Thiazoles Hantzsch reaction

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. 

The stereochemistry of stereogenic centers linked to the thiazole C-2 is directly controlled by the rate of carbocation formation during thiazole formation from thioamide and a-bromoketones in the Hantzsch reaction <20010L3655>. 

Promothiocin A was initially synthesised by a three-component coupling approach <1998CC2049>. A Bohlmann-Rahtz pyridine synthesis established the oxazoyl-thiazole-pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis <2000JA3301>. 

Thiazole and its derivatives are useful compounds in medicinal and agricultural chemistry. The thiazolium ring is present in vitamin B1 and its coenzyme form is important for the decarboxylation of a-keto acids [74]. This heterocyclic system has broad application in drug development for the treatment of inflammation [75] and bacterial [76] and HIV infections [77]. Hence the thiazole nucleus has been much studied in organic and medicinal chemistry. Originally it was synthesized by the Hantzsch reaction (a-halo ketones with thioamides or thioureas) (Equation 4.38) [78]. 

Famotidine, the orally administered H2 receptor antihistamine drug for ulcer, possesses an interesting structure with a guanidine substituent on the 2-position of the thiazole ring. The thiazole is constructed in the early stages of the synthesis via a Hantzsch reaction in 84% yield wherein dichloroacetone and thiourea are condensed. 

The Hantzsch reaction has also been incorporated in a multi-component reaction described by Rao et al. to produce 2-pyrazol 4-yl-substituted diiazole system in one step. The reaction involves a one-pot cyclization to form thiazole, pyrazolone and cyclopropane rings via the reaction of aryl bromomethylketonewith, thiosemicarbazide, and a-acetyl-y-butyro lactone in phosphorus oxychloride. 

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 reaction has also been utilized in the combinatorial synthesis of cyclic peptidomimetics 13 (14ACSCS001), peptide macrocycles 14 (14ACSCS71),oxazole-thiazole bis-heterocyclic compounds (14ACSCS39) (structures not shown). 

This chapter discusses the high S3mthetic perspective of several methods for s)mthesis of thiazoles and its derivatives that have been published in the last three decades. Many pharmaceutically active heterocycles have been obtained based on the reaction of acid hydrazides particularly concerning Hantzsch reaction, Dimroth type rearrangement, Tchernich reaction. 

The Hantzsch reaction, discovered in 1889, remains one of the most reliable routes to thiazoles. The reaction involves a [3 + 2] atom cyclization between thioamide 1, and an a-halo carbonyl compound 2 and is one of the most direct routes to thiazoles. The reaction can also be carried out with thioureas, thiosemicarbazides and other compounds containing the —N-0=S structural unit. " ... 

The Holzapfel-Meyers-Nicolaou modification is a significant improvement over the traditional Hantzsch conditions. However, racemization can still occur in some circumstances. For example, the two-step Hantzsch reaction of thioamide 20 with bromide 19 furnishes thiazole 21 with 60-85% enantiomeric excess due to partial epimerization at the a-stereogenic center. The epimerization issue is obviated when thioamide 20 is replaced with the ketal-protected thioamide 22. Reaction of 19 with 22 delivers 23 with good optical purity (> 96% ee). This thiazole represents the core structure of the potent thiopeptide antibiotic nosiheptide. ... 

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... 

Hantzsch s Synthesis (Type A S—C—N + C—C).—The majority of thiazoles continue to be prepared by this method. The intermediate formation of 4-hydroxy-A -thiazolines (see Vol. 3, p. 567 and Vol. 1, p. 379) has been demonstrated again,whilst Metzger s group has detected thioimidate intermediates in Hantzsch reactions by the use of n.m.r. spectroscopy. 

As in the case of the thiazoles, a variation on the Hantzsch s method has been used. This consists of using a nonhalogenated carbonyl derivative directly in the presence of iodine in the reaction with selenourea (Scheme 7) (20). However, in this case the reaction with selenourea is slower than with thiourea, and normally an excess of carbonyl compound is used. 

Hantzsch and Weber began their description with the compound which led them indirectly to the discovery of the thiazoles the a-thiocyanoacetone imine ( Rhodanpropimin ) of J. Tcherniac and C. H. Norton. C4H6N2S. obtained by reaction of ammonium thiocyanate with chloroacetone. After Tcherniac and Norton (18), the a thiocyanoacetone... 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

The method has not been studied extensively and is restricted to the preparation of alkyl-, aryl-, or alkoxy-substituted thiazoles mostly in 2-, 5-, or 2,5-positions. Yields ranged from 45 to 80%. Sometimes this method gives good results when the usual Hantzsch s synthesis fails. There has been very little speculation about the mechanism of this reaction. 

Attempts to prepare selenazole derivatives were first described by Hofmann,2 a student of Hantzsch, in connection with investigations in the thiazole series. By reaction of selenobenzamide with a-halogeno compounds corresponding to the general reaction (2, R" = CeHg), he synthesized a series of 2-phenylselenazoles. In the same way, several... 

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]... 

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>. 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

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... 

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. 

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