C-F activation for C(sp2)-C(sp3) cross-coupling by a secondary phosphine oxide (SPO)-nickel complex

Article abstract of DOI:10.1021/acs.orglett.0c02609

A secondary phosphine oxide (SPO)-nickel catalyst allowed the activation of otherwise inert C-F bonds of unactivated arenes in terms of challenging couplings with primary and secondary alkyl Grignard reagents. The C-F activation is characterized by mild reaction conditions and high levels of branched selectivity. Electron-rich and electron-deficient arenes were suitable electrophiles for this transformation. In addition, this strategy also proved suitable to heterocycles and for the activation of C-O bonds under slightly modified conditions.

Full text of DOI:10.1021/acs.orglett.0c02609

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Letter
C−F Activation for C(sp2)−C(sp3) Cross-Coupling by a Secondary
Phosphine Oxide (SPO)-Nickel Complex
̈
Valentin Muller, Debasish Ghorai, Lorena Capdevila, Antonis M. Messinis, Xavi Ribas,
and Lutz Ackermann*
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ABSTRACT: A secondary phosphine oxide (SPO)-nickel catalyst
allowed the activation of otherwise inert C−F bonds of unactivated
arenes in terms of challenging couplings with primary and
secondary alkyl Grignard reagents. The C−F activation is
characterized by mild reaction conditions and high levels of
branched selectivity. Electron-rich and electron-deficient arenes
were suitable electrophiles for this transformation. In addition, this
strategy also proved suitable to heterocycles and for the activation
of C−O bonds under slightly modified conditions.
he formation of carbon−carbon bonds via metal-
Tcatalyzed cross-couplings has been recognized as a
powerful tool for molecular synthesis.1 While classical cross-
coupling reactions focused on traditional electrophiles, such as
aryl iodides, triflates, and bromides, the activation of inert C−F
bonds is significantly more challenging.2 The use of fluorine
labeled compounds in absorption distribution metabolism and
excretion (ADME) studies render aryl fluorides especially
useful for early stage as well as late stage modifications.3 While
C(sp2)−F bonds are otherwise inert with a bond dissociation
energy of ∼126 kcal/mol,4 the use of specific nickel catalyst
enabled cross-couplings with these challenging electrophiles.5
Unfortunately, only a few reports on selective C(sp2)−C(sp3)
bond formations are known and are mostly restricted to alkyl
electrophiles with the aid of sterically congested ligands.6
Much less attention has been focused on related reactions with
branched nucleophiles,7 due to competing β-hydride elimi-
nations favored for hemilabile ligands8 as well as highly
nucleophilic transition metals.9 In a seminal report, Kumada
reported one coupling between an aryl fluoride and a
secondary Grignard which was accompanied by an undesired
isomerization (Figure 1a).10 Since then, only selected examples
were disclosed,11 including a major recent advance by Cornella
by highly branch-selective alkylations of aryl fluorides.8a The
key to success was a dialkyl substitution pattern on an air-
sensitive dppe ligand backbone combined with an additional
base (Scheme 1b). Even though this approach enabled the
alkylation at the α-position of some N-containing heterocycles,
a general method toward branched and linear alkylating
reagents, by efficient nickel catalysis, continues to be in high
demand.12 Within our program on nickel catalysis13 with
secondary phosphine oxide (SPO)14 preligands,15 we have
now devised a generally applicable strategy for the nickel-
Figure 1. Nickel catalyzed C−F alkylations.
catalyzed C−F alkylation of unactivated aryl fluorides with
primary and secondary alkylmagnesium reagents. Notable
Received: August 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02609
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 1. Scope of the Linear-Selective Alkylation by SPO-
a
Nickel C−F Activation
Figure 2. Synthesis and molecular structure of complex 3a. Thermal
ellipsoids are drawn at the 50% probability level and carbon bound H
atoms are omitted for clarity.
Table 2. SPO-Nickel Catalyzed Alkylation with Branched
a
Grignard Reagents
a
b
Linear/branched selectivities in parentheses. Byproduct observed.
b
entry
[Ni]
ligand
4af [%]
b/l [%]
Table 1. SPO-Nickel Catalyzed Alkylation with Linear
Grignard Reagents
1
2
3
4
5
6
7
Ni(cod)2
Ni(acac)2
dppe
dppe
−
−
57
56
60
−
−
93/7
93/7
92/8
96/4
95/5
a
c
d
3a
ef
,
84
77
e g
−
b
a
entry
[Ni]
ligand
T/°C
4aa/5 [%]
General reaction conditions: 1a (0.25 mmol), 2f (0.50 mmol), [Ni]
(5.0 mol %), Ligand (5.0 mol %), solvent (0.50 mL), 25 °C, 16 h,
isolated yield. Ratio of 4af/4al determined by H NMR spectros-
copy. PhCH3 as solvent. 2-MeTHF as solvent. 60 °C. 0.50 mmol
scale. 30 min.
