A facile synthesis of benzo[c]phenanthridine alkaloids: Oxynitidine and oxysanguinarine using lithiated toluamide-benzonitrile cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2004.02.031

Benzo[c]phenanthridine alkaloids oxynitidine and oxysanguinarine were synthesized from easily available starting benzonitrile 5 and toluamide 6 using toluamide-benzonitrile cycloaddition reaction in six steps. This method is so highly efficient that it could be a more useful way for preparing fully aromatized benzo[c]phenanthridine compounds.

Full text of DOI:10.1016/j.tetlet.2004.02.031

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2763–2766
A facile synthesis of benzo[c]phenanthridine alkaloids: oxynitidine
and oxysanguinarine using lithiated toluamide–benzonitrile
cycloaddition
Thanh Nguyen Le, Seong Gyoung Gang and Won-Jea Cho*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Yong-Bong dong, Buk-gu,
Kwangju 500-757, South Korea
Received 12 January 2004; revised 31 January 2004; accepted 9 February 2004
Abstract—Benzo[c]phenanthridine alkaloids oxynitidine and oxysanguinarine were synthesized from easily available starting benzo-
nitrile 5 and toluamide 6 using toluamide–benzonitrile cycloaddition reaction in six steps. This method is so highly efficient that it
could be a more useful way for preparing fully aromatized benzo[c]phenanthridine compounds.
Ó 2004 Elsevier Ltd. All rights reserved.
Benzo[c]phenanthridine alkaloids, including nitidine
and sanguinarine, have been attractive to synthetic
organic chemists and biochemists over the last two
decades since such compounds have shown interesting
biological properties.1–4 To date, previously reported
benzophenanthridine synthetic studies have involved
multi-step sequences as well as having a lack of gener-
ality for synthesizing substituted target compounds.5;6
Not only for studying the structure–activity relation-
ships of these molecules, but also for the total synthesis
of alkaloids facile syntheses of these compounds are
needed (Fig. 1).
We recently reported the synthesis of 3-arylisoquinoline
derivatives including biological evaluation.7 The syn-
thetic strategy involved in the cycloaddition reaction of
N-methyl-o-toluamide with benzonitrile to afford
3-arylisoquinolines.8;9 We believe that the above 3-aryl-
isoquinoline synthetic approach could be applied to the
total synthesis of benzo[c]phenanthridine alkaloids. Our
strategy is based on the formation of 3-arylisoquinoline,
which could be transformed to benzo[c]phenanthridine
alkaloids via intramolecular enamide ring formation
reactions. The advantages of this methodology include
easy access to the starting materials and a one pot pro-
cedure for constructing all carbon atoms for alkaloids.
Similar methodologies such as imine–toluamide con-
densation,10;11 cyclization of phenyl ethyl isocyanate,12
homophthalic ester13––and homophthalic anhydride14––
imine condensation have also been reported. However,
limited application to diverse substituted pattern on
aromatic rings of benzo[c]phenanthridine is a barrier for
broadening the utility of this method. Retrosynthetic
consideration of benzo[c]phenanthridine indicates that
the coupling of benzonitrile with o-toluamide might af-
ford 3-arylisoquinoline, which could be converted to an
aldehyde. The C ring of benzo[c]phenanthridine could be
constructed by an intramolecular ring cyclization meth-
od as outlined in Scheme 1.
O
O
O
MeO
O
+
N
+
Me
O
N
Me
nitidine
MeO
O
sanguinarine
Figure 1. Structure of nitidine and sanguinarine.
Keywords: Benzo[c]phenanthridine alkaloids; Nitidine; Sanguinarine;
Synthesis of natural alkaloids.
The starting bromide 1 was treated with CuCN in
DMF15 to give benzonitrile 2 in 66% yield. The acetal
group of 2 was removed by 5% HCl to afford aldehyde
* Corresponding author. Tel.: +82-62-530-2933; fax: +82-62-530-2911;
e-mail: wjcho@jnu.ac.kr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.031

