Azocine derivatives. Part I. Synthesis of 1-benzazocin-6-one derivatives by direct cyclisation

摘要

1972 885Azocine Derivatives. Part I. Synthesis of I -Benzazocin-6-one Deriva-tives by Direct CyclisationBy G. R. Proctor and W. 1. Ross, Department of Pure and Applied Chemistry, University of Strathclyde,Glasgow C.lTetrahydro-I -benzazocin-6 (5H) -one derivatives have been made by Dieckmann cyclisation of appropriate diesters,followed by hydrolysis. Attempts to make tetrahydro-I -benzazocin-5(6H)-ones and a tetrahydro-2-benzazocin-6(5H)-one by similar procedures failed.REDUCED derivatives of monocyclic azocines have beenknown for some time. These have commonly been ob-tained, for example, by Beckmann rearrangement ofcycloheptanone oximes,l Dieckmann cyclisation ofappropriate arnino-diesters,z or Favorskii-type rearrange-ment of a nine-membered l a ~ t a m .~ Azocines themselveshave until recently been less well studied; however,Paquette and his co-workers4 have made notable con-tributions in this area during the last five years. Boththe biological activity of certain azocine derivatives (e.g.benzomorphans 5) and the interesting structural possi-bilities in medium-sized rings prompted us to attemptthe synthesis of some new azocine derivatives bymethods developed by us in the azepine field. Wedeal here with some benzazocinones.We set out to obtain intermediates in which thenitrogen atom of the heterocycle was separated by atleast one carbon atom from a carbonyl group, whichcould then be used to bring about further transform-ations. Accordingly we have considered direct cyclisa-tion of appropriate esters or acids by the Dieckmann andFriedel-Crafts reactions, respectively, leading to re-duced 3-benzazocin-6-ones, 2-benzazocin-6-ones, andl-benzazocin-5- and -6-ones.During our work, Larsen and Scarborough reportedthe synthesis of tetrahydro-3-benzazocin-6 (5H) -ones bydirect Friedel-Crafts cyclisation of N-mesyl and N-tosylacids so we did not pursue our studies of this system.It seemed likely that tetrahydro-3-benzazocin-l(ZH)-ones (I) could be obtained by adaptation of our Friedel-Crafts methods for the corresponding tetrahydro-3-benz-azepin-5-ones,' but since this idea was being exploredelsewhere we attempted first a synthesis of the isomericsystem te trahydro-2-benzazocin-6 (5H) -one e.g.(I I).Experience with l-benzazepine derivatives suggestedthat for ketones (11; R2 = Ts) the Friedel-Craftscyclisation is unsuitable, and because we suspected thatthe diester (111; R = Ts) required for Dieckmanncyclisation to (11; Rg = Ts) might undergo base-catalysed elimination of the tosyl group,1deg; we attemptedF.F. Blicke and N. J. Doorenbos, J . Amer. Chem. Soc.,1954, 76, 2317.N. J . Leonard and T. Sato, J . Org. Chem., 1969, 34, 1066,and earlier papers.H. T. Nagasawa and J. A. Elberling, Tetrahedron Letters,1966, 44, 6393. * L. A. PaquetteandT. Kakihana, J . Amer. Chem. Soc., 1971,93, 174, and earlier papers.K. Kanematsu, M. Takeda, A. E. Jacobson, and E. L. May,J. Medicin. Chem., 1969, 12, 406, and earlier papers.A. A. Larsen and H. Scarborough, U.S.P.3,442,890 (Chem.Abs., 1969, 71, 61,249).to obtain the diester (111; R = Ph) instead. Thiscompound, however, proved inaccessible ; for examplereaction of ethyl y-bromobutyrate with methyl o- (anili-nomethyl) benzoate (IV) gave only the N-phenyliso-indolone (V) .Turning our attention to tetrahydro-l-benzazocin-6(5H)-one derivatives e.g. (VI), we felt that the Dieck-mann reaction, when applied to suitable diesters e.g. (VII ;R = Ts) would lead to cyclisation to (VI ; R1 = C02Et,R2 = Ts) unless a hitherto-unknown elimination re-action intervened as depicted in (VIII). As a pre-caution, we investigated this possibility. 