Nickel-Catalyzed Aromatic Cross-Coupling Difluoromethylation of Grignard Reagents with Difluoroiodomethane

Article abstract of DOI:10.1021/acs.orglett.8b02264

The nickel-catalyzed cross-coupling difluoromethylation of the Grignard reagents with difluoroiodomethane is shown to provide the corresponding aromatic difluoromethyl products in excellent to moderate yields. The difluoromethylation proceeds smoothly within 1 h at room temperature with 1.5 equiv of the Grignard reagents in the presence of Ni(cod)₂/TMEDA (2.5-0.5 mol %). Mechanistic studies clarify that the oxidative addition of the Ni(0) catalyst to difluoroiodomethane provides the TMEDA-Ni(II)(CF₂H)I complex. This intermediate is transformed to TMEDA-Ni(II)(CF₂H)Ph via transmetalation with PhMgBr. The reductive elimination takes place to give the aromatic cross-coupling difluoromethylation product along with regeneration of the TMEDA-Ni(0) catalyst. Electron paramagnetic resonance (EPR) and radical clock analyses of the nickel-catalyzed reaction provide no EPR active Ni(I) and Ni(III) species at around g = 2 and only a trace amount of the cyclization product.

Full text of DOI:10.1021/acs.orglett.8b02264

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Aromatic Cross-Coupling Difluoromethylation of
Grignard Reagents with Difluoroiodomethane
Hirotaka Motohashi and Koichi Mikami*
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: The nickel-catalyzed cross-coupling difluoromethylation of
the Grignard reagents with difluoroiodomethane is shown to provide the
corresponding aromatic difluoromethyl products in excellent to moderate
yields. The difluoromethylation proceeds smoothly within 1 h at room
temperature with 1.5 equiv of the Grignard reagents in the presence of
Ni(cod)2/TMEDA (2.5−0.5 mol %). Mechanistic studies clarify that the oxidative addition of the Ni(0) catalyst to
difluoroiodomethane provides the TMEDA−Ni(II)(CF2H)I complex. This intermediate is transformed to TMEDA−
Ni(II)(CF2H)Ph via transmetalation with PhMgBr. The reductive elimination takes place to give the aromatic cross-coupling
difluoromethylation product along with regeneration of the TMEDA−Ni(0) catalyst. Electron paramagnetic resonance (EPR)
and radical clock analyses of the nickel-catalyzed reaction provide no EPR active Ni(I) and Ni(III) species at around g = 2 and
only a trace amount of the cyclization product.
rganofluorine compounds have attracted explosive
attention in pharmaceutical and agrochemical applica-
Scheme 1. Transition-Metal-Catalyzed Aromatic
Difluoromethylations
O
tions, because fluorinated functional groups confer higher
metabolic stability, mimic effect, and lipophilicity, based on
their unique chemical, biological, and physical properties.1
Particularly, a difluoromethyl (CF2H) group can be employed
as bioisosteres of alcohol and thiol, which function as lipophilic
hydrogen-bonding donors.2 Therefore, highly efficient syn-
thetic methods to introduce a difluoromethyl group into
organic compounds have intensively been developed.3
Difluoromethylated compounds were synthesized via deoxo-
fluorination of aldehydes with DAST (N,N-diethylaminosulfur
trifluoride) derivatives under harsh reaction conditions, in spite
of functional group compatibility.4 Synthetic methods to
provide difluoromethyl arenes via selective benzylic C−H
bonds5 and decarboxylative fluorination of α-fluoroarylacetic
acids6 have also been reported. Recently, direct difluorome-
thylations through carbon-to-carbon bond formation have
appeared.7−9 However, the development of transition-metal-
catalyzed reactions have been quite limited. For example, Pd-,
Ni-, and Cu-catalyzed difluoromethylations of aromatic halides
with several difluoromethyl metal reagents (M−CF2H: M = Si,
Ag, Zn) have been reported (Scheme 1, eq 1).10 These
difluoromethylation reactions generally require high temper-
ature conditions, and the difluoromethyl metal reagents are
thermally unstable. Subsequently, cross-coupling reactions
using difluoromethyl halides as an electrophile have been
reported; metal-difluorocarbene11 and Suzuki−Miyaura12
reactions of arylboronic acid with difluoromethyl halide
catalyzed by palladium or nickel complexes have been reported
(Scheme 1, eq 2). After submitting this paper, Ni-catalyzed
radical13 and Fe-catalyzed14 difluoroalkylation reactions were
reported (Scheme 1, eq 3). However, a conventional and
reliable Ni-catalyzed cross-coupling reaction with organo-
magnesium Grignard reagents of ubiquitous synthetic use has
never been described.
