3- indazoles

5 From benzo five-membered heterocycles 6.2.5.1 Indazoles (cf. Section 6.1.2.1) 

Photolysis of indazole converts it into benzimidazole in 27% yield. 2-Alkylindazoles form 1-alkylbenzimidazoles under the same conditions, but 1-alkylindazoles give 2-alkylamino benzonitriles [12, 13], The reactions appear to have little synthetic significance. 

FIVE-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 

Interposing an additional carbon atom between the indazole nucleus and the acetic acid side chain provides another compound that shows anti-inflammatory activity in model systems. Reduction of the carboxylic acid in the indazole (38-1) by means of hthium aluminum hydride leads to the carbinol (38-2). Alkylation of the enolate from the alcohol with methyl 2-bromo-2-methylpropionate leads to the corresponding ether. Saponification gives the free acid and thus bindarit (38-3) [40]. 

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Benzimidazole (viii) and indazole (ix) differ from the azanaphthalenes in being nitrated at the / -position [C(g)] of the carbocyclic ring. ... 

As another example of nitrene formation, the reaction of o-nitrostilbene (96) with CO in the presence of SnCU affords 2-phenylindole (97). The reaction is explained by nitrene formation by deoxygenation of the nitro group with CO, followed by the addition of the nitrene to alkene. Similarly, the 2//-indazole derivative 99 was prepared by reductive cyclization of the A-(2-nitrobenzyli-dene)amine 98[89]. 

The reaction between 4-aminothiazole and paranitrobenzaldehyde, followed by the cydization of the Schiff base with PfOEtfs, provides 2-(4-thiazolyl)indazole (84a) (1576) (Scheme 59). 

L. C. Behr, R. Fusco, and C. H. Jarboe, iu R. H. Wiley, ed., "Pyrazoles, Pyrazolines, PyrazoUdines, Indazoles and Condensed Rings," Vol. 22 of A. Weissberger, ed.. The Chemistry of ELetero( clic Compounds Wiley-lnterscience, New York, 1967. 

The photorearrangement of pyrazoles to imidazoles is probably analogous, proceeding via iminoylazirines (82AHC(30)239) indazoles similarly rearrange to benzimidazoles (67HCA2244). 3-Pyrazolin-5-ones (56) are photochemically converted into imidazolones (57) and open-chain products (58) (70AHC(ll)l). The 1,2- and 1,4-disubstituted imidazoles are interconverted photochemically. 

Amination at an azole ring nitrogen is known for Af-unsubstituted azoles. Thus 4,5-diphenyl-1,2,3-triazole with hydroxylamine-O-sulfonic acid gives approximately equal amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords (106) and indazole gives comparable amounts of the 1- and 2-amino derivatives. 

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). 

Diazo coupling is expected to occur only with highly reactive systems, and experiment bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the 2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other azoles react only when they contain an amino, hydroxyl, or potential hydroxyl group, e.g. the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all these reactions occur on the corresponding anions). 

Isoxazoles unsubstituted in the 3-position react with hydroxide or ethoxide ions to give )3-keto nitriles (243) -> (244). This reaction involves nucleophilic attack at the 3-CH group. 1,2-Benzisoxazoles unsubstituted in the 3-position similarly readily give salicylyl nitriles (67AHC(8)277), and 5-phenyl-l,3,4-oxadiazole (245) is rapidly converted in alkaline solution into benzoylcyanamide (246) (61CI(L)292). A similar cleavage is known for 3-unsubstituted pyrazoles and indazoles the latter yield o-cyanoanilines. 

Indazole -> benzimidazole photoisomerization involves a singlet state and has been determined to be monomolecular and monophotonic. The UV spectrum of an intermediate with a lifetime of the order of seconds was recorded. Irradiation of the indazole (526) resulted in a 96% yield of the 1-methylbenzimidazole (528) probably via the intermediate (527)... 

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. 

Pyrazoles, Indazoles, and their Derivatives as Starting Materials for the Syntheses of Fused Ring Systems... 

