Studies on the syntheses of heterocyclic compounds. Part 744. A synthesis of 1-benzazocin-5-ones from 2,3-dihydro-1H-pyrrolo1,2-aindoles; a synthetic approach to the mitomycins

摘要

J.C.S. Perkin I Studies on the Syntheses of Heterocyclic Compounds. Part 744.t A Synthesis of 1-Benzazocin-5-ones from 2,3-Dihydro-lH-pyrroloI ,2-a-indoles; a Synthetic Approach to the Mitomycins By Tetsuji Kametani," Kimio Takahashi, Masataka Ihara, and Keiichiro Fukumoto, Pharmaceutical Insti- tute, Tohoku University, Aobayama, Sendai 980, Japan On reduction with sodium borohydride in acetic acid, the 2,3-dihydro-1 H-pyrrolol,2-aindoles (4) and (5) were converted into the indolines (6) and (7). which were treated with cyanogen bromide to give selectively the 5-bromo-1-cyano-1,2,3,4,5,6-hexahydro-l-benzazocines(10) and (11). The bromides (10) and (1 1) were transformed into 1 -cyano-I ,3,4,6-tetrahydro-I -benzazocin-5(2H)-ones (1 3) and (14). which underwent a transannular re- action to yield the 2,3-dihydro-1H-pyrrolol,2-a indoles (4)and (5).RECENTLY,we have reported a ready synthesis of 7-methoxymitosene and desammonoapomitomycin A in synthetic approaches to the mitomycins (1). The introduction of an oxy-substituent at C-9a seems to be one of the most difficult problems in this area, although photo-oxygenation of pyrrolol,2-aindol-9-ones has afforded 9a-oxy-substituted compound^.^ However, the transannular cyclisation of an eight-membered-ring ketone (2a) also seemed a promising approach. Lown t Part 743, T. Kametani, K. Takahashi, M. Ihara, and K. Fukumoto, Heterocycles, 1978, 9, 435. T. Kametani, K. Takahashi, M. Ihara, and K. Fukumoto, J.C.S. Perkin I, 1976, 389.T. Kametani, K. Takahashi, Y. Kigawa, M. Ihara, and K. Fukumoto, J.C.S. Perkin I, 1977, 28. T. Karnetani, T. Ohsawa, K. Takahashi, M. Ihara, and K. Fukumoto, Hetei,ocycles, 1976, 4, 1637; J.C.S. Perkin I, 1978, 460. and Itoh have reported such a reaction to give the pyrrolol,2-aindole (5).* Furthermore, Kishi and his co-workers recently reported a synthesis of deimino-mitomycin A by transannular cyclisation of the eight- membered ring quinone (2b).5 We now describe the conversion of pyrrolol,2-aindoles, easily available by known methods ll6 and important as intermediate for the synthesis of mitosene derivatives, into l-benzazocin- ones. J. W. Lotvn and T. Itoh, Canad. J. Chem., 1975, 53, 960; T. Itoh, T. Hata, and J. W. Lown, Hptcvocycles, 1976, 4, 47.F. Nakatsubo, A. J. Cocuzza, L). E. Keeley, and Y. IGshi, J. Amer. Cheun. Soc., 1977, 99, 4835. 13 G. R. Allen, jun., J. F. Polletto, and M. J. Weiss, J. Org.Chem., 1965, 30,2897. Presented in preliminary form at the 97th Annual Meeting of the Pharmaceutical Society of Japan, Tokyo, April, 1977. Abstracts of papers, 11, p. 182. Preliminary communication, T. Kametani, K. Takahashi, 31. Ihara, and K. Fukumoto, Hetero-c.vcles, 1977, 6, 1371. Reduction of the aldehyde (3) with sodium boro- hydride in glacial acetic acid at 25-30 "C gave a mixture of indolines (6) and (8) as main products to- gether with (4)and (9) as minor ones. On treatment of MeoRMe ketone (13) whereas the bromide (12) gave the aldehyde (15). The complicated course of reduction of the aldehyde (3)seemed to be due to the presence of the labile formyl group.Therefore the aldehyde (3)was converted CHzOH b; X = OMe, Y = SMe, 2 = H (3) R = CHO (6) R= Me (4) R = Me (7) R = H (5) R = H R1 Rz (18) R = Me (19) R = H the mixture with cyanogen bromide, compounds (6) and (8) gave the ring-opened bromides (10) and (12), respec-tively, the structures of which were determined by oxid- (12) R = CHZBr (15) R = CHO R I CN (isj R = Me (17) R = H into the methyl derivative (4)by Wolff-Kishner reduc- tion, and the product (4)was reduced to the indoline (6) with sodium borohydride in acetic acid in high yield. ation with dimethyl sulphoxide in the presence of sodium hydrogen carbonate. The bromide (10) afforded the,,.Gribble,w.G.Eaton, and J. L. Johnson, J. Amer. Chem. SOC.,1974,96, 7812. D. Lord, J. Skotnicki, s. E. Dietz, J. T. Dehydrogenation of (6) with activated manganese dioxide gave back (4). Treatment of (6) with cyanogen bromide in benzene cleaved selectively the N-C(9a) bond to furnish the benzazocine derivative (10). Oxidation of (10)was carried out by heating with dimethyl sulphoxide and sodium hydrogen carbonate, but the desired ketone (13)was obtained in poor yield. The bromide (10) was therefore converted into the ketone (13)in three steps as follows. Dehydrobromination of (10) by heating with 1,5-diazabicycloj5.4.0undec-5-ene (DBU) in tetra-hydrofuran yielded the olefin (16), which was stirred with m-chloroperbenzoic acid in methylene chloride to give the epoxide (18).Treatment of (18) with boron trifluoride-ether in benzene at room temperature for 5 min provided the ketone (13). The 2,3-dihydro-IH-pyrrolol ,Z-aindole (5) was converted into the ketone (14) in a similar manner. Reduction of (5) with sodium borohydride in acetic acid yielded quantitatively the amine (7), the von Braun reaction of which gave the bromide (11). Treatment of (11)with DBU, followed by epoxidation of the resulting (17) afforded (19), which was transformed into the ketone (14). The ketone (14) was also prepared by heating (11) with sodium hydrogen carbonate in dimethyl sulphoxide. Reaction of (14) with paraformaldehyde in the presence of sodium hydride gave the methylene derivative (20).The ketones (13) and (14) were quantitatively con- verted into the pyrrolo;l,2-aindoles (4)and (5) by re- fluxing in ethanolic sulphuric acid. The ring opening of pyrrolo~l,2-aindoles to l-benz-azocin-5-ones may well prove an important process in the synthesis of mitomycins. EXPERIMENTAL h1.p.swere taken with a Yanagimoto niicro-apparatus (MP-S2). 1.r. spectra were measured with a Hitaclii 215 recording spectrophotometer, n.m.r. spectra with a JEOL JNM-PMX 60 spectrophotometer, and mass spectra with a Hitachi RMU-7 spectrometer. High performance liquid chromatography (h.p.1.c.) was carried out with a Hitaclii 635 instrument equipped with a 1 ft x 4 in column of p-Boncla- pak C18.Reduction of 2,3-Dihydro-7-methon.y-6-methyl-lH-fiyrrolo-~1,2-aindole-9-curbuZdehyde(3).-To a stirred solution of the aldehyde (3) (0.92g) in acetic acid (150 nil) was added so-dium borohydride (0.5 g) in small portions. After stirring for 30 min at room temperature, the mixture was diluted with water and extracted with chloroform. The organic layer was washed with water, aqueous sodium hydrogen carbonate, and aqueous sodium chloride, and dried (hra2-SO,). Evaporation gave a syrup, which was triturated J.C.S. Perkin I ArMe), 3.66 (3 H, s, OMe), and 6.20 and 6.40 (each 1 H, each s, 2 x ArH) ; mle 217 (M’). 