L. Wang et al. / Tetrahedron Letters 56 (2015) 3754–3757
3755
Table 2
Previous work
Substrate scope of C–H arylationa,b
a
Pd(II) or Rh(I)
X = Cl, Br or I
X
R
B(OH)2
R
Ph
b
c
[RhCp*Cl2]2
N
N
Pd(II)
Ph
+
+
I
Ph
N
R
N
CF3COOAg
N
N
BF4
N
N
MeOH, 60 oC
R
Pd(II)
R = H, alkyl or aryl
X
1
2a
3
X = BR2, or SiR3
R = 4-Me, 99%, 3ba
R = 4-CO2Me, 94%,
R = 5-Me, 99%, 3da
d
e
R
Ru(II) or Co(III)
3ca
4
X
3
5
X = Cl or Br
Ph
Ph
R
Ph
R = 5-OMe, 97%, 3ea
2
Rh(III)
N
N
+
N
N
3fa
R = 5-OBn, 97%,
R = 5-Cl, 99%, 3ga
SiR3
7
N
X
N
N
N
X
N
N
3ha
R = 5-Br, 98%,
Rh(III)
R = 5-CN, 98%, 3ia
R = 5-NO2, 63%, 3ja
BR2
This work
X = C or N
R = Me, 94%, 3oa
R = CO2Me, 71%,
3ka
R = 6-Me, 99%,
3pa
R = 6-F, 98%, 3la
Scheme 1. Direct C–H arylation of indoles.
3ma
R = 6-Br, 97%,
R = 7-Me, 95%, 3na
Ph
Ph
Ph
N
further improved to 98% and the reaction time could be shortened
to 6 h when AgOOCCF3 was used in this C–H arylation process
(Table 1, entry 5). It was worthy to note that high reaction activity
could be also maintained even at lower reaction temperature
(Table 1, entry 8). Next, a survey of the reaction media revealed
that protic solvents such as EtOH and i-PrOH were effective reac-
tion medium. Other solvents, such as toluene, CH3CN or DMF were
almost ineffective for this transformation (Table 1, entries 12–16).
The control experiment confirmed that the transformation did not
occur in the absence of the catalyst.
N
N
MeO2C
N
N
N
N
N
Br
3qa
3ra
3sa
90%,
98%,
Reaction conditions:
94%,
a
1
(0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (1.0 mol %),
AgOOCCF3 (0.8 mmol) and MeOH (1.0 mL), 60 °C, 4–6 h under Ar.
b
Isolated yields.
loss in reaction efficiency. The reaction showed good functional
group compatibility. The reaction of indoles with electron-with-
drawing groups, such as a fluoro, chloro, bromo, cyano, and ester
groups, worked efficiently and generated the corresponding prod-
ucts 3la, 3ga, 3ha, 3ma, 3ia, and 3ca in excellent yields. These
functional groups could be used for further functionalization and
applications in organic synthesis. Tolerance to strongly electron-
deficient NO2-group, which was less explored in C–H functionliza-
tion of indole core, was especially noteworthy since it was a useful
functional handle for further amination. Perhaps more impor-
tantly, substituents at the C3- and C7-position of indole (3oa,
3pa, and 3na) not only demonstrate that steric interactions were
well tolerated, but also excellent regioselectivity was observed in
our catalytic system. Besides the pyrimidine group, substrate with
pyridine as a directing group also worked well with 94% yield
(3ra). Importantly, this protocol could also be successfully applied
to pyrrole substrate to provide 90% yield of the corresponding pro-
duct 3sa.
With the optimal conditions in hand, we subsequently investi-
gated its scope in the C2-selective arylation of diverse N-pyrimidyl
indoles. As shown in Table 2, N-pyrimidyl indoles containing elec-
tron-donating and electron-withdrawing groups from C3 to C7
position proceeded smoothly to give the desired products in good
to excellent yields in short reaction time. A number of alkyl and
alkyoxyl substituents (3ba, 3da–3fa, 3ka, and 3na) can be incorpo-
rated on the indole ring at various positions without significant
Table 1
Optimization of reaction conditions
B(OH)2
[RhCp*Cl2]2
Oxidant
N
N
+
N
N
N
N
Solvent,
T
1a
2a
3aa
Encouraged by those excellent results, the scope of the C–H ary-
lation reaction was further extended to different functionalized
arylboronic acids (Table 3). A large variety of arylboronic acids
bearing electron-donating (Me, OMe, t-Bu, and OCF3) and elec-
tron-withdrawing (CF3, CN, CO2Me, Cl, and F,) groups proceeded
efficiently to produce the arylated products (3ab–3al) in excellent
yields. These results clearly indicated that there was no obvious
correlation between the yield and the electronic effect of the sub-
stituent. Particularly, substrate with a strongly electron-withdraw-
ing NO2-group could also successfully participate in this catalytic
transformation, affording the corresponding product (3am) with
97% yield. Notably, the acetyl group on the aryl ring was compati-
ble in this catalytic process and the desired product 3ai was
obtained in a nearly quantitative yield. The current catalytic sys-
tem was not restricted to the use of monosubstituted substrate,
but also allowed for different disubstituted arylboronic acids
(3an–3ao). Additionally, the thiopheneboronic acid was also found
to be a good coupling-partner (3ap).
Entrya
Oxidant
Temp (°C)
Solvent
t (h)
Yield (%)b
1
2
3
Ag2O
Cu(OAc)2
AgOAc
Ag2CO3
AgOOCCF3
AgBF4
AgSO3CF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
AgOOCCF3
60
60
60
60
60
60
60
40
25
60
60
60
60
60
60
60
60
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
i-PrOH
t-BuOH
THF
Toluene
CH3CN
DMF
24
24
24
24
6
24
24
24
24
24
24
24
24
24
24
24
24
55
53
91
59
98(98)
23
18
94
55
95
72
10
21
5
4
5c
6
7
8
9
10
11
12
13
14
15
16
17d
8
14
—
MeOH
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (1.0 mol %),
oxidant (0.8 mmol) and solvent (1.0 mL) under Ar.
b
Isolated yields.
In order to gain an understanding of more details on the reac-
tion, the competition experiments between different substituted
indoles indicated that electron-rich indole 1e was preferentially
c
Yield in parentheses without any particular precautions to extrude oxygen or
moisture.
d
Without catalyst.