Pyrazoles, Pyrazolones, and Indazoles

The parent compound pyrazole itself is a colorless crystalline solid with a melting point of 66-70 °C. It is corrosive and is an irritant to both skin and eyes. Pyrazole is a five-membered aromatic heterocycles with two N heteroatoms. Its N-1 is similar to the NH of pyrrole, and its N2 behaves similarly to that pyridine. Pyrazole s aromaticity lies somewhere in the middle of the scale in comparison with other heterocycles  

The bond lengths are shown below, which impact the coupling constants in their H-NMR spectra. 

In pyrazole s H-NMR spectrum, the chemical shift for botii H3 and H5 is the same (thanks to die tautomerization between the two nitrogen atoms) at 7.61 ppm, further down field that that of C4 (6.32 ppm). The phenomenon is readily explained using the two nitrogen atoms inductive effect. Like other NH-containing heterocycles, the chemical shift of pyrazole s NH largely depends on the solvent used to do the NMR spectrum. 

The other parent compound indazole is a white solid at room temperature with a melting point of 147-149 C. It does not have the tautomerization effect due to the restrain of the benzene ring. 

---

Not many pyrazoles and indazoles exist in nature. However, many synthetic medicines do contain pyrazoles, pyrazolones, and indazoles. For instance, an anti-inflammatory cyclooxygenase-2 (COX-2) selective inhibitor celecoxib (Celebrex) has the tri-substituted pyrazole as its core structure. A fully substituted pyrazole, rimonabant (Acomplia), is a selective inverse agonist for the cannabinoid receptor type 1 (CBi). Acomplia was marketed in 56 countries for the treatment of obesity by Sanofi-Aventis starting in... 

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). 

When I started my PhD Thesis, some 60 years ago, I was involved with pyrazoles tautomerism (annular of pyrazoles and indazoles and functional of pyrazolinones, then called pyrazolones). The knowledge about tautomerism was empirical, qualitative, and unsystematic. Owing to the efforts of Alan Roy Katritzky and those of my thesis supervisor, Robert Jacquier, the situation improved considerably resulting in the publication in 1976 ofthe book The Tautomerism of Heterocycles [1]. ... 

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. 

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. 

From a qualitative viewpoint there is no doubt that the compounds classified as aromatic in Section 4.04.1.1 (pyrazoles, indazoles, isoindazoles, pyrazolones, indazolones, mesoionic derivatives) indeed have aromatic properties to a greater or lesser extent. Dihy-drobenz[cd]indazole (115) is also formally an aromatic compound since it has an odd number of electron pairs (n =7). However, due to the presence of two adjacent nitrogen atoms the aromatic tautomer (115a) is not stable, and the compound exists as the 1,5- or 1,3-dihydro tautomers (115b) or (115c) <72JCS(P2)68). The antiaromatic benz[cd]indazole (116), although unstable, has been fully characterized by N, H and NMR spectroscopy... 

Indazole s H-NMR spectrum is much more complicated than those of pyrazole and pyrazolone. With a chemical shift of 8.11 ppm, H3 is the... 

---