Pyrazolo pyridazine

Pyrazolo[3,4-4]pyridazine (555) 69BSF2061, 69JPR1058, 70TL4611, 77JHC375, 77T45, 78JHC813 ... 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

In eontrast, the isomerie 5-alkynylpyrazole-4-diazonium ehlorides eyelized only after heating tol00-105°C for 2 h, giving good yields of the l,3-dimethyl-7-ehloro-l//-pyrazolo[4,3-c]pyridazines 87 [98HEC519 99JCS(P1)3721] (Seheme 137). 

Thus, the Richter reaction of the series of alkynylaminopyrazoles opens up a route to halo derivatives of l//-pyrazolo[3,4-c]pyridazines, 2//-pyrazolo[3,4-c] pyridazines, and lff-pyrazolo[4,3-c]pyridazines. 

The intramolecular cyclization of 2-alkynylaryldiazonium salts (Richter reaction) leads not only to 4-hydroxy- but also to 4-bromo- and 4-chlorocinnolines. The behavior of alkynylpyrazolediazonium chlorides differs from that of their benzene analogs. The Richter reaction of the series of alkynylaminopyrazoles gives only 4-halo derivatives of l//-pyrazolo[3,4-c]pyridazines and l//-pyrazolo[4,3-c] pyridazines, and mainly hydroxy derivatives of 2//-pyrazolo[3,4-c]pyridazines. 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

Diazotization of 4,5-diphenyl-3-amino-l//-pyrazolo[4,3-c]pyridazine gave diazonium salt 290, whose condensation with 2-naphthol gave 291, which cyclized to 292 (91H901) (Scheme 62). 

Palladium-catalyzed [3+3] cycloaddition of (2-(acetoxymethyl)-2-propenyl)-trimethylsilane with azomethine imi-nes, for example, l-benzylidene-3-oxopyrazolidin-l-ium-2-ides, leading to appropriately substituted hexahydro-7-methylene-177-pyrazolo[l,2- ]pyridazin-l-ones has been reported <2006JA6330>. 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

Addition of A-mesityl benzimidazolyl carbene 720 to an a,/3-unsaturated aldehyde generates a homoenolate intermediate that undergoes an addition/acylation sequence with azomethine imine 719 to afford (3R, 5S, 6S )-177-pyrazolo[l,2- ]pyridazine-l,8(5//)-diones 721 with excellent diastereoselectivity. Compound 721 (Ar = R = Ph) treated with sodium hydoxide in methanol or benzylamine provided nearly quantitatively, ring-opened products 722a and 722b, respectively (Scheme 116) <2007JA5334>. 

Tri azo lino [4,3 -a] py ri mi din cs, pyrazolo[3,4-<7]pyridazines and isozazolo[3,4-<7]pyridazines have been synthesized from hydrazonoyl chlorides <06SC97>. 

---