Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1-Bromo-1,1-difluoroalkanes

Article abstract of DOI:10.1002/anie.201601351

A nickel-catalyzed cross-coupling between (hetero)arylborons and unactivated 1-bromo-1,1-difluoroalkanes has been developed. The use of two ligands (a bidentate bipyridine-based ligand, 4,4′-ditBu-bpy, and a monodentate pyridine-based ligand, DMAP) offers a highly efficient nickel-based catalytic system to prepare difluoroalkylated arenes which have important applications in medicinal chemistry. Ligand combo: The title reaction requires the use of a combined (2+1) ligand system, that is, a combination of a bi- and monodentate ligand (4,4′-ditBu-bpy + DMAP). This system allows employment of a wide range of unactivated 1-bromo-1,1-difluoroalkanes as coupling partners, thus providing a highly efficient method for applications in drug discovery and development. bpy=bipyridine, DMAP=4-(N,N-dimethylamino)pyridine.

Full text of DOI:10.1002/anie.201601351

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International Edition: DOI: 10.1002/anie.201601351
German Edition: DOI: 10.1002/ange.201601351
Cross-Coupling
Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with
Unactivated 1-Bromo-1,1-difluoroalkanes
Yu-Lan Xiao+, Qiao-Qiao Min+, Chang Xu, Ruo-Wen Wang, and Xingang Zhang*
Abstract: A nickel-catalyzed cross-coupling between (hetero)-
arylborons and unactivated 1-bromo-1,1-difluoroalkanes has
been developed. The use of two ligands (a bidentate bipyridine-
based ligand, 4,4’-ditBu-bpy, and a monodentate pyridine-
based ligand, DMAP) offers a highly efficient nickel-based
catalytic system to prepare difluoroalkylated arenes which
have important applications in medicinal chemistry.
ably improved metabolic stability of urea transporter B (UT-
B) inhibitor (II), used for edema, has also resulted from
replacement of benzylic CH2 with CF2.[2b] The most common
method to access difluoroalkylated arenes (Ar-CF2-alkyl), in
which the difluorocarbon is substituted by an alkyl group,
relies on the deoxygenative fluorination of a ketone with
aminosulfur trifluorides, such as diethylaminosulfur trifluor-
ide (DAST) or its derivatives.[3] However, such a process is
restricted by its poor functional-group compatibility. To date,
examples of efficient synthesis of Ar-CF2-alkyl are very
D
ifluoroalkylated arenes, in which a methylene group
(CH2) is replaced by its difluorinated counterpart (CF2) at
the metabolically labile benzylic position, constitute a distinct
class of fluorinated compounds in medicinal chemistry
because of the unique properties of CF2 which can enhance
the acidity of its neighboring group and dramatically improve
the metabolic stability of biologically active compounds.[1] As
a result, the incorporation of a CF2 group into organic
compounds at benzylic positions has become one of the useful
strategies for modification of biologically active compounds
(Figure1).[2] For example, application of this strategy led to
a difluorinated nitric oxide synthase (NOS) inhibitor (I) for
chronic neurodegenerative pathologies with improved oral
bioactivity compared to its parent compound.[2a] A remark-
limited.[4] Recently, the direct fluorination of benzylic C H
À
bonds to prepare difluoroalkylated arenes has been
reported.[5] Despite the importance of this method, it cannot
selectively introduce the difluoroalkyl groups at any desired
position on an aromatic ring. In particular, this strategy is not
suitable for late-stage difluoroalkylation of complex mole-
cules because of the limited availability of benzylic precur-
sors. Therefore, developing efficient and mild methods to
synthesize Ar-CF2-alkyl is appealing, and would provide
a useful instrument for drug discovery and development.
