Cobalt-Catalyzed Defluorosilylation of Aryl Fluorides via Grignard Reagent Formation

Article abstract of DOI:10.1021/acs.orglett.0c02752

Transition-metal-catalyzed transformations of the carbon-fluorine bond not only tackle an interesting problem of challenging bond activation but also offer new synthetic strategies where the relatively inert C-F bond is converted to versatile functional groups. Herein we report a practical cobalt-catalyzed silylation of aryl fluorides that uses a cheap electrophilic silicon source with magnesium. This method is compatible with various silicon sources and can be operated under aerobic conditions. Mechanistic studies support the in situ formation of a Grignard reagent, which is captured by the electrophilic silicon source.

Full text of DOI:10.1021/acs.orglett.0c02752

pubs.acs.org/OrgLett
Letter
Cobalt-Catalyzed Defluorosilylation of Aryl Fluorides via Grignard
Reagent Formation
Soobin Lim,† Hyungdo Cho,† Jongheon Jeong, Minjae Jang, Hyunseok Kim, Seung Hwan Cho,
and Eunsung Lee*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02752
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Transition-metal-catalyzed transformations of the
carbon−fluorine bond not only tackle an interesting problem of
challenging bond activation but also offer new synthetic strategies
where the relatively inert C−F bond is converted to versatile
functional groups. Herein we report a practical cobalt-catalyzed
silylation of aryl fluorides that uses a cheap electrophilic silicon source with magnesium. This method is compatible with various
silicon sources and can be operated under aerobic conditions. Mechanistic studies support the in situ formation of a Grignard
reagent, which is captured by the electrophilic silicon source.
etal-mediated cross-coupling reactions offer straightfor-
ward access to the desired functional groups selectively
silicon sources and uses cheap silicon sources is still a desirable
reaction.
M
from their precursors.1 In this context, aryl halides (Ar−X; X =
Cl, Br, I) have been broadly used as the electrophilic
precursors, thanks to the C−X bonds’ ability to undergo
selective oxidative addition to the low-valent transition metal
relative to C−H or C−C bonds.2 On the other hand,
utilization of aryl fluorides (Ar−F) in metal-mediated coupling
reactions is relatively less developed because of the high bond
dissociation energies (BDEs) of C−F bonds (the Ph−F BDE is
127.2 kcal/mol), which makes the bond activation relatively
challenging.3 Nevertheless, C−F bond functionalization not
only provides a unique strategy where the transformation of
otherwise inert C−F bonds allows rapid generation of
structural diversity at a specific point of the synthesis4 but
also offers a chance to exploit the prevalent commercial
sources of aryl fluorides, which constitute more than 30% of
the commercially available halogenated arenes,5 including
fluorine-containing drugs.6 Given these advantages, it is not
surprising that continuous efforts in this area have realized the
successful development of C−C bond-forming reactions,7
aminations,8 borylations,9 and hydrogenations10 of aryl
fluorides.
We envisaged that the known unique reactivity of cobalt-
(I)−1,3-diketiminate complexes, which are capable of cleaving
C−F bonds under mild conditions, could be applied in
catalytic functionalization of aryl fluorides.14 We have
previously shown a successful application of this strategy for
Among them, one particularly interesting transformation is
the silylation of aryl fluorides. Organic silanes are widely used
in organic electronics, photonics, pharmaceuticals, and
polymers.11 Furthermore, they are important precursors in
organic synthesis and can be straightforwardly substituted by
various functional groups either via cross-coupling or
oxidation.12 Therefore, defluorosilylation can give quick access
to synthetic versatility from a generally unreactive part of the
molecule. Although several novel methods for defluorosilyla-
tion of aryl fluorides have been recently reported, they have a
limited scope of silyl groups (Figure 1).5,13 Thus, practical and
mild silylation of aryl fluorides that is compatible with various
Figure 1. Reported silylations of aryl fluorides and a new cobalt
catalysis.
Received: August 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02752
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
the catalytic borylation of aryl fluorides.15 Herein we report the
cobalt-catalyzed C−F bond silylation of aryl fluorides using
cheap chlorosilanes as silicon sources. Importantly, this
method is compatible with various silicon sources and can
be operated under aerobic conditions. Mechanistic studies
support in situ formation of a Grignard reagent from the aryl
fluoride, which is captured by the electrophilic silicon source.
