CATALYTIC CARBONYLATION OF AMINES AND DIAMINES AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: APPLICATION TO SYNTHESES OF THE CORE STRUCTURE OF DMP 323 AND DMP 450 AND OTHER FUNCTIONALIZED UREAS By KEISHA-GAY HYLTON A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2004 Copyright 2004 by Keisha-Gay Hylton Dedicated to my father Alvest Hylton; he never lived to celebrate any of my achievements but he is never forgotten. ACKNOWLEDGMENTS A number of special individuals have contributed to my success. I thank my mother, for her never-ending support of my dreams; and my grandmother, for instilling integrity, and for her encouragement. Special thanks go to my husband Nemanja. He is my confidant, my best friend, and the love of my life. I thank him for providing a listening ear when I needed to “discuss” my reactions; and for his support throughout these 5 years. To my advisor (Dr. Lisa McElwee-White), I express my gratitude for all she has taught me over the last 4 years. She has shaped me into the chemist I am today, and has provided a positive role model for me. I am eternally grateful. I, of course, could never forget to mention my group members. I give special mention to Corey Anthony, for all the free coffee and toaster strudels; and for helping to keep the homesickness at bay. I thank Daniel for all the good gossip and lessons about France. I thank Yue Zhang for carbonylation discussions, and lessons about China. In addition, I would like to thank my other group members for the laughs over the years. iv TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF TABLES............................................................................................................. vi ABSTRACT...................................................................................................................... vii CHAPTER 1 INTRODUCTION ........................................................................................................1 2 W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF AMINES AND DIAMINES: APPLICATION TO SYNTHESIS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP 450.............................22 3 W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION OF SECONDARY AMINES AND DIAMINES: ANALOGS OF THE CORE STRUCTURES OF THE HIV PROTEASE INHIBITORS DMP 323 AND DMP 450. ...................................37 4 APPLICATION OF W(CO)6/I2 CATALYZED OXIDATIVE CARBONYLATION TO THE CARBONYLATION OF AMINO ALCOHOLS........................................46 5 EXPERIMENTAL PROTOCOLS .............................................................................54 LIST OF REFERENCES...................................................................................................80 BIOGRAPHICAL SKETCH .............................................................................................84 v LIST OF TABLES Table page 1-1 Oxidative carbonylation of primary and secondary amines.....................................19 1-2 Oxidative carbonylation of primary diamines..........................................................20 1-3 Oxidative carbonylation of para-substituted benzylamines.....................................21 2-1 Carbonylation of compounds 24-26.........................................................................25 2-2 Optimization studies for the oxidative carbonylation of 26.....................................26 2-3 Oxidative carbonylation of 35 catalyzed by W(CO)6 under various reaction conditions. ................................................................................................................29 2-4 Oxidative carbonylation of 35 using Mo(CO)6 and Cr(CO)6...................................30 2-5 Oxidative carbonylation of 44 under various reaction conditions. ..........................33 3-1 Study of effect of the presence of the benzyl group on the W(CO)6 /I2 catalyzed carbonylation of 1,4-secondary diamines.................................................................39 3-2 Optimization study of the carbonylation of amines 58, 62 and 65 ..........................43 3-3 Effects of base on the oxidative carbonylation of N-ethylbenzylamine, 66 ............44 4-1 Carbonylation of 69 under various reaction conditions. ..........................................48 4-2 Carbonylation of 78 under various reaction conditions. ..........................................52 vi Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CATALYTIC CARBONYLATION OF AMINES AND DIAMINES AS AN ALTERNATIVE TO PHOSGENE DERIVATIVES: APPLICATION TO SYNTHESES OF THE CORE STRUCTURE OF DMP 323 AND DMP 450 AND OTHER FUNCTIONALIZED