Allylic amination and N-arylation-based domino reactions providing rapid three-component strategies to fused pyrroles with different substituted patterns

Article abstract of DOI:10.1021/jo301323r

New three-component domino reaction providing divergent approaches to multifunctionalized fused pyrroles with different substituted patterns have been established (40 examples). The direct C(sp³)-N bond formation was achieved through intermolecular allylic amination in a one-pot operation, and N-arylation of amines was realized by varying N-amino acid enaminones. The reaction is easy to perform simply by mixing three common reactants in acetic acid under microwave heating. The reaction proceeds at fast rates and can be finished within 30 min, which makes workup convenient to give good chemical yields.

Full text of DOI:10.1021/jo301323r

Article
pubs.acs.org/joc
Allylic Amination and N‑Arylation-Based Domino Reactions
Providing Rapid Three-Component Strategies to Fused Pyrroles with
Different Substituted Patterns
Bo Jiang,† Ying Li,† Man-Su Tu,† Shu-Liang Wang,† Shu-Jiang Tu,*,† and Guigen Li*,‡,§
†School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou 221116, PR China
‡Institute of Chemistry & Biomedical Sciences, Nanjing University, Nanjing 210093, PR China
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: New three-component domino reaction provid-
ing divergent approaches to multifunctionalized fused pyrroles
with different substituted patterns have been established (40
examples). The direct C(sp3)−N bond formation was achieved
through intermolecular allylic amination in a one-pot
operation, and N-arylation of amines was realized by varying
N-amino acid enaminones. The reaction is easy to perform
simply by mixing three common reactants in acetic acid under
microwave heating. The reaction proceeds at fast rates and can
be finished within 30 min, which makes workup convenient to
give good chemical yields.
The prevalence of amines in natural products along with their
unique industrial and pharmaceutical applications via inter-
molecular amination remains to be a challenge. On the other
hand, there has been urgent demand in the design of green and
sustainable transformations since the transition metals involved
in these procedures are generally thought not to be
environmentally friendly. Therefore, the development of an
efficient and broadly applicable intermolecular allylic amination
without the use of metal catalysts is more desirable.
In the past several years, we and others have developed a
series of domino reactions that provided easy access to multiple
functionalized ring structures of chemical and pharmaceutical
interest.16−19 We also established new allylic functionalization
to highly substituted indole derivatives.17f During the
continuation of this project, we reasoned that whether the
reaction can be directed toward allylic amination to form fused
pyrrole derivatives when aliphatic carboxylic acids with soft
nucleophilicity were replaced by aromatic amines with stronger
nucleophilicity. With this notion in mind, the one-pot reaction
of arylglyoxal monohydrate, N-aryl enaminones, and aromatic
amines was performed to realize this type of intermolecular
allylic amination. Interestingly, during the study on scope of
enaminones, N-carboxyethyl enaminones were formed and led
to the desired allylic ammoniated products 4, whereas N-
carboxymethyl counterparts occurred along another direction
to form fused pyrroles 5 with different substituted patterns.
INTRODUCTION
■
Fused pyrroles are among the most ubiquitous heterocycles in
nature. They are common structural motifs in many biologically
active molecules and pharmaceutical substances.1 These
compounds are also widely employed as versatile building
blocks in synthetic organic chemistry. In the past several
decades, many methodologies for the synthesis of fused
pyrroles have been developed, which involved rearrange-
ment−cyclization of alkynol,2a alkynyl ketones,2b cycloketone
annulations,3 metal-catalyzed cascade cyclization of alkynes,4
and 1,3-dipolar cycloadditions of muchnone derivatives.5 The
̈
development of new alternate and more efficient strategies to
this family of heterocyclic compounds, minimizing the
formation of waste and byproduct, continues to be of great
interest and challenging. To the best of our knowledge, a one-
pot multicomponent synthesis of fused pyrroles via metal-free
domino reaction involving intermolecular allylic amination has
not been well documented yet.
In the meanwhile, allylic sp3 C−H amination processes that
allow the direct conversion of C−H bonds to C−N bonds are
of utmost importance regarding their potential in organic
chemistry for the synthesis of biologically active nitrogen-
containing compounds.6−9 Many efforts have been devoted to
this methodology to improve its efficiency and selectivity,
which made it more powerful and applicable.10 Among them,
the metal-catalyzed amination reactions have taken a dominant
position, and a variety of transition metal species have been
utilized in N-functionalization of saturated hydrocarbons, such
as Rh,11 Ru,12 Mn,13a Ag,13b Cu,14 Pd,15a Co,15b,c and Fe.15d
Received: June 25, 2012
Published: August 1, 2012
© 2012 American Chemical Society
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Herein, we would like to disclose these novel domino reactions
for the synthesis of polyfunctionalized fused pyrroles with
arylamino groups residing in different positions by varying N-
substituted enaminones (Scheme 1). The attractive aspect of
RESULTS AND DISCUSSION
■
β-Enaminones, as important 1,3-bidonors, had been extensively
applied to the construction of nitrogen-containing hetero-
cycles.20 Arylglyoxal monohydrate, as readily available 1,2-
biacceptors,21 can provide two active sites (C−O and CO
bonds), which can be attacked by the electron-rich β-C atom
and NH group in β-enaminones for C−C and C−N bond
formation via [3 + 2] cyclization mechanism. We devoted our
efforts on this study by using the reaction of 4-tolylglyoxal
monohydrate 1a, a preformed 5,5-dimethyl-3-(4-
bromophenylamino)cyclohex-2-enone 2a and 4-chlorobenzen-
amine 3a as the model reaction. Experiments were carried out
in various solvents, such as DMF, tetrahydrofuran (THF), and
acetic acid (HOAc), at 80 °C to search for suitable conditions
under microwave (MW) irradiation. Only a trace amount of
product was observed when DMF or THF was used as the
solvent without the use of Brønsted acid catalyst. The
incomplete reaction was observed in HCOOH and TFA.
When HOAc was used as the solvent, the reaction proceeded
smoothly to give product 4a in 85% yield. Since metal triflates
were known to show effective Lewis acidity even in the
presence of water,22 two of these Lewis acids, Sc(OTf)3 and
Cu(OTf)2, were then employed attempting to enhance yields,
but complex mixtures were formed, which made purification
difficult. It is anticipated that acetic acid serves as Brønsted acid
catalyst and reaction media for the allylic amination
simultaneously.
Scheme 1. Three-Component Domino Synthesis of Fused
Pyrroles 4 and 5
the present domino reaction is shown by the fact that the
construction of pyrrole skeleton and the direct C(sp3)−N bond
formation were readily achieved via metal-free allylic amination
in an intermolecular manner and in a one-pot operation. The
metal-free N-arylation of amines was easily realized in domino
fashion for the second reaction. During these domino
processes, N-amino acid enaminones play a key role in the
control of reaction pathways.
a
Table 1. Domino Synthesis of Fused Pyrroles 4 under MW
b
d
entry
4
Ar
R
R1
Ar′
time
yield /%
c
c
1
4a
4b
4c
4d
4e
4f
4-Tolyl (1a)
4-Bromophenyl (2a)
4-Chlorophenyl (2b)
4-Chlorophenyl (2b)
Phenyl (2c)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4-Chlorophenyl (3a)
4-Bromophenyl (3b)
4-Nitrophenyl (3c)
Phenyl (3d)
16/60
20
24
18
25
18
20
15
24
18
15
20
25
22
28
20
30
18
30
26
28
20
20
25
30
85/80
2
4-Tolyl (1a)
84
83
75
81
84
80
87
82
86
80
78
83
85
82
84
79
85
81
76
85
67
86
65
83
3
4-Tolyl (1a)
4
4-Tolyl (1a)
5
4-Tolyl (1a)
Phenyl (2c)
4-Bromophenyl (3b)
4-Bromophenyl (3b)
4-Bromophenyl (3b)
4-Chlorophenyl (3a)
4-Chlorophenyl (3a)
4-Nitrophenyl (3c)
4-Bromophenyl (3b)
4-Tolyl (3e)
6
4-Fluorophenyl (1b)
4-Chlorophenyl (1c)
4-Bromophenyl (1d)
Phenyl (1e)
4-Chlorophenyl (2b)
4-Tolyl (2d)
7
4g
4h
4i
8
4-Bromophenyl (2a)
4-Bromophenyl (2a)
4-Chlorophenyl (2b)
4-Chlorophenyl (2b)
4-Chlorophenyl (2b)
Phenyl (2c)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4j
Phenyl (1e)
4k
4l
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Chlorophenyl (1c)
4-Bromophenyl (1d)
Phenyl (1e)
4m
4n
4o
4p
4q
4r
4-Chlorophenyl (3a)
4-Chlorophenyl (3a)
4-Nitrophenyl (3c)
3-Chlorophenyl (3f)
4-Nitrophenyl (3c)
4-Tolyl (3e)
3,4-Dichlorophenyl (2e)
4-Bromophenyl (2f)
4-Chlorophenyl (2g)
4-Bromophenyl (2f)
4-Chlorophenyl (2g)
4-Chlorophenyl (2g)
Carboxyethyl (2h)
Carboxyethyl (2h)
Carboxyethyl (2h)
Carboxyethyl (2h)
Carboxyethyl (2h)
Carboxyethyl (2h)
H
H
Phenyl (1e)
H
4s
4t
Phenyl (1e)
H
4-Nitrophenyl (3c)
4-Bromophenyl (3b)
4-Fluorophenyl (3g)
4-Chlorophenyl (3a)
4-Chlorophenyl (3a)
4-Tolyl (3e)
4-Tolyl (1a)
Me
Me
Me
Me
Me
Me
4u
4v
4w
4x
4y
4-Chlorophenyl (1c)
4-Bromophenyl (1d)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Bromophenyl (3b)
a
b
c
d
Reagents and conditions: 80 °C, HOAc (1.5 mL) microwave heating. Time (min). Conventional heating (80 °C, HOAc, sealed). Isolated yield.
