The synthesis of naphtho[a]carbazoles and benzo[c]carbazoles

Article abstract of DOI:10.1055/s-2003-38352

The synthesis of naphtho[a]carbazoles and benzo[c]carbazoles from indole precursors using a reaction mediated by potassium t-butoxide and light is described. The indole precursors were prepared utilizing Suzuki coupling methodology.

Full text of DOI:10.1055/s-2003-38352

LETTER
705
The Synthesis of Naphtho[a]carbazoles and Benzo[c]carbazoles
The Synthesis of
h
Naphtho[
a
]c
a
arbazole
s
a
r
nd
B
enz
l
o[
c
]car
e
bazole
s
s B. de Koning,* Joseph P. Michael, Johanna M. Nhlapo, Rakhi Pathak, Willem A. L. van Otterlo
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa
Received 6 December 2002
method to the synthesis of naphtho[a]-fused carbazoles as
well as carbazoles containing rings fused on the c-face. In
this paper we disclose our results on the extension of our
work on the synthesis of benzo[a]carbazoles to include
naphtho[a]carbazoles as well as to the synthesis of a ben-
zene ring fused on the c-face to afford benzo[c]carba-
zoles.
Abstract: The synthesis of naphtho[a]carbazoles and benzo[c]car-
bazoles from indole precursors using a reaction mediated by potas-
sium t-butoxide and light is described. The indole precursors were
prepared utilizing Suzuki coupling methodology.
Key words: carbazoles, indoles, naphtho[a]carbazoles, ben-
zo[c]carbazoles, Suzuki coupling
C-6
CHO
C-5
Carbazoles display a range of biological activities making
them attractive compounds to synthetic and medicinal
chemists.1–3 As a result, in the past two decades numerous
carbazole alkaloids and synthetic analogues, many of
them possessing useful pharmacological properties, have
been studied. Some of the most important compounds
with proven chemotherapeutic value belong to the ellipti-
cine class (e.g. 1).4,5 In this class of compound a heteroar-
omatic ring is fused to the b-face of the carbazole.
However, there is a growing number of carbazoles that
contain aromatic or heteroaromatic rings fused to the a- or
c-face of the carbazole nucleus. For example, the synthet-
ic naphtho[a]carbazole 26 is a potential candidate for can-
cer treatment as a result of DNA intercalative binding
properties7 and the well-known indole/naphthalene bio-
isostery,8 while benzo[c]carbazole 39 shows promising
profiles for intra-cyclin dependent kinase selectivity
(Figure 1).
N
N
R
R
Me
Me
Benzo[a]carbazoles
Figure 2
Treatment of the readily available N-methyl-2-bromoin-
dole-3-carbaldehyde 411 with three different boronic acids
5a–c12 under aqueous Suzuki coupling reaction conditions
afforded the desired biaryl compounds 6, 7 and 8 in good
yields (Scheme 1).13 Exposure of each of these substrates
to our novel ring forming reaction conditions (t-BuOK,
DMF, hν) afforded the desired naphtho-fused carbazoles
9, 10 and 11 in fair to good yields (56–85%).14,15
As depicted in the retrosynthesis in Figure 3, we planned
to synthesize benzo[c]carbazoles 12 from indoles such as
13 containing a substituted aromatic ring at the 3-position.
A carbonyl-containing substitutient is required ortho to
the biaryl linkage on the benzene ring, and on the indole
nucleus a methyl substituent at the 2-position is necessary.
The biaryl linkage could be formed using Suzuki coupling
methodology.
OH
Me
N
O
+
N
O
N
H
N
N
OAc-
H
H
3
1
2
O
Figure 1
R
R
N
N
In these laboratories we have developed novel methodol-
ogy for the synthesis of benzo[a]carbazoles and pyri-
do[2,3-a]carbazoles.10,11 This methodology utilizes a
novel light- and base-assisted cyclization reaction to form
a centrally-positioned aromatic ring. We have previously
demonstrated that the synthesis of benzo[a]carbazoles can
be accomplished by our novel ring-forming reaction, in
which the last step is the construction of the C-5/C-6 bond
(Figure 2).11 Therefore we wished to explore the general-
ity of this reaction. In particular we wished to extend this
Me
Me
13a, R=H
13b, R=OMe
12a, R=H
12b, R=OMe
Figure 3
In order to achieve the synthesis of 13a,b, suitable precur-
sors 14a and 14b for the Suzuki coupling reaction were
prepared (Scheme 2). Exposure of 2-methylindole 15a to
molecular bromine followed by protection of the indole
nitrogen by N-methylation afforded 14a in good yield.
