1974 1747Photocyclisation of Enamides. Part V. Photocyclisation of ag-un-saturated AnilidesBy lchiya Ninomiya,' Sadami Yamauchi, Toshiko Kiguchi, Atsuko Shinohara, and Takeaki Naito,Irradiation of N-methyl- and N-benzyl-cyclohex-1 -enecarboxanilide (Ia and b) and N-methyl-3.4-dihydro-naphthalene-1 -carboxanilide ( V I I I ) with a low pressure mercury lamp afforded a mixture of cis- and frans-photo-cyclised products the phenanthridones (11) and (111). and the benzophenanthridinones (IX) and (X), respec-tively, whose ratios were dependent upon the solvent employed. Equilibration and deuterium incorporationexperiments provided important information on the reaction mechanism.Kobe Women's College of Pharmacy, Motoyamakita, Higashinada, Kobe, JapanWE liave developed a photocyclisation of various types Chapmano f N-benzoylenamines and shown its use for the and his co-workers have previously reported the first(a) I.Ninomiya, 'r. Naito, and 'r. Kiguchi, J.C.S. Prvkiri I,1973, 2257; (b) I. Ninomiva, T. Naito, '1. Kiguchi, and T. Mori,ibid., p. 1696; (c) I . Ninomiya, T. Naito, and 2'. Mori, ibid.. p. 505.synthesis of a variety of heterocyclic systems.I . Ninomiya?, T. Naito, and 'I.. Iiiguchi, -1.C.S. I'crkiiz I,1!)73, 22611748 J.C.S. Perkin Inon-oxidative photocyclisation of alkyl anilides? whichcan be regarded as a species of enamide. The stereo-chemistry of the reaction has not yet been clarified,although further examples of photocyclisation have beenr e p ~ r t e d . ~ We now report on stereochemical aspects ofthe photocyclisation of anilides and demonstrate theusefulness of this reaction for the synthesis of phen-anthridine.Acylation of N-alkylanilines with cyclohex-l-ene-carbonyl chloride afforded the corresponding anilides(Ia and b) in good yields.Irradiation of a 0.02~-methanolic solution of the anilides (Ia and b) affordedmixtures of trans- and cis-epimeric products (IIa andb), and (IIIa and b) respectively, the cis-isomers (IIIaand b) being predominant on g.1.c. The ratios ofMeI Y I )Me(YD)* NBS = I - bromosuccinimidea,R=Me; b,R=CH2Ph; c, R=Hepimeric photoproducts were dependent upon thesolvent employed during the irradiation; in proticsolvents such as methanol, the cis-isomers (IIIa and b)were obtained predominantIy while in aprotic solventssuch as benzene, ether, and even dimethyl sulphoxide,the Mum-isomers (IIa and b} were the major products(Table).Isolation of these epimeric products wasaccomplished by repeated chromatography.The cis-N-benzyl-lactam (IIIb) was debenzylated toafford the cis-N-nor-lactam (IIIc) , identified by com-parison with an authentic sample prepared by Masa-mune.6 Similarly , debenzylation of the trans-N-benzyl-3 (a) P. G. Cleveland and 0. L. Chapman, Chem. Comm., 1967,1064; (b) 0. L. Chapman and W. R. Adams, J. Amer. Chem. SOC.,1968, 90. 