Efficient microwave-assisted synthesis of ellipticine through N-(1,4-dimethyl-9h-carbazol-3-ylmethyl)-n-tosylaminoacetaldehyde diethyl acetal

Article abstract of DOI:10.1002/jhet.319

The long-lasting problematic low yield in the D-ring cyclization of ellipticine (1a) was dramatically improved through N-(1,4-dimethylcarbazol-3- ylmethyl)-N-tosylaminoacetaldehyde diethyl acetal with microwave irradiation. The overall yield of 1a starting from indole was significantly increased by 25-fold. This new approach is superior to reported methods in yields and, reaction time, and it provides efficient access to a broad spectrum of ellipticine derivatives.

Full text of DOI:10.1002/jhet.319

454
Efficient Microwave-Assisted Synthesis of Ellipticine through
N-(1,4-Dimethyl-9H-carbazol-3-ylmethyl)-N-
tosylaminoacetaldehyde Diethyl Acetal
Vol 47
Hsueh-Yun Lee,a Grace Shiahuy Chen,b Chien-Shu Chen,a
and Ji-Wang Cherna,c*
aSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan,
Republic of China
bDepartment of Applied Chemistry, Providence University, Shalu, Taichung, Taiwan, Republic of China
cDepartment of Life Science, College of Life Science, National Taiwan University, Taipei,
Taiwan, Republic of China
*E-mail: jwchern@ntu.edu.tw
Received August 14, 2009
DOI 10.1002/jhet.319
Published online 2 March 2010 in Wiley InterScience (www.interscience.wiley.com).
The long-lasting problematic low yield in the D-ring cyclization of ellipticine (1a) was dramatically
improved through N-(1,4-dimethylcarbazol-3-ylmethyl)-N-tosylaminoacetaldehyde diethyl acetal with
microwave irradiation. The overall yield of 1a starting from indole was significantly increased by 25-
fold. This new approach is superior to reported methods in yields and, reaction time, and it provides ef-
ficient access to a broad spectrum of ellipticine derivatives.
J. Heterocyclic Chem., 47, 454 (2010).
INTRODUCTION
total yield of 1a starting from indole was as low as
0.8%.
Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole,
1a), a tetracyclic natural alkaloid, was isolated from
Ochrosia elliptica Labill. in 1959 [1] and found to be a
potent anticancer agent [2]. Analogs bearing substituents
on N-1 and C-9 of ellipticine such as 9-hydroxyellipti-
cine (2) [3] and 9-hydroxy-2-methylellipticium (3)
[4] possess potent antitumor activities as well. The
structures of ellipticine and its analogs are shown in
Figure 1.
The low yield of the D-ring closure leading to ellipti-
cine has been improved to 30% via treating azomethine
with orthophosphoric acid by Dalton et al. [6]. A perusal
of literature revealed the general synthetic strategy to
build up the tatracycline skeleton involving a connection
of substituted indoles and various pyridines through
Diels-Alder annulation, Friedel-Crafts acylation, and
radical reactions. These methods could be simplified as
[2 þ 1] concept. For examples, Diels-Alder annulation
from 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]
indole and 3,4-pyridyne gave a mixture of 1a and isoel-
lipticine (4) in Gribble’s investigation [7]. In addition,
synthesis of ellipticine quinone (5), which could be con-
verted into ellipticine [8], demonstrated an alternative
pathway of [2 þ 1] annulation. Intramolecular reaction
between 2-indolylacyl radicals derived from phenyl
selenoester with pyridines [9] furnished polycyclic
indolylpyridyl ketones including ellipticine quinone.
