SYNTRESIES Aflfi AC LE CATALYZED REA RRARGEMEMT @F M GHQ“ 52$..BESI'EWTEB F: {CYCLG' ($2.25.) OCIA- 5 , '1’ . D iEN - 2. .. 0L3 Tit-tests {fort- {’{m Deqm 3% M . 5. iifiCRlGAN STATE L‘RWEBSEEY Tsuyoghi Kakihama 1966 v7 u“. 2-” ¥ r' LIBRARY ’QTHESIS Michigan State University ABSTRACT SYNTHESIS AND ACID CATALYZED REARRANGEMENT OF HIGHLY SUBSTITUTED BICYCLO[2.2.2]OCTA-5,7-DIEN-2-OLS by Tsuyoshi Kakihana The purpose of this investigation was to synthesize func- tional derivatives of bicyclo[2.2.2]octa-2,5,7-triene ("barrelene") (2). The following scheme was proposed as a route to the desired barrelene derivatives. V R1 H . 2 ‘:TL + R3CECR4'————> AEZ;}//’ 4 \ / R2 R/ R3 R1, R2 = CH3 R3, R4 = "COOCH3 or or R1, R2 = H R3, R4 = ‘CsHS or R3CECR4 = benzyne reductionL acid (OCH /R ——.fi-r—3-> 2 . R4 _ R1 R3 Although this route to barrelenes has thus far been un- successful, various stages of the synthesis have worked Tsuyoshi Kakihana depending on the nature of R groups and a study of these intermediates has led to some unusual rearrangements and bi— and tricyclic systems. Diels-Alder reaction of 3,4,6,6-tetramethylcyclohexa- 2,4-dienone (5) and dimethyl acetylenedicarboxylate gave 3,3,7,8-tetramethyl-5,6-dicarbomethoxybicyclo[2.2.2]octa-5,7- dien-Z-one, 1. 1,5,5,4,7,8-Hexamethyl—5,6-dicarbomethoxybi- cyclo[2.2.2]octa-S,7-dien-2-one, 2, was obtained in a simi- lar manner from 2,3,4,5,6,6-hexamethylcyclohexa-2,4—dienone (4) and dimethyl acetylenedicarboxylate. The reduction of 2 with 1. R1, R2 =H 2. R1, R2 '— l O m w sodium borohydride, lithium borohydride or lithium aluminum hydride gave 1,5,5,4,7,8-hexamethyl-5,6-dicarbomethoxybi- cyclo[2.2.2]octa-5,7-dien-2-ol, 3, dimethyl 2,3,4,5-tetra- methylphthalate, 4 and tetramethylphthalide, 5. XII OOCH3 LiAlH COOCH3 + O, \o /‘ OOCH3 \COOCH3 \ / CH2 2 4 5 Tsuyoshi Kakihana + 7 / Acme, v—‘COOCHg Treatment of 1,5,5,4,7,8-hexamethyl-5,6-benzobicyclo[2.2.2]- octa-5,7-dien-2-ol, 6 (mixture of epimers, a and b) and 1,3,3,4,7,8-hexamethyl-5,6-diphenylbicyclo[2.2.2]octa-5,7- dien-Z-ol, 7 with sodium hydride in dimethylsulfoxide gave 1,2,5,4-tetramethylnaphthalene, 8 and 2,3,4,5-tetramethyl- 1,2-diphenylbenzene, 9, respectively. The mechanism of H \ OH Li. / / NaH/dimethylsulfoxidea 0c 6 8 RE J A7’C6H5 NaH in dimethylsulfoxideL r \\// ‘ CGHS ‘CsHs /\ CeHS 7 9 formation of these aromatic compounds is probably the abstraction of hydroxylic protons from 6 and 7, and subsequent re- arrangement of the resultant alkoxides. It was assumed that aromatization of 2 follows an analogous route involving an Tsuyoshi Kakihana intermediate complex. Diels—Alder reaction of 