Exploiting the trifluoroethyl group as a precatalyst ligand in nickel-catalyzed Suzuki-type alkylations

Article abstract of DOI:10.1039/c9sc00554d

We report herein the exploitment of the partially fluorinated trifluoroethyl as precatalyst ligands in nickel-catalyzed Suzuki-type alkylation and fluoroalkylation coupling reactions. Compared with the [L_nNi^II(aryl)(X)] precatalysts, the unique characters of bis-trifluoroethyl ligands imparted precatalyst [(bipy)Ni(CH₂CF₃)₂] with bench-top stability, good solubilities in organic media and interesting catalytic activities. Preliminary mechanistic studies reveal that an eliminative extrusion of a vinylidene difluoride (VDF, CH₂CF₂) mask from [(bipy)Ni(CH₂CF₃)₂] is a critical step for the initiation of a catalytic reaction.

Full text of DOI:10.1039/c9sc00554d

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10.1039/C9SC00554D.
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Exploiting the Trifluoroethyl Group as a Precatalyst Ligand in
Nickel-catalyzed Suzuki-type Alkylations
Received 00th January 20xx,
Accepted 00th January 20xx
Yi Yang,*,a Qinghai Zhou,b Junjie Cai,a Teng Xue,c Yingle Liu,a Yan Jiang,a Yumei Su,a Lungwa
Chung,*,b and David A. Vicic*,c
DOI: 10.1039/x0xx00000x
We report herein the exploitment of the partially fluorinated trifluoroethyl as precatalyst ligands in nickel-catalyzed
Sukuzi-type alkylation and fluoroalkylation coupling reactions. Compared with the [LnNiII(aryl)(X)] precatalysts, the unique
characters of bis-trifluoroethyl ligands imparted precatalyst [(bipy)Ni(CH2CF3)2] with bench-top stability, good solubilities in
organic media and interesting catalytic activities. Preliminary mechanistic studies reveal that an eliminative extrusion of a
vinylidene difluoride (VDF, CH2=CF2) mask from [(bipy)Ni(CH2CF3)2] is a critical step for the initiation of a catalytic reaction.
www.rsc.org/
A. Well-defined carbon-ligated nickel precatalysts
Introduction
L
L
Cl
Ar
Transition metal catalyzed cross-coupling reactions have
advanced organic synthesis in the last few decades and have
become powerful tools for the generation of molecular
complexity.1 Substantial effort has been devoted to identifying
general and robust transition metal catalytic systems for
reaction methodology research and chemical production
improvement. A prominent example is the development of
Suzuki-Miyaura coupling systems, which now employ a diverse
combinations of transition-metals, supporting ligands, and
coupling partners to construct C(sp2)-C(sp2) bonds.2 Although
Pd catalysts operate with much success in this arena,3 the
development of Ni-catalyzed protocols has been of interest
because of the cost efficiency and complementary
reactivities.4 For instance, Ni-catalyzed couplings are
particularly useful for constructing synthetically challenging
C(sp2)-C(sp3) linkages,5-7 due to the facile oxidation of low-
valent nickel by C(sp3)-centered electrophiles and the
suppression of undesired β-hydrogen eliminations at nickel.4,8
One of the most successful catalysts for nickel-catalyzed
coupling reactions is derived from the [(bipyridine)nickel]
motif which has been widely employed for both traditional
cross-coupling and photoredox catalysis.5-7 However, it should
be noted that the conventional [(bipyridine)nickel] systems
Ni
Ni
Ar = 1-naphthyl, o-tolyl, mesityl
Cl
L
L (monodentate ligand)= PCy3, PPh3,
tmiy (1,3,4,5-tetramethylimidazol-2-ylidine)
L= IMes
R'
L
Ni
Me
Cl
Ni
Cl
L
L
R'= H or Ph;
L= dppf, IPr
L (bidentate ligand)
= dppf, PAd-DalPhos, TMEDA,bipy
B. Fluoroalkyl-bound Ni-based precatalyst for C(sp2)-C(sp3) couplings
N
N
N
N
Ni
Ni
F3CH2C
CH2CF3
H3CH2C
CH2CH3


end-capped with H
end-capped with F
Suzuki-type C(sp2)-C(sp3) couplings
(novel precatalyst)
Figure 1. Strategy for the development of fluoroalkyl-bound
nickel precatalyst.
a. Key Laboratory of Green Catalysis of Higher Education Institutes of Sichuan,
School of Chemistry and Environmental Engineering, Sichuan University of Science
& Engineering, 180 Xueyuan Street, Huixing Lu, Zigong, Sichuan 643000 (China).