In view of the interesting biological activity, it has
attracted great attention to functionalize ellipticine. As
shown in Scheme 1, a five-step synthetic pathway of
ellipticine was first reported by Cranwell and Saxton
[5]: starting from indole (6a) to give 1,4-dimethylcarba-
zole (C-ring formation), then through Vilsmeier-Haack
formylation and Schiff base formation followed by
reduction and isoquinoline cyclization (D-ring forma-
tion) to afford ellipticine. However, the final step of iso-
quinoline cyclization suffered a 9% low yield, and the
C
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2010 HeteroCorporation

March 2010
Efficient Microwave-Assisted Synthesis of Ellipticine through N-(1,4-Dimethyl-
9H-carbazol-3-ylmethyl)-N-tosylaminoacetaldehyde Diethyl Acetal
455
Scheme 2. Synthesis of ellipticine (1a).
Figure 1. Ellipticine and its derivatives.
Friedel-Crafts acylation of N-protected indole with 3-
chlorocarbonylisonicotinic acid methyl ester [8a] was
followed by regioselective C-2 lithiation to yield ellipti-
cine quinine (5). Recently, a radical cascade protocol
has been used for the synthesis of ellipticine in higher
yield [10]. Although these approaches provided better
reaction yields and could be comprehensively applied in
the development of ellipticine analogs, it underwent an
intensively synthetic works to prepare intermediates for
the last annulation steps in comparison to the Saxton’s
approach. Nevertheless, the reported methods were still
unsatisfactory in preparing a number of derivatives for
the development of ellipticine derivatives as potential
anticancer drugs. Microwave (MW) irradiation has been
illustrated to give superior results and to shorten reac-
tion times in various aspects [11]. Further, MW irradia-
tion has been widely applied to the organic synthesis
including the total synthesis of natural products such as
quinazolinobenzodiazepine alkaloids by a one-pot reac-
tion [12] and biphenomycin B by the intramolecular
Suzuki-Miyaura reaction [13] Herein, we report an effi-
cient approach for the preparation of ellipticine by a
modified Saxton’s method with the assistance of MW
irradiation.
at 100ꢀC for 5 min under MW irradiation afforded 1,4-
dimethylcarbazole (7a) in 75% yield (Scheme 2). MW
irradiation shortened the reaction time and improved the
yield as compared with those in the conventional heat-
ing method (45 min, 36%) [5]. Subsequently, Vilsmeier-
Haack formylation of 7a by N-methylformanilide and
POCl3 in o-dichlorobenzene afforded aldehyde 8a in
55% yield. The reaction was proceeded by Bobbitt-
modified Pomeranz-Fritsch reaction [14] in which a
Schiff base would be reduced to an amino-acetal and
followed by a cyclization to isoquinoline. First, a one-
pot reaction of 8a, aminoacetaldehyde diethyl acetal (9),
and NaBH3CN in the presence of catalytic amount of
acetic acid at 70ꢀC for 3 h furnished the desired hydro-
genated N-(1,4-dimethylcarbazol-3-ylmethyl)-aminoace-
taldehyde diethyl acetal (11) in 31% yield. Then, the
use of MW irradiation in this one-pot reaction resulted
in a twofold increase in the yield (68%). This modified
MW-assisted one-pot reaction dramatically shortened
the reaction time and increased the yield for the synthe-
sis of secondary amine 11 in comparison to the Sax-
tons’s method (2 h, 61%) [5]. Accordingly, 11 was sub-
jected to cyclization reaction with concentrated HCl in
ethanol at reflux by conventional heating. Unsurpris-
ingly, ellipticine (1a) was obtained in a low yield of
9.0% as reported [5]. Then again, MW irradiation was
used for the cyclization under the same condition to fur-
nish 1a in 28% yield. MW irradiation improved the
long-lasting problematic low yield in the D-ring
cyclization.
A treatment of indole (6a) with acetonylacetone in
the presence of p-toluenesulfonic acid (PTSA) in ethanol
Scheme 1. Saxton approach for the synthesis of ellipticine (1a).
Nevertheless, a yield of 28% for the D-ring cycliza-
tion is still unsatisfactory in preparing a number of ellip-
ticine derivatives. Birch et al. [15] illustrated that N-
tosylated N-benzylaminoacetaldehyde dimethyl acetals
were cyclized under mild acidic conditions and in good
Journal of Heterocyclic Chemistry
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H.-Y. Lee, G. S. Chen, C.-S. Chen, and J.-W. Chern
Vol 47
Scheme 3. Synthesis of 9-bromoellipticine (1b).
