Core scaffold-inspired stereoselective synthesis of spiropyrazolones via an organocatalytic Michael/cyclization sequence

Article abstract of DOI:10.1021/jo301851a

Herein, the organocatalytic asymmetric Michael/cyclization sequence of α-isothiocyanato imides and esters with a variety of unsaturated pyrazolones is presented, in general, affording functionalized spiropyrazolones containing three contiguous stereogenic

Full text of DOI:10.1021/jo301851a

Article
pubs.acs.org/joc
Core Scaffold-Inspired Stereoselective Synthesis of Spiropyrazolones
via an Organocatalytic Michael/Cyclization Sequence
Luping Liu, Yuan Zhong, Panpan Zhang, Xianxing Jiang,* and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Institute of Biochemistry
and Molecular Biology, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China 730000
S
* Supporting Information
ABSTRACT: Herein, the organocatalytic asymmetric Michael/
cyclization sequence of α-isothiocyanato imides and esters with a
variety of unsaturated pyrazolones is presented, in general,
affording functionalized spiropyrazolones containing three
contiguous stereogenic centers in high levels of diastereo- and
enantioselectivity (up to 20:1 dr and 99% ee). Moreover, the
current protocol provides a highly efficient and convenient
strategy that allows rapid enantioselective construction of
diversely spiropyrazolone skeletons with high optical purity.
Scheme 1. Biologically Active Pyrazolone Derivatives and
Pyrrolidone-Type Spiropyrazolones
INTRODUCTION
■
Pyrazol-3-ones are important structural motifs in organic
synthesis and have been found as key backbones, commonly
shown by a series of biological assays to have potent biological
and pharmaceutical activities, including anti-inflammatory,
antibacterial, HIV inhibition, and clinically useful antitumor
activity.1 Significantly, optically active pyrazolone derivatives as
important synthetic intermediates or products have attracted
intense interest from chemists in recent years.2 Therefore, the
development of highly efficient synthetic methods to access
optically active pyrazolones, in particular spiropyrazolones,
would be of great utility for target-oriented organic synthesis
(Scheme 1). However, this represents a considerable difficulty
due to the synthetic challenges presented by spiro-motifs,
including incorporating heterocycles and obtaining high
enantioselectivity.
To date, although the preparation of such kinds of
pyrazolone skeletons has been partly addressed in elegant
works because of its significant bioactivity,2 the asymmetric
catalytic approaches to access chiral pyrazolones at the C4
position are scarce and only a few examples have been
documented. Especially, the asymmetric synthesis of spiropyr-
azolones via a catalytic cascade approach still remains
challenging. To the best of our knowledge, only one report
of their efficient asymmetric synthesis via an intermolecular
Michael−aldol reaction of aldehydes has been described.2k
Inspired by Feng and co-workers' recent report on the synthesis
of pyrazolone derivatives bearing a quaternary stereocenter at
the C4 position3 by using a metal/N,N′-dioxide complex, we
considered whether the enantioselective construction of this
new type of spiropyrazolone could be achieved via a common
but more efficient bifunctional organocatalytic cascade
cyclization approach,4 thereby providing an elegant starting
point to discover new reaction modes (Figure 1). For these
reasons, in this text, we present our results on this topic.
Recently, α-isothiocyanato imides or esters have emerged as
some of the most attractive reactants in asymmetric organo-
metallic or organocatalytic cascade reactions to furnish masked
chiral β-hydroxyl-α-amino and α,β-diamino acid derivatives.5
Received: August 31, 2012
Published: October 16, 2012
© 2012 American Chemical Society
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a
Table 1. Screening of Reaction Conditions
Figure 1. Proposed model for asymmetric construction of
spiropyrazolones.
Surprisingly, among these protocols, the variant of a catalytic
enantioselective Michael addition6/cyclization sequence of α-
isothiocyanato imides showed a substrate-dependent character-
istic. Notably, methyleneindolinone was employed as an
exclusively suitable Michael acceptor in all of the above related
asymmetric cascade cyclizations.7 Herein, we present a highly
enantioselective [3 + 2] cycloaddition of α-isothiocyanato
imides with unsaturated pyrazolones by using rosin-derived
tertiary amine-thiourea to form functionalized spiropyrazolones
bearing three contiguous stereogenic centers with high levels of
enantio- and diastereoselectivity (up to 20:1 dr and 99% ee).
b
c
entry
catalyst
solvent
yield (%)
ee (%)
dr
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1a
1a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
99
96
10:1
10:1
n.d.
89
86
trace
54
n.d.
65
10:1
10:1
10:1
10:1
n.d.
RESULTS AND DISCUSSION
■
47
78
On the basis of our recent success with the Michael cyclization
reaction of α-isothiocyanato imides 3a by employing rosin-
derived bifunctional thiourea catalysis,8,9 and to gain a better
understanding of the scope of this conceptually catalytic
system, we hoped to expand our studies beyond model
compounds to develop an efficient protocol for accessing
functionalized spiropyrazolones.10 We selected the unsaturated
pyrazolone 2a as a model substrate to start our investigation.
Satisfyingly, we obtained the desired product 4a in high yield
and enantio- and diastereoselectivity (99% yield, 96% ee, and
10:1 dr) in the presence of 15 mol % of 1a at room temperature
in CH2Cl2 (entry 1, Table 1). Subsequently, other available
organocatalysts 1b−e were also evaluated (entries 2−5, Table
1). Although tertiary amine-thiourea 1b, 1d, and 1e could
provide the products, relatively low yields and enantioselecti-
vites were observed. In contrast, thiourea catalyst 1c proved to
be essentially inactive for this transformation (entry 3, Table 1).
Further screening of solvents indicated that CH2Cl2 proved to
be the most suitable reaction media for this asymmetric
process.
