Efficient carbazole synthesis via Pd/Cu-cocatalyzed cross-coupling/ isomerization of 2-allyl-3-iodoindoles and terminal alkynes

Article abstract of DOI:10.1021/ol500119r

The Pd/Cu-cocatalyzed one-pot reaction of 2-allyl-3-iodo-1-tosyl-1H-indoles and terminal alkynes afforded carbazoles highly efficiently via sequential carbon-carbon coupling, isomerization, cyclization, and aromatization forming a benzene ring. Both Pd and Cu are responsible for the coupling step, while K ₂CO₃ was observed to be critical for the subsequent cyclization.

Full text of DOI:10.1021/ol500119r

Letter
pubs.acs.org/OrgLett
Terms of Use
Efficient Carbazole Synthesis via Pd/Cu-Cocatalyzed Cross-Coupling/
Isomerization of 2‑Allyl-3-iodoindoles and Terminal Alkynes
Can Zhu† and Shengming Ma*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China
‡Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
3663 North Zhongshan Lu, Shanghai, 200062, P. R. China
S
* Supporting Information
ABSTRACT: The Pd/Cu-cocatalyzed one-pot reaction of 2-
allyl-3-iodo-1-tosyl-1H-indoles and terminal alkynes afforded
carbazoles highly efficiently via sequential carbon−carbon
coupling, isomerization, cyclization, and aromatization forming
a benzene ring. Both Pd and Cu are responsible for the
coupling step, while K2CO3 was observed to be critical for the
subsequent cyclization.
Scheme 1. Coupling/Cyclization Strategy To Construct
Carbazoles from Indoles
arbazoles are important heteroaromatic compounds in
Cmany natural products and compounds displaying
significant pharmacological and biological activities.1,2 They are
also observed in well-known hole-transporting and electro-
luminescent materials3 and, therefore, are considered as potential
building blocks for functional materials due to electrical and
thermal properties.4 Based on this, chemists devoted themselves
to develop new methods for the synthesis of polysubstituted
carbazoles.5,6 Among them, synthetic pathways to carbazoles
from indoles, which involves the formation of a benzene ring,
have drawn great attention, considering the fact that indole
substances are widely existing compounds.5,7 However, reported
typical methods sometimes suffer from several drawbacks: the
severe conditions combined with poor atom economy and
multistep synthesis may limit their potential application. Thus,
developing novel methodologies involving a simple, mild,
efficient, and diversified preparation toward polysubstituted
carbazoles from indoles is still highly desirable.
Our initial attempt began with the coupling reaction of
iodoindole 1a with phenylacetylene 2a in the presence of
[Pd(PPh3)2Cl2] and [CuI]. Interestingly, when the reaction was
carried out in MeOH at 40 °C with 2.0 equiv of K2CO3 as the
base, the carbazole derivative 3a was obtained in 16% yield,
unexpectedly, while the formation of the coupling product 4a
was not detected (Table 1, entry 1). With these inspiring results
in hand, we turned to optimizing the reaction conditions for
selective formation of 3a. The yield of 3a was improved
dramatically to 58% with only 4% of 4a observed when the
reaction was conducted at 50 °C, while the same reaction at room
temperature led to disappointing results (Table 1, entries 2 and
3). We next turned to examining the solvent effect (Table 1,
entries 4−9), and a mixed solvent of THF and MeOH (1:1) was
observed to be the best, improving the yield of 3a additionally to
75%, with only 6% yield of 4a (Table 1, entry 9). Further
screening was focused on the base effect: other bases such as
Et3N, Na2CO3, and Cs2CO3 failed to show better performance
than K2CO3 (Table 1, entries 10−12). Finally, it was observed
that the amount of K2CO3 was also crucial to the reaction, the
yield of 3a was improved further to 82% with a trace amount of
On the other hand, tandem reactions,8,9 in which multistep
reactions are combined into one synthetic operation, have
attracted much attention for their efficiency in forming a complex
skeleton. For example, the palladium-catalyzed coupling/
cyclization reaction has drawn particular interest because
significant molecular complexity can be obtained in one step
starting from easily available materials.10,11 Recently, we reported
a one-pot reaction for the synthesis of dihydrocycloocta[b]-
indoles from 2-allyl-3-iodoindoles and propargylic bromides12
via palladium(0)-catalyzed carbon−carbon coupling forming the
intermediate 3-allenylindoles Int-A, which was followed by
cycloisomerization to form the 8-membered ring (Scheme 1).
