Heteroatom directed photoannulation: synthesis of indoloquinoline alkaloids: cryptolepine, cryptotackieine, cryptosanguinolentine, and their methyl derivatives

Article abstract of DOI:10.1016/j.tet.2006.04.050

A three-step synthesis of indoloquinoline alkaloids is described. The reaction of 2,3 and 4-substituted haloquinolines with anilines afforded the respective anilinoquinolines, which upon photocyclization gave the indoloquinolines. By regioselective methylation on quinoline nitrogen, furnished the alkaloids cryptotackieine, cryptosanguinolentine, cryptolepine, and the synthetic isomer isoneocryptolepine. Their methyl derivatives were also synthesized in search of new antiplasmodial drugs and DNA intercalating agents.

Full text of DOI:10.1016/j.tet.2006.04.050

Tetrahedron 62 (2006) 6258–6263
Heteroatom directed photoannulation: synthesis of
indoloquinoline alkaloids: cryptolepine, cryptotackieine,
cryptosanguinolentine, and their methyl derivatives
*
T. Dhanabal, R. Sangeetha and P. S. Mohan
Department of Chemistry, Bharathiar University, Coimbatore—641 046, Tamil Nadu, India
Received 28 October 2005; revised 7 April 2006; accepted 20 April 2006
Available online 11 May 2006
Abstract—A three-step synthesis of indoloquinoline alkaloids is described. The reaction of 2,3 and 4-substituted haloquinolines with anilines
afforded the respective anilinoquinolines, which upon photocyclization gave the indoloquinolines. By regioselective methylation on quinoline
nitrogen, furnished the alkaloids cryptotackieine, cryptosanguinolentine, cryptolepine, and the synthetic isomer isoneocryptolepine. Their
methyl derivatives were also synthesized in search of new antiplasmodial drugs and DNA intercalating agents.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recent synthetic studies have detailed the preparation of
indoloquinoline alkaloids by intramolecular reaction of
iminophosphorane with isocyanate,12,13 by the regioselec-
tive thermocyclization of the corresponding azide14 or by
ortho-metalation using a cross-coupling strategy.15
Indoloquinoline alkaloids are receiving prominent attention
in recent years as they are known to act as DNA intercalating
agents1 and exhibit antimalarial properties.2,3 The World
Health Organization placed malaria besides tuberculosis
and AIDS as a major infectious disease. The roots of the
West African plant Cryptolepis sanguinolenta,4 a rich source
of indoloquinoline alkaloids, have been used by Ghanaian
healers to treat a variety of health disorders including
malaria. Since 1974, a decoction of this plant has been used
in the clinical therapy of rheumatism, urinary tract infections,
malaria, and other diseases.5,6 The linear indoloquinoline
alkaloids cryptolepine (1) (5-methyl-5H-indolo[3,2-b]quino-
line), cryptotackieine (2) (neocryptolepine, 5-methyl-5H-
indolo[2,3-b]quinoline), and an angularly-fused alkaloid
cryptosanguinolentine (3) (isocryptolepine, 5-methyl-5H-in-
dolo[3,2-c]quinoline) are three of the characterized alkaloids,
which behave as DNA intercalating agents, inhibiting DNA
replication and transcription. These compounds also exhibit
strong antiplasmodial activity. Cryptolepine binds 10-fold
more tightly to DNA than other alkaloids and proves to be
much more cytotoxic toward B16 melanoma cells.7 It has
been reported8,9 that some methyl-substituted indolo-
quinolines act as cytotoxic agents, liposomally-formulated
anticancer agents,10 and DNA-Topoisomerase II inhibitors.11
Recently, we have reported an efficient photochemical syn-
thesis16 and Fischer indole synthesis17 toward a cryptosan-
guinolentine alkaloid. Here, we describe the synthesis of
the titled alkaloids along with a synthetic indoloquinoline
isomer, isoneocryptolepine (4), which also possesses promis-
ing in vitro antiplasmodial properties.3 An approach based
on a stepwise formation, starting from amination of the
appropriate haloquinolines with anilines is discussed. The
resultant intermediates on photochemical irradiation being
treated in the presence of iodine catalyst for about 48–72 h
undergo oxidative cyclization to afford the corresponding
isomeric indoloquinolines.
In the last few decades, Schultz et al.18,19,20 extensively in-
vestigated heteroatom directed-photoarylation21,22 method
to derive indoles,23,24 benzothiophenes,25 benzofurans,25
and benzoselenophenes22 by involving subsequent elimina-
tion of smaller molecules like H2O, H2, HCl, and MeOH.
Several mechanisms have been considered for this diaryl-
amine photocyclization.26 The term ‘heteroatom-directed
photoarylation’ characterizes photochemically-initiated
electrocyclic reactions originating from the arrangements
of an available electron pair in a heteroatom and those
from at least one aromatic p-bond. An attractive feature of
this technique is the regiospecificity of the aromatic substi-
tution ortho to the heteroatom.
