Hantzsch synthesis thiazoles

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. 

Hansa Yellows, 1, 334 5, 299 Hantzsch synthesis, 2, 87-88 1,4-dihydropyridine, 2, 482 thiazoles, 6, 294-299 A -thiazolines, 6, 314 Hantzsch-Widman names parent names, 1, 35 stem suffixes, 1, 12 Hantzsch-Widman system nomenclature, 1, 11-12 Hardeners in photography... 

A modification of the Hantzsch synthesis of thiazoles has been reported. The reaction of alkoxyoxiranes 16 with A-arylthioureas 17 affords thiazoles such as 20. The mechanism involves the initial P-cleavage of the oxirane to give the hemiacetal... 

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-... 

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

The forward process is the Hantzsch synthesis of thiazoles which, despite its antiquity (it is around 100 years old), is still very widely used. 

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. 

The most commonly used method for the preparation of fused thiazoles involves the reaction of a-mercapto N-heterocyclic compounds of type (138) with an a-halocarbonyl compound or ester to give S-alkylated intermediates (139) which can be dehydrated to (140). When R2 is alkoxy, thiazolones (141) are formed (Hantzsch synthesis). Strong dehydrating agents are necessary to cyclize aldehydes and ketones (139) to fused thiazoles. The method has been used to prepare (dihydro) imidazo[2,l-6]thiazoIes and thiazolo[3,2- ]-s-triazoles (80JHC1321, 78JHC401, 82IJC(B)243). 

The Hantzsch synthesis of thiazoles is an excellent method for the synthesis of simple thiazoles, however for some substituted examples low yields have been reported as a result of dehalogenation of the a-haloketone. An alternative method for the synthesis of highly substituted thiazoles has been reported, thus starting from the 2-bromo-5-chlorothiazole 76 it was possible to introduce substituents selectively at the 2-position by a palladium-catalysed cross coupling reaction to give 77 (74-92%). In order to introduce a substituent into the 5-position,... 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below (note there is an important pyridine ring synthesis, also named a Hantzsch synthesis... 

The Hantzsch synthesis involves three intermediate steps. In the first, the halogen atom of the or-halo aldehyde or a-halo ketone is nucleophilically substituted. The resulting iS-alkyliminium salt 2 undergoes a proton transfer (2 -> 3) cyclization produces a salt of a 4-hydroxy-4,5-dihydrothiazole 4 which is converted into a 2,5-disubstituted thiazole 1 in protic solvents by an acid-catalysed elimination of water. 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below the syntheses of 2,4-dimethylthiazole where the heteroatoms are provided by thioacetamide, " and 2-aminothiazole, in which 1,2-dichloroethyl ethyl ether is utilised as a synthon for chloroethanal and the heteroatoms derive from thiourea. " The use of thioureas as the sulfur component with 2-chloroacetamides as the second unit gives rise to 2,4-diaminothiazoles. " Conversion of 1,3-diketones into their 2-phenyliodonium derivatives and reaction of these with thioureas produces 2-amino-5-acylthiazoles. The first step in such ring syntheses is 5-alkylation. " A useful variant is the use of an a-diazo ketone in place of the a-halocarbonyl component. " ... 

Suppose a case where the reactive building blocks 1-5 (three of each) would be available. Thioureas 1 are polyvalent donor molecules, isothiocyanates 2 and nitriles 3 can be viewed as acceptor-donor molecules, 2-bromoketones 4 are typical bis-acceptors whereas alkyl halides are mono-acceptors. In the typical Hantzsch synthesis of aminothiazoles, 1 is condensed with 4 to give thiazoles 6 which subsequently can be alkylated with 5 to give the final products 7 (27 aminothiazoles). 

The Hantzsch synthesis of thiazoles was presented in Chapter 4 as an example of a modified Paal-Knorr method. The reaction is reproduced here as Scheme 9.15. 

Another application of the Hantzsch method is in the synthesis of the aminothiazole coupling partner in the synthesis of the antibiotic cefdinir. The reactive methylene carbon of ethyl acetoacetate is first functionalized to the oxime after which a-chlorination is brought about to furnish the chloro-oxime substrate for Hantzsch synthesis with thiourea. A,jV-Dimethyl aniline is used as a base in the thiazole formation. ... 

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 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. 

Su nik and co-workers used the Hantzsch synthesis in their preparation of several novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines " (142) as derivatives of imatinib (Gleevec), a protein kinase inhibitor used to treat leukemia. Reaction of a-bromoketone 137 with thioacetamide 138 or 7/,A -dimethyl thioacetamide 140 gave the corresponding thiazole derivatives 139 and 141 in 98% and 61% yields, respectively. 

The Hantzsch synthesis has been employed by several groups in the syntheses of the thiazole rings of dolastatins 3 and 9. The dolastatin family... 

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. 

Holzapfel s modified conditions (not shown), was subject to a second Hantzsch synthesis using Holzapfel s conditions to produce thiazole 168 in 94% yield over two steps. The Hantzsch thiazole synthesis was also used in the same report in a later step in their synthesis of amythiamicin D. 

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. 

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