A Versatile Total Synthesis of Benzo[c]phenanthridine and Protoberberine Alkaloids Using Lithiated Toluamide-Benzonitrile Cycloaddition

Article abstract of DOI:10.1021/jo035836+

A new versatile synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition was carried out. The coupling reaction between benzonitrile 6 with o-toluamides (8a-c) afforded 3-arylisoquinolines (9a-c

Full text of DOI:10.1021/jo035836+

A Ver sa tile Tota l Syn th esis of Ben zo[c]p h en a n th r id in e a n d
P r otober ber in e Alk a loid s Usin g Lith ia ted Tolu a m id e-Ben zon itr ile
Cycloa d d ition
Thanh Nguyen Le, Seong Gyoung Gang, and Won-J ea Cho*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University,
Yong-Bong dong, Buk-gu, Kwangju 500-757 Korea
wjcho@jnu.ac.kr
Received December 17, 2003
A new versatile synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated
toluamide-benzonitrile cycloaddition was carried out. The coupling reaction between benzonitrile
6 with o-toluamides (8a -c) afforded 3-arylisoquinolines (9a -c) that were transformed to the
protoberberines (11a -c) or benzo[c]phenanthridines (14a -c). These compounds were synthesized
by ring closure of the two-carbon chain on either position 2 or 4 of the 3-arylisoquinolinone (9a -c).
Several kinds of substituted benzo[c]phenanthridine alkaloids such as oxysanguinarine, oxyavicine,
and oxynitidine as well as protoberberines such as 8-oxocoptisine, 8-oxopseudoberberine, and
8-oxopseudocoptisine were synthesized.
In tr od u ction
biosynthesized from the corresponding protoberberine
alkaloids presumably via a 3-arylisoquinoline intermedi-
ate.14 We have reported the synthesis of 3-arylisoquino-
line derivatives with biological evaluations.15 For the
model study of these alkaloids, the synthesis of a benzo-
[c]phenanthridine skeleton was performed.16 The syn-
thesis involved the cycloaddition of lithiated o-methyl-
toluamide with benzonitriles to prepare substituted
3-arylisoquinolinones.17 To synthesize both of the natural
alkaloids, the aforementioned synthetic method was
applied. The advantages of this methodology were con-
sidered not only due to easy access to the staring
materials but also because it is a one-pot procedure for
construction of all carbon atoms for both alkaloids.
Natural benzo[c]phenanthridine and protoberberine
alkaloids have been attractive to synthetic organic chem-
ists and biochemists over the last two decades since these
compounds have shown interesting biological properties
such as antitumor,1-6 antiviral,7,8 and antimicrobacterial
activities.9,10 Therefore, much attention has been focused
on the efficient synthesis of these alkaloids.11-13 Benzo-
[c]phenanthridine alkaloids have been considered to be
* To whom correspondence should be addressed. Tel: 82-62-530-
2933. Fax: 82-62-530-2911.
(1) Fleury, F.; Sukhanova, A.; Ianoul, A.; Devy, J .; Kudelina, I.;
Duval, O.; Alix, A. J . P.; J ardillier, J . C.; Nabiev, I. J . Biol. Chem. 2000,
275, 3501-3509.
(2) Nakanishi, T.; Masuda, A.; Suwa, M.; Akiyama, Y.; Hoshino-
Abe, N.; Suzuki, M. Bioorg. Med. Chem. Lett. 2000, 10, 2321-2323.
(3) Ishikawa, T.; Ishii, H. Heterocycles 1999, 50, 627-639.
(4) Fang, S.-D.; Wang, L.-K.; Hecht, S. M. J . Org. Chem. 1993, 58,
5025-5027.
Resu lts a n d Discu ssion
Retrosynthesis of these alkaloids indicates that the
coupling of benzonitrile with o-toluamide might afford
3-arylisoquinolinone that would be a key intermediate
in the synthesis of both alkaloids. Protoberberine or
benzo[c]phenanthridine alkaloids could be synthe-
sized through the ring closure of the two carbon chains,
either on position 2 or 4, of the 3-arylisoquinolinone
(Scheme 1).
(5) Nakanishi, T.; Suzuki, M. J . Nat. Prod. 1998, 61, 1263-1267.
(6) Vavreckova, C.; Gawlik, I.; Muller, K. Planta Med. 1996, 62,
397-401.
(7) Rashid, M. A.; Gustafson, K. R.; Kashman, Y.; Cardellina, J . H.,
II; McMahon, J . B.; Boyd, M. R. Nat. Prod. Lett. 1995, 6, 153-156.
(8) Chang, Y.-C.; Hsieh, P.-W.; Chang, F.-R.; Wu, R.-R.; Liaw, C.-
C.; Lee, K.-H.; Wu, Y.-C. Planta Med. 2003, 69, 148-152.
(9) Huang, F.-C.; Kutchan, T. M. Phytochemistry 2000, 53, 555-
564.
(10) Ishikawa, T. Med. Res. Rev. 2001, 21, 61-72.
(11) Suffness, M.; Cordell, G. A. The Alkaloids; New York, 1985;
Vol. 25, pp 178-189.
(12) Mackay, S. P.; Meth-Cohn, O.; Waich, R. D. Advances in
Heterocyclic Chemistry; Acadenic Press: New York, 1997; Vol. 67, pp
345-389.
(13) Recent papers for the synthesis of benzo[c]phenanthridine
alkaloids: (a) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985-988.
