Facile Synthesis of Carbazoles via a Tandem Iodocyclization with 1,2-Alkyl Migration and Aromatization

Article abstract of DOI:10.1021/acs.orglett.5b01590

A strategy for the synthesis of iodocarbazoles through a tandem iodocyclization with migration and aromatization is presented. This sequential cascade process is concisely conducted at room temperature and in a short time. Moreover, the obtained halides c

Full text of DOI:10.1021/acs.orglett.5b01590

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Carbazoles via a Tandem Iodocyclization with
1,2‑Alkyl Migration and Aromatization
Jia Wang,† Hai-Tao Zhu,§ Yi-Feng Qiu,† Yuan Niu,† Si Chen,† Ying-Xiu Li,† Xue-Yuan Liu,†
and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou, 730000, P.
R. China
§Shannxi Key Laboratory of Phytochemistry, Baoji University of Arts and Sciences, Baoji 721013, China
S
* Supporting Information
ABSTRACT: A strategy for the synthesis of iodocarbazoles through a
tandem iodocyclization with migration and aromatization is presented.
This sequential cascade process is concisely conducted at room
temperature and in a short time. Moreover, the obtained halides can
be further applied to palladium-catalyzed coupling reactions, which act as
the important intermediates for building other valuable compounds.
earrangement1 and migration2 reactions as features in the
Scheme 1. Migration Reactions and Aromatization
Rchemistry field have been the focus of considerable
attention for chemists; these could build surprising and
unexpected structures. Meanwhile, many compounds that are
difficult to synthesize by conventional methods could be gained
easily by rearrangement or migration reactions.3 In recent years,
electrophilic cyclization of nucleophiles with an alkyne4 or
allene5 has proved to be one of the most interesting subjects in
organic chemistry and has been widely used to construct
carbocycles6 and heterocycles.7 Nevertheless, few examples of
sequential tandem iodocyclization to form iodocarbazole have
been reported until now. Furthermore, carbazoles are
important heteroaromatic compounds, which not only show
various pharmacological activities, such as anticancer,8 anti-
microbial,9 antipsychotic,10 and antimitotic,11 but also serve as
building blocks for potential electroluminescent materials due
to their special electrical, thermal, and optical properties.12 As a
result of the remarkable importance of functionalized
carbazoles and their derivatives across many fields, much
attention has been paid to the development of new methods for
the synthesis of carbazoles. Among many useful procedures to
construct carbazoles, synthetic pathways of forming a benzene
ring from indoles are particularly attractive.13 Although great
achievements have been made to prepare carbazoles, seeking
alternative methods for the construction of a carbazole-fused
indole via a tandem iodocyclization with migration and
aromatization is highly desirable.
In 2011, Hashmi’s group described an interesting formation
of benzo[b]furans from 3-silyloxy-1,5-enynes (Scheme 1).14
This reaction is generally believed to go through a stepwise
mechanism. The 2-position attacks the alkyne induced by the
gold catalyst to form a 5-endo-dig cyclization B, then a
Wagner−Meerwein shift delivers intermediate C with a more
stable carboxonium ion. Finally, the product D is afforded by
deprotonation and elimination of silanol. The same principles
subsequently were also applied to other heterocycles,15 and it
could be shown that spirocyclic intermediates do not always
have to be involved.16 Encouraged by this achievement and in
the context of our ongoing interest in iodocyclization,17 we
envisioned that the substrates 1 containing an indole moiety
could undergo a similar migration reaction to give intermediate
F, which could undergo aromatization to form iodocarbazole 2.
Importantly, the starting materials could be synthesized
through classic and mature reactions under the mild conditions.
Herein, we report a concise and effective method for the
synthesis of iodocarbazoles via a 1,2-shift and aromatization.
Our initial study began with 1-(1-methyl-1H-indol-3-yl)-4-
phenylbut-3-yn-1-ol (1a) with 2.0 equiv of ICl in iPrOH (4
mL) at room temperature. To our delight, the desired product
3-iodo-9-methyl-4-phenyl-9H-carbazole (2a) was isolated in
Received: June 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Synthesis of Iodocarbazoles of 2a
41% yield after 0.5 h (Table 1, entry 1). With the addition of
K2CO3 (1.0 equiv), product 2a was gained in 66% yield (entry
a
Table 1. Optimization Studies on the Rearrangement of 1a
b
electrophile
(equiv)
base
(1.0 equiv)
time
(h)
yield
(%)
entry
solvent
iPrOH
1
ICl (2.0)
ICl (2.0)
