Sulfoxide-TFAA and nucleophile combination as new reagent for aliphatic C-H functionalization at indole 2α-position

Article abstract of DOI:10.1039/c2ob26944a

Aliphatic C-H functionalization at indole 2α-position mediated by acyloxythionium species 1 generated from sulfoxide and acid anhydride has been developed. The combination of sulfoxide and TFAA with O-, N- and C-nucleophiles enabled introduction of various substituents in a one-pot procedure. Especially on utilizing DMSO, the combination provided a practical and efficient method for the synthesis of a wide range of 2α-substituted indoles. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob26944a

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Sulfoxide-TFAA and nucleophile combination as new
reagent for aliphatic C–H functionalization at indole
2α-position†‡
Cite this: Org. Biomol. Chem., 2013, 11,
496
Masanori Tayu, Kazuhiro Higuchi,* Masato Inaba and Tomomi Kawasaki*
Aliphatic C–H functionalization at indole 2α-position mediated by acyloxythionium species 1 generated
from sulfoxide and acid anhydride has been developed. The combination of sulfoxide and TFAA with O-,
N- and C-nucleophiles enabled introduction of various substituents in a one-pot procedure. Especially on
utilizing DMSO, the combination provided a practical and efficient method for the synthesis of a wide
range of 2α-substituted indoles.
Received 4th October 2012,
Accepted 7th November 2012
DOI: 10.1039/c2ob26944a
www.rsc.org/obc
The combination of sulfoxide and acid anhydride is a useful
reagent for organic synthesis owing to the powerful electrophi-
licity of acyloxythionium species 1 generated in situ.1 Typical
reactions are Swern–Moffatt type oxidation of alcohols,2 the
oxidation of thiols to disulfides,3 the conversion of amines to
iminosulfuranes,4 and transformations of alkenes, aromatics
and enols to vinyl-,5,6,7a aryl-8 and β-keto-sulfonium salts,9 and
so on.10 Recently, these reactions have been extended to one-
pot multi-component reactions by adding other nucleophiles
for the development of efficient synthetic methods. For
example, acyloxythionium 1-mediated substitution of alcohols
with enolates,11 glycosylation of 1-hydroxy-12 and 1-thiophenyl-
glycocyl derivatives,13 addition of 1 to alkenes followed by
amines or imides sequentially to produce aziridines,7,8a allyl
amines,7,8b or enamides,7,8c and 1-activated 2-amido-14 and
2-hydroxy-glycosylations of glycal enol ethers.15 Especially, many
uses of acyloxythionium species 1 in one-pot multi-component
reactions starting from addition to carbon–carbon double
bond have been reported, although the application of such a
one-pot multi-component reaction to aromatics is limited
because of the stability of the initially generated arylsulfonium
salts. The only known examples are intramolecular aromatic
substitutions.16 In our recent communication, we reported the
acyloxythionium 1-mediated intermolecular C–H functionali-
zation at indole 2α-position utilizing a DMSO-TFAA-nucleo-
phile combination.17 In the present paper, we report the full
details of the combination of the sulfoxides containing DMSO,
Fig. 1 Biologically active 2α-substituted indoles.
TFAA and nucleophiles as efficient reagents for the synthesis
of 2α-substituted indole derivatives, which are attractive inter-
mediates for synthesis of biologically active compounds, NPY
antagonist 2,18 anti-HPV agent 3,19 and PGD2 antagonist 420
(Fig. 1).
C–H functionalization by combination of diaryl sulfoxide-
TFAA
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
E-mail: kawasaki@my-pharm.ac.jp, khiguchi@my-pharm.ac.jp;
Fax: +81 42 495 8763; Tel: +81 42 495 8763
†This work is dedicated to Dr Masanori Sakamoto, Professor Emeritus of Meiji
In order to realize the acyloxythionium species-mediated inter-
molecular C–H functionalization at the 2α-position of indoles,
we initially studied the reaction of tetrahydrocarbazole and the
acyloxythionium species generated from diphenyl sulfoxide
Pharmaceutical University, on the occasion of his 77th birthday (KIJU).
