Enantioselective palladium-catalyzed C(sp2)-H carbamoylation

Article abstract of DOI:10.1016/j.tet.2019.03.038

An enantioselective palladium-catalyzed C(sp²)-H carbamoylation for the preparation of chiral isoindolines was described for the first time. With chiral monophosphorus ligand (R)-AntPhos as the ligand, a series of chiral isoindolines were prepa

Full text of DOI:10.1016/j.tet.2019.03.038

Accepted Manuscript
2
Enantioselective palladium-catalyzed C(sp )-H carbamoylation
Wenfeng Dong, Guangqing Xu, Wenjun Tang
PII:
S0040-4020(19)30335-7
https://doi.org/10.1016/j.tet.2019.03.038
TET 30224
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 February 2019
Revised Date: 19 March 2019
Accepted Date: 22 March 2019
2
Please cite this article as: Dong W, Xu G, Tang W, Enantioselective palladium-catalyzed C(sp )-H
carbamoylation, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.03.038.
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Enantioselective Palladium-Catalyzed
C(sp2)-H Carbamoylation
Wenfeng Dong,a Guangqing Xu,b and Wenjun Tang
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a,b
aSchool of Physical Science and Technology, ShanghaiTech University, Shanghai 200031, China
bState Key Laboratory of Bio-Organic and Natural Products Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road,
Shanghai 200032, China
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Tetrahedron
journal homepage: www.elsevier.com
Enantioselective Palladium-Catalyzed C(sp2)-H Carbamoylation
a,b
Wenfeng Donga, Guangqing Xu,b and Wenjun Tang
aSchool of Physical Science and Technology, ShanghaiTech University, Shanghai 200031, China
bState Key Laboratory of Bio-Organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An enantioselective palladium-catalyzed C(sp2)-H carbamoylation for the preparation of chiral
isoindolines was described for the first time. With chiral monophosphorus ligand (R)-AntPhos
as the ligand, a series of chiral isoindolines were prepared from diarylmethyl carbamoyl
chlorides in excellent yields and enantioselectivities with the palladium loading as low as 1
mol%. Initial mechanistic studies indicated the asymmetric cyclization catalyzed a palladium
species with a single chiral monophosphorus ligand.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Carbamoylation
Enantioselective
isoindolines
Palladium catalysis
Chiral phosphorus ligand
———
Wenjun Tang. Tel: +86-21-54925515; e-mail: tangwenjun@sioc.ac.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Enantioselective palladium-catalyzed carbon-carbon
bond-forming reaction has become one of most important
asymmetric transformations in organic synthesis and has
shown increasing applications. Asymmetric cyclization
using simple and easily accessible starting materials such
as unfunctionalized arenes to build chiral building blocks
or intermediates has become an attractive method. In
particular, the recent advances in palladium-catalyzed
asymmetric C(sp2)-H and C(sp3)-H arylation from aryl
halides has received considerable attention.1 The
palladium-catalyzed carbamoylation using carbamoyl
chlorides as the starting materials is an attractive method to
make amides or lactams. Baudoin and co-workers2 have
recently developed a C(sp3)-H carbamoylation to form a
range of β-lactams (Scheme 1a). With a chiral TADDOL-
derived phosphonite as the ligand, an enantioselective
version was achieved to provide the chiral lactam product
in 84% ee. However, to the best of our knowledge, no
asymmetric C(sp2)-H carbamoylation has ever been
reported.
Isoindolines are important structural units in numerous
natural products and bioactive compounds.3 Synthesis of
chiral isoindolines has gained considerable attention4. Xu
and co-workers5 have recently reported an interesting
enantioselective C-H carbonylation of sulphonamides with
Pd/Cu co-catalysts (Scheme 1b). With a chiral mono-N-
protected amino acid as the ligand, excellent
enantioselectivities (up to 96% ee’s) were achieved on a
series of lactam products, albeit with the requirement of 10
mol% catalyst loading. We reported an asymmetric
intramolecular Pd-catalyzed C(sp2)-H arylation of diaryl
ortho-bromo aryl phosphonates by employing a P-chiral
Scheme 1. Asymmetric C(sp2)-H carbamoylation reaction
We initially chose carbamoyl chloride 2a as the substrate
for study (Table 1 entries 1-4). The reactions were carried out
in toluene at 80 oC for 24 h with cesium carbonate as the base
and PivOH as the additive in the presence of Pd(OAc)2 (5
mol %) and a chiral monophosphorus ligand (5 mol %). To
our delight, the four monophosphorus ligands L1-4 developed
in our group all provided the cyclization product 3a in high
yields, however with no or low enantioselectivities. Among
them, (R)-AntPhos (L3) provided a 37% ee. We thought the
N-R substituent might play a significant influence on the
enantioselectivity, hence carbamoyl chlorides 2b-d with
different N-R substituents were prepared from corresponding
amines 1b-d and cyclization of 2b-d under palladium
catalysis with L3 as the ligand were tested (entries 5-7). Both
substrates 2b-c led to their corresponding cyclization products
with moderate yields and low ees, while the N-phenyl
substrate 2d was inactive. Product 3c was obtained in 45% ee
(entry 6). The main side-reaction during the transformation
was the decarbonylation to form the secondary amine 1b-d.1t-v
Since change of the N-substitution did not provide a
pronounced effect on enantioselectivity, we decided to change
the Pd/L3 ratio of the reaction. Thus, the amount of ligand L3
was changed from 5 mol % to 10, 15, 20 mol % with 2b as the
substrate (entries 8-12). Surprisingly, when 10 mol % of L3
was employed, the ee value of 3b increased to 91% (entry 8).
Further increase of the ligand loading not only enhanced the
enantioselectivity but also the yield of 3b. When 5 mol %
Pd(OAc)2 and 20 mol % of L3 were employed in this reaction,
a 96% ee and 80% isolated yield were achieved (entry 10). A
monophosphorus ligand.6,7 With (
R, R)-Me-AntPhos as the
ligand, a series of P-chiral biaryl phosphonates were
synthesized in high yields (up to 92%) and good
enantioselectivities (up to 88% ee) under mild conditions
(Scheme 1c). We proposed that a similar asymmetric
cyclization could also be developed on carbamoyl
chlorides as the substrates for preparation of chiral lactams.
Herein we report a highly enantioselective palladium-
catalyzed C(sp2)-H carbamoylation of diarylmethyl
carbamoyl chlorides by employing AntPhos as the chiral
ligand, providing a series of chiral isoindolines in excellent
yields and enantioselectivities with the palladium loading
as low as 1 mol% (Scheme 1d).
