Cu(oac)2-promoted cascade carboamination/oxidative cyclization of c-acylimines with alkenes

Article abstract of DOI:10.1021/jo402705w

A Cu(OAc)₂-promoted cascade carboamination/oxidative cyclization of alkenes with a-imino esters has been explored. This transformation provides a concise approach to rapid assembly of 2-oxo-3-iminopyrrole derivatives in moderate to good yields.

Full text of DOI:10.1021/jo402705w

Article
pubs.acs.org/joc
Cu(OAc)2‑Promoted Cascade Carboamination/Oxidative Cyclization
of C‑Acylimines with Alkenes
Ling Dang,† Libo Liang,† Cheng Qian,† Meiqin Fu,† Tongmei Ma,*,† Dingguo Xu,*,‡ Huanfeng Jiang,†
and Wei Zeng*,†
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
‡College of Chemistry, Sichuan University, Chengdu 610064, China
S
* Supporting Information
ABSTRACT: A Cu(OAc)2-promoted cascade carboamination/oxidative cyclization of alkenes with α-imino esters has been
explored. This transformation provides a concise approach to rapid assembly of 2-oxo-3-iminopyrrole derivatives in moderate to
good yields.
Scheme 1. Reactions of Alkyl Radicals with C-Acylimines
INTRODUCTION
■
The development of synthetic transformations that allow for
the rapid construction of heterocycles is a great challenging
subject in organic chemistry. Transition-metal-catalyzed
carboaminations of olefins represent one of the most efficient
and atom-economical approaches to the assembly of such kind
of products.1 Consequently, many efforts have been invested in
the exploration of various reaction systems for this demanding
transformation. The most recent trend has been focused on the
use of different carbon source substrates, which can lead to the
simultaneous formation of C−N and C−C bonds. Since the
Pd-catalyzed aminocarbonylation of alkenes/CO gas system has
been reported by Hegedus and Tamaru,2 transition-metal-
catalyzed intermolecular carboamination of alkene with aryl
bromide,3 alkene/arylboronic acid,4 alkene/N-aryl urea,5
alkene/arene,6 alkene/alkene,7 and intramolecular carboamina-
tion of alkene8 were well developed to furnish different classes
of mono- or fused heterocyclic systems. To date, however,
although zirconium- or titanium-catalyzed carboamination of
imines with alkynes were developed to afford α,β-unsaturated
imines by Bergman and Mindiola, respectively,9 no studies have
been reported for transition-metal-catalyzed carboamination of
alkene/imine system, which will possibly offer a promising
synthetic strategy to access complex nitrogen heterocycles.
On the other hand, as the versatile acceptors of nucleophiles,
acylimines and their corresponding addition reactions with
organometallic reagents and Mannich donors, etc., are widely
utilized in many crucial steps.10 Recently, we realized the
ruthenium(II)-catalyzed regioselective reductive coupling of
unactivated dienes with α-imino esters via an addition of alkyl
ruthenium intermediate to acylimine CN bond to furnish α-
branched allylic α-amino acid derivatives (D) (Scheme 1a).11 In
the course of this study, we discovered that Ru(II)/Et3B system
could produce the unexpected ethylation byproduct (C)
possibly via a radical process;11,12 this result implied that
acylimine could be easily trapped by carbon radical
intermediates. Considering that the Cu(II)-catalyzed intra-
molecular carboamination of arylsulfonamidoalkenes (F)
Received: December 5, 2013
Published: December 31, 2013
© 2013 American Chemical Society
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reported by Chemler involved in a key β-aminoalkyl radical
(H), which derived from the C−Cu(II) homolysis of
organocopper intermediate (G), and carbon radical (H)
could further react with aryl ring (Ar) via an intramolecular
coupling to give the fused heterocyclic product (I) (Scheme
1b),8d we therefore envisioned that the alkyl (R)-substituted
sulfonylamidoalkene (J)/α-imino ester (A) partner could also
first produce a carbonyl radical (K) under the copper(II) salt
system, and then the radical (K) could possibly prefer attacking
the imino carbon instead of the alkyl group (R) from J and lead
to the formation of nitrogen radical L, which could likely
further react with the second α-imino ester molecule A to
provide structurally complex heterocycle (M) via a cascade
process (Scheme 1c). To test this hypothesis, herein we
described the first example of Cu(OAc)2-promoted cascade
carboamination/oxidative cyclization (Cu-PCCOC) of α-imino
esters with alkenes for the rapid assembly of indoline-
substituted-2-oxo-3-iminopyrrole (ISOIP) derivatives, and
most of ISOIP analogues are potent and selective galanin
GAL3 receptor antagonists and DNA gyrase inhibitors.13
(entry 5), this positive result encouraged us to further optimize
the reaction conditions for achieving satisfying yields. Then, we
investigated the effect of various oxidants (1.0 equiv) on the
Cu-PCCOC. Among the tested oxidants (entries 6−9), MnO2
could bring us an improved yield of 3a (entry 9, 64% yield).
Finally, the best yield (71% yield of 3a) was obtained using 1.0
equiv of MnO2 at 135 °C for 24 h (entry 10). By the way, it is
worth noting that no cyclization product 3a was formed in the
absence of KHCO3 (entry 11). Moreover, when methanesul-
fonyl group of 1a was switched to acetyl or methyl group
(entries 12 and 13), no product was obtained, possibly because
of poorer pKa values from N-acetyl or methyl amino group (see
SI for more details).
Having established optimized reaction conditions that enable
the smooth Cu-PCCOC of 1a with 2a, we next investigated its
scope with regard to the substituted N-sulfonyl-2-allylaniline
(1) coupling partner. As illustrated in Table 2, the substitution
on the benzene ring (R1) of 1 showed no significant electronic
effects, the N-methanesulfonyl-2-allylaniline derivatives with
para-electron-donating group or halide (4-Me, 4-MeO, 4-Cl, 4-
Br, 4-F) on the phenyl ring afforded the ISOIP derivatives in
moderate to good yields (52−71%, entries 1−6), and electron-
poor substrates with nitro group or ethoxylcarbonyl group on
the phenyl ring underwent slightly worse conversion and
provided lower yield of desired products (40−53%, entries 7−
9). Compared with the N-methylsulfonyl-2-allylaniline (1a),
the Cu-PCCOC of N-tosyl-2-allylaniline with 2a provided 50%
yield of ISOIP derivative 3j and 42% yield of byproduct 3k,
which was directly derived from the intramolecular carboami-
nation of alkene (entry 10). In addition, unactivated N-tosyl-
(2,2-dimethyl)-pent-4-enylamine was also a suitable substrate
for this transformation and provided 49% yield of the desired
product 3l and 40% yield of the intramolecular carboamination
product 3m (entry 11). The scope of the procedure with regard
to α-imino ester coupling partner was then explored with
particular 1a. Electron-rich, electron-poor, and halide-substi-
tuted N-phenyl α-imino esters underwent smooth conversion
when common functionalities, such as methyl, acetamido,
halide, and alkoxylcarbonyl groups, were present as para- or
meta-substituent on the benzene ring, with the formation of
compounds 3n−3s in moderate to good yield (entries 12−17).
