Visible-light photoredox intramolecular difluoroacetamidation: Facile synthesis of 3,3-difluoro-2-oxindoles from bromodifluoroacetamides

Article abstract of DOI:10.1039/c5ob02121a

We report an operationally simple, visible-light-driven protocol for intramolecular C-H difluoroacetamidation of arenes for the synthesis of biologically relevant 3,3-difluoro-2-oxindoles at room temperature. Using fac-Ir(ppy)₃ as a photocatalyst and a 3 W blue LED as a light source, an array of difluoroxindoles was prepared from rapidly available tertiary aryl bromodifluoroacetamides in moderate to excellent yields.

Full text of DOI:10.1039/c5ob02121a

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DOI: 10.1039/C5OB02121A
Journal Name
RSCPublishing
COMMUNICATION
VisibleꢀLight Photoredox Intramolecular
Difluoroacetamidation: Facile Synthesis of 3,3ꢀ
Difluoroꢀ2ꢀOxindoles from Bromodifluoroacetamides
Cite this: DOI: 10.1039/x0xx00000x
XiaoꢀJing Wei, a Lin Wang,a ShaoꢀFu Du, a LiꢀZhu Wub and Qiang Liua*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report an operationally simple, visibleꢀlightꢀdriven for the introduction of the gem-difluoromethylene group (CF2) into
protocol for intramolecular C−H difluoroacetamidation of organic compounds that have been well developed are consider as
arenes for the synthesis of biological relevant 3, 3ꢀdifluoroꢀ2ꢀ useful synthesis strategy for modification of biologically active
oxindoles at room temperature. Using facꢀIr(ppy)3 as a compounds.4
photocatalyst and a 3W blue LED as a light source, an array
of difluoroxindoles were prepared from rapidly available
Derivatives of oxindoles are an extremely important class of
compounds due to their frequent appearance in a variety of naturally
tertiary aryl bromodifluoroacetamides in moderate to
occurring compounds and their wide range of biological activities.
excellent yields.
Such as these kinds of compounds have been shown to display
Fluorine-containing organic molecules can be extensively found in a antimicrobial, antiviral, anticancer, and antiinflammatory activities.5
number of biologically active natural products, pharmaceutically The 3, 3-difluoro-2-oxindole ring system are of significant biological
relevant candidates, agrochemical reagents, and functional importance as bioisoteric analogues for biological studies in
materials.1 It is an important and general strategy to introduce development of potential medicinal agents. Up to now, numerous
fluorine and fluorinated substitutes in the small molecule for natural compounds containing the 3, 3-difluoro-2-oxindoles ring
structure-based drug development and pharmaceutical research. The moieties revealed potential utilities in biomedical studies.6 Thus,
fluorinated functional groups change their physiochemical properties search for efficiently synthetic methodologies to prepare these
significantly due to the enhanced chemical, physical, and metabolic substrates are very meaningful for the detailed studies of their
stability of the fluorinated moiety. 2 Accordingly, there has been great therapeutic application. 7 Generally, these types of difluoroxindoles
interest and substantial effort in the synthesis of fluorine-containing could be obtained via nucleophilic fluorination of the corresponding
small molecules.3 Especially, various synthetic methods
isatin derivatives with diethylaminosulfur trifluoride (DAST) or
Deoxofluor,8a-8c or by electrophilic fluorination of indoles with
Selectfluor or NFSI.8d It is also possible to access difluoroxindoles via
Cu-mediated intramolecular cyclization of iododifluoroacetamides in
moderate yield.9a Very recently, Buchwald et al. used Pa-catalyzed C-
H difluoroalkylation and BrettPhos as crucial ligand to construct
difluoroxindoles derivatives.9b These valuable protocols have proven
to be efficient for the preparation this kind of compounds. However,
instability of the requisite reagents and bad to modest functional-
group tolerance, expensive fluorination reagents, the production of a
large excess of wastes from reaction systems, the synthesis difficulty
of the required starting materials, as well as the requirement for
rather high reaction temperature et al. remain impediments of these
approaches. Therefore the development of more efficient and
practical strategies in these areas is still highly desirable.
