«nu—n- —e¢ mg. THEREACTIONSOF ESTER mama ; ~ 1 . ‘ 'Ehesisv for "the Degree: off-Phi. D.’ MECH‘GAN STATE UNWERSIW , ~ new E. SifLLEVAN. , ? " 1974. , * ”th hdichigau '3: (328 University l.' This is to certify that the z ’ _ J,thesis entitled THE REACTIONS OF ESTER ENOLATES presented by Donald F. Sullivan has been accepted towards fulfillment of the requirements for W Major professor ABSTRACT THE REACTIONS OF ESTER ENOLATES Donald F. Sullivan Lithium dialkyl amide bases can be used to prepare stable solutions of lithium ester enolates in THF at —78°. The enolate solutions react at -78° with carbonyl compounds to produce, after hydrolysis, B-hydroxy— esters in good yield. Only ethyl isovalerate failed to give high yields of B-hydroxyesters by this procedure. This procedure for generating ester enolates was extended to o,B-unsaturated esters. Stable solutions of a,B-unsaturated ester eno- lates can be generated in THF-HMPA at -78°. Hydrolysis of these solu- tions produces the B,y-unsaturated isomers of the starting esters. These ester enolates also react with alkylating reagents and car- bonyl compounds exclusively at the a carbon. Silylation of ester enolates produces a-silylated esters and/or trialkylsilyl ketene acetals. The course of the reaction is dependent on the structure of the enolate. The synthetic utility of these two products is investigated in a number of reactions. Q. 'l’ as the u ‘II a... S'u'I (Eiéilé ”1 "a“ " “B“;‘hu‘x ‘ firm. Spectral evidence in support of an oxygen—metalated enolate, {, as the preferred structure for an ester enolate, is presented. Kinetic and synthetic data are also given as evidence for the existence of ketene intermediates in the decomposition of ester enolates. M 4-.” I \\OR 8H THE REACTIONS OF ESTER ENOLATES By Donald Ff Sullivan A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1974 To Linda 11 ACKNOWLEDGEMENT The author wishes to extend his appreciation to a fine chemist and a fine friend, Dr. Michael W. Rathke, for his guidance and inspiration throughout this work. The author also appreciates the continued interest and encourage- ment of his parents in his education and hopes that their expectations for him have been adequately fulfilled. The author thanks his*wife for her understanding, interest, and encouragement which made his matriculation at Michigan State University infinitely more enjoyable. Finally, the financial support of Michigan State University, the National Science Foundation, and the Petroleum Research Fund of the American Chemical Society, is gratefully acknowledged. iii THE REACTIONS Introduction Results .. Discussion .. Experimental THE PREPARATION AND REACTIONS OF a,B-UNSATURATED Introduction Results .. Discussion .. Experimental TABLE OF CONTENTS CHAPTER I OF ESTER ENOLATES WITH CARBONYL COMPOUNDS CHAPTER II ESTER ENOLATES iv Page 23 24 30 37 CHAPTER III THE SILYLATION OF ESTER ENOLATES AND THE REACTIONS OF a-SILYLATED ESTERS AND TRIALKYLSILYL KETENE ACETALS Introduction .. .. .. .. .. .. Results .. .. .. .. .. .. .. Discussion .. .. .. .. .. .. .. Experimental .. .. .. .. .. .. CHAPTER IV THE STRUCTURE AND DECOMPOSITION OF ESTER ENOLATES Introduction .. .. .. .. .. .. Results .. .. .. .. .. .. .. Discussion .. .. .. .. .. .. .. Experimental .. .. .. .. .. .. BIBLIOGRAPHY .. .. .. .. .. .. Page .. 41 .. 46 .. 59 .. 74 IN SOLUTION .. 86 .. 88 .. 98 .. 104 .. 109 TABLE II III IV VI VII VIII IX LIST OF TABLES PAGE Yields of B-Hydroxyester Using Lithium Ester Enolates .. .. .. .. .. .. 7 Results of Quenching Ester Enolate Solutions at -780 o. oo no so oo o. co 9 Comparison of Yields of B-Hydroxyesters Obtained via the Reformatsky Reaction and Using Lithium Ester Ester Enolates .. .. 11 Yields of B-Hydroxyester Formed from Ethyl a-Bromoisovalerate, Zinc, and Carbonyl Compound .. .. .. .. .. .. 12 Results of Quenching the Enolate of Ethyl Crotonate .. .. .. .. .. .. 25 Results of Quenching Various u,B-Unsaturated Ester Enolates .. .. .. .. .. 28 Results of Dehydrating Hydroxyesters with Various Reagents .. .. .. .. .. 31 Results of Silylation of Ester Enolates .. 47 Reaction of O-t-Butyldimethylsilyl-O'-ethy1 Ketene Acetal with Acid Chlorides .. .. 55 vi FIGURES 10 LIST OF FIGURES Reaction of Ester Enolate and Carbonyl Compound .. .. .. .. .. .. Stereochemistry of Transition State in Reaction of Ester Enolate and Carbonyl Compound .. .. .. .. .. .. Reaction Apparatus .. .. .. .. .. Ester Enolate Resonance Hybrid .. .. .. Resonance Contributors of a Ketene Acetal .. Transition State of Reaction Between Ketenes and Ketene Acetals .. .. .. .. .. Possible Decomposition Routes of Ester Enolates .. .. .. .. .. .. Decomposition Kinetics of t-Butyl Acetate .. Decomposition Kinetics of Ethyl Hexanoate .. Decomposition Kinetics of Ethyl Isobutyrate .. vii. PAGE 15 15 17 41 44 67 87 91 92 93 m4 CHAPTER I THE REACTIONS OF ESTER ENOLATES WITH CARBONY'L COMPOUNDS INTRODUCTION Although ketone and aldehyde enolates have been used extensively in organic synthesis (1), the chemdstry of ester enolates is a relatively new and little-studied field. While solutions containing equilibrium concentrations of aldehyde or ketone enolates are synthetically useful, eqidJibrium solutions of ester enolates undergo rapid, irreversable «condensations to form B-keto esters (i.e. Claisen condensation) (2). sc—cozn + 3' —> ‘c-cozn + BH 0 | uc-coza + ’c-cozn ———’HC-C-C-COZR + R0- In the past, if ester enolates were to be used in other than Claisen reactions, they were generated from zinc metal and the corresponding a-haloester (Reformatsky reaction) (3). | Zn . | x—clz-coza WBan-C-szR benzene I Due to the instability of zinc enolates at the temperatures required for their generation, further reactions using the ester enolates are limited to those reagents which can be present in the reaction mixture fin?" 5:2: I :bjec 53322; p n‘. n Vebel. the g appro from the beginning. The Reformatsky reaction, though widely used, is subject to a host of side reactions and the yields of B-hydroxyester formed from the reaction of the enolate with carbonyl compound are of ten low. Finally , 2|... ll * l“ I H —(|3-—C02R+ ,c\—> ———§ -—(lJ—-C-COZR the generality of the reaction is limited by the availability of the apprOpriate a-haloester. Direct proton removal from an ester provides a more convenient and general preparation of ester enolates. Such proton removal requires a strong (pKa of an ester 2 24) (4), organic-soluble base. Early attempts (5) to generate ester enolates utilized sodium triphenylmethane as base. The enolates were then reacted with acid halides to obtain B-keto esters. 0 | Nacm I RCOX II | H -- (II-0029. —————>"|c-coza -———> R ——- c —— T — 002R Hauser later developed (6) an alternative procedure by which enolates of t-butyl esters were generated in liquid amonia using lithium amide as base. The enolates were relatively stable at the temperature employed (-37°); however, the sequence had to be completed as rapidly as P0881b1e to avoid appreciable self-condensation. A major disadvan- tage of this method is the use of liquid ammonia as solvent, since this precludes the subsequent use of many reagents such as acid chlorides or the more reactive alkyl halides. Dialkyl amide bases are strong (pKa of the amine > 34) (7), soluble, non-nucleophilic bases capable of generating ester enolates quantita— “3 tively at dry-ice temperatures. At -78°, the enolates are indefinitely T: - ._...n' ‘. A stable. Sodium bis(trimethylsilyl)amide was the first amide used to generate an ester enolate (8). Formed at -65° in ether, sodio ethyl acetate, upon reaction with trimethylchlorosilane (TMCS), produced a mixture of ethyl trimethylsilylacetate (22.32) and O-trimethylsilyl-d-ethyl ketene acetal (13.72). TMCS /0CH2CH3 NaCIizCOZCHZCH3——-—’ (0113) 331012002012033 + CH2- c\ -65° 081(CH3)3 (22.32) (13.72) Lithium bis(trimethylsily1)amide, formed in hexane by reaction of the amine with a commercial butyllithium solution, generated the ester enolate of ethyl acetate quantitatively at -78° in THF (9)- BuLi [(CH3)3Si]2NH ———)[(CH3)381]2NL1 + butane hexane -78° E1 [(CH3)3Si]2NLi + cn3c02cuzcs3——DCHZCOZCHZCH3 + [(CH3)3Si]2NH THF This lithium enolate reacted readily with aldehydes and ketones at -78° to produce, after addition of acid, B-hydroxyesters in excellent yield. o 0" u _ -78° I -—c — + cnzcozcuzcsg ——> —— (I: — CH2C02CH2CH3 on I n“ — c — cszcozcszcng 4L 1 Attempts to extend this procedure to the preparation of other ester enolates proved unsuccessful. For example, addition of ethyl hexanoate to a solution of lithium bis(trimethylsilyl)amide at -78° resulted in a slow condensation of the ester, which was complete in one hour. Subsequently, it was discovered (10) that the base lithium 18OPrOPylcyclohexylamide (LiICA) was capable of generating a variety of stable ester enolates at -78°. No self-condensation products were observed at -78° and the lithium ester enolate solutions, thus pro- duced, can be used as discrete synthetic intermediates. Consequently, a study of the addition reaction between these ester enolates and carbOnyl-containing compounds was undertaken. RESULTS Reaction of the lithium enolates of ethyl acetate, ethyl butyrate, and ethyl isobutyrate with various carbonyl compounds proceeded smoothly at —78° in THT'to produce the corresponding B-hydroxyesters in reason- ably high yields. (Table I). 