Palladium-Catalyzed Enantioselective Heteroannulation of 1,3-Dienes by Functionally Substituted Aryl Iodides

Article abstract of DOI:10.1021/acs.joc.6b01611

The first enantioselective heteroannulation of 1,3-dienes by 2-iodoanilines and 2-iodobenzylic alcohols is described. The application of a BINOL-derived phosphoramidite ligand bearing electron-withdrawing substituents is the key to obtaining high enantios

Full text of DOI:10.1021/acs.joc.6b01611

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Note
Palladium-Catalyzed Enantioselective Hetero-annulation
of 1,3-Dienes by Functionally Substituted Aryl Iodides
Shu-Sen Chen, Jing Meng, Yu-Hui Li, and Zhi-Yong Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01611 • Publication Date (Web): 26 Aug 2016
Downloaded from http://pubs.acs.org on August 27, 2016
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Palladium-Catalyzed Enantioselective Hetero-annulation
of 1,3-Dienes by Functionally Substituted Aryl Iodides
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Shu-Sen Chen, Jing Meng, Yu-Hui Li, Zhi-Yong Han*
Department of Chemistry, University of Science and Technology of China,
Hefei 230026, China
Table of Contents
O2N
Ar
R1
R1
O
O
I
R1
P N
Pd / Chiral Ligand
R
R2
R
+
Nu
X
Ar
readily available
commercial
substrates
23 examples
X = NH, CH2O
up to 83% yield, 87% ee
high ee for both N and O nucleophiles
L: Ar = 3,5-(CF3)2C6H3
Abstract
The first enantioselective hetero-annulation of 1,3-dienes by 2-iodoanilines and
2-iodobenzylic alcohols is described. The application of a BINOL-derived
phosphoramidite ligand bearing electron-withdrawing substituents is the key to
obtain high enantioselectivity. This protocol provides an efficient way to access
optically active chiral indolines and isochromans from readily available starting
materials.
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The development of new methods to obtain novel and valuable compounds in
an efficient and stereoselective way remains a long-standing challenge for
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synthetic
organic
chemistry.
Among
these
procedures
are
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transition-metal-catalyzed cascade reactions feature efficient building up
complex molecules from simple and easily available substrates.1 Palladium
catalyzed annulation of 1,3-dienes by functionally substituted aryl halides
represents one of the best examples in this category.2 In this chemistry,
pioneered by Dieck2a and Larock2b, readily available iodobenzene derivatives and
1,3-dienes undergoes a palladium-catalyzed tandem Heck3/intramolecular
Tsuji-Trost allylation4 process. This methodology provides an ideal approach to
access a large range of heterocycles and all-carbon fused cyclic compounds as
shown in Figure 1b. These cyclic structures, from indolines,
tetrahydroisoquinolines, to dihydrobenzofurans and others, are privileged
structural motifs found in numerous naturally bioactive alkaloids, drugs and
pharmaceutical agents, as exemplified by oleracein A–D,tremetone,
pseudoanguilosporin A, C, et al. (Figure 1c).5
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Figure 1. Palladium-catalyzed hetero-annulation of 1,3-dienes and functionally substituted aryl iodides.
Despite the importance of this versatile methodology, the asymmetric version of
this chemistry has not been accomplished up to now, though sporadic reports
concerning enantioselective tandem Heck/Tsuji-Trost reaction has been found
in the last three decades. Shibasaki’s group reported a Pd/BINAP catalyzed
intramolecular asymmetric Heck reaction-anion capture process and
successfully utilized the methods for the synthesis of a series of natural
products.6 Employing the same catalyst, Overman and co-workers applied a
catalytic intramolecular Heck reaction, followed by capture of the resulting
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η3-allylpalladiumintermediate by a tethered diketopiperazine as the key step in
the concise total synthesis of several natural products.7 Using amino group
tethered 1,3-dienes and iodobenzenes as substrates, Helmchen reported an
tandem Heck/asymmetric Tsuji-Trost reaction catalyzed by Palladium with
PHOX as the ligand.8 In this reaction, besides the limitation of narrow substrate
scope, it requires a ten-day reaction time to obtain an up to 80% enantiomeric
excess with moderate yield. Very recently, Gong reported a Pd/chiral
phosphoramidite catalyzed intermolecular Heck/asymmetric Tsuji-Trost
reaction of iodobenzenes, 1,3-dienes and sodium dialkyl malonates.9 Back to the
chemistry of Dieck and Larock2, the challenging part of the asymmetric version
is to search for ideal ligands that are appropriate for both Heck reaction and
subsequent asymmetric Tsuji-Trost reaction. Herein, we’ll report the first
enantioselective hetero-annulation of 1,3-dienes and functionally substituted
aryl iodides for the synthesis optically active indolines10 and isochromans11
(Figure 1d).
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Our study initiated from the screening of chiral ligands for the reaction of
2-iodoaniline (1a) and (E)-1-phenylbutadiene (2a) in the presence of 5 mol% of
Pd(OAc)2 and K2CO3in THF at 80 oC. The resulting reaction mixture was treated
with AcCl/Et3N to convert the product into more stable Ac-protected indoline.
(R)-BINAP, Trost ligand and chiral phosphinooxazoline-type P, N ligand, which
were frequently employed in the asymmetric Tsuji-Trost reaction and
asymmetric Heck reaction, were not able to provide good results (Table 1, entries
1-3). Then, BINOL derived chiral phosphoramidite ligands were investigated for
the cascade reaction. In the presence of ligand L4, synthesized from
non-substituted BINOL and tetrahydroquinoline, the desired product 3a was
obtained with 25% yield, but without any enantiomeric excess (entry 4).