The formation of Grignard reagents or organometallic
compounds by activation of aryl C−F bonds for further
transformations is still a challenging task16 compared with
other aryl halides such as aryl chlorides or bromides.17
Accordingly, the reaction can be further applied to modular
transformations of aryl fluorides to various functional groups if
other electrophiles are used instead of the chlorosilanes.
We determined that a combination of the salt Co(acac)2 and
1,3-diketiminate ligand L1 in the presence of magnesium and
chlorotrimethylsilane can accomplish the successful conversion
of the model substrate 4-fluorotoluene into 4-trimethylsilylto-
luene at room temperature (99% yield; Table 1, entry 1).
other silanes, reductants, or solvents were used (entries 6−11).
Lower loadings of the catalyst, magnesium, and the
chlorosilane gave lower yields (entries 12−14). No desired
product was observed without the cobalt salt, the ligand, and
magnesium (entries 15−17). Gratifyingly, the reaction can be
conducted under ambient conditions using non-degassed and
nondried solvents (entry 18). However, the addition of water
decreases the yield (entry 19), which could be partially
recovered using an additional 1 equiv of magnesium (entry
20). Finally, 1 equiv of 9,10-dihydroanthracene, a common
radical scavenger,19 did not affect the reactivity (entry 21),
providing a piece of evidence against the radical mechanism.
The scope of the reactions of both aryl fluorides and
chlorosilanes to form aryl silanes is represented in Figure 2.
Although isolation of the model product 2a gave a diminished
yield because of its volatility (bp of 2a = 192.5 °C20), other
simple aryl fluorides (1b and 1c) underwent efficient silylation
to give 2b and 2c, respectively, under the reaction conditions.
A sterically hindered aryl fluoride as well as electron-rich
substrates gave good yields (2e−h). Notably, heterocycle-
containing aryl fluorides were also effective substrates for the
reaction (2i−k). The reaction has fair functional group
tolerance, giving reasonable yields with substrates bearing
neopentylglycolatoboron (2l), protected ketone (2m), and
amide (2n). The method could also be applied to drug
derivatives such as blonanserin (2o), an antipsychotic drug
used for the treatment of schizophrenia, and N-protected
paroxetine (2p).
Importantly, chlorosilanes other than chlorotrimethylsilane
can be also used for the reaction. Triethoxy(aryl)silanes (2q−
u), which are useful cross-coupling partners, were accessed
from the corresponding chlorosilanes and aryl fluorides in
reasonable yields. 1-Methyl-1-arylsiletanes21 (2v−y) and
dimethyl(naphthalen-1-yl)silane (2z) were also obtained in
reasonable yields using a slightly modified reaction procedure
(see the Supporting Information). Finally, the method is also
applicable to the large-scale synthesis (1.0 g scale for 2c, 470
mg scale for 2t, and 290 mg scale for 2z). In addition, under
the standard conditions, an aryl bromide was successfully
converted in slightly reduced yield (68%), which indicates that
this transformation is also applicable to other aryl halides.
Moreover, the reaction with 4-chloro-4′-fluorobiphenyl
showed exclusive silylation at the C(sp2)−Cl bond over the
C(sp2)−F bond, which is in good agreement with the strengths
of their BDEs (see the Supporting Information).
Although we have not yet carried out in-depth studies,
several observations give the contours of the reaction
mechanism. In the absence of chlorotrimethylsilane from the
optimized conditions, the aryl fluoride is not consumed.
Interestingly, when a minimal amount of chlorotrimethylsilane
(0.1 equiv) was used to initiate the reaction, we observed full
consumption of the aryl fluoride after 22 h, as confirmed by
GC−MS (see the Supporting Information). This suggests that
a persistent intermediate that comes from the aryl fluoride is
formed during the reaction. In addition, chlorosilane was found
to be an efficient activator of zinc or magnesium powder.22
Therefore, we believe that a catalytic amount TMSCl is
nessessary to initiate the reaction, possibly to activate
magnesium. This reaction mixture after the full consumption
of the aryl fluoride was subjected to several different conditions
to investigate the reactivity of the intermediate resulting from
C−F bond activation (Figure 3a, (1) and (2)). First, addition
of chlorotrimethylsilane to the mixture gave the desired
Table 1. Effects of the Reaction Parameters
a
entry
variation from the “standard conditions”
none
CoCl2 instead of Co(acac)2
Col2 instead of Co(acac)2
L2 instead of L1
yield (%)
1
2
3
99
95
32
3
4
5
6
7
8
L3 instead of L1
<1
<1
<1
<1
<1
7
Si2Me6 instead of Me3SiCl
Et3SiH instead of Me3SiCl
Me3SiOTf instead of Me3SiCl
DME, toluene, or acetonitrile instead of THF
Na instead of Mg
9
10
11
12
13
14
15
16
17
18
19
20
21
Zn or Mn instead of Mg
5 mol % Co(acac)2 and 5 mol % L1
1 equiv of Mg
2 equiv of Me3SiCl
no Co(acac)2
<1
29
57
94
<1
<1
<1
99
34
60
99
no L1
no Mg
open to air, GR-grade THF
open to air, GR-grade THF + 0.28 equiv of H2O
19 + 1 additional equiv of Mg
1 equiv of 9,10-dihydroanthracene added
a
GC yields using dodecane as an internal standard.