(b) Geen, G. R.; Mann, I. S.; Mullane, M. V.; Mckillop, A. Tetrahedron
1998, 54, 9875-9894. (c) Harayama, T.; Akamatsu, H.; Okamura, K.;
Miyagoe, T.; Akiyama, T.; Abe, H.; Takeuchi, Y. J . Chem. Soc., Perkin
Trans. 1 2001, 523-528. (d) Treus, M.; Estevez, J . C.; Castedo, L.;
Estevez, R. J . Tetrahedron Lett. 2002, 43, 5323-5325. Recent papers
for the synthesis of protoberberine alkaloids: (e) Liu, L. Synthesis 2003,
11, 1705-1706. (f) Orito, K.; Satoh, Y.; Nishizawa, H.; Harada, R.;
Tokuda, M. Org. Lett. 2000, 2, 2535-2537. (g) Singh, K. N. Tetrahderon
Lett. 1998, 39, 4391-4392.
For the lithiated toluamide-benzonitrile cycloaddition
reaction, the starting benzonitrile 6 was synthesized as
(14) (a) Takao, N.; Kamigauchi, M.; Okada, M. Helv. Chim. Acta
1983, 66, 473-484. (b) Cushman, M.; Wong, W. C. J . Org. Chem. 1984,
49, 1278-1280.
(15) (a) Cho, W.-J .; Min, S. Y.; Le, T. N.; Kim, T. S. Bioorg. Med.
Chem. Lett. 2003, 13, 4451-4454. (b) Cho, W.-J .; Kim, E.-K.; Park,
M.-J .; Choi, S.-U.; Lee, C.-O.; Cheon, S. H.; Choi, B.-G.; Chung, B.-H.
Bioorg. Med. Chem. 1998, 6, 2449-2458. (c) Cho, W.-J .; Kim, E.-K.;
Park, I. Y.; J eong, E. Y.; Kim, T. S.; Le, T. N.; Kim, D.-D.; Lee, E.-S.
Bioorg. Med. Chem. 2002, 10, 2953-2961.
(16) Cho, W.-J .; Park, M.-J .; Imanishi, T.; Chung, B. H. Chem.
Pharm. Bull. 1999, 47, 900-902.
(17) Poindexter, G. S. J . Org. Chem. 1982, 47, 3787-3788.
10.1021/jo035836+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/20/2004
2768
J . Org. Chem. 2004, 69, 2768-2772

Total Synthesis of Benzo[c]phenanthridine and Protoberberine Alkaloids
SCHEME 1. Retr osyn th esis of P r otober ber in es
SCHEME 3. Syn th esis of N,N-Dieth yl-o-tolu a m id e
a n d Ben zo[c]p h en a n th r id in e Alk a loid s
Der iva tives 8a -c
SCHEME 4. Syn th esis of P r otober ber in e
Alk a loid s 11a -c
The strategy used was based on the synthesis of
3-arylisoquinolinone 9a -c, which are crucial intermedi-
ates in the formation of a C ring of protoberberine or
benzo[c]phenanthridines. N,N-Diethyl-o-toluamide 8a -c
was deprotonated with n-butyllithium to give the anion,
which was treated with benzonitrile 6 at -78 °C in THF
to afford the 3-arylisoquinoline-1(2H)-one 9a -c.22 Depro-
tection of 9a -c with 10% HCl resulted in the alcohols
10a -c, which were then reacted with p-TsCl in DMF in
the presence of K2CO3 to afford the desired proto-
berberine alkaloids.23 There was a 52-58% yield of
8-oxopseudoberberine 11a , 8-oxocoptisine 11b , and
8-oxopseudocoptisine 11c (Scheme 4).
MOM-protected alcohol 9a -c was treated with MeI/
K2CO3 providing the N-methylated products 12a -c in a
62-90% yield without yielding any o-methylated com-
pounds. The hydrolysis of the MOM group with 10% HCl
gave the alcohols 13a -c. The alcohols were then oxidized
with PCC/NaOAc24 to provide the desired benzo[c]-
phenanthridine alkaloids oxynitidine 14a , oxysangui-
narine 14b, and oxyavicine 14c as shown in Scheme 5.
In this reaction, it was assumed that the oxidation
produced the aldehyde and the intramolecular enamide-
aldehyde cyclization occurred so as to form a C ring of
benzo[c]phenanthridine, and the consecutive dehydration
process, resulting in the aromatized ring system.
SCHEME 2. Syn th esis of Ben zon itr ile Der iva tive
6a
a
Reagents and conditions: (a) 10% HCl, 100%; (b) Ph3P+CH2OMe
I-, n-BuLi, THF, 62%; (c) 5% HCl, acetone, 97%; (d) NaBH4, AcOH,
82%; (e) MOMCl, CH2Cl2, diisopropylethylamine, 96%.
depicted in Scheme 2. Acetal 118 was hydrolyzed with 10%
hydrochloric acid to afford the aldehyde 2, which was
treated with Ph3P+CH2OMe I-/n-BuLi, providing the
styrene 3. The E/Z mixture of stereoisomers (E/Z ) 1/2)
was hydrolyzed without separating them to give the
homobenzaldehyde 4, which was then reduced with
NaBH4. The resultant alcohol 5 was then protected with
methoxymethyl chloride to yield the MOM-protected
benzonitrile 6, in 96% yield.
N,N-Diethyl-o-toluamides 8a , 8b, and 8c were synthe-
sized from the corresponding substituted benzoic acids
7a , 7b, and 7c19-21 by treatment of oxalyl chloride
followed by diethylamine. This resulted in a high overall
yield of 92-95%, as shown in Scheme 3.
