Synthesis of antitumor lycorines by intramolecular Diels-Alder reaction

Article abstract of DOI:10.1021/jo9518415

Pharmacologically interesting lycorines were obtained by a short, efficient method based on an intramolecular Diels-Alder reaction between an α-pyrone and an alkyne, followed by loss of CO₂ in a retro Diels-Alder reaction. The cyclization precursors (pyrones 9) were obtained in good yields in two or three steps from the corresponding homophthalic acid or anhydride.

Full text of DOI:10.1021/jo9518415

1650
J . Org. Chem. 1996, 61, 1650-1654
Syn th esis of An titu m or Lycor in es by In tr a m olecu la r
Diels-Ald er Rea ction †
Dolores Pe´rez, Gema Bure´s, Enrique Guitia´n,* and Luis Castedo*
Departamento de Quı´mica Orga´nica, Universidad de Santiago, and Seccio´n de Alcaloides del CSIC,
15706 Santiago de Compostela, Spain
Received October 12, 1995X
Pharmacologically interesting lycorines were obtained by a short, efficient method based on an
intramolecular Diels-Alder reaction between an R-pyrone and an alkyne, followed by loss of CO2
in a retro Diels-Alder reaction. The cyclization precursors (pyrones 9) were obtained in good yields
in two or three steps from the corresponding homophthalic acid or anhydride.
Sch em e 1
In tr od u ction
The lycorine alkaloids, a group of compounds isolated
from Amaryllidaceae plants1 and characterized by the
skeleton 1, have attracted the attention of chemists and
pharmacologists due to the interesting properties of
certain known lycorines. For example, hippadine (2a )
inhibits fertility in mice,2 anhydrolycorinium chloride3
(3a ) is active against P-388 leukemia, and kalbretorine4
(2b) and ungeremine5 (3b) are active against several
types of tumor.
reported recently.6 We now report the results of the
second approach, which is based on an intramolecular
Diels-Alder reaction between a pyrone and an alkyne,
followed by loss of CO2 in a retro Diels-Alder reaction
(Scheme 1, route B). Reactions of R-pyrones with alkynes
and arynes to afford aromatic compounds are well
known,7 and our group has used intermolecular cycload-
dition with benzyne for the synthesis of benzophenan-
thridine alkaloids.8
Resu lts a n d Discu ssion
Suitable substrates for the intended intramolecular
Diels-Alder reaction, compounds 9, were first prepared
via pyrones 6.9 Condensation of 4,5-dimethoxyhomo-
phthalimide10 (4a ) with trimethyl orthoformate in Ac2O/
DMF afforded 5a , and treatment of 5a with ethyl
cyanoacetate and NaOMe gave pyrone 6a . Reaction of
6a with the tosylate 711 afforded the O-alkylation and
N-alkylation products 8a and 9a in 1:1 ratio and joint
93% yield. Modification of the reaction conditions did not
change the ratio between the two products, which were
separated by chromatography. Compound 8a was re-
cycled by hydrolysis to 6a . Heating of compound 9a in
refluxing nitrobenzene afforded the cycloadduct 10a in
95% yield. A similar route was applied to the synthesis
of the methylenedioxy derivative 10b (Scheme 2).
Retrosynthetic analysis of the basic skeleton of lyco-
rines 1 has led us to develop two new approaches to these
compounds. One, based on intramolecular cycloaddition
of an aryne and an azadiene (Scheme 1, route A), was
† Dedicated to Prof. Antonio Gonza´lez in celebration of his half-
century of contribution to natural product chemistry.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) (a) Wildman, W. C. In The Alkaloids, Chemistry and Physiology;
Manske, R. H. F., Ed.; Academic Press: New York, 1968; Vol. 11, p
307. (b) Fuganti, C. In The Alkaloids, Chemistry and Physiology;
Manske, R. H. F., Ed.; Academic Press: New York, 1975; Vol. 15, p
83. (c) Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 25, p 198. (d) Martin, S. F. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol.
30, p 251. (e) Grundon, M. F. Nat. Prod. Rep. 1984, 1, 349. (f) Grundon,
M. F. Nat. Prod. Rep. 1985, 2, 249. (g) Grundon, M. F. Nat. Prod. Rep.
1987, 4, 89. (h) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 79. (i) Lewis,
J . R. Nat. Prod. Rep. 1992, 9, 183. (j) Lewis, J . R. Nat. Prod. Rep. 1993,
10, 291. (k) Stevens, R. V. in The Total Synthesis of Natural Products;
ApSimon, Ed.; Wiley-Interscience: New York, 1977; Vol. 3, p 439. (l)
Ghosal, S.; Saini, K. S.; Razdan, S. Phytochemistry 1985, 24, 2141.
(2) (a) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm, A.
W. Phytochemistry, 1981, 20, 2003. (b) Chattopadhyay, S.; Chatto-
padhyay, U.; Marthur, P. P.; Saini, K. S.; Ghosal, S. Planta Med. 1983,
49, 252.
