1976 1221A One-step Synthesis of the Phthalidylisoquinoline Alkaloids, Cordrastineand HydrastineBy Tetsuji Kametani,' Toshio Honda, Hitoshi lnoue, and Keiichiro Fukumoto, Pharmaceutical Institute,Tohoku University, Aobayama, Sendai, JapanCordrastine (5a) and hydrastine (5b) were synthesised by condensation of 3.4-dihydro-6.7-dimethoxy-2-rnethyl-(1 a) and 3.4-dihydro-6.7-methylenedioxy-2-methyl-isoquinolinium (1 b) salts, respectively, with methyl 6-diazo-methyl-2.3-dimethoxybenzoate (2a) derived from 6.7-dimethoxyphthalimidine (1 6a). The reaction of (1 a)with methyl 2-diazomethyl-4,5-dimethoxybenzoate (2b) gave the cordrastine isomer (5c).AZIRIDINES and their quaternary salts' are easily alkaIoids.3 Moreover, an aziridine system is assumedattacked by nucleophiles2 or electrophiles3 with form- to be an intermediate in the formation of a variety ofation of ring-opened amines ; this type of reaction has naturally occurring heterocyclic compound^.^D.R. Crist and N. J. Leonard, Angew. Chern., 1969,81,953. Chem. SOL, 1968, 90, 1650.N. J. Leonard and K. Jann, J . Amer. Chem. Soc., 1962, 84,been applied to a Of ibogamine and 3 W. Nagata, S. Hirai, T. Okamura, and K. Kawata, J . Amey.4 T. Kametani and K. Fukumoto, HeterocycZes, 1976, 3, 931,4806. and references cited therein1222 J.C.S. Perkin IWe have reported the synthesis of isopavine5 andbenzazepine systems by ring expansion of 3,4-dihydro-2-methylisoquinolinium salts with diazomethane, byway of aziridinium salt intermediates. As an extensionof this work, we have investigated the reaction of 3,4-dihydro-6, 7-amp;met hoxy-2-met hyl- and 3,4-dihydro-6,7-methylenedioxy-2-methyl-isoquinolium salts (1) with 2-diazomethylbenzoates (2), in the hope of obtaining thegenine (loa) which has been converted into alpinine (6)by Manske '1 or cordrastine (5a).Ethyl 6-bromoveratrate * (14b) was treated withcopper(1) cyanide in refluxing dimethylformamide for 4 hto give the corresponding cyanide (15b) in 85 yield,which was reduced over Raney nickel in ethanol at 80 "Cunder 80 atm of hydrogen to afford 5,6-dimethoxyphthal-imidine (16b).Treatment of this product with sodium:mitvlel- - R 2 T : e 1 - R' /9 ti-? ( 1 ) a; R'=R2=OMe' Ib ; R'R2=0.C H,.O MeO-CMeo2c62 R 3 bsol; ~1O M eR 3 v R LO M e(3)( 2 ) a; R3=OMe,RL=Hb; R3= H,RL=OMe(5) a ; R1=R2=R3=OMe.RL=Hb ; R' R 2 = 0 .C H , . 0 . R3=OMe,RL= Hc ; R'= R2=RL=OMe,R3=HSCHEME 1rheadans (4) or the phthalidylisoquinolines (5). Wereport here one-step syntheses of cordrastine (5a) andhydrastine (5b) by this reaction.Thusit is possible that intramolecular nucleophilic attack ofthe carboxylate group on the aziridinium system (3)could take place by route A or B, leading to oxyalpini-T. Kametani and K. Ogasawara, Chem. and Pharm. Bzcll.