Thioamides reactions

An investigation of the thioamidation reaction on model compounds of PAN under similar conditions and a study of the functional composition of modified copolymers led to the assumption that the most probable course of the two types of side reactions causing the decrease of the number of thioamide groups are hydrolysis and cyclization reactions. 

The Eschenmoser reaction is extremely useful for the conversion of amides into enaminoesters via the thioamide reaction with a-haloesters, and triphenylphosphine mediated sulfide contraction, and we are fortunate that Shiosaki has published a thorough review on this topic [180]. The accompanying scheme shows a typical example for which an organometallic route with a lithium or a zinc enolate was not successful [181]. 

Thioamide enolates may be prepared by conjugate addition of organometallics to a, -unsaturated thioamides. Reaction of these enolates with aldehydes affords anti aldols, often in excellent dia-stereomeric excess (equation 103 Table 15). It is believed that the conjugate addition reactions provide (Z)-enolates, via a cyclic, six-centered transition state. The anti stereochemistry observed in the aldol reactions of these (Z)-enolates would result from a boat-like, chelated transition state. The transition state has boat-like character to avoid a serious gauche interaction between R and the bulky secondary alkyl group in the thioamide enolate. Several of the intermediate enolates in this study e.g. Table 15,... 

A further improvement is embodied in the Klndler variation of the Willgerodt reaction this consists in heating the ketone with approximately equal amounts of sulphur and a dry amine instead of aqueous ammonium polysulphide. The principal product is a thioamide, and hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. 

It has been tentatively suggested that one mechanism underlies the Willgerodt reaction and the Kindler modification of it. A labile intermediate is first formed which has a carbon—carbon bond in the side chain. The scheme is indicated below it postulates a series of steps involving the addition of ammonia or amine (R = H or alkyl), elimination of water, re addition and eUmination of ammonia or amine until the unsaturation appears at the end of the chain then an irreversible oxidation between sulphur and the nitrogen compound may occur to produce a thioamide. 

Moreover, selenamides are more instable than thioamides so P2Se, was replaced by AljSe. In that case the cycle is less broken, but the yield of reaction is not as good. 

Aromatic thioamides can be prepared as described in the literature by different ways, either by S -> O exchange between the corresponding benzamides and phosphorus pentasulfide in pyridine solution in the presence of triethylamine (65, 646) as strong base, or by action of H2S on the appropriate nitrile with pyridine and triethylamine solvents using the method of Fairfull et al. (34, 374, 503). In this reaction, thioacetamide in acidic medium can also be used as a H2S generator with dimethylform-amide as the solvent (485). 

The reaction of a thioamide with a-halocarbonyl compounds has been applied extensively, and many thiazoles (10) with alkyl, aryl, aralkyl, or heteroaryl functional groups at the three 2-, 4-, or 5-positions have been reported (Scheme 6). 

Benzocycloheptathiazoles (60) were prepared by the reaction of 6-bromo-l-benzosuberone (59) with the corresponding thioamides, by refluxing for 4 hr in alcoholic solution (Scheme 27) with R = Me, yield is 35%. 

The use of a reagent bearing a basic center or the addition of a base to the reaction mixture was recognized as necessary to prevent the acid-catalyzed elimination of the elements of water from the intermediates. Since the publication of this work, a number of similar intermediates have been isolated from thioamides and a-halogeno carbonyl compounds (608, 609, 619, 739, 754, 801), and as a result of kinetic studies, the exact mechanism of this reaction has been well established (739, 821). 

II. Thiazoles from a-Halocarbonyl Compounds and Derivatives 211 2. Reaction with N>Substituted Thioamides (ThiazoHum Salts)... 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

With R] different from R2 two isomeric compounds (138 and 139) are possible, depending on the direction of ring closure (86). However, only one form is generally obtained. Finally, the trisubstituted thioureas such as N,N,N -trimethylthiourea react with chloroacetone to give a thiazolium salt, in a reaction identical to that of the N-monosubstituted thioamides (Scheme 67). 

But the reaction with aliphatic a-halocarbonyl compounds is usually complex, and a variety of compounds can be formed depending on the reactants and the reaction conditions. With chloroacetone in neutral medium (alcohol) the acyclic intermediate (144) analogous to those obtained with thiourea and thioamides was isolated (Scheme 70). 

By condensing the salts or the esters of either dithioformic (207) or dithiophenacetic acids with a-aminonitriles (206) 5-aminothiazoles (209), in which R] = hydrogen, benzyl and Rj = phenyl, carbethoxy, or car-bophenoxy, were obtained in fairly good yields (Scheme 108) (271). These reactions were carried out in aqueous ethereal solution at room temperature. Acyclic thioamides as intermediates in this reaction have been isolated in some cases (208). 

Very few 4-aminothiazoles have been synthetized directly. The reaction of a-halonitriles with thioamides generally fails and only extensive decomposition results. However, the benzene sulfonic ester of mandelonit-rile reacts with thiobenzamide to give 2,5-diphenyl-4-aminothiazole (257), Ri = R2 = Ph, in 37% yield (Scheme 132) (417) Similarly, a-cyano-a-acetylthioacetamide condensed with a-chloroacetonitrile give 257, Ri = CH(CN)CH3 and R2 = H (804). 

In catalytic hydrogenation, a compound is reduced with molecular hydrogen in the presence of a catalyst. This reaction has found appHcations in many areas of chemistry including the preparation of amines. Nitro, nitroso, hydroxylamino, azoxy, azo, and hydrazo compounds can all be reduced to amines by catalytic hydrogenation under the right conditions. Nitriles, amides, thioamides, and oximes can also be hydrogenated to give amines (1). Some examples of these reactions foUow ... 

Nitrogen nucleophiles used to diplace the 3 -acetoxy group include substituted pyridines, quinolines, pyrimidines, triazoles, pyrazoles, azide, and even aniline and methylaniline if the pH is controlled at 7.5. Sulfur nucleophiles include aLkylthiols, thiosulfate, thio and dithio acids, carbamates and carbonates, thioureas, thioamides, and most importandy, from a biological viewpoint, heterocycHc thiols. The yields of the displacement reactions vary widely. Two general approaches for improving 3 -acetoxy displacement have been reported. One approach involves initial, or in situ conversion of the acetoxy moiety to a more facile leaving group. The other approach utilizes Lewis or Brmnsted acid activation (87). 

Many azolinethiones show reactions typical of thioamides in particular, they react with electrophiles at the sulfur atom. 

Thiazolines and thiazolidines may also be prepared in this fashion, the structure of the final product determining the substitution pattern to be chosen in the reaction components. Reaction of ethyl bromoacetate with the substituted thioamide (71) resulted in formation of the thiazolidin-4-one (72) (70KGS1621). 

The reactions of the benzenesulfonyl ester of mandelonitrile (177) provide another illustration of the masked bielectrophile approach. On reaction with a primary thioamide the 4-aminothiazole (178) was obtained and this is a convenient route to these derivatives. With a thiourea, the thiazoline (179) was the initial product, and this on treatment with water gave the thiazolidin-4-one (180) (61JOC2715). 

Reaction of 2,5-dimethylisoxazoline-3-thione with thiophenol produced a ring-opened thioamide, while pyrolysis gave two products via a thiocyclopropene intermediate (Scheme 76) (80CPB103). 

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