The Cs2CO3-Catalyzed Reaction of 2-Oxindoles with Enones for the Preparation of Indolin-3-Ones and Their Further Transformation

Article abstract of DOI:10.1021/acs.joc.6b01993

The Cs₂CO₃-catalyzed reaction of 2-oxindoles with enones affords 2,2-disubstituted indolin-3-ones through domino “Michael addition-oxidation-ring-cleavage-C-N coupling” process. O₂ acts as the sole oxidant to accomplish th

Full text of DOI:10.1021/acs.joc.6b01993

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Note
The Cs2CO3-Catalyzed Reaction of 2-Oxindoles with Enones for
the Preparation of Indolin-3-Ones and Their Further Transformation
Ying Shao, Yu-Mei Zeng, Jie-Ying Ji, Xiao-Qiang Sun, Hai-Tao Yang, and Chun-Bao Miao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01993 • Publication Date (Web): 15 Nov 2016
Downloaded from http://pubs.acs.org on November 15, 2016
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The Cs2CO3ꢀCatalyzed Reaction of 2ꢀOxindoles with Enones for the Preparation of
Indolinꢀ3ꢀOnes and Their Further Transformation
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Ying Shao,† YuꢀMei Zeng,† JieꢀYing Ji, XiaoꢀQiang Sun, HaiꢀTao Yang, ChunꢀBao Miao*
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced Catalysis and
Green Manufacturing Collaborative Innovation Center, School of Petrochemical Engineering,
Changzhou University, Changzhou 213164, China.
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Email: estally@yahoo.com
† These authors contributed equally to this work.
Ph
Ph
N
N
NH2
O
O
Ph
R1
O
O
Cs2CO3 (20 mol %)
R2
DMSO, 80 oC, air
O
+
R1
R2
N
O
Ph
N
H
N
H
O
Michael addition – Oxidation – Ring cleavage – Regioselectiv C-N coupling
R1
R2
N
H
O
Abstract
The Cs2CO3ꢀcatalyzed reaction of 2ꢀoxindoles with enones affords 2,2ꢀdisubstituted
indolinꢀ3ꢀones through domino “Michael additionꢀoxidationꢀring cleavageꢀCꢀN coupling” process.
O2 acts as the sole oxidant to accomplish the oxidative process. The indolinꢀ3ꢀones can be further
transformed to pyridazine, azirdineꢀfused 3ꢀoxindoles, 4ꢀquinolone derivatives easily.
2,2ꢀDisubstituted indolinꢀ3ꢀone scaffolds exist in a lot of natural products such as isatisine A,1
2
3
4
5
6
austamide,
aristotelone,
fluorocarpamine,
brevianimide,
diketopiperazine alkaloid,
rauniticine pseudoindoxyl,7 ervaoffines A/B, iboluteine,8 and can be used in the total synthesis of
biologically active alkaloids.9 Therefore, considerable synthetic effort has been devoted to the
synthesis of this valuable scaffold and various preparative methods have been developed. The
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protocol of oxidation of 2,3ꢀdisubstituted indoles followed by rearrangement2,10 or reaction with
Cꢀnucleophiles1a,9a,11 represents one of the most versatile routes to 2,2ꢀdisubstituted indolinꢀ3ꢀone
scaffolds. However, the methodology suffered from some limitations such as stepwise operation,
requirement of stoichiometric amount of oxidants, or using a transitionꢀmetal catalyst. Other
methods for the construction of 2,2ꢀdisubstituted indolinꢀ3ꢀone skeletons possess limited scope
and utility. For instance, the reaction of arynes with amino acid esters,12 the reaction of
orthoꢀbromophenyl ketones with sodium azide via sequential SNAr−Smalley cyclization,13 the
Auꢀcatalyzed reaction of 2ꢀalkynyl arylazides with allylic alcohols or propargylic alcohols,14 the
Auꢀcatalyzed nitroalkyne cycloisomerization followed with an intermolecular/intramolecular
[3+2]ꢀcycloaddition with alkenes,15 the Auꢀcatalyzed Cꢀ2 annulation of 3ꢀphenoxy alkynyl
indoles or an acidꢀcatalyzed cascade oxidative dearomatization/semipinacol rearrangement
reaction of indolꢀ2ꢀyl cyclobutanol with Nꢀsulfonyloxaziridine as oxidant,16 the Rh(III)ꢀcatalyzed
[4+1] annulation reaction of 2ꢀaminobenzaldehydes with allenes,17 and the Pdꢀcatalyzed reaction
of Nꢀbenzylꢀ2ꢀiodoanilines with CO and diazocompounds18 have been documented. Generally, the
substrates in these transition metal catalyzed reaction needed to be prepared by multiꢀstep
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procedures. In continuation of our interest in using molecular oxygen as an ideal green oxidant in
19
organic transformation,
herein, we wish to report the synthesis of 2,2ꢀdisubstituted
indolinꢀ3ꢀones from the easily available 2ꢀoxinoles and enones catalyzed by a base through
domino process.
Scheme 1
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O
O
Ph
O
Ph
Ph
O
conditions
+
O
Ph
N
NH2
N
II
Ph
H
Ph
I
III
acidic condition: (ref. 17c)
HCl (0.15 equiv), DMSO/H2O, air, 90 oC, 22 h 46%
30%
8
9
basic condition:
K2CO3, DMSO, air, 80 oC, 5 h
Cs2CO3, DMSO, air, 80 oC, 1 h
NaOH, DMSO, air, 80oC, 5 h
DBU, DMSO, air, 80oC, 5 h
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
85%
94%
52%
50%
0%
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DMSO, air, 80oC, 12 h
Cs2CO3, DMSO, N2, 80 oC, 4 h
Cs2CO3, DMF, air, 80 oC, 2 h
Cs2CO3, CH3CN, air, 80 oC, 24 h
Cs2CO3, 1,4-dioxane, air, 80 oC, 8 h
Cs2CO3, toluene, air, 80 oC, 8 h
Cs2CO3, ClCH2CH2Cl, air, 80 oC, 8 h
Cs2CO3, EtOH, air, 80 oC, 6 h
0%
94%
38%
0%
0%
0%
10%
Most recently, we have reported a K2CO3ꢀcatalyzed reaction of 2ꢀoxindoles with enones for the
synthesis of 1,4ꢀdiketone compounds bearing amino group via a cascade “Michael
addition−oxidation−ringꢀcleavage” process.19c The product I could be transformed to the
interesting cyclization product indolinꢀ3ꢀone III in 30% yield accompanying with the formation of
46 % yield of quinoline II upon treating with catalytic amount of hydrochloric acid (Scheme 1).
The selectivity was very poor and we attempted to realize the selective conversion to single
product. To our delight, upon changing the acid condition to a basic medium, selective
transformation to III was achieved. When I was treated with 20 mol % of Cs2CO3 in DMSO at 80
ºC in air for 1 h, III was obtained nearly quantitatively (94%). Among the two types of αꢀC of
carbonyl, the CꢀN coupling occurred selectively at the position benefiting to the formation of
fiveꢀmembered ring. Although the K2CO3 was also effective, longer reaction time (5 h vs 1 h) was
needed and the yield was slightly lower (85%) (Scheme 1). At room temperature, the reaction
proceeded very slowly and only trace of product could be observed on TLC after 24 h. Using
NaOH or DBU as the base only gave moderate yield of product. A certain amount of byproducts
with very high polarity was generated under NaOH conditions probably due to its strong basicity,
while many starting material remained uncovered under DBU conditions. Aerobic oxygen and
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base were crucial to the transformation, and no reaction occurred in the absence of base or under
nitrogen atmosphere. The solvent screening showed that only DMSO and DMF were the optimal
solvent. The reaction in CH3CN delivered 38% of the product after 24 h, while using 1,4ꢀdioxane ,
toluene, DCE, or EtOH as the solvent led to failure of the reaction or very low yield.
