Synthesis 2020; 52(03): 441-449
DOI: 10.1055/s-0039-1690699
paper
© Georg Thieme Verlag Stuttgart · New York

Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from α-Aminoacetonitriles

a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
,
Sridharan Ramalingam
a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
,
Mushkin Basha
a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
,
Gopi Kumar Indasi
a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
,
Makonen Belema
b  Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA
,
b  Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA
,
T. G. Murali Dhar
b  Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA
,
Richard Rampulla
b  Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA
,
Arvind Mathur
b  Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA
,
Anuradha Gupta
a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
,
a  Department of Discovery Synthesis, Biocon Bristol Myers Squibb Research Centre, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India   Email: Arunkumar.Gupta@syngeneintl.com
› Author Affiliations
Further Information

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.

Supporting Information

 
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