Azabenzocycloheptenones. Part XVII. Some substitution reactions in tetrahydro-1-benzazepin-5-ones

摘要

1828 J.C.S. Perkin IAzabenzocycloheptenones. Part XV1I.l Some Substitution Reactions inTetrahydro-l -benzazepin-5-onesBy Mary Lennon, Angus McLean, Ian McWatt, and George R. Proctor,* Department of Pure and AppliedChemistry, University of Strathclyde, Glasgow G I 1 XLI ,2,3,4-Tetrahydro-1 -p-tolylsulphonyl-I -benzazepin-5-ones have been detosylated by two methods. N-Alkyla-tion of 1,2,3,4-tetrahydro-I -benzazepin-5-one and 2,3-dihydro-I H-I -benzazepine with several reagents isreported. Substitution of the 4- and 5-positions of 1.2.3.4-tetrahydro-I -p-tolylsulphonyl-1 -benzazepin-5-onehas been studied and several transformation products are described. Dehydrogenation of 5,6-dihydrodibenzb,e -azepin-I 1 -ones has been re-examined : the products are dibenzb,cazepin-I 1 -ones.PREVIOUSLY we have described syntheses 2-3 anddehydrogenation 4-6 of 1,2,3,4-t e trahydro- 1 -benzazepin-5-ones and we now report our studies into the reactivityof several centres in the seven-membered ring of thisseries.Since the most productive synthesis of 1,2,3,4-tetra-hydro-l-benzazepin-5-ones produces the N-tosyl de-rivatives (I; R1 = Ts), it is important to be able toremove the tosyl group.The method employingconcentrated hydrochloric acid, acetic acid, and zincchloride has proved unreliable and we have developedtwo better methods. First, sulphuric acid in aceticacid * is convenient for the N-tosyl ketones (I; R1 =Ts); the optimum time and temperature for eachexample has to be discovered by experimentation.Second, of wider applicability is sodium in liquidammonia: thus, while the N-tosyl ketone (I; R1 =Ts, R2 = H) gives a mixture of the amino-ketonebromine giving (presumably) the 7-bromo-tosyl ketone.Thus it seems that this useful detosylation reaction isinhibited when the carbonyl group cannot enolise toreact rapidly with bromine : we associate rapid pro-duction of hydrogen bromide with successful 5 9 6 de-tosylations although the reaction is also inhibitedby a methyl group at C-2, e.g.in (I; R1 = Ts, R2 =Me). The amino-ketone (I; R1 = H, R2 = Me) ob-tained by the sulphuric acid in acetic acid method, didnot react with an excess of bromine to give (IV; R =Me); thus the unexpectedly large effects of a methylgroup at C-2 are continued 6 9 9 throughout this series.Turning to N-alkylation, we find that rather forcingconditions are required : thus 2,3-dichloropropene andethyl bromoacetate both failed to react with the amino-ketone (I; R1 = R2 = H) but 2-chloro-3-iodopropenereacted slowly when present in considerable excess togive (I; R1 = CH2:CCl=CH2, R2 = H).Reduction ofOH(1) ( JI)(I; R1 = R2 = H) and the amino-alcohol (11; R = H),the propylene acetal of (I; R1 = Ts, R2 = H) reactedwith sodium in ammonia to give the acetal of theamino-ketone (I; R1 = R2 = H) in acceptable yield.The alcohol (11; R = Ts) was smoothly detosylated to(11; R = H) by sodium in ammonia; sulphuric acid inacetic acid was of no use in this case. On the otherhand, the aa-dimethyl-ketone (111; R1 = Ts, R2 =R3 = Me, X,Y = 0) reacted with sodium in am-monia to give only the alcohol (111; R1 = X = H,R2 = R3 = Me, Y = OH.While treatment of the tosyl ketone (I; R1 = Ts,R2 = H) with an excess of bromine in chloroformgave a tetrabromoaminoketone (IV; R = H) in goodyield, the aa-dimethyl ketone (111; R1 = Ts, R2 =R3 = Me, X,Y = 0) reacted only sluggishly withPart XVI, A.McLean and G. R. Proctor, J.C.S. Perkin I,1973, 1084.I. McCall, G. R. Proctor, and L. Purdie, J . Chem. SOC. ( C ) ,1970, 1126.3 G. R. Proctor, W. I. Ross, and A. Tapia, J.C.S. Perkin I ,1972, 1803.G. R. Proctor, J . Chem. SOC., 1961, 3989.E. D. Hannah, W. C. Peaston, and G. R. Proctor, J . Chem.Soc. (C), 1968, 1280.rm, (IY)the latter to the corresponding alcohol (11; R =CH2:CCl*CH2) proceeded uneventfully but the alcoholdid not react with Lewis acids by ring closure onto thechloropropenyl group (cf.ref. lo), instead it underwent( Y) (Yl1simple dehydration to (V; R = CH2:CC1*CH2). 