Azocine derivatives. Part II. Synthesis of benzazocine derivatives by ring-expansion of dihydrobenzazepines with dibromocarbene

摘要

1972 889Azocine Derivatives. Part 1 1 2 Synthesis of Benzazocine Derivatives byRing -expansion of D i hyd ro benzazepi nes with Di bromocar beneBy W. 1. Ross and G. R. Proctor,* Department of Pure and Applied Chemistry, University of Strathclyde, Glasgowc.1Methods of ring-expansion for preparation of benzazocine derivatives have been explored. 2,3,4,5-Tetrahydro-l-p-tolylsulphonyl-I -benzazepin-5(1 H)-one has been converted sequentially into the enol ether, which in turn gavea dibromocarbene adduct. This was ring-expanded t o 2,3,4,5-tetrahydro-I -p-tolylsulphonyl-I -benzazocin-6( 5H)-one and to the corresponding enol ether.WE have previously shown that ring-expansion of1,2-dihydroquinoline derivatives is a useful method forpreparation of some dihydro-l-benzazepin-5-ones andl-benzazepines.It was, therefore, of interest to find ifthe method was applicable to the higher homologuessince the required starting materials, tetrahydrobenz-azepinones, are readily a~ailable.~ We report here onthe scope of the procedure.The tosylate (I; R = tosyl) was converted by re-action with triethyl orthoformate into the enol ether(11; R1 = OEt, R2 = tosyl), which reacted withdibromocarbene prepared either from phenyl(tri-bromomethy1)mercury (50) or from bromoform andsodium t-butoxide in benzene-pentane 5 9 6 (60y0) togive the cyclopropane (111; R1 = OEt, R2 = tosyl).Ring-expansion was achieved in two ways. First,treatment with silver nitrate in aqueous ethanol,' gave aproduct (50), which spectroscopic evidence (seeExperimental section) suggested was the benzazocinonePart I, G.R. Proctor and W. I. Ross, preceding paper.A. Cromarty, K. E. Haque, and G. R. Proctor, J . Chem.SOL (C), 1971, 3536.( a ) I. McCall, G. R. Proctor, and L. Purdie, J . Chem. SOL( C ) , 1970, 1126; (b) M. A. Rehman and G. R. Proctor, ibid.,1967, 58; (c) I. MacDonald and G. R. Proctor, ibid., 1970, 1461.(IV). This conclusion was supported by catalytichydrogenation of the ketone (IV), which gave thehexahydro-alcohol (V), identical with the substanceobtained by reduction of the previously describedketone (VI; R = H), itself the product of directDieckmann cyclisation. Similar ring-expansion of thelower homologue gave a poor yield of the benzazepin-one. We ascribe this to the reactivity of the enone,which contains a doubly activated CH, group; thebenzazocinone (IV) would not, be expected to be undulyreactive.When the adduct (111; R1 = OEt, R2 =tosyl) was heated under reflux in aqueous pyridine aproduct was obtained in 87 yield to which we allocatethe structure (VII) particularly since it could be con-verted into the enone (IV) on treatment with silica gel.The ring-expansion to the dihydrobenzazocine (VII)only proceeded in 14 yield in anhydrous pyridine; 7* (a) D. Seyferth, J. M. Burlitch, and J. K. Heeren, J . Org.Chem., 1962, 27, 1491; (b) J. M. Burlitch and D. Seyferth, J .Organometallic Chem., 1965, 4, 127.6 A. J. Birch, J. M. Brown, and F. Stansfield, J . Chem. SOL,1964, 5343.6 A.J. Birch, J. M. M. Graves, and