Asymmetric Construction of 4 H-Pyrano[3,2-b]indoles via Cinchonine-Catalyzed 1,4-Addition of 2-Ylideneoxindole with Malononitrile

Article abstract of DOI:10.1021/acs.joc.9b00430

A highly enantioselective [4 + 2] annulation of 2-ylideneoxindole with malononitrile has been accomplished by cinchonine catalysis under mild conditions. The corresponding enantiomerically enriched 4H-pyrano[3,2-b]indoles were generated in moderate to hig

Full text of DOI:10.1021/acs.joc.9b00430

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Article
Asymmetric construction of 4H-pyrano[3,2-b]indoles via cinchonine-
catalyzed 1,4-addition of 2-ylideneoxindole with malononitrile
Jin Zhou, Biao Wang, Xiang-Hong He, Li Liu, Jun Wu, Jing Lu, Cheng Peng, Chao-Long Rao, and Bo Han
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00430 • Publication Date (Web): 28 Mar 2019
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Asymmetric construction of 4H-pyrano[3,2-b]indoles via cinchonine-catalyzed
1
,4-addition of 2-ylideneoxindole with malononitrile
§
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Jin Zhou, Biao Wang, Xiang-Hong He, Li Liu, Jun Wu, Jing Lu, Cheng Peng, Chao-Long Rao*
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and Bo Han*
Key laboratory of Characteristic Chinese Resource in Southwest China, School of Pharmacy and School of Public
health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China. E-mail:
raocl@cdutcm.edu.cn, hanbo@cdutcm.edu.cn
√
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√
ABSTRACT: A highly enantioselectivity [4+2] annulation of 2-ylideneoxindole with
malononitrile has been accomplished by cinchonine-catalyzed under mild conditions. The
corresponding Enantiomerically enriched 4H-pyrano[3,2-b]indoles were generated in moderate to
high yields (up to 94%) with excellent enantioselectivities (up to 98% ee). To explain the
stereoselectivity of the organocatalytic Michael-ammonization cascade, we also carried out the
control experiments and proposed plausible transition-state models for the catalytic cycle based on
the observed stereochemistry of the products. In addition, some of the products showed moderate
antibacterial activity against S. aureus and S. epidermidis in vitro, which might be considered as a
potential clue for the discovery of new antimicrobial agents.
INTRODUCTION
Multicyclic scaffolds useful for synthetic chemistry and medicine are attractive in research and
1
industry. A particularly attractive scaffold for drug development is the fusion of pyran with
2
3
indole. The indole scaffold, commonly considered a “privileged structure” in drug discovery, is a
4
5
ubiquitous heterocycle in natural products and compounds used to treat cancer, type II diabetes,
6
and HIV infection. Similarly, pyran-bearing skeletons are presented in various natural products
7
and bioinspired synthetic compounds. 4H-pyran-containing architectures show antibacterial,
8
antiviral and antifungal activities. In 2012, Balasubramanian’s group reported a green, one-pot
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approach to synthesize substituted pyrano[2,3-c]pyrazoles in aqueous ethanol under non-catalytic
conditions. These compounds showed good activity against Gram-positive bacteria (Bacillus
subtilis, Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Pseudomonas
9
aeruginosa), showing minimal inhibitory concentrations (MICs) of 1.56-6.25 μg/mL. In 2017,
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Vinay Sunagar and co-workers demonstrated a green approach to transform 4-formylcou-marins
into 4-coumarin-4H-pyrans, which showed excellent activity against Gram-positive S. aureus and
Gram-negative E. coli with MICs of 0.4-0.8 μg/mL.10 In the same year, Hao’s group synthesized
dihydropyran derivatives via a one-pot reaction in ethanol; the products showed excellent
antibacterial MICs of 0.125-0.220 μg/mL.11
Figure 1. Examples of bioactive compounds with pyran-fused indole structures.
A popular medicinal synthetic target is the pyran-fused indole framework, which exists in many
natural products and pharmaceuticals and which exhibits myriad biological activities (Figure 1).
Pyran-fused indole derivatives I and II show antiproliferative activity,12 derivative III
(Cebranopadol) functions as an opioid analgesic of the benzenoid class,13 and derivative IV
inhibits the RNA polymerase of hepatitis C virus.14 The naturally occurring pyran-fused indole
hyrtimomine A (V) is cytotoxic,15 while the naturally occurring pleiomaltinine (VI) can bypass
multidrug resistance.16 This suggests that the asymmetric construction of pyran-fused indole
compounds may provide leads for drug discovery and for diverse areas of organic synthesis.
Most previous efforts to construct pyrano-fused indoles have focused on the synthesis of chiral
hydropyrano[2,3-b]indoles (Scheme 1a) via N-heterocyclic carbene (NHC) catalysis, calcium
phosphate catalysis, tertiary amine catalysis or N,N’-dioxide/metal catalysis.17 Few methods exist
to transform chiral hydropyrano[3,2-b]indoles, which are the isomeric skeleton of
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hydropyrano[2,3-b]indoles. In 2014, Ender’s group reported NHC-catalyzed enantioselective [3+3]
annulation of indolin-3-ones with bromoenals to furnish 2H-pyrano[3,2-b]indole-2-ones (Scheme
1
b).18 Our group reported secondary amine-catalyzed enantioselective [4+2] annulation of
(Z)-2-benzylidene-indolin-3-one with aldehyde to form chiral 2H-pyrano[3,2-b]indole derivatives
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via inverse-electron-demand oxa-Diels-Alder reaction.19
As part of our continuing interest in applying organocatalysis to the construction of
hydropyrano[3,2-b]indoles based on a variety of annulation types, we report here the application
of cinchonine to catalyse formation of chiral 4H-pyrano[3,2-b]indole derivatives (Scheme 1c).
Scheme 1. Asymmetric synthesis of hydropyran-fused indoles
RESULTS AND DISCUSSION
We initially examined cinchona alkaloid-based thiourea, squaramide or chiral bifunctional-urea
20
as potential catalysts. This is because the acidic α-H of malononitrile can be deprotonated by a
Lewis base, while 2-ylidene-indolin-3-one can be activated by acidic H-bond donors. First, we
selected (Z)-2-benzylideneindolin-3-one (1a) and malononitrile (2) in toluene as the model
o
substrates, and quinine (3a) as the catalyst. Incubating them together at -10 C for 24 h led to
smooth [4+2] annulation, affording the desired product 4a in 88% yield with excellent
enantioselectivity (Table 1, entry 1). Cinchona alkaloid catalysts 3b-3e promoted formation of the
desired products, with catalyst 3c showing the most satisfactory yield of 93% and ee of 95%
(entries 2 and 4-5 vs 3). Other chiral bifunctional catalysts (3f-3h) provided similar yield but lower
enantio-selectivities (entries 6-8). Choice of solvent affected the reaction (entries 9-12); toluene
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provided 4a in good yield with high enantioselectivity (entries 9-12 vs 3). Reducing the reaction
temperature to -20 oC and extending the reaction time led to slightly lower yield but
enantioselectivity of 98% ee (entry 13).
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Table 1. Optimization of asymmetric [4+2] annulation conditions.a
b
c
Entry
3
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
88
90
96
78
85
83
81
<10
90
85
88
30
98
96
94
-93
-92
95
90
94
93
90
--
3g
3h
3c
3c
3c
3c
3c
3c
3c
CH
2
Cl
2
92
0
Et
2
O
11
MeCN
THF
32
35
66
84
98
1
2
13d
Toluene
Toluene
Toluene
1
4e
5f
1
a
Unless other noted, the reaction was carried out with 1a (36.1 mg, 0.1
mmol), 2 (7.9 mg, 0.12 mmol) and catalyst 3 (0.02 mmol) in anhydrous
o
b
c
solvent (2 mL) at -10 C for 24 hours. isolated yield. Determined by HPLC
d
using a chiral stationary phase. The reaction performed at room temperature
for 10 hours. e The reaction performed at 0 C for 18 hours. The reaction
o
f
o
performed at -20 C for 48 hours.
