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J u—v— This is to certify that the thesis entitled THE PREPARATION AND CHARGE PROMOTED AZA-CLAISEN REARRANGEMENT OF N-ALLYLENAMINES presented by Gregory Richard Cook has been accepted towards fulfillment of the requirements for Masters degree in Science (Chemist-W) W ajor professor Date October 1, 1990 0-7639 MS U is an Affirmative Action/Equal Opportunity Institution PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. DATE DUE DATE DUE DATE DUE II | ===fi MSU Is An Affirmative Action/Equal Opportunity Institution ' cmmm THE PREPARATION AND CHARGE PROMOTED AZA-CLAISEN REARRANGEMENT OF N-ALLYLENAMINES By Gregory Richard Cook A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE COLLEGE OF NATURAL SCIENCE DEPARTMENT OF CHEMISTRY 1990 (545 - er? ABSTRACT THE PREPARATION AND CHARGE PROMOTED AZA-CLAISEN REARRANGEMENT OF N-ALLYLENAMINES By Gregory Richard Cook The efficient and facile synthesis of aliphatic N-allylenamines derived from aldehydes and ketones by routes through secondary allylic amides and N-allylenamides was accomplished. The aza- Claisen rearrangement of N-allylenamines has been found to be promoted by Bronsted acids. Promotion with organic electrophiles followed by reduction of the resulting ins-unsaturated iminium salts has afforded 8,e-unsaturated amines. Lewis acids have been employed to accelerate the rearrangement of all N-allylenamines prepared. Both TiCI4 and Me3Al have successfully lowered the temperature of the aza-Claisen rearrangement by as much as 140°C. Rearrangement products, ins-unsaturated imines, were reduced in situ to the secondary amines thereby reducing the sensitivity of the nitrogen functional group. TABLE OF CONTENTS List of Tables iv List of Schemes v Introduction 1 The Claisen Rearrangement 1 Enantioselectivity in the Claisen Rearrangement 5 Promotion of the Claisen Rearrangement 7 The Aza-Claisen Rearrangement 12 Enantioselectivity in the Aza-Claisen Rearrangement 13 Promotion of the Aza- Claisen Rearrangement 15 Preparation of Enamines 20 Results and Discussion 23 Preparation of N-Allylenamines 23 Aza-Claisen Rearrangements Promoted by Electrophiles 29 Aza-Claisen Rearrangements Promoted by Lewis Acids 33 Summary 37 Experimental 39 References 62 Appendix A: 1H NMR Spectra 64 Appendix B: 13C NMR Spectra 85 LIST OF TABLES Table 1: Rearrangements Promoted by Organic Electrophiles 32 Table 2: Rearrangements Promoted by Lewis Acids 36 iv Scheme 1: Scheme 2: Scheme 3: Scheme 4: LIST OF SCHEMES Synthetic Routes to N-Allylenamines 24 Rearrangements Promoted by Organic Electrophiles 32 Unfavorable Rearrangement of Enamides 34 Lewis Acid Catalyzed Rearrangements 35 INIBQDLLQIIQH W The Claisen rearrangement of allyl vinyl ethers (1) has been the focus cf intense study and many of its contributions to synthetic organic chemistry have been reported.1 The Claisen rearrangement involves an intramolecular [3,3]-sigmatropic shift proceeding through geometrically well-defined transition states having either a chairlike or a boatlike conformation (eq. 1). The formation of a new carbon-carbon bond between C(1) and C(6) occurs regiospecifically producing a y,5-unsaturated carbonyl compound (2 and 3) with, potentially, two new asymmetric centers. at o{?— 1 “ R2 ———’ 4 3 6 “NR 5 I \ R4 2 (1) R1 03 2 1 “ R2 . 4 6 R3 5 ,0 \ ., ‘ 3 Asymmetric induction in the Claisen rearrangement is controlled by two variables. One factor is whether the transition state adopts a chairlike or a boatlike conformation. The second factor is the E or deometry of the olefins in the substrate. Schmid 2 has shown the importance of these two factors by thermally rearranging the allyl vinyl ethers 4,5,6 and 7 to the aldehydes 8 and 9 (eq. 2).2-3 It was discovered that the chairlike conformation predominated in the transition state giving rise to 95% of the products in each case. The boatlike transition state would involve eclipsing interactions which are eliminated in the chairlike form. Both the E,E isomer 4 and the 2,2 isomer 5 produced the three aldehyde 8 and the erythro aldehyde 9 in 95.9:4.1 (8:9) and 94.7:5.3 (8:9) ratios, respectively. The opposite was true for the Z,E isomer 6 and the El isomer 7, giving three to erythro ratios of 46:95.4 and 45:95.5, respectively. O/V chair 0/3: (2le O /——\ |\/\ T ‘ / ‘ I \ I”’ I _ 5 4 “\‘ ,”’ 8 ‘\‘ ”I x I” ”7’90 “\ v” boat v: ' \ boat (2) _ r' \ ’ “~ 0N 0 Chair 0/ A chair _. V ‘\/\ \ 6 9 7 erythro It is clear that control of the olefin geometry in the substrate preparation is crucial to controlling the relative stereochemistry of the rearrangement products. Ireland has accomplished some control through the use of ester enolates (eq. 3).4 He showed that Z-crotyl propanoate 10 could be enolized selectively to either the E—(O)-silyl 3 ketene acetal (11) or the Z-(O)-silyl ketene acetal (12) simply by changing the solvent conditions. The [3,3]-sigmatropic rearrangement of 11 produced the three product 13 preferentially (89:11 13:14). Similarly, rearrangement of 12 yielded mainly the erythro product 14 (14:86 13:14). By using the E-crotyl propanoate, Ireland obtained almost the exact opposite ratios of three to erythro products, indicating that the minor isomer, in each case, stemmed from incomplete manipulation of the enolate geometry. OSIMezt'BU O ‘ 0 1": K_/ OJK/ 1 1 I , HNPA-THF 1 O [3.3] OSiMezt-Bu o)V [3.31 > o k_/ \ 1 2 1 4 erythro Others have found moderate to excellent diastereocontrol of the ester enolate Claisen rearrangement using or- and B-hydroxy esters and glycolate esters.5o6 Katsuki has demonstrated that the ester enolate Claisen can be forced to proceed through the boatlike transition state by incorporating bulky ligands onto the counter ion metal of the enolate.7 — — t’BUMOzSI \ N / Ph NPh /II\/R‘ 1) LDEA/THF )—_=\ O 2) TBDMSCI/HMPA 0 R1 VH2 / R2 3 R _ 16 F13 ._ 15 1) [3.3] 2) NH4CI/H20 (4) 15 R‘ R2 R3 17 18 ll a Me Me H 90.7 93 NHPh NHPh b Me n—Pr H 90.9 9.1 R‘ R‘ c Me Me Me 98.1 1.9 o o d Me Me SiMea 992 0.8 "' . R2 ""R2 R3 R3 1 7 ‘I 8 Ketene O,N-acetals have been successfully employed in diastereoselective Claisen rearrangements. The steric influence of a dialkylamino group at C(2) has provided formation of (Z)-ketene O,N-aceta|s selectively.3-9-1° These, coupled with E-crotyl groups, yielded, after rearrangement, erythro:threo ratios of 91:9 and higher. Monoalkylamino groups on C(2) have given much lower, and, in fact, the opposite selectivity (1:2 erythro:threo).11 This has been circumvented by the use of an N-silyl protecting group where a secondary amide product was desired.12 As shown in eq. 4, very good erythro selectivity was obtained due to a predominance of the Z- olefin formation. With increasing steric bulk in R3 (15c and 15d), which should have no effect on the formation of the enolate, the 5 diastereoselectivity of the rearrangement increased. This provided evidence that the enolate was formed with the Z configuration in greater than 99%. The slightly lower selectivity observed for 15a and 15b was thus attributed to an increase in population of the boatlike conformation in the transition state. Substitution at C(5), therefore, provides one more tool for controlling the progress of the Claisen rearrangement. E I' l|"|'|l Cl' B | Incorporation of an asymmetric center directly involved in the 6-membered transition state can only be accomplished at the sp3 C(4) position. One of the first to show transfer of chirality from the C(4) position to a newly developed chiral center was Hill in 1964 (eq. 5).13 Thermally rearranging the vinyl ether of (R)-cyclopenten- 3-ol (19), he was able to obtain an 81% yield of the (R)- cyclopentene-3-acetaldehyde (20). Determination of the transition state conformation was not possible as there were no substituents at the cm position. [a .3] 6 Chan has also studied the effect of chirality at C(4) on the Claisen rearrangement (eq. 6).14 As expected from the chairlike transition state, both the (R)-Z isomer 21 and the (S)-E isomer 22 led to the same (S)-E rearrangement product 23. The enantiomeric excess was high; 98.4% for 21 and 98.0% for 22. O/\ _.> O.::\"(:::}\ H Me ‘ """ I-Bu I H Me \ 21 (R)-Z " ‘ 0/ (6) " 1 \ ’0," o/\ / i-Bu M6 V“ ' 23 (S)-E I-eu““° Me 22 (S)-E _ _ Nakai has achieved 100% chirality transfer with the Ireland- Claisen rearrangement of the ester enolate 24 incorporating asymmetry at C(4) (eq. 7).15 Yields of the rearranged product 25 ranged from 75-85% with greater than 95% of the E olefin geometry (no 2 isomer detected by 13C NMR). OSiMezt-Bu OH o [3 ' 3] o ‘.