Binaphthyl-prolinol chiral ligands: Design and their application in enantioselective arylation of aromatic aldehydes

Article abstract of DOI:10.1039/d1ob00289a

Binaphthyl-prolinol ligands were designed and applied in enantioselective arylation of aromatic aldehydes and sequential arylation-lactonization of methyl 2-formylbenzoate. Under optimized conditions, the reactions provided the desired diarylmethanols and 3-aryl phthalides in up to 96% yields with up to 99% ee and up to 89% yields with up to 99% ee, respectively. In particular, essentially optically pure 3-aryl phthalides (over 99% ee) were obtained in large quantities through recrystallization. This journal is

Full text of DOI:10.1039/d1ob00289a

Organic &
Biomolecular Chemistry
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PAPER
Binaphthyl–prolinol chiral ligands: design and
their application in enantioselective arylation
of aromatic aldehydes†
Cite this: Org. Biomol. Chem., 2021,
19, 3644
Chao Yao,a Yaoqi Chen,a Ruize Sun,a Chao Wang,a Yue Huang,a Lin Lia and
a,b
Yue-Ming Li
*
Binaphthyl–prolinol ligands were designed and applied in enantioselective arylation of aromatic aldehydes
and sequential arylation–lactonization of methyl 2-formylbenzoate. Under optimized conditions, the
reactions provided the desired diarylmethanols and 3-aryl phthalides in up to 96% yields with up to 99%
ee and up to 89% yields with up to 99% ee, respectively. In particular, essentially optically pure 3-aryl
phthalides (over 99% ee) were obtained in large quantities through recrystallization.
Received 16th February 2021,
Accepted 17th March 2021
DOI: 10.1039/d1ob00289a
rsc.li/obc
realized via direct addition of aryl Grignard reagents or other
aryl organometallics to aromatic aldehydes, or using relatively
1. Introduction
1,1′-Binaphthyl-2,2′-diol (BINOL) has played important roles in mild arylboronic acids as aryl surrogates.8 In the presence of a
asymmetric synthesis. So far, a variety of new ligands/catalysts proper chiral catalyst, enantioselective aryl transfer to aromatic
have been developed using BINOL as the starting material.1 As aldehydes would provide products with good enantioselectivity
a consequence, the binaphthyl skeleton has been regarded as and high yields using arylboronic acid as the aryl source.9
one of the most important privileged structures in the design
of new chiral ligands.2 Similarly, excellent performance was
also observed when proline derivatives and related structures
2. Results and discussion
were used as chiral ligands/catalysts in a variety of asymmetric
organic reactions.3 It is our aim to develop new chiral ligands
Enantioselective addition of diphenylzinc to aromatic alde-
using the privileged structure strategy, and to apply the newly
developed chiral ligands in different asymmetric organic reac-
hydes was reported by Fu et al.10 Later, Miyaura et al. reported
the enantioselective addition of organoboronic acids to alde-
tions. Herein, we wish to report our recent progress in the syn-
hydes.11 Compared with organozinc reagents, arylboronic
thesis and structure optimization of new binaphthyl–prolinol
acids were easy to handle, and the reactions could be carried
ligands, and the application of these ligands in enantio-
out under mild conditions. The well documented features of
selective transfer of aryl groups to different carbonyl
this reaction make it an ideal method for the preparation of
optically active diarylmethanols as well as an ideal model to
compounds.
Chiral diarylmethanols are important intermediates for bio-
evaluate the strategy of chiral catalyst design.12
active compounds and pharmaceuticals4 such as antihistamines
In our previous report, we have shown that, a combination of
a binaphthyl skeleton and other chiral elements would provide
(R)-orphenadrine, (R)-neobenodine,5 or (S)-cetirizine (Fig. 1),6
and enantioselective reduction of prochiral diaryl ketones or
chiral ligands with good performance. For example, chiral
enantioselective addition of aryl agents to aromatic aldehydes
ligands 1 incorporating binaphthyl and prolinols or chiral
ligands 2 incorporating binaphthyl and chiral oxazolines could
could be regarded as one of the most straightforward methods
for the preparation of such compounds.7 The latter has been
all be used in enantioselective addition of diethylzinc
to aromatic aldehydes.13 In particular, excellent ee’s were
observed when (Ra,S)-1a was used as the chiral ligand (Fig. 2).13
However, low ee’s were obtained when these chiral ligands
were extended to enantioselective transfer of aryl agents to aro-
matic aldehydes.14 While ligands 1 showed some sort of struc-
ture-dependent stereoselectivity using Bolm’s protocol as a
standard method,9 ligands 2 did not show any stereoselectivity
at all (Table 1).
aState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and
Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin,
People’s Republic of China. E-mail: ymli@nankai.edu.cn
bCAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, People’s Republic of China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00289a
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Fig. 1 Structures of bioactive diarylmethanol derivatives.
Fig. 2 Previously reported binaphthyl-based chiral ligands 1 and 2.
substrate binding.13 Careful examination of the computer
model suggested that the coordination site could be signifi-
cantly affected when an appropriate substituent is introduced to
the 3-possition which is adjacent to the hydroxyl group of the
chiral ligands (Fig. 3, R2 in ligand 3).
Table 1 Catalytic
p-chlorobenzaldehydea
asymmetric
phenyl
transfer
to
To test this assumption, a synthetic route to chiral ligand 3
was proposed using (R)-BINOL as a general starting material
(Scheme 1).13 In our previous report, we have established the
preparation of 2-methoxy-2′-methyl-1,1′-binaphthalene (4)
from BINOL. Lithiation at the 3-position followed by reaction
with iodine furnished compound 5. Cu(I)-Catalyzed coupling
of 5 with methyl fluorosulfonyldifluoroacetate (MFSDA) gave
2-methoxy-2′-methyl-3-trifluoromethyl-1,1′-binaphthalene (6)
which could be converted to 2′-bromomethyl-2-methoxy-3-tri-
fluoromethyl-1,1′-binaphthalene (7) via free radical substi-
tution. Subsequent reaction between 7 and different prolinols
gave compounds 8 which combined both the binaphthyl
moiety and the prolinol moiety. However, demethylation of 8
was found to be difficult, and the desired product 3 could not
be obtained in a reasonable yield in a preliminary test of de-
methylation of 8 (Scheme 1).
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2
78
81
83
54
82
60
64
8
22
37
4
6
0
R
R
R
R
R
R
R
0
a Conditions: reactions were performed on a 0.25 mmol scale. PhB
(OH)2 (2.4 equiv.) and Et2Zn (7.2 equiv.) were stirred in toluene at
60 °C for 12 h. The chiral ligand and p-chlorobenzaldehyde were then
added to the solution. The reaction mixture was stirred at room temp-
erature for 24 h. b Isolated yields. c The ee values were determined by
HPLC (Chiralcel AD-H column, n-hexane : isopropanol = 95 : 5, 1 mL
min−1, UV = 220 nm). d Absolute configuration was assigned by com-
parison to the reported value and sign of specific rotation of the
product.15
The preliminary results indicate that replacing the 2-meth-
oxyl group with another protective group is necessary to facili-
The results in Table 1 suggest that increasing the bulkiness tate the deprotection processes, and 3-acetate would be a good
at the prolinol side of chiral ligands 1 had some impact on the choice due to its ease of removal. Next, a different route was pro-
stereoselectivity of the reaction, and ligand 1c provided the posed starting from 3-iodo-2-methoxy-2′-methyl-1,1′-binaphtha-
highest ee among the ligands tested (Table 1, entries 1 to 3). lene (5). Cleavage of the methyl ether with BBr3 produced
We envisioned that the stereoselectivity of the chiral ligands 3-iodo-2′-methyl-[1,1′-binaphthalen]-2-ol (9) which could be con-
could be further improved when an appropriate substituent is verted to the corresponding acetate 12a in good yield. Cu(I)-
introduced to the binaphthyl part of the chiral ligands.
Catalyzed coupling of 12a with methyl fluorosulfonyldifluoroa-
In their pioneering work, Trost et al. proposed a di-zinc cetate (MFSDA) gave 2-acetoxy-2′-methyl-3-trifluoromethyl-1,1′-
model to interpret the enantioselectivity of a proline-based cata- binaphthalene 12. Alternatively, compound 10 could be syn-
lyst (Fig. 3).16 Our previous study also suggested that a 1c-type thesized via coupling of 5 with PhMgBr, and intermediate 12c
chiral ligand also tended to possess a di-zinc form during the could be obtained via demethylation with BBr3 and subsequent
reaction. In this model, one zinc atom possessed a distorted acetylation of 11. Finally, free radical bromination of 12 gave 2′-
tetrahedral four-coordinate structure to lock the conformation bromomethyl intermediate 13, which could be readily converted
of the catalyst, and another zinc atom possessed a planar three- to intermediate 14. Deacetylation of 14 led to the preparation of
coordination structure which provided an additional site for the desired chiral ligands 3a–3h (Scheme 2).
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Fig. 3 Representative proline-based chiral ligands.
