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Studies related to the thermal rearrangement of 1,2-Divinylcyclopropanes Burmeister, Max Stewart 1981

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STUDIES RELATED TO THE THERMAL REARRANGEMENT OF 1,2-DIVINYLCYCLOPROPANES by MAX STEWART BURMEISTER B. S c , University of Western Ontario, 1976 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1981 © Max Stewart Burmeister, 1981 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e head o f my department o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 Date AUbusr 23 > fid) i i ABSTRACT The work i n this thesis was undertaken i n order to determine the k i n e t i c factors responsible for the r e g i o s e l e c t i v i t y i n enol ether formation i n 2—vinylcyclopropyl cyclohexyl ketone systems. Conversion of commercially a v a i l a b l e 4-carbethoxy-3-methyl-2-cyclo-hexen-l-one (106) into 3,3-dimethylcyclohexanecarboxylic a c i d c h l o r i d e (.105) was accomplished v i a a straightforward sequence of reactions. Treatment of (105) with l i t h i u m (phenylthio)(cis-2-vinylcyclopropyl)cuprate (33) afforded the ketone (101). A l t e r n a t i v e l y , reaction of (105) with a mixture of the cuprate reagent (33) and the isomeric reagent (34), followed by base-catalyzed e q u i l i b r a t i o n of the r e s u l t a n t mixture of ketones, provided the ketone (103). Hydrogenation of c_is-2-vinylcyclo-propyl cyclohexyl ketone (89) with diimide provided the ketone (104). Treatment of the ketone (101) with l i t h i u m diisopropylamide i n tetrahydrofuran at -78°C, followed by trapping of the resultant mixture of enolate anions with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e , gave a mixture of the enol s i l y l ethers (120) and (121) , i n a r a t i o of 12 : 88. Thermolysis of the l a t t e r mixture (160°C, neat) afforded a mixture of the annulated materials (122) and (123) ( r a t i o ~14 : 86), which, upon acid hydrolysis under mild conditions, gave the cycloheptenone (127) and compound (123). The l a t t e r two substances could be separated by column chromatography. Subjection of the ketone (103) to a sequence of reactions s i m i l a r to that described above ( l i t h i u m diisopropylamide, tetrahydrofuran; t e r t -b u t y l d i m e t h y l s i l y l chloride; thermolysis, 240°C, neat; acid hydrolysis) gave the f i n a l products (127) and (123) in a r a t i o of 87 : 13, r e s p e c t i v e l y . i i i Treatment of cis-2-ethylcyclopropyl cyclohexyl ketone (104) with l i t h i u m diisopropylamide i n tetrahydrofuran, followed by trapping of the re s u l t a n t mixture of enolate anions with t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e afforded the two enol s i l y l ethers (125) and (126) in a r a t i o of 1 : 1 . The r e s u l t s summarized above are discussed i n terms of the factors which might be a f f e c t i n g the r e g i o s e l e c t i v i t y of k i n e t i c deprotonation of 2-vinylcyclopropyl cyclohexyl ketone systems. H U C U 5 C 6 H 5 R U C U . C . H , S « = ^ J L » H 33 M — 101 103 125. 12i 127 i v TABLE OF CONTENTS Page TITLE PAGE i . ' ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v ACKNOWLEDGEMENTS v i INTRODUCTION I. THE COPE REARRANGEMENT OF DIVINYLCYCLOPROPANES 1 I I . PREVIOUS WORK 8 I I I . THE PROBLEM 34 DISCUSSION I. THE PREPARATION OF THE TARGET COMPOUNDS 39 I I . ENOL ETHER FORMATION AND REARRANGEMENT. 53 I I I . HYDROLYSIS OF THE THERMOLYSIS MIXTURES 58 IV. FURTHER WORK 61 V. CONCLUSIONS 62 EXPERIMENTAL 66 BIBLIOGRAPHY 98 V LIST OF TABLES Page TABLE I: Enolate Formation of c i s ketone (89) with Various Bases. 32 v i ACKNOWLEDGEMENTS During the course of t h i s work, many people have encouraged me. I would l i k e to thank Dr. Edward Pier s for h i s d i r e c t i o n and the many graduate students past and present for t h e i r humour and friendship. In p a r t i c u l a r , Mr. Michael Chong was very h e l p f u l i n the proofreading of th i s t h e s i s . Ms. Linda Reid must also be thanked f o r her continued support during my research and w r i t i n g and Mrs. Rani Theeparajah for her prompt and accurate typing of this manuscript. L a s t l y , and c e r t a i n l y not l e a s t , f i n a n c i a l support i n the form of graduate fellowships from the University of B r i t i s h Columbia i s g r a t e f u l l y acknowledged. v i i The l i n e between f a i l u r e and success i s so f i n e that we scarcely know when we pass i t : so f i n e that we are often on the l i n e and do not know i t . - E l b e r t Hubbard, The Note Book (1927) -1 INTRODUCTION In the l a s t twenty years the [3,3] sigmatropic Cope rearrangement has come into increasing importance i n modern organic chemistry. Of p a r t i c u l a r i n t e r e s t i s i t s use i n the formation of r i n g systems i n one step that would take many synthetic steps to form by more conventional organic chemistry. I. The Cope Rearrangement of Divinylcyclopropanes"*" When butadiene (1) i s heated at 150-300°C, 1,5-cyclooctadiene (3) 2 i s produced. While i n v e s t i g a t i n g t h i s process, Vogel postulated that a possible intermediate i n the reaction was 1,2-divinylcyclobutane (2). 1 2 3 2 To test t h i s hypothesis, he synthesized cis-1,2-divinylcyclobutane (.2) and found that when i t was heated to 120°C for 10 minutes, i t rearranged to 1,5-cyclooctadiene (3). The trans-1,2-divinylcyclobutane (4) molecule, however, did not rearrange to 1,5-cyclooctadiene (3) but instead decomposed at 240°C to give two 1,3-butadiene u n i t s . Vogel then synthesized a s e r i e s of cis-1,2-divinylcycloalkanes and studied t h e i r rearrangements. He noted that £is-l,2-divinylcyclopropane l a (5) rearranged to 1,4-cycloheptadiene (6) even below room temperature. 5 6 Since he was unable to i s o l a t e the c i s compound, Vogel decided to prepare the isomeric trans-1,2-divinylcyclopropane (7) . When the compound was heated at 190°C f or 2 hours i t also rearranged cl e a n l y to provide 1,4-cycloheptadiene (J5) . Vogel f e l t that t h i s r e s u l t could be r a t i o n a l i z e d by e i t h e r of two routes (Scheme 1). One p o s s i b i l i t y (route A) involved an isomerization of (7) to cis-1,2-divinylcyclopropane (_5) followed by subsequent [3,3] sigmatropic rearrangement (Cope) of the l a t t e r substance to 1,4-cycloheptadiene (6). A l t e r n a t i v e l y (route B), compound (7) could rearrange to 4-vinylcyclopentene (8) which could then undergo rearrangement l a to the f i n a l product (6). Vogel subsequently prepared 4-vinylcyclopentene 8 Scheme 1 (8) and found that i t d i d not isomerize to the cycloheptadiene molecule even at 300°C. Therefore, he preferred route A, Scheme 1. The mechanism of the trans to c i s isomerization i s not f u l l y understood. The isomerization i s thought to involve e i t h e r a one centre or a two centre epimerization of the cyclopropane r i n g p ossibly v i a a r a d i c a l 3 process. Berson has coined the term stereomutation to describe a l l processes i n which stereoisomers interconvert. Using deuterated compounds, Berson found that cyclopropane and phenylcyclopropane isomerizations could 4 best be described by a two centre inversion. Baldwin synthesized a constrained divinylcyclopropane system (9) i n order to determine whether or not the epimerization was a one centre or a two centre inversion. 9 10 11 The compound (9), which was known to possess absolute configuration as shown, rearranged at 195°C i n one hour to give compound (11) which was found to be enantiomerically pure. Baldwin then synthesized the endo compound (10) which also rearranged to give enantiomerically pure compound (11). He concluded that i n th i s case, a one centre epimerization was occurring converting compound (9) into compound (10) and subsequently, the l a t t e r rearranging to compound (11) . A two centre epimerization of compound (9) would have produced the enantiomeric product (12) which was not observed experimentally. 12 The main d r i v i n g force for the Cope rearrangement i n 1,2-divinyl-cyclopropanes i s the r e l i e f of r i n g s t r a i n when the 1,2-divinylcyclopropane rearranges to the corresponding 1,4-cycloheptadiene. This was demonstrated 5 by Vogel"* when he found that cis-1,2-divinylcyclopentane (13) , when heated to 300°C, isomerized to the trans-l,2-divinylcyclopentane (14) rather than undergoing Cope rearrangement to compound (15). Compound (15) i s more highly strained as compared to (13) due to the presence of two trans double bonds ("chair" type t r a n s i t i o n s t a t e ) . 15 I t has been reported" that cis-1,2-divinylcyclopropane (5) could not be i s o l a t e d even at -40°C. However, recent work done by Brown and associates^ demonstrated that t h i s compound could be i s o l a t e d at -20°C and that i t s nmr spectrum could be obtained. I t was found that compound (5) has a h a l f - l i f e of 449 seconds at 20°C. I t has been suggested that Cope rearrangement of c i s - 1 , 2 - d i v i n y l -cyclopropane systems proceeds v i a a "boat" type t r a n s i t i o n state (Scheme 2)^. This t r a n s i t i o n state leads to the cis,cis-1,5-cyclohep.tadiene • 1 Scheme 2 system (6) whereas other possible t r a n s i t i o n states would r e s u l t i n formation of two trans double bonds or a c i s and a trans double bond being formed. This mechanistic proposal was supported by work c a r r i e d out by Baldwin^'^ and Schneider**"^ who studied the Cope rearrangement of various substituted cis-1,2-divinylcyclopropane systems. For example, the c i s , -cis,cis-1,2-dipropenylcyclopropane (16) did not undergo thermal Cope 8 10 rearrangement ' at 179°C, but instead formed an equilibrium mixture with the trans isomer (17) . I t was postulated that t h i s r e s u l t was due to s t e r i c i n t e r a c t i o n s between the methyl substituents on the double bonds and the hydrogen on C-3 of the cyclopropane r i n g i n the required g " b o a t - l i k e " t r a n s i t i o n state. Baldwin also thermolyzed compound (17) at 7 R = Me 17 178°C for 4 h and again obtained an equilibrium mixture of isomers (16) and (17). However, trans,trans,trans-1,2-dipropenylcyclopropane (18) did undergo rearrangement to provide (19) when heated at 178°C for 4 h. This rearrangement probably occurs v i a the c i s isomer (20) i n the required 18 20 19 8 boat type t r a n s i t i o n state. The thermal rearrangement of the former compound (18) was slower, when compared to the parent cis-1,2-divinylcyclopropane (.5), possibly due to the s t e r i c i n t e r a c t i o n of the two methyl groups i n the t r a n s i t i o n state. In general, i t was found that the greater the s t e r i c i n t e r a c t i o n of various "R" groups on the double bond with the proton at C-3 on the cyclopropane r i n g , or with each other [for example compound (20)] the slower the Cope rearrangement. In extreme cases t h i s rearrangement did not occur; instead only c i s to trans isomerization was observed. II Previous Work Although the k i n e t i c s and mechanism of the Cope rearrangement of 1,2-divinylcyclopropanes have received much att e n t i o n , t h i s reaction has not been employed extensively i n organic synthesis. Recently, however, a number of reports concerning the use of t h i s rearrangement as a synthetic method have appeared and these w i l l be discussed b r i e f l y . Marino''""'" prepared the divinylcyclopropane d e r i v a t i v e (21) and thermally rearranged i t , a t 140°C , to the annulation product (22) which, he postulated, r e s u l t s from a 1,3 hydrogen s h i f t i n the i n i t i a l l y formed 12 compound (23) . Marino l a t e r extended t h i s work to include the cycl o -pentenone de r i v a t i v e s (24) and subsequently rearranged them to give (25). Compounds of type (24) were prepared (Scheme 3) by the conversion of 2-methyl-l,3-cyclopentanedione (26) into the sulfoxonium y l i d e s (27). This y l i d e was reacted with a c r o l e i n to produce the 2-cyclopropyl aldehyde (28) which was subsequently reacted with d i f f e r e n t Wittig-type reagents to give compounds (24). 9 SC H , SOC H 10 27 r CHO 24 28 Scheme 3 13 In a l a t e r p u b l i c a t i o n , Marino described a modified procedure to prepare substituted divinylcyclopropanes s t a r t i n g from the enol ether of 2-methyl-l,3-cyclopentanedione (29) and reacting i t with v i n y l c y c l o p r o p y l -l i t h i u m reagents (30) . Work up of the reaction with aqueous ammonium chlor i d e produced the substituted cyclopropanes (31) and (32). 11 P i e r s and Nagakura'1"'* prepared various substituted 3-(2-vinylcyclo-propyl)enones by conjugate ad d i t i o n of l i t h i u m phenylthio ( 2 - v i n y l c y c l o -propyl) cuprate (33) and (34) onto the appropriate 3-iodo enone. For example, the compound (35) was prepared by rea c t i o n of a c i s and trans isomer mixture of the cuprate reagent (33) and (34) with 3-iodo-2-cyclo-hexen-l-one (36). Upon d i s t i l l a t i o n at 62-88°C, a mixture of the trans 12 compound (37) and the product (35) was obtained. Further heating of t h i s mixture at 180°C f or 30 min converted the e n t i r e mixture into compound (35) i n 75% y i e l d (Scheme 4). 3 5 Scheme 4 They a l s o prepared spiro cycloheptadiene compounds such as (38) and (39) by the same route i n reasonable y i e l d s . 