Sulphides, sulphoxides, and sulphones derived from salicyclic acids

摘要

1978 633 Sulphides, Sulphoxides, and Sulphones derived from Salicylic Acids By George R. Brown, Justus K. Landquist,' and David R. Summers, I.C.I. Limited, Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire SK10 4TG Methanesulphenyl chloride with 3-t-butyi-6-methylsalicylic acid (7) and pyridine affords the 5-chloro (9). 5-methylthio (1 0).and 5-pyridinium (11) derivatives. Arenesulphenyl chlorides similarly give chloro and arylthio derivatives. Sulphenylationis favoured by the use of sterically hindered bases. Less substituted salicylic acids give arvl sulPhones bv Friedel-Crafts reactions, and alkyl sulphides, sulphoxides, and sulphones by chlorosulphonation, reductionto the thiol, alkylation, and oxidation. Some electrophilic substitutions of these compounds are described.SALICYLICacids containing alkyl- or aryl-thio, sulphinyl, or sulphonyl substituents were required for studies on the effects of electron withdrawing and lipophilic sub- stituents on the biological activity of salicylanilides. Few such acids have been described hitherto. Stewart prepared 5-methylthiosalicylic acid (1) by chlorosulphon- ation of salicylic acid, reduction of the sulphonyl chloride, and alkylation of the thiol. Kaufmann and Rossbach later prepared this thiol from 5-amino-salicylic acid through the diazonium and 5-thiocyanato compounds, and 4-methylsulphonylsalicylic acid has similarly been made from 4-aminosalicylic acid.3 Some aminophenyl- and aminobenzyl-sulphonylsalicylic acids have been made from 5-chlorosulphonylsalicylic acid through the sulphinic acid,4 and sulphones were obtained by the Fries rearrangement of the toluene-9-sulphonyl esters of methyl salicylate and ~alicylanilide.~ Recently some arylsulphonylsalicylic acids have been made from hydroxydiarylsulphones by the Kolbe-Schmitt re-action.6 J.Stewart, J. Chem. SOC.,1922, 121,2555. H.P.Kaufmann and E. Rossbach, Bey., 1925,58,1556. G. Purrello and G. Zerbo, Boll. sedute accad. Gioenia sci. nut. Catania., 1957, 3, 446 (Chem.Abs., 1958, 52, 20011).1.G. Farbenind., G.P. 436790, 634331; Brit. DyestuffsCorp., U.S.P. 1766951. Salicylanilides are widely used as pesticides and anti- parasitic agents, and like other acidic phenols they interfere with oxidative phosphorylation in mito-chondria, possibly by facilitating the transport of hydrogen ions across the mitochondria1 membrane.' Compounds in which the phenolic hydroxy-group is masked by a bulky lipophilic substituent such as a t-butyl group show particularly high biological activity,* and the preparation of salicylic acids having such sub- stituents has presented some special problems.We have extended Stewart's method to 5-bromo-3- chlorosulphonyl- and 5-chloro-3-chlorosulphonyl-salicylic acid and to 3,5-bis(chlorosulphonyl)salicylicacid, and have oxidised the alkylthio derivatives (2) to the sulphones (3). Nitration of (1) gave 5-methylsulphinyl- 3-nitrosalicylic acid (4) and 5-methylsulphonyl-3-nitro-salicylic acid (5), and bromination gave the 3-bromo derivative (6) from which the sulphone was prepared.Chlorination of (1) occurred in the methyl group and not in the ring; this was shown by acidic methanolysis to J. H. Amin and R. D. Desai, J. Sci. Ind. Res., 1954, 13B, 181. 6 Merck and Co. Inc., N.L. 7008629-Q., U.K. 1264737. 7 A. Finkelstein, Biochem. Biophys. Acta, 1970, 205,1. 8 R.L. Williamson and R. L. Metcalf, Science, 1967, 158,1694. @ J. M. Lavanish, Tetrahedron Letters, 1973, 3847. 