Azinones

The azinones and their reaction characteristics are discussed in some detail in Section II, E. Because of their dual electrophilic-nucleophilic nature, the azinones may be bifunctional catalysts in their own formation (cf. discussion of autocatalysis below) or act as catalysts for the desired reaction from which they arise as byproducts. The uniquely effective catalysis of nucleophilic substitution of azines has been noted for 2-pyridone. 

A bifunctional autocatalytic effect of azinones in general is possible in certain nucleophilic reactions such as amination. Zollinger has found that 2-pyridone is the best catalyst for anilino-dechlorination of various chloroazines. It seems likely that examples of autocatalysis will be found when the substrate contains an azinone moiety. The azinone hy-products of displacement reactions may also function in this way as catalysts for the main reaction. 

Compound 961 has been converted into 3-amino-6-azido-5(2//)[ 1,2,4]tri-azinone 1041, which was employed in a study of azide-tetrazole equilibrium affording 6-amino-8(5//)tetrazolo[5,1-/][1,2,4]triazinone 1042 (79JHC555) (Scheme 196). 

Nitrotoluene is degraded by a strain of Mycobacterium sp. via the corresponding 4-amino-3-hydroxytoluene (Spiess et al. 1998) this is dimerized abiotically to form a dihydrophenox-azinone, and after extradiol cleavage to 5-methylpyridine -2-carboxylate (Figure 2.2d). 

In Scheme 12 several ring openings are summarized that proceed via solvolysis or nucleophilic attack at the six-membered moiety. These reactions take place under relatively smooth conditions in the case of azoloazinium salts or the electron-deficient azinones, but neutral bicyclic heterocycles can also react with strong nucleophiles. 

It has been reported that alkylation of 2-pyridone and 2-quinolone and other related potentially tautomeric azinones under solid-liquid phase-transfer catalytic conditions generally produces the A-alkylated derivatives exclusively in 65-90% yield [58], although it has been suggested that the yield of the O-alkylated derivative can be increased by the use of long-chain quaternary ammonium salts and when bulky alkylating agents are used [69]. 

Ethyl 4,5-difluoro-7-oxo-2,3-dihydro-7//-pyrido[3,2,l-i)][2,l]benzox-azinone-6-carboxylate (98) was formed when ethyl 6,7-fluoro-4-hydroxy-8-(2-hydroxyethyl)quinoline-3-carboxylate (97) was treated with m-chloro-peroxybenzoic acid in chloroform [92JAP(K)92/208287, 92JAP(K)92/ 210656],... 

Fig. 9 X-ray structure of bicyclic piperazinone inhibitor with thrombin (PDB ID 1G37). Piper-azinone inhibitor is shown as yellow sticks, and the receptor binding site is shown as transparent surface. The extensive hydrogen bonding network with receptor and water is shown as yellow dots...

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. 

Aryl halides bearing strong electron-withdrawing groups and thus allowing nucleophilic aromatic substitution can be used for the arylation of azinone anions. 4-(4-Hydroxy-3-methylphenyl)phthalazin-l(2//)-one has been arylated simultaneously at N-2 and at the phenolic OH with 4-chlorobenzonitrile and potassium carbonate in dimethyl-acetamide (DMA) <2005CHJ200>. 

Acylations of anions formed by deprotonation of azinones are not described in previous editions <1984CHEG(2)1, 1996CHEC-II(6)1>. 4,5-Dichloropyridazin-3(2//)-one is smoothly acylated at N-2 with acyl chlorides in the presence of triethylamine in dichloromethane at room temperature, —10 or —22°C <2002S733>. The resulting compounds have been used as mild acylating reagents for amines (see Section 8.01.8.4). 

In this section several azinone derivatizing reactions are collected which do not occur at an anion formed by initial deprotonation of the azinone, because they occur in neutral medium, acidic medium, or via metal-mediated processes. 

Azinones are readily converted into the corresponding chloroazines on treatment with reagents such as phosphorus oxychloride or thionyl chloride (equation 96), via reaction of the carbonyl oxygen atom at the electrophilic phosphorus atom. This method can be used to introduce several chlorine atoms into polyaza heterocycles in a single operation, and the... 

Methyl-2-phenylindolizine reacts with ethoxalyl chloride to give the 1,3-diethoxalyl derivative (17). Heating in ethanolic sodium ethoxide converts 17 partly into cycl[3,2,2]azine (lu) and partly into the salt of a hydroxycycl[3,3,2]azinone (45a) (Section IV).16... 

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