Nickel-Catalyzed Electrochemical C(sp3)?C(sp2) Cross-Coupling Reactions of Benzyl Trifluoroborate and Organic Halides**

Article abstract of DOI:10.1002/anie.202014244

Reported here is the redox neutral electrochemical C(sp²)?C(sp³) cross-coupling reaction of bench-stable aryl halides or β-bromostyrene (electrophiles) and benzylic trifluoroborates (nucleophiles) using nonprecious, bench-stable NiCl₂?glyme/polypyridine catalysts in an undivided cell configuration under ambient conditions. The broad reaction scope and good yields of the Ni-catalyzed electrochemical coupling reactions were confirmed by 50 examples of aryl/β-styrenyl chloride/bromide and benzylic trifluoroborates. Potential applications were demonstrated by electrosynthesis and late-stage functionalization of pharmaceuticals and natural amino acid modification, and three reactions were run on gram-scale in a flow-cell electrolyzer. The electrochemical C?C cross-coupling reactions proceed through an unconventional radical transmetalation mechanism. This method is highly productive and expected to find wide-spread applications in organic synthesis.

Full text of DOI:10.1002/anie.202014244

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Nickel Catalyzed Electrochemical C(sp3)−C(sp2) Cross-Coupling
Reactions of Benzyl Trifluoroborate and Organic Halide
Authors: Jian Luo, Bo Hu, Wenda Wu, Maowei Hu, and Tianbiao Leo
Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014244
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10.1002/anie.202014244
Angewandte Chemie International Edition
RESEARCH ARTICLE
Nickel Catalyzed Electrochemical C(sp3)−C(sp2) Cross-Coupling
Reactions of Benzyl Trifluoroborate and Organic Halide
Jian Luo,[a] Bo Hu,[a] Wenda Wu,[a] Maowei Hu,[a] and T. Leo Liu*[a]
Abstract: Herein, we report redox neutral electrochemical C(sp2)‒
industrial adoption.[7] It is worth noting that recent success in dual
Ni/photoredox catalyzed cross-coupling reactions has opened
novel catalytic routes to advance traditional thermal Ni catalyzed
cross-coupling reactions.[8, 9]
C(sp3) cross-coupling reactions of bench-stable aryl halide or β-
bromostyrene
(nucleophiles)
(electrophiles)
using
and
benzylic
trifluoroborate
bench-stable
non-precious,
NiCl2•glyme/polypyridine catalysts in an undivided cell configuration
under ambient conditions. The broad reaction scope and good yields
of the Ni-catalyzed electrochemical coupling reactions were
confirmed by 50 examples of aryl/β-styrenyl chloride/bromide and
benzylic trifluoroborates. Its potential applications were demonstrated
On the other hand, the existing literature is evidence of the
powerful applications of electrochemistry in organic synthesis.[10-
13]
By precisely controlling redox potential in an electrolyzer cell,
substrates or catalysts can be selectively anodically or
cathodically activated to produce desired reaction sequences.[10-
13] Thereby, electrosynthesis not only migrate the use of reactive
(even dangerous) oxidants and reductants, it enables access of
highly reactive catalytic intermediates which are not easily
handled in traditional thermal reactions, representing a green,
atomically economical synthetic strategy. In spite of being around
for many decades, electrosynthesis has recently aroused
attention as it is believed to have profound impacts on organic
synthesis.[10-13] For instance, anodic reactions including alcohol
by
electrosynthesis
and
late-stage
functionalization
of
pharmaceuticals, and natural amino acid modification. Furthermore,
to testify practical industrial adoption, three electrochemical C−C
cross-coupling reactions were demonstrated at gram-scale in a flow-
cell electrolyzer. An array of chemical and electrochemical studies
mechanistically indicates that the studied electrochemical C−C cross-
coupling reactions proceed through an unconventional radical trans-
metalation mechanism. The presented Ni-catalyzed electrochemical
C(sp2)‒C(sp3) cross-coupling paradigm is highly productive and
expected to find wide-spread applications in organic synthesis.
oxidation,[14]
C−H
functionalization,[15-22]
alkene
functionalization,[23, 24] cyclization,[25, 26] and C−O[27], C-N[28, 29]
,
and C-P[30-32] couplings, and cathodic reactions including arene or
alkene hydrogenation,[33, 34] and arylboronic acid hydroxylation[35]
have demonstrated good selectivity and yields. Ni-catalyzed
cathodic reductive C−C homocouplings were first reported by
Jennings and co-workers in 1976. Ni-catalyzed reductive cross-
electrophile C−C couplings were pioneered by Jutand, Perchion
and coworkers[36-38] and recently have been advanced by several
groups, representing an attractive technology for C-C formation
without using strong, reactive reductants as in traditional thermal
reactions.[39-43]
Introduction
In the past half-century, transition metal catalyzed carbon-
carbon (C−C) cross-coupling reactions have gained significant
advances regarding reaction scopes, selectivity, and catalytic
mechanisms, and have achieved tremendous success in organic
synthesis of pharmaceutical molecules, agrochemicals, and
organic materials.[1-3] Historically, catalyzed C−C cross-coupling
reactions have been dominated by Pd-based catalysts.[4, In
5]
addition to replacing the expensive, precious Pd metal, Ni metal
is characteristic of more negative 2+/0 and 1+/0 redox potential
than Pd2+/0 to enable unique oxidative addition reactivities in
activating C-X (X = Cl and Br) bonds and has found increasing
importance in C-C cross coupling reactions.[6] However, Ni
catalyzed C−C cross-coupling reactions are still limited by a
number of well-known synthetic limitations. Ni-based Kumda,
Negish, and Suzuki, and reductive couplings are hampered by the
use of either strong nucleophiles, sacrificial reductants, or
sensitive Ni0 pre-catalysts, e.g. widely used Ni(COD)2 (where
COD is 1,5-cyclooctodiene) typically require rigid reaction
conditions using an inert atmosphere glovebox or Schenk-line
techniques. The long-standing challenge remains to develop Ni-
catalyzed cross-coupling reactions using bench stable chemicals
and easy handling conditions for widespread academic and
However, Ni-catalyzed redox-neutral cross couplings in which
anodic oxidation of a nucleophile and cathodic reduction of an
electrophile are coupled to forge the C-C bond formation while no
sacrificed stoichiometric electron donor is required, remain very
rare,[44, 45] It is also worth noting that more than 97.5% of ca. 900
electrosynthesis methodologies reported between 2000 and 2017
were based on an anodic or cathodic process.[11] Recent effort
has been made to develop paired redox-neutral Ni-catalyzed
electrosynthesis for C-N, C-S, and C-O bond coupling
reactions.[46-48] The development of paired redox neutral
electrosynthesis has been very challenging as merging an anodic
redox reaction and a cathodic redox reaction is often plagued by
side reactions of reactive intermediates in each redox reaction.[11]
For example, homo-coupling side-reactions can occur in
electrochemical cross coupling reactions. Herein, we report that
the synergic coupling of single electron transfer (SET) anodic
oxidation of nucleophiles and cathodic reduction of organic
halides through Ni catalysis enables efficient redox neutral
electrochemical C−C cross-coupling reactions. The reported Ni
catalyzed redox neutral cross-coupling reactions in this study not
only hold promise for addressing the above-mentioned limitations
of traditional Ni-catalyzed thermal coupling reactions but are also
[a] Dr. Jian Luo, Dr. Bo Hu, Mr. Wenda Wu, Miss Maowei Hu, Dr. Prof T.
