Efficient synthesis of 1,2,3,4-tetrahydro-11H-benzo[a]carbazole and its regioselective oxidation

Article abstract of DOI:10.1055/s-2006-939694

Carbazole derivative 4 was synthesized in an efficient three-step sequence and its further oxidation with dichlorodicyanoquinone gave selectively 4-oxo-1,2,3,4-tetrahydro-11H-benzo[a]carbazole 3. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939694

LETTER
1021
Efficient Synthesis of 1,2,3,4-Tetrahydro-11H-benzo[a]carbazole and its
Regioselective Oxidation
Efficient
S
ynth
a
esis of 1,2
b
,3,4-Tetrahy
i
dro-11
H
e
-benzo[
a
]c
n
a
rbazole Dufour, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Université Paul Verlaine Metz, 1 bd Arago,
57078 Metz-Technopôle, France
Fax +33(3)87315801; E-mail: kirsch@sciences.univ-metz.fr
Received 16 February 2006
O
Abstract: Carbazole derivative 4 was synthesized in an efficient
three-step sequence and its further oxidation with dichlorodicyano-
quinone gave selectively 4-oxo-1,2,3,4-tetrahydro-11H-ben-
zo[a]carbazole 3.
R2
N
R1
H
N
Key words: heterocycles, ellipticines, carbazoles, oxidations,
regioselectivity
3
N
N
H
H
1: R1 = Me, R2 = H
2: R1 = H, R2 = Me
Carbazole units are frequently encountered in natural
products, such as in anticancer ellipticine (1) and oliva-
cine (2, Figure 1). Since many carbazole alkaloids show
biological activity, there is a great interest for using them
in synthetic organic chemistry, as shown by several re-
views on the topic.1–3
4
Figure 1
major drawbacks (respectively poor yield, small amounts
of compounds, or not readily available starting materials).
For developing the synthesis of new analogues of ellipti-
cine, we needed the carbazole intermediate 3 (Figure 1),
not actually described in the literature.
Here was developed an efficient three-step synthesis of 4
starting from commercial phenylhydrazine 5 and a-tetra-
lone 6 (Scheme 1).
After several unsuccessful attempts, we decided to syn-
thesize 3 from 1,2,3,4-tetrahydro-11H-benzo[a]carbazole
(4) and a regioselective oxidation. The latter was de-
scribed in three publications. In 1981, Kano et al. obtained
4 as a by-product from a thermal cyclisation.4 The same
year, Olsen et al. published the synthesis of 4 using a
photochemical reaction.5 In 1988, Moody et al. used
the intramolecular Diels–Alder reaction of 1-(hex-5-
ynyl)pyrano[3,4-b]indol-3-one.6 All these methods show
Fischer indole synthesis from 5 and 6 afforded 7 in an
almost quantitative yield, which after aromatization with
Pd/C (5%) in refluxing xylene gave 8.7 Reduction of 8
to 1,2,3,4-tetrahydro-11H-benzo[a]carbazole (4) was
achieved by using sodium in hot isoamylic alcohol.8
Clean reduction was made in 70% yield. The overall yield
from starting phenylhydrazine and a-tetralone is 54%,
which make the sequence an interesting and cost effective
route to 4. The 1H NMR spectrum of 4 was identical to the
one described by Moody et al.6
37% HCl cat.
EtOH, reflux, 4 h
+
O
N
NH2
H
N
H
95%
7
5
6
Pd/C
Na
xylene, reflux, 1 h
81%
isoamylic
N
N
alcohol, reflux, 1 h
H
H
70%
8
4
Scheme 1
SYNLETT 2006, No. 7, pp 1021–1022
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939694; Art ID: G06406ST
© Georg Thieme Verlag Stuttgart · New York