‡Electronic supplementary information (ESI) available: General synthetic
procedures and NMR data of compounds. See DOI: 10.1039/c2ob26944a
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Table 1 Reactivity of N-substituted indoles
Yielda (%)
Entry
6
R
Temp (°C)
Time (min)
7
8
Recovery of 6 (%)
1
2
3
4
6a
6b
6c
6d
Ac
CO2Me
H
−40 to r.t.
−40 to r.t.
−40
10
30
30
10
7a
7b
7c
7d
9
8a
8b
8c
8d
NDb
ND
ND
33
87
71
ND
ND
20
ND
32
PMB
−40
a Isolated yield. b ND = Not detected.
and TFAA (Table 1). To a solution of N-acetyl tetrahydrocarb-
azole 6a and diphenyl sulfoxide (5a) in dichloromethane was
added TFAA. After the consumption of 6a, MeOH was added to
afford 2α-methoxy compound 7a in 9% yield with recovery of
6a (87%) (entry 1). In the case of N-methoxycarbonyl com-
pound 6b, the desired product 7b was obtained in 20% yield
with recovery of 6b (71%) (entry 2). Since this is attributed to
reduced reactivity of 6a and 6b with an electron-withdrawing
group, we performed the reactions involving N-unsubstituted
6c and electron-donating N-p-methoxybenzyl (PMB) compound
6d. In the case of 6c, the result was disappointing, but the
reaction of 6d afforded desired compound 7d (32%) together
with dimer 8d (33%) (entry 4).21
A plausible reaction mechanism is shown in Scheme 1. The
reaction of sulfoxide 5 and TFAA generates the acyloxythio-
nium species 1, which is subjected to nucleophilic attack of 6d
to produce thionium intermediate 9. After deprotonation to
form enamine 10, subsequent SN2′-type reaction of 10 with
MeOH occurs at the 2α-position of indole to give 7d. Excess
MeOH also attacks the sulfur atom14 of intermediate 9 to
Scheme 1 Plausible reaction mechanism for acyloxythionium mediated
reaction.
regenerate 6d, which is introduced at the 2α-position of 10 to be explained by assuming that the crowded sulfur atom of the
afford dimer 8d.22
acyloxythionium species 1 could not come close to 6d to form
To improve the yield of 7d, the suppression of the above 9 (entries 6 and 7).
dimerization was required. Therefore we examined the substi-
Next, we investigated the equivalent ratio of sulfoxide 5b
tuent effect on the aryl sulfoxide 5 (Table 2). Initially, the use and TFAA (Table 3). The yield of 7d was improved by increas-
of sulfoxides 5b and 5c with an electron-donating group ing the ratio of 5b and TFAA to 6d. As a result, the use of
increased the yield of desired product 7d (42% and 54%) along 3 equiv. to 6d dramatically improved the yield of 7d to 93%
with suppressing the formation of 8d, respectively (entries 2 without dimerization. This can be explained in terms of an
and 3). This result implies that the electron-donating substitu- equilibrium shift toward thionium intermediate 9 by use of
ent of sulfoxide 5 decreased the positive charge on the sulfur excess acyloxythionium species 1.
atom of 9 to prevent the attack of MeOH. In the cases of 5d
Under the optimized conditions, we examined the scope
and 5e with electron-withdrawing groups, the reactions gave and limitation of this reaction (Table 4). In addition to 6-mem-
the undesired dimer 8d (22% and 13%) with recovery of start- bered ring-fused indole 6d (Table 3, entry 3), this reaction
ing material 6d (entries 4 and 5). Electron-deficient sulfoxides could be applied to 5- and 7-membered ring-fused indoles 6e
were inefficient to react with TFAA. Therefore, dimerization and 6f to give 7e and 7f in moderate yields,
occurred before consumption of 6d. On using sulfoxides 5f respectively (entries 1 and 2). On using 2,3-dimethylindole
and 5g with ortho substituent, desired product 7d was 6g, 7g was obtained in 29% yield with recovery of 6g in 12%
obtained in poor yields with recovery of 6d. This result could (entry 3).