95
95
toluene
MeOH
98
90
trace
n.d.
a
Unless noted, the reaction was conducted with 2a (0.10 mmol) and
3a (0.11 mmol) with 15 mol % catalyst at room temperature for 2 h.
The ee values were determined by HPLC. The dr values were
b
c
1
determined by H NMR.
better results in terms of yield and stereochemical outcome. In
addition, the results suggested that the rigid skeleton of the
isoxazolidinone functional group is necesssary for stereocontrol
in this reaction. When methyl isothiocyanato acetate was
employed, the reaction afforded 4q with 71% ee and 3:1 dr.
The absolute and relative configurations of this kind of
spiropyrazolones were unambiguously determined by X-ray
crystallography of 4a (see Supporting Information).
With the successful construction of chiral spiropyrazolone
skeletons as described above, the transformation of the
cycloadduct to a number of valuable compounds was
performed. As illustrated in Scheme 3, product 4a could be
converted smoothly into 5a containing three adjacent chiral
centers through a simple oxidant treatment6a in 98% yield with
a slight loss of enantioselectivity. 4a could also be transformed
to 6a possessing a potential medical skeleton in high yield
(91%) and enantioselectivity (88% ee) under the established
method.5k In addition, conversion of the isoxazolidinone group
proved straightforward. The isoxazolidinone functional group
could be easily transformed into the ester by treatment of 4a
with MeMgI and ethanol in THF, affording 7a in 93% yield and
88% ee. These representative examples demonstrate the
inherent synthetic potential of this methodology.
The results of experiments under optimized conditions that
probed the scope of the reaction are summarized in Scheme 2.
In general, various unsaturated aromatic pyrazolones having
different electronic and steric parameters were tolerated and
gave the corresponding products in good to excellent yields
(71−99%, 4b−p) and diastereoselectivities and high enantio-
selectivities (81−99% ee, 4b−p). Notably, an increase in the
steric hindrance of the R2 group could markedly affect the yield
and stereochemical outcome of the product. When a bulkier 1-
naphthyl group was introduced into R2, 4b was formed with
only 4:1 dr in 72% yield and 81% ee. As expected, the
unsaturated heterocyclic pyrazolones have also proven to be
suitable substrates for this asymmetric process. Although 2-
furyl-substituted pyrazolone gave 4:1 dr, good to excellent
enantioselectivities and yields were still obtained (4l and 4m).
Compared to the planar structure of the furan ring, the
nonplanar structural nature of the thiophene ring could lead to
As a preliminary study, we also decided to evaluate the
biological activities11 of this new kind of spiropyrazolone,
thereby providing a basis for scaffold-inspired synthesis and
further development of new types of candidates for future
biomedical utilities. We chose some representative compounds
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a
Scheme 2. Scope of Substrates
a
The spiropyrazolones with three adjacent stereocenters synthesized by optimal reaction conditions. The ee values were determined by chiral-phase
1
HPLC analysis and the dr values were determined by H NMR.
(4a, 4c, 4e, 4f, and 4i), which were evaluated for their
cytotoxicity in vitro toward the human T-cell leukemia cell line
(jurkat), human cervical cancer cell line (Hela), and human
bladder cancer cell line (5637). We found that 4e exhibited
obvious antiproliferative activity, and detailed results are
presented in the Supporting Information.
biological activity relationships are underway in our group and
will be reported in due course.
EXPERIMENTAL SECTION
■
General Information. All solvents were dried according to
established procedures. Reactions were monitored by thin layer
chromatography (TLC), and column chromatography purifications
were carried out using silica gel GF254. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a 300 MHz
spectrometer in CDCl3, and carbon nuclear magnetic resonance
(13C NMR) spectra were recorded on a 300 MHz spectrometer in
CDCl3 using tetramethylsilane (TMS) as internal standard unless
otherwise noted. Data are presented as follows: chemical shift,
integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), and coupling constant in hertz (Hz).
Infrared (IR) spectra were recorded on an FT-IR spectrometer.
Optical rotations were recorded on a polarimeter. HRMS was
CONCLUSION
■
We have disclosed the synthesis of highly optically active
spiropyrazolones with high levels of enantio- and diastereose-
lectivity (up to 20:1 dr and 99% ee) through an organo-
catalyzed asymmetric [3 + 2] Michael/cyclization sequence of
α-isothiocyanato imides and esters with various unsaturated
pyrazolones. Additional investigations involving the application
of this catalytic approach and intensive studies on structure−
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2923.0, 1781.4, 1704.6, 1498.9, 1391.0, 1363.2, 1298.3, 1263.0, 1222.0,
1123.7, 757.9, 736.0, 695.3 cm−1. HPLC: ee of major diastereoisomer
was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
50/50, 1.0 mL/min, 240 nm), retention time: tminor = 30.60 min, tmajor
= 37.87 min, ee = −81%.
Scheme 3. Construction of Other Chiral Spiropyrazolones
Frameworks
4c: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 90% yield (42 mg). White solid, mp 144−146 °C; [α]20
D
= 2.88 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.84 (br s, 1
H), 7.89−7.91 (d, J = 7.8 Hz, 2 H), 7.38−7.43 (m, 2 H), 7.18−7.26
(m, 3 H), 7.01−7.06 (m, 2 H), 6.41−6.43 (d, J = 6.3 Hz, 1 H), 4.84−
4.86 (d, J = 6.3 Hz, 1 H), 4.31 (br s, 1 H), 4.04 (br s, 1 H), 3.86 (br s,
1 H), 3.31 (br s, 1 H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
195.3, 169.9, 167.5, 157.1, 152.2, 137.4, 130.6, 130.5, 130.2, 128.9,
125.5, 119.0, 116.3, 116.0, 76.3, 67.7, 63.1, 52.4, 42.3, 17.4. HRMS-ESI
(m/z): calcd for C23H19FN4O4S+H+: 467.1184; found: 467.1181, 0.6
ppm. IR: 2921.7, 1782.6, 1704.7, 1499.0, 1390.3, 1363.6, 1267.0,
1219.2, 1121.7, 1037.0, 757.5, 738.2, 693.4 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H, i-
PrOH/hexane = 40/60, 1.0 mL/min, 240 nm), retention time: tmajor
=
20.38 min, ee = >99%.
