Cross-coupling thiazoles

A useful method for the preparation of functionalised thiazoles has been described. Palladium catalysed cross coupling reactions between 4-thiazolyl-5-acetyl triflates 36 and alkynes afforded 4-alkynyl-5-acetylthiazoles 37 in good yields (56-82%). If 37 is then treated with ammonia in methanol, thiazolo[5,4-c]pyridines 39 are formed, probably via the intermediate imine 38 which then undergos a regioselective 6-endo dig cyclisation <99EJOC3117>. 

The Hantzsch synthesis of thiazoles is an excellent method for the synthesis of simple thiazoles, however for some substituted examples low yields have been reported as a result of dehalogenation of the a-haloketone. An alternative method for the synthesis of highly substituted thiazoles has been reported, thus starting from the 2-bromo-5-chlorothiazole 76 it was possible to introduce substituents selectively at the 2-position by a palladium-catalysed cross coupling reaction to give 77 (74-92%). In order to introduce a substituent into the 5-position,... 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

The Pd -catalyzed cross-coupling reactions between stannylthiazoles and bromothiazoles represent an interesting route towards thiazole oligomers which are potential precursors to thiazole polymers <875185,88G2ii>. These cross-coupling reactions allow the preparation of both dimers and trimers (276). 

The unsubstituted 5,5 -isomer (76) is not readily available by the Hantzsch method. It was first prepared (Scheme 29) by diazotization of a diamino derivative (53HCA354) obtained by a benzidine-like rearrangement (51CB518), and has since been prepared by cross-coupling of the chloro- and trimethylstannyl-thiazoles (87S185). The 4,4 -bis(ethoxycar-bonyl) derivative has been prepared from thiooxalic esters by reaction... 

This reaction has also been used in the syntheses toward diamidino 2,5-bis(aryl)thiazoles exhibiting antiprotozoal activity against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f), shown below. Here, the synthesis involved conversion of derivatized thiazoles to bromothiazoles as substrates for Suzuki cross-couplings. ... 

Suzuki-Miyaura reactions are perhaps the most widely employed palladium catalyzed cross-couplings in the realm of thiazole medicinal chemistry. They typically take place only when the thiazole is an electrophile in the transformation. The nucleophilic thiazole boronic acid or ester, especially at the 2-position, is relatively unstable and therefore difficult to prepare. The electrophiles namely the 2-, 4-, or 5-substituted halothiazoles are often readily accessible in terms of their synthetic ease or commercial availability. A remarkable application has been described by Jang et al. in the discovery... 

A novel series of 2,5-disubstituted boryl thiazoles 10 is prepared by means of Hantzsch cyclizations of thioamides with monohalogenated boryl aldehydes 9a/b (14JA17669).These aldehydes are derived from the unsubstituted a-MIDA boryl aldehyde 8 by means of electrophilic halogenation (NBS or NCS, pyrrolidine). Application of these novel boryl thiazoles 10 is demonstrated in cross-coupling reactions (e.g., 11-12). The optimal coupling conditions utilize the Lipshutz surfactant TPGS-750-M in water. The 2,5-disubstituted boryl thiazole intermediate 10 is a versatile intermediate for medicinal chemistry and material science. 

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