Enantioselective palladium-catalyzed arylation of N-tosylarylimines with arylboronic acids using a chiral 2,2′-bipyridine ligand

Article abstract of DOI:10.1039/c5ob02330k

With the aid of an axially chiral 2,2′-bipyridine ligand, we have successfully developed a palladium-catalyzed method for the enantioselective arylation of N-tosylarylimines, furnishing the chiral diarylmethamines with high yields and enantioselectivities

Full text of DOI:10.1039/c5ob02330k

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Enantioselective palladium-catalyzed arylation of
N-tosylarylimines with arylboronic acids using a
chiral 2,2’-bipyridine ligand†
Cite this: DOI: 10.1039/c5ob02330k
Received 13th November 2015,
Accepted 24th November 2015
Xiang Gao, Bo Wu, Zhong Yan and Yong-Gui Zhou*
DOI: 10.1039/c5ob02330k
www.rsc.org/obc
With the aid of an axially chiral 2,2’-bipyridine ligand, we have
successfully developed a palladium-catalyzed method for the
enantioselective arylation of N-tosylarylimines, furnishing the
chiral diarylmethamines with high yields and enantioselectivities
under very mild conditions. An exogenous base was avoided and
imine hydrolysis was inhibited in this transformation.
Transition-metal-catalyzed asymmetric addition of organome-
tallic reagents to imines represents one of the most straight-
forward approaches for the construction of chiral
diarylmethamines, which are synthetically important chiral
building blocks for pharmaceutically active compounds.1
Thanks to the seminal work by Hayashi,2 Carreira3 and Lin,4
the chiral dienes flourished as steering ligands in rhodium-
catalyzed asymmetric reactions, especially the arylation of
imines with excellent yields and enantioselectivities.5
Pioneered by these studies, ene-based ligands were extensively
studied, P-olefin, N-olefin and S-olefin ligands were developed
and applied in rhodium-catalyzed asymmetric addition of
arylboronic acids to enones or imines with excellent stereo-
control.6 Therefore, rhodium complexes coordinated with ene-
based ligands have emerged as the most versatile catalysts for
the asymmetric arylation of imines by arylboronic acids.
In contrast to rhodium, other transition-metals have
received relatively less attention. Several reports have described
the copper- or zirconium-catalyzed asymmetric addition of
allylboronates or dialkylzinc reagents to ketimines.7 Recently,
palladium-catalyzed addition of arylboronic acids to imines
has become a subject of keen interest due to the high efficacy
and robustness of palladium catalysts.8 A wide array of palla-
dium catalysts coordinated with N-heterocyclic carbene,9 pyri-
dine–oxazoline,10 phosphinooxazoline,11 bisoxazoline,12 and
imidazoline13 ligands have been reported in the asymmetric
arylation of imines (Scheme 1).14 These elegant studies by
Scheme 1 Representative ligands in palladium-catalyzed asymmetric
arylation of imines.
Zhang, Hayashi and Peters authenticate that the catalytic profi-
ciency of palladium catalysts has been comparable to that of
the best rhodium catalysts in terms of enantioselectivity and
activity. Despite this valuable progress made in this area,
highly-efficient ligands occupied in this asymmetric transform-
ation are limited and developing new ligands is still desirable.
Herein, we report an example of using palladium complexes
coordinated with axially chiral 2,2′-bipyridine ligands for the
enantioselective arylation of N-tosylarylimines with arylboronic
acids, affording the chiral diarylmethamines with up to 94% ee.
In 2007, Lu and co-workers disclosed a palladium-catalyzed
arylation of N-tosylarylimines promoted by an achiral 2,2′-
bipyridine ligand.15a They found that the 2,2′-bipyridine ligand
was crucial in the reaction by enabling the arylpalladium
species to become more nucleophilic, thus making the
addition reaction possible. However, with no easily accessible
chiral bipyridine ligands in hand, they turned to use chiral
pyridine–oxazoline ligands to study the asymmetric version
and moderate ee values were obtained.15b Recently, we have
reported the design and synthesis of a series of axially chiral
2,2′-bipyridine ligands Cn-ACBP, they exhibited excellent
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China. E-mail: ygzhou@dicp.ac.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob02330k
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stereocontrol in palladium-catalyzed asymmetric carbene
migratory insertion reactions.16 Therefore, we envisioned that
our chiral bipyridine ligands could effectively promote the
palladium-catalyzed asymmetric arylation of N-tosylarylimines
with arylboronic acids.