Leo Liu
Email: leo.liu@usu.edu
Department of Chemistry and Biochemistry
Utah State University
0300 Old Main Hill, Logan Utah, 84322 United States
Supplementary Information provides experimental details, supporting
figures, and supporting tables.
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10.1002/anie.202014244
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RESEARCH ARTICLE
+e
[NiII]
+e
[NiI]
NiII
X
R
(Cathodic reduction)
X
NiIII
R
X
(Cathodic reduction)
-[NiI]
NiIII
X
R
R
R
R'
R'
(Oxidative addition)
(Reductive elimination )
(Radical coordination)
-e
R' LG
-e
-LG
R'
R' LG
R'
-LG
(A catalytic amount of electon donor)
(Oxidative radicalization)
Figure 1. Designed Ni-catalyzed electrochemical C−C cross-coupling reaction. X, halides; LG, leaving groups.
complementary to electrochemical cross-electrophile C−C
couplings by expanding substrate scopes.
in the presence of 3 equivalents 2,2’-bipyridine (2,2’-bpy) ligand,
NiCl2•glyme displayed a reversible redox signal at E1/2 = –1.49 V
(vs. Fc+/0), which corresponds to the NiII/I redox couple. Then, 10
equivalents of organic halides (R−X) were added to the electrolyte
and CV curves were collected again. Among tested organic
halides, C(sp2) precursors (aryl halide and alkenyl bromide) or
C(sp) precursors (alkynyl bromide) could be activated by the NiI
intermediate while C(sp3) precursors were inactive. For example,
when methyl 4-bromobenzoate was added (green trace in Figure
2B(i)), the reductive peak current intensity was obviously
increased, meanwhile, the return peak disappeared -- which
indicates that an irreversible chemical reaction happened
between NiI species and the aryl halide. The same screening
experiments were conducted to the anodic substrates. As shown
in Figure 2B(ii), in 0 – 1.25 V (vs. Fc+/0) potential range, potassium
benzyltrifluoroborate, phenylacetate, and pivalate displayed
remarkable electrochemical reactivity with peak potential at +0.75,
+0.94, and +1.02 V (vs Fc+/0), respectively. Other substrates were
electrochemically inert in the scanned potential range. Based on
the CV screening results for both cathodic and anodic substrates,
C(sp2) precursors (aryl halide and alkenyl bromide) or C(sp)
precursors (alkynyl bromide) and C(sp3) sources (potassium
benzyltrifluoroborate, phenylacetate, and pivalate) were possible
combinations for electrochemical C(sp2)−C(sp3) or C(sp)−C(sp3)
cross-coupling reactions.
Results and Discussion
Instead of randomly testing combinations of nucleophiles,
electrophiles, and catalysts, we first set out to identify individual
anodic and cathodic SET half-cell reactions for the proposed full-
cell C−C coupling reactions using the electrochemical cyclic
voltammetry (CV) method. For the cathodic half-cell reaction, we
aimed to explore the SET reduction of NiII-based catalysts to
activate aryl and vinyl halide electrophiles by the NiIII/I(II/0) redox
cycle to achieve R−NiIII(II)−X intermediate, which is
mechanistically accessible in traditional Ni-based thermal
couplings.[6, 7] For the anodic half-reaction, nucleophiles including
carboxylic acid[10] and organic trifluoroborate[49] are well
documented as carbon radical precursors (Rʹ• in Figure 1) upon
SET oxidation. It is noted that organic trifluoroborates have been
used as versatile radical precursors for metal photoredox catalytic
coupling reactions with aryl halides by Molander and coworkers.[8]
Herein, we chose potassium butyrate, pivalate, phenylacetate,
butyltrifluoroborate and benzyltrifluoroborate as C(sp3) sources;
potassium
benzoate,
3-methylcrotonate,
and
phenyltrifluoroborate as C(sp2) sources; potassium 2-butynoate
as C(sp) source (Figure 2A). The proposed concept is illustrated
in Figure 1. In principle, if adopting a NiIII/I redox cycle, a bench
stable NiII precursor can be activated by one electron reduction
using a catalytic amount of a redox active nucleophile to access
the R−NiIII−X intermediate through oxidative addition. Then, after
another electron reduction while a Rʹ• radical is generated
anodically, the R−NiII−X intermediate can trap the Rʹ• radical to
form a high-valent R−NiIII(X)−Rʹ intermediate through single-
electron transmetallation. Finally, the desired C−C cross-coupling
product would be produced accompanying with the regeneration
of the NiI catalyst through a reductive elimination reaction. The
designed electrochemical C−C cross coupling reaction is (1)
fundamentally attractive as a new means to forge C−C bonds, (2)
practically attractive without involving reactive reactants and
expensive metals, and (3) atomically economic and
environmentally friendly by avoiding the use of sensitive
(sometimes even dangerous) reactants or catalysts.
