Carboxylates, "/-bromo Subject

Milkiewicz et al. <2003TL4257> prepared a series of novel tetrasubstituted furo[3,2-/ ]pyrroles from the methyl or ethyl 3-bromo-2-phenylfuro[3,2-3]pyrrole-5-carboxylate 336. The compounds 336 were subjected to a Suzuki coupling with 4-chlorophenylboronic acid to form 337, which was treated with a variety of alkylating agents to afford the corresponding esters 338. The esters were then saponified to acids 339 (Scheme 34). 

A mild method for generating reactive ketenes has been developed59 which involves the dehalogenation of cc-bromo carboxylic acid chlorides at low temperatures (— 80 C) with pentacarbonylmanganese(IV) anion [Mn(CO),]. For example, subjecting 16 to these conditions provides a practical synthesis of the corresponding eyclobutanediones 18. 

Imidazolecarboxylic acids are stable, crystalline compounds which form salts with metals, and which may exist in zwitterionic forms such as (198 Scheme 106). Such zwitterionic forms have been implicated in the decarboxylation mechanisms of the compounds. The carboxyl functions exert a pronounced base-weakening effect on the parent molecules, but it is surprising that a 5-bromo substituent in imidazole-4-carboxylic acids is not subject to ready nucleophilic displacement by CN or SOs . 

Cyclopropyl thien-2-yl ketone (34), available commercially, was subjected to a Grignard reaction with 21 to yield a carbinol (31) in excellent yield. Bromotrimeth-ylsilane-mediated opening of the cyclopropyl ring led to the 4-bromo derivative 32. Condensation with ethyl i -(-)-pipeildme-3-carboxylate (16) was conducted in isopropyl acetate as a solvent with anhydrous lithium carbonate as the base. The transformation was cleaner and did not provide any of the diene (26) arising from elimination of hydrogen bromide. The alkylation of the nipecotate residue could also be directly effected with a mixture of the tartrate salt of 16, lithium carbonate, and isopropyl acetate. Compound 33 was readily isolated as the hydrochloride isopropyl acetate was superior to all other solvents used in this reaction. Since it is not itself prone to hydrolysis, it is preferable to ethyl acetate. Moreover, it appears to crystallize hydrochlorides much better. 

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