Asymmetric Palladium-Catalyzed C-H Functionalization Cascade for Synthesis of Chiral 3,4-Dihydroisoquinolones

Article abstract of DOI:10.1021/acs.joc.9b01372

A palladium-catalyzed C-H functionalization/intramolecular asymmetric allylation cascade of N-sulfonyl benzamides with 1,3-dienes has been developed. In the presence of a chiral pyridine-oxazoline ligand, this protocol enables the synthesis of chiral 3,4-dihydroisoquinolones in yields of up to 83% with enantioselectivities of up to 96%, using environmentally friendly air as the terminal oxidant.

Full text of DOI:10.1021/acs.joc.9b01372

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Article
Asymmetric Palladium-Catalyzed C#H Functionalization
Cascade for Synthesis of Chiral 3,4-Dihydroisoquinolones
Manman Sun, Haijian Wu, Xiangyu Xia, Weida Chen, Zhiming Wang, and Jianguo Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01372 • Publication Date (Web): 02 Sep 2019
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Asymmetric Palladium-Catalyzed C‒H Functionalization
Cascade for Synthesis of Chiral 3,4-Dihydroisoquinolones
Manman Sun, Haijian Wu, Xiangyu Xia, Weida Chen, Zhiming Wang, and Jianguo Yang*
Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu
Avenue, Taizhou 318000, P. R. China. E-mail: yjg@tzc.edu.cn
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Graphical Abstract
O
O
O
N
SO2R
SO2R
Pd(II)/PyrOx
F3C
N
N
R1
R1
Z
+
H
N
oxidant
air
Z
PyrOx
36 examples
up to 83% yield
up to 96% ee
Z = Aryl, Alkyl, EWG
ABSTRACT
A palladium-catalyzed C‒H functionalization/intramolecular asymmetric allylation cascade of
N-sulfonyl benzamides with 1,3-dienes has been developed. In the presence of a chiral
pyridine-oxazoline ligand, this protocol enables the synthesis of chiral 3,4-dihydroisoquinolones
in yields of up to 83% with enantioselectivities of up to 96%, using environmentally friendly air as
the terminal oxidant.
INTRODUCTION
Chiral isoquinolines and their derivatives constitute an important class of heterocycles and play a
significant role in pharmaceuticals and materials.1 Among them, chiral 3,4-dihydroisoquinolone
frameworks are ubiquitous in various bioactive natural products and medicinal compounds.2 For
example, isoquinolone alkaloids such as (+)-narciclasine (I), (‒)-gusanlung D (II), and
(+)-pancratistatin (III) have shown potent antitumor and antiviral activities (Figure 1),3 and
molecule IV is an effective 5-HT2C agonists (Figure 1).4 Moreover, chiral
3,4-dihydroisoquinolones are also widely employed as valuable precursors in the asymmetric total
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synthesis
of
natural
tetrahydroisoquinoline
alkaloids.2
Traditionally,
chiral
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6
7
8
9
3,4-dihydroisoquinolones are constructed through intramolecular Bischler‒Napieralski,
Pomeranz‒Fritsch‒Bobbitt, Friedel‒Crafts, or Heck reactions from their corresponding chiral
amine substrates.5 The major drawbacks of these classic approaches, however, are multistep
procedures and relatively high costs of starting materials or reagents. In this context, the
development of asymmetric methods to achieve chiral 3,4-dihydroisoquinolones turns out to be a
challenging and meaningful task. Surprisingly, in sharp contrast to their well-developed racemic
versions,6 asymmetric synthetic strategies for chiral 3,4-dihydroisoquinolone construction are
relatively rare.7,8 Very recently, rhodium-catalyzed C‒H functionalization with chiral
cyclopentadienyl ligands has developed to be a robust process for enantioselective synthesis of
3,4-dihydroisoquinolones (Scheme 1 A).7c,d Despite this impressive progress, methods for
preparation of functionalized chiral 3,4-dihydroisoquinolones from more readily available starting
materials and reagents using cascade strategy remain in urgent demand.
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OH
OH
O
O
HO
OH
OH
OH
OH
R
N
O
O
O
O
O
H
H
NH
NH
O
N
NH
OH
O
OH
O
I
IV
5-HT2C receptor agonists ( )
(+)-narciclasine ( )
II
(-)-gusanlung D ( )
III
(+)-pancratistatin (
)
Figure 1. Examples of bioactive molecules with a chiral 3,4-dihydroisoquinolone core.
In the past decade, palladium-catalyzed C‒H functionalization of arenes has dramatically
improved the efficiency and step-economy of the carbon-carbon bond and carbon-heteroatom
bond formations,9 especially the cascade cyclization based on benzamide derivatives.10 Despite
these advances, palladium-catalyzed C‒H functionalization cascade cyclization of benzamides
with alkenes to prepare 3,4-dihydroisoquinolones is still challenging, mainly due to the
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competitive β-hydride elimination followed by intramolecular aza-Wacker-type cyclization or
Michael addition leading to the formation of undesired products.10a,11 The only successful example
is palladium-catalyzed heteroannulation of N-alkoxyl benzamides with 1,3-dienes.12 However, the
yields are relatively low and the reaction scope is unexplored (Scheme 1 B). Inspired by aromatic
C‒H functionalizations assisted by an N-sulfonylcarboxamide group9b,10,11a and
palladium-catalyzed asymmetric cyclization reactions for the synthesis of six-membered
nitrogen-containing frameworks,13 we envisaged that a carefully chosen catalytic system would
promote a palladium-catalyzed C‒H functionalization/intramolecular asymmetric allylation
sequence between N-sulfonyl benzamides and 1,3-dienes, leading to functionalized chiral
3,4-dihydroisoquinolones. As part of ongoing study on the development of heterocyclic compound
formations based on transition-metal-catalyzed approaches,14 herein we report an asymmetric
palladium-catalyzed C‒H functionalization cascade for the regio- and stereoselective synthesis of
functionalized chiral 3,4-dihydroisoquinolones (Scheme 1 C).
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Scheme 1. Transition-metal-catalyzed C‒H functionalizations for synthesis of chiral
3,4-dihydroisoquinolones
A) Asymmetric rhodium-catalyzed C-H functionalization cyclization of N-alkoxyl
benzamides with alkenes
O
O
OR
Rh(III)/Cp*
R3
NH
R3
N
R1
R1
+
H
R2
with internal oxidant
12-94%ee
R2
B) Palladium-catalyzed C-H functionalization cyclization of N-alkoxyl benzamides
with 1,3-dienes
O
O
OR
Pd(II)
N
NOR
R1
Z
+
R1
H
oxidant
Z
Z = Ph or CO2Et, 9 examples, 3-64% yields
This work:
N-sulfonyl benzamides with 1,3-dienes
C)
R1
Asymmetric palladium-catalyzed C-H functionalization cyclization of
O
O
SO2R
SO2R
Pd(II)/PyrOx
oxidant
N
N
R1
Z
+
H
Z
Z = Aryl, Alkyl, EWG, 36 examples, up to 83% yield, up to 96% ee
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RESULTS AND DISCUSSION
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To optimize reaction conditions, we selected N-((4-nitrophenyl)sulfonyl)benzamide (1a) and
(E)-buta-1,3-dien-1-ylbenzene (2a) as model substrates (Table 1). Inspired by asymmetric C‒H
functionalizations in which oxygen or air serves as terminal oxidant,10a,15 we initially performed
the reaction in air in the presence of Pd(TFA)2 (10 mol%) and Cu(OAc)2 (30 mol%). Screening of
various chiral ligands showed that substituting the pyridine-oxazoline-type ligand with an
electron-withdrawing group gave higher yield and enantioselectivity of chiral product 3aa (entries
1‒5). Since yields of 52‒68% exceeded the amount of Cu(OAc)2, we conclude that air was the
terminal oxidant. Exclusion copper oxidant resulted in a sharply decreased yield (entry 6),
suggesting that a reoxidant was needed in addition to air. Under oxygen atmosphere, the yield did
not increase (entry 7). Considering the N‒H bond in sulfonamide requires base-mediated
deprotonation to coordinate with Pd-catalyst,16 and a base can activate aromatic C‒H bonds,17,15b
we added catalytic amount of base to the reaction. To our delight, adding Et3N to the reaction
substantially increased both yield and enantioselectivity (entry 8). Screening of other bases
identified bulkier DIPEA as the best (entries 9‒12). Then other oxidants were examined, and
2,6-DMBQ gave the highes enantioselectivity (entries 13‒16). Reducing the temperature to 80 oC
slightly decreased yield, but increased enantioselectivity (entry 17). Further reducing the
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o
temperature to 70 C gave even higher enantioselectivity, but sharply reduced yield (entry 18).
