Of cinnoline

Comparison of the behaviour of cinnoline 2-oxide (vi, i = O) with that of 2-methoxycinnolinium (vi, R = OMe) suggests that at high acidities the former is nitrated as its conjugate acid (vi, R = OH), but that as the acidity is lowered the free base becomes active. At high acidities 5- and 8-nitration are dominant, but as the acidity is lowered 6-nitration becomes increasingly important. The 5- and 8-nitro compounds are probably formed mainly or wholly by nitration of the conjugate acid, and the 6-nitro compound wholly or mainly from the free base. ... 

The NMR spectra of cinnoline and its derivatives are complex. The unequivocal assignments are based on the complete iterative analysis of the spectra of a large number... 

Cinnolin-3(2//)-one (7) is methylated with diazomethane or methyl sulfate to give 2-methylcinnolin-3(2H)-one. In a similar manner, benzylation with benzyl chloride, cyanoethylation with acrylonitrile in the presence of benzyltrimethylammonium hydroxide and glucosidation with tetra-O-acetyl-a-o-glucopyranosyl bromide in the presence of a base affords the corresponding 2-substituted cinnolin-3(2//)-ones. However, glucosidation of the silver salt of cinnolin-3(2//)-one produces the corresponding O-substituted compound. 

Alkylations of cinnolin-4(lf/)-one (8) with methyl iodide, ethyl iodide, dimethyl and diethyl sulfates, isopropyl bromide, benzyl chloride, etc. take place predominantly at position 2 to give 2-alkyl-4-hydroxycinnolinium anhydro salts (83), together with small amounts of l-methylcinnolin-4-one (84). 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

IV-Oxidation of cinnoline (2) with hydrogen peroxide in acetic acid results in the formation of four products cinnoline 1-oxide (92 26%), cinnoline 2-oxide (93 50%), cinnoline... 

MO calculations of the cinnoline ring system show that the relative order of reactivities for electrophilic substitution is 5=8>6 = 7>3 4. This is confirmed experimentally, as nitration of cinnoline with a mixture of nitric and sulfuric acids affords 5-nitrocinnoline (33%) and 8-nitrocinnoline (28%). Similarly, 4-methylcinnoline gives a mixture of 4-methyl-8-nitrocinnoline (28%) and 4-methyl-5-nitrocinnoline (13%). 

Nitration of cinnolin-4(lFf)-one yields a mixture of the 3-nitro (0.9%), 5-nitro (0.38%), 6-nitro (58.4%), 7-nitro (0.36%) and 8-nitro (39.9%) derivatives. The 3-nitro isomer is postulated to result from nitration of the free base, while the other mononitro isomers are formed from the protonated molecule. 

Nitration of cinnoline 2-oxide takes a different course. With nitric and sulfuric acids or with potassium nitrate and sulfuric acid a mixture of 8-nitrocinnoline 2-oxide, 6-nitrocinno-line 2-oxide and 5-nitrocinnoline 2-oxide is obtained, while with benzoyl nitrate in chloroform only a low yield (1.5%) of the 5-nitro derivative is obtained. 

The reaction of cinnoline 2-oxide with phenylmagnesium bromide gives phenanthrene, trans- and cfs-stilbene, 2,3-diphenyl-l,2-dihydrocinnoline and 2-styrylazobenzene in yields of 1-15%. Analogous results are also obtained from 4-methylcinnoline 2-oxide. 

This type of cyclization is important only for the formation of cinnolines. In all cases, the starting compounds have an ortho amino group, which upon diazotization undergoes ring closure with the other functionality, most frequently with a multiple bond. 

The photodecomposition of benzotriazine A/ -oxides produced 3-substituted 2,1-benzisoxazoles (Scheme 183) (73JA2390). The photolysis of cinnoline 1-oxides produced 3-methyl-2,1-benzisoxazoles (Scheme 183) (74TL2643, 74T2645). 

RICHTER - WIDMAN STOERMER Cinnoline Synthesis Synthesis of cinnolines from substituted anilines via diazonium salts. 

The first synthesis of cinnoline was reported by von Richter in 1883. The diazonium chloride 5 which was obtained from o-aminophenylpropiolic acid (4), was heated in water at 70°C to provide the 4-hydroxycinnoline-3-carboxylic acid (6). When this acid 6 was heated above its melting point, carbon dioxide was liberated and 4-hydroxycinnoline (7) was obtained. Distillation of 4-hydroxycinnoline (7) with zinc dust furnished a small amount of oil, which was assumed to be cinnoline (8). The preparation of 4-hydroxycinnoline (7) was repeated by Busch and Klett, although in lower yield when compared to the original report. Busch and Rast later converted the 4-hydroxycinnoline (7) successfully to cinnoline (8) via the 4-chlorocinnoline (9). ... 

