Efficient synthesis of a new structural phenanthro[9,10,3′,4′] indolizidine starting from pyrrole

Article abstract of DOI:10.1021/jo701590p

(Chemical Equation Presented) A new structural phenanthroindolizidine, 2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]indolizidine, has been synthesized efficiently from pyrrole. An important feature of this synthesis is that intramolecular oxidative coupling

Full text of DOI:10.1021/jo701590p

Efficient Synthesis of a New Structural
Phenanthro[9,10,3′,4′]indolizidine Starting from Pyrrole
Kailiang Wang, Qingmin Wang,* and Runqiu Huang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry,
Nankai UniVersity, Tianjin 300071, People’s Republic of China
wang98h@263.net; wangqm@syn.nankai.edu.cn
ReceiVed July 27, 2007
A new structural phenanthroindolizidine, 2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]indolizidine, has been
synthesized efficiently from pyrrole. An important feature of this synthesis is that intramolecular oxidative
coupling and rearrangement of 6,7-bis(3,4-dimethoxyphenyl)-8-methoxy-1,2,3-trihydroindolizin-5-one by
using VOF3 and TFA have been achieved in one pot.
Introduction
these interesting biological activities, antitumor activity is
most notable,4,6 and thus, it is responsible for considerable
synthetic attention.3,4,7 We have found that (-)-antofine
from Cynanchum komaroVii possesses excellent antiviral activity
against the tobacoo mosaic virus (TMV).8 Recently, we have
developed two different approaches to (+)-tylophorine and
(+)-deoxytylophorinine and found that the two phenanthroin-
dolizidine alkaloids possess good antiviral activity against
TMV.9
The phenanthroindolizidine and phenanthroquinolizidine al-
kaloids are structurally related groups of pentacyclic natural
products, for example, (-)-antofine (1, Figure 1) and (-)-
cryptopleurine (2, Figure 1).1 Since the first isolation of (-)-
tylophorine (3, Figure 1) in 1935,2 more than 60 alkaloids and
their seco analogues have been reported.3,4 These alkaloids
exhibit interesting pharmacological properties.1,4,5 Among
(1) Bick, I. R. C.; Sinchai, W. In The Alkaloids; Rodrigo, R. G. A., Ed.;
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W. Abstracts of Papers, Part 2, 229st Meeting of the American Chemical
Society, San Diego, CA, Mar 13-18, 2005; American Chemical Society:
Washington, DC, 2005; U326-U326 017-ORGN. (g) Furstner, A.; Kennedy,
J. W. J. Chem. Eur. J. 2006, 12, 7398-7410. (h) Camacho-Davila, A.;
Hemdon, J. W. J. Org. Chem. 2006, 71, 6682-6685. (i) Kim, S.; Lee, Y.
M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem.
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M.; Li, G. R.; Yao, Y. C.; Yu, X. S.; Huang, R. Q. Fine Chemical Intermed.
(Chapter) 2007, 37, 20-24.
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10.1021/jo701590p CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
8416
J. Org. Chem. 2007, 72, 8416-8421

Synthesis of a Phenanthro[9,10,3′,4′]indolizidine from Pyrrole
FIGURE 1. Chemical structures of compounds 1-4.
SCHEME 1
SCHEME 2. Synthesis of a New Skeleton Intermediate 13
In order to extend our research work of phenanthroindolizi-
dine alkaloids as antiviral agents and explore further the effect
of the 14-methoxy substituent upon antiviral activity, we planned
to synthesize 14-methoxytylophorine 4 (Figure 1) from pyrrole
(Schemes 1 and 2). However, we were unable to obtain the
desired oxidative coupling product 11 (Scheme 2), so we failed
to gain the desired compound 4. Fortunately, we obtained a new
skeleton structural product 12 (Scheme 2), which is determined
by 1H, 13C NMR, IR, MS, and X-ray diffraction. The compound
12 was used as a key intermediate to synthesize a new structural
phenanthroindolizidine alkaloid, 2,3,6,7-tetramethoxyphenanthro-
[9,10,3′,4′]indolizidine (19), which is different from tylophorine
formulated as 2,3,6,7-tetramethoxyphenanthro[9,10,6′,7′]indo-
lizidine. In this paper, we describe full details of our synthetic
route to the new skeleton structural phenanthroindolizidine
alkaloid 19.
J. Org. Chem, Vol. 72, No. 22, 2007 8417

Wang et al.
