PART I. SYNTHESIS OF NEW BARBITURIC ACID DERIVATIVES PART II. SYNTHESIS OF NEW GLUTAMINE AND AMINOGLUTARIMIDE DERIVATIVES A THESIS Presented to The Faculty of the Graduate Division by John R;) Peters In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Chemistry Georgia Institute of Technology June, 1.974 Original Page Numbering Retained. PART I. SYNTHESIS OF NEW BARBITURIC ACID DERIVATIVES PART II. SYNTHESIS OF NEW GLUTAMINE AND AMINOGLUTARIMIDE DERIVATIVES Approved: A r) 0_ fl' 4 71P . es A. Stanfield, Chgirman J!) Charles L. Liotta -ft, Leon H. Zalkola Date approved by Chairman: 11 ACKNOWLEDGMENTS The author is most indebted to Dr. James A. Stanfield, without whose guidance, supervision, and patience this investigation could not have been possible. Appreciation is expressed to Dr. Charles L. Liotta and Dr. Leon H. Zalkow for serving on the reading committee, and to all the author's course professors for the knowledge they imparted and the stimulation they gave. For the five years of Graduate Assistantships, the author is very grateful to Dr. William M. Spicer, Chairman of the School of Chemistry. He is especially thankful for the patient encouragement of an understanding wife and son. Only because of their unending thoughtful- ness and devotion was the author able to complete his graduate studies. 111 TABLE OF CONTENTS ACKNOWLEDGMENTS LIST OF TABLES LIST OF ILLUSTRATIONS SUMMARY PART I Chapter I. INTRODUCTION 1 II. DISCUSSION OF EXPERIMENTAL OBSERVATIONS 7 III. EXPERIMENTAL 20 Attempted Preparation of 5-(N-acetylsulfanil- amido)-barbituric Acid Under Basic Conditions Synthesis of Diethyl N-Acetylsulfanilamido- malonate Diethyl Isonitrosomalonate Diethyl Aminomalonate Diethyl Aminomalonate Hydrochloride Diethyl N-Acetylsulfanilamidomalonate Attempted Condensation of Diethyl N -Acetylsulfanil- amidomalonate with Urea in Dimethylsulfoxide Attempted Condensation of Diethyl N-Acetyl- sulfanilamidomalonate with Urea in N,N- Dimethylformamide Attempted Synthesis of 5-Ethy1-7-()4-benzensulfon- amido) Uramil Reaction of 5-Bromo-5-ethylbarbituric Acid and Sulfanilamide in Ethanol iv TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Continued) Reaction of 5-Bromo-5-ethylbarbituric Acid and Sulfanilamide in Aqueous Acetone Attempted Preparation of 5-Methy1-5-(N-acetylsulfan- ilamido)-barbituric Acid by Direct Condensation Synthesis of 5 -Methyluramil Diethyl methylmalonate 5 -Methylbarbituric Acid 5-Bromo -5 -methylbarbituric Acid 5-Methyluramil Attempted Reaction of 5-Methyluramil and N-acetylsulfanilyl Chloride in Pyridine Attempted Condensation of 5-Methyluramil and N-Acetyl- sulfanilyl Chloride in Aqueous Trimethylamine Attempted Condensation of 5-Methyluramil and N-Acetylsulfanilyl Chloride in Acetic Acid Attempted Preparation of 5-Ethy1-5-(N-acetyl- sulfani1amido)-barbituric Acid by Direct Condensation Synthesis of 5-Ethyluramil 5-Ethylbarbituric Acid 5 -Bromo -5 -ethylbarbituric Acid 5 -Ethyluramil Attempted Reaction of 5--Ethyluramil and N- Acetylsulfanilyl Chloride in Pyridine Attempted Condensation of 5-Ethyluramil and N-Acetylsulfanilyl Chloride in Aqueous Trimethylamine Attempted Condensation