(Japan), 1973, 21, 893; T. Kametani, S. Hirata, and K. Ogasa-wara, J.C.S. Perkin I, 1973, 1466.T. Kametani, S. Hirata, F. Satoh, and K. Fukumoto, J.C.S.Perkin I, 1974, 2609.K. Orito, R. H. Manske, and R. Rodrigo, J. A m y . Chem.SOL, 1974, 96, 1944.The synthetic route is summarised in Scheme 1.nitrite in concentrated hydrochloric acid at roomtemperature gave the N-nitrosophthalimidine (17b),which was treated with 5~-sodium methoxide in meth-anol by Oppk's method9 to form the unstable diazo-methylbenzoate (2b).An ethereal solution of this wasadded to the 3,4-dihydro-2-methylisoquinolinium iodide(la) in methanol-chloroform (1 : 1, vlv), and the mixturewas kept at room temperature for 2 days to give thephthalidylisoquinoline (5c) lo (ix. and n.m.r. data as* A. Bruggink and A. McKillop, Angew. Chem., 1974,86, 349.A. OppB, Ber., 1913, 46, 1096.M. Shamm and V. St. Georgiev, Tetrahedron Letters, 1974,23391976 1223reported 11) in 10-15y0 yield after purification by silicagel column chromatography. No rheadan-type com-pound (4c) was detected.This method was applied to a synthesis of cordrastine(5a) as follows.Methoxycarbonylation of 2-hydroxy-3-methoxybenzaldehyde (7) with methyl chloroformateand triethylamine in benzene gave the non-phenolicaldehyde (euro;9, which was converted into 3-bromo-2-f ormyl-6-methoxyphenyl methyl carbonate (9) by brom-ination in the presence of iron and sodium acetate inacetic acid at room temperature. Hydrolysis withbenzoate (13), which was also synthesised by oxidationof (11) with silver oxide, followed by methylation withdiazomethane. Cyanation of this bromide (13) withcopper@) cyanide, followed by hydrogenation of theresulting cyanide (15a) over Raney nickel, afforded 6,7-dimethoxyphthalimidine (16a).N-Nitrosation of (16a)with sodium nitrite and concentrated hydrochloric acidprovided (17a), which was treated with sodium methox-ide by Oppi3rsquo;s method 9 to yield the diazo-benzoate (2a).Condensation of this with 3,4-dihydro-6 ,7-dimethoxy-2-methylisoquinolinium iodide (la) gave, in l0-15HO2C ___,OMe OMe OMe(7) R=H (9) R = C02Me (12) R=H(8) R = C02Me (10) R = H (13) R=Me(11) R = MeX 1OMe(16) a; Rrsquo; = OMe, R2 =X = Hb ; Rrsquo;=X=H,R*=OMe(17) a ; R1=OMe,RZ=H,X=NOb ; Rrsquo;=H.R2=OMe,X=N0(14) a ; Rrsquo;=OMe, RZ= H, R3= Me, X = Brb ; Rrsquo; = H, R2= 0 M e. R3= Et ,X = Br(15) a ; Rrsquo;=OMe, R2= H,R3=Me,X=CNb ; Rrsquo; = H. R2= OMe, R3= E t , X = C NSCHEME 2___, Me0+6MeM e o p N M c Me0 bsol;+tH 0I OMeSCHEME 3sodium hydroxide in boiling aqueous methanol afforded6-bromo-2-hydroxy-3-methoxybenzaldehyde (lo), whichwas treated with dimethyl sulphate and potassiumcarbonate to give 6-bromo-2,3-dimethoxybenzaldehyde(11) in 90 yield.Oxidation of the aldehyde (10) withsilver oxide and sodium hydroxide afforded 6-bromo-2-hydroxy-3-methoxybenzoic acid.12 Methylation of (12)with diazomethane gave methyl 6-bromo-2,3-dimet hoxy-l1 T. Kainetani, S. Hirata, RI. Ihara, and K. Fukumoto,Hetevocycles, 1975, 3, 405.yield, cordrastine (5a), characterised as the picrate.The i.r. and n.m.r. spectra of the free base were identicalwith those of an authentic sample. In the above reac-tion no oxyalpinigenine (4a) could be detected.Similarly, condensation of the diazo-compound (2a)with 3,4-dihydro-6,7-met hylenedioxy-2-met hylisoquino-linium iodide (lb) afforded, in 15 yield, hydrastine(5b), which was identical with an authentic sample (i.r.,In this l2 S.Sugasawa, J. Pharm. SOG. Japan, 1934, 54, 295.paper, it was reported that the acid was not crystallisedJ.C.S. Perkin In.m.r., and