2264 J.C.S. Perkin Icine-Substitution in the Thiophen Series; the Behaviour of 4-Nitro-3-thienyl Phenyl Sulphone towards Sodium Arenethiolates in MethanolBy Marino Novi, Giuseppe Guanti,” and Carlo Dell‘Erba. lstituto di Chimica Organica, Palazzo delle Scienze,Domenico Spinelli, Cattedra di Chimica Organica, Facolta di Farmacia dell‘universita, 401 26 Bologna, ItalyCorso Europa, 161 32 Genova, Italy4-Nitro-3-thienyl phenyl sulphone (3) reacts with various sodium arenethiolates in methanol to give 5-arylthio-3-thienyl phenyl sulphones (4) (main products) and 2-arylthio-4-nitrothiophens (2). An anomalous addition-elimination mechanism is suggested to account for the formation of the cine-substitution products (2) and (4).WE have previously reported that 2,3-dinitrothiophenand 3-nitro-2-thienyl and 2-nitro-3-thienyl phenyl sul-phones react with sodium arenethiolates in methanolto give the sulphides derived from normal substitutiontowards a series of sodium o-, m-, and $-substitutedbenzenethiolates in methanol.RESULTS AND DISCUSSIONreactions, in analogy with similar o-nitrobenzene deriv-atives.3 In the first case substitution of the nitro-groupin either the 3- (preferred) or the z-position occurs ; in theA solution of compound (3) in methanol, treated with alarge excess Of substituted sodium benzenethiolate in thepresence of the corresponding free arenethid (see Experi-other two cases only products derived from substitutionof the phenylsulphonyl group were isolated.thiophen deri~ative,~ i.e.3,4-dinitrothiophen (1), a com-pletely different behaviour towards sodium arenethiolateshas been observed : 2-arylthio-4-nitrothiophens (2) wereformed through a cine-substitution reaction [equation(ill a ; L - M e C 6 H L e ; 4-CICgHLmental and Table I) gave a mixture Of twoIn the case of another ‘ ortho-like ’ disubstituted (ii)ArSNa( 4 ) ( 3 )On the basis of this unexpected result it seemed ofinterest to study the reactivity of other 3-substituted 4-nitrothiophens towards nucleophiles.We report herethe behaviour of 4-nitro-3-thienyl phenyl sulphone (3)C. Dell’Erba and G. Guanti, Gazzetta, 1970, 100, 223. * G. Guanti, C. Dell’Erba, and P. Macera, J . Heterocyclic Cltewz.,1971, 8, 537.H. H. Hodgson and E. R. Ward, J . Chem. Soc., 1948, 2017;1949, 1316; J.D. Loudon and N. Shulman, ibid., 1941, 722;J. F. Bunnett and W. D. Merritt, J . Amer. Chem. SOG., 1957, 79,5967.b; 3-MeC6H, f ; 3-CICgHLc . 2-MeC6H, g ; 2-CIC,H,d , Ph h ; 2,4,6-Me3C6H2products. These were separated by column chromato-graphy and identified through analytical and lH n.m.1-.~95data (Tables 2 and 3) as 5-arylthio-3-thienyl phenylsulphones (4a-h) (main products) and 2-arylthio-i-nitrothiophens (2a-h) [equation (ii)] . In some instances[(2b and f) and (4c)l the sulphides were identified byC. Dell’Erba, D. Spinelli, and G. Leandri, Gazzetta, 1969, 99,535.R. A. Hoffman and S. Gronowitz, Arkiv h’emi, 1960, 16,515, 563; L. M. Jackman and S. Sternhell, ‘Applications ofNuclear Magnetic Resonance Spectroscopy in Organic Chemistry,’Pergamon, Oxford, 2nd edn., 19691976 2265oxidation by hydrogen peroxide in acetic acid to thecorresponding sulphones [(2'b and f) and (4'c)l and inother cases by comparison with authentic samples ob-tained by reactions of the dinitrothiophen (1) with thesame arenethi~lates.