E-mail: yangyiyoung@163.com
characterized by a combination of Ni0 catalysts or inorganic NiII
salts with bipyridyl ligand still suffer from some unneglectable
limitations: (i) Commonly used Ni0 sources for catalysis are
expensive and air-sensitive, thus hindering their use out of
glovebox for large-scale synthesis; (ii) The low solubility of
inorganic NiII salts complicates the heteroleptic coordination of
exogenous supporting ligands which could have deleterious
effects on reaction outcomes.
b. Shenzhen Grubbs Institute and Department of Chemistry, Southern University of
Science and Technology, Shenzhen 518055 (China).
oscarchung@sustc.edu.cn
E-mail:
c. Department of Chemistry, Lehigh University, 6 E. Packer Ave., Bethlehem, PA
18015 (USA). E-mail: vicic@lehigh.edu
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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In this context, the development of robust nickel-based
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DOI: 10.1039/C9SC00554D
precatalysts in which the metallic cores are preligated with
privileged ligands is highly desirable and constitutes a viable
solution to address the above-mentioned limitations.9
Recently, the carbon-bound nickel precatalysts have exerted
powers in a variety of coupling reactions as alternatives to the
conventional [LnNiX2] precatalysts (L= P or N ligands).10
Notably, many previously reported carbon-bound Ni
precatalysts [LnNi(X)(R)] feature sterically bulky ligands (R= o-
tolyl, mesityl, 1-naphthyl), or highly stabilizing motifs (R= η3-
allyl, η5-Cp) for sheltering reactive organometallic nickel cores
(Figure 1A).10 Considering that fluoroalkyl ligands are known to
confer enhanced stability to metal complexes relative to their
non-fluorinated alkyl counterparts owing to fluorine's unique
electronic and steric properties,11-13 we wondered whether the
incorporation of selected fluoroalkyl moieties could support
novel nickel-based precatalysts and render new catalytic
activities for use in synthetic methods development (Figure
1B). Herein, we describe the synthesis of such a fluoroalkyl-
bound nickel precatalyst and demonstrate its use in C(sp2)-
C(sp3) Suzuki-type coupling reactions.
Figure 2. ORTEP diagram of precatalyst [(bipy)Ni(CH2CF3)2] 2.
(trans N-Ni-C bond angles: 165.1(2)o and 159.7(2)o) and
[(bipy)Ni(CF2CF3)2] 5 (both at 152.2o),12g,12i indicating fewer
steric and electronic repulsions of the CH2CF3 chains in 2
compared to the perfluorinated derivatives. Interestingly, Ni-C
distances of 2 (1.944(5) and 1.942(4) Å) are substantially
longer than those of 4 (1.872(6) and 1.883(6) Å) and 5
(1.910(6) and 1.911(6) Å). Besides, the value of C(2)-F(3) bond
length [1.366(6) Å, trans coplanar to C(1)-Ni bond] was clearly
larger than the others two carbon-fluorine bonds [C(2)-F(1)
1.346(5) Å; C(2)-F(2) 1.342(6) Å] which implied the possobile
use of β-fluorine elimination for further coupling reaction
development.
Result and Discussion
Although we did not obtain the one fluoroalkyl
accommodated nickel complex [(bipy)Ni(CH2CF3)(I)] 1 which
showed more structural similarities to the reported
At the outset, we began the rational design of precatalyst
based on the principles of utilizing short fluoroalkyl and
bipyridine as supporting ligands for atomic economy and
C(sp2)-C(sp3) coupling reaction efficiency. Specifically, the short
and partially fluorinated CF3CH2 group was selected as
supporting ligand (analogue of ethyl group but end-capped
with fluorines) which was anticipated to render distinctive
[(bipy)Ni(o-tolyl)Cl] precatalyst14b
, we presumed that β-
fluorine elimination16 of [(bipy)Ni(CH2CF3)2] 2 hinted by the C-F
bond length analysis could be leveraged for the in-situ
generation of [(bipy)Ni(F)(CH2CF3)] 2a with concurrent
extrusion of vinylidenedifluoride (CH2=CF2). Notably, the Ni-F
strutural motif of intermediate 2a was supposed to facilitate
the transmetalation of arylboronic acids towards nickel
according to a recent example of base-free Suzuki coupling.4g
Furthermore, the bis-trifluoroethyl structural motifs of
[(bipy)Ni(CH2CF3)2] 2 entails the bench-top stability and
excellent solubility in organic solvents which is of vital
importance for developing nickel-based precatalysts.9,10
thermostability
and
reactivities
versus
both
the
hydrocarbonated [(bipy)Ni(CH2CH3)2]14 and perfluorinated
[(bipy)Ni(CF2CF3)2]12g counterparts (Figure 1B, bipy=2,2’-
bipyridine). Gratifyingly, the reaction of [Ni(COD)2], CF3CH2I,
and 2,2-bipyridine furnished [(bipy)Ni(CH2CF3)2] 2 in 41%
isolated yield (eq 1) presumably via an interesting ligand
redistribution12c,15 of the intermediate [(bipy)Ni(CH2CF3)(I)] 1.
