Studies on the syntheses of heterocyclic compounds. Part 673. New routes to benzoaquinolizines

摘要

1976 2547Studies on the Syntheses of Heterocyclic Compounds. Part 673.t NewRoutes to BenzoaquinolizinesBy Tetsuji Kametani," Hirofumi Terasawa, and Masataka Ihara, Pharmaceutical Institute, Tohoku University,Aobayama, Sendai, JapanHeating 3,4-dihydro-6,7-dimethoxy-l -methylisoquinoline (1 ) with crotonic anhydride (2) gave 3,4.6,7-tetra-hydro-9.1 O-dimethoxy-4-methylbenzoaquinolizin-2-one (5) along with 2-crotonoyl-l.2.3.4-tetrahydro-6.7-dimethoxy-1 -methyleneisoquinoline (3) and N- (2-acetyl-4.5-dimethoxyphenethyl)crotonamide (4). Heating theisoquinoline (1) with glutaconic anhydride (1 7) in pyridine provided 7,6,7,11 b-tetrahydro-9.1 O-dimethoxy-1 1 b-methylbenzoaquinolizin-4-one (1 9).IN approaches to a synthesis of emetine,1-8 which possessesimportant biological activity, numerous methods ofsynthesising benzoa quinolizines have been developed.Recently, the photocyclisation of N-aroyl-l,2,3,4-tetra-hydro-l-methyleneisoquinolines was reported to be suc-cessful in the synthesis of dibenzoa,gquinolizine deriv-ati~es.9~~0 With the intention of studying the cyclis-ation of Y-( a- or p-substituted acryloyI)-l,2,3,4-tetra-hydro- 1 -meth yleneisoquinolines to benzo a quinolizines,we heated 3,4-di hydro-6,7-dimethoxy- 1 -met hylisoquino-line (1) I1 with crotonic anhydride (2) in pyridine; theresulting crude material was purified by alumina columnchromatography to afford three products.The mainproduct (65 yield) was the desired enamide (3), identi-fied by spectroscopic analysis.Irradiation of the en-amide (3) in one of several solvents or treatment withany of several kinds of acid including a Lewis acid gaveone of the minor products isolated originally, which wasidentified as N- (2-acetyl-4,5-dimethoxyphenethyl)croton-amide (4). Its mass spectrum showed a molecular ionpeak at m / e 291 and its n.m.r. spectrum (deuteriochloro-form) exhibited two C-methyl signals 6 1.82 (dd, J 2 and7 Hz) and 2.56 ( s ) in addition to a signal for two 0-methyl groups 6 3.88 (s). Several attempts to cyclisethe enamide (3) to a benzoaquinolizine (6) resulted infailure.The other minor product, obtained in 17.57L yield from(1) showed a molecular ion peak at m/e 273, i.r. carbonylabsorption at 1 605 cm-l (chloroform), and in the n.m.r.spectruni one C-methyl signal at 6 1.32 (d, J 6 Hz), twoO-methyl signals at 6 3.85 and 3.89 (each s), and threeolefinic proton signals a t 6 5.55, 6.64, and 7.11.On thebasis of the above spectral data, two possible structures, (5)t Part 672, T. Kametani, C. Ohtsuka, H. Nemoto, and K.Fukumeto, Chem. and Pharm. Bull. (Japan), 1976, 24, 2525.R. R. Evstiegneeva, R. S. Livishits, L. I. Zakharkin, A$. S.Eainova, and N. A. Preobrazhenskii, Doklady Akad. Nauk S.S.R.,1950, '75, 539.M. Barash and J. 3i. Osbond, Chem. and Itzd., 1958, 490;1959,257.A. t h s s i , M. Baumaiin, and 0. Schnider, Helv. Chim. Acta,1959, 42, 1515; A. Brossj and 0. Schnider, ibid., 1962,45, 1899.