Subsequently, other chiral pyridine-oxazoline-type ligands substituted with electron-withdrawing
groups were screened. Less bulky i-Pr or Ph group in oxazoline sharply diminished
enantioselectivity (entries 19 and 20). CN or NO2 group in pyridine gave lower enantioselectivity
than CF3 group (entries 21 and 22). Using other Pd-catalysts and solvents did not improve yield or
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enantioselectivity (see Supporting Information). Eventually, scaling up the reaction to one gram
gave 3aa in slightly lower yield with maintained enantioselectivity (entry 23). Hence, the optimal
reaction conditions are those shown in entry 17 of Table 1.
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Table 1. Optimization of reaction conditionsa
Pd(TFA)2 (10 mol%)
O
O
ligand (12 mol%)
O
S
O
Ns
additive (20 mol%)
N
N
+
H
oxidant (30 mol%)
Ph
NO2
PhCF3, air
temp., 48 h
3aa
1a
, 1.0 eq
2a
, 2.0 eq
O
Me
PPh2
PPh2
O
P
N
Me
COOH
NHBoc
L1
O
S
N
O
L2
L4
L3
R1
: R1 = CF3, R2 = t-Bu
: R1 = CF3, R2 = i-Pr
: R1 = CF3, R2 = Ph
: R1 = CN, R2 = t-Bu
: R1 = NO2, R2 = t-Bu
L5
L6
L7
L8
L9
O
N
N
R2
entry
1
ligand
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L6
L7
L8
additive
-
oxidant
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
-
temp. (oC)
90
yield(%)b
16
ee(%)c
0
2
-
90
52
0
3
-
90
55
0
4
-
90
61
37
54
52
54
77
80
74
73
55
84
82
80
78
88
90
58
61
86
5
-
90
68
6
7d
-
90
18
-
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
2,6-DMBQh
2,5-DMBQi
BQ
90
63
8
Et3N
90
86
9
DIPEAe
DABCOf
DBUg
pyridine
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
90
87
10
11
12
13
14
15
16
17
18
19
20
21
90
89
90
90
90
90
90
85
90
61
90
79
Ag2CO3
90
57
2,6-DMBQ
2,6-DMBQ
2,6-DMBQ
2,6-DMBQ
2,6-DMBQ
80
83
70
41
80
73
80
80
80
65
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22
23j
L9
L5
DIPEA
DIPEA
2,6-DMBQ
2.6-DMBQ
80
80
73
77
85
88
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Pd(TFA)2 (0.01 mmol), ligand (0.012 mmol), additive (0.02
mmol) and oxidant (0.03 mmol) in PhCF3 (0.2 ml) for 48 h under air. b Isolated yield. c Determined by HPLC.
Under oxygen atmosphere.
1,4-diazabicyclo[2.2.2]octane.
2,6-dimethoxy-1,4-benzoquinone. i 2,5-DMBQ = 2,5-dimethyl-1,4-benzoquinone. j 3.0 mmol scale.
d
e
f
DIPEA
DBU
=
N-ethyl-N-isopropylpropan-2-amine.
DABCO
2,6-DMBQ
=
=
g
h
=
1,8-diazabicyclo[5.4.0]undec-7-ene.
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With the optimized reaction conditions in hand, we firstly investigated the substrate scope of
N-((4-nitrophenyl)sulfonyl) benzamides. As shown in scheme 2, benzamides with
electron-donating groups functioned smoothly in the annulation reactions, affording the desired
chiral 3,4-dihydroisoquinolones 3ba‒3ha in good yields with good enantioselectivities. X-ray
crystallographic analysis of 3ca allowed the absolute configuration of the stereogenic center to be
assigned as S.18 The meta-substituted benzamide containing two possible C‒H functionalization
sites gave only one regioisomer 3fa. Benzamides with electron-withdrawing substituents afforded
3ia‒3na in relatively low yields with moderate ee values. This may be due to the poor solubility of
these amides. Introducing a methoxy group into fluoro-substituted benzamide increased both yield
and ee value of 3oa.
Then we turned our attention to variations of the 1,3-dienes. Para-substituted
(E)-buta-1,3-dien-1-ylbenzenes on phenyl ring with electron-donating and -withdrawing groups
were well tolerated, giving products 3ab‒3af in moderate to good yields and ee values.
Meta-substituted (E)-buta-1,3-dien-1-ylbenzene also reacted well, generating 3ag in 66% yield
with 83% ee. Excitingly, ortho-substituted (E)-buta-1,3-dien-1-ylbenzenes gave higher ee values
up to 96%. We suspect that steric hindrance at the 2-position were beneficial to the
enantioselectivity of 3ah‒3an. In contrast, electron-deficient 1,3-diene only obtained 3ao in
moderate yield with moderate enantioselectivity. Gratifyingly, aliphatic diene also afforded 3ap
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with good enantioselectivity, and only the E-product was obtained even though the
penta-2,4-dien-1-ylbenzene substrate was a mixture of Z/E-isomers (Z/E = 51/49). The result
suggested that there should be an isomerization of the π-allylpalladium intermediate, and the
subsequent reductive elimination gave only the E-product. 1,3-Butadiene could also undergo the
asymmetric cascade reaction when equivalent amount of 2,6-DMBQ was used and the reaction
was carried out in a sealed tube, although the enantioselectivity of 3aq was low.
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Eventually, some N-substituted benzamides were also tested, generating 3pa‒3sa with good
enantioselectivities, although the yield of 3pa was low. The “CF3SO2 group” resulted in reduced
yield and enantioselectivity in the formation of 3ta. Moreover, heterocyclic arylamide was also
compatible with the reaction. 3ua were obtained in moderate yield with moderate
enantioselectivity.
