Direct C2-trifluoromethylation of indole derivatives catalyzed by copper acetate

Article abstract of DOI:10.1016/j.tetlet.2010.09.027

Direct C2-selective trifluoromethylation of indole derivatives was achieved with Togni's hypervalent iodine reagent and CuOAc as a catalyst in MeOH under mild conditions, affording the desired C2-trifluoromethylated indoles in good yield (up to 90%).

Full text of DOI:10.1016/j.tetlet.2010.09.027

Tetrahedron Letters 51 (2010) 5947–5949
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct C2-trifluoromethylation of indole derivatives catalyzed by copper acetate
Ryo Shimizu a,b, Hiromichi Egami a,c, Tatsuya Nagi a, Jungha Chae a, Yoshitaka Hamashima a,
,
Mikiko Sodeoka a,b,c,
⇑
a RIKEN, Advanced Science Institute (ASI), 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan
b Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
c Sodeoka Live Cell Chemistry Project, ERATO, JST, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct C2-selective trifluoromethylation of indole derivatives was achieved with Togni’s hypervalent
iodine reagent and CuOAc as a catalyst in MeOH under mild conditions, affording the desired C2-triflu-
oromethylated indoles in good yield (up to 90%).
Received 13 August 2010
Revised 6 September 2010
Accepted 9 September 2010
Available online 16 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
Indole
Catalysis
Regioselective
Introduction of fluorine into organic compounds generally re-
sults in significant changes of molecular properties, such as higher
hydrophobicity and metabolic stability. In particular, trifluorome-
thylated compounds have become increasingly important in the
pharmaceutical, agrochemical, and material science fields.1 There-
fore, intensive efforts have been made to develop direct trifluorom-
noted that hypervalent iodine reagent showed increased electro-
philicity in the presence of a Lewis acid.12,13 Inspired by these find-
ings, we examined the regioselective trifluoromethylation of indole
derivatives using hypervalent iodine and a metal catalyst (Scheme
1).14 Herein, we report copper-catalyzed C2-selective trifluorome-
thylation of indole derivatives with hypervalent iodine reagent
(Togni’s reagent).
ethylation of
a
wide variety of organic molecules.2 These
trifluoromethylation reactions can be classified into nucleophilic,
electrophilic, and radical types. Among them, electrophilic reac-
tions are still a developing area, and two major types of electro-
philic trifluoromethylation reagents, sulfonium salt type3 and
hypervalent iodine type,4 have been investigated.
On the other hand, the indole framework is a privileged core
structure found in many natural products and bioactive com-
pounds and its trifluoromethylated derivatives have potential
pharmaceutical applications.5 Development of synthetic methods
for trifluoromethylated indole derivatives is, accordingly, a topic
of current interest.6,7 However, direct trifluoromethylation of in-
dole derivatives is still challenging.8–10 Indole derivatives have
generally been used as nucleophiles, but it is well known that in-
dole has several reactive sites, that is, regioselectivity is an issue
in indole functionalization. The problem of regioselectivity has
been overcome in some C–C bond formation reactions by using
metal- or organo-catalysts.11 In addition, Togni and MacMillan
Trifluoromethylation of 3-methylindole was initially examined
in the presence of Togni’s reagent 24 and a catalytic amount of var-
ious metal salts at room temperature under an argon atmosphere
(Table 1). No reaction was observed in the absence of metal cata-
lyst (entry 1).15 The reactions with Co(OAc)2, Ni(OAc)2, and
Zn(OAc)2 provided C2-trifluoromethylation product 3a, albeit with
low yield (entries 3, 4, and 6). Fe(OAc)2 and Cu(OAc)2 gave better
CF3
I
+ M+
O
O
Togni's reagent
F3C
2
I+
O
O
R1
R1
R3
R3
M
CF3
⇑
N
N
Corresponding author. Tel.: +81 48 467 9373; fax: +81 48 462 4666.
E-mail address: sodeoka@riken.jp (M. Sodeoka).
R2
R2
1
3
Present Address: School of Pharmaceutical Sciences, University of Shizuoka, 52-1
Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Scheme 1. Trifluoromethylation of indole derivatives.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.027

