N-Acylsuccinimides: Efficient acylative coupling reagents in palladium-catalyzed Suzuki coupling via C–N cleavage

Article abstract of DOI:10.1016/j.tetlet.2017.08.044

An acylative Suzuki coupling of activated amides with aryl boronic acids has been reported via palladium-catalyzed C–N bond cleavage. This protocol demonstrate amides can be activated by an atom-economic and cheap succinimide, which can be efficiently utilized to synthesize broad array of diaryl ketones in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2017.08.044

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Acylsuccinimides: Efficient acylative coupling reagents
in palladium-catalyzed Suzuki coupling via CAN cleavage
Ming Cui a, Zeyu Chen b, Tingting Liu a, Hui Wang a, Zhuo Zeng a,c,
⇑
a College of Chemistry & Environment, South China Normal University, Guangzhou 510006, China
b Xishuangbanna Entry-Exit Inspection and Quarantine Bureau, Jinghong 666100, China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 LingLing Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An acylative Suzuki coupling of activated amides with aryl boronic acids has been reported via palla-
dium-catalyzed CAN bond cleavage. This protocol demonstrate amides can be activated by an atom-eco-
nomic and cheap succinimide, which can be efficiently utilized to synthesize broad array of diaryl ketones
in moderate to good yields.
Received 6 July 2017
Revised 14 August 2017
Accepted 18 August 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Amide CAN bond cleavage
N-Acylsuccinimides
Diaryl ketones
Acylative Suzuki coupling
High atom utilization
Arylketones are important building blocks since there are
widely existed in compounds of natural products,1 pharmaceuti-
cals2 and act as key intermediate in synthetic chemistry.3
electrophile coupling partner in nickle-catalyzed Suzuki coupling
(Scheme 1, c).11
N-Acylsaccharin has been introduced by our group, which
showed high reactivity in a range of reactions by employing tran-
sition-metal catalysis.12 Szostak demonstrated transition-metal-
catalyzed cleavage of amides CAN bond only for distorted/twisted
amides.13 The utilization of N-acylsuccinimides as acylating agents
were firstly reported by Leach and coworkers in 1972.14 In 2009,
Strydstrup and Daasbjerg demonstrated samarium(II) iodide-
mediated conjugate addition to acrylamides by the utilization of
N-acetyl succinimide and N-trimethylacetylsuccinimides.15 In
2013, Hitchcock employed N-acylsuccinimides as acylating
reagents in transamidation reaction.16 Unfortunately, however,
the low COAN twist angle of N-acylsuccinimide showed low effi-
ciency in transition-metal-catalyzed acylative Suzuki cross cou-
pling reaction.9,10
While all these reported amides showed low atom utilization,
comparing with other amides, N-acylsuccinimides offer several
major following advantages: (a) N-acylsuccinimides demonstrate
high atom utilization in all reported amides; (b) compared with
N-acylglutarimides, N-acylsuccinimides can be efficiently synthe-
sized from succinimide, a widely available commodity chemical.
Recently, Nickle-catalyzed deamidation of planar amides to corre-
sponding hydrocarbon through cleavage of the amide CAN bond
has been reported by Maiti and Lahiri.17 Inspired by Maiti’s work,
we considered that the low twisted N-acylsuccinimides can be har-
Traditionally, arylketones were synthesized by the Friedel–
Crafts acylation, but due to the low functional group tolerance
and poor regioselectivity,4 transition-metal-catalyzed acylative
Suzuki coupling has emerged as an efficient way to synthesize
arylketone. Over the past decade, numerous efforts have been
devoted to this transformation through transition-metal catalyzed
cross coupling of acylative reagents, including acyl chlorides,5
anhydrides6 and esters.7 However, there are few reports on acyla-
tive Suzuki coupling of amides. In 2015, Garg and Houk demon-
strated an elegant nickel-catalyzed activation of amides CAN
bond methodology which could convert amides to esters in one-
step process.8 Inspired by this breakthrough, Zou, Szostak and Garg
independently reported the transition-metal-catalyzed acylative
Suzuki coupling of amides. Zou adopted sulfonyl group to activate
the acyl-nitrogen bond, which has achieved palladium-catalyzed
Suzuki coupling reaction of N-phenyl-N-tosylamides (Scheme 1,
a).9 Pd-catalyzed cross coupling of N-acylglutarimide with aryl
boronic acids were demonstrated by Szostak (Scheme 1, b).10 Garg
reported N-Boc-activated secondary amide that can be utilized as
⇑
Corresponding author at: College of Chemistry & Environment, South China
Normal University, Guangzhou 510006, China.
E-mail address: zhuoz@scnu.edu.cn (Z. Zeng).
http://dx.doi.org/10.1016/j.tetlet.2017.08.044
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cui M., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.08.044

