Synthesis of benzo-γ-carboline alkaloid cryptosanginolentine by reaction of indole-2,3-dicarboxylic anhydrides with anilines

Article abstract of DOI:10.1016/j.tetlet.2007.10.130

1-Benzenesulfonylindole-2,3-dicarboxylic anhydride was reacted with aniline to give the 2-carbamoylindole-3-carboxylic acid as the sole product, but with N-methylaniline, the 3-carbamoylindole-2-carboxylic acid was the major product, which could be transf

Full text of DOI:10.1016/j.tetlet.2007.10.130

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Tetrahedron Letters 48 (2007) 9093–9095
Synthesis of benzo-c-carboline alkaloid cryptosanginolentine
by reaction of indole-2,3-dicarboxylic anhydrides with anilines
Yasuyoshi Miki,* Makoto Kuromatsu, Hideaki Miyatake and Hiromi Hamamoto
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Received 12 September 2007; revised 24 October 2007; accepted 26 October 2007
Available online 30 October 2007
Abstract—1-Benzenesulfonylindole-2,3-dicarboxylic anhydride was reacted with aniline to give the 2-carbamoylindole-3-carboxylic
acid as the sole product, but with N-methylaniline, the 3-carbamoylindole-2-carboxylic acid was the major product, which could be
transformed into the 1-benzenesulfonylbenzo-c-carbolinone in the presence of Pd(OCOCF3)2. The reduction of the benzo-c-carbo-
linone with LiAlH4 gave the cryptosanginolentine in high yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Cryptosanguinolentine (isocryptolepine) (1), isolated
from the West African plant Cryptolepis sanguinolentia
in 1996,1 is a member of the indoloquinoline alkaloids
(benzo-c-alkaloids), which showed antiplasmodial prop-
erties. Molina reported the useful synthesis of 1 by Red-
Al reduction of the benzo-c-carbolinone derivative,
which was prepared by the cyclization of the azide com-
pound, but some difficulties occurred in the preparation
of the benzo-c-carbolinone derivative by using the azide
Me
N
N
cryptosanginolentine (1)
and haloquinoline derivative.5 Merour described the
´
excellent synthesis of benzo-c-carbolinone derivatives
by Heck cyclization of N-(2-iodophenyl)indole-3-
carboxamide prepared from indole-3-carboxylic acid
and 2-iodoaniline.6 The decarboxylative Heck-type
cross-coupling reaction of aromatic carboxylic acids
with olefins in the presence of a palladium catalyst
was reported by Myers.7 Forgione showed the unex-
pected intramolecular palladium-catalyzed reaction of
compound.2 A similar preparation of 1 by the cycliza-
3
´
tion of the azide compound was also done by Timari.
Maes found a novel synthesis of 1 via a palladium-
catalyzed amination–arylation of 4-chloroquinoline
with 2-chloroaniline4 and Mohan showed three syn-
thetic routes of 1 by the Fisher indole synthesis and
photochemical intramolecular cyclization of an imine
NH-R2
R2
R3
R3
O
O
COOH
N
N
+
O
rt
N
N
N
COOH
R2
R3
O
O
R1
R1
R1
2
3
4
a: R1 = SO2Ph
b: R1 = CH2Ph
a: R1 = SO2Ph, R2, R3 = H,
b: R1 = SO2Ph, R2 = Me, R3= H,
c: R1 = SO2Ph, R2 = Me, R3 = I, d: R1 = CH2Ph, R2 = Me, R3 = H
Scheme 1.
*
Corresponding author. E-mail: y_miki@phar.kindai.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.130