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Table 2. Investigation of the scope and limitations of the asymmetric [4+2] annulation.a
Entry
R1
R2
H
PG
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
SO
Product
4a
4b
4c
yield (%)
b
ee (%)
c
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
10
C
6
H
5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
94
91
91
89
93
85
89
85
81
51
85
90
79
86
87
80
81
83
76
77
79
88
64
71
76
98
92
91
98
98
90
97
96
80
64
82
92
83
87
85
93
91
95
86
80
93
80
96
0
2-ClC
3-ClC
4-ClC
6
6
6
H
H
H
4
4
4
H
H
H
4d
4e
2-BrC
3-BrC
4-BrC
6
6
6
H
H
H
4
4
4
H
H
4f
H
4g
4h
4i
4-FC
2,4-Cl
4-NO
6
H
4
H
2
C
6
H
3
H
2
C
6
H
4
H
4j
11
2-MeOC
6
6
H
4
H
4k
4l
1
1
1
1
1
2
3
4
5
6
4-MeOC
H
4
4
H
2-MeC
6
H
H
H
4m
4n
4o
4p
4q
4r
4-MeC
6
4
H
i
4- PrC
6
H
4
H
3,4-(MeO)
2-Furyl
2
C
6
H
3
H
17
H
1
1
8
9
2-Thienyl
H
C
6
C
6
C
6
C
6
C
6
H
5
H
5
H
5
H
5
H
5
5-Cl
6-Br
5-BnO
H
4s
20
4t
2
2
2
2
1
4u
4v
4w
4x
4a
2
3d
H
COMe
4
COOEt
H
SO
2
2
Ph
Ph
2
5f
C
6
H
5
H
SO
95
a
Unless other noted, the reaction was carried out with 1 (0.1 mmol), 2 (7.9 mg, 0.12 mmol)
o
b
and catalyst 3c (5.9 mg, 0.02 mmol) in anhydrous toluene (2 mL) at -20 C for 24-48 hours.
Isolated yield. c Determined by HPLC using a chiral stationary phase. d The reaction
o
f
performed at -10 C for 5days. A gram–scale reaction was conducted with of 1a (1.01g, 2.8
mmol), 2 (0.22g, 3.36 mmol) and catalyst 3c (0.16g, 0.56 mmol) in anhydrous toluene (20 ml)
o
at -20 C for 3days.
With the optimal reaction conditions in hand, we investigated the scope and generality of this
tertiary amine-catalyzed [4+2] annulation. Screening of a series of (Z)-2-arylmethylidenes showed
that the reaction tolerated various substituents on the (Z)-2-arylmethylidenes 1, smoothly affording
the corresponding products in 51-94% yield and 64-98% enantioselectivities (Table 2). Various
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substitutions on the phenyl ring of R generated the 4H-pyrano[3,2-b]indole products in brilliant
yields (51-94% yields) and high to excellent enantioselectivities (64-98% ee), regardless of
whether the substituents were electron-withdrawing (entries 2-10) or electron-donating (entries
1
1
1-16). However, fixing the 4-NO
2
substituent on aromatic R group, an obvious decline was
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observed in the terms of yield and enantioselectivity (51% yield, 64% ee) for product 4j (entry 10).
The reaction also tolerated heteroaryl groups, such as furyl and thienyl groups, furnishing the
desired products 4q with 91% ee and 4r with 95% ee (entries 17-18). For the substituted-oxindole
2
part, substrates bearing Cl, Br or BnO at position 5 or 6 at R generated the corresponding
products 4s-4u in moderate yield (entries 19-21). The protecting group also played a important
role in reaction performance. Fixing a mesyl group on the nitrogen of (Z)-2-ylideneoxindole led to
a remarkable slump in ee from 98% to 80% in spite of slightly loss in yield from 94% to 88%
(
entry 22). While replacing the N-protecting group with acetyl group, a huge decrease was
observed in yield from 94% to 64% with retaining the excellent ee value (entry 23). To further
1
exploring the limitation of this reaction, a modified substrate containing a COOEt group at R was
tested, providing the desired product 4x in good yield, but no enantioselectivity was observed
(entry 24). In order to verify the practical utility of the methodology, we
demonstrated scale-up of synthesis of 4a to the gram level under optimized conditions for 3 days,
smoothly obtaining 0.91 grams of cyclized product in 76% yield with 95% ee (entry 25).
Figure 2. (A) Two configurations of 4a. (B) Calculated ECD spectra for the two configurations of compound 4a
and the experimental ECD spectrum.
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In order to determine the absolute configuration of 4a, the TD-DFT method was used to
theoretically calculate the electronic circular dichroism (ECD) spectra. This method has been used
to predict ECD spectra and assign the absolute configuration of organic molecules.21
First, the theoretical ECD spectra of the two probable configurations (R)-4a and (S)-4a at the
global energy minimum were calculated using the TD-DFT method at the B3LYP/aug-cc-pVDZ
level (Figure 2A). The stability of these conformers was verified using frequency calculations,
which also indicated population percentages. Finally, Multiwfn 3.4 software generated
Boltzmann-averaged ECD spectra, which were compared with the experimental ECD spectrum
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1
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(Figure 2B). The calculated ECD spectrum of (R)-4a was in good agreement with the sign and
shape of the experimental spectrum.
Scheme 2. Proposed mechanism for the synthesis of chiral 4H-pyrano[3,2-b] indoles derivatives.
We propose a mechanism for this cycloaddition (Scheme 2). Catalyst 3c promotes
deprotonation of malononitrile, generating an ion pair. The protonated tertiary amine group and
hydroxyl of 3c may form two hydrogen bonds with the C3 carbonyl of substrate 1a, lowering the
LUMO energy of 1a and generating the transition state (TS). The quinoline moiety effectively
shields the Re-face of TS, inhibiting attack by the cyanogen anion. Instead, approach of the
cyanogen anion toward the exposed Si-face of the 2-benzylideneoxindole is favored, leading to
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ammonization, which generates the R-adduct 4a.
To verify the two hydrogen bonds activation mode, the control experiments were carried out by
using the O-Ac and O-Me protected cinchonine as catalysts under the standard conditions
(Scheme 3). As expected, the corresponding product 4a was afforded in high yields, but with low
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ee values, which indicated that the OH group of cinchonine played a crucial role in the
Michael-ammonization cascade. In the absence of the OH group, the protonated tertiary amine
may not form two stable hydrogen bonds with the C3 carbonyl of substrate 1a and thus led to the
low enantioselectivities of the reaction.
Scheme 3. Control experiments to verify the transition state model
Hydropyrano-fused indole derivatives exhibit moderate to excellent antimicrobial activity,8-10,22
such as the compound prepared by Soorki and colleagues,22a which showed an MIC of 4 μg/mL
against B. subtilis. Therefore we examined whether chiral 4H-pyrano[3,2-b]indole compounds
also exhibit antimicrobial activity. The best MIC of 32 μg/mL was obtained with halogen-free 4v
2
(N-SO Me) against S. aureus and S. epidermidis, comparable to the MIC of 2 μg/mL for the
23
positive control antibiotics levofloxacin hydrochloride. This work suggests that protecting the N
atom of indoles with other groups can lead to chiral 4H-pyrano[3,2-b]indole derivatives with
promising antibacterial activity. For detailed experiments, please see SI.
CONCLUSION
In summary, we demonstrated a chiral tertiary amine-catalysed [4+2] annulation of
(Z)-2-arylmethylidenes with malononitrile that generates densely functionalized chiral
4
H-pyrano[3,2-b]indole derivatives in moderate to excellent yield and enantioselectivities. This
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approach is highly practical and functional group tolerant, which allows for rapid assembly of
substituent divergent products from simple, readily available starting materials. Our laboratory is
now screening the bioactivity of other compounds produced using this approach and carrying out
further chemical biology studies.
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EXPERIMENTAL SECTION
Chemistry
General information
1
13
1
NMR data were obtained for H at 400 MHz and for C at 100 MHz, or for H at 600 MHz and
for 13C at 150 MHz. Chemical shifts were reported in parts per million (ppm) using tetramethyl
6
silane as internal standard with solvent resonance in DMSO-d . Enantiomeric ratios were
determined by comparing HPLC analyses of products on chiral columns with results obtained
using authentic racemates. UV detection was performed at 254 nm. ESI-HRMS spectra were
measured with a Q-TOF instrument. IR spectra were detected with a FT-IR Spectrometer
instrument, Column chromatography was performed on a silica gel (200-300 mesh) using an
eluent of ethyl acetate and petroleum ether. TLC was performed on glass-backed silica plates;
products were visualized using UV light. Melting points were determined on a Mel-Temp
apparatus. All reagents and solvents were obtained from commercial sources and used without
further purification. (Z)-2-arylmethylidenes were prepared according to the literature procedures.24
General procedure for the synthesis of the (Z)-2-arylmethylidene 1
Sodium hydride (1.5 equiv) was added to indole (1.0 equive) with anhydrous THF solution in
ice bath. Then the benzenesulfonyl chloride or methanesulfonyl chloride (1.35 equiv) was added,
and the reaction mixture was stirred at room temperature. After the reaction was completed by
TLC, the mixture was quenched with water and ethyl acetate. The organic layer was dried on
sodium sulphate and concentrated. The residue was purified by flash chromatography on silica gel
to give the protected indole.24b
To a solution of the protected indole (1.0 equiv) and m-CPBA (1.05 equiv) were dissolved in
o
acetic acid at room temperature and then the solution was refluxed at 125 C. After the reaction
was completed and further cooled to room temperature. The solvent was removed by vacuum
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distillation and further the sodium bicarbonate solution was added to give a pH neutral solution.