Although the above procedure was efficient for the
synthesis of 10 (the overall yield from the imides 4 was
around 50%), the preparation of the cyclization precur-
sors was complicated by the need to separate the N- and
O-alkylated products and recycle the latter. To avoid this
problem we introduced the substituent on the nitrogen
(6) Gonza´lez, C; Pe´rez, D.; Guitia´n, E.; Castedo, L. J . Org. Chem.,
1995, 60, 6318.
(7) Ellis, G. P. In Comprehensive Heterocyclic Chemistry; Katritzky,
A., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, part 2B,
pp 647-736.
(8) Pe´rez, D.; Guitia´n, E.; Castedo, L. J . Org. Chem. 1992, 57, 5911.
(9) Pe´rez, D.; Guitia´n, E.; Castedo, L. Tetrahedron Lett. 1992, 33,
2407.
(3) Pettit, G. R.; Gaddamidi, V.; Goswami, A.; Cragg, G. M. J . Nat.
Prod. 1984, 47, 796.
(4) Ghosal, S.; Lochan, R.; Ashutosh, R.; Kumar, Y.; Srivastara, R.
S. Phytochemistry 1985, 24, 1825.
(5) (a) Zee-Cheng, R. K. Y.; Yan, S.-J .; Cheng, C. C. J . Med. Chem.
1978, 21, 199. (b) Cheng, C. C.; Zee-Cheng, R. K. Y. Heterocycles 1981,
15, 1275.
(10) Haworth, R. D.; Pink, H. S. J . Chem. Soc. 1925, 1368.
(11) Eglinton, G.; Whiting, M. C. J . Chem. Soc. 1950, 3650.
0022-3263/96/1961-1650$12.00/0 © 1996 American Chemical Society

Synthesis of Antitumor Lycorines
J . Org. Chem., Vol. 61, No. 5, 1996 1651
Sch em e 2
Sch em e 3
followed by decarboxylation (Cu, quinoline). As trans-
formation of 10d into hippadine (2a )15 and anhydroly-
corinium chloride (3a )16 has already been reported, our
approach provides a route to these biologically active
compounds.
Other pharmacologically interesting lycorines, such as
ungeremine (3b), have an oxygen atom linked to C-2 in
ring C. We achieved this substitution pattern by syn-
thesizing pyrone 9c, in which the desired oxygen is
incorporated in a methoxy group. After several unfruitful
attempts to get 9c by reaction of enamine 15 with methyl
methoxyacetate and various bases under diverse reaction
conditions, we finally obtained the desired pyrone in 90%
yield by reaction of imide 14 with methyl 3-dimethyl-
amino-2-methoxyacrylate (16b), which was prepared by
a published procedure.17 It is important to point out that
as condensation of 14 and 16b involves elimination of
dimethylamine, it is necessary to pass a strong current
of an inert gas through the reaction vessel to remove the
amine from the medium; otherwise, nucleophilic attack
on the pyrone leads to decomposition. Heating pyrone
9c in refluxing nitrobenzene promotes intramolecular
cyclization to compound 10c (60% yield).
In conclusion, this paper describes a versatile new
approach to lycorines with various substitution patterns
that can be applied to the synthesis of natural alkaloids
with biological activity. This approach and that previ-
ously reported6 may be considered as complementary:
the latter, based on intramolecular aryne cycloaddition,
is more suitable for the synthesis of lycorines that are
polysubstituted on ring C; the new approach, based on
intramolecular alkyne cycloaddition, is more useful for
the synthesis of lycorines that are polysubstituted on
ring A.
atom at an earlier stage. To this end, 3-butyn-1-amine
hydrochloride (12) was prepared from tosylate 7 by the
one-pot, two-step route shown in Scheme 3, which
improves on previously reported methods:12 treatment of
7 with sodium azide and reduction of the crude product
with tin(II) chloride, followed by acidic workup, afforded
the stable hydrochloride 12 in quantitative yield (88%
overall from 3-butyn-1-ol).
Since the thermal instability and low boiling point of
the amine prevented the condensation of 3-butyn-1-amine
with homophthalic acids under the usual conditions (200
°C), we tried alternative procedures for imide synthesis
under milder conditions. Treatment of 4,5-(methylene-
dioxy)homophthalic anhydride13 (13) with a solution of
3-butyn-1-amine (freshly obtained by treatment of 12
with 10% NaOH solution), followed by heating of the
resulting salt, afforded imide 14 in 78% yield. Trans-
formation of imide 14 into pyrone 9b was accomplished
by two routes (Scheme 4): treatment with methyl ortho-
formate, aniline, and HOAc furnished enamine 15, which
reacted with ethyl cyanoacetate and t-BuOK to give
pyrone 9b in 68% overall yield; while simply heating 14
with the malonyl derivative 16a achieved the same
transformation in one pot and 60% yield. The key step
in our procedure, heating a solution of 9b in nitrobenzene
at 210 °C, now brought about both intramolecular cy-
cloaddition between pyrone and alkyne, and subsequent
loss of CO2 through a retro-Diels-Alder reaction, afford-
ing 10b in 83% yield. Synthesis of the naturally occur-
ring alkaloid anhydrolycorin-7-one (10d )2a,14 was com-
pleted in 80% yield by hydrolysis of the ethyl ester (KOH)
Exp er im en ta l Section
Gen er a l P r oced u r es. Solvents were dried by distillation
from a drying agent: THF from Na/benzophenone; CH2Cl2,
(12) (a) Dumont, J .-L.; Chodkiewicz, W.; Cadiot, P. Bull. Soc. Chem.