\\‘\ K/ T (7) 24 25 7 Some success has been obtained by placing chirality adjacent to the atoms involved in the transition state. Placing asymmetric centers next to the C(1) position yielded stereofacial selectivities ranging from 2.5:1 to 4.3:1 with diastereoselectivity remaining very high.5'l>-5<>I6d Welch has obtained relative asymmetric induction as high as 6.421 by incorporating chirality near the C(2) position in the ketene 0,N-aceta| rearrangement.16 And Cha has shown a selectivity of 4.4:1 from chirality adjacent to the C(6) position.6a E I' [II EI' E | The general aliphatic Claisen rearrangement has an activation energy of about 30 kcal/mole.17 Therefore, temperatures required for the reaction to proceed are on the order of 150-200°C.1 While protic acids (CF3002H) have greatly accelerated the aromatic Claisen rearrangement (reaction proceeds at room temperature), the aliphatic Claisen rearrangement has shown only a slight rate enhancement (NH4Cl at 135°C).1c Unfortunately, the use of Bronsted acids as catalysts in the aliphatic systems has not been investigated to a significant degree. Within the last decade, several reports of catalysis with palladium compounds have surfaced. These are not true concerted sigmatropic rearrangements as both [1,3] and [3,3] products have been observed. However, reactions proceeded below 100°C with Pd(OAc)2-PPh3 and (dppe)2Pd as catalysts”.19 Oshima has found only [3.3] products with the ortho ester Claisen rearrangement in refluxing p-xylene catalyzed by 0.05 8 equivalents of PdCI2(PPh3)2.2° Ortho ester Claisen rearrangements generally require acidic conditions in order to form the allyl vinyl species and Oshima showed that acid sensitive compounds could be successfully rearranged with the palladium species. OANPh PdCl2(PhCN) oNPn OfNPh o > o o D 46 <1 7h) - ‘Pdl- _ [Pd] - Pd(PPh3)4 l _ - (8) o/\NPI5 + ' _ o/\Nptt o/\NPII mm“ 7 \k” + °7\/l D ~~‘.|'"o D 27 D 28 D [13] [3.3] Bosnich has proposed different mechanisms for the Pd(0) and Pd(ll) catalyzed reaction (eq. 8).21 In his studies of the rearrangement of allyl imidates (26), he found that 0.05 equivalents of Pd(PPh3)4 gave a 1:1 mixture of [1,3] (27) and [3,3] (28) products while PdCl2(PhCN)2 gave exclusively-the [3,3] product 28. For the Pd(ll) catalyzed reaction, he proposed that the allyl olefin is first coordinated with the palladium and then undergoes intramolecular attack by the nitrogen giving an intermediate carbocation leading to the [3,3] product (eq. 8). On the other hand, Pd(0) oxidatively adds to the allyl group forming a (n-allyl)pa|ladium(ll) intermediate which then can give rise to the [1,3] or the [3,3] product. 9 Palladium(ll) catalyzed rearrangement of simple allyl vinyl ethers, where the C(2) position is unsubstituted, gave rise to mainly cleavage products.22 The palladium, apparently, coordinates to the vinyl olefin of the ether cleaving to give the allylic alcohol. Only traces of Claisen products were observed in these cases. However, as shown in eq. 9, substitution at C(1) and C(2) can give high yields (93%) of the rearranged aldehydes at room temperature. While Bickelhaupt rationalized the need of C(2) substitution as a steric block to prohibit palladium coordination,22 Hayashi and Ito believed it was necessary to stabilize the positively charged intermediate of the Pd(ll) catalyzed reaction pathway.28 A report from Nakai indicated that the Pd(ll) catalyzed Claisen rearrangement proceeds through a boatlike transition state with both olefins coordinated to the transition metal.24 Et Et \ OK: 0.05 eq. PdCl2(CH30N)2 29 ‘ r o \ (9) 30 A variety of Lewis acids have successfully catalyzed the aromatic Claisen rearrangement.1c However, only aluminum compounds have proven effective for the aliphatic Claisen. For example Oshima found that reaction of allyl vinyl ether 31 (Rl-n-Bu, R2-H) with M63A| for 15 minutes at room temperature gave the unsaturated, methylated alcohol 32 in 91% yield (eq. 10).25 During rearrangement, the C(2) position was methylated by the 1O organoaluminum species. Et3Al catalysis gave a mixture of the ethylated (75% yield) and the reduced (19% yield) alcohols. Only the reduced products were obtained with (i-Bu)3Al (78-97% yields) and (i-Bu-)2AIH (no reported yields) catalysts. The regular Claisen products, 7,8-unsaturated aldehydes or ketones, were observed upon reaction with Et2AlSPh and Et2AICI-PPh3 (61-87% yields). Olefin selectivities of these reactions were generally poor (about 1:1 52) except where R1=Ph (E only), however, the tremendous rate enhancements and high yields were noteworthy. Me 0/\ M63N 1) [1,3] H0 1 0 /I\/\ [3.3] 2) H20 ( ) F11 R2 R1 R2 3 1 3 2 Yamamoto has extended the scope of the aluminum catalyzed Claisen rearrangements. He has promoted the reaction to -78°C and achieved selectivities that can be manipulated at will.26 The two reagents that have been studied are bis(4-bromo-2,6-di-tert- butylphenoxide)methylaluminum 33 and bis(2,6-diphenylphenoxide)- methylaluminum 34. When the allyl vinyl ether with an isobutyl substituent at C(4) was treated with 2 equivalents of 33, rearrangement took place in 15 minutes at -78°C to yield the aldehyde with a 7:93 ratio of E to Z. Treatment of the same other with 2 equivalents of 34 for 15 minutes at -20°C gave the exact opposite E:Z ratio. Yamamoto has thus made it possible to obtain the 2 product, which has been difficult with thermal and other catalyzed 11 Br 0 0 Br 0 0 \Al/ O \Al’ 0 33 34 rearrangements. The application of these catalysts to an optically active substrate is depicted in eq. 11. When (R)-35 was rearranged with 33, the major product was (S)-36 (84:16 36:37) with 100% enantiomeric excess. Rearrangement with 34 gave almost exclusively (R)-37 with 98% enantiomeric excess. The regiochemistry of bis-allyl vinyl ethers could be controlled with these catalysts as well. In thermal rearrangements, the less substituted allyl system is usually involved in the rearrangement. . The opposite was observed using these aluminum catalysts (eq. 12). Rearrangement of 38 with both 33 and 34 gave 39 as the major product. O/\ V O/ a " i-Bu, I + (11) i-BUJR\/\ — s""~ i-Bu \ n 3 5 3 6 3 7 catalyst yield wee.) 37(e.e.) 33 74% 84(100%) 16(82%) 34 90% 2 98(98%) o/\ o/ 0/ > + 3 8 4 0 catalyst 3 9 3 89 11 34 94 MW (12) The nitrogen analog of the Claisen rearrangement, the aza- Claisen or 3-aza-Cope rearrangement, is the [3,3]-sigmatropic shift of N-allylenamines (41) yielding 7,6-unsaturated 43). defined chairlike or boatlike transition states (eq. 13). I] u I imines (42 and The aza-Claisen rearrangement also proceeds through well- The aza-Claisen investigation as has the oxa-Claisen rearrangement has not seen an extensive rearrangement. Reaction temperatures are higher, on the order of ZOO-250°C, and the activation energy is about 6 kcal/mole higherflavlcrld 13 One of the first to report the thermal rearrangement of a purely aliphatic N-allylenamine was Hill in 1967.27 The aza-Claisen rearrangement of N-methyl-N-allylisobutenylamine was carried out at 250°C for one hour. No yield was reported. Hydrolysis of the resulting imine provided the same y,5-unsaturated aldehyde as would be obtained by the corresponding oxa-Claisen rearrangement. Diastereoselectivity in the aza-Claisen rearrangement has been shown to be analogous to the oxa-Claisen rearrangement. In a modification of Ireland's ester enolate Claisen reaction, Tsunoda has carried out rearrangement of the amide enolate 44 with a selectivity of 99.5:0.5 (45:46) in 92% yield (eq. 14).28 As in the oxa-Claisen rearrangement, attachment of a chiral center at C(4) can influence the stereochemistry of the newly developed chiral centers generated in the aza-Claisen rearrangement. Thermal rearrangement of the chiral enamine 47 gave, after hydrolysis, the two aldehydes 48 and 49 in a ratio of 87:13 with an asymmetric induction of the major isomer (48) calculated at 69% (eq. 15).27.29 14 Ph “KN/Yin“ [3.3] \N/ Ph b /|\/ \ 4 7 (1 5) H30+ ,.Ph Ph 0/ \‘ 0/ '0', + 4 8 4 9 N +N 5 0 5. 1 k/ m R1 R2 $54 n-BuLi a B CHzPh 923 b CH2Ph CHzPh 94:6 0 c i-Pr CHan 973 I R2 (16) R‘ \ d t-Bu CHgPh 982 N 6 Ph CHgPh 7822 5 2 |\/ f t-Bu Me 973 g t-Bu C(Cl-kfizPh 973 [3.3] I" I" 2 2 R1 N/ “‘“R + R‘ N/ R 15 The trivalency of nitrogen provides an added advantage over the oxa-Claisen rearrangement. Chiral auxiliaries can be attached providing chirality in a position not available with allyl vinyl ethers. Kurth- has used optically active cyclic ketene N,O-acetals to place an asymmetric center adjacent to the nitrogen, and, in essence, induce asymmetry on the nitrogen itself.” As shown in eq. 16, the chiral oxazoline 50 was alkylated with allyltosylate to give the iminium salt 51. Treatment with base provided the enamine 52 which yielded, 'after rearrangement, the oxazolines 53 and 54 with selectivities as high as 98:2 (53:54). Kurth has applied this methodology to the synthesis of naturally occurring compounds.31 Further examples of enantioselective aza-Claisen rearrangements are presented in the following section. E I' [II E -G|° B | Many sensitive functional groups cannot tolerate the harsh conditions of the aza-Claisen rearrangement. Therefore, promotion at lower temperatures is even more important than in the oxa- Claisen rearrangement and would bring it into the realm of useful organic reactions. A variety of protic acids (H2804, HCI, H3PO4, CF3002H) have successfully catalyzed the aromatic aza-Claisen rearrangement.” Only one confirmed report of catalysis by Bronsted acids (p- toluenesulfonic acid) of aliphatic N-allylenamines has appeared.32 In a recently reported communication, protic acid-catalyzed rearrangement of an N-allylenamine at room temperature may have 16 occurred through protonation from the conjugate acid formed in the reaction, or during acidic hydrolysis, although this has not been verified.33 Aza-Claisen rearrangements have been promoted to temperatures as low as 80°C by quarternization of the nitrogen with alkyl electrophiles. Opitz has alkylated a number of enamines with allylic and benzylic halides.34 He originally thought that the reaction proceeded via C-alkylation. Brannock attempted the C- alkylation of N,N-dimethylisobutenylamine with saturated alkyl halides and found only N-alkylated products.35 He