Transition-Metal-Free Synthesis of Carbonyl-Containing Oxindoles from N-Arylacrylamides and α-Diketones via TBHP- or Oxone-Mediated Oxidative Cleavage of C(sp2)-C(sp2) Bonds

Article abstract of DOI:10.1021/acs.joc.5b01977

Carbonyl-containing oxindoles can be prepared from N-arylacrylamides and α-diketones by TBHP- or oxone (KHSO₅)-mediated C(sp²)-C(sp²) bond cleavage and new C(sp²)-C(sp³) bond formation. This methodology is characterized by its simple and transition-metal-free conditions and good functional group compatibility utilizing inexpensive and readily available reagents, thus providing a practical and efficient approach to an important class of 3-(2-oxoethyl)indolin-2-ones which are highly valued synthetic intermediates of biologically active molecules. In this transformation, alkylcarbonyl-containing oxindoles were obtained in majority when N-arylacrylamides reacted with asymmetric aliphatic/aromatic α-diketones. On the basis of the preliminary experiments, a plausible mechanism of this transformation is disclosed.

Full text of DOI:10.1021/acs.joc.5b01977

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Article
Transition-Metal-Free Synthesis of Carbonyl-Containing Oxindoles
From N-Arylacrylamides and alpha-Diketones via TBHP- or
Oxone-Mediated Oxidative Cleavage of C(sp2)-C(sp2) Bonds
Ming-Zhong Zhang, Peng-Yi Ji, Yu-Feng Liu, and Can-Cheng Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01977 • Publication Date (Web): 21 Oct 2015
Downloaded from http://pubs.acs.org on October 26, 2015
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Transition-Metal-Free Synthesis of Carbonyl-Containing Oxindoles From
N-Arylacrylamides and α-Diketones via TBHP- or Oxone-Mediated Oxidative
Cleavage of C(sp2)-C(sp2) Bonds
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MingꢀZhong Zhang,† PengꢀYi Ji,† YuꢀFeng Liu,† and CanꢀCheng Guo*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, Advanced Catalytic
Engineering Research Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082, China
Eꢀmail: ccguo@hnu.edu.cn
ABSTRACT: Carbonylꢀcontaining oxindoles can be prepared from Nꢀarylacrylamides and
αꢀdiketones by TBHPꢀ or oxone (KHSO5)ꢀmediated C(sp2)ꢀC(sp2) bond cleavage and new
C(sp2)ꢀC(sp3) bond formation. This methodology is characterized by its simple and
transitionꢀmetalꢀfree conditions and good functional group compatibility utilizing
inexpensive and readily available reagents, thus providing a practical and efficient approach
to an important class of 3ꢀ(2ꢀoxoethyl)indolinꢀ2ꢀones which are highly valued synthetic
intermediates
of
biologically
active
molecules.
In
this
transformation,
alkylcarbonylꢀcontaining oxindoles were obtained in majority when Nꢀarylacrylamides
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reacted with asymmetric aliphatic/aromatic αꢀdiketones. Based on the preliminary
experiments, a plausible mechanism of this transformation is disclosed.
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INTRODUCTION
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Carbonꢀcarbon bond cleavage has gained considerable momentum over the past decade,
holding great promise for constructing useful structural units from simple molecular
skeletons. In this field, transitionꢀmetalꢀcatalyzed cleavages of C=C double bonds,1 C≡C
triple bonds,2 arylꢀcyano C(sp2)ꢀC(sp) bonds,3 and secondary/tertiary alcohol C(sp3)ꢀC
bonds4 have been significantly developed. These discoveries present effective strategies for
the chemoselective construction of the target molecules which take a privileged position in
the fields of pharmaceuticals, biochemistry, and materials science. Despite formidable
success, however, the selective CꢀC bond cleavage of ketones is a longꢀstanding challenge.
By using copper/O2 catalytic oxidation system, Bi and Liu et al. pioneeringly disclosed a
chemoselective oxidative C(CO)ꢀC(methyl) bond cleavage of methyl ketones for accessing
aldehydes.5 Since then, copper catalyzed aerobic oxidative processes for activating inert
ketones have shown considerable promise in this area.6 Our group also disclosed a
copperꢀcatalyzed aerobic oxidative C(CO)ꢀC(alkyl) bond cleavage strategy for the
conversion of ketones to nitriles.7 As part of our continuing interest in CꢀC bond cleavage
and transformation,2a,7,8 herein we present the discovery of a transitionꢀmetalꢀfree oxidative
C(sp2)ꢀC(sp2) bond cleavage strategy to construct carbonylꢀcontaining oxindoles from
Nꢀarylacrylamides and readily available αꢀdiketones (Scheme 1). To the best of our
knowledge, carbonꢀacylation using αꢀdiketones as acyl precursors through C(sp2)ꢀC(sp2)
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bond cleavage mode, particularly from easily available substrates to give highꢀvalue
compounds, have remained relatively underdeveloped.9
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Scheme 1. The Oxidative Cleavage of C(sp2)-C(sp2) Bonds in α-Diketones Leading to
Carbonyl-Containing Oxindoles
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Oxindoles are ubiquitous heterocyclic motifs that are widely present in many naturally
occuring and pharmaceutical molecules.10 Members of the oxindole family have wide
applications in medicinal chemistry owning to their remarkable biological activities, such as
anticancer,11 antitumoral,12 antiꢀinflammatory,13 antimicrobial,14 and antiꢀplasmodium
falciparum.15 Specially, carbonylꢀcontaining oxindoles, including 3ꢀ(2ꢀoxoethyl)indolinꢀ
2ꢀones, are extremely attractive as intermediates in the synthesis of indole alkaloids such as
chimonanthine and folicanthine.16 Thus, the development of an efficient, economical and
environmentally benign approach to access oxindoles, and in particular for
carbonylꢀcontaining oxindoles from easily available chemical materials, would be highly
desirable.17,18 In 2013, Li et al. pioneered the oxidative coupling of alkenes with aldehyde
C(sp2)ꢀH bonds and aryl C(sp2)ꢀH bonds to access carbonylꢀcontaining oxindoles using
o
anhydrous TBHP at 105 C.19 Later on, transitionꢀmetalꢀcatalyzed processes such as
