Microwave mediated syntheses of β -enamino thioic acid derivatives

Reaction of di(benzotriazole-1-yl)methanethione 1 with imines 2a – f gave air and moisture stable benzotriazolyl β -enaminothiones 3a – f . The thioacylbenzotriazoles 3a – f enable simple and efficient preparation of β -enamino thioic acid derivatives (thioamides, thioesters and dithioesters) in 74–99% yields via microwave mediated nucleophilic substitution of the benzotriazolyl moiety. C -Thioacylation with 1-thioacyl-6-nitrobenzotriazoles 7a

We now disclose a novel and efficient synthetic protocol for benzotriazolyl enaminothiones 3a-f from dibenzotriazolylmethanethione 1 and the application of these products to the preparation of β-enamino thioamides 4a-c, thioesters 5a-c, and dithioesters 6a-c.

Results and Discussion
The reaction of thiophosgene with four equivalents of benzotriazole in methylene chloride at 0 °C gave dibenzotriazolylmethanethione 1 in 87% yield (Scheme 1). 20he use of twofold excess of benzotriazole advantageously avoids the precursory generation of either 1-trimethylsilyl benzotriazole 21 or the sodium salt of benzotriazole, 20 required in the previously reported protocols.Excess of benzotriazole and low reaction temperature appear to be essential for successful preparation of 1. 20
Structures 3a-f were supported by their 1 H and 13 C NMR spectra, and elemental analyses (see Experimental Section).In the 1 H NMR spectra of benzotriazolyl enaminothiones 3a-f, the broad singlet signals in the range 13.21-14.95ppm and the singlet signals at 7.16-7.21ppm (for compounds 3a,b,e) corresponding to NH and CH of enamine fragment, respectively, confirmed exclusive existence in the Z-enamine form, resulting from N Treatment of compounds 3a,b under microwave irradiation at 80 °C with secondary amines gave β-enamino thioamides 4a-c (92-95%) (Scheme 1, Table 1).Similar treatment of 3a,b with alcohols or thiols in the presence of sodium or potassium hydroxide afforded thioesters 5a-c (74-99%) and dithioesters 6a-c (85-92%), respectively.As with compounds 3a,b, the 1 H NMR spectra of products 4-6 showed the presence of a broad singlet in the range 11.44-13.16ppm corresponding to NH proton suggesting exclusive Zenaminothione configuration (Scheme 1).
However, under the same conditions, treatment of benzotriazolyl enaminothiones 3c-f with alcohols, thiols or amines resulted in the recovery of 3c-f.Attempted treatments of 3c-f with sodium methoxide in methanol under microwave irradiation caused decomposition of the starting materials, while no reaction occurred upon stirring at room temperature for 48 h.
When group R 1 is aryl or heteroaryl group (compounds 3a,b), which behave as electron withdrawing groups, the electrophilicity of thioacyl group increases, making the benzotriazolyl β-enaminothione reactive toward secondary amines, alcohols and thiols.However, when R 1 is an alkyl group (compounds 3d-f), which behave as electron donating groups, the electrophilicity of the thioacyl group decreases, resulting in no reaction under same reaction conditions.Compound 3c was also unreactive toward secondary amines, alcohols and thiols.
The attempted reaction of benzotriazolyl enaminothione 3a with hydrazine under microwave irradiation at 80 °C failed and resulted in a complex set of polar products.Treatment of 3a with nitromethane or acetonitrile at 20 °C or heating up to 80 °C under microwave irradiation in the presence of sodium hydroxide gave no reaction.

Synthesis of β-enaminothiones
Thioacyl-6-nitrobenzotriazoles 7a-c reacted with ketimine 2a in THF in the presence of ZnBr 2 at 20 °C for 3 d to give β-enamino thiones 8a-c in moderate to good yield (Scheme 2).Unfortunately, similar reactions of thioacylbenzotriazoles 7a with ketimine 2i produced under the same reaction conditions thioamide 9 in low 35% yield instead of the expected β-enamino thione 8 (Scheme 2), while the reactions with imines 2e and 2h resulted in complex mixtures of products.It is possible that the formation of complex mixtures is due to the concurrent addition of ionized thioacylbenzotriazole 7 to the imine bond, followed by hydrolysis to thioamides, such as 9. Structures 8a-c were supported by their 1 H and 13 C NMR spectra, and by elemental analyses (see Experimental Section).
The order of addition significantly influences the chemical yield.Thus, the best results were obtained when the appropriate thioacylbenzotriazole 7 in THF was first treated with ZnBr 2 , followed by slow addition of the corresponding imine 2, in contrast to low yields upon the initial addition of the Lewis acid to a solution of ketimine 2a in THF.

Conclusions
In conclusion, a novel and general approach to β-enamino thioic acid derivatives has been developed.The procedure described appears to be general and represents an efficient, simple and alternative route to β-enamino thioic acid derivatives 4-6.

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus equipped with a digital thermometer and are uncorrected.NMR spectra were recorded on a Varian Gemini 300 spectrometer in CDCl 3 with tetramethylsilane as the internal standard for 1 H (300 MHz) or solvent as the internal standard for 13 C (75 MHz) unless otherwise stated.The elemental analyses were performed on a Carlo Erba EA-1108 instrument.Anhydrous THF was used freshly distilled from sodium/benzophenone. Column chromatography was conducted on silica gel 200-245 meshes.

General procedure for the preparation of benzotriazolyl β-enaminothiones 3a-h
To a solution of dibenzotriazolylmethanethione 1 (280 mg, 1 mmol) in THF (50 mL), appropriate imine 2 (1 mmol) was added at room temperature.The reaction mixture was stirred at the same temperature for 6 h, and then concentrated under vacuum.The residue was dissolved in ethyl acetate (50 mL), and was washed with 5% aqueous Na 2 CO 3 (3×30 mL), followed by brine (30 mL).The organic layer was dried over anhydrous Na 2 SO 4 , and the solvent was removed under vacuum.The residue was either recrystallized from dichloromethane/hexanes or purified by flash chromatography (hexanes/ethyl acetate 5:1) on silica gel to give 3a-h.

General procedure for the preparation of β-enamino thioesters 5a-c
Benzotriazolyl β-enaminothione 3 (0.3 mmol) was dissolved in 2N alcoholic sodium hydroxide (2 mL).The reaction mixture was exposed to microwave irradiation (80 Watts, 80 ºC) for 0.5 h.The solvent was removed under vacuum to dryness.The residue was dissolved in dichloromethane (10 mL) and the solution was washed with 5% aqueous Na 2 CO 3 (3×10 mL), followed by brine (10 mL).The organic layer was dried over anhydrous Na 2 SO 4 .the solvent was removed under vacuum, and the residue was purified by flash chromatography (hexanes/ethyl acetate 5:1) on silica gel to give 5a-c.