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University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Spring 1958 REACTIONS OF 1-METHYL-4-HALO-4-PIPERIDYL PHENYL KETONE AND DERIVATIVES HENRY JOSEPH TROSCIANIEC Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation TROSCIANIEC, HENRY JOSEPH, "REACTIONS OF 1-METHYL-4-HALO-4-PIPERIDYL PHENYL KETONE AND DERIVATIVES" (1958). Doctoral Dissertations. 755. https://scholars.unh.edu/dissertation/755 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. REACTIONS OF 1-METHYL-4-HALO-4-PIPERIDYL PHENYL KETONE AND DERIVATIVES BY HENRY JOSEPH TROSCIANIEC B. S., St, Lawrence University, 1952 M. S., University of New Hampshire, 1955 A THESIS Submitted to the University of New Hampshire In Partial Fulfillment of The Requirements for the Degree of Doctor of Philosophy Graduate School Department of Chemistry June, 1958 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis has been examined and approved. I / j ! ( A m c . j p b \) f p . '■ U ' "t-v -L. b i Datft Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENT The research for this thesis was performed in the chemical laboratories of the University of New Hampshire. The completion of the thesis left the author indebted to Dr. Paul R. Jones who made the determinations of the infrared absorption spectra and Dr. Helmut M. Haendler who made the determinations of the ultraviolet absorption spectra, possible. The author also wishes to express his gratitude to other members of the chemistry staff who by permitting the use of equipment or facilities have made an essential contribution to this investigation. The authors greatest indebtedness, however, lies with Dr. Robert E. Lyle. It was Dr. Lyle who made it possible for the author to study under a National Institute of Health research grant. It was Dr. Lyle who made the thesis possible by so freely rendering his able counsel, assistance, and time. It was Dr. Lyle who made it possible. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS Page I. INTRODUCTION.................... 1 II. DISCUSSION.................... ................ 3 1. Preparation of Starting Materials ...... 3 2. Reactions of l-Methyl-4~halo-4-plperldyl Aryl Ketone Hydrohalides with Nucleophillc A g e n t s .......... 10 3. Reactions of 6-Methyl-2-alkoxy-2-aryl-l- ox-6-azaspiro(2«5)octanes with Organic and Mineral Acids ••«•....•.•••• 19 4. Reactions of l-Methyl-4*a*hydroxy-4-piperidyl Phenyl Ketone ............ 25 5. Reaction of l-Methyl^4abromo-4-plperidyl Phenyl Ketone Hydrobromide with Phenyl- L i t h l u m ........................ ..... ....... 25 6. Reaction of l-Methyl-4-chloro-4-piperidyl Phenyl Ketone Hydrochloride with Phenyl- magnesium bromide •••••••••••••• 30 7. Catalytic Reduction of 1-Methyl-4-halo, hydroxy, acyloxy and aryl-4-plperidyl Phenyl Ketone Hydrohalides •••••••••• 34 8. Reduction of l-Methyl-4~bromo-4-piperidyl Phenyl Ketone Hydrobromide with Sodium Borohydrlde ............ 38 9. Reduction of l-Methyl-4-bromo-4-plperidyl Phenyl Ketone Hydrobromide with Lithium Aluminum Hydride • **•••••• • 46 III. EXPERIMENTAL .............. 59 1. Preparation of l-Methyl-4-plperidyl Aryl Ketones 60 2. Preparation of l-Methyl-4-halo-4-piperidyl Aryl Ketone Hydrohalides .......... 65 3. Reactions of l-Methyl-4-halo-4-piperidyl Aryl Ketone Hydrohalides with Nucleophillc Agents •»•••••• ................ ... 68 4. Preparation of 6-Methyl-2-alkoxy-2-aryl-l- ox-6-azaspiro(2 .5)octanes .......... 76 5. Reactions of 6-Methyl~2-methoxy-2-aryl-l- ox-6-azaspiro(2.5)octanes with Organic Acids 78 6. Preparation of l-Methyl-4-hydroxy-4- piperidyl Aryl Ketones by Reaction of 6- Methyl-2“methoxy-2-aryl-l-ox-6-azaspiro(2.5) octanes with Hydrochloric Acid ••••.... 89 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7. Reduction of 6-Methyl-2-methoxy-2-phenyl-l- ox-6-azasplro(2.5)octane with Lithium Aluminum Hydride .•..••••••••••• 93 8. Reaction of 1-Methyl-4-bromo-4-piperidyl Phenyl Ketone Kydrobromide- with Phenyl- L i t h i u m .............. ..................... 94 9. Preparation of 1-Methy l-4-piperidylldene-rt.~ benzoyloxy-0C-phenylmethanol ••••••••• 97 10. Reaction of l-Methyl-4-chloro-4-piperidyl Phenyl Ketone Hydrochloride with Phenyl- magnesium bromide .......... 99 11. Reaction of Demerol (Ethyl l-Methyl-4- phenylisonipecotate) Hydrochloride with Phenylmagneslura bromide *•••.