An Electrochemically Promoted, Nickel-Catalyzed Mizoroki-Heck Reaction

Article abstract of DOI:10.1021/acscatal.9b02230

Despite significant efforts to replace Pd-based catalysts with those of Ni, the Ni-catalyzed Mizoroki-Heck coupling of aryl halides and alkenes remains challenging. This work details the development of a Mizoroki-Heck reaction of aryl halides and a broad range of alkenes that utilizes electrochemistry as a means to promote Ni-catalyzed coupling under mild conditions. Stoichiometric studies implicate low-valent Ni complexes as key intermediates in route to rapid reactions with even unactivated alkenes. As such, electrochemistry is employed to readily provide the reducing potentials necessary to access these reactive intermediates and render the transformation catalytic. Cyclohexenone was found to be an unreactive substrate but a crucial additive that promotes facile electroreduction of the Ni catalyst and functionalization of other alkenes in high yields. Finally, preliminary mechanistic studies suggest that reactions proceed via an electron-chain transfer process that rapidly terminates but is reinitiated upon electroreduction.

Full text of DOI:10.1021/acscatal.9b02230

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Article
An Electrochemically-Promoted, Nickel-Catalyzed, Mizoroki-Heck Reaction
Benjamin Ronald Walker, and Christo S. Sevov
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02230 • Publication Date (Web): 01 Jul 2019
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ACS Catalysis
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An Electrochemically-Promoted, Nickel-Catalyzed, Mizoroki-Heck
Reaction
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Benjamin R. Walker, Christo S. Sevov*
Department of Chemistry and Biochemistry, The Ohio State University, 151 W Woodruff Avenue, Columbus, OH 43210,
United States
ABSTRACT: Despite significant efforts to replace Pd-based catalysts with those of Ni, the Ni-catalyzed Mizoroki-Heck coupling of
aryl halides and alkenes remains challenging. This work details the development of a Mizoroki-Heck reaction of aryl halides and a
broad range of alkenes that utilizes electrochemistry as a means to promote Ni-catalyzed coupling under mild conditions. Stoichio-
metric studies implicate low-valent Ni complexes as key intermediates in route to rapid reactions with even unactivated alkenes. As
such, electrochemistry is employed to readily provide the reducing potentials necessary to access these reactive intermediates and
render the transformation catalytic. Cyclohexenone was found to be an unreactive substrate, but a crucial additive that promotes facile
electroreduction of the nickel catalyst and functionalization of other alkenes in high yields. Finally, preliminary mechanistic studies
suggest that reactions proceed via an electron-chain transfer process that rapidly terminates but is reinitiated upon electroreduction.
KEYWORDS: electrochemistry, Heck reaction, alkene functionalization, cyclic voltammetry, redox, catalysis
utilization of electrochemistry to promote a rare example of Ni-
catalyzed Heck coupling between aryl halides and a broad range
of activated and unactivated alkenes under mild conditions. Key
to the development of this reaction is the addition of cyclohex-
enone, which itself does not undergo coupling, but was found
to promote reduction of Ni intermediates and coupling of other
alkenes. Finally, preliminary studies suggest that the Heck cou-
pling proceeds via an electron-chain transfer process that rap-
idly terminates but is reinitiated under electroreductive condi-
tions.
INTRODUCTION
Metal-catalyzed C–C bond-forming reactions have revolu-
tionized retrosynthetic approaches to organic synthesis.1,2
Among these transformations, the Mizoroki-Heck coupling of
alkenes and aryl electrophiles to form vinyl arenes has been im-
plemented in both commodity and fine-chemical processes.3–8
While Heck coupling has historically relied on Pd-based cata-
lysts,9–11 recent efforts have been aimed at designing Ni analogs
as inexpensive catalysts for this transformation.12–14 The evolu-
tion of important methodologies to systems that employ cata-
lysts of earth-abundant metals has been realized for an extensive
number of C–C15–24 and C–N25–28 bond-forming reactions that
were once known only for Pd and are now readily catalyzed by
Ni complexes with similar – or greater – rates and turnover
numbers.13
a. observation
Ar
Ph3P
Br
70 °C
12 h
22 °C
3 h
NiII
Br
24% vs. Ni
PPh3
(PPh3)4Ni0
nHex
1
Ar
nHex
2a
70 °C, < 30 min
60% vs. Ni
Ph
Despite parallels in reactivity between Ni and Pd complexes,
Ni-catalyzed Heck reactions of aryl halides remain rare. Such
reactions with even the most activated alkenes require forcing
conditions (>130 °C) and high metal/ligand loadings (>15
mol%), often negating the cost-benefit of Ni.20,29–33 Recently,
Ni-catalyzed Heck reactions have been found to proceed under
mild conditions when conducted with aryl sulfonates or with
added sulfonylating reagents.29,34–36 This strategy exploits the
facile ionization of Ni-sulfonates to form cationic Ni-hydride
intermediates that are more acidic and more readily deproto-
nated for catalyst turnover than a neutral Ni(hydrido)halide.