Worthy of note was that no ISOIP product was observed for
the N-alkyl substituted α-imino ester, and only 59% yield of
hydroamination product 3t from alkene was obtained (entry
18). Finally, we also ran the Cu(II)-promoted cascade
carboamination/cross-oxidative cyclization of 1a (1.0 equiv)
with N-(4-methoxylphenyl)imino ester (1.0 equiv) and N-(4-
methylphenyl)imino ester (1.0 equiv). As expected, we got the
corresponding cross-oxidative cyclization product 3u (50%
yield, entry 19) besides 3a (14% yield) and 3n (17% yield).
Taking previous reports on copper(II)-mediated carboami-
nation into account, and in combination with the byproduct
and intermediate derived from the Cu-PCCOC of alkene 1a
with α-imino ester 2a, we proposed a plausible reaction
mechanism for this novel transformation (Figure 1). It is well-
known that the syn-aminocupraion of alkene 1a gave organo-
copper intermediate 1a-1, and subsequent C−Cu(II) homolysis
furnished β-aminoalkyl radical 1a-2.7b,8d Then alkyl radical 1a-2
attacked the imine carbon14 of 2a and generated the nitrogen
radical intermediate 2a-1, and the following oxidation of N-
radical (2a-1) with either Cu(II) or MnO2 and successive
deprotonation could lead to imine 2a-2, which then
tautomerized to form enamine 2a-3. By the way, the active
RESULTS AND DISCUSSION
■
To begin our study, N-(2-allyl-phenyl)-methanesulfonamide
(1a, 0.18 mmol) was first employed to react with α-imino ester
2a (0.36 mmol) in toluene (3.0 mL) at 120 °C for 48 h under
an Ar atmosphere for screening various copper salts (Table 1,
a
Table 1. Optimization of the Cu(II)-PCCOC
b
entry copper salts
R
temp (°C)
oxidant
yield (%)
1
Cu(OTf)2
CuOAc
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeCO
Me
120
120
120
120
135
120
120
120
120
135
135
135
135
−
−
−
−
−
O2
0
2
21
0
3
CuBr2
4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
45
48
38
0
5
6
7
PhIO
Na2S2O8
MnO2
MnO2
MnO2
MnO2
MnO2
8
54
64
9
c
10
11
12
13
71
d
0
c
0
c
0
a
Unless otherwise noted, the reactions were carried out using alkenes
(1) (0.18 mmol) and α-imino ester (2a) (0.36 mmol) with copper
salts (3.0 equiv) in the presence of oxidant (1.0 equiv) and KHCO3
(1.0 equiv) in solvent (3.0 mL) at 120 °C for 48 h under Ar in a sealed
b
reaction tube, followed by flash chromatography on SiO2. Isolated
c
d
yield. Reaction time of 24 h. KHCO3 was not used.
entries 1−4). To our delight, we quickly found that 3.0 equiv of
Cu(OAc)2 could provide 45% yield of the desired indoline-
substituted-2-oxo-3-iminopyrrole (3a), whose structure was
already unambiguously assigned by its single crystal X-ray
analysis (see Supporting Information (SI) for more details)
(entry 4). Albeit the yield of 3a at 135 °C is still a little lower
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ab
,
Table 2. Copper- Mediated Cascade Carboamination/Oxidative Cyclization of Alkenes with α-Imino Ester
a
All the reactions were carried out using 1 (0.18 mmol) and 2 (0.36 mmol) with Cu(OAc)2 (3.0 equiv) in the presence of MnO2 (1.0 equiv) and
b
KHCO3 (1.0 equiv) in solvent (3.0 mL) at 135 °C for 24 h under Ar in a sealed reaction tube, followed by flash chromatography on SiO2. Isolated
yield.
alkyl radical 2a-1 was also trapped partially by reaction medium
to form byproduct 2a-7.15 Once the enamine 2a-3 is produced,
it would react with another α-imino ester 2a and provided
imine 2a-4. Once again, the second imine/enamiane isomer-
ization process occurred to form enamine intermediate 2a-5.
Subsequently, a intramolecular nucleophilic cyclization from
2a-5 resulted in the formation of 2a-6.16 It is worth noting that
when the reaction progress of Cu-PCCOC of alkene (1a) with
α-imino ester (2a) was monitored by mass spectrometry
experiment, the ESI/MS showed a peak at m/z 578.1826,
which corresponds to [2a-6 + H]+ (see SI for more details).17
Finally, the oxidative dehydrogenation of 2a-6 further led to the
desired ISOIP 3a.
these compounds even more valuable and is also currently
underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in flame-dried
sealed tubes with magnetic stirring. Unless otherwise noted, all
experiments were performed under argon atmosphere. Solvents were
treated with 4 Å molecular sieves or sodium and distilled prior to use.
Flash chromatography was performed on silica gel (40−63 mm) by
standard technique. 1H and 13C NMR spectra were recorded on a 400
MHz spectrometer at room temperature with tetramethylsilane
(TMS) as internal standard. Chemical shifts are reported in parts
per million (ppm), and coupling constants are reported as Hertz (Hz).
Splitting patterns are designated as singlet (s), doublet (d), triplet (t),
quartet (q). Splitting patterns that could not be interpreted or easily
visualized are designated as multiple (m). High resolution exact mass
measurements (HRMS) were performed on a TOF spectrometer
(Micromass). Infrared spectra (IR) were reported as wavelength
numbers (cm−1). Infrared spectra were recorded by preparing a KBr
In conclusion, we have developed the first copper(II)-
mediated cascade carboamination/oxidative cyclization of
alkenes with α-imino esters. The transformation provided a
concise access to complex ISOIP derivatives. Further
investigation of their possible biological activities will make
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over anhydrous MgSO4 and filtered, and volatiles were removed under
reduced pressure to give a mixture of a white solid and oil. The crude
mixture was extracted with hexane, and the white solid removed by
filtration. The hexane was removed under reduced pressure to yield
pale yellow oil, which was distilled at 140 °C, 10−3 mmHg, to give
80% yield of clear oil (8.40 g). Then a 100 mL round-bottom flask was
charged with N-(tert-butoxycarbonyl)-o-allylaniline (4.00 g, 17.2
mmol) and tetrahydrofuran (50 mL), and then LiAlH4 (2.00 g, 52.6
mmol) was cautiously added, and the reaction mixture was heated at
reflux temperature for 24 h. The reaction mixture was cooled to 0 °C
in an ice bath, and water (10 mL) was added dropwise followed by 2
M NaOH (aq) (10 mL). The mixture was then extracted with diethyl
ether (2 × 50 mL), and the combined organic extracts were dried over
anhydrous MgSO4 and filtered. Volatiles were removed under reduced
pressure, and the residue was purified by column chromatography
(hexane:diethyl ether = 15:1).
