahedron Lett. 1978, I9, 4337. Bailey, P. D.; Harrison, M. J. Tetrahedron Lett. 1989, 30, 5341. 0da, J.; Igarashi, T.; Inouye, Y. Bull. Inst. Chem. Res. 1976, 54, 180. Murahashi, S.-I.; Makabe, Y.; Kunita, K. J. Org. Chem. 1988, 53, 4489. (a) Hiroi, K.; Abe, J.; Suya, K.; Sato, S. Tetrahedron Lett. 1989, 30, 1543. (b) Hiroi, K.; Abe, J. Chem. Pharm. Bull. 1991, 39, 616. (c) Hiroi, K.; Abe, J. Tetrahedron Lett. 1990, 31, 3623. (a) Tsunoda, T.; Sasaki, 0.; 118, S. Tetrahedron Lett. 1990, 31, 727. (b) 118, S.; Tsunoda, T. Pure & Appl. Chem. 1990, 62, 1405. (c) Tsunoda, Sakai, M.; T.; Sasaki, 0.; Sako, Y.; Hondo, Y. Ito, S. Tetrahedron Lett. 1992, 33, 1651. (d) Tsunoda, T.; Tatsuki, S.; Shiraishi, Y.; Masumi, A.; ltd, S. Tetrahedron Lett. 1993, 34, 3297. Evans, D. A. in Asymmetric Synthesis, J. D. Morrison, Ed., Academic Press, Orlando, 1984, Vol. 3, p. 1. (a) Kurth, M. J.; Decker, 0. H. W. Tetrahedron Lett. 1983, 24, 4535. (b) Kurth, M. J .; Decker, 0. H. W.; Hope, H.; Yanuck, M. D. J. Amer. Chem. Soc. 1985, 107, 443. (c) Kurth, M. J.; Decker, 0. H. W. J. Org. Chem. 1986,51, 1377. (d) Kurth. M. J.; Brown, E. G. Synthesis 1988, 362. Kurth, M. J.; Soares, C. J. Tetrahedron Lett. 1987, 28, 1031. Johnson, R. L. J. Med. Chem. 1980, 23, 666. Kelly, S. E.; LaCour, T. G. Synth. Comm. 1992, 22, 859. 0verman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. N-protonation has been shown to be the kinetic product of addition of acid to enamines. For a discussion of N versus C protonation, see: (a) Hickmott, P. W. Tetrahedron 1982, 38, 1975. (b) Hinman, R. L. Tetrahedron, 1968, 24, 185. 96 97 16) Chu, M.; Wu, P.-L.; Givre‘, 8.; Fowler, F. w. Tetrahedron Lett. 1986,27, 461. 17) For examples of ring expansion reactions in the 3-aza-Cope rearrangement see: (a) Cid, M. M.; Eggnauer, U.; Weber, H. P.; Pombo-Villar, E. Tetrahedron Lett. 1991, 32,7233. (b) Edstrom, E. D. J. Am. Chem. Soc. 1991, 113, 6690. (c) Hassner,A.; Wiegand, N. J. Org. Chem. 1986, 51, 3652. (d) Kunng, F.-A.; Gu, J.-M.; Chao, S.; Chen, Y.; Mariano, P. J. Org. Chem. 1983, 48, 4262. (e) Mariano, P. S.; Dunaway-Mariano, D.; Huesmann, P. L. J. Org. Chem. 1979, 44, 124. CHAPTER V. AZA-ANNULATION AS A ROUTE TO HYDROXYLATED ALKALOIDS. THE TOTAL SYNTHESIS OF (:t)-PROSOPININE Background: Isolation and Synthesis of Prosopis Africana Alkaloids Seven piperidine alkaloids were isolated from Prosopis africana (Afiican mimosa) ' over two decades ago, and their structures have been rigorously determined.l Two of ' these alkaloids, prosopinine (V -l) and its C-6 epimer prosophylline (V-3) (Figure V-l), have been a target for the synthetic efforts in this group. V-l has been shown to exhibit biological activities, including antibiotic and local anesthetic properties.2 These alkaloids possess structural similarities to sphingosine (V -5) and deoxynorjirimycin (V -6) (Figure V-2). All of these compounds have an arrangement of hydroxyl groups with a stereochemical relationship indentical to glucose (V -7 ). V-S is a common membrane lipid, and V-6 has exhibited antitumor and anti-HIV-l properties through inhibition of or- glucosidase.3 Compounds which combine the two structural features present in V-S and V-6, a polar head group and a lipophilic tail, may provide beneficial biological properties with the ability to penetrate cell membranes while simultaneously acting as a carbohydrate mimic. The Prosopis alkaloids contain both structural features, and more in-depth study of their properties is warranted. = 0 Prosopinine = H,H Desoxoprosopinine X ““0141 Me N OH H V-3: X = 0 Prosophylline V-4: X = H,H Desoxoprosophylline FIGURE V-l. Structures of Some Prosopis Alkaloids 98 99 ”kW/1‘0: 0H V-5 H N 2 OH OH “0’0, “00H HO’ '1, ““0“ OH OH N . HO O H v- 6 V-7 FIGURE V-2. Compounds with Similar Structural Features to Prosopis Alkaloids While prosopinine has not been prepared synthetically, the total synthesis of prosophylline (V-3),4 desoxoprosopinine (V -2),5 and desoxoprosophylline (V .4)5a,5d,5e has been reported. Three main objectives must be integrated in the design of a synthesis of Prosopis alkaloids. These include 1) construction of the piperidine ring, 2) establishment of the stereochemistry around the ring, and 3) the attachment of the aliphatic side chain. The key steps in the synthesis of prosophylline reported by Natsume“ are shown in Scheme V-l. The nitrogen heterocycle V-8 was prepared from pyridine, vinylmagnesium bromide, and benzyl chloroformate. Photooxidation gave an endoperoxide (V -9) which was opened by a SnCl2-promoted addition of trimethylsilyloxybutadiene to give V-10 with the proper stereochemical relationship for prosophylline. Selective reduction of the conjugated olefin and two protection steps afforded V-ll. The vinyl group was cleaved under oxidative conditions to give hydroxylated derivative V-12. The synthesis of prosophylline was completed by homologation via a Wittig reaction, reduction, and deprotection in 2.7% overall yield from pyridine. The synthesis began with the 6- membered ring intact, and used the bicycloperoxide as a template to direct the stereochemistry. Since this was accomplished early, the total synthesis was comprised mainly of functional group manipulations. , 100 SCHEME V-l. Synthetic Route to Pros0phylline. on \ / / I otooxidation '0 N‘oms / ph r o 'I / = one . , / N ' N ”'/ \/\ ~“ N "o/ I | SDC 12 Cbz Cbz (llbz V-8 V-9 V- 10 reduction, protection ll l V-12 Cbz V-ll OM: (Tomi Sign: OM: 0031! Meg/IV\ N "HI/OH Meo)'\/\ ’f %/ Cbz Tadano has reported a synthesis of (-)—desoxoprosopinine and (-)- desoxoprosophylline in which the piperidine ring was formed late in the synthetic sequence (Scheme V-2).5a Starting with V-13, prepared from D-glucose, V-l4 was obtained after 13 steps. Palladium (O) cyclization of V-l4 led to V-lS as a 10:1 mixture of diastereomers. Oxidative cleavage of the olefin and protecting group modification afforded either V-l6 or V-18. Wittig olefination of V-16 gave V-17 as a mixture of olefin isomers, which was carried on to V-2 in 11.6% overall yield from V-13. Interestingly, when V-18, which only differed from V-l6 in the protecting groups, was subjected to Wittig conditions, complete epimerization of the C-6 center was obtained. Thus, V-l9 was carried on to V-4 in 8.3% overall yield. While the overall yields were very good, the synthesis was long, requiring 21 steps from V-l3, over half of which were manipulations of the sugar derivative to prepare the cyclization precursor V-l4. Another route to V-2 and V-4 was reported by Takahashi, in which an aminomercuration cyclization was used to prepare the piperidine ring very late in the synthesis.5d~ 5'3 101 SCHEME V-2. Route to (-)-Desoxoprosopinine and (-)-Desoxoprosophylline. OH 5 (I t : TIOWCI H0 ‘9 : E \ 0 GM: 13 steps (38:: V-l3 V- 14 NaH, PdCPPh3)4. n-Bu4NI Wittig CHOU:— H21Clo%”’/ I, 0%0}.V-1 5 Cbm V- 17 V- 16 OBn OBn U Wittig U HZICIO : \“\ N I,” /OMOM OHC N I, I /0MOM l l Cbm Cbm V-l9 V-18 Ira-1&1 . _ - vA-fl'f l 102 Holmes has reported a synthesis of V-2 in which the nitrogen heterocycle was constructed via a hetero-Diels-Alder reaction to give V-20 (Scheme V-3).5c The bicycloketone was obtained as a mixture of exo and endo isomers (57% and 24% respectively). Baeyer-Villiger oxidation provided the bicyclolactone V-21 with the proper placement of oxygen functionality. Reduction with LiAlH4 afforded triol V-22 which was protected and oxidized to V-23. The aldehyde V-23 was homologated, again, by Wittig olefination, and desoxoprosopinine (V-2) was obtained in 2.2% overall yield after reduction and deprotection. Here, as in the synthesis of prosophylline described above, the relative stereochemistry was controlled by utilizing a rigid bicyclic template. Although the selectivity of the Diels-Alder reaction was not optimal, this route consisted of only ten steps, and quick facile construction of the nitrogen heterocycle with the proper stereochemistry was accomplished. SCHEME V-3. Route to (:t)-Desoxoprosopinine. O O C02Me , arms 0 LT * —" zr ”WM 1 Ts/ /N I /N I T‘ COzMe TS cone V- 20 V- 2 l LiAlH4 \\“O * \“‘OH OHC ‘\ O «I—— /\ ‘9 OH \\“ N HO “ N v.23 Ts v-22 Ts 103 Model Studies for Alkaloid Synthesis Aza-annulation methodology, recently developed in this group, quickly and efficiently provided suitably substituted piperidine derivatives for the construction of Prosopis alkaloids (see Chapter I). As models for the synthesis of V-l and V-3, compounds V-25 and V-27 were prepared (eq. V-l and eq. V-2). Conjugate addition of benzylamine to methyl propiolate resulted in the formation of an enamine, which was annulated with acryloyl chloride to give V-24 in 53% yield. V-26 was prepared in an analogous manner by annulation of the enamine derived from benzylamine and ethyl acetoacetate. Reduction of the double bond gave lactams V-25 and V-27 in nearly quantitative yield. V-27 was obtained as a single isomer detectable by NMR (cis:trans, >98:2). With the model substrates prepared, three aspects of the target synthesis were explored. These three requirements were 1) introduction of the C-2 substituent with proper stereochemical relationship to the C-3 substituent, 2) conversion of the C-3 carboxylate functionality to a hydroxyl group, and 3) homologation of the lactam carbonyl to append the lipid tail of the target compounds. Initial efforts were applied to the introduction of the C-2 substituent via conjugate addition. Treatment of V-24 or V-26 with a variety of cuprate reagents5 failed to give addition products, and-the starting lactams were recovered unchanged. Hydride reduction (N aBH4) of the olefin was attempted as an alternate route to V-27, and, again, only starting materials were recovered. Apparently, the vinylogous carbamate was very stable, and would not succumb even to reaction with strong nucleophiles. Therefore, any functionality at this site needed to be in place prior to annulation. cone 1) BnNHz cone H2. Pd/C cone l 2) flow; I EtOI-I (V1) ll (53%) o 1.. 7... o If Bn Bn V-24 V-25 EtO co E 0 1) EM; C023 112,ch 2t 2) /\coc1 EtOH (86%) 0 Me Bn (>98. 2) V-26 V-27 Attention was next directed toward conversion of the carboxylate group to a hydroxyl group. Several reports of oxidative decarboxylation of carboxylic acids have appeared,7 thus V-25 was hydrolyzed to V-28 with NaOH (eq. V-.3). Submission of the acid V-28 to these literature reaction conditions resulted in the formation of complex product mixtures, from which a hydroxylated compound could not be isolated. A similar oxidative procedure for the introduction of an amino group was utilized (eq. V-4).3 V-28 was treated with DPPA in t-butanol at reflux, and the intermediate t-butylcarbamate was cleaved with HCl to give the primary amine V-29 in low yield (24%). COzMe . C02H o N (90%) V o N l I Bn Bn v.25 V-28 1) DPPA, Et3N C02“ t-butanol NH? 2) HCI : (V-4) 0 If (24%) o If Bn Bn V-28 1 v.29 Periodate oxidation of diols9 was another possible route for introducing the oxygen functionality. Toward this goal, the oxygenated lactam V-31 was prepared. The ketoester V-30 was obtained from benzoyl peroxide and ethyl acetoacetate by a known procedure. 10 Submitting V-30 to the two-step annulation conditions afforded V-31 in 70% yield (eq. 105 V-5). Attempts to hydrogenate the olefin resulted in the formation of two products (eq. V- 6). Hydrogenation with 10% palladium on carbon gave the reduced lactam V-32 and the enamide V-26 in a 49:51 ratio respectively (ratio of diastereomers of V-32; 58:42). Reduction under basic conditions (N azCOg), which has been reported to prevent deprotection of hydroxyl groups,11 resulted in a decreased amount of the desired lactam (29:71, V-32:V-26). The use of platinum oxide as the reduction catalyst afforded similar mixtures (40:60, V-32:V-26). The elimination product, V-26, most likely arose from a n-allyl palladium intermediate. The chemistry of palladium-allyl species has been well documented.12 It was unclear why V-26 would not undergo further reduction to give V- 27 under these conditions. Perhaps the catalyst was poisoned by the presence of benzoate, or was tied up as n-allyl palladium species, and was unavailable for hydrogenation. Further studies on this substrate were not carried out. BK) 082 1) BnNHz co E: 0 2) %eocr 2 mo 4 * (V -5) 0 (70%) 0 1;} Me Bn V- 30 V- 3 l 082 032 c0215: c0213: c0215: C) 11 C) T’ lWe C) T’ lfie Bn Bn Bn V-3 l V-32 V-26 H2, 10% Pd/C, 49 (58:42) 51 EtOH H2, 10% Pd/C, 29 (24:76) 71 EtOH, N32C03 H2. 1’02. 40 (48:52) 60 EtOAc 106 While there are various methods reported for the homologation of lactam carbonyls, many of these procedures were found to be unproductive for our substrates. One such procedure was the selective addition of an alkynylborane to an amide carbonyl, followed by in situ reduction. 13 This borane reagent appeared ideal for our situation, as it was reported to react solely with the amide carbonyl in the presence of an ester. However, treatment of V-25 or V-27 to the reported conditions gave only traces of alkylated products, and the reaction mixture consisted mainly of starting lactam. cone Iawcsson's COzMe Reagent o N (99%) s N Bn Bn V-25 V-33 COZEt Lawesson's COZEt o 1;! Me (99%) 3 If Me Bn Bn V-27 V-34 In order to explore other homologation routes, the thiolactams V-33 and V-34 were prepared in excellent yield (eq. V-7 and eq. V—8).l4 Methylation of V-33 with Mel afforded a thioiminium salt (V -35) (Scheme V-4).14 Attempts to introduce a C-6 alkyl substituent by Grignard addition to V-35, followed by reduction, led only to the formation of the reduced V-37. The Grignard reagent did not add to the electrophilic carbon, but simply deprotonated in the a position to give a N,S-ketene acetal (V -36). Although a G6 alkylated product was not obtained, the formation of V-37 afforded an opportunity to explore an interesting fl-amino acid rearrangement.15 Thus, V-37 was hydrolyzed with base to the acid V-38 in low yield. The acid was heated at reflux in acetic anhydride to give the (LB-unsaturated lactam V-39 in good yield. Compounds with this structure have 107 been oxidized with ozone to give a C-3 oxygenated piperidine ring.15 Therefore, if homologation of the lactam carbonyl of V-25 or V-33 could be accomplished, this rearrangement could be utilized to introduce functionality at C-3 once the C-6 substituent were in place. SCHEME V-4. B-Amino Acid Rearrangement l" - COZMe C02Me congl fl Mel U HMgBr fl f . \+ S N N I Mes | Mes 1;: En - Bn - Bn - .4 V-33 V-35 V-36 NaBH4. MeOH (72%) COZH COZMe 0: - U or 1;, 0 (81%) 7 (27%) If Bn Bn Bn V-39 V-38 V-37 The addition of alkynyllithium reagents to thioiminium salts has been reported,16 and this procedure was explored as a route to the target compound. Methylation of the thiolaCtam V-33 was followed by addition of the alkynyl lithium reagent derived from benzyl protected propargyl alcohol. In situ reduction with NaBH4 provided the piperidine V-40 in 45% isolated yield as a mixture of diastereomers (63:37). The fully reduced V- 37 was a major by-product of this process. While the yield was only moderate, the alkylated product was obtained cleanly after silica gel chromatography. Unfortunately, treatment of V-34, which had a methyl substituent at C-2, under the same reaction conditions gave no alkylated product, and the only isolable material was the reduced piperidine analog of V-37. 108 1) Mel C02Me 2) BnOCHZCCLi COzMe 3) NaBH4 IT (457) t (v-9) S N 0 N I BnO // I Bn Bn V-33 (5337) V-40 The homologation of thiolactams by an Eschenmoser sulfide contraction was next investigated. The thiolactam V-34 was treated with ethyl bromoacetate to form an intermediate thioiminium salt, and the contraction/sulfide extrusion was accomplished with Et3N and PPh3 to afford the enaminoester V-4l in 79% purified yield (eq. V-10).17 V- 41 was obtained as a single isomer and was assumed to have E olefin geometry due to steric constraints. Hydride reduction at pH 4.0 selectively produced V-42a and V-42b in quantitative yield (92:8 respectively) (eq. V-l 1). The selectivity could be reversed by catalytic hydrogenation to give a 15:85 mixture of V-42a and V-42b.18 The stereochemistry of each isomer was determined by NMR nuclear Overhauser enhancement (NOE) techniques (Figure V-3). The ability to selectively produce either isomer was opportune as V-42a possesed the proper stereochemical relationship between C-2 and C-6 as prosopinine (V -l), and V-42b was analogous to prosophylline (V -3). 2) Et3N, PPh3 : EtO c / (V- 10) s N Me (79%) 2 N Me I I Bn Bn V-34 V-4l 109 COZEI (ICOZEI C028! 7 + (v-11) EtOZC \INIMC I \\“ T Me {III Me Bn C0251 Bn COzEt Bn V-4l V-423 V-42b NaBH3CN, pH 4.0 92 8 (100%) H2, 10% Pd/C, 15 85 N32C03 H 8.0% H‘\5.6% H Me H Ph/\ N COZEt Ph/\ N Me H H COzEt V -42a V -42 b FIGURE V-3. NOE for V-42a and V-42b Total Synthesis of (i)-Prosopinine With an efficient method for homologation of the lactam carbonyl, the total syntheses of prosopinine (V-l) and prosophylline (V-3) were undertaken. The preparation of the six-membered nitrogen heterocycle with the hydroxyl functionality in place at the C-2 methylene is shown in eq. V-12 and eq. V-13. The benzyl protected propargyl alcohol (V-43) was deprotonated with n-BuLi, and acylation with ethyl chloroformate afforded an alkynyl ester. The ester was subjected to the two step condensation/aza-annulation conditions without purification to provide V-44 in 38% overall yield. This yield has been increased to 55% overall by another member of this group19 with the use of acrylic anhydride rather than acryloyl chloride. Hydrogenation with 10% Pd/C in the presence of Na2C03, to preserve the benzyl protecting groups, gave lactam V-45 in 55% yield (optimized to 80%”). 110 — COzEt I 1) n-Bqu ll 2>c1c02m ll M‘COCI _ I 12 = ’ OBn (V’ ) (38% from V43) 0 N OBn L OBn lIBn V-43 ‘ v.44 HflPd/C. c025: Na2CO3 c025: mOBn EtOH : mm“ (V-13) o N (55%) o If Bn 3“ (cis:trans, >98:2) V-44 V-45 SCHEME V-S. Introduction of the C-3 Hydroxyl Substituent of Prosopinine19 O l) MeMgBr, Et3N ”\ C E: \\\ 11:2 2) DBU. THF 1L ' OBn 0 OBn (61%) O N N I 1'31: Bn (cis:trans, 28:72) V-45 V-46 MCPB A, CF3C02H (50%) “\OBH l) KOH, H20 \\\OAC IL (85%) m OBn ’ on o N (84%) o N “ Bn En (cis.'trans, l:>99) V-48 V-47 1 1 1 Since placement of the C-3 hydroxyl group could not be obtained directly from the carboxylate functionality, the ester was first converted to a ketone, and then subjected to Baeyer—Villiger oxidation conditions (Scheme V-5).19 Careful addition of methyl magnesium bromide to V-45, in the presence of Et3N,20 was followed by base catalyzed isomerization at room temperature to give ketone V-46 as mostly the trans isomer (cis:trans, 28:72). Baeyer—Villiger oxidation selectively produced trans V-47 in 50% yield.21 The acetate was hydrolyzed with KOH, and protected as the benzyl ether V-48. The 5-1actam template afforded the ability to control the relative stereochemistry of the C-2 and C-3 substituents for the synthesis of the target Prosopis alkaloids. SCHEME V-6. Homologation of the Lactam Carbonyl \ OB mil Lawesson's Reagent m1 OB i 0311 o N n (94%) ‘ s N Bn Bn V-48 V-49 1) BrCHZCOzlit 2) Ph3P, Et3N (81%) v “OBn NaBH3CN ““0311 (I ‘ pH 4 \fl/ 1310 c o, 03,, ‘ EtOzC / OBn 2 \ , If (88%) 1:1 (>90.10) Bn B“ V-Sl V-50 112 The 06 alkyl substituent was introduced via the sulfide contraction process as described previously for V-34. Conversion of lactam V-48 to V-49 was accomplished in excellent yield (Scheme V-6), and the two step Eschenmoser sulfide contraction provided an 81% yield of V-50. NaBH3CN reduction gave the reduced piperidine V-Sl as the major isomer (>90:10), and the stereochemistry was established by NOE (Figure V-4). Unfortunately, V-SO did not react in an analogous fashion towards catalytic hydrogenation as V-4l, and the same major isomer (V -S 1) was obtained (67:33). The ester was reduced with LiAlH4 to alcohol V-5 2 in 87% yield in preparation for subsequent Wittig homologation. 1.5% EtO C 3‘ 2 ‘ H 4.0 % H H OBn Ph/\ N H OBn V-5 1 FIGURE V-4. NOE for V-Sl ““0131: “.0311 (L ”AH-I4 ‘ BO 0 . on ; . (V44) 2 \ \\\ N n (87%) HO/\ “\ N 0311 I I Bn Bn V-Sl V-52 1 13 The aliphatic side chain was introduced via a Wittig olefination, and the preparation of the requisite phosphonium salt is described in Scheme V-7. Monobromination of diol V-53 gave V-54,22 which was oxidized with FCC to afford the corresponding aldehyde. The aldehyde was treated with ethyl magnesium bromide, and subsequent oxidation gave ketone V-SS in 76% yield for the two steps. The ketone functionality was protected as the dioxolane, and treatment with PPh3 gave the corresponding phosphonium salt V-58, which was used without isolation. SCHEME V-7. Preparation of the Aliphatic Wittig Reagent aq. I-IBr HOW = HOW OH (56%) Br V -53 V-54 PCC 1) EtMgBr (74%) 2) FCC Me r = (76%) one W13: 0 V-56 V-55 HOCH2CH20H H2804 (72%) PPh WW Br 4. WW $1,113 Br. 0 o o o | I V-57 | | V-58 1 14 Completion of the synthesis of V-l is shown in Scheme V-8. Alcohol V-52 was oxidized under Swem conditions to V-S9, and olefination with the ylide of V-58 gave V- 60 in 55% overall yield as an 85:15 mixture of cis and trans alkenes. Deprotection of the ketal was carried out with aq. HCl, and hydrogenation affected reduction of the alkene, with simultaneous removal of the benzyl groups, to give V-l in 90% yield. Thus, the total synthesis of prosopinine was accomplished in 3% overall yield from V-43. SCHEME V-8. Wittig Homologation and Deprotection to Give (:t)-Prosopinine (V-l) l” A ““0311 “\OBII 1 \\ OB DMSO, COCl , HO/\ .s If n EQN )2: OHC\ “, If 03,, En Bn V-52 V-59 V-58, n-BuLi (55% from V-52) (ff! _ OBn M CW “o If 1) HCl, H20 2) H2, 10% Pd/C HCl, EtOH (90%) V O ““011 Me W “o N OH I V-l H 115 an Md lllllllllllllllllll'llll[llllllllllllllllllllllllllllllllllllllllllll'lllllllll'lllllllllllllllllllIllllllllllllllllllllllll|lllllllll|llllllli 3.4 3.0 2.6 2.2 1.8 1.4 ppm l [IIIIIIIIIIIIIIIIIII[[111]![11111IllllllIll]lllllllllIllllllllllllllll'llllllllIlllllllllllllll[IIIIIIIIIIIIIIIITTT 220 200 180 160 140 120 100 80 60 40 20 ppm FIGURE V-S. 1H and 13C NMR of Prosopinine V-l 116 Summary Model studies for the synthesis of Prosopis alkaloids were carried out on 8-lactams prepared by aza-annulation of keto and alkynylesters. Direct conversion of the C-3 carboxyl group to a hydroxyl substituent could not be accomplished, but introduction of amino functionality at that site was obtained in low yield. Aza-annulation produced a lactam bearing a C-3 quaternary center in good yield (70%), but clean reduction of the enamide could not be effected. Treatment of S-lactams with Lawesson's reagent afforded quantitative yields of the corresponding lactams. Methylation provided methyl thioiminium salts. These salts would not undergo alkylation upon treatment with Grignard reagents, and subsequent reduction gave only reduced piperidine products, which were hydrolyzed and subjected to a B-amino acid rearrangement. Treatment of the salts with alkynyl lithium reagents afforded modest yields of alkylated products with V-33, however, if a C-2 alkyl substituent was present (V-34), alkylation could not be obtained. Homologation of the lactam carbonyl was carried out via an Eschenmoser sulfide contraction to give good yields of enaminoesters. Reduction of V-4l with NaBH3CN, or catalytic hydrogenation provided for the selective formation of either of the two stereoisomers. The optimal routes for modification of the aza-annulation product for the model compounds, were applied to the total synthesis of (i)-prosopinine. Aza-annulation from V-43 provided V-44 with the appropriate placement of hydroxyl functionality on the C-2 methylene substituent. The G3 hydroxyl was introduced by conversion of the carboxylate to ketone, and subsequent Baeyer-Villiger oxidation, utilizing the 8—lactam template to effect stereochemical control. Thiolactam formation and Eschenmoser contraction was applied with analogous results to the model Compounds. Hydride reduction gave the proper stereochemical relationship for the synthesis of prosopinine, however, hydrogenation was not analogous to the model compound, and the isomer for the preparation of prosophylline could not be obtained selectively. Wittig homologation, deprotection, and reduction completed the synthetic sequence. Thus, the first total synthesis of V-l was accomplished. 