Enantioselective Palladium-Catalyzed Cross-Coupling of α-Bromo Carboxamides and Aryl Boronic Acids

Article abstract of DOI:10.1002/anie.201905174

We herein report an enantioselective palladium-catalyzed cross-coupling between α-bromo carboxamides and aryl boronic acids, generating a series of chiral α-aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium-catalyzed coupling of α-bromo carbonyl compounds.

Full text of DOI:10.1002/anie.201905174

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Accepted Article
Title: Enantioselective Palladium-Catalyzed Cross-Coupling between
α-Bromo Carboxamides and Arylboronic Acids
Authors: Wenjun Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905174
Angew. Chem. 10.1002/ange.201905174
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Angewandte Chemie International Edition
10.1002/anie.201905174
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Enantioselective Cross-Coupling
Enantioselective Palladium-Catalyzed Cross-Coupling between α-Bromo
Carboxamides and Arylboronic Acids
Bowen Li, Tiejun Li,Muinat A. Aliyu, Zhen Hua Li, Wenjun Tang*
Abstract: We herein report an enantioselective palladium-catalyzed
cross-coupling between α-bromo carboxamides and arylboronic
acids, leading to a series of chiral α-aryl carboxamides in good
yields and excellent enantioselectivities. The development of chiral
P,P=O ligand is critical in overcoming the second transmetallation
issue and allows for the first time the asymmetric Pd-catalyzed
coupling of α-bromo carbonyls.
catalyst loading (mostly >5 mol %). An asymmetric cross-coupling
using stable and readily available arylboronic acids as coupling
partners with a palladium catalyst at a lower catalyst loading is
attractive and yet to be realized. In fact, the nonchiral coupling
between α-bromo ester and phenylboronic acid with a palladium
catalyst was reported to provide the desired coupling product in only
2
% yield, and the main products were the reduced ester and
biphenyl derived from homocoupling of phenylboronic acid
6
(
Scheme 1b). Herein we report the first enantioselective palladium-
T
ransition-metal-catalyzed asymmetric aryl-alkyl cross-coupling
catalyzed cross-coupling between α-bromo carboxamides and
arylboronic acids, leading to a series of chiral α-aryl carboxamides
in good yields and excellent enantioselectivities.
1
has received much attention. Despite the recent development of
enantioselective transformations by employing different transition
metal catalysts, practical and synthetically useful asymmetric aryl-
alkyl cross-couplings remain scarce mainly due to the inefficient
catalytic processes or high catalyst loadings (often >5 mol %). The
asymmetric cross-coupling between α-halo carbonyls and aryl metal
reagents is an attractive method for preparing chiral α-aryl carbonyls
The palladium-catalyzed cross-coupling between α-bromo
carbonyls and arylboronic acids remains an unsolved problem
(Scheme 2). The main issue is the special property of α-bromo
carbonyl 1, which after oxidative addition by the Pd(0) species A
forms the O-bound enolate or C-bound form B. Transmetallation of
B with arylboronic acid 2 leads to Pd(II) species C. Instead of
undergoing reductive elimination to form the desired coupling
2
from simple and readily available starting materials. Previous
excellent work from Fu, Zhong and Bian, Nakamura,
accomplished a few enantioselective versions with the employment
of chiral Ni, Co, and Fe catalysts (Scheme 1a) , albeit with high
3
4
5
nd
7
product 3, C proceeds a 2 transmetallation with arylboronic acid
(2) to form the debromo carbonyl 4 and the Pd(II) species D, which
leads to the formation of biaryl 5 after reductive elimination. Thus,
nd
in order to form the desired coupling product 3, the 2
transmetallation from C to D should be effectively inhibited.
