Natural products chemistry. Part 124. Revised structure and synthesis of a new acridone alkaloid, hallacridone fromRuta graveolenstissue cultures

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 1047 Natural Products Chemistry. Part 124.‘ Revised Structure and Synthesis of a New Acridone Alkaloid, Hallacridone from Ruta graveolens Tissue Cultures2 Johannes Reisch * and G. M. Kamal B. Gunaherath Institute for Pharmaceutical Chemistry, University of Munster, HittorfstraBe 58-62,4400Munster, F.R.G. The synthesis of 6-hydroxy-2,12-dimethyl-3H-pyrano[2,3-c]acridine-3,7( 12H)-dione (1) by two different routes revealed the previously proposed structure of hallacridone, to be incorrect. Careful examination of the spectral characteristics, of an authentic sample of hallacridone, led us to suggest a revised structure, 2-acetyl-5-hydroxy-I 1 -methylfuro[2,3-c]acridin-6(11H)-one (2), which we unambiguously confirmed by total synthesis.The biosynthetic significance of hallacridone (2) is discussed. Hallacridone is a minor acridone alkaloid isolated from tissue cultures of Ruta graveolens and structure (1) was assigned to it on the basis of spectroscopic evidence., Prompted by its unique 3-methylcoumarino structure and in our continuing studies on Rutaceae alkaloids we undertook the synthesis of (1) in order to confirm this assignment. /.0 OMe Me (12) 0 OR’ (3) R’ = R2 = R3 = R4 = H, R5 = Me (4) R’ = R2 = R4 = H, R3 = CH2C(=CH2)C02Et,R5= Me (6) R’ = R4 = H, R2 = I, R3 = CH2C(=CH2)C02Et,R5 = Me (7) R’ = R3 = Ac, R2 = I, R4 = CH2C(=CH2)C02Et,R5= Me (8) R’ = R3 = Ac, R2 = H, R4 = CH,C(=CH,)CO,Et, R5= Me (9) R’ = R2 = R3 = H, R4 = CH2C(=CH2)C02H,R5 = Me (13) R’ = R3 = Me, R2 = R5 = H, R4 = CHO (14) R’ = R3 = R5 = Me, R2 = H, R4 = CHO (15) R’ = R2 = H, R3 = R5 = Me, R4 = CHO (16) R’ = R2 = R3 = H, R4 = CHO, R5 = Me 1,3-Dihydroxy- 1 O-methylacridin-9( 10H)-one (3) and ethyl bromomethacrylate were treated to give compound (4), which on heating in PEG 2003 underwent the following: ortho- Claisen rearrangement and ring closure followed by double- bond isomerisation (see Scheme 1).Although the ‘H n.m.r. and i.r. spectra of the product thus obtained showed the appropriate characteristics for an acridone alkaloid containing a 3-methyl- coumarin ring system (see Experimental section), they were not consistent with those reported for hallacridone., Because the ortho-Claisen rearrangement might occur towards either C-4 or C-2 of the acridone nucleus, the possibility arose that it was in fact the linear isomer (5).Further, at this point, the doublet nature of the coumarin CH, signal (6 2.22 d, J 1.4 Hz) in the ‘H n.m.r. spectrum of our synthetic sample and the absence of such a doublet in that of hallacridone led us to doubt the previously proposed structure. The poor solubility of the synthetic com- pound in almost all solvents prevented us in carrying out an n.0.e. experiment (irradiating at the N-Me signal) which would have resolved this problem. Therefore we decided to protect the C-2 