5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

The condensation of 5-aminopyrazole with various bielectrophilic moieties results in the formation of pyrazoloazines, an interesting array of fused heterocyclic systems. The development of new synthetic routes towards pyrazoloazines for their biological and medicinal exploration is an attractive area for researchers throughout the world. The present review focuses on various synthetic methods developed in the last decade for the synthesis of differently substituted pyrazoloazines by a broad range of organic reactions by means of 5-aminopyrazole as a precursor.

In addition to the immense biological potential related to fused pyrazoles, their synthetic potential needs to be reviewed for further improvements and extension of interests. Various efforts have been developed for the synthesis of pyrazole-based fused heterocycles. 5-Aminopyrazoles have been extensively employed as useful synthons in designing and constructing a plethora of fused pyrazoloazines of potential synthetic and medicinal interest viz pyrazolo [3,4-b]pyridines 7 [18], pyrazolo[1,5-a]pyrimidines 8 [19], pyrazolo [3,4-d]pyrimidines 9 [20,21], pyrazolo [3,4-b]pyrazines 10 [22], pyrazolo[5,1-c]-1,2,4-triazines 11 [23], pyrazolo[1,5-a]-1,3,5-triazines 12 [24], pyrazolo [3,4-d] [1,2,3]triazines 13 [25] (Figure 2). A number of review articles have been published by us and others highlighting the synthetic and biological aspects of 5-aminopyrazoles [26][27][28] as well as on the synthesis of fused pyrazole derivatives [25]. However, a perusal of literature reveals that the importance of 5-aminopyrazoles as synthetic precursors for fused heterocycles has not been reported till now to the best of our knowledge. Recent literature shows resurgence of interest in the chemistry and bioactivity of 5-aminopyrazole derivatives leading to improvements in several already known reactions and syntheses of various fused heterocyclic derivatives with various biological activities. Considering the synthetic importance of 5-aminopyrazoles and synthesis of fused pyrazole derivatives with the need for a more general collection, herein we report an exhaustive overview of the main developments in the last decade in the chemistry of 5-aminopyrazoles for the design and synthesis of fused pyrazoloazines.
The typical reactivity of 5-aminopyrazoles 5-Aminopyrazoles are polyfunctional compounds possessing three typical nucleophilic sites: 4-CH, 1-NH and 5-NH 2 with the following reactivity order: 5-NH 2 > 1-NH > 4-CH. These positions have been used to construct various fused heterocyclic rings where 5-aminopyrazoles undergo cyclization and cycloaddition on reaction with bielectrophiles. Due to the large number of references, reactions of 5-aminopyrazoles with various reagents to construct a six membered ring with pyrazole are discussed. The synthetic methods have been arranged in order of the ascending number of heteroatoms in the azine ring. The systematic arrangement in this review explores the possibility of providing practical guidance to synthetic chemists for further research.
Aggarwal et al. [42] reported the regiospecific synthesis of 4-trifluoromethyl-1H-pyrazolo [3,4-b]pyridines 18 by the reaction of 5-aminopyrazole 16 with trifluoromethyl-β-diketones 17 in refluxing acetic acid (Scheme 1). In the same report the other regioisomers 6-trifluoromethylpyrazolo [3,4-b]pyridines 20 were obtained under multicomponent solvent-free conditions by the reaction of hydrazine 14, β-ketonitrile 15 and β-diketone 17 as an exclusive product. The structures of both the regioisomers have been confirmed unambiguously by HMBC, HMQC and 19 F NMR studies. The authors proposed that trifluoromethyl-βdiketone exists mainly in keto form 17 under solvent-free conditions whereas under solvent-mediated conditions the enolic form 21 towards the carbonyl carbon that carries the CF 3 group is predominant. The keto form 17 results in the formation of 6-trifluoromethylpyrazolo [3,4-b]pyridines 20 by attack of the 5-NH 2 group (from 5-aminopyrazole 16) on the more electrophilic carbonyl group attached to CF 3 (from trifluoromethyl-β-diketones 17) whereas the enolic form 21 reacts with the less nucleophilic C-4 of 5-aminopyrazole and leads to the formation of 4-CF 3 product 18. The formation of acetamide 19 as byproduct under solvent-mediated conditions was also observed due to the reaction of NH 2 group with acetic acid.
to the increased electrophilicity of the carbonyl carbon. Electron-donating groups on the contrary decreased the electrophilicity of the carbonyl carbon and hence resulted in lower yields.