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Scheme 2. Scope of asymmetric palladium-catalyzed C-H functionalization cascadesa
5
6
7
8
Pd(TFA)2 (10 mol%)
O
O
L5
(12 mol%)
SO2R
SO2R
DIPEA (20 mol%)
2,6-DMBQ (30 mol%)
PhCF3, air
N
N
H
R1
Z
R1
+
Z
2
9
1
80 oC, 48 h
3
10
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13
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O
O
O
Ns
Ns
Ns
N
N
N
R1
R2
Ph
(R1 = 4-Me): 80%, 84% ee
(R1 = 4-Et): 76%, 86% ee
(R1 = 4-t-Bu): 81%, 87% ee
(R1 = 4-OMe): 62%, 86% ee
(R1 = 3-Me): 80%, 82% ee
(R1 = 2-Me): 72%, 80% ee
(R1 = 2,4-Me): 74%, 82% ee
(R1 = 4-F): 43%, 62% ee
(R1 = 4-Cl): 46%, 73% ee
(R1 = 4-Br): 33%, 78% ee
(R1 = 4-NO2): 52%, 67% eeb
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
R2
(R2 = Me): 80%, 92% ee
(R2 = OMe): 64%, 90% ee
(R2 = OCF3): 78%, 90% ee
(R2 = F): 77%, 92% ee
(R2 = Cl): 78%, 89% ee
(R2 = Br): 68%, 96% ee
(R2 = 2-Br-5-OMe): 62%, 96% ee
(R2 = 4-Me): 82%, 85% ee
(R2 = 4-OMe): 69%, 84% ee
3ah
3ab
3ac
3ad
3ae
3af
3ai
3aj
3ak
3al
2
(R = 4-F): 79%, 76% ee
(R2 = 4-Cl): 73%, 85% ee
(R2 = 4-Br): 59%, 83% ee
(R2 = 3-Br): 66%, 83% ee
3am
3an
3ag
3ja
O
3ka
3la
Ns
N
(R1 = 4-COOMe): 46%, 76% ee
3ma
3na
3oa
COOEt
(R1 = 4-CF3): 42%, 85% ee
3ao
: 56%, 75% ee
(R1 = 3-F-4-OMe): 54%, 82% ee
O
O
Ns
N
Ns
N
Ph
3ca
crystal structure of
(recrystallization, > 99% ee)
c
3ap
: 64%, 90% ee
(formed from mixture of Z/E-dienes)
3aq
: 63%, 21% ee
O
O
S
O
O
S
O
O
S
O
O
O
CF3
N
N
N
Ph
Ph
: 55%, 83% ee
Ph
3pa
: 32%, 80% ee
3ra
: 77%, 86% ee
3qa
O2N
O
S
Ns
O
Ph
O
O
S
O
N
O
O
CF3
Ph
N
N
N
: 78%, 65% ee
Ph
: 70%, 81% ee
3ta
: 45%, 77% ee
3sa
3ua
a Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd(TFA)2 (0.01 mmol), L5 (0.012 mmol), DIPEA (0.02 mmol)
and 2,6-DMBQ (0.03 mmol) in PhCF3 (0.2 ml) at 80 C for 48 h under air. b The reaction was carried out at 100
o
oC. c 2,6-DMBQ (0.1 mmol) was used and the reaction was carried out in a sealed tube.
To demonstrate the synthetic utility of this protocol, we conducted some further transformations
using the recrystallized products (Scheme 3). The N-protecting group in 3aa was smoothly
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removed by p-MePhSH, giving the product 4 with maintained enantioselectivity.19 Taking
advantage of the carbon-carbon double bond left over from the 1,3-diene, the compound 4 was
further converted to tricyclic chiral heterocycle 5. The carbonyl group and the carbon-carbon
double bond were feasibly reduced, giving products 6 and 7 in excellent yields without
racemization.
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Scheme 3. Further synthetic transformations
O
O
O
1) Allyl bromide
NaH, DMF
Ns
NH
N
p-MePhSH
K2CO3
N
(1)
2) Grubbs II
CH2Cl2
Ph
Ph
DMF, rt
5
, 73%, 95% ee
4
3aa,
, 91%, 97% ee
97% ee
(recrystallization)
O
O
LiAlH4
AlCl3
S
CF3
N
THF/Et2O
O
O
S
Ph
, 95%, 97% ee
O
CF3
6
N
(2)
O
O
S
O
Ph
, 96% ee
CF3
Pd/C
3ra
N
H2
(recrystallization)
Ph
, 96%, 98% ee
THF/EtOH
7
According to all above results and previous studies,20 a plausible mechanism is presented in
Scheme 4. First, chiral PyrOx ligand coordinates with Pd(TFA)2 to generate the chiral
Pd(II)-catalyst I. Then deprotonation of the N‒H bond and metallation of the sp2 C‒H bond
generate a five-membered palladacycle II which subsequently undergoes migratory insertion of
the 1,3-diene 2a, leading to the π-allyl palladium complex III. Finally, back attack of the nitrogen
nucleophile to the π-allyl palladium moiety affords chiral product 3aa, with regeneration of the
palladium(0) species IV which can be oxidized to Pd(II)-catalyst I to participate the next catalytic
cycle.
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Scheme 4. Plausible mechanism
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Pd(TFA)2
L5
2,6-DMBQ + H2O
1/2 O2
O
.
Ns
O
2,6-DMBQ 2H
N
9
+
CF3
2 DIPEA +
H
2 DIPEA
N
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N
1a
2,6-DMBQ
Pd
+
TFA
TFA
.
2 HTFA DIPEA
.
2 HTFA DIPEA
I
O
N
O
N
CF3
CF3
N
N
Pd
Pd
IV
Ns
N
O
O
N
CF3
N
O
II
Ns
Ph
Pd
Ns
N
N
O
Ph
Ph
2a
3aa
III
CONCLUSIONS
In summary, we have developed a palladium-catalyzed C‒H functionalization/intramolecular
asymmetric allylation cascade of N-sulfonyl benzamides with 1,3-dienes using a chiral PyrOx as
the ligand and environmentally friendly air as the terminal oxidant. A series of chiral
3,4-dihydroisoquinolones were obtained in yields of up to 83% with enantioselectivities of up to
96%. The obtained chiral products were readily converted to interesting heterocycles via simple
modifications with maintained enantioselectivities. It will be a good development of asymmetric
transition-metal-catalyzed C‒H functionalization cascades.
EXPERIMENTAL SECTION
General Information. 1H NMR and 13C NMR spectra were recorded on Bruker Avance 400, and
tetramethylsilane (TMS) or CDCl3 (7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR) or DMSO-d6
(2.50 ppm for H NMR, 39.5 ppm for 13C NMR) was used as a reference. Data for H were
reported as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublets, m = multiplet, br = broad singlet), coupling constants (Hz), and
1
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integration. Data for 13C NMR were reported as ppm. Optical rotations were determined on
SGW-1. High resolution mass spectra analyses were performed on Waters SYNAPT G2-Si mass
spectrometer. HPLC analyses were carried out on a Shimadzu LC20AR instrument. Melting
points were determined using a X-4 digital micro melting point apparatus. X-ray structural
analysis was conducted on the Gemini A Ultra instrument. Thin-layer chromatography (TLC) was
performed and visualization of the compounds was accomplished with UV light (254 nm). Flash
column chromatography was performed on silica gel (200–300 mesh). Known compounds 1a and
1b,21a 1e‒1g,21a 1i‒1k,21a 1n,21b 1p,21c 1q,21d 1r and 1s,21e 1t,21f 2a‒2e,22a 2f,22b 2g,22c 2h and 2i,22b
2k,22d 2l,22a 2m,22e 2o,22f 2p,22g L4,23a L5,23b L6 and L7,23c,d L8 and L923e were prepared according
to the known literatures and their analysis data was identical with the reported data.
Tetrahydrofuran (THF), and diethyl ether were distilled from sodium/benzophenone prior to use.
Other purchased reagents and solvents were used without further purification.
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Procedure for Preparation of Substituted N-sulfonyl benzamides 1. To a suspension solution
of corresponding acid (6 mmol) in CH2Cl2 (80 ml) was added DMF (11 mg, 0.15 mmol,) at 0 oC.
Oxalyl chloride (1.08 ml, 12 mmol) was subsequently added dropwise by syringe. The reaction
was allowed to warm to room temperature gradually and stirred for another 3 h. Then, the reaction
mixture was evaporated to afford acid chloride which was used without any further purification.
To a round-bottom flask under N2 was added 4-nitrobenzenesulfonamide (1.01 g, 5 mmol),
DMAP (61 mg, 0.5 mmol), Et3N (1.7 mL, 12.5 mmol), and EtOAc (10 mL). The above-mentioned
acid chloride was then added at 0 oC over 15 minutes. The mixture was stirred for 1 hour at 55 °C
under N2, cooled to room temperature and quenched with HCl (1N, 20 mL). The resulting mixture
was then extracted with EtOAc (20 mL ×3). The combined organic layer was dried over
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anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was recrystallized
from ethyl acetate to obtain the pure product 1. Componds 1c, 1d, 1l and 1m were synthesized
from purchased acid chlorides. Componds 1h, 1o and 1u were synthesized from corresponding
acids.