Br
Ar
ArB(OH)2 (2)
NHR'
NHR'
NHR'
R
Ar-Ar
+
R
R
L
+
Pd(OAc)2, L*, base
O
O
O
1
3
4
5
*
Pd
A
1
5
oxidative
addition
reductive
ellimination
*
L
Pd Br
NHR'
*L Pd Br
O
*L Pd Ar
Ar
reductive
ellimination
3
R
R
D
O
NHR'
B
2, OH-
2nd
transmetallation
4, B(OH)3
Scheme 1. Enantioselective palladium-catalyzed cross-coupling of
α-bromo carboxamides and arylboronic acids
transmetallation
*
L
Pd Ar
NHR'
*L Pd Ar
O
[
] Prof. Dr. W. Tang, B. Li, T. Li, M. A. Aliyu, State Key Laboratory
of Bio-Organic and Natural Products Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of
2, OH-
R
-
R
X , B(OH)3
O
NHR'
C
Organic Chemistry, University of Chinese Academy of Sciences,
Proposal to inhibit the 2nd transmetallation and develop an enantioselective coupling:
3
45 Ling Ling Rd, Shanghai 200032.
Chiral sterically bulky P,P=O ligand
E-mail: tangwenjun@sioc.ac.cn
P
Ar Pd
O
P
Ar Pd
O
P
Ar Pd
Ar
Prof. Dr. Z. H. Li, Shanghai Key Laboratory of Molecular
Catalysis and Innovative Materials, Department of Chemistry,
Fudan University, Handan Road 220, Shanghai 200438.
] We are grateful to the Strategic Priority Research Program of
the Chinese Academy of Sciences XDB20000000, CAS
Ar-B
R
P
O
O
O
O
R1
R3
Ar
O
R3
P
O
R'HN
B
NHR'
[
NHR'
R
P
R4
R
OB
R2
(
2
QYZDY-SSW-SLH029), NSFC (21725205, 21432007,
1572246), STCSM-18520712200, and K.C. Wong Education
C
CD
D
Scheme 2. Mechanistic consideration to inhibit 2nd transmetallation
While no method for inhibiting the 2nd transmetallation has
been documented to our knowledge, we propose a bulky phosphorus
Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
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Angewandte Chemie International Edition
10.1002/anie.201905174
ligand, bearing a secondary hemilabile coordination such as
good yields and excellent ees (85-91%). Slightly low
enantioselectivities were observed in coupling products 3m-n with
8
,9
sterically bulky P,P=O ligand, would make it difficult to form the
palladium species D from C through the transition state CD due to
steric hindrance, therefore leading to the reductive elimination of C
to form the coupling product 3. An asymmetric cross-coupling could
also be accomplished when a chiral P,P=O ligand is employed.
Herein we detail our results.
Table 1. Pd-catalyzed coupling between α-bromo carboxamide 1a-h
and 4-MeOC H B(OH) (2a)
6 4 2
The palladium-catalyzed cross-coupling between N-
benzhydryl-2-bromopropanamide (1a) and 4-MeOC
was initially studied. The reactions were carried out in toluene with
PO as the base in the presence of Pd(OAc) (1 mol %) and a
6 4 2
H B(OH) (2a)
a
b
Entries
R’ (1)
Ligand
Base
3
K
3
4
2
ligand (1.2 mol %)(Table 1). Several well-known bisphosphorus
ligands including BINAP, DuPhos, DuanPhos, and WingPhos, as
yield (%)
ee
(
%)
1
2
3
4
5
6
7
8
9
CHPh
CHPh (1a)
2
2
(1a)
(S)-BINAP
(S,S)-DuPhos
(S,S)-DuanPhos
(S,S)-WingPhos
(S)-BI-DIME
(S)-AntPhos
L1
K
3
PO
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
0
0
0
0
0
0
--
--
--
--
--
--
8
well as monophosphorus ligands such as BI-DIME and AntPhos
K PO
3
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
CHPh
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
were employed and all led to the formation of biaryl and debromo
amide products without forming the desired coupling product 3a
(
entries 1-6). These futile results further demonstrated the challenge
10 (3a)
10 (3a)
10 (3a)
35 (3a)
47 (3a)
22 (3a)
52 (3a)
26 (3a)
58 (3a)
70 (3a)
67 (3a)
60 (3a)
69 (3a)
62 (3a)
70 (3a)
46 (3b)
50 (3c)
65 (3d)
77 (3e)
32
19
38
25
33
28
33
23
40
51
55
55
55
53
57
15
18
49
91
in accomplishing this palladium-catalyzed cross-coupling. When a
P,P=O ligand L1 was employed, we were pleased that the desired
product 3a was isolated in 10% yield and in 32% ee. Despite the low
yield and ee, this proof-of-concept result encouraged us to further
investigate the effect of chiral P,P=O ligand on the coupling reaction.