The solubility of complex 2 in benzene facilitated its isolation
from the nickel halide co-products 3. The 19F NMR spectra of 2
exhibited a triplet at δ -47.98 ppm, demonstrating the
presence of CH2CF3 groups and their bonding to Ni core. Dark
red crystals of 2 can be grown from THF/pentane and are air-
stable at room temperature for several weeks.
With [(bipy)Ni(CH2CF3)2] 2 in hand, we initially assessed it as
a precatalyst for the Suzuki-type coupling between CF3CH2I
and arylboronic acids for C(sp2)-C(sp3) bonding. Based upon
previously established Ni-catalyzed trifluoroethylation
conditions,17 we were pleased to find that coupling products
can be obtained in excellent yields at 80 oC with 5 mol%
catalyst loading using K3PO4 as a base and DME as a solvent
(Table 1, entry 1). Use of other solvents decreased the yields,
and only polar non-protic DMSO solvent was comparatively
effective. Furthermore, the use of K3PO4 was critical to the
success of the coupling reaction and suppressing
dehydrofluorination of the final products (for details, see SI
Table S1-S2). The commercialized [(TMEDA)Ni(o-tolyl)Cl]10e,10f
bearing modular TMEDA was found to be less efficient (Yield
35%) with using the privileged bipyridine as the leading
supporting ligand (Table 1, entry 2). In contrast, the bipyridine
preligated [(bipy)Ni(o-tolyl)Cl]14b bearing the previleged o-tolyl
CF3CH2I
Ni(COD)2
bipy
[(bipy)Ni(CH2CF3)(I)]
+
1
(1)
(bipy)Ni(CH2CF3)2
41% isolated yield
(bipy)NiI2
+
1/2
1/2
3
2
insoluble in benzene
X-ray diffraction analysis of 2 confirmed the ligation of two
CH2CF3 groups at nickel (Figure 2). Complex 2 featured a
square planar arrangement at the NiII core with a rough linear
trans N-Ni-C linkage (bond angle: 177.4(2) and 177.8(2)o). In
contrast, more striking distortions were found in the
previously reported and related complexes [(bipy)Ni(CF3)2] 4
2 | J. Name., 2012, 00, 1-3
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ligand improved the coupling yield to 78% but was still inferior nitrogen atoms with Ni. To further exhibit tVhieew AsryticnlethOenltinice
DOI: 10.1039/C9SC00554D
to that of [(bipy)Ni(CH2CF3)2]. These results demonstrated the
praciticality of our precatalyst and trifluoroethylation protocol,
the late-stage modifications of Fenofibrate and Clofibrate
(drugs against cardiovascular disease) were accomplished (7s,
7t). Therefore, this synthetic strategy should provide
important opportunities for making more diverse biologically
active molecules.
Table 1. Survey of reaction conditionsa
B(OH)2
(bipy)Ni(CH2CF3)2
5 mol%
2
CH2CF3
CF3CH2I
K3PO4, DME, 80 o
Ph
Ph
C
Further demonstration of the privileged catalytic utilities of
precatalyst [(bipy)Ni(CH2CF3)2] 2 was showcased by several
types of C(sp2)-C(sp3) Suzuki-type alkylations. Iodoethane (8),
3-iodooxetane (9), ethyl bromoacetate (10), allyl bromide (11),
(4,4,4-trifluoro-3-iodobutyl)benzene (12a), HCF2CH2I (12b) and
FCH2CH2I (12c) were found to successfully couple with a series
of arylboronic acids ranging from electron-poor and electron-
rich types (Table 3). The encouraging results showed that
these primary and secondary alkyl halides were readily
compatible with this catalytic alkylation, regardless of the
possible β-H or β-F elimination problems.8a Furthermore, the
active allyl group can be coupled with the aromatic groups
without detection of the migration of double bond (13d).7
The success of precatalyst 2 for the Suzuki-type alkylations
further encouraged us to investigate the reaction mechanism.