Co(acac)2 is an optimal cobalt salt among others that were
tested (entries 1−3). The structure of ligand L1 is important
for the reactivity, and less than 5% yield of the desired product
was obtained with other 1,3-diketiminate ligands (entries 4 and
5). Further density functional theory (DFT) calculations on
the structural dependence of the ligands18 also supported the
experimental results, showing that L1 has a lower activation
barrier (∼2.4 kcal/mol) for the C−F bond activation than L2
does (see the Supporting Information). Halosilanes, magne-
sium, and THF solvent are crucial for the reactivity, and less
than 10% yield of the desired product was observed when
B
https://dx.doi.org/10.1021/acs.orglett.0c02752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Figure 2. Substrate scope of the cobalt-catalyzed silylation of aryl fluorides. Unless otherwise noted, the reactions were conducted on a 0.4 mmol
scale. b0.15 mmol scale. c0.2 mmol scale. dA modified procedure was used (see the Supporting Information, General Procedure B). e0.1 mmol scale.
silylated product in 90% yield, suggesting that the intermediate
is the catalytically relevant species rather than an off-cycle
byproduct. Second, when D2O was added to the mixture,
deuterated naphthalene was obtained in 88% yield with a 94:6
ratio of the deuterated and protonated products. On the basis
of these observations and the reaction stoichiometry, we
propose an aryl magnesium species as a key intermediate for
the reaction (Figure 3b). Thus, the cobalt(II)−1,3-diketimi-
nate complex is initially reduced by the magnesium to provide
a cobalt(I) species, which is capable of cleaving the C−F bond
of the aryl fluoride to produce an arylcobalt species and a
cobalt fluoride species.14 The arylcobalt complex undergoes
transmetalation to make the arylmagnesium species, which can
be captured by the chlorosilane to produce the desired
product. This transmetalation is reminiscent of the reactivity of
organic halides with cobalt catalysts and organozinc reagents,
which has been intensively studied by the Cahiez, Gosmini,
and Knochel groups.23 Meanwhile, the simultaneously
generated cobalt fluoride species undergo ligand exchange
with the additional equivalent of the chlorotrimethylsilane to
generate the fluorotrimethylsilane, which can be detected by
19F NMR spectroscopy and GC−MS (see the Supporting
Information). This proposal is also consistent with the
method’s compatibility with a wide range of chlorosilanes, as
they provide straightforward reactivity with the arylmagnesium
species. A dimeric magnesium(I)−1,3-diketiminate complex24
or alkylmagnesium−1,3-diketiminate complex25 has been
known to undergo facile C−F activation to give perfluoroar-
enes or fluoroarenes with directing groups under ambient
temperature to generate the 1,3-diketiminate-coordinated
arylmagnesium species. However, the critical role of the cobalt
source in the reaction efficiency (Table 1) and the substrate
scope of the unactivated aryl fluorides beyond perfluorinated
arenes of the reaction suggest evidence against the dimeric
Mg(I) complexes as a major activator of the C−F bond.
