Naphtho1,2-bthiophen. Part 2. Substitution reactions of derivatives with one or more substituents in the thiophen ring and of the 4,5-di-hydro-derivative

摘要

1977 63Naphthol,Z-blthiophen. Part 2.l Substitution Reactions of Derivativeswith One or More Substituents in the Thiophen Ring and of the 4,5-Di-hyd ro-derivat iveBy Kenneth Clarke," Derek N. Gregory, and Richard M. Scrowston, Department of Chemistry, The Uni-versity, Hull HU6 7RXAcetylation, formylation, and bromination of 2- or 3-methylnaphtho 1.2-61 thiophen and bromination of naphtho-1.2-bthiophen-3-carbaldehyde take place in the free thiophen position. Nitration of the 2-methyl compoundgives mainly the 5-nitro-derivative and 2-methyl-2-nitronaphthol,2-bthiophen-3(2H)-one; nitration of the3-methyl compound gives a mixture of the 2- and 5-nitro-derivatives. 2,3-Dimethylnaphtho1,2-6 thiophenundergoes bromination and acetylation in the 5-position. 4.5- Dihydronaphthol.2-6 thiophen undergoes mono-substitution in the 2-position ; attempted nitration of its 2-ethoxycarbonyl derivative gave mainly the aromatisedethyl naphthol,2-6 thiophen-2-carboxylate and its 7-nitro-derivative.SUBSTITUTED naphthol,2-blthiophens 2 9 3 and their 4,5-dihydro-derivatives 495 are being used increasingly asintermediates in the synthesis of biologically activemolecules.However, apart from our study1 of somesubstitution reactions of the parent molecule, thechemistry of naphtho 1,241 thiophen has not been exam-ined systematically. We therefore now describe someelectrophilic substitution reactions of naphtho1,2-b-thiophens containing one or more substituents in thethiophen ring, and of the 4,5-dihydro-derivatives (1) andVilsmeier-Haack formylation, Friedel-Crafts acetyl-ation, and monobromination of 3-methylnaphtho 1,241-(2) *Part 1, K.Clarke, D. N. Gregory, and R. M. Scrowston,0. Dann, G. Volz, E. Demant, W. Pfeifer, G. Bergen, H .B. P. Das, R. T. Cunningham, and D. W. Boykin, J .J.C.S. Perkin I, 1973, 2956.Fick, and E. Walkenhorst, Annulen, 1973, 1112.Medicin. Chem., 1973, 16, 1361.thiophen gave the appropriate substituted derivativein each case, for which the n.m.r. spectrum lacked a(1) X = H ( 3 )(2) X = CqEtquartet due to 2-H the n.m.r. spectrum of a 2-unsubsti-tuted S-methylnaphtho1,2-bthiophen shows a character-istic quartet ( J 2 . 5 ~ ~ ca. 1 Hz). These results were notA. Rosowsky, K. K. N. Chen, and M. Lin, J .Medicin.6 E. F. Elslager, P. Jacob, and L. M. Werbel. J. HeterocyclicChem., 1973, 16, 191.Chem., 1972, 9, 776J.C.S. Perkin Iunexpected, since the parent compound also undergoessubstitution in the 2-position.1 The fact that formyl-ation proceeded smoothly in the presence of phosphorylchloride and dimethylformamide illustrates the enhancedreactivity of the 3-methyl compound; naphtho 1,241-thiophen itself is formylated only in the presence of themore reactive N-rnethylformani1ide.l Nitration of 3-methylnaphthol,2-b thiophen in glacial acetic acid gavea mixture of the 2- (40) and 5-nitro-isomers (60).The 2-nitro-compound was too insoluble to allow asatisfactory n.m.r. spectrum to be obtained. However,it was successively reduced and acetylated, and thespectrum of the resulting acetamido-compound showedclearly the absence of a 2-H signal, As we have alreadyindicated,l the 4- and 5-H signals in the n.m.r.spectra ofnaphtho 1,241 thiophen derivatives are often not wellresolved, thus rendering it almost impossible to differen-tiate between a 4- or 5-substituent. However, advantagecould be taken of the nuclear Overhauser effect to iden-tify 5-substituted naphtholJ2-bthiophen derivatives.Thus, saturation of the 3-Me resonance from the majorisomer from the nitration reaction gives a 20 enhance-ment of the signal at 6 8.48; from the stereochemistry ofthe system, this signal can only be due to 4-H. Chemicalproof of the sfructure of the 5-nitro-compound camefrom its conversion by standard means into 5-bromo-3-rnethylnaphtholJ2-bthiophen; this could also be ob-tained unambiguously by cyclodehydration of (4-bromo-1 -naphthylthio) acetone.Dibromination of 3-methylnaphtho 1,241 thiophengave the 2,5-dibromo-derivative. Its