Active thionium species mediated functionalization at the 2α-position of indole derivatives

Article abstract of DOI:10.1039/c1cc11645b

A combination of dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride (TFAA) mediates functionalization at the 2α-position of indole derivatives. Carbon and heteroatom nucleophiles were directly introduced via a one-pot procedure in excellent yields.

Full text of DOI:10.1039/c1cc11645b

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Active thionium species mediated functionalization at the 2a-position
of indole derivativesw
Kazuhiro Higuchi, Masanori Tayu and Tomomi Kawasaki*
Received 22nd March 2011, Accepted 26th April 2011
DOI: 10.1039/c1cc11645b
A combination of dimethyl sulfoxide (DMSO) and trifluoroacetic
anhydride (TFAA) mediates functionalization at the 2a-position
of indole derivatives. Carbon and heteroatom nucleophiles were
directly introduced via a one-pot procedure in excellent yields.
The active thionium species generated from sulfoxides and
electrophilic reagents is one of the important chemical
intermediates.1 Although many functionalized sulfoxides, such
as 1-benzenesulfinyl piperidine,2 methoxyphenyl benzene
thiosulfinate3 and diphenylsulfoxide,4 have been developed
for active thionium species mediated reactions, DMSO is still
an attractive sulfoxide5 for the potential utility of its simple
structure. In particular, the thionium species from DMSO–TFAA
combination is highly reactive and useful for various reactions:
Swern oxidation of alcohols,5d preparation of iminosulfuranes
with aromatic amines,6 formation of aryl dimethylsulfonium
salts with electron-rich aromatic compounds,7 methyl thiomethyl
etherification,8 and so on.
Fig. 1 Biologically active tetrahydrocarbazoles.
Recently, 1-functionalized tetrahydrocarbazoles have
attracted attention for their biological activities (Fig. 1). For
Initially, we studied the reaction of tetrahydrocarbazole and
the active thionium species generated from diphenylsulfoxide
and TFAA (Table 1). The reaction of N-unsubstituted tetra-
hydrocarbazole 1a resulted in a complex mixture (entry 1). In
the case of N-acetyl and N-methoxycarbonyl compounds,
1-methoxy tetrahydrocarbazoles 3b and 3c were obtained in
yields of 9% and 20%, respectively (entries 2 and 3).
example, 1-phenoxy, 1-benzylamino and 1-carboxymethyl
tetrahydrocarbazoles have been expected to have the potential
activity of a neuropeptide Y antagonist, an anti-human
papillomavirus agent and a prostaglandin D2 receptor antagonist,
respectively.9
To date, a variety of substitution reactions at the 1-position
of tetrahydrocarbazoles through 3-halogenated10–12 or
3-protonated indolenines13,14 have been reported.15 However,
these reactions are limited in terms of the scope of substituents
that can be introduced. Our research program previously
revealed intramolecular SN20 type displacement of carbazole-
sulfoxide under Pummerer reaction conditions using TFAA.16
We became interested that the thionium species activates the
electron-rich indole nucleus which induces following nucleo-
philic substitution. Herein we report that the combination of
DMSO–TFAA mediates a functionalization at the 1-position
of tetrahydrocarbazoles and 2a-position of indoles.
The use of the electron-donating p-methoxybenzyl (PMB)
group for N-protection increased the yield of 3d (32%)
together with the formation of dimer 4 in 33% yield (entry 4).
Next, the use of aryl–methyl sulfoxides improved the yield of
3d (57–80%) with decreasing the formation of 4 (9–15%)
(entries 5–7). N-PMB 1d was treated with DMSO–TFAA to
give 1-methoxy tetrahydrocarbazole 3d in 93% yield without
production of dimer 4 (entry 8). To the best of our knowledge,
this is the first example of an activated DMSO mediated
functionalization involving aromatic compounds.
A plausible reaction mechanism is shown in Scheme 1. The
reaction of sulfoxide 2 and TFAA generates the activated
thionium species 5, which is subjected to nucleophilic attack by
1d to produce thionium intermediate 6. After deprotonation at
the 1-position of tetrahydrocarbazole 6 to form enamine 7,
subsequent SN20 type reaction of 7 with MeOH occurs to give 3d.
Excess MeOH also attacks the sulfur atom of intermediates
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose,
Tokyo 204-8588, Japan. E-mail: kawasaki@my-pharm.ac.jp;
Fax: +81 42 495 8763; Tel: +81 42 495 8763
w Electronic supplementary information (ESI) available: General
synthetic procedures and NMR data of compounds. See DOI:
10.1039/c1cc11645b
c
6728 Chem. Commun., 2011, 47, 6728–6730
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Table 1 Screening of substrates and active thionium speciesz
Table 2 Optimization of the amount of nucleophile
Entry
MeOH (equiv.)
Time/min
Yielda (%)
1
2
3
4
10
10
10
30
30
93
95
72
66
5.0
2.0
1.0
a
Isolated yield.
2
Yielda (%)
R2
R3
3
4
Entry
1
R1
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1d
1d
1d
H
Ac
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
3a
3b
3c
3d
3d
3d
3d
3d
NDb
9
ND
ND
ND
33
15
10
CO2Me
PMB
PMB
PMB
PMB
PMB
20
32
57
74
80
93
Ph
p-Tol
p-Anc
Me
9
ND
a
b
c
Isolated yield, ND = Not detected, p-An = p-MeO–C6H4–.
Fig. 2 Application to other indole derivatives.
(Fig. 2). In the case of 6-methoxy- and 6-bromo-tetrahydrocarba-
zoles, the reactions proceeded smoothly to produce the 1-methoxy
tetrahydrocarbazoles 3e and 3f in 76% and 70% yields,
respectively. Cycloalkano[1,2-b]indoles also afforded compounds
3g and 3h in yields of 88% and 90%, respectively. A tetrahydro-
pyrido[1,2-a]indole derivative17 gave product 3i in 61% yield,
which is an important core structure in biologically active indole
derivatives such as vinpocetine and mitomycin. With 2-ethyl-3-
methylindole, the desired reaction occurred to give 3j in 82% yield.
As shown in Table 3, in addition to a methoxy group, various
substituents were able to be introduced at the 1-position of
tetrahydrocarbazole. p-Cresol and benzylamine were effectively
introduced to afford 3k and 3l in yields of 70% and 82%,
respectively (entries 1 and 2). In the case of TMSN3, the reaction
proceeded smoothly to give the azide compound 3m in quanti-
tative yield (entry 3). As a typical aromatic nucleophile,
N-methylindole was introduced to produce 3n in 97% yield
(entry 4). Next, the utility of representative alkyl Grignard
reagents was studied. Methyl magnesium bromide was effective
as a nucleophile for C–C bond formation at the 1-position of
tetrahydrocarbazole to furnish the methylated product 3o in 99%
yield (entry 5). Vinyl and allyl magnesium bromides were also
useful in this reaction to afford the C2- and C3-units introduced
products 3p and 3q in quantitative yields (entries 6 and 7).
In conclusion, we have developed the active thionium
species from DMSO–TFAA mediated functionalization
involving aromatic compounds. The key findings of this work
are (1) a new type of reaction utilizing the DMSO–TFAA
combination and (2) effective substitution at the 2a-position
Scheme 1 Plausible reaction mechanism for active thionium species
mediated reaction of 1d.
6 and 7 causing regeneration of 1d, which can take part in
nucleophilic attack on 7 to afford dimer 4.
Aiming to limit the excess use of MeOH (10 equivalents), we
next optimized the amount of MeOH before attempting to use
other nucleophiles in this reaction (Table 2). When 5.0 equi-
valents were used, the yield of 3d remained high at 95%
(entry 2). However, further reduction in the amount of MeOH
resulted in decreased yield of 3d (entries 3 and 4).
of indole derivatives with various nucleophiles via
a
With the optimized conditions in hand, we then studied the
application of this reaction to several other indole derivatives
one-pot procedure. Our direct functionalization methodology
will be able to contribute to the concise synthesis of
c
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Chem. Commun., 2011, 47, 6728–6730 6729