The reactivity of the intermediate mixture, resembles that of
the Grignard reagents, gives further support for the
arylmagnesium intermediates (Figure 3a, (3−6)). For instance,
the reactions between the intermediate and the aldehyde (3),
Weinreb amide (4), and diethylchlorophosphate (5) give
reasonable amounts of the corresponding Grignard addition
products. Furthermore, this mixture can be directly applied for
nickel-catalyzed Kumada coupling with aryl bromides to give
the coupling product in 59% yield (6).26 These results not only
provide support for the proposed mechanism but also show
valuable applications of our method that can be used for
various derivatizations. Finally, the aryl silanes obtained from
the reaction can be readily converted into other valuable
C
https://dx.doi.org/10.1021/acs.orglett.0c02752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Figure 3. Mechanistic investigation and other applications: (a) various reactivities of the intermediate; (b) a proposed mechanism.
building blocks (Figure 4). For example, triethoxyarylsilane 2t
can be an efficient cross-coupling partner under palladium
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02752.
Detailed experimental procedures and spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Eunsung Lee − Department of Chemistry, Pohang University of
Science and Technology, Pohang 37673, Republic of Korea;
orcid.org/0000-0002-1507-098X; Email: eslee@
postech.ac.kr
Authors
Soobin Lim − Department of Chemistry, Pohang University of
Science and Technology, Pohang 37673, Republic of Korea
Hyungdo Cho − Department of Chemistry, Pohang University
of Science and Technology, Pohang 37673, Republic of Korea
Jongheon Jeong − Department of Chemistry, Pohang University
of Science and Technology, Pohang 37673, Republic of Korea
Minjae Jang − Department of Chemistry, Pohang University of
Science and Technology, Pohang 37673, Republic of Korea
Hyunseok Kim − Department of Chemistry, Pohang University
of Science and Technology, Pohang 37673, Republic of Korea
Seung Hwan Cho − Department of Chemistry, Pohang
University of Science and Technology, Pohang 37673, Republic
of Korea; orcid.org/0000-0001-5803-4922
Figure 4. Applications of the aryl silanes. a 1H NMR yield.
catalysis (Figure 4a). Siletane 2y and silane 2c undergo
efficient oxidation to give the corresponding phenol27 and aryl
iodide (Figure 4b,c). Finally, the hydrosilane group of 2z can
be used as a directing group to install other valuable functional
groups28 (Figure 4d).
In summary, a practical cobalt-catalyzed silylation of aryl
fluorides that is compatible with various silicon sources has
been demonstrated. Future studies will focus on expanding the
reactivity of the arylmagnesium species toward providing a
modular and general transformation of the aryl fluoride
feedstocks.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02752
Author Contributions
†S.L. and H.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
D
https://dx.doi.org/10.1021/acs.orglett.0c02752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2010, 16, 10332−10336. (i) Nakamura, Y.; Yoshikai, N.; Ilies, L.;
Nakamura, E. Nickel-catalyzed monosubstitution of polyfluoroarenes
with organozinc reagents using alkoxydiphosphine ligand. Org. Lett.
2012, 14, 3316−3319. (j) Guo, W. J.; Wang, Z. X. Cross-coupling of
ArX with ArMgBr catalyzed by N-heterocyclic carbene-based nickel
complexes. J. Org. Chem. 2013, 78, 1054−1061. (k) Wu, D.; Wang, Z.
X. P,N,N-pincer nickel-catalyzed cross-coupling of aryl fluorides and
chlorides. Org. Biomol. Chem. 2014, 12, 6414−6424. (l) Zhu, F.;
Wang, Z. X. Nickel-catalyzed cross-coupling of aryl fluorides and
organozinc reagents. J. Org. Chem. 2014, 79, 4285−4292.
(8) (a) Zhu, F.; Wang, Z. X. Nickel-Catalyzed Coupling of
Fluoroarenes and Amines. Adv. Synth. Catal. 2013, 355, 3694−
3702. (b) Harada, T.; Ueda, Y.; Iwai, T.; Sawamura, M. Nickel-
catalyzed amination of aryl fluorides with primary amines. Chem.
Commun. 2018, 54, 1718−1721. (c) Wang, Y.; Wei, C.; Tang, R.;
Zhan, H.; Lin, J.; Liu, Z.; Tao, W.; Fang, Z. Silver-catalyzed
intermolecular amination of fluoroarenes. Org. Biomol. Chem. 2018,
16, 6191−6194.
(9) (a) Liu, X. W.; Echavarren, J.; Zarate, C.; Martin, R. Ni-
Catalyzed Borylation of Aryl Fluorides via C-F Cleavage. J. Am. Chem.