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Table 2 Substituent effect on aromatic rings of diaryl sulfoxides
Yielda (%)
Entry
1
5
R
Temp (°C)
Time (min)
10
7d
8d
Recovery of 6d (%)
5a
−40
32
33
NDb
2
3
4
5
6
5b
5c
5d
5e
5f
−40
10
10
90
90
90
42
54
ND
ND
4
27
10
22
13
8
ND
ND
42
−40
−40 to r.t.
−40 to r.t.
−40 to r.t.
60
38
7
5g
−40 to r.t.
90
ND
29
28
a Isolated yield. b ND = Not detected.
Next, we investigated the reaction of 6d with various nucleo- instead of desired products 7q and 7o, respectively (entries 7
philes (Table 5). Secondary alcohol afforded 51% yield of the and 8).
corresponding product 7h (entry 1), but tertiary alcohol and
Although the combination of diaryl sulfoxide and TFAA has
n-octanethiol did not form 7i and 7j (entries 2 and 3). Azide and the limitation in some of the applied carbon nucleophiles, we
primary amine were introduced as nitrogen substituents in revealed that the combination of diaryl sulfoxide-TFAA and
good yields (entries 4 and 5). Subsequently, to apply this reac- carbon nucleophile realized its potential for carbon–carbon
tion to C–C bond formation, we tried utilizing several carbon bond formation.
nucleophiles. Although trimethylsilyl cyanide did not undergo
A plausible mechanism of the formation of 11 is shown in
the desired reaction (entry 6), N-methylindole gave product 7n Scheme 2. On the way of the reaction with some organometal-
quantitatively (entry 7).
lic reagents, regenerated sulfoxide 5 attacks to 2α-position of
Additionally, we attempted to introduce carbon substitu- 10, and Kornblum-type oxidation23 of 13 proceeds to afford 11.
ents with various organometallic reagents (Table 6). Methyl-
C–H functionalization by the combination of alkyl sulfoxide-
magnesium iodide gave methylated product 7o in 44% yield
TFAA and nucleophile
(entry 1). When methylmagnesium chloride and bromide were
used, ketone 11 and 5-brominated ketone 12 were obtained
without formation of the desired 7o, respectively (entries 2 and
3). In the cases of trimethylaluminum, dimethylzinc and
diethylzinc, the corresponding alkylated products 7o and 7p
were obtained in good yields (entries 4–6). By using divinylzinc
or lithium dimethylcuprate, however, 11 was obtained
As described above, the reaction utilized the acyloxythionium
species, generated from diaryl sulfoxide, required excess
reagent and restricted the kind of nucleophile to be intro-
duced. Therefore, we further optimized the combined reagent
using various sulfoxides for the expansion of the reaction
scope.
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Table 3 Effect of the amount of acyloxythionium species
Table 6 C–C bond formation with organometallic reagents
Yielda (%)
Yielda (%)
11
Entry
5b (equiv.)
TFAA (equiv.)
7d
8d
Entry
Nu
R
7
12
1
2
3
1.0
2.0
3.0
1.0
2.0
3.0
42
79
93
27
4
1
2
3
4
5
6
7
MeMgI
MeMgCl
MeMgBr
Me3Al
Me2Zn
Et2Zn
Me
Me
Me
Me
Me
Et
7o
7o
7o
7o
7o
7p
7q
44
ND
37
ND
ND
ND
ND
70
NDb
ND
47
ND
ND
ND
ND
ND
ND
58
76
76
NDb
a Isolated yield. b ND = Not detected.
ND
8
Me2CuLi
Me
7o
ND
38
ND
Table 4 Application of p-Tol2SO-TFAA system to other indole derivatives
a Isolated yield. b ND = Not detected.
Recovery
(%)
Entry
6
R1
R2
7
Yielda (%)
1
2
3
6e
6f
6g
–(CH2)2–
–(CH2)4–
7e
7f
7g
72
57
29
6e
6f
6g
NDb
ND
12
H
Me
a Isolated yield. b ND = Not detected.
Table 5 Scope of nucleophiles with p-Tol2SO-TFAA system
Scheme 2 Plausible reaction mechanism of oxidation at 2α-position.
