Palladium Nanoparticles for Direct C2 Arylation of Indoles
is similar to the corresponding homogeneous reaction cata-
FULL PAPER
Table 3. Direct arylation of N-methylindole with various aryl halides.[a]
lyzed by PdACHTUNGTRENNUNG
(OAc)2.[3]
As shown in Table 2, the amount of catalyst is also very
important for this reaction. The reaction does not take place
in the presence of only MIL-101(Cr). The use of 0.05 mol%
Pd catalyst gave only 31% yield (Table 2, entry 13). It is
very interesting that N-methylindole can be activated effec-
tively by only 0.1 mol% Pd catalyst, which gave a very high
yield (86%, Table 2, entry 5). In contrast, higher catalyst
loadings (up to 0.5 mol%) are generally required in the ho-
mogeneous catalyst system.[3–7] It should be noted that in
most cases only traces of the byproduct biphenyl were ob-
tained from the palladium-catalyzed Ullmann coupling reac-
tion of iodobenzene.[3c,12a] However, increasing the amount
of the catalyst (starting from 0.5 mol% Pd) led to a steady
decrease of the yield of the desired product, but an increase
of the yield of the byproduct biphenyl (Table 2, entries 14–
16). This observation indicates that the Ullmann coupling
reaction represents a key competitive process of the direct
C2 arylation of N-methylindoles. Consequently, a decrease
of the catalyst amount can favor the production of the de-
sired product and suppress the formation of biphenyl, which
requires a bimolecular transmetalation of the aryl–palladium
species.[3c] The influence of the reaction time was also exam-
ined. Considering the slow diffusion of the reactants to
reach accessible metal sites in the pores and the low catalyst
loading, a long reaction time (about 24 h) was necessary to
obtain good yields of the desired product. It is worthy
Entry
1
X
I
R3
H
Product
Yield [%][b]
85
2[c]
3[d]
4
Br
Cl
I
H
H
31
21
89
4-CN
5
I
3-CN
83
6
7
8
9
I
I
I
I
4-CF3
4-COOEt
4-Me
88
86
84
74
4-OMe
10
I
I
3-OMe
2-OMe
71
49
noting that reactions catalyzed by PdACTHNUTRGENUG(N OAc)2 also need pro-
11[e]
longed reaction time (24 h) to give good yields.[3]
For comparison, different supported palladium catalysts
have been examined under the same conditions. A commer-
cial Pd/C catalyst (5 wt% Pd) only gave traces of the C2-ar-
ylation product and 22% of the byproduct biphenyl
(Table 2, entry 22). A low activity was also observed for our
previous palladium-supported MIL-53(Al)-NH2 catalyst
(Table 2, entry 23), which exhibits high activity for the
Suzuki reaction.[19] The high activity of Pd/MIL-101(Cr), as
compared to Pd/C and Pd/MIL-53(Al)-NH2, may be as-
cribed to the larger surface area and accessible mesoporous
cages of MIL-101, which may ensure the high dispersion of
the palladium active sites and facilitate the diffusion of the
reactants and the large product molecules in the pores.[12a]
Moreover, it can not be excluded that the enhanced surface
Lewis acidity of MIL-101(Cr) may favor the adsorption of
the aryl halides, and thus enhance the activity.[12a,b]
[a] Conditions: N-methylindole (1 mmol), substituted iodobenzene
(1.2 mmol), CsOAc (2 mmol), cat. (0.1 mol% Pd), DMF (3 mL), 1208C,
24 h, under air. [b] Yield of isolated product. [c] Bromobenzene
(2 mmol), 1508C, 48 h. [d] Chlorobenzene (2 mmol),1508C, 48 h. [e] 2-
Methoxyl-iodobenzene (2 mmol), 5% of the C3-arylation product were
obtained, based on GC-MS.
of substituted iodobenzenes, bearing electron-withdrawing
groups (CN, CF3, and COOEt), with N-methylindole, giving
excellent yields (Table 3, entries 4–7). Electron-rich func-
tional groups in para and meta position to the iodine are
also well tolerated in these reactions. Reactions between N-
methylindole and a variety of iodobenzenes substituted with
electron-donating groups (4-Me, 3-OMe, and 4-OMe) gave
the C2-arylation products in good yields (Table 3, entries 8–
10). Notably, the sterically hindered 2-iodoanisole, bearing
an electron-donating group, also proceeded smoothly, af-
fording the corresponding C2-arylation product in moderate
yield (Table 3, entry 11). It should be noted that only traces
of the C3-arylation product were obtained for the above-
mentioned, substituted iodobenzenes, except for 2-iodoani-
sole (about 5% of the C3-arylation product were obtained,
due to the sterically hindrance).[3]
We next examined the scope of the reactions with a varie-
ty of substituted aryl halides (Table 3). Due to the high
À
À
bond energy of the C Br and C Cl bonds, the activation of
bromobenzene and chlorobenzene is difficult. Therefore, the
reaction of bromobenzene/chlorobenzene with N-methylin-
dole required harsh conditions and extended reaction time.
Unfortunately, even at 1508C after 48 h low yields were ob-
tained for the reaction of bromobenzene/chlorobenzene
with N-methylindole (Table 3, entries 2 and 3), which is sim-
Subsequently, the influence of the substituent group at
the indole on the direct arylation reactions was also exam-
ined. It was found that the process catalyzed by Pd NPs is
ilar to the Pd
the reactions proceeded extraordinarily well with a variety
ACHTUNGTRENNUNG
(OAc)2-catalyzed reactions.[3–7] Interestingly,
Chem. Eur. J. 2011, 17, 12706 – 12712
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12709