Fr. 1967, 2, 588. (b) Taylor, E. C.; Macor, J . E.; Pont, J . L. Tetrahedron
1987, 43, 5145. (c) Do¨tz, K. H.; Scha¨fer, T. O.; Harms, K. Synthesis
1992, 146.
(13) Stevens, T. S.; Wilson, J . L. J . Chem. Soc. 1928, 2827.
(14) Hara, H.; Hoshino, O.; Umezawa, B. Tetrahedron Lett. 1972,
5031.
(15) Cook, J . W.; Loudon, J . D.; McCloskey, P. J . Chem. Soc. 1954,
4176.
(16) Humber, L. G.; Kondo, H.; Kotera, K.; Takagi, S.; Takeda, K.;
Taylor, W. I.; Thomas, B. R.; Tsuda, Y.; Tsukamoto, K.; Uyeo, S.;
Yajima, H.; Yanaihara, N. J . Chem. Soc. 1954, 4622.
(17) Schmidt, R. R.; Betz, R. Synthesis 1982, 748.

1652 J . Org. Chem., Vol. 61, No. 5, 1996
Perez et al.
Sch em e 4
pyridine, and diisopropylamine from CaH2; DMF from P2O5;
MeOH from Mg/I2. Melting points are uncorrected. 1H and
13C NMR spectra were recorded at 250.13 and 62.83 MHz. LR
and HR mass spectra were recorded at 70 eV or using FAB.
TLC was performed on Merck silica gel 60 F254 or Merck
aluminum oxide 60 F254 (type E); chromatograms were visual-
ized with UV light (254 and 360 nm), iodine vapors, and
p-anisaldehyde. Flash column chromatography was performed
on Merck silica gel 60 (ASTM 230-400 mesh). 3,4-Dimethoxy-
homophthalic acid and 3,4-(methylenedioxy)homophthalic acid
were prepared following the procedure described by McKillop.18
6,7-Dim eth oxy-4-(m eth oxym eth ylen e)-1,2,3,4-tetr a h y-
d r oisoqu in olin e-1,3-d ion e (5a ). Methyl orthoformate (200
mg, 1.887 mmol) was added to a suspension of 6,7-dimethoxy-
homophthalimide (4a )10 (200 mg, 0.905 mmol) in 4:1 Ac2O-
DMF (8 mL), and the mixture was gently refluxed for 20 min.
After being cooled to rt, the solution was concentrated to half
its volume, and methanol (5 mL) was added. The precipitate
was collected by filtration affording 5a (180 mg, 76%) as a pale
yellow solid. Mp 216-217 °C (C2H5OH). 1H NMR (CDCl3) δ
8.15 (bs, 1 H); 7.96 (s, 1 H), 7.80 (s, 1 H); 7.63 (s, 1 H); 4.21 (s,
mg, 0.68 mmol) and ethyl cyanoacetate (100 mg, 0.93 mmol)
in dry DMF (2 mL), and the mixture was stirred at 90 °C for
45 min, poured on water (5 mL) containing concd HCl (0.5 mL),
and stirred at rt for 30 min. The resulting orange suspension
was filtered, the solid was redissolved in hot methanol, HCl
was added to pH 4, and stirring was kept up overnight. The
yellow precipitate was filtered out and vacuum-dried, affording
pyrone 6a (155 mg). The filtrate was concentrated and
chromatographed (SiO2; 99:1 CH2Cl2/CH3OH) to obtain ad-
ditional 6a (20 mg, 72%). Mp 290 °C dec, C2H5OH. 1H NMR
(DMSO-d6) δ 9.14 (s, 1 H); 7.63 (s, 1 H); 7.53 (s, 1 H); 4.29 (q,
J ) 7.1 Hz, 2 H); 4.00 (s, 3 H); 3.86 (s, 3 H); 1.30 (t, J ) 7.1
Hz, 3 H). IR (KBr): 1765, 1700, 1670, 1620, 1580 cm-1. UV
(C2H5OH), λmax: 222, 252, 278, 412 nm. LRMS, m/ z (%): 345
(M+, 100); 317 (14); 300 (10); 271 (11). HRMS for C17H15NO7.
Calcd: 345.0848. Found: 345.0856.
Eth yl 8,9-(Meth ylen ed ioxy)-3,6-d ioxo-5,6-d ih yd r o-3H-
p yr a n [2,3-c]isoqu in olin e-2-ca r boxyla te (6b). A solution
of 5b (100 mg, 0.325 mmol) in dry DMF (2 mL) was treated
with ethyl cyanoacetate (45 mg, 0.390 mmol) and KOt-Bu (54
mg, 0.482 mmol), following the procedure described for 6a .
