Rapid trifluoromethylation of indole derivatives

Article abstract of DOI:10.3987/COM-12-S(N)101

Rapid trifluoromethylation of indole derivatives was achieved using trimethylsilyltriflate as the catalyst. Good to high yields were observed within only 5 min at room temperature. This reaction system is able to provide not only the mono-trifluoromethyla

Full text of DOI:10.3987/COM-12-S(N)101

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HETEROCYCLES, Vol. 86, No. 2, 2012
979
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 979 - 983. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 20th July, 2012, Accepted, 24th August, 2012, Published online, 30th August, 2012
DOI: 10.3987/COM-12-S(N)101
RAPID TRIFLUOROMETHYLATION OF INDOLE DERIVATIVES
Ayako Miyazaki,a,b Ryo Shimizu,a,c Hiromichi Egami,a,b and Mikiko
Sodeoka*a,b,c
a
RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198,
Japan
b
Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology
Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
c
Graduate School of Science and Engineering, Saitama University, 255
Shimo-okubo, Sakura-ku, Saitama 351-8570, Japan
Dedicated to Professor Ei-ichi Negishi on the occasion of his 77th birthday.
Abstract – Rapid trifluoromethylation of indole derivatives was achieved using
trimethylsilyltriflate as the catalyst. Good to high yields were observed within
only 5 min at room temperature. This reaction system is able to provide not only
the mono-trifluoromethylated products, but also the di-trifluoromethylated
derivatives, because of its high reaction efficiency.
Indole frameworks have often been found in many natural products and bioactive compounds. Therefore,
transformation of indole derivatives is of great interest in organic chemistry and many functionalizations
of indoles have been investigated for a long time.1 On the other hand, the trifluoromethyl group has
increasingly attracted attention in the pharmaceutical and agrochemical fields. This is because the
presence of the trifluoromethyl group often brings about unique properties to molecules, such as
improved metabolic stability and hydrophobicity.2 Accordingly, trifluoromethylated indole derivatives
would be an intriguing target.3,4 The direct indole trifluoromethylation reaction, in particular the catalytic
version, has recently been developed.5 In 2010, we reported the copper-catalyzed direct
trifluoromethylation of indole derivatives using Togni reagent 26 (Scheme 1a).7 The
C2-trifluoromethylated compounds were selectively obtained, and it was found that the N-protecting
group affected the reactivity and selectivity for this reaction. In the course of this study, we encountered
curious results (Scheme 1b). The desilylated di-trifluoromethylated product 4b was obtained in 10% yield

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HETEROCYCLES, Vol. 86, No. 2, 2012
when N-TMS-3-methylindole 1a was used as
a
substrate, while the reaction of
N-TBDMS-3-methylindole 1c provided only the 2-trifluoromethylated product 3c in 47% yield with the
di-trifluoromethylated product 4c not being detected. In the latter case, the TBDMS group remained intact
on the nitrogen of the indole ring. Based on these results, we hypothesized that the silyl cation would be a
good activator for trifluoromethylation using Togni reagent 2. In this communication, we disclose the
rapid trifluoromethylation of indole derivatives using trimethylsilyltriflate (TMSOTf) under mild
conditions.
(a)
R1
R1
CF3
R2
R2
CuOAc (10 mol%)
MeOH, rt, 6-24 h
I
+
O
CF3
N
R3
N
R3
3: up to 90%
O
1
2
(b)
CF3
CuOAc (10 mol%)
2 (1.2 eq.)
CF3
CF3
+
+
N
H
N
H
MeOH, rt, 12 h
N
TMS
1a
3b: 71%
4b: 10%
CF3
CuOAc (10 mol%)
2 (1.2 eq.)
CF3
CF3
N
N
MeOH, rt, 24 h
N
TBDMS
1c
TBDMS
3c: 47%
TBDMS
4c: 0%
Scheme 1. Copper-catalyzed trifluoromethylation of indole derivatives
Based on our hypothesis, TMSOTf, which is a representative source of a silyl cation species was used as
a catalyst in CH2Cl2 at room temperature. We initially examined the reaction with 3-methylindole 1b. To
our surprise, the rate of this reaction was remarkably fast. Compound 3b was obtained in 71% yield
within only 5 min, together with the di-trifluoromethylated product 4b in 7% yield (Table 1, entry 1).8
This remarkable result prompted us to examine the trifluoromethylation of other indole derivatives. The
electron donating group at the 5-position accelerated the di-trifluoromethylation and the desired products
3d and 4d were obtained in 60% and 19% yields, respectively at 0 °C (entry 2). Various functional groups,
such as aryl bromide, methyl ester, ether, carbamate and amide moieties, were tolerated in this reaction
(entries 3-7).9 Trifluoromethylated products of the tryptophan derivative 3i and 4i were afforded in 48%
and 4% yields, respectively (entry 7). It is noteworthy that the enantiopurity of the derivatives was
conserved under this reaction condition. We next examined 1-substituted indole derivatives.
N-Methyl-3-methylindole 1j was transformed to produce the desired products in high yield (entry 8).
Analogous to the copper-catalyzed system, the N-TBDMS group was intact in this reaction system (entry
9). The reaction with 1k bearing no substituent at the 3-position provided the 2-trifluoromethylated

