2-Oxindole Acts as a Synthon of 2-Aminobenzoyl Anion in the K2CO3-Catalyzed Reaction with Enones: Preparation of 1,4-Diketones Bearing an Amino Group and Their Further Transformations

Article abstract of DOI:10.1021/acs.joc.5b02054

A convenient approach for the synthesis of 1,4-diketones bearing an amino group has been developed through the K₂CO₃-catalyzed reaction of 2-oxindoles with enones with the assistance of atmospheric O₂ via sequential Michael addition-oxidation-ring-cleavage process. The further intramolecular reaction leads to the formation of benzoazepinone, quinoline, and 3-oxindole derivatives.

Full text of DOI:10.1021/acs.joc.5b02054

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Article
2-Oxindole Acts as a Synthon of 2-Aminobenzoyl Anion in the
K2CO3-Catalyzed Reaction with Enones: Preparation of 1,4-
Diketones Bearing an Amino Group and Their Further Transformations
Chun-Bao Miao, Yu-Mei Zeng, Tong Shi, Rui Liu, Peng-Fei Wei, Xiao-Qiang Sun, and Hai-Tao Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02054 • Publication Date (Web): 09 Dec 2015
Downloaded from http://pubs.acs.org on December 15, 2015
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2-Oxindole Acts as a Synthon of 2-Aminobenzoyl Anion in the K2CO3-Catalyzed Reaction
with Enones: Preparation of 1,4-Diketones Bearing an Amino Group and Their Further
Transformations
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ChunꢀBao Miao,* YuꢀMei Zeng, Tong Shi, Rui Liu, PengꢀFei Wei, XiaoꢀQiang Sun, HaiꢀTao Yang
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.
Email: estally@yahoo.com
Abstract
A convenient approach for the synthesis of 1,4ꢀdiketones bearing an amino group has been
developed through the K2CO3ꢀcatalyzed reaction of 2ꢀoxindoles with enones with the assistance of
atmospheric O2 via sequential Michael addition–oxidation–ring cleavage process. The further
intramolecular reaction leads to the formation of benzoazepinone, quinoline, and 3ꢀoxindole
derivatives.
Introduction
1,4ꢀDiketones are useful precursors to a variety of synthetically valuable compounds such as
pyrroles, furans, thiophenes,1 pyridazines,2 and cyclopentenones.3 A number of reactions have
been developed to construct this important structural pattern.4 Among them, the conjugate
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addition of aldehydes onto α,βꢀunsaturated ketones catalyzed by Nꢀheterocyclic carbenes (NHCs),
known as the Stetter reaction, was one of the most important methods to access 1,4ꢀdiketone
skeletons (Scheme 1).5 An acyl anion equivalent was generated through umpolung of aldehydes
catalyzed by NHCs, which was often generated in situ from a five membered nitrogenꢀcontaining
heterocyclic core like thiazolium, triazolium, imidazolium, and imidazolinium salts in the presence
of a base. Recently, the Gravel’s group developed a novel bis(amino)cyclopropenylidene catalyst
as a candidate of NHCs, which even showed high efficiency toward those wellꢀknown unreactive
substrates in the Stetter reaction catalyzed by NHCs.6 Notably, a drawback of the Stetter reaction
was that most of the aldehyde moieties could not contain amino or hydroxyl groups, which
reduced the opportunity for further functionalization of the generated products.
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Scheme 1 2ꢀOxindole as an Equivalent of orthoꢀAminobenzoyl Anion.
Commonly used method:
Ph
O
O
H
O
NHC (cat.)
O
R
R
R
Ph
O
This work:
O
Ph
Ph
O
Ph
Ph
O
K2CO3 (cat.), air
NH2
N
O
H
NH2
3ꢀMonosubstituted 2ꢀoxindole as a good nucleophile is easy to take place Michael addition,7
and Michael addition initiated cascade reaction.8 In terms of 3ꢀunsubstituted oxindole, it is liable
to take place condensation reaction with ketonic compounds9 or double Michael addition reaction
with bisenones10 to form 3ꢀalkylideneoxindoles or spirooxindoles, respectively. The Michael
addition reaction of 3ꢀunsubstituted 2ꢀoxindole with enone to give 3ꢀmonosubstituted 2ꢀoxindole
has only been reported in few literatures in the presence of sodium ethoxide, piperidine, or
proline.11 Here we reported a baseꢀcatalyzed reactions of 2ꢀoxindoles with enones for the
preparation of 1,4ꢀdiketones bearing an amino group through cascade Michael
additionꢀoxidationꢀring cleavage process. The 2ꢀoxindole was used as an equivalent of
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orthoꢀaminobenzoyl anion for the first time (Scheme 1).
Table 1 Primary result.
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yielda
entry
solvent
time
3a + 3b
4aa
5 or 6
1
2
3
4
5
6
7
EtOH
EtOH
EtOH
EtOH
MeOH
MeOH
MeOH
1 h
6 h
71%
trace
5%
0
78%
61%
49%
80%
69%
54%
trace
3%
24 h
48 h
1 h
18%
30%
6%
6%
trace
4%
6 h
12%
19%
24 h
10%
a Isolated yield.
Results and Discussion
Initially, the K2CO3ꢀcatalyzed addition reaction of oxindole 1a with chalcone 2a was carried out
in ethanol at room temperature (Table 1). The Michael adducts 3a and 3b were obtained as the
main products 1 h later.12 With the extension of reaction time, two new products 4aa and 5 were
generated and the amounts of 3a and 3b decreased gradually. The 4aa and 5 could be isolated in
30% and 6% yield 48 hs later, respectively. Undoubtedly, the ethoxyl in carbamate group of 5 was
derived from the ethanol solvent. Changing the solvent from ethanol to methanol gave similar
result. The product 6 was produced instead of 5 and the ratio of 4/6 is about 2.5 times of the ratio
of 4/5.
The product 4aa looked like a Michael adduct of orthoꢀaminobenzoyl anion with 2a. To the best
of our knowledge, the umpolung of 2ꢀaminobenzaldehyde to orthoꢀaminobenzoyl anion in Stetter
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reaction has never been realized. On the other hand, an oxidative process was involved with O2 as
the oxidant and only a catalytic amount of K2CO3 was enough to achieve this interesting
sequential transformation. Molecular oxygen as an ideal green oxidant has attracted considerable
attention in organic transformation owing to its abundance, no cost, nontoxic, and free of
contamination.13 Moreover, the introduction of an amino group into 1,4ꢀdiketone skeletones made
their further transformation more diverse. These inspired us to investigate this interesting
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transformation inꢀdepth.
Table 2 Screening of the Reaction Conditions
O
O
Ph
Ph
O
conditions
+
Ph
Ph
(1 mmol)
N
solvent (3 mL), rt.
O
H
2a
1a
NH2
(1 mmol)
4aa
entry base (equiv)
solvent
CH3CN
THF
time (h) yield (%)a
1
2
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
24
28
20
28
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4
17
trace
11
3
acetone
toluene
DCE
4
trace
trace
70
67
59
69
32
4
5
6
K2CO3 (0.2)
K2CO3 (1)
DMSO
DMSO
DMSO
DMF
7
2.5
12
12
24
24
3
8
K2CO3 (0.05)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
NaOH (0.2)
Et3N (0.2)
9
10
11b
12
13
14
15
16
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
52
8
24
24
24
4
DMAP (0.2)
piperidine (0.2)
DBU (0.2)
9
9
47
a Isolated yield. b Carried out under N2 atomosphere.