1
2
3
4
5
6
7
8
Ni(acac)2
Ni(acac)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
−
dppe
dppe
dppe
(Ph)2P(O)H
L1
100
100
100
25
100
100
100
25
18/20
<10
b
1
c
d
e
f
89/6
g
c
−
63/24
70/20
75/15
While Ni(acac)2 showed minor reactivity without ligand, the
addition of the commonly used phosphine ligand dppe
facilitated the transformation only with a nickel(0) precatalyst
(entries 1−3). Notable, nickel(0) precatalyst combined with
dppe failed to give any conversion at ambient temperature
(entry 4). Hence, we next studied air- and moisture-stable SPO
preligands, resulting in a moderate yield and selectivity (entry
5). In contrast, the bidentate SPO ligand L1 yielded product
4aa in 70% yield and reduced the formation of the undesired
dehalogenation product 5 (entry 6). Subsequent treatment of
Ni(cod)2 with L1 resulted in the formation of complex 3a,
which was isolated and crystallographically characterized
(Figure 2).
3a
cd
,
82/2
a
General reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), [Ni]
(5.0 mol %), Ligand (5.0 mol %), PhCH3 (0.50 mL), T, 16 h, isolated
b
c
yield. Ratio of 4aa/5 determined by 1H NMR spectroscopy. THF as
d
solvent. 0.25 N.
features of our findings include (1) the use of Earth-abundant
nickel catalysis for synthetically meaningful C−F activations,
(2) a novel SPO-nickel complex which was fully characterized
by X-ray diffraction analysis, (3) exceedingly mild reaction
conditions, and (4) outstanding selectivities with secondary
alkylating reagents (Figure 1c).
We commenced our studies by testing a variety of nickel
precursors and ligands for the envisioned C−F alkylation of 1a
(Table 1 and Table S1 in the Supporting Information).
To our delight complex 3a was found to be catalytically
active, yielding the desired product 4aa in an increased yield
and improved selectivity (entry 7). It is assumed that the SPO-
phosphine nickel(II) precatalyst and the Grignard reagent
B
https://dx.doi.org/10.1021/acs.orglett.0c02609
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Letter
a
Scheme 2. Scope of the Branched-Selective Alkylation by SPO-Nickel Catalysis
a
Branched/linear selectivities in parentheses.
a
Scheme 3. C−O Alkylation by SPO-Nickel Catalysis
commonly obtained Ziegler alkylation at the more acidic α-
position to the heteroatom.18 Finally, also an electron-rich N-
protected aniline derivative was converted successfully yielding
4na in good yield and selectivity.
Based on the outstanding selectivity within the linear
alkylation, we became interested in the considerably more
challenging alkylation with secondary alkylmagnesium halides.
We initiated our studies here again with 1a as the model
substrate and sec-butylmagnesium chloride (2f) as the
alkylation reagent (Table 2 and Table S4 in the Supporting
Information). Communally used nickel precursors with
established phosphine ligand failed to facilitate the envisioned
transformation (entries 1−2). In contrast, the well-defined
catalyst 3a proved to be suitable, yielding desired product 4af
in moderate yield and selectivity (entry 3). Further
optimization showed that biomass-derived 2-MeTHF is also
suitable for this transformation (entry 4).19 A slightly increased
temperature is needed for a higher conversion and better
selectivity (entry 6). The high reactivity of catalyst 3a toward
unactivated C−F bonds was further reflected by a high TOF,
yielding 4af in 77% yield after only 0.5 h (entry 7).
Under the optimized reaction conditions, various acyclic
secondary Grignard reagents, such as s-BuMgCl (4af), (4-
phenylbutan-2-yl)magnesium bromide (4ag), and i-PrMgCl
(4bk), were successfully converted by the SPO-nickel catalyst
3a (Scheme 2). All secondary alkylating reagents delivered the
coupling product with excellent selectivities and good yields.
Furthermore, cyclic secondary Grignard reagents, such as a
bulky bicycle- (4ah), cyclpropyl- (4ai), and cyclopentyl (4aj−
4bj) -magnesium halide, were also suitable coupling partners
with excellent yields and high levels of selectivity without
observable ring opening.20 The use of para-substituted arenes
did not influence the reaction (4cf−4ef), and indeed C−O
bonds stay intact during the course of the reaction (4ff). In
a
Linear/branched selectivities in parentheses.
