Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel

Article abstract of DOI:10.1002/anie.201606458

A nickel-catalyzed three-component reaction for the synthesis of difluoroalkylated compounds through tandem difluoroalkylation-arylation of enamides has been developed. The reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The significant advantages of this protocol are the low-cost nickel catalyst, synthetic convenience, excellent functional-group compatibility and high reaction efficiency.

Full text of DOI:10.1002/anie.201606458

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201606458
German Edition: DOI: 10.1002/ange.201606458
Cross-Coupling
Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by
Nickel
Ji-Wei Gu+, Qiao-Qiao Min+, Ling-Chao Yu, and Xingang Zhang*
Abstract: A nickel-catalyzed three-component reaction for the
synthesis of difluoroalkylated compounds through tandem
difluoroalkylation-arylation of enamides has been developed.
The reaction tolerates a variety of arylboronic acids and widely
available difluoroalkyl bromides, and even the relatively inert
substrate chlorodifluoroacetate. The significant advantages of
this protocol are the low-cost nickel catalyst, synthetic con-
venience, excellent functional-group compatibility and high
reaction efficiency.
T
he development of new and efficient methods for the
synthesis of difluoroalkylated compounds have received great
attention recently because of the unique properties of
difluoromethylene group (CF2)[1] and its important applica-
tions in medicinal chemistry.[2] Although significant progress
in this field has been achieved over the past few years, almost
Scheme 1. Hypothesis for a nickel-catalyzed difluoroalkylation reaction
from difluoroalkyl halides.
all the effort mainly focused on the construction of a carbon–
[3]
À
difluorocarbon bond (C CF2) by two-component reactions.
Conceptually, the introduction of a CF2 group into organic
molecules through a multicomponent reaction would be
a more efficient and synthetically convenient strategy to
access difluoroalkylated compounds, in particular for those
compounds which are difficult to prepare through conven-
tional methods. Very recently, we reported a nickel-catalyzed
difluoroalkylation of arylborons with difluoroalkylbromides,
in which a difluoroalkyl radical from a single-electron path-
way (SET), is involved in the reaction.[4–7] Inspired by this
preliminary study,[4] we envisioned the feasibility of a nickel-
catalyzed radical tandem process for the synthesis of difluoro-
alkylated compounds through a three-component reaction.
Our design is based on the hypothesis that a difluoroalkyl
radical is induced by a nickel complex and is then trapped by
an alkene, with a subsequent cross-coupling leading to
a strategy for accessing fluorinated compounds has not been
reported.[8] Even for nonfluorinated substrates, only one
example has been reported during our manuscript prepara-
tion.[9] We have therefore sought after a system to resolve
these substantial challenges. Herein, we describe the first
example of a nickel-catalyzed three-component reaction for
the synthesis of difluoroalkylated compounds through
tandem difluoroalkylation-arylation of enamides, and it
tolerates a variety of low-cost and widely available difluor-
oalkyl bromides/chlorides and arylboronic acids.
According to the hypothesis, our solution to the substan-
tial challenges of such a strategy is based on the consideration
that if an alkene can trap the difluoroalkyl radical (RCF2C)
faster than the nickel complex ([Ni] or [Ni]-Nu) reacts with
RCF2C,[10] and with the aid of a coordinating group on the
alkene to chelate the nickel complex and facilitate its
recombination with the newly formed alkyl radical, it would
be feasible to access the final product and avoid the formation
of some other side products (Scheme 1b). To fulfill this
approach, a commercially available, electron-rich alkene
enamide (2a) with a carbonyl group as a chelating group,
was employed. Furthermore, the resulting b-difluoroalkylated
amines are an important structural motif in medicinal
chemistry, but efficient methods to access such valuable
structures are limited.[11]
À
a difluoroalkylated molecule having two new C C bonds
and a new chiral center (Scheme 1a). However, such a hypo-
thetical reaction is complicated by a number of potential side
reactions, such as cross-couplings between two coupling
partners, dehalohydrogenation or dimerization of difluoro-
alkyl halides, b-hydride elimination from the alkyl metal
intermediates, and so on. As a result, it is extremely difficult
to realize such a strategy. To date, an example of such
[*] J.-W. Gu,[+] Q.-Q. Min,[+] L.-C. Yu, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
[+] These authors contributed equally to this work.
Accordingly, we began by choosing the low-cost and
widely available bromodifluoroacetate (BrCF2CO2Et; 1a),
enamide 2a, and the air-stable arylbronic acid 3a as model
substrates (Table 1). After a survey of the ligands, it was
found that a range of yields (53–69%) of the a,a-difluoro-g-
amino acid 4a could be obtained through a combination of
NiCl2·DME (5 mol%) with some diamine ligands in the
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606458.