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The influence of solvent and base was investigated carefully (Table 2). Different solvents were
evaluated by employing 20 mol % of K2CO3 as the catalyst. Conducting the reaction in THF, DCE,
or toluene only afforded trace of 4aa (Entries 2, 4, and 5). Using NMP (Nꢀmethylpyrrolidone) as
solvent gave 32% yield of 4aa (Entry 10) and much lower yield was obtained in acetonitrile and
acetone (Entries 1 and 3). Upon switching the solvent to DMSO, the yield of 4aa was dramatically
improved to 70% (Entry 6). Although DMF also gave a comparative yield as that of DMSO, the
reaction took much longer time to complete (Entry 9). Further screening different bases for this
transformation in DMSO revealed that organic bases such as Et3N, DMAP, and piperidine afforded
very low yield of 4aa (Entries 13ꢀ15) and the NaOH or DBU only gave moderate yield of 4aa
(Entries 12 and 16). The O2 was proved to be crucial to the reaction and only 4% of 4aa could be
obtained under N2 atmosphere after 24 h (Entry 11). Reducing the loading of K2CO3 to 5 mol %
led to longer reaction time and slightly lower yield (Entry 8). Although employing 1 equiv of
K2CO3 could shorten the reaction time, no noticeable enhancement on the yield was got (Entry 7).
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Table 3 Substrate Scope of the Enones
O
O
R1
R2
K2CO3 (20 mol %)
O
R1
R2
+
N
DMSO (3 mL), air, rt.
O
H
NH2
4
2
1a (1 mmol)
(1 mmol)
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With the optimal conditions in hand (Table 2, entry 6), the scope of the reaction was then
investigated (Table 3). The R1 and R2 substituent of substrate 2 may be either electronꢀrich or
electronꢀdeficient aryl, and alkyl groups. Most of the reactions gave moderate yield of products.
When both of the Aryl groups of R1 and R2 linked with strong electronꢀdonating or strong
electronꢀwithdrawing group, the yield was unsatisfied (4al and 4am). When R2 was a methyl
group, only 20% yield of product (4ar) was obtained. Replacing the methyl group by tertꢀbutyl
group increased the yield to 52% (4as). Pyridyl group was also tolerated in the transformation,
producing the product 4ap in 42% yield. Furyl group gave very low yield of product 4aq. The
structure of product 4al was further established by single crystal Xꢀray crystallographic analysis.
Table 4 Substrate Scope of the Oxindoles
O
O
Ph
Ph
K2CO3 (20 mol %)
O
+
N
O
DMSO (3 mL), rt, air
H
NH2
R
2a (1 mmol)
1 (1 mmol)
R
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O
O
O
O
MeO
Ph
Ph
F
Ph
Ph
Cl
Ph
Ph
O
O
O
O
O
NH2
4ea
(10.5 h, 32%)
NH2
NH2
Cl
NH2
4da
4ba
4ca
Ph
Ph
Ph
(4 h, 50%)
(6.5 h, 65%)
(6.5 h, 64%)
O
O
H3
C
Ph
O2
N
O
NH2
4ga
( 6 h, 54%)
NH2
4fa
Ph
Ph
( 12 h, 30%)
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The applicability of other 2ꢀoxindoles in this conversion was also evaluated by performing the
reaction of them with chalcone 2a (Table 4). The results showed that an obvious electronic
substrate effect existed. Either strong electronꢀdonating or strong electronꢀwithdrawing group
substituted 2ꢀoxindole gave low yield of the product.
To show the practicality of this protocol, a large scale experiment was carried out by performing
the reaction of 1a (2.0 g, 15 mmol) with 3a (3.12 g, 15 mmol) in 40 mL of DMSO in the presence
of 3 mmol of K2CO3 (Scheme 2). In order to increase the concentration of oxygen in the solvent,
air was simultaneously bubbled into the reaction mixture through a glass dropper. This
transformation proceeded smoothly to afford 4aa in 67% yield within 10 h.
Scheme 2 Large Scale Synthesis of 4aa
Among the above investigated reactions, there was no substituent on the nitrogen atom of
2ꢀoxindole. Next, the reactivity of Nꢀsubstituted 2ꢀoxindoles was considered (Scheme 3). For the
reaction of Nꢀphenylꢀ2ꢀoxindole (7) with enone 2u under the standard conditions, although the
1
TLC indicated that full conversion to two almost equal amounts of products had occurred, the H
NMR analysis showed that both of them were not the anticipated product. The product with higher
polarity was assigned as the hydroxylated Michael adduct 9 (35%)14 but not the hydroperoxide.
1
Because the characteristic chemical shifts for ꢀOOH at 9ꢀ10 ppm15 was not observed in the H
NMR spectrum of 9. The product with lower polarity was proved to be a mixture of three
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inseparable compounds. NꢀBoc protected 2ꢀoxindole (8) gave a similar result as that of Nꢀphenyl
3
4
5
6
2ꢀoxindole.
7
8
9
Scheme 3 Reaction of NꢀSubstitutedꢀ2ꢀOxindoles with Enone.
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Me
O
7, R = Ph
N
8
, R = Boc
O
R
+
Me
K
2CO3 (20% mol)
DMSO, rt.,
HO
O
+
inseparable mixture
O
N
9, R = Ph, 13 h, 35%
10
2u
Me
Me
R
, R = Boc, 10 h, 38%
Due to the simultaneous existence of amino and carbonyl group, the synthetic potential of the
products 4 through the intramolecular reaction was investigated (Scheme 4). No reaction occurred
by heating 4aa in ethanol with 20% mol of acetic acid or directly in acetic acid at reflux. When the
HOAc was replaced by TsOH⋅H2O, the 4aa was smoothly converted to benzoazepinone 11 in 77%
yield in ethanol at 40 ºC. It seems that 4aa are liable to convert to 12 through a
condensationꢀoxidation process. However, several oxidation conditions like Cu(OAc)2, PhI(OAc)2,
DDQ, and K2S2O8 could not realize this simple looking conversion. Finally, a concise route to
access 12 through twoꢀstep oneꢀpot reaction was explored. In the presence of 1.2 equiv of I2 and
2.4 equiv of DMAP, 11 could turn into the single product 12 in excellent yield. Surprisely, the
iodine could also catalyze the transformation of 4aa to 11 in DMSO at 80 ºC. It could be explained
by that the formation of HI in the iodination catalyzed the conversion. Thus, a simple oneꢀpot
conversion of 4aa to 12 was realized. A mixture of 4aa and 0.2 equiv of I2 were stirred in DMSO
at 80 ºC for 0.5 h. After cooling to room temperature, 1.0 equiv of I2 and 2.4 equiv of DMAP were
added and the mixture was further stirred at room temperature for 30 min to give 12 in 82% yield.
The structure of product 12 was unambiguously determined on the basis of single crystal Xꢀray
diffraction analysis (see Supporting Information). It was noteworthy that direct reaction of 4aa
with 1.2 equiv of I2 and 2.4 equiv of DMAP lead to a complex mixture with very low conversion.
