Highly Efficient Synthesis of Alkyl Pyrrolylacetates and Dialkyl Pyrrolylmalonates

Article abstract of DOI:10.1021/jo00097a025

N-Pyrrolylmagnesium halides (1, 2) react with alkyl bromoacetates (3a-d) in THF solution to give alkyl 2-pyrrolylacetates (5a-d) in good yields and with very high positional selectivity (C-2:C-3 >/= 25).The high regioselectivity is rationalized in terms of an increased propinquity between C-2 and the bromoacetate methylene group as a consequence of coordination between magnesium and the carbonyl oxygen of the alkylating agent. (2,5-Dimethylpyrrol-N-yl)magnesium chloride (9) and isopropyl bromoacetate (3c) gave the 3-pyrrolylacetate 10 exclusively.Alkoxycarbonylation of the dianions of the above alkyl pyrrolylacetates with alkyl chloroformates gave the corresponding dialkyl pyrrolylmalonates, two of which (16a and 19) were transformed into the dialkyl 1,2-dihydro-3H-pyrrolo<1,2-a>pyrrole-1,1-dicarboxylates (22 and 20, respectively) with 1,2-dichloroethane under phase transfer conditions.Compound 20 was converted into the powerful nonaddicting analgesic ketorolac (21).