We then optimized the NiCl2•glyme/polypyridine catalyst
system using cyclic voltammetry with methyl 4-bromobenzoate as
a model electrophile. As shown in Figure 2C(i), seven different
polypyridine ligands including 4,4'-di-tert-butyl-2,2'-bipyridyl
(dtbbpy), 6,6'-dimethyl-2,2'-bipyridyl (dmbpy), 2,2’-bpy, dimethyl
2,2'-bipyridine-4,4'-dicarboxylate (dmcbpy), 1,10-phenanthroline
(1,10-Phen), 2,2'-biquinoline (biq), and terpyridine were screened
to identify the most suitable ligand for the Ni-catalyst. Among all
the ligands, dtbbpy prompted the strongest current intensity
increase (green curve), indicating that NiI(dtbbpy)+ is the reactive
species for oxidative addition of the C‒Br bond of methyl 4-
bromobenzoate. Besides 2,2’-bpy and dtbbpy, 1,10-Phen also
aroused strong current response (purple curve) and thus can also
be a suitable ligand. Terpyridine ligand displayed the lowest
current response under the same conditions (Figure S5). We
further investigated the effect of Ni/ligand ratio on the reactivity of
the Ni-catalyst. The CV curves of NiCl2•glyme with the addition of
various ratio of dtbbpy ligand showed continuous change (Figure
S5). In the absence of the dtbbpy ligand, no reversible redox
signal was observed. When 1 ‒ 3 equivalents of dtbbpy ligand
Electrochemical screening of the proposed half-cell reactions
was conducted through the cyclic voltammetry (CV) method using
a three-electrode system. As shown in Figure 2B(i) (gray curve),
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10.1002/anie.202014244
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RESEARCH ARTICLE
(A)
Substrate Pools
(i) Cathode Side
(ii) Anode Side
Reaction
Discovery
(B)
Substrate Screening
(ii) Anode Side
100
50
0
(i) Cathode Side
0.4
0.2
0
-50
-100
-150
-1.8
-1.6
-1.4
-1.2
-1
0
0.2 0.4 0.6 0.8
1
)
1.2
Potential (V, vs Fc+/0
)
Potential (V, vs Fc+/0
Reaction
Optimization
(C)
Ligand Screening
tBu
tBu
MeO2C
CO2Me
N
N
N
N
N
N
N
N
N
N
N
N
biq
dmcbpy
dmbpy
2,2'-bpy
dtbbpy
1,10-Phen
(ii) dtbbpy ligand
25
(i)
75
5 eq.
3 eq.
2 eq.
1.5 eq.
1 eq.
0 eq.
25
-25
-75
-25
-75
-125
-175
-125
-175
-2
-1.8
-1.6
-1.4
-2.1 -1.9 -1.7 -1.5 -1.3 -1.1 -0.9 -0.7
Potential (V, vs Fc+/0
Potential (V, vs Fc+/0
)
)
Figure 2. Electrochemical voltammetry screening of cathodic and anodic half-reactions. (A) Selected substrate pools. (B) CV screening to identify reactive
substrates of cathodic (i) and anodic (ii) half-reactions. The CV curves were recorded with 5.0 mM NiCl2.glyme, 15.0 mM 2,2’-bpy, and 50.0 mM organic
halides for the cathode side screening, 0.1 M potassium trifluoroborates or carboxylates for the anode side screening. DMF solvent, 0.2 M LiClO4 supporting
electrolyte, GC working electrode, 100 mV/s scan rate, room temperature. (C) CV screening of the ligand (i) and Ni/ligand ratio (ii) to optimize the cathodic
half-reaction. The ligand screening curves were recorded with 5.0 mM NiCl2.glyme and 15.0 mM ligand in the presence (dash line) and absence (solid line)
of 50.0 mM methyl 4-bromobenzoate. The Ni/ligand ratio screening curves were recorded with 5.0 mM NiCl2.glyme and 50 mM methyl 4-bromobenzoate by
adding various ratio of dtbbpy ligand.
were added, there were two sets of quasi-reversible redox signals. is consistent with a previous UV-Vis study.[28] In the presence of
With a further increase of the ligand ratio to 5 equivalents, the
methyl 4-bromobenzoate substrate, the addition of 1.5 equivalent
redox signals overlapped to one set of fully reversible redox signal. of dtbbpy ligand (Figure 2C(ii), green curve) yielded the highest
This indicates that there is an equilibrium for NiII complexes in the
solution: NiII ↔ NiII(dtbbpy) ↔ NiII(dtbbpy)2 ↔ NiII(dtbbpy)3, which
cathodic current. Adding more ligand (2 ‒ 5 equivalents), the
reductive peak current intensity slightly decreased, and the return
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Table 1. Optimization for the Ni-catalyzed electrochemical C(sp2)‒C(sp3) cross-coupling reactions.