N-Methyl-2-allylaniline (1c).20 Colorless oil; 1.50 g, 59% yield: H
1
NMR (400 MHz, CDCl3) δ 7.18 (m, 1H), 7.03 (d, J = 7.3 Hz, 1H),
6.70 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 5.93 (m, 1H), 5.14−5.04 (m,
2H), 3.74(s, 1H), 3.26 (d, J = 6.1 Hz, 2H), 2.83 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 147.5, 136.2, 129.7, 127.8, 123.6, 117.2, 116.2,
109.9, 36.4, 30.8; IR (KBr) 3025, 2924, 1636, 1603, 1487, 963, 747,
715, 605, 464 cm−1; MS (ESI) m/z 147.2 [M]+.
Figure 1. Proposed mechanism for the copper-mediated cascade
transformation.
pellet containing the title compound. Crystal data were obtained by
employing graphite monochromated Mo Kα radiation (λ = 0.71073 Å)
at 293 (2) K and operating in the φ−ωscan mode. The structure was
solved by direct methods SHELXS-97. All the α-imino esters including
(4-methoxy-phenylimino)-acetic acid ethyl ester (2a),10f p-tolylimino-
acetic acid ethyl ester (2b),10f (4-acetylamino-phenylimino)-acetic acid
ethyl ester (2c),10f (4-fluoro-phenylimino)-acetic acid ethyl ester
(2d),10f (4-chloro-phenylimino)-acetic acid ethyl ester (2e),10f (4-
bromo-phenylimino)-acetic acid ethyl ester (2f),10f (3-ethoxycarbonyl-
phenylimino)-acetic acid ethyl ester (2g,)10f and cyclohexylimino-
acetic acid ethyl ester (2h)10f were prepared using the previous
reported procedure.10f
N-Methylsulfonyl-4-methyl-2-allylaniline (1d).21 White solid; 0.70
g, 76% yield: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 1H),
7.12−7.04 (m, 2H), 6.33 (s, 1H), 5.97 (m, 1H), 5.19 (d, J = 12.0 Hz,
1H), 5.09 (d, J = 16.0 Hz, 1H), 3.43 (d, J = 5.9 Hz, 2H), 3.00 (s, 3H),
2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 136.5, 136.1, 133.0,
132.2, 131.5, 128.4, 124.4, 116.8, 39.8, 36.1, 20.9; IR (KBr) 3619,
3277, 2925, 1638, 1611, 1501, 973, 762, 583, 504 cm−1; MS (ESI) m/z
248.7 [M + Na]+.
N-Methylsulfonyl-4-methoxy-2-allylaniline (1e).18 White solid;
1
0.83 g, 84% yield: H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 9.3
Hz, 1H), 6.77 (d, J = 7.0 Hz, 2H), 6.50 (s, 1H), 5.94 (m, 1H), 5.14 (d,
J = 10.1 Hz, 1H), 5.07 (d, J = 17.1 Hz, 1H), 3.78 (s, 3H), 3.45 (d, J =
5.8 Hz, 2H), 2.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.6,
136.6, 135.8, 127.4, 127.2, 117.0, 116.1, 112.6, 55.5, 39.7, 36.3; IR
(KBr) 3610, 3273, 2935, 1638, 1582, 1499, 1433, 1390, 974, 917, 761,
603, 517 cm−1; MS (ESI) m/z 264.0 [M + Na]+.
Procedures for the Preparation of Olefin Substrates (1a−
1m). Procedure A18 (Synthesis of 1a, 1b, 1d−1m). 2-Allyl
phenylamine (0.55 g, 4.09 mmol, 1.0 equiv) was dissolved in dry
CH2Cl2 (20.5 mL), and the solution was treated with pyridine (1.0
mL, 12.3 mmol, 1.0 equiv) and acyl chloride (4.90 mmol, 1.2 equiv).
After, the corresponding reaction mixture was stirred at room
temperature overnight, diluted with H2O (30 mL), and extracted
with Et2O (3 × 30 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Chromatography of the resulting
crude product on SiO2 (using Et2O/hexanes as eluent) afforded the
corresponding olefin substrates.
N-Methylsulfonyl-4-chloro-2-allylaniline (1f).22 White solid; 0.65
g, 65% yield: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 1H),
7.25 (d, J = 13.4 Hz, 2H), 6.41 (s, 1H), 5.93 (m, 1H), 5.23 (d, J = 10.0
Hz, 1H), 5.09 (d, J = 17.1 Hz, 1H), 3.41 (d, J = 5.5 Hz, 2H), 3.00 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 134.9, 133.5, 131.8, 130.7,
127.8, 124.9, 124.6, 117.7, 40.0, 35.8; IR (KBr) 3634, 3291, 3080,
2927, 1639, 1595, 1484, 970, 754, 517, 453 cm−1; MS (ESI) m/z 268.7
[M + Na]+.
N-Methylsulfonyl-2-allylaniline (1a).18 Yellow liquid; 0.78 g, 90%
1
yield: H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.22
N-Methylsulfonyl-4-bromine-2-allylaniline (1g). White solid; mp
78−79 °C; 0.85 g, 72% yield: 1H NMR (400 MHz, CDCl3) δ 7.38 (d,
J = 6.5 Hz, 2H), 7.38 (s, 1H), 6.52 (s, 1H), 5.92 (m, 1H), 5.22 (d, J =
10.0 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H), 3.40 (d, J = 5.6 Hz, 2H), 3.00
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 134.7, 134.2, 133.7, 130.9,
124.5, 119.4, 117.9, 40.1, 36.1; IR (KBr) 3286, 3079, 2929, 1638, 1591,
973, 762, 677, 549, 517 cm−1; HRMS (ESI-TOF) calcd for [M]+
C10H12BrNO2S 288.9767, found 288.9768.
(m, 3H), 6.62 (s, 1H), 5.96 (m, 1H), 5.17 (d, J = 10.1 Hz, 1H), 5.07
(dd, J = 12.0, 16.0 Hz, 1H), 3.45 (d, J = 6.0 Hz, 2H), 3.00 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 136.0, 134.9, 132.9, 130.9, 127.8, 126.5,
123.8, 116.9, 39.9, 35.9; IR(KBr) 3630, 3077, 2978, 2930, 1843, 1638,
1584, 1493, 1454, 1396, 1329, 971, 750, 655, 515 cm−1; MS (ESI) m/z
234.7 [M + Na]+.
N-Acetyl-2-allyl aniline (1b).19 White solid; 0.62 g, 86% yield: H
1
NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H),
7.23 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.10 (t, J = 7.3 Hz,
1H), 5.95 (m, 1H), 5.15 (d, J = 10.0 Hz, 1H), 5.08 (d, J = 17.2 Hz,
1H), 3.36 (d, J = 6.1 Hz, 2H), 2.12 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 168.5, 136.4, 136.0, 130.5, 130.1, 127.4, 125.4, 124.1,
116.49, 36.8, 24.2; IR (KBr) 3277, 1655, 1586, 1535, 1481, 1449, 969,
752, 606, 533 cm−1; MS (ESI) m/z 175.2 [M]+.
Procedure B (Synthesis of 1c). This preparation is a modification
of a literature procedure.20 A 100 mL round-bottom flask was charged
with o-allylaniline (6.03 g, 45.3 mmol) and tetrahydrofuran (40 mL).
