Copper/B2pin2-catalyzed C-H difluoroacetylation-cycloamidation of anilines leading to the formation of 3,3-difluoro-2-oxindoles

Article abstract of DOI:10.1039/c6cc09643c

An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B₂pin₂-catalyzed difluoroacetylation of aniline via C-H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP₃ receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield.

Full text of DOI:10.1039/c6cc09643c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C6CC09643C
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Copper/B2pin2-Catalyzed C-H Difluoroacetylation -Cycloamidation
of Anilines Leading to the Formation of 3,3-Difluoro-2-oxindoles
Miaolin Ke a, b, Qiuling Song a *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An original and efficient synthesis of 3,3-difluoro-2-oxindole
derivatives has been developed via copper/B2pin2-catalyzed
difluoroacetylation of aniline via C-H activation followed by
intramolecular amidation. In this method, amino groups in
primary, secondary or tertiary anilines are acted as a directing
group provided ortho difluoroacetylative product regioselectively.
And in the first two cases, further intramolecular amidation
renders 3,3-difluoro-2-oxindole derivatives in one-pot strategy.
This method makes the synthesis of compound A as a potent and
selective EP3 receptor antagonist only five steps in 13% yield
instead of previous reported nine steps in overall 4% yield.
Figure 1. Examples of bioactive 3,3-difluoro-2-oxindole derivatives
Several elegant methods have been developed on the preparation
of such unique structural motifs: Middleton and Bing ham reported
the synthesis of 3,3-difluoro-2-oxindole derivatives from isatin with
slight excess of DAST in anhydrous solvent (Scheme1a).7a In 2010,
Hu and co-workers reported a stoichiometric copper-mediated
fluoroalkation reaction with iododifluoroacetamides rendering the
product of intramolecular cyclization (Scheme 1b).7b In 2011, direct
ethoxycarbonyldifluoromethylation of aromatic compounds with
absolute para-substitution using Fenton reagent was reported by
Yamakawa and coworker, further intramolecular amidation under
acidic conditions leading to 3,3-difluoro-2-oxindoles via a two-step
strategy (Scheme 1, 1c).7c In 2014, Buchwald and coworkers
The quest of novel and efficient methods for the synthesis of
difluoroalkylated compounds represents an endeavor of utmost
importance in both academia and industry, due to the beneficial
2
effects, such as increased metabolic stability or lipophilicity,1,
brought forth by the incorporation of fluorine or fluorine-containing
groups in organic molecules. Consequently, the interest in the
development of new methodologies for the introduction of
fluorinated units in organic molecules has been rapidly increased.
3, 4
Compared to fluorination and trifluoromethylation of arenes,
methods for the synthesis of difluoroalkylation of arenes are still
limited. 5, 6 The synthesis of difluorinated heterocyclic is especially
promising but underutilized tactics.
reported
a palladium -catalyzed intramolec ular C -H
difluoroalkylation leading to the synthesis of substituted 3,3-
difluoro-2-oxindoles (Scheme 1d).7d While significant progress has
been achieved on this topic, there are still many constraints which
limit the routine utility of the current methods, such as not-readily-
available or expensive starting materials7a, narrow substrate scope
and poor functional group tolerability,7c the protective substituents
As a unique fluorine-containing structure, 3,3-difluoro-2-oxindole
is an important scaffold which is widely existed in many bioactive
7-9
compounds as well as material related molecules.
For example,
compound A is proposed as a potent and selective EP3 receptor
antagonist,10a compound
B is comducted as an inhibitor of
caspases-3 and -7 in apoptpsis 10b, the compound C was a potential
agent for the treatment of abnormal cell growth,10c compound D
was conducted as the OFox imidate glycosyl donors (Figure 1).10d
7b,7d
7d
on the nitrogen atom,
expensive metal and ligand
and
stoichiometric transition metal usage which leads to high cost as
well as high potential pollution and so on.7b Therefore developing a
reliable method with high generality and practicality for the
construction of 3,3-difluoro-2-oxindole is still a challenge but highly
desirable. On the other hand, directed ortho C-H functionalization
of arenes has become a strongly efficient strategy for building up
substituted arenes in organic synthesis due to the concise steps,
non-prefunctionalization and atom efficiency.11,12 Various nitrogen-
containing groups have been employed as directing groups,
a.Institute of Next Generation Matter Transformation, College of Chemical
Engineering at Huaqiao University
b.College of Materials Science at Huaqiao University, 668 Jimei Blvd, Xiamen,
Fujian, 361021, P. R. China.
