One-pot synthesis of ortho-acylphenols by palladium-catalyzed phenol C–H addition to nitriles

Article abstract of DOI:10.1016/j.tetlet.2017.09.062

The regioselective one-pot synthesis of ortho-acylphenols via the palladium-catalyzed addition of phenols to nitriles and subsequent hydrolysis is reported. The acylation reaction proceeded smoothly using the Pd(OAc)₂/DMSO system and TFA as the additive. This method also provides a direct strategy for the synthesis of a salicylketoxime scaffold.

Full text of DOI:10.1016/j.tetlet.2017.09.062

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of ortho-acylphenols by palladium-catalyzed phenol
C–H addition to nitriles
Tao-Shan Jiang a,c, Bei Gan b,c, Xi Wang b, Xiuli Zhang b,
⇑
a School of Life Sciences, Anhui Agricultural University, Hefei 230036, PR China
b Department of Chemistry, Anhui Agricultural University, Hefei 230036, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective one-pot synthesis of ortho-acylphenols via the palladium-catalyzed addition of phe-
nols to nitriles and subsequent hydrolysis is reported. The acylation reaction proceeded smoothly using
the Pd(OAc)2/DMSO system and TFA as the additive. This method also provides a direct strategy for the
synthesis of a salicylketoxime scaffold.
Received 17 July 2017
Revised 9 September 2017
Accepted 20 September 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-catalyzed addition reaction
ortho-Acylphenols
Salicylketoxime derivatives
Carbopalladation of nitrile
Introduction
a) classic approach (two steps):
O
OH
ortho-Acylphenols are ubiquitous motifs in many biologically
active molecules and natural products,1 and also serve as synthons
for the synthesis of important compounds that possess a number of
biological activities.2 Therefore, their synthesis has aroused consid-
erable interest from organic chemists, and various strategies have
been developed for their preparation. Traditionally, the synthesis
of ortho-acylphenols involves the well-known Fries rearrangement
of phenyl esters (Scheme 1a). However, the use of air-/moisture-
sensitive acylating reagents and the difficulty in separating mix-
tures of ortho- and para-products limits its wide application.
Recently, transition-metal-catalyzed cross-coupling reactions have
been developed for the synthesis of ortho-acylphenols, which effec-
tively circumvents the above drawbacks. For example, the synthe-
sis of ortho-acylphenols from the reactions of phenols and aryl
aldehydes,3 as well as via the palladium-catalyzed direct arene oxi-
dation of ketones have been reported (Scheme 1b).4
OH
OH
O
O
R
Fries
rearrangement
R'
R
R'
R'
and/or
R'
O
R
b) transition-metal-catalysed approach (one step):
OH
O
Ref. 3
OH
OH
O
R'
R
H
R
N
R
R'
H
O
R'
this work
R
Ref. 4
R'
Scheme 1. Synthesis of ortho-acylphenols.
indoles and thiophenes with nitriles.9 Inspired by these results,
we wondered whether nitriles might serve as acylating agents in
the direct synthesis of ortho-acylphenols from phenols. It was
noteworthy that Larock and co-workers reported the synthesis of
ortho-acylphenols when they discussed the palladium-catalyzed
arene C–H addition to nitriles,6c,d however, no in-depth or
systematic investigation was reported. In their work, an excess of
the phenol derivative and the use of TFA as solvent were crucial.
Acidic conditions were also required for the work-up. Herein, we
have established a direct one-pot method for the synthesis of
ortho-acylphenols from phenols and nitriles.
In 1970, Garves reported the first addition reaction of an aryl-
palladium complex into C–N triple bonds and subsequent hydrol-
ysis of the ketimine intermediates to afford ketones.5 Later, the
groups of Larock,6 Lu,7 and others8 further developed and extended
this method for the construction of acylation products. Recently,
we reported the palladium-catalyzed acylation of unprotected
⇑
Corresponding author.
E-mail address: zhxiuli@163.com (X. Zhang).
