Transition-Metal-Free TBAI-Facilitated Addition-Cyclization of N-Methyl-N-arylacrylamides with Arylaldehydes or Benzenesulfonohydrazides: Access to Carbonyl- and Sulfone-Containing N-Methyloxindoles

Article abstract of DOI:10.1021/acs.joc.6b00773

A highly efficient addition-cyclization of N-methyl-N-arylacrylamides with arylaldehydes or benzenesulfonohydrazides was developed using a catalytic amount of the quaternary ammonium salt (TBAI) under metal-free conditions, leading to the carbonyl- and sulfone-containing oxindoles. Compared to previous methods, which require excessive amounts of explosive organic peroxides and precious or toxic metal reagents, the present protocol, which gave access to 3,3-disubstituted oxindoles, is a safe and green approach, resulting in the formation of various useful carbonyl- and sulfone-containing oxindoles in yields of 40-94%.

Full text of DOI:10.1021/acs.joc.6b00773

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Article
Transition-Metal-Free TBAI-Facilitated Addition-Cyclization of N-methyl-
N-arylacrylamides with Arylaldehydes or Benzenesulfonohydrazides:
Access to Carbonyl- and Sulfone-Containing N-methyloxindoles
Peng-yi Ji, Ming-Zhong Zhang, Jing-Wen Xu, Yu-Feng Liu, and Can-Cheng Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00773 • Publication Date (Web): 27 May 2016
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The Journal of Organic Chemistry
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Transition-Metal-Free TBAI-Facilitated Addition-Cyclization of N-methyl-N-
arylacrylamides with Arylaldehydes or Benzenesulfonohydrazides: Access to
Carbonyl- and Sulfone-Containing N-methyloxindoles
9
PengꢀYi Ji, MingꢀZhong Zhang, JingꢀWen Xu, YuꢀFeng Liu, CanꢀCheng Guo*
College of Chemistry and Chemical Engineering, Advanced Catalytic Engineering
Research Center of the Ministry of Education, Hunan University, Changsha 410082,
China
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Eꢀmail: ccguo@hnu.edu.cn
ABSTRACT: A highly efficient additionꢀcyclization of NꢀmethylꢀNꢀarylacrylamides
with arylaldehydes or benzenesulfonohydrazides was developed using catalytic
amount of the quaternary ammonium salt (TBAI) under metal free conditions, leading
to the carbonylꢀ and sulfoneꢀcontaining oxindoles. Compared to previous methods,
which require excessive amounts of explosive organic peroxides and precious or toxic
metal reagents, the present protocol, which gave access to 3,3ꢀdisubstituted oxindoles,
is a safe and green approach, resulting in the formation of various useful carbonylꢀ
and sulfoneꢀcontaining oxindoles in yields of 40 to 94%.
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INTRODUCTION
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The oxindole framework bearing a tetrasubstituted carbon stereocenter at the 3ꢀ
position is a ubiquitous highꢀvalue heterocyclic motif,1 and can also be utilized to
synthesize a series of pyrrolidinoindolines which exist in a number of natural products
and bioactive molecules.2 Owing to its importance and versatility, much effort has
naturally gone into the asymmetric synthesis of 3,3ꢀdisubstituted oxindole framework
through a large family of intramolecular coupling reactions of activated alkenes,3ꢀ9
including arylphosphorylation,3 alkylarylation,4 diarylation,5 arylnitration,6
aryltrifluoromethylation,7 halogenation,8 and azidoarylation9. Despite some success,
however, room still exists for exploring a convenient, green and general method to
construct other important functionalized oxindoles.
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Carbonylꢀcontaining oxindoles, as synthetic intermediates of indole alkaloids,10
exhibit extremely attractive bioactivities and widely exist in natural products.11,12 The
incorporation of arylcarbonyl groups into oxindole molecules has drawn increased
attention. Recently, modern applications of transition metal and photoredox catalysis
have gained momentum as strategies for the formation of carbonylꢀcontaining
oxindoles from Nꢀarylacrylamides, the vast majority of these elegant approaches
undergo a 1,2ꢀacylarylation of Nꢀarylacrylamides to obtain the desired carbon
stereocenters.13 However, the use of toxic metal reagents, highꢀenergy UV light, and
precious photocatalysts might not be considered as advantages of the procedures.
Consequently, there is still an urgent need for chemists to find out a safe and green
process for the construction of carbonylꢀcontaining oxindoles. Owing to our
continuous interest in difunctionalization of activated alkenes,8c,13h we firstly disclose
a metalꢀfree TBAIꢀfacilitated cascade cyclization strategy of activated alkenes for
access to carbonylꢀcontaining oxindoles. Most importantly, this mild, safe, and low
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toxicity catalytic system was successfully applied to the arylsulfonylation of
arylacrylamides with readily available sulfonylhydrazides, resulting in the formation
of various sulfoneꢀcontaining oxindoles in moderate to high yields. As is well known,
sulfoneꢀcontaining oxindoles, which possess inestimable roles in the structural library
design and drug discovery,14,12c have been a source of interest for chemists, and a
variety of inventive synthetic strategies were developed toward its preparation during
the past few years.14a, 15
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Notably, among the previous protocols, there are still a dirth of articles which
describe the work regarding the activated alkenes as carbonꢀbased reagents via TBAIꢀ
catalyzed cycloaddition of arylacrylamides to obtain carbonylꢀ and sulfoneꢀcontaining
oxindoles. Herein, we wish to report a TBAI/K2S2O8 combined strategy for the
synthesis of carbonylꢀ and sulfoneꢀcontaining oxindoles.