Our primary mission was to improve the coupling yield. We thus
screened four P,P=O ligands L1-4 with various substituents at 4
position. While L1-3 bearing either an aryl group or dimethylamino
group showed similarly low yield, L4 bearing a methoxy group at 4
position provided a significantly higher yield (35%, entry 10). This
result indicated the importance of electron-richness of the ligand on
the yield. We then developed a series of P,P=O ligands with various
alkoxy groups at 4 position. The employment of L5 bearing a
benzyloxy group provided an even higher yield (47%, entry 11),
while L6 bearing a phenoxy group led to a much diminished yield
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L11
L11
L11
L11
L11
L11
L11
L11
10
1
1
1
2
13
14
15
16
17
1
1
8
9
Cs
2
CO
CO
3
K
2
3
20
CHPh (1a)
2
CsF
KF
KF
KF
KF
KF
21
22
23
2
CHPh (1a)
Ph (1b)
Bn (1c)
tBu (1d)
CH(2-MeOPh)
24
25
26
27
2
2
(
1e)
CH(4-MeOPh)
(1f)
CH(2,4-
L11
L11
L11
KF
KF
KF
80 (3f)
30 (3g)
53 (3h)
70
93
90
(
entry 12), further indicating the importance of the electronic effect.
Switch to ligand L7 bearing an isopropoxy group at 4 position
further enhanced the yield to 52% (entry 13). Surprisingly, ligand
L8 bearing a tert-butyl group led to an inferior yield (entry 14).
Unsatisfied with the yield, we sought to further enhance the
electron-richness of the ligand. Thus, a dimethylamino group was
installed at 6 position in L9. We were pleased to observe the
dramatic increase of the yield between L4 (entry 10) and L9 (entry
MeO
CH(2-NMe
1h)
2
Ph)
2
(1g)
28
2
Ph)
2
(
1
5). Meanwhile, a significant improvement of ee (40% vs 25%) was
also observed. Employment of L10 bearing an isopropoxy group at
4
7
position and a diphenylamino group at 6 position provided 3a in
1% yield and 51% ee. While a decent yield was finally achieved,
the next challenging task was to improve the enantioselectivity.
Further engineering of the ligand structure led to the development of
L11 with a P(O)Ad
entry 17). Screening of various bases (entries 17-21) proved that
KF provided a slightly better yield (70% yield) and ee (57%, entry
1). Still unsatisfied the ee, we sought to change the N-substituent
2
group at 2 position provided 3a in 55% ee
(
2
on α-bromo carboxamide substrate. While substrates 1b-d bearing
N-phenyl, benzyl, and tert-butyl all provided diminished yields and
ees (entries 22-24), substrate 1e bearing N-CH(2-MeOPh) group
2
provided a good yield (77%) and excellent ee (91%). Thus, the
enantioselective palladium-catalyzed cross-coupling between an α-
bromo carbonyl and an arylboronic acid was achieved successfully
aUnless otherwise specified, all reactions were carried out with 1
0.25 mmol), ArB(OH) (2, 2.0 equiv), Pd(OAc) (1 mol %), ligand (1.2
mol %) and base (2.0 equiv) in toluene at 60 C for 48 h. Isolated yields.
ee values were determined by chiral HPLC analysis.