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Direct intramolecular oxidative C(sp3)−N bond formation through C(sp3)−H amination is an
efficient protocol to construct nitrogenꢀcontaining heterocycles.20 Particularly noteworthy, the
nitrogen sources are mostly limited to amide, sulfonamides carbamate and sulfamate esters, and
transitionꢀmetal catalysts are always needed. The C(sp3)−H activation always need a directing
group on nitrogen atom.21 Developing other nitrogen sources especially the unprotected anilines
to realize the intramolecular C(sp3)−N coupling reaction is more challenging and attractive.
Table 1 Synthesis of Indolinꢀ3ꢀOnes 3 from
2ꢀOxindoles and Enones
O
O
R2
O
Cs2CO3 (20 mol %)
DMSO (2 mL), 80 oC
O
R2
R3
+
N
H
R3
N
H
R1
R1
2
1 (0.5 mmol)
(0.5 mmol)
3
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OMe
O
Me
O
O
O
O
O
4
5
6
7
N
N
N
N
H
H
H
H
O
O
O
O
3ad
3ac
3ab
3aa
(6.5 h, 53%)
(7 h, 50%)
(6 h, 60%)
(6 h, 72%)
Cl
NO2
O
O
O
O
8
9
N
H
N
H
N
H
N
H
O
O
3ag
O
O
3ah
(8 h, 44%)
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3af
3ae
Me
OMe
(8 h, 42%)
(8 h, 50%)a
(6 h, 53%)
OMe
OMe
O
O
O
O
N
H
O
N
H
O
3aj
(22 h, 25%)
N
H
O
N
H
O
3ai
3al
(17 h, 15%)
3ak
(10 h, 45%)
NO2
NO2
OMe
Cl
(8 h, 56%)
Cl
Cl
O
O
O
O
Me
NO2
N
H
N
N
N
H
H
H
O
O
O
O
3ao
3ap
3an
(7 h, 40%)
3am
(25 h, 40%)
(38 h, 25%)
Me
(9 h, 46%)a
OMe
O
O
O
O
F
Cl
O2N
N
H
O
N
N
H
O
N
H
O
Cl
H
O
3ea
(6 h, 56%)
3ca
3da
(6.5 h, 45%)
3ba
(9 h, 35%)
(6.5 h, 50%)
Cl
O
O
Me
N
N
H
O
H
O
3ga
(6 h, 41%)
3fa
(12 h, 18%)
a
o
Reacted at rt. for 1.5 h and then at 40 C for
given time.
In the above cyclizative reaction, the amine source is unsubstituted arylamine and this kind of
intramolecular C(sp3)−H amination has never been reported to the best of our knowledge. With the
primary results in hand, we decided to investigate this kind of reaction inꢀdepth. Taking into
account of the similar basic condition with that of our previously reported K2CO3ꢀcatalyzed
reaction of 2ꢀoxindoles with enones in DMSO at room temperature for the preparation of
1,4ꢀdiketones bearing amino group,19c the possibility of Cs2CO3ꢀpromoted oneꢀstep synthesis of
indolinꢀ3ꢀone 3aa directly from 2ꢀoxindoles with enones was examined by increasing the reaction
temperature to 80 ºC. Fortunately, the 2,2ꢀdisubstituted indolinꢀ3ꢀone 3aa was obtained in 72%
yield via a cascade “Michael additionꢀoxidationꢀring cleavageꢀC−N coupling” process. Various
substrates were examined under the conditions to evaluate the scope and generality of the
methodology (Table 1). Either electronꢀwithdrawing or electronꢀdonating groups on phenyl ring of
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R2 generated the desired products 3 in moderate yields (3aa−3af). For the substrate 2f and 2m,
which linked with an NO2 group, the reaction must be carried out at lower temperature (40 ºC).
Otherwise a very low yield was obtained. In terms of R3, a striking electron effect was observed. A
strong electronꢀwithdrawing group such as NO2 on the phenyl ring resulted in very low yield of
products (3aj and 3al). Either R2 or R3 was replaced by an alkyl group, the reactions proceeded
very slowly and the yields were unsatisfactory (3ao and 3ap). Other 2ꢀoxindoles are also effective
in this conversion (3baꢀ3ga). Strong electronꢀwithdrawing group gave much lower yield (3ba).
4ꢀChloroꢀ2ꢀoxindole gave very low yield of product 3fa partially because of the steric hindrance
(3fa).
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Scheme 2 Large Scale Synthesis of 3aa
O
O
Cs2CO3 (30 mol %)
O
Ph
+
Ph
Ph
N
℃
DMSO( 15 mL), 80
18 h
N
H
1a
2a
H
O
Ph
(1.33 g, 10 mmol)
(2.08 g, 10 mmol)
3aa
(1.57 g, 48%)
To show the practicality of this protocol, a largeꢀscale experiment was carried out by performing
the reaction of 1a (1.33 g, 10 mmol) with 2a (2.08 g, 10 mmol) in 15 mL of DMSO in the
presence of 3 mmol of Cs2CO3 (Scheme 2). This transformation proceeded smoothly to afford 3aa
in 48% yield within 18 h. In order to increase the concentration of oxygen in the reaction mixture,
air was concurrently bubbled into the reaction mixture through a glass dropper.
Scheme 3 The further transformations of 3aa.
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Ph
Ph
NH2NH2•H2O (2 equiv)
HOAc (1 equiv)
EtOH, 40 oC, h
N
N
4
NH2 (62%)
6
7
8
9
O
O
Ph
Ph
Cu(OAc)2 (2.5 equiv)
DMSO, 120 oC, 25 min
+
Ph
N
5b
N
Ph
5a
O
O
O
O
I2 (2 equiv)
DBU (4 equiv)
Ph
10
11
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O
Ph
K2CO3 (20 mol %)
THF, 40 oC, 4.5 h
Ph
N
DMSO, 120 oC
5 h, 92%
Ph
N
H
3aa
5b
(81%)
O
O
Cu(OAc)2 (2.5 equiv)
Ph
Ph
Cs2CO3 (2.5 equiv)
DMSO, 120 oC, 25 min
62%
N
H
O
6aa
Due to the concurrent existence of amino and carbonyl group, the synthetic potential of the
indolinꢀ3ꢀone 3aa through the intramolecular reaction was investigated (Scheme 3). The reaction
of 3aa with hydrazine hydrate in the presence of acetic acid gave 2ꢀ(4,6ꢀdiphenylpyridazinꢀ3ꢀyl)
aniline 4 in 62% yield accompanied by the cleavage of CꢀN bond. Treatment of 3aa with 2.5 equiv
of Cu(OAc)2 in DMSO at 120 ºC for 25 min furnished the two stereoisomers of azirdineꢀfused
3ꢀoxindoles 5a and 5b in 26% and 56% yield, respectively. It was noteworthy that the reaction
proceeded very quickly and further prolonging the reaction time led to complex mixture. In the
presence of 2 equiv of I2 and 4 equiv of DBU, 3aa afforded the main isomer 5b in 81% yield
through intramolecular nucleophilic substitution. When 5b was treated with catalytic amount of
K2CO3 in DMSO, the ring opening of azirdine ring occurred to generate 4ꢀquinolone derivative
6aa in nearly quantitative yield. In consideration of the generation of 5a/5b under Cu(OAc)2
condition, the combination of Cu(OAc)2 with a base to realize the oneꢀstep conversion to 6aa was
tried. The reaction of 3aa with 2.5 equiv of Cu(OAc)2 and 2.5 equiv of Cs2CO3 in DMSO for 25
min indeed provided 6aa in a moderate yield of 62%. However, in the presence of I2, changing the
base from DBU to Cs2CO3 and increasing the temperature from 40 ºC to 120 ºC could not provide
the 6aa.
