Nickel-catalyzed monofluoromethylation of aryl boronic acids

Article abstract of DOI:10.1002/anie.201412026

Aryl boronic acids can be monofluoromethylated under nickel catalysis. The utility of this method is demonstrated by the monofluoromethylation of a borylated and acyl-protected derivative of the statin drug ezetimibe. Mechanistic investigations indicate that a fluoromethyl radical is involved in the Ni^I/Ni^III catalytic cycle.

Full text of DOI:10.1002/anie.201412026

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201412026
German Edition: DOI: 10.1002/ange.201412026
Monofluoromethylation
Nickel-Catalyzed Monofluoromethylation of Aryl Boronic Acids**
Yi-Ming Su, Guang-Shou Feng, Zhen-Yu Wang, Quan Lan, and Xi-Sheng Wang*
The incorporation of fluorine atoms into small organic
molecules can often drastically enhance the metabolic
stability, lipophilicity, and bioavailability, and can also
increase the receptor-binding affinity and the selectivity
relative to the parent molecule.[1] As a result, fluorine-
containing compounds have been widely used in pharma-
ceutical and agrochemical products.[2] Recently, the selective
introduction of monofluoromethyl groups into small organic
molecules has emerged as a new strategy in drug design.
Notably, many biologically active molecules, including the
widely prescribed afloqualone, fluticasone propionate, and
the anaesthetic sevoflurane, contain a CH2F group as an
essential motif.[3]
Although a variety of methods for the transition-metal-
catalyzed trifluoromethylation[4] and difluoromethylation[3b,5]
Scheme 1. Transition-metal-promoted monofluoromethylation.
of arenes have been developed in the past several decades, the
incorporation of methyl groups containing a single fluorine
(CH2F) into arenes has been studied to a lesser extent and
remains a challenge.[6] The only example of a palladium-
mediated direct monofluoromethylation of pinacol phenyl-
boronate was reported by the Suzuki group in 2009.[7] Therein,
a stoichiometric amount of palladium and a large excess of the
boronic ester (40 equiv) were required, and the yield was
modest (57%, Scheme 1). More recently, using fluoromethyl
2-pyridyl sulfone reagents, Hu and co-workers reported
a copper-mediated monofluoromethylsulfonylation of aryl
iodides.[8a,b] Herein, the requirement of the coordinating 2-
pyridylsulfone group prohibits access to other stabilized
monofluoromethylating groups. As in the report from
Suzuki and co-workers, this reaction is also hampered by
the high loading of a transition metal (0.3–2.0 equiv of
copper), and also suffers from operational inconvenience
imparted by the requisite stepwise addition of reagents.
Herein, we report the first example of a nickel-catalyzed
monofluoromethylation of aryl boronic acids, wherein the
fluoromethylating reagents bear either a phenylsulfone or an
ethoxycarbonyl moiety.[9–11]
We commenced our study with phenylboronic acid (1a) as
the pilot substrate and PhSO2CFHI[8] (2) as the coupling
partner in the presence of a catalytic amount of [Ni(acac)2]
(5 mol%) in dichloromethane at 1008C. To our delight, the
desired fluoro(phenylsulfonyl)methylated product 3a was
obtained in 45% yield when XantPhos (10 mol%) was used
as the ligand (Table 1, entry 2). Furthermore, a careful survey
of bases (entries 3–6) and solvents (see Table S2 in the
Supporting Information) was then performed, which showed
the combination of K2CO3 and dicholoromethane to be
optimal. To improve the yield further, a variety of phosphine
and diamine ligands were examined next. In contrast to
previous reports on nickel-catalyzed reactions, in which
diamine ligands are the most effective, phosphine ligands,
including diphosphines (BINAP, dppe and dppf) and mono-
phosphines (PPh3), afforded the desired fluoromethylated
product in up to 87% yield of isolated product (entry 20).
Meanwhile, no improvement was found when the reaction
temperature was changed (entry 21). Additionally, the inves-
tigation of aryl boron reagents showed that triphenylborox-
ine, usually in equilibrium with 1a, gave the isolated products
in slightly lower yield (75%, entry 23), while phenylboronic
ester and trifluoroborate afforded no desired product (see
Table S4 in the Supporting Information). Last, the control
experiment indicated that none of the fluoromethylated
product was obtained without nickel catalyst (entry 24).
With the optimized conditions in hand, we next inves-
tigated the scope of the procedure by testing various aryl
boronic acids in reaction with 2. As shown in Scheme 2, para-,
meta-, and even ortho-substituted aryl boronic acids are all
effective cross-coupling partners, affording the corresponding
fluoromethylated arenes in good yields. Aryl boronic acids
substituted with electron-donating groups are fluoromethy-
lated smoothly to give the desired product with good yields
(3b–3i). A range of halogenated boronic acids are also well-
[*] Y.-M. Su, G.-S. Feng, Z.-Y. Wang, Dr. Q. Lan, Prof. Dr. X.-S. Wang
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
E-mail: xswang77@ustc.edu.cn
[**] We gratefully acknowledge the National Basic Research Program of
China (973 Program 2015CB856600), the National Science Foun-
dation of China (21102138, 21372209), the Chinese Academy of
Sciences, and the Excellent Young Scientist Foundation of Anhui
Province (2013SQRL003ZD, for Q.L.) for financial support. G.-S.F.
is a visiting student from Dalian Institute of Chemical Physics, CAS.
