Part I, Novel reactions with triphenylphosphine dibromide ; Part II, Synthetic routes to substituted α-Dialkylaminomethyl-4-quinolinemethanols Item Type text; Dissertation-Reproduction (electronic) Authors Higgins, Jerry Gene, 1936- Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 06/10/2021 02:23:37 Link to Item http://hdl.handle.net/10150/565128 PART I: NOVEL REACTIONS WITH TRIPHENYLPHOSPHINE DIBROMIDE PART II: SYNTHETIC ROUTES TO SUBSTITUTED at -DIALKYLAMINOMETHYL-4-QUINOLINEMETHANOLS by Jerry Q tf' Higgins A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1 9 6 6 / THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE I hereby recommend that this dissertation prepared under my direction by \ J e r f ~ y G . _____________________ entitled f l i r t £ , hJo\I&i f £ 4 C f ,0 /J s 77-/ t/Uy/phd*?Vf. /7> \?f OMtO ParTIZ* SyA/rhehc toafe*> to ‘Pubzt, fa te d u e th /l- H -4 UtAJoi/AjiMethuto /$ be accepted as fulfilling the dissertation requirement of the degree of PL P.________ Dissertation Director After inspection of the dissertation, the following members of the Final Examination Committee concur in its approval and recommend its acceptance:* XAJc’XJUp'' X % )n/u f / s r / u H / l 1/ f ^ L j l K . *This approval and acceptance is contingent on the candidate's adequate performance and defense of this dissertation at the final oral examination. The inclusion of this sheet bound into the library copy of the dissertation is evidence of satisfactory performance at the final examination. STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the Univer­ sity Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: ACKNOWLEDGMENTS The author wishes to express his thanks to Dr. John P, Schaefer for his contributions and advice during the course of this research. ill To Cynthia Higgins, John Higgins., and Jim and Marie Owen iv TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS 0 0 0 0 0*0 © x LIST OF TABLES oooooeooeooo xi LIST OF SPECTRA. ooooooooooooooooooooeoooo xii ABSTRACT.. oooooooooooooooooo o o o o o o o xv PART I INTRODUCTION... 2 RESULTS AND DISCUSSION.............................. 5 1. Preparation of trans_-l-Bromo-3-vinyl- oyolopontano 5 2. Reaction of Triphenylphosphine Dibromide with Phenols............... 16 3. Reaction of Triphenylphosphine Dibromide with Ketones............... 18 4. Reaction of Lithium Aluminum Hydride with the Triphenylphosphine. Dibromide-Alcohol Complex............ 20 EXPERIMENTAL.............e................. 21 1. General... OO 0 O ©OO ©OOOO ©OOOOOOOOOOO ©©OOO < 21 2 . Purification of Reagents and Solvents. 