Pyrone 6b (102 mg, 96%) was obtained as yellow crystals. Mp
293-294 °C dec, C2H5OH. 1H NMR (DMSO-d6) δ: 9.02 (s, 1
H); 7.87 (s, 1 H); 7.50 (s, 1 H); 6.21 (s, 2 H); 4.26 (q, J ) 7.0
Hz, 2 H); 1.30 (t, J ) 7.1 Hz, 3 H). UV (C2H5OH), λmax: 252,
284, 422 nm. LRMS, m/ z (%): 329 (M+, 19); 149 (37); 97 (88);
69 (100). HRMS for C16H11NO7. Calcd: 329.0535. Found:
329.0536.
3 H); 3.97 (s, 6 H). IR (KBr): 1725, 1640 cm-1
. UV (C2H5-
OH), λmax: 228, 270, 348 nm. LRMS, m/ z (%): 263 (M+, 100);
248 (21); 131 (15); 81 (13). HRMS for C13H13NO5. Calcd:
263.0794. Found: 263.0767.
4-(An ilin om eth ylen e)-6,7-(m eth ylen ed ioxy)-1,2,3,4-tet-
r a h yd r oisoqu in olin e-1,3-d ion e (5b). To a solution of 6,7-
(methylenedioxy)homophthalimide (4b)10 (150 mg, 0.732 mmol)
in DMF (3 mL) were successively added trimethyl orthofor-
mate (115 mg, 1.085 mmol), aniline (70 mg, 0.753 mmol), and
one drop of acetic acid. The mixture was stirred at 90 °C for
1 h and then cooled to 50 °C before addition of ethanol (5 mL).
The precipitate was collected by filtration, affording 5b (105
mg) as yellow crystals. The filtrate was concentrated and
chromatographed (8:1 CHCl3-ethyl ether) to give further 5b
(46 mg, 68%). Mp 328-330 °C (C2H5OH). 1H NMR (CDCl3)
δ 10.92-10.80 (m, 1 H); 8.28 (d, J ) 12.7 Hz, 1 H); 8.17 (bs, 1
H); 7.61 (s, 1 H); 7.57-7.35 (m, 2 H); 7.24-7.17 (m, 3 H); 7.03
(s, 1 H); 6.07 (s, 2 H). IR (KBr): 3330, 1655, 1605, 1590, 1565
cm-1. UV (C2H5OH), λmax: 232, 248, 276, 402 nm. LRMS, m/ z
(%): 308 (M+, 100); 291 (16); 279 (8). HRMS for C17H12N2O4.
Calcd: 308.0797. Found: 308.0786. Anal. for C17H12N2O4.
Calcd: C, 66.23; H, 3.92; N, 9.09. Found: C, 66.21; H, 3.93;
N, 8.92.
Rea ction of P yr on es 6 w ith Tosyla te 7. Rea ction of
6a w ith 7. KOt-Bu (23 mg, 0.20 mmol) was added to a solu-
tion of 6a (58 mg, 0.17 mmol) in dry DMF (1.5 mL) under N2,
and the mixture was refluxed for 1.5 h. A solution of tosylate
711 (100 mg, 0.446 mmol) in DMF (1 mL) was added, and
stirring under reflux was was continued for an additional 10
min. Water (5 mL) and 10% HCl (5 mL) were added, and the
mixture was stirred for 15 min and extracted with CH2Cl2 (2
× 25 mL). The organic phase was dried with Na2SO4, the
solvent was evaporated, and the residue was chromatographed
(15:85 ethyl ether-CHCl3) to afford ethyl 5-(3-butynyl)-8,9-
dimethoxy-3,6-dioxo-5,6-dihydro-3H-pyran[2,3-c]isoquinoline-
2-carboxylate (9a ) (31 mg, 46%) as a yellow solid. Mp 205-
206 °C (C2H5OH). 1H NMR (CDCl3) δ 9.00 (s, 1 H); 7.77 (s, 1
H); 7.22 (s, 1 H); 4.57 (t, J ) 6.7 Hz, 2 H); 4.46 (q, J ) 7.1 Hz,
2 H); 4.10 (s, 3 H); 4.02 (s, 3 H); 2.76 (dt, J ) 6.7, 2.6 Hz, 2 H);
1.96 (t, J ) 2.6 Hz, 1 H); 1.44 (t, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3) δ 164.2; 160.1; 155.3; 154.8; 154.3; 149.7; 146.4; 126.5;
116.1; 109.1; 107.1; 101.5; 95.6; 79.7; 71.1; 62.1; 56.7; 56.6; 40.6;
Eth yl 8,9-Dim eth oxy-3,6-d ioxo-5,6-d ih yd r o-3H-p yr a n -
[2,3-c]isoqu in olin e-2-ca r boxyla te (6a ). Freshly prepared
NaOMe (50 mg, 0.93 mmol) was added to a solution of 5a (180
17.9; 14.5. IR (KBr): 1775, 1670 cm-1. UV (C2H5OH), λmax
226, 272, 320, 400 nm. LRMS (FAB), m/ z (%): 398 (M+ + 1,
:
(18) Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607.