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To the best our knowledge, the benzoazepinone skeleton like 11 and 12 was rather rare.16 If
heating 4aa in a mixed solvent of DMSO/H2O (4:1) in the presence of catalytic amounts of
6
7
8
9
o
hydrochloric acid at 90 C for 22 h, two interesting cyclization products 1317 and 14 were
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provided in 46% and 30% yield, respectively. During the reaction, 11 was quickly formed as the
intermediate. However, the conversion of 11 to 13 and 14 needed very long time.
Scheme 4 Further Transformation of 4aa.
A possible mechanism is depicted in Scheme 5. Initially, Michael addition of 2ꢀoxindole to
enone affords the Michael adduct 3. Under basic condition, the reaction of 3 with O2 generates
peroxide A.15a,18 Intramolecular attacks of peroxide anion on the amide group produce the
dioxetane intermediate B, which undergoes dissociation to generate C. Decarboxylation of C form
the product 4. This type of cleavage of an oxindole ring under basic oxidative conditions has
precedence in the literature.19 However, either large excess amount of NaH (3 equiv) or NaOH (>
10 equiv) was needed19a,b,d or a mixture was generated.19c,d If the reaction was carried out in
methanol or ethanol, the competing intermolecular attack of alkoxy anion at the amide group
provides the intermediate D, which undergoes sequential CꢀC and OꢀO bond cleavage to generate
the side product 5 or 6. At present, we had no a definite explaination to the generation of different
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products for Nꢀprotected 2ꢀoxindoles. It was possible that the substituent on the nitrogen atom was
not benificial to the attack of peroxide anion on the amide group. As a consequence, the oxidation
of starting material by the generated peroxide led to the formation of hydroxylated product.
Under acid conditions, the intramoleclar reaction of amino group with the carbonyl affords
the enamine product 11. The iodination of 11 in the presence of DMAP provides the intermediate
F. Another iodinated product G also could not be exluded.20 Extrusion of HI from F or the imine
H (equilibrates to G) by DMAP would afford the product 12. This indirect route (oneꢀpot, twoꢀstep)
could synthesize 12 in good yield within short time. At high temperature, 11 is slowly oxidized by
O2 to generate 12. Two possible reaction pathways exist for the rapid hydrolysis of 12 in the
presence of H2O under acid conditions. In path a, C=N bond cleavage gives the intermediate I,
which undergoes selective intramolecular Michael addition to afford the product 14. In path b, the
retroꢀAldol condensation generates the intermediate J. The followꢀup selective Aldol condensation
produces the quinoline product 13. The water was essential to the hydrolysis of 12, if water was
not added as the coꢀsolvent, the hydrolysis is very slow. The hydrolysis of 12 is so fast that we
cannot observe the intermediate 12 on TLC during the hydrochloric acidꢀcatalyzed reaction of 4aa
in DMSO/H2O. In order to prove this, the reaction of 12 in the presence of catalytic amount of
hydrochloric acid was conducted in DMSO/H2O at 90 ºC (Scheme 4). Full conversion of 12 was
completed within 25 min along with the formation of 13 and 14 with the ratio of 1:1.
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Scheme 5 Proposed Mechanism
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In summary, the K2CO3ꢀcatalyzed reaction of 2ꢀoxindoles with enones for the preparation of a
variety of 1,4ꢀdiketones bearing an amino group was disclosed. Simple experimental procedures
and mild reaction conditions were used for the successive Michael addition–oxidation–ring
cleavage reactions. The further intramolecular reaction of the 1,4ꢀdiketone produced the
benzoazepinone, quinoline, and 3ꢀoxindole derivatives. Only atmospheric oxygen was needed in
the oxidative process among these transformations.
Experimental Section
General Information.
1H and 13C NMR spectra were recorded on 300 MHz and 500 MHz (75 and 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).
Preparation of Starting Materials
2ꢀOxindoles 1a–g, 7, and 2r are commercially availible. NꢀBocꢀ2ꢀoxindole 8 was prepared from
1a and (Boc)2O according to reported procedure.21 Enones 2a–q and 2s were synthesized from
corresponding ketones and aldehydes catalyzed by NaOH.22 (E)ꢀ1ꢀPhenylꢀ2ꢀbutenꢀ1ꢀone 2t was
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prepared through the FridelꢀCraft reacition of benzene with (E)ꢀ2ꢀbutenoylchlorid.23
K2CO3-Catalyzed Reaction of 2-Oxindole (1a) with Chalcone (2a) in Ethanol or Methanol
A mixture of 2ꢀoxindole (133 mg, 1 mmol), chalcone 2a (208 mg, 1 mmol), and K2CO3 (28 mg,
0.2 mmol) was stirred in 3 mL of ethanol or methanol in a tube (Φ18 × 150 mm) under open air at
room temperature for 48 h or 24 h, respectively. 30 mL of water was added and the mixture was
extracted with dichloromethane (20 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) to provide the corresponding products
5 (or 6), 4aa, and 3a+3b.
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3a: white solid, mp 129ꢀ130 °C. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.1 Hz, 2H), 7.65 (s,
br, 1H), 7.57 (tt, J = 7.3, 1.3 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.08ꢀ7.16
(m, 6H), 7.01 (td, J = 7.6, 1.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 4.17ꢀ4.29 (m, 2H), 3.88 (d, J = 3.4
13
Hz, 1H), 3.56 (dd, J = 20.6 Hz, 8.7 Hz, 1H); C NMR (75 MHz, CDCl3) δ 199.0, 178.4, 141.0,
139.7, 137.2, 133.3, 128.8, 128.5, 128.4, 128.3, 128.2, 128.0, 127.0, 124.9, 122.4, 109.3, 50.1,
42.0, 39.8; HRMS (ESIꢀQꢀTOF) m/z: [M+Na]+ Calcd for C23H19NNaO2 364.1313; Found
364.1309.
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5: yellow solid, 24.2 mg, 6%, mp 42ꢀ43 °C. H NMR (300 MHz, CDCl3) δ 11.09 (s, 1H), 8.46
(dd, J = 8.6, 1.0 Hz, 1H), 8.10 (dd, J = 8.2, 1.5 Hz, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.58 (tt, J = 7.4,
1.3 Hz, 1H), 7.28ꢀ7.36 (m, 4H), 7.19ꢀ7.28 (m, 1H), 7.16ꢀ7.25 (m, 1H), 7.00 (ddd, J = 8.2, 7.4, 1.2
Hz, 1H), 5.37 (dd, J = 10.3, 3.5 Hz, 1H), 4.21 (dd, J = 18.2 Hz, 10.3 Hz, 1H), 4.19 (q, J = 7.1 Hz,
2H), 3.29 (dd, J = 18.2, 3.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 202.6,
198.0, 154.0, 142.3, 138.8, 136.5, 134.9, 133.5, 131.6, 129.5, 128.8, 128.3, 128.1, 127.7, 121.4,
120.9, 119.3, 61.3, 49.5, 44.2, 14.6; HRMS (ESIꢀQꢀTOF) m/z: [M+Na]+ Calcd for C25H23NNaO4
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424.1525; Found 424.1521.