Introducing electron-withdrawing 4-nitrophenyl groups at the 3,3’-positions of
the binaphthyl backbone lead to a drastic increase in the yield albeit still without
enantioselectivity (L5, entry 5). Replacing the 4-nitrophenyl group with
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3,5-(CF3)2C6H3 greatly enhanced the enantioselectivity to 80% ee with a rather
poor yield, however (L6, entry 6). Further modifying the tetrahydroquinoline
moiety revealed that incorporating an electron-withdrawing group at the
7-position could greatly increase the yield without considerable erosion of the
enantioselectivity (entries 7−8). L8 was identified to be the optimal ligand for
the reaction, providing 3a with 78% yield and 80% enantiomeric excess (entry 8).
Noteworthy, L8 was also the optimal ligand for the intermolecular
Heck/asymmetric Tsuji-Trost reaction of iodobenzenes, 1,3-dienes and sodium
dialkyl malonates.9 A screening of the solvents found DME (dimethoxyethane)
to be the best solvent regarding both yield and enantioselectivity (entries 9−12).
The reaction didn’t occur at all without a base. While several bases are suitable
for the reaction, proving satisfying results, KHCO3 could further increase the
optical yield from 80% to 83% ee (entries 13−16). Furthermore, tuning the ratio
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of substrates could slightly increase the enantioselectivity to 84% ee.
Table 1. Optimization of the Reaction Conditions
entry
ligand
L1
solvent
THF
base
conversion (%)
yield (%)b
18
ee (%)c
1d
2d
3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
50
4
4
7
0
0
L2
THF
<5
trace
trace
25
L3
THF
<5
4
L4
THF
45
5
L5
THF
>95
80
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6
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
DIPEA
KHCO3
KHCO3
KHCO3
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34
82
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85
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88
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70
85
85
77
80
70
80
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27
82
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82
82
83
83
84
7
THF
>95
>95
>95
59
8
THF
9
2-Me-THF
tBuOMe
1,4-dioxane
DME
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17e
18f
>95
88
DME
DME
>95
>95
>95
>95
>95
DME
DME
DME
DME
aReaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol %), L (10 mol %), 2a (1.1 equiv), solvent (1 mL), 80 oC,
15 h, under Ar. bBased on 1H-NMR analysis of the crude reaction mixture using trimethyl
benzene-1,3,5-tricarboxylate as an internal standard.cDetermined by HPLC. d5 mol% ligand was used. eThe
f
reaction was carried out with 1a (0.1mmol) and 2a (0.2 mmol). The reaction was carried out of 1a
(0.2mmol) and 2a (0.1 mmol).
Under the optimized conditions, we next explored the generality of the cascade
reaction (Scheme 1). The substrate scope of 1,3-diene was investigated by the
reaction of 2-iodoaniline with various substituted 1,3-butadienes. Generally, the
reactions underwent smoothly to give the desired indo lines in high
enantioselectivities ranging from 75% to 86% ee and up to 78% isolation yield
(Scheme 1, 3a−3i).
Arylbutadienes with either electron-withdrawing or electron-donating
substituents were all tolerable for the protocol. The substitution pattern of
arylbutadienes 2 exhibited little effect on the yield and enantioselectivity.
Notably, cyclohexyl and diphenyl substituted 1,3-butadienes could also undergo
the cascade reaction to afford the desired indoles with high enantioselectivities
(80−82% ee) and moderate yields (3h, 3i). Electron-deficient dienyl ester 2s was
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also applicable for the reaction, providing the product 3s with 40% yield and 79%
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ee (eq 1).
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We then moved on to examine the scope of the other substrate 1 by the reaction
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of
a
variety of commercially available substituted 2-iodoanilines
with1-phenylbutadiene2a (3j−3r). Notably, the position of the substituent on the
benzene ring of 2-iodoanilines exhibited significant effect on both
enantioselectivity and yield. It could be concluded that 5-substituted
2-iodoanilines provided much higher yield and stereoselectivity than those with
substituents at 4-position (3j, 3k, 3l vs 3m, 3n, 3o respectively). Generally,
5-substituted 2-iodoanilines provided the corresponding indolines with high
enantioselectivities (84−87% ee) and good yields (74−75%) while 4-substituted
substrates gave much poorer results (40−83% yield, 58−77% ee). On the other
hand, the electronic property of the substituents showed obscure influence on
the outcome of the reaction.
Scheme 1. Scope of 1,3-dienesa,b
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aReaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), Pd(OAc)2 (5 mol %), L8 (15 mol %), DME
(1.0 mL), 80 oC, 15 h, under Ar. b15 mol% of ligand was used to obtain stable and repeatable
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results except 3a
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In the meantime, we altered the nucleophile from o-iodolanilines to
o-iodobenzyl alcohol under the same reaction condition. To our delight, upon
the reactions with several arylbutadienes, chiral isochromans could also be
obtained with high enantioselectivities and moderate yields (Scheme 2, 5a−5d).
Scheme 2. Synthesis of Isochromanes
aReaction conditions: 4(0.2 mmol), 2 (0.1 mmol), Pd(OAc)2 (5 mol %), L8 (15 mol %), DME (1.0 mL), 80 oC,
48 h, under Ar.
In summary, we have developed, to the best of our knowledge, the first
palladium-catalyzed enantioselective hetero-annulation of 1,3-dienes by
2-iodoanilines and 2-iodobenzylic alcohols. The employment of
a
BINOL-derived phosphoramidite ligand bearing electron-withdrawing
substituents is crucial for the stereo control of the reaction. With the same
ligand, both 2-iodoanilines and 2-iodobenzyl alcohol were well tolerated for this
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cascade reaction. This protocol provides an efficient way to access optically
active chiral indolines and isochromans from readily available starting materials.
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■
EXPERIMENTAL SECTION
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General Method. NMR spectra were recorded on a 400 MHz spectrometer.
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HRMS spectra were recorded on a TOF-Q mass spectrometer. The
enantiomeric excess of the compounds was determined by chiral HPLC using
racemic compounds as references. All solvents were purified and dried
according to standard methods prior to use, unless stated otherwise.
