DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support.

Johnny N Naoum,Mattan Hurevich,Koushik Chandra,Dorit Shemesh,R Benny Gerber,Chaim Gilon

doi:10.3762/bjoc.13.81

Abstract

Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of several primary amine motifs, largely due to inefficient sulfonylation. Here we show that using the superior nucleophilic base DMAP instead of the commonly used base collidine as a sulfonylation additive is essential for the introduction of the o-NBS group to these amine motifs. DFT calculations provide an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three Nα-methylation sites that could not be synthesized using the previously described state-of-the-art methods.

Highlights

Methylated amines and amides are common motifs found in natural and synthetic compounds, e.g., small molecules, peptides, and oligonucleotides [1,2,3,4,5,6,7,8]
We showed that the sulfonylation reaction of o-NBS-Cl using 2,4,6collidine as additive, which is commonly used for this synthetic transformation, is inefficient for several amine motifs. 4-Dimethylaminopyridine (DMAP) has been reported to assist in the sulfonylation and acylation of weak nucleophiles such as secondary amines, alcohols, amides, and sterically hindered amines when used as catalyst in addition to a base additive [28,29,30,31]
This study presents an improved three-step solid-phase synthesis (SPS) N-methylation strategy that allowed accessibility to single and multi-site methylated compounds, which could not be synthesized using the state-of-the-art methods

Summary

Introduction

Methylated amines and amides are common motifs found in natural and synthetic compounds, e.g., small molecules, peptides, and oligonucleotides [1,2,3,4,5,6,7,8]. Many reported mechanistic studies reflect on the unique significance of the para-dialkylamino group [32] to the stabilization of the intermediate, DMAP was never reported to be used as the sole additive for sulfonylation of primary amines with o-NBS-Cl for the purpose of N-methylation on solid support.

Results

Conclusion