of the acridone nucleus of compound (4) and then carry out the Claisen rearrangement in order to obtain (1).It has been rep~rted,~ that iodination of 1,3-dihydroxy-l0-methylacridin-9( 10H)-one (3), and its mono-or di-methyl ethers, with IJHIO, in aqueous ethanol occurs at C-2 of the acridone nucleus.Compound (4) was successfully iodinated by this method to give ethyl 2-( l’-hydroxy-2’-iodo-9’-oxo-9’,10’-dihydroacridin-3’-yloxymethyl)propenoate (6).Treatment of compound (6) with pyridine and acetic anhydride at 100 “C yielded a complex mixture of products, from which ethyl 2-( 1 ’,3’-diacetoxy-2’-iodo-9’-oxo-9’,10’-dihydroacridin-4’-ylmethyl)propenoate(7) and ethyl 2-( 1‘,3’-diacetoxy-9’-oxo-9’, 1 O’-dihydroacridin-4’-ylmethyl)propeno-ate (8) were isolated. The observation that (7) underwent slow decomposition to produce (8) in chloroform solution indicated that the side chain was situated at C-4 of the acridone nucleus. This was confirmed by carrying out an n.0.e.experiment on the acridone (8); the n.0.e. difference spectrum at 300 MHz, showed unambiguous enhancements for 5-H, benzylic CH,, and one of the vinylic proton signals, upon irradiation of the N-Me signal at 6 3.74 of the acridone derivative (8). Ester hydrolysis and deacetylation of compound (8) was effected with K2C03 in methanol under reflux to yield the dihydroxy acid derivative (9). This, when heated in PEG 200, underwent simultaneous3 cyclisation and double bond isomerisation to produce the desired 3-methyl- pyranoacridone (1) (see Scheme 1). This was found to be identical with the product obtained previously, by the direct Claisen rearrangement of (4) and was not comparable with hallacridone (by m.p., mixed m.p., t.l.c., i.r., ‘H n.m.r., and mass spectra).Hence the necessity to revise the structure of hallacridone was established. The 300 MHz ‘H n.m.r. spectrum obtained for authentic hallacridone showed two sharp singlets at 6 7.93 for 1 H and 6 2.63 for 3 H, which had been assigned to protons of the 3-methyl- coumarin ring system.2 However, these two signals show none of the expected and mutual long-range coupling we expected for such a coumarin system.’ Instead the 3 H singlet at 6 2.63 can be attributed more logically to a COCH, group of a 2-acetyl- ii(a) IV Scheme 1. Reagents and conditions: i, BrCH,C(=CH,)CO,Et, anh.K,CO,, dry acetone reflux, 2 h; ii, PEG 200, 220 "C, (a) 0.5 h; (b) 15 min; iii, I,, HIO,, aq. ethanol, room temp., 2 h; iv, pyridine, Ac,O, 100"C, 3 h; v, K,CO,, MeOH, reflux 15 min benzofuran ring system.6 Further evidence for the presence of the COCH, group was provided by the i.r. spectrum which showed strong carbonyl absorption band at 670 cm-l (.p-unsaturated carbony1 group) and the mass spectrum which showed loss of Me (10) (m/z292, Mf -15) followed by loss of J. CHEM. SOC. PERKIN TRANS. I 1989 desired 2-acetyl-5-hydroxy-1 1-methylfuro[2,3-c]acridin-6-(1 lH)-one (2), identical with authentic hallacridone (by m.p., * iv (2) (15) Scheme 3. Reagents and conditions: i, dry