Cinnoline aromaticity

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Fig. 14 Reduction of PhjCSPh by electrochemically generated aromatic anion radicals (in DMF at 25°C). Variation of the rate-determining step rate constant, A , with the standard potential of the aromatic anion radical, p,g (from left to right azobenzene, benzo[c]cinnoline, 4-dimethylaminoazobenzene, terephthalonitrile, naphthacene, phlhalonitrile, perylene, fluoranthene, 9,10-diphenylanthracene). The dotted lines are the theoretical limiting behaviours corresponding to the concerted (right) and stepwise (left) pathways. (Adapted from Severin et al 1988.)...

Nucleophile substitution of the T1 resin synthesis of phenols, biaryls, alkyl arenes, azides, aromatic hydrazines, halides, ester, azo compounds cinnolines, benzotriazoles [129-137, 140, 141]... 

Dibenzo[f,. ]cinnolines 259 have been obtained from 2-naphthylanilines 258 via diazotization followed by intramolecular electrophilic aromatic substitution (Equation 65) <2003BMC1475>. 

Thus, while the 3-hydroxyisoquinoline-3-isoquinolinone equilibrium (80 81) and that of the cinnoline derivatives (82 83) favour the keto forms (81, 83), the proportion of hydroxy tautomers is considerably greater than in the corresponding unfused systems. The benzo-fusion in 2- and 4-quinolinone and in 1-isoquinolinone has the effect of reducing the aromaticity of the heterocyclic ring, and consequently of lowering the proportion of the hydroxy tautomers. 

Although no new method for formation of simple pyridazino[3,4-f]pyridazines has appeared since the publication of CHEC-II(1996), a further method for the construction of benzo-fused derivatives has been described <1997CHE750>. Electrophilic attack of the diazonium salts formed from aromatic amines 5, with sodium nitrite in acetic acid, upon the neighboring methoxyarene results in formation of pyridazino[3,4-f]cinnolines 1. 

In the aromatic series, 2,2 -dinitrobiphenyl has been reduced with zinc and potassium hydroxide [88] or with sodium sulfide to give low yields of benzofc]-cinnoline dioxide, an intramolecular, dimeric, nitroso compound [89, 100] (Eq. 51). 

Reduction of aromatic nitro compounds,2 Aromatic compounds arc reduced to anilines in 90 95% yield by TiCl, (8 equivalents) and HOAc-H20 (1 1, v/v) at room temperature (7 minutes). Nitro derivatives of quinoline, isoquinolinc, and cinnoline are reduced under the same conditions. 

It was previously mentioned1 that cinnoline and 3-substituted cinnolines (94) could be prepared from the condensation products (95) between an o-nitrobenzaldehyde and a nitroalkane by electrochemical reduction. The reaction has been further studied,138 and it was noticed that when the reduction was carried out stepwise, anthranils (96) were formed, especially at elevated temperatures. The final ring closure was catalyzed by traces of oxygen, whereas too much oxygen produced the cinnoline JV-oxide (97) the ring closure was believed to be a radical chain reaction where the formation of the aromatic cinnoline was part of the driving force [Eq. (76)]. 

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

Although coupling of aryl diazonium salts at the -position of dienamines yields indazoles on acid-catalysed cyclization, the presence of an electron-donor substituent may render the aromatic ring sufficiently nucleophilic to cyclize onto the iminium group to give cinnolines or 6,7-diazasteroids2,67 (Scheme 40). 

The most widely used method for forming the benzo[c]cinnoline nucleus has been the reduction of 2,2 -dinitrobiphenyl (3) and its derivatives under alkaline conditions, analogous to the bimolecular reduction of nitroarenes. As in the latter reaction, the end product is a hydrazo compound (Scheme 1), in this case the cyclic 5,6-dihydrobenzo[c]cinnoline (6), but this is so easily oxidized back to the fully aromatic 1 that it is not isolated unless special precautions are taken (Section IV,D). Tauber originally employed 3% sodium amalgam in methanol or zinc and alkali to reduce 2,2 -dinitro-biphenyl, and these reagents have been used subsequently by other work-ers. ° Reductions using sodium sulfide or hydrosulfide and catalyst/hydrogen or catalyst/hydrazine systems have been used... 

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