Standard
conditions
CO2Me
1
BF3K
Br
CO2Me
MeO2C
CO2Me
1'
1 eq
1.5 eq
Variation from standard
conditions [a]
Entry
Conversion (%) [b]
Yield of 1 (%) [c]
Yield of 1’ (%) [c]
1
2
None[d]
100
93
0
5
0
No dtbbpy ligand
0
0
3
No NiCl2.glyme
0
0
4
Na2CO3 instead of K2CO3
KOAc instead of K2CO3
No K2CO3
100 (48 h)
100
78
0
15
86
38
16
9
5
7
100
47
74
89
75
0
8
TBAPF6 instead of LiClO4
KPF6 instead of LiClO4
NaBF4 instead of LiClO4
No current
100 (20 h)
100 (22 h)
100 (20 h)
0
9
10
11
20
0
1.0 mA current
electrolysis[d]
12
13
100 (48 h)
100
48
76
27
23
5.0 mA current
electrolysis[d]
[a] Standard conditions: methyl 4-bromobenzoate (108 mg, 0.5 mmol, 1.0 eq.), potassium benzyl trifluoroborate (149 mg, 0.75 mmol, 1.5 eq.), NiCl2.glyme
(11 mg, 50 μmol, 10 mol%), dtbbpy (20 mg, 75 μmol, 15 mol%), K2CO3 (173 mg, 1.25 mmol, 2.5 eq.), LiClO4 (106 mg, 0.2 M), DMF (5 mL), RVC as anode
and cathode, 3.0 mA current under Ar at room temperature for 28 h. [b] Conversion was measured by 1H-NMR using 4-bromobenzaldehyde as internal
standard. [c] Isolated yield.
peak gradually showed up, which is most likely due to the
decreased reactivity of Ni-catalyst after coordination with multiple
dtbbpy ligands (Ni(dtbbpy)2 and Ni(dtbbpy)3).
1.0 mA, 77% under 5.0 mA current). Under 1.0 mA current
electrolysis, the reaction was significantly decelerated as a
reaction time of 48 h was needed to fully convert the substrate
(entry 6, Table 1). Other solvents, such as THF, MeCN, CH2Cl2,
MeOH, and DMSO were not effective for this reaction (only 0 –
15% yield was observed, Table S1, SI). Similarly, under thermal
reaction conditions,16 the reactivity and selectivity of this reaction
is highly sensitive to the ligand structure (Table S2, SI). In
particular, dtbbpy and 2,2’-bpy ligands exhibited the best
efficiencies with isolated yields of 93% and 87%, respectively.
1,10-Phen and tridentate terpyridine (tpy) ligands gave moderate
yields of 77% and 73%, respectively. It is noteworthy that the best
selectivity between cross-coupling product 1 and homo-coupling
product 1’ was obtained by using the dtbbpy (93% : 5%) and tpy
(73% : 3%) ligands, which tend to suppress the homo-coupling of
strong electrophiles. However, other ligands (dmbpy, dmcbpy,
and biq) were not effective. Moreover, no cross-couping product
Encouraged by the positive observations in the
electrochemical voltammetry studies, we proceeded to test the
C(sp2)‒C(sp3) cross-coupling full-reaction by combining the
oxidative radicalization of benzylic trifluoroborates and Ni-
catalyzed C−X activation of aryl halides in an undivided cell. An
initial electrolysis system consisting of NiCl2•glyme catalyst,
dtbbpy ligand, and LiClO4 -supporting electrolyte confirmed the
cross-coupling of methyl 4-bromobenzoate and potassium
benzyltrifluoroborate in 47% yield (produce methyl 4-
benzylbenzoate, 1) after galvanostatic electrolysis at 3.0 mA for
28 h (entry 7 in Table 1). Dimethyl 4,4'-biphenyldicarboxylate (1’)
from the homo-coupling of methyl 4-bromobenzoate was isolated
as the main by-product in 38% yield. To further improve the
reaction yield, a number of supporting electrolytes (TBAPF6, KPF6, was observed when a bidentate bis-phosphine ligand, 1,2-
and NaBF4) and salt additives (K2CO3, Na2CO3, and KOAc) were
tested to optimize the reaction efficiency (Table 1). It was found
that the yield for 1 was further improved to 93% using K2CO3
additive. The essentiality of NiCl2•glyme catalyst, dtbbpy ligand,
and electrolysis was determined by control experiments (Table 1).
In addition, both reaction selectivity (ratio between 1 and 1’) and
rate were largely affected by current intensity. Lower selectivity
was obtained under a higher or lower current intensity (64% under
bis(diphenylphosphino)benzene (dppb) was used (Table S2, SI).
It was observed that the dppb ligand underwent oxidation near the
oxidation potential of benzyltrifluoroborate, which could
destabilize the corresponding Ni catalyst (Figures S8, SI).
After establishing optimal reaction conditions for yield and
selectivity for the Ni-catalyzed electrochemical C(sp2)‒C(sp3)
cross-coupling, we next tested the reaction scope on both aryl
halide and benzylic trifluoroborate using the most efficient
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10.1002/anie.202014244
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RESEARCH ARTICLE
Ni/dtbbpy catalyst. As shown in Figure 3, a wide range of aryl
X
§ Non-precious, bench
stable catalysts
R
R
R'
R'
Ni
§ Bench stable substrates
§ Sustainable and scalable
BF3K
or
or
R
+
NiCl2.glyme (10%), dtbbpy
Br
§ Broad scope and good
selectivity
or tpy ligand (15%), K2CO3
(2.5 equiv), LiClO4 (0.2 M),
DMF (5 mL), RVC, 3.0 mA
1.5 eq
1 eq
§ Good to excellent yield
Ar-X scope
X = Cl
CO2Me
F
F
COMe
Me
4: 46%
2: 83%*
3: 74%
5: 31%
1: 86%
X = Br
CO2Me
COMe
Me
1: 93%
0.5 g scale: 89%;
2: 91%*
7: 89%
3: 81%
4: 77%
9: 53%
5: 86%
3.0 g flow cell synthesis: 86%
CO2Me
OMe
CO2Me
tBu
CO2Me
OMe
10: 90%
15: 67%
20: 84%
25: 81%
6: 71%
8: 72%
13: 21%**
18: 78%
23: 52%
H
N
O
N
H
CHO
CN
CF3
NHAc
11: 82%*
14: 86%
19: 79%
24: 63%
12: 74%*
17: 71%
22: 64%
O
O
OBoc
OBn
16: 74%
N
N
N
Boc
N
Boc
21: 43%
R-BF3K scope
Ar Br
MeO
OMe
Me
CO2Me
CO2Me
MeO
CO2Me
CO2Me
OMe
29: 95%
CO2Me
26: 82%
30: 88%
27: 80%
31: 74%
28: 77%
32: 72%
2.0 g flow cell synthesis: 92%
O
MeO2C
CO2Me
CO2Me
F3C
CO2Me
33: 47%
Alkenyl Br
MeO2C
OMe
37: 90%**
34: 48%
35: 73%**
36: 92%**
40: 86%**
83%**
MeO
O
O
MeO
OMe
41: 67%**
38: 63%**
39: 72%**
Figure 3. Substrate scope of the Ni-catalyzed electrochemical C(sp2)‒C(sp3) cross-coupling reactions. Yields refer to isolated yields of products after
chromatography on silica gel. Standard conditions: aryl halide or β-bromostyrene substrate (0.5 mmol), trifluoroborate substrate (0.75 mmol), NiCl2.glyme (50
μmol), dtbbpy ligand (75 μmol), K2CO3 (1.25 mmol), LiClO4 (0.2 M), DMF (5 mL), RVC as anode and cathode, 3 mA current electrolysis under Ar at room
temperature for 20 ‒ 36 h. *75 μmol 2,2’-bppy as ligand. **50 μmol tpy as ligand. In case of 13, an inseparable mixture of 13 and 13’ was obtained, 41% purity.