UREAS By Keisha-Gay Hylton May 2004 Chair: Lisa McElwee-White Major Department: Chemistry W(CO)6-catalyzed carbonylation provides an alternative to phosgene or phosgene derivatives such as 1,1-carbonyldiimidazole (CDI) for the conversion of amines to ureas. The core structure of the HIV protease inhibitors DMP 323 and DMP 450 has been prepared by catalytic carbonylation of diamine intermediates from the original syntheses. Yields of the ureas from the catalytic reaction are comparable to those previously reported for reaction of the substrates with stoichiometric CDI. Intermolecular urea formation in related acyclic systems was demonstrated by catalytic carbonylation of O-protected phenylalaninol derivatives. W(CO)6-catalyzed carbonylation has been successfully applied to the preparation of analogs of DMP 323 and DMP 450 and to the carbonylation of amino alcohols to selectively form hydroxyl ureas. vii CHAPTER 1 INTRODUCTION Substituted ureas are interesting compounds because of the broad range of their applications. They have found use in a variety of capacities, for example, as antioxidants in gasoline and have been known to exhibit useful biological activity. Ureas are structural components of drug candidates such as HIV protease inhibitors,1,2 CCK-B receptor antagonists,3,4 and endothelin antagonists.5 In addition, they have found widespread usage as agricultural chemicals, dyes, and intermediates en route to carbamates; and as additives to petroleum compounds and polymers.6 The classical synthetic methodology used to synthesize substituted ureas from amines involves phosgene. Phosgene is useful for the carbonylation of primary and secondary amines (Scheme 1.1). The major drawback of phosgene is that it is a highly toxic and corrosive gas. Because of its toxic nature, it requires special handling. This has discouraged its use in laboratory settings. O O RR'NH O RR'NH Cl Cl -HCl Cl NRR' -HCl R'RN NRR' 1 where R' = H, alkyl, aryl Scheme 1.1 Phosgene production7 and use on an industrial scale raise serious environmental risks and problems connected with the use and storage of large amounts of chlorine, and the transportation and storage of a highly toxic and volatile reagent. Other safer derivatives such as 1,1-carbonylimidazole, triphosgene, and a variety of other reagents 1 2 have been used in the carbonylation of amines to form substituted ureas, and are more common in the laboratory setting. Diphosgene (ClCO2CCl3) behaves in the same manner as phosgene. However, diphosgene is in a liquid state at ambient temperature and pressure, while phosgene is in a gaseous state. Thus, it is much safer and more convenient to transport, store, and use diphosgene. Unfortunately, it decomposes to phosgene and chloroform, and is as toxic and corrosive as its phosgene counterpart. The use of isocyanates (2) is undesirable because of their toxic nature and the need to synthesize them from phosgene (Scheme 1.2). In addition, this method can be used in conversion of primary amines to symmetrical and unsymmetrical ureas. O O O RNH R'NH2 R'N C O 2 Cl Cl -HCl Cl NHR' -HCl HN NH 1 2 R' R where R', R = H, alkyl, aryl Scheme 1.2 Triphosgene [bis(trichloromethyl)carbonate, 3], a crystalline solid, is deemed a safe and stable replacement for phosgene and can be handled without special precautions. It is prepared by exhaustive photochlorination of dimethyl carbonate8 (Eq.1-1). O O Cl2,hv H CO OCH 3 3 CCl4 Cl3CO OCCl3 (1-1) 3 where R' = H, alkyl, aryl An activating nucleophile such as triethylamine, pyridine, or dimethylformamide is needed to activate triphosgene. These liberate three molecules of phosgene in situ on reaction with triphosgene. Triphosgene is useful for a variety of conversions, including 3 the carbonylation of amines to ureas. By no means is triphosgene a perfect reagent. It is expensive; and long-term storage or presence of impurities may lead it to form phosgene. The crystalline solid 1,1-carbonyldiimidazole (CDI, 4) has also been used as an alternative to phosgene. Its commercial availability and ease of handling make CDI a desirable alternative to phosgene. An example of CDI as a carbonylation agent is the synthesis of N, N’-substituted ureas such as the HIV protease inhibitors DMP 323 and DMP 450.1,2 The mechanism of carbonylation using CDI involves the stepwise displacement of imidazole by the attacking amine, to form the corresponding urea. It has been successfully used for the carbonylation of primary amines (Scheme 1.3). O O O RNH RNH N N N 2 HN N 2 N _ N N _ N HN NH R R R N N 4 H H Scheme 1.3 On a large scale, the major drawbacks of using CDI (4) are the