Hantzsch thiazole synthesis

Phenyliodonium ylids of cyclic dicarbonyl compounds (46) react with thiourea to form the thiouronium ylid (47) which on heating is converted into the fused thiazole (48), this method is applicable to subtituted thioureas provided they have at least one free amino group. This reaction can be considered to be a modification of the Hantzsch thiazole synthesis <96JHC575>. 

Another modification of the Hantzsch thiazole synthesis afforded C-4 thiazolylmethyl phosphonium salts (49). These ylids could then undergo Wittig condensations to furnish a wide variety of 2,4-disubstituted thiazoles <96TL983>. 

Aguilar, E., and Meyers, A. I. (1994). Reinvestigation of a modified Hantzsch thiazole synthesis. Tetrahedron Lett. 35, 2473-2476. 

A general scheme, which constructs the thiazolo variety of various bridgehead heterocycles, is basically an extension of HTIB-mediated modification of Hantzsch thiazole synthesis (Scheme 51). Thus, synthesis of 3-substituted-5,6-dihydro-4//-imidazo[2,l-b]thiazoles 202 has been achieved by the treatment of a-tosyloxyacetophenones (generated by the oxidation of 51 with HTIB) with ethylenethiourea [92JCS(P1)707], The method is successfully extended to synthesize 4,5,6,7-tetrahydrothiazolo[3,2-a]pyrimidines 203... 

Other progress in the Hantzsch thiazole synthesis includes a,a-dibromoketones as a superior alternative to a-dibromoketones <07SC2501> and ionic liquid as reaction medium <07T11066>. 

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)]. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Hypervalent iodine reagents has been used in modified Hantzsch thiazole synthesis. Treatment... 

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>. 

Friedel-Crafts reactions have also been employed in the synthesis of benzofurans. Ohishi and co-workers used a Friedel-Crafts acylation protocol to produce a highly substituted benzofuran with inhibitory activity for leukotriene B-4." Reaction of 3-(4-chlorophenyl)benzoftiran with 2-chloroacetyl chloride provided the corresponding benzofuran derivative in good yield with a handle for further functionalization. A Hantzsch thiazole synthesis was then used to produce the final amino-thiazole inhibitor. 

Kaupp et al. employed ball-milling technique to transform thioureas 79 by reaction with phenacyl bromide to 2-amino-4-phenyl-thiazole-hydrobromides 80 in quantitative yields from stoichiometric mixtures of the reagents at room temperature (Scheme 4.21) [14]. In soUd-state conditions, base catalyst was not needed. The water formed in the reaction does not hydrolyze phenacyl bromide under applied mild conditions and was removed by heating at 80°C in vacuo. When the same reaction was performed in a melt at 110°C, partial hydrolysis occurred, which diminishes yield, while yields obtained in solntion were lower (80-90%). This Hantzsch thiazole synthesis starts with nucleophilic snbstitution on snlfur and formation of the carbon-sulfur bond (S-alkylation), followed by further reaction cascade which results in heterocychc ring. 

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. ... 

Other references related to the Hantzsch thiazole synthesis are cited in the literature. 

Hantzsch Thiazole Synthesis James Kempson 5.4.1 Description... 

Other progress in the Hantzsch thiazole synthesis includes a,a-dibromoketones as a superior alternative to a-bromoketones. Indeed, the increased reactivity of the a,a-dibromoketone 30 was able to obtain an 82% yield of 31 in 15 min at room temperature, compared to refluxing in ethanol for 5 h with the corresponding a-bromoketone to obtain the same yield of thiazole 31. 

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. 

The first reaction, reported by Hantzsch in the late 1880s, involved the one-pot condensation of chloroacetone 9 and thioacetamide 59 in refluxing benzene to produce thiazole 60 in near quantitative yeild. Since Hantzsch s original report, the Hantzsch thiazole synthesis has been used to prepare a number of biologically relevant compounds and other functionally important thiazoles. Some of the more recent examples are highlighted below. 

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. 

Hammer and co-workers used the Hantzsch thiazole synthesis to prepare thiazole and thiazole-A -oxide nucleobases with the goal of producing nucleobase analogs with pronounced directional dipoles and the capacity to base pair. Their overall goal was to use these compounds as models to explore the biochemical and biophysical properties of DNA. Treatment of... 

Sun and co-workers used the Hantzsch thiazole synthesis to prepare a series of novel diaryl urea derivatives 136 based on sorafenib as potential candidates for the treatment of nonsmall cell lung cancer and breast cancer. ... 

Poupat and co-workers employed the Hantzsch thiazole synthesis as a key step in their swthesis of an aminothiazole derivative of the antitumor alkaloid girolline. Reaction of a-bromoketone 149, prepared in four steps from commercially available D-(+)-arabitol, with N-Boc protected thiourea 150 in the presence of sodium bicarbonate in DMF at 50 C gave the corresponding aminothiazole 151 in 83%. Five additional steps were required to generate the target compound 5-deazathiogirrolline. 

Kuriyama, Akaji, and Kiso used the Hantzsch thiazole synthesis in their convergent synthesis of (-)-mirabazole Mirabazole alkaloids have a unique architecture consisting of thiazoline, thiazole and oxazole rings, and have been shown to exhibit a diverse array of biological activities. Reaction of 156, prepared in 12 steps from D-alanine with chloroacetone 9 in refluxing ethanol, gave (-)-mirabazole B in 57% yield. 

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