Ligand-Promoted Pd-Catalyzed Oxime Ether Directed C-H Hydroxylation of Arenes

Article abstract of DOI:10.1021/acscatal.5b01700

An efficient Pd-catalyzed oxime ether directed ortho C-H hydroxylation of arenes under neutral conditions has been developed. The efficiency of this hydroxylation is significantly improved by a ligand. Oxone, an inexpensive, readily available, and safe reagent, was employed as terminal oxidant and oxygen source. The challenging electron-deficient substrates could also be monohydroxylated in high efficiency. Drug modification with this protocol was also successfully demonstrated.

Full text of DOI:10.1021/acscatal.5b01700

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Letter
Ligand Promoted Pd-catalyzed Oxime
Ether Directed C-H hydroxylation of Arenes
Yu-Feng Liang, Xiaoyang Wang, Yizhi Yuan, Yujie Liang, Xinyao Li, and Ning Jiao
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 16 Sep 2015
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Ligand Promoted Pd-catalyzed Oxime Ether
Directed C-H hydroxylation of Arenes
†
†
†
†
†
,†,‡
Yu-Feng Liang, Xiaoyang Wang, Yizhi Yuan, Yujie Liang, Xinyao Li, and Ning Jiao*
†
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
‡
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
ABSTRACT. An efficient Pd-catalyzed oxime ether directed ortho C-H hydroxylation of arenes
under neutral conditions has been developed. The efficiency of this hydroxylation is significantly
improved by ligand. Oxone, an inexpensive, readily available, and safe reagent, was employed as
terminal oxidant and oxygen source. The challenging electron-deficient substrates could also be
monohydroxylated in high efficiency. Drug modification with this protocol was also successfully
demonstrated.
KEYWORDS. hydroxylation, C-H functionalization, palladium, oxygenation, chemoselectivity
The hydroxylation of aromatic compounds is a process of considerable industrial and
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academic importance. Direct oxidative hydroxylation of C-H bonds by transition metals has
2
,3
emerged as a powerful strategy for generating phenols in the past decade.
Ortho-
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acylphenols are useful synthetic intermediates and important subunits in bioactive molecules and
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natural products (Fig. 1). The direct C-H hydroxylation of ketones or ketoxime ethers which
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could be very easily converted into ketones, has been an extremely straight-forward and
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attractive strategy for the synthesis of ortho-acylphenols.
By using ketoxime ether substrates,
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Sanford and coworkers pioneeringly disclosed the directed C-H acetoxylation with PIDA or
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b
Oxone/AcOH oxidative system for the synthesis of corresponding esters, which can be
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converted to the hydroxyl products by an additional hydrolysis step (a, Scheme 1). The groups
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of Ackermann, Rao,
Dong, and Kwong groundbreakingly developed the efficient and
selective synthesis of ortho-acylphenols from acyl arenes via in situ hydrolysis of the
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a,12,13
8b
10,12
trifluoroacetoxylated intermediates with PIFA,
b, Scheme 1). Despite the significance, there still are some left challenging issues of this direct
hydroxylation chemistry: 1) The hydroxylation of strong electron-deficient substrates were less
PIDA/TFA or K
2
S
2
O
8
/TFA
reagents
(
8
,10,12,13
efficient,
deficient ortho-acylphenol derivatives especially for the important bioactive molecules (Fig. 1);
) The use of acid TFA or AcOH as solvent limited the functional group compatibility of these
which restricts the application of these protocols in the synthesis of electron-
14
2
transformations; 3) The selectivity for mono- and di-functionalization still has room to improve.
Therefore, a practical and efficient direct C-H hydroxylation under mild and especially neutral
conditions is still highly desired.