And the mixture solution was quenched with dichloride methylene. The organic layer was dried on
sodium sulphate and concentrated. The residue was purified by flash chromatography on silica gel
to give the protected-indolin-3-one.24c
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To a solution of the protected-indolin-3-one C (1.0 mmol, 1 equiv) and aromatic aldehyde (1.2
o
mmol, 1.2 equiv) was stirred at 60 C with pyrrolidine (0.4 mmol, 0.4 equiv) in toluene until the
reaction was completed by TLC. The mixture was purified by flash chromatography on silica gel
1
to give the major isomer (Z)-2-arylmethylidenes 1, which was further analyzed by H-NMR,
13
1
C{ H}-NMR, and HRMS.
1
(
Z)-2-benzylidene-1-(phenylsulfonyl)indolin-3-one (1a): yellow oil, 243.3 mg, 67% yield. H
NMR (400 MHz, CDCl ): δ (ppm) 8.07 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.80-7.77 (m, 2H),
.61-7.57 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.49-7.47 (m, 2H), 7.45-7.42 (m, 1H), 7.35-7.33 (m,
3
7
3H), 7.28-7.24 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 13C{ H} NMR (100
1
MHz, CDCl
3
): δ (ppm) 182.9, 148.4, 136.0, 136.0, 134.1, 133.5, 133.2, 132.2, 131.4, 130.6, 129.1,
128.1, 127.4, 126.6, 125.7, 124.3, 118.9, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
21 3
C H15NO SNa 384.0670; Found 384.0667.
(Z)-2-(2-chlorobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1b): yellow solid, 291.2 mg,74%
1
yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H),
8
.07 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.44 (d, J
13
1
=
7.2 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.26 (t, J = 7.2 Hz, 3H), C{ H}
3
NMR (150 MHz, CDCl ): δ (ppm) 182.9, 148.6, 136.5, 134.2, 131.8, 130.9, 129.3, 129.1, 128.8,
1
28.0, 127.4, 127.2, 126.0, 125.6, 125.0, 124.5, 120.8, 118, HRMS (ESI-TOF) m/z: [M + Na]+
3
Calcd for C21H14NO SClNa 418.0281; Found 418.0282.
(Z)-2-(3-chlorobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1c): yellow solid, 276.5 mg, 70%
1
yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.89 (t, J = 1.6
Hz, 1H), 7.71-7.67 (m, 2H), 7.63 (dd, J = 7.6, 0.8 Hz, 1H), 7.58 (dd, J = 8.4, 1.2 Hz, 2H),
1
7
.57-7.52 (m, 1H), 7.41-7.32 (m, 4H), 7.29-7.25 (m, 1H), 13C{ H} NMR (100 MHz, CDCl
3
): δ
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(
ppm) 182.9, 148.5, 136.3, 136.0, 134.2, 134.1, 133.9, 130.8, 130.6, 130.3, 129.3, 129.2, 127.3,
+
1
25.8, 124.5, 118.7, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21
H14NO
3
SClNa 418.0281;
Found 418.0282.
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(Z)-2-(4-chlorobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1d): yellow solid, 266.7 mg,
1
6
7% yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J
=
8.8 Hz, 2H), 7.70-7.66 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57-7.51 (m, 3H), 7.39-7.33 (m, 4H),
.27 (t, J = 7.6 Hz, 1H), 13C{ H} NMR (100 MHz, CDCl
1
): δ (ppm) 183.0, 148.4, 136.6, 136.2,
7
1
3
36.0, 134.2, 133.8, 132.7, 131.5, 130.7, 129.1, 128.4, 127.4, 126.4, 125.8, 124.4, 118.8, HRMS
+
(ESI-TOF) m/z: [M + Na] Calcd for C21
H14NO
3
SClNa 418.0281; Found 418.0280.
(Z)-2-(2-bromobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1e): yellow solid, 311.2 mg, 71%
1
yield, H NMR (600 MHz, CDCl
3
): δ (ppm) 8.19 (d, J = 8.4 Hz, 1H), 8.11-8.02 (m, 1H), 8.01 (s,
1H), 7.73 (d, J = 7.8 Hz, 2H), 7.66-7.62 (m, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 7.8 Hz,
2H), 7.39 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 13C{ H} NMR (150 MHz, CDCl
1
): δ
3
(ppm) 182.9, 148.5, 136.5, 136.1, 134.2, 132.6, 132.5, 131.9, 130.9, 129.2, 128.8, 128.0, 127.4,
126.6, 125.7, 125.6, 124.5, 120.8, 118.1, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
21 3
C H14NO SBrNa 461.9775; Found 461.9777.
(Z)-2-(3-bromobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1f): yellow solid, 299.5 mg, 68%
1
yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 8.05-8.03 (m, 1H), 7.90 (s,
1
7
H), 7.73 (d, J = 8.0 Hz, 1H), 7.71-7.67 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.59-7.56 (m, 2H),
1
3
1
.56-7.53 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30-7.28 (m, 1H), 7.27-7.25 (m, 1H), C{ H} NMR
(100 MHz, CDCl
3
): δ (ppm) 182.9, 148.5, 136.3, 136.0, 134.2, 134.2, 133.7, 133.2, 130.5, 129.7,
+
1
29.6, 129.2, 127.3, 126.2, 125.8, 124.5, 122.1, 118.7, HRMS (ESI-TOF) m/z: [M + Na] Calcd
3
for C21H14NO SBrNa 461.9775; Found 461.9777.
(Z)-2-(4-bromobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1g): yellow solid, 315.9 mg,
1
7
2% yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J
=
8.8 Hz, 2H), 7.71-7.66 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57-7.51 (m, 5H), 7.35 (t, J = 7.6 Hz,
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H), 7.27 (t, J = 7.2 Hz, 1H), 13C{ H} NMR (100 MHz, CDCl
3
): δ (ppm) 183.0, 148.4, 136.2,
36.0, 134.2, 133.8, 132.8, 131.4, 131.4, 131.1, 129.1, 127.4, 126.4, 125.8, 125.1, 124.4, 118.8,
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21
H14NO
3
SBrNa 461.9775; Found 461.9774.
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(
Z)-2-(4-fluorobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1h): yellow solid, 257.3 mg, 68%
1
yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.94 (dd, J =
8
1
.4, 3 Hz, 2H), 7.71-7.67 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56-7.53 (m, 2H), 7.52 (d, J = 7.2 Hz,
H), 7.35 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 2H), 13C{ H} NMR
1
(150 MHz, CDCl
3
): δ (ppm) 183.05, 164.1(d, JCF = 251.4 Hz), 148.4, 136.2, 135.9, 134.2,
1
33.9(d, JCF = 8.5 Hz), 133.3, 132.2, 129.2, 128.5, 127.5, 126.6, 125.9, 124.4, 119.0, 115.4(d, JCF
+
=
21.6 Hz), HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21
H14NO
3
SFNa 402.0576; Found
4
02.0578.
(Z)-2-(2,4-dichlorobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1i): yellow solid, 303.3 mg,
1
70% yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.18 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.72-7.69
(m, 3H), 7.61 (d, J = 7.2 Hz, 1H), 7.59-7.56 (m, 2H), 7.45 (d, J = 1.8 Hz, 1H), 7.41 (t, J = 7.8 Hz,
1
3
1
3
2H), 7.27 (t, J = 7.8 Hz, 1H)7.24 (dd, J = 8.4, 2.4 Hz, 1H), C{ H} NMR (150 MHz, CDCl ): δ
(ppm) 183.0, 148.7, 136.8, 136.3, 136.1, 135.2, 134.4, 134.1, 132.7, 129.6, 129.3, 129.3, 127.5,
+
1
4
26.6, 125.8, 125.7, 124.7, 118.2, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21
H13NO
3
SCl
2
Na
51.9891; Found 451.9890.