2333.4 (a) Y. Ogata, K. Takagiri, and I. Ishino, J . Ovg. Chem., 1971,88, 3976; (b) M. Ogata and H. Matsumoto, Chern. and Pharm.Bull. (Japm), 1972, 20, 2264.lactam (IIb) afforded the trans-N-nor-lactam (IIc),identical with the authentic sample.6 N-Methylationof a mixture of the N-nor-lactams (IIc) and (IIIc)Solvent effect on the trans : cis ratio of products ofphotocyclisation of anilidesAnilide Et,O iMe,SO C6H6 MeOH(14 4.0 0.9 0.315.6 4.0 1.6 0.46.3 1.6 0.7(Ib)(VIII)afforded a mixture of the corresponding N-methyl-lactams which were identical with the photoproducts(IIa) and (IIIa) from the N-methylanilide (Ia) re-spectively.Irradiation of the N-alkylanilides (Ia and b) in thepresence of iodine afforded the corresponding didehydro-lactams (IVasa and b) respectively which were alsoobtained from the photoproducts (IIa and b) and(IIIa and b) upon treatment with N-bromosuccinimide.Further dehydrogenation of the didehydro-lactam (IVa)with selenium at an elevated temperature afforded theknown phenanthridone (V) .' Lithium aluminium hydridereduction of the photoproducts (Ha) and (IIIa) affordedthe corresponding tertiary amines (VI) and (VII)respectively.Similar photocyclisation was also observed for thenaphthalenecarboxanilide (VIII) which was preparedfrom N-methylaniline with 3,4-dihydronaphthoyl chloridein a good yield.The photoproducts were a mixture oftrans- and cis-lactams (IX) and (X) in the ratio describedin the Table. These were readily separated by chromato-graphy and their structures were determined uponinspecting the coupling constants of the 4b-protons.The ratios of the cis- and trans-products coincided withthose of the anilides (Ia and b). Irradiation of theenamide (VIII) in the presence of iodine afforded theexpected didehydro-lactam (XI) along with the com-pound (XII) with a 4b-hydroxy-group.The possibility of isomerisation between the truns- andcis- lactams (IIb) and (IIIb) during the course of theirformation in the photocyclisation was examined.Whena methanolic solution of either isomer, cis-(IIIb) ortrans-(IIb) , was irradiated or heated under reflux over7 h, no isomerisation was observed. On the other hand,isomerisation was observed when potassium hydroxidewas present: an alkaline methanolic solution of theanilide (IIb) or (ZIIb) when heated under reflux for 7 11gave an equimolar mixture of both lactams (IIb) and(IIlb). This confirmed that the ratios observed in thephotocyclisation of the anilides reflect the stereochemicalcourse of the cyclisation.We also carried out experiments with deuteriatedsolvents in order to examine the possibility of solventincorporation.When irradiation of the anilide (Ib) wascarried out in an ethereal solution saturated with6 G. H. Alt and A. J. Speziale, J . Org. Chem., 1966, 31, 1340.6 (a) T. Masamune, M. Takasugi, H. Suginome, and M. Yoko-yama, J . Org. Chem., 1964. 29. 681; (a) A. Michailidis, J.-P.Brouard, and A. Resplandy, Compt. vend., 1972, 275, 961.7 T. Hase, Acta Chem. Scand., 1964, 18, 18061974 1749deuterium oxide, the photoproduct , which consisted ofalmost pure trans-isomer (IIb) (53) , had incorporatedonly 12 deuterium.On the other hand, the photo-products from irradiation in deuterium methoxidesolution, consisting of almost pure cis-isomer (IIIb)(36) , had incorporated 90 deuterium.Mecvm)Me1 1x1MeI X )Me(XI 1MeThis marked contrast suggests the following mechan-ism for the photocyclisation of anilides: photochemicalelectrocyclic