Synthesis of Perfluoroalkyl-Substituted Oxindoles through Organophotoredox-Catalyzed Perfluoroalkylation of N-arylacrylamides with Perfluoroalkyl Iodides

Article abstract of DOI:10.1055/s-0037-1611781

An efficient process was developed for the perfluoroalkylation of N -arylacrylamides through an organocatalyzed photoredox/cyclization reaction of N -arylacrylamides with inexpensive perfluoroalkyl iodide reagents. The reaction employs an inexpensive organic dye, eosin Y, as the photoredox catalyst and is run under irradiation by a 26 W LED lightbulb.

Full text of DOI:10.1055/s-0037-1611781

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
Z. Yang, A. Tang
Letter
Synlett
Synthesis of Perfluoroalkyl-Substituted Oxindoles through
Organophotoredox-Catalyzed Perfluoroalkylation of N-arylacryl-
amides with Perfluoroalkyl Iodides
Zhiyong Yang*
Anjiang Tang
R2
R2
N
5% mmol eosin Y
1 equiv Cs2CO3
N
O
R1
O
R1
RFI
R3
R4
+
R4
School of Chemical Engineering, Guizhou Institute of Technolo-
gy, Guiyang, 550003, P. R. of China
weyouthem@163.com
26 W lightbulb
DMA, N2, 16 h
R3
RF
3
1
2
R1 = X, Me, i-Pr
2 = Me, Et, i-Pr, Bn, etc.
R3 = H, Me, Bn
4 = H, Me
no transition metal
26 examples
up to 88% yield
RF = (CF2)nCF3 (n = 0, 3, 5, 7)
R
R
Received: 01.01.2019
Accepted after revision: 10.02.2019
Published online: 15.04.2019
carbonyl compounds,11 perfluoroalkylation reactions
through photoredox catalysis have been developed by the
groups of König,12 Sanford,6d Dolbier,13 Qing,7e,14 and others.15
Numerous synthetic strategies have recently been de-
veloped for the syntheses of oxindoles because of the desir-
able biological properties of these compounds.16–22 Among
these strategies, protocols for the synthesis of fluorine-con-
taining oxindoles have been developed by the groups of Liu,
Sodeoka, Nevado, Sheng, Duan, and others.20–22 Liu and
Sodeoka synthesized perfluoroalkyl-substituted oxindoles
by using TMSCF3 or 1-trifluoromethyl-1,2-benziodoxol-3-
(1H)-one (Togni’s reagent), respectively, as sources of the
trifluoromethyl group [Schemes 1(a) and 1(b)]. Because the
generation of perfluoroalkyl radicals by using inexpensive
RFI rather than Togni’s reagent is more attractive, Duan ap-
plied this strategy to the synthesis of perfluorinated oxin-
doles through Pd-catalyzed alkarylation of acrylamides
with RFI [Scheme 1(c)].21c Inspired by these pioneering
works, we have developed a simple procedure for the syn-
thesis of perfluoroalkylated oxindoles through perfluoroal-
kyl radical-mediated cyclization of N-arylacrylamides with
RFI in the presence of an organophotoredox catalyst under
visible light [Scheme 1(d)].
Our initial experiments involved the reaction of N-
methyl-N-phenylmethacrylamide (1a) with n-C4F9I cata-
lyzed by Ru(bpy)3Cl2·6H2O. When 1a was treated with three
equivalents of n-C4F9I in the presence of 5% mmol of
Ru(bpy)3Cl2·6H2O and one equivalent of K2CO3 in DMF at
60 °C for 16 hours, the desired (perfluoroalkyl)oxindole 3a
was obtained in 32% yield (Table 1, entry 1). Because a large
amount of 1a remained intact, we screened various reac-
tion conditions such as the temperature, base, solvent, and
catalyst in an attempt to obtain a better yield. When the
temperature was increased to 65 or 70 °C, the yield in-
creased by about 19% (entries 2 and 3). A further increase in
the yield of the 3a to 61% was obtained when K2CO3 was re-
DOI: 10.1055/s-0037-1611781; Art ID: st-2019-k1743-l
Abstract An efficient process was developed for the perfluoroalkyla-
tion of N-arylacrylamides through an organocatalyzed photoredox/cy-
clization reaction of N-arylacrylamides with inexpensive perfluoroalkyl
iodide reagents. The reaction employs an inexpensive organic dye, eo-
sin Y, as the photoredox catalyst and is run under irradiation by a 26 W
LED lightbulb.