Soc. 2015, 137, 12470−12473. (b) Niwa, T.; Ochiai, H.; Watanabe,
Y.; Hosoya, T. Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes
for Diverse C-F Bond Functionalizations. J. Am. Chem. Soc. 2015, 137,
14313−14318. (c) Zhou, J.; Kuntze-Fechner, M. W.; Bertermann, R.;
Paul, U. S.; Berthel, J. H.; Friedrich, A.; Du, Z.; Marder, T. B.; Radius,
U. Preparing (Multi)Fluoroarenes as Building Blocks for Synthesis:
Nickel-Catalyzed Borylation of Polyfluoroarenes via C-F Bond
Cleavage. J. Am. Chem. Soc. 2016, 138, 5250−5253. (d) Niwa, T.;
Ochiai, H.; Hosoya, T. Copper-Catalyzed ipso-Borylation of
Fluoroarenes. ACS Catal. 2017, 7, 4535−4541. (e) Sakaguchi, H.;
Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. Copper-
Catalyzed Regioselective Monodefluoroborylation of Polyfluoroal-
kenes en Route to Diverse Fluoroalkenes. J. Am. Chem. Soc. 2017, 139,
12855−12862. (f) Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Cu-Catalyzed
Stereoselective Borylation of gem-Difluoroalkenes with B2pin2. Org.
Lett. 2017, 19, 3283−3286.
(10) (a) Sabater, S.; Mata, J. A.; Peris, E. Hydrodefluorination of
carbon-fluorine bonds by the synergistic action of a ruthenium-
palladium catalyst. Nat. Commun. 2013, 4, 2553. (b) Moore, J. T.; Lu,
C. C. Catalytic Hydrogenolysis of Aryl C-F Bonds Using a Bimetallic
Rhodium-Indium Complex. J. Am. Chem. Soc. 2020, 142, 11641−
11646.
(11) (a) Thames, S. F.; Panjnani, K. G. Organosilane polymer
chemistry: A review. J. Inorg. Organomet. Polym. 1996, 6, 59−94.
(b) The Chemistry of Organic Silicon Compounds; Rappoport, Z.,
Apeloig, Y., Eds.; Wiley: New York, 2000. (c) Showell, G. A.; Mills, J.
S. Chemistry challenges in lead optimization: silicon isosteres in drug
discovery. Drug Discovery Today 2003, 8, 551−556. (d) Franz, A. K.;
Wilson, S. O. Organosilicon molecules with medicinal applications. J.
Med. Chem. 2013, 56, 388−405.
(12) (a) Denmark, S. E.; Regens, C. S. Palladium-catalyzed cross-
coupling reactions of organosilanols and their salts: practical
alternatives to boron- and tin-based methods. Acc. Chem. Res. 2008,
41, 1486−1499. (b) Nakao, Y.; Hiyama, T. Silicon-based cross-
coupling reaction: an environmentally benign version. Chem. Soc. Rev.
2011, 40, 4893−4901. (c) Tamao, K.; Ishida, N.; Tanaka, T.;
Kumada, M. Silafunctional compounds in organic synthesis. Part 20.
Hydrogen peroxide oxidation of the silicon-carbon bond in organo-
alkoxysilanes. Organometallics 1983, 2, 1694−1696.
(13) (a) Mallick, S.; Xu, P.; Wurthwein, E. U.; Studer, A.
Silyldefluorination of Fluoroarenes by Concerted Nucleophilic
Aromatic Substitution. Angew. Chem., Int. Ed. 2019, 58, 283−287.
(b) Liu, X. W.; Zarate, C.; Martin, R. Base-Mediated Defluorosily-
lation of C(sp(2))-F and C(sp(3))-F Bonds. Angew. Chem., Int. Ed.
2019, 58, 2064−2068. (c) Kojima, K.; Nagashima, Y.; Wang, C.;
Uchiyama, M. In Situ Generation of Silyl Anion Species through Si-B
Bond Activation for the Concerted Nucleophilic Aromatic Sub-
stitution of Fluoroarenes. ChemPlusChem 2019, 84, 277−280.
(d) Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Fluorinated Vinylsilanes
ACKNOWLEDGMENTS
■
This work was financially supported by the National Research
Foundation of Korea, which is funded by the Korean
Government (NRF-2018R1A4A1024713 and NRF-
2019R1A6A3A13096212).
REFERENCES
■
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; John Wiley & Sons, 2008.
(2) (a) Diefenbach, A.; Bickelhaupt, F. M. Oxidative addition of Pd
to C−H, C−C and C−Cl bonds: Importance of relativistic effects in
DFT calculations. J. Chem. Phys. 2001, 115, 4030−4040. (b) Ahlquist,
M.; Norrby, P.-O. Oxidative Addition of Aryl Chlorides to
Monoligated Palladium(0): A DFT-SCRF Study. Organometallics
2007, 26, 550−553.
(3) (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Activation
of Carbon-Fluorine Bonds by Metal Complexes. Chem. Rev. 1994, 94,
373−431. (b) Blanksby, S. J.; Ellison, G. B. Bond dissociation energies
of organic molecules. Acc. Chem. Res. 2003, 36, 255−263. (c) Luo, Y.-
R. Comprehensive Handbook of Chemical Bond Energies; CRC Press:
Boca Raton, FL, 2007. (d) Amii, H.; Uneyama, K. C-F bond
activation in organic synthesis. Chem. Rev. 2009, 109, 2119−2183.
(e) Clot, E.; Eisenstein, O.; Jasim, N.; Macgregor, S. A.; McGrady, J.
E.; Perutz, R. N. C-F and C-H bond activation of fluorobenzenes and
fluoropyridines at transition metal centers: how fluorine tips the
scales. Acc. Chem. Res. 2011, 44, 333−348. (f) Ahrens, T.; Kohlmann,
J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules
by transition-metal-mediated C-F bond activation to access
fluorinated building blocks. Chem. Rev. 2015, 115, 931−972.
(g) Eisenstein, O.; Milani, J.; Perutz, R. N. Selectivity of C-H
Activation and Competition between C-H and C-F Bond Activation
at Fluorocarbons. Chem. Rev. 2017, 117, 8710−8753.
(4) (a) Moses, J. E.; Moorhouse, A. D. The growing applications of
click chemistry. Chem. Soc. Rev. 2007, 36, 1249−1262. (b) Cernak, T.;
Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The medicinal
chemist’s toolbox for late stage functionalization of drug-like
molecules. Chem. Soc. Rev. 2016, 45, 546−576.
(5) Cui, B.; Jia, S.; Tokunaga, E.; Shibata, N. Defluorosilylation of
fluoroarenes and fluoroalkanes. Nat. Commun. 2018, 9, 4393.
(6) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
pharmaceutical industry: fluorine-containing drugs introduced to the
market in the last decade (2001−2011). Chem. Rev. 2014, 114, 2432−
2506.
̈
̈
(7) (a) Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. Catalytic C−C Bond Formation through Selective
Activation of C−F Bonds. Angew. Chem., Int. Ed. 2001, 40, 3387−
3389. (b) Mongin, F.; Mojovic, L.; Guillamet, B.; Trecourt, F.;
Queguiner, G. Cross-coupling reactions of phenylmagnesium halides
with fluoroazines and fluorodiazines. J. Org. Chem. 2002, 67, 8991−
8994. (c) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. Ni- or Cu-
catalyzed cross-coupling reaction of alkyl fluorides with Grignard
reagents. J. Am. Chem. Soc. 2003, 125, 5646−5647. (d) Ackermann,
L.; Born, R.; Spatz, J. H.; Meyer, D. Efficient aryl-(hetero)aryl
coupling by activation of C-Cl and C-F bonds using nickel complexes
of air-stable phosphine oxides. Angew. Chem., Int. Ed. 2005, 44, 7216−
7219. (e) Yoshikai, N.; Mashima, H.; Nakamura, E. Nickel-catalyzed
cross-coupling reaction of aryl fluorides and chlorides with grignard
reagents under nickel/magnesium bimetallic cooperation. J. Am.
Chem. Soc. 2005, 127, 17978−17979. (f) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. Nickel-catalyzed alkenylation and
alkylation of fluoroarenes via activation of C-H bond over C-F
bond. J. Am. Chem. Soc. 2008, 130, 16170−16171. (g) Yoshikai, N.;
Matsuda, H.; Nakamura, E. Hydroxyphosphine ligand for nickel-
catalyzed cross-coupling through nickel/magnesium bimetallic coop-
eration. J. Am. Chem. Soc. 2009, 131, 9590−9599. (h) Xie, L. G.;
Wang, Z. X. Nickel-catalyzed cross-coupling of non-activated or
functionalized aryl halides with aryl grignard reagents. Chem. - Eur. J.
