Thioamides Hantzsch thiazole synthesis

The classical method of forming 1,3-selenazole derivatives involves a modification of the Hantzsch thiazole synthesis. For this purpose derivatives of selenocarboxamides, in place of thioamides, are allowed to react with ot-halocarbonyl compounds 16 to give the corresponding 1,3-selenazoles (17). - [Eq. (8)]. 

Thiazol-a-amino acids (441) can be prepared by the Hantzsch thiazole synthesis of the thioamide... 

Thiazolin-4-one derivative 29 in hydrazino-hydrazono tautomeric equilibrium is synthesized by cyclization of l,2-diaza-l,3-butadiene 27 with aryl thioamide 28. Subsequent hydrolytic removal of the NH-Boc-hydrazo protecting group provided 5-acetyl-4-hydroxythiazole derivative 30a, which undergoes a-bromination to give a-bromomethyl ketone 30b. This bromide is used to prepare polyfunctionalized 4,5 -bithiazol-4 -ol derivatives via the Hantzsch thiazole synthesis <04SL2681>. 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

The mechanism for the Hantzsch thiazole synthesis begins with deprotonation of thioamide 4 (or thiourea) followed by nucleophilic substitution of the a-haloketone 1 to form G. G then undergoes intramolecular nucleophilic substitution at the ketone to form H, which undergoes rapid base-catalyzed elimination to give the desired thiazole 5. 

The Hantzsch thiazole synthesis, which occurs between a-haloketones and thiourea or thioamides, generally proceeds smoothly to yield the desired thiazole. Most of the efforts that have been made to improve this reaction have focused on controlling the undesired racemization that occurs with chiral starting materials. One of the most important modifications is the Holzapfel modification, which uses neutral reaction conditions and lower temperatures to eliminate potential epimerization reactions. 

Building on Newbury and co-workers work on the synthesis of 2,4-diphenylthiazole-5-acetic acid derivatives as anti inflammatory agents, Ikemoto and co-workers used the Hantzsch thiazole synthesis in their scalable synthesis of a pyridylethanolamine inhibitor of human P3 adrenergic receptor inhibitor (P3 ARI). Treatment of a-bromoketone 65 with thioamide 66 gave the corresponding thiazole 67 in 89% yield. Four additional steps were required to generate the P3 adrenergic receptor inhibitor in 66% overall yield. 

The Hantzsch synthesis has been used to prepare a number of natural and synthetic cyclic peptides incorporating thiazoles. Pattenden and coworkers used the Hantzsch thiazole synthesis in their preparation of an N-Boc protected L-proline thiazole based amino acid, which was subsequently used to generate cyclic hexaeptides and octapeptides. Thioamide 165, prepared from commercially available Boc-L-proline, was subjected to Holzapfel s modified conditions to generate the desired thiazole 166 in 61% yield. The biological evaluation of these compounds is currently under investigation. 

The Hantzsch thiazole synthesis from thioamides and a-halogeno-ketones has been applied to iVAr-(dimethyl)dithio-oxamide to give 2-(dimethylthio-carbamoyl)thiazoles, but in some cases it took another course. Thus, 1-alkylthiocarbamoyl-l-cyanoacetophenones (91) react with bromo-ketones with elimination of alkylamine, giving 2-methylidene-l,3-oxathioles (92). The thio-anilide of acetoacetic acid reacts with 2-bromo-l-tetralone to give the spiro-... 

Todd et al. have reported a very convenient method for the preparation of N-alkylthiazolium salts. The method of Hantzsch thiazole synthesis was modified to obtain direct formation of thiazohmn salts. N- substituted thioamides (e.g. 13) were used instead of the imsubstituted thioamides to obtain the desired thiazohmn salts (e.g. 15) (Todd et al. 1936)... 

Hydrogen sulfide and aliphatic and aromatic thiols react readily with [ C]nitriles to give [ C]thioamides in yields of 45-70%. Upon treatment with a-halocarbonyl compounds they form [ C]thiazoles (Hantzsch thiazole synthesis). This was exploited for the synthesis of 2-(4-chlorophenyl)[2- C]thiazol-4-acetic acid f89. X = COOH) (Figure 7.23) and the 2-(2-phthalimidoethyl)-[2- C]tliiazole derivative 91 °. which were obtained when the corresponding thioamides M and 90 were treated with 1,3-dichloroacetone and bromo-acetaldehyde diethylacetal, respectively. As illustrated by the third example in Figure 7.23,... 

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). 