2. Result and discussion
The preparation of
carbamoyl chlorides 2a-d was
accomplished from corresponding secondary amines 1a-d by
treatment with triphosgene and NEt3 in DCM. After a simple
aqueous work-up, the crude carbamoyl chlorides 2a-d were
used directly without further purifications for the study of
enantioselective palladium-catalyzed cyclization.
o
lower reaction temperature (70 C) was also applicable, albeit
with slightly less ee and yield (entry 11). Despite the excellent
enantioselectivity and good yield, we were not satisfied with

3
Table 1. Enantioselective C(sp2)-H carbamoylation:
optimization of reaction conditions
Table 2. Enantioselective C(sp2)-H carbamoylation:
ACCEPTED MANUSCRIPT
substrate scope [a]
O
O
R
Pd(OAc)2,
PivOH, base
R
triphosgene
Et3N
NH
N
R
N
Cl
DCM
toluene
1
2
3
O
O
O
N
N
N
3a
3e
3f
91% yield, 79% ee
57% yield, 93% ee
74% yield, 99% ee
O
N
O
N
O
N
Entri
es[a]
1
R
L*
CO
(atm)
-
Pd/L*
(mol%)
5/5
T
Yield
(%)[b]
75
Ee%[
c]
(oC)
80
L1
L2
L3
L4
L3
L3
0
0
Me (3a）
Me (3a）
Me (3a）
Me (3a）
iPr (3b)
2
3
4
5
6
-
-
-
-
-
5/5
5/5
5/5
5/5
5/5
80
80
80
80
80
85
90
93
57
61
37
0
3g
3h
3i
80% yield, 97% ee
88% yield, 91% ee
94% yield, 95% ee
30
45
(2’,4’,6’-
(MeO)3Bn
(3c)
O
O
N
O
N
F
7
Ph (3d)
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
-
-
5/5
5/10
5/15
5/20
5/20
1/4
80
80
80
80
70
80
80
80
80
80
0
69
nd
91
94
96
90
75
94
87
79
n.d
N
8
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
iPr (3b)
9
-
75
10f
11e
12
13
14
15
16
-
80
3k
3j
3l
-
72
F
74% yield, 96% ee
77% yield, 99% ee
98% yield, 99% ee
-
41
3
3
3
3
1/4
42
O
N
O
N
MeO
OMe
O
1/3
46
1/2
17
N
F3C
1/1
trace
OMe
17
18
19
iPr (3b)
iPr (3b)
iPr (3b)
L3
L3
L3
6
9
12
1/4
1/4
1/4
80
80
80
85
90
92
92
94
92
CF3
3m
3n
3c
[a] Unless otherwise specified, the reactions were performed at
the designated reaction temperature in toluene (1 mL) with 2 (0.1
mmol), Cs2CO3 (1.0 equiv), and PivOH (30 mol %) under
nitrogen or CO atmosphere for 24 h in the presence of Pd(OAc)2
as the palladium precursor and L* as the chiral ligand. The
absolute configurations of 3a-c were assigned by analogy or by
comparing the sign of their optical rotation with reported data.10
[b] Isolated yield. [c] Ee values were determined by chiral HPLC
on a chiralpak AD-H column.
87% yield, 96% ee
72% yield, 75% ee
61% yield, 96% ee
O
O
O
N
F
Cl
N
N
F
Cl
3o
3p
3q
84% yield, 89% ee
83% yield, 95% ee
91% yield, 92% ee
O
O
O
the high palladium and ligand loading. Considering the
dramatic effect on both ee’s and yields with ligand loading,
we wondered whether the Pd/L3 ratio played a major effect.
Thus, the reaction was performed in the presence of 1 mol %
Pd(OAc)2 and 4 mol % of L3, significant decreases on both ee
and yield was observed (entry 12). However, the ee was not as
low as in entry 5, indicating the ee could be achieved at high
F3C
tBu
N
N
N
CF3
tBu
3r
3s
3t
73% yield, 92% ee
91% yield, 95% ee
90% yield, 96% ee
level even at
1
mol
%
palladium loading. Since
decarbonylation could be the major side-reaction, we thought
weather we could run the reaction under CO8 atmosphere to
inhibit the decarbonylation. Under 3 atm of CO, we were
surprised that the ee significantly increased to 94% ee, albeit
with a similar yield (entry 13). Decrease of the L3/Pd ratio
from 4, to 3, 2, 1 deteriorated both the yield and the ee
(entries 14-16). We thus kept the ratio of L3/Pd as 4 and
further
[a] Unless otherwise specified, the reactions were performed at
80 C under CO (9 atm) for 24 h in toluene (2 mL) with 2 (0.2
mmol), Pd(OAc)2 (1 mol %), L3 (4 mol %), Cs2CO3 (0.2 mmol),
and PivOH (30 mol %); isolated yields; ee values were
determined by chiral HPLC. The absolute configurations by
comparing the sign of their optical rotation with reported data.9
o

4
Tetrahedron
ACCEPTED MANUSCRIPT
increased the CO pressure of the reaction. Pleasingly, the
A
brief mechanistic pathway of the C(sp2)-H
yield dramatically increased under 6 atm of CO, indicating the
effective inhibition of decarbonylation (entry 17). An
excellent ee (94%) and yield (90%) were achieved under 9
atm of CO at 1 mol % palladium loading (entry 18). Further
increase of CO did not provide much improved results (entry
19). We thus chose Pd(OAc)2 (1 mol %), (R)-AntPhos (4
mol %), Cs2CO3 (1 equiv), PivOH (30 mol %), CO (9 atm),
carbamoylation is proposed, as shown in Figure 2. Oxidative
addition of carbamoyl chloride 2l by a Pd (0) species A leads
to the formation of a Pd(II) species B. Under CO atmosphere,
the α-elimination of B to E could be effective inhibited.
Under basic conditions, B undergoes C(sp2)-H activation
through a concerted metalation-deprotonation pathway,10 via
transition state C, to form the palladacyle D. Reductive
elimination of D leads to the formation of product 3l and
regenerates the Pd(0) species A. The transition state C could
have two possible conformers shown in Figure 2. In
conformer b, a steric interaction between the anthryl group of
the ligand and one phenyl substituent of the substrate is much
likely, while the more stable conformer a leads to product 3l
with the observed stereochemistry.
o
toluene as the solvent, and 80 C as the optimized reaction
conditions for further studies.
The substrate scope of this enantioselective palladium-
catalyzed C(sp2)-H carbamoylation was studied under the
optimized reaction conditions. Carbamoyl chlorides 2a-t with
various N-alkyl substituents were subjected for the cyclization
and all provided chiral products in satisfactory yields and
good to excellent ee’s (Table 2). The N-methyl product 3a
was obtained in 79% ee. The relative low ee compared to that
of 3b is possibly due to the smaller size of the methyl group.
Products 3e-m with either primary alkyl groups such as n-
pentyl, isopentyl, isobutyl, and cyclohexylmethyl, or
secondary cyclic and acyclic alkyl groups such as cyclobutyl,
cyclopentyl, cyclohexyl, 3-pentyl and isopropyl, all provided
excellent ee’s and yields. Under the optimized conditions, the
N-(2’,4’,6’-(MeO)3Bn product 3c was also obtained in 96% ee.
Various para-substituted diarylmethyl carbamoyl chlorides
could also be employed. Substituents such as fluoro (3p),
chloro (3q), trifluoromethyl (3r), methyl (3s), and tert-butyl
(3t) were all compatible. Interestingly, asymmetric cyclization
of both meta-substituted diarylmethyl carbamoyl chlorides 2n
and 2o occurred exclusively at the para position to the
substituents, forming 3n and 3o in good enantioselectivities,
respectively. Apparently, much steric hindrance would
encounter if the cyclizations occur at the ortho positions to the
substituents.
