Reaction of noracronycine and 1-hydroxy-3-methoxy-10-methylacridone with alkyl- and aryl-lithiums: formation of quinone methides

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1995 51 1 Reaction of Noracronycine and 1-Hydroxy-3-methoxy-lO-methylacridone with Alkyl- and Aryl-lithiums: Formation of Quinone Methides Catherine Jolivet, Christian Rivalle and Emile Bisagni" URA 1387 CNRS, lnstitut Curie, Section de Biologie, Bat 7 7 0, Centre Universitaire, 9 7 405 Orsay, France Alkyl- and aryl-lithiums reacted with noracronycine and 1-hydroxy-3-methoxy-lO-methylacridone in a one-step addition-dehydration transformation to provide the corresponding 7-and 9-substituted derivatives having a quinone methide function and, therefore, potential alkylating antitumour properties. Acronycine 1 (6-methoxy-3,3,12-trimethyI-3,12-dihydro-7H-noracronycine 3 was allowed to react with butyllithium in pyrano2,3-cacridin-7-one), isolated from Acronychia baueri, diethyl ether at room temperature for 1 h and the reaction an Australian scrub ash from the family of Rutacees 'is a broad mixture then treated with CH,OD, 'H NMR analysis showed spectrum antitumour although its poor solubility in aqueous media has hindered its development as a clinical agent.As a way of solving this problem, various water-soluble acronycine analogues have been prepared of which only 0-dimethylaminoethyl noracronycine 2,4 displayed good antitu- mour activity. This compound is cytotoxic against some multi drug resistant (MDR) cells as is acronycine 1 itself. Through our continuing interest in the search for new antiturnour drugs with improved biological properties and bioavailability, we have synthesized new derivatives of 1 although structural modifications to the model compound were limited by the need to retain antitumour activity and by the numerous analogues and derivatives already ~repared.~-~ Our approach was to substitute the acronycine ring system with hydrophilic side-chains. Here we describe our studies of the reactivity of acronycine 1, noracronycine 3 and the tricyclic model compounds 4, 5 (Scheme 1) in the presence of alkyl-, aryl-, aminoalkyl- and aminoaryl-lithium derivatives.0 OR 0 OR Me 2 1 R=Me 4 R=H 2 R = CH2CH2NMe2 5 R=Me 3 R=H Scheme 1 Results and Discussion We thought that introduction of the hydrophilic aminoalkyl or N-aminoalkylcarboxamido substituents 'could be achieved via the corresponding formyl- or carboxy-substituted compounds.Since the two ortho-directing ether groups in 1were likely to lead to lithiation at the 5-position we attempted such a reaction with lithium diisopropylamide (LDA). 