0 OH H - -78° H+ — C —- + —- C —— C020H2CH3 —'> -_'. "" C — C — C02CH2CH3 | THF l The enolates themselves were produced in quantitative yield at -78° by treatment of the corresponding ester with lithium isoprOpylcyclo- hexylamide in THF. These enolates were stable indefinitely at -78°, decomposing principally to B-keto esters on warming to room temperature. 0 | A llll 2 "c 4020112013 —p "c-c-c-cozcszcna The LiICA was generated by addition of N-isopropylcyclohexylamdne to a butyllithium—hexane solution at 0°. The reaction was complete within 5 minutes. I} Li N T// hexane H + Bum 0o + ‘ T +buume TABLE I Yields of B-Hydroxyester Using Lithium Ester Enolates Yield of Ester Substrate Hydroxy Esterc H l) on R1 1 ' 3 i u 3‘ ' R 44020112013 R -C-R R -C—C—C02CH2CH3 l lul R2 R R2 111-3241 R3 , R‘h- (CH2) ., 65:a R1=R2=CH3 R3 ,R"- (CH2) 5 sub Rl-Rz-Cl'lg R3-H,R‘+-cnzcn3 7513 RlaRz'Cua R3 ,RH- (CH2) 1., 751b Rl-H RZ- CHZCH3 R3,R‘*-(CH2)5 76%al al-H RZ- CH2CH3 R3,R‘*=(CH2)¢, 751a 111-112-0113 R3-H,R‘*-o i 66:b a E glpc yield b E isolated yield 0 ll ' all compounds had spectral and physical data consistent with their assigned structures CO‘. lo que tea Removal of the hexane and addition of THF gave a solution of the amide. This solution was cooled to -78° and the ester was added dropwise. Quenched samples of these solutions showed quantitative recovery of the starting esters. (Table II). For the preparation of the B-hydroxyesters, an ester enolate was generated at -78° and after stirring for 15 minutes the carbonyl com- pound was added slowly over a period of one minute. After five more minutes the solution was quenched and worked-up with ether or pentane. Table I lists some representative yields for this procedure. Under these conditions only ethyl isovalerate failed to yield pure Products. Reaction of the lithitnn enolate of ethyl isovalerate with acetone, diethyl ketone, propionaldehyde, and cyclohexanone invariably yielded an additional product. In the case of diethyl ketone an exten- sive effort was made to ascertain the structure of this side product without success. It was found, however, that the unknown side product could be removed by allowing the reaction mixture (enolate plus ketone) to warm to room temperature for approximately one half hour prior to quenching. This modification, while improving the purity of the crude reaction mixture, drastically reduced the yield of the desired B"hydrm‘yester. In the case of diethyl ketone, only 41% of the eth)’1 3"ethy1‘3-hydroxy-2-isOpropYlpentanoate was obtained under these new conditions . TABLE II Results of Quenching Ester Enolate Solutions at -78° E Ester Recovered ester, 2 Ethyl propionate 90 Ethyl hexanoate 100 tert-Butyl hexanoate 97 Ethyl nonanoate 100 Ethyl isobutyrate 97 Ethyl isovalerate 97 Ethyl cyclohexanecarboxylate 95 Ethyl phenylacetate 98 aDetermined by glpc analysis of aliquots quenched ‘with‘water. Vere thy in th tons 10 DISCUSSION The use of ester enolates to make B—hydroxyesters from aldehydes and ketones provides a convenient alternative to the Reformatsky reaction. The reaction time was much shorter, the reaction conditions were less vigorous, the yields exceeded, or were comparable to, those obtained using the zinc enolates, (Table III), and the o-halo derivatives of the esters were not required. In most cases, the crude B-hydroxyester, after routine work-up, was pure enough to use in further synthetic applications . As noted in Tables I and III, excellent Yields of the B-hydroxyesters were obtained from a variety of esters and carbonyl substrates. Only ethyl isovalerate failed to react as expected. The lithium enolate of ethyl isovalerate is formed at -78° and is stable indefinitely at this temperature. The enolate reacts with benzaldehyde to yield the corresponding B-hydroxyester quantitatively. However, reaction of the enolate with aldehydes or ketones having a protons invariably yields a side product. Ethyl 2-bromoisovalerate behaves similarly when used in the Reformatsky reaction. With the exception of acetone, yields are reported in the literature only when the carbonyl compound has no enolizable pro- tons (Table IV). The increased steric requirements of the enolate of ethyl isovale- rate apparently result in some side reaction, possibly involving enoliza- 11 TABLE III Comparison of Yields of B-Hydroxyesters Obtained via Reformatsky Reaction and Using Lithium Ester Enolate aheonuou.+an .umunooaounnu seams .GamC gm .3 team .80 .mH m "umam .H £0 3 .fifidfl ch Nwh OvhfiflvHflNGOD Nuflhhufipowfi Hhfiufl haemmav use .moc am“ .3 .hxmusahommm Nmn new mvhamnammoamoun mumuhunmonu Hamum .SN .fifl 3Q ..Hm .um .numaaumz Nmm nee unassummmoaomu ousuhuan Hanan .mflda .nomaamz «on Nwo oaosmxmaoauho mumuhusn thum $8: 8 .3». aqua .SUmHHmz Nam non mcosmxmnoaohu mumuhusnomw Henna mumaomm mhxmumauommm anusuaa moamummmm mw> vamww mw> mama» Hacopumo umumm noummhxounhmum Yield Carbony Acetal‘ (1 12 TABLE IV Yields of B-Hydroxyester Formed from Ethyl o-Bromoisovalerate, Zinc, and Carbonyl Compound Carbonyl Compound Yield of Hydroxyester Reference Acetaldehyde None Reported Maturewitsch, J. Russ. Phys. Chem. Soc., 31, 1319 (1909). Isovaleraldehyde None Reported Reformatsky, ibid., 33, 242 (1901). Benzaldehyde 60% Reformatsky, J. Prakt. Chem,, 24, 469, 477 (1896) Acetone 50% ibid. tion of th below. it: n‘"O fi;:; 0 results a 3 Carbo: CarbOn 1‘ The to diiso} Crignard conditio‘ enoliled 13 tion of the carbonyl compound, and subsequent reactions such as shown below. 0 H o H II I _ || - 4, l ——c—-—c|:—— + —c—-COZCHZCH3——>—c——c=c n— \ __ H \0 — C(CH3)3 O (0'13)3 m—o—r‘ O I R A complexation of reactants prior to reaction may favor a six- membered ring transition state leading to the B-oxido esters obtained. (Figure 1) . 0., 0 (fi OLi \/C/\}"L1 ——c/ \Li 1’ I _.c_+ -(f=c\ ——§. {| ——p| OR __° _ /C\c/O /c\C/o l I on OR Figure 1. Reaction of Ester Enolate and Carbonyl Compound The sterochemistry of this transition state suggests that there may be a substantial difference in the relative energies of the transi- tion states of different enolates, as B-substitution in the enolate (Figure 2) is increased (i.e. as the size of R,R' increases). h ..... /_ f /\ R"O Stereochemistry of Transition State in Reaction of Ester Enolate Figure 2. and Carbonyl Compound Before a more quantitative description can be obtained, the preferred configuration of the enolate must be established, and the rate at which the two possible configurations interconvert under the reaction condi- tions must be determined. 16 0L1 OR /\ C R R 17 j—p TO MERCURY BUBBLER A as. ————> i INLET VALVE ' v 1 +— RUBBER SEPTUM CD MAGNETIC STIRRER Figure 3. Reaction Apparatus l8 EXPERIMENTAL 1. Materials Esters All esters were commercially available and were used without fur- ther purification. Carbonyls All ketones and aldehydes were commercially available and used without further purification. II. Preparation of Ester Enolates and their Reaction with Ketones and Aldehydes The ester enolates were prepared and reacted in a manner similar to that described for ethyl acetate. All analyses were performed using a % inch by 6 foot SE-30 column with apprOpriate internal standards. A. Preparation of Lithio Ethyl Acetate A 50 m1 flask equipped as in Figure 3 was flame dried under nitrogen. To this flask was added 2.38 ml (5.25 mmoles) of a 2.2 M commercial solution of butyllithium in hexane. The flask was cooled in an ice bath and 0.89 ml (5.25 mmoles) of N-isopropylcyclohexylamine was added dropwise with stirring. When the evolution of butane was com— Plete, a vacuum was applied until the hexane removal was complete. The flask was flushed with nitrogen and 5 m1 of tetrahydrofuran was 19 added. After dissolution of the oily residue of lithium.N-iso- propylcyclohexylamide was complete, the flask was cooled in a dry ice-acetone bath. The ethyl acetate (0.495 ml; 5.0 mmoles) was added dropwise and after 15 minutes quenched with 5 m1 of a 2 M solution of HCl. The mixture was warmed to room temperature and extracted with pentane. Recovery of the ethyl acetate was essen- tially quantitative. B. Reaction of Ester Enolates with Carbonyl Compounds The preparation of the enolate was as described above. After 15 minutes at -78°, the carbonyl compound was added drapwise. After an additional 15 minutes, the solution was quenched at -78°, as above, and extracted with pentane. The organic layers were collected, dried over K2C03 and examined by glpc. C. Modified Procedure with Lithio Ethyl Isovalerate The procedure as described for diethyl ketone is representative. The enolate of ethyl isovalerate (5.0 mmoles) was prepared, as above. The ketone (0.52 ml; 5.0 mmoles) was added slowly and, after 15 minutes at «78°, the solution was placed in an ice bath. After 30 minutes, the solution was quenched with 2 M HCl and worked-up as described. The glpc yield of ethyl 2-isopropyl-3-ethyl-3- hydroxypenanoate was 41%. groduct Analysis The hydroxyesters synthesized were examined by NMR and/or their 20 physical constants compared with published values. E thyl 2- (1-hydroxycyclopentyl) ace tate NMR(CCl;,): 4.16 (q,2H), 3.16 (5,1H), 2.26 (3,211), 1.56 (broad s, 8H), 1.35 (t,3H). Ethyl 2- (l-hydroxy cyclohe x11) ~2-methy 1p ropanoate o B.p. 126-128°/1l mm. Refractive index 11])23 1.4637. NMR(CCl.,): 4.15 (q,2H), 3.155 (3,13), 1.35 (m,19H). E thjl 2 , 2-dime thy 1- 3-hydroxypentanoate Refractive index nD22-5° 1.4411. NMR(CC1¢,): 4.16 (q,2H), 3.56 (111,111), 3.46 (8,111), 1.16 (m,1'4fl). E thll 2 , 2-dime thyl- 3-pheny1- 3-hydrozgpropanoate B.p. 115°/0.05 nun. Refractive index nD23° 1.5075. NMR(CC1;,): 7.56 (s,5H), 5.06 (3,111), 4.36 (q,2H), 3.856 (3,111), 1.56 (t,3H) 1. 