4ꢀQuinolone scaffolds are commonly used in the pharmaceutical chemistry, constituting a large
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class of marketed antibiotic drug.22 As a result, the synthesis of 4ꢀquinolones has attracted
considerable interest. Herein, a new access to quinolinꢀ4(1H)ꢀones was explored starting from
indolinꢀ3ꢀones 3. Under Cu(OAc)2 and Cs2CO3 conditions, various quinolinꢀ4(1H)ꢀones 6 could be
prepared, however, the yield was unsatisfactory (Table 2).
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Table
Quinolinꢀ4(1H)ꢀones 6
2
Synthesis
of
Various
O
O
R2
Cu(OAc)2 (2.5 equiv)
Cs2CO3 (2.5 equiv)
R2
R3
O
O
R3
DMSO, 120 o
C
N
N
H
R1
H
R1
3
6
OMe
Cl
O
O
O
O
O
O
O
N
O
N
H
N
H
N
H
H
6aa
(25 min, 62%)
6ae
(15 min, 36%)
6ag
(25 min, 55%)
6ac
(30 min, 30%)
OCH3
O
O
O
O
O2N
O
O
O
N
H
N
H
N
H
O
N
H
6ai
6aj
6ba
(30 min, 25%)
6ah
(15 min, 41%)
(20 min, 50%)
(15 min, 61%)
CH3
Cl
NO2
O
O
H3C
Cl
O
N
O
N
H
H
6da
(15 min, 30%)
6ga
(15 min, 43%)
All the new compounds were fully characterized by H NMR, 13C NMR, and HRMS. The
structure of 3aa and 6ai was further established unambiguously by their single crystals (See
SI). The steric configuration of 5a was confirmed by the NOESY spectrum analysis. The methine
proton Ha has correlation with both Hb and Hc on the two different phenyl rings, which indicates
that the phenyl group and the benzoyl group derived from enone are in the transꢀ position (See SI).
Scheme 4 Control Experiments
1
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O
O
×
Cs2CO3 (20 mol %)
DMSO, 80 oC, air, 8 h
66%
O
N
N
H
NH2
O
10
H
7
8
9
Ph
O
O
×
Ph
Cs2CO3 (20 mol %)
DMSO, 80 oC, air, 8 h
45%
Ph
12
N
H
N
NH2
H
11
10
11
12
13
14
15
16
17
18
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20
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O
O
Cs2CO3 (20 mol %)
DMSO, 80 oC, air, 1 h
98%
O
O
13
14
To gain insight into the regioselective intramolecular C−H amination, some control experiments
were carried out (Scheme 4). Firstly, 7 and 8 were prepared and introduced to the Cs2CO3
catalyzed reaction. No intramolecular cyclization product 10 or 12 was detected. Instead, the
ringꢀcleavage products 9 and 11 were isolated in 66% and 45% yield, respectively, which
indicated that an acyl group (in compound I) deriving from the enones played an essential role to
the success of CꢀN coupling reaction. When the 1,2,4ꢀtriphenylꢀ1,4ꢀbutanedione 13, which lacked
an amino group compared with compound I, was treated with catalytic amount of Cs2CO3 in
DMSO at 80 °C for 1 h, the oxidative dehydrogenation product 14 was afforded almost
quntitatively.
Based on these results and our previous work, a possible reaction pathway is described in
Scheme 5. Intermediate 15 is generated under Cs2CO3 conditions through a consecutive “Michael
additionꢀoxidationꢀring cleavage” process.17c Next, under Cs2CO3 conditions 15 reacts with
molecular oxygen to generate the peroxide 16.23 An alternative pathway for the formation of
peroxide involving a single electron transfer from carbonion to oxygen followed by the trap of
Cꢀcentered radical with oxygen was also possible.19b,24 Under basic condition, release of hydrogen
peroxide from 16 gives the key intermediate 17 followed by a regioselective intramolecular
Michael addition to afford the indolinꢀ3ꢀone 3. An alternative pathway to 17 also can’t be
excluded, that is, peroxide 16 reacts with 15 to generate the hydroxylated product 18 followed by
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extrusion of H2O. At present, the reason for the excellent regioselectivity in the CꢀN bond
formation is not clear. Under basic conditions, nucleophilic attack of hydroxyl anion on azirdine
ring leads to ringꢀopening intermediate 19, which abstract proton from the αꢀC of carbonyl
followed by extrusion of hydroxyl anion to afford the quinolinꢀ4(1H)ꢀone 6.
Scheme 5 Proposed Mechanisms
3
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O
O
R1
H
R1
O
R2
O
R2
R2
R1
O
N
O
O
H
O
1
Cs2CO3
Cs2CO3
O2
+
O
O
O
N
H
N
H
N
O
R1
R2
H
2
O
OH
O
O
R1
R1
O
R2
R2
R2
-CO2
O2
-H2O2
×
Cs2CO3
R1
NH2
O
16
Cs2CO3
O
O
15
NH2
NH2
17
15
2
O
O
R1
OH
R2
R1
NH2
O
N
H
3
O
R2
18
O
O
O
O
OH
Ph
OH
Ph
Ph
Ph
Ph
-
-OH
Ph
OH-
Ph
Ph
N
5b
N
H
6
N
N
H
O
H
19
20
O
O
O
Conclusions
In summary, an efficient Cs2CO3ꢀcatalyzed reaction of 2ꢀoxindoles with enones for the
preparation of 2,2ꢀdisubstituted indolinꢀ3ꢀones has been explored through domino “Michael
additionꢀoxidationꢀring cleavageꢀCꢀN coupling” process. A mechanism was proposed according to
the controlling experiments. The final CꢀN coupling reaction displays excellent regioselectivity.
The further transformations of indolinꢀ3ꢀones 3 give an easy access to pyridazine, azirdineꢀfused
3ꢀoxindoles, quinolinꢀ4(1H)ꢀone derivatives.
Experimental Section
General Information.
1H, 13C NMR, NOESY spectra were recorded on 300 MHz or 400 MHz (75 MHz or 100 MHz
for 13C NMR) spectrometer. Melting points were determined on a micromelting point apparatus
without corrections. Flash column chromatography was performed over silica gel (200−300 mesh).
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Preparation of Starting Materials
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Compounds 7 and 8 were prepared according to the reported procedure: Condensation of
2ꢀoxindole with ketonic compounds followed by reduction with NaBH4.25 Compound 13 were
prepared according to the reported procedure.26
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General Procedure for the Cs2CO3ꢀCatalyzed Reaction of 2ꢀOxindoles (1) with Enones (2) in
DMSO for the Preparation of 3
A mixture of 2ꢀoxindoles 1 (0.5 mmol), enones 2 (0.5 mmol), and Cs2CO3 (0.1 mmol) in 2 mL
o
of DMSO was stirred in a tube (Φ18 × 150 mm) under open air at 80 C for a given time. Upon
completion of the reaction as determined by TLC, 20 mL of water was added and the mixture was
extracted with dichloromethane (15 mL× 3). The combined organic phases were dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (ethyl acetate/petroleum ether: 1/10−1/6) to provide the
corresponding products 3. (It was noteworthy that some of the CꢀN coupling products 3 have same
polarity with the uncoupling products in TLC analysis. In this case, the mixture of isopropyl ether
and hexane should be used as the eluent in TLC detection).