b. hypothesis:
comproportionation: Ni0(PPh3)4
comprop.: <1 TON
Ar
Ph3P
Br
alkene
possibly
via
NiII
1
Ln[NiI]
2a
fast
PPh3
e-chem: catalytic
electroreduction
–
+
Figure 1. (a) Observations from stoichiometric reactions. (b) Hy-
pothesis and approach to Ni-catalyzed protocols.
RESULTS AND DISCUSSION
Although uncommon, Heck reactions have been conducted
under reductive conditions,40,41 but are limited to reactions of
activated alkenes, such as styrene,42,43 acrylates,44–46 or eth-
ylene,45 and provide few mechanistic insights to guide develop-
ment of a general process. Moreover, reactions commonly suf-
fer from extensive dimerization of the aryl halide and competi-
tive overreduction. This promising, but poorly-understood, area
was of particular interest to our program that focuses on accel-
erating metal-catalyzed reactions with electrochemistry.
While these transformations are restricted to systems that ac-
cess cationic intermediates, they highlight the dramatic influ-
ence of charge at the metal on reactivity. Similarly, conditions
for Pd-catalyzed Heck coupling have been developed with the
aim of accessing anionic or cationic intermediates that are more
reactive than their neutral analogs.8,10,37–39 Adding to these strat-
egies, this work reveals the influence of electron transfer on the
rate of Ni-catalyzed Heck reactions. Specifically, we report the
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We first evaluated reactions of Ni(II)aryl complexes (1) that
Page 2 of 8
electrolysis with additives that could (i) transiently generate a
redox-active Ni(II)aryl intermediate by ligation (PyCN, BTD),
(ii) serve as a redox mediator (BTD, MMI), or (iii) stabilize
low-valent nickel intermediates (dba, chalcone, CyE).56–59
These experiments revealed that addition of electron-deficient
alkenes dramatically improved reaction yields over those of di-
rect electrolysis of 1. In particular, 1e– electrolysis of the iso-
lated Ni(aryl) complex in the presence of excess aryl bromide
and cyclohexenone (CyE) as an additive formed Heck products
in 115% yield, demonstrating catalytic turnover. In addition,
coupling was observed exclusively with the unactivated alkene
in preference to CyE, which is a common substrate for Heck
coupling with Pd as catalyst.60,61
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3
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5
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7
8
are generally unreactive towards alkenes. As expected, stoichi-
ometric reactions of 1 with excess 1-octene formed low yields
of Heck-coupled products (24% vs. Ni) over the course of 12 h
at 70 °C (Figure 1a, top). However, directly subjecting a com-
bination of aryl bromide, 1-octene, and Ni0(PPh3)4 to 70 °C
formed Heck products in 60% yield within just 30 minutes (Fig-
ure 1a, bottom). No additional product was formed in the sub-
sequent 2 h at 70 °C. Analysis of mixtures that result from stoi-
chiometric reactions with para-fluoro-bromobenzene by 19F
NMR spectroscopy indicated that the resting states of Ni during
this dormant period is the Ni(II)aryl analog of 1.
