Regioselective cycloaddition of acetylenic esters: A one-pot synthesis of novel dihydrobenzo[a]carbazoles

Article abstract of DOI:10.1016/j.tetlet.2011.01.125

A one-pot procedure for the synthesis of highly substituted dihydrobenzo[a]carbazole derivatives via a regioselective cyclocondensation reaction between 2-(2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedinitrile and acetylenic esters is described.

Full text of DOI:10.1016/j.tetlet.2011.01.125

Tetrahedron Letters 52 (2011) 1649–1652
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective cycloaddition of acetylenic esters: a one-pot synthesis
of novel dihydrobenzo[a]carbazoles
Ezhumalai Yamuna a, Matthias Zeller b, Karnam Jayarampillai Rajendra Prasad a,
⇑
a Department of Chemistry, Bharathiar University, Coimbatore 641046, India
b Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot procedure for the synthesis of highly substituted dihydrobenzo[a]carbazole derivatives via a
regioselective cyclocondensation reaction between 2-(2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedi-
nitrile and acetylenic esters is described.
Received 18 December 2010
Revised 19 January 2011
Accepted 27 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrobenzo[a]carbazoles
Acetylenic esters
Cyclocondensation reaction
Triton-B
Carbazoles and related compounds display a range of biological
activities which makes them attractive compounds for both syn-
thetic as well as medicinal chemists.1–3 In the past two decades
numerous carbazole alkaloids and synthetic analogues, many of
them possessing useful pharmacological properties, have been
studied. Recently, Knölker and Reddy extensively reviewed the
synthesis of biologically active carbazole alkaloids.4 Some of the
most important compounds with proven chemotherapeutic value
belong to the ellipticine class (1).5,6 In this class of compounds a
heteroaromatic ring is fused to the b-face of the carbazole. How-
ever, there is a growing number of carbazoles that contain aro-
matic or heteroaromatic rings fused to the a- or c-face of the
carbazole nucleus. For example, among the various benzocarbaz-
oles, a series of simple benzo[a]carbazoles and benzo[b]carbazoles
such as (2) or (3), have been tested as candidates for the treatment
of cancer as a result of their DNA intercalating properties,7 while
benzo[c]carbazoles such as 4 show promising profiles for intra-cy-
clin dependent kinase selectivity8 (Fig. 1). Very recently, several
benzocarbazole analogues have also been explored as functional
building blocks in the construction of organic materials for opto-
electronic devices.9,10
An early synthetic route towards the synthesis of substituted
carbazoles focused mostly on either electrophilic additions or on
ring closure methods.11 Realisation of the potential of benzocar-
bazoles as both therapeutic agents as well as functional materials
has sparked new efforts into finding alternative or more efficient
pathways towards the preparation of these compounds. Methods
that have been used are for example benzannulation,12 Fischer
HO
H3C
AcO
N
N
H
N
N
H
N
H
OAc
C6H5
CH3
CH3
CH3
CH3
Benzo[a]carbazole (2)
Ellipticine (1)
Benzo[b]carbazole (3)
Benzo[c]carbazole (4)
Figure 1. Examples of (1): an ellipticine; (2): of a benzo[a]carbazole; (3): a benzo[b]carbazole; (4) a benzo[c]carbazole.
⇑
Corresponding author. Tel.: +91 422 2422311; fax: +91 422 2422387.
E-mail address: prasad_125@yahoo.com (K.J.R. Prasad).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.125