Results and Discussion
Starting with readily available pyrrole, compound 10 was
rapidly assembled through the sequence of reactions as shown
in Scheme 1 with good yields. Herz and Tocker have reported
the synthesis of 2-acylpyrrole 7 by use of pyrrole, ethyl
magnesium iodide, and 2-(3,4-dimethoxyphenyl)acetyl chloride,
but only in 7.2% yield.10 Friedel-Crafts acylation of pyrrole
with 2-(3,4-dimethoxyphenyl)acetyl chloride afforded 2-acylpyr-
role 7 in poor yield, although it is a convenient reaction for the
acylation of substituted pyrroles.11 We found that the Vils-
meier-Haack condensation of pyrrole with 6 in the presence
of phosphorus oxychloride provided the expected 2-acylpyrrole
7 in 92% yield.
It has been reported that indolizinedione 8 was synthesized
by a five-step sequence from dimethyl squarate and 4-bromov-
eratrole with 59% overall yield.12 Herein, a different reaction
sequence was employed for the preparation of the indolizinedi-
one 8 easily. We found that N-acylation and aldol-type
condensation reaction of the 2-acylpyrrole 7 with 2-(3,4-
dimethoxyphenyl)-2-oxoacetyl chloride in the presence of
Et3N and DMAP have been proceeded in one pot to give the
desired indolizinedione 8 at room temperature in 90% yield.
This new and efficient synthesis of indolizinedione 8 enjoys a
number of advantages in that the reaction is carried out
under mild conditions, starting materials are cheap or easily
prepared, the experimental procedure is very simple, the yield
is high, and this method may be applicable to large-scale
production.
FIGURE 2. Molecular structure of 12 in the crystal.
Borohydride reduction of carbonyl function of 12 gave
alcohol 14 in 98% yield, which was oxidized and demethylated
in one pot by using SOCl2 to obtain 13 with 76% yield.
Interestingly, while increasing the quantities of trifluoroacetic
acid, the reaction of the compound 10 with VOF3 gave the
compound 13 in one step in 91% yield. Thus, an attractive
approach to the synthesis of the new skeleton intermediate 13
involves the rearrangement reaction and oxidative coupling and
demethylation outlined in Scheme 2.
Catalytic hydrogenation of 8 gave an essentially quantitative
yield of 9.12 Compound 9 reacted with MeI in the presence of
NaH to afford methyl ether 10 in 93% yield.
Vanadium-induced organic synthesis has gained significant
importance in recent years.14 Oxovanadium-catalyzed epoxida-
tion is an especially important reaction in organic synthesis.15
Oxovanadium compounds participate in oxo-transfer reactions
and cause either oxygenation or epoxidation. Hence, we propose
that the new skeleton structural product 12 is formed by
rearrangement of an epoxide intermediate 11a in acidic media
(TFA) as outlined in Scheme 3. Epoxidation of the oxidative
coupling product 11 affords an epoxide 11a which rearranges
in acidic media to give 11c. Deprotonation of 11c yields the
isolated product 12, which has a new structural skeleton.
Indeed, vanadium(V) oxytrifluoride has proven to be a highly
efficient reagent for intramolecular biaryl oxidative coupling
of the substituted stilbenes.13 Surprisingly, treatment of 10 with
VOF3 in the presence of trifluoroacetic acid provided 12, not
the desired product 11 (Scheme 2). This transformation involves
oxidative coupling of bis(3,4-dimethoxyphenyl) and rearrange-
ment of 8-methoxy-2,3-dihydroindolizin-5(1H)-one. The im-
portant intermediate 12 was a new skeleton structural phenan-
throindolizidine derivative, which was determined by X-ray
diffraction (Figure 2). The structure of the compound 12 shows
a conjunction of phenanthrene and indolizidine moieties. The
aromatic rings lie almost in the same plane. The observed bond
lengths and angles are normal in their alternate single- and
double-bond display. The pyrrolidine ring is almost coplanar
with the phenanthrene ring. The pyrrolidine ring adopts an
envelope conformation. Crystal 12 provides the first crystal-
lographic evidence of the new structural phenanthro[9,10,3,′,4′]-
indolizidine alkaloid.
The compound 13 was easily converted to 19 as shown in
Scheme 4. First, treatment of the compound 13 with Et3SiH/
CF3COOH16 gave 15 in 92% yield. Then reduction of 15 by
using sodium borohydride afforded hydroxylactam 16 in 96%
yield, which was treated with carbon tetrabromide and triph-
enylphosphine at 50 °C in THF to provide the bromolactam 17
in 96% yield. Upon hydrogenolysis with 10% palladium on
carbon, the compound 17 was converted to 18 in 95% yield.
Finally, the lactam 18 was reduced with a mixture of hydride
reagent from lithium aluminum hydride and aluminum chloride
(10) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77, 6355-6357.