For the synthesis procedure and the Determination of the absolute configuration,
see supporting information.
General Reaction Procedures. To a flame-dried and Ar-purged Schlenk
tube (10 mL) were added Pd(OAc)2 (0.05 equiv.), phosphoramidite L8 (0.15
equiv.), potassium bicarbonate (2.0 equiv.), 2-iodoaniline (2.0 equiv.) and a stir
bar. The Schlenk tube was then evacuated and filled with argon. This cycle was
repeated three times and followed by addition of aryl butadiene (0.1 mmol) and
DME (1 mL) via syringe. The mixture was stirred at 80 °C for 15 h, and then was
cooled down to 0 °C. To the reaction mixture at 0 °C was slowly added Et3N (15
equiv.) and acetyl chloride (10 equiv.). The resulting mixture was stirred at
room temperature for 30 min, and then filtered through silica gel, and washed
with ethyl acetate. The organic phase was concentrated in vacuo. The product
was purified by column chromatography on silica gel (Eluent, PE/EA = 10:1 or
PE/t-BuOH = 20:1).
Characterization of the product 3 and 5.
(S,E)-1-(2-styrylindolin-1-yl)ethanone(3a)
Colorless oil. Yield: 76%, 20.0mg. [α]D20 = -56.0 (c 0.16, CHCl3). Enantiomeric
excess: 84%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 13.35 min (minor), tR = 14.90 min
(major).1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.4 Hz, 1H), 7.34 – 7.15 (m, 7H),
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7.09 – 6.98 (m, 1H), 6.50 (d, J = 15.9 Hz, 1H), 6.20 (dd, J = 15.9, 7.1 Hz, 1H), 5.02 –
4.92 (m, 1H), 3.59 (dd, J = 14.5, 10.2 Hz, 1H), 2.92 (d, J = 15.9 Hz, 1H), 2.27 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 169.2, 142.3, 135.8, 130.6, 129.5, 128.6, 128.4, 128.0,
127.6, 126.5, 124.7, 123.9, 117.5, 62.2, 36.1, 23.9.IR (KBr) γ 2955, 2921, 2850, 1658,
1460, 1396, 1021, 755, 694 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C18H18ON:
264.1383, observed: 264.1378. For the absolute configuration determination
process of 3a, see supporting information.
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(S,E)-1-(2-(4-fluorostyryl)indolin-1-yl)ethanone(3b)
Colorless oil. Yield: 68%, 19.1mg. [α]D20 = -45.6 (c 0.15, CHCl3). Enantiomeric
excess: 86%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 13.29 min (minor), tR = 14.98 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 6.6 Hz, 1H), 7.30 – 7.15 (m, 4H),
7.04 (dd, J = 8.2, 7.5 Hz, 1H), 6.97 (t, J = 8.5 Hz, 2H), 6.45 (d, J = 15.9 Hz, 1H), 6.11
(dd, J = 15.9, 7.0 Hz, 1H), 5.08 – 4.84 (m, 1H), 3.75 – 3.33 (m, 1H), 2.91 (d, J = 15.9
Hz, 1H), 2.26 (s, 3H).13C NMR (101 MHz, CDCl3) δ 169.1, 162.5 (d, J = 247.6 Hz),
142.3, 132.0, 129.5, 129.3, 128.2, 128.0 (d, J = 8.1 Hz), 127.7, 124.8, 123.9, 117.5, 115.5 (d,
J = 21.6 Hz), 62.1, 36.1, 23.9. IR (KBr) γ 2955, 2921, 2851, 1659, 1460, 1379, 1226, 1091,
1020, 756 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C18H17ONF: 282.1289,
observed: 282.1282.
(S,E)-1-(2-(4-methoxystyryl)indolin-1-yl)ethanone(3c)
Colorless oil. Yield: 78%, 22.8mg. [α]D20 = -56.6 (c 0.24, CHCl3). Enantiomeric
excess: 86%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 20.50 min (minor), tR = 22.65 min
1
(major). H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 6.8 Hz, 1H), 7.27 – 7.14 (m,
4H), 7.03 (td, J = 7.5, 0.7 Hz, 1H), 6.88 – 6.72 (m, 2H), 6.43 (d, J = 15.8 Hz, 1H),
6.05 (dd, J = 15.9, 7.2 Hz, 1H), 5.03 – 4.80 (m, 1H), 3.77 (s, 3H), 3.56 (dd, J = 14.7,
13
9.9 Hz, 1H), 2.90 (d, J = 15.9 Hz, 1H), 2.26 (s, 3H). C NMR (101 MHz, CDCl3) δ
169.2, 159.5, 142.4, 130.0, 129.7, 128.5, 127.7, 127.6, 126.2, 124.7, 123.8, 117.4, 114.0,
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62.3, 55.2, 36.2, 23.9. IR (KBr) γ 2955, 2922, 2852, 1658, 1510, 1460, 1395, 1249,
1027cm-1. HRMS (ESI) m/z (M+H)+ calculated for C19H20O2N: 294.1489, observed:
294.1483.
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(S,E)-1-(2-(3-methylstyryl)indolin-1-yl)ethanone(3d)
Colorless oil. Yield: 67%, 18.6mg. [α]D20 = -54.4 (c 0.26, CHCl3). Enantiomeric
excess: 84%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 11.06 min (minor), tR = 13.04 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.0 Hz, 1H), 7.25 – 6.99 (m,
7H), 6.47 (d, J = 15.9 Hz, 1H), 6.19 (dd, J = 15.9, 7.2 Hz, 1H), 5.10 – 4.84 (m, 1H),
3.59 (dd, J = 15.0, 10.1 Hz, 1H), 2.92 (d, J = 15.9 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 169.2, 142.4, 138.2, 135.8, 130.7, 129.6, 128.8, 128.5,
128.2, 127.6, 127.1, 124.7, 123.9, 123.7, 117.5, 62.3, 36.2, 23.9, 21.3. IR (KBr) γ 2954,
2921, 2851, 1660, 1460, 1395, 1021, 756 cm-1. HRMS (ESI) m/z (M+H)+ calculated
for C19H20ON: 278.1539, observed: 278.1535.
