Nucleophilic reactions 2- thiazole

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. 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Oxygen-sulfur heteroatom exchange has been achieved with 3-methyl-benzene thiazole-2-thione in the presence of trifluoroacetic acid and with l-phenyl-5-mercaptotetrazole. Thiirane can be prepared from oxirane on a support impregnated with alkali metal salts, by decomposition of the dithiocarbon-ate formed with carbon disulfide. A macrocyclic ether, perhydrobenzo-18-crown-6, plays a role in the nucleophilic reaction of oxirane with KCNS, which leads to thiirane in good yield. ... 

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). 

The problem is more complicated when the ambident nucleophile. 2-aminothiazole, reacts with an ambident electrophilic center. Such an example is provided by the reaction between 2-amino-5-R-thiazole and ethoxycarbonyl isothiocyanate (144), which has been thoroughly studied by Nagano et al. (64, 78, 264) the various possibilities are summarized in Scheme 95. At 5°C, in ethyl acetate, the only observed products were 145a, 148. and 150. Product 148 must be heated to 180°C for 5 hr to give in low yield (25%) the thiazolo[3.2-a]-s-tnazine-2-thio-4-one (148a) (102). This establishes that attack 1-B is probably not possible at -5°C. When R = H the percentages of 145a. 148. and 150 are 29, 50, and 7%, respectively. These results show that ... 

The preparation of 5-azothiazoles uses the nucleophilic character of C-5 carbon in reaction with the appropriate diazonium salt (402, 586). These 5-azothia2oles form 1 1 complexes with Ag (587). 2-Amino-4-methyl-5-arylazothiazoles give reduction waves involving two-electron transfer the Ej/ values correlate to the angle between the thiazole and phenyl rings (588). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

CycJohexyl free radicals, generated by photolysis of t-butyl peroxide in excess cyclohexane, also possess nucleophilic character (410). Their attack on thiazole in neutral medium leads to an increase of the 2-isomer and a decrease of 5-isomer relative to the phenylation reaction, in agreement with the positive charge of the 2-position and the negative charge of the 5-position (6). 

Some Hammett values for reactions in thiazole and in nucleophile are reported in Table V-3. The observed p values for normal substitution processes (methoxy and thiophenoxysubstitution) are high and positive, indicating that the substituent plays an important role in modifying the stability of the intermediate anion. 

TABLE v-3. p VALUES FOR SOME SUBSTITUTION REACTIONS OF 2-HALOGENO-X-THIAZOLES WITH SUBSTirUTED NUCLEOPHILES... 

The carbon atoms of azole rings can be attacked by nucleophilic (Section 4.02.1.6 electrophilic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Some system for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromati character and usually revert to type if the aromatic sextet is involved in a reaction. Othei such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to additio reactions. 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

Data on reactions of sulfur nucleophiles with azoles are sparse. Oxazoles are transformed in low yield into the corresponding thiazoles over alumina with HiS at 350 °C (74AHC( 17)99). Sulfur nucleophiles such as SH or RS add to 1,3-dithiolylium salts at the 2-position... 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

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). 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

The reaction of difunctional nucleophiles with alkyl isocyanides has been described in an earlier section on imidazoles an example of the use of this simple approach in thiazole synthesis is illustrated in Scheme 114.169... 

Imino-1,2,4-thiadiazoles such as 27 react with electron-deficient alkynes to afford arylimino thiazoles such as 28. There has been some speculation as to the mechanism of this reaction, which may involve a 1,3-dipolar cycloaddition or a stepwise nucleophilic addition (Equation 6) <1996CHEC-II(4)307>. 

Addition of Heterocyclic Compounds Stereocontrolled nucleophilic addition of heterocyclic compounds to chiral nitrones is of great synthetic importance in the synthesis of natural and biologically active compounds. In these reactions, the nitrone group serves as an amino group precursor and the heterocycle furnishes the formyl group (from thiazole) (192, 195, 214, 215, 579) or the carboxyl group (fromfuran) (194-196, 580-584) (Scheme 2.149). 

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. 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

Nucleophilic attack at sulfur is implicated in many reactions of 1,2,4-thiadiazoles <84CHEC-I(6)463> and in general soft nucleophiles attack at sulfur. For example, reaction of 3-hydroxy-5-phenyl-1,2,4-thiadiazole (23) with acetic anhydride in the presence of dbu at 130°C gives the thiazoles (31) and (32) <85JHC1497>. These products may be reasonably explained by the mechanism outlined in Scheme 9 in which the thiadiazole ring is opened by the acetic anhydride carbanion. There is some evidence that (32) may arise from attack of the carbanion on the A-acylated derivative (30a) (Scheme 9) <85JHC1497>. 

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 A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

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