Interestingly, we observed a novel transition-metal-catalyzed
coupling/cyclization reaction when terminal alkynes were
applied under alkalinic conditions via the intermediacy of 3-
alkynylindoles Int-B, and base is responsible for the both steps.
Herein, we disclose our recent observations.
Received: January 14, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Letter
4a when using 2.5 equiv of K2CO3 (Table 1, entries 13−16).
Thus, Pd(PPh3)2Cl2 (2 mol %), CuI (2 mol %), and K2CO3 (2.5
equiv) in the mixed solvent (THF/MeOH = 1:1) at 50 °C have
been defined as the optimized reaction conditions for scope
study.
Table 2. Pd/Cu Co-catalyzed One-Pot Synthesis of
Polysubstituted Carbazoles 3 from Iodoindoles 1 and
Terminal Alkynes 2
a
Table 1. Optimization of the Reaction Conditions for the Pd/
Cu Co-catalyzed Cross-coupling Reaction and
Cycloisomerization of Iodoindole 1a with Phenylacetylene
2a.
b
entry
R1 (1)
R2 (2)
Ph (2a)
time (h) yield of 3 (%)
a
1
2
3
4
5
6
7
8
9
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
5-F (1b)
5-Cl (1c)
6-Cl (1d)
6
10
6
72 (3a)
68 (3b)
70 (3c)
74 (3d)
76 (3e)
68 (3f)
71 (3g)
80 (3h)
3-MeC6H4 (2b)
3-ClC6H4 (2c)
3-H2NC6H4 (2d)
4-MeC6H4 (2e)
4-ClC6H4 (2f)
4-nC5H11C6H4 (2g)
2-thienyl (2h)
3-thienyl (2i)
10
7
7
b
yield (%)
10.5
6
c
entry
base (equiv)
solvent
4a
3a
1a recovered
c
c
6
71 (3i)
1
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
Et3N (2.0)
MeOH
MeOH
MeOH
THF
16
58
73
d
10
nC5H11 (2k)
14
6
42 (3p)
62 (3j)
52 (3k)
53 (3l)
2
4
d
11
12
13
4-MeC6H4 (2e)
4-MeC6H4 (2e)
4-MeC6H4 (2e)
3
99
49
5
4
99
46
96
82
98
6
5
5
toluene
dioxane
EtOH
1
a
6
The reaction was conducted at 50 °C in the mixed solvent (THF/
MeOH = 1:1) with 1 (0.30 mmol, c = 0.15 M), 2 (0.45 mmol) and
K2CO3 (0.75 mmol) in the presence of Pd(PPh3)2Cl2 (2 mol %) and
CuI (2 mol %). Yield of isolated product. Isolated yield after
chromatography on silica gel and then recrystallization from
dichloromethane and petroleum ether. K2CO3 (3.5 equiv) was used.
7
18
8
MeCN
b
c
e
9
mixed
75
8
e
10
11
12
13
14
15
16
mixed
82
98
d
e
Na2CO3 (2.0)
Cs2CO3 (2.0)
mixed
e
mixed
54
Scheme 2. Gram-Scale Reaction of 1a with 2d
e
mixed
96
e
K2CO3 (1.0)
K2CO3 (2.5)
K2CO3 (3.0)
mixed
90
10
82
68
e
mixed
e
mixed
a
The reaction was conducted in solvent (2 mL) with 1a (0.30 mmol),
2a (0.45 mmol) and base in the presence of Pd(PPh3)2Cl2 (2 mol %)
b
and CuI (2 mol %). Determined by 1H NMR analysis with
c
nitromethane as the internal standard. The reaction was carried out at
d
e
40 °C. The reaction was carried out at room temperature. THF/
MeOH = 1:1.