2-Pyrrolid-onesll have been obtained as shown in (IX) but thebase-catalysed tosyl elimination has previously been seento operate only between carbon and nitrogen atomsalready joined by a a-bond, i.e.in such a way as toproduce initially an imine.1deg; Suitable model com-pounds were constructed to explore the possibility that acarbanion could form a o-bond to a nitrogen atom withconcomitant loss of the P-tolylsulphinyl anion. Thus theester (X) and the ketones (XI ; R = Me or PhCH,), madeby conventional procedures,12 were treated with variousbases. In every case the starting material was recovered.Accordingly the process depicted in (VIII) would not beexpected to take place in preference to Dieckmanncyclisation, and in fact this proved to be the case.Treatment of methyl N-tosylanthranilate with ethyl5-bromovalerate (cf. ref. 9) gave the diester (VII; R =Ts), which was treated with sodium hydride in di-methylformamide to give the keto-ester (VI; R1 =C02Et, R2 = Ts).Acid hydrolysis of the product gavethe ketone (VI; R1 = H, R2 = Ts) in 30 overallyield from methyl N-tosylanthranilate. The N-mesylester (VII; R = MeSO,) was made similarly and iso-lated, but on treatment with sodium hydride in di-methylformamide gave an intractable product.We have explored the detosylation of the ketone (VI;R1 = H, R2 = Ts) and the possibility of finding trans-annular reactions involving C-5 and the nitrogen atom.Controlled bromination of compound (VI; R1 = H,7 hf. A. Rehman and G. R. Proctor, J . Chem. SOC. ( C ) , 1967,58; I. MacDonald and G. R. Proctor, ibid., 1969, 1312.8 R. E. Partch and J .Schlademan, personal communication.9 I. McCall, G. R. Proctor, and L. Purdie, J . Chem. SOG. (C),1970, 1126, and earlier papers.lo E. D. Hannah, G. R. Proctor, and M. A. Rehman, J . Chem.SOC. (C), 1967, 256.l1 D. B. Astill and V. Boekelheide, J . Amer. Chem. SOC , 1956,77, 4079; J. Braunholtz and F. G. Mann, J . Chem. SOL, 1968,3377; G. R. Proctor and R. H. Thomson, ibid., 1957, 2302.l2 M. A. Rehman, Ph.D. Thesis, University of Strathclyde,1966J.C.S. Perkin Inot entirely due to the presence of a carbony1 group atC-6, since we have previously 12 found that treatment ofthe favourably constructed tertiary alcohol (XIII) withacid did not lead to any tosyl elimination. Treatmentof the ketone (VI; R1 = H, R2 = Ts) with sodiumethoxide in benzene caused a reaction but we were un-able to purify the products.The ketone (VI; R1 = H,R2 = Ts) was reduced by sodium borohydride to thecorresponding alcohol, which was detosylated by sodiumin liquid ammonia to the expected amino-alcohol (XIV),the yields in both steps being nearly quantitative.In order to obtain also tetrahydro-l-benzazocin-5(6H)-ones we have synthesised the diesters (XV; R = MeSO,or Ts) by conventional procedures, but in the Dieckmann - ---.lction they gave intractable products: we can offer no-Thus, of the cases we have examined, only tetrahydro-l-benzoazocin-6(5H)-one derivatives have been obtained,but the procedure used is simple and yields are satis-886R2 = TS) gave Successively the monobromo- (VI;R1 = Br, R2 = Ts) and aa-dibromo-ketones; treatment( 1 1 (IT1~ e ~ ~ 2 3 ' c o 2 , ,R cm1 N: IIE,ion G ml) ?lanation for this.