A metal-free route to CF3-containing oxindoles by PhI(OAc) 2-mediated trifluoromethylation of N-arylacrylamides with TMSCF 3

Article abstract of DOI:10.1002/ejoc.201301512

A mild and efficient PhI(OAc)₂-mediated trifluoromethylation reaction of N-arylacrylamides with TMSCF₃ under metal-free conditions was developed. This method provides convenient access to a variety of useful CF₃-containing

Full text of DOI:10.1002/ejoc.201301512

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301512
A Metal-Free Route to CF3-Containing Oxindoles by PhI(OAc)2-Mediated
Trifluoromethylation of N-Arylacrylamides with TMSCF3
Weijun Fu,*[a] Fengjuan Xu,[b] Yuqin Fu,*[a] Chen Xu,[a] Shihui Li,[a] and Dapeng Zou*[b]
Keywords: Synthetic methods / Amides / Fluorine / Iodine / Heterocycles
A mild and efficient PhI(OAc)2-mediated trifluoromethyl-
ation reaction of N-arylacrylamides with TMSCF3 under
metal-free conditions was developed. This method provides
convenient access to a variety of useful CF3-containing ox-
indoles in moderate to good yields.
fluoromethyl group enhances the biological and therapeutic
activities of organic compounds. In 2012, Liu and co-
workers reported the intramolecular oxidative aryltrifluoro-
methylation of N-arylacrylamides by using TMSCF3 in the
presence of Pd(OAc)2 (Scheme 1).[10] Another efficient
strategy to build the oxindole scaffold was based on Cu-
and Ru-catalyzed trifluoromethylation of N-arylacryl-
amides with Togni’s reagent developed by the groups of
Sodeoka[11] and Zhu,[12] respectively. More recently,
Nevado and co-workers described the first example of a
copper-promoted trifluoromethylation/aryl migration/de-
sulfonylation and C(sp2)–N bond formation of conjugated
tosyl amides by using Togni’s reagent as the radical trifluor-
omethylthiolating reagent.[13] Although these methods are
advantageous for the synthesis of the trifluoromethylated
oxindole scaffold, these methods do require transition-
metal catalysts or expensive Togni’s reagent.
Recently, the metal-free hypervalent iodine promoted tri-
fluoromethylation of arenes and alkenes was developed.[14]
For instance, Shibata reported an efficient oxidative tri-
fluoromethylation of arenes by using a simple combination
of trifluoromethanesulfinate and phenyliodine bis(trifluoro-
acetate).[15] Zhou et al. also described the intermolecular
phenyliodine diacetate (PIDA)-mediated trifluoromethyl-
ation of 2-isocyanobiphenyls with CF3SiMe3 for the synthe-
sis of 6-(trifluoromethyl)phenanthridines.[16] Encouraged by
these results and in our continuing efforts to develop new
and efficient strategies towards CF3-containing heterocycles
and related libraries,[17] we envisaged that this metal-free
strategy could be applied as a general approach for the syn-
thesis of CF3-containing oxindoles starting from readily
available N-arylacrylamides. Given that hypervalent iod-
ine(III) promoted trifluoromethylation is generally per-
formed at ambient temperature, a wider substrate scope and
higher reaction yields were expected.
Introduction
The trifluoromethyl moiety is one of the key structural
units found in pharmaceuticals, agrochemicals, and func-
tional materials mainly because of its excellent metabolic
stability, elevated electronegativity, and extremely high lipo-
philicity.[1,2] Consequently, extensive efforts have been de-
voted to incorporating the trifluoromethyl group into a
series of skeletal structures. Transition-metal-catalyzed tri-
fluoromethylation reactions starting from aryl halides,[3]
boronic acids,[4] arenes substituted with directing groups,[5]
alkynes,[6] and alkenes[7] have been recognized as powerful
methods for the preparation of CF3-containing compounds.
Effective transition-metal catalysts are mainly based on pal-
ladium, copper, and others. However, the use of expensive
metal catalysts and the problems involved in removing the
residual metals from the final products, which is usually a
difficult and tedious process, limits the practical applica-
tions of this strategy. Hence, the development of alternative
metal-free, direct trifluoromethylation reactions performed
under milder conditions are highly desirable.[8]
The oxindole unit is a ubiquitous structural motif fre-
quently found in many natural products and synthetic mo-
lecules with varied bioactivities.[9] In particular, CF3-con-
taining oxindoles are of significant interest because the tri-
[a] College of Chemistry and Chemical Engineering, Luoyang
Normal University,
Luoyang 471022, P. R. China
E-mail: wjfu@lynu.edu.cn
lyfuyuqin@126.com
[b] College of Chemistry and Molecular Engineering, Zhengzhou
University,
Zhengzhou, Henan 450052, P. R. China
E-mail: zdp@zzu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301512.
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W. Fu, F. Xu, Y. Fu, C. Xu, S. Li, D. Zou
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Scheme 1. The main approaches to CF3-containing oxindoles.
Table 1. Optimization of the reaction conditions for 2a.[a]
Results and Discussion
We commenced the investigation with N-arylacrylamide
1a as a model substrate under various conditions, and the
results are summarized in Table 1. The trifluoromethylation
reagent CF3SO2Na was first attempted with PIFA [phen-
yliodine bis(trifluoroacetate)], but no desired product was
formed (Table 1, entry 1). To our delight, 1a reacted with
TMSCF3 (4.0 equiv.) and PhI(OAc)2 (2.0 equiv.) as the oxi-
dant in the presence of K2CO3 at room temperature to give
trifluoromethylated 2a in 54% yield (Table 1, entry 2).
Among the inorganic bases examined, NaOAc was best,
and K2CO3 and Cs2CO3 were less effective (Table 1, en-
tries 2–4). The use of 6.0 equiv. of TMSCF3 gave a good
yield, but if the amount of TMSCF3 was increased to
8.0 equiv., the yield of 2a did not increase further (Table 1,
entries 5 and 6). The reaction proceeded well in N-methyl-
pyrrolidone (NMP), and DMF provided a slightly lower
yield of the product, whereas other solvents such as
CH3CN and CH2Cl2 were found to be less effective in this
reaction (Table 1, entries 7–9).
Entry CF3 reagent
(equiv.)
Oxidant Solvent
Base
Yield[b]
[%]
1
2
3
4
5
6
7
8
9
CF3SO2Na (2.0)
PIFA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
HFIP
NMP
NMP
NMP
NMP
NMP
DMF
–
0
TMSCF3 (4.0)
TMSCF3 (4.0)
TMSCF3 (4.0)
TMSCF3 (6.0)
TMSCF3 (8.0)
TMSCF3 (6.0)
TMSCF3 (6.0)
TMSCF3 (6.0)
K2CO3
NaOAc
Cs2CO3
NaOAc
NaOAc
NaOAc
54
65
51
78
79
60
25
CH3CN NaOAc
CH2Cl2 NaOAc trace
[a] Reaction conditions: 1a (0.3 mmol) and oxidant (2.0 equiv.) in
solvent (1.0 mL) at room temperature for 12 h. [b] Isolated yield.
position on the benzene ring proceeded well. In compari-
With the optimized reaction conditions in hand, we fur- son, ortho substituents on the benzene ring reduced the
ther explored the scope of the trifluoromethylation reaction yields of the products (see 2o and 2p). Cyclization of meta-
with a variety of N-arylacrylamides (Scheme 2). It was methyl-substituted substrates resulted in a mixture of re-
found that substrates containing various N-protecting gioisomers 2r in a 2:1 ratio. 3,5-Disubstituted N-arylacryl-
groups, such as isopropyl, butyl, benzyl, and phenyl, were amide 1q was also transformed into desired product 2q in
tolerated in this transformation (Scheme 2, see 2b–f). How- 81% yield. However, upon using bulky 1-naphthyl-sub-
ever, the use of N-free N-arylacrylamides resulted in no re- stitued 1t, desired product 2s was obtained in low yield.
action (Scheme 2, see 2g). Subsequently, the effect of sub- Additionally, good results were obtained with tetra-
stituents on the N-aryl moiety was examined. Both elec- hydroquinoline derivative 1t as the substrate. The molecular
tron-donating and electron-withdrawing groups located in structure of representative product 2n was determined by
the para and ortho positions of the aromatic rings were X-ray crystallography (see the Supporting Information).[18]
found to be tolerated in this reaction, and these substrates
On the basis of the above results and related litera-
furnished the corresponding CF3-containing oxindoles in ture,[9c–9g,12,16] a plausible reaction mechanism is depicted
moderate to good yields (Scheme 2, see 2h–p). N-Arylacryl- in Scheme 3. Initially, PIDA reacts with TMSCF3 to give
amides possessing electron-donating groups (see 2h and 2i) intermediate A upon release of TMSOAc. The following
gave the desired products in higher yields than substrates homolysis generates hypervalent iodine(III) centered radical
·
bearing electron-withdrawing groups (see 2j–n). Moreover, B and the CF3 radical. Subsequently, the addition of the
the procedure seemed sensitive to steric effects. Generally, ·CF3 radical to N-arylacrylamide 1 generates alkyl radical
reactions with substrates possessing substituents in the para C, followed by an intramolecular radical cyclization to give
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Eur. J. Org. Chem. 2014, 709–712