ring closure of the 6 x-electron enamidesystem gives an intermediate, which would thenundergo a thermal hydrogen shift in both a stepwise andconcerted manner, to afford a mixture of cis- andtrans-lactams in the ratio observed. In an aproticsolvent, hydrogen would be ' shifted concertedly foafford the trans-lactam predominantly, while in aprotic solvent, a stepwise hydrogen shift (deprotonationand protonation) occurs, therefore affording a mixtureof cis- and trans-lactams; the reason for the preponder-ance of the cis-lactam is yet to be examined.EXPERIMENTAL1.r.spectra were recorded for solutions in chloroform,'H n.m.r. spectra for solutions in deateriochloroform on aVarian A-60D instrument, and mass spectra on a JEOL-JMS-O1SG machine. M.p.s were determined with aKofler hot-stage apparatus. Photochemical reactions werecamed out as described previously.1N-Mettaylcyclohex-l-enecarboxanilide (Ia) .-To a stirredsolution of N-methylaniline (34 g) and triethylamine(6.8 g) in anhydrous benzene (100 ml), a solution of cyclo-hex-l-enecarbonyl chloride (4.6 g) in anhydrous benzene(60 ml) was added dropwise with ice-cooling. The resultingsolution was heated under reflux for 2 h, then diluted withbenzene, washed with water, and dried.The solvent wasremoved and the residue chromatographed on alumina.Elution with benzene afforded the aiailide (Ia) as an oil(6.0 g, 88), b.p. 123-127" at 2 mmHg), vmk 1625 cm-'(N-CO-GC), 6 5-83 (lH, m, CH) and 3.33 (3H, s, NMe)(Found: C, 77.75; H, 8.0; N, 6.7. C,,H,,NO requires C,78.1; H, 7.95; N, 6.5).N-Benzylcyclohex- l-enecarboxanilide (Ib) .-A similar re-action of N-benzylaniline (6.3 g) with cyclohex- l-ene-carbonyl chloride (5.5 g) afforded the anilide (Ib) (9 g,goyo), m.p. 76" (from n-hexane), vmx 1623 cm-' (N-CO-C=C) ,8 5-88 (lH, m, CH=C) and 4.99 (ZH, s, NCH,Ph) (Found:C, 82.7; HI 7.4; N, 4.55. C,,H,,NO requires C, 82-46;H, 7.25; N, 4.8).cis- and trans-6a,7,8,9,10,1Oa-Hexahydr~5-methylfiken-anthridin-6(5H)-one (IIIa and IIa) .-A 0.02~-solution ofthe anilide (Ia) (1.6 g) in methanol, ether, or benzene(400 ml) was irradiated with a low pressure mercury lampat room temperature over 40 h.The solvent was removedi n vacuo at room temperature to yield a residue which waschromatographed on silica gel. The fraction eluted withbenzene afforded a pale yellow oil (30--69), b.p. 138-143' (bath temp.) at 1 mmHg, v,, 1660 cm-I (NCO),which was a mixture of the cis- and truns-lactams, andtheir ratios were determined by g.1.c. as in the Table. Thestereoisomers were separated by preparative t.1.c. or g.1.c.The cis-lactam (IIIa) had b.p. 138-143" (bath temp.) at1 mmHg, vmx. 1660 cm-I (NCO), 6 3-65 (3H, s, NMe)(Found: C, 78-5; HI 8.0; N, 6.55.C,,H,,NO requiresC, 78.1; H, 8.0; N, 6.5). The trans-lactam (Ha) hadm.p. 98-99" (from n-hexane), v,, 1660 cm-l (NCO),6 3.63 (3H, s, NMe) (Found: C, 77.95; H, 8.05; N, 6.6).The cis-lactam (IIIa) was identical with a sampleprepared by methylation of the N-nor-lactam (IIIc) pro-vided by Professor Masamune.6-cis- and trans-5-BenzyZ-6aJ7,8,9, 10,lOa-hexahydrophen-anthridin-6(5H)-one (IIIb and IIb) .