Initially, we examined the use of aryl methyl and dimethyl
sulfoxides instead of diaryl sulfoxide (Table 7). In comparison
with diphenyl sulfoxide (5a) (Table 2, entry 1), the use of
methyl phenyl sulfoxide (5h) improved the yield of desired
product 7d (57%) through decreased formation of dimer 8d
(15%) (Table 7, entry 1). On using p-tolyl and p-anisyl methyl
sulfoxides (5i and 5j), the yield of 7d were dramatically
increased (entries 2 and 3). To our surprise, we found that
DMSO 5k gave 7d in 93% yield without the formation of dimer
8d (entry 4).
Entry
Nu
7
R
Yielda (%)
1
2
3
4
5
6
7
iPrOH
7h
7i
7j
7k
71
7m
7n
iPrO
tBuO
nOctS
N3
BnNH
CN
51
tBuOH
nOctSH
TMSN3
BnNH2
TMSCN
NDb
ND
93
75
ND
99
Secondly, the effect of nucleophile usage under DMSO-T-
FAA conditions was optimized. Several experiments showed
a Isolated yield. b ND = Not detected.
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Table 7 Further optimization with alkyl sulfoxides
Table 9 Introduction of various nucleophiles using DMSO-TFAA system
Entry
1
Nu
7
R
Yielda (%)
70
7v
2
3
4
5
TMSN3
BnNH2
MeMgBr
7k
7l
7o
7q
N3
NHBn
Me
Quant
82
99
Yielda (%)
Quant
6
7
7w
7n
Quant
97
Entry
5
R
Time (min)
MeOH (equiv.)
7d
8d
1
2
3
4
5
6
5h
5i
5j
5k
5k
5k
Ph
10
10
10
30
30
30
10.0
10.0
10.0
10.0
5.0
57
74
80
93
95
76
15
10
p-Tol
p-An
Me
Me
Me
9
NDb
ND
ND
5.0
a Isolated yield.
a Isolated yield. b ND = Not detected.
obtained in excellent yield (entry 7). The DMSO-TFAA system
achieved remarkable improvement in the yield of 7 with
Grignard reagents in comparison with that of the p-Tol2SO-T-
FAA system (Table 6).
Table 8 Application of the DMSO-TFAA system to various indole derivatives
Conclusions
We have developed a new procedure for C–H functionalization
at the indole 2α-position mediated by the combination of sulf-
oxide-TFAA and nucleophile. Especially, the DMSO-TFAA
system gave the best results in the desired C–H functionaliza-
tion including C–C bond formation, which is a useful method
for the synthesis of natural products and biologically active
compounds.24
Entry
6
R1
R2
R3
X
7
Yielda (%)
1
2
3
4
5
6
6e
6f
6r
6s
6t
6u
PMB
PMB
PMB
PMB
PMB
–(CH2)3–
–(CH2)2–
–(CH2)4–
–(CH2)3–
–(CH2)3–
H
H
MeO
Br
H
7e
7f
7r
7s
7t
7u
72
90
76
70
82
61
Me
Me
Me
H
Our extended studies of this reaction to an asymmetric
version and synthesis of biologically active compounds such as
2 and 3 are under investigation in our laboratory.
a Isolated yield.
that the amount of MeOH could be reduced to 5 equiv.
(entry 5).
Acknowledgements
With these improvements (Table 7), we found a practical
method for C–H functionalizing at the indole 2α-position by
utilizing the DMSO-TFAA system. We applied the optimized
reaction conditions to various indoles (Table 8). As a result,
indoles 6e, 6f and 6r–6u gave the corresponding products in
high yields. Subsequently, we investigated a variety of nucleo-
philes (Table 9). In addition to MeOH as oxygen nucleophile,
p-cresol afforded aryl ether 7v in 70% yield (entry 1). Azide and
amine as nitrogen nucleophiles also gave the corresponding
products 7k and 7l in high yields (entries 2 and 3). With
Grignard reagents, methyl, vinyl and allyl groups were intro-
duced quantitatively (entries 4–6). When N-methylindole as
aromatic nucleophile was used, the desired product 7n was
This work was supported by a grant from the High-Tech
Research Center Project, the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan (S0801043). We
thank N. Eguchi, T. Koseki, and S. Yamada at the Analytical
Center of our university for performing microanalysis, NMR
and mass spectral measurements.
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502 | Org. Biomol. Chem., 2013, 11, 496–502
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