At the start, we intended to determine whether the activation
mode of [(bipy)Ni(CH2CF3)2] was consistent with our β-fluorine
elimination hypothesis. The precatalyst could undergo β-
fluorine elimination to afford [(bipy)Ni(F)(CH2CF3)] 2a with
extrusion of CH2=CF2, or alternatively undergo reductive
elimination like the analogous [(bipy)Ni(CH2CH3)2]14 to
generate a [(bipy)Ni(0)] species and CF3CH2CH2CF3. Heating
precatalyst 2 at elevated temperature indicated the clear
formation of CH2=CF2 rather than CF3CH2CH2CF3 through
continuous 1H and 19F NMR monitoring (for details, see SI
Figure S122-S123) which illustrated the direct formation of
7a
6a
Entry
1
Variation from standard conditions
None
Isolated Yield
93%
[(TMEDA)Ni(o-tolyl)Cl] (5.0 mol%) and 2,2-
bipyridine (5.0 mol%) instead of 2
2
35%
3
4
[(bipy)Ni(o-tolyl)Cl] (5.0 mol%) instead of 2
[(dppf)Ni(o-tolyl)Cl] (5.0 mol%) instead of 2
78%
25%
[Ni(COD)2] (5.0 mol%) and 2,2-bipyridine (5.0
5
6
7
40%
13%
55%
mol%) instead of 2
[(bipy)NiEt2] (5.0 mol%) instead of 2
[(MeCN)2Ni(CF2CF3)2] (5.0 mol%) and 2,2-
bipyridine (5.0 mol%) instead of 2
[(MeCN)2Ni(CF3)2] (5.0 mol%) and 2,2-
bipyridine (5.0 mol%) instead of 2
8
51%
6
7
2.5 mol% loading of precatalyst 2
1.0 mol% loading of precatalyst 2
91% (83%b)
79%
aGeneral conditions: 4-biphenylboronic acid (0.3 mmol), CF3CH2I (0.2 mmol),
K3PO4 (0.4mmol), 5.0 mol% precatalyst loading of 2, DME (1.0 mL).
bGram-scale synthesis.
importances of supporting ligation groups of both
trifluoroethyl and bipyridine in the structural motif of
[(bipy)Ni(CH2CF3)2] (Table 1, entries 2-3). Even the classical
[(dppf)Ni(o-tolyl)Cl]10c or [Ni(COD)2]/bipyridine18 combined
system gave unsatisfactory yield (25-40%) compared with the
use of 2 (Table 1, entries 4-5). For further demonstrating the
distinctive role of partially fluorinated trifluoroethyl ligand, we
compared its catalytic performance with those surrogating
low-valent
nickel
species
like
[(bipy)Ni(0)]
from
[(bipy)Ni(CH2CF3)2] 2 is less likely (Scheme 1A).19 Additionally,
the identification of CH2=CF2 and Ar-CH2CF3 (Ar= 4-biphenyl) in
GC-MS and NMR analysis of the reactions in Table 3 (e.g. 14b,
coupling between 4-biphenylboronic acid and 3-iodooxetane
in Scheme 1B) revealed the important roles of the
trifluoroethyl groups bound to nickel core (for details, see SI
Figure S124-S125 and Table S5). These results suggested that
the first trifluoroethyl group functioned as the mask of the
suggested active species [(bipy)Ni(F)(CH2CF3)] 2a via a CH2=CF2
extrusion and the second trifluoroethyl moiety contributed as
coupling partner for the formation of Ar-CH2CF3. Interestingly,
the finding of byproduct CH3OCH(Ar)CH2OCH3 and
ArCH2OCH2CH2OCH3 (Scheme 1B) illustrated plausible radical
activation of DME through abstraction of etheral α-hydrogens
by solvent-caged alkyl radicals.20
[(bipy)NiEt2]14c
,
[(bipy)Ni(CF2CF3)2]12i and [(bipy)Ni(CF3)2]12i
(Table 1, entries 6-8). It was found that these fully
hydrocarbonated and fluorinated courterpart complexes can
not furnish comparable catalytic outcomes. Gratifyingly, the
tests of decreasing the precatalyst loading and gram-scale
synthesis also provided the coupling product in comparatively
good yields (Table 1, entries 6-7). These results demonstrated
proof-in-principle of the excellent catalytic efficiency of
precatalyst 2 for the targeted Suzuki-type couplings.