Synthesis of Antitumor Lycorines
J . Org. Chem., Vol. 61, No. 5, 1996 1653
20.5); 397 (16); 231 (32); 154 (100). Anal. for C21H19NO7
Calcd: C, 63.47; H, 4.82; N, 3.53. Found: C, 63.21; H, 4.90;
N, 3.49. Ethyl 6-(3-butynyloxy)-8,9-dimethoxy-3-oxo-3H-py-
ran[2,3-c]isoquinoline-2-carboxylate (8a ) was also isolated (31
mg, 46%). Mp 235-237 °C (C2H5OH). 1H NMR (CDCl3) δ 9.08
(s, 1 H); 7.56 (s, 1 H); 7.38 (s, 1 H); 4.73 (t, J ) 6.6 Hz, 2 H);
4.44 (q, J ) 7.1 Hz, 2 H); 4.11 (s, 3 H); 4.03 (s, 3 H); 2.83 (dt,
J ) 6.6, 2.7 Hz, 2 H); 2.05 (t, J ) 2.7 Hz, 1 H); 1.43 (t, J ) 7.1
Hz, 3 H). 13C NMR (CDCl3) δ 164.5; 162.8; 158.2; 157.0; 155.3;
149.8; 145.1; 131.5; 113.2; 112.1; 104.2; 101.3; 100.7, 80.0; 70.2;
at atmospheric pressure, and the flask containing the white
solid residue was evacuated and filled with argon twice before
being heated at 220 °C (external temperature, sand bath) until
5 min after the solid melted. The residue was chromato-
graphed (SiO2, CH2Cl2) to afford imide 14 (249 mg, 79%) as a
white solid. Mp 171-176 °C (sublimed). 1H NMR (CDCl3) δ
7.56 (s, 1 H); 6.66 (s, 1 H); 6.07 (s, 2 H); 4.16 (t, J ) 7.3 Hz, 2
H); 3.94 (s, 2 H); 2.55 (dt, J ) 7.3, 2.6 Hz, 2H); 1.97 (t, J ) 2.6
Hz, 1 H). 13C NMR (CDCl3) δ 169.7; 163.9; 152.66; 147.8;
130.3; 119.3; 107.9; 106.4; 102.1; 80.7; 69.7; 38.2; 36.4; 17.5.
UV (C2H5OH), λmax: 208, 228, 272, 310 nm. LRMS, m/ z (%):
257 (M+, 77.8); 218 (24.9); 205 (34.7); 189 (100). HRMS for
C14H11NO4. Calcd: 257.0688. Found: 257.0691.
4-(An ilin om et h ylen e)-2-(3-b u t yn yl)-6,7-(m et h ylen e-
d ioxy)-1,2,3,4-tetr a h yd r oisoqu in olin e-1,3-d ion e (15). To
a solution of imide 14 (45 mg, 0.175 mmol) in DMF (3 mL)
containing one drop of acetic acid, solutions of trimethyl
orthoformate (56 mg, 0.526 mmol) and aniline (50 mg, 0.526
mmol) in DMF (1 mL each) were successively added. The
resulting mixture was heated at 90 °C for 3.5 h, concentrated
65.7; 61.9; 56.5; 56.2; 19.1; 14.3. IR (KBr): 1740, 1715 cm-1
.
UV (C2H5OH), λmax: 226, 252, 276, 282, 318, 392 nm. LRMS,
m/ z (%): 397 (M+, 30); 167 (100). HRMS for C21H19NO7.
Calcd: 397.1162. Found: 397.1161. Treatment of a solution
of 8a (10 mg, 0.025 mmol) in C2H5OH (2 mL) with 36% HCl (1
mL) for 1 h at 70 °C, removal of the ethanol, partition of the
mixture between H2O and CH2Cl2, and chromatography (1%
CH2Cl2-MeOH) recovered 6a (7 mg, 80%).
Rea ction of 6b w ith 7. Pyrone 6b (125 mg, 0.380 mmol)
in DMF (4 mL) was reacted with KOt-Bu (54 mg, 0.408 mmol)
and tosylate 7 (225 mg, 1 mmol) for 1.5 h, as described above,
to afford 5-(3-butynyl)-8,9-(methylenedioxy)-3,6-dioxo-5,6-di-
hydro-3H-pyran[2,3-c]isoquinoline-2-carboxylate (9b) (45 mg,
31%) and 6-(3-butynyloxy)-8,9-(methylenedioxy)-3-oxo-3H-py-
ran[2,3-c]isoquinoline-2-carboxylate (8b) (50 mg, 35%). Da ta
for 9b. Mp 210-211 °C (acetone). 1H NMR (CDCl3-CD3OD
50:1) δ 8.94 (s, 1 H); 7.51 (s, 1 H); 7.40 (s, 1 H); 6.14 (s, 2 H);
4.63 (t, J ) 6.6 Hz, 2 H); 4.39 (q, J ) 7.1 Hz, 2 H); 2.76 (dt, J
) 6.6, 2.6 Hz, 2 H); 2.04 (t, J ) 2.6 Hz, 1 H); 1.39 (t, J ) 7.1
Hz, 3 H). 13C NMR (CDCl3-CD3OD 50:1) δ 163.8; 162.9; 158.0;
157.0; 153.8; 148.2; 145.2; 133.4; 113.3; 113.0; 102.5; 102.1;
101.7; 98.7; 79.9; 70.1; 65.7; 61.8; 18.9; 14.1. IR (KBr): 1775,
1735, 1675 cm-1. UV (C2H5OH), λmax: 226, 242, 284, 392 nm.