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oxidative cascade coupling of activated alkenes with aryl aldehydes,20 decarboxylative
acylarylation of activated alkenes with αꢀoxocarboxylic acids,21 and oxidative
1,2ꢀcarboacylation of activated alkenes with alcohols22 have also been proposed
as complementary methods for the preparation carbonylꢀcontaining oxindoles. Nevertheless,
these wellꢀestablished approaches suffered from one or more limitations including limited
functional group tolerance, the use of expensive radical initiator or starting material (e.g.,
anhydrous TBHP and αꢀoxocarboxylic acids), and/or precious or toxic metal reagents,
which may limit their applicability in the areas of pharmaceutical industry, etc. Recently,
Xia et al. disclosed a very attractive access to carbonylꢀcontaining oxindoles through UV
lightꢀmediated difunctionalization of alkenes using benzoin as the benzoyl precursor;23
however, the requirement for ultraviolet light irradiation and excessive solvent (50 mL
solvent for 0.3 mmol substrate) make this reaction operationally and economically
unfavorable. Based on these concerns as well as our ongoing efforts in the development of
green and sustainable methods towards oxindoles,24 we report our recent progress in this
field (Scheme 1). The significance of the present finding is threeꢀfold: (1) This work
demonstrates the first construction of carbonylꢀcontaining oxindoles via oxidative cleavage
mode of C(sp2)ꢀC(sp2) bond mediated by TBHP or oxone (KHSO5). (2) Simple and
transitionꢀmetalꢀfree conditions, good functional group compatibility utilizing inexpensive
and readily available αꢀdiketones as acyl precursors, thus becoming a powerful alternative
for accessing these highly valuable compounds in an expeditious manner. (3) By using
oxone (KHSO5) as a safe and environmentally benign oxidant, the transformation was
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successfully conducted on gramꢀscale (65% yield), which make this unprecedented protocol
very attractive for potential pharmaceutical and industrial applications.
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RESULTS AND DISCUSSION
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We initiated our investigation by reacting Nꢀarylacrylamide (1a) with αꢀdiphenyl ketone
(2a) as the model reaction, and the effects of various temperatures, solvents, and oxidants
were systematically examined (Table 1). An initial experiment using 3.0 equiv of TꢀHydro
o
(70% tertꢀbutyl hydroperoxide in water) as the oxidant, THF as the solvent, and at 100 C
under a N2 atmosphere for 24 h lead to the formation of the expected product 3a in 59%
yield (entry 1). Control experiments without TBHP showed no formation of the desired
product 3a, pointing at the decisive role of oxidant in this transformation (entry 2). To our
delight, the best yield (78%) was achieved when decreasing the reaction temperature to
80 °C (entry 3). In comparison, when anhydrous TBHP (5 M in decane) was used as the
oxidant, a slightly decreased yield (75%) of 3a was obtained (entry 4). With continued use
of TꢀHydro as the oxidant, other solvents were tested including CH3CN, DMF, DMSO,
DCE, dioxane, and EtOAc, all which had a deleterious effect on reactivity (entries 5ꢀ10). In
light of these results, the effect of various organic oxidants such as diꢀtertꢀbutyl peroxide
(DTBP), dicumyl peroxide (DCP), tertꢀbutyl peroxybenzoate (TBPB), benzoyl peroxide
(BPO), and oꢀidoxybenzoic acid (IBX) were examined. The results showed that TꢀHydro to
be the ideal choice for this transformation (entry 3 vs entries 11ꢀ15).
Table 1. Optimization of Reaction Conditionsa
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entry oxidant
solvent
THF
temp (°C) yield (%)b
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1c
TBHP
none
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59
2
THF
0
3c
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
DCP
THF
78
4d
5c
THF
75
CH3CN
DMF
DMSO
DCE
0
6c
23
7c
trace
trace
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8c
9c
dioxane
EtOAc
THF
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trace
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THF
21
TBPB
BPO
THF
16
THF
30
IBX
THF
trace
aReaction conditions: Nꢀarylacrylamide (1a, 0.3 mmol), αꢀdiphenyl ketone (2a, 0.45 mmol),
b
c
oxidant (0.9 mmol), solvent (2.0 mL), N2, 24 h. Yield of isolated product. TꢀHydro.
dTBHP (anhydrous, 5 M in decane).
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Encouraged by these findings, we turned our attention to explore the scope of
Nꢀarylacrylamides (1) with 2a (Table 2). The effect of various substitution patterns on the
Nꢀaryl moiety was first investigated. The substrates with haloꢀsubstituents (F, Cl, Br, and I)
were well tolerated under the optimized conditions, leading to the corresponding
carbonylꢀcontaining oxindoles in yields ranging from 72%ꢀ80% (3b-3e), which enable
further functionalization or modification of these molecules. However, strong
electronꢀwithdrawing substituents, such as a NO2 group on the Nꢀaryl moiety did not result
in any product (3f). To our delight, electronꢀdonating substituents, such as Me, and OMe
groups on the aryl ring were tolerated well, providing the corresponding products in good to
high yields (82% and 85%, 3g and 3h). Interestingly, the sterically congested
orthoꢀsubstituted substrates were also reacted satisfactorily to deliver the desired oxindole
products 3i and 3j in 70% and 55% yield, respectively. Next, we focused on
Nꢀarylacrylamides bearing different substituents at the N atom (R2). As a special example,
the Nꢀethylꢀsubstituted substrate, which bearing a meta methyl group on the aryl ring, could
also serve as suitable reaction partner in this protocol and afforded a mixture of two
regioisomers in 80% yield (3k /3k’ in a ratio of 1:1.5). Moreover, a Nꢀbenzyl derivative and
a tetrahydroquinoline derivative were also compatible with the reaction conditions,
affording the corresponding oxindoles 3l and 3m in 79% and 84% yield, respectively.
