Thiazole-4-carboxylates, arylation

Esters of 2-thiazole carboxylic acids (75) (383) are also prepared from ethyl monothiooxamate (74) (Scheme 34), and several compounds of this type with hydrogen, alkyl, or aryl groups in the 4- or 5-position (201, 209, 210, 242, 294) or a nitro group in the 5-position (674) have been reported. 

The effect of the halogen of the aryl halide was also carefully studied using bromobenzene and chlorobenzene as the electrophile. When the arylation was performed on ethyl 4-oxazole carboxylate using di-tert-butyl(methyl)phosphine as the Ugand and cesium carbonate as the base, the product of C5 arylation B was obtained when bromobenzene was used as the electrophile. Conversely, the product of C2 arylation A was formed if chlorobenzene was employed (eq 16). Similar results were obtained for the arylation of tert-butyl 4-thiazole carboxylate when mbidium carbonate was used as the base (eq 16). Again, it should be noted that the regioselectivity is highly dependent on the choice of the base and the phosphine. 

The above transformation takes place via the catalytic effect of copper (I), which generated the corresponding carbenoid from a-diazo-p-keto esters. These Cu-carbenoides react with the thiocarbonyl group of thioamides, after cyclocondensation to afford 2-aryl-l,3-thiazole-5-carboxylates (Scheme 18).40... 

The secondary amino group of 3-(Al-ethylaminomethyl)-7-[2-(2-amino-thiazol-4-yl)-2-(Z-1 -carboxy-1 -methylethoxyimino)acetamido]ceph-3-em-3-carboxylic acid was arylated with 8-methylthiopyrido[l,2-a]pyrimidi-nium salt in dimethylformamide in the presence of triethylamine at 40°C (89MIP2). 

The direct synthesis of aryl- or alkyl nitriles from cyanide and organohalide precursors is revered in synthetic chemistry, as the nitriles represent a flexible functionality that can easily be converted into (for example) carboxylic acids, esters, amides, amidines, amines and various hetero cycles [67], such as thiazoles, oxazolidones, triazoles and tetrazoles [68]. The tetrazole group... 

Thiazole and its simple alkyl or aryl derivatives are not polarographically reducible. Substitution in the thiazole ring with electron-attracting groups may render the nucleus reducible. Derivatives of thiazole-2-carboxylic acid are reducible in alkaline solution, and the reduction is assumed to take place in the nucleus [282]. 

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 synthesis of aryl or alkyl nitriles from halides is valued in medicinal chemistry, because the nitriles themselves constitute a flexible building block that easily can be converted into carboxylic acids, amides, amines, or a variety of heterocyclic compounds [103], for example thiazoles, oxazolidones, triazoles, and tetrazoles [104]. 

In addition, oxazole-4-carboxylate 10 can be subjected to direct Pd-catalyzed alkenylation, benzylation, and alkylation in the 2-position [257]. Recently, direct 2-C-H-functionaUzation (alkylation and arylation) has been reported for oxazoles (as well as thiazoles and benzazoles) with free 2-position utihzing chelated Ni/Cu-catalysts derived from 2,2 -bis(dimethylamino)diphenylamine [258] or chelated Cu/Pd-complexes derived from Xantphos ]259] in the presence of a base. 

The decarboxylative arylation of thiazole- and oxazole-5-carboxylic acids with aryl halides occurs in the presence of a Pd/Ag system (Scheme 4.46) [51]. The azole-azole coupling also proceeds through decarboxylation and C-H bond cleavage (Scheme 4.47) [52]. 

Aromatic thioamides react with MeC(0)CHClC(0)C02Et to give a 3 1 ratio of ethyl 5-acetyl-2-aryl-thiazole-4-carboxylates and the isomeric products (2). Modifications of the Hantzsch synthesis continue to appear. Thus, 2-aryl-5-aroyl-thiazoles may be prepared from the JV -thioaroyl-iViV-dimethyl-formamidines ArC(S)N=CHNMea and a-bromo-ketones [strictly speaking, this is a Type F (C—N—C—S + C) synthesis], whilst 5-amino-2-phenyl-l,2,3-thiadiazolium salts [e.g. (3)] and compounds with the general structure RCHgCN (e.g. R = CN or COaEt) yield 4-amino-thiazoles. ... 

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