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Table 1: Representative results for optimization of the nickel-catalyzed
difluoroalkylation-arylation of 2a.[a]
Table 2: Nickel-catalyzed difluoroalkylation-arylation of 2a with bromo/
chlorodifluoroacetate and the arylboronic acids 3.[a]
Entry
1a/2a/3a
[Ni]
Yield [%][b]
(equiv)
4a
5a
6a
7a
1
2
3
4
5
6
7
8
1/1/2
NiCl2·DME
NiCl2·DME
NiCl2·(PPh3)2
NiCl2·(dppf)
Ni(NO3)2·6H2O
Ni(OTf)2
Ni(COD)2
NiCl2·DME
NiCl2·DME
–
69
77
49
23
67
64
55
77
10
24
36
24
33
30
27
16
n.d.
n.r.
2
5
13
6
5
2
5
4
n.d.
n.r.
–
6
7
55
7
5
11
7
n.d.
n.r.
1.5/1/2
1.5/1/2
1.5/1/2
1.5/1/2
1.5/1/2
1.5/1/2
1.5/1/1.5
1.5/1/1.5
1.5/1/1.5
9[c]
10
(94)
n.r.
[a] Reaction conditions (unless otherwise specified): 1a (1.0–1.5 equiv),
2a (0.2 mmol, 1.0 equiv), 3a (1.5–2.0 equiv), [Ni] (5 mol%), 4,4’-diMeO-
bpy (5 mol%), and K2CO3 (3.0 equiv), 1,4-dioxane (2 mL), 808C, 24 h.
[b] Determined by 19F NMR spectroscopy using fluorobenzene as an
internal standard. Value within parentheses is yield of the isolated
product. [c] DME was used as the solvent. bpy=2,2’-bipyridine,
DME=1,2-dimethoxyethane, dppf=1,1’-bis(diphenylphosphanyl)ferro-
cene), n.d.=not determined, n.r.=no reaction, Tf=trifluoromethane-
sulfonyl.
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol,
1.5 equiv), 2a (0.4 mmol, 1.0 equiv), 3 (0.6 mmol, 1.5 equiv), 808C, 24 h.
All reported yields are those of the isolated products. [b] Gram-scale
synthesis. [c] 1 (0.6 mmol, 1.5 equiv), 2a (0.4 mmol, 1.0 equiv), 3
(0.8 mmol, 2.0 equiv), NiCl2·DME (5 mol%), bpy (5 mol%), 1,4-dioxane
(4 mL), 808C, 24 h.
presence of K2CO3 in 1,4-dioxane at 808C (for details see the
Supporting Information). And 4,4’-diMeO-bpy proved to be
the superior ligand, thus providing 4a in 69% yield along with
some side products [the aryldifluoroacetate 5a (10% yield)
and hydrodebrominated product 6a (2% yield); entry 1]. But
the triamine ligands terpyridine and Pybox failed to provide
4a. The ratio of 1a/2a/3a and the nickel sources are critical to
the reaction efficiency (for details see the Supporting
Information). Increasing the amount of 1a benefited the
reaction efficiency, but the yield of 5a was increased and
accompanied by the Heck-type product 7a (entries 2–8).
Among the tested nickel catalysts, NiCl2·DME was still the
best choice. Other nickel sources, such as [NiCl2(PPh3)2],
[NiCl2(dppf)], and [Ni(COD)2] led to lower yields of 4a and
increased yields of 5a and 7a (for details see the Supporting
Information). Finally, the optimized reaction conditions were
identified by switching the solvent from 1,4-dioxane to 1,2-
dimethoxyethane (DME), and 94% yield of 4a could be
obtained when the reaction was carried out with 1a
(1.5 equiv), 2a (1.0 equiv), 3a (1.5 equiv), NiCl2·DME
(5 mol%), 4,4’-diMeO-bpy (5 mol%), and K2CO3
(3.0 equiv) in DME at 808C (entry 9). No desired product
was obtained without either the nickel catalyst or ligand
(entry 10), thus demonstrating the essential role of nickel
catalyst in promoting the reaction.
when 1a was employed as a coupling partner (Table 2). Many
versatile functional groups, such as alkoxycarbonyl, formyl,
enolizable ketone, cyano, thioether, and silyl groups showed
excellent compatibility in the reaction (4g–m). In addition,
the successful formation of 4n and 4o in good yields with
intact chloride and bromide groups provide good opportu-
nities for downstream transformations. Most remarkably,
chlorodifluoroacete (ClCF2CO2Et; 1b) was also applicable to
the reaction when 1,4-dioxane was used as a solvent, and even
higher yields of 4 were provided in some cases (4c, 4d, 4 f, and
4l), thus demonstrating the advantages of this catalytic
system. It is also possible to access the desired product on
gram-scale through current process. For example, a yield as
high as 89% was obtained for the gram-scale synthesis of 4c.