13 38 39 Piers - 1" 3 l a t e r extended t h i s idea by preparing the isomeric l i t h i u m phenylthio[2,2-dimethyl-cis-(and-trans-)3-vinylcyclopropyl] cuprates (40) and (41) from the i s o m e r i c a l l y pure bromides (42) and (43). The cuprates were allowed to react with various B-iodo enones, as previously described, to produce the highly f u n c t i o n a l i z e d isomeric divinylcyclopropane deriva-t i v e s (44) and (45) ( c i s s e r i e s ) ; and (46) and (47) (trans s e r i e s ) . These compounds were prepared to study the e f f e c t s of s t r u c t u r a l v a r i a t i o n on the course of the Cope rearrangement and to act as s u i t a b l e precursors f o r na t u r a l product syntheses. The c i s compound (44) rearranged to the cycloheptadiene system (48) on r e f l u x i n g for 4 h i n hexane (bp 69°C). Thermolysis of compound (48) or the c i s compound (44) b r i e f l y at 110°C gave the conjugated ketone (49) in >90% y i e l d . Compound (44) was i n f a c t found to rearrange to (48) slowly upon standing at room temperature. 45 15 46 47 16 P P 49 The analogous compound with a methyl group i n the apposition (45) was more r e s i s t a n t to Cope rearrangement.* This compound required higher temperatures ( r e f l u x i n g 0-xylene, bp 144°C, 48 h) to e f f e c t the rearrange-ment to give the methyl d e r i v a t i v e (50) as well as a s i g n i f i c a n t amount of isomerized s t a r t i n g material (4.7) which was stable under the reaction 17 conditions. This s i g n i f i c a n t difference between the thermal rearrangement of compound (44) and compound (45) can be r a t i o n a l i z e d as follows: i n the b o a t l i k e t r a n s i t i o n state proposed f o r divinylcyclopropane rearrange-ments, there i s a s t e r i c i n t e r a c t i o n i n compound (45) between the a methyl group and one of the methyls on the cyclopropane r i n g . H - J C 45 The trans compound (46) was rearranged at a higher temperature (0-dichlorobenzene, sealed tube, 220°C) than the c i s compound (44) to give the rearranged product (49) i n 59% y i e l d . 46 49 The corresponding trans compound with an a methyl group (47) was thermolyzed under s i m i l a r conditions, as described above, to produce the annglated product (50). However, i t also produced a predominance of trienone (51) , presumably because of a homo-[l,5]-sigmatropic hydrogen s h i f t . 18 Wender"""" prepared various divinylcyclopropane d e r i v a t i v e s by a 13 method s i m i l a r to Marino . For example, the 3-alkoxyenone (52) was allowed to react with a s o l u t i o n of l - l i t h i o - 2 - v i n y l c y c l o p r o p a n e (30) (R=R'=H, c i s and trans) and the r e s u l t i n g reaction mixture was poured into aqueous hydrochloric a c i d to give the divinylcyclopropane (53). Compound (.53) was thermolyzed at 170-180°C for 2 h (sealed tube) to give the cycloheptadiene (54) i n 73% y i e l d . Wender"*"^  modified t h i s sequence to prepare the natural product tearahanaenone (55) (Scheme 5) . The 2-vinylcyclopropyl ketone (56) was prepared v i a rea c t i o n of a mixture of c i s - and trans- l - l i t h i o - 2 - m e t h y l -19 52 30 R = R ' = H 0 54 2-vinylcyclopropane (57) with isobutyraldehyde followed by oxidation of the resultant product. The ketone (56) was treated with a solution of lithium diisopropyl-amide in tetrahydrofuran and the resulting enolates were trapped with trimethylsilyl chloride to give the enol s i l y l ethers (58) (cis and trans). The enol s i l y l ethers (58) were thermolyzed at 165-175°C and the resultant product (59) was desilylated (n-butyllithium) to provide karahanaenone (55) in 54% overall yield based on isobutyraldehyde. In a later publication, Wender"^ used these Cope rearrangements to prepare the natural products (±)-d'amsinic acid (60) and (±)-<?onfertin (61) . 20 55 Scheme 5 Both compounds were derived from a common precursor. The 3-a]k]oxyenone (62) was allowed to react with the l-lithio-l-methyl-2-vinylcyclopropane mixture (30; R=Me, R'=H) to make isomers (31) and (32) . Wender observed mainly r i n g opened product (63) when he t r i e d to 21 rearrange the mixture of divinylcyclopropanes (31) and (32) (>140°C); presumably because of a homo-[1,5]-sigmatropic hydrogen s h i f t as observed by P i e r s ^ . The expected product (64) was the minor component (<20%) . Thermolysis at a lower temperature (98°C) gave about the same amount of (64), a trace of compound (63) and mainly the trans isomer (32). The s t e r e o s e l e c t i v e preparation of the cis-isomer (31) would have circumvented t h i s problem, but Wender found that photo isomerization of the mixture (31) and (32) was most convenient. This was accompanied by 22 0 31 + 32 11 simultaneous thermolysis (at 98°C) of the mixture to give the desired product (64) as the major product i n a 80-90% y i e l d with only a trace of (63). The k e t a l (65) was used as the general precursor for the natural products (60) and (61). 65 23 P i e r s and Ruediger synthesized (±)-£-himachalene (66) v i a a Cope rearrangement. The trans-l-bromo-l-methyl-2-isobutenyl cyclopropane (67) was prepared and converted to i t s l i t h i u m phenylthiocuprate (68). The cuprate s o l u t i o n was allowed to react with the B-iodo enone (36) to give the divinylcyclopropane (69) which was thermolyzed (m-xylene, bp 138°C, 3 h) to give the cycloheptadiene system (70). 70 69 24 The cycloheptadiene system (70) was methylated and the re s u l t a n t product (71) was hydrogenated [H_, ($_P)-RhCl, C.H ] to give the cyc l o -Z J J D O heptene system (72) . This was transformed into the enol phosphate (73) which was reduced with l i t h i u m to give (+)-3-himachalene (66). 66 25 19 Recently Wender has used divinylcyclopropane Cope rearrangements to prepare more complicated multiple r i n g systems. A model system for h i s study was the t r i c y c l i c methoxyketone (74). Natural products with structures r e l a t e d to compound (74) are known and i t was Wender's hope that they could be prepared v i a a thermal Cope rearrangement. The postulated precursor to compound (74) would be compound (75) which could rearrange to (74) upon heating. Compound (75) was novel because of the oxygen f u n c t i o n a l i t y (as the methyl enol ether) that was a to the ketone. The e f f e c t of the oxygen f u n c t i o n a l i t y on the Cope rearrangement was unknown. 15 17 As previously discussed ' , systems with an a l k y l group a to the a,g-unsaturated ketone are known to have a s t e r i c e f f e c t on the course of the rearrangement, but no system with an oxygen f u n c t i o n a l i t y had been t r i e d . Wender prepared the l-bromo-2-vinylcyclopropane (76) i n s i x steps from the a-bromoenone (77). Compound (76) was treated with t e r t - b u t y l l i t h i u m , to e f f e c t l i t h i u m halogen exchange, and a so l u t i o n of the r e s u l t i n g l i t h i u m d e r i v a t i v e was allowed to react with 2,3-dimethoxy-2-vinylcyclo-propane (78) to produce, a f t e r work up, the 1,2 adduct (79). 26 0 74 Treatment of compound (79) with a 0.01 N aqueous s u l f u r i c a c i d s o l u t i o n i n acetone at room temperature f or seven minutes gave the rearranged product (74) d i r e c t l y presumably v i a the divinylcyclopropane (75) - although compound (75) was not detected. Werider also synthesized the a-methoxyenone (80) and found that i t rearranged with a h a l f - l i f e of 9.3 h at room temperature. As a comparison, 27 the a-methylenone (31; R=R'=H) had a h a l f - l i f e of 316 h at room temperature and s u b s t i t u t i n g the cyclopropane r i n g i n (31) with a methyl group (31; R=Me, R'=H) lowered the h a l f - l i f e to 54 h at room temperature. 19 Although these were cursory studies, Wender states that these r e s u l t s seem to suggest that r e p l a c i n g the a-methyl group with an oxygen f u n c t i o n a l i t y and increasing the a l k y l s u b s t i t u t i o n on the cyclopropane r i n g both contribute to the reduction of the h a l f l i f e of compound (75). 80 31 R-= R'f = H 31 R = Me R' = H 75 Piers and R e i s s i g ^ further extended the methodology of Wender''"*' to more complicated systems. A solu t i o n of cis-l-bromo-2-vinylcyclopropane * (81) i n ether was allowed to react with t e r t - b u t y l l i t h i u m . Successive The c o n f i g u r a t i o n a l s t a b i l i t y of li t h i o v i n y l c y c l o p r o p a n e s generated 21,22 from the analogous bromo compounds i s w e l l known 28 addition of tetrahydrofuran and phenylthiocopper produced a s o l u t i o n of the cuprate reagent (33). The cuprate reagent s o l u t i o n (33) was allowed to react with c y c l o -pentanecarboxylic acid c h l o r i d e (82) and the reaction mixture was worked up to give the 2-vinylcyclopropyl ketone (83) in high y i e l d . A s o l u t i o n of the ketone (83) was allowed to react with l i t h i u m diisopropylamide, under k i n e t i c conditions, and the r e s u l t i n g enolate was trapped with t r i m e t h y l s i l y l c h l o r i d e to give the enol s i l y l ether (84). L i C u S C c H c H >^ i i i i s i 29 The enol s i l y l ether (84) was thermolyzed and the rearranged enol s i l y l ether (85) was hydrolyzed with aqueous 1 N hydrochloric a c i d i n methanol to give the spi r o cycloheptenone (86) i n 70% o v e r a l l y i e l d from (82). 0 86 The above procedure was also used to prepare the cyclobutane d e r i -v a t i v e (87) and the n-butane d e r i v a t i v e (88) in good y i e l d s . 33 ^ 0 87 88 30 When the cis-cyclohexane d e r i v a t i v e (89) was prepared and subsequent-l y k i n e t i c a l l y deprotonated and the enolate trapped with t r i m e t h y 1 s i l y l c h l o r i d e , a mixture of enol s i l y l ethers (90) and (91) re s u l t e d . These were obtained i n a r a t i o of approximately 1 : 1 i f l i t h i u m diisopropylamide was the base used. (See Scheme 6). Thermolysis of the mixture of enol s i l y l ethers (90) and (91) at 150°C f or 30 min leads to the products (92) and (93) . Hydrolysis of the mixture s e l e c t i v e l y hydrolyzed the enol s i l y l ether (92) to the ketone (94) and l e f t the s i l y l ether (93) untouched. Compound (93) r e s u l t s from a vinylmethylenecyclopropane rearrangement. , Generation of the enolates of the c i s ketone (89) with various bases, under k i n e t i c conditions, followed by trapping with t r i m e t h y l s i l y l c h l o r i d e or t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e , produced d i f f e r e n t r e l a t i v e amounts of the enol s i l y l ethers (90) and (91). These r e s u l t s are 24 summarized i n Table I As previously stated, l i t h i u m diisopropylamide (LDA) generated an approximately 1 : 1 mixture of enolates. A more s t e r i c a l l y hindered base, 25 l i t h i u m 2,2,6,6-tetramethylpiperidide (LiTMP) removed the less s t e r i c a l l y hindered proton i n preference to the more hindered one and so the observed r a t i o of enol s i l y l ethers (90) and (91) changed to 3 : 7 r e s p e c t i v e l y . A less s t e r i c a l l y hindered base such as li t h i u m diethylamide gave an observed r a t i o of enol s i l y l ethers (90) and (91) of 7 : 3 re s p e c t i v e l y . For a further discussion of t h i s type of thermal rearrangement, see reference 23 and references c i t e d therein. 94 S c h e m e 6 32 Table I. Enolate Formation of c i s Ketone (89) with Various Bases. OSiR. 031 R„ 89 90 91 R = Me; Me2, _t-Bu Base Relative Ratio of Enol S i l y l Ethers (90) and (91) •N-Li (LDA), THF, -78°C 1 : 1 N-Li (LiTMP), THF, -78°C 3 : 7 Et N-Li, THF, -78°C 7 : 3 3 3 Treatment of the c i s cycloheptyl ketone (95) with l i t h i u m d i i s o -propylamide and subsequent trapping of the enolates, as described above, gave the enol s i l y l ethers (96) and (97) i n a r a t i o of approximately 4 : 1 res p e c t i v e l y . . 95 ' 96 97_ R = Me; Me 2 > _t-Bu The c i s neo-pentyl substituted compound (98) gave an approximately 1 : 1 mixture of enolates when treated with l i t h i u m diisopropylamide under k i n e t i c conditions. 98 99 The cyclohexylcyclopropyl ketone (99) when reacted under the same conditions, as described above, gave 100% enolate formation towards the cyclohexane r i n g . In this case, i t was postulated that the absence of a c i s v i n y l group on the cyclopropane r i n g caused the cyclopropane proton adjacent to the ketone to become less a c i d i c . 34 In a l l of the trans v i n y l cases studied, the deprotonation with l i t h i u m diisopropylamide followed by trapping of the r e s u l t i n g enolate with t r i m e t h y l s i l y l c hloride or t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e gave only the enol s i l y l ether r e s u l t i n g from deprotonation of the respective "R" group i n (100) 0 R/V" "-O.O.-HVn-CsH,, H * = 100 These observations further support a possible e l e c t r o n i c e f f e c t of a c i s v i n y l group on the outcome of the deprotonation. However, there may also be s t e r i c e f f e c t s , i n the trans cases (100), due to i n t e r a c t i o n between the v i n y l group and the proton c i s to i t on the cyclopropane r i n g . III The Problem The previously mentioned work, i n our laboratory, l e f t questions unanswered as to the factors a f f e c t i n g enolate formation. Of p a r t i c u l a r i n t e r e s t was the observed s t e r i c f a c t o r i n the case of the ci s - c y c l o h e x y l 35 ketone (89). As discussed above, the r a t i o of enolates changed when a more s t e r i c a l l y hindered or l e s s s t e r i c a l l y hindered base as compared to li t h i u m diisopropylamide was used to deprotonate the ketone. In the case of l i t h i u m diisopropylamide, a 1 : 1 r a t i o of enolates (90) and (91) resu l t e d . 