Unprecedented N → C[1,4] Boc migration: synthesis of 3-carboxyl functionalized 7-azaindolo[2,1-c][1,4]benzoxazine ring system

Use of 1 equiv excess n-BuLi in synthesis of azaindolo[2,1-c][1,4]benzoxazine heterocycles furnished the corresponding 3-(tert-butyloxycarbonyl) derivatives presumably via an unprecedented intramolecular N -> C[1,4] Boc migration. Thus, treatment of N-Boc-2-aminopicoline 1a with 3 equiv of n-BuLi at -15 degrees C, to generate the dianion Li-2-1a, followed by the reactions with Weinreb amides 2a-h at -40 degrees C, and then allowing the reaction mixture to warm upto it in a controlled manner (-40 to 0 degrees C, 2 h; 0 degrees C to rt, 16 h) led to formation of a series of Boc-group migrated products 7a-h generally in good yield (similar to 70% isolated yield). Surprisingly, going from cyclopentylene to cydohexylene cases (2d-e to 2g-h), the desired [1,4] Boc migration was found to be a minor fate (yield similar to 20%). In these instances, N -> ortho-C[1,31 Boc-migrated compounds 9g-h (to ortho-aryl position) were obtained as major products. Plausible mechanisms have been invoked for the formation of tetracyclic heterocycle 3a, as well as for the observed N -> C[1,41 Boc-group migration phenomena supported by data from anion quenching experiments. (C) 2012 Elsevier Ltd. All rights reserved.