Indole-to-Carbazole Strategy for the Synthesis of Substituted Carbazoles under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.6b02762

An efficient indole-to-carbazole strategy has been developed under metal-free conditions. This carbazole formation was highly promoted by NH₄I with high regioselectivity through formal [2 + 2 + 2] annulation of indoles, ketones, and nitroolefins. It thus conveniently enabled the assembly of a large number of diversified carbazole products with good tolerance of a broad range of functional groups.

Full text of DOI:10.1021/acs.orglett.6b02762

Letter
pubs.acs.org/OrgLett
Indole-to-Carbazole Strategy for the Synthesis of Substituted
Carbazoles under Metal-Free Conditions
Shanping Chen, Yuxia Li, Penghui Ni, Huawen Huang,* and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
S
* Supporting Information
ABSTRACT: An efficient indole-to-carbazole strategy has
been developed under metal-free conditions. This carbazole
formation was highly promoted by NH4I with high
regioselectivity through formal [2 + 2 + 2] annulation of
indoles, ketones, and nitroolefins. It thus conveniently enabled
the assembly of a large number of diversified carbazole
products with good tolerance of a broad range of functional
groups.
arbazoles represent an important class of nitrogen-
containing heterocyclic compounds, many of which
Scheme 1. Indole-to-Carbazole Transformations
C
have found a wide range of applications as biologically active
agents in medicinal chemistry.1 Additionally, the carbazole
moiety has found applications as a key building block in
materials science, especially as organic light-emitting materials,
due to its wide band gap and high luminescent efficiency.2
Given the tremendous importance of carbazoles to those fields,
various synthetic methods have been developed to construct
functionalized carbazoles during the past several decades. While
at an early stage the carbazole synthesis mainly relies on the
Fischer−Borsche synthesis via a multistep procedure;3 in recent
years, intramolecular cross coupling by transition-metal (TM)
catalysis for carbazole synthesis has been a subject of great
interest.4 Despite the primary efficiency of these methods,
prefunctionalization of the precursors is an essential prereq-
uisite in most cases.
Indole-based synthesis is still a hot field of research due to its
significance in pharmaceutical chemistry and natural chemistry
as well as synthetic methodology.5 In this context, indole-to-
carbazole transformation represents an advanced method for
carbazole constructions, offering convenient opportunities to
achieve desirable synthetic convergence and function-installing
flexibility.6 For example, the Miura group developed a Pd-
catalyzed [2 + 2 + 2]cycloaddition of indoles with diary-
lacetylenes to give tetraarylated carbazoles. When terminal
alkenes or alkynes were used, palladium, gold, and rhodium
were successfully used as the catalysts to selectively provide 1,3-
disubstituted carbazoles (Scheme 1a). In addition, the Itami
and Lei groups cooperatively found that a Pd−Cu−Ag
trimetallic system could convert indoles to carbazoles using
electron-deficient alkenes. In our recent work, a formal cross-
coupling of indoles with cyclohexanone as the aryl source has
been well developed (Scheme 1b), in which 3-vinylindole was
demonstrated as the key intermediate and it could readily
transfer into 3-arylindoles7a and benzothieno[2,3-b]indoles7b
under oxidative systems. On the basis of this observation and as
our continuing interest in indole functionalization,7c−e we
herein suppose a new carbazole assembly through oxidative
annulations of the 3-vinylindole in situ formed and the third
component as a two-carbon source such as alkenes, alkynes, etc.
(Scheme 1c). In such a transformation, high regioselectivity
could be expected, which thereby conveniently enables
diversified carbazole products with a broad range of functional
groups.
Initially, we screened a range of alkenes under the previously
mentioned DEPphos/O2-based system (Scheme 2). While
most of them were found to be unfruitful for the carbazole
formation, styrene could serve as the two-carbon source for the
Received: September 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02762
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
transformation to give the carbazole in good yield (entry 6).
This catalyst might serve as a Brønsted acid to promote the
reaction because elemental I2, KI, and (Me)4NI could not
improve the formation of 4a (entries 7−9). However, the
Brønsted acids such as AcOH, CF3COOH, and TfOH could
not give better results than NH4I. We then screened the
reaction atmosphere and reaction temperature (entries 10−13)
and found the reaction performed under Ar at 150 °C gave a
higher yield of the product (entry 12). Finally, excessive
cyclohexanone (2a) was found to be the key for a full
consumption of the indole; thereby, the yield of the reaction
enhanced to 95% with a higher loading of the catalyst (entry
14).
