One-pot synthesis of benzo[c]carbazoles by photochemical annulation of 2-chloroindole-3-carbaldehydes

Article abstract of DOI:10.1039/b808854c

A novel and efficient procedure for the synthesis of benzo[c]carbazoles has been achieved in moderate to high yields by the one-pot photochemical annulations of 2-chloroindole-3-carbaldehydes by styrenes via photodechlorination-initiated coupling of 2-chloroindole-3-carbaldehydes with styrenes, electrocyclic reactions and deformylative aromatization in the presence of pyridine. The Royal Society of Chemistry.

Full text of DOI:10.1039/b808854c

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One-pot synthesis of benzo[c]carbazoles by photochemical annulation
of 2-chloroindole-3-carbaldehydesw
Cailin Wang, Wei Zhang,* Shenci Lu, Jingfei Wu and Zongjun Shi
Received (in Cambridge, UK) 27th May 2008, Accepted 11th August 2008
First published as an Advance Article on the web 12th September 2008
DOI: 10.1039/b808854c
A novel and efficient procedure for the synthesis of benzo[c]-
carbazoles has been achieved in moderate to high yields by the
one-pot photochemical annulations of 2-chloroindole-3-carbal-
dehydes by styrenes via photodechlorination-initiated coupling of
2-chloroindole-3-carbaldehydes with styrenes, electrocyclic reactions
and deformylative aromatization in the presence of pyridine.
Scheme 1
lenes in the presence of oxygen5e has also been reported, but there
Photoarylation of alkenes, alkynes and arenes by aryl halides has
are no procedures for a direct synthesis of benzo[c]carbazoles by
the photocycloaddition of indoles with olefins. Herein we
received great attention in recent years,1 due to the wide-ranging
application in the metal-free synthesis of aryl-substituted alkyla-
mines, alkanols, alkynes, ketones, aldehydes and biaryls. Albini
describe the first construction of benzo[c]carbazoles by the novel
photochemical annulation of readily available 2-chloroindole-3-
carbaldehydes6 with styrenes (Scheme 1).
and co-workers were engaged in the extensive research on the
inter- and intermolecular photoarylation of electron-rich alkenes,
We first optimized photoreaction conditions using 2-chloro-1-
phenylindole-3-carbaldehyde (1a) as a model reactant. No great
alkynes and arenes by amino- and alkoxyl-substituted aryl
halogens.1a–d Comparatively, investigation on the photoarylation
of alkenes by halogenated heteroaromatics was rare.2 We are
interested in the photocoupling reactions of halogenated hetero-
difference was found for the reaction of 1a and 2a in the presence
or absence of oxygen in CH2Cl2 solutions, but the photoreaction
was greatly affected by solvents and bases as shown in Table 1.
aromatics with olefins in relation to the synthetic method and the
The conversion of 1a and the yield of 3a in CH2Cl2 were low and
the solution turned dark in a short time while in acetone a little
improvement was observed. This result may be derived from the
reaction mechanism. We envisioned that the photoreaction of
2-chloro-1-phenylindole-3-carbaldehyde (1a) with styrene (2a)
would serve as an attractive synthetic route to a polycyclic
sensitization effect of acetone to 1a because ET = 326 kJ molꢀ1 7a
,
compound indolo[1,2-a]quinoline-7-carbaldehyde by photodisso-
ciation of the C–X bond and subsequent addition of the s-indolyl
radical to 2a and the annulation of the adduct radical on the
1-phenyl group. Contrary to our expectation, the main product
obtained was not indolo[1,2-a]quinoline-7-carbaldehyde, but
benzo[c]carbazole (3a) which seemed to be derived from cyc-
loaddition of the s-indolyl radical with 2a and subsequent
deformylation as shown in Scheme 1.
of acetone is higher than that for 1a (ET = 275 kJ molꢀ1,7b). The
conversion of 1a and yield of 3a, however, were increased greatly
by the addition of base such as pyridine or sodium carbonate
because the solution could be irradiated for much longer time
without turning dark. Obviously pyridine or sodium carbonate
retarded the oligomerization of indole derivatives induced by HCl
and light. Therefore acetone with the addition of pyridine was
selected as the solvent in all photoreactions.