structure followedfrom the observation that it could also be obtained bybromination of either 5-bromo-3-methyl- or 2-bromo-3-methyl-naphthol,2-b thiophen.Next we prepared 2-methylnaphthol,2-bthiophen,both by Huang-Minlon reduction of the correspondingaldehyde and, preferably, by reductive silylation 6 ofthe readily available 2-carboxylic acid in the presenceof trichlorosilane and triethylamine, followed by alkalinehydrolysis of the resulting trichloro- (2-napht ho 1,241 -thienylmethy1)silane.PreviouslyJ7 we had shown thatthe isomeric 2-met h ylnapht ho 2,l -b t hiop hen undergoessubstitution in the 5-positionJ rather than in the remain-ing free thiophen position. We suggested that thisbehaviour might be due to steric interaction between thel-position (corresponding to the 3-position in the 1,2-b-isomer) and the 9-position. Since a steric effect of thistype is not possible for the lJ2-b-isomer, we expectedthat the 3-position in 2-methylnaphtholJ2-b thiophenwould be activated towards electrophiles by the methylgroup (cf. the behaviour of 2-methylbenzobthiophenOur predictions were confirmed : bromination, acetyl-ation, and formylation of 2-methylnaphtholJ2-blthio-phen each gave a 3-substituted derivative, which lackedCf.R. A. Benkeser, K. M. Foley, J. M. Gaul, and G. S. Li, J .I. Clarke, G. Rawson, and R. M. Scrowston, J . Chem. Soc.B. Iddon and R. M. Scrowston, Adv. Heterocyclic Chem.,Amer. Chem. SOC., 1970, 92, 3232.( C ) , 1969, 1274.1970, 11, 177.a signal due to 3-H in its n.m.r. spectrum. When the2-methyl compound was treated with bromine (2 mol.equiv.) the second bromine atom entered the methylgroup. The resulting 3- bromo-2- bromomet hylnapht ho-1,2-bthiophen could not be obtained pure, probablybecause of the lability of the bromine atom in the side-chain. It was converted into the corresponding ethoxy-methyl compound merely by heating with ethanol.Nitration of 2-methylnaphthol,2-bthiophen gave amixture of seven components, from which 2-methyl-5-nitronaphthol,2-bthiophen ( 16y0) and 2-methyl-2-nitronaphtho 1,241 thiophen-3(2H)-one (3) (10) wereisolated ; surprisingly, no 3-nitro-compound was detected.An $so-nitration product analogous to the ketone (3)is also formed during the nitration of 2-bromo-3-methyl-benz~bjthiophen.~ Spectroscopic evidence for struc-ture (3) is cited in the Experimental section.Thestructure of the 5-nitro-compound did not follow im-mediately from its n.m.r. spectrum (cj. discussion above).However, by comparing the spectrum of 5-nitronaphtho-1,2-bthiophen with that of naphthol,2-bthiophenJ1Osubstituent chemical shifts for a 5-nitro-substituent inthe naphtholJ2-b thiophen nucleus could be calculated.When these values were added to the chemical shift ofeach proton in 2-methylnaphtho1,2-bjthiophen, theresulting calculated chemical shifts corresponded closelywith those observed for the product from the nitrationreaction.The structure was confirmed by convertingthe 5-nitro-compound into the corresponding 5-bromo-compound ; this was identical with a sample of 5-b1 omo-2-methylnaphtho1,2-bthiophen prepared unambigu-ously from the corresponding 2-carboxylic acid.We next prepared 2,3-dimethylnaphtho1,2-bthiophenby Huang-Minlon reduction of S-methylnaphthol,2-b-thiophen-2-carbaldehyde and established that it under-went bromination in the 5-position by demonstratingthat an identical product could be obtained by successivef ormylation and Huang-Minlon reduction of 5-bromo-3-methylnaphthol,2-bthiophen. Earlier workers l1 be-lieved that 2,3-dimethylnaphtho1,2-bthiophen under-went Friedel-Crafts acetylation in the 6-position.How-ever, such a result would not fit in with the pattern whichour work had indicated for the order of reactivity towardselectrophiles of the various positions in substitutednaphtholJ2-bthiophens (i.e. 2 3 5). We thereforeobtained the 5-carbonitrile from the 5-bromo-compound,treated it with methylmagnesium iodide, and confirmedthat the resulting ketone was indeed identical with theacetylation product.We have already shown1 that the presence of theelectron-withdrawing 2-ethoxycarbonyl substituent inthe naphtholJ2-bthiophen