9094
Y. Miki et al. / Tetrahedron Letters 48 (2007) 9093–9095
Red-Al 2)
Table 1.
n-Bu4NF
9
Entry
2
R1
R2
H
R3 Solvent
Time (h)
Yield
(%)
O
3
4
Me
Me
N
LiAlH4
N
1
2
3
4
5
a
a
a
a
b
SO2Ph
I
CH2Cl2
CH2Cl2
CH3CN
CH3CN 72
CH3CN
0.5
0.5
0.5
—
99
dioxane
1 h
N
SO2Ph Me
SO2Ph Me
SO2Ph Me
Ch2Ph Me
H
H
I
39 60
73 22
N
SO2Ph
77
78
9
5
5
H
1
cryptosanginolentine (1)
Scheme 2.
heteroaromatic carboxylic acids with bromobenzene.8
However, there is no report of the intramolecular
decarboxylative Heck-type reaction of indolecarboxylic
acids and the synthesis of benzocarboline derivatives.
Recently, we have shown that the indole-2,3-dicarb-
oxylic anhydride (2) is a useful synthon in the synthesis
of olivacine9 and caulersin.10 In this Letter, we report
the efficacy of anhydrides 2 and its application to the
simple and useful synthesis of cryptosanginolentine (1)
by applying Myers method.7
The reaction of 1-(benzenesulfonyl)indole-2,3-dicarbox-
ylic anhydride (2a) with 2-iodoaniline at room tempera-
ture gave the 2-carbamoylindole-3-carboxylic acid (4a)
in 99% yield as the sole product, but the corresponding
Table 2.
Products
Entry
3
Pd(OCOCF3)2 (20 mol %)
Ag2CO3 (3 equiv)
Me
Me
O
O
O
Me
N
N
N
+
1
5%DMSO in DMF
80 °C 1 h
N
N
N
COOH
SO2Ph
6 (24%)
O
SO2Ph
SO2Ph
3b
5 (45%)
Me
Me
O
N
N
"
5
2
+
80 °C 8 h
I
N
N
I
COOH
SO2Ph
(13%)
SO2Ph
7 (37%)
3c
O
Me
O
Me
Me
N
N
"
3
100 °C 10 h
N
N
COOH
CH2Ph
CH2Ph
3d
8 (20%)
Me
O
N
O
N
"
x
4
5
N
N
H
140°C 4 h
COOH
H
3e
9
"
5 (71%)
+
6 (12%)
3b
50°C 48 h