(11) (a) Ripas, R. N.; Buu-Hoi, N. P. J. Org. Chem. 1959, 24, 372-
374. (b) Loader, C, E.; Anderson, H. J. Tetrahedron 1969, 25, 3879-3885.
(c) Heine, H. W.; Peavy, R.; Durbetaki, A. J. J. Org. Chem. 1966, 31, 3924-
3927. (d) Berger, J. G.; Teller, S. R.; Pachter, I. J. J. Org. Chem. 1970, 35,
3122-3126. (e) Anderson, H. J.; Huang, C. W. Can. J. Chem. 1967, 45,
897-902. (f) Badger, G. M.; Ward, A. D. Aust. J. Chem. 1964, 17, 649-
660.
(14) (a) Hirao, T. Chem. ReV. 1997, 97, 2707-2724. (b) Reddy, P. P.;
Chu, C. Y.; Hwang, D. R.; Wang, S. K.; Uang, B. J. Coord. Chem. ReV.
2003, 237, 257-269.
(15) (a) Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
10452-10453. (b) Hoshino, Y.; Murase, N.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 2000, 73, 1653-1658. (c) Bolm, C.; Kuhn, T. Synlett 2000, 6,
899-901. (d) Murase, N.; Hoshino, Y.; Oishi, M.; Yamamoto, H. J. Org.
Chem. 1999, 64, 338-339. (e) Bolm, C.; Luong, T. K. K.; Harms, K. Chem.
Ber./Recl. 1997, 130, 887-890. (f) Berrisford, D. J.; Bolm, C.; Sharpless,
K. B. Angew. Chem., Int. Ed. 1995, 34, 1059-1070. (g) Sharpless, K. B.;
Michaelson, R. C. J. Am. Chem. Soc. 1977, 99, 1990-1992.
(16) (a) Ha, D. C.; Yun, C. S.; Lee, Y. J. Org. Chem. 2000, 65, 621-
623. (b) Pansare, S. V.; Jain, R. P. Org. Lett. 2000, 2, 175-177. (c) Ewing,
G. J.; Robins, M. J. Org. Lett. 1999, 1, 635-636.
(12) Yerxa, B. R.; Yang, K.; Moore, H. W. Tetrahedron 1994, 50, 6173-
6180.
(13) (a) Liepa, A. J.; Summons, R. E. Chem. Commun. 1977, 826-827.
(b) Buckley, T. F., III; Rapoport, H. J. Org. Chem. 1983, 48, 4222-4232.
(c) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.; Dc Vries, K. M. J. Am.
Chem. Soc. 1993, 115, 6426-6427. (d) Ciufolini, M. A.; Roschangar, F. J.
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8418 J. Org. Chem., Vol. 72, No. 22, 2007

Synthesis of a Phenanthro[9,10,3′,4′]indolizidine from Pyrrole
SCHEME 3
SCHEME 4
(3:1)17 to afford 2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]-
indolizidine (19) in 89% yield (Scheme 4).
method of the new skeleton structural phenanthro[9,10,3′,4′]indo-
lizidine alkaloids for biochemical and pharmaceutical studies.
Insummary,thefirstsynthesisof2,3,6,7-tetramethoxyphenanthro-
[9,10,3′,4′]indolizidine (19) was accomplished from com-
mercially available chemicals in high overall yield. Intramo-
lecular oxidative coupling and rearrangement of 6,7-bis(3,4-
dimethoxyphenyl)-8-methoxy-1,2,3-trihydroindolizin-5-one (10)
was successfully achieved in one pot by using VOF3 and
TFA.The chemistry described here provides a practical synthetic
Experimental Section
2-(3,4-Dimethoxyphenylacetyl)pyrrole (7). To a magnetically
stirred and cold (0 °C) solution of 6 (13.25 g, 0.05 mol) in
anhydrous 1,2-dichloroethane (40 mL) was added dropwise freshly
distilled phosphorus oxychloride (10 mL). The reaction mixture
was stirred at 0 °C for 10 min and then at room temperature for 4
h. A solution of freshly distilled pyrrole (3.35 g, 0.05 mol) in
anhydrous 1,2-dichloroethane (60 mL) was added at 0 °C. Then
the reaction mixture was refluxed for 5 h and cooled. A 10%
(17) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64,
8648-8659.