Scheme 1 Preliminary preparation of chiral ligands via the 2-methoxyl protocol. Results and conditions: (a) n-BuLi, TMEDA, then I2, 0 °C, THF, 2 h,
47%; (b) CuI, MFSDA, HMPA, DMF, 70 °C, 8 h, 71%; (c) NBS, AIBN, DCE, 80 °C, 6 h, 71%; and (d) ((S)-2-(pyrrolidin-2-yl) propan-2-ol, K2CO3, NaI,
CH3CN, 16 h, 66%.
With the new ligands 3a–3h in hand, the application of suggest that the most suitable amount of chiral ligand was
these ligands in the arylation of p-chlorobenzaldehyde was 10 mol%, and the most suitable solvent was toluene (Table 3,
tested using phenylboronic acid as the phenyl source. The pre- entries 1 to 4). The reaction was carried out on a 0.25 mmol
liminary results in Table 2 reveal that the introduction of scale at 0 °C for 24 h. Both DiMPEG 2000 and DiMPEG 500
different substituents at the C-3 position significantly were effective additives, and the ee’s could be further improved
improved the enantioselectivity of the reactions, and the 3-tri- upon addition of these polyethers, possibly due to the suppres-
fluoromethyl substituted ligand 3f gave the most promising sion of the unwanted nonasymmetric pathways by these addi-
result. The results from 3e and 3g suggested that the stereofa- tives through deactivating the (achiral) metal catalysts and pre-
cial selection of the reaction was mainly governed by the proli- venting their nonenantioselective contribution to the overall
nol moiety, and that the matching between the central chirality process.14a DiMPEG 2000 was finally chosen as the additive
of the amino alcohol and axial chirality was important as well due to its ease of handling.
(Table 2, entries 5 and 8).
After the optimization of the reaction conditions, different
Next, the reaction conditions were optimized using 3f as substrates were tested to study the scope of the reaction
the chiral ligand.17 Previously reported protocols were (Table 4).18 Gratifyingly, good to excellent yields (74–96%) and
adopted. The preliminary results are shown in Table 3. They good to excellent enantioselectivities (81–99% ee) were
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Scheme 2 Preparation of chiral ligands 3. Results and conditions: (a) BBr3, DCM, 0 °C, 1 h, 99%; (b) Ac2O, pyridine, 25 °C, 6 h, 99%; (c) CuI, MFSDA,
HMPA, DMF, 70 °C, 8 h, 78%; (d) PhMgBr, (NiCl2)dppp, THF, 60 °C, 12 h, 86%; (e) BBr3, DCM, 0 °C, 1 h, 96%; (f) Ac2O, pyridine, 25 °C, 6 h, 88%; (g)
NBS, AIBN, DCE, 80 °C, 6 h, 58–75%; (h) amino alcohols, K2CO3, NaI, CH3CN, 16 h, 48–82%; and (i) NaOH, MeOH, 75 °C, 3 h, 81–95%.
Table 3 Optimization of the reaction conditions for 3f-promoted
asymmetric phenyl transfer to p-chlorobenzaldehydea
Table 2 Catalytic asymmetric phenyl transfer to p-chlorobenzaldehydea
Entry
3f (mol%)
Solvent
Temp. (°C)
Yieldb (%)
eec (%)
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
10
10
10
10
10
10
20
5
Toluene
DCE
Xylene
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
25
25
25
25
25
25
25
0
96
86
83
84
96
91
86
83
93
88
88
81
86
85
93
92
76
81
95
91
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
87
62
70
82
87
96
35
82
23
35
38
54
73
88
22
43
R
R
R
R
R
R
R
S
5d
6e
7d
8d
9d
10d
3g
3h
10
10
−10
a Conditions: reactions were performed on a 0.25 mmol scale with
PhB(OH)2 (2.4 equiv.) and Et2Zn (7.2 equiv.) in toluene (stirring at a Reaction conditions: reactions were performed on a 0.25 mmol scale
60 °C for 12 h), followed by the addition of the ligand and aldehyde, with PhB(OH)2 (2.4 equiv.) and Et2Zn (7.2 equiv.) in toluene (stirring at
with stirring for 24 h. b Isolated yields. c The ee values were deter- 60 °C for 12 h), followed by the addition of 3f, the additive and alde-
mined by HPLC. d Absolute configuration was assigned by compari- hyde. Reaction time = 24 h. b Isolated yields. c The ee values were deter-
son to the reported value and sign of specific rotation of the mined by HPLC (Chiralcel OD-H column). d In the presence of
product.15
10 mol% DiMPEG 2000. e In the presence of 10 mol% DiMPEG 500.
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Table 4 Enantioselective arylation of aromatic aldehydes using 3f as a
achieved for various aromatic aldehydes irrespective of the posi-
tion and electronic nature of the substituents on the phenyl
rings. Bulky aldehydes such as naphthaldehydes also gave the
desired products in satisfactory yields (Table 4, entries 12
and 13). Heterocyclic aromatic rings displayed high enantio-
selectivity as well (Table 4, entries 14 and 15). In the presence of
the same chiral ligand 3f, both enantiomers of the corres-
ponding diarylmethanols could be readily prepared with excel-
lent yields and high enantioselectivities with the variation of the
substituents on aldehyde and arylbronic acids15,19 (Table 4,
entries 2 vs. 17, 4 vs. 18, 5 vs. 19, 6 vs. 20 and 9 vs. 21). Chiral
diarylmethanols containing two different substituted aryl groups
could be easily synthesized with the combination of arylboronic
acids and aromatic aldehydes (Table 4, entries 22 and 23).
To demonstrate the utility of the catalytic system, arylation
of 2-methylbenzaldehyde and 4-methylbenzaldehyde was
carried out at a 5 mmol scale, and the subsequent functional
group transformation provided the important antihistamines
(R)-orphenadrine and (R)-neobenodine in 60% overall yield
with 98% ee and 63% overall yield with 98% ee, respectively
(Scheme 3).
After the enantioselective arylation of different aromatic
aldehydes, our attention turned to sequential arylation–lacto-
nization of 2-formylbenzoates. 3-Aryl phthalides are important
intermediates for organic synthesis and drug synthesis,20 and
an enantioselective arylation–lactonization cascade was proved
to be an efficient route to this type of important compounds.21
Different arylboronic acids were subjected to enantioselective
arylation–lactonization of methyl 2-formylbenzoate to test the
scope of the substrates. The chiral ligand 3f was tested in
enantioselective arylation–lactonization of methyl 2-formylbenzo-
ate under previously optimized conditions, and the reaction time
was extended to 36 h to ensure high conversion of the substrates.
Representative results are shown in Table 5. To our delight,
this protocol could serve as a general approach to different
optically active 3-substituted phthalides, and the products
could be obtained in good yields with excellent enantio-
selectivities. The electronic properties of aromatic rings had
chiral liganda
Entry
Ar′ (Ar = Ph)
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
4-ClPh
4-BrPh
2-BrPh
4-MePh
3-MePh
2-MePh
3,4-DiMePh
4-MeOPh
3-MeOPh
2-MeOPh
4-CF3Ph
1-Naphthyl
2-Naphthyl
2-Thienyl
2-Furyl
PhCHvCH–
4-BrPh
4-MePh
3-MePh
2-MePh
96
92
95
90
89
88
95
91
96
92
74
90
86
92
96
78
93
93
78
81
90
95
94
96
98
95
98
94
98
99
94
92
86
97
97
95
91
88
88
81
92
99
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
S
9
10
11
12
13
14
15
16
17
18
19
20
21
S
S
S
S
3-MeOPh
a Conditions: reactions were performed on a 0.25 mmol scale with PhB
(OH)2 (2.4 equiv.) and Et2Zn (7.2 equiv.) in toluene (stirring at 60 °C
for 12 h), followed by the addition of 3f (10 mol%), DiMPEG 2000
(10 mol%) and aldehyde at 0 °C, with stirring for 24 h. b Isolated
yields. c The ee values were determined by HPLC. d Absolute configur-
ations were assigned by comparison to the reported values and signs
of specific rotations of the products.15,19
Scheme 3 Preparation of antihistamines using chiral biarylmethanols as key intermediates.
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Table 5 The scope of arylation–lactonization reactions of methyl
2-formylbenzoatea
recrystallization, revealing the application potential of the
method in asymmetric synthesis of chiral aryl phthalides.
4. Experimental sections
4.1. General experimental information
Air-sensitive reactions were conducted in oven-dried glassware
equipped with tightly fitted rubber septa and under a positive
pressure of dry argon. Unless otherwise indicated, commercial
reagents were used as received without further purification.
