2-chloro-5- thiazole

Treatment of a-thiocyanatoketones at low temperature with dry hydrogen chloride in ether solution gives satisfactory yields of 2-chloro-thiazole derivatives (188). The use of phosphorus pentachloride leads to the same results, but in this case chlorination can also occur at the 5-position (Scheme 97) (18, 68). 

The first examples for the oxidative addition of 2-chloro thiazoles to complexes of cf or metal centers were reported by Roper et al. more than 30 years ago [107, 108]. In 2001 Cavell and Yates showed by detailed experimental studies supported by DFT calculations that the oxidative addition of the C2-X bond of imidazolium... 

This method, initiated by Marchesini in 1893 (i893G(24)65) (Scheme 177), consists of the condensation of an a-halocarbonyl compound with ammonium thiocarbamate (244 R2 = NH4) or its esters (244 R2 = alkyl). The reaction is carried out at low temperature in aqueous medium and then allowed to stand overnight. 2-Hydroxythiazoles (244 R2 = H) give 2-chlorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride. This constitutes a convenient synthetic method for these compounds when the conversion of 2-amino- into 2-chloro-thiazole fails. 

Chloro-thiazol-5-yl-methyl)-4-nitroimino-5-n-propoxymethyl-perhydro-1,3,5-oxadiazine... 

Chloro-thiazol-5-yl-methyl)-4-nitroiminino-perhydro-l,3,5-oxadiazine (5 mmol) was dissolved in 15 ml of DMF and NaH (6 mmol) added. The mixture was stirred at room temperature 15 minutes, propoxymethyl chloride (10 mmol) added, then the mixture stirred overnight. Thereafter, the mixture was concentrated, the residue extracted twice with CH2CI2, the product purified by chromatography on silica gel with acetonitrile/water, 70 30, and isolated in 29% yield, having a logP = 1.7 (pH = 2) (Note 2). 

When the author reacted 2-chloro-5-chloromethyl-thiazole, (II), with 3-methyl-4-nitroamine-l,2,3,6-tetrahydro-5-(2-chloro-thiazole-4-yl)-methyl-l,3,5-oxadiazine, the Step 3 product, 3-methyl-4-nitroamine-l,2,3,6-tetrahydro-5-(2-chloro-thiazole-4-yl)-methyl-l,3,5-oxadiazine, (III), was isolated. 

Compounds (397) can be prepared by reaction of 4-chloro-thiazole-5-carbonitriles with ethyl 2-thioacetate or a 2-thioacetamide <92T7689>. The thieno [2,3-d]thiazole-5-carboxamides (397b) obtained in that way lead to thiazolo[4, 5 4,5]-thieno[3,2-d]pyrimidin-5(6//)-one (398) upon treatment with triethyl orthoformate in acetic anhydride (Scheme 99). 

The synthesis involved construction of a heteroaryl-aryl coupling, where the chloro-thiazole[5,4-i/]pyrimidine was coupled with p-fluorophenyl boronic acid in a Suzuki coupling. The reaction proceeded well even in the presence of a free amino group on the pyrimidine. 

Nucleophilic Substitution.— The reactivities of 2-halogeno-thiazoles with arenethiols are explained by the existence of an acid-base equilibrium preceding the substitution step the formation of an ion-pair or of thiazolium and arene-thiolate ions is the rate-determining step. Some 4- or 5-substituted 2-chloro-thiazoles apparently react with methoxide ion in a normal aza-activated nucleophilic substitution, the reaction being influenced by the substituent. In the case... 

Action of HSO3CI on 2-substituted thiazoles affords the 5-chlorosulfonyl derivatives (337, 338). Addition of 6-phenylthiazolo[2,3-e]tetra2ole to oleum opens the tetrazole ring to form 2-azido-4-phenyI-thiazolyl-5-sulfonic acid, isolated as its salt (339). 5-Chloro-sulphonyl derivative is obtained similarly by action of HSO,Cl. 

Ethyl-4,5-thiazole dicarboxylates (77), R =H, Me, Et, Ph, or heteroaryl, were prepared from diethyl-a-chloro-/3-ketosuccinate (76) and thioamides in boiling ethanol (Scheme 35) (103, 110, 145, 298, 577, 639). 

Thiazole acetic acids and their hotnologs can also be prepared by cyclization procedures 4-thiazole alkanoic acids and their salts were prepared by treating a thioamide with a -y-chloro- or 7-bromoacetoacetic or their a-alkyl derivatives (4, 10, 16, 22, 273, 275, 281, 640, 647, 695). 

Ethyl-cf-chloroacetoacetate gives 5-carbethoxy-4-methyl-2-thiazole thiol (387), while 3-chloro-2,4-pentanedione affords the 2-mercapto-4-methyl-5-thiazolylmethylketone in good yield (74%) (387). 

Other sulfur compounds such as thiourea, ammonium dithiocarbamate, or hydrogen sulfide also lead to 2-mercaptothiazoles. Thus thiourea has been used in the syntheses of 4,5-dimethyl (369) and 4-aryl-2-mercapto-thiazoles (Table 11-30) (519). The reactions were carried out by condensing the ia -thiocyanatoketones with thiourea in alcohol and water acidified with hydrochloric acid. By this procedure, 4-aryl-2-mercaptothiazoles were obtained in yields of 40 to 80% with bis-(4-aryl-2-thiazolyl) sulfides as by-products (519). These latter products (194) have also been observed as a result of the action of thiourea on 2-chloro-4-arylthiazole under the same experimental conditions. They can be separated from 2-mercaptothiazoles because of their different degrees of solubility in sodium hydroxide solution at 5%. In this medium bis-(4-phenyl-2-thiazolyl)sulfide is... 

The behavior of the 2-mercapto-4-arylthiazoles in this reaction would seem to be analogous to that of the 2-mercaptobenzothiazoles (137). It appears that monosulfide compound (195) cannot be obtained from 2-chloro- and 2-mercapto-4-phenylthiazoles (given the difficulty of preparing it in this way) but rather by the action of the 2-mercapto-4-phenyl-thiazole on the intermediary, 4-phenyl-2-isothiazolyl isothiouronium chloride (194), as in Scheme 101. 

Benzisothiazoles can be prepared by the reaction of aromatic chloro compounds with sulfur and ammonia. Thus, 2,6-dichlorobenzylidene chloride gives 4-chloro-l,2-benzisothiazole (72AHC(14)43), and 2-chlorobenzophenone gives 3-phenyl-l,2-benziso-thiazole (79GEP27 34866). 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

The thiazole ring has been found to be an occasional surrogate for a phenyl ring in certain antiinflammatory agents. Note that the side chain is restricted to a simple acetic acid in this series. Reaction of p-chloro-2-mercaptoacetophenone (198) with ethyl cyanoacetate in the presence of base affords thiazole 200. The reaction may involve an adduct such as the iminothioether 199 as an intermediate. Saponification of the ester moiety of 200 then gives the antiinflammatory agent fenclozic acid... 

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