nucleus leads to electro-philic attack in the 5-position.We now wished toexamine the effect of an electron-withdrawing group* J. Cooper and R. M. Scrowston, J . Chsm. Soc. ( C ) , 1971,lo D. F. Ewing and -R. M. Scrowston, Org. Magnetic Resonance,l1 P. Cagniant, D. Cagniant, and P. Faller, Bull. SOC. chim.3052.1971, 3, 405.France, 1964, 17561977 65in the 3-position, and therefore brominated naphtho- 1,241 thiophen-3-carbaldehyde. The aldehyde was con-veniently obtained from the 3-bromomethyl compoundvia the Sommelet reaction. Bromination took placewith difficulty in the 2-position, thus illustrating againthe high reactivity of this position. The result wasunexpected, because the corresponding aldehyde in thenaphtho(2,l-blthiophen series is brominated in the5-position.Further, benzob thiophen-3-carbaldehyderesists bromination, even under forcing conditions,12 andis nitrated entirely in the benzenoid ring.13Finally, we obtained 4,5-dihydronaphtho 1,241 thio-phen from the readily available ester (2), in order tocompare its substitution reactions with those of naph-thol,2-b thiophen and those of 9,lO-dihydrophenan-threne. I t is believed l4 that the substitution patternsof fluorene, 9,1O-dihydrophenanthrene, and relatedcompounds are governed by the mesomeric interactionsof the two benzene rings, and that the alkyl chain simplymodifies these interactions by altering the angle betweenthe planes of the two aromatic nuclei which it links.Models show that the 4,5-bridge in the dihydro-com-pound (1) causes the two aryl groups to have roughly thesame spatial relationship as the two phenyl groups in9,lO-dihydrophenanthrene. It might be expected, there-fore, that 4,5-dihydronaphthol,2-bthiophen, like 9,lO-dihydrophenanthrene,l49l5 would undergo substitutionfirst in the 2-position, then in the 7-position.However,the possibility of the second substituent entering theremaining vacant position in the thiophen ring could notbe discounted.The results of bromination (bromine-acetic acid),iormylation, and monoacetylation reactions confirmedour predictions. Each reaction gave the appropriate2-substitu t ed 4,5-dihydronaph t ho 1,241 t hiophen, whichwas converted (see Experimental section) into 4,5-dihydronaphtho 1,241 thiophen-2-carboxylic acid inorder to confirm its structure.Treatment of thedihydro-compound (1) with N-bromosuccinimide gavemainly naphthol,2-bthiophen (6176) cf. the dehydro-genation (880/'0) of the ester (2) by N-bromosuccinimide l,together with starting material (15y0), 2-bromo-4,5-dihydronaphthol,2-bthiophen ( 14y0), and an unidenti-fied product (10). The acetylation reaction withacetyl chloride (1 mol. equiv.) gave the 2-acetyl compound(83) and a diacetyl derivative (16). When acetylchloride (2 mol. equiv.) was used the proportion of thelatter increased to 40 ; the n.m.r. spectrum showedclearly that the second acetyl group occupied either the7- or the 8-position, but no firm distinction was possible.However, we shall show that the ester (2) undergoessubstitution in the 7-position; by analogy, it seemslikely that the second acetyl group of the diacetyl com-pound occupies the 7-position.Further, 2-phenylthio-l2 Y . Matsuki and T.-C. Lee, J . Chem. SOC. Japan, 1966, 87,l3 G. C. Brophy, S. Sternhell, N. M. D. Brown, I. Brown, K. J.l4 P. B. D. de la Mare, E. A. Johnson, and J. S. Lomas, J.186.Armstrong, and M. Martin-Smith, J. Chem. SOC. { C ) , 1970, 933.Chem. SOC., 1963, 6973; 1964, 6317.phen, which is structurally analogous to the dihydro-naphthothiophen (1), undergoes substitution l6 first inthe thiophen ring, then in the para-position of the benzen-oid ring; the latter position corresponds to the 7-positionin the dihydro-compound (1).In common with thenitration reactions already described, the nitration of4,5-dihydronaphthol,2-bthiophen did not proceedsmoothly. Nitration with nitric acid under variousconditions or with copper(r1) nitrate in acetic anhydridegave a tar in each case, from which 4,5-dihydro-2-nitro-naphthol,2-bthiophen (ca. 10) could be isolated.Its structure was not immediately evident because therelevant peaks in the n.m.r. spectrum