Quinoline alkaloids: Synthesis of pyrano[2,3,-b]quinolines, khaplofoline, lunacrine, and demethoxylunacrine

Article abstract of DOI:10.1021/np970005i

Polyphosphoric acid (PPA)-catalyzed cyclization of 2-ono-3- vinylquinolinecarboxylic acid (1) yielded 3,4-dihydro-2,2-dimethyl-2H- pyrano[2,3-b]quinoline (4). The same reaction of 4-methoxy-2-oxo-3- vinylquinolinecarboxylic acid (1g) afforded 4-methoxy-2,2-dimethylpyrano[2,3- b]-quinoline (4g), which on hydrolysis with ethanolic hydrochloric acid gave khaplofoline (5). The Prevost reaction of 4-methoxy-3-prenylquinolin-2-one (6) using I₂/HgO in acetic acid yielded 4-methoxy-2-isopropylfuro[2,3- b]quinoline (7). Compound 7 on reduction with H₂/Pd-C followed by N- methylation and de-O-methylation afforded lunacrine (10a). A similar reaction sequence on 6b gave demethoxylunacrine (10b).

Full text of DOI:10.1021/np970005i

294
J . Nat. Prod. 1998, 61, 294-296
Qu in olin e Alk a loid s: Syn th esis of P yr a n o[2,3-b]qu in olin es, Kh a p lofolin e,
Lu n a cr in e, a n d Dem eth oxylu n a cr in e
M. Sekar and K. J . Rajendra Prasad*
Department of Chemistry, Bharathiar University, Coimbatore 641 046, India
Received December 6, 1996
Polyphosphoric acid (PPA)-catalyzed cyclization of 2-ono-3-vinylquinolinecarboxylic acid (1)
yielded 3,4-dihydro-2,2-dimethyl-2H-pyrano[2,3-b]quinoline (4). The same reaction of 4-meth-
oxy-2-oxo-3-vinylquinolinecarboxylic acid (1g) afforded 4-methoxy-2,2-dimethylpyrano[2,3-b]-
quinoline (4g), which on hydrolysis with ethanolic hydrochloric acid gave khaplofoline (5). The
Prevost reaction of 4-methoxy-3-prenylquinolin-2-one (6) using I2/HgO in acetic acid yielded
4-methoxy-2-isopropylfuro[2,3-b]quinoline (7). Compound 7 on reduction with H2/Pd-C followed
by N-methylation and de-O-methylation afforded lunacrine (10a ). A similar reaction sequence
on 6b gave demethoxylunacrine (10b).
The plant family Rutaceae is known1,2 to be a prolific
source of pyrano[2,3-b]quinoline and furo[2,3-b]quino-
line alkaloids. These alkaloids have been reported3-11
to be associated with interesting pharmacological as
well as biological properties and have been synthesized
by several methods. The synthetic method for the
preparation of the pyranoquinoline system is based on
either oxidative cyclization of 4-hydroxy-3-(3′-methybut-
1′-enyl)-2-quinolinones with DDQ12 or the Prevost reac-
tion of 3-prenyl-2-quinolones.13 Though these methods
have proven to be fairly satisfactory, the overall yield
of the alkaloids was only 15-35% because the routes
to obtain the precursor prenylquinolines gave low yields
(21-35%)14,15 and often were attended by undesired side
reactions (such as the formation of unwanted 3-(3′-
methylbut-1′-enyl)-2-quinolinones as the major prod-
uct15). This note reports a facile novel one-pot synthesis
of 3,4-dihydro-2,2-dimethyl-2H-pyrano[2,3-b]quinolines
(4). khaplofoline (5), lunacrine (10a ), and demethoxy-
lunacrine (10b) utilizing 3-(1′-carboxy-3′-methylbut-1′-
enyl)-2-quinolinones14 (1).
Treatment of the carboxy derivative of the 2-quino-
linone14 1a with polyphosphoric acid (PPA) at 140 °C
for 4 h furnished in 60% yield the desired 6-methyl-3,4-
dihydro-2,2-dimethylpyrano[2,3-b]quinoline (4a ), identi-
cal with an authentic sample.14 Extension of this
method to compounds 1b-f gave the respective pyra-
noquinolines 4b-f. Analytical and spectroscopic data
were consistent with the proposed structures 4 (Scheme
1).
khaplofoline (5), identical with the natural product by
mixed mp and superimposable IR spectra.