2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3aa (yellow solid, 117.8 mg, 72%, mp 149ꢀ150
oC): 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.2 Hz, 2H), 7.53ꢀ7.61 (m, 4H), 7.40ꢀ7.52 (m, 3H),
7.24ꢀ7.32 (m, 2H), 7.21 (tt, J = 7.2, 1.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.81 (ddd, J = 7.8, 7.2,
13
0.7 Hz, 1H), 6.31 (s, br, 1H), 4.45 (d, J = 18.0 Hz, 1H), 3.18 (d, J = 17.9 Hz, 1H); C NMR (75
MHz, CDCl3) δ 200.8 (C=O), 197.9 (C=O), 160.4, 138.1, 137.9, 136.7, 133.9, 128.9, 128.8, 128.2,
127.7, 125.8, 125.4, 119.0, 118.2, 111.9, 69.4 (NHC−CO), 44.8 (COCH2); HRMS (ESIꢀQꢀTOF)
m/z [M + H]+ calcd for C22H18NO2 328.1338, found 328.1326.
2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3ab (yellow solid, 110.4 mg,
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60%, mp 186ꢀ188 oC): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2H), 7.54ꢀ7.61 (m, 2H),
7.41ꢀ7.53 (m, 3H), 7.05 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.95 (d, J = 8.2 Hz,
1H), 6.81 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.27 (s, br, 1H), 5.84ꢀ5.93 (m, 2H), 4.37 (d,
J = 18.0 Hz, 1H), 3.11 (d, J = 18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 200.8 (C=O), 198.0
(C=O), 160.2, 148.1, 147.2, 137.9, 136.6, 133.9, 132.0, 128.9, 128.2, 125.7, 119.0, 118.8, 118.1,
111.9, 108.4, 106.3, 101.2, 69.1 (NHC−CO), 44.7 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+
Calcd for C23H18NO4 372.1236; Found 372.1229.
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2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3ac (yellow solid, 89.0 mg, 50%,
mp 120ꢀ122 oC): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 2H),
7.40ꢀ7.51 (m, 5H), 6.94 (d, J = 8.3 Hz, 1H), 6.76ꢀ6.84 (m, 3H), 6.30 (s, br, 1H), 4.39 (d, J = 17.9
Hz, 1H), 3.72 (s, 3H), 3.14 (d, J = 17.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 201.1 (C=O), 197.9
(C=O), 160.3, 159.0, 137.7, 136.6, 133.7, 130.1, 128.7, 128.1, 126.6, 125.6, 118.7, 118.2, 114.1,
111.9, 68.9 (NHC−CO), 55.2 (OCH3), 44.6 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C23H20NO3 358.1443; Found 358.1440.
2ꢀ(4ꢀmethyphenyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3ad (yellow solid, 90.3 mg, 53%, mp
206ꢀ207 oC): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 7.1 Hz, 2H), 7.54ꢀ7.61 (m, 2H), 7.38ꢀ7.52
(m, 5H), 7.09 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 6.80 (ddd, J = 7.8, 7.2, 0.7 Hz, 1H),
6.26 (s, br, 1H), 4.42 (d, J = 18.0 Hz, 1H), 3.16 (d, J = 18.0 Hz, 1H), 2.26 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 200.9 (C=O), 197.9 (C=O), 160.4, 137.8, 137.4, 136.7, 135.1, 133.8, 129.6, 128.8,
128.2, 125.7, 125.3, 118.9, 118.3, 111.8, 69.3 (NHC−CO), 44.7 (COCH2), 21.1 (CH3); HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H20NO2 342.1494; Found 342.1490.
2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3ae (yellow solid, 96.1 mg, 53%, mp
151ꢀ153 oC): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.55ꢀ7.63 (m, 2H), 7.42ꢀ7.55
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(m, 5H), 7.25 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.3 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.30 (s, br,
1H), 4.39 (d, J = 18.0 Hz, 1H), 3.15 (d, J = 18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 200.4
(C=O), 197.8 (C=O), 160.2, 138.1, 136.8, 136.4, 134.0, 133.7, 128.91, 128.89, 128.2, 127.0, 125.8,
119.2, 118.0, 112.0, 68.9 (NHC−CO), 44.9 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C22H17ClNO2 362.0948; Found 362.0942.
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2ꢀ(4ꢀnitrophenyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3af (yellow solid, 93.7 mg, 50%, mp
o
1
195ꢀ197 C): H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 7.1 Hz, 2H),
7.79 (d, J = 9.0 Hz, 2H), 7.51ꢀ7.65 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.87
(t, J = 7.4 Hz, 1H), 6.35 (s, br, 1H), 4.45 (d, J = 18.2 Hz, 1H), 3.24 (d, J = 18.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 199.2 (C=O), 197.6 (C=O), 160.2, 147.5, 145.9, 138.5, 136.2, 134.4, 129.1,
128.2, 126.8, 125.9, 123.9, 119.7, 117.8, 112.3, 69.3 (NHC−CO), 45.5 (COCH2); HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H17N2O4 373.1188; Found 373.1182.
2ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ag (yellow solid, 74.8 mg, 42%,
mp 202ꢀ203 oC): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 9.0 Hz, 2H), 7.52ꢀ7.66 (m, 3H), 7.49
(ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.28 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 6.6 Hz, 2H), 6.96 (d, J = 8.2
Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.80 (t, J = 7.4 Hz, 1H), 6.37 (s, br, 1H), 4.39 ( d, J =17.7 Hz,
1H), 3.86 (s, 3H), 3.10 (d, J = 17.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 201.0 (C=O), 196.4
(C=O), 164.1, 160.4, 138.2, 137.9, 130.6, 129.8, 128.8, 127.6, 125.7, 125.5, 118.9, 118.2, 114.0,
111.9, 69.5 (NHC−CO), 55.7 (OCH3), 44.3 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C23H20NO3 358.1443; Found 358.1440.
2ꢀ(2ꢀ(4ꢀmethylphenyl)ꢀ2ꢀoxoethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ah (yellow solid, 75.2 mg, 44%, mp
180ꢀ181 oC): 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.52ꢀ7.60 (m, 3H), 7.48 (ddd,
J = 8.3, 7.1, 1.3 Hz, 1H), 7.17ꢀ7.31 (m, 5H), 6.95 (d, J = 8.3 Hz, 1H), 6.80 (ddd, J = 7.8, 7.1, 0.8
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Hz, 1H), 6.35 (s, br, 1H), 4.42 (d, J = 17.9 Hz, 1H), 3.13 (d, J = 17.9 Hz, 1H), 2.39 (s, 3H); C
NMR (100 MHz, CDCl3) δ 200.9 (C=O), 197.5 (C=O), 160.4, 144.8, 138.2, 137.9, 134.3, 129.5,
128.8, 128.4, 127.6, 125.7, 125.5, 118.9, 118.2, 111.9, 69.5 (NHC−CO), 44.6 (COCH2), 21.8
(CH3); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H20NO2 342.1494; Found 342.1489.
2ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ai (yellow solid, 101.8 mg, 56%, mp
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172ꢀ174 C): H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H),
7.46ꢀ7.56 (m, 3H), 7.42 (d, J = 8.7 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 6.97
(d, J = 8.3 Hz, 1H), 6.82 (ddd, J = 7.8, 7.2, 0.7 Hz, 1H), 6.23 (s, br, 1H), 4.38 (d, J = 17.9 Hz, 1H),
3.16 (d, J = 17.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 200.6 (C=O), 196.7 (C=O), 160.3, 140.4,
138.03, 137.95, 135.0, 129.6, 129.2, 128.9, 127.8, 125.8, 125.4, 119.1, 118.3, 111.9, 69.3
(NHC−CO), 44.9 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H17ClNO2 362.0948;
Found 362.0945.