(22) For enhancing the chemical yield of this toluamide-benzonitrile
cycloaddition, various bases were conducted. When N,N-diethyl-o-
toluamide and benzonitrile were used as starting materials, 3-phe-
nylisoquinolin-1-(2H)-one was obtained in the following yields: s-BuLi
(25%), t-BuLi (30%), LDA (55%), and n-BuLi (62%).
(23) Beugelmans, R.; Bois-Choussy, M. Tetrahedron 1992, 48, 8285-
8294.
(18) Fitzgerald, J . J .; Michael, F. E.; Olofson, R. A. Tetrahedron Lett.
1994, 35, 9191-9194.
(19) Clark, R. D.; J ahangir J . Org. Chem. 1987, 52, 5378-5382.
(20) De Silva, S. O.; Reed, J . N.; Billedeau, R. J .; Wang, X.; Norris,
D. J .; Snieckus, V. Tetrahedron 1992, 48, 4863-4878.
(21) Kupchan, S. M.; Wormser, H. C. J . Org. Chem. 1965, 30, 3792-
3800.
(24) Hanaoka, M.; Motonishi, T.; Mukai, C. J . Chem. Soc., Perkin
Trans. 1 1986, 2253-2256.
J . Org. Chem, Vol. 69, No. 8, 2004 2769

Le et al.
and extracted with ethyl acetate. The ethyl acetate extracts
were washed with water and brine and dried over anhydrous
sodium sulfate. After removal of the solvent, the residue was
purified by column chromatography on silica gel with n-hex-
anes-ethyl acetate (1:1) to give the aldehyde 4 as a solid (3.84
g, 97%). Mp ) 78-80 °C. IR (cm-1): 2220 (CN), 1720 (CdO),
1300-1000 (CO). 1H NMR (CDCl3) δ: 9.78 (s, 1H), 7.06 (s, 1H),
6.75 (s, 1H), 6.10 (s, 2H), 3.93 (s, 2H). EIMS: m/z 189 (M+,
100). Anal. Calcd for C10H7NO3: C, 63.49; H, 3.73; N, 7.40.
Found: C, 63.65; H, 3.78; N, 7.46.
SCHEME 5. Syn th esis of Ben zo[c]p h en a n th r id in e
Alk a loid s 14a -c
6-(2-Hydr oxyeth yl)ben zo[1,3]dioxole-5-car bon itr ile (5).
To a solution of aldehyde 4 (3.02 g, 16 mmol) in acetic acid
(20 mL) was added NaBH4 (1.14 g, 30 mmol). After the reaction
was complete, acetic acid was removed in vacuo and the
residue was poured into water and extracted with ethyl
acetate. The organic solvent was evaporated off, and the
residue was purified by column chromatography with n-hex-
ane-ethyl acetate (1:1) to give the alcohol 5 as a yellow solid
(2.51 g, 82%). Mp ) 70.4-72.3 °C. IR (cm-1): 3360 (OH), 2220
(CN), 1720 (CdO), 1300-1000 (C-O). 1H NMR (CDCl3) δ: 6.98
(s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.86 (t, J ) 6.5 Hz, 2H), 2.99
(t, J ) 6.5 Hz, 2H). EIMS: m/z 191 (M+, 100). Anal. Calcd for
C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.78; H, 4.69;
N, 7.34.
In conclusion, the synthesis of natural protoberberine
and benzo[c]phenanthridine alkaloids through the same
intermediates 9a -c in three or four steps, respectively,
from the benzonitrile 6 and toluamde 8a -c was success-
ful. This methodology is considered to be a more direct
route to benzo[c]phenanthridine or protoberberine syn-
thesis than the previous reported condensation routes.25-27
We believe that this synthetic application would broaden
the utility of this methodology for preparation of the
analogues on a multigram scale, which are necessary to
define structure-activity relationships or to identify the
biological target of these compounds.
6-(2-Meth oxym eth oxyeth yl)ben zo[1,3]d ioxole-5-ca r bo-
n itr ile (6). To a solution of alcohol 5 (2.54 g, 13.3 mmol) in
CH2Cl2 (25 mL) at 0 °C were added diisopropylethylamine
(DIPEA) (3.25 g, 30 mmol) and chloromethylmethyl ether (2.02
g, 20 mmol). The reaction mixture was stirred overnight, and
CH2Cl2 was evaporated off to give the residue, which was
purified by column chromatography with n-hexanes-ethyl
acetate (3:1) to give benzonitrile 6 as a yellow oil (3.01 g, 96%).
IR (cm-1): 2230 (CN), 1300-1000 (CO). 1H NMR (CDCl3) δ:
6.99 (s, 1H), 6.85 (s, 1H), 6.04 (s, 2H), 4.60 (s, 2H), 3.77 (t, J
) 6.5 Hz, 2H), 3.30 (s, 3H), 3.05 (t, J ) 6.5 Hz, 2H). EIMS:
m/z 235 (M+, 100). HRMS-EI (calcd for C12H13NO4): 235.2354,
found 235.2358.
Exp er im en ta l Section
6-F or m ylben zo[1,3]d ioxole-5-ca r bon itr ile (2). The ac-
etal 1 (8.3 g, 37 mmol) in 10% HCl was warmed at 50-60 °C
for 5 min. The resulting solid was collected, washed with
water, and dried to give a pale yellow solid which was
recrystallized with n-hexane to afford the aldehyde 2 (6.57 g,
100%). Mp ) 162-164 °C. IR: 2230 (CN), 1690 (CO). 1H NMR
(CDCl3) δ: 10.24 (s, 1H), 7.44 (s, 1H), 7.44 (s, 1H), 6.20 (s,
2H). EIMS: m/z 175 (M+, 100). Anal. Calcd for C9H5NO3: C,
61.72; H, 2.88; N, 8.00. Found: C, 61.83; H, 2.96; N, 8.06.
