Cinnoline ketones

CINNOLINES AND QUINOXALINES Replacement of a methine in oxolinic acid (46) by nitrogen is apparently consistent with retention of antibacterial activity. One approach begins with reduction of nitroacetophenone 144 to afford the corresponding aminoketone (145). Treatment of this intermediate with nitrous acid leads to the diazonium salt the diazonium group condenses with the ketone methylene group (as its enol form) to lead to the cyclized product, cinnoline 147. Bromination proceeds at the position adjacent the enol grouping (148) ... 

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. 

A new, efficient and general synthesis of 4-amino-3-arylcinnolines has been described recently, starting from arylhydrazines and aryl trifluoromethyl ketones, and the following is a typical example. Addition of a THF solution of the hydrazone formed from phenylhydrazine and 2-trifluoroacetylthiophene to 5 equivalents of KHMDS in THF at -78°C, then slow warming of the mixture to room temperature and stirring at room temperature for several hours, gave 4-amino-3-(2-thienyl)cinnoline in 68% yield after work-up (quench with ether, then a wash with brine). 

Benzo[c]cinnolinium acylimides reacted with 2,3-diphenylcyclopropenone to give ben-zo[c]cinnoline 22 and the oxazinones 21. With excess of the ketone, benzo[c]cinnoline 22 reacted... 

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 practice, the azide decompositions are usually carried out in boiling toluene or xylene and give good yields of 3-alkyl-170,184,187 and 3-aryl-anthranils.185,188 Yields of 3-unsubstituted anthranils from o-azidoben-zaldehydes are generally much lower.170 The method has also been used to prepare 3-(j3-styryl)anthranils (106) from o-azidochalcones,189 3-methyl-naphtho[2,3-c]isoxazoles from 3-acetyl-2-azidonaphthalene,190 and 3-(2-pyridyl)anthranils from o-azidophenyl pyridyl ketones.191 This last reaction is of interest in that 2-(2-azido-3,5-dibromobenzoyl)pyridine in boiling toluene yields almost equal amounts of 5,7-dibromo-3-(2-pyridyl)anthranil (43%) and the zwitterionic pyrido[l,2-f>] cinnolin-6-ium 139 (41%). 

Cinnolines are prepared by an intramolecular cyclization of o-alkenyl or o-alkynyl aryldiazonium salts. For instance, (o-aminophenyl)alkynes 6 or alkyl(o-aminophenyl)ketones 8 (via the enol form) yield 4-hydroxycinnolines 7 (the v. Richter and Borsche syntheses, respectively), o-Aminostyrenes 10 afford 3,4-disubstituted cinnolines 11 (Widman-Stoermer synthesis) ... 

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. 

Cinnoline Aldehydes and Ketones conditions for controlled hydrolysis of the cyano group ]... 

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. ... 

The Borsche (or Borsche-Herbert) cinnoline synthesis constitutes the cyclization of an ort/zo-diazonium aryl ketone to form a 4-cinnolone, or 4-hydroxycinnoline. It is mechanistically related to the Widman-Stoermer and Richter cinnoline syntheses, which involve the cyclization of ortho-diazonium aryl olefins and ortho-diazomnm aryl alkynes, respectively. 

---