Keywords: Indoloquinoline alkaloids; Photoannulation; Cryptolepine;
Cryptotackieine; Cryptosanguinolentine.
* Corresponding author. Tel.: +91 422 2422222x343; fax: +91 422
2422387; e-mail: ps_mohan_in@yahoo.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.050

T. Dhanabal et al. / Tetrahedron 62 (2006) 6258–6263
6259
H
N
2. Results and discussion
Br
+
NH2
X
a
To achieve our objective toward the synthesis of cryptotack-
ieine (Scheme 1), cryptosanguinolentine (Scheme 2), and
cryptolepine (Scheme 3), we have started from commer-
cially available haloquinolines (5–7) and anilines (8a–d).
N
X
N
13
7
8
b
H
N
+
NH
NH2
X
X
N
14
+
Cl
N
15
a
c
N
N
9
N
H
8
5
c
b
N
N
CH3
1
N
c
N
H
N
10
N
N
N
CH3
CH3
2
4
Where
Where
8a) X = Cl, 8b) X = H, 8c) X = OH, 8d) X = OMe
8a) X = Cl, 8b) X = H;
H :CH OH:H SO4 (60:30:1, v/v/v), I2, rt.;
a) 200 °C, 5h; b) hν, C6
c) Me2SO4, CH3CN, reflux, 6 h, K2CO3, 80%
6
3
2
a) 200 °C, 5h; b) h , C H :CH OH:H SO4 (60:30:1, v/v/v), I
c) Me2SO4, CH3CN, ref6lux, 6 h3, K2CO3, 82-85%
ν
2, rt.;
6
2
Scheme 1.
Scheme 3.
be noted that the product yield for photocyclization in
protic solvents was significantly higher than that in benzene
alone. Consequently, all subsequent photoreactions were
performed on 9(a–d), 11(a–d), 13(a,b), 17(b,e,f), and
21(b,e,f) in benzene/methanol/sulfuric acid solution
(60:30:1, v/v/v) in the presence of traces of iodine, which
led via oxidative photocyclization to afford indoloquinolines
10, 12, 14, 15, 18(b,e,f), and 22(b,e,f). The cyclization of the
resultant intermediates 9(a–d) were found to occur at C-3
and not at C-1 position of the quinoline ring since the cycli-
zation at the C-1 position requires carbon–nitrogen bond for-
mation and would end with a net loss of aromaticity. In the
final step, compound 4 was subjected to selective methyla-
tion on the quinoline nitrogen8,12a,29 using (CH3)2SO4 in
CH3CN or toluene refluxed for 6 h in the presence of
K2CO3 to afford cryptotackieine (2). The same procedure
was applied to compound 12 (Scheme 2), which afforded
angularly-fused indoloquinoline alkaloid, cryptosanguino-
lentine (3).
Cl
N
HN
NH2
X
a
X
+
N
b
6
8
11
N
HN
c
N
N
12
CH3
3
Where
8a) X = Cl, 8b) X = H, 8c) X = OH, 8d) X = OMe
a) 200 °C, 5h; b) h , C H :CH OH:H SO4 (60:30:1, v/v/v), I2, rt.;
c) Me2SO4, CH3CN, reflux, 6 h, K2CO3, 83%
ν
6
6
3
2
Scheme 2.
Interestingly, in the case of the reaction of 3-bromoquinoline
with aniline (Scheme 3), the resulting intermediate 13 gave
both linearly- and angularly-fused products. When irradi-
ated, linear fusion provides quindoline as a minor product
(16%), which on selective methylation on the quinoline
nitrogen afforded the alkaloid, cryptolepine. On the other
hand, the angularly-fused indoloquinoline (51%) 15 on
methylation afforded isoneocryptolepine (4), which is a
synthetic indoloquinoline alkaloid.28a
It has been reported27a–j that aniline condenses with 2- and 4-
chloroquinolines and many derivatives of haloquinolines on
cautious heating at temperatures in the range of 100–200 ꢀC.
As a first step toward the synthesis of cryptotackieine
(Scheme 1), regioselective amination of 2-chloroquinoline
with 2-chloroaniline was carried out (5/9a). Several
reports28a–c have appeared for such amination detailing the
use of new catalysts. We have found the classical proce-
dure27a–h more fruitful because the familiar procedure like
Hartwig–Buchwald type amination requires expensive
palladium catalysts.
The methyl derivative of the alkaloids 2 and 3 was also
prepared starting from 4-methyl-2-hydroxyquinoline and
2-methyl-4-hydroxyquinoline. On treatment with POCl3
both compounds yielded their corresponding chloro-deriva-
tives (16 and 20). Compounds 16 and 20, on reaction with
anilines (8b,e,f), followed by photochemical cyclization
and regioselective methylation on the quinoline nitrogen,
gave the newer derivatives 19(b,e,f) and 23(b,e,f), respec-
tively (Schemes 4 and 5).
