Photoredox-catalyzed tandem radical cyclization of N-arylacrylamides: General methods to construct fluorinated 3,3-disubstituted 2-oxindoles using fluoroalkylsulfonyl chlorides

Article abstract of DOI:10.1021/ol502163f

Fluorinated radicals were generated from R_fSO₂Cl by photoredox catalysis under mild conditions, where R_f = n-C₄F₉, CF₃, CF₂H, CH₂F, CH₂CF₃, and CF₂CO₂Me. This method provided a general way to construct fluorinated 2-oxindoles from reaction with N-arylacrylamides via a proposed tandem radical cyclization process.

Full text of DOI:10.1021/ol502163f

Letter
pubs.acs.org/OrgLett
Photoredox-Catalyzed Tandem Radical Cyclization of
N‑Arylacrylamides: General Methods To Construct Fluorinated 3,3-
Disubstituted 2‑Oxindoles Using Fluoroalkylsulfonyl Chlorides
Xiao-Jun Tang, Charles S. Thomoson, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States
S
* Supporting Information
ABSTRACT: Fluorinated radicals were generated from RfSO2Cl by
photoredox catalysis under mild conditions, where Rf = n-C4F9, CF3,
CF2H, CH2F, CH2CF3, and CF2CO2Me. This method provided a
general way to construct fluorinated 2-oxindoles from reaction with
N-arylacrylamides via a proposed tandem radical cyclization process.
he discovery of isatin in the early 19th century has led to
methods. Various fluoroalkylsulfonyl chlorides, RfSO2Cl, are
Textensive investigation of the reactivity and synthesis of commercially available or may be readily prepared from
indole containing motifs.1 In particular, 3,3-disubstituted 2-
inexpensive starting materials. Our current work was
conceived with the knowledge that Baran’s RfSO2M reagents
were prepared from their respective sulfonyl chlorides,12b and
our hypothesis was that it might therefore prove advantageous
if one could use these sulfonyl chlorides directly for radical
formation.13 The results outlined in this current communica-
tion represent our efforts to demonstrate that sulfonyl
chlorides can be effectively used as synthetic sources of a
variety of fluoroalkyl radicals. We believe that the direct use of
these sulfonyl chlorides constitutes a viable alternative to the
previous mentioned methods. Although photosensitized
approaches to the generation of fluorinated radicals from RfI
have recently received much attention due to the excellent
reductive ability of a photocatalyst in the excited state under
mild conditions,14 to the best of our knowledge, the only
fluoroalkylsulfonyl chloride that has thus far been reportedly
used for Rf radical generation has been CF3SO2Cl.15 In
general, fluoroalkylsulfonyl chlorides have more positive
reductive potentials, lower volatility, and a higher boiling
point compared to the respective fluoroalkyl iodides,16 so they
should be better candidates for photosensitized radical
generation than the analogous iodides. Thus, in this paper
we describe the photocatalyzed reaction of a number of
fluoroalkylsulfonyl chlorides (RfSO2Cl) with N-arylacryla-
mides, reactions which prove to be effective for the
construction of the respective fluorinated 2-oxindoles.
oxindoles, an isatin derivative, have attracted much attention
due to the stereogenic center located at C3 and because of the
increased bioavailability of pharmaceuticals containing these
moieties.2 Therefore, these structural entities continue to be
an attractive synthetic target. It is also well-known that the
introduction of fluorinated substituents can significantly alter
the physical, chemical, and biological properties of the parent
compound.3 Thus, incorporation of fluorinated substituents
into potential pharmaceuticals and agrochemical agents
continues to attract considerable attention from synthetic
chemists. When introduced into pharmaceuticals, a fluorinated
substituent can enhance membrane permeability, bioavail-
ability, binding affinity, and lipophilicity.4
Recently, 3,3-disubstituted 2-oxindoles bearing the CF3
group have been synthesized using the Togni reagent,5
TMSCF3,6 or CF3SO2Na.7 However, increasing the diversity
of available methodology in this area remains of considerable
interest. Thus far, the reported methods have been limited to
introduction of the CF3 moiety. Therefore, there is an
incentive to broaden the methodology to apply to other
fluorinated groups with respect to preparation of 3,3-
disubstituted 2-oxindole systems. Among the various methods
available to prepare 3,3-disubstituted 2-oxindole compounds,
perhaps the most efficient route involves the cyclization
reactions of N-arylacrylamides.8 These reactions can be
initiated by the reaction of radicals with C−C double bonds
followed by intramolecular radical cyclization onto the aryl
substituent. Consistent with these findings, we hypothesized
similar reactions could be carried out using a large variety of
fluorinated radicals to construct a diverse series of fluorinated
2-oxindoles. Fluorinated radicals can be generated in many
ways,9 but the reduction of RfX (X = I, Br, Cl) using
In our preliminary experiments, N-methyl-N-phenyl-
methacrylamide, 1a, and CF3SO2Cl were selected as model
substrates. An initial experiment using 1 mol % Ru(phen)3Cl2
as the catalyst, MeCN as the solvent, and K2HPO4 as an
added base led to formation of the expected product 2aa in
68% yield, as determined by 19F NMR: (δ −62.0, t, J = 11.0
10
reductive reagents such as Na2S2O4 or transition metals11 or
Received: July 22, 2014
Published: August 19, 2014
oxidation of RfSO2M (M = Zn or Na)12 are two preferred
© 2014 American Chemical Society
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Letter
a
Hz). Under these initial conditions, 38% of byproducts were
observed (singlets at −61.2, −62.1, and −62.2 ppm), and
these peaks were attributed to products obtained from direct
trifluoromethylation of the phenyl ring.15a Results from
optimization experiments are provided in Table 1. With
Scheme 1. Substrate Scope Catalyzed by Ru(phen)3Cl2
Table 1. Optimizations of Reaction Conditions
a
entry
solvent
base
yield
68%
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
K2HPO4
Na2CO3
K3PO4
2
40%
20%
15%
67%
74%
60%
54%
35%
24%
84%
3
4
NaHCO3
K2CO3
5
6
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
7
8
DMF
9
acetone
DMAc
HOAc
HOAc
HOAc
MeCN
10
11
12
13
14
b
c
NaOAc
92% (88% )
49%
no base
no base
48%
a
Reactions were run with 0.5 mmol of 1a, 1 mmol of CF3SO2Cl, 1.5
mmol of base, and 0.01 mmol of Ru(phen)3Cl2 in 5 mL of solvent. All
b
yields were based on 1a using PhCF3 as the internal standard. 1.75
c
mmol (3.5 equiv) of NaOAc was used. Isolated yield based on 1a.