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a
Table 2. Domino Synthesis of Fused Pyrroles 5 under MW
b
entry
5
Ar
R
R1
Ar′
time/min
yield /%
1
5a
5b
5c
5d
5e
5f
4-Tolyl (1a)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2i)
Carboxymethyl (2j)
Carboxymethyl (2j)
Carboxymethyl (2j)
Carboxymethyl (2j)
Carboxymethyl (2j)
Carboxymethyl (2j)
Me
Me
Me
Me
Me
Me
Me
Me
H
4-Chlorophenyl (3a)
4-Bromophenyl (3b)
4-Fluorophenyl (3g)
4-Bromophenyl (3b)
4-Chlorophenyl (3a)
4-Bromophenyl (3b)
4-Chlorophenyl (3a)
4-Bromophenyl (3b)
4-Chlorophenyl (3a)
4-Fluorophenyl (3g)
4-Chlorophenyl (3a)
4-Bromophenyl (3b)
4-Tolyl (3e)
26
22
20
28
28
25
20
26
25
32
30
32
26
28
30
88
82
75
67
62
79
65
63
71
66
89
87
74
74
85
2
4-Tolyl (1a)
3
4-Tolyl (1a)
4
4-Chlorophenyl (1c)
4-Bromophenyl (1d)
4-Bromophenyl (1d)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Tolyl (1a)
5
6
7
5g
5h
5i
8
9
10
11
12
13
14
15
5j
4-Tolyl (1a)
H
5k
5l
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
4-Methoxyphenyl (1f)
H
H
5m
5n
5o
H
H
4-Fluorophenyl (3g)
3-Bromophenyl (3h)
Carboxymethyl (2j)
H
a
b
Reagents and conditions: 80 °C, HOAc (1.5 mL) microwave heating. Isolated yield.
With these optimized conditions in hand, we examined the
Scheme 2. Selective Synthesis of Fused Pyrroles 4t−4y and 5
scope of this intermolecular C−H amination process by using
various easily available starting materials. As revealed in Table 1,
the reaction resulted in corresponding target products in good
to excellent yields. The intermolecular C−H amination is easy
to perform simply by subjecting a mixture of arylglyoxal
monohydrate, various enaminones 2, and aromatic amines 3 in
acetic acid to microwave heating. Subsequently, the enami-
nones scope of this transformation was investigated (Table 1).
The intermolecular C−H amination showed tolerance of some
functional groups in the substrates including ether and C−Cl
(or Br) bonds. The 5,5-unsubstituted enaminones 2f and 2g
were subjected to this reaction providing corresponding
amination products 4o−4s in 79−85% yields. Next, we began
to examine the generality of this system. Various amine
substrates 3 were used to give the corresponding arylamino
substituted fused pyrroles through metal-free intermolecular
allylic amination. 4-Nitrophenylamine 3c was also suitable for
this domino reaction. Furthermore, functional groups like
bromide and chloride were well tolerated. These functional
groups provide ample opportunity for further functional group
manipulations, for example, by modern cross-coupling
reactions.24,25
In view of these results, we turned our attention to
investigate several differently substituted enamines. The
reactions of arylglyoxal monohydrate 1, N-amino acid
enaminones 2 with aromatic amines 3 in acetic acid were
performed under the conditions described above for a short
period (20−32 min). Interestingly, N-carboxyethyl substituents
afforded the allylic aminates 4t−4y, whereas the reaction
underwent another direction of N-arylation to form multi-
functionalized fused pyrroles 5 with different substituted
patterns when the N-carboxymethyl counterparts were
employed in these reactions (Table 2 and Scheme 2). The
resulting functionalities of these fused pyrroles offer a great
flexibility for further structural modifications. These special N-
protected α-amino acids may be directly useful for drug design,
discovery and development and for peptide/protein mimetic
research. Indeed, the protocol provides a straightforward
pathway to N-arylation of amines, which are generally prepared
via metal-catalyzed coupling reactions.23,24
regioselectivity of the sequence starting from very common and
easily accessible inexpensive starting materials. The structural
elucidation and the attribution of regioselectivity were
unequivocally determined by NMR spectroscopic analysis. In
order to further ascertain structures of the newly synthesized
fused pyrrole derivatives, single crystals of 4f and 5a were
successfully obtained with their structures unambiguously
confirmed by X-ray diffraction analysis (see the Supporting
Information). Furthermore, the reaction occurred at a very fast
speed with all cases finished within 15−32 min. Water is nearly
a sole byproduct, which makes the workup convenient. In most
cases, the products can precipitate out after cold water was
poured into the reaction mixture.
During these domino processes, the formation of pyrrole
skeleton and its amination were readily achieved via
regioselective three-component domino reaction in a one-pot
operation. Up to three sigma-bonds including a C(sp3)−N bond
were formed accompanied by the cleavage of CO and C−O
bonds of the aryl glyoxal via intermolecular allylic amination
(Scheme 3).
On the basis of all the above results, reasonable mechanisms
have been proposed for the divergent formations of multi-
functionalized fused pyrroles 4 and 5 as shown in Scheme 3.
The former involves the ring closure cascade reactions that
consist of initial condensation, isomerization, intramolecular
cyclization (A to B), and double bonds nucleophilic
substitution (B to 4). The latter underwent protonation of
imines (C to C′), intermolecular nucleophilic addition (C′ to
D), intramolecular proton transfer (D to D′), and cyclization
(D to 5) leading to final fused pyrroles 5. We reasoned that
In all cases, the functional complexity of resulting products
from this new reaction illustrates the remarkable chemo- and
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Scheme 3. Reasonable Mechanism for the Selective Formation of 4 and 5
room temperature and then diluted with cold water (20 mL). The
such a divergence in reaction pathways would be caused by the
different acidity of N-substituted amino acids 2h−2j. Compared
with acidity of acetic acid and N-substituted amino acids 2h,
enaminones 2i, 2j possess stronger acidity due to field effect of
its amino group,25 which favors protonation of imines through
intramolecular proton transfer (C to C′). This would prevent
isomerization to form enamine intermediate A. Further
investigations regarding acid-controlled regioselectivity are in
progress in our laboratory.
In conclusion, we have developed a three-component
domino reaction (arylglyoxal monohydrates, enaminones and
aromatic amines) as an alternative method for divergent
synthesis of fused pyrroles with different substituted patterns by
varying N-substituted enaminone substrate. The former
reaction proceeds by domino [3 + 2] heterocyclization
obtaining fused pyrroles 4a−4y in good yields through allylic
amination, showing that the synthetic route allows us to build
blocks of pyrrole derivatives with a wide diversity of
substituents. The latter gave the different substituted patterns
on the fused pyrrole frameworks 5a−5o through intermolecular
N-arylation. Features of this strategy include the mild
condition, convenient one-pot operation, short reaction periods
of 15−32 min, and excellent regio- and chemoselectivities.
solid product was collected by Buchner filtration and was purified by
̈
flash column chromatography (silica gel, mixtures of petroleum ether/
acetone, 7:1, v/v) to afford the desired pure fused pyrroles 4a as a
1
white solid (0.453 g, yield 85%, mp 206−207 °C): H NMR (400
MHz, CDCl3) δ 7.40 (s, 1H, ArH), 7.12−6.92 (m, 8H, ArH), 6.82 (s,
1H, ArH), 6.68 (s, 1H, ArH), 6.26 (d, J = 7.2 Hz, 2H, ArH), 3.99 (s,
1H, NH), 3.96 (s, 1H, CH), 2.77 (d, J = 17.2 Hz, 1H, CH2), 2.26 (s,
3H), 2.18 (d, J = 17.2 Hz, 1H, CH2), 1.14 (s, 3H, CH3), 1.08 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 193.6, 145.7, 144.8, 137.8,
137.5, 136.1, 132.6, 129.2, 129.1, 128.3, 122.7, 122.1, 119.8, 113.7,
105.1, 55.3, 47.8, 40.3, 27.0, 26.7, 21.2; IR (KBr, ν, cm−1) 3303, 1652,
1597, 1491, 1453, 1281, 1215, 1076, 818, 808; HRMS (ESI) m/z calcd
for C29H26BrClN2NaO, 555.0809 [M + Na]+, found 555.0794.
7-(4-Bromophenylamino)-1-(4-chlorophenyl)-6,7-dihydro-
6,6-dimethyl-2-p-tolyl-1H-indol-4(5H)-one (4b). A white solid:
1
0.448 g, yield 84%; mp 234−235 °C; H NMR (400 MHz, CDCl3) δ
7.26 (s, 1H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.02 − 6.89 (m, 7H,
ArH), 6.69 (s, 1H, ArH), 6.22 (d, J = 8.0 Hz, 2H, ArH), 4.00 (d, J =
9.2 Hz, 1H, NH), 3.92 (d, J = 9.2 Hz, 1H, CH), 2.77 (d, J = 17.2 Hz,
1H, CH2), 2.27−2.17(m, 4H, CH2, 1H, CH3, 3H), 1.14 (s, 3H, CH3),
1.08 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 193.5, 146.2,
144.9, 137.8, 135.5, 134.6, 131.8, 129.5, 129.1, 128.2, 128.2, 119.7,
114.1, 108.9, 105.0, 55.1, 47.7, 40.2, 26.9, 26.6, 21.1; IR (KBr, ν, cm−1)
3305, 1652, 1587, 1511, 1491, 1452, 1249, 1195, 1070, 818, 806;
HRMS (ESI) m/z calcd for C29H26BrClN2NaO, 555.0809 [M + Na]+,
found 555.0835.
