Gold- and indium-catalyzed synthesis of 3- and 6-sulfonylindoles from ortho-alkynyl-N-sulfonylanilines

Article abstract of DOI:10.1002/anie.200604038

(Chemical Equation Presented) Consecutive formation of C-N and C-S bonds: The gold-catalyzed intramolecular aminosulfonylation of 2-alkynyl-N- sulfonylanilines 1 (R¹ = H) produces 3-sulfonylindoles 2 in good to high yields, whereas the indium-c

Full text of DOI:10.1002/anie.200604038

Communications
DOI: 10.1002/anie.200604038
Cyclization
Gold- and Indium-Catalyzed Synthesis of 3- and 6-Sulfonylindoles from
ortho-Alkynyl-N-sulfonylanilines
Itaru Nakamura,* Uichiro Yamagishi, Dschun Song, Sayaka Konta, and Yoshinori Yamamoto
Sulfonylindoles are found in a wide variety of biologically
active compounds, such as L-737126[1] and RO4368554.[2]
However, it is difficult to synthesize sulfonylindoles directly
from the corresponding unsubstituted indoles by electrophilic
substitution because the electrophilicity of sulfonyl groups is
much lower than that of acyl groups and halogens.[1] Although
Yadav et al. recently reported that the indium-catalyzed
reaction of indoles with sulfonyl chlorides leads to 3-
sulfonylindoles,[3,4] the development of an efficient and
robust method to synthesize sulfonylindoles, which could
lead to the discovery of new bioactive compounds,[5] is still a
challenge in organic synthesis.
Several groups, including ourselves, have recently
reported that the reactions of ortho-alkynylanilines,[6] ortho-
alkynylphenyl ethers,[6a,b,7] and ortho-alkynylphenyl sulfides[8]
with a migrating group (E) on the heteroatom (Y) give the
corresponding 2,3-disubstituted indoles, benzofurans, and
benzothiophenes, respectively, in the presence of transition-
metal catalysts [Eq. (1)].
First, the catalytic activity of transition-metal compounds
was tested with N-methyl-2-(1-pentynyl)-N-tosylaniline (1a)
as substrate [Eq. (4)]. AuBr3 showed the highest selectivity
among the transition-metal complexes examined. Thus, the
reaction of 1a in the presence of 10 mol% AuBr3 in toluene at
808C for one hour yielded N-methyl-2-propyl-3-tosylindole
(2a) in 60% yield along with N-methyl-2-propyl-6-tosylin-
dole (3a)[9] and N-methyl-2-propyl-4-tosylindole (4a), which
are derived from an unprecedented sulfonyl migration to the
benzene ring of the indole skeleton, in 17% and 12% yields,
Acyl, allyl, a-alkoxyalkyl, and methoxyphenylmethyl
(MPM) groups can be employed as migrating groups. In this
article, we report that the reactions of the ortho-alkynyl-N-
sulfonylanilines 1b–o give the corresponding 3-sulfonylin-
doles 2b–o in good to excellent yields in the presence of a
catalytic amount of AuBr3 [Eq. (2)].
In addition, with InBr3 as catalyst the cyclization of 2-
alkynyl-6-methoxy-N-sulfonylanilines 1p–x proceeds by an
unprecedented 1,7-migration of the sulfonyl group to produce
the 6-sulfonylindoles 3 as the major product in good to high
yields [Eq. (3)].
respectively. In our previous metal-catalyzed migration of
ortho-alkynylacetanilides,[6d] ortho-alkynylphenyl acetals,[7f]
and ortho-alkynylphenyl sulfides,[8] we did not observe sub-
stitution of the benzene ring by the migrating groups. The
reaction of 1a in the presence of PtCl2 or PdCl2 produced a 1:1
mixture of 2a and 3a, while the use of indium complexes led
to a mixture of 2a, 3a, and 4a (see the Supporting
Information).