LRMS, m/ z (%): 381 (M+, 100); 329 (86); 301 (59). HRMS for
C20H15NO7. Calcd: 381.0848. Found: 381.0844. Anal. for
C20H15NO7. Calcd: C, 62.99; H, 3.96; N, 3.67. Found: C,
62.72; H, 3.81; N, 3.97. Da ta for 8b. Mp 220-221 °C
(acetone). 1H NMR (CDCl3) δ 9.02 (s, 1 H); 7.60 (s, 1 H); 7.47
(s, 1 H); 6.19 (s, 2 H); 4.70 (t, J ) 6.6 Hz, 2 H); 4.44 (q, J ) 7.1
Hz, 2 H); 2.80 (dt, J ) 6.6, 2.6 Hz, 2 H); 2.06 (t, J ) 2.6 Hz, 1
H); 1.45 (t, J ) 7.1 Hz, 3 H). 13C NMR (CDCl3) δ 163.8; 162.8;
158.2; 156.8; 153.7; 148.2; 144.9; 133.5; 113.4; 102.2; 101.7;
under reduced pressure, and treated with CH3
OH (3 mL). The
resulting suspension was filtered to afford enamine 15 (36 mg)
as a yellow solid, and the filtrate was concentrated to dryness
and chromatographed (5% ethyl ether-CH2Cl2), yielding ad-
ditional 15 (20 mg, 89% yield). Mp 214-216 °C (C2H5OH),
bright yellow crystals. 1H NMR (CDCl3) δ 12.29 (bd, J ) 12
Hz, 1 H); 8.25 (d, J ) 12.5 Hz, 1 H); 7.63 (s, 1 H); 7.45-7.39
(m, 2 H); 7.26-7.16 (m, 3 H); 6.99 (s, 1 H); 6.05 (s, 2 H); 4.32
(t, J ) 7.3 Hz, 2 H); 2.65-2.60 (m, 2 H); 1.99 (bs, 1 H).
13C
NMR (CDCl3) δ 166.1; 162.9; 153.0; 146.0; 142.9; 139.4; 132.1;
130.0; 125.0; 117.3; 115.9; 107.3; 101.8; 97.0; 96.6; 81.2; 69.6;
38.2; 17.6. UV (C2
H OH), λmax: 232, 312, 402 nm. LRMS, m/ z
5
(%): 360 (M+, 100); 308 (67); 292 (31); 291 (20). HRMS for
C21H16N2O4. Calcd: 360.1110. Found: 360.1111. Anal. for
C21H16N2O4. Calcd: C, 69.99; H, 4.48; N, 7.77. Found: C,
69.48; H, 4.54; N, 7.62.
E t h yl 5-(3-Bu t yn yl)-8,9-(m et h ylen ed ioxy)-3,6-d ioxo-
5,6-d ih yd r o-3H -p yr a n [2,3-c]isoq u in olin e-2-ca r b oxyla t e
(9b). F r om en a m in e 15. KOt-Bu (34 mg, 0.3 mmol) was
added to a solution of 15 (72 mg, 0.2 mmol) and ethyl
cyanoacetate (34 mg, 0.3 mmol) in dry DMF (2 mL), and the
mixture was stirred at 90 °C for 1 h. HCl (36%, 1 mL) was
added, stirring was continued at rt for 3 h, and the resulting
orange suspension was filtered. The solid was redissolved in
hot methanol, HCl was added to pH 4, and stirring was
continued overnight. The solvent was removed under reduced
pressure, water (2 mL) was added, and the resulting suspen-
sion was extracted with CH2Cl2 (3 × 3 mL). The organic phase
was dried with Na2SO4 and was chromatographed (4% ethyl
ether-CH2Cl2) to afford pyrone 9b (30 mg, 76%). F r om im id e
14. A mixture of imide 14 (26 mg, 0.10 mmol) and ethoxym-
ethylene diethyl malonate (16a ) (24 mg, 0.11 mmol) was sealed
in a tube in an argon atmosphere and heated for 10 min at
200 °C (external temperature, sand bath). Chromatography
of the mixture (2:8 ethyl ether-CH2Cl2) then afforded pyrone
9b (23 mg, 60%).
98.7; 80.0; 70.1; 65.7; 61.8; 19.0; 14.2. IR (film): 1755 cm-1
.
UV (C2H5OH), λmax: 222, 254, 268, 330, 382 nm. LRMS, m/ z
(%): 381 (M+, 35); 329 (35); 280 (85); 229 (55); 69 (100). HRMS
for C20H15NO7. Calcd: 381.0848. Found: 381.0847.
