This dissertation has been 64—7055 microfilmed exactly as received SINKULA, Anthony Arthur, 1938— I. SYNTHESIS OF A SERIES OF 2,2-CYCLO- ALKYL BENZOTHIAZOLINES. H. A PRELIM­ INARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES. The Ohio State University, Ph.D., 1963 Chemistry, pharmaceutical University Microfilms, Inc., Ann Arbor, Michigan I . SYNTHESIS OF A SERIES OF 2,2-CYaOALKYL BENZOTHIAZOLINES I I . A PRELHaNARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES A DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School o f The Ohio S tate U niversity % Anthony Arthur Sinkula, B. S., M. Sc. The Ohio S tate U niversity 1963 Approved by Adviser Department of Pharmacy ACKNOWLEDGMENTS Ify sincere thanks and appreciation are extended to Dr. Jules B, La Pidus, my adviser, for his suggestions and constructive criticism given during the tenure of this problem, I am grateful to many others, fellow graduate students and faculty members alike, for their excellent suggestions, interest, and moral support. To Betty, for her encourage­ ment and understanding, saying thank you is inadequate. Finally, I would like to thank the Public Health Service who supported this investigation by a PutCLio Health Service Fellowship (MPM-11, 876-02) from the National Institute of Mental Health, i i CONTENTS Page ACKNOWLEDGMENTS................ ..... ...... ................................................................ ü TABLES...................... v i PART I . SYNTHESIS OF A SERIES OF 2 ,2-CYCLOALKÏL BENZOTHIAZOLINES INTRODUCTION AND STATEMENT OF PROBLEM ........................................................ 1 HISTORICAL REVIEW............................................•................................................... ^ Rie Benzothiazoles ....... ............................................................... ^ A old chlorides ............................................................................................ 4 Carboxyl ! 0 acids ................. ..... ...... 7 E sters .................................................................................................................. 7 A ldehydes .................................................................................. 9 Ketones ......... 13 The Benzothiazolines ...................................................... 17 EXPERIMENTAL................................................................... 22 R e a g e n ts ................................................................................................................. 22 Instruments ...... .................................................................................... 23 Synthesis of Benzothiazoline Derivatives . ......................................... 23 1. Preparation of 2,2-tetramethylene benzothiazoline .... 23 2. Preparation of 2,2-pentamethylene benzothiazoline .... 26 3. Preparation of 2,2-hexamethylene benzothiazoline .... 27 4. Preparation of 2,2-(2‘-methyl) pentamethylene benzothiazoline .............................................................. 27 5. Preparation of 2,2-(3'-methyl) pentamethylene benzothiazoline ............................................................................... 28 6. Preparation of 2,2-(4'-methyl) pentamethylene benzothiazoline ..................................................................... 29 7. Preparation of 1,2'-4,2'-cyclohexylidene bis- benzothiazoline ...................................... ..... 29 8. Preparation of 2,4'-(l*-methyl) piperidyl benzothiazoline .......................................... ......... 30 Attempted Formation of 2,4‘- (l‘-Methyl) Piperidyl Benzothiazoline Hydrochloride .................................................. 31 Attenç>ted Formation of 2,4'-(l*-Methyl) Piperidyl Benzothiazoline Methiodide ...... .................................................... 31 i i i CONTENTS (contd.) Page Preparation of the Picrate Salt of 2,^ '-(I’-Kethyl) Piperidyl Benzothiazoline ..................................................................... 32 9. Preparation of ,5'-henzo-8-methyl-spiro (8-aza-bioyclo- C3.2.1]-octane-3i2'-l',3'~azathiolane) hydrochloride . 32 Formation of ij-',5'-Benzo-8-Methyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2'-1',3'-Azathiolane) 34 Preparation of 4',5'-Benzo-8-Mothyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2*-l’,3'-Azathiolane) Picrate .......................... 34 Formation of 4 ',5'"Benzo-8-Methyl-Spiro (8-Aza-Bicyclo- [3.2.1]-0ctane-3,2'-1,3-'Azathiolane) M ethiodide .............. 35 Attempted Preparation of a 2,2-Cydoalkyl Benzothiazoline- 1,1-Dioxlde . ............................................................................................ 