Finally, the substituent effect at the 2 position (R3) of the acrylamide moiety was
investigated. Gratifyingly, both CH2OAc and 1,3ꢀdioxoisoindolinꢀ2ꢀyl groups were
tolerated in this reaction (products 3n and 3o).
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Table 2. Synthesis of Carbonyl-Containing Oxindoles: Scope of N-Arylacrylamidesa,b
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aReaction conditions: Nꢀarylacrylamides (1, 0.3 mmol), αꢀdiphenyl ketone (2a, 0.45 mmol),
o
b
TꢀHydro (0.9 mmol), and THF (2.0 mL) at 80 C under a N2 atmosphere for 24 h. Isolated
yields.
Furthermore, the reactivity of different asymmetric αꢀdiketones (2) was tested with 1a as
the reaction partner, and the results are given in Table 3. It was found that asymmetric
aromatic/aliphatic αꢀdiketones, such as 1ꢀphenypropaneꢀ1,2ꢀdione (2b) and 1ꢀphenylbutaneꢀ
1,2ꢀdione (2c), reacted smoothly with 1a to generate the corresponding products in good
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total yields (entries 1 and 2). Interestingly, a series of asymmetric aromatic benzil
derivatives (2d-2h) with both electronꢀwithdrawing and electronꢀdonating groups on the
aryl rings showed the selective formation of carbonylꢀcontaining oxindoles with ratios
ranging from 43:25 to 51:19 (entries 3ꢀ7). Compared to aromatic/aromatic benzil
derivatives, aromatic/aliphatic ones gave the alkylcarbonylꢀcontaining products in majority,
the reason may be due to the reactivity of arylcarbonyl reacted with free radical is superior
to that of alkylcarbonyl with the same radical.25 These results encouraged us to further
investigate the reactivity of dialkyl substituted αꢀdiketones. As expected, both symmetrical
and asymmetric aliphatic/aliphatic αꢀdiketones, such as 2,3ꢀbutanedione (2i), and
2,3ꢀpentanedione (2j) were performed well in this transformation (for details, see the
Supporting Information).
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Table 3. TBHP-Mediated Oxidative Cleavage of C(sp2)-C(sp2) Bonds in Asymmetric
α-Diketones Leading to Carbonyl-Containing Oxindolesa,b
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aReaction conditions: Nꢀarylacrylamide (1a, 0.3 mmol), αꢀdiketones (2, 0.45 mmol),
o
b
TꢀHydro (0.9 mmol), and THF (2.0 mL) at 80 C under a N2 atmosphere for 24 h. Isolated
yields.
To determine whether the selective acylarylation can take place between two αꢀdiketones
with Nꢀarylacrylamides, a competition experiment was designed (Scheme 2). An equimolar
mixture of symmetrical αꢀdiketones 2a and 2k was submitted to the standard conditions,
producing a 55:21 ratio of both carbonylꢀcontaining oxindoles 3a and 3v. This suggests that
the introduction of a functional group on the aryl ring of the αꢀdiketone molecules affects
the selectivity of this transformation.
Scheme 2. Competition experiment
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In view of the potential applications of these molecules in the field of pharmaceutical
industry,16 we next considered the possibility of achieving this transformation by using the
safe inorganic oxidant. Obviously, inexpensive and environmentally benign persulfates or
monopersulfates are more attractive. To realize such an organoperoxideꢀfree protocol, we
tested various reaction parameters for the conversion of model substrates 1a and 2a into
carbonylꢀcontaining oxindole 3a (Table 4). Unfortunately, the combination of K2S2O8 and
(NH4)2S2O8 with different solvents, such as CH3CNꢀH2O, CH3CN, or THF, turned out not to
be successful (entries 1ꢀ4). To our delight, the desired transformation was successfully
achieved with oxone (KHSO5), yielding the corresponding product 3a in 59% yield (entry
5). Interestingly, the yield of 3a was further improved to 71% when increasing the
o
temperature to 100 C (entry 6), while decreasing the temperature lead to a decrease in
reaction efficiency (entries 7 and 8). Screening on the amount of oxone revealed that 2.5
equiv of oxone was perfect (entry 6 vs entries 9 and 10). Among the effects of the solvents
examined, it was found that THF to be the best choice (entry 6 vs entries 11ꢀ17). In addition,
a 1 g (5.7 mmol) scale reaction of Nꢀarylacrylamide 1a is successfully performed with
αꢀdiphenyl ketone 2a, giving 3a in good yield (entry 18).
Table 4. Evaluation of the Reaction Conditions for the Synthesis of
Carbonyl-Containing Oxindoles from N-Arylacrylamides and α-Diketones Using the
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Safe Oxidanta
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oxidant
entry (equiv.)
T
yieldb
(%)
trace
0
solvent
CH3CNꢀH2O
CH3CNꢀH2O
CH3CN
THF
(°C)
80
1c
2c
3
K2S2O8 (2.5)
(NH4)2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
oxone (2.5)
oxone (2.5)
oxone (2.5)
oxone (2.5)
oxone (3.0)
oxone (2.0)
oxone (2.5)
oxone (2.5)
oxone (2.5)
oxone (2.5)
oxone (2.5)
80
80
trace
trace
59
4
80
5
THF
80
6
THF
100
60
71
7
THF
29
8
THF
30
trace
68
9
THF
100
100
100
100
100
100
100
10
11
12c
13
14
15
THF
64
CH3CN
CH3CNꢀH2O
DCE
15
trace
trace
trace
40
DMF
dioxane
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16
oxone (2.5)
DMSO
toluene
THF
100
100
100
0
17
oxone (2.5)
oxone (2.5)
trace
65
18d
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aReaction conditions: Nꢀarylacrylamide (1a, 0.3 mmol), αꢀdiphenyl ketone (2a, 0.45 mmol),
b
c
oxidant (2.5 equiv), solvent (3.0 mL), N2, 24 h. Yield of isolated product. CH3CNꢀH2O
(v:v, 1:1). d1a (1 g, 5.7 mmol) and solvent (15 mL) for 36 h.