proposed that an aza-Claisen rearrangement was taking place in the reactions carried out by Opitz. He demonstrated this by treating the N,N- dimethylenamine 55 with crotyl bromide at 80°C. After hydrolysis, the Claisen product 56 was obtained (eq. 17). Likewise, treatment of the N-allylenamine 57 with MeOTs at 80°C also gave the Claisen product 58 after hydrolysis (eq. 18). Me\ N \ . Me/ 55 Me\ \ 1)80°C / + -——> Me/fi/K/Y 2)H20 I> Cg (17) WW / - - 56 Me\ Me\ 1)80°C N \ MeOTs N \ 2 H O / /\<——> Me/ N ) 2 pg (18) \ 57 58 17 A few other reports of aza-Claisen rearrangements of quaternary enammonium salts have appeared in the last two decades, all proceeding at temperatures as low as 80°C.36 This methodology has been applied by Oda, lgarashi, and lnouye to a chiral substrate (59) as depicted in eq. 19 to give a 45% enantiomeric excess of the product 60.37 PhM OH F_’h 1)80°C ' 2) H20 /\N/\//\/ _4_,/\+"‘\ :e/\/ 3)[O] >o (19) 59 It'lle so K/ 61 \ Palladium(ll) species have been unsuccessful in catalyzing the aza-Claisen rearrangement; however, palladium(0) compounds with protic acid coécatalysts have been effective as demonstrated by Murahashi (eq. 20).38 Acceleration of the reaction required the presence of both catalysts. Treatment of the N-allylenamine 61 with equimolar amounts (0.1 equiv.) of Pd(PPh3)4 and trifluoroacetic \ 0.1 equiv. Pd(PPh3)4 Ph\ / V \ 61 62 acid for 20 hours at 100°C provided a 99% yield of the imine 62. Lowering the reaction temperature to 50°C dropped the yield to 82%. In some cases, [1,3] products were obtained, again, indicating that this is not a concerted sigmatropic rearrangement. Analogous to the 18 oxa-Claisen case, these reactions were thought to proceed by oxidative addition of palladium to the protonated enamine giving a (n-allyl)palladium(ll) complex. Murahashi has found that these N- allylenamines could be generated in situ from the corresponding secondary allylamine and aldehyde with these catalysts, and then rearranged. He has applied this to a chiral substrate (eq. 21).38b The chiral amine 63 and the aldehyde 64 were successfully condensed and rearranged with 0.05 equivalents of Pd(PPh3)4 and 0.025 equivalents of CF3COgH. Only a 12% enantiomeric excess was obtained after hydrolysis to the aldehyde 65 (84% yield). A O 1)Pd(0),H” / Ph NH H * v+ P" H 2) 30 , G (21) 63 64 65 Virtually unexplored, the catalysis of the aliphatic aza- Claisen rearrangement with Lewis acids has only been reported three times. The discovery that TiCl4 catalyzes enamine formation (described in the following section) led Hill to use this method to prepare N-allylenamines. He found that TiCl4 also catalyzed the aza-Claisen rearrangement in refluxing benzene and even slowly at room temperature.29 TiCl4 would not catalyze the Claisen rearrangement of crotyl vinyl ether. He determined that the Lewis acid-catalyzed reaction proceeds with the same stereochemical bias as the uncatalyzed reaction. By applying 0.25 equivalents of TiCI4 to the same reaction as outlined in eq. 15, he obtained the same product 19 ratios as the thermal rearrangement (90:10 48:49) with nearly the same asymmetric induction (67%). Therefore, TiCl4 catalysis does not change the chairlike character of the transition state. Unfortunately, his yields were quite low, ranging from 16-68%. His reactions were limited to disubstituted aldehydes, as linear aldehydes gave mixed results, and ketones (acetophenone and cyclohexanone) would not react at all. Ph ' Ph '- 0 Ph /\ NH Ph \l/t toluene, reflux /\ N /\< |\/{ H > KA 66 / 67 6 a / ncu. 55°C (22) P. Eh - Ph Ph 5 Ph 0/ + O/ A 1430* /\ ”CE \ ""0” \ 6 9 \ 7 o 7 1 ' ' Recently, Bailey reported a stereoselective aza-Claisen rearrangement catalyzed by TiCl4 (eq. 22).39 Condensing the chiral amine 66 with 2-phenylpropionaldehyde 67 in refluxing toluene gave, presumably, the enamine 68. Treatment, in situ, with TiCl4 at 55°C gave the imine 69 which was hydrolyzed to a 6:1 mixture of the aldehydes 70 and 71. The enantiomeric excess of 70 was 90% and for 71, 98%. Interestingly, when the same reaction was carried out in benzene, the diastereomeric excess was only 40% and the enantiomeric excess decreased dramatically (70 - 1% e.e.; 71 - 12% 20 e.e.). Reaction times and catalyst amounts were not reported and overall yields were low (16-56%). Organoaluminum catalysts, as in the oxa-Claisen rearrangement, have shown great promise for the aliphatic aza- Claisen rearrangement as demonstrated by Barta, Voss, and Stille.32v4o Me3A| and (i-Bu)2AlH have promoted the rearrangement of N-allyl-N-isobutylisobutenylamine to completion in 6 hours at 111°C. Promotion with (PhO)2AIMe gave complete conversion at room temperature in 12 hours, and with bis(2,4,6-trichlorophenoxy)- methylaluminum, the rearrangement was complete in less than 2 hours at room temperature. E I' t E . A variety of methods for the synthesis of enamines have appeared.41 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. 23). R2 0 R1 - R1 R3 \NH + /u\ H20 4» \N \ (23) ,l R2 CHRaR‘ l R R1 R4 Mannich and Davidsen first reported that secondary amines and aldehydes condensed in the presence of potassium carbonate to give enamines.42 Reactions proceeded at temperatures as low as 5°C. Ketones required calcium oxide and higher temperatures and resulted 21 in poor yields. Almost two decades later, Herr and Heyl reported that enamines of ketones and aldehydes could be more easily prepared in benzene with azeotropic removal of water.43 In some cases, the addition of a catalytic amount of p-toluenesulfonic acid was required. Yields were generally good (60-90%). Other drying agents have been employed as well. One example is the use of magnesium sulfate. Ketones and. amines could be condensed over magnesium sulfate in the absence of any solvent providing good yields (77-84%) of enamines at room temperature.44 In 1967, White and Weingarten reported that enamines could be obtained from secondary amines and carbonyl compounds in the presence of TiCl4.45 The Lewis acid acts both as a catalyst and a water scavenger (eq. 24). This method has since been studied and optimized providing good yields of enamines with short reaction times.46 R3\ 0 6 [NH + 2 R‘\/u\ + TiCl4 '- 3 R2 R (24) 3 R3 R3 R \N/ / 1 R3 R / R2 While the TiCl4 procedure works well for the two most commonly studied amines (morpholine and pyrrolidine), as Hill demonstrated, the use of an allylic amine gives the rearranged product and notthe pure enamine.29 Furthermore, a large excess of 22 the amine is required and this method would not be efficient if a costly chiral amine were used. E I' [El-EIII . As was described previously, the synthesis of enamines usually involves the condensation of a secondary amine and a carbonyl compound. Likewise, the synthesis of an N-allylenamine would require a secondary allylic amine. Unfortunately only one, N- allylaniline, is commercially available. Any routes to N- allylenamines, therefore, would probably begin with a primary amine. Secondary amines can be prepared by alkylating primary amines with alkyl halides, however, a large excess of the amine is required to minimize dialkylation. Therefore, clean, simple, and efficient methods for preparing N-allylenamines needed to be explored. I The synthesis of N-allyl-N-isobutylisobutenylamine 77 has been accomplished through a variety of routes (Scheme 1). Beginning with allylamine 72, two routes to the secondary allylic amine 75 were explored. Treating allylamine 72 with isobutyraldehyde in diethyl ether, using potassium carbonate or 4A molecular sieves to absorb the water, afforded a 74% isolated yield of the imine 73. Allylamine 72 was also treated with isobutyryl chloride and triethylamine to give a 95% yield of the allylic amide 74. Both the imine 73 and the amide 74 were reduced with LiAIH4 to N- allylisobutylamine 75 in 68% and 88% yields, respectively. Both routes provided the secondary allylamine free from any dialkylated 23 24 0 4 7 3 1) LiAIH4 Cl 2) H20 Q 4; ° < 1) LWH4 2) H20 H+ ‘§= 1 <2 0 N 0’ 1) LiAlH4 H. H 2) H20 Scheme 1: Synthetic Routes to N-Allylenamines 25 products. Condensation of the amine 75 with isobutyraldehyde and a catalytic amount of p-toluenesulfonic acid, with azeotropic removal of water in benzene, gave the enamine 77 in 65% yield. The reaction took ‘24 hours and the product obtained was a mixture (8:1) of the enamine 77 and either the rearranged y,8-unsaturated imine or the enamine of N-isobutylpropyl amine. The saturated secondary amine could have been formed by reduction of the allyl group while preparing the secondary amine 75. It Was discovered that the enamide 76 could be reduced cleanly with LiAlH4 to the desired enamine 77 in high yield (98%). Two routes to this enamide were investigated. The imine 73 was acylated with isobutyryl chloride in the presence of triethylamine providing an almost quantitative yield (99%) of the enamide 76. Since acylation proceeded in such high yield, the imine 73 was prepared from allylamine 72 and isobutyraldehyde in refluxing benzene and acylated without isolation to provide the enamide 76 in 94% overall yield for the two steps. This indicated that imine formation can occur to a greater extent than the 74% yield that was isolated. The second route involved the condensation of the allylamide 74 with isobutyraldehyde. The enamide 76 was thus obtained in 85% yield; however, longer reaction times (3 days) and a greater amount of p-toluenesulfonic acid catalyst were required as compared to the analogous condensation of the allylamine 75. The quickest and most efficient route to the enamine 77 from allylamine 72 was found to be the ”one-pot" synthesis of enamide 76 followed by LiAlH4 reduction. There were several advantages to proceeding through this route on the path to enamines. First, the 26 enamides are more stable than enamines and can be stored for longer periods without threat of hydrolysis. Secondly, the enamides can be reduced in high yields cleanly with no rearranged by-products. And finally, the enamides, and thus, the enamines, can be prepared with shorter reaction times and under milder conditions than any of the other routes described. The "one-pot" method was applied to the synthesis of the enamide 78 derived from another disubstituted aldehyde (eq. 25). Condensation of allylamine 72 and 2-phenylpropionaldehyde in benzene, followed by acylation afforded N-allyl-N-(2- phenyl)propenylisobutyramide 78 in 79% yield. The product was a mixture of E and Z isomers in a ratio of 1.3:1 respectively. Subsequent reduction to the enamine 79 with LiAlH4 proceeded, as expected, in high yield (95%). The isomeric ratio, after reduction, was roughly 6:1 (E:Z). Attempts to alter the olefin geometry ratio in the reduction step by changing the reaction time and workup conditions failed. 