RESULTS AND DISCUSSION
Inspired by the elegant work of Wu and coꢀworkers,16 who demonstrated that the
reaction of peroxydisulfate with TBAB under thermal conditions could generate
activated tetrabutylammonium sulfate radical anions, which could mediate oxidative
tandem coupling of alkynoates with aldehydes via a selective cycloaddition with acyl
radical. We hypothesized that K2S2O8/quaternary ammonium salt combined strategy
could be applied to carboacylation/arylation of arylacrylamides under metalꢀfree
conditions. Then, NꢀmethylꢀNꢀphenylmethacrylamide 1a and pꢀmethoxybenzaldehyde
2a were chosen as model substrates to optimize conditions for this reaction (Table 1).
The results suggested that the catalysts employed, the oxidant ammounts, and the
temperatures are variables that can be modulated to obtain the desired reactivity.
Firstly, in order to confirm the effects of the counter ions on the reaction,17 a series of
quaternary ammonium salts as catalysts were tested, most of quaternary ammonium
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salts especially TBAI and TBAC displayed good catalytic activity in this tandem
reaction, and then catalytic amount of potassium iodide were added alone or
combined with TBAI gave the product 4 in trace amount or 69% yields, which
indicated that the counter ions might have a minor effect on the reaction (entries 1ꢀ8,
Table 1). By comparison, the TBAI may shows a better catalytic compatibility since
the iodide ion probably has a stronger separation ability to split from quaternary
ammonium salts. And then only 8% yields of 4 were detected without the presence of
TBAI (entry 9, Table 1), so we chose the TBAI as the most suitable catalyst according
to the experimental results thus obtained. Worth to note, decreasing or increasing the
amount of TBAI or K2S2O8 both led to lower yield of product 4, suggested that
suitable amount of catalyst and oxidant was necessary for good yield of desired
product (entries 10ꢀ13, Table 1). Finally, the temperature screening indicated that 90
oC was the most suitable temperature for this protocol (entries 14ꢀ16, Table 1).
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Table 1 ： Screening Optimal Conditions of synthesis of product 4
Entry
Catalyst (mol %)
Oxidant (equiv)
T (oC) Yield[c] (%)
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4
5
TBAI
TBAF
TBAC
TBAB
TEAB
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
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90
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7[b]
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TBAHS
K2S2O8
K2S2O8
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90
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69
trace
8
TBAI/KI
KI
K2S2O8
90
9
no catalyst
TBAI (5)
TBAI (20)
TBAI
K2S2O8
90
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K2S2O8
90
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K2S2O8
90
K2S2O8 (2 eq)
K2S2O8 (4 eq)
K2S2O8
90
TBAI
90
TBAI
70
TBAI
K2S2O8
100
110
TBAI
K2S2O8
[a] General reaction conditions: 1a (0.2 mmol), 2a (1.2 eq), catalyst (10 molꢀ%),
oxidant (3 eq), solvent (2 mL), 90 °C for 24h. [b] TBAI (10 molꢀ%), KI (10 molꢀ%).
[c] Yield detected by LC. TBAI: Tetrabutylammonium Iodide; TBAB:
Tetrabutylammonium Bromide; TEAB: Tetraethylammonium Bromide; TBAF:
Tetrabutylammonium Fluoride; TBAC: Tetrabutylammonium Chloride; TBAHS:
Tetrabutylammonium Hydrogen Sulfate.
With the optimized conditions in hand, we explored the scope of Nꢀarylacrylamides
and aldehydes for the annulation reaction (Table 2). Initially, a number of aldehydes
without electronꢀwithdrawing groups were investigated, and respective products were
obtained in good isolated yields (69% and 65%, 4 and 5). Strong electronꢀ
withdrawing substituent nitro group did not result in any desired product (6).
However, F and CN groups at the paraꢀposition and F group at the metaꢀposition
survived well to give the corresponding products in 40% to 48% yields (7ꢀ9), which
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enabled a potential application in further functionalization.18 Subsequently, the effects
of various substitution patterns on the Nꢀaryl moiety of Nꢀarylacrylamides were
explored. Several substituents at the paraꢀposition provided the corresponding
products in moderate yields (10-11). The nitro group at the paraꢀposition was also
tried, unfortunately, we failed to get the desired product under optimal conditions (12).
Iodo substituent at the metaꢀposition was well tolerated (13), and the result
encouraged us to take a step forward to test the compatibility of oꢀPh group under
optimal conditions, to our delight, it eventually gained 14 in 49% yields. Nꢀbenzyl Nꢀ
phenylmethacrylamide could be smoothly converted into the desired oxindoles in 72%
yields (15).