2
M. Cui et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Pd(OAc)2 and PCy3 was used as catalyst system, boric acid as addi-
tive with K2CO3 in tetrahydrofuran. After a survey of several reac-
tions parameters, we found that using K3PO4 as base and toluene as
solvent in the same catalyst system offered the desired coupling
product, with 70% yields (Table 1, entries 1–3). Szostak demon-
strated that the rate of this acylative Suzuki coupling of amides
is proportional to the degree of distortion.10 We attempted to
accelerate the rate of coupling by raising reaction temperature.
Delightfully, we noted that a good yield (83%) of 3aa could be pro-
vided through enhancing reaction temperature up to 110 °C
(Table 1, entry 4). Moreover, it seems that boric acid play an impor-
tant role in this reaction, but we found 3aa could be furnished in
the absence of boric acid in excellent yield (90%) (Table 1, entry
5). A range of solvents were examined and we found that toluene
was an excellent solvent for this transformation. However, many
other solvents furnished significantly lower yields (Table 1, entries
1, 2 and 7). Different bases were evaluated and K3PO4 gave the
highest yield (Table 1, entries 5–6). Examination of several Pd-cat-
alysts (Table 1, entries 8–11) indicated that Pd(OAc)2 was the opti-
mal catalyst. Testing several phosphine ligands (Table 1, entries
12–14) showed that ligands are keys to achieving this transforma-
tion, and interestingly, no products was observed with PCy3HBF4
and tri(2-fuyl)phosphine (Table 1, entries 12, 14). The catalyst con-
centration influenced the reaction yields, decreasing the concen-
tration from 5 mol% to 1 mol% led to significantly decreasing
from 90% to 28% (Table 1, entries 5, 15, 16). Thus, the optimized
reaction conditions for this transformation were set as 5 mol% Pd
(OAc)2, 20 mol% PCy3, K3PO4 (2 equiv) in toluene at 110 °C.
Scheme 1. Palladium-catalyzed acylative Suzuki coupling of amides.
nessed as electrophile coupling partner in palladium-catalyzed
Suzuki coupling reaction.
To test our hypothesis, we selected N-benzoylsuccinimide 1a
and phenylboronic acid 2b as model substrate. Optimization of
the reaction is shown in Table 1 in the supplementary data. Ini-
tially, the benzophenone 3aa was obtained only 40% yields when
The distorted geometries of amide bonds characterized by med-
ium
s
and vN values.13a The sum of distortion parameters
+ vN) was used as evidence to explain the reactivity
P
(
s
of sterically distorted amides.18 Twisted amides N-Boc and
N-Ts amides and cyclic amides of relevance to amide NAC
Table 1
Optimation of the reaction conditions.a
Pd(OAc)2 5 mol %
PCy3 20 mol %
O
O
O
Ph
K3PO4 2.0 equiv
N
Ph B(OH)2
Ph
Ph
3aa
toluene, 110 °C, 4 h
O
1a
2a
Entry
Catalyst
Ligand
Additive
Base
Solvent
Yieldb (%)
1c
2c
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)Cl2
Pd(dba)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2 3%
Pd(OAc)2 1%
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3HBF4
X-PHOS
P(2-furyl)3
PCy3 12%
PCy3 4%
H3BO3
H3BO3
H3BO3
H3BO3
None
None
None
None
None
None
None
None
None
None
None
None
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
THF
40
57
70
83
90
72
0
Toluene
Toluene
Toluene
Toluene
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
38
41
28
0
44
0
46
28
a
Reaction conditions (unless otherwise noted): 1a (0.2 mmol), 2b (0.24 mmol), catalyst (5 mol%), ligand (20 mol%), base (2 equiv, 0.4 mmol), additive (2.0 equiv), solvent
(2 mL). The mixture stirred and heated at 110 °C for 4 h.
b
Isolated yield.
The mixture stirred and heated at 65 °C for 15 h.
c
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M. Cui et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Cross-coupling were demonstrated by szostak.10,19,20 Under the
Table 2
Scope of boronic acid coupling partners.
optimized conditions, we evaluated a variety of electronically
and sterically different amides (Scheme 2). N-Arylated substrates
4a and 4b were not compatible with the reaction conditions in this
transformation, providing low yield. The low distortion parameters
of N-benzoylphthalimide 4c and N-benzoylsaccharin 4d showed
low reactivity in this reaction. Surprisingly, N-benzoylglutarimide