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These data led us to hypothesize that unlike Pd-catalyzed
Heck reactions,10,39 the Ni(II)aryl complex (1) alone is kinet-
ically incompetent for Heck coupling. Rather, product for-
mation requires a combination of both 1 and a low-valent Ni
species. Nickel complexes are well-known to undergo compro-
portionation,47,48 and this electron-transfer process is possible at
the onset of reactions containing Ni0(PPh3)4 (Figure 1b). Fol-
lowing oxidative addition, remaining Ni(0) can serve as a re-
ductant to enable turnover of Ni(hydride) intermediates, or to
form a low-valent Ni(aryl) complex that reacts rapidly with al-
kenes. Migratory insertion at Ni(I) centers has been recently im-
plicated as an elementary step in Ni-catalyzed alkene function-
alization49–51 or haloarene carboxylation.52,53 However, Ni(0)
eventually forms the thermodynamically-preferred complex 1,
as detected by NMR spectroscopy, and can no longer serve as a
reductant to promote Heck coupling. This process suppresses
catalysis as yields are limited to less than one turnover of nickel.
Nonetheless, these insights suggest that sustained reduction of
1 would enable Heck couplings of aryl bromides that are (i) cat-
alyzed by inexpensive complexes of Ni, (ii) rapid under mild
conditions, and (iii) compatible with a broad scope of alkenes.
These insights guided development of a catalytic methodol-
ogy using biphenylbromide and 1-octene as model substrates
(Table 1). Competing protodehalogenation to form biphenyl
could be easily monitored by gas chromatography, and catalysts
that successfully couple these unbiased substrates would likely
be reactive towards more activated alkenes. Ultimately, con-
stant-current electrolysis of an inexpensive catalyst system,
based on the combination of NiBr2•3H2O and tri-
phenylphosphine (PPh3), in an undivided cell with a Ni cathode
and Fe anode led to >95% yields of Heck products and less than
2% protodehalogenation (entry 1).
Table 1. Reaction Developmenta
10 mol% PPh3
5 mol% NiBr2•3H2O
Ph
Ar
nHex
+
nHex
pyridine (2 equiv)
2a
Br
cyclohexenone (0.3 M)
NaI (0.1 M), DMF, 70 °C
(+)Fe/(-)Ni, 6 mA, 2.5 F
+ branched
isomer
1 equiv
7 equiv
entry
deviation from standard
% conversion % yield (l:b)
none
1
2
3
100
<5
15
>95 (4:1)
0
0
no electrochemistry
no NiBr2•3H2O
nHex
Ar–Br,
A
Ar
A
99
100
59
21
29
9
4
5
6
no cyclohexenone
no PPh3
Zn anode
Ar
LnNiII
LnNiII Ar
nHex
70 °C, 25 min
additive
+ e–
2a
redox
in-active
2.5 equiv Zn0 powder as reductant
(1 equiv vs. Ni)
7
redox active
35
31
(Ar = 4-Ph-Ph–)
8
no pyridine
98
57
CO2Me
N
S
9
Et3N instead of pyridine
25 mol% pyridine
2,2'-bipyridine instead of PPh3
dppe instead of PPh3
Ph2P(2-pyridyl)
100
100
97
45
99
55
88
23
41 (1:1)
>95
CN
Ph
Ph
O
O
N
10
11
12
13
Ph
no
additive
N+
N
O
Ph
---
PyCN
BTD
MMI
dba
chalcone
CyE
aGC yields of combined linear and branched isomers. dppe = 1,2-
bis(diphenylphosphino)ethane.
39%
39%
11%
45%
54%
93%
115%
Figure 2. Electroreduction in the presence of additives. Yields are
calculated by GC analysis based on complex 1. Reactions were
conducted with 0.250 mmol ArBr, 1.25 mmol 1-octene, 0.038
mmol 1, and 0.038 mmol e– (1e– vs. Ni). PyCN = 4-cyanopyridine,
BTD = benzothiadiazole, MMI = N-methyl methylisonicotinate io-
dide, dba = dibenzylideneacetone, CyE = cyclohexenone.