Under the optimized conditions, a wide array of arylboronic
acid coupling partners were found to successfully participate in
the Suzuki-type trifluoroethylation catalyzed by 2 (Table 2).
Both the electron-donating and electron-withdrawing groups
substituted arylboronic acids were competent substrates and
gave the desired product in moderate to good yield. Broad
functional groups were well tolerated, including ethers (7c-7e),
aldehydes (7f, 7j), enolizable ketones (7g, 7k), esters (7h, 7l)
and nitriles (7i, 7m). Notably, the nitrogen-containing
heterocyclic boronic acids (7o, 7p) proceeded smoothly with
good yields despite the potential strong binding affinity of the
Next, a series of radical inhibition experiments were
conducted to verify the possibilities of radical intermediacy
(for details, see SI Table S8-S10). It was found that the radical
scavenger TEMPO shut down the coupling reactions
completely when using the 3-iodooxetane or CF3CH2I as the
alkyl electrophiles. Instead, TEMPO-Alkyl (alkyl = 3-oxetanyl or
trifluoroethyl) adducts 17 and 18 were observed in the GC-MS
analysis, respectively. Also, when a radical-clock cyclopropane-
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based substrate was used, a few ring-opening products like the
CF3CH2-merged product 20 and aryl-incorporated product 21
were identified. These experimental results suggested the
Table 2. Substrate scope of (hetero)arylboronic acid partnersa
View Article Online
DOI: 10.1039/C9SC00554D
2.5 mol% of 2
(Het)Ar-CH2CF3
(Het)Ar-B(OH)2
+
CF3CH2I
K3PO4, DME, 80 o
C
7
6
CH2CF3
O
O
CH2CF3
CH2CF3
CH2CF3
CH2CF3
tBu
MeO
OHC
O
BnO
7e, 80%b
7f, 70%b
7b, 79%b
7c, 86%b
7d, 83%b
CH2CF3
CH2CF3
CH2CF3
OHC
CH2CF3
CH2CF3
O
MeO2C
NC
Ph
7j, 48%b
7k, 67%b
7g, 74%b
7h, 80%b
7i, 72%b
CH2CF3
CH2CF3
CH2CF3
MeO2C
CH2CF3
NC
CH2CF3
N
OMe
N
7l, 63%b
7m, 44%b
7n, 74%b
7p, 82%b
7o, 78%b
O
O
CH2CF3
O
O
O
O
CH2CF3
OEt
F3CH2C
F3CH2C
7q, 70%c (36%)
7r, 87%c (42%)
7s, 61%b (Fenofibrate analogue)
7t, 44%b,d (Clofibrate analogue)
o
b
aGeneral conditions: (Hetero)arylboronic acid (0.6 mmol), CF3CH2I (0.4 mmol), base (0.8mmol), 2.5 mol% precatalyst loading, DME (2.0 mL), 80 C. Isolated
c
yield. Yield determined by 19F NMR spectroscopy using PhCF3 as an internal standard due to the volatility of naphathalene products. Data in parentheses
refer to yields of isolated products. d5.0mol% precatalyst loading.
involvement of CF3CH2● radicals (or R radicals) as well as aryl- NiI/NiIII catalytic cycle was highly likely to be superior to Ni0/NiII
bound nickel intermediates in the reaction profile.
counterpart in the current reaction systems.