36 (d,6H) . E thyl 2- (1-hydroxycy clopentyl) -2-me tfllp rapanoate O Refractive index nD22-5 1.4593. NMRccc1t): 4.15 (q,2H), 3.05 (8.111), 1.66 (broad 9,811), 1.16 (m,9H) Eth 1-2- l-h dro c clohe 1 butanoate O Refractive index nD23-5 1.4616. NMR(cc1.): 4.15 (q,2H), 2.655 (8.1H), 2.15 (t,1H), 1.45 (m, 18H)- 21 Ethyl 2-(lehydroxycyclopentyl)butanoate o B.p. 70°/0.02 mm. Refractive index nD23-S 1.4540. NMR(CC15): 4.16 (q,2H), 2.656 (s,1H), 1.506 (m,11H), 1.16 (t,3H), 0.986 (t,3H). Ethyl 3-ethyl-B-hydroxy-Z—isoprOpylpentanoate o Refractive index 11DZ3-S 1.4412. NMR(CCln): 4.156 (q,2H), 3.156 (s,1H), 2.36 (m,1H), 1.16 (m,20H). CHAPTER II THE PREPARATION AND REACTIONS OF a,B-UNSATURATED ESTER ENOLATES 22 23 INTRODUCTION Since Bauer's initial observations (15, 16) it has been well established that enolate anions derived from a,B-unsaturated ketones react predominantly at the alpha carbon. In contrast, almost nothing is known about the chemistry of enolate anions derived from a,B-unsaturated ester derivatives of carboxylic acids. , Early investigations into the chemistry of the o,B-unsaturated ester system involved attempts to isomerize the double bond to the B,y-position. (17) . Except in cases involving unusual steric or electronic requirements, poor yields of the (Ly-unsaturated material were obtained. As a result, more elaborate synthetic methods have been developed to prepare these compounds; (18, 19) however, none involve generation of enolate anions of the (LB-unsaturated esters. Although methods now exist for generating metal enolates of 01,8- unsaturated esters, they are not as general or as convenient as the forma- tion of Simple lithium ester enolates from a lithium dialkyl amide and the corresponding ester. With this in mind, we attempted to develop a parallel Procedure which would provide a convenient synthetic source of the lithium enolate anions of a,B-unsaturated esters. 24 RESULTS Treatment of a l M solution of lithium isopropylcyclohexylamide (LiICA) in THF at -78° with ethyl crotonate, followed by quenching with dilute HCl, yielded two products, the starting ester and its B.Y-unsatu- rated isomer in yields of l and 222 respectively. 1 M LiICA 11+ cu3cu-cn-cozcuzcu3 ———-> ——-> cnz-cn-cuz-cozcazcu3(22z) -78° THF + cs 3cu-cncozn (11) . The total recovery of material and the relative product ratio was only slightly affected by replacing ethyl crotonate with its t-butyl analog or by prolonged reaction times with LiICA at -78°. 0 ll 1 M LiICA 11+ (3113*- CH=CH — c — 0+- —-—-——D ——-> CHZ-CH-CHZ-COZ + (192) THE, -78° + CH 3-c11-ca-c02 + (2%) When hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO) or bis(Z-methoxyMiethyl ether (diglyme) were used as co-solvents, the total yield and product ratio changed. (Table V). Replacing LiICA as the amide base with lithio-2,2,6,6-tetramethyl- Results of Quenching the Enolate of Ethyl Crotonate 25 TABLE V a Ester Za,8 ZB,Y Solvent Base Concentration THF LiICAb 1.0 M 1 22 THF LiTMPc 1.0 M 12 72 THF-HMPA (20% by vol.) LiICA 1.0 M 9 55 THF-HMPA (402 by vol.) LiICA 1.0 M 14 39 THF-DMSO (202 by vol.) LiICA 1.0 M 9 21 THF-Diglyme (202 by vol.) LiICA 1.0 M 13 27 THF LiICA 0.5 M 3 31 THF-HMPA (201 by vol.) LiICA 0.5 M 13 87 :Ethyl crotonate was used throughout as the ester substrate Lithium N-isopropylcyclohexyl amide c Lithium 2,2,66,-tetramethy1piperidine 26 piperidine resulted in an 842 total product recovery (72% non-conjugated ester and 12% starting material): Li N -78° 11* CH3-CH -CH-C02CH2CH3 + ——-D —> CH3-CH=CH—C02CH2CH3 (122) ' THF + CH2=CH-CH2-'C02CH2CH3 (72:) The yield of recovered material was also dependent on concentration. Treatment of a 0.5 M solution of LiICA in THF, with an equivalent amount of ethyl crotonate gave, after quenching, 312 of the non-conjugated material and 32 starting ester. 0.5 M LiICA CH2'CH-CH2-C02CH2CH3 (311) CH ch-CH-COZCHZCH3 -—————) + THF, -78° CH3CH-CH-C02CH2CH3 (3%) Finally, when a 0.5 M solution of LiICA was used with 202 (by volume) added HMPA, a quantitative yield of the non-conjugated and conjugated pro- ducts was obtained in a ratio of 87:13. Under these conditions, the lithium enolate of ethyl crotonate was stable indefinitely at -78°, but decomposed slowly (32 life - 1 hour) at room temperature to undetermined products. 0 Z recovery :| 25° 11* cuzacn-CHZCOZR 78 58 37 CH2 ‘4‘ ~ ,’C ———-’ ——’ + 7.;61/ \OEt THF,HMPA Starting Material 3 4 3 time (min) 5 25 100 Win-uranium . E 27 This procedure for isomerizing an 0,8—unsaturated ester to its (Ly-unsaturated isomer was then applied to a variety of unsaturated esters with the results shown in Table VI. I H LiICA, HMPA H+ | | —T————c=(|:—(I:——002R H -78°, THF H The result obtained with methyl 2-butynoate was especially interes- ting. Quenching of the anion derived from this ester provided a sim- ple synthesis of the allenic ester, methyl 2,3-butadienoate. 0.25 M LiICA 11+ ‘ CHs-csc-cowns ~:> ——-> CH2=C=CHCOZCH3 (602) HMPA, THF -78° The enolate derived from ethyl crotonate was alkylated with methyl iodide by addition of the enolate solution at 0° to a 50:50 mixture of THF—HMPA containing excess alkyl halide. The non—conjugated, alkylated ester was obtained exclusively in an 87% yield. 0.5 M LiICA 01131 CHg-CH-CH—COZCHZCH3 4’ ) CH2=CH -— CH —— 00261120113 THF, HMPA 0° -78° CH3 28 TABLE VI Results of Quenching Various a,B-Unsaturated Ester Enolates Conjugated Ester, Non-Conjugated Ester, Ester 2a 2b Ethyl crotonate 13 87 Ethyl 3-methy1-2-butenoate 19 81 Ethyl 2-hexenoate 12 88 Methyl 24butynoate ——-—D cnz-ca — cu - 0020120113 THF, HMPA 0° -78° CHZ¢ Finally, treatment of the enolate of ethyl crotonate with 1 equiva- lent of acetone at -78°, followed by the addition of dilute HCl, yielded ethyl 2-viny1-3-hydroxy-3—methylbutenoate. 0 II 1 0.5 M LiICA CH3-— 0 -—— 0113 H chosen-0020112013 + + —D Gila-CH — CH -— c02<3Hz<533 THF, HMPA -78° ‘780 CH3 — C — OH C113 30 DISCUSSION Treatment of o,B—unsaturated esters with alkoxide bases yields an equilibrium mixture of starting material and the isomeric B.Y-unsaturated ester. The conjugated ester predominates 0 H II R'o- I c—OR———)-T=(l2—(lm—cozR+—c-—c-c——002R over the non-conjugated material in almost all cases. Dehydration of B—hydroxyesters, readily available via the Reformatsky reaction, yields more of the desired isomer but significant amounts of the conjugated isomer (Table VII) are also formed. (3). 3'1 0 I -H20 ——c—0R —————> -c=c——c~002R —n—m ——-n—o l —0— A8 a result of these limitations, more elaborate methods for the synthe818 of B,Y-unsaturated esters have been devised. Fittig's procedure for condensing sodium succinate with aliphatic aldehydes yielded 8,7-unsaturated acids. (20). 31 TABLE VII Results of Dehydrating Hydroxyesters with Various Reagents B-Hydroxyester Percentage of a,B-Unsaturated Ester P205 P0013 SOClz (fused) KHSOQ CH3 CZH5-l-—CHZCOZC2H5 39 62 53' 57 OH C235 C2H5—f—CH2C02C2H5 23 68 50 63 OH C337 C3HT-‘C‘—'CH2C02C2H5 24 51 31 51 OH 02115 CH3 CZHS—C--CHCOZCZH5 28 43 33 28 OH OH 19 43 32 45 cuzcozczns OH 30 58 50 38 32 0 H COZNa A R -— 0 ~— H + | —-—-’ R-CH-CH-CHZCOZH fuz “C02 T“ C02N3 Malonic acid condensed with butyl aldehyde in the presence of a variety of amines to yield major amounts of 3-hexenoic acid. (21). R3N 01130112082080 + CH2(C02H)2 —-§ cuchZ-CH-ca-caz-cozn With triethanolamine a 37% yield of the Eff-unsaturated acid alone was realized . More recently, conjugated esters have been transformed into their non-conjugated isomers via irradiation (22, 23)- The yields were high (351) and the procedure has been applied in a number of syntheses. Iron pentacarbonyl has been used as an isomerization catalyst, but other isomers, in addition to the 8.Y-unsaturated material, were formed. 