J. Org. Chem, Vol. 72, No. 22, 2007 8419

Wang et al.
aqueous solution of sodium carbonate (250 mL) was added, and
the resulting mixture was stirred slowly at first and then as rapidly
as possible with vigorous stirring. The resulting mixture was
refluxed for 15 min, and then the organic phase was separated and
the aqueous phase was extracted with CH2Cl2. The combined
organic solution was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The dark solid was purified
by flash column chromatography on silica gel and recrystallized
from ethanol to give 7 (11.27 g, 92%) as a white solid: mp 101-
102 °C (lit.10 mp 99 °C); 1H NMR (300 MHz, CDCl3) δ 9.57 (br,
1H), 7.03 (m, 2H), 6.81-6.85 (m, 3H), 6.29-6.32 (m, 1H), 4.02
(s, 2H), 3.88 (s, 3H), 3.87 (s, 3H).
quenched with H2O carefully. The aqueous phase was extracted
with CH2Cl2. The extracts were washed with brine, dried over
MgSO4, and evaporated in vacuo to yield a light yellow solid.
Recrystallization from methanol gave the desired product 10 (1.92
g, 93%) as a colorless solid: mp 180-182 °C; 1H NMR (300 MHz,
CDCl3) δ 6.62-6.74 (m, 6H), 4.22-4.27 (m, 2H), 3.85 (s, 3H),
3.81 (s, 3H), 3.64 (s, 6H), 3.27 (s, 3H), 3.20-3.25 (m, 2H), 2.21-
2.36 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 159.7, 148.3, 148.1,
147.7, 147.0, 140.1, 136.7, 128.5, 128.1, 127.5, 123.9, 122.8, 114.8,
113.7, 110.6, 110.5, 60.7, 55.9, 55.81, 55.77, 55.71, 49.7, 29.1,
21.51; IR (KBr, cm-1) 3070, 3021, 2986, 2934, 2904, 2877, 2831,
1648, 1604, 1463, 1261; EI-MS m/z 437 (M+, 100), 422 (30), 394
(8), 391 (5), 363 (4), 348 (3), 211 (4), 68 (3), 41 (3); HRMS (EI)
calcd for C25H27NO6 (M+) 437.1838, found 437.1831.
6,7-Bis(3,4-dimethoxyphenyl)indolizin-5,8-dione (8). To a
solution of 1,2-dimethoxybenzene (6.58 g, 0.05 mol), ethyl oxalyl
chloride (6.82 g, 0.05 mol), and 1,2-dichloroethane (50 mL) was
added anhydrous aluminum chloride (6.04 g, 0.045 mol) portionwise
at 0 °C. Then the reaction mixture was refluxed for 8 h and poured
into ice-cold 5% dilute hydrochloric acid (100 mL). To the mixture
was added CH2Cl2 (200 mL) with shaking. The organic layer was
washed with a 10% aqueous solution of sodium carbonate (100
mL). The aqueous layer was separated, filtered, and made acidic
with concentrated hydrochloric acid, and the product was extracted
with CH2Cl2 (150 mL) and crystallized from ethyl acetate to yield
2-(3,4-dimethoxyphenyl)-2-oxoacetic acid (8.11 g, 81%) as a light
2,3,6,7,14a-Pentamethoxyphenanthro[9,10,3′,4′]-9,14-indoliz-
idinedione (12). To the solution of 10 (1.0 g, 2.29 mmol) in 8 mL
of dry CH2Cl2 containing two drops of trifluoroacetic anhydride
was added vanadium oxytrifluoride (0.62 g, 5.04 mmol) at -18 °C
under N2, and then to the reaction mixture were added trifluoroacetic
acid (1 mL) and two drops of trifluoroacetic anhydride in CH2Cl2
(8 mL) dropwise slowly. The dark brown mixture was stirred for
an additional 10 h in an ice-salt bath, and CH2Cl2 (20 mL) was
added. The mixture was quenched with cold 1 M aqueous citric
acid, and the organic phase was washed successively with 1 M
aqueous citric acid (2 × 20 mL), 3 M NH4OH (3 × 30 mL), H2O
(2 × 20 mL), and brine (2 × 20 mL), dried over Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure, and
the residue was purified by flash column chromatography on silica
gel to recover the material 10 (0.37 g) and obtain the product 12
(0.53 g, 82%, based on the reacted materials), which was recrystal-
lized from CH2Cl2/Et2O to give a light yellow solid: mp 265 °C
1
yellow solid: mp 136-138 °C (lit.18 mp 136-138 °C); H NMR
(400 MHz, CDCl3) δ 8.25 (d, 3JHH ) 8.4 Hz, 1H), 7.81 (d, 4JHH
)
1.6 Hz, 1H), 6.94 (q, 3JHH ) 8.4 Hz, 4JHH ) 1.6 Hz, 1H), 3.99 (s,
3H), 3.95 (s, 3H).
