Synthesis of oxindoles through silver-catalyzed trifluoromethylation-, difluoromethylation- and arylsulfonylation-cyclization reaction of N-arylacrylamides

Article abstract of DOI:10.1002/ejoc.201400087

Efficient synthesis of trifluoromethyl and difluoromethyl-substituted oxindoles was achieved by reacting Langlois reagent or Baran reagent with N-arylacrylamides. However, the reaction of aryl sulfinic acid sodium salts with N-arylacrylamides did not give the desulfinative products, instead, aryl sulfonated products were produced. Copyright

Full text of DOI:10.1002/ejoc.201400087

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FULL PAPER
DOI: 10.1002/ejoc.201400087
Synthesis of Oxindoles through Silver-Catalyzed Trifluoromethylation–,
Difluoromethylation– and Arylsulfonylation–Cyclization Reaction of
N-Arylacrylamides
Jidan Liu,[a] Shaobo Zhuang,[a] Qingwen Gui,[a] Xiang Chen,[a] Zhiyong Yang,[a] and
Ze Tan*[a]
Keywords: Synthetic methods / Homogenous catalysis / Nitrogen heterocycles / Silver
Efficient synthesis of trifluoromethyl and difluoromethyl-sub-
stituted oxindoles was achieved by reacting Langlois reagent
or Baran reagent with N-arylacrylamides. However, the reac-
tion of aryl sulfinic acid sodium salts with N-arylacrylamides
did not give the desulfinative products, instead, aryl sulfon-
ated products were produced.
tical molecules.[17] Therefore, extensive research effort has
been devoted to the development of methods for convenient
access to oxindoles. Among the reported synthetic strate-
gies, Pd-catalyzed oxidative difunctionalization of alkenes
in ortho-nonfunctionalized N-arylacrylamides through C–
H bond cleavage is one of the most investigated synthetic
routes.[18] Regardless of these advances, investigations of the
direct functionalization-cyclization of N-arylacrylamides by
using cheap and environmentally-benign catalysts are
highly desirable for drug discovery and medicinal chemis-
try.[19–23] For example, the Yang group recently disclosed a
silver-catalyzed direct phosphorylation-cyclization and azi-
dolation-cyclization reaction of N-arylacrylamides to de-
liver corresponding phosphorylated and azidolated oxind-
oles.[20] Li and co-workers discovered a Fe-catalyzed oxi-
dative alkylation-cyclization reaction of N-arylacrylamides
to provide various alkoxylated oxindoles.[21] Duan et al. de-
veloped a silver-catalyzed decarboxylative acylation reac-
tion of N-arylacrylamides with a-oxocarboxylic acids to
yield various acylated oxindoles.[22] Later, Li and Duan in-
dependently reported the oxidative benzylation-cyclization
reaction of N-arylacrylamides to form alkyl-substituted ox-
indoles through a tandem radical addition/cyclization reac-
tion.[23] Very recently, metal-free radical acetylation,[24a]
sulfonylation,[24b] azidolation,[24c] and hydroxylalkyl-
ation[24d] of N-arylacrylamides were also reported to deliver
various functionalized oxindoles. As for the synthesis of tri-
fluoromethyl containing oxindoles, in 2012, Liu reported a
Pd-catalyzed trifluoromethylation-cyclization of N-aryl-
acrylamides by using TMSCF3 as the trifluoromethyl group
source under mild conditions (Scheme 1, a).[25a] However,
the use of rather expensive TMSCF3 in conjunction with
PhI(OAc)2 makes large scale application of this reaction
less desirable. Very recently, Sodeoka described a similar
transformation by using CuI/Togni’s reagent system
(Scheme 1, b).[25b] Although this reaction could be operated
Introduction
The introduction of fluorinated moieties into organic
molecules has become important in pharmaceutical and ag-
rochemical research owing to a change in the physical,
chemical and biological properties of fluorine-containing
compounds.[1] The trifluoromethyl substituent has gained
considerable attention owing to its metabolic stability, lipo-
philicity and electron-withdrawing properties.[1] Conse-
quently, development of mild and practical synthetic meth-
ods for generating C–CF3 bonds has become a field of sig-
nificant research effort.[1,2] Among these methods, transi-
tion-metal-mediated or -catalyzed trifluoromethylation has
received great attention.[3–15] Over the past few years, Stra-
tegies based on Pd or Cu catalysis have been investigated for
the trifluoromethylation of halides,[3a,3b,4,5] boronic acids,[6]
carboxylic acids,[7] sulfonates,[8] and aromatic amines.[9] Ad-
ditionally, described methods for the trifluoromethylation
of olefins,[10] allylsilanes[11] or allylhalides[12] by means of
copper catalysis have also proved attractive to provide ver-
satile trifluoromethylated allylic compounds. Moreover, the
oxytrifluoromethylation reaction of multiple bonds could
be achieved under mild conditions in the presence or ab-
sence of metal catalysts.[13] Recent advances in the direct
trifluoromethylation of C–H bonds in arenes,[14] heteroar-
enes[15] and alkynes[16] have provided efficient protocols for
the construction of C(sp2)–CF3 and C(sp)–CF3 bonds.