To this was added di-tert-butyl-dicarbonate (9.80 g, 44.9 mmol) and
triethylamine (6.3 mL, 45.5 mmol). After the solution was heated at
reflux temperature for 24 h, the solvent was removed under reduced
pressure, and ethyl acetate (100 mL) was added to the corresponding
residue. Then the solution was washed with 1 M citric acid (aq) (3 ×
70 mL) and saturated NaCl (aq) (50 mL). The organic layer was dried
N-Methylsulfonyl-4-fluoro-2-allylaniline (1h).22 White solid; 0.63
g, 67% yield: 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 8.0, 8.0 Hz,
1H), 6.95 (m, 2H), 6.59 (s, 2H), 5.93 (m, 2H), 5.19 (d, J = 9.4 Hz,
1H), 5.09 (d, J = 17.1 Hz, 1H), 3.45 (d, J = 6.0 Hz, 2H), 2.99 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 136.3, 135.0, 130.5, 126.8, 126.7,
117.6, 114.5, 117.3, 114.6, 114.4, 39.9, 36.1; IR (KBr) 3643, 3273,
2924, 1631, 1591, 967, 758, 501 cm−1; MS (ESI) m/z 252.0 [M +
Na]+.
N-Methylsulfonyl-4-nitro-2-allylaniline (1i). Pink solid; mp 86−87
°C; 0.73 g, 70% yield: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 11.6
Hz, 2H), 7.71 (s, 1H), 5.99 (m, 1H), 5.30 (d, J = 9.8 Hz, 1H), 5.15 (d,
J = 17.2 Hz, 1H), 3.52 (d, J = 5.9 Hz, 2H), 3.15 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 144.0, 141.5, 133.8, 129.8, 126.2, 123.7, 119.2,
118.6, 40.6, 35.8; IR (KBr) 3440, 2924, 1639, 1519, 967 cm−1; HRMS
(ESI-TOF) calcd for [M]+ C10H12N2O4S 256.0512, found 256.0512.
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N-Methylsulfonyl-3-ethyl formate-2-allylaniline (1j). Yellow
liquid; 1.03 g, 89% yield: H NMR (400 MHz, CDCl3) δ 7.747.66
125.5, 121.2, 114.5, 114.2, 113.5, 62.1, 56.4, 55.5, 35.7, 34.9, 20.9, 13.5;
IR (KBr) 3861, 3656, 3053, 2930, 1729, 1607, 1511, 1463, 1375, 1249,
974, 703, 566, 423 cm−1; HRMS (ESI-TOF) calcd for [M + Na]+
C31H31N3O7SNa 612.1744, found 612.1775.
1
(m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 6.07−5.95 (m, 1H), 5.17 (d, J = 12.0
Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.76 (d, J
= 5.6 Hz, 2H), 3.01 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 167.5, 136.5, 135.6, 132.9, 127.8, 127.5, 126.4, 116.6,
61.4, 40.3, 32.6, 14.2; IR (KBr) 3616, 3209, 2929, 1636, 1585, 1460,
979, 756, 655, 515 cm−1; HRMS (ESI-TOF) calcd for [M]+
C13H17NO4S 283.0873, found 283.0870.
Ethyl-3-(5-methoxy-1-(methylsulfonyl)indolin-2-enyl)-1-(4-me-
thoxyphenyl)-4-(4-methoxyphenylimino)-5-oxo-4,5-dihydro-1H-
1
pyrrole-2-carboxylate (3c). Red oil; 69.7 mg, 64% yield: H NMR
(400 MHz, CDCl3) δ 7.33 (m, 3H), 7.14 (d, J = 8.9 Hz, 2H), 6.89 (d,
J = 8.9 Hz, 2H), 6.82−6.71 (m, 4H), 5.68 (dd, J = 8.0, 4.0 Hz, 1H),
4.12 (m, 1H), 4.02 (m, 1H), 3.80 (d, J = 2.2 Hz, 9H), 3.67 (m, 1H),
3.41 (dd, J = 4.0, 8.0 Hz, 1H), 2.79 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 160.6, 160.2, 159.0, 157.2, 156.1,
149.1, 140.4, 140.2, 135.7, 132.9, 127.5, 126.7, 120.8, 115.8, 114.2,
113.5, 112.8, 110.9, 62.1, 56.6, 55.8, 55.5, 35.8, 34.61, 13.5; IR (KBr)
3743, 3641, 2928, 1725, 1607, 1511, 1464, 973, 770, 551, 516 cm−1;
HRMS (ESI-TOF) calcd for [M + Na]+ C31H31N3O8SNa 628.1724,
found 628.1740.
N-Methylsulfonyl-4-ethyl formate-2-allylaniline (1k). Yellow
1
liquid; 0.93 g, 80% yield: H NMR (400 MHz, CDCl3) δ 8.12 (d, J
= 1.3 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.82
(s, 1H), 5.95 (m, 1H), 5.20 (d, J = 12.0 Hz, 1H), 5.08 (d, J = 16.0 Hz,
1H), 4.38 (q, J = 7.1 Hz, 2H), 3.53 (d, J = 6.0 Hz, 2H), 3.07 (s, 3H),
1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.9, 137.8,
135.18, 134.9, 130.9, 130.4, 127.4, 124.5, 117.7, 61.3, 40.4, 36.2, 14.3;
IR (KBr) 3894, 3559, 3275, 3080, 2981, 1639, 1611, 1575, 974, 761,
661, 515 cm−1; HRMS (ESI-TOF) calcd for [M]+ C13H17NO4S
283.0873, found 283.0870.
Ethyl-3-(5-chloro-1-(methylsulfonyl)indolin-2-enyl)-1-(4-methox-
yphenyl)-4-(4-methoxyphenylimino)-5-oxo-4,5-dihydro-1H-pyrrole-
2-carboxylate (3d). Red oil; 66.9 mg, 61% yield: 1H NMR (400 MHz,
CDCl3) δ 7.32 (t, J = 8.2 Hz, 3H), 7.16 (m, 4H), 6.90 (d, J = 8.7 Hz,
2H), 6.78 (d, J = 8.8 Hz, 2H), 5.79 (dd, J = 4.0, 8.0 Hz, 1H), 4.16−
4.01 (m, 2H), 3.80 (m, 6H), 3.68 (m, 1H), 3.44 (d, J = 16.4 Hz, 1H),
2.83 (s, 3H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
160.6, 160.4, 159.1, 156.1, 141.0, 140.2, 133.5, 1287.4, 124.9, 121.1,
115.3, 114.2, 113.6, 62.1, 56.4, 55.5, 35.7, 35.2, 29.7, 13.5. IR (KBr)
3657, 3060, 2927, 1725, 1607, 1510, 973, 736, 557, 427 cm−1; HRMS
(ESI-TOF) calcd for [M]+ C30H28ClN3O7S 609.1331, found 609.1324.