'H NMR monitoring of CH,OD-quenched samples showed the absence of lithiation between -78 and -20 "C. We then attempted hydrogen- deuterium exchange using tert-butyl-, butyl- and methyl-lithium in various solvents (tetrahydrofuran or diethyl ether) at different temperatures (-78, -20 and 0 OC, reflux) and with crown ether 12C4 or tetramethylethylenediamine (TMEDA). Our results with acronycine 1, even in the presence of TMEDA (for decomplexation of alkyllithium reagent), show that, as reported for acridone,6 there is no exchange with alkyllithium reagents.For acronycine 1 this may be explicable in terms of steric hindrance near the position 5. Thus, when the appearance of new signals in the 1-2 and 7-8.5 ppm regions, a 0.4 ppm shielding for the 5-H signal (without decrease of its intensity), a 0.2 ppm shielding for I-H and 2-H, and the disappearance of the 6-OH peak. Further, thin layer chromatography showed the presence of a new product, characterized by a blue colour, the mass spectrum (CI, isobutane) of which had a peak at mi2 348 (M + 1) corresponding to butyllithium addition and subsequent dehydration. 'H NMR spectral analysis together with an elemental analysis supported identification of the product as compound 6. Addition of butyllithium to the 7-carbonyl group followed by dehydration (see Scheme 2) accounts for the observed Li RO HO 6 R=Bu 11 7 R=Me 8 R=Ph 9 R = C6H4NMe2-4 10 R = CH2CH,CH,NM+ Scheme 2 transformation.This mechanism is in agreement with those involved in the reduction of quinizarin by an excess of sodium borohydride to give 1,4-anthraquinone.* Reactivity differences observed for the carbonyl groups of acronycine 1 and noracronycine 3 may be explained in terms of activation of this group by the lithium atom bound to the oxygen atom in theperi position. Attempted verification of this failed, since there was no reaction when the tricyclic model compound 5 was treated under similar conditions in the presence of LiClO,, a Lewis acid carbonyl-activating com-pound.' The blue colour of compound 6 (and analogues) may result from conjugation similar to that found in azulenes; thus comparison of the UV spectra of noracronycine 3 (410 cm-') and compound 6 (614 cm ') is characterized by a blue shift.Extending our work to the functionalization of the 7-position, we allowed noracronycine 3 to react with methyl-, phenyl-, p-dimethylaminophenyl- and 3-dimethylaminopropyl- lithium to give the corresponding compounds 7-10. Methyl-lithium gave the by-product 11 in addition to the expected condensation product 7, a compound also prepared in low yield by lithium aluminium hydride reduction of noracronycine 3. Formation of 11 with the methyllithium reaction probably resulted from a reduction involving an unknown source of hydrogen. The addition of organolithium reagents to other carbonyl compounds having a peri hydroxy group was extended by treating the tricyclic compound 4 with butyl-, p-dimethylaminophenyl-and 3-dimethylaminopropyllithium (Scheme 3) to give compounds 12, 13, 14, respectively.0 OH RO / r 0. OMe RLi /~amp;-' OMeY Me file 4 12 R = CsH4NMe2-4 13 R=Bu 14 R = CH2CH2CH2NMe2 Scheme 3 In order to optimize yields (61-68) in this work, 3 equiv. at least of the organolithium reagents were required: it was also possible to use 1 equiv. of methyllithium and 2 equiv. of another alkyl- or aryl-lithium derivative. To demonstrate the reactivity of the quinone methides prepared, 13 was treated with a nucleophile (methyllithium) and a reducing agent (lithium aluminium hydride) to give compounds 15 and 16 respectively (Scheme 4); this probably resulted from a 1,4-15 and a 1,2-addition followed by a tautomerization 16, respectively.Bu 0 OMe OMe Me the 13 15 R=Me 16 R=H Scheme 4 Experimental Melting points were measured with an Electrothermal appar- atus using capillary tubes and are uncorrected and with a Reichert microscope for compounds 6, 7, 8, 11. 