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Table 3 Introduction of various nucleophiles at the 1-position of
tetrahydrocarbazole 1d
TLC, MeOH (81 mL, 2.0 mmol) was added to the reaction mixture and
stirred for 10 min at the same temperature. The reaction was quenched
with saturated aqueous NaHCO3 (5.0 mL), and extracted with dichloro-
methane (20 mL ꢁ 3). The organic layer was washed with brine
(15 mL), dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica-gel column chromatography
(ethyl acetate/n-hexane = 1/15) to provide 3d (0.12 g) in 95% yield.
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70
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97
99
5
6
MeMgBr
Quant
Quant
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a
Isolated yield.
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Financial support from the High-Tech Research Center
Project, the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), Japan (S0801043), is gratefully
acknowledged. We thank N. Eguchi, T. Koseki, and S. Kubota
at the Analytical Center of our university for performing
microanalysis, NMR, and mass spectral measurements.
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Notes and references
z Representative procedure: under an argon atmosphere, a dichloro-
methane (2.0 mL) solution of tetrahydrocarbazole 1d (0.12 g, 0.40 mmol)
and DMSO (29 mL, 0.40 mmol) was treated with TFAA (56 mL, 0.40 mmol)
at ꢀ40 1C. When 1d was completely consumed by monitoring with
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c
This journal is The Royal Society of Chemistry 2011
6730 Chem. Commun., 2011, 47, 6728–6730