2,3-Di/iydro-7-methoxy-6,9-dimetlzyZ-lH-pyrrole1,2-azndoZe(4) was eluted after 3 min and crystallised from ether to afford prisms, n1.p.128-130” (Found: C, 77.95; H, 8.05; N, 6.45. C1,HI7NO requires C, 78.1; H, 7.95; N, 6.5); s(CC1,) 2.12 and 2.22 (each 3 H, each s, 2 x ArMe), 3.74 (3 H, s, OMe), and 6.60 and 6.70 (each 1 H, each s, 2 x ArH) ; wz/e 215 (ATT). The third product (8),eluted after 7 tnin, afforded a syrup, S(CC1,) 1.34 (3 H, s, 9-Me), 2.04 and 2.22 (each 3 H, each s, 2 x ArMe), 3.20 and 3.68 (each 3 H, each s, 2 x OMe), and 6.08, 6.18, 6.60,and 6.78 (each 1 H, each s, 4 x ArH) ; nz/e 430 (M+) and 217 (base), which did not crystallise. 2,3-L>zlzydro-7-nzethoxy-6,9-dimethyl- lH-PyvroZo 1,2-a-indole (4).-(u) A mixture of the aldehyde (3) (2.29 g), hydrazine hydrate ( 1 ml), potassium hydroxide (1.4 g), and diethylene glycol (45 ml) was refluxed for 6 h, then extracted with benzene.The extract was washed with aqueous socliuni chloride, dried (Na,SO,), and evaporated. The residue was chromatographed on silica gel (benzene) to give a solid, recrystallisation of which from ether afforded (4) (1.61 g, 75) as prisms, identical (m.p., i.r., and n.m.r. spectra) with the sample described above. (b) A mixture of compound (6) (200 mg), activated man- ganese dioxide (1.0 g), and methylene chloride (5 ml) was stirred at room temperature for 2 h in a current of nitrogen, then filtered through Celite. The Celite and inorganic material were washed with methylene chloride. The com- bined filtrate and washings were concentrated to leave a solid, which was recrystallised from ether to give (4) (165 mg, 83) as prisms, iclentical (m.p.and spectral data) with the sample prepared by method (a). 5-Br0~~0-l-cyano- 1,2,3,4,5, G-/iexuliydro-8-methoxy-6,9-dimethyl- l-benzazocine ( 10) und 2-( 3-Browopvopy1)- l-cyano- 2,3-dilzydro- 3- (2,3-dihydro-7-nzethoxy-6-methyl- 1H-pyvrolo- 1,2-aindol-9-yZmet?iyl)-5-nzethoxy-3,6-dimethylindole( 12).-The crude product of sodium borohydride reduction of the aldehyde (3) (0.92 g) in acetic acid (150 nil) described above was dissolved in benzene (50 ml), and to the stirred solution was added cyanogen bromide (0.48 g). A4fter stirring for 30 rnin in a current of nitrogen, the mixture was washed with water, dried (Na,SO,), and evaporated. The residue was chromatographed on silica gel in benzene to afford a solid, recrystallisation of which from n-hexane gave (12) as fivistns (390 mg, 36(y0),m.p.199-201” (Found: C, 65.1; H, 6.45. C,,H,,BrN,O, requires C, 64.9; H, 6.4y0),vrnnX. (CHC1,) 2 210 cm-l (CX); 6 (CC1,) 1.36 (3 H, s, 3-Me),2.16 and 2.26 (each 3 H, each s, 2 x ArMe), 3.10 and 3.64 (each 3 H, each s, 2 x OMe), and 5.46, 6.14, C.80,arid 6.90 (each 1 H, each s, 4 x ArH); nzle 537, 535 (M+),323, 321, and 201 (base peak). Further elution with benzene gave a solid which was recrystallisecl from n-hexane to give (10) as prisms (330 nig, 26y0), n1.p. 137-138” (Found: C, 56.05; H, 5.8; K, 8.6 C,,H,,BrN,O requires C, 55.7; H, 5.9; Ir;, 8.65*/,); 6 (CC1,) 1.44 (3 H, d, J 7 Hz, Me), 2.18 (3 H, s, ArMe), 3.86 with methanol to give 2,2’,3,3’-tetra/iydro-7,7’-dimet/zoxy-(3 H, s, OMe), and 6.76 and 7.16 (each 1 H, each s, 2 x 6,6’-dimethyl-9,9’-nzet/zylenedi-lH-pyrrolo 1,2-aindole (9) as prisms, ni.p.233-234” (Found: C, 78.3; H, 7.2; N, 6.7. C,7H,oN,0, requires C, 78.25; H, 7.3; N, 6.75); S(CDC1,) 2.26 (6 H, s, 2 x ArMe), 3.84 (6 H, s, 2 x OMe), 3.98 (2 H, s, ArCH,Ar), 6.82 and 6.86 (each 2 H, each s, 4 x ArH); m/e 414 (M’). The mother liquor was purified by h.p.1.c. with methanol-water (3 : 1 v/v) as solvent (Aow rate 3 ml min-l). The first product (6), eluted after 2 min gave a syrup, 6(CC1,) 1.26 (3 H, d. 7 Hz, Me), 2.06 (3 H, s, ArH); m/e 324, 322 (M+),and 201 (base peak). 