form a nickel/magnesium bimetallic catalytic species that
carries out push−pull cooperative activation of the aryl
fluoride.5i,m,16 Lowering the reaction temperature and
changing the solvent to THF improves the yield and
suppresses the formation of 5 (entry 8). Subsequently, we
explored the catalyst’s versatility, with respect to the viable
structures of fluoroarenes 1 and alkyl nucleophiles 2. Notably,
a wide range of fluoroarenes 1 and alkylmagnesium bromides 2
were converted in an efficient manner to provide the
corresponding products 4 in excellent yield (Scheme 1). The
C(sp2)−C(sp3) bond formation of arylfluoride 1a was
successful performed with different alkylmagnesium reagents,
delivering the corresponding products 4aa−4ba in up to 82%
yield. The tether had no major influence (2b−2d). In addition,
also the branched reagent 2e delivered 4be selectively without
isomerization. The variation with respect to fluoroarene 1 was
not limited to naphthalene derivatives. Indeed, also structural
motifs such as phenyl (4ca), biphenyl (4ea), and pyrene (4ga)
were efficiently transferred. To our delight, the C−O bond
successfully survived under the reaction conditions (4fa),
without interference, indicating notable innate chemoselectiv-
ity. Finally N-protected indoles (4ha, 4he, and 4ja) show high
catalytic performance yielding otherwise difficult to synthesize
motifs that were studied in C−H transformations.17 In
addition, pyridines (1k−m) are tolerated by the SPO-nickel
regime, showing no deactivation of catalyst 3a by potentially
coordination, generating (4ka−4ma) in good yield without
C
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Letter
́
Lorena Capdevila − Institut de Quımica Computacional i
addition, pyrene fluorophores proved to be compatible within
the SPO-nickel catalysis regime (4gf). Biologically relevant
heterocyclic motifs, such as indole, are well tolerated (4ik, 4jf,
and 4if). Pyridine motifs were selectively converted with s-
BuMgCl (4kf-mf), (4-phenylbutan-2-yl)magnesium bromide
(4kg), and i-PrMgCl (4lk and 4mk). Finally, also an electron-
rich N-protected aniline derivative is converted successfully
with acyclic coupling reagents yielding the para alkylated
products 4nk and 4nf in good yield and moderate selectivity,
whereas a cyclic nucleophile generated the product with
excellent selectivity (4ni). Importantly, no substitution in the
α-position to the heteroatom was observed, highlighting the
selectivity of the SPO-nickel regime.
̀
́
Catalisi (IQCC) and Dep. Quımica, Universitat de Girona, E-
17003 Girona, Catalonia, Spain
Antonis M. Messinis − Institut fu
Biomolekulare Chemie, Georg-August-Universitat Gottingen,
̈
r Organische und
̈
̈
̈
37077 Gottingen, Germany
́
̀
Xavi Ribas − Institut de Quımica Computacional i Catalisi
́
(IQCC) and Dep. Quımica, Universitat de Girona, E-17003
Girona, Catalonia, Spain; orcid.org/0000-0002-2850-
4409
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02609
In consideration of the activity of the SPO-nickel catalyst 3a
to C−F bonds, we became intrigued regarding the selectivity
toward other inert bonds. Indeed, we could achieve the
activation of 2-naphthyl methyl ether with 3a under slightly
altered reaction conditions,21 notably without any isomerized
product being formed for the linear-selective alkylation and
moderate selectivity for the branched-selective alkylation
(Scheme 3).22
In conclusion, we have developed a well-defined novel SPO-
phosphine nickel catalyst, for the activation of otherwise inert
C−F bonds. The cross-coupling with the air-stable nickel(II)
enabled primary and secondary alkylations with high levels of
selectivity. A wealth of electron-rich and electron-deficient
arenes proved suitable electrophiles for this transformation
under mild reaction conditions. Finally, the SPO-nickel catalyst
3a proved valid for C(sp2)−OMe alkylations, prompting future
methodological developments.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support by the DFG (Gottfried-Wilhelm-Leibniz-
Preis to L.A.) and European Research Council (FP7 2007−
2013)/ERC Grant Agreement No. 307535 to L.A. and ERC-
2011-StG-277801 to X.R.) is gratefully acknowledged. We
̈
thank Dr. Christopher Golz (Gotingen University) for
assistance with the X-ray diffraction analysis and the COST
Action CHAOS (CA15106). X.R. is thankful for an ICREA
Acad award.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02609.
Detailed experimental procedures, compound character-
ization data, X-ray crystallography data, and NMR
spectra (PDF)
̈
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Nickel-Catalyzed Csp2−Csp3 Cross-Coupling via C−O Bond Activa-
Accession Codes
CCDC 1991589 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Lutz Ackermann − Institut fu
Chemie and Wohler Research Institute for Sustainable
Chemistry (WISCh), Georg-August-Universitat Gottingen,
̈
r Organische und Biomolekulare
̈
̈
̈
̈
37077 Gottingen, Germany; orcid.org/0000-0001-7034-
8772; Email: Lutz.Ackermann@chemie.uni-goettingen.de
Authors
Valentin Mu
̈
ller − Institut fur Organische und Biomolekulare
̈
̈
̈
̈
Chemie, Georg-August-Universitat Gottingen, 37077 Gottingen,
Germany
Debasish Ghorai − Institut fur Organische und Biomolekulare
̈
Chemie, Georg-August-Universitat Gottingen, 37077 Gottingen,
Germany; orcid.org/0000-0001-7051-1613
̈
̈
̈
D
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G
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