EXPERIMENTAL SECTION
■
7-(4-Nitrophenylamino)-1-(4-chlorophenyl)-6,7-dihydro-6,6-
General Methods. Microwave irradiation was carried out with
Initiator 2.5 Microwave Synthesizers from Biotage, Uppsala, Sweden.
The reaction temperatures were measured by infrared detector during
microwave heating.
dimethyl-2-p-tolyl-1H-indol-4(5H)-one (4c). A yellow solid: 0.413
1
g, yield 83%; mp 206−207 °C; H NMR (400 MHz, CDCl3) δ 7.98
(d, J = 8.8 Hz, 2H, ArH), 7.08 (s, 1H, ArH), 6.99 (d, J = 8.0 Hz, 3H,
ArH), 6.93 (d, J = 8.0 Hz, 3H, ArH), 6.84 (s, 1H, ArH), 6.71 (s, 1H,
ArH), 6.32 (d, J = 8.8 Hz, 2H, ArH), 4.64 (d, J = 9.6 Hz, 1H, NH),
4.21 (d, J = 9.6 Hz, 1H, CH), 2.74 (d, J = 17.2 Hz, 1H, CH2), 2.32−
2.27(m, 4H, CH2, 1H, CH3, 3H), 1.21 (s, 3H, CH3), 1.09 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 192.4, 153.8, 143.1, 137.0,
136.8, 135.7, 135.4, 133.1, 129.0, 128.1, 128.0, 119.7, 104.1, 52.8, 47.9,
26.1, 25.2, 20.6; IR (KBr, ν, cm−1) 3293, 1656, 1592, 1494, 1455,
1322, 1307, 1266, 1191, 1111, 828, 754; HRMS (ESI) m/z calcd for
C29H26ClN3NaO3, 522.1554 [M + Na]+, found 522.1569.
Example for the synthesis of 4a: 7-(4-Chlorophenylamino)-1-(4-
bromophenyl)-6,7-dihydro-6,6-dimethyl-2-p-tolyl-1H-indol-4(5H)-
one (4a).
Microwave Heating. Typically, 2,2-dihydroxy-1-p-tolylethanone
(1a, 1 mmol, 0.166 g, 1.0 equiv) was introduced in a 10-mL Initiator
reaction vial, and 3-(4-bromophenylamino)-5,5-dimethylcyclohex-2-
enone (2a, 1.0 mmol, 0.294 g, 1.0 equiv) and 4-chlorobenzenamine
(3a, 1.0 mmol, 0.127 g, 1.0 equiv) as well as acetic acid (1.5 mL) were
then successively added. Subsequently, the reaction vial was closed and
then prestirred for 10 s. The mixture was irradiated (time, 16 min;
temperature, 80 °C; absorption level, high; fixed hold time) until TLC
(petroleum ether/acetone 3:1) revealed that conversion of the starting
material 1a was complete. The reaction mixture was then cooled to
6,7-Dihydro-6,6-dimethyl-1-phenyl-7-(phenylamino)-2-p-
tolyl-1H-indol-4(5H)-one (4d). A light yellow solid: 0.315 g, yield
75%; mp 224−225 °C; 1H NMR (400 MHz, CDCl3) δ 7.24−7.13 (m,
4H, ArH), 7.10−6.79 (m, 8H, ArH), 6.76 (s, 1H, ArH), 6.22 (d, J =
8.4 Hz, 2H, ArH), 4.02 (s, 1H, NH), 3.58 (s, 1H, CH), 2.82 (d, J =
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17.2 Hz, 1H, CH2), 2.26−2.23 (m, 4H, CH2, 1H and CH3, 3H), 1.15
(s, 3H, CH3), 1.11 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
193.7, 145.8, 144.6, 134.3, 131.2, 129.6, 128.3, 127.3, 126.8, 112.7,
105.4, 55.3, 47.7, 40.2, 26.8, 26.7, 20.3; IR (KBr, ν, cm−1) 3312, 1659,
1600, 1492, 1462, 1253, 1189, 1064, 957, 822, 794; HRMS (ESI) m/z
calcd for C29H28N2NaO, 443.2093 [M + Na]+, found 443.2105.
7-(4-Bromophenylamino)-6,7-dihydro-6,6-dimethyl-1-phe-
nyl-2-p-tolyl-1H-indol-4(5H)-one (4e). A white solid: 0.404 g, yield
81%; mp 203−204 °C; 1H NMR (400 MHz, CDCl3) δ 7.31−7.24 (m,
2H, ArH), 7.06 (d, J = 8.4 Hz, 3H, ArH), 6.95 (s, 6H, ArH), 6.72 (s,
1H, ArH), 6.16 (d, J = 8.4 Hz, 2H, ArH), 4.01 (d, J = 9.2 Hz, 1H,
NH), 3.81 (d, J = 9.2 Hz, 1H, CH), 2.80 (d, J = 9.2 Hz, 1H, CH2),
2.25−2.17 (m, 4H, CH2,1H and CH3, 3H), 1.15 (s, 3H, CH3), 1.07 (s,
3H, CH3); 13C NMR (100 MHz, CDCl3) δ 192.6, 147.4, 144.7, 136.6,
136.5, 136.5, 130.8, 128.8, 128.5, 128.2, 127.8, 119.2, 113.7, 105.7,
104.0, 53.1, 47.5, 26.1, 26.0, 20.6; IR (KBr, ν, cm−1) 3316, 1658, 1591,
1519, 1489, 1462, 1282, 1215, 810, 700; HRMS (ESI) m/z calcd for
C29H27BrN2NaO, 521.1998 [M + Na]+, found 521.1245.
1597, 1512, 1491, 1459, 1247, 1194, 819, 763; HRMS (ESI) m/z calcd
for C28H24BrClN2NaO, 541.0652 [M + Na]+, found 541.0653.
7-(4-Nitrophenylamino)-1-(4-chlorophenyl)-6,7-dihydro-6,6-
dimethyl-2-phenyl-1H-indol-4(5H)-one (4j). A yellow solid: 0.418
1
g, yield 86%; mp 283−284 °C; H NMR (400 MHz, CDCl3) δ 7.98
(d, J = 8.8 Hz, 2H, ArH), 7.28 (s, 1H, ArH), 7.19 (s, 3H, ArH), 7.05−
7.04 (m, 3H, ArH), 6.93−6.85 (m, 2H, ArH), 6.74 (s, 1H, ArH), 6.34
(d, J = 8.8 Hz, 2H, ArH), 4.76 (d, J = 9.6 Hz, 1H, NH), 4.22 (d, J = 9.6
Hz, 1H, CH), 2.75 (d, J = 17.2 Hz, 1H, CH2), 2.30 (d, J = 17.2 Hz,
1H, CH2), 1.21 (s, 3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 194.1, 170.7, 161.7, 150.3, 137.9, 137.8, 126.5, 107.3,
89.4, 75.2, 48.8, 40.7, 32.9, 27.5; IR (KBr, ν, cm−1) 3321, 1648, 1595,
1504, 1495, 1313, 1270, 1112, 832, 763; HRMS (ESI) m/z calcd for
C28H24ClN3NaO3, 508.1396 [M + Na]+, found 508.1400.
7-(4-Bromophenylamino)-1-(4-chlorophenyl)-6,7-dihydro-2-
(4-methoxyphenyl)-6,6-dimethyl-1H-indol-4(5H)-one (4k). A
1
light yellow solid: 0.438 g, yield 80%; mp 206−207 °C; H NMR
(400 MHz, CDCl3) δ 7.11 (d, J = 8.8 Hz, 2H, ArH), 6.97 (d, J = 8.8
Hz, 6H, ArH), 6.71 (d, J = 8.8 Hz, 2H, ArH), 6.66 (s, 1H, ArH), 6.21
(d, J = 8.8 Hz, 2H, ArH), 4.00 (d, J = 9.6 Hz, 1H, NH), 3.81 (d, J = 9.6
Hz, 1H, CH), 3.74 (s, 3H, CH3), 2.77 (d, J = 17.2 Hz, 1H, CH2), 2.24
7-(4-Bromophenylamino)-1-(4-chlorophenyl)-2-(4-fluoro-
phenyl)-6,7-dihydro-6,6-dimethyl-1H-indol-4(5H)-one (4f). A
1
yellow solid: 0.452 g, yield 84%; mp 235−236 °C; H NMR (400
(d, J = 17.2 Hz, 1H, CH2), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3); 13
C
MHz, CDCl3) δ 7.42 (s, 1H, ArH), 7.13−7.00 (m, 5H, ArH), 6.90−
6.79 (m, 3H, ArH), 6.69 (s, 1H, ArH), 6.25 (d, J = 8.0 Hz, 2H, ArH),
4.01 (d, J = 8.0 Hz, 1H, NH), 3.82 (d, J = 8.4 Hz, 1H, CH), 2.77 (d, J
= 17.2 Hz, 1H, CH2), 2.24 (d, J = 17.2 Hz, 1H, CH2), 1.15 (s, 3H,
CH3), 1.09 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 193.5,
NMR (100 MHz, CDCl3) δ 193.9, 146.2, 145.1, 137.7, 135.4, 134.7,
131.8, 131.1, 129.5, 128.4, 128.3, 127.5, 119.7, 114.1, 108.9, 105.4,
55.1, 47.6, 40.2, 26.8, 26.6; IR (KBr, ν, cm−1) 3309, 1656, 1597, 1557,
1518, 1492, 1460, 1249, 1177, 1110, 1070, 817, 775; HRMS (ESI) m/
z calcd for C29H26BrClN2NaO2, 571.0758 [M + Na]+, found 571.0763.
