Pyrazolo pyridin-6-ones

Pyrazolo[4,3-c]pyridine, 2-benzyl- H NMR, 5, 308 <73X441) Pyrazolo[3,4-b]pyridin-3-one, 6-metbyl-4-pbenyl-IR, 5, 332 <69M1250)... 

Pyrazolo[3,4-b]pyridin-4-one, 1,3,6-trimetbyl- C NMR, 5, 332 <75JHC517) Pyrazolo[3,4-b]pyridin-6-one, 1,3,4-trimetbyl- C NMR, 5, 332 <75JHC517) Pyrazolo[l,5-a]pyrimidine electron density, 5, 306 <75CJC119) Pyrazolo[3,4-d]pyrimidine electron density, 5, 306 <58JCS2973, 69CJC1129) Pyrazolo[3,4-d]pyrimidine, 4-amino- C NMR, 5, 310 <58JCS2973) Pyrazolo[4,3- /]pyrimidine electron density, 5, 306 <58JCS2973)... 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

Reproduoed with permission One-Pot and Convenient Conversion of 5-Azidopyrazole-4-oarboxaldehyde to Pyrazolo[3,4-b]pyridines A. Zheng etal. 2006 Taylor Franois Ltd. 

A one-pot, two-step synthesis of a wide variety of pyrazolo[3,4-3]pyridines has been reported by Zheng in situ diazo transfer followed by Friedlander cyclization affords good yields of the desired products (Equation 54 Table 30) <2006SC1549>. 

Reproduoed with permission One-Pot and oonvenient oonversion of 5-azidopyrazoie-4-oarboxaidehyde to pyrazolo[3,4-b]pyridines S. P. Singh et al. 2006 Tayior Franois Ltd. 

A new synthesis of the pyrazolo[4,3-r ]pyridine core based on an unusual one-step tandem ring closure and rearrangement of bisacetylenic N-acylated hydrazones using aqueous ammonia has been reported (Equation 81 Table 34) <2004T933>. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Cyclocondensation of 3-amino-2-pyrazolin-5-ones (22) with )S-diketones affords either pyrazolo[3,4-d]pyridines 23 or pyrazolo[l,5-a]pyrimidines 24. In acid 24 is produced, whereas under alkaline conditions 23 is the major product (60CB1106 62LA104). 

Pyrazolo[l,5-a]pyrimidin-7-ones 220 rearrange on treatment with sodium hydroxide into the pyrazolo[3,4-fc]pyridines 221 (77USP4048184). 

A benzenediazonium salt in pyridine coupled with 2,3-diphenylpyrazolo-[4,3-c]pyridin-4,6-dione in the 7-position.140 Similar treatment of 1,3-disub-stituted pyrazolo[3,4-h]pyrid-4-ones afforded the 5-arylazo products.222... 

A mixture of 1- and 2-alkylated products was obtained from reaction of 5-methylpyrazolo[4,3-b]pyridine with methyl iodide in ethanolic sodium hydroxide.111 Methylation of reduced pyrazolo[4,3-c]pyrid-3-ones gave either 1- or 3a-substituted products (Scheme 3).149... 

Replacement of a hydroxy with a thiol group, using phosphorus penta-sulfide in refluxing pyridine, has been reported for pyrazolo[4,3-c]pyrid-4-(54-75%)144,146 and pyrazolo[3,4-c]pyrid-7-ones (67%). 10... 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

The Ulmann reaction of 4-bromo-3-(2-aminophenyl)thiomethyl-3-pyra-zolin-5-ones (74) in a nonpolar solvent such as xylene and in the presence of a small amount of pyridine afforded 1,2,4,10-tetrahydro-3//-pyrazolo[3,4-c][l,5]benzothiazepin-3-ones (75). However, when the same reaction was... 

Monothiomalonic acid hydrazides (398), prepared by the reaction of cyanoacetohydrazides with H2S, react with diketones (e.g. (397)) to give pyridine-2-thiono-3-carboxhydrazides (399) which cyclize with the loss of H2S to give 1-substituted pyrazolo[3,4-Z>]pyridin-3-ones (e.g. (400)) (Scheme 44) <85S861>. 

Compound (408), which was prepared by the condensation of the amine (407) with benzaldehyde in the presence of piperidine, upon treatment with phenylhydrazine afforded the orange pyrazolo[3,4-6]pyridin-2-one (410) (69%) (Scheme 45) <9iPS(63)ll9>. The structure (410) was confirmed by an alternative synthesis involving a reversal of the reactants. In this case compound (407) was initially reacted with phenylhydrazine to give compound (409) and subsequent condensation with benzaldehyde gave the product (410). 

Ring opening of 3-(phenylsulfonyloxy)pyrido[3,4-d]pyrimidine-2,4-dione (587) with sodium methoxide, followed by a Lossen rearrangement gave the hydrazinopyridine ester (588) which in refluxing acid yielded 1 //-pyrazolo[3,4-c]pyridin-3-one (589) (Scheme 75) <74JHC163>. 

Using the general method described in Section 7.08.10.2 <74JHC163> 3-(phenylsulfonyloxy) pyrido[4,3-fi ]pyrimidine-2,4-dione (590) ring opens with sodium methoxide and rearranges to a hydrazinopyridine ester, which in refluxing acid yields l//-pyrazolo[4,3-c]pyridin-3-one (591) (Equation (59)). 

Photochemical irradiation of 4-hydrazinoisoxazolo[5,4- ]pyridines affords pyrazolo[4,3-c]py-ridines via cleavage of the N—O bond to give nitrene intermediates which then evolve into the final products by an intramolecular attack of the hydrazine group <88H(27)1899>. For example, irradiation of 6-chloro-4-hydrazino-3-methylisoxazolo[5,4- ]pyridine (592) with a water-cooled low-pressure mercury immersion lamp (6W) gave l-amino-6-chloro-3-methylpyrazolo[4,3-c]pyridin-4-one (593) (60%) (Scheme 76). 

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