Nickel-Catalyzed Cross-Electrophile Coupling Reactions for the Synthesis of gem-Difluorovinyl Arenes

Article abstract of DOI:10.1021/acscatal.0c03993

A nickel-catalyzed cross-electrophile coupling reaction between (hetero)aryl bromides and 2,2-difluorovinyl tosylate is presented. This protocol provides facile incorporation of the gem-difluorovinyl moiety in organic molecules. The method features mild reaction conditions, good functional group tolerance, and excellent yields. Furthermore, mechanistic experiments and DFT studies indicate a Ni(0)/Ni(II) catalytic cycle, thus differing from the currently accepted catalytic cycle for nickel-catalyzed C(sp2)-C(sp2) cross-electrophile coupling reactions.

Full text of DOI:10.1021/acscatal.0c03993

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Letter
Nickel-Catalyzed Cross-Electrophile Coupling Reactions for the
Synthesis of gem-Difluorovinyl Arenes
Baojian Xiong,⊥ Ting Wang,⊥ Haotian Sun, Yue Li, Søren Kramer,* Gui-Juan Cheng,* and Zhong Lian*
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ABSTRACT: A nickel-catalyzed cross-electrophile coupling reac-
tion between (hetero)aryl bromides and 2,2-difluorovinyl tosylate is
presented. This protocol provides facile incorporation of the gem-
difluorovinyl moiety in organic molecules. The method features mild
reaction conditions, good functional group tolerance, and excellent
yields. Furthermore, mechanistic experiments and DFT studies
indicate a Ni(0)/Ni(II) catalytic cycle, thus differing from the
currently accepted catalytic cycle for nickel-catalyzed C(sp2)−C(sp2) cross-electrophile coupling reactions.
KEYWORDS: nickel catalysis, cross-electrophile coupling, gem-difluoroalkenes, 2,2-difluorovinyl tosylate, DFT studies
Table 1. Influence of Various Reaction Parameters on the
Yield of the Cross-Electrophile Coupling Reaction
he gem-difluorovinyl moiety is present in a broad array of
a
T
biologically active compounds1 and pesticides,2 and it
serves as an important carbonyl bioisostere3 (Scheme 1a). In
addition, gem-difluoroalkenes are utilized for synthesis of
Scheme 1. Overview of gem-Difluoroalkenes and C(sp2)−
C(sp2) Cross-Electrophile Coupling Reactions
b
entry
deviation from standard conditions
yield of 3a (%)
c
1
none
99 (96)
2
3
Mn instead of Zn
Mg instead of Zn
22
0
4
5
6
7
8
9
10
11
12
13
14
NiBr2 instead of NiCl2
Ni(OTf)2 instead of NiCl2
Ni(COD)2 instead of NiCl2
NiCl2 DME instead of NiCl2
L2 instead of L1
L3 instead of L1
L4 instead of L1
DMF instead of DMA
MeCN instead of DMA
dioxane instead of DMA
THF instead of DMA
17
13
24
72
95
93
90
16
40
0
0
a
b
The reactions were set up on 0.2 mmol scale. Yields determined by
c
GC analysis using n-dodecane as the internal standard. Isolated yield
in the parentheses.
Received: September 11, 2020
Revised: October 29, 2020
https://dx.doi.org/10.1021/acscatal.0c03993
© XXXX American Chemical Society
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¶
Scheme 2. Scope of the Cross-Electrophile Coupling Reaction
¶
Standard conditions (unless otherwise specified): aryl bromide (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv), NiCl2 (0.02 mmol, 0.1 equiv), L1
a
b
(0.024 mmol, 0.12 equiv), Zn (0.4 mmol, 2.0 equiv), DMA (1 mL), 90 °C, 16 h. 100 °C instead of 90 °C. Aryl dibromide (0.2 mmol, 1.0 equiv),
2 (0.8 mmol, 4.0 equiv), NiCl2 (0.04 mmol, 0.2 equiv), L1 (0.048 mmol, 0.24 equiv), Zn (0.8 mmol, 4.0 equiv), DMA (1 mL), 90 °C, 16 h.
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Scheme 3. (a) Examination of Other Electrophiles; (b)
Gram-Scale Reaction of Cross-Coupling
Scheme 5. Mechanistic Investigation
Scheme 4. Mechanistic Investigation
Figure 1. Proposed reaction mechanisms involving Ni(0)/Ni(II).
are no examples of gem-difluorovinyl arene synthesis from
aromatic halides by cross-electrophile coupling reactions
directly.
The nickel-catalyzed cross-electrophile coupling reaction
between two electrophiles, aryl or vinyl, has evolved to be an
important protocol for the construction of C(sp2)−C(sp2)
bonds.9,10 The currently accepted catalytic cycle for these