3l
2l
L
Pd(0)-
A
Ph
Ph
O
Ph
CO
Ph
Cl
Ph
N
Pd
N
Pd Cl
CO
iBu
iBu
L:
R
)-AntPhos
(
L
N
Pd
L
L
iBu
B
E
D
O
CsOPiv
PivOH
Ph
Cs2CO3, PivOH
CsCl
H
O
N
Pd
iBu
O
tBu
L
O
C
O
P
O
P
O
O
O
O
Pd
Pd
H
H
O
O
The high enantioselectivity achieved at L3/Pd ratio of 4
deserved further elaboration. Cyclization of 2l with a scalemic
composition of AntPhos showed a good linear relationship of
ee’s between the ligand and 3a (Figure 1), indicating the
reaction catalyzed by a palladium catalyst with a single
AntPhos ligand. Thus, we speculated that the role of the
excess ligand in the transformation was to inhibit background
or non-enanatioselective side-reaction. In particular, the
secondary amine derived from decarbonylation could play a
role for the enantiomeric loss. Under CO atmosphere, the
decarbonylation was effectively inhibited and a low palladium
loading of 1 mol % was successfully achieved.
N
N
H
b
a
Figure 2. Mechanistic consideration
To demonstrate the practicality of this asymmetric
cyclization, the synthesis of 3l was carried out at a gram scale
(Scheme 2). Thus, amine 1l was transformed to 2l by
treatment
dichloromethane. After aquesous workup, the crude 2l was
subjected for the asymmetric palladium-catalyzed
of
triphosgene
and
triethylamine
in
carbamoylation under the optimized reaction conditions and
the desired product 3l was isolated in 90% yield (0.99 g) and
96% ee.
ee of AntPhos (%)
Scheme 2. Gram-scale preparation of 3l
Figure 1. A linear relationship of ees between ligand AntPhos
and product 3l

5
3. Conclusion
NMR (125 MHz, CDCl ) δ 144.61, 128.42, 127.39, 126.84,
ACCEPTED MANUSCRIPT
3
64.29, 46.12, 23.23; HR-MS (ESI): Calculated for C16H19N
[M+H]: 226.1589 Found: 226.1590.
In summary, we have described an enantioselective
palladium-catalyzed C(sp2)-H carbamoylation. With chiral
monophosphorus ligand (R)-AntPhos as the ligand, a series of
chiral isoindolines were prepared from diarylmethyl
Compound 1e: 90% yield; colorless oil; 1H NMR (500 MHz,
CDCl3) δ 7.42(d, J = 7.5 Hz, 4H), 7.31 (t, J = 7.5Hz, 4H),
7.22 (t, J = 7.5 Hz, 2H), 4.84 (s, 1H) 2.59 (t, J = 7.0 Hz, 2H),
1.55(m, 2H), 1.31(m, 4H), 0.90 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 144.18, 128.43, 127.29, 126.92, 67.60,
48.28, 29.84, 29.54, 22.61, 14.05; HR-MS (ESI): Calculated
for C19H23N [M+H]: 254.1903, Found 254.1903
carbamoyl
chlorides
in
excellent
yields
and
enantioselectivities with the palladium loading as low as 1
mol %. Mechanistic studies indicated the asymmetric
cyclization catalyzed a palladium species with a single chiral
monophosphorus ligand. This practical method has provided a
facile and valuable avenue for preparing chiral lactams in
particular chiral isoindoline products for medicinal chemistry.
1
Compound 1f: 88% yield (1.88 g); colorless oil; H NMR
4. Experimental section
(500 MHz, CDCl3) δ 7.41(d, J = 8.5 Hz, 4H), 7.30 (t, J = 8.5
Hz, 4H), 7.21(t, J = 7.5 Hz, 2H), 4.82 (s, 1H), 2.10 (t, J = 7.5
Hz, 2H), 1.66 (m, 1H), 2.10 (m, 2H), 0.88 (d, J = 6.5 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 144.39, 128.41, 127.25,
126.87, 67.77, 46.46, 39.40, 26.04, 22.70; HR-MS (ESI):
Calculated for C18H24N [M+H]: 254.1902, Found: 254.1903
4.1 General procedures
NMR spectra and data were recorded on a Bruker
DRX 500 NMR Spectrometer with CDCl3, DMSO-D6 or
CD3OD as the solvent. 13C chemical shifts were acquired
with 1H decoupling. MS data were measured on an
Agilent 1100 Series LC/MSD mass spectrometer.
Column chromatography was performed with silica gel.
All reagents were used as received from commercial
sources unless otherwise specified or prepared as
described in the literature. All reagents were weighed and
handled in air and refilled with an inert atmosphere of
nitrogen an inert atmosphere of nitrogen except for
special description in the experimental procedure.
1
Compound 1g: 54% yield (1.05 g); colorless oil; H NMR
(500 MHz, CDCl3) δ 7.42 (d, J = 7.5 Hz, 4H), 7.31(t, J = 7.5
Hz, 4H), 7.23 (t, J = 7.5 Hz, 2H), 4.85 (s, 1H), 3.2 (m, 1H),
2.20 (m, 2H), 1.63-1.80 (m, 3H), 1.55 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 143.81, 128.45, 127.35, 127.02, 64.48,
52.07, 31.37, 14.71; HR-MS (ESI): Calculated for C17H20N
[M+H]: 238.1590, Found: 238.1590
1
Compound 1h: 80% yield (1.65 g); colorless oil; H NMR
4.2 Synthetic procedures of ligand
(500 MHz, CDCl3) δ 7.44 (d, J = 7.5 Hz, 4H), 7.34 (t, J = 7.5
Hz, 4H), 7.24 (t, J = 7.5 Hz, 2H), 4.95 (s, 1H), 3.0-3.1 (m,
1H), 1.85-1.92 (m, 2H), 1.67-1.76 (m, 2H), 1.38-1.58 (m,
4H); 13C NMR (125 MHz，CDCl3) δ 144.33, 128.43, 127.47,
126.91, 65.73, 57.66, 33.19, 23.87; HR-MS (ESI): Calculated
for C18H22N [M+H]: 252.1746, Found: 252.1747
P-Chiral monophosphorus ligands were prepared according
to procedures described in our previous reports.11,7b,7d
4.3 Synthesis procedures of secondary amines
4.3.1 General procedure
1
Compound 1i: 93% yield (2.03 g); colorless oil; H NMR
(500 MHz, CDCl3) δ 7.41 (d, J = 7.5 Hz, 4H), 7.32 (t, J = 7.5
Hz, 4H), 7.22 (t, J = 7.5 Hz, 2H), 5.07 (s, 1H), 2.39-2.50 (m,
1H), 1.95-2.03 (d, 2H), 1.67-1.77 (m, 2H), 1.59 (m, 1H), 1.08-
1.26 (m, 5H); 13C NMR (125 MHz ， CDCl3) δ 144.78,
128.39, 127.40, 126.79, 63.66, 53.96, 33.94, 26.24, 25.12;
HR-MS (ESI): Calculated for C19H24N [M+H]: 266.1902,
Found: 266.1903
Substrates 1a-b, 1e-t was prepared as follows: To a
solution of benzophenone (1.5 g, 8.23 mmol) in DCM (40
mL) was charged secondary amine (2.0 equiv) followed by
slow addition of TiCl4 (1.2 mL, 1.2 equiv) at 0 oC. The
resulting mixture was stirred at rt for 8 h followed by the
addition of NaBH3CN (600 mg in 10 mL THF). The mixture
was stirred for additional 4 hours before addition of aqueous
NaOH solution (20% w/w, 100 mL) to quench the reaction.