mass spectra), and was characterised as thepicrate.The formation of this type of phthalidylisoquinolinepresumably proceeds via the aziridinium salt (3) by routeB in Scheme 1; the isolation of azirino2,3-aisoquino-line methiodides and the formation of benzazepines fromhydrastinine and diazoalkanes has been reported.13* l4However, the lack of formation of the oxyrheadans (4)suggests that the mechanism shown in Scheme 3 is alsoa possibility.EXPERIMENTALN.m.r. spectra were measured with a JNM-PMX-60spectrophotometer, i.r.spectra (for solutions in chloroform)with a Hitachi 215 spectrophotometer, and mass spectrawith a Hitachi RMU-7 spectrometer.2-Formyl-6+nethoxyflhenyl Methyl Carbonate (8) .-To asolution of 2-hydroxy-3-methoxybenzaldehyde (7) (25 g) inbenzene (300 ml) containing triethylamine (17 g), methylchloroformate (20 g) was added dropwise with stirring at5-10 "C. Stirring was continued for 2 h at room tempera-ture. The benzene layer was washed with water, 10hydrochloric acid, and water, dried (Na,SO,) , and evapor-ated to give (8) as an oil, b.p. 150" a t 5 mmHg (Found: C,57.1; H, 4.75. C1oH1oO5 requires C, 57.15; H, 4.8),v,, 1 760 (GO) and 1 690 cm-l (GO), G(CC1,) 3.79 (3 H, s,OCH,), 3.83 (3 H, s, OCH,), 7.10-7.33 (3 H, m, ArH),and 10.07 (1 H, s, CHO).3-Bromo-2-formyl-6-methoxy~henyl Methyl Carbonate (9).-To a stirred solution of the aldehyde (8) (20 g) in aceticacid (200 ml) containing a catalytic amount of iron powderwas added a solution of bromine (22 g) in acetic acid (100ml) dropwise a t room temperature.After continuousstirring for 5 h, the mixture was poured into water andextracted with chloroform. The organic layer was washedwith water, 5 sodium thiosulphate solution, and water,dried (Na,SO,); and evaporated to afford a pale reddishsolid ; recrystallisation from propan-2-01 gave the bromide(9) (22.5 g) as needles, m.p. 120-122" (Found: C, 41.85;H, 3.35.CloHgBr05 requires C, 41.55; H, 3.15), vmx.1760 (GO) and 1690 cm-1 (C=O), a(CDC1,) 3.78 (3 H, s,OCH,), 3.88 (3 H, s, OCH,), 7.07 (1 H, d, J 8 Hz, ArH),7.47 (1 H, d, J 8 Hz, ArH), and 10.22 (1 H, s, CHO).6-Bromo-2-hydroxy-3-methoxybenzaldehyde ( 10) .-A mix-ture of the aldehyde (9) (38 g), 10 sodium hydroxide (200ml), and methanol (750 ml) was refluxed for 2 h, thenevaporated. The residue was acidified with concentratedhydrochloric acid and extracted with chloroform. Theextract was washed with water and dried (Na,SO,). Thesolvent was distilled off to give the product (10) (24 g) as apale yellowish powder, which was recrystallised from pro-pan-2-01 to afford needles, m.p. 93-95" (Found: C, 41.6;H, 3.05. C,H,BrO, requires C, 41.85; H, 3.2y0), v,, 1 635cm-l ( G O ) , G(CDC1,) 3.88 (3 H, s, OCH,), 6.88 (1 H, d, J 9Hz, ArH), and 7.08 (1 H, d, J 9 Hz, ArH).6-Bromo-2,3-dimethoxybenzaldehyde ( 1 1) .