A. NMR studies on the activation of precatalyst 2
With the above clues of reaction scenarios in hand, we
conducted further interrogations on whether the reactions
proceeded via a Ni0/NiII or NiI/NiIII redox shuttle. The important
findings of bis-trifluoroethyl ligands of 2 serving as CH2=CF2
mask and operational ligand for producing Ar-CH2CF3 inspired
us to devise a stoichiometric reaction of complex 2 with 4-
biphenylboronic acid as control experiment (Scheme 2A). The
intermediate [(bipy)Ni(F)(CH2CF3)] 2a could be generated in-
situ under the reaction conditions which was supposed to
further undergo a facile Ni-B transmetalation4g to deliver
[(bipy)Ni(Ar)(CH2CF3)] 2b (Ar= 4-biphenyl). However, the
putative [(bipy)Ni(Ar)(CH2CF3)] intermediate did not proceed
through a Ni(II)/Ni(0) reductive elimination10e to furnish Ar-
CH2CF3. In addition, CF3CH2F and CF3CH2CH2CF3 were also not
found which disfavored the scenario of Ni0 formation from the
reductive elimination of 2a and 2. Taken together, these
divalent organonickel intermediates (2, 2a and 2b) were not
productive for the corresponding NiII/Ni0 reductive elimination
under this current reaction system. Interestingly, the product
Ar-CH2CF3 was almost comparably efficiently obtained when
the precatalyst 2 was replaced by the putative [(bipy)NiI(Br)]
complex21 for the coupling between ArB(OH)2 and CF3CH2I
(Scheme 2B). These experimental results suggested that a
(bipy)Ni(F)(CH2CF3) 2a
path i
+
CH2=CF2

d6-DMSO
(bipy)Ni(CH2CF3)2
heat
[(bipy)Ni(0)] 2a'
2
path ii
+

CF3CH2CH2CF3
B. Probe the role of the nickel-bound trifluoroethyl as coupling partner
3-iodooxetane
B(OH)2
30 mol% (bipy)Ni(CH2CF3)2
Ar
O
K3PO4, DME, 80 o
C
Ph
GC-MS identified products:
(Ar= 4-biphenyl)
CH2=CF2 m/z 64
Ar CH2CF3 m/z 236
detected in the reaction system
( eliminative extrusion product)
isolated yield 11%
CH3OCH(Ar)CH2OCH3
ArCH2OCH2CH2OCH3
m/z 242
m/z 242
Scheme 1. Control experiments for identifying the role of
trifluoroethyl ligands in precatalyst 2
4 | J. Name., 2012, 00, 1-3
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Table 3. Versatility of precatalyst 2 for aryl-alkyl cross-coupling reactions
CH3CH2I 8; 3-iodooxetane 9
BrCH2CO2Et 10; ally-Br 11;
2.5 mol% of 2
(Het)Ar-R
CF3
(Het)Ar-B(OH)2
+
K3PO4, DME, 80 oC
PhCH2CH2CH(I)CF3 12a;
HCF2CH2I 12b; FCH2CH2I 12c
O
Et
CH2CO2Et
Ph
MeO2C
R
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
13f, 41%b,e(R= CF2H);
13g, 58%b,e(R= CH2F).
13e, 75%b,d
CF3
13d, 71%b
13a, 78%b
13b, 46%b
14b, 57%b
15b, 81%b
13c, 72%b
O
O
Et
CH2CO2Et
R
Ph
Ph
Ph
Ph
Ph
Ph
Ph
14f, 75%b,e(R= CF2H);
14g, 78%b,e(R= CH2F).
14c, 87%b
14d, 95%c
14a, 80%c
14e, 90%b,d
CF3
Et
CH2CO2Et
R
Ph
tBu
tBu
tBu
tBu
tBu
tBu
15f, 44%b,e(R= CF2H);
15g, 56%b,e(R= CH2F).
15c, 75%b
15a, 65%c
15d, 69%b
15e, 51%b,d
CF3
O
Et
CH2CO2Et
R
Ph
N
OMe
N
OMe
N
OMe
N
OMe
N
OMe
N
OMe
16f, 52%c,e(R= CF2H);
16g, 62%b,e(R= CH2F).
16a, 72%c
16c, 51%b
16d, 67%b
16b, 42%b
16e, 85%b,d
aGeneral conditions: (Hetero)arylboronic acid (0.6 mmol), the indicated R-X (0.4 mmol), base (0.8 mmol), 2.5 mol% precatalyst loading, DME (2.0 mL), 80 oC.
c
bIsolated yield. Yield determined by 1H NMR spectroscopy using Cl2CHCHCl2 as an internal standard due to the difficulties in separation of product from
deboronative byproduct. dUsing 5.0 mol% precatalyst loading and DMSO as the solvent instead of DME. eUsing 5.0 mol% precatalyst loading.