continued use of CH3CN as solvent, other bases were tested
including Na2CO3, K3PO4, and NaHCO3, all which gave poor
yields of 2aa. When K2CO3 or NaOAc was used as the base,
improved yields were obtained, and the Ar−CF3 products
were suppressed (<5%). Variation of the solvent led to the
discovery that acetic acid was an excellent solvent for this
reaction, when used in conjunction with the buffer base,
NaOAc (entries 11 and 12). As shown by the last two entries,
the presence of a base is definitely advantageous, its role most
likely being the removal of coproduct HCl from the reaction.
One would expect the phen ligand of Ru(phen)3Cl2 to be
sensitive to the presence of HCl.
Using these optimized reaction conditions, the cyclization
reactions of CF3SO2Cl with various N-arylacrylamides were
explored. As shown in Scheme 1, various functional groups
were well tolerated, and substrates with both electron-
donating and -withdrawing substituents performed well
under the reaction conditions. For acrylamides 1l, 1n, and
1o, the lack of substitution on the amide, or replacement of
the methyl by either a carbonyl or sulfonyl substituent, shut
down the cyclization process completely, as did the lack of a
substituent at the α-position of the acrylamide 1m. The lack
of reactivity of compounds 1l, 1m, and 1p is perhaps best
understood in terms of conformational effects. All of the
substrates, except 1l, 1m, and 1p, are sterically hindered from
maintaining a ground-state planar conformation for the
acrylamide. Thus, the vinyl group for all reactive substrates
is likely not well conjugated with the carbonyl function, which
should enhance these substrates’ reactivities with the
a
0.1 M acrylamindes in 0.5 mmol scale, isolated yield based on 1.
inherently reactive, but electron-deficient trifluoromethyl
radical.
The lack of reactivity of the N-acyl and N-sulfonyl amides,
1n and 1o, is probably an indication of the need for some
electron donation into the aryl group by the amide nitrogen
in order to stabilize the cyclized radical intermediate and/or
to foster oxidation of this radical to its respective carbocation.
Moreover, our initial experiments using fluorinated sulfonyl
chlorides other than CF3SO2Cl involved the use of n-
C4F9SO2Cl and MeO2CCF2SO2Cl, which proved to have high
reactivity under the prescribed conditions.
When it was attempted to extend the work to the addition
of the CF2H radical, it was found that under the conditions
that were optimal for CF3SO2Cl, HCF2SO2Cl only yielded
trace amounts of the desired product, with substrate 1h being
essentially completely recovered (Table 2, entry 1). Since the
reductive potential of HCF2SO2Cl should be more negative
than that of CF3SO2Cl, the Ru(phen)3Cl2 (E1/2III/*II = −0.87
V vs SCE in MeCN) catalyst might not be effective in
reducing HCF2SO2Cl to provide the CF2H radical. Consistent
with this assumption, similarly poor results were obtained
when Ru(bpy)3Cl2 (E1/2III/*II = −0.81 V vs SCE in MeCN)
was used as the catalyst. In contrast, when fac-Ir(ppy)3
(E1/2
IV/ III
*
= −1.73 V vs SCE in MeCN)17 was used as the
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Letter
Table 2. Optimization of Conditions for the Reaction of
HCF2SO2Cl
Scheme 2. Substrate Scope Catalyzed by fac-Ir(ppy)3
a
entry
cat.