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Table 2. Synthesis of Carbonyl-Containing Oxindoles: Scope of N-
Arylacrylamides
Product
Entry
Amide 1
Aldehyde 2
(Yield [%][b])
1
2
4 (69)
1a
1a
2a
2b
5 (65)
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6 (0[c])
7 (48)
8 (40)
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2c
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2d
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11 (47)
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13 (56)
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14 (49)
15 (72)
1g
[a] General reaction conditions: 1 (0.2 mmol), 2 (1.2 eq), catalyst (10 molꢀ%), oxidant
(3 eq), solvent (2 mL), 90 °C for 24h. [b] Isolated yield. [c] Yield detected by GCꢀ
MS.
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To demonstrate further the synthetic practicality of this quaternary ammonium salt
catalytic oxidation system, we wondered whether this mild condition could acquit
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splendidly
while
NꢀmethylꢀNꢀphenylmethacrylamide
1a
and
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benzenesulfonohydrazide 3a were employed as model substrates. Surprisingly, Nꢀ
methylꢀNꢀphenylmethacrylamide could be transformed into sulfoneꢀcontaining
oxindole with benzenesulfonohydrazide in excellent 85% isolated yields in the
presence of catalytic amount of TBAI and 3 equiv of K2S2O8, even when the
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o
temperature dropped to 60 C (Table S1, see the Supporting Information, S2). The
wonderful results inspired us to carry out further work about this coupling reaction.
Subsequently, the scope of the Nꢀarylacrylamides 1 was investigated, and the
results are summarized in Table 3. A wide range of functional groups at the aryl ring
reacted smoothly to give the desired products in good yields ranging from 55% to 85%
(16ꢀ22), despite those well tolerated substituents, only trace of 23 was detected by
GCꢀMS. Orthoꢀsubstituted arylacrylamides, which could not be efficiently
transformed in the reported protocol,15b were proved to be accessible under optimized
conditions(24-25). Notably, 44% yields of 25 were obtained, even considering the
great steric effects of bezene group. Nꢀunsubstituted NꢀmethylꢀNꢀ
phenylmethacrylamide was failed to transform into the desired oxindole (26),
subsequently, electronꢀdonating group such as benzyl group was also examined under
standard conditions to give the corresponding products in 94% yields (27). Finally,
the substituent effect at the 2ꢀposition (R3) of the acrylamide moiety was investigated.
As shown in Table 3, CH2OH group was found to be not suitable as a substrate for
this reaction(28), but it was noted that 1,3ꢀdioxoisoindolinꢀ2ꢀyl group was compatible
with optimal conditions, and transformed into corresponding product in 48% isolated
yields(29).
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Table 3. Synthesis of Sulfone-Containing Oxindoles: Scope of N-Arylacrylamides
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[a] General reaction conditions: 1 (0.2 mmol), 3a (1.2 eq), catalyst (10 molꢀ%),
oxidant (3 eq), solvent (2 mL), 60 °C for 24h. [b] Yield detected by GCꢀMS.
We next turned to evaluate the scope of the substituted sulfonylating agents
through oxidative coupling reactions with NꢀmethylꢀNꢀphenylmethacrylamide 1a
(Table 4). Benzenesulfonohydrazides with different substituents (Cl, Me, OMe) at the
paraꢀposition were tolerated in this reaction, only failed in the transformation of
substrate with nitro group (30ꢀ33). Nitro group at the orthoꢀposition was transformed
into the desired product 34 in 45% yields.
Table 4. Scope of Sulfonylating Agents 3
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[a] General reaction conditions: 1a (0.2 mmol), 3 (1.2 eq), catalyst (10 molꢀ%),
oxidant (3 eq), solvent (2 mL), 60 °C for 24h. [b] Yield detected by GCꢀMS.
To understand the mechanism of this reaction, a number of control experiments
were performed. As shown in scheme 1, the presence of 2 equiv. of radical inhibiters,
such as TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) or BHT (butylated
hydroxytoluene), had obvious suppression to both reactions. In addition, in order to
confirm the cycloaddition process is via a radical pathway, 3 equiv. of Diꢀtꢀbutyl
peroxide (DTBP) were employed as the oxidant under general conditions.
Interestingly, the corresponding products 4 and 16 were obtained in 15% and 33%
isolated yields, respectively. From the above, the experimental results thus obtained
may further prove the proposed mechanism.
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Scheme 1: Experiments for Mechanism
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Based on the experimental results and precedent literature,13a,15b,16,19 a radical
pathway have been proposed (Figure 1). At the beginning, potassium persulfate
(K2S2O8) is able to convert into the tetrabutylammonium sulfate radical anions I in the
presence of quaternary ammonium salt. The acyl radical IIa is obtained by hydrogen
abstraction of aldehyde (2a) under the action of the resulting radical anions I,13a
which probably is similar with the other process, in this process, the sulfonyl radical
IIb is generated by hydrogen abstraction of benzenesulfonohydrazide (3a) with the
release of N2.15b Simultaneously, equal of KHSO4 and tetrabutylammonium cations
are released from the hydrogen abstraction process, and the tetrabutylammonium
cations combine with KI to retrieve the catalysts TBAI, then the catalysts are ready to
enter their next catalytic cycle. Subsequently, selective freeꢀradical addition of IIa or
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IIb to activate alkene generate radical intermediate IIIa or IIIb, and then followed by
intramolecular cyclization of intermediate IIIa or IIIb with aryl ring leading to the
formation of radical intermediate species IVa or IVb. Finally, corresponding products
4 or 16 are obtained via a deprotonation process of radical intermediate species IVa or
IVb.
