Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines

Abstract

Molecules displaying an α-trialkyl-α-tertiary amine motif provide access to an important and versatile area of biologically relevant chemical space but are challenging to access through existing synthetic methods. Here, we report an operationally straightforward, multicomponent protocol for the synthesis of a range of functionally and structurally diverse α-trialkyl-α-tertiary amines, which makes use of three readily available components: dialkyl ketones, benzylamines, and alkenes. The strategy relies on the of use visible-light-mediated photocatalysis with readily available Ir­(III) complexes to bring about single-electron reduction of an all-alkyl ketimine species to an α-amino radical intermediate; the α-amino radical undergoes Giese-type addition with a variety of alkenes to forge the α-trialkyl-α-tertiary amine center. The mechanism of this process is believed to proceed through an overall redox neutral pathway that involves photocatalytic redox-relay of the imine, generated from the starting amine-ketone condensation, through to an imine-derived product. This is possible because the presence of a benzylic amine component in the intermediate scaffold drives a 1,5-hydrogen atom transfer step after the Giese addition to form a stable benzylic α-amino radical, which is able to close the photocatalytic cycle. These studies detail the evolution of the reaction platform, an extensive investigation of the substrate scope, and preliminary investigation of some of the mechanistic features of this distinct photocatalytic process. We believe this transformation will provide convenient access to previously unexplored α-trialkyl-α-tertiary amine scaffolds that should be of considerable interest to practitioners of synthetic and medicinal chemistry in academic and industrial institutions.

Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

“…The turnover-limiting step of the cycle is either radical addition to the styrene or regeneration of the photocatalyst, and a quantum yield measurement suggests some contribution from a radical chain process. In summary, we believe that the unique disconnection enabled by this new HAA protocol, together with its operational simplicity and sustainability, will help streamline the synthesis of complex alkyl­amines in both academia and industry …”

Radical Redox Cycloadditions: A General Light-Driven Meth-od for the Synthesis of Saturated Heterocycles

“…Additionally, 1,1-disubstituted and trisubstituted styrenes are effective annulation partners, providing pyrrolidines 6 and 9 bearing fully substituted ⍺-centers, a challenging structural motif to access in a general fashion. [57][58][59] Although simple, unactivated alkyl olefins were ineffective substrates under the standard conditions, we found that aryl-substituted ⍺,β-unsaturated carbonyls and dienes proved amenable to annulation. Specifically, pyrrolidines 7 and 8 were generated in 42% and 60% yield from an ⍺-phenyl acrylate ester and an ⍺-phenyl acrylamide, respectively.…”

An organophotocatalytic late-stage N–CH3oxidation of trialkylamines toN-formamides with O2in continuous flow

“… 10 This allowed direct C–H functionalizations α to N, of benzylic amines with nucleophiles 11 and a few examples of aliphatic amines with electrophiles. 12 A direct and highly N–CH 3 -selective LSF of trialkylamines was achieved using stoichiometric quantities of an SET-generated hydrogen atom transfer agent (DABCO˙ + ). 13 Powerful catalytic or photocatalytic LSF strategies for complex trialkylamines have emerged, but remain scarce.…”