2ꢀ(2ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3aj (yellow solid, 47.1 mg, 25%, mp
o
1
166ꢀ167 C): H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H),
7.58 (d, J = 7.8 Hz, 1H), 7.48ꢀ7.56 (m, 3H), 7.20ꢀ7.34 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 6.84 (t, J
= 7.4 Hz, 1H), 6.14 (s, br, 1H), 4.42 (d, J = 18.0 Hz, 1H), 3.29 (d, J = 18.0 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 200.2 (C=O), 196.5 (C=O), 160.3, 150.7, 140.8, 138.1, 137.8, 129.3, 129.0, 128.0,
125.8, 125.3, 124.1, 119.4, 118.3, 112.0, 69.1 (NHC−CO), 45.7 (COCH2); HRMS (ESIꢀQꢀTOF)
m/z [M+H]+ Calcd for C22H17N2O4 373.1188; Found 373.1180.
2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)indolinꢀ3ꢀone 3ak (yellow solid, 87.1
mg, 45%, mp 61ꢀ63 C): 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 7.8
o
Hz, 1H), 7.43ꢀ7.51 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.75ꢀ6.84 (m, 3H),
6.36 (s, br, 1H), 4.34 (d, J = 17.7 Hz, 1H), 3.86 (s, 3H), 3.72(s, 3H), 3.06 (d, J = 17.7 Hz, 1H); 13C
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NMR (75 MHz, CDCl3) δ 201.3 (C=O), 196.5 (C=O), 164.1, 160.3, 159.1, 137.8, 130.6, 130.2,
129.8, 126.7, 125.7, 118.8, 118.3, 114.2, 114.0, 111.9, 69.1 (NHC−CO), 55.6 (OCH3), 55.3
(OCH3), 44.2 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C24H22NO4 388.1549; Found
388.1544.
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2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(2ꢀ(4ꢀnitrophenyl)ꢀ2ꢀoxoethyl)indolinꢀ3ꢀone 3al (yellow solid, 30.3 mg,
o
15%, mp 89ꢀ90 C): 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz,
2H), 7.58 (d, J = 7.8 Hz, 1H), 7.50 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.45 (d, J = 8.9 Hz, 2H), 6.97 (d,
J = 8.3 Hz, 1H), 6.78ꢀ6.86 (m, 3H), 6.11 (s, br, 1H), 4.36 (d, J = 17.9 Hz, 1H), 3.73 (s, 3H), 3.25
(d, J = 17.9 Hz, 1H); 13C NM R (75 MHz, CDCl3) δ 200.6 (C=O), 196.6 (C=O), 160.2, 159.3,
150.7, 140.9, 138.0, 129.6, 129.3, 126.5, 125.8, 124.1, 119.3, 118.4, 114.4, 112.0, 68.7 (NHC−CO),
55.3 (OCH3), 45.6 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H19N2O5 403.1294;
Found 403.1290.
2ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)ꢀ2ꢀ(3ꢀnitrophenyl)indolinꢀ3ꢀone 3am (yellow solid, 88.2
mg, 46%, mp 118ꢀ120 oC): 1H NMR (300 MHz, CDCl3) δ 8.51 (t, J = 2.0 Hz, 1H), 8.07 (ddd, J =
8.2, 2.2, 0.9 Hz, 1H), 7.97 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 7.8
Hz, 1H), 7.53 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H),
6.90 (d, J = 9.0 Hz, 2H), 6.85 (t, J = 7.5 Hz, 1H), 6.48 (s, br, 1H), 4.37 (d, J = 17.9 Hz, 1H), 3.85
(s, 3H), 3.17 (d, J = 17.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 199.8 (C=O), 195.9 (C=O), 164.4,
160.3, 148.5, 141.0, 138.4, 132.0, 130.6, 129.6, 129.3, 125.7, 122.6, 121.1, 119.6, 117.8, 114.1,
112.5, 68.9 (NHC−CO), 55.7 (OCH3), 44.9 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C23H19N2O5 403.1294; Found 403.1298.
2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(2ꢀoxoꢀ2ꢀ(pꢀtolyl)ethyl)indolinꢀ3ꢀone 3an (yellow solid, 75.0 mg, 40%,
mp 151ꢀ152 oC): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H),
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7.44ꢀ7.54 (m, 3H), 7.20ꢀ7.26 (m, 4H), 6.95 (d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 6.37 (s, br,
1H), 4.36 (d, J = 17.9 Hz, 1H), 3.10 (d, J = 18.0 Hz, 1H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 200.5 (C=O), 197.4 (C=O), 160.3, 145.0, 138.1, 136.9, 134.0, 133.6, 129.6, 128.8, 128.3, 127.0,
125.7, 119.1, 118.0, 112.0, 69.0 (NHC−CO), 44.7 (COCH2), 21.8 (CH3); HRMS (ESIꢀQꢀTOF) m/z
[M+H]+ Calcd for C23H19ClNO2 376.1104; Found 376.1100.
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2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(3,3ꢀdimethylꢀ2ꢀoxobutyl)indolinꢀ3ꢀone 3ao (yellow solid, 68.2 mg, 40%,
mp 130ꢀ132 oC): 1H NMR (300 MHz, CDCl3) δ7.55 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H),
7.49 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.80 (ddd, J
= 7.8, 7.1, 0.7 Hz, 1H), 6.32 (s, br, 1H), 3.88 (d, J = 18.1 Hz, 1H), 2.62 (d, J = 18.1 Hz, 1H), 1.05
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 214.2 (C=O), 200.5 (C=O), 160.0, 138.0, 136.8, 133.6,
128.7, 127.0, 125.7, 119.1, 118.1, 112.0, 68.7 (NHC−CO), 44.6, 43.9, 26.1 (CMe3); HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C20H21ClNO2 342.1261; Found 342.1258.
2ꢀmethylꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)indolinꢀ3ꢀone 3ap (yellow solid, 32.9 mg, 25%, mp 114ꢀ115
oC): 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.59 (tt, J =
7.4, 1.2 Hz, 1H), 7.42ꢀ7.50 (m, 3H), 6.84 (d, J = 8.3 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 5.73 (s, br,
1H), 3.64 (d, J = 17.7 Hz, 1H), 2.92 (d, J = 17.7 Hz, 1H), 1.45 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 204.2 (C=O), 198.5 (C=O), 159.9, 137.6, 136.9, 133.8, 128.8, 128.2, 125.2, 119.0, 118.6, 112.4,
64.6 (NHC−CO), 43.9 (COCH2), 22.0 (CH3); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C17H16NO2 266.1181; Found 266.1179.
5ꢀnitroꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ba (yellow solid, 65.0 mg, 35%, mp
207ꢀ208 oC): 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 2.3 Hz, 1H), 8.38 (dd, J = 9.1 Hz, 2.3 Hz,
1H), 7.91 (d, J = 7.1 Hz, 2H), 7.60 (tt, J = 7.4, 1.3 Hz, 1H), 7.41ꢀ7.55 (m, 4H), 7.23ꢀ7.36 (m, 3H),
7.10 (s, br, 1H), 6.98 (d, J = 9.1 Hz, 1H), 4.48 (d, J = 18.1 Hz, 1H), 3.28 (d, J = 18.1 Hz, 1H); 13C
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NMR (75 MHz, CDCl3) δ 198.8 (C=O), 197.3 (C=O), 162.3, 139.9, 136.5, 136.1, 134.2, 133.0,
129.1, 129.0, 128.3, 128.2, 125.2, 123.1, 117.7, 111.1, 70.9 (NHC−CO), 44.7 (COCH2); HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H17N2O4 373.1188; Found 373.1186.