DMF, POCI,, room temp., 1.5 h; ii, MeI, Ag,O, dry DMF, room temp., 16 h; iii, BCI,, dry CH,Cl,, room temp., 72 h; iv, CICH,COCH,, anh.K,CO,, dry acetone, reflux, CO (1 1) (mi. 264, M+ -43) (see Scheme 2). From this analysis 2 h 0 0 Me -Meqo1;4 -\ +cro+ (2) m/~307 (lOOo/o) (11) m/Z 264 (2So/o) OH + + + Scheme 2. Mass spectral fragmentation of hallacridone (2) of the spectral data we arrived at the structure of hallacridone as 2-acetyl-5-hydroxy- 1 1 -methylfuro[2,3-c]acridin-6-( 11H)-one (2). This result was unambiguously confirmed by a total synthesis of the compound. Thus the product (12), obtained by condensation of o-chlorobenzoic acid and 3,5-cr-methoxyaniline under Ullman conditions, upon treatment with DMF/POCl, underwent simultaneous formylation ' and cyclisation to yield 4-formyl- 1,3-dimethoxyacridin-9( 10H)-one (13).The position of the formyl group was confirmed by an n.0.e experiment after the N-methylation of compound (13) with MeI/Ag,O in DMF.8 The n.0.e difference spectrum at 300 MHz showed enhance- ments for 5-H and CHO signals upon irradiation at the N-Me protons at 6 3.65 of 4-formyl- 1,3-dimethoxy-l0-methylacridin-9( 10H)-one (14). Demethylation of the formyldimethoxy-acridone (14) with boron trichloride in CH,Cl, over a period of 15 min gave exclusively the monomethoxy compound (15) * while complete demethylation, to yield the dihydroxy compound (16), was achieved only when the reaction time was Biogenetic aspects.-Ruta graveolens has been subjected to extensive chemical investigation and the presence of several furoacridones including rutacridone (16), rutacridone epoxide (17), gravacridondiol (18) and some of their glucosides have been reported.' lP1' A detailed biosynthetic pathway has been proposed for the origin of these furoacridones implicating rutacridone (16) as precursor.l6 As rutacridone (16), rutacridone epoxide (17), gravacridone-chlorine (19),and hallacridone (2) all occur in the same extract of Rut" grciueolens tissue cultures * a biosynthetic relationship may exist between them as shown in Scheme 4.Although grav- acridondiol (18) has not been detected in these particular * The position of the methoxy group was established by the comparison of chemical shift values of CHO, NCH,, and OH signals of compound (15) with those of dimethoxy- and dihydroxy-formyl acridones (14) and (16) (see Experimental section).J. CHEM. SOC. PERKIN TRANS. I 1989 OH OHT"CO, HYH (16) (18) Scheme 4. Possible biosynthetic relationship between hallacridone (2) and some furoacridones isolated from roots and tissue cultures of Ruto gm1~c~oI.rl.sL extracts of tissue cultures,, it has been previously isolated from another extract of Ruta gruveolens tissue culture.16 Experimental General Procedures.-M.p.s were determined on a Kofler hot- stage apparatus and are uncorrected. 1.r. spectra were recorded for KBr discs with a Pye Unicam SP 3-200 spectrophotometer. 