In one approach, photochemical irradiation of anilinoquino-
lines in the absence of protic acid did not afford the desired
products (10 and 12) when X¼OH, and the yields were
found to be ca. 55–60% when X¼Cl, H, and OMe. Hence,
we employed an acidic solvent system for the effective
conversion to the desired photoproducts. Moreover, it should

6260
T. Dhanabal et al. / Tetrahedron 62 (2006) 6258–6263
CH3
300 mass spectrometer. Elemental analyses were recorded
CH3
N
NH2
on EL III, Elementar Analysen Systeme. 2-Chloroquinoline,
4-chloroquinoline, 2-chloroaniline, and 3-bromoquinoline
were purchased and used as received. 2-Methyl-4-hydroxy-
quinoline and 4-methylquinolin-2(1H)-one were prepared
by using reported procedures.30a,b Photolysis was carried
out in a RPR-100 Photochemical Reactor, fitted with 16
RPR UV lamps and using quartz tube.
a
c
+
N
N
H
Cl
R
R
R
17
16
8
b
CH3
CH3
N
N
N
R
N
CH3
4.2. Preparation of anilinoquinolines and their deriva-
tives: 9(a–d), 11(a–d), 13(a,b), 17(b,e,f), and 21(b,e,f)
H
18
19
Where
8b) R = H, 8e) R = o-Me, 8f) R = p-Me,
4.2.1. Preparation of anilinoquinolines: 9(a–d), 11(a–d),
and 13(a,b). Equimolar mixture (10 mmol) of the com-
pounds 2-chloroquinoline (1.63 g) (5) and 2-chloroaniline
(1.24 g) (8a) were heated in flame, and then a violent reaction
occurred at 200 ꢀC. The reaction mixture was cooled; crystals
of the product (9a) were crashed out. This was heated in
NaOH (dilute), cooled down, and recrystallized with alcohol
(yield: 72%, 1.83 g). Similarly, other anilinoquinolines were
prepared using appropriate haloquinolines and anilines.
a) Dry ethanol, reflux, 12h; b) hν, C6H6:CH3OH:H2SO4 (60:30:1, v/v/v), I2, rt.;
c) Me2SO4, CH3CN, reflux, 6 h, K2CO3, 81-82%
Scheme 4.
Cl
HN
R
NH2
a
+
R
R
N
CH3
N
b
CH3
4.2.2. Preparation of anilinoquinoline derivatives:
17(b,e,f) and 21(b,e,f). To 2-chloro-4-methylquinoline
(1.77 g, 10 mmol) (16) dissolved in dry ethanol was added
aniline (0.91 g, 10 mmol) (8b) and then the mixture was
refluxed for about 12 h. Then the excess of ethanol was
distilled off and the residue was then subjected to silica
gel-column chromatography using petroleum ether/ethyl
acetate (85:15, v/v) as eluants, yielded the product (17b)
in 74%. Similarly, its derivatives 17(e,f) and 21(b,e,f) were
prepared by treating 2-chloro-4-methylquinoline and 4-
chloro-2-methylquinolines (20) with their respective ani-
lines (8b,e,f). Since these methyl derivatives 16 and 20
were aminated using this procedure we did not opt the other
procedures.
20
8
21
N
HN
R
c
N
CH3
N
22
CH3
CH3
23
Where
8b) R = H, 8e) R = o-Me, 8f) R = p-Me,
a) Dry ethanol, reflux, 12h; b) h , C6H6:CH3OH:H2SO4 (60:30:1, v/v/v), I2, rt.;
c) Me2SO4, CH3CN, reflux, 6 h, K2CO3, 80-83%
ν
Scheme 5.
4.3. Preparation of isomeric indoloquinoline moieties:
10, 12, 14, 15, 18(b,e,f), and 22(b,e,f)
3. Conclusion
We have developed an efficient three-step synthesis of the
alkaloids cryptotackieine, cryptosanguinolentine, and crypto-
lepine. Due to the easy availability of the starting materials
and high yields realized in the different steps, this approach
proves to be more attractive. We have followed the synthet-
ically-useful method of ‘heteroatom-directed photoannula-
tion technique’ for the construction of linearly, as well as
angularly-fused indoloquinoline alkaloids.
4.3.1. Photochemical cyclization of the compound 9b:
6H-indolo[2,3-b]quinoline. Irradiation of a solution of 9b
(1.1 g, 5 mmol) in the solvent system benzene/methanol/
sulfuric acid (60:30:1, v/v/v) with iodine (25 mg, 0.1 mmol)
was carried out in a RPR-100 Photochemical Reactor, fitted
with 16 RPR UV lamps. The solution placed in a quartz flask
was irradiated for 48 h. When the reaction controlled by TLC
showed complete disappearance of 9b the solvent was re-
moved in vacuo and then the residue was subjected to column
chromatography on silica gel using petroleum ether/ethyl
acetate (80:20, v/v) as eluants, which afforded the pure
photoproduct 10 (0.76 g); 70%, mp >300 ꢀC. Likewise, 12
(78%, 0.85 g) (from 11a), 14 (16%, 0.17 g) and 15 (51%,
0.56 g) (from 13b), 18b (70%, 0.83 g), 18e (67%, 0.82 g),
18f (68%, 0.83 g), 22b (65%, 0.75 g), 22e (63%, 0.77 g),
22f (69%, 0.85 g) werepreparedfromtheir appropriateanilino-
quinolines on photochemical irradiation.
