Discovery of an α-amino C-H arylation reaction using the strategy of accelerated serendipity

Abstract

Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.

Fig. 1

Approach to reaction discovery without preconceived design via the concept of accelerated serendipity. R indicates a generic organic substituent; X and Y, heteroatoms.

Fig. 2

Discovery of a new photoredox amine C–H arylation reaction. Ph phenyl group; DMF, N,N-dimethylformamide; DMA, N,N-dimethylacetamide.

Fig. 3

Photoredox C–H arylation: amine scope. R, generic alkyl or aryl substituent. Data reported as entry, % isolated yield, regiomeric ratio (r.r., determined by ¹H nuclear magnetic resonance analysis). 2.5 to 3.0 equivalents of amine used (see fig. S6 for stoichiometry effects).

Fig. 4

Photoredox C–H arylation: arene and heteroarene scope. Ar, generic aryl group; X, CH or heteroatom; EWG, electron-withdrawing functional group. Data reported as entry, % isolated yield. 3.0 equivalents of amine used (see fig. S6 for stoichiometry effects). *Run with 5 mol % catalyst.† Leaving group is a chloride; photocatalyst is Ir(ppy)₂(dtbbpy)PF₆. ‡Reaction time is 72 hours.

Fig. 5

Photoredox C–H arylation: proposed mechanistic pathway. R, generic alkyl or aryl substituent; SET, single-electron transfer.