4d: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 91% yield (44 mg). White solid, mp 124−126 °C; [α]20
D
= 4.00 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.85 (br s, 1
H), 7.88−7.91 (d, J = 8.7 Hz, 2 H), 7.38−7.43 (t, J = 15.9 Hz, 2 H),
7.30−7.33 (m, 2 H), 7.19−7.23 (m, 3 H), 6.40−6.43 (d, J = 6.9 Hz, 1
H), 4.82−4.85 (d, J = 6.6 Hz, 1 H), 4.27−4.35 (m, 1 H), 4.02−4.11
(m, 1 H), 3.79−3.88 (m, 1H), 3.29−3.37 (m, 1H), 1.41 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 195.2, 169.9, 167.4, 157.0, 152.2, 137.4,
135.3, 132.7, 130.0, 129.3, 128.9, 125.5, 118.9, 76.2, 67.6, 63.0, 53.5,
42.3, 17.4. HRMS-ESI (m/z): calcd for C23H19ClN4O4S+H+:
483.0888; found: 483.0891, 0.5 ppm. IR: 3277.2, 2921.9, 1781.4,
1703.3, 1497.6, 1390.7, 1364.6, 1267.7, 1218.5, 1122.4, 1095.7, 1036.5,
757.7, 690.2 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
40/60, 1.0 mL/min, 255 nm), retention time: tminor = 18.47 min, tmajor
= 11.63 min, ee = 98%.
measured with a mass spectrometer, and the mass analyzer type is Q-
Tof. The ee value determination was carried out using chiral high-
performance liquid chromatography (HPLC) with Daicel Chiracel
AD-H column on Waters with a 2998 UV-detector, and the dr values
1
were determined by 300 Hz H NMR.
Representative Procedure for the Asymmetric Michael/
Cyclization Reactions. Catalyst 1a (0.015 mmol, 15 mol %), 4-
benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 2a (0.1 mmol,
1.0 equiv), and α-isothiocyanato imide 3a (0.11 mmol, 1.1 equiv) were
dissolved in 1.0 mL of CH2Cl2 at room temperature. After the reaction
was completed (monitored by TLC), the resulting mixture was
concentrated under reduced pressure and the residue was purified by
column chromatography on silica gel (CH2Cl2/EtOAc, 100:8) to
afford the product. The enantiomeric purity of the product was
4e: The title compound was isolated as a mixture of
1
determined by HPLC, and the dr value was determined by H NMR
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
spectroscopy (300 Hz). 4b−q were prepared using the same method.
4a: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 99% yield (52 mg). White solid, mp 181−183 °C; [α]20
D
= 2.8 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.89 (br s, 1
H), 7.88−7.91 (d, J = 8.4 Hz, 2 H), 7.38−7.49 (m, 4 H), 7.13−7.23
(m, 3 H), 6.41−6.43 (d, J = 6.6 Hz, 1 H), 4.81−4.84 (d, J = 6.6 Hz, 1
H), 4.27−4.32 (m, 1 H), 4.02−4.11 (m, 1 H), 3.82−3.88 (m, 1 H),
3.29−3.38 (m, 1 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ
195.1, 169.9, 167.4, 157.0, 152.2, 137.3, 133.2, 132.3, 130.3, 128.8,
125.5, 123.4, 118.9, 76.1, 67.5, 63.0, 52.5, 42.3, 17.5. HRMS-ESI (m/
z): calcd for C23H19BrN4O4S+H+: 527.0383; found: 527.0388, 0.9
ppm. IR: 3279.6, 2922.1, 1782.2, 1703.5, 1595.2, 1498.3, 1390.9,
1364.8, 1268.1, 1218.5, 1123.1, 1036.8, 758.0, 708.7, 690.3 cm−1.
HPLC: ee of major diastereoisomer was determined by HPLC analysis
(Chiralcel AD-H, i-PrOH/hexane = 40/60, 1.0 mL/min, 240 nm),
retention time: tminor = 25.65 min, tmajor = 17.26 min, ee = 99%.
4f: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 99% yield (44.5 mg). White solid, mp 139−140 °C;
1
[α]20 = 2.3 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 9.00
D
(br s, 0.09 H), 8.91 (br s, 0.86 H), 7.89−7.92 (d, J = 9.0 Hz, 2 H),
7.40−7.43 (t, J = 7.5 Hz, 2 H), 7.31−7.37 (m, 3 H), 7.18−7.25 (m, 3
H), 6.41−6.47 (m, 1 H), 4.81−4.86 (m, 1 H), 4.22−4.30 (m, 1 H),
3.76−3.96 (m, 2 H), 3.16−3.25 (m, 1H), 1.37 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 195.4, 170.1, 167.6, 157.4, 152.2, 137.4, 134.2, 129.3,
129.0, 128.8, 128.6, 125.4, 118.9, 76.4, 67.8, 63.0, 53.1, 42.3, 17.3.
HRMS-ESI (m/z): calcd for C23H20N4O4S+H+: 449.1278; found:
449.1281, 0.7 ppm. IR: 3276.7, 2923.6, 1782.5, 1705.4, 1595.9, 1498.7,
1391.8, 1363.8, 1268.2, 1220.4, 1038.1, 758.3, 735.9, 703.8, 654.8,
553.9 cm−1. HPLC: ee of major diastereoisomer was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane = 40/60, 1.0 mL/
min, 245 nm), retention time: tminor = 26.49 min, tmajor = 16.30 min, ee
= 96%.