5-mercaptosalicylic acid. 5-Methylsulphonylsalicylic acid was not attacked by bromine, but it could be nitrated. The chlorosulphonation route to thio deriva- tives was found to have limitations. Thymotic acid (3-isopropyl-6-methylsalicylic acid), for example, was not attacked by chlorosulphonic acid at 130', and at higher temperatures decomposition occurred. Similarly, sulphonyl chlorides were not obtained from amp;nitro- salicylic acid, 3-phenylsalicylic acid, or 3-t-butyl-6-methylsalicylic acid (7). The latter compound loses its t-butyl group when it is treated with Lewis acids at temperatures above 5-10'.We therefore investigated the reaction of salicylic acids with sulphenyl chlorides under basic conditions.1deg; In our initial experiments we added the sulphenyl chloride dissolved in chloroform to a solution of the salicylic acid and two or three molar equivalents of pyridine in tetrachloroethane. Substitution did not occur when only one equivalent of base was used, and the addition of silica gel l1 did not facilitate these re- actions.$-Nitrophenylsulphenyl chloride reacted with a number of alkylsalicylic acids to give the expected 5-p-nitrophenylthio derivatives in moderate yield, and similarly o-nitrophenylsulphenyl chloride and 2,4-di-nitrophenylsulphenyl chloride with (7) gave good yields of the nitrophenylthio derivatives (8a and b). When (7) was treated with m-nitrophenylsulphenyl chloride, however, the m-nitrophenylthio derivative (yield 80) was accompanied by 7 of 3-t-butyl-5-chloro-6-methyl-salicylic acid (9). Formation of a chlorosalicylic acid was more marked when arylsulphenyl chlorides devoid of nitro groups were used. 4-Chlorophenylsulphenyl chloride with 3-methylsalicylic acid gave 5-p-chloro-phenylthio-3-methylsalicylic acid (40) and 5-chloro- 3-methylsalicylic acid (9yo),but with (7) the results were variable; the chloro acid (9) was formed in up to 75 yield, and the arylthio derivative (8c) was obtained, in small yield, in only a few experiments. Under similar conditions the reactions of methane- sulphenyl chloride with (7) were varied and irrepro- ducible.The usual product was (9), but in some experiments the 5-methylthio derivative (10) was formed. A third product that was isolated was identi- fied as the pyridinium salt (11). The formation of this compound requires an attack by pyridine, and further- more sulphenyl halide may be lost by formation of the methylthiopyridinium ion ( 12).12 To prevent this the sterically hindered base 2,6-lutidine was used instead of pyridine.It gave consistent but small yields of (10). The use of 2,6-lutidine or the hindered base ethyldi- isopropylamine in the reaction of p-chlorophenyl-sulphenyl chloride with (7) gave consistent and good yields of (8c) (Table l),whereas with triethylamine only the chloro compound (9) was formed. Arylthio deriva- lo S. Andreades, J. F. Harris, and W. A. Sheppard, J. Org.Chem., 1964, 29, 898. l1 M. Hojo and R. Masuda, Synth. Comm., 1975, 5, 173. l2 G. K. Helmkamp, D. C. Owsley, W. M. Barnes, and H. N. Cassey, J. Amer. Chem. SOC.,1968, 90, 1635; V. J. Traynelis and J. N. Rieck, .I. Org. Chem., 1973, 38, 4334. J.C.S. Perkin I tives have been obtained from several salicylic acids and numerous arylsulphenyl chlorides using 2,6-lutidine, X (11 (21 a; X(31=CI a; X=Br b; XzCI b; X = S02Me c; X= SMe MeS MeSO (61 (dl (5) (7) (8 1 (9) a; X=H,Y=NO2 b; X=Y NO2 C; X=CI,Y=H (131 (141 a;R=H a = HN03-AcOH b = Br2-AcOH b;R=Me TABLE1 Reaction of 4-chlorophenylsulphenyl chloride with (7) Yield (yo) Base Aryl-S-c1 Pyridine 0-10 75 2,6-Lutidine 50 2 Pr21NEt 33 18 NEt, 0 74 but chloromethanesulphenyl chloride and trichloro-methanesulphenyl chloride did not react with (7) under these conditions.There have been a few reports l3 of chlorination by sulphenyl chlorides, but in most cases the evidence was equivocal because free chlorine was present during the reactions. The sulphenyl chlorides used in our experi- l3 R.T. Wragg, J. Chem. SOC.,1964, 5482; M. Oki and K. Kobayashi, Bull. Chem. SOC.Japan. 