Considering the ready availability of 1-bromo-1,1-
difluoroalkanes[6] and arylmetals, we envisioned that the
transition-metal-catalyzed difluoroalkylation of arylboronic
acids with unactivated 1-bromo-1,1-difluoroalkanes would be
a straightforward and facile access to Ar-CF2-alkyl com-
pounds. Although examples of transition-metal-catalyzed
difluoroalkylation of aromatics have been reported, all of
the difluoroalkylating reagents (XCF2R1) used for the
reported reactions require
a p-system to activate the
XCF2R1 (R1 = p-system).[7,8] Very recently, a nickel-catalyzed
Suzuki-cross coupling of unactivated 1-halo-1-fluoroalkanes
(XFCH-Alkyl, X = Cl, Br, I) for the synthesis of secondary
alkyl fluorides was reported by Gandelman and co-workers.[9]
However, to the best of our knowledge, the use of unactivated
XCF2R1 (R1 = alkyl) to prepare Ar-CF2-akyl compounds
through such a strategy has not been reported and remains
a challenge[9,10] because of the difficulties in the oxidative
addition and in suppressing b-hydride elimination and
dehalogenation.[11] Additionally, the competitive defluorina-
tion reaction is also another hurdle to realizing such
a reaction.[12] In this study, we describe the discovery,
development of the reaction which meets these challenges.
Inspired by our previous work on nickel-catalyzed
difluoroalkylation of arylboronic acids with functionalized
difluoroalkyl bromides (XCF2R1, R1 = p-system),[8c] initially,
we focused our efforts on the cross-coupling of phenylboronic
acid (2a) with (5-bromo-5,5-difluoropentyl)benzene[6a] (1a)
in the presence of NiCl2·DME (5 mol%), with bipyridine
(bpy) as a ligand (Table 1). It was found that 19% yield of the
product 3a along with the hydrodebrominated 4a (3% yield)
Figure 1. Representative biologically active molecules containing
difluoroalkyl arene moieties.
[*] Y.-L. Xiao,[+] Q.-Q. Min,[+] C. Xu, Dr. R.-W. Wang, 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.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601351.
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Table 1: Representative results for the optimization of the nickel-
catalyzed cross-coupling of 1a with 2a.[a]
Table 2: Nickel-catalyzed difluoroalkylation of arylboronic acids 2 with
1a.[a]
Entry
L
Solvent
Additive
(mol%)
Yield [%][b]
3a
(mol%)
4a 1a
1
2
3
4
5
6
7
8
bpy (5)
bpy (5)
L (5)
L (5)
L (5)
L (5)
L (5)
L (5)
L (5)
–
1,4-dioxane
triglyme
triglyme
triglyme
triglyme
triglyme
triglyme
triglyme
triglyme
triglyme
–
–
–
19
43
52
80
3
6
6
6
6
5
5
2
69
51
38
12
6
0
35
–
Py (10)
4-MeOPy (10) 86
DMAP (10)
4-CF3Py (10)
DMAP (20)
DMAP (20)
DMAP (20)
94
55
94 (92)
n.r.
n.r.
9[c]
10
[a] Reaction conditions (unless otherwise specified): 1a (0.3 mmol,
1.0 equiv), 2a (1.5 equiv), solvent (2 mL), 12 h. [b] Determined by
19F NMR spectroscopy using fluorobenzene as an internal standard.
Value within parentheses is the yield of the isolated product. [c] Reaction
was carried out in the absence of NiCl2·DME, 12 h. DME=
1,2-dimethoxyethane.
and unreacted 1a (69% yield) were obtained (entry 1). But
the b-hydride elimination product (5a) was not observed.[13]
To improve the reaction efficiency further, we examined
a range of solvents, nickel catalysts, ligands, and bases (for
details, see the Supporting Information). Ethereal solvents
have a beneficial effect on the reaction, and triglyme was the
best choice, thus providing 3a in 43% yield (entry 2). Among
the tested ligands, the use of the bipyridine-based ligand 4,4’-
ditBu-bpy (L) improved the yield of 3a to 52% (entry 3), but
4a (6% yield) and 1a (38% yield) were still observed under
these reaction conditions. This outcome is probably a result of
the low reactivity of 1a. We envisioned that if we used another
tunable ligand to increase electron density at the nickel
center, it would be feasible to accelerate the oxidative
addition step and improve the yield of 3a further. Apparently,
with this combined ligand system [(2 + 1) a bidentate ligand
plus a monodentate ligand], it would be easy to modulate the
electronic and steric properties of the nickel center without
tedious preparation of complicated ligands. Accordingly,
different pyridine derivatives were tested (entries 4–8). As
expected, the electronic nature of pyridine dramatically
influenced the reaction efficiency, and electron-rich 4-
MeOPy afforded a higher yield of 3a (86%), as compared
to that obtained with the electron-deficient 4-CF3Py (55%;
entries 5 and 7). To our delight, a highest yield (94%) was
produced with the more electron-rich 4-(N,N-dimethylami-
no)pyridine (DMAP) as a co-ligand (entry 6). The use of
20 mol% of DMAP is required because of the reproducibility
of the reaction (entry 8). The absence of either the nickel
catalyst or ligand resulted in no product (entries 9 and 10),
thus demonstrating that the NiCl2·DME/L does play an
essential role in promoting the catalytic cycle.
