7-Amino-3 pyrazolo methylation

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 rapid and high yielding synthesis of pyrazolo[3,4- pyrimidinones by reaction of aromatic aldehydes with 4-amino-l-methyl-3-propyl-177-pyrazole-5-carboxamide intermediates in the presence of copper chloride has recently been reported for the synthesis of Viagra analogues <2005H(65)1821>. 

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-6]quinolin-5(6//)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-l//-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). 

The synthesis of l-methyl-l,4-dihydro-9H-pyrazolo[4,3-(i]quinoline-9-one 72, inhibitor of protein kinase C, has been performed by means of cyclization of 4-[(4-fluorophenyl)amino]-l-methyl-lH-pyrazole-5-carboxylic acid (Scheme 33) [227]. The main trends in development of research studies in the field of [b]-annelated fluoroquinolones are dealt with use of these compounds for the synthesis of novel [ij]-annelated systems, a varying of substituents at C-7, and also with obtaining of new 2-substituted fluoroquinolones. 

SCHEME 48 Synthesis of fused 6-amino-3-methyl-4-aryl-lH-pyrazolo[3,4-6]pyridine-5-carbonitrile. 

Zarea et al. [126] reported an efficient multicomponent reaction for the synthesis of fused 6-amino-3-methyl-4-aryl-lH-pyrazolo[3,4-b]pyridine-5-carbonitrile (185) from substituted aldehydes (182), malononitrile (183), and 3-amino-5-methylpyrazole (184) (Scheme 48). The reaction has been carried out in the absence of catalyst and with the assistance of ultrasoxmd irradiation. Reported yields were good to excellent (85-98%) in short reaction times (8-10 min). 

L. Zare, N.O. Mahmoodi, A. Yahyazadeh, M. Mamaghani, Convenient ultrasound-promoted regioselective synthesis of fused 6-amino-3-methyl-4-aryl-lH-pyrazolo [3,4-6]pyridine-5-carbonitrile, Synth. Commun 41 2323-2330. (http //www.tandfonline.com/toc/ lsyc20/41/152011). 

Aryl-7-(4 -diethylamino-2 -methylphenyl)imino-6-methyl-pyrazolo[5,1-r] [1,2,4]triazoles 57 <2002ARK133> 7-ben-zylidenc-6-mcthyl-3-phenylimino-2//-pyrazolo[5,l-r [ 1,2,4]triazole 58 and 6-benzylidene-6-methyl-2-phenyl-3-phenyli-minopyrazolo[5,l -z][ 1,2,4]triazoIe 59 < 1998PS( 134/135)119> 3-phenyIamino(l//)pyrazolo[5,l -r 1,2,4]triazol-6-oI 60 and l-phenyl-3-phenylamino(l//)pyrazolo[5,l-r][l,2,4]triazol-6-ol 61 <1999EJC175> 6-amino-7-cyano-3-phenylpyra-... 

Reaction of 2-amino-3-phenylazo-5-methyl-6,7-dihydropyrazolo [ 1,5-a] -pyrimidine-7-one (209) with ACOH/H2SO4 gives the pyrazolo[l,5-a]-pyrimidine derivative 210 (77JHC155). This reaction can be looked at as electrophilic substitution of the arylazo function by the proton. Similarly, 4,5,6,7-tetrahydro-2-phenyl-3-phenylazo-5-oxopyrazolo[l,5-a] pyrimidine gives 4,5,6,7-tetrahydro-2-phenyl-5-oxopyrazolo[l,5-a]pyrimidine 212 by the action of acetic/hydrochloric acid (75T63). 

Cyclization of an N-amino group with an a-methyl substituent in 7V-aminoazinium salts or in N-aminoazoles is the most frequently used route to pyrazolo-fused systems (92AHC(53)85). Thus, (V-amino-imidazolium and -thiazolium salts (23 Z = NR, S) on heating with anhydrides in the presence of a base, are cyclized to give (25 Z = NR, S). The acyl group in (25) results from acylation of the initially formed pyrazoloazole (24). 

Benzoylamido-4-diazo-l-methyl-3-phenylpyrazole (62a), which exists in the zwitterionic form, reacted under alkaline conditions to furnish 4-methyl-6-phenyl-3,4-dihydropyrazolo[3,4-reaction product (Scheme 12). This reaction, which is believed to proceed via a 5-amino-4-diazo intermediate (63), needs to be carried out in the dark since compound (62a) itself is very sensitive to irradiation <84H(22)2309>. The urea derivatives (62b,c) react analogously, affording compound (64b) after a short reflux in KOH solution. Treatment of the same substrate with triethylamine yielded the carboxyamides (65b,c), hydrolysis of which gave the unsubstituted pyrazolo[3,4-. 

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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