Amide-Type Substrates in the Synthesis of N-Protected 1-Aminomethylphosphonium Salts

Dominika Kozicka,Jakub Adamek,Paulina Zieleźny,Karol Erfurt

doi:10.3390/catal11050552

Abstract

Herein we describe the development and optimization of a two-step procedure for the synthesis of N-protected 1-aminomethylphosphonium salts from imides, amides, carbamates, or lactams. Our “step-by-step” methodology involves the transformation of amide-type substrates to the corresponding hydroxymethyl derivatives, followed by the substitution of the hydroxyl group with a phosphonium moiety. The first step of the described synthesis was conducted based on well-known protocols for hydroxymethylation with formaldehyde or paraformaldehyde. In turn, the second (substitution) stage required optimization studies. In general, reactions of amide, carbamate, and lactam derivatives occurred at a temperature of 70 °C in a relatively short time (1 h). On the other hand, N-hydroxymethylimides reacted with triarylphosphonium salts at a much higher temperature (135 °C) and over longer reaction times (as much as 30 h). However, the proposed strategy is very efficient, especially when NaBr is used as a catalyst. Moreover, a simple work-up procedure involving only crystallization afforded good to excellent yields (up to 99%).

Highlights

In 2017, we reported the synthesis of 1-imidoalkylphosphonium salts and their application as α-imidoalkylating agents [32]
We would like to present our research on the two-step preparation of N-protected 1-aminomethylphosphonium salts from amides, carbamates, lactams, or imides
It can be considered as an interesting complement to previously described methods, especially for the synthesis of imidoalkylphosphonium salts

Summary

Introduction

The crucial step in such reactions is the generation of the proper α-amidoalkylating agents (N-acylimines 3 or N-acyliminium cations 4) from the relevant precursors 1. For this purpose, it is necessary to use catalysts, either bases Interesting exceptions are N-protected 1-aminoalkylphosphonium salts 2. This particular structure, especially the presence of a positively charged triarylphosphonium group (which departs as a triarylphosphine) in the direct vicinity of the N-acylamino group, facilitates the formation of N-acyliminium-type cations [16,29]. The reactivity of compounds 2 can be increased by structural modifications within the phosphonium moiety, e.g., by the introduction of electron-withdrawing substituents, which reduce the

Methods

Results

Conclusion