Table 2 Palladium-catalyzed asymmetric addition of phenylboronic
acid 2a to N-tosylarylimines 1 a
We began our investigation on the addition of phenylboro-
nic acid to (E)-N-(4-chlorobenzylidene)-4-methylbenzene-sulfo-
namide 1a catalyzed by Pd(L1)(OCOCF3)2 in trifluoroethanol
(TFE) at 60 °C. Gratifyingly, the reaction proceeded smoothly
without an exogenous base and furnished 3aa in 99% yield
and 82% ee (Table 1, entry 1). Notably, imine hydrolysis
couldn’t be detected even when the reaction was performed in
air. Lowering the reaction temperature resulted in a slight
improvement of enantioselectivities (Table 1, entries 2–4). To
our satisfactory, the reaction even proceeded well at 0 °C,
affording 3aa in 99% yield and 89% ee within 12 h (Table 1,
entry 5). Next, a solvent screening revealed that dichloro-
methane and 1,2-dichloroethane led to a drastic decrease in
both reactivity and enantioselectivity (Table 1, entries 6 and 7).
Surprisingly, no product was detected when employing MeOH
as the solvent (Table 1, entry 8). While reactivity retained,
Entry
Ar
t (h)
Yieldb (%)
eec (%)
1
2
3
4
4-ClC6H4 (1a)
4-BrC6H4 (1b)
2-BrC6H4 (1c)
4-MeC6H4 (1d)
4-MeOC6H4 (1e)
2-HOC6H4 (1f)
2-MeOC6H4 (1g)
3,4-(MeO)2C6H3 (1h)
3,5-(MeO)2C6H3 (1i)
3,4,5-(MeO)3C6H2 (1j)
2-Br-4,5-(MeO)2C6H2 (1k)
1-Naphthyl (1l)
12
35
24
22
35
35
24
42
22
36
21
24
99 (3aa)
96 (3ba)
90 (3ca)
91 (3da)
99 (3ea)
76 (3fa)
95 (3ga)
94 (3ha)
90 (3ia)
99 (3ja)
99 (3ka)
99 (3la)
89 (S)
89 (S)
90 (S)
90 (S)
91 (S)
91 (−)
91 (S)
92 (−)
90 (−)
92 (−)
93 (−)
90 (S)
5
6d
7
8
9
10
11
12
a Reaction conditions: Pd(L1)(OCOCF3)2 (5.0 mol%), 1 (0.20 mmol), 2a
(0.30 mmol), TFE (3.0 mL), 0 °C. b Isolated yield. c Determined by
HPLC. d Determined by HPLC of the product after being protected by
benzoyl chloride.
there was
a significant drop in enantioselectivity when
utilizing C2-ACBP L2 as the ligand (Table 1, entry 9), and the
low enantioselectivity might be ascribable to the small
dihedral angle.17 C4-ACBP L3 was also examined and a slightly
lower ee value was obtained (Table 1, entry 10). Therefore, the
optimal reaction conditions were established: using Pd(L1)
(OCOCF3)2 as the catalyst and TFE as the solvent to perform
the reaction at 0 °C.
Having identified the optimal reaction conditions, we
turned to investigate the substrate scope, and the results are
summarized in Table 2. Excellent yields could be obtained
regardless of electronic properties of N-tosylarylimines
(Table 2, entries 1–12). Though a slight decrease in reactivity
was observed when electron-deficient N-tosylarylimines were
used (Table 2, entries 2 and 3), enantioselectivities were
consistently maintained (89–90% ee). It is noteworthy that
electron-rich N-tosylarylimines gave relatively higher ee
values than the electron-deficient ones (Table 2, entries 4–12),
excellent enantioselectivities were generally obtained
(90–93% ee). ortho-Substituents on the N-tosylarylimines
dramatically decreased the activity, but excellent yields and
enantioselectivities could still be achieved after a prolonged
time (entries 6 and 7).
