Halothiazoles

Bromothiazoles were more reactive than their chloro analogs. For example, 2,4-di-bromo-5-(hydroxymethyl)thiazole was completely debrominated to give 5-(hy-droxymethyl)thiazole in 94% yield at 23 °C for 12 h, while the corresponding dichloro analog gave only 28% yield of 5-(hydroxymethyl)thiazole even at 60°C for 60 h the major product was 4-chloro-5-(hydroxymethyl)thiazole (63%). 

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Halothiazoles are usually obtained from 2-aminothiazoles through the Sandmeyer reaction. Nevertheless, ammonolysis has sometimes proved useful for the preparation of 2-aminothiazole derivatives. Detweiler et al. (18) obtained 2-(u-pyridinylamino)thiazole (1) from 2-bromothiazole (Scheme 1). The reaction is easier if a nitro group occupies the 5-position of the thiazole ring (19-21). Ethylene diamine derivatives undergo this reaction with 2-haiothiazoles (22-24). 

Tertiary amines may be obtained from alkaline alkylation of secondary amines (46), but mixtures are obtained (see Section III.l.B) hence heterocyclization and ammonolysis of 2-halothiazoles are to be preferred. 

Charge diagrams suggest that the 2-amino-5-halothiazoles are less sensitive to nucleophilic attack on 5-position than their thiazole counterpart. Recent kinetic data on this reactivity however, show, that this expectation is not fulfilled (67) the ratio fc.. bron.c.-2-am.noih.azoie/ -biomoth.azoie O"" (reaction with sodium methoxide) emphasizes the very unusual amino activation to nucleophilic substitution. The reason of this activation could lie in the protomeric equilibrium, the reactive species being either under protomeric form 2 or 3 (General Introduction to Protomeric Thiazoles). The reactivity of halothiazoles should, however, be reinvestigated under the point of view of the mechanism (1690). 

Mercuration occurs m the 5-position (4501 as demonstrated b the subsequent conversion of the mercurated derivatives (209) to the corresponding 2-amino-5-halothiazoles (Scheme 132) (396. 451). The reaction is favored by the presence of sodium acetate (452). Nitrogen mercurated intermediates have never been isolated. 

Since the exocyclic sulfur is more reactive in the ambident anion than in A-4-thiazoIine-2-thione. greater nucleophilic reactivity is to be expected. Thus a large variety of thioethers were prepared in good yields starting from alkylhalides (e.g.. Scheme 38 (54, 91, 111, 166-179). lactones (54, 160), aryl halides (54, 152. 180, 181), acyl chlorides (54. 149, 182-184). halothiazoles (54, 185-190), a-haloesters (149. 152. 177. 191-194), cyanuric chloride (151). fV.N-dimethylthiocarbamoyl chloride (151, 152. 195. 196), /3-chloroethyl ester of acrylic acid (197), (3-dimethylaminoethyl chloride (152). l,4-dichloro-2-butyne (152), 1,4-dichloro-2-butene (152), and 2-chloro-propionitrile (152). A general... 

Thioethers can be obtained either by heterocyclization (Chapter II) or from the reaction between 2-halothiazoles (102) and the sodium salt of... 

Sulfones and sulfoxides (145) are obtained usually from the corresponding sulfide by oxidation (Scheme 75) (341). though some of them were prepared from a halothiazole and metal sulfinate (342). 2-Amino-5-acetamidophenylsulfonylthiazole has been prepared by direct heterocycli-zation (343. 344). 

The activation of halothiazoles toward nucleophilic displacement is discussed in Chapter V no unique conclusion can be drawn because of the various possible interactions between the halothiazole base and the electrophilic counterpart of the nucleophile. 

Mercurated thiazoles also yield 5-halothiazoles by the replacement of Hg by halogen. 

The halothiazoles are distillable oils under reduced pressure. The 2-fluOrothiazole is extremely volatile at room temperature and must be handled with care. 

Ru, Os, and Ir carbene complexes have been prepared from reactions of anionic or low-valent metal complexes with some organic salts or neutral compounds with highly ionic bonds. Oxidative addition of halothiazole and -oxazole species to IrCl(CO)(PMe2Ph)2 affords Ir(III) complexes which on protonation yield cationic carbenes (69), e.g.,... 