5948
R. Shimizu et al. / Tetrahedron Letters 51 (2010) 5947–5949
Table 1
R1
R1
CF3
Screening of reaction conditionsa
CuOAc (10 mol%)
MeOH, rt
I
+
N
O
CF3
N
R2
R2
O
CF3
I
1i-n
3i-n
2
catalyst (10 mol%)
solvent, rt, 6 h
(1.2 equiv.)
CF3
+
O
N
H
N
H
O
1a
3a
2
CF3
CF3
CF3
(1.2 equiv.)
N
N
N
Me
Bn
Ac
3i, 6 h: 90%
3j, 18 h: 67%
3k, 24 h: 5%
Entry
Catalyst
Solvent
Yieldb (%)
(95%)a
(85%)a
(16%)a
1
2
3
4
5
6
7
8
Nonec
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
N.R.d
58
13
15
55
Fe(OAc)2
Co(OAc)2
Ni(OAc)2
Cu(OAc)2
Zn(OAc)2
CuOAc
CF3
CF3
N
CF3
N
N
Bn
Me
Boc
3m, 6 h: 58%b
23
3l, 24 h: 39%
3n, 6 h: 58%
79 (95)e
55
(60%)a
(76%)a
(62%)a
CuOAc
9
CuOAc
CuOAc
CuOAc
CuOAc
MeCN
THF
CH2Cl2
Toluene
24
51
68
16
Scheme 3. C2-selective trifluoromethylation of indole derivatives. aThe numbers in
parentheses are yields based on recovered starting material. bThe reaction was
carried out at 50 °C.20
10
11
12
a
The reactions were carried out in MeOH (1.5 ml) on a 0.15 mmol scale with
catalyst (10 mol %) and 2 (1.2 equiv.) under an Ar atmosphere.
b
Under the optimized conditions, we examined the trifluorom-
ethylation of various C3-substituted indole derivatives (Scheme
2).17 Introduction of an electron-withdrawing group at the C3
position diminished the reaction rate and yield (3b). Coupled
with the result in the case of 1a, this result suggests that the elec-
tronic properties of the five-membered ring of indoles are impor-
tant for the present trifluoromethylation reaction. In contrast,
substituents at C5 had less effect on the reaction (3c and 3d).
Since our reaction can be conducted under mild conditions, vari-
ous functional groups were tolerant. Reactions of 3-(3-indo-
lyl)propionic acid ester 1e, tryptamine derivative 1f, and
melatonin 1g proceeded without difficulty to give the C2-trifluo-
romethylated products 3e–g in good yield. It is noteworthy that
tryptophan derivative 1h could be converted to the corresponding
trifluoromethylated product 3h without racemization under these
reaction conditions.
Isolated yield.
No catalyst was used.
No reaction was observed.
The number in parenthesis is yield based on recovered starting material.
c
d
e
results and an acceptable yield of 3a was obtained by using CuOAc
(entries 2, 5, and 7). In order to optimize the reaction conditions,
the reaction solvent was next screened, as shown in Table 1 and
MeOH was found to be the best solvent for the present reaction
(entries 7–12). Although, C4-trifluoromethylated 3-methylindole
was generated in less than 6% yield as a by-product in all cases,
high C2-selectivity was observed.16
Finally, the effect of a substituent at N1 position was investi-
gated (Scheme 3). As expected, the reaction of N-alkylated 3-
methylindoles proceeded smoothly with good to high yield. In par-
ticular, trifluoromethylated compound 3i provided as high as 90%
yield in the reaction of N-methyl 3-methylindole 1i. In accord with
the result in the case of 1b, however, the reaction of 1k and 1l hav-
ing electron-withdrawing group at N1 position resulted in low
yield. When simple indole was subjected to our reaction, chemical
yield was only 35%. To our delight, however, the yields of the de-
sired products were enhanced by the introduction of a substituent
at the N1 position. Notably, C2-trifluoromethylated products were
obtained selectively in these reactions, even though, the C3 posi-
tions of 1m and 1n were not substituted in these cases (3m18
and 3n).19
In summary, we have demonstrated regioselective trifluorome-
thylation of indole derivatives catalyzed by CuOAc. This reaction
proceeded under mild conditions with only a small excess of Tog-
ni’s reagent and 10 mol % of the catalyst and selectively provided
C2-trifluoromethylated indoles. Further study on the mechanism
of this reaction is in progress.
R1
R1
CF3
R3
R3
CuOAc (10 mol%)
MeOH, rt
I
+
O
CF3
N
N
O
H
H
1b-h
3b-h
2
(1.2 equiv.)
CO2Me
MeO
Br
CF3
CF3
CF3
N
H
N
H
N
H
3b, 24 h: 28%
3c, 18 h: 72%
3d, 24 h: 74%
(58%)a
(88%)a
(90%)a
CO2Me
CF3
NHBoc
CF3
NHAc
CF3
MeO
N
N
N
H
H
H
3e, 24 h: 72%
3f, 24 h: 68%
3g, 24 h: 79%
(79%)a
(76%)a
(93%)a
NHBoc
CO2Me
CF3
N
H
Acknowledgments
3h, 24 h: 48%
This work was supported by a Grant-in-Aid for Scientific Re-
search on a Priority Area (No. 19028065, ‘Chemistry of Concert
Catalysis’) and by Special Project Funding for Basic Science from
RIKEN.
(86%)a
Scheme 2. Trifluoromethylation of 3-substituted indole derivatives. aThe numbers
in parentheses are yields based on recovered starting material.

R. Shimizu et al. / Tetrahedron Letters 51 (2010) 5947–5949
5949
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hypervalent iodine reagent with a sub-stoichiometric amount of Zn(NTf2)2 was
reported. Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131,
951.
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14. Direct ortho-trifluoromethylation of pyridylarenes via C–H activation was
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3648.
15. The reaction without methal catalyst in non-degassed solvent or under aerobic
conditions gave a small amount of 3a. This result is consistent with a previous
report: see Ref. 8.
16. For example, the 4-trifluoromethylated derivative was obtained in 4% yield
from the reaction described in entry 7 of Table 1.
17. Typical procedure of trifluoromethylation of indoles: To a solution of CuOAc
(1.8 mg, 0.015 mmol) and hypervalent iodine reagent 2 (56.9 mg, 0.18 mmol)
in degassed MeOH (1.5 ml) was added N-methyl-3-methylindole 1i (21.8 mg,
0.15 mmol) under an argon atmosphere at room temperature. The reaction
mixture was stirred for 6 h, then diluted with Et2O. To the mixture was added
saturated NaHCO3 solution (0.5 ml), and the whole was extracted with Et2O
(3 ml  3). The combined organic layer was dried over Na2SO4. The solid was
filtered off and the filtrate was evaporated in vacuo. The residue was subjected
to preparative TLC on silica gel to give trifluoromethylated compound 3i as a
yellowish oil (28.8 mg, 90%).
18. Although the inseparable mixture of regioisomers was obtained, careful
analysis of the by-products revealed that 3- and 4-trifluoromethylated N-
methylindoles were also formed in 13% and 7% yield, respectively.
19. Copper-catalyzed regioselective arylation of indoles with hypervalent iodine
reagent has been reported, see: Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 8172.
20. N-Methyl-2-trifluoromethylindole 3l was obtained in 48% at room
temperature.