-To a solutionof the phenol (10) (27 g) in dimethylformamide (100 ml)containing potassium carbonate (32 g) was added dimethylsulphate (18 g), dropwise a t 100-120 "C with stirring.Stirring was continued for 4 h a t the same temperature.After cooling, the mixture was poured into water and ex-tracted with chloroform.The organic layer was washedwith water, dried (Na,SO,), and evaporated to give a palereddish solid ; recrystallisation from propan-2-01 gave (1 1)(22 g) as needles, m.p. 71-73" (Found: C, 44.1; H, 3.66.CgHgBrO, requires C, 44.35; H, 3.95), vmx. 1695 cm-l(GO), 6 3.85 (3 H, s, OCH,), 3.88 (3 H, s, OCH,), 6.93 (1 H,d, J 8 Hz, ArH), 7.30 (1 H, d, J 8 Hz, ArH), and 10.24(1 H, s, CHO).6-Bromo-2,3-dimethoxybenzoic Acid (13) .-To a solutionof the aldehyde (1 1) (4.1 g) and silver nitrate (3.0 g) in water(20 ml) was added 20 sodium hydroxide (20 ml) dropwisewith stirring during 30 min a t 80-90" C.After continuousstirring for 30 rnin a t the same temperature, the mixturewas filtered, and the filtrate was acidified with concentratedhydrochloric acid and extracted with chloroform. Theextract was washed with water, dried (Na,SO,), and evapor-ated to give a powder; recrystallisation from benzene-n-hexane afforded the carboxylic acid (3.0 g) as needles, m.p.83-85' (Found: C. 41.6: H, 3.65. CgHgBr04 requires C,41.4; H, 3.45), vmx.1 725 cm-l (GO), G(CDC1,) 3.83 (3 H,s, OCH,), 3.86 (3H, s, OCH,), 6.80 (1 H, d, J 9 H z, ArH),and 7.26 (1 H, d, J 9 Hz, ArH).6-Bromo-2-hydroxy-3-methoxybenzoic Acid ( 12) .-The oxid-ation of the aldehyde (10) (2 g) was carried out in the samemanner as the synthesis of (13) to give the carboxylic acid(1.8 g) as a gum, which was used without further purific-ation.Methyl 6-Bromo-2,3-dinzethoxybenzoate (14a) .-A mixtureof the acid (1 3) (3 g) and an excess of diazomethane in etherwas kept overnight a t room temperature. The solvent andthe excess of diazomethane were evaporated off and theresidue was extracted with chloroform. The organic layerwas washed with water, 5 sodium hydrogen carbonatesolution, and water, dried (Na,SO,), and evaporated t oafford the ester (14a) (2.8 g) as an oil (Found: C, 44.25; H,4.3.CloHllBrO, requires C, 43.65; H, 4.05), vmaX 1725cm-l (GO), G(CDC1,) 3.82 (3 H, s, OCH,), 3.91 (3 H, s,OCH,), 6.79 (1 euro;5, d, J 9 Hz, ArH), and 7.15 (1 H, d, J 9 Hz,ArH) .The reaction of the acid (13) (1 g) with an excess of diazo-methane in ether also gave the ester (l4a) (0.8 g), identicalwith the sample just described.Methyl 6-Cyano-2,3-dimethoxybenzonte ( 15a) .-A solutionof the ester (14a) (7.0 g) and copper(1) cyanide (3.5 g) indimethylformamide (30 ml) was refluxed for 4 h withstirring. The mixture was poured into water, acidified withconcentrated hydrochloric acid , and then extracted withbenzene. The extract was washed with water, dried(Na,SO,), and evaporated to afford a pale yellowish solid;recrystallisation from ethanol gave the cyanide (15a) (4.8 g)as needles, m.p.137-140" (Found: C, 59.6; H, 5.1; N,6.3. CllHllNO, requires C, 59.7; H, 5.0; N, 6.35), vmx.2 230 ( E N ) and 1715 cm-l (GO), G(CDC1,) 3.88 (3 H, S,OCH,), 3.94 (3H, s, OCH,), 3.97 (3H,s, OCH,), 6.97 (1 H,d, J 9 Hz, ArH), and 7.39 (1 H, d, J 9 Hz, ArH).6,7-DiunethoxyplzthaEi.wLidine ( 16a) .