Synthesis 2005(2): 330-333  
DOI: 10.1055/s-2004-831226
PSP
© Georg Thieme Verlag Stuttgart · New York

Free Radical-Mediated Aryl Amination: A Practical Synthesis of (R)- and (S)-7-Azaindoline α-Amino Acid

Jayasree M. Srinivasan, Heather E. Burks, Colin R. Smith, Rajesh Viswanathan, Jeffrey N. Johnston*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405, USA
Fax: +1(812)8558300; e-Mail: [email protected];
Further Information

Publication History

Received 26 May 2004
Publication Date:
16 September 2004 (online)

Abstract

Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline α-amino acid have been prepared and isolated as their trifluoroacetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase transfer catalyzed glycine alkylation and free radical-mediated aryl amination. Implementation of the solid-liquid phase transfer conditions requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme [1] ).

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18

In our hands, a noticeable improvement of enantioselection is observed for this transformation if the crystalline ammonium salt is chromatographed (ref.1a).