The organic layer was separated and the aqueous phase was
extracted with DCM. The combined organic phases were
dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica gel column
chromatography to give product.
1
Compound 1j: 85% yield (1.77 g); colorless oil; H NMR
(500 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 4H), 7.32 (t, J = 7.5
Hz, 4H), 7.23 (t, J = 7.5 Hz, 2H), 4.99 (s, 1H); 2.42 (m, 1H),
1.49 (m, 4H), 0.91 (t, J = 7.5 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 144.82, 128.36, 127.49, 126.81, 63.97, 56.42, 25.68,
9.67; HR-MS (ESI): Calculated for C18H24N [M+H]:
254.1903, Found: 254.1903.
1
1
Compound 1k: 87% yield (1.87 g); colorless oil; H NMR
Compound 1a: 95% yield; colorless oil; H NMR (500 MHz,
(500 MHz, CDCl3) δ 7.33 (dd, J = 5.5, 2.5 Hz, 4H) 6.99 (t, J =
8.5 Hz, 4H) 4.94 (s, 1H); 2.71 (m, 1H), 1.08 (d, J = 6.5 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 161.77 (d, J = 243.8 Hz),
140.16 (d, J = 2.5 Hz), 128.69 (d, J = 8.75 Hz), 115.23 (d,
J=21.25Hz), 62.86, 46.07, 23.15; HR-MS (ESI): Calculated
for C16H18F2N [M+H]: 262.1402, Found :262.1402; 19F NMR
(300 MHz, CDCl3) δ -116.37
CDCl3) δ7.41 (d, J=8.0 Hz, 4H), 7.32 (m, J = 7.0 Hz, 4H),
7.23 (d, J = 6.5 Hz, 2H), 4.72 (s, 1H), 2.44 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 143.93, 128.46, 127.26, 126.98, 69.58,
35.12; HR-MS (ESI): Calculated for C14H15N [M+H]:
198.1276 Found: 198.1277
1
Compound 1b: 95% yield; colorless oil; H NMR (500 MHz,
CDCl3) δ 7.42 (d, J = 8.0 Hz, 4H), 7.32 (t, J = 7.5 Hz, 4H),
7.23 (t, J = 7.5 Hz, 2H), 5.01 (s, 1H), 1.10-1.14 (m, 6H); 13C

6
Tetrahedron
ACCEPTED MANUSCRIPT
1
1
Compound 1l: 94% yield (1.85 g); colorless oil; H NMR
Compound 1s: 93% yield; light yellow oil; H NMR (500
(500 MHz, CDCl3) δ 7.44 (d, J = 7.5 Hz, 4H), 7.32 (t, J = 7.5
Hz, 4H), 7.22 (t, J = 7.5 Hz, 2H), 4.82 (s, 1H), 2.42 (d, J = 7.0
Hz, 2H), 1.80 (m, 1H), 0.96 (d, J = 6.5 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 144.51, 128.41, 127.29, 126.87, 67.65,
56.26, 28.63, 20.74; HR-MS (ESI): Calculated for C17H22N
[M+H]: 240.1746, Found: 240.1747
MHz, CDCl3) δ 7.31 (d, J = 10.0 Hz, 4H), 7.12 (d, J = 10.0
Hz, 4H) 4.76 (s, 1H), 2.41 (d, J = 10.0 Hz, 2H), 2.32 (s, 6H),
1.79 (m, 1H), 0.94 (d, J = 10.0 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 141.19, 136.32, 129.10, 127.10, 67.03, 56.26, 28.61,
21.07, 20.76; HR-MS (ESI): Calculated for C19H26N [M+H]:
268.2058, Found: 268.2060
1
1
Compound 1t: 78% yield; white solid; H NMR (500 MHz,
Compound 1m: 83% yield (1.9 g); colorless oil; H NMR
CDCl3) δ 7.32 (dd, J = 25, 7.5 Hz, 8H), 4.75 (s, 1H), 2.39 (d,
J = 7.0 Hz, 2H), 1.78 (m, 1H), 1.29 (s, 18H), 0.92 (d, J = 7.0
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 149.48, 141.50,
126.87, 125.24, 67.00, 56.27, 34.39, 31.38, 28.55, 20.75; HR-
MS (ESI): Calculated for C25H38N [M+H]: 352.2996, Found:
352.2999
(500 MHz, CDCl3) δ 7.43 (d, J = 7.5 Hz, 4H), 7.31 (t, J = 7.5
Hz, 4H), 7.22 (t, J = 7.5 Hz, 2H), 4.81 (s, 1H), 1.89 (s, 1H),
1.79-1.82 (d, 2H), 1.64-1.76 (m, 3H), 1.46-1.56 (m, 1H),
1.12-1.32 (m, 3H), 0.89-0.98 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 144.40, 128.41, 127.30, 126.88, 67.67, 54.98, 37.24,
31.50, 26.73, 26.11; HR-MS (ESI): Calculated for C20H26N
[M+H]: 280.2060, Found: 280.2060
1
4.3.2 Synthesis of compound 1c
Compound 1p: 86% yield (1.95 g); colorless oil; H NMR
(500 MHz, CDCl3) δ 7.34 (dd, J = 5.5, 3.0 Hz, 4H), 6.98 (t, J
= 9.0 Hz, 4H), 4.75(s, 1H), 2.35 (d, J = 7.0 Hz, 2H), 0.92 (d, J
= 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 161.80 (d, J =
243.7 Hz), 140.06 (d, J = 3.8 Hz) 128.59 (d, J = 8.75 Hz)
115.24(d, J = 21.2 Hz) 66.19, 56.09, 28.60, 20.67; HR-MS
(ESI): Calculated for C17H19F2N [M+H]: 276.1558, Found:
276.1558; 19F NMR (300MHz, CDCl3) δ -116.29
Compound 1q: 90% yield (2.3 g); colorless oil; 1H NMR (500
MHz, CDCl3) δ 7.32 (d, J = 8.5 Hz, 4H), 7.26 (d, J = 8.5 Hz,
4H), 4.73(s, 1H), 2.35 (d, J=6.5Hz, 2H), 1.74 (m, 1H), 0.92
(d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 142.57,
132.74, 128.66, 128.48, 128.47, 66.35, 56.07, 28.61, 20.66;
HR-MS (ESI): Calculated for C17H20Cl2N [M+H]: 308.0966,
Found: 308.0967
To a mixture of diphenylmethylamine (1.0 g ， 5.45
mmol 1.0 equiv) and 2,4,6-trimethoxybenzaldehyde (1.07 g
5.45 mmol, 1.0 equiv) in dichloroethane (20 mL) at rt was
added NaBH(OAc)3 (2.3 g, 10.85 mmol, 2.0 equiv) followed
by dropwise addition of AcOH (0.62 mL, 10.85 mmol, 2.0
equiv). The mixture was stirred until the starting material
disappeared completely by TLC. Water (30 mL) was added to
quench the reaction. The organic layer was separated and the
aqueous phase was extracted with dichloroethane (20 mL).
