Elsevier

Tetrahedron

Volume 66, Issue 17, 24 April 2010, Pages 3228-3241
Tetrahedron

One-pot synthesis of unsymmetrical disulfides using 1-chlorobenzotriazole as oxidant: Interception of the sulfenyl chloride intermediate

https://doi.org/10.1016/j.tet.2010.02.077Get rights and content

Abstract

A high-yielding and low temperature one-pot procedure is described for unsymmetrical disulfide synthesis from two different thiols using 1-chlorobenzotriazole (BtCl) as oxidant. The mechanism of the coupling involves in situ trapping of the sulfenyl chloride intermediate R1SCl by nucleophilic benzotriazole (BtH) to form R1SBt, which protects R1SCl from forming the homodimer R1SSR1. The methodology is applicable to all types of thiol (aliphatic, aromatic, heteroaromatic), with a variation developed for aliphatic–aliphatic couplings. Differentially N-protected cysteines couple to afford the unsymmetrical cystine derivatives in high yield (90%), which serves as a model for the one-pot intermolecular coupling of cysteine-containing peptides to form peptide disulfide heterodimers. Minimal exchange in aromatic–aromatic disulfide synthesis is noted on account of the mild conditions.

Introduction

Whilst many oxidants exist for the efficient conversion of a thiol into its symmetrical disulfide, the synthesis of an unsymmetrical disulfide in an efficient manner from two different thiols is a far more subtle methodological challenge in view of the possibility of forming three possible disulfide products as R1SSR1 (homodimer 1), R2SSR2 (homodimer 2) and the desired R1SSR2 (heterodimer). Published methods for this transformation are based mainly on the coupling of two different thiols via activating one of them to a sulfenyl derivative. Alternatively, though less conveniently, one may access the sulfenyl derivative by cleavage of a symmetrical disulfide with an electrophilic reagent, in which case the disulfide must be available. By comparison, methodologies for unsymmetrical disulfide synthesis from a symmetrical disulfide or via miscellaneous groups without the intervention of a sulfenyl derivative are far less common,1 with a recently reported rhodium-catalysed disulfide exchange protocol holding the most promise.2, 2(a), 2(b) The sulfenyl-based methodology involving thiols as starting materials involves using an electrophilic reagent to convert one of them into a sulfenyl derivative R1SLG (LG=Leaving Group), which can then be used as a sulfur electrophile in a nucleophilic substitution (thiolysis) reaction with a second thiol to form the desired product. In this regard, a plethora of different leaving groups based on different heteroatoms have been identified with varying levels of reactivity. Scheme 1 reveals the various equations involved in the methodology, and highlights a major potential drawback in that R1SLG, once formed, can go on to react with thiol 1 to form homodimer 1 resulting in the formation of a high percentage of homodimer 1 (Eq. 2) depending on the ratio of k1/k2.

If R1SLG is a reactive intermediate that is difficult to isolate, inevitably it gets transformed as a mixture, Scheme 1. Indeed, the first reported example a hundred years ago by Zincke3 of R1SLG formation from a thiol in the form of a sulfenyl chloride illustrates this point in that reaction of thiophenol with chlorine resulted in the formation of both diphenyl disulfide (homodimer 1) and benzenesulfenyl chloride. Over the years, the range of leaving groups have diversified but the aforementioned principle has remained. Thus, following pioneering work by Swan on Bunte salts (thiosulfates),4 Hiskey on sulfenylthiocyanates,5, 5(a), 5(b), 5(c) Mukaiyama on sulfenylhydrazides using DEAD6, 6(a), 6(b) and Harpp and Boustang simultaneously on sulfenylimides7, 7(a), 7(b) over a period spanning the 1950s through to the 1970s, other S-based groups8, 9, 10, 11, 12 to include bis-heteroaromatic disulfides13, 14, 15 as an extremely popular variant as well as other N-based16, 17 leaving groups have followed to the present day.

As a result of thiol competition in Eq. 2 of Scheme 1, the aforementioned sulfenyl methodologies have inevitably involved at least a two-step procedure with a purification step for R1SLG where possible. A major drawback of most of these methods, however, is the need to use a harsh, toxic electrophilic agent such as bromine, thionyl chloride or sulfuryl chloride to gain access to R1SLG. For instance, sulfenimides as one of the more popular types still in modern usage are prepared most conveniently from a disulfide, an imide such as phthalimide and bromine.18 The exceptions are the cluster of reactions involving heteroaromatic disulfides such as bis-benzothiazoyl disulfide,14 in which R1SLG can be relatively easily accessed as a stable intermediate via exchange of R1SH with the disulfide. However, here too, some degree of homodimer 1 production is inevitable from over-reaction with R1SH.

In response to this overall limitation, we have recently introduced a new methodology19 involving 1-chlorobenzotriazole as the oxidant in a one-pot transformation that minimizes the formation of homodimer 1. 1-Chlorobenzotriazole (BtCl) was introduced as a novel oxidant in 1968 by Rees20 and may be cheaply and readily prepared in multigram quantities by the oxidation of benzotriazole (BtH) with bleach in aqueous acetic acid. The product precipitates out of solution and can be crystallized and stored in the refrigerator for long periods. Although BtCl has found usage as both an oxidant as well as a chlorinating agent in synthetic organic chemistry, its application to sulfur chemistry has not developed. Our new methodology for one-pot unsymmetrical disulfide synthesis using BtCl owes its innovation to an in situ trapping step, in which the initial formed R1SCl (as R1SLG) is ‘protected’ from further thiol attack by rapid transformation into R1SBt (trapped R1SLG), which undergoes minimal reaction with R1SH under the conditions of its formation (−78 °C), because k2<<k1 (Scheme 1) where k2 refers to trapped R1SLG. Subsequent reaction with R2SH may then proceed with overall minimization of homodimer 1 formation. In this full paper, we give a full account of the development and scope of our novel methodology and discuss how it can be used for the high-yielding one-pot intermolecular coupling of differentially protected cysteine thiols to afford unsymmetrical cystine derivatives as a model reaction for intermolecular peptide disulfide heterodimer synthesis.

Section snippets

Results and discussion

Our new reaction was discovered while investigating the potential of BtCl as an alternative to N-chlorosuccinimide21 (NCS) in the context of unsymmetrical disulfide synthesis. Thus, reaction of p-methoxybenzenethiol as a representative thiol at −78 °C with BtCl (1.5 equiv) in DCM for 2 h led to two more polar (relative to the thiol) closely running product spots on TLC that were later separated and identified by 1H NMR spectroscopy as the two isomeric Bt derivatives of the thiol assigned overall

General

Thin layer chromatography (TLC) was used to monitor reactions using aluminium-backed plates coated with silica-gel F254. Compounds on TLC plates were observed by a combination of ultra-violet light, iodine vapour, or by spraying with a 2.5% solution of anisaldehyde in a mixture of sulfuric acid and ethanol (1:10 v/v) and then heating at 150 °C. Column chromatography was performed using silica-gel 60 mesh. All chromatography was carried out using either petroleum ether (bp 40–60 °C) or ethyl

Acknowledgements

We thank the South African National Research Foundation, the University of Cape Town and the Claude-Leon Foundation for financial support.

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