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

• Published in: Tetrahedron 2013-01, Vol.69 (4), p.1354-1362
• Main Authors: Kurhade, Santosh, Ramaiah, Parimi Atchuta, Prathipati, Philip, Bhuniya, Debnath
• Format: Article
• Language: English
• Subjects: 3-(tert-Butyloxycarbonyl)-7-azaindolo[2,1-c][1,4]benzoxazine; 7-Azaindolo[2,1-c][1,4]benzoxazine; N→C[1,4] Boc-group migration; Reaction mechanism
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2012.11.073

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 °C, to generate the dianion Li2-1a, followed by the reactions with Weinreb amides 2a–h at −40 °C, and then allowing the reaction mixture to warm upto rt in a controlled manner (−40 to 0 °C, 2 h; 0 °C to rt, 16 h) led to formation of a series of Boc-group migrated products 7a–h generally in good yield (∼70% isolated yield). Surprisingly, going from cyclopentylene to cyclohexylene cases (2d–e to 2g–h), the desired [1,4] Boc migration was found to be a minor fate (yield ∼20%). In these instances, N→ortho-C[1,3] 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[1,4] Boc-group migration phenomena supported by data from anion quenching experiments. [Display omitted]