89 90 91 1 : 1 I t was f e l t that the approach of the base to the cyclohexane r i n g proton adjacent to the ketone (arrow) was s t e r i c a l l y hindered by the c i r c l e d protons above, i n a 1,3 d i a x i a l sense. To t e s t t h i s s t e r i c e f f e c t , one of the c i r c l e d protons from above was replaced with a methyl group which would presumably make the r i n g proton adjacent to the ketone more s t e r i c a l l y congested. Treatment with l i t h i u m diisopropylamide should r e s u l t i n a d i f f e r e n t r a t i o of enolates. The dimethyl ketone (101) was synthesized and treated with l i t h i u m diisopropylamide followed by trapping of the enolates under i d e n t i c a l conditions as the ci s - c y c l o h e x y l ketone (89). In each of the trans ketone cases studied (100) enolate formation was only towards the respective "R" group (102). I t was postulated, that one of the c o n t r o l l i n g factors i n t h i s deprotonation was a s t e r i c i n t e r -a c t i o n between the v i n y l group and the proton c i s to i t (H_) , f o r 36 100 102 R1 = t Bu, Me2 example, the trans cyclohexyl ketone (100, R = ). The analogous 3,3-dimethyl d e r i v a t i v e (103) with a trans geometry was prepared to see i f increasing the s t e r i c hindrance, to base attack, at H A would change the r a t i o of enolates that r e s u l t e d . 37 100 103 Also of i n t e r e s t , i n t h i s study, was the possible e l e c t r o n i c e f f e c t that a v i n y l group had on the proton trans to i t [ c i r c l e d proton i n compound (89) below]. The v i n y l group may be increasing the a c i d i t y 89 9j> of t h i s proton since i n the c i s cyclohexyl ketone (89), a mixture of enolates r e s u l t s but i n the cyclohexyl cyclopropyl ketone (99) enolate formation i s only observed towards the cyclohexane r i n g . The model compound for t h i s study was the cis - 2 - e t h y l c y c l o p r o p y l cyclohexyl ketone (104). This compound was k i n e t i c a l l y deprotonated and the r e s u l t i n g enolates were trapped under i d e n t i c a l conditions as compound (89). This thesis describes the preparation of the compounds (101), (103) and (104), t h e i r enol s i l y l ether formation, and subsequent thermal 38 rearrangement of the ethers derived from compounds (101) and (103) to try to understand the previously mentioned ideas. I Discussion The Preparation of the Target- Compounds. The syntheses of compounds (101), (103) and (104) w i l l be discussed i n t h i s section. _cis-2-Vinylcyclopropyl ketones have been prepared in our laboratory v i a a cuprate type reaction on the appropriate acid c h l o r i d e . The s t a r t i n g material f o r compounds (101) and (103) was therefore the a c i d chloride (105). This compound was prepared i n the following manner. 104 .105 Hagemann's ester, 4-carbethoxy-3-methyl-2-cyclohexen-l-one (106), which i s commercially a v a i l a b l e , was hydroly.zed i n r e f l u x i n g methanol and aqueous 2 N sodium hydroxide f o r 24 h. The r e s u l t i n g s o l u t i o n was worked up by the addition of acid to give 3-methyl-2-cyclohexen-l-one (107) i n 71% y i e l d a f t e r d i s t i l l a t i o n . The compound (107) had the c h a r a c t e r i s t i c i n f r a r e d bands at 1660 and 1630 cm due to the a,g-unsaturated ketone f u n c t i o n a l i t y . 40 0 0 C0 2Et 106 107 The ketone (107) was converted into 3,3-dimethylcyclohexanone (108) , .26,27 with a copper catalyzed Gngnard re a c t i o n using cupric acetate as the c a t a l y s t . A s o l u t i o n of methylmagnesium iodide i n anhydrous ether was added to a s o l u t i o n of the ketone (107) and the c a t a l y s t i n anhydrous tetrahydrofuran. The r e s u l t i n g ketone (108), a f t e r work up, could be further p u r i f i e d by high pressure l i q u i d chromatography (HPLC) on s i l i c a g e l . The i n f r a r e d spectrum of the product (108) showed an absorbance at 1710 cm ^ c h a r a c t e r i s t i c of a cyclohexanone carbonyl group and the nmr spectrum did not show any s i g n a l due to an o l e f i n i c proton. High r e s o l u t i o n mass spectrometry indicated the correct molecular mass. Approximately 3% of the 1,2 addition product r e s u l t i n g from the reaction was separated by HPLC. 0 0 107 108 41 At this point in the synthesis, i t was necessary to convert the dimethyl ketone (108) into 3,3-dimethylcyclohexanecarboxylic acid. Many 28 papers have been published on one carbon homologations, but i t was found that a convenient method was to prepare the enol ether (109) and later hydrolyze this material to the aldehyde (110). The enol ether (109) was synthesized via a Wittig reaction u t i l i z i n g the commercially available (methoxymethyl)triphenylphosphonium chloride ( H I ) . 108 109 110 • © © ( C 5 H 5 ) 3 P C H 2 O C H 3 C l 111 The anion of the phosphonium salt (111) was i n i t i a l l y generated by treatment of this substance with n-butyllithium in ether or tetrahydrofuran, 29 since this had been previously reported using a phenyllithium solution. Possibly due to the easy enolizability of the ketone (108), only starting material was recovered in this case. C o r e y r e p o r t e d that the Wittig reaction proceeds much faster and more effici e n t l y using the methylsulfinyl carbanion (112) in dimethyl sulfoxide. He generated the anion in situ using sodium hydride and then immediately used i t . We found that we obtained better results i f a 42 HoC 'CH-112 standardized ( t i t r a t e d ) s o l u t i o n of t h i s base was used. The anion s o l u t i o n (112) could be stored for months i n the freezer. The m e t h y l s u l f i n y l carbanion (112) s o l u t i o n i n dimethyl sulfoxide was added to a s o l u t i o n of the phosphonium s a l t (111) i n dimethyl sulfoxide u n t i l the reddish colour of the anion p e r s i s t e d . A s o l u t i o n of the ketone (108) i n dimethyl sulfoxide was then added and the r e s u l t i n g mixture was s t i r r e d for 2 h at room temperature. A mixture of the enol ethers (109) with an E : Z r a t i o of approximately 1 : 1 (glc analysis) resulted, i n a y i e l d of 90%. The methyl groups of the two isomeric enol ethers had d i f f e r e n t chemical s h i f t s i n the nmr spectrum (6 3.56, 3.53) as did the protons on the double bond (6 5.73, 5.88). The enol ethers (109) were hydrolyzed to the aldehyde (110) using a s o l u t i o n of 70% aqueous p e r c h l o r i c acid i n ether. The nmr spectrum of the aldehyde showed a peak at 6 9.75, a t t r i b u t a b l e to the aldehyde proton, as a doublet with a coupling constant of 2 Hz. The i n f r a r e d spectrum had an absorbance at 2700 cm due to the aldehydic C-H s t r e t c h and a carbonyl absorbance at 1725 cm \ I f the enol ether mixture (109) was p u r i f i e d by HPLC on s i l i c a gel, and then hydrolyzed, as above, a s o l i d with melting point 124-126°C 43 r e s u l t e d . This s o l i d was i d e n t i f i e d as the trimer (113) of the aldehyde. The i n f r a r e d spectrum showed no carbonyl or aldehydic proton s t r e t c h . The "Sr nmr spectrum had a peak at 6 4.43 as a doublet ( J = 5 Hz) due to the proton between the two oxygens i n structure (113). The high r e s o l u t i o n mass spectrum had a fragmentation pattern consistent with that expected for the trimer (113). The aldehyde (110) was oxidized by the method of Jones (CrO^/ ^SO^/IL^O/acetone) to form the carboxylic a c i d (114) . The p u r i f i e d carboxylic acid, as an o i l , exhibited, i n the i n f r a r e d spectrum, a broad band at 3200-2500 cm ^ due to the hydroxyl group on the a c i d and an absorbance at 1700 cm ^ due to the carbonyl f u n c t i o n a l i t y . The "*"H nmr spectrum had a m u l t i p l e t at 6 2.34-2.72 due to the r i n g proton adjacent to the carboxylic a c i d and a broad peak at 6 10.5 due to the proton on the carboxylic a c i d . 113 110 31 110 114 105 44 The carboxylic a c i d c h l o r i d e (105) was prepared by r e f l u x i n g a s o l u t i o n of the carboxylic acid (114) i n two equivalents of th i o n y l 32 c h l o r i d e , as per Vogel . The carboxylic a c i d c h l o r i d e (105) was thus obtained in high y i e l d . The s i g n a l i n the nmr spectrum assigned to the proton adjacent to the carbonyl i n (105), appeared as a m u l t i p l e t a t <5 2.70-3.10. The i n f r a r e d spectrum showed a carbonyl s t r e t c h at 1790 cm \ I t was now necessary to prepare the 1,l-dibromo-2-vinylcyclopropane 33 (115). This was synthesized by a carbenoid reaction on 1,3-butadiene. The butadiene was condensed into a f l a s k and bromoform, methylene chloride, and the phase transf e r c a t a l y s t benzyltriethylammonium c h l o r i d e (TEBA), were added. Ethyl alcohol was also added and a 50% aqueous sodium hydroxide s o l u t i o n was added dropwise. The reaction mixture was s t i r r e d f o r 8 h at approximately -5°C ( r e f l u x i n g butadiene) and subsequently the mixture was worked up. The crude dibromo compound (115) was reduced with a suspension of zinc i n g l a c i a l a c e t i c a c i d and ether. A g l c analysis of the product showed that i t was an approximately 82 : 18 mixture of the c i s and trans isomers of l-bromo-2-vinylcyclopropane (81) and (116) r e s p e c t i v e l y . These 1 34 compounds could be distinguished by H nmr spectroscopy . The pure c i s + 115 81 116 isomer (81) was obtained by a c a r e f u l f r a c t i o n a l d i s t i l l a t i o n (140 torr) of the mixture through a Vigreux column. 45 I n i t i a l l y , a mixture of c i s and trans ketones (.101) and (103) were prepared. A s o l u t i o n of the c i s and trans bromide mixture (81) and (116) (approximately 1 : 1) i n anhydrous ether was allowed to react with t e r t -b u t y l l i t h i u m at -78°C for 2 h. This effected l i t h i u m bromine exchange. 35 Phenylthiocopper and anhydrous tetrahydrofuran were added and a cl e a r brown so l u t i o n r e s u l t e d . The l i t h i u m phenylthiocuprates (33)- and (34) are stable at -20°C. B SAT H H 81 Br'' H 116 LiCuSC 6H 5 33 + LiCu5C 6H 5 34 The mixture of cuprate reagents (33) and (3_4) was allowed to react with the previously prepared carboxylic a c i d c h l o r i d e (105) to form the 2-vinylcyclopropyl ketone mixture (101) and (103). The ketone mixture (101) and (103) was analyzed by glc which indicated that they were present i n a r a t i o of approximately 1 : 1 . The mixture appeared as one spot when observed by th i n layer chromatography. 46 101 •3-3 + 34 + 105 103 The i n f r a r e d spectrum of the mixture of (101) and (103) showed a weak absorbance at 3060 cm \ c h a r a c t e r i s t i c of the C-H s t r e t c h of a cyclopropane r i n g , an absorbance at 1685 cm ^ due to the carbonyl group, and an absorbance at 1630 cm due to the double bond s t r e t c h of the 34 1 v i n y l group . The H nmr spectrum indicated a complex m u l t i p l e t at 6 4.88-5.85 due to the protons on the double bond. A high r e s o l u t i o n mass spectrum measurement showed the correct molecular mass. The c i s - 2 - v i n y l c y c l o p r o p y l ketone (101) was prepared i n a manner analogous to that described above. A s o l u t i o n of cis-l-bromo-2-vinyl-cyclopropane (81) (from f r a c t i o n a l d i s t i l l a t i o n , 95% pure) i n anhydrous ether was treated with a t e r t - b u t y l l i t h i u m s o l u t i o n at -78°C and the r e s u l t i n g mixture was s t i r r e d f o r 2 h. Anhydrous tetrahydrofuran and 35 s o l i d phenylthiocopper were added as before. A s o l u t i o n of the acid c h l o r i d e (105) i n anhydrous tetrahydrofuran was added to the mixture. Usual work up of the r e a c t i o n mixture, by addition of ether, and f i l t e r i n g the r e s u l t a n t suspension through a short column of F l o r i s i l , 47 gave the c i s ketone (101)• D i s t i l l a t i o n of the product gave an 87% y i e l d of a co l o u r l e s s o i l which appeared as a s i n g l e component when analyzed by g l c . The i n f r a r e d spectrum showed an absorbance at 1690 cm ^ due to the -1 34 carbonyl group and an absorbance at 1630 cm due to the C=C s t r e t c h of the v i n y l group. The "^H nmr spectrum of t h i s material was more c l e a r l y 101 defined as compared to that of the mixture. The proton H^ (see diagram) appears as a doublet of doublets with one coupling constant of 10 Hz, due to the c i s H^, H^ coupling, and a geminal coupling H^, H^ of 2.5 Hz. These coupling constants are i n the normal range for t h i s s o r t of double bond 36 proton . Proton E resonated at 6 5.17 as a doublet of doublets with a trans coupling (H^, H^) of 17 Hz. Proton H^ gave r i s e to a doublet of doublet of doublets centred at 6 5.66 with, besides the above mentioned couplings, a coupling of 8 Hz between i t s e l f and proton H^. The trans-2-vinylcyclopropyl ketone (103) was prepared by treatment of a s o l u t i o n of the mixed ketones (101) and (103) (1 : 1 from above) i n anhydrous tetrahydrofuran with a s o l u t i o n of potassium tert-butoxide in t e r t - b u t y l a l c o h o l . The r e s u l t i n g mixture was s t i r r e d f o r 3 h at room temperature. The r e a c t i o n s o l u t i o n was worked up with 1 N hydrochloric acid and the resultant o i l was analyzed by g l c . This a n a l y s i s revealed 48 a trans : c i s r a t i o of approximately 93 : 7 r e s p e c t i v e l y . Longer reaction times C.