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6: yellow solid, 37.9 mg, 10%, mp 97ꢀ99 °C. 1H NMR (300 MHz, CDCl3) δ 11.13 (s, 1H), 8.44
(dd, J = 8.5, 0.8 Hz, 1H), 8.10 (dd, J = 8.2, 1.3 Hz, 1H), 7.98 (d, J = 7.1 Hz, 2H), 7.57 (tt, J = 7.4,
1.3 Hz, 1H), 7.20ꢀ7.36 (m, 5H), 7.00 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H), 5.36 (dd, J =10.4, 3.5 Hz, 1H),
4.21 (dd, J = 18.1, 10.4 Hz, 1H), 3.74 (s, 3H), 3.28 (dd, J = 18.1, 3.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 202.6, 198.0, 154.3, 142.1, 138.7, 136.3, 134.9, 133.5, 131.6, 129.4, 128.7, 128.3, 128.0,
127.6, 121.5, 120.9, 119.2, 52.3, 49.5, 44.2; HRMS (ESIꢀQꢀTOF) m/z: [M+Na]+ Calcd for
C24H21NNaO4 410.1368; Found 410.1366.
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General Procedure for the K2CO3-Catalyzed Reaction of 2-Oxindoles (1) with Enones (2) in
DMSO for the Preparation of 4.
A mixture of 2ꢀoxindoles 1 (1 mmol), enones 2 (1 mmol), and K2CO3 (0.2 mmol) was stirred in
3 mL of DMSO in a tube (Φ18 × 150 mm) under open air at room temperature for a given time.
Upon completion of the reaction as determined by TLC, 30 mL of water was added and the
mixture was extracted with dichloromethane (20 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) to provide the corresponding products
4.
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4aa: yellow solid, 230 mg, 70%, mp 77ꢀ79 °C. H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.1
Hz, 2H), 7.91 (d, J = 7.7 Hz, 1H), 7.55 (tt, J = 7.3 Hz, 1.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H),
7.28ꢀ7.39 (m, 4H), 7.14ꢀ7.25 (m, 2H), 6.53ꢀ6.63 (m, 2H), 6.21 (s, br, 2H), 5.34 (dd, J = 10.0, 3.8
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Hz, 1H), 4.19 (dd, J = 18.0, 10.0 Hz, 1H), 3.23 (dd, J = 17.9, 3.8 Hz, 1H); C NMR (75 MHz,
CDCl3) δ 200.7, 198.3, 151.2, 139.9, 136.7, 134.3, 133.3, 131.8, 129.2, 128.7, 128.3, 128.1, 127.2,
117.5, 116.0, 48.9, 43.9; HRMS (+ESI) m/z: [M+H]+ Calcd for C22H20NO2 330.1494; Found
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330.1490.
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4ab: yellow solid, 231 mg, 62%, mp 120ꢀ121 °C. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.1
Hz, 2H), 7.91 (dd, J = 8.6, 1.4 Hz, 1H), 7.56 (tt, J = 7.3, 1.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.20
(ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 6.84 (s, 1H), 6.82 (dd, J = 8.3, 1.9 Hz, 1H), 6.74 (dd, J = 7.5, 0.9
Hz, 1H), 6.55ꢀ6.63 (m, 2H), 6.20 (s, br, 2H), 5.92 (d, J = 1.4 Hz, 1H), 5.90 (d, J = 1.4 Hz, 1H),
5.26 (dd, J = 9.8, 4.0 Hz, 1H), 4.12 (dd, J = 18.0, 9.8 Hz, 1H), 3.21 (dd, J = 18.0, 3.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 200.7, 198.3, 151.2, 148.2, 146.8, 136.7, 134.3, 133.6, 133.3, 131.7,
128.7, 128.3, 121.4, 117.5, 117.4, 116.0, 108.9, 108.4, 101.2, 48.4, 43.9; HRMS (ESI) m/z:
[M+H]+ Calcd for C23H20NO4 374.1392; Found 374.1384.
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4ac: yellow solid, 180 mg, 50%, mp 135ꢀ136 °C. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.1
Hz, 2H), 7.91 (dd, J = 8.6, 1.6 Hz, 1H), 7.55 (tt, J = 7.4, 1.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.27
(d, J = 8.9 Hz, 2H), 7.17 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 6.84 (d, J = 8.9 Hz, 2H), 6.54ꢀ6.62 (m,
2H), 6.20 (s, br, 2H), 5.29 (dd, J = 9.8, 4.0 Hz, 1H), 4.14 (dd, J = 17.9, 9.8 Hz, 1H), 3.75 (s, 3H),
13
3.21 (dd, J = 17.9, 4.0Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.9, 198.4, 158.7, 151.2, 136.6,
134.2, 133.2, 131.8, 131.7, 129.1, 128.6, 128.2, 117.44, 117.35, 115.9, 114.5, 55.3, 47.9, 43.9;
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C23H22NO3 360.1600; Found 360.1596.
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4ad: yellow solid, 178 mg, 52%, mp 61ꢀ63 °C. H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 7.1
Hz, 2H), 7.91 (dd, J = 8.5, 1.3 Hz, 1H), 7.52 (tt, J = 7.3, 1.3 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.23
(d, J = 8.0 Hz, 2H), 7.15 (ddd, J = 8.3, 7.2, 1.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.52ꢀ6.59 (m,
2H), 6.20 (s, br, 2H), 5.30 (dd, J = 10.0, 3.8 Hz, 1H), 4.16 (dd, J = 18.0, 10.0 Hz, 1H), 3.19 (dd, J
= 18.0, 3.8 Hz, 1H) , 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.8, 198.3, 151.1, 136.8, 136.7,
136.6, 134.1, 133.1, 131.7, 129.8, 128.6, 128.1, 127.8, 117.4, 117.3, 115.8, 48.4, 43.9, 21.0;
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C23H22NO2 344.1651; Found 344.1642.
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4ae: yellow solid, 182 mg, 50%, mp 99ꢀ101 °C. H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.1
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Hz, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.55 (tt, J = 7.3, 1.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.25ꢀ7.32
(m, 4H), 7.19 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 6.54ꢀ6.62 (m, 2H), 6.22 (s, br, 2H), 5.33 (dd, J = 9.7,
4.1 Hz, 1H), 4.13 (dd, J = 18.0, 9.7 Hz, 1H), 3.22 (dd, J = 17.9, 4.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 200.2, 197.9, 151.2, 138.3, 136.4, 134.4, 133.3, 133.0, 131.5, 129.4, 129.2, 128.6, 128.1,
117.5, 117.0, 115.8, 47.9, 43.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19ClNO2
364.1104; Found 364.1097.
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4af: yellow solid, 150 mg, 40%, mp 137ꢀ139 °C. 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 8.8
Hz, 2H), 7.98 (d, J = 7.1 Hz, 2H), 7.83 (dd, J = 8.3 Hz, 1.3 Hz, 1H), 7.52ꢀ7.61 (m, 3H), 7.46 (t, J =
7.5 Hz, 2H), 7.22 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 6.56ꢀ6.65 (m, 2H), 6.26 (s, br, 2H), 5.48 (dd, J =
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9.2 Hz, 4.4 Hz, 1H), 4.16 (dd, J = 17.9 Hz, 9.2 Hz, 1H), 3.30 (dd, J = 17.9 Hz, 4.5 Hz, 1H); C
NMR (75 MHz, CDCl3) δ 199.3, 197.4, 151.5, 147.4, 147.1, 136.3, 134.9, 133.6, 131.3, 129.1,
128.8, 128.3, 124.4, 117.7, 116.9, 116.1, 48.4, 43.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C22H19N2O4 375.1345; Found 375.1336.
