Synthesis of Thioamides

Recognition of these drawbacks prompted the Ley group to design a new polymer-supported reagent 9 for direct amide thionation149. Preparation of this immobilised 

GC conversion 96 - 99% GC purity 92-98% Cyclic amides, 2 examples GC conversions 99% GC purity 97-98% 

Further studies have shown that the same reagent species can be effectively constructed on a silica backbone giving appreciable increased reactivity151 (S.V. Ley, unpublished results). A silica-based support provides advantages in terms of more effective heating profiles because of the superior absorbency of the silica and increased compatibility with 

Addition of Grignard reagent to isothiocyanates provides secondary thioamides.24 

Reaction of isothiocyanates with resorcinol derivatives in the presence of boron trifluoride-acetic acid complex for overnight at 0-5 °C affords the corresponding thioamides.25 

Treatment of nitriles with gaseous hydrogen sulfide in the presence of anion exchange resin (Dowex 1X8, SH from) at room temperature affords the corresponding primary thioamides.27 Treatment of nitriles with 70% sodium hydrosulfide hydrate and magnesium chloride hexahydrate in DMF or methanol affords primary thioamides in high yields.28 Primary thioamides have been 

R1 Tf20 (1.3 equiv), Pyridine (3.5 equiv) Ri H2S, Pyridine (3.5 equiv) Ri 

A -Allylthioamides have been prepared by the reaction of allyl isothiocyanate with 1,3-diketones in acetonitrile solution in the presence of 1,8-diazabi-cyclo[5.4.0]undec-7-ene (DBU)  

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Selected examples of the synthesis of thioamides from nitriles ... 

An attractive method of preparation of the dithioesters of N-protected amino acids was described by Thorsen et a I.194 The methyl dithioesters were used in an activated form of amino acids for the synthesis of thioamide-modified peptides (see Section 10.9.1). 

Support-bound C,F I-acidic compounds, such as acetoacetamides, react with isocyanates under basic conditions to yield amides through C-carbamoylation [71]. Similarly, polystyrene-bound aryllithium compounds can be converted into benzamides by treatment with isocyanates [111]. These reactions are closely related to C-thiocarbamoyla-tion, which has been used for the solid-phase synthesis of thioamides (see Section 13.9). Amides have also been prepared by C-alkylation of resin-bound N-acylaminals with allyltrimethylsilane or diethylzinc (Entry 11, Table 13.7). 

Thiatriazolines have been described as transient intermediates in the synthesis of thioamides under mild conditions <2006TL1163>. The outcome of the reaction of dithioacids 43 (X = S) with electron-deficient organic azides 44 depends on the reaction conditions. When triethylamine was used as the base, thioamides 47 were formed (Scheme 9). Electron-rich azides (e.g., benzyl azide) need significantly longer times for conversion, and the yield is... 

Sulfur can be activated by the presence of bases, e.g. amines (R2NH). Such proton-bearing amines cleave the S8 ring and also will react with the thiolation products. This procedure is used in the synthesis of thioamides (9) from the methylarenes (10) (Scheme 5). 

The most widely used synthesis of thioamides (86) involves thionation of the corresponding amides by heating with phosphorus pentasulfide in xylene (Hofmann, 1878) (Scheme 45). In the preparation of primary thioamides (87) by this procedure, care must be taken to avoid the decomposition of the product into the nitrile and hydrogen sulfide—the reverse of the earliest preparative route to thioamides (Gay Lussac, 1815) (Scheme 46). 

A general synthesis of thioamides from nitriles which utilizes thioacetamide as the source of hydrogen sulfide under acidic conditions is reported by Taylor and Zoltewicz.1 The thioamides are formed in good yield and high purity and the method is equally applicable to aliphatic nitriles and to aromatic nitriles containing either electronreleasing, electron-withdrawing, or potentially reducible substituents. One equivalent of the nitrile is heated on a steam bath for 15-30 min. with 2 eq. of thioacetamide in s s... 

A one-pot procedure for the synthesis of thioamides relies on the successive reaction of Grignard reagents with carbon disulfide and then with Tf20 to generate a mixed anhydride intermediate. This intermediate reacts with amines to generate thioamides (eq 86). ... 

Several improvements of the method have been introduced. The solvent-less, microwave-assisted protocol of Varma and Kumar works well with amides too. It has been further developed and applied for a very efficient parallel synthesis of thioamide libraries. The thionation of different types of amides in anhydrous THF at temperatures below 80 °C has turned out to be advantageous. Also the modified reagenf (13) has been successfully used. ... 

Reviews.—Two reference books that deal with topics covered in this chapter have been published, and there have been reviews of the chemistry of aromatic thioureas and of the applications in organic synthesis of thioamides and thioureas, and of thiophosgene. ... 

A review on A-functional derivatives of thiocarboxylic acids, covering the synthesis of thioamides, thioureas, and thiocarbamates, has appeared in Methodicum Chimicum. ... 

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