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chlorides including both electron-rich and electron-deficient
arenes were suitable to this Ni-catalyzed electrosynthesis system
(1 to 5). The electron-deficient aryl chlorides (1 to 3, 74% to 86%
yield) delivered better yield than the electron-rich ones (4 and 5,
46% and 31% yield). It is probably due to the low activity of
electron-rich aryl chloride substrates with the NiI intermediate.
Aryl bromides displayed better efficiencies than the
corresponding aryl chlorides, as 1 to 5 were isolated in 77% to
93% yield by using aryl bromide substrates. The reaction
exhibited comparable efficiency upon scale-up, for example, 89%
yield was obtained on a 2.5 mmol scale reaction of 1 (0.5 g). The
substituent position of aryl bromide displayed a moderate effect
on the reaction efficiency, as the para-, meta- and ortho-
substituted methyl bromobenzoate delivered 93%, 71%, and 89%
yield (1, 6, and 7), respectively. Aryl bromides with functional
groups as diverse as ester (1, 6, 7, and 10), ketone (2), fluoride
(3), methoxy group (9 and 10), amide (14 and 15), aldehyde (11),
nitrile (12) and alkenyl (19) were effective in this reaction.
Substrates possessing strongly electron-donating substituents
such as t-butyl and methoxy groups could also provide moderate
to good yield (72% for 8 and 53% for 9). When 4-bromo-phenol
was used as the electrophile as a control experiment for entry 9,
no cross-coupling product was observed, which is attributed to the
oxidation of the substrate itself at a less positive potential than the
borate nucleophile. The observation emphasizes the protection of
oxidation-susceptible functional groups under the investigated
electrochemical conditions. It is interesting that for the substrates
possessing strong electron-withdrawing substituents such as
aldehyde, acetyl, and cyano groups, best results were obtained
by using 2,2’-bpy ligand (83% and 91% yield for 2 from chloride
and bromide, respectively, 82% yield for 11, and 74% yield for 12).
Furthermore, in the case of 4-bromo(trifluoromethyl)benzene, the
homo-coupling product, 4,4'-bis-(trifluoromethyl)biphenyl (13’),
was obtained as the only product when using dtbbpy and 2’2-bpy
ligands. Interestingly, 21% yield of cross-coupling product 13 was
obtained by using the tpy ligand, implying that the Ni/tpy ligand
combination is more compatible with electron deficient
electrophiles to suppress homo-coupling.
The substrate scope of benzylic trifluoroborate salts was also
investigated. As shown in Figure 3, both electron-rich and
electron-deficient benzylic trifluoroborates proved efficient carbon
radial precursors in this cross-coupling reaction (26 to 31, 74% to
95% yield). Functional groups, including esters, methoxy group,
and trifluoromethyl group tolerated this Ni-catalyzed
electrosynthesis. The substituent positions displayed negligible
effects to the reaction efficiency, as comparable yield was
obtained for the para-, meta-, and ortho-substituted benzylic
trifluoroborates (26 to 28, 77% to 82% yield). In the presence of
two strong electron-donating methoxy (MeO-) groups, the highest
yield, 95%, was gained for 29, which is interpreted as the
favorable oxidation kinetics of the corresponding trifluoroborate
substrate. The π-conjugation extended naphthalen-2-ylmethyl
trifluoroborate is also highly productive in this electrochemical
C(sp2)‒C(sp3) cross-coupling reaction, as 72% yield was obtained
for 32. Beside the benzylic trifluoroborates, (benzyloxy)methyl
trifluoroborate also manifested reasonable reactivity in this
reaction with a yield of 47% (33).
In the CV screening studies (Figure 2B), β-bromostyrene
also showed reactivity in the cathodic half-reaction and thus was
briefly examined as an electrophile for the Heck-type like C(sp2)‒
C(sp3) cross-coupling. In the reaction of β-bromostyrene and
potassium trifluoro(4-(methoxycarbonyl)benzyl)borate, 48% yield
of product 34 and 47% yield of the homo-coupling product 34’
were obtained by using the dtbbpy ligand. According to entry 13,
the tpy ligand exhibited the better selectivity by suppressing the
homo-coupling product. Then the coupling reaction using β-
bromostyrene was optimized with the typ ligand. The improved
yield and selectivity for the cross-coupling product 34 were
obtained in the presence of the tpy ligand (83% yield, 90%
selectivity) (Table S3, SI). As shown in Figure 3, both electron-
rich and electron-deficient benzylic trifluoroborates were efficient
in this cross-coupling reaction (34 to 40, 63% to 92% yield).
Functional groups including esters, methoxy group, and
benzodioxol group were tolerant in this Ni-catalyzed
electrochemical reaction. The
π-conjugation
extended
naphthalen-2-ylmethyl trifluoroborate also provided good
reactivity in this reaction, as 67% yield was obtained for 41.