0 O O Phj/uxH N/ Ph or N Ph L1A|H4 \/ V \l/\ gPh \/ 27 Once methods had been worked out for the preparation of enamines derived from disubstituted aldehydes, enamines from monosubstituted or linear aldehydes were investigated. Attempts to synthesize enamine 82 by condensation of N-allylisobutylamine 75 and n-butanal by the general procedure in refluxing benzene resulted in a mixture of products. The enamine was present; however, it was accompanied by aldol condensation products. Likewise, application of the ”one-pot” synthesis to obtain the enamide 81 by forming the imine in refluxing benzene and acylating with isobutyryl chloride also yielded aldol condensation impurities. It was necessary, therefore, to prepare and isolate the imine 80 at lower temperatures in order to minimize these side products. Reaction of allylamine 72 with n-butanal in the presence of potassium carbonate for two hours at ambient temperature gave a 68% distilled yield of the imine 80 (eq. 26). Acylation with isobutyryl chloride gave the enamide 81. This enamide was, again, a mixture of E and Z c A)» NA/a \HLC, NW 72 - L/ao 81 K/E LiAlH4 (26) V \l/\N/\/Et 82 K/ 28 isomers. The isomer ratio could be changed slightly by using a different base in the reaction. When triethylamine was used a 90% yield was obtained of a 1.7:1 mixture of E and Z isomers. When pyridine was employed, the ratio changed to 2.4:1 (E:Z) providing an 86% yield of the enamide 81. Reduction with LiAlH4 rendered an 88% yield of the enamine 82. Only one isomer was detected by NMR and was presumed to be the E isomer. The NMR data for enamine 82 showed 6% of N-allylisobutylamine, the result of hydrolysis of the enamine either during the reduction workup or while preparing the NMR sample. Enamines of two ketones, cyclopentanone and cyclohexanone, were also prepared (eq. 27). Since ketones are less prone to aldol condensation, both enamide 83 and enamide 84 could be successfully synthesized via the ”one-pot" method. With cyclopentanone, the enamide 83 was acquired in 68% yield and with cyclohexanone, the yield of the enamide 84 was 77%. As compared to the aldehyde enamides, the yields of the ketone enamides were slightly lower. This is not surprising as ketones are less reactive toward nucleophilic addition than aldehydes. Consequently, imine formation was sluggish. It should be noted that in an attempt to prepare the enamine 86 by condensation of N-allylisobutylamine 75 and cyclohexanone catalyzed by p-toluensulfonic acid, the reaction was not complete after heating at 111°C for two weeks with azeotropic removal of water and a mixture of products was observed. Reduction of the enamides 83 and 84 to the enamines 85 and 86 proceeded in high yield (90% and 98%, respectively). Like the previous enamine derived from n-butanal, these enamines are 29 monosubstituted at the C(1) position. NMR analysis of the enamines also showed hydrolyzed products (13% for 85 and 5% for 86). Hydrolysis most likely occurred during handling although hydrolysis during the water/NaOH workup of the reduction has not been ruled out. as 3 £3 £3 or . \l/LC' n=2 83 n-2,3 n-3 84 (27) LiAlH4 N \ T.v n-3 86 All of the monosubstituted enamines investigated decomposed more readily than the disubstituted enamines. Since hydrolysis of enamines would have to involve protonation of the C(1) position at some point, these observations were not unexpected. Protonation at the less substituted C(1) position would be more facile. In order to make the aza-Claisen rearrangement more widely applicable to organic synthesis, it is essential that the reaction be promoted so that milder temperatures can be used. Furthermore, as 30 many natural products contain nitrogen, it would be desirable to preserve the nitrogen in the final product rather than hydrolyzing the resulting imine to a carbonyl compound. 'It is clear that the development of positive charge on the nitrogen of an N-allylenamine accelerates the aza-Claisen rearrangement. One method of inducing positive charge is the addition of an electrophile producing a quaternary ammonium salt. The simplest of all electrophiles, and the least studied in the charge promoted' Claisen rearrangements, is, of course, the proton. As depicted in eq. 28, HCI was found to be an efficient catalyst. N- alIyI-N-isobutylisobutenylamine 77, in dioxane, was treated with 0.5 equivalents of an anhydrous HCI (1M solution in diethyl ether). No rearrangement was observed below 50°C, but heating at reflux (101°C) for 5 hours was sufficient to {drive the reaction to completion. By reduction of the xii-unsaturated imine with LiAlH4 to the amine 87, retention of the nitrogen was accomplished. The overall yield for the two-step process was 73% after distillation. [3.3] (23) + 7 \ H \ 31 Methyl electrophiles have been used in the past to promote the aza-Claisen rearrangement, however, the products were always hydrolyzed to the corresponding carbonyl compounds.35v35° This procedure was investigated and the products were reduced to preserve the nitrogen moiety. The results of these studies, as depicted in Scheme 2, are summarized in Table 1. Both methyl iodide and methyl tosylate were examined under a variety of conditions. Entries a and b show the promoted rearrangement with 1 equivalent of the electrophile in acetonitrile followed by NaBH4 reduction to the amine 88. In both cases, the reaction did not proceed cleanly and many products were formed, among which, two rearranged products, E-H,Me, could be detected by GLC. In entries 0 and d, the solvent was changed to dioxane so that LiAlH4 could be used as the hydride source. For both 1 equivalent of Mel and MeOTs, the reactions did proceed cleanly giving only two products. With Mel (entry c), the ratio of the products, obtained in 55% yield, was 89:11 (EaHzMe). MeOTs (entry d) afforded a 72:28 (E-H,Me) mixture in 65% yield. There are at least two possible explanations for the appearance of the major product (E-H). Either the counter ion (iodide or tosylate) or the hydride could execute a nucleophilic displacement of nitrogen on the methyl group of the iminium ion. The results of entry 0 and d indicated that the counter ion may have such an effect. In entry c, where Mel was employed, the ratio of products was higher than in entry (I. This is consistent with the fact that the iodide ion is a much stronger nucleophile than the tosylate ion. 32 + / Y?” A LiAlH4 or NaeH4 \I/EN \ \ E=Me,Ac Scheme 2: Rearrangements Promoted by Organic Electrophiles TABLE1: Rearrangements Promoted by Organic Electrophiles. ENIBIBEAGENIIIMESQLELENPHIQBLQEEBQQLLCISD a Mel 22 hr MeCN NaBH4 many b MeOTs 19 hr MeCN NaBH4 many 0 Mel 17 hr dioxane LiAIH4 88, E=H:Me (89:11) d MeOTs 17 hr dioxane LiAlH4 88, E=H:Me (72:28) e Mel 10 hr dioxane NaBH4 manyc f MeOTs 10 hr dioxane NaBH4 polymers 9 CH3000I 9 hr dioxane NaBH4 manyd h CH3COCI 9 hr dioxane LiAlH4 manye (a) Reactions were carried out at the temperature of the refluxing solvent. (b) Ratios were determined by NMR and compared to a standard of N-methyI-N-isobutyl-(2,2- dimethyl)-4-pentenylamine prepared by Mel addition to N-isobutyI-(z,2-dimethyl)-4- pentenylamine. (c) The ratio of 88, E=H:Me in the product mixture was lower than that for eatery 2. 54d) 47% of the product mixture was 88, E=H. (e) 84% of the product mixture was , =- . 