Quinoline alkaloids. Part 26. Pseudobases from the reaction of furoquinolinones with methyl iodide. A new route to 3-(3-methyl-2-oxobutyl)quinolin-2(1H)-ones

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 Quinoline Alkaloids. Part 26.' Pseudobases from the Reaction of Furoquinolinones with Methyl Iodide. A new Route to 3-(3-Methyl-2-oxobutyl)-quin01in-2(1H)-ones John L. Gaston and Michael F. Grundon * Department of Chemistry, The University of Ulster, Coleraine, Northern Ireland ~~ Reaction of 2-isopropyI-9-methyIf u ro2,3-61quinoIin-4 (9H)-ones (5) w ith methyI iodide gave saIts believed to be pseudobase hydriodides (7),which were converted with base into 4-methoxy-I -methyl-3-(3-methyl-2-oxobutyl)quinolin-2(1H)-ones (6);the analogous pseudobase derivative (12) from the furoquinoline alkaloid skimmianine gives the furoquinolin-4-one isoskimmianine on further reaction with methyl iodide. The mechanisms of these reactions and of the acid-catalysed rearrangement of furoquinolinones (5) are discussed.Several quinolin-2-one alkaloids containing a ketonic group in a hemiterpenoid side-chain occur in rutaceous plants. Thus, lunidonine (1) was obtained first from Lunasia arnara and was later isolated from Ptelea trifoli~ta;~N-demethyl-lunidonine (2) and 6-methoxylunidonine (3) also occur in the latter species. We planned to develop a general preparation of these (1) R1 = H,R2 = Me (2) R1 = R2 = H R* (3) R1 = OMe, RZ = Me compounds from furoquinolinium salts (4), in the expectation that reaction of hydroxide ion at C-9a would result in cleavage of the furan ring. The 4,6,8-trimethoxyfuroquinoliniumiodide (4a), m.p. 184-1 89 OC, was obtained by refluxing the quinolin-4-one (5a) with methyl iodide in methanol, but treatment of the quaternary salt with sodium hydroxide in aqueous methanol gave back the quinolin-4-one (5a) almost quantitatively; appar-ently cleavage of the 4-methoxy group occurred in preference to nucleophilic attack at C-9a.When the furoquinolinone (5a) was refluxed in methyl iodide alone a precipitate formed slowly; crystallisation of the product from methanol-ether gave a new salt, m.p. 141-143 "C, which on reaction with base gave back the quinolin-4-one (5a) (25) and the required ketone (6a) (60). The structure of the latter compound was indicated by i.r. absorption at 1 715 (ketonic CO) and 1 658 cm-' (quinolin-2-one CO) and by the 'H n.m.r. spectrum. Reaction of the furoquinolin-4-ones (5b) and (5c) with methyl iodide gave salts (7b) and (7c), respectively, but increasing time of reflux was required in the series (5a) -(5b) ---+(5c).Compounds (7b) and (7c) were converted into ketones (6b) (81) and (6c) (70), respectively,by treatment with sodium hydroxide. Although the synthetic objectives were obtained in this way it was clearly of interest to examine the structures and properties of the new salts. In the case of the compound formed by reaction of the 6,8-dimethoxyfuroquinolin-4-one (5a) with methyl iodide, n.m.r. spectroscopy indicated that the most probable structure (7a) is that of a hydriodide salt of a pseudobase.6 Thus, in the 'H n.m.r. spectrum (Table l), three-proton singlets at 6 4.74, 4.09, and 3.96 were assigned to methoxy groups at C-4, C-8, and C-6, respectively and confirmed by substantial n.0.e.