The mixture of 2-(3,4-dimethoxyphenyl)-2-oxoacetic acid (8 g,
38 mmol), CH2Cl2 (30 mL), dimethylformamide (one drop), and
oxalyl chloride (10.2 g, 80 mmol) was refluxed for 2 h, and then
the solvent and excess oxalyl chloride were removed under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL) and added
dropwise to a solution of the ketone 7 (4.65 g, 19 mmol),
triethylamine (3.8 g, 38 mmol), and DMAP (0.46 g, 3.8 mmol) in
CH2Cl2 (50 mL) at 0 °C. The reaction mixture was warmed to room
temperature, and stirring was continued for 10 h. The organic phase
was washed successively with 10% aqueous hydrochloric acid,
water, and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel and recrystallized from CH2Cl2/Et2O to give 8 (7.15
g, 90%) as a red prism: mp 200-202 °C (lit.12 mp 196-198 °C);
1
(dec); H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 7.85 (s, 1H),
7.83 (s, 1H), 7.59 (s, 1H), 4.40-4.45 (m, 1H), 4.16 (s, 3H), 4.14
(s, 3H), 4.11 (s, 3H), 4.03 (s, 3H), 3.33-3.51 (m, 1H), 3.10-3.20
(m, 1H), 3.00 (s, 3H), 2.52-2.59 (m, 1H), 2.25-2.37 (m, 1H),
2.06-2.21 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 201.1, 168.2,
151.0, 150.2, 149.9, 149.4, 135.2, 127.3, 126.4, 123.9, 121.8, 121.6,
106.7, 104.8, 103.0, 102.9, 94.2, 56.1, 50.0, 37.3, 35.4, 27.4; IR
(KBr, cm-1) 3091, 2995, 2935, 2883, 1731, 1698, 1622, 1444, 1257;
EI-MS m/z 451 (M+, 30), 423 (8), 392 (84), 380 (16), 190 (7), 31
(100); HRMS (EI) calcd for C25H25NO7 (M+) 451.1631, found
451.1637.
3
4
1H NMR (300 MHz, CDCl3) δ 7.67 (dd, JHH ) 3.0 Hz, JHH
)
14a-Hydroxy-2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]-9,-
14-indolizidinedione (13) from 10. To the solution of 10 (1.5 g,
3.43 mmol) in 15 mL of dry CH2Cl2 containing two drops of
trifluoroacetic anhydride was added vanadium oxytrifluoride (0.94
g, 7.55 mmol) at -18 °C under N2, and then to the reaction mixture
were added trifluoroacetic acid (10 mL) and two drops of
trifluoroacetic anhydride in CH2Cl2 (5 mL) dropwise slowly. The
mixture was stirred for 10 h in an ice-salt bath, and CH2Cl2 (20
mL) was added. The mixture was quenched with colded 1 M
aqueous citric acid, and the organic phase was washed successively
with 1 M aqueous citric acid (2 × 20 mL), 3 M NH4OH (3 × 30
mL), H2O (2 × 20 mL), and brine (2 × 20 mL), dried over Na2-
SO4, and filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by flash column chroma-
tography on silica gel to recover the material 10 (0.4 g) and obtain
the product 13 (1.0 g, 91%, based on the reacted materials) as a
light yellow solid: mp >300 °C;1 H NMR (300 MHz, DMSO) δ
8.68 (s, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.59 (s, 1H),
4.14-4.23 (m, 1H), 4.10 (s, 3H), 4.07 (s, 3H), 3.92 (s, 3H), 3.85
(s, 3H), 3.40-3.52 (m, 1H), 3.13-3.23 (m, 1H), 2.37-2.45 (m,
1H), 2.22-2.34 (m, 1H), 1.88-2.00 (m, 1H); 13C NMR (75 MHz,
DMSO) δ 203.0, 166.3, 150.6, 149.7, 149.4, 148.3, 139.3, 126.8,
125.5, 121.4, 121.1, 120.8, 107.6, 104.2, 104.0, 103.9, 89.3, 56.0,
55.9, 55.4, 55.3, 36.7, 34.7, 27.5; IR (KBr, cm-1) 3448, 3005, 2923,
2832, 1727, 1687, 1622, 1522, 1484, 1216; MS (EI) m/z 437 (M+,
42), 409 (100), 380 (34), 296 (13), 148 (16); HRMS (MALDI)
calcd for C24H24NO7 (M + H)+ 438.1547, found 438.1543.