We thank Prof. Benjamin J. Stokes from UC Merced for helpful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412026.
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Table 1: Nickel-catalyzed monofluoromethylation of phenylboronic
acids: optimization of reaction conditions.[a]
Entry
Ligand
Base
Yield [%][b]
1
2
3
4
5
6
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XPhos
No
0
Cs2CO3
K2CO3
KOtBu
KOAc
DABCO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
45
48
37
0
0
7
7[c]
8[d]
9[e]
10
11
12
13
14
15
16
17
18
19
20
21[g]
22[h]
23[i]
24
0
28
20
0
81
79
89
11
31
0
27
41
97 (87[f])
70
53
75[f]
0[j]
SPhos
BINAP
dppf
dppe
P(o-tol)3
P(2-furyl)3
bpy
TMEDA
DMEDA
PPh3
PPh3
PPh3
PPh3
PPh3
[a] Reaction conditions (unless otherwise noted): PhSO2CFHI
(0.2 mmol, 1.0 equiv), 1a (2.0 equiv), [Ni(acac)2] (5 mol%), ligand
(10 mol%), base (1.5 equiv), CH2Cl2 (2.0 mL), 1008C, 24 h. [b] Yields
determined by GC analysis. [c] CHCl3 was used as solvent. [d] DMF was
used as solvent. [e] Toluene was used as solvent. [f] Yield of isolated
product. [g] Reaction at 808C. [h] 1a (1.0 equiv) was used. [i] Triphenyl-
boroxine (1.0 equiv) was used instead of 1a. [j] No [Ni(acac)2].
tolerated by this method (3j–3m). The presence of halo
substituents in the products offers the potential for further
synthetic elaboration through metal-catalyzed coupling reac-
tions. In particular, aryl boronic acids containing electron-
withdrawing groups, including trifluoromethyl (3n–3p),
cyano (3q), ester (3r), and nitro groups (3s), were also
fluoroalkylated with satisfactory yields in our catalytic
system. Although a higher catalyst and ligand loading is
typically required, these arenes are usually ineffective part-
ners in nickel-catalyzed cross-coupling reactions.[10a,11] Addi-
tionally, boronic acids derived from polycyclic and hetero-
cyclic arenes, such as p-biphenyl (3t), 2-naphthyl (3u),
thiophene (3v–3w), dibenzothiophene (3x), and dibenzo-
furan (3y), are also compatible with the reaction conditions.
Finally, even a tyrosine derivative and a flavanone derivative
may be monofluoromethylated, leading to 3z and 3za,
respectively, both in satisfactory yields.
Scheme 2. Scope of substituted phenylboronic acid substrates. Reac-
tion conditions (unless otherwise noted): PhSO2CFHI (0.2 mmol,
1.0 equiv), 1 (2.0 equiv), [Ni(acac)2] (5 mol%), PPh3 (10 mol%), K2CO3
(1.5 equiv), CH2Cl2, 1008C, 24 h. Yields of isolated products are
reported. [a] [Ni(acac)2] (20 mol%), PPh3 (40 mol%). [b] [Ni(acac)2]
(10 mol%), PPh3 (20 mol%). [c] [Ni(acac)2] (20 mol%), PPh3
(40 mol%), and 1 (2 equiv) were added in two batches (50% each
time). [d] [Ni(acac)2] (10 mol%), PPh3 (20 mol%), and 1 (2 equiv)
were added in two batches (50% each time). [e] No racemization.
ing 2-fluoro-2-aryl acetates in yields on par with those
observed
in
the
fluoro(phenylsulfonyl)methylations
(Scheme 3). Both electron-donating groups, such as methyl,
methoxy, and thiomethyl (5b–5g), and electron-withdrawing
groups, such as fluoro, chloro, bromo, trifluoromethyl, cyano,
ethoxycarbonyl, acyl, and even an aldehyde (5h–5r), are well-
tolerated using this protocol. A dibenzothiophene-derived
boronic acid is also a suitable coupling partner of this
fluoroacetation, leading 5u in a good yield. Again, biologi-
cally relevant tyrosine- and flavanone-derived boronic acids
To test whether this method could be extended to
fluoromethylating reagents other than sulfone 2, we exam-
ined ethyl 2-bromo-2-fluoroacetate (4) as a fluoromethylator.
To our excitement, phenylboronic acid was fluoroacetated in
excellent yield (94%, Scheme 3, 5a). The optimized reaction
conditions were applied to a variety of boronic acids, furnish-
2
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of a radical scavenger, namely 2,2,6,6-tetramethyl-1-piperidi-
nyloxy (TEMPO), the monofluoromethylated product 3a was
not obtained [Eq. (1), Scheme 4]. This observation is consis-
Scheme 4. Radical trapping experiments.
tent with reports that the oxidative addition step in nickel-
catalyzed cross-couplings proceeds through a radical path-
way.[12] We were also able to trap the PhSO2CHF· radical
using b-pinene 6 under our standard conditions, affording the
ring-opened diene 7 as a mixture of isomers [Eq. (2),
Scheme 4), which further implicated the generation of the
fluoro(phenylsulfonyl)methyl radical in the catalytic cycle.
