Pyrazolo 4-amino-2- -, preparation

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

Pyrazolo[l,5-a]pyrimidine-6-carboxylates (1402) were prepared in 70% yields in the reaction of 3-aminopyrazoles and diethyl amino(trichloro-methyl)methylenemalonate in boiling ethanol in the presence of sodium ethoxide for 6 hr (78JPR533). 

A range of trifluoromethyl-containing pyrazolo[3,4- ]pyridines have been prepared, in good yield, from the reaction of 4,4,4-trifluoro-3-oxobutanoates with electron-rich amino pyrazoles (Equation 53 Table 29) <2003S1531>. 

The reaction of 1,3-dicarbonyl compounds with 3-amino-5-pyrazolones has been used extensively in the preparation of pyrazolo[3,4-b]pyridines. A number of products are possible, depending on the reagent used and the direction of cyclization. As a consequence, many of the early reports proposed incorrect structures. 

Unexpected results lead to the discovery of pyrazolo[4,3-r/][2,3]benzodiazepine 87 preparation from l -(/V,Ar-diaroyl)-amino-4-phenyl-[l,2,3]triazol-5-yl-methyltriphenylphosphonium ylide 85. Ylide formation was followed by a Dimroth-type rearrangement to 86 and to product 87 <1995TL5637> (Scheme 17). 

Pyrazolo[l,5-a]pyrimidines and imidazo[l,2-fc]pyrazoles have been prepared from phosphine derivatives of 5-amino-3-phenylpyrazole in aza-Wittig reactions with selected a -chloroketones. 24°... 

Stadlbauer, W. et al, J. Chem. Soc., Perk. I, 2000, (18), 3085 A literature preparation of this compound by diazotisation of 3-amino-4-hydrazino-l//-pyrazolo[3,4-b]quinoline was found to give the still more energetic isomer 4-azido-3-diazo-3//-pyrazolo[3,4-b]quinoline. 

This high-pressure methodology was later used by several groups, e.g., for the preparation of 4-(dimethylamino)pyridine (DMAP) derivatives [91] and oligoanilines [92]. More intriguingly, the synthesis of enantiomerically pure C-6 substituted pyrazolo[3,4-d]pyrimidines 147 has been performed by SNAr reaction of 4-amino-6-chloro-l-phenylpyrazolo[3,4-d]pyrimidine (145) under high-pressure conditions at ambient temperature. Conventional synthetic conditions (reflux at 0.1 MPa) were unsuccessful. The S enantiomer displayed higher affinity and selectivity for the adenosine Al receptor than the R enantiomer (Scheme 40) [93]. 

Pyrazolo[3,4-c][l,2,5]oxadiazole-5-oxides (73) have been prepared from the corresponding 3-amino-4-(hydroxyiminomethyl)-l,2,5-oxadiazoles by sequential treatment with bromine and dibromoisocyanurate (DBI) (Equation (9)) <93MC120>. 

Thermal cyclization was also the route employed to prepare 9-hydroxy-7-methyl-l/f-pyrazolo[3,4-/]quinoline (74) from the 6-aminoindazole/ethyl acetoacetate condensation adduct shown in Equation (41) <92JMC4595>. The hydroxyl substituent of compound (74) was then converted (POCl3, DMF) to a chloro, which in turn was displaced by treatment with aryl amines to give tricyclics with potent in vivo immunostimulatory activity like that noted for regioisomeric l//-imidazo[4,5-/]quinolines but unlike the inactive pyrazolo[4,3-/]quinolines. Although it was noted with some interest that none of the linear tricyclic isomer had been isolated, this finding actually parallels that reported earlier for the similar condensation of 1- and (V(6)-alkyl and unsubstituted 6-amino-indazoles with diethyl ethoxymethylenemalonate <83JHC1351>. 

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