Table 1
Comparison of reaction time and yields by microwave irradiation and
conventional heating.
MW irradiation
Heatinga
Reaction Time (min) Yield (%) Time (min) Yield (%)
6a ! 7a
8a ! 11
8a ! 12a
11 ! 1a
12a ! 1a
5
5
5
1
1
75
68
68
28
76
45
120b
36
b
61.
60
9
Overall yield from 6a to 1a
Path
Method
Yield (%)a
6a ! 7a ! 8a ! 10 ! 11 ! 1a
6a ! 7a ! 8a ! 11 ! 1a
6a ! 7a ! 8a ! 12a ! 1a
Heating
MW
MW
0.8
7.8
21.3
approach with MW irradiation. The slightly decrease in
overall yield of 1b with regard to ellipticine (1a) was
due to the lower yield in the formylation reaction of 6-
bromo-1,4-dimethylcarbazole (7b).
a Data taken from ref. 5.
b Total yield in 2 steps of 8a ! 10 ! 11.
Birch et al. [15] reported that sufficiently activating
substituents on the benzyl group were required for the
cyclization of the N-benzyl-N-tosylaminoacetaldehyde
dimethyl acetals to isoquinolines. Otherwise, cyclization
failed and the N-benzyl-N-tosyl acetals would be first
hydrolyzed to N-benzyl-N-tosylaminoacetaldehyde and
then N-tosylbenzylamine. To investigate this substituent
effect in the synthesis of ellipticine derivatives, a direct
nitration of 8a led to 1,4-dimethyl-6-nitrocarbazole-3-
carbaldehyde (8c) which was condensed with aminoace-
taldehyde diethyl acetal (9) to the Schiff base and
reduced in situ under MW irradiation (Scheme 4). With-
out further isolation and purification, a subsequent treat-
ment with tosyl chloride at 55ꢀC yielded the N-tosylated
compound 12c in 19% (three steps). Then, compound
12c was cyclized to 9-nitroellipticine (1c) in 37% yield
under the same conditions as described above. The cy-
clization to isoquinoline was proposed as electrophilic
substitution on the benzene ring [15], and lacking of
sufficiently activated substituents on the aromatic ring
failed in cyclization. Although a lower yield of 37%
was obtained, the cyclization to 9-nitroellipticine was
yields to isoquinolines in a one-pot reaction when the
benzyl groups were substituted with sufficiently activat-
ing groups. The carbazole moiety is a well known
strong electron donor [16]. We expected that the 1,4-
dimethylcarbazol-3-ylmethyl group could act as an acti-
vated group, and an N-tosylated derivative of 11 might
lead to ellipticine in an improved yield. Thus, N-(1,4-
dimethylcarbazol-3-ylmethyl)-N-tosylaminoacetaldehyde
diethyl acetal (12a) was obtained by a treatment of 11
with tosyl chloride in quantitative yield. Subsequently,
N-tosylated diethyl acetal 12a was subjected to cycliza-
tion to afford 1a in 76% yield in a reaction time of 1
min under the same condition as for the cyclization of
11 to 1a. As a result, a 51% yield of ellipticine from
aldehyde 8a was obtained through an N-tosylated acetal
12a together with the assistance of MW irradiation. This
approach improves the yield by nine folds in compari-
son to the Saxton’s method (5.5%). Importantly, the
overall yield of ellipticine starting from indole (6a) was
significantly increased by 25-fold (21%) as compared to
that (0.8%) reported by Saxton (Table 1).