solvent
base
yield
<1%
1
2
3
4
5
6
7
Ru(phen)3Cl2
Ru(bpy)3Cl2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
HOAc
HOAc
HOAc
MeCN
HOAc
MeCN
MeCN
NaOAc
NaOAc
NaOAc
NaOAc
K2HPO4
K2HPO4
K2HPO4
<1%
59%
41%
52%
b
80% (77% )
75%
c
a
Reactions were run with 0.5 mmol of 1h, 1 mmol of HCF2SO2Cl, and
0.005 mmol of catalyst in 5 mL of solvent. All yields were based on 1h
b
c
using PhCF3 as the internal standard. Isolated yield based on 1h. 1.5
mmol (3 equiv) of K2HPO4 was used.
catalyst, generation of the CF2H radical was observed, with
formation of 59% of product 2dh. In optimizing the use of
this catalyst, it was found that a combination of K2HPO4 as
the base and acetonitrile as the solvent provided the best
results (Table 2, entry 6), with the desired cyclized product
being formed in 80% yield. It should also be noted that no
byproducts from addition of the CF2H radical directly to the
aryl group were detected under these conditions.
a
b
0.1 M acrylamindes in 0.5 mmol scale, isolated yield. 19F NMR
yield; this product was not isolated due to low yield. c Reactions were
It was found that the 2,2,2-trifluoroethyl radical could also
be effectively generated from CF3CH2SO2Cl by the use of this
same Ir catalyst, although the yields were more modest for
this radical. The results obtained for these two fluorinated
sulfonyl chlorides in reacting with a variety of N-
arylacrylamides are given in Scheme 2. Good yields (55−
82%) were obtained when using CF2HSO2Cl, but
CF3CH2SO2Cl provided only 46−54% yields of the desired,
cyclized products. Yields were not improved by using longer
reaction times. In attempts to use H2CFSO2Cl as a source of
the CH2F radical in the reaction with N-methyl-N-phenyl-
methacrylamide 1a, only a 16% yield of desired product 2fa
could be obtained under the reaction conditions of Table 2.
The yields of cyclized products (2fa, 2fh, and 2fk) were
improved to 45−48% when the reactions were run at 105 °C
using DCE instead of MeCN as the solvent. It is apparently
even more difficult to reduce CH2FSO2Cl than in the cases of
HCF2SO2Cl and CF3CH2SO2Cl.
run at 105 °C in DCE.
Scheme 3. DLP-Initiated Radical Cyclization Reactions
Scheme 4. Proposed Radical Cyclization Mechanism for
Photocatalyzed Reactions
Interestingly, it was found that use of an unambiguous
thermal free radical initiator, dilauryl peroxide (DLP), in
reactions of 1a with CF3SO2Cl, HCF2SO2Cl, or H2CFSO2Cl
gave rise to the corresponding cyclized products with yields of
63%, 54%, and 70%, respectively (Scheme 3).
Although authors reporting the similar preparations of CF3-
containing 2-oxindoles by the use of Togni reagent/CuCl5c or
6b
TMSCF3/Pd(OAc)2 invoked mechanisms involving cycliza-
tion of carbocations, based on the results of Scheme 3, we
believe that a radical cyclization mechanism, followed by
oxidation of a cyclized radical intermediate is more credible
for our reactions of fluorinated sulfonyl chlorides (Scheme 4).
In summary, a general way of generating fluorinated radicals
from fluorinated sulfonyl chlorides via photoredox catalysis
under mild conditions has been reported. This method can be
used to generate CF3, CF2CO2Me, and n-C4F9 radicals, but it
also has been modified to allow the generation of other
fluorinated radicals such as CF2H, CH2F, and CF3CH2. The
utility of this process has been demonstrated through the
preparation of a variety of fluorinated 3,3-disubstituted 2-
oxindoles. Additional applications for the use of these new
fluoroalkylation reagents are currently under investigation.
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Organic Letters
Letter
Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle,
́
B.; Sach, N.;
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization, and NMR spectra
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org
■
Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95.
(13) ATRA reaction of CF3SO2Cl and C4F9SO2Cl catalyzed by
Ru(PPh3)3Cl2 at 120 °C was reported; see: (a) Kamigata, N.;
Fukushima, T.; Terakawa, Y.; Yoshida, M.; Sawada, H. J. Chem. Soc.,
Perkin Trans. 1 1991, 627. (b) Kamigata, N.; Fukushima, T.; Yoshida,
M. J. Chem. Soc., Chem. Commun. 1989, 1559.
S
(14) For selected reports: see: (a) Wallentin, C. J.; Nguyen, J. D.;
Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134,
8875. (b) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.;
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D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wrd@chem.ufl.edu.
Notes
The authors declare no competing financial interest.
(15) (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(b) Oh, S. H.; Malpani, Y. R.; Ha, N.; Jung, Y.; Han, S. Org. Lett.
2014, 16, 1310. (c) Jiang, H.; Cheng, Y.; Zhang, Y.; Yu, S. Eur. J.
Org. Chem. 2013, 24, 5485.
ACKNOWLEDGMENTS
■
Support of this research by a grant from Syngenta Crop
Protection is gratefully acknowledged.
(16) For example, the reduction potential of CF3I and CF3SO2Cl is
−1.52 V vs SCE and −0.18 V vs SCE, respectively; see ref 15a. The
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(17) For a review on photoredox catalysis, see: Prier, C. K.; Rankic,
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