100/8) in 85% yield (46 mg). White solid, mp 138−140 °C; [α]20
D
1
= 4.1 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.99 (br s,
4b: The title compound was isolated as a mixture of
0.11 H), 8.90 (br s, 0.88 H), 7.89−7.92 (d, J = 7.5 Hz, 2 H), 7.37−
7.42 (t, J = 15.9 Hz, 2 H), 7.17−7.22 (m, 1 H), 7.11 (br s, 4 H), 6.39−
6.45 (m, 1 H), 4.77−4.82 (m, 1 H), 4.23−4.28 (m, 1 H), 3.78−3.97
(m, 2 H), 3.21−3.29 (m, 1 H), 2.32 (s, 3 H), 1.38 (s, 3 H); 13C NMR
(75 MHz, CDCl3): δ 195.5, 170.1, 167.7, 157.6, 152.2, 139.2, 137.5,
131.1, 129.6, 128.8, 128.4, 125.3, 118.9, 76.5, 67.8, 63.0, 52.9, 42.3,
21.2, 17.3. HRMS-ESI (m/z): calcd for C24H22N4O4S+H+: 463.1435;
found: 463.1436, 0.4 ppm. IR: 3277.2, 2923.1, 1783.1, 1705.0, 1595.3,
1499.2, 1391.1, 1363.7, 1267.3, 1218.8, 1122.3, 1037.1, 758.1, 737.7,
693.0 cm−1. HPLC: ee of major diastereoisomer was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane = 40/60, 1.0 mL/
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 72% yield (36 mg). White solid, mp 151−152 °C; [α]20
D
1
= 1.45 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 9.00 (br s,
0.19 H), 8.95 (br s, 0.68 H), 7.84−7.95 (m, 5 H), 7.62−7.64 (d, J =
7.2 Hz, 1 H), 7.50−7.53 (m, 2 H), 7.39−7.44 (m, 3 H), 7.19−7.24 (m,
1 H), 6.64−6.68 (m, 1 H), 5.89−5.92 (d, J = 6.9 Hz, 1 H), 4.07−4.15
(m, 1 H), 3.47−3.82 (m, 2 H), 3.08−3.17 (m, 1 H), 1.06 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 195.6, 170.1, 167.8, 157.4, 152.2, 137.5,
133.7, 131.1, 130.0, 129.6, 129.0, 128.9, 127.6, 126.5, 125.5, 124.9,
122.1, 119.0, 77.2, 67.9, 62.7, 46.5, 42.2, 17.1. HRMS-ESI (m/z): calcd
for C27H22N4O4S+H+: 499.1435; found: 499.1438, 0.6 ppm. IR:
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min, 238 nm), retention time: Retention time: tminor = 33.72 min, tmajor
= 15.62, ee = 93%.
40/60, 1.0 mL/min, 240 nm), retention time: tminor = 32.52 min, tmajor
= 15.00 min, ee = 81%.
4g: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
4k: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 75% yield (38 mg). White solid, mp 179−181 °C;
100/8) in 95% yield (44.5 mg). White solid, mp 103−104 °C;
1
1
[α]20 = 3.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.92
[α]20D = 2.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.56
D
(br s, 0.08 H), 8.82 (br s, 0.82 H), 7.89−7.91 (d, J = 7.8 Hz, 2 H),
7.37−7.42 (t, J = 15.9 Hz, 2 H), 7.12−7.22 (m, 3 H), 7.01−7.04 (m, 2
H), 6.38−6.43 (m, 1 H), 4.76−4.80 (m, 1 H), 4.23−4.31 (m, 1 H),
3.80−3.95 (m, 2 H), 3.17−3.26 (m, 1 H), 2.30 (s, 3 H), 1.37 (s, 3 H);
13C NMR (75 MHz, CDCl3): δ 195.4, 170.1, 167.6, 157.5, 152.2,
138.9, 137.4, 134.1, 129.9, 129.2, 128.9, 128.8, 125.4, 125.3, 118.9,
76.4, 67.8, 63.0, 53.1, 42.3, 21.3, 17.2. HRMS-ESI (m/z): calcd for
C24H22N4O4S+H+: 463.1435; found: 463.1438, 0.7 ppm. IR: 3283.9,
2922.1, 1782.5, 1705.3, 1595.8, 1498.4, 1391.0, 1364.1, 1267.4, 1220.0,
1038.0, 757.7, 705.7 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane = 40/
(br s, 1 H), 8.46 (br s, 1 H), 7.91−7.94 (d, J = 7.8 Hz, 2 H), 7.38−7.42
(t, J = 15.9 Hz, 2 H), 7.17−7.22 (t, J = 14.7 Hz, 1 H), 6.77−6.86 (m, 3
H), 6.34−6.38 (m, 1 H), 5.17−5.19 (d, J = 7.5 Hz, 1 H), 4.25−4.34
(m, 1 H), 3.68−3.97 (m, 2 H), 3.72 (s, 3 H), 3.68 (s, 3 H), 3.26−3.33
(m, 1 H), 1.55 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ 196.1, 170.6,
167.7, 157.3, 153.1, 152.0, 151.4, 137.6, 128.8, 125.3, 123.5, 118.9,
115.6, 111.9, 77.20, 75.8, 67.0, 62.9, 55.8 55.4, 42.4, 16.6. HRMS-ESI
(m/z): calcd for C25H24N4O6S+H+: 509.1489; found: 509.1491, 0.3
ppm. IR: 2923.6, 1785.4, 1706.9, 1501.4, 1389.8, 1364.2, 1265.6,
1229.5, 1122.4, 1040.8, 740.4, 704.0 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H, i-
PrOH/hexane = 40/60, 1.0 mL/min, 240 nm), retention time: tminor
=
60, 1.0 mL/min, 255 nm), retention time: tminor = 43.20 min, tmajor
=
40.62 min, tmajor = 17.13 min, ee = 85%.
