Synthesis of oxindoles through trifluoromethylation of: N -aryl acrylamides by photoredox catalysis

Article abstract of DOI:10.1039/c8ob01922c

Mild and direct intramolecular oxidative aryltrifluoromethylations of activated alkenes have been established through visible light photocatalysis, affording a range of CF₃-containing oxindoles or isoquinolinediones in the presence of an organic fluorophore-type photocatalyst 4CzIPN, oxygen and visible light irradiation under strong oxidant and transition metal free conditions. A variety of frequently encountered functional groups are well tolerated in this transformation.

Full text of DOI:10.1039/c8ob01922c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C8OB01922C
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Synthesis of oxindoles through trifluoromethylation of N-aryl
acrylamides by photoredox catalysis†
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
a
Maojian Lu, Zhiji Liu, Jinwang Zhang, Yu Tian, Honggui Qin, Mingqiang Huang,
a
a,b
Shirong Hu and Shunyou Cai*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Mild and direct intramolecular oxidative aryltrifluoromethylations the fact that it is easy to handle. A pioneering work by Baran
of activated alkenes have been established through visible light and cowrokers disclosed an inspirational trifluoromethylation
photocatalysis, affording a range of CF
isoquinolinediones in the presence of an organic fluorophores- reagent. Subsequently, this work has inspired several other
type photocatalyst 4CzIPN, oxygen and visible light irradiation studies aimed at using CF SO Na as the trifluoromethyl radical
under the strong oxidant and transition metal free conditions. A source to construct a variety of bioactive molecules.
3
-containing oxindoles or of medicinally relevant heterocycles by using Langlois
5
a
3
2
variety of frequently encountered functional groups are well
tolerated in this transformation.
Previous work
R3
R3
a) tBuOOH/Cu(NO
b) K (S
)/80 oC or (NH
c) Hypervalent iodines, high temperature
3 2
)
R1
O
S
CF
3
R1
+
F3
C
ONa
2
2
O
8
4 2 2 8 3
) S O /AgNO
N
R2
O
O
N
2
R
Introduction
Our work
Cz
Cz
R3
Because of the unique biological properties of CF
3
-containing
R
3
organic
photocatalyst
NC
Cz
CN
Cz
O
R1
R1
CF
3
1
+
F3
C
S
ONa
molecules, such as metabolic stability, lipophilicity, elevated
electronegativity, and bioavailability, and great synthetic
efforts have been considered to develop new, mild, and
efficient methodologies enabling their preparations, and such
blue LEDs
N
R2
O
O
N
strong oxidant and
transition metal free!
2
Cz = carbazol-9-yl
Photocatalyst
R
3
Scheme 1. Various approaches to CF -containing oxindole
2
,3
activities have been frequently reported and reviewed.
Recently, significant achievements in disclosing synthetic formation
reactions regularly rely on free-radical-promoted, as well as
The strategy has been successfully utilized to yield a range
of trifluoromethylated oxindoles through oxidative
trifluoromethylation of activated alkenes with Langlois
transition-metal-catalyzed trifluoromethylation. Among the
established radical systems, a variety of reagents involving
Ruppert-Prakash reagent (TMSCF
trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole
and 1-trifluoro-methyl-1,2-benziodoxol-3-(1H)-one),
Umemoto’s reagent [S-(trifluoromethyl)dibenzothiophenium
tetrafluoroborate], CF X (X = Br, I), or CF SO Cl, have been
3
), Togni’s reagent (1-
5
reagent. In 2013, Lipshutz and Liang reported an efficient method
for diverse CF -containing oxindoles syntheses via Cu(NO ) /TBHP-
3
3 2
catalyzed trifluoromethylation of N-arylacrylamides and CF SO Na
3
2
5b
(
Scheme 1a). Subsequently, a metal-free approach for direct
3
3
2
oxidative carbotrifluoromethylation of activated alkenes was
employed as trifluoromethyl radical sources. In contrast to
these reagents, it is more appealing to take advantage of
developed by Wang et al. to CF -containing oxindoles by emplying
3
K S O as the oxidant and CF SO Na as the CF source (Scheme
2
2
5c
8
3
2
3
sodium trifluoromethanesulfinate (CF
3
SO
2
Na, Langlois
1
b). Organic hypervalent iodines were demonstrated to be
4
reagent) due to its stable and inexpensive characteristics and
5d-5f
effective in similar scenarios (Scheme 1c).