Scheme 2. Control experiments to support NiI/NiIII redox
A. Stoichiometric reaction of 4-biphenylboronic acid with precatalyst 2
shuttle in the catalytic cycle
K3PO4 (2.0 equiv)
[(bipy)Ni(CH2CF3)2]
(1.0 equiv)
6a
+
(1.0 equiv)
7a
X
DME, 80 o
C
(none)
Based on the above-mentioned experimental results and
relevant previous reports,5,6,13,22 a plausible mechanism was
proposed for these current cross-couplings (Scheme 3). The
catalysis commences with an eliminative liberation of a
CH2=CF2 mask and 2a. Intermediate 2a is proposed to undergo
transmetalation and subsequent abstraction of halogen atom
from R-X to afford (bipy)NiIII(Ar)(CH2CF3)(X) A. Reductive
elimination of A has been fingerprinted by the formation of Ar-
CH2CF3 and delivered a key catalytic species (bipy)NiI(X) B.
Upon the participation of B into the conventional NiI/NiII/NiIII
catalytic cycle, the shuttles via transmetalation/oxidative
addition22/reductive elimination provided efficient platform
for the above described Suzuki-type C(sp2)-C(sp3) alkylation
couplings.23
GC-MS identified products:
CH2=CF2
m/z 64
biphenyl
m/z 154
deborylation
product
detected in reaction system
(evidence for eliminative extrusion)
Not detected:
(Ar= 4-biphenyl)
CF3CH2CH2CF3
Ar-CH2CF3
CF3CH2F
B. Trifluoroethylation catalyzed by a putative univalent [(bipy)NiI(Br)]
CF3CH2I
10 mol% [(bipy)NiI(Br)]
Ar-B(OH)2
Ar-CH2CF3
K3PO4, DME, 80 o
(Ar= 4-biphenyl)
C
7a, 81%
6a
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Journal Name
shadow depicted species in precatalyst initiation and radical-
relay side reactions were fingerprinted by GC-MS.View Article Online
DOI: 10.1039/C9SC00554D
Conclusions
In conclusion, we demonstrated that the nickel-based
precatalyst 2 [(bipy)Ni(CH2CF3)2] can be employed in Suzuki-
type coupling reactions between (hetero)arylboronic acids and
a variety of alkyl halides including several typical partially
fluorinated alkyl halides bearing susceptible β-fluorine atoms
(2-iodo-1,1,1-trifluoroethane and 12a-12c), leading to new
A. Precatalyst Initiation:
CH2=CF2
(bipy)NiII(CH2CF3)2
(bipy)NiII(F)(CH2CF3)
2
2a
C(sp2)-C(sp3)
linkages.
Catalytic
performance
tests
R-X
R
ArB(OH)2
(bipy)NiII(Ar)(CH2CF3)
demonstrated the advantages of the trifluoroethyl ligand
motifs in the precatalyst [(bipy)Ni(CH2CF3)2] versus serveral
sibling perfluorinated and hydrocarbonated counterparts.24
The critical roles of trifluoroethyl groups of precatalyst 2 as
both CH2=CF2 mask and triggering coupling-ligand in these
nickel-catalyzed Suzuki-type alkylations were elucidated
through mechanistic investigations. We believe that the initial
success outlined here could prompt the utilization of more
fluoroalkyl binding moieties for the development of new
metal-based precatalysts with tailored activities. Further
studies towards this endeavor and mechanistic details are
underway in our laboratory, and the results will be reported in
due course.
base
2b
RE
(bipy)NiI(X)
(bipy)NiIII(Ar)(CH2CF3)(X)
B
A
Ar-CH2CF3
B. Side reactions of R radical intermediate:
DME
CH3OCH2CH(Ar)OCH3
CH3OCH2CHOCH3
R-H
R
C. Possible Catalytic cycle (L= bipy):
LNiIX
ArB(OH)2
base
Ar-R
(B)
Acknowledgements
RE
TM
We thank National Natural Science Foundation of China
(21502131, 21672096, 21702095), Science & Technology
Department of Sichuan Province (2018JZ0061, 2018HH0128),
Education Department of Sichuan Province (18CZ0024), Key
Laboratory of Vanadium and Titanium of Sichuan Province
(2018FTSZ03), Sichuan University of Science and Engineering
(2017RCL03), Shenzhen Nobel Prize Scientists Laboratory
Project (C17213101) and Office of Basic Energy Sciences of the
U.S. Department of Energy (DE-SC0009363) for funding this
work.