Anhydrous dichloromethane was distilled from CaH2 and
Entry
Ar
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
Ph
76 (81)e
78 (70)e
80 (76)e
64 (76)e
74
95 (99) f
97 (99) f
98 (99) f
94 (99) f
90
R
R
R
R
R
R
R
R
R
R
R
R
R
4-MePh
3-MePh
2-MePh
3-MeOPh
1-Naphthyl
4-BrPh
4-ClPh
3-ClPh
4-FPh
toluene was distilled from sodium silk prior to use. 1H and 13
C
65 (82)e
81 (93)e
81 (91)e
83 (88)e
85 (83)e
84
86 (99) f
97 (99) f
97 (99) f
94 (99) f
96 (99) f
98
NMR spectra were recorded in CDCl3 on a 400 MHz spectro-
meter at 298 K using tetramethylsilane (TMS) as an internal
standard. Chemical shifts are reported in parts per million
(ppm). Column chromatography separations were performed
by employing 200–300 mesh silica gel. Melting points were
measured on digital melting-point apparatus without correc-
tion of the thermometer. Infrared spectra were reported in
wave number. HRMS spectra were obtained on a Varian
FTICR-MS 7.0T mass spectrometer. HPLC analyses were
carried out using Chiralcel OD-H, AD-H or OB-H.
9
10
11
12
13
3-CF3Ph
2,4-DiFPh
3-Thienyl
89 (92)e
77
91 (99) f
87
a Conditions: reactions were performed on a 0.25 mmol scale with PhB
(OH)2 (2.4 equiv.) and Et2Zn (7.2 equiv.) in toluene (stirring at 60 °C
for 12 h), followed by the addition of 3f (10 mol%), DiMPEG 2000
(10 mol%) and aldehyde at 0 °C, with stirring for 36 h under an atmo-
sphere of argon. b Isolated yields. c The ee values were determined by
HPLC (Chiralcel OD-H column). d Absolute configurations were
assigned by comparison to the reported values and signs of specific
rotations of the products.15 e In parentheses: the mass recovery after
recrystallization. f In parentheses: the ee values after recrystallization.
4.2. Preparation of chiral ligands
(R)-3-Iodo-2-methoxy-2′-methyl-1,1′-binaphthalene (5). To a
solution of (R)-2-methoxy-2′-methyl-1,1′-binaphthalene
4
(5.00 g, 16.8 mmol) in THF (100 mL) was added dropwise
n-BuLi (15.6 mL, 42.0 mmol, 2.7 M solution in n-heptane) at
−78 °C for 30 min. The mixture was warmed to 0 °C and
stirred for 2 h. The mixture was treated with iodine (10.66 g,
42.0 mmol) at −78 °C. After stirring for an additional 1 h, satu-
rated aqueous solution of Na2SO3 was added. The aqueous
phase was extracted with ethyl acetate (100 mL × 3) and the
combined organic layer was washed with saturated aqueous
NaCl (100 mL), dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane = 1/100) to provide 5 as a white solid
(3.60 g, 47% yield), m.p. = 88–90 °C; [α]2D0 = −23.8 (c = 1.00,
little effect on the enantioselectivity of the reactions, and all
the tested substituted aryl boronic acids gave satisfactory
enantioselectivities with up to 98% ee (Table 4, entries 1–13).
The reactions were sensitive to the steric effect of the
nucleophiles, and only 86% ee was observed when bulky
1-naphthaleneboronic acid was used (Table 5, entry 6).
Aromatic heterocyclic boronic acid also gave good results with
77% yield and 87% ee values (Table 5, entry 13). The reaction
could be carried out on a 1 mmol scale without the loss of
enantioselectivity. Furthermore, the ee’s of the products could
be further improved to over 99% ee after simple recrystalliza-
tion, demonstrating the application potential of this method
for the preparation of important 3-substituted phthalides.
1
THF). H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.88 (dd, J =
8.2, 5.3 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.4 Hz,
1H), 7.40–7.35 (m, 2H), 7.24–7.20 (m, 2H), 7.13 (d, J = 8.4 Hz,
1H), 7.01 (d, J = 8.5 Hz, 1H), 3.30 (s, 3H), 2.12 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 153.8, 139.2, 135.3, 133.7, 133.2, 132.5,
132.1, 131.6, 128.8, 128.5, 128.3, 128.1, 127.1, 127.0, 126.4,
3. Conclusions
In summary, a series of new chiral ligands were designed, and 125.9, 125.8, 125.7, 125.1, 92.9, 60.7, 20.7. HRMS-ESI (m/z): M+
were applied in enantioselective arylation of aromatic alde- calcd for C22H17IO 424.0324, found 424.0317.
hydes as well as enantioselective arylation–lactonization of
(R)-2-Methoxy-2′-methyl-3-(trifluoromethyl)-1,1′-binaphthalene
methyl 2-formylbenzoate. Under optimized conditions, the (6). All flasks used in the reaction were heated under vacuum
reactions provided the desired diarylmethanols and 3-aryl for 30 minutes and purged with argon for 10 minutes. To a
phthalides in up to 96% yields with up to 99% ee and up to solution of CuI (3.08 g, 16.0 mmol), HMPA (5.6 mL,
89% yields with up to 99% ee, respectively. The reaction could 32.0 mmol) and 5 (3.45 g, 8.0 mmol) in dry DMF (60 mL) was
be carried out on a 5 mmol scale, and it could facilitate the added dropwise FSO2CF2CO2Me (3.10 g, 16.0 mmol) at room
asymmetric synthesis of optically pure antihistamines such as temperature, and the resulting mixture was stirred under an
(R)-orphenadrine or (R)-neobenodine. Furthermore, 3-aryl argon atmosphere for 8 h at 70 °C. The reaction mixture was
phthalides with 99% ee could be easily obtained through then cooled to room temperature and diluted with CH2Cl2
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(200 mL). The solution was washed with saturated aqueous (36 mL, 36.0 mmol, 1 M in DCM) over a period of 1 h at 0 °C
NaCl (3 × 50 mL), dried over MgSO4 and concentrated in vacuo. under argon. The reaction was monitored with TLC (petroleum
The crude product was purified by silica gel chromatography ether). After the completion of the reaction, the mixture was
(petroleum ether) to give product 6 (2.62 g, 71% yield) as a poured into ice water, extracted with DCM (20 mL × 3). The
1
white solid, m.p. = 65–66 °C; [α]2D0 = −37.2 (c = 1.00, DCM). H combined organic layer was washed with saturated aqueous
NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.91–7.72 (m, 3H), 7.42 NaCl (50 mL), dried over MgSO4 and concentrated in vacuo. The
(d, J = 8.4 Hz, 1H), 7.40–7.27 (m, 2H), 7.25–7.11 (m, 2H), 7.07 crude product was purified by silica gel chromatography (pet-
(d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 3.16 (s, 3H), 2.06 (s, roleum ether) to give product 9 (3.65 g, 99% yield) as a white
1
3H). 13C NMR (100 MHz, CDCl3): δ 152.8, 135.7, 135.4, 133.3, solid, m.p. = 81–83 °C; [α]2D0 = +39.1 (c = 1.00, DCM). H NMR
132.2, 130.9, 129.4, 129.3, 129.2, 128.9, 128.7, 128.6, 128.2, (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.96–7.89 (m, 2H),
128.1 (q, 3J = 5.7 Hz), 126.6, 126.0, 125.9, 125.6, 125.2, 125.0 7.80–7.74 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47–7.41 (m, 1H),
1
2
(q, JC–F = 272.5 Hz), 123.7 (q, JC–F = 30.0 Hz), 61.3, 20.6. 19F 7.37–7.32 (m, 1H), 7.32–7.27 (m, 1H), 7.25–7.21 (m, 1H), 7.15
NMR (CDCl3): δ −62.6. HRMS-ESI (m/z): [M + H]+ calcd for (dd, J = 8.4, 1.0 Hz, 1H), 6.96–6.91 (m, 1H), 5.25 (s, 1H), 2.14 (s,
C23H18F3O 367.1310, found 367.1303.
3H). 13C NMR (100 MHz, CDCl3): δ 149.0, 139.1, 136.9, 133.4,
(R)-2′-(Bromomethyl)-2-methoxy-3-(trifluoromethyl)-1,1′- 132.9, 132.6, 130.6, 129.4, 129.1, 129.0, 128.3, 127.4, 127.2,
binaphthalene (7). To a solution of 6 (293 mg, 0.8 mmol) and 127.1, 125.7, 125.3, 124.9, 124.4, 118.2, 86.0, 20.3. HRMS-ESI
AIBN (15 mg, 0.1 mmol) in DCE (30 mL) was added dropwise a (m/z): M+ calcd for C21H15IO 410.0168, found 410.0175.
solution of NBS (156 mg, 0.9 mmol) in DCE (10 mL) with stir-
(R)-2-Methoxy-2′-methyl-3-phenyl-1,1′-binaphthalene
(10).