However, transition-
metal catalysts and strong oxidants were still involved in these
established protocols. Therefore, it remains a strong need for
uncovering new and efficient approaches to construction of CF3-
containing oxindoles with less employment of oxidants and
transition metal catalysts under milder reaction conditions.
a
Key Laboratory of Modern Analytical Science and Separation Technology of Fujian
Province, School of Chemistry, Chemical Engineering and Environment, Minnan
Normal University, Zhangzhou, 363000, China. E-mail: caishy05@mnnu.edu.cn
Key Laboratory of Chemical Genomics, School of Chemical Biology and
b
Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055
China.
†
Stimulated by an ongoing research program focusing on the
6
-9
Electronic Supplementary Information (ESI) available: [details of any discovery and design of visible-light-enabled catalysis
supplementary information available should be included here]. See
processes for generation of bioactive molecules in a safe and
practical manner from stable and inexpensive substrates, we
DOI: 10.1039/x0xx00000x
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reported herein that, through careful optimizations of reaction degassed the reaction mixture by purging thoroughly with
conditions, a direct carbotrifluoromethylation was disclosed nitrogen (with 0.5 mol% of oxygen) for 10 minutes and found
on a variety of N-arylacrylamides, providing an approach for that 3a could be isolated in a good yield (72% yield, entry 8).
convenient preparations of highly functionalized CF
3
-
Furthermore, a series of solvents (DCM, ACN, DMSO, and
containing oxindoles utilizing CF SO Na as the trifluoromethyl chlorobenzene) were screened (entries 9-12) next under
3
2
source (Scheme 1). Compared with previous established otherwise identical reaction conditions, but all led to either a
methodologies, this protocol refrains from employing strong lower product yield or complete inhibition in reactivities.
oxidants, transition-metal catalysts, and unstable and Fortunately, a respectable 83% yield of 3a was observed by
3 2
expensive substrates and operates efficiently at room increasing the loading of CF SO Na up to 2.0 equiv (entry 13).
temperature.
It was found that the photocatalysts significantly affect the
efficiency of the reaction, since attempts using
Results and discussion
Ir(ppy)
2
(dtbpy)PF (Ir-cat. 1), Ir[dF(CF
6
3 2 6
)ppy] (dtbpy)PF (Ir-cat.
2
), or Ru(bpy)
3
Cl as an alternative photocatalyst only resulted
2
Table 1. Screenings of the optimal reaction conditions
in critical reductions or complete inhibitions in reactivities
(entries 14-16).
Me
Me
Me
Me
photocatalyst
additive, solvent, rt, N2
O
S
CF3
+
F3C
ONa
N
O
O
blue LEDs, 8-12 h
c = 0.02 M
N
1a
Me
2 (x equiv)
3a
Me
PC (x mol%)h
yield (%)g
entry 2a (equiv)
additive (equiv)
solvent
DCE
1a
2a
3b
4b
5b
6b
7b
8b,c
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
eosin Y (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
4CzIPN (2)
/
trace
18
/
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
ACN
DMSO
/
47
NaOAc (1.0)
HOAc (1.0)
decomp
21
H O (1.0)
2
62
MeOH (1.0)
33
H O (1.0)
2
72
9b,c
H O (1.0)
34
2
2
1
1
1
1
1
1
1
0b,c
1b,c
2b,c
H O (1.0)
26
H O (1.0)
2
decomp
H2O (1.0)
C6H5Cl
DCE
47
3b,c
4b,c,d
5b,c,e
6b,c
2.0
2.0
2.0
2.0
4CzIPN (2)
[Ir-cat. 1] (2)
[Ir-cat. 2] (2)
H O (1.0)
83
2
H2O (1.0)
DCE
64
H2O (1.0)
DCE
71
[Ru(bpy) Cl ] (2) H O (1.0)
3
2
2
DCE
trace
aIrradiation with white LEDs. bIrradiation with blue LEDs. cReaction mixture was
purged thoroughly with nitrogen for 10 mins. d[Ir-cat. 1] = Ir(ppy)2(dtbpy)PF6. e[Ir-cat.
2
1
] = Ir[dF(CF3)ppy]2(dtbpy)]PF6. fNo light. gYield of isolated product. h4CzIPN =
,2,3,5-tetra-kis(carbazol-9-yl)-4,6-dicyanobenzene.