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4-Ethyl-N-((4-nitrophenyl)sulfonyl)benzamide (1c): White solid; 1.44 g; 86% yield; mp = 167–168
ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br, 1H), 8.53–8.42 (m, 2H), 8.34–8.25 (m, 2H), 7.89–
7.79 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 166.0, 150.7, 150.6, 145.2, 129.8, 129.2, 129.0, 128.5, 124.9, 28.6,
15.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C15H14N2O5SNa) 357.0521, found 357.0523.
4-(Tert-butyl)-N-((4-nitrophenyl)sulfonyl)benzamide (1d): White solid; 1.48 g; 82% yield; mp =
210–211 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (br, 1H), 8.55–8.43 (m, 2H), 8.35–8.25 (m,
2H), 7.92–7.82 (m, 2H), 7.61–7.49 (m, 2H), 1.28 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 165.9, 157.2, 150.7, 145.2, 129.8, 129.0, 128.8, 126.0, 124.9, 35.3, 31.2; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C17H18N2O5SNa) 385.0834, found 385.0834.
2,4-Dimethyl-N-((4-nitrophenyl)sulfonyl)benzamide (1h): White solid; 1.39 g; 83% yield; mp =
157–158 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.78 (br, 1H), 8.55–8.43 (m, 2H), 8.32–8.22 (m,
2H), 7.43 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 2.30 (s, 3H), 2.20 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 168.0, 150.7, 145.2, 142.1, 137.5, 132.2, 130.0, 129.7,
129.0, 126.7, 125.0, 21.3, 20.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C15H14N2O5SNa)
357.0521, found 357.0523.
4-Nitro-N-((4-nitrophenyl)sulfonyl)benzamide (1l): White solid; 1.26 g; 72% yield; mp = 222–223
ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.50–8.42 (m, 2H), 8.34–8.29 (m, 2H), 8.29–8.23 (m, 2H),
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8.14–8.08 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.3, 150.7, 150.5, 145.5, 137.8,
130.6, 129.9, 124.9, 124.1; HRMS (ESI-TOF) m/z calcd for [M - H]- (C13H8N3O7S) 350.0083,
found 350.0086.
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Methyl 4-(((4-nitrophenyl)sulfonyl)carbamoyl)benzoate (1m): White solid; 1.42 g; 78% yield; mp
= 207–208 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.50–8.44 (m, 2H), 8.30–8.24 (m, 2H), 8.08–
8.03 (m, 2H), 8.02–7.97 (m, 2H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.9,
165.8, 150.7, 145.1, 135.8, 133.9, 129.9, 129.7, 129.4, 125.0, 53.0; HRMS (ESI-TOF) m/z calcd
for [M - H]- (C15H11N2O7S) 363.0287, found 363.0288.
3-Fluoro-4-methoxy-N-((4-nitrophenyl)sulfonyl)benzamide (1o): White solid; 1.43 g; 81% yield;
mp = 173–174 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.48–8.44 (m, 2H), 8.27–8.23 (m, 2H), 7.80–
7.74 (m, 2H), 7.31–7.27 (m, 1H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.6 (d, J
= 2.3 Hz), 152.0 (d, J = 10.4 Hz), 151.2 (d, J = 243.8 Hz), 150.7, 145.2, 129.8, 126.9 (d, J = 3.4
Hz), 124.9, 123.8 (d, J = 5.8 Hz), 116.4 (d, J = 19.8 Hz), 113.9 (d, J = 1.0 Hz), 56.9; HRMS
(ESI-TOF) m/z calcd for [M - H]- (C14H10N2O6SF) 353.0244, found 353.0235.
1-Methyl-N-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxamide (1u): Yellow solid; 1.40 g; 78%
yield; mp = 198–199 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.32 (br, 1H), 8.51–8.44 (m, 2H),
8.41 (s, 1H), 8.32–8.26 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 7.6
Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.1,
150.5, 146.0, 137.4, 136.5, 129.6, 126.9, 124.9, 123.4, 122.5, 121.2, 111.3, 106.6, 33.9; HRMS
(ESI-TOF) m/z calcd for [M + Na]+ (C16H13N3O5SNa) 382.0474, found 382.0478.
Procedure for Preparation of dienes 2. To a solution of sodium hydroxide (1.2 g, 30 mmol) in a
mixture of ethanol (16 mL) and water (48 mL) was added aldehyde (30 mmol). The mixture was
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stirred at 0 oC for 10 minute. Then 40 percent acetaldehyde (6.6 g, 60 mmol) was added dropwise
to the mixture over 3 h at the same temperature. Stirring was continued for 8 h at room
temperature. The resulting solution was extracted with DCM, the combined organic layer was
washed with water and brine three times, and dried with anhydrous Na2SO4. The solution was
concentrated and purified by flash chromatography on silica gel (petroleum ether/ethyl acetate,
15:1) to give the pure α,β-unsaturated aldehydes. To a suspension of methyltriphenylphosphonium
bromide (4.3 g, 12 mmol) in THF (50 mL) at 0 °C was added dropwise n-butyllithium (4.8mL, 2.5
M in Hexane, 12 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for
30 min until all phosphonium bromide dissolved. Then a solution of substituted α,β-unsaturated
aldehyde (10 mmol) in THF (5 mL) was added dropwise. After stirring 1 hour, the mixture was
warmed to room temperature and stirred for additional 2 hours. Then the mixture was quenched
with saturated solution of NH4Cl (50 mL), extracted with Et2O (3 ×50 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash
column chromatography on silica gel (petroleum ether/ether, 40:1) to give the desired product 2.
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(E)-1-(Buta-1,3-dien-1-yl)-2-(trifluoromethoxy)benzene (2j): Colorless oil; 1.82 g; 85% yield; H
NMR (400 MHz, CDCl3) δ 7.64–7.60 (m, 1H), 7.27–7.20 (m, 3H), 6.86–6.77 (m, 2H), 6.60–6.51
(m, 1H), 5.39 (dd, J = 16.9, 1.5 Hz, 1H), 5.25 (dd, J = 10.0, 1.5 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 146.4 (d, J = 1.8 Hz), 137.1, 132.2, 130.5, 128.5, 126.9, 126.5, 125.2, 121.4 (d, J
= 1.2 Hz), 120.6 (q, J = 255.9 Hz), 119.0; HRMS (EI) m/z calcd for [M]+ (C11H9OF3) 214.0605,
found 214.0609.
1
(E)-1-Bromo-2-(buta-1,3-dien-1-yl)-4-methoxybenzene (2n): Yellow oil; 1.53 g; 64% yield; H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 6.89 (d, J = 15.4 Hz,
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1H), 6.75–6.67 (m, 2H), 6.57 (dt, J = 16.8, 10.1 Hz, 1H), 5.40 (d, J = 16.7 Hz, 1H), 5.26 (d, J =
9.8 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.9, 137.5, 136.9, 133.6, 132.2,
131.4, 119.0, 115.2, 114.8, 111.5, 55.5; HRMS (EI) m/z calcd for [M]+ (C11H11OBr) 237.9993,
found 237.9992.
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General Procedure for Preparation of Chiral 3,4-Dihydroisoquinolones 3. An 10 ml
oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar,
substrate 1 (0.1 mmol), Pd(TFA)2 (3.3 mg, 0.01 mmol, 10 mol%), L5 (3.3 mg, 0.012 mmol, 12
mol%), 2,6-DMBQ (5.0 mg, 0.03 mmol, 30 mol%), DIPEA (2.5 mg, 0.02 mmol, 20 mol%) and
PhCF3 (0.2 ml). After stirred at 80 ºC for 10 minutes under air, diene 2 (0.2 mmol, 2.0 eq) was
added to the mixture via syringe, and stirred at 80 ºC for 48 h. The residue was cooled to room
temperature and purified by column chromatography on silica gel (petroleum ether/ethyl acetate,
5:1 or 3:1) to give the pure product 3.
