Thioamidation

This preparation illustrates the ready formation of the thiazole ring by the condensation of an ot-halogeno-ketone and a thioamide. Thus chloroacetone, which may conveniently be represented in the enol form (I), condenses with thiourea (II) to give 2-amino-4-methylthiazolc (III). 

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. 

The preparation of these [4-hydroxy-THISs, (1), X = O] by cydization of a-carboxy-N-arylthiobenzimides (5) by treatment with acetic anhydride and triethylamine has been investigated in detail, and the structure has been revised for the compound previously described as 2.3-diphenyl-4-hydroxythiazolium hydroxide inner salt (1, X = 0, R = R = Ph, R = H) (Scheme 5) (3, 10). 4-Hydroxy-THlSs also arise by condensation of gem-dicyanoepoxides with thioamides (Scheme 6) (8). 

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

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. 

The cyclization of -halocarbonyl compounds is carried out with a great variety of reactants including thioamides, thioureas, their mono- or disubstituted derivatives, and salts and esters of monothiocar-bamic acid, leading to variously substituted thiazoles. 

When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz s method (222), 2-substituted thiazoles are obtained (4, 10,"22, 175). 

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). 

Aliphatic thioamides cyclized with a,/3-dibromoether in the presence of MgCO, as base, yield the corresponding 2-alkylthiazoles in the 20 to 60% range (578). 

When thioamides such as thiobenzamide are used directly, neither dioxane nor magnesium carbonate is necessary. Instead absolute alcohol with fused sodium acetate in the presence of piperidine is used (457). 

Owing to the instability of a-halogenoaldehydes it is occasionally preferable to use more stable derivatives, such as enol acetate prepared according to Bedoukian s method (204) and a-bromoacetals (4, 8, 10, 16, 22, 67, 101, 426). An advantage is said to be in the yield however, this appears to be slight. The derivatives react in the same sense as the aldehydes themselves, that is, the acetal group as the more polarized reacts first and enters the C-4 position. It is likely that the condensation and cyclization occur by direct displacement of alkoxide ions. Ethyl-a,/3-dihalogeno ethers (159, 164, 177, 248) have also been used in place of the free aldehydes in condensation with thioamides. 

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). 

Dimethylaminoethylthiazoles (17) were prepared from thioamides and l-bromo-4-dimethylamino-2-butanone (16), with R, =Me, CH2Ph, (CH2)NHCOPh, and (Ac)2NCH2 (Scheme 9) (337, 392). 

In a similar way, dl-2-(q-hydroxyalkyl)- and 2-(a-alkoxycarbonyl)-4-methyl-5-(/3-hydroxyethyl)thiazoles were synthetized from the corresponding thioamides and 4-hydroxy-3-bromo-2-pentanone (615). 

The cyclization of pentaacetyl-o-gluconic thioamide with chloroacetone and of pentaacetyl-D-galactonic acid thioamide with phenacyl bromide give the corresponding 4-substituted 2-(D-galactopentaacetoxypentyl)-thiazoles (27) (660) but in low yield (23 to 27%) (Scheme 13). The products may be deacetylated in the usual way. These compounds are interesting from a pharmacological point of view. 

A series of meta- and para-bis (2-thiazolyI) benzenes and of meta- and para-bis(4-thiazolyl)benzenes of general formula 35 and 36 was prepared in higher yields (60-90%) from the appropriate bis-(haloacetyl)benzenes with a suitable thioamide (Scheme 18a and Table JI-8) (573, 574),... 

Bromomethyl-l-adamantyl ketones were condensed with thioamides of carboxylic or carbonic acids to give the corresponding thiazoles (613). 

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%. 

Similarly, ethyl (or methyl) a-formyl chloroacetate (69), Rj = H, and its substituted derivatives, condensed with thioformamide or higher thioamides give 5-ethyl- or 5-rnethyl-thiazole carboxylates (70) in good... 

Ethyl-4,5-thiazole dicarboxylates (77), R =H, Me, Et, Ph, or heteroaryl, were prepared from diethyl-a-chloro-/3-ketosuccinate (76) and thioamides in boiling ethanol (Scheme 35) (103, 110, 145, 298, 577, 639). 

Thiazole acetic acids and their hotnologs can also be prepared by cyclization procedures 4-thiazole alkanoic acids and their salts were prepared by treating a thioamide with a -y-chloro- or 7-bromoacetoacetic or their a-alkyl derivatives (4, 10, 16, 22, 273, 275, 281, 640, 647, 695). 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

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)... 

N-Monosubstituted thioamides (96) have been cyclized with a-halocarbonyl compounds to give thiazolium salts (97) in excellent yields (89, 99. 102, 305, 722). 

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). 

CONHj, COjEt, were also prepared by ring closure of thioamides such as RiCONHCH(R2)C(=S)NH2 with polyphosphoric acid (2 hr at 120°C) (718). 

Thiazoles were obtained from the corresponding thioamides [RiCONHCHfRjlC S) ] by refluxing them 30 min in acetic anhydride. 

The action of thioamides (1) on a-haloacids or esters gives the same products (230) in moderate yields (20 to 30%) through intermediates analogous to 229. In 230, Ri is phenyl, benzyl, or -pyridyl, Rj is methyl or hydrogen (287, 324). 

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). 

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