4ag: yellow solid, 202 mg, 54%, mp 141ꢀ142 °C. 1H NMR (300 MHz, CDCl3) δ 8.26 (t, J = 1.9
Hz, 1H), 8.09 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.87 (dd, J = 8.7, 1.5 Hz,
1H), 7.73 (dt, J = 7.7, 1.3 Hz, 1H), 7.58 (tt, J = 7.3, 1.3 Hz, 1H), 7.42ꢀ7.53 (m, 3H), 7.23 (ddd, J =
8.5, 7.2, 1.4 Hz, 1H), 6.58ꢀ6.66 (m, 2H), 6.27 (s, br, 2H), 5.49 (dd, J = 9.3, 4.5 Hz, 1H), 4.18 (dd, J
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= 18.0, 9.3 Hz, 1H), 3.33 (dd, J = 18.0, 4.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 199.4, 197.5,
151.5, 148.7, 141.9, 136.3, 134.8, 134.5, 133.6, 131.3, 130.1, 128.8, 128.2, 123.1, 122.4, 117.7,
116.8, 116.1, 47.9, 43.5; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19N2O4 375.1345;
Found 375.1341.
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4ah: yellow solid, 172 mg, 48%, mp 77ꢀ78 °C. H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 9.0
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Hz, 2H), 7.91(d, J = 8.0 Hz, 1H), 7.27ꢀ7.39 (m, 4H), 7.13ꢀ7.24 (m, 2H), 6.90 (d, J = 9.0 Hz, 2H),
6.53ꢀ6.61 (m, 2H), 6.21 (s, br, 2H), 5.33 (dd, J = 10.0, 3.8 Hz, 1H), 4.13 (dd, J = 17.8, 10.0 Hz,
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1H), 3.85 (s, 3H ), 3.19 (dd, J = 17.8, 3.8 Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.8, 196.8,
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163.6, 151.2, 140.0, 134.2, 131.7, 130.5, 129.7, 129.1, 128.0, 127.1, 117.45, 117.41, 115.9, 113.7,
55.5, 48.8, 43.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C23H22NO3 360.1600; Found
360.1592.
4ai: yellow solid, 189 mg, 55%, mp 69ꢀ71 °C. 1H NMR (300 MHz, CDCl3) δ 7.86ꢀ7.94 (m, 3H),
7.27ꢀ7.38 (m, 4H), 7.13ꢀ7.25 (m, 4H), 6.53ꢀ6.62 (m, 2H), 6.21 (s, br, 2H), 5.33 (dd, J = 10.0, 3.8
Hz, 1H), 4.16 (dd, J = 17.9, 10.0 Hz, 1H), 3.21 (dd, J = 17.9, 3.8 Hz, 1H), 2.39 (s, 3H ); 13C NMR
(75 MHz, CDCl3) δ 200.7, 197.8, 151.2, 143.9, 139.9, 134.13, 134.10, 131.7, 129.2, 129.1, 128.3,
128.0, 127.1, 117.4, 117.3, 115.7, 48.7, 43.7, 21.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C23H22NO2 344.1651; Found 344.1647.
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4aj: yellow solid, 247 mg, 68%, mp 115ꢀ116 °C. H NMR (300 MHz, CDCl3) δ 7.85ꢀ7.92 (m,
3H), 7.37 (d, J = 8.6 Hz, 2H), 7.24ꢀ7.35 (m, 4H), 7.09ꢀ7.24 (m, 2H), 6.49ꢀ6.58 (m, 2H), 6.22 (s, br,
2H), 5.31 (dd, J = 10.0, 3.7 Hz, 1H), 4.12 (dd, J = 17.9, 10.1 Hz, 1H), 3.15 (dd, J = 18.0, 3.8 Hz,
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1H); C NMR (75 MHz, CDCl3) δ 200.5, 197.1, 151.2, 139.8, 139.6, 135.0, 134.3, 131.7, 129.7,
129.2, 128.9, 128.0, 127.3, 117.5, 117.3, 115.9, 48.9, 43.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+
Calcd for C22H19ClNO2 364.1104; Found 364.1095.
4ak: yellow solid, 150 mg, 40%, mp 135ꢀ136 °C. 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 9.0
Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 7.87 (dd, J = 8.2 Hz, 1.1 Hz, 1H), 7.29ꢀ7.38 (m, 4H), 7.16ꢀ7.27
(m, 2H), 6.53ꢀ6.64 (m, 2H), 6.23 (s, br, 2H), 5.34 (dd, J = 10.1, 3.7 Hz, 1H), 4.19 (dd, J = 18.0,
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10.1 Hz, 1H), 3.21 (dd, J = 17.9, 3.8 Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.2, 197.1, 151.3,
150.4, 141.1, 139.5, 134.5, 131.8, 129.4, 129.3, 128.0, 127.5, 123.9, 117.5, 117.1, 116.0, 49.2, 44.3;
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HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19N2O4 375.1345; Found 375.1338.
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4al: yellow solid, 97 mg, 25%, mp 132 °C. H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 9.0 Hz,
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2H), 7.92 (dd, J = 8.7 Hz, 1.5 Hz, 1H), 7.27 (d, J = 8.9 Hz, 2H), 7.17 (ddd, J = 8.3, 7.3, 1.4 Hz,
1H), 6.91 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.54ꢀ6.61 (m, 2H), 6.20 (s, br, 2H), 5.28
(dd, J = 9.8, 4.0 Hz, 1H), 4.09 (dd, J = 17.7, 9.8 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.17 (dd, J =
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17.7, 4.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ 201.2, 197.0, 163.6, 158.7, 151.2, 134.2, 132.0,
131.8, 130.5, 129.9, 129.1, 117.6, 117.5, 116.0, 114.6, 113.8, 55.6, 55.3, 48.0, 43.6; HRMS
(ESIꢀQꢀTOF) m/z: [M+Na]+ Calcd for C24H23NNaO4 412.1525; Found 412.1516.
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4am: yellow solid, 88 mg, 21%, mp 78ꢀ79 °C. H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 9.0
Hz, 2H), 8.26 (t, J =2.0 Hz, 1H), 8.16 (d, J = 9.0 Hz, 2H), 8.12 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H),
7.82 (dd, J = 8.2, 1.1 Hz, 1H), 7.72 (dt, J = 7.9, 1.3 Hz, 1H), 7.52 (t, J =8.0 Hz, 1H), 7.24 (ddd, J =
8.4 Hz, 7.1 Hz, 1.4 Hz, 1H), 6.58ꢀ6.66 (m, 2H), 6.29 (s, br, 2H), 5.48 (dd, J = 9.7, 4.2 Hz, 1H),
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4.23 (dd, J = 18.0, 9.6 Hz, 1H), 3.29 (dd, J = 18.0, 4.1 Hz, 1H); C NMR (75 MHz, CDCl3) δ
198.9, 196.3, 151.6, 150.5, 148.8, 141.5, 140.7, 135.0, 134.3, 131.3, 130.3, 129.3, 124.0, 123.0,
122.6, 117.8, 116.4, 116.2, 48.2, 43.9; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H18N3O6
420.1196; Found 420.1189.