of 5-Ethyluramil and N- Acetylsulfanilyl Chloride in Dimethyl- sulfoxide TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Continued) Synthesis of 5,7 -Disubstituted -7 -sulfanilyluramils Synthesis of 5 -Phenyl -7 -propyl -7 -sulfanilyluramil 5-Phenyl-7-propyluramil 7-p-Nit robenzenesulfonyl-5-phenyl - 7- propyluramil 7-(N-acetylsulfanily1)-5-pheny1-7- propyluramil 5-Phenyl-7-propyl-7-sulfanilyluramil Synthesis of 7-Benzy1-5-ethy1-7-sulfanilurRmi1 7 -Benzyl -5 -ethyluramil 7 -Benzyl -5 -ethyl -7 -(N -acetylsulfanily1) -uramil IV. CONCLUSIONS 44 V. RECOMMENDATIONS APPENDIX A 46 LITERATURE CITED 50 PART II Chapter I. INTRODUCTION 53 II. DISCUSSION OF EXPERIMENTAL OBSERVATIONS 65 III. EXPERIMENTAL 106 Attempted Synthesis of 4-Chloroglutarimide Synthesis of 8-Chloroglutaric Acid Acetonedicarboxylic Acid Diethyl Acetonedicarboxylate vi TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Continued) Diethyl B-Hydroxyglatarate Diethyl $-Chloroglutarate B-Chloroglutaric Acid Attempted Dehydration of Ammonium B-Chloro- glutarate Attempted Cyclization of B-Chloroglutaric Acid in Formamide Attempted Cyclization of B-Chloroglutaric Acid with Sulfamide Synthesis and Attempted Reduction of 4-Imino- glutarimide Preparation of 4-Iminoglutarimide Ethyl B-Iminoglutaramate 4-Iminoglutarimide Attempted Hydrogenation of 4-Iminoglutarimide Synthesis of B-Glutanic Acid Attempted Preparation of B-Glutamic Acid from Diethyl acetonedicarboxylate Tosylhydrazone Diethyl Acetonedicarboxylate Tosylhydrazone Attempted Hydrogenolysis of Diethyl Acetone- dicarboxylate Tosylhydrazone Preparation of 5 -Glutamic Acid from Diethyl 3 -Iminoglutarate Diethyl B-Iminoglutarate Diethyl B-Aminoglutarate B-Glutamic Acid Synthesis of Substituted Glutamine Derivatives vii TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Continued) Preparation of Carbobenzoxyglutamines Carbobenzoxyglutamic Acid Carbobenzoxyglutamic Anhydride N 5 -Benzyl Carbobenzoxyglutamine N 5 -Benzyl Carbobenzoxyglutamine Methyl Ester N 5-Phenyl Carbobenzoxyglutamine Preparation of N 5-Substituted Glutamines N 5-Benzyl Glutamine N 5-Phenyl Glutamine Determination of the a--Amino Acid Content of N5-Substituted Glutamines Synthesis of 5-Glutamine Derivatives Preparation of CarbobenzoXy-I3-glutamic Acid Preparation of Carbobenzoxy-8-glutamine Preparation of N 5-Substituted Carbobenzoxy- 0-glutamine Derivatives N 5 -Benzyl Carbobenzoxy--glutamine N 5-Propyl Carbobenzoxy-(3-glutamine N 5-Propyl Carbobenzoxy-13-glutamine Methyl Ester Preparation of N 5-Substituted i-Glutamines N 5-Benzyl 5-Glutamine N 5-Propyl Glutamine Preparation of f3-Glutamine Ethyl Ester Acetate Salt Synthesis of a-Carbobenzoxyaminoglutarimides Preparation of a-Carbobenzoxyaminoglutaximide Attempted Preparation of N-Benzyl a-Carbo- benzoxyaminoglutarimide viii TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Continued) Attempted Preparation of N 1 -Phenyl a-Carbo- benzoXyaminoglutarimide Synthesis of 18-Carbobenzoxyaminoglutarimide Derivatives Preparation of 13-Carbobenzoxyaminoglutarimide Preparation of N 1-Propyl ....Carbobenzoxyamino- glutarimide Preparation of N 1 -Benzyl -Carbobenzoxyamino - glutarimide Sulfonamide Derivatives of Substituted Glutamines Preparation of N 2-(p-Nitrobenzenesulfony1)- glutamine Preparation of N2-[p-Nitrobenzenesulfony1)- glutamine Ethyl Ester Preparation of N 2-(N-Acetylsulfanilyl)glutamine Preparation of N-Benzyl N-(p-Nitrobenzene- sulfonyl) glutamine Preparation of N-Phenyl N -(p-Nitrobenzene - sulfonyl) isoglutamjne Sulfonamide Derivatives of -Glutsnic Acid Preparation of p-Nitrobenzenesulfonyl-f3- glutamic Acid Attempted Preparation of N 3-(p-Nitrobenzenesulfony1)- . f3-glutamine Attempted Preparation of N 5-Propyl p-Nitrobenzene- sulfonyl-F3-glutamine ix TABLE OF CONTENTS (Continued) Page Chapter III. EXPERIMENTAL (Concluded) Attempted Preparation of N 5-Benzyl p-Nitrobenzene- sulfony1-13-glutamine Attempted Preparation of N 3 -(N-Acetylsulfanily1) - (3 -glutamine Ethyl Ester Synthesis of Sulfonamide Derivatives of Amino- glutarimides Preparation of a-(p-Nitrobenzenesulfonylamido)- glutarimide Preparation of a-(N-Acetylsulfanilamido) glutarimide Attempted Preparation of N 1 -Benzyl a-(p-Nitro- benzenesulfonamido) glutarimide Preparation of N 1 -Benzyl 13-(p-Nitrobenzene- sulfonylamido)glutarimide Preparation of New Sulfanilamide Derivatives N 5-Benzyl Sulfanilylglutanine N 5-Phenyl Sulfanilylisoglutamine Sulfanily1-13-Glutamic Acid Sulfanilyl-a-aminoglutarimide IV. CONCLUSIONS 166 V. RECOMMENDATIONS 167 APPENDIX A 168 APPENDIX B 186 APPENDIX C 190 x TABLE OF CONTENTS (Concluded) Page APPENDIX D 194 APPENDIX E 198 LITERATURE CITED 200 VITA 203 xi LIST OF TABLES PART I Table Page 1. New Compounds 19 PART II 1. New Compounds 87 2. NMR Shift Values in Units of 6 for Derivatives of Glut amine 89 3. NMR Shift Values in Units of 6 for Derivatives of $-Glutamic Acid 91t 4. NMR Shift Values in Units of 6 for Derivatives of Glut arimide 101 xi i LIST OF ILLUSTRATIONS PART I Figure Page 1. Common Barbiturates 2 2. Common "Sulfa" Drugs 2 3. Uramil 3 4. Sulfanilyluramils 3 5. 7-(4-benzenesulfonamido)urRmils 4 6. Synthesis of Typical Barbituric Acids 5 7. Synthesis of Typical Uramils 6 8. Synthesis of Typical Sulfanilamides 6 9. Proposed Path to Su1fanilyluramil 7 10. Proposed Synthesis of 5-Ethyl-7-(4-benzenesu1fonamido)- uramil 9 11. Resonance of Sulfanilamides 10 12. First Proposed Path to 5-Ethyl-7-sulfanilyluramil 11 13. Reaction of 5-Methylurami1 and N-Acetylsulfanilyl Chloride in Acetic Acid 13 14. Resonance of Sulfanilyl Chlorides 14 15. Formation of Zwitterionic 5-Methyluramil 15 16. Enolized Forms of 5-Methyluramil 16 17. Possible Alternative 5-Methyluramil Structure 16 18. Synthesis of 5,7-Dialky1-7-(N-acetylsulfanily1) uramils . 18 19. Hydrolysis of N-Acetylsulfanilyluramils 17 LIST OF ILLUSTRATIONS (Continued) Figure Page 20. Infrared Spectrum of 5-Ethyluramil. 47 21. Infrared Spectrum of 5-Phenyl-7-propyluramil 47 22. Infrared Spectrum of 7-(p-Nitrobenzenesulfony1)-5-phenyl- 7-propyluramil 4 8 23. Infrared Spectrum of 7-(N-Acetylsulfanily1)-5-pheny1-7- propyluramil 48 24. Infrared Spectrum of 5-Phenyl-7-propyl-7-sulfanilyl- uramil 49 PART II 1. Structure of Glutamine 53 2. Structure of Glutarimide 53 3. Structure of Glutamic Acid 54 4. Synthesis of Substituted