2,3,4,5,6,6- hexamethylcyclohexa-2,4-dien-2-one (4) and diphenylacetylene gave 1,3,5,4,7,8-hexamethyl-5,6-diphenylbicyclo[2.2.2]octa- 5,7-dien-2-one, 10. Compound 10 was isomerized to 1,5,4,5,8,8- hexamethyl-B,7-diphenylbicyclo[5.2.1]octa-5,6—dien-2-one, 11, when treated with acid. Reduction of 10 with lithium aluminum \ O\ 65 v 6 J ”H CsHs —+‘” ”4.6% \CsHs 10 11 / H .22 ,,C6H5 + 6H5 // / \CeHs ———>H / Q CBHS 7 12 hydride gave 1,5,3,4,7,8-hexamethyl-S,6-diphenylbicyclol2.2.2]- octa-S,7-dien-2-ol, 7. Acid treatment of 7 gave 2-methylene- 5,6,7,8,8-pentamethyl-5,4-diphenylbicyclo[5.2.1]octa-5,6-diene, 12. Reaction of 2,3,4,5,6,6-hexamethylcyclohexa-2,4-dienone (4) and 5,4,6,6-tetramethylcyclohexa-2,4-dienone (5) with benzyne generated by the reaction of anthranilic acid and isoamyl nitrite (9) gave 1,5,5,4,7,8-hexamethyl—5,6-benzobi- cyclo[2.2.2]octa-5,7-dien-2-one, 13, and 5,5,7,8-tetramethyl— bicyclo[2.2.2]octa-5,7—dien-2-one, 14, reSpectively. Tsuyoshi Kakihana Reduction of 15 and 14 gave the correSponding alcohols, 6 (isomers, a and b), and 15 (isomers, a and b). Qualitative determination of the orientation of hydroxyl groups of these H\ng (113 /H R \i/ 15. R1, R2 = CH3 major isomer minor isomer 6a. R1, R2 = CH3 6b. R1,R2 = CH3 14:. R11 R2 _ H 15a. R1, R2 = H 15b. RlIR2 = H isomeric alcohols was made by an nmr study of these alcohols and 5,5-dimethyl-5,6-benzobicyclo[2.2.2]octa—5,7-dien-2-ol, 16 (a and b). Treatment of 6 (a,b) with concentrated sulfuric \/ H ,DH OH \ fl 16a Q 16b {3 acid gave 1,4,5,6,7,8-hexamethyl-2,3-benzobicyclo[5.5.0.0]— octa-2,5-diene, 17. Acid treatment of 15(a,b) lead to the formation of 3,4-benzo—6-methylene-7,8,8-trimethyltricyclo- [5.2.1.0]octane, 18. SYNTHESIS AND ACID CATALYZED REARRANGEMENT OF HIGHLY SUBSTITUTED BICYCLO[2.2.2]OCTA-5,7-DIEN-2-OLS BY Tsuyoshi Kakihana A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1966 ACKNOWLEDGEMENT The author wishes to express his sincere appreci- ation to Professor Harold Hart for his guidance and understanding during the course of this investigation. Appreciation is extended to the United States Civil Administration of the Ryukyu Islands for providing financial assistance from July, 1963 through June, 1965, and to Michigan State University for offering a graduate assistantship during the academic year 1966. The author is also grateful to Mr. Michael Gross for the operation of Varian Associates, HA-1OO and DA-60-I nuclear magnetic Spectrometer and interpretation of some nmr Spectra, and to Mr. Roger K. Murray, Jr. for his kind assistance and advice in writing this thesis. ii TABLE OF CONTENTS Page INTRODUCTION . 