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Figure 1: Proposed Mechanism
CONCLUSIONS
In summary, a mild, green and versatile approach for access to carbonyl/sulfoneꢀ
containing oxindoles has been systematic developed, the protocol allows a great
progress on preparing of these two kinds of significant functional oxindoles. At the
same time, utilizing stable oxidant K2S2O8 and substoichiometric amount of readily
available catalysts (TBAI) through intramolecular cyclization of arylacrylamides
endows this protocol with great application prospect in pharmaceutical fields. Further
experimental study to explicit a broader capability and application scope of this
oxidative difunctionalization system is underway by our group.
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EXPERIMENTAL SECTION
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General Methods. Materials obtained from commercial suppliers were used as
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received unless mentioned otherwise. Products were purified by flash chromatography
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on silica gel (300ꢀ400 mesh), and were characterized by H NMR, and C NMR. H
NMR spectra were recorded on 400 MHz spectrometer and the chemical shifts (δ)
were reported in ppm relative to internal standard TMS (0 ppm) for CDCl3. The peak
patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet;
m, multiplet; q, quartet; brs, broad singlet. The coupling constants, J values, are given
in Hertz (Hz).13C NMR spectra were obtained at 100 MHz spectrometer and
referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3). Copies
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of H NMR and 13C NMR spectra are provided as Supporting Information. Highꢀ
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resolution mass spectra (HRMS) were measured on a double focusing mass
spectrometer with EI source.
Experimental procedures for the synthesis of starting materials 1. Nꢀ
Arylacrylamide substrates 1 were prepared according to the literature.12,13a,14
Typical experimental procedure for the formation of Carbonyl-Containing
Oxindoles from N-Arylacrylamides. To a mixture of 1 (0.2 mmol), 2 (0.24 mmol) in
2.0 ml of DCE was added TBAI (7.4 mg, 10 molꢀ%) and K2S2O8 (162.2 mg, 3 equiv)
at room temperature in a Schlenk tube. The resulting mixture was stirred at 90 °C
under N2 for 24 h. Then the resulting reaction solution was cooled to room
temperature, diluted and washed with H2O, the aqueous phase was extracted with
ethyl acetate. The combined organic extracts was dried over anhydrous Na2SO4 and
concentrated in vacuum, and the resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 5:1) to afford the desired product.
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Typical experimental procedure for the formation of sulfone-Containing
Oxindoles from N-Arylacrylamides. To a mixture of 1 (0.2 mmol), 3 (0.24 mmol) in
2.0 ml of DCE was added TBAI (7.4 mg, 10 molꢀ%) and K2S2O8 (162.2 mg, 3 equiv)
at room temperature in a Schlenk tube. The resulting mixture was stirred at 60 °C
under N2 for 24 h. Then the resulting reaction solution was cooled to room
temperature, diluted and washed with H2O, the aqueous phase was extracted with
ethyl acetate. The combined organic extracts was dried over anhydrous Na2SO4 and
concentrated in vacuum, and the resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 4:1) to afford the desired product.
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3-(2-(4-Methoxyphenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one
(4).13a
Following the general procedure, the product was isolated as a colorless oil in 69 %
yield (46.7 mg); 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.82 (d,
J = 8.7 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), 6.97 (t, J = 7.5 Hz,
1H), 6.87 (dd, J = 13.6, 8.3 Hz, 3H), 3.82 (s, 3H), 3.68 (d, J = 17.7 Hz, 1H), 3.60 (d, J
= 17.7 Hz, 1H), 3.31 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.9, 26.4,
45.3, 45.6, 55.4, 108.1, 113.5, 121.7, 122.0, 127.7, 129.4, 130.2, 133.8, 143.8, 163.4,
180.7, 194.5; HRMS m/z (EI) calcd for C19H19NO3 [M+]: 309.1365; found 309.1362.
1,3-Dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (5). 13a Following the general
1
procedure, the product was isolated as a colorless oil in 69 % yield (41.7 mg); H
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.40 (m,
2H), 7.28 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 7.8
Hz, 1H), 3.69 (q, J = 17.9 Hz, 2H), 3.31 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 24.9, 26.4, 45.2, 46.0, 108.1, 121.7, 122.1, 127.8, 127.9, 128.4, 133.1,
133.7, 136.3, 143.8, 180.5, 196.1; HRMS (EI) m/z calcd for C18H17NO2 [M+]:
279.1259; found 279.1258.
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3-(2-(4-Fluorophenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one (7).13b Following
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the general procedure, the product was isolated as a yellow oil in 48 % yield (31.1
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mg); mp = 108ꢀ111 C; H NMR (400 MHz, CDCl3) δ 7.87 – 7.84 (m, 2H), 7.28 –
7.24 (t, J = 7.7 Hz, 1H), 7.14 – 7.12 (d, J = 7.3 Hz, 1H), 7.08 – 7.04 (t, J = 8.3 Hz,
2H), 7.00 – 6.96 (t, J = 7.5 Hz, 1H), 6.91 – 6.89 (d, J = 7.8 Hz, 1H), 3.72 – 3.57 (m,
2H), 3.31 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.9, 26.5, 45.2, 45.9,
108.1, 115.4, 115.7, 121.6, 122.1, 127.9, 130.5, 130.6, 132.7, 132.7, 133.6, 143.8,
165.7 (d, 1JCꢀF = 253.0 Hz) , 180.2, 195.8; HRMS (EI) m/z calcd for C18H16FNO2
[M+]: 297.1165; found 297.1158.