Herein, we wish to report the Ni-catalyzed cross-coupling
reaction of the Grignard reagents under mild reaction
conditions even at ambient temperature (Scheme 1, eq 4).
The mechanism is revealed to involve the Ni(0)/Ni(II)
catalytic cycle rather than the Ni(I)/Ni(III) cycle; the
Received: July 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02264
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxidative addition of a LnNi(0) catalyst to difluoroiodo-
methane (I−CF2H), the transmetalation of the Grignard
reagents (Ar−MgBr), and the reductive elimination complete a
catalytic cycle to afford the difluoromethyl arenes (Ar−CF2H)
and to regenerate the Ni(0) catalyst.
Table 2. Ni-Catalyzed Difluoromethylation with Grignard
Reagents
A nickel-catalyzed difluoromethylation reaction of phenyl-
magnesium bromide 1a with difluoroiodomethane15 2 was
carried out (Table 1). No reaction occurred in the absence of
Table 1. Optimization of Difluoromethylation Reactions
a
entry 1a (X equiv) precatalyst (mol %) ligand (mol %) yield (%)
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.5
1.5
1.5
−
−
0
16
61
4
8
8
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
NiCl2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (2.5)
Ni(cod)2 (2.5)
Ni(cod)2 (0.5)
DPPF (10)
TMEDA (10)
TEEDA (10)
L1 (10)
L2 (10)
L3 (10)
7
8
L4 (10)
L5 (10)
9
16
>99
>99
59
>99
>99
>99
10
11
12
13
14
15
TMEDA (10)
TMEDA (10)
TMEDA (10)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (0.5)
c
b
a
Yields were determined by 19F NMR analysis using benzotrifluoride
b
c
as an internal standard. The reaction time was 1 h. The reaction
time was 5 min.
a
Reaction conditions: 0.2 mmol of diluoroiodomethane (1.2−1.5 M),
0.3 mmol of ArMgBr (ca. 0.5 M), 2.5 mol % of Ni(cod)2 and
TMEDA in 1 mL of THF. Yields were determined by 19F NMR
analysis using benzotrifluoride as an internal standard. Isolated yields
are shown in parentheses. ArMgBr prepared by the reaction of the
corresponding ArI with iPrMgBr. Gram-scale synthesis: 10 mmol of
b
c
diluoroiodomethane, 15 mmol of 4-biphenylmagnesium bromide, 2.5
mol % of Ni(cod)2 and TMEDA in 50 mL of THF. 1.87 g of 3b was
isolated.
either nickel precatalyst or (di)phosphine and amine ligands
(entry 1). When 2 equiv of 1a and difluoroiodomethane were
treated with NiCl2 and dppf (10 mol %) in THF at ambient
temperature for 20 h, desired product 3a was generated, albeit
in low yield (16%) (entry 2). With TMEDA as a ligand, the
yield was improved to 61% (entry 3). Extensive screening of
diamine ligands clarified that TMEDA is the best ligand
(entries 4−9). A significant improvement in yield up to 99%
yield was attained by changing nickel precatalyst from NiCl2 to
Ni(cod)2 in combination with the best ligand, TMEDA (entry
10). Reduction of the amount of 1a to 1.5 equiv did not show
any change in yield, but further reduction to just an equimolar
amount of 1a decreased the yield to 59% (entries 11, 12). Even
when the amount of the catalyst was reduced to 2.5 mol %, no
significant change in yield was observed and the reaction was
completed within 5 min (entries 14, 15). The amount of the
catalyst could be further reduced to 0.5 mol % to give a
quantitative yield (entry 15).
Biphenyl, naphthyl, phenanthryl, and fluorenylmagnesium
bromide afforded difluoromethylated arenes 3b−3g in good
to excellent yields, respectively. Gram-scale synthesis of 3b was
carried out with 10 mmol of difluoroiodomethane 2 and 1.5
equiv of 4-biphenylmagnesium bromide 1b to give the desired
compound 3b in almost the same yield (87% yield, 1.87 g) as
in a small scale reaction. Arylmagnesium bromide with both
electron-donating and -withdrawing substituents in the para-
position showed good reactivity to give desired products 3h−
3q in good yields within 1 h. Methoxy and ethoxycarbonyl
substituents at the meta-position did provide good yields 3r−
3t, while a decrease in yield was observed with ortho-
substituted compounds 3u−3v. Heterosubstituted compounds
such as p-1-carbazophenylmagnesium bromide afforded
product 3w quantitatively.