~ The total yield was high (90%)in the majority of cases (Table 1).The lower yield ob-served for (4g and h) and (2g and h) can be explained byReaction times and yields of cine-substitution products (2)and (4) in the reaction of 4-nitro-3-thienyl phenyl sul-phone (3) with sodium arenethiolates in methanolTABLE 1Arenethiolate4-MeC613,SNa3-MeC,H4SNa2-MeC,H4SNaPhSNa3-C1C,H4SNaZ-ClC,H,SNa2,4, 6-Me,C,H2SNa4-C1C6H,SNaReactiontime a71014142131(days)1 "0.4Yield (%)-713.5 76.56 8712 7812 7810 8413 839 666 47(2) (4)a At room temperature unless otherwise noted. Probableerror f 5 % ; all experiments were carried out at least induplicate. .4t reflux.partial decomposition, as ascertained independently, ofthe products under the conditions (reflux) required forthe reactions of (3) with Z-chloro- and 2,4,6-trimethyl-benzenethiolate.In all cases lower yields were obtainedby carrying out the reactions under reflux, e.g. withsodium 2-methylbenzenethiolate the combined yield of(2) and (4) fell to 53.4%.As previously found for the dinitrothiophen (1): theseresults indicate that even in this case cine-substitutioninstead of the expected normal substitution occurs,From the data of Table 1 the following further pointsemerge.(a) The ratio of the yields of (4) and (Z), alwaysgreater than unity, indicates that in the cine-substitutionsstudied the nitro-group is the preferred leaving group.(b) The same ratios are essentially independent of thesubstituent in the sodium arenethiolate as well as of theexperimental conditions. The ratios fluctuate between5 : 1 and 15 : 1 in a way which cannot be rationalized interms of substituent effects. (c) The reaction times(determined by t.1.c. analysis) are affected by the sub-stituent in sodium arenethiolate : an electron-withdraw-ing group in the meta- or @wa-position decreases the rate,and the opposite effect is observed €or electron-releasing* Methanol, a protonating agent for carbanion precursors of(a) J.F. Bunnett and R. E. Zahler, Chem. Rev., 1951, 49,273;T. Kauffmann, Angew. Chena. Internat. Edsz., 1965, 4, 513.8 T. Kauffmann, J. Hansen, K. Udluft, and R. Wirthwein,Angew. Chem. Internat. Edn., 1964, 3, 650; T. Kauffmann, R.Kiirnberg, and K. Udluft, Chem. Bey., 1969, 102, 1177,a (a) P. Buck, Angew. Chem. Internat. Edn., 1969, 8, 120;(3) J. 17. Bnnnett, Qztavt. Rev., 1958, 12, 1.10 R. W. Hoffrnann, ' Dehydrobenzene and Cycloalkynes,'Academic Press, New York, 1967, p. 66.l2 Ref. 10, p. 290.arynes, should inhibit the EA mechanism.8( b ) F. Pietra, Quart. Rev., 1969, 23, 504.Ref. 10, pp. 49, 50.R. Stoermer and B. Kahlert, Chem. B e y . , 1902, 35, 1633;€1.J . den Hertog and H. C. van der Plas, Adz!. Heterocyclic Ciiern.,1065, 4, 121.groups. (d) The reaction rate is influenced by stericeffects : the ortho-substituted benzenethiolates are lessreactive than the meta- and j!wa-isomers.Two mechanisms may be invoked to explain the for-mation of the sulphides (2) and (4): an elimination-addition (EA) mechanism via a heteroaryne intermediate,or an anomalous addition-elimination ( A Ea) mechan-Neither the effect of the substituent in thearenethiolate on the reaction rate nor the values of theyield ratios help in choosing between these mechanisms.The lower electronic density at the a-position adjacentto the nitro-group in (3) could favour both nucleophilicattack at this carbon atom and proton abstraction fromthis position.However, an EA mechanism is unlikelyfor several reasons (e.g. experimental conditions,*absence of methoxy-derivatives among reaction pro-ducts), especially the following. (a) Even though bothnitro and phenylsulphonyl groups are easily replaced bynucleophiles via a normal aromatic substitution, neitheris a good leaving group for the formation of a r y n e ~ , ~ J ~as demonstrated from the stability of a-nitro- 9a and o-phenylsulphonyl-phenyl-lithium.1° Moreover in ananionic intermediate like (5) or (6) the possibility of the-. YQX( 5 )( 5 )X = NO,, Y = PhSO,X = PhSO,, Y = NO,Y XH aArS( 7 ) X = NO,, Y = PhSO,( 8 ) X = PhSOZ, Y = NO,loss of group Y with its bonding electrons is greatlydecreased l1 because of the electronic effects of both theneighbouring group X and the sulphur atom,12 whichinductively stabilize the negative charge.