À
In light of the abundance of fluoroalkyl chlorides (Rf Cl) in
raw industrial materials, we believe that this process will
À
prompt the research in fluoroalkylation reactions with Rf Cl.
In addition to demonstrating the substrate scope of this
reaction, a variety of difluoroalkyl bromides were examined
(Table 3). Good yield was obtained when bromodifluoroacet-
amide was examined (8a). The protic amide did not interfere
with the reaction efficiency, and even higher yield was
afforded (8b). Although a mixture of diastereoisomers in
a 1:1 ratio was provided when amino-acid-derived bromodi-
fluoroacetamide was used as a coupling partner, these two
To ascertain the substrate scope of this method, a variety
of arylboronic acids were investigated and provided the a,a-
difluoro-g-amino acid derivatives 4 in moderate to high yields
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Table 3: Nickel-catalyzed difluoroalkylation-arylation of 2 with the
provided 8k in a synthetically useful yield. However, the 1,2-
substituted enamide (E)-1-(prop-1-en-1-yl)pyrrolidin-2-one
(2d) led to some uncertain side products.
difluoroalkyl halides 1 and arylboronic acids 3.[a]
The significant advantages of this strategy can be demon-
strated by the rapid synthesis of biologically active molecules
Scheme 2. Reactions with the enamides 2 and stereoconvergent syn-
thesis of compound 4a. THF=tetrahydrofuran.
in a one-pot reaction. As shown in Scheme 2a, after the
commercially available 2-vinylisoindoline-1,3-dione 2e was
treated with 1b and the arylboronic acid 3c under standard
reaction conditions, the resulting b-difluoroalkylated amino
acid ester was subsequently deprotected by hydrazine and
subsequent cyclization produced the lactam 9 with high
efficiency (53% overall yield). This highly efficient procedure
highlighted the four-step synthesis in a one-pot reaction, and
[a] Reaction conditions (unless otherwise specified): 1 (0.8 mmol,
2.0 equiv), 2a (0.4 mmol, 1.0 equiv), 3 (0.8 mmol, 2.0 equiv), NiCl2·DME
(5 mol%), 4,4’-diMeO-bpy (5 mol%), and K2CO3 (4.0 equiv), 1,4-dioxane
(4 mL), 808C, 48 h. [b] NiCl2·DME (8 mol%) and 4,4’-diMeO-bpy
(8 mol%). [c] 1 (0.6 mmol, 1.5 equiv), 2a (0.4 mmol, 1.0 equiv), 3
(0.6 mmol, 1.5 equiv) and K2CO3 (3.0 equiv), 1,4-dioxane (4 mL), 808C,
24 h. [d] NiCl2·DME (8 mol%), 4,4’-ditBu-bpy (8 mol%). [e] NiCl2·DME
(5 mol%), 4,4’-ditBu-bpy (5 mol%). [f] ClCF2CO2Et was used as a sub-
strate and 3.0 equiv of K2CO3 was used. TBS=tert-butyldimethylsilyl.
À
formation of two new C C bonds, one new amide bond, and
a chiral center, thus demonstrating the synthetic convenience
and utility of current process. Because 9 is an important
fluorinated structure in the drug discovery and develop-
ment,[13] we view this transformation as a facile route for
applications in organic synthesis and medicinal chemistry.
Most importantly, the utility of this protocol can also be
demonstrated by its potential to stereoselectively synthesize
difluoroalkylated compounds. As shown in Scheme 2b, 4a
can be stereoconvergently prepared in 18% ee under stan-
dard reaction conditions with a chiral diamine ligand.
Although low enantioselectivity is observed, it provides
a good opportunity for catalytic, enantioselective synthesis
of difluoroalkylated molecules through nickel-catalyzed
cross-coupling.[14] It should be mentioned that no enantio-
selective nickel-catalyzed three-component reaction has been
reported so far. Thus, we believe that this method will prompt
the research in nickel-catalyzed asymmetric synthesis.
