Pyrazolo pyrazines preparation

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

Lindsley and co-workers developed a general procedure towards the collection of diverse heterocyclic scaffolds from common 1,2-diketone intermediates 96. Substituted quinoxalines 97, fused pyrazolo [ 4,5-g ] quinoxalines 98 and imidazolo[3,4-g]quinoxalines 99 as well as pyrido[2,3-fo]pyrazines 100 and Ihicno[3,4-fo Ipyrazincs 101 have been prepared in excellent yields [132] (Scheme 54), employing optimized reaction conditions (microwave heating of equimolar mixtures of 1,2-diketone 96 and diamine components at 160 °C for 5 min in 9 1 MeOH - AcOH). The use of microwave irradiation resulted in reduced reaction times (5 min vs. 2-12 hours), improved yields as well as the suppressed formation of polymeric species a characteristic of traditional... 

Only one aldehyde derivative has been prepared. Treatment of l-(2-hydroxyethyl)-l//-pyrazolo[3,4-b]pyrazine-5-carboxylaldoxine (272a) with sodium nitrite and HC1 gave the aldehyde (273) (92%) which is readily converted into the imine (272b) on treatment with cyclohexylamine (Equation (33)) <90JAP02172988>. 

Pyrazolo[3,4-b]pyrazines are useful intermediates for the preparation of 2-aminopyrazine-3-carboxamides such as 49, much used in pteridine syntheses. For example, reductive cleavage of the 1-substituted 3-hydroxy compound 48 with Raney nickel results in smooth breakdown of the pyrazole ring to give the product 49. 

The fused pyrazolo[3,4-b]pyrazines 34 were prepared by Quiroga and coworkers by microwave-assisted cyclocondensation reaction of ortho-aminonitrosopyrazoles 32 with cyclic p-diketones 33. Dimethylformamide (DMF) was proven to be the most suitable solvent for giving high yields under microwave irradiation, taking less than 18 min for completion. The synthesis showed a good substrate scope of 26 examples, affording the desired products in 40-85% yield (Scheme 12.12) [30]. 

Base-sugar condensations have been used to prepare 2 -deoxyribosides of pyrazin-2-ones,30.31 3,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines,32 and indazoles, where about equal amounts of 1- and 2-glycosylated products were obtained, although with P-selectivity.33 Reaction of 2-deoxy 3,5-di-O-toluoyl-a-D-cryt/iro-pentofuranosyl chloride with 2-amino-6-chloropurine under Seela s phase-transfer conditions gives the p-A. giy osylated product as the major isomer.34... 

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