Suzuki Coupling of Amides via Palladium-Catalyzed C–N Cleavage of N-Acylsaccharins

Article abstract of DOI:10.1002/adsc.201600555

A palladium-catalyzed cross-coupling of activated amides with arylboronic acids has been developed via C–N bond cleavage. This approach demonstrated high tolerance to a variety of alkyl, aryl, heterocyclic and vinyl substituents. Unsymmetrical ketones could be achieved in excellent yield under mild conditions with 1% catalyst loadings. (Figure presented.).

Full text of DOI:10.1002/adsc.201600555

UPDATES
DOI: 10.1002/adsc.201600555
Suzuki Coupling of Amides via Palladium-Catalyzed C–N
Cleavage of N-Acylsaccharins
Hongxiang Wu,a Yue Li,a Ming Cui,a Junsheng Jian,a and Zhuo Zenga,b,*
a
College of Chemistry and Environment, South China Normal University, Guangzhou 510006, Peopleꢀs Republic of China
Fax : (+86)-20–3931-0187; e-mail: zhuoz@scnu.edu.cn
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345
b
Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Received: May 24, 2016; Revised: August 29, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600555.
Abstract: A palladium-catalyzed cross-coupling of
activated amides with arylboronic acids has been
developed via C–N bond cleavage. This approach
demonstrated high tolerance to a variety of alkyl,
aryl, heterocyclic and vinyl substituents. Unsymmet-
rical ketones could be achieved in excellent yield
under mild conditions with 1% catalyst loadings.
energy of C–N bond.[9] In recent years, Zou,[10] Szos-
tak[11] and Garg[12] (Scheme 1) have reported twisted
amides as conveniently available coupling partners in
metal-catalyzed cross-coupling reactions, independ-
ently. The use of amides as coupling partners to syn-
thesize ketones is a powerful strategy, which would
provide another option in synthetic chemistry and
biochemistry.
Although significant progress has been made, long
reaction times or additional ligands were required in
Keywords: N-acylsaccharins; C–N bond cleavage;
ketones; Suzuki coupling; twisted amides
Carbon-nitrogen bonds widely exist in thousands of
natural products and play a crucial role in the con-
struction of pharmaceutical molecules.[1] In the past
decades, transition metal-catalyzed C–N bond forma-
tion approaches have made great advances in the syn-
thesis of indoles,[2] pyrroles[3] and other nitrogen-con-
taining molecules.[4] In contrast, the disconnection of
C–N chemical bonds through transition metal-cata-
lyzed processes is less explored due to their inert
nature. However, the vast sources of C–N bonds
make the strategy of C–N bond cleavage and transfor-
mation an attractive focal point of study.[5]
Acylative coupling provides an efficient access to
new carbon-acyl bonds, providing ketones, and it has
been utilized in the preparation of pharmaceuticals
and functional materials.[6] In order to extend the sub-
strate scope and optimize the reaction conditions,
many cross-coupling partners have been employed in
the synthesis of ketones, including anhydrides, esters,
nitriles and aldehydes.[7] Also transition metal-cata-
lyzed carbonylation reactions through a CO-free
pathway, employing a solid carbon monoxide precur-
sor have been investigated.[8]
Compared with other carboxylic acid derivatives in
the acylative Suzuki coupling reactions, the reactivity
Scheme 1. Pd-catalyzed acylative Suzuki cross-coupling of
of amides is low due to the high bond dissociation amides.
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Table 1. Effects of catalyst, solvent and base.[a]
these protocols. Therefore the coupling of amides re-
mains a challenge and it is worthwhile to develop
a highly reactive amide as an electrophile for use in
the Suzuki cross-coupling reaction.
Two features of N-acylsaccharins that make them
attractive candidates for further investigation include:
(i) the significant electron-withdrawing property of
saccharin and (ii) N-acylsaccharins can be efficiently
synthesized from readily available and low-cost sac-
charin.
Herein, we report a novel Suzuki coupling by utiliz-
ing N-acylsaccharins as a coupling partner via palladi-
um-catalyzed C–N cleavage. This protocol works
under mild conditions, tolerating sensitive functional
group such as halides, aldehydes, ketones, esters and
heterocycles. Notably, this study demonstrated a new
strategy in C–N bond cleavage to afford unsymmetri-
cal ketones, containing a variety of substituents, in
high yield.
