DBU-Mediated cleavage of aryl-and heteroaryl disulfides

The capacity of the nitrogen nucleophile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to reduce aryl-and heteroaryl disulfides to the corresponding mercaptans is demonstrated. While dicarboxylated disulfide analogues afford the mono-DBU disulfide salts, as confirmed by X-ray crystallography, the corresponding methyl esters are cleaved normally .


Introduction
3][4] As part of our ongoing research on applications of Baylis-Hillman methodology, 5 we reported the convenient, one-step synthesis of the thiochromenes 3a-g via the 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)-catalyzed reaction of 2,2'-dithiodibenzaldehyde 1a with activated alkenes 2a-g (Scheme 1). 6The thiochromenes 3ag were obtained in a single step − an observation that suggested the capacity of DBU to reduce the disufides 4a-g (formed via the Baylis Hillman reaction), possibly via the sequence outlined in Scheme 1. 6 Phosphine nucleophiles have been implicated in the direct cleavage of disulfides, 7 while photo-induced cleavage via disulfide radical anions has been attributed to electron transfer from excited-state aniline 8 and various amines have been used in large excess (40 eq.) to produce, in situ at elevated temperatures, benzenethiyl radicals from diphenyl disulfide via a single electron transfer process. 9DBU has been used as a base in thiazolium salt-catalyzed disufide reduction−aldehyde oxidation processes 10 but, to our knowledge, its role as a nucleophile in the direct cleavage of disulfides is unprecedented.We now report the results of further research directed at exploring the general capacity of DBU to reduce diaryl and heterodiaryl disulfides to mercaptans in the absence of an activated alkene, thus precluding involvement of a Baylis-Hillman adduct, as suggested in Scheme 1. Scheme 1. Synthetic pathway and putative mechanism to account for the formation of the thiochromenes 3a-g. 6

Results and Discussion
In order to investigate the potential of DBU to serve as a disulfide reducing agent, solutions of the nine disulfides 1a-i (Scheme 2) in chloroform were treated with DBU in the same molar ratios and under the same reaction conditions used in the previously reported Baylis-Hillman reactions, 6 but without any activated alkene.[Under these conditions, accommodation of the nucleofugal sulfide by a pre-formed Baylis-Hillman adduct (as suggested in Scheme 1) would be precluded.]In most cases, the expected mercaptans (9a-f) were, in fact, isolated in low to moderate yield (13 -53%), demonstrating the ability of DBU to effect reductive cleavage of the disulfide bonds in these compounds.The carboxylic acid derivatives 1g-i, however, afforded crystalline products, NMR analysis of which initially suggested possible trapping of the putative oxidised DBU cation 8 (Scheme 1).Single-crystal X-ray analysis (Figure 1) of the product obtained using the dicarboxylic acid 1i, however, confirmed the formation of the corresponding mono-DBU-disulfide salt 10i. 11Formation of the salts 10g-i prompted synthesis of the corresponding methyl esters 1d-f.When the substrate 1a was dissolved in CDCl3 alone, no change was observed after 14 days, confirming that DBU is, in fact, responsible for the observed disulfide cleavage.When the disufide 1a was treated with DBU in the dark, normal disulfide cleavage was observed thus excluding a photo-induced, free-radical process.Scheme 2. Reaction of disulfides 1a-i with DBU in chloroform.

Conclusions
DBU is clearly capable of direct reductive cleavage of the diaryl and heterodiaryl disulfides 1a-f.Optimization and extension of the methodology to aliphatic disulfides may provide an effective alternative, in certain applications, to the use of more established reagent systems.The thiophilicity of DBU 7 in these reactions may be attributable to the intramolecular delocalisation effects illustrated in structure 7 in Scheme 1.

Experimental Section
General.Reagents, as supplied by Aldrich-Sigma, and solvents were used without further purification. 1H and 13 C NMR spectra were recorded on Bruker AMX400 or Avance II + 600 MHz spectrometers, and were calibrated using solvent signals; coupling constants are given in Hertz (Hz).Melting points were determined using a hot-stage apparatus, and are uncorrected.IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer.High-resolution mass spectra were recorded by the University of Stellenbosch Mass Spectrometry Unit.Flash chromatography was carried out using Merck silica gel 60 [230-240 mesh (particle size 0.040-0.063mm)] and preparative layer chromatography was conducted using silica gel 60 PF254.HPLC was carried out on a Partisil 10 Magnum 6 normal phase column using a Spectra-Physics P100 isocratic pump and a Waters K1410 differential refractometry detector.
General procedures and analytical data for new compounds are as follows.

Figure 1 .
Figure 1.X-Ray crystal structure of the mono-DBU salt 10i of dicarboxylic acid 1i showing the crystallographic numbering for the asymmetric unit and thermal ellipsoids drawn at the 50% probability level.