2-Dimethylaminoethyl chloride only reacted with theamino-ketone (I; R1 = R2 = H) in the presence ofsodamide giving (I; R1 = CH2CH2NMe2, R2 = H)6 A. Cromarty, G. R. Proctor, and M. Shabbir, J.C.S. Perkin I ,W . H. Bell, E. Hannah, and G. R. Proctor, J . Chem. Soc.,8 P. D. Carpenter and M. Lennon, J.C.S. Chem. Comm., 1973,Q A. Cromarty, K. E. Haque, and G. R. Proctor, J . Chem. SOC.l o D. N. Gupta, I. McCall, A. McLean, and G. R. Proctor, J .1972,2012.1964, 4926.664.( C ) , 1971, 3636.Chem. SOC.( C ) , 1970, 21911974 1829but the amine (V; R = H) proved just as unreactiveto this reagent giving (V; R = CH,CH,NMe,) so thelack of reactivity might not be wholly due to the electron-attracting effect of the carbonyl group being transmittedto the nitrogen atom via the benzene ring. Con-trastingly, however, the amine (V; R = H) couldbe methylated easily giving (V; R = Me). Theamino-ketone ( I ; R1 = R2 = H) reacted with dimethylacetylenedicarboxylate to give the N-substituted ad-duct I; R1 = C(CO,Me):CHCO,Me, R2 = HI but theamino-ketone ( I ; R1 = H, R2 = Me) failed to react.3,4-Dihydro-l-benzazepin-5-ones (VI) have neverbeen isolated. We find that amino-ketones (I; R1 =H) cannot be directly dehydrogenated by, for example,manganese dioxide, palladised charcoal , or mercuricacetate.ll This is in contrast to amino-alcohols (11;Y = OH) which react with manganese dioxide to givethe imino-alcohols (VII; R = H and Me respectively).Repeated attempts to oxidise the alcohol (VII; R = H)led only to decomposition so we conclude that (VI)is reactive.This was further suggested by the reaction of diethylazodicarboxylate l2 with the amino-ketone (I; R1 =H) in chloroform from which only the correspondinghydrazine could be isolated.R = H) and (111; R 1 = X = H, R 2 = R 3 = M e,(XI; X = H) are readily available.,.* In this waythe substituted products (XI; R1 = Me or Et, R2 = H,X = CH,CCl:CH,, CH,CO,Et, or Me) were made ingood yield with 2,3-dichloropropene, ethyl bromo-acetate, or methyl iodide respectively.Ester inter-change took place on prolonged refluxing in alcohols.It should be noted, however, that alkaline hydrolysisof the diesters (XI; R1 = Et and Me, R2 = H, X =CH,CO,Et) yielded the corresponding diacid (XI ; R1 =R2 = H, X = CH,CO,H) rather than the expecteddecarboxylated product. These lteto-esters (XI ; X =H) exist largely as enols which may explain why theyfail to undergo some typical reactions of p-keto-esters,e.g. with guanidine and acetamidine; l8 but it is notclear why the keto-ester (XI; R1 = Et, R2 = X = H)is attacked by sodium borohydride yielding a diol(XII). Acid treatment of the latter in aromatic solventscaused reaction with the solvent, presumably via anallylic carbonium ion formed from a dehydrated inter-mediate.An interesting exception to the general C-4 alkylationbehaviour was encountered using dimethyl acetylene-dicarboxylate.In this case the product still containedthe enolisable P-keto-ester chromophore although themolecular formula was that expected from a 1 : 1adduct with (XI; R1= Et, R2 = X = H). This0 n 0It is interesting that manganese dioxide is efficaceousin dehydrogenating amino-ketones (VIII; R = Hand Cl) to imino-ketones (IX; R = H and Cl) in whichC-2 of the seven-membered ring is benzylic. Doubts l3have been expressed about the veracity of our claim14to have synthesised the imino-ketone (IX; R = H)but we have repeated this work and append furtherdetails (see Experimental section) along with thepreparation of the chloro-compound (IX; R = Cl).It is advantageous to use manganese dioxide preparedby ozonising manganous nitrate.15 We conclude thatsubstitution of C-2 of the tetrahydro-l-benzazepinesystem can best be attained l6 via the 2-oxo-derivatives(X) for which an excellent general synthesis has recentlybeen pub1ished.l'Substitution of the 4-position in tetrahydro-l-benz-azepines is straightforward since the p-keto-esters* Unless Bhe crude cyclisation product (XI ; X = R2 = H) wasexhaustiveIy refluxed with ethanol, some batches containedmixtures of the methyl and ethyl esters (XI; X = R2 = H,R1 = Me and Et).l1 M.F. Grundon and B. E. Reynolds, J . Chem. Soc., 1964,2446.l2 F. Yoneda, K. Suzuki, and Y . Nitta. J .Amer. Chem. Soc.,1966, 88. 