22 3. Oxidation of Norcamphor.0000000000900 o oo 22 4. N,N-Dimethyl cis-3-Hydroxycyclopentyl- acetamide.....e. 23 v vi TABLE OP CONTENTS— Continued Page 5. N,N-Dlmethyl-cls-3-hydroxyoyclopentyl- ethyleneamlne. OOOOOOOOOOOOOOOOOOOOOOO 23 6. cls-3-Vlnylcyclopentanol o, oooooooooooooo 24 7 o cls-(3-Vlnylcyclopentyl)-3, 5-dlnltro- benzoate,■OOOOOOOOOOOOOOOOOOOOOOOOOOOO 25 8. trans-1-Bromo-3-vlnylcyc1opentane 25 9. cls-3-Vlnylcyclopentyl Tosylate.. e o o o o o 26 10. Aoetolysis of els-3-Vlnylcyclopentyl Tosylate©....... ©..... 0 0-0 0 00000900 26 11. Solvolysis of trans-1-Bromo-3-vinyl- cyclopentane,>0000000000000000000000000 27 12. Solvolysis of trans-1-Bromo-3-vinyl- cyclopentane in 50-50 Ethanol-Water, 28 13. Solvolysis of trans-l-Bromo-3-vinyl- cyclopentane in Aqueous Silver Nitrate...............o.*.. 28 14. 2-Bromonaphthalene,•ooeoeoooooooooo 0 09900 29 15. 2-Bromotoluene...o.©................... 31 16. 3 —Bromopyndme................o....... 32 17. Cmnamy 1 Bromide ...............o....... 33 18. 1—Bromonaphthalene.......o............. 34 19. 2 -Bromopy r id m e ....e.........©......... 35 20. 8-Bromoqumoline .........e............. 36 21. Toluene from Benzyl Alcohol............ 37 vii TABLE OF CONTENTS--Continued Page 22. n-Octane from n-Octanol................. 37 23. Reaction of 2-Methylcyclohexanol- Triphenylphosphine Dibromide Complex with Lithium Aluminum ■ Hydride 060000-000 00000 0 00 0 00-60000 38 24. 1-Bromocyclopentene.................... 39 25. trans-Stilbene from Desoxybenzoin...... 40 26. Desoxybenzoin-dg....................... 40 27. Reaction of Desoxybengoin-dg with Triphenylphosphine Dibromide......... 41. PART II INTRODUCTION..............................a......... 44 1. History of the Cinchona Alkaloids...... 44 2. Important Cirichona Alkaloids........... 45 3. Suggested Biogenetic Relationships In the Cinchona Alkaloids............... 46' 4. Synthetic Sequences.................... 49 5 . Syntheses of Substituted 4-Qulndllhe- methano1s............................ 49 RESULTS AND DISCUSSION.............................o 59 1. Synthetic Routos............o.......... 59 EXPERIMENTAL....................................oo.. 72 viii TABLE OF CONTENTS--Continued Page 1 o Gr O Z IG 3? 3.- loooooooocoooooooooooooooooooooeoo 72 2„ 2-(2-Thienyl)cinchoninic Acid 00900000000 72 3» 2-(2-Thienyl)-4-quinolinecarbonol o o o o e o e 73 4„ 2-(2-Thienyl) -4-quinolinealdehyde. 74 5. 2-(2-Thienyl)-4-quinolinealdehyde S 3 T I1 Z L O S - X 1 " b O Z O T l - O OO&OOOOOOOOOOOOOOOO&OO&OO 76 6 . 2-(2-Thienyl)-4-quinolinealdehyde Bisulfite Adduct 76 7. 2-(2-Thienyl)-4-quinolinecyanohydrin.... 77 8. 2-(2-Thienyl)cinchoninoyl Chloride 77 2-(2-Thienyl)-4-(N,N-dimethyl-l, 3-propylenediamine)quinoline- carboxamide.... oooooooooooooooooooo 78 10 , 2-(2-Thienyl)-4-p-anisidinequinoline- carboxamide,'OOOOOOOOOOOOOOOOOOOOOOOO OOO 78 11, 2-(2-Thienyl)cinchoninoylphenyl- Z'3- d.6 ooooooooooooooooooooooooo oooo 79 . 12 2-(2-Thienyl)cinchoninoyl-N,N-diethyl- 0 "tiny lono di&iniLnG ooooooo»ooooooooooooooo 79 13. Hydrolysis of 2-(2-Thienyl)-4-quino­ linecyanohydrin. 