PART i THE SYNTHESES OF ‘ 2,5-D!0X0~ CYCLOPENFANEPROPEOMC AGED . I ' PART :1 THE SYNTHESIS AM) . PHO‘EOREARRANGEMENT 0F, TWO SSS-moms Dissertation for the Degree of Ph. D. EgiiCHEGM STATE Ué‘élVERSSTY fiEFFREY EARL ‘E‘ELSCHGW 1974 .... .a—H-‘ "c.-. 95 401’4‘6'43 IGAN STATE UNIVERSITY U A - , s. . Illlllllllllllll Illll llflll llllllllllllllll L ti» 3 1293 00628 1251 l I I I I This is to certify that the thesis entitled I--The Synthesis of 2,5-Dtoxo-cyclopentanepropionic Acid II--The Synthesis and Photorearrangement of Two BaY-Enones presented by Jeffrey Earl Telschow has been accepted towards fulfillment of the requirements for Ph .132 degree in .Qhfifliifly— 2/4/41: ,‘A ,L/ pawl Major professor Date Se er 12 1974 0-7639 alumna av ‘: HMS & SUNS' 300K BINDERY INC. LIBRARY amosns QQIIMMJIHIGII ABSTRACT PART I THE SYNTHESIS OF 2,5-DIOXO-CYCLOPENTANE- PROPIONIC ACID PART II THE SYNTHESIS AND PHOTOREARRANGEMENT OF TWO BpY-ENONES BY Jeffrey Earl Telschow PART I The title compound,\g4 was desired as an intermediate in a proposed total synthesis of the alkaloid cephalotaxine. The successful synthesis of\g, gig the cyclopentane-l,2,4- trionekgl and two unsuccessful approaches to‘£~are described. Base catalyzed condensation of diethyl oxalate and ethyl 5-oxo-hexanoate {ll yielded the ethoxalyl trione\g, which on hydrolysis gave\3; Wolff-Kishner reduction of the 1-semicarbazone of this trione yielded the desired dione acid 3‘. O HO COzC H O (COzEt) 2 O 2 5 //”\\,/”\\¢CO C H ‘———__——" " 2 2 5 NaOEt cznsozc OH 0 Q ~l~ ca \:130 3 o co H co H 2 1) H2NNHCONH2 2 ‘1: on 2) KOH, (ChZOH)2, A OH O \A \.3/\ Jeffrey Earl Telschow The structure of\g~was proven by methylation to give the known dione ester\§4 which was independently synthe- sized from 2-methylcyclopentane-l,3-dione and methyl acrylate. O C02CH3 O 5 k” PART II Initially, a new synthesis of the sesquiterpene bulnesol was to be developed, using as a key step the an- ticipated photorearrangement of B,y-enone‘lJ R = H to its tricyclic isomer\g4 This proposed 1,2-acyl shift failed to occur on photolysis of 1. M O hv O ' O R e, R=H Because the photochemical consequences of minor struc- tural changes in B,Y-enones are not well understood, the photochemistry of enone‘lJ R = CH3 was investigated and compared to that of the unmethylated compound. Direct photolysis of\lJ R = H or CH3 produced (via a 1,3-acyl shift) the cyclobutanone\§4 which subsequently Jeffrey Earl Telschow underwent photodecomposition to a diene‘g‘and a cyclopro- pane\§: In the case of R = CH3, a substantial amount of O hv ..‘;> benzene I 0. hv O 0 ‘\~ lflllll *' R . ‘;> to ‘0 R 4 5 \A \I\ nonvolatile material was also produced. Acetone sensitized irradiation of\l1 R = H produced no new volatile products, but with R = CH3, six or seven unidentified components were formed in addition to the usual photoproducts. The synthesis of\l1 R = H or CH3 was achieved by . selective ketalization of enedione\1~which, for R = CH3, was prepared by hydrogenation of the dibromomethylene derivative\§‘ O O 3 H2 -———> CBr2 R R=CH3 6 7 PART I THE SYNTHESIS OF 2,5-DIOXO-CYCLOPENTANE- PROPIONIC ACID PART II THE SYNTHESIS AND PHOTOREARRANGEMENT OF TWO B,Y-ENONES BY Jeffrey Earl Telschow A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1974 ACKNOWLEDGMENTS The author expresses his appreciation to Professor William H. Reusch for his patient guidance, his careful and constructive evalua- tion of my ideas, and for arranging financial support. ii TABLE OF CONTENTS Page PART I INTRODUCTION 0 O O O O O O O O O O O O O O O O O O O 2 RESULTS AND DISCUSSION. . . . . . . . . . . . . . . 6 EXPERIMENTAL O O O O O O O O O I O O O O O C O O O I l 2 General 0 O O O O O O O O O O O O O O O I O O O 12 5—Oxo'hexanoic acid (19) . . . . . . . . . . . 13 Ethyl S—oxo-hexanoate £21) . . . . . . ... . . 14 2, 4—Dioxo—octanedioic acid . . . . . . . . l4 Dimethyl 2 ,4-dioxo—octanedioatetggll . . . . . 15 Ethyl 4—ethoxalyl«2, 3 ,5—trioxo—cyclopentanee propionate L25) . . . . . ..- . . a . . 15 2, 3, S—Trioxo—cyclopentanepropionic acid {Lg} . 16 Methyl 2, 3, 5~triox0vcyclopentanepropionate . . 17 2 ,5-Dioxo—cyclopentanepropionic acid (1) . . 18 Methyl 2 ,5~dioxo-1-methylcyclopentanev . propionate {25} . . . . . . . . . . . . . . 19 APPENDIX C O O O O O O 0 O O O O O O O O O I O O O O 2 1 PART II INTRODUCTION 0 O O O O O O O O O O O O O O O O O O O 4 3 RESULTS AND DISCUSSION 0 O O C O O O O O O O O O I O 58 EXPERIMENTAL. . . . . . . . . . . . . . . . . . . . 73 General 0 O O O O O O O O O O O O O O O 7 3 2-Methy1- -3- (l-pyrrolidyl) -2-cyclohexene- -1- one 60 C O O O O O O O U C 7 3 2, 6- -Dimethyl- -3- (1- pyrrolidyl) -2-cyclohexene- l‘One (73). o o o o o o o o o o o 73 2, 4- Dimethy I- 3- (l—pyrrolidyl) -2-cyclohexene- l-One (63). o o o o o o o o o o o o o o o o 75 L/K iii TABLE OF CONTENTS--Continued Page Reaction of\§§\with methyl vinyl ketone. . . . 76 2, 4- -Dimethy1- 2'(3-oXobuty1)-cyclohexane-1, 3- dione (éIl‘. . . . . . . . . . . . 77 1, 3- Dimethy bicyclo-[4. 4. 0] -dec- 6-ene-L 8- dione 6 . . . . . . . . . . . . . 77 Reaction 0 \vfi‘with methyl vinyl ketone. . . . 77 8- -Ethoxy-1-methylbicyclo-[4. 4.0]-dec-5, 7- diene- 2-one $281. . . . . . . . . . . . 78 5- -Dibromomethylene-l-methylbicyclo-[4. L 0]- dec- -6-ene- 2, 8- dione ~80 . . . . . . . . . . 79 l, 5- Dimethylbicyclo-[4. 4. -dec-6-ene-2, 8- dione 57 . . . . . . . . . . . . . 80 1—Methylbicyclo-[4. 4. 0]-dec- -5-ene- 2, 8- dione- 8- ethylene ketal (g). . . . . . . . . . . . . 81 1,5-Dimethy1bicyclo-[4.4.0] -dec-5-ene-2, 8- dione-B-ethylene ketal (58) . . . 81 Photolysis of l-methylbicyc o-[4. 4.0] -dec-5- ene-2,8-dione- -8- -ethylene ketal and 1,5-dimethy1bicyclo-[4.4.0]-dec-5-ene- 2,8-dione-8-ethylene ketal {58) . . . . . . 82 Preparation of 4-methy1-3-viny1-3-cyclo- hexene-l-one ethylene ketal £22) and 4-methyl-3-cyclopropyl-3-cyclohexene-l-one ethylene ketal (91) . . . . 83 Preparation of 4-m3Ehy1- 3- (2-oxocyclobutyl)- 3-cyclohexene- l-one ethylene ketal ‘82) . . 84 Photolysis ofxgywith a mercury resonance lamp. 84 Photolysis of‘gain acetone . . . . . . . . . . 85 Photolysis of 2 in the presence of 1,3-penta- diene . . . . . . . . . . . . . . . . 85 Photolysis of 2 with added internal standard . 85 Photolysis of\§§‘in benzene solution . . . . . 86 4-Methyl-3-(l-methy1-2~oxocyclobutyl)-3- cyclohexene-l-one ethylene ketal (9;) . . . 87 4-Methyl-3-(2-propeny1)-3 -cyclohexene-l-one ethylene ketal (962 . . . . . 87 4-Methyl-3-(1-methy cyclopropyl)- 3-cyclo-. hexene-l-one ethylene ketal £312. . . . . . 87 Photolysis of 58 in acetone. . . . . . . . . 88 Photolysis of\3"in the presence of 1,3-penta- diene . . . . . . . . . . . . . . . . . . . 88 APPENDIX...................... 89 BIBLIOGRAPHY. . . . . . . . . . . . . . . . . . . . 127 iv LIST OF FIGURES AND CHARTS FIGURE PART I 1. Infrared spectrum of dimethyl 2,4-dioxo- octanedioate (21). . . . . . . . . . . . . . . w 2. Infrared spectrum of ethyl 4-ethoxa1yl-2,3,5- trioxo-cyclopentanepropionate (24) . . . . . . M 3. Infrared spectrum of 2,3,5-trioxo-cyclopentane- prOpionic acid (22). . . . . . . . . . . . . . 4. Infrared spectrum of methyl 2,3,5-trioxo- cyclopentanepropionate . . . . . . . . . . . . 5. Infrared spectrum of 2,5-dioxo-cyclopentane- propionic acid £1) . . . . . . . . . . . . . . 6. Infrared spectrum of methyl 2,5-dioxo-l- methylcyclopentanepropionate (25). . . . . . . M 7. Nmr spectrum of 5-oxo-hexanoic acid (19) (CCl 1.) o o o o o o o o o o o o o o o o o o o o 8. Nmr spectrum of ethyl 5-oxo-hexanoate (23) (CCl I.) o o o o o o o o o o o o o o o o o o o o 9. Nmr spectrum of dimethyl 2,4-dioxo-octane- dioate ‘21) (CDCl 3 ) o o o o o o o o o o o o o o 10. Nmr spectrum of ethyl 4-ethoxalyl-2,3,5- trioxo-cyclopentanepropionate (24) (CDCls) . . 11. Nmr spectrum of 2,3,5-trioxo-cyclopentane- propionic acid (22) (CD3COCD3) . . . . . . . . 12. Nmr spectrum of methyl 2,3,5-trioxo-cyclo- pentanepropionate (CDCla). . . . . . . . . . . 13. Nmr spectrum of 2,5-dioxo-cyclopentane- prOpioniC aCid g2 (CD 3COCD3 ) o o O o o o o c 0 V Page 21 22 23 24 25 26 27 28 29 30 31 32 33 LIST OF FIGURES AND CHARTS--C0ntinued FIGURE 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. Nmr spectrum of 2,5-dioxo-cyclopentane- propionic acid (12 (CDasOCDa). . . . . . . Nmr spectrum of methyl 2,5-dioxo-l-methy1- cyclopentanepropionate (25) (CClu) . . . . Mass spectrum of dimethyl 2,4-dioxo-octane- dioate 21) O O C O O O O O O O O O C O O 0 Mass spectrum of ethyl 4-ethoxa1y1-2,3,5- trioxo-cyclopentanepropionate (24) . . . . Mass spectrum of 2,3,5-trioxo-cyclopentane- propionic acid (22). . . . . . . . . . . . Mass spectrum of methyl 2,3,5-trioxo-cyclo- pentanepropionate. . . . . . . . . . . . . Mass spectrum of 2,5-dioxo-cyclopentane- propionic acid (12 . . . . . . . . . . . . Mass spectrum of methyl 2,5-dioxo-1-methy1- cyclopentanepropionate (25). . . . . . . . PART II Infrared spectrum of 2,6-dimethyl-3-(l-pyrro- lidyl)-2-cyclohexene-1-one (73). . . . . . \A Infrared spectrum of 2,4-dimethyl-3-(1-pyrro- lidyl)-2-cyclohexene-l-one (63). . . . . . \” Infrared spectrum of 2,4-dimethyl-2-(3-oxo- butyl)-cyclohexane-l,3-dione (62). . . . . Infrared spectrum of 1,3-dimethylbicyclo- [4.4.0]-dec-6-ene-2,8-dione (64) . . . . . Infrared spectrum of 5-dibromomethylene-1~ methylbicyclo-[4.4.0]-dec-6-ene-2,8-dione (85) Infrared spectrum of 1,5-dimethylbicyclo- [4o4oOJ-deC-6-ene-2’8-dione (57) o o o o o o o \A vi Page 34 35 36 37 38 39 40 41 89 90 91 92 93 94 LIST OF FIGURES AND CHARTS--Continued FIGURE Page 28. Infrared spectrum of 1,5-dimethylbicyclo- [4.4.0J-dec-5-ene-2,8—dione-8'ethylene ketal (582. . . . . . . . . . . . . . . . . . . . . 