Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile

Article abstract of DOI:10.1021/acs.oprd.9b00232

While reductive cross-electrochemical coupling is an attractive approach for the synthesis of complex molecules at both small and large scale, two barriers for large-scale applications have remained: the use of stoichiometric metal reductants and a need for amide solvents. In this communication, new conditions that address these challenges are reported. The nickel-catalyzed reductive cross-coupling of aryl bromides with alkyl bromides can be conducted in a divided electrochemical cell using acetonitrile as the solvent and diisopropylamine as the sacrificial reductant to afford coupling products in synthetically useful yields (22-80%). Additionally, the use of a combination of the ligands 4,4′,4″-tri-tert-butyl-2,2′:6′,2′-terpyridine and 4,4′-di-tert-butyl-2,2′-bipyridine is essential to achieve high yields.

Full text of DOI:10.1021/acs.oprd.9b00232

Communication
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings
of Aryl and Alkyl Bromides in Acetonitrile
Robert J. Perkins,†,§ Alexander J. Hughes,†,∥ Daniel J. Weix,‡ and Eric C. Hansen*,†
†Chemical Research and Development, Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States
‡Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
S
* Supporting Information
alcohol derivatives,11 and decarboxylative couplings of redox-
active esters.12
ABSTRACT: While reductive cross-electrochemical cou-
pling is an attractive approach for the synthesis of complex
molecules at both small and large scale, two barriers for
large-scale applications have remained: the use of
stoichiometric metal reductants and a need for amide
solvents. In this communication, new conditions that
address these challenges are reported. The nickel-
catalyzed reductive cross-coupling of aryl bromides with
alkyl bromides can be conducted in a divided electro-
chemical cell using acetonitrile as the solvent and
diisopropylamine as the sacrificial reductant to afford
coupling products in synthetically useful yields (22−80%).
Additionally, the use of a combination of the ligands
4,4′,4″-tri-tert-butyl-2,2′:6′,2′-terpyridine and 4,4′-di-tert-
butyl-2,2′-bipyridine is essential to achieve high yields.
While uptake in both academia and medicinal chemistry has
been rapid, uptake of cross-electrophile coupling in process
chemistry has been slowed by several challenges. Although
these cross-electrophile coupling reactions avoid the need to
preform organometallic reagents (Scheme 1), stoichiometric
metals such as Zn or Mn are generally used as terminal
reductants. This is undesirable because inconsistencies in the
purity and activation state of commercial metal reductants
could lead to reproducibility problems.3,13 At larger scales, the
generation of stoichiometric metal waste can lead to
complications in waste disposal, even for relatively nontoxic
metals like zinc.14 Finally, amide solvents have particular
environmental and regulatory concerns,15,16 but most cross-
electrophile couplings require them.17 If these limitations
could be addressed, cross-electrophile coupling could become
a more important tool in chemical development.
KEYWORDS: electrochemistry, electrosynthesis,
nickel catalysis, reductive coupling, cross-coupling
Electrochemical methods would be ideal for reductive
coupling18,19 because the reduction potential and the rate of
reduction can be easily adjusted without designing a new
catalyst or reagent.20 Such tuning is more challenging with
other approaches, such as the use of organic reductants17 or
photoredox cocatalysis.21 However, significant challenges exist
for realizing the promise of electrochemical methods. The
most well-developed electrochemical method for nickel-
catalyzed reductive C−C bond-forming chemistry uses a
sacrificial metal anode in an undivided cell.20a,e,g,22 Because
of the ease of oxidation of the anode, this approach avoids
problems of incompatibility and unproductive oxidation of the
ickel-catalyzed reductive cross-coupling has been dem-
Nonstrated in recent years to be a versatile method for the
formation of C(sp2)−C(sp3) bonds (Scheme 1).1,2 The
general methods detailed several years ago3 have been
extended to a wide variety of substrates, including hetero-
cycles,4,5 fluorobromoalkanes,6 amino acids,7 enantioconver-
gent couplings,8 unhindered vinyl bromides,9 tertiary alkyls,10
Scheme 1. Cross-Electrophile Coupling in Industry
catalyst or substrate that can plague reactions with soluble
22
sacrificial reductants.22a Pioneered by the group of Perichon,
́
it has also recently been applied successfully to the coupling of
aryl bromides with alkyl bromides18b and aryl iodides with N-
hydroxyphthalimide (NHP) esters.18d While this approach
avoids the use of metal powders, stoichiometric metal salts are
still generated, and amide solvents appear to be required.