Y. Miki et al. / Tetrahedron Letters 48 (2007) 9093–9095
9095
3-carbamoylindole-2-carboxylic acid (3a) was not
References and notes
isolated (entry 1). The treatment of 2a with N-methyl-
aniline in CH2Cl2 afforded a mixture of the indole-2-
carboxylic acid (3b) and indole-3-carboxylic acid (4b)
in 39% and 60% yields, respectively, but in aceto-
nitrile, 3b was isolated in 73% yield as the major prod-
uct along with 4b (22%) (entries 2 and 3). Compound
2a was also reacted with N-methyl-2-iodoaniline at
room temperature for 72 h to provide a mixture of the
indole-2-carboxylic acid (3c) and indole-3-carboxylic
acid (4c) in 77% and 9% yields, respectively (entry
4). The reaction of 1-benzylindole-2,3-dicarboxylic
anhydride (2b) with N-methylaniline in acetonitrile
gave the corresponding indole-2-carboxylic acid (3d) in
78% yield as the major product (Scheme 1, Table 1,
entry 5).
1. Sharaf, M. H. M.; Schiff, P. L.; Tackie, A. N.; Phoebe, C.
H.; Martin, G. E. J. Heterocycl. Chem. 1996, 33, 239–
243.
2. Fresneda, P. M.; Molina, P. M.; Delgado Tetrahedron
Lett. 1999, 40, 7275–7278; Fresneda, P. M.; Molina, P.
M.; Delgado Tetrahedron 2001, 57, 6197–6702.
´
´
´
3. Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067–1068.
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4. Jonckers, T. H. H.; Maes, B. U. W.; Lemiere, G. L. F.;
Rombouts, G.; Pieters, L.; Haemers, A.; Dommisse, R. A.
Synlett 2003, 615–618.
5. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron
2006, 62, 6258–6263; Dhanabal, T.; Sangeetha, R.;
Mohan, P. S. Tetrahedron Lett. 2005, 46, 4509–4510;
Kumar, R. N.; Suresh, T.; Mohan, P. S. Tetrahedron Lett.
2002, 43, 3327–3328.
´
6. Mouladdib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.
Synthesis 2000, 549–556.
The decarboxylative Heck-type cyclization of 1-benzene-
sulfonylindole-2-carboxylic acid (3b) was performed by
treatment with Pd(OCOCF3)2 (20 mmol %)7 and
Ag2CO3 in DMSO and DMF at 80 °C to give a mixture
of the 11-benzenesulfonyl-5-methylindolo[3,2-c]quino-
line (5)11 and decarboxylation product (6) in 45% and
24% yields, respectively, but from the 2-iodo derivative
(3c), 5 was isolated in a low yield (13%) along with the
decarboxylation product (7) (37%) (entries 1 and 2).
However, several efforts (Pd(PPh3)4 or Pd(OAc)2,
Ag2O, AgO, or Cs2CO3) were made to obtain the
cyclization product (8) and (9) from the 1-benzylindole
compound (3d) and NH compound (3e), but the results
were less than satisfactory (entries 3 and 4). Finally, 5
was obtained in fairly good yield (71%) at 50 °C for
48 h (entry 5, Table 2). The 11-benzenesulfonyl-5-
methylindolo[3,2-c]quinoline (5) could be converted to
cryptosanguinolentine (1)12 by treatment with tetra-
butylammomium fluoride (rt, 6 h in THF, 80%)
followed by treatment with Red-Al (110 °C, 32 h in
toluene, 53%),2 but the reduction of 5 with LiAlH4 in
hot dioxane produced 1 in 98% yield (Scheme 2).
7. Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 10323–10333; Tanaka, D.; Myers, G. Org. Lett.
2004, 6, 433–436; Myers, A. G.; Tanaka, D.; Mannion, M.
R. J. Am. Chem. Soc. 2002, 124, 11250–11251.
8. Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.;
Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128,
11350–11351.
9. Miki, Y.; Tsuzaki, Y.; Hibino, H.; Aoki, Y. Synlett 2004,
2206–2208.
10. Miki, Y.; Aoki, Y.; Miyatake, H.; Minematsu, T.; Hibino,
H. Tetrahedron Lett. 2006, 47, 5215–5218.
11. 11-Benzenesulfonyl-5-methylindolo[3,2-c]-quinoline (5):
mp 212–214 °C (MeOH). IR (Nujol) cmÀ1: 1645. 1H
NMR (CDCl3) d: 3.84 (3H, s, Me), 7.08–7.18 (2H, m,
arom), 7.20–7.28 (2H, m, arom), 7.30–7.56 (5H, m, arom),
7.65 (1H, ddd, J = 8.5, 8.0, 2.0 Hz, arom), 8.24–8.35 (2H,
m, arom), 8.82 (1H, dd, J = 8.0, 2.0 Hz, arom). HRMS
(EI) m/z: calcd for C23H18O5N2S, 388.0881; found,
388.0872. Anal. Calcd for C23H18O5N2S: C, 68.02; H,
4.15; N, 7.21. Found: C, 68.15; H, 4.12; N, 7.33.
12. Cryptosanguinolentine: mp 134–135 °C (CH3CN) (lit.,3
132–133 °C). IR (Nujol) cmÀ1: 1636, 1612, 1596, 1455,
1
1225, 746, 736. H NMR (DMSO-d6) d: 4.32 (3H, s, Me),
7.29 (H, br t, J = 7.5 Hz, H-8), 7.47 (1H, dt, J = 7.5,
1.0 Hz, H-9), 7.77 (1H, br t, J = 8.0 Hz, H-2), 7.80 (1H, br
d, J = 7.5 Hz, H-10), 7.90 (1H, dt, J = 8.0, 1.0 Hz, H-3),
8.13 (1H, br d, J = 8.0 Hz, H-4), 8.16 (1H, br d, J = 7.5 Hz,
H-7), 8.78 (1H, dd, J = 8.0, 1.0 Hz, H-1), 9.51 (1H, s, H-6).
13C NMR (DMSO-d6) d: 151.49, 150.74, 139.63, 135.78,
130.16, 126.21, 126.05, 124.95, 124.21, 120.72, 120.16,
119.99, 118.14, 117.47, 115.77, 42.81. HRMS m/z (M+)
calcd for C16H12N2, 232.1000; found, 232.0986.
Acknowledgments
This work was supported by ‘High-Tech Research
Center Project’ for Private Universities and matching
fund subsidy from MEXT (2007) and Kinki University.