2328; but cf. G. W. Kenner and R. J. Stedman, J .Chem. SOC., 1952, 2089; R. Huisgen and F. Jakob, Annalen, 1964,590, 37.result can only be explained l9 by assuming that a polaraddition reaction took place leading to eventual ring-expansion to (XIV) via the cyclobutene (XV). Pre-cedents exist for such reactions with enamines. Weare looking into the generality of this reaction.,OR2 amp; R' amp;JCH*O"Ts Ts TS(XI) (XII) cxm,Alkylation of C-4 in ketones e.g. (I; R1 = Ts, R2 =H) is unpredictable. Thus while methylation withmethyl iodide and potassium t-butoxide proceedednormally giving (111; R1 = Ts, R2 = R3 = Me; X,Y = O) and reaction with ethyl formate proceeded4l3 R. G. Cooke and I. M. Russell, Austral. J .Chem., 1972, 25,l4 I. McDonald and G. R. Proctor, J . Chem. Soc. (C), 1969,l5 J. S. Belew and C . Tek-ling, Chem. and Ind., 1967, 1958.l6 A. H. Rees and K. Simon, Canad. J . Chem., 1969, 47, 1227.17 J. Witte and V. Boekelheide, J . Org. Chem., 1972, 37, 2849.18 B. Smith, unpublished results.lS I. W. Sinclair, personal communication.20 C. D. Gutsche and D. Redmore, ' Carbocyclic Ring Expan-sion Reactions,' Academic Press, New York, 1968, p. 173 et seq.2421.13211830 J.C.S. Perkin Iat Oo, ethyl bromoacetate failed to react even underforcing conditions.As expected, substitution at C-5 can he broughtabout by reaction of ketones (I ; R1 = Ts) with Grignardreagents, although in the two cases we studied, thereaction was sluggish yielding (XIII; R = PhCH,and m-hZeOC6H,CH,) ; however, the Wittig reactionfailed even when the phosphonate carbanion from(EtO),P(O)CH,CO,Et 21 was employed.EXPERIMENTAL2,3,4,5-Tetrahyrlro-lH-l-benzazepin-5-ol (11; R = H).--To2,3,4,5-tetrahydro- 1-p-tolylsulphonyl- 1 H- l-benzazepine-5-01 (11; R = Ts) (30.4 g, 96-5 mmol) in ammonia (1200 ml)was added sodium (7-75 g, 0.34 g atom) over 30 min,causing the colour to remain blue finally.After 3 ininammonium chloride (in excess) was added and the ammoniaallowed t o evaporate. Working up the basic fractiongave the crude product (13.5 g, 85) which crystallisedfrom niethylene dichloride-light petroleum (b.p. 40-60")as material (11.4 g, 73:/0), m.p. 88-90" (Found: C, 73-6;H, 8.0; N, 8-9. CloHllNO requires C, 73.6; H, 8.05;N, 8-55?;), villas.(Xujol) 3300 cm-l (NH and OH), 7 2.7-3.4 (4H, in, Ar), 5.2br (lH, m, 5-H), 6.7 (2H, s, esch.,NH and OH), 7.0 (2H, m, 2-H), and 8.1 (4H, in, 3- andReaction of 1,2,3,4-Tetral~ydro-l-p-tolylsul~J~onyl-l-bem-azepin-5-one ( I ; K1 = Ts, R2 = H) with Sodium in Ant-monia.-To the tosyl ketone (31-75 g, 0.11 mol) in drytetrahydrofuran (THF) and ammonia (700 nil) was addedsodium (5-2 g) over 30 min and then ammonium chloride(excess) as before. The basic fraction was chromato-graphed on alumina; elution with benzene gave 1,2,3,4-tetrahydro-1-bcnzazepin-5-one ( I ; 13' = R2 = H) (8 g).Ether eluted 2,3,4,5-tetrahydro- 1H- 1-benzazepin-5-01 (3.6g) (11; R = H), n1.p. 88-90", as above.Reaction of the Tosyl Ketone ( I ; R1 = Ts, R2 = H) withSulplzuric and Acetic Acid.-The tosyl ketone (44 g),concentrated sulphuric acid (150 ml), and acetic acid (450ml) were stirred together a t 70-75" for 22 h.bsol;Vorkingup the basic fraction gave 1,2,3,4-tetrahydro- I-benzazepin-5-one ( I ; lil L= R2 = H) (15 g, 700/,), m.p. 68-70".1,2,3,4-Tetrahydro-2-r)zethyl-l-benzazepin-5-one ( I ; R1 =H, R2 == Me) .-1,2,3,4-Tetrahydr0-2-methyl- l-p-tolylsul-phonyl-I-benzazepin-5-one ( I ; R' = Ts, R2 = Me) (2 g),concentrated sulphuric acid (10 ml), and acetic acid (15 ml)were stirred together for 8 h at 70'. Working up aspreviously gave the product (550 mg) from light petroleum(b.p. 60-80") as blades, m.p. 75" (Found: C, 75-9; H,7.65; N, 8.25. C,,H,,NO requires C, 75.5; H, 7.5; N,8.0y0), v,,~ 3300 (NH) and 1650 (GO) cm-l, 7 3.2-2.35( l H , m, Ar), 2.7-2.9 (IH, m, Ar), 3-15 (2H, m, Ar), 5.78br(IH, s, esch.), 6.i-7.1 (2H, ni, 4-H), 7.3-7.6 ( l H , dq, J8 and 2 Hz, 2-H), 7.7-8-2 (2H, m, 3-H), 8.7 (3H, d, J8 Hz, Me).4-H).1,2,3,4-?'etval~ydr0-4,4-dinzetl~yl- I-p-tolylsulpl~o~~ytyl- l-benz-azepin-5-one (111; K1 = Ts, It2 = R3 = Me, S , Y = O).