However, other anodic nucleophiles (3-bromopropiolate,
phenylacetic acid, potassium pivalate, and potassium
In addition to examining the substituent positions and
functional groups of the aryl halide substrates, we also
investigated the tolerance of nucleophiles to common protecting
groups which are widely used in organic synthesis, such as amide, phenyltrifluoroborate) didn’t provide satisfactory results (see
tert-butyloxycarbonyl (Boc), benzyl ether (BnO), and acetal. All of
these protecting groups were well tolerated, as evidenced by
good isolation yield of 14 to 18 (67% to 86% yield). The π-
conjugation extended aryl bromide substrates including 4-
bromophenylethene, 3-bromofluorene, and 2-bromonaphthalene
and also smoothly processed this cross-coupling reaction with
moderate to good yield (19 to 21, 43% to 84% yield). Moreover, a
variety of aryl bromides consisting of nitrogen-containing
Figure S10 and the SI for more discussions).
To demonstrate potential applications of this Ni-catalyzed
electrochemical C(sp2)‒C(sp3) cross-coupling methodology, we
first exploited the synthesis of pharmaceutical molecules
containing the diphenylmethane structural component.
Beclobrate analog (42,
a
hypolipidemic candidate[50]
)
and
Bifemelane (43, an antidepressant candidate[51]
)
were
synthesized with 74% and 56% overall yield, respectively (Figure
4A and 4B). We further utilized this methodology in late-stage
functionalization of pharmaceuticals which is a popular way for
heterocyclic
groups
including
and Boc
6-bromoquinoline,
protected
6-
6-
bromoisoquinoline,
bromotetrahydroisoquinoline, and 5-bromoindole, which are
prevalent building blocks in bio-active molecules, delivered
moderate to good yield (22 to 25, 52% to 81% yield).
fast discovery of new drug candidates. Fenofibrate is a
pharmaceutical molecule of the fibrate class and used to treat
abnormal blood lipid levels.[52] As shown in Figure 4C, Fenofibrate
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RESEARCH ARTICLE
(A)
(B)
Br
OBoc
OBoc
BF3K
Standard
condition
Br
BF3K
O
O
Cl
Standard
condition
O
H
N
HBr
O
O
Cl
O
O
Beclobrate analog
Bifemelane
43: 56% overall
42: 74%
(C)
O
O
O
O
CF3
O
Standard
condition
46: 41%
44: 72%
45: 79%
O
Cl
O
R
O
CF3
O
O
O
O
Fenofibrate
O
47: 86%
48, 81%
(D)
(F)
(G)
Br
Standard
condition
O
O
flow cell
O
O
O
O
O
49, 63% yield
Clofibrate derivative
reservoir
pump
Standard
condition
Br
(E)
NHBoc
NHBoc
tBuO2C
tBuO2C
Phenylalanine derivative
50, 83% yield
Figure 4. Applications of the Ni-catalyzed electrochemical C(sp2)‒C(sp3) cross-coupling reaction. Electrosynthesis of pharmaceutical molecules Beclobrate
analog (A) and Bifemelane (B). Late-stage functionalization of Fenofibrate (C), Clofibrate derivative (D), and modification of brominated phenylalanine (E).
(F) schematic drawing and (G) experimental setup of the electrosynthesis flow-cell. Yields refer to isolated yields of products after chromatography on silica
gel.
was successfully converted to a series of brand-new compounds
(44 to 48, 41% to 86% yield) in up to 2.5 mmol (0.93 g) scale from
a regular vial electrolyzer cell. Another new Clofibrate derivative
(a lipid-lowering agent) was synthesized using this
electrochemical approach (49, 63% yield) (Figure 4D). In addition,
the electrochemical C−C cross-coupling reaction was also
effective in modification of brominated natural amino acids, e.g.
phenylalanine, (Figure 4E) (50, 83% yield). For practical
applications of electrosynthesis, we believe flow cell electrolyzers
are the appropriate reaction platform beyond vial cells. In fact,
flow cells have been extensively used in organic redox flow
To gain mechanistic understandings of this Ni-catalyzed
electrochemical C(sp2)‒C(sp3) cross-coupling reaction, a radical-
trapping experiment was conducted for the anodic half-reaction.
As shown in Figure 5A, controlled potential electrolysis (at 1.2 V,
vs.
(methoxycarbonyl)benzyl)borate
piperidinyloxy (TEMPO) in
Fc+/0
)
of
the
potassium
and 2,2,6,6-tetramethyl-1-
divided-cell produced radical
trifluoro(4-
a
coupling product 51 with 86% isolated yield, which confirms the
formation of 4-(methoxycarbonyl)benzyl free radical in the anodic
oxidation process. In addition, plots of overpotential over the
logarithm of kinetic current and the corresponding fitted Tafel plots
were constructed to determine charge transfer rate constants (k0)
of potassium benzyltrifluoroborate and phenylacetic acid in the
presence of 2.5 equiv Cs2CO3 in the anodic oxidation process
(Figure 5B and see the SI for detail). k0 of potassium
benzyltrifluoroborate and cesium phenylacetate were calculated
as 5.56 × 10-5 cm/s and 1.39 × 10-5 cm/s, respectively. The higher
charge transfer rate constant of potassium benzyltrifluoroborate
indicates faster electrochemical reactivity to generate carbon
radicals than cesium phenylacetate, which is consistent with the
better efficiency of potassium benzyltrifluoroborate in the cross-
coupling reaction over phenylacetic acid / Cs2CO3 (30% yield). It
is believed that the quick formation of the carbon radical is critical
batteries[53] and have also received increasing attention in organic
55]
electrosynthesis.[54,
To further demonstrate the potential
industrial adoption of the present electrochemical cross-coupling
reaction, flow cell synthesis (Figure 4F and 4G) was
demonstrated with compounds 1, 29 and 48 with a reaction scale
greater than 2.0 g (see part 6 Flow Cell Synthesis in the SI). It
should be noted that reaction solutions were only flushed with
nitrogen gas in the flow cell synthesis without using rigid glovebox
or Schlenk-line techniques. Under the flow-cell condition, all three
compounds were obtained with good to excellent yields (86% for
1 at 3.0 g scale, 92% for 29 at 2.0 g scale, and 84% for 48 at 3.0
g scale).