-A similar irradiationof the anilide (Ib) (2.3 g) in methanol, ether, or benzene, asin the case of (Ia) afforded the photocyclised product as amixture of cis- and irans-stereoisomers (IIIb) and (IIb).Their ratios were determined by g.1.c. as in the Table.The product was obtained in 48-67y0 yield, as crystals,m.p.109-111" (Found: C, 82-65; H, 7.25; N, 4.8.C,H,,NO requires C, 82.45; H, 7.25; N, 4.8), and wasseparated by preparative g.1.c. The cis-lactam (IIIb) had6 6.10 and 5.35 (2H, ABq, J 16 Hz, NCH,Ph). The frans-lactam (IIb) gave crystals, m.p. 118-119: from n-hexane,vmk 1670 cm-l (NCO), 6 4.95 and 5.45 (2H, ABq, J 16 Hz,NCH,Ph) (Found: C, 82.6; HI 7.35; N, 4.75).(IVa) .-(a) Oxidative Photocyclisation of the ennnlide (Ia).The enamide (Ia) (1.6 g) in methanol (400 ml) was irradiatedin the presence of iodine (1.0 g) over 48 h. The solvent wasevaporated and the dark brown residue was dissolved inchloroform and washed with aqueous sodium thiosulphate,water, and dried. Evaporation of the solvent afforded aresidue which was chromatographed on silica gel.Elutionwith chloroform gave a viscous oil, which was distilled,b.p. 170-180' (bath temp.) at 1 nimHg, to give thedidehydro-lactam (IVa),sa as a pale yellow oil (0-5 g, 30),vmk 1634 cm-l (N-CO-GC), 6 3.72 (3H, s, NMe) (Found:C, 78-8; H, 6.95; N, 6.35. Calc. for C,,H,,NO: C, 78-85;H, 7.1; X, 6.55).(b) Ilehydrogenation of the trans- or cis-ladant (IIa orIIIa). A mixture of the trans-lactam (IIa) (144 mg) andR. 13. Woodward and R. Hoffmann, ' The Conservation ofOrbital Symmetry,' Academic Press, New York, 1970.7,8,9,1 O-Tetrahydro-5-methylphenanthridin-6( 5H) -on1750 J.C.S. Perkin IN-bromosuccininiide (95 mg) in carbon tetrachloride (8 ml)was stirred at 30-40" for 6 h. The succinimide formedwas filtered off and the filtrate was evaporated to give aresidue which was purified by preparative t.1.c.to affordthe didehydro-lactam (IVa) (35 mg, 31y0), and startingmaterial (56 nig). The product was identical with thesample obtained from the oxidative photocyclisationdescribed in (a).Similarly, the didehydro-lactam (Wa) (1 1 mg, 107,) wasobtained from the cis-lactam (IIIa) (112 mg) along withrecovered starting material (88 mg).S-h4ethylphenanthridin-6(5H)-one (V) .-A mixture of thedidehydro-lactam (IVa) (48 mg) and selenium (73 mg) washeated at 240-250" (metal-bath) for 3.5 h. The mixturewas extracted with hot chloroform, and the chloroformlayer was filtered and evaporated to give a residue whichwas purified by preparative t.1.c.to give crystals of (Va)(20 mg, 43y0), m.p. 106-108" (lit.,' 107-108"), identicalwith an authentic sample.(IVb).--A similar irradiation in the presence of iodine wascarried out on the N-benzylanilide (Ib) (2.0 g) and affordedthe didehydro-lactam (1Vb) (0.7 g, 35), m.p. 123-124", aspale yellow crystals from n-hexane, v , , ~ 1643 cm-l(N-euro;O-C=C), 6 5.58 (2H, s, NCH,Ph) (Found: C, 83.15;H, 6.5; N, 4.8. C2,H1,N0 requires C, 83.0; H, 6.6; N,4085).(IIIc).-To a mixture of the N-benzyl-lactam (IIb) (0.4 g)in liquid ammonia (200 ml), metallic sodium (0.25 g) wasadded in small pieces over a period of 30 min. Themixture was stirred for a further 1 h before excess ofammonium chloride was added t o stop the reaction.