Initially, N-benzoylsaccharin 1a was selected as an
electrophile to couple with phenylboronic acid 2a to
form the benzophenone in the presence of a palladium
catalyst (Table 1). After several experiments, we
found that Pd(PPh3)2Cl2 gave the best results
(Table 1, entries 1–4). For example, by contrast, the 17
target compound 3a was obtained at low yield (21%)
En- Catalyst
Ligand
(mol%)
Base
Yield
[%]
try
(mol%)
1
2
Pd(PPh3)2Cl2 (5)
PdCl2 (5)
none
none
none
none
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
73
31
15
21
61
45
trace
trace
25
3
4
5
Pd(TFA)2(5)
Pd(OAc)2(5)
PdCl2 (5)
PCy3(10)
P(furyl)3 (10) K3PO4
P(t-Bu)3 (10) K3PO4
dppp (5)
dppf (5)
Xantphos (5) K3PO4
none
none
none
6
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
7[b]
8
K3PO4
K3PO4
9
PdCl2 (5)
10
11
12
PdCl2 (5)
trace
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Cs2CO3 41
Na2CO3 36
13[c] Pd(PPh3)2Cl2 (5)
14[d] Pd(PPh3)2Cl2 (5)
15[e] Pd(PPh3)2Cl2 (5)
16[d] Pd(PPh3)2Cl2 (1)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
91
93
61
93
trace
trace
35
none
none
none
Pd(PPh3)2Cl2 (0.5) none
18[f] Pd(PPh3)2Cl2 (1)
none
none
none
19[g] Pd(PPh3)2Cl2 (1)
in the presence of 5 mol% Pd(OAc)2 catalyst with
K3PO4 as base in toluene.
20[h] Pd(PPh3)2Cl2 (1)
23
[a]
The ligand also plays an important role in deter-
mining the yield. Tri(phenyl)phosphine appears to be
the best ligand in this protocol since poor yields were
observed on employing tri(cyclohexyl)phosphine,
tri(2-fuyl)phosphine, and tri(tert-butyl)phosphine
(Table 1, entries 5–10) under the same conditions.
Also, bidentate phosphines such as dppp, dppf and
xantphos were chosen to investigate the effect of the
ligand. Some common bases were utilized to replace
the K3PO4, but none of them gave high yields
(Table 1, entries 11 and 12).
Conditions: 1a (0.5 mmol), 2a (0.5 mmol), base
(0.5 mmol), toluene, 1008C. Trace=less than 5%.
10 wt% in hexanes.
At 808C.
At 658C.
At 508C.
In DMSO.
In DMF.
In 1,4-dioxane.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
In order to examine the scope and limitations of
With these conditions in hand, the reaction temper- this approach, a variety of boronic acids was used to
ature was further optimized, and to our delight, the synthesize aromatic ketones under the optimized re-
desired product could be obtained in good yield at action conditions (Scheme 2). To study the influence
a mild temperature (Table 1, entries 13–15). The cata- of electronic and steric factors, a sequence of arylbor-
lyst loading in this approach also influenced the yield onic acids (2b–2g) with electron-donating groups in
of benzophenone, for example, decreasing the loading para, meta, ortho-positions were coupled to N-ben-
from 5 mol% to 0.5 mol% led to a significant de- zoylsaccharin to provide aryl ketones with good to ex-
crease in yield.
cellent yields. Also, the disubstituted arylboronic
In almost every case when toluene was employed acids (2h, 2i) were tested, achieving 89% and 49%
as the solvent, a better result was obtained compared yields, respectively. Further, the arylboronic acids (2j,
to those experiments which employed polar solvents 2k) with formyl and acetyl groups in the para-position
such as DMSO, DMF or 1,4-dioxane (Table 1, en- were employed as electron-deficient substrates and
tries 18–20). It was also observed that the reaction did resulted in moderate yields. Other arylboronic acids
not occur in the absence of a base.
2l–2p provided aryl ketones in 81–91% yields. To our
Finally, the best conditions for this Suzuki coupling delight, the utilization of heteroarylboronic acids pro-
reaction via C–N cleavage of N-acylsaccharins were vided excellent yields. These experiments revealed
set as 1 mol% Pd(PPh3)2Cl2 in the presence of K3PO4 that halides, aldehydes, ketones, esters and heterocy-
(1 equiv.) in toluene at 658C.
cles were all tolerated, except for the case where the
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Scheme 3. Scope of amides in the cross-coupling with boron-
ic acids.
amide 1t were utilized to compare with N-benzoylsac-
charin under the same conditions. N-Benzoyl saccha-
rin demonstrated higher reactivity than the other
amides (Scheme 4).