4. Experimental
4.1. General methods
1H NMR and 13C NMR (400 and 100 MHz) spectra were re-
corded in CDCl3 and TMS was used as an internal reference.
Melting points were determined and were uncorrected.
Chromatographic purification was conducted by column
chromatography using 60–120 mesh silica gel. Reagent
grade aniline and ethyl acetoacetate were used after usual
purification methods (for the preparation of the compounds
16 and 20). Reaction progress was monitored by thin layer
chromatography. Mass spectra were recorded on a JMS-D-
4.4. Preparation of isomeric indoloquinoline alkaloids 2,
3, 1, and 4 and their derivatives 19(b,e,f) and 23(b,e,f)
4.4.1. Regioselective methylation of indoloquinolines.
Regioselective methylation was done using the reported

T. Dhanabal et al. / Tetrahedron 62 (2006) 6258–6263
6261
procedure.8 The methylated products 2 (80%, 0.37 g), 3
(83%, 0.38 g), 1 (82%, 0.094 g), 4 (84%, 0.19 g), 19b
(82%, 0.40 g), 19e (81%, 0.42 g), 19f (82%, 0.425 g), and
23b (82%, 0.40 g), 23e (80%, 0.42 g), 23f (83%, 0.43 g)
were obtained from 10 (2 mmol), 12 (2 mmol), 14
(0.5 mmol), 15 (1 mmol), 18(b,e,f), and 22(b,e,f)
(2 mmol), respectively.
(3H, s, Ar–CH3), 6.75 (1H, s, Quin–C3–H), 7.05–7.38 (5H,
m, Ph–H), 7.66 (1H, t, J¼7.4 Hz, C6–H), 7.89 (1H, t,
J¼8.0 Hz, C7–H), 7.97 (1H, d, J¼8.2 Hz, C5–H), 8.08
(1H, d, J¼8.2 Hz, C8–H), 10.51 (1H, br s, NH); 13C NMR:
0
0
C4–CH3-20.01, 0C3-10.38,00C4-119.60, C4 -121.70, C2 - and
00
C2 -124.70, C3 - and C3 -125.33, C6-125.52, C5-127.94,
0
C7-130.02, C8-134.08, C4a-135.00, C1 -135.78, C8a-152.15,
C2-153.94. EIMS (70 eV, m/e): 234 (M+); Anal. Calcd for
C16H14N2: C 82.02, H 6.02, N 11.96. Found: C 82.07,
H 6.03, N 11.95.
Compound 9a. Yield: 72% (1.83 g); mp 137 ꢀC; IR (KBr):
1
1046, 3215, 1610 cmꢁ1; H NMR (CDCl3): d 6.75 (1H, d,
J¼7.2 Hz, Quin–C3–H), 7.05–7.42 (m, 4H, Ph–H), 7.66
(1H, t, J¼7.8 Hz, C6–H), 7.89 (1H, t, J¼7.8 Hz, C7–H),
7.99 (1H, d, J¼7.2 Hz, C5–H), 8.08 (1H, d, J¼7.2 Hz, C4–
Compound 18b. Yield: 72% (0.83 g); mp 206 ꢀC; IR (KBr):
1
3196, 2921, 2845 cmꢁ1; H NMR (CDCl3): d 2.50 (3H,
s, C11–CH3), 7.25–8.00 (6H, m, Ar–H), 8.11 (1H, d,
H), 8.19 (1H, d, J¼8.2 Hz, C8–H), 10.81 (1H, br s, NH);
13
0
0
C3 -121.54, C6-121.92, C5-125.25, C3 -125.32, C7-126.45,
C NMR (CDCl3): C3-118.23, C4 -119.37, C2 -119.52,
J¼8.12 Hz, C4–H), 8.36 (1H, d, J¼8.10 Hz, C10–H), 10.75
00
0
(1H, br s, NH); 13C NMR (CDCl3): C11–CH3-20.35, C10a
-
00
0
C4-127.43, C8-128.05, C4a-129.11, C2 –Cl-135.71, C1 -
148.23, C8a-148.61, C2-159.24. EIMS (70 eV, m/e): 254
(M+), 256 (M+2). Anal. Calcd for C15H11N2Cl: C 70.73, H
4.35, N 11.00. Found: C 70.56, H 4.37, N 10.96.
