8-Chloro- and 5,8-Dichloro1-naphthoic Acids

In connection with our program directed toward the development of structure-activity relationships of cannabimimetic 1-alkyl-3-(1-naphthoyl)indoles1,2 we needed synthetically useful quantities of 8-chloro-1-naphthoic acid (1). The synthesis of acid 1 from 1,8-naphthalic anhydride (2) via anhydro-8-hydroxymercuri-1-naphthoic acid (3) and 8-chloromercuri-1-naphthoic acid (4) by treatment with the elemental halogen was described originally by Whitmore during the course of his studies on the mercuration of aromatic compounds is shown in Scheme 1.3,4 A modification of the Whitmore procedure was employed by Rule and Barnett to obtain modest yields of acid 1 and 8-bromo-1-naphthoic acid (5).5 Although Rule and Barnett mention that 8-chloromercuri-1-naphthoic acid was prepared as described by Leuck et al.3 there is no mention of chloromercuri acid 4 in the paper which was cited. However the preparation of a mixture of acid 4 and its 5-isomer was described by Whitmore and Fox.4 Although acid 1 has been the subject of several physical organic studies, either no reference is given to the method of synthesis, or reference was given to the Whitmore-Rule procedure.6–9 Shechter’s group modified the classical Whitmore procedure and employed it for the preparation of 8-bromo acid (5) and extended it to the preparation of 8-iodo-1-naphthoic acid (6).10 These workers employed anhydro-8-hydroxymercuri-1-naphthoic acid (3) as an intermediate, however treatment of 3 with chlorine gave 5,8-dichloro-1-naphthoic acid (7) as the only isolable product. Scheme 1 a) 0.58 M NaOH, H2O, reflux: b) Hg(OAc)2, from HgO, HOAc, reflux 48 h: c) NaOH, NaCl followed by HCl; d) Cl2, HOAc. We were able to repeat the preparation of anhydro acid 3 and its reaction with bromine and iodine to provide bromo and iodo acids 5 and 6 in unoptimized yields of 84% and 52% respectively.11 Initially, in order to avoid the use of elemental chlorine and hopefully to suppress the formation of 5,8-dichloro-1-naphthoic acid, numerous attempts were made under a variety of conditions to prepare acid 1 by reaction of anhydro acid 3 with N-chlorosuccinimide or 1,3-dichloro-5,5-dimethylhydantoin as a chlorine source. In one experiment a 36% yield of crude acid 1 was obtained; however, this compound could not be obtained even under apparently identical conditions. In another run, the crude reaction products were converted to mixtures of methyl esters, which were analyzed by GC/MS. The principal constituents of this mixture were methyl 8-chloro-1-naphthoate (41%) and a dichloro ester, presumably methyl 5,8-dichloro-1-naphthoate (53%). A methyl trichloro-1-naphthoate (7%) was found in low yield but was not otherwise characterized. 8-Chloromercuri-1-naphthoic acid (4) was prepared from 1,8-naphthalic acid as described by Whitmore and Fox.4 Reaction of 4 with chlorine in acetic acid at room temperature gave a mixture of carboxylic acids that was converted to the corresponding methyl esters using CH3I and K2CO3 in dried acetone. Analysis of this mixture by GC/MS indicated that the original reaction mixture contained 8-chloro-1-naphthoic acid (1, 17%), 5,8-dichloro-1-naphthoic acid (7, 28%) and 1-naphthoic acid (28%). In another experiment methyl 8-chloro-1-naphthoate was isolated by chromatography and hydrolyzed (KOH/H2O) to provide 8-chloro-1-naphthoic acid 1 in poor (35%) yield. The presence of 5,8-dichloro-1-naphthoic acid in the mixture of chlorination products was confirmed by preparation of an authentic sample via chlorination of 8-chloro-1-naphthoic acid.4 Not only was the chromatographic purification of the methyl ester tedious, but repeated repetition of this procedure did not reliably produce 8-chloro-1-naphthoic acid; it was concluded that since electrophilic chlorination of 8-chloro-1-naphthoic acid affords 5,8-dichloro-1-naphthoic acid occurs under very mild acid catalysis,4 the formation of the 5,8-dichloro acid in the reaction of 4 with chlorine was the result of further chlorination of the desired product. Accordingly, the reaction was carried out in a 1:1 mixture of acetic acid and dichloromethane at ice bath temperature, and in several experiments this procedure provided acid 1; however, the results were variable and frequently mixtures of products, including 1-naphthoic acid, were obtained. In Rule and Barnett’s modification of Whitmore’s procedure, it is explicitly stated that dried 8-chloromercuri-1-naphthoic acid (4) be employed.5 It was ultimately found that it is essential that this key intermediate is dried in a vacuum oven at a temperature not to exceed 50°C. The 8-chloromercuri acid (4) is thermally unstable and decomposes at temperatures greater than 50°C, as indicated by changes in the 1H NMR spectrum. This procedure provides a reliable method for the preparation of 8-chloro-1-naphthoic acid (1). The 1H and 13C NMR spectra of this product are in agreement with the assigned structure, which was confirmed by X-ray crystallography.