-The tosyl ketone ( I ; R1 = Ts, R2 = H) (20 g), potassiumt-butoxide from potassium (6.6 g), methyl iodide (25 g),and t-butyl alcohol (200 ml) were reflused and stirred to-gether for 24 ll.After acidification, addition of water,and extraction, the Pvodzcct (23 g) was obtained fromethanol in needles, ni.p. 164" (Found: C, 66-55; H, 6.55;N, 4.2. C,,H,,NO,S requires C, (iG.55; H, 6-15; N,2,3,4,5-Tetraliydro-4,4-dillietli~il- 1 H- 1 -benzazepin-6-ol (111 ;R1 = X = H, R2 = 1i3 -= Me, Y == OH).-To the previousketonc (5 g, 14.6 mmol), THF (25 nil), and ammonia (150ml) was added sodium (1-58 g, 0.069 g atom) slowly withstirring. After evaporation of ammonia, working up ofthe basic fraction and chromatography on silica gel elutionwith ether-light petroleum (b.p.40-60") gave the pro-duct ( 1 g, 36), m.p. 101-102" (froni etlianol) (Found:C,, 75.15; H, 8.7; N, 7.35. C12Hl,S0 requires C, 75-3;H, 8-95; N, 7-33,), vrI,,,. (Nujol) 3200--3300 cm-l (NH,OH),T 3.6-3.2 (4H, m, Ar), 5.85 ( l H , s, 5-H), 6.32 (2H, s,exch., NH, OH), 6.9 (2H, m, 2-H), 7-!) (113, m, 3-H), 8-7( l H , ni, 3-H), 8.9 (3H, s, Me), and 9.2 (3H, s, hle).R =I Me).-The previous amino-alcohol (0-48 g), activemanganese dioxide (1 g), and dry benzene (60 ml) werestirred together and refluxed 30 min.Filtration aridevaporation left the product (0.43 g, !I0 yo) which sublimedat 80" a t 0.1 nimHg and Iiad m.p. 90-91' (Found: C,76.65; H, 7-85; N, 7.47:; A P , 189*1166!). C,,H,,NOrequires C, T6-15; H, 8-0; N, 7.4";, M , 189-11536), v,~,,~.(Nujol) 3340 and 3290 (OH) cni.-l, 7 2-8-34 (4H, m,Ar), 4.8 (lH, cl, J 7 Hz, 2-H), 5.7 ( l H , s, 5-H), 6.0 ( l H , s,exch., OH), 8.0 ( l H , dd, J 7 and 1 3 Hz, 3a-H), 8.35 ( l H , d,J 13 Hz, 3b-H), 8.8 (3H, s, Me), and 9-1 (3H, s, Me).4,,5-Dilrydro-3H- 1-benzazefiin-5-01 (bsol;-I1 ; R -= H) .--2,3,4,5-~l'etraliydro-lH-l-benzazepi1i-5-ol (I1 ; I = H) (4-3g), actibsol;:e manganese dioxidc l5 (10 g), and dry benzene (150ml) bsol;bsol;.(!re stirred and reflused together for 3 11.'l'he pro-duct (3.7 g ) was distilled (b.p. 105-110" a t 0.1 nimHg)and crystallised froni methylenc dicliloride-light petroleum(b.p. 40-60") to yield plates, 11i.p. 88-89' (Found: C,74.3; H, 6.9; N, 8-'1. CloHl,NO requires C, i4.5; H,6.85; S, 8.7(), vlllaX. (Nujol) 3290 cm-' (OH), 7 2.8-3-5 (4H, m, Xr), 4.7 ( l H , d, J 6 Hz, 2-H), 5.0 ( l H , m,5-H), 5.7 ( l H , s, cxch., OH), ant1 7*$-8-1 (4H, ni, 3-and 4-H).phonyl- I-benzazepin-5-one.- 1,2',3,4-Tetrahydro-i,4-di-methyl- 1-p-tolylsulphonyl- I-benzazepin-5-one ( 2 g, 5-8niniol), bromine (6-2 g, 38.8 mmol), and chloroform (30 ml)were stirred for 24 h at 20". Ilfter bcing washed withaqueous sodium hydrogen carbonate the organic layerwas washed and evaporated to ykltl a brown solid (2.4 g ) .Crystallisation from ethanol gave needles (O.!) p, 377;),m.p.169-170" (Found: C, 54-1; H, 4.95; N, 3-35. C1,H20-RrN0,S requires C, 54-1; H, 4-75; N, 3-30;), vmX. (Nujol)1700 ( G O ) mi-', 7 2.3-2- 8 (7H, m, Ar), 6-2 (2H, 111,2-H), 7.6 (3H, s, hle of tosyl), 8.3 (2H, ni, 3-H), and 9.0I'rimetliylene Acetnl ($ the Tosyl Ketone ( I ; R' = Ts,R2 = H).----The tosyl ketone ( 2 0 g ) , toluene (900 inl),propane- 1,3-diol (5 g) , and toluene-p-sulplionic acid ( 1 g )21 W. S. Wadsorth, jun., and W. L). Emmons, J . Amev. Chew.Soc., 1961, 83, 1733.4- 1 3b).4,5-l~ilrydvo-4,4-dimetJayl-3H- l-henanzt?pin-5-ol ( V I I ;7-Broiwo- 1,2,3,4-tetvaliydro-4,4-di~nethyl- l-p-tolylsul-(6H, S , 4-Mc)1974 1831were refluxed with a Dean-Stark trap, and three furtherquantities of propane-1,3-diol (5 g) were added every 12 h.After 48 11 tlie reaction was cooled and evaporated.Crystallisation of the residue (26 g) from ethanol gave prisms(15 g, 630;,), m.p.130-131' (Founcl: C, 64.35; H, 6.4;N, 3-95. C,oH,3Xc'0,S requires C, 64.35; H, 6.2; K,3.7504). The i.r. spectruni contained no carbonyl ab-sorption.Reactioii of tlie AcetaZ of 1,2,3,4-Tetrahydro- l-p-tolyl-sul~Jionyl- J -betizcizepin-5-one with Sodium in Awznzonia.