(b) Althoughfive-membered heteroarynes have been proposed asreaction intermediates,13 recent papers 14915 havesuggested these claims to be ' ambiguous '.16It is therefore likely that in the reaction studied anAE, mechanism is operative. This mechanism shouldinvolve in the first step nucleophilic attack of the arene-thiolate anion at an a-position of (3) to give intermediatesl4 G. Wittig and M. Rings, Annalen, 1968, 719, 127; M. G.Reinecke and H. W. -4dickes, J . Amer. Chem. Soc., 1968, 90, 511;D. -4. de Bie, H. C. van der Plas, and G. Geurtsen, Rec. Tvav.chim., 1971, 90, 594; M. G. Reinecke and T.~ 2 . Hollingworth,J . Oyg. Chem., 1972, 37, 4257; D. A. de Bie, H. C. van der Plas,G. Geurtsen. and K. Nijdam, Rec. Trav. chim., 1973, 92, 245;M. G. Reinecke, W. B. Mohr, H. W. Adickes, D. A. de Bie, H. C.van der Plas, and I. Nijdam, J . Ovg. Chem.. 1973, 38, 1365.l5 Ref. 10, p. 293; H. J. den Hertog and H. C. van der Plasin ' Chemistry of Acetylenes,' ed. H. G. Viche, Dekker, New York,1969, p. 1149.l6 M. G. Reinecke and J. G. Newsom, -4bstracts, Fifth Inter-national Congress of Heterocyclic Chemistry, Lpblyana, 1975,p. c1like (7) and (€9, which, after protonation (or proton-assisted transfer) on the adjacent P-carbon atom followedby elimination of nitrous or benzenesulphinic acid, canfurnish the cine-substitution products (2) and (4),respectively.This pathway, completely different fromthat observed for 3-nitro-2-thienyl and 2-nitro-3-thienylphenyl sulpliones,2 and similar to that suggested for thereaction of the dinitrothiophen (1) with arenethi~lates,~can be related to the high degree of single-bond character l7between C-3 and C-4 in the substrates (1) and (3). Thehigher yield of (4) can be related to the fact that thenitro-group delocalizes the negative charge in the trans-ition states better than the phenylsulphonyl group,18favouring the formation of (8) with respect to (7).Moreover, steric factors could favour nucleophilic attacka t C-5, since it is likely that the phenylsulphonyl groupexerts a larger primary steric effect than the nitro-group.EXPERIMENTALlH N.m.r.spectra of solutions in CDC1, were measuredwith a Varian XL 100 instrument (Me,Si as internal ref-erence).4-Nitro-3-tlaienyl Phenyl Sulplzone (3) .-Oxidation of4-nitro-3-thienyl phenyl sulphide (see below) with 30%hydrogen peroxide in glacial acetic acid gave the sulphone,m.p. 162" (from ethanol) (Found: N, 5.3; S, 23.8.C,,H,NO,S, requires N, 5.2; S, 23.8%); 6 8.50 (1 H, d,J 3.96 Hz), 8.36 (1 H, d, J 3.96 Hz), 7.96-8.14 (2 H, ni),and 7.52-7.70 (3 H, m).4-Nitro-3-thienyl Phenyl Su1phide.-This sulphide wasprepared in one step (hydrolysis followed by decarboxylation)from methyl 4-nitro-3-phenylthio-2-thenoate lB as follows.The ester (2 g), suspended in 9M-sulphuric acid (20 nil) wasrefluxed for 2 h, cooled, and poured into ice-water, and theproduct was extracted with ether.The extract was washedwith water and 5% sodium carbonate solution, dried (Na,-SO,), and evaporated to give a solid (1.1 g, 69y0), whichcrystallized from light petroleum; m.p. 73" (Found: N,5.85; S, 26.95. C,,H,NO,S, requires N, 5.9; S, 27.0%);6 8.40 (1 H, d, J 3.92 Hz), 6.28 (1 H, d, J 3.92 Hz), and 7.38-7.70 (5 H, m).Reactions of 4-Nitro-3-thienyl Plaenyl Sulphone (3) withSodium Arenethio1ates.