Control experiments demonstrate that electrochemistry,
nickel, CyE, and phosphine are all crucial for high yields (en-
tries 2-5). Reactions performed with a Zn anode in place of Fe
suffered from surface passivation of the anode and required cell
potentials of >2 V to maintain the applied current (see the SI,
Figure S3). The catalyst is likely incompatible with the high cell
voltage, as reactions resulted in incomplete conversion and low
yields (9%, entry 6). Efforts to promote the reaction with an ex-
cess of Zn0 powder as a chemical reductant in place of electro-
reduction similarly resulted in low yields (31%, entry 7). The
choice of pyridine as base was particularly important for reac-
tions that afford products in high yields. Heck couplings require
base to both promote catalyst regeneration and sequester acidic
byproducts. Thus, the low yields obtained from reactions with-
out pyridine were expected (entry 8). However, reactions con-
ducted with a variety of other bases, including Et3N (entry 9),
resulted in yields that were nearly identical to those of reactions
lacking base altogether. While these non-pyridyl bases had no
Our approach to rendering this challenging reaction catalytic
was to utilize electrochemistry as a means for reduction of 1.
While electrochemistry can easily access the reducing poten-
tials of Ni(0), phosphine-ligated complexes of Ni generally
have ill-defined redox events at potentials that allow compe-
tetive protodehalogenation of the aryl halides (vide infra; < –2
V vs. Ag/Ag+).54,55 As evidence, 1e– reduction of 1 in the pres-
ence of excess 1-octene and biphenylbromide primarily results
in dehalogenation, but does form Heck products in 39% yield
vs. Ni (Figure 2).
To promote reduction of 1 in preference to the aryl bromide,
and thus mitigate protodehalogenation, we performed
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effect on the reaction outcome, the addition of just 25 mol%
products in just over 3 h that can be isolated in good yields
(Chart 1). Linear products were formed in preference to
branched products, and highest linear selectivities were ob-
served from reactions with the most electron-deficient aryl hal-
ides (2e vs 2b). Reactions of polarized alkenes were found to
generate only linear products. Styrenyl substrates readily un-
dergo coupling to generate stilbenes (3a-b) with some dimin-
ished yield due to oligomerization. Finally, these electrochemi-
cal conditions were readily scaled without additional optimiza-
tion to generate 2a in 70% yield on a gram scale.
1
2
3
4
5
6
7
8
pyridine to reaction mixtures afforded products in 88% yield
(entry 10). The positive effect of even substoichiometric quan-
tities of pyridine on the reaction led us to evaluate pyridyl com-
plexes of Ni as catalyst. However, reactions conducted with
chelating tri- and bipyridines led to low yields (entry 11). Other
chelating ligands, including bisphosphines, similarly formed in-
active catalysts for Heck coupling (entry 12). Despite the pos-
sibility for chelation, reactions with (2-pyridyl)diphe-
nylphosphine generated products in excellent yields that are
comparable to those of reactions with inexpensive PPh3 (entry
13).
9
Not limited to just activated alkenes, we evaluated reactions
of a range of aliphatic alkenes. Surprisingly, high selectivities
for linear products were observed from reactions of alkenes that
had just minor steric or electronic perturbations of the π system.
As examples, reactions of allyl tetramethylsilanes (4), vinyl
ethers (5), homoallylic alcohols (6), and homoallylic sulfones
(11) form coupled products in excellent yields, from which lin-
ear products can be isolated in good yields. The linear vinyl
ethers formed from this electrochemical methodology comple-
ment the branched products that are prone to hydrolysis to acyl
arenes and formed by previously-reported systems.29 Finally,
the high yield of 6 highlights tolerance of free alcohols under
the electroreductive conditions and that chain walking to form
aldehydic products is slow.65–67
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Finally, reactions of the model substrates provided insights
into the selectivity for linear versus branched products. With the
exception of entry 12, linear products were formed in prefer-
ence to branched products with a ratio of 4:1 from all reactions
in Table 1, as well as from the stoichiometric reactions illus-
trated in Figure 1. The similarities in product selectivity from
reactions with and without PPh3 (entry 1 vs. entry 5) suggest
that C–C bond formation is mediated by an organometallic in-
termediate that lacks a bound phosphine. Similar linear-to-
branched ratios of 4:1 have been observed from alkene arylation
reactions with “ligandless” Pd complexes, which further sup-
ports the intermediacy of a phosphine-free complex under the
electrochemical conditions.10,62,63 In contrast, Heck coupling
catalyzed by cationic Ni intermediates predominantly forms
branched products.29,64 The complementary selectivities of
these Ni-catalyzed methodologies can be attributed to the dis-
tinct strategies in reaction design. These data represent a rare
example of Ni-catalyzed Heck coupling that directly replicates
the reactivity and selectivity observed from catalysts of Pd.
