Synthesis of C3-Fluorinated Oxindoles through Reagent-Free Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1002/anie.201701329

Reported herein is an unprecedented synthesis of C3-fluorinated oxindoles through cross-dehydrogenative coupling of C(sp³)-H and C(sp²)-H bonds from malonate amides. Under the unique and mild electrochemical conditions, the requisite oxidant and base are generated in a continuous fashion, allowing the formation of the base- and heat-sensitive 3-fluorooxindoles in high efficiency with broad substrate scope. The synthetic usefulness of the electrochemical method is further highlighted by its easy scalability and the diverse transformations of the electrolysis product.

Full text of DOI:10.1002/anie.201701329

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701329
German Edition: DOI: 10.1002/ange.201701329
Cross-Coupling Very Important Paper
Synthesis of C3-Fluorinated Oxindoles Through Reagent-Free Cross-
Dehydrogenative Coupling
Zheng-Jian Wu and Hai-Chao Xu*
Abstract: Reported herein is an unprecedented synthesis of
C3-fluorinated oxindoles through cross-dehydrogenative cou-
pling of C(sp3)-H and C(sp2)-H bonds from malonate amides.
Under the unique and mild electrochemical conditions, the
requisite oxidant and base are generated in a continuous
fashion, allowing the formation of the base- and heat-sensitive
3-fluorooxindoles in high efficiency with broad substrate
scope. The synthetic usefulness of the electrochemical method
is further highlighted by its easy scalability and the diverse
transformations of the electrolysis product.
O
rganofluorine compounds have attracted broad interest
from chemists due to their wide application in pharmaceutical
and agrochemical industries.[1] Although trifluoromethyl- and
difluoroalkyl-bearing compounds can be prepared via radical
fluoroalkylation with relatively satisfactory efficiency, the
lack of convenient precursors and initiating systems for the
generation of monofluoroalkyl radicals has limited their
utility in the synthetic applications.[2] The few isolated
examples on formation of monofluoroalkyl radicals generally
rely on activation of a C-heteroatom bond.[3] Nonetheless,
Wang and Ji[4] have recently reported the oxidative radical
reactions of 2-fluoro-1,3-dicarbonyl compounds, although
a high temperature and an excess of MnIII salt[5] are needed
(Scheme 1a).
Scheme 1. Oxidative formation and reaction of monofluoroalkyl radi-
cals.
reported.[10] Aerobic oxidation using copper catalysis at
temperatures of above 1008C was also found to promote
similar reactions.[11] Despite these progresses, it is still highly
desirable and yet challenging to develop mild catalytic
conditions for the synthesis of 3,3-disubstituted oxindoles
À
through cross-coupling of C H bonds, especially in a reagent-
free fashion. We[12] have developed electrosynthesis of several
classes of heterocycles through radical-mediated cross-cou-
[13]
À
À
pling of C H and N H bonds. Herein we report a new
On the other hand, the promising therapeutic potentials of
3-fluorooxindoles have stimulated synthetic efforts toward
their preparation,[6] which are achieved through derivatiza-
tion of existing oxindoles,[7a–c] Pd-catalyzed cross-coupling
using arylbromide,[7d] or fluoroarylation of diazoacetamid-
es.[7e] Although these methods provide very useful access to 3-
fluorooxindoles, they require functionalized or even hazard-
ous precursors. The groups of Kꢀndig[8a] and Taylor[8b]
independently reported the synthesis of 3,3-disubstituted
oxindoles through straightforward cross-dehydrogenative
coupling[9] of N-aryl amides using stoichiometric amounts of
CuII salt and Na(K)OtBu. Following these pioneering studies,
other oxidizers including Ag2O, I2, and DDQ were
strategy for the generation of functionalized monofluoroalkyl
radicals through electrochemical activation of C H bonds
and its application in the unprecedented synthesis of 3-
fluorooxindoles through cross-coupling of C(sp3)-H and C-
(sp2)-H bonds (Scheme 1b).[15]
[14]
À
The cost-effective organometallic compound ferrocene
(Cp2Fe) was employed as a redox catalyst for the electro-
chemical cyclization of the model substrate 1 because Cp2Fe+
is known to promote oxidative radical reactions
(Table 1).[12a,b,16] After some experiments, the optimal reac-
tion conditions were defined as electrolyzing 1 at 08C in
a mixed solvent of MeOH/THF (1:2) using 10 mol% of Cp2Fe
as the catalyst and 30 mol% of LiCp as additive. The constant
current electrolysis was conducted in an undivided cell
equipped with a reticulated vitreous carbon (RVC) anode
and a Pt plate cathode. Under these mild conditions, the
desired 3-fluorooxindole 2 was isolated in 82% yield after the
consumption of 2.5 F of charge. Running the reaction without
Cp2Fe (entry 2) or in the presence of triarylamine-type redox
catalysts (entry 3–4) led to substrate decomposition and
either no or low yield of 2. The basic additive LiCp was also
important for optimal yield as its absence (entry 5) or
replacing it with NaHCO3 (entry 6), or Na2CO3 (entry 7) or
LiOMe (entry 8) all led to inferior results.[17] The proper
anode material was critical for success as the use of platinum
[*] Z.-J. Wu, Prof. Dr. H.-C. Xu
iChEM, State Key Laboratory of
Physical Chemistry of Solid Surfaces
Key Laboratory of Chemical Biology of Fujian Province
and College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005 (P.R. China)
E-mail: haichao.xu@xmu.edu.cn
Homepage: http://chem.xmu.edu.cn/groupweb/hcxu/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701329.