(S,E)-1-(2-(2-fluorostyryl)indolin-1-yl)ethanone(3e)
Colorless oil. Yield: 64%, 18.0mg. [α]D20 = -37.8 (c 0.28, CHCl3). Enantiomeric
excess: 75%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 11.37 min (minor), tR = 19.42 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 6.7 Hz, 1H), 7.35 (td, J = 7.7, 1.6
Hz, 1H), 7.25 – 7.12 (m, 3H), 7.10 – 6.94 (m, 3H), 6.66 (d, J = 16.1 Hz, 1H), 6.29 (dd,
J = 16.1, 7.3 Hz, 1H), 5.07 – 4.88 (m, 1H), 3.60 (dd, J = 14.6, 10.3 Hz, 1H), 2.92 (d, J
= 16.0 Hz, 1H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.1, 160.3 (d, J = 249.8
Hz), 142.3, 131.1 (d, J = 3.9 Hz), 129.5, 129.3 (d, J = 8.4 Hz), 127.7, 127.5 (d, J = 3.6
Hz), 124.7, 124.1 (d, J = 2.5 Hz), 123.9, 123.7 (d, J = 12.7 Hz), 123.3 (d, J = 2.1 Hz),
117.5, 115.8 (d, J = 22.1 Hz), 62.5, 36.1, 23.9. IR (KBr) γ 2955, 2922, 2851, 1660, 1482,
1460, 1395, 756 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C18H17ONF: 282.1289,
observed: 282.1283.
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(S,E)-1-(2-(2-methoxystyryl)indolin-1-yl)ethanone(3f)
Colorless oil. Yield: 68%, 19.9mg. [α]D20 = -19.7 (c 0.20, CHCl3). Enantiomeric
excess: 79%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 13.20 min (minor), tR = 15.06 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 6.8 Hz, 1H), 7.34 (dd, J = 7.6,
1.6 Hz, 1H), 7.24 – 7.11 (m, 3H), 7.08 – 6.96 (m, 1H), 6.92 – 6.80 (m, 3H), 6.21 (dd,
J = 16.0, 7.8 Hz, 1H), 5.12 – 4.78 (m, 1H), 3.81 (s, 3H), 3.58 (dd, J = 15.5, 10.0 Hz,
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1H), 2.92 (d, J = 16.0 Hz, 1H), 2.28 (s, 3H). C NMR (101 MHz, CDCl3) δ 169.3,
156.8, 142.4, 129.8, 129.1, 129.0, 127.5, 126.9, 125.9, 124.8, 124.7, 123.7, 120.6, 117.5,
110.9, 62.9, 55.4, 36.3, 24.0. IR (KBr) γ 2955, 2920, 2850, 1657, 1461, 1395, 1247, 1023,
754 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C19H20O2N: 294.1489, observed:
294.1484.
(S,E)-1-(2-(2-(naphthalen-2-yl)vinyl)indolin-1-yl)ethanone(3g)
Colorless oil. Yield: 58%, 18.1mg. [α]D20 = +17.9 (c 0.07, CHCl3). Enantiomeric
excess: 77%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 16.88 min (minor), tR = 18.51 min
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(major). H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 6.8 Hz, 1H), 7.84 – 7.63 (m,
4H), 7.54 – 7.36 (m, 3H), 7.27 – 7.16 (m, 2H), 7.05 (td, J = 7.4, 0.9 Hz, 1H), 6.64 (d,
J = 15.8 Hz, 1H), 6.31 (dd, J = 15.9, 7.1 Hz, 1H), 5.10 – 4.91 (m, 1H), 3.60 (dd, J = 14.7,
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10.1 Hz, 1H), 2.95 (d, J = 15.9 Hz, 1H), 2.29 (s, 3H). C NMR (101 MHz, CDCl3) δ
169.2, 142.4, 133.4, 133.2, 133.1, 130.7, 129.6, 128.7, 128.3, 127.9, 127.7, 127.6, 126.7,
126.4, 126.1, 124.8, 123.9, 123.3, 117.5, 62.3, 36.2, 23.9. IR (KBr) γ 2955, 2921, 2850,
1459, 1376, 1093, 1022, 756 cm-1. HRMS (ESI) m/z (M+H)+ calculated for
C22H20ON: 314.1539, observed: 314.1534.
(S,E)-1-(2-(2-cyclohexylvinyl)indolin-1-yl)ethanone(3h)
Colorless oil. Yield: 54%, 14.5mg. [α]D20 = -12.4 (c 0.26, CHCl3). Enantiomeric
excess: 80%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 10.33 min (minor), tR = 12.10 min
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(major). 1H NMR (400 MHz, CDCl3) δ 8.21 (t, J = 12.9 Hz, 1H), 7.24 – 7.10 (m, 2H),
7.01 (t, J = 7.4 Hz, 1H), 5.57 (dd, J = 15.5, 6.4 Hz, 1H), 5.41 (dd, J = 15.6, 7.3 Hz, 1H),
4.73 (t, J = 8.0 Hz, 1H), 3.50 (dd, J = 15.6, 9.9 Hz, 1H), 2.80 (d, J = 15.9 Hz, 1H),
2.22 (s, 3H), 1.99 – 1.85 (m, 1H), 1.75 – 1.55 (m, 4H). 1.38 – 0.86 (m, 6H). 13C NMR
(101 MHz, CDCl3) δ 169.3, 142.4, 138.0, 129.8, 127.5, 126.6, 124.6, 123.7, 117.4, 62.4,
40.0, 36.3, 32.7, 32.6, 26.0, 25.9, 23.9.IR (KBr) γ 2954, 2923, 2852, 1662, 1459, 1396,
1022, 755 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C18H24ON: 270.1852,
observed: 270.1849.