7:3... , . _ EXPERIMENTAL General Methods For general experimental methods see General Methods in Chapter II. Preparation of V-24: Benzyl amine (10.716 g, 100 mmol) was added to a cooled (0 °C) solution of methyl propiolate (8.407 g, 100 mmol) in Et20 (100 mL). The mixture was warmed to ambient temperature, stirred for 12 hours, and the solvent was evaporated. The crude enamine was dissolved in THF (600 mL), and acryloyl chloride (9.917 g, 110 mmol) was added. After heating for 16 hours, the solution was washed with sat. aq. NaHCO3 (200 mL), and the aqueous layer was extracted with 3 x 200 mL Et20. The combined organic layers were dried over MgSO4. Purification by silica gel chromatography (70:30, petroleum etherzlitzO) gave V-24 (13.118 g, 53 mmol) in 53% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 6 2.61 (s, 4 H), 3.68 (s, 3 H), 4.71 (s, 2 H), 7.19-7.35 (m, 6 H); 13C NMR (75.5 MHz) (CDCl3) 6 19.8, 30.7, 49.8, 51.5, 108.8, 127.6, 127.8, 128.8, 136.4, 139.4, 166.6, 169.6; IR (neat) 3080, 3065, 3032, 2951, 2905, 2849, 1690, 1649, 1439, 1377, 1294, 1254, 1184, 1121, 729, 700 cm’l. Preparation of V-26: Benzyl amine (10.716 g, 100 mmol), ethyl acetoacetate (13.014 g, 100 mmol), and a catalytic amount of p-toluenesulfonic acid were heated in benzene (600 mL) with azeotropic removal of water for 5 hours. The solvent was evaporated and the crude enamine was dissolved in THF (600 mL). Acryloyl chloride (9.015 g, 100 mmol) was added and the mixture was heated at reflux for 16 hours. The solvent was evaporated, and purification by silica gel chromatography (70:30, petroleum ethenEtzO) gave V-26 (23.37 g, 86 mmol) in 86% yield as a white solid (mp 74-76 °C): 1H NMR (300 MHz) (CDCl3) 6 117 ii“: 49... 118 1.27 (t, J = 7.1 Hz, 3 H), 2.33 (bs, 3 H), 2.55-2.69 (m, 4 H), 4.15 (q, J = 7.1 Hz, 2 H), 5.00 (s, 2 H), 7.11 (bd, J = 6.9 Hz, 2 H), 7.17-7.33 (m, 3 H); 13C NMR (75.5 MHz) (CDC13) 8 14.3, 16.4, 21.2, 31.3, 44.9, 60.3, 109.4, 126.1, 127.1, 128.7, 137.5, 148.4, 167.5, 171.1; IR (neat) 3087, 3063, 3032, 2978, 2903, 2847, 1686, 1622, 1385, 1365, 1271, 1184, 1121, 1049, 725, 696 cm'l. General Method for the Hydrogenation of Enamides: A mixture of enamide (1 eq.) and 10% palladium on carbon (0.1 g/mmol enamide) in EtOH (0.05-0.2 M) was stirred under an atmosphere of H2 (45 psi) for 16-48 hours. Na2CO3 (3.0 eq.) was added to the reaction mixture to avoid deprotection of 0-benzyl groups, if present. The solids were removed by filtration and the solvent evaporated to afford the lactam. V-25: (5.225 g, 21.66 mmol) in 95% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 8 1.98 (ddt, J = 6.0, 13.5, 9.6 Hz, 1 H), 2.12 (m, 1 H), 2.45 (ddd, J = 6.3, 9.6, 17.8 Hz, 1 H), 2.59 (ddd, J = 5.2, 6.3, 17.8 Hz, 1 H), 2.76 (dddd, J = 3.9, 5.8, 9.9, 12.4 Hz, 1 H), 3.36 (ddd, J = 1.1, 5.8, 12.4 Hz, 1 H), 3.42 (dd, J = 8.5, 12.4 Hz, 1 H), 3.63 (s, 3 H), 4.50 (d, J = 14.7 Hz, 1 H), 4.67 (d, J = 14.7 Hz, 1 H), 7.20- 7.36 (m, 5 H) 13C NMR (75.5 MHz) (CDCl3) 8 23.8, 30.6, 38.9, 47.9, 50.0, 52.0, 127.4, 128.0, 128.5, 136.6, 168.8, 172.4; IR (neat) 3086, 3063, 3030, 2953, 2875, 1736, 1642, 1495, 1454, 1437, 1381, 1356, 1332, 1264, 1204, 1171, 1013, 727, 700 cm’l. V-27 : (5.20 g, 18.90 mmol) in 99% yield as a white solid (mp 52-53 °C): 1H NMR (300 MHz) (CDC13) 8 1.09 (d, J = 6.6 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.97- 2.18 (m, 2 H), 2.43 (ddd, J = 1.4, 9.1, 18.4 Hz, 1 H), 2.56 (ddd, J = 2.8, 6.9, 18.4 Hz, 1 H), 2.76 (dt, J = 11.8, 4.9 Hz, 1 H), 3.77 (quint, J = 6.3 Hz, 1 H), 3.94 (d, J = 15.1 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 5.22 (d, J = 15.1 Hz, 1 H), 7.17-7.31 (m, 5 H); 13c NMR (75.5 MHz) (CDCl3) 5 14.0, 15.0, 18.1, 30.3, 43.8, 48.2, 52.1, 60.8, 127.3, 119 127.7, 128.5, 137.3, 169.0, 171.4; IR (neat) 3087, 3065, 3031, 2978, 2930, 2875, 1734, 1644, 1468, 1451, 1260, 1235, 1173, 1030, 696 cm’l. V-45: (0.63 g, 1.65 mmol) in 55% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 5 1.12 (t, J = 7.2 Hz, 3 H), 2.04 (m, 1 H), 2.21 (m, 1 H), 2.46 (dd, J = 8.2, 18.4 Hz, 1 H), 2.60 (dd, J = 7.7, 18.4 Hz, 1 H), 2.78 (dt, J = 13.2, 4.4 Hz, 1 H), 3.51 (d, J = 4.9 Hz, 2 H), 3.87-4.06 (m, 3 H), 4.13 (d, J = 15.1 H, 1 H), 4.36 (S, 2 H), 5.22 (d, J = 15.1 Hz, 1 H), 7.17-7.37 (m, 10 H); 13C NMR (75.5 MHZ) (CDCl3) 5 13.9, 19.3, 30.2, 42.5, 49.3, 56.3, 60.8, 68.8, 73.3, 127.3, 127.5, 127.7, 127.8, 128.3, 128.6, 137.3, 137.4, 169.7, 171.2; IR (neat) 3088, 3063, 3031, 2980, 2960, 2938, 2905, 2870, 1786, 1734, 1647, 1497, 1464, 1453, 1414, 1379, 1306, 1235, 1200, 1171. 1105, 1030, 737, 698 cm'l. Hydrolysis of V-ZS to Acid V-28: V-ZS (3.00 g, 12 mmol) and NaOH (0.96 g, 24 mmol) were placed in a mixture of THF (50 mL) and water (200 mL). The solution was stirred for 20 hours, and brought to pH >3.0 by addition of conc. HCl. The mixture was extracted with 3 x 75 mL of CHC13, and the organic layer was dried over MgSO4. Evaporation of the solvent afforded V-28 (2.68 g, 10.8 mmol) in 90% yield as a white solid (mp 156-157 °C): 1H NMR: (300 MHz) (CDC13) 8 1.96'(m, 1 H), 2.13 (m, 1 H), 2.50 (ddd, J = 6.3, 9.3, 17.9 Hz, 1 H), 2.63 (dt, J = 17.9, 5.5 Hz, 1 H), 2.76 (m, 1 H), 3.38 (dd, J = 5.8, 12.5 Hz, 1 H), 3.43 (dd, J = 8.5, 12.5 Hz, 1 H), 4.43 (d, J = 14.6 Hz, 1 H), 4.74 (d, J = 14.6 Hz, 1 H), 7.16-7.35 (m, 5 H), 11.24 (br s, 1 H); 13C NMR: (75.5 MHz) (CDC13) 5 23.6, 30.4, 38.8, 48.0, 50.5, 127.6, 128.1, 128.7, 136.2, 170.0, 175.7; IR (neat) 3070, 3029, 2930, 2872, 2780, 2670, 2492, 1940, 1713, 1591, 1455, 1421, 1375, 1302, 1223, 980, 752, 698 cm'l. 120 Curtius Rearrangement of V-28 to Give V-29: To a solution of V-28 (0.748 g, 3.0 mmol) in t-butanol (10 mL) was added DPPA (0.826 g, 3.0 mmol) and Et3N (0.303 g, 3.0 mmol). The mixture was heated at reflux for 18 hours, diluted with toluene (30 mL), and sequentially washed with 2 x 10 mL 5% aq. citric acid, 2 x 10 mL, sat. aq. NaHCO3, and finally 10 mL sat. aq. NaCl. The organic layer was dried over N azCO3, and the solvent was evaporated. The oil was dissolved in MeOH (70 mL), and cone. HCl (5 mL) was added. The mixture was stirred for 4 hours, brought to pH >12 by addition of solid NaOH, extracted with 3 x 50 mL CH2C12, and dried over K2CO3. The solvent was evaporated and Kugelrohr distillation provided V-29 (0.149 g, 0.72 mmol) in 24% yield (oven temp 140-160 °C, <1 mmHg): 1H NMR: (300 MHz) (CDC13) 8 1.58 (m, 3 H), 1.86 (m, 1 H), 2.34 (ddd, J = 6.6, 9.9, 17.9 Hz, 1 H), 2.49 (ddd, J = 4.9, 6.3, 17.9 Hz, 1 H), 2.82 (dd, J = 8.2, 11.8 Hz, 1 H), 3.07 (m, 1 H), 3.19 (ddd, J = 1.7, 4.9, 11.8 Hz, 1 H), 4.45 (d, J = 14.7 Hz, 1 H), 4.53 (d, J = 14.7 Hz, 1 H), 7.12-7.30 (m, 5 H); 13C NMR: (75.5 MHz) (CDCl3) 8 29.7, 30.2, 45.5, 49.8, 54.3, 127.2, 127.8, 128.3, 136.7, 168.9; IR (neat) 3330, 3285, 3061, 3031, 2930, 2872, 1716, 1638, 1541, 1495, 1455, 1422, 1358, 1260, 1196, 747, 704 cm'l. Preparation of V-30: Ethyl acetoacetate (13.014 g, 100 mmol) was added to a slurry of NaH (1.20 g, 50 mmol) in benzene (250 mL), and the mixture was stirred for 20 minutes. Benzoyl peroxide (12.112 g, 50 mmol) and the mixture was stirred for 3.5 hours. The solution was diluted with CHC13, (200 mL) and washed with 1 M aq. H3PO4 (200 mL), sat. aq. NaHCO3 (200 mL), and sat. aq. NaCl (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The excess ethyl acetoacetate was removed under vacuum (<1 mmHg) at 55 C. Purification by silica gel chromatography (50:50, petroleum etherzEtzO) afforded V-30 (11.162 g, 44.5 mmol) in 89% yield as an oil: 1H NMR (300 MHz) (CDCl3) 8 1.28 (t, J = 7.1 Hz, 1 H), 2.39 (s, 3 H), 4.28 (q, J = 7.1 Hz, 2 H), 5.69 (s, 1 H), 7.44 (m, 2 H), 121 7.59 (a, J = 1.1, 7.7 Hz, 1 H), 8.20 (m, 2 H); 13c NMR (75.5 MHz) (CDCl3) 5 14.0, 27.3, 62.5, 78.2, 128.2, 128.7, 130.0, 133.8, 164.5, 165.0, 197.7; IR (neat) 3065, 3036,2986,2942,2911,2876,1730,1601,1452,1360,1277,1179,1117,1055,1022, 858,712, 687 em-l. Annulation of V-30 to Give V-3l: Benzyl amine (1.072 g, 10 mmol), V-30 (2.503 g, 10 mmol), and a catalytic amount of p-toluenesulfonic acid were heated in benzene (50 mL) with azeotropic removal of water for 14 hours. The solvent was evaporated and the crude enamine was dissolved in THF (50 mL). Acryloyl chloride (0.902 g, 10 mmol) was added and the mixture was heated at reflux for 16 hours. The solution was washed with sat. aq. NaHCO3 (50 mL), the aqueous layer was extracted with 3 x 50 mL Et20, and the organic layer was dried over MgSO4. The solvent was evaporated, and silica gel chromatography (50:50, petroleum ether:Et20) gave V-3l (2.76 g, 7 mmol) in 70% yield as a pale yellow solid (mp 106-108 °C): 1H NMR (300 MHz) (CDCl3) 8 1.20 (t, J = 7.1 Hz, 3 H), 2.62 (m, 1 H), 2.74-2.91 (m, 3 H), 4.19 (dq, J = 12.9, 7.1 Hz, 1 H), 4.23 (dq, J = 12.9, 7.1 Hz, 1 H), 4.71 (d, J = 5.0 Hz, 1 H), 4.78 (d, J = 3.0 Hz, 1 H), 4.99 (d, J = 15.8 Hz, 1 H), 5.06 (d, J = 15.8 Hz, 1 H), 7.18-7.36 (m, 5 H), 7.43 (m, 2 H), 7.58 (tt, J = 1.1, 7.7 Hz, 1 H), 7.96 (m, 2 H); 13C NMR: (75.5 MHz) (CDCl3) 5 13.8, 26.5, 28.3, 47.2, 62.2, 79.7, 98.3, 126.8, 127.2, 128.5, 128.6, 129.1, 129.8, 133.6, 136.4, 141.5, 165.1, 168.3, 168.6; IR (neat) 3085, 3063, 3032, 2982, 2930, 2890, 2875, 1746, 1725, 1680, 1630, 1452, 1377, 1360, 1287, 1267, 1200, 1096, 1071, 1026, 712 cm‘l. Preparation of Thioamides V-33, V-34, and V-49: Lawesson's reagent (0.5 eq.) was added to a solution of the lactam (1.0 eq.) in THF (0.4 M), and the mixture was stirred for 4-12 hours. The solvent was evaporated, diluted with EtOAc (3 times the volume of THF), and the solution was washed sequentially 122 with 3 portions of aq. sat. NaHCO3 (1/3 the volume of EtOAc) followed by 2 portions of sat. aq. NaCl (1/5 the volume of EtOAc). The aqueous layers were combined and extracted with 2 portions of EtOAc (1/2 the volume of EtOAc). The organic layers were combined and dried over Na2SO4. Silica gel chromatography (Et20) afforded the pure thiolactam. v.33: (5.410 g, 20.4 mmol) in 99% yield as a white solid (mp 63-65 °C): 1H NMR: (300 MHz) (CDCl3) 8 1.87 (ddt, J = 5.8, 13.7, 9.1 Hz, 1 H), 2.00 (dq, J = 13.7, 5.8 Hz, 1 H), 2.78 (m, 1 H), 2.97 (ddd, J = 6.3, 8.8, 18.2 Hz, 1 H), 3.14 (dt, J = 18.2, 5.8 Hz, 1 H), 3.42-3.56 (m, 2 H), 3.56 (s, 3 H), 5.12 (d, J = 14.5 Hz, 1 H), 5.40 (d, J = 14.5 Hz, 1 H), 7.18-7.29 (m, 5 H); 13c NMR: (75.5 MHz) (CDC13) 5 23.0, 38.6, 40.3, 50.0, 52.0, 57.1, 127.6, 127.7, 128.5, 134.8, 172.0, 199.7; IR (neat) 3080, 3030, 2951, 2860, 1734, 1514, 1453, 1348, 1200, 1169, 1043, 704 cm'l. V-34: (2.280 g, 7.82 mmol) in 99% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 8 1.17 (d, J = 6.6 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.93-2.13 (m, 2 H), 2.77 (ddd, J = 4.7, 5.8, 11.5 Hz, 1 H), 3.14 (dt, J = 8.5, 19.5 Hz, 1 H), 3.29 (ddd, J = 3.3, 6.6, 19.5 Hz, 1 H), 3.98 (dq, J = 5.8, 6.6 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2 H), 4.45 (d, J = 14.8 Hz, 1 H), 6.23 (d, J = 14.8 Hz, 1 H), 7.23-7.35 (m, 5 H); 13C NMR (75.5 MHz) (CDC13) 8 14.0, 14.7, 18.3, 40.0, 43.5, 54.9, 55.8, 61.0, 127.5, 127.7, 128.7, 135.3, 170.8, 199.8; IR (neat) 3087, 3061, 2980, 2938, 1732, 1497, 1452, 1348, 1171, 961, 708 cm'l. V-49: (1.453 g, 3.36 mmol) in 94% yield as a yellow solid (mp 81-82 °C): 1H NMR (300 MHz) (CDCl3) 8 1.83-2.05 (m, 2 H), 3.10 (ddd, J = 4.4, 6.1, 19.0 Hz, 1 H), 3.30 (ddd, J = 7.1, 9.6, 19.0 Hz, 1 H), 3.49 (dd, J = 6.6, 10.2 Hz, 1 H), 3.58 (dd, J = 4.4, 10.2 Hz, 1 H), 3.85 (m, 1 H), 3.91 (m, 1 H), 4.24 (d, J = 11.8 Hz, 1 H), 4.35 (d, J = 11.8 Hz, 1 H), 4.40-4.50 (m, 3 H), 6.45 (d, J = 15.1 Hz, 1 H), 7.14-7.40 (m, 15 H); 13C NMR (75.5 MHz) (CDCl3) 8 22.7, 37.3, 55.5, 61.1, 69.1, 70.0, 72.2, 73.3, 127.2, 127.4, 127.5, 127.6, 127.9, 128.2, 128.5, 135.2, 137.1, 137.7, 201.8; IR (neat) 3100, 3090, 3031, 2940, 2867, 1497, 1453, 1345, 1173, 1073, 1028, 733, 696 cm'l. 123 Preparation of V-37: Thiolactam V-33 (1.245 g, 4.72 mmol) and Mel (6.714 g, 47.2 mmol) were stirred for 3 hours. The excess Mel was removed under vacuum and the salt was dissolved in THF (20 mL). N ,N,N',N '-Tetramethyl ethylenediamine (4 mL) was added to help solubilize the salt. The mixture was cooled to -78 °C and a solution of propyl magnesium bromide (4.72 mmol) in Et20 (10 mL) was added. The solution was stirred for 20 minutes, warmed to 0 °C over 20 minutes, and stirred an additional 15 minutes. NaBH4 (0.893 g, 23.6 mmol) followed by MeOH (10 mL) were added. After 6 hours, the solution was washed with water (50 mL), and extracted with 3 x 50 mL CH2C12. The organic layers were combined, dried over Nags O4, and concentrated. The oil was purified by silica gel chromatography (60:40, petroleum etherzEt20) to give V-37 (0.790 g, 3.4 mmol) in 72% yield: 1H NMR: (300 MHz) (CDCl3) 5 1.38-1.64 (m, 2 H), 1.70 (m, 1 H), 1.90 (m, l H), 2.03 (dt, J = 2.7, 10.7 Hz, 1 H), 2.20 (t, J = 10.4 Hz, 1 H), 2.57 (tt, J = 3.8, 10.2 Hz, 1 H), 2.71 (dt, J = 11.3, 3.8 Hz, 1 H), 2.93 (ddd, J = 1.7, 3.6, 11.3 Hz, 1 H), 3.47 (d, J = 13.3 Hz, 1 H), 3.53 (d, J = 13.3 Hz, 1 H), 3.63 (s, 3 H), 7.19- 7.31 (m, 5 H); 13C NMR: (75.5 MHz) (CDCl3) 8 24.5, 26.9, 41.8, 51.4, 53.5, 55.3, 63.2, 126.9, 128.1, 128.9, 138.2, 174.6; IR (neat) 3087, 3063, 3029, 2950, 2855, 2803, 2768, 1736, 1455, 1435, 1221, 1194, 1179, 1152, 1134, 739, 698 cm‘l. Hydrolysis of V-37 to Acid V-38: V-37 (0.79 g, 3.38 mmol) and NaOH (0.27 g, 6.76 mmol) were heated at 66 °C in a mixture of THF (20 mL) and water (60 mL) for six hours, and then stirred at ambient temperature for 12 hours. The THF was evaporated and the solution was brought to pH 6 by careful addition of cone. HCl. The solution was saturated with NaCl, extracted with 4 x 50 mL CHC13, and dried over Na2804. The solvent was evaporated to give V-38 (0.20 g, 0.91 mmol) in 27% yield as a white solid (mp 172-175 °C): 1H NMR: (300 MHz) (CDC13) 8 1.64-1.89 (m, 4 H), 2.50-3.00 (m, 5 H), 3.80 (s, 2 H), 7.32 (s, 5 H), 11.0 124 (br. s, 1 H); 13C NMR: (75.5 MHz) (CDCl3) 5 22.1, 26.2, 40.5, 52.2, 54.3, 61.5, 128.4, 128.6, 130.1, 133.0, 176.7; IR (neat) 3085, 3070, 3031, 2980, 2932, 2870, 2541, 1962,1715, 1578, 1456, 1399, 1254, 1011, 954, 752, 702 cm-1. B-Aminoacid Rearrangement of V-38 to V-39: V-38 (0.175 g, 0.798 mmol) was dissolved in acetic anhydride and heated to reflux. After 3 hours, the solution was cooled to 0 °C and a solution of K2C03 (10 g) in water (20 mL) was added. The mixture was stirred for 2 hours, extracted with 3 x 20 mL CH2C12, and dried over Na2804. Purification by silica gel chromatography (60:40, petroleum ether:Et20) provided V-39 (0.130 g, 0.646 mmol) in 81% yield as a viscous oil: 1H NMR: (300 MHz) (c1303) 5 1.77 (quint, J = 6.1 Hz, 2 H), 2.52 (tt, J = 1.4, 6.3 Hz, 2 H), 3.24 (dd, J = 5.8, 6.0 Hz, 2 H), 4.62 (s, 2 H), 5.27 (q, J = 1.8 Hz, 1 H), 6.23 (q, J = 1.8 Hz, 1 H), 7.17-731 (m, 5 H): 13c NMR: (75.5 MHz) (CDCl3) 5 23.0, 30.0, 47.7, 50.6, 121.8, 127.2, 127.9, 128.5, 137.1, 137.7, 164.2; IR (neat) 3087, 3063, 3031, 2932, 2865, 1658, 1615, 1487, 1452, 1341, 1294, 1223, 1198, 1080, 938, 801. 737, 704 cm'l. Preparation of V-40: Thiolactam V-33 (0.633 g, 2.4 mmol) and Mel (0.546g, 3.85 mmol) were stirred in THF (2.5 mL) at room temperature, and then cooled to -78 °C. A solution of the alkynyl lithium (1.2 eq., 2.88 mmol), prepared by n-BuLi addition to benzyl protected propargyl alcohol, in THF (2.5 mL) was added. After 2 hours, NaBH4 (0.454 g, 12.0 mmol) followed by MeOH (5 mL) was added, and the solution was allowed to warm to room temperature. The mixture was stirred for 12 hours, washed with H20 (10 mL), and extracted with 3 x 10 mL CH2C12. Silica gel chromatography (80:20, petroleum etherzEtzO) afforded V-40 (0.405 g, 1.08 mmol) in 45% yield as a viscous oil (63:37 mixture of diastereomers): 1H NMR: (300 MHz) (CDCl3) 5 1.77 (m, 1 H), 1.80-1.99 (m, 125 2 H), 2.11 (m, 1 H), 2.53-2.77 (m, 2 H), 2.89 (dt, J = 11.8, 3.6 Hz, 1 H), 2.91 (t, J = 3.6 Hz, 1 H, minor isomer), 3.50 (m, 1 H), 3.60 (d, J = 13.5 Hz, 1 H), 3.60-3.72 (m, 2 H, minor isomer), 3.66 (s, 3 H), 3.84 (d, J = 13.5 Hz, 1 H), 4.29 (d, J = 1.7 Hz, 2 H), 4.31 (d, J = 1.7 Hz, 2 H, minor isomer), 4.67 (s, 2 H), 4.70 (s, 2 H, minor isomer) 7.23- 7.45 (m, 10 H); 13C NMR: (75.5 MHz) (CDC13) 8 (major isomer) 23.0, 29.8, 40.1, 41.8, 49.9, 51.9, 57.3, 59.9, 71.2, 81.6, 82.8, 126.9, 127.9, 128.0, 128.1, 128.3, 128.8, 137.4, 138.0, 174.0, (minor isomer) 22.7, 29.1, 40.1, 41.8, 49.6, 51.3, 57.3, 60.0, 71.1, 82.6, 84.4, 127.0, 127.7, 127.9, 128.0, 128.1, 128.3, 128.8, 137.4, 138.1, 174.1; IR (neat) 3087, 3063, 3031, 2951, 2853, 1736, 1495, 1455, 1437, 1356, 1292, 1217, 1191, 1173, 1123, 1074, 1028, 982, 739, 698 cm'l. General Method for Eschenmoser Sulfide Contraction: The thiolactam (1.0 eq.) and ethyl bromoacetate (1.2 eq,) were stirred in Et20 (1 M) for 24-36 hours. The solvent was evaporated and the thionium salt was dissolved in CH3CN (0.2 M). Triphenylphosphine (1.2 eq.) was added and the mixture was allowed to stir for 10 minutes. Triethylamine (1.5 eq.) was added and the solution was heated to reflux. After 26 hours, the solids were filtered and the resultant solution was concentrated. Silica gel chromatography (90:10 - 70:30, petroleum ether:Et20) provided the pure enaminoesters. V-4l: (0.426 g, 1.23 mmol) in 79% yield as a white solid (mp 69-71 °C): 1H NMR: (300 MHz) (CDCl3) 8 1.12 (d, J = 6.4 Hz, 3 H), 1.18 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.89-2.11 (m, 2 H), 2.86-3.00 (m, 2 H), 3.62 (ddd, J = 3.1, 6.7, 18.7 Hz, 1 H), 3.80 (quint, J = 6.3 Hz, 1 H), 3.99 (dq, J = 3.4, 7.0 Hz, 2 H), 4.02 (dq, J = 3.4, 7.0 Hz, 1 H), 4.14 (q, J = 7.0 Hz, 2 H), 4.26 (d, J = 16.5 Hz, 1 H), 4.55 (d, J = 16.5 Hz, 1 H), 4.63 (s, 1 H), 7.17 (d, J = 7.0 Hz, 2 H), 7.22-7.37 (m, 3 H); 13C NMR: (75.5 MHz) (CDC13) 8 14.0, 14.5, 14.6, 17.0, 25.4, 44.1, 54.0, 54.8, 58.2, 60.6, 85.7, "'1‘“me 126 126.4, 127.1, 128.6, 136.1, 159.8, 168.6, 171.8; IR (neat) 3100, 3080, 3030, 2978, 2920, 2870, 1734, 1682, 1561, 1136, 1060, 1030, 966, 791, 727, 696 cm’l. V-SO: (1.22 g, 2.51 mmol) in 81% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 8 1.17 (t, J = 7.1 Hz, 3 H), 1.85 (m, 1 H), 1.95 (m, l H), 2.95 (dt, J = 18.1, 6.2 Hz, 1 H), 3.41 (dd, J = 6.7, 9.7 Hz, 1 H), 3.50 (m, 1 H), 3.51 (dd, J = 4.5, 9.7 Hz, 1 H), 3.61 (ddd, J = 2.8, 4.4, 7.1 Hz, 1 H), 3.86 (ddd, J = 3.0, 4.4, 6.9 Hz, 1 H), 3.98 (dq, J = 3.8, 7.1 Hz, 1 H), 4.01 (dq, J =-3.8, 7.1 Hz, 1 H), 4.35 (d, J = 16.5 Hz, 1 H), 4.41 (s, 2 H), 4.43 (d, J = 14.6 Hz, 1 H), 4.52 (d, J = 14.6 Hz, 1 H), 4.53 (d, J = 16.5 Hz, 1 H), 4.60 (s, 1 H), 7.18-7.36 (m, 15 H); 13C NMR (75.5 MHz) (CDCl3) 8 14.6, 22.2, 22.3, 53.9, 58.2, 62.5, 70.1, 70.2, 73.2, 73.3, 84.8, 126.6, 127.0, 127.4, 127.5. 127.6, 127.8, 128.3, 128.4, 128.5, 136.3, 137.6, 138.2, 161.7, 168.9; IR (neat) 3100, 3080, 3031, 2980, 2934, 2867, 1680, 1561, 1497, 1455, 1362, 1142, 1094, 1073, 735. 696cm'1. General Method for the NaBH3CN Reduction of Enaminoesters: The enaminoester (1.0 eq.) was dissolved in MeOH (0.2 M) with a trace of bromocresol green as indicator. NaBH3CN (1.0 eq) was added. A 5% methanolic HCl solution was added drowpise until a yellow color persisted. The solution was stirred for 2 hours, with the periodic addition of HCl to maintain a yellow color. The mixture was diluted with CH2C12 (5 times the volume of MeOH), washed with 10% aq. NaHCO3 (0.5 times the volume of CH2C12), and the organic phase was dried over Na2804. The solvent was evaporated and silica gel chromatography (70:30, petroleum etherzEtzO) afforded the pure piperidines. V-42: (0.113 g, 0.318 mmol) in 100% yield as a viscous oil (mixture of diastereomers, V-42a:V-42b, 92:8): 1H NMR: (300 MHz) (CDCl3) 5 (major isomer) 0.98 (d, J = 6.9 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H), 1.37 (dq, J = 5.2, 12.4 Hz, 1 H), 1.56 (dq, J = 13.2, 3.0 Hz, 1 H), 1.72-1.92 (m, 2 H), 2.19 (dd, 127 J = 7.4, 14.8 Hz, 1 H), 2.46 (dd, J = 6.9, 14.8 Hz, 1 H), 2.78 (dt, J = 4.9, 11.8 Hz, 1 H), 3.22 (dq, J = 4.7, 6.9 Hz, 1 H), 3.34 (m, 1 H), 3.67 (s, 2 H), 3.93-4.12 (m, 4 H), 7.12-7.31 (m, 5 H), (minor isomer) 0.93 (d, J = 7.0 Hz, 3 H), 1.19 (t, J = 7.3 Hz, 3 H), 1.20 (t, J = 7.3 Hz, 3 H), 1.62-1.77 (m, 3 H), 1.84 (m, 1 H), 2.34 (dd, J = 10.3, 14.2 Hz, 1 H), 2.65 (dd, J = 3.4, 14.2 Hz, 1 H), 2.73 (m, 1 H), 3.22-3.35 (m, 2 H), 3.72 (d, J = 14.3 Hz, 1 H), 3.78 (d, J = 14.3 Hz, 1 H), 4.06 (q, J = 7.3 Hz, 2 H), 4.08 (q, J = 7.3 Hz, 2 H), 7.17-7.34 (m, 5 H); 13C NMR: (75.5 MHz) (CDCl3) 8 (major isomer) 10.4, 14.1, 21.2, 28.2, 40.1, 41.5, 50.7, 51.9, 53.2, 60.1, 60.4, 126.6, 127.8, 128.2, 140.6, 172.1, 174.1; IR (neat) 3087, 3063, 3029, 2980, 2940, 2874, 2853, 1734, 1495, 1453, 1370, 1200, 1152, 1034, 733, 698 cm'l. V-Sl: (0.6148 g, 1.267 mmol) in 88% yield (mixture of isomers, >90:10): 1H NMR (300 MHz) (CDCl3) 8 (major isomer) 1.17 (t, J = 7.2 Hz, 3 H), 1.53-1.78 (m, 3 H), 1.99 (m, 1 H), 2.43 (dd, J = 8.7, 14.2 Hz, 1 H), 2.60 (dd, J = 5.3, 14.2 Hz, 1 H), 2.95 (dt, J = 7.0, 4.5 Hz, 1 H), 3.24 (m, 1 H), 3.54 (dt, J = 4.2, 7.5 Hz, 1 H), 3.71 (m, 3 H), 4.03 (m, 1 H), 4.04 (q, J = 7.2 Hz, 2 H), 4.36 (s, 2 H), 4.42 (d, J = 11.4 Hz, 1 H), 4.55 (d, J'= 11.4 Hz, 1 H), 7.16—7.38 (m, 15 H); 13C NMR (75.5 MHz) (CDCl3) 5 (major isomer) 14.1, 24.7, 25.4, 33.9, 52.7, 59.2, 60.2, 68.8, 70.8, 72.9, 74.2, 126.5, 127.3, 127.4, 127.5, 127.6, 128.0, 128.2, 128.3, 128.4, 138.4, 138.8, 140.7, 172.6; IR (neat) 3087, 3063, 3031, 2980, 2936, 2865, 1732, 1495, 1452, 1368, 1290, 1157, 1096, 1028, 737, 698 cm'l. Preparation of V-44: To a solution of V-43 (5.84 g, 40 mmol) in THF (100 mL), cooled to -78°C, was added n-BuLi (16 mL, 40 mmol, 2.5 M in hexane). The solution was stirred for 15 minutes, and ethyl chloroformate (4.341 g, 40 mmol) was added. Afert 15 minutes, the mixture was warmed to room temperature, and stirred an additional 20 minutes. The solution was washed with water (100 mL), extracted with 3 x 100 mL of Et20, and dried 128 over MgSOd. Concentration afforded the crude ester which was dissolved in benzene (20 mL). Benzyl amine (4.286 g, 40 mmol) was added, and the mixture was stirred for 12 hours. The solvent was removed by rotary evaporation, and the crude enamine was dissolved in THF (300 mL). Acryloyl chloride (3.606 g, 40 mmol) was added, and the mixture was heated at reflux for 12 hours. The solution was washed with sat. aq. NaHCO3, extracted with 3 x 200 mL Et20, and concentrated. The enamide was purified by silica gel chromatography (60:40, petroleum ether, EtzO) to afford V-44 (5.82 g, 15.3 mmol) in 38% yield as a yellow solid (mp 85-86 °C): 1H NMR (300 MHz) (CDCl3) 8 1.28 (t, J = 7.1 Hz, 3 H), 2.50-2.59 (m, 2 H), 2.64-2.72 (m, 2 H), 4.18 (1, J = 7.1 Hz, 2 H), 4.58 (s, 2 H), 4.62 (s, 2 H), 5.13 (s, 2 H), 7.0 (m, 1 H), 7.03 (m, 1 H), 7.17-7.40 (m, 8 H); 13C NMR (75.5 MHz) (CDCl3) 8 14.1, 21.6, 30.7, 44.4, 60.7, 63.5, 72.6, 113.5, 126.0, 126.9, 128.0, 128.3, 128.6, 137.6, 137.9, 146.0, 166.6, 170.8; IR (neat) 3085, 3063, 3031, 2980, 2905, 2870, 1688, 1628, 1497, 1455, 1373, 1323, 1287, 1267, 1183, 1125, 1071, 727, 696 cm‘l. Reduction of V-51 to V-SZ: V-Sl (0.167 g, 0.342 mmol) was dissolved in Et20 and LiAlH4 (0.1 g, 2.63 mmol) was added. The mixture was stirred for 2 hours and quenched by addition of H20 (0.1 mL), 15% aq. NaOH (0.1 mL), and H20 (0.3 mL). After 1 hour, the mixture was filtered and the solvents were evaporated to give V-52 (0.1325 g, 0.297 mmol) in 87% yield as a viscous oil: 1H NMR (300 MHz) (CDCl3) 8 1.16 (m, 1 H), 1.27 (s, 1 H), 1.41 (m, 1 H), 1.68 (m, 1 H), 1.94 (m, 1 H), 2.09 (m, 1 H), 2.27 (m, 1 H), 2.91 (m, 1 H), 3.40 (dt, J = 2.2, 10.5 Hz, 1 H), 3.48-3.68 (m, 3 H), 3.62 (d, J = 13.2 Hz, 1 H), 3.74 (dd, J = 8.0, 9.9 Hz, 1 H), 3.86 (dd, J = 3.7, 9.9 Hz, 1 H), 4.11 (d, J = 13.2 Hz, 1 H), 4.41 (d, J = 11.5 Hz, 1 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.58 (d, J = 12.1 Hz, 1 H), 4.61 (d, J = 11.5 Hz, 1 H), 7.20-7.38 (m, 15 H); 13C NMR (75.5 MHz) (CDC13) 8 22.6, 26.6, 30.9, 50.6, 54.4, 57.1, 62.9, 68.2, 70.4, 72.3, 73.3, 126.9, 127.3, 127.4, 127.6, 129 128.3, 129.0, 138.2, 138.7, 140.0; IR (neat) 3405, 3087, 3063, 3029, 2936, 2861, 1495, 1455, 1100, 1075, 733, 698 cm’l. Preparation of V-54: 1,8-0ctanediol (28.78 g, 196.8 mmol) and 48% aq. HBr (24.6 mL, 236.2 mmol HBr) were heated at reflux in benzene (400 mL) for 16 hours with azeotropic removal of water. The solvent was evaporated and the bromoalcohol was purified by silica gel chromatography (60:40, petroleum etherzEt20). Distillation provided V-54 (23.67 g, 110.2 mmol) in 56% yield (oven temp 85-90 °C, <1 mmHg): 1H NMR (300 MHz) (CDCl3) 8 1.23-1.32 (m, 6 H), 1.33-1.43 (m, 2 H), 1.50 (m, 2 H), 1.79 (quint, J = 6.9 Hz, 2 H), 2.07 (s, l H), 3.35 (t, J = 6.9 Hz, 2 H), 3.56 (t, J - 6.6 Hz, 2 H); 13C NMR (75.5 MHz) (CDCl3) 8 25.5, 28.0, 28.6, 29.1, 32.5, 32.7, 33.9, 62.7; IR (neat) 3337, 2932, 2857, 1464, 1437, 1246, 1057, 723, 644 cm'l. Preparation of V-SS: To a solution of FCC (21.556 g, 100 mmol) in CH2C12 (100 mL) at 0 °C was added V-54 (10.456 g, 50 mmol). The mixture was warmed to ambient temperature and allowed to stir for 10 hours. The chromium salts were removed by filu'ation through a celite/silica gel mixture, and the aldehyde was purified by silica gel chromatography (320). The solvent was evaporated to give V-SS (7.624 g, 37 mmol) in 74% yield: 1H NMR (300 MHz) (CDC13) 8 1.23-1.45 (m, 6 H), 1.59 (m, 2 H), 1.81 (quint, J = 7.0 Hz, 2 H), 2.39 (dt, J = 1.8, 7.4 Hz, 2 H), 3.36 (t, J = 6.8 Hz, 2 H), 9.72 (t, J = 1.8 Hz, 1 H); 13c NMR (75.5 MHz) (CDCl3) 8 21.8, 27.8, 28.4, 28.8, 32.5, 33.8, 43.7, 202.6; IR (neat) 2934, 2859, 2679, 1709, 1464, 1429, 1412, 1279, 1244, 1215, 941, 725, 644 cm'l. 130 Preparation of V-56: Ethyl bromide (3.923 g, 36 mmol) was added over a 1 hour period to magnesium (4.4 g, 180 mmol) in Et20 (40 mL) at ambient temperature. The mixture was allowed to stir for an additional 45 minutes, and then added to a cooled (-30 °C) solution of V-SS (6.213 g, 30 mmol) in Et20 (50 mL). The solution was warmed to 0 °C over 45 minutes, and then quenched by addition of sat. aq. NH4C1 (40 mL). 