Bronsted acid mediated tandem diels-alder/ aromatization reactions of vinylindoles

Article abstract of DOI:10.1021/jo900104r

A Bronsted acid catalyzed tandem Diels - Alder/aromatiza-tion reaction of 2-vinylindoles has been developed. The reaction provides a highly efficient and concise approach to 3-indolyl-substituted tetrahydrocarbazoles with various substituents in high yiel

Full text of DOI:10.1021/jo900104r

variety of reactions because of their facile accessibility, easy
operation, and stability against moisture and oxygen.5 Despite
advances,6 the search for Brønsted acid promoted tandem sequences
that allow increasingly rapid access to structural complexity remains
a preeminent goal.
Brønsted Acid Mediated Tandem Diels-Alder/
Aromatization Reactions of Vinylindoles
Cai-Bao Chen, Xu-Fan Wang, Yi-Ju Cao,
Hong-Gang Cheng, and Wen-Jing Xiao*
The tetrahydrocarbazole architecture widely exists in various
naturally occurring alkaloids and synthetic analogues of me-
dicinal importance,7-9 some of which can be potentially used
Key Laboratory of Pesticide and Chemical Biology, Ministry
of Education, College of Chemistry, Central China Normal
UniVersity, 152 Luoyu Road, Wuhan, Hubei 430079, China
(3) For selected reviews on organocatalytic domino reactions, see: (a) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b)
Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
wxiao@mail.ccnu.edu.cn
ReceiVed January 16, 2009
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A Brønsted acid catalyzed tandem Diels-Alder/aromatiza-
tion reaction of 2-vinylindoles has been developed. The
reaction provides a highly efficient and concise approach to
3-indolyl-substituted tetrahydrocarbazoles with various sub-
stituents in high yields under mild conditions.
The development of new catalytic transformations for the
construction of “privileged” structural motifs presented in biologi-
cally active compounds or natural isolates is of considerable current
interest.1 Many advances in this endeavor have focused on metal-
catalyzed tandem, domino, or cascade reactions, in which multiple
bond formations can be realized in a highly concise fashion in
contrast to traditional “step-by-step” operations.2 More recently,
significant efforts have been made to develop organocatalytic
variants of such processes.3,4 In this context, the employment of
Brønsted acids as catalysts has proven to be highly popular in a
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134. (b) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 5962.
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2005, 44, 1602. (d) Zhu, J.; Benayme´, H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005. (e) Tietze, L. F.; Brasche, G.; Gericke, K. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (f) Guo, H.-C.;
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2006, 62, 1619. (h) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1.
3532 J. Org. Chem. 2009, 74, 3532–3535
10.1021/jo900104r CCC: $40.75 2009 American Chemical Society
Published on Web 03/31/2009