The combined organic phase was dried over anhydrous
sodium sulfate, filtered, and concentrated. The residue was
purified by silica gel column chromatography to provide
1
Compound 1n: 94% yield; light yellow oil; H NMR (500
MHz, CDCl3) δ 7.69(s, 2H), 7.58 (d, J = 5.0 Hz, 2H), 7.49 (d,
J = 5.0 Hz, 2H), 7.43 (t, J = 5.0 Hz, 2H), 4.89 (s, 1H), 2.37
(d, J = 10.0 Hz, 2H), 1.76 (m, 1H), 0.94 (d, J = 5.0 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 144.65, 130.9 (d, J = 32.5 Hz),
130.6 (d, J = 1.3 Hz), 129.1, 124.1 (d, J = 27.0 Hz), 124.2 (d,
J = 3.8 Hz), 123.9 (d, J = 3.8 Hz), 123.0, 67.0, 56.1, 28.6,
20.6; HR-MS (ESI): Calculated for C19H20F6N [M+H]:
376.1493, Found: 376.1494; 19F NMR (300 MHz, CDCl3) δ -
62.91
1
product 1c as white solid. Compound 1c: 94% Yield; H
NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.5 Hz, 4H), 7.30 (t, J
= 7.5 Hz, 4H), 7.21 (t, J = 7.5 Hz, 2H), 6.14(s, 2H), 4.82(s,
1H), 3.84(s, 3H), 3.79(s, 2H), 3.75(s, 6H); 13C NMR (125
MHz, CDCl3) δ 160.32, 159.48, 144.65, 128.20, 127.55,
126.67, 109.30, 90.42, 66.34, 55.52, 55.34, 39.84; HR-MS
(ESI): Calculated for C23H26NO3 [M+H]: 364.1906, Found:
364.1907
1
Compound 1o: 88% yield; light oil; H NMR (500 MHz,
CDCl3) δ 7.17-7.25 (m, 6H), 7.03 (d, J = 10.0 Hz, 2H), 4.73(s,
1H), 2.40 (d, J = 5.0 Hz, 2H), 2.34 (s, 6H), 1.80 (m, 1H), 0.94
(d, J = 10.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 144.49,
137.93, 128.27, 128.26, 127.97, 127.61, 124.30, 67.62, 56.30,
28.55, 21.51, 20.75; HR-MS (ESI): Calculated for C19H26N
[M+H]: 268.2059, Found: 268.2060
4.3.3 General procedures for carbamoyl chloride
formation and enantioselective palladium-catalyzed
cyclization
1
Compound 1r: 90% yield; light yellow oil; H NMR (500
MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 4H), 7.53 (d, J = 8.5 Hz,
4H), 4.89 (s, 1H), 2.37 (d, J = 6.5 Hz, 2H), 1.77 (m, 1H), 0.93
(d, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 147.58,
129.56 (q, J = 32.5 Hz), 127.49, 125.59 (q, J = 3.8 Hz),
124.06 (q, J = 270 Hz), 67.01, 56.08, 28.65, 20.61; 19F NMR
(300 MHz, CDCl3) δ -62.86; HR-MS (ESI): Calculated for
C19H20F6N [M+H]: 376.1495, Found: 376.1494
To a solution of amine 1 (0.2 mmol, 1.0 equiv) and
trimethylamine (0.086 mL, 3.0 equiv) in dichloroethane (2.0
mL) at 0 ℃ was added dropwise a solution of triphosgene
solution (0.2 mmol in 2 mL DCM). The mixture was allowed

7
to warm to rt and stirred for 6 h. Saturated sodium bicarbonate
123.46, 122.97, 64.30, 38.45, 37.02, 25.82, 22.65, 22.20;
ACCEPTED MANUSCRIPT
MS (ESI): [M+H+] 280.05; HR-MS (ESI): calculated for
C19H21NO [M+H]: 280.1694, found: 280.1696; [α]D = -
solution (20 mL) was added to quench this reaction. The
organic layer was separated and the aqueous phase was
extracted with dichloroethane for 3 times (2 mL X 3). The
combined organic phase was dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was used
directly for the next step without any further purification. To
the mixture of Pd(OAc)2 (0.4 mg, 1 mol %), (R)-AntPhos (3.0
mg, 4 mol %), PivOH (7.0 mg, 30 mol %), Cs2CO3 (66 mg,
1.0 equiv) and substrate 2 (~0.2 mmol) was added toluene (2
mL) in the glove box. The mixture was then transferred to an
autoclave and charged with CO pressure (9 atm). The mixture
was stirred at 80 for 24 h. Water (2 mL) was added to the
mixture to quench the reaction. The organic layer was
separated and the aqueous phase was extracted with EtOAc (2
mL X 3). The combined organic phase was dried over
anhydrous sodium sulfate, filtered, and concentrated. The
residue was purified by silica gel column chromatography to
give product 3, whose enatiomeric excess was determined by
chiral HPLC.
25
62.38 (c = 1, CHCl3)
Product 3g: 80% yield; 94% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3) δ 7.82-7.86 (m, 1H), 7.39-7.44 (m, 2H), 7.30-7.36 (m,
3H), 7.18-7.22 (m, 2H), 7.09-7.13 (m, 1H), 5.56 (s, 1H), 4.5
(m, 1H), 2.50 (m, 1H), 2.23(m, 1H), 2.12 (m, 1H), 1.90 (m,
1H), 1.55-1.65 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
168.98, 146.53, 138.81, 131.67, 129.01, 128.31, 128.17,
126.96, 123.40, 122.80, 109.99, 64.26, 48.17, 29.10, 28.44,
15.73; MS (ESI): [M+H+] 264.00; HR-MS (ESI): calculated
1
25
for C19H21NO [M+H]: 264.1382, found: 264.1383; [α]D = -
22.95 (c = 0.5, CHCl3)
Product 3h: 88% yield; 91% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
Product 3a: 91% yield; ee 79%; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
CDCl3) δ 7.80-7.87 (t, J = 5.0 Hz 1H), 7.39-7.44 (m, 2H),
7.29-7.34 (m, 3H), 7.17-7.21 (d, J = 10.0 Hz, 2H), 7.06-7.10
(t, J = 5.0 Hz, 1H), 5.49 (s, 1H), 4.20 (m, 1H), 1.98 (m, 1H),
1.80-1.89 (m, 1H), 1.71-1.76 (m, 1H), 1.41-1.64 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 169.11, 146.67, 138.81, 131.95,
131.54, 128.91, 128.35, 128.11, 127.27, 123.20, 122.81,
64.96, 55.24, 29.81, 29.39, 23.91, 23.68; MS (ESI): [M+H+]
278.00; HR-MS (ESI): calculated for C19H19NO [M+H]:
278.1538, found: 278.1539; [α]D25 = -127.76 (c = 1, CHCl3)
1
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3) δ 7.86-7.9 (m, 1H), 7.42-7.47 (m, 2H), 7.20-7.40 (m,
3H), 7.10-7.20 (m, 3H), 5.34 (s, 1H), 2.98 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.70, 146.03, 136.96, 131.64, 129.13,
128.64, 128.44, 128.42, 128.28, 127.39, 123.43, 122.93,
66.60, 27.49; MS (ESI): [M+H+] found: 224.05; HR-MS
(ESI): calculated for C15H13NO [M+H]: 224.1070, found:
224.1074; [α]D25 = -61.04 (c = 1, CHCl3).