were unresolved.It was therefore aromatised with N-bromosuccinimide,to give 2-nitronaphthol,2-bthiophen which, becauseit was too insoluble for examination by n.m.r. spectro-scopy, was converted by the route already described intothe 2-acetamido-compound. An identical product wasobtained from the Beckmann rearrangement of 2-acetyl-naphthol,2-b thiopheii oxime.We next attempted to acetylate ethyl 4,5-dihydro-naphthothiophen-2-carboxylate (2) in the hope that thestructure of the product could be related to that of thediacetyl compound already described.However, undermild conditions no reaction was observed; under moreforcing conditions only intractable products wereobtained. We therefolle nitrated the ester (2) in orderto observe how the presence of an electron-withdrawinggroup in the 2-position affected the substitution patternof the dihydro-system (1). However, the major product(73) was ethyl naphtho 1,2-bthiophen-2-carboxylate,thus confirming our previous observation that the ester(2) is readily dehydrogenated. The other products wereethyl 7-nitronaphthol,2-b thiophen-2-carboxylate (9)and ethyl 4,5-dihydro-7-nitronaphthol,2-bthiophen-2-carboxylate (18).Only the former was obtainedpure, but the structural relationship between the twoproducts was evident from a spectroscopic examinationof the mixture and from the fact that the mixture wasconverted almost quantitatively into the former productby dehydrogenation. As before, the splitting patternin the n.m.r. spectrum of ethyl 7-nitronaphthol,2-b-thiophen-2-carboxylate was consistent with the presenceof either a 7- or an 8-substituent. However, the sub-stituent chemical shifts for the nitro-group in benzeneare well authenticated; l7 knowing the chemical shiftsfor 6-, 7-, 8-, and 9-H in ethyl naphthol,2-bthiophen-2-carboxylate (8 7.88, 7.58, 7.51, and 8.11, respectively),it is possible to predict the chemical shifts of the ABXsystem for both a 7- and an 8-nitro-substituent.Thecalculated 8 values for 6-, 8-, and 9-H in the 7-nitro-compound are 8.83 (8.85), 8.46 (8.38), and 8.28 (8.30),respectively; the observed values are quoted in paren-theses. For the 8-nitro-compound, the calculated 8l5 Cf. J. W. Krueger and E. Mosettig, J. Ovg. Chem., 1938, 3,340; N. P. Buu-Hoi, P. Mabille, and D.-C. Thang, Bult. SOC.chim. France, 1966, 1667.16 S. Gronowitz and N. Gjers, Acta Chey. Scand., 1967, 21, 2823.17 L. M. Jackman and S. Sternhell, Applications of NuclearMagnetic Resonance Spectroscopy in Organic Chemistry,' 2ndedn., Pergamon, Oxford, 1969, p. 20266 J.C.S.Perkin Ivalues are 8.05 (6-H), 8.53 (7-H), and 9.06 (9-H). Thesedata show that the nitro-compound is almost certainlythe 7-nitro-isomer. Ethyl naphtho 1,241 thiophen-2-carboxylate is nitrated in the 5-position,l so the 7-nitro-derivative just described must have been formed bynitration of the dihydro-compound (2), followed bydehydrogenation.We calculated electron densities and localisationenergies (cf. ref. 1) for each of the naphthol,2-bthiophenson which we had carried out substitution reactions;3-methyl-2-(o-tolyl) thiophen was used as a model forour calculations on 4,5-dihydronaphthol,2-b thiophen.Except for 2- and 3-methylnaphthol,2-b thiophen, therewas poor correlation between these values and the ob-served position of substitution, thus highlighting theinadequacies (cf.ref. 1) of LCAO-MO Hiickel calculationsas applied to polycyclic thiophen derivatives.EXPERIMENTALGeneral experimental details and general procedures forsubstitution reactions are described in Part 1 .l(4-Bromo- 1-naphthy2thio)acetone.-Prepared (6 1 yo) from4-bromonaphthalene-l-thiol la by the usual method (cf. ref.19), this was obtained as an oil, b.p. 180-186" a t 0.5 mmHg(Found: C, 52.7; H, 3.7; M+, 294/296. Cl,HllBrOSrequires C, 52.9; H, 3.75 ; M+, 294/296), v,,,. (film) 1 705cm-1 ( G O ) .3-Methy2naphtho1,2-bthiophen.