24 hrs 0531 1CH-CHC02CH3———-’ chach-cucnzcozcng, (7:) 125° Fe(CO)5 + other isomers (852) 33 Isomerization via the metal enolate of an a,B-unsaturated ester has been accomplished in the case of ethyl y,y,y-trichlorocrotonate (25). Treat- ment of the ester with isopropyl magnesium chloride at -78° in THF, followed by addition of H20, gave ethyl 4,4-dichloro-3-butenoate in 76% yield. )— MgCl __ C13C-CH-CHC02Et ————b [C12C-CH-CHC02Et -78° C12C=CH-CHC02Et 3,0 I 0 Clzc-CH-CHZCOZEt <————— Clzc-CH-CH-C — OEt] (762) The presence of the Mg enolate was confirmed by its ready reaction saith a variety of electrophiles to yield the corresponding ethyl-3- tnatenoates, substituted exclusively in the a-position. cuzocna 30011201 I c120=c11 —— cu — COzEt 0\CHCH2CH3 c12c-cn-EH002E1: —> C12C=CH — cnoozrc CH3CH2CHO 0§c — 0113 A920 012C=CH —— CH —— 002m: 34 Similar behavior was observed in the reactions of the dianions of 2-hexenoic acid. (26). Treatment of 2-hexenoic acid with two equiva- lents of LiDIPA in THF followed by addition of H20, yielded the non- conjugated isomer exclusively. Alkylation of the 21.1019». H20 CH3CH2CHZCH-CHC02H ————§ ——+—> cagcnzcn-cncnzcozn H we‘n‘ m I l dianion with CH31 proceeded solely at the 01 carbon resulting in formation of 2—methyl-3-hexenoic acid. A more general procedure for generating a,B-unsaturated ester enolates used NaNH2 as base. (27). No B,y-unsaturated esters were reported synthesized in this fashion, but several different ester enolates were alkylated with butyl bromide to give B,y-unsaturated esters substituted in the 2-position. ' NaN n-BuBr R2 cn-cn-cu-cozcua 5 4 R2 0:011 --CHC02CH 3 NH 3 (1 ) Bu 4-Bromocrotonate esters, when added to zinc, reacted at the 2- position to give non-conjugated products. However attack also occurred 35 Br OH I 2n H20 | I -—C-—CH=CH—C02R } ’—C—-C—CH=CHCOZR l 0 l l // ‘\. + —C=CH-—CH--C02R -'C -—'OH at the 4-position. This product ratio was affected by substitution in the ester and in the carbonyl substrate. Choice of reaction conditions was also important. Cyclohexanone reacted to give predominantly the 4-substituted product in refluxing benzene and the 2-substituted product in refluxing ether. (30). OH CH2CH'CHC02CH3 (30%) 0 benzene BrCHZCH-CHCOZCH3 + OH COZCH3 + Zn ether CH HC = CH2 (602) Protonation of the lithium enolates of a,B-unsaturated ester enolates, generated from dialkyl amide bases, produced the B,Y-unsaturated isomer 111 high yield. The generality of the procedure has been demonstrated sand it also provides a convenient method for the generation of stable, tnisaturated.eeter enolates under these reactions conditions. 36 These enolates reacted with other electrOphiles at the a position. Heating, as in the Reformatsky reaction, did not affect the course of addition tn) carbonyls. Attempts to isomerize the addition product formed with acetone to the 4-substituted isomer resulted only in loss of the a-substituted product. COZEt 0Li A CH2 = CH — CH X a (CH3)2C — CH =cu -— 002Et CH3 ——c -- 0Li CH3 37 EXPERIMENTAL I. Materials The ethyl crotonate, diethyl isopropylidenemalonate, and ethyl 2- hexenoate were obtained commercially and used without further purifica- tion. The methyl 2-butynoate was provided by Dr. E. LeGoff and used directly. The ethyl 3-methy1-2-butenoate was prepared from the commercially available acid in 88% yield by the procedure described in Org. $23., 3, 714. II. Isomerization of a,B-Unsaturated Esters The procedure using ethyl crotonate is representative. A 50 m1 flask as shown in Figure 3 was flame-dried. A hexane solution of 5.25 mmoles of lithium N-isopropylcyclohexyl amide was prepared as described in Chapter 1. After removal of the hexane, 10 ml of tetrahydrofuran were added and, after dissolution of the amide, the flask was cooled to -78°. Two ml of HMPA were added (f.p. 7.2 ). The ethyl crotonate (0.62 ml; 5.0 mmoles) was added slowly. After 15 minutes the solution was quenched with 5 m1 of a 2 M solution of HCl. The solution was extracted with pentane; the organic layers were combined and dried over K2003. The product mixture was examined by glpc and shown to contain 871 ethyl 3-butenoate and 132 ethyl crotonate. Product Analysis All o,B-unsaturated esters produced in the above manner were 38 separated from isomeric starting ester by a k inch by 6 foot column of SE - 30. The products were collected directly from the gas chromato- graph and analyzed by NMR. Ethyl 2-deuterio-3-butenoate NMR(CC1E): 5.86 (m,1H), 5.256 (d.1H), 5.06 (m,1H), 4.16 (q,2H), 3.06 (m,1H), 1.26 (t,3H). Ethyl 4-deuteriocrotonate NMR(CClt): 6.956 (m,1H), 6.056 (m,1H), 5.756 (m,1H), 4.26 (q,2H), 2.06 (d,2H), 1.36 (t,3H). Methyl 2,3-butadienoate NMR(CC1E): 5.56 (m,1H), 5.16 (m,2H), 3.76 (8,3H). Ethyl 3-methy1-3-butenoate NMR(CC1E): 4.856 (m,2H), 4.16 (q,2H), 2.956 (d,2H), 1.86 (d,3H), 1.15 (t,3H) Diethyl (2-isopropeny1)malonate NMR(CC1E): 5.06 (m,2H), 4.26 (q,4H), 4.06 (s,1H), 1.96 (m,3H), 1.35 (t,3H). Ethyli3-hexenoate NMR(CCln): 5.56 (m,2H), 4.156 (q,2H), 3.06 (m,2H), 2.06 (m,2H), 1.36 (m,6H). 39 III. Reactions of Lithio Ethyl Crotonate A. Alkylation The reaction of the enolate with CH3I is representative. The 5.0 moles of enolate was prepared as described above. A 1 M solu— 1...... tion of methyl iodide (1.25 ml; 10 mmoles) in THF (6 m1)-HMPA (4 m1) at.0o was prepared in a 50 m1 round-bottom flask. The cold (-783) enolate solution was added to the methyl iodide solution over the course of 3-5 minutes. After 60 minutes the solution was quenched with 2 M HCl and extracted. After the usual work-up, 872 of ethyl 2-methylbutenoate was obtained. NMR (CC14): 5.956 (septet, 1H), 5.16 (m, (m,2H), 4.16 (q,4H), 3.16 (m,2H), 1.36 (t,3H), 1.286 (d,3H). B. ‘With Carbonyls The enolate (5.0 mmoles) was generated as described above. To the cold (-78°) enolate solution was added 0.37 ml (5.0 mmoles) of acetone, dr0pwise. After 15 minutes the solution was quenched with HCl and worked-up in the usual fashion with pentane. The yield of ethyl 3-hydroxy-3-methyl-2-viny1butanoate was 78%. NMR (CClé): 6.06 (m,1H), 5.36 (s,1H), 5.056 (doublet of doublets, 1H), 4.156 (q,2H), 2.95 (d+s,2H), 1.26 (m,9H). CHAPTER III THE SILYLATION OF ESTER ENOLATES AND THE REACTIONS OF a-SILYLATED ESTERS AND TRIALKYL KETENE ACETALS 40 41 INTRODUCTION Ester enolates are ambident anions capable of undergoing reaction with electrophiles at either carbon or oxygen. (Figure 4). f I /O- E -= c\ Figure 4. Ester Enolate Resonance Hybrid Alkyl halides (10) and acyl halides (31) react with lithium ester enolates at carbon, producing the corresponding chain-extended esters and B-keto esters. ‘3 <:i/R——->R '--C--C02R+LiX lol I RCOC1 R'-—c—(|:——c02R+Lix Reaction of ester enolates with trimethylchlorosilane (TMCS) can generate o-silyl esters and/or O—trialkylsilyl-dLalkyl ketene acetals.’ 42 0Li I I //—TM—C-S——pESi——(l:—COZR c—C I \ OR \ | 085 TMCS . C _ c/ I \OR Hauser (32) first prepared C-silylated esters by reaction of the enolates of acetates with TMCS. Rochow (8) has synthesized a mixture of both C- and O-silylated ethyl acetate via the sodium enolate of ethyl acetate using NaHMDS. _ + _ 0H3cozcnzcu3 + (381)2N Na —>cn2 — 00201120113 + (331)2NH IOSiE HZC - C . + ESl-CHz-COzCHzCHg f—J \ TMCS 001120113 (13.71) (22 . 3%) Choice of solvent has been shown to affect the course of silyla- tion of mercuric salts of acetate anions with triethylllfl-Y1 109193 (TESI). (33). y 43 CHC13 > (Et)3Si -— CH2 — 00201120113 //// TESI XHgCHzCOZCH2CH3 5,, H2O ===c TESI OCHZCH3 The O-silylated acetal obtained was rearranged to the C—silylated ester by mercuric iodide . OSiEt3 H812 H20 a: c ————-> Et3SiCH2C02R A ocuzcna More recently, trialkylsilyl ketene acetals have been prepared via the reaction of disubstituted malonic esters with sodium in xylene (360») and by the direct silylation. of lithium ester enolates with TMCS. (35) . 0CH3 TMCS Rilizcmozcna)2 + Na ——-p RIRZC — c 051(CH3)3 + C0 + CH30$13 44 0 081(CH3)3 TMCS _ II / -c—c—00H3 —’ c—c THF \ OCH3 In a similar manner, disilyl dialkyl ketene acetals have been prepared from metalated carboxylic acids using TMCS. (36). 0 ZTMCS I 051(CH3)3 051(CH3)3 Ketene acetals react with a variety of electrophilic reagents. (37) . The simple resonance picture (Figure 5) of ketene acetals pre- dicts the a carbon to be the preferred site of reaction with electro- philes, and this qualitative representation can be used to predict the structure of products in these reactions. +0 12' c/OR' I /°—R' .. / /°—R' OR \O—R | H l \+0--R Figure 5. Resonance Contributors of a Ketene Acetal 45 In such a fashion, ketene acetals reacted with bromine to give the a-bromo esters, alkylhalides to give chain-extended esters, acid halides to give B-keto ester derivatives, and water to regenerate the ester . Br BIZ I -—-C ---CO R + RB 0R / A, I 2 r I / c—c PI. R'XA ' \0R\— ’ ’-—C—C02R+RX H20 ab —— CH — 002R + ROH 11+ \ Our purpose in this study was to determine the products of reaction of lithium ester enolates with various electrophiles, including silyl halides, and to investigate the value of these products for more elaborate synthetic procedures. 46 RESULTS I. Preparation of 0— and C—Silylated Esters Addition of TMCS to a THF solution of lithio methyl acetate at -78° produced a mixture of O-silylated (652) and C-silylated (352) products. 0Li 031(cu3)3 / TMCS RT H—c—c $——>cn2——cozcu3+cuzac | \ THF, -78° \ H OCH3 $1 R3Si—-cH—COZCH2CH3 THF, -78° / o c t CHO ,_ -78° RT ‘\\ 0 R3Si—CH—C02CH2CH3 + ——-) ——? CH2(3113 H The scope of this reaction has subsequently been studied by another worker . (40) . 