-d N P t ., 6' bsol;R* N y- CH 2 14 C02Et factory.('IIII1 REXPERIMENTAL(TI) cm: 1Ethyl y- N- (o-Ethoxycarbonylmethylphenyl) -p-tolylsul-phonylauninobutyrate (XV; R = Ts).-A mixture of ethylo-(F-tolylsulphony1amino)phenylacetate lo (9 g) , ethyl y-bromobutyrate (10 g ) , and anhydrous potassium carbonate(14 g) was refluxed in dry acetone (150 ml) with stirring for18 h, and filtered. The filtrate was evaporated in vacuuto leave a red oil which was chromatographed on neutralalumina. Elution with benzene gave unchanged ethyly-bromobutyrate and then the product (XV; R = Ts)(10.1 g, 83) as a viscous yellow liquid which could not becrystallised or distilled, vmX. (film) 1725 cm-l (C=O).Thecorresponding diacid crystallised from ethanol-water aswhite needles, m.p. 175-176" (Found: C, 58.4; H, 5.2; N,I 3.6. C,,H,,NO,S requires C, 58.6; H, 5.4; N, 3.6),vmX. (Nujol) 1710 cm-l (GO). TsAttempted Cyclisation of the Diester (XV; R = Ts).-(a)To a stirred solution of the diester (4.47 g, 0.01 mol) in drydimethylformamide (200 ml) under dry, prepurified nitro-gen, was added sodium hydride (50 dispersion; 0.48 g,0.01 mol) during 1 h. The mixture was then stirred for 2 h,and the temperature raised to 80" and maintained there for18 h. After cooling, the mixture was poured into an excessof ice-dilute hydrochloric acid and extracted with benzene.The extract was washed with saturated sodium hydrogencarbonate solution and water, dried, and evaporated invacuo to leave a dark oil (1.32 g) which was shown (t.1.c.)to be a complex mixture.This material was refluxed in amixture of glacial acetic acid (10 ml), concentrated hydro-chloric acid (5 ml) , ethanol (5 ml) , and water (5 ml) , for 96 h,N-ICH2 13CO2 E t and cooled. The mixture was then diluted with water andI extracted with benzene. The extract was washed withsaturated sodium hydrogen carbonate solution and water,TsTs(UIIIJN-CH214*CH (C02Et)zI(XI)(XI TsBrIXII)= !) - e c 6 H 4' so 2(XY1 Rwith an excess of bromine yielded the tetrabromo-com- dried, and evaporated in vaCuO to leave a red Oil (0.15 g),pound (XII). These results parallel those obtained for from which no products werethese bromides underwent any reaction with silver per-chlorate in dimethylformamide O r with anhydrousaluminium bromide in benzene, reactions designed tocreate carbonium ions at c-5 which might have initiateda Ts+ elimination cj.(IX). These failures are probablythe corresponding 1-benzazepine derivatives.13 None of (b) To a stirred suspension Of potassium (0'98 gJg-atom) in dry toluene (100 ml) at 75-80' under dry, pre-purified nitrogen, was added t-butyl alcohol (1.85 g, 0.025mol) in toluene (50 ml), and the mixture was stirred for 2 h.The diester (4-47 g, 0.01 mol) in toluene (75 ml) was added13 E. D. Hannah, W. C . Peaston, and G. R. Proctor, J . Cheun.SOC. (c), 1968, 12801972during 0.5 h and the mixture was then stirred for 1 h a t 80deg;,refluxed for 1 h, and cooled.Ethanol was carefully added,then water (excess), and the layers were separated. Theorganic layer was washed with dilute hydrochloric acid,saturated sodium hydrogen carbonate solution, and water,dried, and evaporated in vacuo to leave a dark yellow gum(0.04 g) which was not further investigated.Ethyl o-(N-Methylsu1phonylamino)phenylacetate.