Highly efficient synthesis of aryl ketones by PEPPSI-palladium catalyzed acylative Suzuki coupling of amides with diarylborinic acids

Article abstract of DOI:10.1016/j.tetlet.2018.05.003

An improved acylative cross-coupling of various N-methyl-N-tosyl amides with diarylborinic acids for synthesis of aryl ketones is developed. In most cases, aryl ketones could be obtained in excellent yields by using 1 mol% 2,6-diisopropylphenylimidazolylidene and 3-chloropyridine co-supported palladium chloride as catalyst in the presence of 3 equiv. K₂CO₃ as base in refluxing THF. The readily prepared and cost-effective substrates, N-methyl-N-tosylamides and diarylborinic acids, and the commercially available catalyst system promise a practical and efficient access to aryl ketones.

Full text of DOI:10.1016/j.tetlet.2018.05.003

Accepted Manuscript
Highly efficient synthesis of aryl ketones by PEPPSI-palladium catalyzed acy-
lative Suzuki coupling of amides with diarylborinic acids
Chen Wang, Lingyun Huang, Fengze Wang, Gang Zou
PII:
S0040-4039(18)30584-7
https://doi.org/10.1016/j.tetlet.2018.05.003
TETL 49950
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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24 April 2018
2 May 2018
Please cite this article as: Wang, C., Huang, L., Wang, F., Zou, G., Highly efficient synthesis of aryl ketones by
PEPPSI-palladium catalyzed acylative Suzuki coupling of amides with diarylborinic acids, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.003
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Highly efficient synthesis of aryl ketones by
PEPPSI-palladium catalyzed acylative
Suzuki coupling of amides with diarylborinic
acids
Leave this area blank for abstract info.
Chen Wang, Lingyun Huang, Fengze Wang and Gang Zou*

1
Tetrahedron Letters
Highly efficient synthesis of aryl ketones by PEPPSI-palladium catalyzed acylative
Suzuki coupling of amides with diarylborinic acids
Chen Wang, Lingyun Huang, Fengze Wang and Gang Zou *
a School of Chemistry & Molecular Engineering, East China University of Science & Technology, 130 Meilong Rd, Shanghai, China. Phone: 86-21-64253881,
Email: zougang@ecust.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An improved acylative cross-coupling of various N-methyl-N-tosyl amides with diarylborinic
acids for synthesis of aryl ketones is developed. In most cases, aryl ketones could be obtained in
excellent yields by using 1mol% 2,6-diisopropylphenylimidazolylidene and 3-chloropyridine co-
supported palladium chloride as catalyst in the presence of 3 equiv. K2CO3 as base in refluxing
THF. The readily prepared and cost-effective substrates, N-methyl-N-tosylamides and
diarylborinic acids, and the commercially available catalyst system promise a practical and
efficient access to aryl ketones.
Available online
Keywords:
Acylative Suzuki coupling
N-heterocyclic carbene
Aryl ketones
2018 Elsevier Ltd. All rights reserved.
Amides
Diarylborinic acid
1. Introduction
to be used in excess, 2 equivalent in most cases, due to the
protodeboronation although alkyl(aryl)zinc reagents have also
been applied.10, 25 As part of our on-going research on the use of
high-order arylborons, in particular, diarylborinic acids, as cost-
effective alternative to arylboronic acids in arylation reactions,26-
30 we have extended the nucleophile counterparts in the acylative
Suzuki coupling of amides to high-order arylborons, e.g.
diarylborinic acids and tetraarylboronates.31 However, the
reactivity of high-order arylborons was found to be lower than
the corresponding arylboronic acids using the original catalyst
system, PdCl2(PCy3)2, thus requiring a secondary activating
group, e.g. 3,5-bis(trifluoromethyl)phenyl, on the N-atom of N-
tosyl amides (Cacyl−N(Ar)Ts) to offer satisfactory yields, which
decreased practicality of the protocol. Therefore, it is necessary
to improve the acylative cross-coupling of diarylborinic acids.
Szostak and co-workers have reported that sterically demanding
N-heterocyclic carbene (NHC) palladium co-supported by a
secondary weakly coordinating ligand displayed high
efficiency in acylative Suzuki-coupling of activated amides.32-34
On the other hand, we have reported that 2,6-diisopropylphenyl
imidazolylidene (IPr) phosphite palladium catalysts, e.g.
(IPr)PdCl2/P(OPh)3, could efficiently catalyze Suzuki coupling of
diarylborinic acids and esters with aryl chlorides.35, 36 Inspired by
these results, we herein report the acylative cross-coupling of
diarylborinic acids with simple N-methyl-N-tosyl amides by
using 2,6-diisopropylphenyl imidazolylidene (IPr) and 3-
chloropyridine (3-ClPy) co-supported palladium chloride, the so-
called PEPPSI (pyridine-enhanced precatalyst preparation
stabilization and initiation) catalyst developed by Organ and co-
workers.37
Transition metal catalyzed acylative cross-couplings of
amides via Cacyl−N bond activation to synthesize aryl ketones
have attracted increasing attentions because of the privileges of
amides, e.g. bench-stability, high abundance and lack of toxicity,
over the other carboxylic acid derivatives.1-3 Since the seminal
reports by Szostak,4 Garg,5 and ourselves,6 independently, about
three years ago, great progresses have been made with respect to
activated amide counterparts, e.g. N-Acyl imides,7-9 N-Ts and N-
10-17
Boc amides,6,
N-Acylsaccharins,18-22 and amides of
heteroaromatic compounds23, 24 etc. (Scheme 1).
Scheme 1. Amide precursors in acylative Suzuki coupling
Comparably, carbon-centered nucleophile counterparts are
still overwhelmingly dominated by arylboronic acids, which have