The most widely employed synthetic approach for the preparation of thiazoles is the condensation of an a-halocarbonyl compound with a reactant bearing the N—C—S fragment such as thioamides, thioureas, or dithiocarbamic acid derivatives <84CHEC-i(6)294>. When the Hantzsch s synthesis is employed for the preparation of chiral substituted thiazoles such as 2-aminomethyl thiazoles some foresight must be considered in order to prevent racemization (see Section 3.06.11). 

The Hantzsch synthesis has been used to generate pyrroles, thiazoles and dihydropyridine derivatives. Pyrroles (3) are generated from the reaction of P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones (path A). Thiazoles (5) are generated from the reaction between a-haloketones and thiourea or thioamide derivatives (path B). Dihydropyridines (7) are generated from the reaction of aldehydes with p-ketoesters and ammonia or ammonia derivatives, or enamines derived from the reaction of ketones or P-ketoesters with amines (path C). Dihydropyridines can be readily converted to the corresponding pyridine derivatives and so this reaction is often termed the Hantzsch pyridine synthesis. 

Hantzsch s Synthesis (Type A, S—C—N + C—Q.— Various forms of Hantzsch s synthesis continue to be widely employed for producing both old and new types of thiazole derivatives (see Table 1). In a useful procedural variation, a thioamide is generated from the corresponding amide by the action of phosphorus pentasulphide in dioxan, and condensed in situ with the a-halogenocarbonyl compound. The effectiveness of the... 

Various more or less efficient methods have been reported for the synthesis of 2-(l-ami-noalkyl)thiazole-4-carboxylic acids and their suitably protected derivatives. 237,539,541,558-568 Optimal conditions must be selected in these syntheses to prevent racemization at the chiral aminoalkyl moiety, e.g. when applying a modified Hantzsch synthesis 559 racemization has been observed to occur at the level of the starting Na-protected amino acid thioamide as well as in the base-mediated dehydration step of the intermediate hydroxydihydrothiazoles. 558 The 2-(aminoalkyl)thiazole-4-carboxylic acids are incorporated into the linear precursors by standard procedures of peptide synthesis, 237,514,529,539,552,555,558,564,569 and cyclization is pref-... 

Preparation of thiazole Hantzsch synthesis can be applied to synthesize the thiazole system from thioamides. The reaction involves initial nucleophilic attack by sulphur followed by a cyclocondensation. 

Peptide-Based Thiazoles via the Condensation of 5-Halo- -oxo Esters with Thioamides A Modified Hantzsch Synthesis... 

The mechanism of the Hantzsch synthesis has been established and is shown in Scheme 165. Substitution of the halogen atom of the a-halo ketone by the sulfur atom of the thioamide occurs first to give an open-chain a-thioketone (232), which under transprotonation proceeds to give a 4-hydroxy-A2-thiazoline (233) in aprotic solvents, or a thiazole (234) by acid-catalyzed dehydration of the intermediate thiazoline in protic solvents. 

In contrast to the intermolecular Hantzsch reaction, which has been widely used, intramolecular examples have been scarce in the literature. Recently, an elegant Hantzsch macrocylization has been applied to the synthesis of IB-01211. ° Application of the Holzapfel-Meyers-Nicolaou modification to a-bromoketone-thioamide 27 brings about intramolecular thiazole formation with concomitant dehydration of the primary alcohol to give IB-01211 in moderate yield. This reaction is remarkable, especially considering the fact that the macrocyclization through amide formation at either bond a or b fails to produce any cyclized product. 

Bray and Oiasoji employed the Hantzsch reaction in their total synthesis of (+) bacillamide a compound with potential antibiotic activity. The authors used Schmidt s modification of Holzapfel s method in order to avoid racemisation. Treatment of thioamide 163 with ethyl bromopyruvate 104 and ethyloxirane in isopropanol at 60 °C for 30 min, followed by careful addition of TFAA gave the chiral thiazole 164 in 58% yield. Bray and Olasoji s synthesis of bacillamide B follows on the heels of work by Xu and co-workers on the total synthesis of bacillamide... 

In the mechanism of the Hantzsch synthesis, primarily nucleophilic displacement of halogen in the a-halogeno carbonyl system by the thioamide C=S functionality takes place. The resulting S-alkyliminium salt 18 cyclizes after proton transfer N O (18 -> 19) and carbonyl activation to the salt 20 ofa 4-hydroxy-4,5-dihydrothiazole, which is converted to the thiazole 17 by elimination of H2O and HX. 

Sokolenko TM, Davydova YA, Yagupolskii YL (2012) Efficient synthesis of 5 -fluoro dkoxy-thiazoles via a-bromo-a-fluoroalkoxyacetophenones Hantzsch type cyclization with thioureas or thioamides. J Fluorine Chem 136 20-25. doi 10.1016/j.jfluchem.2012.01.005... 

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