3
4
1.5 Hz, 1H), 7.24 (dd, JHH ) 3.6 Hz, JHH ) 1.5 Hz, 1H), 6.75-
6.79 (m, 3H), 6.73 (d, JHH ) 1.8 Hz, 1H), 6.61-6.62 (m, 1H),
4
4
3
6.57 (d, JHH ) 1.8 Hz, 1H), 6.47 (t, JHH ) 3.3 Hz, 1H), 3.86 (s,
3H), 3.85 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H). Anal. Calcd for C24H21-
NO6: C, 68.73; H, 5.05; N, 3.34. Found: C, 68.51; H, 5.08; N, 3.53.
6,7-Bis(3,4-dimethoxyphenyl)-8-hydroxy-1,2,3-trihydroindolizin-
5-one (9). 6,7-Bis(3,4-dimethoxyphenyl)indolizine-5,8-dione (8)
(300 mg, 0.71 mmol) was dissolved in ethanol (200 mL), and
palladium on carbon (200 mg, 10% Pd-C) was added. H2 was
bubbled through the solution, which was then stirred for 3 h. The
catalyst was filtered off, and the filtrate was concentrated in vacuo
to obtain a light yellow solid (0.3 g, 99%): mp 186-188 °C (lit.12
mp 184-185 °C); 1H NMR (300 MHz, CDCl3) δ 6.81 (d, 3JHH
)
8.4 Hz, 1H), 6.72 (dd, 3JHH ) 6.6 Hz, 4JHH ) 1.8 Hz, 1H), 6.62-
4
6.67 (m, 3H), 6.51 (d, JHH ) 1.8 Hz, 1H), 4.65 (br, 1H), 4.19-
4.24 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H),
3.12-3.18 (m, 2H), 2.19-2.29 (m, 2H).
6,7-Bis(3,4-dimethoxyphenyl)-8-methoxy-1,2,3-trihydroin-
dolizin-5-one (10). To the solution of 9 (2.0 g, 4.7 mmol) in THF
(150 mL) was added NaH (0.56 g , 60%, 14.1 mmol). The mixture
was refluxed at 66 °C for 1 h, and then a solution of MeI (1.68 g,
11.83 mmol) in THF (30 mL) was added dropwise at 66 °C. After
being stirred at 66 °C for 3 h, the mixture was cooled to 0 °C and
(18) Palasz, P. D.; Utley, J. H. P.; Hardstone, J. D. Acta Chem. Scand.
B 1984, 38, 281-292.
8420 J. Org. Chem., Vol. 72, No. 22, 2007

Synthesis of a Phenanthro[9,10,3′,4′]indolizidine from Pyrrole
14-Hydroxy-2,3,6,7,14a-pentamethoxyphenanthro[9,10,3′,4′]-
9-indolizidinone (14). To the solution of 12 (0.45 g, 1 mmol) in
ethanol (50 mL) was added sodium borohydride (0.08 g, 2.1 mmol)
in three portions at 0 °C. The mixture was warmed to room
temperature over a period of 6 h. Ice-water (10 mL) was added,
followed by a saturated aqueous solution of ammounium chloride
(15 mL). The mixture was extracted with dichloromethane. The
extracts were dried with MgSO4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
to give 14 (0.44 g, 98%) as a white solid: mp 216 °C dec;1 H
NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.10 (s, 1H), 7.69 (s,
1H), 7.65 (s, 1H), 4.21-4.34 (m, 1H), 4.05 (s, 3H), 4.02 (s, 3H),
3.95 (s, 6H), 3.28-3.41 (m, 1H), 2.90 (s, 3H), 2.72-2.83 (m, 1H),
saturated aqueous NaHCO3. After extraction with CH2Cl2, the
extracts were washed with brine and dried (MgSO4). After filtration
and removal of solvent, the resulting mixture was purified by flash
column chromatography on silica gel to afford 17 (1.17 g, 96%)
as a light yellow solid: mp 172 °C dec;1 H NMR (400 Hz, CDCl3)
δ 8.83 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 4.93 (d,
3JHH ) 6.6 Hz, 1H), 4.55-4.63 (m, 1H), 4.14 (s, 3H), 4.12 (s,
3H), 4.10 (s, 3H), 4.08 (s, 3H), 3.64-3.70 (m, 1H), 3.07-3.16
(m, 1H), 2.42-2.50 (m, 1H), 2.22-2.35 (m, 1H), 1.86-1.98 (m,
1H), 1.66-1.78 (m, 1H); 13C NMR (100 Hz, CDCl3) δ 168.6, 150.6,
149.9, 149.8, 148.1, 141.8, 127.1, 125.4, 122.7, 122.3, 121.1, 108.5,
104.6, 103.2, 102.9, 64.4, 56.3, 56.2, 55.0, 38.9, 36.9, 26.2; IR
(KBr, cm-1) 3092, 2937, 2834, 1679, 1621, 1520, 1480, 1429, 1405,
1260, 1217, 1201, 1160, 1043; m/z (ESI+) 486 [M + H]+; HRMS
(ESI) m/z calcd for C24H25NO5Br (M + H)+ 486.0911, found
486.0903.
