2-chloro-4-methyl-5- thiazole

An operationally simple halogenation of 4,5-dimethyl-2-arylthiazoles provides a regioselective approach to bromo- or chloro-methyl substituted thiazoles <04TL69>. Thus, treatment of 117 and its hydrochloride salt with NBS and NCS affords 4-bromothiazole 118 and 4-chlorothiazole 119, respectively, with >99% regioselectivity. The remarkable regioselectivity observed may arise from a Pummerer-type rearrangement mechanism via 120. 

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). 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

Among the volatile compounds listed in Table II, only thiazole compounds are derived from the thermal degradation of thiamin. 5-(2-hydroxyethyl)-4-methylthiazole and 4-methyl-5-vinylthiazoIe are well-known thermal degradation products of thiamin. 5-(2-Chloro-ethyl)-4-methylthiazole may form through the interaction of 5-(2-hydroxyethyl)-4-methylthiazole with hydrogen chloride. However, the most abundant product, 4-methylthiazole, has never been identified as a decomposition product of thiamin. The mechanism for its formation is not clear. 

Thiazole itself can be obtained by condensing chloroacetaldehyde and thioformamide (Scheme 159). The reaction is explosive and proceeds in low yield because of the instability of the thioformamide under acid conditions. Higher thioamides are more stable and react under milder conditions with chloroacetaldehyde, affording 2-substituted thiazoles in moderate yields. It is possible, and often preferable, to prepare the thioamide in situ in dioxane solution by the action of phosphorus pentasulfide on the corresponding amide and in the presence of solid MgC03 (Scheme 160). With arylthioamides, except for some nitrothiobenzamides, yields are usually higher and the cyclization is carried out over several hours in boiling absolute alcohol. Chloroacetaldehyde can be replaced in these reaction by derivatives such as 1,2-dichloro- or dibromo-ethyl methyl or ethyl ether, 1,2-dichloro- or dibromo-ethyl acetate, 2-chloro- or dibromo-ethyl acetate, and 2-chloro or bromo-diethyl-acetal. 

Azine approach. The parent cation and substituted derivatives are available by acid-catalyzed cyclization of 2-/3-oxoalkylthiopyridines (401) using an acid such as sulfuric, phosphoric or PPA. Chloro or nitro substituents in the pyridine ring do not seriously interfere (66JHC27). The cyclization of 3-hydroxypyridine analogues (402) is also at the nitrogen to yield the thiazole derivatives. The cyclization, however, is sensitive to the peri interaction between 3- and 5-substituents. In 3,5-dimethyl derivatives (403 R2 = R3 = Me) the steric repulsion is apparent by the unusually low field signals for the methyl protons <81H(15)1349>. 

Chloro-7-methyl-1 H-indazol-3 -yl) -5 -pyridin-3 -yl-thiazole-4-carboxylic acid [3-(5-oxo-4,5-dihydro-lH-pyrazol-4-yl)-propyl]-amide aOJ tQTn o Y-O HN 7 H N... 

Chloro-7-methyl-lH-indazol-3-yl)-5-pyridin-3-yl- thiazol-4-yl]-(2,3,5,6-tetrahydro-[l,2 ]bipyrazinyl-4-yl)- methanone Clvk-N, r N o n- n Y... 

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. 

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-l//-pyrazoles by reaction of a-chloro-/ -arylacrylonitriles with hydrazine hydrate <2004RJ01518>. Reaction of 2-(3,3-dicyano-2-propenylidene)-4,4,5,5-tetra-methyl-l,3-dioxolane 641 with hydrazine afforded 3-(2-hydroxy-l,l,2-trimethylpropoxy)pyrazole 642 (Equation 134) <2003RJ01016>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic, and sulfonyl hydrazines led to the synthesis of N-l-substituted 3-acyM-cyano-5-aminopyrazoles, which are versatile intermediates for the synthesis of many biologically active scaffolds <2006TL5797>. 2-Hydrazinothiazol-4(5//)-one reacted with a variety of cinnamonitrile derivatives and activated acrylonitriles to yield annelated pyrazolopyrano[2,3-rf thiazole <1998JCM730>. 