In order to avoid the formation of stoichiometric metal salts,
the reductive cross-electrophile coupling reaction at the
cathode would have to be paired with the oxidation of a
soluble sacrificial reductant at the anode. A divided cell is
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00232
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Organic Process Research & Development
Communication
typically used to minimize side reactions.20a,e While this
strategy has been successful in oxidative chemistry,20 its
application to metal-catalyzed reductive chemistry to form C−
C bonds has been more limited.23 Recently, the decarbox-
ylative coupling of aryl iodides with NHP esters in a divided
cell with triethylamine as a sacrificial reductant was
reported.18c This was an important advance, but on the basis
of the mechanism proposed, this approach would not work
with substrates that are more difficult to reduce, such as alkyl
bromides.24,25 This mechanism also required high concen-
trations of the nickel catalyst (30 mol %) in order to favor
radical capture by nickel over other radical side reactions.
Herein we report an electrochemically driven cross-electro-
phile coupling that (1) avoids high catalyst loadings, (2) uses
diisopropylamine as the sacrificial reductant, (3) runs in
acetonitrile26 instead of amide solvents, and (4) works with
less reactive organic bromides (Scheme 1).
Table 1. Optimization of Electrochemical Ni-Catalyzed
Coupling Conditions in a Divided Cell
b
yields (%)
a
entry
deviation from above conditions
none
L1 only
1
3
4
Initial optimization studies were carried out for the coupling
of ethyl 4-bromobenzoate (1) (6.5 mmol scale, 1.5 g) and 1-
bromo-3-phenylpropane (2) (1.3 equiv), passing 25 mA of
current until the theoretical minimum charge of 2.0 F/mol
(i.e., 2 equiv of electrons) was met (Table 1).27 While pyridine
carboxamidine ligands were found to be excellent in our
previous electrochemical study18b in N,N-dimethylacetamide
(DMA), their low solubility in MeCN forced us to examine
more common bipyridine and terpyridine ligands.21c,28 While
4,4′-di-tert-butyl-2,2′-bipyridine (L2) alone was a poor ligand
1
2
3
36
38
62
61
7
3
2
c
L2 only
3
30
5
9
0
21
3
4
10
2
2
3
4
5
6
7
8
9
10
11
12
2:1 L1:L2
0.5 equiv of pyridine added
no electricity
24
24
100
38
39
34
89
33
30
61
52
0
no NiBr2(dme)
1
NiCl2(dme) instead of NiBr2(dme)
Ni foam cathode instead of RVC
LiBF4 instead of Bu4NPF6
Bu4NBF4 instead of Bu4NPF6
15 mA instead of 25 mA
50 mA instead of 25 mA
50 mA, 3.3 F/mol
59
61
3
56
58
70
́
(entry 3), 4,4′,4″-tri-tert-butyl-2,2′:6′,2′-terpyridine (L1) alone
(entry 2) or combined with a small amount of L2 provided
reasonable yields of the product (entries 1 and 4).29 While
combinations of L1 with L2 provided the same yield as pure
L1 in this case (entries 1 and 4), different ratios proved to be
helpful with other substrates (Scheme 2), provided homoge-
neous solutions of the precatalyst,30 and minimized the
amount of relatively expensive L1 required.