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5ꢀfluoroꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ca (yellow solid, 86.6 mg, 50%, mp
149ꢀ150 oC): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.1 Hz, 2H), 7.51ꢀ7.62 (m, 3H), 7.45 (t, J
= 7.6 Hz, 2H), 7.18ꢀ7.33 (m, 5H), 6.94 (dd, J = 8.6, 3.6 Hz, 1H), 6.17 (s, br, 1H), 4.41 (d, J =
17.9Hz, 1H), 3.21 (d, J = 17.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 200.6 (d, J4,C−F = 3.3 Hz,
C=O), 197.6 (C=O), 157.1, 156.4 (d, J1,C−F = 239.5 Hz), 154.8, 137.9, 136.5, 133.8, 128.84,
128.80, 128.2, 127.8, 125.9 (d, J2,C−F = 25.7 Hz), 125.4, 118.6 (d, J3,C−F = 7.3 Hz), 113.0 (d, J3,C−F
= 7.4 Hz), 110.2 (d, J2,C−F = 22.5 Hz), 70.4 (NHC−CO), 45.0 (COCH2); HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calcd for C22H17FNO2 346.1243; Found 346.1240.
5ꢀchloroꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3da (yellow solid, 81.3 mg, 45%, mp
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148ꢀ149 oC): H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.1 Hz, 2H), 7.58 (tt, J = 7.4 Hz, 1.3 Hz,
1H), 7.40ꢀ7.55 (m, 6H), 7.29 (t, J = 7.2 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H),
6.31 (s, br, 1H), 4.42 (d, J = 18.0 Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 199.7 (C=O), 197.5 (C=O), 158.6, 137.7, 136.4, 133.9, 128.9, 128.8, 128.2, 127.8, 125.3, 124.8,
123.9, 119.2, 113.1, 70.1 (NHC−CO), 44.8 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C22H17ClNO2 362.0948; Found 362.0943.
6ꢀchloroꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ea (yellow solid, 101.6 mg, 56%, mp
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174ꢀ175 oC): H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 2H), 7.59 (tt, J = 7.4 Hz, 1.3 Hz,
1H), 7.42ꢀ7.55 (m, 5H), 7.30 (t, J = 7.2 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 6.97 (d, J = 1.4 Hz, 1H),
6.77 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 6.38 (s, br, 1H), 4.43 (d, J = 18.0 Hz, 1H), 3.19 (d, J = 18.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 199.4 (C=O), 197.7 (C=O), 160.5, 144.3, 137.7, 136.4, 133.9,
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128.89, 128.85, 128.2, 127.8, 126.7, 125.3, 119.7, 116.7, 111.7, 69.9 (NHC−CO), 44.8 (COCH2);
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H17ClNO2 362.0948; Found 362.0953.
4ꢀchloroꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3fa (yellow solid, 33.3 mg, 18%, mp
108ꢀ110 oC): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.52ꢀ7.62 (m, 3H), 7.45 (t, J
= 7.6 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.1 Hz, 1H), 6.92 (d, J
= 8.7 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.44 (s, br, 1H), 4.45 (d, J = 18.0
Hz, 1H), 3.20 (d, J = 18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 198.0 (C=O), 197.8 (C=O),
161.4, 138.0, 137.7, 136.5, 134.0, 133.4, 128.89, 128.87, 128.2, 127.9, 125.4, 119.9, 114.9, 110.1,
69.7 (NHC−CO), 45.1 (COCH2); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H17ClNO2
362.0948; Found 362.0945.
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5ꢀmethylꢀ2ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ2ꢀphenylindolinꢀ3ꢀone 3ga (yellow solid, 70.2 mg, 41%, mp
180ꢀ181 oC): 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 2H), 7.50ꢀ7.60 (m, 3H), 7.45 (t, J
= 7.6 Hz, 2H), 7.37 (s, 1H), 7.33 (dd, J = 8.3, 1.5 Hz, 1H), 7.23ꢀ7.31 (m, 2H), 7.20 (tt, J = 7.4, 1.3
Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.13 (s, br, 1H), 4.42 (d, J = 17.9 Hz, 1H), 3.18 (d, J = 17.9 Hz,
13
1H), 2.28 (s, 3H); C NMR (75 MHz, CDCl3) δ 200.9 (C=O), 197.9 (C=O), 158.9, 139.4, 138.4,
136.7, 133.8, 128.9, 128.8, 128.5, 128.2, 127.6, 125.4, 125.0, 118.4, 111.9, 69.7 (NHC−CO), 44.9
(COCH2), 20.6 (CH3); HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H20NO2 342.1494; Found
342.1492.
Conversion of 3aa to 4 with NH2NH2·H2O and HOAc in EtOH
85% Concentration of NH2NH2·H2O (11 ꢁL, 0.193 mmol) and HOAc (5.5 ꢁL, 0.095 mmol)
were added to a solution of 3aa (31 mg, 0.095 mmol) in EtOH (0.6 mL). The mixture was stirred
at 40 °C for 4.5 h until the disappearance of 3aa as determined by TLC. 20 mL of aqueous solution
of Na2CO3 was added and the mixture was extracted with dichloromethane (15 mL × 3). The
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combined organic phases were dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether: 1/8−1:4) to provide the corresponding products 4 (19.1 mg, 62%).
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2ꢀ(4,6ꢀdiphenylpyridazinꢀ3ꢀyl)aniline 4 (yellow solid, mp 190ꢀ191 C): H NMR (300 MHz,
CDCl3) δ 8.13ꢀ8.20 (m, 2H), 7.93 (s, 1H), 7.48ꢀ7.60 (m, 3H), 7.27ꢀ7.37 (m, 5H), 7.10 (ddd, J = 8.1,
7.4, 1.5 Hz, 1H), 6.81 (dd, J = 8.1, 0.9 Hz, 1H), 6.72 (dd, J = 7.7, 1.5 Hz, 1H), 6.50 (td, J = 7.5,
13
1.0 Hz, 1H), 4.72 (s, 2H); C NMR (75 MHz, CDCl3) δ 158.7, 157.9, 146.0, 140.6, 137.2, 136.3,
132.1, 130.2, 130.0, 129.2, 129.0, 128.9, 128.8, 127.2, 125.5, 121.3, 118.0, 117.1; HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H18N3 324.1501; Found 324.1500.
Reaction of 3aa with Cu(OAc)2 for the Synthesis of 5a and 5b
A mixture of 3aa (65.4 mg, 0.2 mmol) and Cu(OAc)2 (91 mg, 0.5 mmol) in 2 mL of DMSO was
stirred at 120 °C for 25 min until the disappearance of 3aa as determined by TLC. After cooling to
room temperature 20 mL of water was added and the mixture was extracted with dichloromethane
(15 mL× 3). The combined organic phases were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by column chromatography on
silica gel (ethyl acetate/petroleum ether: 1:15−1/6) to provide the corresponding products 5a
(lower polarity, 16.6 mg, 26%) and 5b (higher polarity, 36.6 mg, 56%).
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cisꢀ1ꢀbenzoylꢀ7aꢀphenylꢀ1Hꢀazirino[1,2ꢀa]indolꢀ7(7aH)ꢀone 5a (yellow solid, mp 132ꢀ134 C):
1H NMR (300 MHz, CDCl3) δ 7.88ꢀ7.93 (m, 2H), 7.82ꢀ7.88 (m, 2H), 7.66 (ddd, J = 7.6, 1.2, 0.7
Hz, 1H), 7.58 (tt, J = 7.4, 1.4 Hz, 1H), 7.36ꢀ7.51 (m, 7H), 7.23 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H) 4.33
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 195.7 (C=O), 190.4 (C=O), 160.5, 135.7, 135.4, 134.5,
133.4, 131.4, 129.0, 128.9, 128.8, 128.7, 127.6, 126.9, 124.9, 122.9, 72.3, 58.2; HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H16NO2 326.1181; Found 326.1174.