'H N.m.r. spectra were recorded in CDCl, at 60 MHz or 300 MHz with SiMe, as internal reference on a Varian 60 A or Bruker WM 300 spectrometer. Mass spectra were obtained on a Varian MAT 44s instrument at 70 eV.Silica-gel 60 F254 (pre-coated aluminium sheets; 0.2 mm thickness; Merck 5549) were used for analytical t.1.c. whilst for preparative work silica- gel 60 F254 (pre-coated glass plates 2 mm thickness; Merck 5717 and 0.25 mm thickness; Merck 5715) were employed. Light petroleum had b.p. 30-40 "C. Bromomethacrylic acid was obtained from Aldrich Chemical Co. Ethyl Bromomethctc~r~~late.-Bromomethacrylicacid was esterified with ethanol in the presence of Me,SiCl at 50 OC,18 to yield ethyl bromomethacrylate as a colourless liquid; 6(60 MHz) 6.26, 5.90 (1 H each, br s, =CH,), 4.25 (2 H, q, J 7 Hz, OCH,Me), 4.18 (2 H, s, BrCH,), and 1.33 (3 H, t, J 7 Hz, CH,Me).Prc./luration of Ethyl 2-( 1'-Hydroxy-1Of-methyl-9'-o.uo-9', 10'- ~[ih},duoac.ri~in-3'-?..k,.icllnzerh/lllpropenoute(4).-Ethyl bromo-methacrylate (0.75 g) and anhydrous K,CO, (1.3 g) were added to a solution of 1,3-dihydroxy- lO-methylacridin-9( 10H)-one (3) (0.625 g) in dry acetone (250 ml) and the mixture was heated under reflux for 2 h. It was then filtered and the solids were washed with dichloromethane. The combined filtrates were evaporated to dryness to give a yellow solid which on recrystallisation from CHC1,-MeOH yielded (4) as yellow needles (0.670 g, 7373, m.p. 139-140 "C (Found: C, 67.85; H, 5.35; N, 4.0. C20H19N05 requires C, 67.96; H, 5.42; N, 3.96%); v,,,. 3 66&3 250br, 2 980, 1720, 1640, 1 595, 1 550, 1 500, 1470,1410,1400,l 380,l 335,1280,1235,l 175,l 150,1085, 1 030, 980, 920, 830, and 755 cm-'; 6(60 MHz) 14.76 (1 H, s, OH),8.35(1 H,dd,J8and2Hz,8-H),7.83-7.06(3H,m,ArH), 6.46 (1 H, br s, =CH), 6.25 (2 H, br s, 2-and 4-H), 6.05 (1 H, br s, ZH), 4.81 (2 H, br s, OCH,), 4.31 (2 H, q, J7 Hz), 3.73 (3 H, s, NMe), and 1.36 (3 H, t, J 7 Hz, OCH2Me); nijz 353 (M', 11"/;1), 308 (6), 280 (loo), 254 (8), 212 (39), 197 (8), 184 (6), 169 (6), 154 (8), 140 (6), 128 (5), 115 (6), and 85 (6).Conversion of the Acridone (4) into the 3-Methylpyrano-acridone (l).-The acridone (4) (0.080 g) was heated with polyethylene glycol (PEG 200) (15 ml) at 220 "C for 0.5 h with ~tirring.~The reaction mixture was poured into cold water and extracted with ether.The extract was washed with brine, dried (Na,SO,), and evaporated to dryness. Purification of the product by column chomatography on silica gel under medium pressure (eluant: 2% MeOH in CH,CI,) and recrystallisation from toluene yielded (1) (0.038 g, 55%) as golden yellow needles, m.p. 328 "C (decomp.) (Found: C, 69.9; H, 4.3; N, 4.5. C18H13N04 3 620- requires C, 70.34; H, 4.26; N, 4.56%); vmaX, 3 300,l 720,l 625,l 605,l 565,1495,1460,l 335,l 305,l 270, 1220, 1 170, 1 150, 1 105, 1065, 1040, 922, 912, 820, 770, 760, 748, and 700 cm-'; 6(300 MHz) 15.8 1 (1 H, s, OH), 8.50 (1 H, dd, J 1.8 and 7.8 Hz, 8-H), 7.97 (1 H, br s, 1-H), 7.81 (1 H, ddd, J8.7, 6.9, and 1.8 Hz, 10-H),7.57 (1 H, br d, J8.8 Hz, 11-H), 7.38 (1 H, br t, J 7.8 Hz, 9-H), 6.73 (1 H, s, 5-H), 3.85 (3 H, s, NMe), and 2.19 (3 H, d, J 1.4 Hz, 2-Me); mjz 307 (M', loo%), 279 (61), 264 (40), 250 (18), 236 (lo), 222 (16), 208 (6), 179 (lo), 154 (14), 140 (15), 126 (16), 112 (8), 104 (8), 89 (13), and 77 (30).Iodination of the Acridone (4).