An investigation of the chemistry of cinnolines

• Main Author: Atkinson, Charles W.
• Published: Durham University 1948
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.585578

Earlier work which has resulted in the synthesis of cinnolines is reviewed. The strictly historical approach has been modified to accommodate a classification based upon the type of cinnoline involved. Preparative routes to 4-chloro-2-amlnoacetophenone are described. Reaction between the acid chloride of 4-chloro-2- phthallmldobenzoic acid and diethyl sodiomalonate followed by hydrolysis gives the pure amine via the acetamido-compound. A second route which utilises 4-chloro-2-nitrobenzovl chloride and ethyl sodioacetoacetate leads to 4-chloro-2-nitroaceto-phenone and thence to the amine, Diazotisation of 4rohloro-2-aminoacetophenone and subsequent ring closure produces 7-chloro-U-hydroxycinnoline.Nitration of 4-Ghloro-2-acetamidoacetophenone has given the 5-nitro-derivatlve with some of the 3-nitro-isomer. Hydrolysis to the corresponding nitro-amines and diazotisation of these in sulphuric acid yields 6-nitro-7-chloro- and 8-nitro-7-chloro-U-hydroxycinnoline. In hydrochloric acid, however, the corresponding dichloro-4-hydroxycinnolines are formed, the replacement (nitro →chloro) taking place before cyclisation to the cinnoline. Attempts to prepare 4-chloro-2-aminopropiophenone are described, and work on the projected synthesis of 7-methoxy-4-hydroxyclnnoline is reported. Widman's synthesis of 7-methylcinnoline-7-carboxylic acid has been repeated; in general, the original results are confirmed but the acid is best purified via the ethyl ester. 4-Methylcinnoline and the 6- and 7-chloro-compounds have been prepared by ring closure of the diazotised o-isopropenylanilines; these are formed by dehydration of the corresponding carbinols which arise from the o-amino-acetophenones or methyl anthranilates by a Grignard reaction. The 4-methylcinnolines are characterised by their green picrates and red ethiodldes. The application of a wide variety of reactions to estimate the reactivity of the methyl group in 4-methyl-cinnoline has had little success. Confirmation of enhanced reactivity and hence of the postulate that is N(_1) the basic centre of the molecule is provided by the formation of 4-p-dimethylaminostyryl-l-ethylcinnollnlum iodides. Reduction of a number of cinnolines with sodium and alcohol has been carried out. Qualitative examination has shown partial conversion to the corresponding indoles of 4-(4'-hydroxyphenyl)oinnoline, the 3-methyl compound and of 3-methyl-4-P-anisylclnnollne; 3-phenyl-4-p-anisylcinnoline and the deraethylated compound are virtually unchanged. 4-Methylclnnoline and its 6- and 7-chloro-derivatives all give 3-niethylindole as the final-product but data on the intermediate stages is incomplete. Estimation of the ammonia liberated in each case confirms the above findings. Attempts to repeat Stolle and Becker's synthesis of 3-phenylcinnoline-4-carboxylio acid are reported.