This lack of olefin isomerization led us to probe the selectiv-
ity of ß-hydride elimination by studying reactions of allylben-
zene. Carbonickelation of allylbenzene with varying aryl sub-
strates would form Ni(alkyl) intermediates that can undergo β-
hydride elimination at two benzylic positions. Hydrogen atoms
at these positions are likely distinguishable only by the elec-
tronic effects imparted by the adjacent aryl groups. Palladium
analogs of such pseudo-symmetric intermediates have been
shown to undergo elimination with the most hydridic H atom,
which is at the benzylic position of the most electron-donating
aryl fragment.68 Reactions under our electrochemical conditions
generated ratios of isomers that are nearly identical to those
generated by Pd catalysts. Product 7a was formed with a 2.1:1
preference for elimination toward the electron-donating (dime-
thylamino)phenyl group, while 7b was formed with a 1.1:1
preference for elimination away from the electron-withdrawing
aryl group. These product mixtures likely represent catalyst se-
lectivity, rather than a thermodynamic ratio of products from
isomerization, because other kinetic isomers have been ob-
served under the reaction conditions. Specifically, significant
amounts of unconjugated, allylic products were generated in re-
actions that form 2a-2e, and product 5 was formed in a 4:1 ratio
favoring the Z over E isomer.
In addition to terminal alkenes, cyclic substrates are reactive
under the developed conditions (9, 10a-g). A range of electro-
philic, acidic, and basic functional groups are tolerated to form
allylic products. Formation of these products supports a mech-
anism that involves syn carbonickelation across the alkene, fol-
lowed by elimination of the only syn-coplanar ß-hydrogen. The
mild conditions employed for the generation of allylic products
contrast the conditions required for conventional Ni-catalyzed
Heck couplings (150 °C), which generate vinylic products ex-
clusively.33
Chart 1. Substrate Scope. Yields shown are isolated yields from
a
reactions of 0.3 mmol of ArX. Ratio of linear to branched prod-
ucts. b9 mA at 100 °C. c9 mA at 70 °C. d9 mA at 85 °C. e3 mA at
70 °C.f97% GC yield from iodide. g70% isolated yield from 1.05 g
reaction. h3 mA with 150 mM alkene. PMP = para-methoxyphenyl.
Tol = para-tolyl
Finally, ethyl acrylate is reactive under the conditions, but re-
actions yield only alkyl products from a formal reductive-Heck
process (8). While acrylates are common substrates for Pd-cat-
alyzed Heck reactions,31,32 this result indicates that further re-
duction outcompetes ß-hydride elimination of the Ni(alkyl)
With these conditions in hand, we explored the scope of the
electrochemically-promoted reaction. Reactions of 1-octene
with a variety of aryl bromides or iodides generate Heck
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intermediate. Despite this reactivity with ethyl acrylate, the cy-
clic analog and key additive, CyE, does not undergo competi-
tive coupling with the aryl halides and only 5-15% is lost over
the course of the reaction.
Page 4 of 8
efficiency of e- utilization, both generating 1.33 equivalents of
product for every e- passed. This catalytic utilization of elec-
trons indicates that Ni-catalyzed Heck coupling does not require
stoichiometric reduction, as would be expected if electroreduc-
tion served only to assist with turnover of a Ni(hydride) inter-
mediate. Rather, these data, and those of Figure 3, are more con-
sistent with a reaction that is net redox-neutral and that relies on
electroreductive activation of a Ni(II)aryl intermediate.