-The acridone (4) (0.502 g) in ethanol (75 ml) was iodinated with a solution of iodine (0.305 g) and periodic acid (0.060 g) in 85% ethanol (40 ml) at room temperature for 2 h. A solid separated and this was collected, washed with water, dried at the pump, and recrystallised from chloroform-methanol to give the iodoacridone (6) as pale yellow needles (0.610 g, 90%), m.p. 195-196 "C (Found: C, 50.15; H, 3.8; I, 26.5; N, 2.95. C,,H1,INO5 requires C, 50.10; H, 3.78; I, 26.49; N, 2.92%);vmaX.3 660-3 640, 3 000, 2 940, 1 720, 1 635,l 595,l 550,1480,1440,l 390,l 310,1272,l 240,l 180, 1 110,1090,1028,940,810,780,760,710, and 660 crn-'; 6(300 MHz), 15.90 (1 H, s, OH), 8.37 (1 H, dd, J 8 and 1.6 Hz, 8-H), 7.73 (1 H, ddd, J8.6,7.4, and 1.6 Hz, 6-H), 7.52 (1 H, br d, J8.6, 5-H), 7.27 (1 H, br t, J7.4,7-H), 6.52,6.41 (1 H each, br s,=CH,), 6.27 (1 H, S, 4-H), 4.91 (2 H, S, OCH,), 4.32 (2 H, 9, J 7 Hz, OCH,Me), 3.83 (3 H, s, NMe), and 1.38 (3 H, t, J 7 Hz, OCH2Me); m/z 479 (M+, 32%), 434 (4), 406 (lo), 380 (lo), 367 (20), 352 (74), 338 (lo), 324 (43), 306 (41), 279 (loo), 250 (30), 21 1 (30), 183 (49), 171 (74), 163 (46), 154 (30), 140 (24), 128 (47), 102 (13), and 77 (43).Claisen Rearrangement of the Iodoacridone (@.-The iodoacridone derivative (6) (0.50 g) dissolved in pyridine (5 ml) was treated with acetic anhydride (2 ml) at 100 "C for 3 h.The solid, obtained on removal of solvents under reduced pressure, was chromatographed on silica (eluant: 1% MeOH in CH,Cl,) to yield the rearranged diacetoxyacridones (7) as a crystalline yellow solid (0.040 g, 7%) and (8) as pale green-yellow crystals (0.148 g, 32%). Ethyl 2-( 1',3'-O-diacety1-2'-iodo-9'-0~0-9',10'-dihydro-acridin-4'-ylmethyI)propenoate(7). M.p. 144-145 "C (Found: M+,563.0438.C,,H,,INO, requires M, 563.0439);v,,,. 2 940, 1 780,l 720,l 635,l 610,l 570,1490,l 365,l 255,l 185,1095, 725,860,760, and 700 cm-'; 6 (60 MHz) 8.23 (1 H, dd, J 8 and 2 Hz, 8-H), 7.83-7.03 (3 H, m, ArH), 6.33,5.46 (1 H each, br s, =CH,), 4.30 (2 H, q, J7 Hz, OCH,Me), 3.83 (2 H, br s, ArCH,), 3.73 (3 H, s,NMe), 2.56, 2.33 (3 H each, s, 2 x OCOMe), and 1.33 (3 H, t, J 7 Hz, CH,Me); m/z 563 (M', 12%), 521 (loo), 479 (57), 434 (22), 406 (44), 378 (26), 366 (22), 352 (36), 324 (40), 278 (52), 250 (48), 235 (20), 222 (23), 196 (28), 167 (28), 152 (25), 140 (25), 127 (30), and 77 (78).Ethyl 2-( 1',3'-diacetoxy-9'-0~0-9,1O-dihydroacridin-4'-ylmethy1)propenoate (8). M.p. 128-1 30 "C (Found: C, 65.75; H, 5.4; N, 3.25. C,,H,,NO,, requires C, 65.88; H, 5.30; N, 3.20%); vmaX.3 000, 2 940, 1 765, 1 700, 1 640, 1 610, 1 505, 1 495, 1 400, 1 370, 1 280, 1 200, 1 170, 1 150, 1 095, 1 020,950, 935, 880, 780, 770, and 690 cm-'; 6(300 MHz) 8.28 (1 H, dd, J 7.9 and 1.6 Hz, 8-H), 7.67 (1 H, ddd, J 8.5, 7.0, and 1.6 Hz, 6-H), 7.37 (1 H, br d, J 8.3 