10% aq. HCl was added until all the solids had dissolved. The mixture was extracted with 3 x 100 mL B20, and the organic layers were combined and dried over MgSO4. The solvent was evaporated and the crude alcohol was added to a cooled (0 °C) mixture of FCC (9.7 g, 45 mmol) in CH2C12 (100 mL). The solution was warmed to ambient temperature, stirred for 3 hours, and filtered through a mixture of celite/silica gel. Kugelrohr distillation provided V-S6 (5.339 g, 22.8 mmol) in 76% yield (oven temp 75-90 °C, <1 mmHg): 1H NMR (300 MHz) (CDC13) 8 1.02 (t, J = 7.3 Hz, 3 H), 1.20-1.45 (m, 6 H), 1.55 (m, 2 H), 1.82 (quint, J = 7.1 Hz, 2 H), 2.37 (t, J = 7.4 Hz, 2 H), 2.39 (q, J = 7.3 Hz, 2 H), 3.37 (t, J = 6.8 Hz, 2 H); 13c NMR (75.5 MHz) (CDCl3) 5 7.7, 23.6, 27.9, 28.4, 28.9, 32.6, 33.8, 35.8, 42.2, 211.7; IR (neat) 2938, 2857, 1715, 1460, 1375, 1113, 725, 644 cm'l. Preparation of V-57 V-56 (5.13 g, 21.8 mmol), ethylene glycol (1.354 g, 21.8 mmol), and H2804 (2 drops) were heated at reflux in benzene (75 mL) with azeotropic removal of water for 5 hours. The solution was washed with sat. aq. NaHCO3 (40 mL), extracted with 3 x 50 mL Et20, and dried over Na2804. Evaporation afforded an oil which was purified by silica gel chromatography (90:10, petroleum etherzEtzO) to give V-57 (4.361 g, 15.7 mmol) in 72% yield: 1H NMR (300 MHz) (CDCl3) 8 0.85 (t, J = 7.5 Hz, 3 H), 123-1.44 (m, 8 H), 1.54 (m, 2 H), 1.58 (q, J = 7.5 Hz, 2 H), 1.80 (quint, J = 7.0 Hz, 2 H), 3.35 (t, J = 6.9 Hz, 2 H), 3.88 (s, 4 H); 13C NMR (75.5 MHz) (CDCl3) 8 8.1, 23.6, 28.0, 131 28.6, 29.6, 29.7, 32.7, 33.9, 36.6, 64.9, 112.0; IR (neat) 2938, 2880, 2859, 1464, 1202, 1163, 1074, 947, 920, 646 cm'l. Swern Oxidation of V-52 to V-59: To a solution of oxalyl chloride (0.057 g, 0.45 mmol) in CH2C12, cooled to -70 °C, was added a solution of DMSO (0.070 g, 0.90 mmol) in CH2C12 (1 mL). After 10 minutes, V-52 (0.133 g, 0.297 mmol) in CH2C12 (2 mL) was added. The mixture was allowed to stir for 45 minutes at -65 °C, and Et3N (0.182 g, 1.8 mmol) was added. The mixture was stirred for 20 minutes at -65 °C and warmed to ambient temperature for 1 hour. The mixture was washed with 10% aq. NaHCO3 and extracted with 3 x 10 mL CH2C12. The solvents were evaporated and the aldehyde was used immediately without further purification. Wittig Homologation of V-59 to V-60: The bromide V-57 (0.1675 g, 0.6 mmol) and triphenylphosphine (0.1574 g, 0.6 mmol) were heated at reflux in toluene (2 mL) for 48 hours. The solvent was removed under vacuum and THF (2 mL) was added. The solution was cooled to -78 °C and n-BuLi (2.5 M in hexane, 0.24 mL, 0.6 mmol) was added. The mixture was stirred for 15 minutes at -78 °C and 1 hour at ambient temperature. The ylide solution was cooled to -78 °C and a solution of V-S9 in THF (1 mL) was added. The mixture was warmed to -45 °C over 2 hours, stirred at that temperature for an additional hour, warmed to 0 °C for 3 hours, and stirred an aditional 2 hours at ambient temperature. The solution was washed with H20 (10 mL) and extracted with 3 x 20 mL CH2C12, dried over Na2804, and concentrated. The oil was purified by silica gel chromatography (90: 10 - 80:20, petroleum etherzEtzO) to give V-60 (0.1029 g, 0.163 mmol) in 55% yield as a viscous oil (cis:trans 85:15): 1H NMR (300 MHz) (CDCl3) 8 0.89 (t, J = 7.4 Hz, 3 H), 1.20-1.38 (m, 8 H), 1.44-1.75 (m, 6 H), 1.88-2.20 (m, 4 H), 2.22-2.35 (m, 2H) 2.58 (m, 1 H, trans isomer), 132 2.69 (m, 1 H), 2.83 (dt, J = 7.4, 3.8 Hz, 1 H, trans isomer), 3.01 (dt, J = 7.4, 4.3 Hz, 1 H), 3.54 (m, 1 H), 3.68-3.78 (m, 3 H), 3.91 (s, 4 H), 4.06 (d, J = 14.0 Hz, 1 H, trans isomer), 4.08 (d, J = 13.7 Hz, 1 H), 4.39 (s, 2 H), 4.42 (d, J = 11.5 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 1 H, trans isomer), 4.55 (d, J = 11.5 Hz, 1 H, trans isomer), 4.56 (d, J = 11.5 Hz, 1 H), 5.21 (m, 1 H), 5.34 (m, 1 H), 7.16-7.41 (m, 15 H); 13C NMR (75.5 MHz) (CDC13) 8 (cis isomer) 8.1, 23.7, 25.0, 25.4, 27.4, 29.1, 29.2, 29.4, 29.5, 29.6, 29.7, 29.8, 52.5, 55.0, 58.9, 64.9, 68.7, 70.8, 72.9, 74.6, 112.1, 126.4, 127.2, 127.3, 127.4, 127.6, 128.0, 128.3, 128.4, 131.1, 138.4, 138.8, 141.1, (trans isomer) 8.1, 23.5, 25.0, 27.2, 29.1, 29.2, 29.4, 29.5, 29.6, 29.7, 29.8, 52.4, 54.8, 58.8, 64.9, 68.7, 70.8, 72.9, 74.6, 112.0, 126.2, 126.9, 127.3, 127.4, 127.7, 127.8, 128.2, 128.3, 128.4, 131.3, 138.4, 138.9, 141.2; IR (neat) 3100, 3080, 3029, 2930, 2855, 1453, 1075, 733, 696 cm'l. Preparation of V-l: V-60 (0.0989 g, 0.158 mmol) was dissolved in THF (8 mL) and 10% aq. HCl (4 mL) was added. The mixture was stirred for 2 hours, washed with sat. aq. NaHCO3 (10 mL), and extracted with CH2C12. The organic layers were dried over Na2CO3, and concentrated. The residue was dissolved in EtOH (10 mL), and conc. HCl (20 drops) was added. 10% Pd on carbon (0.05 g) was added and the mixture was stirred under H2 (50 psi) for 24 hours. The solution was filtered, and the solvents were evaporated. The residue was washed with sat. aq. NaHCO3, extracted with 4 x 20 mL CHC13, and dried over Na2SO4. The residue was filtered through basic alumina with CHC13, and MeOH and the solvents were evaporated. The crystals were washed with a minimum amount of acetone and dried under vacuum to give V-l (0.043 g, 0.142 mmol) in 90% yield as white crystals (mp 88-89 °C): 1H NMR (300 MHz) (CDC13) 8 1.05 (t, J = 7.3 Hz, 3 H), 1.23- 1.41 (m, 13 H), 1.44-1.61 (m, 5 H), 1.66 (m, 1 H), 1.74 (m, 1 H), 2.07 (br. s, 3 H), 2.39 (t, J = 7.5 Hz, 2 H), 2.41 (q, J = 7.3 Hz, 2 H), 2.76 (m, 1 H), 2.87 (dt, J = 5.5, 7.7 133 Hz, 1 H), 3.53 (ddd, J = 4.0, 5.6, 6.9 Hz, 1 H), 3.61 (dd, J = 5.4, 10.5 Hz, 1 H), 3.65 (dd, J = 7.8, 10.5 Hz, 1 H); 13C NMR (75.5 MHz) (CDCl3) 8 7.8, 23.9, 26.3, 27.4, 28.6, 29.2, 29.3, 29.4, 29.6, 33.9, 35.8, 42.4, 49.7, 58.1, 62.3, 68.1, 212.0; IR (neat) 3320, 2926, 2855, 1717, 1460, 1377, 1275, 1119,1073, 723 cm'l. 1) 2) REFERENCES (a) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-Huu, Q.; Goutarel, R. Bull. Soc. Chim. France 1966, 2945. (b) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull Soc. Chim. Belg. 1972, 81, 425. (c) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull Soc. Chim. Belg. 1972, 81, 443. (a) Fr. Patent; FR 1524395, [CA 71 :91733w]. (b) Bourrinet, P.; Quevauviller, A. Ann. Pharm. Fr. 1968, 26, 787, [CA 71 :29012g]. (c) Bourrinet, P.; Quevauviller, A. Compt. Rend. Soc. Biol. 1968, 162, 1138, [CA 70:95233K 1. For information on hydroxylated piperidine alkaloids, see: (a) van den Brock, L. A. G. M.; Vermaas, D. J.; Heskamp, B. M.; van Boeckel, Y.; Miedema, F. Reel. Trav. Chim. Pays-Bas 1993, 112, 82. (b) Fairbanks, A. J.; Carpenter, N. D.; Fleet, G. W. J.; Ramsden, N. G.; de Bello, I. C.; Winchester, B. G.; Al-Daher, S. S.; Nagahashi, G. Tetrahedron 1992, 48, 3365. (c) Fleet, G. W. J .; Fellows, L. B.; Winchester, B. Plagiarizing Plants: Aminosugars as a Class of Glycosidase Inhibitors, in: Bioactive Compounds from Plants, p 112-125, Wiley, Chichester (Ciba Foundation Symposium 154) 1990. (d) Legler, G. Adv. in Carbohydr. Chem. and Biochem. 1990, 48, 319. Natsume, M.; Ogawa, M. Heterocycles 1981, 16, 973. (a) Tadano, K.; Takao, K.; Nigawara, Y.; Nishino, B.; Takagi, 1.; Maeda, K.; Ogawa, S. SYNLETT 1993, 565. (b) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K. H.; Byme, N. E. J. Am. Chem. Soc. 1989, III, 3473. (c) Holmes, A. B.; Thonpson, J.; Baxter, A. J. G.; Dixon, J. J. Chem. Soc., Chem. Commun. 1985, 37. (d) Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. Jpn. 1981,54, 488. (e) Saitoh, Y.; Moriyama, Y.; Takahashi, T.; Khuong-Huu, Q. Tetrahedron Lett. 1980, 21, 75. (a) Dodd, D. S.; Oehlschlager, A. C. Tetrahedron Lett. 1991, 32, 3643. (b) Lipshutz, B. H. Synthesis 1987, 325. (c) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903. (d) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruyama, K. J. Org. Chem. 1982, 47, 119. (a) Fang, F. G.; Danishefsky, S. J. Tetrahedron Lett. 1989, 30, 3621. (b) Kienzle, F.; Holland, G. W.; Jemow, J. L.; Kwoh, S.; Rosen, P. J. Org. Chem. 1973, 38, 3440. (c) Barton, D. H. R.; Coates, I. H.; Sammes, P. G. J. Chem. Soc., Perkin Trans. 1 1973, 599. (d) Denney, D. B.; Sherman, N. J. Org. Chem. 1965, 30, 3760. 134 10. 11. 12. 13. 14. 15. 16. 17. 135 (a) Mostowicz, D.; Belzecki, C.; Chmielewski, M. Synthesis 1991, 273. (b) Sato, M.; Katagiri, N.; Takayama, K.; Hirose, M.; Kaneko, C. Chem. Pharm. Bull. 1989, 3 7, 665. (c) Eaton, P. E.; Shankar, B. K. R. J. Org. Chem. 1984, 49, 185. (d) Haefliger, W.; Kldppner, E. Helv. Chim. Acta. 1982, 65, 1837. (e) Chantegrel, B.; Gelin, S. Synthesis 1981, 315. (t) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30, 2151. (g) Kaisen, C.; Weinstock, J. Org. Synth. 1973, 51, 48. (a) Chiara, J. L.; Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991, 32, 1125. (b) Chmielewski, M.; Kaluza, Z.; Abramski, W.; Belzecki, C. Tetrahedron Lett. 1987, 28, 3035. (c) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, r" 3353. (d) Ona, H.; Uyeo, S.; Fukao, T.; Doi, M.; Yoshida, T. Chem. Pharm. ‘ ' Bull. 1985,33, 4382. " Hecker, S. J.; Werner, K. M. J. Org. Chem. 1993, 58, 1762. (a) Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438. (b) Kazmierczak, F.; Helquist, P. J. Org. Chem. 1989, 54, 3988. (a) Trost, B. M. Pure & Appl. Chem. 1992, 64, 315. (b) Trost, B. M.; Vos, B. A.; Brzezowski, C. M.; Martina, D. P. Tetrahedron Lett. 1992, 33, 717. (c) Morizawa, Y.; Oshima, K.; Nozaki, H. Isr. J. Chem, 1984,24, 149. (d) Hayashi, T.; Konisha, M. J. Chem. Soc., Chem. Commun., 1984, 107. (e) Hasyashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc., 1983, 105, 7767. (t) Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett., 1982, 23, 2871. (g) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (h) Larock, R. C.; Burkhart, J. P. Synth. Commun. 1979, 9, 659. (i) Trost, B. M. Tetrahedron 1977, 33, 2615. (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 1719. (b) Yamaguchi, M.; Waseda, T.; Hirao, 1. Chem. Lett. 1983, 35. Jain, S.; Sujatha, K.; Rama Krishna, K. V.; Roy, R.; Singh, J.; Anand, N. Tetrahedron 1992, 48, 4985. (a) Rueppel, M. L.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 3877. (b) Ferles, M. Coll. Czech. Chem. Commun. 1964, 29, 2323. (a) Takahata, H.; Takahashi, K.; Wang, E.-C.; Yamazaki, T. J. Chem. Soc., Perkin Trans. I 1989, 1211. (b) Tominaga, Y.; Kohra, S.; Hosomi, A. Tetrahedron Lett. 1987, 28, 1529. (a) Hart, D. J.; Kanai, K. J. Am. Chem. Soc. 1983, 105, 1255. (b) Hart, D. J.; Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665. 18. 19. 20. 21. 22. 136 Hydrogenation of V-4l at 1 atm H2 only proceeded to ~50% conversion after 48 hours. The crude products consisted of a mixture of V-4l, V-42a and V-42b (15:85, respectively), and a small amount of the N-debenzylated analog. Reduction at higher pressures (50 psi) resulted in nearly complete removal of the benzyl group, and gave the deprotected analogs of V-42a and V-42b in the same ratio (15:85, respectively). Work was carried out by Lars Beholz. Kikkawa, 1.; Yorifugi, T. Synthesis 1980, 877. Cana Koch, S. S.; Charnberlin, R. Synth. Commun. 1989, 19, 829. Kang, S.-K.; Kim, W.-S.; Moon, B.-H. Synthesis, 1985, 1161. rinted from The Journal of Organic Chemistry. 1001, Vol. 5‘ hemlcal Society and reprinted by per-babe of Rep Copyright © 1991 by the American C the cepyrkhs ewner. Preparation and 3-Aza-Cope Rearrangement of N -A1kyl-N -allyl Enamines Gregory R. Cook and John R. Stille‘ Department of Chemistry. Mickie!!! State University, East Lansing, Michigan 48834 Received March 22, 1991 The [3.31 chanccelmud mutant of N-lnyl-N-isobutyl enamine ”boom to 7.6-um 1111111- rem products and subsequent reduction to the corresponding N-alkyl 8.1-unsaturated amines is Several routes to the N allyl N isobutyl enamines were established for the enamine prepared from isobutyraldehyde. With use of the most efficient route developed, enamines derived from butanal, 2-phenylpropanal. and cyclopentanone were prepared m 58 to 92% overall yield in three steps from Martens. lnthecmeofbutnal. the E Isomer was formed exclusively, while the enamine from 2 phenylpropanal was prepared with an 8 to Z seisctivityof86:14. HeatingtheseN allyl- N-isobutylenaminminrefluxingdioranswithOhequivofHClprodnmd [3, 3] rearrangement for substrates derived from isobutyraldehyde, 2- phenylpropanal. and cyclohexanonetthe enamines of n-butanal and cyclopentanone were found to react through alternate pathways. The study of the Claisen rearrangement. the [3,3] sig- matropic shift of allyl vinyl ethers, has provided many valuable contributions to the areas of mechanistic and synthetic chemistry.‘ Several features, including the convergent nature of the allyl enol ether preparation and subsequent C-C bond formation. have contributed to the extensive use of this reaction in organic synthesis. The products of this pericyclic process. 7.6-unsaturated car- bonyl compounds. are valuable synthons with different functionality at each terminus. Because of the different reactivity at each end. subsequent synthetic elaboration or incorporation of this fragment into a larger target molecule can be efficiently accomplished. The nitrogen analogue of the Claisen rearrangement. the 3-aza-Cope rearrangement of 1, has been reported to un- dergo thermally induced [3.3] sigmatropic rearrangement to the corresponding imine at 250 °C, and subsequent hydrolysis of the imine produced 3.’ Several approaches to rate enhancement of this transformation have been made through the electronic modification of the enamine functionality. Thermal rearrangement of the aniline-de- rived N-phenyl-N-allyl enamine was found to occur at a somewhat reduced temperature of 205 °C. ’ Rearrange- ment at lower reaction temperatures could he achieved by substrates with oxygen substituents at C-2. For example, (1) Porgeneralreviews ' rearrangemeMs. MSMI Reulins.NR.0rgReact(Y...)1fl|23.1(blZieghr. 5.93.1". Acc. Chem. Res. 1m, 10. 227. (c) Bennett.G. 3. Synthesis 1m. ((1) Bartlett. P. A. Tetrahedron 1900. 3. Na (0) Gaiewehiul." drocerbon’lhe rmollsomsn’rations: Academic: New York. 1%1. (0 R. K. Chirality Transfer via Sigmatropic Rearrangements. In Asym- metric Synthesis; Morrison. J. 0.. Ed.; Academic: New York. 1984; Vol 3. p 503. (g) Ziegler. l". E. Chem. Rev. 1983. 88. 1423. (h) Blechert. 8. Synthesis 1’". 71. (2) Hill. R. K; Gilmen. N. W. Tetrahedron Lett. 1901. 1421. ketene N,O-acetals underwent thermal sigmatropic transformation at 180 ‘C,’ and allylamide enolatm were found to rearrange at 130 'C.‘ The temperatures nec- essaryfor rearrangementtooccurhavebeenamajorlim- iting feature of the 3-aza-Cope rearrangement. At the elevated temperatures for thermal rearrangement, tech- nical difficulties commonlyarise in settingupthereacfion. monitoring its progress, and workup of the reaction mix- ture. Typically, in these cases the [3.3) transformation must be incorporated into multistep synthetic sequences early, so as not to disturb sensitive functionality. Methods of promoting the ass-Cope rearrangement at even lower temperatures have involved the formation of cationic quaternary nitrogen centers. As shown in eq 1, one way to access an intermediate such as 2 has been accomplished by methylation of the N-alkyl-N-allyl en- amine 1. Under the 80 ‘C conditions for methylation of “95% “Ewe-:35; ydes, rearrangement aho occurred and of the reaction mixture produced 8.“ A modification of themethylation promdummethylationofanN-allylimins .;Seneratne. . (c)Weich.J. T.; DeCorte.B.: DaKhnpaNJHOIIChssLlM 0022-3268/ 91 / 1956-5578802.50/0 0 1991 American Chemical Society 137 138 .‘V-Alkyl-N-allyl Enamine Rearrangement followed by the addition of a base, was found to produce rearrangement at 25 °C.“ More commonly, these qua- ternary ammonium intermediates have been obtained by allylation of N .N-dielkyl enamines at 80 °C. but problems involving N- versus C-allylation have limited the synthetic utility of this route to the use of symmetrical allyl groups.‘ Conjugate addition of a tertiary amine to ethyl propiolate has also been reported to produce [3,3] rearrangement through a charge-accelerated process? Through these methods of rearrangement acceleration, reaction temper— atures have been reduced by over 150 ’C. In most cases. access to synthetically useful products was gained by by- drolytic removal of the amine functionality to form the corresponding carbonyl compound. In a similar manner of reaction acceleration, Lewis acid catalysis of the aliphatic sea-Cope rearrangement ha been reported! In a landmark paper by Hill. N-phenyl-N-allyl enamines were found to rearrange at 80 'C when treated with 0.25 equiv of TiCl..’ Coordination of the amine to the Lewis acid, generating an electron-deficient nitrogen center analogous to 2, has been suggested to produce this rate acceleration. Hill found that the in situ condensation of a carbonyl compound with a secondary amine. [3,3] rearrangement. and workup generally gave as high as 68% yield using aldehydes having only one a hydrogen. Un- fortunately. only a 27% yield was obtained when straight chain aldehydes were used. and the reaction did not pro- ceed with lretones as the carbonyl source. Bailey extended this chemistry to chiral substrates and was able to obtain asymmetric induction as high as 90% ee.‘° The use of Pd(PPh,). also has been reported to catalyze the rear- rangement of either N-phenyl- or N-methyl-N-allyl en- amines at 50 °C.u Although this reaction was found to work well for enamines derived from ketones or a-disub- stituted aldehydes, r-allyl palladium intermediates were involved and the reaction did not proceed through a pericyclic reaction. Two aspects of this chemistry have prevented the gen- eral application of the 3-aza-Cope rearrangement in organic synthesis. The first involves the limited methods available for preparation of the N-alkyl-N-allyl enamine substrates. Two methods have been reported for the synthesis of the required alkylallyl enamines. The most commonly used method is simply condensation of an acyclic secondary N-alkyl-N-allyl amine with aldehydes, accompanied by (.6) (a) Opits. G.; Mildenberger, H. Angew. Chem. 1990. 72. 169. (b) Elkik. E. Bull. Soc. Chim. Fr. 1999. 972. to) its. G.; Mildenberger. H. Liebigs Ann. Chem. 1941. 649. 26. (d) Opits. .; Hellmann. H.; Milden- berger. H.; Suhr. H. Liebigs Ann. Chem. 1941. 649. 36. (e) 0pitz, G.; Mildenberger. H.; Suhr. H. Liebigs Ann. Chem. 1991. 649, 47. (0 09in. G. Liebigs Ann. Chem. 1941. 650. 122. (g) Stork. G.; Brimlara, A.; Lendeemen. H.; Elkik. E. C. R. Seances Acad. Sci. 1999. 267. 623. (i) Barthelsmy. M.; Month-rd. J.-P.: ' Y. Bull. Soc. Chim. b. 1999. 2725. 21m 8. Bull. Soc. Chim. h. 1999. 903. (k) Hiroi. X.; Yemede. S.-l. C m. Pharm. Bull. 1972. 20. 246. (l) Hiroi. K.: Yamada, S.-l. Chem. Pharm. Bull. 1973. 21. 47. (m) McCurry. P. M., Jr.: Singh, R. K. Tetrahedron Lett. 1973. 3325. (n) Houdewind. P.; Pandit, U. K. Tetrahedron Lett. 1974. 2359. (0) Martin. S. F.; Gompper. R. J. Org. Chem. 1974, .19. 2814. (p) Ode. J.; lgerashi. T.; Inouye, Y. Bull. Inst. Chem. Rea. Kyoto Univ. 1979. 54. 180: Chem. Abstr. 1977. 8‘, Wm. ( ) Whitesell. J. K.: Felmen. S. W. J. Org. Chem. 1977. 42. 1663. (r) tannin. S. F.; Puckstte. T. A.; Colapret. J. A. J. Org. Chem. 1979. 44. 331. (a) 8mm U. K. Reel. Trev. Chim. Pays-Bee 1979. Q. 4”. (7) (a) P. 8.: ey-Marienc. D.: Huesmann, P. L. J. . Chem. (979. 44. 124. (b) Kunng, P.-A.: Gu. J.-M.; Chao, S.; Chen, .; Mariano. P. S. J. Org. Chem. 1993, 48. 4262. (8) PorereviewonthecatalyeisoftheCopeendCleisenreerrengs- meats. see: (a) Lute. R. P. Chem. Rev. 1994. 84. 206. (b) 0verman, L. 3. Angew. Chem.. Int. Ed. Engl. 1994. 23. 579. (9) Hill. R. X.; Khatri, H. N. Tetrahedron Lett. 1978. 4337. (10) Bailey. P. 1).: Harrison, M. J. Tetrahedron Lett. 1999. so. 5341. (11) (a) Murehmhi. S.-l.; Makabe. Y. Tetrahedron Lett. 1999. x. 5663. (b) Murah-h'. 3.4.; Makabe, Y.; Kunita. K. J. Org. Chem. 1’9. 53. 44’. (c) Hiroi. K; Abe. J. Tetrahedron Lett. 1990. 31. 3623. J. Org. Chem, Vol. 56, No. 19, 1991 5579 Scheme I. Different Synthetic Routes to la ""1 v removal of water. to form the corresponding ' “m In practice, this works well for aldehydm that are branched at the a carbon but has been less effective at enamine formation from straight-chain aldehydes or ketones. In a second method, an N-alkyl-N-ellyl amine ha been used in condensation with ketones and diethyl (diuomethyl)- phosphonate to again produce the N-elkyl-N-allyl enamine of a 2-substituted aldehyde.“b The second limiting feature of the 3-aza-Cope reaction has been the difficulty in pro- moting the reaction at a reasonable temperature to obtain, upon reduction of the resulting imine. 