Simple Microwave-Assisted Method for the Synthesis of Primary Thioamides from Nitriles

Abstract

Primary thioamides are prepared in excellent yield from the corresponding nitrile by treatment with ammonium sulfide in methanol, at room temperature for electron-deficient aromatic nitriles or under microwave irradiation at 80 °C or 130 °C in 15-30 minutes for other aromatic and aliphatic nitriles. This procedure avoids the use of gaseous H₂S under high pressure, proceeds in the absence of base and provides thioamides usually without the need for chromatographic purification.

Key words

thioamides - nitriles - microwaves

References

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21

General Procedure for Reaction of Nitriles 1 and Ammonium Sulfide at Room Temperature (Method A). A solution of nitrile 1 (0.5 mmol, 1 equiv) and (NH₄)₂S (0.5 mmol, 1 equiv; 50 wt.% in H₂O) in MeOH (5 mL) was stirred at r.t. for 18 h, evaporated in vacuo and partitioned between EtOAc (10 mL) and H₂O (10 mL). The aqueous layer was further extracted with EtOAc (2 × 5 mL) and the organic extracts were combined, washed with brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo to give thioamide 2.

22

General Procedure for Microwave-Assisted Reaction of Nitriles 1 and Ammonium Sulfide (Method B). A solution of nitrile 1 (0.5 mmol, 1 equiv) and (NH₄)₂S (0.5 mmol, 1 equiv; 50 wt.% in H₂O) in MeOH (5 mL) was irradiated for 15 min in a self-tunable CEM microwave Discover synthesizer at 80 °C (initial power 100 W) and then cooled using a flow of compressed air, evaporated in vacuo and partitioned between EtOAc and H₂O. The aqueous layer was further extracted with EtOAc (2 × 5 mL) and the organic extracts were combined, washed with brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo to give thioamide 2.

26

The nitriles depicted in Figure [1] gave only unreacted starting material under ambient and microwave-assisted conditions, according to methods A and B, respectively, except for acrylonitrile which instead reacted by conjugate addition with ammonium sulfide.

27

The reaction of 2-cyanopyridine(1a) with ammonium sulfide according to method A has been conducted on a larger scale (10 mmol) to give thioamide 2a without any reduction in yield.

28

With a volatile aliphatic nitrile, such as 1c, evaporation in vacuo after an aqueous work-up removed unreacted starting material. For reactions that were not quantitative, purification by column chromatography on silica was usually required. For experiments that gave >98% yield (Table [2] , entries 1-5, 10, 14, 15, and 26), no purification on silica or recrystallisation of the product was necessary.