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HETEROCYCLES, Vol. 86, No. 2, 2012
981
product 3k, albeit in 26% yield (entry 10). In this case, dimer 5 was generated as the main product in 47%
yield.10 Unfortunately, we could not isolate 4k and a complex mixture of mono- and di-
trifluoromethylated indoles, with yet to be identified structures was obtained.
Table 1. Trifluoromethylation of indole derivatives using TMSOTfa
R1
R1
CF3
R1
TMSOTf (20 mol%)
R2
R2
R2
2 (1.3 equiv.)
+
CF3
CF3
N
R3
N
R3
N
R3
CH2Cl2, rt, 5 min
1
3
4
entry
1
substrate
product [%]b
entry
substrate
product [%]b
NHAc
MeO
3b; 71%, 4b; 7%
6
7
3h; 63%, 4h; 10%
1b
1h
N
H
N
H
NHBoc
MeO
2c
3d; 60%, 4d; 19%
3i; 48%, 4i; 4%
1d
CO2Me
1i
N
H
N
H
Br
3
4
3e; 67%, 4e; 9%
3f; 59%, 4f; 5%
8
9
3j; 75%, 4j; 9%
3c; 55%, 4c; 0%
1e
1j
N
H
N
CO2Me
1f
1c
N
N
H
TBDMS
NHBoc
3k; 26%, 4k; NDd
1k
5
3g; 68%, 4g; 8%
10
1g
N
N
H
a The reactions were carried out with TMSOTf (20 mol%) and Togni reagent 2 (1.3
b
c
N
equiv.) in CH2Cl2 on a 0.5 mmol scale. Isolated yield. The reaction was carried
out at 0 °C for 15 min on a 0.2 mmol scale. d Not determined.
N
5
Inspired by these results, we investigated the reaction using an excess amount of Togni reagent 2 to
obtain a higher amount of the di-trifluoromethylated product (Scheme 2). The di-trifluoromethylated
compound 4d was produced under the described conditions in 42% yield, together with 3d in 35% yield.
CF3
TMSOTf (1 equiv.)
MeO
MeO
MeO
2 (3 equiv.)
+
CF3
CF3
CH2Cl2, rt, 5 min
N
N
H
N
H
H
1d
3d: 35%
4d: 42%
Scheme 2. Trifluoromethylation using an excess amount of Togni reagent 2

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HETEROCYCLES, Vol. 86, No. 2, 2012
In summary, we achieved the rapid trifluoromethylation of indole derivatives using TMSOTf as a catalyst.
This reaction was operated under very mild conditions and the desired trifluoromethylated products were
obtained in high yield within 5 minutes. In addition, a reasonable amount of the di-trifluoromethylated
product could be obtained when an excess amount of Togni reagent was used. This reaction system
provides a quick method for the synthesis of trifluoromethylated indole derivatives.
ACKNOWLEDGEMENTS
This work was supported in part by MEXT (Grant-in-aid for Young Scientists (B) No. 23750116) and by
Funding from RIKEN.
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