The 4,8-dimethoxy-3-prenyl-2-quinolinone (6a )23 on
reaction with Prevost reagent (I2/HgO) in acetic acid
afforded 4,8-dimethoxy-2-isopropylfuro[2,3-b]quinoline
(7a ).23 Catalytic hydrogenation of 7a using Pd-C (5%)
in ethanol solution at 50 psi gave 2-isopropyldihydro-
furoquinoline (8a ).24 Compound 8a was heated with
methyl iodide for 20 min and then allowed to stand
overnight. The lunasine (9a ) obtained was directly
converted into lunacrine, 8-methoxy-N-methyl-2,3-di-
hydro-2-isopropylfuro[2,3-b]quinoline (10a ), by treat-
ment with anhydrous lithium bromide in acetonitrile.
The physical and spectroscopic data of compounds 7a ,
8a , 9a , and 10a were identical with those of the
authentic samples.
The same procedure yielded demethoxylunacrine
(10b) from the starting quinolinone 6b.
Exp er im en ta l Section
Gen er al Exper im en tal P r ocedu r es. Melting points
were determined on a Boetius microheating table or a
Mettler FP5 apparatus and are uncorrected. 1H NMR
spectra were recorded on Varian EM-360 (90 MHz) XL
100 (100 MHz) and General Electric QE-300 (300 MHz)
spectrometers in CDCl3. Chemical shifts are reported
downfield from TMS, and coupling constants are in Hz.
IR spectra were recorded on a Perkin-Elmer 597 spec-
trophotometer in KBr or Nujol. Mass spectra were
recorded on Finnigan MAT-8230 and J EOL-J MS-D 300
instruments. Microanalyses were performed on Carlo-
Erba 1106 and Perkin-Elmer Model 240 CHN analyzers.
P r ep a r a tion of 2-Oxo-3-vin ylqu in olin eca r boxy-
lic Acid s 1a -g. A mixture of quinolineacetic acid (0.02
mol), isobutyraldehyde (0.2 mol), sodium acetate (4.5 g),
acetic acid (20 mL), and acetic anhydride (25 mL) was
heated on a steam bath for 1.5 h and then poured into
ice-water. The aqueous solution was then extracted
with CHCl3, washed with aqueous NaHCO3 and water,
and then dried over anhydrous Na2SO4. The residue
obtained was mixed with aqueous NaOH (2 N, 75 mL),
and the reaction mixture was heated on a steam bath
The formation of 4 from 1 can be assumed to proceed
via the decarboxylated product 2 formed in situ under
acidic condition at high temperature.16,17 Compound 2
is isomerized to a more stable isoprenyl cation, which
then cyclizes to product 4.
A similar polyphosphoric acid reaction of 4-methoxy-
2-ono-3-vinylquinolinecarboxylic acid (1g) yielded the
quinoline derivative 4g, identical with an authentic
sample12 in all respects. Compound 4g was refluxed
with 10% ethanolic hydrochloric acid for 30 h to give
* To whom correspondence should be addressed. Tel.: (0422)
422222. Fax: (091) 422-422387. E-mail: regr@as250.bharathi.ernet.in.
S0163-3864(97)00005-0 CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 02/03/1998

Notes
J ournal of Natural Products, 1998, Vol. 61, No. 2 295
Sch em e 1
for 1 h. It was cooled and acidified with dilute hydro-
chloric acid. The solid obtained was filtered, dried, and
recrystallized with a C6H6-EtOH mixture. 1a : mp 240
°C (lit.14 mp 241-242 °C). 1b: mp 234-235 °C (lit.14
mp 235-236 °C). 1c: mp 234 °C (lit.14 mp 235-236
°C). 1d : mp 227-229 °C (lit.14 mp 229-230 °C). 1e:
mp 252-254 °C (lit.14 mp 253-254 °C). 1f: mp 218-
220 °C (lit.14 mp 220-221 °C). 1g: mp 314 °C.
pyranoquinoline 4g (250 mg) was refluxed with 10%
ethanolic hydrochloric acid (10 mL) for 30 h. The
solution was concentrated to a small bulk and poured
into water. The precipitated product was collected by
filtration and recrystallized from EtOAc to yield khap-
lofoline (5) as fine crystals: yield 96%; mp 270-272 °C
(lit.22 mp 272-274 °C); IR (KBr) νmax 3340, 2995, 1635
cm-1; anal. C 73.32%, H 6.59%, N 6.11%, calcd for
C14H15NO2, C 73.36%, H 6.64%, N 5.98%.
Syn t h esis of 3,4-Dih yd r o-2,2-d im et h ylp yr a n o-
[2,3-b]qu in olin es 4a -g. The 2-ono-3-vinylquinolin-
ecarboxylic acid (1a -g, 2 mmol) was heated with freshly
prepared polyphosphoric acid (1 g) (2.5 g of P4O10 and 1
mL of H3PO4) in an oil bath at 140 °C under a nitrogen
atmosphere. The course of the reaction was followed
by TLC analysis on silica gel with petroleum ether (60-
80 °C)-EtOAc (3:1) as solvent system. The reaction was
usually complete within about 4 h. After completion,
the solution was cooled in an ice bath and poured into
crushed ice (100 g). The yellow pyranoquinoline that
separated was filtered, washed, dried, and chromato-
graphed over alumina with petroleum ether (60-80
°C)-EtOAc (2:1, 3 × 100 mL). The solvent mixture was
evaporated under reduced pressure to give solid 4a -g.