'H NMR spectra were obtained in CDCl, or C2H,-DMS0 using an AC- 200MHz Bruker spectrometer. Chemical shifts are reported in ppm. relative to deuteriated solvent as internal standard and all J. CHEM. SOC. PERKIN TRANS. I 1995 coupling constants (J) are given in Hz. UV spectra were obtained on a Varian DMS 200 spectrophotometer. The mass spectra were recorded on AEI.MS-50 (MS-EI) or AE1.MS-9 (MS-CI) spectrometers and, as for the elemental analyses, they were performed in ICSN/CNRS, Gif sur Yvette, France.Acronycine 1.-This compound, prepared by a literature ' synthesis, was recrystallized from ethanol to give yellow needles, mp 173-175 "C (lit.," 175-176 "(2); 6,(2H6-DMSO) 8.13(1 H,dd1J8and1.5,8-H),7.77(1H1td,J8and1.5,9-H), 7.60(1 H,dd, J8and 1.5, 11-H),7.31 (I H, td, J8and 1.5, 10- H), 6.75 (1 H, d, J9.7, 1-H), 6.43 (I H, S, 5-H), 5.67 (1 H, d, J 9.7,2-H), 3.88 (3 H, s, NMe), 3.86 (3 H, s, OMe) and 1.55 (6 H, s, 3-Me2). Noracronycine 3.-This compound, prepared by a litera-ture l' synthesis, recrystallized from ethyl acetate as yellow needles, mp 201-203 "C (lit.," 20amp;201 "C); amp;,,,,(EtOH)/nm 410 (4290), 285 (38 700) and 256 (23 100); dH(2H6-DMSO) 14.95(1 H,s,6-OH),8.27(1 H,dd, J8and 1.4,8-H),7.91 (1 H, td,J8and1.4,9-H),7.75(1H,dd,J8and1.4,ll-H),7.43(1H, td, J8 and 1.4, 10-H),6.80 (1 H, d, J9.7, I-H), 6.20 (1 H, s, 5-H), 5.66 (1 H, d, J9.7,2-H), 3.96 (3 H, s, NMe) and 1.53 (6 H, s, 3- Me 2).1-Hydroxy-3-methoxy-10-methylacridone 4.-To a solution of 1,3-dihydroxy-lO-methylacridonelo (2.95 g, 12.2 mmol) in acetone (122 cm3), potassium carbonate (1.85 g, 13.4 mmol) and iodomethane (0.84 cm3, 13.5 mmol) were added. The mixture was stirred at reflux for 15 h, cooled, filtered and evaporated under reduced pressure. The crude oil was extracted with methylene dichloride and the extract washed with 1 mol dm-3 aqueous sodium hydroxide, brine and water, dried (MgSO,) and concentrated. The residue was recrystallized from ethyl acetate to give the pure product 4 (2.4 g, 77) as yellow needles, mp 164165deg;C (Found: C, 70.3; H, 5.3; N, 5.6; 0, 18.8.C,,H,,NO, requires C, 70.6; H, 5.1; N, 5.5; 0, 18.8); A,,,(EtOH)/nm 391 (3540), 271 (28900) and 263 (25700); GH(CDC13)8.44 (1 H, dd, J 8 and 1.6,8-H), 7.69 (1 H, td, J 8 and 1.6, 6-H), 7.46 (1 H, dd, J8 and 1.6, 5-H), 7.27 (1 H, td, J8 and 1.6, 7-H), 6.29 (2 H, s, 2-H and 4-H), 3.88 (3 H, s, OMe) and 3.77 (3 H, s, NMe); d,2H6-DMS0 14.90 (1 H, s, I-OH). 1,3-Dimethoxy-10-methylacridone 5.