3-Bu tyn -1-a m in e Hyd r och lor id e (12). (i) NaN3 (5.62 g,
117.19 mmol) was added to a solution of 3-butynyl p-toluene-
sulfonate (7)11 (5.25 g, 23.44 mmol) in dry DMF (30 mL), and
the resulting suspension was stirred for 24 h. The mixture
was partitioned between H2O (100 mL) and ethyl ether (100
mL), the aqueous phase was extracted with ethyl ether (50
mL), and the combined organic phase was thoroughly washed
with H2O (5 × 25 mL), dried with MgSO4, and concentrated
to remove most of the ether. The resulting clear liquid,
containing 3-butynyl azide, was used in step ii without further
purification. (ii) The reaction crude obtained as above was
dissolved in CH3OH (75 mL), SnCl2‚2H2O (10.58 g, 46.88
mmol) was added, and stirring at rt was kept up for 24 h. The
solvent was evaporated at reduced pressure, the residue was
dissolved in 10% aqueous NaOH, and this solution was
extracted with CH2Cl2 (5 × 40 mL). The combined organic
phase was dried with Na2SO4, a saturated solution of HCl in
ethyl ether (20 mL) was added, and the resulting precipitate
was collected by filtration, affording 12 (2.14 g) as a white solid;
the filtrates were concentrated to dryness to obtain additional
12 (310 mg, quantitative yield). Spectroscopic data were
identical with those reported in the literature.12c
5-(3-Bu tyn yl)-2-m eth oxy-8,9-(m eth ylen ed ioxy)-5,6-d i-
h yd r o-3H-p yr a n [2,3-c]isoqu in olin e-3,6-d ion e (9c). A so-
lution of methyl 3-(dimethylamino)-2-methoxyacrylate (16b)17
(48 mg, 300 mmol) in CH2Cl2 (0.5 mL) was added to imide 14
(51 mg, 0.198 mmol). The mixture was heated for 10 min at
180 °C (external temperature, sand bath) under a strong
current of argon. The crude residue was chromatographed (4%
ethyl ether-CH2
Cl2) to afford pyrone 9c (60 mg, 90%) as a
white solid. Mp 227-228 °C (CH2Cl2-hexanes). 1H NMR
(DMSO-d6) δ 7.81 (s, 1 H); 7.70 (s, 1 H); 7.51 (s, 1 H); 6.20 (s,
2 H); 4.24 (t, J ) 7.2 Hz, 2 H); 3.85 (s, 3 H); 2.87 (t, J ) 2.4
Hz, 1 H); 2.60 (m, 2 H). 13C NMR (DMSO-d6) δ 158.4; 154.7;
153.0; 147.3; 143.8; 139.7; 129.3; 117.3; 113.6; 105.2; 102.6;
100.9; 94.2; 80.7; 73.1; 57.0; 17.2. UV (C2H5OH), λmax: 226,
260, 278, 360 nm. LRMS, m/ z (%): 339 (M+, 100); 296 (63);
244 (79); 177 (28). HRMS for C18H13NO6. Calcd: 339.0743.
Found: 339.0736.
2-(3-Bu t yn yl)-6,7-(m e t h yle n e d ioxy)-1,2,3,4-t e t r a h y-
d r oisoqu in olin e-1,3-d ion e (14). Hydrochloride 12 (650 mg,
6.16 mmol) was dissolved in 10% aqueous NaOH (5 mL), the
solution was extracted with CH2Cl2 (3 × 2 mL), and the
combined organic phase was dried over Na2SO4. The solution
of 3-butyn-1-amine so obtained was added at rt to a solution
of anhydride 1313 (258 mg, 1.22 mmol) in CH2Cl2 (5 mL), and
stirring was continued for 20 h. The solvent was distilled off
Cycliza tion of P yr on es 9. Gen er a l P r oced u r e.
A
solution of pyrone 9 in nitrobenzene is heated under argon
until the starting material has been consumed (TLC). The

1654 J . Org. Chem., Vol. 61, No. 5, 1996
Perez et al.
solvent is removed by vacuum distillation, and the residue is
chromatographed to afford 10.
as a white solid. Mp 268-269 °C (CH3OH). 1H NMR (CDCl3)
δ 7.91 (s, 1 H); 7.46 (s, 1 H); 7.16 (s, 1 H); 6.94 (s, 1 H); 6.13
(s, 2 H); 4.47 (t, J ) 8.0 Hz, 2 H); 3.89 (s, 3 H); 3.39 (t, J ) 8.0
Hz, 2 H). 13C NMR (CDCl3) δ 158.9; 156.9; 151.7; 148.5; 133.9;
132.2; 130.3; 123.4; 116.6; 112.9; 106.9; 102.4; 102.0; 100.8;
56.1; 46.1; 27.4. UV (C2H5OH), λmax: 204, 244, 284, 360, 344
nm. LRMS, m/ z (%): 295 (M+, 96); 280 (100); 222 (13).
HRMS for C17H13NO4. Calcd: 295.0845. Found: 295.0841.
