1.2- Benzodiazine

Alternate Names benzopyridazine benzodiazine cinnoline 4(l//)-cinnoline cinnaline. 

Solubility soluble in benzene, chloroform, dimethylformamide, and toluene. 

Purification preparative TEC (1 1 4 CH2Cl2/EtOAc/hexanes) cinnoline (Rf = 0.10-0.20).2 

Handling, Storage, and Precautions avoid contact with skin and eyes. Provide appropriate exhaust ventilation at places where dust is formed. Keep container tightly closed in a dry and well-ventilated place. 

C-3 Substitution. Recently, a new method to promote the regioselective C-3 functionalization of 1,2-benzodiazine was developed using TMP-magnesium-based metalation (TMP = tetramethylpiperidine) that also employs a stoichiometric quantity of BF3-OEt2 (eq 1). Subsequent Pd-catalyzed crosscoupling occurs in moderate yields with bromo- or iodoarenes. 

Cinnoline 1 (benzo[c]pyridazine), phthalazine 2 (benzo[ /]pyridazin), quinazoline 3 (benzo[ i]-pyrimidine) and quinoxaline 4 (benzopyrazine) are benzene-fused diazines. Of the dibenzo-annulated systems, only phenazine 5 (dibenzopyrazine) will be discussed. 

The spectroscopic features of the benzodiazines resemble those of the parent diazines, quinoline and isoquinoline. This is evident from the UV and NMR data  

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols  

The C-4 reactivity of quinazoline, which is responsible for the anomalous basicity (see p 434), applies to other nucleophiles, e.g. the addition of Grignard compounds, enolates, cyanide or hydrogensulfite  

Side-chain reactivity is also observed in benzodiazines. For instance, 4-substituents in quinazolines react selectively, as is shown by the Mannich reaction of 2,4-dimethylquinazoline  

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When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Benzodiazines bind to GABAa receptors, and they have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties. They increase stage 2 sleep and decrease REM and delta sleep. 

These compounds have also been called pyridopyridines and benzodiazines. The early literature describes 1,5-naphthyridine as isonaphthyridine and the 1,6-isomer as 2,6-naphthyridine. Prior to 1950, the 2,7-naphthyridines were referred to as derivatives of copyrine. Fortunately, the nomenclature has now been standardized and much of the confusion has been eliminated. 

The six possible pyridopyridine systems have been known almost universally since circa 1930 as 1,5- (1), 1,6- (2), 1,7- (3), 1,8- (4), 2,6- (5), and 2,7-naphthyridine (6), However, the occasional use of an appropriate pyridopyridine or diazanaphthalene may still be found in some publications, Historically, the word naphthyridin(e) was coined by Arnold Reissert in 1893 specifically for the 1,8-naphthyridine system (4) and was so used for some years, especially in the German literature. Other terms, such as isonaphthyridine [for 1,5-naphthyridine (1)], benzodiazines (very misleading), pyridinopyridines , 2,5-naphthyridine [for 1,6-naphthyridine (2)], and copyrin(e) 13,40 or copurine39 [for 2,7-naphthyridine (6)] have appeared in the literature. 

For pyridine, monocyclic diazines and benzodiazines a good linear relationship has been demonstrated between experimental pK values and ab initio calculated HOMO energies, suggesting that the basicities of azines may be directly interpreted in terms of HOMO energies <1995JMT(339)255>. 

Muniz-Miranda M, Neto N, Sbrana G (2003) SERS intensities of benzodiazines adsorbed on silver nanoparticles. J Mol Struct 651-653 85-90... 

Fig. 20.3 SERS excitation profiles of benzodiazines, compared with the extinction spectra of ligand/Ag colloids...

Mongin, F., Queguiner, G. Advances in the directed metallation of azines and diazines (pyridines, pyrimidines, pyrazines, pyridazines, quinolines, benzodiazines and carbolines). Part 1 Metallation of pyridines, quinolines and carbolines. Tetrahedron 2001, 57,4059-4090. 

The pyridopyridines, also called benzodiazines, and more commonly naphthyridines, consist of a group of diazanaphthalenes with one nitrogen in each ring and none at the bridgehead position. From the six possible isomers, one example of each of the series 1-X and 2-X, and the numbering scheme, are represented in (1) and (2). 

Several general reports covered more than one type of diazine. For example, Cu(II) complexes of a diverse set of alkoxy diazine ligands were prepared, and their magnetic properties investigated. X-ray crystal structure determinations of many of these were included <04IC4278>. New sulfinylcinnolines, quinoxalines, quinazolines, and phthalazines were prepared from appropriate halobenzodiazines. These were converted to sulfanyl benzodiazines, which in turn... 

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