To explore the general application of this approach,
condensation of 5-bromoindole (6b) with acetonylace-
tone was proceeded, and the resulting carbazole 7b was
formylated to the aldehyde 8b by N,N-dimethylforma-
mide (DMF) and POCl3 (Scheme 3). Compound 8b then
reacted with aminoacetaldehyde diethyl acetal (9) under
MW irradiation, and the resulting Schiff base was
reduced in situ. Removal of solvent followed by tosyla-
tion afforded N-tosylated derivative 12b, which was
cyclized under acidic condition with MW irradiation to
9-bromoellipticine (1b) in 72%. As a result, the bromo
substituent has little effect to the reactions in this
Scheme 4. Synthesis of 9-nitroellipticine (1c).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Efficient Microwave-Assisted Synthesis of Ellipticine through N-(1,4-Dimethyl-
9H-carbazol-3-ylmethyl)-N-tosylaminoacetaldehyde Diethyl Acetal
457
184ꢀC (lit. [17] 184ꢀC); MS (ESI):m/z ¼ 493.3 (M-Hþ); 1H
NMR (400 Hz, DMSO-d6): d ¼ 0.88 (t, J ¼ 7.0 Hz, 6H), 2.38
(s, 3H), 2.41 (s, 3H), 2.73 (s, 3H), 3.01 (d, J ¼ 5.36 Hz, 2H,
CH2), 3.08 (m, 2H), 3.30 (m, 2H), 4.04 (t, J ¼ 5.24 Hz, 1H),
6.94 (s, 1H), 7.15 (t, J ¼ 7.5 Hz, 1H), 7.36 (t, J ¼ 7.77 Hz,
1H), 7.41 (d, J ¼ 7.97 Hz, 2H), 7.50 (d, J ¼ 8.06 Hz, 1H),
7.75 (d, J ¼ 8.05 Hz, 2H), 8.14 (d, J ¼ 7.97 Hz, 1H),11.17 (s,
1H); 13C NMR (100 Hz, DMSO-d6): d ¼ 15.5, 16.0, 17.1,
21.5, 49.8, 51.2, 62.6, 101.1, 111.5, 117.5, 119.2, 121.6, 122.8,
123.9, 123.7, 125.3, 127.6, 129.0, 130.1, 130.3, 136.9, 139.2,
140.7, 143.7.
still succeeded in this case. Apparently, the 1,4-dime-
thylcarbazole moiety could serve as an electron-efficient
aromatic moiety even with a strong deactivated nitro
group substituted at position 6.
In summary, we have developed a fast, efficient, and
high-yield approach for the synthesis of ellipticine and its
derivatives through N-(1,4-dimethylcarbazol-3-ylmethyl)-
N-tosylaminoacetaldehyde diethyl acetals by the use of
MW irradiation. In this modified process, MW irradiation
increased the overall yield by 10-fold as compared with
the reported yield (0.8%) in considerably shortened reac-
tion time. In an effort to synthesize the derivatives of
ellipticine efficiently, the key step of D-ring construction
is modified by converting the secondary amine to N-tosy-
lated derivative based on Birch’s investigation [15]. The
long-lasting problematic low yield in the D-ring cycliza-
tion was dramatically improved in this study. Even a
strong electron-withdrawing substituent on the 1,4-dime-
thylcarbazole moiety was endured in this method. This
new approach is superior to previously reported methods
in yields, reaction time, and versatility, and it will allow a
broad evaluation of this highly promising class of poten-
tial antitumor drugs.
N-(6-Bromo-1,4-dimethyl-9H-carbazol-3-ylmethyl)-N-(2,2-
diethoxyethyl)-4-methylbenzenesulfonamide (12b).þWhite
solid, mp 196–197ꢀC; MS (ESI): m/z ¼ 571.2 (M-H ); 1H
NMR (200 Hz, DMSO-d6): d ¼ 0.88 (t, J ¼ 7.0 Hz, 6H), 2.39
(s, 3H), 2.41 (s, 3H), 2.70 (s, 3H), 3.0–3.2 (m, 4H), 3.3–4.1
(m, 2H), 4.49 (s, 2H), 7.00 (s, 1H), 7.41 (d, J ¼ 8.4 Hz, 1H),
7.75 (d, J ¼ 8.4 Hz, 1H), 8.23 (s, 1H), 11.40 (s, 1H); 13C
NMR (50 Hz, DMSO-d6): d ¼ 15.0, 15.5, 16.6, 21.0, 49.3,
50.5, 62.0, 100.6, 110.7, 112.9, 117.3, 120.2, 123.7, 124.4,
125.1, 127.1, 127.2, 129.2, 129.8, 129.9, 136.4, 138.9, 139.2,
143.2. Anal. Calcd for C28H33BrN2O4S): C, 58.64; H, 5.80; N,
4.88; S, 5.59. Found, C, 58.27; H, 6.08; N, 4.76; S, 5.38.