J. B. Siddall, J . Chem.SOC., 1963, 4324.7 W. E. Parham, R. W. Soeder, J. R. Throckmorton, J.Kunel, and R. M. Dodson, J . Amer. Chem. SOC., 1965, 87, 321890 J.C.S. Perkin I(tribromomethy1)mercury ; * the alternative method (seebefore) 596 failed. However, the adduct was very stable,being recovered after heating under reflux in such diversereagents as quinoline, silver nitrate in aqueous ethanol,and silver acetate in acetic acid. The enol acetate9(VIII) gave the corresponding dibromocarbene adduct,but treatment with potassium hydroxide in aqueousethanol lo resulted in an intractable gum. We were un-able to obtain enol ethers from the N-phenyl (I; R =Ph), N-methyl (I; R = Me), or N-acetyl ketone (I;R = Ac):so it would appear that at present this trans-formation is limited to N-sulphonyl enol ethers.Tetrahydro-3-benzazepin-l-one 3b failed to form theenol ether or acetate (IX; R = OEt or OAc).Thecorresponding olefin 3b (IX; R = H), however, was ob-tained and treated with phenyl(tribromomethy1)mercuryto give the expected adduct in 40 yield. This adduct,like the corresponding l-benzazepine derivatives (I11 ;R1 = H, R2 = tosyl) did not undergo ring-expansionand since we have previously found the enol ether in-accessible in the tetrahydro-2-benzazepinone series 3c(X), the possibilities for ring-expansion seem to belimited to the l-benzazocines.Ring-expansion by two carbon atoms is attractive.Cyclohexanone enamines have been shown to react withdimethyl acetylenedicarboxylate leading eventually tosubstituted cyclo-octadienes; l1 enol ethers l2 andenamines l3 of 5-membered ring N-heterocycles havebeen similarly expanded. Unfortunately we have beenfrustrated in attempts to use these methods for azocinederivatives since the enamine l4 of N-methylpiperid-4-one gave many products with dimethyl acetyl-enedicarboxylate and also we could not prepare mor-pholine or pyrrolidine enamines from the tetrahydro-quinol-4-ones (XI; R1 = C1 l5 or H, R2 = tosyl orAc16).The enol ether of the 6-methoxy-derivative ofthe quinolone (XI; R1 = H, R2 = tosyl) reacted slowlywith dimethyl acetylenedicarboxylate but gave manyproducts.this implies the assistance of water in the transfer of aproton from the intermediate ally1 cation to the base,pyridine.The ketone (IV) could not be transformedinto its enol ether (VII) by treatment with triethylorthoformate, and the enol ether (VII) failed to undergoR-To 5EtO BrTo sR 'To sOAcaddition with tetracyanoethylene,0dr bsol; R2d-j Tos11x10R* N Tos( X I XI 1The successful ring-expansion of the adduct (I11 ;R1 = OEt, R2 = tosyl) makes several l-benzazocinederivatives available since we find that the tetrahydro-benzazocinone (IV) is not available by dehydrobromin-ation of the 5,5-dibromo-derivative 1 (VI; R = Br)(cf. the corresponding l-benzazepines in ref. 2). Wefeel that the bulk of the tosyl group interferes withapproach of the base since brominated, detosylatedderivatives of the tetrahydroketone (I; R = H) havebeen dehydrobrominated recently, and we havedemonstrated that replacement of tosyl by the mesylgroup in 1,2-dihydropyridines causes a dramatic stericeffect during reaction a t an apparently distant centre.The adduct (111; R1 = H, R2 = tosyl) was obtained(80) from the dihydrobenzazepine (11; R1 = H, R2 =tosyl) only by generating dibromocarbene from phenyl-8 A.Cromarty, Ph.D. Thesis, University of Strathclyde,9 E. D. Hannah, W. C. Peaston, and G. R. Proctor, J . Chem.10 B. August. M. Nussim, and G. Stork, Tetrahedron. 