33 The effect of the hydride was investigated by using the weaker reducing agent, NaBH4 (entries 9 and f). with MeOTs (entry f), only polymeric materials were obtained. With Mel (entry e), again, a mixture of many products was found. Two of the products were, in fact, the compounds 88 where EaH and E=Me. Although ratios could not be determined due to overlapping NMR signals, the ratio was less than that for entry 0. These data show that the hydride is playing a role in the formation of the major product (E=H). Most likely, both the counter ion and the hydride are causing nucleophilic displacement. Also, it is clear that NaBH4 is a poor choice for the reduction of these iminium ions under these conditions. Acetyl chloride was briefly investigated as a possible promoting electrophile. Reduction with both NaBH4 and LiAlH4 gave a mixture of products (entries 9 and h). Only one rearrangement product was detected in the mixtures; that in which EsH. With NaBH4, 47% of the product mixture was 88 (E-H), and with LiAlH4, 84% of the product mixture was 88 (E-H). No products were observed containing either an ethyl group or an acetyl group. Presumably, the rearrangement that did occur was catalyzed by HCI rather than acylation of the nitrogen. E-Ql' 8 IE IIII'E'I Lewis acid catalysis of the aza-Claisen rearrangement of N- allylenamides, precursors to the N-allylenamines, was attempted and no rearrangement products were obtained. There are two possible explanations for the reluctance of enamides to rearrange. 34 As shown in Scheme 3, Lewis acid coordination would occur on the more Lewis basic site, oxygen, resulting in a sp2 hybridized nitrogen by delocalization of the lone pair. Thus, a suitable transition state for the rearrangement to occur may be unattainable. Furthermore, if the rearrangement occurred, an ”allene-type" product would be obtained, and the reaction would be uphill thermodynamically. MLn+\ MLn+\ .0 .0 + N’\ ML" __ R’k , RJ=N"’ Scheme 3: Unfavorable Rearrangement of Enamides 0 JL R (3 On the other hand, the N-allylenamines rearranged with ease. All of the enamines previously synthesized have been subjected to either 0.1 equivalents of TiCl4 or 1.2 equivalents of AlMe3 and the rearrangement products reduced with LiAlH4 (Scheme 4). All reactions were carried out at 111°C in refluxing toluene and the results are summarized in Table 2. These reaction conditions represent those optimized by Voss for the Lewis acid-catalyzed aza-Claisen rearrangement.” Enamine 77 was treated with TiCl4. After 75 hours, the yield of the y,5-unsaturated imine was greater than 95% (determined by GLC with m-xylene as an internal standard), and a 56% yield of the amine 87 was isolated after reduction. Interestingly, when the enamine 79 was subjected to TiCI4, no rearrangement products were 35 Scheme 4: Lewis Acid Catalyzed Rearrangements 3 6 TABLE 2: Rearrangements promoted by Lewis Acids.a ENAMLNELEMEAQIE’IIME EBQQUQIXIELQC 7 7 TiCl4 75 hr 8 7 56%(>95%) 79d TiCl4 38.5 hr polymers ------ 7 9 AIMe3 9 hr 8 9 92% 8 2 AlMe3 9 hr 9 0 84% 8 5 AIMea 9 hr 9 1 67% 8 6 TiCI4 93.5 hr 9 2 78%(>95%) 8 6 A|M93 9 hr 9 2 59% (a) All reactions were carried out in refluxing toluene. (b) Catalyst amounts were as follows: TiCl4 - 0.1 equiv., AlMea - 1.2 equiv. (c) Yields are of isolated products after reduction. Yields in parenthesis are of the 7,8- unsaturated imines as determined by GLC by comparison to m-xylene internal standard. (d) No starting material or new products were detected by GLC after 21 hours of reflux. detected and only polymeric materials were obtained. AlMe3; however, worked extremely well, providing a 92% yield of the amine 89 after only 9 hours. The rearrangement cf enamine 82, derived from a linear aldehyde, also proceeded well. Reaction with AlMe3 for 9 hours afforded, cleanly, an 84% yield of the amine 90. Moderate yields were obtained from the rearrangement of the enamines 85 and 86. AlMe3 catalysis of 85 gave, after reduction, 67% of the amine 91. With 86, the yield with AlMe3 was slightly lower (59%). Reaction of 86 with TiCl4 was much slower, but a higher yield was obtained (78% for 92, greater than 95% for the y,5- unsaturated imine as determined by GLC). Of the two catalysts studied with these substrates, AIMe3 was found to be superior. Shorter reaction times were required for AIMe3 than for TiCI4. Also, TiCl4 appeared to catalyze polymerization of the styrene type enamine (79). Furthermore, 37 AIMes did not methylate the rearranged product as was observed in the analogous oxa-Claisen rearrangement.25 The successful Lewis acid-catalyzed rearrangement of substrates 82,85, and 86 suggest that the limitations encountered by Hill with straight chain aldehydes and ketones29 were not due to the [3,3] sigmatropic rearrangement. Most likely the problems lie in the condensation step of enamine formation. In the presence of a strong Lewis acid like TiCl4, aldol condensation of the linear aldehydes could occur giving a mixture of products. As it was found that the condensation of ketones and secondary amines was extremely slow, Hill's observation that ketones would not react under his conditions is not surprising. SUMMABI N-allylenamines, derived from aldehydes and ketones, have been efficiently and cleanly synthesized from readily available starting materials. A variety of pathways to these enamines, starting from primary allylic amines, could be followed. Charge promoted aza-Claisen rearrangement of these enamines has been accomplished by development of positive charge on the nitrogen by the addition of several types of electrophiles. Reduction of the resulting y,8-unsaturated imines to the figs-unsaturated amines has been realized with LiAlH4, thereby preserving the nitrogen for further synthetic manipulation. Protic acids, such as HCI, catalyzed the rearrangement, reducing the temperature by 150°C. Alkylation with Mel and MeOTs, producing a quaternary ammonium salt, has 38 promoted rearrangement; however, reduction of the iminium salts provided a mixture of secondary and tertiary amines. Both TiCl4 and AIMe3 have successfully coordinated with the electron rich nitrogen, thus accelerating the rearrangement. AIMe3 provides the most hope for wide application of Lewis acid catalysis in the aza-Claisen rearrangement. GeneLaLMstds All flasks used for moisture or oxygen sensitive reactions were subjected to repetitive vacuum-argon purges, while heating. All reactions were carried out under an inert atmosphere of nitrogen or argon. Benzene, toluene, tetrahydrofuran, and diethyl ether were distilled from sodium-benzophenone ketyls. Dichloromethane, acetonitrile, pyridine, and triethylamine were dried over calcium hydride and distilled. Dioxane was dried over LiAIH4 and distilled. Other solvents and reagents were used as provided by the manufacturer or distilled prior to use. NMR spectra were obtained on a Varian Gemini 300 spectrometer. Gas chromatographic analyses were carried out isothermally on a Perkin-Elmer 8500 instrument using a 50 meter OV-17 capillary column and an FID detector at 200°C oven temperature, 220°C injector temperature, and 300°C detector temperature. Helium gas pressure was set at 15 psi with a flow rate of 2 mL/min. Infrared spectra were recorded on a Nicolet 42 FT-IR instrument. S II . [El-Elll' I III . 13 To 100 mL of dry diethyl ether, were added 3.54 g (62 mmol) of allylamine and 4.47 g (62 mmol) of isobutyraldehyde. Molecular sieves were added to absorb the water formed. After stirring at 39 4o ambient temperature for two hours, the solution was filtered via canula. The ether was removed by distillation and the imine was distilled at atmospheric pressure to give 5.113 g (74% yield) of 73 (b.p. 112-114°C/760 mm Hg): 1H NMR (300 MHz) (CDCI3) 8 1.05 (d, 6 H, J=6.9 Hz), 2.42 (dsept., 1 H, J=4.9, 6.9 Hz), 3.95 (d, 2 H, J=5.6 Hz), 5.05 (dd, 1 H, J=1.8, 10.3 Hz), 5.10 (dd, 1 H, J= 1.8, 17.2 Hz), 5.93 (ddt, 1 H, J=-10.3, 17.2, 5.6 Hz), 7.51 (d, 1 H, 3.4.9 Hz); 130 NMR (75.5 MHz) (CDCI3) 6 19.3, 34.1, 63.2, 115.5, 136.1, 170.9; IR (neat) 3083, 3013, 2967, 2932, 2874, 2824, 2674, 1466, 1456, 1437, 136.6. 1103, 1019, 995, 916 cm'l. N- 1 li ' 74 To 600 mL of dry THF, were added 9.02 g (158 mmol) of allylamine and 12.48 g (158 mmol) of pyridine. The solution was cooled to 0°C and 16.84 g (158 mmol) of isobutyryl chloride were added dropwise. After heating at reflux for five hours, the mixture was washed with 50 mL of 15% aqueous NaOH and the organic layer was separated. The aqueous layer was extracted with 20 mL of ether. All organic layers were combined, dried over M9804 and filtered. The solvents were removed by rotary evaporation under reduced pressure. The oil was distilled at under vacuum to give 18.99 g (95% yield) of the amide 74 (b.p. 78°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 5 1.13 (d, 6 H, J-6.9 Hz), 2.37 (sept., 1 H, J=6.9 Hz), 3.84 (dddd, 2 H, J=1.6, 1.6, 5.7, 6.6 Hz), 5.09 (ddt, 1 H, J-1.4, 10.2, 1.6 Hz), 5.14 (ddt, 1 H, J-1.4, 17.1, 1.6 Hz), 5.81 (ddt, 1 H, J=-10.2, 17.1, 6.6 Hz), 5.85 (br. s, 1 H); 13C NMR (75.5 MHz) (CDCI3) 5 41 19.3, 35.3, 41.5, 116.2, 134.6, 177.3; IR (neat) 3293, 3085, 3015, 2971, 2934, 2876, 1645, 1545, 1470, 1422, 1387, 1242, 1098, 988, 918 cm'l. BII' [ZBIII-Elll'lll' 25 To 0.76 g (20 mmol) of LiAlH4 in 100 mL of dry diethyl ether, cooled to 0°C, were slowly added 2.00 g (18 mmol) of N- allylisobutylideneamine 73. The mixture was heated at reflux for two hours. Then, the solution was cooled to 0°C and Quenched by addition of 0.76 mL water, followed by 0.76 mL of 15% aqueous NaOH, followed by 2.28 mL of water. After stirring one hour, the mixture was filtered through Na2$O4 and the ether was removed by rotary evaporation under reduced pressure at 0°C. The allylic amine was distilled (bulb to bulb) under vacuum to give 1.392 g (68% yield) of 75 (b.p. 30-40°C/20 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.87 (d, 6 H, J-6.7 Hz), 1.00 (br. s, 1 H), 1.70 (tsept., 1 H, J-6.8, 6.7 Hz), 2.38 (d, 2 H, J-6.8), 3.20 (ddd, 2 H, J-1.4, 1.4, 6.0 Hz), 5.04 (ddt, 1 H, J-1.7, 10.2, 1.4 Hz), 5.13 (ddt, 1 H, J-1.7, 17.2, 1.4 Hz), 5.88 (ddt, 1 H, J-10.2, 17.2, 6.0 Hz); 