Carbazoles via AuCl3-catalyzed cyclization of 1-(indol-2-yl)-3-alkyn-1-ols

Article abstract of DOI:10.1021/ol3029498

AuCl₃-catalyzed reaction of 1-(indol-2-yl)-3-alkyn-1-ols occurred smoothly in toluene at room temperature to form a benzene ring leading to a series of carbazole derivatives efficiently. A possible mechanism has been proposed for the formation of carbazoles.

Full text of DOI:10.1021/ol3029498

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6198–6201
Carbazoles via AuCl3‑Catalyzed
Cyclization of 1‑(Indol-2-yl)-3-alkyn-1-ols
Youai Qiu, Wangqing Kong, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, Zhejiang, P. R. China
masm@sioc.ac.cn
Received October 26, 2012
ABSTRACT
AuCl3-catalyzed reaction of 1-(indol-2-yl)-3-alkyn-1-ols occurred smoothly in toluene at room temperature to form a benzene ring leading to a
series of carbazole derivatives efficiently. A possible mechanism has been proposed for the formation of carbazoles.
Carbazolesare important heteroaromatic compoundsin
many biologically active products.1 They also serve as
building blocks for potential electroluminescent materials2
due to their electrical3 and thermal4 properties and host
materials for triplet emitters in organic light-emitting
diodes.5 Therefore, they are attractive targets for organic
synthesis. Although there are a number of useful synthetic
procedures to prepare carbazoles,6ꢀ9 there remain some
limitations such as low yields, poor atom economy, and
harsh reactionconditionsin these methods. Thus, a simple,
mild, efficient, regiocontrolled, and diversified preparation
of carbazole alkaloids with specific substitution patterns is
still highly desirable.
On the other hand, the intramolecular hydroarylation
reaction of alkyne is of particular interest, since valuable
carbo- and heterocycles can be readily formed under rela-
tively mild conditions.10ꢀ12 For example, gold- or platinum-
catalyzed cyclization reactions of indoles with alkynes are
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r
10.1021/ol3029498
Published on Web 12/10/2012
2012 American Chemical Society