ring at room temperature, and the resulting mixture was 1,3-Bis(diphenylphosphino)propane nickel(II) chloride (650 mg,
refluxed for 6 h. After the reaction was completed, the reaction 1.2 mmol) and iodide 5 (4.24 g, 10.0 mmol) were weighed into a
mixture was cooled to room temperature and was concentrated 250 mL 3-neck flask and the flask was flushed with argon. Dry
in vacuo to afford 7 (214 mg, 71% yield); m.p. = 75–76 °C, [α]2D0 THF (100 mL) was added through a syringe. The mixture was
1
= −53.7 (c = 1.00, DCM). H NMR (400 MHz, CDCl3): δ 8.32 (s, cooled to 0 °C, and PhMgBr (3.0 M in THF, 14.0 mL,
1H), 8.01 (dd, J = 17.2, 8.4 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 40.0 mmol) was added dropwise. The reaction suspension was
7.78 (d, J = 8.6 Hz, 1H), 7.54–7.47 (m, 2H), 7.38–7.29 (m, 2H), allowed to warm to room temperature in a period of 2 h and
7.18 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.49–4.32 (m, refluxed for an additional 12 h. It was then cooled to 0 °C and
2H), 3.23 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 151.7, 133.3, quenched by slow addition of 1 M HCl aqueous solutions. The
3
133.0, 131.7, 129.7, 129.5, 129.2, 128.9 (q, JC–F = 5.7 Hz), organic layer was separated and the aqueous phase was
1
128.8, 128.4, 128.0, 127.2, 126.7, 126.6, 126.3, 123.1 (d, JC–F
=
extracted with AcOEt (50 mL × 3). The combined organic layer
272.2 Hz), 122.4 (q, JC–F = 31.1 Hz), 61.7, 32.5. 19F NMR was washed with saturated aqueous NaCl (50 mL), dried over
2
(CDCl3): δ −61.5. HRMS-ESI (m/z): [M + Na]+ calcd for MgSO4 and concentrated in vacuo. The crude product was puri-
C23H16BrF3ONa 467.0234, found 467.0229.
fied by silica gel chromatography (petroleum ether) to give
(Ra,S)-2-(1-((2′-Methoxy-3′-(trifluoromethyl)-[1,1′-binaphthalen]- product 10 (3.21 g, 86% yield) as a white solid, m.p. = 90–92 °C;
2-yl) methyl) pyrrolidin-2-yl) propan-2-ol (8). Compound 7 was [α]2D0 = −16.9 (c = 1.00, DCM). 1H NMR (400 MHz, CDCl3): δ 7.96
added to
a
mixture of (S)-2-(pyrrolidin-2-yl)propan-2-ol (s, 1H), 7.94–7.85 (m, 3H), 7.78–7.69 (m, 2H), 7.52 (d, J = 8.5 Hz,
(196 mg, 1.2 mmol), potassium carbonate (215 mg, 1.6 mmol) 1H), 7.47–7.36 (m, 5H), 7.31–7.20 (m, 3H), 7.09–7.03 (m, 1H),
and NaI (15 mg, 0.1 mmol) in acetonitrile (20 mL). The 3.02 (s, 3H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.6,
mixture was stirred at room temperature for 16 h. Crude 139.0, 135.3, 135.1, 133.5, 133.2, 132.6, 132.2, 131.1, 130.4,
product was purified by silica gel chromatography (petroleum 129.5, 128.8, 128.4, 128.2, 128.1, 127.8, 127.4, 126.5, 126.2,
ether : ethyl acetate = 1 : 1) to give product 8 as a white powder 126.1, 125.6, 125.2, 124.9, 60.4, 20.8. HRMS-ESI (m/z): M+ calcd
(260 mg, 66% yield), m.p. = 99–101 °C; [α]D20 = −158.0 (c = 1.25, for C28H22O 374.1671, found 374.1664.
1
DCM). H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 7.86 (d, J =
(R)-2′-Methyl-3-phenyl-[1,1′-binaphthalen]-2-ol (11). Compound
8.5 Hz, 1H), 7.84–7.77 (m, 2H), 7.76 (d, J = 8.1 Hz, 1H), 11 was prepared according to the procedure of 9 and was iso-
7.34–7.23 (m, 2H), 7.16–7.05 (m, 2H), 7.01 (d, J = 8.5 Hz, 1H), lated as a white solid (2.93 g, 96% yield) after flash chromato-
6.90 (d, J = 8.5 Hz, 1H), 3.73 (d, J = 14.1 Hz, 1H), 3.37 (d, J = graphy (petroleum ether), m.p. = 66–67 °C; [α]2D0 = +35.6 (c =
14.1 Hz, 1H), 3.06 (s, 3H), 2.71–2.58 (m, 1H), 2.45–2.32 (m, 1.00, DCM). 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H),
1H), 2.24 (dd, J = 8.9, 5.0 Hz, 1H), 1.62–1.48 (m, 1H), 1.47–1.34 7.96–7.86 (m, 3H), 7.77–7.70 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H),
(m, 3H), 0.75 (s, 3H), 0.64 (s, 3H). 13C NMR (100 MHz, CDCl3): 7.47–7.24 (m, 7H), 7.22–7.18 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H),
δ 151.9, 138.0, 135.9, 133.4, 132.8, 130.7, 129.2, 129.1, 128.7, 4.99 (s, 1H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 148.4,
3
128.5, 128.4 (q, J = 5.8 Hz), 128.2, 127.5, 126.6, 126.1, 126.0, 138.1, 137.2, 133.3, 133.0, 132.7, 130.4, 130.1, 129.8, 129.32,
1
2
125.8, 125.6, 123.84 (q, JC–F = 272.6 Hz), 123.82 (q, J = 30.2 129.28, 129.1, 128.5, 128.4, 128.3, 127.7, 126.9, 126.8, 125.6,
Hz), 73.3, 72.2, 61.3, 61.2, 55.3, 28.3, 27.7, 25.1, 25.0. 19F NMR 124.6, 123.9, 118.6, 20.4. HRMS-ESI (m/z): [M + Na]+ calcd for
(CDCl3):
C30H31F3NO2 494.2307, found 494.2300.
δ −61.6. HRMS-ESI (m/z): [M +
H]+ calcd for C27H20ONa 383.1412, found 383.1406.
(R)-3-Iodo-2′-methyl-[1,1′-binaphthalen]-2-yl acetate (12a). To
(R)-3-Iodo-2′-methyl-[1,1′-binaphthalen]-2-ol (9). To a solu- a solution of 9 (3.60 g, 8.0 mmol) in dry DCM (30 mL) was
tion of 5 (3.80 g, 9.0 mmol) in 30 mL of DCM was added BBr3 added acetic anhydride (1.64 g, 16.0 mmol) and pyridine
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(3.2 mL, 40.0 mmol) at room temperature. The mixture was (m/z): [M + Na]+ calcd for C23H16BrIO2Na 552.9276, found
stirred for 6 h until the starting material was consumed. The 552.9276.
crude product was purified by silica gel chromatography (pet-
(R)-2′-(Bromomethyl)-3-(trifluoromethyl)-[1,1′-binaphthalen]-
roleum ether) to give product 12a (3.56 g, 99% yield) as a white 2-yl acetate (13b). Compound 13b was prepared according to
1
solid, m.p. = 96–97 °C; [α]2D0 = +7.6 (c = 1.20, DCM). H NMR the procedure of 13a and was isolated as a white solid (3.80 g,
(400 MHz, CDCl3): δ 8.52 (s, 1H), 7.89–7.80 (m, 3H), 7.49–7.37 64% yield) after flash chromatography (petroleum ether); m.p.
1
(m, 3H), 7.32–7.22 (m, 2H), 7.16–7.05 (m, 2H), 2.08 (s, 3H), = 81–83 °C, [α]2D0 = +3.3 (c = 0.70, DCM). H NMR (400 MHz,
1.73 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.1, 146.3, 139.1, CDCl3): δ 8.40 (s, 1H), 8.07–8.02 (m, 1H), 8.00 (d, J = 8.5 Hz,
133.4, 133.1, 132.6, 132.0, 130.5, 130.1, 128.7, 128.5, 127.8, 1H), 7.91–7.86 (m, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.59 (ddd, J =
127.5, 127.2, 126.7, 126.3, 126.2, 126.0, 125.2, 90.5, 20.6, 20.4. 8.2, 6.8, 1.2 Hz, 1H), 7.50–7.42 (m, 2H), 7.33–7.25 (m, 2H),
HRMS-ESI (m/z): [M + Na]+ calcd for C23H17IO2Na 475.0171, 7.14–7.08 (m, 1H), 4.43 (d, J = 10.7 Hz, 1H), 4.22 (d, J = 10.7
found 475.0166.
Hz, 1H), 1.68 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.5,
(R)-2′-Methyl-3-(trifluoromethyl)-[1,1′-binaphthalen]-2-yl acetate 143.1, 135.1, 134.8, 133.1, 132.2, 130.7, 130.6, 130.1, 130.0,
3
(12b). Compound 12b was prepared according to the procedure 129.8, 129.2, 128.9 (q, JC–F = 5.5 Hz), 128.1, 127.8, 127.6,
1
of 6 and was isolated as a white solid (3.90 g, 78% yield) after 127.5, 127.1, 127.0, 126.8, 123.2 (q, JC–F = 273.4 Hz), 122.3 (q,
flash chromatography (petroleum ether), m.p. = 73–75 °C; 2JC–F = 31.8 Hz), 32.6, 20.0. 19F NMR (CDCl3): δ −61.6.