4a : yield 60%; mp 148-150 °C (lit.15 mp 150-151 °C);1H
NMR (CDCl3, 100 MHz) δ 7.30-7.90 (4H, m, H-5,6,8,9),
3.00 (2H, t, J ) 7 Hz, H-4), 2.50 (3H, s, 7-CH3), 1.90
(2H, t, J ) 7 Hz, H-3), 1.50 (6H, s, CMe2); anal. C
79.18%, H 7.44%, N 6.14%, calcd for C15H17NO, C
79.26%, H 7.54%, N 6.16%.
Syn t h esis of 4,8-Dim et h oxy-2,3-d ih yd r o-2-iso-
p r op ylfu r o[2,3-b]qu in olin e (8a ). 4,8-Dimethoxy-2-
isopropylfuro[2,3-b]quinoline23 (7a , 0.270 g, 0.001 mol)
in pure ethanol (50 mL) was shaken with 5% Pd/C (100
mg) in an atmosphere of hydrogen at 50 psi in a Parr
hydrogenator for 3.5 h. The catalyst was removed by
filtration, and the filtrate was concentrated to a small
bulk under reduced pressure. The residue obtained was
placed over a column of neutral alumina and eluted with
petroleum ether-EtOAc mixture (96:4) to yield 4,8-
dimethoxy-2,3-dihydro-2-isopropylfuro[2,3-b]quinoline
(8a ) (58%) after evaporation of the solvent: mp 130-
132 °C (lit.24 mp 130-131 °C). Treatment of 7b23
yielded 8b: 60%; mp 124-126 °C (lit.24 mp 125-126
°C).
Syn th esis of Lu n a sin e (9a ). A solution of 8a (136
mg, 0.5 mol) and methyl iodide (15 mL) was heated on
a steam bath for 20 min and then allowed to stand
overnight. Evaporation of the excess reagent followed
by crystallization from benzene yielded lunasine (9a )
as fine crystals in 58% yield: mp 130-132 °C (lit.24 mp
130-131 °C); anal. C 71.08%, H 7.28%, N 4.74%, calcd
for C17H21NO3, C 71.04%, H 7.37%, N 4.80%. Similar
treatment of 8b yielded (9b 60%): mp 124-126 °C (lit.25
mp 125-126 °C); anal. C 73.76%, H 7.38%, N 5.78%,
calcd for C15H18NO2, C 73.73%, H 7.43%, N 5.73%.
4b: yield 60%; mp 93-95 °C (lit.15 mp 95-96 °C);1H
NMR (CDCl3, 100 MHz) δ 7.20-7.93 (5H, m, H-5,6,7,8,9),
2.93 (2H, t, J ) 6.9 Hz, H-4), 1.86 (2H, t, J ) 6.9 Hz,
H-3), 1.50 (6H, s, CMe2); anal. C 78.78%, H 7.16%, N
6.48%, calcd for C14H15NO, C 78.84%, H 7.09%, N 6.56%.
Syn th esis of Kh a p lofolin e (5). The 4-methoxy-

296 J ournal of Natural Products, 1998, Vol. 61, No. 2
Notes
(3) Rideau, M.; Yerchere, C.; Hibon, P. Phytochemistry 1979, 18,
155-159.
(4) Andre, S.; Lasselain, M. J .; Pareyere, C.; Deysson, G; Chenieux,
J . C.; Rideau, M. Ann. Pharm. Fr. 1981, 39, 255-262.
(5) Ayafor, J . F.; Sondengam, B. L.; Nagadjui, B. T. Planta Med.
1982, 44, 139-144.
(6) Das, B. P.; Chowdhury, D. N.; Chowdhury, B.; Mester, I. Indian
J . Chem. 1982, 21B, 76-79.
(7) Gainer, F. E.; Arnett, W. A. J . Pharm. Sci. 1969, 58, 1548-1552.
(8) Yajima, T.; Kato, N.; Munakata, K. Agri. Biol. Chem. 1977, 41,
1263-1268.
(9) Chou, E. Y.; Hostettmann, K.; Kubo, I.; Nakanishi, K.; Taniguchi,
M. Heterocycles 1977, 1, 969-978.
(10) Kovolenko, V. Farmatsiya 1946, 9, 20; Chem. Abstr. 1947, 41,
6989-6995.
(11) Berezhinskaya, V. V.; Trutnova, E. A. Farmakol. Toksikol. 1963,
26, 707: Chem. Abstr. 1964, 60, 13751-13758.
