Nickel-catalyzed cross-coupling of functionalized difluoromethyl bromides and chlorides with aryl boronic acids: A general method for difluoroalkylated arenes

Article abstract of DOI:10.1002/anie.201405653

Transition-metal-catalyzed difluoroalkylation of aromatics remains challenging despite the importance of difluoroalkylated arenes in medicinal chemistry. Herein, the first successful example of nickel-catalyzed difluoroalkylation of aryl boronic acids is described. The reaction allows access to a variety of functionalized difluoromethyl bromides and chlorides, and paves the way to highly cost-efficient synthesis of a wide range of difluoroalkylated arenes. The notable features of this protocol are its high generality, excellent functional-group compatibility, low-cost nickel-catalyst, and practicality for gram-scale production, thus providing a facile method for applications in drug discovery and development.

Full text of DOI:10.1002/anie.201405653

Angewandte
Chemie
DOI: 10.1002/anie.201405653
Synthetic Methods
Nickel-Catalyzed Cross-Coupling of Functionalized Difluoromethyl
Bromides and Chlorides with Aryl Boronic Acids: A General Method
for Difluoroalkylated Arenes**
Yu-Lan Xiao, Wen-Hao Guo, Guo-Zhen He, Qiang Pan, and Xingang Zhang*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
Abstract: Transition-metal-catalyzed difluoroalkylation of
aromatics remains challenging despite the importance of
difluoroalkylated arenes in medicinal chemistry. Herein, the
first successful example of nickel-catalyzed difluoroalkylation
of aryl boronic acids is described. The reaction allows access to
a variety of functionalized difluoromethyl bromides and
chlorides, and paves the way to highly cost-efficient synthesis
of a wide range of difluoroalkylated arenes. The notable
features of this protocol are its high generality, excellent
functional-group compatibility, low-cost nickel-catalyst, and
practicality for gram-scale production, thus providing a facile
method for applications in drug discovery and development.
ever, such a transformation remains challenging for the
difluoroalkylation of arenes because: 1) some of the difluoro-
alkylated metal species formed from the reaction of a tran-
À
sition metal and Rf X are prone to decomposition and lead to
difluoroalkanes, difluoroalkyl dimers, and/or other uncertain
by-products;[8] and 2) the reductive elimination of the tran-
sition-metal intermediate arylmetal fluoroalkyl [ArM(Ln)Rf]
is slower compared to its nonfluorinated counterpart.[5f] As
a result, it is difficult to control the catalytic cycle to obtain the
desired difluoroalkylated arenes.
To date, the palladium-[5d–g,9] and copper-catalyzed[5a–c,10]
fluoroalkylation of arenes have become two major methods
to access fluroalkylated arenes. However, the former method
requires an expensive palladium catalyst and phosphine
ligands, and the latter method is limited by substrate scope
and/or expensive fluoroalkylated reagents. Yet the use of
other abundant and cost-efficient transition metals as cata-
lysts has been scarcely explored.[11] Recently, the preparation
of nickel(II) fluoroalkyl complexes has been documented.[12]
But all of these prepared nickel(II) species were thermally
stable and failed to produce fluoroalkylated arenes under
thermal conditions.[12a] To the best of our knowledge, the
F
luorinated arenes are an important class of substituted
aromatic compounds owing to their presence in numerous
biologically active molecules and functional materials.[1]
Although great endeavors have been made in introducing
fluoroalkylated groups onto aromatic rings and significant
progress has been achieved over the past few years,[2]
developing reliable methods with high generality and practi-
cality remains appealing in this area.[3] Particularly, in the case
of difluoroalkylation of arenes, only a few examples have
been reported so far because of the lack of general and
efficient strategies.[4,5] In view of the unique properties of the
difluoromethylene group (CF2), which can serve as a bioisos-
tere for an oxygen atom or a carbonyl group[6] and has
important applications in biologically active molecules,[7] it is
highly desirable to develop a general strategy and efficient
methods for the preparation of such a valuable structural
motif. In this context, the transition-metal-catalyzed difluoro-
nickel-catalyzed fluoroalkylation of arenes using aryl metals
[13]
À
and Rf X (Rf = CF2R, CF3) have not been reported so far,
and the nickel-catalyzed fluoroalkylation reactions remain
underdeveloped, thus representing a great challenge. What is
À
more, to date, although fluoroalkyl chlorides (Rf Cl) are
among one of the cheapest sources of Rf groups, the
transition-metal-catalyzed cross-coupling between aryl
À
metals and Rf Cl (Rf = CF2R, CF3) has never been reported
À
À
alkylation of aromatics between fluoroalkyl halides (Rf X)
because of their relatively stronger C Cl bond.