- Toethyl o-aminophenylacetate lo (25 g) in pyridine (150 ml)at 0" was added methanesulphonyl chloride (35 g); themixture was set aside for 18 h, and then poured into anexcess of ice-dilute hydrochloric acid. The solid productformed needles, m(52 98-99' (from ethanol) (Found: C,51-65; H, 5.75; 14;W55.C,,H,,N04S requires C, 51.45;H, 5.85; N, 5.457(0), T 2-OSbr (lH, s, exch., NH), 2-42-2-83(4H, m), 5.84 (2H, q), 6-29 (2H, s), 6-95 (3H, s), and 8.73(3H, t), vmx. (Nujol) 3310 (N-H) and 1720 cm-l (C=O).Ethyl y-N-(o-Ethoxycarbonylmethy1phenyl)methylsul-phonylaminobutyrate (XV ; R = MeSO,) .-A vigorouslystirred mixture of the foregoing ester (40 g), ethyl y-bromo-butyrate (39 g), and anhydrous potassium carbonate (21 g)was refluxed in dry acetone (450 ml) for 3 h, and cooled.The mixture was diluted with water and benzene. Theorganic layer was washed, dried, and evaporated in vacuoto give the product as a yellow liquid which slowly solidified.Recrystallisation from methylene dichloride-light petro-leum (b.p. 60-80") yielded white prisms (52 g, 92y0), m.p.68-70" (Found: C, 55.45; H, 6.8; N, 4.0.C1,H2,N0,Srequires C, 54.95; H, 6.8; N, 3-8), 7 2-5-2.8 (4H, m),5.75-6-03 (4H, m), 6-24 (2H, s), 6-38 (ZH, t), 7.08 (3H, s),7.68 (ZH, t), 8.17 (2H, t), and 8.76 (6H, m), vmak (Nujol)1730 cm-l ( G O ) .Reaction of Aniline with Methyl o-Byomomethylbenzoate.-Aniline (7 g , 0,075 mol), methyl o-bromomethylbenzoate l4(13.1 g, 0.075 mol), and anhydrous potassium carbonate(10.5 g, 0.075 mol) were refluxed in dry acetone (200 ml)with stirring for 16 h. The cooled mixture was then dilutedwith water and benzene. The organic layer was washedthoroughly with dilute hydrochloric acid and then concen-trated hydrochloric acid.The dilute hydrochloric acid washings were neutralisedwith dilute sodium hydroxide solution and extracted withmethylene dichloride.The organic extract was washed,dried, and evaporated in vacuo to leave methyl o-(anilino-methy1)benzoate (IV) as a red oil (8.01 g) which was notfurther purified, v-. (film) 3400 (N-H) and 1700 cm-l( G O ) . Similar work-up of the concentrated hydrochloricacid washings gave dimethyl ad-phenyliminodi-p-toluoateas a brown solid which crystallised from chloroform-ethanol, as white prisms (3.9 g), m.p. 164-166" (Found:C, 73-85; H, 6.4; N, 3.6. C,4H,,N04 requires C, 74-05;H, 5.9; N, 3.6), T 1.91-3048 (13H, m), 4.94 (4H, s), and6.15 (6H, s), vmx. (Nujol) 1700 cm-l (GO).Reaction of Methyl o- ( A nilinomethyl) benzoate with Ethyly-Bromobutyrate.-The amine (6.25 g), ethyl y-bromo-butyrate (5.85 g), and anhydrous potassium carbonate (4.1g) were refluxed with stirring in dry acetone (50 ml) for16 h.The cooled mixture was diluted with water andmethylene dichloride and the organic layer was washed,dried, and evaporated i n vacuo to leave a dark oil whichsolidified. Recrystallisation from ethanol gave 2,3-di-hydro-N-phenylisoindol-l-one (V) (4-5 g) as plates, m.p.160-161" (Found: C, 80.95; H, 5.55; N, 7-1. C,,H,,NOrequires C, 80.45; H, 5.3; N, 6-75y0), z 2-18-2.91 (9H, m)and 5.18 (ZH, s), v-. (Nujol) 1680 cm-l (GO).Ethyl 1,2,3,4,5,6-Hexahydro-6-oxo-N-p-tolylsul~honyl- 1-benzazocine-5-carboxylate (VI ; R1 = CO,Et, R2 = Ts) .