4e, which the sum of distortion parameters is around 90°
(s + vN = 94.6), however, a sharp decrease in the reactivity was
observed in this reaction under optimized condition. Delightfully,
the geometry of N-benzoylsuccinimide is located around
(
s
+
v
N = 56.6), which showed high activity in this reaction. This
result may be associated with proton affinities (PA) and differences
between N- and O-protonation affinities (
PA).21 There is an
D
excellent positive correlation between proton affinity difference
P
and the sum of distortion parameters (
+ v
N).13a It means
s
that the activation of the high twisted amides more depend on
N-Protonation than the low twisted amides.10 Therefore, when
no acidic additives promote this transformation, the low twisted
amide 1a shows higher reaction activity than the high twisted
amide 4e in this reaction.
With the optimized conditions in hand, we turned toward test-
ing the substrate scope of aromatic boronic acids (Table 2). The
reaction of para-methoxyl, meta-methoxyl, and ortho-methoxyl-
substituted aryl boronic acids all worked well and furnished the
corresponding diaryl ketones in moderate to good yields (3ab–
3ad). Employing electron-donating aryl boronic acids (2e and 2f)
gave products in excellent yields. The aromatic boronic acids bear-
ing halide substituents (2g and 2h) were also both tolerated in this
transformation. Notably, 1-naphthylboronic acid exhibited higher
reactivity than 2-naphthylboronic acid in this reaction, which fur-
nished products in high yield (3ai, 95%; 3aj, 71%). 4-biphenyl-
boronic acid (2k) was well transformed to corresponding product
with moderate yield. Heteroaromatic boronic acid, such as thienyl
(2l), resulted in high reaction efficiency (3al: 85%).
Table 3
Scope of amide coupling partner.
Next, the scope of amides electrophile coupling partners was
evaluated with p-methoxylphenylboronic acid (Table 3). The
para-methyl, para-, meta-methoxyl, and ortho-methyl substituted
N-benzoylsuccinimides were all compatible with this transforma-
tion and generated the desired products in moderate yields
(3bb–eb, 51–65%). Amides bearing fluorine substituent showed
good reactivity in this transformation, while substrates bearing
chlorine substituent provided a much lower level of yield (3fb,
91%; 3gb, 62%). The reaction tolerates a variety of electron-with-
drawing amides, such as p-trifluoromethyl-(1h), nitriles-(1i),
nitro-(1j), N-(4-trifluoromethylbenzoyl)succimide (1h) and N-(4-
nitrobenzoyl)succimide (1j) furnished the corresponding products
nearly quantitative (3hb, 98%; 3jb, 97%). Electron-rich substituted
amide (1k) actively coupled with good yields, while amides 1c and
1d provided relatively low yields. Naphthyl-(1l) amide was
tolerated in this reaction and provided the products with high
reaction efficiency (3lb, 94%).
On the basis of the mechanistic studies of the amide CAN bond
cleavage,13b,19,21,22
mechanism for this transformation was
a
proposed (Scheme 3). Oxidative addition of N-acylsuccinimides
to the Pd(0)-species generates an acylpalladium complex II;
following transmetallation, the complex III was generated.
Scheme 2. Evaluating of different amides.
Please cite this article in press as: Cui M., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.08.044

4
M. Cui et al. / Tetrahedron Letters xxx (2017) xxx–xxx
data may be available free of charge via the Internet or the author.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.08.
044.
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Scheme 3. Proposed mechanism for palladium-catalyzed acylative Suzuki coupling
of N-acylsuccinimides.
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Acknowledgments
The authors gratefully acknowledge the support of National
Natural Science Foundation of China (21272080). The Scientific
Research Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry.
A. Supplementary data
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Supplementary data including optimisation of the reaction con-
ditions table, the experimental details, NMR spectra, MS, HRMS
Please cite this article in press as: Cui M., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.08.044