À
and aryl metals would be attractive, as the C C bond
As a part of ongoing efforts on the transition-metal-
catalyzed direct introduction of fluorinated functional groups
into organic molecules,[5b–e,14] we herein demonstrate the first
example of nickel-catalyzed difluoroalkylation of aryl boronic
acids. The reaction provides a variety of functionalized
difluoromethyl bromides and chlorides (RCF2X, X = Br, Cl;
R = CO2Et, CONR3R4, COR5, heteroaryl), and paves the way
for highly efficient synthesis of a wide range of difluoroalky-
lated arenes. This protocol has several notable advantages:
1) broad substrate scope; 2) excellent functional-group com-
patibility, even towards bromide; 3) 2.5–5 mol% Ni-
(NO3)2·6H2O as the catalyst; and 4) practical for gram-scale
production. Therefore, this route represents a highly cost-
efficient method for the general synthesis of difluoroalkylated
arenes. To demonstrate the usefulness of this protocol, late-
formation catalyzed by transition metals has proven to be
a powerful strategy owing to its high efficacy, broad substrate
scope, and excellent functional-group compatibility. How-
[*] Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan, 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
[**] This work was financially supported by the National Basic Research
Program of China (973 Program) (No. 2012CB821600), the NSFC
(21172242 and 21332010), and SIOC.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405653.
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stage functionalization for the synthesis of difluoroalkylated
bioactive molecules has been performed.
19F NMR spectroscopy) of 3a was also obtained when 3,3’-
dimethyl-2,2’-bipyridine (L5) was tested (Table 1, entry 8).
However, other diamine ligands were less effective. Encour-
aged by these results, we investigated a variety of nickel
catalysts, bases, and solvents, and found that the reaction was
not sensitive to the nature of nickel salts (for details, see the
Supporting Information), and low-cost Ni(NO3)2·6H2O was
the optimum precatalyst, thus providing 3a in 91% yield
(determined by 19F NMR spectroscopy) along with 4% yield
of 4 (Table 1, entry 9). However, the choice of solvent and
base are crucial for the reaction efficiency, and 1,4-dioxane
and K2CO3 were the best choice (for details, see the
Supporting Information). Other solvents and bases led to
either lower yields or no product. Finally, the optimal reaction
conditions were identified by decreasing the reaction temper-
ature to 608C and using 2.5 mol% Ni(NO3)2·6H2O and
2.5 mol% bpy for 24 hours, thus providing 3a in 87% yield
upon isolation (Table 1, entry 10). No product was observed
in the absence of the nickel catalyst or ligand, thus demon-
strating that nickel does play a catalytic role to promote the
reaction in a highly efficient way.
We began this study by choosing bromodifluoroacetate
(1a) as one of the difluoroalkyl halides because of its low cost,
ready availability, and the potential for various modifications
of the CO2Et moiety in subsequent transformations. Initially,
when 1a was treated with air-stable phenyl boronic acid (2a)
in the presence of NiCl2· DME (5 mol%), terpyridine (tpy)
(5 mol%), and K2CO3 (2 equiv) in 1,4-dioxane at 808C, some
unidentified by-products were detected instead of the desired
product 3a (Table 1, entry 1). In addition, the side-product
Table 1: Representative results for optimization of nickel-catalyzed
cross-coupling of bromodifluoroacetate (1a) with phenyl boronic acid
(2a)[a]
With the optimized reaction conditions, a wide range of
difluoroacyl arenes were generated by this method (Table 2).