~18 h) resulted i n approximately the same trans : c i s r a t i o . 0 103 The XH nmr spectrum of th i s ketone (103), showed a doublet of doublets due to H 1 at 6 4.98 with a coupling of 9 Hz and a H.^ H 2 coupling of approximately 3 Hz. Proton also gave r i s e to a doublet of doublets with coupling of 17 Hz f o r E , H^, the same geminal coupling as mentioned above (3 Hz), and a chemical s h i f t of 6 5.14. The proton H^» i n t h i s case, resonated as a complex m u l t i p l e t at 6 5.28-5.70. The cis-2 - e t h y l c y c l o p r o p y l ketone (104) was also synthesized. I t 89 104 was f e l t that t h i s ketone could be prepared by hydrogenation of the corresponding c i s - 2 - v i n y l c y c l o p r o p y l ketone (89). The c i s - 2 - v i n y l c y c l o p r o p y l ketone (89) was synthesized by means of a cuprate reaction, as described above, using the cis-l-bromo-2-vinyl-49 cyclopropane (81) and cyclohexanecarboxylic acid c h l o r i d e , i n 78% y i e l d . This ketone (89) was p u r i f i e d by chromatography on a s i l i c a gel column (R^ = 0.55). The column was eluted with a mixture of petroleum ether and ether i n a r a t i o of 7 : 1 r e s p e c t i v e l y . The i n f r a r e d spectrum of the p u r i f i e d material exhibited absorbances at 1690 cm ^ due to the carbonyl group and at 1635 cm ^ due to the o l e f i n i c double bond. The nmr spectrum had a doublet of doublets centred on & 4.94 a t t r i b u t a b l e to proton H^, with coupling constants of 10.5 Hz for H^, H„ (see diagram) and 2.3 Hz f o r H., , H 0. The proton H 0 resonated at 6 5.13 89 as a doublet of doublets and i s coupled to proton H^ with a coupling constant of 17 Hz as well as being coupled to proton H^, as described above. The s i g n a l due to proton H^ appeared as a doublet of doublet of doublets centred at 6 5.62 with, besides the above mentioned couplings, a coupling of 9 Hz between i t s e l f and proton H^. I t was expected that the desired product (104) could be prepared 37 from ketone (89) v i a a c a t a l y t i c hydrogenation. Heathcock reported that the c a t a l y t i c hydrogenation of various substituted v i n y l cyclopropane 38 d e r i v a t i v e s (117) proceeded most e f f i c i e n t l y i f he used Wilkinson's c a t a l y s t , tris(triphenylphosphine)rhodium c h l o r i d e (118). 50 H K C 5 H 5 ) 3 P ! 3 R h C l 117 118 Ri = R2 = R 3 = H Rl = Me; R 2 = R3 = H Rl = R 2 = H; R3 = Me Rl = H; R2 = R3 = Me Rl = R 3 = Me; R2 = H R]_ = R2 = R 3 = Me The c i s - 2 - v l n y l c y c l o p r o p y l cyclohexyl ketone (89) was hydrogenated with 5 mole % of Wilkinson's c a t a l y s t i n benzene at atmospheric pressure and room temperature. However, none of the expected product (104) was obtained and only a small amount of s t a r t i n g material (89) was recovered with no other i d e n t i f i a b l e products. Other hydrogenation c a t a l y s t s were also used (10% Pt/C; 5% Rh/alumina), in benzene or isopropyl alcohol, as solvents, with varying r e s u l t s . These c a t a l y s t s gave poor y i e l d s of the hydrogenated product (104). 0 89 104 51 To circumvent t h i s problem, i t was f e l t that a diimide reduction 39 might work i n th i s case. Following the method of Fieser , a s o l u t i o n of the c i s ketone (89) i n eth y l alcohol and 95% hydrazine hydrate was put i n a round bottomed f l a s k at 0°C. A drop of an approximately 1% aqueous cupric s u l f a t e pentahydrate s o l u t i o n was added followed by a 30% hydrogen peroxide s o l u t i o n and the mixture was allowed to warm to room temperature and s t i r r e d f o r 5 h. The cis -2 - e t h y l c y c l o p r o p y l cyclohexyl ketone (104) was obtained i n 69% y i e l d . A glc analysis of t h i s o i l showed only one component and no s t a r t i n g m a t e r i a l . The i n f r a r e d spectrum had an absorbance at 1685 cm ~^ due to the carbonyl group and the nmr spectrum had a t r i p l e t centred at 6 0.85 due to the methyl group of the e t h y l substituent. The proton on the cyclo-propane r i n g adjacent to the ketone (H^) appeared as a m u l t i p l e t at 6 2.02-2.12 while the proton on the other side of the ketone (H^) resonated as a m u l t i p l e t at 6 2.42-2.55. .104 To prove that no c i s to trans isomerization of the substituted v i n y l c y c l o p r o p y l ketone (89) had taken place during the diimide reduction the analogous trans compound (100, R = (^) ) was prepared and reduced under conditions i d e n t i c a l with those described above. This ketone was synthesized by treatment of a s o l u t i o n of the c i s ketone (89) i n t e t r a -52 119 hydrofuran with a s o l u t i o n of potassium tert-butoxide i n t e r t -b utyl a l c o h o l as previously described. A glc analysis of the product (100) indicated one peak with a retention time s i m i l a r to that of the c i s ketone (89). The nmr spectrum showed a m u l t i p l e t at 6 2.55-2.68 due to the cyclohexane r i n g proton adjacent to the carbonyl group. Proton HL appeared 0 100 as a doublet of doublets centred on 6 4.96 with geminal coupling of 2.4 Hz and H^, H^ coupling of 7.8 Hz. Proton H^ resonated at 6 5.12 as a doublet of doublets with, besides the previously mentioned geminal 53 coupling, a coupling between and of 15 Hz, Proton H^ appeared as a complex m u l t i p l e t between 6 5.28 and 6 5.70. The trans v i n y l ketone (100) was reduced under s i m i l a r diimide reduction conditions, as previously described, to give the trans-2-ethyl-cyclopropyl cyclohexyl ketone (119) i n 65% y i e l d . The product, upon glc analysis, had a retention time s i m i l a r to that of the c i s ketone (104). The ^H nmr spectrum d i f f e r e d from that of ketone (104). A m u l t i p l e t at 6 0.67-0.74 was due to one of the cyclopropane protons. The methyl of the e t h y l substituent appeared as a t r i p l e t centred at 6 0.96. The cyclohexane proton adjacent to the carbonyl group resonated as a m u l t i p l e t at 6 2.42-2.55. II Enol Ether-Formation and Rearrangement The enol ether formation of compounds (101), (103) and (104) and thermal rearrangement of those r e s u l t i n g from (101) and (103) w i l l be discussed i n t h i s s e c t i o n . 101 103 104 A s o l u t i o n of the - c i s ketone (101) i n anhydrous tetrahydrofuran was added dropwise to a s o l u t i o n of l i t h i u m diisopropylamide (LDA) i n anhydrous tetrahydrofuran at -78°C. The r e s u l t i n g mixture of enolates 54 was trapped at -78°C by the addition of a s o l u t i o n of f r e s h l y sublimed t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e i n anhydrous tetrahydrofuran followed by dry hexamethylphosphoramide (HMPA). The mixture was subsequently s t i r r e d f o r 15 min at -78°C and 3 h at room temperature. Following work-up, a glc analysis of the r e s u l t i n g o i l (87% y i e l d ) revealed that i t consisted of a mixture of enol s i l y l ethers (120) and (121) in a r a t i o of approximately 12 : 88 r e s p e c t i v e l y . 101 120 121 The i n f r a r e d spectrum of t h i s mixture had an absorbance at 1760 cm x which was a t t r i b u t e d to the double bond s t r e t c h of the bond exo to the cyclopropane r i n g i n compound (121) . The nmr spectrum had a peak at 5 0.16 as a s i n g l e t due to the methyl group protons on the enol s i l y l ethers. This 12 : 88 mixture of (120) and (121) was thermolyzed neat at 160°C f o r 45 min in a previously e q u i l i b r a t e d Kugelrohr d i s t i l l a t i o n apparatus, under an argon atmosphere, to give the rearranged products (122) and (123) i n a 88% y i e l d a f t e r d i s t i l l a t i o n . Compound (123) r e s u l t s from 23 a vinylmethylenecyclopropane rearrangement as previously discussed A glc analysis of the mixture (122) and (123) revealed that the compounds were present i n a r a t i o of approximately 14 : 86 r e s p e c t i v e l y . The two compounds (122) and (123) could not be separated v i a column chro-matography on s i l i c a g e l or F l o r i s i l . 55 120 + 121 122 123 The i n f r a r e d spectrum of the mixture of (122) and (123) showed an absorbance at 1630 cm ^ due to an o l e f i n i c double bond s t r e t c h . The ''"H nmr spectrum had the following peaks a t t r i b u t e d to the major product (123). A s i n g l e t at 6 -0.04 was due to the methyl group hydrogen of the s i l y l ether. A broad s i n g l e t at 6 4.88 was assigned to proton which i s long range coupled with H^. This broadening i s due to trans v i n y l i c 40 coupling which i s reported to be i n the range of 0.5-2.5 Hz. A sharp s i n g l e t at 6 5.02 was assigned to the proton H 0 (geminal coupling must be 123 <1 Hz). Proton H^ appeared as a m u l t i p l e t at 6 6.04-6.20, deshielded by the exo double bond and proton H^ appeared as a m u l t i p l e t at 6 5.86-6.01. The trans ketone (103) (trans :: c i s , 93 : 7) was also treated with 56 li t h i u m diisopropylamide, under k i n e t i c conditions and the r e s u l t i n g mixture of enolates was trapped with t e r t - b u t y l d i m e t h y l s i l y 1 c h l o r i d e i n the presence of hexamethylphosphoramide, as previously described. A glc . analysis of the d i s t i l l e d o i l (84% y i e l d ) revealed that the mixture was composed of compounds (124) and (121) in a r a t i o of approximately 87 : 13 re s p e c t i v e l y . 103 124 121 The i n f r a r e d spectrum had an absorbance at 1660 cm ^ due to the double bond exo to the cyclohexane r i n g . The nmr spectrum had a p a i r of s i n g l e t s at 6 0.10 and 6 0.13 due to the methyl group hydrogens on the enol s i l y l ethers. The enol s i l y l ether mixture (124) and (121), from above, was thermolyzed at 230°C f or 1 h i n a previously e q u i l i b r a t e d Kugelrohr d i s t i l l a t i o n apparatus (argon). The mixture was d i s t i l l e d (72% y i e l d ) and the r e s u l t i n g o i l was analyzed by glc which showed that i t consisted of a mixture of compounds (122) and (123) i n a r a t i o of approximately 82 : 18 r e s p e c t i v e l y . An i n f r a r e d spectrum of the mixture was s i m i l a r to that r e s u l t i n g from the c i s compound (101) . The ''"H nmr spectrum had the following peaks a t t r i b u t a b l e to the major product (122). The enol s i l y l ether methyl 57 124 4- 121 t 122 123 groups appeared as a p a i r of s i n g l e t s at <S 0.17 and 0.19. Proton H. appeared as a t r i p l e t centred at 6 4.72 and protons H 2 and H^ gave r i s e to a m u l t i p l e t at 6 5.60-5.86. The enol s i l y l ethers of the cis- 2 - e t h y l c y c l o p r o p y l ketone (104) were prepared, as described above, by treatment of the ketone with l i t h i u m diisopropylamide and trapping the r e s u l t i n g enolates with t e r t -b u t y l d i m e t h y l s i l y l c h l o r i d e in the presence of hexamethylphosphoramide. Work up of the mixture and d i s t i l l a t i o n of the r e s u l t i n g o i l gave a 74% y i e l d of the enol ethers (125) and (126). A glc analysis of t h i s o i l had one major peak (~97%). However, the i n f r a r e d spectrum, of t h i s material, showed an absorbance at 1765 cm ^ due to a double bond exo to the cyclopropyl r i n g and an absorbance at 1670 cm ^ due to an o l e f i n i c 1 122 58 104 125 126 bond exo to the cyclohexane r i n g . This indicated that both isomers were present. The r a t i o of the two enol s i l y l ethers (125) and (126) was determined by c a r e f u l i n t e g r a t i o n of the methyl signals of the s i l y l ethers on a high r e s o l u t i o n nmr spectrometer. Integration showed the mixture of (125) and (126) was i n a r a t i o of approximately 1 : 1 . I I I . Hydrolysis of the Thermolysis, Mixtures The thermolysis mixtures, from the c i s and trans ketones (101) and (103) r e s p e c t i v e l y , were not separated at t h i s stage but instead each mixture was allowed to react with a sol u t i o n of 1 N hydrochloric acid i n tetrahydrofuran. This e f f e c t i v e l y hydrolyzed the enol s i l y l ether f u n c t i o n a l i t y i n compound (122) . The r e s u l t i n g mixtures were then 122 59 chromatographed and the pure compounds were characterized. The thermolysis mixture (122) and (123) from the c i s ketone (101), in a r a t i o of approximately 14 : 86 r e s p e c t i v e l y , was hydrolyzed i n a so l u t i o n of 1.5 mL of tetrahydrofuran and 0.75 mL of 1 N hydrochloric a c i d . The r e s u l t i n g mixture was analyzed v i a glc and was found to be a mixture of compounds (127) and (123) i n a r a t i o of approximately 10 : 90 r e s p e c t i v e l y . This mixture was subjected to column chromatography on s i l i c a g e l . The column was eluted with a petroleum ether : ether mixture (approximately 7 : 1 respectively) to give the s i l y l ether (123) (R, = 0.64). The i n f r a r e d spectrum of the p u r i f i e d s i l y l ether (123) had an absorbance at 1630 cm ^ due to the o l e f i n i c double bond s t r e t c h and also —1 36 a peak at 1250 cm c h a r a c t e r i s t i c of the m e t h y l - s i l i c o n s t r e t c h . The "*"H nmr spectrum had a s i n g l e t at <5 -0.07 due to the s i l y l methyl groups. 