The synthesis of isomeric tetracyclic pyrazolo [3,4-b]pyridinebased coumarin chromophores 27 and 28 was reported by Chen et al. [47] starting from 7-diethylaminocoumarin-3-aldehyde (26) and 5-aminopyrazole derivatives 16 (Scheme 4). The structure of the synthesized compounds was confirmed by X-ray crystallography, 1 H and 13 C NMR and HRMS studies. The relationships between the structures and chemical properties of these compounds were also investigated by techniques like fluorescence spectroscopy, single photon counting technique, cyclic voltammetry, thermogravimetric analysis, and DFT calculations.
Aziz et al. [51] developed an acid-catalyzed synthesis of pyrazolo [3,4-b]pyridine derivatives 40 through the reaction of enaminone 38 with 5-aminopyrazole (R = Ph, 16) in acetic acid (Scheme 7). The proposed reaction mechanism involves the generation of new enaminone intermediate 39 which underwent condensation and cyclization within C-4 of 5-aminopyrazole and the carbonyl group of the enaminone to generate pyrazolo [3,4-b]pyridine derivatives 40. However, the formation of pyrazolo[1,5-a]pyrimidine 41, a structural isomer of 40 was obtained when 1-NH-5-aminopyrazole (R = H, 16) was condensed with 38. It was attributed to cyclocondensation between 1-NH (5-aminopyrazole) and the carbonyl carbon of the enaminone. The compounds were found to have cytotoxicity against the normal fibroblast (BHK) cell line and antitumor activity against the colon cancer cell line CaCO-2.
Lin et al. [52] developed the synthesis of pyrazolo [3,4-b]pyridine derivatives 45 via aza-Diels-Alder reaction of pyrazolylimines 43 with maleimides 44 (Scheme 8). Pyrazolylimines 43 were in turn obtained from the reaction of 5-aminopyrazole 16 with diisopropylformamide dimethyl acetal (R' = isopropyl, 42). The reactions were carried out with various metal catalysts in acetic acid and acetonitrile solvents but reactions carried in acetic acid in presence of silica gel impregnated with indium trichloride provided the best results. Júnior et al.    Jiang et al. [54] described the synthesis of macrocyclane-fused pyrazolo [3,4-b]pyridine derivatives 49 by the reaction of 5-aminopyrazole derivative 46, arylaldehydes 47 and cyclic ke-tones 48 in various solvents like acetonitrile, ethylene glycol, acetic acid, DMF under MW conditions at 80 °C (Scheme 9). The best results (72-80% yields) were obtained by carrying out pyrazole (R = H, R 1 = Me, 16), isatin 54 and α-cyanoacetic ester 62 or 15 in aqueous-mediated reaction in presence of NaCl. Regioisomeric pyrazolo[1,5-a]pyrimidines 65 were not formed in any of the tried reaction conditions. An increase in the amount of NaCl from 2.5 to 10 mol % resulted in gradual increase of the yield of the desired product 63 from 85% to 89% and 93%, respectively (Scheme 14). Recently, Jiang et al. [61] have also developed a microwave-assisted synthesis of spiropyrazolo [3,4- with acenaphthenequinone 67 and β-ketonitrile derivative 68 in glacial acetic acid instead of expected spiropyrazolo [3,4b]pyridines 69 (Scheme 15). The structures of the products were confirmed by spectral and X-ray crystallographic data. This method provides the first direct conversion of acenaphthenequinone to a naphthoic acid fragment via C-C bond cleavage in a single step.
