Thioacetalization of the carbonyl function, transthioacetalization of acetals, ketals, oximes and hydrazones catalysed by aqueous hydrobromic acid

Thioacetalization of a variety of aldehydes and ketones was achieved in excellent yields at room temperature using thiols or dithiols in aqueous hydrobromic acid. Thioacetals were also prepared by transthioacetalization of oximes, hydrazones, acetals and ketals under similar conditions. The use of aqueous hydrochloric acid, hydrofluoric acid and hydriodic acid for this transformation was also explored.


Introduction
The protection of the carbonyl group as thioacetal is often a necessary step in the synthesis of complex organic molecules due to its inbuilt stability for acidic or basic conditions.Thioacetals are also useful in organic synthesis as acyl carbanion equivalents in C-C bond forming reactions. 1Preparation of thioacetals 2 generally involves reaction of carbonyl compounds with thiols in presence of protic or Lewis acids in various dry organic solvents many of which are environmentally hazardous.
Though there are a number of reagents reported for preparation of thioacetals, the continuous search for novel reagents with selectivity, ease of operation or increase in yields has resulted in several publications in recent years.2g-o Water is considered as a favorable solvent in many organic transformations 3 and thioacetalization in aqueous medium has been reported recently using indium tribromide 4 and dodecylbenzenesulfonic acid 5 but the possibility of preparing thioacetals using aqueous halo acids (hydrobromic, hydrochloric and hydrofluoric) has not been explored.We ventured to explore the possibility of preparing thioacetals in aqueous medium using various halo acids as catalyst and wish to report herein our results demonstrating use of catalytic amount of hydrobromic acid to prepare thioacetals from aldehydes and ketones as well as for transthioacetalization of acetals, ketals, oximes and hydrazones as shown in Scheme 1.

Results and Discussion
Reaction of 3,4,5-trimethoxybenzaldehyde with ethanedithiol in the presence of commercially available aqueous hydrobromic acid (48% w/w aq.) at room temperature afforded the corresponding thioacetal in high yield.The generality of this transformation was confirmed by reacting various carbonyl compounds with dithiols under similar conditions.Table 1 shows the results of the thioacetalization of various carbonyl compounds including variably substituted aldehydes.This protocol was also effective for ketones as exemplified by entries 13 and 14 in Table 1.
The desired products were obtained in high isolated yields.Similarly 3,4,5trimethoxybenzaldehyde when treated with ethanethiol under same conditions resulted in the corresponding thioacetal in high yield.It was noted that when syringaldehyde (entry 12, Table 1) was subjected to protection with ethanedithiol the complete conversion took longer time and with slight reduction in the yield which may be as a result of deactivation of carboxaldehyde due to the free hydroxyl in the para position.
In order to examine the utility of other halo acids in thioacetalization, 3,4,5trimethoxybenzaldehyde was reacted with ethanedithiol in presence of commercially available aqueous hydrochloric acid (36 % w/w aq., 0.2 eq.), or hydrofluoric acid (40 % w/w aq., 0.2 eq.) or hydriodic acid (57 % w/w aq., 0.2 eq.) under identical conditions and it was observed that the corresponding thioacetal was obtained in comparable yield from all the experiments.

Scheme 2
Due to the stability of thioacetals, they have been of great interest to organic chemists and there are a number of reports of transthioacetalization of acetals, ketals or O, S-acetals 6 , oximes 7 and hydrazones 8 .The results obtained in case of thioacetalization prompted us to study the scope of the utility of halo acids for transthioacetalization.Accordingly, acetals, ketals, oximes and hydrazones were reacted with dithiols in presence of aqueous hydrobromic acid (48 % w/w) (Scheme 3) and it was found that the thioacetals were obtained in high isolated yields (Table 2).

Scheme 3
Transthioacetalization of acetals and ketals was achieved at room temperature while oximes and hydrazones required refluxing temperature and somewhat longer reaction times.It is evident from Table 2 that the transthioacetalization of oximes and hydrazones using aqueous hydrobromic acid (48 % w/w aq.) can be achieved successfully irrespective of the electronic nature of functional groups.Typical experimental procedure for thioacetalization To a mixture of 3,4,5-trimethoxybenzaldehyde (0.50 g, 2.55 mmol) and 1,2-ethanedithiol (0.29 g, 3.06 mmol) in water (5 ml), was added aqueous hydrobromic acid (48 % w/w, 0.06 ml, 0.51 mmol).The reaction mixture was stirred at room temperature for 15 min and the reaction was monitored by thin layer chromatography (Table 1, entry 1).The reaction mixture was then extracted with chloroform (2 x 15 ml), combined organic layer was washed with 10 % sodium hydroxide solution (10 ml) followed by water (10 ml) and brine (5 ml).Concentration of organic layer under reduced pressure and purification of residue by passing through silica gel furnished 2-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (0.69 g, 94 %) as a pale yellow solid.
X= F, Cl, Br or I

Table 2 .
Transthioacetalization of oximes, hydrazones and ketals in the presence of hydrobromic acid (0.2 eq., 48 % w/w aq.) 93neral Procedures.Melting points are uncorrected. 1MR and13C NMR spectra were recorded on a Bruker Avance DPX 200 (200 and 50.3 MHz, respectively) spectrometer in organic solvents with TMS as internal standard.IR spectra were recorded on Perkin-Elmer Spectrum 683 B or 160S FT IR spectrophotometer.Elmental analysis was performed on a Perkin-Elmer Model 2400 analyser.Thin layer chromatography was performed on silica/alumina plates.Column chromatography was performed on silica gel (60-120 mesh).Preparation of oximes, phenylhydrazones and oxyacetals were carried out according to the general procedure.9