-A solution of compound (3) (0.5 g,1.86 mmol), the sodium arenethiolate (18.6 mmol), and thearenethiol (18.6 mniol) in methanol (100 ml) was kept a troom temperature or at reflux for the time indicated inTable 1. The methanol was evaporated off in vacuo andthe residue extracted with benzene.The extract waswashed with 5% sodium hydroxide solution (to remove theexcess of arenethiol) and water, dried (Na,SO,) , concentrated,and chromatographated on silica gel column (eluant 1 : 4benzene-light petroleum). After the initial fractions (con-taining diary1 disulphide) the 2-arylthio-4-nitrothiophen (2)was obtained. Further elution with benzene yielded the5-arylthio-3-thienyl phenyl sulphone (4). Mixed m.p.s ofthe sulphides (Za, c, d, g, and h) with the analogous com-pounds obtained from (1) as previously, showed no depres-sion. Compounds (2b and f) and (4c) were oils and werel7 M. Nardelli, F. Fava, and G. Giraldi, Acta Cryst., 1962, 15,737, and references therein; A. J. H. Wachters and D. W. Davies,Tetrahedron, 19f4, 20, 2841.J.Miller, Aromatic Nucleophilic Substitution,' Elsevier,Amsterdam, 1968, p. 166.Light petroleum had b.p. 30-50 "C.J.C.S. Perkin Icharacterized as sulphones [(2'b and f ) and (4'c)l obtainedby oxidation with hydrogen peroxide in glacial acetic acid.TABLE 2Physical and analytical dataFurther data are given in Tables 1-3.Cryst.Compd.* solvent t M.p. ("C)(2'b) B-LP" 83(2e) LP 59(2'f) MeOH 107-109(4a) NeOH 77-78(4b) LPc 62( 4 ' ~ ) RleOH 125-126(4d) MeOH 12&-121(4e) MeOH 141-142(4f) AleOH 88-89(4g) MeOH 93-94(4h) MeOH 121Calc. (%) [Found (?(,)IN, 4.95; S, 22.6[N, 5.0; S, 22.61C1, 13.1; N, 5.15; S, 23.55[Cl, 13.26; N, 5.2; S, 23.351C1, 11.7; N, 4.6; S, 21.1[CI, 11.85; N, 4.65; S, 21.251C, 58.95; H, 4.05; S, 27.75[C, 58.6; H, 4.05; S, 27.71C, 58.95; H, 4.05; S, 27.75[C, 59.05; H, 4.1; S, 27.751C, 53.95; H, 3.7; S, 25.4[C, 54.05; H, 3.65; S, 25.453C, 57.85; H, 3.6; S, 28.9[C, 57.95; H, 3.65; S, 28.851CI, 9.7; S, 26.2[Cl, 9.8; S, 25.953C1, 9.7; S, 26.2C1, 9.7; S, 26.2C, 60.95; H, 4.8; S, 25.65[C, 60.65; 13, 4.8; S, 25.41[Cl, 9.75; s, 25.951[CI, 9.8; s, 25.951"B.P.60-80". 6B.p. 30-50". 'B.P. 80-100".* Primed numbers indicate the corresponding sulphones. t B = benzene; L P = light petroleum.TABLE 3Chemical shifts (6) and coupling constantsH-P H-x Jap/Compd.* (1 H, d) (1 H, d) Hz(2'b) 8.10 8.46 1.657.74 8.30 1.618.14 8.49 1.65( 4 4 7.40 8.08 1.52(2:)(2 f )(4b) 7.44 8.10 1.50( 4'c) 7.84 8.32 1.50(4d) 7.43 8.10 1.60( 4 4 7.47 8.16 1.50(44 7.49 8.18 1.50(4g) 7.53 8.23 1.50(4h) 7.08 7.82 1.50Other7.34-7.50 (2 H, m), 7.74-7.887.16-7.32 (4 H, m) (ClC,H,S)7.40-7.66 (2 H, m), 7.80-8.00(2 H, m) (ClC,H,*SO,)7.48-7.68 (3 H, m), 7.90-8.05(2 H, m) (PhSO,) ; 7.02-7.30(4 H, m), 3.34 (3 H, s)(MeC,H,S)7.50-7.64 (3 H, m), 7.90-8.06(2 H, m) (PhSO,) ; 6.96-7.24(4 H, m), 2.30 (3 H. s)(hfeC,H,S)7.20-7.70 (6 H, m), 7.90-8.06(2 H, m), 5.04-8.22 (1 H, m),2.56 (3 H, s) (PhSO, andMeC,H,*S02)7.48-7.62 (3 H, m), 7.88-8.04(2 H, m) (PhSO,); 7.15-7.30(5H, m) (PhS)7.50-7.62 (3 H, m), 7.90-8.04(2 H, m) (PhSO,) ; 7.08-7.347.50-7.62 (3 H, m), 7.90-8.04(2 H, m) (PhSO,) ; 7.12-7.247.80-7.63 (3 H, m), 7.92-8.06(2 H, m) (PhSO,) ; 6.86-7.387.46-7.62 (3 H, m), 7.86-8.02(2 H, m) (PhSO,) ; 6.96 (2 H,s), 2.27 (3 H, s), 2.41 (6 H, s)(2 H, m), 2.44 (3 H, s)(JleC,H,*SO,)(4H, m) (ClC,H,S)(4 H, m) (C1C,H,S)(4H, m, (C1C6H4S)(Me3C6H2S) * Primed numbers refer to the corresponding sulphones.[6/662 Received, 5th April. 1976)1s D. Spinelli, G. Guanti, and C. Dell'Erba, J.C.S. Perkin 11,1972,441
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