13C NMR (75.5 MHz) (CDCI3) 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'1. BII' [ZIIEI-EIII'III' 15 To 1.847 g (48.6 mmol) of LiAIH4 in 200 mL dry diethyl ether, were added 5.617 g (44.2 mmol) of N-allylisobutyramide 74. The 42 mixture was heated at reflux for three hours, after which, the solution was cooled to 0°C and quenched by addition of 2 mL of water, followed by 2 mL of 15% aqueous NaOH, followed by 6 mL of water. After stirring for two hours, the solution was filtered through Na2$O4 and the solvent was removed under reduced pressure at 0°C by rotary evaporation. The residue was distilled at atmospheric pressure to give 4.577 g (88% yield) of the allylic amine 75 (b.p. 125°C/760 mm Hg). Spectroscopic data was consistent with that reported for the reduction of 73. II; o -_ --°eo co 3| .u.: o 0.0:. .0. To 20 mL of benzene were added 1.02 g (9 mmol) of N- allylisobutylamine 75, 0.792 g (11 mmol) of isobutyraldehyde, and 0.004 g (0.02 mmol) of p-toluenesulfonic acid. The flask was fitted with a Dean-Stark trap containing 4A molecular sieves. The solution was heated at reflux for 24 hours and then the benzene was removed by rotary evaporation under reduced pressure. The enamine 77 was distilled (bulb to bulb) under vacuum to give 0.971 g (65% yield) of an 8:1 mixture of 77 and either 87 or the enamine of N- isobutylpropylamine (b.p. 30-40°C/<1 mm Hg). To 100 mL of dry THF were added 2.00 g (18 mmol) of N- allylisobutylideneamine 73 and 1.82 g (18 mmol) of triethylamine. The solution was cooled to 0°C and 1.92 g (0.018 mmol) of isobutyryl chloride was added dropwise. After heating at reflux for two hours the solution was washed with 30 mL of 15% aqueous NaOH and the organic layer was separated. The aqueous layer was extracted with two 75 mL portions of ether and dried over Na2804. The solvents were removed by rotary evaporation under reduced pressure. The enamide was distilled (bulb to bulb) under vacuum to give 3.24 g (99% yield) of 76 (b.p. 55-65°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 1.02 (d, 6 H, J-6.8 Hz), 1.57 (s, 3 H), 1.70 (s, 3 H), 2.65 (sept., 1 H, J=6.8 Hz), 3.89 (d, 2 H, J-6.2 Hz), 5.04 (dd, 1 H, J=1.6, 11.3 Hz), 5.06 (dd, 1 H, J-1.6, 16.0 Hz), 5.74 (ddt, 1 H, J-11.3, 16.0, 6.2 Hz), 5.85 (s, 1 H); 13C NMR (75.5 MHz) (CDCI3) 6 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'1. 1|: 0 ‘-; -A-.oo 3| ee .“0; o e |:”.|;-"e To 700 mL of benzene were added 14.273 g (250 mmol) of allylamine and 18.028 9 (250 mmol) of isobutyraldehyde. The flask was fitted with a Dean-Stark trap and the solution was heated to reflux. After 19.5 hours, the water was drained and 4A molecular 44 sieves were added to the Dean-Stark trap and reflux was continued for two hours. The solution was cooled to ambient temperature and 25.25 g (250 mmol) of triethylamine followed by 26.65 g (250 mmol) of isobutyryl chloride were added. The solution was heated at reflux for three hours. The benzene was removed by rotary evaporation under reduced pressure and the crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 70:30 diethyl ether:petroleum ether). The solvents were evaporated and the enamide was distilled under vacuum to give 42.68 g (94% yield) of 76 (b.p. 50-54°C/<1 mm Hg). Spectroscopic data was consisitent with that reported for the acylation of 73. To 2.508 g (66 mmol) of LiAIH4 in 300 ‘mL of dry diethyl ether cooled to 0°C were slowly added 10.867 g (60 mmol) of the enamide 76 and the mixture allowed to warm to ambient temperature. After stirring for six hours, the solution was cooled to 0°C and quenched with 2.5 mL of water, followed by 2.5 mL of 15% aqueous NaOH, followed by 7.5 mL of water. The mixture was stirred for 1.5 hours, filtered, and the ether was removed by rotary evaporation under reduced pressure. The enamine was distilled under vacuum to give 9.844 g (98% yield) of 77 (b.p. 54-55°C/8 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.83 (d, 6 H, J-6.6 Hz), 1.58 (d, 3 H, J=1.3 Hz), 1.58 (tsept., 1 H, J=7.3, 6.6 Hz), 1.65 (d, 3 H, J=1.3 Hz), 2.25 (d, 2 H, J-7.3 Hz), 3.15 (ddd, 2 H, J21.6, 1.6, 6.2 Hz), 5.02 (ddt, 1 H, J=2.0, 10.2, 1.6 Hz), 5.08 (ddt, 1 H, J=2.0, 17.2, 1.6 Hz), 5.22 (sept., 1 H, J=1.3 Hz), 5.81 45 (ddt, 1 H, 10.2, 17.2, 6.2 Hz); 130 NMR (75.5 MHz) (00013) 5 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'l. ll: 0 ‘-; 'A' -e|:| 000:. on .“e: 20 |: To -250 mL benzene were added 2.855 g (50 mmol) of allylamine and 6.709 g (50 mmol) of (1)-2-phenylpropionaldehyde. The flask was fitted with a Dean-Stark trap and the solution was heated to reflux. After 22 hours, the water was drained and 4A molecular sieves were added to the Dean-Stark trap. Reflux was continued for six more hours and then the flask was cooled to ambient temperature and then 5.05 g (50 mmol) of triethylamine and 5.33 g (50 mmol) of isobutyryl chloride were added. The mixture was heated to reflux. After 1.5 hours, the solution was cooled, filtered, and the solvents removed by rotary evaporation under reduced pressure. The crude oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 7o;3o diethyl ether:petroleum ether). The solvents were evaporated and the enamide was distilled under vacuum to give 9.559 g (79% yield) of 78 (b.p. 112-115°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 (E isomer) 1.10 (d, 6 H, J-6.7 Hz), 2.02 (d, 3 H, J-1.4 Hz), 2.80 (sept., 1 H, J=6.7 Hz), 4.15 (ddd, 2 H, J-1.3, 1.3, 6.2 Hz), 5.14 (ddt, 1 H, J-1.1, 10.4, 1.3 Hz), 5.17 (ddt, 1 H, J=1.1, 17.0, 1.3 Hz), 5.85 (ddt, 1 H, J=10.4, 17.0, 6.2 Hz), 6.43 (q, 1 H, J-1.4 Hz), 7.33 (m, 5 H), (2 isomer) 46 1.00 (d, 6 H, J=6.8 Hz), 2.10 (d, 3 H, J=1.4 Hz) 2.91 (sept., 1 H, J-6.6 Hz), 3.64 (ddd, 2 H, J=1.3, 1.3, 6.0 Hz), 4.99 (ddt, 1 H, J=1.2, 17.0, 1.3 Hz), 5.06 (ddt, 1 H, J=1.2, 10.4, 1.3 Hz), 5.70 (ddt, 1 H, J=10.4, 17.0. 6.0 Hz), 6.26 (q, 1 H, J=1.4 Hz), 7.33 (m, 5 H); 13c NMR (75.5 MHz) cocna) 6 15.6, 16.6, 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, 126.3, 126.7, 126.6, 133.2, 133.5, 134.2, 136.3, 138.8, 140.0, 177.5, 177.6; IR (neat) 3083, 3059, 3025, 2971, 2874, 1663, 1401, 1231, 995, 909 cm'1. ::0 CI 0 3 e A-; -‘J 00 - -0I:I o eo;I .III: To 0.920 g (24.2 mmol) of LiAlH4 in 110 mL dry diethyl ether cooled to 0°C were added 5.35 g (22 mmol) of N-allyl-N-(2- phenyl)propenylisobutyramide 78. The mixture was allowed to warm to ambient temperature. After stirring for 13 hour, the solution was cooled to 0°C and quenched by addition of 1 mL of water, followed by 1 mL of 15% aqueous NaOH, followed by 3 mL of water. The mixture was stirred for two hours and then filtered through Na2$O4. The ether was removed by rotary evaporation under reduced pressure and the enamine was distilled under vacuum to give 4.774 (95% yield) of 79 (b.p. 105°Cl<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 (E isomer) 0.91 (d, 6 H, J=6.6 Hz), 1.76 (tsept., 1 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, 1 H, J=1.9, 10.2, 1.5 Hz), 5.20 (ddt, 1 H, J-1.9, 17.2, 1.5 Hz), 5.91 (ddt, 1 H, J-10.2, 17.2, 5.9 Hz), 6.15 (q, 1 H, J=1.2 Hz), 7.30 (m, 5 H), (Z isomer) 0.86 (d, 6 H, J=6.6 Hz), 1.75 (tsept., 1 H, J=7.4, 6.6 Hz), 1.98 (d, 3 H, J=1.2 Hz), 2.51 (d, 2 H, J=7.4 47 Hz), 3.26 (ddd, 2 H, J=1.4, 1.4, 5.9 Hz), 5.02 (m, 1 H), 5.66 (m, 1 H), 5.64 (q, 1 H, J=1.2 Hz), 7.30 (m, 5 H); 130 NMR (75.5 MHz) (00013) 6 15.4, 20.2, 56.3, 62.4, 116.4, 125.2, 125.5, 126.2, 128.3, 136.4, ' 139.3, 143.5; IR (neat) 3079, 3059, 3029, 2955, 2936, 2670, 2813, 1632, 1597, 1495, 1460, 1445, 1204, 1121, 918 cm'1. E || . [II-EIIII Il'l . Ell 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 under reduced pressure. The imine was distilled (bulb to bulb) under vacuum to give 3.02 g (68% yield) of 80 (b.p. 30-40°C/25 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 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, J21.03, 17.2, 5.7 Hz), 7.61 (t, 1 H, J=4.9 Hz); 130 NMR (75.5 MHz) (CDCI3) 6 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-1. I I O O I I: e A'A -I0- :I on -IIo: 3 o .‘_ ._ oI e :I To 12.521 9 (100 mmol) of imine 80 and 7.910 g (100 mmol) of pyridine in 500 mL of dry diethyl ether were slowly added 10.660 9 48 (100 mmol) of isobutyryl chloride. The solution was heated to reflux. After six hours, the solution was filtered and washed with 100 mL aqueous saturated sodium bicarbonate then 100 mL of water. The organic layer was dried over MgSO4 and filtered. The ether was removed by rotary evaporation under reduced pressure and the enamide was distilled under vacuum to give 15.567 9 (86% yield) of 81 (b.p. 57-62°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 (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, 1 H), 5.73 (m, 1 H), 6.78 (d, 1 H, J=14.0 Hz), (2 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, 1 H), 5.73 (m, 1 H), 7.21 (d, 1 H, J-12.8 Hz); 13C NMR (75.5 MHz) (CDCI3) 6 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-1. To 2.09 g (55 mmol) of LiAlH4 in 250 mL of dry diethyl ether cooled to 0°C were slowly added 9.0649 (50 mmol) of the enamide 81. The solution was heated to reflux. After four hours, the solution was cooled to 0°C and quenched by addition of 2.1 mL of water, followed by 2.1 mL of 15% aqueous NaOH, followed by 6.3 mL of water. The mixture was allowed to stir at ambient temperature for on half hour and then filtered. The ether was removed by rotary 49 evaporation under reduced pressure and the enamine was distilled under vacuum to give 7.381 g (88% yield) of 82 (b.p. 27-44°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.63 (d, 6 H, J-6.7 Hz), 0.92 (t, 3 H, J=7.4 Hz), 1.82 (tsept., 1 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, 1 H, J-1.4, 10.2, 1.5 Hz), 5.09 (ddt, 1 H, J-1.4, 17.1, 1.5 Hz), 5.77 (ddt, 1 H, J-10.2, 17.1, 5.8 Hz), 5.69 (dt, 1 H, J=13.8, 1.2 Hz); 130 NMR (75.5 MHz) (00013) 6 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'1. II: 0 A7; ‘A' oo:I :I so .IIe: 3 e I: "OI:- To 800 mL of benzenewere added 17.127 9 (300 mmol) of allylamine and 25.236 9 (300 mmol) of cyclopentanone. The flask was fitted with a Dean-Stark trap and heated to reflux. After 20 hours, the water was drained and the Dean-Stark trap was filled with 4A molecular sieves. Reflux was continued for one hour more and then the benzene was removed by rotary evaporation under reduced pressure. The oil was washed with 100 mL of saturated aqueous sodium bicarbonate and extracted with three 100 mL portions of ether. The organic layers were combined and dried over Na2$O4. After filtration, the ether was removed by rotary evaporation under reduced pressure. The oil was distilled under vacuum to give 39.55 g (68% yield) of the crude enamide 83 (b.p. 50 100-130°C/<1 mm Hg). A portion of the yellow oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 70:30 diethyl ether:petroleum ether) for further reactions and spectroscopic analysis: 1H NMR (300 MHz) (CDCI3) 6 1.05 (d, 6 H, J=6.7 Hz), 1.91 (m, 2 H), 2.33 (m, 4 H), 2.79 (sept., 1 H, J=6.7 Hz), 3.99 (d, 2 H, J=5.9 Hz), 5.06 (m, 2 H), 5.50 (s, 1 H), 5.74 (ddt, 1 H, J=10.2, 17.0, 5.9 Hz); 13C NMR (75.5 MHz) (CDCI3) 6 19.8, 22.1, 30.0, 31.0, 33.1, 48.7, 116.8, 126.9, 134.1, 177.0; IR (neat) 3081, 2967, 2934, 2672, 2651, 1649, 1460, 1400, 1370, 1225, 995, 909 cm—l. . ::0 0| 0 3 e A-A -I-' so oo:I :I .III: To 0.334 g (8.8 mmol) of LiAlH4 in 40 mL of dry diethyl ether cooled to 0°C were slowly added 1.546 g (8 mmol) of the enamide 83. The solution was allowed to warm to ambient temperature. After stirring for 13 hours, the mixture was cooled to 0°C and quenched by addition of 0.33 mL of water, followed by 0.33 mL of 15% aqueous NaOH, followed by 0.99 mL of water. The solution was stirred for one half hour and then filtered. The ether was removed by rotary evaporation under reduced pressure and the enamine was distilled (bulb to bulb) under vacuum to give 1.288 g (90% yield) of 85 (b.p. 50-60°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 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 (br. s, 1 H), 5.05 (ddt, 1 H, Ja-1.6, 10.5, 1.4 Hz), 5.07 (ddt, 1 H, J-1.6, 17.0, 1.4 Hz), 5.77 (ddt, 1 H, J-10.5, 17.0, 5.5 Hz); 130 NMR (75.5 MHz) (CDCI3) 6 20.2, 26.9, 30.5, 32.3, 38.2, 53.8, 58.4, 92.3, 115.7, 135.6, 137.3; IR (neat) 51 3087, 2964, 2915, 2874, 1670, 1634, 1607, 1561, 1468, 1418, 1391, 1341', 1238, 1096, 991, 909 cm'1. I I I I II: o -- -I- eI;.:I so .IIe: 3‘ 0 I: OI:— To 800 mL of benzene were added 17.127 g (300 mmol) of allylamine and 29.442 g (300 mmol) of cyclohexanone. The flask was fitted with a Dean-Stark trap and the solution was heated to reflux. After 19 hours, the water was drained and 4A molecular sieves were added to the Dean-Stark trap. Reflux was continued for one hour and then the benzene was removed by rotary evaporation under reduced pressure. The oil was washed with 100 mL of saturated aqueous sodium bicarbonate and extracted with three 100 mL portions of ether. The organic layers were combined and dried over Na2304. After filtration, the ether was removed by rotary evaporation under reduced pressure and the oil was distilled under vacuum to give 47.84 g (77% yield) of the crude enamide 83 (b.p. 80- 120°C/<1 mm Hg). A portion of the yellow oil was purified by flash column chromatography (silica, 230-400 mesh; eluent - 70:30 diethyl ether:petroleum ether) for further reactions and spectrosc0pic analysis: 1H NMR (300 MHz) (CDCI3) 6 1.03 (d, 6 H, J-6.8 Hz), 1.52 (m, 2 H), 1.64 (m, 2 H), 2.02 (m, 4 H), 2.66 (sept., 1 H, J=6.8 Hz), 3.87 (d, 2 H, J-6.3 Hz), 5.04 (m, 2 H), 5.55 (dd, 1 H, J-3.8, 3.8 Hz), 5.74 (ddt, 1 H, J-10.2, 17.0, 6.3 Hz); 13C NMR (75.5 MHz) (CDCI3) 6 19.9, 21.2, 22.5, 24.4, 28.7, 31.0, 48.9, 117.0, 127.1, 134.3, 52 139.0, 176.9; IR (neat) 3081, 2967, 2936, 2863, 2840, 1649, 1480, 1400, 1360, 1245, 909 cm'1. ::0 0| 0 3‘ e A'.‘. -I-' so oI:,:I .III: To 0.334 g (8.8 mmol) of LiAlH4 in 40 mL of dry diethyl ether cooled to 0°C were slowly added 1.659 g (8 mmol) of the enamide 83. The solution was allowed to warm to ambient temperature. After stirring for 13 hours, the mixture was cooled to 0°C and quenched by addition of 0.33 mL of water, followed by 0.33 mL of 15% aqueous NaOH, followed by 0.99 mL of water. The solution was stirred for one half hour and then filtered. The ether was removed by rotary evaporation under reduced pressure and the enamine was distilled (bulb to bulb) under vacuum to give 1.520 g (98% yield) of 85 (b.p. 50-60°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 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, 1 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, 1 H, J-10.3, 17.3, 5.7); 13C NMR (75.5 MHz) (CDCI3) 6 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. 53 . - - n . co ;. -;o o..v.lv. . . .I'. . To 30 mL of dry dioxane were added 1.004 g (6 mmol) of the enamine 77 and 3 mL (3 mmol) of a 1M solution of HCI in diethyl ether. The solution was heated to reflux. After 5.5 hours, the solution was cooled and 6.6 mL (66 mmol) of a 1M solution of LiAlH4 in THF were added. After stirring for two hours at ambient temperature, the solution was quenched by addition of 0.25 mL of water, followed by 0.25 mL of 15% aqueous NaOH, followed by 0.75 mL of water. The mixture was allowed to stir for one hour and then filtered. An excess of aqueous HCI was added and the solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14. The amine was extracted with three 50 mL portions of ether and the organic layer was dried over MgSO4. The ether was removed by rotary evaporation and the oil was distilled (bulb to bulb) under vacuum to give 0.745 g (73% yield) of 87 (b.p. 50-60°C/8 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.85 (s, 6 H), 0.86 (d, 6 H, J=6.6 Hz), 1.71 (tsept., 1 H, J-6.9, 6.6 Hz), 1.98 (d, 2 H, J=7.5 Hz), 2.29 (s, 2 H), 2.35 (d, 2 H, J-6.9 Hz), 4.99 (m, 2 H), 5.79 (ddt, 1 H, J-9.2, 17.9, 7.5 Hz); 13C NMR (75.5 MHz) (CDCI3) 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'l. 54 II: o A-u=l -A-' H - "“3! won“ -n|: To 25 mL of dry acetonitrilewere added 0.847 g (5 mmol) of the amine 87 and 0.710 g (5 mmol) of Mel. The solution was heated to reflux. After 12.5 hours the solution was cooled and the acetonitrile was removed by rotary evaporation under reduced pressure. The residue was washed with 10 mL of 15% aqueous NaOH and extracted with three 50 mL portions of ether. The organic layers were combined and dried over MgSO4. After filtration, the ether was removed by rotary evaporation under reduced pressure. The amine was distilled (bulb to bulb) under vacuum to give 0.739 g (81% yield) of N-Methyl-N-isobutyl-(2,2-dimethyl)-4-pentenylamine (b.p. 60-70°C/10 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.82 (s, 6 H), 0.87 (d, 6 H, J-6.6 Hz), 1.65 (tsept., 1 H, J=7.4, 6.6 Hz), 1.97 (d, 2 H, J-7.4 Hz), 2.07 (s, 2 H), 2.10 (d, 2 H, J-7.4 Hz), 2.16 (s, 3 H), 4.97 (m, 2 H), 5.81 (ddt, 1 H, J=11.0, 18.8, 7.4 Hz); 13C NMR (75.5 MHz) (CDCI3) 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, 2786, 1640, 1470, 1385, 1366, 1250, 1105, 1040, 993, 909, 850 cm'1. WW To 15 mL of dry dioxane were added 1.338 g (8 mmol) of the enamine 77 and 1.135 g (8 mmol) of Mel. The solution was heated to reflux. After 17 hours, the solution was cooled to 0°C and 16.0 mL (16 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was allowed to stir at ambient temperature for two hours. 55 The solution was then cooled to 0°C and quenched by addition of 0.6 mL of water, followed by 0.6 mL of 15% aqueous NaOH, followed by 1.8 mL of water. After stirring for one hour, the mixture was filtered and then treated with an excess of aqueous HCI. The solution was concentrated by rotary evaporation under reduced pressure and the residue was treated with 15% aqueous NaOH to a pH of 14. The amine 886 was extracted with three 50 mL portions of ether and the organic layer was dried over MgSO4. The ether was removed 'by rotary evaporation and the oil was distilled (bulb to bulb) under vacuum to give 0.808 g (55% yield) of an 89:11 mixture of N-isobutyl-(2,2-dimethyI)-4-pentenylamine and N-Methyl-N- isobutyl-(2,2-dimethyl)-4-pentenylamine (b.p. 60-65°C/10 mm Hg). WWW To 15 mL of dry dioxane were added 1.338 g (8 mmol) of the enamine 77 and 1.489 g (8 mmol) of MeOTs. The solution was heated to reflux. After 17 hours, the solution was cooled to 0°C and 16.0 mL (16 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was allowed to stir at ambient temperature for two hours. The solution was then cooled to 0°C and quenched by addition of 0.6 mL of water, followed by 0.6 mL of 15% aqueous NaOH, followed by 1.8 mL of water. After stirring for one hour, the mixture was filtered and then treated with an excess of aqueous HCI. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14. The amine 88d was extracted with three 50 mL portions of 56 ether and the organic layer was dried over MgSO4. The ether was removed by rotary evaporation and the oil was distilled (bulb to bulb) under vacuum to give 0.948 g (65% yield) of a 72:28 mixture of N-isobutyl-(2,2-dimethyl)-4-pentenylamine and N-Methyl-N- isobutyl-(2,2-dimethyI)-4-pentenylamine (b.p. 60-65°C/10 mm Hg). To 100 mL of dry toluene were added 3.01 g (18 mmol) of the enamine 77. The solution was cooled to -78°C and 0.34 g (1.8 mmol) of TiCI4 were added. The mixture was heated to reflux. After 75 hours, at which time GLC analysis showed a >95% yield of the 7,6- unsaturated imine as compared to m-xylene internal standard, the mixture was cooled to -78°C and 36.0 mL (36 mmol) of a 1M solution of LiAlH4 In THF were added. After stirring for six hours, the reaction was quenched, at -78°C, by addition of 1.4 mL of water, followed by 1.4 mL of 15% aqueous NaOH, followed by 4.2 mL of water. The solution was allowed to warm to room temperature. The mixture was filtered and the filtrate was treated with excess aqueous HCI. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14 and extracted with four 100 mL portions of ether. The organic layers were combined and dried over Na2$O4. After filtration, the ether was removed by rotary evaporation under reduced pressure and the amine was distilled (bulb to bulb) under vacuum to give 1.70 g (56% yield) of 87 (b.p. 50-60°C/8 mm Hg). 57 Spectroscopic data was consistent with compound 87, obtained by the HCI catalyzed rearrangement. To 25 mL of dry toluene were added 1.147 g (5 mmol) of the enamine 79. The solution was cooled to -78°C and 3.0 mL (6 mmol) of a 2M solution of AIMe3 in toluene were added. The mixture was heated to reflux. After nine hours, the solution was cooled to 0°C and 5.5 mL (5.5 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was stirred for two hours at ambient temperature and then cooled to 0°C. The reaction was quenched by addition of 0.2 mL of water, followed by 0.2 mL of 15% aqueous NaOH, followed by 0.6 mL of water. After stirring one hour, the mixture was filtered and the solvents were removed by rotary evaporation under reduced pressure. The amine was distilled (bulb to bulb) under vacuum to give 1.058 g (92% yield) of 89 (b.p. 60-75°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.76 (dd, 6 H, J-6.6, 2.5 Hz), 1.34 (s, 3 H), 1.63 (tsept., 1 H, J=6.8, 6.6 Hz), 2.29 (dd, 2 H, J=3.3, 6.9 Hz), 2.35 (dd, 1 H, J=7.6, 13.8 Hz), 2.52 (dd, 1 H, J-6.6, 13.8 Hz), 2.63 (d, 1 H, J=11.5 Hz), 2.80 (d, 1 H, J-11.5 Hz), 4.94 (d, 1 H, J-10.0 Hz), 4.99 (d, 1 H, J-17.1 Hz), 5.57 (ddt, 1 H, J-10.0, 17.1, 6.6 Hz), 7.25 (m, 5 H); 13C NMR (75.5 MHz) (CDCI3) 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, 959 cm‘1. 58 AIM” -._ :0 ::. -I0:II:I 0 3 00” :0 0 3:0, .011 0 N- To 50 mL of dry toluene were added 1.673 g (10 mmol) of the enamine 82. The solution was cooled to -78°C and 6.0 mL (12 mmol) of a 2M solution of AIM63 in toluene were added. The mixture was heated to reflux. After nine hours, the solution was cooled to 0°C and 20.0 mL (20 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was stirred for 2.5 hours at ambient temperature and then cooled to 0°C. The reaction was quenched by addition of 0.8 mL of water, followed by 0.8 mL of 15% aqueous NaOH, followed by 2.4 mL of water. After stirring one hour, the mixture was filtered and an excess of aqueous HCI was added. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14 and extracted with four 100 mL portions of ether. The organic layers were combined and dried over Nast4. After filtration, the ether was removed by rotary evaporation under reduced pressure. The amine was distilled (bulb to bulb) under vacuum to give 1.422 g (84% yield) of 90 (b.p. 70- 80°C/8 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.85 (t, 3 H, J-7.4 Hz), 0.85 (d, 6 H, J-6.6 Hz), 1.29 (m, 2 H), 1.48 (ddq, 1 H, J-6.4, 6.4, 7.4 Hz), 1.50 (ddq, 1 H, J-6.4, 6.4, 7.4 Hz), 1.69 (tsept., 1 H, J=6.7, 6.6 Hz), 2.04 (dddd, 2 H, J-1.3, 1.3, 6.1, 7.2 Hz), 2.34 (d, 2 H, J- 6.7 Hz), 2.44 (d, 1 H, J-6.4 Hz), 2.45 (d, 1 H, J-6.4 Hz), 4.95 (ddt, 1 H, J-1.1, 10.0, 1.3 Hz), 4.99 (ddt, 1 H, J=1.1, 17.2, 1.3 Hz), 5.76 (ddt, 1 H, J=10.0, 17.2, 7.2 Hz); 13C NMR (75.5 MHz) (CDCI3) 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, 59 2959, 2928, 2874, 2813, 1640, 1466, 1381, 1366, 1125, 995, 911 cm'l. To 30 mL of dry toluene were addecd 1.076 g (6 mmol) of the enamine 85. The solution was cooled to -78°C and 3.6 mL (7.2 mmol) of a 2M solution of AIM63 in toluene were added. The mixture was heated to reflux. After nine hours, the solution was cooled to 0°C and 6.6 mL (6.6 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was stirred for six hours at ambient temperature and then cooled to 0°C. The reaction was quenched by addition of 0.25 mL of water, followed by 0.25 mL of 15% aqueous NaOH, followed by 0.75 mL of water. After stirring one hour, the mixture was filtered and an excess of aqueous HCI was added. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14 and extracted with four 100 mL portions of ether. The organic layers were combined and dried over Na2$O4. After filtration, the ether was removed by rotary evaporation under reduced pressure. The amine was distilled (bulb to bulb) under vacuum to give 0.719 g (67% yield) of 91 (b.p. 30-40°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.86 (d, 6 H, J-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=6.9, 11.5 Hz), 2.39 (dd, 1 H, J=6.6, 11.5 Hz), 2.96 (dt, 1 H, J=5.8, 6.0 Hz), 4.94 (dd, 1 H, J=1.2, 10.1 Hz), 5.00 (dd, 1 H, J=1.2, 17.1 Hz), 5.79 (ddt, 1 H, J-10.1, 17.1, 6.7 Hz); 60 13C NMR (75.5 MHZ) (CDCI3) 8 20.6, 21.0, 28.3, 30.7, 32.7, 41.9, 56.5, 61.5, 115.1, 138.7; IR (neat) 3349, 3077, 2955, 2870, 2011, 1642, 1470, 1387, 1366, 1138, 993, 911 cm'1. To 30 mL of dry toluene were added 1.160 g (6 mmol) of the enamine '86. The solution was cooled to -78°C and 3.6 mL (7.2 mmol) of a 2M solution of AIM63 in toluene were added. The mixture was heated to reflux. After nine hours, the solution was cooled to 0°C and 6.6 mL (6.6 mmol) of a 1M solution of LiAlH4 in THF were added. The mixture was stirred for six hours at ambient temperature and then cooled to 0°C. The reaction was quenched by addition of 0.25 mL of water, followed by 0.25 mL of 15% aqueous NaOH, followed by 0.75 mL of water. After stirring one hour, the mixture was filtered and an excess of aqueous HCI was added. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14 and extracted with four 100 mL portions of ether. The organic layers were combined and dried over Na2804. After filtration, the ether was removed by rotary evaporation under reduced pressure. The amine was distilled (bulb to bulb) under vacuum to give 0.693 g (59% yield) of 91 (b.p. 40-50°C/<1 mm Hg): 1H NMR (300 MHz) (CDCI3) 6 0.87, (d, 6 H, J-6.6 Hz), 1.30 (m, 4 H0, 1.50 (m, 4 H), 1.67 (m, 3 H), 1.95 (m, 1 H), 2.15 (m, 1 H), 2.26 (dd, 1 H, J-6.8, 11.3 Hz), 2.38 (dd, 1 H, J-6.8, 11.3 Hz), 2.59 (m, 1 H), 4.93 (ddt, 1 H, J-1.1, 61 10.3, 1.4 Hz), 4.96 (ddt, 1 H, J=1.1, 16.8, 1.4 Hz), 5.75 (ddt, 1 H, J=10.3, 16.6, 6.7 Hz); 130 NMR (75.5 MHz) (CDCI3) 6 20.6, 22.5, 23.0, 27.1, 28.4, 26.6, 33.4, 39.1, 55.4, 57.1, 115.3, 136.6; IR (neat) 3359, 3077, 2926, 2659, 2605, 1642, 1470, 1366, 1130, 1103, 993, 909 cm'1. To 25 mL of dry toluene were added 0.967 g (5 mmol) of the enamine 86. The solution was cooled to -78°C and 0.095 g (0.5 mmol) of TiCl4 were added. The mixture was heated to reflux. After 93.5 hours, at which time GLC analysis showed a >95% yield of the y,6-unsaturated imine as compared to m-xylene internal standard, the mixture was cooled to -78°C and 10.0 mL (10 mmol) of a 1M solution of LiAlH4 in THF were added. After stirring for six hours, the reaction was quenched, at -78°C, by addition of 0.4 mL of water, followed by 0.4 mL of 15% aqueous NaOH, followed by 1.2 mL of water. The solution was allowed to warm to room temperature. The mixture was filtered and the filtrate was treated with excess aqueous HCI. The solution was concentrated by rotary evaporation under reduced pressure. The residue was treated with 15% aqueous NaOH to a pH of 14 and extracted with three 50 mL portions of ether and dried over Na2804. After filtration, the ether was removed by rotary evaporation under reduced pressure to give 0.763 g (78% crude yield) of the amine 92. Spectroscopic data was consistent with compound 92 obtained by AIM93 catalyzed rearrangement. 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APPENDICES 33333333333333333333 Compound 73 Compound 74 Compound 75 Compound 76 Compound 77 Compound 78 Compound 79 Compound 80 Compound 81 : Compound 82 : Compound 83 : Compound 84 : Compound 85 : Compound 86 : Compound 87 : N-Methyl-N-isobutyl-(2,2-dimethyl)-4-pentenylamine : Compound 89 : Compound 90 : Compound 91 Compound 92 APPENDIX A 1H NMR Spectra 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 65 m.m~ «.m vd mK o.m m.m .11. 1|; ..I.I.. .ILJ .II. .LJ 0 Ian." m m w m w n m _.....hh.-—ph-_..p.—.-..—.-.-_-..—..—.—P_P-_p.-__...—-..__..._...-I—-__-—...._ IIIII 1 I. 1.1 I; W11 IIIIIIIIJI IIJIIHII III,III|I IIII... . I. Ii _ I‘sIIII .|\I hm 23:28“; 2o W NMWMWW“ Qfimnu a... 3%... ocu< 3 ._uz<.— mo: om zomo wz \ vmw. 3 n.............. Emfiwzwafihaeammfijfz 2 2:858 ”F E: I. 66 3E 12 15%.: m...“ 3. ncsanoo ”N ~32 IF mm.m« - u 0 mm. .8“ av m .LJn mv n m _ o 2&« m m v m m N Lrp_h___.._..___.__.___.-__h~__..._~__.._._.__ p...__—h._e~_..._..-rbp--_..h._ |I 71 .Il . III .I : I . 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