1973, 46, 687; Synthesis, 1975, 196; R. M. Scribner, J. Org. Chem., 1966, 81, 3671. ments were free from excess of chlorine but in some instances they gave high yields of chlorination products. Modena and his co-workers l4 have shown that sulphenyl chlorides form ionic dimers (13) in certain solvents, and it is conceivable that these dimers are chlorinating agents, the formation of stable disulphides being the driving force. The failure of o-and p-nitroarylsulphenyl chlorides to chlorinate salicylic acids may reflect a failure to dimerise. However, the presence of dimers in our reaction mixtures has not been demonstrated. An attempt to suppress the postulated dimerisation by adding chloride ions (as tetrabutylammonium chloride) in the reaction of 9-chlorophenylsulphenyl chloride and (7) with pyridine stopped both the chlorination and the sulphenylation reactions.We have regarded the sul- phenylation as a straightforward electrophilic sub-stitution, but it is possible that the reaction occurs through formation of a sulphenic ester and subsequent rearrangement by cleavage of the sulphenate ion and nucleophilic attack in the para-position.* This would explain the formation of (11) and the chlorination reactions as well as the formation of the thio derivatives, and would accord with the greater difficulty of sulphenyl-ating sterically hindered acids such as (7).T.1.c. examination of our reaction mixtures, however, gave evidence only of the starting materials and the final products. Methylthio derivatives of (7) are obtained more readily by reaction of (7) or its methyl ester with dimethyl sulphoxide and perchloric acid l5to give the 5-dimethyl- sulphonium perchlorates (14) which may be demethyl- ated with aqueous potassium chloride. Esterification of (7) is conveniently done in hexamethylphosphoramide-alcohol mixtures.16 The alkyl and arylthio compounds were oxidised with hydrogen peroxide in acetic acid, reaction at room temperature affording sulphoxides whereas at 100" sulphones were usually produced, Sulphones were also obtained directly from arylsulphonyl chlorides and 3-met hylsalicylic acid and thymotic acid under Friedel-Crafts conditions at lower temperatures than those reported for Fries rearrangements.Separ-ation of the arylthio and arylsulphonylsalicylic acids from starting materials or other reaction products was often facilitated by the solubility of their sodium salts in organic solvents. EXPERIMENTAL 5-Bromo-3-chlorosulphonylsalicylic A cid.-5-Bronio-salicylic acid (97.6 g) was added gradually with stirring to clilorosulphonic acid (179 ml) at 15-20". The mixture was heated for 3 h at 65" and was then cooled and poured on to crushed ice (2 kg) with vigorous stirring. The gummy product was rapidly extracted with ether and the solution was dried (Sa,SO,) and evaporated. The residue was crystallised from toluene, giving the sulplzonyl chloride (44 g), m.p.196-198" (Found: C, 27.1; H, 1.5. C,H,BrClO,S requires C, 26.6; H, 1.3). * We are indebted to Dr. TI.R. Hogg for this suggestion. l4 G. Capozzi, V. Lucchini, G. Modena, and F. Rivetti, J.C.S. Perkan I, 1975, 361. 