By using this optimized organoperoxideꢀfree protocol, we converted a variety of
structurally different substrates selectively into the respective carbonylꢀcontaining oxindoles.
As listed in Table 5, Nꢀarylacrylamides with both electronꢀwithdrawing and
electronꢀdonating groups on the aryl ring showed better reactivity (products 3b-e and 3h).
Besides, Nꢀbenzyl and tetrahydroquinoline derivatives also showed reactivity in this
reaction with synthetically useful yields (products 3l and 3m). Furthermore, different
asymmetric αꢀdiketones such as 1ꢀphenypropaneꢀ1,2ꢀdione 2b and 1ꢀ(4ꢀmethoxyphenyl)
ꢀ2ꢀphenylethaneꢀ1,2ꢀdione 2h were also applied in this unprecedented transformation, and it
was found that the selectivity were nearly consistent with those described in Table 3. We
believe these results nicely illustrate the high reactivity of this novel oxoneꢀmediated
protocol.
Table 5. Oxone-Mediated Oxidative Cleavage of C(sp2)-C(sp2) Bonds in α-Diketones
Leading to Carbonyl-Containing Oxindolesa,b
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aReaction conditions: Nꢀarylacrylamides (1, 0.3 mmol), αꢀdiketones (2, 0.45 mmol), oxone
(2.5 equiv), and THF (3.0 mL) at 100 oC under a N2 atmosphere for 24 h. bIsolated yields.
Finally, to ascertain whether this oxoneꢀmediated oxidative transformation is applicable
to other ketones, a range of ketone derivatives were investigated (for details, see the
Supporting Information). It was shown that this oxoneꢀmediated protocol can tolerate a
range of αꢀdiketones and represents a safe and effective approach for the preparation of
carbonylꢀcontaining oxindoles.
Since the peroxide bond of oxone can be activated by temperature to generate hydroxyl
and sulfate radicals,26 and these two radicals are powerful oxidants that capable of initiating
radical reaction,27 hence, we could not immediately rule out possible mechanisms involving
the
radical
process.
Accordingly,
when
radical
scavengers,
such
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2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO), and 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT)
were added to the present reaction system, the desired transformation was completely
suppressed (Scheme 3a,b), while the corresponding radical adduct 2,2,6,6ꢀ
tetramethylpiperidinꢀ1ꢀyl benzoate (4) was obtained in 12% yield (for details, see the
Supporting Information). These observations suggested that the reaction should proceed
through a radical pathway. Subsequently, control experiments with possible intermediates
were designed and investigated. When 2ꢀhydroxyꢀ1,2ꢀdiphenylethanꢀ1ꢀone (5) was utilized
for this reaction, only a trace amount of the desired product 3a was observed (Scheme 3c).
Furthermore, benzaldehyde (6) and benzoic acid (7) did not react under these conditions
(Scheme 3d,e). These results might exclude 5, 6, or 7 as the possible intermediates of this
oxoneꢀmediated transformation.
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Scheme 3. Control Experiments
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On the basis of these experimental evidences as well as previous related reports, two
mechanistic scenarios are proposed and shown in Scheme 4 (by employing
Nꢀarylacrylamide 1a and αꢀdiphenyl ketone 2a as the model). Consistent with the
previously established mechanism for the Pdꢀcatalyzed oxidative carboꢀacylation reactions
of 2ꢀarylpyridines/indoles with these αꢀdiketones,9b,c we propose that the benzoyl radical C
is initially generated by the oxidative cleavage of αꢀdiphenyl ketone 2a with TBHP (method
a, bottom right). Then, this active radical C selectively added to the carbonꢀcarbon double
bond of 1a to lend alkyl radical E.19ꢀ23 Through an intramolecular radical cyclization, this
alkyl radical intermediate E would convert to the cyclized radical intermediate F.19ꢀ23
Finally, abstraction of an aryl hydrogen in intermediate F by TBHP takes place to furnish
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carbonylꢀcontaining oxindole 3a.19 Alternatively, in oxone (KHSO5)ꢀmediated pathway
(method b, top right), the initial step of the reaction involves the formation of intermediate
αꢀhydroxyketone A, which had also been proposed by Borhan et al.28 in an oxoneꢀmediated
oxidative esterification reaction. Since it has been demonstrated that the reaction should
proceed through a radical pathway (Scheme 3a,b), an argument could be made this
αꢀhydroxyketone intermediate A could be further oxidized to radical intermediate B. It is
very likely that the present heating conditions could induce these activated species such as
hydroxyl and sulfate radicals, which could play the role of the oxidant in this step.26,27 This
proposal was also supported by the results obtained from entries 6ꢀ8 in Table 4. Further
βꢀfragmentation of radical intermediate B (in an irreversible way) leads to CꢀC bond
cleavage, affording benzoyl radical C along with the formation of intermediate D.29 The
unstable intermediate D which could not be isolated, is rapidly split into some fragment ions.
From this reaction we detected the corresponding benzoic acid, which could also provide
support in favor of the rationality of the aforementioned pathway. The subsequent reaction
of benzoyl radical C and 1a furnishes alkyl radical intermediate E,19ꢀ23 which underwent an
intramolecular radical cyclization to form the cyclized intermediate F.19ꢀ23 Finally, oxidation
of F afforded the corresponding carbocation G, followed by proton loss (ꢀH+), thus leading
to carbonylꢀcontaining oxindole 3a (method b).17a
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Scheme 4. Possible Mechanisms
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CONCLUSIONS
In summary, we have developed a novel protocol for the carboacylation/arylation of
Nꢀarylacrylamides via oxidative cleavage of C(sp2)ꢀC(sp2) bonds. Such a novel and green
protocol, which utilizes transitionꢀmetalꢀfree and simple reaction conditions, and
inexpensive and readily available reagents, provides a convenient and highly efficient
access to carbonylꢀcontaining oxindoles. The good functional group compatibility profile
suggest that our protocol could be an alternative en route to these highly valuable
compounds. Furthermore, the preparative practicality of this transformation is highlighted
through gramꢀscale reaction of NꢀmethylꢀNꢀphenylmethacrylamide with αꢀdiphenyl ketone
by using oxone as a safe and environmentally benign oxidant. Further experimental studies
to elucidate the mechanistic details and further investigation of relevant reactions based on
this transitionꢀmetalꢀfree oxidative C(sp2)ꢀC(sp2) bond cleavage mode are currently
underway, and these studies will be reported in due course.