-Under argon, sodium hydride (352 mg, 8.8 mmol) was added to a solution of 1,3- dihydroxy- 10-methylacridone (513 mg, 2.2 mmol) in dried N,N-dimethylformamide (8 cm3).After 15 min, dimethyl sulfate (1.3 cm3, 13.2 mmol) was added to the mixture which was then stirred for 15 h. After this it was poured onto water and extracted with methylene dichloride and the extract dried (MgSO,) and evaporated to dryness under reduced pressure. Chromatography of the residue on a silica gel column, eluting with a heptane-ethyl acetate gradient (1 :1 to 1 :4), gave the pure title product 5 (254 mg, 42) as yellow crystals, mp 167- 168 "C (lit.," 163-165 "C); 6,(CDCl3) 8.46 (1 H, dd, J 8 and 1.6,8-H), 7.63 (1 H, td, J8 and 1.6,6-H), 7.41 (1 H, dd, J8 and 1.6, 5-H), 7.24 (1 H, td, J 8 and 1.6, 7-H), 6.44 (1 H, d, J 1.8, 4-H), 6.29 (1 H, d, J 1.8, 2-H), 3.99 (3 H, s, OMe), 3.95 (3 H, s, 0Me)and 3.81 (3 H, s,NMe).7-Butyl-3,3,12-trimethyl-3,12-dihydro-6H-pyrano2,3-c-acridin-6-one 6.-To a solution of noracronycine 3 (311 mg, 1.01mmol) in dry diethyl ether (50 cm3) was added butyllithium (1.6 mol dm-3 solution in hexane; 3.1 cm3, 4.96 mmol) under argon. After 1 h at room temperature, the mixture was poured onto ice-water (100 cm3) and extracted with methylene dichloride. The extract was washed with water, dried (MgSO,) and evaporated on a rotatory evaporator. The residue was chromatographed on a silica gel column with heptane-ethyl J. CHEM. SOC. PERKIN TRANS. I 1995 acetate (1 :2) as eluent. Evaporation of the solvent and trituration of the residue with hexane provided 6 (1 79 mg, 50) as an amorphous solid, mp 153-161 "C (Found: C, 79.3; H, 7.2; N, 3.95; 0,9.55.C23H25N02 requires C, 79.5; H, 7.25; N, 4.05; 0, 9.2); i,,,(EtOH)/nm 614 (3690) and 315 (36 800); G,(CDCl,) 8.41 (1 H, dd, J8 and 1.3,8-H), 8.05 (1 H, td, J8 and 1.3, 10-H), 7.92 (1 H, dd, J8 and 1.3, 11-H), 7.76 (I H, s, 5-H), 7.69 (1 H, td, J8 and 1.3, 9-H), 6.57 (1 H, d, J9.8, 1-H), 5.61 (I H, d, J 9.8, 2-H), 4.32 (3 H, s, NMe), 3.92 (2 H, m, a-CH,), 1.90-1.62 (4 H, m, P,y-CH2), 1.56 (6 H, s, 3-Me,) and 0.99 (3 H, t, J 6.8, Me); mlz 348 (MH'). 3,3,7,12-Tetrumethyl-3,12-dihydro-6H-pyrano2,3-c acridin- 6-one 7.-Under argon, methyllithium (1.6 mol dm-3 solution in diethyl ether; 3.1 cm3, 5 mmol) was added to a solution of noracronycine 3 (308 mg, 1 mmol) in dry diethyl ether (50 cm3). The mixture was refluxed for 2 h after which the cooled solution was poured onto ice-water (100 cm3).The resulting blue aqueous layer was quickly separated and extracted with methylene dichloride. The combined ether layer and extract were washed with water, dried (MgSOJ and evaporated under reduced pressure. Chromatography of the residue on a silica gel column with methylene dichloride and then methylene dichloride -ethanol (96 :4) as eluent gave, after precipitation in hexane, the expected compound 7 (210 mg, 69) as a blue amorphous solid, mp 134143 "C (Found: C, 77.5; H, 6.6; N, 4.25; 0,1 1.65. C20H1 9N02-0.25H20 requires C, 77.55; H, 6.35; N, 4.5; 0,11.6); ;I,,,(EtOH)/nm 612 (3510), 316 (28 500) and 240 (1 5 300);dH(cDc13) 8.09 (1 H, dd, J 8.3 and 1.2,8-H), 7.66 (1 H, td, J8.3and 1.2, 10-H),7.41 (1 H,dd, J8.3and 1.2,11-H), 7.31 (1 H, td, J8.3 and 1.2, 9-H), 6.40 (1 H, d, J9.9, 1-H), 6.05 (1 H, s, 5-H), 5.55 (1 H, d, J9.9,2-H), 3.90(3 H, s, NMe), 3.20 (3 H, s, 7-Me) and 1.48 (6 H, s, 3-Me2); m/z 306 (MH').Continuing elution gave the by-product 11 (11 mg, 4) described below. 