Procedures for the facile synthesis of benzo[c]carbazoles are of
interest since a number of biologically active alkaloids contain this
unit3 and some substituted benzo[c]carbazoles possess potential
kinase inhibitory4a and antitumor activities.4b,c Several strategies
have been reported for the construction of benzo[c]carbazole
systems. For example, Bu3SnH-mediated radical cyclization
of 1-(3-iodioindol-2-yl)-2-phenylethene, palladium-catalyzed
cyclization of 1-(2-nitrophenyl)naphthalenes driven by CO as the
stoichiometric reductant;5b microwave-enhanced reductive cycliza-
tion reaction of 1-(2-nitrophenyl)naphthalenes by triethyl
phosphate.5c The formation of benzo[c]carbazoles by photo-
;cyclization of 2-methyl-3-(20-acetylphenyl)indoles assisted by
t-BuOꢀK+,5d and photocyclization of 2-phenylaminonaphtha-
Having established the optimal photoreaction conditions,
we then examined a variety of 2-chloroindole-3-carbaldehydes
and styrenes to explore the generality of this new one-pot
Table 1 Optimization of photoreaction conditions of 1a with 2a
Entry
Solvent
t/h
Conv.a (%)
Yieldb (%)
1
2
3
4
5
a
CH2Cl2
8
12
16
16
20
51
69
77
95
87
20
32
52
70
53
CH3COCH3
CH2Cl2–pyridine
CH3COCH3–pyridine
CH3COCH3–Na2CO3
b
State Key laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, China. E-mail: zhangwei6275@lzu.edu.cn;
Fax: +86 (931) 8625657; Tel: +86 (931) 8912545
w Electronic supplementary information (ESI) available: Spectro-
scopic data. CCDC 679088. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b808854c
Conversion based 1a. Isolated yield.
ꢁc
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Table
styrenes
2
Photoreaction of 2-chloroindole-3-carbaldehydes with
Table 3 Photoreaction of 2-chloroindoles with different substituents
at 3-position with styrenes
Conv.a
(%)
Yieldb
(%)
Conv.a Yieldb
Entry
R
R3
Prod.
t/h
Entry
R1
R2 R3
R4
Prod. t/h (%)
(%)
1
2
3
4
5
6
7
a
1d
1d
1d
1e
1e
1f
COMe
COMe
COMe
H
H
Et
H
3e
3f
3g
3e
3f
24
20
20
36
36
36
48
85
88
85
46
49
37
—
53
46
48
32
37
25
—
1
2
3
4
5
6
7
8
1a Ph
1a Ph
1a Ph
1a Ph
1b Me
1b Me
1b Me
H
H
H
H
H
3a
3b
3c
16 95
12 90
24 96
12 92
12 69
12 71
30 91
36 95
16 60
24 65
30 88
12 82
70
41
82
36
54
35
65
45
48
37
56
33
Me
Ph
H
Me
Me
Me
H
H
Me
H
Me
Ph
H
MeO 3d
H
H
H
H
3e
3f
3g
3e
—
H
H
Me
Ph
H
1g
CO2Et
b
Conversion based 1d–f. Isolated yields.
1b Me Me
MeO 3h
9
1c
1c
1c
1c
H
H
H
H
H
H
H
H
H
3i
3j
3k
10
11
12
a
H
H
Me
Me
Ph
H
lifetimes than 1e and 1f. In the case of 1g, no reaction can be
detected even after prolonged irradiation.
MeO 3l
b
Conversion based 1a–c. Isolated yield.
We analyzed the reaction mixtures and found that some non-
cyclization adducts of 1a–d with 2a–d were produced besides the
cyclization products 3a–l. For example, 1-methyl-2-(2-phenyl-2-
propenyl)indole-3-carbaldehydes (4f) and 2-(2,2-diphenylethenyl)-
3-carbaldehydes (4k) were separated from the reaction mixture of
1b with 2b and 1c with 2c, respectively (Scheme 2). Irradiation of
4k gave the cyclization product benzo[c]carbazole 3k (Scheme 3),
but no change could be detected after prolonged irradiation of the
other non-cyclization adduct 4f. These results illustrate that 4k
may be the intermediate of multiple photoreaction and its photo-
cyclization is a key step in the formation of benzo[c]carbazole 3k.
No reports for electrocyclic reaction with the elimination of a
formyl or a alkyl group have been found in the literature, but
deformylative or dealkylative aromatization have been reported
in the formation of heteroaromatics, such as 3-benzoylpyrrole
from deformylation of 3-formyl-3-benzoylpyrrole;8 2,6-dimethyl-
pyridine-3,5-dicarboxylate from dealkylation of 4-alkyl-substi-
tuted Hantzsch 1,4-dihydropyridines.9
photochemical annulation reaction.z The reactions were con-
ducted under the above reaction conditions for 12–60 h and
the expected benzo[c]carbazoles were obtained as major
products in all cases (Table 2). All products were fully
1
identified by H, 13C NMR and MS, and the structure of 3h
was further confirmed by X-ray crystallography (Fig. 1).y It is
noteworthy that the conversion of 1a–c and the yields of 3a–l
are increased when irradiation is prolonged and the presence
of substituents (R1 = Ph, Me) in 1a and 1b is favourable for
longer irradiation; substituents (R2, R3 = Me) in 2b and 2d are
unfavourable to the yields of benzo[c]carbazoles.