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4-(2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)benzonitrile (8).13a Following the
general procedure, the product was isolated as a colorless oil in 40 % yield (26.6 mg);
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.29
(t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8
Hz, 1H), 3.66 (s, 2H), 3.30 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.9,
26.5, 45.2, 46.2, 108.3, 116.5, 117.8, 121.7, 122.3, 128.1, 128.4, 132.4, 133.1, 139.1,
143.8, 180.1, 194.9; HRMS (EI) m/z calcd for C19H16N2O2 [M+]: 304.1212; found
304.1208.
3-(2-(2-Fluorophenyl)-2-oxoethyl)-1,3-dimethylindolin-2-one (9).13h Following
the general procedure, the product was isolated as a colorless oil in 42 % yield (27.2
mg); 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.62 (m, 1H), 7.49 – 7.44 (dd, J = 13.3, 7.2
Hz, 1H), 7.28 – 7.24 (m, 1H), 7.14 – 7.08 (dd, J = 15.0, 7.5 Hz, 3H), 6.98 (m, 1H),
6.90 (d, J = 7.8 Hz, 1H), 3.78 – 3.61 (m, 2H), 3.31 (s, 3H), 1.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 25.0, 26.4, 45.3, 50.8, 50.8, 108.0, 116.4, 116.6, 121.5, 122.0,
124.3, 124.7, 127.7, 130.6, 134.7, 133.7, 143.8, 161.9 (d, 1JCꢀF = 253.0 Hz), 180.5,
194.1; HRMS (EI) m/z calcd for C18H16FNO2 [M+]: 297.1165; found 297.1159.
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5-Fluoro-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (10).13b Following
the general procedure, the product was isolated as a colorless oil in 45 % yield (29.1
mg); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.83 (d, J = 8.1 Hz, 2H), 7.52 – 7.51 (d, J
= 8.0 Hz, 1H), 7.42 – 7.38 (d, J = 7.8 Hz, 2H), 6.97ꢀ6.89 (m, 2H), 6.83ꢀ6.80 (m, 1H),
3.66 (s, 2H), 3.30 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.7, 26.5,
45.6, 45.9, 108.5, 109.9, 110.2, 113.6, 113.9, 127.9, 128.4, 130.0, 133.3, 135.4, 136.0,
139.7, 159.1 (d, 1JCꢀF = 239.0 Hz), 180.2, 195.9; HRMS (EI) m/z calcd for
C18H16FNO2 [M+]: 297.1165; found 297.1155.
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5-Bromo-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (11).13h Following
the general procedure, the product was isolated as a yellow oil in 47 % yield (37.2
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mg); H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.9 Hz, 2H), 7.54 (m, 1H), 7.43 –
7.37 (dd, J = 17.2, 8.7 Hz, 3H), 7.23 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.69 (s, 2H),
3.30 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 24.8, 26.5, 45.3, 46.0,
109.5, 114.7, 124.9, 127.9, 128.5, 130.6, 133.3, 135.9, 136.0, 143.0, 179.9, 195.7;
HRMS (EI) m/z calcd for C18H16BrNO2 [M+]: 357.0364; found 357.0357.
7-Iodo-1,3-dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one (13).13h Following the
general procedure, the product was isolated as a yellow oil in 56 % yield (47.9 mg);
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.53
(m, 1H), 7.42 – 7.39 (t, J = 8.ii0 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 6.68 – 6.65 (t, J =
8.0 Hz, 1H), 3.69 (s, 5H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 25.3, 30.3,
44.8, 46.3, 71.9, 121.2, 123.8, 127.9, 128.5, 133.3, 136.1, 136.8, 140.3, 144.2, 181.3,
195.8; HRMS (EI) m/z calcd for C18H16INO2 [M+]: 405.0226; found 405.0221.
1,3-Dimethyl-3-(2-oxo-2-phenylethyl)-7-phenylindolin-2-one (14).13h Following
the general procedure, the product was isolated as a yellow oil in 49 % yield (37.1
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mg); H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.53 (dd, J =
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17.4, 7.8 Hz, 3H), 7.43 – 7.39 (t, J = 8.0 Hz, 7H), 7.11 (d, J = 7.8 Hz, 1H), 7.04 (d, J
= 7.05 Hz, 1H), 6.91 – 6.88 (t, J = 7.6 Hz, 1H), 3.93 (d, J = 14.5 Hz, 1H), 3.73 (d, J =
14.5 Hz, 1H), 2.71 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 25.4, 30.5,
44.7, 46.5, 120.7, 121.5, 125.5, 127.5, 128.0, 128.5, 130.0, 130.8, 133.1, 134.8, 136.4,
139.2, 140.8, 181.7, 196.2; HRMS (EI) m/z calcd for C24H21NO2 [M+]: 355.1572;
found 355.1565.