(12) Piozzi, F.; Venturella, P.; Bellino, A. Gazz. Chim. Ital. 1969, 99,
711-715.
(13) Subramaniam, M.; Mohan, P. S.; Shanmugam, P.; Rajendra
Prasad, K. J . Z. Naturforsch. 1992, 47b, 1016-1020.
(14) Oels, P.; Storer, R.; Young, D. W. J . Chem. Soc., Perkin Trans.
1 1977, 2546-2551.
Syn th esis of Lu n a cr in e (10a ). A mixture of luna-
sine (9a , 125 mg) and anhydrous LiBr (2.5 g) in CH3-
CN (20 mL) was refluxed for 4 h and then poured into
ice-water. It was extracted with CHCl3 and then dried
over anhydrous Na2SO4. The residue obtained from the
extract was purified by passing through a column of
alumina and eluting with petroleum ether-EtOAc
mixture (95:5) to afford 8-methoxy-N-methyl-2,3-dihy-
dro-2-isopropylfuro[2,3-b]quinoline (10a ) (95%): mp
145-147 °C (lit.24 mp 146-148 °C); IR (KBr) νmax 1620,
1
1590, 1500, 1080 cm-1; H NMR (CDCl3, 100 MHz) δ
8.00 (1H, dd, J ) 1.6, 5.5 Hz, H-5), 7.05-7.75 (2H, m,
H-6 and H-7), 4.75 (1H, m, H-2), 3.90 (3H, s, OCH3),
3.80 (3H, s, N-CH3), 3.30 (2H, m, 2H-3), 2.05 (1H, m,
-CHMe2), 1.00 (6H, d, J ) 6 Hz, CHMe2); anal.
C
70.34%, H 7.04%, N 5.16%, calcd for C16H19NO3, C
70.29%, H 7.01%, N 5.12%.
Similar treatment of 9b gave 10b (95%): mp 152-
153 °C (lit.24 mp 152-154 °C); IR (KBr) νmax 2990, 1610,
1550, 1060 cm-1; 1H NMR (CDCl3, 100 MHz) δ 7.90 (1H,
d, J ) 8.2 Hz, H-5), 7.00-7.65 (3H, m, H-6, H-7, H-8),
4.50 (1H, m, H-2), 3.65 (3H, s, NCH3), 3.50 (2H, dd, J )
16, 5.5 Hz, 2H-3), 2.20 (1H, m, CHMe2), 1.00 (6H, d, J
) 6 Hz, -CHMe2); anal. 74.38%, H 6.62%, N 5.86%,
calcd for C15H17NO2, C 74.34%, H 6.66%, N 5.78%.
(15) Ramesh, M.; Mohan, P. S.; Shanmugam, P. Tetrahedron 1984,
40, 4041-4048.
(16) Taylor, R. In Comprehensive Chemical Kinetics; Bamford, T., Ed.;
Elsevier Publishing Co.: New York, 1972; Vol. 13, pp 1-406.
(17) Brown, B. R. Quart. Rev. Chem. Soc. 1951, 5, 131-135.
(18) Cram, D. J .; Ford, W. T.; Gosser, L. J . Am. Chem. Soc. 1968,
90, 2598-2606.
(19) Ford, W. T.; Cram, D. J . J . Am. Chem. Soc. 1968, 90, 2606-
2611.
Ack n ow led gm en t. One of us (M.S) is thankful to
CSIR, India, for the award of a Senior Research Fel-
lowship.We also thank SIF, IISc Bangalore, and CDRI,
Lucknow, India, for the NMR spectra and microana-
lytical data.
(20) Wong, S. M.; Fischer, H. P.; Cram, D. J . J . Am. Chem. Soc. 1971,
93, 2235-2243.
(21) Bowman, R. M.; Grundon, M. F.; J ames, K. J . J . Chem. Soc.,
Perkin Trans. 1 1973, 1055-1059.
(22) Bowman, R. M.; Grundon, M. F. J . Chem. Soc. C 1966, 1004-
1009.
(23) Subramaniam, M.; Rajendra Prasad, K. J .; Shanmugam, P.
Synthesis 1989, 10, 777-779.
Refer en ces a n d Notes
(24) Ramesh, M.; Mohan, P. S.; Shanmugam, P. Tetrahedron 1984,
40, 3431-3436.
(25) Huffman, J . W.; Cecil, J . H. J . Org. Chem. 1969, 34, 2183-2187.
(1) Grundon, M. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
London, 1988; Vol. 32, pp 341-439.
(2) Sainsbury, M. In Rodd’s Chemistry Of Carbon Compounds;
Coffey, S., Ed.; Elsevier Publishing Co.: New York, 1978; Vol.
IVG, pp 171-225.
NP970005I