Fig. 1. Examples of biologically significant molecules containing 3, 3-difluoro-2-
oxindoles.
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DOI: 10.1039/C5OB02121A
Table 1. Optimization of reaction conditions
a) Previous work
NFSI, TBHP, K2HPO4
PhMe/MeCN (4:1), 70-120
F
F
℃
R1
R1
O
then Et3N,100
℃
N
N
R
R
F
F
O
(MeOCH2CH2)2NSF3
R1
O
R1
O
CH2Cl2, r.t.1-3 days
N
N
Entrya Solvent
Photocatalyst
Base
Yield(%)b
R
R
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
Ru(bpy)3Cl2·6H2O
Ru(phen)3Cl2
Re[phen(CO)3]NCS
TBAꢀeosinY
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
fac- Ir(ppy)3
fac ꢀIr(ppy)3
fac ꢀIr(ppy)3
--
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2HPO4
NaHCO3
K2CO3
58
62
Trace
Trace
91
Trace
72
41
F
R1
N
F
Cu powder
O
R1
O
DMSO,
R1
65 ℃
N
R
CF2I
30-60 % yield
F
2 mol% [Pd2dba3]
8 mol% BrettPhos
1.5 equiv K2CO3
R1
N
F
O
R1
O
R1
59
N
CF2Cl
CPME,
120
℃, 20 h
10
11c
12d
K2HPO4
K2HPO4
K2HPO4
93
R
N.D.e
N.D.
b) Our Strategy
fac ꢀIr(ppy)3
F
R1
N
F
visible light
a Reaction conditions: a mixture of 1a (0.20 mmol), base (0.24 mmol, 1.2
O
R1
O
equiv), and photocatalyst (0.5 mol %) in solvent was irradiated with a 3 W
blue LEDs at room temperature for 24 h b Isolated yield. Irradiated without
R1
room temperature
CF2Br
N
R
c
d
e
facꢀIr(ppy)3. The reaction was conducted in dark. N.D. = not detected.
DMF = N, Nꢀ dimethylformamide
Scheme 1. Different protocols for the syntheses of 3, 3ꢀdifluoroꢀ2ꢀoxindoles.
the aimed product 2a was obtained in 58% yield after 24 hours'
For the past few years, photocatalysis reactions, especially the use
of visible light as a nearly non-polluting energy source to enable
sustainable organic synthesis have attracted great interest.10 Visible-
light photocatalysis reactions avoided the disadvantage of high-
energy ultraviolet radiation, and as the high transparency of most
organic compounds in visible-light region, it is helpful to minimize side
reactions which is often associated with the employment of UV light.
Photoredox catalysis with transitional metal complexes has emerged
as a powerful tool for redox reactions due to its ability to cause
efficient photo-induced electron transfer processes under mild
conditions. For instance, fac-Ir(ppy)3, an Ir polypyridine complexe with
high reducibility in the excited state has been well demonstrated by
some valuable work that generated carbon-centered radicals from
organohalides.11 During the course of our investigations on the
applications of photoredox catalysis in organic synthesis,11h,12 we
found a promising approach for synthesizing an array of substituted
difluoroacetamidated arenes via intermolecular radical addition to
arenes.12a We speculated that this strategy might also be effective for
providing intramolecular aminocarbonyldifluoromethyl radical
addition to arenes to afford biologically relevant 3,3-difluoro-2-
oxindoles.13
irradiation (blue LEDs,
λ = 450 nm) at room temperature when the
reaction was performed in N,N-dimethylformamide (DMF) with
Ru(bpy)3Cl2·6H2O as photocatalyst and Na2CO3 as base (Table 1, entry
1). Several photocatalysts were applied to this reaction to replace
Ru(bpy)3Cl2·6H2O (Table 1, entries 2-5). It was found that when
Ru(phen)3Cl2 was applied in this reaction conditions, the reaction
yields rose to 62% (Table 1, entry 2), but when Re[phen(CO)3]NCS or
organic photocatalyst TBA-eosinY was tested in the reaction (Table 1,
entries 2-3), just trace amount of desired product was found. When
fac-Ir(ppy)3 was used in the reaction, the yields rose to 91%
dramatically. Therefore we choose fac-Ir(ppy)3 as the ideal
photocatalyst. Other different bases including Na2HPO4, NaHCO3,
K2CO3, K2HPO4 were then tested (Table 1, entries 6-10), and the best
result was achieved when K2HPO4 was introduced to the system. In
this case we obtained the desired product 2a in 93% isolated yield. In
addition, when the reaction was carried out in the absecne of fac
-
Ir(ppy)3 or in the dark (Table 1, entry 11 and 12), no conversion could
be observed, which indicated that the reaction was indeed a visible-
light-driven photoredox process.