[α]2D0 = +72.3 (c = 1.30, DCM). 1H NMR (400 MHz, CDCl3): HRMS-ESI (m/z): [M
+
Na]+ calcd for C24H16BrF3O2Na
δ 8.35 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.88 (t, J = 7.9 Hz, 2H), 495.0183, found 495.0176.
7.61–7.53 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.45–7.34 (m, 2H), (R)-2′-(Bromomethyl)-3-phenyl-[1,1′-binaphthalen]-2-yl acetate
7.31–7.18 (m, 2H), 7.17–7.08 (m, 1H), 2.11 (s, 3H), 1.64 (s, 3H). (13c). Compound 13c was prepared according to the procedure
13C NMR (100 MHz, CDCl3): δ 168.3, 143.0, 136.1, 134.8, 132.6, of 13a and was isolated as a white solid (1.36 g, 75% yield)
132.0, 131.7, 130.6, 129.4, 129.3, 129.2, 128.8, 128.7, 128.2 (q, after flash chromatography (petroleum ether); m.p.
=
3JC–F = 5.5 Hz), 127.9, 127.1, 126.4, 126.2, 125.3, 123.5 (q, 59–61 °C, [α]D20 = +51.4 (c = 1.25, DCM). 1H NMR (400 MHz,
1JC–F = 273.5 Hz), 122.3 (q, 2JC–F = 32.4 Hz), 20.4, 20.0. 19F NMR CDCl3): δ 8.03 (s, 1H), 7.97–7.89 (m, 2H), 7.85 (d, J = 8.2 Hz,
(CDCl3): δ −61.5 HRMS-ESI (m/z): [M + Na]+ calcd for 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.47–7.38
C24H17F3O2Na 417.1078, found 417.1073.
(m, 4H), 7.36–7.22 (m, 4H), 4.61–4.10 (m, 2H), 1.40 (s, 3H). 13
C
(R)-2′-Methyl-3-phenyl-[1,1′-binaphthalen]-2-yl acetate (12c). NMR (100 MHz, CDCl3): δ 168.7, 145.1, 137.9, 134.9, 134.6,
Compound 12c was prepared according to the procedure of 133.1, 132.7, 132.6, 132.1, 130.6, 129.3, 128.5, 128.4, 128.2,
12a and was isolated as a white solid (3.90 g, 78% yield) after 127.9, 127.8, 127.4, 126.91, 126.85, 126.7, 126.5, 32.8, 20.2.
flash chromatography (petroleum ether), m.p. = 80–82 °C; HRMS-ESI (m/z): [M + Na]+ calcd for C29H21BrO2Na 503.0623,
[α]2D0 = +21.7 (c = 0.50, DCM). 1H NMR (400 MHz, CDCl3): found 503.0615.
δ 8.00 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.5, 1.9 Hz,
(Ra,S)-2′-((2-(2-Hydroxypropan-2-yl) pyrrolidin-1-yl) methyl)-
2H), 7.64–7.56 (m, 2H), 7.48–7.31 (m, 6H), 7.31–7.21 (m, 3H), 3-iodo-[1,1′-binaphthalen]-2-yl acetate (14a). Compound 13a
7.15 (d, J = 8.4 Hz, 1H), 2.15 (s, 3H), 1.39 (s, 3H). 13C NMR (1.06 g, 2.0 mmol) was added to a mixture of (S)-2-(pyrrolidin-
(100 MHz, CDCl3): δ 168.6, 144.8, 138.2, 135.1, 133.0, 132.7, 2-yl) propan-2-ol (500 mg, 3.0 mmol), potassium carbonate
132.2, 132.1, 131.1, 129.9, 129.4, 129.3, 128.7, 128.42, 128.38, (544 mg, 4.0 mmol) and NaI (30 mg, 0.2 mmol) in acetonitrile
128.1, 127.8, 127.6, 126.9, 126.2, 125.9, 125.1, 20.5, 20.1. (40 mL) with stirring at room temperature for 16 h. The
HRMS-ESI (m/z): [M + Na]+ calcd for C29H22O2Na 425.1517, organic layer was separated and the aqueous phase was
found 425.1518.
extracted with AcOEt (30 mL × 3). The combined organic layer
(R)-2′-(Bromomethyl)-3-iodo-[1,1′-binaphthalen]-2-yl acetate was dried over anhydrous Na2SO4, filtered and concentrated in
(13a). To a solution of 12a (2.71 g, 6.0 mmol) and AIBN vacuo. The crude product was purified by silica gel chromato-
(100 mg, 0.6 mmol) in DCE (80 mL) was added dropwise a graphy (petroleum ether : ethyl acetate = 1 : 1) to give product
solution of NBS (1.19 g, 6.6 mmol) in DCE (30 mL) with stir- 14a as a white powder (891 mg, 77% yield), m.p. = 101–102 °C;
ring at room temperature, and the resulting mixture was [α]2D0 = +11.8 (c = 0.60, DCM). 1H NMR (400 MHz, CDCl3): δ
refluxed for 6 h. After the reaction was completed, the reaction 8.45 (s, 1H), 7.90–7.68 (m, 4H), 7.40–7.28 (m, 2H), 7.20–7.12
mixture was cooled to room temperature and was concentrated (m, 2H), 7.07–7.01 (m, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.72 (d, J =
in vacuo. Purification was carried out by column chromato- 14.6 Hz, 1H), 3.38 (d, J = 14.5 Hz, 1H), 2.72 (dd, J = 7.7, 3.3 Hz,
graphy (petroleum ether) to afford product 13a as a white solid 1H), 2.39–2.23 (m, 2H), 1.94–1.75 (m, 1H), 1.65 (s, 3H),
(1.85 g, 58% yield). m.p. = 97–99 °C, [α]2D0 = −12.6 (c = 0.60, 1.58–1.45 (m, 3H), 0.84 (s, 3H), 0.77 (s, 3H). 13C NMR
1
DCM). H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 7.97 (d, J = (100 MHz, CDCl3): δ 167.9, 145.7, 139.3, 137.4, 133.6, 133.3,
8.6 Hz, 1H), 7.86 (dd, J = 13.1, 8.2 Hz, 2H), 7.72 (d, J = 8.6 Hz, 132.6, 132.4, 130.4, 129.6, 128.7, 127.8, 127.32, 127.26, 126.8,
1H), 7.52–7.43 (m, 2H), 7.35–7.25 (m, 2H), 7.13 (t, J = 10.2 Hz, 126.7, 126.4, 126.3, 125.7, 90.6, 73.3, 72.4, 60.9, 55.2, 28.3,
2H), 4.38 (d, J = 10.6 Hz, 1H), 4.24 (d, J = 10.6 Hz, 1H), 1.77 (s, 27.8, 25.2, 25.1, 20.7. HRMS-ESI (m/z): [M + H]+ calcd for
3H). 13C NMR (100 MHz, CDCl3): δ 168.3, 146.5, 139.8, 134.6, C30H31INO3 580.1349, found 580.1346.
133.3, 133.1, 132.2, 131.3, 129.6, 128.2, 128.0, 127.8, 127.5,
(Ra,S)-2′-((2-(3-Hydroxypentan-3-yl) pyrrolidin-1-yl) methyl)-
127.2, 127.1, 127.0, 126.9, 126.8, 90.2, 32.5, 20.7. HRMS-ESI 3-iodo-[1,1′-binaphthalen]-2-yl acetate (14b). Compound 14b
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was prepared according to the procedure of 14a and was iso- 7.38–7.25 (m, 2H), 7.19–7.13 (m, 1H), 7.12–6.95 (m, 2H), 3.64
lated as a white powder (633 mg, 70% yield) after flash chrom- (d, J = 14.3 Hz, 1H), 3.43 (d, J = 14.2 Hz, 1H), 2.66–2.52 (m,
atography (petroleum ether : ethyl acetate = 1 : 1), m.p. = 1H), 2.52–2.29 (m, 2H), 1.62–1.37 (m, 7H), 1.28 (dd, J = 14.3,
1
142–143 °C; [α]2D0 = +9.4 (c = 0.40, DCM). H NMR (400 MHz, 7.4 Hz, 1H), 1.12–0.90 (m, 2H), 0.82–0.73 (m, 1H), 0.60 (t, J =
CDCl3): δ 8.43 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.82–7.70 (m, 7.6 Hz, 3H), 0.49 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
3H), 7.39–7.28 (m, 2H), 7.18–7.10 (m, 2H), 7.03 (d, J = 8.6 Hz, CDCl3): δ 168.1, 142.4, 139.4, 137.8, 135.4, 132.7, 132.5, 131.3,
3
1H), 6.96 (d, J = 8.5 Hz, 1H), 3.64 (d, J = 14.2 Hz, 1H), 3.39 (d, J 130.6, 129.6, 129.4, 128.9, 128.56 (q, JC–F = 5.3 Hz), 127.3,
1
= 14.2 Hz, 1H), 2.69–2.50 (m, 1H), 2.51–2.34 (m, 2H), 1.69–1.51 127.2, 126.4, 126.4, 125.9, 123.35 (q, JC–F = 272.7 Hz), 122.54
2
(m, 5H), 1.50–1.41 (m, 2H), 1.33–1.24 (m, 1H), 1.11–0.92 (m, (q, JC–F = 31.4 Hz), 75.7, 70.4, 61.1, 54.7, 28.9, 27.3, 25.8, 25.0,
2H), 0.79 (dd, J = 14.4, 7.7 Hz, 1H), 0.59 (t, J = 7.6 Hz, 3H), 0.52 19.9, 8.0, 7.8. 19F NMR (CDCl3): δ −62.6. HRMS-ESI (m/z): [M +
(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 167.8, 145.8, H]+ calcd for C33H35F3NO3 550.2569, found 550.2580.
