Thiazoles direct arylations

In this chapter we examine in turn the properties of alkyl and aryl-thiazoles that do not possess functional groups bonded directly to the thiazole ring. The general trends are underlined, and the applications of certains thiazole compounds in such areas as polymers, flavorings, and pharmacological and agricultural chemicals are discussed. 

Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

Thiazole /V-oxides are also highly reactive substrates in direct arylation [80]. For example, the direct arylation of several thiazole /V-oxides with arylbromides in the presence of a palladium catalyst and a Buchwald ligand can be achieved at 25 °C,... 

Scheme 14 Thiazole N-oxides in palladium-catalyzed direct arylation...

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

In 2011, Itami and Studer [183] developed a palladium-catalyzed C4-selective arylation of thiophenes and thiazoles with arylboronic acids. Although they had already reported the C4(/J)-selective arylation of thiophenes with aryl iodides [88] (Scheme 17.18), this C-H/C-B coupling method [using a Pd"/hipy or phen/TEMPO ((2,2,6,6-tetramethylpiperidin-l-yl)oxyl) catalyst system] enabled the use of thiazoles as aryl nucleophiles. They also applied this coupling reaction to the synthesis of the core structure of SCH-785532, which is known as a BACE inhibitor. In the same year, Itami [184] reported a direct arylation of a PAH with arylboronic acids to generate a 7t-expanded PAH. Treatment of pyrene 142 with arylboroxine 143 in the presence of Pd(OAc)2 and o-chloranil as an oxidant, followed by cydiza-tion under stoichiometric FeClj, produced PAH 144. Key to the unprecedented C-H arylation was a notable combination of Pd" and o-chloranil. 

Fagnou and co-workers succeeded to combine Heck cyclization with direct arylation in 2009. This interesting domino palladium-catalyzed Heck-intermolecular direct arylation reaction gave new access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene could be employed as the direct arylation coupling partner as well and resulted in yields up to 99% (Scheme 2.35). As the authors demonstrated, in addition to... 

Palladium-catalyzed Direct Arylation of Pyridine N-Oxides, Pyrazine N-Oxides, Pyridazine N-Oxides, Pyrimidine N-Oxides, and Thiazole N-Oxides. Pyridine W-oxides can be efficiently ary-lated at the C2 position using aryl halides as the electrophile, palladium acetate as the catalyst, tri-tert-butylphosphonium tetraflu-oroborate as the ligand, and potassium carbonate as the base (eq 19). In this protocol, 3 equiv of pyridine Al-oxide are utilized to generate the corresponding 2-aryl derivatives. ... 

Pd-catalyzed Direct Arylation of Heterocycles. Microwave conditions were developed to access biheteroaryls using PivOH and PCys. Heteroarenes, such as benzothiophene, N-methylimidazole, thiophene, furan, thiazole, and benzothiazole, reacted efficiently with aryl bromides containing varying electronic and sterically challenging substituents (eq 18). 

Thiazolium salts can be obtained successfully by a modification of the Hantzsch s thiazole synthesis. This method is particularly valuable for those thiazolium compounds in which the substituent on the ring nitrogen cannot be introduced by direct alkylation, for example, aryl or heteroaryl thiazolium salts (Scheme 42). 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

These preceding properties imply that the thiazole has to be introduced in various molecules, by direct cyclization or with precursors already bearing the thiazole ring. Among these last products the clomethiazole. nitrothiazole, and aryl or alkylthiazoles with the functional group on the aryl or alkyl substituent have been widely used. 

Anthranilide derivatives in which an aryl group was directly connected to the anthranilide unit were also reported [63]. Similarly, anthra-nilides connected to a five-membered heterocycle such as thiazole, thiophene, or pyrazole were also covered by the patent literature [64]. Representative examples of these two classes are analogs 16 and 17. 

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>. 

Russian authors investigated this important reaction type to prepare a wide range of aryl-, alkyl-, and acyl-substituted imidazo[2,l-ft]thiazoles (70KGS508, 70KGS512 71KGS389). Several 2-mercaptoimidazoles react with a-halo ketones in one step directly to the bicyclic products 35 under reflux in butanol or ethanol followed by basification. Yields vary between 52 and 99%, but the two-step cyclization route requires isolation of the intermediates 34 and subsequent heating in phosphorus oxychloride. 

These methods are limited in scope. Direct thiation has been reported for the transformation of vicinal diketones to [3,4]-annelated thiophenes <1996CHEC-II(7)49>. Thionations and selenations of vicinal halomethyl ketones with thioacetamide or iV,iV-diethylselenopropionamide as sulfur and selenium donors, respectively, have also been reported <1996CHEC-II(7)49>. In a recent example, thieno[3,4-f]pyrazoles 160 were readily prepared from aryl 5-bromomethyl-l//-l-phenylpyrazole-4-yl ketones 159 by reaction with thioacetamide (Equation 35) <1998JHC71>. Additionally, an example of an amination cyclization by reaction of 161 with benzylamine to afford pyrrolo[3,4-i/ thiazole 162 has been described (Equation 36) <1998JHC71>. 

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... 

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. 

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