5,5'-Dibromo-3,3'-dicarboxy-2,2'-dihydroxydi~henyl Di-suZ~hide.-5-Bromo-3-chlorosulphonylsalicylicacid (44 g) dissolved in ethanol (312 ml) was stirred at 0-5" and zinc dust (91 g) was added gradually. Concentrated hydro- chloric acid (220 ml) was added with cooling during 15 min, and the mixture was stirred for 2.5 h at 15-20'. Some white solid that precipitated was redissolved by addition of ethanol and the filtered solution was treated with a 25 solution of iron(m) chloride in ethanol (307 ml) with addition of concentrated hydrochloric acid to prevent formation of a purple iron complex.After 1 h the di- sulphide was precipitated with water and was purified by solution in aqueous sodium carbonate and reprecipitation with hydrochloric acid, yield 28 g, m.p. 276-277" (Found: C, 34.4; H, 1.9. C1,H8Br20,S, requires C, 33.9; H, 1.6). 3,3'-Dicarboxy-5,5'-dichloro-2,2'-dihydroxydi~henyldisul-phide, m.p. 275-278", was prepared similarly from 5-chloro- 3-chlorosulphonylsalicylic acid (Found : C, 4 1.6 ; H, 2.2. C14H8C120,S2 requires C, 41.3; HI 2.0). 3,5-Bis(chloro-sulphonyl) salicylic acid was reduced similarly and the filtered solution was concentrated (without oxidation) to yield the crude dithiol as a yellow solid that could not be purified.5-Chloro-3-methylthiosalicylicA cid (2b) .-3,3'-Dicarboxy- 5,5'-dichloro-2,2'-dihydroxydiphenyl sulphide (4 g) and N-sodium hydroxide solution (30 ml) were boiled under reflux for 0.5h and the solution was cooled and was shaken with dimethyl sulphate (2 ml). Methylation was rapid and the sodium salt crystallised out. After acidification with concentrated hydrochloric acid the methylthio acid was collected and crystallised from water, yield 1.8 g, m.p. 185-187" (Found: C, 44.0; H, 3.3. C8H,C10,S requires C, 43.9; H, 3.2). Similar fission and alkylation of appropriate disulphides using butyl iodide instead of dimethyl sulphate, with acetone added to give a homogeneous solution, afforded 5-bromo-2-n-butylthiosalicylic acid, m.p.132-134" (from benzene) (Found: C, 42.7; H, 4.2. C,,H,,BrO,S requires C, 43.3; HI 4.3y0), and 5-isobutylthiosalicylic acid, m.p. 101-103" (from water) (Found: C, 58.2; H, 6.2. C,,H,,O,S requires C, 58.4; H, 6.2). 3,5-Bis(methylthio)salicylicAcid.-Crude 3,5-dimercapto-salicylic acid (2 g) dissolved in N-sodium hydroxide (30 ml) was stirred with dimethyl sulphate (3.76 g). After 3 min the solution was acidified with hydrochloric acid to pre- cipitate the product (1.0 g), m.p. 181-183" (from toluene) (Found: C, 47.4; H, 4.3. C,H,,O,S, requires C, 47.0; H, 4.35). Samples of the starting material having a high disulphide content were best reduced with glucose and sodium hydroxide before methylation. 3-Bromo-5-methylthiosalicylic Acid (2a) .-5-Methylthio- salicylic acid (1) (18.4 g) in glacial acetic acid (180 ml) was stirred and treated dropwise with bromine (16 g) in acetic acid (20 nil).After 16 h the solution was concentrated under reduced pressure to give the bromo acid (11.3 g), m.p. 162-164" (from acetic acid-water) (Found: C, 37.1; H, 2.6. C,H,BrO,S requires C, 36.5; H, 2.7), TCDCl,- (CD,),SO 2.1 (2 H, q, J 2 Hz) and 7.1 (3 H, s). Nitration of 5-Methylthiosalicylic A cid.-Nitric acid (8.0g, d 1.5) in acetic acid (20 ml) was added cautiously to (I) (23g) dissolved in acetic acid (120 ml), and the mixture was l5 S. Ukai and K. Hirose, Chem. Pharm. Bull. (Japan), 1968,16,195; Yakugaku Zasshi, 1966, 86, 187. l6 P. E. Pfeffer, T.A. Foglia, P. A. Barr, I. Schmeltz, and L. S. Silbert, Tetvahedron Letters, 1972, 4063. stirred and heated under reflux for 2 h and was allowed to cool overnight. 