Toluene → Sodium borohydride

Participants

Reaction Steps

Hydrogenation of the obtained (E)-ethyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-2-yl)acrylate derivatives (4) over a catalyst such as Pd—C 10% or PtO2 in an aprotic solvent such as EA followed by reaction with KOtBu in an aprotic solvent such as THF gives the corresponding tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene and subsequent reductive aminations with, first, benzylamine in the presence of a reducing agent such NaBH(OAc)3 in an aprotic solvent such as DCM, and with, second, an appropriate aldehyde (as precursor of R3) in the presence of a reducing agent such NaBH4 in a protic solvent such as MeOH gives the corresponding N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-amine derivatives (6). Friedel-Craft acylation with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-(benzylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (7). Debenzylation by hydrogenation over a catalyst such as Pd—C 10% in a protic solvent such as EtOH or by reaction with 1-chloroethyl chloroformate and MeOH in an aprotic solvent such as DCM gives the respective N-substituted methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (8). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I) (Method A).

Provenance & Evidence