7-(p-Tolylamino)-1-(4-chlorophenyl)-6,7-dihydro-2-(4-me-
thoxyphenyl)-6,6-dimethyl-1H-indol-4(5H)-one (4l). A white
1
4
162.1 (JCF = 246.7 Hz), 145.5, 145.0, 136.6, 135.7, 132.6 (JCF = 2.5
3
2
Hz), 130.1 (JCF = 8.2 Hz), 129.0, 122.8, 122.1, 119.7, 115.5 (JCF
=
21.5 Hz), 113.6, 105.4, 55.2, 47.7, 40.2, 26.9, 26.5; IR (KBr, ν, cm−1)
3325, 1659, 1594, 1490, 1455, 1214, 1157, 1015, 818, 804; HRMS
(ESI) m/z calcd forC28H23BrClFN2NaO, 559.0558 [M + Na]+, found
559.0565.
1
solid: mp 0.379 g, yield 78%; mp205−206 °C; H NMR (400 MHz,
CDCl3) δ 7.22 (s, 1H, ArH), 7.03−6.80 (m, 7H, ArH),), 6.70 (d, J =
8.4 Hz, 2H, ArH),), 6.66 (s, 1H, ArH),), 6.25 (d, J = 8.4 Hz, 2H,
ArH), 4.00 (s, 1H, NH), 3.75 (s, 1H, CH), 3.73 (s, 3H, CH3), 2.82 (d,
J = 17.2 Hz,1H, CH2), 2.23−2.19 (m, 4H, CH2, 1H, CH3, 3H), 1.14
(s, 3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
193.8, 158.8, 145.4, 144.8, 137.2, 135.5, 134.2, 129.6, 123.7, 119.4,
113.7, 112.7, 104.5, 55.3, 55.1, 47.7, 40.2, 26.8, 26.7, 20.3; IR (KBr, ν,
cm−1) 3345, 1658, 1613, 1517, 1455, 1408, 1291, 1215, 1177, 1089,
1048, 1024, 851; HRMS (ESI) m/z calcd for C30H29ClN2NaO2,
507.1809 [M + Na]+, found 507.1797.
7-(4-Bromophenylamino)-2-(4-chlorophenyl)-6,7-dihydro-
6,6-dimethyl-1-p-tolyl-1H-indol-4(5H)-one (4g). A light yellow
1
solid: 0.426 g, yield 80%; mp 220−221 °C; H NMR (400 MHz,
CDCl3) δ 7.11 (d, J = 7.6 Hz, 3H, ArH), 7.05 (d, J = 8.0 Hz, 2H,
ArH), 6.98 (d, J = 7.6 Hz, 3H,), 6.75−6.71 (m, 3H, ArH), 6.18 (d, J =
8.0 Hz, 2H, ArH), 4.00 (s, 1H, NH), 3.93 (s, 1H, CH), 2.77 (d, J =
17.2 Hz, 1H, CH2), 2.28 (s, 3H, CH3), 2.21 (d, J = 17.2 Hz, 1H, CH2),
1.15 (s, 3H, CH3), 1.04 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
193.3, 146.4, 145.6, 139.0, 136.4, 134.0, 133.2, 131.6, 130.1, 129.3,
128.5, 119.5, 114.3, 108.7, 105.4, 55.2, 47.8, 40.2, 26.9, 26.6, 21.2; IR
(KBr, ν, cm−1) 3360, 1654, 1588, 1515, 1488, 1460, 1216, 822, 813,
746; HRMS (ESI) m/z calcd for C29H26BrClN2NaO, 555.0809 [M +
Na]+, found 555.0815.
7-(4-Chlorophenylamino)-6,7-dihydro-2-(4-methoxyphen-
yl)-6,6-dimethyl-1-phenyl-1H-indol-4(5H)-one (4m). A light
1
yellow solid: 0.389 g, yield 83%; mp 207−208 °C; H NMR (400
MHz, CDCl3) δ 7.30 (s, 1H, ArH), 7.25−7.21 (m, 1H, ArH), 7.08 (s,
1H, ArH), 6.98−6.92 (m, 6H, ArH), 6.69−6.67 (m, 3H, ArH), 6.22
(d, J = 8.8 Hz, 2H, ArH), 4.00 (d, J = 6.4 Hz, 1H, NH), 3.88 (d, J = 7.2
Hz, 1H, CH), 3.72 (s, 3H, CH3), 2.80 (d, J = 17.2 Hz, 1H, CH2), 2.22
7-(4-Chlorophenylamino)-1,2-bis(4-bromophenyl)-6,7-dihy-
dro-6,6-dimethyl-1H-indol-4(5H)-one (4h). Pale white solid: 0.520
g, yield 87%; mp 222−223 °C; 1H NMR (400 MHz, CDCl3) δ 7.43 (s,
1H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 7.26 (s, 1H), 7.12 (d, J = 8.0
Hz, 1H, ArH), 6.99 (d, J = 8.4 Hz, 2H, ArH), 6.91 (d, J = 8.0 Hz, 3H,
ArH), 6.79 (s, 1H, ArH), 6.74 (s, 1H, ArH), 6.25−6.19 (m, 2H, ArH),
4.01 (d, J = 6.8 Hz, 1H, NH), 3.76 (d, J = 7.2 Hz, 1H, CH), 2.77 (d, J
= 17.2 Hz, 1H,CH2), 2.25 (d, J = 17.2 Hz, 1H, CH2), 1.14 (s, 3H,
CH3), 1.09 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 193.6,
145.6, 145.5, 136.4, 135.7, 132.8, 131.9, 131.7, 130.1, 129.7, 129.1,
123.0, 122.2, 121.8, 119.9, 114.2, 113.7, 105.9, 55.2, 47.7, 40.2, 26.9,
26.5; IR (KBr, ν, cm−1) 3344, 1658, 1597, 1491, 1448, 1253, 1192,
1073, 1012, 813; HRMS (ESI) m/z calcd for C28H23Br2ClN2NaO,
618.9757 [M + Na]+, found 618.9764.
7-(4-Chlorophenylamino)-1-(4-bromophenyl)-6,7-dihydro-
6,6-dimethyl-2-phenyl-1H-indol-4(5H)-one (4i). A white solid:
0.424 g, yield 82%; mp 247−248 °C; 1H NMR (400 MHz, CDCl3) δ
7.40 (s, 1H, ArH), 7.18−7.05 (m, 6H, ArH), 6.99 (d, J = 8.0 Hz, 2H,
ArH), 6.82 (s, 2H, ArH), 6.73 (s, 1H, ArH), 6.26 (d, J = 8.0 Hz, 2H,
ArH),4.01 (s, 1H, NH), 3.91 (s, 1H, CH), 2.78 (d, J = 17.2 Hz, 1H,
CH2), 2.23 (d, J = 17.2 Hz, 1H, CH2), 1.15 (s, 3H, CH3), 1.09 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 193.6, 145.7, 145.1, 137.7,
136.1, 132.6, 131.2, 129.1, 128.5, 128.4, 127.6, 122.8, 122.2, 119.9,
113.7, 105.6, 55.3, 47.8, 40.3, 27.0, 26.7; IR (KBr, ν, cm−1) 3328, 1656,
(d, J = 17.2 Hz, 1H, CH2), 1.15 (s, 3H, CH3), 1.06 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3) δ 194.1, 144.8, 143.8, 138.5, 137.6, 134.4,
131.6, 129.8, 129.2, 128.3, 128.2, 127.3, 122.4, 121.4, 114.3, 105.6,
45.2, 33.2, 28.4, 21.1; IR (KBr, ν, cm−1) 3309, 1656, 1597, 1557, 1518,
1492, 1460, 1249, 1177, 1110, 1070, 817, 775. HRMS (ESI) m/z calcd
for C29H27ClN2NaO2, 493.1653 [M + Na]+, found 493.1632.
7-(4-Chlorophenylamino)-1-(3,4-dichlorophenyl)-6,7-dihy-
dro-2-(4-methoxyphenyl)-6,6-dimethyl-1H-indol-4(5H)-one
1
(4n). A white solid: 0.457 g, yield 85%; mp 228−229 °C; H NMR
(400 MHz, CDCl3) δ 7.13−6.83 (m, 6H, ArH), 6.79−6.55 (m, 4H,
ArH), 6.33−6.27 (m, 2H, ArH), 4.06 (s, 1H, NH), 3.98 (s, 1H, CH),
3.75 (s, 3H, CH3), 2.76 (d, J = 16.4 Hz, 1H, CH2), 2.23 (d, J = 16.4
Hz, 1H, CH2), 1.18 (s, 3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 193.5, 159.1, 145.9, 144.4, 138.9, 137.6, 131.8, 129.6,
128.8, 123.1, 120.0, 113.8, 109.3, 104.8, 55.2, 47.9, 40.1, 29.9, 26.3; IR
(KBr, ν, cm−1) 3307, 1651, 1615, 1594, 1492, 1452, 1296, 1251, 1177,
1130, 1074, 1034, 838, 819; HRMS (ESI) m/z calcd for
C29H25Cl3N2NaO2 563.0843 [M + Na]+, found 563.0837.
