Pyrazolo pyrimidines alkylation

Pyrazolopyrimidines, amino-acidity, 5, 309 alkylation, 5, 310 N-oxide synthesis, 5, 324 synthesis, 4, 525 5, 328 Pyrazolopyrimidines, dimethyl-synthesis, 5, 316 Pyrazolo[ 1,5-a]pyrimidines electrophilic attack, 5,311 synthesis, 5, 271, 320, 331 Pyrazolo[ 1,5-c]pyrimidines electrophilic attack, 5, 312 Pyrazolo[3,4- d]pyrimidines nucleophilic attack, 5, 313 synthesis, 5, 161, 272, 323, 334 tautomerism, 5, 309 Pyrazolo[4,3-d]pyrimidines alkylation, 5, 310 synthesis, 5, 272... 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Whereas 1-alkyl substituted 5-aminopyrazoles 12 (R = alkyl or aryl) cyclize on treatment with -keto esters into pyrazolo[3,4-h] pyrimidines, cyclocondensation of 12 (R = Ts Ts, p-toluenesulfonyl) with / -keto esters affords pyrazolo[l,5-a]pyrimidines (71JPR969). 

Azoloazines having NH functions are weakly acidic and are also basic. TV-Alkylated derivatives act only as bases. Carbon-13 NMR studies on l-isopropyl-4-amino-pyrazolo[3,4-r/]pyrimidine and isomeric 2-isopropyl derivative indicate that N-5 and N-7 are the respective protonation sites <77JA7257>. Allopurinol as well as its derivatives have been shown by UV and NMR to form mono-and diprotonated species in sulfuric acid solutions <75KGS838>. 

Alkylation of pyrazolo[3,4-triethyl orthoformate gives the N-l ethyl derivative <88KGS914>. Phase-transfer methylation of 4-methoxy-l//-pyrazolo[3,4-d]pyrimidines gives a mixture (2 1) of N-l and N-2 methylated derivatives <85JOC1847>. 

Aldehydes, arylideneanilines, carboxylic acids and orthoesters have been used as one-oarbon units for binding the two amino functions of 4-amino-l-alkyl-3-propylpyrazole-5-oarboxamide to give l,6-dihydro-pyrazolo[4,3-<7]pyrimidin-7-ones <05MC619 05JHC751>. A modified efficient synthesis of variably substituted pyrazolo[4,3-<7]pyrimidm-7-ones has been described using a pyrazole-5-carboxylic acid, which was selectively brominated at position 4 and then converted into the carboxamide. Microwave irradiation gave better yields in the conversion of the carboxamides to pyrazolo[4,3-J]pyrimidinones <05JHC1085>. 

Cycloaddition and cyclization routes were used to access certain 1,3-diazines. The 4+2 cycloaddition reaction of 4-(N-allyl-N-aryl)amino-l,3-diaza-l,3-butadienes with vinyl-, isopropenyl-, and chloroketene led to pyrimidinone-fused pyrimidinones <97T13841>. Cis-cyclopenta[d]pyrimidines were derived from cis-2-amino-l-cyclopentanecarboxylates by cyclization with KOCN and KSCN <97JHC1211>. 2-Thioxopyrido[3, 2 4,5]thieno[3,2-r/]pyrimidin-4(3//)-ones 19 were prepared by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-/)]pyridines and isothiocyanates <97JHC937>. Thiazolyl-benzimidazoles derived from 2-cyanomethyl-l//-benzimidazole and 2,3-dihydrothiazole-2-(3//)-thiones were cyclized to the corresponding thiazolo[4,5-r/]pyrimidines <97PHA346>. Reductive cyclization of 6-cyanomethyl-5-nitropyrimidines afforded 7-alkyl-5//-pyrrolo[3,2-r/]pyrimidines and 6-amino-7,7-dialkyl-7//-pyrrolo[3,2-rf]pyrimidines <97T391>. 7-Methyl-5-alkyl-2-vinyl-pyrazolo[3,4-r/]pyrimidine-4,6(5//,7//)-diones arose from cyclization and alkylation of... 

Cyclocondensation of 3-alkyl(or aryl)-5-amino-4-formyl-1 -phenyl-1 /f-pyrazoles with cyanoacetamide in the presence of sodium methoxide in methanol gives pyrazolo[3,4-f>]-pyrimidines which are elaborated to yield pyrazolo[3, 4 5,6]pyrido[2,3- flpyrimidines 36 by acetylation and subsequent cyclization <97MI03 97CA(126)8064>. 

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Pryadeina MV, Burgart YV, Saloutin VI, Slepukhin PA, Sadchikova EV, Ulomskii EN (2009) Synthesis of derivatives of pyrazolo[l, 5-a]pyrimidines and imidazo[l,5-a]pyrimidines proceeding from alkyl 2-benzylidene-3-oxo-3- fluoroalkylpropionates. Rus J Oig Chem 45 242-247... 

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