103.65, C9-121.67, C8-122.48, C10b-122.62, C10-124.03,
C1-124.34, C2-126.63, C3-127.86, C7-128.11, C4-129.88,
C11a-130.07, C6a-132.79, C11-143.55, C4a-149.47, C5a-
161.56. EIMS (70 eV, m/e): 232 (M+). Anal. Calcd for
C16H12N2: C 82.73, H 5.21, N 12.06. Found: C 82.60,
H 5.23, N 12.01.
Compound 10. Yield: 70%, 0.761 g (from 9b); mp >300 ꢀC;
IR (KBr): 1615, 3156 cmꢁ1; 1H NMR (CDCl3): d 7.05–7.95
(m, 5H, Ar–H), 7.98 (1H, d, J¼7.4 Hz, C4–H), 8.11 (1H, d,
J¼7.8 Hz, C1–H), 8.25 (1H, d, J¼8.0 Hz, C10–H), 9.05 (1H,
s, C11ꢁH), 11.61 (1H, br s, NH); 13C NMR (CDCl3): C7-
111.13, C4-118.97, C9-119.94, C11a-120.51, C10-122.03, C2-
122.91, C10a-123.92, C1-127.33, C11-127.74, C10b-128.17,
C3-128.41, C8-128.83, C4a-141.53, C6a-146.72, C5a-154.40.
EIMS (70 eV, m/e): 218 (M+); Anal. Calcd for C15H10N2: C
82.55, H 4.62, N 12.84. Found: C 82.41, H 4.63, N 12.80.
Compound 19b. Yield: 82% (0.40 g); mp >250 ꢀC; IR
1
(KBr): 2916, 2874, 1612 cmꢁ1; H NMR (CDCl3): d 2.44
(3H, s, C11–CH3), 3.66 (3H, s, C5–CH3), 7.25–7.87 (7H,
m, Ar–H), 8.41 (1H, d, J¼8.24 Hz, C10–H); 13C NMR
(CDCl3): C11–CH3-21.63, C5–CH3-46.65, C10a-105.39,
C9-121.07, C10b-122.57, C10-123.53, C8-123.55, C1-
124.03, C2-125.36, C7-129.25, C4-129.60, C3-127.94,
C11a-130.14, C6a-131.30, C11-141.22, C4a-147.23, C5a-
158.83. EIMS (70 eV, m/e): 278 (M+); Anal. Calcd for
C19H22N2: C 81.97, H 7.97, N 10.06. Found: C 81.73, H
7.99, N 10.02.
Compound 11a. Yield: 74% (1.88 g); mp 142 ꢀC; IR (KBr):
1
1045, 3220, 1610 cmꢁ1; H NMR (CDCl3): d 6.77 (1H, d,
J¼7.2 Hz, Quin–C3–H), 7.04–7.43 (4H, m, Ph–H), 7.66
(1H, t, J¼7.6 Hz, C6–H), 7.90 (1H, t, J¼8.0 Hz, C7–H),
7.98 (1H, d, J¼7.2 Hz, C5–H), 8.09 (1H, d, J¼7.6 Hz, C8–
Compound 21b. Yield: 70% (1.64 g); mp 162 ꢀC; IR (KBr):
1
3234, 2941, 2886 cmꢁ1; H NMR (CDCl3): d 2.41 (3H, s,
H), 8.63 (1H, d, J¼8.2 Hz, C2–H), 10.71 (1H, br s, NH);
Ar–CH3), 6.49 (1H, s, Quin–C3–H), 7.08–7.48 (5H, m,
Ph–H), 7.67 (1H, t, J¼7.6 Hz, C6–H), 7.89 (1H, t,
J¼7.6 Hz, C7–H), 8.02 (1H, d, J¼8.0 Hz, C5–H), 8.12
(1H, d, J¼8.2 Hz, C8–H), 10.18 (1H, br s, NH); 13C NMR:
13
00
C1 -121.07, C6-124.78, C7-127.52, C4 -127.76, C2 -129.63,
0
C NMR: C3-107.11, C3 -115.37, C3 -119.71, C5-120.33,
0
0
0
00
C8-130.82, C4a-132.13, C2 –Cl-145.39, C4-145.79, C8a-
149.01, C2-151.32. EIMS (70 eV, m/e): 254 (M+), 256
(M+2); Anal. Calcd for C15H11N2Cl: C 70.73, H 4.35, N
11.00. Found: C 70.56, H 4.31, N 10.96.
0
00
0
C2–CH3-27.34,0 C3-110.78, C3 - and C3 -115.71, C2 - and
00
C2 -119.42, C4 -120.11, C5-120.45, C6-124.33, C7-127.62,
0
C8-129.15, C4a-131.77, C1 -144.79, C8a-149.34, C2-155.13,
C4-157.50. EIMS (70 eV, m/e): 234 (M+); Anal. Calcd for
C16H14N2: C 82.02, H 6.02, N 11.96. Found: C 81.95, H
6.03, N 11.89.
