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Xerox University Microfilms, Ann Arbor, Michigan 48106 77-2404 GILBERT3 David Philip, 1949- THE SYNTHESIS OF 2,3-DISUBSTITUTED INDOLES. The Ohio State University, Ph.D., 1976 Chemistry, organic Xerox University Microfilms,Ann Arbor, Michigan 48106 THE SYNTHESIS OF 2,3-DISUBSTITUTED INDOLES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By David P. G ilbert, B.S. * * * * The Ohio State University 1976 Reading Committee: Approved by Professor Paul G. Gassman Professor John A. Secrist, III Professor John S. Swenton / <.2 cast? j Adviser Department of Chemistry To Cynthia ACKNOWLEDGMENTS The author wishes to thank Dr. Paul G. Gassman for the ideas he has given during this project. His friendship, support, and suggestions have been greatly appreciated. Special thanks also go to Mr. Richard C. Howard, who provided an early insight into science. The author also thanks his coworkers for their help and cooperation. The author is especially grateful for the assistance and never ending encouragement of both his and his wife's families. The author is continually amazed by his wife's love, assistance, patience, and sacrifice. Without Cynthia, this work would not have been possible. iii VITA May 1 , 1949 .......................................................Born, Schenectady, New York 1971 ................................................................... ..B.S. in Chemistry, Hobart College 1971-1972 ...........................................................Teaching A ssistant, The Ohio State University 1972-197 4 ...........................................................Research Assistant, The Ohio State University 1974-1976 ...........................................................Research Assistant, University of Minnesota PUBLICATIONS P.G. Gassman, D.P. Gilbert, and T.J. van Bergen, Chem. Commun., 201 (1974). P.G. Gassman, T.J. van Bergen, D.P. Gilbert, and B.W. Cue, J r ., J. Amer. Chem. Soo., 96, 5495 (1974). J.H.M. Hill, D.P. Gilbert, and A. Feldsott, J. Ovg. Chem., 40, 3735 (1975). FIELDS OF STUDY Major field : Organic Chemistry iv TABLE OF CONTENTS Section Page ACKNOWLEDGMENTS-------------------------- ------------ iii VITA--------------- iv LIST OF TABLES------------------------------------- ix INTRODUCTION----------------------------------------------------- - . — 1 RESULTS AND DISCUSSION------------------ 21 PART I. Synthesis of 2,3-Disubstituted Indoles --------------------------- 21 PART II. Alkaloid Synthesis ------------------------------------------------------------- 43 EXPERIMENTAL ---------- 6 6 General Procedure for the Preparation of 2,3-Disubstituted In d o le s ----------------------------------------------------------------------------------------------- 6 6 3-Bromo-2-butanone (62)r\y\j -------------------------------------------------------------------- 67 3-Methylthio-2-butanone (53Ja) -------------------------------------------------------- 67 2 ,3-Dimethyl indole (61 b ) ---------------------------------------------------- 6 8 ^ OA/VU 2-Bromo-3-pentanone (63) ------------- 69 2-Methylthio-3-pentanone (53^) ------------------------------------------------------ 70 2-Ethyl-3-methyl indole (61^) ------------------------------------------------- 70 3-Bromo-2-pentanone (64) ------------------------------------------------------------------ 71 3-Methylthio-2-pentanone (53^d) ------------------------------------------------------ 72 3-Ethyl-2-methylindole (b^d) ---------------------------------------------------------- 73 4-Methyl-3-methylthio-2-pentanone (53js) --------------------------------------- 73 3-Isopropyl-2-methylindole (61^e) --------------------------------------------------- 74 v Section Page 1-Chloro-1-phenyl-2-propanone ( 6 6 ) --------------------------------------------------- 75 1 -Methyl thio-l -phenyl -2-propanone (53^) ------------------------------------------75 2-Methyl-3-phenylindole (5 H ) ----------------------------------------------------------- 76 1-il/-Ani lino-1-methyl thi o-l-phenyl-2-propanone (72MO ----------------------77 a-Methylthiopropiophenone (53^) ------------- 78 3-Methyl-2-phenylindole (61^) ------------------------------------------------------------78 a-Methylthiobutyrophenone (53Ji) ------------------------------------------------------ 78 3-Ethyl-2-phenyl indole (jBTJi) ------------------------------------------------------------- 79 3-Methyl-2-phenylindole by Chlorine-Sulfide Complex (61^cj) ----------- 80 3-Methylthio-3-buten-2-one (98 d) ---------------------------------------------------- 82 3-Ethyl-2-methyl indole by the Chlorine-Sulfide Complex (j51^d) — 82 Tetrahydrocarbazole (78) by the Chlorine-Sulfide Complex --------------- 83 2-Methyloxindole ( 6 8 ) ---------------------------------------------------------------------------85 