To investigate the scope and the mechanism of the photo-
chemical process, we have tested the reactivity of other reactants
with different substituents at the 3-position of 2-chloroindole
under similar conditions. It is observed from Table 3 that the
photoreaction of 1d, 1e and 1f with 2a or 2b can all produce
benzo[c]carbazoles in moderate yields from dechlorination,
cyclization and deacetylation or dealkylation. Comparatively,
the time needed for the photoreaction of 1d is relatively short,
but much more time is needed for the reaction of 1e or 1f to
attain high conversions. It seems reasonable to ascribe the
differences to carbonyl compounds 1a–d having longer triplet
The UV spectrum of 1b shows three absorptions at lmax
=
226 nm (K band), 246 nm (K band) and 298 nm (R band).
Pyrex can filter the K bands and the triplet state of 1b is only
produced from the absorption of the R band or energy transfer
from the triplet of acetone. ET of 1b should be near that of
indole-3-aldehyde which shows ET = 275 kJ molꢀ1 7b
since 1b
,
Fig. 1 X-Ray crystal structure of 3h.
Scheme 2
ꢁc
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with water. This carbocation may be the coupling product of
the s-indolyl radical from dechlorination of the anion radical
of 1b with the cation radical of 2a.
According to the above experimental results, a possible
mechanistic rationalization for the formation of benzo[c]carbazole
3e is depicted (Scheme 5).
We thank the National Natural Science Foundation of
China (20872056) for financial support.
Scheme 3
has a similar absorption, fluorescence emission and phospho-
rescence emission spectra to those of indole-3-carbaldehyde.7b,10
This energy is insufficient for homolytic fission of the C–Cl
bond in 1b as compared with the estimation of D’Auria that the
dissociation energy of the C–Br bond in 5-bromofuran-2-
Notes and references
z Typical experimental procedure: 1a (0.256 g, 1.0 mmol) and styrene
2a (0.104 g, 2.25 mmol) and pyridine (0.119 g, 1.5 mmol) were
dissolved in 25 mL dry acetone. The solution was distributed into five
10 mL Pyrex tubes and deaerated by bubbling Ar for 30 min and
irradiated at l Z 300 nm with a high-pressure mercury lamp (500 W)
at ambient temperature. The progress of reaction was monitored by
TLC at regular intervals. After the solvent was removed under reduced
pressure, the residue was separated by column chromatography on
silica gel eluted by hexane–ethyl acetate 10 : 1 (v/v) to afford product
3a. The solid was further purified by recrystallization from methanol.
y Crystal data for 3h (recrystallized from acetone–hexane). C19H17NO,
Mr = 275.34, monoclinic, space group P21/c, a = 11.209(3), b =
7.292(2), c = 18.864(4) A, b = 114.178(13)1, V = 1406.6(6) A3,
colorless plates, Dc = 1.300 g cmꢀ3, T = 293(2) K, Z = 4, m(Mo-Ka)
= 0.71073 mmꢀ1, 2ymax = 511, 2600 reflections measured, 1984
unique (Rint = 0.1591) which were used in all calculations. The final
wR(F2) was 0.0720 (for all data), R1 = 0.0583.
carbaldehyde is 70 kcal molꢀ1 2c
Thus it could be supposed
.
that the photoreaction of 1b with 2a is initiated not by the direct
C–Cl fission but by the formation of an exciplex and subsequent
single electron transfer which promotes the cleavage of C–Cl
bond. Support for this proposal is the difference of photo-
reaction of 1b in aqueous acetone in the presence of 2a and in
the absence of 2a under irradiation of l Z 300 nm as shown in
Scheme 4.
That no substitution reaction took place for 1b in aqueous
acetone or in methanol in the absence of 2a indicated that
there was no s-indolyl cation produced under direct photo-
lysis; Comparatively in the presence of 2a, the photoreaction
of 1a with 2a could proceed smoothly to produce 3a in both
solvents. A reasonable explanation as to the difference is the
electron transfer from 2a to excited 1b can promote the fission
of a C–Cl bond. The minor product 5 in aqueous acetone
seems to be derived from the combination of a carbocation
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1988.
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Scheme 4
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Scheme 5
ꢁc
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5178 | Chem. Commun., 2008, 5176–5178