13.85 min, ee = 90%.
4l: The title compound was isolated as a mixture of
4h: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 71% yield (31 mg). White solid, mp 125−126 °C; [α]20
100/8) in 95% yield (45 mg). White solid, mp 132−134 °C; [α]20
D
D
= 2.8 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.67 (br s, 1
H), 7.87−7.90 (d, J = 7.8 Hz, 2 H), 7.37−7.42 (t, J = 15.9 Hz, 3 H),
7.17−7.22 (t, J = 14.7 Hz, 1 H), 6.25−6.35 (m, 2 H), 6.21−6.23 (m, 1
H), 5.00−5.04 (m, 1 H), 4.34−4.42 (m, 1 H), 4.13−4.22 (m, 1 H),
3.95−4.01 (m, 1 H), 3.52−3.61 (m, 1 H), 1.60 (br s, 3 H); 13C NMR
(75 MHz, CDCl3): δ 194.8, 169.9, 167.2, 157.5, 152.5, 147.6, 143.1,
137.4, 128.9, 125.5, 119.0, 111.1, 110.6, 77.2, 75.5, 65.5, 63.2, 46.3,
42.6, 15.3. HRMS-ESI (m/z): calcd for C21H18N4O5S+H+: 439.1071;
found: 439.1072, 0.3 ppm. IR: 2922.7, 1781.8, 1707.2, 1500.5, 1392.0,
1365.8, 1264.5, 1222.4, 1122.9, 1036.6, 738.2, 701.6 cm−1. HPLC: ee
of major diastereoisomer was determined by HPLC analysis (Chiralcel
AD-H, i-PrOH/hexane = 40/60, 1.0 mL/min, 255 nm), retention
time: tminor = 26.38 min, tmajor = 21.55 min, ee = 73%.
1
= 3.1 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.96 (br s,
0.10 H), 8.84 (br s, 0.85 H), 7.89−7.92 (d, J = 7.8 Hz, 2 H), 7.37−
7.42 (t, J = 15.9 Hz, 2 H), 7.19−7.22 (t, J = 7.5 Hz, 1 H), 7.04−7.07
(d, J = 7.5 Hz, 1 H), 6.93−6.96 (d, J = 8.1 Hz, 2 H), 6.37−6.43 (m, 1
H), 4.73−4.78 (m, 1 H), 4.23−4.31 (m, 1 H), 3.77−3.97 (m, 2 H),
3.21−3.29 (m, 1 H), 2.21−2.22 (d, J = 5.1 Hz, 6 H), 1.37 (s, 3 H); 13C
NMR (75 MHz, CDCl3): δ 195.4, 170.2, 167.6, 157.7, 152.2, 137.7,
137.5, 137.3, 131.4, 130.1, 129.7, 128.8, 125.7, 125.3, 118.9, 77.2, 67.8,
63.0, 52.9, 42.3, 19.6, 19.5, 17.3. HRMS-ESI (m/z): calcd for
C25H24N4O4S+H+: 477.1591; found: 477.1593, 0.4 ppm. IR: 3281.5,
2923.0, 1783.1, 1705.0, 1595.7, 1500.1, 1391.6, 1364.2, 1267.9, 1220.1,
1123.2, 1038.4, 757.8, 737.1, 695.2, 651.8 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H, i-
4m: The title compound was isolated as a mixture of
PrOH/hexane = 40/60, 1.0 mL/min, 255 nm), retention time: tminor
33.39 min, tmajor = 9.64 min, ee = 89%.
4i: The title compound was isolated as a mixture of
=
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 99% yield (45 mg). White solid, mp 128−130 °C; [α]20
D
1
= −2.1 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.87 (br s,
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 88% yield (42 mg). White solid, mp 123−124 °C; [α]20
0.07 H), 8.76 (br s, 0.94 H), 7.89−7.91 (d, J = 7.8 Hz, 2 H), 7.38−
7.43 (t, J = 15.9 Hz, 2 H), 7.18−7.24 (m, 2 H), 7.02−7.03 (m, 1 H),
6.96−6.99 (m, 1 H), 6.43−6.49 (m, 1 H), 5.13−5.18 (m, 1 H), 4.30−
4.38 (m, 1 H), 4.06−4.15 (m, 1 H), 3.85−3.94 (m, 1 H), 3.39−3.47
(m, 1 H), 1.49 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ 194.7, 169.4,
167.2, 157.3, 152.4, 137.4, 135.0, 128.8, 127.8, 125.7, 125.5, 119.0,
76.2, 67.6, 63.1, 48.0, 42.4, 16.6. HRMS-ESI (m/z): calcd for
C21H18N4O4S2+H+: 455.0842; found: 455.0847, 0.9 ppm. IR: 3281.4,
2921.0, 1780.6, 1703.5, 1594.9, 1498.1, 1391.2, 1363.8, 1299.6, 1259.7,
1219.9, 1122.0, 1036.7, 757.7, 694.9 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H, i-
D
1
= 6.0 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 9.06 (br s,
0.07 H), 9.00 (br s, 0.87 H), 7.89−7.92 (d, J = 7.8 Hz, 2 H), 7.37−
7.42 (t, J = 15.6 Hz, 2 H), 7.15−7.22 (m, 3 H), 6.82−6.85 (d, J = 8.7
Hz, 2 H), 6.39−6.45 (m, 1 H), 4.78−4.83 (m, 1 H), 4.24−4.31 (m, 1
H), 3.95−4.03 (m, 1 H), 3.78−3.87 (m, 1 H), 3.78 (s, 3 H), 3.24−3.33
(m, 1 H), 1.42 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ 195.4, 170.1,
167.7, 159.9, 157.7, 152.2, 137.5, 129.9, 128.8, 126.0, 125.3, 118.9,
114.2, 77.2, 67.8, 63.0, 55.2, 52.5, 42.3, 17.4. HRMS-ESI (m/z): calcd
for C24H22N4O5S+H+: 479.1384; found: 479.1386, 0.5 ppm. IR:
3054.3, 2926.5, 1786.8, 1706.1, 1595.9, 1497.8, 1390.4, 1364.6, 1265.1,
1122.0, 1035.2, 896.0, 739.8, 705.7 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H, i-
PrOH/hexane = 40/60, 1.0 mL/min, 255 nm), retention time: tminor
23.13 min, tmajor = 29.29 min, ee = 91%.
