Synthesis from Thiazoles

Synthesis from Thiazoles.—2-Aryl-4-cyanomethyl-thiazoles condense with the cation Me2NCH=CPhCH=NMe2+ in the presence of base, and the products 

Hisano and M. Ichikawa, Ghent, and Pharm. Bull. Japan), 1974, 22, 2051. 

Lechartier, and P. Demerseman, Bull. Soc. chim. France, 1973, 3017. 

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A synthesis from thiazole precursors occurred when 2-imino-3,4-diarylthiazolines (234) were cyclized with formaldehyde to give 236 [79IJC(B)632]. 

These a-acylaminoketones also provided a convenient synthesis of thiazoles on treatment with phosphorus pentasulfide (Gabriel s method). Although yields range from 45 to 80%, substituents are usually restricted to alkyl, aryl and alkoxy derivatives. Thus, reaction of the a-acylaminoketone (4) with P4S1Q gave the thiazole (5), and thiazole (7) itself was prepared in this manner in 62% yield from formylaminoacetal (6) (14CB3163). The corresponding 5-ethoxy compound was obtained from the a-formamidoester and phosphorus pentasulfide in an inert solvent. 

A variation of the general method for the synthesis of 2-amino-selenazoles is to avoid the use of the free a-halogenocarbonyl compound and in its place react the corresponding ketone and iodine with selenourea.This procedure is also taken from thiazole chemistry. By contrast with thiourea, the reaction with selenourea needs a longer reaction time and the work up of the reaction mixture is somewhat more difficult. Usually an excess of the ketone is used. In the preparation of 2-amino-4-( n-nitrophenyl)selenazole, a very high yield, calculated on the amount of iodine used, was obtained. To explain this peculiar result, the oxidative action of the nitro group was invoked. This liberates free iodine from some of the hydrogen iodide eliminated in the condensation reaction, and the free iodine then re-enters into the reaction. 

Addition of Heterocyclic Compounds Stereocontrolled nucleophilic addition of heterocyclic compounds to chiral nitrones is of great synthetic importance in the synthesis of natural and biologically active compounds. In these reactions, the nitrone group serves as an amino group precursor and the heterocycle furnishes the formyl group (from thiazole) (192, 195, 214, 215, 579) or the carboxyl group (fromfuran) (194-196, 580-584) (Scheme 2.149). 

The trisubstituted amidinothioureas (98) required as precursors of the thiadiazolines are obtained by the interaction of isothiocyanate esters and s-diarylguanidines,115 or by the action of aromatic amines on dithiazolidines (102).117 The former reaction might conceivably yield the isomeric amidinothioureas (98a) instead if so, however, oxidation and isomerization would give rise to a 2-(diphenylguanidino)benz-thiazole (100a) isomeric with, but different from, the product (100) actually obtained. The structure of this product is confirmed by synthesis from 2-aminobenzthiazole (101) and carbodiimides.115... 

Thiazole-aldehyde synthesis Preparation of aldehydes from C-2 substituted thiazoles by thiazolyl-to-formyl conversion, see A. Dondoni, Carbohydrate synthesis via thiazoles, in Modem Synthetic Methods, R. Scheffold, ed., Verlag Helvetica Chimica Acta, Basel, 1992, p. 377 A. Dondoni, Acyclic diastereoselective synthesis using functionalized thiazoles. Routes to carbohydrates and related natural products, in New Aspects of Organic Chemistry, Z. Yoshida and Y. Ohshiro, eds., Kodansha, Tokyo, and VCH, Weinhcim, 1992, p. 105. 

The synthesis of thiazoles from dihydrothiazoles (thiazolines) has experienced broad application as a method for incorporating thiazoles into the backbone of peptides (see also Vol. E 22 b, Section 6.8.5.2.2). The ability to incorporate thiazoles into the backbone of peptides by oxidation of dihydrothiazole precursors is consequently limited to the methods available for the synthesis of the required dihydrothiazole precursors. The most straightforward approach would allow for a peptide containing natural amino acids to serve as a precursor to... 

Thiazole-containing linear peptides have also been isolated from tunicates. Virenamides A-E (412-416) were obtained from the didemnid tunicate Diplosoma virens, which contains symbiotic prokaryotic algae in its cloacal cavity. The structures of virenamides A-C were determined by HPLC analysis using Marfey s procedure [323] while the absolute stereochemistry of virenamide E (416) was proven by its synthesis from virenamide A (412) [324], Compounds 412-416 showed modest cytotoxicity toward a panel of cultured cells and 412 also exhibited topoisomerase II inhibitory activity. 

Qualitatively the novelty of reactions is difficult to assess. One can for example compare a novel reaction with different similar reactions known from literature in terms of mechanism, educts and products and scope and limitation. Scheme 3.4 compares three reactions Schollkopf s thiazole synthesis, the thiazole 4-CR described by us in 1999 and the classical U-4CR. The shaded areas show the common educts and products of these reactions. Obviously reaction 2 has common educts and products with reactions 1 and 3. Each reaction also has at least two unique components. The products of all the reactions are not identical. Thus reactions 1... 

I. Synthesis from Preformed Thiazole Rings or from Other Heterocycles. . 11... 

I. SYNTHESIS FROM PREFORMED THIAZOLE RINGS OR FROM OTHER HETEROCYCLES... 

Ethylenethiourea reacted with DMAD to give 5,6-dihydroimidazo[2,1 -b ]thiazol-3(2//)-one (233), as shown by unambiguous synthesis from imidazothiazolone (234) <71JCS(C)3062>. On the other hand, N- methylimidazolidine-2-thione and DMAD in methanol gave (237), presumably via intermediate (236), formed by addition of methanol to (235) <81JCS(Pl)415). 

Another approach to the solid phase synthesis of thiazoles involves an interesting C-sulfanylation step. The starting material for this synthesis is a resin bound piperazine 55 which is converted into a thiourea and then treated with an a-bromoketone to give the thiazole 56. Treatment of 56 with either thiols or disulfides and iodine or sulfonyl chlorides with iodine and triphenylphosphine afforded 5-sulfanylthiazoles 57, which could be obtained in high yields and purity after cleavage from the resin <02EJOC2953>. 

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,... 

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