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transꢀ1ꢀbenzoylꢀ7aꢀphenylꢀ1Hꢀazirino[1,2ꢀa]indolꢀ7(7aH)ꢀone 5b (yellow solid, mp 161ꢀ162
oC): 1H NMR (300 MHz, CDCl3) δ 7.80ꢀ7.88 (m, 3H), 7.75 (d, J = 7.8 Hz, 1H), 7.70 (dd, J = 7.0,
1.3 Hz, 1H), 7.62ꢀ7.68 (m, 2H), 7.55 (tt, J = 7.4, 1.3 Hz, 1H), 7.36ꢀ7.45 (m, 3H), 7.21ꢀ7.32 (m,
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3H), 3.92 (s, 1H); C NMR (75 MHz, CDCl3) δ 196.7 (C=O), 188.2 (C=O), 165.9, 136.3, 135.5,
134.1, 128.9, 128.7, 128.55, 128.49, 128.45, 128.38, 127.2, 126.3, 122.0, 73.1, 59.4; HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H16NO2 326.1181; Found 326.1177.
Reaction of 3aa with I2 for the synthesis of 5b
A mixture of 3aa (31.0 mg, 0.095 mmol), I2 (49 mg, 0.191 mmol), and DBU (58 mg, 0.38 mmol)
was stirred in 0.8 mL of THF at 40 °C for 4.5 h until the disappearance of 3aa as determined by
TLC. The reaction mixture was quenched with aqueous Na2S2O3 and extracted with
dichloromethane (15 mL × 3). The organic extracts were dried over sodium sulfate, filtered, and
concentrated to give a residue, which was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether: 1/6) to afford the product 5b (25.0 mg, 81%).
K2CO3 Catalyzed Isomerization of 5b to 6aa
A mixture of 5b (13.0 mg, 0.040 mmol) and K2CO3 (1.1 mg, 0.008 mmol) was stirred in 0.4 mL
of DMSO at 120 °C for about 5 h until the disappearance of 5b as determined by TLC. The
reaction mixture was extracted with dichloromethane (10 mL × 3). Then the organic extracts were
dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by
column chromatography on silica gel (ethyl acetate/petroleum ether: 1/6−1:3) to afford the product
6aa (12.0 mg, 92%).
General Procedure for Cu(OAc)2 and Cs2CO3 Mediated Transformation of 3 to 6 in DMSO
A mixture of 3 (0.1 mmol), Cu(OAc)2 (0.25 mmol), and Cs2CO3 (0.25 mmol) in DMSO (0.8 mL)
were stirred at 120 °C for less than 0.5 h until the disappearance of 3 as determined by TLC. 15
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mL of water was added and the mixture was extracted with dichloromethane (15 mL× 3). The
combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl acetate/petroleum ether: 1/6−1:3) to
afford the corresponding products 6.
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2ꢀbenzoylꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6aa (white solid, 20.3 mg, 62%, mp 270ꢀ273 C): H
NMR (300 MHz, d6ꢀDMSO) δ 9.50 (s, br, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.52ꢀ7.65 (m, 3H),
7.29ꢀ7.40 (m, 3H), 7.24 (d, J = 7.0 Hz, 2H), 7.17 (t, J = 7.7 Hz, 2H), 7.07 (t, J = 7.2 Hz, 2H), 7.00
(t, J = 7.1 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 191.5 (C=O), 175.3 (C=O), 144.7, 139.4,
134.64, 134.59, 133.8, 132.4, 130.9, 129.6, 129.0, 127.6, 127.1, 125.5, 125.3, 123.9, 119.4, 118.6;
HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H16NO2 326.1181; Found 326.1177.
2ꢀbenzoylꢀ3ꢀ(4ꢀmethoxyphenyl)quinolinꢀ4(1H)ꢀone 6ac (yellow solid, 10.8 mg, 30%, mp >300
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oC): H NMR (300 MHz, d6ꢀDMSO) δ 12.28 (s, br, 1H), 8.21 (dd, J = 8.2, 1.2 Hz, 1H), 7.69ꢀ7.79
(m, 3H), 7.60 (t, J = 8.2 Hz, 2H), 7.37ꢀ7.47 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz,
2H), 3.64 (s, 3H); 13C NMR (75 MHz, d6ꢀDMSO) δ 191.7 (C=O), 175.5 (C=O), 158.2, 144.4,
139.4, 134.6, 132.3, 132.1, 129.6, 129.0, 125.8, 125.5, 125.2, 123.7, 119.0, 118.6, 113.8, 113.1,
54.9; HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H18NO3 356.1287; Found 356.1284.
2ꢀbenzoylꢀ3ꢀ(4ꢀchlorophenyl)quinolinꢀ4(1H)ꢀone 6ae (white solid, 13.0 mg, 36%, mp 292ꢀ293
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oC): H NMR (300 MHz, d6ꢀDMSO) δ 12.42 (s, br, 1H), 8.22 (dd, J = 8.1, 1.1 Hz, 1H), 7.72ꢀ7.81
(m, 3H), 7.60 (t, J = 7.9 Hz, 2H), 7.40ꢀ7.49 (m, 3H), 7.24 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz,
2H); 13C NMR (75 MHz, d6ꢀDMSO) δ 191.4 (C=O), 175.1 (C=O), 144.8, 139.3, 134.8, 134.5,
132.8, 132.6, 132.6, 131.8, 129.7, 129.1, 127.7, 125.5, 125.3, 124.0, 118.7, 118.1; HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H15ClNO2 360.0791; Found 360.0786.
2ꢀ(4ꢀmethoxybenzoyl)ꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6ag (white solid, 19.4 mg, 55%, mp
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299ꢀ300 oC): H NMR (300 MHz, d6ꢀDMSO) δ 12.30 (s, br, 1H), 8.20 (dd, J = 8.2, 1.1 Hz, 1H),
7.68ꢀ7.77 (m, 3H), 7.61 (d, J = 8.0 Hz, 1H), 7.40 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.07ꢀ7.22 (m, 5H),
6.94 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, d6ꢀDMSO) δ 189.6 (C=O), 175.2
(C=O), 164.2, 145.3, 139.4, 134.0, 132.33, 132.29, 130.8, 127.6, 127.5, 127.0, 125.5, 125.3, 123.8,
119.0, 118.6, 114.4, 55.8; HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C23H18NO3 356.1287;
Found 356.1283.
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2ꢀ(4ꢀmethylbenzoyl)ꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6ah (white solid, 13.8 mg, 41%, mp >300 oC):
1H NMR (300 MHz, d6ꢀDMSO) δ 12.32 (s, br, 1H), 8.21 (dd, J = 8.1, 1.1 Hz, 1H), 7.73 (ddd, J =
8.4, 7.0, 1.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.41 (ddd, J = 8.0, 6.9, 0.9
Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.07ꢀ7.19 (m, 5H), 2.31 (s, 3H); 13C NMR (75 MHz, d6ꢀDMSO)
δ 190.9 (C=O), 175.3 (C=O), 145.5, 145.0, 139.3, 133.9, 132.4, 132.1, 130.9, 129.8, 129.6, 127.6,
127.0, 125.5, 125.3, 123.8, 119.1, 118.6, 21.3; HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for
C23H18NO2 340.1338; Found 340.1335.