The synthesis of methoxyindole 14b was accomplished
from 15b, but in this case the bromination of 15b was ac-
complished with N-bromosuccinimide (NBS), as the use
Synlett 2003, No. 5, Print: 10 04 2003.
Art Id.1437-2096,E;2003,0,05,0705,0707,ftx,en;D27802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

706
C. B. de Koning et al.
LETTER
B(OH)2
CHO
ii
5a
N
i
N
Me
Me
CHO
Br
9
6
N
Me
4
B(OH)2
CHO
5b
ii
i
N
N
Me
Me
OMe
10
7
CHO
B(OH)2
OMe
5c
i
OMe
ii
OMe
N
N
Me
Me
MeO
MeO
8
11
Scheme 1 Reagents and conditions: i, 10 mol% Pd(PPh3)4, DME/EtOH, 2 M aq Na2CO3, reflux 48 h; 6, 99%; 7, 86%; 8, 60%. ii, t-BuOK,
DMF, hν, 10 min; 9, 85%; 10, 56%; 11, 86%.
of molecular bromine resulted in simultaneous bromina-
tion of the electron-rich aromatic ring. Both 14a and 14b
were unstable and had to be used immediately in subse-
quent steps.
Acknowledgment
This work was supported by the National Research Foundation
(NRF), Pretoria, and the University of the Witwatersrand. We also
thank the Mellon Postgraduate Mentoring Programme (sponsored
by the Andrew W. Mellon Foundation) for funding for JMN.
Br
R
R
i, ii
N
H
References
N
Me
14a, R=H
14b, R=OMe
(1) (a) Husson, H.-P. In The Alkaloids, Chemistry and
Pharmacology, Vol. 26; Brossi, A., Ed.; Academic Press,
Inc.: Orlando, 1985, Chap. 1, 1–51. (b) Knölker, H.-J.;
Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(2) Chakraborty, D. P. In The Alkaloids, Chemistry and
Pharmacology, Vol. 44; Cordell, G. A., Ed.; Academic
Press, Inc.: San Diego, 1993, Chap. 4, 257–364.
(3) Leonard, J. Nat. Prod. Rep. 1999, 16, 319; and previous
reviews in this series.
15a, R=H
15b, R=OMe
Scheme 2 Reagents and conditions: 15a→14a i, Br2, DMF, r.t.,
99%; ii, (MeO)2SO2, NaH, THF, 18 h, 99%. 15b→14b i, NBS,
CH2Cl2, cat. SiO2, 30 min, 99%; ii, (MeO)2SO2, NaH, THF, 48 h,
94%.
Treatment of both 14a and 14b under non-aqueous Suzuki
coupling conditions with the commercially available bo-
ronic acid 16 resulted in the formation of the desired biar-
yl compounds 13a and 13b in good yields (Scheme 3).
Exposure of 13a and 13b to potassium t-butoxide in the
presence of light gave the desired benzo[c]carbazoles 12a
and 12b in good yield.16
(4) Gribble, G. W. Synlett 1991, 289.
(5) Gribble, G. W. In The Alkaloids, Vol. 39; Brossi, A., Ed.;
Academic Press, Inc.: San Diego, 1990, Chap. 7, 239–352.
(6) Routier, S.; Coudert, G.; Mérour, J.-Y. Tetrahedron Lett.
2001, 42, 7025.
(7) Bailly, C.; Qu, X.; Chaires, J. B.; Colson, P.; Houssier, C.;
Ohkubo, M.; Nishimura, S.; Yoshinari, T. J. Med. Chem.
1999, 42, 2927.
(8) Yous, S.; Andrieux, J.; Howell, H. E.; Morgan, P. J.; Renard,
P.; Pfeiffer, B.; Lesieur, D.; Guardiola-Lemaitre, B. J. Med.
Chem. 1992, 35, 1484.