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RESEARCH ARTICLE
(A)
LiClO4 0.2 M
dry DMF
BF3K
N
O
RVC(+), divided cell
1.2 V (vs. Fc+/0) CPE
under Ar
N
O
MeO2C
1 eq
MeO2C
3 eq
51: 86%
(i) bromide substrate
(ii) dtbbpy ligand
(C)
(B)
0.2
0.1
0
(iii) dtbbpy + NiCl2•glyme
0.2
0.4
0.6
0.8
1
Potential (V, vs Fc0/+
)
(iv) dtbbpy + NiCl2•glyme
+ bromide substrate
50 μA
-3
-2.5
-2
-1.5
Potential (V, vs Fc+/0)
Figure 5. Reaction mechanism studies of the Ni-catalyzed electrosynthesis system. (A) Carbon free radical trapping reaction. (B) Plots of overpotential over
the logarithm of kinetic current and the fitted Tafel plots of phenyl trifluoroborate (green) and cesium phenylacetate (orange). Inset: CV curves of potassium
phenyl trifluoroborate (green) and cesium phenylacetate (orange); conditions: 10 mM in DMF, LiClO4 (0.2 M) supporting electrolyte, GC working electrode,
and 100 mV/s scan rate. (C) CV curves of 50 mM methyl 4-bromobenzoate (gray), 15 mM dtbbpy ligand (blue), 5 mM NiCl2•glyme + 25 mM dtbbpy (green),
and 5 mM NiCl2•glyme + 15 mM dtbbpy + 50 mM methyl 4-bromobenzoate (orange) in DMF with 0.2 M LiClO4 supporting electrolyte.
to trap the R-NiII-X intermediate, otherwise the R-NiII-X
intermediate can promote the homo-coupling side reaction.
Electrochemical studies were conducted to gain additional
mechanistic insights for the cathodic process. As shown in Figure
5C, methyl 4-bromobenzoate substrate displayed irreversible
redox signal with onset potential at -2.05 V (vs Fc+/0) and dtbbpy
ligand delivered reversible redox signal with E1/2 = -2.70 V (vs.
Fc+/0), respectively. The mixture of NiCl2•glyme and 1.5 equiv
dtbbpy ligand exhibits three redox peaks at E1/2 = -1.74 V, -2.44
V, and -2.70 V (vs. Fc+/0), which corresponds to NiII/I, NiI/0 redox
couples, and the free ligand. When the methyl 4-bromobenzoate
substrate was added, apparent increase of reductive current and
disappearance of the return peak was observed for the NiII/I redox
couples. This indicates that the NiI species, (dtbbpy)NiIBr
(intermediate B in Figure 6B) is the reactive species for the
oxidative addition of aryl halide and results in the formation of
(dtbbpy)ArNiIIIBr2 (intermediate D in Figure 6B). The increased
current intensity from 94 µA for the NiII/I redox couple to 134 µA in
the presence of methyl 4-bromobenzoate is attributed the
reduction of (dtbbpy)ArNiIIIBr2 to (dtbbpy)ArNiIIBr (intermediate E
in Figure 6B). In addition, CV curves of the reaction mixture
displayed -1.60 V and 0.33 V (vs. Fc+/0) onset potentials for
cathodic and anodic half-reactions, respectively (Figure S11). The
potential of cathode was retained between -1.7 and -1.9 V (vs.
Fc+/0) during the reaction (Figure S12), and the observation further
confirms that the NiI/0 redox couple is not involved in the cathodic
process.
reactions, a suit of control experiments was conducted. As shown
in Figure 6A, after 50% conversion of a standard reaction between
benzyl trifluoroborate and methyl 4-bromobenzoate, the
electrodes and reaction mixture were separated (reaction 1 in
Figure 6A). For the reaction mixture part, two fresh electrodes
were added, and the resulting reaction mixture was electrolyzed
at 3 mA current (reaction 2). The cross-coupling product, methyl
4-benzylbenzoate (1) was obtained in a yield of 94% after the
bromide substrate was fully converted. The used electrodes were
rinsed with dry DMF and then directly used as electrodes for a
fresh reaction mixture in which no NiCl2.glyme/dtbbpy catalyst
was added (reaction 3 in Figure 6A). However, no cross-coupling
product was observed in reaction 3 after electrolysis. We then
further tested the catalytic capability of the Ni catalyst using the
second batch of the substrate mixture which was added as solid
into the reaction solution of reaction 2. For the second batch
reaction (reaction 4 in Figure 6A), a yield of 92% was obtained,
giving a total yield of 93% for methyl 4-benzylbenzoate (1). The
CV curves which were collected after reaction 2 displayed the
redox features as those of fresh NiCl2.glyme/dtbbpy catalyst
(Figure S13), indicating the good stability of the Ni catalyst.
Classic Chugaev’s reagent (dimethylglyoxime) tests were
performed to confirm the quantitative retention of Ni2+ ions in the
reaction solution after electrolysis in reaction 2 (Figure S14).