95 29. Infrared spectrum of 4-methy1-3-vinyl-3- cyclohexene-l-one ethylene ketal (90) . . . . 96 30. Infrared spectrum of 4-methy1-3-cyclopropyl- 3-cyclohexene-l-one ethylene ketal (91) . . . 97 31. Infrared spectrum of 4-methy1-3-(2-oxocyclo- butyl)-3-cyclohexene-l-one ethylene ketal (822. . . . . . . . . . . . . . . . . . . . . 98 32. Infrared spectrum of 4-methyl-3-(1-methyl-2- oxocyclobutyl)-3-cyclohexene-l-one ethylene ketal (95). o o o o o o o o o o o o o o o o o 99 33. Infrared spectrum of 4-methy1-3-(2-propeny1)- 3-cyclohexene-1-one ethylene ketal (96) . . . 100 34. Infrared spectrum of 4-methyl~3-(l-methyl- cyclopropyl)~3-cyclohexene-1-one ethylene ketal (97). o o o o o o o o o o o o o o o I o 101 35. Nmr spectrum of 2,6-dimethy1-3-(l-pyrrolidy1)- 2-cyclohexene-1-one (73), (CDCla) . . . . . . 102 36. Nmr spectrum of 2,4-dimethyl-3-(l-pyrrolidy1)- 2-cyclohexene-1-one (63), (CDC13) . . . . . . 103 37. Nmr spectrum of 1,3-dimethylbicylo-[4.4.0]- deC-é-ene-Z'B-dione 64), (CClk). o o o o o o 104 38. Nmr spectrum of 5-dibromomethylene-1-methy1- bicyclo-[4.4.0]-dec-6-ene-2,8-dione (85 , (CDCla) o o o o o o o o o o o o o o o o o o o 105 39. Nmr spectrum of 1,5-dimethylbicyclo-[4.4.0]- dec-6-ene-2'8-dione 57), (CClk). o o o o o o 106 40. Nmr spectrum of 1,5-dimethy1bicyclo-[4.4.0]- dec-S-ene-Z,8-dione-8—ethy1ene ketal (58 , (CClH)ovo o o o o o o o o o o o o o o o o o o 107 vii LIST OF FIGURES AND CHARTS--Continued FIGURE 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. Nmr spectrum of 4-methy1-3-viny1-3-cyclo- hexene-l-one ethylene ketal (90 , (CC1u). . . Nmr spectrum of 4-methy1-3-cyclopropyl-3- cyclohexene-l-one ethylene ketal (91 , (CClu) Nmr spectrum of 4-methyl-3-(2-oxocyclobuty1)- 3-cyclohexene-l-one ethylene ketal (89), (CClu) o o o o o o o o o o o o o o o o o o o o Nmr spectrum of 4-methy1-3-(1-methy1-2-oxo- cyclobutyl)-3-cyclohexene-1-one ethylene ketal (95) ’ (CCll+) o o o o o o o o o o o o o o Nmr spectrum of 4-methy1-3-(2-propenyl)-3- cyclohexene-l-one ethylene ketal (96), (CC1.) \IN Nmr spectrum of 4-methyl-3-(l-methylcyclo- propyl)-3-cyclohexene-1-one ethylene ketal (97),,(CC1Q)0 o o o o o o o o o o o o o o o 0 Mass spectrum of 2,6-dimethyl-3-(l-pyrro- lidyl)-2-cyclohexene-l-one (73) . . . . . . . Mass Spectrum of 2,4-dimethyl-3-(l-pyrro- lidyl)-2-cyclohexene-l-one (63) . . . . . . . K" Mass spectrum of 2,4-dimethyl-2-(3-oxobuty1)- CYCthexane-l I 3-dione (62) o o o o o o o o o 0 V‘ Mass spectrum of 1,3—dimethy1bicyclo-[4.4.0]— deC‘G'ene-Z I 8-dione (64) o o o o o o o o o o 0 Mass spectrum of 5-dibromomethy1ene-l-methy1- bicyclo-[4.4.0]-dec-6-ene-2,8-dione (85). . . Mass spectrum of 1,5-dimethylbicyclo-[4.4.0]- deC‘é-ene-Z I 8-dione (57) o o o o o o o o o o o K.” Mass spectrum of 1,5-dimethy1bicyclo-[4.4.0]- dec-5-ene-2,8-dione-8-ethy1ene ketal (58) . . V‘ Mass spectrum of 4-methy1-3-viny1-3-cyclo- hexene-l-one ethylene ketal (90). . . . . . . viii Page 108 109 110 111 112 113 114 115 116 117 118 119 120 121 LIST OF FIGURES AND CHARTS--C0ntinued FIGURE 55. 56. 57. 58. 59. CHART 1. 2. Mass spectrum of 4-methy1-3-cyclopropyl- 3-cyclohexene-l-one ethylene ketal (91). . . . Mass spectrum of 4-methy1-3-(2-oxocyclobuty1)- 3-cyclohexene-1-one ethylene ketal (89). . . . Mass spectrum of 4-methy1-3-(l-methyl-Z-oxo- cyclobutyl)-3-cyclohexene-l-one ethylene ketal (95) . . . . . . . . . . . . . . . . . . . . . w Mass spectrum of 4-methy1-3-(2-propenyl)- 3-cyclohexene-1-one ethylene ketal (96). . . . Mass spectrum of 4-methy1-3-(l-methylcyclo- pr0pyl)-3-cyclohexene-l-one ethylene ketal (‘9’.7) O O O I O O O O O O O O O O O O O O C O 0 Direct Irradiation of Some B,Y-Enones. . . . . Examples of ByY-Enones Which Give Both 1,2- and l I 3"ShiftS o o o o o o o o o o o o o o o 0 ix Page 122 123 124 125 126 46 51 PART I THE SYNTHESIS OF 2,5-DIOXO-CYCLOPENTANEPROPIONIC ACID INTRODUCTION The title compound\l\was desired as an intermediate in a projected total synthesis of the alkaloid cephalotaxine ‘3‘ natural esters of which possess potent antileukemic properties.1 0 Cl. COzH OH The proposed initial reactions using dione are out- 2. lined below and are based on Mondon's work with a structural- ly analogous system in the synthesis of Erythrina alkaloids.2 In the second stage of this study, the possibility of effecting rearrangement of the ring systemrink§~to the cephalotaxine skeleton was to be explored. Since cyclopentane-1,3-diones are relatively rare in contrast to the cyclohexane-1,3-diones, a brief discussion of some of the synthetic routes to the former compounds is desirable. The synthesis of 2-substituted cyclopentane-1,3-diones could be achieved by alkylating the parent B-diketone‘gJ‘ an approach that appears to be well suited for the prep- aration ofkl4 Michael addition of the enolate of\§~to methyl acrylate, for example, should give the desired product after hydrolysis of\24 01 ' 2 1) base 02CH3 H‘OQ 3' u“ I. OH 2)//—C02Me OH The drawback of this synthetic strategy is that the unsubstituted compound is not readily available, and its .9. syntheses suffer from a combination of many steps, difficult workup conditions, and low yields. A better route to alkylated cyclopentane-l,3-diones would incorporate all necessary carbon atoms at once. There are two important condensation reactions which lead to 2-substituted cyclopentane-l,3-diones. The simpler method involves a reaction between succinic anhydride and an enol ester as illustrated in Scheme 1. The intermediate acetyl compound(10 can be isolated if R = H.3 Scheme 1 r- '1 O O O o " R e R OCCHa A1C13 H30 0 —— ——F O ———. H CH3 .H O O L 3 e. e. .10. ‘11 Although this condensation is direct and gives good yields when R = CH3,“ it has not been used for more complex R groups. The other important route to\I1\requires several steps (see Scheme 2) but is a well established pathway. A methyl ketone 12 is allowed to react with diethyl oxalate, and the resulting tetraketo-ester‘13 is de-ethoxalylated to a cyclopentane-1,2,4-trione.14. The 1-carbonyl function can be removed by Wolff-Kishner reduction of the corresponding semicarbazones or by catalytic hydrogenolysis.6 Scheme 2 O O 2(C02Et)2 HO R H 09 //u\\¢,R 1.. -— ~3————O> 5 NaOEt, A C2H502C O A H o \134 \Efi‘ 14 9 11 Hz/Pt or Pd, H 1) HzNNHCONHz \_’\ .‘11 11 2) KOH,(CH20H)2p A The good to excellent yields in these reactions and the great synthetic versatility of the a variety of substituted cyclopentanes Scheme 2 particularly attractive. The achieved using this general procedure. triones 14 in making makes the route in synthesis of\;~was RESULTS AND DISCUSSION The first attempt to synthesize 2,5-dioxo-cyclopentane- propionic acid\1‘used a modification of the route outlined in Scheme 1. Since an enol ester is required for this reaction, and since‘lficontains a carboxyl group, the enol lactone\I§‘seemed to be a logical choice for the proposed condensation (equation 1). O A1C13 O + -——-———C> [::: \\_ O O (1) . ‘15 8 M H30Q O When‘Ig‘was subjected to reaction conditions analogous to those used in successful condensations of this type,3’“ \Ikcould not be isolated from the many products produced. Therefore this approach was abandoned. The dione acid\Il< R = (CH2)5C02H had been prepared previously by Collins g£_31.‘c by the route outlined in Scheme 2, starting with‘12, R = (CH2)7C02H.A The 1-carbonyl group of‘Ig‘was removed via catalytic hydrogenation (pal- ladium on carbon) in an acetic acid solution containing sulfuric acid. The similarity betweenkli, R = (CH2)5C02H and‘1‘suggested that the latter compound could be synthe- sized from 5-oxo-hexanoic acid\Ig, using Collins' methods. Compound\12\was prepared by a Michael addition of ethyl acetoacetate\Iz\to methyl acrylate, followed by hydrolysis and decarboxylation of 187’8 (equation 2). O O //“\\/.C02C2H5 EfBuOKr ESBUOHy’. ‘/)u\7//“\\/rC02CH3 (2) ' Aér—COZMe C02C2Hs 17 (18 A306, A O MCCzH ‘19 In an attempt to produce intermediate‘23\directly,‘12\ was allowed to react with diethyl oxalate in the presence of potassium Efbutoxide. Hydrolysis of the resulting crude mixture gave a small amount of diacid‘agxas the only iso- lated product (equation 3). Cyclization to the desired product,\33< may have been prevented by the heterogeneity of the reaction medium in the first step. OH 1) Eyauox,‘(c02Et)z /J\\o/jL\V/"\v/CO H 1 9 . . \ 2 (3) 7" 2) 2.5 N HCl, A HOZC 20 \-—N O OH O C02H CH3OZCW COzCHa O OH 0 “2"1‘ 3.1 The dimethyl ester 21, formed by diazomethane treat- ment of 20, was more easily-purified and characterized than the diacid. The fact that.21 shows the same nmr pattern as (19 for the three methylene groups in the chain indicates that‘21 1s st111 acyclic. The uv spectrum of‘21 (Aa°1d 284 nm, e 7.7 x 103, Abase 320 nm, e 1.3 x 10“) is max ma X consistent with the spectra of other 2,4-dioxo esters.9 The solubility problem associated with the use of‘I9 was overcome by using its ethyl ester 23 in the condensa- tion reaction with diethyl oxalate. A good yield of the ethoxalyl-cyclopentane-l,2,4-trione‘intermediate.24 was obtained when sodium ethoxide was used as the base (equation 4). EtOH NaOEt M C02C2H5 ' ’ 2(C02Et)21 A (4) 451 C02C2H5 HO II C2H502C OH 0 24 VIN The spectral data forkgg agree with those expected for compounds of this type.6°'1° The nmr is noteworthy, since the two methylene groups of the propionic acid side chain have, by chance, the same chemical shift and appear as a singlet at 62.64. Hydrolysis of\gg\with hydrochloric acid gave\3;4 as expected. The remaining requirement for conversion to\1‘was removal of the l-keto function, but Collins' method of catalytic reduction failed when applied to‘33\(no reaction occurred). However, Wolff-Kishner reduction of the semi- carbazone derivative of 22 gave the desired dione acidyl‘ L/N (equation 5). O . COZH D COZH 1) HzNNHCONHz » (5) '$ 2) KOH, (CHZOH)2, A OH OH O 22 l 10 A remarkable feature of\l‘is its unusually simple nmr spectrum. In d5 acetone all eight methylene hydrogens appear as a singlet at 62.42. In (16 dimethyl sulfoxide the two sets of adjacent methylene groups occur as two equally intense singlets at 62.31 and 62.40. In neither spectrum was a signal corresponding to the enolio and carboxylic hydrogens detected. Although the other spectral data were consistent with the assigned structure of\l, its peculiar nmr behavior prompted a chemical structure proof. Methylation of\l‘gave the known dione ester\3§< which was independently synthe- sized from commercially available 2-methy1cyclopentane-l,3- dione\3§\(equation 6). The nmr and ir spectra of\a§‘pro- duced by the two pathways were superimposable, thus veri- fying the structure of\14 1) NaH, DMF EfBuOH O (6) 2) Mel . C02CH3 Ma, 0 9 COM DMF // 26 3.1 O 11 Because both,27 and‘zg have previously been used for the synthesis of natural prostaglandins,‘c'1°'11'12 com— pounds\1‘and\gg\should also be useful synthons for prosta- glandin analogs. Furthermore, the discovery that several cyclopentanepropionic acid derivatives are metabolites of the natural prostaglandins E2 and F2a13'1“'15 suggests that‘I‘and‘ZZ would also be of interest as snythetic pre- cursors of such metabolites. o O (CH2)6C02H I (CH2)5C02H OH OH ' O 27 28 EXPERIMENTAL General Infrared spectra were recorded on a Perkin-Elmer 237B spectrophotometer. Nuclear magnetic resonance spectra were taken on a Varian T-60 spectrometer, using tetramethylsilane as an internal standard. Ultraviolet spectra were recorded on a Unicam SP-800 spectrophotometer. A Hitachi RMU-6 mass spectrometer was used to obtain the mass spectra. Melting points were taken on a Reichert hot stage microsc0pe and are uncorrected. Microanalyses were performed by Galbraith Laboratories, Knoxville, Tennessee, or by Spang Microanalytical Laboratory, Ann Arbor, Michigan. All reactions were magnetically stirred and run under an inert atmosphere of nitrogen or argon. Organic extracts were dried over anhydrous sodium sulfate, and solvents were evaporated under reduced pressure unless otherwise indicated. Craig tubes were used for recrystallization in most cases. All spectral data are described in this section except the mass spectra which appear in the Appendix only. 12 13 5-Oxo-hexanoic acid (19)7’° M To a solution of potassium Efbutoxide, prepared from 0.3 g of potassium and 50 m1 of dry Efbutanol, was added 65.0 g (0.50 mol) of ethyl acetoacetate. Slow addition of 44.8 g (0.52 mol) of methyl acrylate to this solution was effected with rapid stirring and intermittent cooling to maintain the temperature at about 25°. This reaction mix- ture was stirred overnight at room temperature, acidified with 0.45 ml of acetic acid, and stripped of solvent. A chloroform solution of the residue was washed with water and brine and, after concentration of the dried extracts, the residue was distilled at 87°/l mm, yielding 82.9 g (77%) of methyl 4-carbethoxy-5-oxo-hexanoate\IE; This com- pound was hydrolyzed without further characterization by refluxing it for four hours in a solution containing 150 m1 of concentrated hydrochloric acid and 100 ml of water. After evaporation of the solvent, the residue was dissolved in methylene chloride, and the resulting solution was washed twice with brine and evaporated. Distillation of this crude product (bp 95°/o.15 mm) gave 46.0 g (92.5%) of colorless Sfoxo-hexanoic acid 19. t,“ On standing in moist air‘lg‘formed a colorless hydrate, mp 32-35° (lit16 mp 34-36°). Anhydrous\12‘showed nmr absorption (CClu) at 61.82 (m, 2H, C-3 CH2), 2.06 (s, 3H, COGHg), 2.38 (m, 4H, C-2, C-4 methylene protons), 10.94 (s, 1H, C025). 14 Ethyl 5-oxo-hexanoate (32)7 A solution consisting of 10.4 g (0.08 mol) ofég4 200 mg of pftoluenesulfonic acid, 25 m1 of absolute ethanol, and 10 ml of benzene was refluxed for three hours through a Dean Stark trap. At 20 min intervals, 5 to 10 ml of distillate was drawn off from the trap. Finally the solvent was allowed to distill, leaving about 20 ml of concentrate which was diluted with methylene chloride, washed once with 10% sodium bicarbonate and twice with brine. Evaporation of all solvents left 11.2 g (88%) of colorless\33‘which was pure enough to use in subsequent reactions. Ester\32‘Showed nmr absorption (CC1.) at 61.20 (t, 3H, J 7H2, 01129113), 1.82 (m, 2H, c-3 egg), 2.03 (s, 3H, coc_:r_13), 2.30 (m, 4H, C-2, C-4, methylene protons), 3.97 (q, 2H, J 7Hz, grizcna). 2,4-Dioxosoctanedioic acid (32) To a refluxing, mechanically stirred suspension of potassium E-butoxide, prepared by dissolving 13.5 g (0.345 9 atom) of potassium in 200 ml of dry tfbutanol, was added a solution of 13.0 g (0.10 mol) of keto acid\12\in 32.0 g (0.22 mol) of freshly distilled diethyl oxalate. After re- fluxing 3.5 hours, the thick orange mixture was acidified with 30 m1 of concentrated hydrochloric acid, and the pre- cipitated potassium chloride was filtered and washed with 15 chloroform. Evaporation of the filtrate left a brown oil, which was refluxed with 50 ml of 2.5 N hydrochloric acid for 90 min. The brown solution was concentrated, and the resulting solid was filtered, washed with water and ethyl acetate, and air dried to give 4.7 g (4.3%) of light brown diacid 33‘ Compound‘22~was very difficult to purify (recrystalli- zation from acetone gave mp 155-175°, dec) and hence was characterized as its dimethyl ester 21. Dimethyl 2,4-dioxo-octanedioate (31) A solution of 184 mg of crude\39‘in 2 m1 of methanol was treated with an excess of ethereal diazomethane. After evaporation of the solvents the resulting yellow solid was recrystallized several times from ether to give white crystals: mp 66-67°; ir (KBr) 1725, 1635, 1600 cm-1; nmr (CDCla) 61.97 (m, 2H, C-6 CH3), 2.43 (m, 4H, C-5, C-7 methylene protons), 3.60 (s, 3H, cnzcozgga), 3.82 (s, 3H 1;?8-C02C§;), 6.25 (s, 1H, vinylic proton), 13.65 (brd s, 1H, enolic proton) Anal. Calcd for Clofiluos: C, 52.17; H, 6.13. Found : C, 52.09; H, 6.13. Eth‘l 4-ethoxalyl-2,3,5-trioxo-cyclo- pentanepropionate (24) Vs To a chilled (0°) sodium ethoxide solution, prepared from 2.80 g (0.122 9 atom) of sodium and 50 ml of absolute 16 ethanol, was added a solution of 8.70 g (0.055 mol) of keto esterEiin 23.6 g (0.162 mol) of diethyl oxalate. ‘The resulting solution was stirred at room temperature for 30 minutes, refluxed for 30 minutes, and then acidified with 9.6 m1 of concentrated hydrochloric acid.‘ The pre« cipitated sodium chloride was filtered and washed with ethanol, and the filtrate was concentrated. Crystallizae tion of a carbon tetrachloride solution of the residue gave 9.6 g of yellow—orange\24; The concentrated mother liquors were dissolved in ethyl acetate and extracted with 10% sodium.bicarb0nate to remove the acidic\35: The aqueous solution, washed with ether, acidified, and extracted with chloroform, gave an additional 5.9 g of crystalline\3£‘for a total of 15.5 g (90%). An analytical sample of\24\was obtained'by‘recrystalv lization from ether: mp 80—8l.5°; ir (KBr) 3180, 1750, 1725, 1625 cm'l; nmr (CDClg) 61.30 (overlapping triplets, 6H, J 7Hz, COZCH2CH3), 2.64 (s, 4H, cggcgg), 4.20 (over- lapping quartets, 4H, J 7Hz, COZCH3CH3), 9.85 (brd s, 2H,. CH); uv max (95% EtOH) 258 nm (8 12,600), 323 nm (e 6500). Anal. CalCd for CIHHLGOO 5 C, 53.85; HI 5016 "" Found : c, 53.98; H, 5.30. 2,3,5-Trioxo-cyclopentanepropionic acid (22) \A A solution of 3.120 g (0.010 mole) of 24 in 30 ml of 3N hydrochloric acid was refluxed for five hours and then l7 concentrated. The solid residue was boiled twice with 40 m1 of chloroform to give 1.728 g (94%) of crude\32: a Since trione acid\23\was difficult to purify, its methyl ester was prepared for analysis. The purest sample of\32~was obtained after several recrystallizations from acetone: mp 141-144°; ir (KBr) 3400-2900, 1740, 1685 cm-1; nmr (d5 acetone) 62.68 (s, 4H, Cchgg), 2.92 (s, 2H, COCHzCO), 9.06 (brd s, 2H, COzg, OH); uv max (95% EtOH) 274 nm (e 9300), 316 nm (e 4650). Methyl 2,3,5-trioxo-cyclopentanepropionate A solution consisting of 276 mg (1.5 mmol) of\33< 3 ml of methanol, 0.33 ml (3.0 mmol) of trimethyl ortho- formate, and two crystals of pftoluenesulfonic acid was refluxed for three hours. The reaction mixture was distilled to remove 1.5 m1 of solvent, diluted with water, and ex- tracted with methylene chloride. The organic extracts were washed first with 5% hydrochloric acid and then twice with 10% sodium bicarbonate. The aqueous bicarbonate solution was acidified and extracted with methylene chloride to yield 124 mg (42%) of brown oil. Two bulb to bulb distillations (150°/0.05 mm) of this crude product gave nearly colorless methyl 2,3,5-trioxo-cyclopentanepropionate: ir (neat) 3600- 2500, 1735, 1685, 1655 cmfl; nmr (CDCla) 62.65 (s, 4H, cggcgz), 2.89 (s, 3H, COCEgCQ), 3.64 (s, 3H, cozcgs). 