Oxindoles are privileged heterocyclic scaffolds found in
a wide range of bioactive natural products and pharmaceu-
[a] State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan
University,
Changsha 410082, P. R. China
E-mail: ztanze@gmail.com
http://cc.hnu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400087.
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J. Liu, S. Zhuang, Q. Gui, X. Chen, Z. Yang, Z. Tan
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Scheme 1. Strategies toward trifluoromethyl-substituted oxindoles.
under mild conditions, this procedure suffered from ex- (Table 1, Entries 15–18). It should be noted that running
pensive and relatively unstable trifluoromethylating rea- the reaction at either 25 or 70 °C gave slightly inferior re-
gents. Herein we wish to report a new way of synthesizing sults, showing temperature is important to the product yield
trifluoromethyl-substituted oxindoles though silver-cata- (Table 1, Entries 19 and 20). The control reaction showed
lyzed trifluoromethylation-cyclization reaction of N-aryl- that without AgNO3, desired product 2a was not formed
acrylamides by using sodium trifluoromethanesulfinate
(CF3SO2Na, Langlois reagent) as the trifluoromethyl
source. In addition, difluoromethylation and sulfonylation
reactions could be also achieved through a similar radical
procedure when Langlois reagent was replaced by zinc di-
fluoromethanesulfinate [Zn(SO2CF2H)2, also known as Ba-
ran reagent] and arylsulfinic acid sodium salt (Scheme 1, c).
Table 1. Optimization of reaction conditions.[a]
Results and Discussion
Our initial reaction-optimization studies focused on the
AgNO3-catalyzed reaction of N-methyl-N-phenylmeth-
acrylamide (1a) with NaSO2CF3 and (NH4)2S2O8 at 40 °C
in CH2Cl2/H2O. With 0.2 equiv. of AgNO3, desired tri-
fluoromethylated oxindole product 2a was isolated in 42%
yield (Table 1, Entry 1). Changing the solvent to acetone/
H2O, CH3CN/H2O or dimethyl sulfoxide (DMSO)/H2O led
to increased yields of desired product (Table 1, Entries 2–
4). A better yield (67%) was obtained when the reaction
was conducted in tBuOH/H2O (Table 1, Entry 5). However,
when the reaction was carried out in pure water, the yield
of 2a decreased drastically (Table 1, Entry 6). Much to our
delight, a further increase in the amount of AgNO3 had a
beneficial effect on the reaction, and the yield of desired
product 2a was raised to 81% (Table 1, Entry 7). Other sil-
ver salts, such as Ag2O, Ag2CO3 and other metal salts such
as FeCl3, FeCl2, FeSO4·7H2O, CuI, Cu(OAc)2, were less ef-
fective than AgNO3(Table 1, Entries 8–14). Further investi-
gations showed that other oxidants, including K2S2O8, di-
tert-butyl peroxide (DTBP), tert-butyl hydroperoxide
[a] Reaction conditions: under
(0.3 mmol), NaSO2CF3 (0.9 mmol), oxidant (0.9 mmol), catalyst,
solvent (1:1, 2 mL) at 40 °C for 12 h. [b] Isolated yield. [c] 25 °C.
a nitrogen atmosphere, 1a
(TBHP), and H2O2, were less efficient than (NH4)2S2O8 [d] 70 °C.