-Ammonia was evaporated off and water was added t o theresidue. This was extracted with chloroform, and thechloroform layer was dried and evaporated t o give aresidue which crystallised upon trituration with methanolto give the lactam (IIIc) (0-13 g, 39), m.p.208-211"(lit.,6 211-212"), vmx. 3430 (NH) and 1675 cm-l (NCO),identical with an authentic sample supplied by ProfessorLMasamune.6atrans-6a1 7,8,9,10,1 Oa-Hexahydrophenanthridin-6( 5H)-one(IIc).-Similar treatment as in the case of the cis-isomer(IIIb) of the trans-N-benzyl-lactam (IIb) (0.5 g) affordedthe trans-lactam (IIc) (0.21 g , 61y0), m.p. 227" (lit.,6a220-221"), vmax. 3430 (NH) and 1675 cm-l (XCO) (Found:C, 77-45; H, 7-3; 3-, 6.7. Calc. for C,,H,,KO: C, 77.6;H, 7.5; N, 7*0q/,). This compound was identical with thecompound reported 6 (i.r.and n.m.r. spectra).6(5H)-one (IIIa) .--A mixture of the cis-lactam (IIIc)(45 mg) and sodium liydride (12 mg) in anhydrous benzene(15 ml) was heated under reflux for 15 min and cooled.Methyl iodide was added and the mixture was heatedunder reflux for 7 h. After cooling, the mixture wasdiluted with water, extracted with benzene, and thebenzene layer was washed with water, dried, and evapor-ated. The residue was purified by preparative t.1.c. toafford the cis-N-methyl-lactam (IIIa), which was identicalwith the photocyclised cis-lactam (IIIa) (i.r. spectra and5-Renzyl- 7 , 8,9,10-tetrahydrophenanthridin-6 (5H) -onecis-6a, 7,8,9,10,10a-Hexahydro~henanthridin-6(5H)-onecis-6a1 7,8,9,10,1Oa-Hexahydro-5-methyl~henanthridin-g.1.c.).trans-f3a, 7,8,9,10,l0a-euro;euro;exaliydro-5-~nethylflhenanthridin-6(5H)-one (IIa) .-By a similar methylation, the trans-lactam (IIc) (45 mg) was converted into the trans-N-methyl-lactam ( IIa) (20 mg, 42O/,), which was identicalwith the sample obtained from the photocyclisation of theN-methylanilide (Ia) ,trans-5,6,6aI 7,8,9,10,1Oa-Octa1iydro-5-inethylphenanthri-dine (VI) .-An anhydrous suspension of the trans-lactam(IIIa) (100 mg) and lithium aluminium hydride (80 mg) inether (60 ml) was refluxed for 1 11 on a steam-bath.Waterwas added t o decompose excess of lithium aluminiunihydride and the resulting mixture was extracted withether. The combined ether extracts were washed withwater, dried, and evaporated to afford an oily residue,which was distilled to give compound (VI) as an oi1,6(89 mg, 95?/0), b.p.150-160" (bath tetnp.) at 1 mmHg.cis-5,6,6a, 7,8,9,10,10a-0ctahyd~o-5-methyl~henanthridine(VII) .-Similarlv, reduction of the cis-lactam (IIIa) (100mg) with lithium aluminium hydride afforded the cis-phenanthridine (VII) (92 mg, ! W k ) , b.p. 125-130"(bath temp.) a t 1 mmHg.N-Methyl-3,4-dihydronaphtIialene- l-carboxanilide (VI 11).-Acylation of lV-methylaniline (3-5 g) with 3,4-dihydro-l-naphthoyl chloride (4.83 g ) was carried out as in thepreparation of (Ia) and (Ib) and the product was purified bychromatography on silica gel. The anilide (VIII) (5-57 g,84.5) was obtained, b.p. 140--160" (bath temp.) at3 x lo-, mmHg, vnlalL 1640 cni-l (SCO) and 1615 cm-l,6 5.97 (lH, t, J 4-52 Hz, HC=C-CO) and 3.47 (3H, s,NMe) (Found: C, 82-05; H, 6.45; S, 5.4.C,,H,,NOrequires C, 82.1; H, 6.5; N, 5.3).Photocyclisutiotz of the Anilide (VI11) .