2ꢀ(4ꢀchlorobenzoyl)ꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6ai (yellow solid, 18.0 mg, 50%, mp 280ꢀ281
oC): H NMR (300 MHz, d6ꢀDMSO) δ 12.12 (s, br, 1H), 8.22 (d, J = 7.3 Hz, 1H), 7.60ꢀ7.81 (m,
1
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4H), 7.36ꢀ7.53 (m, 3H), 7.06ꢀ7.25 (m, 5H); C NMR (75 MHz, d6ꢀDMSO) δ 190.7 (C=O), 175.1
(C=O), 144.4, 139.6, 139.4, 133.8, 133.4, 132.4, 131.4, 130.9, 129.1, 127.6, 127.1, 125.5, 125.4,
123.9, 119.5, 118.9; HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H15ClNO2 360.0791; Found
360.0789.
2ꢀ(4ꢀnitrobenzoyl)ꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6aj (yellow solid, 22.5 mg, 61%, mp 295ꢀ297
oC): 1H NMR (300 MHz, d6ꢀDMSO) δ 12.42 (s, br, 1H), 8.23 (dd, J = 8.1, 1.0 Hz, 1H), 8.16 (d, J =
8.9 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.53 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H),
7.44 (ddd, J = 7.9, 6.6, 0.8 Hz, 1H), 7.05ꢀ7.20 (m, 5H); 13C NMR (75 MHz, d6ꢀDMSO) δ 190.9,
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175.4 (C=O), 150.2 (C=O), 143.4, 139.5, 139.4, 133.5, 132.6, 131.1, 130.8, 127.7, 127.4, 125.54,
125.45, 124.1, 123.9, 120.0, 118.8; HRMS (ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H15N2O4
371.1032; Found 371.1030.
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2ꢀbenzoylꢀ6ꢀnitroꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6ba (white solid, 9.3 mg, 25%, mp >300 oC): 1H
NMR (300 MHz, d6ꢀDMSO) δ 12.88 (s, br, 1H), 8.96 (d, J = 2.6 Hz, 1H), 8.51 (dd, J = 9.1, 2.7 Hz,
1H), 7.77ꢀ7.84 (m, 3H), 7.60 (tt, J = 7.4, 1.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.09ꢀ7.23 (m, 5H);
13C NMR (75 MHz, d6ꢀDMSO) δ 191.0 (C=O), 175.3 (C=O), 145.5, 143.2, 143.1, 134.9, 134.3,
132.7, 130.7, 129.7, 129.1, 127.8, 127.6, 126.5, 124.4, 122.2, 121.0, 120.6; HRMS (ESIꢀQꢀTOF)
m/z [M+H]+ Calcd for C22H15N2O4 371.1032; Found 371.1028.
2ꢀbenzoylꢀ6ꢀchloroꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6da (yellow solid, 10.7 mg, 30%, mp 257ꢀ259
1
oC): H NMR (300 MHz, d6ꢀDMSO) δ 12.54 (s, br, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.73ꢀ7.79 (m,
3H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (tt, J = 7.4, 1.3 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.06ꢀ7.19 (m,
5H); 13C NMR (75 MHz, d6ꢀDMSO) δ 191.4 (C=O), 174.2 (C=O), 145.0, 138.1, 134.7, 134.5,
133.4, 132.6, 130.8, 129.6, 129.0, 128.5, 127.6, 127.2, 126.3, 124.4, 121.2, 119.7; HRMS
(ESIꢀQꢀTOF) m/z [M+H]+ Calcd for C22H15ClNO2 360.0791; Found 360.0794.
2ꢀbenzoylꢀ6ꢀmethylꢀ3ꢀphenylquinolinꢀ4(1H)ꢀone 6ga (yellow solid, 14.7 mg, 43%, mp >300 oC):
1H NMR (300 MHz, d6ꢀDMSO) δ 12.27 (s, br, 1H), 8.01(s, 1H), 7.73 (d, J = 7.2 Hz, 2H),
7.51ꢀ7.61 (m, 3H), 7.41 (t, J = 7.7 Hz, 2H), 7.05ꢀ7.18 (m, 5H), 2.46 (s, 3H); 13C NMR (75 MHz,
d6ꢀDMSO) δ 191.6 (C=O), 175.0 (C=O), 144.3, 137.4, 134.6, 134.5, 134.0, 133.8, 133.2, 130.9,
129.5, 128.9, 127.5, 126.9, 125.3, 124.6, 119.1, 118.5, 20.9; HRMS (ESIꢀQꢀTOF) m/z [M+H]+
Calcd for C23H18NO2 340.1338; Found 340.1335.
Cs2CO3ꢀCatalyzed Transformation of 7/8 to 9/11
A mixture of 7 or 8 (0.30 mmol) and Cs2CO3 (0.06 mmol) in 1.3 mL of DMSO was stirred at
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80 °C until the disappearance of 7 or 8 as determined by TLC. After cooling to room temperature,
15 mL of water was added and the mixture was extracted with dichloromethane (15 mL× 3). The
combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether:
1:20−1:10) to provide the corresponding products 9 (32.1 mg, 66%)27 or 11 (30.4 mg, 45%)28.
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1ꢀ(2ꢀaminophenyl)ꢀ2ꢀmethylpropanꢀ1ꢀone 9: H NMR (300 MHz, CDCl3) δ 7.77 (dd, J = 8.3,
1.5 Hz, 1H), 7.25 (ddd, J = 8.2, 7.1, 1.5 Hz, 1H), 7.60ꢀ7.70 (m, 2H), 6.30 (s, br, 2H), 3.59 (heptet,
J = 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H).
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1ꢀ(2ꢀaminophenyl)ꢀ2ꢀphenylpropanꢀ1ꢀone 11: H NMR (300 MHz, CDCl3) δ 7.78 (dd, J = 8.2,
1.2 Hz, 1H), 7.30(d, J = 4.4, 4H), 7.14ꢀ7.25 (m, 2H), 6.50ꢀ6.64 (m, 2H), 6.32(s, 2H), 4.72 (dd, J =
13
13.7, 6.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 202.8 (C=O), 151.2, 142.5, 134.2, 131.6, 129.0,
127.7, 126.8, 117.5, 117.3, 115.8, 47.7, 19.9.
Cs2CO3ꢀCatalyzed Transformation of 13 to 14
A mixture of 13 (18.0 mg, 0.06 mmol) and Cs2CO3 (4 mg, 0.01 mmol) in DMSO (0.5 mL) were
stirred at 80 °C for 1 h until the disappearance of 13 as determined by TLC. 10 mL of water was
added and the mixture was extracted with dichloromethane (10 mL× 3). The combined organic
phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/petroleum ether: 1:20−1:10) to afford the
product 14 (17.5 mg, 98%)29.
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1,2,4ꢀtriphenylbutꢀ2ꢀeneꢀ1,4ꢀdione 14: H NMR (300 MHz, CDCl3) δ 7.95ꢀ8.03 (m, 4H),
7.39ꢀ7.67 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 197.7 (C=O), 188.3 (C=O), 156.5, 137.4, 136.1,
134.9, 133.5, 133.5, 130.9, 129.3, 128.9, 128.9, 128.8, 128.7, 127.4, 121.0, 116.9.
Acknowledgments
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We are grateful for the financial support from the National Natural Science Foundation of
China (Nos. 21202011), Natural Science Foundation of Jiangsu Province (BK20141171), the
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110), and
Jiangsu Province Key Laboratory of Fine Petrochemical Engineering (KF1303)
Supporting Information
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1H and 13C NMR spectra of the products, H−H COSY and NOESY spectra of 5a, and Xꢀray
crystallographic data of 3aa and 6ai. This material is available free of charge via the Internet at
http://pubs.acs.org.
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