Scheme 2. Screening Different Alkenes for the Carbazole
Formation
The high-yield and the high regioselectivity of the trans-
formation highlight the reaction to be a new method for the
carbazole assembly with diverse functional groups through the
designation of different reactants. First, a series of ketones were
tested to probe the generality of the annulation (Scheme 3).
formal [2 + 2 + 2] cycloaddition, giving the carbazole 4a in a
low yield. To our delight, both the alkenyl sodium sulfonate
and nitroolefin gave promising transformation of the desired
reaction, generating the carbazole in 20% and 25% yield,
respectively.
Scheme 3. Various Ketones for the Carbazole formation
With these observations in hand, we next chose N-
methylindole (1a), cyclohexanone (2a), and (E)-(2-nitrovinyl)-
benzene (3a) as the model system to optimize the reaction
conditions (Table 1). When various phosphorus reagents were
used under air atmosphere, the intermediate 3-vinylindole
could not be fully consumed in all cases (entries 1−3). These
results triggered us to probe other kinds of catalysts. While N-
heterocycles such as DMAP and 1,10-Phen afforded no desired
products (entries 4 and 5), inorganic NH4I enhanced the
a
Table 1. Screening the Reaction Conditions
b
c
entry
catalyst
atmosphere
temp (°C)
yield (%)
1
DPEphos
X-phos
Ph3P
air
air
air
air
air
air
air
air
air
Ar
O2
Ar
Ar
Ar
140
140
140
140
140
140
140
140
140
140
140
150
160
150
30
24
2
3
ND
ND
ND
58
4
DMAP
1,10-Phen
NH4I
5
6
7
I2
21
8
KI
9
9
(Me)4NI
NH4I
ND
62
10
11
12
13
NH4I
30
NH4I
77
a
b
c
Reaction on a 20 mmol scale. Using 5 equiv of acetone. The yield
NH4I
68
of two isomers.
d
14
NH4I
95
a
General conditions: 1a (0.2 mmol), 2a (0.2 mmol, 1.0 equiv), 3a (0.2
Cycloketones such as cyclopentanone, cycloheptanone, and
cyclooctanone were also tolerated well in this system (4b−d).
Excessive acetone seemed essential for a complete conversion
of indole and furnished the corresponding products in excellent
yield. Acycloketones acetone and pentan-3-one were compat-
ible as well (4e,f). Pentan-2-one and decan-2-one as unsym-
metrical ketones delivered two isomers of the carbazole
products in good overall yield with 3:2 regioselectivity (4g,h).
mmol, 1.0 equiv), catalyst (0.02 mmol, 10 mol %), toluene (0.5 mL,
sealed tube), 30 h. Abbreviations: DPEphos = bis[(2-
diphenylphosphino)phenyl] ether; X-phos = 2-(dicyclohexylphosphi-
b
no)-2′,4′,6′-triisopropylbiphenyl; DMAP = N,N-dimethylpyridin-4-
c
amine; 1,10-Phen = 1,10-phenanthroline. Reported yields are
determined by GC analysis using dodecane as the internal standard.
d
Catalyst (0.04 mmol, 20 mol %) and 2a (0.6 mmol, 3.0 equiv) were
used. ND = not detected.
B
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Organic Letters
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Then we subjected a range of acetylarenes to the present
system. A broad range of functional groups on the benzene ring
were tolerated well such as methylsulfonyl, nitrile, chloro,
bromo, iodo, and nitro group, affording the corresponding
products in good to excellent yields (5a−j). The steric effect of
the substituent was obvious since 1-(2-chlorophenyl)ethanone
gave a moderate yield of the carbazole 5n (versus 5h (4-Cl)
84% yield). Then we found that 1-(thiophene-2-yl)ethanone
reacted well in the annulation and gave a good yield of the
desired thiophenyl carbazole 5p.
good yields (7h,i). Notably, (Z)-(2-nitroprop-1-en-1-yl)-
benzene reacted well to afford the 1,9-dimethyl-2,4-diphenyl-
9H-carbazole 7j in good yield.
When we replaced the ketone component by an aliphatic
aldehyde (8), moderate yields of the desired products were
obtained, with the alkyl substituent at the C3 position of the
carbazole ring (eq 1), which further highlights the synthetic
Subsequently, a wide range of substituted indoles were
screened to couple with acetophenone and 3a (Scheme 4).
Scheme 4. Various Indoles and Nitrovinylarenes for the
Carbazole Formation
flexibility of this indole-to-carbazole method. For the cyclo-
hexanone-derived carbazole 4a, dehydroaromatization was
smoothly realized by the iodine-catalyzed aerobic oxidation,
providing benzo[c]carbazole product 10 in excellent yield (eq
2).