-To the foregoing acetal (10 g, 26.8 mmol), THF (200 ml),and ammonia (1 100 nil) was added sodium (1.02 g, 0.043 gatom) over 30 min with stirring.After addition of am-monium cliloridc (excess) ammonium was allowed t oevaporate, water was added, and the product extractedwith chloroform .* After treatment with aqueous ethanolcontaining toluene-p-sulplionic acid (0.5 g) for 24 h a t 20deg;,cliromatograpliy gave 1,2,3,4-tetrahydro- l-benzazepin-5-one ( I ; R1 -= RZ = H) (2.1 g, 48) as before, 't 2-1-3.3 (4H, 111, Ar), 5.3 ( l H , s, excli., NH), 6-6-69 (2H, m,4-H), 7.0---7.3 (2H, ni, 2-H), and 7.7-8.0 (2H, ni, 3-H).1,2,:1,4-'l'elvaJiydvo- 1- (2-cJiZovoprop-2-enyl)- l-benzazepin-amp;one ( I ; K1 = CH,CCl:CH,, R2 = H).--l,S,3,4-Tetra-liydro- 1-benzazepin-5-one (2 g) in 2-chloro-3-iodopropene 2(40 g ) was held a t 60" in a pressure bottle for 48 h. Chrom-atography on silica gel (elution with 5y:, ether-benzene)gave the pvoduct (1.G g), m.p.81-82" from benzene-light petroleum (b.p. 60-8Oo) (Found: C, 66.2; H,6.1; S, M ) 5 . C1,H1,CINO requires C, 66.15; H, 6.0;S, 5.9q.I), vllIns. (Nujol) 1672 (GO) cm-l, 7 2-25 (1H. dd,J 12 and 2 Hz, G-H), 2-55-3-45 (3H. m, Ar), 4.55-4.8(2H, ni, XH,), 5-8 (2H, s, -CH,-), 6.63 (2H, t, 4-H), 7.18(2H, t , 2-H), and 7-5--8-0 (2H, m, 3-H).2,3-Tlihydvo-1-(2-cJ1lo~o~~op-2-enyZ)-lH- l-benzazepim (V;R = CH,(XI:CH,) .-'Tlie foregoing ketone (1-3 g), lithiumaluminium liydride (130 mg), and dry ether (80 ml) werestirred a t 20" for 24 h. The intermediate obtained in theusual way was an oil (1.2 g ) , v,,,,,. 3450 cm-l (OH), whichwas stirred lvith polyphosphoric acid (I5 g) at 55" for- 1 h.'L'he product was chromatographed on silica gel ; elutionwith benzenc-light petroleum (b.p.60-80") (50) gavethe poduct (550 mg), n1.p. 55" (Found: C, 70.8; H, 6.5;W, 6.75; C1, 16.1. C1:3H15CIS requires C , 50.95; H,6.4; N, 6.4; C1, 15.9deg;,amp;), 7 2-5-3.35 (4H, m, Ar), 2.6--2.75(IH, ni, 5-H), 3.85-4.2 ( l H , ni, 4-H), 4.5-4.7 (2H, ni,XH,), 6.0 (2H, s, -CH,-), 6.77 (2H, t, 2-H), and 7.4-7-65 (219, 111, 3-H). Treatment of this material with poly-phosphoric acid at up to 120" or with 900,(, sulphuricacid a t 0" caused only slight decomposition, and no newproducts could be detected.Reaction of 1,2,3,4-Tetva Jiydro- l-benzazepin-5-one withZimethyl A cetyZenedicarboxyZate.-The amino-ketone (I ;It1 = 1, = H) (4.5 g), diniethyl acetylenedicarbosylate(4.95 g), and anhydrous methanol (55 ml) were refluxedtogether for 48 h.Evaporation of solvent left l-(l,bis-ilzethoxycarbonylvinyl) - 1,2,3,4-tetrahydro- 1-benzazepin-5-onewhich crystallised from ether in cubes (4.88 g, 57y0), m.p.143-144" (Found: C, 63.4; H , 5.7; K, 4.6. Cl6H1,NO5requires C, 634; H , 5.65; X, 4-6y0), v,,,,,. (Nujol) 1725* Prepuxtivc t.1.c. of a sample (390 mg) on silica gel elutingwith ether-benzene (1 : 10) gave 1,2,3,4-tetrahydro-l-benzazapin-amp;one (40 mg) and its trimethyl acetal (140 mg) as an oil, b.p. 1.36'a t 0.1 n m Hg (Found: Mf, 219.124921. C,,H,,NO, requiresM , 819.125053), vlllar. (Nujol) 3340 cm-', T 2.2-3-6 (4H, in, Ar),5.9---6.3 (4H, in, CH,O), 6.6-7-0 (3H, ni, 2-H antl NH, exch.),antl 7.6-8.4 (6H, m, 3- and 4-H and CH, of acetal ring).(ester) and 1665 (ArCO) crn-l, T 1.9-2.7 (4H, ni, Ar),4.9 (lH, s, XH), 6.2 (3H, s, Oh!le), 6.4 (3H, s, Ohle), 6.3-6.45 (2H, m, 4-H), 7.2 (2H, m, 2-H), and 7.8 (2H, m,Hydrobromide of 3,3-Dihydro- l-wiethyl- 1H- 1 -benzazepine(V; R = Me).-2,3-L)ihydro-lH-l-benzazepine (V; K =H) (2 g), anhydrous methanol (25 nil), anhydrous potassiumcarbonate (4 g), and methyl iodide (4.8 g) were stirredand refluxed together for 18 h.Filtration and evaporationgave an oil (2 g) which was chromatographed (silicagel, benzene) to give a pale yellow oil (1.43 g, 65) whichdarkened on standing. Treatment of a chloroform solutionwith hydrogen bromide precipitated the product whichcrystallised from acetone in prisms, m.p.176-177" (Found:C, 55.5; H , 6.2; N, 5-6. C1,,Hl4BrK requires C, 55-05;H, 5.1); S, 5.80,amp;), vIfias. (Nujol) 2450 (SH) cm-l, 7 -3-5br( l H , s, escli., S H ) 1-5-2.6 (4H, in, Ar), 3.35 ( l H , (1, -110 Hz, 5-H), 3.8 ( l H , m, 4-H), 5-9 ( l H , ni, 2-H), 6.4 (IH,ni, 2H), 6-9 (3H, d, J 2 Hz, NMe), and T.0 (SH, ni, 3-H).1-(2- IlimetJiylaminoetJiy1)- 1,2,3,4-tetrahydru- l-benzazepin-5-0,~ ( I ; 13' = Me,NCH,CH,, I, = H).