18 8.05 (brd s, 1H, cg). Found : C, 54.39; H, 5.15 2,5-Dioxo-cyglopentanepropionic acid (I) To a solution of 368 mg (2.0 mmol) of triketo acid \Za‘and 168 mg (2.0 mmol) of sodium bicarbonate in 3wml of water was added a solution of 240 mg (2.15 mmol) of semicarbazide hydrochloride and 320 mg of sodium acetate trihydrate in 2 ml of water. The resulting suspension was stirred at room temperature for two hours, acidified to pH 2, cooled in ice, filtered, and washed with water. After drying in a vacuum the light yellow, powdery semi- carbazone derivative weighed 407 mg (85%) and was used in the next step without further purification or characteriza- tion. A solution of 560 mg (2.32 mmol) of the 3-semicarbazone derivative of\32‘and 1.23 g of potassium hydroxide in 5.5 ml of ethylene glycol was heated at 200° for six hours and then concentrated. An aqueous solution (3 ml) of the resi- due was acidified, filtered, and extracted 14 times with ethyl acetate to afford 327 mg (83%) ofkl: Several recrystal- lizations of\I‘from methanol produced white crystals: mp 168-171°; ir (KBr) 3300-2500, 1690, 1595, 1560 cm"; nmr (d5 acetone) '2.42 (s, 8H, methylene protons of ring and side chain), (d5 DMSO) 2.31 (8, 4H), 2.40 (3, 4H); uv max (95% EtOH) 248 nm (a 11,150). 19 Found : C, 56.50; H, 5.93 Methyl 2,5-dioxo-l-methylcyclopentaner propionate (2 )‘ The known compound\3§i7 was prepared by the method of Kessar gt_§l.1° and by the methylation of\1: a) To a solution of sodium tfbutoxide, prepared by dissolving 3 mg of sodium in 0.3 ml dry tfbutanol, was added a solution of 224 mg (2.0 mmol) of 2-methylcyclo- pentane-l,3-dione in 4 m1 of dry dimethylformamide (DMF) and 0.52 ml (5.8 mmol) of methyl acrylate. After heating at 140° for 12 hours the brown solution was concentrated, diluted with water, and extracted with methylene chloride. The organic extract was washed successively with 10% sodium bicarbonate, water, and brine, and then concentrated. Bulb to bulb distillation of the residue gave 50 mg (12.6%) of light yellow oil, and another bulb to bulb distillation (100°, 0.3 mm) gave\3§\as a nearly colorless liquid: ir (neat) 1715-1745 cm-l; nmr (001.) 61.03 (s, 3H, C-l c133), 2.01 (Asz, 4H, side chain methylene protons), 2.67 (s, 4H, ring methylene protons), 3.50 (s, 3H, C02C§3)- Anal. Calcd for C10H1.o. : C, 60.59; H, 7.12 Found : C, 60.69; H, 7.12 b) To a suspension of 0.69 mmol of sodium hydride (from 28 mg of 57% oil dispersion washed with pentane) in 0.8 ml of dry DMF was added a solution of 51 mg (0.30 mmol) 20 of dione acid‘I‘in 0.2 m1 of dry DMF. After adding 0.070 ml of dry Efbutanol and 0.040 ml (0.6 mmol) of methyl iodide, the solution was stirred at room temperature for 90 min, acidified, diluted with water, and extracted with ethyl acetate to give 40 mg of oil. Preparative thick layer chromatography (silica gel, ether) gave 6 mg (10.8%) of\3§‘having ir and nmr spectra superimposable on those of the compound as prepared in part (a). APPENDIX 100 ) 8 L O 0“ o mmsmnuncem) N O 4000 3500 3000 2500 2000 1500 mom w v c( M ') 100 TRANSMITTANCE(%) 0 . 3 , . 2000 1800 1600 _l400 1200 1000 800 "£00!ch (CM ') Figure 1. Infrared spectrum of dimethyl 2,4-dioxo- octanedioate (21). w 8 TRANSMITTANCE(%) & O N O §°. ‘ ' 71-1. 3500 3000 2500 2000 I500 HIEOINM V ((4.) - TRANSMITYANCEHG) ccrc,H. 1800 1600 I400 ., 1200 1000 ' 800 IliOU N! V :(M '| Figure 2. Infrared spectrum of ethyl 4-ethoxa1y1-2,3,5- trioxo-cyclopentanepropionate (24). M 23 - ...- u.- -- -.o-.—p.. . - o n. -—-..-0— .- u . 1.. W, poo-n- .- -— - 1 .I'I 2000 L . m a m 0 w 4 3.... muz0on0flUIm.N mo Esuuommm . ...—...J.. . v¢AU oxx o9\ oW‘ u$s 9? 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IIIOIIIIIL |!.]1v8 . _ .-;oo\ apaa 9393 go afiéquaoxaa PART II THE SYNTHESIS AND PHOTOREARRANGEMENT OF TWO BIY'ENONES 42 INTRODUCTION The initial goal of this study was development of a new and facile synthesis of the sesquiterpene bulnesol,.l: A key step in the proposed synthesis (Scheme 1) was the anticipated photorearrangement of B,Y-unsaturated ketone \g‘to the tricyclic isomer\;{ Scheme 1 1) Ph‘3P=CH2 2) Hz/Pd/C 0 9 I1 2) CH3L1 \ 2) Ph3P=C’ \ Me 'I . c1130 0Q ' 43 44 Although photorearrangement of B,y-enones is well established, the factors controlling the course of these rearrangements have not been completely elucidated. Before proceeding further, therefore, a survey of the "state of the art" is necessary. Interest in this area of photochemistry originated in Bfichi's observation in 196019 of the photointerconversion of\1~and\§‘by a 1,3-acyl shift (equation 1). One of the O O hv ______.L ..———- I (1) 7 8 M L" first examples of a 1,2-acyl shift, corresponding to that desired for the bulnesol synthesis, was noted by Williams and Ziffer in 1967.2° These two types of rearrangement are usually the major photoreactions of B,y-unsaturated ketones (Scheme 2); however, other transformations such as 3 decarbonylation,21'22 hydrogen abstraction,2 and reduc- 2kI25 tion are frequently encountered and may even predom- inate in certain cases. 45 Scheme 2 O R. R5 R2 L; 10 11 The 1,3- and l,2-shifts normally arise respec- tively, from the n,n* singlet and triplet excited states..”’26 The mechanisms of these rearrangements and the structural features which influence them generally remain poorly defined. Some B,Y-enones show exclusive 1,3- or l,2-shifts, whereas others exhibit both reactions simultaneously. In many cases a 1,3-shift is obtained on direct irradiation (presumably gig the n,n* singlet) and a l,2-shift is the major product on sensitized irradiation (gig a triplet state). These facts illustrate the com- plexity of B,Y-enone photochemistry and the difficulty in predicting how a particular compound will behave on exposure to light. Chart 1 contains several examples of structurally re- lated B,Y-unsaturated ketones which, with the exception of 12, undergo exclusively one type of photoreaction on direct irradiation. The rare examples of direct triplet l,2-shifts Chart 1. (7) 46 Direct Irradiation of Some B,Y-Enones ' (Reference) hv isooctane . " 0 + (25) triplet + trans ‘13 14 h"' 513.1011 , .p, (20) triplet (1,2) 0, 16 hv, benzene O T singlet (1,3) . 18 11V: E’BUOH .> > (28) triplet (1,2) 0 20 v hv, t-BuOH Major Product - =5» incorporates (28) EfBuOH .rl . singlet (1,3) (29) 47 Chart 1 (cont'd.) (Reference) 0 hv, ether 0 I (8) V ‘ (22) singlet (1,3) . 24 25 0 R R hv ether (9) ' > / \ + co (22) singlet ___ R=H,CH3 26 27 0 O (10) hv, ether db } (22) triplet(?) (1.2) 28 29 Lax 48 for compounds\i§<‘i2< and (probably)‘Z§~must occur gig fairly rapid intersystem crossing (isc) of the initial n,n* singlet excited state of the ketone. As expected of typical triplet reactions, these exhibit quenching (except \Eggwhich is unaffected) and increased rate on triplet sensitization (e.g., acetone). The fact that the reac- tion of\3§gcannot be quenched with piperylene but can be sensitized is unusual. Either product\22\can arise from both a singlet and a triplet intermediate (which would be exceptional), or isc occurs, and subsequent rearrangement from the triplet state is faster than diffusion control. In comparing equations 2, 3, and 4, one sees a marked variance in reaction pathway with changes in ring size of the enone. Excessive ring strain probably prevents product formation gig a l,2- or 1,3-shift for‘iZ: Compound\iz‘ neither undergoes isc (as\i§\does) nor produces a cyclo- propyl ketone (1,2-shift) on triplet sensitization. This lack of similarity between the photoisomerizations Of.£§~ andxiz‘is difficult to explain. The triplet rearrangement of steroid\i2\is analogous to reaction 3. But surprisingly, the isomeric steroidéi~ incorporates solvent on photolysis; no cyclopropyl ketone was detected. Compound‘EE: although structurally similar to\i2‘and‘3i£ has increased conjugation with the aromatic ring, which seems to retard isc and favor a singlet 1,3-shift. A triplet 1,2-shift is observed, however, on 49 photosensitized irradiation of\234259 It is apparent from Chart 1 that rather subtle factors must contribute to the variation in reactivity among similar molecules. It should be noted that the 1,3-acyl shifts illus- trated in equations 1,4,7, and 8 are reversible. Such photoisomerizations frequently reach a steady state in which the equilibrium favors the isomer having the lower molar absorptivity, e. The magnitude of 6 reflects the prob- ability of electronic transition and hence is proportional to the rate of reaction. Molecular geometry can greatly 9 affect the position of such equilibriaz since 6 becomes more intense as the degree of n-orbital interaction between 0 the carbonyl and double bond increases.3 Some 1,3-acyl shifts are irreversible as the conversions of 30 to 3126e w“ and 32 to 3326h illustrate. \Aw ether 31 v‘ 0 [it 30 n» ‘ -———————+> O benzene I 32 33 V‘ 50 Much of the photochemistry of B,Y-enones suggests that, ordinarily, direct irradiation produces a 1,3-shift, 2‘ Some typical and sensitization produces a 1,2-shift. examples of this behavior are found in Chart 2. The reactions of\4g\are particularly instructive since the singlet pathway creates the skeleton of the guiane sesquiterpenes (e.g., bulnesol), and the triplet route yields a structure (:22 similar to proposed inter- mediate\;_(Scheme l). The synthetic utility of\£3‘as a guiane precursor is limited, however, by its low yield (50% based on recovered\i£l and the unsatisfactory location of functionality. In contrast with the photochemistry of\ii‘are the related systemség‘and‘ig4 which give only cyclobutanolé—ZK 31 and oxetane,49, respectively, on direct irradiation. 