An h yd r olycor in -7-on e (10d ). A solution of 10b (11 mg,
0.033 mmol) in a 10% ethanolic solution of KOH (1 mL) was
heated at 80 °C for 15 min. The solvent was removed under
reduced pressure, and the solid residue was suspended in cold
10% HCl (1 mL) and stirred for 15 min. The solvent was
decanted, the solid was dried under vacuum and suspended
in freshly distilled quinoline (2 mL), Cu bronze was added (15
mg), and the mixture was heated under argon for 2.5 h at 220
°C (external temperature, sand bath). The crude reaction
mixture was filtered through Celite, using CH2Cl2 (20 mL) to
wash the solid. The filtrate was extracted with 10% HCl (3 ×
10 mL), and the organic phase was dried with Na2SO4,
concentrated, and chromatographed (10% ethyl ether-CH2-
Cl2) to afford 10d (9 mg, 80%) as a white solid. Mp 230-231
°C (C2H5OH) [lit.: 228-230 °C2a (C6H6-C2H5OH); 232-234
°C14 (CHCl3-CH3OH). Spectroscopic data were identical with
those reported in the literature.14
Eth yl 9,10-Dim eth oxy-7-oxo-4,5-d ih yd r o-7H-p yr r olo-
[3,2,1-d e]p h en a n th r id in e-2-ca r boxyla te (10a ). Pyrone 9a
(4 mg, 0.01 mmol) was refluxed for 8 h in nitrobenzene (2 mL).
Chromatography (0.5% CH2Cl2-MeOH) afforded 10a (4 mg,
quantitative yield) as a white solid. Mp 228-229 °C (C6H6-
hexanes). 1H NMR (CDCl3) δ 8.57 (s, 1 H); 7.96 (s, 1 H); 7.92
(s, 1 H); 7.60 (s, 1 H), 4.53 (t, J ) 8.2 Hz, 2 H); 4.42 (q, J ) 7.1
Hz, 2 H); 4.12 (s, 3 H); 4.05 (s, 3 H); 3.46 (t, J ) 8.2 Hz, 2 H);
1.45 (t, J ) 7.1 Hz, 3 H). 13C NMR (CDCl3) δ 166.8; 160.0;
153.4; 150.2; 142.8; 131.1; 128.3; 125.7; 124.5; 122.5; 121.4;
116.1; 108.9; 103.3; 61.1; 56.4; 56.3; 46.9; 27.0; 14.4. IR
(film): 1710, 1645, 1605 cm-1. UV (C2H5OH), λmax: 254, 266,
274, 302, 314, 328, 344 nm. LRMS, m/ z (%): 353 (M+, 100);
308 (23). HRMS for C20H19NO5. Calcd: 353.1263. Found:
353.1262. Anal. for C20H19NO5. Calcd: C, 67.98; H, 5.42; N,
3.96. Found: C, 67.92; H, 5.15; N, 4.33.
E t h yl 9,10-(Met h ylen ed ioxy)-7-oxo-4,5-d ih yd r o-7H -
p yr r olo[3,2,1-d e]p h en a n th r id in e-2-ca r boxyla te (10b). Py-
rone 9b (15 mg, 0.04 mmol) was refluxed for 7 h in nitroben-
zene (2 mL). Chromatography (0.5% CH2Cl2-MeOH) afforded
10b (11 mg, 83%) as a white solid. Mp 237-238 °C (CH3OH).
1H NMR (CDCl3) δ 8.54 (s, 1 H); 7.97 (s, 1 H); 7.91 (s, 1 H);
7.66 (s, 1 H); 6.16 (s, 2 H); 4.53 (t, J ) 8.2 Hz, 2 H); 4.43 (q, J
) 7.1 Hz, 2 H); 3.46 (t, J ) 8.2 Hz, 2 H); 1.45 (t, J ) 7.1 Hz,
3 H). 13C NMR (CDCl3) δ 166.7; 155.2; 152.3; 148.4; 131.1;
130.4; 125.8; 124.7; 123.1; 122.6; 116.1; 106.8; 102.3; 101.1;
61.1; 46.9; 27.0; 14.4. IR (film): 1710, 1645, 1605 cm-1. UV
(C2H5OH), λmax: 220, 232, 242, 252, 268, 276, 302, 328, 344
nm. LRMS, m/ z (%): 337 (M+, 100); 308 (29); 292 (39); 264
(21); 206 (13); 178 (14). HRMS for C19H15NO5. Calcd: 337.0950.
Found: 337.0940. Anal. for C19H15NO5. Calcd: C, 67.65; H,
4.48; N, 4.15. Found: C, 67.39; H, 4.70; N, 4.06.
Ack n ow led gm en t. Financial support from the DGI-
CYT (PB90-0764) is gratefully acknowledged. D.P.
thanks the Spanish Ministry of Education for the award
of a research grant.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for compounds 5a , 6a ,b, 8a ,b, 14, 9c, and 10c (8
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
2-Meth oxy-9,10-(m eth ylen ed ioxy)-4,5-d ih yd r o-7H-p yr -
r olo[3,2,1-d e]p h en a n th r id in -7-on e (10c). Pyrone 9c (19
mg, 0.056 mmol) was heated for 4 h at 230 °C (external
temperature, sand bath) in nitrobenzene (0.5 mL). Chroma-
tography (4% ethyl ether-CH2Cl2) afforded 10c (10 mg, 60%)
J O9518415