(20-23 enhancement) arising by interaction with protons at C-3, C-7, and C-5, respectively. A three-proton singlet at 6 4.67 is due + + to the NHMe group compared with 3.84 for =N(Me)-in methiodide (4a) and a high-field resonance at 3.59, which is n Me I ,MeOH KL Me OH- I- Me R ' W N' OMe 0- Me OMe R2 Me (91 a; R' = RZ = OMe b R' = OMe, R2 = H C; R' = RZ = H d; R' = H, R2 = OMe Scheme 1. absent from the spectrum of the methiodide, is attributed to the methoxy group at C-9a. The 13C n.m.r. spectrum (see Experimental section) supports structure (7a) and was assigned completely on the basis of off-resonance decoupling at 0 and 8 p.p.m.and by comparison with the I3C n.m.r. spectra of related hemiterpenoid quinolines.' The assignment of the C-2 resonance was apparent from long-range couplings to protons at C-3 and CHMe,. A key feature of the 13C spectrum is the 906 J. CHEM. SOC. PERKIN TRANS. I 1989 Table 1. 'H N.m.r. chemical shifts (6) of compounds (4a) and (7) in CDCI, and (12) in CD,OD Compound Arom. 5-H Other ArH -CH= 9a-OMe 4-OMe 6-OMe 8-OMe amp;Me CHMe, CHMe, (7a) 7.25 7.0 1 7.37 3.59 4.74 3.96 4.09 4.67 3.22 1.25 (4a) 7.34 7.34 7.52 4.59 3.97 4.08 3.84 3.10 1.40 (7b) 7.80 8.30, 7.60 7.30 3.60 4.70 3.94 4.60 3.30 1.40 (7c) (12) 8.55-7.50 7.75 8.32 7.40 8.10, 3.60 3.50 4.75 4.70 4.10 4.52 4.60* 3.30 1.43 7.70 * Also a signal at 4.00 (7-OMe).resonance at 6, 107.1 (C-9a), which shows long-range coupling to the olefinic proton at C-3 and has a chemical shift com- parable in value with that observed for quaternary carbons of ortho esters (e.g. 6,112.5 for triethyl orthoformate' and 6,119.0 for the orthoacetate group of the terpenoid phragmalin 9, when allowance is made for reduced deshielding by a nitrogen compared with an oxygen atom. Salts (7b) and (7c) derived from other furoquinolinones have similar 'H n.m.r. spectra (Table 1). When tested with silver nitrate solution, compound (7a) was shown to contain iodide ion. Elemental analysis of the salts gave a value for the percentage of carbon -2 higher than required by structures (7a+), perhaps indicating partial loss of hydrogen iodide.When the methiodide (4a) was refluxed with methyl iodide for 24 h, partial conversion into the pseudobase derivative (7a) was shown by t.1.c. to occur. The normal methiodides (4) are therefore likely to be intermediates in the formation of com- pounds (7) from furoquinolinones (5); if some methanol is formed by hydrolysis of methyl iodide during the prolonged reaction, a possible mechanism involves addition of methanol + to the -N(Me)=C bond of the methiodides (4) favoured by the aprotic medium, followed by transfer of a proton from oxygen to nitrogen. A possible route to the furoquinolin-4-ones (5) then involves addition of hydroxide ion at C-4 of pseudobases (8),followed by elimination of the methoxy group at this centre route (a) (Scheme 1). Alternatively, splitting of the C-0 bond of compounds (8) route (b) can result after subsequent hydrolysis of the 2-methoxyquinoline derivative (9) in conversion into ketones (6).Since the reactions of isopropylfuroquinolin-4-ones (5) with methyl iodide were reminiscent