2764
T. N. Le et al. / Tetrahedron Letters 45 (2004) 2763–2766
O
H
R'
C
N
D
R'
R
A
B
R
R
N
Me
Me
Me
O
O
benzo[c]phenanthridine
MOMO
Me
O
R'
MOMO
H
N
R'
R
NC
NH
O
3-arylisoquinoline
Scheme 1. Retrosythesis of benzo[c]phenanthridines.
O
O
CHO
CN
O
O
O
O
O
5%HCl
O
O
CuCN
MeOH
y. 100%
DMF
y. 66%
O
CN
Br
3
2
1
O
O
NaBH4
OMOM
CN
MOM-Cl
OH
AcOH
y. 78%
CH2Cl2, DIEA
y. 92%
O
O
CN
5
4
Scheme 2. Synthesis of benzonitrile 5.
3, which was then reduced with NaBH4 followed by
MOM protection to provide the desired benzonitrile 5 in
good yield as shown in Scheme 2. When benzyl or
p-methoxybenzyl was introduced on to the hydroxyl
group, the desired coupling reaction did not occur.
Toluamides 6a–c16 were synthesized from the corre-
sponding substituted benzoic acids by treatment of
oxalyl chloride followed by methylamine or diethyl-
amine in good yield. In a model study, unsubstituted
starting material, N-methyl-o-toluamide 6a was used for
cycloaddition. The deprotonation of 6a with 2 equiv
n-BuLi gave dianion, which was treated with MOM
protected benzonitrile 5 to afford the 3-arylisoquinoline-
1(2H)-one 7a in 82% yield. Compound 7a was then
reacted with MeI in the presence of 60% NaH to give N-
methylated compounds 8a without giving an O-methyl-
ated one. Deprotection of 8a with 10% HCl followed by
oxidation with PDC to afford aldehyde 9a, which were
then treated with Ph3PCH2OMe/n-BuLi to give the
olefins 10a as an E/Z (1:1.5) mixture. Hydrolysis of 10a
with 10% HCl produced the desired benzo[c]phenan-
thridine compound 12a in 88% yield. In this reaction we
assumed that hydrolysis produced the aldehyde 11a and
the consecutive intramolecular enamide–aldehyde cycli-
zation occurred under an acidic condition as shown in
Scheme 3.17 After ring formation, dehydration would
easily occur thus producing a fully aromatized ring
system of benzo[c]phenanthridine. For the preparation
of oxynitidine 12b, the readily available N-methyl tolu-
amide was condensed with 5 as before. However, the
desired cycloaddition product 7b was not obtained due
to it having a weak solubility in organic solvents
(DMSO, THF, dioxane, etc.,). Therefore, we modified
the N-methyl toluamides to N,N-diethyl toluamides 6b,
c, which are soluble in THF and as expected, the
cycloaddition reaction proceeded to furnish the desired
products 7b,c. The consecutive N-methylation, depro-
tection with 10% HCl, oxidation with PDC and Wittig
reaction followed by hydrolysis afforded the desired
natural benzo[c]phenanthridine alkaloids18; oxynitidine
12b and oxysanguinarine 12c in a 20.5% and 20.7%
overall yield, respectively. Herein, we have also accom-
plished the formal synthesis of nitidine and sanguinarine
because the process to these alkaloids from the corre-
sponding oxynitidine and oxysanguinarine were already
established.5
Thus we have synthesized the benzo[c]phenanthridine
alkaloids in six steps from benzonitrile 5 and toluamide
6. This cycloaddition method could be added an
advanced alternative procedure for a construction of
benzo[c]phenanthridine framework and provide the
facile access to diverse analogues of it in multi-gram
scale, which are necessary to study structure–activity
relationships for the development of new chemothera-
peutic agents.

T. N. Le et al. / Tetrahedron Letters 45 (2004) 2763–2766
2765
MOMO
O
O
R1
R2
Me
NaH, THF
MeI
O
O
n-BuLi
MOMO
R1
R2
R
N
+
THF
NH
R
NC
O
R3
O
6
R3
5
7a (82%)
7b (50%)
7c (59%)
a: R1=R2=R3=H, R=H, Me
b: R1= R2= OCH3, R3=H, R=Et
c: R1 =H, R2+ R3 =OCH2O, R=Et
O
N
MOMO
O
O
O
H
O
Ph3P+CH2OMeI-
1) HCl 10%
R1
R2
R1
R2
O
2) PDC
CH2Cl2
N
n-BuLi, THF
Me
Me
O
R3
R3
8a (77%)
8b (78%)
8c (90%)
9a (70%)
9b (85%)
9c (70%)
H
O
MeO
O
O
O
O
H
O
O
R1
HCl 10%
R1
R2
R1
R2
N
Me
R2
N
Me
N
O
R3
Me
O
R3
O
R3
12
10a (74%)
10b (70%)
10c (66%)
11a-11c
benzo[c]phenanthridine (12a): R1 =R2=R3=H (88%)
oxynitidine (12b): R1=R2=OCH3, R3=H (88%)
oxysanguinarine (12c): R1 =H, R2+ R3 =OCH2O (85%)
Scheme 3. Synthesis of benzo[c]phenanthridine alkaloids.
7. (a) Cho, W.-J.; Park, M.-J.; Chung, B.-H.; Lee, C.-O.
Bioorg. Med. Chem. Lett. 1998, 8, 41–46; (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.; Jeong, E. Y.; Kim, T. S.; Le, T. N.; Kim, D.-D.; Lee,
E.-S. Bioorg. Med. Chem. 2002, 10, 2953–2961; (d) Cho,
W.-J.; Min, S. Y.; Le, T. N.; Kim, T. S. Bioorg. Med.
Chem. Lett. 2003, 13, 4451–4454.
Acknowledgements
This work was supported by a grant from the Korean
Ministry of Health and Welfare (01-PJ1-PG3-21500-
0018).
References and notes
8. Cho, W.-J.; Park, M.-J.; Imanishi, T.; Chung, B. H. Chem.
Pharm. Bull. 1999, 47, 900–902.
1. Fleury, F.; Sukhanova, A.; Ianoul, A.; Devy, J.; Kudelina,
I.; Duval, O.; Alix, A. J. P.; Jardillier, 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. 2000,
10, 2321–2323.
3. 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. Poindexter, G. S. J. Org. Chem. 1982, 47, 3787–3788.
10. Clark, R. D.; Jahangir J. Org. Chem. 1988, 53, 2378–2381.
11. Clark, R. D.; Jahangir J. Org. Chem. 1988, 52, 5378–5382.
12. Shamma, M.; Tomlinson, H. H. J. Org. Chem. 1978, 43,
2852–2855.
13. Cushman, M.; Cheng, L. J. Org. Chem. 1978, 43, 286–
288.
14. Irie, H.; Shiina, A.; Fushimi, T.; Katakawa, J.; Fujii, N.;
Yajima, H. Chem. Lett. 1980, 875.
4. Ishikawa, T. Med. Res. Rev. 2001, 21, 61–72.
5. Mackay, S. P.; Meth-Cohn, O.; Waich, R. D. Adv.
Heterocycl. Chem. 1997, 67, 345–389.
6. 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.;
Mckilop, A. Tetrahedron 1998, 54, 9875–9894; (c) Hara-
yama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.;
Akiyama, T.; Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin
Trans. 1 2001, 523–528.
15. Hill, R. K.; Carson, R. M. J. Org. Chem. 1965, 30, 1571.
In this paper, pyridine was used as a solvent. When we
carried out the reaction in pyridine the desired compound
was obtained in low yield (20–30%). Various solvents were
tested for increasing the chemical yield and finally we
found that DMF was the best for the reaction.
16. Kupchan, S. M.; Wormser, H. C. J. Org. Chem. 1965, 30,
3792–3800.
17. Hanaoka, M.; Motonishi, T.; Mukai, C. J. Chem. Soc.,
Perkin Trans. 1 1986, 2253–2256.