123 60 Proton IL^  appeared as a broad s i n g l e t at <5 4.88 due to a small trans v i n y l i c coupling with proton H^, as previously discussed. Proton resonated as a sharp s i n g l e t at 6 5.02. Protons and each appeared as mu l t i p l e t s at 6 6.04-6.20 and 6 5.86-6.00 r e s p e c t i v e l y . A high r e s o l u t i o n mass spectrometric measurement gave the correct molecular mass for the compound (123). The thermolysis mixture (122) and (123) from the trans ketone (103), in a r a t i o of approximately 82 : 18 r e s p e c t i v e l y , was hydrolyzed i n a so l u t i o n of 2 mL of tetrahydrofuran and 1 mL of 1 N hydrochloric a c i d . The r e s u l t i n g mixture of compounds (127) and (123) was analyzed by glc and the two compounds were found to be present i n a r a t i o of approximately 87 : 13 r e s p e c t i v e l y . This o i l was subjected to column chromatography on s i l i c a . The column was eluted with a petroleum ether : ether mixture (approximately 7 : 1 respectively) to give the p u r i f i e d ketone (127) (R f = 0.36). The i n f r a r e d spectrum of the p u r i f i e d ketone (127), as an o i l , had a sharp absorbance at 1690 cm ^ due to the carbonyl f u n c t i o n a l i t y . The "Si nmr spectrum had a p a i r of s i n g l e t s at 6 0.76 and 0.91 due to the two methyl groups. The two o l e f i n i c protons appeared as complex mul t i p l e t s 127 61 at 6 5.72-5.84 and 5 5.86-5.97. A high r e s o l u t i o n mass spectrometric measurement gave the correct molecular mass f o r the compound (127) . IV F u r t h e r Work 24 To r e a f f i r m the previously observed r e s u l t that cyclohexyl cyclopropyl ketone (99) deprotonated only towards the cyclohexane r i n g , i t was prepared and i t s enol s i l y l ether formed. 99 128 The ketone was synthesized v i a a cuprate reaction of the l i t h i u m (phenylthio)cyclopropylcuprate with cyclohexanecarboxylic a c i d c h l o r i d e . The enol s i l y l ether (128) was prepared by t r e a t i n g the ketone (99) with l i t h i u m diisopropylamide and trapping the r e s u l t i n g enolate with a t e r t - b u t y l d i m e t h y l s i l y l chloride s o l u t i o n as described previously. A glc a n a lysis of the i s o l a t e d product showed that i t consisted of one component. The i n f r a r e d spectrum had an absorbance at 1660 cm ^ c h a r a c t e r i s t i c of a double bond exo to the cyclohexane r i n g . The "^H nmr spectrum had a s i n g l e t at 6 0.13 due to the methyl groups on the enol s i l y l ether. The four protons a to the double bond on the cyclohexane r i n g appeared as a p a i r of m u l t i p l e t s at <5 2.11-2.18 and 6 2.21-2.80. 62 V " Conclusions As shown e a r l i e r , generation of the enolates of the c i s - 2 - v i n y l -cyclopropyl ketone (89) with l i t h i u m diisopropylamide, followed by trapping of these enolates gave an approximately 1 : 1 mixture of enol s i l y l ethers (90) and (91). The use of a more s t e r i c a l l y or l e s s s t e r i c a l l y hindered base (see Table I ) , to form the enolates, and the trapping of these, gave d i f f e r e n t r a t i o s of enol s i l y l ethers, suggesting that a s t e r i c e f f e c t may be a f f e c t i n g the deprotonation although t h i s may not be the only e f f e c t . The more congested 3,3-dimethyl d e r i v a t i v e (101), when treated with l i t h i u m diisopropylamide and trapping of the enolates, was expected to show more enolate formation towards the cyclopropane r i n g i f there was a s t e r i c e f f e c t . Indeed, formation of the enolates with l i t h i u m diisopropylamide followed by the trapping of these under conditions i d e n t i -c a l with those used i n the cyclohexyl case (89), gave a r a t i o of the enol s i l y l ethers (120) and (121) of 12 : 88 re s p e c t i v e l y . This confirmed 89 90 91 0SiMe ,Bu* + 101 120 121 12 : 88 63 that there Is some s t e r i c hindrance to base attack i n t h i s system. The trans-2-vinylcyclopropyl ketone (100), when allowed to react with l i t h i u m diisopropylamide followed by trapping of the r e s u l t i n g enolate, gave exclusive e n o l i z a t i o n towards the cyclohexane r i n g [compound (102)]. In f a c t , i n a l l trans compounds studied, e n o l i z a t i o n occurred only towards the respective "R" group (see previous d i s c u s s i o n ) . We were interes t e d i n seeing how the more congested trans-3,3-dimethyl d e r i v a t i v e (103) would react under s i m i l a r enol ether forming conditions. When the d e r i v a t i v e (103) was allowed to react with l i t h i u m d i i s o p r o p y l -amide followed by trapping of the enolates, i t gave a mixture of enol ethers (124) and (121) i n a r a t i o of approximately 87 : 13 re s p e c t i v e l y . This again confirmed a s t e r i c e f f e c t . 103 124 121 87 : 13 64 As discussed above, the c i s - 2 - v i n y l c y c l o p r o p y l ketone (89) gave a 1 : 1 mixture of enol s i l y l ethers when treated with l i t h i u m d i i s o p r o p y l -amide followed by trapping of the r e s u l t i n g enolates. The cyclohexyl cyclopropyl ketone (99) when reacted, under i d e n t i c a l conditions as above, gave enolate formation only towards the cyclohexane r i n g . These observations suggested that the v i n y l substituent may have some sor t of e l e c t r o n i c e f f e c t on the cyclopropane proton [ c i r c l e d i n (89)] beside the ketone. The replacement of the v i n y l substituent in compound (89) 0 99 128 with an ethyl group should reduce any e l e c t r o n i c e f f e c t of the c y c l o -propane proton adjacent to the ketone. Thus, the cis - 2 - e t h y l c y c l o p r o p y l ketone (104) was expected to give, upon deprotonation and trapping of the r e s u l t i n g enolates, mainly enol s i l y l ether formation towards the 65 104 cyclohexane ring. Formation and trapping of the enolate generated from the ketone (104) gave an approximately 1 : 1 mixture of enol s i l y l ethers. This resu l t seems to disprove an electronic effect of a v i n y l substituent, although more work w i l l have to be done in this area to further understand the above mentioned r e s u l t . 66 Experimental General Information Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. D i s t i l l a t i o n temperatures are also uncorrected and those indicated as a i r - b a t h temperatures r e f e r to short path (Kugelrohr) d i s t i l l a t i o n s . Infrared ( i r ) spectra were recorded on a Perkin-Elmer model 710 B i n f r a r e d spectrophotometer and were c a l i b r a t e d using the 1601 cm band of polystyrene f i l m . The proton nuclear magnetic resonance (^ H nmr) spectra were taken i n deuterochloroform so l u t i o n and were recorded using Varian Associates HA-100, XL-100 spectrometers or a Bruker WP-80 spectrometer. The 270 MHz spectra were recorded on a unit comprised of an Oxford Instruments 63.4 KG superconducting magnet and a N i c o l e t 1,6'K computer attached to a Bruker TT-23 console. Signal p o s i t i o n s are given i n parts per m i l l i o n (6) from tetramethylsilane (TMS) as i n t e r n a l standard. In the case of compounds containing t e r t - b u t y l -d i m e t h y l s i l y l groups, the resonance positions were determined v i a deuterium lock (CDClg) on the nmr spectrometer. The m u l t i p l i c i t y , number of protons, coupling constants (where possible) and assignments are indicated i n parentheses. Low r e s o l u t i o n mass spectra were recorded with a Varian/MAT CH4B mass spectrometer. High r e s o l u t i o n mass spectra were recorded with a Kratos/AEI MS 50 or MS 902 mass spectrometer. A n a l y t i c a l gas l i q u i d chromatography (glc) was performed on a Hewlett-Packard HP 5832A gas chromatograph. The following columns were used: (A) 6 f t x 0.125 i n . , 3% 0V-17 on Chromosorb W (HP) (80-100 mesh); (B) 6 f t x 0.125 i n . , 5% OV-210 on Chromosorb W (HP) (80-100 mesh); (C) 6 f t x 0.125 i n . , 3% Carbowax 20M on Chromosorb W (HP) (80-100 mesh). 67 Column chromatography was done on e i t h e r s i l i c a gel (E. Merck 70-230 mesh) or F l o r i s i l (J.T. Baker Chemical Co., 100-200 mesh). A n a l y t i c a l t h i n - l a y e r chromatography ( t . l . c . ) was c a r r i e d out on commercial, pre-coated S i l i c a Gel plates with fluorescent i n d i c a t o r (Eastman Kodak, Sheet Type 13181) and v i s u a l i z e d by iodine vapour s t a i n i n g . Preparative high pressure l i q u i d chromatography (HPLC) was done on a Waters Prep LC/System 500 instrument with Prep Pak-500 s i l i c a c a r t r i d g e containing chromatographic grade s i l i c a . A l l reactions i n v o l v i n g moisture and a i r s e n s i t i v e reagents were c a r r i e d out under an atmosphere of argon using c a r e f u l l y flame dried glassware. Solvents and Reagents Solutions of n-butyllithium, methyllithium, and t e r t - b u t y l l i t h i u m were obtained from A l d r i c h Chemical Company Inc. and were standardized 41 using Gilman's procedure . The t e r t - b t t t y l d i m e t h y l s i l y l c h l o r i d e ( A l d r i c h Chemical Co. Inc.) was sublimed at 20 torr and used immediately. Petroleum ether r e f e r s to the reagent grade mixture that has a b o i l i n g range of 30-60°C. Ether r e f e r s to reagent grade d i e t h y l ether. Tetrahydrofuran and d i e t h y l ether were d i s t i l l e d from sodium 42 benzophenone k e t y l under nitrogen. Diisopropylamine was d i s t i l l e d from calcium hydride and stored over o f r e s h l y a c t i v a t e d 3A molecular sieves. Dimethyl sulphoxide was d i s t i l l e d from calcium hydride at reduced pressure (20 t o r r ) . 68 Hexamethylphosphoramide (HMPA) was d i s t i l l e d from barium oxide under reduced pressure (vacuum pump) and stored over f r e s h l y activated 3 A and 13X molecular sieves. The 4-carbethoxy-3-methyl-2-cyclohexen-l-one (Hagemann's e s t e r ) , (methoxymethyl) triphenylphosphonium ch l o r i d e , and potassium t e r t -butoxide were obtained from A l d r i c h Chemical Company Inc. A l l extraction solvents were reagent grade and were used as received. The sodium m e t h y l s u l f i n y l methide (dimsyl sodium) s o l u t i o n was prepared by addition of sodium hydride (6 g., 50% wt/wt i n mineral o i l ) to a dry f l a s k , with r e f l u x condenser under an atmosphere of argon. The sodium hydride was rinsed with petroleum ether (3 x 25 mL), to remove the mineral o i l , dry dimethyl sulphoxide (50 mL) was added, and the mixture heated at 65°C for 3 h. The r e s u l t i n g grey, cloudy s o l u t i o n was standardized by quenching 1 mL with water and t i t r a t i n g the r e s u l t a n t basic s o l u t i o n with standardized 0.1 normal hydrochloric acid (1% phenolphthalein s o l u t i o n as i n d i c a t o r ) . The t i t r a t e d s o l u t i o n could be stored i n a round bottom f l a s k with a septum cap in the freezer and added v i a syringe to the reaction mixture. The 1,3-butadiene (gas) was purchased from the Matheson D i v i s i o n of G.D. Searle and Co. of Canada Ltd. 69 Preparation of 3-Methyl-2-Cyclohexen-l-one (107) 107 To a flame-dried 250 mL f l a s k equipped with a magnetic s t i r bar, a r e f l u x condenser, and an argon i n l e t tube was added 26.1 g ( f r e s h l y d i s t i l l e d , 0.14 mol ) of 4-carbethoxy-3-methyl-2-cyclohexen-l-one (Hagemann's e s t e r ) , reagent grade methyl alcohol (40 mL) and 2 N aqueous sodium hydroxide (30 mL). The r e s u l t i n g mixture was refluxed for 24 h. The reaction was worked up by the addition of 1 N hydrochloric a c i d , u n t i l the so l u t i o n was s l i g h t l y a c i d i c , and the mixture was extracted with ether (2 x:200 mL) . The combined extract was washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of the ether followed by d i s t i l l a t i o n of the resultant o i l (air-bath temperature 90-95°C, 20 torr) gave 11.19 g (71%) of the ketone (107) as a colourless o i l . A glc analysis of t h i s material (column A) exhibited one peak. IR ( f i l m ) : 2940, 2860, 1660, 1630, 1430, 1380, 1350, 1325, 1250, 1195, 890 cm"1; 1H nmr (CDC1 ) 6 : 1.85-2.22 (m, 2 H ) , 1.92 (s, 3H, Me), 2.17-2.54 (m, 4H), CH C-, ), 5.81-5.90 (m, 1H, ). Exact mass calcd, CH„ >-l3 for 0: 110.0732; found: 110.0733. 70 Preparation of 3,3-Dimethylcyclohexanone (108.) 