5-MethyZsuZphinyZ- 3-nitrosalicyZic acid (4) (6.4 g) was filtered off and gave pale yellow crystals (from methanol), m.p. 233" (Found: C, 38.5; H, 2.9; N, 5.5. C,H,NO,S requires C, 39.2; H, 2.9; N, 5.7y0), m/e 245 (Mf), T(CD,),SO 1.55-1.65 (2 H, q, J 2 Hz) and 7.2 (3 H, s). The filtrate was heated with 27.5 hydrogen peroxide (80 ml) at 90" for 40 min, and after dilution with water the solution was evaporated under reduced pressure to give 5-methyZsuZphonyZ-3-nitrosaZicyZicacid (5) (7 g), pale yellow crystals, m.p. 242-244: (from water) (Found: C, 36.8; H, 2.9; N, 5.3.C,H,NO,S requires C, 36.8; H, 2.7; N, 5.4y0), T(CD,),SO 1.6 (2 H, q, J 2.5 Hz) and 6.8 (3 H, s). This compound was obtained in 34 yield by nitrating 5-methylsulphonylsalicylic acid under similar conditions. 5-Isobutylthiosalicylic acid was nitrated similarly (95" for 5 h) and the reaction mixture was oxidised with hydrogen peroxide to give 5-isobutyZsuZ~hon~Z-3-nitrosaZicyZicacid, pale yellow crystals, m.p. 196-1 98" (from water) (Found : C, 43.6; H, 4.4; N, 4.3. C,,H1,NO,S requires C, 43.6; H, 4.3; N, 4.6). 5-Methylsul~honyZsaZicyZic Acid.-Compound ( 1) (5 g), acetic acid (50 ml), and 27.5 hydrogen peroxide (20 ml) were heated at 90-95" for 40 min, and after dilution with water the solution was evaporated to small bulk under reduced pressure to give the sulphone (4.9 g), m.p.201- 203" (from water) (Found: C, 44.0; H, 3.8. C,H,O,S requires C, 44.4; H, 3.7y0), .(CD,),SO 1.7-3.0 (3 H, m) and 6.84 (3 H, s). The following were prepared similarly : 3,5-bis(methyZ-suZphony1)saZicylic acid (3b), m.p. 264-266" (from acetic acid) (Found: C, 36.2; H, 3.4. C,H,,O,S, requires C, 36.7; H, 3.4), T(CD,),SO 2.65 (2 H, q, J 2.6 Hz), 6.65 (3 H, s), and 6.75 (3 H, s); 5-chZoro-3-methyZsuZphonyZ-salicylic acid (3a), m.p. 205-207" (from water) (Found: C, 38.0; H, 2.9. C,H,ClO,S requires C, 38.3; H, 2.8); 3-bromo-5-methyZsul~honylsalicylicacid, n1.p. 257-259" (from water) (Found: C, 32.1; H, 2.4. C,H,BrO,S requires C, 32.5; H, 2.4), -r(CD,),SO 1.72 (2 H, s) and 6.74 (3 H, s); 5-bromo-3-n-butyZsuZ~honyZsalicyZic acid, m.p.169-170" (from water) (Found: C, 38.5; H, 3.9. CllH,,BrO,S requires C, 39.2; H, 3.90/6), r(CD,),SO 1.9 (2 H, q, J 2.5 Hz), 6.5 (2 H, t),8.5 (4 H, m), and 9.1 (3 H, t). 2-Acetoxy-5-methylsuZ~honyZbenzoic Acid.-5-Methylsul-phonylsalicylic acid (1 g) and acetyl chloride (7 ml) were boiled under reflux for 7 h and cooled to give the acetyl derivative, m.p. 159-1 60",which was rapidly hydrolysed by moisture (Found: C, 46.6; H, 4.0. Cl0HloO,S requires C, 46.5; H, 3.9). Reactions with SuZphenyl ChZorides.-5-p-ChZorophenyZ-thio-6-methyl-3-t-butyZsalzcyZicacid (8c) (method a). 4,4'-Dichlorodiphenyl disulphide (18.9 g, M/16 + 5) was suspended in dry chloroform (185 ml) and was treated with chlorine at 10" until it dissolved.A slow stream of chlorine was passed into the solution for a further 10 min and the solution was then evaporated to 5/6 of its volume at 20-25" under reduced pressure. It was then added at 10-15" to a stirred solution of (7) (26 g, M/8) and 2,6-lutidine (26.8 g, M/4) in tetrachloroethane (300 ml) with careful exclusion of moisture. Stirring was continued overnight at room temperature and the solution was washed in water J.C.S. Perkin I organic phase was treated with N-NaOH solution (3 x 150 ml), each addition causing the separation of a red oily gum at the interface. This gum was collected and was triturated with concentrated hydrochloric acid with cooling, giving a paste that was filtered, dried, and crystallised from acetic acid to yield the product (19.6 g) (Table 2). 