Recently, D. Anand et al. [63] have reported the synthesis of pyrazolo [3,4- Recently the reaction of β-ketoesters 81 as in the three-component reaction with 5-aminopyrazoles 16 and substituted salicylic aldehydes 83 was also studied by Fan et al. [69]. An extensive survey of catalysts and solvents identified 0.2 equivalents of FeCl 3 and ethanol as optimal catalyst and solvent, respectively, with which o-hydroxyphenylpyrazolo [3,4-b]pyridine derivatives 85 were obtained in 89% yields with no formation of the cyclized isomer chromenopyrazolo [3,4-  Hill et al. [72,73] reported the synthesis of pyrazolo [3,4b]pyridines 89 from the reaction β-ketonitriles 15 with 5-aminopyrazole 16 and aldehydes 47 (1 equiv each) in presence of triethylamine (2 equiv) by heating the reaction mixture at 90 °C in DMF for 16 hours followed by treatment with sodium nitrite (3 equiv) in acetic acid at ambient temperature. In addition, when the R 1 group has significant bulk (R 1 = tert-butyl) the reaction results in the formation of pyrazolo[1,5-a]pyrimidine derivative 90 as an additional product. The authors proposed that the bulky group had significantly slowed down the rate of electrophilic aromatic substitution at C-4 on 1H-pyrazol-5amine due to which the aza-Michael addition becomes competitive at N-1 which ultimately provides pyrazolo[1,5-a]pyrimidine derivative 90 as additional product (Scheme 25). The synthesized pyrazolo [3,4-b]pyridines 89 were found to be good mGluR5 positive allosteric modulators (PAMs) and therefore can be used to develop antipsychotic drugs to treat schizophrenia.
In an interesting report Aggarwal et al. [74]
Ma et al. [110] reported the synthesis of 3-cyano-6,7diarylpyrazolo[1,5-a]pyrimidines 179 comprising the reaction of 1.5 equivalents of 5-aminopyrazole 126 with 1 equivalent of isoflavones 178 in the presence of 3 equivalents of sodium methoxide in methanol (Scheme 50). The method has the merits of being simple in operation with mild reaction conditions and good yields of fused pyrazole derivatives.
Quiroga et al. [144] studied the reaction of o-aminonitrosopyrazoles 227 and cyclic β-diketones 58 in various solvents like pyridine, acetic acid and N,N-dimethylformamide for the synthesis of pyrazolo [3,4-b]pyrazines 228 (Scheme 62). No measurable product was observed in acetic acid and pyridine but reaction in DMF provided promising results with good yields of the pyrazolo [3,4-b]pyrazines 228 in short reaction time. The reaction under microwave irradiation (100 W at 80 °C) in DMF provided the desired product in 85% yield in just 9 min. Easy work-up, mild reaction conditions and good yields makes this protocol a simple procedure for the synthesis of pyrazolo [3,4-b]pyrazines.

Synthesis of pyrazolo[3,4-d][1,2,3]triazine
Pyrazolo [3,4-d] [1,2,3]triazines are important fused pyrazole derivatives because of their biological activity and are valuable synthons in organic transformations. These are also structural analogues of adenosine and guanosine [157,158]. But surprisingly, only a few literature reports are available for synthesis and biological potential of this nucleus.

Conclusion
In this review article, we have systematically summarized various synthetic methods developed in the last decade for the construction of various pyrazoloazines as a group of fused pyrazolo derivatives utilizing 5-aminopyrazole as a synthetic precursor. The 5-aminopyrazole nucleus possesses ubiquitous distinctive structural features and its coupling reactions with different types of electrophilic reagents like aldehydes, ketones, β-diketones, β-ketoesters, and α,β-unsaturated ketones truly justifies its synthetic potential to construct fused heterocycles. This review opens the scope for future developments in new methodologies which promise the synthesis of novel fused heterocyclic systems with a wide range of medicinal and synthetic applications.