3,3,12-Trimethyl-7-phenyl-3,12-dihydro-6H-pyruno2,3-c-acridin-6-one 8.-To a solution of noracronycine 3 (310 mg, 1.01 mmol) dissolved in dry diethyl ether (50 cm3), phenyllithium (2 rnol dm-3 solution in cyclohexane-diethyl ether; 2.5 cm3, 5 mmol) was added. After 1.5 h at reflux, the cooled mixture was poured onto ice-water (100 cm3) and extracted with diethyl ether.After work-up, the crude product was crystallized from hexane to give 8 (3 16 mg, 75) as a blue amorphous solid, mp 214-221 "C (Found: C, 81.45; H, 6.2; N, 3.45; 0,8.9. C25H21N02 requires C, 81.75; H, 5.75; N, 3.8; 0, 8.7); /?,,,(EtOH)/nm 632 (3940), 317 (32 000) and 309 (28 400); GH(CDC13) 7.64 (1 H, td, J 1.5 and 8.4, 10-H), 7.5amp; 7.05 (8 H, m, Ar-H), 6.49 (1 H, d, J9.8, 1-H), 5.78 (1 H, s, 5-H), 5.61 (1 H, d, J9.8,2-H), 3.99 (3 H, s, NMe) and 1.50 (6 H, s, 3-Me,); mi. 367 (M+, 100) and 352 (73, M -CH,). 4-Dimethyluminophenyllithium.'-To a solution of p-bromo-N,N-dimethylaniline (1 g, 5 mmol) in dry diethyl ether (30 cm3), lithium cut into pieces (1.52 g, 220 mmol) was added under argon.Gentle heating was necessary to start the reaction after which the remaining p-bromo-N,N-dimethylaniline (22.5 g. 1 13 mmol) dissolved in dry diethyl ether (50 cm3) was added dropwise so that a gentle reflux was maintained. After 5 h at reflux, the mixture was cooled and kept under argon in the reaction flask. Titration of the solutionI2 showed that its concentration was 0.9 mol dm-3. 7-(4- Dimethyluminophenyl)- 3,3,12-trimethy1-3,12-dihydro-6H-pyruno2,3-cucridin-6-one9.-To a solution of noracrony- cine 3 (321 mg, 1.04 mmol) in dry diethyl ether (50 cm3), 4- dimethylaminophenyllithium (0.9 mol dm-3 solution in diethyl ether; 3.5 cm3, 3.15 mmol) was added. The mixture was stirred 513 at reflux for 2 h and then poured onto ice-water (100 cm3).The aqueous layer was quickly separated and extracted with diethyl ether. The combined ether layer and extract were washed with water, dried (MgS04) and then evaporated under reduced pressure to give 9 which crystallized from diethyl ether as blue crystals (345 mg, 7573, mp 255 "C (Found: C, 79.0; H, 6.55; N, 6.7; 0,7.75. C27H26N202 requires C, 79.0; H, 6.4; N, 6.8; 0, 7.8); amp;,,,(EtOH)/nm 622 (4320), 317 (37600) and 309 (33 800); GH(CDC13) 7.65 (1 H, td, J 8.3 and 1.3, 10-H), 7.50 (1 H, dd, J8.3 and 1.3, 8-H), 7.44 (1 H, dd, J8.3 and 1.3, 11-H), 7.14 (1 H, td, J 8.3 and 1.3, 9-H), 7.05 (2 H, d, J 8.6, 3'-H), 6.80 (2 H, d, J8.6, 2'-H), 6.48 (1 H, d, J9.8, 1-H), 5.98 (1 H, S, 5-H), 5.59 (1 H, d, J9.8, 2-H), 3.99 (3 H, s, NMe), 3.00 (6 H, s, NMe,) and 1.50 (6 H, s, 3-Me2);m/z 410 (M', loo), 409 (91, M -H) and 395 (40, M -CH,).3-Dimethyluminopropyllithium.,-To a mixture of granular lithium (3 g, 0.43 mol) and dry diethyl ether (40 cm3) under argon, freshly distilled 3-dimethylaminopropyl chloride (22 g, 0.15 mol) was added by way of a dropping funnel. After a gentle heating to initiate the reaction, the reagent was added dropwise so that a reflux was maintained. After complete addition, stirring was continued for 1 h. The resulting cooled mixture was used for the reactions described below. 