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1-Benzyl-3-methyl-3-(2-oxo-2-phenylethyl)indolin-2-one (15).13b Following the
general procedure, the product was isolated as a white solid in 72 % yield (54.5 mg);
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mp=157ꢀ159 C; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 2H), 7.53 – 7.49
(t, J = 8.0 Hz, 1H), 7.43 – 7.37 (dd, J = 14.7, 7.4 Hz, 4H), 7.35 – 7.31 (t, J = 8.0 Hz,
2H), 7.25 – 7.23 (d, J = 7.0 Hz, 1H), 7.14 – 7.08 (dd, J = 14.6, 7.4 Hz, 2H), 6.94 –
6.92 (d, J = 7.7 Hz, 1H), 6.74 – 6.72 (d, J = 7.7 Hz, 1H), 5.10 – 5.06 (d, J = 15.8 Hz,
1H), 4.98 – 4.94 (d, J = 15.8 Hz, 1H), 3.80 – 3.69 (m, 2H), 1.49 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 25.4, 43.9, 45.3, 45.7, 109.2, 121.6, 122.1, 127.1, 127.3, 127.6,
127.9, 128.4, 128.6, 133.1, 133.7, 136.2, 142.8, 180.5, 195.8; HRMS (EI) m/z calcd
for C24H21NO2 [M+]: 355.1572; found 355.1572.
1,3-Dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one (16).15a Following the
general procedure, the product was isolated as a white solid in 85 % yield (64.8 mg);
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mp=159ꢀ161 oC; H NMR (400 MHz, CDCl3) δ 7.54 – 7.47 (m, 3H), 7.38 – 7.34 (t, J
= 8.0 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.89 – 6.84 (dd, J = 13.2,
7.6 Hz, 2H), 3.88 (d, J = 14.6 Hz, 1H), 3.71 (d, J = 14.6 Hz, 1H), 3.16 (s, 3H), 1.38 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 25.3, 26.4, 45.4, 61.7, 108.3, 122.4, 123.9, 127.6,
128.5, 128.7, 129.3, 133.2, 139.7, 143.1, 177.5; HRMS (EI) m/z calcd for
C17H17NO3S [M]+: 315.0929, found 315. 0926.
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5-Fluoro-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one
(17).15a
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Following the general procedure, the product was isolated as a white solid in 72 %
yield (57.5 mg); mp=168ꢀ170 oC; 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.52 (m, 3H),
7.43 – 7.39 (m, 2H), 7.00 – 6.95 (dd, J = 8.8, 2.4 Hz, 1H), 6.79 – 6.70 (m, 2H), 3.87
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(d, J = 14.6 Hz, 1H), 3.66 (d, J = 14.6 Hz, 1H), 3.19 (s, 3H), 1.39 (s, 3H); C NMR
(100 MHz, CDCl3) δ: 25.2, 26.7, 46.0, 61.6, 108.8, 112.2, 112.4, 114.9, 115.1, 127.7,
129.0, 131.1, 133.6, 139.2, 139.9, 157.8, 160.2 (d, 1JCꢀF = 240.0 Hz), 177.3; HRMS
(EI) m/z calcd for C17H16FNO3S [M+]: 333.0835; found, 333.0834.
5-Chloro-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one
(18).15a
Following the general procedure, the product was isolated as a white solid in 65 %
yield (54.0 mg); mp=147ꢀ149 C; 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 1H), 7.47
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(d, J = 7.6 Hz, 2H), 7.41 – 7.37 (t, J = 8.0 Hz, 2H), 7.22 (dd, J = 8.3, 1.9 Hz, 1H),
6.80 (dd, J = 8.7, 5.1 Hz, 2H), 3.89 (d, J = 14.7 Hz, 1H), 3.68 (d, J = 14.7 Hz, 1H),
3.21 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 25.1, 26.6, 45.6, 61.6,
109.2, 124.4, 127.4, 127.7, 128.5, 128.8, 130.9, 133.5, 139.6, 141.9, 177.1; HRMS
(EI) m/z calcd for C17H16ClNO3S [M+]: 349.0539; found, 349.0538.
5-Bromo-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one
(19).15a
Following the general procedure, the product was isolated as a yellow solid in 59 %
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yield (54.3 mg); mp=161ꢀ163 C; H NMR (400 MHz, CDCl3) δ 7.61 – 7.57 (t, J =
8.0 Hz, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.41 – 7.38 (dd, J = 13.8, 7.7 Hz, 3H), 6.92 (s,
1H), 6.75 (d, J = 8.2 Hz, 1H), 3.89 (d, J = 14.8 Hz, 1H), 3.68 (d, J = 14.7 Hz, 1H),
3.21 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 25.1, 26.6, 45.6, 61.6,
109.8, 115.0, 127.0, 127.4, 128.8, 131.3, 131.4, 133.6, 139.5, 142.4, 177.0; HRMS
(EI) m/z calcd for C17H16BrNO3S [M+]: 393.0034; found, 393.0031.