of the traditional method of con- verting furoquinoline alkaloids, e.g. (lo), into the isoalkaloids, e.g. (ll), by heating at 80 "C in a sealed tube with methyl iodide," we refluxed skimmianine (10) with methyl iodide (Scheme 2). A pseudobase hydriodide structure (12) was assigned to the crystalline product on the basis of the 'H n.m.r. spectrum (Table 1); reaction of this compound with methyl iodide at 80 "C gave the N-methylfuroquinolin-4-one iso-skimmianine (1 1; R = OMe) (62 yield).The is0 rearrangement is usually regarded as occurring through a methiodide such as (13),as shown in Scheme 2, but the present results indicate that a pseudobase derivative may also participate. Dehydration of' Dihydro(hydroxypropan-2-yl)furoyuinolin-4-onrs.-Isopropylfuroquinolin-4-ones (5) that were required as starting compounds for this study were prepared by dehydr- ation of the corresponding dihydro(hydroxypropan-2-y1)furo-quinolin-4-ones (14),as described previously. Since, however, the method was found to be more complex than anticipated, a discussion is warranted. Reaction of the 6,s-dimethoxy derivative (14a) with conc.sulphuric acid for 1 h gave the furoquinolinone (5a) (5373, Me0amp;bsol; Me0 Me0 / bsol; OMe Me H (10) 1 (12) +Iii 1-ii 0 R'amp; R Me (11; R=OMel Scheme 2. Reqents and conditions: i, MeI, reflux; ii, MeI, 80 "C but in this case an isomeric compound was also isolated, in 207( yield. The minor product was shown to be the angular quinolinone (17a) by the i.r. absorption at 1 660 cm-' and by the absence in the 'H n.m.r. spectrum of a signal lower than 6 6.99; by contrast, the linear quinolinone (5a) showed in the 'H n.m.r. spectrum a doublet at 6 7.65, which is attributed to the proton at C-5 adjacent to the carbonyl group. Similar dehydration of dihydro(hydroxypropan-2-yl)furoquinolin-4-one(14c) (iso-platydesmine) and its 6-methoxy derivative (14b) also gave the corresponding linear and angular furoquinolinones that were identified by i.r. and 'H n.m.r.spectroscopy (Table 2). The proportion of the two isomers obtained depended on the reaction time. Thus, in the case of dehydration of the 6-methoxyquinolin-4-one (14b), the yields of linear furo-quinolinone (5b) and angular furoquinolinone (17b) after treatment with conc. sulphuric acid for 2 min were 85 and 14"/d, respectively; after 30 min 42 and 38; and after 1 h 20 and 75x. These results suggest that the linear compounds (5) undergo acid-catalysed rearrangement to the angular isomers (17). In support of this proposal we found that reaction of the linear 6,S- dimethoxyfuroquinolinone (5a) with conc.sulphuric acid for 2 h gave a product that was shown by 'H n.m.r. spectroscopy to contain the linear quinolinone (5a) and the angular quinolinone (17a) in the ratio 2: 1. The linear compound (5a) was unaffected by sodium hydroxide, indicating that the base used in the work-up procedure was not responsible for the rearrangement. A plausible mechanism (Scheme 3) involving formation of protonated enol ethers (15), cleavage to the ketones (16), and then cyclisation to the more stable angular furoquinolinones (17) is analogous to the mechanism proposed" for rearrange- ment of the furoquinolinone isodictammine (11; R = H) with polyphosphoric acid. Reaction of the 8-methoxyquinolin-4-one (5d) with hydrobromic acid at 75 "C gave the isopropylfuro- quinolinone (17d) in 35;;) yield, apparently by a similar route.J. CHEM. SOC. PERKIN TRANS. I 1989 Table 2. 