6-(2-Meth oxyvin yl)ben zo[1,3]dioxole-5-car bon itr ile (3).
To a solution of (methoxymethyl)triphenyl phosphonium chlo-
ride (9.58 g, 28 mmol) in dry THF (50 mL) was added
n-butyllithium (18 mL, 28.8 mmol) at 0 °C, and the solution
was stirred at 0 °C for 1 h. To this mixture was added the
aldehyde (3.5 g, 20 mmol) in THF (20 mL) and the resulting
mixture stirred at room temperature for 30 min. The reaction
was quenched with water and extracted with ethyl acetate.
The organic layers were washed with water and brine and
dried over sodium sulfate. After removal of the solvent in
vacuo, the residue was purified by column chromatography
with n-hexanes-ethyl acetate (3:1) to afford the E/Z isomers
(1/2) of 3 as a yellow solid (2.5 g, 62%). 1H NMR (300 MHz,
CDCl3) δ: (Z isomer) 7.66 (s, 1H), 6.94 (s, 1H), 6.02 (s, 2H),
6.26 (d, J ) 7.1 Hz, 1H), 5.58 (d, J ) 7.1 Hz, 1H), 3.82 (s, 3H);
(E isomer) 7.10 (d, J ) 12.8 Hz, 1H), 6.94 (s, 1H), 6.85 (s, 1H),
6.02 (s, 2H), 6.04. (d, J ) 12.8 Hz, 1H), 3.73 (s, 3 H).
2-Meth yl-4, 5-d im eth oxy-N,N-d ieth ylben za m id e (8a ).
To a suspension of 2-methyl-4,5-dimethoxybenzoic acid 7a (5
g, 19.9 mmol) in CH2Cl2 (50 mL) containing pyridine (3.23 g,
40.8 mmol) was slowly added oxalyl chloride (17.8 mL) with
stirring. After an additional 2 h of stirring, the excess oxalyl
chloride was removed in vacuo and the last traces of oxalyl
chloride were removed by co-distillation with benzene. The acid
chloride obtained was dissolved in CH2Cl2 (20 mL) and
carefully treated with diethylamine (18.65 g, 255 mmol) at 0
°C. After the reaction mixture was diluted with water, the
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The organic portions were washed with
water and brine, dried over anhydrous sodium sulfate, and
then evaporated to give 2-methyl-4,5-dimethoxy-N,N-diethyl-
benzamide 8a (6.07 g, 95%) as an oil. IR (cm-1): 1631 (NCO).
1H NMR (CDCl3) 6.68 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3,-
75-2.90 (m, 4H), 2.23 (s, 3H), 1.50-0.85 (m, 6H). EIMS: m/z
251 (M+, 24).
5-Meth ylben zo[1,3]d ioxole-4-ca r boxylic Acid Dieth yl-
a m id e (8b). The procedure described for compound 8a was
used with carboxylic acid 7b (4.2 g, 23 mmol) to give N,N-
diethyltoluamide 8b (5.12 g, 94%). IR (cm-1): 1642 (NCO). 1H
NMR (300 MHz, CDCl3) δ: 6.70 (d, J ) 7.9 Hz, 1H), 6.65 (d,
J ) 7.9 Hz, 1H), 5.94 (m, 2H), 3.44-3.40 (m, 2H), 3.27-3.18
(m, 2H), 2.20 (s, 3H), 1.28 (t, J ) 7.1 Hz, 3H), 1.08 (t, J ) 7.1
Hz, 3H). EIMS: m/z 235 (M+, 93).
6-(2-Oxoeth yl)ben zo[1,3]d ioxole-5-ca r bon itr ile (4). The
reaction mixture of E/Z isomer 3 (4.1 g, 20 mmol) in acetone
(30 mL) and 5% HCl (10 mL) was refluxed for 5 h. The acetone
was evaporated off, and water was poured into the residue
6-Meth ylben zo[1,3]d ioxole-5-ca r boxylic Acid Dieth yl-
a m id e (8c). The procedure described for compound 8a was
used with carboxylic acid 7c (1.68 g, 9.2 mmol) to give N,N-
diethyltoluamide 8c (2 g, 92%). IR (cm-1): 1651 (NCO). 1H
NMR (300 MHz, CDCl3) δ: 6.66 (s, 1H), 6.64 (s, 1H), 5.93 (s,
2H), 3.20-3.12 (m, 4H), 2.19 (s, 3H), 1.22 (t, J ) 7.1 Hz, 3H),
1.08 (t, J ) 7.1 Hz, 3H). EIMS: m/z 235 (M+, 86).
(25) Clark, R. D.; J ahangir J . Org. Chem. 1989, 54, 1174-1178.
(26) Shamma, M.; Tomlinson, H. H. J . Org. Chem. 1978, 43, 2852-
2855.
(27) Cushman, M.; Cheng, L. J . Org. Chem. 1978, 43, 286-288.