--l,2,3,4-Tetra-hydro-l-benzazepin-5-one ( I ; It1 = I* = H) (3 g) in drytoluene (25 ml) was added with stirring to freshly preparedsodamide from sodium (2 g) in ammonia (400 nil), fol-lowed bj- 2-dimetliylaniinoethyl chloride from its liydro-chloride (10 g) in toluene (25 inl). After the ammoniahad evaporated off the product was obtained by cliromato-grapliy on alumina.Elution with ether gave an oil (810mg), b.p. 140" at 0.1 mmHg (Found: C, 71.95; H, 8-65:hi, 11-50,;; Mt, 232.1573. C14H,oX,0 requires C, 52-45;H, 8.7; XI 13.050,;; M , 232-1576), 7 2.3 (lH, dd, J 8 and1.5 Hz, 6-H), 2.65-2.85 ( l H , ni, Ar), 3.09-3.37 (BH, ni,Ar), 6.42 (2H, t , -CH,-), 6-72 (2H, t, -CH,-), 5.25 (2H, t,-CH,-), 5.44 (2H, t, -CH,-), 7.5-7-9 (2H, m, 3-H), and7.7 (6H, s, NMe).2,3-Dihydro- 1-(2-divnethyZaminoetJzyl)-lH- l-benzazepine(V; I = CH2CH,NMe,).-2,3-Lihydro-lH-l-benzazepine( V ; R = H) (2 g) was submitted t o the same treatmentas in the previous experiment. The product (510 mg)had b.p. 125-130 at 0.1 mmHg (Found: C, 77.55; H ,8.8. C14HzoX2 requires C, 77.85; H , 9 - 3 ~ o ) , 7 2-8-3-8(5H, m, 4 Ar and 4-H), 4.0-4-25 (lH, m, 5-H), 6.6 (2H, t,-CH,-), 6.83 (2H, t , -CH,-), 7.4-7.6 (4H, m, 2- and 3-H),and 7.74 (6H, s, XMe).8-Methoxydibenzb,eazepin-l l-one l4 (IX; I = H) .-5,fi-Dihydro-8-methoxydibenzb,eazepin-l l-one l4 (VIII ;R = H) (1 g ) , dry benzene (200 ml), and manganese di-oxide l5 (2 g ; previously dried by refluxing in benzene)were refluxed for 30 h (Dean-Stark).After filtration andevaporation of solvent tlie product (980 nig) was re-crystallised from toluene in yellow needles, ni.p. 142-145' (decomp.) (Found: C, 76.2; H , 4.55; N, 6-05. Calc.for C15HllSO2: C, 76.0; H, 4.5; N, 5.9), v,,,. (Nujol)1640 (GO) and 1620 (C=X) cni-l, 7 1.3 (lH, s, 6-H), 1.75-2.85 (7H, m, Ar), and 6.08 (3H, s, OMe), A,, ,:,*. 211, 244,and 364 nm ( E 12,095, 21,502, and 3808).4-C~1Zoro-S-m-methoxybenzyl-N-p-toZylsul~~ionylanth~anilicR cid.-Methyl 4-chloro-~V-p-tolylsulphonylanthranilate(71.2 g ) , nz-methoxybenzyl bromide 22 (61 g), and freshlyroasted potassium carbonate (70 g) were stirred togethera t 140" for 24 11. After cooling, leaching with methylenedicliloride, filtration, and evaporation of the filtrate, the22 W.Q. Beard, D. N. van Eenam, and C. I. Hauser, J . Ovg.Cheiiz.. 1961, 28, 2310.3-H).4-J.C.S. Perkin ILmethyl ester (93.5 g), m.p. 85" (from ethanol), was obtained.The latter (65 g) was hydrolysed as in a previous case l4to give the Product (46 g), m.p. 182" (from toluene) (Found:C, 59.7; H, 4.7; S, 3.45.C22H2,C1N05S requires C, 59.3;H, 4-55: N, 3*15o/b).3-Chloro-5,6-dihydro-8-methoxy-rbsol;;-p-tolylsulphonyld~benz-b,eazepin-1 l-one.-The foregoing acid (47.3 g) wascyclised as previously described for the parent system l4and gave the product (42 g), purified by chromatographyon alumina (benzene elution) and by crystallisatioii fromethanol, m.p. 238" (Found: C1, 8-3; N, 3.3; Mf,429.0603, 427.0578. C2,H18ClN0,S requires C1, 8.05;N, 3.5 ; M , 429.0616, 427.0645). Consistently lowcarbon analyses were obtained.3-ChZoro-5,6-dihydro-8-nzethoxydibenzb,eazepin- 1 l-one(VIII; R = Cl).-The previous N-tosyl ketone (5 g) andpolyphosphoric acid (62 g) were stirred at 110" for 5 h.The basic fraction (2 g ) was purified by chromatographyon silica gel (benzene elution) and by crystallisation frombenzene-light petroleum (b.p.60-80") (1 : I ) , m.p. 148"(Found: C, 66.35; H, 4.4; N, 5.05. C15H12C1N02 requiresC, 65-9; H, 4.45; N, 6.15), vnlax (Nujol) 3290 (NH)and 1700 (GO) cm-l.3-Chloro-8-methoxydibenzb,eazepin- 1 l-one (IX ; R =C1).