Preparation of symmetric bis-sulfides via reductive thiolation of dicarbonyl with thiols or of carbonyl compounds with dithiols in the presence of triethylsilane and boron trifluoride monohydrate 1

Symmetric organic bis-sulfides were prepared via reductive thiolation of dicarbonyl compounds with thiols or of carbonyl compounds with dithiols in the presence of triethylsilane and boron trifluoride monohydrate.


Introduction
Organic bis-sulfides are generally synthesized by the nucleophilic substitution of alkyl halides with thiolates. 2This procedure can be carried out by reacting either dithiols with monohalides or dihalides with monothiols.Other methods of preparation of bis-sulfides have also appeared sporadically in the literature.They usually deal with some specific types of bis-sulfides.For example, 1-n-butylthio-2-(1,1diaryalkylthio)ethanes and -propanes can be obtained by treating corresponding 2,2-diaryl-1,3-dithiolanes and -1,3-dithianes with nbutyl lithium followed by addition of alkyl halides.3a Vicinal bissulfides were prepared by either BF3 catalyzed addition of disulfides to alkenes or radical addition of two molar equivalents of thiol to acetylenes.3b,c We have earlier reported boron trifluoride monohydrate catalyzed one flask preparation of sulfides from carbonyl compounds with thiols and triethylsilane (eqn.1). 4 Kikugawa reported a similar transformation by using pyridineborane complex in trifluoroacetic acid medium. 5Our method 4 is more general and works well with aliphatic ketones.No hydrogen gas is generated as in the case with Kikugawa's procedure.A comprehensive review on silicon mediated synthesis of sulfur containing molecules has appeared. 6We would like to report now the extension of our earlier method 4 for the preparation of organic bis-sulfides.

Results and Discussion
Aromatic dicarbonyl compounds react readily with two molar equivalents of thiol in the presence of triethylsilane and boron trifluoride monohydrate to give the corresponding bis-sulfides. 7When terephthaldicarboxaldehyde was reacted with ethanethiol and 1-propanethiol, α,α′-bis(alkylthio)-p-xylenes were obtained in excellent yields (See Table 1), eqn. 2.
However, with 2-methyl-2-propanethiol and thiophenol, slow addition of the silane and proper amount of solvent were necessary to ensure formation of the bis-sulfides in good yield.Otherwise, precipitation occurred and lower yields of products ensued.Reaction of 1,4-diacetylbenzene with ethanethiol proceeded well to produce α,α′bis(ethylthio)-p-diethylbenzene (eqn.3).
Thiolation of aliphatic dicarbonyl compounds was also studied.When 1,4-cyclohexandione was treated with ethanethiol and 2propanethiol, two stereo isomers, equatorial-equatorial and equatorialaxial, were obtained in a 1.3:1 ratio in both cases (by GC analysis), eqn.4.1,4-Cyclohexandione was also reacted with 2-methyl-2propanethiol, with the expectation of changing the isomer ratio by increasing the bulkiness of the alkyl group of the thiol.The reaction, however, led to complex mixtures of products.This is in contrast to what was earlier observed in the monothiolation of carbonyl compounds with 2-methyl-2-propanethiol.In those cases, desired sulfides were obtained in good yields. 4However, it is difficult to rationalize these contrasting results.Reaction of 1,3-pentandione with thiols gives two diastereomers in each case.The isomer ratios (anti over syn or vice versa) for 1,3bis(ethylthio)pentane and 1,3-bis(i-propylthio)pentane, determined by GC analysis are 1.4 and 1.3, respectively (eqn.5).
When benzil and 1,2-butandione were used as substrates, desired vicinal bis-sulfides were obtained along with a series of other products.These by-products were, however, not separated and identified.
Another route to bis-sulfides that was explored was the reaction of dithiols with monocarbonyl compounds (eqn.6).Aliphatic dithiols, wherein the thiol groups are separated by at least four methylene units, react with ketones cleanly to provide the expected bis-sulfides.Otherwise significant amount of cyclization products (i.e.thioacetals), derived from reaction of dithiols with one carbonyl group, are obtained.
In case of aliphatic aldehydes, the needed separation is five methylene units.Besides cyclization, thiolation of aliphatic aldehydes is known to be affected by condensation of alkenyl sulfides 4 generated in situ by dehydration of hemithioactals. 8We have encountered similar difficulties in the preparation of monosulfides. 4Lower boron trifluoride content hydrates 9 such as BF3:1.25 H 2 O, BF 3 :1.45H 2 O, and BF 3 :2 H 2 O were also investigated for the reaction, in hope of lessening the degree of condensation by reducing the acidity of the catalyst systems.However, the reactions proceed more sluggishly with increasing water content in the catalysts with no significant improvement in the yield of the desired products.Inverse addition of acids to mixture of dithiols and propionaldehyde led to partial reduction of the aldehyde.
Commercially available 1,3-benzenedithiol was also reacted as a representative aromatic dithiol.Good yield of m-(i-propylthio)benzene was obtained in the reaction with acetone.Lower yield of bis-sulfide was obtained in the reaction of 1,3-benzenedithiol with n-propionaldehyde (eqn.7).
One flask preparation of unsymmetrical bis-sufides by described method was also attempted by sequential addition of two different thiols to terephthaldicarboxaldehyde.Along with the desired unsymmetrical bis-sulfides, some symmetric ones were also obtained.We further found that when terephthaldicarboxaldehyde reacted with only one molar equivalent of a single thiol, bis-sulfide was among the products.
In conclusion, we have found that reductive thiolation of carbonyl compounds is a general method for preparation of symmetric bissulfides.

Experimental Section
General Procedures.All carbonyl compounds and thiols used were purchased from Aldrich, and used without further purification.Boron trifluoride was from Matheson Gas Products.Boron trifluoride hydrates were prepared according to a reported procedure. 10MR spectra were obtained on either a Varian Associates Model Unity-300 NMR spectrometer or a Varian Associates Model VXR-200.GCMS (EI Mode) analyses were performed on a Hewlett Packard 5971 Mass spectrometer.CIMS analyses were carried out on a Finnigan Incos-50 MS instrument.High resolution MS analyses of all new compounds were conducted at the University of California at Riverside.

General procedure for preparation of bis-sulfides via reductive thiolation of carbonyl compounds
To a well stirred solution of 10 mmol dicarbonyl compound (or dithiol) and 20 mmol thiol (or carbonyl compound) in 15-30 ml CH 2 Cl 2 at 0°C was added dropwise 2 ml of BF 3 :H 2 O (40 mmol).After 5-10 minutes, triethylsilane (22 mmol) diluted in 10 ml CH 2 Cl 2 was added dropwise.The reaction mixture was then stirred for 2 hours at room temperature, followed by quenching with ice water.The quenched mixture was extracted with CH 2 Cl 2 ( 3 x 25 ml).The combined organic extract was washed sequentially with aq.10% KOH solution and water, dried (over CaCl 2 ) and evaporated in a rotary evaporator.The product was further purified either by distillation or recrystallization.α,α'-Bis(ethylthio)-p-xylene (4a = Et; b, R = i-Pr