N-(2,2-Diethoxyethyl)-N-(1,4-dimethyl-6-nitro-9H-carbazol-
3-ylmethyl)-4-methylbenzenesulfonamide (12c). Yellow solid.
mp 190–192ꢀC; MS (ESI): m/z ¼ 538.3 (M-Hþ); 1H NMR
(400 Hz, acetonitrile-d3): d ¼ 0.92 (t, J ¼ 7.0 Hz, 6H), 2.35
(s, 3H), 2.37 (s, 3H), 2.62 (s, 3H), 3.06 (d, J ¼ 5.33 Hz, 2H),
3.13 (m, 2H), 3.35 (m, 2H), 4.14 (t, J ¼ 5.31 Hz, 1H), 4.41 (s,
2H), 6.99 (s, 1H), 7.35 (d, J ¼ 7.9 Hz, 2H), 7.43 (d, J ¼ 8.49
Hz, 1H), 7.71 (d, J ¼ 8.07 Hz, 2H), 8.17 (d, J ¼ 8.70 Hz,
1H), 8.80 (s, 1H), 9.99 (s, 1H); 13C NMR (50 Hz, DMSO-d6):
d ¼ 15.0, 15.4, 16.6, 21.0, 62.8, 100.7, 118.2, 120.8, 121.1,
122.7, 125.5, 127.2, 129.8, 130.0, 130.2, 136.4, 139.7, 140.0,
142.4, 143.3, 143.8. Anal. Calcd for C28H33N3O6Sꢁ0.33H20: C,
61.63; H, 6.22; N, 7.70. Found, C, 61.77; H, 6.00; N, 8.08.
General procedure for the synthesis of Ellipticine (1). A
mixture of 12a (1.0 g, 2.02 mmol), dioxane (3 mL), and 6M
HCl (1.0 mL) was placed in a sealed microwave tube. The
mixture was irradiated by microwave (180 W) at 140ꢀC for 1
min and then purified with column chromatography to afford
1a.
EXPERIMENTAL
The reactions assisted by microwave were achieved on Biot-
age EmrysTM Optimizer and Biotage InitiatorTM. Reaction
temperatures were observed using built-in IR-sensor. Melting
points were taken on Laboratory Devices, INC. (Box 6402)
melting point apparatus and are uncorrected. 1H and 13C nu-
clear magnetic resonance spectra were obtained on Bruker
AMX-400 and DPX-200 spectrometers. Mass spectra were
obtained on Finnigan TSQ 7000 mass spectrometer. Elemental
analysis for C, H, S, and N was carried out on Heraeus Vari-
oEL III-CHNS apparatus. Thin layer chromatography (TLC)
was carried out on precoated plates (silical gel, Kieselgel
60F254, Merck). Column chromatography was performed with
Kieselgel Si 60 (40–63 lm, Merck). All starting materials
were obtained from commercial suppliers (Acros, Lancaster
Ellipticine (1a). Mp 309–310ꢀC (dec.; lit. [5] 309–313ꢀC,
dec.); MS (ESI): m/z ¼ 245.0 (M-Hþ) 1H NMR (400 Hz,
DMSO-d6): d ¼ 2.78 (s, 3H), 3.24 (s, 3H), 7.24 (t, J ¼ 7.1
Hz, 1H), 7.51 (t, J ¼ 7.7 Hz, 1H), 7.58 (d, J ¼ 7.95 Hz, 1H),
7.91 (d, J ¼ 6.03 Hz, 1H), 8.36 (d, J ¼ 7.90 Hz, 1H), 8.40 (d,
J ¼ 6.0 Hz, 1H), 9.68 (s, 1H), 11.59 (s, 1H); 13C NMR (100
Hz, DMSO-d6): d ¼ 12.0, 14.4, 108.1, 110.8, 116.0, 119.2,
121.9, 123.1, 123.5, 123.8, 127.1, 128.1, 132.5, 140.2, 140.7,
142.7, 149.5.