=
4n: The title compound was isolated as a mixture of
PrOH/hexane = 40/60, 1.0 mL/min, 255 nm), retention time: tminor
33.14 min, tmajor = 15.66 min, ee = 90%.
4j: The title compound was isolated as a mixture of
=
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 95% yield (45 mg). White solid, mp 93−95 °C; [α]20
=
D
2.7 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.95 (br s, 1 H),
7.91−7.94 (d, J = 7.8 Hz, 1.83 H), 7.69−7.71 (d, J = 7.8 Hz, 0.18
H),7.28−7.43 (m, 5 H), 7.07−7.24 (m, 3 H), 6.40−6.46 (m, 0.9 H),
5.96−5.98 (m, 0.1 H), 4.80−4.85 (m, 0.9 H), 4.60−4.63 (m, 0.1 H),
4.21−4.31 (m, 1 H), 3.76−3.94 (m, 2 H), 3.16−3.24 (m, 1 H), 1.34−
1.61 (m, 2 H), 0.93−0.99 (t, J = 15.3 Hz, 0.18 H), 0.75−0.86 (m, 1
H), 0.68−0.73 (t, J = 14.7 Hz, 2.74 H); 13C NMR (75 MHz, CDCl3):
δ 195.8, 170.2, 167.7, 160.1, 152.2, 137.7, 134.4, 129.2, 128.9, 128.8,
128.7, 125.2, 118.8, 76.6, 67.8, 63.0, 53.3, 42.3, 32.8, 18.1, 13.6.
HRMS-ESI (m/z): calcd for C25H24N4O4S+H+: 477.1591; found:
477.1607, 3.3 ppm. IR: 3287.6, 2963.6, 2929.9, 1783.8, 1704.8, 1597.0,
1498.4, 1390.9, 1359.9, 1268.4, 1220.2, 1124.4, 1037.1, 909.4, 733.8,
703.2, 649.1 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 88% yield (42 mg). White solid, mp 109−111 °C; [α]20
D
1
= 3.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 9.00 (br s,
0.09 H), 8.90 (br s, 0.87 H), 7.89−7.91 (d, J = 7.8 Hz, 2 H), 7.37−
7.42 (t, J = 15.9 Hz, 2 H), 7.12−7.22 (m, 3 H), 6.99−7.04 (m, 2 H),
6.38−6.44 (m, 1 H), 4.76−4.81 (m, 1 H), 4.22−4.30 (m, 1 H), 3.76−
3.95 (m, 2 H), 3.17−3.25 (m, 1 H), 2.30 (s, 3 H), 1.37 (s, 3 H); 13C
NMR (75 MHz, CDCl3): δ 195.3, 170.1, 167.6, 159.7, 157.4, 152.3,
137.4, 135.6, 130.1, 128.8, 125.4, 120.6, 118.9, 115.0, 113.7, 76.3, 67.7,
63.0, 53.3, 53.1, 42.3, 17.2.HRMS-ESI (m/z): calcd for C24H22N4O5S
+H+: 479.1384; found: 479.1387, 0.6 ppm. IR: 3280.8, 2923.9, 1782.2,
1705.3, 1597.0, 1497.0, 1391.4, 1364.3, 1265.8, 1122.7, 1038.7, 757.5,
737.0, 703.5 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
10232
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The Journal of Organic Chemistry
Article
40/60, 1.0 mL/min, 240 nm.) tminor = 28.99 min, tmajor = 14.64 min, ee
= 93%.
433.1508, 0.3 ppm. IR: 3309.1, 2920.5, 1779.1, 1682.9, 1594.0, 1495.7,
1392.7, 1361.8, 1300.1, 1231.6, 1206.3, 1127.8, 1106.9, 1036.5, 731.5,
701.1 cm−1. HPLC: ee of major diastereoisomer was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane = 50/50, 1.0 mL/
min, 240 nm), retention time: tminor = 28.73 min, tmajor = 15.63 min, ee
= 85%.
General Procedure for the Synthesis of 6a. To a mixture of 4a
(0.1 mmol, 44.8 mg) and anhydrous K2CO3 (1.10 equiv, 60 mg) in 2.5
mL of acetone was added MeI (2.0 equiv, 12.0 μL) at 0 °C. Then the
reaction was left overnight. After the reaction was completed
(monitored by TLC), the resulting mixture was concentrated under
reduced pressure and the residue was purified by column
chromatography on silica gel (CH2Cl2/EtOAc, 100:8) to afford the
product 6a.