6,s-unsaturetsd amine products. A related system, the charge-accelerated 2-aza-Cope rearrangement developed by 0verman, also hm been promoted at mild temperatures. This methodology has led to many valuable contribution to synthetic organic chemistry including a number of elegant syntheses of hi- ologically active alkaloids.u Our interests have focused on the use of the Seen-Cope rearrangement as an effective and convergent method of forming carbon-carbon bonds. This report describes the various routes used to efficiently prepare a variety of N-allryl-N-allyl enamines, the proton-catalysed [3,3] re- arrangement of these compounds, and subsequent reduc- tion of the intermediate imines to 4.4-unsaturated amine products. Results and Discussion Substrate Synthesis. Four different routes for the synthesis of substrate 8a starting from allylamine were explored. Starting from allylamine, two approaches were studied forthcformationofhwhichhmbsenthestederd intermediate for previous synthetic approaches to com- pounds similsr to 8a (Scheme 1). The condensation of allylamine with isobutyraldehyde rmultsd in the formation of the desired imine 4a, which could be isolated in 74% 112) (s)messn.B.J.:iavin.J40vsrmn.LB.J.Am.Chem.8ee. 1989,110.4329. (b)0verman.LB.:Rohsrmu.G.hl.;RoMA.J. J. Am. Chem. Soc. 1991. m. “sadder-seem 5580 J. Org Chem. Vol. 56. .V'o. 19, 1991 Table 1. Isolated Yields for .V-Alkyl-N-ellyl Enamine Formation and Rearrangement yield. ’i t 1 8 10 a o 94 98 81 b 68 90' 95 0 d a 79' 98" 77 f a 82 98 99 g a 68 90 10 'Cerried on to 1 without isolation. ‘Mixture of isomers bto (83:37). 'Mixture of isomers d:e (57:431. ‘ Mixture of isomers the (88:14). distilled yield. Reduction of this imine gave the corre- sponding amine 5 in 84% isolated yield. Alternatively, intermediate 5 could be prepared by acylation of allylamine with isobutyryl chloride to provide 6 in 95% yield. and subsequent LiAlH. reduction gave 5 in 88% isolated yield. Enamine formation by condensation of isobutyraldehyde with 5. catalyzed by p-toluenesulfonic acid, produced 8a in 80% distilled yield. Amide 6 could also be used for enamide formation with isobutyraldehyde. which gave an 85% yield of 1a. but the reaction took 66 h to reach com- pletion. A third route to 8a was completed by the LiAlH. reduction of 1a in 98% isolated yield. The final route was found to be the most efficient for the general preparation of N-alkyl-N-allyl enamine substrates. This route involved acylation of imine in to form enamide 1a in 99% isolated yield. The efficiency of this route could be optimized by initial formation of imine is in benzene. Subsequent ad- dition of NEt, and isobutyryl chloride. without isolation of the intermediate imine. resulted in a 94% isolated yield of enamide 1e from allylamine. These enamide interme- diates were more resistant to hydrolysis than the corre- sponding enamines and could be purified by silica gel chromatography. The previously described reduction with LiAlI'l. completed the synthesis of 8a in 92% overall yield in the three~step process from allylamine. With use of the optimum sequence for the synthesis of 8a. the .V-alltyl-N—allyl enamine derivatives of butanal. 2-phenylpropanal. cyclohexanone. and cyclopentanone were also prepared (Scheme 11. Table l). The N-alltyl- N-allyl enamine of butanal was prepared through the standard three-step process in order to investigate the seleCtiVity of enamme formation. Reaction of n-butanal with allylamine gave predominantly the corresponding imine 4b. Due to the volatility of the compound. isolation of «1b was limited to 68% yield. but purification was nec- essary prior to acylation due to minor amounts of dimeric byproducts generated during imine formation. Acylation produced a 63:37 mixture of two enamine geometric iso- mers in 90% isolated yield. From ‘H NMR analysis using nuclear Overhauser enhancement. the major isomer was 7b. the E enamine isomer. with the minor isomer 1c having 2 geometry. Acylation employing a different base. pyri- dine. produced e slightly higher 71:29 ratio of 1bz7c in 86% yield. Reduction of the enamide mixture with LiAlI-l. gave a 95% yield of a single enamine isomer having E geometry (8b). The nature of the isomerization process of the minor product to the more thermodynamically stable enamine. whether during reduction conditions or workup of the reaction. has not yet been determined. Similar results were observed for selective enamine formation using 2-phenylpropanal as the carbonyl source. Imine formation with allylamine in benzene. followed by reaction with isobutyryl chloride and NEt, without isolao tion of 4d. gave 1d in 79% overall yield for the two-step process. As was observed for the preparation of 1b. the product was isolated as s 57:43 mixture of geometric en- 139 Cook and Stills Scheme 11. Synthesis and Rearrangement of .V-Allyl-N -isobuty1 Enamine Substrates o R' 0 vs. ”V“. ~)\/~ hia Aim/Q” a. i a. \ * v v " .... , v " O Hunt. 3‘“ .s R. I‘ p I "AU nuns. «Aruba ‘3‘!- «W _ ~ _ m to 9 9 .- n' at a It Us h D H C I a I IO U I It I h e is use H I «can, u 9 109' 1' amine isomers. On the basis of nuclear Overhauser en- hancement N MR experiments. the major enamine isomer was assigned as 1d with E enamine geometry. Reduction of this mixture with LiAll-i. also produced a change in the isomeric ratio. From reduction of the 57:43 mixture of isomers. an 86:14 mixture of isomers 8d28e was obtained. Enamine formation from cyclic ketone was also studied by using cyclohexanone and cyclopentanone. The reaction of allylamine with cyclohexanone produced imine 41, Which could be taken on without purification to enamide 11 in 82% overall yield from allylamine. Hydride reduction efficiently produced Sf in 98% yield. Preparation of the cyclopentanone imine was more difficult to drive to con. pletion and displayed somewhat greater semitivity toward hydrolysis. As a result. acylation of the intermediate imine tg gave a reduced 68% yield of isolated 1‘. A 90% yield of the desired enamine 8g was obtained upon reduction with LiAlH.. Rearrangement and Reduction of N-Alkyl-N-ellyl Enamines. An initial approach to the the-unsaturated amine product We utilized the known methylation of 8a to produce acceleration of the [3.3] rearrangement and formation of 11 (eq 2). Methylation with Mel or MeOTs is ‘u ”I a, X no 3:. nor ‘s/ Ms “M ' 2 3.1] “K 1 . (2) V nuance" a u. Inlet. “ \’~ 18 in refluxing dioxane produced complete rearrangement to 11 within 17 h. Although treatment of each reaction mixture with NaBH. at ambient temperature gave mul- tiple products. theuseofUAlI-Lunderthesemeconditiom gave more selective reduction of 11. Reduction of the Mel-promoted rearrangement using LiAlH. produced an 89:11 mixture of 10a112 in 59% isolated yield. and the corresponding reaction with MeOTs gave a lower 12:28 ratio of 10n:12 in 68% yield.” An alternate method. the proton-catalysed rearrange- mentof8nto9efollowedbyLiAlHueductionto New. much more effective. Initial evidence for this transfor- 113) Thistertiaryeminewasprsparedindepasdsntlybymsthyletin of [On to give 12. .\'-Alkyl-.‘v'-silyl Enamine Rearrangement Table 11. Various Conditions for BCI-Catelyaed rangement of 8a to 9a HCl. equiv time. h solvent; temp. °C GLC yield. $ 0.3 20 dioxane/101 74 0.3 8 toluene / 1 11 70 0.5 6 dioxano/ 101 82 0.5 3 toluene / l 11 82 0.5 6 toluene] so 63 0.8 6 toluene! 111 82 metion under protic conditions wu observed when the reaction of 5 to 8a was performed in toluene instead of benzene. Through azeotropic removal of water with re- fluxing benzene at 80 'C. 8a was the only product of the acid-catalyzed enamine formation. However. at the higher temperature required for removsl of water with refluxing toluene (111 °C). small amounts of acidocatalyzed rear- rangement were observed after an extended period of time. In order to optimize reaction acceleration as well as faci- litete reaction workup. anhydrous HCl was studied as a means of promoting these reactions.“ Table II summa- rizes the results of the rearrangement of 8a to So using different equivalents of HCl. various reaction tempera- tures. and dioxane or toluene as solvent for the reaction. Optimum conditions were found to require 0.5 equiv of HCl at reflux in either toluene or dioxane. These condi- tiorn produced So as the only volatile product in 82% yield by GLC analysis and. on s preparative scale. in situ re- duction of 9s allowed isolation of 1011 in 81% yield for the two-step process from Be. At lower temperatures (80 °C) or fewer equivalents of HCl (0.3 equiv). GLC reaction yields were slightly lower. The rearrangement of 8 to 10 was highly dependent on the properties and substituent pattern of the enamine functionality. For the aldehyde substrates 8b and 8d. success was mixed. Substrate 8d. which was similar in substitution pattern to 8n. underwent complete rear- rangement promoted by 0.5 equiv of HC1 and. following LiAlH. reduction. 10d was isolated in 17% yield. When a straight-chain aldehyde enamine such as 8b was treated with HCl. a mixture of products resulted that did not contain 10b after reduction. Although N-protonation of enamines has been reported to be kinetically favored by hard acids such as HCl. the thermodynamic product was the iminium ion resulting from C-protonation.“ If the resulting iminium salts were unsubstituted or to the ni- trogen and had minimal steric hindrance at the nucleo- philic carbon of the corresponding enamine. rapid oligom- erization was found to occur.m Similar N- versus C-al- kylation pathways have led to reduced product selectivity during the previously mentioned allylation of related en- amines“ and have limited the methylation charge-accel- eration studies of N-alltyl-N-sllyl enamines to the deriv- atives of 2-substituted aldehydes.‘ Similarly. proton-catalyzed rearrangement of the two ketone-derived substrates was found to be highly de- pendent on the properties of the carbonyl compound. Rearrangement of the cyclohexanone derivative 81 pro- ceeded quantitatively to 91. Subsequent reduction of this imine without prior isolation gave 101'. which was obtained in 99% yield as e 90:10 mixture of diutereomers resulting from reduction with LiAli-I.. The use of more selective reducing agents was not pursued. In contrast. the results obtained for the cyclopentanone enamine 8g were poor. C0114)HClisovailebls-elMsolutioninEmftomAldflchChomicnl (15) Hickman. P. W. Tetrahedron 1981.38.1975. Protonetion of enamines is discussed on pages 1998-2000. (16) Hinman, R. L. Tetrahedron 1968. 24. 185. and references therein. 140 J. Org. Chem. Vol. 56. No. 19. 1991 5581 As was found for the enamine of n-butanal. protonation at the nucleophilic carbon of the enamine to form 13 ep- pesred to dominate over N-protonetion. Because inter- molecular oligomerization pathways were lam favorable for the more sterically hindered iminium salt 13. u compared to that of the aldehyde iminium salt produced by pro- tonation of 8b. alternate monomeric products were formed. Upon reduction of the reaction mixture containing 13 and 8g with LiAlH..1t(36%).10g(lO‘h). and unreacted 8g (9%) were obtained as a mixture of the only volatile products (eq 3)." lncressingthoemountofcetelystto 1.0 equiv of I-lCl gave increased oligomerizstion of the substrate and. thus. resulted in reduced product recovery. a“ “Qua :2 '____>uns .N’Om 0"” / an“ a. 19 18 Summary An efficient and general synthesis of N—allyi-N-isobutyl enamines 8 from allylamine has been established. Initial condensation of the appropriate carbonyl compounds with allylamine formed the intermediate imines 4. which were treated with isobutyryl chloride to produce the corre- sponding enamide substrates 1. Reducn'tm of the enamide intermediates with LiAlH. gave 8 in good yield. For substrates that could produce isomeric (E)- and (ll-8. dominant formation of the enamine with E geometry w. observed. The E isomeric selectivity for the 2-phonyl- propanal enamine was 86:14 while that of n-butanal wm observed to produce exclusively the E enamine isomer. Proton-catalyzed [3.3] rearrangement and subsequent imine reduction to form the corresponding 5.e-unseturatsd amines was efficiently accomplished for the substrates prepared from isobutyraldehyde (81%). 2rphenylpropanal (77%). and cyclohexanone (99%). However. the eneminm derived from butanal and cyclopentanone did not undergo high- yielding charge-accelerated [3. 3] rearrangement but instead gavemixuiresofproductsresultingpredominantly from protonation at carbon. Experimental Section General Methods. All reactions were carried out by using standard inert atmosphere techniques to exclude moisture and oxygen. and reactions were performed under an atmosphere of either nitrogen or argon. Benzene. toluene. totrahydrofuran (THF). and 131,0 were distilled from sodium/bensophonooe im- mediately prior to use. Dichlorometheno. acetonitrile. pyridine. and triethylamine were heated at reflux over calcium hydride for a minimum of 12 h and then distilled immediately prior to use. 1.4-Dionne was dried over LiAlii. and distilled. Solutions of HClllMinEgOMndLiAlHJlMinTI'Mwuoobtainsdhu AldrichChemicelCo. Unleaspecifificonmtrstitmofmixturm was performed on e Buchi rotary evaporator. Gas chromatographic (GLC) analyses were carried out an a Perkin Elmer 8500 instrument using a 50-m Rsuzoo capillary column (5% methyl phenyl silicone) and an RID dotoctu m a 220 °C injector temperature and 300 'C detectartsmpsreture. Heliumgsspressurewmsetst l5peiwitheflowreteaf2ml. min. NMR spectra were obtained on Varian Gemini too or spectrometers using CDCl, as solvent. Data are reported I follows: chemical shift relative to residual CBC]. (1.24 ppm). multiplicity (s '- singlet. d I doublet. t I triplet. q - quartet. sept I septot). integration. and coupling. Infrared spectra were recorded on e Nicolot t2 FTJR instrument. 17)Thistortia_ryamino proparodindepodutlybyLlAlfluo- duétion of the imine formod'gom allylaminsand Wid- lowedbyroectianwithisohutyrylehloride ndrodnctiutogivolt. 5582 J. Org. Chem. Vol. 56. No. 19. 1991 NoAllyl-N-laobutylldeneamine (4a). A mixture of allylamine (3.54 g. 62 mmol). isobutyraldehyde (4.47 g. 62 mmol). and 441 molecular sieves in 100 ml. of Ergo was stirred for 2 h at ambient temperature. The solution was then removed from the insoluble material via cannula and distilled at atmosphericp reaaureto give 4a (5.11 g. 50 0 mmol) in 74% yield (bp 112-114p °C): ‘H NMR (300 MHZ)(CDC!1)61.05(d.6 H. JI I6 9 Hz). 2.42 (dsept. 1 H. JI4.9. 6.9Hz). 3.95(d. 2H. JI I.5.6Hz) 5..05(dd 1H. JI 1..8 10.3Hz).5.10(dd.1H.JI1.8.172.Hz)5.93(ddt.1H.JI103. 17.2. 5.6 Hz). 7.51 (d. 1 H. J I 4.9 Hz): 1.C NMR (75.5 MHz) (CDCU 4 19.3. 34.1. 63.2. 115.5. 136.1. 170.9: IR (neat) 3133. (1)13. w. 2932. 2874. 2824. 2674. 1466. 1456. 1437. 1366. 1103. 1019. 995. 916 cm". N-Allylleobutyramlde (5). To a mixture of allylamine (9.02 g. 158 mmol) and pyridine (12.48 g. 158 mmol) in 600 mL ofdry THFI at 0 'C was added isobutyryl chloride ( 16.84 g. 158 mmol) at a dropw'us rats. After addition was complete. die mixture was heated at reflux for 5 b. cooled to ambient temperature. and then waited with 50 ml. of 15% aqueous NaOH. The aqueous layer w- then extracted with 4 x 20 mL of Etao. and the organic ' fractions were combined and dried over MgSO.. After removal of solvents by rotary evaporation. the resulting oil was distilled to give s (1&99 g. 149 mmol) in 959. yield (bp 73 °C. <1 mmHg): ‘H NMR (Ill) MHz) (CDCl,) 6 1.13 id. 6 H. J I 6.9 Hz). 2.37 (sept. 1 H. J I 6.9 Hz). 3.84 (ddd. 2 H. J I 1.6. 1.6. 6.6 Hz). 5.09 (ddt. 1H.J I l.4.10.2.1.6 Hz). 5.14 (ddt. 1 H. J I 1.4.17.1. 1.6 Hz). 5.81(ddt. 1 H. J - 10.2. 17.1.6.6 Hz). 5.35 (br s. 1 H); uC NMR (75.5 MHz) (CD03) 619 3. 35.3. 41.5. 116 2. 134.6. 177.3; IR (neat) 3293. 3085. 3015. 2971. 2934. .1576. 1645. 1545. 1470. 1422. 1387. 1242. 1098. 988. 918 cm“. Anal. Calcd for C1HuNO: C. 66.11; H. 10.30: N. 11.01. Found: C. 66.04: H. 9.91; N. 11.85. Reduction of 4a to N-Ailyl-N-isobutylamine (5). To a suspension of LiAlH. (1.37 g. 36 mmol) in 150 m1. of £90 at 0 'C was slowly added 3.34 g '30 mmol) of N-allyl-N-iso- butylideneamine 14a). After being stirred for 2 h. the solution was cooled to 0 °C and quenched by addition of 1.4 ml. of H20. followed by 1.4 ml. of 15% aqueous NaOH. and finally 4.1 mL ofH,0. Themixturewmstirred for 1 hand then filteredthrough Na,$0.. Solvent was removed and the allylic amine was distilled at atmospheric pressure to give 5 (2.84 g. 25.1 mmol) in 84% yield (bp 122-124 'C): ‘H NMR (300 MHz) (CDCl,) 6 0.87 (d. 6 H. J I 6.7 Hz). 1.00 (br s. 1 H). 1.70 (tsept, 1 H. J I 6.8. 6.7 Hz). 2.38 (d. 2 H. J I 6.8). 3.20 (ddd. 2 H. J I 1.4. 1.4. 6.0 Hz). 5.04 (ddt. 1 H. J I 1.7.10.2. 1.4 Hz). 5.13 (ddt. 1 H.J I 17. 17.2.1.4 Hz). 5.88 (ddt. 1 H. J - 10.2. 17.2. 6.0 Hz); 1’C NMR (75.5 MHz) (CDCl‘) 6 20.7. 28.3. 52.6. 57.5. 115.5. 137.2; IR (neat) 3407. 3081. 2959. 2934. 2874. 2811. 1646. 1466. 1385. 1368. 1129. 918 cm". Anal. Calcd for C~H,,N: C. 74.27: H. 13.36; N. 12.37. Found: C. 74.43; H. 13.69: N. 12.21. Reduction of 6 to N-Allyl-N-lsobutylamine (5). To a suspension of LiAlH. (1.85 g. 48.6 mmol) in 200 m1. of Et,0 at 0 ‘C we slowly added 5.62 g (44.2 mmol) of N-allylisobutyramide i6). The mixture was heated at reflux for 3 h. after which the solution was cooled to 0 °C and quenched by addition of 2 mL of water. followed by 2 ml. of 15% aqueom NaOH. and again with 6 mL of water. After being stirred for 2 h. the solution was filtered through Na-,SO. and the solvent was removed by rotary evapo- ration at 0 ’C. The residue was distilled at atmospheric premure to give 5 (4.38 g. 38.7 mmol) in 88% yield (bp 125 °C). Spec- troacopic data were identical with that reported for the product obtained by reduction of 4a. Synthesis of 7a by Acylation of la. To 100 m1. of dry THF were added 7.00 g (18 mmol) of N allyl- N isobutylideneamine (4a) and 1. 82 g (18 mmol) of NEtg. The mixture was cooled to 0 'C andl..92g(0018mmol)ofisobutyrylchloridewasaddeddropw'ne. After being heated at reflux for 2 h. the solution was cooled to ambient temperature and washed with 30 ml. of 15% aqueous NaOH. The aqueous layer was extracted with 2 x 75 mL of 8110 and then dried over Na,SO.. The solvents were removed under reduced pressure. and the resulting enamide was distilled via Kugelrohr distillation under vacuum to give 7a (3.24 g. 17.9 mmol) in 99% yield (bp 55—65 'C. <1 mmHg): ‘H NMR (300 MHz) (CDC13)0 1.02 (d. 6 H. J I 6.8 Hz). 1.57 (s. 3 H). 1.70 (s. 3 H). 2.65 (sept. 1 H. J I 6.8 Hz). 3.89 (d. 2 H. J I 6.2 Hz). 5.04 (dd. 1 H. J I 1.6. 11.3 Hz). 5.06 (dd. 1 H. J I 1.6. 16.0 Hz). 5.74 (ddt. l H. J I 11.3. 16.0. 6.2 Hz). 5.85 (s. l H): "C NMR (75.5 MHz) 141 Cook and Stills (CDClQ 6 173. 18.8. 21.5. 30.9. 50.0. 116.9. 1% 133.4. 135.9. 177.7: IR (neat) 3083. 2975. 2936. 2876. 1653. 1472. 1404. 1242. 1208. 1092. 993. 920 cm". Anal. Calcd for CuHDNO: C. 72.88; H. 10.56; N. 7.73. Found: C. 72.84: H. 10.78; N. 7.72. Preparation of 8a by Condensation of Isobutyl-aldehyde with 5. A flask containing 5 ('1. 70 g. 15 mmol). isobu (1 .08g. 15 mmol). and p-toluenesulfonicacid (0M g.0.04 mmol) in75mLofbenssnewasfittedwithaDean-Starktrapoontaimiu 4-A molecular sieves. The solution w- heated et reflux for 28 h and the cooled to ambient temperature. After removing the benxeneunder reduced preasure.theresuitingoiiwsadiatilled via Kugelrohr distillation under vacuum to give 8a (2.1!) g. 12.0 mmol)in8)%yield(‘bp45—60'C.mmflg)'8 HNMINMMHx) (CDC1,)60.83(d.6H.JI66Hz).1.58(d.3H.JI13Hx).1.58 (tsept. 1H. JI7.3 ....66H1).165(d.3H JI1.3Hz).2.25(d. 2H..II7..3Hz) 3.15lddd. 2H. JI 1.6.1.6.62Hx). 5.02(ddt. l H. J I 2.0. 10.2. 1.6 Hz). 5.08 (ddt. 1 H.J I 2.0. 17.2. 1.6 Hz). 5.22 loo. 1 H. J I 1.3. 1.3 Hz). 5.81 (ddt. 1 H.J I 10.2. 17.2. 6.2 Hz); “C NMR (75.5 MHz) (CDCU 4 17.4. 20.4. 22.0. 27.4. 59.6. 63.1. 115.9. 122.8. 135.8. 136.9: IR (neat) ”1. 3M. 2965. 326. 2870. 2803. 1676. 1644. 1468. 1449. 1377. 1337. 1194. 1117. 1101. 995. 916 cm“. Anal. Calcd for CuHuN: C. 78.98; H. 12.65; N. 837. Found: C. 79.;18 H. 12.83; 14.8.48. Formation of 7a from Condensation of Isobutyraldehyh with6. ToSOOmLofbemenewereaddedN-all (3 51 g. 27. 6 mmol). isobutyraldehyde (2.38 g. 33. 1 mmol). and p-toluenesulfonic acid (0. 48 g. 2.8 mmol). The reaction fish w- fitted with a Dean-Stark trap containing 4-A molecular sieves. and the solution was heated at reflux for 66 h. After cooling the mixture. the volatiles were removed under reduced procure. and the enamide was distilled under vacuum to give N-allyl-N-iao- butylideneiaobutyramide (7a. 4.24 g. 23.4 mmol) in 65% yield (bp 60—70 °C. <1 mmHg). Spectroscopic data were identical with that reported for the product obtained by acylation of 4a. General Method for fire-Step Synthesis of 7 from Al- ylamine. Allylamine (50 to 250 mmol. 1.0 equiv) and the nec- eeaary aldehyde (1.0 equiv) were taken up in benzene (0.35-0.375 M solution). A Dean-Stark trap was fitted on the apparaun and the solution was heated to reflux to azeotropically remove the resultingwater. After heatingfor 19-flh.thewaterwmremovd. 4-A molecular sieves were added to the Dean-Stark trap. and refluxwucontinued for2h. Thesolutionwmcooledtoambiant temperature and N816 (1.0 equiv) and isobutyryl chloride (1.0 equiv) were added. sequentially. and then heated at reflux for 3h. The mixturewmfdteredtoremovesolidaandafterbensane was removed under reduced premurs. the crude oil was purified by flash column chromatography (silica. 230-400 mesh; eluent 7030 Et,0:petroleum ether). The solvents were evaporated and the enamide was distilled under vacuum to give 7. 7a: 42.68 g. (23.5 mmol. 94% yield) (bp 50-54 “G. <1 mmHg). Spectroscopic data were identical with that reported for the product obtained by acylation of 4a. General Method for Reduction of 7 to N-Aliyl-Nolsobutyl Enamines 8. To a suspension of LiAlH. (1.1 mmol/1.0 mmol 7) in 86,0 i0.2 M solution) at 0 °C was added 7 (1.0 equiv. 9 to 66 mmol reaction scale) slowly via syringe. After addition was complete. the reaction was warmed to ambient temperature and stirred for ‘2-3 h. The reaction wm then cooled to 0 'C and quenched by addition of water (1 mL/g LiAlHJ. 15% aqueom NaOH (1 mL/g W0. and then again wail (3 mL/g LiAlHJ. ’I'hemixturewmstirredfor2handthenfilteredthroughNafiO. Solvent was removed under reduced premure and enamine 8 wm distilled via short-path or Kugelrohr distillation. 8n: 9.84 g (58.8 mmol. 98% yield) (bp “-65 'C. 8 mmHg). Spectroscopic data were consistent with that reported for the preparation of 8a by condensation of 5 with ' yde. General Procedure for 8C1 Rearraaament of 8 Followed by Reduction to lo. Enamine 6 (1.0 equiv) was dissolved in 1.4-dioxane (0.2 M solution) and 0.5 equiv of HCl (1 M solution of HCl in Et10) and then heated to reflux. After 9-10 h. the solution waacooled to ambienttempuatureand LiAIH.(1.1eqdv. 1M inTHF) wassdded. Aiterbeingstirredfcr2h.thesolution was then cooled to 0 °C and quenched by addition of water (1 mL/g LiAlH.).15‘7o aqueous NaOH (1 mL/g LiAlHJ. and then again water (3 mL/g LiAlHJ. The mixture was allowed to stir for l h and then filtered to remove aluminum salts." Solvent was removed under reduced pressure and the oil was Kugelrohr distilled under vacuum to give 10. 10a: 1.37g (81 mmol. 81% yield) (bp 50-60 'C. 8 mmHg); 'H NMR (300 MHz) (CDCl;) 6 0 85 (s. 6 H). 0.86 (d. 6 H. J - 6..6H1)0.87(b&1H).l.7.1(teept1H.J'6..9 8...8Hz).198(d 2 H. J =- 7.5 Hz). 2.29 is. 2 H). 2.35 (d. 2 H. J 'I 6.9 Hz). 4.99 (In. 2 H). 5.79 lddt. l H. J a 9.2. 17.9. 7.5 Hz): laC NMR (75.5 MHz) (CDCl,) 6 20.6. 25.5. 27.9. 34.4. 44.7. 59.1. 60 3. 116.8. 135.7; IR (neat) 3359. 3077. 3005. 2957. 2872. 2811. 1640. 1466. 1385. 1364. 