-Toa stirred solution of methyl N-$-tolylsulphonylanthranilate(45.75 g, 0.15 mol) in dry dimethylformamide (800 ml) underdry, prepurified nitrogen, sodium hydride (50 dispersion;7.2 g, 0.15 mol) was slowly added during 1 h.After a further2 h, ethyl 5-bromovalerate (31.5 g, 0.15 mol) in dry dimethyl-formamide (20 ml) was added, and the temperature wasraised to 80" and maintained there for 18 h. To the cooledmixture was added sodium hydride (50 dispersion; 7-2 g,0.15 mol) and stirring was continued at room temperaturefor 2 h, and then a t 80" for 18 h. The mixture was thencooled, diluted with an excess of ice-dilute hydrochloricacid, and extracted with benzene. The extract was washedwith saturated sodium hydrogen carbonate solution andwater, dried, and evaporated in vacuo to leave a red oil(46 g), a sample of which crystallised from ethanol to giveprisms, m.p.152-153" (Found: C, 62.6; H, 5.55; N, 3-4.C,,H,,NO,S requires C, 62.8; H, 5.3; N, 3-5), -T -2.5 (lH,s, exch.), 2.43-2.98 (8H, m), 5.78 (2H, q), 6-24 (2H, m),7.3 (2H, m), 7.61 (3H, s), 8-52 (2H, m), and 8-69 (3H, t),vmx. (Nujol) 1645 cm-l ( G O ) .2,3,4,5-Tetrahydro-N-p-tolylsul~honyl-l-benzazocin-6 (1H)-one (VI; R2 = H, R2 = Ts).-The foregoing crude keto-ester (45 g) was refluxed in a mixture of glacial acetic acid(220 ml), concentrated hydrochloric acid (40 ml), ethanol(100 ml), and water (40 ml) for 96 h, and cooled. Themixture was then added to an excess of water and extractedwith benzene. The extract was washed with saturatedsodium hydrogen carbonate solution and water, dried, andevaporated in vacuo to leave a yellow solid (16-85 g, 30overall) which crystallised from ethanol as prisms, m.p.144-145" (Found: C, 65-6; H, 5.95; N, 4.45.C,,H,,-NO,S requires C, 65.6; H, 5.8; N, 4-25), T 1.96-2-78(8H, m), 6.32 (2H, t), 6-8 (ZH, t), 7.61 (3H, s ) , and 8.3 (4H,m), v-. (Nujol) 1665 cm-l (GO).Reaction of 2,3,4,5-Tetrahydro-N-p-tolylsulfihonyl- 1 -benz-azocin-6( 1H) -one with Hydroxylamine.-A mixture of theketone (0.5 g), hydroxylamine hydrochloride (0.5 g), andanhydrous sodium carbonate (1 g) was refluxed in absoluteethanol (25 ml) for 2 h, and filtered. On cooling, the oximecrystallised as white plates (0.45 g), m.p. 208-210" (Found:C, 62-85; H, 5.7; N, 8-25. C,,H,,N,O,S requires C, 62.8;H, 5.8; N, 8.1), T (C,D,N) 1.84-2-99 (8H, m), 52br (lH,s), 6.33 (2H, t), 6.57 (2H, t), 7.78 (3H, s), and 8.37 (4H, m),vmX.(Nujol) 3400 cm-l (O-H).Reaction of Methyl N-Methylsulphonylanthranilate withEthyl 5-Bromovalerate.