Hz, 5-H),6.81 (1 H, s, 2-H), 6.36, 5.49 (1 H each, br s, =CH,), 4.30 (2 H, q, J 7 Hz, OCH,Me), 3.82 (2 H, br s, ArCH,), 3.74 (3 H, s, NMe), 2.49, 2.25 (3 H each, s, 2 x OCOMe), and 1.35 (3 H, t, J 7 Hz, OCH,Me); m/z 437 (M', 16%), 395 (loo), 352 (43, 336 (36), 322 (16), 308 (24), 280 (68), 264 (16), 252 (45), 240 (18), 228 (13), 198 (lo), 149 (8), 127 (6), and 77 (14).Preparation of 241',3'-Dihydroxy-9'-0~0-9',10'-dihydro-acridin-4'-ylmethyl)propenoic Acid (9).-Anhydrous K2C03 (20 mg) was added to a solution of the diacetoxyacridone (8) (30 mg) in methanol (5 ml) and the mixture was heated under reflux for 15min. The mixture was then evaporated, diluted with water, acidified with dilute HC1, and extracted with ethyl acetate.The extract was washed with water, dried, and evaporated and the residue was crystallised from methanol- chloroform to give the dihydroxyacridone (9) as fine yellow needles (0.017 g, 7773, m.p. 215-217 "C (Found: M+, 325.096. C,,H, 5N05 requires M, 325.095; v,,,. 3 700-3 200, 2 940, 1 680,l 625,l 600,l 575,l 515,1405,l 390,l 260,l 220,l 210, 1 155,l 130,l 095,825,800,760, and 710 cm-'; 6(60 MHz) 8.26 (1 H,dd, J8and 2 Hz, 8-H),7.83-7.10(3 H,m,ArH),6.40(1 H, br s, =CH), 6.30 (1 H, s, 2-H), 5.56 (1 H, br s, SH), and 3.81 (5 H, br s, ArCH, and NMe); m/z 325 (M', loo), 307 (88), 280 (90), 254 (60), 240 (20), 227 (ll), 212 (12), 198 (17), 184 (8), 154 (13), I39 (1 l), 125 (9), 104 (lo), and 77 (25).Conuersionofthe Dihydroxy Acid (9) into the 3-Methylpyrano- acridone (l).-The dihydroxyacridone (9) (0.015 g) suspended in PEG 200 (5 ml) was heated at 220 "C for 15min. The solution was then poured into water and extracted with ether. The ether J. CHEM. SOC. PERKIN TRANS. I 1989 layer was washed with brine, dried, and evaporated and the crude product was subjected to preparative t.1.c. and recrystal- lisation from chloroform to yield (1) as yellow needles (0.010 g, 71%), m.p. 328 "C (decomp.). M.p., mixed m.p., i.r., 'H n.m.r., ms.,and t.1.c. were identical with those recorded for the compound synthesized previously by heating the compound (4) in PEG 200 (see above). Preparation of the Diphenylamine (12).'9-o-Chlorobenzoic acid (5.0 g) and 3,5-dimethoxyaniline (6.5 g) were condensed in the presence of anhydrous K,CO, (6.0 g) and Cu powder (0.70 g) in dry DMF at 80 "C for 6.5 h. Work-up ' gave (12) as a pale green solid which on recrystallisation from ethanol-water gave pale green needles (3.64 g, 42%), m.p. 157-158 "C (lit.," 147 "C). Conversion of the Diphenylamine (12) into 4-Formyl-1,3- dimethoxyacridin-9( 10H)-one (13).-The diphenylamine (12) (1.3 g) was slowly added (45 min at room temperature) to a well stirred mixture of dry DMF (2 ml) and POCl, (1 ml), and stirring was continued for a further 1.5h.7 The dark red viscous liquid was diluted with ice, and 2~ NaOH solution (20 ml) was added.,' The solution was boiled for 0.5 h and filtered.The precipitate was washed with water, dried at the pump, and recrystallized from methanol to give the formyldimethoxy- acridone (13) as off-white needles (0.205 g, 15%), m.p. 258-260 "C (Found: C, 67.7; H, 4.75; N, 5.0. C,,H,,NO, requires C, 67.82; H, 4.62; N, 4.94%); v,,,. 