Ethyl-3-(5-bromo-1-(methylsulfonyl)indolin-2-enyl)-1-(4-methox-
yphenyl)-4-(4-methoxyphenylimino)-5-oxo-4,5-dihydro-1H-pyrrole-
2-carboxylate (3e). Red oil; 64.7 mg, 55% yield: 1H NMR (400 MHz,
CDCl3) δ 7.33 (d, J = 8.5 Hz, 4H), 7.27 (d, J = 3.9 Hz, 1H), 7.14 (d, J
= 8.1 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.79
(dd, J = 4.0, 4.0 Hz, 1H), 4.16−4.00 (m, 2H), 3.80 (s, 6H), 3.68 (m,
1H), 3.44 (m, 1H), 2.83 (s, 3H), 0.97 (t, J = 6.9 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.7, 160.4, 159.1, 156.1, 148.4, 141.6, 140.0,
133.9, 130.5, 128.3, 127.8, 127.4, 121.1, 116.6, 115.7, 114.2, 113.6,
62.1, 56.3, 55.5, 35.8, 35.2, 29.7, 13.5; IR (KBr) 3645, 2925, 1724,
1610, 1510, 1468, 972, 551, 430 cm−1; HRMS (ESI-TOF) calcd for
[M]+ C30H28BrN3O7S 653.0826, found 653.0822.
Ethyl-3-(5-fluoro-1-(methylsulfonyl)indolin-2-enyl)-1-(4-methox-
yphenyl)-4-(4-methoxyphenylimino)-5-oxo-4,5-dihydro-1H-pyrrole-
2-carboxylate (3f). Red oil; 57.6 mg, 54% yield: 1H NMR (400 MHz,
CDCl3) δ 7.25 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.84 (m, 4H), 6.70
(d, J = 8.0 Hz, 2H), 5.70 (dd, J = 4.0, 4.0 Hz, 1H), 4.05 (m, 1H), 3.95
(m, 1H), 3.71 (d, J = 3.6 Hz, 6H), 3.61 (m, 1H), 3.36 (m, 1H), 2.73
(s, 3H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
160.5, 160.4, 159.1, 156.1, 148.6, 140.2, 140.0, 138.3, 133.6, 128.2,
127.4, 127.1, 121.0, 115.5, 115.4, 114.2, 113.6, 112.2, 111.9, 62.1, 56.6,
55.5, 35.4, 35.3, 29.7, 13.5; IR (KBr) 3746, 3644, 2925, 1724, 1607,
1511, 1442, 975, 569, 430 cm−1; HRMS (ESI-TOF) calcd for [M +
H]+ C30H29FN3O7S 594.1705, found 594.1713.
N-Tosyl-2-allylaniline (1l).8a White solid; 1.12 g, 95% yield: H
1
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.9
Hz, 1H), 7.23−7.16 (m, 3H), 7.14−7.04 (m, 2H), 6.62 (s, 1H), 5.84−
5.70 (m, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.94 (d, J = 16.0 Hz, 1H),
3.03 (d, J = 5.9 Hz, 2H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
143.8, 136.8, 135.6, 135.0, 132.0, 130.5, 129.6, 127.7, 127.1, 126.3,
124.5, 117.1, 36.2, 21.5; IR (KBr) 3283, 3071, 2978, 2922, 1637, 1596,
1492, 996, 711, 665, 566 cm−1; MS (ESI) m/z 287.1 [M]+.
N-Tosyl-(2,2-dimethyl)-pent-4-enylamine (1m).8a White solid;
1
0.79 g, 72% yield: H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2
Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.72 (m, 1H), 5.04−4.95 (m, 2H),
4.46 (t, 1H, J = 9.0 Hz), 2.67 (d, 2H, J = 6.0 Hz), 2.42 (s, 3H), 1.96 (d,
J = 7.4 Hz, 2H), 0.85 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 143.3,
137.0, 134.3, 129.7, 127.1, 117.8, 52.9, 43.9, 34.1, 24.8, 21.5; IR 3287,
3072, 2964, 1639, 1598, 1422, 997, 666, 556 cm−1; MS (ESI) m/z
268.3 [M + 1]+.
General Procedure for the Synthesis of the Compound 3a−
3u. Cu(OAc)2 (0.54 mmol, 3.0 equiv), KHCO3 (0.18 mmol, 1.0
equiv), MnO2 (0.18 mmol, 1.0 equiv), sulfonamide substrate (0.18
mmol, 1.0 equiv), and α-imino ester (0.36 mmol, 2.0 equiv) were
dissolved in 2.0 mL of toluene in a tube, and then the tube was sealed
under Ar and heated at 135 °C in an oil bath for 24 h. The reaction
progress was monitored by TLC method, after the starting material
disappeared; the corresponding reaction mixture was then cooled
down and filtrated. Removal of the solvent in vacuo and
chromatography on SiO2 (using ethyl acetate/hexane as eluent)
afforded the corresponding desired products.
Ethyl-1-(4-methoxyphenyl)-4-(4-methoxyphenylimino)-3-(1-
(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyrrole-2-
1
carboxylate (3a). Red solid; mp 68−69 °C; 73.0 mg, 71% yield: H
NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.7
Hz, 2H), 7.24 (t, J = 6.5 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.11 (t, J =
7.4 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.78
(q, 1H), 4.23−4.09 (m, 1H), 4.09−3.98 (m, 1H), 3.81 (d, J = 6.2 Hz,
6H), 3.75−3.69 (m, 1H), 3.47 (m, 1H), 2.85 (s, 3H), 0.98 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 159.0, 156.2, 148.7,
142.3, 140.1, 131.4, 128.3, 127.7, 127.4, 127.2, 124.8, 124.1, 121.5,
114.2, 113.5, 62.1, 56.1, 55.5, 55.5, 35.6, 35.6, 13.5; IR (KBr) 3748,
3646, 2934, 1725, 1606, 1510, 973, 587, 549, 512, 421 cm−1; HRMS
(ESI-TOF) calcd for [M+H]+ C30H30N3O7S 576.1799, found
576.1799.
Ethyl-1-(4-methoxyphenyl)-4-(4-methoxyphenylimino)-3-(1-
(methylsulfonyl)-5-nitroindolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyr-
1
role-2-carboxylate (3g). Red solid; 49.1 mg, 44% yield: H NMR
(400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.42 (d, J
= 8.9 Hz, 1H), 7.27 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.92
(d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.9 Hz, 2H), 6.04 (dd, J = 8.0, 4.0 Hz,
1H), 4.12 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.74 (d, J = 11.8 Hz,
1H), 3.53 (d, J = 16.0 Hz, 1H), 2.92 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 161.1, 160.1, 159.2, 156.1, 148.1,
Ethyl-1-(4-methoxyphenyl)-4-(4-methoxyphenylimino)-3-(5-
methyl-1-(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-
pyrrole-2-carboxylate (3b). Red solid; mp 73−75 °C; 55.0 mg, 52%
yield: 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.8 Hz, 2H), 7.30−
7.25 (m, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 9.6 Hz, 2H), 6.89
(d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 5.68 (dd, J = 4.0, 4.0 Hz,
1H), 4.16−4.06 (m, 1H), 4.05−3.95 (m, 1H), 3.79 (s, 6H), 3.66 (m,
1H), 3.40 (dd, J = 16.0, 16.0 Hz, 1H), 2.80 (s, 3H), 2.33 (s, 3H), 0.95
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 160.3,
159.0, 156.1, 149.1, 140.2, 139.9, 133.9, 131.4, 128.2, 127.5, 126.8,
147.9, 143.8, 140.4, 139.7, 132.9, 128.3, 127.6, 127.4, 124.6, 120.7,
120.4, 114.3, 113.7, 112.5, 62.2, 56.9, 55.5, 37.9, 34.6, 29.7, 13.6; IR
(KBr) 3754, 2927, 1724, 1605, 1514, 972, 559, 514 cm−1; HRMS
(ESI-TOF) calcd for [M]+ C30H28N4O9S 620.1572, found 620.1565.