6-MethyZ-5-m-nitrophenylthio-3-t-butylsaZicyZzc acid (method b).The sulphenyl chloride prepared from 3,3'- dinitrodiphenyl disulphide (10 g) in dry chloroform (100 ml) as in the foregoing preparation was added during 5 min to a solution of (7) (13 g) and pyridine (10.8 ml) in tetrachloro- ethane (150 ml) at 10-15" with exclusion of moisture and the mixture was stirred overnight at room temperature. It was then washed with water (2 x 70 ml) and treated with N-NaOH solution (4 x 200 nil) which caused the precipitation of a gum at the interface. The gum was separated by decantation and was triturated with concen- trated hydrochloric acid to yield the product which was crystallised from xylene (Table 2).Acidification of the alkaline extract gave the chloro acid (9) (1.0 g). In some analogous preparations, e.g. with p-nitrophenylsulphenyl chloride, the sodium salt of the product was not pre-cipitated by the sodium hydroxide solution and the product was recovered by acidification of this solution. 5-Methanesulphony l-6-methyl- 3-t-buty ZsaZicylic acid ( 10). Dimethyl disulphide (17.7 g, 3~/16) cooled to -20" was treated with chlorine until 8.8 g (M/8) had been absorbed. The temperature of the solution was allowed to rise to 0" and the sulphenyl chloride was used immediately (chlorin- ation of the disulphide with sulphuryl chloride, or the use of distilled methanesulphenyl chloride gave similar results).The sulphenyl chloride was added below 0" to a well stirred solution of (7) (26 g) and pyridine (20 ml) in tetra- chloroethane (130 nil) protected from moisture. The mixture was stirred at 0" for 1 h and then at room tem- perature for 2 h and it was then poured into water (ca. 150 ml). The solid that separated was collected and crystallised from acetic acid to give 1-(5-carboxy-4-hydroxy- 6-methyl-3-t-butyZPhenyl)~yridiniumchloride (1 1) (1.1 g), m.p. 254" (decomp.) (Found: C, 63.5; H, 6.2; N, 4.3; C1, 11.0. C,,H,,CINO, requires C, 63.45; H, 6.2; N, 4.35; C1, ll.Oyo),.c(CF,CO,D) 1.12 (3 H, m), 1.54-1.7 (2 H, m), 2.35 (1 H, s), 7.6 (3 H, s), and 8.47 (9 H, s), m/e 242 (M -C1 -CO,). A solution of this compound (0.2 g) in hot water treated with sodium acetate (0.2 g) gave the betaine hydrate (0.15 g), m.p.288" (decomp.) (Found: C, 68.0; H, 7.0; N, 4.7. C,,H,,NO,,H,O requires C, 67.3; H, 6.9; N, 4.6), T(CD,),SO 0.75 (2 H, d), 1.1 (1 H, t), 1.63 (2 H, t),2.65 (1 H, s), 7.64 (3 H, s), and 8.62 (9 H, s). The organic phase from the reaction mixture was extracted with N-NaOH solution (2 x 100 ml) and the extract was acidified with hydrochloric acid to give a solid from which the methylthio derivative (10) could not readily be separ- ated. The crude mixture (ca. 11 g) was therefore oxidised with 27.5 hydrogen peroxide (50 ml) in acetic acid (100 ml) for 40 min at 90-100". After cooling and dilution with water the methylsulphonyl derivative (1.3 g) crystal-lised, pale yellow crystals, m.p.232" (decomp.) (from chlorobenzene) (Found: C, 54.3; H, 6.2. C,,H,,O,S requires C, 54.5; H, 6.3y0), T(CD,),SO 2.02 (1 H, s), 6.8 (3 H, s), 7.28 (3 H, s), 8.6 (9 H, s). In other experiments (2 x 80 ml), N-NaOH solution (4 x 150 ml), and 6~-only the chloro acid (9) was isolated; the use of 2,6-lutidine hydrochloric acid (2 x 100 ml). Acidification of the instead of pyridine consistently gave the methylthio acid alkaline extract gave 5-chloro-6-methyl-3-t-butylsalicylic(isolated as the sulphone). Similarly, methanesulphenyl acid (9) (0.5 g), m.p. 209-211" (lit.,,, 208-211"). The 17 Monsanto, U.K. 1,139,638. 