3 62&3 320, 3 120, 2 960, 1 640,l 620,l 600,l 570,l 532,l 470,1440,1412,l 398,l 370, 1320, 1245, 1212, 1 150, 1 130, 990, 940, 925, 795, 778, 768, 735, and 705 cm-'; 6(60 MHz) 12.83 (1 H, br s, NH), 10.13 (1 H, s, CHO), 8.13 (1 H, dd, J 8 and 2 Hz, 8-H), 7.86-7.10 (3 H, m, ArH), 6.13 (1 H, s, 2-H), and 4.12 and 4.07 (3 H each, s, 2 x OMe); m/z 283 (M+,1000/,), 266 (14), 254 (58), 237 (9), 224 (12), 211 (lo), 196 (ll), 183 (6), 167 (6), 154 (6), 140 (6), 126 (7), 113 (5), 91 (3), 77 (ll), and 63 (7).Methylation of Compound (13).*-Silver(1) oxide (1.0 g) and iodomethane (1 ml) were added to a well stirred solution of compound (13) (0.148 g) in dry DMF (20 ml) and stirring was continued for 16 h at room temperature. The reaction mixture was diluted with CHCl, (200 ml), filtered, and the solids were washed with CHCl, (50 ml). The combined organic solutions were washed with water, dried, and evaporated to dryness to give a 4-formyl- 1,3-dimethoxy- 10-methylacridin-9( 1OH)-one (14) which on recrystallisation from methanol yielded pale yellow needles (0.1 18 g, 76%), m.p. 218-219 "C (Found: C, 68.75; H, 5.15; N, 4.8%; M, 297.0997. C,,H,,NO, requires C, 68.66; H, 5.09; N, 4.71%; M, 297.1001);v,,,.2 900, 1 670, 1 620, 1 600,l 570,l 495,1470,l 380,l 370,l 300,1225,l 200,l 190, 1 135,l 120,l 060,1010,870,795,770,750,735, and 710 cm-'; 6(300 MHz) 10.34 (1 H, s, CHO), 8.40 (1 H, dd, J7.9 and 1.6 Hz, 8-H),7.68(1H,ddd,J8.6,7.0,and1.6Hz,6-H),7.48(1H,brd,J 8.4 Hz, 5-H),7.32 (1 H, ddd, J7.9,7.0 and 0.7 Hz, 7-H), 6.29 (1 H, s, 2-H),4.12,4.07 (3 H each, s 2 x OMe), and 3.65 (3 H, s, NMe); m/z 297 (M', loo%), 280 (22), 268 (78), 250 (32), 236 (20), 225 (14), 208 (lo), 196 (13), 180 (7), 167 (13), 154 (lo), 139 (13), 127 (17), 119 (22), 104 (14), 89 (17), 77 (53), and 63 (27). Conversion of Compound (14) into the Monomethoxyacridone (15).'-BCl, (0.1 ml) was added to a solution of the formyl- dimethoxyacridone (0.020 g) dissolved in CH,Cl, and cooled to -lO°C, and the resulting mixture was stirred at room temperature for 15 min.It was then diluted with CH,CI,, washed with water, dried, and evaporated and the resulting product recrystallised from MeOH to yield the monomethoxy- acridone (15) as golden yellow needles (0.017 g, 89%), m.p. 229-230 "C (Found: M+, 283.0845. C,,H13N0, requires M, J. CHEM. SOC. PERKIN TRANS. 1 1989 283.0845);v,,,. 3 600-3 160br,2 940,2 885,l 650,l 620, 1 590, 1 550,1470,1455,l 395,l 320,l 240,1205,l 170,l 125,l 100, 1 065,1040,965,955,895,815,790,770,745,725,and 700 cm-'; 6(300 MHz) 16.05 (1 H, s, OH), 10.31 (1 H, s, CHO), 8.42 (1 H, dd, J 8 and 1.3 Hz, 8-H), 7.81 (1 H, ddd, J 8.6, 7.3, and 1.3 Hz, 6-H), 7.62 (1 H, br d, J 8.6 Hz, 5-H),7.42 (1 H, br t, J 7.6 Hz, 7-H), 6.30 (1 H, s, 2-H), 4.03 (3 H, s, OMe), and 3.73 (3 H, s, NCH,); m/z 383 (M', 28%), 266 (40), 251 (lo), 234 (7), 11 1 (24), 83 (loo), 77 (lo), and 55 (70).0-Demethylation of Compound (14) to produce the Dihydroxyucridone (16).