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Table 1: Optimization of reaction conditions.[a]
Entry Conditions
Yield [%][b]
1
2
1
Cp2Fe (10 mol%), MeOH/THF (1:2), LiCp
(30 mol%), 4 ꢀ MS, nBu4NPF6, 08C, 7.5 mA
entry 1 but no Cp2Fe
entry 1 but (4-BrPh)3N as mediator
entry 1 but (4-MePh)3N as mediator
entry 1 but no LiCp
entry 1 but replacing LiCp with NaHCO3
entry 1 but replacing LiCp with Na2CO3
entry 1 but replacing LiCp with LiOMe
entry 1 but Pt or graphite plate anode
(1 cmꢁ1 cm)
0
86(82)
2
3
4
5
6
7
8
9
35
75
70
43
37
30
0
0
9
9
33
39
41
64
61– trace
80
0
10[c] entry 1 but 15 mA
79
[a] Reaction conditions: RVC anode (100 PPI, 1.2 cmꢁ1.2 cmꢁ0.6 cm),
Pt plate cathode (1 cmꢁ1 cm), 1 (0.3 mmol), nBu4NPF6 (0.6 mmol),
1
solvent (6 mL), argon, 2.7 h (2.5 F). [b] Yield determined by H NMR
analysis using 1,3,5-trimethoxybenzene as the internal standard. Isolated
yield in parenthesis. [c] Reaction time=1.3 h.
or graphite plate as the anode led to only trace amount of
product formation (entry 9). The reaction may be conducted
using higher current of 15 mA to reduce the reaction time
with small yield loss (entry 10).
Subsequent investigation of the reaction scope revealed
a broad tolerance of substituents with diverse electronic
properties at all positions on the N-aryl group of the amide
substrate (Scheme 2). Highly functionalized oxindoles could
be conveniently prepared from substrates bearing a multi-
substituted N-aryl group (19–24). Meta-substitution resulted
in the formation of two separable regioisomers (21, 22). On
the other hand, oxindoles bearing diverse N-substituents
including functionalized alkyl groups (27–33) and an aryl
group (34) could be accessed. The electrochemical oxidation
process showed satisfactory compatibility with a multitude of
functional groups, including the full range of halogens (5–8),
alkyne (14–16), aminoester (15), alcohol (16, 27), pyridine
(25,26), silylether (28), ester (29), and redox sensitive pyrrole
(13), carbozole (22), and N-phenyl carbamate (30). However,
it should be noted that the oxindole products bearing
electron-withdrawing groups (5–7, 9–11, 25) were prone to
base-induced decomposition even at 08C. Thus, the reaction
temperature needed to be lowered to À308C to obtain
optimal yields (Table S1, the Supporting Information).
In the cases of synthesis of 32 and 33, the intended
oxindole products were obtained in high yields despite the
Scheme 2. Scope of 3-fluorooxindole synthesis. Reaction conditions:
Table 1, entry 1. [a] Yield of isolated product. [b] Reaction at À308C.
[c] The reaction time was 4 h (3.7 F). [d] Reaction at reflux. [e] Two
separable isomers.
The electrolytically driven C3-fluorinated oxindole syn-
thesis could also be performed on a larger scale (Scheme 3).
The electrolysis of 10.2 grams (29 mmol) of 35 proceeded
smoothly to furnish the desired product 8 in 82% yield in less
than 3 h, with similar yield and current efficiency to the same
reaction on a smaller scale (see Figure S1 in the Supporting
Information for reaction setup). The ester group in 8 was
activated by the neighboring fluoro and amide substituents,
which greatly facilitated its aminolysis by a primary or
secondary amine to afford amides 36–38. In the presence of
À
presence of better radical acceptors, that is, a C C double or
triple bond, to compete with the phenyl group. Tertiary
amides bearing a phenyl group and an unhindered alkyl group
on the amidyl nitrogen existed predominately in the cis form
(as illustrated for amide 1 in Table 1).[18] The activation energy
for the cis/trans isomerization of amide is usually higher than
that of radical cyclization.[19] As a result, the regioselectivity
was dictated by the conformational preference of the starting
amide.