EXPERIMENTAL SECTION
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General Methods. All reagents and solvent used were obtained commercially and used
without further purification unless indicated otherwise. All solvents were dried and distilled
prior to use according to the standard protocols. Products were purified by flash
chromatography on silica gel (300ꢀ400 mesh, Merck), and were characterized by 1H NMR,
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1
13C NMR and all subject products were further characterized by HRMS. H NMR spectra
13
were recorded on 400 MHz in CDCl3 and C NMR spectra were recorded on 100 MHz in
CDCl3 using TMS as internal standard. Multiplicities are indicated as s (singlet), d (doublet),
t (triplet), q (quintet), m (multiplet) and coupling constants (J) are reported in hertz.
Preparation of N-Arylacrylamides. NꢀArylacrylamide Substrates 1a-o were prepared
according to the literature.17l,w,30
Typical Experimental Procedure for the Synthesis of Carbonyl-Containing
Oxindoles from N-Arylacrylamides and α-Diketones via TBHP-Mediated Cleavage of
C(sp2)-C(sp2) Bonds. To a 25 mL Schlenk tube were added Nꢀarylacrylamide 1 (0.3 mmol),
αꢀdiketone 2 (0.45 mmol), TꢀHydro (0.9 mmol) and THF (2.0 mL). Then the tube was
o
charged with nitrogen, and was stirred at 80 C for 24 h until complete consumption of
starting material as monitored by TLC. After the reaction was finished, the reaction mixture
was cooled to room temperature, and ethyl acetate (EtOAc) (20 mL) and water (10 mL)
were added. The organic layer was separated, and the aqueous phase was extracted with
ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuum. The resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate) to afford the desired product.
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Typical Experimental Procedure for the Synthesis of Carbonyl-Containing
Oxindoles from N-Arylacrylamides and α-Diketones via Oxone-Mediated Cleavage of
C(sp2)-C(sp2) Bonds. To a 25 mL Schlenk tube were added Nꢀarylacrylamide 1 (0.3 mmol),
αꢀdiketone 2 (0.45 mmol), oxone (0.75 mmol) and THF (3.0 mL). Then the tube was
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charged with nitrogen, and was stirred at 100 C for 24 h until complete consumption of
starting material as monitored by TLC. After the reaction was finished, the reaction mixture
was cooled to room temperature, and ethyl acetate (EtOAc) (20 mL) and water (10 mL)
were added. The organic layer was separated, and the aqueous phase was extracted with
ethyl acetate. The combined organic layers dried over Na2SO4, filtered, and concentrated in
vacuum. The resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate) to afford the desired product.
Experimental Procedure for the Gram-Scale Reaction of N-Arylacrylamide 1a with
α-Diphenyl Ketone 2a (Table 4, entry 18). To a 100 mL Schlenk tube were added
Nꢀarylacrylamide 1a (1 g, 5.7 mmol, 1.0 equiv), αꢀdiphenyl ketone 2a (1.8 g, 8.55 mmol,
1.5 equiv), oxone (2.5 equiv) and THF (15 mL). The tube was evacuated and back filled
o
with N2 three times. The reaction mixture was stirred at 100 C for 36 h. Upon completion,
the solvent was evaporated under vacuum. Then, the residue was diluted by EtOAc and
washed with H2O. The organic phase was separated, dried over anhydrous Na2SO4, filtered,
and the solvent was then removed under vacuum. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate) to afford the desired product 3a in
65% yield (1.03 g).
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1,3-Dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3a):19-23 By following the typical
procedure, the product was isolated as a colorless oil, 65.4 mg (78 %), flash chromatography
(hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 2H), 7.52 (t,
J = 7.4 Hz, 1H), 7.40 (t, J = 7.3 Hz, 2H), 7.26 (t, J = 7.3 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H),
6.98 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 3.75ꢀ3.64 (m, 2H), 3.32 (s, 3H), 1.45 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 196.1, 180.6, 143.8, 136.3, 133.7, 133.2, 128.5, 127.9,
127.8, 122.2, 121.7, 108.2, 46.0, 45.3, 26.4, 24.9; IR (neat film, cmꢀ1) 1705, 1622, 1348,
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1190; HRMS m/z (ESI) calcd for C18H17NO2 [M+]: 279.1259; found 279.1261.
+
5-Fluoro-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3b):21 By following the
typical procedure, the product was isolated as a yellow oil, 66 mg (74 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5
Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 6.97ꢀ6.89 (m, 2H), 6.82ꢀ6.79 (m,
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1H), 3.68 (s, 2H), 3.30 (s, 3H), 1.43 (s, 3H); C NMR (100 MHz, CDCl3) δ 195.9, 180.3,
160.3, 157.9, 139.7, 136.1, 135.5, 135.4, 133.3, 128.5, 127. 9, 113.9, 113.7, 110.2, 110.0,
108.5, 108.4, 45.9, 45.7, 26.6, 24.7; IR (neat film, cmꢀ1) 1710, 1625, 1358, 1201; HRMS
+
m/z (ESI) calcd for C18H16FNO2 [M+]: 297.1165; found 297.1169.