'H N.m.r. chemical shifts (6) of compounds (5)and (17) in CDCl, Arom. 5-H Compound or 9-H Other ArH -CH= (5a) 7.65 6.79 6.65 (17a) 6.99 6.62 6.65 (5b) (17b) 8.05 7.30 7.5G7.30 7.2c7.10 6.70 6.62 (5c) 8.50 7.65-7.05 6.60 (17c) 7.96 7.55-7.20 6.65 (174 7.70-6.88 6.64 I 0 Me (161 (151 a; R' = R2 = OMe b; R' = OMe, R2 = H c; R' = R2 = H d; R' = H, R2 = OMe Scheme 3. Experimental 'H N.m.r. spectra were determined with a Perkin-Elmer R12 (60 MHz) or R32 (90 MHz) spectrometers with tetramethyl- silane as internal standard, i.r. spectra with a Perkin-Elmer 457 spectrophotometer, and mass spectra with an AE1 MS9 instrument.Deliydrution of 2-(1-Hydroxy-1-methylethyl)-9-methyl-2,3-dihydrofuro2,3-bquinolin-4(9H)-ones(14).-A solution of the dihydrofuroquinolin-4-one (14a) ' (0.49 g) in conc. sulphuric acid (5 ml) was kept for 1 h, diluted with water (20 ml), made basic with 2~-aqueous sodium carbonate, and extracted with chloroform. Evaporation of the solvent and crystallisation OMe NMe CHMe, CHMe, 4.1 5, 3.95 3.97, 3.90 3.95 3.93 3.15 3.12 1.36, 1.27 1.44, 1.30 3.95 3.70 3.95 3.89 3.10 3.10 1.35, 1.25 1.40, 1.30 3.78 2.95 1.35, 1.23 3.77 3.14 1.43, 1.31 4.00 3.9 1 3.12 1.36 R, 0.16, and 2-isopropyl-6,8-di~~et~zo.~y-5-methy~uro3,2-c-yuinolin-4(5H)-one(17a) (0.09 g, 20) (from ethyl acetate), m.p.129-1 30 "C; v,,,,(KBr) 1 660 cm-' (C=O)(Found: C, 67.5; H, 6.2; N, 4.970. After treatment with conc. sulphuric acid for 2 h, compound (5a) (50 mg) was shown by t.1.c. and 'H n.m.r. spectroscopy to be converted into a mixture of (5a) and (17a) in the ratio 2: 1. Application of the procedure to the dihydrofuroquinolin-4- one (14b) ' gave 2-isopropyl-6-methoxy-9-methylfuro2,3-b-quinolin-4(9H)-one (5b) (from ethyl acetate), m.p. 187-189 "C; v,,,,(KBr) 1 630 cm-* (Found: C, 70.0; H, 6.4; N, 4.9. C,,H, ,NO, requires C, 70.8; H, 6.3; N, 5.2), and the angular furoquinolin-4-one (17b) (from ethyl acetate), m.p. 181 "C; vmaX. 1 660 cm-', which was not characterised fully. Dehydration of the dihydrofuroquinolin-4-one (14c) ' with conc.sulphuric acid for 3 min gave 2-isopropyl-9-methylro- 2,3-bquinolin-4(9H)-one(5c) (83), m.p. 145-146 "C (from ethyl acetate); v,,,.(KBr) 1 630 cm-' Found: M+, 241.1087 (58.7). C, gH1,NO2 requires M, 241.1 1031 and 2-isopropyl- 5-methylfuro3,2-cquinolin-4(5H)-one(17c) (25"/;;), m.p. 1 12- 118 "C, identical ('H n.m.r. and i.r.) with an authentic sample.' With Kevin J. Jurnes. A mixture of dihydrofuroquinolin-4- one (14d) ( -t)-balfourodine l5 (6.24 g) in 48 hydrobromic acid (10 ml) was heated at 75 "C for 4 h and diluted with water (20 ml). After neutralisation, extraction with chloroform gave an oil, which was chromatographed on alumina. Elution with light petroleum (b.p. 40-60 "C)-ether (3 :2) gave 2-isopropyI-6- r~zetho.uy-5-methylfuro3,2-cquinolin-4(5H)-one (17d) as needles (0.079 g, 3573, m.p. 75 "C; v,,,,(KBr) 1 665 cm-' (Found: C, 70.8; H, 6.4; N, 5.2.C,,H,,NO, requires C, 70.8; H, 6.3; N, 5.2). The 'H n.m.r. data for compounds (5) and (17) are given in Table 2. Rructions qfthe Furoyuinolin-4-ones(5)ttqith Methyl Iodide.