via CꢀH bond activation.12 Later, he also developed a
palladium migration process involving CꢀH bond activa-
tion to provide the same subunit.13 Recently, Cheng
carried out the Pd-catalyzed cascade reaction of oxime
directed dual CꢀH activation and Heck cyclization to
furnish fluorenones.14 Shi at a similar time also addressed
the same issue by a different protocol.15 In this context,
the independent reports by Cheng16 and Shi17 have dis-
closed dual CꢀH activation of diarylketones to provide
fluorenones.
Table 1. Optimization of Reaction Conditionsa
yieldb (%)
temp
For those reactions involving CꢀH activation, directing
groups are often required to assist in activating the CꢀH
bond. Various functional groups were reported as direct-
ing groups; however, there are only two examples regard-
ing the Pd-catalyzed nitrile directed CꢀH functionaliza-
tion.18 Our experience in the catalytic coupling reactions
involving nitriles19 encouraged us to explore the possibility
for the combination of CꢀH bond activation with
1,2-insertion of nitriles. Herein, we wish to report the first
example of an efficient and convenient Pd-catalyzed syn-
thetic pathway for the CN directed remote CꢀH and dual
CꢀH bond activation with intramolecular 1,2-insertion of
nitriles.
We initiated our studies by using 2-phenylbenzonitrile
(1a) as a model substrate (Table 1, entry 1), which was
treated with 10 mol % of Pd(OAc)2 in TFA at 120 °C for
24 h. However, only 12% NMR yield of desired product
(4a) was observed. Some of the substrate was maintained,
but most of them underwent hydrolysis to form corre-
sponding amide (5a).
entry
[Pd]
additive
solvent
TFA
PivOH
AcOH
TFA
(°C) 1a 4a 5a
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
none
none
none
120 15 12 54
120 92
120 60
0
3
0
26
140
120 43 28 16
AgTFA Benzene/TFA 120 27 68
0 27 52
5
AgTFA TFA
6c
7c
8c
9c
0
AgTFA DMF/TFA
AgTFA DME/TFA
AgTFA DMA/TFA
AgTFA DMSO/TFA
AgTFA DMA/TFA
AgTFA DMA/TFA
AgTFA DMA/TFA
AgTFA DMA/TFA
120 96
120 62
120 85
120 97
0
0
8
0
0
31
0
10c Pd(OAc)2
11c Pd(OAc)2
12c,d Pd(OAc)2
13c Pd(OAc)2
14c,d Pd(TFA)2
15c,d Pd(MeCN)2Cl2 AgTFA DMA/TFA
16c,d Pd(PPh3)2Cl2 AgTFA DMA/TFA
17c,d none
0
140 67 26
0
140
160
140
140
140
0
3
0
0
0
84
74
79
91
62
0
0
6
0
0
0
0
AgTFA DMA/TFA
140 94
a Reactions were carried out using 0.2 mmol (1.0 equiv) of 1a with
10 mol % of [Pd], 20 mol % of additive and H2O (1.1 equiv) in 0.45 mL of
solvent at the indicated temperature for 24 h. b 1H NMR yields based on
internal standard mesitylene. c TFA (0.3 mL), cosolvent (0.15 mL). d 72 h.
To understand the nature of present Pd-catalyzed nitrile
directed remote CꢀH bond activation with nitrile inser-
tion, the effect of solvents, additives, reaction tempera-
tures, and palladium sources were investigated (Table 1).
It was found that the use of other organic acids as solvents
could not improve the catalytic reaction (entries 2 and 3).
In addition, we further investigated the additives and
found that AgTFA significantly reduced the rate of hydro-
lysis. Other additives performed as Lewis acids, facilitating
thehydrolysis butnotimprovingthecyclization.20 Wethen
reduced the amount of TFA and employed other cosol-
vents (entries 6ꢀ10). It was observed that the highly polar
solvents such as DMF, DMA, and DMSO successfully
suppressed the formation of amide (5a), and DMA was
found to be superior to other solvents. Increasing the reac-
tion temperature and reaction time led to higher con-
version of desired product (entries 11ꢀ13). The presence
of palladium sources were also surveyed for the Pd catalysis
(entries 14ꢀ16); among the various palladium complexes
employed, Pd(MeCN)2Cl2 was found to be the most
effective for this transformation, increasing the yield of
4a to 91% NMR yield (entry 15). Moreover, the desired
product was not obtained in the absence of palladium
complex (entry 17).
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The Pd-catalyzed CꢀH activation with nitrile insertion
was successfully extended to various substrates (1), and the
results are listed in Scheme 1. The reactions required at
least 72 h to fully consume the substrates (1). As indicated,
reactions worked well for various substrates and elec-
tron density of the terminal aryl ring dramatically affects
the cyclization (Scheme 1). Thus, substrates with an
2012, 48, 9379.
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(20) See the Supporting Information for detailed studies.
B
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