Journal of the American Chemical Society
Communication
product 4 (entry 1), the choice of bidentate ligands was critical
to the coupling efficiency (see the Supporting Information for
details). A high level of chemoselectivity and catalytic activity
was observed when β-diketiminate ligands were employed. In
particular, derivatives having 2,6-dimethyl (L3) or 2,4,6-
trimethylphenyl substituents (L4) were the most effective
(entries 4 and 5). However, ligands of a strong electronic bias
(e.g., L1 or L5) were less effective.
Scheme 2. Working Hypothesis on β-Arylation of Carbonyls
An additional screen of base and oxidant additives showed
that a high efficiency could be achieved by tBuONa base (0.4
equiv) in combination with di-tert-butyl peroxide oxidant
(DTBP, 4 equiv) under the Cu/L4 catalyst system (entry 7).
However, moderate product yield was obtained with a
stoichiometric amount of DTBP under otherwise identical
conditions (entry 8). While most reported HAA processes
require substrates in excessive amounts,9c,12b,c the desired
arylation product 3 was obtained in good to high yields even
when 1.0−1.5 equiv of silyl enol ether 1 was employed (entries
9 and 10). The O-silyl group was found to be critical to the
coupling performance, as trimethylsilyl (TMS) and triisopro-
pylsilyl (TIPS) were less effective when compared to t-
BuSiMe2 (TBS, entries 13 and 14).
copper species.9c,12,13 In this process, the hydrogen atom
abstraction (HAA) from B was assumed to be catalyzed by
copper. Subsequently, the high-valent copper intermediate D
would undergo a reductive elimination to afford the desired β-
aryl ketones F. In this pathway, two allylic radical species (C
and C′) can be generated depending on which hydrogen is
abstracted (C3−H and C6−H), thus leading to regioisomeric
β-aryl and α-aryl carbonyl products, respectively.
At the outset, on the basis of our previous study in the
copper-catalyzed coupling of hydrocarbons with polyfluoroar-
enes,9c optimization of the current reaction conditions was
attempted by using a pregenerated O-silyl enol ether 1 (Table
1). While the reaction of 1 with tetrafluorobenzene derivative 2
was not effective without ligand mainly giving a biaryl side
Considering that O-silyl enol ethers can be easily accessible
from the corresponding carbonyls and that the O-silyl arylated
products are also readily desilylated, we envisioned to perform
the desired β-arylation of carbonyls without isolating two O-
silyl enol ethers for the preparative convenience (eq 1).
Table 1. Optimization of Coupling Conditions with
a
Pregenerated O-Silyl Enol Ethers 1
With the above optimized conditions in hand, the scope of
polyfluoroarenes was first explored in reactions with in situ
generated O-silyl enol ether 1, which was used without
purification (Scheme 3, conditions A). It also needs to be
emphasized that, upon the copper-catalyzed coupling of 1 with
fluoroarenes, initially arylated O-silyl enol products were
desilylated without isolation, eventually furnishing β-aryl
cyclohexanones. Tetrafluorobenzene derivatives having various
aryloxy or alkoxy substituents were all smooth in coupling with
1 to furnish the desired β-aryl cyclohexanone products upon
O-desilylation (5−9, 73%−91%). The structure of product 5
was confirmed by an X-ray crystallographic analysis. Notably,
product yields obtained from conditions A were generally
comparable to those of a procedure where a purified O-silyl
enol ether 1 was employed to couple with polyfluoroarenes
(conditions B). Fluoroarenes with phenyl, benzyl, alkyl, allyl,
or alkynyl substituents underwent the coupling efficiently to
afford the corresponding products in 50−78% yields (10−14).
The current catalyst system showed excellent functional group
tolerance, as demonstrated by the compatibility of secondary
and tertiary benzylic and even allylic C−H bonds. Moreover,
reactants containing heteroatomic substituents such as thio,
silyl, or amino were also compatible (15−19).
b
yield (%)
entry ligand 1 (equiv) tBuONa (equiv) DTBP (equiv)
3
4
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.5
1.5
1.5
1.5
0.8
0.8
0.8
0.8
0.8
0.8
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
4.0
4.0
4.0
4.0
4.0
4.0
4.0
1.0
4.0
4.0
4.0
4.0
4.0
4.0
7
18
6
30
61
34
<1
<1
14
<1
<1
<1
<1
<1
<1
<1
6
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
86
92
50
93
53
91
61
57
67
9
9
10
11
12
13
14
c
d
e
f
Penta- and isomeric tetrafluorobenzenes were facile toward
the current coupling with 1 under conditions A or B (20−22).
When bromo- or chloro-substituted fluorobenzenes were
subjected to the coupling conditions A, the reaction took
place selectively at the more acidic C−H bonds (23 and 24).
Likewise, difluoropyridine was also reacted at the C4 position
69
a
b
TBS was used as the silyl group except entries 13 and 14. NMR
c
d
e
yields of the crude reaction mixture. At 40 °C. At 80 °C. Si =
f
SiMe3. Si = Si(i-Pr)3.
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX