Copper-Catalyzed Aminodifluoroalkylation of Alkenes with α-Bromodifluoroacetamides: Synthesis of 3,3-Difluoropyrrolidin-2-ones

Article abstract of DOI:10.1002/adsc.201700559

Copper-catalyzed external-oxidant-free regioselective aminodifluoroalkylation of alkenes with readily available α-bromodifluoroacetamides was realized. This reaction exhibits good functional group tolerance with respect to alkenes and α-bromodifluoroacetamides in affording 3,3-difluoropyrrolidin-2-ones. A mechanism involving copper-catalyzed generation of a difluoroalkyl radical is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201700559

Title: Copper-Catalyzed Aminodifluoroalkylation of Alkenes with α-
Bromodifluoroacetamides: Synthesis of 3,3-Difluoropyrrolidin-2-
ones
Authors: Yunhe Lv, Weiya Pu, Qingqing Wang, Qian Chen, Jiejie Niu,
and Qian Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700559
Link to VoR: http://dx.doi.org/10.1002/adsc.201700559

Advanced Synthesis & Catalysis
10.1002/adsc.201700559
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Aminodifluoroalkylation of Alkenes with α-
Bromodifluoroacetamides: Synthesis of 3,3-Difluoropyrrolidin-
-ones
2
a
a
a
a
a
b
Yunhe Lv, * Weiya Pu, Qingqing Wang, Qian Chen, Jiejie Niu, and Qian Zhang *
a
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 455000, P. R. China.
E-mail: luyh086@nenu.edu.cn; lvyunhe0217@163.com
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry,
b
Northeast Normal University, Changchun, 130024, P. R. China.
E-mail: zhangq651@nenu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract:
Copper-catalyzed
external-oxidant-free
regioselective aminodifluoroalkylation of alkenes with
readily available α-bromodifluoroacetamides was realized.
This reaction exhibits good functional group tolerance with
respect to alkenes and α-bromodifluoroacetamides in
affording 3,3-difluoropyrrolidin-2-ones.
A mechanism
involving copper-catalyzed generation of a difluoroalkyl
radical is proposed.
Keywords:
alkenes;
copper;
radical
reactions;
aminodifluoroalkylation; fluorinated nitrogen-containing
heterocycles
The gem-difluoro group, a bio-isostere of alcohols
and thiols as well as lipophilic hydrogen-bond
donor,[ has unique physical and chemical properties
in agricultural, medicinal, imaging, and material
sciences.[ Therefore, development of new synthetic
methods for the efficient incorporation of gem-
difluoro group into organic molecules has important
1]
2]
[3]
implications in these fields. However, most work
[
4]
has
focused
on
monofluorination
and
[
5]
trifluoromethylation, while efficient and general
difluoromethylation methods are relatively limited.
Recently,
transition-metal-catalyzed
radical
Scheme 1. Aminodifluoroalkylation of alkenes.
difluoromethylation has been explored to achieve
efficient difluoromethylation of alkanes, arenes and
heteroarenes
using
halodifluoroacetates
or
It is well-known that nitrogen-containing
heterocycles such as pyrrolidines and pyrrolidinones
halodifluoroacetamides as a difluoromethyl radical
reagent via cleavage of C-X bond.[ In particular,
difunctionalization of unsaturated carbon−carbon
bonds invoking difluoromethylation, such as
hydrodifluoroacetamidation, aryldifluoroalkylation,
and oxydifluoromethylation of alkenes, has emerged
as a powerful tool for the introduction of gem-
difluoro group.[ Further exploration of the versatility
and efficiency of radical difluoroalkylation is still
highly desired.
6]
[8]
are key motifs in numerous bioactive molecules.
Therefore, efficient synthesis of fluorinated nitrogen-
containing heterocycles, such as N-amido-3,3-
difluoropyrrolidin-2-ones, is highly desirable for
[9]
exploration of new pharmaceuticals.
However,
methods for the synthesis of this important class of
compounds are extremely limited. Concomitant
introduction of a gem-difluoro group and an amide
moiety into olefin, the aminodifluoroalkylation of
7]
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700559
alkenes, should serve as an ideal entry to
2,2'-bipyridine (bipy) was employed as ligand,
intermolecular aminodifluoroalkylation product 3a
(CCDC-1539928) was generated in 15% yield (Table
1, entry 2). 1,10-Phenanthroline (Phen) was found to
be the optimum ligand, which delivered 3a in 81%
yield (Table 1, entries 3-5). Control experiments
demonstrated that base and catalyst were essential
difluoromethylene-containing heterocycles. Recently,
Zhu[
10]
group developed a dual catalyst system
comprised of an iridium photocatalyst and iodide
catalyst for achieving aminodifluoroalkylation of
alkenes, during which iodination was necessary for
the key nucleophilic substitution cyclization. In
addition, only styrene derivatives and vinyl ether are
effective (Scheme 1a). Dolbier[ and co-workers
(Table 1, entries 6 and 7). Other bases, such as
11]
t
KO Bu and Cs
2
CO
3
, were not as effective as K
2
CO
3
developed
an
efficient
photoredox-catalyzed
(Table 1, entries 8 and 9). With CuBr, CuCl, and
Cu(OTf) as catalysts, 3a was obtained in 56, 21, and
intramolecular aminodifluoromethylation of alkenes
bearing a tethered nitrogen nucleophile, wherein a
2
48% yields, respectively (Table 1, entries 10-12).
Other solvents (e.g., DMF, DCE, EtOAc) were also
examined but did not lead to significant improvement
(Table 1, entries 13-15). When the reaction was
combination of a Cu(dap)
2
Cl and 2.0 equiv Ag
2
CO
3
was crucial to suppressing
a
competing
chlorodifluoroalkylation process (Scheme 1b).
However, stoichiometric oxidant was utilized for this
transformation, which presumably facilitated
oxidative C-N bond formation. Herein we report a
o
performed at 90 C, 3a was isolated in 36% yield
(Table 1, entry 16).
general
external-oxidant-free
intermolecular
Table 2. Reactions of styrenes 1 with 2a.[a,b]
aminodifluoroalkylation of alkenes that works for a
variety of olefin substrates, such as styrenes, allylic
hydrocarbons, N-vinyl heterocyclic, alkyl vinyl ethers,
aliphatic
alkenes,
trimethyl(vinyl)silane, and
heterocyclic alkenes (Scheme 1c).
Table 1. Optimization of the reaction conditions.[a]
[
b]
Entry
Metal
CuI
Ligand
none
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
K
2
CO
CO
CO
CO
3
3
3
3
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
0
15
12
5
CuI
bipy
K
2
CuI
pyridine
K
2
CuI
Ph
3
P
K
2
CuI
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
K CO
2
3
CH
3
81
trace
0
CuI
none
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
none
CuI
K
2
CO
3
t
KO Bu
30
36
56
21
48
20
11
18
36
CuI
3
Et N
1
1
1
1
1
1
0
1
2
3
4
5
CuBr
CuCl
Cu(OTf)
CuI
K
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
K
2
2
K
2
K
2
DMF
DCE
CuI
K
2
CuI
K
2
EtOAc
[
c]
1
6
CuI
K
2
3
CH CN
[
a]
Reactions were carried out with 1a (0.36 mmol), 2a (0.3
mmol), metal (10 mol %), ligand (10 mol %) and
additive (2.0 equiv) in 3 mL solvent under air
[
a]
o
Reactions were carried out with 1 (0.36 mmol), 2a (0.3
mmol), CuI (10 mol %), Phen (10 mol %) and K CO
(2.0 equiv) in CH CN (3 mL) under air atmosphere at
atmosphere at 110 C for 2 h, unless noted otherwise.
[
[
b]
c]
2
3
Yield of the isolated product.
The reaction was performed at 90 C.
o
3
o
1
10 C for 2 h.
[
[
b]
c]
Initially, styrene 1a and 2-bromo-2,2-difluoro-N-
p-tolyl)acetamide 2a were chosen as the model
Yield of the isolated product.
Recovery of 2a.
(
substrate for the optimization of reaction conditions
Table 1). With CuI as the catalyst and K CO as base
in MeCN, the reaction at 110 °C failed to give any
desired product (Table 1, entry 1). When 10 mol %
With the optimized reaction conditions in hand
Table 1, entry 5), the scope of the
aminodifluoroalkylation of styrenes was examined
and the results are summarized in Table 2. The
(
2
3
(
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700559
styrenes with both electron-donating and electron-
withdrawing groups all worked well with 2a,
affording the desired aminodifluoroalkylation
products 3b-3u in 50–92% yields. Halogen
substituents, which could be very useful for further
allylisoindoline-1,3-dione, 4d was obtained in 55%
yield. 9-vinyl-9H-carbazole and 1-vinylpyrrolidin-2-
one gave the corresponding aminodifluoroalkylation
products 4e and 4f in 86% and 78% yields. Alkyl
vinyl ethers, such as 2-methyl-1-(vinyloxy)propane
transformations,
aminodifluoroalkylation reaction (1b–1e, 1l–1p, 1t,
u). In addition, starting from 1,3,5-trimethyl-2-
were
tolerated
in
the
and
(vinyloxy)cyclohexane
underwent
aminodifluoroalkylation reaction to provide the
corresponding products 4g and 4h in 88% and 94%
yields, respectively. Aliphatic alkenes, such as 4-
vinylcyclohex-1-ene, also provided the desired
aminodifluoroalkylation product 4i in 48% yield.
Notably, the aminodifluoroalkylation reaction of
trimethyl(vinyl)silane provided the desired product 4j
in 45% yield. The present condition is also suitable
for heterocyclic alkenes. Starting from 4-
vinylpyridine, 4k was obtained in 50% yield.
1
vinylbenzene (1r), the corresponding product 3r
could be obtained in 54% yield. Notably, 1,1-
disubstituted styrenes such as 1s–1u were also
effective to provide 3s–3u in moderate yields.
Table 3. Reactions of alkenes 1 with 2a.[a,b]
Table 4. Reactions of 1a with α-bromodifluoroacetamides
[
a,b]
2
.
[
a]
Reactions were carried out with 1a (0.36 mmol), 2 (0.3
mmol), CuI (10 mol %), Phen (10 mol %) and K
2 3
CO
[
a]
Reactions were carried out with 1 (0.36 mmol), 2a (0.3
mmol), CuI (10 mol %), Phen (10 mol %) and K CO
2.0 equiv) in CH CN (3 mL) under air atmosphere at
(
1
2.0 equiv) in CH CN (3 mL) under air atmosphere at
10 C for 2 h.
3
2
3
o
(
3
[
[
b]
c]
Yield of the isolated product.
Recovery of 2.
o
1
10 C for 2 h.
[
[
[
b]
c]
d]
Yield of the isolated product.
.6 mmol 1 was used.
The ratio of the two diastereomers is given within
0
To further explore the potential of this efficient
aminodifluoroalkylation reaction, a variety of α-
bromodifluoroacetamides were investigated. As
shown in Table 4, α-bromodifluoroacetamides
bearing a variety of substituents at the aromatic ring
could be converted to the desired products 5b-5f in
moderate to good yields. To our delight, 2-bromo-
parentheses.
In Zhu’s cascade photoredox/iodide catalytic
system, only styrenes and vinyl ether were effective,
presumably due to the involvement of stable β-
difluoroalkylated carbocation intermediate. To our
delight, the current method displays a broader
substrate scope than the above dual catalyst system.
Besides styrene and vinyl ether, other alkenes, such
as allylic hydrocarbons, N-vinyl heterocyclic, alkyl
vinyl ethers, non-activated aliphatic alkenes,
trimethyl(vinyl)silane, and heterocyclic alkenes were
also suitable substrates. As shown in Table 3, the
desired aminodifluoroalkylation products 4a-4k were
obtained in satisfactory yields. Allylic hydrocarbons,
such as allylbenzene, 1-allyl-4-methoxybenzene and
2
,2-difluoro-N-(naphthalen-2-yl)acetamide 2g could
also give the desired product 5g in 78% yield.
Notably, N-alkyl-2-bromo-2,2-difluoroacetamides,
such as N-cyclohexyl-2-bromo-2,2-difluoroacetamide
h and N-cycloheptyl-2-bromo-2,2-difluoroacetamide
i, were not reactive, which suggests that an aromatic
functionality is required to stabilize the active species.
2
2
4
-allyl-1,2-dimethoxybenzene were also effective,
providing 4a–4c in 53–60% yields. Starting from 2-
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700559
II
As
a
representative
example,
atom transfer from Cu to the adduct radical produces
the aminodifluoroalkylation product and regenerates
aminodifluoroalkylation of 1a on 5 mmol scale
offered an efficient gram scale synthesis of 3a in 75%
yield (Eq 1).
I
Cu , which enters into the next catalytic circle (path
[14]
a). On the other hand, path b could not be excluded:
II
Cu -amido species reacts with benzyl radicals to
III
[15]
generate alkyl-Cu -amido species C, which then
undergoes the facile reductive elimination to give the
aminodifluoroalkylation product 5b (path b). IN
agreement
with
this,
N-alkyl-2-bromo-2,2-
difluoroacetamides 2h and 2i were not effective for
this aminodifluoroalkylation reaction, presumably
owing to the reduced acidity of amide, causing it
difficult for to be transformed to intermediate B in the
presence of weakly basic K
2
CO
3
.
To gain insight into the mechanism of this
transformation, some mechanistic experiments were
performed. When the radical scavenger 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.)
was added to the aminodifluoroalkylation reaction of
In summary, we have developed a novel copper-
catalyzed
intermolecular
radical
aminodifluoroalkylation reaction between alkenes
and α-bromodifluoroacetamides for the synthesis of
3,3-difluoropyrrolidin-2-ones.
The
high
1
a under the optimal conditions, no desired products
regioselectivity, broad substrate scope, no
requirement of extra oxidant, and low loading of the
copper catalyst make the aminodifluoroalkylation
reactions very attractive. It is anticipated that this
novel alkene aminodifluoroalkylation strategy will
play an important role for designing more types of
aminodifluoroalkylation reaction of other unsaturated
was isolated and 78% 2a was recovered. Moreover,
in the presence of 2.0 equivalent of 2,6-di-tert-butyl-
4
-methylphenol (BHT), under the standard reaction
conditions, the yield of 3a fell to 10% (Eq 2). The
results indicate that a radical pathway may be
involved. Further evidence for a radical mechanism
was demonstrated by the radical clock experiment
compounds
and
will
make
α-
with (1-cyclopropylvinyl)benzene (6) as the substrate. bromodifluoroacetamides an attractive reagent for the
The reaction of 6 with 2g under the standard reaction
synthesis
of
difluoromethylene-contained
conditions produced the ring-expanded products 7 in
heterocycles. Further studies on the mechanism and
aminodifluoroalkylation of other unsaturated
compounds such as alkynes and cyclopropropenes are
underway in our lab.
12]
7
4% yield (Eq 3).[
Experimental Section
Typical Procedure for the Aminodifluoroalkylation of
Alkenes (3a)
To
tolyl)acetamide 2a (79.2 mg, 0.3 mmol) in CH
was added the styrene 1a (41 μL, 0.36 mmol), Phen (5.4
mg, 0.03 mmol), CuI (5.7 mg, 0.03 mmol), and K CO
a
solution of the 2-bromo-2,2-difluoro-N-(p-
3
CN (3.0 ml)
2
3
(
82.9 mg, 0. 6 mmol) in screw-cap test tube. The reaction
o
mixture was stirred at 110 C for 2.0 h. After the reaction
finished, the reaction mixture was cooled to room
temperature and quenched by water. The mixture was
extracted with EtOAc (5.0 mL×3), the combined organic
2 4
phases were dried over anhydrous Na SO and the solvent
was evaporated under vacuum. The residue was purified by
column chromatography to give the corresponding
products 3a (69.8 mg, 81%).
Scheme 2. Proposed mechanism.
X-ray Crystal Structure of 3a
Although
the
mechanistic
details
of
CCDC-1539928
contains
the
supplementary
aminodifluoroalkylation are not very clear at the
moment, based on the present experimental results
and literature precedent, a possible mechanism was
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
proposed in Scheme 2. The catalyst CuI reacts with
II
2
b to form a radical A and Cu species via a single
[6a,7c,13]
electron transfer (SET) process.
Subsequently, Acknowledgements
the addition of A to alkenes affords benzyl radical,
II
which intercepts Cu species to produce the
We gratefully acknowledge the Henan Province Key Laboratory
of New Opto-Electronic Functional Materials, the Science &
Technology Foundation of Henan Province, the National NSF of
[7]
intermediate B in the presence of K
2
3
CO .
Nitrogen
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700559
China (21372041) and Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis (130028651) for
financial support.
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