Ethyl-2-(2-(ethoxycarbonyl)-1-(4-methoxyphenyl)-4-(4-methoxy-
phenylimino)-5-oxo-4,5-dihydro-1H-pyrrol-3-enyl)-1-
(methylsulfonyl)indoline-4-carboxylate (3h). Red oil; 61.7 mg, 53%
yield: H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.29−7.25 (d, J = 7.9 Hz,
1H), 7.14 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 9.0
1
773
dx.doi.org/10.1021/jo402705w | J. Org. Chem. 2014, 79, 769−776

The Journal of Organic Chemistry
Article
Hz, 2H), 5.84 (dd, J = 8.0, 4.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H),
4.17−4.10 (m, 1H), 4.09−3.99 (m, 2H), 3.80 (s, 3H), 3.78 (s, 3H),
3.73 (m, 1H), 2.84 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.1, 160.5, 160.4, 159.0,
156.2, 148.5, 143.5, 139.9, 134.4, 128.3, 127.9, 127.4, 127.3, 127.0,
125.4, 121.6, 118.1, 114.2, 113.5, 62.0, 61.1, 56.3, 55.5, 55.5, 36.9, 35.9,
14.4, 13.6; IR (KBr) 3736, 2928, 1715, 1607, 1512, 1454, 956, 588,
513 cm−1; HRMS (ESI-TOF) calcd for [M]+ C33H33N3O9S 647.1932,
found 647.1927.
1H), 7.24−7.12 (m, 5H), 7.07 (d, J = 7.6 Hz, 4H), 7.00 (d, J = 8.2 Hz,
2H), 5.66 (dd, J = 8.0, 4.0 Hz, 1H), 4.11 (m, 1H), 4.04−3.91 (m, 1H),
3.71−3.67 (m, 1H), 3.46−3.43 (m, 1H), 2.83 (s, 3H), 2.31 (d, J = 10.5
Hz, 6H), 0.91 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
160.4, 155.32, 151.3, 145.0, 142.0, 141.9, 137.7, 137.6, 132.4, 130.9,
129.5, 129.0, 127.8, 124.9, 124.3, 121.9, 62.2, 56.2, 35.8, 35.2, 21.2,
21.1, 13.4; IR (KBr) 3799, 2924, 1713., 1648, 1601, 1539, 1513, 971,
544 cm−1; HRMS (ESI-TOF) calcd for [M + Na]+ C30H29N3O5SNa
566.1720, found 566.1704.
Ethyl-2-(2-(ethoxycarbonyl)-1-(4-methoxyphenyl)-4-(4-methoxy-
phenylimino)-5-oxo-4,5-dihydro-1H-pyrrol-3-enyl)-1-
(methylsulfonyl)indoline-5-carboxylate (3i). Red oil; 46.6 mg, 40%
yield: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 1H), 7.89 (s,
1H), 7.40 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 8.7
Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 5.89 (dd, J
= 8.0, 8.0 Hz, 1H), 4.37 (m, 2H), 4.16−4.02 (m, 2H), 3.81 (s, 3H),
3.78 (s, 3H), 3.74−3.69 (m, 1H), 3.49 (d, J = 16.0 Hz, 1H), 2.87 (s,
3H), 1.40 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 166.3, 160.7, 160.3, 159.1, 156.2, 146.4, 140.1, 139.9,
131.5, 130.2, 128.4, 127.5, 127.4, 126.1, 125.9, 121.4, 114.2, 113.6,
112.9, 62.1, 60.9, 56.5, 55.5, 36.7, 35.0, 29.7; IR (KBr) 3748, 3379,
2959, 2853, 1714, 1608, 1513, 973, 736, 588, 557, 515 cm−1; HRMS
(ESI-TOF) calcd for [M]+ C33H33N3O9S 647.1932, found 647.1927.
Ethyl-1-(4-methoxyphenyl)-4-(4-methoxyphenylimino)-5-oxo-3-
(1-tosylindolin-2-enyl)-4,5-dihydro-1H-pyrrole-2-carboxylate (3j).
Ethyl-1-(4-acetamidophenyl)-4-(4-acetamidophenylimino)-3-(1-
(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyrrole-2-
1
carboxylate (3o). Red oil; 23.8 mg, 21% yield: H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.6 Hz, 5H), 7.23 (d, J
= 7.6 Hz, 2H), 7.18−7.07 (m, 5H), 5.68 (dd, J = 4.0, 4.0 Hz, 1H),
4.12−4.08 (m, 1H), 3.98−3.96 (m, 1H), 3.72−3.69 (m, 1H), 3.45−
3.42 (m, 1H), 2.84 (s, 3H), 2.12 (d, J = 6.4 Hz, 6H), 0.93 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.4, 160.3, 142.0, 131.0,
127.9, 126.5, 124.9, 124.4, 119.9, 119.3, 114.5, 62.4, 56.1, 35.7, 35.1,
29.7, 24.6, 13.5; IR (KBr) 3363, 2925, 1669, 1602, 1514, 973, 548
cm−1; HRMS (ESI-TOF) calcd for [M + H]+ C32H32N5O7S 630.2017,
found 630.2018.
Ethyl-1-(4-fluorophenyl)-4-(4-fluorophenylimino)-3-(1-
(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyrrole-2-
1
carboxylate (3p). Red oil; 63.5 mg, 64% yield: H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 8.1 Hz, 1H), 7.24−7.17 (m, 4H), 7.08 (m, 5H),
6.95 (t, J = 8.5 Hz, 2H), 5.66 (dd, J = 4.0, 8.0 Hz, 1H), 4.13 (m, 1H),
4.0−3.93 (m, 1H), 3.71−3.68 (m, 1H), 3.45−3.42 (m, 1H), 2.84 (s,
3H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.1,
160.6, 160.1, 155.4, 151.4, 143.3, 141.9, 141.8, 130.8, 127.9, 127.9,
127.8, 124.9, 124.4, 124.1, 124.0, 121.1, 116.1, 115.9, 115.4, 115.2,
114.6, 62.4, 56.0, 35.6, 34.9, 13.4; IR (KBr) 3630, 3373, 2925, 1730,
1600, 1507, 1455, 972, 544 cm−1; HRMS (ESI-TOF) calcd for [M +
H]+ C28H24F2N3O5S 552.1399, found 552.1404.