7-(4-Nitrophenylamino)-1-(4-bromophenyl)-2-(4-chloro-
phenyl)-6,7-dihydro-1H-indol-4(5H)-one (4o). A yellow solid:
0.438 g, yield 82%; mp 288−289 °C; 1H NMR (400 MHz, DMSO-d6)
δ 7.89 (d, J = 8.6 Hz, 2H, ArH), 7.62 (d, J = 8.0 Hz, 1H, NH), 7.35−
7.32 (m, 5H, ArH), 7.13−7.10 (m, 3H, ArH), 6.78 (s, 1H, ArH), 6.51
7501
dx.doi.org/10.1021/jo301323r | J. Org. Chem. 2012, 77, 7497−7505

The Journal of Organic Chemistry
Article
(d, J = 8.8 Hz, 2H, ArH), 4.83−4.81 (m, 1H, CH), 2.69−2.65 (m, 1H,
3-(7-(4-Fluorophenylamino)-2-(4-chlorophenyl)-4,5,6,7-tet-
rahydro-6,6-dimethyl-4-oxoindol-1-yl)propanoic acid (4u).
White solid: 0.388 g, yield 85%; mp 204−205 °C; H NMR (400
CH2), 2.44−2.26 (m, 2H, CH2), 2.11 (d, J = 10.6 Hz, 1H, CH2); 13
C
1
NMR (100 MHz, CDCl3) δ 192.8, 152.4, 143.2, 136.1, 135.7, 135.4,
132.3, 128.5, 125.9, 121.8, 121.4, 105.6, 43.7, 33.6, 28.8; IR (KBr, ν,
cm−1) 3280, 1651, 1599, 1541, 1477, 1457, 1315, 1113, 1092, 1011,
833, 752; HRMS (ESI) m/z calcd for C26H18BrClN3O3, 534.0214 [M
− H]−, found 534.0227.
MHz, DMSO-d6) δ 12.18 (s, 1H, COOH), 8.03 (d, J = 8.0 Hz, 2H),
7.58−7.52 (m, 4H, ArH), 7.41 (s, 1H, ArH), 7.36 (s, 2H, ArH), 6.45
(d, J = 7.2 Hz, 1H, NH), 4.66 (d, J = 9.2 Hz, 1H, CH), 2.97−2.90 (m,
1H, CH2), 2.64−2.62 (m, 2H, CH2), 2.00 (d, J = 16.0 Hz, 1H, CH2),
1.75 (d, J = 17.2 Hz, 1H, CH2), 1.64 (d, J = 16.0 Hz, 1H, CH2), 0.98
(s, 3H, CH3), 0.67 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ193.4, 174.1, 168.1 (JCF1 = 240.5 Hz), 140.4, 137.7, 134.8 (JCF4 = 1.7
7-(3-Chlorophenylamino)-2-(4-bromophenyl)-1-(4-chloro-
phenyl)-6,7-dihydro-1H-indol-4(5H)-one (4p). A white solid: 0.44
1
g, yield 84%; mp 245−246 °C; H NMR (400 MHz, CDCl3) δ 7.34
3
Hz), 133.8, 131.8, 130.7, 130.1 (JCF = 7.8 Hz), 129.3, 129.0, 126.9,
(d, J = 8.4 Hz, 3H, ArH), 7.24 (s, 2H, ArH), 7.06 (t, J = 8.0 Hz, 1H,
ArH), 6.93 (d, J = 8.4 Hz, 3H, ArH), 6.78 (s, 1H, ArH), 6.71 (d, J =
8.8 Hz, 1H, ArH), 6.48 (s, 1H, ArH), 6.39 (dd, J = 8.0, 2.0 Hz, 1H,
ArH), 4.47 (s, 1H, NH), 4.16 (d, J = 8.4 Hz, 1H, CH), 2.78 (m, 1H,
CH2), 2.49 (m, 1H, CH2), 2.43−2.34 (m, 1H, CH2), 2.23 (m, 1H,
CH2); 13C NMR (100 MHz, CDCl3) δ 193.6, 158.9, 146.0, 144.5,
135.4, 134.5, 131.8, 129.6, 123.5, 119.6, 113.8, 108.9, 104.5, 55.2, 55.0,
47.6, 40.2, 26.8, 26.6; IR (KBr, ν, cm−1) 3327, 1651, 1598, 1517, 1495,
1459. 1181, 1093, 1011, 833, 806, 759; HRMS (ESI) m/z calcd for
C26H19BrCl2N2NaO, 548.9922 [M + Na]+, found 548.9934.
116.0 (JCF2 = 21.6 Hz), 105.7, 55.7, 49.7, 37.5, 36.7, 33.9, 29.1, 28.0; IR
(KBr, ν, cm−1) 3417, 3091, 1753, 1692, 1588, 1564, 1496, 1441, 1402,
1354, 1290, 1188, 11117, 1090, 1003, 832, 819; HRMS (ESI) m/z
calcd for C25H23ClFN2O3, 453.1376 [M − H]−, found 453.1396.
3-(7-(4-Chlorophenylamino)-2-(4-bromophenyl)-4,5,6,7-tet-
rahydro-6,6-dimethyl-4-oxoindol-1-yl)propanoic acid (4v).
1
White solid: 0.348 g, yield 67%; mp 202−203 °C; H NMR (400
MHz, DMSO-d6) δ 12.30 (s, 1H, COOH), 7.63 (d, J = 8.0 Hz, 2H,
ArH), 7.41 (d, J = 8.0 Hz, 2H, ArH), 7.08 (d, J = 8.4 Hz, 2H, ArH),
6.88 (d, J = 8.4 Hz, 2H, ArH), 6.41 (s, 1H, ArH), 6.30 (d, J = 9.6 Hz,
1H, NH), 4.79 (d, J = 9.6 Hz, 1H, CH), 4.11−3.99 (m, 2H, CH2),
2.82 (d, J = 16.4 Hz, 1H, CH2), 2.41−2.35 (m, 1H, CH2), 2.28−2.18
(m, 1H, CH2), 1.96 (d, J = 16.4 Hz, 1H, CH2), 1.09 (s, 3H, CH3), 1.00
(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 192.3, 171.4, 147.3,
143.7, 134.4, 131.7, 131.1, 130.7, 128.7, 121.4, 119.0, 118.7, 113.1,
105.4, 56.0, 47.4, 34.4, 26.2, 18.5; IR (KBr, ν, cm−1) 3291, 1710, 1651,
1595, 1528, 1488, 1454, 1409, 1385, 1317, 1279, 1230, 1190, 1074,
1010, 832, 815; HRMS (ESI) m/z calcd for C25H23BrClN2O3,
515.0555 [M − H]−, found 515.0556.
7-(4-Nitrophenylamino)-1-(4-bromophenyl)-6,7-dihydro-2-
phenyl-1H-indol-4(5H)-one (4q). A white solid: 0.395 g, yield 79%;
1
mp 226−227 °C; H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.8
Hz, 2H, ArH), 7.64 (d, J = 8.0 Hz, 1H, NH), 7.43−7.23 (m, 7H, ArH),
7.11(d, J = 7.2 Hz, 2H, ArH), 6.73 (s, 1H, ArH), 6.52 (d, J = 8.8 Hz,
2H, ArH), 4.83−4.81 (m, 1H, CH), 2.74−2.67 (m, 1H, CH2), 2.39−
2.31 (m, 2H, CH2), 2.12−2.09 (m, 1H, CH2); 13C NMR (100 MHz,
CDCl3) δ 193.0, 152.8, 142.9, 136.8, 136.1, 135.5, 133.1, 131.0, 129.6,
128.4, 128.2, 127.5, 126.0, 121.4, 105.1, 43.7, 33.6, 28.8; IR (KBr, ν,
cm−1) 3298, 1643, 1598,1533, 1493, 1478, 1461, 1312, 1203, 1111,
831, 761; HRMS (ESI) m/z calcd for C26H19BrN3O3, 502.0583 [M −
H]−, found 502.0594.
3-(7-(4-Chlorophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-6,6-dimethyl-4-oxoindol-1-yl)propanoic acid
1
(4w). White solid: 0.402 g, yield 86%; mp 197−198 °C; H NMR
7-(p-Tolylamino)-1-(4-chlorophenyl)-6,7-dihydro-2-phenyl-
(400 MHz, DMSO-d6) δ 12.29 (s, 1H, COOH), 7.36 (d, J = 8.8 Hz,
2H, ArH), 7.08 (d, J = 8.8 Hz, 2H, ArH), 7.00 (d, J = 8.8 Hz, 2H,
ArH), 6.87 (d, J = 8.8 Hz, 2H, ArH), 6.32−6.28 (m, 2H, ArH, 1H and
NH, 1H), 4.78 (d, J = 10.0 Hz, 1H, CH), 4.10−3.93 (m, 2H, CH2),
3.79 (s, 3H, CH3), 2.82 (d, J = 16.4 Hz, 1H, CH2), 2.41−2.32 (m, 1H,
CH2), 2.28−2.18 (m, 1H, CH2), 1.94 (d, J = 16.4 Hz, 1H, CH2), 1.09
(s, 3H, CH3), 1.00 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
192.4, 171.6, 159.0, 146.2, 143.5, 135.4, 130.2, 129.5, 124.2, 123.8,
118.6, 114.2, 111.8, 104.4, 55.1, 52.3, 47.5, 34.4, 26.5), 20.0; IR (KBr,
ν, cm−1) 3414, 3305, 1709, 1649, 1595, 1527, 1490, 1446, 1409, 1249,
1175, 1110, 1038, 838; HRMS (ESI) m/z calcd for C26H26ClN2O4,
465.1576 [M − H]−, found 465.1555.