(
2
2
o
b
for the first time. To understand the effect of N-CH(Ar)
2
substituent
electron-defficient arylboronic acids. Excellent ees were also
achieved in products 3o-p with meta-substituents, while a low ee of
3q was obtained bearing an ortho-substituent. A series of 3,4-
disubstituted arylboronic acids were also employed, providing
coupling products 3r-w in satisfactory yields and ees. Product 3x
bearing an ortho-fluoro substituent was also formed in 62% yield
and 75% ee. Substituted naphthyl and anthrylboronic acids were
also applicable, providing corresponding coupling products 3y-z in
excellent ees. Because of the mild reaction conditions compared to
previous reports with Ni, Fe, and Co catalysis, a series of
heteroarylboronic acids were successfully employed, forming chiral
products 3aa-ae in 61-72% yields and 81-91% ees. Various α-
bromo carboxamides were also suitable substrates, providing
on both yield and ee, substrates 1e-h were further investigated and it
1
0
appeared that the N-CH(Ar)
also the enantioselectivity. The N-CH(2-MeOPh)
be the best in terms of both yield and enantioselectivity, possibly
2
group affected not only the yield but
2
group proved to
1
1
due to a combination effect of both electronic and steric properties.
With L11 as the ligand, the substrate scope of the Pd-catalyzed
cross-coupling of α-bromo carboxamides and arylbronic acids was
explored. At 1 mol % Pd loading, a series of α-aryl carboxamides
were obtained in good yields and excellent ees. Electron-rich 4-
substituted arylboronic acids provided the coupling products 3e-l in
2
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Angewandte Chemie International Edition
10.1002/anie.201905174
coupling products 3af-ai in moderate yields and excellent ees. The
relative low yields were mainly due to the formation of -hydride
elimination side-products.
racemization or reaction was observed in the absence of the
palladium catalyst, demonstrating the process free of background
reaction under the reaction conditions (equation 5). All these
experiments demonstrated the presence of a palladium-catalyzed
racemization as well as a ligand-controlled enantioselective cross-
coupling during this transformation.
Table 2. Substrate scope of Pd-catalyzed cross-coupling between α-
a
bromo carboxamides and arylboronic acids
R' = CH(2-MeOPh)2
4
-MeOC6H4B(OH)2 (2a)
Br
Pd(OAc)2 (1 mol %)
L11 (1.2 mol %)
Br
O
O
O
O
NHR'
NHR'
NHR'
+
1
)
NHR'
NHR'
NHR'
NHR'
MeO
Ph2N
MeS
KF, Toluene, 60 oC, 24 h
O
O
O
MeO
3
e
3i
3j
60% yield, 85% ee
3k
71% yield, 90% ee
7
7% yield, 91% ee
75% yield, 90% ee
R' = CH(2-MeOPh)2
S)-1e
3
0% conversion
(
(S)-1e
3e
74 % ee
O
O
O MeO
NHR'
O
91 % ee
75 % ee
NHR'
NHR'
F
NHR'
4-MeOC6H4B(OH)2 (2a)
Ph
EtOOC
3nb
Br
Pd(OAc)2 (1 mol %)
L11 (1.2 mol %)
Br
3
l
3m
3o
2
)
NHR'
8
0% yield, 90% ee
52% yield, 77% ee
52% yield, 82% ee
62% yield, 91% ee
NHR'
NHR'
+
KF, Toluene, 60 oC, 24 h
O
O
O
MeO
PhO
O
O
F
O
O
R' = CH(2-MeOPh)2
5
0% conversion
NHR'
NHR'
NHR'
NHR'
Ph
(R)-1e
(R)-1e
3e
3
p
3q
3r
60% yield, 89% ee
3s
90 % ee
73 % ee
94 % ee
6
3% yield, 84% ee
62% yield, 35% ee
70% yield, 80% ee
4
-MeOC6H4B(OH)2 (2a)
MeO
Cl
O
MeO
F
O
F3C
O
Cl
O
Br
Pd(OAc)2 (1 mol %)
rac-
L11 (1.2 mol %)