5-Bromo-l-cyuno-1,2,3,4,5,6-/zexu/zy~~o-8-methoxy-6,9-dimethyl- l-benzazocine (10).-To a stirred solution of coni-pound (4) (2.15 g) in acetic acid (100 ml) was added sodium borohydride (1.0g) in small portions at room temperature.After stirring for 30 min, the mixture was diluted with water and extracted with chloroform. The extract was washed with water, aqueous sodium hydrogen carbonate, and aqueous sodium chloride, and dried (Na,SO,) . Evaporation afforded 2,3,9,9a-te trahydro- 7-me thoxy- 6,9-dime thyl-1H-pyrrolol,2-aindole (6)as a syrup, identical (i.r. and n.m.r. spectra) with the sample described above. The product was treated with cyanogen bromide (1.2g) in benzene (100 ml). Work-up as above gave (10)(1.4g, 43), identical (i.r. and n.m.r. spectra) with the sample described above. l-Cyano-1,3,4,6-tetrahydro-8-methoxy-6,9-dimethyl-2,3-benzazocin-5(2H)-one (13).-(a) A mixture of the bromide (10)(320 mg), sodium hydrogen carbonate (80 mg), and dimethyl sulphoxide (10ml) was heated at 145-150 "C for 0.5 h in a current of nitrogen, The mixture was poured into water and extracted with ether.The extract was washed with aqueous sodium chloride, dried (Na2S04), and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave a solid which was re- crystallised from ethanol to give (13)as needles (6 mg, 2), m.p. 149-150" (Found: C, 68.9; H, 7.1; N, 10.6y0; M', 258.1366. C15H18N,0,*0.25H,0 requires C, 68.5; H, 7.05; N, 10.65. C15H,,N202requires M, 258.1368); 6 (CDC1,) 1.40(3H, d, J 7 Hz, 6-Me), 2.12 (3 H, s, ArMe), 3.80 (3 H, s, OMe), and 6.62 and 7.08 (each 1 H, each s, 2 x ArH); m/e258 (M').(b) A solution of the epoxide (18) (258 mg) and boron tri- fluoride-ether (0.2ml) in benzene (10ml) was stirred at room temperature for 5 min. The mixture was poured into water and extracted with chloroform. The extract was washed with aqueous sodium chloride, dried (Xa2S04), and evaporated. The residue was chromatographed on silica gel with benzene to give a solid, recrystallisation of which from ethanol gave (13) (105 mg, 41) as needles, identical (i.r., n.m.r., and mass spectral data) with the above sample. l-Cyano-2-formylethyl) -2,3-dihydro-3- (2-(2,3-dihydro-7-methoxy-6-methyl- 1H-pyrrolo 1,2-aindol-9-ylmethyl)-5-methoxy-3,6-dimethylindoline ( 15).-A mixture of the bromide ( 12)(214mg), sodium hydrogen carbonate (32mg), and dimethyl sulphoxide (10ml) was heated at 150 "C for 15 min in a current of nitrogen, then poured into water and extracted with ether. The extract was washed with aqueous sodium chloride, dried (Na,SO,), and evaporated. The residue was chromatographed on silica gel (benzene) to give a solid, which was recrystallised from n-hexane to afford (15)(110mg, 58) as prisms, m.p.177-178" (Found: C, 73.95; H, 6.65; N, 8.7. C,,H,,N,O, requires C, 73.85; H, 7.05;N, 8.9); vmat (CHC1,) 2 210 (CN) and 1720 cm-' (GO); 6 (CDCl,) 1.36 (3 H, s, 3-Me), 2.14 and 2.22(each 3 H, each s, 2 x ArMe), 3.08and 3.58(each 3 H, each s, 2 x OMe), 5.56, 6.04, 6.72, and 6.78(each 1 H,each s, 4 x ArH), and 9.82(1H, s,CHO); m/e 471 (?