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Figure 1. Electron-deficient Ortho-acylphenols with Biological Activity.
a) Pd-catalyzed acetoxylation of ketoxime ethers with PIDA or Oxone/AcOH
O
O
OCOCH3
O
H
N
O
/
AcOH
O
N
OH
N
I
R2
Ph
OCOCH3 ref. 7a
hydrolysis
R1
R2
R2
R1
R1
Oxone/AcOH ref . 7b
b) Pd, Ru-catalyzed hydroxylation of ketones with PIFA, PIDA/TFA or K S O /TFA
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OCOCF3
O
O
H
O
ref. 8a,12,13
H
O
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aqueous
workup
Ph
OCOCF3
F3C
O
O
R2
R2
R1
R2
R1
OCOCH3
ref . 8b
/CF3COOH
R1
I
Ph
OCOCH3
K S O /CF COOH ref. 10,12
2
2
8
3
c) Pd-catalyzed direct hydroxylation of ketoxime ethers with Oxone (this work)
direct hydroxylation
O
cat.: Pd(OAc)2
O
H
N
OH
N
neutral conditions
electron deficient
substrates tolerated
ligand: PPh3 or DEAD
R2
Oxone
R2
R1
R1
CHCl CHCl
2
2
highly selective
mono-hydroxylation
Scheme 1. Strategies for C-H Hydroxylation.
Herein, we report a Pd-catalyzed direct ortho C-H hydroxylation ketoxime ether (c, Scheme 1).
The following significances exist in this chemistry: 1) The substrate scope is broad including the
challenging electron-deficient substrates with highly selectively monohydroxylated products
formation; 2) The inexpensive, readily available, easily handled, and safe solid oxidant Oxone
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(
potassium peroxymonosulphate), was employed as oxidant and oxygen source; 3) The reaction
proceeded cleanly under neutral condition without addition of acid and could be easily scalable;
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) The modification of drug derivative, which contains a thioether moiety, was demonstrated by
this protocol.
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Table 1. Optimization of the Reaction Conditions
a
Standard conditions: 1a (0.3 mmol), [Pd] (5 mol%), ligand (10 mol%), oxidant (1.2 equiv),
o
b
2 2
solvent (1 mL) was stirred at 100 C for 24 h under air. Isolated yields. TCE = CHCl CHCl .
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With our continuous interest the oxidative hydroxylation of C-H bonds, we initially tried to
investigate the direct hydroxylation of the corresponding O-methyl oxime derivative of 4-
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,10,12,13
nitroacetophenone (Table 1), which could not be hydroxylated in previous methods.
our delight, when 1a was stirred in DMF in the presence of Pd(OAc) , the hydroxylated product
2a was obtained although in low yield (entry 1). Solvent screening showed that CHCl CHCl
was superior to CH CN, DCE, and PhCl (entries 2-3, also see SI). It is noteworthy that
significant improvement was achieved when PPh was employed as ligand (87% yield, entry
). Since the phosphine compound could be oxidized to phosphine oxide in oxidative
To
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conditions, in contrast, the reaction proceeded sluggishly when POPh was used as ligand, which
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indicated the active ligand was PPh
3
itself not its oxide POPh
3
(entry 5). But it should be
mentioned that there were lots of PPh
3
was oxidized to POPh after the reaction (see SI).
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However, the use of 2,2'-bipyridine or 1,10-phenanthroline did not work (see SI). Interestingly,
diethyl azodicarboxylate (DEAD) could also be an efficient ligand with a slightly low efficiency
(
entry 6). On the contrary, other oxidants such as K S O , TBHP, H O , as well as O were found
2 2 8 2 2 2
to be ineffective (entries 7-8, also see SI). Some other Pd catalysts were tested in the reaction as
well, such as PdCl , PdTFA , and Pd dba , but were less efficient than Pd(OAc) (entries 9-11).
Clearly, product 2a was not generated in the absence of a palladium catalyst or an oxidant
entries 12-13).
2
2
2
3
2
(
a
Table 2. C-H Hydroxylation of Electron-deficient Acetophenone Oxime Ethers
a
Reaction conditions: 1 (0.3 mmol), Pd(OAc)
2
(5 mol%), PPh
3
(10 mol%), Oxone (1.2 equiv),
o
b
CHCl
Pd(OAc)
2
CHCl
3 2
and 20 mol% of PPh . With 10 mol% of Pd(OAc) and 20 mol% of DEAD.
2
(1 mL) was stirred at 100 C for 24 h under air. Isolated yield. With 10 mol% of
c
2
With these optimized conditions in hand, we were extremely interested in the present
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transformation with electron-deficient substrates (Table 2). Significantly, the hydroxylation of
substrates with electron-withdrawing substituents, such as NO , CF , CN, COOCH , Ms, and
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COOH, was very efficient and produced high yields of corresponding products (2a-2f), which
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demonstrates a good complementary to previous hydroxylation methods.