7-(3-Dimethyluminopropy1)-3,3,12-trimethyl-3,12-dihydro-12H-pyruno2,3-cucridin-6-one10.-To a solution of noracro- nycine 3 (1 g, 3.3 mmol) in dry diethyl ether (160 cm3) under argon, the above mentioned solution of 3-dimethylaminoprop- yllithium (20 cm3) was added. The mixture was heated at reflux for 18 h and then poured onto ice-cooled brine. The organic layer was separated and the aqueous solution was extracted with diethyl ether.The combined ether layer and extract were washed with water, dried (MgS04) and evaporated under reduced pressure. The residue was chromatographed on a silica gel column with initially methylene dichloridesthanol (95 :5) as eluent and then finally the same mixture plus triethylamine (91 :4.5 :4.5). After evaporation of the solvent, the residue was taken up in hexane to obtain the expected product 10 (290 mg, 20) as blue crystals, mp 108-109 "C (Found: C, 75.5; H, 8.25; N, 7.4; 0,8.85.C,4H2,N,02~0.3C,H,,0 requires C, 75.9; H, 7.85; N, 7.05; 0, 9.25); A,,,(EtOH)/nm 618 (3740) and 316 (32 700); GH(CDC1,) 8.16 (1 H, dd, J 8.1 and 1.3, 8-H), 7.70 (1 H, td, J8.1 and 1.3, 10-H), 7.42(1 H,dd, J8.1 and 1.3, 11-H), 7.37(1 H, td, J8.1 and 1.3,9-H),6.41 (1 H,d, J9.9, 1-H),5.97(1 H, s, 5-H), 5.58 (1 H, d, J9.9,2-H), 3.91 (3 H, s, NMe), 3.71 (2 H, m, or-CH,), 3.10 (2 H, t, J 7.1, y-CH,), 2.64 (6 H, s, NMe,), 2.13 (2 H, qn, J 7.1, P-CH,) and 1.50 (6 H, s, 3-Me,); m/z 376 (M', 11) and 318 loo, M -CH,=N+(CH,),. 3,3,12-Trimethy1-3,12-dihydro-6H-pyrano2,3-cucridin-6-one 11.-To a solution of noracronycine 3(311 mg, 1.O1 mmol) in dry diethyl ether (50 cm3), lithium aluminium hydride (190 mg, 5 mmol) was added under argon.After being stirred at room temperature for 1 h, the mixture was poured onto ice-water (100 cm3), acidified with 1 mol dm-3 hydrochloric acid and extracted with diethyl ether. The combined ether layer and extract were washed with water, dried (MgSO,) and evaporated under reduced pressure. The crude blue product was purified on a silica gel column with methylene dichloride and then methylene dichloride-ethanol (95 :5) as eluent to provide the expected product 11(27 mg, 9) as blue amorphous solid, mp 208-2 15 "C (Found:C, 78.85; H, 6.3; N, 4.65. C,,HI7NO, requires C, 78.35; H, 5.9; N, 4.8); ;I,,,(EtOH)/nm 619 (4270), 315 (34200), 309 (33 400) and 239 (1 3 600); 6,( C2H6-DMSO) 8.90 (1 H, s, 7-H),8.14(1 H,dd, J8and 1.2,8-H),7.91 (1 H, td, J8and 1.2, 10- H),7.78(1H,dd,J8and1.2,ll-H),7.49(1H,td,J8and1.2,9-H), 6.80 (1 H, d, J9.7, 1-H), 5.68 (1 H, S, 5-H), 5.69 (1 H, d, J 9.7, 2-H), 4.08 (3 H, s, NMe) and 1.52 (6 H, s, 3-Me2);m/z 292 (MH').9-(4-Dimethylaminophenyl)-3-methoxy-1 O-methyl- 1 H-acri- din-I -one 12.