4an: yellow solid, 206 mg, 51%, mp 177ꢀ178 °C. 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 9.0
Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 7.87 (dd, J = 8.2 Hz, 1.1 Hz, 1H), 7.26 (d, J = 8.9 Hz, 2H), 7.20
(ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.55ꢀ6.63 (m, 2H), 6.21 (s, br, 2H), 5.29
(dd, J = 10.0, 3.9 Hz, 1H), 4.15 (dd, J = 18.0, 10.0 Hz, 1H), 3.76 (s, 3H), 3.19 (dd, J = 17.9, 3.9 Hz,
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1H); C NMR (75 MHz, CDCl3) δ 200.5, 197.2, 158.9, 151.3, 150.4, 141.2, 134.5, 131.8, 131.4,
129.3, 129.0, 123.9, 117.5, 117.1, 116.0, 114.7, 55.4, 48.3, 44.3; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calcd for C23H21N2O5 405.1450; Found 405.1440.
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4ao: yellow solid, 202 mg, 50%, mp 158 °C. H NMR (300 MHz, CDCl3) δ 8.26 (t, J = 1.9 Hz,
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1H), 8.08 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.88 (dd, J = 8.6 Hz, 1.3 Hz,
1H), 7.73 (dt, J = 7.8 Hz, 1.3 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.22 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H),
6.93 (d, J = 8.9 Hz, 2H), 6.58ꢀ6.65 (m, 2H), 6.27 (s, br, 2H), 5.48 (dd, J = 9.2, 4.5 Hz, 1H), 4.12
(dd, J = 17.8, 9.3 Hz, 1H), 3.87 (s, 3H), 3.29 (dd, J = 17.7, 4.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 199.6, 195.9, 163.8, 151.5, 148.7, 142.0, 134.8, 134.5, 131.3, 130.6, 130.0, 129.4, 123.1,
122.4, 117.7, 116.9, 116.1, 113.9, 55.6, 48.0, 43.2; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C23H21N2O5 405.1450; Found 405.1442.
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4ap: yellow solid, 151 mg, 42%, mp 118ꢀ120 °C. 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 4.4
Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.93 (dd, J = 8.7 Hz, 1.4 Hz, 1H), 7.80 (td, J = 7.7 Hz, 1.7 Hz,
1H), 7.45 (ddd, J = 7.5 Hz, 4.8 Hz, 1.2 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.18 (ddd, J = 8.4, 7.3,
1.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.55ꢀ6.63 (m, 2H), 6.20 (s, br, 2H), 5.27 (dd, J = 10.1, 4.0
Hz, 1H), 4.41 (dd, J = 18.8, 10.2 Hz, 1H), 3.75 (s, 3H), 3.47 (dd, J = 18.8, 4.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 201.1, 200.1, 158.6, 153.1, 151.1, 149.1, 136.9, 134.1, 131.9, 131.8, 129.2,
127.3, 121.9, 117.4, 115.8, 114.4, 55.3, 48.0, 43.2; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C22H21N2O3 361.1552; Found 361.1544.
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4aq: yellow solid, 27 mg, 8%, mp 69 °C. H NMR (300 MHz, CDCl3) δ 7.99 (dd, J = 8.2, 1.3
Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.33 (dd, J = 1.8, 0.8 Hz, 1H), 7.21ꢀ7.28 (m, 3H), 6.60ꢀ6.69 (m,
2H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.20 (s, br, 2H), 6.15 (d, J = 3.2 Hz, 1H), 5.48 (dd, J = 9.7, 4.1
13
Hz, 1H), 4.14 (dd, J = 17.9, 9.7 Hz, 1H), 3.39 (dd, J = 17.9, 4.1Hz, 1H), 2.41 (s, 3H); C NMR
(75 MHz, CDCl3) δ 198.3, 197.5, 152.7, 151.3, 144.2, 142.1, 134.6, 134.1, 131.7, 129.4, 128.4,
117.5, 117.2, 116.1, 110.8, 107.1, 42.2, 40.4, 21.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C21H20NO3 334.1443; Found 334.1433.
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4ar: yellow solid, 53 mg, 20%, mp 257 °C. 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 8.2 Hz,
1.4 Hz, 1H), 7.23ꢀ7.30 (m, 4H), 7.12ꢀ7.22 (m, 2H), 6.58 (dd, J = 8.3, 0.9 Hz, 1H), 6.53 (ddd, J =
8.2, 7.0, 1.2 Hz, 1H), 6.22 (s, br, 2H), 5.12 (dd, J = 9.9, 4.2 Hz, 1H), 3.55 (dd, J = 17.8, 9.8Hz, 1H),
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2.71 (dd, J = 17.8, 4.2Hz, 1H), 2.18 (s, 3H); C NMR (75 MHz, CDCl3) δ 207.2, 200.7, 151.2,
139.9, 134.3, 131.8, 129.2, 127.9, 127.2, 117.4, 117.3, 115.9, 49.0, 48.3, 30.2; HRMS (ESIꢀQꢀTOF)
m/z: [M+H]+ Calcd for C17H18NO2 268.1338; Found 268.1330.
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4as: yellow solid, 178 mg, 52%, mp 99ꢀ101 °C. H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.2
Hz, 1H), 7.18ꢀ7.25 (m, 4H), 7.13 (t, J = 7.5 Hz, 1H), 6.53 (t, J = 7.6 Hz, 2H), 6.23 (s, br, 2H), 5.13
(dd, J = 9.5, 4.4 Hz, 1H), 3.59 (dd, J = 18.0, 9.6Hz, 1H), 2.76 (dd, J = 18.0, 4.4 Hz, 1H), 1.13 (s,
13
9H); C NMR (75 MHz, CDCl3) δ 214.0, 200.3, 151.1, 138.4, 134.3, 132.8, 131.4, 129.3, 129.1,
117.4, 117.0, 115.8, 47.7, 43.9, 41.9, 26.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
C20H23ClNO2 344.1417; Found 344.1406.
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4at: yellow solid, 147 mg, 55%, mp 76ꢀ77 °C. H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.1
Hz, 2H), 7.91 (dd, J = 8.2, 1.1 Hz, 1H), 7.55 (tt, J = 7.3, 1.3 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.26
(ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 6.62ꢀ6.72 (m, 2H), 6.22 (s, br, 2H), 4.12ꢀ4.28 (m, 1H), 3.69 (dd, J
= 18.0, 8.1 Hz, 1H), 3.06 (dd, J = 18.0, 5.2 Hz, 1H), 1.29 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 205.4, 198.7, 151.1, 136.8, 134.3, 133.2, 131.2, 128.6, 128.2, 117.6, 116.8, 116.0, 42.4,
36.4, 18.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C17H18NO2 268.1338; Found 268.1330.