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(S)-1-(2-(2,2-diphenylvinyl)indolin-1-yl)ethanone(3i)
Colorless oil. Yield: 30%, 10.1mg. [α]D20 = -143.5 (c 0.12, CHCl3). Enantiomeric
excess: 82%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 11.07 min (major), tR = 12.59 min
(minor). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.3 Hz, 1H), 7.53 – 7.35 (m, 3H),
7.26 – 7.14 (m, 9H), 7.03 (td, J = 7.4, 1.0 Hz, 1H), 6.14 (d, J = 9.5 Hz, 1H), 4.84 (t, J
= 8.6 Hz, 1H), 3.59 (dd, J = 15.2, 10.1 Hz, 1H), 3.09 (d, J = 15.8 Hz, 1H), 1.97 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 169.2, 142.7, 142.2, 140.8, 138.7, 129.8, 129.7, 128.6,
128.3, 128.2, 128.0, 127.9, 127.7, 127.4, 124.6, 123.8, 117.5, 59.3, 37.0, 23.7. IR (KBr) γ
2955, 2921, 2851, 1460, 1378, 1093, 1023, 762 cm-1. HRMS (ESI) m/z (M+H)+
calculated for C24H22ON: 340.1696, observed: 340.1687.
(S,E)-1-(6-chloro-2-styrylindolin-1-yl)ethanone(3j)
Colorless oil. Yield: 75%, 22.3mg. [α]D20 = -64.7 (c 0.10, CHCl3). Enantiomeric
excess: 85%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 10.72 min (minor), tR = 12.30 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.34 – 7.23 (m, 5H), 7.06 (d, J
= 7.9 Hz, 1H), 6.99 (dd, J = 7.9, 1.9 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 6.17 (dd, J =
15.9, 7.1 Hz, 1H), 5.09 – 4.88 (m, 1H), 3.52 (dd, J = 15.7, 9.8 Hz, 1H), 2.87 (d, J =
13
16.0 Hz, 1H), 2.25 (s, 3H). C NMR (101 MHz, CDCl3) δ 169.3, 143.3, 135.6, 133.1,
130.8, 128.6, 128.1, 128.0, 127.9, 126.5, 125.4, 123.8, 117.7, 62.7, 35.6, 23.8. IR (KBr) γ
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2955, 2921, 2851, 1664, 1474, 1418, 1390, 1093, 1022 cm-1. HRMS (ESI) m/z (M+H)+
calculated for C18H17ONCl: 298.0993, observed: 298.0987.
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Colorless oil. Yield: 75%, 20.9mg. [α]D20 = -72.9 (c 0.14, CHCl3). Enantiomeric
excess: 85%, determined by HPLC (CHIRALPAK IC-H, hexane/isopropanol =
70/30, flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 10.47 min (minor), tR = 11.67
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min (major). H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.33 – 7.19 (m, 5H), 7.04
(d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 6.18 (dd, J =
15.9, 7.1 Hz, 1H), 5.02 – 4.86 (m, 1H), 3.52 (dd, J = 14.5, 10.2 Hz, 1H), 2.85 (d, J =
13
15.8 Hz, 1H), 2.36 (s, 3H), 2.25 (s, 3H). C NMR (101 MHz, CDCl3) δ 169.1, 142.4,
137.5, 135.9, 130.4, 128.6, 128.5, 128.0, 126.6, 126.4, 124.6, 124.3, 118.2, 62.5, 35.8, 23.9,
21.6. IR (KBr) γ2955, 2921, 2850, 1658, 1460, 1378, 1022, 755 cm-1. HRMS (ESI) m/z
(M+H)+ calculated for C19H20ON: 278.1539, observed: 278.1534.
(S,E)-methyl 1-acetyl-2-styrylindoline-6-carboxylate(3l)
Colorless oil. Yield: 74%, 23.8mg. [α]D20 = -97.8 (c 0.50, CHCl3). Enantiomeric
excess: 84%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 56.31 min (minor), tR = 61.99 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H),
7.32 – 7.20 (m, 6H), 6.50 (d, J = 15.9 Hz, 1H), 6.19 (dd, J = 15.9, 7.0 Hz, 1H), 5.14 –
4.92 (m, 1H), 3.91 (s, 3H), 3.62 (dd, J = 15.0, 9.6 Hz, 1H), 2.97 (d, J = 16.6 Hz, 1H),
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2.23 (s, 3H). C NMR (101 MHz, CDCl3) δ 169.2, 167.0, 142.5, 135.7, 134.9, 130.8,
130.0, 128.6, 128.2, 127.9, 126.5, 125.9, 124.6, 118.2, 62.3, 52.1, 36.2, 23.9. IR (KBr) γ
2922, 1717, 1663, 1433, 1392, 1277, 1088, 758 cm-1. HRMS (ESI) m/z (M+H)+
calculated forC20H20O3N: 322.1438, observed: 322.1434.
(S,E)-1-(5-chloro-2-styrylindolin-1-yl)ethanone(3m)
Colorless oil. Yield: 48%, 14.3mg. [α]D20 = +7.6 (c 0.18, CHCl3). Enantiomeric
excess: 67%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 85/15,
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flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 16.81 min (minor), tR = 18.29 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.7 Hz, 1H), 7.32 – 7.11 (m, 7H),
6.47 (d, J = 15.9 Hz, 1H), 6.16 (dd, J = 15.9, 7.1 Hz, 1H), 5.04 – 4.82 (m, 1H), 3.54
(dd, J = 15.6, 9.9 Hz, 1H), 2.87 (d, J = 16.2 Hz, 1H), 2.24 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 169.1, 141.0, 135.6, 131.5, 130.8, 128.7, 128.6, 128.4, 128.1, 127.8, 127.5, 126.5,
124.9, 118.3, 62.3, 35.9, 23.8. IR (KBr) γ 2955, 2921, 2851, 1661, 1468, 1392, 1091, 1021
cm-1. HRMS (ESI) m/z (M+H)+ calculated for C18H17ONCl: 298.0993, observed:
298.0989.
