3-Substituted indazoles

Pyrazoles, and some indazoles, substituted on the nitrogen by B, Al, Ga, In, Si, Ge, Sn, P and Hg are known. Poly(pyrazol-1 -yl)borates have been studied by Trofimenko (72CRV497) who found that they were excellent ligands (Section 4.04.2.1.3(vi)). The parent ligands (282), (283) and (284) are available by the reaction of an alkali metal borohydride with pyrazole, the extent of substitution depending on the reaction temperature (Scheme 22). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

NH2- condensed pyridines (Skraup reaction) NH2-+N2 -+H, Cl, I, CN,... C02H->Br (Hunsdiecker reaction) Br-+H (Na/Hg) etc. As a matter of fact, the whole spectrum of aromatic reactivity can be transferred to indazoles substituted at the fused benzene ring. Compare, for example, the reactions described by Suschitzky et al. (68JCS(C)1937) for 2-azidonaphthalene (432) and for 5-azidoindazole (433). Pyrolysis of these compounds in a mixture of acetic and polyphosphoric acid yields (434) and (435), respectively. 

The above considerations do not necessarily apply to reactions of electrophilic reagents with pyrazole and imidazole anions (108,109). The imidazole anion is sometimes substituted in the 2-position (113) and the indazole anion in the 3-position (cf. Section 4.02.1.4.5). 

Irradiation of l//-indazoles under nonacidic conditions resulted in isomerization to benzimidazoles and also ring opening to isomeric benzonitriles. With 1-substituted benzimidazoles and sensitized irradiation, nitriles were formed, but these are only minor products with other substitution patterns 67HCA2244, 64TL2999). Irradiation of benzimidazoles leads to oxidative dimerization. 

Figure 16 Numbering of indazole and isoindazole as substituted pyrazoles...

When R = H, in all the known examples, the 3-substituted tautomer (129a) predominates, with the possible exception of 3(5)-methylpyrazole (R = Me, R = H) in which the 5-methyl tautomer slightly predominates in HMPT solution at -17 °C (54%) (77JOC659) (Section 4.04.1.3.4). For the general case when R = or a dependence of the form logjRTT = <2 Za.s cTi + b Xa.s (Tr, with a>0,b <0 and a> b, has been proposed for solutions in dipolar aprotic solvents (790MR( 12)587). The equation predicts that the 5-trimethylsilyl tautomer is more stable than the 3-trimethylsilylpyrazole, since experimental work has to be done to understand the influence of the substituents on the equilibrium constant which is solvent dependent (78T2259). There is no problem with indazole since the IH tautomer is always the more stable (83H(20)1713). 

A well-known example of non-prototropic tautomerism is that of azolides (acylotropy). The acyl group migrates between the different heteroatoms and the most stable isomer (annular or functional) is obtained after equilibration. In indazoles both isomers are formed, but 2-acyl derivatives readily isomerize to the 1-substituted isomer. The first order kinetics of this isomerization have been studied by NMR spectroscopy (74TL4421). The same publication described an experiment (Scheme 8) that demonstrated the intermolecular character of the process, which has been called a dissociation-recombination process. 

Substituted indazolones exist in the OH form (143b) and 2-substituted indazolones exist in the NH form (144a), whereas the structure of AC-unsubstituted indazolones varies with the physical state. This difference of behaviour, depending on the position of the A -R substituent, corresponds to the aromatic structure of the indazole derivatives compared with the quinonoid structure of isoindazoles. 

Having its pyrazolic 4-position substituted, electrophilic attack on indazoles takes place in the 3-position and in the homocycle (the 5- and 7-positions). The condensation of a benzene ring results in a decrease of the aromaticity of the pyrazole moiety, as in naphthalene compared to benzene, and therefore basic ring cleavage is easier in indazoles than in pyrazoles (Section 4.04.2.1.7(v)). 

The basicities of indazole (1.31), 1-methyl (0.42) and 2-methyl (2.02) derivatives and of eight other substituted indazoles have been measured (67BSF261 The effect of substituents in the 3-position is similar in pyrazoles and indazoles with Api values as follows Me, 0.80 and 0.86 Cl, -3.01 and -2.98 Br, -2.85 and -2.82, respectively. A nitro group in the homocycle has an expected base-weakening effect of -2 pK units, whether it is at the 5- or the 6-position. 

Indazole adds to acrylonitrile and 4-vinylpyridine giving 1- or 2-substituted derivatives depending on the 7-substituents (69BSF2064). It also reacts with epoxystyrene to form (259). 

Phosphorus derivatives of different structures have been prepared including pyrazol-1-ylphosphines PPzs, PhPPz2 and Ph2PPz (Pz for pyrazolate anion (72CRV497,80MI40402)). By transamination with tris(dimethylamino)phosphine, pyrazoles and indazole are converted into (291) and (292), respectively (67CR(C)(265)1507). 3,5-Dimethylpyrazole reacts with amidodichlorophosphates to yield triamides (293) whereas 1-substituted pyrazolones yield amidophosphates (294) (71LA(750)39). 

As discussed in the theoretical section (4.04.1.2.1), electrophilic attack on pyrazoles takes place at C-4 in accordance with localization energies and tt-electron densities. Attack in other positions is extremely rare. This fact, added to the deactivating effect of the substituent introduced in the 4-position, explains why further electrophilic substitution is generally never observed. Indazole reacts at C-3, and reactions taking place on the fused ring will be discussed in Section 4.04.2.3.2(i). Reaction on the phenyl ring of C- and A-phenyl-pyrazoles will be discussed in Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i), respectively. The behaviour of pyrazolones is quite different owing to the existence of a non-aromatic tautomer. 

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

In the search for new structures with antiinflammatory activities some 1-substituted 3-dimethylaminoalkoxy-lJ/-indazoles (704) have been synthesized and pharmacologically tested (66JMC38). Doses of 20-40 mg g i.p. produced sedation, muscle relaxation and motor incoordination, whereas doses of 80-100 mg kg produced depression. Toxicity was fairly constant in all series, varying from 120 to 150 mg kg i.p., with the exception of compounds possessing a nitro group or an amino group in the indazole nucleus, which provoked cyanosis. 

Indazole, 5,5-dimethyl-3-trifluoromethyl-4,5-dihydro-trichomonacidal activity, 5, 291 Indazole, 2-ethoxycarbonyl-reactions, 5, 269 Indazole, 3-fluoro-synthesis, S, 263 Indazole, 1-germyl-synthesis, 5, 236 Indazole, 1-glycosyl-synthesis, 5, 289 Indazole, 2-glycosyl-synthesis, 5, 289 Indazole, halo-reactions, S, 266 Indazole, 2-hydroxy-methylation, 5, 269 Indazole, 3-hydroxy-reactions, S, 264 Indazole, 6-hydroxy-diazo coupling, 5, 86 Indazole, hydroxyphenyl-synthesis, S, 288 Indazole, 3-iodo-synthesis, S, 241 Indazole, l-isopropyl-3-phenyl-reduction, 5, 243 Indazole, 3-mercapto-1 -substituted tautomerism, 5, 265 Indazole, methoxy-... 

Few heteroaryl-substituted 37/-azepines are known however, photolysis of 2-(2-azidophenyl)-pyridine (80) in diethylamine provides Ar,Ar-diethyl-3-(2-pyridyl)-3/f-azepin-2-amine(81), along with minor amounts of pyrido[3,2-6]indole (82) and the mesoionic pyridofl, 2-7>]indazole (83).191... 

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