2
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Silver-Catalyzed Oxindole Synthesis
(Table 1, Entry 21). In the absence of (NH4)2S2O8, AgNO3 used as the substrate expected product 2x was afforded in
alone did not promote this reaction (Table 1, Entry 22). 73% yield. Next, we continued to explore the effect of sub-
With the optimized conditions in hand, we set out to stituents on the olefin in N-arylacrylamides. No product
examine the scope of this reaction. The results are summa- was observed when N-methyl-N-phenylacrylamide was sub-
rized in Table 2. We first investigated the scope of substrates jected to the reaction (case 2y) whereas substrates bearing
1 with various N-protecting groups. A screening disclosed benzyl, acetoxymethyl, and phthalimidylmethyl at the α-po-
that N-alkyl or N-aryl protecting groups worked well to de- sition of the acrylamides reacted smoothly to furnish corre-
liver the desired products in good yields, whereas N-acetyl sponding oxindoles 2z, 2aa and 2ab in yields above 73%.
and N-unprotected substrates did not work at all (2a–2h). Finally, an N-arylacrylamide with two methyl groups at
Next, we turned our attention to the substituent effect on both the α- and β-position of the double bond could be
the aromatic ring of N-arylacrylamides. Both electron-do- used as a viable substrate to generate desired product 2ac
nating and electron-withdrawing groups on the para-posi- (68%, dr Ͼ 20:1).
tion of the aromatic ring reacted efficiently with CF3SO2Na
It is well known that the CF2H group can act as a lipo-
to give desired products 2i–2o in yields 52–79%. Further- philic hydrogen-bond donor as well as an isoster to OH or
more, ortho-substituted substrates could participate in the SH.[26] Therefore, methodologies for the introduction of a
transformation as well, but the yields are slightly lower, CF2H unit into molecules are of high interest. Baran re-
which indicated the transformation was sensitive to steric cently reported a direct transfer of a CF2H group to het-
hindrance (2p–2v). As for meta-substituted substrates, the eroarenes with Zn(SO2CF2H)2 in a radical pathway.[27] In-
reaction provided a mixture of two regioselective products spired by this work, we envisaged that a difluorometh-
(case 2w and 2wЈ) in good yield, however the regioselectivity ylation-cyclization reaction of N-arylacrylamide could be
is rather poor. When a tetrahydroquinoline derivative was also achieved by employing the same reagent. Fortunately,
we found that the difluoromethylated products can be pro-
duced in good yields when Zn(SO2CF2H)2 was used in this
Table 2. Silver-catalyzed trifluoromethylation-cyclization reactions
of arylacrylamides.[a]
reaction under standard conditions (Table 3). A few di-
fluoromethylated oxindoles were synthesized in moderated
to good yields by using this protocol (Table 3, Entries 1–5).
Table 3. Silver-catalyzed difluoromethylation-cyclization reactions
of arylacrylamides.[a]
[a] Reaction conditions: under
a
nitrogen atmosphere,
1
[a] Reaction conditions: under
(0.3 mmol), NaSO2CF3 (0.9 mmol), (NH4)2S2O8 (0.9 mmol),
AgNO3 (0.09 mmol), tBuOH/H2O (1:1, 2 mL) at 40 °C for 12 h.
a
nitrogen atmosphere, 1a
(0.3 mmol), Zn(SO2CF2H)2 (0.9 mmol), (NH4)2S2O8 (0.9 mmol),
AgNO3 (0.09 mmol), tBuOH/H2O (1:1, 2 mL) at 40 °C for 12 h.
[b] Isolated yield.
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J. Liu, S. Zhuang, Q. Gui, X. Chen, Z. Yang, Z. Tan
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Arylsulfinic acid sodium salts, which are relatively stable Table 4. Silver-catalyzed sulfonylation-cyclization reaction of aryl-
acrylamides.[a]
and easily prepared from sulfonyl chlorides, are mainly used
as sulfonylation reagents for preparing organosulfonyl com-
pounds.[28] Recent studies revealed that aryl sulfinic acid
salts could also work as an arene source by means of desulf-
inative reactions.[29] We reasoned that an aryl group, instead
of the trifluoromethyl group, could be introduced into the
oxindoles if the Langlois reagent was replaced by arylsulf-
inic acid sodium salt. However, when the reaction was con-
ducted in CH3CN/H2O under otherwise standard condi-
tions with phenyl sulfinic acid sodium salt, we were sur-
prised to see that the desired product was not formed, in-
stead, product 5a was formed in 85% yield.[30] Clearly, de-
sulfination did not take place as expected. Encouraged by
this result, we next investigated the scope of the reaction. A
wide variety of functionalized arylsulfinic acid sodium salts
including methoxy-, methyl-, tert-butyl-, fluoro-, chloro-
and bromo-substituted arylsulfinic acid sodium salts re-
acted well under the optimal reaction conditions and the
desired products were isolated in moderate to good yields
(Table 4, Compounds 5a–5g). Low yields were obtained
when (3-nitrophenyl)sulfinic acid sodium salt was used
(Table 4, Compound 5h). 2-Naphthylsulfinic acid sodium
salt could participate in the coupling as well, furnishing the
desired product in 76% yield. Substituted arylacrylamides
were also investigated for this transformation and it was
found that they all successfully coupled with phenylsulfinic
acid sodium salt to give the desired products in 55–80%
yields (Table 4, Compounds 5j–5n).