1966,1971.SOC. ( C ) , 1968, 1280.Suppl. 8, 165. '1459.11 G. A. Berchtold and G. F. Uhlig, J . Org. Chem., 1963, 28,EXPERIMENTAL2,3-Dihydro-5-ethoxy-l-p-tolylsul~honyl-lH-l-benzazepine(11; R1 = OEt, R2 = tosyl) .-2,3,4,5-Tetrahydro-l-p-tolyl-sulphonyl-l-benzazepin-5( 1H)-one 3a (15 g), triethyl ortho-formate (20 ml), and toluene-p-sulphonic acid (0.2 g) wereheated in absolute ethanol (180 ml) for 3 h under reflux,cooled, neutralised with potassium ethoxide-ethanol,poured into an excess of water and extracted with benzene.The organic layer was washed and dried, and the solventwas evaporated in vacuo to give an oil, which yielded thedesired firoduct from light petroleum (b.p.80-100deg;) aswhite needles (14-05 g, 86) m.p. 97-98' (Found: C,66-25; H, 6.35; N, 4.25. C,,H21N03S requires C, 66.45;l3 T. W. Doyle, Canad. J . Chem., 1970, 48, 1629, 1633.l3 M. S. Lin and V. Snieckus, J . Org. Chem., 1971, 36, 645.l4 G.Bianchetti, R. Fusco, and S. Rossi, Gazzetta, 1961, 91,15 W. S. Johnson, E. L. Woroch, and B. G. Buell, J. Amer.16 G. R. Clemo and H. J. Johnson, J . Chem. SOC., 1930, 2133.825.Chem. SOC., 1949, 71, 19011972H, 6-15; N, 4.1y0), 7 2-2-2-8 (8H, m), 5.3 (lH, t), 5.89(2H, t), 6-64 (2H, q), 7.56 (3H, s), 7.86 (2H, m), and 8.75(3H, t), vmX. (Nujol) 1650 cm-l (C=C).1,l-Dibromo-8b-ethoxy-1,la,2,3,4,8b-hexahydro-4-p-tolyl-sulphonylcyclo~ro~ad lbenzazepine (I11 ; R1 = OEt, R2 =tosyl) .-(a) A solution of the foregoing benzazepine tosylate(10 g) in dry benzene (100 ml) was added to a stirred suspen-sion of sodium t-butoxide (9-6 g) in dry n-pentane (100 ml)and the mixture cooled to -20". Bromoform (25.3 g) indry benzene (10 ml) and dry n-pentane (10 ml) was addeddropwise during 45 min, the temperature never exceeding-15".When addition was complete, the mixture wasstirred a t -15" for 1 h and then a t room temperature for1 h, poured into an excess of water, and the organic layerwas separated, washed, dried, and evaporated in vacuo t oleave the product, as white needles (9-1 g, SOY0), m.p. 148-149" (from ethanol).(b) A mixture of the tosylate (11; R1 = OEt, R2 =tosyl) (4 g ) and phenyl(tribromomethy1)mercury 46 (8 g)was heated under reflux in dry benzene (100 ml) withstirring for 4 h. After cooling and filtration, the solventwas evaporated in vacuo to leave a dark brown oil whichwas chromatographed on neutral alumina. Benzene elutiongave after discarding a fore-run containing phenylmercury-(11) bromide the desired product (3.07 g, 51y0), m.p.147-149" undepressed on admixture with a sample prepared asin (a) (Found: C, 46.8; H, 4.15; N, 2.7. C2,H2,Br,N03Srequires C, 46.75; H, 4-1; N, 2.7), z 1-96-2.66 (8H, m),6.02-6.8 (6H, m), 7.55 (3H, s), 8-07 (lH, t), and 8.82 (3H,5-Bromo- 6-ethoxy- 1,2-dihydro- 1 -p-tolylsulphonyl- l-benzazo-cine (VII) . T h e previous