These authors contributed equally to this work.
c
https://doi.org/10.1016/j.tetlet.2017.09.062
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
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2
T.-S. Jiang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Table 2
Results and discussion
Palladium-catalyzed acylation of phenols with nitriles.a
Based on our previous protocols9 and the conditions reported
by Larock and co-workers,6c,d the one-pot reaction of 4-tert-
butylphenol 1a (0.2 mmol) with 4-methylbenzonitrile 2a
(1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), DMSO
(2.0 equiv.), TFA (2 mL), and H2O (2 equiv.) at 90 °C for 24 h was
initially conducted. Unfortunately, the desired product 3a was
obtained in only 12% isolated yield and most of nitrile was
hydrolyzed (Table 1, entry 1). To our delight, the yield was
increased to 20% using TFA (0.5 mL) and DCE (1 mL) at 90 °C
(Entry 2). Further optimization of the temperature revealed that
a promising yield (58%) was obtained at 120 °C (Entries 3–5).
Screening other additives and solvents indicated TFA and DCE,
respectively, were optimal (Entries 5–9). Next, the amount of the
TFA additive was examined. The yield was slightly increased to
62% when the volume of TFA was decreased from 0.5 to 0.2 mL
(Entry 10), while further decreasing the amount of TFA only gave
3a in 47% yield (Entry 11). Similarly, decreasing the amount of
DCE to 0.5 mL afforded the desired product in 70% yield (Entry
12). Much to our pleasure, when 0.1 mL H2O was used for the
hydrolysis, the yield was improved to 79% (Entry 13). The
reaction did not occur in the absence of Pd(OAc)2 (Entry 14).
Under the optimized conditions (Table 1, entry 13), the general-
ity of the direct acylation of phenols was explored (Table 2). Firstly,
the substrate scope with respect to the nitrile component was
examined. Both electron-donating and electron-withdrawing sub-
stituents on the benzonitrile rings were tolerated and a variety of
ortho-acylation products 3a–h were formed in good to high yields
(56–87%). Electron-donating groups on the benzonitrile gave
higher yields than electron-withdrawing groups, possibly due to
lower levels of hydrolysis (3a–d vs 3f–h). Thiophene-2-carbonitrile
and 4-hydroxybenzonitrile also reacted with 4-tert-butylphenol to
afford the corresponding acylated products 3d and 3e in 87% and
OH
OH
O
Pd(OAc)2 (10 mol%)
DMSO (2 equiv.)
R
N
R
R'
R'
TFA/DCE, H2O
120 °C, 24 h
1
2
3
OH
O
OH
O
OH
O
OMe
OMe
t
t-Bu
-Bu
3b
t-Bu
b
3c
, 73%
3a
, 82%
O
, 79%
OH
O
OH
OH
O
S
OH
Br
t-Bu
t
t-Bu
-Bu
3f
3e
, 56%
O
3d, 87%
, 75%
OH
F
OH
O
OH
O
NO2
t-Bu
t-Bu
3i, 68%
3g, 63%
3h
, 67%
OH
O
OH
O
OH
O
3k, 48%
3j, 41%
OH
3l
, 53%
O
O
OH
O
OH
Ac
Ph
3m, 47%b
Br
3n, 39%b
b
3o
, 28%
OH
O
OH O
OH
O
Table 1
Optimization of the reaction conditions.a
t-Bu
3p, 71%
t
-Bu
3q, 65%c (30a)
Ph
3r
OH
, 46%c (24a)
OH
O
Pd(OAc) (10 mol%)
2
DMSO (2 equiv.)
NC
a
Reagents and conditions:
1
(0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (10 mol%),
DMSO (0.4 mmol), TFA (0.2 mL), H2O (0.1 mL), DCE (0.5 mL), 120 °C, 24 h.
additive, solvent
b
Reaction run for 36 h. cReagents and conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%),
H O, 120 °C, 24 h
t-Bu
1a
2
DMSO (0.4 mmol), CH3SO3H (10 equiv.), H2O (0.1 mL), MeCN (0.5 mL), 120 °C, 24 h.