(
Z)-2-(4-nitrobenzylidene)-1-(phenylsulfonyl)indolin-3-one (1j): yellow solid, 285.2 mg, 70%
1
yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.25-8.23 (m, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.97 (s,
1
H), 7.87 (d, J = 8.4 Hz, 2H), 7.74-7.70 (m, 1H), 7.65-7.61 (m, 3H), 7.61-7.57 (m, 1H), 7.43-7.39
1
(
m, 2H), 7.31-7.27 (m, 1H), 13C{ H} NMR (100 MHz, CDCl
3
): δ (ppm) 182.9, 148.7, 148.1,
1
38.8, 136.9, 136.1, 135.2, 134.5, 131.5, 129.3, 128.0, 127.3, 126.0, 125.6, 124.7, 123.3, 118.4,
+
14 2 5
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21H N O SNa 429.0521; Found 429.0519.
(
Z)-2-(2-methoxybenzylidene)-1-(phenylsulfonyl)indolin-3-one (1k): yellow solid, 279.1 mg,
1
7
3
1% yield. H NMR (400 MHz, CDCl ): δ (ppm) 8.22 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.81 (dd,
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J = 7.6, 1.2 Hz, 1H), 7.68-7.59 (m, 4H), 7.54-7.50 (m, 1H), 7.43-7.38 (m, 1H), 7.37-7.33 (m, 2H),
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1
7
.26-7.22 (m, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), C{ H} NMR
(
100 MHz, CDCl ): δ (ppm) 182.8, 158.3, 148.3, 136.1, 135.8, 133.9, 133.0, 132.3, 132.0, 128.9,
3
1
28.5, 127.5, 126.7, 125.5, 124.2, 121.2, 119.7, 118.7, 110.3, 55.6, HRMS (ESI-TOF) m/z: [M +
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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2
3
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2
3
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6
7
8
9
0
+
Na] Calcd for C22
H17NO
4
SNa 414.0776; Found 414.0778.
(Z)-2-(4-methoxybenzylidene)-1-(phenylsulfonyl)indolin-3-one (1l): yellow solid, 288.3 mg,
1
7
2
4% yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.0 Hz,
H), 7.97 (s, 1H), 7.69-7.64 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.49 (t, J
=
7.2 Hz, 1H), 7.33-7.29 (m, 2H), 7.26 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 3.88 (s, 3H),
13
1
C{ H} NMR (150 MHz, CDCl
3
): δ (ppm) 182.7, 162.0, 148.0, 135.7, 135.6, 134.3, 134.2, 133.9,
1
31.99, 128.9, 127.4, 127.1, 125.7, 125.1, 124.1, 119.0, 113.7, 55.4, HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C22
H17NO
4
SNa 414.0776; Found 414.0779.
(Z)-2-(2-methylbenzylidene)-1-(phenylsulfonyl)indolin-3-one (1m): yellow solid, 243.8 mg,
1
65% yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.18 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.71-7.66
(m, 1H), 7.64 (dd, J = 8.4, 1.2 Hz, 2H), 7.61-7.59 (m, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J = 7.6 Hz,
1H), 7.41-7.31 (m, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.27-7.23 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 2.34
1
(
s, 3H), 13C{ H} NMR (150 MHz, CDCl
3
): δ (ppm) 182.9, 148.5, 137.7, 136.2, 136.2, 134.2,
1
33.3, 131.5, 130.6, 130.4, 130.1, 130.0, 129.1, 127.4, 126.4, 125.6, 125.3, 124.4, 118.5, 20.3,
+
3
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C22H17NO S Na 398.0827; Found 398.0828.
(Z)-2-(4-methylbenzylidene)-1-(phenylsulfonyl)indolin-3-one (1n): yellow solid, 257.2 mg,
1
6
7
=
3
8% yield. H NMR (600 MHz, CDCl ): δ (ppm) 8.15 (t, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.86 (t, J =
.8 Hz, 2H), 7.68-7.64 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.4, 7.2 Hz, 2H), 7.49 (t, J
13
1
7.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.26-7.22 (m, 3H), 2.40 (s, 3H), C{ H} NMR (150 MHz,
CDCl
3
): δ (ppm) 182.8, 148.2, 141.5, 135.8, 135.8, 134.0, 133.8, 132.9, 131.7, 129.4, 129.0,
+
1
28.9, 127.4, 126.8, 125.7, 124.2, 118.9, 21.7, HRMS (ESI-TOF) m/z: [M + Na] Calcd for
22 3
C H17NO SNa 398.0827; Found 398.0828.
(Z)-2-(4-isopropylbenzylidene)-1-(phenylsulfonyl)indolin-3-one (1o): yellow solid, 288.2 mg,
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5
5
5
5
5
5
5
5
5
6
1
7
1% yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.15 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J
=
7.8 Hz, 2H), 7.67-7.65 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55-7.54 (m, 2H), 7.52-7.50 (m, 1H),
7
.33 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 8.4 Hz, 1H), 2.97 (dq, J = 21.0, 7.2
Hz, 1H), 1.29 (s, 3H), 1.28 (s, 3H), 13C{ H} NMR (150 MHz, CDCl
1
): δ (ppm) 182.9, 152.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
48.3, 135.9, 135.9, 134.1, 134.0, 133.1, 132.0, 129.9, 129.1, 127.5, 126.9, 126.4, 125.8, 124.3,
+
1
19.1, 34.4, 23.8, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
3
H21NO SNa 426.1140; Found
4
26.1137.
(
Z)-2-(3,4-dimethoxybenzylidene)-1-(phenylsulfonyl)indolin-3-one (1p): yellow solid, 291.1
1
mg, 69% yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.18 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.4
Hz, 1H), 7.97 (s, 1H), 7.67-7.64 (m, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.4, 1,8 Hz, 1H),
7
3
.51-7.47 (m, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.27-7.25 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.98 (s,
H), 3.95 (s, 3H), 13C{ H} NMR (150 MHz, CDCl
1
): δ (ppm) 183.2, 152.0, 148.4, 148.1, 135.8,
3
135.7, 135.1, 134.0, 132.1, 129.0, 127.8, 127.5, 127.3, 125.8, 125.7, 124.2, 119.3, 114.3, 110.5,
+
56.1, 56.1, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C23
H19NO
5
SNa 444.0882; Found
444.0880.
(Z)-2-(furan-2-ylmethylene)-1-(phenylsulfonyl)indolin-3-one (1q): yellow solid, 255.6 mg,
1
7
1
7
1
2% yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.29 (d, J = 3.6 Hz, 1H), 8.18 (d, J = 8.4 Hz,
H), 8.02 (s, 1H), 7.71-7.64 (m, 3H), 7.61-7.58 (m, 2H), 7.50-7.47 (m, 1H), 7.34-7.30 (m, 2H),
.29-7.25 (m, 1H), 6.62-6.61 (m, 1H), 13C{ H} NMR (100 MHz, CDCl
1
): δ (ppm) 182.5, 149.8,
3
47.8, 146.3, 136.1, 135.6, 134.0, 130.3, 129.1, 127.3, 126.3, 125.5, 124.0, 119.5, 118.3, 118.0,
+
1
13.5, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C19
H13NO
4
SNa 374.0463; Found 374.0460.
(
Z)-1-(phenylsulfonyl)-2-(thiophen-2-ylmethylene)indolin-3-one (1r): yellow solid, 267.8 mg,
1
7
3% yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.32 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.83 (d, J
=
3.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.69-7.66 (m, 1H), 7.65-7.64 (m, 1H), 7.56 (dd, J = 8.0,
13
1
0
.8 Hz, 1H), 7.50-7.45 (m, 1H), 7.32-7.26 (m, 3H), 7.21 (dd, J = 5.2, 4.0 Hz, 1H), C{ H} NMR
(
100 MHz, CDCl
3
): δ (ppm) 182.9, 147.9, 138.7, 136.2, 135.9, 135.6, 134.0, 133.8, 130.0, 129.1,
+
1
27.6, 127.3, 126.4, 125.6, 124.8, 124.1, 118.6, HRMS (ESI-TOF) m/z: [M + Na] Calcd for
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19 3 2
C H13NO S Na 390.0235; Found 390.0232.
