Synthesis of Cinnolines

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). ... 

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>. 

WIDMAN-STOERMER SYNTHESIS. The synthesis of cinnolines by cyclization of diazotized o-aminoarylethylenes at room temperature. 

Preparations of cinnolines by expansion of five-membered heterocycle rings include the oxidation of A-aminooxindoles 232 (Scheme 132) <1988JHC847>, the treatment of isatogens 233 with ammonia (Scheme 133), and the base-catalyzed conversion of 1-aminodioxindoles 234 into cinnolin-3-ones 235 (Scheme 134) <1960JA4634>. Additional examples of the synthesis of cinnolines by transformation of another ring are available in CHEC-III . 

In a cyclization reaction similar to the Widman- Stoermer synthesis of cinnolines (see Houben-Weyl, Vol. E9a, p 691), the diazotization of 2-(l-methylvinyl)pyridin-3-aminc in dilute hydrochloric acid gives 4-methylpyrido[3,2-c]pyridazine (3) in low yield.104... 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

This approach was described in CHEC-I as of importance only for the synthesis of cinnolines <84CHEC-i(3B)i>. Most of the examples given involve the insertion of nitrogen as the sixth atom by diazotization of o-aminophenyl derivatives, in which the ortho substituent is generally an alkene, alkyne, or enolisable ketone. Another example is the synthesis of 3-substituted-4(l//)-cinnolinones via diazotisation of o-aminophenylalkynes (Scheme 90) the precursor is readily made by palladium and copper iodide catalysis <89H(29)1255>. 

In a novel approach to the synthesis of cinnolines, iron cyclopentadienyl complexes of 3-(2-chlorophenyl)propanones are cyclized with hydrazine and the 1,4-dihydrocinnoline complexes demetalated with sodium amide to give 3- or 3,4-disusbstituted cinnolines (Scheme 99). Yields of both steps are 70--80% and the cinnoline 4-substituent can be varied by alkylation of the intermediate... 

This reaction provides a general synthesis of cinnoline derivatives. 

Walther Borsche and Alfred Herbert first reported the spontaneous cyclization of an ort/io-diazonium acetophenone in 1941, as part of a larger study on the synthetic transformations of 2-bromo-5-nitroacetophenone carried out at the University of Frankfurt am Main. The authors did not draw especial attention to this observation, and it was not until four years later that Schofield and Simpson suggested that this reaction might offer a general route to 4-cinnolones. After 70 years, this general reaction yielding 4-cinnolones remains one of the most useful methods for the synthesis of cinnolines. 

Topoisomerase-targeting agent Scheme 3.58 Copper-catalyzed synthesis of cinnolines. 

Scheme 5-124. Palladium-catalyzed alkynylation reaction on triazenes synthesis of cinnolines.

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