Orthogonal sp3 C1–H and N–H Bond Functionalization of 1,2,3,4-Tetrahydroisoquinolines via the Ugi Four-Component Reaction

Abstract

A new protocol for orthogonal sp3 C1?H and N?H bond functionalization of 1,2,3,4-tetrahydroisoquinolines has been established via the Ugi four-component reaction with aldehydes, isonitriles, and carboxylic acids. It was revealed that only the N?H bond could be functionalized when the reaction was performed in acetonitrile at room temperature; however, when the reaction was carried out in toluene at 80??C, redox-neutral sp3 C1?H bond functionalization of 1,2,3,4-tetrahydroisoquinolines was achieved. Differing from the common role of carboxylic acid as a promoter in redox-neutral amine ?-functionalization, the carboxylic acid employed herein is also a reactant. The orthogonal process is compatible with various substrates and provides an appealing? access to a library of structurally diverse 1,2,3,4-tetrahydro?isoquinolines.

Iminium and azonium-activated metal and oxidant-free C–H functionalization of aliphatic amines

“…A closely related a-amidation reaction of THIQ 126 to the corresponding imide 137 has been developed by Feng and coworkers (Scheme 12, eqn ( 2)). 32 The regioselectivity of this fourcomponent reaction involving THIQ, aldehydes, isonitriles, and carboxylic acids was highly dependent on the reaction conditions. The reaction carried out at high temperature in toluene gave imide 137.…”

“…31 However, under anhydrous conditions (in the presence of molecular sieves), carboxylic acid reacted with nitrilium ion 140 , producing intermediate 141 , which after rearrangement, afforded the observed imide 137 . 32…”

“…31 However, under anhydrous conditions (in the presence of molecular sieves), carboxylic acid reacted with nitrilium ion 140, producing intermediate 141, which after rearrangement, afforded the observed imide 137. 32 Seidel and co-workers showed that enolizable ketones 142 or 144 could be used as effective nucleophiles for a-alkylation of N-heterocycles to provide the ring-substituted b-amino ketones 143 and 145 with moderate yields (Scheme 13). 33 The use of 2,6dichlorobenzaldehyde 77 and slow addition of a solution of a mixture (1 : 1.5) of 2,6-dichlorobenzaldehyde (77) and ketone to pyrrolidine were essential to obtain satisfactory yields of aalkylated product 143.…”