E
https://dx.doi.org/10.1021/acs.orglett.0c02752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
from the Copper-Catalyzed Defluorosilylation of Fluoroalkene
Feedstocks. Angew. Chem., Int. Ed. 2018, 57, 328−332. (e) Coates,
G.; Tan, H. Y.; Kalff, C.; White, A. J. P.; Crimmin, M. R.
Defluorosilylation of Industrially Relevant Fluoroolefins Using
Nucleophilic Silicon Reagents. Angew. Chem., Int. Ed. 2019, 58,
12514−12518.
(14) (a) Dugan, T. R.; Sun, X.; Rybak-Akimova, E. V.; Olatunji-Ojo,
O.; Cundari, T. R.; Holland, P. L. A masked two-coordinate cobalt(I)
complex that activates C-F bonds. J. Am. Chem. Soc. 2011, 133,
12418−12421. (b) Dugan, T. R.; Goldberg, J. M.; Brennessel, W. W.;
Holland, P. L. Low-Coordinate Cobalt Fluoride Complexes: Syn-
thesis, Reactions, and Production from C−F Activation Reactions.
Organometallics 2012, 31, 1349−1360.
Cross-Coupling of Organozinc Halides with Bromoalkynes. Adv.
Synth. Catal. 2014, 356, 2937−2942. (e) Benischke, A. D.; Knoll, I.;
Rerat, A.; Gosmini, C.; Knochel, P. A practical cobalt-catalyzed cross-
coupling of benzylic zinc reagents with aryl and heteroaryl bromides
or chlorides. Chem. Commun. 2016, 52, 3171−3174. (f) Thomas, L.;
Lutter, F. H.; Hofmayer, M. S.; Karaghiosoff, K.; Knochel, P. Cobalt-
Catalyzed Diastereoselective Cross-Couplings between Alkynylzinc
Pivalates and Functionalized Cyclic Iodides or Bromides. Org. Lett.
2018, 20, 2441−2444.
(24) (a) Bakewell, C.; White, A. J.; Crimmin, M. R. Addition of
Carbon-Fluorine Bonds to a Mg(I)-Mg(I) Bond: An Equivalent of
Grignard Formation in Solution. J. Am. Chem. Soc. 2016, 138, 12763−
12766. (b) Coates, G.; Ward, B. J.; Bakewell, C.; White, A. J. P.;
Crimmin, M. R. Reactions of Fluoroalkanes with Mg-Mg Bonds:
Scope, sp(3) C-F/sp(2) C-F Coupling and Mechanism. Chem. - Eur.
J. 2018, 24, 16282−16286. (c) Coates, G.; Rekhroukh, F.; Crimmin,
M. R. Breaking Carbon−Fluorine Bonds with Main Group
Nucleophiles. Synlett 2019, 30, 2233−2246.
(25) (a) Davin, L.; McLellan, R.; Kennedy, A. R.; Hevia, E. Ligand-
induced reactivity of beta-diketiminate magnesium complexes for
regioselective functionalization of fluoroarenes via C-H or C-F bond
activations. Chem. Commun. 2017, 53, 11650−11653. (b) Bole, L. J.;
Davin, L.; Kennedy, A. R.; McLellan, R.; Hevia, E. Magnesium-
mediated arylation of amines via C-F bond activation of fluoroarenes.
Chem. Commun. 2019, 55, 4339−4342.
(26) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M.
Highly selective biaryl cross-coupling reactions between aryl halides
and aryl Grignard reagents: a new catalyst combination of N-
heterocyclic carbenes and iron, cobalt, and nickel fluorides. J. Am.
Chem. Soc. 2009, 131, 11949−11963.
(15) Lim, S.; Song, D.; Jeon, S.; Kim, Y.; Kim, H.; Lee, S.; Cho, H.;
Lee, B. C.; Kim, S. E.; Kim, K.; Lee, E. Cobalt-Catalyzed C-F Bond
Borylation of Aryl Fluorides. Org. Lett. 2018, 20, 7249−7252.
(16) Fujii, I.; Semba, K.; Li, Q. Z.; Sakaki, S.; Nakao, Y.
Magnesiation of Aryl Fluorides Catalyzed by a Rhodium-Aluminum
Complex. J. Am. Chem. Soc. 2020, 142, 11647−11652.
(17) Garst, J. F.; Soriaga, M. P. Grignard reagent formation. Coord.
Chem. Rev. 2004, 248, 623−652.
