4- cinnoline acylation

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. 

Unsubstituted 7-oxo-l,2,3,7-tetrahydropyrido[3,2,l-i ]cinnoline-8-carboxylates were A-alkylated with dialkyl sulfates, and they were also A-acylated with acetic anhydride in acetic acid to give the 1-substituted derivatives (92EUP470578). The 1-hydroxymethyl derivatives were prepared from the 1-unsubstituted compound with formalin in acetic acid. 

Alkylation of ll-mercaptopyrido[l,2-h]cinnolin-6-ium hydroxide inner salts (e.g., 41) with ethyl bromoacetate gave ll-(ethoxycarbonylmethyl(thio derivatives 64 (R = H), which could be hydrolyzed to the ll-(carboxy-methyl)thio derivative or back to the starting compound 41 (74JHC125). Hydrolysis of the ll-bis(methoxycarbonyl)methylene 66 (R = H), and 2-cyano derivatives of 17 (R = H) in boiling HCl afforded 11-methyl and 2-carboxylic acid derivatives, respectively (74JHC125). The 2-nitro derivative of 17 (R = H) was reduced to the 2-amino derivative over Pd/C with NaBH4 in aqueous methanol, and the 2-amino group was acylated with acetic anhydride at 100°C. 

An unexpected reaction which leads to pyrrolo[3,4-c]pyridazines is the action of acid on the 3-diazopyrrole (106), obtained from the corresponding amine. Although pyrrolocinnolines were the target compounds, the pyrrolopyridazine (107) was obtained (60%) (Equation (32)) <84H(22)2269>. However, the cinnoline product is obtained when the carbethoxy group is present instead of the acyl group at position 4 <83H(20)255>. 

Alkenyl-, 0-alkynyl-, and 0-acyl-diazonium ions cyclize spontaneously to give cinnolines 220 or cinnolones 221 (Scheme 127) . 

The monoaminobenzo[c]cinnolines form intensely colored solutions in mineral acids (for discussion, see Lewis and Reiss ). In their reactions, acylation, diazotization, etc., they behave as typical aromatic amines. 

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. 

C, h > 50%) and thence l,2-bis(chloroacetyl)-6,7-dimethyl-2,3-dihydro-4(l/f)-cinnolinone (54) (CICH2COCI, EtaN, see original for details) 2,3-dihydro-4(177)-cinnolinone (52, R = H) with 3-chloropropionyl chloride gave 2,3,5,6-tetrahydro-17/-pyrazolo[l,2-fl]cinnoline-3,6-dione (55) as the final product (PhH, reflux, 10 h 54%) " also another A -acylation. ... 

This chapter deals with nuclear and extranuclear cinnolinecarboxylic acids and the corresponding carboxylic esters, acyl halides, carboxamides, carbohydrazides, carbonitriles, and carbaldehydes, and the ketonic acylketones. To avoid repetition, the interconversion of these cinnoline derivatives are discussed only at the first opportunity for example, the esterification of cinnolinecarboxylic acids is covered as a reaction of cinnolinecarboxylic acids rather than as a preparative route to carboxylic esters, simply because the section on acids precedes that on esters. To avoid any confusion, appropriate cross-references have been included. 

Note-. These acylcinnolines have been made by primary synthesis (see Chapter 1), Reissert-type addition to cinnoline (Section 2.1.3), oxidation of alkylcin-nolines (Section 2.2.2), displacement of halogeno substituents (Section 3.2), hydrolysis of dihalogenomethylcinnolines (Section 3.2), N-acylation of tautomeric cinnolinones (Section 4.1.2.2), oxidation of extranuclear hydro-xycinnolines (Section 4.2), or as illustrated here. 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

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