(Z)-2-benzylidene-5-chloro-1-(phenylsulfonyl)indolin-3-one (1s): yellow solid, 265.5 mg, 67%
1
yield. H NMR (600 MHz, CDCl
3
): δ (ppm) 8.11 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.88-7.87 (m,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
H), 7.63 (dd, J = 9.0, 2.4 Hz, 1H), 7.57-7.55 (m, 4H), 7.46-7.44 (m, 3H), 7.40-7.37 (m, 2H),
1
3
1
3
C{ H} NMR (150 MHz, CDCl ): δ (ppm) 181.7, 146.7, 136.0, 135.7, 134.3, 134.3, 133.4, 132.0,
31.9, 131.6, 131.1, 130.3, 129.3, 128.3, 127.5, 124.0, 120.3, HRMS (ESI-TOF) m/z: [M + Na]+
1
3
Calcd for C21H14NO SClNa 418.0281; Found 418.0279.
(Z)-2-benzylidene-6-bromo-1-(phenylsulfonyl)indolin-3-one (1t): yellow solid, 269.9 mg, 61%
1
yield. H NMR (400 MHz, CDCl
3
): δ (ppm) 8.38 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.86-7.85 (m,
2
H), 7.62-7.58 (m, 2H), 7.58-7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.47-7.44 (m, 2H), 7.42 (d, J
13
1
=
3
1.6 Hz, 1H ), 7.41 (d, J = 1.6 Hz, 1H ), 7.40-7.38 (m, 2H), C{ H} NMR (100 MHz, CDCl ): δ
(ppm) 181.7, 148.9, 135.9, 134.4, 133.6, 133.2, 132.0, 131.4, 131.0, 130.9, 129.3, 128.2, 127.4,
+
125.3, 125.3, 121.9, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C21
H
14NO
3
SBrNa 461.9775;
Found 461.9772.
(Z)-2-benzylidene-5-(benzyloxy)-1-(phenylsulfonyl)indolin-3-one (1u): yellow solid, 286.2 mg,
1
6
1
=
1% yield, H NMR (600 MHz, CDCl
3
): δ (ppm) 8.02 (d, J = 7.2 Hz, 2H), 7.99 (d, J = 8.0 Hz,
H), 7.47 (t, J = 7.2 Hz, 2H), 7.45-7.41 (m, 3H), 7.39 (d, J = 4.2 Hz, 4H), 7.33 (m, 4H), 7.24 (t, J
1
3
1
3
7.2 Hz, 2H), 7.06 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), C{ H} NMR (150 MHz, CDCl ): δ (ppm)
1
1
86.4, 157.6, 144.6, 135.8, 134.4, 133.9, 133.4, 133.0, 132.7, 130.8, 129.7, 128.7, 128.6, 128.3,
+
28.2, 128.1, 127.5, 125.1, 122.3, 106.8, 70.5, HRMS (ESI-TOF) m/z: [M + Na] Calcd for
28 4
C H21NO SNa 490.1089,Found 490.1091.
1
(Z)-2-benzylidene-1-(methylsulfonyl)indolin-3-one (1v): yellow solid, 201.6 mg, 67% yield. H
NMR (400 MHz, CDCl
3
): δ (ppm) 8.00-7.97 (m, 3H), 7.89 (s, 1H), 7.82 (dd, J = 7.6 Hz, 1H),
.69-7.65 (m, 1H), 7.44-7.43 (m, 3H), 7.33 (t, J = 7.2 Hz, 1H), 2.92 (s, 3H), 13C{ H} NMR (100
1
7
MHz, CDCl
3
): δ (ppm) 182.7, 148.1, 136.4, 133.3, 132.4, 132.2, 132.2, 131.5, 130.7, 128.2, 125.6,
+
1
24.7, 117.7, 36.5, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C16
H
13NO
3
SNa 322.0514; Found
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22.0516.
General procedure for the synthesis of the chiral hydropyrano[3,2-b]indole derivatives 4
The reaction was carried out with (Z)-2-arylmethylidenes (1) (0.10 mmol), malononitrile (2)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(7.93 mg, 0.12 mmol) and Cinchonine (3c) (5.89 mg, 0.02 mmol) with 4Å MS in anhydrous
o
toluene (2.0 ml) at -20 C for 24-48 hours under N
2
. The reaction mixture was direct purified by
flash chromatography on a silica gel (Petroleum ether/Ethyl Acetate = 3:1) to give the chiral
1
4
H-pyrano[3,2-b]indoles compounds, which were dried under vacuum and further analyzed by H
13
1
NMR, C{ H} NMR, HRMS , HPLC and IR.
(R)-2-amino-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4a):
25
o
1
white solid, 40 mg , 94% yield, ee 98%, [α]
D
= -150.98 (c 0.1, DCM), m.p. >200 C, H NMR
6
(400 MHz, DMSO-d ) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 12.4, 7.6 Hz, 3H), 7.52 (d, J
= 8.0 Hz, 1H), 7.45 (dd, J = 11.6, 7.6 Hz, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.34-7.25 (m, 3H),
7.19-7.05 (m, 4H), 5.26 (s, 1H), 13C{ H} NMR (100 MHz, DMSO-d
1
) δ (ppm) 159.3, 143.8,
6
136.3, 136.0, 134.6, 134.0, 129.6, 128.6, 127.5, 127.1, 126.5, 126.4, 124.8, 120.3, 119.9, 118.5,
-
1
117.1, 115.1, 59.1, 54.9, IR (CH
2
Cl
2
, cm ): 3425, 3327, 2201, 1732, 1664, 1637, 1598, 1450,
+
1398, 1358, 1174, 754, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
H
17
N
3
O
3
SNa, 450.0888;
Found 450.0889.
(R)-2-amino-4-(2-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
2
5
o
itrile (4b): white solid, 42 mg, 91% yield, ee 92%, [α]
D
= -89.99 (c 0.1, DCM), m.p. >200 C,
1H NMR (400 MHz, DMSO-d
J = 7.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 7.28 (t, J =
) δ (ppm) 8.05 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (d,
6
1
3
1
7
.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.12 (s, 2H), 6.98 (d, J = 7.2 Hz, 1H), 5.76 (s, 1H), C{ H}
NMR (100 MHz, DMSO-d ) δ (ppm) 159.7, 140.4, 137.1, 136.2, 134.6, 134.1, 132.3, 129.8, 129.7,
6
, cm-1):
2 2
28.7, 127.7, 126.6, 126.2, 124.8, 120.1, 119.4, 117.2, 117.0, 115.0, 57.3, 55.0, IR (CH Cl
1
3
422, 3336, 2195, 1658, 1637, 1593, 1450, 1408, 1369, 1169, 749, HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C24
H
16
N
3
O
3
SClNa 484.0499; Found 484.0497.
(R)-2-amino-4-(3-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
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5
itrile (4c): white solid, 42 mg, 91% yield, ee 91%, [α]
D
= -145.98 (c 0.1, DCM), m.p. 196-198
) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H),
.62 (d, J = 7.2 Hz, 1H), 7.55-7.44 (m, 4H), 7.43-7.31 (m, 3H), 7.18 (s, 2H), 7.13 (s, 1H), 7.10 (d,
o
1
C, H NMR (400 MHz, DMSO-d
6
7
13
1
J = 7.2 Hz, 1H), 5.31 (s, 1H), C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 159.3, 146.2, 136.5,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
36.0, 134.7, 134.1, 133.1, 130.6, 129.6, 127.2, 127.1, 126.6, 126.5, 126.2, 124.9, 120.2, 119.7,
-
1
1
1
4
17.5, 117.2, 115.1, 58.5, 54.9, IR (CH
2
Cl
2
, cm ): 3419, 3328, 2201, 1732, 1663, 1638, 1593,
+
450, 1400, 1361, 1175, 746, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
H
16
N
3
O
3
SClNa
84.0499; Found 484.0498.
(
R)-2-amino-4-(4-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
25
o
itrile (4d): white solid, 41 mg, 89% yield, ee 98%, [α]
D
= -299.95 (c 0.1, DCM), m.p. >200 C,
1H NMR (400 MHz, DMSO-d
.55-7.43 (m, 4H), 7.40 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.22-7.07 (m, 4H), 5.29 (s,
) δ (ppm) 8.05 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 12.4, 7.6 Hz, 3H),
6
7
1H), 13C{ H} NMR (100 MHz, DMSO-d
1
) δ (ppm) 159.3, 142.7, 136.5, 136.0, 134.6, 134.1,
6
131.7, 129.6, 129.3, 128.6, 126.6, 126.4, 124.9, 120.3, 119.8, 117.9, 117.2, 115.1, 58.6, 54.9, IR
-
1
(CH
2
Cl
2
, cm ): 3412, 3358, 2186, 1658, 1621, 1594, 1449, 1399, 1372, 1170, 725, HRMS
+
(ESI-TOF) m/z: [M + Na] Calcd for C24
H
16
N
3
O
3
SClNa 484.0499; Found 484.0500.
