Heterocycles Using Thioamides

Cyclocondensation of thioamides and alkynyl(aryl)iodonium reagents affords 1,3-thiazoles in the presence of solid K2C03.37 Reaction of 

Cyclodehydration of p-hydroxythioamides under Mitsunobu conditions (Method a) has provided peptide thiazoline in 80% yield with 78 22 ratio of A B and 56% de. Treatment of p-hydroxythioamides with Me02CNS02NEt3, 

Method a PhaP, DIAD, CHjClj, -78- 22°C, 30 min Method b Burgess-Reagent, THF, 65°C, 10 min 

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Tominaga, Y., Y. Matsuoka, Y. Oniyama et al. 1990. Polarized ethylenes. IV. Synthesis of polarized ethylene using thioamides and methyl dithiocarboxylates and their application to syntheses of pyrazoles, pyrimidines, pyrazolo[3,4-d]pyrimidines and 5-aza[2.2.3] cyclazines. J Heterocycl Chem 27 (3) 647-660. 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

There is an enormous literature on thiocarbonyl compounds, due in part to the technical and industrial importance of many of them, including thioamides, thioureas, xanthates, dithiocarbamates and so forth. An excellent, and recent, general review is available.107 There are also specialized reviews germane to the present chapter Griffin, Woods, and Klayman2 discussed the use of thioureas in the synthesis of heterocycles the preparation of thiazoles from thioamides is included in a three-part volume on Thiazoles 108 the use of carbon disulfide in the synthesis of trithiones and related heterocycles has been reviewed by Mayer109 and Huisgen110 has reported numerous examples of 1,3-dipolar cycloadditions in which carbon disulfide was used. 

Thioamides and their use in the preparation of the heterocyclic compounds are widely reported in the literature. Also they attract considerable interests in peptide chemistry. Molecular and crystal structures of some thioamide derivatives have been confirmed by X-ray diffraction data.8 10 Lawesson s reagent or phosphorus pentasulfide (P4S10) is actively used for the synthesis of thio-carbonyl compounds. Their preparation methods, reactions, applications in the synthesis of heterocycles and biological effects are mainly described in this section. 

Trialkyloxonium ions have been extensively used to carry out O-alkylation of lactams, amides, sulfoxides, oxo-sulfonium ylides, iV-alkylation of iV-heterocycles, 5-alkylation of thioethers, thioacetals, thioamides, and thiolactams.1,90 Although trialkyloxonium ions do not alkylate benzene or toluene directly, alkylations readily occur in combination with highly ionizing superacids such as HS03F-SbF5. This may indicate protosolvation of a nonbonded electron pair on oxygen in the superacid medium. 

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

The Kindler modification of the Willgerodt reaction uses sulfur and dry amines, ammonia, primary amines or secondary amines, which leads to the formation of thioamides (conversion of thioamides to amides cf Section 2.3.1.7). This reaction can also be extended to aldehydes, hydrocarbons and heterocyclic ketones. Due to the usually low to moderate yields this reaction has not found general application. 

A large body of work has been directed toward synthesis and applications of thioamides. The most important uses are as synthetic intermediates " and in heterocyclic synthesis. " Among the wealth of synthetic methods that lead to thioamides, thioacylation routes are certainly of prime importance. 

Thioamides are useful synthons for the preparation of different types of nitrogen-sulfur heterocycles for instance, thiazoles (95) are synthesised by condensation of a thioamide with an a-chlorocarbonyl compound (96) (Scheme 53). Vitamin B1 (thiamine) (97a) (Figure 5) is a thiazole derivative and is a member of the vitamin B complex required for growth and the proper functioning of the nervous system. It is a cofactor in biological decarboxylation reactions and exists... 

Thioamides as useful synthons in the synthesis of heterocycles 03CRV197. 

The conventional preparations of thiazoles and 2-aroylbenzo[6]-furans require the use of lachrymatory a-haloketones and thioureas (or thioamides). In a process which eliminates this problem, Vanna et al. have now synthesized various heterocycles via simple solvent-free reaction of thioamides, ethylenethioureas, and salicylaldehydes with a-tosyloxyketones that are generated in situ from arylmethyl ketones and [hydroxy(tosyloxy)iodo] benzene (HTIB) under MW irradiation conditions (Scheme 4). 

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