1121.995.912 cm“. Anal. Calcd for C,.H.N: C. 78.04; H. 13.69: N. 8.27. Found: C. 77.64; H. 13.87; N. 7.68. N -MethyloN -lsobutyl-2.2-dlmethylpent+ennmlne (12). To 25 ml. of dry acetonitrile were added 0.847 g (5 mmol) of “in and 0.710 g (5 mmol) of Mel. The solution ves heated to reflux for 12.5 h and then cooled to ambient temperature. Solvent m removedunderreduced andthereeiduewmwmhedwith 10 mL of 15% aqueous NaOH and extracted with 3 X 50 ml. portions of Etgo. The organic layers were combined. dried (M1800, filtered. end concentrated under reduced pressure. Kugelrohrdistillationundervncuum gavel) 739g(4..0mmol 81% yield) of 12 (bp 60-70 ‘C. 10 mmHg): 1H NMR (300 MHZ) (CDCl3) 6 0.82 (a. 6 H). 0.87 (d. 6 H. J = 6.6 Hz). 1.65 (tsept. 1 H. J 8 7.4. 6.6 Hz). 1.97 (d. 2 H. J a 7.4 Hz). 2.07 (s. 2 H). 2.10 (d. 2 H. J I 7.4 Hz). 2.18 (s. 3 H). 4.97 (m. 2 H). 5.61 (ddt. 1 H. J - 11.0. 18.8. 7.4 Hz); uC NMR (75.5 MHZ) (CDC13) 6 20.6. 25.4. 26.8. 36.0. 44.9. 45.0. 69.5. 70.2. 116.6. 136.4; IR (neat) 3077. 2978. 2843. 27%. 1640. 1470. 1385. 1366. 1250. 1105. 1040. 993. 909. 850 cm". Ansl. Calcd for CanN: C. 78.62; H. 13.74; N. 7.64. Found: C. 78.55; H. 13.48; N. 7.70. (18) In thecaseotthemorevolatile compounds lOaand 10b.anexc. 0! aqueous HC) um added. and the solution was concentrated under reduced pee-sine. The residue um treated with 15% aqueous NaOH to apHol14.theaminewasextracted mthlx SOmLportiomolEt-IO. and the organic leyere were dried ngSO.) prior to distillation. 142 Mel-Promoted Renrrsngement e! 8e Followed by LIME. Reduction. To 15 m1.ot'1.4-dioxanewereaddsd 1.34 g (8 mmol) of enamine 8a and 1.14 g (8 mmol) of Mel. The solution m heated to reflux for 17 hand thencooledtOO'C. Therm was reduced by addition of LiAlH. (16.0 ml... 1 M in THF. 18 mmol). warming to ambient temperature. and then stirring for 2 h. The solution was then cooled to 0 'C and quenched by addition of 0. 6 ml. of water. 0. 6 mL of 15% equeous NaOH. and 1.8mLofwater. Afterbeingetirredbrlhthemimrew- wastrcatedwith 15% aqueouNeOHtoapHdu. Theamine productswereextrectedwithsxsomLporticuofMend theorgeniclayer'esdrieMMgSOJ. Volatilmvereremoeedhy rotary evaporation end the oil m K distilled and. vacuum to give 0.81 g (59% yield) a! an $31 mixture of N-ho- butyl-2.2—dimethylpentr4-enamine (10o) and N-methyl-N-iso- butyl- 2.2-dmethylpent-4-ennmine (12) (bp ”-68 'C. 10 mmHg). MeOTs-Promoted Rearrangement o! la Followed by 11MB. Reduction. The reaction wm patched unit condition identical with those described above. using 1.49 g (8 mmol) 08 MeO’l‘s. Distillation alter workup gave 0.96 g (68% yield) of a 72:28 mixture of N-isobutyl-2.2-dimethylpent-4-enamlne (10a) and N-methyl-N-iaobutyl-22-dimethylpenb4-enamine (11) (bp 60-65 'C. 10 mmHg). Acknowledgment. We ere grateful to Michigan State University for support of this resenrch. The NMR data were obtained on instrumentation purchssed in pert with funds from NIH grant 1-S10—RRO4750-01 end from NSF grant CHE-8800770. Supplementary Meterial Avnilehle: Experimentnlproce- duresand physical dataforthesen'mdcompotmrhb-gwpqm). Ordering information a given on any current mastheed pegs. Reprinted from The Journal of Organic Chemistry. 1992. Vol. 57. Copyright © 1992 by the American Chemical Society and reprinted by permission of the copyright owner. Lewis Acid-Promoted 3-Aza-Cope Rearrangement of N -Alkyl-N -allylenamines Gregory R. Cook. Nancy S. Berta. and John R. Stille' Department of Chemistry. Michigan State University. East Lansing. Michigan 48824 Received August 2. I991 The 3-ass-Cope rearrangement of the N-alkyl-N-allylenaminss derived from isobutyraldehyde. which proceefi thermally at 250 °C. has been accelerated by a variety of electrophilic reagents to give 1. 6-unsaturated imines. Protic acids. such as HCl «0. 5 equiv). and the Lewis acidic reagents TiCI. (0. 1-0. 2 equiv). sneer, (0. 5 equiv). and AlMe. (1. 0 equiv) produced complete [3. 3] rearrangement of substrates at 111 ’C. By increasing the Lens acidity of the alumrnum reagents. this transformation was achieved at 50 ‘C with ClAlMeg. Cl,AlMe.and methylaluminum bisl2 .6-diphenylphenoxide). Reaction conditions were studied initially by GLC analysis of the N-isobutyl derivative. These optimum conditions were then used to obtain isolated yields of 59-99‘5 for rearrangement and in situ LiAlH. reduction of the analogous N-methylcyclohexyl substrate to the correspondirm 6.1-unsaturated amine Substrates derived from 2- -phen_vlpropanal. n-butanal. cyclohexanone. and cyclopenmnone were used to examme the general effectiveness of HCl. TiCl.. and AlMe3 as reagents for acceleration of the [3.3] rearrangement. The most versatile and efficient reagent for promoting this reaction. AlMe3, produced overall yields of 83-96% for the two-step rearrangement and reduction of these substrates. Introduction The [3.3] sigmatropic shift of allyl vinyl ethers, the Claisen reanangement. has had significant impact on the regio- and stereochemically controlled formation of car- bon-carbon bonds. and mechanistic studies of this rear- rangement have provided important insight into these and related pericyclic proceeses.‘ While the analogous 3- aza-Cope rearrangement of allylenamine substrates has many of the same advantages. there are intrinsic properties of this nitrogen system that provide for some unique synthetic opportunities (1 to 2. Scheme 1). Included in these features are the higher E-Z control of enamine ge- ometry. which presents a valuable alternative to the less selective enol ether formation.“ and the availability of optically active allylamines from amino acid sources} A rather intriguing feature of this substrate is the presence of an asymmetric heteroatom at the 3-position. a property which the allyl vinyl ether substrates lack.“1 1“ For reviews on {3.3) sigmatropic rearrangements see: (a) Rhonda. S. J.; Raulins. N. R. Org. React. (New York). 1975. 22. 1. lb) Ziegler. I". 8. Acc. Chem. Res. 1977. 10.227. 1c) Bennett. G. 8. Synthesis 1977. 5‘. (d) Bartlett. P. A. Tetrahedron 1980. as. 3. (e) Gaiswski. J. Hydrocarbon Thermal lsomerrsatrons: Academic: New York. 1981. (1') Hill. R. K. Chirality Transfer via Sigmatropic Rearrangements. In Asymmetric Synthesis: Marriott. J. 0.. Ed.; Academrc: New York. 1984: Vol 3. p 503. lg) Ziegler. F. 8. Chem. Rev. 1988. 88. 1423. lb) Blechert. 5. Synthesis 1989. 71. For renews on as [3.3) sigmatropic rearrangements. see: ti) Winterfeldt. 8. Pamela. Chem. Fem-h. 1971. 16. 75. (j) Heimgartner. H.; Hansen. H. -J.; Schmd. H. Adv Org. Chem. 1979. 912L655. (2) (a)Luly. J. R.; DellariaJ. F.; Plattner. J. J.. SodarquistJ. L; Yi. N. J. Org Chem. 1987. 52. 1487 lb) Momva'ae. T.; Hamano.$ I.;Seito. 5.. Toni. S. Chem. Lett. 1981 2085. lo) Monwake. T.; Hamano. S.-l.: Saito. 5.; Torii. S. J. Org. Chem. 1989. 54. 4114. id) Luly. J. R.; Hello. C.-N.; BaMaung. N.; Plattner. J. J. J. Org. Chem. 1988. 53. 6109. (e) Rosagay. A.; Taub. D. Synth. Commun. 1989. 1137. (1') Sasaki. N. A.; Hashimoto. C.; Pauly. R. Tetrahedron Lett. 1989. 30. 1943. lg) than. 3.; Dan. 8. C. Tetrahedron Lett. 1989. 30. 2801. (3) For use of asymmetric nitrogen in the Ileana-Cope rearrangement of [VD-ketene aoatala. see: Ia) Kurth. M. J.; Decker. 0. H. W.; Hope. H.; Yanuck, M. D. J. Am. Chem. Soc. 1985. 107. 443. (b) Kurth. M. J.; Decker. O. H. W. J. Org. Chem. 1986. 5!. 1377 and references crted therein. 0022-3263;“ 92/ 1957-046190300/0 Scheme I “:33 ‘5? l J." ' .a‘nerao.’ . ml-R'fia' :/‘um1'.nt as if 3‘ l’ O u N as I h In 9 Despite the attractive possibilities of this reaction. the 3-aza-Cope rearrangement has been of limited synthetic utility due. in part. to the elevated temperatures required for thermally induced meat. 250 'C for 1a to la and 205 °C for 1b to 2b.‘ In order to overcome these limitations. a number of methods for accelerating this rearrangement have appeared involving manipulation of the electron density of the atoms in the six-membered transition state. An increase in electron density at the enamine functionality through the use of N-allylketene N,O-acetals produced rearrangement at 180-190 'C. a significant decrease from the 250 '0 required for the corresponding enamines.” A similar [3.3] Wt occurred for a substrate with a dialkylamine substituent. an. (4) Hill. R. X.; Gilman. N. W. Tetrahedron Lett. I967. 1621. 15) (a) Corbier. J.; Cremott. P.: Jolene. P. C. R. Acad. Sci. Paris 1979. C270. 1890. lb) Inland. R. B.; Willard. A. K. J. Org. Chem. 1976. 3. 421. © 1992 American Chemical Society 143 162 J Orr Chem. 1‘01. .57. No. 2. 1992 an .V-alkvlketene NIX-acetal. at 200 °C.“ Increasing electron density at the enamine by formation of the N- allylamide enolates further reduced the temperature re- quired for rearrangement to 135 °C.‘ Other methods of promoting the 3-aza-Cope rear- rangement through charge-accelerated processes have in- cluded reducing the electron density on the nitrogen. The effectiveness of this approach is apparent from the slightly lower reaction temperature required for the less Lewis basic aniline derivative 1b 1205 °C) than for the rear- rangement of 1a lScheme 1).‘ Further reduction in the electron density at nitrogen. by forming a cationic qua- ternary nitrogen center. has produced rearrangement at a temperature as low as 80 °C. The quaternary ammonium intermediate 4a has been accessed by methylation of 1a as shown in Scheme 1.7 and a modification of the meth- ylation procedure. methylation of an .V-allylimine followed by the addition of a base. has been found to produce re- arrangement at 25 °C.‘ A more common route to 4 has been the allylation of .V..V-dialk_vlenamines.9 Unfortu- nately. symmetrical allyl groups must be used to avoid problems associated with N- versus C-allylation in this method. Another type of route has been reported that used conjugate addition of a tertiary amine to ethyl pro- piolate to form the cationic nitrogen species.“ In most of these cases in which the tetraalkvl ammonium species was generated. product isolation was limited to hydrolysis of the iminium ion 5 to the corresponding aldehyde 3. the same product accessible through C laisen rearrangement. The use of nonocarbon electrophiles. in the form of Lewis acid catalysts. have been explored as well.” Although Lewis acid catalysis of the C laisen rearrangement has been studied extensively.‘~-~ only one method of promoting the aliphatic Base-Cope sigmatropic rearrangement has been reported. in this case. the use of 0.25 equiv of TiCl. ‘6) Tsunoda. T.. Sasaki. 0; Ito. S Tetrahedron Lett. 1990. 31. 727. '7) la) Brannock. K. L' . Burpitt. R. D. J Org. Chem. 1981. 26. 3576. -hi Hilbert. -l C. Seneratne. K P. A. Tetrahedron Lett. 1984. 25. 2303. ’3‘) “elm. l l‘ . Dc Curie. B . De Kimpe. N. J. Org. Chem. 1990. 55. 1981. -9) (at 0pm. G.; Mildenberger. H. Angew. Chem. 1980. 72. 169. lb) Elkik. E. 81.... Sm: Chim. Fr 1960.972. 11.900111. 0.. Mildenberger. H. {...-mm Ann. 1 mm. 1961.649. .‘6. 1d10pnz. G.; Hellmann. H.; Milden- berger. H. 51hr. H L10 mes lnn them. 1961. 649. 36. le) Opiu. G.; \fildenbcrzer. H. Suhr. H. L.z-?~ii's.1nn Chem. 1981. 649. 4‘7. in 0pitz. u’. Lune; «la-i, than. 1961. "5'l. 1:2. 'rl Stork. 0.. Brizzolara. A.; landesman. 'ri . Srmuszkoncz. J . Terrell. R. J. .lm. Chem. Soc. 1968. 85. :07 «hi Krrrran. A . rilkik. E. 1‘ R Nearer Acad. Sci. 1968. 267. 623. ~- Barthelems, \l . \lnntheard. J.-P . BessiereoChretien. Y, Bull. Soc. ' hi”! Fr 1989. £735. an Elkik. E. Ball. 50C. Chim. Fr. 1989. 903. lk) Hiroi. K. \imida. 5 1 Chem. Pharm Bull. 1972. 20. 248. ll) Hiroi. K.; “i made. .9.-l t, hem. r’harm. Bali. 1973. .31. 12'. um) McCurry. P. M..Jr.; Smith. R. K Tetrahedron Left. 1973. .1325 in) Houdewind. P.; Pandit. l'. K. Ttlrranearam Lett. 1971. 3359. in: Martin. S. 17.. Gompper. R. J. um. Chem. 1974. .19. .1814. lpi Oda. J.; Igarashi. T.; lnouye. Y. Bull. Inst. 1' heat. Res. Kyoto Limo. 1978. 54. 180: Chem. Abstr. 1977. 86. 88836m. uq) Whitesell. J. K.; Felmen. S. W. J. Orr. Chem. 1977. #2. 1663. lr) Martin. S. F . Puchette. T. A. Colapret. J. A. J. Org. Chem. 1979. 44. 3391. 19l Bierautel. H.; Pundit. L'. K. Recl. Trot: Chim. Pays-Baa 1979. m. 4%. «10) ll) Mariano. P 5.; Dummy-Mariano. D.; Huesmann. P. L. J. llrg. Chem. 1979. 44. 124. 0b) Kunna. l" -A.. Gu. J.-M.; Chao. 5.: Chen. Y.; Mariano. P S. J. Org. Chem. 1983. 48. «1262. c l 1) For a review on the catalysis oi' the Cope and Claisen re menu. see: is) Lute. R. P. Chem. Rev. 1984. 84. 205. lb) 0verman. L E. Angew. t‘hem.. Int. Ed. Engl. 1984. 23. 579. :12) Lewis acid promotion of the Claisen rearrangement has been .ichieved with alummum completes. ll) Takai. K.. Mori. 1.; Cabins. K4 Nozaki. H. Te'mhedmn Lett. 1981. )2. 3985. lb) Stevenson. J. W. 3.; Bryson. T. A. Tetrahedron Lett. 1982. 2.3. 3143. lc) Takai. K.; Mori. 1.; Oshima. K.. Norah. H. Bull. Chem. Soc. Jpn. 1984. 57. 446. (d) Maruoha. H.; Nonoshita. K.. Banno. H.; Yamamoto, H. J. Am. Chem. Soc. 1988. III). 7922. re) Maruoka. K. Banno. H.; Nonoshita. K.; Yamamoto. H. Tetrahedron Left. I989. .70. 1.265. in Nonoshita. K.. Banno. H.; Maruoka. K . Yamamoto. 11.-l. Am Chem. Soc. 1990. 112.316. lg) Yamamoto. H.; \laruolta. K. Pure .lppl. Chem. 1990. 62. 2063. lb) Maruoka. X.; Banno. H : Yamamoto. H. J Am. Chem. Soc. 1990. 112. 7791. Ii) Paquette. L. A.; Friedrich. 0.; Rogers. R. D J. Ore. Chem 1991. 56. 3841. 144 Cook et al. Scheme ll 3:. W“ .. 1 .1. ”GI 73?; .12.: m r Iofi.m m 9’ " ..M““ Mr G 1331 “— as H are “A” nuns. RA” fl 11‘“ 9 Fr 98. h 9’ ..c" “.Iweg promoted transformation of 1b to 2b at 80 °C." Com- plexation of the enamine to the Leeds acid. generating an electron-deficient nitrogen center. has been suggested to produce this rate enhancement. However. this in situ carbonyl condensationand rearrangement procedure was less effective for straight-chain aldehydes (20-30%) and was unsuccessful for ketones. A recent report by Bailey has extended the use of TiCl. to obtain asymmetric in- duction as high as 90%ee for substratm where R‘NH, was (R)- (+) a-methylbenzylamine. “ In each case. this methodology has been limited to the use of enamines formed from 2-substituted aldehydes." Our own research interests have focused on the use of the aliphatic 3-azs-Cope rearrangement in organic syn- thesis. In order to develop this method into a useful synthetic carbon-carbon bond-forming reaction. we found it necessary to determine which of a variety of catalysts would promote the rearrangement of 1 to 2 most effi- ciently. The generality of the electrophilic reagents was investigated for a variety of enamine substrates prepared from the aldehydes 2-methylpropanal. 2-phenylpropanal. and n- -butanal and from the ketones cyclohexanone and cyclopentanone. Hydride reduction of mine 2 would then provide a route to the correspond.“ 6.4-madame. whichbasfoundcreativeuseintheformationofniu'ogsn heterocycles. 1‘ (13) Hill. R. R.; Khatri, H. N. Tetrahedron Lett. 1978.087. (14) Bailey P. 0.; Harrison. M. J. TetrahedronLett. 1989. ”.8841. (15) The use of PlePh.). also was reportedto promote rear-m: mentofbothN—phenyl- andN methyl- N-allylenamiuatw'c. but reaction was found to proceed through r-allylpalhdiumin andnotthrougha apericyclicreection. la) Murah-ES- L:Mahah.Y. Tetrahedron Lett.1988.26.5563. (b) Marsha-hi. S.-1.;Mahabe. Y.; Kunita.K. J. Org. Chem. 1988. 53. use. lc)Hiroi.K.; Abeul. Tetra- hedron Lett.19”.31.3623. (16) For representative examples of heterocycle form from 4.0. unsaturated secondaryamines. see: (a) Tokuda. M.; Yamada. Y.; nome. H. Chem. Lett.1988.1289. lb) William. D. R.; Brown. D. Benbow. J. W. J. Am. Chem. Soc. 1989. 111. 1923:1c) Haitians. H.; more. N.; Canon. 8. J. Org. Chem. 1987. 52. 5492. (d) lhota. N.; Hanahi. A. Chem. Pharm. Bull. 1999. 38. 2712. .‘I a "‘ L‘Ass A- «a. F“.. Sana-Cope Rearrangement of .\'-Alkyl-N-allylenamines Results and Discussion Substrate Preparation. Determination of the ability of Lewis acid catalysts to accelerate the 3«aza-Cope rear- rangement required the preparation of two N-allyl-N-al- kylenamine substrates lScheme II). For the purposes of optimizing reaction conditions by capillary gas chroma- trography (GLC l. 8 was ideal for analysis of the reaction progress and product formation. However. the product of rearrangement and reduction. 10. proved to be some- what volatile, and the use of substrate 12 was preferable to facilitate the process of obtaining optimum isolated yields for the the-unsaturated amine. Synthesis of 8 and 12 was accomplished from allylamine through the route illustrated in Scheme 11. [mine for- mation from the reaction of allylamine with isobutyr- aldehyde gave 6 in 75% yield. and subsequent reaction of 6 with isobutyryl chloride and NEt. produced a 90% yield of reported.‘7 Reduction of enamide 7 with LiAlH. gave 8 as the only product in 98% distilled yield. In the same manner. compound 11 was prepared by nation of 6 with cyclohexanecarbonyl chloride in 84 % yield or. if the re- action mixture containing 6 was acylated without prior isolation of the imine. 11 was isolated in 68% yield in two steps from allylamine. Reduction of enamide 11 with LiAlH. produced a 99% yield of the desired enamine 12. Substrates 15. 18.21. and 24 legs 1 and ‘2). which vary in enamine substituent pattern. were prepared by the same route from the corresponding carbonyl compound as pre yiously reported."T Rearrangement Promoted by Proton Sources. Ca- talysis ot‘ the [3.3} rearrangement by protic acids was first observed during the preparation of 8 through a more es- tablished route for enamine formation.“ Heating N-al- lyl-N-isobutylamine and isobutyraldehyde in the presence of 0.0025 equiv of p-toluenesulfonic acid. with azeotropic removal of H30. produced the corresponding enamine 8. If the enamine condensation reaction mixture was heated to reflux in benzene t80 °C). the reaction was found to give 8 in 80% yield as the only product. However. with the use of toluene to azeotrOpe the water (111 °C). the rear- rangement product 9 was formed from 8 to an extent of 10—15% over the course of 72 h. In order to enhance the converSion to 9. increased amounts of a stronger acid were reqmred." HCl as the proton source produced efficient transfor- mation of 8 to 9. and conditions of the reaction were op. timized by GLC analysis (Fable 1). This acid-promoted rearrangement required only 0.3 equiv of HCl for complete converswn to 9 Within 6 h in refluxing toluene." The use of 0.5 equiv of HCl produced a slight increase in yield. optimized at 82 %. but further increase in the amount of catalyst to 0.8 equiv of HCl offered no synthetic advantage. Complete conversion was achieved at a lower temperature (80 °C) with 0.5 equiv of HCl. but the yield was signifi- cantly reduced. Product isolation by in situ reduction of the imine with LiAlH. gave the corresponding amine 10 in 81% yield.” Rearrangement and reduction of the less volatile 12 under the same conditions produced a slightly improved 85% isolated yield of 14.“ I17) Cook. G. R.; Stille. J. R. J, Orr. Chem. 1991. 56. 5578. «18) Weaker lCld catalysts. such as phenol or 2.6-diphenylphenol (0.5 equivi. produced only minor amounts of 9 st 111 °C dunng consumption of 8 under a variety of reaction conditions. .19. Reaction mixtures were quenched With a 10% my solution of NaOMei MeOH for analysis by GLC '-’ncer the quenching conditions. loss of 8 or 9 was not observed even after an extended period of time at hl. 145 J Org. (Them. Vol. 5?. No. 2. 1992 363 Table 1. Catalytic Acceleration of the S-Axa'Cops Rearrangement'I yields 1%) reagent equiv time/temp th/°Cl GLC‘ isolated‘ HCl 0.3 6: 111 '.'0 0.5 31111 82 85 0.5 6.80 64 0.8 61111 8‘2 TiCl. 0.1 2s/111 33 73‘ 0.3 24/111 64 0.5 fill“ 56 0.5 24/80' 8 (ArO)gTiCl-_i 0.5 24/111 80 71 0.5 481111 87 Ego-BF, 0.5 229/80 59 0.5 2.4/Ill 82 59 1.0 9/111 75‘ 1.5 ‘ 5/111 7 SnCl. 0.1 48/111‘ 14 ZnCl, 1.0 12/111 86 1.0 241111 74 ”All reactions were run 0.2 M in toluene. ’Rearrsngement of 8 to 9 was performed on a 1.0 mmol scale. Yields were determined by capillary gas chromatographic tGLC) analysis of the quenched reaction mixture (10% wxv MeONs/ MeOH) using internal stand- ards and correcting for detector response (ref 19). Values were based on reacted substrate. ‘ Isolated yield of 14 after rearrange- ment of 12 (5 mmoll followed by in situ reduction of 13. ‘0.2 equiv of catalyst required on 5.0 mmol scale. '18$ conversion. " 97% conversion. “34% conversion. Rearrangement by Metal Halldes. The use of TiCL. which has been reported to promote rearrangement in similar systems.‘3 was examined as a means of promoting the transformation of 8 to 9 under a variety of condition: Carbon—carbon bond formation was found to proceed within 24 h in refluxing toluene with as little as 0.1 equiv of Lewis acid. Increasing the quantity of TiCl. still pro- duced a single volatile product. but caused a decrease in yield presumably through enhanced substrate oligomeri- cation. At a lower reaction temperature of so °C. 0.5 equiv of this Lewis acid only produced 18% conversion to 9 within 24 h. 011 a larger reaction scale. 0.2 equiv of TiCl. was typically required to achieve complete conversion to imine product.” Catalysis of the rearrangement of 8 to 9 with 0.2 equiv of TiCl4. followed by in situ reduction of the resulting imine with LiAlH.. produced 10 in 71% isolated yield.’" Similarly. transformation of 12 to 14 was accomplished in 73% yield. Steric and electronic modio fication of the titanium catalyst. by the exchange of ligands to form bist2.6-diphenylphenoxy)TiClg.“ promoted rear- i201 1n the case of the more volatile compound 10. an excess of aqueous HCl was added. and the solution was concentrated under re- duced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14. the same was extracted with 3 x 50 m1. portions of BnO. and the organic layers were dried tMgSO.) prior to distillation. i211 For transformations with some of the electrophilic resgsnm con. tanning halogens tHCl. C HlMeg. and ClyAlMel. GLC yields were lower than isolated yields in some cases due possibly to ammonium chloride salt formation prior to analysis. i221 Because hydrolysis of TiCl. could produce up to 4 equiv of HCL which was also found to promote rearrangement. the TiCL wm distilled prior to use and rigorous measures were taken to exclude oxygen and water from the reaction mixtures. in each case. the characteristics of the TiCL-catalyzed rearrangements were very different from those of the HCl reactions (23) The addition ofTiCl. to theenamine producsdsnoil on thesidss of the flask. which could be a mixture of the salts corresponding to d and 5. The increased amount at catalyst required to get complete conversion of 8 to 9 could be due to the decreased surface arse/volume ratio of the reaction vessel as the reaction is scaled up. As a result. the surface area of the 0in intermediate was decreased. and the reaction slowed. :24) Ill Dilworth. J. R.; Hanich. J.. Krestal. M.; Beck. J.; Strahle. J J. Ureanomet. Chem. 1986. 315. (’9. (hi Chesnut. R. W.; Durfee. L. D.. anwick. P B.; Rothwell. l. P.; Folting. R.; Huffman. J. C. Polyhedron 1987. 6. 2019. 146 £64 J Ore Chem.. Vol. 57. No. 2. 1992 Table 11. Studies of (3.3) Rearrangement Promoted by Aluminum Reagents‘ yields 1%) reagent equiv time. temp ll'l, °C) GLC" isolated" 313101 0.5 .‘9/ 111 100 1.0 12: 111 100 99 1.5 6: 111 100 l 5 24160 100 CiAiMe, 0.2 24/ 1 ii 50‘ 0.5 24. 80 71' 1.0 24. 25 S4 [.0 24: 50 88 91 1.0 9:60 83 1.0 3 '30 96 96 CLAlMe 1.0 24. so 79 37 1.0 1'3. 30 91 84 'Armfilhle 1.0 24 40 :57 80 1.0 1'2 no 34 (‘LAl 10 .