- (a) A solution of the furoquinolin-4-one (5a) (70 mg) in methanol (10 ml) and methyl iodide (2 ml) was refluxed for I2 h and evaporated. Crystallisation of the residue from methanol- ether gave 2- isopropyI-4,6,8 -trinietho.uy-9-methj-ljuro2,3- b -quinolinium iodide (4a) (78 mg) m.p. 184-189 "C (Found: C, 49.1; H, 5.25; N, 3.3. Cl,H221N04 requires C, 48.8; H, 5.0; N, 3.2). The methiodide (40 mg) in 2~-methanolic sodium hydroxide was kept for 16 h to give the furoquinolin-4-one (5a) (26 mg, 9573.(b) The furoquinolin-4-one (5a) (75 mg) in methyl iodide (5 ml) was refluxed for 24 h. Evaporation and crystallisation of the residue from methanol-ether gave the pseudobase hydviodide (7a) (64 mg), m.p. 141-143 from methanol-ether gave 2-isoprop?,l-6,8-dinzet~io-~y-9-met~i}~l-firro2,3,bquinolin-4(9H)-one(5a) (0.15 g), m.p. 14amp;142 "C; v,,,.(KBr) 1 640 cm-' (C=O) (Found: C, 67.3; H, 6.1; N, 4.4. C1,H19N04 requires C, 67.7; H, 6.35; N, 4.6). Evaporation of the methanokther solution and preparative t.1.c. (p.1.c.) of the residue on silica with chloroform gave a further quantity of the furoquinolin-4-one (5a) (0.095 g, total yield 5373, "C; G,(CDCI,) 165.1 (C-2), 161.2 (C-4), 158.4 (C-6), 157.8 (C-8a), 152.2 (C-8), 122.8 (C-3a), 122.0 (C-4a), 107.1 (C-7), 107.1 (C-9a), 100.9 (C-3), 95.3 (C-5), 61.9 (4-OMe), 57.2 (8-OMe), 56.1 (6-OMe), 54.0 (9a-OMe), 40.3 (amp;Me), 28.2 (CHMe,), and 20.3 (CHMe,) (Found: C, 50.0; H, 5.4; N, 2.8.C,,H,,INO, requires C,48.1; H, 5.5; N, 2.90/:,). The quinolinium iodide (4a) was refluxed with methyl iodide 908 for 24 h; t.1.c. of the product on silica with chloroform-methanol (10: 1) showed the presence of the pseudobase salt (7a), R, 0.2. The furoquinolin-4-one (5b) was refluxed with methyl iodide for 48 h to give the pseudobase hydriodide (7b) as needles, m.p. 160-162 "C (from methanol-ether) (Found: C, 50.6; H, 5.5; N, 3.3. C,,H,,INO, requires C, 48.0; H, 5.3; N, 3.1).After refluxing with methyl iodide for 4 days, the furoquinolin-4-one (Sc) gave the salt (7c), m.p. 131-135 "C (from methanol- ether) (Found: C, 51.3; H, 4.0; N, 3.8. C,,H,,INO, requires C, 49.2; H, 5.3; N, 3.3). Reactions of Pseudobase Salts (7) with Sodium Hjdroside.-A solution of compound (7a) (100 mg) in 2~-methanolic sodium hydroxide (14 ml) was kept for 8 h. The products were obtained by evaporation of methanol, addition of water, and extraction with chloroform; p.1.c. on silica with chloroform-methanol ( 10: 1) gave 4,6,8-triniet/io..cll- l-methyl-3-(3-rnethyI-2-o.xobutyl)-yuinolin-2(1 H)-one (6a) as needles (42 mg, 60x), R, 0.91; m.p. 92-98 "C (from cyclohexane); vmaX,1 715 (CH,C=O) and 1 658 cm-' (NC=O); GH(CDC1,) 6.95 (1 H, d, ArH), 6.74 (1 H, d, ArH), 3.90 (14 H, s, 3 x OMe, NMe, and CH,), 2.88 (1 H, m, CHMe,), and 1.2 (6 H, d, CHMe,) (Found: C, 64.7; H, 6.8; N, 3.8.C,,H,,NO, requires C, 64.8; H, 6.95; N, 4.2); and then the furoquinolin-4-one (5a) (1 7 mg, 25). Application of the procedure to compound (7b) (1 13 mg) gave 4,6-dimetho.u~~-1-met/1491-3-(3-methyl-2-o.xobutyl)quinolin-2(1H)-one (6b) as prisms (79 mg, 81), R, 0.46; m.p. 86-87 "C (from cyclohexane); v,,,, 1 700 and 1 640 cm-'; GH(CDC1) 7.82 (3 H, br s, ArH), 3.90 (s) and 3.70 (s) (11 H, 2 x OMe, NMe, and CH,), 2.90 (1 H, m, CHMe,), and 1.20 (6 H, d, CHMe,) (Found: 67.2; H, 6.85; N, 4.8. C,,H,,NO, requires C, 67.3; H, 7.0; N, 4.6"); and the furoquinolin-4-one (5b) (10 mg, 1273.Application of the procedure to compound (7c) (100 mg) gave 4-nzetho.