1650
E. Yamuna et al. / Tetrahedron Letters 52 (2011) 1649–1652
indolization,13 modified Nenitzescu reaction,14 cycloaddition reac-
tion,15 cycloaromatisation,16coupling reactions,17 or radical reac-
tions18 and most recently annulations based on cycloaddition
reactions,19 to name just a few.
isolated in nearly 80% yield, and no side products such as 3a were
observed.
The reaction was found to be general and use of this method
with various other substituted 2-(2,3,4,9-tetrahydro-carbazol-1-
ylidene)-propanedinitriles 1 gave highly substituted benzo[a]carb-
azoles21 in good yield as shown in Scheme 1 (Table 2, entries 2–5).
Subsequently, we also investigated the reaction of compounds 1
with methyl propiolate instead of DMAD. Reactions proceeded
smoothly and gave another series of regioselectively substituted
benzo[a]carbazoles in excellent yields (Table 2, entries 6–10).
The structures of the products were deduced from their elemen-
tal analysis data, and from their IR, mass, 1H NMR and 13C NMR
spectra. The structure of one of the products was also confirmed
by single crystal X-ray diffraction.
The IR spectrum of 2a, for example, shows absorption peaks at
3438, 3375, 3342, 2211, 1733 and 1688 cmÀ1 which attest to the
presence of amino, indole NH, cyano and ester groups, respectively.
For compound 2f the IR spectrum showed an unusually low fre-
quency for the ester carbonyl group of 1688 cmÀ1, indicating H-
bonding between the amino group and the ester carbonyl group,
confirming that the ester group must be in the C3 position. The
other IR frequencies of 2f at 3450, 3346 and 3271 cmÀ1 for the
NH2 and carbazole NH groups, and at 2207 cmÀ1 for the cyano
group were again as expected. The 1H NMR spectra of compounds
2a–i were as expected. 2a, for example, exhibits a series of signals
in the aromatic region of the spectrum, two singlets arising from
the two sets of methoxy protons (d 3.86 and d 3.94) and a broad
singlet for the two amine protons (d 6.57). The identities of the
other compounds 2b to 2i were established in a similar ways with
all spectroscopic data readily assignable. Finally, the structure of
one of the members of the series, 2c, was confirmed by single crys-
tal X-ray analysis (Fig. 2).
As would be expected for a family of compounds as diverse as
the benzocarbazoles, synthetic results have been varied and are
highly dependent on the method used and the substitution pattern
of the specific target compound. Harsh reaction conditions, multi-
step sequences and expensive starting materials or catalysts are
commonly encountered problems. The most serious drawbacks of
the established methods are however a lack of flexibility and toler-
ance of functional groups, and regiochemical ambiguities originat-
ing from orienting effects of the substituents. There is thus still a
considerable need for the development of more versatile and reg-
ioselective synthetic routes towards highly substituted benzocar-
bazoles, especially with respect to tolerance of a wider variety of
functional groups.
As part of our ongoing studies on the development of facile
methods for the synthesis of organic compounds from readily
available starting materials, we would like to here describe a
new versatile method designed to help address these needs, the
reaction of 2-(2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedi-
nitrile with acetylenic esters in the presence of a base, leading to
highly substituted benzocarbazoles in a one-pot addition reaction.
In our initial endeavour, we investigated the reaction of 2-(6-
methyl-2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedinitrile
1a with dimethyl acetylene dicarboxylate using various base cata-
lysts in different solvents (methanol and acetonitrile) and temper-
atures (Table 1). The starting material 1a is easily prepared20 and
can be obtained by the reaction of 6-methyl-2,3,4,9-tetrahydro-
carbazol-1-one 3a with malononitrile.
Using triethyl amine, potassium carbonate or sodium methox-
ide as the base the target product 2a was obtained in only low yield
along with the side product 3a (entries 1–6). With piperidine as the
base a moderate yield of around 60% could be achieved (entries 7
and 8). The best yield for the reaction between 1a and dimethyl
acetylene dicarboxylate was obtained by switching to benzyltrim-
ethylammonium hydroxide (Triton-B) as the base in refluxing ace-
tonitrile as the solvent (Table 1). Under these conditions 2a was
The reaction mechanism for the formation of the substituted
benzo[a]carbazoles 2 from the (2,3,4,9-tetrahydro-carbazol-1-yli-
dene)-propanedinitriles 1 by reaction with acetylenic esters is
composed of several distinct steps. The reaction sequence is most
likely initiated by base abstraction of a proton from 1, followed
by nucleophilic attack at the b-position of the acetylenic ester,
resulting in the formation of the first intermediate with tautomeric
Table 1
Reaction of 2-(6-methyl-2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedinitrile 1a with dimethyl acetylene dicarboxylate, under various conditions
Entry
Solvent
Base
Time/h
T (°C)
Yield (%)
2a
3a
1
2
3
4
5
6
7
8
CH3OH
CH3CN
CH3OH
CH3CN
CH3OH
CH3CN
CH3OH
CH3CN
CH3OH
CH3CN
CH3CN
CH3CN
Et3N
Et3N
K2CO3
K2CO3
CH3ONa
CH3ONa
Piperidine
Piperidine
Triton-B
Triton-B
Triton-B
Triton-B
6
6
6
6
6
6
6
6
4
4
4
4
60
60
80
80
80
80
80
80
80
60
70
80
15
20
38
45
22
28
56
64
62
66
70
78
38
35
40
34
30
25
15
12
0
9
10
11
12
0
0
0