51 II. Attempted OvAlkylation of Ester Enolates Only TMCS gives ketene acetals when reacted with ester enolates. Methyl iodide, triethyloxonium fluoroborate, methyl sulfate, and methyl- fluorosulfonate all gave C—alkylated products when reacted with variety of lithium ester enolates. RI - R'X I “"T—“CozR ‘—--—> — CH3 —-- (I: -—- 00201120113 CH3 0CH2CH3 OSlR3 In the presence of ICA, the O-silyl ketene acetal derivatives of both ethyl isobutyrate and ethyl hexanoate were converted back to the starting esters upon peracid treatment followed by water work-up. nun-«7.12 . 5n... 53 Reaction of the ICA with the perbenzoic acid to form hydroxylamine and m—chlorobenzoic acid could explain the formation of the esters (41). CO3H ”1* + Q17 ‘15 Q... CO H 2 OSlR3 C1 I / © +C|I==C ———‘,—CH—C02R+R3$1—02C 51 \OR I The more acid-resistant t-butyldimethylsilyl derivative of ethyl hexanoate was prepared and reacted with m—chloroperbenzoic acid under the same conditions that proved successful in the oxidation of the ketene acetal of ethyl isobutyrate. Only ethyl hexanoate was identi- fied in the reaction mixture. /’ Bu OSi \\ // ‘\ THF /0 = c\ + RCO3H ~———> Bu — CH2 —— cozcuzcn3 H ocnzcna C. With Iodine Due to the inability to separate acid sensitive ketene acetals from ICA, only electrophiles which can tolerate the presence of the 54 amine appear to have general synthetic value. Thus, addition of I2 to a solution of O-trimethylsilyl-O'-ethy1 butylketene acetal and ICA in THF at -78° yielded the o-iodo ester in 90% yield on work-up. Bu OSiR3 C = C > Bu —— CH — C02CH2CH3 / \ THF, -78° H OCHzCH3 I 12 901 D. With Acid Chloride and Triethylamine The trialkylsilyl ketene acetal, I, reacted with THF solutions of acid chlorides in the presence of triethylamine to yield silylated derivatives of B-keto esters. (Table IX) / / 081 -I— 0 081 -+— / \ I II Et3N \ CH2 — + R — C — CC1 ————>R—C =— C — 01120020113011 + \ I m I 0CH2CH3 / 051 I I I .\\-+- R —-— C — C — cncozcazcua 55 TABLE IX Reaction of O-t-Butyldimethylsilyl-O'-ethyl Ketene Acetal with Acid Chlorides Acid Chloride Product (yield, glpc)a Acetyl chloride CH2=C(OSiR3)CH2C02Et (86x) Butyryl chloride CH3CHZCH=C(OSiR3)CH2C02Et (851) Isobutyryl chloride (CH3)2C'C(OSIR3)CH2C02EE (35:) 081R3 + (CH3)2CHC=CHC02Et (352) Crotonoyl chloride CH2=CHCH=C(031R3)CH2C02Et (351) Benzoyl chloride OSiR3 C5H5C=CHC02Et (62%) Pivaloyl chloride OSiR3 (CH3)3CC=CH002Ec (40%) CYelohexanecarboxoyl chloride k . - C (031R3)CH2002Ec (31%)b OSiR3 C'CHCOzEt (58%) (a) All products were isolated by vacuum distillation. Structures were established by proton nut and by hydrolysis to the corres- ponding B-keto esters. WEAK“. '_— 56 Reaction of the ketene acetal with acetyl or butyryl chloride in the absence of triethylamine was slow and generated only small amounts (10-251) of the siloxy-a,B-unsaturated esters. / / 0—Si—I— 0 Si—I-o / \ I m \ II + R—C—Cl————>R—- /C\ CH OCHZCH3 OCH2CH3 //°_'° 8H Ketene acetals substituted with one group on the alpha carbon under- went the reaction only after prolonged treatment with acid chloride and Et3N. / Bu 031 -+- 0 03i-I— / \ II ha“ I \ / \ 16*: hrs | \CHZCOZEt H 0CH2CH3 H 612 “.0-Disubstituted ketene acetals, under the same conditions, were inert. “’ no reaction / \O THF CH3 57 V. Reaction of Electron-rich Double Bonds with ¢3CBF4 Addition of 03CBFn to a 1 M solution of O-trimethylsilyl-O'-ethyl dimethyl ketene acetal in CH2012, followed by addition of H20 after 5 minutes, resulted in a 1:1 mixture of ethyl isobutyrate and ethyl 2- '- methyl-Z-propenoate. CH3 OSiR3 CH2 0 \ CH2C12 H20 \\ // c—C +¢3CBFH ———> ————> C—C / \ RT / \ . CH3 OCH2CH3 CH3 OCH2CH3 + (CH3)2CHCOzEt Since there were a limited number of substituted ketene acetals available free of contaminating amine, the synthetic utility of this reaction was investigated using a variety of siloxyolefins (42). 1-Siloxycyclohexene was prepared and reacted with 03CBFt in 082012 at room.temperature. After addition of one equivalent of a N82C03 solution, a mixture of cyclohexenone (55%) and cyclohexane (232) was obtained. OSiR3 1) CH2C12 + 03CBF1, —-—-——“" + + ¢3CH + ¢3COH 2) NaHCOg 55% 23% 58% 40% 58 Triphenylmethane (58%) and triphenylmethanol (40%) were also present in the reaction mixture. The yield of cyclohexenone could not be improved upon any mani- pulation of the reaction conditions. The use of acetonitrile,pentane, DMSO, or benzonitrile as solvent afforded no increase in the amount of cyclohexenone formed. Tropylium fluoroborate, trityl antimonyhexafluorate, DDQ, and trityl perchlorate all proved less effective than trityl fluoroborate in generating cyclohexenone from l—silyoxycyclohexene. Trityl fluoroborate was subsequently reacted with a number of siloxyalkenes. l-Siloxycyclopentene afforded 332 of the corresponding o,B-unsaturated ketone. 081R 0 + 03CBFH -l> 332 All other substrates used in the reaction failed to react as expected, returning only ester on work-up; a-siloxy styrene yielded an addition product, 3,3,3-triphenylpr0piophenone. OSiR3 ° CH2C12 T + ¢3CBFQ “——'—"‘—' © ¢ A [LA I 59 DISCUSSION I. Preparation of O-, C-Silylated Esters The alkali metal enolates of ketones react with alkyl halides to I produce o-substituted ketones (1). }'-£ 0 =0 I Rx+—"C-—C-— ’R—C—C— Only when more reactive electrophiles such as acid chlorides and acid anhydrides are employed does reaction at oxygen predominate. 0 0 O ——'C -—'R II _ II R—C—x + ———C——C-—-—————>——-c==c/ \ Trialkylhalosilanes react with ketones or their enolates to produce siloxyalkenes exclusively (42-46). Ketones substituted in the a position With trialkylsilyl groups are unstable relative to their O-silylated isomers (47). and readily rearrange under the influence of heat or a variety of catalysts (48)- 0 I II A I R351 "'"‘ C _— C -— G, C = C or catalyst | 60 Ester enolates did not invariably produce O-silylated products when reacted with trimethylchlorosilane. The products obtained depended heavily on the structure of the ester enolate used. Although the results suggest that the reaction path was determined by steric considerations, an explanation of the results obtained is not easily provided. The reaction at oxygen of the more highly arsubstituted esters was easily attributed to the steric inaccessability of the a car- bon of the ester enolate. But increased substitution on the alcohol portion of the ester can not be used to explain the preference for C-silylation of t-butyl ester enolates. The availability of the carbon or the oxygen for reaction in an ester enolate appears to be equally affected by a change in substitution in the alcohol portion of an ester enolate. \ ._ I /C ‘~.,” 0 OR Based on these results, this simple description is not sufficient for predicting the course of reaction of ester enolates. A more elabo- rate description is required, possibly including the amine used to generate the enolate. Evidence for a strong association of amine with €8ter enolates and acid dianions has been presented (10, 49)- Any attempt to predict the outcome of the reaction of such an associated 61 species without more information on its conformation is impossible. II. Reaction of 0-Tria1kylsilyl-O'-alkyl Ketene Acetals A. With Acids Alkylation of an ester, treatment of an ortho-ester with a Lewis acid, and protonation of ketene acetals at low temperature produce 2- alkyl-l,3-dioxolenium ions,%$. (50). Rx R' — 002R" O __ R" “3 + R' -— C(OR)3 } R' ——c 0 -—-R 0R" n+x' 5.4 I \ OR When treated with a nucleOphile, the oxonium ions react by one of two pathways: addition to the central carbon bearing positive charge (route A) to form an ortho-ester derivative or displacement of one of the alkyl groups on oxygen to generate an ester (route B). ?R A R'._C+ I OR B OR R"“—'CO R.+ RY 2 ‘2‘- .n o". c 62 Dioxolenium ions usually react to give orthoester derivatives only with more nucleophilic anions such as alkoxide or cyanide. O-trialkylsilyl-O'-alkyl ketene acetals when treated with acid were expected to initially produce the silyl analogs of 1,3-dioxolenium ions, ££L‘ OSiR3 OSiR3 I / a l +/ 0 -== c\ ———-——> CH —— c I OR' OR' HA Reaction of these oxonium ions with the potent nucleophile butyllithium was expected to yield the 0-tria1kylsilyl-0'-alky1 ketal as product. I +///°SiR3 OSiR3 H -—-c ——-c + BuL1——-—>H-—c——c—Bu I ‘\\\0R. | I OR' However, when O-trimethylsilyl-O'-ethyl dimethylketene acetal was subjected to these reaction conditions only ethyl isobutyrate was identified as a product. In the case of the l-trialkylsilyl-l,3-dioxo- lenium ions, route B, displacement of the trialkylsilyl group, was 63 preferred. 05133 I / I a-—-<:——c+ +BuL1———-——> H—C—COZR' +R381Bu I \ OR' The reactions of the trialkylsilyl dioxolenium ions parallel the reactions of protonated esters,'5¥. Treatment of these dioxolenium ions with a nucleophile also results in regeneration of ester. 