d
e
13
14
15
26
trace
trace
f
g
83 (76 )
77 (70 )
7
8
h
g
5 mol % catalyst, 50 mA, 2.9 F/mol
a
Reactions were conducted in a divided H-cell with a Nafion
membrane and run on a 6.5 mmol scale (1.5 g of 1). [Ni] =
NiBr2(dme). Each chamber contained an RVC electrode and 25 mL
of MeCN. Reactions were run at a constant current of 25 mA until 2.0
These initial reactions were selective for the product,
providing a 62% yield of 3 with only a 3% yield of the
hydrodehalogenation side product (4) and trace biaryl
product, but a significant amount (36%) of ArBr starting
material 1 remained (Table 1, entry 1). Consistent with
reports on the use of L1 for the homodimerization of
bromoalkanes,28c,d more alkyl homodimer was observed in
reactions run with L1 alone (10%) than with the ligand
combination (7%) (see the Supporting Information for more
details). An intermediate L1:L2 ratio of 2:1 led to a similar
yield of product but suffered from decreased selectivity and the
formation of unidentified byproducts (entry 4). The addition
of a third ligand, pyridine, was not beneficial (entry 5).
Control experiments demonstrated the necessity of both the
electrochemical reduction and the nickel catalyst to the
reaction. No reaction occurred when no current was passed,
with full recovery of the starting materials (Table 1, entry 6).
Removal of the nickel catalyst led to a complex reaction
mixture that contained no product 3 but significant amounts of
hydrodehalogenated side product 4 and buildup of a dark-
orange polymer on the cathode surface (entry 7).
b
F/mol was passed (14.0 h). Determined by a calibrated UPLC assay
c
with an internal standard. The remainder of ArBr was converted to
d
e
f
g
h
Ar−Ar. 22.2 h. 7.0 h. 11.5 h. Isolated yield. 10.1 h.
vitreous carbon (RVC) to nickel foam also showed no
considerable effect on the reaction outcome (entry 9).
While electrochemical conditions can avoid the need for
stoichiometric metal reductants, electrolyte must still be added
to both compartments to minimize the resistance of the cell to
the flow of electricity. The amount of electrolyte required is
cell-dependent, and the 3.8 equiv used in this study could be
decreased in a cell configuration with a smaller electrode gap.
In the case of an amine terminal reductant, amine oxidation
would generate additional cations during the reaction, which
could further diminish the amount of electrolyte required.
Preliminarily, it appears that the cation Bu4N+ is essential
−
(Table 1, entries 1 and 10), but PF6 could be replaced with
−
another noncoordinating counterion, BF4 (entry 11). With
LiBF4, conversion of the aryl bromide was very poor, and most
of the consumed aryl bromide was hydrodehalogenated rather
than cross-coupled.
Finally, the reaction could be driven to completion by
passing additional electrons (∼3 F/mol), and the reaction time
could be minimized by increasing the current density (∼10.5 h
reaction time at 3 F/mol). It was initially thought that the
charge inefficiency of the reaction (64% conversion at 2 F/
Changing the nickel precatalyst and cathodic materials had
little effect on the reaction. Use of NiCl2(dme) instead of
NiBr2(dme) showed little effect on the reaction selectivity and
yield (Table 1, entries 1 and 8), though 15−20% of the alkyl
bromide was converted to the much less reactive alkyl chloride
in this case. Changing the cathode material from reticulated
B
DOI: 10.1021/acs.oprd.9b00232
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Communication
a b
,
Scheme 2. Substrate Scope of Metal-Free Electrochemical Cross-Electrophile Coupling in Acetonitrile
a
Standard conditions: in the cathodic chamber, 1 equiv of aryl bromide (6.2 mmol for 3 and 7, 3.1 mmol for 9), 1.3 equiv of alkyl bromide, 7 mol
% NiBr2(dme), 7 mol % ligands, 0.8 equiv of Bu4NPF6; in the anodic chamber, 6 equiv of NH(iPr)2, 3 equiv of Bu4NPF6; each chamber equipped
b
c
with an RVC electrode; 50 mA (6.2 mmol) or 25 mA (3.1 mmol) passed until completion. Isolated yields are shown. All of the alkyl bromide was
d
e
consumed at roughly 50% conversion of the aryl bromide. Isolated as a 73 wt % mixture with inseparable 1,3-diphenylhexane. NMR yield with an
internal standard.