1022
F. Dufour, G. Kirsch
LETTER
DDQ
O
+
AcOH
H2O
N
N
N
H
H
H
3
9
4
O
42%
4%
Scheme 2
1,2,3,4-Tetrahydro-11H-benzo[a]carbazole (4)
Preparation of 3 by oxidation of 4 was tried using various
conditions (selenium dioxide, potassium permanganate,
Jones reagent, chloranil, cerium ammonium nitrate,
manganese dioxide). All the attempts failed. Only the use
of DDQ in aqueous acetic acid9 gave compound 3 in good
yield (42%) along with a small amount (4%) of the isomer
9 (Scheme 2). Compounds 3 and 9 could be separated by
a column chromatography on silica gel.
To a solution of 8 (4.38 g, 20 mmol) in 80 mL of hot isoamylic al-
cohol, while maintaining a gentle reflux was added Na (2.3g, 0.1
mol) in portions. Reflux was continued 1 h after the addition of Na.
The mixture was poured onto H2O (300 mL) and extracted with 100
mL of EtOAc. After drying over MgSO4 and evaporation, crystalli-
zation from PE gave 3.1 g of 4 as a white solid. Yield 70%; Rf = 0.5
(cyclohexane–CH2Cl2 50:50); mp 172–173 °C (Lit.6 164–165 °C).
1H NMR (CDCl3): d = 2.00 (m, 4 H), 2.95 (m, 4 H), 7.00 (d, 1 H),
7.20 (d, 1 H), 7.40 (m, 2 H), 7.80 (d, 1 H), 7.90 (br, 1 H), 8.05 (d, 1
H). GCMS: m/z = 221.
Structures of the unknown compounds 3 and 9 were
assigned based on the proton shift of the NH group. In 3
the shift is at 8.2 ppm, as in other carbazoles derivatives
of Scheme 1. In 9, deshielding by the ketone gave a signal
for NH at 10.6 ppm.
3-Oxo-1,2,3,4-tetrahydro-11H-benzo[a]carbazole (3)
To a solution of 4 (0.23 g, 1 mmol) in AcOH (100 mL) and H2O (20
mL), DDQ (0.68 g, 3 mmol) was added and the mixture was stirred
at r.t. overnight. It was poured onto 300 mL of H2O and extracted
with EtOAc (2 × 100 mL). After drying over MgSO4 and evapora-
tion, crude product was chromatographed on silica gel (CH2Cl2,
CH2Cl2–EtOAc 95:5) to afford 0.10 g of 5 as a beige solid. Yield
In conclusion, we were able to synthesize 1,2,3,4-tetra-
hydro-11H-benzo[a]carbazole in a three-step reaction
with a good overall yield from simple starting materials.
The regioselective oxidation allowed us the access to
ketone 4 which will be used for building the missing
pyridine ring for acceding to new ellipticine analogues.
1
42%, Rf = 0.35 (CH2Cl2–EtOAc 95:5); mp 224–225 °C; H NMR
(CDCl3): d = 2.30 (quint, 2 H), 2.80 (t, 2 H), 3.15 (t, 2 H), 7.30 (m,
2 H), 7.50 (m, 2 H), 8.00 (s, 1 H), 8.10 (s, 1 H), 8.20 (br, 1 H), GC-
MS: m/z = 235.
The amount of 10 mg (4%) of less polar isomer 9 was isolated.
Rf = 0.55 (CH2Cl2–EtOAc 95:5), mp 162–163 °C. 1H NMR
(CDCl3): d = 2.25 (quint, 2 H), 2.75 (t, 2 H), 3.15 (t, 2 H), 7.05 (d,
1 H), 7.25 (d, 1 H), 7.50 (m, 2 H), 8.05 (d, 1 H), 8.20 (d, 1 H), 10.60
(br, 1 H). GCMS: m/z = 235.
Melting points were measured with a SMP3 Stuart Scientific appa-
ratus. 1H NMR spectra were recorded on an ACS250 Bruker (250
MHz) apparatus. The chemical shifts (d) are given in ppm down-
field from the deuterated solvent. GCMS molecular pick values
were given by a Varian Saturn 2000 spectrometer. Commercial
reagents were used as received.
Acknowledgment
5,6-Dihydro-11H-benzo[a]carbazole (7)
We thank La Ligue Contre le Cancer, Comité de Moselle for finan-
cial support, V. Poddig for recording H NMR spectra and PhD
student G. Frache from LSMCL for GCMS spectra.
A mixture of phenylhydrazine (4.41 g, 50 mmol) and a-tetralone
(7.31 g, 50 mmol) in 100 mL of EtOH and 5 mL of concd HCl was
heated under reflux for 4 h. Solvent was evaporated to dryness, re-
crystallization from cyclohexane–toluene 50:50 gave 10.4 g of 7 as
a beige solid. Yield 95%; Rf = 0.4 (cyclohexane–CH2Cl2 50:50);
mp 163–164 C (Lit.7 163–164 C). 1H NMR (CDCl3): d = 3.05 (m, 4
H), 7.25 (m, 6 H), 7.40 (d, 1 H), 7.60 (d, 1 H), 8.15 (br, 1 H).
1
References
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11-H-Benzo[a]carbazole (8)
Compound 7 (6.63 g, 30 mmol) in 50 mL of xylene was heated un-
der reflux with 2 g of 5% palladium/charcoal for 1 h. After cooling,
50 mL of EtOAc were added and the mixture was filtered through
Celite®. Solvent was evaporated. Crystallization from PE and filtra-
tion gave 5.3 g of 8 as a white solid. Yield 81%; Rf = 0.4 (cyclohex-
ane–CH2Cl2 50:50); mp 230–231 °C (Lit.10 227–229 °C). 1H NMR
(CDCl3): d = 7.30–7.70 (m, 6 H), 8.00–8.20 (m, 4 H), 8.80 (br, 1 H).
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Synlett 2006, No. 7, 1021–1022 © Thieme Stuttgart · New York