-A solution of thecyanide (15a) (5.0 g) in ethanol (50 ml) was hydrogenatedover Raney nickel (2 g) a t 80 "C under 80 atm of hydrogenuntil uptake ceased. The mixture was filtered and thefiltrate was evaporated to give a solid ; recrystallisationfrom propan-2-01 afforded the lactam (16a) (3.5 g) asneedles, m.p.140-141" (Found: C, 62.05; H, 5.75; N,7.2. CloHllNO, requires C, 62.15; H, 5.7; N, 7.25),vmx. 3 450 (NH) and 1 680 cm-l (GO), G(CDC1,) 3.88 (3 H,13 R. 0. Bernhard and V. Snieckus, Tetrahedron. 1971, 27,2091.14 B. Gobar and G. Engelhardt, Pharmazie, 1969, 24, 4231976 1225s, OCH,), 4.06 (3 H, s, OCH,), 4.12 (2 H, s, ArCH,*N), and7.04 (2 H, s, ArH).6,7-Dimethoxy-2-nitrosofihthalimidine (1 7a) .-To a stirredsolution of the lactam (16a) (1 g) in concentrated hydro-chloric acid (8 ml) was added a solution of sodium nitrate(1.4 g) in water (10 ml), dropwise, a t 0 "C. After continuousstirring for 10 min, the precipitate was collected, washedwith water, and recrystallised from ethanol to give thenitroso-compound (17a) (0.8 g) as yellowish Needles, m.p.145-147" (Found: C, 53.9; H, 4.6; N, 12.55.Cl,HloN,04requires C, 54.05; H, 4.55; N, 12.6), vmx. 1680 cm-1(GO), G(CDC1,) 3.88 (3 H, s, OCH,), 4.12 (3 H, s, OCH,),4.23 ( 2 H, s, ArCH,-N), 7.04 (1 H, d, J 8 Hz, ArH), and 7.26(1 H, d, J 8 Hz, ArH).Ethyl 2-Cyano-4,5-dimethoxybenzoate (15b) .-A solution ofthe bromobenzoate (14b) (7 g) and copper(1) cyanide (3.5 g)in dimethylformamide was refluxed for 4 h. The mixturewas poured into water, then treated with concentratedhydrochloric acid, and extracted with benzene. The organiclayer was washed with water and dried (Na,SO,) . Removalof the solvent left a pale yellowish solid, which was recrystal-lised from ethanol to give the cyanide (15b) (4.5 g) as needles,m.p. 114119deg; (Found: C, 61.45; H, 5.35; N, 5.75.C1,H1,N04 requires C, 61.25; H, 5.55; N, 5.95), v- 2 230( E N ) and 1 705 cm-l (GO), G(CDC1,) 1.46 (3 H, t, J 8 Hz,CH,*CH,), 3.98 (6 H, s, 2 x OCH,), 4.46 (2 H, q, J 8 Hz,CH,*CH,), 7.17 (1 H, s, ArH), and 7.57 (1 H, s, ArH).4,5-0imethox~~hthalimidine (16b) .-Catalytic reductionof the cyanide (15b) (5 g) was carried out as described in thesynthesis of (16a) ; recrystallisation of the product fromethanol afforded (16b) (3.8 g) as needles, m.p.229-231"(Found: C, 62.05; H, 5.75; N, 7.3. C1,HllNO, requiresC, 62.15; H, 5.75; N, 7.25), v,, 3 450 (NH) and 1680cm-1 (GO), S(CDC1,) 3.88 (2 H, s, CH,), 3.90 (6 H, s, 2 xOCH,), 6.91 (1 H, s, ArH), and 7.53 (1 H, s, ArH).5,6-Dirnethoxy-2-nitrosophthalimidine (1 7b) .-The nitroso-compound (17b) was obtained from the lactam (16b) (1 g)by the same procedure as in the preparation of (17a).Recrystallisation from ethanol afforded yellowish needles (0.8 g),m.p. 128-129' (Found: C, 54.0; H, 4.5; N, 12.6. Clo-H10N204 requires C, 54.05; H, 4.55; N, 12.6), vms. 1 680cm-1 (GO), G(CDCl,), 3.88 (3 H, s, OCH,), 3.90 (3 H, s,OCH,), 3.96 (2 H, s, CH,*N), 6.92 (1 H, s, ArH), and 7.52(lH, s, ArH).Methyl 6-Diazomethyl-2,3-dimethoxybenzoate (2a) .-To astirred solution of 5~-sodium methoxide in methanol (2 mol.equiv.) was added the nitroso-compound (17a) (300 mg) insmall portions during 2 h at room temperature. Stirringwas continued for 15 min, and the mixture was treated withcarbon dioxide gas and filtered. The filtrate was concen-trated to half volume, poured into water, and extracted withether.The ethereal layer was washed with sodium chloridesolution and dried (K,CO,) v- 2 055 (N,) and 1 715 cm-l15 R. D. Haworth and A. R. Pinder, J . Chem. Soc., 1960, 1776.16 V. Smula, N. E. Cundasawmy, H. 0. Holland, and D. B.MacLean, Canad. J . Chem. , 1973,51,3287.