Control experiments were conducted to clarify the reaction
pathway of the three-component annulation (Scheme 5). First,
Scheme 5. Control Experiments
3-vinylindole B was generated through the combination of
ketone and indole under the standard conditions, which
undergoes nucleophilic addition of indole to the carbonyl
followed by the elimination of H2O (Scheme 5a).7a,b In
contrast, NH4Cl, a second amine such as piperidine and
proline, a Lewis acid such as AlCl3, and boron trifluoride−ether
did not promote this procedure, and only trace of B was
observed when acetic acid was used (see the Supporting
Information). These observations revealed that the formation
of B would not proceed through a Friedel−Crafts reaction. In
addition, vinylindole readily coupled with nitroalkene 3a to
furnish the final carbazole product even in the absence of
catalyst (Scheme 5b). We proposed a Michael-type addition
followed by nucleophilic annulation to give tetrahydrocarbazole
intermediate E. A Diels−Alder process is also possible. Then,
the elimination of nitro group releasing nitrous acid and
While 1,5-dimethyl-1H-indole afforded the corresponding 6a in
95% yield, both the reactants with electron-donating −OMe
(6b) and electron-withdrawing −CO2Me (6f) decreased the
yield to 74% and 61% yield, respectively. The indoles with
halogen −F, −Cl, and −Br were all accommodated well and
furnished the desired products in good to excellent yields (6c−
e,g,h). Then we found the N-benzylindole afforded the
respective product 6j in 70% yield and unprotected 1H-indole
decreased the yield of the transformation to 56% (6k). When
different functional nitrovinylarenes were screened, good yields
of the desired adducts were generally obtained (7a−g).
Naphthyl and thienyl carbazoles were readily prepared in
C
DOI: 10.1021/acs.orglett.6b02762
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Letter
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subsequent aromatization formed carbazole product (Scheme
5b).8
In summary, we have developed a highly efficient method for
carbazole formation through the three-component assembly of
indoles, ketones, and nitroalkenes under metal-free conditions.
This indole-to-carbazole protocol was demonstrated by the
preparation of a broad range of functionalized carbazoles in
moderate to excellent yields and features advantages including
easily available starting materials, metal-free conditions, high
regioselectivity, and wide functional group tolerance. Mecha-
nistic studies indicate a condensation/nucleophilic annulation/
aromatization cascade, in which 3-vinylindole is involved as the
key intermediate. Further studies on the detailed mechanism
and synthetic application are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02762.
Experimental procedures, characterization data for all
new compounds, and X-ray crystallographic data for
compound 4a (PDF)
(7) (a) Chen, S.; Liao, Y.; Zhao, F.; Qi, H.; Liu, S.; Deng, G.-J. Org.
Lett. 2014, 16, 1618. (b) Liao, Y.; Peng, Y.; Qi, H.; Deng, G.-J.; Gong,
H.; Li, C.-J. Chem. Commun. 2015, 51, 1031. (c) Xiao, F.; Chen, H.;
Xie, H.; Chen, S.; Yang, L.; Deng, G.-J. Org. Lett. 2014, 16, 50.
(d) Xiao, F.; Xie, H.; Liu, S.; Deng, G.-J. Adv. Synth. Catal. 2014, 356,
364. (e) Huang, H.; Cai, J.; Ji, X.; Xiao, F.; Chen, Y.; Deng, G.-J.
Angew. Chem., Int. Ed. 2016, 55, 307.
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Shu, W.-M.; Zheng, K.-L.; Ma, J.-R.; Wu, A.-X. Org. Lett.
2015, 17, 5216. (b) Ghosh, M.; Mishra, S.; Hajra, A. J. Org. Chem.
2015, 80, 5364. (c) Bergner, I.; Opatz, T. J. Org. Chem. 2007, 72, 7083.
(d) Liu, X.; Wang, D.; Chen, B. Tetrahedron 2013, 69, 9417.
(e) Abdukader, A.; Xue, Q.; Lin, A.; Zhang, M.; Cheng, Y.; Zhu, C.
Tetrahedron Lett. 2013, 54, 5898.
*E-mail: hwhuang@xtu.edu.cn.
*E-mail: gjdeng@xtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21602187, 21572194,
21372187), the Hunan Provincial Innovative Foundation for
Postgraduate (CX2016B260), and the Program for Innovative
Research Cultivation Team in University of Ministry of
Education of China (1337304).
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D
DOI: 10.1021/acs.orglett.6b02762
Org. Lett. XXXX, XXX, XXX−XXX