ICl (3.0)
ICl (3.5)
ICl (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
I2 (3.0)
none
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
41
66
89
87
17
22
24
23
72
83
41
45
88
50
87
89
2
iPrOH
iPrOH
iPrOH
CH3CN
CH2Cl2
CH3COCH3
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KOH
3
4
5
6
7
8
9
EtOH
10
11
12
13
14
15
16
n-PrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
IBr (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
ICl (3.0)
K3PO4
K2CO3
a
All reactions were run under the following conditions, unless
otherwise indicated: 0.20 mmol of 1a, 3.0 equiv of ICl, and 1.0 equiv
b
of base in 4 mL of solvent were stirred at room temperature. Yields of
isolated products.
2). By increasing the amount of ICl to 3.0 equiv, the yield of 2a
dramatically increased to 89%. However, further increasing the
amount of ICl to 3.5 equiv gave a slightly lower yield of 2a
(entry 4). After screening a series of solvents such as CH3CN,
CH2Cl2, CH3COCH3, THF, EtOH, and n-PrOH, we found
that iPrOH was the best (entries 3 and 5−10). Regretfully,
other electrophiles including I2 and IBr gave unsatisfactory
yields of the desired products (entries 11−12). Afterward, the
study of bases showed that Na2CO3, KOH, and K3PO4 could
not give a superior yield (entries 13−15). In addition,
prolonging the reaction afforded the same result as before
(entries 3 and 16). From the series of detailed investigations
mentioned above, the combination of 1.0 equiv of 1a, 3.0 equiv
of ICl, and 1.0 equiv of K2CO3 in iPrOH at room temperature
for 0.5 h was determined as the optimum reaction conditions.
To investigate the generality and the scope of this migration
and aromatization reaction, various 1-(1-methyl-1H-indol-3-yl)-
4-phenylbut-3-yn-1-ol derivatives were subjected to the above-
mentioned conditions, as summarized in Table 2. The reactions
of substrates 1b−1e bearing the electron-donating aromatic
groups (R1) at the alkynyl carbon resulted in the corresponding
products 2b−2e in excellent yields (entries 2−5). The structure
of the representative product 2e was determined by X-ray
crystallographic analysis (Figure 1). Subsequently, we designed
compounds 1f−1i with electron-withdrawing aromatic groups
(R1) and obtained the desired products 2f−2i in good yields
(entries 6−9). Remarkably, in contrast to product 2e, the yield
of 2i decreased with the increase of electronegativity on the
substituent R1 group (entry 5 vs 9). This might be due to the
electron-withdrawing substituents impairing the activity of the
alkyne group. In the meantime, the product 2j was obtained in
83% yield. However, substrate 1k only led to 2k in 37% yield
for the weak nucleophilicity of the aliphatic alkyne. It is
noteworthy that the yields of 2l and 2m decreased successively
with electron waning on the substituent R2. This should be
attributed to the electron-rich substituent on R2 enhancing the
nucleophilicity of the 3-position, which is the most nucleophilic
position of the indole system.18 In particular, substrate 1n with
an electron-withdrawing substituent (Ts) on R2 failed to afford
the corresponding product 2n, owing to the reduced
nucleophilicity of the 3-position (entry 14). The reactions
also worked well with substrates 1o−1r with electron-donating
or -withdrawing substituents on R3, furnishing the expected
B
DOI: 10.1021/acs.orglett.5b01590
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Organic Letters
Letter
Scheme 3. Palladium-Catalyzed Coupling Reactions
Figure 1. Solid state molecular structure product of 2e.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, spectral data, and CIF for all
new compounds are provided. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01590.
■
S
products 2o−2r in good yields. Meanwhile, the substrate 1s
with thienyl and 1t with naphthyl afforded the corresponding
products 2s and 2t in 82% and 88% yields, respectively. In
addition, the products 2u and 2v were obtained with migration
and aromatization with the alkynyl chains attached to the α-
position of indoles. The structure of the representative product
2v was determined by X-ray crystallographic analysis (see the
Supporting Information).
AUTHOR INFORMATION
Corresponding Author
■
On the basis of the above observations, the following
mechanism was proposed and outlined in Scheme 2. The
*E-mail: liangym@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
Scheme 2. Proposed Reaction Mechanism
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF 21272101,
21472074, 21472073 and 21302076). We also acknowledge
support from the “111” Project (J1103307) and Program for
Changjiang Scholars and Innovative Research Team in
University (IRT1138).
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