Palladium-catalyzed oxidative trifluoromethylation of indoles at room Temperature

Article abstract of DOI:10.1002/chem.201100283

Incorporation of fluorine atoms into organic molecules significantly enhances many of their properties, such as solubility, metabolic stability, and bioavailability. Among organofluorine molecules, trifluoro ACHTUNGTRENUNGmethylated compounds play a unique and important role in agricultural and medicinal chemistry.[2] As a consequence, the exploitation of efficient methods to construct C-CF₃ bond has received much attention.

Full text of DOI:10.1002/chem.201100283

COMMUNICATION
DOI: 10.1002/chem.201100283
Palladium-Catalyzed Oxidative Trifluoromethylation of Indoles at Room
Temperature
Xin Mu,[a] Shujun Chen,[b] Xingliang Zhen,[b] and Guosheng Liu*[a]
Incorporation of fluorine
atoms into organic molecules
significantly enhances many of
their properties, such as solubil-
ity, metabolic stability, and bio-
availability.[1] Among organo-
fluorine molecules, trifluoro-
ACHTUNGTRENNUNG
agricultural
and
medicinal
chemistry.[2] As a consequence,
the exploitation of efficient
À
methods to construct C CF3
bond has received much atten-
tion.[3]
The introduction of a CF3
moiety onto aromatic com-
pounds is generally achieved by
using the Swarts reaction[4] or
the cross-couplings of aromatic
halides with
a stoichiometric
amount of CuCF3 reagents gen-
erated in situ.[5] Recent studies
demonstrated that the forma-
À
tion of Aryl C CF3 bonds could
be achieved through a reductive
elimination of palladium com-
À
plexes (Ar)Pd CF3 in different
reaction conditions.[6] Several
major progresses on this chal-
lenging transformation have
been made by using a catalytic
amount of palladium catalysts.[7]
Scheme 1. Pd-catalyzed trifluoromethylation of aromatic compounds.
For instance, Buchwald and co-workers reported a Pd-cata-
lyzed cross-coupling reaction of aryl chloride and Et3SiCF3
[a] X. Mu, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai, 200032 (P.R. China)
Fax : (+86)21-64166128
by using
a
sterically hindered phosphine ligand
(Scheme 1A).[7a] Yu and co-workers explored a Pd-catalyzed
À
aryl C H trifluoromethylation by using Umemotoꢀs electro-
+
philic CF3 reagent.[7b] The mechanistic studies reported by
E-mail: gliu@mail.sioc.ac.cn
Sanford and co-workers demonstrated the formation of an
[b] S. Chen, Dr. X. Zhen
À
aryl C CF3 bond from the reductive elimination of a
Department of Chemistry
Changsha University of Science and Technology
Changsha, 410114 (P.R. China)
(Ar)PdIV CF3 complex, which was generated from the oxi-
À
dative addition of the (Ar)PdII complex to CF3 reagents
+
(Scheme 1B).[6c] Herein, we report a novel Pd-catalyzed tri-
fluoromethylation of indoles at room temperature, in which
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100283.
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Table 1. The results of the screening: Pd-catalyzed trifluoromethylation
the Ruppert–Prakash reagent TMSCF3 is used as CF3
of indole 1a.[a]
source. In this reaction, the formation of the (Ar)PdIV CF3
À
intermediate possibly occurs through oxidation by using
+
PhIACHTUNGTRENNUNG
(OAc)2 (Scheme 1C),[8] rather than the previous CF3
pathway (Scheme 1B).
Indoles containing a CF3 group on the pyrrole ring are a
key moiety in biological and medicinal chemistry,[9] and
therefore the synthesis of these compounds is of great inter-
est.[10] Among the investigated methods, the directed tri-
fluoromethylation of indoles represents the most efficient
synthetic strategy. In our previous studies on the fluorina-
Entry
Ligand
Base
Oxidant
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OPiv)2
PhI(TFA)2
3
4
5
6
7
Yield [%][b]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
AgF
CsF
KF
G
36
45
33
0
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
NaF
ZnF2
CsOAc
KOAc
K2CO3
CsF
CsF
CsF
CsF
–
–
–
–
CsF
CsF
CsF
CsF
CsF
CsF
ACHTUNGTRENNUNG
À
tion of unactivated alkenes, the formation of C F bond un-
R
0
À
derwent an oxidative cleavage of the C Pd bond by using
N
21
33
30
0
42
0
34
0
0
(OAc)2/AgF at room temperature.[11] The postulation
ACHTUNGTRENNUNG
PhI
ACHTUNGTRENNUNG
that AgCF3 species possesses similar reactivity with AgF
9[c]
10
11
12
ACHTUNGTRENNUNG
À