(S,E)-2-((4-Nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3aa): Light yellow
solid; 36 mg; 83% yield; 88% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 15.8 min (major) and tR = 40.0
min (minor)]; mp = 198–199 ºC; [α]D20 = +78.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.29–8.24 (m, 4H), 7.99 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H),
7.31–7.20 (m, 6H), 6.71 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.1 Hz, 1H), 5.71–5.66 (m, 1H),
3.73 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 162.9, 150.5, 144.7, 136.8, 135.2, 134.6, 134.4, 130.8, 129.1, 128.8, 128.7, 128.4, 127.8, 127.2,
126.6, 125.3, 123.7, 58.0, 34.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa)
457.0834, found 457.0836.
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(S,E)-6-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one
(3ba):
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Light yellow solid; 35.8 mg; 80% yield; 84% ee; [determined by HPLC analysis Daicel Chirapak
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IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.9 min (major) and tR =
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50.7 min (minor)]; mp = 180–181 ºC; [α]D = +210.2 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.23 (m, 4H), 7.86 (d, J = 8.0 Hz, 1H), 7.31–7.27 (m, 3H), 7.22–7.20 (m, 2H), 7.15
(d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.1 Hz, 1H), 5.68–
5.64 (m, 1H), 3.68 (dd, J = 16.2, 5.9 Hz, 1H), 3.03 (dd, J = 16.3, 2.0 Hz, 1H), 2.37 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.4, 145.6, 144.8, 136.8, 135.2, 134.5, 130.8, 129.2,
129.0, 128.8, 128.8, 128.7, 126.6, 125.4, 124.5, 123.7, 58.1, 34.9, 21.8; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0991.
(S,E)-6-Ethyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ca): Light
yellow solid; 35.1 mg; 76% yield; 86% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.6 min (major) and tR = 49.5
min (minor)]; mp = 137–139 ºC; [α]D20 = +117.1 (c = 0.9, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.28–8.23 (m, 4H), 7.89 (d, J = 8.1 Hz, 1H), 7.33–7.17 (m, 6H), 7.04 (s, 1H), 6.71 (d, J = 15.7 Hz,
1H), 6.02 (dd, J = 15.7, 8.1 Hz, 1H), 5.69–5.65 (m, 1H), 3.70 (dd, J = 16.2, 5.9 Hz, 1H), 3.05 (dd,
J = 16.3, 2.0 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 163.0, 151.7, 150.4, 144.8, 136.9, 135.2, 134.5, 130.8, 129.3, 128.8, 128.7, 127.8, 127.6,
126.6, 125.5, 124.7, 123.7, 58.1, 34.9, 29.0, 14.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C25H22N2O5SNa) 485.1147, found 485.1147.
(S,E)-6-(Tert-butyl)-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3da):
Light yellow solid; 39.7 mg; 81% yield; 87% ee; [determined by HPLC analysis Daicel Chirapak
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1
47.9 min (minor)]; mp = 110–112 ºC; [α]D = +147.4 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.23 (m, 4H), 7.90 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.32–7.22 (m,
5H), 7.20 (s, 1H), 6.73 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 15.7, 8.2 Hz, 1H), 5.69–5.65 (m, 1H),
3.72 (dd, J = 16.2, 5.9 Hz, 1H), 3.07 (dd, J = 16.4, 2.0 Hz, 1H), 1.31 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 162.9, 158.6, 150.4, 144.8, 136.6, 135.3, 134.5, 130.8, 129.0, 128.8, 128.7, 126.6,
125.6, 125.2, 125.2, 124.4, 123.6, 58.2, 35.3, 35.1, 31.0; HRMS (ESI-TOF) m/z calcd for [M +
Na]+ (C27H26N2O5SNa) 513.1460, found 513.1461.
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(S,E)-6-Methoxy-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one
(3ea):
Light yellow solid; 28.8 mg; 62% yield; 86% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 22.9 min (major) and tR =
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63.4 min (minor)]; mp = 69–70 ºC; [α]D = +109.56 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.28–8.22 (m, 4H), 7.93 (d, J = 8.7 Hz, 1H), 7.32–7.27 (m, 3H), 7.22–7.20 (m, 2H),
6.85–6.82 (m, 1H), 6.70 (d, J = 19.3 Hz, 1H), 6.68 (s, 1H), 6.02 (dd, J = 15.8, 8.2 Hz, 1H), 5.67–
5.63 (m, 1H), 3.84 (s, 3H), 3.69 (dd, J = 16.3, 5.9 Hz, 1H), 3.03 (dd, J = 16.3, 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.4, 162.6, 150.4, 144.9, 139.3, 135.2, 134.5, 131.5, 130.8,
128.8, 128.7, 126.6, 125.4, 123.6, 119.7, 113.6, 113.2, 58.0, 55.6, 35.2; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C24H20N2O6SNa) 487.0940 found 487.0944.
(S,E)-7-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3fa): Light
yellow solid; 35.8 mg; 80% yield; 82% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.8 min (major) and tR = 55.3
min (minor)]; mp = 180–181 ºC; [α]D20 = +160.75 (c = 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3)
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δ 8.29–8.23(m, 4H), 7.78 (s, 1H), 7.34–7.27 (m, 4H), 7.22–7.20 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H),
6.70 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.7, 8.1 Hz, 1H), 5.68–5.64 (m, 1H), 3.67 (dd, J = 16.2,
5.9 Hz, 1H), 3.06 (dd, J = 16.3, 1.9 Hz, 1H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
163.2, 150.4, 144.7, 137.8, 135.3, 135.2, 134.5, 133.8, 130.8, 129.3, 128.8, 128.7, 128.3, 126.9,
126.6, 125.4, 123.7, 58.1, 34.4, 21.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C24H20N2O5SNa) 471.0991, found 471.0991.
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(S,E)-8-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one
(3ga):
Light yellow solid; 32.2 mg; 72% yield; 80% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 12.2 min (major) and tR =
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31.2 min (minor)]; mp = 147–148 ºC; [α]D = +174.03 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.30–8.25 (m, 4H), 7.35 (t, J = 7.6 Hz, 1H), 7.31–7.23 (m, 5H), 7.14 (d, J = 7.7 Hz, 1H),
7.06 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 15.7 Hz, 1H), 6.02 (dd, J = 15.8, 7.8 Hz, 1H), 5.64–5.60 (m,
1H), 3.66 (dd, J = 16.0, 5.8 Hz, 1H), 3.07 (dd, J = 16.0, 2.1 Hz, 1H), 2.54 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 163.3, 150.3, 145.2, 142.9, 137.8, 135.4, 134.5, 133.3, 131.7, 130.5, 128.7,
128.6, 126.6, 126.5, 125.4, 125.3, 123.7, 57.4, 35.8, 22.7; HRMS (ESI-TOF) m/z calcd for [M +
Na]+ (C24H20N2O5SNa) 471.0991, found 471.0994.
(S,E)-6,8-Dimethyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ha):
Light yellow solid; 34.2 mg; 74% yield; 82% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 13.7 min (major) and tR =
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36.1 min (minor)]; mp = 194–195 ºC; [α]D = +54.6 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.24 (m, 4H), 7.35–7.24 (m, 5H), 6.94 (s, 1H), 6.86 (s, 1H), 6.72 (d, J = 15.7 Hz,
1H), 6.03 (dd, J = 15.8, 7.8 Hz, 1H), 5.62–5.69 (m, 1H), 3.62 (dd, J = 15.9, 5.8 Hz, 1H), 3.00 (dd,
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J = 16.0, 2.2 Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 150.3,
145.3, 144.2, 142.9, 137.9, 135.5, 134.4, 132.6, 130.4, 128.7, 128.5, 127.2, 126.6, 125.5, 123.7,
122.7, 57.4, 35.8, 22.6, 21.5; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C25H22N2O5SNa)
485.1147, found 485.1146.