Product 3i: 94% yield; 95% ee; white solid; chiral HPLC
Product 3b: 90% yield; ee 94%; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
1
CDCl3) δ 7.84-7.88 (m, 1H), 7.41 (m, 2H), 7.30-7.34 (m, 3H),
7.16-7.20 (m, 2H), 7.03-7.06 (m, 1H), 5.49 (s, 1H), 3.94-4.02
(m, 1H), 1.74-1.85 (m, 3H), 1.51-1.64 (m, 3H), 1.21-1.32 (m,
2H), 1.06-1.17 (m, 1H), 0.93-1.04 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 168.85, 146.93, 139.00, 131.76, 131.55,
128.77, 128.35, 128.08, 127.58, 123.31, 122.86, 63.86, 53.41,
31.58, 31.10, 26.06, 25.93, 25.36; MS (ESI): [M+H+] 292.20;
HR-MS (ESI): calculated for C20H21NO [M+H]: 292.1694,
found: 292.1696; [α]D25 = -130.69 (c = 1, CHCl3)
CDCl3) δ 7.86 (m, 1H), 7.42 (m, 2H), 7.32 (m, 3H), 7.19 (m,
2H), 7.07 (m, 1H), 5.48 (s, 1H), 1.35 (d, J = 10.0 Hz, 3H),
1.03 (d, J = 10.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
168.81, 146.79, 138.82, 131.93, 131.59, 128.82, 128.42,
128.14, 127.69, 123.26, 122.87, 63.83, 45.22, 21.24, 20.58;
MS (ESI): [M+H+] found: 252.10; HR-MS (ESI): calculated
25
for C17H17NO [M+H]: 252.1383, found: 252.1387;[α]D = -
54.88 (c = 1, CHCl3).
Product 3e: 57% yield; 93% ee; white solid; chiral HPLC
Product 3j: 77% yield; 99% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
1
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3) δ 7.86-7.91 (m, 1H), 7.42-7.48 (m, 3H), 7.10-7.20 (m,
3H), 5.44 (s, 1H), 3.92 (m, 1H), 2.85 (m, 1H), 1.53 (m, 2H),
1.27 (m, 4H), 0.84 (t, J = 10.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.53, 146.22, 137.15, 131.56, 129.05, 128.58,
128.23, 127.53, 123.49, 122.97, 64.38, 40.13, 28.97, 27.91,
22.31, 13.90; MS (ESI): [M+H+] 280.00; HR-MS (ESI):
calculated for C19H21NO [M+H]: 280.1696, found: 280.1696;
[α]D25 = -51.97 (c = 1, CHCl3)
CDCl3) δ 7.85-7.90 (m, 1H), 7.41-7.47 (m, 2H), 7.27-7.33 (m,
3H), 7.11-7.17 (m, 2H), 7.03-7.08 (m, 1H), 5.41 (s, 1H), 3.84
(m, 1H), 1.67-1.86 (m, 2H), 1.17-1.30 (m, 2H), 0.730-0.815
(m, 6H); 13C NMR (125 MHz, CDCl3) δ 169.57, 146.72,
138.56, 131.95, 131.62, 128.64, 128.56, 128.33, 128.18,
123.35, 123.01, 64.11, 57.38, 26.32, 25.93, 11.48, 11.39; MS
(ESI): [M+H+] 280.45; HR-MS (ESI): calculated for
C19H21NO [M+H]: 280.1695 found: 280.1696; [α]D25 = -36.50
(c = 1, CHCl3)
Product 3f: 74% yield; 99% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
Product 3k: 74% yield; 96% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3) δ 7.51 (dd, J = 10.0, 5.0 Hz, 1H), 7.10-7.20 (m, 3H),
6.95-7.05 (m, 3H), 5.45 (s, 1H), 4.29 (m, 1H), 1.33 (d, J = 5.0
Hz, 3H) 1.03 (d, J = 5.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 7.80-7.90 (m, 1H), 7.40-7.50 (m, 2H), 7.26-7.32 (m,
3H), 7.10-7.18 (m, 2H), 7.03-7.08 (m, 1H), 5.41 (s, 1H), 3.82-
3.91 (m, 1H), 1.68-1.84 (m, 2H), 1.85-1.30 (m, 2H), 0.74-0.82
(m, 6H); 13C NMR (125 MHz, CDCl3) δ 168.43, 146.21,
137.12, 131.78, 131.55, 129.05, 128.60, 128.23, 127.56,
1

8
Tetrahedron
CDCl ) δ 167.49 (d, J = 2.5 Hz), 163.83 (d, J = 26.3 Hz),
402.10; HR-MS (ESI): calculated for C H F NO [M+H]:
20 17 6
ACCEPTED MANUSCRIPT
3
161.9 (d, J = 25.0 Hz), 141.99, 134.16 (d, J = 2.5 Hz), 134.0
(d, J = 8.8 Hz), 129.3 (d, J = 8.8 Hz), 124.4 (d, J = 8.8 Hz),
119.3 (d, J = 23.8 Hz), 115.98 (d, J = 21.3 Hz), 110.02 (d, J =
22.5 Hz), 62.72, 45.45, 21.16, 20.55; MS (ESI): [M+H+]
288.05; HR-MS (ESI): calculated for C17H15F2NO [M+H]:
288.1193, found: 288.1194; 19F NMR (300 MHz, CDCl3): δ-
113.25; [α]D25 = -38.97 (c = 1, CHCl3)
402.1284, found: 402.1287 [α]D25 = -50.45 (c = 1, CHCl3)
Product 3o: 84% yield, 89% ee; white solid; chiral HPLC
conditions: Chiralpak IB, 20 ℃, flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
CDCl3) δ7.77 (d, J = 10.0 Hz, 1H), 7.24 (t, J = 10.0 Hz, 2H),
7.13 (d, J = 5.0 Hz, 1H), 6.93-6.97 (m, 2H), 6.87 (s, 1H), 5.36
(s, 1H), 3.73 (dd, J = 10.0, 5.0 Hz, 1H), 2.64 (dd, J = 10.0, 5.0
Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 1.87-1.97 (m, 1H), 0.88
(dd, J = 10.0 Hz, 5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
168.97, 146.71, 142.21, 138.87, 137.19, 129.31, 129.21,
129.01, 128.87, 127.88, 124.72, 123.40, 123.34, 64.53, 47.33,
27.55, 21.84, 21.41, 20.41, 19.85; MS (ESI): [M+H+] 294.45;
HR-MS (ESI): calculated for C20H23NO [M+H]: 294.1853,
found: 294.1855 [α]D25 = -43.85 (c = 1, CHCl3)
Product 3l: 98% yield; 99% ee; white solid; Chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
CDCl3) δ 7.90 (m, 1H), 7.45 (dd, J = 5.6, 3.1 Hz, 2H), 7.31-
7.37 (m, 3H), 7.14-7.18 (m, 1H), 7.1-7.13 (m, 2H), 3.73 (dd, J
= 15.0, 10.0 Hz, 1H) 2.66 (dd, J = 15.0, 10.0 Hz, 1H); 1.88-
1.99 (m, 1H) 0.89 (dd, J = 15.0, 10.0 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 168.86, 146.24, 137.7, 131.62, 129.08,
128.60, 128.25, 127.55, 123.61, 122.96, 64.78, 47.45, 27.57,
20.40, 19.86; MS (ESI): [M+H+] 266.15; HR-MS (ESI):
calculated for C18H19NO [M+H]: 266.1538, found: 266.1539;
[α]D25 = -109.92 (c = 1, CHCl3)