0H R—C )R—cozk'I-HY OR' This parallel behavior may be due to the greater electropositive character of the silicon. B. Beactions with Peracids and Iodine Only one useful preparation of a-hydroxyesters has been demonstrated in the past 10 years (51). The procedure required prior synthesis of u‘keuo ketals which were prepared from ester and methylsulfinyl carbanion (52) , 64 + H RCOZR' + zcnzsocug ——-——p ——————-p RCOCHZSOCH3 H+,12 . Rcocuzsocu3 ———————> R —— cocu(ocu3)2 CH30H Treatment of the a-keto ketal with stannic chloride resulted in good yields of the corresponding a—hydroxyester. + SnClg H Rcocu(ocu3)2+ H20 ———————§ ———§ Rcuoucozcua cu3ou The oxidation of the reactive double bond in 0-trialkylsilyl-O'- alkyl ketene acetals to form a-hydroxyesters would be a more convenient source of these compounds. However, the use of peracids to effect the oxidation must be ruled out except for the most acid-insensitive ketene acetals. A more acid-resistant silyl ketene acetal must be synthesized, or a non-acidic oxidizing reagent is needed. Partial success in pre- paring oxidized esters from silyl ketene acetals has been reported using non-acidic reagents. Treatment of O-trimethylsilyl-O'-trimethy1- silyl t-butylketene acetal with singlet oxygen yielded the silylated peroxyester derivative (53). 65 102 ? (CH3)3CCH - C[OSi(CH3)3]2 ————-§ (CH3) 3CC|3’00251(C33)3 0231(CH3)3 The value of this approach was verified by the reaction of ketene . acetals with iodine. Although a-iodoesters can be prepared in high yield by direct iodination of ester enolates (54), the preparation of ethyl u-iodohexanoate from the corresponding ketene acetal demonstrated that synthetically valuable reactions using silyl ketene acetals required non-acidic electrophiles. Ideally, these reagents should also be able to tolerate the presence of the amine used to generate the silyl ketene acetal. However, this difficulty may be circumvented by the use of more volatile secondary amines in the preparation of ester enolates. Evaporation of solvent and amine yielded silyl ketene acetals of sufficient purity for further reaction. C. With Acid Halides and Triethylamine O—t-butyldimethylsilyl ketene acetal, l, is the first trialkylsilyl ketene acetal to be used as a reagent in the preparation of fi—keto esters via their silyl enol ether derivatives. 66 / /—I— 031 -I— 0 031 / \ I II EtsN \ cu2=c +R—c—cc1——~>R—c=c—cuzcozc113cn+ \\ | THF I ocuzcn3 ,/ 031 I I I \—+— R —— c —— c — cncozcuzcua Although the reaction of trialkylsilyl ketene acetals had been previously known (11, 39, 55), the ketenes used were generated from the trialkylsilyl ketene acetals themselves and the reaction was limited to the formation of "Claisen-type" B-keto ester derivatives. OSiR3 I A I Iz=c ————>(I:=c=o+nasiocu3 ocu3 I I //OSiR3 I ISiRal c=c:o+c=c ———>c=m—m-mwm I I \ I I ocu, The reaction has been proposed to proceed through a six-membered transition state (39). (Figure 6). 67 \_ w /—C SiR3 7\\I:/O OR Figure 6. Transition State of Reaction Between Ketenes and Ketene Acetals However, in view of the results obtained with pivaloyl and benzoyl chloride, the intermediate acyl ammonium salt formed must also be cap- able of reaction. o 0 II .. R-—C-—Cl+Et3N a) R—c—fitt3x o H 031113 0 //o R—c—fiEtx'4- c—c ——>R-—c—caz—c—ozt+n351c1 H 03: + EC3N O 0 -" 51113 n Et3N R "'"" CCH2C02CH2CH3 + R331C1 '—“'—" R “_ C - CHCOZCH2CH3 The last step, the Silylation of a a—keto ester, is a rapid process catalyzed by the triethylamine (56). 68 Since free B-keto esters are sensitive to decarboxylation, this procedure provides a method of synthesizing these labile compounds in a derivatized form of long shelf life. The B-keto ester can be generated as needed by mild acid treatment of the siloxy derivative. OSiR3 -— c = c —— CHZCOZEt o + H” fl? RCCHZCOZEt H20 OSiR3 R -— c = CHCOZEt III. Reaction of ElectronétkgLDouble Bonds with Trityl Fluoroborate Ionic trityl compounds of the form ¢3CX have long been used as hydride abstractors in organic synthesis (57, 58). In view of the potential stabilization inherent in the two oxygens present, ketene acetals should behave as ready hydride donors when treated with trityl salts. 8,1-Unsaturated esters are the expected products of this reaction. 69 OR + OR / 4’30 + +/ —'CH—'(I'=C ——’ -C—C-=C (0R) 0 —C=-C—C H etc. I \ I I I I \ OR OR —C=C—CO 2 R Indeed, when 0,0'-dimethyl dimethylketene acetal was treated with trityl bromide in the presence of mercuric bromide, an intermediate come pound was formed which when heated further yielded methyl 2—methyl-2- propenoate and triphenylmethane (S9). ¢3CBr . A (CH3)2c =- C(OCH3)2 ——> [ x ] ———+ on =- ccozcn3 + ¢3cu H3332 I c113 H Although formally a hydride abstraction, the reaction has been proposed to be an addition-elimination reaction with the intermediate first formed having the structure of methyl 2-tritylisobutyrate, x. X E (CH3)2CC02CH3 C -- c — (Izncozcmna) THF Si(CH3)3 —cI: — CHC02C(CH3)3 4———J- RT The unsaturated esters were free of any u,B-unsaturated isomers (< 12). When cyclohexanone was added to a l M solution of lithio t- butyl 2-trimethylsilylacetate at -78° and then warmed to room temperature, t-butyl Z-cyclohexylideneacetate was the only product obtained. Rapid quenching of this solution at -78°, after mixing, yielded 901 of the same product and 52 of KIN. This compound was readily isolable and supports the claim that elimination of lithium trimethylsiloxide occurred rapidly at -78° to form the a,B-unsaturated ester (40). 73 + . -78° H + (CH3)3SiCHCOZC(CH3)3 -———-> ———> ‘cozcmaga + OH cacozcmua) 3 51(cn3)3 ¥£& The modification of the Wittig reaction (62) using phosphonate esters is the only comparable method capable of producing a,B-unsaturated esters, essentially free of contaminating B,Y-unsaturated isomers. base Ic\+ (RO)2P —- cnzcozcuzcu3 + — c =— cncozcnzcu3 A o o H H However, this procedure requires much more vigorous reaction con- ditions than the addition of carbonyl compounds to the enolates of u- silyl esters, and care must be taken to exclude any excess base used to generate the ylid to avoid isomerization of the products. 74 EXPERIMENTAL I. Materials All esters and ketones were used without further purification. The trimethylchlorosilane was obtained from.Aldrich and distilled (b.p. 57°/atm. press.) prior to use. The N-isopropylcyclohexyl amine (b.p. l729/atm. press.) and the diisopropyl amine (b.p. 83°latm. press.) were also distilled. All solvents employed were used directly except for the HMPA.which was distilled from sodium. The t-butyldimethylchlorosilane (BDCS) was prepared as described by Corey, et. al., JACS, 6190, 23 (1972). The silane was dissolved in pentane to form a 3.6 M solution that was used in all reactions requiring BDMS. II. Preparation of C-silylated Acetates This procedure applies equally well to the preparation of ethyl or t-butyl 2-trimethylsilylacetate. The use of HMPA was optional in the preparation of the C-silylated t-butyl acetate. The procedure described here used ethyl acetate as the ester substrate. A l M THF solution of LiICA (5.25 mmoles) was prepared as described in Chapter I and cooled to -78°. One ml of HMPA.was added and the ethyl acetate (0.495 ml; 5.0 mmoles) was added slowly. After 15 minutes, 75 0.70 ml (5.5 mmoles) of trimethylchlorosilane was added. After 15 addi- tional minutes, the solution was allowed to warm to room tempera- ture. The reaction mixture was extracted with 2 M HCl and pentane. The yield of ethyl 2-trimethylsily1acetate obtained was 902. Ethyl 2-Trimethylsilylacetate B.p. 154°latm. press. Refractive index ns3o 1.4150. NMR(CClu): 4.055 (q,2H), 1.85 (s,2H), 1.25 (c.3n), 0.15 (3,93). ' t-Butyl Z-Trimethylsilylacetate B.p. l69°/atm. press. Refractive index n5“.5 1.4166. NMR(CClu): 1.755 (3,2H), 1.455 (s,9H),0.156 (s,9H). III. Preparation of O-Silylated Acetals The use of trimethylchlorosilane is recommended only for the more acid-insensitive ketene acetals such as 0-trimethylsilyl-O'-ethyl dimethylketene acetal. To obtain less substituted acetals free of amine, the t-butyldimethylsilyl derivative is the preferred one. Both pro- cedures are given here. A. O-Trimethylsilyl-O'-ethy1 Dimethylketene Acetal A l M solution of 5.25 mmoles of LiICA was prepared as described previously. The solution was cooled to -78° and 1.34 ml (5.0 mmoles) of ethyl isobutyrate was added slowly. After 15 minutes, a 102 excess (0.70 ml; 5.5 mmoles) of trimethylchlorosilane was added. 76 The reaction mixture was warmed to 0° after 5 minutes at -78°. Pentane was added. The amine may be extracted from the cold solution using dilute HCl, but the use of acetic acid (0.30 ml; 5.25 mmoles) in 5 ml of H20 afforded much milder conditions while being just as effective. The O—trimethylsilyl-O'-ethyl dimethyl- ketene acetal was obtained in 90% yield. O-Trimethylsilyl-O'-ethyl Butylketene Acetal B.p. 96.5°/19 mm. Refractive index néu°5 1.4264. NMR(CClg): 3.756 (m,3H), 1.96 (m,2H), 1.16 (m,10H), 0.26 (8,9H). 0-Trimethylsilyl-0'-ethy1 Dimethyl Ketene Acetal B.p. 75°/4l mm. NMR(CClk): 3.76 (q,2H), 1.556 (s,3H), 1.56 (s,3H), 1.25 (t,3H), 0.185 (s,9H). 0-Trimethylsily170'-ethyl Cyclohexylideneketene Acetal NMR(CClg): 3.76 (q,2H), 2.06 (broad band, 4H), 1.456 (broad band, 6H), 1.16 (t,3H), 0.156 (8,9HL O-t-Butyl-O'-trimethylsilyl Ethylketene Acetal NMR(CClg): 3.756 (t,lH), 1.96 (m,2H), 1.36 (8,9H), 0.26 (8,9H). t-Butyl 2—Trimethylsilylbutanoate NMR(CC1q): 1.85 (t,lH), 1.55 (3,9H), 1.15 (m,5H), 0.15 (s,9H). 