-The above amino-ketone (230 mg) and active man-ganese dioxide (370 mg) were treated as for the parentsubstance. The product (160 mg) crystallised from toluenein needles, m.p. 163" (Found: C, 66-25; H, 4.05; N,5.15 ; M , 273.0381, 271.0395. Cl,Hl,CINO, requiresvmx. (Nujol) 1640 cm-l (GO), A,, 210, 246, and 364 nm( E 15,634, 28,352, and 5367).Reaction of 4-Ethoxycarbonyl- 1,2,3,4-tetrahydro-l-p-tolyl-sulphonyl-l-benzazepin-5-one with Dirnethyl Acetylenedicarb-oxy1ate.-The keto-ester (XI; R1 = Et; R2 = X =H)2(7.75 g), sodium methoxide from sodium (0.5 g ) , andmethanol were stirred together for 0.5 h: the solventwas then evaporated and the residual sodium salt stirredwith toluene ( 150 ml) and dimethyl acetylenedicarboxylate(3 g) for 2 h.After being washed with dilute hydrochloricacid and water, the solution was dried and evaporated.The tarry product (9 g ) crystallised from ethanol giving4-ethoxycarbonyl- 1, 2,3,6-tetrahydro-5,6-bismethoxycarbonyZ-l-p-tolylsulphonyl- l-benzazonin-7-one (XIV) (7.2 g ) , m.p.141-144" (Found: C, 59-1; H, 5.0; N, 2.83y0; M ,529.1419. C2,H2,N0,S requires C, 59.05; H, 5-15; N,2.65; M , 529.1406)) vmx. (Nujol) 1710-1740br (ester)and 1650 (H-bonded ester) cm-1, T -3.2 (lH, s, exch.),2-2-2.75 (SH, m, Ar), 5.9 (2H, q, OCH,CH,), 6.12 (3H, s,CO,Me), 6-35 (3H, s, C02Me), 6.0-6.3 (IH, m, 2-H),6.7-7-4 (3H, m, 2- and 3-H), 7.52 (3H, s, ArMe), and8.9 (3H, t, CH,CH,O).hydro-l-p-tolylsulphonyl- l-benzazepin-$one (XI ; R' = Et,R2 = H, X = CH,*CCl:CH,).-The mixed keto-esters (XI;R1 = Me and Et, R2 = X = H)2 (1.24 g), 2,3-dichloro-propene (0.4 g), sodium hydride (0.3 g ; 50), and drydimethylformamide (25 ml) were stirred under nitrogenat 85' for 3.5 h.The product was obtained in the usualway and purified by chromatography on silica gel (2ether-benzene) to give needles (900 mg), m.p. 129-130'(from ethanol) (Found: C, 59.8; H, 5-35; N, 3.05. C23-H24CIN0,S requires C, 59-8; H, 5-25: N, 3-05y0), v,,(Nujol) 1745 (ester) and 1690 (GO) cm-', z 2-4-2.8 (8H,m, Ar), 4.8 (ZH, d, XH), 5-8-6-2 (4H, m, :CH2 and OCH,C, 66.5; H, 3-75; N, 5.1; M , 273-0371, 271-0400),4- (2-Chloroprop-2-enyl)-4-ethoxycarbonyl- 1,2,3,4-tetra-CH,), 6.9-7-2 (2H, m, 2-H), 7.6 (3H, s, ArMe), 7.95-8.25 (ZH, m, 3-H), and 7.9 (3H, t, CH,CH,O).1H-l-benzazepin-5-01 (XII) .-The keto-ester (XI ; R1 =Et, R2 = X = H) (10.25 g ) , absolute ethanol (200 ml),and sodium borohydride (2.15 g) were stirred together for48 h.The usual work-up gave a solid (7-1 g), m.p. 106-108" (from benzene-ethanol) (Found: C, 61.85; H, 5.95;N, 4-25. C1,H2,NO4S requires C, 62-2; H, 6.1; N, 4.05y0),vmk (Nujol) 3300br (OH) cm-'.When this compound (3.5 g) was refluxed for 48 h inbenzene with toluene-p-sulphonic acid (0.5 g) , the product(2.3 g) was purified by chromatography on alumina andcrystallisation from light petroleum (b.p. 40-60") to giveprisms, m.p. 7 9-40", of 4-benzyl-2,3-dihydro- 1 -p-tolyl-sulphonyl-1H-l-benzazepine (Found: C, 74.0; H, 6.05;N, 3-6. C,,H2,N02S requires C, 74.0; H, 5-95; N, 3-6y0),7 24-3-1 (SH, m, Ar), 4.08 (lH, s, 5-H), 6.25 (2H, t,2-H), 6-8 (2H, s, CH2Ph), 7.6 (ZH, t, 3-H), and 7.66 (3H,s, Me). Refluxing in toluene gave a similar product as awaxy solid having an almost identical n.m.r. spectrum withan additional signal, T 7.72 (3H, s, 1Me).2,3,4,5-Tetrahydro-5-m-methoxybenzyl- 1 -p-tolylsulphonyl-1H-l-benzazepine (XIII ; R = m-MeOC,H,CH,) .-Thetosyl ketone (I; R1 = Ts, R2 = H) (19-3 g ) in dry THF(100 ml) was added to the Grignard reagent prepared frommagnesium (1.8 g) and m-methoxybenzyl bromide (15.8 g)in dry ether (100 ml).After being refluxed for 3 h withstirring, the mixture was worked up to yield the product(19-7 g), m.p. 116-118" (from ethanol) (Found: C, 68.6;H, 6.2; N, 3.2. C2,H2,N04S requires C, 68.7; H, 6.15;N, 3.45y0), vmak (Nujol) 3505 (OH) cm-'. ,4 similar re-action using benzylmagnesium bromide and the tosylketone (29 g) gave 5-benzyZ-2,3,4,5-letrahydro-l-p-tolyZ-sul~honyl-lH-l-benzaze~an-5-ol (XIII ; R = PhCH,)(18.9 g), m.p. 122.5-124" (Found: C, 70.4; H, 5-85: N,3.4. C,4H2,N0,S requires C, 70.75; H, 6.2; N, 3.45).Significantly lower yields were obtained using shorterreaction times.Reaction of 4-Ethoxy( and 4-methoxy-) carbonyl- 1,2,3,4-R1 = Me and Et, R2 = X = H) with Ethyl Brotnoacetate.