Overall, aromatic boronic acids bearing either electron-rich
Entry
[Ni] (x)
Ligand (y)
3a/4
Yield [%][b]
1
2
3
4
5
6
7
8
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
NiCl2·DME (5)
Ni(NO3)2·6H2O (5)
Ni(NO3)2·6H2O (2.5)
tpy (5)
phen (5)
bpy (5)
L1 (5)
L2 (5)
L3 (5)
L4 (5)
L5 (5)
bpy (5)
bpy (2.5)
1/7
32/13
86/2
51/12
13/8
58/6
0/2
87/<1
91/4
Table 2: Nickel-catalyzed difluoroalkylation of organoboronic acids with
bromo/chlorodifluoroacetate.[a]
9
10[c]
98 (87)/2
[a] Reaction conditions (unless otherwise specified): 1a (0.3 mmol,
1.0 equiv), 2a (1.5 equiv), 1,4-dioxane (2 mL), 8 h. [b] Determined by
19F NMR spectroscopy using fluorobenzene as an internal standard and
the number within parentheses represents the yield of the isolated
product. [c] 1a (0.6 mmol, 1.0 equiv), 2a (1.5 equiv), 1,4-dioxane (4 mL)
at 608C for 24 h. DME=dimethyl ether.
HCF2CO2Et (4; 7% yield) and the homocoupled product
(CF2CO2Et)2 (5; 3%) were also detected in the reaction. To
suppress the competitive side reactions and improve the
reaction efficiency, different tri-/diamine ligands were exam-
ined because the tri-/diamine ligands can stabilize the
homogenous nickel complexes by chelation and increase
electron density at the nickel center (Table 1, entries 2–8).
Among the tested ligands, the triamine ligand pybox led to
similar negative results (for details, see the Supporting
Information). But the diamine ligand, 1,10-phenanthroline
(phen) furnished 3a in 32% yield, albeit with the generation
of 13% yield of 4 (Table 1, entry 2). Importantly, the
formation of the homocoupled by-product 5 was totally
inhibited by using diamine ligands. To our delight, when
bipyridine (bpy) was examined a dramatically improved yield
of 3a (86%, determined by 19F NMR spectroscopy), along
with 2% yield of the protonated side-product 4, was obtained
(Table 1, entry 3). A comparable yield (87% determined by
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol), 2
(1.5 equiv), 1,4-dioxane (4 mL), 24 h. [b] Reaction conducted at 808C.
[c] 1 (0.6 mmol), 2 (2.0 equiv), Ni(NO3)2·6H2O (5 mol%), bpy
(5 mol%), PPh3 (5 mol%), 808C. [d] Reaction carried out on a gram
scale.
or electron-deficient substituents all led to 3 in moderate to
high yields. Many important functional groups, such as the
alkoxycarbonyl, enolizable ketone, nitrile, and methylsul-
fonyl, were quite well-tolerated (3 f–i). Most remarkably,
aromatic boronic acids bearing a bromide underwent reaction
smoothly with yield as high as 95% (3k). Even benzyl
bromide, an active electrophile, was compatible with the
present catalytic system, thus providing 3l in good yield.
