Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

Mahesh K Lakshman,Domenick Wagner,Vijayender R Yedulla,Asha Matin,Manish K Singh,Lijia Yang,Raghu Ram Chamala,Mukesh Kumar,Sadia Ahmad,Evan Leung

doi:10.3762/bjoc.10.200

Abstract

(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{1H}, [18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO− is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π–allyl complexes by departure of BtO− has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.

Highlights

Benzotriazole derivatives are of importance in diverse contexts
This line of reasoning would suggest that 1-alkoxy-1H-benzotriazoles may be obtainable from the reactions of alcohols with BOP, and that different reaction pathways may be operative depending upon the nature of the nucleophile (Scheme 2)
The formation of 1-alkoxy-1H-benzotriazoles by such an approach appeared implausible on the basis of prior observations, where no reaction of BOP with the free hydroxy groups of nucleosides was observed [23,25]

Summary

Introduction

Benzotriazole derivatives are of importance in diverse contexts. As examples, in medicinal chemistry substituted benzotriazoles have been evaluated as inhibitors of respiratory syncytial virus [1], halogenated benzotriazoles have been shown to inhibit helicase activity of hepatitis C [2], N-alkylbenzotriazoles were shown to be active and selective towards HCV NTPase/heli-Beilstein J. We report a facile approach to 1-alkoxy-1H-benzo- (BtOR) and 7-azabenzotriazoles (At-OR) by a previously unstudied reaction of benzotriazole-based peptide-coupling reagents with alcohols [21]. Reaction of phenol with Bt-OTs resulted in the formation of the phenyl tosylate (Table 2, entry 16), indicating the potential use of this reagent as a tosylating agent for phenols.

Results

Conclusion