-The mixture of esters (12.1 g), sodium hydride (1.35 g ;60y0), and 1,2-dimethoxyethane (50 ml) were stirred to-gether and refluxed for 2 h.To the cooled suspension,was added ethyl bromoacetate (6 g) in 1,2-dimethoxy-ethane (75 ml). After being stirred overnight, the mixturewas refluxed for 3 h, cooled, and poured into an excess ofwater. Extraction with chloroform gave the product,which was rapidly chromatographed on alumina (800 g;24 h deactivation). Elution with 250; ether-benzenegave an oil (14-4 g) which decomposed on attempteddistillation. I t appeared to be a mixture of methylethyl and diethyl esters (XI; R1 = Me and Et, K2 = H,X = CH,CO,Et) (Found: Mf, 473.1467 and 459.1379.Calc.for C,4H2,N0,S: M , 473.1508; Calc. for C,,H,,NO,S:M , 459-1352), vmBx. (film) 1730 (ester) and 1690 (ArCO) cm-l.The mass spectrum and the n.m.r. spectruni indicatedthat the mixture contained ca. 50 of each product.phonyl-1H-l-benzaze~ine-4-carboxylic acid (XI ; R' =Ra = H, X = CH,CO,H).-The previous diesters (9 g),ethanol (75 ml), and aqueous sodium hydroxide (10excess) were refluxed for 1 h and left for 18 h at 20"; dilu-tion with water, extraction with benzene, and acidification4-Hydroxymethyl-2,3,4,5-tetrahydro- l-p-tolylsulphonyl-tetrahydro- l-p-tolylsulphonyl- l-benzazepin-5-one (XI;4-Carboxymet hyl-2,3,4,5-tetrahydro-5-0~0- l-p-tolylsul1974 1833of the aqueous layer gave the hydrated product (6.65 g),m.p. 161-162" (from ether) (Found: C, 55.35; H, 4.85;N, 3.6; S, 7-25.C,,H,,NO,S,H,O requires C, 55.2; H,4.85; S, 3.2; S, 7-35y0), vmx- 2640br (OH) and 1700br(C0,H) cm-l, 7 (CI,CN) 2.05-3-2 (8H, m, Ar), 2.7-3.lbr (2H, OH), 6.2-6.6br (213, s, H,O), 7.0-7.3 (2H, m,4-CH2), 7.47-7.66 (2H, m, 2-H), 7.6 (3H, s, Me), and8.1-8.45 (2H, m, 3-H).Acid Hydrolysis of the Diesters (XI; R1 = Me and E t ,R2 = H, X = CH,CO,Et).-The diesters (1.72 g), glacialacetic acid (24 g), ethanol (8 ml), concentrated hydro-chloric acid (4 ml), and water (4 ml) were refluxed for20 h. Working up the acidic fraction gave 4-eth0.t.y-carbonyl-2,3,4,5-tetrahydro-5-0~0- 1-p-tolylsulphonyl- 1 H- 1-benzazepine-4-acetic acid (XI; R1 = Et, R2 = H, X =CH,CO,H), b.p. 160' a t 0.15 mmHg (Found: C, 59.9;H, 5.7; N, 3.45; M+, 445.1190. C2,H,,N0,S requiresC, 59-4; H , 5.2; N, 3.15; M, 445.1195), vmx. (Nujol)2650-2750br (OH), 1735 (ester), 1720 (CO,H), and 1690(Arc-) cm-l, 7 2.3-3.05 (8H, m, Ar), 5.9-6-2 (2H, q,OCH,CH,), 6.4 (2H, s, -CH,CO,H), 6.8 ( l H , s, exch.,CO,H), 7.2-7.3 (2H, m, 2-H), 7.6 (3H, s, ArMe), 7-55-7.75 (2H, m, 3-H), and 8.9 (3H, t, CH,CH,O).4-MethoxycarbonyZ-4-methyl- 1,2,3,4-tetrahydro- 1-p-tolyl-sulphonyl-1-benzazepin-amp;one (XI; R1 = X = Me, R2 =H).-The keto-esters (XI; R' = Me and Et, R2 = X = H)(7.5 g), dimethylformamide (75 ml), and sodium hydride(1.5 g; 80) were stirred and heated for 1 h at 60-70'before addition of methyl iodide (4 ml), and for 1 h after-wards. After dilution with water, acidification (pH 4),and extraction with chloroform, the product (10 g) wascrystallised from methanol in prisms, m.p. 118" (Found:C, 62-25; H, 5.55; N, 3-6. CZoH2,NO,S requires C,62.05; H, 5-45; N, 3.6y0), vmr (Nujol) 1750 (ester) and1690 (Arc*) cm-l, 7 2-4-2-85 (8H, m, Ar), 5.9-6.3(2H, m, 2-H), 6-41 (3H, s, CO,Me), 7.6 (3H, s, ArMe),8-05-8-35 (2H, m, 3-H), and 8.7 (3H, s, 4-Me). Re-fluxing for 2 h with ethanolic aqueous sodium hydroxideconverted the ester into 1,2,3,4-tetralzydro-4-nzethyE-l-p-tolylsulphenyl-1-benzazepin-5-one (111; R1 = Ts, R2 = H,R3 = Me, X,Y = 0), which crystallised from ethanolin prisms, m.p. 126" (Found: C, 65.3; H, 5.75; X, 4.4.Cl,Hl,NO,S requires C, 65.7; H, 5.8; S, 4*25y0), vmx.(Nujol) 1675 cm-l (ArCZO), T 2.2-2.8 (8H, m, Ar), 5.65-5.9 (lH, m, 4-H), 64-6.7 (lH, m, 2-H), 7.2-7.45 ( l H , m,2-H), 7-6 (3H, s, ArMe), 7.6-7.9 (IH, m, 3-H), 8.2-8.6(lH, m, 3-H), and 8.92 (3H. d, 4-Me).We thank Dr. D. N. Gupta for technical assistance andAllen and Hanburys Ltd. for a studentship (to I. McW.).4/650 Received, 19th Mavch, 1974