•••••• 107 12. Preparation of 1-Methy1-4-pheny1-4- piperidyldiphenylmethanol • 108 13. Prepar-atlon of 1-Methyl-4-hydroxy-4- piperidylphenylmethane ....... ........ 109 14. Catalytic Reduction of 1-Methy1-4-halo, hydroxy and aryl-4-piperldyl Phenyl Ketone Hydrohalides ••••* .............. Ill 15. Reaction of 1-Methyl-4-bromo-4-piperidyl Phenyl Ketone Hydrobromide with Sodium Borohydrlde •••••••• ................ 116 16. Reaction of 1-Methyl-4-bromo-4-piperldyl Phenyl Ketone Hydrobromide with Lithium Aluminum Hydride • ••••••••«...•. 122 17. Preparation of l-Methyl-4~benzyl-l,2,3,6,- tetrahydropyridlne •••.*♦... ........ 135 18. Reaction of l-Methyl-4-benzy1-1,2,3,6,- tetrahydropyrldlne with Alcoholic Potassium Hydroxide at High Temperatures ••••••«• 136 19. Reactions of 1-Methy1-1,2,3,6,-tetrahydro- 4-pyridylphenylmethanol o.... ........ • 139 IV. APPENDIX 142 1. Table I • . ................................. ... 2. Table ..................................... ... 3. Ultraviolet Absorption Spectrum of • 1-Methy1-4-piperidylidene- -benzoyloxy- - phenylmethane Hydrobromide ........ ..••• 144 4. Ultraviolet Absorption Spectra of Products Obtained from the Reduction of 1-Methyl—4- bromo-4-piperidyl Phenyl Ketone Hydrobromide with Sodium Borohydrlde ..................... 145 5. Ultraviolet Absorption Spectra of Products Obtained from the Reduction of 1-Methy1-4- bromo-4-plperldyl Phenyl Ketone Hydrobromide with Lithium Aluminum Hydride .............. 146 V. SUMMARY ......................... ........ x47 VI. BIBLIOGRAPHY......................................•, r, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION The investigation of the physical properties and reactions of oC-ha loke tones has led to the discovery of many interesting features of these compounds which have two strong dipoles in close proximity.* A variety of different reaction pathways apparently are available for the <*-haloke tones to lose halogen, for acids (l) or their derivatives (2 ), epoxides (3) or acetals (4 ), saturated ketones (5 ), ^-substi­ tuted ketones (6), and o£-ethylenic ketones (7) have been isolated from such reactions. The relative importance of the factors which govern the particular pathway that the dehalogenation will follow have not been evaluated so that it is often difficult, if not impossible, to predict which type or types of compounds vvill arise as products from a given reaction of a ed-haloketone. These factors include such variables as; the structure (8) and conformation (9) of the oi-haloketone, the nature of the reagent (1 0 ), the solvent medium (1 1 ), the nature of the halogen (1 2 ), and the reaction conditions (1 3 ). Although numerous acyclic, carbocyclic, aromatic, and aliphatic et-haloke tones have been studied, heterocyclic oC-haloketones have not been investigated to any great extent. In view of this, a study of the effect of a heterocyclic *0ne important series of investigations concerning the conformation of cyclic tf-haloketones is not pertinent to this Thesis but is reviewed (15) elsewhere. 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 . ring system, containing a basic nitrogen atom, on the reaction of o(-haloketones could offer an important contribution to this area, and thus an investigation was undertaken. l-Methyl-4- halo-4-pip^ridyl phenyl ketone (XIII) was selected for this purpose for the conformation of the groups could be predicted as being halo (axial) and benzoyl (equatorial) and the reac­ tion products had the potential of being pharmacologically active. The latter advantage is particularly true of any 4 ,4 -disubstituted piperidines which could result from this study. Considerable interest, in recent years, has developed in this class of compounds since the discovery of their value as synthetic pharmaceuticals (14). The synthesis and reactions of l-methyl-4-halo-4- piperidyl phenyl ketone (XIII) and its derivatives are herein described. Reactions characteristic of organic halogen and carbonyl compounds using nucleophilic, organometallic, and homolytic agents were investigated, and the way in which the influence of the heterocyclic ring system and the unreactive dipole altered the properties of the dipole under­ going reaction, was demonstrated. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DISCUSSION Reproduced with permission of the copyright

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