¨
and Riedel-de Haen) and used without purification.
General procedure for the synthesis of N-(2,2-Diethox-
yethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-4-methyl-
benzenesulfonamide (12). A mixture of 3-formyl-1,4-dime-
thylcarbazole (8a, 1.0 g, 4.48 mmol), sodium cyanoborohy-
dride (0.35 g, 5.57 mmol), 9 (0.7 mL, 5.25 mmol) and acetic
acid (0.1 mL) in methanol (4 mL) was placed in a sealed tube.
Reaction was heated by microwave (75 W) at 70ꢀC for 5 min.
Methanol was removed in vacuo, and then ethyl acetate (EA,
100 mL) was added. The solution was purified through column
chromatography to afford viscous residue. To the residue, 4-
tolueneulfonyl chloride (0.9 g, 4.72 mmol), triethylamine (0.5
mL, 4.94 mmol), and EA (30 mL) were added and stirred at
room temperature for 2 h. The mixture was subsequently puri-
fied with column chromatography.
9-Bromoellipticine (1b). Mp 330–332ꢀC (lit. [6] 318–
1
319ꢀC); MS (ESI): 323.0 (M-Hþ); H NMR (200 Hz, DMSO-
d6): d ¼ 2.74 (s, 3H), 3.19 (s, 3H), 7.49 (d, J ¼ 8.6 Hz, 1H),
7.64 (d, J ¼ 8.6 Hz, 1H), 7.92 (d, J ¼ 6.0 Hz, 1H), 8.41 (s,
2H), 9.68 (s, 1H), 11.53 (s, 1H); 13C NMR (50 Hz, DMSO-
d6): d ¼ 12.0, 14.3, 108.6, 111.0, 112.5, 116.0, 122.0, 122.9,
125.0, 125.9, 128.9, 129.6, 132.7, 140.6, 140.8, 141.4, 149.9.
9-Nitroellipticine (1c). Mp (dec.) 352ꢀC (dec., lit. [6]
350ꢀC, dec.); MS (ESI): 290.1 (M-Hþ); 1H NMR (400 Hz,
DMSO-d6): d ¼ 2.75 (s, 3H), 3.08 (s, 3H), 7.61 (d, J ¼ 8.6
N-(2,2-Diethoxyethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-
4-methylbenzenesulfonamide (12a). White solid, mp 183–
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H.-Y. Lee, G. S. Chen, C.-S. Chen, and J.-W. Chern
Vol 47
D. J.; Davis, D. A.; Saulnier, M. G.; Pelcman, B.; Barden, T. C.; Sibi,
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Hz, 1H), 7.91 (d, J ¼ 6.1 Hz, 1H), 8.38 (d, J ¼ 9.0 Hz, 1H),
9.47 (d, J ¼ 5.9 Hz, 1H), 9.02 (s, 1H), 9.71 (s, 1H), 12.13 (s,
1H); 13C NMR (100 Hz, DMSO-d6): d ¼ 11.9, 14.3, 108.5,
110.9, 112.4, 115.9, 121.9, 122.3, 125.0, 125.8, 128.9, 129.5,
132.7, 140.6, 140.7, 141.4, 149.8.
Acknowledgment. The authors thank the National Science
Council, Taiwan, ROC (NSC93-2320-B-002-113, 94-2320-B-
002-039, and 95-2320-B-002-010) for generous financial
support.
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Journal of Heterocyclic Chemistry
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