1978 637 chloride with salicylic acid and 2,6-lutidine gave (1) (34), The organic phase was washed with saturated NaHCO, m.p.123-126", which was characterised by oxidation to solution, separated, and steam distilled. The residue was the sulphone, m.p. 201-203". acidified with hydrochloric acid and the oily product was 5-p-ChZoro~henyZsuZ~honyZ-3-iso~vo~yZ-6-methyZsaZicyZiccollected and crystallised from xylene-light petroleum to acid (method d). Thymotic acid (5.7 g) was added to give the sulphone (1.9 g), m.p. 165-166' (Table 2). Under TABLE 2 Arylthio-, arylsulphinyl-, and arylsulphonyl-salicylic acids (A) R' O/Found (76) Required ( /o ) Yield Ar n R1 R2 Formula M.p. ("C) C H N C H N Method (I C6H6 0 But Me C18H2003S 169-1 70 68.0 6.4 08.4 6.3 a 31 C6H6 2 But Me C18H2006S 172-174 61.9 5.7 62.1 5.7 C 36 PMe C, H 2 Me H C15H1406S,0.5H,0 250-252 57.5 4.7 57.2 4.7 d 12 4-MeC,H4 0 But Me ClgH,,O,S,0.5H2O 163-164 67.7 6.6 67.3 6.8 a 25 PMeC,H, 2 Rut Me C19H2205S 187-1 88 62.4 6.1 63.0 6.1 C 67 4-ClC6H4 0 Me H Cl,HllC1O,S 175-176 56.8 3.7 57.0 3.7 b 40 674-ClCeH4 2 Me H 237-238 52.0 3.8 51.5 3.4 {: d 12 4-CIC6 H 4 2 H H 2 18-219 49.6 2.9 49.9 2.9 15 4-ClC6H4 2 Pri Me 165-166 55.9 4.7 55.4 4.6 d 17 CClC,H, 0 But Me 172-174 61.3 5.4 61.6 5.4 a 50 4-ClCeH4 2 But Me 396-1 97 56.6 5.0 56.5 5.0 C 67 4-BrC,H4 0 But Me 172-174 54.4 4.8 54.7 4.8 a 40 PBr-3-MeC,H3 0 But Me 193-195 55.3 5.1 55.7 5.1 a 50 4-Br-3-MeC,H3 2 Rut Me 192-1 94 51.5 4.8 51.7 4.8 C 45 3,4-C1,C,H3 0 But Me 163-164 55.9 4.7 56.1 4.7 a 33 3,4-Cl,C6H3 2 But Me 191-192 51.7 4.3 51.8 4.3 C 54 2, 5-C1,C,H3 0 But Me 202-204 55.5 4.6 a 52 2, 5-Cl2C,H3 2 Rut Me 252-253 51.5 4.3 C 37 2,4,5-C13C6H, 0 But Me 216-21 8 50.4 4.0 50.4 4.2 a 67 2,4,5-C1,C,H2 1 But Me 207-209 49.5 3.9 49.6 3.9 C 33 4-BrC,H4 2 Me H 233-235 45.4 3.2 45.3 3.0 d 16 2-NOZC6H4 0 But Me 218-220 59.9 5.3 3.8 59.8 5.3 3.9 b 69 2-NO,C,H, 2 But Me 237-238 55.1 5.0 3.5 55.0 4.8 3.6 C 65 3-NOzC6H4 0 But Me 185-188 59.8 5.4 3.9 b 80 3-NO,C,H, 2 But Me 190-191 55.1 4.9 3.5 C 69 4-NOZCRH4 0 Me H 199-201 54.9 3.5 4.1 55.1 3.6 4.6 b 37 4-NO,C,H, 1 Me H 253-255 52.1 3.5 4.2 52.3 3.4 4.4 e 61 4-N0,C6H4 2 Me H 258-260 50.0 3.4 4.1 49.9 3.3 4.2 C 70 PNO,C,H, O Pri Me 177-179 58.8 4.9 3.8 58.8 4.9 4.0 b 8 4-NO,C,H, 1 Pri Me 133-1 35 56.1 4.9 3.9 56.2 4.7 3.9 e 80 4-NOZCaH4 2 Pri Me 2 14-2 16 53.8 4.6 3.6 53.8 4.5 3.7 C 92 4-NO2C6H4 0 But H 184-185 58.7 5.0 3.6 b 35 4-N02C,H4 2 But H 199-201 53.9 4.5 3.5 C 76 4-NOZCBH4 0 But Me 195-197 59.9 5.4 3.9 b 53 CNO,C,H, 1 But Me 201-202 57.3 5.2 3.7 57.3 5.0 3.7 e 40 4-NO,C,H4 2 But Me 222-224 55.6 5.0 3.1 C 85 2,4-(NO,),C,J 3 0 But Me 258 53.3 4.5 6.7 53.2 4.4 6.9 b 51 (decomp.) But Me 228 51.2 4.3 6.5 51.2 4.3 6.6 e 7431 (decornp.2,4-(NO,),C,H, 2 But Me 240 49.5 4.1 6.3 49.3 4.1 6.4 C 59 (decornp.) 2-C1-5-NO,C,H, 0 But Me C18H18C1N05S 220-221 54.3 4.5 3.4 54.6 4.6 3.5 b 37 2-C1-5-NO,C,H, 1 But Me C18H1bClNO6S 224-225 52.2 4.4 3.3 52.5 4.4 3.4 C 2-C1-5-NO,C,H, 2 But Me C18H18ClN0,S 275 50.5 4.4 3.2 50.5 4.2 3.3 C (decornp.) Q-CI-2-NO,C,H, O But Me C,,H,8CIN06S 223-225 54.3 4.6 3.3 b 65 4-Cl-2-NOZC6H3 2 But Me C,,Hl,ClN07S 244-245 50.0 4.3 3.0 C 60 4-C1-3-NO,C,H, 0 But Me Cl,Hl,ClN06S 173-174 54.8 4.6 3.5 b 64 4-C1-3-N0,C,H3 2 But Me C,8Hl,ClN07S 206-208 50.4 4.2 3.2 C 69 a Sulphenyl chloride and 2,6-lutidine.Sulphenyl chloride and pyridine. H,O,-acetic acid, 90-95". Friedel-Crafts. H,O,-acetic acid, 15-20". aluminium chloride (8.1 g) in dry nitrobenzene (35 ml) . similar conditions salicylic acid gave 5-p-chlorophenyl-After gas cvolution had ceased p-chlorobenzenesulphonyl suZphonyZsaZicyZic acid (Table 2) in which the proton in the chloride (6.3 g) was added and the mixture was heated for 3-position was characterised by the doublet at T 2.8 at 4 h at 90-100". The mixture was cooled, decomposed with higher field than the other aromatic protons in (CD,),SO.dilute hydrochloric acid, and extracted with ethyl acetate. 