0 OH. hv DI cyclohexane \\ .46 47 O hv ;. o cyclohexane ‘ 48 51 Chart: 2. Examples of 8,Y-Enones Which.Give Both l,2- JL,.3 Product 1,2 Product (Reference) (26a) 0 34 36 K.” / O hv hv (26b) various 38 cetone solvents "“ IO ‘ / .° 37 39 52 Chart 2 (cont'd.) 1,3 Product 112 Product (Reference) Ph hv 41 hv, benzene EtOH “A \AcPh Ph A/l Ph 0 I . O 40 ’ 42 \.,\ C03? hv hv hexan:(/// 44 acetone (26f) \_/\ 53 In acetone solution,‘i§ and‘iz merely photoisomerized to the corresponding a,B-enones. Again we note the striking effect of ring size on the course of reaction. A recent study26h reveals that the number of a-alkyl substituents influences the competition between isc and 1,3-acy1 shift. In particular, the rate of singlet reac- tion seems to be enhanced by a-methylation (Scheme 3). Scheme 3 b hv enzene O” or 4. C acetone 0 .13. Si 0 4L -—————%> .9 acetone 0.:1. benzene . +3.2 0 50 52 . ‘ } e —> . a acetone benzene 55’. O 54 Compound\l§1 as previously noted, undergoes isc and exhibits no singlet reaction.' Addition of one a-methyl group {all reduces the amount of l,2-shift, and rearrange- ment to\§g\begins to occur from the singlet state. Two c-methyl substituents further increase the rate of the 1,3 shift leading tog;z An alternative explanation where- in a-substitution is said to decrease the rate of isc is considered unlikely by the authors. Moreover, differences in the geometry and a values of these ketones are small and provide no adequate explanation for the observed differ- ences in photochemical behavior. At present, the above results await both a theoretical interpretation and a corre- lation with other B,Y-enones. Because the photochemical consequences of minor struc* tural changes in B,Y-enones are not well understood, the photorearrangements of both\g‘and\§§‘were investigated. Presumably, only the influence of the y-methyl group in\§§\ would account for any differences in photochemistry between these two ketones. The objective of this comparison was to gain some knowledge about the effects of double bond sub- stitution on photorearrangement, rather than to use\§§~in a synthesis. 55 O O .9 O 0.. o 3. éi 3;. . .9 Q. o 0 '. O 57 58 Some background regarding the synthesis of both\3~and 58 is in order. Ketal \gycan be prepared from Wieland- Miescher ketone 56,32 but neither 58 nor its logical pre- \.A LA cursor enedione 57 has been reported. Enone alcohol 59 has M w been synthesized from 56 in eight steps33 and could be oxidized to afford 57. However, a more direct route to the latter compound was sought. HO Modification of 56 is less efficient than incorporation of the 5-methyl group early in the synthesis of enedione Consideration of a synthetic method used by Coates3“ 57. \l‘ (Scheme 4) suggested a possible approach to the problem. 56 Scheme 4 O 0 AA 9 O 63 57 O O wfifi—A / °9 N N .9 «9 65 66 O \\T::::t::::LO O ‘Nkliiliillllt 64 0 *0. L7 N 67 \"\ Coates devised conditions for the conversion of enamino ketone 60 to enedione 61. A synthesis of 57 might M M \_.4-\ proceed via the methylated enamino ketone 63! provided that 'cyclization could be made selective. If trione 62 is the \A precyclization intermediate, then differentiation between 57 ‘the cyclohexanedione carbonyls will be lost, and cycliza- tion would be expected to give mainly the isomeric enedione 64. \‘ However, if 65 and‘66 are the precyclization inter- mediates, selective cyclization to dione 67 would ulti- mately yield 57 exclusively, since the necessary differentiation of carbonyls would be maintained. Both modification of‘56 and the enamino ketone route were explored as potential synthetic pathways to 57. RESULTS AND DISCUSSION Much of the synthetic effort in the course of this research was directed toward the preparation of enedione ‘51& Therefore, investigations related to its synthesis will be described first. The enamino ketone\63, required for the proposed route to‘ézkoutlined in the Introduction, has not been reported in the literature. However, the recently described prep- aration 35 of aby y-methylation of a conjugate base derived from the parent pyrrolidino enone‘gg‘suggested a means of effecting a synthesis of 63. \_.-A ‘68 69 63 w 58 59 Alkylation of dienolate anion\§2‘at the y-position is unusual, inasmuch as the fully-conjugated dienolates of a,B-unsaturated ketones react with alkylating agents exclu- sively at the on-position."’6 Unfortunately, the reported conversion °f\§§~t0\124 with nfbutyl lithium at low temperature, could not be dupli- cated, nor did these conditions, when applied to\§9£ yield ‘63: Previous successful application of 2°-amide bases in the formation of enolate anions37 suggested their use here, and lithium diisopropyl amide (LDIA) was found to be effec- tive under equilibrating conditions (Scheme 5). Scheme 5 o 09 09 excess LDIA 60 _. ...—EL THF HMPA ‘- ‘D ”O ”Q 60 71 72 1 CH 31 lea. I O O ‘63 D N 73 60 Initial formation of the kinetically favored cross- conjugated dienolate 71 was expected from previous work in this laboratory37 as well as Stork's a'-allylation of enol ether 74 using this amide base.38 0 09 o LDIA [fl A Br .__. ___.. I THF 74 75 76 \_/\ Compound 73 was distinguished from its isomer 63 by \lg \IK : hydrolysis to 2,4-dimethylcyclohexane-l,3-dione 77, followed by reaction with pyrrolidine (at the lessrhindered carbonyl) I. to regenerate 73. The nmr spectra of 73‘produced by methyl- ation of 60 and by the above procedure were superimposable. 61 The equilibrium between the cross- and fully-conjugated dienolates (Scheme 5) was expected to favor the latter, since the additional charge delocalization in‘zg‘should enhance its thermodynamic stability. Methylation of the equilibrated conjugate base did in fact take place at the y-position, giving\§§\essentially uncontaminated with the a'—isomer\Z§4 Scheme 6 illustrates the results of using Coates' reaction conditionsa“ for the condensation of vinylogous amide,63 (or\13) with methyl vinyl ketone (MVK). Scheme 6 r 1 O O benzene, MVK, A (or 73) b __. D V‘ H20, HOAc, NaOAc o o n. d 63 62 O O ... o O 64 57 Both.63 and 73 yielded a mixture of isomeric enediones .64 and‘57 in a ratio of 5:1, respectively. Compound 57 was identified by comparison of its glpc retention time with a known sample prepared by an alternative route. Both 62 and 62 \§g\were isolated by preparative glpc and tentatively identi- fied by their ir and mass spectra. In addition,\64‘was synthesized gig methylation of the known dienol ether\Z§f9 (equation 11). Samples of\§£\produced by these two routes had the same glpc retention times and ir spectra. o o 1) LDIA, THF 11 a» ( ) 0c H 2) Cfiaé ‘o 2 5 3) H30 78 64 Unfortunately, under a variety of anhydrous conditions (to prevent formation of 62) the reaction of 63 With methyl vinyl ketone failed to produce significant amounts of the annelation product‘57 (or 64). A different synthetic approach was ultimately successful. The structural similarity between Wieland-Miescher ketone‘56 and the A- and B-rings of A“-3-ketosteroids 79 is obvious. Therefore, modification of‘56 to yield 57 should be possible by methods paralleling the synthesis of 6-methyl- A“-3-ketosteroids (80 from 79). w w 0 O \ \\ “"9 O. ---> O. o o o o 5 57 ’ 79 80 '6 63 One method which reportedly effects this transformation, without the need to protect other carbonyl functions, is the reaction of a dienol ether derivative (81) with carbon tetrabromide"o (Scheme 7). The mechanism whereby\82\is formed is unknown. Scheme 7 l)collidine 79 6% V“ 2) H3 0 CBr 81 82 3 ”\‘\‘ 3H2,Pd/SrC03 “\\\ 80 ‘1F-——— ~‘n Et3N 0 CB]: 2 83 When applied to 56 this approach did provide some 57, although the yields were poor. The expected tribromomethyl and unconjugated enones, analogous to\82\and\844 were not isolated in our sequence, which began with the dienol ether 78 (Scheme 8). Incomplete reaction presented difficulties in the conversion of 78 to,85, and the separation of 57 from 64 six or seven other hydrogenation products required careful chromatography. Scheme 8 O O CBr 4 ° .0 .....5 ’ . Hinze/smog,$ 5 0(3sz pyridine O Et3N, THF 5’73 dioxane CBr2 78 85 The final synthetic requirement was selective ketal- ization of enediones 56 and\51: Ketal~g‘has been prepared from‘56 by two rather limited methods.32 Direct ketaliza- tion (equation 12) gives a mixture of‘a‘and 86 which can be separated by chromatography. However, the reaction is not reproducible and generally favors the thermodynamically more stable ketal 86. \_’~ 0 I O O (CHZOH)2 rt ~§’ + (12) o PTSA . :> O 'o 56 2 benzene \—v\ u-s \86__ 65 A selective cross-ketalization procedure was developed uSing 2-ethyl*2-methyl-l,3-dioxolane 87. When 56 was refluxed in excess,82 with an acid catalyst, ketal\2_could be crystallized from the crude product mixture in 43% yield. No chromatography is necessary, and the mother liquors can be hydrolyzed to 56 for recycling. Use of 87 as the O ,0 0 22+ )K/ :&+§i+ N 87 ‘88 reaction solvent helps to shift the equilibrium to the right. Similar conditions were used to prepare the methylated ketal 58 in 68% yield from 57. O 0 | 58 Photolysis of the BpY-unsaturated ketone‘gl either directly or with acetone sensitization, gave none of the desired 1,2-acyl shift product. Only products derived from a 1,3-shift were observed. 