(C=O)J, and this solution was used without further purific-ation.(f)-Cordrastine (6a) .-A mixture of 3,4-dihydro-6,7-dimethoxy-2-methylisoquinolium iodide (la) (500 mg) inmethanol-chloroform (1 : 1 v/v; 20 ml) and the abovediazo-compound in ether was kept a t room temperature for2 days. The solvent was then removed and the residuewas chromatographed on silica gel (30 g). Elution withbenzene-ethyl acetate (1 : 1 v/v) gave (+)-cordrastine asa gum (70 mg), v,, 1 750 cm-l (GO), G(CDC1,) 2.57 (3 H, s,NCH,), 3.36 (3 H, s, OCH,), 3.85 (3 H, s, OCH,), 3.87 (3 H,s, OCH,), 4.05 (3 H, s, OCH,), 5.57 (1 H, d, J 4 Hz, ArCH-0),6.29 (1 H, s, ArH), 6.52 (1 H, d, J 8 Hz, ArH), 6.58 (1 H,s, ArH), and 7.06 (1 H, d, J 8 Hz, ArH).The picrateformed yellowish needles (from ethanol), m.p. 198-199O(f)-Hydrastine (5b) .-The reaction of 3,4-dihydro-6,7-methylenedioxy-2-methylisoquinolinium iodide ( lb) ( 1.5 g)with the diazo-compound (2a) from the nitroso-compound(1 g), carried out similarly, gave (-J-)-hydrastine as a gum(220 mg), v- 1755 cm-l (GO), B(CDC1,) 2.53 (3 H, s,NCH,), 3.86 (3 H, s, OCH,), 4.03 (3 H, s, OCH,), 5.43 (1 Hd, J 4 Hz, ArCeO), 5.79 (2 H, s, O*CH,*O), 6.40 (1 H, s,ArH), 6.53 (1 H, s, ArH), 6.46 (1 H, d, J 8 Hz, ArH), and7.03 (1 H, d, J 8 Hz, ArH); the picrate formed yellowishneedles (from ethanol), m.p.210-212'.MethyZ 2-Diazomethyl-4,5-dimethoxybenzoate (2b) .-To astirred solution of sodium methoxide (2 mol. equiv.) inmethanol was added the nitroso-compound (17b) (600 mg)in portions a t room temperature during 2 h. The mixturewas worked up as described for the preparation of (2a).The product showed vmS. 2 055 (N,) and 1 705 cm-l (GO),and the ethereal solution was used without purification.5,6-Dimethoxy-3-( 1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyZ-isoquinolin-l-yl)$hthaZide (5c) .-A mixture of the diazo-compound (2b) in ether and 3,4-dihydro-6,7-dimethoxy-2-methylisoquinolinium iodide (la) (900 mg) was kept at roomtemperature for 2 days. The solvent was then removed andthe residue was chromatographed on silica gel. Elutionwith benzene-ethyl acetate (1 : 1 v/v) gave an oil, which wasrecrystallised from ethanol to afford the phthalidyliso-quinoline (5c) (160 mg), m.p. 166-167" (1it.,lo 157-159*),vwx. 1755-1 750 cm-1, G(CDC1,) 2.58 (3 H, s, NCH,), 3.78(3 H, s, OCH,), 3.86 (3 H, s, OCH,), 3.92 (6 H, s, 2 x OCH,),(1 H, s, ArH), and 6.48 (1 H, s, ArH), identical with anauthentic sample.ll(1it.,15J16 2020).4.07 (1 H, d, J 4 Hz, Ha), 5.56 (1 H, d, J 4 Hz, Hb), 6.18We thank Dr. S. Teitel, Hoffmann-La Roche Inc., Nutley,New Jersey, for gifts of natural cordrastine hydrochlorideand (-) - p-hydrastine hydrochloride, and Mr. K. Kawa-mura, Mmes. R. Kobayashi, A. Satoh, and C. Koyanagi,and Misses R. Suenaga, E. Nagaoka, and Y . Yokohama formicroanalyses and spectral measurements.5/2380 Received, 8th December, 1976
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