To probe the mechanism of this new transformation, a
control experiment was conducted. When the reaction of 1a
with sodium trifluoromethanesulfinate was carried out in
the presence of radical scavenger 2,2,6,6-tetramethyl-1-pip-
eridinyloxy (TEMPO) under standard reaction conditions
(Scheme 2) the formation of trifluoromethylated oxindole
was totally suppressed and TEMPO-CF3 adduct 6 was de-
tected in 35% yield by 19F NMR spectroscopy. This result
suggested that the reaction is likely to involve a CF3 radical,
which is consistent with literature precedent.[7b,15c,31]
[a] Reaction conditions: under
(0.3 mmol), ArSO2Na (0.9 mmol), (NH4)2S2O8 (0.9 mmol), AgNO3
(0.09 mmol), CH3CN/H2O (1:1, 2 mL) at 40 °C for 12 h.
a
nitrogen atmosphere,
1
A plausible mechanism for the Ag-catalyzed trifluoro-
methylation-cyclization reaction of N-arylacrylamide is de-
picted in Scheme 3 based on the above evidence and earlier
similar studies.[7b,15c,31] Initially, oxidation of silver(I) to sil-
ver(II) is effected by the persulfate anion, which itself dis-
proportionates into sulfate dianion and sulfate radical
–
anion. In the presence of silver(II) ions, CF3SO2 is oxid-
·
ized to CF3SO2 , which subsequently releases one molecule
of SO2 to generate a trifluoromethyl radical. Addition of
the in situ generated trifluoromethyl radical to the double
Scheme 3. Proposed mechanism.
Scheme 2. Radical capture experiment in the presence of TEMPO.
4
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Silver-Catalyzed Oxindole Synthesis
N-arylacrylamide
1
(0.3 mmol), Zn(SO2CF2H)2 (0.9 mmol),
bond of 1a leads to the formation of radical intermediate
A, which subsequently undergoes intramolecular cyclization
to give radical intermediate B. After being oxidized by the
sulfate radical anion and aromatization, intermediate B is
transformed into desired trifluromethylated oxindole 2a.
(NH4)2S2O8 (0.9 mmol), and AgNO3 (0.09 mmol). After tBuOH/
H2O (1 mL: 1 mL) was added the reaction tube was charged with
argon and stirred at 40 °C for 12 h. After the reaction was com-
plete, saturated aqueous NaCl (10 mL) and CH2Cl2 (10 mL) were
added successively to the cooled reaction mixture. The organic
phase was separated, and the aqueous phase was further extracted
with CH2Cl2 (3ϫ 30 mL). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated under vacuum. Purifica-
tion was performed by flash column chromatography on silica gel
to give corresponding pure product 3.
Conclusions
In summary, an efficient method for the synthesis of tri-
fluoromethyl and difluoromethyl-substituted oxindoles has
been developed. By treating N-arylacrylamides with Lang-
lois reagent or Zn(SO2CF2H)2 in the presence of a catalytic
amount of AgNO3 and by using (NH4)2S2O8 as the oxi-
dant, N-arylacrylamides were found to undergo addition
with the in situ generated trifluoromethyl and difluoro-
methyl radical followed by subsequent cyclization to pro-
vide a variety of trifluoromethyl and difluoromethyl-substi-
tuted oxindoles in 40–86% yields. In sharp contrast, the
reaction of aryl sulfinic acid sodium salts with N-arylacryl-
amides did not give the arylated oxindoles; instead, sulfon-
ated products were formed in 45–85% yields. This new pro-
tocol is operationally simple and can be conducted under
mild conditions. Preliminary mechanistic studies indicated
that a radical process may be involved in the reaction. Fur-
ther studies towards understanding the mechanistic detail
and synthetic application of these reactions are ongoing in
our laboratory.