Br
NHR'
NHR'
NHR'
NHR'
NHR'
NHR'
NHR'
3)
+
MeO
BnO
KF, Toluene, 60 oC, 24 h
R' = CH(2-MeOPh)2
O
3
tb
3ub
3v
71% yield, 81% ee
3w
O
O
MeO
6
4% yield, 92% ee
70% yield, 94% ee
70% yield, 87% ee
5
0% conversion
(
R)-1e
(R)-1e
3e
F
O
O
O
90 % ee
64 % ee
52 % ee
O
NHR'
NHR'
MeO
NHR'O
4-MeOC6H4B(OH)2 (2a)
MeO
NHR'
Br
Pd(OAc)2 (1 mol %)
L11 (1.2 mol %)
Br
3
x
3yb
72% yield, 94% ee
3zb
65% yield, 91% ee
3aa
NHR'
NHR'
NHR'
6
2% yield, 75% ee
61% yield, 91% ee
+
4
)
KF, Toluene, 60 oC, 40 h
80% conversion
O
O
O
MeO
O
O
O
R' = CH(2-MeOPh)2
O
O
O
N
NHR'
rac-1e
(S)-1e
3e
O
NHR'
NHR'
NHR'
N
MeO
33 % ee
91 % ee
3ab
3ac
70% yield, 91% ee
3adb
66% yield, 87% ee
3ae
7
2% yield, 87% ee
70% yield, 84% ee
Br
Br
Ph
4-MeOC6H4B(OH)2 (2a)
NHR'
NHR'
NHR'
+
5
)
KF, Toluene, 60 o
C
O
O
O
O
MeO
O
O
O
NHR'
R' = CH(2-MeOPh)2
0% conversion
MeO
NHR'
NHR'
NHR'
MeO
MeO
R
( )-1e
MeO
(R)-1e
3e
3
afb
0% yield, 90% ee
3agb
3ahb
42% yield, 91% ee
3aib
90 % ee
90% ee
0% yield
5
54% yield, 92% ee
50% yield, 90% ee
aUnless otherwise specified, the reactions were carried out with α-
Scheme 3. Mechanistic investigation
bromo carboxamides (0.25 mmol), ArB(OH)
Pd(OAc) (1 mol %), L11 (1.2 mol %) and KF (0.5 mmol, 2.0 equiv) in
toluene at 60 C for 48 h, isolated yield, ee values were determined by
2
(0.5 mmol, 2.0 equiv),
A stereochemical model of the palladium(II) complex at
reductive elimination stage is proposed, as depicted in Figure 1.
Based on our previous report on the palladium complex with a
2
o
9a
b
2 3
chiral HPLC. K CO instead of KF was employed as the base. R’ =
P,P=O ligand and
a
brief calculation on Pd(L11)(4-
CH(2-MeOPh)
2
.
MeOPh)(MeCHCONHR’), the 4-MeOPh group tends to be trans to
the P coordination and the MeCHCONHR’ component is likely to
be trans to the P=O coordination because of the steric influence
from the two adamantyl substituents. The R’ group of the
MeCHCONHR’ component tends to direct downward in Figure 1,
opposite to the tert-butyl group of L11. Thus, isomers A and B are
likely to be the two major contributing intermediates during the
reductive elimination stage.
Since racemic α-bromo carboxamide was employed in the
reaction, this cross-coupling proved to be a dynamic kinetic
resolution (DKR) process. To further understand the role and effect
of L11 in this process, both (S)- and (R)-enriched α-bromo
carboxamide 1e were subjected to cross-coupling with the Pd-L11
catalyst (Scheme 3). The fact that both (S)- and (R)-enriched α-
bromo carboxamides led to 3e with the same configuration
demonstrated the transformation through a catalyst-controlled DKR
process and oxidative addition of (R)-1e seemed to be faster than
that of (S)-1e according to the different conversions after 24 h
(
1
equations 1&2). Partial racemization of enantiomerically enriched
e was observed in both cases, showing a reversible oxidative
addition process. The fact that different ees were observed,
indicating the rate of inversion of the stereocenter on Pd is
comparable to the rate of the reductive elimination. Coupling of
enantiomerically enriched (R)-1e with racemic L11 formed 3e in
5
2% ee at 50% conversion, demonstrating a matched and
mismatched substrate-catalyst kinetic process (equation 3).