4o: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 82% yield (40 mg). White solid, mp 114−116 °C; [α]20
D
= 0.9 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 9.12 (br s, 1
H), 7.55−7.57 (d, J = 8.4 Hz, 2 H), 7.29−7.33 (m, 3 H), 7.22−7.24
(m, 4 H), 7.06−7.11 (t, J = 14.7 Hz, 1 H), 6.15−6.22 (m, 1 H), 4.92−
4.97 (m, 1 H), 4.00−4.23 (m, 2 H), 3.55−3.80 (m, 2 H), 1.51 (s, 9
H); 13C NMR (75 MHz, CDCl3): δ 198.2, 168.5, 168.4, 165.9, 152.6,
137.4, 131.9, 130.6, 128.7, 128.5, 127.8, 125.1, 119.3, 77.4, 77.2, 66.3,
63.0, 50.0, 42.4, 36.7, 30.4. HRMS-ESI (m/z): calcd for C26H26N4O4S
+H+: 491.1748; found: 491.1767, 4.0 ppm. IR: 3282.9, 2964.4, 2925.1,
1780.2, 1715.9, 1596.3, 1499.3, 1392.8, 1366.6, 1283.1, 1222.6, 1119.3,
1037.0, 911.5, 756.8, 733.5, 703.8 cm−1. HPLC: ee of major
diastereoisomer was determined by HPLC analysis (Chiralcel AD-H,
i-PrOH/hexane = 40/60, 1.0 mL/min, 240 nm), retention time: tminor
= 14.80 min, tmajor = 48.49 min, ee = 95%.
6a: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 91% yield (42 mg). White solid, mp 61−63 °C; [α]20
=
D
1.1 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.70−7.88 (d, J
= 6.0 Hz, 1.47 H), 7.67−7.70 (d, J = 7.8 Hz, 0.65 H), 7.11−7.29 (m, 8
H), 6.53−6.56 (d, J = 7.2 Hz, 0.68 H), 6.27−6.29 (d, J = 8.4 Hz, 0.30
H), 4.82−4.85 (d, J = 7.5 Hz, 0.68 H), 4.53−4.56 (d, J = 8.4 Hz, 0.36
H), 4.21−4.30 (m, 1 H), 3.82−3.98 (m, 2 H), 3.23−3.37 (m, 1 H),
2.65 (s, 3 H), 2.25 (s, 0.96 H), 1.48 (s, 2.32 H); 13C NMR (75 MHz,
CDCl3): δ 170.4, 170.2, 169.5, 169.2, 168.6, 166.8, 157.1, 155.9, 153.0,
152.5, 137.5, 134.5, 132.2, 130.1, 129.1, 128.8, 128.7, 128.6, 128.5,
127.6, 125.3, 125.2, 118.9, 118.7, 79.0, 78.5, 76.6, 75.1, 62.5, 62.4, 57.8,
55.8, 42.4, 42.3, 17.5, 14.3, 14.2, 13.9. HRMS-ESI (m/z): calcd for
C24H22N4O4S+H+: 463.1453; found: 463.1436, 0.2 ppm. IR: 3418.2,
2957.0, 2925.5, 1826.7, 1752.8, 1715.7, 1595.4, 1553.0, 1498.1, 1439.4,
1409.2, 1365.7, 1314.2, 1265.5, 1121.1, 1051.2, 758.9, 736.7, 699.2
cm−1. HPLC: ee of major diastereoisomer was determined by HPLC
analysis (Chiralcel AD-H, i-PrOH/hexane = 40/60, 1.0 mL/min, 240
nm), retention time: tminor = 13.85 min, tmajor = 9.57 min, ee = 88%.
General Procedure for Synthesis of 7a. 4a (0.1 mmol, 44.8 mg)
was dissolved in dry THF (2.0 mL) and then cooled in an ice bath. A
solution of methylmagnesium iodine (2 M in diethyl ether, 0.25
mmol) in ethanol (1.0 mL) was added at dropwise at 0 °C. The
reaction was then warmed to room temperature and stirred for 2 h.
After the reaction was complete (monitored by TLC), the reaction was
quenched by aqueous phosphate buffer solution. The mixture was
concentrated under reduced pressure, and the residue was taken up in
2 M HCl and CH2Cl2. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (×3). The organic phases
were combined, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (CH2Cl2/EtOAc,
100:2) to afford the product 7a.
4p: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 97% yield (46 mg). White solid, mp 115−117 °C; [α]20
D
= 3.9 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.51 (br s, 1
H), 7.89−7.92 (d, J = 7.8 Hz, 2 H), 7.31−7.42 (m, 5 H), 7.17−7.25
(m, 3 H), 6.45−6.47 (d, J = 6.6 Hz, 1 H), 4.70−4.72 (d, J = 6.6 Hz, 1
H), 3.86−3.89 (d, J = 8.4 Hz, 1 H), 3.50−3.53 (d, J = 8.7 Hz, 1 H),
1.45 (s, 3 H), 1.37 (s, 3H), 0.68 (s, 3 H),; 13C NMR (75 MHz,
CDCl3): δ 195.3, 169.8, 167.9, 157.1, 152.7, 137.5, 134.6, 129.3, 129.2,
128.8, 128.7, 125.3, 119.0, 76.2, 75.7, 68.3, 60.6, 53.2, 24.8, 22.9, 17.4.
HRMS-ESI (m/z): calcd for C25H24N4O4S+H+: 477.1591; found:
477.1593, 0.5 ppm. IR: 2925.2, 1777.4, 1706.7, 1596.1, 1498.5, 1364.0,
1305.5, 1248.6, 1179.7, 1099.1, 1032.6, 759.8, 736.0, 703.4 cm−1.
HPLC: ee of major diastereoisomer was determined by HPLC analysis
(Chiralcel AD-H, i-PrOH/hexane = 40/60, 1.0 mL/min, 240 nm),
retention time: tminor = 15.29 min, tmajor = 10.87 min, ee = 95%.