2770 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of Benzo[c]phenanthridine and Protoberberine Alkaloids
6,7-Dim et h oxy-3-[6-(2-m et h oxym et h oxyet h yl)b en zo-
[1,3]d ioxol-5-yl]-2H-isoqu in olin -1-on e (9a ). A solution of
N,N-diethyltoluamide 8a (2.01 g, 8 mmol) and benzonitrile 6
(1.41 g, 6 mmol) in THF (20 mL) was added dropwise to a
solution of n-butyllithium (10 mL of 1.6 M in hexane, 16 mmol)
in THF (15 mL) at -70 °C, and then the reaction mixture was
stirred at the same temperature for 6 h. The reaction was
quenched with water, extracted with ethyl acetate, and dried
over sodium sulfate. After removal of the solvent, the residue
was purified by column chromatography with n-hexanes-ethyl
acetate (1:1) to afford the product 9a as an orange solid (1.27
g, 50%). Mp ) 180-183 °C. IR (cm-1): 3400 (NH), 1630
(CdO). 1H NMR (300 MHz, CDCl3) δ: 10.3 (s, 1H), 7.79 (s,
1H), 6.90 (s, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 6.39 (s, 1H), 6.02
(s, 2H), 4.72 (s, 2H), 4.01(s, 3H), 4.00(s, 3H), 3.87 (m, 2H), 3.36
(s, 3H), 2.85 (t, J ) 5.7 Hz, 2H). EIMS: m/z 413 (M+, 36). Anal.
Calcd for C22H23NO7: C, 63.91; H, 5.61; N, 3.39. Found: C,
63.69; H, 5.48; N, 3.40.
7-[6-(2-Met h oxym et h oxyet h yl)b en zo[1,3]d ioxol-5-yl]-
8H-[1,3]d ioxolo[4,5-h ]isoqu in olin -9-on e (9b). The proce-
dure described for compound 9a was used with toluamide 8b
(2.83 g, 12 mmol) and benzonitrile 6 (2.35 g, 10 mmol) to afford
compound 9b as an orange solid (1.48 g, 38%). Mp ) 157-159
°C. IR (cm-1): 3400 (NH), 1665 (CdO). 1H NMR (300 MHz,
CDCl3) δ: 10.17 (s, 1H), 7.16 (d, J ) 8.4 Hz, 1H), 7.02 (d, J )
8.2 Hz, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 6.35 (s, 1H), 6.21 (s,
2H), 6.01 (s, 2H), 4.70 (s, 2H), 3.87 (t, J ) 5.7 Hz, 2H), 3.39 (s,
3H), 2.85 (t, J ) 5.7 Hz, 2H). EIMS: m/z 397 (M+, 68). Anal.
Calcd for C21H19NO7: C, 63.47; H, 4.82; N, 3.52. Found: C,
63.56; H, 4.71; N, 3.59.
scribed for the compound 10a was used with compound 9c (200
mg, 0.48 mmol) and 10% HCl (5 mL) to give alcohol 10c as a
yellow solid (150 mg, 85%). Mp ) 198-201 °C. IR (cm-1): 3400,
3300 (NH, OH), 1636 (CdO). 1H NMR (300 MHz, CDCl3) δ:
11.46 (s, 1H), 7.56 (s, 1H), 7,21 (s, 1H),7.02 (s, 1H), 6.96 (s,
1H), 6.22 (s, 2H), 6.11 (s, 2H), 5.17 (t, J ) 4.5, 1H), 3.68-3.62
(m, 2H), 2.73 (t, 2H). EIMS: m/z 353 (M+, 71). Anal. Calcd for
C
19H15NO6: C, 64.59; H, 4.28; N, 3.96. Found: C, 64.51; H,
4.17; N, 3.85.
10,11-Dim eth oxy-5,6-dih ydr o[1,3]dioxolo[4,5-g]isoqu in o-
[3,2-a ]isoqu in olin -8-on e (Oxyp seu d ober ber in e, 11a ). The
mixture of compound 10a (100 mg, 0.28 mmol), tosyl chloride
(115 mg, 0.6 mmol), and K2CO3 (138 mg, 1 mmol) in DMF (8
mL) was stirred at 100 °C for 4 h. Water was added, and the
reaction mixture was extracted with ethyl acetate. The ethyl
acetate extracts were washed with water and brine and dried
over anhydrous sodium sulfate. After removal of the solvent,
the residue was purified by column chromatography on silica
gel with n-hexanes-ethyl acetate (1:2) to give 8-oxypseudo-
berberine 11a as a yellow solid (57 mg, 58%). Mp ) 266-268
1
°C dec. IR (cm-1): 1650 (amide). H NMR (300 MHz, CDCl3)
δ: 7.78 (s, 1H), 7.21 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.71 (s,
1H), 6.01 (s, 2H), 4.33 (t, J ) 6.0 Hz, 2H), 4.01 (s, 3H), 4.00 (s,
3H), 2.88 (t, J ) 6.0 Hz, 2H). EIMS: m/z 351 (M+, 100). Anal.
Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99. Found: C,
68.17; H, 4.91; N, 3.91.
Oxycop tisin e (11b). The procedure described for compound
11a was used with compound 10b (30 mg, 0.085 mmol), tosyl
chloride (38 mg, 0.2 mmol), and K2CO3 (68 mg, 0.5 mmol) to
give 8-oxycoptisine 11b as an orange solid (15 mg, 53%). Mp
) 289-291 °C (lit.28 mp 282-284 °C). IR (cm-1): 1645 (amide).
1H NMR (300 MHz, CDCl3) δ: 7.20 (s, 1H), 7.16 (d, J ) 8.1
Hz, 1H), 7.01 (d, J ) 8.1 Hz, 1H), 6.74 (s, 1H), 6.70 (s, 1H),
6.21 (s, 2H), 6.04 (s, 2H), 4.27 (t, J ) 6.0 Hz, 2H), 2.88 (t, J )
7-[6-(2-Met h oxym et h oxyet h yl)b en zo[1,3]d ioxol-5-yl]-
6H-[1,3]d ioxolo[4,5-g]isoqu in olin -5-on e (9c). The proce-
dure described for compound 9a was used with toluamide 8c
(1.39 g, 5.9 mmol) and benzonitrile 6 (1.15 g, 4.9 mmol) to
afford compound 9c as an orange solid (936 mg, 40%). Mp )
6.0 Hz, 2 H). EIMS: m/z 335 (M+, 100). Anal. Calcd for C19H13
-
1
NO5: C, 68.06; H, 3.91; N, 4.18. Found: C, 68.32; H, 3.76; N,
4.21.