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(S,E)-1-(5-methyl-2-styrylindolin-1-yl)ethanone(3n)
Colorless oil. Yield: 53%, 14.9mg. [α]D20 = -29.1 (c 0.14, CHCl3). Enantiomeric
excess: 77%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 13.26 min (minor), tR = 16.14 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 1H), 7.33 – 7.20 (m, 5H),
7.10 – 6.89 (m, 2H), 6.47 (d, J = 15.9 Hz, 1H), 6.18 (dd, J = 15.9, 7.1 Hz, 1H), 4.93 (t,
J = 7.3 Hz, 1H), 3.54 (dd, J = 15.4, 9.9 Hz, 1H), 2.85 (d, J = 15.9 Hz, 1H), 2.30 (s, 3H),
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2.23 (s, 3H). C NMR (101 MHz, CDCl3) δ 168.8, 140.1, 135.8, 133.5, 130.4, 129.6,
128.6, 128.5, 128.0, 128.0, 126.4, 125.4, 117.2, 62.2, 36.1, 23.8, 20.9. IR (KBr) γ 2955,
2921, 2851, 1460, 1378, 1093, 1022, 761 cm-1. HRMS (ESI) m/z (M+H)+ calculated
for C19H20ON: 278.1539, observed: 278.1535.
(S,E)-methyl 1-acetyl-2-styrylindoline-5-carboxylate(3o)
Colorless oil. Yield: 40%, 12.8mg. [α]D20 = +24.0 (c 0.28, CHCl3). Enantiomeric
excess: 58%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 21.70 min (major), tR = 24.53 min
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(minor). H NMR (400 MHz, CDCl3) δ 8.38 – 8.14 (m, 1H), 7.98 – 7.93 (m, 1H),
7.86 (s, 1H), 7.36 – 7.20 (m, 5H), 6.50 (d, J = 15.9 Hz, 1H), 6.20 (dd, J = 15.9, 7.2
Hz, 1H), 5.25 – 4.91 (m, 1H), 3.89 (s, 3H), 3.61 (dd, J = 15.6, 10.0 Hz, 1H), 2.97 (d, J
= 16.1 Hz, 1H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.7, 166.7, 146.2, 135.6,
131.0, 130.3, 129.8, 128.7, 128.2, 127.9, 126.5, 126.3, 125.6, 116.7, 62.6, 51.9, 35.7, 24.1.
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IR (KBr) γ 2955, 2922, 2851, 1716, 1669, 1448, 1382, 1261, 1212 cm-1. HRMS (ESI) m/z
(M+H)+ calculated for C20H20O3N: 322.1438, observed: 322.1429.
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Brown oil. Yield: 83%, 24.3mg. [α]D = -28.7 (c 0.44, CHCl3). Enantiomeric
excess: 67%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 21.55 min (minor), tR = 24.83 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 1H), 7.34 – 7.20 (m, 5H),
6.86 – 6.67 (m, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.20 (dd, J = 15.9, 7.1 Hz, 1H), 4.97
(t, J = 8.1 Hz, 1H), 3.78 (s, 3H), 3.59 (dd, J = 16.0, 9.7 Hz, 1H), 2.89 (d, J = 16.1 Hz,
1H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.5, 156.5, 136.1, 135.8, 131.2, 130.5,
128.6, 128.3, 128.1, 126.5, 118.1, 112.1, 111.0, 62.4, 55.6, 36.3, 23.7. IR (KBr) γ 2956,
2924, 2852, 1652, 1487, 1460, 1395, 1272, 1192, 1033 cm-1. HRMS (ESI) m/z (M+H)+
calculated for C19H20O2N: 294.1489, observed: 294.1486.
(S,E)-1-(5-fluoro-2-styrylindolin-1-yl)ethanone(3q)
Colorless oil. Yield: 72%, 20.2mg. [α]D20 = -52.5 (c 0.34, CHCl3). Enantiomeric
excess: 74%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 95/5,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 50.12 min (minor), tR = 54.70 min
(major). 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 4.7 Hz, 1H), 7.34 – 7.21 (m, 5H),
7.00 – 6.72 (m, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.18 (dd, J = 15.9, 7.1 Hz, 1H), 4.98 (t,
J = 7.6 Hz, 1H), 3.57 (dd, J = 15.9, 9.8 Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H), 2.25 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 168.9, 159.4 (d, J = 242.4 Hz), 138.5, 135.7, 131.6
(d, J = 8.3 Hz), 130.8, 128.6, 128.1, 128.0, 126.5, 118.2 (d, J = 7.8 Hz), 113.9 (d, J =
22.6 Hz), 112.0 (d, J = 24.0 Hz),111.9, 62.4, 36.0, 23.7. IR (KBr) γ 2955, 2924, 1659,
1481, 1393, 1356, 1259, 1180, 751 cm-1. HRMS (ESI) m/z (M+H)+ calculated for
C18H17ONF: 282.1289, observed: 282.1285.
