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

Ananta Karmakar; Sridharan Ramalingam; Mushkin Basha; Gopi Kumar Indasi; Makonen Belema; Nicholas A. Meanwell; T. G. Murali Dhar; Richard Rampulla; Arvind Mathur; Anuradha Gupta; Arun Kumar Gupta

doi:10.1055/s-0039-1690699

Synthesis, Table of Contents

Synthesis 2020; 52(03): 441-449
DOI: 10.1055/s-0039-1690699

paper

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

Ananta Karmakar

^aDepartment 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

^aDepartment 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

^aDepartment 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

^aDepartment 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

^bDepartment of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA

,

Nicholas A. Meanwell

^bDepartment of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA

,

T. G. Murali Dhar

^bDepartment of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA

,

Richard Rampulla

^bDepartment of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA

,

Arvind Mathur

^bDepartment of Discovery Synthesis, Bristol-Myers Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543-4000, USA

,

Anuradha Gupta

^aDepartment 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

,

Arun Kumar Gupta ∗

^aDepartment 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

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Abstract

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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 - cyclization

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References

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Supplementary Material

Supporting Information