(
R)-2-amino-4-(2-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
2
5
o
itrile (4e): white solid, 47 mg, 93% yield, ee 98%, [α]
D
= -236.96 (c 0.1, DCM), m.p. >200 C,
1H NMR (600 MHz, DMSO-d
) δ (ppm) 8.06 (d, J = 12.0 Hz, 1H), 7.63 (t, J = 6.0 Hz, 2H), 7.58
d, J = 6.0 Hz, 2H), 7.52 (d, J = 6.0 Hz, 1H), 7.50-7.45 (m, 3H), 7.41 (t, J = 9.0 Hz, 1H), 7.25 (s,
6
(
H), 7.21-7.17 (m, 1H), 7.13 (s, 2H), 5.75(s, 1H), 13C{ H} NMR (150 MHz, DMSO-d
1
1
1
6
) δ (ppm)
59.6, 137.1, 136.3, 134.6, 134.1, 133.1, 129.7, 128.9, 128.2, 126.6, 126.2, 124.8, 122.8, 120.1,
-
1
119.3, 117.2, 115.0, 57.4, 54.9, IR (CH
2
Cl
2
, cm ): 3424, 3336, 2194, 1657, 1637, 1593, 1450,
+
1
407, 1369, 1169, 725, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
H
16
N
3
O
3
SBrNa 527.9993;
Found 527.9994.
(
R)-2-amino-4-(3-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
25
o
itrile (4f): white solid, 43 mg, 85% yield, ee 90%, [α]
D
= -204.97 (c 0.1, DCM), m.p. >200 C,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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6
1H NMR (400 MHz, DMSO-d
) δ (ppm) 8.08 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.63 (t,
6
J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.52-7.44 (m, 4H), 7.41 (t, J = 7.6 Hz, 1H), 7.33-7.26
1
3
1
(
m, 2H), 7.19 (s, 2H), 7.15 (d, J = 8.0 Hz, 1H), 5.32 (s, 1H), C{ H} NMR (100 MHz, DMSO-d
6
)
δ (ppm) 159.4, 146.4, 136.5, 136.0, 134.6, 134.1, 130.8, 130.0, 129.6, 126.6, 126.4, 124.8, 121.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1
1
20.2, 119.7, 117.5, 117.2, 115.1, 58.6, 54.9, IR (CH
2 2
Cl , cm ): 3448, 3355, 2190, 1652, 1628,
1
588, 1451, 1403, 1370, 1171, 754, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
24 16 3 3
C H N O SBrNa 527.9993; Found 527.9990.
(R)-2-amino-4-(4-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
25
o
itrile (4g): white solid, 45 mg, 89% yield, ee 97%, [α]
D
= -120.98 (c 0.1, DCM), m.p. >200 C,
1H NMR (400 MHz, DMSO-d
.51-7.45 (m, 6H), 7.39 (t, J = 7.6 Hz, 1H), 7.16 (s, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.27 (s, 1H),
) δ (ppm) 8.05 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.4 Hz, 3H),
6
7
1
3
1
C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 159.2, 143.1, 136.4, 136.0, 134.6, 134.1, 131.5,
2
Cl ,
129.7, 129.6, 126.6, 126.4, 124.9, 120.2, 120.2, 119.8, 117.8, 117.2, 115.1, 58.6, 55.1, IR (CH
2
-
1
cm ): 3409, 3326, 2193, 1659, 1635, 1595, 1447, 1398, 1370, 1171, 724, HRMS (ESI-TOF) m/z:
+
[M + Na] Calcd for C24
H N
16 3
O
3
SBrNa 527.9993; Found 527.9991.
(R)-2-amino-4-(4-fluorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon
2
5
o
itrile (4h): white solid, 38 mg, 85% yield, ee 96%, [α]
D
= -272.96 (c 0.1, DCM), m.p. >200 C,
1H NMR (600 MHz, DMSO-d
) δ (ppm) 8.03 (d, J = 12.0 Hz, 1H), 7.64 (d, J = 12.0 Hz, 2H), 7.61
6
(t, J = 12.0 Hz, 1H), 7.51 (d, J = 6.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 3H), 7.38 (t, J = 6.0 Hz, 1H),
.17-7.10 (m, 6H), 5.28 (s, 1H), 13C{ H} NMR (150 MHz, DMSO-d
1
7
2
1
3
6
) δ (ppm) 161.7 (d, JCF =
41.8 Hz), 159.3, 140.0, 136.4, 136.0, 134.7, 134.2, 129.6, 129.5 (d, JCF = 8.1 Hz) ,126.6, 126.5,
-
1
2 2
24.9, 120.4, 119.9, 118.3, 117.2, 115.4(d, JCF = 21.5 Hz), 115.1, 59.0, 54.9, IR (CH Cl , cm ):
431, 3319, 2194, 1659, 1601, 1506, 1446, 1396, 1357, 1169, 1151, 722, HRMS (ESI-TOF) m/z:
+
[
M + Na] Calcd for C24
H N
16 3
O
3
SFNa 468.0794; Found 468.0798.
(R)-2-amino-4-(2,4-dichlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-car
25
bonitrile (4i): white solid, 40 mg, 81% yield, ee 80%, [α]D = -227.96 (c 0.1, DCM), m.p. >200
o
1
6
C, H NMR (400 MHz, DMSO-d ) δ (ppm) 8.01 (d, J = 8.4 Hz, 1H), 7.62-7.54 (m, 3H), 7.53 (d,
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J = 2.0 Hz, 1H), 7.50-7.39 (m, 4H), 7.35 (t, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (s,
2
1
1
1
5
H), 6.94 (d, J = 7.2 Hz, 1H), 5.69 (s, 1H), 13C{ H} NMR (100 MHz, DMSO-d
1
6
) δ (ppm) 159.7,
39.4, 137.2, 136.3, 134.6, 134.2, 133.2, 132.4, 131.6, 129.7, 129.1, 127.8, 126.7, 126.1, 124.8,
-
1
20.0, 119.3, 117.2, 116.4, 115.0, 56.8, 54.9, IR (CH
2
Cl
2
, cm ): 3427, 3361, 2183, 1653, 1611,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
583, 1448, 1381, 1170, 724, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
H
15
N
3
O
3
SCl
2
Na
18.0109; Found 518.0110.
(R)-2-amino-4-(4-nitrophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonit
25
o
1
rile (4j): white solid, 24 mg, 51% yield, ee 64%, [α]
D
= -254.96 (c 0.1, DCM), m.p. >200 C, H
NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.18 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.74 (d, J
=
7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.52-7.45 (m, 3H), 7.41 (t, J =
1
8
.0 Hz, 3H), 7.25 (s, 2H), 5.48 (s, 1H), 13C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 159.4,
1
50.9, 146.5, 136.7, 136.0, 134.7, 134.2, 129.7, 128.7, 126.8, 126.5, 125.0, 123.9, 120.2, 119.5,
-
1
117.3, 116.9, 115.1, 99.5, 57.8, IR (CH
2
Cl
2
, cm ): 3419, 3322, 2204, 1661, 1635, 1592, 1520,
+
1448, 1404, 1345, 1170, 747, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C24
H
16
N
4
O
5
SNa
495.0739; Found 495.0741.
(R)-2-amino-4-(2-methoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carb
2
5
o
onitrile (4k): white solid, 39 mg, 85% yield, ee 82%, [α]
D
= -38.99 (c 0.1, DCM), m.p. >200 C,
1H NMR (400 MHz, DMSO-d
) δ (ppm) 8.04 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.51 (d,
6
J =7.6 Hz, 3H), 7.44 (t, J = 7.6 Hz, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.27-7.21 (m, 1H), 7.02 (d, J =
1
3
1
8
.4 Hz, 1H), 6.95 (s, 2H), 6.85-6.78 (m, 2H), 5.60 (s, 1H), 3.72 (s, 3H), C{ H} NMR (100 MHz,
DMSO-d ) δ (ppm) 160.0, 156.8, 136.7, 136.3, 134.5, 133.9, 131.4, 129.6, 128.7, 128.4, 126.2,
6
-
1
1
2 2
26.1, 124.6, 120.6, 120.3, 12.0.0, 118.1, 116.9, 114.9, 112.0, 58.0, 55.9, 55.0, IR (CH Cl , cm ):
3
430, 3325, 2198, 1661, 1638, 1597, 1491, 1451, 1400, 1358, 1173, 757, HRMS (ESI-TOF) m/z:
+
[
M + Na] Calcd for C25
H N
19 3
O
4
SNa 480.0994; Found 480.0996.