important because significant molecular complexity can be
obtained in one step starting from an easily accessible
system.13,14
Our initial investigation focused on the reaction of 1-(1-
ethyl-1H-indol-2-yl)-2-methyl-4-phenyl-3-butyn-1-ol (2a)
in toluene under the catalysis of PtCl2 (5 mol %). Inter-
estingly, 9-ethyl-2-methyl-4-phenyl-9H-carbazole (3a) was
indeed formed in 62% NMR yield (entry 1, Table 1).
When AgOTf was used instead of PtCl2, the yield of this
reaction was only 35% (entry 2, Table 1), and Zn(OTf)2
was totally inactive (entry 3, Table 1). However, the
combined use of AuCl(PPh3) and AgOTf as catalyst
could improve the yield to 87% (entry 4, Table 1). AuCl-
(t-Bu3P)/AgOT catalyzed this transformation afford-
ing 3a in 88% yield (entry 5, Table 1). Further study
Recently, we developed a route to construct carbazole
alkaloids via the Pt-catalyzed cyclization of terminal 1-
(indol-2-yl)-2,3-allenols 1 (Scheme 1),15 which may be
easily prepared from the In-mediated reaction of indole-
2-carbaldehydes and primary 1-alkynyl bromides in an
aqueous phase.15,16 Interestingly, 1-(indol-2-yl)-3-alkyn-1-
ols 2 were formed when non-terminal secondary 1-alky-
nyl bromides were used.17 Considering our interests in
synthesis of heterocyclic compounds, we reasoned that
cyclization of homoproparylic alcohols 2 may also
afford carbazole alkaloids following a similar elimina-
tion of water to form the aromatic ring15 (Scheme 1).
In this paper, we report our observation of such a
reaction.
18
showed that AuCl3 is the best catalyst for this reac-
tion, affording 3a in 93% yield (entry 6, Table 1)!
Several solvents were also tested for the AuCl3-catalyzed
reaction of 2a at room temperature with toluene still
being the best (entries 7ꢀ9, Table 1). When 1 mol % of
AuCl3 was used, the yield of 3a was slightly lower (entry
10, Table 1). Thus, we defined the standard conditions
as follows: 5 mol % of AuCl3 in toluene at room tem-
perature (entry 6, Table 1). The structure of 3a was
further confirmed by the X-ray crystal diffraction study
(Figure 1).19
Scheme 1
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst (5 mol %)
PtCl2
solvent time (h) yieldb of 3a (%)
1
2
toluene
toluene
toluene
toluene
36
23
12
12
12
3
62
35
0
(10) For reviews of hydroarylation of alkynes, see: (a) Nevado, C.;
Echavarren, A. M. Synthesis 2005, 167. (b) Bandini, M.; Eichholzer, A.
Angew. Chem., Int. Ed. 2009, 48, 9608. (c) Skouta, R.; Li, C.-J. Tetra-
hedron 2008, 64, 4917. (d) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008,
AgOTf
3
Zn(OTf)2
4
AuCl(PPh3)/AgOTf
87
88
93
36
51
85
82
€
108, 3239. (e) Shen, H. C. Tetrahedron 2008, 64, 3885. (f) Furstner, A.;
ꢀ
Davies., P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (g) Jimenez-
5
AuCl(t-Bu3P)/AgOTf toluene
ꢀ~
Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (h) Hashmi,
6
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
toluene
CH2Cl2
CH3CN
acetone
toluene
A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (i)
Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (j) Krause, N.; Winter, C.
Chem. Rev. 2011, 111, 1994. (k) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
7
5
8
5
ꢀ
ꢀ~
Chem. Rev. 2008, 108, 3351. (l) Jimenez-Nunez, E.; Echavarren, A. M.
9
10c
5
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Chem. Rev. 2008, 108, 3326. (m) Chianese, A. R.; Lee, S. J.; Gagne, M. R.
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a The reaction was conducted with 0.2 mmol of 2a and 0.01 mmol of
catalyst in 1 mL of solvent. b Determined by 1H NMR of crude product
using dibromomethane as internal standard. c AuCl3(1 mol %) was used.
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M.; Cheng, C.-H. Chem.;Eur. J. 2007, 13, 8285. (b) Lu, Y.; Du, X.; Jia,
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Angew. Chem., Int. Ed. 2006, 45, 1105. (b) Ferrer, C.; Amijs, C. H. M.;
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Org. Lett., Vol. 14, No. 24, 2012
6199