6-MethyZ-5-p-nitro~henyZsuZ~honyZ-3-t-butyZsaZicyZicacid J.C.S. Perkin I (method c). 6-Methyl-5-~-nitrophenylthio-3-t-butylsalicylicbutylsalicylate (4.25 g) was added with stirring and cooling acid (3 g) in acetic acid (30 ml) and 27.5 hydrogen ((5") to phosphoryl chloride (8 ml) and 70 perchloric peroxide (18.5 ml) was heated 40 min at 90-95" and the acid (10 ml). Dimethyl sulphoxide (1.6 g) was added mixture was poured into water (100 nil). The product was dropwise below 5" and the mixture was stirred for 1 h at filtered off and crystallised from toluene (Table 2). 5-10" and for 2 h at 15-20", and was allowed to stand 6-Methyl-5-p-nitrophenylsulphinyl-3-t-butylsalicylicacid overnight.The solution was poured into ice and water (method e). 3-t-Butyl-6-methyl-5-p-nitrophenylthiosalicylic(100 g) and the precipitated sulphonium salt (4.8 g) was acid (2 g) dissolved in acetic acid (200 ml) was stirred for 6 h at room temperature with 27.5 hydrogen peroxide (11 ml) and then added to water (700 ml). The product was filtered off and crystallised from acetic acid (Table 2). Methyl 6-methyl-3-t-butylsalicylate.The acid (7) (10.4 g) dissolved in hexamethylphosphoramide (50nil) and ethanol (50 ml) was treated with powdered potassium hydroxide (3 g), the mixture was stirred and heated to 50" and methyl iodide (14.5 g) was added. Stirring at 50" was continued for 3 h, and the mixture was cooled and added to 3~-hydrochloric acid (500 ml).The ester separated as an oil which solidified and was crystallised from ethanol, yield 6.2 g, m.p. 72-73" (Found: C, 70.3; H, 8.4. Camp;1@3 requires C, 70.3; H, 8.1y0), -r(CU,),SO 2.95 (2 H, q, J 8 Hz), 6.0(3 H, s), 7.5 (3 H, s), and 8.55 (9H, s). Ethyl 6-methyl-3-t-butylsalicylatewas made similarly, using ethyl iodide, and had m.p. 45-46" (Found: C, 71.2; H, 8.5. Cl4H2,O3 requires C, 71.2; H, 8.5). 4-Hydroxy-3-methoxycarbonyl-2-methyl- 5-t-butylphenyldi- methylsulphonium perchlorate ( 14b). Methyl 6-methyl-3-t- collected and crystallisecl from ethanol, forming white needles, n1.p. 200-201" (Found: C, 47.0; H, 6.0;S, 8.4. C,,H,,ClO,S requires C, 47.1; H, 6.0; S, 8.4y0), -r(CDCl,- (CD,),SO 2.2 (1 H, s), 4.1 (3 H, s), 4.77 (6H,s), 7.47(3H, s), and 8.6 (9H, s). Methyl 6-methyl-5-~tlethylthio-3-t-butylsalicylate.The fore- going sulphonium salt (2 g) and saturated potassium chloride solution (30 nil) were boiled under reflux for 5 11, The cooled mixture was diluted with water (50nil) and the product was recovered by extraction with ether, yield 1 g. m.p. 95-96' (from acetic acid) (Found: C, 63.1; H, 7.7, C1,H,,O,S requires C, 62.7; H, 7.5:4,), T(CDC1,) 2.55 (1 H. s), 6.1(3 H, s), 7.45 (3 H, s), 7.75 (3 H, s), and 8.7(9H, s). 3-Carboxy-4-hydroxy-2-nzethyl-5-t-butylphenyldimethyl-sulphoniuun perchlorate ( 14a), m.p. 274" (decomp.), was prepared in the same way as the ester (Found: C, 45.6; H, 5.8; S, 8.4. Cl,H2,C10,S requires C, 45.6; H, 5.7; S, 8.7), T(CD,),SO 2.25 (1 H, s), 6.75 (6 H, s), 7.53 (3H, s),and 8.65(I)H, s). 7/137 Received, 27th July, 19771