mol; Table 1, entry 1) was due to the rate of nickel catalyst
diffusion to and from the electrode along with the rate of
reaction in solution being too low relative to the rate of
reduction set by the current.18b Lowering the current from 25
to 15 mA, however, afforded little change in the conversion
and yield (entry 12), suggesting that the observed charge
inefficiency was not strongly correlated with reduction rate and
was likely the result of an unidentified off-cycle but
nondestructive pathway.
Doubling the current to 50 mA, the maximum stable current
that could be achieved with this cell setup, provided a similar
yield of product in half the amount of time (7 h; Table 1, entry
13). Ultimately, the reaction at 50 mA was pushed to
completion with a charge of 3.3 F/mol being passed, again
with the excess charge being nondestructive to the reactants,
affording an 83% assay yield and 76% isolated yield of cross-
coupled product (entry 14). A reaction run at a lower catalyst
loading of 5 mol % still proceeded well, with only a slightly
lower yield than with 10 mol % catalyst (entry 15). This is in
contrast to the previous report in a divided cell, where 30 mol
% catalyst was required for high yields.18c We decided to use 7
mol % catalyst for our substrate screen (Scheme 2).
With the optimized conditions for our model reaction in
hand, we proceeded to test the scope of these conditions over a
variety of aryl bromide coupling partners with a catalyst
loading of 7 mol % (Scheme 2). While each individual reaction
was not rigorously optimized, it was quickly found that the 4:1
ratio of L1 to L2 was not ideal for all aryl substrates. For
example, for the couplings of p-CF3-substituted aryl bromide
6a, using an L1:L2 ratio of 4:1 led to complete consumption of
alkyl bromide 2 to form the alkyl homodimer before full
consumption of 6a could be achieved. Changing to a 1:1 ratio
of ligands, however, allowed for full consumption of 6a with
less alkyl dimer to give a 65% yield of cross-coupled product
7a. Conversely, as another example, p-CN-substituted aryl
bromide 6b cross-coupled well with the original 4:1 ligand
C
DOI: 10.1021/acs.oprd.9b00232
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Organic Process Research & Development
Communication
ratio in 63% yield but with a 1:1 ligand ratio gave a lower yield
of 40%, with the difference in yields arising from the formation
of the aryl homodimer in the latter case. Thus, it was found
that the L1:L2 ratio could be adjusted to compensate for the
relative reactivity between the aryl and alkyl bromide coupling
partners. The reaction proceeded in moderate to good yields
for the couplings shown in Scheme 1. In general, reactions with
this catalyst system performed better with electron-poor
aromatic rings. o-Acyl-substituted aryl bromide 6g suffered
from an especially low yield compared with other aryl
bromides, giving the dehalogenated aryl as the predominant
byproduct.
Attention was then turned to investigating the scope of alkyl
bromide coupling partners compatible with these reaction
conditions (Scheme 2). This series of substrates was run in a
slightly smaller electrochemical cell on a 3.1 mmol scale at a
proportionally lower current of 25 mA. The reaction
conditions were compatible with alkyl bromides with various
functionalities, including secondary cyclic (8e−g) and acyclic
(8d) partners. As observed with the various aryl bromide
coupling partners, changing the L1:L2 ratio was found to
improve the yields for reactions that provided low yields under
the standard conditions. Qualitatively, we observed that the
amount of the tridentate ligand L1 was correlated with the
activation of the alkyl halide. For example, reactions that
generate a significant amount of alkyl dimer side product
typically benefit from a decrease in the amount of L1.