followed by nucleophilic attack of indolyl C3 to the
metal-activated electrophilic CꢀC triple bonds. The six-
membered intermediate M2 may be afforded via deme-
talation of M1 regenerating the catalytically active Au3þ
species. Subsequent elimination of H2O would afford the
target carbazole 3.15,12l,23
Scheme 2
Figure 1. ORTEP representation of 3a.
This new transformation is quite general, and some
typical results are listed in Table 2. The 1-position of
indoles may be substituted with alkyl (entries 1ꢀ7, 9 and
10, Table 2) orbenzylgroups(entries 8, 11and 12, Table2).
Substituents on the 5-position could be methyl (entries
4ꢀ6, Table 2), methoxy, which is the vital functional group
for the synthesis of many natural tricyclic carbazole alka-
loids21 (entry 7, Table 2), or bromine,20 which could easily
transform to many useful functional groups in the synthesis
ofbiologicallyactivecarbazolealkaloids21 (entry8,Table2).
Substituents may also be introduced to the 4- or 7-position
(entries 9ꢀ10, Table 2). R3 could be an alkyl (entries 1ꢀ5
and 7ꢀ12, Table 2) or an aryl group (entry 6, Table 2).
Moreover, R4 could be an alkyl (entries 2ꢀ4, 6, 7, 9, and 11,
Table 2) or an aryl group (entries 1, 5, 8, 10, and 12,
Table 2).
In conclusion, we have developed a simple and mild
AuCl3-catalyzed reaction of 1-(indol-2-yl)-3-alkyn-1-ols to
provide an efficient route to differently substituted carba-
zoles in moderate to good yields under very mild condi-
tions. A rationale hasalso been proposedfor the formation
of carbazoles. Because of the easy availability of the
starting materials and potential of the products, this
method would be useful in organic synthesis and medicinal
chemistry. Further studies on the synthetic applications of
this reaction are being carried out in our laboratory.
Table 2. AuCl3-Catalyzed Cyclization Reaction of
1-(Indol-2-yl)-3-alkyn-1-ols 2a
Acknowledgment. Financial support from the Major
State Basic Research and Development Program
(2009CB825300) and the National Natural Science
(15) (a) Kong, W.; Fu, C.; Ma, S. Chem. Commun. 2009, 4572. (b)
Kong, W.; Fu, C.; Ma, S. Chem.;Eur. J. 2011, 17, 13134. (c) Kong, W.;
Fu, C.; Ma, S. Org. Biomol. Chem. 2012, 10, 2164. (d) Kong, W.; Qiu, Y.;
Fu, C.; Ma, S. Adv. Synth. Catal. 2012, 354, 2399.
entry
2
R1, R2, R3, R4
time (h)
yieldb of 3 (%)
(16) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C.
Eur. J. Org. Chem. 2005, 98. (b) Kong, W.; Fu, C.; Ma, S. Org. Biomol.
Chem. 2008, 6, 4587.
(17) (a) Lee, P. H.; Kim, H.; Lee, K. Adv. Synth. Catal. 2005, 347,
1219. (b) Patman, R. L.; Williams, V. M.; Bower, J. F.; Krische, M. J.
Angew. Chem., Int. Ed. 2008, 47, 5220. (c) Masuyama, Y.; Watabe, A.;
Kurusu, Y. Synlett 2003, 11, 1713.
(18) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285.
(19) Crystal data for compound 3a: C21H19N, MW = 285.37,
monoclinic, space group P21, final R indices [I > 2σ(I)], R1 =
0.0395, wR2 = 0.0972, R indices (all data) R1 = 0.0590, wR2 =
1
2
2a Et, H, Me, Ph
2b Et, H, Me, Et
3
3a, 90
3b, 81
3c, 74
3d, 72
3e, 79
3f, 64
3g, 60
3h, 72
3i, 65
3j, 90
3k, 58
3l, 62
12
3
2c
Et, H, Me, n-C4H9
19.5
11.5
14
4
2d Et, 5-Me, Me, n-C4H9
2e Et, 5-Me, Et, Ph
5
6
2f
Et, 5-Me, Ph, n-C4H9
11
7
2g Et, 5-OMe, Me, n-C4H9
2h Bn, 5-Br, Et, Ph
11.5
13
8
9
2i
2j
Et, 4-Me, Me, n-C4H9
3
10
11
12
Et, 7-Me, Me, Ph
12
˚
˚
˚
0.0889, a = 8.9461(6) A, b = 8.9810(6) A, c = 20.0010(13) A, R =
3
˚
2k PMB, H, Me, n-C4H9
2l Bn, H, Et, Ph
12
90°, β = 90.115(5)°, γ = 90°, V = 1606.98(18) A , T = 293(2) K, Z = 4,
reflections collected/unique: 8159/4822 (Rint = 0.0252), number of
observations [> 2σ(I)] 3681, parameters: 402. CCDC 906003.
(20) For the orthogonality of gold and palladium catalysis, see:
12
a Reaction conditions: 0.2 mmol of 1-(indol-2-yl)-3-alkyn-1-ols 2,
€
0.01 mmol of AuCl3 in 1 mL of toluene. b Isolated yield.
€
Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Ackermann, M.; Becker,
J. D. B.; Rudolph, M.; Scholz, c.; Rominger, F. Adv. Synth. Catal. 2012,
354, 133.
A mechanism is proposed for the reaction (Scheme 2).10,15,22
The reaction of Au3þ with 2 would form intermediate M1
via the coordination of the alkyne with the Au3þ species
€
(21) Schmidt, A. W.; Reddy, K. R.; Knolker, H. J. Chem. Rev. 2012,
110, 3193.
(22) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(23) Hashmi, A. S. K.; Wolfle, M. Tetrahedron 2009, 65, 9021.
€
6200
Org. Lett., Vol. 14, No. 24, 2012

Foundation of China (21232006) is greatly appreciated.
S.M. is a Qiu Shi Adjunct Professor at Zhejiang Uni-
versity. We thank Ms. X. Xie in our group for repro-
ducing the results presented in entries 4, 5, and 9 of
Table 2.
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6201