0090000000000000000 80 14. 2-Acetylthiophene.. ooooooooooooo 81 3. ^ o Et/lnyi Bromomalonate * 00000000000000060000 81 16. Diethyl N,N-Diethylaminomalonate........ 82 17. Ethyl N #N-Diethylaminoaeetate........... 83. lx TABLE OF CONTENTS— Continued Page 18. Ethyl 2-(2-Thienyl)cinchoninafce < o o o o o o o 83 19. 6-Chloro-2-(2-thienyl)cinchoninic Acid.LOOOOOOOOO oooooooooooooooeooooo 84 20 „ Methyl 6-Chloro-2-(2-fchienyl)cinchoni- I T l d r i v O OOOOOGOOOOOOOOOOOOOOOOOOOOOOOOOOO 85 21. Ethyl 6-ChlorO“2-(2-thienyl)cinchdni- 3 f X 3 i i s 6 OOOOOOOOOOQOOOOOOOOOOOOOOOOOOOOOO 85 22. 2-(2-Thienyl)cinchoninoyloctadecyl- d i l l i H 2 D . 0 OOOOOGOOOGOOOOOOOOOOOOOOOOO. OOOOO 86 23. Ethyl N- 2-(2-Thienyl)cinchoninoyl Glycinate,■OOOO OOOGOOOOOOOOOOOOOOOOOOOO 86 24. Ethyl -£2-(2-Thienyl)cinchoninoyl]' - N,N-diethyl Glycine,ooooooooogoooogo 87 25. Reduction of Ethyl -£2-(2-Thienyl) cinchoninoyl] -N,N-diethyl Glycine with Sodium Borohydride to Give the !D 3. 01 OOOOOOOOOOOOOOOOOOOOOOOOQOOOOOOOO 88 26. Ethyl @V-(2-Thienyl)-6-chlorocinchoni- noy1-N,N-die thy1 Glycine............. 88 APPENDIX I. IR and NMR Spectra from Part I ooooooeo 90 APPENDIX II. IR and NMR Spectra from Part II o o o o o e o 100 LIST OP REPERENOES oooooooooooooooooooooooeoooooooooe 110 P I^eoooooeoooooooeoooooooooooooooooooooo 110 P Ctr’fc II o ©©©ooooooeooooooeoooeoooo 00000000 112 LIST OF ILLUSTRATIONS PART I Figure Page Kinetic Plots of Cyclopentyl Bromide as Compared to trans-1-Bromd-3-vinyl- cyclopentane, OQOOOOOOOOOOOOOO 14 PART II Figure Page lo Hypothetical Relations of the cinchona Alkaloids Q 0 & O G 060000000 00000060000 48 2. Synthetic Routes to 4-Quinolinemethanols0„0„ 58 3- Attempted Synthetic Route to 4-Amino- ' " qu mo 1m e m e thano1seooeoeoooooooooooooooooo 60 4. Synthses of 4-Quinolinecarboxamides.„„„6 e „„ 62 . 5: IR Spectrum of ^ -Substituted~N,N-diethyl . Glycine Ethyl Ester....................... 65 6. NMR Spectrum of -Substituted-N#N-diethyl Glycine Ethyl Ester...........o.......... 66 7. NMR Spectrum of p^-Substituted-N*N-diethyl Glycme Ethyl Ester..........o............ 70 8. IR Spectrum of '=^-Substituted-N,N-diethyl Glycme Ethyl Ester.....e... 71 x LIST OF TABLES PART II Table 1 Anfcimalarial Compounds.„ LIST OF SPECTRA PART I Page Baeyer-Vi11iger Oxidation Product of Norcamphor,„. ooooooooooooooooooooooooooooo 91 NfN-Dimethyl cis-3-Hydroxyeyelopentyl- acetamide,OOOOOOOOOOOOOOO OOOOOOOOOOO0OOOCOO 91 N ,N-Dime thy1-2-(3-cyclopentanolyl)-ethylene- a m i n e ooooooo ooooooooeooooooooooooooooooooo 91 cis-3-Vinylcyelopentanol „ „„„„ 0 0 „ „ 92 trans-3-Vinyleyc1openty1 Bromide’ O 0O OOOOOOOO 92 3-Vinyl.cyclopentyl Acetate'O O O O o 0 0.0 O o O o o o o o o o 92 3-Vlnylcyclopentanol from Solvolysis with AgNO^0000000000600000060000000060000000 93 3-Vinyleyclopentyl Nitrate Ester G OOOOOOOOOOO 93 3-Vinylcyclopentanol