Pyrazolo indazoles

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

A heterocyclization involving the N-2 atom of indazole affords [l,2,4]triazino[4,5-h]-indazoles (561) from the 3-carbohydrazinoindazole (78JHC1159,79JHC53). The corresponding pyrazolo[l,5-tf][l,2,4]triazine (562) has been prepared by the same procedure (8UHC1319). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

A solution of 1-phenyl-1//-pyrazolo[3,4-rf]pyridazinc-7-carbonitrilc (150 mg. 0.68 mmol) and A,A-diethyl-prop-l-ynamine(151 mg, 1.36 mmol) in l,4-dioxane(2 mL) was refluxed for 5 h. After cooling, the reaction mixture was poured onto excess ice, and extracted with CHC13. The extract was washed with H20, dried (Na2S04) and concentrated under reduced pressure. Purification by chromatography (silica gel, benzene then bcnzene/EtOAc 20 1) gave, from the benzene eluate, 6-diethylamino-1 -phenyl-1 //-indazole-7-carbo-nitrile [yield 81 mg (39 %) mp 104-105 C (benzene/petroleum ether)] as slightly yellow prisms and, from the second eluate, the diazocine 5 as yellow needles yield 90 mg (40 %) mp 121-122 C (benzene/ petroleum ether). 

Indazolo[2,l-a]indazole (dibenzo[6,/]-3a,6a-diazapentalene) IV,B,2 Pyrazolo[l,2-a]benzotriazole (benzo[6]-l,3a,6a-triazapentalene) ... 

Diphenylhydrazine (Ph2NNH2) is converted into indazole (215) by Cl2C = NMe2. Oxidative cyclizations are also known thus, fully methylated 6-(benzylidenehydrazino)uracils (216) on photolysis or in hot AcOH give the pyrazolo[3,4-d]pyrimidines (217) (75BCJ1484,92KGS219). 

Since 1974 two publications have appeared dealing with the preparation of monocyclic 1,2,3,5-tetrazines (76BCJ1339, 79LA870). Beside these two articles, Ege and his group have published the synthesis of condensed 1,2,3,5-tetrazines such as pyrazolo[5,l-rf]-[l,2,3,5]tetrazin-4-ones (25) and l,2,3,5-tetrazino[5,4-6]indazol-4-ones (26) (79TL4253). 

Thermal cyclization was also the route employed to prepare 9-hydroxy-7-methyl-l/f-pyrazolo[3,4-/]quinoline (74) from the 6-aminoindazole/ethyl acetoacetate condensation adduct shown in Equation (41) <92JMC4595>. The hydroxyl substituent of compound (74) was then converted (POCl3, DMF) to a chloro, which in turn was displaced by treatment with aryl amines to give tricyclics with potent in vivo immunostimulatory activity like that noted for regioisomeric l//-imidazo[4,5-/]quinolines but unlike the inactive pyrazolo[4,3-/]quinolines. Although it was noted with some interest that none of the linear tricyclic isomer had been isolated, this finding actually parallels that reported earlier for the similar condensation of 1- and (V(6)-alkyl and unsubstituted 6-amino-indazoles with diethyl ethoxymethylenemalonate <83JHC1351>. 

Tu and co workers [114] reported a series of new pyrazolo[4,3-/ quinolin-7-ones 68 synthesized by a MCR of an aromatic aldehyde with Meldrum s acid and l//-indazol-5-amine in ethylene glycol without any catalyst under microwave irradiation. Among various polar solvents tested, ethylene glycol gave the highest yields. Various (hetero)aromatic aldehydes could be used (Scheme 52). 

The most attractive application of the 3//-indazole route is the synthesis of the first cyclo-propapyridine In contrast, the biradicals formed upon irradiation of 9,9-dimethyl-9//-l,2,4-triazolo[h]pyrazolo[4,3-<7]pyridazines 5 did not cyclize to a cyclopropa[<7]pyridazine-type Structure. ... 

Other studies (see, e.g., ref. 187c and references cited therein) have revealed that, in systems containing only O and N as heteroatoms, the azide form 184 is usually the only isomer observable in solution or in the solid state, whatever the position of the heteroatoms. Recent work has shown that the tetrazole forms are predominant in systems containing only nitrogen as the heteroatom in two special cases. If a proton is removed from the azide (e.g., 305), the anion 306 cyclizes to the tetrazole 306b. The cyclized form is likewise formed from the anions of azido-indazoles, -imidazoles, and -benzimidazoles but cycliz-ation is only partial with s-triazoles and negligible with tetrazoles. It is possible to trap the cyclized anions (e.g., 306b) by methylation - (Section IV,C,2) and obtain stable pyrazolo[l,5-rf]tetrazoles, 307 and 308. 

Die Umsetzung von 2-Amino-1,3-dimethyl-lH-indazolium-(2,4,6-trimethyl-benzolsulfonat) mit 2,4-Dioxo-pentan in Gegenwart von Triethylamin/DMF liefert bei 20c 3-Acetyl-2,8-dime-thy 1-3a,8-dihydro-1 H- pyrazolo[2,3-b]indazol 555 (30% Schmp. 73-75°) ... 

Eine weitcre Uberbriickungzwischen Heterocyclus und Carbocyclus gelingt bci der Reaktion von 7-Amino-IH-indazol mit 2,4-Pentandion mit anschlieBender reduktiver Cyclisierung. Dabei wird die Bildung dia-stereomerer 4,6-Dimethyl-4,5,6,7-tetrahydro-[Pg.850]

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