Substrate generality was realized under the optimal reaction
conditions (2.5 mol % of the Ni precatalyst Ni(cod)2 and the
TMEDA ligand, 0 °C to rt 1 h reaction time). Difluoromethy-
lated aryls were synthesized through cross-coupling difluor-
omethylation of a variety of the Grignard reagents 1 (Table 2).
The reaction mechanism of a nickel-catalyzed coupling
reaction poses a challenge, as highlighted in the Ni(I)/Ni(III)
catalytic cycles.16 A stoichiometric reaction was hence
conducted with all components, Ni(cod)2, TMEDA, and
B
DOI: 10.1021/acs.orglett.8b02264
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
difluoroiodomethane, in equal amounts. An oxidative addition
intermediate (A) was quantitatively observed by 19F NMR (δF
−107.9, d, JF−H = 51.5 Hz) as compared with the recent
report.13 In order to further clarify the oxidative addition
intermediate on the basis of the P−F coupling constant, we
employed diphosphine DPPF instead of diamine TMEDA as a
ligand. Another oxidative addition intermediate (A′) was thus
detected by 19F NMR (δF −79.7, ap q, JF−H = JF−P = 48.9
Hz).17 When 1 equiv of TMEDA was added to diphosphine
complex A′, ligand exchange occurred to give indeed the
diamine complex A. The Grignard reagent 1a (1.5 equiv) was
then added at 0 °C to give the coupling product 3a
quantitatively at room temperature (Scheme 2).
Scheme 3. Plausible Catalytic Cycle
Scheme 2. Investigation of Reaction Mechanism
temperature. It has been mechanistically clarified that the
oxidative addition of the Ni(0) catalyst to I−CF2H provides a
TMEDA−Ni(II)(CF2H)I complex and that Ni(Ar)CF2H
generated by transmetalation promotes the final reductive
elimination. EPR and radical clock analyses of the nickel-
catalyzed reaction provide no ERR active Ni(I) species at
around g = 2 and only a trace amount of a cyclization product.
The plausible reaction mechanism is thus visualized for
construction of the Ni(0)/Ni(II) catalytic cycle rather than
the Ni(I)/Ni(III) or radical cycles. Development of practical
and reliable catalytic difluoromethylation reactions using other
difluoromethylating and organometallic reagents under tran-
sition-metal catalysis is in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02264.
A radical clock experiment was additionally conducted.12b
When an equimolar amount of diallyl ether 4 was added to the
standard catalytic reaction conditions, the same high yield of
the difluoromethylated aryl product 1a was obtained as in the
usual difluoromethylation reaction without a radical clock; only
2% of the ring-closing product 5 was obtained with the radical
clock, diallyl ether.
Finally, the progress of the nickel-catalyzed difluoromethy-
lation reaction was traced by electron paramagnetic resonance
(EPR) spectroscopic analyses; EPR active chemical species
such as Ni(I) and Ni(III) complexes at around g = 2 were not
observed at all.18−21 These results indicate Ni(I) or Ni(III)
species are not involved in this nickel-catalyzed difluorome-
thylation.
Based on these results, a plausible reaction mechanism is
visualized for construction of the Ni(0)/Ni(II) catalytic cycle
rather than the Ni(I)/Ni(III) or radical cycles (Scheme 3).
Initially, the oxidative addition of difluoroiodomethane to
TMEDA−Ni(0) (C) leads to A at room temperature.
Subsequently, the transmetalation of the aryl Grignard reagent
1 to produce B and finally the reductive elimination thereof
afford the desired aromatic cross-coupling difluoromethylation
products 3.
Experimental procedures, compound characterization
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mikami.k.ab@m.titech.ac.jp.
ORCID
Koichi Mikami: 0000-0002-7093-2642
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Mr. Sota Kato and Prof. Hideyuki
Otsuka (Tokyo Institute of Technology) for carrying out EPR
measurements. We thank Rigaku Inc. for support of X-ray
single crystallography. We appreciate the Nichia Corporation
for offering Ni(cod)2. This research was supported by the
Japan Science and Technology Agency (JST) (ACT-C:
Creation of Advance Catalytic Trans-formation for the
Sustainable Manufacturing at Low Energy, Low Environmental
Load).
In summary, we have succeeded in the development of the
cross-coupling difluoroiodomethylation of organomagnesium
reagents with difluoroiodomethane in the presence of the Ni
catalyst under the mild reaction conditions even at ambient
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DOI: 10.1021/acs.orglett.8b02264
Org. Lett. XXXX, XXX, XXX−XXX