as tumor growth inhibitors and protein kinase C inhibitors.10
As a consequence, many elegant methods for the preparation
of various tetrahydrocarbazole derivatives have been developed
in the past years,11 including reductive cyclization of 2-nitrobi-
phenyl,11q-s Pd-catalyzed oxidation cyclization of 3-(3′-
alkenyl)indoles,11tintramoleculararylationofN,N-diaryl-amines,11u,v
and alkyllithium-mediated intramolecular anionic cyclization.11w
However, many of these methods involve harsh reaction
conditions, expensive reagents, complex handling, and low
yields of products. Thus, it was desirable to develop operation-
ally simple, more efficient, and practical catalytic approaches
for the construction of tetrahydrocarbazoles. As part of our
ongoing project on the synthesis of carbo- and heterocyclic
compounds,12 we report herein a straightforward method for
the preparation of 3-indolyl-substituted tetrahydrocarbazole
derivatives by trifluoroacetic acid (TFA)-catalyzed tandem
Diels-Alder/aromatization reactions of 2-vinylindoles.
Initial studies were focused on examining the feasibility of
the tandem reaction and at optimizing reaction conditions that
could be applied to various vinylindoles. The reaction of
1-benzyl-2-vinyl-1H-indole (1a) was chosen as a model reaction
and a series of Brønsted acid catalysts (Table 1) were tested.
The catalyst screening indicated that trichloroacetic acid,
p-toluenesulfonic acid monohydrate, trifluoromethanesulfonic
acid, perchloric acid, and (()-camphorsulfonic acid could
efficiently promote the transformation to generate 9-benzyl-3-
(1-benzyl-1H-indol-2-yl)-2,3,4,9-tetrahydro-1H-carbazole (2a)
TABLE 1. Optimization of Brønsted Acid Catalysts in the
Tandem Diels-Alder Cyclization/Aromatization Sequencea
entry
acid
time
yield (%)b
1
Cl3CCO2H
TsOH·H2O
TfOH
70 min
50 min
30 min
55 min
60 min
7 h
3 min
72 h
72 h
68
61
72
96
90
95
94
tr
2c
3d
4
HClO4
5e
6
7
(()-CSA
NCCH2CO2H
TFA
CH3CO2H
DNBA
8
9f
10g
tr
tr
(()-BNP-H
120 h
a Reaction conditions: 1a (0.25 mmol), acid (0.075 mmol), CH2Cl2
(0.5 mL). b Isolated yield. c TsOH·H2O: p-toluenesulfonic acid
monohydrate. d TfOH: trifluoromethanesulfonic acid. e (()-CSA: (()-
camphorsulfonic acid. f DNBA: 3,5-dinitrobenzoic acid. g (()-BNP-H:
(()-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate.
TABLE 2. Effect of Solvent and Catalyst Loading on Tandem
Diels-Alder/Aromatization of 1aa
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entry
solvent
CHCl3
ClCH2CH2Cl
CH2Cl2
toluene
CH3CN
Et2O
t-BuOMe
DMF
MeOH
i-PrOH
CH2Cl2
CH2Cl2
TFA (mol %)
time (min)
yield (%)b
1
2
3
4
5
6
7
30
30
30
30
30
30
30
30
30
30
10
5
5
5
3
68
70
94
70
82
53
43
NR
NR
NR
92
83
5
30
300
300
8c
9c
10c
11
12
5
60
a Reaction conditions: 1a (0.25 mmol), TFA (0.0125-0.075 mmol),
solvent (0.5 mL). b Isolated yield. c No reaction.
in good to excellent yields (Table 1, entries 1-5). In particular,
TFA proved to be the most effective catalyst for this tandem
Diels-Alder/aromatization reaction in dichloromethane at room
temperature in terms of the yield (94%) and the reaction time
(3 min) (Table 1, entry 7). Cyanoacetic acid is also an excellent
catalyst for this reaction; however, the reaction takes a longer
time for completion (Table 1, entry 6). Other Brønsted acids,
such as acetic acid (Table 1, entry 8), 3,5-dinitrobenzoic acid
(Table 1, entry 9), and (()-1,1′-binaphthyl-2,2’-diyl hydrogen
phosphate (Table 1, entry 10), were not effective for this
transformation, and the starting material was recovered.
As shown in Table 2, the tandem Diels-Alder/aromatization
reaction of 1a is readily accomplished in a wide variety of
solvents. Using TFA as the catalyst, we found that the reaction
works well in halogenated solvents (entries 1-3), toluene (entry
4), or CH3CN (entry 5) but less so in diethyl ether (entry 6) or
(12) (a) Chen, J.-R.; Li, C.-F.; An, X.-L.; Zhang, J.; Zhu, X.-Y.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2008, 47, 2489. (b) Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.;
An, J.; Yao, C.-J.; Ming, Z.-H.; Xiao, W.-J. J. Am. Chem. Soc. 2008, 130, 6946.
(c) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett.
2007, 9, 1847.
J. Org. Chem. Vol. 74, No. 9, 2009 3533