General Procedure for the Silver-Catalyzed Sulfonylation–Cycliza-
tion of N-Arylacrylamides: A 25 mL tube was charged with N-aryl-
acrylamide 1 (0.3 mmol), sulfinic acid sodium salts 4 (0.9 mmol),
(NH4)2S2O8 (0.9 mmol), and AgNO3 (0.09 mmol). After CH3CN/
H2O (1 mL: 1 mL) was added, the reaction tube was charged with
argon and stirred at 40 °C for 12 h. After the reaction was com-
plete, saturated aqueous NaCl (10 mL) and CH2Cl2 (10 mL) were
added successively to the cooled reaction mixture. The organic
phase was separated, and the aqueous phase was further extracted
with CH2Cl2 (3ϫ 30 mL). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated under vacuum. Purifica-
tion was performed by flash column chromatography on silica gel
to give corresponding pure product 5.
Procedure for the Control Experiment in the Presence of TEMPO:
A 25 mL tube was charged with N-arylacrylamide 1 (53 mg,
0.3 mmol), CF3SO2Na (140 mg, 0.9 mmol), (NH4)2S2O8 (205 mg,
0.9 mmol), AgNO3 (15 mg, 0.09 mmol) and TEMPO (141 mg,
0.9 mmol). After tBuOH/H2O (1 mL: 1 mL) was added, the reac-
tion tube was charged with argon and stirred at 40 °C for 12 h. 19
F
NMR spectroscopic analysis of this reaction mixture revealed that
TEMPO-CF3 adduct 6 was formed in the reaction mixture in 35%
yield. 19F NMR (377 MHz, CDCl3): δ = –55.52 ppm (s, 3 F). The
19F NMR spectrum was in accordance with the literature data.[10c]
Experimental Section
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data, and copies of NMR spectra of all final
products.
General Remarks: All the solvents and commercially available rea-
gents were purchased from commercial sources and used directly.
1H NMR and 13C NMR spectroscopic data were recorded in
CDCl3 at room temperature with a Varian INOVA-400 spectrome-
ter (400 MHz for 1H nuclei) or with a Bruker spectrometer
Acknowledgments
1
(400 MHz for H nuclei). TMS was used as the internal reference.
This work is supported by grants from the National Natural Sci-
ence Foundation of China (NSFC) (grant number 21072051),
NCET program (NCET-09-0334) and the Fundamental Research
Funds for the Central Universities, Hunan University.
The peak patterns are indicated as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; qui, quintet; sxt, sextet. Mass
spectroscopic data were collected on an HRMS (ESI) instrument.
Products were purified by flash column chromatography on 200–
300 mesh silica gel, SiO2.
General Procedure for the Silver-Catalyzed Trifluoromethylation–
Cyclization of N-Arylacrylamides: A 25 mL tube was charged
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1 (0.3 mmol), CF3SO2Na (0.9 mmol),
(NH4)2S2O8 (0.9 mmol), and AgNO3 (0.09 mmol). After tBuOH/
H2O (1 mL: 1 mL) was added the reaction tube was charged with
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phase was separated, and the aqueous phase was further extracted
with CH2Cl2 (3ϫ 30 mL). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated under vacuum. Purifica-
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to give corresponding pure product 2.
General Procedure for the Silver-Catalyzed Difluoromethylation–
Cyclization of N-Arylacrylamides: A 25 mL tube was charged with
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40087
/KAP1
Date: 04-04-14 11:24:27
Pages: 8
Silver-Catalyzed Oxindole Synthesis
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Received: January 18, 2014
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O40087
/KAP1
Date: 04-04-14 11:24:27
Pages: 8
J. Liu, S. Zhuang, Q. Gui, X. Chen, Z. Yang, Z. Tan
FULL PAPER
Oxindole Synthesis
J. Liu, S. Zhuang, Q. Gui, X. Chen,
Z. Yang, Z. Tan* .............................. 1–8
Synthesis of Oxindoles through Silver-
Catalyzed
Trifluoromethylation–,
Di-
fluoromethylation– and Arylsulfonylation–
Cyclization Reaction of N-Arylacrylamides
Efficient synthesis of trifluoromethyl and
difluoromethyl-substituted oxindoles was
achieved by the reaction of Langlois re-
agent or Baran reagent with N-aryl-
acrylamides in tBuOH/H2O by using
AgNO3 as the catalyst and (NH4)2S2O8 as
the oxidant. Sulfonylation could also be
achieved through a similar radical pro-
cedure when Langlois reagent was replaced
by arylsulfinic acid sodium salt.
Keywords: Synthetic methods / Homogen-
ous catalysis / Nitrogen heterocycles / Silver
8
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