Nickel chloride catalyzed arylation of 3-nlercaptopropionic acid : a facile one step route to 3-aryltnercaptopropionic acids frmn unactivated aryl halides and arenes

Nickel chloride catalyzed arylation of 3-mcrcaptopropionic acid by (i) unactivatcd aryl halidcs (path a) and (ii) diphcnyliodonium bromide (path b) gave 3-aryl mcrcaptopropionic acid (3) in good yield. 3- Aryl mercaptopropionic acids (3) are the key intcnne diates in the synthesis of thiochroman-4-ones (4). A vari ety of thiochroman-4-ones have been shown to exhibit antitumour, antifertility, anticonvulsant. antidepressant, antihypertensive, anti amebic, antimicrobial and anti-inf1am matory properties 1• Our continuing interest 2 in the syn thesis of thiochroman-4-one derivatives, required a facile synthesis of 3. Nucleophilic displacement of halogen of activated aryl halides by 3-mercaptopropionic acid has been frequently used for the preparation of 3 3, however. method serious drawback as undesir substituents remain associated to the aryl ring in


3-Aryl mercaptopropionic acids
are the key intcnnediates in the synthesis of thiochroman-4-ones (4). A variety of thiochroman-4-ones have been shown to exhibit antitumour, antifertility, anticonvulsant. antidepressant, antihypertensive, anti amebic, antimicrobial and anti-inf1ammatory properties 1 • Our continuing interest 2 in the synthesis of thiochroman-4-one derivatives, required a facile synthesis of 3. Nucleophilic displacement of halogen of activated aryl halides by 3-mercaptopropionic acid has been frequently used for the preparation of 3 3 , however. this method suffers from a serious drawback as undesirable substituents remain associated to the aryl ring in the final product. Recently, a few techniques have been de-veloped4-6 which do not require the presence of activating groups for the nucleophilic displacement of halogens from aryl halides. The use of 11 6 arene tricarbonylchromiurn complex of aryl halide is one such technique which facilitates the nucleophilic displacement of halogen from arene substrates 7 -9 . But as hexacarbonylchromium complex is an expensive reagent, this process has not been economically viable for the large scale halide displacements. While looking for other possible facile and more practical procedures, we noticed that cuprous rnercaptides have been used to effect the nucleophilic displacement of halides from unactivated aryl halides in pyridine : quina-. line mixture to give the corresponding sulphides 4 . In a quest to develop a procedure which avoided the preparation of cuprous mercapticles and generated 3 in one step directly from unactivated aryl halides and mercaptopropionic acid, we discovered in the present work that NiC1 2 .6H 2 0 was a better catalyst (path a) to effect this reaction (Scheme I).
The procedure consisted of heating an equimolecular mixture of aryl bromide/iodide (0.0 l mol), 3-mercaptopropionic acid (0.01 mol) and catalytic amount of NiC1 2 . 6H 2 0 (0.00 l mol) in pyridine :quinoline mixture (1 : 3, v/ v. 10 ml) for 2 h. Addition of cone. HCl (!0 ml) precipitated pure 3 from the reaction mixture in high yield. The procedure described opens the possibility of using an unactivated aryl halides for the preparation of 3 .The process worked well on aryl halides containing electron releasing substituents. (Table la).
Arylation of mercaptans by diaryliodoniurn salts 10 too has been known. Phenylation of thioglycollic acid with diphenyliodonium chloride has been reported to give phenyl mercaptoacetic acid 5 . Use of copper oxide 11 has been shown to catalyze the process. This result prompted us to use diphenyliodonium bromide for the phenylation of 3-mercaptopropionic acid through path-b with NiC1 2 .  and catalytic amount of NiCI 2 .6H 2 0 (0.00 I mol) in pyridine: quinoline mixture (1 : 3 v/v, 10 ml) for 2.5 h. Addition of cone. HCI (10 ml) precipitated pure 3a from the reaction mixture in a moderate yield ( Table I b).
Six coordinated nickel complexes of general formula NiL2.6H 2 0 and Ni X 2 L 2 have been reported with deprotonated ligands of mercaptoacetic acids and mercapto . .
succmtc act s . e belteve that a weak complex of Ni 11 species is formed from 3-mercaptopropionic acid, the active mercaptide centre of which enters into the nucleophilic displacement of xfrom Ar-X and x-+ Arl from Ar 2 r+x-. As diaryliodonium salts are not readily available commercially and its preparation is cumbersome, we found path-a, a more practical and viable route for the preparation of 3.
Characterization of the products 3a-d was made by spectroscopic means as well as by direct comparison with authentic samples prepared through known routes 16-18_ Experimental All the melting points are uncorrected. IR spectra were recorded on Pye Unicam Model SP3-300 infracord in nujol and on KBr pellets. 1 H NMR spectra were recorded on Varian EM 360 L using CDCI 3 as solvent and TMS as internal reference.