1H-indol-4(5H)-one (4r). A white solid: 0.361 g, yield 85%; mp
1
245−246 °C; H NMR (400 MHz, CDCl3) δ 7.25−7.20 (m, 6H,
ArH), 7.09 (s, 3H, ArH), 6.98 (d, J = 8.0 Hz, 2H, ArH), 6.79 (s, 1H,
ArH), 6.47 (d, J = 8.0 Hz, 2H, ArH), 4.47 (s, 1H, NH), 4.04 (s, 1H,
CH), 2.84−2.75 (m, 1H, CH2), 2.46 (s, 2H, CH2), 2.25 (s, 3H, CH3),
2.18−2.11 (m, 1H, CH2); 13C NMR (100 MHz, CDCl3) δ 194.4,
144.3, 143.6, 137.5, 135.9, 134.3, 131.4, 130.1, 129.5, 128.5, 127.6,
121.9, 114.0, 106.2, 45.4, 33.1, 28.1, 20.5; IR (KBr, ν, cm−1) 3357,
1653, 1616, 1519, 1304, 1214, 1090, 842, 733, 696; HRMS (ESI) m/z
calcd for C27H22ClN2O, 425.1415 [M − H]−, found 425.1417.
7-(4-Nitrophenylamino)-1-(4-chlorophenyl)-6,7-dihydro-2-
phenyl-1H-indol-4(5H)-one (4s). A yellow solid: 0.371 g, yield 81%;
3-(7-(p-Tolylamino)-4,5,6,7-tetrahydro-2-(4-methoxyphen-
yl)-6,6-dimethyl-4-oxoindol-1-yl)propanoic acid (4x). White
1
mp 274−276 °C; H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.8
Hz, 2H, ArH), 7.65 (d, J = 8.0 Hz, 1H, NH), 7.30−7.23 (m, 7H, ArH),
7.12−7.11 (m, 2H, ArH), 6.73 (s, 1H, ArH), 6.52 (d, J = 8.8, 2H,
ArH), 4.83−4.81 (m, 1H, CH), 2.74−2.68 (m, 1H, CH2), 2.39−2.30
(m, 2H, CH2), 2.13−2.08 (m, 1H, CH2); 13C NMR (100 MHz,
DMSO-d6) δ 193.0, 152.8, 142.9, 136.8, 136.2, 136.0, 131.0, 129.9,
128.4, 127.5, 125.9, 121.6, 121.4, 105.1, 43.7, 33.6, 28.8; IR (KBr, ν,
cm−1) 3301, 1644, 1598, 1496, 1460, 1312, 1204, 1110, 831, 760;
HRMS (ESI) m/z calcd for C26H20ClN3NaO3, 480.1085 [M + Na]+,
found 480.1099.
1
solid: 0.291 g, yield 65%; mp 206−208 °C; H NMR (400 MHz,
DMSO-d6) δ 12.27 (s, 1H, COOH), 7.35 (d, J = 8.0 Hz, 2H, ArH),
7.00 (d, J = 8.4 Hz, 2H, ArH), 6.89 (d, J = 8.0 Hz, 2H, ArH), 6.76 (d, J
= 8.0 Hz, 2H, ArH), 6.27 (s, 1H, ArH), 5.87 (d, J = 10.0 Hz, 1H, NH),
4.75 (d, J = 9.6 Hz, 1H, CH), 4.06−3.97 (m, 2H, CH2), 3.79 (s, 3H,
CH3), 2.85 (d, J = 16.4 Hz, 1H, CH2), 2.44−2.35 (m, 1H, CH2),
2.28−2.19 (m, 1H, CH2), 2.14 (s, 3H, CH3), 1.92 (d, J = 16.4 Hz, 1H,
CH2), 1.08 (s, 3H, CH3), 0.99 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 192.4, 171.5, 159.0, 146.2, 143.5, 135.4, 130.2, 129.5,
124.2, 123.8, 118.6, 114.2, 111.8, 104.4, 55.1, 52.3, 47.5, 34.4, 26.5,
20.0; IR (KBr, ν, cm−1) 3414, 3370, 1721, 1616, 1521, 1494, 1475,
1303, 1280, 1251, 1215, 1186, 1032, 817, 804; HRMS (ESI) m/z calcd
for C27H29N2O4, 445.2122 [M − H]−, found 445.2109.
3-(7-(4-Bromophenylamino)-4,5,6,7-tetrahydro-6,6-dimeth-
yl-4-oxo-2-p-tolylindol-1-yl)propanoic acid (4t). White solid:
0.376 g, yield 76%; mp 205−206 °C; 1H NMR (400 MHz, DMSO-d6)
δ 12.29 (s, 1H, COOH), 7.32 (d, J = 7.6 Hz, 2H, ArH), 7.25 (d, J = 7.6
Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 2H,
ArH), 6.34 (s, 1H, ArH), 6.31 (s, 1H, NH), 4.79 (d, J = 10.0 Hz, 1H,
CH), 4.10−3.97 (m, 2H, CH2), 2.81 (d, J = 16.4 Hz, 1H, CH2), 2.34
(m, 4H, CH3, 1H and CH2, 1H), 2.27−2.19 (m, 1H, CH2), 1.95 (d, J
= 16.4 Hz, 1H, CH2), 1.09 (s, 3H, CH3), 1.00 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ 192.3, 171.4, 147.7, 143.0, 137.5, 135.7,
131.5, 129.4, 129.0, 128.6, 118.8, 113.7, 106.0, 104.6, 56.0, 52.0, 47.4,
34.3, 26.3, 20.7, 18.5; IR (KBr, ν, cm−1) 3294, 1705, 1650, 1589, 1527,
1487, 1467, 1451, 1319, 1279, 1191, 1069, 814, 790; HRMS (ESI) m/
z calcd for C26H26BrN2O3, 495.1105 [M − H]−, found 495.1096.
3-(7-(4-Bromophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-6,6-dimethyl-4-oxoindol-1-yl)propanoic acid
(4y). Pale white solid: 0.423 g, yield 83%; mp 202−203 °C; 1H
NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H, COOH), 7.36 (d, J = 7.6
Hz, 2H, ArH), 7.19 (d, J = 7.6 Hz, 2H, ArH), 7.00 (d, J = 7.6 Hz, 2H,
ArH), 6.84 (d, J = 7.6 Hz, 2H, ArH), 6.32 (d, J = 9.6 Hz, 1H, NH),
6.28 (s, 1H, ArH), 4.79 (d, J = 9.2 Hz, 1H, CH), 4.05−4.00 (m, 2H,
CH2), 3.79 (s, 3H, CH3), 2.82 (d, J = 16.0 Hz, 1H, CH2), 2.42−2.20
(m, 2H, CH2), 1.94 (d, J = 16.0 Hz, 1H, CH2), 1.09 (s, 3H, CH3), 1.00
(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 192.3, 171.5, 159.0,
7502
dx.doi.org/10.1021/jo301323r | J. Org. Chem. 2012, 77, 7497−7505

The Journal of Organic Chemistry
Article
147.7, 142.8, 135.6, 130.2, 124.1, 118.7, 114.2, 113.7, 106.0, 104.4,
55.1, 52.0, 47.4, 34.3, 26.3; IR (KBr, ν, cm−1) 3302, 1707, 1648, 1589,
1468, 1409, 1294, 1248, 1038, 838, 814; HRMS (ESI) m/z calcd for
C26H26BrN2O4, 511.1054 [M − H]−, found 511.1037.
ArH), 6.38 (d, J = 7.6 Hz, 2H, ArH), 4.64 (s, 2H, CH2), 2.68 (s, 2H,
CH2), 2.22 (s, 2H, CH2), 1.07 (s, 6H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 191.5, 169.6, 147.3, 143.0, 131.5, 130.9, 129.1, 128.0,
121.2, 120.2, 114.9, 113.9, 107.0, 52.1, 46.1, 35.1 34.7, 28.1; IR (KBr,
ν, cm−1) 3551, 3477, 3414, 3301, 1717, 1614, 1487, 1470, 1386, 1344,
1268, 1170, 1096, 1014, 832, 820; HRMS (ESI) m/z calcd for
C24H21Br2N2O3, 544.9895 [M − H]−, found 544.9860.
2-(3-(4-Chlorophenylamino)-4,5,6,7-tetrahydro-6,6-dimeth-
yl-4-oxo-2-p-tolylindol-1-yl)acetic acid (5a). Pale white solid:
1
0.385 g, yield 88%; mp 215−215.5 °C; H NMR (400 MHz, DMSO-
d6) δ 13.07 (s, 1H, COOH), 7.21−7.14 (m, 3H, ArH, 2H and NH,
1H), 7.10 (d, J = 7.6 Hz, 2H, ArH), 6.96 (d, J = 8.4 Hz, 2H, ArH),
6.43 (d, J = 8.4 Hz, 2H, ArH), 4.59 (s, 2H, CH2), 2.67 (s, 2H, CH2),
2.29 (s, 3H), 2.22 (s, 2H, CH2), 1.07 (s, 6H, CH3); 13C NMR (100
MHz, DMSO-d6) δ 191.6, 169.7, 147.2, 142.5, 137.2, 129.1, 126.9,
119.7, 119.3, 114.3, 113.9, 52.1, 46.0, 35.1, 34.7, 28.2, 20.7; IR (KBr, ν,
cm−1) 3551, 3412, 3300, 1717, 1613, 1471, 1402, 1344, 1270, 1099,
823; HRMS (ESI) m/z calcd for C25H24ClN2O3, 435.1470 [M − H]−,
found 435.1468.
2-(3-(4-Chlorophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-6,6-dimethyl-4-oxoindol-1-yl)acetic acid (5g).