R
LNiIAr
Ar
NiIII
NiI/NiII/NiIII shuttle
L
(C)
X
(E)
R
R-X
+
radical
rebound
halogen
abstraction
LNiII(Ar)(X)
(D)
Scheme 3. Proposed reaction mechanism for Suzuki-type
alkylation couplings based on control experiments. The
Science, 2015, 349, 1087; (d) Z. Feng, Q.-Q. Min, X.-P. Fu, L.
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EtOCOCH2-) which could be ascribed to the abstraction of
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C.-P. Zhang, H. Wang, A. Klein, C. Biewer, K. Stirnat, Y.
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This journal is © The Royal Society of Chemistry 20xx
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Beromi, G. W. Brudvig, N. Hazari and D. J. Vinyard, Angew.
Journal Name
addition/transmetalation/ reductive eliminVaiteiwoAnrticleoOrndliener
should be plausible. The observed inDerOtIn: e10s.s10o3f9/[C(b9iSpCy0)0N5i5IB4rD]
towards CF3CH2I seemed to rule out the oxidative
addition/transmetalation/ reductive elimination sequence.
For some references about related [LnNiIAr] complexes: (a) J.
B. Diccianni, J. Katigbak, C. Hu and T. Diao, J. Am. Chem. Soc.,
2019, 141, 1788; ref. 10i. More corroborative computational
studies can be found in these references: (b) Z. Li, Y.-Y. Jiang
and Y. Fu, Chem. Eur. J., 2012, 18, 4345; (c) X. Lin and D. L.
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(d) G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R. E.
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Chem. Int. Ed., 2015, 54, 13352. It was characterized by IR
and XPS due to its bad solubility for single crystal formation
(for details, see SI). Very recently, Hazari group disclosed the
synthesis of [(neocuproine)2NiI](Cl) which had a similar
skeleton: (b) M. MohadjerꢀBeromi, G. W. Brudvig, N. Hazari,
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dol: 10.1002/anie.201901866.
22 For selected example of radical-rebound oxidative addition
of alkyl halide: (a) Z. Ruan, S. Lackner and L. Ackermann,
Angew. Chem., Int. Ed., 2016, 55, 3153. If the radical-chain
mechanism was operative, the cage-escaped radicals should
dimerize via radical recombination. Also, we did not detect
any radical dimerization products (R-R) in these experiments
which could support a fast cage-rebound other than cage-
escape process. For our recent report about the radical-
rebound oxidative addition step in the nickel-catalyzed 24 GC-MS analysis of the reaction mixtures (Table 1, entries 7-8)
Suzuki-type fluoroethylation: (b) Y. Yang, J. Cai, G. Luo, Y.
Jiang, Y. Su, Y. Su, C. Li, Y. Zheng, J. Zeng and Y. Liu, Org.
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Wodrich and X. Hu, J. Am. Chem. Soc., 2013, 135, 12004.
23 According to the recent reports about the catalytic activities
of [LnNiIAr], the catalytic shuttle started from the species
[LnNiIX] B via a transmetalation/oxidative addition/reductive
revealed no formation of Ar-CF2CF3 or Ar-CF3, respectively.
These results demonstrated quite different catalytic profiles
in which CF3CF2 and CF3 did not serve as coupling ligands.
Unlike the CF3CH2 counterpart, their reluctance to contribute
as triggering coupling-ligand might be explained by the
challenging Ar-Rf (Rf= perfluoroalkyl) reductive elimination.
For related reference: G. G. Dubinina, W. W. Brennessel, J. L.
Miller and D. A. Vicic, Organometallics, 2008, 27, 3933.
elimination
sequence
other
than
oxidative
Graphical Abstract
Fabulous Fluorine
R
(Het)Ar
(Het)Ar
+
(bipy)Ni(CH2CF3)2
B(OH)2
2
47 examples
(bipy)Ni(CH2CF3)2
(bipy)Ni(CH2CH3)2
2
2.5-5 mol%
C(sp3) -X
vs
K3PO4, DME, 80 oC
R
X
42% -93% yield
 Novel fluoroalkyl coordinated Ni-precatalyst
 Extrusion of CH2=CF2 mask for initiating catalysis
 Untouched CF3CH2 serving as trigger coupling ligand  Versatility for catalyzing Suzuki alkylations
A bis-trifluoroethyl coordinated nickel/bipyridine complex has been developed as efficient precatalyst for diverse Suzuki-type
alkylations which features unconventional precatalyst initiation mode.
8 | J. Name., 2012, 00, 1-3
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