Isothiazole, and Pyrazole

Isoxazole is brominated in the expected 4-position in 42% yield (60G356), whereas the 3- and 4-phenyl derivatives are brominated almost exclusively in the phenyl rings (98% para in the latter case) [67G1604 76CI(M)880], The result for the 3-phenyl compound is surprising and sug- 

2193823). 1-Phenylpyrazole is always brominated initially in the phenyl ring (66AHC(6)391) (cf. nitration), and further bromination gives a tri-bromo derivative, probably l-(p-bromophenyl)-4,5-dibromopyrazole (61JCS2769). 3-Methyl-1-phenylpyrazole is brominated at the para- and 

4- positions (61JCS2769). As in the case of imidazole, 1-methylpyrazole is more reactive than pyrazole itself, by a factor of —2.0, (cf. —4.0 for imidazole) such N-methylation also facilitates iodination [55LA (593)200], The combined activation by 3,5-dimethyl substituents in bromination is 3.7 x 103 over pyrazole itself (71AJC1413) the individual 3- and 

A study of the iodination of pyrazole and 1-alkylpyrazoles has led to the conclusion that the reactivity of the anion (conjugate base) is enhanced relative to the neutral species by io9 5-12 8 (67JA6218). The reactivity of the 4(5)-positions of imidazole (statistically corrected) to that of the 4-position of pyrazole has been determined as 1.3 (64JA2857), which agrees with the localization energy calculated for these positions of -2.103 and -2.13(3, respectively (55AJC100). 

Bromination of thienylpyrazoles and their N-methyl derivatives (7.67 and 7.68) took place as expected at the 5-position of the thiophene rings. Compound 7.67 (R = Me) is brominated 5.4 times faster than 7.69, which 

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Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

Scheme 14 Synthesis of tetrameric acid containing isothiazole and pyrazole rings...

Electrophilic sulfonation of isoxazole is of no preparative value the substitution of only the phenyl-substituent of 5-phenylisoxazole with chlorosulfonic acid makes the same point. Both isothiazole and pyrazole can be satisfactorily sulfonated at C-4. 

Ring-opening reactions of dithiolium salts with amines continue to receive attention. The behaviour of 3-styryl derivatives deuteriated in various positions/ and of 3-ethoxy-1,2-dithiolium salts/ has been studied. Further examples have been provided of the formation of isothiazoles and pyrazoles by the action of ammonia and hydrazine, respectively. 3,5-Di-isopropyl-l,2-dithiolium cations are deprotonated by aqueous ethanolic ammonia to give the dithiole (29). ... 

These results reveal that both isothiazoles and pyrazoles phototranspose by the electrocycKc ring closure-heteroatom migration mechanism and that tricycKc zwitterionic intermediates, once thought to be important in thiazole and isothiazole photochemistry, need not be invoked. 

Sulfur. Thiophene and benzo[ >] thiophene are both aromatic heterocycles, as discussed earlier in this review. Isothiazole is a planar molecule with an aromaticity comparable with those of thiazole and pyrazole, and higher than those of isoxazole and oxazole,122 140 as evaluated on the basis of Bird s aromaticity index A, based upon the statistical degree of uniformity of the bond orders of the ring periphery. Theoretical calculations and experimental data in connection with the aromaticity of isothiazole have been reviewed.141 Thiazole is also viewed as an aromatic molecule, similar to thiophene. It lacks an experimental aromaticity value, but the heat of formation together with bond lengths and angles have been calculated by various computational meth-... 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

This analysis suggests that condensation of 4.10 with hydroxylamine 4.11, hydrazine 4.12, or thiohydroxylamine 4.13 should give the corresponding 1,2-azole..This approach represents an important route to isoxazoles and pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable for synthetic purposes. The synthesis of isothiazoles will be mentioned later. The mechanism of the forward process is illustrated by the preparation of isoxazole 4.14 and is simply two consecutive condensations. 

Isothiazoles and nitrogen-blocked pyrazoles can be deprotonated at the C5 position with alkyl lithium reagents, and the resultant carbanions quenched with a wide range of electrophiles, as in the preparation of 4.33 and 4.34. 

For azoles with heteroatoms in the 1,2-positions (7.22), reasoning similar to that above predicts the reactivity order 5 > 3 > 4, and the highest reactivity of the 5-position has been confirmed for isothiazole (66JA4263 69JHC199) and pyrazole (70JOC1146). 

Pyrazole is a much weaker base than imidazole. Both have resonance-stabilized conjugate acids (Figure 14) but in the case of the pyrazolium cation 64 the direct linking of the quaternary nitrogens has a base-weakening effect. This additional effect also contributes to the low basicities of isothiazoles and isoxazoles (65 and 66). 

Oxygen-containing heterocycles are always less aromatic than their sulfur and nitrogen counterparts, e.g., imidazole thiazole >> oxazole and pyrazole > isothiazole > isoxazole. These trends follow those of pyrrole, thiophene and furan (Section 2.3.4.2). 1,2,3-Oxadiazole is unknown and all attempts to synthesize this compound have been unsuccessful. Although it is not the least aromatic of the oxadiazoles based on the HOMA index (cf. 1,3,4-oxadiazole), its instability can be attributed to easy isomerization to the acyclic valence tautomer (i.e., 85 - 86). 

Dialkylaminomethylene dithiomalonates have been recently condensed with hydrazines, hydroxylamine and amidine to yield pyrazoles, isothiazoles and pyrimidines, respectively346 (equation 263). 

Table 17 Comparative aromaticity criteria for isothiazole, thiazole, pyrazole, and isoxazole.

Pyrazole, isothiazole and isoxazole undergo straightforward nitration, at C. With acetyl nitrate or dinitrogen tetraoxide/ozone, 1-nitropyrazole is formed, but this can be rearranged to 4-nitropyrazole in acid at low temperature. ... 

Halogenation of pyrazole gives 4-monohalo-pyrazoles, for example 4-iodo-, or 4-bromopyrazole under controlled conditions. Poor yields are obtained on reaction of isothiazole and isoxazole " with bromine, again with attack at C-4, but with stabilising groups present, halogenation proceeds betteC and efficient... 

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