Heterocyclics pyrazolo pyridines

Formation of Complex Heterocycles. The C—H activation of pyridine (generally used in excess amount) has enabled the synthesis of more complex heterocycles such as imidazo and pyrazolo pyridines as well as indolizines. Copper metal salt... 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

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). 

As reported in <1996GHEC-II(7)283>, no specific study on the mass spectra of these classes of compounds has been reported, although this analytical method has only been used as a tool for structure elucidation or reference without critical analysis. Some examples are reported in <1996GHEC-II(7)283>. Further information on the MS of heterocycles can be found in <2001MI1>. The mass spectral data for imidazopyridines, pyrazolo[3,4- ]pyridines, oxazolo-pyridines, ioxazolopyridines, isothiazolopyridines, 377-1,2-dithiolo[3,4- ]pyridines, and l,3-dithiolo[4,5- ]pyridines were reported in <1996GHEG-II(7)283>, but there have been no further reports in this area. 

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>. 

Hetero-Diels-Alder reactions provide an attractive means of rapidly constructing complex heterocyclic ring systems. Cycloaddition of pyrazolyl imines with a variety of electron-deficient dienophiles has been used to assemble pyrazolo[3,4,1 ]pyridines in a focused microwave reactor under solvent-free conditions53. The reactions proceeded in modest to excellent yield, depending upon the choice of diene and dienophile (Scheme 3.32). 

New C-4 fused heterocyclic systems in DHPs, AHC-52 (94) (methyl 2-(N-benzyl-N-methylamino) ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[l,5-a]-pyridine-3-yl)-l,4-dihydropyridine-3,5-dicarboxylate) and its pyridine analog AHC-93 (95) has also been reported to reverse MDR by inhibiting Pgp [123-125]. 

A number of heterocycles with bridged head nitrogen such as pyrazolo[l,5-a]pyrimidines 64, triazolo[l,5-a]pyrimidines 65, pyrimido[l,2-a]benzimidazole 66 and pyrimido-pyrazolo[3,4-6]pyridines 67 have been prepared. ... 

Treatment of 2-alkyl- or 2-hydroxymethyl-l-aminopyridinium salts with acyl or aroyl chlorides in the presence of base causes cyclization to pyrazolo[l,5-a]pyridine derivatives. If the 3-position is unsubstituted, acylation occurs at this position under the reaction conditions (Eq. 13).18141 There is good evidence that the initial step is acylation of the iV-amino group. This reaction has been extended to the synthesis of various bridgehead nitrogen heterocyclic systems including pyrazolodiazines (11),9 pyrazolo[5,l- ]thiazole (12),142 and imidazo[l,2-h]pyrazole (13).142... 

Thermal behavior of a variety of pyridine JV-imidoylimines has been studied. Thermolysis of 100 in refluxing xylene gives 1,5-cyclization product 101, together with six-membered betaine 102. The 2-methylpyridine congener gives pyrazolo[l,5-a]pyridine 104 in addition to 103.59,60 By contrast N-imine 105 undergoes an intramolecular displacement to give a heterocyclic product 106.59,60... 

The novel fused heterocyclic system pyrazolo[4, 3 5,6]pyrido-[2,3-b]-1,5-benzoxepine (53) and its benzothiazepine analogue have been obtained by cyclisation of a substituted pyrazolo[3,4-b]-pyridine derivative. 

Condensed and other multimembered heterocycles Benzoylacetonitrilehydrazones reacted with TCNE to yield pyrazolo[3,4-Z7]pyridines Pyrazolopyrimidines 403 have been obtained from arylazoaminopyrazoles and TCNE. The first step of the reaction is the formation of a charge-transfer complex". ... 

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