139.4, 137.3, 133.7, 133.2, 132.6, 132.4, 130.7, 129.5, 128.6,
(Ra,S)-2′-((2-(Hydroxydiphenylmethyl) pyrrolidin-1-yl) methyl)-
127.7, 127.2, 127.1, 126.7, 126.5, 126.4, 126.3, 125.7, 90.4, 75.6, 3-(trifluoromethyl)-[1,1′-binaphthalen]-2-yl acetate (14f).
70.3, 60.9, 54.6, 28.9, 27.2, 25.8, 24.9, 20.6, 8.1, 7.8. HRMS-ESI Compound 14f was prepared according to the procedure of
(m/z): [M
+
H]+ calcd for C32H35INO3 608.1662, found 14a and was isolated as a white powder (1.10 g, 72% yield)
608.1657.
after flash chromatography (petroleum ether : ethyl acetate =
1
(Ra,S)-2′-((2-(Hydroxydiphenylmethyl) pyrrolidin-1-yl) methyl)- 4 : 1), m.p. = 99–101 °C; [α]2D0 = +12.6 (c = 0.50, DCM). H NMR
3-iodo-[1,1′-binaphthalen]-2-yl acetate (14c). Compound 14c was (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.88 (dd, J = 14.2, 8.4 Hz,
prepared according to the procedure of 14a and was isolated 2H), 7.82–7.68 (m, 2H), 7.48–7.40 (m, 1H), 7.37–7.24 (m, 5H),
as a white powder (420 mg, 59% yield) after flash chromato- 7.15–7.08 (m, 4H), 7.05–6.97 (m, 1H), 6.94–6.81 (m, 4H), 6.46
graphy (petroleum ether : ethyl acetate
=
4 : 1), m.p.
=
(d, J = 8.5 Hz, 1H), 4.66 (s, 1H), 3.62 (dd, J = 9.1, 4.2 Hz, 1H),
98–100 °C; [α]2D0 = +6.1 (c = 0.70, DCM). 1H NMR (400 MHz, 3.09–2.89 (m, 2H), 2.78 (d, J = 15.1 Hz, 1H), 2.43–2.27 (m, 1H),
CDCl3): δ 8.50 (s, 1H), 7.96–7.74 (m, 4H), 7.47–7.33 (m, 6H), 1.81–1.66 (m, 1H), 1.65–1.52 (m, 3H), 1.49 (s, 3H). 13C NMR
7.22–6.93 (m, 9H), 6.47 (s, 1H), 4.66 (s, 1H), 3.77–3.58 (m, 1H), (100 MHz, CDCl3): δ 168.2, 147.6, 146.5, 142.1, 137.2, 134.9,
3
3.12–2.77 (m, 3H), 2.37–2.21 (m, 1H), 1.81 (d, J = 8.5 Hz, 1H), 132.5, 132.2, 130.7, 130.4, 129.6, 129.2, 128.9, 128.4 (q, JC–F
=
1.69–1.59 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 167.9, 147.5, 5.5 Hz), 128.3, 128.1, 128.0, 127.8, 127.0, 126.3, 126.2, 126.1,
1
146.5, 145.4, 139.3, 136.7, 133.2, 133.0, 132.4, 132.2, 129.0, 126.0, 125.8, 125.7, 125.4, 125.2, 123.3 (q, JC–F = 272.8 Hz),
128.6, 128.1, 128.0, 127.7, 127.0, 126.5, 126.3, 126.2, 126.0, 122.3 (q, 2JC–F = 31.4 Hz), 78.1, 71.3, 58.0, 55.2, 29.8, 24.6, 19.9.
125.6, 125.3, 90.4, 78.0, 71.0, 57.9, 55.1, 29.7, 24.5, 20.6. 19F NMR (CDCl3): δ −62.5. HRMS-ESI (m/z): [M + H]+ calcd for
HRMS-ESI (m/z): [M + H]+ calcd for C40H35INO3 704.1662, C41H35F3NO3 646.2569, found 646.2555.
found 704.1667.
(Ra,S)-2′-((2-(2-Hydroxypropan-2-yl) pyrrolidin-1-yl) methyl)-
(Ra,S)-2′-((2-(2-Hydroxypropan-2-yl) pyrrolidin-1-yl) methyl)- 3-phenyl-[1,1′-binaphthalen]-2-yl acetate (14g). Compound 14g
3-(trifluoromethyl)-[1,1′-binaphthalen]-2-yl acetate (14d). was prepared according to the procedure of 14a and was iso-
Compound 14d was prepared according to the procedure of lated as a white powder (329 mg, 82% yield) after flash chrom-
14a and was isolated as a white powder (680 mg, 61% yield) atography (petroleum ether : ethyl acetate = 4 : 1), m.p. =
1
after flash chromatography (petroleum ether : ethyl acetate = 125–127 °C; [α]2D0 = +19.1 (c = 0.90, DCM). H NMR (400 MHz,
1
1 : 1), m.p. = 103–105 °C; [α]2D0 = +5.8 (c = 0.45, DCM). H NMR CDCl3): δ 8.05 (s, 1H), 8.03–7.83 (m, 4H), 7.66–7.57 (m, 2H),
(400 MHz, CDCl3): δ 8.27 (s, 1H), 7.98–7.80 (m, 3H), 7.78 (d, J = 7.52–7.36 (m, 5H), 7.31–7.25 (m, 3H), 7.13 (d, J = 8.5 Hz, 1H),
8.2 Hz, 1H), 7.47–7.43 (m, 1H), 7.34–7.25 (m, 2H), 7.18–7.11 3.97 (d, J = 14.2 Hz, 1H), 3.58 (d, J = 14.2 Hz, 1H), 2.85 (dt, J =
(m, 1H), 7.06–7.03 (m, 2H), 3.73 (d, J = 14.6 Hz, 1H), 3.41 (d, J 11.0, 5.7 Hz, 1H), 2.65–2.41 (m, 2H), 2.02 (s, 1H), 1.79–1.56 (m,
= 14.6 Hz, 1H), 2.72 (dt, J = 11.4, 5.4 Hz, 1H), 2.45–2.25 (m, 4H), 1.42 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H). 13C NMR (100 MHz,
2H), 1.67–1.42 (m, 7H), 0.82 (s, 3H), 0.73 (s, 3H). 13C NMR CDCl3): δ 168.2, 144.2, 138.2, 137.4, 135.2, 133.3, 132.8, 132.7,
(100 MHz, CDCl3): δ 168.1, 142.4, 137.8, 135.3, 132.7, 132.5, 132.0, 131.2, 130.1, 129.2, 128.8, 128.4, 128.4, 128.3, 127.7,
3
131.3, 130.6, 129.4, 129.3, 129.0, 128.5 (q, JC–F = 5.4 Hz), 127.6, 127.0, 126.7, 126.5, 126.3, 126.2, 125.6, 73.3, 72.4, 61.1,
1
127.8, 127.2, 126.7, 126.5, 126.4, 126.3, 125.8, 123.3 (q, JC–F
=
55.1, 28.4, 27.8, 25.1, 25.1, 20.1. HRMS-ESI (m/z): [M + H]+
272.8 Hz), 122.6 (q, 2JC–F = 31.3 Hz), 73.4, 72.4, 61.0, 55.2, 28.3, calcd for C36H36NO3 530.2695, found 530.2701.
27.8, 25.1, 19.9. 19F NMR (CDCl3): δ −62.3. HRMS-ESI (m/z): [M
(Ra,R)-2′-((2-(3-Hydroxypentan-3-yl) pyrrolidin-1-yl) methyl)-
3-(trifluoromethyl)-[1,1′-binaphthalen]-2-yl acetate (14h).
+ H]+ calcd for C31H31F3NO3 522.2256, found 522.2249.