3
2.58 (d, JHH ) 8.4 Hz, 1H), 1.73-2.10 (m, 3H), 1.40-1.56 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 167.3, 150.6, 150.0, 149.8,
149.0, 139.9, 127.2, 125.9, 123.8, 122.1, 121.4, 107.4, 105.0, 103.0,
102.8, 93.1, 76.1, 56.1, 56.0, 50.2, 35.3, 30.1, 24.5; IR (KBr, cm-1
)
2,3,6,7-Tetramethoxyphenanthro[9,10,3′,4′]-9-indolizidino-
ne (18). To the solution of 17 (0.2 g, 0.4 mmol) in EtOAc (100
mL) was added 10% palladium on carbon (0.2 g). H2 was bubbled
through the solution and stirred for 15 h at 40 °C. The catalyst was
filtered off to obtain a clear solution, and the filtrate was
concentrated in vacuo. Purification of the residue by flash column
chromatography on silica gel afforded the desired product 18 (0.16
3440, 3093, 2937, 2850, 1676, 1624, 1521, 1480, 1430, 1264, 1157,
1046; MS (EI) m/z 453 (M+, 75), 438 (100), 421 (45), 393 (34),
378 (7), 362 (22), 350 (16), 325 (66); HRMS (EI) calcd for C25H27-
NO7 (M+) 453.1788, found 453.1791.
14a-Hydroxy-2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]-9,-
14-indolizidinedione (13) from 14. SOCl2 (0.3 g, 2.52 mmol) in
CH2Cl2 (4 mL) was added to the solution of 14 (0.3 g, 0.66 mmol)
in CH2Cl2 (5 mL) at room temperature. The mixture was stirred
for 20 min at room temperature and then quenched with water.
The aqueous layer was extracted with CH2Cl2, and the combined
organic extracts were washed successively with water and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel to afford
the desired product 13 (0.22 g, 76%) as a light yellow solid.
2,3,6,7-Tetramethoxyphenanthro[9,10,3′,4′]-9,14-indolizidinedi-
one (15). To the solution of 13 (1.31 g, 3 mmol) in CH2Cl2 (5 mL)
were added trifluoroacetic acid (15 mL) and triethylsilane (1.74 g,
15 mmol). The mixture was stirred at room temperature for 10 min,
diluted with 15 mL of distilled water, and extracted with CH2Cl2
(50 mL). The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. Purification of the residue
by flash column chromatography on silica gel gave 15 (1.16 g,
92%) as a white solid: mp 230-240 °C dec; 1H NMR (400 MHz,
CDCl3) δ 8.81 (s, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 7.44 (s, 1H),
5.28 (s, 1H), 4.52-4.58 (m, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 4.10
(s, 3H), 4.04 (s, 3H), 3.47-3.55 (m, 1H), 2.64-2.72 (m, 1H), 2.53-
2.60 (m, 1H), 2.23-2.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
203.6, 169.8, 150.8, 149.8, 149.1, 135.8, 127.3, 125.4, 122.6, 122.0,
121.5, 107.2, 104.6, 103.3, 102.9, 66.8, 56.3, 56.2, 38.9, 38.1, 24.2;
IR (KBr, cm-1) 3095, 2934, 2835, 1715, 1675, 1622, 1522, 1481,
1449, 1256, 1217, 1199, 1169, 1047; MS (FAB) m/z 421 (M+, 13),
307 (12), 154 (100), 136 (76), 88 (33); HRMS (MALDI) calcd for
C24H24NO6 (M + H)+ 422.1598, found 422.1598.
1
g, 95%) as a white solid: mp 221-223 °C; H NMR (300 MHz,
CDCl3) δ 8.80 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 6.94 (s, 1H),
4.49-4.55 (m, 1H), 4.32-4.37 (m, 1H), 4.03 (s, 9H), 3.93 (s, 3H),
2.92-3.04 (m, 1H), 2.44-2.54 (m, 1H), 1.87-1.96 (m, 1H), 1.57-
1.85 (m, 2H), 1.31-1.47 (m, 1H), 0.99-1.11 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 167.9, 150.1, 149.5, 149.2, 148.8, 142.2, 126.6,
124.5, 122.5, 122.2, 120.5, 104.5, 104.0, 103.8, 102.8, 58.1, 56.0,
39.6, 33.2, 26.1, 24.1; IR (KBr, cm-1) δ 3093, 2937, 2831, 1676,
1624, 1521, 1480, 1430, 1264, 1256, 1209, 1157, 1046, 761; MS
(EI) m/z 407 (M+, 18), 201 (50), 183 (30), 84 (82), 51 (46); HRMS
(ESI) m/z calcd for C24H26NO5 (M + H)+ 408.1806, found
408.1807.