0n prolonged irradiation with a 400-W Hanovia lamp fitted with a Corex filter, a 0.05 M benzene (or ether) solution of enone ‘2‘ yielded two photo- products, identified as diene 90 and cyclopropane 91 (equation 13). Use of an internal standard revealed that 66 90 and 91 were the only Significant products and were pro- duced in a ratio of 2.2:1, respectively. At shorter irradiation times the 1,3-acyl shift product cyclobutanone 89 was also observed. Its concentration increased initially and then decreased gradually as the reaction continued. O hv,Corex O ‘ benzene <13) ‘01) 2 a O + \\ .“;> '0 9O Since cycloelimination and decarbonylation are prinr cipal photoreactions of cyclobutanones,"1 the formation of these two products is not surprising. The absence of a l,2-shift on direct photolysis of\2‘ is also not unusual, since B,Y-enones ordinarily require triplet sensitization for this type of rearrangement. However, enone\g‘gave no detectable l,2-shift product when irradiated in 0.05 M acetone solution. The disappearance of starting material was much slower in acetone than in benzene, and sizable amounts of nonvolatile, polar materials were produced, as evidenced by tlc. Cyclobutanone\82‘and cyclopropane 91 were present, but only a trace of diene 90 67 was detected by glpc analysis. This last fact may indicate that triplet sensitization of\82‘favors decarbonylation (to give\91), or that\29‘forms but is subsequently consumed by reaction with solvent. Because the photorearrangement of\2_was slightly faster in benzene than in ether, an experiment was performed to determine whether benzene was sensitizing this reaction. Benzene (Amax 256 nm) absorbs light of 253.7 nm strongly, but ether is transparent at this wavelength. During irradi- ation of\gfiwith a mercury resonance lamp (253.7 nm), the initial rate of reaction was about four times faster in a 0.05 M benzene solution than in an equimolar ether solution. Glpc analysis revealed that the usual photoproducts were produced in benzene, but that diene\99 was absent in ether, although\§g‘and\91\were present. Tlc showed substantial amounts of nonvolatile substances in the benzene solution but not in the ether solution. The above facts suggest that the rate of consumption of‘g‘during irradiation at 253.7 nm may be faster in benzene because of energy transfer from, and/or reaction with, this solvent. The rate of the 1,3-acy1 shift of\gJ on irradiation in benzene or ether with the Hanovia lamp, was compared for reactions with and without added 1,3-pentadiene. The enone reacted about 1/2 as fast in benzene and 1/5 as fast in ether when 2M piperylene was present. The photodecomposition 68 of cyclobutanone\§g\seemed to be less retarded by the added diene. Because this photorearrangement appears to be sensi- tized by benzene and partially quenched by piperylene, some of the 1,3-shift may arise from the triplet excited state of\3; However, there is evidence that benzene (in fluid solution) can act as a singlet sensitizer"2 because its singlet and triplet lifetimes are about the same (“~2 x 10"‘°sec),"2 and its intersystem crdssing efficiency is low (0.24, based on 1.00 for benzophenone)."3 In addi- tion, concentrated solutions (1-10 M) of 1,3-pentadiene have been shown to quench the excited singlet states of ketones.”“ Thus, the assumption that piperylene acts exclusively as a triplet quenching agent is not always justified. The apparent inability of acetone to sensitize the photoreaction ofyg‘is also inconsistent with the occur~ rence of a triplet 1,3-shift in this case. The nature of the excited state from which\g~undergoes rearrangement remains unclear, but one would certainly expect a singlet 1,3-acyl shift based on the work described earlier in this thesis. There seems to be no report of a simple triplet 1,3-shift, although both a triplet 1,2- and 1,3-shift occur concurrently in the sensitized photolysis of enone 9223 (equation 14). 69 0 hv /’ o *0 + C> acetone éflL 93 O 94 The photoreactions of the methylated enone 58 (equa- tion 15) were conducted in the manner already described for ‘34 After complete reaction in benzene solution, the vola- tile photoproducts were diene 96 and cyclopropane 97 in a 1:1 ratio, and a small amount (<1%) of a mixture of at least two unidentified components. hv ‘::> benzene O (15) 621‘ a O + O + nonvolatile \\ EL~J> ..\J> mixture ' A 'o 96 97 In contrast to the relatively clean reaction of\34 about 40% of the total product mixture from 58 consisted of nonvolatile substances of unknown composition (tlc shows only a streak near the origin). As expected, cyclobutanone 95 was isolated after short irradiation. 70 As noted withng the photoreaction of\§§\in benzene was slowed but not stopped by the addition of 1,3—penta— diene (2M). In acetone solution, the disappearance of\5§‘was very slow relative to irradiation of an equimolar benzene solu— tion. Both‘gé‘and\91\were produded, but the latter compound predominated. In addition, six or seven new volatile photo- products were detected by glpc, which suggests that addi- tional reactions, probably with solvent, were taking place. The possibility that some 1,2-shift occurs in the photo- reactions of\5§\cannot be ruled out. It is evident from the data presented here that the photochemistry of B,y-unsaturated ketones\;‘and\§§‘has both similarities and differences. The products of the 1,3- photorearrangement of each enone are analogous, although their relative amounts differ. Photolysis of‘;.is a "clean" process, whereas\5§\yields substantial amounts of unknown by-products. The reaction of each enone is slower in ace- tone than in benzene solution; but‘Egl unlike\24 produces new volatile substances on photosensitization. Compounds‘gyand\§§\have very similar ultraviolet absorption spectra (Am (32 290 nm [e 31], A ax max (56) 290 nm [e 30]). Consequently, the different photochemical behavior of 58 is almost certainly due to the influence of its extra % methyl group on steps subsequent to the absorption of light. 71 One can only speculate about what processes are modified by this substitution factor. One effect of the y-methyl substituent might be that an additional photoreaction pathway is created. Studies of cyclobutanones have shown that successive introduction of a-alkyl substituents changes the proportions of the photo- products.“ Besides decarbonylation and cycloelimination, cyclobutanones may also undergo ring enlargement via carbenes (Scheme 9), and this process is enhanced by Ot-alkyl substitution. " 1 Scheme 9 :< + CH2=C=O m 101 M Acloelimination .0 , ' hv ' decarbonylation —-> ’ . - co l: < 102 . VK 3,94 3,9, ing expansion 0. OR ROH O -——> O 103 72 Without added nucleophiles (e.g., ROH), a high energy intermediate such as 122 could conceivably give rise to a variety of products (such as dimers). Therefore, it is possible that cyclobutanone\2§‘ because of its extra a-substituent, may produce some nonvolatile photodecomposi- tion products derived from a carbene, even though 89 does not. EXPERIMENTAL General In addition to the instruments described in Part I, a Cary 17 Spectrophotometer was used to record two of the ultraviolet spectra, and the Varian Aerograph 90-P3 and Series 1200 gas chromatographs were used for glpc work. All mass spectral data can be found in the Appendix. 2-Methy1-3-(lepyrrolidyl)-2-cyclohexene- l-one 60) . The procedure of Coates3“ was used and the product was purified by crystallization from ether, mp 37-39°. Enamino ketones 60, 63, and 73 are deliquescent and air uk/\ v‘ sensitive, so careful handling is necessary. 2,6-Dimethyl-3-(lepyrrolidyl)-2-cyclo- hexene-l-one (73) To a chilled (0°) solution of 0.31 ml (2.2 mmol) of diisopropylamine in 1 m1 of dry tetrahydrofuran (THF) was added 1.0 m1 of a 2.15 M solution of nfbutyl lithium in hexane. The resulting solution of lithium diisopropylamide (LDIA) was stirred at 0° for 30 min before a solution of 358 mg (2.0 mmol) of enamino ketone‘ég‘in 1 m1 of THF was added. 