5-Chloro-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3c):21 By following the
typical procedure, the product was isolated as a pale yellow oil, 67.8 mg (72 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6
Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.24ꢀ7.21 (m, 1H), 7.10 (d, J =
1.9 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.69 (s, 2H), 3.30 (s, 3H), 1.43 (s, 3H); 13C NMR
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(100 MHz, CDCl3) δ 195.8, 180.2, 142.5, 136.1, 135.6, 133.3, 128.5, 128.0, 127.7, 127.5,
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122.3, 109.1, 46.0, 45.4, 26.6, 24.8; IR (neat film, cmꢀ1) 1709, 1615, 1360, 1195; HRMS
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m/z (ESI) calcd for C18H16ClNO2 [M+]: 313.0870; found 313.0873.
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5-Bromo-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3d):20c By following the
typical procedure, the product was isolated as a yellow oil, 83.8 mg (78 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5
Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43ꢀ7.37 (m, 3H), 7.23 (d, J = 1.6 Hz, 1H), 6.78 (d, J =
8.4 Hz, 1H), 3.69 (s, 2H), 3.30 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.8,
180.0, 143.0, 136.0, 135.9, 133.4, 130.6, 128.6, 128.0, 125.0, 109.6, 46.1, 45.4, 26.6, 24.9;
IR (neat film, cmꢀ1) 1711, 1619, 1362, 1188; HRMS m/z (ESI) calcd for C18H16BrNO2 [M+]:
+
357.0364; found 357.0368.
5-Iodo-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3e):21 By following the
typical procedure, the product was isolated as a yellow solid, 97.2 mg (80 %), flash
chromatography (hexane/ethyl acetate, 10/1); mp 161ꢀ163 oC; 1H NMR (400 MHz, CDCl3)
δ 7.84 (d, J = 7.4 Hz, 2H), 7.58ꢀ7.51 (m, 2H), 7.42ꢀ7.38 (m, 3H), 6.69 (d, J = 8.2 Hz, 1H),
3.69 (s, 2H), 3.29 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.8, 179.9, 143.6,
136.6, 136.3, 136.0, 133.3, 130.4, 128.5, 127.9, 110.2, 84.7, 46.0, 45.2, 26.5, 24.8; IR (neat
+
film, cmꢀ1) 1715, 1677, 1339, 1201; HRMS m/z (ESI) calcd for C18H16INO2 [M+]:
405.0226; found 405.0231.
1,3,5-Trimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3g):23 By following the typical
procedure, the product was isolated as a pale yellow oil, 72.2 mg (82 %), flash
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chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.5
Hz, 2H), 7.50 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H), 6.96 (s,
1H), 6.79 (d, J = 7.9 Hz, 1H), 3.73ꢀ3.63 (m, 2H), 3.29 (s, 3H), 2.27 (s, 3H), 1.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 196.1, 180.5, 141.4, 136.3, 133.7, 133.1, 131.5, 128.4, 128.0,
127.9, 122.6, 107.8, 45.9, 45.3, 26.4, 24.9, 21.0; IR (neat film, cmꢀ1) 1716, 1638, 1348,
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1191; HRMS m/z (ESI) calcd for C19H19NO2 [M+]: 293.1416; found 293.1412.
5-Methoxy-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3h):20a By following
the typical procedure, the product was isolated as a pale yellow oil, 78.9 mg (85 %), flash
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chromatography (hexane/ethyl acetate, 6/1); H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5
Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 6.82ꢀ6.76 (m, 3H), 3.73 (s, 3H),
3.67 (s, 2H), 3.29 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.1, 180.3, 155.7,
137.4, 136.3, 135.2, 133.2, 128.5, 128.0, 111.5, 110.0, 108.3, 55.7, 46.0, 45.7, 26.5, 24.9; IR
(neat film, cmꢀ1) 1701, 1605, 1367, 1189; HRMS m/z (ESI) calcd for C19H19NO3 [M+]:
+
309.1365; found 309.1362.
1,3-Dimethyl-3-(2-oxo-2-phenylethyl)-7-phenylindolin-2-one (3i): By following the
typical procedure, the product was isolated as a yellow oil, 74.6 mg (70 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4
Hz, 2H), 7.54ꢀ7.39 (m, 8H), 7.14ꢀ7.12 (m, 1H), 7.09 (dd, J = 7.7, 1.0 Hz, 1H), 6.99 (t, J =
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7.5 Hz, 1H), 3.78ꢀ3.69 (m, 2H), 2.84 (s, 3H), 1.50 (s, 3H); C NMR (100 MHz, CDCl3) δ
196.2, 181.7, 140.8, 139.2, 136.4, 134.8, 133.1, 130.8, 129.9, 128.4, 127.9, 127.6, 127.5,
125.5, 121.5, 120.6, 46.4, 44.6, 30.5, 25.4; IR (neat film, cmꢀ1) 1720, 1682, 1319, 1181;
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HRMS m/z (ESI) calcd for C24H21NO2 [M+]: 355.1572; found 355.1569.
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typical procedure, the product was isolated as a yellow oil, 66.9 mg (55 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.6
Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.04 (d,
J = 7.2 Hz, 1H), 6.66 (t, J = 7.7 Hz, 1H), 3.69 (d, J = 2.2 Hz, 5H), 1.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 195.9, 181.4, 144.3, 140.4, 136.9, 136.1, 133.3, 128.5, 127.9, 123.8,
121.3, 71.9, 46.3, 44.8, 30.4, 25.3; IR (neat film, cmꢀ1) 1713, 1685, 1327, 1188; HRMS m/z
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+
(ESI) calcd for C18H16INO2 [M+]: 405.0226; found 405.0230.