3 2
N-methyl-N-(p-tolyl)-methacrylamide 1a and CF SO Na were
1
utilized as model substrates in our preliminary experiments to Scheme 2. Reactivity screenings on substituent R
optimize the reaction conditions (Table 1). No desired product
was observed when the reaction was conducted in 1,2-
dichloroethane (DCE) with organic-dye type eosin Y (2 mol%)
as the photocatalyst in presence of a ballooned N
2
atmosphere
with 0.5 mol % of oxygen) under white light emitting diode
LED) irradiation (entry 1, Table 1). When 1,2,3,5-
(
(
1
0
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN)
was
employed in place of eosin Y under otherwise identical
reaction conditions, the desired CF -containing oxindole 3a
3
was produced in 18% yield (entry 2). The reaction mixture was
subsequently subjected to blue LEDs irradiation, a dramatic
improvement in the yield of 3a was recorded (47%, entry 3).
When a basic NaOAc (entry 4), or protic acid HOAc (entry 5)
was used as the additive, the reaction was discovered to be
completely futile. We were pleased to find the yield of 3a was
increased to 62% when 1.0 equiv of water was purposefully
introduced into the reaction mixture (entry 6). As
a
2
comparison, methanol was demonstrated to be less effective Scheme 3. Reactivity screenings on substituents R and R
3
(
33%, entry 7). So we believed that the promoting effect of
water additive possibly originated from its ability in increasing
the solubility of CF SO Na. Subsequently, we carefully
With the optimal reaction conditions identified, the
substrate scope was probed, and the results were illustrated in
Scheme 2. A variety of N-arylacrylamides could undergo
3
2
2
| J. Name., 2012, 00, 1-3
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smoothly to produce the corresponding products CF
containing oxindoles in moderate-to-excellent isolated yields to complete inhibition of the reactivity under otherwise
41-91% yield). The substrates 1a-1c with electron-donating standard reaction conditions, indicating that 0.5 mol% oxygen
3
-
(with 0.5 mol% of oxygen) to high purity argon (> 99.999%) led
3
(
groups at the para-position on the aromatic ring were readily in nitrogen should function as the practical oxidant. The widely
implementable. Notably, the substrates bearing halogen atoms, used radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
such as Br, Cl, and F as well as CF
3
on the N-aryl moiety could
3i
proceed unambiguously to furnish the desired products 3d
-
in various isolated yield (52-91% yield), thereby providing
significant freedom for further structural manipulations. A
series of the frequently encountered election-withdrawing
groups, such as the carbonyl (3j-3l), sulfonyl (3m), cyano (3n),
and nitro (3o and 3p) group, were shown to be well-tolerated
in the reactions in terms of isolated yield (41-85%).
To further expand the substrate scope of this methodology,
3
2
series of N-arylacrylamides 4 carrying different R /R
a
substituents were next subjected to the optimal reaction
conditions. As summarized in Scheme 3, the substrates bearing
aryl (4a), acyl (4b), and alkyl (4c
-
4e) substituents at the N atom
R ) provided the corresponding oxindoles 5a-e in moderate-
to-good isolated yields (38-89%). α-substituted olefins with
various substituents, e.g., n-butyl 4f), benzyl 4g), and
2
(
Scheme 5. Control experiments
TEMPO) was purposefully added into the reaction mixture,
(
(
(
complete inhibition in reactivity was observed. Thus, a radical
pathway should be involved in this addition/cyclization process.
)
ethyoxyl (4h), were also demonstrated to be compatible with
3
this catalytic system; when R is a aryl group, such as phenyl (5i
The less sterically hindered substrates 8-10 were exposed to
or p-Cl-phenyl (5j), the reactions only gave the radical
conjugate addition adducts. Furthermore, the heterocyclic
substrate was found to be successful in this
trifluoromethylation/arylation process and delivered 5k in 68%
yield. Notably, tricyclic oxindoles 5l could be smoothly
assembled in 83% yield.
the optimal reaction conditions, but all resulted in complicated
mixtures. These results collectively demonstrated that the
conformational effects had definitely
a rather sensitive
influence on the reactivity. Finally, continuous stimulation of
visible light was required to achieve a comparable yield in the
experiment of on-off switching of the light source. The
Me
CF3
O
O
O
4
CzIPN (2 mol%)
quantum yield in the reaction of 1a with 2 was determined to
O
S
N2 (with 0.5 mol% of O2)
R1
N
R1
+
F3C
ONa
N
be 3.33, suggesting that a short chain processes should be
12
involved in this transformation.