(S,E)-1-(2-styryl-6-(trifluoromethyl)indolin-1-yl)ethanone(3r)
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Brown oil. Yield: 75%, 24.8mg. [α]D = -57.5 (c 0.48, CHCl3). Enantiomeric
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excess: 87%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 95/5,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 27.32 min (minor), tR = 29.43 min
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(major). H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.35 – 7.23 (m, 7H), 6.51 (d, J
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= 15.9 Hz, 1H), 6.19 (dd, J = 15.9, 7.1 Hz, 1H), 5.14 – 4.89 (m, 1H), 3.62 (dd, J = 16.0,
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10.0 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.29 (s, 3H). C NMR (101 MHz, CDCl3) δ
169.5, 142.8, 135.5, 133.5, 131.1, 130.2 (q, J = 32.0 Hz), 128.7, 128.3, 127.7, 126.5, 124.9,
124.2 (q, J = 272.4 Hz), 120.9 (q, J = 3.8 Hz), 114.4, 62.4, 36.1, 23.9. IR (KBr) γ 2955,
2922, 2852, 1667, 1438, 1395, 1324, 1290, 1162, 1122, 1060, 1022, 751 cm-1. HRMS (ESI)
m/z (M+H)+ calculated for C19H17ONF3: 332.1257, observed: 332.1251.
(S,E)-ethyl 3-(1-acetylindolin-2-yl)acrylate(3s)12
Yellow oil. Yield: 40%, 10.3mg. [α]D20 = -77.1 (c 0.14, CHCl3). Enantiomeric excess:
79%, determined by HPLC (CHIRALPAK IC, hexane/isopropanol = 70/30, flow
rate 1.0 mL/min, T = 30°C, 254 nm): tR = 16.97 min (minor), tR = 20.55 min
(major). 1H NMR (400 MHz, DMSO) δ 8.04 (d, J = 7.0 Hz, 1H), 7.30 – 7.12 (m,
2H), 7.03 (t, J = 7.5 Hz, 1H), 6.88 (dd, J = 15.5, 5.1 Hz, 1H), 5.77 (dd, J = 15.7, 1.0 Hz,
1H), 5.29 (dd, J = 9.6, 5.5 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.53 (dd, J = 16.4, 9.3
Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H), 2.12 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, DMSO) δ 168.52, 165.14, 146.97, 142.04, 129.61, 127.30, 125.12, 123.76, 120.02,
116.44, 60.23, 59.78, 39.52, 34.22, 23.40, 14.00.
(S,E)-3-styrylisochroman(5a)
20
Colorless oil. Yield: 36%, 8.5mg. [α]D = -91.0 (c 0.13, CHCl3). Enantiomeric
excess: 80%, determined by HPLC (CHIRALCEL OD-H, hexane/isopropanol =
70/30, flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 6.70 min (minor), tR = 11.47
min (major). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.5
Hz, 2H), 7.27 – 7.14 (m, 4H), 7.07– 6.98 (m, 1H), 6.72 (d, J = 16.0 Hz, 1H), 6.36
(dd, J = 16.0, 5.9 Hz, 1H), 5.01 – 4.84 (m, 2H), 4.46 – 4.31 (m, 1H), 2.96 (dd, J =
13
16.2, 10.4 Hz, 1H), 2.87 (dd, J = 16.2, 3.6 Hz, 1H). C NMR (101 MHz, CDCl3) δ
136.7, 134.5, 132.9, 131.0, 129.4, 128.8, 128.5, 127.7, 126.5, 126.5, 126.1, 124.2, 75.1, 68.0,
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34.2. IR (KBr) γ 2955, 2921, 2851, 1460, 1377, 1271, 1023, 750 cm-1. HRMS (ESI) m/z
(M+H)+ calculated for C17H17O: 237.1274, observed: 237.1272.
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(S,E)-3-(4-fluorostyryl)isochroman(5b)
Colorless oil. Yield: 50%, 12.7mg. [α]D20 = -102.0 (c 0.20, CHCl3). Enantiomeric
excess: 79%, determined by HPLC (CHIRALPAK ID, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 5.16 min (minor), tR = 6.05 min
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(major). H NMR (400 MHz, CDCl3) δ 7.41 – 6.96 (m, 8H), 6.68 (d, J = 16.0 Hz,
1H), 6.27 (dd, J = 15.9, 5.4 Hz, 1H), 5.01 – 4.81 (m, 2H), 4.44 – 4.27 (m, 1H), 3.02 –
13
2.72 (m, 2H). C NMR (101 MHz, CDCl3) δ162.4 (d, J = 246.9 Hz), 134.4, 132.9,
132.8, 129.8, 129.2 (d, J = 2.2 Hz), 128.8, 128.0 (d, J = 8.0 Hz), 126.5, 126.2, 124.2,
115.5 (d, J = 21.6 Hz), 75.0, 68.0, 34.2. IR (KBr) γ 2922, 2849, 1507, 1276, 1261, 1227,
1088, 965, 748 cm-1. HRMS (ESI) m/z (M+H)+ calculated for C17H16OF: 255.1180,
observed: 255.1176.
(S,E)-3-(4-methoxystyryl)isochroman(5c)
Colorless oil. Yield: 46%, 12.2mg. [α]D20 = -39.2 (c 0.24, CHCl3). Enantiomeric
excess: 80%, determined by HPLC (CHIRALPAK ID, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 7.36 min (minor), tR = 8.18 min
1
(major). H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.22 – 7.09 (m,
3H), 7.07 – 6.95 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.22
(dd, J = 16.0, 6.0 Hz, 1H), 5.00 – 4.81 (m, 2H), 4.41 – 4.27 (m, 1H), 3.81 (s, 3H),
13
3.05 – 2.74 (m, 2H). C NMR (101 MHz, CDCl3) δ 159.3, 134.5, 133.1, 130.7, 129.4,
128.8, 127.7, 127.2, 126.4, 126.1, 124.23, 114.0, 75.3, 68.0, 55.3, 34.3. IR (KBr) γ2922,
2849, 1507, 1276, 1261, 1227, 1088, 748cm-1. HRMS (ESI) m/z (M+H)+ calculated
for C18H19O2: 267.1380, observed: 267.1380.