2
Tetrahedron
2. Results and discussion
Investigation on the substrate scope showed a good generality
for the (IPr)PdCl2(3-ClPy)-catalyzed acylative cross-coupling of
N-methyl-N-tosyl amides with diarylborinic acids (Table 2).
Reaction of N-methyl-N-tosylbenzamide (1a) with dehydrate-
resisting bis(p-tolyl)borinic acid (2a) was used as the model
reaction to establish an optimal condition (Table 1). Both the
large steric hindrance of NHC and the ancillary ligand appeared
to be crucial to the catalytic activity of the palladium catalysts,
consistent with the PEPPSI concept. For example, sluggish
reaction was observed when 1mol% (IPr)PdCl2(CH3CN),
(IPr)PdCl2(Py) or (IMes)PdCl2(3-ClPy) was used as catalyst in
THF in the presence of 3 equiv. K2CO3 as base at 65oC while the
desired aryl ketone (3aa) was isolated from 0.75 equiv. 2a (1.5
equiv. with respect to aryl group) in 85% yield with (IPr)PdCl2(3-
ClPy) as catalyst under the otherwise identical conditions (Table
1, entries 1-4). The yield of 3aa could be further increased to
97% when the loading of 2a was increased to 1.0 equiv. (2.0
equiv. with respect to aryl group) (Table 1, entry 5). The stable
Weinreb amide, N-methoxy-N-tosylbenzamide 1b, could also
react smoothly to give 3aa albeit in lower yield (78%) (Table 1,
entry 9). Mesyl (Ms) and tert-butoxycarbonyl (Boc) groups
appeared to be less effective than Ts group in activating the
Table 2. Scope of Pd-PEPPSI-catalyzed acylative Suzuki
coupling of diarylborinic acids with activated amides a
C
acyl−N bond (Table 1, entries 10 and 11). The common solvents,
e.g. toluene (56%), DMF (30%), dioxane (49%) and tert-butanol
(70%), and bases, e.g. Na2CO3 (57%), Cs2CO3 (30%), K3PO4
(63%) and NaOAc (31%), performed less efficiently than the
combination of THF and K2CO3 (Table 1, entries 12-19).
Therefore, the optimal condition for the model reaction was set
as 1mol% (IPr)PdCl2(3-ClPy) catalyst in the presence of 3 equiv.
K2CO3 as base in THF.
Table 1. Optimization of the model reactiona
Entry
1
Cat. (mol%)
Base
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Yield %
trace
31
1
2ab
0.75 (IPr)PdCl2(CH3CN) (1)
0.75 (IPr)PdCl2(Py) (1)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
2
3
0.75 (IPr)PdCl2(3-ClPy) (1)
0.75 (IMes)PdCl2(3-ClPy) (1)
85
4
23
5
1.0
(IPr)PdCl2(3-ClPy) (1)
97
6
0.65 (IPr)PdCl2(3-ClPy) (1)
76
7
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
(IPr)PdCl2(3-ClPy) (0.5)
(IPr)PdCl2(3-ClPy) (0.3)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
(IPr)PdCl2(3-ClPy) (1)
83
8
72
9
78
10
11
12
13
14
15
16
17
18
19
76
50
31
Na2CO3 THF
57
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
63
a 1 (0.5 mmol), 2 (1.0 mmol), (IPr)PdCl2(3-ClPy) (1 mol%), K2CO3 (3 equiv.),
THF (4 mL), 65 oC, 12 h; 3 obtained in isolated yields.
THF
30
DMF
Toluene
30
N-methyl-N-tosyl-2-methylbenzamide (1e) reacted with 2a to
give o-tolyl(p-tolyl)methanone (3ea) in 96% yield, comparable to
those obtained for its para (3fa, 95%) and meta (3ga, 94%)
isomers, indicating a small steric hindrance could be readily
overcome. The electronic influence from acyl moiety of N-
methyl-N-tosyl amides on the product yields proved to be
negligible. For example, reaction of bis(p-tolyl)borinic acid (2a)
with activated benzamides afforded aryl ketones in excellent
56
Dioxane 49
t-BuOH 70
a1a (0.5 mmol), base (3 equiv.), sol. (4 mL), 65 oC, 12 h; 3aa obtained in
isolated yields. b equiv. of 2a.