*A. IV. Burgstahler and Z. J. Bithos, J . Amev. Chem. SOC.,1959, 81, 503; 1960, 82, 5466.:' A.R. Battersby and J. C. Turner, J . Chem. Soc., 1960, 717.D. 1:. Clark, R. P. K. Meredith, A. C. Ritchie, and T. Walker,J . Chew. Sac., 1962, 2490. ' E. E. van Tamelen, G P. Schiemenz, and H. L. Arons,Trtvuhedi (312 Letters, 1963, 1005; E. E. van Tamelen, C. Placeway,G. P. Scliiernenz, and I. G. IVright, J . Amev. Chem. SOG., 1969, 91.7359.and (6), were considered for the product. Tlie compoundwas then hydrogenated over Adams catalyst and theresulting material was compared with the methyl-benzoaquinolizin-4-one (1 1) , synthesised as follows.Heating 3,4-dimethoxyphenethylamine (7) with 3-methylglutaric acid (8) at 240 "C yielded the glutarimide(9) in 52 yield, which was reduced in ethanol withsodium borohydride in the presence of hydrochloric acid l2to furnish the ethoxypiperidine (10) in 917; yield. Re-fluxing the amide (10) with toluene-$-sulphonic acid inbenzene l2 provided a ca.1 : 1 epimeric mixture ofbenzoaquinolizin-4-ones (1 1) in 94 yield. This sampleof (11) was not identical with the foregoing reductionproduct (t.1.c. and spectral comparison), thus excludingstructure (6). Reduction of (11) with lithium aluminiumhydride followed by preparative t.1.c. gave two com-pounds (12) and (13) in 32 and 37 yield, respectively.Because both compounds showed Bohlmann-type i.r.absorptions a t 2 800-2 700 cm-l (chloroform) and noangular llb-proton signal below 6 3.8 in their n.m.r.spectra (deuteriochloroform) 1 3 9 1 4 they are considered toexist in the trans-form. Compound (12) showed the C-methyl signal at 6 1.10 as a doublet, J 6 Hz, whereascompound (13) showed the corresponding signal at 6 1.02as a doublet, J 5 Hz.Compound (5) was dehydrogenated by refluxing withpalladium oxide in xylene to give the dienone (15), M+271, 6 (CDC1,) 2.39 (s, Me) and 6.24, 6.72, 6.73, and 7.17(each lH, s, olefinic), identical with material synthesisedfrom 1,6,7,11 b-tetrahydro-9,10-dimethoxy-4-met hyl-benzoaJquinolizin-one ( 14)15 by oxidation with potas-sium permanganate or palladium oxide.It was con-sidered that compound (5) was formed via the enamineH. T. Openshaw and N. Whittaker, J . Chew. SOC. ( C ) , 1969,G. Lenz, J . Org. Chem., 1974, 39, 2839, 2846.lo I. Ninomiya, T.Naito, and H. Takasugi, J.C.S. P ~ r k i n I,l1 E. Spath, Bev., 1935, 71, 113.l2 J. C. Hubert, W. N. Speckamp, and H. 0. Huisman,TetiTahedron Letters, 1972, 4493; J. B. P. A. Wijnberg, W. N.Speckamp, and H. E. Schoemaker, ibid., 1974,4073 ; J. C. Hubert,J. Is. P. A. Wijnberg, and W. N. Speckamp, Tetvahedron, 1975,31,1437.l3 M. UskokoviC, H. Bruderer, C. von Planta, T. Williams, andA. Brossi, J . Amev. Chem. SOC., 1964, 86, 3364.l4 