1-Ethyl-3,6-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one
and
1-Ethyl-3,4-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3k + 3k’): By following the
typical procedure, the product was isolated as a yellow oil, 73.8 mg (80 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 7.8
Hz, 3.11H), 7.50 (t, J = 7.3 Hz, 1.62H), 7.38 (t, J = 7.7 Hz, 3.09H), 7.15 (t, J = 7.8 Hz, 1H),
7.03 (d, J = 7.2 Hz, 0.58H), 6.79 ꢀ6.72 (m, 3.11H), 3.97ꢀ3.66 (m, 6.73H), 2.37 (s, 1.91H),
2.30 (s, 2.9H), 1.49 (s, 3H), 1.42 (s, 2H), 1.37ꢀ1.27 (m, 6.47H); 13C NMR (100 MHz, CDCl3)
δ 196.1, 196.1, 180.4, 180.0, 143.0, 142.8, 137.6, 136.4, 136.2, 133.0, 132.9, 131.0, 130.6,
130.0, 128.4, 128.4, 127.9, 127.9, 127.5, 124.5, 122.4, 121.6, 109.3, 106.1, 46.1, 45.9, 45.0,
44.8, 34.7, 34.6, 25.0, 22.9, 21.8, 18.2, 12.3, 12.2; IR (neat film, cmꢀ1) 1720, 1725, 1681,
+
1690, 1335, 1341, 1190, 1203; HRMS m/z (ESI) calcd for C20H21NO2 [M+]: 307.1572;
found 307.1569.
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1-Benzyl-3-methyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3l):21 By following the
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typical procedure, the product was isolated as a white solid, 84.2 mg (79 %), flash
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chromatography (hexane/ethyl acetate, 10/1); mp 158ꢀ160 oC; H NMR (400 MHz, CDCl3)
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δ 7.87 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.43ꢀ7.31 (m, 6H), 7.27ꢀ7.23 (m, 1H),
7.14ꢀ7.08 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.08 (d, J = 15.8 Hz,
1H), 4.96 (d, J = 15.8 Hz, 1H), 3.80ꢀ 3.70 (m, 2H), 1.50 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 195.9, 180.6, 142.8, 136.3, 136.2, 133.7, 133.1, 128.6, 128.4, 128.0, 127.6, 127.3,
127.2, 122.2, 121.6, 109.2, 45.8, 45.3, 43.9, 25.5;
+
IR (neat film, cmꢀ1) 1722, 1621, 1348, 1192; HRMS m/z (ESI) calcd for C24H21NO2 [M+]:
355.1572; found 355.1575.
1-Methyl-1-(2-oxo-2-phenylethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-on
e (3m):23 By following the typical procedure, the product was isolated as a yellow oil, 80
mg (84 %), flash chromatography (hexane/ethyl acetate, 6/1); 1H NMR (400 MHz, CDCl3) δ
7.83 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.00 (d, J = 7.5
Hz, 2H), 6. 87 (t, J = 7.4 Hz, 1H), 3.82ꢀ3.78 (m, 2H), 3.72ꢀ3.60 (m, 2H), 2.88ꢀ2.75 (m, 2H),
2.12ꢀ2.03 (m, 2H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.3, 179.4, 139.5, 136.4,
133.0, 132.1, 128.4, 127.9, 126.6, 121.6, 120.1, 119.8, 46.6, 45.8, 38.9, 24.6, 24.5, 21.2; IR
+
(neat film, cmꢀ1) 1736, 1645, 1358, 1213; HRMS m/z (ESI) calcd for C20H19NO2 [M+]:
305.1416; found 305.1415.
(1-Methyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)methyl acetate (3n):21 By
following the typical procedure, the product was isolated as a pale yellow oil, 70 mg (69 %),
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flash chromatography (hexane/ethyl acetate, 5/1); H NMR (400 MHz, CDCl3) δ 7.83 (d, J
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7
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= 7.6 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H),
7.18 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 10.8
Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.85 (d, J = 17.9 Hz, 1H), 3.70 (d, J = 17.9 Hz, 1H),
3.32 (s, 3H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.3, 177.2, 170.2, 144.6, 136.1,
133.3, 129.2, 128.6, 128.5, 127.9, 122.8, 122.2, 108.2, 67.5, 49.2, 41.9, 26.5, 20.6; IR (neat
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+
film, cmꢀ1) 1750, 1721, 1632, 1360, 1195; HRMS m/z (ESI) calcd for C20H19NO4 [M+]:
337.1314; found 337.1316.
2-((1-Methyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)methyl)isoindoline-1,3-dione
(3o):21 By following the typical procedure, the product was isolated as a pale yellow solid,
o
1
76.4 mg (60 %), flash chromatography (hexane/ethyl acetate, 2/1); mp 205ꢀ207 C; H
NMR (400 MHz, CDCl3) δ 7.87ꢀ7.83 (m, 4H), 7.73ꢀ7.69 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H),
7.39 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.95ꢀ6.90 (m, 2H),
4.10ꢀ3.87 (m, 4H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195. 6, 177.5, 168.2, 144.4,
136.1, 134.1, 133.2, 131.7, 129.7, 128.6, 128.5, 128.0, 123.5, 122.4, 122.0, 108.4, 49.4, 43.5,
43.3, 26.6; IR (neat film, cmꢀ1) 1762, 1725, 1620, 1355, 1189; HRMS m/z (ESI) calcd for
+
C26H20N2O4 [M+]: 424.1423; found 424.1426.
1,3-Dimethyl-3-(2-oxopropyl)indolin-2-one (3p):22 By following the typical procedure,
the product was isolated as a pale yellow oil, 34.5 mg (53 %), flash chromatography
1
(hexane/ethyl acetate, 6/1); H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.16 (m, 1H), 7.07 (d, J =
7.2 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 3.19 (s, 3H), 3.08ꢀ2.98 (m,
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2H), 1.91 (s, 3H), 1.26 (s, 3H), 1.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.6, 180.3,
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143.7, 133.4, 127.9, 122.2, 121.8, 108.2, 50.5, 45.2, 29.9, 26.4, 24.3; IR (neat film, cmꢀ1)
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+
1722, 1624, 1368, 1150; HRMS m/z (ESI) calcd for C13H15NO2 [M+]: 217.1103; found
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217.1101.