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(S,E)-6-Fluoro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ia): Light
yellow solid; 19.4 mg; 43% yield; 62% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 14.2 min (major) and tR = 36.5
min (minor)]; mp = 174–175 ºC; [α]D20 = +107.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.29–8.24 (m, 4H), 8.01 (dd, J = 8.8, 5.6 Hz, 1H), 7.32–7.27 (m, 3H), 7.23–7.20 (m, 2H), 7.04 (td,
J = 8.5, 2.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.4 Hz, 1H), 6.70 (d, J = 15.7 Hz, 1H), 5.99 (dd, J = 15.7,
8.0 Hz, 1H), 5.70–5.67 (m, 1H), 3.72 (dd, J = 17.0, 5.3 Hz, 1H), 3.09 (dd, J = 16.5, 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.22 (d, J = 256.1 Hz), 162.0, 150.5, 144.5, 140.0 (d, J =
9.4 Hz), 135.0, 134.8, 132.2 (d, J = 10.0 Hz), 130.9, 128.8, 128.8, 126.6, 124.9, 123.7, 123.5 (d, J
= 2.7 Hz), 115.5 (d, J = 22.1 Hz), 115.4 (d, J = 22.2 Hz), 57.9, 34.9; HRMS (ESI-TOF) m/z calcd
for [M + Na]+ (C23H17N2O5SFNa) 475.0740, found 475.0746.
(S,E)-6-Chloro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ja): Light
yellow solid; 21.5 mg; 46% yield; 73% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 14.9 min (major) and tR = 34.8
min (minor)]; mp = 220–222 ºC; [α]D20 = +244.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.29–8.24 (m, 4H), 7.92 (d, J = 8.4 Hz, 1H), 7.35–7.20 (m, 7H), 6.69 (d, J = 15.7 Hz, 1H), 5.97
(dd, J = 15.7, 8.0 Hz, 1H), 5.70–5.67 (m, 1H), 3.70 (dd, J = 16.4, 5.9 Hz, 1H), 3.08 (dd, J = 16.8,
2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 150.5, 144.4, 140.9, 138.5, 134.9, 134.9,
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130.9, 130.7, 128.9, 128.4, 128.4, 126.6, 125.6, 124.8, 123.7, 57.9, 34.7; HRMS (ESI-TOF) m/z
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calcd for [M + Na]+ (C23H17N2O5SClNa) 491.0444, found 491.0444.
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(3ka):
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Light yellow solid; 16.9 mg; 33% yield; 78% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 16.0 min (major) and tR =
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35.9 min (minor)]; mp = 201–202 ºC; [α]D = +208.5 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.28–8.24 (m, 4H), 7.84 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4z, 1H), 7.42 (s, 1H), 7.32–
7.26 (m, 3H), 7.23–7.20 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.97 (dd, J = 15.7, 8.0 Hz, 1H), 5.70–
5.66 (m, 1H), 3.71 (dd, J = 16.4, 5.9 Hz, 1H), 3.07 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 162.3, 150.5, 144.4, 138.6, 134.9, 131.4, 131.4, 130.9, 130.7, 129.6, 128.9, 126.6,
126.1, 124.8, 123.7, 57.9, 34.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SBrNa)
534.9939, found 534.9941.
(S,E)-6-Nitro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3la): Light
yellow solid; 24.9 mg; 52% yield; 67% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 30.1 min (major) and tR = 49.1
min (minor)]; mp = 204–205 ºC; [α]D20 = +69.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.31–8.26 (m, 4H), 8.22–8.16 (m, 2H), 8.12 (s, 1H), 7.32–7.26 (m, 3H), 7.20–7.17 (m, 2H), 6.67
(d, J = 15.6 Hz, 1H), 5.94 (dd, J = 15.7, 7.6 Hz, 1H), 5.78–5.75 (m, 1H), 3.79 (dd, J = 16.5, 5.9
Hz, 1H), 3.27 (dd, J = 16.5, 2.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 151.0, 150.7,
143.9, 138.5, 135.3, 134.6, 132.2, 131.0, 130.7, 129.0, 128.9, 126.6, 124.2, 123.8, 123.5, 122.7,
57.7, 34.9; HRMS (ESI-TOF) m/z calcd for [M - H]- (C23H16N3O7S) 478.0709, found 478.0705.
(S,E)-Methyl
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(3ma):
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Light yellow solid; 22.6 mg; 46% yield; 76% ee; [determined by HPLC analysis Daicel Chirapak
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60.0 min (minor)]; mp = 193–194 ºC; [α]D = +172.4 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.33–8.23 (m, 4H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.30–
7.26 (m, 3H), 7.20–7.18 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.96 (dd, J = 15.7, 7.9 Hz, 1H), 5.75–
5.68 (m, 1H), 3.93 (s, 3H), 3.74 (dd, J = 16.4, 5.8 Hz, 1H), 3.19 (dd, J = 16.4, 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 162.2, 150.6, 144.3, 136.9, 135.1, 134.9, 134.8, 130.9,
130.7, 129.6, 129.3, 128.8, 128.7, 126.6, 124.8, 123.7, 57.9, 52.7, 34.8; HRMS (ESI-TOF) m/z
calcd for [M - H]- (C25H19N2O7S) 491.0926, found 491.0925.
(S,E)-2-((4-Nitrophenyl)sulfonyl)-3-styryl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one
(3na): Light yellow solid; 21.1 mg; 42% yield; 85% ee; [determined by HPLC analysis Daicel
Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 9.0 min (major)
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and tR = 17.4 min (minor)]; mp = 214–215 ºC; [α]D = +34.4 (c = 1.0, CH2Cl2); H NMR (400
MHz, CDCl3) δ 8.30–8.25 (m, 4H), 8.12 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 (s,
1H), 7.32–7.28 (m, 3H), 7.23–7.19 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.96 (dd, J = 15.7, 7.9 Hz,
1H), 5.75–5.72 (m, 1H), 3.76 (dd, J = 16.4, 5.9 Hz, 1H), 3.19 (dd, J = 16.5, 2.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.8, 150.6, 144.2, 137.6, 135.7 (q, J = 32.7 Hz), 135.1, 134.8, 130.9,
130.2, 129.8, 128.9, 128.8, 126.6, 125.4 (q, J = 3.7 Hz), 124.7 (q, J = 3.6 Hz), 124.6, 123.7, 123.2
(q, J = 271.3 Hz), 57.8, 34.8; HRMS (ESI-TOF) m/z calcd for [M - H]- (C24H16N2O5SF3)
501.0732, found 501.0738.
(S,E)-7-Fluoro-6-methoxy-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one
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(3oa): Light yellow solid; 26.0 mg; 54% yield; 82% ee; [determined by HPLC analysis Daicel
Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.9 min (major)
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and tR = 45.4 min (minor)]; mp = 175–176 ºC; [α]D = +100.0 (c = 1.0, CH2Cl2); H NMR (400
MHz, CDCl3) δ 8.28–8.23 (m, 4H), 7.67 (d, J = 11.2 Hz, 1H), 7.32–7.28 (m, 3H), 7.24–7.21 (m,
2H), 6.74–6.69 (m, 2H), 6.01 (dd, J = 15.7, 8.2 Hz, 1H), 5.68–5.64 (m, 1H), 3.93 (s, 3H), 3.69
(dd, J = 16.5, 6.0, 1H), 3.02 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8,
152.8, 151.6 (d, J = 257.6 Hz), 150.5, 144.6, 135.0, 134.7, 134.5 (d, J = 3.5 Hz), 130.9, 128.9,
128.8 (d, J = 4.0 Hz), 126.6, 125.0, 123.7, 119.7 (d, J = 6.5 Hz), 116.3 (d, J = 40 Hz), 112.0 (d, J
= 1.2 Hz), 58.1, 56.4, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H19N2O6FSNa)
505.0846, found 505.0854.