dibromocyclopropa-derivative(0.5 g) was heated under reflux in pyridine-water (30 ml;1 : 1 v/v) for 18 h, cooled, poured into an excess of crushedice-dilute hydrochloric acid and extracted with benzene.The extract was washed with dilute hydrochloric acid andwater, dried, and the solvent was evaporated in vacuo leav-ing the product as a light yellow solid (0.34 g, 81) whichwas crystallised from light petroleum (b.p.60-80") asneedles, m.p. 152-153' Found: C, 55-1; H, 4.7; N,3.1504 ; M (mass spectroscopy), 433.033827. C2,H2,79Br-N03S requires C, 55.25; H, 4.65; N, 3.25; M ,433.0347711, T 2.2-2.98 (8H, m), 4.06 (lH, dt), 4.85 (lH,dt), 5.28-6.05 (2H, m), 6.24 (2H, q), 7.56 (3H, s), and 8.7(3H, t), vmx. (Nujol) 1650 cm-l (C=C).6(lH)-one (ZV).-The cyclopropadlbenzazepine (111;R1 = OEt, R2 = tosyl) (3 g) was dissolved in ethanol (100ml), and silver nitrate (4.2 g) in water (5 ml) added to themixture, which was heated under reflux for 3 h. Aftercooling and filtration to remove the precipitated silverbromide, the mixture was poured into an excess of waterand extracted with benzene.The organic layer wasseparated, washed, and dried, and the solvent was evap-orated irs zlucuo to leave a brown solid which was chromato-graphed on neutral alumina. Elution with benzene-ether (19 : 1) gave the desired product (1-2 g, 48) as paleyellow prisms, m.p. 183-184" from benzene-light petro-leum (b.p. 60-80") (Found: C, 53.35; H, 3.95; N, 3-35.Cl,H1,BrNO,S requires C, 53-2; H, 3.95; N, 3-45), T2.14-2-92 (9H, m), 6-22 (2H, t), 7.58 (3H, s), and 7.81(2H, m), vmax. (Nujol) 1655 cm-1 (GO).Hydrolyszs of 5-Bromo-6-ethoxy-1,2-dihydro-l-p-tolylsul-fihonyl-l-benzazocine (VII) .-The enol ether (0-32 g) inbenzene was poured onto a column of silica gel and leftt).5-Bromo- 2, 3-dihydro- l-p-tolylsulphonyl- l-benzazocin-for 16 h.Elution with benzene-ether (19: 1) gave thel-benzazocin-6(1H)-one (IV) (0.23 g, 78) which waspurified as before and had m.p. 182-184" undepressed onadmixture with a sample prepared as before.Reduction of the l-Benzazocin-6( 1H)-one (IV) .--The titlecompound (31 mg) was hydrogenated (1 atm) in ethanol (60ml) over palladised charcoal (20 mg, 10) for 24 h. Afterfiltration and removal of solvent, the residue (13 mg) wasrecrystallised from light petroleum (b.p. 60-80") in needles,m.p. 16G165O. This was identical (i.r., t.l.c., and mixedm.p.) with 1,2,3,4,5,6-hexahydro-l-p-tolylsul~honyZ-l-benz-azocin-6-01 (V) prepared by catalytic hydrogenation (condi-tions as above) of 2,3,4,5-tetrahydro- l-p-tolylsulphonyl-1-benzazocin-6( 1H)-one (VI ; R = H).A ttewzpted Dehydrobromination of 5,5-Dibromo-2,3,4, amp;tetra-hydro-l-p-tolylsulphonyl-l-benzazocin-6( 1H)-one (VI ; R =Br) .-The dibromide was recovered after treatment withtriethylamine in chloroform for 24 h a t 20".Heating themixture for 8 h under reflux caused extensive decomposi-tion.1, l-Dibromo-l,la,2,3,4,8b-hexahydro-4-p-tolylsul~honyl-cyclo~ropadlbenzazefiine (111; R1 = H, R2 = tosyl) .