Halothiazoles reactions

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). 

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. 

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

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]. 

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. 

Ion pair mechanism, in reaction of benzene-thiolate with 2-halothiazole, 404 Ion pairs, in ambident reactivity, 40 Iron, 153... 

Salicylaldehyde, Schiff base with, 99 Salmonella typhi, 152 Salts, of acetamido thiazoles, 91 Sandmeyer reaction, in halothiazoles synthesis, 12... 

The reaction of carbanions with hetaryl halides has been reported. Thus, pinacolone enolate ion reacts with 2-halothiazoles (127) affording the substitution product 128 in good yields (44-67%) (equation 87)176. 

In the case of the halothiazole presented in Table 4, if the pinacolate anion is replaced by an a-cyano-carbanion, the expected product is still formed, but in this case the dark reaction works better than the photostimulated one, suggesting that products are photodegraded [124], The authors interpretation was... 

Besides halothiazoles, thiomethyl groups have also found utility as leaving groups in the Negishi eoupling reaetion of thiazoles [26]. For instance, reaction of 43 with benzyl-zinc bromide under the normal Negishi conditions resulted in 44. 

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 appropriate olefins. With respect to the heteroaryl Heck reaction using a thiazole as a coupling partner, the addition occurs regioselectively at the electron-rich C(5) position, whereas it occurs at C(2) for benzothiazole. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

For halothiazoles the conditions for selective deprotonations at the thiazole nucleus are quite variable depending on both the kind and position of the halogen atom (see Section 3.06.7.9.2). Thus, butyllithium deprotonates selectively 2-chlorothiazole at C-5 <90JCS(Pi)329> and 4-bromothiazole at the C-2 <92JCS(P1)215>. The same reaction cannot be carried out with 2-bromothiazole due to the halogen-lithium exchange much faster than with 2-chlorothiazole. Deprotonation at C-5 in 2-bromothiazole must be done with LDA <88CJC1617>. In a similar way 2,4-dihalothiazoles yield the... 

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