The complexes ML2, where M = Co, Cu, Ni, Zn HL = 2-hydroxy-5-(chloro/ nitro)-benzaldehyde[4-(3-methyl-3-mesitylcyclobutyl)-l,3-thiazol-2-yl]hydra-zone, give IR spectra indicating chelation of L through azomethine N and phenolate O atoms.509 Coordination of the 5-(2 -carboxyphenylazo)-8-hydro-xyquinoline to Co, Ni, Cu or U022+ via CN, N=N, COOH and OH was shown by IR spectroscopy.510 IR data for M(II) (=Co, Ni, Cu, Zn) complexes of A -salicyloyl-A"-/)-hydroxythiobenzohydrazide and related ligands show coordination by thiolato S, enolic O and two hydrazine N atoms.511... 

A large-scale synthesis of the unsubstituted thiazole has been described starting from chloro-acetaldehyde and methyl dithiocarbamate <85S948>. Condensation of the two reagents affords 2-methylthiothiazole (272) which upon treatment with lithium in liquid ammonia and protonation with ammonium chloride yields thiazole (Scheme 69). 

Fig. 13. Chemical structures for allosteric and ATP-competitive Eg5 inhibitors, (a) Monastrol ((S)-ethyl 1,2,3,4-tetrahydro-4-(3-hydroxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate), the first compound discovered which bound to the allosteric pocket the compound has an IC50 of 22 uM. (b) CK-f 06023 (N-((R)-f-(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)propyl)-4-bromo-N-(3-(dimethylamino)propyl) benzamide), which binds to the same allosteric pocket as Monastrol and has a Ki of f 2 nM. (c) CK-238273 N-(3-aminopropyl)-N-((R)-f -(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)-2-methylpropyl)-4-methylbenzamide), an optimized analog of CK-f 06023 which is in phase II and has a Ki of f. 7 nM. (d) 4-(2-(f -phenylethyl)thiazol-4-yl)pyridine, an ATP-competitive thiazole compound which was an initial hit from the Merck compound collection the compound has an IC50 of f f uM. (e) 4-(2-(f -(4-chlorophenyl)cyclo-propyl)thiazol-4-yl)pyridine, an optimized ATP-competitive thiazole compound with an IC50 of 290 nM.

The direct coupling of t-butyl thiazole-4-carboxylate at C-2 is successful with a wide range of (hetero) aryl halides, the hindered ester (rather than the methyl ester), together with the use of tri-o-tolylphosphine as ligand, giving optimum selectivity for C-2 vs. C-5 for iodoarenes and heteroarenes. Changing the ligand to JohnPhos allows extension to chloro- and bromo-heterocycles. ... 

The interaction of comparable heterocyclic methylureas (177) and chloro-thioformyl chloride (179) gives in some, but not all, cases identical results, due to initial loss of methyl isocyanate from 177. Alternatively, the urea moiety may be preserved, when 2-heteryl-l,2,4-thiadiazolidine-3,5-diones are formed, as described immediately above. The observations on record are too varied and extensive to be adequately summarized. A typical example of the reaction is the production of 2-(thiazol-2-yl)-4-methyl-1,2,4-thiadiazoli-dine-3,5-diones (169, Aik = Me, Ar = thiazol-2-yl).163... 

The synthesis of hitherto inaccessible thienylpyrazolones has been described. The reaction of (174) with methyl bromoacetate, followed by base-catalysed cyclization, gave (175). The corresponding thiazole-fused system, on the other hand, was prepared through the reaction of 2-phenyl-5-chloro-4-formylthiazole with thioglycollic acid in the presence of sodium methoxide. Another route to thienothiazoles consists in the reaction of (104) with CSa and sodium hydroxide. ... 

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