Key words oxindoles, cyclization, perfluoroalkylation, photoredox re-
action
Fluoroalkylated molecules are important due to their
unique physical, chemical, and biological properties, which
can be applied in a wide range of fields, including materials,
agrochemicals, and pharmaceuticals.1,2 Among organofluo-
rine compounds, trifluoromethyl- and perfluoroalkyl (RF)-
substituted compounds have attracted significant interest,
particularly because of their metabolic stability, lipophilici-
ty, and electron-withdrawing properties.1,2 In recent de-
cades, numerous methods for the introduction of trifluoro-
methyl and perfluoroalkyl groups to form alkyl–RF bonds3
and aryl–RF bonds4–7 have been developed. In particular,
practical procedures that do not require the use of expen-
sive catalysts are important and have obvious advantages in
terms of cost.6d,8–12 For example, perfluorinated alkyl radi-
cals can be generated from perfluoroalkyl iodides by treat-
ment with sodium dithionate, and new C–C bond can be
formed through subsequent radical addition and substitu-
tion under mild conditions.8–10 Another more attractive ap-
proach is organocatalytic photoredox trifluoromethylation
and perfluoroalkylation. Since MacMillan and co-workers
introduced the concept of organophotoredox fluoroalkyla-
tion, which has been successfully applied in the organocat-
alytic -trifluoromethylation and -perfluoroalkylation of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
Z. Yang, A. Tang
Letter
Synlett
a) Liu's work:
R1
Table 1 Reaction Conditions Optimizationa
R2
R2
N
Pd(OAc)2/L
Yb(OTf)3
N
O
N
catalyst
base
O
N
O
R1
O
R3
n-C4F9I
+
TMSCF3, CsF
PHI(OAc)2
EtOAc, rt
R3
26 W lightbulb
solvent, N2
n-C4F9
3a
F3C
b) Sodeoka's work:
1a
2a
R2
R2
O
N
Entry
Catalyst
Base
Solvent
Temp
(°C)
Yieldb (%)
CuI
R1
N
O
O
R1
O
R3
+
CH2Cl2
I
R3
40–80 °C
1
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
eosin Y
K2CO3
DMF
DMF
DMF
60
65
70
65
65
65
65
65
65
65
65
65
65
65
65
65
65
42
51
49
61
44
36
31
5
CF3
F3C
O
2
K2CO3
K2CO3
c) Duan's work:
N
N
3
O
PdCl2/L
4
Cs2CO3
Na2CO3
NaOAc
NaHCO3
–
DMF
+
RFI
diglyme
100 °C
5
DMF
RF
6
DMF
d) This work:
7
DMF
R2
R2
photocatalysis
26 W lightbulb
N
O
8
DMF
N
R1
R1
O
+
RFI
R4
9
NaOH
DMF
45
75
85
43
0
Cs2CO3, DMA
R3
R4
R3
10
11
12
13
14
15
16c
17
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMA
DMA
DMSO
toluene
diglyme
MeOH
DMA
DMA
RF
Scheme 1 Synthesis of fluorine-containing oxindoles
eosin Y
placed with Cs2CO3 (entry 4). However, replacing K2CO3
with other bases (Na2CO3, NaOAc, NaHCO3, or NaOH) had a
negative effect on the yield; when no base was used, only a
5% yield was obtained (entries 5–9). The effect of various
solvent on the yield was also examined. When DMF was re-
placed with N,N-dimethylacetamide (DMA), the yield rose
to 75% (entry 10). Because organic dye photocatalysts have
been shown to be as effective as Ru(bpy)3Cl2·6H2O, we re-
placed this photocatalyst with eosin Y. As expected, this
had beneficial effect on the reaction, giving a yield of 85%
under the optimized conditions (entry 11). Changing the
solvent to toluene, diglyme, or MeOH afforded no product,
and the starting material remained intact (entries 13–15). A
control reaction showed that visible light was essential for
this transformation to proceed (entry 16). On the basis of
these results, the optimal reaction conditions for the reac-
tion were one equivalent of N-methyl-N-phenylmethacryl-
amide (1a) with three equivalents of F3CCF2sI and one
equivalent of Cs2CO3 in the presence of 5 mmol% eosin Y in
DMA with irradiation by a 26 W compact LED lightbulb at
65 °C for 16 hours.