4q: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 92% yield (36 mg). White solid, mp 162−164 °C; [α]20
D
1
= 0.5 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 8.73 (br s,
0.24 H), 8.62 (br s, 0.74 H), 7.89−7.91 (d, J = 7.8 Hz, 2 H), 7.38−
7.44 (m, 2 H), 7.33−7.35 (m, 3 H), 7.21−7.23 (m, 3 H), 5.83−5.87
(m, 1 H), 4.29−4.32 (m, 1 H), 3.38 (s, 3 H), 1.29 (s, 3 H); 13C NMR
(75 MHz, CDCl3): δ 195.5, 170.0, 168.9, 168.1, 157.8, 137.4, 134.7,
131.0, 129.2, 129.1, 128.9, 128.7, 128.0, 127.8, 126.8, 125.5, 119.5,
119.2, 120.0, 77.2, 65.0, 53.5, 53.2, 53.0, 52.5, 16.8. HRMS-ESI (m/z):
calcd for C21H19N3O3S+H+: 394.1220; found: 394.1227, 1.8 ppm. IR:
3436.1, 2924.1, 2853.7, 1702.5, 1640.0, 1498.4, 1364.4, 1299.7, 1228.4,
758.3, 697.5 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
40/60, 1.0 mL/min, 240 nm), retention time: tminor = 13.38 min, tmajor
= 9.64 min, ee = 71%.
General Procedure for Synthesis of 5a. 4a (0.1 mmol, 44.8 mg)
was dissolved in CH2Cl2 (3 mL), and the solution was cooled in an ice
bath. Then H2O2 (30%, 1.0 mL) and formic acid (80%, 1.0 mL) were
added, respectively, to the solution dropwise. The reaction was then
warmed to room temperature and stirred for 5 min. After the reaction
was completed (monitored by TLC), CH2Cl2 (50 mL) was added, and
the organic phase was washed with water (×3). The organic layer was
dried over Na2SO4 and then concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(CH2Cl2/EtOAc, 100:8) to afford the product 5a.
7a: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/2) in 93% yield (38 mg). Yellow oily solid; [α]20 = 1.5 (c =
D
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.65 (br s, 0.16 H), 8.56
(br s, 0.74 H), 7.89−7.91 (d, J = 7.8 Hz, 1.91 H), 7.79−7.82 (d, J = 7.8
Hz, 0.19 H),7.38−7.44 (t, J = 15.9 Hz, 2 H), 7.29−6.34 (m, 3.31 H),
7.19−7.25 (m, 2.72 H), 5.80−5.84 (m, 1 H), 4.29−4.32 (d, J = 6.6 Hz,
1 H), 3.81−3.97 (m, 2 H), 1.29 (s, 3 H), 0.72−0.77 (t, J = 14.4 Hz, 3
H); 13C NMR (75 MHz, CDCl3): δ 195.5, 170.0, 167.6, 157.8, 137.4,
134.8, 129.1, 128.9, 128.2, 125.5, 119.0, 118.9, 64.9, 61.8, 53.6, 16.9,
13.4. HRMS-ESI (m/z): calcd for C22H21N3O3S+H+: 408.1376;
found: 408.1384, 1.8 ppm. IR: 3271.5, 2925.6, 1740.9, 1707.8,
1596.0, 1498.1, 1462.0, 1363.1, 1298.5, 1224.6, 1021.7, 758.0, 736.2,
699.3, 657.6 cm−1. HPLC: ee of major diastereoisomer was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane =
30/70, 1.0 mL/min, 230 nm), retention time: tminor = 16.14 min, tmajor
= 10.13 min, ee = 88%.
5a: The title compound was isolated as a mixture of
diastereoisomers by column chromatography (CH2Cl2/EtOAc =
100/8) in 98% yield (42 mg). White solid, mp 133−135 °C; [α]20
D
1
= 2.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 7.87−7.90
(m, 2 H), 7.27−7.42 (m, 7 H), 7.09−7.21 (m, 2 H), 6.13−6.16 (d, J =
6.9 Hz, 1 H), 4.75−4.77 (d, J = 6.9 Hz, 1 H), 4.22−4.30 (m, 1 H),
3.77−3.95 (m, 2 H), 3.16−3.25 (m, 1H), 1.35 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 170.1, 168.7, 168.2, 156.7, 152.2, 137.4, 134.6, 129.2,
129.0, 128.8, 128.6, 125.3, 118.9, 68.4, 62.9, 61.3, 51.2, 42.3, 17.3.
HRMS-ESI (m/z): calcd for C23H20N4O5+H+: 433.1506; found:
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
10233
dx.doi.org/10.1021/jo301851a | J. Org. Chem. 2012, 77, 10228−10234

The Journal of Organic Chemistry
Article
Shen, F.-F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328. (l) Chen,
W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org.
Lett. 2011, 13, 2472.
(6) For a recent review on the Michael addition, see: Vicario, J. L.;
Badía, D.; Carrillo, L.; Reyes, E. In Organocatalytic Enantioselective
Conjugate Addition Reactions; Spivey, J. J., Ed.; The Royal Society of
Chemistry: Cambridge, 2010.
AUTHOR INFORMATION
Corresponding Author
*E-mail: (R.W.) wangrui@lzu.edu.cn, bcrwang@polyu.edu.hk;
(X.J.) xianxingjiang@163.com.
Notes
■
The authors declare no competing financial interest.
(7) For recent examples Michael reactions of α-isothiocyanato
imides, see: (a) Cao, Y.-M.; Jiang, X.-X.; Liu, L.-P.; Shen, F.-F.; Zhang,
F.-T.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124. (b) Tan, B.;
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F. Chem.Eur. J. 2012, 18, 63.
ACKNOWLEDGMENTS
■
We are grateful for the grants from the National Natural
Science Foundation of China (nos. 90813012, 20932003, and
21202072) and the Key National S&T Program “Major New
Drug Development” of the Ministry of Science and Technology
of China (2012ZX09504-001-003).
(8) For selected examples of bifunctional amine-thiourea catalyst
reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520. (b) Connon, S. J. Chem.Eur. J. 2006, 12, 5418. For
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