-2,3-Dihydro-l-p-tolylsulphonyl-lH-l-benzazepine (4 g)and phenyl(tribromomethy1)mercury 4b (8 g) were heatedunder reflux with stirring in dry benzene (100 ml) for 7 h.After cooling, the mixture was filtered and the solvent wasevaporated in zlucuo to leave a dark oil, which was chromato-graphed on neutral alumina. Benzene elution gave afterdiscarding a fore-run containing phenylmercury (11) bromidethe desired Product as a light yellow oil (5.2 g, 81) whichcrystallised from ethanol as white needles, m.p.134-136'(Found: C, 45.5; H, 3-85; N, 2-95. C1,H,,Br2NO2S re-quires C, 45.95; H, 3.6; N, 2-95y0), z 2.2-2-7 (8H, m),5.67 (2H, td), 6.52 (2H, m), 7.55 (3H, s), 8.0 (lH, d), and8.33 (lH, td).Attempted Ringexpansion of l,l-Dibrowzo-l,la,2,3,4,8b-hexahydro-4-p-tolylsul~honylcyclo~ro~ad 11 benzazepine .-(a) The dibromocyclopropa-derivative was unaffected onheating with pyridine, quinoline, silver nitrate in aqueousethanol, silver acetate in acetic acid, or triethylamine underreflux.(b) To a stirred solution of the dibromocyclopropa-derivative (0.47 g) in pyridine (20 ml) was added a solutionof sodium hydroxide (0-05 g) in ethanol (20 ml) and themixture stirred a t room temperature for 4.5 h, poured intoan excess of ice-dilute hydrochloric acid and extracted withbenzene.The organic extract was washed and dried, andthe solvent was evaporated in vacuo to leave a dark oil(0-41 g), which could not be crystallised. Attemptedchromatography on neutral alumina gave intractable mix-tures, from which no identifiable products could be isolated.1, l-Dibromo-l,1a,2,3,4,8b-hexahydro-2-p-tolylsul~honyl-cyclopropaa3benzazepine Dibrowzocarbene Adduct of(IX ; R = H) .--1,2-Dihydro-3-p-tolylsulphonyl-3-benz-azepine 3b (IX; R = H) (3 g) and phenyl(tribromomethy1)-mercury 4b (8 g) were heated under reflux with stirring indry benzene (100 ml) for 15 h. After being cooled, themixture was filtered and the solvent was evaporated invacuo to leave an oil which was chromatographed on silicagel.Elution with benzene gave the desired product as anoil, which crystallised from benzene-light petroleum (b.p.60-8O0) as white needles (1.7 g, 38), m.p. 150-151'Found: C, 45-65; H, 3.45; N, 3-15y0; M (mass spectro-scopy), 472.929942. C1,H,7*1Br2N02S requires C, 45.95 ;H, 3.6; N, 2.95; M , 472.9308331, z 1-97-2.85 (8H, m)J.C.S. Perkin I6.43 (2H, t), 6.68 (2H, t), 6.95 (lH, d), 7-15 (lH, d), and7-49 (3H, s).This compound was unaffected on heating with eithersilver nitrate or silver perchlorate in aqueous ethanolunder reflux.4-Acetyl- 1,1,5,7-tetrabromo-l, la, 2,3,4,8b-hexahydrocyclo-$ropad) l)benzazepin-8b-yl A cetate Dibronzocarbene adductof (VIII) .-l-Acetyl-7,9-dibromo-2, 3-dihydro- 1H- l-benz-azepin-5-yl acetate 9 (1.4 g) and phenyl(tribromomethy1)-mercury 4b (5.08 g) were heated in dry benzene (120 ml)under reflux with stirring for 17 h. On cooling, the mixturewas filtered and the solvent was evaporated in vacuo t oleave a brown oil which yielded the desired product frommethanol as light brown prisms (0.48 g, 24), m.p. 202-204' Found: C, 31-75; H, 2.1; N, 2.25; M (massspectroscopy), 5 7 4- 7 5 7 434. C1,H1,79Br,*lBr,N0, requiresC, 31-45; H, 2.3; N, 2.45; M , 574.7591571, vmax (Nujol)1750 ( G O ; ester) and 1650 cm-1 ( G O ; amide).We thank Roche Products for a Research Grant.1/2135 Received, 12th November, 1971