eosin Y
eosin Y
0
eosin Y
0
eosin Y
0
–
0
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), base (0.3 mmol), cat-
alyst (5 mmol %), solvent (0.2 M in substrate), 65 °C, 16 h, 26 W compact
LED lightbulb.
b Isolated yield.
c No illumination.
worked well to deliver the desired products 3k–p in yields
of 67–83% (entries 11–16). However, none of the desired
product was obtained when an N-unprotected N-arylmeth-
acrylamide was used (entry 10). Replacement of n-C4F9I
with CF3I, n-C6F13I, or n-C8F17I afforded the corresponding
products in yields of 58–88%. In addition, 2-benzyl-N-
methyl-N-phenylacrylamide also reacted smoothly to deliv-
er the corresponding oxindole 3q in 66% yield (entry 17). It
is interesting to observe that the reactions of RFI with N-
arylacrylamides containing two methyl groups on the dou-
ble bond proceeded without any problem to generate the
anti-isomers of the products with high stereoselectivity
(dr > 20:1), albeit with a slightly inferior yields of less than
50% (entries 24–26). We tentatively assigned the major
product as the anti-isomer on the basis of the NOESY spec-
tra of 3x.
The scope and limitations of this reaction were next ex-
amined (Table 2). The reaction worked satisfactorily when
an electron-donating or electron-withdrawing substituent
was present in the ortho-or para-position of the aromatic
ring of the N-methyl-N-arylmethacrylamide, affording the
desired products 3a–i in yields of 61–85% (Table 2, entries
1–9). All substrates with N-protecting alkyl or aryl groups
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
Z. Yang, A. Tang
Letter
Synlett
Table 2 Photocatalyzed Perfluoroalkylation/Cyclization of Arylacryl-
Entry Arylacrylamide
RFI
Products
Yieldb
(%)
amidesa
R2
N
5% Eosin-Y
1 equiv Cs2CO3
26 W light bulb
R2
N
N
O
O
N
O
R1
R1
O
9
n-C4F9I
76
0
+
RFI
R4
R3
R4
R3
DMA, 65 °C, 16 h
n-C4F9
3i
RF
1
2
3
H
N
O
O
10
n-C4F9I
n-C4F9I
–
Entry Arylacrylamide
RFI
Products
Yieldb
(%)
N
N
O
N
O
O
N
1
n-C4F9I
85
75
11
71
n-C4F9
n-C4F9
3a
3k
N
N
O
N
O
2
n-C4F9I
N
O
O
12
n-C4F9I
80
83
n-C4F9
3b
n-C4F9
n-C4F9
n-C4F9
3l
Bu
N
CH2(CH2)2CH3
N
O
N
O
O
3
n-C4F9I
72
N
O
13
n-C4F9I
n-C4F9
3c
3m
Ph
N
Ph
N
N
O
N
O
O
4
n-C4F9I
n-C4F9I
n-C4F9I
n-C4F9I
65
77
82
61
O
F
14
15
16
n-C4F9I
n-C4F9I
CF3I
67
73
64
F
n-C4F9
3d
3n
N
N
O
N
O
O
N
5
6
7
O
Cl
Br
Cl
n-C4F9
3e
n-C4F9
3o
Bn
N
Bn
N
O
N
O
N
O
O
Br
n-C4F9
3f
F3C
3p
N
N
N
O
O
O
H3CO
Cl
N
O
17
18
CF3I
58
66
H3CO
n-C4F9
3g
F3C
3q
Cl
N
N
O
N
O
8
n-C4F9I
80
N
O
O
n-C4F9I
Bn
n-C4F9
Bn
3h
n-C4F9
3r
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
Z. Yang, A. Tang
Letter
Synlett
is likely to involved a radical process. To determine whether
the alkyl radical is formed directly from excited eosin Y or
whether it is the related radical anion formed by reaction
with the amide, DIPEA was treated with n-C4F9I under the
optimized condition.23 No perfluorobutylation of DIPEA
was detected, showing that the alkyl radical is probably
formed directly from excited eosin Y.