TABLE 3. Scope of TFA-Mediated Tandem Diels-Alder/
SCHEME 1. Possible Pathway for Brønsted Acid Mediated
Tandem Diels-Alder/Aromatization Sequence
Aromatization Reactions of 2-Vinylindolesa
substrate
entry
R1
R2
R3
product time (min) yield (%)b
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
5
10
60
15
30
120
90
150
5
90
180
30
540
10
10
360
180
180
24 h
92
83
65
84
85
93
68
65
63
90
90
88
69
90
82
85
70
74
47
5-MeO
5-Cl
5-F
5-Me
5-F
5-Cl
5-Br
H
Bn
Me
Me
Me
Me
Me
Me
Me
Me
allyl
allyl Me
H
Bn
Bn
Ts
9
substituted indoles can readily participate in the reaction without
significant loss in reaction efficiency (entries 8 vs 13, and 10
vs 11). Note that the internal vinyl indoles employed were
isomeric mixtures and the reactions afforded the corresponding
diastereoisomeric products. Perhaps more importantly, the
2-vinylindole without the protecting group on the nitrogen atom
successfully underwent the cyclization to generate the expected
product in 85% yield with great diastereoselectivity (entry 16).
Furthermore, 2-vinylindoles bearing two substituents with
different electronic properties were found to be quite reactive
(entries 17 and 18). The structure of 2 was proposed by NMR
and unambiguously confirmed by X-ray diffraction of 2e as the
representative.14
10
11c
12c
13c
14
15c
16c
17
18
19d
5-MeO
Me 5-MeO
Me
Me 5-Br
H
H
H
H
H
Me
H
H
4-Cl-7-Me
6-Cl-7-Me
5-MeO
H
a Reaction conditions: vinylindole (0.25 mmol), TFA (0.025 mmol),
CH2Cl2 (0.5 mL). b Isolated yield. c The diastereoselectivity of product
was determined by 1H NMR; see Supporting Information. d Ts:
p-toluenesulfonyl.
On the basis of these results, a possible pathway for the
Brønsted acid mediated tandem Diels-Alder/aromatization
reactions of 2-vinylindoles is outlined in Scheme 1. The
protonation of the C(3)-position of the vinylindole (1) may
generate an iminium intermediate I, which undergoes Diels-Alder
reaction with another 2-vinylindole 1 to generate intermediate
II. The subsequent aromatization of intermediate II would afford
3-indolyl-substituted tetrahydrocarbazole (2), with regeneration
of the catalyst.15
To support this proposed mechanism, we have carried out
D-labeling experiments. When 1.0 equiv of deuterated TFA was
used in the reaction of 1a, the corresponding deuterated product
2a′ was obtained in 90% isolated yield with almost 100% D
incorporation at the 3′-position (eq 1).
tert-butyl methyl ether (entry 7). Highly polarized aprotic
solvents such as DMF (entry 8) or polar protonic solvents such
as MeOH and i-PrOH (entries 9 and 10) proved detrimental for
this tandem sequence. As shown in entry 11, lower catalyst
loading (10 mol %) was possible without significant loss in
reaction efficiency. Further decreasing the catalyst loading to 5
mol % resulted in somewhat lower yield and extended reaction
time (entry 12). Accordingly, the superior levels of reaction
efficiency observed with 10 mol % of TFA in CH2Cl2 at room
temperature (92% yield in 5 min) prompted us to select these
reaction conditions for further exploration.
Experiments that probe the scope of the vinylindole compo-
nent are summarized in Table 3. The reaction appears quite
general with respect to the nature of the nitrogen substituents
(R1 ) Bn, Me, allyl, p-toluenesulfonyl). This tandem process
is also general with respect to indole architecture. Incorporation
of alkyl and alkoxy substituents at the C(5)-indole position
reveals that electronic modification of the indole ring can be
accomplished with little influence on reaction yield (entries 2,
5, 10, and 11). Moreover, we have successfully utilized electron-
deficient substrates in the context of 5-halogen-substituted
vinylindoles (entries 3, 4, 6-8, and 13). Such halogenated
3-indolyl-substituted tetrahydrocarbazoles should be valuable
synthons for further functional group transformation with the
use of organometallic technologies.13 The reaction appears quite
tolerant with respect to the steric contribution of the olefin
substituent of the substrate. Both terminal and internal vinyl-
Furthermore, cross Diels-Alder/aromatization reactions of two
different 2-vinylindole components were also performed. First,
a relatively more active 2-vinylindole 1a and a less active 1f
were subjected to the optimal reaction conditions. According
to the above suggested mechanism, the protonation of more
electron-enriched 1a will be favorable to generate dienophile
3. Subsequent Diels-Alder/aromatization with more active 1a
will result in the formation of 2a. When substrate 1a is totally
consumed, the same reaction of 1f will occur and afford product
2f (eq 2).
(13) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508, and references therein.
3534 J. Org. Chem. Vol. 74, No. 9, 2009