Me Me
rt, c = 0.02 M, DCE
Me
6
2 (3.0 equiv)
blue LEDs
7
O
Me
CF3
O
Me
CF3
O
Me
CF3
O
Me
CF3
O
Me
MeO
F
N
N
N
N
Me
Me
Me
Me
O
O
O
O
7
a: 71%
7b: 83%
7c: 85%
7d: 78%
Scheme 4. Trifluoromethylated isoquinolinediones 7 syntheses
Finally, this new visible-light-promoted photoredox catalytic
trifluoromethylation/arylation technology was also confirmed
to be efficient in the synthesis of trifluoromethylated
isoquinolinediones 7, which are present in naturally occurring
1
1
products as well as agrochemicals and pharmaceuticals. As Scheme 6. Proposed mechanistic network
shown in Scheme 4, substrates carrying methyl (6b), methoxyl
4,5,8
These observations, as well as previous literature
(
6c), and fluoro (6d) groups at the para-position of the aryl ring
reports,
collectively point to
a
plausible reaction
were well tolerant and efficiently transformed into the
mechanism depicted in Scheme 6. In the presence of visible
light irradiation, the excited state species 4CzIPN would
corresponding trifluoromethylated isoquinolinediones
excellent yields.
7 in
capture an electron from CF
relatively stable trifluoromethyl radical along with the release
of SO . Subsequently, the radical anion 4CzIPN could be
oxidized by the oxygen to return to its ground state, thereby
accomplishing crucial step. On the other hand, the
trifluoromethyl radical would add to alkene to yield the
significant radical intermidate A/B. Finally, radical cyclization
would take place, followed by sequential oxidation-
3 2
SO Na, thus converting it into a
To get further insights into the potential reaction
mechanism, a series of control experiments were conducted
2
(see the Supporting Information), and some results were
exemplified in Scheme 5. Reactions carried out under the
absence of either visible light irradiation or a photocatalyst
confirmed explicitly that the reproducible generation of 3a
needs both. Notably, a switch of the industrial-grade nitrogen
a
1
a
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deprotonation process, to lead to final CF
3
-containing oxindole
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Hu, Chem. Rev., 2015, 115, 765; (g) H. Guyon, H. Chachignon
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Conclusions
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3
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We are pleased to disclose herein that a range of CF3-
containing oxindoles bearing numerous useful functionalities
could be conveniently prepared with the use of Langlois
reagent CF SO Na as the trifluoromethyl source by means of
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3
2
visible-light photoredox catalysis under considerably mild
reaction conditions. It is worth noting that, compared with
previous reports, strong oxidants as well as transition-metal
catalysts are not necessary in our established method, which
will dramatically add its practicality. Further investigations on
the applications of this novel visible-light-mediated
trifluoromethylation technology for the preparation of other
trifluoromethylated complex molecules are currently
underway in our laboratory.
2
2
016, 138, 15547; (h) N. Noto, T. Koike, M. Akita, Chem. Sci.,
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(
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A flame-dried flask (15 mL) was equipped with magnetic stir
bar and charged with N-aryl-acrylamides
equiv), CF SO Na (0.29 mmol, 2.0 equiv), 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) (0.00290
mmol, 0.02 equiv), H O (0.145 mmol, 1.0 equiv) and DCE (8.0
1 (0.145 mmol, 1.0
3
2
2
D.-H. Guo, X.-Y. Liu and Y.-M. Liang, Chem. – Eur. J., 2015, 21
468.
,
2
1
mL). The reaction mixture was degassed by purging thoroughly
with nitrogen (with 0.5 mol % of oxygen) for 10 minutes, then
irradiated by blue LEDs (18 W) under a balloon nitrogen
atmosphere (with 0.5 mol % of oxygen) at room temperature
until the starting material disappeared from the TLC. After that
the reaction mixture was directly concentrated under reduced
pressure and the crude product was purified by silica gel
column chromatography using hexane/EtOAc to afford the
5
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desired pure product
.
Acknowledgements
6
7
For selected reviews on photo-redox catalysis, see: (a) N.
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The work is supported by the National Natural Science
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Journal Name
Graphical Abstract
A photocatalytic trifluoromethylation of activated alkenes
have been established to access CF3-containing oxindoles
under the strong oxidant and transition metal free
conditions.
6
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB01922C
Graphical Abstract
R3
O
O
R1
CF3
N
R1
O
N
Me Me
O
S
O
S
R2
F3C
ONa
F3C
ONa
Me
CF3
O
R3
R1
R1
N
O
N
Me
R2
O
strong-oxidant-free
transition-metal-free
good functional group tolerance
readily available starting materials
A photocatalytic trifluoromethylation of activated alkenes have been established
to access CF -containing oxindoles under the strong oxidant and transition metal
free conditions.
3