Entry Arylacrylamide
RFI
Products
Yieldb
(%)
N
N
O
N
O
19
n-C6F13
n-C6F13
n-C6F13
n-C8F17
n-C8F17
n-C4F9I
I
I
I
I
I
87
86
81
88
82
50
n-C6F13
3s
On the basis of reports in the literature,4f,20,23 we pro-
pose
a plausible mechanism for this transformation
O
(Scheme 2). Eosin Y acts as a photoredox catalyst and, after
its excitation with visible light, it transforms n-C4F9I (2a)
into a perfluoroalkyl radical through single-electron trans-
fer. Addition of this radical to the double bond of 1a leads to
the formation of a radical intermediate A which subse-
quently undergoes intramolecular cyclization to give radi-
cal intermediate B. Intermediate B provides an electron for
the reductive quenching of the eosin Y radical cation and is
oxidized in the process to give species C. Finally, C is trans-
formed into the desired perfluoralkylated oxindole 3a by
reaction with the base.
N
O
20
n-C6F13
3t
N
O
N
O
21
22
23
24
Cl
Cl
n-C6F13
3u
N
O
N
O
N
O
n-C8F17
N
O
3v
n-C4F9
N
1a
A
N
O
O
n-C4F9I
C4F9 + I
2a
n-C8F17
3w
SET
N
O
N
N
N
O
O
O
N
eosin Y*
eosin Y
O
n-C4F9
3x
n-C4F9
B
hv
N
eosin Y
O
25
26
n-C4F9I
47
40
N
O
N
n-C4F9
Cs2CO3
3y
HCO3
O
+
n-C4F9
n-C4F9
N
C
3a
O
n-C6F13
I
Scheme 2 Proposed mechanism
n-C6F13
3z
In summary, we have developed a transition-metal-free
method for the synthesis of perfluoroalkylated oxindoles
from N-arylacrylamides and RFI by using visible light as the
reaction initiator.24 Success of the reaction was critically de-
pendent on the use of the inexpensive organic dye eosin Y
as a photocatalyst. It is certain that this process shows con-
siderable advantages in terms of the simplicity of the reac-
tion procedure.
a Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), base (0.3 mmol), eosin
Y (5 mmol %), DMA (0.2 M in substrate), 65 °C, 16 h, 26 W compact LED
lightbulb.
b Isolated yield.
To probe the mechanism of this transformation, we per-
formed several control experiments under the optimized
conditions. None of the desired product was detected when
a stoichiometric amount of the radical scavenger TEMPO
was added to the reaction mixture, suggesting that reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
Z. Yang, A. Tang
Letter
Synlett
Funding Information
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Funding Information: Joint Funds of the Department of Science
of Guizhou Province for the Guizhou Institute of Technology,
(Grant/Award Number: QKH20167093)
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Acknowledgment
Yang would like to thank the Joint Funds of the Department of Sci-
ence of Guizhou Province for the Guizhou Institute of Technology for
financial support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611781.