(Ra,S)-2′-((2-(3-Hydroxypentan-3-yl) pyrrolidin-1-yl) methyl)- Compound 14h was prepared according to the procedure of
3-(trifluoromethyl)-[1,1′-binaphthalen]-2-yl acetate (14e). 14a and was isolated as a white powder (209 mg, 48% yield)
Compound 14e was prepared according to the procedure of after flash chromatography (petroleum ether : ethyl acetate =
14a and was isolated as a white powder (440 mg, 79% yield) 1 : 1), m.p. = 110–112 °C; [α]2D0 = +43.7 (c = 1.10, DCM). 1H NMR
after flash chromatography (petroleum ether : ethyl acetate = (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.41 (s, 1H), 8.04 (dd, J =
1 : 1), m.p. = 101–102 °C; [α]2D0 = +11.1 (c = 0.90, DCM). 1H NMR 12.6, 8.4 Hz, 2H), 7.92 (d, J = 8.2 Hz, 1H), 7.66–7.57 (m, 1H),
(400 MHz, CDCl3): δ 8.28 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.90 7.55–7.43 (m, 2H), 7.28 (d, J = 14.3 Hz, 2H), 7.25–7.17 (m, 2H),
(d, J = 8.5 Hz, 1H), 7.84–7.71 (m, 2H), 7.53–7.43 (m, 1H), 4.79 (d, J = 13.6 Hz, 1H), 4.07 (d, J = 13.6 Hz, 1H), 3.80–3.22
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(m, 2H), 3.21–2.91 (m, 1H), 2.48–2.28 (m, 1H), 2.23–2.02 (m, J = 7.2 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 3.67 (dd, J = 9.4, 4.4
1H), 1.75–1.46 (m, 7H), 1.44–1.35 (m, 1H), 1.24–1.09 (m, 1H), Hz, 1H), 2.98–2.83 (m, 3H), 2.21–2.05 (m, 1H), 1.84–1.72 (m,
0.69 (t, J = 7.5 Hz, 3H), 0.38 (s, 3H). 13C NMR (100 MHz, 1H), 1.67–1.52 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 148.8,
CDCl3): δ 142.6, 135.1, 133.4, 132.0, 130.5, 130.4, 130.3, 129.8, 136.7, 134.3, 133.3, 132.5, 131.0, 130.8, 130.0, 129.4, 129.3,
3
129.4, 129.2 (q, JC–F = 5.1 Hz), 129.1, 128.0, 127.7, 127.0, 129.2, 129.1, 128.8, 128.7, 128.6, 127.8, 127.54, 127.48, 126.6,
1
2
126.7, 126.6, 123.2 (q, JC–F = 272.8 Hz), 122.3 (q, JC–F = 31.8 124.6, 124.1, 116.8, 77.4, 70.3, 58.7, 55.0, 28.5, 26.8, 26.3, 23.4.
Hz), 75.8, 70.1, 28.8, 28.6, 24.9, 21.3, 20.1, 7.8, 7.2. 19F NMR IR (KBr): ν = 3378, 3054, 2974, 1736, 1201, 824 cm−1
(CDCl3): −62.7. HRMS-ESI (m/z): [M
H]+ calcd for HRMS-ESI (m/z): [M + H]+ calcd for C38H33INO2 662.1556,
C33H35F3NO3 550.2569, found 550.2580.
(Ra,S)-2′-(((S)-2-(2-Hydroxypropan-2-yl) pyrrolidin-1-yl) methyl)-
.
δ
+
found 662.1555.
(Ra,S)-2′-(((S)-2-(Hydroxydiphenylmethyl) pyrrolidin-1-yl) methyl)-
3-iodo-[1,1′-binaphthalen]-2-ol (3a). Compound 14a (580 mg; 3-(trifluoromethyl)-[1,1′-binaphthalen]-2-ol (3d). Compound 3d
1.0 mmol) and NaOH (88 mg; 2.2 mmol) were dissolved in was prepared according to the procedure of 3a and was iso-
methanol (20 mL) and the mixture was refluxed for 3 h to give lated as a white powder (590 mg, 94% yield) after flash chrom-
product 3a as a white powder (483 mg, 90% yield) after flash atography (petroleum ether : ethyl acetate = 1 : 1), m p =
1
chromatography (petroleum ether : ethyl acetate = 1 : 1), m.p. = 119–120 °C, [α]2D0 = −11.3 (c = 1.10, DCM). H NMR (400 MHz,
1
110–112 °C, [α]2D0 = +28.3 (c = 0.80, DCM). H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.90 (dd, J = 8.6, 3.1 Hz, 1H), 7.82 (dd, J
CDCl3): δ 8.51 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.5 = 8.2, 3.7 Hz, 2H), 7.58 (dd, J = 8.5, 3.2 Hz, 1H), 7.41–7.30 (m,
Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.79 (dd, J = 8.4, 1.2 Hz, 1H), 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.17–7.05 (m, 3H), 6.65 (dd, J =
7.50 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.37–7.27 (m, 2H), 8.7, 3.0 Hz, 1H), 3.76 (dd, J = 12.8, 3.3 Hz, 1H), 3.58 (dd, J =
7.25–7.18 (m, 2H), 6.85–6.79 (m, 1H), 4.10 (t, J = 8.4 Hz, 2H), 12.8, 3.2 Hz, 1H), 3.05–2.94 (m, 2H), 2.49–2.43 (m, 1H),
3.42 (d, J = 12.8 Hz, 1H), 3.25–3.06 (m, 1H), 2.91 (d, J = 7.1 Hz, 2.00–1.90 (m, 1H), 1.76–1.74 (m, 3H), 0.97 (s, 3H), 0.82 (s, 3H).
1H), 1.92–1.70 (m, 2H), 1.26–1.15 (m, 2H), 1.13 (s, 3H), 0.77 (s, 13C NMR (100 MHz, CDCl3): δ 153.1, 136.0, 134.9, 134.3, 133.8,
3
3H). 13C NMR (100 MHz, CDCl3): δ 150.5, 140.0, 134.3, 134.2, 133.5, 129.2, 128.7, δ 128.4 (q, JC–F = 5.4 Hz), 128.3, 128.2,
1
133.7, 132.4, 130.3, 130.2, 129.6, 128.7, 128.5, 128.0, 127.6, 128.1, 127.0, 126.9, 126.6, 126.4, 124.8, 123.6, 124.4 (d, JC–F
=
2
127.32, 127.27, 126.6, 124.7, 124.5, 116.8, 88.8, 70.1, 58.6, 55.4, 272.4 Hz), 122.3 (q, JC–F = 29.2 Hz), 122.2, 74.7, 72.3, 63.5,
28.3, 26.3, 26.0, 23.3. IR (KBr): ν = 3420, 3055, 2939, 1728, 56.9, 27.9, 27.5, 24.8, 24.6. 19F NMR (CDCl3): δ −62.7. IR (KBr):
1197, 820 cm−1
C28H29INO2 538.1243, found 538.1241.
(Ra,S)-2′-((2-(3-Hydroxypentan-3-yl) pyrrolidin-1-yl) methyl)-
.
HRMS-ESI (m/z): [M
+
H]+ calcd for ν = 3381, 3059, 2972, 1728, 1206, 823 cm−1. HRMS-ESI (m/z):
[M + H]+ calcd for C29H29F3NO2 480.2150, found 480.2148.
(Ra,S)-2′-(((S)-2-(3-Hydroxypentan-3-yl) pyrrolidin-1-yl) methyl)-
3-iodo-[1,1′-binaphthalen]-2-ol (3b). Compound 3b was pre- 3-(trifluoromethyl)-[1,1′-binaphthalen]-2-ol (3e). Compound 3e
pared according to the procedure of 3a and was isolated as a was prepared according to the procedure of 3a and was iso-
white powder (349 mg, 83% yield) after flash chromatography lated as a white powder (360 mg, 95% yield) after flash chrom-
(petroleum ether : ethyl acetate = 1 : 1), m p = 122–123 °C, [α]2D0 atography (petroleum ether : ethyl acetate = 1 : 1), m p =
1
1
= +10.1 (c = 0.86, DCM). H NMR (400 MHz, CDCl3): δ 8.48 (s, 116–117 °C, [α]2D0 = +21.5 (c = 0.80, DCM). H NMR (400 MHz,
1H), 7.98 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.73 (dd, J CDCl3): δ 8.16 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.88–7.81 (m,
= 11.9, 8.4 Hz, 2H), 7.46 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.43–7.34 (m, 1H), 7.25–7.08 (m,
7.28–7.23 (m, 3H), 7.19–7.12 (m, 2H), 6.76 (dd, J = 8.4, 1.1 Hz, 4H), 6.69 (d, J = 8.4 Hz, 1H), 3.74 (d, J = 12.9 Hz, 1H), 3.55 (d, J
1H), 3.80 (d, J = 13.1 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), = 12.9 Hz, 1H), 3.04 (dd, J = 8.5, 5.8 Hz, 1H), 2.96–2.77 (m,
3.03–2.88 (m, 2H), 2.50 (dd, J = 11.1, 5.9 Hz, 1H), 1.92–1.62 (m, 1H), 2.52–2.37 (m, 1H), 1.90–1.78 (m, 1H), 1.78–1.60 (m, 3H),
5H), 1.58–1.49 (m, 1H), 1.31–1.20 (m, 2H), 1.15 (dt, J = 14.8, 1.50–1.41 (m, 1H), 1.17–1.05 (m, 2H), 1.02–0.93 (m, 1H), 0.66
7.3 Hz, 1H), 1.09–1.00 (m, 1H), 0.74 (t, J = 7.5 Hz, 3H), 0.65 (t, J (t, J = 7.5 Hz, 3H), 0.56 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
= 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 152.3, 139.0, CDCl3): δ 152.2, 136.0, 135.5, 133.8, 133.4, 133.1, 129.3, 128.9,
3
135.5, 134.3, 133.5, 133.1, 129.8, 128.6, 128.1, 127.8, 127.0, 128.5 (q, JC–F = 5.5 Hz), 128.3, 128.2, 127.1, 126.7, 126.6,
126.8, 126.6, 126.5, 126.2, 124.8, 123.4, 118.7, 75.6, 71.3, 62.9, 126.5, 125.5 (q, 1JC–F = 271.9 Hz), 124.8, 123.8, 122.0, 121.53 (q,
56.2, 28.3, 26.8, 26.1, 24.6, 7.8, 7.6. IR (KBr): ν = 3477, 3056, 2JC–F = 29.6 Hz), 121.5, 75.6, 71.6, 63.2, 56.6, 28.3, 26.8, 26.3,
2937, 1736, 1188, 823 cm−1. HRMS-ESI (m/z): [M + H]+ calcd 24.6, 7.9, 7.6. 19F NMR (CDCl3): δ −62.7. IR (KBr): ν = 3518,
for C30H33INO2 566.1556, found 566.1555.