‘4 30 36 1.0 24160 63 ’ All reactions were run 0.2 M in toluene. ’ Rearrangement of 8 to 9 was performed on a 1.0 mmcl scale. Yields were determined by capillary gas chromatographic lCLCl analysis of the quenched resetion mixture 110% wlv MeONa MeOH) using internal stand- irds are correcting for detector response iref 19!. Values were based on reacted substrate. ~ lsolated yield of H after rearrange- rnent nt' 12 .5 mmoli followed by :n iltu reduction of 13. ’ 19% unversion to product. '80": cuniersion to product. rangement of 8 to 9 at 111 °C in 87% yield by GLC analysis. Rearrangement of 12 to 13. followed by reduction with LiruH.. gave 14 in 71% isoiated yield with use of this catalyst. Although there has been one report in which 81“. was used as a catalyst for formation of an N -allyl NJV-ltetene acetal at :30 °C. there was no evidence for charge accel- erated rearrangement under the reaction conditions.” However. rearrangement of substrate 8 was promoted by Et;O‘BF . at a higher temperature of 111 °C. For complete conversion to 9 within 24 h. a minimum of 0.5 equiv of catalyst was required. and increasing quantities of BnO-BF. gave progressively decreasing yields. At a milder temperature of 80 °C. conversion to 9 by using 0.5 equiv of BnO-BF. was only 97% complete after :24 h with a somewhat lower yield of 59%. With use of the optimum conditions. transformations of 12 to 14 was achieved in 39% isolated yield. Rearrangement promoted by ZnClg. one of the most effective catalysts reported for the rear- rangement of allylaniline substrates.“ produced less se- lective transformation of 8 to 9. When 1.0 equiv of the Lewis acid was used. rearrangement required 12 h to reach completion with 86% GLC yield of 9. but 8-15% of an unidentified side product was unavoidably generated in the process. Further exposure to the reaction conditions caused degradation of 9 over the course of time. Rearrangement by Organoaluminum Complexes. As found for the Claisen rearrangement. complexes of aluminum were the most effective catalysts for the 3- aza-C ope rearrangement.” Acceleration of the 3-azaoCope rearrangement with aluminum reagents also paralleled that of the C laisen rearrangement in that stoichiometric amounts of the complexes were necessary to produce complete transformation of 8 to 9. For example. the use of 0.5 equiv of AlMe. at 111 °C produced 59% conversion of 8 to 9 after 6 h. but the reaction only progressed to 68% .‘51 Fit-int. J.. Barbara. C. Tetrahedron Lett 1968. 6425. Cook et al. Table 111 Yields of the J-Asa-Cops Rearrangement! Reduction as a Function of Reagent and Enamine Substitution Pattern‘ reagent (equiv) substrate product HC! (0.5) TiCl. (0.2) AlMe3 (1.0) 8 10 81 71 95 12 1t 85 73 99 15' 17 77 88 92 18 20 0 0 84 21 23 99 92 98 2t 28 10' 3‘ 83 ' Isolated yields of reactions performed 0.2 M in refluxing tolu- ene followed by treatment with LiAlH.. '81 I 88:18. ‘Purifiad yields (ref 29). conversion after an additional 18 h (Table II). Incoming the initial amount of Lewis acid to 1.0 equiv. produced complete transformation within 12 h at 111 °C in 100% GLC yield. Under these optimum conditions. the rear- rangement. and reduction of 8 produced 10 in 95% yield.” and the same transformation with 12 gave a 99% isolated yield of 14. Complete conversion to product was also achieved at a temperature as low as 80 °C within 24 h. but required the use of 1.5 equiv of AlMe3. Although the Claisen rearrangement of allyl vinyl ethers with We, was found to result in addition of a methyl group to the re- sulting aldehyde. addition of a methyl group to the imines 9 or 13 was not observed after the analogous {lass-Cope transformation.“ As expected. increasing the Lewis acidity of the alu- minum catalystproducedconversionof8to9witbreduced reaction times or at lower reaction temperatures (Table 11). By the use of 1.0 equiv of ClAlMe, at 80 °C. the reaction was complete within 5 h in 98% yield by GLC analysis. With the use of these conditions for rearrange- ment of 12 and subsequent reduction of 13 gave a 98% yield of the corresponding secondary amine.n Complete conversion of 12 to 13 also was achieved within 24 h at a temperature of 50 °C in 88% yield by GLC. This reaction temperature represents an overall decrease of 200 °C from the conditions necessary for thermal rearrangement! As was discussed for Alli/leg. ClAlMe, also was required in stoichiometric amounts. Rearrangement of 8 at 111 °C with 0.2 equiv of catalyst was only 19% complete after 24 h. The use of 0.5 equiv of Lewis acid at 80 °C gave a 57% conversion to 9 in 3 h. but the reaction advanced to only 60% conversion after an additional 21 1:. Further increme of the aluminum Lewis acidity. by the use of ClelMe. produced results similar to those observed for ClAlMez. At 80 °C. a 91% GLC yield of 8 to 9 was obtained. and the reaction of 12 under these same conditions gave an 84% isolatsdyieldoflt. Comparablsyieldswereobtained at 50 ‘C. An aluminum catalyst of similar oxidation state. me- thylaluminum bisl2.6-diphenylphsnoxide).m was also a very efficient catalyst for facilitating the 3-axa-Cops re- arrangement. Rearrangement of 8 to 9 usim this catalyst wmcompletewithin 24hat25'Ctogivea59% yieldsnd a yield of 87% was obtained by promoting the reaction at 40 °C. Similarly. the rearrangement and reduction of 12 under these conditions produced an NS yield of 14. To ‘26) The preparation of the product of methyl addition to 9. N42- methyl- i-propylloN-t 12.2.trimethylpenM-en-loyllsmine. wm patella-d by the addition of methylmsgneeiinn bromide to 9 followed by aqueom workup. 3-Aza-Cope Rearrangement of .V-Alkyl-N-allylenamines complete the methyl- and chloro-substituted series of aluminum Lewis acids. C1.Al was used as a catalyst for the transformation of 8 to 9. This catalyst produced signifi- cantly lower yields of product under the same rearrange- ment conditions as those used for ClgAlMe. Variation of Enamine Substitution. In order to determine the versatility of the different types of reagents (protic acids. metal halides. and organoaluminum species) on various substrates. three representative reagents were studied. These reagents. HCl. TiCL. and AlMe3. were each used to promote rearrangement of substrates [8. 18. 21. and 24. which all differed in enamine substitution pattern. The results are shown in Table III. The 3-aza-Cope rearrangement of the aldehyde en- amines was highly dependent on both the enamine sub- stituent pattern and the type of electrophile used. With the traditionally successful geminally disubstituted en- amine substrates}9 such as 8 and 12. rearrangement and subsequent reduction gave good yields of 10 and l4.as previously discussed. The substrate derived from 2- phenylpropanal. 15. gave similar results (eq 1). Rear- iv‘ ' is. 80 "' an H m .“ x~Af_m M ‘N s n. —. ———. 1‘) m v as. V animal‘s s s is Iranians. is is it a'ae'ei is is so rangement of 15 to 16 followed by LiAlH. reduction pro- duced isolated yields which ranged from 77% to 92% for the three reagents. Substrate 18. with only one alkyl substituent on the nucleophilic enamine carbon. was much more sensitive toward these reaction conditions. Treat- ment with HCl (0.5 or 1.0 equiv) or TiCL (0.1 to 1.0 equiv) under a variety of conditions produced complete degra- dation of 18 to oligomeric products. In contrast. treatment of 18 with AlMe. resulted in rearrangement to 19 as the only volatile product. and reductive workup gave an 84% isolated yield of 20. The properties of the carbonyl compound had an enormous effect on the success of the acceleration of the 3-aza-Cope rearrangement for the ketone-derived sub- strates. The transformation of 21 to 22 proceeded quan- titatively with each electrophilic reagent used. and re- duction of the intermediate imine with LiAlH. gave 23 as a 90:10 mixture of diastereomers (eq 2).-’7 For each "98:? 8 '52 29 an 28 reagent. isolatsdyielrhofgreaterthan92% wereobtained. However. the results obtained for rearrangement and re- duction of 24 were poor with the use of HCl or TiCl4. Rearrangement with HCl for lengthy reaction times. fol- lowed by reduction with LiAlH.. resulted in a mixture of unreacted 24 (9%). N-isobutyl-N-allylcyclopentylamine (27. 36%).” and 28 (10%) as the only distillable products." (27) The use of other hydride reducing agents to achieve greater as- lectivity is currently being investigated. (28) Tertiary amine 18 was prepared through an independent routs. .‘Vo allylcyclopentylamins was made by LiAlH. reduction of the imine formed from allylamine and cyclopentanone. Reaction with 2- methyl- propanoyl chloride and NEt, gave the corresponding secondary amide. which was reduced to 18 with LiAlH. (29) A mixture of products was obtained by distillation (40-44% mam recovery). and the individual yields were calculated on the contribution of each compound to this purified product mixture. 147 J. Org. C hem. Vol. 57. No. 2. I992 485 The reaction with TiCl. resulted in a similar mixture of 24 (11%). 27 (26%). and 28 (3%). and the use of an al- ternate catalyst. ELJO‘BFJ (0.5 equiv). gave a somewhat improved mixture of 27 (11%) and 28 (43%). As was found for 18. the other substrate sensitive to HCl and TiCL conditions. a stoichiometric amount of AlMe3 successfully promoted the 3-aza-Cope rearrangement of 24. Carbon- carbon bond formation and imine reduction produced an 83% yield of 28 as a 90:10 mixture of diastereomers.” There are several features that made AlMe3 a rather unique reagent for the acceleration of the 3-an-Cops rs- arrangement. The most apparent difference wm that We, mint be used in stoichiometric quantities for 3- asa-Cope rearrangement to reach completion. Thsss ob- servations suggest that the aluminum reagent formed a complex with the nitrogen of the imine product (5) that wanotemilyrecycledtoformthscomplsawithsulntrnte 4. Although requiring 1.0 equiv of AlMe, places a limi- tation on this methodology. this same affinity for nitrogen maybedirectlyrelatedtotheefl’ectivensmofthisrsqsnt. Ashes beendemonstratedmnnminesulltntmwhichwsrs more subject to electrophilic attack at carbon. such as 18 and 24. react through alternate pathways with HCl and TiC1..3° However. the differing properties of the Lewis acid/ base interaction of the aluminum with the enamines made this reagent much more compatabls with sensitive enaminesubstrates. Asaresult.AlMe,wmaversatileand efficient reagent for carbon-carbon bond formation through the charge-accelerated 3-ua«Cops rearrangement with all substrates tested. Summary Acceleration of the 3-aza-Cope rearrangement of the N—alkyl-N-allylenamines derived from isobutyraldehyde was accomplished at temperatures as low as 25 °C. which represents a decrease in reaction temperature of greater than 200 °C from that of the thermal rearrangement. A variety of catalysts. including protic acids(1-1C1). transi- tion-metal halides (TiCL. BF3. ZnC1,). and organometsllic reagents (“Megs"). effectively promotedresrramemsnt of the N-alkyloN-allylenamine to the corresponding imine. Each type of electrophilic reagent demoutrated diflerent stoichiometry requirements. from 0.1 to 1.0 equiv. for complete conversion of substrate to product. Reduction of the intermediate imine. without prior isolation. gave 14 in 59 to 99% isolated yields for the two-step process from 12. The substitution pattern of the enamine substrates was critical to successful 3-a1s-Cope rearrangement by HCl and TiCl.. but AlMe. produced efficient product formation with even the most sensitive enamine substrates. Experimental Section General Methods. All reactions were carried out performing standard inert atmosphere techniques to exclude moisture and oxygen. and reactions were performed under an atmosphere of either nitrogen or argon. Benzene. toluene. tstrahydrofuran (THF). and Etgo were distilled from sodium/bamophsnons im- mediately prior to use. Thisthylamins w- hsatsd at reflux over calcium hydride for a minimum of 12 h and then distillsd' im- msdiatelypriortotns. SolutionsofHCl(1.0MinEt,O).LiAll'l. (1.0MinTl-1F). andCl,AlMs(1.0Minhsxanml wersobtainsd fromAldrichChemicalCo. SdudomdMMgandClAanflln M in toluene) were prepared from neat organoaluminum com- pounb obtained from Aldrich ChamimlCnC chlorides. isobutyryl chloride. allyl amine. TiCL. and zoo-er. were distilled prior to use. Addition were made with gm tight (30) FordiscussionsofN- versinC protonation Hm (a) Hickmott. P. W. Tetrahedron 1982.38. 1978. (b) Kin-emit]. Tetre- hedron 1988.24. 188. and Manne- therein. 466 J. Org. Chem. Vol. 57. No. 2. 1992 syringes or via cannula transfer under nitrogen. Unless specified. concentration of solutions after workup wm performed on e such: rotary evaporator. Gas chromatographic (GLC) analyses were carried out on a Perkin-Elmer 8500 instrument with a 50 m RSL-200 capillary column (5% methyl phenyl silicone). an FID detector at a 220 'C injector temperature and a 300 'C detector temperature. Heliumgas prenuewssaetat15psia-itheflowrsteof2mL/min. NMR spectra were obtained on Varian Gemini 300 or VRX- 300 spectrometerswithCDChassolvent. Dataarereportedssfollows: chemical shift relative to residual CHCl, (7.24 ppm). multiplicity (s I singlet. d I doublet. t I triplet. q I quartet. sept I septet). integration. and coupling. Infrared spectra were recorded on a Nicoiet 42 PT [R instrument. N Allylisobutylidensamine (6). Allylamine (3. 54 g. 62 mmol) was added to a flash containing 100 ml. of _Et,0 and 14 g of 4% molecular sieves. Over the period of 10 min. isobutyraldehyde (4.47g.62 mmol)wmaddeddropwiseat25°C. Afterbeingm'rred at ambient temperature overnight. the solution was filtered and the remaining solids were washed with two 50-mL portions of 390. The mixture then was distilled under nitrogen at atmos- pheric pressure to give 6 (5.13 g. 46.0 mmol) in 75% yield (bp 112-114 ’C): 'H NMR (800 MHz) (CDCl,)61.05(d. 6 H. J I 6.9 Hz). 2.42 (dsept, 1 H. J I 4.9. 6.9 Hz). 3.95 (d. 2 H. J I 5.6 Hz). 5.05 (dd. 1 H. J I 1.8. 10.3 Hz). 5.10 (dd. 1 H. J I 1.8. 17.2 Hz). 5.93 (ddt. 1 H. J I 10.3. 17.2. 5.6 Hz). 7.51 (d. 1 H. J I 4.9 Hz); ”C NMR (75.5 MHz) (CDCl.) 6 19.3. 34.1. 63.2. 115.5. 136.1. 170.9: 1R (neat) 3083. 3013. 2967. “.2932. 2874. 2824. 2674. 1466. 1456. 1437. 1366. 1103. 1019. 995. 916 cm". Synthesis of 7 by Acylation o! 6. To 50 ml. of dry THF were added 6 (3.34 g. 30 mmol) and Nil-It. (3.54 g. 33 mmol). The solution was cooled to 0 °C. and isobutyryl chloride (3.50 g. 33 mmol) in 20 m1. ol'THF was added dropwrse overs 30-min period After being heated at reflux for 1.5 h. the solution was cooled to ambieng temperature and filtered through a pad of silica on a glass frit. and the solids were washed with two portions of tho. The solvents were removed under reduced pressure. and the crude oil was purified by flash column chromatography (silica. 2130-40) mesh: eluent 5050 Ergo-petroleum ether). The solvents were evaporated. and the enamide was isolated via Kugelrohr distil- lation under vacuum to give 7 (4.88 g. 27 mmol) in 90% yield (bp 55-65 “G (<1 mmHg)): ‘H NMR (300 MHz) (CDCig) 6 1.02 (d. 6 H. J I 6.8 Hz). 1.57 (s. 3 H). 1.70 (s. 3 H). 2.65 (sept. 1 H. J I 6.8 Hz). 3.89 (d. 2 H. J I 6.2 Hz). 5.04 (dd. 1 H. J I 1.6. 11.3 Hz). 513 (dd. 1 H.J I 1.6. 16.0 Hz). 5.74 (ddt. 1 H. J I 11.3. 16.0. 6.2 Hz). 5.85 (s. 1 H): l"C NMR (75.5 MHz) (CDCl,) 6 17.3. 18.8. 21.5. 30.9. 50.0. 116.9. 123.5. 133.4. 135.9. 177.7; [K (neat) 3083. 2975. 2936. 2876. 1653. 1472. 1404. 1242. 1%. 1092. 993. 920cm". Anal. Calcd for C¢H,,N: C. 74.27: H. 13.36; N. 12.37. Found: C. 74.43; H. 13.69: N. 12.21. Reduction of 7 to 8. To a flask containing LiAlH. (2.51 g. 66 mmol) was added 300 mL of Ergo. and the suspension was cooled to 0 °C. Amide 7 (10.87 g. 60 mmol) in 30 m1. of Eco was added dropwise over a 45-min period. The solution was warmed to room temperature and stirred for 6 h. After the solution was cooled to 0 °C. the nation was quenched by addition of 2.5 ml. of H10. followed by 2.5 m1. of 15% aqueous NaOH. and then again by 7.5 m1. of H30. The solution was stirred for 1.5 h and then dried with K3C03. The solids were removed by filtration. and the solvent was removed under reduced pressure. Enamine 8 was isolated via Kugelrohr distillation (bp 54-55 °C (8 mmHg). 9.84 g. 98% yield): 'H NMR (300 MHz) (CDCl;) 6 0.83 (d. 6 H. J I 6.6 Hz). 1.58 (d. 3 H. J I 1.3 Hz). 1.58 (tsept. 1 H. J I 7.3. 6.6 Hz). 1.65 (d. 3 H. J I 1.3 Hz). 2.25 (d. 2 H. J I 7.3 Hz). 3.15 (dt. 2 H. J I 1.6. 1.6. 6.2 Hz). 5.02 (ddt. 1 H. J I 2.0. 10.2. 1.6 Hz). 5.08 (ddt. 1 H. J I 2.0. 17.2. 1.6 Hz). 5.22 (‘10. 1 H. J I 1.3. 1.3 Hz). 5.81 (ddt. 1 H.J I 10.2..17.2. 6.2 Hz): ”C NMR (75.5 MHz) (CDClg) 6 17.4. 20.4. 22.0. 27.4. 59.6. 63.1. 115.9. 122.8. 135.8. 136.9; IR (neat) 3081. 3009. 2955. 2926. 2870. 2803. 1676. 1644. 1468. 1449. 1377. 1337. 1194. 1117. 1101. 995. 916 cm". General Procedure for Baarrsnpementoflto’. Allnssh used in rearrangement studies were heated under vacuum for 20-30 min and then purged with argon (or 10 min. A solution containing 8 (0.167 g. 1 mmol). o-xylene (0.121 mL. 1 mmol. internal GLC standard). and 5 ml. or toluene was cooled to- 148 Cook et aL °C. Afteraninitialguchromatographwmtaksndhelewisacid reagents (see Tables 1 and 11 (or equiv) were added at -78 °C or the HCl was added at 0 'C or the HCl was added at 0 'C. For Cl,“ and (ArOhAlMe accelerated reaction. a solution of 8 was addedtotbecatalystin 25mLoi‘tolueneviacannulaat-78'C. Allaliquotaforanalysiswereremovedfromthereactionvemsl viacannula.qusnchsdinEt,Owith 10% w/vsolutionoleOMe inMeOH.anddr-isdover Na,S0.orK,CO,pr-iorteGLCanalys’n. Preparation of 11 by Acylation of 6. imine 6 (2.44 g. 22 mmol)andNEt,(3.69ml..26.4 mmol)weretshlsupin150ml.. ofTHandcoolsdtoO‘C. Cyclohasnscarbonylchloriduw g.24mmol)in35mLolTHI-‘wesaddeddropwissovera2-h period. Thereactionwsssllowedtowsrmtoroomtempcatine duringtheadditirmandthmwmbroqhttorduxfaflh. All. the solution w- cooled to ambient temperature. solids were removedbyfiltrationthroughapadofsilicsonaglasstritand thenwashadwithtwoportionsothqo. Thesolventswarere- moved via rotary evaporation. and the remaining oil was purified by column chromatography (silica. W mull; eluent (”:70 ethsr)andisolstedviaKmelrohrdistillationto give 11 (75-100 °C. (<1 mmHg). 3.35 g. 69% yield): ‘H NMR (300 MHz) (CDCl,) 6 1.21 (m. 4 H). 1.43 (m 2 H). 1.61 (m. 4 H). 1.60 (s. 3 H). 1.75 (s. 3 H). 2.38 (m. 1 H). 3.96 (d. 1 H.J I 6.2 Hz). 5.02 (d. 1 H. J I 11.5 Hz). 5.04 (d. 1 H. J I 15.8 Ha). 5.72 (ddt, 1 H. J I 11.5. 15.8. 6.2 Hz). 5.82 (s. 1 H). “C NMR (75.5 MHz) (CDCIQ 8 17.6. 21.8. 25.7. 28.9. 41.5. 50.0. 116.7. 12.13. 133.3. 135.9. 176.0. IR (neat) 3101. 2030. 2855. 1653. 1451. 1427. 1342. 1256. 1206. 1123. 990. 918. 895. 831 cm". Anal. Calcd for $11575le C. 72.88: H. 10.56: N. 7.73. Found: C. 7m H, 10.”; . .72. Two-Step Synthesis of 11 from Allylamine. Allylamine (2.20 g. 30.0 mmol) and hobutyrsldehyde (1.74 g. 30.0 mnml) were takenupinSSmLotbermne. ADeanoStarktrspwssiittadcn the apparatus. and the solution was heated to reflux to asso- tropically remove the resultmxwater. Altar being heated 19-22 h.tbewsterwmremoved. molecularsievsswersaddsdto tbeDean-Starhtrap. andrel'luxwascontinuadlorZh. The solution was cooled to ambient temperature. and NEt, (3.03 g. 30.0 mmol) and cyclohexanecarbonyl chloride (4.40 g. 31.0 mmol) wereadded.ssqusntially.sndthenheatedatre0\nfor3h. Alter benasnewuremovedtmderreducsdprmntbecrudooilw- purified byflssbcolumnchromatogrsphflsilicam-Mmmh: eluent 30:70 Ergo-petroleum ether). The solvents were evapo- rated. and the enamide was distilled under vacuum to give 4.53 101' 11 (Z15 mmoL68'l- yield). Spactrosoopicdatawmidsntiml tothatreportedforthsproductobtainsdbyacylationoiisolatsd Reduction of 11 to 12. Enamide 11 (4. 71 g. 21.0 mmol)‘ in 40 mLofEkOwssaddeddropwisetoasuspensionot‘LiAlH. (0.89 g. 23.0 mmol) in 300 mL of 81.0 at 0 'C over a 1-h period. The reaction mixture was warmed to room temperature and then stirred for 5 h. The LiAlH. was quenched at 0 ’C through slow addition of 0.9 mL of H20. 0.9 mL of 15% NaOH. and than 2.7 mLofH,O.Al’terbeingstirredl'or1h.thesolidswsr-eremoved byfiltrauomandthesolventswereremovedviarotaryevaporation to give an oil. The oil was isolated via Kugelrohr distillation to give 4.15 g of 12 (70-60 °C (5 mmHg). 95% yield): ‘H NMR (ill) MHz) (CDCl,) 6 0.83 (m. 2 H). 1.15 (m 4 H). 1.30 (m. 1 H). 1.59 (8. 1 H). 1.65 (s. 3 H). 1.75 (s. 3 H). 2.1!) (d. 2 H. J I 7.2 Hz). 3.14 (d. 2 H. J I 6.1 Hz). 5.02 (dd. 1 H. J I 10.2. 2.0 Hz). 5.09 (dd. 1 H. J I 17.3. 2.0 Hz). 5.22 (s. 1 H). 5.81 (ddt. 1 H. J I 17.3. 10.2. 6.1). uC NMR (75.5 MHz) (CDCl,) 6 17.6. 22.3. 26.2. 26.9. 31.8. 37.1. 59.6. 61.9. 115.7. 122.0. 135.7. 13.8: IR (neat) 3091. 3923. 2851. 2797. 1650. 1600. 1449. 1374. 1337. 1263. 1263. 1178. 1123. 993. 9163. 843 cm“. Representative Procedure for Charge-Accelerated 2- Asa-Cope Rearrangement and Rednecks Workup (12 to 14). Allflssksusedinrearrangementstudiaswereheatsdundsr vacuumfor20-30minandpurgedwithsrgonior 10min. The electrophilicreagents(ssa'1‘ablsslsnd llforsquiv)wereaddsd toasolutioncontsinim 12 (1.04 g.5.0mmol)in25ml..o(toluam togiveaflnslconcmtrationofMMofu. liswhacimweresddsd at -78 °C. and HCl w- added at 0°C. For C1,Alsnd (NOW accelerated reactions. a solution of 12 was added to the catalym in 25 mLol'tolueneviacannulaat-78°C. Tharaactionmixune was heated until complete conversion of 12 to 13 had occurred “‘29- _1 _A“_L_& .p __ ____ .... E 3-Aza-Cope Rearrangement of .V'-A1kyl-N-allylenamines (see Tables 1 and 11 for temperatures and reaction times). 1'" ol- lowing rearrangement. the reaction was placed in an ice bath. and 5.5 ml. of 1.0 M LiAlH. solution was added.’I After 3 h. the reduction was quenched at 0 °C through slow addition of 0.2 ml. of H30. 0.2 ml. of 15% NaOH. and then 0.6 ml. of H30. The solids were removed by filtration through sodium sulfate on a glam frit. Solvents were removed by rotary evaporation and the oil was isolated via Kugelrohr distillation to give 14. 14: (bp 70-80 'C (<1 mmHg)): ‘H NMR (300 MHz) (CDCl.) 6 0.89 (s. 6 H). 1.31 (m 4 H). 1.40 (m. 1 H). 1.72 (m. 6 H). 1.96 (d. 2 H. J I 7.5 Hz). 2.28 (s. 2 H). 2.37 (d. 2 H. J I 6.8 Hz). 4.97 (d. 1 H. J I 16.6 Hz). 4.98 (d. 1 H. J I 12.2 Hz). 5.78 (ddt. 1 H. J I 16.6. 12.2. 7.5 Hz): l3C NMR (75.5 MHz) (CDCIQ 6 25.5. 26.1. 26.8. 31.4. 37.6. 44.7. 57.8. 60.5. 116.6. 135.7; IR (neat) 3350. 3074. 2923. 2853. 2807. 2753. 1639. 1462. 1447. 1364. 1127. 995. 913 cm". Anal. Calcd for CuHflN: C. 80.31; H. 13.00. N. 6.70. Found: C. 79.00: H. 12.49: N. 6.85. 10. (bp 50-60 'C (8 mmHg)): ‘H NMR (300 MHz) (CDCl,) 6 0.85 (3. 6 H). 0.86 (d. 6 H. J I 6.6 Hz). 0.87 (be. 1 H). 1.71 (tsept. 1 H. J I 6.9. 6.6 Hz). 1.98 (d. 2 H. J I 7.5 Hz). 2.29 (s. 2 H). 2.35 (d. 2 H. J I 6.9 Hz). 4.99 (m. 2 H). 5.79 (ddt. 1 H. J I 9.2. 17.9. 7.5 Hz): 1‘"C NMR (75.5 MHz) (C001) 6 20.6. 25.5. 27.9. 34.4. 44.7. 59.1. 60.3. 116.6. 135.7: IR (neat) 3359. 3077. 3005. 2957. 2872. 2811.1640.1466.1385. 1364. 1121. 995. 912 cm". Anal. Calcd for CanN: C. 78.04: H. 13.69: N. 8.27. Found: C. 77.64: H. 13. 87; N. 7 .68 17: (bp 60-70 'C (<1 mmHg): ‘H NMR (300 MHz) iCDClg) 6 0.75 (d. 3 H. J I 6.6 Hz). 0.77 (d. 3 H. J I 6.6 Hz). 088(1):. 1 H). 1.34 (s. 3 H). 1.63 (mom. 1 H. J I 6.8.6.6 Hz). 2.29 (dd. 1 H. J I 11.8. 6.8 Hz). 2.32 (dd. 1 H. J I 11.8.6.8 Hz). 2.35 (dd. 1 H. J I 7.6. 13.8 Hz). 2.52 (dd. 1 H. J I 6.6. 13.8 Hz). 2.63 (d. 1 H. J I 11.5 Hz). 2.30 (d. 1 H. J I 11.5 Hz).4.94(d.1H.J I 10.0 Hz). 4.99 (d. 1 H. J I 17.1 Hz). 5.57 (dddd. 1 H. J I 10.0. 17.). 7.6.6.6 Hz). 7.25 (m. 5 H): 1‘C NMR (75.5 MHz) (CDCl.) 6 20.2. 23.2. 27.6. 41.7. 45.0. 58.6. 60.6. 117.2. 126.0. 126.7. 128.4. 135.3. 146.5; IR (neat) 3337. 3061. 3025. 2957. 2928. 2872. 2811. 1640. 1601. 1497. 1466. 1447. 1379. 1123. 959cm". Anal. Calcd for C,3H25N: C. 83.06: H. 10.89: N. 6.05. Found: C. 82.73: H. 10.93: N. 6.08. 20: (bp 70-80 'C (8 mmHg)): ‘H NMR (300 MHz) (CDC11) 60.85 (t. 3 H. J I 7.4 Hz). 0.85 (d. 6 H. J I 6.6 Hz).1.29(m. 2 H). 1.48 (ddq. 1 H. J I 6.4. 6.4. 7.4 Hz). 1.50 (ddq. 1 H. J I 6.4. 7.4 Hz). 1.69 (tsept. 