Product 3p: 83% yield; 95% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 ℃, flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
1
CDCl3) δ7.55 (dd, J = 10.0, 5.0 Hz, 1H); 7.16 (td, J =10.0, 5.0
Hz, 1H), 7.00-7.13 (m, 5H), 5.41 (s, 1H), 3.70(dd, J = 10.0,
5.0 Hz, 1H), 2.63 (dd, J = 10.0, 5.0 Hz, 1H), 1.90 (m, 1H),
0.88 (dd, J = 10.0, 5.0 Hz, 6H); 13C NMR (125 MHz , CDCl3 )
δ 167.53 (d, J = 3.8 Hz), 163.92 (d, J = 20.0 Hz), 161.90 (d, J
= 21.3 Hz), 141.45 (d, J = 1.3 Hz), 133.72 (d, J = 8.8 Hz),
132.5 (d, J = 2.5 Hz), 129.24 (d, J = 7.5 Hz), 124.51 (d, J =
8.8 Hz) 119.25 (d, J = 23.8 Hz), 116.22 (d, J = 21.3 Hz),
110.39 (d, J = 23.8 Hz), 63.68, 47.62 , 27.56 , 20.35, 19.82;
MS (ESI): [M+H+] 302.05; HR-MS (ESI): calculated for
C18H17F2NO [M+H]: 302.1349, found: 302.1351; 19F NMR
(300MHz, CDCl3): δ -113.00; [α]D25 = -72.78 (c = 1, CHCl3)
Product 3m: 87% yield; 96% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm. H NMR (500 MHz,
1
CDCl3) δ 7.80-7.90 (m, 1H), 7.42-7.47 (m, 2H), 7.30-7.37 (m,
3H), 7.14-7.17 (m, 1H), 7.10-7.13 (m, 2H), 5.45 (s, 1H), 3.78
(dd, J =15.0, 10.0 Hz, 1H), 2.66 (dd, J = 15.0, 10.0 Hz, 1H),
1.57-1.67 (m, 6H), 1.10-1.20 (m, 3H), 0.92-1.02 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 168.86, 146.23, 137.13, 131.62,
131.58, 129.06, 128.58, 128.23, 127.55, 123.58, 122.95,
64.99, 46.26, 36.89, 31.08, 30.52, 26.33, 25.81, 25.70; MS
(ESI): [M+H+] 306.40; HR-MS (ESI): calculated for
25
C21H23NO [M+H]: 306.1851, found: 306.1852; [α]D = -
94.39 (c = 1, CHCl3)
Product 3q: 91% yield; 92% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 ℃, flow rate: 0.7 mL/min,
1
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
Product 3c: 61% yield, 96% ee; white solid; chiral HPLC
CDCl3) δ 7.86 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 10.0, 2.5 Hz,
1H), 7.33 (d, J = 10.0 Hz, 2H), 7.07 (d, J = 10.0 Hz, 1H), 7.04
(d, J = 10.0 Hz, 2H), 5.40 (s, 1H), 3.70 (dd, J = 15.0, 10.0 Hz,
1H), 2.63 (dd, J = 15.0, 5.0 Hz, 1H), 1.84-1.94 (m, 1H), 0.88
(dd, J = 15.0, 5.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
167.33, 143.88, 135.05, 134.88, 134.81, 133.33, 131.95,
129.49, 128.84, 124.20, 123.90, 63.76, 47.62, 27.54, 20.35,
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
1
hexanes/isopropanol: 80/20, 254 nm. H NMR (500 MHz,
CDCl3) δ 7.88 (d, J = 10.0 Hz, 1H), 7.33-7.41 (m, 2H); 7.22-
7.28 (m, 3H), 7.03 (d, J = 5.0 Hz, 1H), 7.0 (m, 2H), 6.0 (s,
2H), 5.16 (s, 0.5H), 5.13 (s, 1H), 4.27 (d, 15.0 Hz, 1H), 3.79
(s, 3H), 3.57 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 168.32,
161.06, 159.74, 146.74, 138.26, 131.26, 131.17, 128.39,
127.79, 127.66, 126.97, 123.42, 122.74, 104.95, 89.91, 63.91,
55.37, 55.28, 33.07; MS (ESI): [M+H+] 390.20; HR-MS
(ESI): calculated for C24H23NO4 [M+H] 390.1705, found:
90.1703; [α]D25 = -26.44 (c = 1, CHCl3)
19.81; MS (ESI): [M+H+] 334.20; HR-MS (ESI): calculated
25
for C18H17Cl2NO [M+H]: 334.0759, found :334.0760; [α]D
=
-74.69 (c = 1, CHCl3)
Product 3r: 73% yield; 92% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 ℃, flow rate: 0.7 mL/min,
1
Product 3n: 72% yield; 75% ee; white solid; chiral HPLC
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3 δ 8.19(s, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7.65 (d, J =
10.0 Hz, 2H), 7.28 (t, J = 5.0 Hz, 3H), 5.58 (s, 1H), 3.79 (dd,
J = 10.0, 7.5 Hz, 1H), 2.66 (dd, J = 15.0, 5.0 Hz, 1H), 1.88-
1.98 (m, 1H), 0.9 (dd, 15.0, 5.0 Hz, 6H); 13C NMR (150 MHz,
CDCl3 ) δ 167.35, 148.50, 140.24, 132.30, 131.51(dd, J =
88.5, 55.5Hz), 131.50 (dd, J = 42.0, 9.0 Hz) , 128.8 (dd, J
=7.5, 3.0 Hz), 127.88, 126.44 (dd, J = 7.5, 4.5 Hz), 124.59 (d,
J = 4.5 Hz), 123.67, 122.78 (d, J = 4.5 Hz), 121.34 (dd, J =
7.5, 4.5 Hz), 64.13, 47.73, 27.58, 20.37, 19.82; MS (ESI):
[M+H+] 402.15; HR-MS (ESI): calculated for C20H17F6NO
1
CDCl3) δ 8.04 (d, J = 10.0 Hz, 1H), 7.77 (d, J = 5.0 Hz, 1H),
7.66(d, J = 10.0 Hz, 1H), 7.53 (t, J = 10.0 Hz, 1H), 7.42 (d, J
= 5.0 Hz, 2H), 7.29 (d, J = 10.0 Hz, 1H), 5.57 (s, 1H), 3.77
(dd, J = 15.0, 5.0 Hz, 1H), 2.65 (dd, J = 15.0, 10.0 Hz, 1H),
1.92 (m, 1H), 0.90 (dd, J = 20.0, 10.0 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 167.32, 145.68, 137.26, 133.95 (dd, J = 64.5,
31.5 Hz), 131.93 (dd, J = 64.5, 33.0 Hz), 130.75, 130.11,
129.37, 126.14 (dd, J = 6.0, 3.0 Hz), 124.57, 124.51 (d, J =
7.5 Hz), 124.48, 122.70(d, J = 7.5Hz), 120.22 (d, J = 4.5 Hz),
64.22, 47.76, 27.57, 20.34, 19.81; MS （ ESI ） : [M+H+]
25
[M+H]: 402.1284, found: 402.1287; [α]D = -74.41 (c = 1,
CHCl3)

9
E.; Baudoin O. ACS Catal. 2015, 5, 4300. (s) Yang, L.; Melot, R.;
Product 3s: 91% yield; 95% ee; white solid; chiral HPLC
ACCEPTED MANUSCRIPT
Neuburger, M.; Baudoin, O. Chem. Sci. 2017, 8, 1344. (t) Tsukano, C.;
Okuno, M.; Takemoto, Y. Angew. Chem. Int. Ed. 2012, 51, 2763. (u)
Tsukano, C.; Okuno, M.; Takemoto, Y. Chem. Lett. 2013, 42, 753. (v)
Tsukano, C.; Muto, N.; Enkhtaivan, I.; Takemoto. Y. Chem. Asian. J.
