Substituted halothiazoles

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). 

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. 

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]. 

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. 

There are many examples of halogen at a 2-position undergoing nucleophilic displacement, for example 2-halothiazoles with sulfur nucleophiles (indeed, more rapidly than for 2-halopyridines), 2-halo-1-substituted imidazoles, and 2-chloroox-azoles with nitrogen nucleophiles. 

The first report of a Sonogashira coupling reaction of an oxazole was by Yamanaka in 1987. Oxazoles substituted with bromine at the 4- or 5-positions were coupled with phenylacetylene yielded the alkyne in 83% and 89% yield, respectively. The Sonogashira reaction with 2-halooxazoles was not attempted however, 2-halothiazoles and 2-halo-A -methylimidazoles were subjected to Sonogashira conditions. Yields in both cases were low and not synthetically useful. 

Suzuki-Miyaura reactions are perhaps the most widely employed palladium catalyzed cross-couplings in the realm of thiazole medicinal chemistry. They typically take place only when the thiazole is an electrophile in the transformation. The nucleophilic thiazole boronic acid or ester, especially at the 2-position, is relatively unstable and therefore difficult to prepare. The electrophiles namely the 2-, 4-, or 5-substituted halothiazoles are often readily accessible in terms of their synthetic ease or commercial availability. A remarkable application has been described by Jang et al. in the discovery... 

Only one or/Ao-aryne 533 is possible in a thiazole ring. Its intermediacy was first considered in the reaction of 4>halothiazoles (534) with methoxide ion as a possible rationale for the surprisingly similar reactivity of these compounds and the 2- and 5-halo isomers. This hypothesis was consistent with the small element effect, the rapid base-catalyzed exchange of the 5-proton, and the exclusive formation of the normal substitution product 535 as would be expected if nucleophilic addition to the aryne 533 was determined by the stability of the resulting anion 536 with the negative charge adjacent to the sulfur atom. The fact that the 5-phenyl derivative 537, which cannot form an aryne 533, reacts at a comparable rate to 534 rules out the possibility of an elimination-addition mechanism, however. 

The aryne 533 was also considered and rejected as an intermediate in the nucleophilic substitution of 5-halothiazoles (538) based on the following evidence only normal substitution to 539 is obtained, inconsistent with the expected formation of 535 from the aryne 533 as described above no exchange of the 4-proton is observed the reactivity of the 4-phenyl derivative 540, which cannot form the aryne 533, is similar to that of 538 and finally no aryne... 

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