8-Chloro- and 5,8-Dichloro-1-naphthoic Acids

Abstract

In connection with our program directed toward the development of structure-activity relationships of cannabimimetic 1-alkyl-3-(1-naphthoyl)indoles 1,2 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.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 Nchlorosuccinimide 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.

Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: Steric and electronic effects of 4- and 8-halogenated naphthoyl substituents

“…27 Acceptable yields of 8-chloro-1-naphthoic acid ( 26 ) were ultimately obtained using chlorine in acetic acid and carrying out the reaction at ice bath temperatures in acetic acid-dichloromethane. 28 In view of the rather lengthy synthesis of 8-fluoro-1-naphthoic acid, this compound was not prepared. 29 …”

“…From 0.700 g (3.34 mmol) of 1-propylindole and 0.549 g (2.66 mmol) of 8-chloro-1-naphthoic acid 28 there was obtained after chromatography (petroleum ether: ether, 2:1) 0.425 g (46%) of 1-propyl-3-(8-chloro-1-naphthoyl)indole as a yellow gum: 1 H NMR (300 MHz, CDCl 3 ) δ 0.85 (t, J = 6 Hz, 3H), 1.75-1.87 (m, 2H), 4.00 (t, J = 6 Hz, 2H), 7.20 (s, 1H), 7.29-7.37 (m, 3H), 7.41(t, J = 9 Hz, 1H), 7.53-7.57 (m, 3H), 7.85 (d, J = 9 Hz, 1H), 7.96 (dd, J = 6 Hz, 3 Hz, 1H), 8.35 (s, 1H); 13 C NMR (75.5 MHz, CDCl 3 ) δ 11.2, 23.0, 48.7, 109.9, 118.6, 122.5, 122.7, 123.3, 125.4, 126.2, 126.7, 127.5, 127.8, 128.1, 128.7, 129.9, 130.8, 135.6, 137.0, 137.1, 139.0, 192.5; GC/MS (EI) m/z (rel intensity) 347 (97), 312 (100), 270 (42); HRMS (ES + ) m/z calcd for C 12 H 18 ClNO: 348.1155; found: 348.1161.…”