Table 1 Optimization of reaction parametersa
Entry
L
Solvent
T (°C)
Yieldb (%)
eec (%)
In addition, a variety of arylboronic acids was examined for
addition to different N-tosylarylimines (Table 3). Steric pro-
perties of the substrates obviously affected the reaction activity
(Table 3, entries 1–6), the reaction could complete within 24 h
when using p-tolylboronic acid (Table 3, entry 1), however,
when o-tolylboronic acid was used, it would take 10 days
before the total consumption of 1 (Table 3, entry 3). It is
amazing to see that the catalyst remained active in such a long
reaction time and no imine hydrolysis or aryl–aryl coupling
was detected during this period. The desired product was
obtained with 97% yield and 94% ee. It was also found that
the electronic properties of the arylboronic acids had little
influence on enantioselectivities (Table 3, entries 1–10),
arylboronic acids bearing electron-withdrawing group Br and F
all gave excellent yields and enantioselectivities (Table 3,
entries 7 and 8). Extending the reaction time could give
complete conversion for all cases, furnishing the corres-
1
2
3
4
5
6
7
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
TFE
TFE
TFE
TFE
60
40
25
10
0
0
0
0
0
0
99
99
99
99
99
41
59
N/R
99
99
82
83
86
87
89
89
88
—
4
TFE
DCM
DCE
MeOH
TFE
8
9d
10d
TFE
88
a Reaction conditions: Pd(L)(OCOCF3)2 (5.0 mol%), 1a (0.20 mmol), 2a
(0.30 mmol), solvent (3 mL), 5–96 h. b Isolated yield. c Determined by
HPLC. d The catalyst was prepared in situ. N/R: No reactivity, DCM:
dichloromethane, DCE: 1,2-dichloroethane.
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chiral diarylmethamines could be obtained with up to 94% ee.
This represents the first example of palladium-catalyzed aryl-
ation of N-tosylarylimines promoted by a chiral 2,2′-bipyridine
ligand. Highlights of this methodology involve an exogenous-
base-free transmetalation process, inhibition of imine hydro-
lysis, and mild reaction conditions. Studies to extend the
scope of this methodology and probe the reaction mechanism
are currently underway in our laboratory.
Table 3 Palladium-catalyzed asymmetric addition of arylboronic acids
2 to N-tosylarylimines 1 a
Entry
1
Ar2
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1k
1k
1k
1k
1k
1k
1k
1k
1k
1k
1d
1d
1h
1h
1j
4-MeC6H4 (2b)
3-MeC6H4 (2c)
2-MeC6H4 (2d)
4-MeOC6H4 (2e)
3-MeOC6H4 (2f)
2-MeOC6H4 (2g)
4-FC6H4 (2h)
24
36
240
24
36
24
120
144
24
168
24
36
24
98 (3kb)
99 (3kc)
97 (3kd)
98 (3ke)
99 (3kf)
99 (3kg)
99 (3kh)
95 (3ki)
99 (3kj)
99 (3kk)
87 (3db)
77 (3dg)
98 (3hb)
80 (3hg)
99(3jb)
93 (+)
93 (+)
94 (+)
92 (+)
93 (+)
94 (+)
94 (+)
93 (+)
92 (+)
92 (+)
90 (S)
90 (R)
90 (−)
90 (+)
92 (+)
90 (+)
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21372220 & 21532006).
4-BrC6H4 (2i)
9
4-BnOC6H4 (2j)
1-Naphthyl (2k)
4-MeC6H4 (2b)
2-MeOC6H4 (2g)
4-MeC6H4 (2b)
2-MeOC6H4 (2g)
4-MeC6H4 (2b)
2-MeOC6H4 (2g)
10
11
12
13
14
15
16
Notes and references
48
24
48
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protocol by employing Pd-bipyridine complexes as catalysts for
asymmetric arylation of N-tosylarylimines, the corresponding
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