[a] Reaction conditions (unless otherwise specified): 1a (0.6 mmol,
1.0 equiv), 2 (1.5–2.0 equiv), triglyme (4 mL), 12–24 h. All reported yields
are those of the isolated products. [b] NiCl2·DME (2.5 mol%), L
(2.5 mol%), DMAP (10 mol%), 708C, 24 h. [c] Reaction run for 48 h.
[d] Yield determined by 19F NMR spectroscopy. The compound 3e is
unstable upon purification with silica gel chromatography.
To ascertain the substrate scope of this method, a variety
of arylboronic acids were investigated (Table 2). Overall,
arylboronic acids bearing electron-donating or electron-with-
drawing groups all underwent the reaction smoothly. Notably,
in the case of 4-(diphenylamino)phenyl boronic acid (2e),
only 2.5 mol% NiCl2·DME/L was used, and provided the
corresponding difluoroalkylated arene 3e with high effi-
ciency. Importantly, a variety of important functional groups,
including base- and nucleophile-sensitive moieties, such as an
enolizable ketone, formyl, alkoxycarbonyl, cyano, and meth-
ylsulfonyl groups, tolerated the reaction quite well (3j–q),
thus providing good opportunities for downstream trans-
formation without protection and deprotection steps. In
addition, (9-phenyl-9H-carbazol-3-yl)boronic acid was also
applicable to the reaction and provided 3r in 88% yield.
However, vinyl, benzyl, and aliphatic boronic acids were not
suitable substrates, and will be the subject of future work.
In addition to demonstrating the substrate scope of this
reaction, a variety of difluoroalkyl bromides (1) were
examined. As shown in Table 3, 1-bromo-1,1-difluorononane
(1b) and (2-bromo-2,2-difluoroethyl)benzene (1c) furnished
the corresponding difluoroalkylated arenes with good yields
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Table 3: Nickel-catalyzed difluoroalkylation of arylboronic acids 2 with
Table 4: Nickel-catalyzed difluoroalkylation of heteroarylborates 7 with
1a.[a]
1.[a]
[a] Reaction conditions (unless otherwise specified): 1a (0.3 mmol,
1.0 equiv), 7 (0.45 mmol, 1.5 equiv), triglyme (2 mL), 24 h. All reported
yields are those of the isolated products. [b] NiCl2·DME (15 mol%), L
(15 mol%) and 7 (0.6 mmol, 2.0 equiv) were used. [c] [NiCl2·DME]
(15 mol%) and L (15 mol%) were used. The yield was determined by
19F NMR spectroscopy because of the instability of 8d upon purification
using silica gel chromatography.
3-pyridylboronic acid (7a’) was used as a coupling partner.
However, after extensive efforts, we found that switching 7a’
with lithium triisopropyl 3-pyridylborate (7a), which was
previously demonstrated to be stable against protodeborna-
tion,[14] afforded 8a in 51% yield. Encouraged by these
results, other heterarylborates, such as quinolone-, indole-,
and pyrimidine-containing lithium triisopropyl borates were
also examined and provided corresponding products in good
yields (8c–e). Because heteroaromatics are a class of impor-
tant structural motif in numerous pharmaceuticlas and agro-
chemicals, we view this transformation would be a useful
instrument for drug discovery and development.