which provide a highly concise route to the preparation of
synthetically important tetrahydrocarbazole derivatives in good
to excellent yields. The broad substrate scope, short reaction
time, high yield, mild reaction conditions and operational
simplicity make this protocol very useful and attractive.
Experimental Section
General Procedure for the TFA-Catalyzed Diels-Alder/
Aromatization. To a stirred solution of 2-vinylindole 1a (58.3 mg,
0.25 mmol) in CH2Cl2 (0.5 mL) was added TFA (1.9 µL, 0.025
mmol) at room temperature, and the color of the mixture changed
from colorless to dark purple immediately. After the reaction was
completed (TLC), the reaction mixture was subjected to flash
column chromatography on silica gel with petroleum ether/ethyl
acetate (15:1) as eluent to obtain 2a as a white solid (53.6 mg,
Then, an experiment of two vinylindoles with similar activity
was carried out. As expected, a cross-product was indeed
isolated in 49% isolated yield (eq 3).14 These results are
consistent with the proposed mechanism.
1
92%): mp 85-87 °C; H NMR (600 MHz, CDCl3) δ 2.05-2.09
(m, 1H), 2.20 (d, J ) 12.0 Hz, 1H), 2.64-2.74 (m, 2H), 2.94-2.98
(m, 1H), 3.13-3.19 (m, 2H), 5.24 (dd, J ) 16.8, 23.4 Hz, 2H),
5.41 (s, 2H), 6.45 (s, 1H), 6.95 (d, J ) 7.2 Hz, 2H), 6.99 (d, J )
7.2 Hz, 2H), 7.01-7.13 (m, 4H), 7.19-7.26 (m, 8H), 7.44 (d, J )
6.0 Hz, 1H), 7.59 (d, J ) 6.6 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ 21.9, 28.4, 29.7, 32.5, 46.2, 46.3, 98.2, 109.0, 109.5, 117.7, 119.0,
119.6, 120.0, 121.0, 125.7, 126.1, 127.2, 128.1, 128.7, 128.7, 134.8,
136.8, 137.0, 137.9, 138.0, 145.1. MS: m/z ) 466.5. Anal. Calcd
for C34H30N2: C, 87.52; H, 6.48; N, 6.00. Found: C, 87.46; H, 6.39;
N, 5.93.
In summary, we have developed Brønsted acid catalyzed
tandem Diels-Alder/aromatization reactions of 2-vinylindoles,
Acknowledgment. We are grateful to the National Science
Foundation of China (20672040 and 20872043) and the Program
for Academic Leader in Wuhan Municipality (200851430486)
for the support of this research.
(14) For the X-ray crystal structure of the representative compound 2e and
other details, please see Supporting Information.
(15) A possible product, 2′, was not found in this reaction presumably because
the nucleophilicity at the C3 position is greater than that at C2′ of the substrate
1.
Supporting Information Available: Typical experimental
procedures, spectroscopic details for all new compounds, and
1
copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900104R
J. Org. Chem. Vol. 74, No. 9, 2009 3535