1 H. J I 6.7.6.6 Hz). 2.04 (dddd. 2 H. J I 1.3. 1.3. 6.1. 7.2 Hz). 2.341d. 2 H. J I 6.7 Hz). 2.44 (d. 1 H. J I 6.4 Hz). 2.45 (d. l H. J I 6.4 Hz). 4.95 (ddt. 1 H. J I 1.1. 10.0. 1.3 Hz). 4.99 (ddt. 1 H. J I 1.1. 17.2. 1.3 Hz). 5.76 (ddt. 1 H. J I 10.0. 17.2. 7.2 Hz): ”C NMR (75.5 MHZ) (CDC1.)6 10.8. 20.4. 24.3. 28.0. 36.3. 39.3. 53.0. 58.3. 115.8. 137.5: IR (neat) 3418. 3079. 2959. 2928. 2874. 2813. 1640. 1466. 1381. 13661125. 995. 911cm“. Anal. Calcd for CHHQN‘ C. 78.04: H. 13.69: N. 8.27. Found: C. 77.65; H. 13.66: N. 8.25. 23: (bp 40-50 °C (<1 mmHg)): ‘H NMR (300 MHz) (CDCl.. major diastereomer) 6 0.87. (d. 6 H. J I 6.6 Hz). 1.30 (tn. 4 H). 1.50 (m. 4 H). 1.67 (m. 3 H). 1.95(m. 1H). 2.15 (m. 1 H). 2. 26 (dd. 1 H.J I 6.8. 11.3 Hz). 2.38 (dd. 1 H.J I 6.8. 11.3 Hz). 2.59 (tn. 1 H). 4.93 (ddt. 1 H. J I 1.1. 10.3. 1.4 Hz). 4.98 (ddt. 1 H. J I 1.1. 16.8. 1.4 Hz). 5.75 (ddt. 1 H. J I 10.3. 16.8. 6.7 Hz): 1"C NMR (75.5 MHz) (CDC).) 6 20.6. 22.5. 23.0. 27.1. 28.4. 28.8. 33.4. 39.1. 55.4. 57.1. 115.3. 138.6: IR (neat) 3359. 3077. 2928. 2859. 2805. 1642. 1470. 1366. 1130. 1103. 993. 909 cm". Anal. Calcd for CnHaN: C. 79.93; H. 12.90: N. 7.17. Found: C. 80.16; H. 12.03: N. 7.47. 26: (bp 30—40 'C(<1mmHg)): ‘H NMR (300 MHz) (CDCl,. major diastereomer) 6 0.86 (d. 6 H. J I 6.7 Hz). 1.43 (m. 3 H). 1.65 (m. 4 H). 1.90 (m. 2 H). 2.17 (m. 2 H). 2.27 (dd. 1 H. J I 6.9. 11.5 Hz). 2.39 (dd. 1 H. J I 6.6. 11.5 Hz). 2.96 (dt. 1 H. J I 5.8. 6.0 Hz). 4.94 (dd. 1 H. J I 1.2. 10.1 Hz). 5.00 (dd. 1 H. J I 1.2. 17.1 Hz). 5.79 (ddt. 1 H. .I - 10.1. 17.1.6.7 Hz): ”C NMR (75.5 MHZ) (CDClg) 6 20.6. 21.0. 28.3. 30.7. 32.7. 41.9. 56.5. 61.5. 115.1. 138.7: 1R (neat) 3349. 3077. 2955. 2870. 2011. 1642. 1470. 1387. (31) in situ reduction of rearrangements catalvzed by TiCl. were performed at -78 °C to word reduction or the alkene functionality by titanium hydride species. 149 J Org. Chem. Vol. 57. No. 2. I992 467 1366. 1138. 993. 911 cm“. Anal. Calcd for C.;HnN: C. 79.49: H. 12.79: N. 7.72 Found: C. 79.17: H. 12.70: N. 7.68. Preparation of N -Allv1-N -cyclopenty1a.mina. Allylamine (5.71 g. 100 mmol). cyclopentanone (8.41 g. 100 mmol). and heneene (300 mL) were added to a flask fitted witha Dean-Stark trap. and the solution was then heated at reflux for 15 h. The water was drsined from the trap. and 4-A molecular sieves were added. Reflux was continued for 2 h more to remove the final traces of water from the reaction mixture. The benzene was removed by distillation. and the remaining oil wm isolated via Kugelrohr distillation to give N-allylcyclopsntylidsnsamine (ace g. 66 mmol) in 66% yield (50-70 °C (10-15 mmHg)). ToasmpsmionofLS2g(48mmol)LiAlH.ianLofEth wmadded4.93g(40mmol)ol'N- solution was stirred for 4 h at ambient temperatureand wmthsn quenchedwith 1.8de1110. followsdby 1.8de15‘5 aquam- NaOH. and then by 5.4 ml. of H20. After being stirred for 1 h. the solution was filtered to remove the aluminum salts and the solvent concentrated to an oil. which w. distilled under vacuum to give N-allyl-N-cyclopentylamine (4.36 g. 35 mmol) in 87 % yield (60-70 °C (15 mmHg)): lH NMR (300 MHa)(CDC13)61.28(m. 2 H). 1.50 (m. 3 H). 1.64 (m. 2 H). 1.81 (m. 2 H). 3.06 (tt. 1 H. J I 6.7. 6.8 Hz). 3.20 (ddd. 2 H. J I 1.2. 1.2. 6.1 Hz). 5.03 (ddt. 1 H. J I 1.3. 10.2. 1.2 Hz). 5.12 (ddt. 1 H.J I 1.3. 17.1. 1.2 Hz). 5.89 (ddt. 1 H. J I 10.2. 17.1. 6.1 Hz): uC NMR (75.5 MHz) (CDCl.) 6 24.0. 33.1. 51.3. 59.2. 115.5. 137.2. N -Allyl-N -laobutylcyclopenty1amine (27). To a solution of N-allyl-Ncyclopentylamine (3.76 g. 1!) mmol) and triethylamine (3.33 g. 33 mmol) was added isobutyryl chloride (3.20 g. 30 mmol) dropwise. The solution was stirred at ambient temperature for .5 h and then filtered through a pad of silica. Removal of solvent produced an oil. which was isolated via Kugelrohr distillation to give .V-allyl-N-cyclopentylisobutyramide (5.14 g. 26.4 mmol) in 88% yield (75-85 °C (<1 mmHg)). Toasuspension ofLiAlH. (0.912 g.24 mmol) in 1mmLoftho was added N-sllyl-N-cyclopentylisobutyramfle (4.1!) g. 20.4 mmol) in a dropwise manner. After addition wm complete. the solution was stirred at ambient temperature for 2 h. The reaction we quenched by addition of 0.9 ml. of H10. followed by 0.9 ml. of 15% aqueous NaOH. followed by 2.7 ml. of HgO. and was then stirred for 1 h. After removal of solids by filtration. the solvent was removed and the resulting oil was isolated via Kugelrohr distillation to give 27 (3.27 g. 20.4 mmol) in quantitative yield (50-65 ’C (4 mmHg)): ‘H NMR (300 MHz) (CDCl,) 6 0.64 (d. 6 H. J I 6.6 Hz). 1.35 (m. 2 H). 1.45 (m. 2 H). 1.59 (m. 2 H). 1.70 (m. 3 H). 2.14 (d. 2 H. J I 7.1Hz). 3.00(tt.1H.J I 7.3. 7.4. Hz). 3.11 (ddd. 2 H. J I 1.9. 2.1.6.4 Hz). 5.04 (ddt. 1 H. J I 1.6. 10.2. 2.1 Hz). 5.121ddt. 1 H. J I 1.7. 17.1. 1.9 Hz). 5.87 (ddt. 1 H. J I 10.2. 17.1. 6.4 Hz); “C NMR1755 MHz) (CDC1.)6 21.0. 24.1. ‘69. 29.2. 55.7. 59.5 63 4 116.1 136.8. Anal. Calcd forCanN: C. 79.:48 H. 12. 79. N. ..72 .Found: C. 79.36. H. 12. 79: N.7.99. Acknowledgment. We are grateful to Michigan State University for financial support of this research. Michigan State University is gratefully acknowledged for a College of Natural Sciences Research Fellowship to N.S.B. Spectral product characterization wm performed on NMR instrumentation purchased in part with funds from NIH grant 1-SlO-RR04750-01 and from NSF grant CHE-88- 00770. Registry No. 4. 69882-86-6: 7. 135535-73-8: 6. 135535-74-9: 9.137496-49-2: 16. 135535-761: 11. 137496-505: 12. 13745-516: 13.137496-52-7: 14. 137515-62-9: 16.1374m-53-8; 16.13743-64-9: 17. 135535910: 18. 137496-550: 19. 13743561; so. 13745572 21. 135535-896: 22. 137496-583: cis-22. 137496-594: trons-23. 137496-630: 24. 135535-909. 25. 1374966”: tie-26. 137496-616: trans-26. 137496-644: 27. 135535-807; HgNCH3CH-CH3. 107- 11-9. i-PrCHO. 78-84-2:i-PrCOC1. 79-30-1: C.H.£OCL 2719-27-9. MMC'g. 75-24-1; HCl. 7647-01-0: TiCL. 7550-45-0; 8610-383. 109-63-7: bis(2.6-diphenylphenoxy)TiCl,. 110M616; N-allyl- N-cyclopentylamine. 55611-39-7: cyclopentanone. 120-92-3: al- lvlcyclopentylideneamine. 30533-03-0: N-allyl-N-cyclopsntyliso- butyramide. 137496-62-9. 7133 tinted from The Journal of Organic Chemistry. 1992. Vol. 57. Coma: G) 1999 by the American Chemical Society and reprinted by permission of the copyright owner. Studies of the Regiospecific 3-Aza-Cope Rearrangement Promoted by Electrophilic Reagents NancyS. Barta.GregoryR.Cook.MargaretS.Landis.andJohnR.Stills' Department of Chemistry. Michigan State University. East Lansing. Michigan 46994 Received August 6. 1992 Thai)- ass-Cops rsarrangsmentof N-slhyl-N-allyl enamine substrates. which aired temperamduo 'CtoprocssdthermallymsspromotedstIll’Cintheprmsncsof M mad-H0105”; rsgiosslsctivityof electrophilic “C1. (0... “ equiv). AlMe, (1. 2 equiv). or (ArO),AlMe (1. 2 equiv). In order to probe the accelerated carbon-carbon bond forming process under these reaction conditions. several enamine cyclohexanone. werspreparsdfrombothisobutyraldehydsand Eachnibstratet-sdinthsassnidimw- havinganunsymmstrical N allylic group. substituted with eitheranalkylorphsnyl substituentatths4cr9 pcsitionofths3-ua-Copsframeworh. lnallcassssaaminsd.reactionaccelerationbyths electrophilic“. WMI3.3|WmmscumpcndimimmsnpmdmmM[u1m werenot observed. Hydride reduction of the rssultmg imines gensratedtheu-unsaturatedaminasinw-fli wmflyisumthemreesupmndsmdu-mmngemt-redmfionpmhomtbumndandm Introduction Regiochemical control is an essential feature of any successful carbon-carbon bond forming process. and in- tramolecular approaches have been important strategies for achieving regioselective methodologies. A prominent example of this strategy has been the Claisen rearrange- ment. the [3.3] sigmatropic shift of allyl enol ether sub- strates (l. RLX I 0 Scheme l).‘ in a sense. this reaction constitutes a concerted SN2’ allylation of a carbonyl de- rivative. and such intramolecular thermal rearrangement have led to regiospecific carbon-carbon bond formation. Thermal 3-aza-Cope rearrangement of N-alkyl-N-allyl enamine substrates (1. X I N). the nitrogen analog ofthe Claisen rearrangement. also resulted in regiospecific for- mation of 5 after hydrolysis.2 Because the Claisen and 3-aza-Cope rearrangements typically proceed at tempera- tures ranging from 180 to 250 °C. studies have been di- rected toward acceleration of these reactions in order to promote substrate rearrangement at lower reaction tem- peratures.‘| Acceleration of the [3 .3] sigmatropic rearrangement of allyl vinyl ethers having unsymmetrical allyl groups ha been achieved primarily through the use of stoichiometric aluminum reagents. One group of aluminum reagents. the di- and triallrylaluminum complexes including EW. AlMe3. and Al(iBu)3. has produced regiospecific rear- rangement of substrates followed by reduction of the re- sulting carbonyl functionality.‘ In addition to alkyl substitution on the allyl group (R‘ or R‘ I alkyl). regios- pecific [3.3] rearrangement occurred even when R‘ I (1) Forrevrewsonl33| icrsarrsngsmsntssss: (s)Rhoads. S. J.; RaulirmN ..R.Org React.(N...Y)1915.22.1(b)Zisgler. P. fiAcc. Chem. Res. 1917.10.227. (clasnnsttG. 8. Synthesis 1911.5”. (d) Bartlett. P. A. Tetrahedron 1999. as. 3. (s) Gajswshi. J. Hydrocarbon Thermal lsomerisations: Academic: New Yorh.1991. (1) Hill. R. K. Chirality Transfer via Sigmatropic Rearrangements. 1n Asymmetric SynthesisiMorrh-J. D.. Ed.; Academe NewYothm; V013. pm (g) Ziegler. P. B. ChemReo.1999.88. 1423. (h)Blschsrt.S Synthesis 1999 . (2) For reviews on are-(3.3] sigmatrop ic rsarrangsmen tease: (a) Winterfeldt. B. Fortshr. Chem. Forsch. 1971. 16. 75. (b) How. H.; Hansen.H..;-J Schmid.H.Adu. Org. Chem. 1919.9. Part2.p955. (3) ForreviswsonthecatalysisonthsCopsandClaisenrsarrsngr msots.sss: (a)l.utx.R. P. Chem. Rev. 1994. 84. 205. (b)0vsrmaa.l. E. Angew.Chem..Int. Edingl. 1994.23. 579. (4) (s)Tahai.K.: Mori.1.;0shima. K.; Norah. H. Tetrahedron Lett. 1991. 22. M5. (b)Stevsnaon.J. W 3.. Bryson.T. ATetmhedronLett. 1999. 23. 3143. (c) Mori.1.;Tahai. K.; Oshima. K.; Nosahi. H. Tetrahe- dron1994. 40. 4013. (d)Tahai. K.; Mori.1.; 0shima.K.: NoeahiH. Bull. Chem. Soc. Jpn. [$4.57. 446. (e) Piers. E; Flemir'. F. 1". J. Chem.Soc.. Chem. Commun. 1999. 1666. (f) Paquette. 1.. A.; Prisdrich.D.; Rogers. R. D. J. Org. Chem. 1991. 56. 3941. (g) Philippa. C. M. 0.. Vo. N. H.; Paquette. 1.. A. J. Am. Chem. Soc. 1991. 113. 2762. 0022-3263 / 92 / 1957-7188503.00/0 Scheme 1. Approaches to the Allylatlaa sf Carbonyl Derivatives Pb.” Recantadvancssinthissrsahavebsmrsportsd forreagentsofthszArO),AlMs‘mwsllmthsclosaly relatedbinaptholrsagent. whichpromotsdrearrangsmsnt at temperatures as low as -78 '0 without subsequent re- duction of the carbonyl product.‘ However. al complete [3.31rearrangemsn twmachisvedwithR‘orR‘ substratssha' (5)(s)Mamoha.K.;Noneshita.K.;Bano. Chem.Soc. 1999.110. 7921. (”WK-.1 Yamamoto.l-1. 1 (8)(a)Maruoha.K.: BsnnaH.;Yamuaoto.H.J.Am.ChemSoe. 1999.112.7791.(b)Maruoha.K.;8anno.H.;Yalaameto.1£Tsn'ahe- mgr-yam 19911947. (c)Mluoha.K-;Y_~.H.8ynlm4 1991 " G 1992 American Chemical Society 150 ngiospecific 3-Asa-Cops Rearrangement of both [1.3] and [3.3] rearrangement. A nonconcerted reaction was proposed in which initial bond breakage generated ionic intermediate 2 followed by recombination to give the observed product distribution. Regiospecific [3.3] rearrangement of 1 (R' I H. RLX I 0). in which regiochemical control was proposed to result from initial C-C bond formation followed by C-O bond cleavage. has also been promoted by Pd(11) catalysis.1 A different re- action pathway was followed for the tetrahydrofuran substrates (R‘ I C0,Et. R‘R‘ I -CH,CH,-). which gen- erated products of [1.3] and [3.3] rearrangement resulthig from r-allylpalladium intermediates! Comparatively. the 3-asa-Cope reaction has been in- vestigated far less extensively than the Claisen rear- rangement. In part. the high temperatures required for thermal rearrangement when X I N (250 °C)” or with N-allyl-N.O-kstsne acetal substrates (R2 I OR. 180 'C)” has placed limitations on this synthetic method. Charge acceleration of the 3-aaa-Cope rearrangement. by quater- ' niaation of the nitrogen (4). has been accomplished by allylationofdialkylenaminesubsmtesi3.x I N). When crotyl bromide (11‘ I Me) was used to alkylate dialkyl enamine substrates in which R‘.R" at H. products from initial N-alkylation (4) and subsequent [3.3] rearrangement produced 5 after hydrolysis.” However. when enamines derived from cyclopentanone.)2 cyclohexanone.” or buta- nal“ were treated with crotyl bromide. the products of C-alkylation (6) contributed from 10 to 100% of the final reaction mixture. Studies of unsymmetrical allyl sub- straws were limited to the crotyl group. and have not included substrates with R‘ I alkyl. Acceleration of the 3-aza-Cope rearrangement has been achieved with titanium catalysts. and substrates having unsymmetrical allyl groups were investigated.“ Both reports studied the rearrangement of enamines in which R‘.R" I H. In an example having R‘ I Me. 1 was transformed regiospecifically to 5 as a 90:10 ratio of E:Z olefin isomers!“ In contrast. acceleration of the 3-axa- Cops rearrangement by reaction with PdfPPhg./CF,CO,H proceeded through a e-allyl intermediate. and only prod- uctsof [1.3] rearrangementwere observed when R‘ I Ms.“ Recently. we reported the electrophile-promoted 3-axa- Cops rearrangement for N-alkyl-N-allyl enamine sub- strates." In these studies. the effectiveness of protic and (7) (a) Oshima. M.; Murakami. M.; Mukaiyama. T. Chem. Lett. 1994. 1535. (b) van der Bean. .1. L.; Bickslhaupt. 1". Tetrahedron Lett. 1999. 27. 6267. (c) Mikami. K.; Takahashi. K.; Nakai. T. Tetrahedron Lett. 1991. 28. 5879. (d) Haymhi. T.; Yamamoto. A.; lto. Y. Synth. Commun. 1999. 19. 2109. (8) (a) Trost. B. M.; Rungs. T. A.; Junghsim. L N. J. Am. Chem. Soc. 1999. 102. 2940. (b) Trost. B. M.; Jungheim. L. N. J. Am. Chem. Soc. 190. 102. 7910. (c) Tsuji. J.; Kobayashi. Y.; Kataoka. H.; Takahashi. ‘1‘. Tetrahedron Lett. 1944. 21. 1475. (d) Trost. B. M.; Runes. ’1‘. A. J. Am. Chem. Soc. 1991.11”. 2499. (e)'1‘rcst. B. M.; Runs. '1‘. A. J. Am. Chem. Soc. 1991. 109. 7590. (9) 11111. R K.: Gilman. N. W. Tetrahedron Lett. 1941. 1421. (10) (a) Corbisr. J.; Crsmon. P.: Jslsnc. P. C. R. Acad. Sci. Paris 1919. 0270. 190. (b) inland. R. B.; Willard. A. K. J. Org. Chem. 1974. 39. 421. (c) Kurth. M. J.; Decker. O. H. W. J. Org. Chem. 1999. 51. 1377. and geese-03 therein (11) Kurth. M. J.; Scares. C. J. Tetrahedron Lett. 1447. . 1 1. (11) (a) OpitI. G.; Mildenberger. H. Angew. Chem. 1999. 72. 199. (b) Brannock. K C.; B ' R. D. J. Org. Chem. 1941. N. 3579. (c) 0pite. G.; Hsllmann. H.; M . H.; Suhr. H. Liebigs Ann. Chem. 1991. 649. 39. (d) McCurry. P. M.. Jr.; Singh. R. K. Tetrahedron Lett. 1979. 3325. 9112), 0pit4. G.; Mildew . H.; Stills. H. Liebigs Ann. Chem. 1991. 94 4 (13) (a) 0pita. G. Liebigs Ann. Chem. 1991. 650.122. (b) Houdewind. P.; Pandit. U.K. Tetrahedron Lett. 1974. 2359. (14) OpitI. G.; Mildenberger. H. Liebigs Ann. Chem. 1991. 649. 29. (15) (a) Hill. R. K.; Khatri. H. N. Tetrahedron Lett. 1979. 4387. (b) Bailey. P. D.; Harrison. M. J. Tetrahedron Lett. 1999. so. 5341. (19) (a) Micah-H. S.-1.:Mahabs. Y. Tetrahedron Lett. 1999. 25. 5563. (b) Murahmbi. S.-1.; Makabs. Y.; Kunita. K. J. Org. Chem. 1999. 53. 4499. 151 J. Org. Chem. Vol. 57. No. 26. 1992 7199 Lewis acids in sceeleratiru the management of subsn-ates was examined for a variety of enamine substitution pat- terns: a symmetrical allyl group was used in each case. A study of the regiochemical selectivity of this charge-ac- celerated reaction. with respect to the [1.3) or [3.3] nature of this rearrangement. is presented. Acceleration of the 3-aaa-Cope rearrangement with HCl. TiCL. AlMe3. and (ArOhAlMe was examined for substrates derived from isobutyraldehyde and cyclohexanone and having a phenyl or alkyl substituent at the R‘ (allylic) or R‘ (terminal vinylic) position. Results and Discussion In order to examine the ' ° ' d the 9am-Cops rearrangement with aldehyde derived N-alkyl-N-allyl sn- aminesubstrates. twopairsofenaminssubstratsswsrs selected. Onspairbadn-PI'OPYUnPrhutntittmtsatths allylicandterminalvinylicpositiomwhilsthscthsrpair had phenyl substituents at those positions (Scheme 11). Rearrangementofthesesubtl’atmthrm'ha [3.3] procms wouldtransform llto 13and 12to14. flimsrelatedsets of enamine substrates were designed so that if [1.3] rear- rangement occurred to any extent during the charge-ac- celerated rearrangement. then 11 would produce 14. and the rearrangement of 12 would give 19. In order to gen- erate substrates 11 and 12 by enamine condensation with isobutyraldehyde. amines 9 and 10 were prepared. Synthesis of the required secondary amines was accom- plished using several different routes. The amines sub- stimtedintheallylicpcsitiondaandfimersmadsfrcm products obtained through Overman's 1.3 transposition of alcohol and amine functionality (eq 1).u The hydrolysis C), m 12'. m, A“... m (1) N N tin-at. a” up 7 9 9 a new 99.9?) of7a produced9mwhichwmthenalkylatedbyssqusntial trsaunentwith isobutyraldehydeandthenlJAll'Ltoyield 9a. In a similar manner. imine formation followed by reductiongave9bfrom9hin81% yield. Secondaryamins 10s was obtained in 86% overall yield by tosylation of 2-hexen-1-ol and subsequent reaction with isobutylamine (eq 2). The reduction of the imine formed from unannent of cinnamaldehyds with isobutylamine provided 10b (eq 3). (611‘ on 3'73 or. own. NH -—):——. -—-—-. Kb (2) / nPr / oh oh 1“ 0 less). m‘n ”w Im‘nn (3) it that. 1“ Formation of enamines 11 and 12 wu most effectively accomplishsdbythsreactionof9or19withisobutyr- aldehyde and stOH in benzene. and the condensation was driven to completion by azeotropic removal of 11.0. Under these conditions. conversion of 9a to 11s we achieved without formation of 19a or 14a. Amine 19a required the use of toluene as the solvent for effective formation of 12a. and production of 14a as a result of (17) (a) Cook. 6. R.; Stille. J. R. J. Cook. G. R.; Berta. N. 8.; Stille. J. R. J. . Chem. 1991. 59. 9679. (b) . Chem. 1992. 57. 491. 7190 J. Org. Chem, Vol. 57. No. 26, 1992 Scheme 11. Charge-Accelerated Rearrangement of N-Alhyl-N-allyl Enamine Substrates .3u\ NH RV H‘ 1W“ 0 ”.1 H‘ W Me 180 . my" 3"». \ ”‘ JV M. 17 R 133 I. M. Me vs 12 11.31,." :(x (3.31 Home ' \ Me .../91,“, SUV .. 1:1 11 \ \ n 14 noun. 1)L1NH. 21'4“. 2) NIOH. up 14,0 Me Me WU“. 'Buxt‘ctm 13 n \ \ a 15 . Rmflpf b Raph catalysis by stOH at these higher temperatures was not observed. Complications arose with the condensation of isobutyraldehyde with 911; under the conditions used to generate the enamine in benzene at reflux (80 'C). facile rearrangement of 11b to 1311 occurred. Although a solution of 11b was never obtained for separate rearrangement studies. the regiochemistry of this two-step process. the condensation reaction coupled to the sigmatropic rear- rangement. was investigated for selected catalysts. In contrast to the reactivity observed for 9h. formation of 12b from 10b was achieved through azeotropic removal of H20 with benzene; even with the use of toluene as solvent. heating the mixture at reflux in the presence of stOH did not promote rearrangement of 14b. In preparation for the rearrangement studies. benzene was removed in vacuo from substrates 11a and 12 and replaced with toluene. Rearrangement of 11a and 12a was investigated using the three types of reagents previously reported to effi- ciently promote the 3-aza-Cope rearrangement (Table 1).” The reagents examined in this regiochemicel study were theproticacidHCl (0.5equ1v) the metalhalideLewisacid catalyst TiCl. (0. 2 equiv). and the organoaluminum com- plexee AlMe, and [bis(2, 6-diphenylphenoxy)methyl]alu- minum. which were required' in a stoichiometric amount to achieve complete conversion of substrate to product. In each case. heating the substrate and reagent to reflux in (19) Overman. 1.. E. J. Am. Chem. Soc. 1979. Q. 2901. (19) Compound lhcouldahobeprepered inamannsrsimilartothat illustrated in Scheme 111. Hydrolysis of the appropriate trichloroacet- amide. “ followed by condensation with isobutyraldehyde and acylation with isobutyryl chloride produced the corresponding enamide. LiAlH. reductiongaveenamine 12a. Thissourceof 12awasusedfortherear- rangement studies with TiCl. and (Arc) AlMe. 152 Bartaetal. Table 1. Regiaepecifie J-Aza-Cepe Rearrangement and Reduction of 11 and 12 conditions‘ substrate‘ reagent‘ temp ('CH 19: 19‘ yield (5 1‘ 11a HCl 9/111 >se.1 es TiCl. 24/111 >993! 79 AlMe3 24/111 >99“ m (ArOlgAlMJ 24/111 >911 91 12. HCl 30]!“ 1:)” 79 TiCL (”I 11.1 1:)“ 7’ AIM” 8/111 1:)“ 97 (AlOlgAlW 30/111 1999 w 1 1b HCl 49]” *1 91 stOH 49]” >991! fl TiCl. 49]” m1 N 135 HCl 24]!“ h TiCl. 24/111 1 AIM” 5/111 11>” 59 (AIOHAW 19/111 1:)” 55 'Subetratssweregeneratedineitubycondensatienof9or19 with isobutyraldehyde in either benaene or toluene catalysed by stOH. ’Reagent (equiv): HCl (0.9). pTeOH (0.09). TiCL (0.2). AlMe, (1.1). and (ArO),AlMe (1.1). ‘ Resumes-cam were run 0.2 M at reflux in toluene (111 ‘C) or beans (00 °C). ‘In eachcase. the product of [1.3) rearrangement wm not detected by ‘H NMR or capillary GC. 'Overall isolated yield of condensed. and reduced products from 9 or 10. ’ArO I Mphenfiphsnasy. 'See ref 19. "Destruction ofstartirg mateth ‘i’ormationofuor l4 wu not observed. toluene promoted regiospecific rearrangement of 11a to 13aand 12sto 14a(SchemeII)." Reductionoftheimines produced 15a and 19a. respectively. which were then iso- lated in 61-87% yield for the three-step condensation- rearrangement—reduction process from 9a and 10a. As a result of the rearrangement and reduction of 11a. only the E alkene isomer of 15a was observed. Evidence for the formation of the E isomer was the characteristic E alkene absorbance at 970 cm", and the absence of the corre- sponding Z alkene abaorbance around 690 cm". Inter- esdngly.atreactiontimesinsuficienttoproducecomp1ete conversionof12ato l4a.reductitmofthereactionmixnne generated from 12a with 11C] or TiCl. resulted in forma- tion of small amounts of 17a (eq 4).” Evidence of [1.3] Ck H Bu 9 MI flu M. \N’ rims. ‘N/\< ‘ NM; .1... Me ——— m (1 / mason. / it?! up oh 179 rearrangement through an intermediate such as 2 or by a [1. 3] sigmatropic shift. by formation of 14 from 11 or 19 from 12.wasnotdetected bycapillarygaschromatcgraphy or ‘H NMR spectral analys is. The phenyl-substituted ”allyl substrates. 11b and 1211. also rearranged to give exclusive formation of [3.31 Prod- ucts 13b and 14b. respectively. but these substrates were muchmoresensitivetothereutionconditions. Aphenyl substituent in the allylic position produced significant acceleration of the reaction. During the condenmtion of 9b to 1111. facile rearrangement to 1811 was promoted by either HCl or stOH in benzene at so °C. Because 11b could not be isolated. the charge-accelerated 3-aza-Cope reanangement of 11b was not examined. However. the ureoftheTiChreactionconditionsreportedbyHilLen- (20) FordiscusaionsefN vereusC-protaimtieaef mean (at Hickman. P. W. Tetrahedron 1992. 39.1979. (bl Hie-an. R. I. Tetra- hedron 1999. 24. 