E. Yamuna et al. / Tetrahedron Letters 52 (2011) 1649–1652
1651
Scheme 1. Synthesis of 2-amino-1-cyano-5,6-dihydro-11H-benzo[a]carbazole-carboxylic ester.
Table 2
Reaction of 2-(2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedinitriles 1 with acetylene esters, in the presence of Triton-B
Entry
R1
R2
R3
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
CH3
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
COOCH3
COOCH3
COOCH3
COOCH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
78
75
80
78
70
82
77
85
84
74
H
Cl
CH3
H
H
H
COOCH3
H
H
H
H
H
Cl
2j
forms I and II as shown in Scheme 2. The negative charge at the a-
carbon in form I, stabilized by the electron-withdrawing capability
of the adjacent ester group, allows for an intramolecular nucleo-
philic ring closure to follow, and subsequent aromatisation via a
tautomeric 1,5-H shift yields the final stable compound 2. The
reactions are straightforward, but yields were found to be variable
depending on the base that was used. Purification was however
readily accomplished by simple recrystallization for all com-
pounds. In the case of the reaction with methyl propiolate (to yield
compounds 2f–j), the reaction was found to be highly regiospecific
yielding only the product resulting from nucleophilic attack at the
alkyne carbon b to the ester functionality. A possible explanation
for this selectivity might be found in the greater stability of the
intermediate carbanion (Scheme 2).
In conclusion, we have established a novel one-pot regioselec-
tive synthesis of dimethyl 2-amino-1-cyano-5,6-dihydro-11H-
Figure 2. X-ray crystal structure of compound 2c.
Scheme 2. Mechanism for the formation of 2-amino-1cyano-5,6-dihydro-11H-benzo[a]carbazole-carboxylic esters.

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E. Yamuna et al. / Tetrahedron Letters 52 (2011) 1649–1652
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Acknowledgements
Our sincere thanks goes to the Director, ISO Quality Assurance
Cell, IICT, Hyderabad, and SAIF, IIT Madras, Chennai and the Chair-
man, NMR Research Centre, IISc, Bangalore, for providing access to
their Mass and NMR spectral facilities. The diffractometer was
funded by NSF Grant 0087210, by the Ohio Board of Regents Grant
CAP-491, and by Youngstown State University.
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Supplementary data
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Supplementary data (experimental details, spectral data, and
crystallographic data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.01.125.
References and notes
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21. General procedure for the synthesis of 5,6-dihydro-11H-benzo[a]carbazoles
(2): A mixture of 2-(2,3,4,9-tetrahydro-carbazol-1-ylidene)-propanedinitrile
(1, 1 mmol) and acetylene esters (dimethyl acetylenedicarboxylate (or) methyl
propiolate) (1 mmol) was refluxed with CH3CN in the presence of Triton-B.
After completion of the reaction as judged by TLC, the solvent was removed
under reduced pressure. The product was purified by silica gel column
chromatography using petroleum ether and ethyl acetate (95:5) to yield the
highly substituted benzo[a]carbazole and crystallised using ethyl acetate.
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Dimethyl
3,4-dicarboxylate (2a):Yellow solid (0.303 g, 78%); mp: 193 °C; IR (KBr) 3438,
3375, 3342, 2211, 1733, 1688 cmÀ1 1H NMR (400 MHz, CDCl3): d (ppm) 2.45
2-amino-1-cyano-8-methyl-5,6-dihydro-11H-benzo[a]carbazole-
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;
(s, 3H, CH3), 2.79 (t, 2H, J = 8.0 Hz, 5-2H), 2.94 (t, 2H, J = 8.0 Hz, 6-2H), 3.86 (s,
3H, COOCH3), 3.94 (s, 3H, COOCH3), 6.57 (s, 2H, NH2), 7.14 (d d, 1H, Jo = 8.4 Hz,
Jm = 1.2 Hz, 9-H), 7.34 (d, 1H, J = 8.4 Hz, 10-H), 7.36 (d, 1H, Jm = 1.2 Hz, 7-H),
9.25 (br s, 1H, N–H); 13C NMR (125 MHz, CDCl3) d (ppm) 19.1 (CH2), 20.8 (CH3),
25.4 (CH2), 52.3 (OCH3), 52.3 (OCH3), 90.1 (C), 105.0 (C), 111.4 (CH), 118. 2
(CN), 119.3 (CH), 120.1 (CH), 120.8 (C), 122.2 (C), 127.2 (C), 127.9 (C), 129.5 (C),
136.1(C), 136.2 (C), 138. 8 (C), 151.4 (C), 166.9 (C@O), 168.3 (C@O); MS, m/z
(%): 389 (M+, 100), 358 (38), 299 (86), 271 (75), 256 (35), 247 (40); Anal. Calcd
for C22H19N3O4: C, 67.86; H, 4.88; N, 10.79%. Found: 67.81; H, 4.84; N, 10.72%.