Two double bonds. This is the most important class which includes the aromatic compounds pyrazole (3), indazole (4) and isoindazole (5), their non-aromatic isomers, pyrazolenines (or 3iL-pyrazoles 6), isopyrazoles (or 4JT-pyrazoles 7) and 3JT-indazoles (8), and the carbonyl derivatives of pyrazolines with the endocyclic double bond in positions 1, 2 or 3, i.e. (9), (10) and (11), respectively. The indazolones (12) and the pyrazolidinediones (13) and (14) also belong to this group. 

Only three systems belong to this group pyrazole (3), l//-indazole (4) and 2//-indazole (isoindazole 5). The fused carbon atoms in indazoles are numbered 3a and 7a. When R = H, annular tautomerism (76AHC(Si)i) makes the 3- and 5-positions of pyrazoles equivalent and thus the name 3(5)-R-pyrazole means that the compound is a mixture of tautomers with the substituent R in position 3 and in position 5. The same applies to TV-unsubstituted indazoles however, the numbering is identical in both tautomers and thus 3-R-indazole means either (4) or (5) (R or R = H). Since the indazole tautomer is largely predominant (Section 4.04.1.5.1), indazoles are usually represented by the formula (4). 

Indazoles have been subjected to certain theoretical calculations. Kamiya (70BCJ3344) has used the semiempirical Pariser-Parr-Pople method with configuration interaction for calculation of the electronic spectrum, ionization energy, tt-electron distribution and total 7T-energy of indazole (36) and isoindazole (37). The tt-densities and bond orders are collected in Figure 5 the molecular diagrams for the lowest (77,77 ) singlet and (77,77 ) triplet states have also been calculated they show that the isomerization (36) -> (37) is easier in the excited state. 

On the other hand, theoretical methods allow an insight into the structure of non-existent molecules like 2//-indazole (37) or the anion of indazole (38). INDO calculations have been performed by Palmer et al. on the anion of indazole (38) (75JCS(P1)1695). The optimized geometry obtained by them is shown in Figure 7. The N—N bond distance is longer in the... 

Figure 7 INDO optimized geometry for indazole anion...

Table 3 Experimental Dipole Moments of Pyrazoles and Indazoles at 25 °C...

The indazole molecular structure (Figure 11) shows the tautomeric proton bonded to N-1 (1//-indazole. Section 4.04.1.5.1). A linear correlation between the bond lengths and the bond orders calculated by the CNDO/2 method was observed (74T2903). 

Figure 11 Bond lengths and bond angles of indazole X-ray structure...

The excellent book by the late Professor T. J. Batterham contains all the available information (up to 1973) on pyrazoles and their non-aromatic derivatives (B-73NMR165) and on indazoles (B-73NMR263). The bibliography for pyrazoles and pyrazolones has been updated in (B-76MI40402). It should be emphasized that almost all the principal results about the H NMR spectra of these heterocycles were published at that time, and thus only a summary of the principal conclusions is needed here. 

Work on indazoles has the drawback of having to employ computer procedures to analyze the ABCDX system of C-unsubstituted indazoles. The first five examples in Table 9 correspond to LAOCOON-analyzed spectra and the last two to simpler systems for which the first-order analysis gives acceptable chemical shifts. 

The most characteristic coupling constant in indazoles is the cross-ring Vs, present both in indazoles and in isoindazoles unsubstituted in positions 3 and 7. 2-Methyl isomers show an additional Vmc.h coupling which can serve to identify an isoindazole unsubstituted in position 3. In 3-azidoindazole, as in 3-azidopyrazole (56), the prototropic exchange is slowed down sufficiently to allow the measurement of a zig-zag /i,4 coupling constant. The deshielding effects observed in A-acetyl derivatives, e.g. 1-acetyl (60) on H-7 and 2-acetyl (61) on H-3, are related to a preferred E conformation (Section 4.04.1.4.3). 

Table 10 NMR Spectral Data for Pyrazole and Indazole Cations...

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