T. Kametani, K. Fukumoto, M. Ihara, A. ITjiie, and H.Koizumi, J . Org. Chem., 1975, 40, 3280.l5 M. von Strandtmann, M. P. Cohen, and J. Shavel, jun., J .Org. Chem., 1966 31 797.89.1975, 17202548 J.C.S. Perkin IMe( 1 IMe( 3 )+HO2C COZHI t( 6 1 MeMe(121i-- - -Me(13 IMe(911(I410(15)(16) produced by Michael addition of the 3,P-dihydro-l-methylisoquinoline (1) to crotonic anhydride (2).Heating the 3,4-dihydro-l-methylisoquinoline (I) at100 "C with glutaconic anhydride in pyridine followedby chromatography on alumina afforded, in 56 yieldas the sole product, 1,6,7,1 lb-tetrahydro-9,lO-dimethoxy-11 b-methylbenzoaquinolizin-4-one (19).The massspectrum showed the molecular ion peak at m / e 273 andthe i.r. spectrum (chloroform) exhibited carboiiyl ab-sorption at 1625 cm-l. In the n.m.r. spectrum one C-methyl signal was observed at 6 (CDC1,) 1.69 ( s ) , two0-methyl signals a t 3.84 and 3.87, two aromatic protonsignals at 6.57 and 6.72 (singlets), and resonances for twoolefinic protons at 5.75 (dt, J 3.4 and 10 Hz) and 6.18 (d,J 10 Hz).Structure (19) was further supported by the13C n.m.r. spectrum (deuteriochloroform), which showedsignals for sixteen carbon atoms, assigned by comparisonswith models 14916917 and on the basis of splitting patternsin the off-resonance-decoupled spectrum : 1 lb-Me at 1976 254930.9, C(1) at 30.3 and/or 34.9, C(2) at 131.4, C(3) at 119.4,C(4) at 165.9, C(6) at 30.3 and/or 34.9, C(7) at 27.8, C(7a)at 125.8, C(8) at 110.8, C(9) and C(l0) at 146.8, C(11) at107.9, C(l1a) at 131.4, C(l1b) at 59.6, and two O-Meat 55.4 and 55.0. Compound (19) was presumablyformed by nucleophilic attack of the methylene carbonof glutaconic anhydride at C-1 of the dihydroisoquinoline(1) ,15 followed by cyclisation of the resulting anhydride(18) accompanied by decarboxylation.j - c o 22 (19)EXPERIMENTAL1.r.spectra were taken with a Hitachi EPI-3 recordingspectrometer, n.m.r. spectra with a JEOL JNM-PMX-60spectrometer, 13C n.m.r. spectra with a JEOL JNM-PFT-100system equipped with a JNM-PS-100 spectrometer, andmass spectra with a Hitachi R M U - 7 spectrometer.2-Crotonoyl- 1,2,3,4-tetrahydro-6,7-dirnethoxy- I-methylene-isoquinoline (3), N-( 2-AcetyZ-4,5-dimethoxyphenethyZ)cro-tonarnide (4), and 3,4,6,7-Tetrahydro-9,1O-dimethoxy-4-methyZ-benzoaquinolizin-2-one (5) .-TO a solution of 3,4-dihydro-6,7-dimethoxy- l-methylisoquinoline (1) l1 (1,5 g ) in pyri-dine (2 ml), crotonic anhydride (2) (1.2 g) was added, andthe resulting mixture was heated on a water-bath for 2 hunder nitrogen.After cooling, water (20 ml) was added andthe solution was extracted with benzene. The extract waswashed with water, dried (Na,SO,), and evaporated to givea red syrup (2.2 g), which was chromatographed on neutralalumina (grade 111). Elution with benzene afforded theenamide (3), which was recrystallised from n-hexane to giveneedles, m.p. 125", vmax (CHCl,) 1655 and 1605 cm-1; 6(CDCl,) 1.85 (3 H, d, J 6 Hz, Me), 2.83 (2 H, t, J 6.5 Hz,ArCH,), 3.86 (3 H, s, OMe), 3.90 (3 H, s, OMe), 4.03 (2 H,t, J 6.5 Hz, CH,*N), 4.87 and 5.57 (each 1 H, each s, XH,),6.25-7.20 (2 H, m, 2 x olefinic H), 6.56 (1 H, s, 5-H), and7.09 (1 H, s, 8-H); m/e 273 (M+) (Found: C, 70.1; H, 6.95;N, 5.0. C,,H,,NO, requires C, 70.3; H, 7.0; N, 5.15).Further elution with benzene-methanol (99 : 1 v/v) gave theamide (4) (150 mg, 7), which was recrystallised frombenzene to afford needles, m.p. 146", vmax (CHC1,) 1655,16 E.Wenkert, B. Chauncy, K. G. Dava, A. R. Jeffcoat, F. M.Schell, and H. P. Schenk, J . Amer. Chem. SOC., 1973, 95, 8427;E. Wenkert, J. S. Bindra, C.- J. Chang, D. W. Cochran, and F. 31.Schell, Accounts Chem. Res., 1974, 7, 46.1 625, and 1600 cm-1; G(CDC1,) 1.82 (3 H, dd, J 2 and 7 Hz,Me), 2.56 (3 H. s, Ac), 2.99 (2 H, t, J 6.5 Hz, ArCH,), 3.50 (2H, t, J 6.5 Hz, CH,*N), 3.88 (6 H, s, 2 x OMe), 5.75 (1 H, d,J 15 Hz, COCH=), 6.41 - 7.25 (1 H, m, COCH=CH), 6.73 (1H, s, 5-H), and 7.14 (1 H, s, 8-H); rn/e 291 ( M f ) (Found: C,65.7; H, 7.15; N, 4.7. C16H,1N04 requires C, 65.95; H,7.25; N, 4.8).Further elution with benzene-methanol(98 : 2 v/v) gave the benzoaquinoZizine (5) (350 mg, 17.5),which was recrystallised from benzene to afford pale yellowneedles, m.p. 156-157", vmx. (CHCl,) 1 605 and 1 580 cm-l;G(CDC1,) 1.32 (3 H, d, J 6 Hz, Me), 2.05-3.80 (7 H, m), 3.85(3H,s,OMe),3.89(3H,s,OMe),5.55(lH,s,l-H),6.64(1H,s, 5-H), and 7.11 (1 H, s, 8-H); wz/e 273 (M+) (Found: C,70.2; H, 6.9; N, 5.05. C1,H1,NO, requires C, 70.3; H,7.0; N, 5.15).(9) .-Amixture of 3,4-dimethoxyphenethylamine (7) (1.8 g) and 3-methylglutaric anhydride (8) (1.5 g) was heated a t 240 "Cuntil the formation of water had ceased. After cooling,the mixture was dissolved in chloroform, which was thenwashed with aqueous 5 sodium hydroxide and saturatedaqueous sodium chloride solution, dried (Na,SO,), andevaporated.The resulting solid, after trituration with coldbenzene, was crystallised from benzene-n-hexane to affordthe glutarimide (9) (1.5 g, 52) as scales, m.p. 123" (lit.,I*116.5-118"), v,,,. (CHCl,) 1715 and 1665 cm-1; 6 (CDCl,)1.05 (3 H, d, J 6 Hz, Me), 3.83 (3 H, s, OMe), 3.86 (3 H, s,OMe), and 6.73 (3 H, s, 3 x ArH).idone (10) .-Sodium borohydride (250 mg) was added insmall portions to a stirred solution of the glutarimide (9)(250 mg) in ethanol (25 ml) a t -10 "C. At regular intervals(ca. 15 min), 2-3 drops of 4~-hydrochlork acid were addedduring 4 h, with stirring. The excess of sodium borohydridewas decomposed by slow addition of hydrochloric acid to thecooled solution, until pH 3 was reached.The mixture wasthen stirred for an additional 45-60 min a t 50 "C, neutralisedwith ethanoIic 1 potassium hydroxide and evaporated.Extraction of the residue with chloroform, followed by evap-oration, afforded the amide (10) (200 mg, 