S
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p
p
orti
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gInformati
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Primary Data
for this article are available online at https://doi.org/10.1055/s-0037-
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
Z. Yang, A. Tang
Letter
Synlett
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amide 1 (0.3 mmol), RFI 2 (0.9 mmol), Cs2CO3 (0.3 mmol), and
eosin Y (5% mmol). DMA (2 mL) was added and the tube was
purged with argon. The mixture was stirred and irradiated with
a 26 W compact LED lightbulb at 65 °C for 16 h until the reac-
tion was completed. H2O (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 (3 × 30 mL). The combined organic layers
were dried (Mg2SO4) and concentrated under vacuum. The
residue was purified performed by flash column chromatogra-
phy (silica gel).
1,3-Dimethyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-1,3-
dihydro-2H-indol-2-one (3a)
Isolated by flash column chromatography [silica gel, PE–EtOAc
(50:1)] as a yellow oil; yield: 100 mg (85%). IR (neat): 2979,
1719, 1619, 1470, 1126, 947 cm–1 1H NMR (400 MHz, CDCl3):
.
 = 1.44 (s, 3 H), 2.54–2.68 (m, 1 H), 2.83–2.95 (m, 1 H), 3.25 (s,
3 H), 6.89 (d, J = 8.0 Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 7.28 (d, J =
7.6 Hz, 1 H), 7.32 (t, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
 = 25.8, 26.4, 26.5, 36.9 (t, J = 20.1 Hz), 44.1 (d, J = 1.8 Hz),
108.4, 122.6, 123.1, 123.4, 123.5, 128.5, 128.8, 131.2, 142.8,
178.5.19F NMR (376 MHz, CDCl3):  = –125.64 to –125.42 (m,
2 F), –124.21 (d, J = 9.4 Hz, 2 F), –114.68 to –113.84 (m, 1 F),
–
108.96 to –108.16 (m, 1 F), –80.76 (t, J = 9.4 Hz, 3 F). HRMS
(ESI): m/z [M+] calcd for C15H12F9NO: 393.0775; found:
393.0778.
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2016, 18, 4928.
1,3,7-Trimethyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-1,3-
dihydro-2H-indol-2-one (3b)
Isolated by flash column chromatography [silica gel, PE–EtOAc
(50:1)] as a yellow oil; yield: 91 mg (75%). IR (neat): 2918, 1722,
1621, 1410, 1145, 670 cm–1. 1H NMR (400 MHz, CDCl3):  = 1.40
(s, 3 H), 2.60 (s, 3 H), 2.50–2.63 (m, 1 H), 2.82–2.95 (m, 1 H),
3.53 (s, 3 H), 6.97 (t, J = 7.6 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 7.10
(d, J = 6.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 19.1, 26.4,
29.9, 37.1 (t, J = 20.3 Hz), 44.5 (d, J = 1.9 Hz), 120.1, 121.3, 121.4
(2 C), 122.5, 131.9, 132.2 (2 C), 140.6, 179.3. 19F NMR (376 MHz,
CDCl3):  = –125.71 to –125.50 (m, 2 F), –124.27 (d, J = 9.8 Hz,
2 F), –114.03 to –113.94 (m, 1 F), –109.01 to –108.24 (m, 1 F),
–80.86 to –80.79 (m, 3 F). HRMS (ESI): m/z [M+] calcd for
(23) Srivastavaa, V.; Singh, P. P. RSC Adv. 2017, 7, 31377.
(24) (a) Organocatalyzed
tion/Cyclization of
Photoredox
N-Arylacrylamides
Perfluoroalkyla-
Perfluoroalkyl
Iodides; General Procedure
A 25 mL tube was charged with the appropriate N-arylacryl-
C16H14F9NO: 407.0932; found: 407.0931.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F