prompted us to make an attempt to build a C CF3 bond at
G
mild reaction conditions. To test this hypothesis, electron-
ACHTUNGTRENNUNG
rich indoles were chosen to corroborate the feasibility be-
13[d]
14[d]
15
[12]
À
cause of the easy formation of the Ar Pd bond.
Our initial studies focused on the trifluoromethylation of
N-methyl-3-methylindole 1a with AgCF3, which was gener-
ated in situ from the reaction of TMSCF3 and AgF (Table 1,
entry 1).[13] We were pleased to discover that the desired 2-
trifluoromethylated product 2a (36% yield) was obtained in
0
0
16
17[e]
18[e]
19[e]
20[e]
21[e,f]
22[e,g]
Bpy
BC
L1
L2
L2
L2
PhI
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
A
41
50
58
64
68
82
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
the presence of PdACHTUNGTRENNUNG(OAc)2 at room temperature. When CsF
AHCTUNGTRENNUNG
À
and KF were used as FÀ sources to generate CF3 , the reac-
tions also gave 2a in moderate yield, and CsF gave the best
yield (Table 1, entries 2 and 3). But other fluoride salts, such
as NaF and ZnF2, failed to give product 2a (Table 1, en-
tries 4 and 5). Some nonfluoride bases have also been used
AHCTUNGTRENNUNG
À
to generate CF3 for this trifluoromethylation, albeit in
slightly lower yields (Table 1, entries 6–8). No reaction oc-
curred in the absence of the Pd catalyst (Table 1, entry 9).
Interestingly, a screening of potential oxidants revealed that
[a] Reaction conditions: 1a (0.1 mmol), PdACTHNUTRGENUG(N OAc)2 (10 mol%), oxidant
only hypervalent iodine reagents such as PhI
PhI(OPiv)2 were effective (Table 1, entries 1 and 10). The
cyclic iodine(III) oxidant 3 gave a slightly lower yield
(34%). But PhI(TFA)2 could not afford the desired product
ACHTUNGRTEN(NUNG OAc)2 and
(0.2 mmol), TMSCF3 (0.4 mmol), and base (0.4 mmol) in CH3CN
(1.0 mL) at room temperature. [b] Yield determined by 19F NMR analysis
with trifluoromethylbenezene as internal standard. [c] Without Pd cata-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
lyst. [d] Another CF3 reagent (4 equiv) was used instead of CF3À. [e] A
+
ACHTUNGTRENNUNG
ligand (15 mol%) was used. [f] 2,6-Di-tert-butylphenol (0.5 equiv) was
added. [g] TEMPO (0.5 equiv) was added.
owing to its strong oxidizing property (Table 1, entries 11
and 12). Furthermore, the controlling experiments demon-
+
strated that the electrophilic CF3 reagents 4[14] and 5[15]
were inappropriate for the transformation (Table 1, en-
tries 13 and 14). The reactions using the F+ reagent as an
oxidant also failed to generate the desired product (Table 1,
entries 15 and 16). Considering the potential effectiveness of
peridinyloxyl (TEMPO) and 2,6-di-tert-butylphenol were
conducted. Indeed, the side reaction was inhibited (Table 1,
entries 21 and 22). To our delight, the addition of TEMPO
(50 mol%) significantly improved the yields of product 2a
(82% yield). This observation is also a solid proof against
the possible radical pathway.
With the optimized reaction condition, the scope of this
trifluoromethylation was investigated with a variety of in-
doles, and the results are summarized in Table 2. First, dif-
ferent substituents on nitrogen were screened. Similar to N-
methyl-3-methylindole, the reactions of N-alkyl-3-methylin-
doles gave the corresponding products 2b–2d in moderate
to good yields, whereas N-phenyl-3-methylindole and N-
SEM-3-methylindole gave products 2e and 2 f in slightly
lower yields. However, only trace amount of 2g was ob-
ligands,
a series of nitrogen-containing ligands were
screened and ligand L2 proved to be the best (Table 1, en-
tries 17–20). However, in depth optimization of reaction
conditions, including the use of longer reaction time, in-
creased reaction concentration, and/or elevated tempera-
tures, did not improve the yields, whereas the starting mate-
rial 1a was completely consumed under these conditions.
Meanwhile, a small amount of side-product containing CF3
group on the benzene ring was isolated. These observations
implied the possible involvement of radical process in the
reaction which might account for the side reaction. Thus, at-
tempts to add radical traps, such as 2,2,6,6-tetramethyl-1-pi-
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Chem. Eur. J. 2011, 17, 6039 – 6042