1
Red oil; 58.6 mg, 50% yield: H NMR (400 MHz, CDCl3) δ 7.63
(m, 3H), 7.25−7.19 (m, 2H), 7.17−7.11 (m, 4H), 7.05 (m, 3H), 6.92
(d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.71 (dd, J = 8.0, 4.0 Hz,
1H), 4.22−4.08 (m, 2H), 3.81 (d, J = 8.4 Hz, 6H), 3.35 (m, 1H), 3.25
(m, 1H), 2.33 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 160.5, 158.9, 156.1, 148.3, 143.8, 142.6, 139.9, 135.0, 131.9,
129.5, 127.6, 127.3, 127.3, 124.4, 123.7, 121.8, 115.1, 114.2, 113.4,
62.1, 55.5, 35.3, 29.7, 21.5, 14.1, 13.6; IR (KBr) 3849, 3582., 2922,
1713, 1604, 1511, 1461, 812, 751, 574, 543, 449 cm−1; HRMS (ESI-
TOF) calcd for [M + Na]+ C36H33N3O7SNa 674.1931, found
674.1931.
Ethyl-1-(4-chlorophenyl)-4-(4-chlorophenylimino)-3-(1-
(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyrrole-2-
1
carboxylate (3q). Red oil; 60.9 mg, 58% yield: H NMR (400 MHz,
8-Methyl-10a,11-dihydro-10H-5-thia-4b-aza-benzo[b]fluorine-
5,5-dioxide (3k).8d Colorless solid; 21.6 mg, 42% yield: 1H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H),
7.11−6.97 (m, 4H), 6.89 (t, J = 7.3 Hz, 1H), 4.87−4.74 (m, 1H),
3.38−3.28 (m, 1H), 3.25−3.24 (m, 1H), 3.02−2.93 (m, 1H), 2.85−
2.81 (m, 1H), 2.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 143.2,
142.2, 135.7, 134.6, 130.1, 129.8, 128.1, 127.9, 124.8, 124.0, 115.9,
61.2, 36.1, 33.6, 21.5; IR (KBr) 2920, 1659, 1600, 1512, 1474, 974,
699, 666, 526, 451, 427 cm−1; MS (ESI) m/z 286.7 [M + 1]+.
Ethyl-3-(4,4-dimethyl-1-tosylpyrrolidin-2-enyl)-1-(4-methoxy-
phenyl)-4-(4-methoxyphenylimino)-5-oxo-4,5-dihydro-1H-pyrrole-
2-carboxylate (3l). Red oil; 55.7 mg, 49% yield: 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 6.6 Hz, 2H), 7.10 (d, J
= 7.9 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.75
(d, J = 8.8 Hz, 2H), 5.21 (m, 1H), 4.22−4.08 (m, 2H), 3.74 (d, J = 7.1
Hz, 6H), 3.35 (m, 2H), 2.46−2.34 (m, 1H), 2.29 (s, 3H), 1.86 (dd, J =
8.0, 8.0 Hz, 1H), 1.18 (s, 6H), 1.02 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 160.4, 159.9, 158.9, 155.8, 142.7, 141.1, 140.2, 129.4,
128.4, 127.0, 125.7, 114.2, 113.3, 62.04, 61.0, 55.5, 53.2, 38.8, 29.7,
25.9, 25.6, 21.5, 13.7; IR (KBr) 3376, 2924, 1729, 1607, 1512, 1463,
914, 685, 545 cm−1; HRMS (ESI-TOF) calcd for [M + H]+
C34H38N3O7S 632.2425, found 632.2437.
CDCl3) δ 7.41 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.25−7.19
(m, 4H), 7.16−7.07 (m, 3H), 6.96 (d, J = 8.3 Hz, 2H), 5.63 (dd, J =
8.0, 4.0 Hz, 1H), 4.13 (m, 1H), 4.05−3.95 (m, 1H), 3.71−3.68 (m,
1H), 3.45−3.42 (m, 1H), 2.83 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 160.0, 154.9, 152.1, 145.9, 142.3, 141.9,
133.7, 133.3, 132.6, 130.6, 129.2, 128.6, 128.0, 126.9, 124.9, 124.5,
122.3, 121.1, 114.6, 62.6, 55.9, 35.6, 34.9, 13.4; IR (KBr) 3650, 2928,
1732, 1642, 1598, 1490, 1461, 972, 658 cm−1; HRMS (ESI-TOF)
calcd for [M + Na]+ C28H23N3O5SCl2Na 606.0628, found 606.0632.
Ethyl-1-(4-bromophenyl)-4-(4-bromophenylimino)-3-(1-
(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihydro-1H-pyrrole-2-
1
carboxylate (3r). Red oil; 62.9 mg, 52% yield: H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 8.6 Hz, 2H), 7.40 (t, J = 8.5 Hz, 3H), 7.22 (t, J =
6.9 Hz, 2H), 7.08−7.06 (m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 5.62 (dd, J
= 4.0, 4.0 Hz, 1H), 4.19−4.08 (m, 1H), 4.05−3.95 (m, 1H), 3.71−3.68
(m, 1H), 3.45−3.42 (m, 1H), 2.84 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 160.0, 154.8, 152.1, 146.5, 142.1,
141.9, 133.8, 132.2, 131.6, 130.6, 128.1, 127.2, 124.9, 124.5, 122.4,
121.6, 121.1, 120.5, 114.6, 62.6, 55.9, 35.6, 34.8, 13.4; IR (KBr) 3651,
2923, 1735, 1655, 1598, 1490, 972, 548 cm−1; HRMS (ESI-TOF)
calcd for [M + H]+ C28H24Br2N3O5S 673.9783, found 673.9769.
Ethyl-1-(3-(ethoxycarbonyl)phenyl)-4-(3-(ethoxycarbonyl)-
phenylimino)-3-(1-(methylsulfonyl)indolin-2-enyl)-5-oxo-4,5-dihy-
2,2,7-Trimethyl-2,3,9,9a-tetrahydro-1H-4-thia-3a-aza-
cyclopenta[b]naphthalene-4,4- dioxide (3m).23 Colorless oil; 19.1
1
1
dro-1H-pyrrole-2-carboxylate (3s). Red oil; 62.9 mg, 53% yield: H
mg, 40% yield: H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz,
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.3 Hz, 1H), 7.83 (d, J = 8.3
Hz, 2H), 7.61 (s, 1H), 7.44−7.40 (m, 3H), 7.36 (t, J = 7.9 Hz, 1H),
7.26−7.19 (m, 2H), 7.16 (d, J = 7.9 Hz,1H), 7.09 (t, J = 7.4 Hz, 1H),
5.65 (dd, J = 8.0, 4.0 Hz, 1H), 4.36−4.34 (m, 2H), 4.33−4.30 (m,
2H), 4.12 (m, 1H), 3.95 (m, 1H), 3.74−3.71 (m, 1H), 3.51−3.48 (m,
1H), 2.86 (s, 3H), 1.37−1.35 (m, 6H), 0.90 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 166.1, 165.4, 159.9, 154.8, 152.9, 148.3,
142.9, 141.9, 134.9, 131.6, 131.1, 130.5, 130.2, 129.1, 129.0, 128.6,
128.1, 127.2, 126.6, 125.1, 124.5, 123.7, 120.9, 120.7, 114.6, 62.6, 61.3,
61.1, 56.1, 35.7, 34.8, 14.3, 14.3, 13.4; IR (KBr) 3649, 3372, 3065,
1H), 7.20 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 4.35−4.26 (m, 1H), 3.48−
3.43 (m, 1H), 3.17 (d, J = 9.1 Hz, 1H), 2.69 (d, J = 15.1 Hz, 1H), 2.55
(d, J = 9.1 Hz, 1H), 2.40 (s, 3H), 1.81 (dd, J = 8.0, 8.0 Hz, 1H), 1.28−
1.24 (m, 1H), 1.15 (s, 3H), 0.95 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 142.9, 134.9, 134.3, 130.5, 127.7, 124.7, 61.7, 58.6, 45.9,
36.8, 31.6, 25.9, 21.6; IR (KBr) 2959, 1729, 1604, 1575, 1468, 954,
687, 645, 585 cm−1; MS (ESI) m/z 266.8 [M + 1]+.