-To a stirred solution of the sul-phonamide (11.5 g, 0.005 mol) in dry dimethylformamide(75 ml) under dry, prepurified nitrogen, sodium hydride(50 dispersion; 2.4 g, 0.05 mol) was slowly added during1 h. After a further 1.5 h, ethyl 5-bromovalerate (10.5 g,0.05 mol) in dry dimethylformamide (25 ml) was added,and the temperature was raised to 90" and maintained therefor 16 h. The cooled mixture was diluted with water,acidified, and extracted with ether. The extract waswashed, dried, and evaporated in vacuo to leave a darkliquid (17-74 g) which was chromatographed on silica gel.Elution with benzene-ether (19 : 1) gave a mixture ofstarting materials and then ethyl 5"- (o-methoxycarbonyl-phenyl)methylsul~honylaminovalerate (1 4.5 g, 8 1 yo) (VII ;R = MeSO,) as a yellow liquid which could not be crystal-lised or distilled (Found: C, 54.35; H, 6.9; N, 4.1.C1,-H2,N0,S requires C, 53.85; H, 6.5; N, 3.9), T 2.05-2-62l4 E. L. Eliel and D. E. Rivard, J . Org. Chew., 1952, 17, 1262J.C.S. Perkin I(4H, m), 5-84 (2H, q), 6-11 (3H, s), 6.38 (2H, m), 7.06 (3H,S ) , 7.73 (2H, m), 8.4 (2H, m), 8.62 (2H, t), and 8.79 (3H, t),v,, (film) 1720 cm-1 (GO).Reaction of the Diester (VII; R = MeSO,) with SodiumHydride.-To a stirred solution of the diester (3.5 g, 0.01mol) in dry dimethylformamide (200 m1) under dry, pre-purified nitrogen, sodium hydride (50 dispersion; 0.48 g,0.01 mol) was added during 1 11.The mixture was thenstirred for 2 h, and the temperature raised to 80" and main-tained there for 11 h. The cooled mixture was then pouredinto an excess of ice-dilute hydrochloric acid and extractedwith benzene. The extract was washed with saturatedsodium hydrogen carbonate solution and water, dried, andevaporated in vacuo to leave a black oil (2.01 g). Thismaterial was refluxed in a mixture of glacial acetic acid (10ml), concentrated hydrochloric acid (5 ml), ethanol (5 ml),and water (5 ml) for 96 h, and cooled. The mixture wasthen diluted with water and extracted with benzene. Theextract was washed with saturated sodium hydrogencarbonate solution and water, dried, and evaporated invacuo, but no product was obtained.The acidic and alkalinewashings were neutralised and extracted with methylenedichloride. The acidic washings gave no product and thealkaline washings gave a yellow oil (0.2 g) from which noidentifiable products were isolated.5-Brouno-2,3,4,5-tetmhydro-N-p-tolylsul~honyl- l-benzazo-cin-6(1H)-one (VI; R1 = Br, R, = Ts).-2,3,4,5-Tetra-hydro-N-p-tolylsulphonyl-l-benzazocin-6( 1H)-one (2 g) inchloroform (20 ml) was treated with bromine (0-3 ml);the mixture was stirred at room temperature for 2 h, thenevaporated in vacuo to leave a yellow solid (2.2 g) whichyielded plates, m.p. 142-143" (from ethanol) (Found: C,53.25; H, 4-55; N, 3.85. Cl,Hl,BrNO,S requires C, 52.95;H, 4-4; N, 3.45), vm, (Nujol) 1695 cm-1 (GO).Themonobromide was recovered unchanged from heating witheither silver perchlorate in dimethylformamide a t 100" oraluminium bromide in refluxing benzene.5,5-Dibromo-2,3,4,5-tetrahydro-N-p-tolylsul~honyl- 1 -benz-azocin-6( 1H)-one.- 2,3,4,5-Tetrahydro-N-P-tolylsulphonyl-l-benzazocin-6(1H)-one (1 g) in chloroform (20 m1) wastreated with bromine (0.3 ml) ; the mixture was stirred atroom temperature for 3 h, then evaporated in vacuo, andthe residue crystallised from ethanol to give plates (0.92 g),m.p. 125-126" (decomp.) (Found: C, 44.7; H, 3-55; N, 2.75.C,,H,,Br,NO,S requires C, 44.35; H, 3.5; N, 2.85),vmX. (Nujol) 1720 cm-l (GO).Reaction of 5,5-Dibromo-2,3,4,5-tetrahydro-N-p-tolylsul-9honyl- l-benzazocin-6( 1H) -one with Zinc.