THE CATALYTIC HYDROGENATION OF BENZODIAZINES: I. PHTHALAZINE II. QUINAZOLINE A Dissertation Presented to the Department of Chemistry Brigha~ Young University In Partial Fulfillment of the Requirements for the Degre~ Doctor of Philosophy by Danny Lee Elder August 1969 This dissertation, by Danny Lee Elder, is accepted in its present form b y the Department of Chemistry of Brigham Young University as satisfying the dissertation requirement for the degree of Doctor of Philosophy. ii . , TO Lynette, David, and Douglas iii ACKNOWLEDGEMENTS Deep appreciation is expressed to Dr. H. Smith Broadbent, without whose friendly association, patient help, and kindly ex- · tended advice this research problem could not have been carried out. Gratitude is also expressed £or the many extra-academic endeavors Dr. Broadbent has made on my behalf. Appreciation is extended to the Department of Chemistry of Brigham Young University for financial support in the form of teaching and research assistantships. My wife deserves special thanks for her encouragement, patience, understanding, and especially, for making it all worth- while. Finally, sincere thanks go to a great group of fellow-graduate students--Craig Argyle, Weldon Burnham, Vic Mylroie, Wes Parish, and Walter Sudweeks--for helpful discussions, comrade- ship, and most of all, for the memorable hours spent at such places as Anderson Lake, Four-Lakes Basin, Klondike Bluff, and of course, "Organic Pass, 11 (Grosebeck Pass). iv TABLE OF CONTENTS Chapter Page I. INTRODUCTION • • • • • • • • • • • • • • • 1 II. LITERATURE REVIEW • • • • • • • • • • • • 4 Phthalaz~ne • • • • . 4 Structure and properties • • • • • • • • • · 4 Synthesis of phthalazine • • • • • • • • • 8 Reduced phthalazines • • • • • • • • • • 10 Quinazoline • • • • • • . 12 Structure and properties • . • 12 Synthesis of quinazoline • • • • • 15 Reduced quinazolines • • • • 18 Catalytic Hydrogenation of Benzoazines and Benzodiazines • • • • • • • • 20 Quinoline . 21 . Isoquinoline • • . 22 Quinoxalin e . .. • 23 Cinnoline . 24 Phthalazine • 24 III. EXPERIMENT AL • . • • • • • • 26 ,General Experimental Information •••••. 26 Synthesis of Starting Materials • • • • • • . 30 Phthalazine. • 30 Quinazoline • • . • 35 Preparation of Authentic Samples . 38 V Chapter Page Phthalazine hydrogenation products • • • • 38 Quinazoline hydrogenation products . • • • 46 Hydrogenation of Phthalazine and Quinazoline . • . • . • • • • • 48 General procedures • • • • • .-- 48 Preparation of certain inter .. mediates • • • • • • • • . .. 52 IV. DISCUSSION . 55 Synthesis of Starting Materials • • • • • • • 55 Phthalazine. • • • • • • • • 55 Quinazoline. • • • • • • • • 56 Proposed Hydrogenation Products • • • • • • 57 Proposed phthalazine hydrogenation products • • • • • • • • • • • 58 Proposed quinazoline hydrogenation products • • • • • • • • • • • • • • 59 Identification of Hydrogenation Products 62 Phthalazine hydrogenation products • • • • 62 Quinazoline hydrogenation products • • . • 70 "Minor" quinazoline hydr~genstion products • • • • • • • • • • • • • • 7 2 Quantitative Analysis of Product Mixtures 75 Phthalazine low-pressure hydro .. g enations • • • . • • • • • • • • . • 7 5 Quinazoline low .. pressure hydro-:- g enations • • • . • • • • . • • . 79 Phthalazine high ...pressure hydro- :genations • • . • • • • • • • • • . • 79 Quinazoline high .. pressure hydro ... genations • • • • •. • • • • • • • • • 83 Observations and Conclusions. • • • • • • • 83 vi Chapter Page Relative Activity of Catalysts • • • • • • • • 83 Low-pressure phthalazine hydro .. genations., ••• ., ., •• ., • . .. .. .. .. 85 Low .. pressure quinazoline hydro .. genations • • ,; .; • . .. .. .. .. • • • • • 87 High .. Pressure Reactions . • • • • 87 High .. pressure phthalazine hydro- genations • • • • • • • • •.. • • 88 High-pressure quinazoline hydro .. g enations • • • .; • • .; .; • .; .; 89 Proposed Pathway of Hydrogenations. 90 Phthalazine hydrogenation pathway • • • • 90 Quinazoline hydrogenation pathway. • • • • 96 v. SUMMARY •• . .. .. .. .. .110 VI. LITERATURE CITED . .111 vii LIST OF TABLES Table Page 1. Chromatographic Data • • • • e • • ■ • • I • • 64 2. Low .. Pressure Hydrogenation of Phthalazine • • • • • • • • . 76 3. Low .. Pressure Hydrogenation of Quinazoline • • . • . • • • . 80 4. High--Pressure Hydrogenation of Phthalazin e • • • • • • • • . 81 5. High-Pressure Hydrogenation of Quinazoline . • • . • . • • . 84 6. Hydrogenation of Certain Intermediates 94 viii LIST OF F1GURES Figure Page 1. Proposed Phthalazine Hydrogenation Products . 60 2. Proposed Quinazoline Hydrogenation Products • • • • • • • • • • • • • • • • • • 61 3. Proposed Pathway for Hydrogenation of Phthalazine • • • • • • • • • • • • • • . 