.
Angewandte
Communications
Table 1: Selected optimization of the reaction conditions.[a]
would be a more step-economical approach to synthesize
o-acylphenols if ketones could be directly employed as the
DG for the catalytic arene hydroxylation reaction.[22]
Although rare compared to other directed reactions,
À
ketone-directed catalytic C H functionalization has been
documented for almost two decades since the pioneering
Entry Catalyst
Oxidant[b] Solvent
DCE
T [8C] Conv.
Yield
[%][c]
À
work on Ru-catalyzed C H/olefin coupling reactions by
[%][c]
Murai et al.[23] However, most of these transformations are
[24]
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2 DIB
Pd(OAc)2 DIB
80
80
80
80
80
80
80
80
80
80
80
80
80
<5
12
100
30
17
22
100
100
15
8
100
12
0
0
83
7
8
0
79
78
0
0
84
4
À
restricted to C C bond formations (by the groups of Murai,
AcOH
DCE
dioxane
THF
MeCN
DCE
DCE
Chatani,[25] Miura,[26] Brookhart,[27] Cheng,[28] Glorius,[29]
Jeganmohan,[30] Shi,[31] and others). Only recently, the
groups of Liu[32] and Glorius[33] reported the first ketone-
Pd(TFA)2 BTI
Pd(TFA)2 BTI
Pd(TFA)2 BTI
Pd(TFA)2 BTI
Pd(OAc)2 BTI
Pd(OPiv)2 BTI
À
À
directed C N and C Br/I bond-forming reactions using Pd
and Rh catalysts, respectively. To the best of our knowledge,
À
catalytic ketone-directed arene oxidation to form C O bonds
PdCl2
Pd(TFA)2 DIB
BTI
DCE
has not been previously described. The likely challenges are:
1) As a hard Lewis base and even weaker s donor (compared
to oximes, amides, carboxylic acids, and esters), ketones
generally do not coordinate strongly with TMs,[34] which leads
to lower reactivity. 2) Undesired oxidations (particularly with
oxygen-based oxidants) can occur either at the enolizable
DCE
DCE
DCE
DCE
11[d] Pd(TFA)2 BTI
12 Pd(TFA)2 KPS
13[e] Pd(TFA)2 KPS
(TFA)
Pd(OAc)2 KPS
Pd(OAc)2 KPS
36
17
14
15
TFA
TFA/DCE
(1:1)
50
100
88
77
50
100
À
À
a C H bond or at the a C C bond of the ketone through
a Baeyer–Villiger-type oxidation.[35]
16
17
–
–
BTI
DCE
80
50
<5
<5
0
0
À
Stimulated by the previous success of C H activation
KPS
TFA
driven by weak coordination[15,17] and the need for efficient
synthesis of o-acylphenols from arylketones, we pursued this
challenge using a Pd-catalyzed formal arene hydroxylation
reaction. It was envisioned that the above-mentioned chal-
lenges could potentially be overcome by: 1) increasing the
Lewis acidity of the metal and 2) using milder oxidants and
reaction conditions. Herein, we report the use of ketone
carbonyls as DGs for a Pd-catalyzed ortho-selective formal
hydroxylation of arenes to provide various 2-acylpheonols;
preliminary results of the first ketone-directed oxidative
carbonylation to give an unusual ketal–lactone are also
described.
[a] The reactions were run on a 0.2 mmol scale with 1 mL solvent over
3 h. [b] In all cases, 2 equiv of oxidant was used. [c] Determined by
1H NMR spectroscopy using mesitylene as the internal standard.
[d] 2mol% catalyst loading, reaction time 9 h. [e] Reaction time 9 h.
BTI=[bis(trifluoroacetoxy)iodo]benzene, DCE=1,2-dichloroethane,
DIB=(diacetoxyiodo)benzene, KPS=K2S2O8, Piv=pivaloyl, TFA=tri-
fluoroacetic acid.
place of BTI, even when using Pd(TFA)2 as a catalyst
(entry 10; see below for a mechanistic discussion). Further-
more, the reaction gives full conversion with 84% yield in 9 h
when the catalyst loading is lowered to 2 mol% (entry 11).
Less expensive inorganic oxidants, such as K2S2O8 (KPS),
have also been examined. The desired product was obtained
in 4% yield by simply replacing BTI with KPS (entry 12). The
yield was improved to 17% when 2 equiv of TFA was added
(entry 13). Towards the end, complete conversion with 88%
yield was obtained when using TFA as the solvent and KPS
(2 equiv) as the oxidant (entry 14). Note that the reaction
proceeds at a lower temperature (508C) with the less
expensive Pd(OAc)2 as a pre-catalyst, thus it is complemen-
tary to the conditions described in entry 11. Although it is well
recognized that BTI is able to oxidize electron-rich aromatic
compounds through a single-electron transfer mechanism,[38]
control experiments indicated that neither of the conditions in
entries 16 or 17 showed significant reactivity in the absence of
Pd.
We initiated our studies by examining the ortho-oxidation
of 2,2-dimethylpropiophenone, a problematic substrate for
the Fries-rearrangement.[36] Different PdII precatalysts, oxi-
dants, and solvents were tested (Table 1). Not surprisingly, the
standard Pd(OAc)2 and PhI(OAc)2 (DIB) combination,
which is commonly used in nitrogen-based DG-directed
C H oxidations,[19,14c] did not give any of the desired product
À
at 808C in 1,2-dichloroethane (DCE) or AcOH (Table 1,
entries 1 and 2). A search for more electrophilic catalysts and
oxidants was pursued. Eventually, Pd(TFA)2 (5 mol%) with
PhI(TFA)2 (BTI; 2 equiv) was found to give quantitative
conversion with 83% yield of the desired ortho-oxidation
product (entry 3). Trifluoroacetate 3a is the initial product
generated, which is confirmed by both GC-MS and NMR
analysis. We were delighted to discover that compound 3a is
labile, and readily converts into the corresponding phenol
(2a) upon purification by column chromatography with silica
gel. The use of other solvents, such as dioxane, THF, and
MeCN, in place of DCE proved much less effective (entries 4–
6). Interestingly, when BTI is used as an oxidant, comparable
yields can be obtained when Pd(TFA)2 is replaced by either
With the optimized conditions in hand, we next inves-
tigated the substrate scope of this reaction (Scheme 2). A
variety of aromatic ketones smoothly underwent the ortho-
hydroxylation. Both aryl and alkyl-substituted ketones with
different steric properties gave satisfying yields of the
correspond o-acylphenols. Note that benzylic and enolizable
hydrogens, which can participate in various oxidation reac-
Pd(OAc)2 or Pd(OPiv)2, whereas this was not the case for
[37]
PdCl2
(entries 7–9). In contrast, DIB cannot be used in
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 13075 –13079