† email: qsong@hqu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1. Optimization of reaction conditiona
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DOI: 10.1039/C6CC09643C
Scheme 1. Approaches to 3,3-difluoro-2-oxindole
however, ortho C-H functionalization of arenes directed by primary
or secondary amines is still limited.13 Very recently, a novel and
efficient Cu/B2pin2 catalytic system was developed in our group
(Scheme 2).14 Based on our experience, we envisioned that amino
group in aryl amines might serve as a directing group to promote a
new C-CF2COOR bond formation with the in-situ generated
•CF2COOR radical under our copper/B2pin2 catalytic system via the
single electron transfer (SET) process.15,16 Further intramolecular
lactam formation between ester and amino groups (primary and
secondary ones) might render 3,3-difluoro-2-oxindole derivatives.
Herein, we report a novel and practical strategy for the construction
of 3,3-difluoro-2-oxindole derivatives via Cu/B2pin2 cocatalyzed a
tandem ortho C-H difluoroacetylation cyclization of anilines
(Scheme 1e), this method features with readily available starting
materials, excellent functional group tolerability and novel catalytic
system.
entries 9-13). The substituents on the aromatic ring of ligands had
little effect on the transformation. After the screening of solvents,
1,2-dicloroethane was the optimal choice (Table 1, entries 14-17).
Increasing the temperature to 100 oC, delightedly, a much higher
yield of desired product was obtained (Table 1, entry 18). Control
experiments suggested that B2pin2, Cu(OAc)2·H2O, NaOAc and
ligand L1 are prerequisite for the success of the reaction (table S5,
see the Supporting Information).
With the optimized reaction condition established, we next
investigated the scope of this reaction (Scheme 3). Anilines that
bear electron-donating (Scheme 3, 3-9) or electron-withdrawing
groups (Scheme 3, 10-13) at the para position of the aromatic ring
were efficiently transformed into the corresponding target products.
Bis-substituted aniline was compatible as well under the standard
condition albeit with lower yield (Scheme 3, 14). Compared to para-
substituted anilines, sterically hindered o-aniline gave lower yields
(Scheme 3, 15-16), and in some case the para-difluoroacetylated
product was generated as the byproduct (Scheme 3, 17). The effect
of different protective groups on the nitrogen atom were
investigated as well: methyl-protected aniline underwent the
reaction smoothly, leading to the desired product (Scheme 3, 18);
We initially investigated the reaction of p-toluidine (1) with 2.0
equivalent of bromodifluoroacetate 2 in the presence of 10 mol%
o
CuBr2 and 30 mol % B2pin2 in dioxane at 80 C (Table 1, entry 1). To
our delight, we found that the desired 3,3-difluoro-5-methyl-2-
oxindole 3 was formed in 40% isolated yield, whose structure was
confirmed by X-ray analysis. Various inorganic bases were tested in
the reaction (Table, entries 2-4), and NaOAc showed the superior
reactivity over other bases (Na2CO3, K2CO3, NaHCO3). It was found
that the desired product was not increased when the loading of
B2pin2 was enhanced to 50 mol % (Table, entry 5), which suggested
that the loading of B2pin2 was not the crucial factor. When different
copper catalysts were examined, Cu(OAc)2·H2O was the most
effective one, providing 3 in 55% yield (entries, 6-8). A series of
bidentate nitrogen ligands were further investigated (Table 1,
N-
N’–dimethyl
aniline
derivatives
rendered
ortho
difluoroacetylated products without further intramolecular cycloa-
midation (Scheme 3, 19, 20). Furthermore, it was found that the
benzene ring could also be effectively replaced by naphthalene moi-
ety and the structure of 21 was confirmed by X-ray analysis
(Scheme 3, 21, 22). Noteworthily, cyclic amines, such as carbazole
and 1,2,3,4-tetrahydroquinoline were proven to be good candidates
for C-H difluoroacetylation with good regioselectivity (compound 23
was confirmed by X-ray analysis) in decent yield and the latter one
went further cycloamidation to lead to tricyclic compound 24
(Scheme 3, 23, 24).