1,3-Dimethyl-3-(2-oxobutyl)indolin-2-one (3q):22 By following the typical procedure,
the product was isolated as a pale yellow oil, 32.6 mg (47 %), flash chromatography
1
(hexane/ethyl acetate, 6/1); H NMR (400 MHz, CDCl3) δ 7.27ꢀ7.23 (m, 1H), 7.13 (d, J =
7.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.27 (s, 3H), 3.08 (s, 2H),
2.36ꢀ2.20 (m, 2H), 1.33 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
207.3, 180.4, 143.7, 133.5, 127.8, 122.2, 121. 7, 108.2, 49.3, 45.1, 35.9, 26.4, 24.4, 7.3; IR
(neat film, cmꢀ1) 1729, 1633, 1358, 1161; HRMS m/z (ESI) calcd for C14H17NO2 [M+]:
+
231.1259; found 231.1260.
3-(2-(4-Fluorophenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one (3r):23 By following the
typical procedure, the product was isolated as a yellow oil, 22.3 mg (25 %), flash
1
chromatography (hexane/ethyl acetate, 10/1); H NMR (400 MHz, CDCl3) δ 7.87ꢀ7.84 (m,
2H), 7.25 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 8.6 Hz, 2H), 6.98 (t, J =
7.5 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.70ꢀ3.60 (m, 2H), 3.30 (s, 3H), 1.43 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.5, 180.4, 166.9, 164.4, 143.8, 133.6, 132.7, 130.6, 130.5,
127.8, 122.1, 121.7, 115.6, 115.4, 108.1, 45.8, 45.2, 26.4, 24.9; IR (neat film, cmꢀ1) 1711,
1620, 1348, 1157; HRMS m/z (ESI) calcd for C18H16FNO2 [M+]: 297.1165; found
+
297.1168.
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3-(2-(2-Fluorophenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one (3s): By following the
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typical procedure, the product was isolated as a yellow oil, 17.8 mg (20 %), flash
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9
1
chromatography (hexane/ethyl acetate, 10/1); H NMR (400 MHz, CDCl3) δ 7.65ꢀ7.61 (m,
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1H), 7.49ꢀ7.43 (m, 1H), 7.27ꢀ7.23 (m, 1H), 7.14ꢀ7.07 (m, 3H), 6.98 (t, J = 7.4 Hz, 1H), 6.90
(d, J = 8.0 Hz, 1H), 3.76ꢀ3.64 (m, 2H), 3.31 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.4, 194.2, 180.5, 163.2, 160.7, 143.8, 134.7, 134.7, 133.7, 130.6, 130.6, 127.7,
124.8, 124.7, 124.3, 124.3, 122.1, 121.5, 116.6, 116.4, 108.1, 50.8, 50.7, 45.4, 26.4, 25.0; IR
(neat film, cmꢀ1) 1732, 1629, 1357, 1160; HRMS m/z (ESI) calcd for C18H16FNO2 [M+]:
+
297.1165; found 297.1167.
4-(2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)benzonitrile (3t):19 By following the
typical procedure, the product was isolated as a colorless oil, 14.6 mg (16 %), flash
chromatography (hexane/ethyl acetate, 10/1); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2
Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.99 (t,
J = 7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.66 (s, 2H), 3.30 (s, 3H), 1.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 194.9, 180.1, 143.8, 139.2, 133.2, 132.4, 128.4, 128.1, 122.3, 121.7,
117.8, 116.5, 108.3, 46.2, 45.3, 26.5, 24.9; IR (neat film, cmꢀ1) 1725, 1630, 1368, 1201;
+
HRMS m/z (ESI) calcd for C19H16N2O2 [M+]: 304.1212; found 304.1215.
1,3-Dimethyl-3-(2-oxo-2-(p-tolyl)ethyl)indolin-2-one (3u):20c By following the typical
procedure, the product was isolated as a colorless oil, 29 mg (33 %), flash chromatography
1
(hexane/ethyl acetate, 10/1); H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H),
7.17ꢀ7.04 (m, 4H), 6.87 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 3.58 (q, J = 17.9 Hz,
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2H), 3.22 (s, 3H), 2.27 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.6, 180.7,
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143.9, 143.7, 133.8, 133.7, 129.1, 128.0, 127.7, 122.1, 121.6, 108.1, 45.8, 45.2, 26.4, 24.8,
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+
21.5; IR (neat film, cmꢀ1) 1719, 1620, 1355, 1191; HRMS m/z (ESI) calcd for C19H19NO2
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[M+]: 293.1416; found 293.1415.
3-(2-(4-Methoxyphenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one (3v):20a By following
the typical procedure, the product was isolated as a colorless oil, 17.6 mg (19 %), flash
1
chromatography (hexane/ethyl acetate, 6/1); H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8
Hz, 2H), 7.26ꢀ7.22 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.90ꢀ6.84 (m,
3H), 3.82 (s, 3H), 3.63 (q, J = 17.7 Hz, 2H), 3.30 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.5, 180.7, 163.4, 143.7, 133.8, 130.2, 129.4, 127.7, 122.0, 121.7, 113.5, 108.0,
55.3, 45.6, 45.3, 26.4, 24.9; IR (neat film, cmꢀ1) 1720, 1612, 1348, 1185; HRMS m/z (ESI)
+
calcd for C19H19NO3 [M+]: 309.1365; found 309.1366.
2,2,6,6-Tetramethylpiperidin-1-yl benzoate (4): The product was isolated as a colorless
1
solid, 9.4 mg (12 %), flash chromatography (hexane/ethyl acetate, 30/1); H NMR (400
MHz, CDCl3) δ 8.09ꢀ8.07 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H),
1.82ꢀ1.57 (m, 5H), 1.48ꢀ1.44 (m, 1H), 1.28 (s, 6H), 1.12 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 166.4, 132.8, 129.7, 129.6, 128.4, 60.4, 39.1, 32.0, 20.8, 17.0; HRMS m/z (ESI)
+
calcd for C16H23NO2 [M+]: 261.1729; found 261.1732.
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