With the optimal reaction conditions in hand, we then turned
to investigating the substrate scope. First, differently substituted
terminal aryl-substituted alkynes together with iodoindole 1a
were examined: the analogues substituted with m-Me, m-Cl, p-
Me, p-Cl, and p-nC5H11 groups all afforded good yields of the
products, exhibiting diversity (Table 2, entries 2, 3, and 5−7). It
is worth mentioning that free p-NH2 substituent on the benzene
ring was observed to be compatible under the standard reaction
conditions, affording the corresponding product 3d in 74%
(Table 2, entry 4). The reaction worked equally well using
heteroaryl-substituted terminal alkynes: 2-thienyl- and 3-thienyl-
substituted alkynes produced 3h and 3i in 80% and 71% yields,
respectively (Table 2, entries 8 and 9). Furthermore, alkyl-
substituted alkyne could also be successfully employed (Table 2,
entry 10). Notably, different R1 groups, such as fluoro and chloro
substituents at the 5-position (Table 2, entries 11 and 12) and the
chloro substituent at the 6-position (Table 2, entry 13) may be
introduced to the indole unit, leading to the corresponding
carbazole derivatives in moderate to good yields.
Figure 1. ORTEP representation of 3a.
3a−l and 3p were determined by the X-ray single-crystal
diffraction study of 3a (Figure 1).13
Further studies were focused on the coupling/cyclization
reaction using TMS-substituted (TMS = trimethylsilyl)
acetylene (2j) with differently substituted 3-iodioindoles 1 in a
two-step manner given the fact that TMS-acetylene was unstable
under K2CO3/MeOH conditions (Scheme 3). When R3 was H
It is easy to conduct the reaction of 1a and 2d to afford 3d in
77% yield on a 1-g scale (Scheme 2). The structures of products
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Letter
or Ph, the corresponding desilylated products 3m and 3n were
also formed in good yields, 70% and 72%, respectively.
Moreover, substrate with a chloro substituent at the 5-position
of the indole unit afforded carbazole derivative in a relatively
lower yield (50%).
Scheme 5. Mechanistic Studies
Scheme 3. Reactions of Iodoindoles 1 with TMS-Substituted
Acetylene 2j (TMS = Trimethylsilyl)
the copper acetylide Int-2 generated from phenylacetylene 2e
and CuI in the presence of base would afford the palladium
complex Int-3. Reductive elimination of Int-3 gives rise to the
coupling product 4e,16 which has been identified in the previous
mechanistic studies (see Scheme 5). The presence of K2CO3
would lead to deprotonation of 4e resulting in the formation of
Int-4, which was followed by isomerization and protonation to
generate the intermediate Int-5.17 Finally, 6π-electrocyclization
of Int-5 afforded the intermediate Int-6. Subsequent isomer-
ization involving aromatization afforded carbazole derivative 3e-
d′. Base was observed to be essential for both of the coupling and
cyclization steps.
Finally, the structure of the products 3m−o was determined by
the X-ray single-crystal diffraction study of 3m (Figure 2).14
Scheme 6. A Possible Mechanism
Figure 2. ORTEP representation of 3m.
In order to show the synthetic potential of the current method,
4-(3-aminobenzyl)-3-phenyl-9-tosyl-9H-carbazole (3d) was
treated with KOH/EtOH at 80 °C for 12 h to afford the NH
carbazole derivative 5 in 86% yield (Scheme 4).15
Scheme 4. Detosylation of 3d
To investigate the mechanism, the reaction was conducted in
THF with Et3N as the base, and the coupling product 4e was
obtained in 71% isolated yield. Subsequent treatment of 4e in
MeOH at 50 °C for 5 h afforded a trace amount of the expected
carbazole product 3e, with 99% recovery of 4e (Scheme 5 (a)).
