Hantzsch synthesis of thiazoles

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... 

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 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,... 

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. 

First described in 1887 (1887CB3118) by Hantzsch, the cyclization of a-halocarbonyl compounds by a great variety of reactants bearing the N—C—S fragment of the ring is still the most widely used method of synthesis of thiazoles. 

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... 

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 first synthesis of thiazole was described by Arthur Hantzsch in 1887. This reaction in its most fundamental form as well as other forms with variations has been widely applied in the construction of a variety of molecules since then. In its most basic form, the reaction is illustrated in the scheme below and involves the use of an a-halocarbonyl compound with reactants comprising the N-C-S linkage. 

Extension of the Hantzsch s Synthesis to Thiazole Carboxylic and Thiazole Acetic Acids (Table II-IO). Mono-, di-, and tricarboxylic acids are among the most easily prepared thiazole derivatives. 

Faneti/ole (122) is a biological response modifier with significant immunosuppressant activity It can be synthesized by conversion of 2 phen> lethylamine (120) with ammonium thio cyanate to the corresponding thiourea analogue 121 The synthesis of faneli/ole (122) concludes by thiazole nng formation of 121 by reaction with phenacylbromide Thus its synthesis involves use of the classic Hantzsch procedure in which a bromoacetone analogue and an appropriate thio urea denvative are reacted 143]... 

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... 

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... 

Thiazoles may be prepared by a Hantzsch-type process, by reaction of N-protected thioamino acids with bicarbonate and BrCH2C0C02Et, followed by TFAA in 2,6-lutidine (equation 205). This reaction has been used as one of the important steps in the total synthesis of (—)-bistatramide C721. 

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). 

Khan et al. [9] reported the environment friendly microwave-assisted synthesis of substituted steroidal[6,7-d]thiazoles (iv). The key step involved the reaction of a-haloketones (iii) and thiourea/substituted thiourea via hantzsch protocol. 

In a synthesis of pateamine A, it was found that the optimum yield could only be obtained from a Hantzsch-type thiazole formation by isolation and purification of the nonaromatic intermediate. This was followed by dehydrogenation by treatment with TFAA, pyridine, and Hiinig s base, giving a 62% yield over the two steps (Scheme 25) <2004JA10582>. 

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). 

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