-Treatment of (l-naph-thylthio) acetone with polyphosphoric acid a t 80-90 "Cfor 4 h gave a mixture (8 : l), b.p. 120-126" a t 0.2 mmHg,m.p. 62-68' (lit.,19 m.p.60.5-61.5"), of 3-methylnaphtho-l,Zbthiophen and 3-methylnaphthol,8-bcthiopyran.Fractional crystallisation from ethanol gave the former(39) as prisms, m.p. 76-77" (lit.,11 7 7 O ) , 6 2.46 (d, Me) and7.08 (4, 2-H, J 1.0 Hz). Attempted purification of thelatter via the picrate gave material of only 70 purity,6 2.84 (Me).Similar cyclisation of (4-bromo- l-naphthy1thio)acetonegave a homogeneous product, from which 5-bromo-3-methyl-nuphtho 1,2-bthioPhen (65) was obtained as needles, m.p.115.5-117deg; from ethanol (charcoal) (Found: C, 56.6;H, 3.5; M+, 276/278. Cl,HoBrS requires C, 56.35; H,3.25 ; M f 276/278), 6 2.33 (d, Me) and 7.02 (9, 2-H, J 0.8Hz).3-MethyZnaphtho 1,2-bthioPhen-2-carbaZdehyde.- 3-Meth-ylnaphtho 1,2-b thiophen was formylated with phosphorylchloride and dimethylformamide, to give the aldehyde (75),m.p.209-210" (prisms from ethanol) (Found: C, 74.5;H, 4.6; M , 226. C,,H,,OS requires C, 74.3; H, 4.45;M , 226), vmax. 1640 cm-l ( G O ) , 6 10.34 (CHO) (no 2-Hsignal).Obtained similarly from 5-bromo-3-methylnaphtho 1,241-thiophen, 5-bromo-3-methyZnaphthol,2-bthio~hen-2-carb-aldehyde (31) formed yellow prisms, m.p. 163-166' (fromethanol) (Found: C, 55.35; H, 3.0; M+, 304/306.Cl,HoBrOS requires C, 55.1; H, 2.95; M+, 304/306),vmx. 1665 cm-l (GO), 6 2.77 (s, Me), 8.08 (s, 4-H), and10.28 ( s , CHO).2-A cetyZ-3-methylnaphtho 1,2-bthiophen.- Friedel-Craftsacetylation of 3-methylnaphtho 1,2-b thiophen with acetylJ . E. Banfield, W.Davies, N. W. Gamble, and S. Middleton,J . Chem. SOC., 1956, 4791.chloride in methylene chloride gave prisms (70y0), m.p.138-139" (1it.,l1 141") (from ethanol), vmx. 1 640 cm-l (GO).The acetyl group was reduced by the Huang-Minlonmethod, to give 2-ethyZ-3-methylna$htho 1, 2-bIthiophen(55y0), m.p. 42-44" (prisms from ethanol) (Found: C,79.9; H, 6.4; M , 226. C15Hl,S requires C, 79.6; H,6.25 ; M , 226).Bromination of 3-Methylnaphtho 1,2-b thiophen .-Treat-ment with bromine (1 mol. equiv.) in carbon tetrachloridegave 2-bromo-3-methyZnuphtho 1,2-bthiophen (93) asneedles, m.p. 120-122" (from ethanol) (Found: C , 56.0;H, 3.4; M+, 276/278. Cl,H,BrS requires C, 56.3; H,3.25 ; M+, 276/278).Use of bromine (2.01 mol. equiv.) in boiling glacial aceticacid gave the 2,5-dibromo-com~ound (78y0), m.p.133-136"(needles from ethanol) (Found: C, 43.8; H, 2.6; M+,354/356/358. C,,H,Br,S requires C , 43.85; H, 2.3; Mf,354/356/358), 6 2.35 (Me) and 7.87 (4-H). The same productwas obtained (70 and SOY0, respectively) by treatment ofeither 5-bromo-3-methyl- or 2-bromo-3-methyl-naphtho-1,2-bthiophen with bromine (1 mol. equiv.) in acetic acid.Nitration of 3-MethyZnaphtho 1,2-bthiophen.-Nitrationin acetic acid gave a mixture of two components 3 : 2 (g.l.c.)from which 3-methyZ-2-nitronaphtho 1,ZbIthiophen (theminor component) was obtained by several recrystallis-ations from ethanol. It formed yellow feathers, m.p.245-248" (Found: C, 63.7; H, 3.95; N, 6.0; M , 243.Cl,H9N0,S requires C, 64.15; H, 3.75; N, 5.75; M , 243).The 5-nitro-isomer was obtained from the mother liquors aspale red needles, m.p.154.5-155.5" (from light petroleum)(Found: C, 64.05; H, 3.6; N, 5.7; M , 243), 6 2.51 (d,Me), 7.24 (q, 2-H, J 1.0 Hz), and 8.48 (s, 4-H).The 2-nitro-compound was reduced with Raney nickel andhydrazine hydrate by the method used for 5-nitronaphtho-1,2-bthiophen.l The resulting amine was acetylated withacetic anhydride in pyridine, to give 2-acetamido-3-methyl-naphthol,2-bthiophen (87y0), m.p. 222-223.5' (from eth-anol) (Found: C, 70.6; H, 5.0; N, 5.25; M , 255.C15Hl,NOS requires C , 70.55; H, 5.15; N, 5.5; M , 255).Similar reduction of the 5-nitro-isomer gave the corres-ponding $mine, the hydrochloride of which had m.p.230-233" (from ethanol). The diazotised amine was treatedwith copper(1) bromide in hydrobromic acid,20 t o give5-bromo-3-methylnaphtho 1,2-b thiophen, m.p. and mixedm.p. 115-1 17".2-Methylnaphtho 1,2-bthiophen.