-A solution of 4-formyl-N-methyl- acridone (14) (0.038 g) in dry CH,Cl, was treated with BC1, (0.5 ml) at -10°C as above and stirred for 72 h at room temperature. The reaction mixture was diluted with CH,Cl, washed with water, dried, and evaporated to dryness, and the residue purified by preparative t.1.c. (eluant: 5% toluene in CHCI,, two developments) to yield essentially pure 4-formyl- 1,3-dihydroxy- lO-methylacridin-9( 10H)-one (16) as an off-white solid (0.022 g, 64%), m.p.228-230°C (Found: M+, 269.0686. C, 5H1lNO, requires M, 269.0688); vmax.3 600-3 360br, 3 320, 2 920, 1625, 1620, 1600, 1555, 1390, 1370, 1280, 1250, 1190, 1135, 1095, 1065, 1045, 1025, 820, 810, 805,770, and 705 cm-I; 6(300 MHz) 15.64 (1 H, s, OH), 13.13 (1 H, s, OH), 10.01 (1 H, s, CHO), 8.46 (1 H, dd, J8 and 1.5 Hz, 8-H), 7.85 (1 H, ddd, J8.6, 7.4, and 1.5 Hz, 6-H), 7.57 (1 H, br d, J 8.6Hz, 5-H), 7.48 (1 H, br t, J7.8 Hz, 7-H),6.22(1H,s,2-H),and 4.1 1 (3 H, s, NMe); m/z 269 (M+,18"/,), 252 (22), 234 (7), 209 (6), 149 (8), 125 (12), 111 (24), 105 (32), 97 (64), 83 (66), 77 (36), 71 (74), 69 (loo), and 67 (48). Conversion of the Formyfdihydroxymethyfacridone(16) into Huffucridone (2).-Anhydrous K,CO, (0.035 g) and chloro- acetone (0.2 ml) were added to a solution of the formyldi- hydroxymethylacridone (16) (0.020 g) dissolved in dry acetone (10 ml) and the mixture was heated under reflux for 2 h." The reaction mixture was filtered, the solids were washed with CHCI,, and the combined organic solutions were evaporated.Subsequent purification of the residue by preparative t.1.c. (eluant: 1% MeOH in CH,Cl,, two developments) yielded hallacridone (2) (0.01 1 g, 50"/,),which on recrystallisation from CHC13 gave yellow needles, m.p. 295-297 OC (lit.,, 295-298 "C),indistinguishable (by m.p., mixed m.p., i.r., 'H n.m.r., m.s., and t.1.c.) from an authentic sample of hallacridone (Found: M', 307.0847. C, ,H13N04 requires M, 307.0845); vmax,3 700-3 200,2 960,l 670,l 625,l 600,l 580,l 548,1490, 1460,l 450,l 365,l 340,l 300,l 270,l 240,1200,l 140,1095, 1085, 1 040,950,930, 810, 790, 760, 695, and 650 cm-'.Acknowledgements We thank Professor Dr. D. Groger (Institute of Plant Biochemistry, Academy of Sciences of the G.D.R., G.D.R.) for an authentic sample of hallacridone and copies of its 'H n.m.r. and i.r. spectra; Mr. D. Kaiser and Mrs. K. Busse (Organic Chemistry Institute, University of Munster) for technical assistance in obtaining n.0.e. difference spectra; Mrs. K. Rausse for typing the manuscript; 'Deutsche Forschungsgemeinschaft' for financial assistance; and the Heinrich Hertz foundation for the award of a fellowship to G. M. K. B. G. References 1 Part 123, J. Reisch and W.Probst, Arch. Pharm. (Weinheim, Ger.), 1989, 322, 31. 2 A. Baumert, D. Groger, J. Schmidt, and C. Mugge, Pharmazie, 1987, 42, 67; A. Baumert, D. Groger, J. Schmidt, I. N. Kuzovkina, and C. 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