-To a solution of 1-hydroxy-3-methoxy-10-methylacridone 4 (1 g, 3.9 mmol) in dry diethyl ether (1 15 cm3), 4-dimethylaminophenyllithium (0.9 mol dm-, solution in diethyl ether; 13cm3, 11.7mmol) was added under argon. After 1 h at reflux, the mixture was poured onto ice-water (300 cm3) and extracted with diethyl ether. The combined ether layer and extract were washed with water, dried (MgSO,) and evaporated to dryness to provide compound 12 which was crystallized from diethyl ether (1.27 g, 90) to give purple crystals, mp 274-275 "C (Found: C, 77.35; H, 6.45; N, 7.8.C,,H,,N,O, requires C, 77.05; H, 6.2; N, 7.8); A,,,(EtOH)/nm 563 (6360), 308 (34 600) and 258 (25 700); G,(CDCI,) 7.61 (1 H, td, J 8.4 and 1.3,6-H), 7.52 (1 H, dd, J8.4 and 1.3, 8-H), 7.46 (1 H, dd, J8.4 and 1.3, 5-H), 7.08 (1 H, td, J8.4 and 1.3, 7-H), 7.04 (2 H, d, J 8.8, 3'-H), 6.83 (2 H, d, J8.8,2'-H), 5.83 (1 H, d, J 1,4-H), 5.67 (1 H, d, J 1, 2-H), 3.80 (3 H, s, NMe), 3.78 (3 H, s, OMe) and 3.00 (6 H, s, NMe,); m/z 358 (M', 52) and 357 (100, M -H). 9-Butyl-3-methoxy- 10-methyl- 1H-acridin-1-one 13.-To a solution of 1-hydroxy-3-methoxy-1O-methylacridone 4 (263 mg, 1.03 mmol) in dry diethyl ether (30 cm3), butyllithium (1.6 mol dm-, solution in hexane; 3.2 cm3, 5.12 mmol) was added under argon and the mixture was stirred at reflux for 1 h.The cooled mixture was then poured onto ice-water (100 cm3) and the aqueous layer, quickly separated and extracted with diethyl ether. The combined ether layer and extract were washed with water, dried (MgSO,) and evaporated under reduced pressure. The residue was chromatographed on a silica gel column with heptane+thyl acetate (1 :4) as eluent. After recrystallization from ethyl acetate, the pure product 13 (200 mg, 66) was obtained as purple crystals, mp 157 "C (Found: C, 77.55; H, 7.05; N, 4.65; 0, 10.75. C,,H,,NO, requires C, 77.25; H, 7.15; N, 4.75; 0, 10.85); A,,,(EtOH)/nm 562 (6460) and 306 (38 800); G,(CDCI,) 8.18 (1 H, dd, J 8.5 and 1.2, 8-H), 7.71 (1 H, td, J8.5and 1.2,6-H),7.52(1H,dd, J8.5and 1.2,5-H),7.34 (1 H, td, J8.5 and 1.2, 7-H), 6.21 (1 H, d, J 1.5,2-H), 5.75 (1 H, d, J 1.5,4-H), 3.85 (3 H, s, OMe), 3.83 (2 H, m, a-CHz), 3.82 (3 H, s, NMe), 1.69 (4 H, m, 0, y-CH,) and 1.03(3 H, t, J 6.9, Me); m/z 295 (M', 46) and 266 (100, M -CH,CH,).9-(3-Dimethylaminoprupyl)-3-methoxy-1O-methyl-1 H-acri-din-1-one 14.-To a solution of 1-hydroxy-3-methoxy-10-methylacridone 4 (1 g, 3.9 mmol) in diethyl ether (1 10 cm3), the above mentioned solution of 3-dimethylaminopropyllithium (20 cm3) was added under argon. After 5 h under reflux, the mixture was poured onto ice-cooled brine. The aqueous layer was extracted with diethyl ether and the combined ether layer and extract were washed with water, dried (MgSO,) and evaporated under reduced pressure.Crystallization of the residue from diethyl ether provided the desired product 14 (3 12 mg, 25) as purple needles, mp 132-133 "C (Found: C, 73.65; H, 7.55; N, 8.75; 0, 10.05. C,,H,,N,O, requires C, 74.05; H, 7.45; N, 8.65; 0, 9.85); A,,,(EtOH)/nm 565 (5670) and 306 (36 700); G,(CDCI,) 8.19 (1 H, dd, J 1.2 and 8.4, 8-H), 7.66 (1 H, td, J 1.2and 8.4,6-H), 7.45 (1 H, dd, J 1.2and 8.4,5-H), 7.29 (1 H, td, J 1.2 and 8.4,7-H), 5.97 (1 H, d, J2.3,2-H), 5.64 (1 H, d, J 2.3, 4-H), 3.84 (2 H, t, J 7.2, a-CH,), 3.83 (3 H, s, NMe), 3.74 (3 H, s, OMe), 2.71 (2 H, t, J 7.2, y-CH,), 2.38 (6 H, s, NMe,) and 1.97 (2 H, qn, J 7.2, P-CH,); m/z 324 (Mf, 7) and 266 loo, M -CH,=N+(CH,),.9-Butyl-1-hydroxy-3-rnethoxy-9,1 O-dimethyl-9,1 O-dihydru- acridine 15.