With the optimized condition in hand, we examined the substrate
scope of this visible-light-driven synthesis of 3,3-difluoro-2-oxindoles. A
Herein, We started our investigation by exploring the reaction of 2-
broad array of substituted 2-bromo-2,2-difluoro-N-phenylacetamides
bromo-2,2-difluoro-
N
-methyl-
N
-phenylacetamide
(1a) in various
can efficiently convert to the corresponding 3,3-difluoro-2-oxindoles
derivatives in moderate to excellent yields (Table 2, entries 1-14). When
the electron-withdrawing groups such as fluoro, ethoxycarbonyl and
methoxycarbonyl which located at para positions of the
photochemical conditions toward the synthesis of 3,3-difluoro-2-
oxindoles. It was encouraging to see that
phenylacetamide, the aimed product 2b, 2c, 2d can be produced
Table2 Scope survey of visible-light catalyzed synthesis of 3,3-difluoro-2-oxindoles.a,b
2 | J. Name., 2012, 00, 1-3
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Entry
Substrate
Product
Yield (%) c
Entry
Substrate
Product
Yield (%) c
1
93
2
97
1a
1b
2b
2a
2c
2e
3
5
93
4
90
69
1d
1f
1c
1e
2d
76
40
6
8
2f
7
57
1g
2h
2j
2g
2i
1h
1j
10
12
79
88
9
92
80
1i
11
1k
1l
2k
2l
85
14
13
90
1m
1n
2m
2n
a
Reaction conditions: a mixture of 1a (0.20 mmol, 1.0 equiv), K2HPO4 (0.24 mmol, 1.2 equiv) and photocatalyst facꢀIr(ppy)3 (0.5 mol %) in DMF (3 mL)
was irradiated with a 3 W blue LEDs at room temperature for 24 h b Yield of isolated product.
smoothly in excellent yields (Table 2, entries 2-4). Moreover, this kind of cases (Table 2, entry 7). In general, arenes bearing electron-withdrawing
reaction was successfully applied to the 2-bromo-2,2-difluoro-
N-
substituents afforded higher yields than those with electron-donating
phenylacetamides with electron-donating groups at the arenes (Table groups. The lower transformation of 2-bromo-2,2-difluoro-
N-
2, entries 5 and 6). The substrate with di-substituted aniline 1g was also phenylacetamides with electron-donating groups may be attributed to
compatible with this new visible-light-driven cyclization approach, the inefficient electron transfer between the excited photocatalyst and
although the reaction proceeded less efficiently than mono-substituted the substrates.