161.3-165.2 °C. IR (cm-1): 3400 (NH), 1665 (CdO). H NMR
(300 MHz, CDCl3) δ: 10.33 (s, 1H), 7.75 (s, 1H), 6.88 (s, 1H),
6.86 (s, 1H), 6.80 (s, 1H), 6.35 (s, 6.35), 6.08 (s, 2H), 6.01 (s,
2H), 4.72(s, 2H), 3.89 (t, J ) 5.4 Hz, 2H), 3.32 (s, 3H), 2.84 (t,
J ) 5.7 Hz, 2H). EIMS: m/z 397 (M+, 41%). Anal. Calcd for
Oxyp seu d ocop tisin e (11c). The procedure described for
compound 11a was used with compound 10c (80 mg, 0.23
mmol), tosyl chloride (115 mg, 0.6 mmol), and K2CO3 (130 mg,
0.92 mmol) to give 8-oxypseudoberberine 11c as a yellow solid
(41 mg, 52%). Mp ) 276-279 °C dec (lit.29 HCl salt form mp
C
21H19NO7: C, 63.47; H, 4.82; N, 3.52. Found: C, 63.71; H,
4.78; N, 3.55.
1
270 °C). IR (cm-1): 1650 (amide). H NMR (300 MHz, CDCl3)
3-[6-(2-H y d r o x y e t h y l)b e n z o [1,3]d i o x o l-5-y l]-6,7-
d im eth oxy-2H-isoqu in olin -1-on e (10a ). To a solution of
compound 9a (200 mg, 0.48 mmol) in THF (15 mL) was added
10% HCl (5 mL), and the reaction was refluxed for 2 h. The
reaction mixture was poured into water and extracted with
ethyl acetate. The ethyl acetate extracts were washed with
water and brine and dried over anhydrous sodium sulfate.
After removal of the solvent, the residue was purified by
column chromatography on silica gel with CH2Cl2/MeOH (20:
1) to give an alcohol 10a as a yellow solid (122 mg, 68%). Mp
δ: 7.77(s, 1H), 7.22(s, 1H), 6.89(s, 1H), 6.73(s, 1H), 6.71 (s,
1H), 6.07 (s, 2H), 6.01(s, 2H), 4.32 (t, J ) 6.1 Hz, 2H), 2.90(t,
J ) 6.4 Hz, 2H). EIMS: m/z 335 (M+, 79). Anal. Calcd for
C
19H13NO5: C, 68.06; H, 3.91; N, 4.18. Found: C, 68.02; H,
3.85; N, 4.12.
6,7-Dim et h oxy-3-[6-(2-m et h oxym et h oxyet h yl)b en zo-
[1,3]d ioxol-5-yl]-2-m eth yl-2H-isoqu in olin -1-on e (12a ). The
mixture of compound 9a (150 mg, 0.36 mmol), K2CO3 (275 mg,
2 mmol), and methyl iodide (141 mg, 1.0 mmol) in DMF (8
mL) was heated at 100 °C for 3 h. The reaction was quenched
with water and extracted with ethyl acetate. The combined
ethyl acetate extracts were washed with water and brine and
dried over anhydrous sodium sulfate. After removal of the
solvent, the residue was purified by column chromatography
on silica gel with n-hexanes-ethyl acetate (1:1) to give
compound 12a as an oil (110 mg, 72%). IR (cm-1): 1646
(CdO). 1H NMR (300 MHz, CDCl3) δ: 7.82 (s, 1H), 6.90 (s,
1H), 6.83 (s, 1H), 6.70 (s, 1H), 6.34 (s, 1H), 6.02 (s, 2H), 4.51
(s, 2H), 4.03 (s, 3H), 3.98 (s, 3H), 3.62 (m, 2H), 3.31 (s, 3H),
3.20(s, 3H), 2.77-2.57 (m, 2 H). EIMS: m/z 427 (M+, 100).
HRMS-EI (calcd for C23H25NO7): 427.4461, found 427.4467.
7-[6-(2-Meth oxym eth oxyeth yl)ben zo[1,3]d ioxol-5-yl]-8-
m eth yl-8H-[1,3]d ioxolo[4,5-h ]isoqu in olin -9-on e (12b). The
procedure described for the compound 12a was used with
compound 9b (300 mg, 0.75 mmol), K2CO3 (550 mg, 4 mmol),
1
) >250 °C. IR (cm-1): 3400 (NH, OH), 1642 (CdO). H NMR
(300 MHz, CDCl3) δ: 11.30 (s, 1H), 7.55 (s, 1H), 7.16 (s, 1H),
6.96 (s, 1H), 6.89 (s, 1H), 6.39 (s, 1H), 6.05 (s, 2H), 5.06 (t, J
) 4.5 Hz, 1H), 3.87(s, 3H), 3.86 (s, 3H), 3.57 (m, 2H), 2.67 (t,
J ) 6.7 Hz, 2H). EIMS: m/z 369 (M+, 67). Anal. Calcd for
C
20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.08; H,
5.20; N, 3.81.