~j~-l-methyl-3-(3-metlzyl-2-oxobutyl)quinolin-2( 1H)-one (6c) as needles (46 mg, 70), R, 0.52; m.p. 80--8 1 "C (from cyclohexane); v,,, 1705 and 1640 cm-'; G,(CDCl,) 7.9-7.1 (4 H, m, ArH), 3.90 (3 H, s, OMe), 3.85 (2 H, s, CH,), 3.70 (3 H, s, NMe), 7.85 (1 H, m, CHMe,), and 1.22 (6 H, d, CHMe,) (Found: C, 70.5; H, 7.4; N, 5.3. C,,H,,NO, requires C, 70.3; H, 7.0; N, 5.1); and the furoquinolin-4-one (5c) (15 mg, 25). Reactions of Skimmianine (lo).-A solution of skimmianine (10) (50 mg) in methyl iodide was refluxed for 6 h and evaporated; crystallisation from methanokther gave the pseudobase hydriodide (12) as needles (33 mg), m.p. 166-J.CHEM. SOC. PERKIN TRANS. I 1989 167 "C (Found: C, 49.8; H, 5.0; N, 3.8. C,,H,,INO, requires C, 44.3; H, 4.6; N, 3.20/,). The salt (12) (30 mg) was heated in a sealed tube with methyl iodide at 80 "C for 5 h. Evaporation of methyl iodide and p.1.c. of the residue on silica with chloroform- methanol (10: 1) gave isoskimmianine (11; R = OMe) (12 mg, 6770, m.p. 188-190 "C (lit.,I6 189-- 190 "C); G,(CDCl,) 8.33 (1 H, d, 5-H), 7.03 (1 H, d, 6-H), 7.23 (1 H, d) and 7.20 (1 H, d) (2- and 3-H), 4.17 (3 H, s), 3.99 (3 H, s), and 3.86 (3 H, s) (2 x OMe and NMe). Acknowledgements We thank Drs. N. J. McCorkindale and D. S. Rycroft for the 13C n.m.r. spectroscopic data, and the Department of Education for Northern Ireland for a postgraduate studentship (to J.L. G.). References 1 Part 25, J. L. Gaston, R. J. Greer, and M. F. Grundon, J. Chem Rcs. S, 1985, 135. 2 Preliminary report: M. F. Grundon, in 'The Alkaloids,' ed. A. Brossi, Academic Press. London, 1988, vol. 32, p. 373. 3 A. Rueggcr and D. Stauffacher, Helc. Chin7. Acta, 1963, 46, 2329. 4 K. Szendrei, M. Petz, I. Novak, J. Reisch, H. E. Bailey, and V. L. Bailey, Herhu Hung, 1974, 13, 49 (C'hem. Ahtr., 1975, 83, 40169). 5 L. A. Mitscher, M. S. Bathala, G. W. Clark, and J. L. Beal, Llojdiu, 1975, 38, 117. 6 For review of heterocyclic pseudobases see J. W. Bunting, Ado. Heterocyrl. Chem., 1979, 25, 1. 7 N. M. D. Brown, M. F. Grundon, D. M. Harrison, and S. A. Surgenor, Tetrahedrun, 1980, 36, 3579. 8 L. F. Johnson and W. C. Tankowski, 'Carbon-13 NMR Spectra,' Wiley, New York, 1972, p. 279. 9 J. D. Connolly, C. Labbe, and D. S. Rycroft, J. Chem. Soc., Pcd-in Trans. I, 1978, 285. 10 Y. Asahina, T. Ohta, and M. Inubuse, Ber. Dtsch. Chem. Ges., 1930, 63, 2045. 11 H. Rapoport and K. G. Holden, J. An?. Clieni. Sac.. 1960, 82, 4395. 12 J. F. Collin?, G. A. Gray. M. F. Grundon, D. M. Harrison, and C. G. Spyropoulos, J. Chtwi. Soc., Perhin T~UFIJ.1, 1973, 94. 13 J. L. Gaston and M. F. Grundon, J. Chrm. Soc., Pevkin Trans. 1, 1980, 2294. 14 R. M. Bowman and M. F. Grundon, J. Cheni. Soc. C, 1966, 1504. 15 E. A. Clarke and M. F. Grundon, J. Cheni. Soc., 1964, 4196. 16 A. V. Robertson, Aust. J. Cheni., 1963, 16, 451. Received 19t/i September 1988; Paper 8/03602K