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DOI: 10.1039/C5OB02121A
Next, we examined 2-bromo-2,2-difluoroacetamides with different
amine moieties instead of -methylaniline. The reactions of 2-bromo-
2,2-difluoro- -methyl- -(naphthalen-2-yl)acetamide (1h) generated 2h
F
F
O
N
-Ir(ppy) (0.5 mol%), K HPO (1.2 eq.)
fac
3
2
4
Br
O
N
N
N
DMF (2 mL),
ν = 450 nm
h
N
F
F
as the only product (Table 2, entry 8). When tetrahydrobenzoazepine (1i
and tetrahydroquinoline (1j) were employed as the amine moiety of the
substrate, tricyclic products 2i and 2j were formed in 79% and 92%
yields, respectively (Table 2, entries 9 and 10). In addition, 2-bromo-2,2-
)
1a
2a
hv
-*[IrIII(ppy) ]
fac
-[IrIII(ppy) ]
fac
3
3
Photoredox
Catalysis
SET
- Br-
SET
difluoro-
N
-phenyl-acetamides possessing
N
-protecting groups such as
phenyl(1k
)
, cyclohexyl(1l), 2-cyanoethyl
(
1m) and 2-hydroxyethyl (1n)
F
-[IrIV(ppy) ]
F
also resulted in satisfactory yields, highlighting the potential of the
method in organic synthesis.
O
fac
3
F
O
N
F
F
H
N
F
3
O
0.5 mol % fac-Ir(ppy)3
K2HPO4 (1.2 eq.)
5
O
N
N
O
O
Br
Me
Me
Me
Me
N
N
O
+
+
4
3 W 450 nm LEDs
DMF (2 mL), r.t.
N
F
F
F
F
2.0 equiv
[M+H]+ 341.2036
Scheme 4. Proposed Mechanism Cycle.
0.5 mol % fac-Ir(ppy)3
K2HPO4 (1.2 eq.)
O
expensive fluorination reagent, complex ligand and high temperature.
Moreover, this method is also an efficient method for the C-H
difluoroalkylation with readily available starting materials.
We thank the financial support from NSFC (No. 21172102), the
Ministry of Science and Technology of China (973 Program,
2013CB834804), and the Fundamental Research Funds for the Central
Universities (lzujbky-2013-47).
Br
N
O
3 W 450 nm LEDs
DMF (2 mL), r.t.
F
F
O
OH
N
[M+H]+ 404.2391
2.0 equiv
F
F
Scheme 3. Mechanism investigation
In order to understand the reaction mechanism and to verify the
generation of the 2,2-difluoro- -methyl- -phenylacetamide radical
the initial step of the reaction, the radical inhibitors such as BHT and
N
N
3 at Notes and references
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou
TEMPO were introduced into the photochemical system, and no 3,3- University, 222 South Tianshui Road, Lanzhou 730000, P. R. China.
difluoro-2-oxindole 2a was detected in both cases. To our delight, the Email: liuqiang@lzu.edu.cn
b
adduct of 2,2-difluoro-
N-methyl-
N
-phenylacetamide radical
3
with the
Key Laboratory of Photochemical Conversion and Optoelectronic
radical inhibitors were detected by ESI-HRMS, thus providing Materials, Technical Institute of Physics and Chemistry, University of
straightforward evidence of the formation of the radical (Scheme 3). Chinese Academy of Sciences, Haidian District, Beijing, 100190, P. R.
3
Based on the radical trapped experimental results and our previous China.
work in this field,12 we proposed a possible mechanism. Visible-light † Electronic Supplementary Information (ESI) available: Experimental
irradiation of the photoredox catalyst fac-IrIII(ppy)3 produced the excited procedures, characterization data, and copies of NMR spectra. See
3
[
fac-IrIII(ppy)3]*,
which
can
reduce
2-bromo-2,2- DOI: 10.1039/c000000x/
difluorophenylacetamide 1a by single electron transfer (SET). The SET
procedure generates electron-deficient radical
along with fac-IrIV(ppy)3.
Then intramolecular π-addition of the radical produces
cyclohexadiene radical . The α-proton of radical
is highly acidic14
1
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3
a
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photocatalysis for the first time. The highlight of this photo-reaction is
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DOI: 10.1039/C5OB02121A
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