Employment of Two-Acid Promoter System in Pictet–Spengler Reaction: A Robust Two-Step Synthesis of Aza-Heterocycles

TL;DR

This paper introduces a sustainable two-step method for making aza-heterocycles using a two-acid promoter system, which is efficient and produces high yields with minimal waste.

Contribution

A novel two-acid promoter system using graphene oxide and Amberlyst 15 for the Pictet–Spengler reaction is introduced.

Findings

The method achieves up to 92% yield without further purification.

Promoters can be reused over multiple cycles while maintaining efficiency.

The approach is tolerant to various functional groups and avoids interference between acids.

Abstract

The growing demand for increasingly sustainable chemical
processes
continues to stimulate organic chemistry to develop highly efficient,
low-energy-consuming new reactions that require minimal effort to
isolate intermediates and produce reduced waste. In this context,
two-step reactions play an important role, and a good approach is
the two-step synthesis, in which reagents and catalysts or promoters
are introduced sequentially. Among these, the Pictet–Spengler-type
cyclization (PS) is a powerful stepwise strategy for the synthesis
of heterocyclic compounds. This article presents a novel and environmentally
friendly two-step strategy for the Pictet–Spengler reaction,
employing graphene oxide and Amberlyst 15 as acid promoters that yields
a diverse product library (up to 92% yield) without the need for further
purification. Both promoters can be reused over multiple reaction
cycles, maintaining high efficiency. The methodology demonstrates
broad functional group tolerance and provides a sustainable route
to various tetrahydro-β-carbolines (THβCs), including
biologically relevant compounds, and, above all, avoids negative interference
between the two acidic promoters.

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