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(S,E)-3-(4-Methylstyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ab):
Light yellow solid; 36.7 mg; 82% yield; 85% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 16.1 min (major) and tR =
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46.1 min (minor)]; mp = 189–190 ºC; [α]D = +103.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.23 (m, 4H), 7.98 (d, J = 7.8Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz,
1H), 7.23 (d, J = 7.5 Hz, 1H), 7.12–7.07 (m, 4H), 6.68 (d, J = 15.7 Hz, 1H), 5.94 (dd, J = 15.7, 8.2
Hz, 1H), 5.69–5.64 (m, 1H), 3.72 (dd, J = 16.3, 5.9 Hz, 1H), 3.09 (dd, J = 16.3, 2.0 Hz, 1H), 2.32
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 150.4, 144.7, 138.8, 136.9, 134.6, 134.4,
132.3, 130.9, 129.5, 129.1, 128.4, 127.8, 127.2, 126.5, 124.1, 123.7, 58.2, 34.9, 21.3; HRMS
(ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0993.
(S,E)-3-(4-Methoxystyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ac):
Light yellow solid; 32.1 mg; 69% yield; 84% ee; [determined by HPLC analysis Daicel Chirapak
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59.1 min (minor)]; mp = 141–142 ºC; [α]D = +178.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.22 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz,
1H), 7.23 (d, J = 7.6 Hz, 1H), 7.16–7.14 (m, 2H), 6.82–6.80 (m, 2H), 6.67 (d, J = 15.7 Hz, 1H),
5.85 (dd, J = 15.7, 8.3 Hz, 1H), 5.67–5.63 (m, 1H), 3.80 (s, 3H), 3.72 (dd, J = 16.3, 5.8 Hz, 1H),
3.08 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 160.0, 150.4, 144.7,
136.9, 134.3, 134.2, 130.8, 129.1, 128.4, 127.9, 127.8, 127.2, 123.6, 122.8, 114.2, 58.3, 55.3, 35.0;
HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O6SNa) 487.0940, found 487.0943.
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(S,E)-3-(4-Fluorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ad):
Light yellow solid; 35.7 mg; 79% yield; 76% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.9 min (major) and tR =
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39.7 min (minor)]; mp = 163–164 ºC; [α]D = +76.2 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.27–8.26 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz,
1H), 7.25–7.18 (m, 3H), 7.00–6.94 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.94 (dd, J = 15.8, 8.1 Hz,
1H), 5.69–5.65 (m, 1H), 3.72 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 162.9, 162.8 (d, J = 247.3 Hz), 150.5, 144.7, 136.7, 134.4, 133.4,
131.3 (d, J = 3.4 Hz), 130.8, 129.1, 128.4, 128.3 (d, J = 8.0 Hz), 127.9, 127.1, 125.0 (d, J = 2.3
Hz), 123.7, 115.8 (d, J = 21.6 Hz), 57.9, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C23H17N2O5SFNa) 475.0740, found 475.0743.
(S,E)-3-(4-Chlorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ae):
Light yellow solid; 34.2 mg; 73% yield; 85% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.8 min (major) and tR =
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37.2 min (minor)]; mp = 170–171 ºC; [α]D = +115.6 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.29–8.25 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz,
1H), 7.26–7.23 (m, 3H), 7.17–7.13 (m, 2H), 6.68 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.0 Hz,
1H), 5.69–5.65 (m, 1H), 3.71 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.5, 134.4, 133.6, 133.3, 130.8, 129.1,
129.0, 128.4, 127.9, 127.8, 127.1, 126.0, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for [M +
Na]+ (C23H17N2O5SClNa) 491.0444, found 491.0443.
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(S,E)-3-(4-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3af):
Light yellow solid; 30.3 mg; 59% yield; 83% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.9 min (major) and tR =
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38.9 min (minor)]; mp = 174–175 ºC; [α]D = +64.4 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.30–8.25 (m, 4H), 7.98 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.41–7.35 (m, 3H),
7.24 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 15.7 Hz, 1H), 6.02 (dd, J = 15.7, 7.9
Hz, 1H), 5.69–5.65 (m, 1H), 3.71 (dd, J = 16.3, 6.0 Hz, 1H), 3.09 (dd, J = 16.3, 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.5, 134.4, 133.6, 133.3, 130.8,
129.1, 129.0, 128.4, 127.9, 127.8, 127.1, 126.0, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for
[M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9937.
(S,E)-3-(3-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ag):
Light yellow solid; 33.8 mg; 66% yield; 83% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.1 min (major) and tR =
36.4 min (minor)]; mp = 96–97 ºC; [α]D20 = +32.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 8.30–8.25 (m, 4H), 7.99 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.39–7.35 (m, 3H), 7.24 (d,
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J = 7.6 Hz, 1H), 7.17–7.11 (m, 2H), 6.63 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 15.8, 7.8 Hz, 1H),
5.69–5.66 (m, 1H), 3.71 (dd, J = 16.3, 6.0 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 137.3, 136.5, 134.5, 133.0, 131.5, 130.8, 130.3, 129.3,
129.2, 128.4, 128.0, 127.1, 127.0, 125.4, 123.8, 122.9, 57.7, 34.7; HRMS (ESI-TOF) m/z calcd for
[M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9945.
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(S,E)-3-(2-Methylstyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ah):
Light yellow solid; 35.8 mg; 80% yield; 92% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 15.8 min (major) and tR =
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33.0 min (minor)]; mp = 134–135 ºC; [α]D = +48.2 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.31–8.27 (m, 4H), 7.98 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 15.1 Hz, 1H), 7.35 (t, J = 7.6
Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.24–7.06 (m, 4H), 6.94 (d, J = 15.6 Hz, 1H), 5.90 (dd, J =
15.6, 7.6 Hz, 1H), 5.72–5.69 (m, 1H), 3.72 (dd, J = 16.3, 5.8 Hz, 1H), 3.12 (dd, J = 16.3, 2.0 Hz,
1H), 2.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0,150.5,144.8, 136.8, 135.9, 134.4,
134.4, 132.4, 130.7, 130.5, 129.0, 128.5, 128.4, 127.8, 127.3, 126.7, 126.2, 125.5, 123.7, 58.0,
34.9, 19.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found
471.0999.
(S,E)-3-(2-Methoxystyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ai):
Light yellow solid; 29.6 mg; 64% yield; 90% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.8 min (major) and tR =
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54.8 min (minor)]; mp = 126–127 ºC; [α]D = +167.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.33–8.31 (m, 2H), 8.24–8.22 (m, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H),
7.35 (t, J = 7.6 Hz, 1H), 7.26–7.22 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 15.8 Hz, 1H),
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6.86 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 5.95 (dd, J = 15.8, 8.5 Hz, 1H), 5.71–5.67 (m,
1H), 3.80 (s, 3H), 3.73 (dd, J = 16.0, 5.6 Hz, 1H), 3.10 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 163.0, 156.8, 150.4, 144.7, 137.1, 134.3, 131.0, 129.8, 129.1, 128.4, 127.7,
127.2, 126.8, 125.5, 124.2, 123.6, 120.7, 110.9, 58.6, 55.5, 35.0; HRMS (ESI-TOF) m/z calcd for
[M + Na]+ (C24H20N2O6SNa) 487.0940, found 487.0944.
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(S,E)-2-((4-Nitrophenyl)sulfonyl)-3-(2-(trifluoromethoxy)styryl)-3,4-dihydroisoquinolin-1(2H)-on
e (3aj): Light yellow solid; 40.4 mg; 78% yield; 90% ee; [determined by HPLC analysis Daicel
Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 10.3 min (major)
and tR = 19.7 min (minor)]; mp = 76–77 ºC; [α]D20 = +55.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 8.31–8.26 (m, 4H), 7.98 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz,
1H), 7.31–7.16 (m, 5H), 6.89 (d, J = 15.8 Hz, 1H), 6.08 (dd, J = 15.9, 7.6 Hz, 1H), 5.75–5.70 (m,
1H), 3.73 (dd, J = 16.3, 5.8 Hz, 1H), 3.12 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.4, 130.8, 129.7, 129.1, 128.7, 128.6, 128.3, 127.9, 127.4,
127.2, 127.1, 127.0, 123.7, 121.5, 120.4 (q, J = 257.0 Hz), 57.7, 34.7; HRMS (ESI-TOF) m/z
calcd for [M + Na]+ (C24H17N2O6F3SNa) 541.0657, found 541.0665.
