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DOI: 10.1055/s-0039-1690699
Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from α-Aminoacetonitriles
Publication History
Received: 12 July 2019
Accepted after revision: 16 September 2019
Publication Date:
01 October 2019 (online)
Abstract
An efficient and practical synthetic protocol for the synthesis of 1,4-disubstituted pyrrolo[1,2-a]pyrazine derivatives is described that originates from α-substituted pyrroloacetonitriles which, in turn, are readily available from aryl and alkyl aldehydes. The α-pyrroloacetonitriles were subjected to a Friedel–Crafts acylation with methyl chlorooxoacetate followed by reduction of the nitrile group under Pd-catalyzed hydrogenation conditions and finally aromatization with DDQ leading to the desired pyrrolo[1,2-a]pyrazine derivatives. This method was generalized and successfully applied to various aryl, heteroaryl, and alkyl substrates. The developed protocol provides direct and convenient access to 1,4-disubstituted ring systems in moderate to good overall yields (51–68%) without the need for purification of the intermediates. Further functionalization via the stepwise halogenation (bromination, iodination) and nitration was also demonstrated. In addition, the potential of the ester functionality for elaboration was demonstrated by manipulating into heterocyclic ring systems, exemplified by conversion into benzoxazole derivatives.
Key words
pyrrolo[1,2-a]pyrazine - α-aminoacetonitriles - Clauson–Kass reaction - aromatization - cyclizationSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690699.
- Supporting Information