91) as an oil,vmaZ (CHCl,) 1 630 cm-1; 6 (CDC1,) 0.83 (3 H, d, J 6 Hz, Me),1.07 (3 H, t, J 7 Hz, CH,IMe), 4.13 (1 H, t, J 3 Hz, EtOCH-N),and 6.62 (3 H, s, 3 x ArH), which was used withoutfurther purification.1,2,3,6,7,1 lb-Hexahydro-9,10-dirulethoxy-2-wethylbenzo a-quinolizin-4-one( 11). -A solution of the amide (10) (200mg) in benzene (50 ml) containing toluene-fi-sulphonic acid(70 mg) was refluxed for 3 h. After cooling, the benzenelayer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried(Na,SO,), and evaporated to leave the product (11) as anoily mixture of epimers (160 mg, 94) vmX (CHClJ 1620cm-l; 8 (CDC1,) 1.11 (3 H, m, Me), 3.83 (6 H, s, 2 x OMe),4.40-5.15 (2 H, m, 6- and Ilb-H), 6.58 (1 H, s, ArH), and6.63 (1 H, s, ArH), which was used without further purific-ation.1,3,4,6,7,1 lba-Hexahydro-9,10-dimethox~y-2~-metlzyl-2H-benzoaquinoZizine Racemate of (12) and its 2a-MethylIsomer Racemate of ( 13) .-To a suspension of lithium alu-minium hydride (15 mg) in dry tetrahydrofuran (20 rnl), asolution of compound (1 1) (100 mg) in dry tetrahydrofuranl7 R.H. Levin, J.-Y. Lallemand, and J. D. Roberts, J . 09.g.lS T. Kametani, T. Hayasaka, S.Takano, and S. Akaboshi, J .N- (3,4-DimethoxyphenethyZ) - 3-methylgZutarivnideN- (3,4-DimethoxyphenethyZ) - 6-ethoxy-4-methyl-2-fiiper-Chem., 1972, 38, 1983.Pharm. SOC. Japan, 1962, 82, 9562550 J.C.S. Perkin I(10 ml) was added dropwise with stirring a t room temper-ature. After stirring for further 0.5 h, the solution was re-fluxed for 3 h and the excess of lithium aluminium hydridewas then decomposed by slow addition of aqueous 40 so-dium hydroxide. The solution was evaporated to give anoil which was extracted with ether. The extract was washedwith saturated aqueous sodium chloride, dried (Na,SO,) , andevaporated to leave an orange oil (80 mg) , which was puri-fied by a preparative t.1.c. on silica gel benzene-ethylacetate-methanol (5 : 5 : 2 v/v) to afford the products(12) (30 mg, 32), as an oil, vm9.(CHC1,) 2 800-2 700 and1600 cm-l; G(CDC1,) 1.10 (3 H, d, J 6 Hz, Me), 3.80 (6 H,s, 2 x OMe), 6.53 (1 H, s, ArH), and 6.62 (1 H, s, ArH) ; wz/e261 (M+) the hydrochloride formed needles, n1.p. 215-216"(from ethanol-ether) (Found: C, 64.05; H, 8.15; N, 4.6.C1,H24C1N02 requires C, 64.5; H, 8.1; N, 4.7), and (13)(35 mg, 37), as an oil, vnmx. (CHC1,) 2 800-2 700 and 1 600cm-l; 6 (CDC1,) 1.02 (3 H, d, J 5Hz, Me), 3.82 (6H,s, 2 xOMe), 6.55 (1 H, s, ArH), and 6.68 (1 H, s, ArH); nz/e 261(M+) the hydrochloride formed needles, m.p. 195-198" (fromethanol-ether) (Found: C, 63.45; H, 8.35; N, 4.45.C,,H2,C1N02,0.25H,0 requires C, 63.55; H, 8.15; N,4.65y0).5,6-Dihydro-9,1O-dimethoxy-4-wzethylbenzofaquinoZizin-2-one (15) .-(a) Oxidation of compound (14).