4- Bromo-5-substituted thiazoles

The use of halogen dance methodology has been developed in the thiazole series thus, for example, exposure of bromothiazole 324 to LDA, then an electrophile, gave rise to 4-bromo-5-substituted thiazoles 325 <2005JOC567>. 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

Chloro substituted thiazoles can be prepared by the reaction of phosphorus oxychloride with the corresponding 4-hydroxythiazoles. This method is also applicable for the preparation of 4-bromo-2-phenylthiazole. 

A related reaction is the bromine-induced oxidative cyclization of l-acyI-3-(3-thienyl)-thioureas to 2-acylaminothieno[3,2-d]thiazoles the reaction probably proceeds through the formation of the sulfenyl bromide (Scheme 23) (78JHC81). The corresponding 2-thienyl derivatives, however, gave only bromo substituted products (Scheme 23). A similar cyclization is brought about on treatment of /3-(3-benzo[6]thienyl)-a-mercaptoacrylic acids (129) with iodine in THF, when the tricyclic compounds (130) are formed (70AHC(ll)l77>. 

Also, a novel synthesis of methyl 5-substituted thiazole-4-carboxylates (43) was reported. The reaction of methyl ( )- and/or (Z)-3-substituted 3-bromo-2-isocyanoacrylates (40) with hydrogen sulfide (1.2eq) and triethylamine at room temperature afforded the desired thiazoles (43) in good yield. The substitution reaction of the first sulfide with 40 may proceed with... 

Thiazole itself can be obtained by condensing chloroacetaldehyde and thioformamide (Scheme 159). The reaction is explosive and proceeds in low yield because of the instability of the thioformamide under acid conditions. Higher thioamides are more stable and react under milder conditions with chloroacetaldehyde, affording 2-substituted thiazoles in moderate yields. It is possible, and often preferable, to prepare the thioamide in situ in dioxane solution by the action of phosphorus pentasulfide on the corresponding amide and in the presence of solid MgC03 (Scheme 160). With arylthioamides, except for some nitrothiobenzamides, yields are usually higher and the cyclization is carried out over several hours in boiling absolute alcohol. Chloroacetaldehyde can be replaced in these reaction by derivatives such as 1,2-dichloro- or dibromo-ethyl methyl or ethyl ether, 1,2-dichloro- or dibromo-ethyl acetate, 2-chloro- or dibromo-ethyl acetate, and 2-chloro or bromo-diethyl-acetal. 

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,... 

The halogen dance reaction is also applied to the synthesis of the 5-substituted 4-bromo-2-chlorothiazole derivatives 89 <07SL3016>. Treatment of 5-bromo-2-chlorothiazole with 1.2 equiv. of LDA at -80 °C brings about full conversion to the halogen dance product 88, which is trapped with various electrophiles to give the 5-substituted thiazoles 89. For example, 4-bromo-5-trimethylsilyl-thiazole is obtained in 71% yield when 5-bromo-2-... 

JCS(P1)1153>. On the other hand, compounds (294) give the expected 5-substituted thiazoles (296) when are treated with y-bromo crotonic acid derivatives (Scheme 74) <92LA415>. 

An operationally simple halogenation of 4,5-dimethyl-2-arylthiazoles provides a regioselective approach to bromo- or chloro-methyl substituted thiazoles <04TL69>. Thus, treatment of 117 and its hydrochloride salt with NBS and NCS affords 4-bromothiazole 118 and 4-chlorothiazole 119, respectively, with >99% regioselectivity. The remarkable regioselectivity observed may arise from a Pummerer-type rearrangement mechanism via 120. 

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). 

Bromoacetylthianthrene, which can be produced by direct acylation as well as via bromination of 2-acetylthianthrene (63MI2) (for comparable dibromination of 2,7-diacetylthianthrene, see 64MI1), has been used in its capacity as an a-bromo-ketone to produce thianthren-2-yl-substituted heterocycles such as 55, 56, 57 (63MI2 73BSF1460), and 2-amino-4-(thianthren-2-yl)thiazole (63MI2), by condensation with 2-aminopyridine,... 

A study of reactions of NBS in acetic acid and acetic anhydride with thiophenes substituted in the a-position by groups such as 4-thiazolyl or 2-quinolinyl demonstrated that after initial perbromide formation (at around 20°C), slow conversion into C-brominated products followed. Reactions carried out above 40°C with one molar equivalent of NBS gave 5-bromo products only, but introduction of electron-donating groups into the thia-zole substituent and excess brominating agent led to some thiazole bromi-nation. With a 2-aminothiazolyl substituent, bromination took place exclu-... 

Mesoionic systems may be readily substituted by electrophiles. Thus the thiazolo mesoion (342) will couple with diazonium salts despite their relatively weak electrophilicity (80KGS621). Substitution in a fused heteroaromatic betaine azine ring, e.g. (343), also takes place with ease. The resonance form (344) of the mesoion (343) shows that the electrophile will attack at C-6. The substitution in this position is also predicted by MO calculations (73JHC487). Similarly the pyridine ring in pyridinium olates is active towards electrophiles and is substituted in the positions ortho and para to the olate function. Bromination of the 5-methyl derivative (321 R = Me) occurs exclusively in the 7-position which is rationalized via the intermediate (345). In the absence of a 5-substituent, attack in either the 5- or 7-position occurs the dibromide is readily formed. No bromination in the thiazole ring is observed. The 2-bromo derivative (346) has been made, however, by condensation between the appropriate mercaptopyridine and 1,1,2,2-tetrabromoethane. 

Examples of the ipso-nitration of halogen-substituted isothiazoles [387] and thiazoles [388-390] are known. 2,4-Disubstituted 5-bromo- and 5-iodooxazoles react with nitrogen tetroxide to form the 5-nitro derivatives [391],... 

Barradai et al. [8] described the synthesis of imidazo[2,l-b]thiazole carbohydrate derivatives (ii). The substituted imidazo [2,1-b] thiazoles were obtained by a convergent synthetic pathway from either 6-bromo-6-deoxy-l,2-0-isopropylidene-3-0-methyl-a-D-xylo-hexofuranos-5-ulose/6-bromo-6-deoxy-l,2-0-isopropyli-dene-3-0-methyl-a-D-xylo-hexofuranos-5-ulose (i). The synthesized derivatives proved to be potential antiviral agents. 

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