3
12. Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J. –N.;
yields (92-96%) irrespective of an electron-withdrawing or
donating group, except for NO2 (1m), at the para-position of the
aromatic ring, e.g. F (1n), CF3 (1k), CO2Me (1j) and CN (1l).
Furan- and thiophene-2-carboxamides (1q and 1p), cinnamyl
amide (1r) as well as alkyl amides (1s-1u) also reacted smoothly
to afford the corresponding aryl ketones (3qa, 3pa, 3ra and 3sa-
3ua), respectively, in good to excellent yields. Similarly, both
electronic and steric effects from diarylborinic acids were also
negligible, if any. A variety of diarylborinic acids with
electronically and sterically various aryl groups,38 e.g. Ph, (2b),
o-tolyl (2c), m-tolyl (2d), 2-EtPh (2e), o-anisyl (2f), m-anisyl
(2g), p-anisyl (2h), 1-naphthyl (2k) or 4-FPh, (2i) and 4-CF3Ph
(2j), efficiently coupled with benzamide 1a to give the diaryl
ketones 3ab-3ak in excellent yields (92-97%).
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Conclusion
In summary, acylative cross-coupling of Ts-activated simple
amides with diarylborinic acids has been effected to offer a
variety of aryl ketones in good to excellent yields by using
commercially available 2,6-diisopropylphenyl imidazolylidene
and 3-chloropyridine co-supported palladium chloride as catalyst
under mild condition. Both the sterically demanding N-
heterocyclic carbene and the 3-chloropyridine ancillary ligand
appeared to be crucial to the catalytic activity of the palladium
catalyst. The availability and cost-effectiveness of the substrates,
N-methyl-N-tosyl amides and diarylborinic acids, as well as the
catalyst promise a practical and efficient access to aryl ketones.
Acknowledgments
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This work was financially supported by the National Natural
Science Foundation of China (21472041).
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Supplementary Material
Supplementary data (experimental methods, characterization
data) associated with this article can be found, in the online
version.
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4
Tetrahedron
Highlights
Highly efficient acylative Suzuki coupling of
diarylborinic acids
Practical synthesis of aryl ketones in excellent
yields
Readily prepared and cost-effective substrates
Commercially available catalyst
Wide substrate scope