-A mixture of naphtho-1,2-bthiophen-2-carboxylic acid l (4.56 g, 0.02 mol),trichlorosilane (1 6.3 g, 0.12 mol) , and dry acetonitrile (40 ml)was heated under reflux for 1 h. The cooled solution wasthen treated dropwise with triethylamine (5.75 g, 0.057 mol)a t such a rate that the temperature did not exceed 15 "C,and heated under reflux overnight. Ether (150 ml) wasadded to the cooled solution to precipitate the amine hydro-chloride, then the filtered solution was evaporated underreduced pressure.The residual oil was boiled with meth-anol (10 ml) for 1 h, then the mixture was heated underreflux overnight with potassium hydroxide (1 1 g) in methanol(20 ml) and water (5 ml), and poured into water. Extrac-tion with ether gave the product as a pale yellow oil (3.15 g,79), b.p. 108-115" at 0.1 mmHg (Iit.,l 110-118" a t 0.1mmHg).lo W. Knapp, Monatsh., 1932, 60, 189.2o A. I. Vogel, 'A Text-book of Practical Organic Chemistry,'3rd edn., Longmans, London, 1956, p. 6021977 67Obtained similarly, 5-bromo-2-methyZna~htho 1,2-bthio-phen (48) formed needles, m.p. 90-90.5" (from ethanol)(Found: C, 56.55; H, 3.7; M+, 276/278. C,,H,BrSrequires C, 56.35; H, 3.25; Mf, 276/278), 6 2.60 (d, Me)and 6.96 (q, 3-H, J 1.0 Hz).Substitution Reactions of 2-MethyZnaphtho lJ2-bthiophen.-(a) Formylation.Use of phosphoryl chloride and N-methylformanilide gave 2-methyZnaphtho1,2-bthiophen-3-curbaldehyde (53) as off-white needles, m.p. 133.6135"(from ethanol) (Found: C, 74.4; H, 4.4; MI 226), vmx.1 665 cm-l (C=O), 6 10.01 (s, CHO).(b) A cetylation. 3-A cetyZ-2-methyZnaphtho 1,2-bthiophen(83) was obtained as prisms, m.p. 81-83" (from ethanol)(Found: C, 74.8; H, 4.9; M , 240. C,,H,,OS requiresC, 74.95; H, 5.05; M , 240), vmax. 1 665 cm-l (GO).(c) Brovninution. Use of bromine (1 mol. equiv.) incarbon tetrachloride gave 3-bromo-2-methyZnu~hthol,2-b-thiophen (72) as needles, m.p. 98-100" (from ethanol)(Found: C, 56.0; H, 3.25; M+, 276/278).Use of bromine (2 mol. equiv.) in boiling acetic acid gave3-bromo-2-bromomethylnaphtho 1,2-bthiophen as an oil(Found: M+, 354/356/358), 6 4.68 (s, 2 H, CH,Br).Boilingthe crude product with ethanol gave 3-bromo-2-ethoxy-methyZna~htho1,2-bthiophen (31 overall) as needles, m.p.65-67' (from ethanol) (Found: Mf, 319.9861. C15H13-7QBrOS requires M, 319.9870), 6 3.93 (9, O*CH,Me) and4.37 (s, ArCH,-0).The mixture obtainedby carrying out the nitration reaction in acetic acid waschromatographed on silica gel. Elution with benzene gave2-methyZ-5-nitronuphtho1,2-bthiophen ( 16y0), m.p. 156-157" (yellow needles from ethanol) (Found: C, 64.5; H,(d) Nitration (with G. RAWSON).3.95; N, 5.7; M , 243), 6 7.13 (7.16) (3-H), 7.61 (7.59)(7-H), 7.63 (7.67) (8-H), 8.05 (8.16) (6-H), 8.43 (8.43) (4-H),and 8.59 (8.56) (9-H); calculated chemical shifts (see text)are given in parentheses.The nitro-compound was con-verted as before into 5-bromo-2-methylnaphtho 1,241-thiophen, identical with authentic material.Chromatography of the nitration product on alumina(grade 11) and elution with benzene gave first a brown oil,then a yellow oil. The latter solidified on trituration withhexane-chloroform (1 : l), to give 2-methyl-2-nitronaphtho-1,2-bthiophen-3(2H)-one (3) (10) as yellow prisms,m.p. 139-141" (from ethanol) (Found: M+, 259.0328.C,,H,NO,S requires M , 259.0303), vmax 1702 (GO), 1335,and 1465 cm-l (NO,), 6 2.26 (s, Me).2, 3-Dimethylnaphtho 1,2-bthiophen.-Obtained (70) byHuang-Minlon reduction (cf. ref. 1) of 3-methylnaphtho-1,2-bthiophen-2-carbaldehyde, this had m.p.100.5-102.5" (lit.,,, 108.5-109.5") (from ethanol), 6 2.44 and 2.51(2 x Me).5-Bromo-2,3-dimethyZnaphtho 1, 2-bthiophen, obtainedsimilarly by reduction of the appropriate 2-carbaldehydeformed prisms (68), m.p. 98-99.5" (from ethanol) (Found:C, 57.9; H, 4.0; M+, 290/292. C1,H,,BrS requires C,57.75; H, 3.8; M , 290/292), 6 2.25 and 2.47 (2 x Me)and 7.86 (4-H). The same bromo-compound was obtained(62) by treatment of 2,3-dimethylnaphtho 1,2-b thiophenwith bromine (1 mol. equiv.) in carbon tetrachloride.5-AcetyZ-2, S-dimethyZnaphtho 1,2-bthiophen.-(a) A stir-red mixture of the foregoing bromo-compound (0.25 g),copper(1) cyanide (0.1 g), and quinoline (10 ml) was heatedunder reflux for 2 h, then cooled and poured into an excessof dilute hydrochloric acid.Extraction with chloroformgave a green oil which was filtered in benzene throughalumina, to give 2,3-dimethyZnaphtho 1,2-bthiophen-5-cur-bonitrile (0.16 g, 78) as needles, m.p. 140-142" (frombenzene-light petroleum) (Found: C, 75.95; H, 4.5; N,5.9; M , 237. C,,H,,NS requires C, 75.9; H, 4.65;N, 5.9 ; M , 237), v,, 2 225 cm-l ( E N ) .