Next, we changed the tosyl group for a mesyl group. The
results of the reaction of ortho-alkynyl-N-mesylanilines 1b–l
[*] Dr. I. Nakamura, U. Yamagishi, Dr. D. Song, S. Konta,
Prof. Dr. Y. Yamamoto
Department of Chemistry
Graduate School of Science
Tohoku University
Sendai 980-8578 (Japan)
Fax : (+81)22-795-6784
E-mail: itaru-n@mail.tains.tohoku.ac.jp
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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with AuBr3 as catalyst are summarized in Table 1. The
reaction of N-mesyl-N-methyl-2-(1-pentynyl)aniline (1b) in
the presence of 10 mol% of AuBr3 in toluene at 808C for one
Many attempts to synthesize 4- or 6-sulfonylindoles as the
major products by varying the reactions conditions (solvent,
ligands, additives, and temperature) only led to a mixture of 2,
3, and/or 4. We then modified the substrate by adding
functional groups. Among the substrates prepared, 2-alkynyl-
6-methoxysulfonanilides 1p–x, which have a methoxy group
at the 6-position of the aniline moiety, were mainly converted
into the corresponding 6-sulfonylindoles 3p–x in the presence
of catalytic amounts of InBr3 [Eq. (3)]. The results are
summarized in Table 2. The reaction of 1p in the presence
of 5 mol% of InBr3 in toluene at 808C for two hours gave an
87:13 mixture of 3p and 2p in 95% combined yield (Table 2,
Table 1: AuBr3-catalyzed cyclization of 1b–o.[a]
Table 2: InBr3-catalyzed cyclization of 1p–x.[a]
Entry
1
R1
R2
R3
Yield [%]
3 and 4[c]
2[b]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
nPr
cyclohexyl
tBu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
p-anisyl
p-AcC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
95
62
38[d]
92
87
81
51
71
–
25
10
2
–
5
Ph
p-tolyl
p-anisyl
p-F3CC6H4
H
CO2Et
nPr
nPr
nPr
nPr
nPr
20
–
9
decomp[e]
Entry
1
R1
R2
Yield [%][b]
3/2[c]
10
11
12
13
14
44
60
52
85
80
–
–
22
7
1
2
3
4
5
6
7
8
9
1p
1q
1r
1s
1t
1u
1v
1w
1x
nPr
nPr
nPr
nPr
cyclohexyl
Ph
p-MeOC6H4
p-CF3C6H4
H
Me
MeO
H
NO2
Me
Me
Me
Me
Me
95
99
98
99
97
99
98
88
73
87:13
84:16
78:22
66:34
87:13
90:10
85:15
83:17
54:46
iPr
Me
Me
Me
5
[a] The reaction of 1b–o (0.25 mmol) was carried out in the presence of
10 mol% of AuBr3 in toluene at 808C for 1 h. [b] Yield of isolated product.
[c] Yield of an inseparable mixture of 3 and 4 determined by GC.
[d] Substrate 1d was recovered in 29% yield. [e] A mixture of unidentified
products was obtained.
[a] The reactions of 1p–x were carried out in the presence of 5 mol% of
InBr3 in toluene at 808C. [b] Yield of the isolated mixture of 2 and 3.
[c] The ratio was determined by 1H NMR spectroscopy.
hour gave 3-mesyl-1-methyl-2-propylindole (2b) in 95% yield
(Table 1, entry 1). No other regioisomers derived from
aromatic substitution were obtained. The reaction of 1b in
the presence of AuCl3 or PtCl2 gave 2b in 85% and 93%
yield, respectively. Substrates 1c and 1d, where R1 is a
cyclohexyl or tert-butyl group, were converted into 2c and 2d
in 62% and 38% yields, respectively (Table 1, entries 2 and
3). The reaction of the 2-(arylethynyl)-N-tosylanilines 1 f and
1g, where R1 is an electron-rich aromatic ring, gave 2 f and 2g
in good yields, while the reaction with 1h, which is substituted
with an electron-deficient aromatic ring, produced 2h in
lower yield along with significant amounts of the other
regioisomers (Table 1, entries 5–7). The terminal alkyne 1i
was converted into the 3-mesyl-substituted indole 2i in 71%
yield, while the reaction of the ynoate 1j led to a mixture of
unidentified products (Table 1, entries 8 and 9, respectively).
The reaction of N-benzyl-N-sulfonylaniline (1k) and N-
isopropyl-N-sulfonylaniline (1l) afforded the corresponding
indoles 2k and 2l in moderate yields (Table 1, entries 10 and
11, respectively). The reaction of the arylsulfonanilides 1m–o
gave 2m–o along with considerable amounts of the other
regioisomers (Table 1, entries 12–14).
entry 1). The reaction of 1p in the presence of AuBr3 or PdBr2
gave 3p and 2p with lower regioselectivities (Supporting
Information). The reaction of 1q, which has an electron-
donating methoxy group on the arylsulfonyl moiety, produced
the 6-sulfonylindole 3q with higher regioselectivity than that
of 1s, which contains an electron-withdrawing nitro group
(Table 2, entries 2 and 4, respectively). Substrate 1t, which
has a cyclohexyl group at R1, was converted into 3t with high
regioselectivity (Table 2, entry 5). The ratio of 3 to 2 was not
affected by the electronic properties of the R1 substituent
(Table 2, entries 6–8), although it was lower when terminal
alkyne 1x was employed as substrate (Table 2, entry 9). The
reaction of the N-mesylaniline 1y afforded a mixture of
unidentified products, and 5a–c, which have a methoxy group
at the 3-, 4-, and 5-position, respectively, reacted sluggishly to
give inseparable mixtures of unidentified products.