77 O-t-Butyldimethylsilyl-O'~ethyl Butylketene Acetal The ester enolate (5.0 mmoles) of ethyl hexanoate (0.825 ml) was prepared in the same manner as lithio ethyl isobutyrate. Prior to addition of 1.4 m1 of the 3.6 M solution of BDCS in pentane, 0.4 m1 of HMPA (2.5 mmoles) was injected in to the solution. The solution was warmed to room temperature. Pentane was added and the solution was extracted with H20 to remove the HMPA. The reaction mixture was then cooled to 0° and 0.30 ml (5.25 mmole) of HOAC in 5 ml of H20 was added slowly with stirring. Enough water was added to dissolve any precipitate. The organic layers were collected, dried and evaporated. The 0-t-butyldimethylsilyl- 0'-ethy1 butylketene was obtained quantitatively. This crude reaction product was sufficiently pure to be used further without distillation, thereby avoiding any thermal decomposition. NMR(CClu): 3.955'(t,1n), 3.755 (q,2H), 2.05 (m,2H), 1.355 (m,10H), 1.056 (3,93), 1.056 (s,9H), 0.256 (8,6H). O-t-Butyldimethylsilyl-O'-ethy1 Ketene Acetal B.p. 30°/0.2 mm. NMR(CC1g): 3.735 (q,2H), 3.15 (d,1H), 2.95 (5,1u), 1.36 (t,3H), 0.956 (8,9H), 0.156 (s,6H). O-t-Butyldimethylsilyl-O'-ethyl Vinylketene Acetal B.p. 60°/0.4 mm. NMR3 5.06 (s,1H), 4.16 (q,2H), 1.36 (t,3H), 1.156 (s,9H), 1.06 (s,1H), 2.56 (s,6H). Ethyl 3-t-Buty1dimethysiloxy-3-cyclohexylidenepropionate and ethyl 3-t-ButyldimethylsiloxyrB-cyclohexyl-ngropenoate (38:51 mixture) B.p. 120°l0.7 mm. NMR 011—0021: I slow I Figure 7. Possible Decomposition Routes of Ester Enolates 88 RESULTS An NMR spectrum of lithio t-butyl acetate generated from lithium hexamethyldisilazane in THF at -60°, revealed two broad signals at 62.72 and 62.55 (relative to the HMDS) and two singlets, the larger at 61.3 and the smaller at 61.35. As the solution was warmed to 35°, the smaller singlet increased in intensity at the expense of the singlet at 61.3. New singlets appeared at 61.05, 61.68, and 64.5. The broad signals at 62.72 and 62.55 also disappeared. The new sin- glets were in the approximate ratio of l:3:9:9 (low field to high field). The decomposition product has been assigned the structure of the enolate of t-butyl acetoacetate. 21150 —— C02C(CH3)3 ’ 011300 ——‘011 —— 0020(0113)3 Lithio t-butyl acetate has also been isolated free from contamina- ting amine, taking advantage of the fact that this low molecular weight enolate is relatively insoluble in non-polar solvents. A solu- tion of lithio t-butyl acetate in hexane was prepared in the usual fashion, using lithium isoprOpylcyclohexyl amide as base. The enolate solution was clear at -78°; however, a precipitate formed on warming the solution to room temperature. Removal of the supernatant liquid resulted in a 40-42% yield of solid lithio t-butyl acetate. Quenching Of the supernatant liquid with dilute acid produced an additional 50% recovery of t-butyl acetate. The solubility of lithio t-butyl acetate 89 in hexane was attributed to the presence of amine. Indeed, isolated lithio t-butyl acetate had no solubility in hexane at room.temperature, as shown by glpc examination of a hexane-lithio t-butyl acetate mix- ture. Addition of an amine to this mixture, either HMDS or ICA, resulted in greatly enhanced enolate solubility. It has been found that two moles of amine are required to dissolve one mole of lithio t-butyl acetate in hexane at room temperature. _ 2 amines _ CHZCOZC(CH3)3 + ( CHZCOZR)'(2 amines) [insoluble in hexane] [soluble in hexane] When lithium diisopropyl amide was used to generate the lithio t-butyl acetate in hexane, a precipitate again formed upon warming of the enolate solution. However, the use of this more volatile amine permitted evaporation of amine with solvent, producing a 90% yield of solid lithio t—butyl acetate. The NMR spectrum of lithio t-butyl acetate in benzene showed two broad singlets at 2.45 and 62.2 (relative to benzene at 67.25). In addition there was a sharp singlet at 61.6. Integration of these peaks showed their ratio to be 1:1:9 (low field to high field). Solutions of lithio t-butyl acetate reacted exothermically with one equivalent of cyclohexanone in toluene to produce the corresponding 90 B-hydroxyester. Acetone reacted in a similar fashion. Both B-hydroxy- esters were produced quantitatively. 1) . cnzcozcama) 3 + ‘OH + _CH2COZC(CH3)3 1) CH3COCH3 + (CH3) zcoucnzcozc (CH3) 3 2) 11+ Solutions of lithio t-butyl acetate, generated using LiICA in THF, decomposed at 23 1 1° following a first order rate law (63). A graph of the log of the change in recovered t-butyl acetate concentration vs time yielded a straight line (Figure 8). Solutions of lithio ethyl isobutyrate and lithio ethyl hexanoate showed approximately the same first order decomposition kinetics (Figures 9, 10). This kinetic data discounted a direct dimerization route in the decomposition of the enolates. 1.1 r 0.9 I. J O H Figure 8. 0.8 L 91 l 200 J 180 I 11 140 160 l 120 1 100 60 40 l l l l L 1 I so In <1- 7‘ c: <3 c: c: 1n(l/l-Ax)- Decomposition Kinetics of t-Butyl Acetate O O 0.3 0.2 0.1 Time (minutes) 92 1 180 1 160 140 1 120 1 100 - c: <- - O N l 1 1 1 l I l 1 l l 1 r4 c: a) ¢> 5' ‘0 ‘0 ‘I "2 °i '1 c2 .4 .4 <5 :5 C> C> C> C’ c’ c’ c’ c’ 1n(1/1-Ax) Figure 9. Decomposition Kinetics of Ethyl Hexanoate Time (minutes) 93 40 60 80 100 120 140 160 180 200 Time (minutes) 20 111 1 1 1 1. 1 1 1 1 .1 -4 <3 as a: l\ ~o In <- «I :1 F: <2 F; F; c; c: c> c: c> c: c: <3 c: <3 1n(1/1-Ax) Figure 10. Decomposition Kinetics of Ethyl Isobutyrate 94 2 LiCH2C02C(CH3) 3 —’ LiCH2C0CH2C02C(CH3) 3 Two other possible routes remained under consideration (see Figure 7): proton abstraction by the enolate from solvent or amine to form ester or formation of ketene. Of these, the formation of ketene was the most appealing, and steps to trap or isolate such an intermediate were undertaken. Addition of two equivalents of phenyl magnesium bromide to a solution of lithio t-butyl acetate at -78° produced, on warming, a 13% yield of acetophenone. Acetophenone was the expected product of reaction of the Grignard reagent with ketene. LiCH2C02C(CH3)3 1, CH2 =- C =- 0 + LiC0(CH3)3 11+ 0112 -- 0 - 0 + C5H5MgBr —————>'01120006H5 ————) 01130005115 However, acetophenone may also be formed by reaction of the Grignard with free ester. 9S SH LiCH2C020(CH3)3 vb cu3cozc(cu3)3 CH3C02C(CH3)3 + C5H5MgBr a» 01130006115 I .I II 'I cuacocsus + 8’ ’ 11120006115 + BK B- = C5H5- or RZN The excess Grignard reagent, or amide formed by reaction with the excess Grignard reagent, may enolize any acetophenone formed, preventing any further reaction. No diphenylmethylcarbinol was found in the reaction mixture. The replacement of the Grignard reagent with other nucleophiles yielded no identifiable additional products. Due to the ambiguous results obtained in the trapping experiments, our attention was turned toward the possible isolation of a ketene intermediate. The reactivity of ketenes is largely dependent on the degree of substitution at the methylene carbon of the ketene. Substitution of the methylene carbon with groups having large steric requirements produces a less reactive ketene (64). Since t-butyl 2-trimethylsilylacetate had previously been prepared, the introduction of a second trimethylsilyl group a to the carbonyl would produce an 96 ester whose enolate could generate an extremely hindered ketene, bis (trimethylsilyl)ketene. R3SICH2002C (CH3) 3 :’ (R3Si)2CHC02C(CH3) 3 (1135320 — c - 0 t (R3Si)2-CC02C(CH3)3 R-CH3 The enolate of t-butyl 2-trimethylsilylacetate was generated at -78° using lithium diisopropyl amide as base. The enolate was recovered quantitatively on quenching with HCl. Addition of one equivalent of trimethylchlorosilane to this enolate solution at -783 followed by warming to room temperature, yielded two products. Treatment of the solution with water removed the lower boiling material and distillation of the water-washed reaction mixture yielded 602 of t-butyl 2,2-bis(trimethylsilyl)acetate and 312 recovered starting material. The enolate of t-butyl 2,2-bis(trimethylsilyl)acetate was generated at -78°, again using lithium diisopropyl amide. Upon warms ing, the enolate solution produced only one product, which was isolated by preparative glpc. The NMR showed one peak at 60.28 and the infrared spectrum revealed intense signals at 2965, 2075 and 97 1260 cm-1 (65). Addition of two draps of concentrated H280“ to an ethanol solution of this material yielded ethyl 2,2-bis(trimethylsily1)- acetate as the only product. H [(0113) 351120110020 (CH3) 3 > [(0113) 351]zccozc(cu3) 3 EtOH On the basis of this information, the structure of the product isolated in the decomposition of t-butyl 2,2-bis(trimethylsilyl)acetate has been assigned that of bis(trimethylsilyl)ketene. 98 DISCUSSION The oxygen-metalated enolate, II, rather than the carbon-metalated ester, I, is thought to be the preferred structure of the enolates of Reformatsky reagents and halomagnesium enolates (67, 68, 69, 14). l I / 51—0—0028. c—c M - -ZnX, -ng, -Li The NMR of lithio t—butyl acetate in benzene and THF also suggests that II (MPLI) is the preferred structure of a lithium ester enolate. The protons of a carbon-metalated structure would be expected to be equivalent. The non-equivalence of the a protons in the NMR of lithio t-butyl acetate indicates a large degree of double bond character in the anion. The reactions of t-butyl acetate are those of a typical lithium ester enolate, and the isolation of lithio t-butyl acetate provides a convenient reagent for the facile introduction of a t-butyl acetate moiety into a compound via a Reformatsky-type reaction. 