(R)-2-amino-4-(4-methoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carb
25
o
onitrile (4l): white solid, 41 mg, 90% yield, ee 92%, [α]
D
= -302.95 (c 0.1, DCM), m.p. >200 C,
1H NMR (600 MHz, DMSO-d
) δ (ppm) 8.02 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.58 (d,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
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J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 15.6, 7.8 Hz, 3H), 7.38 (t, J = 7.8 Hz, 1H),
1
3
1
7
.05 (s, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.19 (s, 1H), 3.74 (s, 3H), C{ H}
NMR (150 MHz, DMSO-d ) δ (ppm) 159.1, 158.3, 136.1, 136.1, 135.9, 134.5, 134.0, 129.5, 128.5,
6
-
1
1
2 2
26.4, 126.3, 124.7, 120.3, 112.0, 119.0, 117.0, 115.0, 113.9, 59.4, 55.1, IR (CH Cl , cm ): 3424,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
301, 2196, 1656, 1632, 1591, 1507, 1444, 1404, 1359, 1168, 743, HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C25
H
19
N
3
4
O SNa 480.0994; Found 480.0996.
(R)-2-amino-5-(phenylsulfonyl)-4-(o-tolyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile
25
o
1
(
4m): white solid, 35 mg, 79% yield, ee 83%, [α]
) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (d, J
7.6 Hz, 1H), 7.51-7.36 (m, 6H), 7.24 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.05 (s, 2H),
D
= -30.95 (c 0.1, DCM), m.p. >200 C, H
NMR (400 MHz, DMSO-d
6
=
13
1
7
.02 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.61 (s, 1H), 2.58 (s, 3H), C{ H} NMR (100
MHz, DMSO-d ) δ (ppm) 159.3, 142.2, 136.6, 136.2, 135.1, 134.6, 133.8, 130.6, 129.6, 127.7,
2
126.8, 126.7, 126.5, 126.3, 124.7, 120.1, 120.1, 118.7, 117.0, 114.9, 58.6, 54.9, 18.8, IR (CH Cl ,
6
2
-
1
cm ): 3427, 3307, 2190, 1656, 1626, 1594, 1490, 1449, 1398, 1362, 1168, 723, HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C25
H
19
N
3
O
3
SNa 464.1045; Found 464.1046.
(R)-2-amino-5-(phenylsulfonyl)-4-(p-tolyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile
25
o
1
(
4n): white solid, 38 mg, 86% yield, ee 87%, [α]
D
= -305.95 (c 0.1, DCM), m.p. >200 C, H
NMR (600 MHz, DMSO-d
6
) δ (ppm) 8.03 (d, J = 18.0 Hz, 1H), 7.70-7.30 (m, 9H), 7.16-7.05 (m,
1
3
1
4
1
H), 6.99 (s, 2H), 5.20 (s, 1H), 2.29 (s, 3H), C{ H} NMR (150 MHz, DMSO-d
6
) δ (ppm) 159.2,
40.8, 136.3, 136.1, 134.5, 134.0, 129.5, 129.1, 127.3, 126.4, 126.3, 124.7, 120.3, 119.9, 118.7,
-
1
1
1
4
17.0, 115.0, 59.2, 20.63, IR (CH
2
Cl
2
, cm ): 3410, 3324, 2193, 1659, 1634, 1596, 1447, 1508,
+
447, 1400, 1371, 1174, 763, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C25
H
19
N
3
O
3
SNa
64.1045; Found 464.1044.
(R)-2-amino-4-(4-isopropylphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-car
25
bonitrile (4o): white solid, 41 mg, 87% yield, ee 85%, [α]
D
= -245.96 (c 0.1, DCM), m.p. >200
o
1
C, H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.03 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),
7
.56-7.51 (m, 3H), 7.48-7.36 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.08 (s, 2H), 7.04 (d, J = 8.0 Hz,
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H), 5.22 (s, 1H), 2.92-2.81 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H), 13C{ H} NMR (100 MHz,
DMSO-d ) δ (ppm) 159.4, 147.2, 141.2, 136.1, 134.6, 133.9, 129.5, 127.3, 126.5, 126.5, 126.3,
6
-
1
1
24.7, 120.3, 120.0, 118.8, 117.1, 115.0, 99.5, 59.3, 33.05, 23.86, IR (CH
2
Cl
2
, cm ): 3457, 3353,
+
2
190, 1654, 1621, 1586, 1450, 1404, 1365, 1167, 749, HRMS (ESI-TOF) m/z: [M + Na] Calcd
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23 3 3
for C27H N O SNa 492.1358; Found 492.1361.
(
R)-2-amino-4-(3,4-dimethoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-c
25
arbonitrile (4p): white solid, 39 mg, 80% yield, ee 94%, [α]
D
= -158.97 (c 0.1, DCM),
o
1
m.p. >200 C, H NMR (400 MHz, DMSO-d
6
) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.63-7.54 (m,
3
H), 7.51 (d, J = 7.6 Hz, 1H), 7.48-7.36 (m, 4H), 7.04 (s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.67 (d, J
2.0 Hz, 1H), 6.59 (dd, J = 8.4, 2.0 Hz, 1H), 5.19 (s, 1H), 3.74 (s, 3H), 3.61 (s, 3H), 13C{ H}
1
=
NMR (100 MHz, DMSO-d
6
) δ (ppm) 159.2, 148.5, 148.0, 136.2, 136.0, 134.5, 134.1, 129.4, 126.3,
-
1
1
24.7, 120.2, 112.0, 119.6, 118.8, 117.1, 115.0, 112.0, 111.5, 59.3, 55.5, 55.4, IR (CH Cl , cm ):
2 2
3419, 3354, 2190, 1646, 1611, 1591, 1513, 1448, 1400, 1366, 1169, 718, HRMS (ESI-TOF) m/z:
+
[M + Na] Calcd for C26
H N
21 3
O
5
SNa 510.1100; Found 510.1102.
(R)-2-amino-4-(furan-2-yl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile
25
o
1
(4q): white solid, 34 mg, 81% yield, ee 89%, [α]
NMR (400 MHz, DMSO-d ) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.64 (t, J
7.6 Hz, 1H), 7.54-7.43 (m, 5H), 7.38 (t, J = 7.6 Hz, 1H), 7.21 (s, 2H), 6.42 (dd, J = 2.8, 2.0 Hz,
D
= -127.98 (c 0.1, DCM), m.p. >200 C, H
6
=
1
1
1
H), 6.27 (d, J = 3.2 Hz, 1H), 5.46 (s, 1H), 13C{ H} NMR (100 MHz, DMSO-d
6
) δ (ppm) 160.3,
54.3, 142.4, 136.5, 136.0, 134.7, 134.0, 129.7, 126.5, 126.5, 124.8, 120.3, 119.8, 1171, 116.1,
-
1
115.1, 110.7, 106.6, 56.0, 33.1, IR (CH
2
Cl
2
, cm ): 3458, 3356, 2187, 1649, 1610, 1591, 1455,
+
1
403, 1368, 1169, 744, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C22
H
15
N
3
4
O SNa 440.0681;
Found 440.0682.
(
R)-2-amino-5-(phenylsulfonyl)-4-(thiophen-2-yl)-4,5-dihydropyrano[3,2-b]indole-3-carbonit
25
o
1
rile (4r): white solid, 36 mg, 83% yield, ee 95%, [α]
D
= -147.98 (c 0.1, DCM), m.p. >200 C, H
6
NMR (400 MHz, DMSO-d ) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.66-7.61 (m, 3H), 7.51 (d, J = 8.0
Hz, 1H), 7.49-7.45 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 2.0 Hz,
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
1
H), 7.16 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 5.29 (s, 1H), 13C{ H} NMR (100 MHz, DMSO-d
6
) δ
(
ppm) 159.3, 146.4, 136.5, 136.0, 134.7, 134.1, 130.9, 130.0, 129.6, 126.6, 126.4, 124.9, 121.7,
-
1
1
1
4
20.2, 119.7, 117.5, 117.2, 115.1, 58.5, 38.7, IR (CH
2
Cl
2
, cm ): 3426, 3323, 2193, 1658, 1635,
+
593, 1449, 1410, 1372, 1170, 747, HRMS (ESI-TOF) m/z: [M + Na] Calcd for C22
H
15
N
3
O
3
S
2
Na
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
56.0453; Found 456.0451.