Conversely, reactions that generate aryl byproducts, leaving the
alkyl bromide unreacted, typically benefit from higher levels of
L1 in the ligand ratio in order to maintain optimal cross
coupling selectivity.
equipped with an RVC electrode, and the appropriate leads
from the potentiostat were attached. Constant current was
passed until the reaction was deemed complete on the basis of
consumption of the aryl bromide.
The reaction mixture was then cooled to room temperature.
The cathodic solution was transferred to a round-bottom flask,
rinsing with acetonitrile. This solution was concentrated on a
rotary evaporator. The solution was then diluted with 15 mL of
methyl tert-butyl ether (MTBE) and filtered through a short
pad of Celite, washing the filter cake with MTBE (2 × 15 mL).
The organic solution was washed with water (2 × 15 mL). If a
significant rag layer formed or solids precipitated, the mixture
was filtered before the extraction was continued. The aqueous
washes were then back-extracted with MTBE (1 × 20 mL).
The combined organic layers were washed with brine (1 × 10
mL), dried over sodium sulfate, and then decanted, and the
solution concentrated in vacuo. The crude material was
purified via silica gel chromatography to give ethyl 4-(3-
phenylpropyl)benzoate (1.32 g, 76%).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00232.
■
S
Additional tables of optimization experiments, CV data,
detailed experimental procedures, product character-
ization data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: eric.hansen@pfizer.com.
■
In summary, we have demonstrated that electrochemically
reduced nickel catalysts can carry out reductive coupling
between aryl and alkyl bromides in a more process-friendly
solvent without the production of stoichiometric metal waste.
These conditions should be more amenable to scale-up31 than
previous work while still providing synthetically useful yields
across a range of coupling partners.
ORCID
Eric C. Hansen: 0000-0002-5057-4577
Present Addresses
§R.J.P.: Department of Chemistry, Saint Louis University, St.
Louis, MO 63103.
∥A.J.H.: Department of Chemistry, Vanderbilt University,
Nashville, TN 37235.
Procedure (6.5 mmol scale): To a round-bottom flask
under nitrogen were added NiBr2(dme) (0.20 g, 0.65 mmol,
10 mol %), L1 (0.22 g, 0.52 mmol, 8 mol %), L2 (0.035 g. 0.13
mmol, 2 mol %), and Bu4NPF6 (2.1 g, 5.2 mmol, 0.8 equiv)
followed by acetonitrile (25 mL). The solution was degassed
via sonication under light vacuum followed by sparging with
nitrogen for 10 min. This light-green catalyst slurry was stirred
at room temperature for 1 h under nitrogen. Bu4NPF6 (7.7 g,
19 mmol, 3 equiv) and acetonitrile (25 mL) were added to a
separate round-bottom flask under nitrogen. The solution was
degassed via sonication under light vacuum followed by
sparging with nitrogen for 10 min. The solutions were then
transferred to their respective chambers of the divided cell
reactor (see the Supporting Information for details of the
reactor setup) under nitrogen, first the anodic solution
containing only electrolyte to the anodic chamber, followed
by the nickel-containing slurry to the cathodic chamber. The
cell was heated to an internal temperature of 60 °C (glycol
heater temperature set to 74−77 °C, which compensated for
heat losses through the transmission lines) with magnetic
stirring in each chamber (400 rpm). Diisopropylamine (2.6 g,
26 mmol, 4 equiv) was then added to the anodic chamber, and
1-phenyl-3-bromopropane (1.7 g, 8.5 mmol, 1.3 equiv) and
ethyl-4-bromobenzoate (1.5 g, 6.5 mmol, 1.0 equiv) were
added to the cathodic chamber. Each chamber was then
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was influenced by the ongoing efforts of the Non-
Precious Metal Catalysis Alliance among Pfizer, Boehringer-
Ingelheim, AbbVie, and Asymchem.
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