It is also possible to prepare difluoroalkylated arenes on
a gram scale. As shown in Table 3 and Scheme 1a, good yields
were provided for the gram-scale synthesis of 6k and 3o,
respectively, thus offering a reliable and practical access to
highly functionalized difluoroalkylated arenes. Importantly,
3o can be easily transformed into the aryl borate 9,[15] thus
providing good possibilities for the synthesis of complex
fluorinated molecules. To demonstrate the importance and
utility of this method, the late-stage difluoroalkylation of
Fenofibrateꢀ, a drug against cardiovascular disease,[16] was
[a] Reaction conditions (unless otherwise specified): 1 (0.6 mmol,
1.0 equiv), 2 (1.5 equiv), triglyme (4 mL). All reported yields are those of
the isolated products. [b] NiCl2·DME (2.5 mol%), L (2.5 mol%), DMAP
(10 mol%), 708C, 24 h. [c] Reaction run on a gram scale. Boc=tert-
butoxycarbonyl, TBS=tert-butyldimethylsilyl, Ts =4-toluenesulfonyl.
(6a–f). Excellent functional-group compatibility was also
observed for difluoroalkyl bromides. The substrates 1, bearing
important functional groups, such as enolizable alkoxycar-
bonyl, tosyloxy, hydroxy, amide, nitrile, ferrocenyl, and
thiazole, all underwent the reactions smoothly (6g, 6h,
6m–t, 6w). Remarkably, the successful formation of 6l with
an intact bromide also highlighted the advantage of the
present reaction. The reaction also delivered the compounds
6o and 6q, which are key intermediates in the preparation of
a nitric oxide synthase (NOS) inhibitor (I)[2a] and anti-HIV
agent (III), respectively.[2c] Moreover, the amino-acid-con-
taining difluoroalkyl bromide 1n was a competent coupling
partner and afforded 6u and 6v with good to high yields
without erosion of the enantioselectivity (for details, see the
Supporting Information). This fact is noteworthy, as the
fluorinated amino acids and their derivatives have important
applications in the chemical biology.
The reaction can also be extended to heteroarylboron
compounds (Table 4). Initially, no product was obtained when
Scheme 1. Synthesis of difluoroalkylated arenes for biologically active
molecules.
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successfully performed (Scheme 1b), thus featuring the
applicability of this protocol in medicinal chemistry.
key intermediates for the synthesis of biologically relevant
compounds. We believe that this method will not only provide
a useful instrument for drug discovery and development, but
also prompt research in transition-metal-catalyzed fluoro-
alkylation reactions with unactivated halofluoroalkanes. Fur-
ther studies to develop derivative reactions are underway in
our laboratory and will be reported in due course.
To establish whether DMAP serves as a co-ligand to
coordinate to the nickel complex and thus facilitate the
catalytic cycle, a nickel complex [NiCl2(4,4’-ditBu-bpy)] (13)
was prepared.[17] When the reaction of 2a with 1a was carried
out in the presence of 13, DMAP, and K2CO3 in triglyme at
808C, a comparable yield of 3a was provided (Scheme 2a). A
similar finding was also observed by using [NiCl2(DMAP)4]
(14) as a precatalyst and 4,4’-ditBu-bpy as a ligand (Sche-
me 2b). Thus, these results demonstrated that DMAP can
function as a co-ligand to facilitate the nickel-based catalytic
cycle, and the combined ligands (4,4’-ditBu-bpy + DMAP)
offered a highly efficient nickel-based catalytic system for the
preparation of Ar-CF2-alkyl compounds, which are important
in medicinal chemistry.
Acknowledgements
This work was financially supported by the National Basic
Research Program of China (973 Program) (No.
2012CB821600 and 2015CB931900), the NSFC (21425208,
21421002, and 21332010), and SIOC.
Keywords: arenes · cross-coupling · fluorine · ligand design ·
nickel
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5837–5841
Angew. Chem. 2016, 128, 5931–5935
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Received: February 6, 2016
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Published online: April 6, 2016
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