(S,E)-3-(2-Fluorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3ak):
Light yellow solid; 34.8 mg; 77% yield; 92% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.4 min (major) and tR =
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35.9 min (minor)]; mp = 180–181 ºC; [α]D = +86.8 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.32–8.26 (m, 4H), 7.99 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz,
1H), 7.26–7.15 (m, 3H), 7.05–7.00 (m, 2H), 6.81 (d, J = 15.9 Hz, 1H), 6.08 (dd, J = 15.9, 7.9 Hz,
1H), 5.72–5.68 (m, 1H), 3.73 (dd, J = 16.3, 5.9 Hz, 1H), 3.12 (dd, J = 16.4, 1.9 Hz, 1H); 13C{1H}
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NMR (100 MHz, CDCl3) δ 162.9, 160.3 (d, J = 248.7 Hz), 150.5, 144.6, 136.7, 134.4, 130.8,
130.0 (d, J = 8.4 Hz), 129.1, 128.3, 128.2 (d, J = 5.2 Hz), 127.9, 127.7 (d, J = 3.4 Hz), 127.2 (d, J
= 3.2 Hz), 127.2, 124.3 (d, J = 3.5 Hz), 123.7, 123.1 (d, J = 12.0 Hz), 116.0 (d, J = 21,7 Hz), 58.0,
34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SFNa) 475.0740, found 475.0746.
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(S,E)-3-(2-Chlorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3al):
Light yellow solid; 36.5 mg; 78% yield; 89% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.9 min (major) and tR =
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35.2 min (minor)]; mp = 153–154 ºC; [α]D = +61.4 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.34–8.25 (m, 4H), 7.99 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.38–7.33 (m, 2H),
7.26–7.07 (m, 5H), 5.97 (dd, J = 15.7, 8.0 Hz, 1H), 5.75–5.72 (m, 1H), 3.74 (dd, J = 16.3, 5.8 Hz,
1H), 3.13 (dd, J = 16.4, 2.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 150.5, 144.6,
136.8, 134.4, 133.5, 133.3, 130.9, 130.9, 129.9, 129.6, 129.1, 128.4, 128.2, 127.9, 127.2, 127.0,
126.9, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SClNa)
491.0444, found 491.0453.
(S,E)-3-(2-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one
(3am):
Light yellow solid; 34.9 mg; 68% yield; 96% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.8 min (major) and tR =
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35.8 min (minor)]; mp = 240–241 ºC; [α]D = +76.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.34 (d, J = 9.0 Hz, 2H), 8.27 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.56–7.52
(m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.26–7.09 (m, 4H), 7.05 (d, J = 15.6 Hz, 1H), 5.93 (dd, J = 15.6,
8.0 Hz, 1H), 5.75–5.72 (m, 1H), 3.74 (dd, J = 16.3, 5.8 Hz, 1H), 3.13 (dd, J = 16.4, 2.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.7, 135.3, 134.4, 133.5, 133.1, 130.9,
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129.9, 129.2, 128.4, 128.3, 127.9, 127.6, 127.2, 127.1, 123.8, 123.7, 57.7, 34.7; HRMS (ESI-TOF)
m/z calcd for [M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9945.
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(3an): Light yellow solid; 33.6 mg; 62% yield; 96% ee; [determined by HPLC analysis Daicel
Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.6 min (major)
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and tR = 41.5 min (minor)]; mp = 152–153 ºC; [α]D = +75.6 (c = 1.0, CH2Cl2); H NMR (400
MHz, CDCl3) δ 8.35–8.27 (m, 4H), 7.99 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.43–7.41
(m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 15.6 Hz, 1H), 6.71–6.68
(m, 2H), 5.90 (dd, J = 15.6, 7.9 Hz, 1H), 5.75–5.70 (m, 1H), 3.77–3.72 (m, 4H), 3.12 (dd, J =
16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 158.9, 150.5, 144.5, 136.7, 136.0,
134.4, 133.7, 133.5, 131.0, 129.2, 128.4, 128.4, 127.9, 127.2, 123.7, 115.1, 114.4, 113.1, 57.6,
55.6, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H19N2O6SBrNa) 565.0045, found
565.0051.
(S,E)-Ethyl
3-(2-((4-nitrophenyl)sulfonyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)acrylate
(3ao): White solid; 24.1 mg; 56% yield; 75% ee; [determined by HPLC analysis Daicel Chirapak
IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.5 min (major) and tR =
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29.8 min (minor)]; mp = 168–169 ºC; [α]D = +80.6 (c = 1.0, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 8.38–8.28 (m, 4H), 7.96 (dd, J = 7.9, 1.3 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (t,
J = 7.7 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 15.6, 6.1 Hz, 1H), 5.93 (dd, J = 15.6, 1.5
Hz, 1H), 5.70–5.66 (m, 1H), 4.19–4.06 (m, 2H), 3.66 (dd, J = 16.4, 6.2 Hz, 1H), 3.10 (dd, J =
16.5, 2.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 162.6,
150.7, 144.2, 143.3, 135.9, 134.6, 130.8, 129.2, 128.3, 128.1, 127.0, 124.8, 123.9, 61.0, 56.0, 33.6,
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14.1; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C20H18N2O7SNa) 453.0732, found 453.0733.
(S,E)-2-((4-Nitrophenyl)sulfonyl)-3-(3-phenylprop-1-en-1-yl)-3,4-dihydroisoquinolin-1(2H)-one
(3ap): Light yellow solid; 28.7 mg; 64% yield; 90% ee; [determined by HPLC analysis Daicel
Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.2 min (major)
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and tR = 49.8 min (minor)]; mp = 176–177 ºC; [α]D = +246.0 (c = 1.0, CH2Cl2); H NMR (400
MHz, CDCl3) δ 8.15–8.08 (m, 4H), 7.95 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.36 (t, J =
7.7 Hz, 1H), 7.29–7.23 (m, 4H), 6.97 (d, J = 6.4 Hz, 2H), 5.88–5.80 (m, 1H), 5.56–5.53 (m, 1H),
5.45 (dd, J = 15.1, 7.2 Hz, 1H), 3.63 (dd, J = 16.2, 5.7 Hz, 1H), 3.29 (dd, J = 15.0, 6.8 Hz, 1H),
3.16 (dd, J = 15.0, 7.6 Hz, 1H), 3.02 (dd, J = 16.0, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 163.0, 150.3, 144.5, 139.0, 137.0, 134.3, 134.1, 130.7, 129.0, 128.7, 128.4, 128.3, 127.7, 127.7,
127.3, 126.5, 123.6, 57.2, 38.5, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+
(C24H20N2O5SNa) 471.0991, found 471.0996.
(S)-2-((4-Nitrophenyl)sulfonyl)-3-vinyl-3,4-dihydroisoquinolin-1(2H)-one (3aq): Light yellow
solid; 22.6 mg; 63% yield; 21% ee; [determined by HPLC analysis Daicel Chirapak IC,
n-hexane/i-PrOH = 80/20, 254 nm UV detector, 1.0 mL/min, tR = 36.6 min (major) and tR = 41.5
min (minor)]; mp = 169–170 ºC; [α]D20 = +20.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
8.41–8.28 (m, 4H), 7.94 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.21
(d, J = 7.6 Hz, 1H), 5.79–5.70 (m, 1H), 5.55–5.51 (m, 1H), 5.28 (d, J = 17.0 Hz, 1H), 5.19 (d, J =
10.2 Hz, 1H), 3.62 (dd, J = 16.2, 5.9 Hz, 1H), 3.04 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.0, 150.5, 144.7, 136.7, 134.8, 134.3, 130.7, 128.9, 128.2, 127.7, 127.3, 123.7,
119.1, 57.8, 34.4; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C17H14N2O5SNa) 381.0521, found
381.0519.
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