O
R
Br
R
R
ii
i
(9) Carini, D. J.; Kaltenbach, R. F. III.; Liu, J.; Benfield, P. A.;
Boylan, J.; Boisclair, M.; Brizuela, L.; Burton, C. R.; Cox,
S.; Grafstrom, R.; Harrison, B. A.; Harrison, K.; Akamike,
E.; Markwalder, J. A.; Nakano, Y.; Seitz, S. P.; Sharp, D. M.;
Trainor, G. L.; Sielecki, T. M. Bioorg. Med. Chem. Lett.
2001, 11, 2209.
(10) de Koning, C. B.; Michael, J. P.; Rousseau, A. L.
Tetrahedron Lett. 1998, 39, 8725.
(11) de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem.
Soc., Perkin Trans. 1 2000, 1705.
N
(HO)2B
N
N
Me
Me
Me
O
14a, R=H
14b, R=OMe
12a, R=H
12b, R=OMe
16
13a, R=H
13b, R=OMe
Scheme 3 Reagents and conditions: i, 20 mol% Pd(PPh3)4, DMF,
K3PO4, 100 °C, 65 h, 13a, 83%; 13b, 80%. ii, t-BuOK, DMF, hν, 10
min, 12a, 71%; 12b, 70%.
Synlett 2003, No. 5, 705–707 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Synthesis of Naphtho[a]carbazoles and Benzo[c]carbazoles
707
(12) Typical Experimental Procedures: The preparation of the
three boronic acids was accomplished as follows: (a) 2-
Methyl-1-naphthylboronic Acid 5a. n-Butyllithium (1.2
M, 3.9 cm3, 4.7 mmol) was added dropwise to a solution of
1-bromo-2-methylnaphthalene (1.01 g, 4.57 mmol) in THF
(30 cm3) at –78 °C. The reaction mixture was stirred for 30
min at –78 °C, then B(OMe)3 (1.39 g, 1.50 cm3, 13.4 mmol)
was added. The resulting mixture was stirred at –78 °C for a
further 30 min and then allowed to warm to r.t. The reaction
mixture was acidified with aq 10% HCl solution and
extracted with Et2O (3 × 30 cm3). The organic layer was then
dried with MgSO4 and concentrated under vacuum to afford
an off-white crystalline material, 2-methyl-1-naphthyl-
boronic acid 5a (0.74 g, 87%), which was used without
further purification or characterization. (b) Budac, D.; Wan,
P. Can. J. Chem. 1996, 74, 1447. (c) 1-Methyl-2-
quenched with H2O (20 cm3). The organic material was
extracted with CH2Cl2 (3 × 30 cm3) and the solvent was
evaporated under reduced pressure. The crude product was
subjected to column chromatography (2–10% EtOAc–
hexane) to afford 1-methyl-2-(2-methyl-1-naphthyl)-1H-
indole-3-carbaldehyde 6 as an off-white solid (0.13 g, 99%).
Mp 146–147 °C. (Found: M+ 299.1307, C21H17NO requires
M, 299.1310). IR (CHCl3): νmax =1655 (C=O) and 1579
(ArC=C) cm–1. 1H NMR (300 MHz, CDCl3, Me4Si): δ = 2.28
(3 H, s, ArCH3), 3.42 (3 H, s, NCH3), 7.23 (1 H, m, ArH),
7.35–7.51 (6 H, m, 6 × ArH), 7.91 (1 H, d, J = 8.0 Hz, ArH),
7.96 (1 H, d, J = 8.5 Hz, ArH), 8.48 (1 H, m, Ar-H) and 9.45
(1 H, s, CHO). 13C NMR (75 MHz, CDCl3): δ = 20.5
(ArCH3), 30.2 (NCH3), 109.8, 122.3, 123.3, 123.8, 125.0,
125.7, 127.4, 128.1 (× 2) and 130.2 (ArCH), 116.4, 124.4,
125.3, 131.7, 133.6, 137.3, 137.6 and 149.4 (ArC), 186.0
(CHO). MS: m/z (%) = 299 (100) [M+], 284 (38), 282 (55),
254 (19), 127.
naphthylboronic Acid 5b. n-Butyllithium (1.4 M, 2.1 cm3,
2.9 mmol) was added dropwise to a solution of 2-bromo-1-
methylnaphthalene (0.50 g, 2.3 mmol) in THF (15 cm3) at
–78 °C. The reaction mixture was then treated as described
above and B(OMe)3 (0.70g, 0.75 cm3, 6.69 mmol) was
added. An off-white crystalline material, 1-methyl-2-
naphthylboronic acid 5b (0.39 g, 93%) was produced, which
was used without further purification or characterization.