0 108 • To a 250 mL flame-dried f l a s k , equipped with a dry i c e condenser, a septum cap, an argon i n l e t tube and a magnetic s t i r bar, were added magnesium turnings (2.87 g, 0.118 mol) and 25 mL of anhydrous ether. Methyl iodide (6.79 mL, 0.109 mol) was added c a r e f u l l y . Anhydrous ether (60 mL) was added and the r e s u l t i n g s o l u t i o n was allowed to r e f l u x for 30 min and then cooled to 0°C. To a second 250 mL, flame-dried f l a s k , equipped with a pressure equalizing dropping funnel (100 mL) containing a septum cap, an argon i n l e t tube and a magnetic s t i r bar, was added 3-methyl-2-cyclohexen-l-one (107) (10 g, 0.091 mol), cupric acetate (1.65 g, 9.1 mmol), and 43 mL of anhydrous tetrahydrofuran. The f r e s h l y prepared s o l u t i o n of Grignard reagent was transferred v i a cannula to the dropping funnel of the second f l a s k . This s o l u t i o n was added dropwise to the cooled (0°C), vigorously s t i r r e d mixture i n the second f l a s k over 1 h. The r e s u l t i n g mixture was allowed to warm to room temperature and s t i r r i n g was continued for an a d d i t i o n a l 2 h. The reaction mixture was poured into a s l u r r y of 100 mL of crushed ice and d i l u t e hydrochloric acid and the r e s u l t a n t mixture was extracted with 2 x 200 mL of ether. The combined extracts were washed with brine, dried over anhydrous magnesium s u l f a t e and the solvent 71 was evaporated to give 10.45 g (91%) of the crude ketone (108) as an o i l . A glc analysis of t h i s material (column A) showed that i t contained approximately 3% of the 1,2 addition product and approximately 97% of the desired 3,3-dimethylcyclohexanone (108). The mixture was conveniently p u r i f i e d by column chromatography on s i l i c a gel or by HPLC. In each case, a 3 : 2 mixture of petroleum ether and ether was used as the e l u t i n g solvent. Pure 3,3-dimethylcyclohexanone (108) exhibited IR ( f i l m ) : 2960, 2870, 1710, 1460, 1420, 1370, 1315, 1295, 1265, 1230 cm"1; """H nmr (CDCl ) 6: 0.99 (s, 6H, methyls), 1.45-2.08 (m, 4H), 2.10-2.43 (m, 4H, 0 -C-CH.)„). Exact mass calcd. for C oH n,0: 126.1044; found: 126.1040. —z 2 8 14 Preparation of the Enol Ether C1H9J To a dry, 50 mL f l a s k equipped with a dropping funnel, a septum cap, an argon i n l e t tube and a magnetic s t i r bar was added (methoxymethyl) triphenylphosphonium chloride (3.47 g, 10.12 mmol) and 20 mL of dry dimethyl sulphoxide. Sodium m e t h y l s u l f i n y l methide (dimsyl sodium) so l u t i o n (2.65 M) was added dropwise to the mixture u n t i l a red colour p e r s i s t e d . Further dimsyl sodium s o l u t i o n was then added (3.82 mL, 10.12 mmol) and the r e s u l t i n g red s o l u t i o n was s t i r r e d f o r 15 min at room temperature. A so l u t i o n of the ketone (108) (850 mg, 6.75 mmol) in 5 mL 72 of dry dimethyl sulphoxide was added over a period of 10 min and the r e s u l t i n g s o l u t i o n was s t i r r e d for an a d d i t i o n a l 2 h. The reaction mixture was poured into 50 mL of water and the mixture thus obtained was extracted with ether (2 x 50 mL). The combined extracts were washed ft with brine, dried over anhydrous magnesium s u l f a t e , and the solvent was removed to give an o i l . The o i l was dissolved i n hexanes and the r e s u l t i n g s o l u t i o n was passed through a short column of F l o r i s i l . The column was eluted with further volumes of hexanes. Removal of the solvent from the combined eluate gave 940 mg (90%) of an o i l which was s u i t a b l e for the next reaction. The material could be p u r i f i e d further by means of HPLC using petroleum ether and ether (7 : 1) as the e l u t i n g solvent mixture. A glc a n a l y s i s (column B) of the p u r i f i e d material showed i t to be an approximately 1 : 1 mixture of JE and _Z isomers IR (film) : 2910, 2890, 2855, 2830, 1680, 1460, 1440, 1380, 1360, 1230, 1205, 1145, 1120, 990, 975cm _ 1; 1H nmr ( C D C l ^ 5: 0.86, 0.90 (s, s, 6H, methyls), 1.20-2.22 (complex m, 8H), 3.56, 3.53 (s, s, 3H, -0CH 3), 5.72, 5.88 (brs, brs, IH, v i n y l proton). Exact mass calcd. f o r Cir.H. 0 t ) : 154.1358; 1U l o found: 154.1362. Preparation of 3,3-Dimethylcyclohexanecarboxaldehyde (llOJ 110 73 To a c o l d (0°C), s t i r r e d s olution of 70% aqueous p e r c h l o r i c a c i d (8.25 mL) i n ether (25 mL) , under an atmosphere of argon, was added a s o l u t i o n (ether, 5 mL) of the enol ethers (109) (0.52 g, 3.38 mmol). The r e s u l t i n g s o l u t i o n was allowed to warm to room temperature and was s t i r r e d f o r 2 h. The mixture was c a r e f u l l y poured into saturated aqueous sodium bicarbonate (~60 mL) and the r e s u l t a n t mixture was extracted with ether (2 x 50 mL). The combined extracts were washed with water and dried over anhydrous magnesium s u l f a t e . Removal of the solvent gave an o i l which was f i l t e r e d through a short column of F l o r i s i l ( further e l u t i o n with petroleum ether). Removal of the solvent from the combined eluate gave 370 mg (94%), of the desired aldehyde (110) as an o i l . A glc analysis of t h i s material (column A) showed that i t contained no s t a r t i n g material (109) and was 94% pure. The aldehyde (110) could be used for the following reaction without further p u r i f i c a t i o n . IR (film) 2910, 2930, 2850, 2700, 1725, 1460, 1380, 1260,cm"1; ^ nmr (CDC1 ) 6 : 0.91, 0.94, (s, s, 6H, methyls), 1.02-2.60 (complex m, 9H), 9.75 (d, J = 2 Hz, IH, -CHO) . I f HPLC p u r i f i e d enol ethers (109) were used i n the reaction, a c r y s t a l l i n e product (mp 124-126°C), i d e n t i f i e d as the trimer (113), was obtained. This material exhibited the following spectra: IR (CHCl^) : 3000, 2 940, 2915, 2850, 2840, 1460, 1450, 1380, 1365, 1345, 1190, 1140, 1130, 1110, 1070, 1040 cm"1; ^ nmr (CDClj) <5: 0.91, 0.94 (s, s, 18H, methyls), 1.0-2.48 (complex m, 27H), 4.43 (d, J = 5 Hz, 3H, — { )• , + r-o H > Exact mass calcd for C y H j , ^ (M -1) : 419.3525; found: 419.3510; calcd. for C 9H 1 60 (monomer): 140.1201; found: 140.1201. Preparation of 3 , 3-Dimethylcyclohexanecarboxylic Acid ( U L 4 J To a cold (0°C), vigorously s t i r r e d s o l u t i o n of the crude aldehyde (110) (0.37 g, 2.64 mmol) in reagent acetone (16 mL), was added over a 31 period of 5 min, a f r e s h l y prepared s o l u t i o n of Jones' reagent (0.60 mL, 8 N, 4.8 mmol). The mixture was allowed to warm to room temperature and s t i r r i n g was continued f o r an a d d i t i o n a l 1 h. The solu t i o n was di l u t e d with anhydrous ether ( ~30 ml), and f i l t e r e d through a short column of F l o r i s i l . The column was eluted further with anhydrous ether 75 (100 mL)• The combined eluates were dried over anhydrous magnesium s u l f a t e and the solvent was evaporated to give 0.27 g (65%) of an o i l . This material was further p u r i f i e d by d i s s o l v i n g i t in ether and successively extracting the r e s u l t i n g s o l u t i o n with 1 N aqueous sodium hydroxide. The base extracts were a c i d i f i e d and then re-extracted with ether. The ether extracts were dried over anhydrous magnesium s u l f a t e , the solvent was evaporated and the r e s u l t i n g o i l was d i s t i l l e d (air-bath temperature 150-160°C, 20 torr) to give 107 mg of the a c i d (114) as a colourless o i l . A glc analysis (column A) indicated that t h i s material consisted of one component. IR ( f i l m ) : 3200-2500 (OH), 2940, 2850, -C00H). Exact mass calcd. f o r C H 0 : 156.1151; found: 156.1157. Preparation of 3,3-Dimethylcyclohexanecarboxylic Acid Chloride C L Q 5 ) . The p u r i f i e d carboxylic acid (114) (1.0 g, 6.41 mmol) was weighed into a 10 mL, flame-dried f l a s k equipped with a magnetic s t i r bar and a r e f l u x condenser with a drying tube attached. The f l a s k was p a r t i a l l y immersed i n a warm water bath (~40°C) and thio n y l c h l o r i d e (0.94 mL, 12.82 mmol) was added dropwise. The s o l u t i o n was s t i r r e d f o r 5 min. The 105 76 water bath was replaced by a heating mantle and the mixture was refluxed f o r an a d d i t i o n a l 2 h. The so l u t i o n was allowed to cool and the excess thi o n y l chloride was removed under reduced pressure (water aspirator, 20 t o r r , 30 min). The r e s i d u a l o i l was d i s t i l l e d (air-bath temperature 110-120°C, 20 torr) to give 1.09 g (98%) of the a c i d chloride (10.5) as a colour l e s s o i l . A glc analysis of th i s material (column A) indicated that i t consisted of one component. IR ( f i l m ) : 2940, 2850, 1790, 1460, 1390, 1370, 1340, 1280, 1180, 1000, 970, 925, 900, 820, 750, 725, 705 cm"1; "Si nmr (CDCI^) 6: 0.95, 0.99 (s, s, 6H, methyls), 1.06-2.24 (complex m, 8H) , 2.70-3.10 (m, IH, \c-C0Cl) . Exact mass calcd. for C H O 3 7 CI: H 176.0782; found: 176.0766; f o r C QH._0 3 5C1: 174.0811; found: 174.0800. y 1 J 33 Preparation of l,l,-Dibromo-2-vinylcyclopropane (115) Butadiene (193 mL, 2.2 mol) was condensed into a cold (-78°C), 1 L f l a s k equipped with a dry i c e condenser, a 50 mL addition funnel, a gas i n l e t tube and a drying tube. Bromoform (19.3 mL, 0.22 mol), methylene chl o r i d e (20 mL), benzyltriethylammonium chloride (TEBA, 0.5 g, 2.2 mmol) and ethanol (100%, 1.74 mL) were added and the cooling bath was removed. A 50% aqueous sodium hydroxide so l u t i o n (35.2 g, 0.44 mol) was added dropwise to the mixture (vigorous s t i r r i n g ) over a period of 15 min and 115 77 s t i r r i n g was continued for 8 h at ~-5°C ( r e f l u x i n g butadiene) . The dry i c e condenser was removed and the butadiene was allowed to evaporate over-night. The remaining mixture was f i l t e r e d through a wide column of F l o r i s i l . The column was eluted with methylene chloride (150 mL). The combined eluate was washed with water ( u n t i l n e u t r a l ) , brine, and dried over anhydrous magnesium s u l f a t e . The solvent was evaporated to give 43 g of an o i l which, on the basis of g l c analysis (column A), consisted mainly (~88%) of the desired product, l,l-dibromo-2-vinylcyclopropane (115). This material was not p u r i f i e d further, but was used d i r e c t l y for the next reactio n . IR ( f i l m ) : 3060, 3000, 1630, 1435, 1425, 1220, 1190, 1145, 1105, 1050, 1010, 985, 920, 720 cm"1. Preparation of a Mixture of the _c_js_ and trans,-l-Bromo-2-vinylcyclopropanes (11) and (1161. H H Br'' H 81 116 To a cold (0°C) dry f l a s k , under an argon atmosphere, was added a s o l u t i o n of the crude dibromide (115) (43 g) i n a mixture of anhydrous ether (438 mL) and g l a c i a l a c e t i c a c i d (219 mL). Zinc dust (124 g) was added i n portions over a period of 15 min and the''.resultant mixture was s t i r r e d for 30 min at 0°C and at room temperature for 2 h. The reaction mixture was f i l t e r e d through a short column of F l o r i s i l . The column was 78 eluted with ether. The combined eluate was washed with water u n t i l neutral and further washed with a saturated aqueous sodium bicarbonate s o l u t i o n (2 x 75 mL), water, and dri e d over anhydrous magnesium s u l f a t e . The solvent was removed by c a r e f u l d i s t i l l a t i o n (atmospheric pressure) to give 12.24 g of an o i l (38% over 2 steps). A glc analysis (column A) of t h i s material showed that i t consisted of a mixture of c i s and trans isomers (81) and (116) in a r a t i o of approximately 82 : 18 r e s p e c t i v e l y . The mixture was separated v i a c a r e f u l f r a c t i o n a l d i s t i l l a t i o n through a Vigreux column (45 min) at 125 t o r r . The following f r a c t i o n s were c o l l e c t e d ; f r a c t i o n 1: bp 64-70°C, 1.03 g; f r a c t i o n 2: bp 72-74°C, 1.97 g; and f r a c t i o n 3: bp 74°C, 3.61 g. A glc analysis (column A) of these f r a c t i o n s indicated c i s and trans isomer (81) and (.116) r a t i o s of approximately 47 : 53; 67 : 33 and 95 : 5 r e s p e c t i v e l y . The residue, on the basis of a g l c analysis (column A) contained n e i t h e r of the isomers. The p u r i f i e d cis-l-bromo-2-vinylcyclopropane (81) (95%) exhibited IR (film) 3060, 2990, 2960, 1630, 1430, 1260, 1040, 980, 800 cm"1; 1H nmr (CDC1 ) Br H Br H 6: 0.80-1.02 (m, IH,-C—C ), 1.12-1.86 (m, 2H, -CHCH=CH2, -C—C ), 3.18 Br H H H H (m, HC- ), 5.10-5.88 (m, 3H, o l e f i n i c protons). Preparation of a Mixture of the _c_js_ and trans-2-Vinylcyclopropyl Ketones  (101) and (103). 101 103 79 To a 25 mL, flame-dried f l a s k , equipped with a septum cap, an argon i n l e t tube, a magnetic s t i r bar, and a stopper was added a so l u t i o n of the mixture of the 2-vinylcyclopropyl bromides (81) and (116) ( c i s : trans ~47 : 53, f r a c t i o n 1 from above d i s t i l l a t i o n ; 253 mg, 1.72 mmol) i n anhydrous ether (8 mL). The solu t i o n was cooled (-78°C) and a so l u t i o n of tert-buty11ithium (1.26 M i n pentane, 2.46 mL, 3.10 mmol) was added dropwise and s t i r r i n g was continued f o r 2 h a t t h i s temperature. At t h i s 35 point, anhydrous tetrahydrofuran (8 mL) and s o l i d phenylthiocopper (297 mg, 1.72 mmol) were added and the reaction mixture was allowed to.-warm to -20°C and s t i r r i n g was continued at t h i s temperature for 30 min. The r e s u l t i n g c l e a r brown s o l u t i o n was cooled to -78°C and a s o l u t i o n of the ac i d c h l o r i d e (105) (200 mg, 1.15 mmol) in 1 mL of anhydrous tetrahydrofuran was added. S t i r r i n g was continued at -78°C for 15 min and the so l u t i o n was allowed to warm to -20°C with continued s t i r r i n g for 1 h. The sol u t i o n was subsequently warmed to room temperature and s t i r r e d for 2 ad d i t i o n a l hours. The reaction was quenched by the addition of spectro-photometry grade methanol (~1 mL) . The resultant mixture was d i l u t e d with ether and then f i l t e r e d through a short column of F l o r i s i l . The column was eluted with ether. The combined eluate was evaporated and the re s i d u a l o i l was d i s t i l l e d ( air-bath temperature 90-110°C, 0.4 torr) giving 174 mg (73%) of the product as a colourless o i l . A glc analysis (column A) of t h i s material indicated that i t was an approximately a 1:1 mixture of c i s and trans isomers (101) and (103). IR (film) : 3060, 2990, 2940, 2910, 2850, 1685, 1630, 1460, 1380, 1080, 900 cm"1; XH nmr (CDCl ) <5: 0.92 (s, 6H, methyls), 1.0-2.84 (complex m, 13H), 4.88-5.85 (m, 3H, -CH=CH_2) . Exact  mass calcd. f o r C 1 /H 9 90: 206.1670; found: 206.1672. 