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was shown to increase with the strength (trace c vs. e) and
concentration (traces d–g) of the base. In fact, this trend
continued even after the concentration of LiOMe exceeded
that of 1 (traces f–g), suggesting that 1 did not undergo
substantial deprotonation by methoxide.[21] On the other
hand, we discovered that the catalytic current also gained in
strength when a higher concentration of 1 was used while the
amount of base (LiOMe) remained unchanged (traces b’–e’).
Taken together, these results suggested that 1 was oxidized by
Cp2Fe+ through a rate-limiting deprotonation step followed
by a quick electron transfer.[22]
Based on the above-mentioned findings, a possible mech-
anism for the electrochemical dehydrogenative cross-cou-
pling reaction was proposed (Scheme 5). As a start, the
Scheme 3. Gram-scale synthesis and product transformations. [a] Allyl-
amine, MeOH, 508C, 94%. [b] Propargylamine, MeOH, 508C, 96%.
[c] Pyrrolidine, ZnCl2, THF, 08C, 60%. [d] 4-MePhNH2, AlMe3, toluene,
08C-RT, 39%. [e] Propargyl alcohol, (iPr)2NEt, RT, 93%. [f] Allylbro-
mide, Cs2CO3, MeOH, RT, 71%.
p-toluidine and AlMe3,[20] both of the ester group and the C F
À
bond underwent aminolysis to generate 3-aminooxindole 39.
In addition, the ester group could be removed (40) or
replaced in a single step by an allyl substituent (41). These
diverse transformations highlighted the potential of the
current electrochemical method in medicinal chemistry.
To investigate the reaction mechanism, we first compared
the cyclic voltammograms of Cp2Fe in the absence or
presence of 1 (Scheme 4). The absence of any detectable
changes between the two voltammograms (traces a vs. b)
suggested that there was no electron transfer between the
electrochemically generated Cp2Fe+ and the starting sub-
strate, which could be rationalized by the large potential
difference between the two species (Ep/2 = 0.52 V and 1.93 V
vs. SCE for Cp2Fe and 1, respectively). However, a catalytic
current was observed when a base such as LiCp (trace c) or
LiOMe (trace e) was included. The intensity of the current
Scheme 5. Mechanistic proposal.
application of a potential difference across the electrolysis cell
triggers the anodic oxidation of Cp2Fe and the cathodic
reduction of MeOH. The resultant MeOÀ or added LiCp[23]
then abstracts the malonyl proton from 1 to give rise to its
conjugate base I with equilibrium lying far to the side of 1.[24]
This unfavorable deprotonation is driven forward by the
following reaction of I, which involves facile electron transfer
with Cp2Fe+ to form the key carbon radical intermediate II
and regenerate the redox catalyst Cp2Fe followed by radical
cyclization and rearomatization to furnish the final oxindole
2.
In summary, we have developed an efficient and highly
chemoselective electrochemical cross-coupling reaction of
C(sp3)-H and C(sp2)-H bonds employing Cp2Fe as the redox
catalyst, leading to a straightforward, modular and efficient
synthesis of functionalized 3-fluorooxindoles. The in situ
generation of the requisite oxidant and base at relatively
low temperature and in a continuous fashion allow the base-
and heat-sensitive fluorinated oxindoles to be formed with
high efficiency. Importantly, we have demonstrated that
electrochemical oxidation using redox catalysis can provide
an effective entry into functionalized monofluoroalkyl radi-
À
cals through activation of C H bonds. Application of these
fluorinated C-radicals to the development of new fluoroalky-
lation reactions are currently underway in our laboratory.
Scheme 4. Cyclic voltammograms of Cp2Fe (3 mm) in 2:1 THF/MeOH
(0.1m nBu4NBF4). a) Cp2Fe. b) Cp2Fe, 1 (36 mm). c) b + LiCp
(36 mm). d) b + LiOMe (18 mm). e) b + LiOMe (36 mm). f) b +
LiOMe (72 mm). g) b + LiOMe (108 mm). a’) Cp2Fe. b’) Cp2Fe, LiOMe
(36 mm), 1 (18 mm). c’) Cp2Fe, LiOMe (36 mm), 1 (36 mm). d’) Cp2Fe,
LiOMe (36 mm), 1 (72 mm). e’) Cp2Fe, LiOMe (36 mm), 1 (108 mm).
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Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclization · electrochemistry · ferrocene · radicals ·
redox chemistry
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generated MeOÀ.
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Manuscript received: February 7, 2017
Final Article published: && &&, &&&&
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Communications
Cross-Coupling
Z.-J. Wu, H.-C. Xu*
&&&& — &&&&
Synthesis of C3-Fluorinated Oxindoles
Through Reagent-Free Cross-
Dehydrogenative Coupling
À
C H functionalization: A ferrocene-cata-
lyzed electrochemical cross-coupling
reaction of C(sp3)-H and C(sp2)-H centers
has been developed to give access to C3-
fluorinated oxindoles using fluorinated
malonate amides. The electrosynthetic
method is characterized by mild reaction
conditions, broad substrate scope, high
functional group tolerance, and easy
scalability.
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!