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Table 3: Nickel-catalyzed difluoroalkylation of organoboronic acids with
These results are in sharp contrast to those of previous
palladium-catalyzed reactions, in which bromide-containing
aryl boronic acids are unsuitable substrates.[5d] Furthermore,
the sterically hindered o-tolylboronic acid was also a compe-
tent coupling partner leading to high product yield (3c). On
the contrary, no 3c was provided when palladium was used as
the catalyst. Thus, compared to previous methods,[5a,d] the
present nickel catalytic system not only features its low cost,
but also exhibits a wide substrate scope towards the formation
of difluoroalkylated arenes. It is also possible to prepare
difluoroalkylated arenes on a gram scale. High yield was
obtained for the gram-scale synthesis of 3k, thus offering
a reliable and practical access to highly functionalized
difluoroalkylated arenes.
functionalized difluoromethyl bromides and chlorides.[a]
To demonstrate the generality of this catalytic system, the
chlorodifluoroacetate (1b) was explored. To our delight, by
increasing the amount of Ni(NO3)2·6H2O to 5 mol% in
conjuction with PPh3 (5 mol%) as a ligand, good yields of the
difluoroacyl arenes were still obtained (3a–e). Although
some functional groups containing aryl boronic acids led to
low yields (3 f and 3h), this is the first example of transition-
À
metal-catalyzed fluoroalkylation of aryl metals with Rf Cl.
We believe that this cross-coupling process will prompt the
research in nickel-catalyzed fluoroalkylation reactions with
À
Rf Cl.
This advantage has been further demonstrated by extend-
ing the scope of the difluoroalkyl halides to bromo/chlorodi-
fluoroacetamides and a-bromo/chloro-a,a-difluoroketones
(Table 3). Good yields were obtained when bromo/chlorodi-
fluoroacetamides were examined (6a,b). Importantly, the
protic amide did not interfere with the reaction (6b). The a-
bromo-a,a-difluoroacetophenones were also suitable sub-
strates, thus providing their corresponding difluoroalkylated
arenes with high efficiency (6c–e). This reactivity is note-
worthy, as it has been demonstrated that the a-aryl-a,a-
difluoroacetophenone products could be converted into
various difluoroalkylated molecules.[5f] It should be men-
tioned that the alkyl-substituted a-bromo-a,a-difluoroketone
also reacted smoothly, thus providing 6 f in high yield (93%).
To the best of our knowledge, this is the first example to
access such difluoroalkylated arenes through a transition-
metal-catalyzed process, thus further highlighting the wide
application scope of the present catalytic system. What is
more, the a-chloro-a,a-difluoroketone was also a competent
coupling partner, thus providing its corresponding product in
good yield (6c).
The reaction was not restricted to bromo/chlorodifluoro-
acetate (1a,b) and their derivatives, as some other function-
alized difluoromethyl bromides and chlorides were also
investigated. Bromodifluoromethylbenzoxazole[15] furnished
the corresponding aryl(heteroayl)difluoromethane in good
yields (6g–m). The bromodifluoromethylated thiazole and
benzoimidazole[15] were also applicable to the cross-coupling
reactions, thus providing 6n and 6o, respectively, with high
efficiency. This reactivity is noteworthy, as benzoxazole,
benzoimidazole, thiazole, and their derivatives are a class of
prominent structural motifs in numerous pharmaceuticals and
agrochemicals.[16] Importantly, heteroaryl difluoromethyl
chlorides also underwent the reactions smoothly, thus provid-
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol), 2
(1.5 equiv), Ni(NO3)2·6H2O (2.5 mol%), bpy (2.5 mol%), 1,4-dioxane
(4 mL), 24 h. [b] 1 (0.6 mmol), 2 (2.0 equiv), Ni(NO3)2·6H2O (5 mol%),
bpy (5 mol%), PPh3 (5 mol%). [c] [NiCl2(dppe)] (2.5 mol%). [d] Ni-
(NO3)2·6H2O (5 mol%), bpy (5 mol%). dppe=1,2-Bis(diphenylphos-
phino)ethane.
ing the corresponding products in even higher yields (6g–l,o).
To date, however, there has been no efficient and reliable
method to access such difluoroalkylated arenes.[17] Thus, the
present process provides a facile route for applications in drug
discovery and development.