t-Bu
2a
3a
56% yield, respectively. Next, the scope of the phenol component
was explored, where obvious substituent effects were present. 4-
Methoxy and 4-nitro substituted phenols (not shown) did not
afford the desired products, and compared to 4-tert-butylphenol,
other phenol substituents were less reactive. In general, moderate
electron-donating and electron-withdrawing substituents on phe-
nol reacted with 4-methylbenzonitrile to give the desired products
(3i–o) in moderate yield (28–68%). Electron-withdrawing sub-
stituents on phenols 3m–o gave lower yields (47–28%) even with
extended reaction times, while some unreacted starting material
and nitrile hydrolysis products were detected. The meta-substi-
tuted substrates demonstrated that this approach has high regios-
electivity, and only the less hindered ortho-acylated product (3k)
was obtained. Finally, we examined the reaction of phenols with
alkyl nitriles. Using 4-tert-butylphenol, phenylacetonitrile could
be employed and afforded 3p in 71% yield, however, a lower yield
(30%) was obtained for the reaction with acetonitrile. Replacing
TFA with CH3SO3H (10 equiv.) in acetonitrile (0.5 mL) allowed the
reaction to proceed smoothly, and provided ortho-acylated phenol
Entry
Additive
Solvent
Temp. (°C)
Yield 3a (%)
1
2
3
4
5
6
7
8
TFA (2 mL)
90
90
12
20
33
45
58
21
38
40
<5
62
47
70
79
0
TFA (0.5 mL)
TFA (0.5 mL)
TFA (0.5 mL)
TFA (0.5 mL)
HOAc (0.5 mL)
MsOH (5 equiv)
TFA (0.5 mL)
TFA (0.5 mL)
TFA (0.2 mL)
TFA (0.1 mL)
TFA (0.2 mL)
TFA (0.2 mL)
TFA (0.2 mL)
DCE
DCE
DCE
DCE
DCE
DCE
1,4-Dioxane
DMA
DCE
DCE
DCE
DCE
DCE
100
110
120
120
120
120
120
120
120
120
120
120
9
10
11
12b
13c
14d
a
Unless otherwise specified, all reactions were carried out using 1a (0.2 mmol),
2a (0.3 mmol), Pd(OAc)2 (10 mol%), DMSO (2 equiv.), H2O (0.4 mmol) in solvent
(1.0 mL), 24 h.
b
DCE (0.5 mL) was used.
H2O (0.1 mL) was used.
Reaction was carried out without Pd(OAc)2.
c
d
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T.-S. Jiang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
3q in 65% yield. The reaction of 4-phenylphenol with acetonitrile
had a similar result.
provides the r-aryl intermediate A. Subsequently, an active catio-
nic palladium complex B is generated under the acidic condition,
which further coordinates with the nitrile to give intermediate C,
and is converted into ketimine complex D through a carbopallada-
tion process. Finally, protonation of complex D and subsequent
hydrolysis leads to the ortho-acylphenol product. The valence state
of the palladium catalyst is unchanged throughout the catalytic
cycle.
To further demonstrate the practicality of this ortho-acylation
process, 4,40-biphenol was reacted with either 4-methylbenzoni-
trile or acetonitrile. Only the mono-acylated products 3s and 3t
were obtained in 45% and 41% isolated yield, respectively Scheme 2.
Furthermore, ortho-acylated product 3t could be easily converted
to the corresponding salicylketoxime derivative which displays
antiproliferative activities.10
Based on the above experimental results and literature prece-
Conclusion
dent,8,9,11
a possible reaction mechanism for the palladium-
catalyzed ortho-acylation of phenols with nitriles was proposed
(Scheme 3). First, ortho-electrophilic palladation of phenol
In summary, a highly selective and practical method has been
developed for the synthesis of a variety of ortho-acylated phenols
via the palladium(II)-catalyzed addition of phenols with nitriles.
Further research regarding the application of this method in
organic synthesis or other medicinal usage is ongoing.
O
OH
OH
NC
Pd(OAc)2 (10 mol%)
DMSO (2 equiv.)
Acknowledgements
TFA /DCE, H2O
Financial support from the National Natural Science Foundation
of China (21702002), the Natural Science Foundation of Anhui
Provincial Education Department (KJ2017A146), and the Natural
Science Foundation of Anhui Province (1608085MB26) is gratefully
acknowledged.
120 °C, 36 h
OH
OH
OH
3s, 45%
OH
O
OH
OH
N
Pd(OAc)2 (10 mol%)
DMSO (2 equiv.)
A. Supplementary data
ref.10b
CH3CN, H2O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.09.
062.
CH3SO3H
120 °C, 36 h
OH
OH
3t
OH
, 41%
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R
OH
O
1
Pd(II)Ln
OH
R'
R
Pd(II)OAcLn
3
R
A
TFA
H+, H2O
OH
HOAc
NPd(II)Ln
R'
OH
Pd(II)Ln
R
R
D
B
OH
N
R'
2
Pd(II)
Ln
N
R'
R
C
Scheme 3. Proposed reaction mechanism for the ortho-acylation of phenols with
nitriles.
Please cite this article in press as: Jiang T.-S., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.09.062