Metallated thiazole

The 2-metalated thiazoles react with a variety of electrophilic substrates in a standard way, leading to addition products with aldehydes, ketones, carbon dioxide, epoxides, nitriles, Schiff bases, and to substitution products with alkyl iodides (12, 13, 437, 440). 

Lithiothiazoles are the starting material for the preparation of other metallated thiazoles. Thus, transmetallation of 2-lithiothiazole with trimethylsilyl chloride can be carried out in one-pot and multigram scale to give the stable and synthetically important 2-trimethylsilylthiazole (707) (84CC655,... 

The crystal structure of a dimer of 4-i-butyl-2-lithiothiazole incorporating two molecules of diglyme has been determined by X-ray analysis (95AG(E)487). The structure features the lithium atom positioned halfway between nitrogen and C-2, thus providing a carbenoid nature to this metallated thiazole. 

The chemistry of the thiazoles does, of course, bear some similarity to that of the oxazoles. Metallated thiazoles and thiazole derivatives have found use, for example, both as carbonyl equivalents and masked acetaldehyde enolates. Additionally, as will be exemplified below, thiazole derivatives have served as catalysts for benzoin-type condensations, and they have provided access to a unique class of activated acid derivatives. 

The results described in the following, part of which have been presented as a preliminary communication, are collected in a full paper. A. Dondoni, S. Franco, F. Junquera, F. L. Merch n, P. Merino, T. Tejero, and V. Bertolasi, Stereoselective homologation-amination of aldehydes by addition of their nitrones to C-2 metalated thiazoles. A general entry to a-amino aldehydes and amino sugars, Chem. Eur. J. 1 505 (1995). 

Metallated thiazoles show expected properties. Thus 2-lithiothiazole reacts normally, as shown in Scheme 153. Acetoxymercuriothiazoles are hydrodemetalled by hydrochloric acid and converted into the corresponding bromo derivative by bromine in carbon tetrachloride (see Section 4.19.2.1.4(vii) Scheme 154). 

Unstable metalated thiazoles can be generated in situ from 2-lithiothiazole (219) by trans-metalation with an appropriate reagent. The cuprate is obtained by the use of a suspension of copper(I) bromide in THF <87JOM(332)95> the magnesium bromide and ethylaluminum chloride are obtained by the use of magnesium bromide etherate or diethylaluminum chloride, respectively... 

This situation may arise when the rates of the Reactions (1) and (2) in the above sequence are comparable. Examples are 2-metallated thiazole, imidazole, pyridine and metallated formamides. Yields of the mono-alkylation products are low, except in the case of CH3I and other reactive alkyl halides (where Reaction (1) is fast). 

Metalated thiazoles are only stable at low temperatures. The formation of an isonitrile in the procedure below clearly shows this poor stability (compare Ref. [189]). On the other hand the methylthio derivative of benzothiazole is formed in good yield upon addition of a methythiolation reagent to the solution resulting from the interaction between benzothiazole and sodamide in liquid ammonia. This situation may be analogous to the ambident behaviour of 2-lithio-4,5-diphenyl-oxazole [193]. 

The use of metallated thiazoles, thiazolines, oxazolines, and dihydrooxazines as anion-equivalents in organic syntheses has been advanced extensively [1-6]. Table 7 summarizes the conditions for preparative metallations of a numbers of substituted heterocycles. 

The 2-metalated thiazoles can be utilized for the (electrophihc) introduction of other functionalities (e.g., by carboxylation, alkylation, halogenation, etc.). 

However, 2-TST (1) turned out to be unreactive toward nitrones as electrophiles. To overcome this difficulty and accomplish the homologation of aldehydes to a-amino aldehydes, Dondoni and coworkers reported the use of C-2 metalated thiazoles, instead of 2-TST (1), and nitrones as derivatives of the aldehydes (eq 26). ... 

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