-To a solution of 13 (255 mg, 0.86 mmol) in diethyl ether (20 cm3), methyllithium (1.6 mol dm solution in J. CHEM. SOC. PERKIN TRANS. I 1995 hexane; 4.85 cm3, 7.75 mmol) was added dropwise under nitrogen. After being stirred at room temperature for 30 h, the mixture was poured onto ice-water and extracted with methylene dichloride. The organic layer was then washed with water, dried (MgSO,) and evaporated under reduced pressure. The crude product was purified on a silica gel column with heptane-ethyl acetate (1 :1) as eluent. After recrystallization from hexane, the product 15 (130 mg, 60) was obtained as white crystals, mp 131-132 "C (Found: C, 77.0; H, 7.9; N, 4.85; 0,10.25.C20H25N02 requires C, 77.15; H, 8.1; N, 4.5; 0, 10.3); d,(CDCI,) 7.35 (1 H, dd, J 8 and 1.5, 8-H), 7.13 (1 H, td, J8 and 1.5,6-H), 6.88 (1 H, td, J8 and 1.5, 7-H), 6.78 (1 H, dd, J8 and 1.5,5-H), 6.03 (1 H, d, J2.4,2-H), 5.84(1 H, d, J2.4, 4-H), 3.77 (3 H, s, OMe), 3.32 (3 H, s, NMe), 2.43 (1 H, m, a-CH), 1.78 (3 H, s, 9-Me), 1.70 (1 H, m, a-CH), 1.11 (2 H, m, y-CH,), 0.91 (2 H, m, P-CH,) and 0.71 (3 H, t, J7, Me). 9-Butyl-1-hydroxy-3-methoxy-I O-methyl-9,1 O-dihydroacrid- ine 16.-Compound 13 (170 mg, 0.58 mmol) dissolved in dry tetrahydrofuran was added dropwise to a solution containing lithium aluminium hydride (35 mg, 0.92 mmol) in dry tetrahydrofuran (5 cm3).The mixture was stirred at room temperature for 22 h after which it was quenched by the addition of ethyl acetate (2 cm3) and then water (1 cm3) and evaporated under reduced pressure. The residue was then extracted with methylene dichloride and the extract was washed with water, dried (MgSO,) and evaporated under reduced pressure. The residue was chromatographed on a silica gel column with heptane-ethyl acetate (1 :1) as eluent to provide compound 16 which was crystallized from acetonitrile (1 27 mg, 74) as white crystals, mp 188-189deg;C (Found: C, 76.9; H, 7.55; N, 4.9; 0,10.65. C,,H,,NO, requires C, 76.75; H, 7.8; N, 4.7; 0,10.75); G,(CDCl,) 7.18 (1 H, td, J 8 and 1.4,6-H), 7. I2 (1 H, dd, J8 and 1.4,8-H), 6.91 (1 H, td, J8 and 1.4,7-H), 6.87 (1 H,dd, J8and 1.4,5-H),6.09(1H,d, J2.2,2-H), 6.04(1 H,d, J2.2,4-H), 4.08 (I H, t, J6.9, 9-H), 3.77 (3 H, s, OMe), 3.32 (3 H, s, NMe), 1.48 (2 H, m, a-CH,), 1.21 (4 H, m, P,y-CH,) and 0.79 (3 H, t, J 6.9, Me).References 1 G. K. Hughes, F. N. Lahey, J. R. Price and L. J. Webb, Nature, 1948, 162, 223; F. N. Lahey and W. C. Thomas, Aust. J. Sci. Rex, Ser. A, 1949, 2,423. 2 G. H. Svoboda, Lloydia, 1966, 29, 206; H. L. Shieh, J. 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Paper 4/05665E Received 1 6th September 1994 Accepted 17th November 1994 ~~ ~~~~ 0Copyright 1995 by the Royal Society of Chemistry