7-[6-(2-Hyd r oxyeth yl)ben zo[1,3]d ioxol-5-yl]-8H-[1,3]d i-
oxolo[4,5-h ]isoqu in olin -9-on e (10b). The procedure de-
scribed for compound 8a was used with compound 9b (200 mg,
0.48 mmol) and 10% HCl (5 mL) to give alcohol 10b as a yellow
solid (70 mg, 41%). Mp ) 237-239 °C. IR (cm-1): 3400, 3300
1
(NH, OH), 1636 (CdO). H NMR (300 MHz, CDCl3) δ: 11.17
(s, 1H), 7.34 (d, J ) 8.1 Hz, 1H), 7.11 (d, J ) 8.1 Hz, 1H), 6.95
(s, 1H), 6.89 (s, 1H), 6.37 (s, 1H), 6.19 (s, 2H), 6.04 (s, 2H),
5.06 (t, J ) 4.5 Hz, 1H), 3.58 (m, 2H), 2.68 (t, J ) 6.6 Hz, 2H).
EIMS: m/z 353 (M+, 71). Anal. Calcd for C19H15NO6: C, 64.59;
H, 4.28; N, 3.96. Found: C, 64.61; H, 4.30; N, 3.91.
(28) Li, M.; Chen, X.; Tang, Q. M.; Zhang, J . S. Planta Med. 2001,
67, 189-90.
(29) Zhang, G. L.; Rucker, G.; Breitmaier, E.; Mayer, R.; Steibeck,
C. Planta Med. 1998, 64, 165-171.
7-[6-(2-Hyd r oxyeth yl)ben zo[1,3]d ioxol-5-yl]-6H-[1,3]d i-
oxolo[4,5-g]isoq u in olin -5-on e (10c). The procedure de-
J . Org. Chem, Vol. 69, No. 8, 2004 2771

Le et al.
and methyl iodide (280 mg, 2.0 mmol) to give compound 12b
as an oil (280 mg, 90%). IR (cm-1): 1655 (CdO). 1H NMR (300
MHz, CDCl3) δ: 7.16 (d, J ) 8.4 Hz, 1H), 6.96 (d, J ) 8.2 Hz,
1H), 6.88 (s, 1H), 6.69 (s, 1H), 6.30 (s, 1H), 6.23 (m, 2H), 6.02
(m, 2H), 4.51 (s, 2H), 3.61 (m, 2H), 3.24 (s, 3H), 3.20 (s, 3H),
2.75-2.59 (m, 2H). EIMS: m/z 411 (M+, 100). HRMS-EI (calcd
for C22H21NO7): 411.4038, found 411.4039.
7-[6-(2-Meth oxym eth oxyeth yl)ben zo[1,3]d ioxol-5-yl]-6-
m eth yl-6H-[1,3]d ioxolo[4,5-g]isoqu in olin -5-on e (12c). The
procedure described for compound 12a was used with com-
pound 9c (300 mg, 0.75 mmol), K2CO3 (520 mg, 3.75 mmol),
and methyl iodide (270 mg, 1.9 mmol) to give the product 12c
as an oil (190 mg, 62%). IR (cm-1): 1655 (CdO). 1H NMR (300
MHz, CDCl3) δ: 7.79 (s, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 6.69 (s,
1H), 6.29 (s, 1H), 6.07 (s, 2H), 6.02 (s, 2H), 4.50 (s, 2H), 3.63-
3.58 (m, 2H), 3.29 (s, 3H), 3.20 (s, 3H), 2,78-2.56 (m, 2H).
EIMS: m/z 411 (M+, 100). HRMS-EI (calcd for C22H21NO7):
411.4038, found 411.4040.
3-[6-(2-H y d r o x y e t h y l)b e n z o [1,3]d i o x o l-5-y l]-6,7-
d im eth oxy-2-m eth yl-2H-isoqu in olin -1-on e (13a ). To a so-
lution of compound 12a (90 mg, 0.21 mmol) in THF (10 mL)
was added 10% HCl (3 mL), and the mixture was refluxed for
2 h. The reaction mixture was poured into water and extracted
with ethyl acetate. The ethyl acetate extracts were washed
with water and brine and dried over anhydrous sodium sulfate.
After removal of the solvent, the residue was purified by
column chromatography on silica gel with with n-hexanes-
ethyl acetate (1:2) to give alcohol 13a as a solid (63 mg, 78%).
Mp ) 191-194 °C. IR (cm-1): 3356 (OH), 1642 (CdO). 1H
NMR (300 MHz, CDCl3) δ: 7.78 (s, 1H), 6.88 (s, 1H), 6.81 (s,
1H), 6.71 (s, 1H), 6.34 (s, 1H), 6.03 (s, 2H), 4.02(s, 3H), 4.01
(s, 3H), 3.73 (m, 2H), 3.30 (s, 3H), 2.71-2.62 (m, 2H). EIMS:
m/z 383 (M+, 100). Anal. Calcd for C21H21NO6: C, 65.79; H,
5.52; N, 3.65. Found: C, 65.53; H, 5.82; N, 3.69.
Oxyn itid in e (14a ). To a solution of alcohol 13a (40 mg,
0.10 mmol) in CH2Cl2 (8 mL) were added PCC (45 mg, 0.21
mmol) and NaOAc (15 mg, 0.18 mmol) at room temperature.
After being stirred for 6 h, the reaction mixture was filtered
and washed with CH2Cl2. The solvent was evaporated off, and
the residue was purified by column chromatography on silica
gel with n-hexanes-ethyl acetate (1:1) to afford oxynitidine
14a as a white solid (23 mg, 63%). Mp ) 284-285 °C (lit.30
mp 280-283 °C, lit.31 mp 284-285 °C). IR (cm-1): 1642 (Cd
O). 1H NMR (300 MHz, CDCl3) δ: 8.00 (d, J ) 9.0 Hz, 1H),
7.91 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.57 (d, J ) 8.8 Hz,
1H), 7.17 (s, 1H), 6.10 (s, 2H), 4.10 (s, 3H), 4.04 (s, 3H), 3.97
(s, 3 H). EIMS: m/z 363 (M+, 100). Anal. Calcd for C21H17
-
NO5: C, 69.41; H, 4.72; N, 3.85. Found: C, 69.44; H, 4.62; N,
3.76.
Oxysa n gu in a r in e (14b). The procedure described for
compound 14a was used with compound 13b (20 mg, 0.10
mmol), PCC (25 mg, 0.21 mmol), and NaOAc (8 mg, 0.18 mmol)
to afford oxysanguinarine 14b as a white solid (16 mg, 61%).
Mp ) 360-362 °C (lit.32 mp 366-368 °C). IR (cm-1): 1652 (Cd
O). 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J ) 8.6 Hz, 1H),
7.96 (d, J ) 8.6 Hz, 1H), 7.53 (s, 1H), 7.52 (d, J ) 8.6 Hz, 1H),
7.23 (d, J ) 8.6 Hz, 1H), 7.16 (s, 1H), 6.27 (s, 2H), 6.09 (s,
2H), 3.90 (s, 3H). EIMS: m/z 347 (M+, 100). Anal. Calcd for
C
20H13NO5: C, 69.16; H, 3.77; N, 4.03. Found: C, 69.36; H,
3.95; N, 4.13.
Oxya vicin e (14c). The procedure described for compound
14a was used with compound 13c (50 mg, 0.136 mmol), PCC
(87 mg, 0.21 mmol), and NaOAc (27 mg, 0.18 mmol) to afford
oxyavicine 14c as a white solid (36 mg, 76%). Mp ) 279-282
°C (lit.33 mp 276-277 °C, lit.34 mp 278-283 °C). IR (cm-1):
1631(CO). H NMR (300 MHz, CDCl3) δ: 7.93 (d, J ) 8.6 Hz,
1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.56 (d, J ) 8.6,
1H), 7.18 (s, 1H), 6.13 (s, 2H), 6.10 (s, 2H), 3.97 (s, 3H).
EIMS: m/z 347 (M+, 61). Anal. Calcd for C20H13NO5: C, 69.16;
H, 3.77; N, 4.03. Found: C, 69.24; H, 3.69; N, 4.14.
7-[6-(2-Hyd r oxyeth yl)ben zo[1,3]d ioxol-5-yl]-8-m eth yl-
8H-[1,3]d ioxolo[4,5-h ]isoqu in olin -9-on e (13b). The proce-
dure described for compound 13a was used with compound
12b (250 mg, 0.6 mmol) and 10% HCl (10 mL) to give alcohol
13b as a solid (177 mg, 80%). Mp ) 199-200.5 °C. IR (cm-1):
Ack n ow led gm en t. This work was supported by a
grant from the Korean Ministry of Health and Welfare
(01-PJ 1-PG3-21500-0018, 100-PJ 1-PG1-CH15-0002).
1
3300 (OH), 1654 (CdO). H NMR (300 MHz, CDCl3) δ: 7.16
(d, J ) 8.1 Hz, 1H), 6.95 (d, J ) 8.1 Hz, 1H), 6.87 (s, 1H), 6.71
(s, 1H), 6.30 (s, 1H), 6.23 (q, J ) 1.4 Hz, 2H), 6.02 (q, J ) 1.4
Hz, 2H), 3.73 (m, 2H), 3.23 (s, 3H), 2.75-2.55 (m, 2H). EIMS:
m/z 367 (M+, 100). Anal. Calcd for C20H17NO6: C, 65.39; H,
4.66; N, 3.81. Found: C, 65.43; H, 4.68; N, 3.71.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and MS charts of compounds 9a -c, 11a -c, and 14a -c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
7-[6-(2-Hyd r oxyeth yl)ben zo[1,3]d ioxol-5-yl]-6-m eth yl-
6H-[1,3]d ioxolo[4,5-g]isoqu in olin -5-on e (13c). The proce-
dure described for compound 13a was used with compound
12c (105 mg, 0.26 mmol) and 10% HCl (3 mL) to give alcohol
13c as a solid (73 mg, 76%). Mp ) 208.2-209.7 °C. IR (cm-1):
J O035836+
(30) Clark, R. D.; J ahangir J . Org. Chem. 1988, 53, 2378-2381.
(31) Hanaoka, M.; Yamagishi, H.; Marutani, M.; Mukai. C. Tetra-
hedron Lett. 1984, 25, 5169-5172.
1
3300 (OH), 1654 (CdO). H NMR (300 MHz, CDCl3) δ: 7.75
(32) Pandey, V. B.; Ray, A. B.; Dasgupta, B. Phytochemistry 1979,
18, 695-696.
(s, 1H), 6.87 (s, 1H), 6.80 (s, 1H), 6.70 (s, 1H), 6.29 (s, 1H),
6.08 (s, 2H), 6.02 (m, 2H), 3.73 (m, 2H), 3.28 (s, 3H), 2.75-
2.56 (m, 2H), 1.60 (s, 1H). EIMS: m/z 367 (M+, 100). Anal.
Calcd for C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C,
65.41; H, 4.79; N, 3.74.
(33) Gopinath, K. W.; Govindachari, T. R.; Viswanathan, N. Tetra-
hedron 1961, 14, 322-325.
(34) Ninomiya, I.; Naito, T.; Ishii, H.; Ishida, T.; Ueda, M.; Harada,
K. J . Chem. Soc., Perkin Trans. 1 1975, 8, 762-764.
2772 J . Org. Chem., Vol. 69, No. 8, 2004