Thiazole derivatives, formation

In the case of a diketone (e.g., 3-tosyloxypentane-2,4-dione), the formation of 5-acetyl-4-methyl-2-aryl-l,3-thiazole derivatives can be realized in very good yields (86-89%) (Scheme 7). All these experiments where performed in a Sears Kenmore unmodified household microwave oven (990 W) equipped with a turntable. The average bulk temperature was estimated by inserting a thermometer in the alumina bath housing the reaction vessel. 

Removal of the chloroacetyl protection in this molecule is accomphshed in the following manner. Subsequent reaction of the product (32.1.2.71) with thiourea in the presence of sodium bicarbonate results in the formation of a new thiazole derivative. Subsequent cleaving of the resulting secondary heteroaromatic amine with formic acid gives ceftriaxone... 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

Intramolecular cyclizations involving amino and thiocyano groups favorably placed sterically in relation to each other are well known and are responsible for the formation of numerous thiazole derivatives.82 The special feature of the present synthesis, however, is the attachment of the thiocyanate group at a nitrogen instead of a carbon atom, which seems to enhance its reactivity. 

The first published example of the anodic cyclization with carbon-sulfur bond formation was the oxidation of thiobenzanilide to 2-phenyl-l,3-benzothiazole.120 The oxidation of the thioacetanilides (106) and /V-(3-coumaryl)thioacetamide (108) at a platinum electrode in CH3CN-Et4NC104 gave the expected 1,3-thiazole derivatives 107 and 109 in 60-75% yield169 [Eqs. (81) and (82)]. 

The imidazole derivative (217) underwent a series of reactions with diazomethane which resulted in the formation of products (222) and (223). Thus, AT-methylation of compound (217) gave compound (219), which participated in a 1,3-dipolar cycloaddition giving cycloadduct (220). This cycloadduct then eliminated nitrous acid and the resulting product tautomerized giving heterocycle (221), which was further methylated giving a mixture of the products (222) and (223) <82IJC(B)997>. Thiazole derivative (218) underwent a similar reaction. 

In contrast, reaction of 5,5-diphenyl thiohydantoin with l-bromo-2-chloroethane generates two isomeric imidazo(2,l-b)thiazole derivatives (97 and 98) through intramolecular S,N-dialkylation.235 The formation of imidazo(2,l-b)thiazoles by this kind of process is rather common.236 Similarly, reaction with 1,3-dibromopropane gives two isomeric diphenylimidazothiazines.2 3 7,2 3 8... 

Pathways for formation of thiazole derivatives and 2-acetylthiazole have been proposed by Vemin and Parkanyi (1982) and by Mulders (1973c) respectively. Mottram (1991) extensively reviewed the numerous interactions of possible precursors of thiazoles. 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

In 2007, Renuga et al. investigated the solvent-free reaction of bis(aroylmethyl) sulfides 208 with aromatic aldehydes 207 and ammonium acetate for the synthesis of various thiazole derivatives 209 under microwave irradiation (Scheme 13.50a) [87]. These reactions led to the formation of the desired products in moderate yields (62-73%), in short reaction times (10min). The suggested mechanism is shown in Scheme 13.50b. 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

Active Raney nickel induces desulfurization of many sulfur-containing heterocycles thiazoles are fairly labile toward this ring cleavage agent. The reaction occurs apparently by two competing mechanisms (481) in the first, favored by alkaline conditions, ring fission occurs before desul-, furization, whereas in the second, favored by the use of neutral catalyst, the initial desulfurization is followed by fission of a C-N bond and formation of carbonyl derivatives by hydrolysis (Scheme 95). 

Physical Chemical Characterization. Thiamine, its derivatives, and its degradation products have been fully characterized by spectroscopic methods (9,10). The ultraviolet spectmm of thiamine shows pH-dependent maxima (11). H, and nuclear magnetic resonance spectra show protonation occurs at the 1-nitrogen, and not the 4-amino position (12—14). The H spectmm in D2O shows no resonance for the thiazole 2-hydrogen, as this is acidic and readily exchanged via formation of the thiazole yUd (13) an important intermediate in the biochemical functions of thiamine. Recent work has revised the piC values for the two ionization reactions to 4.8 and 18 respectively (9,10,15). The mass spectmm of thiamine hydrochloride shows no molecular ion under standard electron impact ionization conditions, but fast atom bombardment and chemical ionization allow observation of both an intense peak for the patent cation and its major fragmentation ion, the pyrimidinylmethyl cation (16). 

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

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