(18) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; et al. Gaussian 16, rev. A.03; Gaussian, Inc.:
Wallingford, CT, 2016. (b) Perdew, J. P.; Wang, Y. Accurate and
simple analytic representation of the electron-gas correlation energy.
Phys. Rev. B: Condens. Matter Mater. Phys. 1992, 45, 13244−13249.
(c) Becke, A. D. Density-functional thermochemistry. III. The role of
exact exchange. J. Chem. Phys. 1993, 98, 5648−5652. (d) Marenich, A.
V.; Cramer, C. J.; Truhlar, D. G. Universal solvation model based on
solute electron density and on a continuum model of the solvent
defined by the bulk dielectric constant and atomic surface tensions. J.
Phys. Chem. B 2009, 113, 6378−6396.
(27) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Oxidation of carbon-
silicon bonds: the dramatic advantage of strained siletanes. Org. Lett.
2003, 5, 4571−4573.
(28) Su, B.; Hartwig, J. F. Iridium-Catalyzed, Silyl-Directed, peri-
Borylation of C-H Bonds in Fused Polycyclic Arenes and
Heteroarenes. Angew. Chem., Int. Ed. 2018, 57, 10163−10167.
(19) (a) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. Copper-
catalyzed intermolecular amidation and imidation of unactivated
alkanes. J. Am. Chem. Soc. 2014, 136, 2555−2563. (b) Comanescu, C.
C.; Vyushkova, M.; Iluc, V. M. Palladium carbene complexes as
persistent radicals. Chem. Sci. 2015, 6, 4570−4579.
(20) Soffer, H.; Vries, T. D. Dipole Moments of Aromatic
Derivatives of Trimethylsilane. J. Am. Chem. Soc. 1951, 73, 5817−
5819.
(21) (a) Okumura, S.; Sun, F.; Ishida, N.; Murakami, M. Palladium-
Catalyzed Intermolecular Exchange between C-C and C-Si sigma-
Bonds. J. Am. Chem. Soc. 2017, 139, 12414−12417. (b) Chen, H.;
Chen, Y.; Tang, X.; Liu, S.; Wang, R.; Hu, T.; Gao, L.; Song, Z.
Rhodium-Catalyzed Reaction of Silacyclobutanes with Unactivated
Alkynes to Afford Silacyclohexenes. Angew. Chem., Int. Ed. 2019, 58,
4695−4699.
(22) (a) Picotin, G.; Miginiac, P. Activation of Zinc by
Trimethylchlorosilane - an Improved Procedure for the Preparation
of Beta-Hydroxy Esters from Ethyl Bromoacetate and Aldehydes or
Ketones (Reformatsky Reaction). J. Org. Chem. 1987, 52, 4796−4798.
(b) Uchida, T.; Kita, Y.; Maekawa, H.; Nishiguchi, I. Mg-promoted
reductive coupling of aromatic carbonyl compounds with trimethyl-
silyl chloride and bis(chlorodimethylsilyl) compounds. Tetrahedron
2006, 62, 3103−3111. (c) Knochel, P. Organomagnesium and
Organozinc Chemistry. Organometallics in Synthesis 2013, 223−372.
(d) Bourne-Branchu, Y.; Gosmini, C.; Danoun, G. Cobalt-Catalyzed
Esterification of Amides. Chem. - Eur. J. 2017, 23, 10043−10047.
(e) Silverman, G.; Rakita, P. Grignard Reagents and Silanes; Marcel
Dekker, 1996.
(23) (a) Begouin, J. M.; Rivard, M.; Gosmini, C. Cobalt-catalyzed C-
SMe bond activation of heteroaromatic thioethers. Chem. Commun.
2010, 46, 5972−5974. (b) Dorval, C.; Dubois, E.; Bourne-Branchu,
Y.; Gosmini, C.; Danoun, G. Sequential Organozinc Formation and
Negishi Cross-Coupling of Amides Catalysed by Cobalt Salt. Adv.
Synth. Catal. 2019, 361, 1777−1780. (c) Cahiez, G.; Moyeux, A.
Cobalt-catalyzed cross-coupling reactions. Chem. Rev. 2010, 110,
1435−1462. (d) Corpet, M.; Bai, X.-Z.; Gosmini, C. Cobalt-Catalyzed
F
https://dx.doi.org/10.1021/acs.orglett.0c02752
Org. Lett. XXXX, XXX, XXX−XXX