A Metal-Free Route to CF3-Containing Oxindoles
Scheme 2. Scope of the N-arylacrylamides. Reaction conditions: N-arylacrylamide 1 (0.3 mmol), TMSCF3 (1.8 mol), NaOAc (0.6 mmol),
and PhI(OAc)2 (0.6 mol) in NMP (1.0 mL) at room temperature for 12 h.
cyclized radical intermediate D. A single-electron oxidation fluoromethyl group through oxidative aryltrifluoromethyl-
of intermediate D by intermediate B forms cyclohexadienyl ation of N-arylacrylamides with the use of TMSCF3 under
cation E, which undergoes dehydrogenation to give product metal-free conditions. The process showed considerable
2.
synthetic advantages in terms of the functional group toler-
ance, substrate scope, the simplicity of the reaction pro-
cedure, and mild reaction conditions.
Experimental Section
General Procedure for the Aryltrifluoromethylation of N-Arylacryl-
amides: TMSCF3 (1.8 mmol) was added to a mixture of N-aryl-
acrylamide 1 (0.30 mmol), PhI(OAc)2 (0.6 mmol), and NaOAc
(0.6 mmol) in NMP (1.0 mL). After stirring at room temperature
for 12 h, the reaction mixture was diluted by adding EtOAc and
brine. The aqueous layer was extracted with EtOAc. The combined
organic layer was dried with MgSO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel to give desired oxindole 2.
Supporting Information (see footnote on the first page of this arti-
1
cle): Synthesis, characterization data, and copies of the H NMR
and 13C NMR spectra.
Scheme 3. Plausible reaction mechanism.
Acknowledgments
Conclusions
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (project numbers U1204205, 21202078, and
In conclusion, we have developed a mild and efficient
method for the construction of oxindoles bearing a tri- 21272110)
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Received: October 5, 2013
Published Online: December 19, 2013
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