+) and 214 (M+-c15H17N202)'2,3,9,9a-Tetrahydro-7-methoxy-6-methyl-lH-fiyrrolo1,2-a-indole (7).-To a solution of compound (5) (2.6g) in acetic acid ( 100ml) was added sodium borohydride (1.3g) in small portions during 1 h.The mixture was diluted with water and extracted with chloroform. The extract was washed with water, aqueous sodium hydrogen carbonate, and aqueous sodium chloride, dried (Na2S0,), and evaporated to leave a syrup, 6 (CC1,) 2.12 (3 H, s, ArMe), 3.66 (3 H, s, OMe), and 6.26 and 6.46 (each 1 H, each s, 2 x ArH); m/e 203 (M+),which was used in the next step without purification. 5-Bromo- l-cyano- 1,2,3,4,5,6-hexahydro-8-methoxy-9-methyl- l-benzazocine ( 11).-A solution of compound (7) from 2.6g of (5)and cyanogen bromide (1.3g) in benzene (300ml) was stirred at room temperature in a current of nitrogen for 1 h.The mixture was washed with water, 665 dried (Na,SO,), and evaporated to leave a solid, which was chromatographed on silica gel. Elution with benzene gave a solid, recrystallisation of which from ether afforded (11) (1.96g, 49) as prisms, m.p. 132-133" (Found: C, 54.4; H, 5.3; N, 9.25. C14H,,BrN,0 requires C, 53.9; H, 5.2; N,9.05); vmx. (CHC1,) 2 210 cm-l (CN); 6 (CCI,) 2.14 (3H, s, ArMe), 3.82 (3 H, s, OMe), and 6.66 and 7.06(each 1 H, each s, 2 x ArH) ; m/e310/308(M+). l-Cyano-1,3,4,6-tetrahydro-8-methoxy-9-methyl-l-benz-azocin-5(2H)-one (14) .-(a) A mixture of the bromide (11) (155mg), sodium hydrogen carbonate (80mg), and dimethyl sulphoxide (10ml) was heated at 145-150 "C for 1 h.Work-up as above gave the ketone (14)(8 mg, 7) as needles,m.p. 127-129" (from ether) (Found: C, 68.8; H, 6.4; N, 11.4. C1,H16N202 requires C, 68.85; H, 6.6;N, 11.45); v,,,. (CHCl,) 2 210 (CN) and 1 705 cm-l (C=O); 6 (CDC1,) 2.16 (3 H, s, ArMe), 3.74 (2 H, s, ArCH,), 3.80(3 H, s, OMe), and 6.60and 7.10 (each 1 H, each s, 2 x ArH); m/e244 (M'). (b)A solution of the epoxide (19) (2.44 g) and boron tri- fluoride-ether (2ml) in benzene (50ml) was stirred at room temperature for 5 min. Work-up as above gave the ketone (14)(1.58g, 65) as needles, identical (m.p., Lr., and n.m.r. spectra) with the sample prepared by method (a).l-Cyano-1,2,3,4-tetrahydro-8-methoxy-6,9-dimethyl-1-benzazocine (16) .-A solution of the bromide (10)(323mg) and 1,5-diazabicyclo5.4.Oundec-5-ene(304 mg) in tetra- hydrofuran (20ml) was heated under reflux for 15 h in a current of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel with chloroform to give (16) (189 mg, 78) as a syrup, v,,,. (CHC1,) 2 220 cm-l (CN); 6 (CCl,) 2.10br (3 H, s, 6-Me), 2.16 (3 H, s, ArMe), 3.80 (3 H,s, OMe), 5.50-6.00 (1H, m, 5-H), and 6.62and 7.02(each 1 H, each s, 2 x ArH); m/e 242 (M+), which did not crystallise. L-Cyano-1,2,3,4-tetrahydro-8-methoxy-9-metJzyl-1-benz-azocine (17).-A solution of the bromide (1 1) (1.5g) and 1,5-diazabicyclo5.4.0undec-5-ene (1.5g) in tetrahydrofuran (50 ml) was heated under reflux for 15 h in a current of nitrogen.Work-up as above gave (17) (1.02 g, 89) as a syrup, vm?x. (CHC1,) 2 220 cm-l (CN); 6 (CCl,) 2.16 (3 H, s, ArMe), 3.76 (3 H, s, OMe), 5.50-6.00 (1H, m, 5-H), 6.36 (1H, d, J 10 Hz, 6-H),and 6.44and 7.02(each 1 H, each s, 2 x ArH) ; m/e228 (M+),which did not crystallise. l-Cyano-5,6-e~oxy-l,2,3,4,5,6-hexahy~~o-8-methoxy-6,9-dimethyl- l-benzazocine (1 8).