However, there was no Ni detected in the used cathode in
reaction 2. To further confirm there was no Ni deposition on the
cathode electrode, a SEM study was conducted with the used
carbon cathode in reactions 2 and 4, and no Ni element was
detected (Figure S15). These control experiments collectively
To confirm the homogeneous reaction nature and stability of
the Ni catalyst in the studied electrochemical C-C cross-coupling
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10.1002/anie.202014244
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RESEARCH ARTICLE
N
N
(B)
X
X
tBu
tBu
(A)
BF3K
NiII
Br
CO2Me
+
N
N
N
N
A
=
+e
(1) standard conditions
X = Cl, Br
X
Cathode
Ar
R
Ar
X
N
50% conversion
I
NiI
B
C
X
N
(3) used RVC
electrodes in (1)
and a fresh
reaction solution
without the Ni
catalyst
(Reductive
elimination)
(Oxidative
addition)
(2) fresh RVC
electrodes
and the reaction
solution from (1)
R
X
Ar
N
Ar
NiIII
N
N
D
NiIII
X
N
No cross-coupling
product
X
+e
Cathode
H
X
CO2Me
(Single-electron
transmetallation)
yield, 94%
N
N
NiII
Ar
(4) add a second
batch of substrates
X
E
Anode
-e
BF3K
R
Cross-coupling product:
(i) second batch, 92%
(ii) total yield for two batches, 93%
R
G
F
BF3
Figure 6. (A) Control experiments to confirm the homogeneous nature and stability of the NiCl2.glyme/dtbbpy catalyst and (B) Proposed reaction mechanism
for the Ni-catalyzed electrochemical C(sp2)‒C(sp3) cross-coupling reaction.
confirmed that the homogeneous nature and stability of the Ni
catalyst for the studied cross-coupling reactions, which is
consistent with observed potential profile at -1.75 V of the cathode
during electrolysis (Figure S12).
effective to handle reactive alkyl radicals under the investigated
reaction conditions. Through optimization of reaction conditions
and catalysts, it is promising to expand the scope of nucleophiles
to alkyl and phenyl trifluoroborates, and even carboxylic acids for
electrochemical cross couplings. It is also noted that after the
public disclosure of this work as a pre-print version in ChemRxiv,
Based on the chemical and electrochemical studies, a
reaction mechanism for this Ni-catalyzed electrochemical C(sp2)‒
C(sp3) cross-coupling is proposed and illustrated in Figure 6. The
reaction is initiated by the electrochemical reduction of NiII catalyst
A to NiI species B, the latter further oxidative addition to aryl halide
substrate C to generate an Ar‒NiIII complex D. D is subsequently
electrochemically reduced to Ar‒NiII species E. Simultaneously, a
benzylic carbon free radical G generated through oxidative
degradation of benzylic trifluoroborate or phenylacetate substrate
F in the anode side is captured by E to form a high-valent Ar‒NiIII‒
Bn species H. Then, H undergoes reductive elimination to
produce the cross-coupling product I and recover the NiI catalyst
B.
[44]
Hu et al. reported Ni catalyzed electrochemical cross-coupling
reactions of toluene derivatives and aryl halides,[45] which is
interesting and important for the challenging paired redox neutral
electrosynthesis. We observed that reaction scope and efficiency
of our work is better than those reported in Hu’s work. In Hu’s
work, benzyl radicals were electrochemically generated through
benzyl C-H activation. However, benzyl C-H activation is limited
to electron rich toluene derivatives and is believed to limit the
reaction scope and efficiency. In addition, we used a more
affordable carbon anode than an FTO anode used in Hu’s work.
Conclusion
Compared to the reported photocatalytic cross coupling of
benzoic trifluoroborates and aryl halides by Molander and
coworkers,[8] which relies on an iridium photocatalyst to activate
trifluoroborates and regenerate a Ni0 catalyst, the key mechanistic
difference of the present electrochemical coupling is that both the
reactive carbon radical and NiI intermediate are generated
electrochemically. Without using the expensive iridium
photocatalyst and the reactive Ni0 catalyst, the present
electrochemical cross coupling is more affordable, scalable, and
practical. Molander’s photocatalytic cross coupling is also capable
of using alkyl trifluoroborate nucleophiles as radical precursors.[56]
Nevertheless, our electrochemical cross-coupling protocol is not
In summary, a Ni-catalyzed electrochemical cross-coupling
methodology was developed to forge the C(sp2)‒C(sp3) bond with
broad substrate scope, excellent functional group tolerance,
selectivity, and good yields. The present electrochemical
approach is advantageous as all reactants and catalysts are
bench stable, without using reactive oxidants/reductants, and
complex inert atmosphere techniques as demonstrated in the
flow-cell synthesis. As exemplified in gram-scale synthesis in the
flow-cell synthesis and the late-stage functionalization of
pharmaceuticals, this electrochemical C−C coupling methodology
is expected to be widely applied to the construction of C(sp2)‒
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10.1002/anie.202014244
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RESEARCH ARTICLE
C(sp3) bonds in developing pharmaceutical molecules,
agrochemicals, and organic materials. The Ni-catalyzed
electrochemical C-C cross coupling reactions can be further
advanced for broader substrates and extended to other types of
coupling reactions. Moreover, the present new C-C bond
formation paradigm (and also extended reactions) can offer rich
opportunities to pursue fundamental mechanistic studies and thus
lead to the discovery of new catalytic knowledge at the interface
of synthetic chemistry and electrochemistry.
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Acknowledgements
We thank Utah State University for financial support for this
research provided through faculty startup funds (to T. L. L.). B.
H. and M. W. H. are grateful for the China CSC Fellowship which
is supported by the China CSC Study Abroad program. We
acknowledge that the NMR studies are supported by NSF's MRI
program (award number 1429195).
Keywords: Cross-coupling • Electrosynthesis • Ni catalysis
Conflict of interest: A patent application including the submitted
results was filed.
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10.1002/anie.202014244
Angewandte Chemie International Edition
RESEARCH ARTICLE
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This article is protected by copyright. All rights reserved.

10.1002/anie.202014244
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Jian Luo, Bo Hu, Wenda Wu, Maowei Hu, and T. Leo Liu*
Page No. – Page No.
Nickel Catalyzed Electrochemical C(sp2)−C(sp3) Cross-
Coupling Reactions of Benzyl Trifluoroborate and
Organic Halide
A redox neutral electrochemical C(sp2)‒C(sp3) cross-coupling
paradigm is developed using bench stable substrates and Ni
catalysts. The Ni-catalyzed electrochemical cross-coupling
exhibits good reaction efficiency and practical applications and
expands the synthetic toolbox to forge carbon-carbon bonds.
[a] Department of Chemistry and Biochemistry
This article is protected by copyright. All rights reserved.
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