Cinnolines nucleophilic substitution

The activation in cinnolines is sufficient to enable nucleophilic substitution of poor leaving groups such as amino and phenoxy... 

The effect of the leaving group and of other substituents on nucleophilic substitution of cinnolines is discussed in Sections II, D and II, E, respectively. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

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]... 

In CHEC-II(1996) only one example of N-alkylation of a cinnolin-4(l//)-one is given <1996CHEC-II(6)1>. Nowadays, N-alkylation of pyridazinones is a quite general reaction. In most cases alkylations are achieved by a nucleophilic substitution reaction of the deprotonated azinone on alkyl halides and exceptionally also on aryl halides. Reagents other than halides are also used. 

The only recorded nucleophilic substitutions of benzo[c]cinnoline are with lithium dialkylamides. The reaction with lithium dimethylamide in dimethylamine gives 4-dimethylaminobenzo[c]cinnoline, further at-... 

There are a number of important reactions in this category and all of them involve at least one heteroatom functioning as a nucleophile and another as an electrophile. Diazo-tization of a variety of ortho-substituted anilines for instance, followed by intramolecular nucleophilic trapping of the corresponding diazonium salts by either nitrogen or carbon nucleophiles, is the basis of a series of very important syntheses of 1,2,3-benzotriazine and cinnoline derivatives, and this general approach has been widely exploited for the preparation of polycyclic systems. Representative examples are given in equations (51)—(54). 

The reduction of compounds suitably substituted with reducible functional groups can be advantageously used for the preparation of heterocyclic ring systems 15 5 The guiding principle here is to form a nucleophilic center in the molecule by cathodic reduction of a functional group and then have this to react with an electrophilic center (which may also be formed in an electrochemical process or be present in the starting material) suitably positioned for ring closure. Thus, 2,2-dinitrobiphenyl can be reduced to benzo[c] cinnoline in acid solution ... 

Particularly useful is a synthetic approach utilizing the diazotization of 0-alkynylanilines 222 followed by cyclization of intermediate diazonium salts 223 (the Richter method) (Scheme 128) . In this reaction a nucleophile attacks the C(l) of the alkyne moiety in the diazonium intermediate 223, allowing substitution in the C(4) position of the cinnoline 224. Classically, water was used as the attacking species in the Richter reaction but more recently chloride and bromide nucleophiles have been successfully utilized <1995LA775, 2004T7983>. 

Cyclopropanation of steroids (363) at the 1,2-position with malonate in the presence of potassium t-butoxide and tetramethylguanidine takes place with formation of the di(alkoxycarbonyl)cyclopropane derivatives (364) accompanied by steroidal cyano-alkoxycarbonylcyclopropanes (365). When the reaction is carried without tetramethylguanidine only minor amounts of cyclopropyl steroids are isolated The formation of the cyano compound is explained by an initial nucleophilic displacement of bromine by the tetramethylguanidine moiety, followed by several steps (equation 119). Although the reaction of equation 120 cannot be classified as a MIRC reaction sensu strictu the formation of cyclopropa[c]cinnolines (367) via an intramolecular 1,1-cycloaddition of nitrilimines is mentioned here. Treatment of o-vinylphenyl-substituted chloroglyoxylate... 

Benzo[c]cinnoline is a weak base with a of 2.2 in water and 1.6 in 50% aqueous ethanol.Cryoscopic measurements show that it is dipro-tonated to some extent in 100% sulfuric acid. Well-defined quaternary salts result from heating benzo[c]cinnoline with alkyl halides and sul-fates. These are reported to decompose on treatment with ammonia, regenerating benzo[c]cinnoline, but apparently nucleophilic displacements of halogen by amines have been carried out on certain highly substituted examples in the synthesis of cationic dyestuffs. Quaternizations of benzo[c]cinnoline with a,a)-dibromo-propane and -butane are accompanied by hydrogen bromide elimination to give the cyclic iminium salts 40 and 41. When 40 is dehydrogenated, or merely refluxed in ethanol. 

The reactivity of pyridazines, cinnolines, and phthalazines toward substitution and coupling reactions was investigated in 2013. The Giomi group examined nucleophilic aromatic substitutions on 4,5-dicyanopyridazine... 

Concept II (Scheme 45) represents a straightforward synthesis of benzoan-nelated heterocycles (e.g. cinnolines, benzotriazoles, etc.) via a diazonium intermediate and a nucleophilic orfho-substituent. While the diazonium group is lost as dinitrogen upon cleavage from the resin, a suitable nucleophilic ortho-substituent favors cyclization to give heterocycHc structures 319. Benzotriazoles, for example, are accessible from o-aminoaryl-substituted triazenes after a two-step reaction sequence a nucleophilic displacement followed by cleavage/heterocyclization [239 ]. 

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