Diazine ring

Isolated and benzo-fused diazine rings are key structural elements in many natural and synthetic compounds of current interest. This contribution relates highlights from many of the studies on the diazines pyridazine, pyrimidine, pyrazine, and their benzo-fused derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine published in English in the journal literature during 1996, as covered by Chem. Abstr. through volume 126, issue 5. 

Dipyrrolo[l,2- 2, l - ]pyrazines, for example, 47, and related dipyrrolopyrimidines can be partially reduced in the central diazine ring under Birch reduction conditions to give the corresponding dihydro derivative 48 (Equation 5) <2005JOC2054>. 

Qu6guiner and co-workers found that some diazinylazides suitable for formation of fused tetrazoles can be obtained via metallation of the diazine ring as shown in Scheme 19 <1996S838>. 

Diazines are generally resistant to electrophilic attack on carbon, and, as for pyridine, addition on nitrogen is observed. Alkyl halides give mono-quaternary salts di-quatemary salts are not formed under normal conditions. Of conrse, if the diazine ring carries a snbstitnent that makes the starting... 

Antwerp (2004), and Strasbourg (2006) in the covered period of this chapter. Certainly there has been a lot of activity in the pyridazine and benzo derivative field in the 1996-2006 period. A search on the Web of Science revealed 1756 articles for the topic pyridazin , 574 for phthalazin and 168 for cinnolin . The same search on the Scifinder database revealed 5203, 1943 and 462 hits for the concepts pyridazin , phthalazin , and cinnolin , respectively. Patents have only been taken into account in Section 8.01.12. In this chapter emphasis has been put on new and adapted older methods, as well as new interesting examples of well established methods. Selections necessarily had to be made due to the large amount of material published within the considered timeframe. Fully conjugated pyridazines, phthalazines and cinnolines as well as (partly) reduced and oxo forms (both only in the 1,2-diazine ring) are covered in this work. 

Pyrrolo[2, l-b]quinazolines (49) were obtained through the formation of their diazine ring by condensation of an anthranilic acid derivative with a pyrrole derivative such as O-alkylbutyrolactimes (48) [60GEPI088968 ... 

Indolo[ 1,2-a]quinazoline s (67) were prepared through the formation of their diazine rings, by cyclizing 2-acylamino-l-phenyl-indoles (66) with phosphoryl chloride (81KGS844). 

Laser irradiation of isatin (70) gave 71 as a result of bimolecular condensation (78TL3007). The diazine ring of 73 was formed during the cyclocondensation of anthranilic acids with the imidate esters derived from indolinone (72) (81AP271). 

Consecutive formation of the two diazine rings was the approach for synthesizing the pyrazino[2,l-6]-quinazo ine (567) from methyl anthrani-late and the protected glycylglycine dipeptide (565), according to the indicated sequence of reactions (80MI4). 

One of the most common and versatile methods for the S3mthesis of polyfunctional pyridazines consists in the formation of the diazine ring from maleic anhydride or its mono- and disubstituted analogs and an unsubstituted, mono-, or disubstituted hydrazine. Pyridazinones of the types 21 and 22 are obtained in good yields. 

Patsenker, L. D. Theoretical study of the pathway for diazine ring formation in a series of 4-dimethylaminonaphthalic acid derivatives under Viismeier-Haack reaction conditions. Theoretical and Experimental Chemistry (Translation of Teoreticheskaya i EksperimentaTnaya Khimiya) 2001, 36, 183-186. 

FIGURE 19.3 In a rather complex molecule, the simple shift of a nitrogen atom to another position of the diazine ring atom abohshes almost completely the affinity for the CRF receptor. 

Heating an -pyridazinyUhiosemicarbazide with two molar equivalents of diethyl azodicarboxylate (DEAD) leads to the fonnation of a new fused thia-diazine ring in good yield. 

Most of the synthetic methods for pyridopyridazine derivatives are modifications of the general preparative methods of phthalazine chemistry (see Vol. E 9a, p 744) and involve the elaboration of the diazine moiety on a pyridine ring. The alternative route which requires the formation of a pyrido ring on a diazine ring is, in most cases, less attractive. 

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 ... 

Reaction of thieno[3,4- ] compound 79 (X = Z = CH, Y = S) with acetic acid and polyphosphoric acid resulted in two products the C-3-methylated 477-benzo-l-thia-2,4-diazine 1,1-dioxide 97 (21% yield) and the thienopyridone 98 (33% yield). The latter is considered to be formed by initial acylation at N-4 of the benzo-l-thia-2,4-diazine ring followed by ring cleavage and intramolecular aldol cyclization (Equation 7) <2004JHC45>. 

Allowing amidoxime 167 to stir in CHCI3 at room temperature for 2-3 days results in complete conversion to the l-oxa-2,4-diazinone 131, which is also formed when 167 is refluxed in the same solvent for 6h (Equation 29) <2004TL8913>. Opening of the l-oxa-2,4-diazine ring of 131 with amino acids is considered in Section 9.05.7.5. 

Review of Sections 9.06.9 and 9.06.10 reveals that each of the l-oxa-2,5-diazine and l-thia-2,5-diazine ring systems covered in this chapter is unique with respect to degree of unsaturation, oxidation or substitution and synthetic approach, except for 677-l-oxa-2,5-diazines such as 9 (see Scheme 3) and 41 (see Figure 5). 

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