4. 0 II R L10H20020(cn3)3 + -— c —— ———————> ————b -— (Izoucu20020(cu3)3 99 Although the structure of ester enolates in solution appears well established, the decomposition path of ester enolates is less certain. The fact that acetophenone was obtained when phenylmagnesium bromide was added to an enolate solution supports all three suggested mechanisms. -CH2C02C(CH3)3—, CH2 = C = 0 CGHSMgBr _ _ 3+ CH2C02C(CH3)3 + C6H5MgBr cazcoceus —+ cn3cocsns l)C6H5MgBr 2)B' -CH2C02C(CH3) 3 —-—" CH3C02C(CH3) 3 However, the kinetics of decomposition displayed by the enolates eliminates the direct enolate coupling. This path requires that the decomposition be second order in enolate concentration. 2 LiCH2C02C(CH3)3 X f, Li — C — C0 — CH2 — COZR 100 Either of the two remaining schemes under consideration was expected to display first order kinetics if the rate determining step was the formation of either a ketene intermediate or ester. C I- C =3 0 LiCH2002C(CH3)3 BH slow CH3C02C(CH3)3 The assumption that the first step in each suggested mechanism (see Figure 7) is the rate-determining step is a reasonable one. Since, ketenes react with organometallic reagents readily, even at low tempera- tures (65), the reaction of a ketene with ester enolate was expected to be rapid. The reaction of an ester with an enolate was also expected to be a rapid reaction at room temperature (63). A ketene intermediate has been proposed in the decomposition of zinc ester enolates. The resultant ketene reacted with the ester enolate to produce a dimer, which gave B-keto esters on hydrolysis (14). 101 XZn—c—cozn ’(lza-c—o \ T“ r~c c\ OR + | | I | H uc-—co—-c~—cozn Xan-C-C02R. + c-c-o-——————I> -—-————i> | | ‘\~<¢9 O Ketenes are also produced in the thermal decomposition of silicon ester enolates (39). 05133 + C==C==O +CH3081R3 OCH3 A ketene intermediate in the decomposition of lithium ester enolates could be isolated provided the reaction with alkoxide or with ester enolate can be prevented. 102 ’—E—c02R I \-IC-_‘C02R I >—'cl':——co—c|:—c02R Increased substitution at the methylene carbon of a ketene has been shown to produce unreactive ketenes. Di-t-butyl ketene, £££’ has been prepared and proved to be remarkably unreactive (70). (CH3)3C —" C - C .9 0 (CH3)3SiC - C — 0 C(CH3)3 Si(CH3)3 H}. H The silyl analogue of di-t-butyl ketene, bis(trimethylsilylketene), $X’ is expected to have similar properties. In fact, the larger steric requirements of the silicone may increase the silyl ketene's unreactivity. With this in mind, the t-butyl ester of 2,2-bis(trimethyl- sily1)acetic acid was prepared and the enolate of this ester allowed to decompose. While other esters invariably produce higher boiling decomposition products, the only product obtained from the enolate of tébutyl 2,2-bis(trimethylsily1)acetate was bis(trimethylsilyl)ketene 103 in quantitative yield. [(CH3)3Si]2-C — C02C(CH3)3 D [(cu3)331]zc — c — o The isolation of this ketene provides firm support for the suggestion that ester enolates decompose via ketene intermediates. 104 EXPERIMENTAL I. Decomposition of Ester Enolates The enolate of t-butyl acetate (13.4 ml) was prepared on a 50.0 mmole scale using LiICA (50.0 mmoles) as described in Chapter I. An internal standard was added, toluene, and the flask removed from the dry-ice bath and placed in an oil bath at 23° i 1°C after a sample had been removed and examined by glpc. All samples removed were quenched with a 2 M solution of NHnCl. The organic layers were collected and dried. The samples were removed according to the schedule below and the recovery of t-butyl acetate noted. Ax, Change in Enolate Conc. t (min.) (lM-Z Recovery TBA) ln(l/l-AX) 100 0 0.00 0.000 10 0.01 0.004 20 0.11 0.050 30 0.23 0.113 45 0.33 0.172 60 0.46 0.264 75 0.56 0.358 90 0.62 0.418 120 0.74 0.592 150 0.80 0.700 105 The enolates of ethyl hexanoate and ethyl isobutyrate decomposed much more slowly. The recovery of starting esters at 50‘ i 1" are given below: Ethyl Hexanoate Ethyl Isobutyrate L '1 t(min.) Ax 1n(1/1-Ax) t(min.) Ax ln(l/1-Ax) 0 .00 0.000 0 .000 0.000 30 .20 0.097 30 .090 0.042 60 .39 0.232 60 .210 0.102 90 .58 0.394 90 .255 0.128 150 .84 0.813 120 .300 0.154 300 .87 0.996 150 .383 0.210 210 .418 0.236 131R of Lithio t-Butyl Acetate in THF with HMDS as Base The enolate was prepared on a 5.0 mmole scale in the usual fashion using hexamethyldisilazane (1.05 ml) as the amide base. THF-(D3) was “sad as solvent. The solution was added by syringe to an NMR tube maintained at -78°. An NMR obtained at -60° on a Varian A 56/60 revealed two singlets at 61.3 and 61.35 (relative to the methyls of the silyl amine), a broad band at 62.72 and a broad band at 62.55. As the solution 106 was warmed to 35°, the band at 61.3 diminished while the signal at 61.35 increased. A singlet at 61.05 appeared as did a singlet at 64.5. A sharp signal also appeared at 61.68. When the sample reached 35°, the signals at 2.55, 2.72, and 61.3 were gone, and the peaks at 4.5, 1.68, 1.35 and 61.05 integrated as 18: 3H: 9H: 9H. III. Preparation of Solid Lithio t-Butyl Acetate A 50.0 ml flask equipped as in Figure 1 was charged with 26.25 mmoles (11.2 ml of 2.34 M in hexane) of butyllithium. Fourteen ml of hexane were added to the solution and the flask was cooled to 0°. Diisopropyl amine (26.25 mmoles; 3.5 ml) was added dropwise. The LiDIPA - hexane in solution was cooled to -78° and the t-butyl acetate (25.0 mmoles; 3.35 ml) was added slowly. After 15 minutes, the solution was warmed to room temperature and the solvent evaporated. Any yellow discolora- tion was removed by trituration with hexane at 0°. The yield of the vacuum - dried, white powder was 902. IV. §pectrum and Reactions of Lithio t-Butyl Acetate To a 50 m1 flask equipped as in Figure l was charged 5.0 mmoles (0.61 g) of lithio t-butyl acetate. Benzene (5 ml) was added. When toluene was used as internal standard, glpc examination of a quenched aliquot of this clear solution afforded a quantitative recovery of t-butyl acetate. The NMR of this solution revealed two broad singlets at 63.45 and 63.2 (relative to benzene at 67.25) and a singlet at 61.6. The relative peak intensities were 1:1:9. 107 When toluene (5 ml) was used in place of the benzene, and the solution cooled to 0°, addition of one equivalent of cyclohexanone (0.49 ml), followed by acid addition in 5 minutes, produced t-butyl (1—hydroxycyclohexy1)acetate in quantitative yield. Addition of acetone (0.37 ml; 5.0 mmoles), rather than cyclohexanone, yielded t- I butyl-3-methyl-3-hydroxybutyrate quantitatively. V. Reaction of Lithio t-Butyl Acetate with Phenyl Magnesium Bromide V The enolate (5.0 mmoles) was prepared at -78° as described above. To this solution was added two equivalents of phenyl magnesium bromide in 10 m1 of THF. The solution was warmed to room temperature for 3 hours. After quenching with dilute HCl, the mixture was examined by glpc and found to contain 132 acetOphenone, as identified by comparison of glpc retention times with authentic material. VI. Preparation of Bis(trimethylsilyl)ketene t-Butyl 2-(trimethylsilyl)acetate (2.50 mmoles; 55 ml) was added to a.l M solution of LiDIPA (262.5 mmoles) in THF at -78°. The amide was prepared as described previously (Chapter I and above). After 15 minutes, trimethylchlorosilane (262.5 mmoles; 33.6 ml) was added, and the solution was warmed to room temperature for 30 minutes. Two pro- duct peaks were observed by glpc. Treatment of the reaction mixture with 25 m1 of H20 for one hour replaced the lower boiling peak with starting ester. The organic layers were then separated and dried, 108 evaporated and the residue distilled under vacuum. Starting material (311) and 60% of t-butyl 2,2-bis(trimethylsily1)acetate were obtained. B.p. 60°/1 mm. NMR(CC1q)2 1.416 (s,1OH), 0.16 (s,18H). An NMR of neat material revealed a third signal at 61.33. A 50 m1 flask with 5.0 mmoles of LiDIPA at -78° was again prepared. To the flask was added 5.0 mmoles of t-butyl 2,2-bis(trimethylsily1)- acetate (1.50 ml). The solution was maintained at -78° for 45 minutes. The flask was removed from the dry-ice bath for 1 hour. Only one pro- duct, in quantitative amounts, was present as revealed by glpc. The bis(trimethylsilyl)ketene had the expected NMR, in 0C1“: a singlet at 60.2 (relative to benzene at 67.25). The mass spectrum showed a parent peak at 186 (calc. 186.40). Ketene was inert to short treatment with weak acid or weak base. The ketene reacted with a trace of sulfuric acid in ethanol (anhydrous) to yield ethyl 2,2—bis(trimethylsily1)- acetate quantitatively, which was identified by NMR. BIBLIOGRAPHY 109 BIBLIOGRAPHY (1) H. House, "Modern Syn. Reactions", 2nd ed., W. A. Benjamin, Jr., 1972. (2) Hauser & Hudson, 953; Reactions, 1, 266 (1942). (3) R. Shriner, Org. 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