Furthermore, catalytic (5 mol%) and stoichiometric amounts
of [Ni(PPh3)4] were subjected to the standard conditions,
respectively, but gave none or only trace amounts of 3a, thus
indicating that the Ni0 species might not be involved in the
catalytic cycle (see the Supporting Information for a detailed
discussion).
On the basis of the above results and previous reports,[13]
a plausible mechanism involving a NiI/NiIII catalytic cycle was
proposed (Scheme 5). The transmetalation between aryl
Scheme 3. Scope of substituted phenylboronic acid substrates. Reac-
tion conditions (unless otherwise noted): EtO2CCFHBr (0.2 mmol,
1.0 equiv), 1 (2.0 equiv), [Ni(acac)2] (5 mol%), PPh3 (10 mol%), K2CO3
(1.5 equiv), CH2Cl2, 1008C, 24 h. Yields of isolated products are
reported. [a] [Ni(acac)2] (10 mol%), PPh3 (20 mol%). [b] [Ni(acac)2]
(10 mol%), PPh3 (20 mol%) and 1 (2 equiv) were added in two
batches (50% each time). [c] [Ni(acac)2] (20 mol%), PPh3 (40 mol%),
and 1 (2 equiv) were added in two batches (50% each time). [d] [Ni-
(acac)2] (20 mol%), PPh3 (40 mol%). [e] No racemization.
Scheme 5. Possible mechanism.
boronic acid 1 and the initial NiI species A, which may be
produced through the comproportionation reaction of in situ
generated Ni0 and the remaining NiII species,[13a,j] could
generate NiI–Ar species B, which subsequently activates 2
through a single-electron transfer to afford NiII intermediate
C and the corresponding alkyl radical. Intermediate C is then
further oxidized to NiIII species D through an oxidative
radical addition, followed by reductive elimination to liberate
the final monofluoromethylated product 3.
The reductive desulfonylation of 3 mediated by Na(Hg)
proceeded smoothly with both electron-donating and elec-
tron-withdrawing substituents on the phenyl ring in MeOH/
THF at À208C,[14] affording the fluoromethyl arenes 8a–8 f in
excellent yields (Scheme 6). In addition, the fluoroacetated
arenes 5 can be hydrolyzed under very mild conditions to
were monofluoromethylated smoothly under the reaction
conditions to give the fluoroalkyl products 5v and 5w,
respectively, with acceptable yields. Notably, a vinyl boronic
acid was also compatible with this method, giving the product
in an acceptable yield (63%, 5x). While electron-deficient
aryl- and heteroaryl boronic acids were not suitable coupling
partners in the palladium-catalyzed method developed by
Qing and co-workers,[9d] our nickel-catalyzed system enables
these reagents to be useful coupling partners.
To gain insight into the mechanism of this transformation,
a number of control experiments were carried out. First, when
the reaction was performed in the presence of 1.0 equivalent
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Scheme 6. Reductive desulfonylation. Reaction conditions: 3
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To demonstrate both the potential pharmaceutical rele-
vance and the functional-group tolerance of this method, we
next attempted to perform a fluoromethylation of ezetimibe,
a drug known to lower plasma cholesterol levels.[2c] As shown
in Scheme 7, the monofluoromethylation of boronic acid 9,
Scheme 7. Fluoro(phenylsulfonyl)methylation of ezetimibe derivative 9
and elaboration to ezetimibe-CH2F 10. Reaction conditions:
[a] PhSO2CFHI (1.0 equiv), 9 (2.0 equiv), [Ni(acac)2] (10 mol%), PPh3
(20 mol%), K2CO3 (1.5 equiv), CH2Cl2, 1008C, 83%. [b] K2CO3, MeOH/
THF, 82%. [c] Na(Hg), MeOH, 91%.
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yield after subsequent deacylation and desulfonylation. This
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In summary, we have developed novel monofluorome-
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acids using nickel catalysis. Both electron-rich and electron-
deficient aryl boronic acids were compatible with this new
transformation. Mechanistic investigations indicated that
a monofluoromethyl radical is involved in the catalytic
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Keywords: aryl boronic acid · catalysis ·
monofluoromethylation · nickel · radicals
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Received: December 15, 2014
Revised: February 16, 2014
Published online: && &&, &&&&
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Communications
Monofluoromethylation
Y.-M. Su, G.-S. Feng, Z.-Y. Wang, Q. Lan,
X.-S. Wang*
&&&& — &&&&
Nickel-Catalyzed Monofluoromethylation
of Aryl Boronic Acids
Aryl boronic acids can be monofluoro-
methylated under nickel catalysis. The
utility of this method is demonstrated by
the monofluoromethylation of a borylated
and acyl-protected derivative of the statin
drug ezetimibe. Mechanistic investiga-
tions indicate that a fluoromethyl radical
is involved in the NiI/NiIII catalytic cycle.
6
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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