80 Preparation of the c i s - 2 - V i n y l c y c l o p r o p y l Ketone (101). 101 The procedure followed was i d e n t i c a l with that described above except that the cuprate reagent was prepared from the ^is-l-bromo-2-vinyl-cyclopropane (81) (1.13 g, 7.72 mmol, f r a c t i o n 3 from above d i s t i l l a t i o n ) . A t e r t - b u t y l l i t h i u m s o l u t i o n (1.26 M i n pentane, 11.03 mL, 13.90 mmol) was added dropwise, as previously described, to a s o l u t i o n of the bromide (81) in 35 mL of anhydrous ether. Anhydrous tetrahydrofuran 35 (35 mL) and s o l i d phenylthiocopper (1.33 g, 7.72 mmol) were added as before. The acid c h l o r i d e (10.5) (0.895 g, 5.51 mmol) was added in 2 mL of anhydrous tetrahydrofuran. The mixture was worked up as described above to give 1.12 g (>100%) of an o i l which was d i s t i l l e d (air-bath temperature 90-95°C, 0.25 torr) to give 922 mg (87%) of the c i s ketone (101) as a colourless o i l . A glc analysis (column A) of the d i s t i l l e d material indicated the presence of only one component. IR ( f i l m ) : 3060, 2990, 2910, 2850, 1690, 1630, 1460, 1280, 1260, 1080, 900 cm"1; 1H nmr (CDC1 ) 6: 0.94 (s, 6H, Me), 1.0-2.82 (complex, m, 13H), 4.98 (dd, J = 10 Hz, J' = 2.5 Hz, IH, HC = C< ), 5.17 (dd, J = 17 Hz, J' = 2.5 Hz, IH, I •& a I HC = C< ), 5.66 (ddd, J = 17 Hz, J' = 10 Hz, J" = 8 Hz, IH, HC = CH„) . H Exact mass calcd. for C,.H„ o0: 206.1670; found: 206.1669. 14 22 81 Preparation of the trans-2-Vinylcyclopropyl Ketone (1Q3J 103 To a s t i r r e d s o l u t i o n of dry t e r t - b u t y l alcohol (3 mL) and 71 mg (0.63 mmol) of potassium tert-butoxide (Aldrich) was added dropwise a sol u t i o n of a mixture of the isomers (101) and (103) (87 mg, 0.42 mmol, above preparation) i n 3 mL of anhydrous tetrahydrofuran. The r e s u l t i n g yellow s o l u t i o n was s t i r r e d f o r 3 h at room temperature. Hydrochloric a c i d ( I N , 2 mL) was added and the r e s u l t a n t mixture was extracted with 2 x 20 mL hexanes. The combined extracts were washed with brine, dried over anhydrous magnesium s u l f a t e and the solvent was evaporated to give 80.5 mg (93%) of the ketone (103) as an o i l . A g l c analysis (column C) of thi s material showed that i t consisted of a mixture of the trans and c i s ketones (101) and (103), i n a r a t i o of approximately 93 : 7 res p e c t i v e l y . This r a t i o did not change with the length of the reaction time. The isomers (101) and (103) could not be separated by d i s t i l l a t i o n or by column chromatography. IR ( f i l m ) : 3060, 2990, 2910, 2850, 1690, 1630, 1460, 1380, 1360, 1120, 1080, 1030, 980, 900 cm"1; \ nmr (CDC1 3) 6: 0.94 (s, 6H, methyls), 1.02-2.14 (complex m, 12H), 2.48-2.86 (m, IH, 0 I H C- ), 4.98 (dd, J = 9 Hz, J' = 3 Hz, IH, HC=c( ), 5.14 (dd, I 5 | S J = 17 Hz, J' = 3 Hz, IH, HC=c( ), 5.28-5.70 (m, IH, HC=CH ) . 82 Conversion of the ^ js.-2-Vinylcyclopropyl Ketone (101) into the Enol S i l y l  Ethers (120) and (121") and Thermal Rearrangement of the l a t t e r into (122)  and (123) . 122 123 To a cold (0°C), flame-dried f l a s k equipped with a gas i n l e t tube, a magnetic s t i r bar, and a septum cap, was added a solu t i o n of d i i s o p r o p y l -amine (50uL, 0.39 mmol) i n 1 mL of anhydrous tetrahydrofuran. A solu t i o n of n -butyllithium (1.7.1 M i n hexane, 0.18 mL, 0.32 mmol) was added dropwise and the re s u l t a n t mixture was s t i r r e d f o r 15 min at 0°C. The so l u t i o n was cooled to -78°C and a s o l u t i o n of the c i s ketone (101) (50 mg, 0.24 mmol) i n 0.5 mL of anhydrous tetrahydrofuran was added slowly v i a syringe and s t i r r i n g was continued f o r 50 min. A solu t i o n of f r e s h l y sublimed tert-butyIdimethy1silyl chloride (80 mg before sublimation, 0.53 83 mmol) i n anhydrous tetrahydrofuran (1 mL) was added dropwise. Dry hexamethylphosphoramide (HMPA, 84 uL, 0.48 mmol) was added and the r e s u l t i n g mixture was s t i r r e d for an a d d i t i o n a l 15 min at -78°C, allowed to warm to room temperature, and s t i r r i n g was continued for 3 h. The so l u t i o n was poured i n t o a saturated aqueous sodium bicarbonate s o l u t i o n (10 mL) and the res u l t a n t mixture was extracted with 2 x 20 mL hexanes. The combined extracts were washed with brine (4 x 20 mL), dried over anhydrous magnesium s u l f a t e and the solvent was evaporated. D i s t i l l a t i o n (air-bath temperature 95°C, 0.25 torr) of the r e s i d u a l o i l gave 67 mg (87%) of a mixture of enol ethers (120) and (121) as an o i l . A g l c analysis (column A) of t h i s material showed i t consisted of the enol ethers (120) and (121) i n a r a t i o of approximately 12 : 88 re s p e c t i v e l y . IR ( f i l m ) : 3060, 2930, 2900, 2840, 1760 (exo double bond to cyclopropane r i n g ) , 1630 ( v i n y l ) , 1470, 1460, 1360, 1250 ( O ^ - S i ) , 1235, 840, 780 cm - 1; 1H nmr (CDC13) 6: 0.16 (s, 6H, M e ^ S i ) , 0.89 (s, 15H, Me2-C, t e r t - b u t y l - S i ) , 1.02-2.50 (complex m, 12H), 4.80-5.63 (m, 3H, HC=CH2). The enol s i l y l ether mixture (120) and (121) from above (67 mg, 0.21 mmol) was placed i n a dry round bottomed f l a s k to which was attached a Kugelrohr r e c e i v e r . The system was flushed thoroughly with argon and then the f l a s k containing the enol s i l y l ethers was heated at 160°C for 45 min i n a previously e q u i l i b r a t e d Kugelrohr d i s t i l l a t i o n apparatus. D i s t i l l a t i o n ( air-bath temperature 95°C, 0.25 torr) of the o i l gave 59 mg (88%) of a mixture of the rearranged products (122) and (123) as an o i l . A glc analysis (column A) of the d i s t i l l e d material showed i t to be composed of (122) and (123) i n a r a t i o of approximately 14 : 86, respect-i v e l y . This material was used without further p u r i f i c a t i o n because attempted separation of the products by column chromatography on s i l i c a 84 gel or on F l o r i s i l resulted i n decomposition. IR ( f i l m ) : 3060, 3040, 2 930, 2900, 2870, 2840, 1630, 1470, 1460, 1255, 1200, 1090, 840, 780 cm"1; 1H nmr [CDCl , major product (123)] 6: -0.04 (s, Me S i ) , 0.75-1.03 (series of I s, Me2C, t e r t - b u t y l - S i ) , 1.13-2.85 (complex m), 4.88 (brs, 1H, R 5.02 (s 6.20 (m H>=f r H>=T r , I H , FL/ ) , 5.86-6.01 (m, I H , H ' V - ^ , I H , ! ) = C J ^ H ), 6.04-H Conversion of the trans-2-Vinylcyclopropyl Ketone ILQJ1) into the Enol  S i l y l Ethers (124) and (121) and Thermal Rearrangement of the l a t t e r into (122.) and (123) . 103 0 S i M e 2 B u t 124 0SiMe 2Bu* 05iMe 2 Bu t 121 0SiMe 2Bu' 122 123 The procedure used was i d e n t i c a l with that described above. The l i t h i u m diisopropylamide s o l u t i o n was prepared using 90 y l of diisopropylamine (0.64 mmol) i n 1.5 mL of anhydrous tetrahydrofuran and a solu t i o n of h-b u t y l l i t h i u m (1.71 M i n hexane, 0.31 mL, 0.53 mmol) was added at 0°C. 85 After the appropriate amount of time a so l u t i o n of the tra n s - 2 - v i n y l -cyclopropyl ketone (103) (84 mg, 0.41 mmol, trans : c i s ; 93 : 7) i n an-hydrous tetrahydrofuran (0.5 mL) was added. S t i r r i n g was continued f o r 50 min at -78°C and a so l u t i o n of f r e s h l y sublimed t e r t - b u t y l d i m e t h y l s i l y l chloride (136 mg before sublimation, 0.9 mmol) i n 1 mL anhydrous t e t r a -hydrofuran and hexamethylphosphoramide (HMPA, 0.14 mL, 0.82 mmol) were added. There was obtained, a f t e r the usual work up and d i s t i l l a t i o n (air-bath temperature 90°C, 0.2 torr) of the crude product, 110 mg (84%) of a mixture of the enol ethers (124) and (121) as an o i l . A g l c analysis (column A) of the l a t t e r showed that i t consisted of the two enol s i l y l ethers (124) and (121) i n a r a t i o of approximately 87 : 13 r e s p e c t i v e l y . IR ( f i l m ) : 3060, 2930, 2900, 2840, 1660, 1630, 1470, 1460, 1360, 1250, 1180, 1100, 840, 780 cm"1; 1H nmr (CDC1 3) 6: 0.10, 0.13 (s, s, 6H, Me^i-) , 0.78-1.00 (series of s, 15H, Me2C, t e r t - b u t y l - S i ) , 1.08-2.23 (complex m, 12H), 4.80-5.63 (m, 3H, HC=CH„). Exact mass c a l c d for C o o H o , 0 S i : 320.2535; — — z z U 3D found: 320.2540. The enol s i l y l ether mixture (124) and (121) from above (97 mg, 0.30 mmol) was placed i n a dry round bottomed f l a s k to which was attached a Kugelrohr receiver. The system was flushed thoroughly with argon and heated at 230°C for 1 h as described above. D i s t i l l a t i o n ( air-bath temperature 110°C, 0.35 torr) of the thermolysis products gave 70 mg (72%) of the mixture of (122) and (123) as an o i l . A glc analysis (column A) of the d i s t i l l e d material showed i t to be composed of (122) and (123) i n a r a t i o of approximately 82 : 18 re s p e c t i v e l y . IR ( f i l m ) : 3010, 2930, 2900, 2870, 2840, 1630, 1470, 1460, 1255, 1150, 880, 840, 760 cm - 1; 1H nmr [CDC1 3 > major product (122)] 6: 0.17, 0.19 (s, s, Me 2Si), 0.75-1.00 (series of s, Me C, t e r t - b u t y l - S i ) , 1.01-2.75 (complex m), 86 H 4.72 ( t , 1H, H ), 5.60-5.86 (m, 2H, ) . Hydrolysis of the 14 : 86 Mixture of Thermolysis Products C122-) and (12-3.) and the Characterization of (12 3). To a dry f l a s k equipped with an argon gas i n l e t tube and a magnetic s t i r r i n g bar was added a s o l u t i o n of 1 N hydrochloric acid (0.75 mL) i n 1.5 mL of tetrahydrofuran. A s o l u t i o n of the thermolysis products (122) and (123) in a r a t i o of approximately 14 : 86 r e s p e c t i v e l y (59 mg, 0.18 mmol) i n tetrahydrofuran (0.5 mL) was added and the r e s u l t i n g mixture s t i r r e d f o r 3 h at room temperature. The s o l u t i o n was treated with 20 mL of a saturated aqueous sodium bicarbonate s o l u t i o n . The r e s u l t i n g mixture was extracted with hexanes (2 x 20 mL) and the combined extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . The solvent was evaporated and the r e s i d u a l o i l was d i s t i l l e d (air-bath temperature 95-105°C, 0.25 torr) to give 46.8 mg of an o i l . A glc an a l y s i s (column A) of t h i s o i l showed i t consisted of (127) and (123) i n the r a t i o of approximately 10 : 90 r e s p e c t i v e l y . IR ( f i l m ) : 3040, 2930, 2900, 2835, 1690, 1635, 1470, 1460, 1250, 1200, 1180, 970, 840, 122 123 127 780 cm 1 ; \ nmr (CDC1 3) <5 : -0.07 (s, 6H, Me 2Si), 0.75-1.00 (series of s, 15H, Me C, t e r t - b u t y l - S i ) , 1.13-2.63 (complex m) , 4.88 (brs, IH, ^ ) = ^ _ 87 Cm, IH, H H H ) , 5 .02 (s, IH , H ) = V = ^ H H ) , 6 . 04 - 6 . 20 (m, I H , R ) H ) , 5 . 86 -6 . 01 ) . The above mixture of (127) and (123) (30 mg) in a r a t i o of approximately 10 : 90 r e s p e c t i v e l y was loaded on a s i l i c a gel column (130 mm height x 7 mm inside diameter, 3 g). The mixture was eluted with a petroleum ether and ether s o l u t i o n i n the r a t i o of approximately 7 : 1 r e s p e c t i v e l y . After 4 mL of eluate was c o l l e c t e d , 0.5 mL f r a c t i o n s were c o l l e c t e d . Fractions 3-7 contained the s i l y l ether (123) (20 .9 mg, R f = 0 .64) as a colou r l e s s o i l . Fractions 8-20 contained nothing. A g l c analysis (column A) showed that f r a c t i o n s 3-7 contained 94% s i l y l ether (123) and no cycloheptenone (127). IR ( f i l m ) : 3060, 3040, 2930, 2900, 2870, 2840, (s, 6H, Me 2Si), 0 . 75 - 1 . 00 (s with m underneath, 17H, Me2C, t e r t - b u t y l - S i , 2 other protons), 1 .06 -2 .63 (complex m, 9H), 4.88 (brs, IH , 1630, 1470, 1460, 1250, 1200, 1080, 840, 780 cm' - 1 1. H nmr (CDCl.) 6: - 0 . 0 7 ) , 5.02 (s, IH , ) , 5 . 86 -6 . 00 (m, IH , ) . H H Exact mass calcd. f o r C H OSi : 320.2535; found: 320.2514. 88 Hydrolysis of the 82 : 18 Mixture of Thermolysis Products (122) and (123)  and Characterization of (122). OSiMe 2Bu t 0SiMe 2 Bu t 122 123 127 The procedure used was i d e n t i c a l with that described above. A so l u t i o n of the thermolysis mixture (122) and (123) (70 mg, 0.22 mmol, 82 : 18 respectively) i n tetrahydrofuran (0.5 mL) was added to a s o l u t i o n of 1 N hydrochloric a c i d (1 mL) in tetrahydrofuran (2 mL). Usual work up and d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 95-105°C, 0.25 torr) gave 33 mg of an o i l . A glc analysis (column A) of t h i s material showed that £he mixture consisted of (127) and (123) i n a r a t i o of approximately 87 : 13 r e s p e c t i v e l y . IR ( f i l m ) : 3010, 2940, 2920, 2880, 2850, 1690, 1635, 1460, 1440, 1380, 1360, 1250, 1100, 1080, 840, 770 cm"1; ^ nmr (CDC1,,) 6: -0.03 (s, 6H, Me^Si), 0.73-0.98 (series of s, 15H, Me0C, t e r t - b u t y l - S i ) , 1.08-3.03 (complex m), 4.88 (brs H 5.02 (s ), 5.70-6.03 (m, 2H, *4j--H ) , ) The above mixture of (127) and (123) (47.6 mg) i n a r a t i o of approximately 87 : 13 res p e c t i v e l y was- loaded on a s i l i c a gel column (130 mm height x 7 mm in s i d e diameter, 5 g). The column was eluted with a petroleum ether and ether s o l u t i o n i n a r a t i o of approximately 7 : 1 r e s p e c t i v e l y . After 89 8 mL of eluate was c o l l e c t e d , 1.0 mL f r a c t i o n s were c o l l e c t e d . Fractions 2-6 contained the cyclopentadiene system (123) (R^ = 0.64) and fr a c t i o n s 19-23 contained the cycloheptenone system (127) (18.9 mg, R^ = 0.36) as a colourless o i l . There were no mixed f r a c t i o n s . A glc analysis (column A) of t h i s o i l showed that i t was 98% pure. IR ( f i l m ) : 3000, 2930, 2900, 2880, 2850, 2825, 1690, 1460, 1440, 1390, 1370, 1340, 1300, 1180 cm"1; 1H nmr (CDC1 3) 6: 0.76 (s, 3H, Me), 0.91 (s, 3H, Me), 1.00-2.87 (complex m, 14H), 5.72-5.84 (m, IH, o l e f i n i c proton), 5.86-5.97 (m, IH, o l e f i n i c proton). Exact mass cal c d f o r C 1 4 H 2 2 ° : 206.1670; found: 206.1683. Preparation of the cas.