To find out if the migration of the sulfonyl group occurs in
an intramolecular or intermolecular fashion, we performed
crossover experiments [Eqs. (5) and (6)]. The reaction of a 1:1
mixture of 1e and 1n in the presence of a catalytic amount of
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hours, thereby suggesting that interconversion between the
products does not take place under the reaction conditions
[Eq. (7)].
AuBr3 gave the corresponding products 2e and 2n in 66%
and 65% yields, respectively [Eq. (5)]; the crossover products
were not detected by GC-MS or NMR spectroscopy.
Mixing indoles 6a and 6b with tosyl chloride in the
presence of AuBr3 or InBr3 did not give the corresponding
sulfonylindoles 2, 3, and 4 [Eq. (8)].[3] Accordingly, it is
unlikely that electrophilic substitution of the indole with tosyl
halides occurs under these reaction conditions.
Furthermore, the InBr3-catalyzed reaction of a 1:1 mix-
ture of 1q and 1w afforded the products 3q and 2q, derived
from 1q, and 3w and 2w, derived from 1w [Eq. (6)]; again, no
crossover products were obtained. These results clearly
indicate that the present reaction proceeds in an intra-
molecular manner.
The above experimental results led us to propose the
mechanism for the cyclization of 1 shown in Scheme 1. The
Lewis-acidic transition metal coordinates to the triple bond of
1 to form the p-complex 7. Nucleophilic attack of the nitrogen
atom to the alkynyl moiety then leads to the cyclized
intermediate 8. For the gold-catalyzed reaction of 1a–o, the
sulfonyl group intramolecularly migrates to the 3-position of
The isolated products 2a, 3a, and 4a remain unchanged in
the presence of InBr3 or AuBr3 in toluene at 808C for two
Scheme 1. Proposed mechanism for the catalytic formation of 2 and 3
from 1.
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Chemie
the indole skeleton (cycle A),[10] and elimination of AuBr3
from 9 then gives the 3-sulfonylindole 2. In the indium-
catalyzed reaction of substrates 1p–x, unprecedented consec-
utive 1,7-sulfonyl and 1,5-proton shifts take place instead
(cycle B).[11] Elimination of InBr3 from the resulting inter-
mediate 11 then gives the 6-sulfonylindoles 3. An interaction
between the benzene ring on the sulfonyl group and the
indium catalyst might play a crucial role in selectively
producing 6-sulfonylindoles 3, since the InBr3-catalyzed
reaction of N-mesylaniline 1y gives a complex mixture of
unidentified products.
The present reaction proceeds by formal addition of a
nitrogen–sulfur bond to a triple bond, a so-called amino-
sulfonylation.[12] It is therefore likely that this method could
be applicable in an efficient and environmentally benign
synthesis of a wide variety of 3- and 6-sulfonylindoles.[13]
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[4]We have repeated this reaction several times but so far we have
not been able to obtain 3-sulfonylindoles in good yields—the
reaction of indole and tosyl chloride under the conditions
mentioned in reference [3]gave 3-tosylindole in only 16% yield
in our hands.
[5]a) R. Ragno, M. Artico, G. De Martino, G. La Regina, A.
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[9]CCDC 622538 ( 3a) 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.
[10]For migration of sulfonyl groups, see: a) S. Roy, I. Das, K.
Bhanuprakash, B. D. Gupta, Tetrahedron 1994, 50, 1847 – 1858;
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Experimental Section
AuBr3-catalyzed cyclization of 1b: Toluene (0.5 mL) was added to a
mixture of AuBr3 (0.025 mmol) and 1b (0.25 mmol) in a pressure vial
under argon. After stirring at 808C for 1 h, the reaction mixture was
filtered through a short SiO2 pad. The crude product was purified by
silica gel column chromatography with hexane/ethyl acetate as eluent
to afford 2b (95%).
InBr3-catalyzed cyclization of 1p: Toluene (1 mL) was added to a
mixture of InBr3 (0.0125 mmol) and 1p (0.25 mmol). After stirring at
808C for 2 h, the reaction mixture was purified by Florisil column
chromatography with hexane/ethyl acetate as eluent to afford 3p
(83%) and 2p (12%). Further purification was performed by gel
permeation chromatography.
Received: September 30, 2006
Revised: December 16, 2006
Keywords: cyclization · fused-ring systems · gold · indium ·
.
synthetic methods
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