1
2
3
4
5
6
7
8
We investigated the role of CyE by comparing electrode po-
tentials during electrolysis to potentials of redox events identi-
fied by cyclic voltammetry (CV). Measurements against a
Ag/Ag+ quasi-reference electrode during the course of the reac-
tion revealed an anodic potential of -0.4 V (Figure 3a, blue
trace) and a cathodic potential of -1.5 V (red trace). These po-
tentials are consistent with the cell voltage of ~1.1 V that is
commonly observed for reactions. The anodic potential at -0.4
can be ascribed to oxidation of the sacrificial Fe anode,69 but
reduction at -1.5 V was not of the Ni(II)aryl complex 1 alone
(Figure 3b, black trace). Scanning to increasingly negative po-
tentials of a reaction mixture containing 1 in the absence of CyE
revealed no well-defined reduction of the complex. Rather, the
observed current at an onset of -2.1 V is that of haloarene re-
duction. In contrast, CV of the same solution after addition of
CyE revealed a reduction event with an onset potential of -1.5
V (red trace). This reduction event has a potential that matches
that of the cathode during electrolysis and is exclusively ob-
served when both 1 and CyE are present in solution. CyE alone
undergoes reduction at the more negative potential of -2.2 V
(blue trace). These data implicate a stabilizing interaction be-
tween the electron deficient additive and the reduced nickel in-
termediate to allow reactions to be conducted at mild potentials
that preclude degradation of the aryl bromide.
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Figure 4. Product formation during periodic electrolysis.
The short period of product formation following electrolysis
further supports this hypothesis. Once electrolysis ends, the
Ni(0) generated from catalyst turnover can continue to facilitate
the reaction as a homogeneous reductant. This radical-chain
process eventually terminates when Ni(0) undergoes oxidative
addition of an aryl bromide to form of an unreactive Ni(II)aryl
complex. Reactivation of this complex requires an exogenous
reductant. Overall these insights underscore the use of electro-
chemistry as an effective means for activation of inexpensive,
but unreactive, complexes to catalyze desirable transfor-
mations.
a.
– e–
1/2Fe2+
Fe0
O
+ e–
[NiII] Ar
product formation
CONCLUSION
In summary, we report rare examples of Ni-catalyzed Heck
couplings of aryl bromides with both activated and unactivated
alkenes under mild conditions. The hypothesis-driven approach
to reaction development relied on mechanistic data that impli-
cate low-valent analogs of Ni(aryl) complexes in Heck coupling
reactions. We demonstrate that electrochemistry is a facile
means for accessing the low potentials required for reduction of
the unreactive Ni(II) complexes. As a result, this work repre-
sents an electrochemical activation of an unreactive first-row
metal complex to mimic the high catalytic activity of precious-
metal analogs. Detailed mechanistic studies to identify reactive
intermediates and develop processes for substoichiometric re-
duction are ongoing.
e- transferred (mAh)
b.
Ar
Ph3P
Br
start
NiII
PPh3
O
O
Ar
Ph3P
NiII
+
Br
PPh3
V vs. Ag/Ag+
ASSOCIATED CONTENT
Supporting Information
Figure 3. a) Voltaic profiles of the anode (blue) and cathode (red)
for the standard reaction. b) CVs of complex 1 and CyE at 70 °C
(return sweeps were omitted for clarity).
Experimental procedures, cell design, characterization of com-
pounds, spectroscopic data, electrochemical data, and additional
experiments are supplied. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, we monitored product formation during the course of
a reaction that was periodically electrolyzed to gain insight into
the Faradaic efficiency (Figure 4). As expected, the NiBr2 pre-
cursor was inactive without electrochemistry. Application of a
constant current generated a non-linear yield-response that is
consistent with consumption of electrons for precatalyst activa-
tion. Despite this nonproductive initial use of electrons, 1.05
equivalents of product had been formed for every e- passed.
Subsequent electrolysis periods further highlight the high
AUTHOR INFORMATION
Corresponding Author
sevov.1@osu.edu
ACKNOWLEDGMENT
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We thank Mr. Kevin Miller for his assistance in reaction develop-
Coupling. ACS Catal. 2018, 8, 9245–9251.
1
2
3
4
ment. Additionally, we thank The Ohio State University and the
American Chemical Society Petroleum Research Fund (59129-
DNI1) for support of this work.
(18)
Gallego, D.; Brück, A.; Irran, E.; Meier, F.; Kaupp, M.; Driess,
M.; Hartwig, J. F. From Bis(Silylene) and Bis(Germylene)
Pincer-Type Nickel(II) Complexes to Isolable Intermediates of
the Nickel-Catalyzed Sonogashira Cross-Coupling Reaction. J.
Am. Chem. Soc. 2013, 135, 15617–15626.
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