(d) Parham, W. E.; Reiff, H. E.; Swartzentruber, P. J. Am.
Chem. Soc. 1956, 78, 1437. (e) 1,4-Dimethoxy-3-methyl-
2-naphthylboronic Acid 5c. 2-Bromo-1,4-dimethoxy-3-
methylnaphthalene was prepared according to: Adams, R.;
Geissman, T. A.; Baker, B. R.; Teeter, H. M. J. Am. Chem.
Soc. 1941, 63, 528; this was then treated as described above
to afford the desired boronic acid 5c..
(14) 11-Methyl-11H-naphtho[2,1-a]carbazole 10. t-BuOK
(0.12 g, 1.1 mmol), was added to 1-methyl-2-(1-methyl-2-
naphthyl)-1H-indole-3-carbaldehyde 7 (0.085 g, 0.28 mmol)
dissolved in dry DMF (10 cm3), and the mixture was heated
under N2 at 80 °C while being irradiated with a high pressure
mercury lamp through a quartz filter for 10 min. The reaction
mixture was quenched with H2O (50 cm3) and extracted into
Et2O (3 × 50 cm3). The organic layer was dried with MgSO4
and filtered. It was then evaporated and subjected to column
chromatography (5–20% EtOAc–hexane) to afford the
product 10 (0.045 g, 56%) as an off-white solid. Mp 213–
216 °C. (Found: M+ 281.1209, C21H15N requires 281.1204).
IR (CHCl3): νmax = 1617 and 1572 (ArC=C) cm–1. 1H NMR
(300 MHz, CDCl3, Me4Si): δ = 4.43 (3 H, s, NCH3), 7.33
(1 H, m, ArH), 7.50–7.71 (4 H, m, 4 × ArH), 7.86 (1 H, d,
J = 9.2 Hz, ArH), 7.94 (1 H, d, J = 7.6 Hz, ArH), 8.20 (1 H,
d, J = 7.8 Hz, ArH), 8.35 (1 H, d, J = 8.7 Hz, ArH), 8.60 (1
H, d, J = 8.7 Hz, ArH), 8.71 (1 H, d, J = 9.2 Hz, ArH), 8.82
(1 H, d, J = 8.3 Hz, ArH). 13C NMR (75 MHz, CDCl3): δ =
34.4 (NCH3), 109.0, 114.8, 119.2, 119.5, 119.8, 121.0,
123.5, 125.3, 125.8, 126.1, 126.7 and 128.4 (ArCH), 120.7,
122.8, 129.7, 131.1, 131.2, 137.0 and 141.6 (ArC). MS: m/z
(%) = 281 (100) [M+], 266 (22), 252 (3), 140(2).
(13) 1-Methyl-2-(2-methyl-1-naphthyl)-1H-indole-3-
carbaldehyde 6. A solution of 2-bromo-1-methyl-1H-
indole-3-carbaldehyde 4a (see ref.11) (0.10 g, 0.42 mmol) in
DME (2 cm3) was deoxygenated by passing N2 through the
mixture for 5 min. The deoxygenated mixture was added to
Pd(PPh3)4 (10 mol%, 0.048 g, 0.04 mmol) and stirred under
N2 for 10 min at r.t. A solution of 2-methyl-1-naphthyl-
boronic acid 5a (0.11 g, 0.59 mmol) in EtOH (1.5 cm3) was
deoxygenated and added to the reaction mixture. The
mixture was stirred for a further 10 min. A deoxygenated 2
M aq Na2CO3 solution (3.0 cm3, 6.0 mmol) was added and
the reaction mixture stirred at r.t. for 5 min before being
heated at reflux for 2 d. The mixture was cooled to r.t. and
(15) This work is taken from the PhD of R. Pathak.
(16) This work is taken from the MSc of J. M. Nhlapo.
Synlett 2003, No. 5, 705–707 ISSN 0936-5214 © Thieme Stuttgart · New York