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5-Iodo-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one (20). 14a Following
the general procedure, the product was isolated as a white solid in 58 % yield (58.8
mg); mp=173ꢀ175 oC; 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.52 (m, 2H), 7.44 – 7.37
(dd, J = 15.3, 7.6 Hz, 4H), 7.04 (s, 1H), 6.66 – 6.63 (d, J = 8.2 Hz, 1H), 3.88 (d, J =
14.8 Hz, 1H), 3.65 (d, J = 14.8 Hz, 1H), 3.20 (s, 3H), 1.34 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 25.2, 26.6, 45.4, 61.7, 85.1, 110.4, 127.4, 128.9, 131.6, 132.6, 133.8,
137.4, 139.6, 143.2, 176.8; HRMS (EI) m/z calcd for C17H16INO3S [M+]: 440.9896;
found, 440.9882.
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1,3-Dimethyl-2-oxo-3-((phenylsulfonyl)methyl)indoline-5-carbonitrile (21).14a
Following the general procedure, the product was isolated as a white solid in 80 %
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yield (65.4mg); mp=173ꢀ175 C; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.58 (m, 2H),
7.51 (d, J = 7.7 Hz, 2H), 7.44 (m, 2H), 7.13 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 3.91 (d,
J = 14.7 Hz, 1H), 3.73 (d, J = 14.7 Hz, 1H), 3.28 (s, 3H), 1.40 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 25.0, 26.8, 45.2, 61.4, 105.6, 108.8, 118.7, 127.2, 127.4, 129.1, 130.4,
133.8, 138.9, 139.6, 147.2, 177.4; HRMS (EI) m/z calcd for C18H16N2O3S [M+]:
340.0882; found, 340.0881.
5-Methoxy-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one
(22).14a
Following the general procedure, the product was isolated as a white solid in 55 %
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yield (51.3mg); mp=128ꢀ130 C; H NMR (400 MHz, CDCl3) δ 7.55 – 7.48 (m, 3H),
7.40ꢀ7.36 (t, J = 8.0 Hz, 2H), 6.81ꢀ6.74 (m, 2H), 6.58 (s, 1H), 3.88 (d, J = 14.6 Hz,
1H), 3.67 – 3.64 (d, J = 11.5 Hz, 4H), 3.16 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 25.3, 26.6, 46.0, 55.5, 61.8, 108.7, 111.1, 113.3, 127.8, 128.7, 130.6, 133.2,
136.7, 140.0, 155.8, 177.2; HRMS (EI) m/z calcd for C18H19NO4S [M+]: 345.1035;
found, 345.1030.
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7-Iodo-1,3-dimethyl-3-((phenylsulfonyl)methyl)indolin-2-one (24). Following
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mg); mp=180ꢀ183 C;1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.59 –
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7.52 (m, 3H), 7.45 – 7.41 (t, J = 7.7 Hz, 2H), 7.05 – 7.03 (d, J = 7.3 Hz, 1H), 6.64 –
6.61 (t, J = 7.7 Hz, 1H), 3.90 (d, J = 14.5 Hz, 1H), 3.65 (d, J = 14.5 Hz, 1H), 3.51 (s,
3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 25.9, 30.5, 45.1, 61.8, 71.7, 123.9,
124.1, 127.8, 128.9, 132.3, 133.5, 139.5, 141.2, 143.6, 178.3; HRMS (EI) m/z calcd
for C17H16INO3S [M+]: 440.9896; found, 440.9888.
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1,3-Dimethyl-7-phenyl-3-((phenylsulfonyl)methyl)indolin-2-one
(25).14a
Following the general procedure, the product was isolated as a yellow solid in 44 %
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yield (40.2 mg); H NMR (400 MHz, CDCl3) δ 7.58 – 7.52 (m, 3H), 7.42 – 7.39 (m,
7H), 7.11 – 7.03 (m, 2H), 6.91 – 6.87 (t, J = 8.0 Hz, 1H), 3.92 (d, J = 14.5 Hz, 1H),
3.72 (d, J = 14.5 Hz, 1H), 2.70 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
25.8, 30.6, 45.0, 62.2, 121.8, 122.9, 125.7, 125.8, 127.7, 127.8, 128.9, 130.0, 130.3,
131.5, 133.3, 138.7, 140.1, 140.2, 178.6; HRMS (EI) m/z calcd for C23H21NO3S [M+]:
391.1242; found, 391.1236.
1-Benzyl-3-methyl-3-((phenylsulfonyl)methyl)indolin-2-one (27).14a Following
the general procedure, the product was isolated as a colorless oil in 94 % yield (86.0
mg); 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.50 (dd, J = 7.1, 4.5 Hz, 3H), 7.38 – 7.24
(m, 7H), 7.14 – 7.10 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.82 – 6.79 (m, 1H),
6.70 (d, J = 7.9 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.8 Hz, 1H), 3.93 (d,
J = 14.5 Hz, 1H), 3.75 (d, J = 14.6 Hz, 1H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 25.9, 44.1, 45.6, 61.5, 109.4, 122.4, 123.8, 127.2, 127.5, 127.6, 128.3, 128.7, 128.8,
129.4, 133.3, 135.7, 140.0, 142.3, 177.7; HRMS (EI) m/z calcd for C23H21NO3S [M+]:
391.1242; found, 391.1238.