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4ba: yellow solid, 236 mg, 65%, mp 59ꢀ60 °C. H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.1
Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.55 (tt, J = 7.3, 1.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.19ꢀ7.35
(m, 5H), 6.57 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 8.7 Hz, 2.0 Hz, 1H), 6.31 (s, br, 2H), 5.25 (dd, J =
10.2, 3.7 Hz, 1H), 4.18 (dd, J = 18.0, 10.2 Hz, 1H), 3.21 (dd, J = 18.0, 3.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 200.0, 198.3, 152.0, 140.1, 139.6, 136.5, 133.4, 133.1, 129.3, 128.7, 128.2, 128.0,
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127.4, 116.6, 116.4, 115.9, 49.0, 43.9; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19ClNO2
364.1104; Found 364.1095.
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4ca: yellow solid, 232 mg, 64%, mp 126ꢀ127 °C. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.3
Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.21ꢀ7.38 (m,
5H), 7.13 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 6.21 (s, br, 2H), 5.24 (dd, J = 10.3,
3.5 Hz, 1H), 4.19 (dd, J = 18.0, 10.3 Hz, 1H), 3.24 (dd, J = 18.0, 3.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 199.8, 198.2, 149.7, 139.2, 136.5, 134.3, 133.4, 130.8, 129.4, 128.7, 128.3, 128.0, 127.5,
120.2, 118.9, 118.0, 48.9, 44.0; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19ClNO2
364.1104; Found 364.1101.
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4da: yellow solid, 174 mg, 50%, mp 104 °C. 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz,
2H), 7.52ꢀ7.61 (m, 2H), 7.44 ( t, J = 7.5 Hz , 2H), 7.20ꢀ7.38 (m, 5H), 6.96 (ddd, J = 9.0, 7.7, 2.9
Hz, 1H), 6.55 (dd, J = 9.1, 4.7 Hz, 1H), 6.07 (s, br, 2H), 5.21 (dd, J = 10.3, 3.5 Hz, 1H), 4.19 (dd,
13
J = 18.0, 10.3 Hz, 1H), 3.23 (dd, J = 18.0, 3.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 199.8 (d,
J4,C−F = 2.8 Hz), 198.2, 153.3 (d, J1,C−F = 234.2 Hz), 147.7, 139.2, 136.4, 133.3, 129.3, 128.6, 128.2,
127.9, 127.4, 122.4 (d, J2,C−F = 23.6 Hz), 118.6 (d, J3,C−F = 7.0 Hz), 116.7 (d, J4,C−F = 5.5 Hz),
116.1 (d, J2,C−F = 22.4 Hz), 48.9, 44.0; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H19FNO2
348.1400; Found 348.1392.
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4ea: yellow solid, 116 mg, 32%, mp 88ꢀ90 °C. H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.1
Hz, 2H), 7.55 (tt, J = 7.3, 1.3 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.29ꢀ7.39 (m, 5H), 7.18ꢀ7.25 (m,
1H), 6.87 (dd, J = 9.0, 2.9 Hz, 1H), 6.56 (d, 9.0 Hz, 1H), 5.93(s, br, 2H), 5.29 (dd, J = 9.9, 3.8 Hz,
1H), 4.18 (dd, J = 18.0, 9.9 Hz, 1H), 3.66 (s, 3 H), 3.22 (dd, J = 17.9, 3.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 200.1, 198.3, 150.0, 146.0, 140.0, 136.7, 133.3, 129.3, 128.7, 128.3, 128.0, 127.3,
123.6, 118.9, 117.1, 113.8, 55.8, 49.4, 43.9; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for
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C23H22NO3 360.1600; Found 360.1593.
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4fa: yellow solid, 112 mg, 30%, mp 196ꢀ197 °C. 1H NMR (300 MHz, CDCl3) δ 8.99 (d, J = 2.5
Hz, 1H), 7.96ꢀ8.06 (m, 3H), 7.58 (tt, J = 7.4, 1.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 8.03 (dd, J =
9.2, 2.5 Hz, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.23ꢀ7.31 (m, 1H), 6.98(s, br, 1H), 6.59 (d, J = 9.2 Hz,
1H), 5.33 (dd, J = 10.7, 3.2 Hz, 1H), 4.23 (dd, J = 18.2 Hz, 10.7 Hz, 1H), 3.30 (dd, J = 18.1 Hz,
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3.2 Hz, 1H); C NMR (75 MHz, CDCl3) δ200.2, 198.2, 155.5, 138.5, 136.9, 136.3, 133.6, 129.6,
129.4, 129.2, 128.8, 128.3, 128.0, 127.8, 117.3, 115.3, 49.0, 44.0; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calcd for C22H19N2O4 375.1345; Found 375.1340.
4ga: yellow solid, 184 mg, 54%, mp 132 °C. 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz,
2H), 7.71 (s, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.1 Hz, 2H), 7.29 (t,
J = 7.5 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 6.99 (dd, J = 8.4, 1.7 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H),
6.05 (s, br, 2H), 5.35 (dd, J = 9.9, 3.8 Hz, 1H), 4.18 (dd, J = 17.9, 9.9 Hz, 1H), 3.22 (dd, J = 18.0,
13
3.9 Hz, 1H), 2.17 (s, 3H); C NMR (75 MHz, CDCl3) δ 200.4, 198.3, 149.1, 140.0, 136.6, 135.4,
133.1, 131.2, 129.1, 128.5, 128.1, 128.0, 127.1, 124.5, 117.5, 117.2, 48.6, 43.8, 20.5; HRMS
(ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C23H22NO2 344.1651; Found 344.1642.
K2CO3-Catalyzed Reactions of N-Phenyl-2-Oxindole (7) or N-Boc-2-Oxindole (8) with Enone
2u.
A mixture of Nꢀphenyl 2ꢀoxindole 7 or Nꢀphenyl 2ꢀoxindole 8 (1 mmol), enone 2u (1 mmol), and
K2CO3 (0.2 mmol) was stirred in 4 mL of DMSO at room temperature under open air condition for
given time. After completion of the reaction determined by TLC, 30 mL of water was added and
the mixture was extracted with dichloromethane (20 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) to provide two fractions. The
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first fraction with low polarity was mixture of three inseparable compounds and the second
fraction with high polarity corresponds to product 9 (162 mg, 35%) or 10 (186 mg, 38%).
9: white solid, mp 201ꢀ203 °C. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.59 (dd,
J = 7.2, 1.2 Hz, 1H), 7.30ꢀ7.40 (m, 3H), 7.21ꢀ7.29 (m, 3H), 7.18 (td, J = 7.5, 1.4 Hz, 1H),
6.84ꢀ6.92 (m, 2H), 6.69ꢀ6.77 (m, 4H), 6.49 (d, J = 7.7 Hz, 1H), 4.00ꢀ4.13 (m, 2H), 3.52ꢀ3.68 (m,
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2H), 2.41 (s, 3H), 2.23 (s, 3H); C NMR (75 MHz, CDCl3) δ 198.6, 177.2, 144.2, 144.1, 137.0,
134.49, 134.47, 133.6, 129.8, 129.5, 129.4, 129.0, 128.6, 128.4, 128.2, 127.8, 126.5, 125.1, 123.1,
109.6, 79.7, 49.2, 38.5, 21.7, 21.0; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C31H28NO3
462.2069; Found 462.2059.