Scheme 2. Our Cu/B2pin2 catalytic system for activation of
BrCF2COOR to .CF2COOR radical.
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Scheme 3. Substrate scope of anilines
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DOI: 10.1039/C6CC09643C
Scheme 5. Preliminary mechanistic studies.
the reaction. Furthermore, radical-clock experiment was
a
conducted using cyclopropylstyrene as a radical trapping agent
(Scheme 5, eq 2). Rearranged product 29 was obtained when 28
was reacted with 2 under the standard condition. The finding
demonstrated that a difluoroalkyl radical was generated in this
transformation.
In order to figure out the sequence of the tandem reaction, 2-
bromo-2,2-difluoro-N-phenylacetamide 30 was prepared firstly and
it was subjected to the standard condition.17 Interestingly, the
desired product was not obtained (detected by MS). Instead, the
compound 31 was observed in 12% yield (Scheme 5, eq 3). The
To demonstrate the synthetic utility of this copper/B2pin2
promoted C-H difluoroalkylation of anilines, a total synthesis of a result as well as the examples 19, 20 and 23 suggested that the
potent and selective EP3 receptor antagonist the compound A was
carried out (Scheme 4).9a The known synthesis of compound A
demands nine steps according to previous report, with our strategy,
the key core of 3,3-difluoro-2-oxindole 16 was constructed readily
from o-bromoaniline and bromodifluoroacetate (2) under our
standard conditions in 38% yield, further Heck coupling leads to
activation of C-H bond should be prior to the formation of lactam.
Based on the results and our previous work (Scheme 2)14, we
proposed a tentative mechanism for this reaction: Initially, LCu(I)-
Bpin species II is generated between LCuX (I) and B2pin2 in the
presence of base, BrCF2COOR is activated by species II to afford
•CF2COOR radical. Amino group of aniline serves as a directing
group and a new C-CF2COOR bond is constructed with the in-situ
generated •CF2COOR radical to lead to VI. Subsequent SET pathway
and intramolecular cycloamidation between ester and amino
groups eventually renders 3,3-difluoro-2-oxindole derivatives
compound 25 in 58% yield.
N-protection with 2,4-
dichlorobenzylchloride renders 26 in 91% yield. Subsequent
saporification and amidation eventually afford compound A in
overall 13% yield in total 5 steps vs 4% yield in nine steps in
previous report.
To further understand the mechanism, radical trapping (Scheme 6).
experiment was performed with compound 1 in the presence of
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as a radical scavenger
(Scheme 5, eq 1). The compound 3 was completely inhibited in the
reaction, demonstrating that a radical process may be involved in
Scheme 6. Tentative mechanism
In conclusion, an efficient and novel method for the
construction of 3,3-difluoro-2-oxindole derivatives catalyzed
by copper/B2pin2 system via C-H difluoroacetylation-
intramolecular amidation was disclosed in our group. This
difluoroalkylation reaction is regiospecific at the ortho position
to the amino group with a broad substrate scope. More
importantly, the unprecedented copper/B2pin2 catalytic
protocol not only expands the scope of directing groups but
also provides a novel tandem C-H functionalization of anilines
from readily available starting materials offering 3,3-difluoro-
Scheme 4. Synthesis of EP3 receptor antagonist compound A.
3 | J. Name., 2012, 00, 1-3
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2-oxindole derivatives, which are of great synthetic value in
both organic and pharmaceutical chemistry. To some extent,
our method provides a concise strategy for the synthesis of
3,3-difluoro-2-oxindole derivatives, which has been
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DOI: 10.1039/C6CC09643C
demonstrated by the total synthesis of compound A, a potent
and selective EP3 receptor antagonist, in only 5 steps in overall
13% yield vs. 9 steps in previous report with overall 4% yield.
Further studies to provide a thorough understanding of the
reaction mechanism and synthetic applications are ongoing in
our laboratory
Notes and references
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