The parent 2-tributylstannylpyridine has been used in cross-coupling reactions with aryl iodides [66], bromobenzyl phosphonates [67], and bromophosphinine 81, although the lifetime of mono-coupled pyridylphosphinine 82 was rather short [68]. Moreover, ample examples have been found for the cross-coupling of pyridylstannanes with halothiophenes [69-71], halothiazoles [72], halopyrimidines [45], halofuran, and halopyrroles [73]. 

Thiazole is a jt-electron-excessive heterocycle. The electronegativity of the N-atom at the 3-position makes C(2) partially electropositive and therefore susceptible to nucleophilic attack. In contrast, electrophilic substitution of thiazoles preferentially takes place at the electron-rich C(5) position. More relevant to palladium chemistry, 2-halothiazoles and 2-halobenzothiazoles are prone to undergo oxidative addition to Pd(0) and the resulting o-heteroaryl palladium complexes participate in various coupling reactions. Even 2-chlorothiazole and 2-chlorobenzothiazole are viable substrates for Pd-catalyzed reactions. 

Two of the most frequently used approaches for halothiazole synthesis are direct halogenation of thiazoles and the Sandmeyer reaction of aminothiazoles. The third method, an exchange between a stannylthiazole and a halogen, is not practical in the context of palladium chemistry simply because the stannylthiazole can be used directly in a Stille coupling. 

The Sandmeyer reaction converts aminothiazoles, often commercially available, to halothiazoles via the intermediacy of diazonium salts. For instance, 2-aminothiazole was transformed into 2-iodothiazole [7, 8]. The reaction tolerates a number of functional groups including nitro and ester groups as shown below [9]. 

Some variants of the classic Sandmeyer conditions have been used for halothiazole synthesis. For example, sodium nitrite can be replaced with isoamyl nitrite or rm-buty] nitrite as illustrated by the transformation of 2-aminobenzothiazole 6 to 2-bromobenzothiazole 7 [10,11]. 

Thiazoleboronic acids are not trivial to make. Attempts to prepare 2-thiazoleboronic acid were unsuccessful [21], As a consequence, halothiazoles are chosen as the electrophilic coupling partners in the Suzuki reactions with other boronic acids. For instance, 2,5-di-(2-thienyl)thiazole (28) was installed by the union of 2,5-dibromothiazole and easily accessible 2-thiopheneboronic acid [21], Unfortunately, the yield was poor and analogous reactions of 2,5-dibromothiazole with 3-thiopheneboronic acid and 2-selenopheneboronic acid both failed. 

In 1987, Yamanaka s group described a Pd-catalyzed reaction of halothiazoles with terminal acetylenes [51]. While the yield for the Sonogashira reaction of 2-bromo-4-phenylthiazole (89) with phenylacetylene to afford 90 was moderate (36% after desilylation), the coupling of 4-bromothiazole and 5-bromo-4-methylthiazole with phenylacetylene gave the desired internal acetylenes 91 and 92 in 71% and 65% yield, respectively. 

For the Heck reactions involving halothiazoles, 2-bromo- and 4-bromothiazoles tend to give resinous products, whereas some 5-bromothiazoles may form the desired Heck adduct with... 

In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [22a]. Submission of 4-bromo- and 5-bromo-4-methyloxazoles to the Sonogashira reaction conditions with phenylacetylene led to the expected internal acetylenes. 

Halothiazoles give Grignard reagents and lithio derivatives. 2- and 5-Bromothiazoles give halogen-lithium exchange on treatment with n-butyllithium to afford 2- and 5-lithiothiazoles, respectively. The... 

Tn addition to arylthiazoles, heteroarylthiazoles also have been synthesized using halothiazoles and heteroarylboronic acids. Suzuki coupling of 2-bromothiazole and 5-indolylboronic led to 5-substituted indole 32 [24]. The Suzuki coupling of 2,4-dibromothiazole with 2,4-di-f-butoxy-5-pyrimidineboronic acid (33) resulted in selective helreoarylation at the 2-position to give pyrimidylthiazole 34 although the yield was low [25-27]. 

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