--.kcording tothe procedure given for (Ia) and (Ib), irradiation ofthe anilide (VIII) (455 mg) in methanol was carriedout over 23 h and afforded, upon chroniatography 0x1silica gel, trans-6, lob, 11,12-tetrahydro-6-methylbenzoi-phenanthridin-5(4bH)-one (I?() (80 mg, 1776), m.p. 177-178" from methanol, vnUx 1670 (XCO) and 1605 cm-l (C=C),6 3.48 (lH, d, J 13 Hz, 4b-H) and 3-45 (3H, s, XMe) (Found:C, 82.0; H, 6.45; XI 5.3. C,,H,,NO requires C, 82.1; H,6.5; N, 5.3o/b), eluted by benzene, and the cis-isomer (X)(120 mg, 25-50,) eluted by benzene-chloroform, n1.p.138-140" from methanol, v,.1663 (NCO) and 1600 cm-l(C=C), 6 3-85 ( l H , d, J 6 Hz, 4b-H) and 3-37 (3H, s, XMc)(Found : iVi-, 259.12599. C,,H,,SO requires M, 279.12593).The starting anilide (VIII) (110 mg, 26.2) was elutedby chloroform. Further elution by chloroform yielded anoil which was purified by preparative g.1.c. to afford11 , 12-dihydr0-6-~neth~~Ibenzoilphenanthridi~~-5(6H)-one (XI)in low yield, vnLlx 1632 (C=C-COS) and 1590 cm-l (CZC),6 8.70 (1H, m, 4-H), 3.75 (3H, s, SMe), and 3.00-2-80 (1H,m, 11- and 12-H,), m/e 261 (amp;I*).Oxidative Pliotocyc/isation of thc .4 nilide (VII I) .--Accord-ing to the procedure given for (Iva), irradiation of tlicanilide (VIII) (553 mg) in the presence of iodine (233 m g )afforded pale yellow crystals, m.p.181-183" from methanol,of cis-6, lob, 11,12-tetvahydr0-4b-hydroxy-6-methylbenzo~i~-flhenanthridin-5(4bH)-one (XII) (159 mg, 27-2), vIIuz 3480(OH) and 1663 cm-1 (NCO), 6 (C,n,S) 4-58 ( l H , s, OH,disappeared on D,O addition), 3-53 ( l H , ddd, J 8, 3, and1 Hz, 1Ob-H), and 3-36 (3H, s, SMe) (Found: -If-',279-1260. C,8H,,S0, requires -11, 27!b1259). From themother liquors of the crystallisation of the hydroxy-lactani(XII), the didehydro-lactam (XI) was obtained uponpreparative g.1.c.Photocyclisation of the X-Benzylanilide (Ib) i?t DeuteriatedSolvent.-(a) In D,O-treated ether. Irradiation of the A'-benzylanilide (Ib) (300 mg) in ether (40 ml) which wassaturated with I)@ was carried out over 22 h. .Afte1974 1751evaporation of the solvent, clironiatograpliy on silica gelafforded a crystalline product (170 mg, 53), eluted bybenzene, which was recrystallised from ether t o givecrystals, m.p. 112--113O, which consisted of the almostpure trans-lactam (g.1.c.). The relative intensity of thepealts a t m / e 292/291 (ill+) demonstrated deuteriumincorporation by 12.The N-benzylanilide (Ib)(140 mg) was irradiated in MeOD (10 ml; 0 . 0 4 ~ ) over22 11. The solvent was evaporated off to afford a residue(b) In nzetlznlz2HJoZ solution.which was chromatographed on silica gel. Elution withbenzene afforded a crystalline product (50 mg, 36)which showed the ratio of cis : trans to be 10 (g.1.c.). Therelative intensity of the m/e 292/291 peaks showed 90deuterium incorporation.We thank Professor T. Masamune for generous gifts ofsamples and Miss I. Saiki for mass spectral measurements.4/499 Received, 13th Mavch, 1974
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