91 4. Proposed Pathway for Hydrogenation of Quinazoline • • • • • • • • . • . • • • 97 S. Graph of Molar ,Uptake of Hydrogen with Respect to Time in Low-Press~re Hydrogenations • • • • • • • • • • • • • • • 100 ix LIST OF INFRARED, NUCLEAR MAGNETIC RESONANCE, AND MASS SPECTRA Spectrum .Page Infrared Spectra 1. o<, ~ 1 -Diamino-~-xylene • • • • • • • • • • • • 104 2. £_-Methyl benzylamine . 104 3. 1, 3-Dihydroisoindole • . 104 4. Phthalazine • • • • • • 105 5. 1, 2-Dihydrophthalazine . 105 6. 1, 2, 3, 4-Tetrahydrophthalazine . 105 Nuclear Magnetic Resonance Spectra 7. Phthalazine • • • • • • • • • . 101 8. 1, 2, 3, 4-Tetrahydrophthalazine . 101 9. 1, 2-Dihydrophthalazine . 101 10. o(,cx' -Diamino-~-xylene • • • • • • • • • • • • 102 11. £_-Methylbenzylamine. 102 12. 1, 3-Dihydroisoindole • . 102 13. Quinazoline • • • • . 103 14. 3, 4-Dihydroquinazoline . .. 103 X Spectrum .Page Mass Spectra 15. 1, 2, 3, 4-Tetrahydrophthalazine . .. 106 16. 1, 3-Dihydroisoindole. 106 17. Phthalazine • • • • • • 107 18. 1, 2-Dih ydrophthalazine • . 107 19. (/..~c,:.. 1 -Diamino-;:-xylene . 108 20. £_--Methyl benz ylamine . 109 xi I. INTRODUCTION . Catalytic hydrogenation is one of the most powerful tools available to the synthetic organic chemist. It provides a rela- ti vely simple means of bringing about transformations in organic molecules which might be much more difficult to ' achieve by other chemical methods. A great advantage of catalytic hydro- genation is the convenience with which a reaction can be effected, Many hydrogenation reactions consist of merely agitating catalyst and substrate in a suitable solvent under hydrogen pressure until the theoretical amount of hydrogen has reacted. After filtering the reaction mixture free of catalyst, one can then obtain the desired prodµct by distillation, extraction, or other conventional separation procedure, In many reactions, conditions can be chosen so that high-reaction selectivity-is achieved, giving quantitative yields of the desired product. A great deal of research effort has been expended in improv- ing the technique of catalytic hydrogenation. Many workers have studied the types of transformations which can be brought -about by hydrogenation. Much has been done to develop better 1 2· catalyst systems, and to determine the reaction selectivity of various hydrogenation catalysts. One important area of study has been the catalytic hydrogen .. ation of heterocyclic compounds. Many reports have appeared in the literature concerning the catalytic hydrogenation of hetero-- cycles. However, relatively few of the studies reported have been concerned with the unsubstituted parent-heterocycles, Conspicuously absent from the group of heterocycles which have been studied are the benzodiazines, This group of compounds is comprised of quinoxaline, quinazoline, cinnoline, and phthaiazine, Of these four compounds, quinazoline has received the most at- tention in connection with its catalytic hydrogenation. However, · the variety of catalyst systems and conditions reported is very limited. A systematic study of the catalytic hydrogenation of the ben"". zodiazines was undertaken at Brigham Young University several years ago. Studies of the hydrogenation of quinoxaline and cinno ... line have already been carried out and are reported (23, 98). Ini- tial research on quinazoline has also been carried out (101), but a more complete study is necessary. Phthalazine, the fourth benzodiazine, had not been studied. The catalytic hydrogenation of quinazoline and phthalazine, reported herein, was undertaken with the following objectives in 3 mind: (1) to determine the structure of compounds obtained by hydrogenation of phthalazine and quinazoline, (2) to determine the relative activity of various catalysts in the hydrogenation of phthal .. azine and quinazoline, (3) to elucidate the pathway of hydrogen .. ation for each heterocycle, (4) to determine the synthetic utility of hydrogenation for obtaining the various products formed in the hydrogenation reactions, (5) and to obtain data which would be of value in predicting the course of hydrogenation in other hetero- c ye lie systems. II. LITERATURE REVIEW PHTHALAZINE Structure and Properties Phthalazine or benzo d pyridazine is illustrated below and is num- bered according to the system employed in Chemical Abstracts (72). 8 I :oo~: 5 4 Phthalazine is a white, crystalline substance. It forms white, hard prisms when crystallized from ethyl ether (54). It is very soluble in water, ethanol, benzene, and ethyl acetate; less soluble in ether; and insoluble in ligroin ( 41). When boiled at atmospheric pressure, it gives off ammonia (41, 55), but it is stable when distilled in vacuo. It forms mono-acid salts, Physical data for phthalazine are listed below: Physical Properties 3. 5 (5) 0 mp 90--91