Quenching the reaction of racemic substrate at 80% conversion with
Pd-L11 catalyst provided 3e in a reliable 91% ee and the recovered
substrate 1e was isolated in 33% ee (equation 4). Finally, no
Figure 1. A proposed stereochemical model during reductive
elimination stage
3
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Angewandte Chemie International Edition
10.1002/anie.201905174
The methyl group at the α-carbonyl position in isomer B could
provide more steric influence to the 4-MeOPh coordination during
reductive elimination or transmetallation stage. The methyl group at
the α-carbonyl position in isomer B could provide more steric
influence to the 4-MeOPh coordination during reductive elimination
or transmetallation stage, and conformer A is likely to be favored,
leading to the coupling product with the observed stereochemistry.
obtained in 52% yield and 89% ee. Acidic treatment of 3r led to the
formation of (R)-flurbiprofen in 89% ee.
1
5
In conclusion, we have developed an enantioselective
palladium-catalyzed cross-coupling between α-bromo carboxamides
and arylboronic acids, leading to a wide series of chiral α-aryl
carboxamides in good yields and excellent enantioselectivities. The
nd
development of chiral P,P=O ligand is critical in overcoming the 2
Cl
Br
transmetallation issue and allows for the first time the asymmetric
Pd-catalyzed cross-coupling of α-bromo carbonyl substrate. The low
catalyst loading (as low as 0.5 mol %) of this asymmetric cross-
coupling protocol in contrast to other transition metal catalysis
makes it attractive for making anti-inflammatory drugs including
ibuprofen, naproxen, flurbiprofen. The concept of employing
sterically bulky phosphorus ligand with a secondary hemilabile
Cl
Br
NH2CH(2-MeOPh)2 (7)
NHR'
1
)
COOH
DCC, HOSu
O
7
2%
R' = CH(2-MeOPh)2
6
8
Pd(OAc)2 (1 mol %)
L11 (1.2 mol %)
Cl
CONHR'
1) CF3COOH, DCM
2) LiAlH4, THF
4
-MeOC6H4B(OH)2 (2a)
nd
coordination in inhibiting a 2 transmetallation as well as -hydride
OMe
K2CO3, toluene
7
5% (2 steps)
9
elimination should be applicable in developing a range of new
asymmetric transformations and research on this aspect is ongoing
in our laboratory.
5
1% yield, 90% ee
H
NH2
Cl
N
Ni(acac)2, SIPr
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
NaOtBu, Dioxane
OMe 80% yield
OMe
10
11
Keywords:
transmetallation
aryl
ꞏ
alkyl
palladium
cross-couplingꞏ
ꞏ chiral phosphorus
2nd
2 N HCl, 80 o
C
O
COOH
2
)
ligands ꞏ flurbiprofen
References
NHR'
80%
R' = CH(2-MeOPh)2
[1] For reviews on enantioselective and enantiospecific aryl-alkyl
couplings: (a) A. H. Cherney, N. T. Kadunce, S. E. Reisman,
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T. F. Jamison, Nature. 2014, 509, 299.
[2] For transition-metal free cross-coupling, see: (a) C. Li, Y.
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Chem. 2018, 130, 7294.
3k
Ibuprofen (12)
9
0% ee
90% ee
O
3
)
N HCl, 80 o
COOH
2
C
NHR'
MeO
85%
MeO
R' = CH(2-MeOPh)2
Naproxen (13)
3% ee
3
y
9
9
4% ee
Br
[
3] (a) X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem. Soc. 2008,
130, 3302. (b) P. M. Lundin, J. Esquivias, G. C. Fu, Angew.
Chem., Int. Ed. 2008, 48, 154; Angew. Chem. 2008, 121, 160.
F
B(OH)2 Pd(OAc)2 (0.5 mol %)
NH
O
R'
+
L11 (0.6 mmol %)
KF, toluene, 70 oC
4
)
Ph
R' = CH(2-MeOPh)2
(c) P. M. Lundin, G. C. Fu, J. Am. Chem. Soc. 2010, 132,
2r
1e
11027. (d) S. Lou, G. C. Fu, J. Am. Chem. Soc. 2010, 132,
F
1264. (e) Q. M. Kainz, C. D. Matier, A. Bartoszewicz, S. L.
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Ma, S. Hou, S. Liu, M. Wang, M. Wang, Q. Bian, Chem. Eur. J.