Compound 12. Yield: 78%, 0.85 g (from 11a); mp >220 ꢀC
(decomp.). Spectral and analytical data of this compound
coincide with our earlier reported one.16
Compound 22b. Yield: 65% (0.75 g); mp 235 ꢀC; IR (KBr):
3207, 2936, 2885 cmꢁ1; 1H NMR (CDCl3): d 2.43 (3H, s, C6–
CH3), 7.33–7.88 (7H, m, Ar–H), 8.07 (1H, d, J¼8.04 Hz, C4–
H), 10.51 (1H, br s, NH); 13C NMR (CDCl3): C6–CH3-23.14,
C10-118.64, C9-119.54, C7-120.29, C6a-122.57, C8-124.43,
C2-124.69, C3-126.73, C6b-126.78, C1-127.41, C4-129.44,
C11b-130.11, C10a-135.67, C11a-136.73, C4a-150.17, C6-
154.75. EIMS (70 eV, m/e): 232 (M+); Anal. Calcd for
C16H12N2: C 82.73, H 5.21, N 12.06. Found: C 82.66,
H 5.22, N 12.10.
Compound 13. Yield: 70% (1.54 g); mp 116 ꢀC; IR (KBr):
3276, 1611 cmꢁ1 1H NMR (CDCl3): d 6.94–7.48 (5H,
;
m, Ph–H), 7.66 (1H, t, J¼7.8 Hz, C6–H), 7.89 (1H, t,
J¼7.8 Hz, C7–H), 7.99 (1H, d, J¼8.0 Hz, C5–H), 8.09 (1H,
s, C4–H), 8.23 (1H, d, J¼8.2 Hz, C8–H), 8.42 (1H, s, C2–
13
0
0
H)0,0 10.44 (1H, 0br s, NH)0;0 C NMR: C4 -104.26, C3 - and
C3 -114.27, C2 - and C2 -119.46 and 120.34, C5-123.19,
C6-124.44, C7-127.06, C8-128.13, C4-129.77, C4a-131.31,
0
C1 -142.87, C3-150.02, C8a-150.98, C2-151.51. EIMS
(70 eV, m/e): 220 (M+); Anal. Calcd for C15H12N2: C
81.79, H 5.49, N 12.72. Found: C 81.61, H 5.51, N 12.69.
Compound 23b. Yield: 82% (0.40 g); mp 197 ꢀC; IR (KBr):
1
Compound 17b. Yield: 74%, (1.73 g); mp 145 ꢀC; IR (KBr):
2922, 2857, 1606 cmꢁ1; H NMR (CDCl3): d 2.43 (3H, s,
C6–CH3), 3.75 (3H, s, C5–CH3), 7.36–7.92 (7H, m, Ar–H),
1
3256, 2925, 2857, 1605 cmꢁ1; H NMR (CDCl3): d 2.49

6262
T. Dhanabal et al. / Tetrahedron 62 (2006) 6258–6263
8.26 (1H, d, J¼7.86 Hz, C4–H); 13C NMR (CDCl3):
C6–CH3-22.14, C5–CH3-41.12, C10-117.23, C9-118.49,
C7-121.34, C8-123.45, C6a-123.54, C2-124.55, C3-126.30,
Jr.; Crouch, R. C.; Martin, G. E.; Hadden, C. E.; Guido, J. E.;
Mills, K. A. Magn. Reson. Chem. 2003, 41, 577–584; (n)
Cimanga, K.; DeBruyne, T.; Lasure, A.; Poel, B. V.; Pieters,
L.; Claeys, M.; Berghe, D. V.; Vlietinck, A. J. Planta Med.
1996, 62, 22–27.
C1-127.81, C4-129.66, C11b-130.05, C10a-135.03, C11a
-
135.41, C6b-136.07, C4a-149.69, C6-157.61. EIMS (70 eV,
m/e): 246 (M+); Anal. Calcd for C17H14N2: C 82.90, H
5.73, N 11.37. Found: C 82.67, H 5.74, N 11.41.
5. (a) Bever, B. E. P. O. Medicinal Plants in Tropical West Africa;
Cambridge University Press: Cambridge, 1986; Vol. 131; pp
18–41; (b) Boakye-Yiadom, K. Q. J. Crude Drug Res. 1979,
17, 78–80; (c) Boye, G. L.; Ampofo, O. Proceeding of the
First International Symposium on Cryptolepine; Boakye-
Yiadom, K., Bamgbose, S. O. A., Eds.; University of Science
and Technology: Ghana, 1983; pp 37–40.
6. Bierer, D. E.; Fort, D. M.; Mendez, C. D.; Luo, J.; Imbach,
P. A.; Dubenko, L. G.; Jolad, S. D.; Gerber, R. E.; Litvak, J.;
Lu, Q.; Zhang, P.; Reed, M. J.; Waldeck, N.; Bruening, R. C.;
Noamesi, B. K.; Hector, R. F.; Carlson, T. J.; King, S. R.