To probe whether a difluoroalkyl radical exists in the
reaction, radical inhibition experiments (for details see the
Supporting Information) and a radical-clock experiment were
performed. When 1a was treated with a-cyclopropylstyr-
ene[15] (10) in the presence of 3a under the standard reaction
conditions, the ring-expanded product 11 was formed in 18%
yield (Scheme 3a). The product 12 was also obtained in 11%
yield, thus indicating that a difluoroalkyl radical is involved in
the reaction process and the pathway hypothesized in
Scheme 1a is reasonable. The formation of a radical inter-
isomers could be easily resolved by flash chromatography
(8c). The difluoroalkyl bromide can also be extended to
a bromodifluoromethylphosphonate (8d). Given that the
phosphonyldiflluoromethyl group [CF2PO(OR)2] has impor-
tant applications in medicinal chemistry, this transformation
may have potential applications in drug discovery and
development. Furthermore, aryldifluoromethyl bromide and
bromodifluoromethylated benzoxazole were also applicable
to the reaction (8e and 8 f). Although 35% yield of 8 f was
provided, a multistep procedure to prepare such a structure
would be required if conventional methods was used.
Remarkably, the unactivated 1-bromo-1,1-difluoroalkanes
were also viable in the reaction, thus providing 8g–i with
À
good yields. The chemoselective reaction of the Br CF2 bond
À
with 2a, with an intact Br CH2 bond, proceeded smoothly,
thus demonstrating that the difluoroalkyl bromide is more
reactive than its nonfluorinated counterpart. This result may
be ascribed to the high electronegativity of the fluorine atom,
which makes it easier for the difluoroalkyl bromide to accept
an electron relative to its nonfluorinated counterpart.[12] The
reaction was not restricted to 2a, as 3-vinyloxazolidin-2-one
(2b) was also a suitable substrate and provided the corre-
sponding product 8j in good yield. Furthermore, the acyclic
enamide 2c was amenable to the reaction conditions and
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Keywords: boron · cross-coupling · fluorine · nickel ·
synthetic methods
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mediate was further confirmed by an ESR study of reaction of
1a with the spin-trapping agent phenyl tert-butyl nitrone
(PBN) in the presence of 3a (Scheme 3b), in which EtOC-
(O)CF2CHPhN(OC)-tBu (13) was produced as a spin adduct of
the trapped EtOC(O)CF2C radical. Thus, these results clearly
demonstrate that a free fluoroalkyl radical is involved in the
reaction.
In conclusion, the first example of a nickel-catalyzed
tandem difluoroalkylation-arylation of enamides with widely
available difluoroalkyl halides by a three-component reaction
has been developed. The reaction tolerates a variety of
arylboronic acids and difluoroalkyl bromides, even the
“inert” chlorodifluoroacetate is a competent coupling part-
ner, thus featuring the generality of this protocol. The
efficient formation of a,a-difluoro-lactam provides a facile
route for applications in drug discovery and development.
Because of its low-cost nickel catalyst, synthetic simplicity,
excellent functional-group compatibility, and high reaction
efficiency, we believe this nickel-catalyzed three-component
reaction will prompt research in cost-efficient synthesis of
fluoroalkylated compounds from simple substrates. Impor-
tantly, this nickel-catalyzed radical/cross-coupling process
also provides a good opportunity for catalytically enantiose-
lective synthesis of difluoroalkylated compounds. Further
studies to explore the derivative reactions, as well as the
asymmetric synthesis of fluorinated compounds through this
strategy are now in progress in our laboratory.
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Acknowledgements
This work was financially supported by the National Basic
Research Program of China (973 Program) (No.
2012CB821600 and 2015CB931900), the Strategic Priority
Research Program of the Chinese Academy of Sciences (No.
XDB20020000), the National Natural Science Foundation of
China (No. 21425208, 21332010, 21421002, and 21672238),
and SIOC. We thank Chang Xu for the stereoconvergent
synthesis of 4a.
4
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Received: July 4, 2016
Published online: && &&, &&&&
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Communications
Cross-Coupling
J.-W. Gu, Q.-Q. Min, L.-C. Yu,
X. Zhang*
&&&& — &&&&
Tandem Difluoroalkylation-Arylation of
Enamides Catalyzed by Nickel
All about efficiency: The title reaction
tolerates a variety of arylboronic acids
and widely available difluoroalkyl bro-
mides, and even the relatively inert sub-
strate chlorodifluoroacetate. The protocol
provides a highly efficient method for the
catalytic synthesis of difluoroalkylated
compounds.
6
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