Moreover, the
halogen substituents were well tolerated under the oxidizing reaction conditions (2g-2k). The
meta-substituted substrates afforded the less sterically crowded isomers (2l-2n). The ortho-
3
substituted acetophenone oxime ethers resulted in trace amount of products by using PPh as
ligand, which was likely due to steric congestion between the directing group and the ortho
substituent. To our delight, the efficiency could be significant improved by the use of DEAD as
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additive (2o and 2p).
Table 3. C-H Hydroxylation of Electron-neutral and Electron-rich Acetophenone Oxime
a
Ethers
a
Reaction conditions: 3 (0.3 mmol), Pd(OAc)
2
(5 mol%), PPh
3
(10 mol%), Oxone (1.2 equiv),
o
b
o
c
CHCl
mol% of Pd(OAc)
2 2
CHCl (1 mL) was stirred at 100 C for 24 h under air. Isolated yield. At 80 C. With 10
d
2
3 2
and 20 mol% of PPh . With 10 mol% of Pd(OAc) and 20 mol% of DEAD.
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Furthermore, a variety of electron-neutral and electron-rich acetophenone oxime ethers were
readily converted to the corresponding products (4a-4j) in excellent yields (Table 3). Substrate
containing two oxime ether directing groups could afford product (4k) with two OH groups.
In addition, the different O-methyl oximes as substrates were also tested (Table 4).
Interestingly, in contrast to previous work which afforded a mixture of products in many
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examples,
the reactions highly selectively generated monohydroxylated products (6a-6g)
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without the detection of dihydroxylated products or C(sp )-H functionalized products. It is
noteworthy that the OH, Cl, COOEt and acrylic ester groups were well compatible (6h-6k).
Interestingly, the hydroxylation of 4-tert-butylbenzaldehyde O-methyl oxime could also
proceeded although gave the hydroxylated product in relative low yield (6l). Moreover, the
cyclic O-methyl oximes can be tolerated in this transformation to produce desired products in
excellent yields (6m-6o). The reaction of 2-acetonaphthone O-methyl oxime generated the β’-
hydroxylated product (6p).
Table 4. Substrate Scope of Different O-methyl Oximes
O
O
H
N
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
OH
N
R2
Oxone
R2
R1
R1
CHCl CHCl
2
2
o
5
80 C, 24 h
6
O
O
O
OH
N
OH
N
OH
N
6a: R = H, 96%
6b: R = CH3, 98%
6c: R = OCH3, 96%
6d: R = F, 96%a
R
R
6e: 88%
6f: 94%
O
O
O
O
OH
N
OH
N
OH
OH
N
OH
N
OH
Cl
COOCH3
O
5
Ph
N
6g: 96%
6h: 78%
6i: 95%
6j: 72%
OH
O
N
O
N
O
H
OH
OH
N
COOEt
R
X
t-Bu
6
6
m: R = H, X = CH2, 94%
n: R = H, X = O, 85%
k: 52%a,b
6l: 32%a,b
6p: 78%
6
6o: R = OCH , X = CH , 93%
3
2
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a
o
b
At 100 C. With 10 mol% of Pd(OAc)
2
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and 20 mol% of PPh .
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Notably, this hydroxylation process with Oxone is extremely attractive because it can be easily
performed in gram-scale [eq. (1)], which shows great potential for further applications. The
oxime group could be easily reduced to amino group by ZrCl and NaBH to afford ortho-
aminomethylphenol 7. And the removal of the directing group to afford ortho-acylphenol 8 was
also easily achieved by the treatment with HCl in Et O [eq. (1)].
4
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2
In order to demonstrate the synthetic utility of this C-H hydroxylation reaction to complex
bioactive molecules, zaltoprofen (a nonsteroidal anti-inflammatory drug) O-methyl oxime
methyl ester derivative 9 was conducted under the hydroxylation conditions with DEAD as
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ligand. We successfully isolated the hydroxylated product 10 in 62% yield [eq. (2)], which can
offer a novel protocol for the synthesis of zaltoprofen analogues. The thioether moiety was well
compatible with this C-H hydroxylation process.