2766
T. N. Le et al. / Tetrahedron Letters 45 (2004) 2763–2766
1
18. All synthesized compounds were fully characterized by
spectroscopy. Selected data for key compounds: Com-
pound 7b; mp: 151.0–154.2 °C. IR (cmꢀ1): 3400 (NH), 1657
(CO). 1H NMR (300 MHz, CDCl3): d: 9.62 (s, 1H), 7.78 (s,
1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.06
(s, 2H), 4.80 (s, 2H), 4.46 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H),
3.44 (s, 3H). EIMS m=z (%) 399 (Mþ, 17), 354 (20), 336
(100). Compound 7c; mp: 151–153 °C. IR (cmꢀ1): 3400
(NH), 1665 (CO) 1H NMR (300 MHz, CDCl3) d: 9.38 (s, 1
H), 7.18 (d, J ¼ 8:2 Hz, 1H), 7.04 (d, J ¼ 8:2 Hz, 1H), 6.94
(s, 1H), 6.93(s, 1H), 6.39 (s, 1H), 6.04 (s, 2H), 4.77 (s, 2H),
4.45 (s, 2H), 3.51 (s, 3H). EIMS m=z (%) 383 (M, 17), 338
(20), 320 (100), 292 (27). Compound 12b (oxynitidine); mp:
284–285 °C (lit.10 mp: 280–283 °C, lit.19 mp: 284–285 °C).
IR (cmꢀ1): 1642 (C@O). H NMR (300 MHz, CDCl3) d:
8.00 (d, J ¼ 9:0 Hz, 1H), 7.91 (s, 1H), 7.63(s, 1H), 7.58 (s,
1H), 7.57 (d, J ¼ 8:8 Hz, 1H), 7.17 (s, 1H), 6.10 (s, 2H), 4.10
(s, 3H), 4.04 (s, 3H), 3.97 (s, 3H). EIMS m=z (%) 363 (Mþ,
100). Compound 12c (oxysanguinarine); mp: 360–362 °C
(lit.20 mp: 366–368 °C). IR (cmꢀ1): 1652 (C@O). 1H NMR
(300 MHz, CDCl3) d: 7.99 (d, J ¼ 8:6 Hz, 1H), 7.18 (d,
J ¼ 9:6 Hz, 1H), 7.53(s, 1H), 7.52 (d, J ¼ 8:6 Hz, 1H), 7.18
(d, J ¼ 9:6 Hz, 1H), 7.16 (s, 1H), 6.20 (s, 2H), 6.09 (s, 2H),
3.90 (s, 3H). EIMS m=z (%) 347 (Mþ, 100).
19. Hanaoka, M.; Yamagishi, H.; Marutani, M.; Mukai, C.
Tetrahedron Lett. 1984, 25, 5169–5172.
20. Pandey, V. D.; Ray, A. B.; Dasgupta, B. Phytochemistry
1979, 18, 695–696.