73 74 This enolate solution was stirred at 0° for 30 min, following which 0.15 ml (2.4 mmol) of methyl iodide was added. The resulting mixture was warmed to room tempera- ture, stirred for 15 min, and then diluted with a little water before being concentrated. An ethyl acetate solution of the residue was extracted three times with small amounts of water, and the aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were washed with brine and evaporated to leave 351 mg (91%) of light brown oil which crystallized when chilled. Compound\zg\was also synthesized by treatment of its hydrolysis product, dione\zz, with pyrrolidine. A solution of 96.5 mg (0.5 mmol) of enamino ketone\13‘(prepared as described above) in five drops of 5% hydrochloric acid was heated at 110° for 10 min and then extracted with ethyl acetate. The organic extract was washed with brine and evaporated to give 65 mg of yellow crystals of‘Zl1 A solu- tion of\zz‘in 3 ml of benzene and 0.075 ml of pyrrolidine was refluxed through a Dean Stark trap for 75 min and then concentrated. An nmr spectrum of this crude product was superimposable on that of‘lg‘produced by methylation of‘gg; Several recrystallizations of‘zgfifrom ether gave colorless deliquescent crystals: mp 27-35°; ir (neat) 1540, 1605 cm": nmr (c0013) 51.04 (d, 3H, J 6.5 Hz, C-6 75 pyrrolidine methylenes), 1.86 (s, 3H, C-2 C33), 2.50 (brd t, 2H, C-4 CH2), 3.45 (m, 4H, C-2' and C-5' pyrrolidine :methylenes); uv max (95% EtOH) 317 nm (e 2.63 x 10“). Found: C, 74.66; H,10.01; N, 7.29 2,4—Dimethyl-3-(lepyrrolidyl)-2-cyclo- hexene-l-oneST63T To a solution of 4.6 mmol of LDIA in 2.5 ml of THF at 0° was added a solution of 895 mg (5.0 mmol, 8.7% excess) of\§2‘and 2.5 ml of dry hexamethylphosphoramide (HMPA) in 2.5 ml of THF. The resulting enolate solution was stirred at room temperature for 21 hr and then at 40° for 3 hr. After the solution was cooled to 0°, 0.35 ml (5.6 mmol) of methyl iodide was added, and the mixture was allowed to return to room temperature for 1.5 hr. This mixture was concentrated, diluted with 10 m1 of water, and extracted six times with ethyl acetate, giving 986 mg of yellow oil (contaminated with a little HMPA) on evaporation of the solvent. Column chromatography (silica gel, 10% methanol-ether) of 748 mg of this oil gave 403 mg (63% based on LDIA and normalized to account for material not chromatographed) of light tan oil. Several recrystallizations from ether gave colorless crystals: mp 27-35°; ir (neat) 1540, 1605 cm‘l; nmr (CDC13) 61.20 (d, 3H, J 7H2, C-4 CH3), 1.87 (brd m, 6H, C-5 CEZI C-3' and C-4' pyrrolidine methylenes), 1.91 (s, 3H, 76 C-2 CH5), 2.36 (brd t, 2H, C-6 CH2), 2.55 (brd m, 1H, C-4 CH), 3.56 (m, 4H, C-2' and C-5' pyrrolidine methylenes); uv max (95% EtOH) 323 nm (e 2.63 x 10“). Found: C! 74.56; HI 9.95; NI 7.18 Reaction of\63\with methyl vinyl ketpne To a solution consisting of 0.13 ml of water, 0.13 ml of acetic acid, and 62 mg of sodium acetate was added 0.070 ml of methyl vinyl ketone and 193 mg (1.0 mmol) of égfiin 1 ml of benzene. The mixture was refluxed for 4.5 hr, cooled, diluted with benzene, and extracted four times with 5% hydrochloric acid. The organic phase was washed successively with water, 10% sodium bicarbonate, and brine, and gave 142 mg of yellow oil on concentration. Glpc analysis (5' 4% QF-l, 175°) of this oil revealed three components. Enediones\£4\and\51‘were present in a ratio of about 5:1 respectively. The concentration of the third constituent, trione\§2: diminished greatly in the final product compared to its concentration after only 3 hr of reaction. Both\62\and‘§4\were isolated by preparative glpc (10' 4% QF-l, 190°) and were tentatively identified by their mass and ir spectra. In addition, enedione‘gg‘was synthesized gig methylation of dienol ether\Z§, and both samples of 64 were shown to have the same glpc retention 77 times and ir spectra. Enedione‘57 was identified in the mixture by comparing its glpc retention time with that of an authentic sample. Spectral characteristics for 62 and 64 are given below. V‘ 2,4-Dimethy1-2—(3-oxobuty1)-cyclohexane-l,3*dione (62) ir (c011) 1695, 1720 cm-1; mol wt 210 1,3-Dimethy1bicyclo-I4.4.01-dec-6-ene-2,8-dione (64) ir (001.) 1615, 1675, 1710 cm-1; mol wt 192 Reaction of\13\with methyllvinyl ketOne To a solution consisting of 0.13 ml of water, 0.13 ml of acetic acid, and 62 mg of sodium acetate was added 0.100 ml of methyl vinyl ketone and 215 mg (1.11 mmol) of zgain 1 ml of benzene. The mixture was refluxed for 4 hr and worked up as described in the previous section, giving 179 mg of a yellow oil. Glpc analysis of this oil indicated that only enediones\§4‘and\51‘were present in a ratio of about 5:1. -Dimethylbicyclo-[4.4.0]-dec-6-ene- -dione (64) M To a solution of 0.50 mmol of LDIA in 0.5 ml of THF 1,3 2,8 at -78° was added a solution of 103 mg (0.50 mmol) of dienol ether 78 in 0.7 m1 of THF. The resulting greenish 78 solution was stirred at -78° for 20 min, and then treated with 0.035 ml (0.60 mmol) of methyl iodide. This solution was stirred at —78° for 10 min and at room temperature for 30 min, and then it was diluted with water and ether. The organic phase was washed successively with 5% hydrochloric acid, water, and brine giving 103 mg of methylated dienol ether after evaporation of the solvent. This crude product was hydrolyzed in a solution con— taining 1 m1 of THF, one drop of 6N hydrochloric acid, and several drops of water. After standing for 3 hr at room temperature, the solution was worked up as usual to give 83 mg (87%) of methylated enedione‘ég: Purificationzia. preparative glpc (10' 4% QF—l, 200°) gave a light yellow Oil: ir (neat) 1615, 1670, 1710 cm-l; nmr (coin-mixture of epimers, main peaks are 61.02 (d, 3H, J 6.5 Hz C-3 CH3), 1.41 (s, 3H, C-l CH3), 1.46—3.07 (brd m, 9H, C94, C-5, C-9, C-10 methylenes, C-3 CH), 5.61 (m, 1H, vinyl proton). 8PEthoxy-l-methylbicyclo-[4.4.0]*dec- 5,7-dienee2-one (78) A solution consisting of 35 m1 of benzene, 9 ml (54 mmol) of distilled triethyl orthoformate, 15 mg of pftoluenesulfonic acid (PTSA), and 8.9 g (50 mmol) of Wieland—Miescher ketone\§§‘wasstirred at room temperature for 4 hr. Analysis by glpc indicated complete conversion of 56 to a new product. M 79 The reaction mixture was neutralized with three drops of triethylamine, diluted with 35 m1 of ether, and extracted successively with 15 m1 of 10% sodium bicarbonate, 20 ml of water, and 20 m1 of brine. Evaporation of the solvents left a yellow oil, which could be used without further purification or crystallized from ether, mp 39-43°. 5-Dibromomethylene-l-methylbicyc1owl4t4.Q17 dec-6-ene-2,8-dione (85) A solution containing 618 mg (3.0 mmol) of dienol ether‘sz 2.00 g (6.0 mmol) of carbon tetrabromide, 3 ml of pyridine, and 3 ml of dioxane was maintained at room temper- ature for 24 hr and then heated at 45° for 24 hr. The resulting dark solution was filtered to remove the crystalline pyridinium hydrobromide-carbon tetrabromide complex, and the filtrate was concentrated, acidified, and extracted with ethyl acetate. The organic extract was washed three times with 6N hydrochloric acid to remove colored impurities and then with 10% sodium bicarbonate and brine. Evaporation of solvents gave 954 mg of a brown semisolid which was chromatographed (silica gel, ether) to yield 514 mg (50%) of brown\8§: Several recrystallizations from methylene chloride-ether gave white crystals: mp 85-86°, ir (KBr) 1565, 1610, 1665, 1720 cm‘l; nmr (CDCla) 61.36 (s, 3H, CH3), 1.87-2.84 (m, 8H, C-3, C-4, C-9, C-10 methylenes), 6.25 (s, 1H, vinyl proton); uv max (95% EtOH) 260 nm (shoulder) (a 5,700), 287 nm (6 7,600). 80 Anal. C31Cd for C12H12Br202: C, 41.41; H, 3.48 Found: C, 41.44; H, 3.38 1,5-Dimethy1bicyclo-[4.4.0]-dec-6-ene- 2,8-dione 57) To a suspension of 800 mg of 2% Pd/SrC03 catalySt (saturated with hydrogen) in 6 ml of dry THF was added a solution of 1.740 g (5.0 mmol) of‘gé‘and 1.4 ml (10 mmol) of triethylamine in 8 ml of THF. The suspension was stirred vigorously and allowed to absorb 376 ml (15.0 mmol) of hydrogen at atmospheric pressure. After filtration, the catalyst was washed well with THF, and the filtrate was concentrated. An ether solution of the residue was extracted with water and brine and evaporated to give 987 mg of a yellow oil which was chroma- tographed (silica gel, 30% ethyl acetate-hexane). The fractions containing\52\were evaporated, leaving 312 mg (32%) of a light yellow oil. An nmr spectrum of this product showed that it was a mixture of epimers. The more stable equatorial methyl epimer could be isolated after equilibration of the product in a carbon tetrachloride solution containing gaseous hydrogen chloride. Recrystallization of the equilibrated product from ether-petroleum ether solution gave white- needles: mp 28-34°, ir (KBr) 1605, 1665, 1710 cm-1; nmr (cc1.) 61.18 (d, 3H, J 6.5 Hz, c-5 egg), 1.39 (s, 3H, c-1 81 CH3), 1.50-2.90 (m, 9H, C-3, C-4, C-9, C-10 methylenes and C-5 CH), 5.60 (d, 1H, J 2 Hz, vinyl proton). Found: C, 74.83; H. 8.31 l-Meth 1bicyclo-[4.4.0]-dec-5-ene-2,8- dione-8-ethy1ene ketal (a) A solution of 356 mg (2.0 mmol) of\2§\and 10 mg of PTSA in 5 ml of 2-ethy1-2-methyl-l,3-dioxolane (HZ) was distilled (bp 68-80°) slowly for 2 hr to remove methyl ethyl ketone. 'The cooled solution was diluted with 5 m1 of ben- zene and extracted twice with 10% sodium bicarbonate and once with brine. Evaporation of the solvents left 430 mg of a yellow oil which, when crystallized from ether- petroleum ether, gave 191 mg (43%) of ketal‘g: Recrystal- lization from the same solvent mixture produced white needles, mp 68-70° (litaz mp 63-64.5°). The ir and nmr spectra agree with those reported32 for\3§ 1,5-Dimethy1bicyclo-[4.4.01-dec-5-ene- 2,8-dione-8-ethylene ketal (58) \,~ A solution-of 515 mg (2.68 mmol) of enedione 57 and 12 mg of PTSA in 5 m1 of 87 was refluxed for 11 min (dura- tion of reflux is critical). The solution was cooled, stirred for 10 min with ten drops of 10% sodium bicarbonate, and diluted with 5 m1 of ether. 