2,3,6,7-Tetramethoxyphenanthro[9,10,3′,4′]indolizidine (19).
To a stirred suspension of LiAlH4 (0.11 g, 3 mmol) and AlCl3 (1.2
g, 9 mmol) in dry THF (30 mL) was added the solution of 18 (0.41
g, 1 mmol) in THF (20 mL) at -15 °C, and the mixture was stirred
at -15 °C for 1 h and then at room temperature for 6 h under
nitrogen. The reaction mixture was poured over ice, and the solid
was filtered. The filtrate was washed with water and dried over
MgSO4. After filtration and removal of solvent, the resulting mixture
was purified by flash column chromatography on silica gel to afford
19 (0.35 g, 89%) as a white solid: mp 210-219 °C dec; 1H NMR
(300 MHz, CDCl3) δ 7.83 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H), 7.00
(s, 1H), 4.45-4.57 (m, 2H), 4.30-4.34 (m, 1H), 4.11 (s, 6H), 4.02
(s, 3H), 4.01 (s, 3H), 3.32-3.37 (m, 1H), 3.04-3.19 (m, 1H), 2.24-
2.39 (m, 1H), 1.88-2.00 (m, 1H), 1.40-1.85 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 149.0, 148.8, 148.7, 148.5, 136.6, 131.2, 124.6,
124.1, 122.7, 122.3, 104.7, 104.6, 104.0, 103.8, 65.2, 56.1, 55.9,
55.1, 49.2, 29.6, 23.7, 22.3; IR (KBr, cm-1) 3101, 2941, 2924, 2833,
1620, 1519, 1476, 1431, 1255, 1211, 1158, 1036, 841, 771; m/z
(ESI+) 394 [M + H]+; HRMS (ESI) m/z calcd for C24H28NO4(M
+ H)+ 394.2013, found 394.2008.
14-Hydroxy-2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]-9-in-
dolizidinone (16) was prepared from 15 by the same method as
1
14 in 96% yield: mp 238-240 °C; H NMR (300 MHz, DMSO)
δ 8.81 (s, 1H), 8.24 (s, 1H), 8.05 (s, 2H), 5.82 (d, 3JHH ) 5.7 Hz,
4
1H), 4.58 (d, JHH ) 8.7 Hz, 1H), 4.24-4.38 (m, 1H), 4.07 (s,
3H), 4.05 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 2.83-3.12 (m, 2H),
1.94-2.11 (m, 1H), 1.67-1.87 (m, 2H), 1.28-1.46 (m, 1H); 13C
NMR (75 MHz, DMSO) δ 167.0, 150.2, 149.1, 149.0, 148.1, 143.2,
126.1, 124.6, 121.7, 121.6, 121.5, 108.9, 104.1, 103.9, 73.8, 63.9,
55.9, 55.8, 55.3, 55.2, 38.2, 34.4, 24.1; IR (KBr, cm-1 3332.43,
3100, 2936, 2835, 1647, 1623, 1520, 1481, 1428, 1262, 1198, 1159,
1045; MS (EI) m/z 423 (M+, 56), 366(18), 205 (36), 149 (74), 69
(88), 57 (100); HRMS (ESI) m/z calcd for C24H26NO6 (M + H)+
424.1755, found 424.1746.
14-Bromo-2,3,6,7-tetramethoxyphenanthro[9,10,3′,4′]-9-in-
dolizidinone (17). To the solution of the alcohol 16 (1.06 g, 2.5
mmol) in dry THF (50 mL) were added PPh3 (1.31 g, 5 mmol)
and CBr4 (1.66 g, 5 mmol) at room temperature, and the mixture
was warmed to 50 °C, stirred for 3 h, and then quenched with
Acknowledgment. We thank the National Key Project for
Basic Research (2003CB114404), Program for New Century
Excellent Talents in University (NCET-04-0228), the National
Natural Science Foundation of China (20472039 and 20421202),
and the Key Project of Chinese Ministry of Education (106046).
Supporting Information Available: General experimental
methods, synthesisof N-(3,4-dimethoxyphenylacetyl)morpholine (6),
spectroscopic data for 6-10 and 12-19, and crystallographic data
for 12 (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO701590P
J. Org. Chem, Vol. 72, No. 22, 2007 8421