(i) With potassiumpermangannte. A mixture of compound (14) (50 mg), po-tassium permanganate (29 mg), and acetone (10 ml) wasstirred for 5 h a t room temperature. Manganese dioxidewas precipitated out and the solution became colourless.The mixture was filtered through Celite and evaporated toafford a powder (45 mg), which was recrystallised from ace-tonetogive thedienone (15) (40mg, 80) as needles, m.p. 262",v,,,. (CHCl,) 1 630 and 1 610 cm-1; 6 (CDC1,) 2.39 (3 H, s,Me), 2.98 (2 H, t, J 7 Hz, ArCH,), 3.89 (3 H, s, OMe), 3.91(3H, s, OMe), 4.02 (2H, t, J 7, CH,*N), 6.24 (1 H, d, J 2.5Hz, 1- or 3-H), 6.72 (1 H, s, 8-H), 6.73 (1 H, d, J 2.5 Hz, 1-or 3-H), and 7.17 (1 H, s, 11-H); wale 271 (MT) (Found: C,70.45; H, 6.35; N, 5.1.C1,H1,NO, requires C, 70.85; H,6.3; N, 5.15).A suspension of compound (1 4)(100 mg) and palladium oxide (100 mg) in xylene (10 ml)was refluxed for 20 h. After cooling, the mixture was filtered(ii) With palladium oxide.through Celite and evaporated to afford a powder (80 mg),which was recrystallised from acetone to give (15) (70 mg,70) as needles, m.p. 262", the spectral data of which wereidentical with those of the above compound.(b) Dehydrogenation of compound (5) with palladium oxide.A suspension of compound (5) (60 mg) and palladium oxide(80 mg) in xylene (5 ml) was refluxed for 24 h. After cooling,the mixture was filtered through Celite and evaporated togive a black oil (50 mg) , which was purified by preparativet.1.c. on silica gel benzene-ethyl acetate-methanol (5 : 5 : 2v/v).A fraction of RB 0.2 gave compound (15) (15 mg,30) as needles, m.p. 262", with spectral data identicalwith those of the foregoing product.1,6,7,1 lb-Tetmhydro-9,lO-dimethoxy-1 lb-methylben,zoa-qztinolizin-4-one (1 9) .-A solution of 3,4-dihydro-6,7-d;-methoxy- 1-niethylisoquinoline ( 1) (200 mg) and glutaconicanhydride (17) lg (1 10 mg) in pyridine (2 ml) was heated ona water-bath for 3 h. After cooling, water (5 ml) was addedt o the resulting red solution, which was then extracted withether. The extract was washed with saturated aqueoussodium chloride, dried (Na,SO,), and evaporated to give anorange oil (1 90 mg) , which was chromatograplied on neutralalumina (grade 111). Elution with benzene afforded asolid which was recrystallised from n-hexane to give theproduct (19) (150 mg, 56) as needles, m.p. 115", vmax. (CHCl,)1 625 cm-1; 6 (CDCl,) 1.69 (3 H, s, Me), 2.36-3.43 (5 H, m,1-H2, 6-H, and 7-H,), 3.84 (3 H, s, OMe), 3.87 (3 H, s, OMe),4.93-5.25 (1 H, m, 6-H), 5.75 (1 H, dt, J 3.4 and 10 Hz,2-H), 6.18 (1 H, d, J 10 Hz, 3-H), 6.57 (1 H, s, ArH), and6.72 (1 H, s, ArH); m/e 273 (M+) (Found: C, 70.1; H,6.85; N, 4.9. C,,H,,NO, requires C, 70.3; H, 7.0; N,5.150,;) *We thank Dr. M. Koizumi, Mr. K. Kawamura, Mrs. C.Koyanagi, Miss K. Mushiake, Mrs. R. Kobayashi, Miss R.Suenaga, Miss E. Nagaoka, Miss XI. Tanno, and Miss H.Koizumi for microanalyses and spectral measurements.6/1323 Reccived, 7th July, 19761l9 W. H. Perkin, jun., and G. Tattersall, J . Chem. Soc., 1905,87, 364