-2-Vinylcyclopropyl Ketone (89) . 0 89 To a 250 mL, flame-dried f l a s k , equipped with a septum cap, an argon i n l e t tube, a magnetic s t i r bar and a stopper was added a so l u t i o n of the c i s - 2 - v i n y l c y c l o p r o p y l bromide (1.24 g, 8.43 mmol) (81) i n 50 mL of anhydrous ether. The mixture was cooled to -78°C and a s o l u t i o n of tert-buty11ithium (1.1 M i n pentane, 13.8 mL, 15.17 mmol) was added dropwise and s t i r r i n g was continued f o r 2 h at th i s temperature. At th i s 35 point, anhydrous tetrahydrofuran (50 mL) and phenylthiocopper (1.45 g, 8.43 mmol) were added and the reaction mixture was allowed to warm to -20°C and s t i r r i n g was continued at t h i s temperature f o r 30 min. The 90 mixture was cooled to -78°C and cyclohexanecarboxylic a c i d chloride (0.75 mL, 5.61 mmol) was added dropwise. S t i r r i n g was continued at -78°C for 15 min and the s o l u t i o n was warmed to -20°C with continued s t i r r i n g f o r 1 h. The s o l u t i o n was subsequently allowed to warm to room tempera-ture and s t i r r e d f o r an a d d i t i o n a l 2 h. The reaction was quenched by the addition of spectrophotometric grade methanol (~1 mL) . The resultant mixture was d i l u t e d with ether and then f i l t e r e d through a short column of F l o r i s i l . The column was eluted with ether. The combined eluate was evaporated and the r e s i d u a l o i l was d i s t i l l e d ( air-bath temperature 65-75°C, 0.21 torr) giving 779 mg (78%) of the ketone (89) as a colourless o i l . A glc a n a l y s i s (column A) of t h i s material showed that i t consisted mainly of one component i n 96% p u r i t y . The ketone (89) (779 mg) was loaded on a s i l i c a gel column (78 g) and the column was eluted with a mixture of petroleum ether and ether i n a r a t i o of 7 : 1 r e s p e c t i v e l y . A column volume of 150 mL was eluted and 15 mL f r a c t i o n s were c o l l e c t e d . Fractions 8-9 were a mixture of c i s and trans ketones (glc analysis, column A) of approximately 93 : 7 r e s p e c t i v e l y (243 mg). A g l c analysis of f r a c t i o n s 10-12 showed the f r a c t i o n s consisted of only one component i d e n t i f i e d as the c i s ketone (89) (449 mg, = 0.55). The p u r i f i e d material exhibited the following s p e c t r a l data; IR ( f i l m ) : 3060, 3000, 2910, 2840, 1690, 1635, 1455, 1390, 1295, 1240, 1150, 1075, 1010, 910, 845 cm - 1; "Si nmr (CDCl ) <5: 0.96-2.60 (complex m, 15H) , 4.94 (dd, J = 10.5 Hz, J' = 2.3 Hz, IH, HC=C^ ), 5.13 (dd, J = 17 Hz, J' = 2.3 Hz, | H - | IH, HC = C ^ ), 5.62 (ddd, J = 17 Hz, J 1 = 10.5 Hz, J" = 9 Hz, IH, HC = H CH„) . Exact mass calcd. for O.-H.-O: 178.1358; found: 178.1358. 2. l z lo 91 Preparation of the cis-2-Ethylcyclopropyl Ketone (104) 104 To a cold (0°C) dry f l a s k equipped with a drying tube and a magnetic s t i r r i n g bar, was added a so l u t i o n of the c i s - 2 - v i n y l c y c l o p r o p y l ketone (89) (200 mg, 1.12 mmol) i n 4 mL of e t h y l a l c o h o l (100%). A hydrazine hydrate s o l u t i o n (95%, 0.38 mL, 7.87 mmol) and an approximately 1% aqueous cupric s u l f a t e pentahydrate s o l u t i o n (~2 drops) were added to the cooled (0°C) mixture. This was followed by dropwise a d d i t i o n of an aqueous hydrogen peroxide so l u t i o n (30%, 0.21 mL, 2.02 mmol) over 5 min. The r e s u l t i n g mixture was s t i r r e d for an a d d i t i o n a l 5 min at 0°C and subsequently allowed to warm to room temperature. The mixture was s t i r r e d f or 5 h at room temperature. The reaction mixture was poured into 10 mL of water and the r e s u l t i n g mixture was extracted with ether (2 x 30 mL). The combined ethereal layers were further extracted with a d i l u t e aqueous f e r r i c s u l f a t e s o l u t i o n (4 x 10 mL), water, and brine. The combined ether extracts were dried over anhydrous magnesium s u l f a t e , the solvent was evaporated,and the residue was d i s t i l l e d ( air-bath temperature 85°C, 0.3 torr) to give 140 mg (69%) of the product (104) as an o i l . A glc analysis (column A) showed t h i s o i l consisted of only one component. IR ( f i l m ) : 3060, 2980, 2940, 2900, 2840, 1685, 1450, 1400, 1150, 1090, 1075, 1000, nmr (CDC1 3) 6: 0.85 ( t , 3H, Me), 0.90-0.98 (m, IH, H 92 1.00-1.08 (m, 1H, V7^H H ), 1.10-1.50 (complex m, 7H), 1.60-1.98 T' P (complex m, 6H) , 2.02-2.12 (m, IH, jj _ ), 2.42-2.55 (m, IH, 0 II c - ). Exact mass calcd. for C1 2H 2 0 ° : 1 8 0 - 1 5 1 ' 4 ; found: H 180.1511 Conversion of the cis-2-Ethylcyclopropyl Ketone (IDA) into the Enol  S i l y l Ethers (12-5.) and (12&) . 0 5 i M e 2 B u t 104 125 OSiMejBu* 126 To a cold (0°C) flame-dried f l a s k equipped with an argon i n l e t tube a septum cap and a magnetic s t i r bar, was added a solution of diisopropylamine (70 y l , 0.5 mmol) i n 1 mL of anhydrous tetrahydrofuran. A s o l u t i o n of methyllithium (1.18 M i n ether, 0.31 mL, 0.36 mmol) was added dropwise to the mixture and s t i r r i n g was continued f o r 15 min at 0°C. The mixture was cooled to -78°C and a so l u t i o n of the c i s - 2 -ethylcyclopropyl ketone (104) (50 mg, 0.28 mmol) in 0.5 mL of anhydrous tetrahydrofuran was added and s t i r r i n g was continued f o r 50 min. A solut i o n of t e r t - b u t y l d i m e t h y l s i l y l c h l o r i d e (92 mg before sublimation, 0.6 mmol) i n 1 mL of anhydrous tetrahydrofuran and hexamethylphosphoramide (97 y l , 0.56 mmol) were added at -78°C. The mixture was s t i r r e d f o r 15 min 93 at t h i s temperature and allowed to warm to room temperature with continued s t i r r i n g f o r 3 h. Usual work up as above gave an o i l that was d i s t i l l e d (air-bath temperature 80°C, 0.2 torr) to give 60.7 mg (74%) of the mixture (125) and (126) as an o i l . A glc analysis (column A) indicated only one peak i n 97% p u r i t y . The r a t i o of the two enol s i l y l ethers (125) and (12 6) was determined by c a r e f u l i n t e g r a t i o n of the Me^Si peaks on a high r e s o l u t i o n nuclear magnetic resonance spectrometer. Integration showed the mixture (125) and (126) consisted of the two isomers i n a r a t i o of approximately 51 : 49. IR ( f i l m ) : 3080, 2930, 2900, 2830, 1765, 1670, 1490, 1480, 1460, 1270, 1190, 1090, 870, 860, 800 cm"1; 1H nmr (CDCLj) 6: 0.11, 0.14 (s, s, 6H, Me^ i ) , 0.87-1.03 (s with overlapping t, 12H, CH_3-CH2-, t e r t - b u t y l - S i ) , 1.18-1.90 (complex m, 12H) , 2.02-2.27 (m, 4H) . Exact mass c a l c d . for C ^ H ^ O S i : 294.2378; found: 294.2380. Preparation of the _trans-2-Vinylcyclopropyl Ketone (100) . 0 100 To a s t i r r e d s o l u t i o n of dry t e r t - b u t y l alcohol (2 mL) and 95 mg (0.84 mmol) of potassium tert-butoxide ( A l d r i c h ) , was added dropwise a so l u t i o n of the cis-ketone (89) (95 mg, 0.56 mmol) in 2 mL anhydrous tetrahydrofuran. The r e s u l t i n g yellow so l u t i o n was s t i r r e d f o r 3 h at room temperature. Usual work up as described above gave an o i l which 94 was d i s t i l l e d (air-bath temperature 80°C, 0.4 torr) to give 66.8 mg (70%) of the ketone (100) as a col o u r l e s s o i l . A glc a n a l y s i s (column A) indicated only one component with a retention time i d e n t i c a l with that of the cis-ketone (89). The nmr spectrum of the product (100) showed that i t d i f f e r e d from the cis-ketone (89). IR ( f i l m ) : 3070, 2990, 2910, 2840, 1685, 1635, 1450, 1390, 1150, 1100, 1070, 1010, 910, 840 cm"1; hi nmr (CDC1,,) <5: 0.83-2.15 (complex m, 14H), 2.25-2.68 (m, IH, H 12 0 j r A ~ c _ ) s 4 , 9 6 ( d d > J = 7 , 8 Hz> J ' = Z A H z» 1H» H C = C ^ ), 5. J H X H (dd, J = 15 Hz, J' =2.4 Hz, IH, HC=C^ ), 5.28-5.70 (m, IH, HC=CH ) Preparation of the trans-2-Ethylcyclopropyl Ketone (119) To a cold (0°C) dry f l a s k equipped with a magnetic s t i r r i n g bar, and a drying tube was added a solu t i o n of the trans-2-vinylcyclopropyl-ketone (100) (61 mg, 0.34 mmol) in 1.5 mL of eth y l alcohol (100%). A hydrazine hydrate s o l u t i o n (95%, 0.12 mL, 2.4 mmol) and an approximately 1% aqueous cupric s u l f a t e pentahydrate s o l u t i o n (~2 drops) were added to the mixture. This was followed by dropwise addition of an aqueous hydrogen peroxide s o l u t i o n (30%, 63 y l , 0.62 mmol) over 5 min at 0°C. The s o l u t i o n was allowed to warm to room temperature and s t i r r i n g was 95 continued f o r 5 h. Usual work up as described above gave an o i l that was d i s t i l l e d ( air-bath temperature 65-75°C, 0.35 torr) to give 40 mg (65%) of the trans ketone (119) as a colourless o i l . A glc analysis (column A) indicated only one component. IR ( f i l m ) : 3060, 2995, 2910, 2840, 1690, 1455, 1405, 1350, 1150, 1100, 1010, 900 cm"1; "Si nmr (CDCl,) 6: 0.67-0.74 (m, IH, R ), 0.96 ( t , 3H, methyl), 1.14-1.45 (complex m, 8H), 1.60-1.98 (complex m, 7H), 2.42-2.55 (m, IH, ^ / s ~ C ~ Exact mass ca l c d . f o r C 1 2 H 2 0 ° : 1 8 0 - 1 5 1 4 J found: 180.1513. Preparation of Cyclohexyl Cyclopropyl Ketone (99) 9 9 To a cold (-78°C) flame-dried 25 mL f l a s k equipped with a septum cap, an argon i n l e t tube and a stopper, was added a s o l u t i o n of cycl o -propyl bromide (0.60 g, 4.96 mmol) i n anhydrous tetrahydrofuran (8 mL). A sol u t i o n of t e r t - b u t y l l i t h i u m (2.1 M i n pentane, 4.25 mL, 8.93 mmol) was added dropwise and the mixture was s t i r r e d for 2 h at -78°C. 35 Anhydrous tetrahydrofuran (8 mL) and phenylthiocopper (856 mg, 4.96 mmol) were added, the mixture was warmed to -20°C, and s t i r r i n g was continued for 30 min. The so l u t i o n was recooled to -78 6C and cyclohexanecarboxylic a c i d c h l o r i d e (0.44 mL, 3.31 mmol) was added. The reaction mixture was 96 s t i r r e d f o r an a d d i t i o n a l 15 min at -78°C and then was allowed to warm to -20°C with continued s t i r r i n g f o r 1 h. The s o l u t i o n was subsequently warmed to room temperature and s t i r r e d for an a d d i t i o n a l 2 h. Usual work up as described above and d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 65 °C, 0.45 torr) gave 499 mg (100%) of the ketone (99) as an o i l . A glc analysis (column A) showed the o i l consisted of one component. IR ( f i l m ) : 3080, 3000, 2910, 2840, 1685, 1450, 1390, 1150, 1090, 1070, 1000, 920 cm - 1; "'"H nmr (CDC1 3) 6: 0.78-0.87 (m, 2H, cyclopropane), 0.93-1.01 (m, 2H, cyclopropane), 1.12-1.46 (complex m, 5H), 1.56-2.03 (complex r  0 f~\ II m, 6H), 2.42-2.55 (m, IH, f\~^~ Exact mass c a l c d . f o r C H 0: 152.1201; found: 152.1200. ± U l o Preparation of the Enol S i l y l Ether C1Z8) of the Cyclohexylcyclopropyl  Ketone (99). 0 S i M e 2 B u t 99 128 To a cold (0°C) flame-dried f l a s k equipped with a septum cap, a magnetic s t i r bar and an argon i n l e t tube, was added a so l u t i o n of d i i s o -propylamine (0.17 mL, 1.18 mmol) i n 1 mL anhydrous tetrahydrofuran. A so l u t i o n of methyllithium (2.17 M i n ether, 0.38 mL, 0.86 mmol) was added and the mixture s t i r r e d for 15 min at 0°C. The mixture was cooled to 97 -78°C and a s o l u t i o n of the ketone (99) (100 mg, 0.66 mmol) in 0.5 mL anhydrous tetrahydrofuran was added. The s o l u t i o n was s t i r r e d f o r 50 : at t h i s temperature and a solu t i o n of t e r t - b u t y l d i m e t h y l s i l y l chloride was added. Hexamethylphosphoramide (0.23 mL, 1.32 mmol) was added dropwise and the s o l u t i o n was s t i r r e d for 15 min at -78°C and then allowed to warm to room temperature with continued s t i r r i n g f o r 3 h. Usual work up of the mixture as described above gave 181 mg (100%) of a colourless o i l . A glc analysis (column A) showed t h i s o i l to be 96% pure enol s i l y l ether (128) as a s i n g l e component. IR ( f i l m ) : 3060, 2940, 2910, 2840, 1660, 1470, 1465, 1450, 1360, 1260, 1240, 1210, 1175, 1140, 1120, 1080, 1010, 960, 860, 840, 780 cm"1; \ nmr (CDC1 3) 6: 0.13 (s, 6H, M e ^ S i ) , 0.51-0.57 (m, 2H, cyclopropane), 0.62-0.69 (m, 2H, cyclopropane), 0.96 (s, 9H, H (218 mg before sublimation, 1.45 mmol) i n 1 mL of anhydrous tetrahydrofuran t e r t - b u t y l ) , 1.35-1.54 (m, 7H), 2.11-2.18 (m, 2H, ) , 2.21-2.80 (m, 2H, ). Exact mass calcd. f o r C.^ITOSi: 30 266.2065; found: 266.2065. 98 Bibliography a) E. Vogel, Angew. Chem., Int. Ed. Engl., 2_, 1 (1963). b) W. Von E. Doering and W.R. Roth, Angew. Chem., Int. Ed. Engl., 2, 115 (1963). c) S.J. Rhoads, Molecular Rearrangements, Vol. 1, P. de Mayo ed, John Wiley and Sons, Inc. , New York, (1963) p. 655. d) S.J. Rhoads, Org. React., 2_2, 1 (1965). E. Vogel, Justus Liebigs Ann. Chem., 615, 1 (1958). J.A. Berson, L.D. Pederson and B.K. Carpenter, J. Amer. Chem. S o c , 98, 122 (1976). J.E. Baldwin and K.E. G i l b e r t , J . Amer. 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