To further investigate the high reactivity of N-acyl
saccharins, the X-ray structure of 1j was generated
Scheme 2. Scope of boronic acids in the cross-coupling of
amides.
arylboronic acid bearing a functional group in the (Figure 1). Compared with planar amide (formamide),
ortho-position, in which case lower yields were ob- the X-ray structure indicates that 1j contains a highly
tained, for the examples 3d and 3g. When vinylboron- distorted amide bond (t=20.98, cN =10.68, cC =1.98).
ic acid was employed under the same conditions, it
was found that no reaction occurred.
Next, both electron-deficient and electron-rich N-
acylsaccharins were employed in this catalytic system
to investigate the electronic effects. Irrespective of
electron-donating groups in para, meta and ortho-po-
sitions including 3,4,5-trimethoxy substitution in the
benzene ring, the corresponding products (3b, 3e, 3f,
3g, 3u) were formed in excellent yields. Electron-with-
drawing group such as cyano and trifluoromethyl also
demonstrated good reactivity and provided the de-
sired products in 80% and 89% yields (3v, 3w). Cou-
pling of 4-fluoro- or 4-chloro-N-acylsaccharins with
phenylboronic acid gave the corresponding ketones in
85% and 79% yields, respectively (Scheme 3). Fur-
thermore, when 2-naphthyl, styryl, 2-furyl and 2-thien-
yl amides were employed in this approach, the corre-
sponding aryl ketones were generated with yields in
the range of 72–88%. Meanwhile, acetophenone 3z
(81%), 3aa (50%) and 3ab (73%) could be synthe-
sized via this protocol from the corresponding N-acyl-
saccharins.
Two previously reported amides (1r, 1s) which have
been employed in Pd catalysis systems and a similar Scheme 4. Control reactions.
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merous aryl alkyl, aryl vinyl or diaryl ketones were
obtained in 47–93% yields. A variety of ketones can
be generated by employing different amides and aryl-
boronic acids as substrates. The low catalyst loadings
and tolerance to functional groups provides an attrac-
tive approach to access ketones. Compared with pre-
vious studies on C–N bond cleavage of activated
amides, this protocol demonstrates high efficiency,
under mild reaction conditions, and short reaction
times.
Figure 1. Crystal structure of 1j. CCDC 1500576 contains
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic
Data
Centre
via
Experimental Section
General Experimental Details
These three independent distortion parameters of the
amide bond in N-acylsaccharins support ground-state
destabilization which could account for its high reac-
tivity.[13]
On the basis of typical Suzuki cross-coupling, the
hypothesis of whole catalytic cycle was proposed.
(Scheme 5): Oxidative addition took place at the C–N
bond of the N-acylsaccharin to form an acylpalladiu-
m(II) complex II; following transmetallation, the
complex III was generated; then, reductive elimina-
tion occurred to form the new C–C bond and regener-
ate the Pd(0) species.
An oven-dried flask (10 mL) equipped with a stir bar was
charged with boronic acid (1.0 equiv.), N-acylsaccharin
(1.0 equiv.), K3PO4 (1.0 equiv.) and Pd(PPh3)2Cl2 (1 mol%).
After standard cycles of evacuation and backfilling with dry
nitrogen, toluene (5 mL) was added with vigorous stirring at
room temperature. The reaction mixture was placed in an
oil bath and stirred for 4 h at 658C. After cooling to room
temperature, the mixture was diluted with EtOAc (20 mL),
filtered and concentrated. The residue was purified by
column chromatography to afford the desired product.
In conclusion, a novel strategy for C–N bond cleav-
age by utilizing N-acylsaccharins as electrophiles to
couple with arylboronic acids has been reported. Nu-
Acknowledgements
The authors gratefully acknowledge the support of National
Natural Science Foundation of China (21272080) and the Sci-
entific Research Foundation for the Returned Overseas Chi-
nese Scholars, State Education Ministry.
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6 Suzuki Coupling of Amides via Palladium-Catalyzed C–N
Cleavage of N-Acylsaccharins
Adv. Synth. Catal. 2016, 358, 1 – 6
Hongxiang Wu, Yue Li, Ming Cui, Junsheng Jian,
Zhuo Zeng*
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