82 The ether solution was washed with water and brine, and, after concentration, yielded 633 mg of an orange oil. Crystallization of this oil from ether afforded 318 mg of \ng The mother liquors were purified by preparative thick layer chromatography (silica gel, 60% ether—petroleum ether) and yielded an additional 110 mg of\§§\for a total yield of 68%. Recrystallization from ether gave colorless needles: mp 86-88°, ir (KBr) 1710 cm'l; nmr (CClu) 61.18 (s, 3H, C—l, CH3), 1.60 (m, 7H, C-5 CH3, C-9 and C-10 methylenes), 2.30 (m, 6H, C-2, C-3, and C-7 methylenes), 3.79 (s, 4H, dioxolane methylenes), uv max (95% EtOH) 290 nm (e 30). Anal. Calcd for Clquooat C, 71.16; H, 8.53 Found: C, 71.04; H, 8.68 Photolysis of 1-methylbicyc10914.4.Oledec— S—ene-ZJ8-dione—8-ethylene.keta£H_ and 1,5-dimethylbicyclo—I4.4.0]-dec-5-ene- . 2,8-dione-8-ethylene ketal (58) M General Procedure: Except as noted, all photolyses were conducted using a 500-W medium pressure Hanovia lamp suspended in a water cooled quartz housing and fitted with a Corex filter. Solutions of ketals\g~and‘ig\in spectral grade solvents were placed in quartz test tubes and degassed by bubbling nitro- gen through them for about 10 min. After sealing with a rubber septum, the test tubes were affixed to the side of 83 the quartz housing, and the apparatus was partially im- mersed in an ice water bath. At specified intervals during irradiation, samples were removed from the test tubes and analyzed by glpc, using a 6 ft 4% SE-30 column at 130-150°. Preparation of 4-methyl-3-viny1-3-cyclo- hexene-l-one ethylene ketal (ngiand 4-methyl-3-cyc19propyl-3-cyclohexene-l- one ethylene ketal £31) A total of 9 ml of a 0.05 M solution ofkg‘in benzene was irradiated for 2 hr and then concentrated. Compounds \gg\and\gl‘were collected by glpc (10' 4% SE-30, 160°) as colorless liquids, having spectral data as follows. 39: ir (neat) 1590, 1635 cm'l; nmr (coin 61.67 (t sub- merged under other signals, 2H, C-6 CH;), 1.80 (s, 3H, C-4 CH3), 2.26 (m, 4H, C-2 and C-5 methylenes), 3.93 (s, 4H, dioxolane methylenes), 4.98 (overlapping d of d, 2H, C=CH;), 6.76 (d of d, 1H, J 17 Hz, J 18 Hz, CHfCHz). 5221' Calcd for C11H1502: C, 73.30; H, 8.95 Found: C, 73.33; H, 8.90 91: nmr (CClu) 60.43 (m, 4H, cyclopropane methylenes), 160 (m, 5H, cyclopropane CH, C-2 and C-6 methylenes), 1.77 (s, 3H, C-4 CH3), 2.10 (brd t, 2H, C-5 CH;), 3.86 (s, 4H, dioxolane methylenes). Found: C, 74.13; H, 9.42 84 Preparation.of 4-methyl-3-(2-oxocyclobutyl)- 3-cyclohexene-1-one ethylene ketal (89) A 0.10 M solution of\3‘in benzene (5 ml) was irradi- ated for 90 min and then concentrated. Preparative glpc (5' 4% QF-l, 160°) afforded\Hg‘as a light yellow oil: ir (neat) 1770 cm“; nmr (001.) 61.60 (m, 5H, 0-4 0H3, C-6 ng), 2.17 (m, 6H, C-2, C-5, and C-4' [cyclobutanone ring] methylenes), 2.87 (m, 2H, COCHg), 3.78 (s, 4H, dioxolane methylenes), 4.17 (t, 1H, J 9 Hz, C-l' COCH). Anal. Calcd for C13H1303: C, 70.24; H, 8.16 Found: C, 70.05; H, 8.22 Photolysis of\3.with a.mercury resonance lamp Two 15-W fluorescent lamps producing greater than 99% of their light at 253.7 nm were situated so as to face each other a few inches apart. Quartz test tubes containing 1 ml of a 0.05 M solution of ketal\;‘in benzene or ether was positioned between the lamps. The course of the photolysis was monitored by glpc at varying intervals for 4 hr. No starting material remained in the slightly yellow benzene solution, and substantial amounts of nonvolatile materials were detected by tlc (silica gel, 2:1 ether-petroleum ether). Glpc analysis indicated that the initial rate of disappearance of\g‘was about four times faster in benzene than in ether solution and that diene 90 was absent in the ether solution, although 85 89 and,9l were produced (after 4 hr the ratio ofm’:H~ggl was 1.5:l.3:1). Photolysis of‘3_in acetone A 0.05 M solution of‘3~in acetone (3 ml) was irradi- ated by the Hanovia lamp for 9.5 hr. Glpc analysis at the end of this time showed about equal amounts of‘g‘and\HH, a smaller amount of cyclopropane\2}, and only a trace of diene\294 Much polar, nonvolatile material was evident by tlc. Photolysis of‘3_in the presence of 1,35pentadiene The rate of disappearance of\g was compared for 0.05 M solutions of\;‘(absorbance at 290 nm is about 1.5) in benzene and ether, both with and without added 1,3-penta- diene (2 M, absorbance at 290 nm is about 0.3). The rate of consumption of starting material was reduced by a factor of five in ether, and a factor of two in benzene, by photolysis in the presence of piperylene. Photolysis of\3‘with added internal standard Known quantities of the pure products 90 and 91 were mixed with known amounts of pure dodecane (C12H26, mol wt 170.33), and the relative peak areas of the standard and each product were determined via glpc (5' 4% SE-30, 140°). 86 A solution of 11.1 mg (0.050 mmol) of‘gaand 5.15 mg of dodecane in 1 m1 of benzene was irradiated until only‘gg‘ and\21‘remained.' The peak areas of these two products were compared with the peak area of the added standard, and the molar amounts of each product were calculated. For two trials the combined amounts of\gg~and\gl\were 5.01 and 4.90 x 10“2 mmol. Within experimental error, products\gg‘ and 91 account for all 5.0 x 10'2 mmol of starting material. Photolysis of 58 in benzene solution A total of 10 ml of a 0.05 M solution of 58 in benzene was irradiated for 50 min, concentrated, and then chroma- tographed of a 2 mm layer of silica gel (30% ether-petroleum ether) to give the following amounts of products: a 1:1 mixture of diene 96 and cyclopropane 97, 25 mg; cyclo- butanone 95, 23.5 mg; recovered 58, 28.5 mg; a nonvolatile M % mixture, 23 mg. ' t The mixture of 96 and 97 was separated by glpc (10 4% QF-l, 138°) to afford these two products as colorless liquids. Cyclobutanone 95 was rechromatographed and ob- tained as a yellowish oil. The mixture of nonvolatile compounds was found by glpc analysis to contain small amounts of three or four unidentified volatile components (thermal degradation products?). Characteristics of 95, 96, and 97 k” \m x» are given below. 87 -Methy1-3-(1-metHyl-2-oxocyclobutyl)- -cyclohexene-l-one ethylene ketal (95) :1 3 Light yellow oil: ir (neat) 1765 cm'l; nmr (CClu) 61.28 (8, 3H, C-l' COCCHg), 1.57 (m, 5H, C-4 C=CCH3, C‘6 CH2), 2.03 (m, 6H, C-2, C-5, and C-4' [cyclobutanone ring] methylenes), 2.86 (t, 2H, J 8 Hz, COCHz), 3.81 (s, 4H, dioxolane methylenes). Anal. Calcd for 011H2003: C, 71.16; H, 8.53 Found: C, 71.15; H, 8.60 4-Methyl-3-(2:propenyl)-3-cyclohexene-l- one ethylene ketal (96) KA Colorless liquid: ir (neat) 1630 cm‘l; nmr (CCLu) 61.60 (S, 3H, CH2=C-C§3), 1.63 (m, 2H, C-6 Cflz), 1.70 (s, 3H, C-4 CH3), 2.08 (m, 4H, C-2, C-5 methylenes), 3.80 (s, 4H, dioxolane methylenes), 4.18 (s, 1H, vinyl proton E£22§.t° ring), 4.78 (s, 1H, vinyl proton gig to ring). Anal. Calcd for C12H1302: C, 74.19; H, 9.34 Found: C, 74.03; H, 9.33 4-Methy1-3-(l-methylcyclopropyl)-3-cyclo- hexene-l-one ethylene ketal (97) Colorless liquid: nmr (CClu) 60.38 (m, 4H, cyclo- propane methylenes), 1.03 (s, 3H, cyclopropane CH3), 1.55 (m, 2H, C-6 CH2), 1.68 (s, 3H, C-4 CH3), 1.97 (m, 4H, C-2, C-5 methylenes), 3.78 (s, 4H, dioxolane methylenes). Anal. Calcd for C13H2002: C, 74.96; H, 9.68 Found: C, 75.08; H, 9.65 88 Photolysis of 58 in acetone k/x After irradiation of 0.5 m1 of a 0.05 M acetone solu- tion of 58 for 5.5 hr, glpc analysis showed the presence of six or seven new products in addition to the usual photoproducts and starting material. The new materials constituted at least half of the total volatile product. Photolysis of 58 in the presence of 1,3- pentadiene K’”‘ Conditions and results for the quenched photolysis of \Hgain benzene were the same as those described earlier for ketal ‘2‘ APPENDIX 89 100 3 S 8 TRANSMITTANCE(%) N O 0 ' , I . V 4000 3500 3000 2500 2000 l 500 ”I! OU‘NCV TRANSMITTANCE(%) 1800 1600 1400 1200 1000 800 IIIOHINCV KM II Figure 22. Infrared spectrum of 2,6—dimethyl—3-(l—pyrrolidyl)- 2-cyclohexene—l—one (73). Va 90 100 :::‘,3 7' 4 7. I e41 —« m o .1”. L 1 .7 0 C TRANSMITTANCE(%) 1 .. 1..-...1-i_._. _ I 1 =21 . ' ' _ I}- .. 11-....7.-.i-.e.'.-,_?..111---“ _.:_..-. ..i 7 1H” *I . " 77 II 40 7,; +~4«— 7-1111- U -I w - - we 1 7 ;~ ~;-hfq 4o ._ 771;} 7 . . . . . . - 7 7 7‘ 7. 7" ”“1--. -- . 7 I , 1-.- _- .. . g ‘7“ I ' '1 ! N f 1 . i 1 20 --;~-+-—+~~I——I --I 7 O 7- —» -- -;---:- ., - 20 —-7-; III : 7+ ~—;--+- ------ +7 7-.. - “7‘: 7 7 -r--7-~;~-1Ur *'-i-7- . - ' 7 7 I i 2 f 7 I 1 1 I I I 1 I ' 4000 3500 3000 2500 2000 1500 IRWJUIva |(M '1 100 100 80 a) O 60 40 TRANSMITTANCE(%) & O 20 M O 0 2000 1800 1600 1400 1200 1000 800 ”"0111 NLV I‘ M 'I Figure 23. 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I IIIWN .I II .r: IIII.~ ..-»-.o..IIWIdfl..IIIII-.1 ,_ - . . .f . ... I... . . . _ . . _ ..-. . . -.. . .. . ..... . ... . ,_ . , u. . I . ..I . p ..I M _. I; _ II I w I LI I I“... IIII. TI. . . » IIII. H _ -..:- .. o 3 .m .u . .. . a . n I u .+ A .. . .. ..;: .... .. .m 4 .. u H _ .. u _ ... . _ g .9 IIIJI III .I Ij I I. {..3 I III 14.1II . o I IIv.- IIII.I I III... III . Ila: o-I II 1% i u . .3 . . . . . . . _ u .. . .. . I I I i '. I .- '1 I I I , I --.;-‘...J...- " c—oc} -. . . g, . m m m . m m .. . o I .I I .II I . .IW.I.IHII..LII. IlIrI-I VIII .u hIIp . - I, -I..L..v°6 _ .Mf _ . a . _ . ..... - .m.“a “L...-- o - III-...... ...-IS _ _ . o . . . . , . . 1 . _ . . . . . .. ; _ .--.TIT if-.- I. -..-.-..-I +-?II . ...I. , ....--I. ..-..I- ..:-II. I m _ . . o - m _ ...... I . . ...-4‘--—Q-—-o 0 . a . _ . . . m . _ .y . H . . u H h... .-. v _ .0 r. . . ...:..rfl . . _ . ,. . . H . w . 5 w . L m . . , . . xeea 3323 30 abaquaozaa BIBLIOGRAPHY 10. ll. 12. 13. BIBLIOGRAPHY K. L. 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