-A solution of the olefinic compound ( 16) (242 mg) and m-chloroperbenzoic acid (350 mg) in methylene chloride (10ml) was stirred at room tem- perature for 15 h in a current of nitrogen. The solution was washed with aqueous sodium hydrogen sulphite, aqueous sodium hydrogen carbonate, and aqueous sodium chloride.The organic layer was evaporated to give a solid, recrystallis- ation of which from ether gave (18) (189 mg, 73) as needles,m.p. 186-188" (Found: C, 69.5,H,7.1;N, 10.75. Cl,HIBN,O, requires C, 69.75; H,7.0; N, 10.85); vmx. (CHC1,) 2 220 cm-l (CN) ; 6 (CDCl,) 1.70 (3H, s,6-Me), 2.20 (3H,s, ArMe), 3.86 (3 H, s, OMe), and 6.86 and 7.04(each 1 H, each s, 2 x ArH); m/e 258 (Mf). l-Cyano-5,6-epoxy-1,2,3,4,5,6-hexahydro-8-methoxy-9-methyl- 1-benzazocine (19).-A solution of the olefinic com- pound (17) (228 mg) and m-chloroperbenzoic acid (350mg) in methylene chloride (10ml) was stirred at room tempera- ture for 15h in a current of nitrogen; work-up as above gave a solid, recrystallisation of which from ether afforded (19) (204mg, 84) as needles,m.p.153-154" (Found: C,68.65; HI 6.45; N, 11.55. C,,Hl,N20, requires C, 68.85; H, 6.6; N, 11.45); v,,,. (CHC1,) 2 220 cm-' (CN); 6 (CDCl,) 2.16 (3 H, s, ArMe), 3.84 (3 H, s, OMe), and 6.86 and 6.92 (each 1 H, each s, 2 x ArH); m/e 244 (M+). 1-Cyano-1,3,4,6-tetrahydro-8-methoxy-9-methyl-6-methyl-ene- l-benzazocin-5( 2H)-one (20) .-A stirred mixture of the ketone (488 mg) and 50 sodium hydride (100mg) in tetra- hydrofuran ( 10 ml) was treated with gaseous formaldehyde under ice cooling. The mixture was stirred at -20 "C for 30 min. An excess of ammonium chloride was added and the mixture was extracted with chloroform. The extract was chromatographed on silica gel (chloroform) to give a solid, recrystallisation of which from ethanol gave (20) (320 mg, 63) as needles, m.p.147-148" (Found: C, 68.05; H, 6.25; N, 10.45 ; Mf, 256.1207. C,,H,,N202.0.5 H20 requires C, 67.9; H, 6.45; N, 10.55. C,,Hl,N202 requires M, 256.1211); vmax. (CHCl,) 2 220 cm-l (CN); 6 (CCl,) 2.22 (3 H, s, ArMe), 3.86 (3 H, s, OMe), 5.66 and 6.08 (each 1 H, each d, J 2 Hz, 2 x olefinic H),and 6.78 and 7.16 (each 1 H, each s, 2 x ArH); m/e 256 (Mf). Transannular Cyclisation of l-Cyano- 1,3,4,6-tetrahydro-8- methoxy-9-methyl- l-benzuzocin-5( 2H)-one ( 14).-A solution of the ketone (14) (49 mg) and aqueous 10 sulphuric acid J.C.S. Perkin I (1 ml) in ethanol (5 ml) was refluxed for 2 h. The mixture was diluted with water, basified with aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with aqueous sodium chloride solution, dried (Na,SO,), and evaporated to leave a solid, recrystallisation of which from methanol gave (5) (37 mg, 93) as needles, m.p. 116-117" (lit.,, 116--118°), with i.r. and n.m.r. spectra identical with those of a sample prepared by a known method. Transannular Cyclisation of l-Cyano- 1,3,4,6-tetrahydro- 8-methoxy-6,9-dimethyl- l-benzazocin-5( 2H)-one (13).-A solution of the ketone (13) (51 mg) and aqueous 10 sul-phuric acid (1 ml) in ethanol (5 ml) was refluxed for 2 h. Work-up as above gave a solid, which was recrystallised from ether to give (4)as needles (38 mg, 88), m.p. 128-129O, identical with the sample described above. We thank the Mitsubishi Foundation for financial help. We also thank Mr. K. Kawamura, Mrs. C. Koyanagi, Miss K. Mushiake, Mrs. R. Kobayahsi, Miss R. Suenaga, Miss E. Nagaoka, and Miss M. Tanno for microanalyses and spectral measurements, 7/1667 Received, 21st Sefitember, 19771