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2-((1-Methyl-2-oxo-3-((phenylsulfonyl)methyl)indolin-3-yl)methyl)isoindoline-
1,3-dione (29). Following the general procedure, the product was isolated as a white
solid in 48 % yield (50.5 mg); mp=168ꢀ170 oC; 1H NMR (400 MHz, CDCl3) δ 7.83 –
7.81 (dd, J = 4.7, 3.7 Hz, 2H), 7.73 – 7.71 (m, 2H), 7.55 – 7.49 (dd, J = 17.5, 7.8 Hz,
3H), 7.39 – 7.35 (t, J = 7.6 Hz, 2H), 7.33 – 7.29 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.6
Hz, 1H), 6.89 – 6.85 (m, 2H), 4.07 (s, 2H), 3.96 (d, J = 14.2 Hz, 1H), 3.81 (d, J = 14.2
Hz, 1H), 3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 26.7, 44.1, 49.3, 59.3, 108.6,
122.3, 123.6, 124.8, 125.4, 127.8, 128.8, 129.4, 131.5, 133.3, 134.2, 139.9, 143.8,
167.9, 174.8; HRMS (EI) m/z calcd for C25H20N2O5S [M+]: 460.1093; found,
460.1088.
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3-(((4-Chlorophenyl)sulfonyl)methyl)-1,3-dimethylindolin-2-one
(30).15a
Following the general procedure, the product was isolated as a white solid in 73 %
o
1
yield (61.9 mg); mp=169ꢀ173 C; H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (dd, J =
14.9, 8.0 Hz, 5H), 7.00 (d, J = 7.3 Hz, 1H), 6.91 – 6.89 (m, 1H), 6.85 (d, J = 7.8 Hz,
1H), 3.91 (d, J = 14.6 Hz, 1H), 3.69 (d, J = 14.6 Hz, 1H), 3.17 (s, 3H), 1.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 25.5, 26.5, 45.5, 61.9, 108.4, 122.5, 123.9, 128.7,
129.0, 129.2, 129.2, 138.1, 140.0, 143.2, 177.4; HRMS (EI) m/z calcd for
C17H16ClNO3S [M+]: 349.0539; found, 349.0535.
1,3-Dimethyl-3-(tosylmethyl)indolin-2-one (32).15a Following the general
procedure, the product was isolated as a white solid in 60 % yield (45.6 mg);
o
mp=132ꢀ134 C; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.1 Hz, 2H), 7.29 (d, J =
7.7 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.94 – 6.90 (m, 1H),
6.84 (d, J = 7.8 Hz, 1H), 3.85 (d, J = 14.5 Hz, 1H), 3.66 (d, J = 14.5 Hz, 1H), 3.16 (s,
3H), 2.39 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 21.5, 25.4, 26.4, 45.6,
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61.8, 108.3, 122.4, 124.1, 127.8, 128.5, 129.4, 129.5, 137.0, 143.2, 144.2, 177.6;
HRMS (EI) m/z calcd for C18H19NO3S [M+]: 329.1086; found, 329.1081.
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3-(((4-Methoxyphenyl)sulfonyl)methyl)-1,3-dimethylindolin-2-one
(33).15a
9
Following the general procedure, the product was isolated as a white solid in 55 %
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o
yield (45.6 mg); mp=120ꢀ124 C; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8 Hz,
2H), 7.31 – 7.27 (m, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.96 – 6.92 (m, 1H), 6.83 (m, 3H),
3.86 (d, J = 16.4 Hz, 4H), 3.66 (d, J = 14.5 Hz, 1H), 3.15 (s, 3H), 1.38 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 25.5, 26.5, 45.6, 55.6, 62.0, 108.4, 114.0, 122.5, 124.1,
128.5, 129.6, 130.0, 131.4, 143.2, 163.4, 177.7; HRMS (EI) m/z calcd for
C18H19NO4S [M] +: 345.1035; found, 345.1026.
1,3-Dimethyl-3-(((2-nitrophenyl)sulfonyl)methyl)indolin-2-one (34). Following
the general procedure, the product was isolated as a yellow solid in 45 % yield (39.3
mg); mp=142ꢀ144 oC; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 7.8 Hz, 1H), 8.08 (s,
1H), 7.86 (d, J = 7.7 Hz, 1H), 7.64 – 7.60 (t, J = 7.9 Hz, 1H), 7.24 – 7.20 (t, J = 7.6
Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.79 – 6.71 (dt, J = 14.8, 7.3 Hz, 2H), 4.00 (d, J =
14.8 Hz, 1H), 3.75 (d, J = 14.8 Hz, 1H), 3.24 (s, 3H), 1.39 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 25.3, 26.6, 45.4, 62.1, 108.8, 122.3, 123.3, 127.8, 128.8, 129.0, 130.3,
133.1, 141.9, 143.5, 177.1; HRMS (EI) m/z calcd for C17H16N2O5S [M+]: 360.0780;
found, 360.0770.
ASSOCIATED CONTENTS
Supporting Information
Copies of H and 13C spectra for all products are available free of charge via the
1
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail: ccguo@hnu.edu.cn.
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Notes
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The authors declare no competing financial interest.
9
Acknowledgements
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Financial support from the National Science Foundations of China (No.21372068,
21572049) are gratefully acknowledged.
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