(
R)-2-amino-8-chloro-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carboni
25
o
1
trile (4s): white solid, 35 mg, 76% yield, ee 86%, [α]
D
= +59.99 (c 0.1, DCM), m.p. >200 C, H
6
NMR (400 MHz, DMSO-d ) δ (ppm) 8.05 (d, J = 9.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (dd, J
13
1
=
8.8, 1.2 Hz, 2H), 7.52-7.41 (m, 4H), 7.35-7.25 (m, 3H), 7.13-7.09 (m, 4H), 5.24 (s, 1H), C{ H}
6
NMR (100 MHz, DMSO-d ) δ (ppm) 159.1, 143.5, 135.9, 135.3, 134.8, 132.4, 129.7, 129.3, 128.6,
-
1
1
2 2
27.5, 127.2, 126.5, 126.3, 121.5, 120.3, 119.7, 116.7, 116.5, 59.1, 54.9, IR (CH Cl , cm ): 3431,
3
326, 2203, 1731, 1661, 1635, 1598, 1448, 1407, 1366, 1173, 714, HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C24
H
16
N
3
3
O SClNa 484.0499; Found 484.0498.
(R)-2-amino-7-bromo-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carboni
25
o
trile (4t): white solid, 39 mg , 77% yield, ee 80%, [α]
D
= +130.98 (c 0.1, DCM), m.p. >200 C,
1H NMR (400 MHz, DMSO-d
) δ (ppm) 8.13 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 7.2 Hz
6
1
3
H), 7.48 (t, J = 8.4 Hz, 3H), 7.34-7.23 (m, 3H), 7.11 (d, J = 8.0 Hz, 4H), 5.21 (s, 1H), 13C{ H}
6
NMR (100 MHz, DMSO-d ) δ (ppm) 159.1, 143.5, 135.9, 135.9, 134.9, 134.6, 129.8, 128.6, 127.9,
-
1
1
27.4, 127.2, 126.4, 119.8, 119.4, 119.3, 119.0, 118.9, 117.4, 59.1, 58.0, IR (CH
2 2
Cl , cm ): 3428,
3
328, 2204, 1731, 1662, 1599, 1449, 1401, 1361, 1170, 720, HRMS (ESI-TOF) m/z: [M + Na]+
16 3 3
Calcd for C24H N O SBrNa 527.9993; Found 527.9992.
(
R)-2-amino-8-(benzyloxy)-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-ca
2
5
rbonitrile (4u): white solid, 42 mg , 79% yield, ee 93%, [α]
D
= +56.99 (c 0.1, DCM), m.p. >200
) δ (ppm) 7.94 (d, J = 9.2 Hz, 1H), 7.65-7.55 (m, 3H),
.49-7.43 (m, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.36-7.29 (m, 3H), 7.26 (t, J = 7.2 Hz, 1H), 7.17-7.10
o
1
C, H NMR (400 MHz, DMSO-d
6
7
m, 3H), 7.08 (s, 2H), 7.01 (d, J = 2.4 Hz, 1H), 5.23 (s, 1H), 5.15 (s, 2H), 13C{ H} NMR (100
1
(
MHz, DMSO-d
6
) δ (ppm) 159.3, 155.9, 143.8, 136.8, 136.5, 135.9, 134.5, 129.6, 128.6, 128.5,
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4
5
6
7
8
9
1
27.9, 127.6, 127.4, 127.1, 126.4, 121.4, 119.9, 119.3, 116.4, 115.9, 100.4, 69.7, 59.1, 54.9, IR
-
1
(CH
2
Cl
2
, cm ): 3424, 3330, 2198, 1660, 1637, 1595, 1487, 1450, 1411, 1360, 1155, 698, HRMS
+
(ESI-TOF) m/z: [M + Na] Calcd for C31
H
23
N
3
O
4
SNa 556.1307; Found 556.1309.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-2-amino-5-(methylsulfonyl)-4-phenyl-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4v):
o
25
1
white solid, 32 mg , 88% yield, ee 80%, m.p. >200 C, [α]
400 MHz, DMSO-d ) δ (ppm) 7.88 (dd, J = 6.4, 2.0 Hz, 1H), 7.66-7.61 (m, 1H), 7.48-7.41 (m,
H), 7.33 (t, J = 7.2 Hz, 2H), 7.26 (dt, J = 7.2, 1.2 Hz,1H), 7.15-7.04 (m, 4H), 5.07 (s, 1H), 2.81 (s,
D
= +42.99 (c 0.1, DCM), H NMR
(
6
2
3
1
3
H), 13C{ H} NMR (100 MHz, DMSO-d
1
) δ (ppm) 159.4, 143.5, 134.6, 133.7, 128.6, 127.6,
6
-1
27.2, 126.0, 124.2, 120.0, 119.6, 118.6, 116.9, 114.2, 59.1, 39.8, 38.8, IR (CH
Cl
2 2
, cm ): 3421,
328, 2194, 1729, 1660, 1638, 1595, 1489, 1451, 1407, 1364, 1166, 749, HRMS (ESI-TOF) m/z:
+
[
M + Na] Calcd for C19
H N
15 3
O
3
SNa 388.0732; Found 388.0733.
(R)-5-acetyl-2-amino-4-phenyl-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4w): white
25
o
1
solid, 21 mg , 64% yield, ee 96%, [α]
D
= +121.98 (c 0.1, DCM), m.p. >200 C, H NMR (600
MHz, DMSO-d ) δ (ppm) 8.07 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.45-7.42 (m, 1H),
6
7.40 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 4H),
5.29 (s, 1H), 3.34 (s, 3H), 13C{ H} NMR (150 MHz, DMSO-d
1
) δ (ppm) 169.4, 159.4, 143.6,
6
1
35.3, 133.4, 128.8, 127.0, 125.9, 123.7, 120.2, 119.4, 117.8, 116.5, 116.0, 59.0, 55.0, 26.5, IR
-
1
(CH
2
Cl
2
, cm ): 3374, 3209, 2201, 1695, 1662, 1600, 1455, 1401, 1373, 699, HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C20
H
15
N
3
O
2
Na 352.1062; Found 352.1065.
Ethyl 2-amino-3-cyano-5-(phenylsulfonyl)-4,5-dihydropyrano [3,2-b]indole- 4-carboxylate
o
1
(4x): white solid, 30 mg, 71% yield, ee 0%, m.p. 178-180 C, H NMR (400 MHz, CDCl
3
) δ (ppm)
.00 (d, J = 8.4, 1H), 7.82 (d, J = 7.6, 2H), 7.55 (t, J = 7.6, 1H), 7.45 (q, J = 8.0, 3H), 7.36 (t, J =
.6, 1H), 7.27 (t, J = 7.6, 1H), 4.94 (s, 2H), 4.91 (s, 1H), 4.37-4.25 (m, 2H), 1.36 (t, J = 7.2, 3H),
8
7
13
1
C{ H} NMR (100 MHz, CDCl
3
) δ (ppm) 170.1, 160.7, 138.0, 136.4, 134.2, 134.2, 129.4, 126.8,
-1
1
26.4, 124.2, 120.0, 118.6, 117.48, 114.5, 113.8, 62.2, 55.9, 39.6, 14.2, IR (CH
Cl
2 2
, cm ): 3476,
3
342, 2195, 1733, 1663, 1625, 1583, 1452, 1412, 1364, 1181, 746, HRMS (ESI-TOF) m/z: [M +
+
Na] Cacld for C21
H
17
N
3
O
5
SNa 446.0787; Found 446.0784.
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ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
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Antibacterial activity of compound 4;
Assignment of the absolute configuration of compound 4a by TD-DFT calculation;
NMR spectra of substrate 1;
NMR spectra, HPLC chromatograms and IR spectra for products 4.
AUTHOR INFORMATION
Corresponding Authors
*
*
E-mail: hanbo@cdutcm.edu.cn.
E-mail: raocl@cdutcm.edu.cn.
ORCID
Bo Han: 0000-0003-3200-4682
Author Contributions
§J. Z. and B. W. contributed equally to this work.
Notes
The authors declare no competing financial interest
ACKNOWLEGEMENTS
We are grateful for financial support from the National Natural Science Foundation of China
(81573588, 81773889, 81630101), the Science & Technology Department of Sichuan Province
(2017JZYD0001, 2017JY0323, 2018JY0255).
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