1 RESULTS AND DISCUSSION . PART A Synthesis of 1,5,5,4,7,8-hexamethyl-5,6-dicarbo- methoxybicyclo[2.2.2]octa-5,7-dien-2-one, V and 5,5,7,8-tetramethyl-5,6-dicarbomethoxy- bicyclo[2.2.2]octa-5,7-dien-2-one, VI. 4 Abnormal reduction of 1,5,5,4,7,8-hexamethyl—5,6- dicarbomethoxybicyclo[2.2.2]octa-5,7-dien-2- one, V . 6 Mechanism for Formation of Aromatic Product(s) in Reduction of V . 9 PART B Synthesis of Benzo and Diphenyl Substituted Bicyclo[2.2.2]octadienones . 14 Acid Catalyzed Isomerization of 1,3,5,4,7,8-Hexa- methyl-5,6-dipheny1bicyclo[2.2.2]octa-5,7- dien-2-one, XV . 18 1,5,5,4,7,8-Hexamethyl-5,6-diphenylbicyclo- [2.2.2]octa-5,7-dien-2-ol, XXI . 2O 1,3,3,4,7,8-Hexamethyl-5,6-benzobicyclo[2.2.2]- octa-5,7-dien-2-ol (epimers XXIIE and XXIIb) . 21 3,3,7,8-Tetramethyl-5,6-benzobicyclo[2.2.2]octa- 5,7—dien-2-ol (XXIIIa and XXIIIb). 22 3,5-Dimethyl-5,6-benzobicyclo[2.2.2]octa-5,7- dien-2-ol (XXIVa and XXIVb) and Qualitative Determination of the Orientation of the Hydroxyl Group in the Reduction Products of XVI, XVII and XVIII. 25 iii TABLE OF CONTENTS - Continued Page The Preparation of 6,7,8,8-Tetramethyl-2- trifluorocarbomethoxy-S,4-benzobicyclo- [5.2.1]octa-5,6-diene, XXV. 25 The Preparation of 2-Methylene-5,6,7,8,8-penta— methyl-3,4-diphenylbicyclo[5.2.1]octadiene, XXVII . 26 The Preparation of 5,4-Benzo-6—methylene—7,8,8— trimethyltricyclo[5.2.1.0]octane, XXXI. 29 1,4,5,6,7,8-Hexamethyl-2,5-benzotricyclo- [3.5.0.0]octa—2,5-diene, XXXV . 31 EXPERIMENTAL. 58 A. 1,5,5,4,7,8-Hexamethyl-5,6—dicarbomethoxy- bicyclo[2.2.2]octa-5,7—dien-1-one, V. 58 5,5,7,8—Tetramethyl—5,6-dicarbomethoxybi- cyclo[2.2.2]octa-5,7-dien-2-one, VI . 59 5,5,7,8-Tetramethyl-5,6-dicarbomethoxybi- cyclo[2.2.2]octa-5,7-dien-2-ketoxime. 4O Reduction of VI with Sodium Borohydride . 4O Reduction of V with Lithium Borohydride . 41 Reduction of V with Lithium Aluminum Hydride. 42 5,4,5,6-Tetramethyl-1,2-diphenyl benzene, XV. 42 1,2,5,4-Tetramethylnaphthalene, XII . 45 Attempted Isolation of Isobutyraldehyde from the Crude Solid Obtained in Section H . 44 1,5,5,4,7,8-Hexamethyl-5,6—benzobicyclo[2.2.2]- OCta-S, 7-dien-2-One, XVI. o o o o o o o o o 0 44 K. Reduction of XVI with Lithium Aluminum Hydride L. Treatment of XXII(a,b) with Trifluoroacetic ACid. C O O C . O C . O C O O O C . C O . 46 iv TABLE OF CONTENTS - Continued Page M. 1,4,5,6,7,8—Hexamethyl—2,3-benzotricyclo— [5.5.0.0]octa-2,6—diene, XXXV. 47 N. 1,5,3,4,7,8-Hexamethyl-5,6-diphenylbicyclo- [2.2.2]octa—5,7-dien-2—one, XV . 48 0. Reduction of XV with Lithium Aluminum Hydride. 49 P. Acid Catalyzed Isomerization of XV . 49 Q. 2-Methylene-5,6,7,8,8-Pentamethyl-5,4-di- phenylbicyclo[5.2.1]octa-5,6-diene, XXVII.