Trifluoromethylation of Indoles
COMMUNICATION
Table 2. Pd-catalyzed oxidative trifluoromethylation of indoles.[a]
groups react slower, which indicated that the palladation of
indole proceeds through an electrophilic substitution pro-
cess. The highly selective trifluoromethylation of N-methyl-
indole is also in agreement with the strong preference for
the electrophilic substitutions of indoles at the C-3 posi-
tion.[16]
2i 75%
2j 71%
2k 61%
2l 70%
2m 66%
2q 60%
2n 33%
2o 56%[b]
2s 70%
2p 60%[b]
2t 51%
2r 67%
Based on the results shown above, possible catalytic
cycles were proposed: electrophilic palladation of indole
generates an (Ar)PdII intermediate, this species then under-
À
goes oxidation by PhIACTHNUTRGNEUNG
(OAc)2/TMSCF3 to form a (Ar)PdIV
R=Me 2u
65%
2w 39%
CF3 intermediate. Reductive elimination from the inter-
[6,7b]
À
mediate generates the aryl C CF3 bond (Scheme 1C).
R=Ph 2v
66%
In conclusion, we have developed a novel palladium-cata-
lyzed oxidative trifluoromethylation of indoles at room tem-
[a] Reaction conditions: 1 (0.2 mmol), Pd
ACHTUNGRTEN(NUNG OAc)2 (10 mol%), L2 (15 mol%),
PhI(OAc)2 (0.4 mmol), TEMPO (0.1 mmol), TMSCF3 (0.8 mmol), and CsF
(0.8 mmol) in CH3CN (2.0 mL) at room temperature; Yield of isolated prod-
uct. [b] CH3CN (4.0 mL).
ACHTUNGTRENNUNG
perature, in which PhIACTHNUTRGNE(NUG OAc)2 was used as an oxidant and
Ruppert–Prakash reagent, TMSCF3 as a trifluoromethyla-
tion reagent. Addition of the bidental nitrogen-containing
ligand L2 resulted beneficial to the reaction. In this reaction,
a PdII/IV pathway is proposed to lead to aryl C CF3 bond
À
tained from N-tosyl-3-methylindole. 3-methylindole is not
compatible for the oxidative condition owing to rapid de-
composition. Second, the indoles containing alkyl substitu-
ents, such as cyclic alkyl, isopropyl, and linear alkyl groups
(2i–2m), proved to be good substrates for this transforma-
tion, whereas indoles bearing electron-withdrawing groups
in C-3 position gave product 2n in poor yield. A variety of
functional groups on the benzene ring were also tolerated:
the electron-donating groups (2o–2q) or electron-withdraw-
ing groups (2r–2t) both provided moderate yields. Com-
pared with substrate 1a, the electron-rich substrates provid-
ed decreased yields despite rapid conversion (2o–2q, less
than 10 min), which implied that oxidative decomposition of
indoles might be a competitive process for these electron-
rich substrates. Finally, indoles bearing substituents in C-2
positions were also successfully transformed to 3-trifluoro-
methylated indoles (2u–2v) in good yields. Notably, the tri-
fluoromethylation of simple indoles (2w) exclusively took
place at the C-3 position, albeit in low yield.
formation. Further applications of this catalytic system to
new trifluoromethylation reactions are in progress.
Experimental Section
A representative procedure: In a 4 mL TFE sealed glass vial, Pd
ACHTUNGTRENNUNG(OAc)2
(4.4 mg, 0.02 mmol), PhI(OAc)2 (129 mg, 0.4 mmol), ligand L2 (9.8 mg,
AHCTUNGTRENNUNG
0.03 mmol), and TEMPO (15 mg, 0.1 mmol) were added. The glass vial
was transferred to a glove box to add CsF (122 mg, 0.8 mmol), and the
solution of indole 1 (0.2 mmol) in anhydrous CH3CN (2 mL) was added.
Sequentially, TMSCF3 (0.8 mmol, 120 mL) was immediately added and
the mixture was stirred for 6 h at RT. After the reaction was completed,
the solvent was removed under reduced pressure, and the residue was pu-
rified by fast chromatography in silica gel to give the desired com-
pound 2.
Acknowledgements
To gain some mechanistic insight into the process of this
reaction, a series of competition experiments were conduct-
ed in low conversion [Eq. (1)]. The indoles bearing an elec-
tron-donating group react faster than their unsubstituted
counterpart, and indoles bearing electron-withdrawing
We are grateful for the financial support from the Chinese Academy of
Sciences, the National Nature Science Founding of China (20821002,
20872155, 20972175, and 20923005), the Science and Technology Com-
mission of the Shanghai Municipality (08dj1400100), and 973 Program of
China (2009CB825300).
Chem. Eur. J. 2011, 17, 6039 – 6042
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www.chemeurj.org
6041

G. Liu et al.
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Commun. 2009, 1909; d) Q.-Y. Chen, S.-W. Wu, Chem. Commun.
1989, 705.
Keywords: homogeneous catalysis · indoles · oxidation ·
palladium · trifluoromethylation
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[14] The reaction can be achieved by using oxidant 3, but the corre-
+
sponding CF3 reagent can not. This observation rules out the possi-
+
ble pathway in which the electrophilic CF3 generated in situ acts as
À
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+
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À
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Received: January 26, 2011
A
Published online: April 19, 2011
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