Arylation of thiazoles

The palladium- and copper-mediated C-2 arylation of thiazole with 4-iodoanisole under ligandless and base-free conditions provides 2-(4-methoxyphenyl)thiazole in good yield <06EJOC1379>. However, the scope of this selective C-2 arylation has not been disclosed. 

A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 <030L3607>. According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication <06OL2899>. 

The arylation of heteroaromatic compounds is also achieved by aryl-aryl coupling reaction. The arylation of A-methylimidazole with bromobenzene occurs under palladium catalysis (Equation (62)).72 The arylation of thiazole with aryl iodide occurs at the 2-position under PdCl2(PPh3)2/CuI catalysis.73 In this case, tetrabutylammonium fluoride improves the activity of the catalyst. Alternatively, thiazoles and benzothiazole are efficiently arylated... 

Two methodologies for the direct C-2 arylation of thiazoles have been reported. The first one is mediated by both palladium and copper <07T1970>. Thus, the C-2 arylation of thiazole and benzothiazole with aryl iodides is carried out using copper iodide (2 equiv.) and a catalytic amount of palladium acetate under base-free conditions. The other method involves copper-catalyzed arylation with aryl iodides in the presence of lithium t-butoxide <07JA12404>. In general, reactions with lithium tert-butoxide provide better yields than those with potassium fert-butoxide. In addition, arylation with phenyl bromide, chloride or tosylate fails to provide any desired arylation products. 

The free radical arylation of thiazole (391) has been performed either by the Gomberg-Bachmann (392) decomposition of aryldiazonium chlorides (119,393), by the thermal decomposition of benzoyl peroxide (394-397) or N-nitrosoacetanilide (398), or by the photolysis of benzoyl peroxide or iodobenzene (398). The three monophenylthiazoles are obtained in the practically constant proportions 2-phenyl, 60% 5-phenyl, 30% 4-phenyl, 10%, giving the order, 2>5>4, of decreasing reactivity of the three positions of thiazole toward phenyl radicals (398). Competition reactions with nitrobenzene (397) gave an estimation of the globed reactivity of thiazole relative to benzene of 0.75 with the partial rate factors f2 = 2.2, /s=1.9, /4 = 0.5. When the thermolysis of benzoyl peroxide is performed in acetic acid solution, the substrate in reaction is the conjugate acid of thiazole the global reactivity is enhanced to 1.25,... 

TABLE ra-28. PERCENTAGE OF ARYLISOMERS FROM THE ARYLATION OF THIAZOLE AND ALKYLTHIAZOLES WITH p-SUBSTITUTED BENZOYL PEROXIDES (182, 189)... 

Doucet has reported that activated aryl chlorides can be employed in the arylation of thiazoles if PdCl(dppb)C3H5 catalyst is used (Scheme 6) [42], Acetyl, formyl, nitro, cyano, ester, and trifluoromethyl substituted aryl chlorides are reactive. However, 4-chlorofluorobenzene was not reactive. Use of the same catalyst system was shown to be effective for the arylation of oxazole and benzoxazole with activated aryl chlorides [43],... 

The 2,5-diarylation of thiazole can be carried out effectively with a bulky phosphine ligand. In this case, no monoarylated product is observed even in the early stage of the reaction, suggesting that the second arylation proceeds relatively fast (Eq. 61) [ 142]. The selective 2-arylation is accomplished by using Cul and BU4NF as cocatalyst and base, respectively (Eq. 62) [143]. By using a catalyst system of Co(OAc)2-IMes (IMes=l,3-bis-mesitylimidazolyl carbene),the 5 position is arylated selectively [144]. The Pd-catalyzed arylation of thiazole and 1-methyl-pyrrole with a polymer-linked aryl iodide has been reported [145]. 

Scheme 15 Sequential direct arylation of thiazole A/-oxide (a) versus thiazole (b) with aryl halides.

In both reports, C4-arylation takes place in the last step due to the poorest reactivity of this position. In order to obtain 4-aryl, 2,4-diaryl, or 4,5-diaryl substituted 1,3-azoles in an efficient manner, Itami came up with a new strategy for regioselective C4-arylation of thiazoles (Scheme 16) (2014CSC123). A diphenylmethanol group, based on Mori s procedure for the synthesis of 2,5-diarylthiazoles (2009H303), was introduced as protecting group at C2 followed by C4-arylation with an arylboronic acid (41 42). Deprotection... 

Scheme 16 C4-selective C—H arylation of thiazoles with arylboronic acids.

C5-Arylated 1,3-Azoles The first C5-selective arylation of thiazoles was reported by Ohta in 1992 [5c]. Thereafter, in 1998, Miura and Nomura [99a] demonstrated the C5- or C2-selective arylation and diarylation of 1,3-azoles with various aryl halides by using the catalytic system Pd(0Ac)2/CuI/Cs2C03 in DMF at 140 °C. 

An efEcient regioselective arylation of thiazole 68 via Pd-catalyzed C—H activation has been reported (130L5774).The optimized conditions involve Pd(OPiv)2 (10mol%) CS2CO3 (1.0 eq) in DMF (2.0) at 100°C. Interestingly, addition of Pd(0) species, such as Pd2(dba)3, results in significantly... 

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]. 

Arylation of Thiazoles and Oxazoles. The protocol that was previously developed for the C-H activation of azine and diazine (V-oxides with aryl triflates was used to effect the arylation of flve-membered ring heterocycles, such as oxazoles and thiazoles. In contrast to another protocol that was previously reported by the same group, the transformation did not require an V-oxide function. However, in order to direct the arylation at the C4-position, to prevent the formation of a mixture of regioisomers, and to minimize the generation of diarylated products, a C5-chloride was used as a blocking group. The procedure, which is promoted by palladium acetate and di-tert-butyl(methyl)phosphonium tetrafluoroborate, uses an aryl bromide as the electrophile. 

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