2014, 9, 2628. (w) Han, H.; Zhang, T.; Yang. S.-D.; Lan, Y.; Xia, J.-B.
Org. Lett. 2019, 21, 1749.
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
1
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
CDCl3) δ 7.69 (m, 1H), 7.25 (m, 1H), 7.14 (d, J = 5.0 Hz,
2H), 7.04 (d, J = 5.0 Hz, 1H), 6.98 (d, J = 10.0 Hz, 2H), 5.38
(s, 1H), 3.71 (dd, J = 15.0, 10.0 Hz, 1H), 2.64 (dd, J = 15.0,
5.0 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 1.87-1.97 (m, 1H),
0.88 (dd, J = 10.0, 5.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 168.92, 143.78, 138.32, 138.20, 134.25, 132.56, 131.77,
129.70, 127.44, 123.74, 122.64, 64.33, 47.37, 27.57, 21.31,
21.15, 20.40, 19.85; MS (ESI): [M+H+] 294.40; HR-MS
(ESI): Calculated for C20H23NO [M+H]: 294.1851, found
:294.1852; [α]D25 = -71.68 (c = 1, CHCl3)
2. Dailler, D.; Rocaboy, R.; Baudoin, O. Angew. Chem. Int. Ed. 2017, 56,
7218.
3. For select papers see: (a) Speck, K.; Magauer.; T. Beilstein. J. Org. Chem.
2013, 9, 2048. (b) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J.
R.; Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley,
T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8,
1499. (c) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun, H.; Schilling,
S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67,
8726.
Product 3t: 91% yield; 96% ee; white solid; chiral HPLC
conditions: Chiralpak AD-H, 20 , flow rate: 0.7 mL/min,
1
hexanes/isopropanol: 80/20, 254 nm; H NMR (500 MHz,
4. For selected examples, see: (a) Ye, B.-H.; Cramer, N. Angew. Chem., Int.
Ed. 2014, 53, 7896. (b) Li, T.; Zhou, C.; Yan, X.-Q.; Wang, J. Angew.
Chem. Int. Ed. 2018, 57, 4048. (c) Nishimura, T.; Nagamoto, M.; Ebe, Y.;
Hayashi, T. Chem. Sci. 2013, 4, 4499. (d) Austin, K. A. B.; Herdtweck,
E.; Bach, T. Angew. Chem. Int. Ed. 2011, 50, 8416. (e) Deng, L.; Xu, T.;
Li, H.-B.; Dong, G.-B. J. Am. Chem. Soc. 2016, 138, 369. (f) Guo, S.-M.;
Xie, Y.-J.; Hu, X.-Q.; Xia, C.-G.; Huang, H.-M. Angew. Chem. Int. Ed.
2010, 49, 2728.
CDCl3) δ 7.92 (d, J = 5.0 Hz, 1H), 7.48 (dd, J = 10.0, 5.0 Hz,
1H), 7.34 (d, J = 10.0 Hz, 2H), 7.10 (d, J = 10.0 Hz, 1H), 7.03
(d, J = 10.0 Hz, 2H), 5.40 (s, 1H), 3.75 (dd, J = 15.0, 10.0 Hz,
1H), 2.66(dd, J = 15.0, 5.0 Hz), 1.90-1.99 (m, 1H), 1.35(s,
9H), 1.30 (s, 9H), 0.89 (dd, J = 10.0, 5.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 169.23, 151.62, 151.39, 143.69, 134.09,
131.43, 128.94, 127.10, 125.90, 122.47, 120.25, 64.15, 47.35,
34.97, 34.58, 31.44, 31.28, 27.60, 20.43, 19.87; MS (ESI):
[M+H+] 378.20; HR-MS(ESI): calculated for C26H35NO
5. Bai, X.-F.; Mu, Q.-C.; Xu, Z.; Yang, Q.-F.; Li, L.; Zheng, Z.-J.; Xia, C.-
25
[M+H]: 378.2791, found: 378.2891; [α]D = -53.88 (c = 1,
G.; Xu, L.-W. ACS Catal. 2019, 9, 1431.
CHCl3)
6. Xu, G.; Li, M.; Wang, S.; Tang, W. Org. Chem. Front. 2015, 2, 1342.
7. For a review of chiral monophosphorus ligand, see: (a) Fu, W.; Tang, W.
ACS Catal. 2016, 6, 4814. For application of chiral AntPhos ligand, see:
(b) Fu, W.; Nie, M.; Wang, A.; Cao, Z.; Tang, W. Angew. Chem., Int.
Ed. 2015, 54, 2520. (c) Nie, M.; Fu, W.; Cao, Z.; Tang, W. Org. Chem.
Front. 2015, 2, 1322. (d) Hu, N.; Li, K.; Wang, Z.; Tang, W. Angew.
Chem., Int. Ed. 2016, 55, 5044. (e) Cao, Z.; Du, K.; Liu, J.; Tang, W.
Tetrahedron 2016, 72, 1782. (f) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.;
Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.;
Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2012, 14, 2258. (g) Xu, G.; Fu, W.; Liu,
G.; Senanayanke, C. H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570. (h)
Li, C.; Chen, D.; Tang, W. Synlett 2016, 27, 2183. (i) Zhao, G.; Xu, G.;
Qian, C.; Tang, W. J. Am. Chem. Soc. 2017, 139, 3360. (j) Du, K.; Yang,
H.; Guo, P.; Feng, L.; Xu, G.; Zhou, Q.; Chung, L. W.; Tang, W. Chem.
Sci. 2017, 8, 6247. (k) Xu, G.; Senananayake, C. H.; Tang, W. Acc.
Chem. Res. DOI: 10.1021/acs.accounts.9b00029.
Acknowledgements
We are grateful to the Strategic Priority Research Program of the
Chinese Academy of Sciences XDB20000000, CAS (QYZDY-SSW-
SLH029), NSFC-(21725205, 21432007, 21572246, 21702223), and
K.C.Wong Education Foundation.
Supplementary data
Supplementary data associated with this article can be found in the
online version.
Notes and references
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