35 Approach A .................................................................................................. 35 Preparation of sodivun o-aminobenzenesulfonate ....................... 36 Preparation of sodim o-(acetylamino)-benzenesrulfonate . 37 Attempted preparation of o-(acetylamino)-benzenesulfonyl c h l o r i d e ............................................................................................. 37 Phosphorous o x y c h lo rid e ..................................................................... 37 Thionyl chloride ..................................... 38 Approach B ............................. 38 Preparation of o-(aminophenyl) methylsulfide hydriodide . 39 Preparation of o-(aminophenyl) methylsulfide .................. 39 Preparation of 2-(acetylamino) phenylmethylsulfide .....40 Preparation of 2-(acetylamino) phenylmethyl sulfone ...... 41 Preparation of 2-(aminophei%rl) methyl sulfone hydrochloride . 42 Preparation of 2-(amlnophenyl) methyl sulfone . ...... 42 Approach C Attempted oxidation of 2,2-pentamethylene benzothiazoline . 44 Preparation of 2,2-pentamethylene-3-acetyl benzothiazoline . 44 Attempted oxidation of 2,2-pentamethylene-3-a cetyl benzothiazoline ................................................. 45 Attempted Reaction of 2,2-Pentamethylene Benzothiazoline w ith Methyl Magnesium I o d i d e ........................................................ 45 D is c u s s io n ......................................... 4? SUMMARY AND CONCLUSIONS............................................................................. 60 iv CONTENTS (con td .) Page PART I I . A PRELIMINARY INVESTIGATION OF SOME SYNTHETIC ROUTES LEADING TO THE FORMATION OF PHENOLIC ARYLPROPANOLAMINES INTRODUCTION AND STATEMENT OF PROBLEM................................................. 63 HISTORICAL REVIEW ............................................................. 65 Phenylpropanolamine ............................................................................................ 65 l-(o-Hydroxyphenyl)-2-Amino-l-Propanol 69 l-(p-Ifydroxyphenyl)-2-Amino-1-Propanol ...................................... 70 l-(m-Hydroxyphenyl)-2-Amino-l-Propanol ........................................... ?2 l-(3 ‘,^’-Dihydroxyphenyl)-2-Amino-l-Propanol ........................ ?2 EXPERIMENTAL ............................................................................................ 78 Preparation of l-(p-%droxyphenyl)-2-Amino-l-Propanol ..... ?8 1. Formation of phenyl propionate .................................. ?8 2. Formation of p-hydroxypropiophenone ....................... ?8 3 . Formation of p-benzyloxypropiphenone ....................... 79 4. Formation of oL -bromo-p-benzyloxypropiophenone ...... 80 5 . Attempted formation of ot--amino-p-benzyloxypropiophenone 81 6. Preparation of iso-butyl nitrite .......................... ..... 82 7. Preparation of oC -oximino-p-benzyloxypropiophenone . 82 8. Catalytic reduction of p-benzyloxy- 06-oximinopropio- p henone ..................................................................... 83 Preparation of l-(m-%droxyphenyl)-2-Amino-1-Propanol ..... 85 1. Formation of m-benzyloxypropiophenone 85 2. Formation of oL -oximino-m-benzyloxypropiophenone .... 85 3 . Catalytic reduction of c/--oximino-m-benzyloxypropio- phenone .......................................... ...... 86 Preparation of l-(3',4'-Dihydroxyphenyl)-2-Amino-l-Propanol . 86 1. Formation of 3 ', ^ ' -dihydroxypropiophenone .............................. 86 2. Attempted preparation of 3 ',4 ' -dihydroxypropiophenone using boron trifluoride . ......................... 8? 3 . Attempted formation of 3 ' -dibenzyloxypropiophenone . 88 Discussion ................................................................... 88 SUMMARY AND CONCLUSIONS......................’ 92 BIBLIOGRAPHY . ........................ 93 AUTOBIOGRAPHY.................................................................... 103 V TABLES Table Page 1. Infrared Spectra of Benzothiazolines .... .............................. 36 v i INTRODUCTION AND STATEMENT OF PROBLEM The search for new and better medicinal agents containing the phenothiazine nucleus is constantly being expanded. The pharmacology of üiese agents has been extensively investigated (1-4). Increased knowledge of the pharmacology and chemistry of phenothiazines and re la te d compounds has le d to widespread u tiliz a tio n of these drugs. Currently their major uses are as antihistaminics (5)t pre- and post­ operative antiemetics (6), and sedatives (?). Chlorpromazine (Thorazine), prochlorperazine (Compazine), and trifluoperazine (Stolazine) find wide application as tranquilizers (8-10) and in certain forms of mental illness, particularly schizophrenia (11,12). While the above-mentioned agents serve