(S,E)-3-(2-(naphthalen-2-yl)vinyl)isochroman(5d)
Colorless oil. Yield: 76%, 21.7mg. [α]D20 = -63.3 (c 0.45, CHCl3). Enantiomeric
excess: 71%, determined by HPLC (CHIRALPAK ID, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30°C, 254 nm): tR = 6.32 min (minor), tR = 7.01 min
1
(major). H NMR (400 MHz, CDCl3) δ 7.88 – 7.72 (m, 4H), 7.63 (dd, J = 8.6, 1.4
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Hz, 1H), 7.49 – 7.36 (m, 2H), 7.22 – 7.12 (m, 3H), 7.07 – 6.99 (m, 1H), 6.87 (d, J =
16.0 Hz, 1H), 6.48 (dd, J = 16.0, 5.9 Hz, 1H), 5.03 – 4.86 (m, 2H), 4.49 – 4.34 (m,
13
1H), 3.08 – 2.80 (m, 2H). C NMR (101 MHz, CDCl3) δ 134.5, 134.2, 133.6, 133.1,
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133.0, 131.1, 129.8, 128.9, 128.2, 128.0, 127.7, 126.6, 126.5, 126.3, 126.2, 125.9, 124.2,
123.5, 75.2, 68.1, 34.3. IR (KBr) γ 2922, 2849, 1507, 1276, 1261, 1227, 1088, 748 cm-1.
HRMS (ESI) m/z (M+H)+ calculated for C21H19O: 287.1430, observed: 287.1429.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI: 10.1021/
Complete description of methods and additional results;
spectroscopic data for all new compounds; synthesis procedures for
substrates (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: hanzy2014@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support from the NSFC (21502183), and the
Fundamental Research Funds for the Central Universities (WK2060190041).
REFERENCES
(1) (a) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (b) Metal
Catalyzed Cascade Reactions; Müller, T. J. J., Ed.; Springer-Verlag: Berlin
Heidelberg, 2006; Vol. 19. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) (a) Oconnor, J. M.; Stallman, B. J.; Clark, W. G.; Shu, A. Y. L.; Spada, R. E.;
Stevenson, T. M.; Dieck, H. A. J. Org. Chem. 1983, 48, 807. (b) Larock, R. C.;
Fried, C. A. J. Am. Chem. Soc. 1990, 112, 5882. (c) Larock, R. C.; Berrios-Pena, N.;
Narayanan, K. J. Org. Chem. 1990, 55, 3447. (d) Wang, Y.; Huang, T.-N.
Tetrahedron Lett. 1998, 39, 9605. (e) Larock, R. C. J. Organomet. Chem. 1999,
576, 111. (f) Rozhkov, R. V.; Larock, R. C. Org. Lett. 2003, 5, 797. (g) Rozhkov, R.
V.; Larock, R. C. J. Org. Chem. 2003, 68, 6314. (h) Rozhkov, R. V.; Larock, R. C.
Tetrahedron Lett. 2004, 45, 911. (i) Rozhkov, R. V.; Larock, R. C. Adv. Synth. Catal.
2004, 346, 1854.
(3) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122.
(4) Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996, 96, 395.
(5) (a) Harada, I.; Hirose, Y.; Nakazaki, M. Tetrahedron Lett. 1968, 9, 5463. (b)
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7
8
9
Kawase, Y.; Yamaguchi, S.; Inoue, O.; Sannomiya, M.; Kawabe, K. Chem. Lett.
1980, 1581. (c) Rakhit, A.; Hurley, M. E.; Tipnis, V.; Coleman, J.; Rommel, A.;
Brunner, H. R. J. Clin. Pharmacol. 1986, 26, 156. (d) Xiang, L.; Xing, D.; Wang, W.;
Wang, R.; Ding, Y.; Du, L. Phytochemistry 2005, 66, 2595. (e) Rusman, Y.; Held,
B. W.; Blanchette, R. A.; Wittlin, S.; Salomon, C. E. J. Nat. Prod. 2015, 78, 1456.
(6) (a) Kagechika, K.; Shibasaki, M. J. Org. Chem. 1991, 56, 4093. (b) Kagechika,
K.; Ohshima, T.; Shibasaki, M. Tetrahedron 1993, 49, 1773. (c) Ohshima, T.;
Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1996,
118, 7108.
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11
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16
17
18
19
20
21
22
23
24
25
26
27
28
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56
57
58
59
60
(7) (a) Overman, L. E.; Rosen, M. D. Tetrahedron 2010, 66, 6514. (b) Overman,
L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39, 4596.
(8) Flubacher, D.; Helmchen, G. Tetrahedron Lett. 1999, 40, 3867.
(9) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem.
Soc. 2015, 137, 13476.
(10) For reviews, see: (a) Liu, D.-Y.; Zhao, G.-W.; Xiang, L. Eur. J. Org. Chem.
2010, 32, 3975. (b) Zhang, B.-L.; Qin W.; Duan Y.-C.; Chinese. J. Org. Chem. 2012,
32, 1359. For selected examples: (c) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube,
D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614. (d) Trost, B. M.; Quancard, J. J. Am.
Chem. Soc. 2006, 128, 6314. (e) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou,
Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909. (f) Nakanishi, M.; Katayev, D.;
Besnard, C.; Kündig, E. P. Angew. Chem., Int. Ed. 2011, 50, 7438. (g) Wang, D.-S.;
Tang, J.; Zhou, Y.-G.; Chen, M.-W.; Yu, C.-B.; Duan, Y.; Jiang, G.-F. Chem. Sci.
2011, 2, 803. (h) Saget, T.; Lemouzy, S. J.; Cramer, N. Angew. Chem., Int. Ed. 2012,
51, 2238.
(11) (a) DeNinno, M. P.; Perner, R. J.; Morton, H. E.; DiDomenico, S. J. Org.
Chem. 1992, 57, 7115. (b) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 7198. (c) Maity, P.; Srinivas, H. D.; Watson, M. P. J. Am. Chem. Soc.
2011, 133, 17142.
(12) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066.
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