# Heterogeneous photocatalytic aldehyde alkylative amination for multicomponent synthesis of α-branched amines

## TL;DR

A new photocatalytic method efficiently synthesizes complex a-branched amines and aza-heterocycles from common starting materials using TiO2.

## Contribution

A TiO2-based photoredox catalytic strategy for aldehyde alkylative amination is developed, enabling scalable synthesis of α-branched amines and pharmaceutical compounds.

## Key findings

- The AAA approach produces over 80 examples of α-branched amines, amino acids, and aza-heterocycles.
- The method enables reductive alkylation of inert amides and is scalable via a recirculating-flow system.
- Mechanistic studies reveal that TiO2's mixed-phase structure enhances photocatalytic activity through improved charge transfer.

## Abstract

α-Branched amines and aza-heterocycles are crucial motifs commonly found in natural products and pharmaceutical compounds, and development of mild and sustainable methods to synthesize them from abundant feedstocks is urgently needed. Herein, a powerful and straightforward TiO2 (P25) photoredox catalytic decarboxylative alkylation strategy is designed for universal aldehyde alkylative amination (AAA) using readily available aldehydes, amines and carboxylic acids. This AAA approach facilitates rapid access to a wide range of complex α-branched amines, amino acids and aza-heterocycles (>80 examples). Notably, this strategy can also be extended to the reductive alkylation of inert amides, which is of significant practical utility. To showcase its effectiveness, this AAA protocol was employed to streamline the synthetic routes of numerous pharmaceutical-related molecules, which can be easily scaled up using a recirculating-flow system. Mechanistic studies suggest that the photogenerated holes on TiO2 oxidized the chemisorbed carboxylic acid to release CO2 and R• radicals. Simultaneously, the photogenerated electrons reduced Ti(IV) to Ti(III), enabling the retrieval of an electron from reactive intermediates to complete the catalytic cycle. Additionally, transient absorption decay and theoretical calculations revealed that mixed-phase TiO2 (P25) exhibited enhanced charge transfer dynamics and thermodynamics, resulting in superior photocatalytic activity. This study provides guidance for future materials design in oxidative decarboxylation.

This work develops an efficient and straightforward three-component a-branched amine synthesis strategy from accessible aldehydes, amines and carboxylic acids, and uncovers the activity trend of different TiO2 crystal phases in photocatalytic decarboxylative addition.