Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1980 Synthesis of heterocycles via carbonylation or olefination of organopalladium intermediates Constance Anne Fellows Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Fellows, Constance Anne, "Synthesis of heterocycles via carbonylation or olefination of organopalladium intermediates " (1980). Retrospective Theses and Dissertations. 6721. https://lib.dr.iastate.edu/rtd/6721 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. 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ZEEB ROAD, ANN ARBOR, Ml 48106 18 BEDFORD ROW, LONDON WCIR 4EJ, ENGLAND 8106009 FELLOWS, CONSTANCE ANNE SYNTHESIS OF HETEROCYCLES VIA CARBONYLATION OR OLEFINATION OF ORGANOPALLADIUM INTERMEDIATES Iowa State University PH.D. 1980 University Microfilms In ter n siti O n 31 300 N. Zeeb Road, Ann Arbor, MI 48106 Synthesis of heterocycles via carbonylatlon or olefination of organopalladium intermediates by Constance Anne Fellows A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OP PHILOSOPHY Department: Chemistry Major: Organic Chemistry Approved : Signature was redacted for privacy. In Charge of Major Work Signature was redacted for privacy. For the Major 'Department Signature was redacted for privacy. For the Graduate College Iowa State University Ames, Iowa 1980 li TABLE OF CONTENTS I. GENERAL INTRODUCTORY NOTE 1 II. SYNTHESIS OP 3-CHL0R0-A°''^-BUTENOLIDES VIA MERCURATION-CARBONYLATION OP PROPARGYLIC ALCOHOLS 3 A. Introduction 3 B. Results and Discussion 9 1. Preparation and carbonylation of 8-chloro-Y-hydroxyvinylmercurials 9 2. Palladium chloride-catalyzed carbonylation 14 3. Mechanism 22 C. Conclusion 24 D. Experimental Section 25 1. Reagents 25 2. Mercuration of a propargyllc alcohol 26 3. Palladium catalyzed carbonylation 27 III. SYNTHESIS OF AROMATIC ESTERS, LACTONES, AND OTHER HETEROCYCLES VIA THALLATION- CARBONYLATION OF ARENES 29 A. Introduction 29 B. Results and Discussion 44 1. Preliminary studies 44 2. Phthalides 57 3. 3 J4-Dihydroisocoumarins 84 4. Other heterocycles 102 5. Mechanism ll6 C. Conclusion 120 Ill D. Experimental Section 122 1. Reagents 122 2. Preparation and use of thalliura(III) trifluoroacetate 124 3. Thallatlon of arenes 125 4. Carbonylatlon of arylthallium intermediates 128 IV. SYNTHESIS OF ARYL OLEFINS, ISOCOUMARINS, AND OTHER HETEROCYCLES VIA THALLATION- OLEFINATION OF ARENES 134 A. Introduction 134 B. Results and Discussion l4l 1, Preliminary studies l4l 2, Isocouraarins l44 3. Other heterocycles 152 4. Mechanism 154 C. Conclusion 160 D. Experimental Section l6l 1. Reagents I6l 2. Thallatlon of arenes l6l 3. General procedure for the olefination of arylthallium compounds I6l V. • CONCLUSION 164 VI. BIBLIOGRAPHY 16? VII. ACKNOWLEDGEMENTS 178 1 I. GENERAL INTRODUCTORY NOTE Synthetic organic chemists who prepare biologically active compounds for medicinal or agricultural purposes normally use naturally occurring compounds of known activity as a starting point. Total syntheses of these compounds are developed, and structural analogs are made In the hope of finding even more potent agents with fewer undesirable side effects. The industrial research chemist must then find ways of simplifying and streamlining his procedures so that these compound classes can be produced cheaply and in high volume for testing and for eventual marketing. Here one can invoke the guiding maxim of Nobel laureate H. C. Brown, who believes that nature is basically simple [1], There are many ways of simplifying synthetic routes, and often the judicious use of catalysts can accomplish this. Since many classes of biologically active compounds Include oxygen-containing ring systems [2]. we have attempted to develop a unified synthetic strategy for the production of certain ring systems using a palladium catalyst. The following chapters of this dissertation will describe the syntheses of these various heterocycles, First, butenolides were prepared by mercuration and carbonylatlon of propargylic alcohols; the carbonylatlons were effected using a catalytic amount of palladium chloride. Second, phthalides and 2 3,4-dihydroisocoumarins were prepared by thallatlon and palladium chloride-catalyzed carbonylation of benzyl and 3- phenethyl alcohols. Similarly, cyclic aryl acid anhydrides and imides were made by thallation and subsequent carbonyla­ tion of the corresponding aryl acids and amides. Finally, the production of isocoumarlns, benzoxeplns, and other heterocycles by thallation and palladium-assisted olefination of aryl substrates was explored. For most of the compound classes studied, our method, which employs organometallic intermediates, is significantly shorter and more efficient than most older methods. 3 II. SYNTHESIS OF g-CHLORO-A®»^-BUTENOLIDES VIA MERCUHATION-CARBONYLATION OF PROPARGYLIC ALCOHOLS A. Introduction Unsaturated five-membered ring lactones occur in many natural products [2], They have been called "butenolides" since I898 [3], with Greek letters used to denote the position a ft of the double bond. Thus, compound ^ is A * -butenolide, while 2^ is A^'^-butenolide. Many authors also use the term By V a ^ 0 0 1 1 2 "crotonolactones". To avoid confusion. Chemical Abstracts recently adopted the furanone nomenclature; they list compound 1 as 2(5H)-furanone, and 2 as 2(3H)-furanone. Two extensive reviews have detailed the syntheses and reactions of such furanones [4,53. The Reformatsky reaction of acetoxy ketones or acetylenic carbonyl compounds with bromoacetic ester appears to be the most widely used route to 2(5H)- furanones (eqs, 1,2). There are literally dozens of other 0 0 OH 0 R RÏoHgoScHj BrCH"cO,C,H, > R-fcHjOSoHj '7^0 5 CHgCOgCgH^ ^ ^0/ H Zn T 2) K0H^^^^H2^S=\ (2) PhCsCCR BrCH^SO,C,H=> PhCEC-C-CHgCOgCgHs 0 R 3 HO 4 methods for the synthesis of furanones, including thermal re­ arrangements, Darzens-type condensations [4,5], and the carbonylation of acetylenes [6,7]; these are covered exhaustively in the reviews mentioned. Butenolides are found in many different plant, species, ranging from the simple metabolites of molds and yeasts [8] to the steroidal glycosides extracted from the foxglove (Digitalis) and from members of other plant families [9]. Amongst animals, sponges [10] and insects [11] are known to produce butenolides. Butenolides exhibit an unusually wide range of biological activity, which some examples will illustrate. Compound 3 is a patented insecticide [12]. 3 thai doses range from 0.1 ;ig to 25 Ug per insect Compound 3-(a-iininoethyl)-5-methyl~tetronic acid, is a chlorophyll inhibitor and herbicide [13,14]. Cucumber and CH 0 II HO r_CH 3 5 5 wheat seeds treated with ^ failed to develop normally, producing yellow leaves. These later turned white, and the plants died. However, 3-acetyl-5-methyl-tetronic acid, actually stimulates seedling development in wheat [l4]. Certain butenolides show marked antifungal activity [15], for example, compounds 6-£, and some are especially useful for 0 9 controlling fungus diseases in plants. Compound £ prevents rice blast infections [16]. Recently a new class of halo- genated butenolides has been isolated from the red seaweed Delisea fimbriata [17,18], The most active of