Methyl 4-Methylthioacetoacetate (85^) ----------------------------------------------85 Methyl 2-(3-Methyl thioindolyl)acetate ( 8 6 ^ ) ----------------------------------- 87 Methyl 2-Indolylacetate (8£,j0 -------------------------------------- 87 Ethyl 4-Methylthioacetoacetate (85Jb) --------------------------------------------- 8 8 Ethyl 2-(3-Methyl thioindolyl )acetate (8J5J)) ------------------------------------- 8 8 Ethyl 2-Indolylacetate ( 8 ^ 0 ------------------------------------------------------------- 89 Methyl 2-Methylacetoacetate ( 8 8 ) ------------------------------------------------------ 89 Methyl 2-Methyl-4-methylthioacetoacetate (89) ------------------------------- 90 Methyl a-Methyl-2-(3-methylthioindolyl)acetate (90) --------------------- 90 Methyl a-Methyl-2-indolylacetate (91^) ----------------------------------------------- 91 vi Section Page Ethyl 4-Methylthiobutyroacetate (92) ----------------------------------------------- 91 'VO y-(l-Butenyl)pi peridine (111) -------------------------------------------------------------92 VXAi 4-Formylcapronitrile (112) ---------------------------------------------------------------93 r\y\Aj 4-Formylcapronitrile-1,3-dioxolane (113) ---------------------------------------- 93 'WO 1-Benzyl-3-ethyl-1,4,5, 6 -tetrahydropyridine (114) ------------------------- 94 'O'O'O l-Benzyl-4a-ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (1 0 4 )------------ 94 'WO 4a-Ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quinolone (115) --------- 94 VIA) W-Ch1oroacetyl-4a-ethyl-2,3,4,4a,5,6,8,8a-octahydro-7(lH)-quin- olone (116) ---------------------------------------------------------- 95 o/vo 6 a-Ethy1-4,5, 6 , 6 a ,7,8,9a ,9b-octahydro-9H-pyrrolo[3,2,1-ij]-qui n- olin-2,9(lH)-dione (117) -------------------------------- 95 x ' ‘W O 6 a-Ethyl-l,2,4, 6 , 6 a,7,8,9a,9b-decahydro-9H-pyrrolo[3,2,1-ij]- quinolin-9-one (120) --------------------------------------------------------------------- — 96 n m Ethylene Ketal of Methyl 4-Methyl thioacetoacetate (,124). -----------------97 Ethylene Ketal of 1-Methylthio-4-hydroxy-2-butanone (125) ----------- 97 'WO 1-Methylthio-4-hydroxy-2-butanone (126)'WO ------------------------------------------ 98 1-Methylthio-3-buten-2-one (,123) ------------------------------------------------------ 99 1-Benzyl-4a-ethyl- 8 -methylthi o-2,3,4,4a,5,6, 8 ,8a-octahydro-7- (IH)-quinolone (105) ---------------------------------------- 100 4-Ethyl-2-methylthio-4-(N-benzyl-3-ami nopropyl)-2-cyclohexen-l - one (124) ------------------------------------------------------------------ - 100 'WO 5-(N-carboethoxyamino)-2-ethylperitanal-l ,3-dioxalane (1^28) ----------101 5-(N-Methyl ami no)-2-ethyl pentanal-1,3-dioxalane (1^29) ------------------ 102 1-Methyl=3-ethylrl,4,5, 6 -tetrahydropyridine (V30) ----------------------- 103 vii Section Page 4a-Ethy1-1-methyl- 8 -methylthi o-2,3,4,4a,5, 6 ,8,8a-octahydro-7- (lH)-quinolone ) -----------------------------------------------------------------------104 trans-8,10-Dimethyl-1(9)-octal-2-one (,134) ----------------------------------- 104 8,10-Dimethyl-1-methylthio-2-decalone (,133) --------------------------------- 105 3-Methyl -2-methyl thiocyclohexanone (53^) -------------------------------------106 Methyl 4-Methyl thi obutyroacetate (53^) ---------------------------------------- 107 General Procedure for the Preparation of Aniline Azasulfonium Salts for NMR Examination ----------------------------------------------------------------- 108 Preparation of the Aniline Azasulfonium Salt 54 b via the Chloro- sulfonium Salt of 53 b ---------------------------------------------------------------------- 108 W \A; LIST OF REFERENCES ---------------------------------------------------------------- --------------------1 1 1 APPENDIX---------------------------------------------------- -------------------------------------------------118 LIST OF TABLES Table Page I. Yields of Indoles from a-Methylthioketones and Substi­ tuted Anilines 16 II. Yields of 2,3-Disubstituted Indoles (61 b-h) Based on Starting Aniline ----------------------------------------------------------------------------- 28 III. NMR Data of the Anil in -. Azasulfonium S a l t s -----------------------------------61 IV. Experimental Conditions for the Preparation of Aniline Azasulfonium Salts ------------------------------------------------------------------------- 109 ix INTRODUCTION Organic chemists have long recognized the significance of carbonium ions (1) in modern organic chemistry. These trivalent electron defi- '1/ cient species and their reactions have been extensively studied under a variety of conditions and applications. Surprisingly, the nitrogen ana­ logue of 1 , the nitrenium ion ( 2 ), was not extensively discussed
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