Ethyl-3-(1-(methylsulfonyl)indolin-2-enyl)-5-oxo-1-p-tolyl-4-(p-
tolylimino)-4,5-dihydro-1H-pyrrole-2-carboxylate (3n). Red oil; 71.4
1
mg, 73% yield: H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz,
774
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Article
2983, 1734, 1647, 1586, 1482, 1353, 972, 622 cm−1; HRMS (ESI-
TOF) calcd for [M]+ C34H33N3O9S 659.1932, found 659.1934.
1H-Indole,2,3-dihydro-2-methyl-1-(methylsulfonyl) (3t).24 White
solid; 22.2 mg, 59% yield: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J =
8.0 Hz, 1H), 7.21 (t, J = 7.3 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 4.47−
4.43 (m, 1H), 3.49−3.42 (m, 1H), 2.84 (s, 3H), 2.74−2.66 (m, 1H),
1.46 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 141.0, 130.5,
127.9, 125.5, 124.1, 115.2, 58.8, 36.5, 36.3, 23.3.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (No. 21072063, No. 21107026, No.
21073125, and No. 31170675) and GNSF (No.
10351064101000000) for financial support. The authors are
also grateful to Prof. Yuanfu Deng (School of Chemistry and
Chemical Engineering, SCUT) for the X-ray single-crystal
analysis.
Ethyl-4-(4-methoxyphenylimino)-3-(1-(methylsulfonyl)indolin-2-
enyl)-5-oxo-1-p-tolyl-4,5-dihydro-1H-pyrrole-2-carboxylate (3u).
1
Red oil; 50.3 mg, 50% yield: H NMR (400 MHz, CDCl3) δ 7.39
(d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 7.24−7.16 (m, 4H),
7.13−7.06 (m, 3H), 6.76 (d, J = 8.9 Hz, 2H), 5.76 (dd, J = 4.0, 8.0 Hz,
1H), 4.11−4.06 (m, 1H), 4.06−3.97 (m, 1H), 3.79 (s, 3H), 3.72−3.68
(m, 1H), 3.45−3.42 (m, 1H), 2.83 (s, 3H), 2.35 (s, 3H), 0.93 (t, J =
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 155.9, 148.6,
142.3, 140.0, 137.6, 132.9, 131.3, 129.5, 127.7, 127.2, 125.7, 124.8,
123.9, 121.9, 114.4, 113.5, 62.0, 56.1, 55.5, 35.6, 29.7, 21.1, 13.4; IR
(KBr) 3361, 2925, 1726, 1605, 1514, 1461, 973, 736, 583 cm−1;
HRMS (ESI-TOF) calcd for [M + H]+ C30H30N3O6S 560.1850, found
560.1850.
General Procedure for the Preparation of Intermediate (2a-
7). Cu(OAc)2 (0.54 mmol, 3.0 equiv), KHCO3 (0.18 mmol, 1.0
equiv), N-methylsulfonyl-2-allylaniline 1a (0.18 mmol, 1.0 equiv), and
α-imino ester 2a (0.36 mmol, 2.0 equiv) were dissolved in 2.0 mL of
toluene in a tube, and then the tube was sealed and heated at 135 °C
under Ar in an oil bath for 8 h. Then the reaction mixture was cooled
down and filtrated. The corresponding filtrate was concentrated in
vacuo to give crude residue, and the further chromatography on SiO2
(20% ethyl acetate in hexanes) afforded the purified product 2a-7.
Ethyl-2-(4-methoxyphenylamino)-3-(1-(methylsulfonyl)indolin-2-
enyl)propanoate (2a-7). Yellow oil; 9.0 mg, 12% yield: 1H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 1H), 7.25−7.19 (m, 2H), 7.09 (t,
J = 7.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.9 Hz, 2H),
4.64 (m, 1H), 4.14 (m, 3H), 3.74 (s, 3H), 3.44−3.41 (m, 1H), 2.92−
2.90 (m, 1H), 2.77 (s, 3H), 2.34−2.32 (m, 1H), 2.17−2.09 (m, 1H),
1.18 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.4, 152.9,
140.9, 130.9, 128.2, 125.6, 124.9, 116.4, 115.5, 114.9, 61.3, 59.9, 55.7,
55.1, 39.90, 35.8, 34.5, 29.7, 14.1; IR (KBr) 3861, 3850, 2925, 1732,
1598, 1514, 1463, 1347, 824, 753, 634 cm−1; HRMS (ESI-TOF) calcd
for [M + H]+ C21H28N2O5S 419.1635, found 419.1638.
Notes: When equal amounts of both alkene 1a (0.18 mmol, 1.0
equiv) and α-imino ester 2a (0.18 mmol, 1.0 equiv) were subjected to
react under the same conditions, only 7% yield of 2a-7 (5.3 mg) was
obtained.
General Procedure for Monitoring the Reaction Progress
Using HPLC Method. The HPLC-MS spectra about the [2a-6 + H]+
was obtained in absence of MnO2 under the following reaction
conditions: The mixture of Cu(OAc)2 (0.54 mmol, 3.0 equiv),
KHCO3 (0.18 mmol, 1.0 equiv), N-methylsulfonyl-2-allylaniline 1a
(0.18 mmol, 1.0 equiv), and α-imino ester 2b (0.36 mmol, 2.0 equiv)
were dissolved in 2.0 mL of toluene in tube, and then the tube was
sealed and heated at 135 °C in an oil bath for 8 h. Then the
corresponding mixture was monitored by HPLC−MS to get the
corresponding MS spectra of 2a-6.
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■
S
* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: tongmei@scut.edu.cn.
*E-mail: dgxu@scu.edu.cn.
*E-mail: zengwei@scut.edu.cn.
(15) We have already separated and characterized the byproduct 2a-7
1
by H NMR, 13C NMR, and HRMS spectra (see SI for more detail).
775
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Article
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