-The dibromide(1.3 g) and zinc dust (2 g) were refluxed in methanol for2 h; the mixture was filtered and the filtrate was evap-orated in vacuo to leave 2,3,4,5-tetrahydro-N-p-tolylsul-phonyl-l-benzazocin-6( 1H)-one as a yellow oil (0.84 g)which crystallised from ethanol as needles, m.p.and mixedm.p. 143-145".2,3,4,5-Tetrahydro-5,5,8,10-tetrabrouno- 1-benzazocin-6 (1H) -one (XII) .-To a solution of 2,3,4,5-tetrahydro-N-p-tolyl-sulphonyl-l-benzazocin-6( 1H)-one (0.85 g) in chloroform(3 ml) was added a solution of bromine (1 ml) in chloroform(5 ml) and the resultant fuming solution was left for 48 h.The yellow precipitate (1.02 g, 82) afforded the tetrabromideas yellow prisms, m.p. 195-196" (from ethanol) (Found:C , 26.95; H, 1.55; N, 3-05.C,,H,Br,NO requires C, 26.85;H, 1-8; N, 2-85y0), vmX (Nujol) 3280 (N-H) and 1715 cm-lThe tetrabromide was recovered unchanged from heating(C=O) .with either silver perchlorate in dimethylformamide at 100"or aluminium bromide in refluxing benzene.1,2,3,4,5,6-Hexahydro-N-p-tolylsul~honyl-l-benza~ocin-6-ol .--Sodium borohydride (0- 15 g) was added in portions toa solution of 2,3,4,5-tetrahydro-N-~-tolyisulphonyl-l-benz-azocin-6(1H)-one (1-1 g) in absolute ethanol; the mixturewas stirred at room temperature for 16 h then treated withan excess of ice-dilute hydrochloric acid and extracted withchloroform. The extract was washed with sodium carbon-ate solution and water, dried, and evaporated in vacuoto leave the product (1.05 g, 95), which crystallised frommethanol as white prisms, n1.p.166-168" (Found: C, 65.8;H, 6.4; N, 4.05. C,,H,,NO,S requires C, 65-35; H, 6.35;N, 4.25), vm (Nujol) 3470 cm-l (0-H).Reaction of 1,2,3,4,5,6-Hexahydro-N-p-tolylsulphonyl-l-benzazocin-6-01 with Sodium in Liquid Ammonia.-To astirred suspension of the alcohol (0.52 g, 0-0016 mol) inliquid ammonia (ca. 25 ml) was added sodium (0.16 g,0.007 mol). After 10 min, while the blue colour persisted,ammonium chloride was added. When the solution wascolourless, the ammonia was allowed to evaporate, andmethanol, then water and chloroform were added. Theorganic layer was washed, dried, and evaporated in vacuo toleave 1,2,3,4,5,6-hexahydro-l-benzazocin-6-ol (XIV) (0-26 g,93 ) which crystallised from methylene dichloride-lightpetroleum (b.p.60-80") as white plates, m.p. 86-88"(Found: C, 74-05; H, 8-35; N, 8.05. C,,H,,NO requiresC, 74-55; H, 8-5; N, 7.9), z 2.8-3.15 (4H, m), 5.14 (lH,m), 5-62br (2H, s, exch., OH and NH), 6-96 (2H, m), and7.9-8.8 (6H, m), v,,, (Nujol) 3320, 3240, and 3220 cm-1(N-H and 0-H) .Reaction of 2,3,4,5-Tetrahydro-N-p-tolylsul~honyl-l-benz-azocila-6( 1H) -one with Sodium Ethoxide.-A solution of theketone (1 g) in dry benzene (10 ml) was added to a stirredsuspension of sodium ethoxide from sodium (0-5 g) in drybenzene (10 ml); the mixture was stirred for 12 h, afterwhich time all the starting material had reacted (t.1.c.).The mixture was diluted with water and the layers wereseparated.The organic layer was washed, dried, andevaporated in vacuo to leave a yellow oil (0.52 g) from whichno identifiable products were isolated. Attempted acetyl-ation also failed to provide any recognisable products.No toluene-P-sulphinic acid was detected after neutralis-ation and extraction of the aqueous layer.N-p-Tolylsul~honyl-4-anilin0butan-l-ol.