(b) A solution of the 5-carbonitrile (0.5 g) in ether (20 ml)was added dropwise during 15 min t o a stirred solution ofmethylmagnesium iodide from magnesium (0.1 g) in ether(10 ml). The mixture was kept at 0 "C overnight, thenpoured into ice and concentrated hydrochloric acid. Ex-traction with ether gave the ketone (0.3 g, 56y0), m..p.117-119" (1it.,l1 116-117") (from ethanol), identical withthe product obtained by Friedel-Crafts acetylation of 2,3-dimethylnaphthol, 2-blthiophen.Nuphthol,2-bthiophen-3-carbuZdehyde.-(a) Brominationof 3-methylnaphtho 1,241 thiophen with freshly recrystal-lised N-bromosuccinimide in the usual way gave 3-bromo-methylnaphthol,2-bthiophen (71) as needles, m.p.85-87' (from light petroleum), M+ 276/278, 6 4.65 (CH,Br).(b) A solution of the bromomethyl compound (8.0 g) indry chloroform (40 ml) was added slowly t o a boiling solutionof hexamethylenetetramine (4.0 g) in chloroform (30 ml).The mixture was heated under reflux for 3 h, then cooledand filtered. The hexamine salt was washed light petrol-eum (b.p. 40-60') and dried, then heated under reflux for3 h with aqueous 50 acetic acid (35 ml).Water (30 ml)and concentrated hydrochloric acid (7 ml) were added, thenthe mixture was boiled for 5 min and kept a t 0 "C overnight.The precipitate was filtered off and crystallised from aqueousethanol, to give yellow prisms (3.8 g, 62), m.p. 81.5-83'(Found: C, 73.3; H, 3.8; M , 212. C,,H,OS requiresC, 73.55; H, 3.8 : M , 212), vmaX. 1 675 cm-l (CEO), 6 10.15(s, CHO).2-Bromonaphtho 1,2-b thiophen-3-cavbddehyde .-The fore-going aldehyde was brominated in chloroform for 9 h at40 'C, t o give needles (51), m.p. 139-142" (from ethanol-water) (Found: C, 53.6; H, 2.5 ; M+, 290/292. C,,H,Br-0s requires C, 53.6; H, 2.4 ; M , 290/292), vmx, 1 675 cm-l(GO), 6 7.87 (d, 5-H), 8.38 (d, 4-H, J 8.6 Hz), and 10.13 (s,CHO) (no 2-H signal).4,5-Dihydronaphtho 1,2-bthiophen (1) .-Hydrolysis of theester (2) with ethanolic sodium hydroxide gave 4,5-dihydro-naphtho1,2-bthiophen-2-carboxyZic; acid (99) as prisms,m.p.199-200" (from ethanol) (Found: C, 68.0; H, 4.5 ;M , 230. C1,HloO,S requires C, 67.8; H, 4.4; M , 230),vmax. 1 660 cm-l (GO). This was decarboxylated withcopper in quinoline at 210 'C (cf. Part 1 I), to give an oiZ(87y0), b.p. 97-106' a t 0.1 mmHg (Found: C, 77.5; H,5.4; M , 186. C,,HloS requires C, 77.35; H, 5.4; M ,186), 6 2.80 (m, CH,*CH,).Bromination of 4,5-Dihydrona~hthol,2-bthiophen (1) .-(a) Use of N-bromosuccinimide under the conditions alreadydescribed gave the results indicated in the text.(b) Use of bromine (1 mol.equiv.) in glacial acetic acid inthe presence of an iron catalyst gave a dark residue whichwas distilled under nitrogen, to give the 2-bromo-compound(81) as an unstable, pale green oil, b.p. 114-116' at 0.1mmHg (Found: M+, 264/266. C,,H,BrS requires M ,The bromo-compound was heated with copper(1) cyanidein quinoline under the conditions already described, t o give4,5-dihydrona~htho1,2-bthiophen-2-carbonitriZe (75) as adark red oil, b.p. 176-178" a t 1.0 mmHg (Found: C, 73.4;H, 4.35; N, 6.8; M , 211. C,,HQNS requires C, 73.9;H, 4.3; N, 6.65; M , 211), vmx. 2 210 cm-l (C-").264/266), 6 6.72 (s, 3-H)68 J.C.S. Perkin IThe nitrile was hydrolysed with sodium hydroxide inethanol-water (1 : l), to give 4,5-dihydronaphtholJ2-b-thiophen-2-carboxylic acid (73 ), identical with authenticmaterial.4,5-Dihydro-2-nitronaphtho 1,2-b thiophen.--Nitration ofthe dihydro-compound (1) in acetic acid gave an oily mixture(1 : 2) of starting material and the 2-nitro-compound (g.1.c.).Chromatography on silica gel and elution with benzenegave the nitro-compound as the slower running component.It formed yellow prisms (12), m.p.117-119' (fromethanol) (charcoal) (Found: C, 62.45; H, 3.65; N, 6.25;M , 231. C12H,N02S requires C, 62.3; H, 3.9; N, 6.05;M , 231), 6 2.92-2.98 (m, CH,*CH2).Nitration with nitric acid in AcOH-Ac,O a t 0 "C or withcopper(I1) nitrate in Ac20 at 40 "C gave similar mixtures ofproducts, admixed with tarry material.Identification of 4,5-Dihydro-2-nitronaphtho lJ2-bthiophen.