Only a limited number of cinnoline derivatives have been prepared via the von Richter cinnoline synthesis. ... 

Amino-pyrazines and -pyridazines have been shown to exist predominantly in the amino form by infrared spectroscopic studies (cf. Table VI). Ultraviolet spectral data have been interpreted to indicate that 4-aminocinnoline exists predominantly in the imino form 256, but this conclusion, which was based on comparison of its spectrum with those of cinnolin-4-one and 4-ethoxycinnoline, is probably incorrect. Ultraviolet spectroscopic data strongly support the predominance of amino structures for 2-aminopyrazine (257) and 2-aminoquin-oxaline how ever, the former compound was at first erroneously concluded to exist in the imino form from ultraviolet spectral evidence. Isolation of two isomers of 2-amino-8-dimethylamino-3-methylphenazine, assigned the amino and imino structures 258 and 259, respectively, has been claimed, but it is very unlikely that these assignments are correct. 

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. 

It should be emphasized, however, that classical syntheses of cinnolines by conventional methods are reported to give higher yields. For example, Jacobs and Winstein (1946) obtained 4-methylcinnoline in 90% yield by diazotization of 2-(2 -amino-phenyl)propene in 10% aqueous H2S04, storing the solution diluted ten-fold for three days, rendering alkaline with NaOH, and extracting with benzene. 

The classical literature on modifications of cinnoline syntheses was reviewed by Leonard (1945) and more recently by Wulfman (1978, p. 277) and by Saunders and Allen (1985, p. 467). The question of why cinnolines without a substituent in the 4-position were not obtained by the intramolecular C-coupling of 2-aminostyrene has, so far as we know, still not been answered. 

Reaction of cinnolin-4-amine with pivaloyl chloride yielded the expected corresponding amide as well as a disub-stituted compound resulting from the reaction of 4-pivaloylaminocinnoline with a second molecule pivaloyl chloride at N-1 <1995T13045>. Similarly, other amides have been made from 5-aminopyridazin-3(277)-ones... 

This approach is important for the synthesis of cinnolines. CHEC(1984) <1984CHEC(2)1> already covered several examples. The methodology used starts with an aniline ortho substituted with an alkene (Widman-Stoermer type), alkyne (Richter type), or enolisable ketone (Borsche type) which is diazotisized, delivering the sixth atom, allowing cyclization. CHEC-II(1996) <1996CHEC-II(6)1> gave more examples. 

Although the [5+1] strategy is generally considered to be only useful for the synthesis of cinnolines, some examples appeared for the synthesis of pyridazine derivatives. Michael addition of 2-arylhydrazono-3-oxobutanoates 260 on acrylonitrile 261 yielded pyridazin-4(l//)-ones 262 (Scheme 65) <2001SC2569>. 

Several other sequences based on the alkylation of cinnoline derivatives have been reported to furnish betaines (233). Treatment of 4-methoxy- and 4-phenoxycinnolines with methyl iodide gives 2-methylcinnolinium iodides (237 R = Me or Ph) which are converted to 2-methylcinnolinium-4-olate (243) by hot hydrobromic acid. In a closely related approach 4-amino-or 4-methylaminocinnolines have been methylated and the 2-methyl-4-aminocinnolinium salts (238 R = H or Me) subsequently hydrolyzed to the betaine (243) by hot aqueous alkali. ... 

See the Borsche Cinnoline Synthesis and the von Richter Cinnoline Synthesis for other preparations of cinnolines. 

The reductions of cinnolines and phthalazines were discussed in Part I, Section IV,B (Ring Contractions) or V,D. 1-Methylisoindole (190) has since been isolated as a hydrochloride from reduction in hydrochloric acid of 1-methylphthalazine with strict control of the potential to avoid further reduction to methylisoindoline (191). Purification requires acidic conditions the free base turned quickly to a tar299,300 [Eq. (113)]. 

Preparations of cinnolines by expansion of five-membered heterocycle rings include the oxidation of /V-aminooxindoles (241 — 242), the treatment of isatogens with ammonia (Scheme 30) and the base-catalyzed conversion of 1-aminodioxindoles (243) into cinnolin-3-ones. 

A number of cinnolines have been obtained by alkali treatment of isatins. Thus, 214 gave 215,88-70 while isatin on treatment with base followed by hydrogen and palladium, diazotization, and reduction gave 3-hydroxycinnoline.62 4... 

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