Nucleophilic substitution thiazoles

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). 

Nucleophilic substitution of the 5-halo substituent on a thiazole ring by a thiocyanato group (348, 362, 370-376) or a thiouronium group (364, 377) affords the thiocyanato and thiouronium precursors."... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

A more unusual fact observed in thiazole chemistiy is that also the other positions (4 and 5) are activated toward the nucleophilic substitution, as found independently by Metzger and coworkers (46) and by Todesco and coworkers (30, 47). Some kinetic data are reported in Table V-2. As the data in Table V-2 indicate, no simple relationship between nucleophilic reactivity and charge density, or other parameters available from more or less sophisticated calculation methods, can be applied. As a... 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

The thiadiazoline (50) (Ar = p-Tol) reacts with electron-deficient alkynes (51) to give arylimino-thiazoles (53). It has been suggested that the reaction proceeds via a 1,3-dipolar cycloadduct (52) (Scheme 13) <75TL459> or by a stepwise nucleophilic substitution reaction <84CHEC-I(6)463>. 

The authors of this review article suggest that the results indicated in Schemes 34, 35 and 36 are consistent with a stepwise nucleophile substitution mechanism (64JA107) as outlined in Scheme 37. When Z is nitrogen the driving force for the reaction is the ease of cleavage of the N—S bond by a soft nucleophile with a concerted elimination of phenylcyanamide. In the thiazole (Z = CH), however, the stable C—S bond precludes ring fission by a nucleophilic attack at sulfur and the initial adduct (79) (presumably trans) is obtained as a stable product. 

Nucleophilic substitution occurs readily in either ring. The bromine at C-3 in the thiazole (113) is substituted by a methoxy group (73CJC1741), and in the uracil derivative (114) it is a 3-methylthio substituent which is replaced by an amino nucleophile (79H(12)485). Aminoly-sis in an activated azine position proceeds in the usual manner as shown for the 6-chloride (115) (70GEP1950990). 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

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