J. Med. Chem. 1998, 41, 894–901.
7. Dassonviville, L.; Bonjean, K.; De Pauw-Gillet, M. C.; Colson,
P.; Houssier, C.; Quetin-Leclercq, J.; Angenot, L.; Bailly, C.
Biochemistry 1999, 38, 7719–7726.
8. Peczyriskc-Czoch, W.; Pognan, F.; Kaczmarck, L.; Boratyriski,
J. J. Med. Chem. 1994, 37, 3503–3510.
The spectral data for the compounds 2 (Yield 80%, 0.37 g),
3 (Yield 83%, 0.38 g), and 1 are identical with those
reported4d,4e,4a–c for the natural products, respectively. The
spectral data of 15 and 4 coincide with the earlier reported
compound.28a
Acknowledgements
T.D. thanks CSIR, New Delhi for the award of Senior
Research Fellowship. P.S.M. thanks CSIR-New Delhi for
financial assistance (CSIR-Major project). Authors thank
SIF, IISc, Bangalore, and IICT, Hyderabad for providing
the spectral and analytical data.
9. Sundaram, G. S. M.; Venkatesh, C.; Kumar, U. K. S.; Ila, H.;
Junjappa, H. J. Org. Chem. 2004, 69, 5760–5762.
10. Kociubinska, A.; Gubernator, J.; Godlewska, J.; Stasiuk, M.;
Kozubek, A.; Peczynska-Czoch, W.; Opolski, A.; Kaczmarek,
L. Cellular and Molecular biology letters, Seminar no. 28, 7.
Conference on Molecular Biology Seminars, University of
Wroclaw, Wroclaw, Poland, 2002.
11. Kaczmarek, L.; Peczynska-Czoch, W.; Opolski, A.; Wietrzyk,
J.; Marcinkowska, E.; Boratynski, J.; Osiadacz, J. Anticancer
Res. 1998, 18, 3133–3138.
References and notes
1. Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla,
J.; Pascula-Terasa, B.; Gago, F.; Rodrigo, M. M.; Ballestros, M.
J. Org. Chem. 1996, 61, 5587–5599.
2. Cimanga, K.; DeBruyne, T.; Pieters, L.; Vlietinck, A. J.;
Turger, C. A. J. Nat. Prod. 1997, 60, 688–691.
3. (a) Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.;
Houghton, P. J. Planta Med. 2000, 66, 30–34; (b) Miert, S. V.;
Hostyn, S.; Maes, B. U. M.; Cimanga, K.; Brun, R.; Kaiser,
M.; Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.;
Pieters, L. J. Nat. Prod. 2005, 68, 674–677.
12. (a) Molina, P.; Fresneda, P. M.; Delgado, S. Synthesis 1999, 2,
326–329; (b) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron
1990, 46, 1063–1078.
4. (a) Gellert, E.; Hamet, R.; Schlitter, E. Helv. Chim. Acta 1951,
34, 642–651; (b) Dwuma-Badu, D.; Ayim, J. S. K.; Fiagbe,
N. Y. Y.; Knapp, J. E.; Schiff, P. L., Jr.; Slatkin, D. J.
J. Pharm. Sci. 1978, 67, 433–439; (c) Ablordeppey, S. D.;
Hufford, C. D.; Bourne, R. F.; Dwuma Badu, D. Planta Med.
1990, 56, 416–417; (d) Cimanga, K.; DeBruyne, T.; Pieters,
L.; Claeys, M.; Vlietinck, A. Tetrahedron Lett. 1996, 37,
1703–1706; (e) Pousset, J. L.; Martin, M. T.; Jossang, A.;
Bodo, B. Phytochemistry 1995, 39, 735–736; (f) Tackie,
A. N.; Sharaf, M. H. M.; Schiff, P. L., Jr.; Boye, G. L.;
Crouch, R. C.; Martin, G. E. J. Heterocycl. Chem. 1991, 28,
1429–1435; (g) Spitzer, T. D.; Crouch, R. C.; Martin, G. E.;
Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Boye, G. L.