-(a) 2-Acetamidonaphtho 1,2-bthiophen. Powdered phos-phorus pentachloride (0.5 g) was added in portions to astirred solution of 2-acetylnaphtho 1,241thiophen oxime(0.5 g) in dry ether (100 ml).The resulting solution waskept a t room temperature for 3 h, then it was washed (H20and ~ M - N ~ O H ) , dried, and evaporated. The residue formedwhite needles (0.3 g, 60), m.p. 194-195.5' (from benzene)(charcoal) (Found: C, 69.6; H, 4.7; N, 5.8; M , 241.C,,H,,NOS requires C, 69.7; H, 4.6; N, 5.8; M , 241),vmaX 1 650 ( G O ) and 3 240 (NH) cm-l.(b) 2-Nitronaphtho 1,2-bthiophen. The 4,5-dihydro-2-nitro-compound was aromatised with N-bromosuccinimideby the method described in Part 1,l to give brownneedles (Six), m.p.161.5-163.5" (from ethanol) (Found:C, 62.5; H, 3.1; N, 5.9; M , 229. C,,H,NO,S requiresC, 62.85; H, 3.1; N, 6.1; M , 229), i.r. spectrum wasidentical with that of the minor product from the nitrationof naphthol,2-bthiophen.(c) Reductive acetylation of 2-nitronaphtho 1,2-bthiophen.A solution of the nitro-compound (0.1 g) in glacial aceticacid (30 ml) and acetic anhydride (1 ml) was shaken over-night with hydrogen in the presence of Adams catalyst (30mg), then filtered. The filtrate was poured into water andneutralised with sodium hydrogen carbonate. Extractionwith ether gave the 2-acetamido-compound (0.04 g, 38),m.p. 192-194", identical with that obtained in (a).FriedeGCrafts Acetylation of 4,5-Dihydronaphtho 1,2-b-thiophen.-Use of acetyl chloride (1 mol.equiv.) gave amixture of mono- and di-acetyl compounds (5 : 1) (g.l.c.),which was resolved by chromatography on silica gel andelution with chloroform. The 2-acetyl compound, elutedfirst, formed long yellow needles, m.p. 112-115" (fromethanol) (Found: C, 73.45; H, 5.4; M , 228. C,,H,,OSrequires C, 73.65; H, 5.3: M , 228), vmax. 1 640 cm-l (GO),6 2.54 (s, Ac) and 2.90 (m, CH,CH,).Continued elution gave the 2,7-diacetyl compound, whichcrystallised from ethanol as pale yellow needles, m.p. 141-143.5" (Found: C, 70.8; H, 5.25; M , 270. C,,H,,O,Srequires C, 71.1; H, 5;2; M , 270), vmx. 1650 and 1 670cm-l (CSO), 6(C,D,) 2.10 and 2.17 (s, 2 x Ac), 2.30-2.57(m, CH,CH,), 7.01 (s, 3-H), 7.19 (dd, 9-H), 7.52 (dd, 8-H),and 7.66 (dd, 6-H) (JS,* 8.5, J6.8 1.5, J6.9 0.5 Hz).Thediacetyl compound was obtained in 40 yield when acetylchloride (2 mol. equiv.) was used for the acetylation.Oxidation of the 2-acetyl compound with sodium hypo-iodite in dioxan gave 4,5-dihydronaphtho 1,241 thiophen-2-carboxylic acid (68) , identical with authentic material.4,5-Dihydronaphtho 1,2-bthioPhen-2-carbaZdehyde.-Form-ylation of the dihydro-compound (1) with phosphorylchloride and dimethylformamide gave a pale yellow oil(70), b.p. 138-142' a t 0.1 mmHg (Found: C, 72.7; H,4.9; M , 214. C,,H,,OS requires C, 72.85; H, 4.7;M , 214), vmx. 1660 cm-l (GO), 6 2.82-2.97 (ma CH,*CH2)and 9.82 (s, CHO).It was oxidised by silver oxide (cf. ref. 1) to the corres-ponding 2-carboxylic acid (70), identical with authentic 1material.Nitration of Ethyl 4,5-Dihydronaphtho 1,2-bthiophen-2-carboxylate (2) --Nitration of the ester (2) in boiling glacialacetic acid for 1 h gave a solid product which containedthree components ( 8 : 2 : 1) (g.1.c.). Chromatography onsilica gel and elution with benzene gave first the majorcomponent, ethyl naphtho 1,241 thiophen-2-carboxylate,m.p. and mixed m.p. 86-88' (lit.,l 87-88") (from ethanol).Continued elution gave a crystalline mixture (1 : 2) of ethyl7-nitronaphtho 1,241 thiophen-2-carboxylate and the cor-responding 4,5-dihydro-compound. Recrystallisation fromethanol gave the former as yellow needles, m.p. 194-195.5'(from ethanol), M+ 301, v,, 1 715 cm-l ( G O ) ; see Discus-sion for details of the n.m.r. spectrum. The mixture of the7-nitro-compound and its 4,bdihydro-derivative wasconverted entirely into the former by heating i t withN-bromosuccinimide in carbon tetrachloride for 1 h.We thank the S.R.C. for a research studentship (toD. N. G.). We are grateful to F. Brown, G. Collier,A. D. Roberts, and Dr. D. F. Ewing for obtaining physicaldata.6/1053 Received, 3rd June, 1976