~~-Ethyl y-(N-phenyl-p-tolylsulphonylamino) butyrate l1 (36.1 g ) in drytetrahydrofuran (100 ml) was added with stirring during1.5 h under nitrogen to lithium aluminium hydride (1.9 g) indry tetrahydrofuran (50 ml). After being refluxed for 2 hand cooled, the mixture was poured into ice-dilute hydro-chloric acid and extracted with chloroform. The extractwas washed with dilute sodium hydroxide solution andwater, dried, and evaporated leaving the product (22 g)which crystallised from benzene-light petroleum (b.p.60-SO") as needles, m.p. 71" (Found: C . 83-45; H, 6.5; N, 4.25.Cl,H,,NO,S requires C, 63-9; H, 6.6; N, 4-25), v,,(Nujol) 3268 cm-l (OH).N-4-Bronzobutyl-N-p-tolylsul~honylaniline.12-To the fore-going alcohol (21 g) in dry benzene (60 ml) a t 0-5" wasadded phosphorus tribromide (7 g) in dry benzene (50 ml)with stirring. After 12 h at 0", the mixture was filtered,and the filtrate washed with aqueous sodium carbonatesolution (5) and water, and dried. Chromatographyon neutral alumina elution with light petroleum (b.p. 60-80deg;)-benzene (4 : l) and crystallisation from light petro1972 889leum (b.p. 8amp;100deg;) gave cubes, m.p.78-78.5" (13.6 g)(Found: C, 53.75; H, 5.4; Br, 20-6; N, 3.9. C15H2o-BrN02S requires C, 53.35; H, 5.2; Br, 21.0; N, 3.9).Diethyl N-p-Tolylsulphonylamino-4-anilinob~tylrnalonate(X).12-Diethyl malonate (4-5 g) was added to sodiumethoxide from sodium (0.7 g) in ethanol (10 ml) and then,with vigorous stirring, the foregoing bromide (10.7 g) inethanol (15 ml) was added during 1 11. The mixture wasrefluxed for 2 h and then the solvent was removed in vacuo.The crude product was chromatographed on silica gel;elution with benzene-light petroleum (b.p. 60-80") (1 : 1)gave a yellow oil (9.2 g), b.p. 185-190" a t 0.1 mmHg (Found:C, 66.8; H, 7.2; N, 3.25. C2,H,,NOGS requires C, 67.1; H,7.3; N, 3.25), vnUx (film) 1730 cm-l (ester). This materialwas unchanged after treatment with (a) sodium ethoxide intoluene at 20", (b) sodium hydride in tetrahydrofuran a treflux, or (c) potassium t-butoxide in dimethyl sulphoxide a t20".N-p-Tolylsulphonyl-o-methylaminoacetophenone (XI : R =Me). 15-N-~-T~lyl~~lphonyl-o-aminoacetophenone (1 g) andbenzene (100 ml) were shaken for 1 h with an ion-exchangeresin (IRA 410; 20 g) which had been previously washedwith sodium hydroxide solution and water. Methyl iodide(12 ml) was then added and the mixture was left a t 20" for96 h. After filtration and removal of solvent, the product(960 mg) crystallised from methanol in cubes, m.p. 116"(Found: C, 63.4; H, 5.5; N, 4.65. CiGH17N03S requiresC, 63.35; H, 5.5; N, 4.6y0), v,,,. (Nujol) 1686 cm-1 (GO).The same product was obtained by the reaction of methyliodide and o-aminoacetophenone in aqueous sodium hydro-gen carbonate at 1 00", followed by treatment with toluene-p-sulphonyl chloride in pyridine.N-p-Tolylsulphonyl-o-benzylarninoacetophenone l5 (XI ;R = PhCH,).-This was obtained like the methyl analogueand crystallised from ethanol in cubes, m.p. 130" (Found : C,69.6; H, 6.0. C,,H,,NO,S requires C, 69.65; H, 5.55).Both sulphonamides were unchanged after treatment with(a) sodium methoxide in toluene a t 120", (b) potassium t-butoxide in dimethyl sulphoxide a t 20", or (c) sodiumhydroxide in ethylene glycol a t reflux.We thank Roche Products for a research grant.1/1923 Received, 20th October, 1971115 W. Paterson, Ph.D. Thesis, University of Glasgow, 1964