J. Heterocycl. Chem. 1991, 28, 2065–2070; (h) Tackie, A. N.;
Boye, G. L.; Sharaf, M. H. M.; Schiff, P. L., Jr.; Crouch,
R. C.; Spitzer, T. D.; Jhonson, R. L.; Dunn, J.; Minick, D.;
Martin, G. E. J. Nat. Prod. 1993, 56, 653–670; (i) Crouch,
R. C.; Davis, A. O.; Spitzer, T. D.; Martin, G. E.; Sharaf,
M. H. M.; Schiff, P. L., Jr.; Phoebe, C. H., Jr.; Tackie, A. N.
J. Heterocycl. Chem. 1995, 32, 1077–1080; (j) Paulo, A.;
Gomes, E. T.; Hougton, P. J. J. Nat. Prod. 1995, 58, 1485–
1491; (k) Fort, D. M.; Litvak, J.; Chen, J. L.; Lu, Q.; Phuan,
P. W.; Cooper, R.; Bierer, D. E. J. Nat. Prod. 1998, 61, 1528–
1530; (l) Hadden, C. E.; Sharaf, M. H. M.; Guido, J. E.;
Robins, R. H.; Tackie, A. N.; Phoebe, C. H., Jr.; Schiff, P. L.,
Jr.; Martin, G. E. J. Nat. Prod. 1999, 62, 238–240; (m) Blinov,
K.; Elyashberg, M.; Martirosian, E. R.; Molodtsov, S. G.;
Williams, A. J.; Tackie, A. N.; Sharaf, M. M. H.; Schiff, P. L.,
13. Fresneda, M.; Molina, P.; Delgado, S. Tetrahedron Lett. 1996,
40, 7275–7278.
14. Trecourt, F.; Mongin, F.; Mallet, M.; Queguiner, G. Synth.
Commun. 1995, 25, 4011–4024.
15. Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067–1068.
16. Nandhakumar, R.; Suresh, T.; Mohan, P. S. Tetrahedron Lett.
2002, 43, 3327–3328.
17. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron Lett.
2005, 46, 4509–4510.
18. Schultz, A. G.; Fu, W. Y.; Lucci, R. D.; Gail Kurr, B.; Lo,
K. M.; Boxer, M. J. Am. Chem. Soc. 1978, 100, 2140–2149.
19. Schultz, A. G.; Sha, Chin-Kang. Tetrahedron 1980, 36, 1757–
1761.
20. Schultz, A. G. J. Org. Chem. 1975, 40, 3466–3467.
21. Dittami, J. P.; Ramanathan, H.; Breining, S. Tetrahedron Lett.
1989, 30, 795–798.
22. Ho, J.-H.; Ho, T.-I. Chem. Commun. 2002, 270–271.
23. Schultz, A. G.; Hagmann, W. K. J. Org. Chem. 1978, 43, 3391–
3393.
24. Schultz, A. G.; Hagmann, W. K. J. Org. Chem. 1978, 43, 4231–
4233.
25. Hagmann, W. K. Ph.D. Dissertation, Cornell University, 1978.
26. Padwa, A.. Organic Photochemistry; Marcel Deckker: New
York, NY, 1983; Vol. 6; pp 7–10.
27. (a) Munchen, Z. Chem. Ber. 1885, 1528–1533; (b) Kermark,
W. O.; Smith, J. F. J. Chem. Soc. 1930, 1999–2010; (c) Curd,
F. H. S.; Raison, C. G.; Rose, F. L. J. Chem. Soc. 1947, 899–
909; (d) Price, C. C.; Maynert, E. W.; Boekelheide, V. J. Org.

T. Dhanabal et al. / Tetrahedron 62 (2006) 6258–6263
6263
Chem. 1949, 14, 484–487; (e) Adams, W. J.; Hey, D. H.
J. Chem. Soc. 1950, 3254–3259; (f) Anderson, P. C.; Staskun,
B. J. Org. Chem. 1965, 30, 3033–3037; (g) Partridge, M. W.;
Sprake, J. M.; Vipond, J. J. Chem. Soc. C 1966, 1245–1249;
(h) Soulen, R. L.; Kundiger, D. G.; Searles, S., Jr.; Sanchez,
R. A. J. Org. Chem. 1967, 32, 2661–2663; (i)
Thiruvikraman, S. V.; Seshadri, S. Indian J. Chem., Sect. B
1987, 26B, 695–696; (j) Kidwai, M.; Kohli, S. Indian J.
Chem., Sect. B 2001, 40B, 248–249.
61, 1571–1577; (b) Yin, J. J.; Zhao, M. M.; Huffman, M. A.;
McNamara, J. M. Org. Lett. 2002, 4, 3481–3484; (c) Jonckers,
T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.;
Pieters, L.; Haeners, A.; Dommisse, R. A. Synlett 2003, 615–618.
29. Dubovitskii, S. V.; Radchenko, O. S.; Novikov, V. L. Izv. Akad.
Nauk, Ser. Khim. 1996, 11, 2795–2796; [Russ. Chem. Bull.
1996, 45, 2656–2657 (Engl. Transl.)].
30. (a) Reynolds, G. A.; Hauser, C. R. Organic Synthesis; Hornig,
E. C., Ed.; Wiley: New York, NY, 1955; Vol. 3, pp 580–581,
593; (b) Khan, K. A.; Shoeb, A. Indian J. Chem., Sect. B
1985, 24B, 62–65.
28. (a) Hostyn, S.; Maes, B. V. W.; Pieters, L.; Lemiere, G. L. F.;
Matyus, P.; Hajos, G.; Dommisse, R. A. Tetrahedron 2005,