2018, 24, 2059.
F
COOH
CONHR'
2
N HCl, 80 o
C
8
2% yield
[
3r
(R)-Flurbiprofen (14)
5
2% yield, 89% ee
89% ee
Scheme 4. Synthetic applications (DCC = dicyclohexylcarbodiimide,
HOSu = N-hydroxysuccinimide, THF = tetrahydrofuran, acac =
acetylacetonate,
dihydroimidazol-2-ylidine)
SIPr
=
1,3-bis(2,6-diisopropylphenyl)-4,5-
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137, 7128. (b) T. Iwamoto, C. Okuzono, L. Adak, M. Jin, M.
Nakamura, Chem. Commun. 2019, 55, 1128.
To demonstrate the synthetic utility of this asymmetric
transformation, the syntheses of several therapeutic agents were
studied. Thus, condensation between α-bromo carboxylic acid 6 and
[
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5
[
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Tetrahedron Lett. 2002, 43, 2525. (c) J. Wang, G. Meng, K.
Xie, L. Li, H. Sun, Z. Huang, ACS Catal. 2017, 7, 7421.
NH
provided amide 8 in 72% yield. Coupling of 8 with 2a in the
presence of Pd(OAc) (1 mol %) and L11 (1.2 mol %) led to the
formation of 9 in 51% yield and 90% ee. TFA treatment to remove
the N-CH(2-MeOPh) group followed by LiAlH reduction formed
the primary amine 10 in 75% overall yield over two steps.
2 2
CH(2-MeOPh) (7) under conditions of DCC and HOSu
2
[
8] For reviews on ligand development and cross-coupling: (a) G.
Xu, C. H. Senanayake, W. Tang, Acc. Chem. Res. 2019, 52,
2
4
1101. (b) H. Yang, W. Tang, Chem. Rec. 2019, DOI:
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2016, 27, 2183.
1
2
Intramolecular Ni-catalyzed C-N coupling formed 11, a CNS
1
3
agent
inflammatory drug ibuprofen (12) was formed in 80% yield from
k by acidic treatment with 2N HCl. Likewise, naproxen (13) was
in 80% yield. Meanwhile, the nonsteroidal anti-
1
4
[
[
9] (a) C. Li, T. Chen, B. Li, G. Xiao, W. Tang, Angew. Chem., Int.
Ed. 2015, 54, 3792; Angew. Chem. 2015, 127, 3863. (b) T. Si,
B. Li, W. Xiong, B. Xu, W. Tang, Org. Biomol. Chem. 2017,
3
obtained in 85% yield from 3y under similar reaction conditions. To
test the practicality of this asymmetric cross-coupling, reaction of 1e
and 2r was studied at a gram scale in the presence of Pd(OAc)
1
5, 9903.
2
(0.5
10] L. Chu, X.-C. Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu,
mol %) and L11 (0.6 mol %) and the desired product 3r was
J. Am. Chem. Soc. 2013, 135, 16344.
4
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Angewandte Chemie International Edition
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[
[
2
11] The electronic properties of the N-CH(2-MeOPh) group is also
important to both the yield and the ee since the number and
position of the methoxy groups have shown significant effects
shown in entries 26 and 27.
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Fort, Org. Lett. 2003, 5, 2311.
[
[
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(
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(
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5
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Angewandte Chemie International Edition
10.1002/anie.201905174
Enantioselective Cross-Coupling
Bowen Li, Tiejun Li, Muinat A. Aliyu,
Zhen Hua Li, Wenjun Tang* __________
Page – Page
Enantioselective Palladium-Catalyzed
Cross-Coupling between α-Bromo
Carboxamides and Arylboronic Acids
An enantioselective palladium-catalyzed cross-coupling between α-bromo carboxamides
and arylboronic acids is developed with the palladium loading as low as 0.5 mol %, leading
to a series of chiral α-aryl carboxamides in good yields and excellent enantioselectivities.
The development of chiral P,P=O ligand is critical in overcoming the second
transmetallation issue and allows for the first time the asymmetric Pd-catalyzed coupling of
α-bromo carbonyls.
6
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