However, when 4e was treated with K2CO3 in methanol-d4 at 50
°C, the corresponding products (3e/3e-d/3e-d′ = 7:40:53) were
obtained in 73% combined yield, indicating the intermediacy of
3-alkynylindole 4e and the fact that K2CO3 was indispensable for
the cyclization step (Scheme 5 (b)).
On the basis of these results, a mechanism was proposed to
explain the coupling/cyclization reaction affording poly-
substituted carbazoles (Scheme 6): Oxidative addition of 3-
iodoindole 1a with Pd(0) followed by a transmetalation step with
In conclusion, we have developed a Pd/Cu-cocatalyzed one-
pot reaction for the synthesis of polysubstituted carbazoles from
2-allyl-3-iodo-1-tosyl-1H-indoles and terminal alkynes. The
coupling/cyclization approach is highly efficient and proceeds
via sequential carbon−carbon coupling, isomerization, and
cyclization involving aromatization forming a benzene ring.
The role of the base effect has been identified in both steps of the
coupling and cyclization. This chemistry will be of great interest
to organic and medicinal chemists for further studies in this area.
Further studies are currently underway in our laboratory.
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(c) Liu, T.-P.; Xing, C.-H.; Hu, Q.-S. Angew. Chem., Int. Ed. 2010, 49,
2909. (d) Jia, Z.-X.; Luo, Y.-C.; Wang, Y.; Chen, L.; Xu, P.-F.; Wang, B.
Chem.Eur. J. 2012, 18, 12958. (e) Cai, Q.; Liang, X.-W.; Wang, S.-G.;
Zhang, J.-W.; Zhang, X.; You, S.-L. Org. Lett. 2012, 14, 5022.
(10) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
(11) For selected examples, see: (a) Roesch, K. R.; Larock, R. C. Org.
Lett. 1999, 1, 553. (b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67,
1905. (c) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86.
(d) Zhu, C.; Ma, S. Org. Lett. 2013, 15, 2782. (e) Kim, H.; Lee, K.; Kim,
S.; Lee, P. H. Chem. Commun. 2010, 46, 6341.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: masm@sioc.ac.cn.
Notes
(12) Zhu, C.; Zhang, X.; Lian, X.; Ma, S. Angew. Chem., Int. Ed. 2012,
51, 7817.
The authors declare no competing financial interest.
(13) Crystal data for 3a: C32H25NO2S, MW = 487.59, monoclinic,
space group P2(1)/c, final R indices [I > 2σ(I)], R1 = 0.0572, wR2 =
0.1336, R indices (all data), R1 = 0.0643, wR2 = 0.1379, a = 10.2775(6)
Å, b = 11.5290(7) Å, c = 21.0711(12) Å, α = 90.00°, β = 101.4250(10)°,
γ = 90.00°, V = 2447.2(2) Å3, T = 293(2) K, Z = 4, reflections collected/
unique: 13011/4813 (R(int) = 0.0240), no. of observations [>2σ(I)]
4318; parameter: 326. Supplementary crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre. CCDC
979538 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(14) Crystal data for 3m: C20H17NO2S, MW = 335.41, monoclinic,
space group P2(1)/c, final R indices [I > 2σ(I)], R1 = 0.0448, wR2 =
0.1114, R indices (all data), R1 = 0.0564, wR2 = 0.1185, a = 12.928(2) Å,
b = 11.9718(19) Å, c = 11.6528(18) Å, α = 90.00°, β = 114.040(2)°, γ =
90.00°, V = 1647.1(4) Å3, T = 293(2) K, Z = 4, reflections collected/
unique: 8407/3231 (R(int) = 0.0208), no. of observations [>2σ(I)]
2629; parameter: 219. Supplementary crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre. CCDC
979539 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
ACKNOWLEDGMENTS
■
Financial support from National Basic Research Program
(2011CB808700) and National Natural Science Foundation of
China (21232006). We thank Mr. Y. Qiu of our research group
for reproducing the results of 3d and 3k of Table 2 and 3n of
Scheme 3.
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