(Ra,S)-2′-((2-(Hydroxydiphenylmethyl) pyrrolidin-1-yl) methyl)- calcd for C31H33F3NO2 508.2463, found 508.2461.
3-iodo-[1,1′-binaphthalen]-2-ol (3c). Compound 3c was prepared (Ra,S)-2′-(((S)-2-(Hydroxydiphenylmethyl) pyrrolidin-1-yl) methyl)-
3057, 2945, 1727, 1203, 819 cm−1. HRMS-ESI (m/z): [M + H]+
according to the procedure of 3a and was isolated as a white 3-(trifluoromethyl)-[1,1′-binaphthalen]-2-ol (3f). Compound 3f
powder (290 mg, 87% yield) after flash chromatography (pet- was prepared according to the procedure of 3a and was iso-
roleum ether : ethyl acetate = 2 : 1), m p = 112–114 °C, [α]D20
=
lated as a white powder (890 mg, 93% yield) after flash chrom-
+34.7 (c = 1.00, DCM). 1H NMR (400 MHz, CDCl3): δ 8.48 (s, atography (petroleum ether : ethyl acetate = 1 : 1), m p =
1
1H), 7.95 (d, J = 8.6 Hz, 1H), 7.91–7.83 (m, 1H), 7.74 (dd, J = 121–122 °C, [α]2D0 = +89.1 (c = 0.44, DCM). H NMR (400 MHz,
18.1, 8.4 Hz, 2H), 7.43 (ddd, J = 7.3, 5.5, 1.7 Hz, 5H), 7.31 (t, J = CDCl3): δ 8.19 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.83 (dd, J =
7.5 Hz, 1H), 7.23–7.16 (m, 3H), 7.14–7.02 (m, 5H), 6.98 (t, 12.7, 8.2 Hz, 2H), 7.67 (d, J = 8.7 Hz, 1H), 7.38–7.26 (m, 6H),
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7.17–7.08 (m, 4H), 7.03–6.87 (m, 5H), 6.43 (d, J = 8.5 Hz, 1H), 10 mol%) and DiMPEG 2000 (50 mg, 10 mol%) in 1 mL dry
3.60 (dd, J = 9.6, 4.1 Hz, 1H), 2.94–2.71 (m, 3H), 2.07–2.01 (m, toluene was added through a syringe. The reaction mixture
1H), 1.79–1.66 (m, 1H), 1.61–1.43 (m, 3H). 13C NMR (100 MHz, was stirred for 30 min followed by the addition of the aldehyde
CDCl3): δ 147.6, 147.1, 146.4, 139.2, 135.4, 133.2, 132.4, 129.9, (0.25 mmol). After reacting at 0 °C for 24 h (36 h for arylation–
129.1, 128.5, 128.4, 128.2, 128.1, 127.5, 127.3, 126.7, 126.6, lactonization reaction), the reaction mixture was carefully
126.5, 126.4, 125.6, 125.4, 125.2, 125.1, 124.8, 124.5, 123.8 (q, quenched by the addition of 1 M HCl. The mixture was
2
1JC–F = 272.5 Hz), 119.3, 118.4 (q, JC–F = 31.2 Hz), 78.2, 71.0, extracted with ethyl acetate (10 mL × 3). The combined organic
58.2, 55.9, 29.4, 24.3. 19F NMR (CDCl3): δ −62.3. IR (KBr): ν = layers were washed with brine, dried over anhydrous MgSO4
3325, 3052, 2974, 1735, 1205, 815 cm−1. HRMS-ESI (m/z): [M + and concentrated in vacuo, and were purified using flash
H]+ calcd for C39H33F3NO2 604.2463, found 604.2459.
chromatography to afford the product. The enantiomeric
(Ra,S)-2′-((2-(2-Hydroxypropan-2-yl) pyrrolidin-1-yl) methyl)- excess of the product was determined by HPLC analysis.
3-phenyl-[1,1′-binaphthalen]-2-ol (3g). Compound 3g was pre-
pared according to the procedure of 3a and was isolated as a
white powder (290 mg, 88% yield) after flash chromatography
Conflicts of interest
(petroleum ether : ethyl acetate = 2 : 1), m p = 140–141 °C, [α]D20
= +49.3 (c = 0.50, DCM). 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J The authors declare no competing financial interest.
= 8.5 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J =
11.1, 8.2 Hz, 2H), 7.63 (d, J = 6.9 Hz, 2H), 7.57–7.51 (m, 3H),
7.46 (t, J = 7.3 Hz, 1H), 7.43–7.35 (m, 3H), 7.30–7.25 (m, 2H),
6.90 (d, J = 8.4 Hz, 1H), 4.24 (d, J = 12.5 Hz, 1H), 4.05 (d, J =
Acknowledgements
12.7 Hz, 1H), δ 3.39 (d, J = 18.7 Hz, 1H), 3.13–2.96 (m, 2H), We acknowledge the financial support from the National
1.92–1.80 (m, 2H), 1.29 (d, J = 13.1 Hz, 5H), 0.96 (s, 3H). 13C Natural Science Foundation of China (NSFC 21672106 and
NMR (100 MHz, CDCl3): δ 148.8, 136.7, 134.3, 133.3, 132.5, NSFC 21272121).
131.0, 130.8, 130.0, 129.4, 129.3, 129.2, 129.1, 128.8, 128.7,
128.6, 127.8, 127.5, 127.5, 126.6, 124.6, 124.1, 116.8, 77.4, 70.3,
58.7, 55.0, 28.5, 26.8, 26.3, 23.4. IR (KBr): ν = 3377, 3054, 2972,
References
1731, 1196, 821 cm−1. HRMS-ESI (m/z): [M + H]+ calcd for
C34H34NO2 488.2590, found 488.2588.
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1
136–138 °C, [α]2D0 = +61.1 (c = 0.50, DCM). H NMR (400 MHz,
CDCl3): δ 8.28 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.95–7.85 (m,
3H), 7.53–7.44 (m, 1H), 7.38–7.30 (m, 1H), 7.26–7.17 (m, 2H),
7.08 (dd, J = 8.6, 1.1 Hz, 1H), 6.64 (dd, J = 8.5, 1.1 Hz, 1H), 4.73
(d, J = 12.3 Hz, 1H), 4.11–4.00 (m, 2H), 3.70–3.57 (m, 1H), 3.23
(s, 1H), 2.27–2.16 (m, 1H), 2.10–2.06 (m, 1H), 2.03–1.96 (m,
1H), 1.75–1.52 (m, 3H), 1.42–1.32 (m, 1H), 1.28–1.23 (m, 1H),
0.97 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 152.1, 136.9, 136.2, 134.3, 133.0, 129.3,
3
128.8 (q, JC–F = 4.9 Hz), 128.7, 128.6, 128.3, 128.2, 127.1,
126.9, 126.8, 124.6, 124.1, 124.09 (1JC–F = 273.6 Hz), 121.7 (q,
3JC–F = 30.1 Hz), 120.3, 80.3, 75.9, 74.4, 72.8, 29.0, 27.4, 24.8,
21.3, 7.9, 7.3. 19F NMR (CDCl3): δ −62.6. IR (KBr): ν = 3516,
3056, 2941, 1725, 1203, 818 cm−1. HRMS-ESI (m/z): [M + H]+
calcd for C31H33F3NO2 508.2463, found 508.2461.
4.3. General procedure for enantioselective arylation of
aromatic aldehydes
Under an argon atmosphere, Et2Zn (7.2 equiv., 1.8 mmol,
1.8 mL, 1.0 M in toluene) was added slowly to a solution of
arylboronic acid (2.4 equiv., 0.6 mmol) in dry toluene (2 mL)
and the latter was heated at 60 °C for 12 h. After the mixture
was cooled to 0 °C, a solution of chiral ligand 3f (14 mg,
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