To further probe the reaction mechanism, some control experiments were investigated. Firstly,
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the reaction proceeded well under Ar or O
2
atmosphere instead of air and none of O-labled
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product was detected [eq. (3)]. When H
2
O (2.0 equiv) was added into the reaction, the yield
1
8
was significant decreased without the detection of 4a- O [eq. (4)], which excludes the
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possibilities of the oxygen atom in the produced hydroxyl group generated from O in air or
2
water in the solvent. These results suggest that the additional oxygen atom in product originated
from Oxone. No superoxide radical or hydroxyl radical signal was observed when this reaction
was detected in situ by EPR (electron paramagnetic resonance) (see SI). In addition, it is well
2
1
recognized that Oxone could generate singlet oxygen, which would be the species responsible
for this oxidative hydroxylation. However, the trapping experiment with 9,10-
dimethylanthracene 11 under the standard conditions did not afford the endoperoxide product 12
1
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1
formed through [4+2] cycloaddition involving O
2
[eq. (5)], which indicated that the O
2
was
not produced in this transformation. Furthermore, the intermolecular k
H
D
/k of 3a was determined
to be 2.6 [eq. (6)], which indicated that the C-H activation process should be irreversible.
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
Ar: 4a, 87%
3
a
a
Oxone
Oxone
(3)
CHCl2CHCl2
100 oC, 24 h
Ar or 18O2
18O2: 4a, 87%
a-18O, 0%
4
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
(4)
3
4a, 10%
CHCl2CHCl2
o
4a-18O, 0%
1
00 C, 24 h, air
18
H2 O (2.0 equiv)
O
Pd(OAc)2 (5 mol%)
O
PPh3 (10 mol%)
Oxone
1
1
(5)
(6)
CHCl2CHCl2
100 oC, 24 h, air
9
5% recovered
1
1
12, 0 %
O
O
D
N
O
N
N
OH
D
D
one pot
KIE = 2.6
H/D
D
3a
3a-d5
4a/4a-d4
D
On the basis of above results, although the mechanism is not completely clear yet, a catalytic
II
cycle of the present Pd -catalyzed direct C-H hydroxylation is tentatively illustrated in Scheme 2.
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II
II
Initially, the active Pd L
2
catalyst is generated from the combination of Pd salt and ligand,
II
followed by coordination of the N atom of oxime ether to Pd and the subsequent C-H activation
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produces intermediate A. Then the oxidation of the intermediate A by potassium
IV
peroxymonosulphate (KOSO
2
OOH), the active ingredient of Oxone, affords a Pd intermediate
B, which finally, undergoes reductive elimination to form the desired hydroxylated product with
II
the regeneration of Pd -catalyst. The important role of ligand may accelerate the C-O bond
0
II
reductive elimination step. Alternatively, the Pd /Pd catalytic cycle could not be excluded.
Scheme 2. Proposed Reaction Mechanism
In summary, we have developed an efficient ligand promoted Pd-catalyzed oxime ether
directed ortho C-H hydroxylation of arenes using Oxone as oxidant. The protocol features an
ample substrate scope particularly for the challenging electron-deficient substrates. The highly
selective mono-hydroxylated products were obtained in high efficiencies. Deep studies into the
detailed reaction mechanism and further application are ongoing in our laboratory.
ASSOCIATED CONTENT
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Supporting Information. Experimental procedures, analytical data for products, NMR spectra
of products. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jiaoning@pku.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Basic Research Program of China (973 Program) (grant No.
2015CB856600) and National Natural Science Foundation of China (Nos. 21325206, 21172006)
and National Young Top-notch Talent Support Program are greatly appreciated. We thank Kai
Wu in this group for reproducing the results of 2h and 4k.
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hydroxylation. DEAD may play as a ligand in this transformation.
(
20) The use of PPh
yield. Both PPh and DEAD played important role in this transformation. Except for the
substrates with steric effect, such as ortho-substituted acetophenone oxime ethers 1o, 1p, and 3j,
3
instead of DEAD as ligand produced the hydroxylated product in 25%
3
3
or thio-containing substituents, such as substrate 9, PPh is more efficient than DEAD for this C-
H hydroxylation.
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