1
White solid: 0.296 g, yield 65%; mp 201−203 °C; H NMR (400
MHz, CDCl3) δ 7.71 (s, 1H, NH), 7.15 (d, J = 8.4 Hz, 2H, ArH), 6.87
(d, J = 8.4 Hz, 4H, ArH), 6.50 (d, J = 8.4 Hz, 2H, ArH), 4.49 (s, 2H,
CH2), 3.78 (s, 3H), 2.63 (s, 2H, CH2), 2.30 (s, 2H, CH2), 1.15 (s, 6H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ 192.8, 169.5, 158.7, 144.8,
141.3, 130.7, 127.6, 126.1, 122.0, 121.2, 121.1, 115.3, 113.7, 112.7,
54.7, 51.8, 45.5, 35.3, 34.7, 28.2; IR (KBr, ν, cm−1) 3551, 3434, 3298,
1714, 1604, 1492, 1474, 1354, 1253, 1172, 1100, 1053, 1031, 822;
HRMS (ESI) m/z calcd for C25H24ClN2O4, 451.1419 [M − H]−,
found 451.1402.
2-(3-(4-Bromophenylamino)-4,5,6,7-tetrahydro-6,6-dimeth-
yl-4-oxo-2-p-tolylindol-1-yl)acetic acid (5b). Pale white solid:
0.393 g, yield 82%; mp 204−205 °C; 1H NMR (400 MHz, DMSO-d6)
δ 13.20 (s, 1H, COOH), 7.17 (s, 3H, ArH, 2H and NH, 1H), 7.12 −
7.05 (m, 4H, ArH), 6.39 (d, J = 7.6 Hz, 2H, ArH), 4.59 (s, 2H, CH2),
2.67 (s, 2H, CH2), 2.28 (s, 3H, CH3), 2.21 (s, 2H, CH2), 1.07 (s, 6H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ 191.5, 169.7, 147.7, 142.5,
137.2, 130.8, 129.4, 129.1, 126.8, 119.4, 114.8, 113.9, 106.6, 52.1, 46.0,
35.1, 34.7, 28.2, 20.8; IR (KBr, ν, cm−1) 3552, 3479, 3414, 3300, 1717,
1611, 1487, 1470, 1402, 1354, 1270, 1171, 1099, 1052, 985, 821;
HRMS (ESI) m/z calcd for C25H24BrN2O3, 481.0948 [M − H]−,
found 481.0969.
2-(3-(4-Bromophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-6,6-dimethyl-4-oxoindol-1-yl)acetic acid (5h).
1
White solid: 0.312 g, yield 63%; mp 208−208.5 °C; H NMR (400
MHz, DMSO-d6) δ 13.18 (s, 1H, COOH), 7.13 (d, J = 8.8 Hz, 3H,
ArH, 1H and NH, 1H), 7.05 (d, J = 8.4 Hz, 2H, ArH), 6.93 (d, J = 8.4
Hz, 2H, ArH), 6.40 (d, J = 8.4 Hz, 2H, ArH), 4.56 (s, 2H, CH2), 3.75
(s, 3H), 2.66 (s, 2H, CH2), 2.21 (s, 2H, CH2), 1.09 (s, 6H, CH3); IR
(KBr, ν, cm−1) 3530, 3449, 3299, 1714, 1603, 1570, 1509, 1487, 1344,
1253, 1173, 1098, 1029, 836, 819; 13C NMR (100 MHz, CDCl3) δ
198.4, 174.7, 163.9, 149.8, 146.3, 135.9, 135.7, 130.3, 127.3, 126.8,
121.4, 119.0, 117.7, 114.4, 60.0, 57.0, 50.7, 40.6, 40.0, 33.5; HRMS
(ESI) m/z calcd for C25H24BrN2O4, 497.0897 [M − H]−, found
497.0888.
2-(3-(4-Fluorophenylamino)-4,5,6,7-tetrahydro-6,6-dimeth-
yl-4-oxo-2-p-tolylindol-1-yl)acetic acid (5c). Pale white solid:
0.317 g, yield 75%; mp 205−206 °C; 1H NMR (400 MHz, DMSO-d6)
δ 13.21 (s, 1H, COOH), 7.21−7.14 (m, 3H, ArH, 2H and NH, 1H),
7.10 (d, J = 8.0 Hz, 2H, ArH), 6.95 (d, J = 8.8 Hz, 2H, ArH), 6.42 (d, J
= 8.8 Hz, 2H, ArH), 4.59 (s, 2H, CH2), 2.67 (s, 2H, CH2), 2.28 (s,
3H), 2.21 (s, 2H, CH2), 1.07 (s, 6H, CH3); 13C NMR (100 MHz,
2-(3-(4-Chlorophenylamino)-4,5,6,7-tetrahydro-4-oxo-2-p-
tolylindol-1-yl)acetic acid (5i). Pale yellow solid: 0.291 g, yield
1
71%; mp 220−221 °C; H NMR (400 MHz, DMSO-d6) δ 13.24 (s,
CDCl3) δ 191.5, 168.8, 153.7 (JCF1 = 241.1 Hz), 143.3 (JCF4 = 2.4 Hz),
1H, COOH), 7.19 (d, J = 7.2 Hz, 2H, ArH), 7.14 (s, 1H, NH), 7.09
(d, J = 7.2 Hz, 2H, ArH), 6.95 (d, J = 8.0 Hz, 2H, ArH), 6.44 (d, J =
8.4 Hz, 2H, ArH), 4.60 (s, 2H, CH2), 2.77 (s, 2H, CH2), 2.30 (s, 2H,
CH2), 2.28 (s, 3H, CH3), 2.04 (s, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6) δ 192.1, 169.7, 147.1, 143.5, 137.2, 129.4, 129.2, 128.9,
128.0, 126.9, 120.0, 119.3, 114.9, 114.4, 46.0, 38.1, 22.8, 21.4, 20.7; IR
(KBr, ν, cm−1) 3551, 3477, 3414, 3235, 1750, 1637, 1600, 1492, 1385,
1238, 1097, 983, 819; HRMS (ESI) m/z calcd for C23H20ClN2O3,
407.1157 [M − H]−, found 407.1165.
2
142.4, 136.1, 128.5, 128.2, 126.8, 126.2, 120.3, 113.7, 113.6 (JCF
=
3
22.5 Hz), 113.2 (JCF = 8.1 Hz), 52.1, 46.0, 35.1, 34.7, 28.1, 20.7; IR
(KBr, ν, cm−1) 3553, 3478, 3414, 3301, 1718, 1616, 1471, 1344, 1270,
1099, 1053, 823; HRMS (ESI) m/z calcd for C25H24FN2O3, 419.1765
[M − H]−, found 419.1759.
2-(3-(4-Bromophenylamino)-2-(4-chlorophenyl)-4,5,6,7-tet-
rahydro-6,6-dimethyl-4-oxoindol-1-yl)acetic acid (5d). White
1
solid: 0.337 g, yield 67%; mp 201−202 °C; H NMR (400 MHz,
DMSO-d6) δ 7.46 (d, J = 8.0 Hz, 2H, ArH), 7.28−7.20 (m, 3H, ArH,
2H and NH, 1H), 7.08 (d, J = 8.0 Hz, 2H, ArH), 6.39 (d, J = 8.0 Hz,
2H, ArH), 4.64 (s, 2H, CH2), 2.68 (s, 2H, CH2), 2.22 (s, 2H, CH2),
1.07 (s, 6H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 191.6, 169.6
147.4, 143.0, 132.6, 131.2 130.9, 128.7, 128.6, 120.2, 114.9, 113.9,
107.0, 52.1, 46.0, 35.1, 34.7, 28.1; IR (KBr, ν, cm−1) 3552, 3479, 3414,
3304, 1718, 1613, 1488, 1470, 1400, 1345, 1268, 1097, 834, 820;
HRMS (ESI) m/z calcd for C24H21BrClN2O3, 501.0398 [M − H]−,
found 501.0433.
2-(3-(4-Fluorophenylamino)-4,5,6,7-tetrahydro-4-oxo-2-p-
tolylindol-1-yl)acetic acid (5j). Pale yellow solid: 0.259 g, yield
1
66%; mp 219−220 °C; H NMR (400 MHz, DMSO-d6) δ 13.21 (s,
1H, COOH), 7.17 (d, J = 7.2 Hz, 2H, ArH), 7.09 (d, J = 7.2 Hz, 2H,
ArH), 6.90 (s, 1H, NH), 6.78−6.74 (m, 2H, ArH), 6.45−6.43 (m, 2H,
ArH), 4.60 (s, 2H, CH2), 2.76 (s, 2H, CH2), 2.31 (s, 2H, CH2), 2.28
(s, 3H, CH3), 2.04 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ
1
4
192.4, 169.7, 154.6 (JCF = 230.3 Hz), 144.2 (JCF = 1.4 Hz), 143.3,
137.1, 129.4, 129.1, 127.8, 127.2, 121.2, 114.6, 114.5 (JCF2 = 21.9 Hz),
2-(3-(4-Chlorophenylamino)-2-(4-bromophenyl)-4,5,6,7-tet-
3
114.1 (JCF = 7.3 Hz), 46.0, 38.0, 22.9, 21.4, 20.8; IR (KBr, ν, cm−1)
rahydro-6,6-dimethyl-4-oxoindol-1-yl)acetic acid (5e). White
1
3524, 3438, 3378, 1740, 1642, 1599, 1507, 1467, 1416, 1219, 1098,
1023, 824; HRMS (ESI) m/z calcd for C23H20FN2O3, 391.1452 [M −
H]−, found 391.1467.
solid: 0.313 g, yield 62%; mp 199−202 °C; H NMR (400 MHz,
DMSO-d6) δ 13.27 (s, 1H, COOH), 7.59 (d, J = 7.8 Hz, 2H, ArH),
7.25 (s, 1H, NH), 7.16 (d, J = 8.0 Hz, 2H, ArH), 6.97 (d, J = 8.0 Hz,
2H, ArH), 6.43 (d, J = 8.0 Hz, 2H, ArH), 4.64 (s, 2H, CH2), 2.68 (s,
2H, CH2), 2.22 (s, 2H, CH2), 1.07 (s, 6H, CH3); 13C NMR (100
MHz, DMSO-d6) δ 191.6, 169.6, 146.9, 143.0, 131.5, 131.4, 129.1,
128.1, 127.9, 121.2, 120.4, 119.6, 114.4, 113.9, 52.1, 46.1, 35.1, 34.7,
28.1; IR (KBr, ν, cm−1) 3552, 3478, 3414, 3302, 1719, 1613, 1529,
1470, 1398, 1344, 1268, 1096, 1015, 832; HRMS (ESI) m/z calcd for
C24H21BrClN2O3, 501.0398 [M − H]−, found 501.0430.