185. and references therein. Regiospecific 8-Aza.Cope Rearrangement Scheme III. The Synthetic Reuse to 22 C31: on n €1.ch HN’KO VFW " ' ' "_'- vna“ 19 (mm. ""1 / K -W 20 um. N51) amine formation driven by 0.25 equiv TiCl. and subse- quent 3-aza-Cope rearrangement accelerated by the product(s) of the TiCl. with 1 equiv of H30 (generated during the enamine condensation). could be tested. Thus same conditions also produced 13b stereospecifically from 9b. For each catalyst studied. the condensation. rear- rangement. and reduction of 9b produced only the E olefin isomerof15b.mevidenced bythe l9Hzcouplingconstsnt measured for the olef’inic protons. Substrate 12b. which was prepared by condemtion of 10b in benzene, was very sensitive to the conditions for promoting rearrangement due to the styrene-like moiety in the molecule. Treatment with HCl (80 ‘C) or TiCl. (80 or 111 '0) resulted only in the destruction of 12b without formation of 12b or 14b. and stOH would not cause rearrangement at 111 '0. However. both organoaluminum catalysts effectiwa gen- erated 14b at 111 °C. and reduction with LiAlH. gave exclusively 16b in moderate yield. In order to examine the regiospecificity ofthe San-Cope rearrangement with enamines derived from ketones. sub- strate 23 was prepared by the route illustrated in Scheme 111. Although enamine formation by condensation of cyclohexanone with the corresponding secondary amine could not be used to obtain 23. the reaction of cyclo- hexanone with 20 efficiently produced 21. Acylation of 21 withbohrtyrylchhride/NEanveninfl‘h yieldforths two-step process from 20. and LiAlH. reduction of 22 generated the desired enamine substrate 23. The rear- rangementcf29t024wmacceleratedbyeechofthefour electrophilic reagents listed in Table II. and subsequent treatment of the ketimine with iBu,AlH gave 29 as a mixtureoftwocompoundshq 9). Analysisofthein- a“\~’©’~w ‘1 M“ 1 ‘Cc wlep as termediate reaction mixture revealed that rearrangement occurred in a regiospecific manner to generate a mixture 153 J. Org. Chem.. Vol. 57. No. as. 1992 7191 Table 11. Regioeeecifle 9-Aas-Cepe Ream 1a Reduction of 29 reactiim 29 time‘ di-teream- yield reagent‘ (h) ratif (%1‘ H01 24 94:49 N TiCl. 49 99:49 72 e, 24 97:92 94 (NOW 24 77:22 79 ‘Reuent (equiv): HCl (1.0). T101. (0.19). All“. (1.1). end (ArO),AlMe(1.1). ' wmenmuhlasnhxia toluene. ‘Ratiodsterminedby‘l'lm ‘hdatedyieldofreo Mnegedandreduaedproductsflfromfl. mic-m xy. ofdimtereomericiminm(24).andthmlwdrldersductim1 with iBu,Ali-Iwasdirsctsdcompletelybythebulkya- iminesuhstitnenttostereoeelecuvelypraducefl asthe samemixtureofallylicdiastereomers. Summary The value of the electrophile-promoted 9-aaa-Cope re- arrangement is evident from the unique features of this process. Therehavebeenanumberofproblsrmtypically associated with the 3-aza-Cope rearrangement. One of theselimitationshasbeenthelechofregimpea’ficcar— hon-carbon bond formation by systmm such a allylation of dialkylenamines derived from ketones as well as the rearrangement promoted by Pd catalysis. In addition. problems have been encountered with enunine euhetratm derived from ketones. Ketone-derived enamines produce low yields from in situ titanium condensation and reu- rangement. andthe regimelecuvity minim fran enamine allylation was poor. The inability to stereoepecifically produce E olefins from dialhyl enamine allylation has she provided a limitation. and the in situ titanium reaction produced only a 90:10 ratio of E:Z olefin isomer-a Acceleration of the 3-azs-Cope new with HCI. TiCL. AlMe3. or (ArO)2AlMe providedm a complementary method to these procedures. Whensubetratas haviu unsymmetrical N-allyl groups. having an alkyl or aryl substituent at either the 4 or 6 position ofths rearrange- ment framework. were treated with these electrophilic reagents. regiospecific [3,3] rearrangement occurred. Substrates derived from either isobutyraldehyde or cy- clohexanone were found to produce regiospecific carbon- carbon bond formation. and for substrates with an alkyl or phenyl substituent at 04. only the E M isomer wm produced. The use of the aluminum reagents. especially AlMe3. was particularly advantageous. AlMe, the 3—aza-Cope rearrangement with the highest yields for each of the enamine substrates obtained. standardinertatmospheretechniqueetoexciudemoisnireand oxygen!l Benzene. toluene tetrabydrofm'anfl'I-Il"). andEth weredistilledfromsodium/benaophenoneimmediatalypriorto use. Triethylaminewmheatsdatrefluxovercalcimuhydride foraminimumof12handthendhtilledimmedhte1y Co. (ArO),AlMewasprepared WW (2.0squiv) intoiuene(2M)folloIedbythedowdditindAlhb. (ZiiPormoredetailsdGenerallxparb-talpremhesnumthme labs.seeref17b. 154 7192 J. Org. Chem. Vol. 57. No. 26. I992 (1.0sqflv);thsmixunewmetirredatmomtemperatinefor30-60 min prior to addition to the enamine solution.‘ Compound 19 was prepared according to a literature procedure." Unless specified. concentration of mixtures after workup w. performed using a Buchi rotary evaporator. 3—(N-(Zohlethylprep-l-yl)amine)o1-bexene (ea). Tri- chloroecttamide7a(25g.102mmol)”washydmlyssdin Mml. of6NNa0Hfor48h. Theorganicportionwmexu'actedining 3 x 1mmLofEt.O.andthssolutionwucarefullyconcenu-atsd onsrotaryevspmatabelow0°0 Afl-hccntainimthsraulting amine. 5a. and isobutyraldehyde (7.3 g. 101 mmol) in benssne (Mwwmeqinppedsn'thaDean-Starkuspthatcontained4-A molecularsievse. Themixturewasheatsdtorefluxuntilimins formation was complete. Solid LiAlH. (3.86 g. 102 mmol) was addedslowlyover20minat0‘C.thssolutionwasstirredfor1 h. and than AlMa, (25.4 mi... 2.0 M in toluene. 50.8 mmol) w- addeddropw'msviscannulnoveraperiodofwminatO’C. Alter 24h.thssolutionwmqusnchsdat0‘bethsssqusnu'sladditimi of 4.0 m1. of H,O. 4.0 mL of 15% w/v aqueous NaOH. and 12.0 mLofH,0.sndthenthemixturewasstirredfor4h. The aluminum salts were removed by filtration. and the combined filtratsandwashingswersconcentratedanddistiiled (80'C.35 mmHg)togive9a(3.2g.20.5mmol) inm‘l. overallyield;‘HNMR (300 MHLCDCI.) 50.86 (d.J I 6.6 Hz. 6 H). 0.87 (t.J I 6.9 Hz. 3 H). 1.2-1.5 (m. 4 H). 1.65 (nonet. J I 6.6 Hz. 1 H). 2.26 (dd. J I 11.5.6.6 Hz. 1 H). 2.38 (dd.J I 11.5. 7.1 Hz. 1 H). 2.90 (dt. J I 5.5. 7.5 Hz. 1 H). 4.98—5.07 (m. 2 H). 5.53 (ddd. J I 17.6. 9.5. 8.1 Hz. 1 H). NH not observed: l3(3 NMR (75.5 MHz. CDCl,) 5 14.1. 19.1. 20.7. 20.8. 28.4. 37.9. 55.4. 61.8. 115.3. 141.9: almost) 3337. 3077. 2959. 2872. 1641,1117 cm"; HRMS calcd for CanN m/r (MH’) 156.1676. found 156.1762. 3-(N-(2-Methylprep-l-yl)amino)-3-phsnyl-l-prepsne (9b). A flaskcontainime (7.0g. 53 mmol)" and isobutylaldahyde(3.79 g. 53 mmol) in benzene (0.2 M) was equipped with a Dean-Stark napthatcontained4-Amolecularsieves. Themixturewmheated at reflux for 2 h until imine formation was complete as judged by gas chromatographic analysis. Solid LiAll-L (2.0 g. 53 mmol) was added at 0 ‘C. and the mixture was warmed to room tem- perature and stirred for 10 h. The reaction was quenched at 0 °C by the sequential addition of 2.0 m1. of H20. 2.0 m1. of 15% w/v aqueous NaOH. and 6.0 m1. of H,O. After stirring for 4 h. thealuminmsaltswereremovdbyfiltrationandthecombined filtrate and washings were concentrated and distilled to give 9b (8.1 g. 42.8 mmol) in 81% yield (65 °C. <1 mmHg): ‘H NMR (300 MHz. CDCl,) 6 0.89 (d. J I 6.6 Hz. 6 H). 1.34 (be. 1 H). 1.65 (nonst. J I 6.6 Hz. 1 H). 2.19 (dd. J I 6.9. 11.4 Hz. 1 H). 2.35 (dd.J I 6.6. 11.4 Hx. l H). 4.14 (d. J I 7.1 Hz. 1 H). 5.06 (ddd. J I 0.9. 1.5. 10.1 Hz. 1 H). 5.19 (dt. J I 17.1. 1.6 Hz. 1 H). 5.85 (ddd.J I 7.1. 10.1. 17.1 H2. 1 H). 7.22-7.39 (m. 5 1'1): uC NMR (75.5 MHz. CDCl;) 5 20.67. 20.72. 28.4. 55.6. 66.2. 114.7. 127.0. 127.2. 128.2. 141.4. 143.2; IR (neat) 3310. 3027. 2955. 2870. 1620. 1116 cm“: HRMS calcd for C.;H.,N m/z 189.1513. found 189.1520. (B)-l-(N-(z-Methylprep-1-yl)amino)hex-2-ene (10s). A small amount of 1.10-phenanthraline was added to a solution of 2-hsxen-1-ol (4.01 g. 40 mmol) in 250 m1. of THF.” The solution was cooled to -78 'C. and n-BuLi (28 ml... 1.6 M in hexanea) was addeduntilthsorange.1.10-phenanthralsnssndpointwmvisihh. Tosyl chloride (7.63 g. 40 mmol) wu added in a single portion. andthemixturswmstirrsdat-78 °C for72h. Thereactionwm workadupbydilutingwith500mLofcoldpetroleumethsr.and wmhimwith2 x INmLofoold50‘l. saturatedaqusotn NaHCO, followed by 1 x 100 ml. of saturated aqueoin NaHC03. The aqueous lsysrwerecombinedandextracted with 1 x 70mLof petroleumethermndthecombinedorgsnicfractionsweredried over K,CO,. After filtration and concentration of the mixture. thetosylatewestaksnupin200mLofEt,0.dried.filtered.end concentratedinthesamemanner. Thecrudetoaylstewasthsn added to isobutylamine (17.5 g. 240 mol) at 0 'C. and stirred atroomtemperatursfor24h. Excemisobutylsminewmrsmoved invacuo.andtheremainingoilwupurif'iedbyKugelrohrdis- tillation (25 mmHg. 80-100 °C) to give 10a (5.47 g. 35.3 mmol) (22) Porssimilarprocedmase: Kurth.M.J.;Decher.O. H. W.J. Org. Chem. 1985. 50. 5789. Bertaetal. in 68% yield; IH NMR (300 MHz. CDCl,) 4 0.84 (t. J I 7.4 Hz. 3 H). 0.85 (d. J I 6.8 Hz. 6 H). 1.33 (sext. J I 7.4 Hz. 2 H). 1.68 (nonet.JI 6.811;. 1 H). 1.94 (m.2H).2.35(d.JI6.8Hs.2H). 3.12 (d. J I 5.0 Hz. 2 H). 5.40-5.58 (m. 2 H). NH not observed: uC NMR (75.5 MHz. CDCl,) 5 13.6. 20.7. 22.4. 26.3. 34.4. 52.0. 57.5. 128.6. 1323; IR (neat) 3301. 2959. 2872. 2610. 1670. 1121. 970 cm“: HRMS calcd for Owl-lull at]: 155.1”. found 155.1683. (E)-3-(N-(2-Methylprop-1-y1)am1ne)ebenylprep-l~ene (10b). Amixtureofcinnamaldehyde (15 g. 114mmol) andiso- butylsm:ne(8.1g.111mmol) in3flmLofEt10wasstirredovu K.CO.(~15mo.12a Thsmixttirewmllltmsdndthsselib wesswsshsdwith50mLofEtgo. Acaticacidl34g.570mmol) wmaddsdtothecomh'medorganich'actimnandthssohnicnwm stirredatroomtmnpsrannsfcmmin. NaBH.(1.12g.3mmol) wasaddsdslowlyover20minatO'C.andthsmixturswas warmedtoroomtsmperatureandetirredforBh. Thereection waqusnchedatO'C withamixtureofsaturated column chromatographybyalutingthecolumnfirstwithape- troleum ether/31,0 (80:20) toremovs neural-impurities. and thsnwithEQOtogivstheciuda 10b. Slut-pathdistillatiimgave 10b (32 g. 16.9 mmol) in 15% yield (bp 90-95 °C. <1 mmHg): IH NMR (300 MHz. CDC13) 5 0.91(d. J I 6.7 Ha. 6 H). 1.33 (b. 1H).1.76(nonet.JI6.7 Hs.1H).242(d.JI6.7Hs.2H).3.38 (dd. J I 6.3. 1.2 He. 2 H). 6.31 (dt. J I 15.9. 6.2 He. 1 H). 6.51 (bd. J I 15.9 Hz. 1 H). 116-7.39 (m. 5 H): l"C (75.5 We. C170,) 6 20.7. 28.4. 52.1. 57.5. 126.2. 127.2. 128.4. 128.7. 131.0. 137.1: IR (neat) 3316. 30%. 2955. 2870. 2810. 1599. 1119. 966 cm“: HRMS calcd for C.,H.,N m/s 189.1513. found 1U.1510. Preparation of N-(ZoMethylo1-prepenyl)-N-(l')-hex-2- en-l-yI-Z-methylprepanamide. The trichloroacetamide (33.7 mmol. 8.20 g)" was added to 200 m1. of6 N NaOH. and heated etrefluxfor15h. Following theaminewas andtheaqueous layerwuwasbedwith2x 15mLportionsof benzene. The organic layers were combined with 15 m1. of ado ditional benzene. isobutyraldehyde (1% mmol. 7.21 g) w- added. sndthemixtursw'mheatedatrefluxwithansotropicrsmovslof water usingaglass trap containing sieves. W20 h. ErgN (36mmoL5.03mL)wasadded.sndthemixturewu cooledtoO'C. Isobumylchloridewasaddedviasyringeover a10-minperiod. T'hereactionwasthensh’rredfor36h.filtesed throughapadofsilica.andwuhsdwithpstrolsumether. The solvents wereconcsntrsted. and thecrudeenamide wespurifled by column chromatography (1:9 EtOAc/petroleum ethc). Ku- gelrohr distillation (60-70 °C. <1 mmHg) gave 3.26 g of the enamide (44% yield). ‘H NMR (300 MHz. CDCl.) 5 0.83 (t. J I 7.2 Hz. 3 H). 1.01 (d. J I 6.7 1'12. 6 1'1). 1.32(|081.J I 7.2 1‘12. 2 H). 1.54 (s. 3 H). 1.70 (s. 3 H). 1.92 (q. J I 6.9 Hz. 2 H). 2.68 (hept. J I 6.7 Hz. 1 H). 3.91 (d. J I 6.3 1'18. 2 H). 5.35 (dt. J I 15.3. 6.3 Hz. 1 H). 5.47 (dt. J I 15.3. 6.5 He. 1 H). 5.79014. 1 H): uC NMR (75.5 MHz. CDCl:) 5 13.5. 17.6. 19.1. 21.8. 22.2. 31.1. 34.2. 49.3. 123.3. 124.7. 133.8. 135.6. 177.2; IR (neat) 2%7. 2874. 1736. 1653. 1406. 1236. 970 cm“. HRMS mind for C..H.N0 m/z 223.1936. found 223.1940. Preparation of N o(E)-Hex-2an-l-yl-N-(2-methyl-1— prepyl)-2-methylprepenylamine (12a). The enamide (4.0 mmol.0.89g)wsstahenupin5mLofdryEt,O.andLAH(5.0 mmol.5ml..1.0MinTHF)wasaddeddropwiseovera15-min period. After 1.5h.thsmixturewmcoolsdtoO'Candqusnchsd asdescribed fortiuworkupoftbsLiAllhreductiontomshsh. After 1.511. MgSO.wasaddad.andthemixmrewasstirredfor ansdditionalmmin. Thssolidswereremnvedhyfiltration.and themixturewaeconcentrated. Theenaminswaspurifledby Kugelrohrdistillation (60-65'0. <1 mmHg) togive0.83gcf12a (99% yield): ‘H NMR (300 MHz. CDC!) 5 0.82 (d. J I 6.7 He. 6 H). 0.89 (t. J I 7.4 Hz. 3 H). 1.30-1.42 (m. 3 H). 1.58 (s. 3 H). 1.65 (s. 3 H). 1.96 (m. 2 H). 2220!. J I 7.3 Hz. 2 H). 3.“ (d.J I4.3H&2H).5.19(he.110.536—556(III.2H);“CNMR(75.5 MHz. CDClg) ‘ 13.6. 17.7. ”.7. me 22.5. 270‘s 340‘s “’e We 122.4. 128.1. 132.4. 135.7: 111(neat) M. 2313. 1673. 1468. 1377. 1188. 970 cm" (in heptane): HRMS calcd for C..H.-,N m/r 209.2143. found 206.2126. General Procedures fer lsebutyraldshyds Cendsneatisn and 3-Axa-Cepe Rearrangements with 9 and 10. A mixture ofthesscondaryamins(1.0sqdv.2-5mmel.0.2Mlnsolvent). Regiospecific 3oAsa-Cope Rearrangement isobutyraldehyde (3.0 equiv. 6—15 mmol). and stOH (0.0025 equiv) was taken up in benzene (or toluene for 10s) and heated to reflux. The mixture was heated to reflux with azeotropic removalofwater.”sndreactionprogresawasmoniteredbyGLC for disappearance of amine.“ Once the condsrnation was com- plete 112-24 11).” the mixture was cooled to room temperature andthebenssnewmrsmovedin vacuo. Thecrudeenaminewas taken up in toluene (0.2 M). and the appropriate reagent was added at room temperature (see Table 1). After complete rear- rsngemsntinrefluxingteluene.“theiminewasreducsdat0’C by the addition of LiAlH. (1.1 equiv. 1.0 M in THF)." After stirringfor6h.tbersactionwasquenchadbythessquentisi addition of H10 (1 mL/1. 0 g 1.iA1H.).15$ w/v aqueotn NaOH (1mL/1..0g1.iA1H.) andthenH,C (3mL/1.0gLiAli-1.).The quenchedmixturewaastirredatroomtemperatureovernight. filureddumnhKfiogconmnuamdsndpurifiedbyKugelrohr distillation to give the corresponding product of condensation. rearrangement. and reduction (see Table l for yields). (B-l-(N-(thlsthylprop-l-yl)amino)-2.2-dimsthyl-4-octsns (16a): bp 70—1!) '0 (<1 mmHg): lH NMR (300 MHz. CDCl,) 5 0.831s. 6 H). 0.86 (t. J I 7.3 Hz. 3 H). 0.86 (d. J I 6.6 Hz. 6 H). 1.35 (sextet. J I 7.2 Hz. 2 H). 1.72 (nonet. J I 66 Ha. 1 H). 1.87-1.99011. 4 H). 228(1. 2 H). 235 (d. J I 69 Ht. 2 H). 5.35-5.41 (m. 2 H). NH not observed: l’C NMR (75.5 MHz. CDCl,) 5 13.7. 20.6. 22.8. 25.6. 28.0. 34.4. 34.8. 43.4. 59.1. 60.4. 126.9. 132.7: IR (neat) 3352. 2959. 2872. 2810. 1670. 1120. 970 cm“; HRMS calcd for C..H,,N m/r 211.2293. found: 211.2281. (E)-1-(N-(2-Methylprop-1-yl)amino)-2.2-dlmethyl-5- phenyl-4-pentene (15b): bp 70—80 °C (<1 mmHg); ‘H NMR (300 MHz. CDCl,) 50.89 (d. J I 6.7 Hz. 6 H). 0.93 (s. 6 H). 1.74 (nonet. J I 6.7 He. 1 H). 2.15 (dd. J I 7.3. 0.8 Hz. 2 H). 2.36 (s. 2 H). 2.39 (d. J I 6.9 Hz. 2 H). 6.25 (dt. J I 7.3. 15.9 Hz. 1 H). 6.38 (bd, J I 15.9 Hz. 1 H). 7.15-7.37 (m. 5 H). NH not observed: ”N NMR (75.5 MHz. CDC13) 5 20.6. 25.7. 27.9. 35.1. 43.8. 59.0. 60.4. 125.9. 126.8. 127.7. 128.4. 131.9. 137.8; IR (neat) 3325. 3083. 3061. 3027. 2955. 2870. 2811. 1599. 1117. 966 cm“: HRMS cala'l {0f CnHflN 775/1 265.2163. found 245.2172. 1-(N -(2-Methylprop-1-yl)amino)-2.2-dlmethyl-3-propyl-4- pentane (16a): bp 70-80 'C (<1 mmHg): ‘H NMR (300 MHz. CDC13) 5 0.78 (I. 6 H). 0.85 (d. J I 6.1 Hz. 6 H). 0.86 (t. J I 6.7 1'12. 3 H). 0.99-1.19 (m. 2 H). 1.30-1.42 (m. 2 H). 1.69 (nonet. J I 6.6 Hz. 2 H). 4.90 (dd. J I 10.3. 2.4 Hz. 1 H). 4.96 (dd. J I 10.3. 2.4 Hz. 1 H). 5.55 (dt. J I 17.0. 10.3 Hz. 1 H). NH not observed: "C NMR (75.5 MHz. CDCl,) 5 14.1. 20.6. 21.1. 23.3. 23.6. 27.9. 30.5. 36.2. 51.0. 59.1. 59.6. 115.7. 140.2; 1R(nut) 3310. 3075. 2959. 2872. 2811. 1638. 1119. cm". HRMS calcd for CHHaN m/r 211.2293. found 211.2264. 1-(N- (2- Methylprop- l-yl )amino)-2.2-dlmethyl-3-phenyl- 4~pentene (16b): bp 70-80 °C (<1 mmHg): ‘H NMR (300 MHz. CDCl.) 50.82 (s.3 H). 0.37 (d. J . 6.7 Hz. 3 H). 0.89 (d. J . 6.7 Hz. 3 H). 0.90 (s. 3 H). 1.70 (nonet. J I 6.7 Hz. 1 H). 2.20 (d. J I 11.7 111.111). 2.31(d. J I 7.0 Hz. 2 H). 2.34 (d. J I 11.7 Hz. 1 H). 3.25 (bd. J I 10.1 Hz. 1 H). 5.01-5.09 (m. 2 H). 6.28 (m. 1 H). 7.10-7.30 (1'11. 5 H). NH not observed; "C NMR (75.5 MHZ. CDCl.) 6 20.7. 23.6. 23.7. 28.1. 37.6. 57.3. 59.0. 59.3. 116.2. 126.0. 127.8. 129.3. 138.8. 142.5; IR (neat) 3320. 3077 . 3069. 3029 . 2057. (23)Underthmaeonditiom.tbwss trandormsdto13b.theproduct ofcondensation with isobutyraldehyde followed by [3 3| rearrangement. The addition of HCl a TiCl. also resulted in the formation of 13b from 9b under these reaction conditions (see text and Table l) (24) Samples of tin reaction mixture were quenched with a 10% w/v solution of NaOMe/MeOH for analysis by GC. Under the q conditions. in. of 11. 12. 13. or 14 was not observed even after exposure (24 h). (25) in the examples in which 9b was transformed into 135 in a Hons-pot condensationsndresrrsngementsomeliydrolys'eof l3btoths corresponding aldehyde occurred under the reaction conditions. When hydrolysis occurred. enough isobutylamrne w. added during the asso- 1ropic removal of H10 to regenerate 13b from the corrsapaiding aldeh- yde.26 26)tsRearrsngemen promoted by TiCl. were first partially reduced withLiAIHut -78'Cfor 1 h. quenchedat-7 8°C. andthenallowedto warm to room temperature. After stimng for 1-12 h. the solution w- filtered to remove the alumuium and titanium salts. This modified procedure was performed in order to avmd reduction of the aliens functiorialitymsresultoftituiium hydride species” Thscrudssolution of imine was then reduced as described in the general procedure. 155 J. Org. Chem. Vol. 57. No. 26. 1992 7193 2872. 2811. 1636. 1601. 1117 cm": HRMS calm! for Cal-11118 m/s 245.2143. found 245.2206. (E)-1-(N.N-Bls(2-methylprep-l-yl)amine)-2-hexsne (17a). Isobutyryl chloride (0.106 g. 1. 0 mmol) was added slowly to a mixtureofamine10a(0.155g.1...0mmol)endNEtg(015g.11 mmol) intolueneatO‘C. Thereectionmixturswmallowedto wanntoroomtemperstureandstirfor48h. Thesolutionwm wuhed througha plug ofsilicageLconcsntratsd.snd purified byKinelrohrdistiilation (70-86 °C. <1 mmHg)toglve 17a (0.144 g.0.66 mmol) in66$ yield: ‘HNMRMNMHLCDCkHOM (d. JI6..6Hs.12H) 0..86(t.JI73Hx.3H).1.31-1.43(m.2 H).1..59-174(m.2H). 1.93-20e(n.11-l).2os(d.JI1.21-1s. 410.291 (dJ-ssflazm.s.3e-ass(n.2mz"cmm MHnCDCl,” 13.7. 20.9. 226.265.345.57.me 1323 IR (neat) 3311. 2959. 2872. 2810. 1670. 1121. 971 cm“: 1111“ calcd for C..H,N m/s 211. moo. found 211.237. (m-Hept—m-l-ylamlne (26). Compound 16 (3670 g. 150 mmol)wmt:eatsdwith6NaqusomNaOH(-flml.)mdhsfid torefluxfor36h. Theaminewasentractedfromthesqueom mixturswith4 x150mLofM.mdthsoomblnsdorganimwme driedoverKfiO, Theoilwmconcantrmaduiddhtillsdtogive 20(14.27g.126.01nmol)in84% yield(bpfl)-70’C. 22mmHg): ‘HNMR(3NMH1.CDC1,)50...64(t.JI74Hs.3H) 1.15-1.35 (m.6H).1.97(m.2H).3.19(m.2H).5.50(lI.2H):“CNMR (75.5 MHz. CDCl,) 5 13.9. 22.1. 31.5. 31.9. 44.1. 131.7. 131.2; IR (neat) 3371. 3300. 3020. 2959. 2925. 2673. 2859. 1669. 969 cm“. N-Cyclohexenyl-N- (E)ohept-2-en-l-yl-2.methylprepan- amide(22). Amine20(1. 81 g. 16mmol)sndcyclohsxanons(1.57 g. 16 mmol)werecondensedinref1uxingtolusnewitb removal of water to form 21. which was used without isolation. To the imine solution was added NEt, (1.78 g. 17.6 mmol). fol- lowed bytheslowadditionofisobutyrylcbloride(1.71g.16mmol). The mixturewasetirred for3hatroomtempsratureandthsn filtered through a pad ofsilica gel/alumina. The enamide w- concentrated. purified by silica gel fI-h chmatogrsphy (70:!) EW/mmleum ether). and then distilled to give 22 (3.76 g. 14.3 mmol) in 89% yield (bp 90-100 ‘C. <1 mmHg): ‘H NMR (300 MHz. CDCl.) 50.82 “J I 7.2 Hz. 3 H). 1.03 (d.JI 6.7 H26 H). 1.17-1.34 (m. 4 H). 1.54 (m. 2 H). 1.64 (In. 2 H). 1.90-2.10 (m. 6 H). 2.71 (sept. J I 6.7. 1 H). 3.90 (ha. 2 H). 5.29-6.531111. 2H). 5.52 (m. 1 H): “C NMR(75.5MHs.CDC1.)513.6.m1.2L5. 22.0. 22.7. 24.7. 3.0. 31.2. 31.3. 31.8. 48.1. 1255. 1.3.9. 134.0. 136.6. 176.4: 111 (neat) 3027. 2960. 2931. 2873. 1651. 970 cm": HRMS calcd for C..H,NO m/r 263.2249. found 263.2248. (E)-N-(2-Methylpropo1-yl)-N-hept-2-en-1-ylo1~eyele- hexenamine (23). Compound 22 (3.16 g. 12 mmol) wm slowly sddedtoasusparuionoflJAlH.(0502g. 13.2mmo1)inEt.O(50 m1.) and stirred at room temperature for 2 h. The solution wm quenched at 0 °C by the sequential addition of 3.0 m1. of H.O. 3.0 m1. of 15% w/v aqueous NaOH. and 9.0 m1. of H10. Afler stirring for 4 h. the aluminum salts were removed by filtration. and the combined filtrate and washings were concentrated and distilled to give 23 (2.90 g. 11.6 mmol) in 97% yield (bp 75-90 °C. <1 mmHg): l1-1 NMR (300 MHz. CDCla) 5 0.82 (d. J I 6.6 H2. 6 H). 0.86 (t. J I 7.2 1‘12. 3 1'1). 1.22-1.37 (Ill. 4 11). 1.49113. 2 H). 1.65 (m. 2 H). 1.84 (nonet. J I 6.9 H8. 1 H). 1.93-2.11 (III. 6 H). 2.63 (d. J I 7.1 112. 2 H). 3.49 (d. J I 5.5 Hz. 2 H). 4.41 (dd.JI 1.2.3.6Han).5.29-5.56(m.2H):"CM(75.5W1I. CDCI.) 513.9 206. 221 229 236.24.? 268.273.315.326“; 56.3.9611. 126..9132.3. 143.5;1R(neat)3022.2958.2929.2§72. 1685.1653. 1646.970 cm". General Procedure for t of 23 and laden- tion of24To lee25. 'i‘oa0.2 Msolutionof23 (3-7 mmol) 3-asa-Cope Table llforieactiontimee). Aftercoolimtoroom iBu,AlH (1.2equiv.2Minhexsnse)wmaddsdslowly."'1'he mixturewsastirrsdfor24hatroom sndthm (2WThemint1nsresultirufromM by I. quenchedwithalOieodiumofNeOMs'm ”Inha- ofthealuminumhydrideresgent.‘ 7194 we purified by silica gel flash column chromatogaphy’ (eluent. 50.50 BnO/petroleum ether) and purified by Kugelrohr distillation to give 25 as a mixture of diastereomers (see Table 11 for yields anddiutereomm ratios) (bp 75415 °C. <1 mmHg): ‘H NMR (300 MHnCDClg) (major isomer)50.85 (t,JI I.67 Hz. 3H). 0.89(d. JI6..5Hs.6H)1...00-174(m16H).1..79-200(m.2H).2.14 (dd. J I 6.7. 11.2 Hz. 1 H) 2.47 (dd. J I 6.4. 11.2 Hz. 1 H). 2.82 (bq. J I 2.5 He. 1 H). 4.91 (dd. J I 2.2. 17.0 Hz. 1 H). 4.93 (dd. J I 22. 10.1 Hz. 1 H). 5.47 (ddd. J I 9.8. 10.1. 17.0 1'12. 1 H): (minor isomer) 5 0.83 (t. J I 6.7 He. 3 H). 0.86 (d. J I 6.7 He. 6 H). 1.00-1.74 (m. 16 H). 1.79-2.00 (m. 2 H). 2.06 (dd. J I 6.7. 11.2 Hz. 1 H). 2.38 (dd. J . 6.4. 11.2 Hx. 1 H). 2.67 (bq. J - 2.8 112. 1 H). 4.94 (dd. J I 2.2. 17.0 Hz. 1 H). 4.96 (dd. J I 2.2. 10.1 Hi. 1 1115.53 (ddd. J - 9.6. 10.1. 17.0 Hz. 1 H); 11C NMR (7.5.5 14112. CDC1,) (major isomer) 5 14.1. 19.9. 20.9. 21.0. 22.8. 25.4. 26.7. 28.7. 29.3. 31.1. 45.1. 46.7. 53.7. 55.9. 114.9. 143.0. (minor (28) After rearrangement promotsdby ArO),AlMe and reduction of 24.amine25wmtreetedwithHC1(3mL1MinEt,O). loadedoneilia geLandwashedwith90- .01 petroleumether/Etfltoremove the 2.6-di- phsnylphenol. The product was then eluted with 95: 5 ether/NEH to remove 25 from the column. the solvent removed. and the product dllr tilled. (29) Silica gel wm wmhed with a solution of 5'!) NEt, in 1:21.,0 prior to loading the products on the column in order to enhance resolution of the eluting compoum. 156 isomer) 6 14.0. 20.0. 20.8. 21.0. 22.8. 24.8. 26.7. 28.8. 29.4. 31.8. 45.6. 46.4. 54.1. 55.7. 114.4. 142.3: IR (neat) 3360. 3074. 2955. 2930. 2857. 1640 cm": HRMS cald for CanN m/r 251.2613. found 251.2606. Acknowledgment. We are grateful to Michigan State University for financial support of this research. Michigan State University is gratefully acknowledged for a College of Natural Sciences Research Fellowship to N .S.B. and a Ronald E. McNair Undergraduate Research Fellowship for M.S.L. Spectral product characterisation wu performed on N MR instrumentation purchued in part with funds from NIH Grant 1-SlO-RR04750-01 and from NSF Grant CHE.88-00770. Mass spectral data were obtained at the Michigan State University Mass Spectrometry Facility. whichissupported.inpart. byagrant (DREW) from theBiotechnologyResourcesBrsnch.Divisionomesarch Resources. National Institutes of Health. Supplementary Material Available: Copies of |H and uC NMR spectra of all compounds in the Experimental Section (30 mm). This material iscontained inmany lihrarimon miadichs. immediately follows this article in the microfilm version of the Journal. and can be ordered from the ACS; see any current masthead page for ordering information. RIES "1111111111111 1 1