10: white solid, mp 77ꢀ79 °C. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.59 (d, J
= 7.9 Hz, 1H), 7.41 (dd, J = 7.4, 1.0 Hz, 1H), 7.32 (td, J = 7.7, 1.4 Hz, 1H), 7.17ꢀ7.25 (m, 3H),
6.85 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 8.1 Hz, 2H), 3.79ꢀ4.01 (m, 3H), 3.47ꢀ3.61 (m, 1H), 2.39 (s,
13
3H), 2.18 (s, 3H), 1.48 (s, 9H); C NMR (75 MHz, CDCl3) δ 198.4, 177.0, 148.2, 144.0, 139.8,
136.8, 134.3, 133.7, 129.9, 129.3, 128.7, 128.5, 128.3, 127.0, 124.6, 124.3, 115.0, 83.9, 79.1, 49.4,
38.0, 27.9, 21.7, 21.0; HRMS (ESIꢀQꢀTOF) m/z: [M+Na]+ Calcd for C30H31NNaO5 508.2100;
Found 508.2092.
TsOH•H2O Catalyzed-Intramolecular Reaction of 4aa for the Synthesis of 11.
A mixture of 4aa (53 mg, 0.16 mmol) and TsOH•H2O (3.1 mg, 0.016 mmol) in ethanol (0.4 mL)
were stirred at 40 °C for 4 h until the disappearance of 4aa determined by TLC. Saturated aqueous
solution of NaHCO3 (15 mL) was added and the mixture was extracted with dichloromethane (15
mL × 3). The combined organic layers was dried over MgSO4, and concentrated in vacuo.
Purification on silica gel (ethyl acetate/petroleum ether) afforded the product 11 (38.5 mg, 77%).
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11: yellow solid, mp 80ꢀ81 °C. H NMR (300 MHz, CDCl3) δ 8.00 (dd, J = 8.0, 1.6 Hz, 1H),
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7.45ꢀ7.51 (m, 2H), 7.27ꢀ7.45 (m, 9H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H),
6.66 (s, br, 1H), 5.29 (dd, J = 7.0, 1.7 Hz, 1H), 4.29 (d, J = 7.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 185.2, 144.3, 141.5, 137.3, 137.1, 132.7, 131.2, 129.6, 129.4, 129.0, 128.5, 127.3, 125.4,
119.5, 118.3, 105.7, 57.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H18NO 312.1388;
Found 312.1380.
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One-pot Two-Step Conversion of 4aa to 12.
A mixture of 4aa (36 mg, 0.11 mmol) and I2 (5.5 mg, 0.02 mmol) was stirred in 0.4 mL of
DMSO at 80 °C for half an hour until the disappearance of 4aa as determined by TLC. After
cooling to room temperature, I2 (27 mg, 0.11 mmol) and DMAP (32 mg, 0.26 mmol) was added
and the mixture was stirred at room temperature for 30 min. Upon completion of the reaction, the
mixture was quenched with saturated aqueous solution of Na2S2O3 and then extracted with
dichloromethane (3× 15 mL). The organic extracts were dried over sodium sulfate and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl
acetate/petroleum ether) to provide the product 12 (27.8 mg, 82%).
12: yellow solid, mp 250 °C. 1H NMR (300 MHz, CDCl3) δ 8.03ꢀ8.10 (m, 2H), 7.94 (dd, J = 7.9,
1.5 Hz, 1H), 7.89 (dd, J = 8.0, 0.9 Hz, 1H), 7.75 (ddd, J = 8.1, 7.2, 1.6 Hz, 1H), 7.65ꢀ7.72 (m, 2H),
13
7.49ꢀ7.56 (m, 4H), 7.48 (s, 1H), 7.40ꢀ7.47 (m, 3H); C NMR (75 MHz, CDCl3) δ 192.3, 159.9,
151.6, 146.1, 140.8, 137.2, 135.1, 132.9, 131.4, 130.7, 129.6, 128.9, 128.8, 128.8, 128.6, 128.3,
128.2, 125.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H16NO 310.1232; Found 310.1224.
The Hydrochloric Acid-Catalyzed Transformation of 4aa to 13 and 14 in DMSO/H2O.
Hydrochloric acid (12 mol/L, 2.5 ꢁL, 0.03 mmol) was added to a solution of 4aa (65.5 mg, 0.2
mmol) in DMSO/H2O (0.4 mL/0.1 mL). The mixture was stirred at 90 °C under open air condition
for 22 h. After completion of the reaction as determined by TLC, the mixture was quenched with
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saturated NaHCO3 and then extracted with dichloromethane (20 mL × 3). The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue,
which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether) to
afford product 13 (28.4 mg, 46%, lower polarity) and product 14 (19.4 mg, 30%, higher polarity.
The compound 14 has same polarity with 4aa in the eluent of ethyl acetate/petroleum ether.
However, they can be separated on TLC using isopropyl ether/nꢀhexane = 5:4 as the eluent).
13: yellow solid, mp 105ꢀ106 °C. 1H NMR (300 MHz, CDCl3) δ 8.27 (ddd, J = 8.5, 1.1, 0.6 Hz,
1H), 8.13ꢀ8.19 (m, 2H), 7.89ꢀ7.94 (m, 2H), 7.88 (s, 1H), 7.83ꢀ7.89 (m, 1H), 7.78 (ddd, J = 8.4, 6.9,
1.4 Hz, 1H), 7.66 (tt, J = 7.4, 1.3 Hz, 1H), 7.44ꢀ7.57 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 196.4,
156.6, 148.8, 145.4, 139.0, 136.7, 134.3, 130.5, 130.35, 130.33, 129.8, 129.0, 128.9, 127.6, 127.4,
125.2, 124.0, 117.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calcd for C22H16NO 310.1232; Found
310.1223.
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14: yellow solid, mp 150 °C. 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 2H), 7.52ꢀ7.61
(m, 4H), 7.40ꢀ7.52 (m, 3H), 7.28 (tt, J = 6.9, 1.5 Hz, 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, 0.7 Hz, 1H), 6.31 (s, br, 1H), 4.45 (d, J = 18.0 Hz, 1H), 3.18 (d,
13
J = 17.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 200.8, 197.9, 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, 44.8; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calcd for C22H18NO2 328.1338; Found 328.1326.
Conversion of 12 to 13 and 14 with Catalytic Amount of Hydrochloric Acid in DMSO/H2O.
Hydrochloric acid (12 mol/L, 2.5 ꢁL, 0.03 mmol) was added to a solution of 12 (55 mg, 0.18
mmol) in DMSO/H2O (0.4 mL/0.1 mL). The mixture was stirred at 90 °C until the completion of
reaction as determined by TLC (within 25 min). The resulting mixture was quenched with
saturated aqueous NaHCO3 and extracted with dichloromethane (3 × 15 mL). The organic extracts
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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) to afford product 13 (24.4 mg,
44%) and product 14 (24.7 mg, 42%).
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Acknowledgments
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
13
1H and C NMR spectra of the products and Xꢀray crystallographic data of 3a, 4al and 12. This
material is available free of charge via the Internet at http://pubs.acs.org.
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The 3a and 3b are hard to separate on silica gel column. Luckily, single crystal of 3a can be
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