2-(3-(4-Chlorophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-4-oxoindol-1-yl)acetic acid (5k). Pale white solid:
1
0.381 g, yield 89%; mp 205−205.5 °C; H NMR (400 MHz, DMSO-
d6) δ 13.10 (s, 1H, COOH), 7.13 (d, J = 8.8 Hz, 3H, ArH, 1H and
NH, 1H), 6.97−6.93 (m, 4H, ArH), 6.45 (d, J = 8.0 Hz, 2H, ArH),
4.60 (s, 2H, CH2), 3.74 (s, 3H, CH3), 2.77−2.75 (m, 2H, CH2), 2.35−
2.26 (m, 2H, CH2), 2.09−2.00 (m, 2H, CH2); 13C NMR (100 MHz,
DMSO-d6) δ 192.2, 169.7, 158.9, 147.1, 143.3, 130.9, 128.7, 128.0,
121.9, 119.8, 119.3, 114.9, 114.4, 114.0, 55.0, 45.9, 38.1, 22.9, 21.4; IR
(KBr, ν, cm−1) 3524, 3414, 3372, 1738, 1642, 1493, 1246, 1097, 1021,
833, 809; HRMS (ESI) m/z calcd for C23H20ClN2O4, 423.1106 [M −
H]−, found 423.1100.
2-(3-(4-Bromophenylamino)-2-(4-bromophenyl)-4,5,6,7-tet-
rahydro-6,6-dimethyl-4-oxoindol-1-yl)acetic acid (5f). White
1
solid: 0.430 g, yield 79%; mp 212−213 °C; H NMR (400 MHz,
DMSO-d6) δ 13.27 (s, 1H, COOH), 7.59 (d, J = 7.6 Hz, 2H, ArH),
7.27 (s, 1H, NH), 7.16 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H,
7503
dx.doi.org/10.1021/jo301323r | J. Org. Chem. 2012, 77, 7497−7505

The Journal of Organic Chemistry
Article
2-(3-(4-Bromophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
Jiangsu Higher Education Institutions, Robert A. Welch
Foundation (D-1361), NIH (R21DA031860-01), the NSF of
Jiangsu Education Committee (11KJB150016), and Jiangsu
Science and Technology Support Program (No. BE2011045).
thoxyphenyl)-4-oxoindol-1-yl)acetic acid (5l). Yellow solid: 0.407
1
g, yield 87%; mp 193−194 °C; H NMR (400 MHz, DMSO-d6) δ
12.59 (s, 1H, COOH), 7.13 (s, 3H, ArH, 1H and NH, 1H), 7.07 (d, J
= 8.0 Hz, 2H, ArH), 6.94 (d, J = 7.6 Hz, 2H, ArH), 6.41 (d, J = 8.0 Hz,
2H, ArH), 4.59 (s, 2H, CH2), 3.74 (s, 3H, CH3), 2.76 (s, 2H, CH2),
2.30 (s, 2H, CH2), 2.04 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-
d6) δ 192.2, 172.0, 169.7, 158.9, 147.6, 143.3, 130.9, 130.8, 128.9,
121.9, 119.6, 115.0, 114.9, 114.0, 106.8, 55.0, 46.0, 38.1, 22.9, 21.4,
21.0; IR (KBr, ν, cm−1) 3551, 3413, 3372, 1737, 1644, 1491, 1384,
1246, 1021, 825; HRMS (ESI) m/z calcd for C23H20BrN2O4, 469.0584
[M − H]−, found 469.0567.
REFERENCES
■
(1) (a) Pyrroles, The Synthesis, Reactivity, and Physical Properties of
Substituted Pyrroles, Part II; Jones, R. A., Ed.; Wiley: NewYork, 1992.
(b) Jacobi, P. A.; Coults, L. D.; Guo, J. S.; Leung, S. I. J. Org. Chem.
2000, 65, 205−213. (c) Furstner, A. Angew. Chem., Int. Ed. 2003, 42,
3528−3603. (d) Furstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am.
̈
2-(3-(p-Tolylamino)-4,5,6,7-tetrahydro-2-(4-methoxyphen-
yl)-4-oxoindol-1-yl)acetic acid (5m). Pale white solid: 0.304 g,
yield 75%; mp 216−217 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.09
(s, 1H, COOH), 7.15 (d, J = 8.8 Hz, 2H, ArH), 6.92 (d, J = 8.8 Hz,
2H, ArH), 6.74 (d, J = 8.0 Hz, 3H, ArH, 1H and NH, 1H), 6.38 (d, J =
8.0 Hz, 2H, ArH), 4.59 (s, 2H, CH2), 3.73 (s, 3H, CH3), 2.77−2.74
(m, 2H, CH2), 2.34−2.27 (m, 2H, CH2), 2.09 (s, 3H, CH3), 2.07−
1.98 (m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 192.7, 169.8,
158.7, 145.1, 142.9, 130.9, 128.7, 127.2, 124.9, 122.4, 121.4, 114.4,
114.0, 113.6, 55.0, 45.9, 38.0, 22.9, 21.4, 20.0; IR (KBr, ν, cm−1) 3554,
3413, 3374, 1740, 1647, 1615, 1514, 1490, 1414, 1245, 1218, 1021,
836, 809; HRMS (ESI) m/z calcd for C24H23N2O4, 403.1652 [M −
H]−, found 403.1656.
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2-(3-(4-Fluorophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-4-oxoindol-1-yl)acetic acid (5n). Pale white solid:
0.301 g, yield 74%; mp 218−219 °C; 1H NMR (400 MHz, DMSO-d6)
δ 13.20 (s, 1H, COOH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 6.93 (d, J = 8.0
Hz, 2H, ArH), 6.89 (s, 1H, NH), 6.79−6.75 (m, 2H, ArH), 6.45−6.43
(m, 2H, ArH), 4.59 (s, 2H, CH2), 3.73 (s, 3H, CH3), 2.76 (s, 2H,
CH2), 2.31 (s, 2H, CH2), 2.04 (s, 2H, CH2); 13C NMR (100 MHz,
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DMSO-d6) δ 192.5, 169.7, 158.8, 154.6 (JCF1 = 230.0 Hz), 144.2 (JCF
2
= 1.3 Hz), 144.2, 143.1, 130.9, 127.6, 121.1, 114.6 (JCF = 21.9 Hz),
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114.5, 114.2 (JCF = 8.1 Hz), 114.1, 55.0, 45.9, 38.0, 22.9, 21.4; IR
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(KBr, ν, cm−1) 3554, 3414, 3370, 1731, 1687, 1583, 1556, 1494, 1460,
1089, 1010, 983, 814; HRMS (ESI) m/z calcd for C23H20FN2O4,
407.1402 [M − H]−, found 407.1400.
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2-(3-(3-Bromophenylamino)-4,5,6,7-tetrahydro-2-(4-me-
thoxyphenyl)-4-oxoindol-1-yl)acetic acid (5o). Pale yellow solid:
0.397 g, yield 85%; mp 218−219 °C; 1H NMR (400 MHz, DMSO-d6)
δ 13.23 (s, 1H, COOH), 7.25 (s, 1H, NH), 7.13 (d, J = 8.8 Hz, 2H,
ArH), 6.95 (d, J = 8.8 Hz, 2H, ArH), 6.90−6.86 (m, 1H, ArH), 6.61−
6.58 (m, 2H, ArH), 6.46−6.41 (m, 1H, ArH), 4.60 (s, 2H, CH2), 3.74
(s, 3H, CH3), 2.33−2.30 (m, 2H, CH2), 2.35−2.28 (m, 2H, CH2),
2.08−2.03 (m, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 192.2,
169.7, 158.9, 149.8, 143.3, 130.9, 130.1, 129.0, 121.9, 121.8, 119.2,
118.4, 115.2, 114.8, 114.1, 112.0, 55.1, 46.0, 38.1, 22.9, 21.4; IR (KBr,
ν, cm−1) 3552, 3475, 3388, 1747, 1650, 1597, 1573, 1422, 1240, 1177,
1101, 1024, 985, 845, 812; HRMS (ESI) m/z calcd for C23H20BrN2O4,
469.0584 [M − H]−, found 469.0567.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all pure products and X-ray crystal
data (CIF) for 4f and 5a. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Fax: 86-516-83500065; 806-742-1289. E-mail: laotu@jsnu.
edu.cn; guigen.li@ttu.edu.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful for financial support from the NSFC (No.
20928001, 21072163, 21002083, and 21102124), PAPD of
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