To demonstrate the importance and utility of this method,
the late-stage difluoroalkylation of biologically active mole-
cules was performed. As shown in Scheme 1a–c, treatment of
the flavanone-derived aryl boronic acid 7 with the difluoro-
alkyl bromides 1a and 1j afforded difluoroalkylated com-
pounds 8 and 9, respectively, with good efficiency (Sche-
me 1a,b). This transformation provides a highly valuable
possibility for drug discovery and development because of the
significant bioactivities of flavanone, as well as unique
characteristics of CF2 group. Furthermore, the difluoroalky-
lated estrone derivative 11 was obtained in good yield, thus
further highlighting the importance of this protocol (Sche-
me 1c).
On the basis of previous reports,[18] a plausible reaction
mechanism involving a NiI/NiIII catalytic cycle was proposed
(Scheme 2). The transmetalation between [NiILn] (A) and
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Keywords: boronic acids · cross coupling ·
.
fluorine · nickel · synthetic methods
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simultaneously.
In conclusion, we demonstrated the first successful
example of nickel-catalyzed difluoroalkylation of aryl boronic
acids. Using the diamine ligand bpy is critical for the reaction
efficiency. The reaction allows a variety of functionalized
difluoromethyl bromides and chlorides, and provides a gen-
eral method for efficient and practical synthesis of difluor-
oalkylated arenes. Because of the low cost of the nickel
catalyst, as well as broad substrate scope and excellent
functional-group compatibility of this method, we believe that
it will not only be useful for drug discovery and development,
but also prompt the research for nickel-catalyzed fluoroalky-
lation reactions, in particular with fluoroalkyl chlorides.
Further studies to uncover the reaction mechanism and to
develop derivative reactions are underway in our laboratory.
Received: May 26, 2014
Published online: && &&, &&&&
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Am. Chem. Soc. 2006, 128, 13175; d) V. B. Phapale, E. Bunuel,
M. Garcia-Iglesias, D. J. Cardenas, Angew. Chem. 2007, 119,
8946; Angew. Chem. Int. Ed. 2007, 46, 8790; e) X. Lin, D. L.
Phillips, J. Org. Chem. 2008, 73, 3680; For an overview of
mechanistic issues regarding nickel-catalyzed cross-couplings of
unactivated alkyl halides, see: f) X. Hu, Chem. Sci. 2011, 2, 1867.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan,
X. Zhang*
&&&& — &&&&
Nickel-Catalyzed Cross-Coupling of
Functionalized Difluoromethyl Bromides
and Chlorides with Aryl Boronic Acids: A
General Method for Difluoroalkylated
Arenes
Simple and easy: The first example of
nickel-catalyzed difluoroalkylation of aryl
boronic acids with functionalized
has been developed. This cross-coupling
process features a broad substrate scope,
a cheap catalyst, and excellent functional-
group compatibility.
difluoromethyl bromides and chlorides
Synthesemethoden
Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan,
X. Zhang*
&&&& — &&&&
Nickel-Catalyzed Cross-Coupling of
Functionalized Difluoromethyl Bromides
and Chlorides with Aryl Boronic Acids: A
General Method for Difluoroalkylated
Arenes
Einfach und leicht: Die ersten Beispiele
einer Nickel-katalysierten Difluoralkylie-
rung von Arylboronsꢀuren mit funk-
tionalisierten Difluormethylbromiden
und -chloriden wurden entwickelt. Dieser
Kreuzkupplungsprozess hat einen großen
Substratbereich, setzt einen preiswerten
Katalysator ein und toleriert zahlreiche
funktionelle Gruppen.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan,
X. Zhang*
&&&& — &&&&
Nickel-Catalyzed Cross-Coupling of
Functionalized Difluoromethyl Bromides
and Chlorides with Aryl Boronic Acids: A
General Method for Difluoroalkylated
Arenes
Simple and easy: The first example of
nickel-catalyzed difluoroalkylation of aryl
boronic acids with functionalized
has been developed. This cross-coupling
process features a broad substrate scope,
a cheap catalyst, and excellent functional-
group compatibility.
difluoromethyl bromides and chlorides
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!