reactions proceeds by initial oxidative addition of Ni(0) into one
of the aryl or vinyl electrophiles (Scheme 1c). The generated
E1−Ni(II) intermediate is then reduced to E1−Ni(I) by zinc.
Next, this E1−Ni(I) species undergoes oxidative addition into
the second aryl or vinyl electrophile forming E1−Ni(III)−E2.
Finally, reductive elimination from the Ni(III)-complex affords
the cross-coupling product, E1−E2, and a Ni(I)-complex, which
is reduced to Ni(0) by zinc.9g
Here, we report a cross-electrophile coupling reaction
between (hetero)aryl bromides and 2,2-difluorovinyl tosylate
leading to gem-difluorovinyl arenes via nickel-catalyzed cross-
electrophile C(sp2)−Br and C(sp2)−O bond cleavage (Scheme
1d). Advantages of this method include mild reaction
a
With ZnBr2 (20 mol %).
functional organic polymers.4 The traditional routes to gem-
difluoroalkenes include classical Wittig olefination and Julia−
Kocienski reaction (Scheme 1b).5 However, these approaches
require strong bases or harsh reaction conditions leading to
limited functional group tolerance. In recent years, the
difluoromethylenation of diazo compounds6 and defluorination
of trifluoromethyl alkenes7 have also been developed as
alternative pathways to gem-difluoroalkenes. Finally, Skrydstrup
and co-workers have demonstrated that 2,2-difluorovinyl
tosylate can serve as the electrophile in the palladium-catalyzed
cross-coupling reaction with arylboronic acids.8 However, there
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Figure 2. DFT studies of Ni-catalyzed cross-electrophile coupling with and without the assistance of Zn. All relative Gibbs free energies and electronic
energies (at 363.15 K and 1 atm) are in kcal/mol.
conditions, broad substrate scope, and excellent yields. The
method can be applied to the facile synthesis of derivatives of
bioactive compounds. Importantly, preliminary mechanistic
investigations indicate that the reaction proceeds by a Ni(0)/
Ni(II) cycle, thus differing from the currently accepted catalytic
cycle for C(sp2)−C(sp2) cross-electrophile coupling reactions.
We initiated the study by investigating the cross-electrophile
coupling between 2-bromonaphthalene (1a) and 2,2-difluor-
ovinyl tosylate (2). After extensive screening of various reaction
parameters, we found that the cross-coupling product 3a could
be isolated in an excellent yield when NiCl2(10 mol %) and 2,2′-
bipyridine (L1, 12 mol %) were employed as catalyst precursors,
Zn (2.0 equiv) as reductant, and DMA as solvent at 90 °C
(Table 1, entry 1). Control experiments revealed that Zn as
reductant is essential for this cross-coupling reaction, as the use
of other reductants (Mn and Mg) afforded little or none of the
desired product (entries 2−3). Other nickel sources, such as
NiBr2, Ni(OTf)2, Ni(COD)2, and NiCl2·DME also led to
decreased product formation when compared with NiCl2
(entries 4−7). Interestingly, the use of 2,2′-bipyridine ligands
bearing either electron-donating or electron-withdrawing
substituents only had a small impact on the yield (entries 8−
10). In contrast, the reaction was very sensitive to the solvent as
replacing DMA by DMF, MeCN, dioxane, or THF led to
significantly decreased yields (entries 11−14).
Bromobenzenes bearing a phenyl substituent in the ortho,
meta, or para position afforded the cross-electrophile coupling
products in good yields (3b−d). Additional vinyl groups were
also well-tolerated (3e−f). Next, electron-rich aryl bromides
were evaluated. The use of MeO-, PhO-, and Ph2N-substituted
bromobenzenes led to clean formation of the corresponding
gem-difluorovinyl arenes (3g−i). Notably, an aryl-TMS
functionality also survived the cross-electrophile coupling
reaction (3j). Other electron-rich substrates such as bromo-
benzenes bearing a benzyl group (3k) or an alkyl group (3l−m)
also afforded the desired product in good to high yields.
Substrates bearing weak C−O bonds were examined next. The
C−O bond in aryl acetates,11 triflates,12 and tosylates13 can all be
cleaved easily by nickel complexes, but to our surprise, substrates
bearing these functional groups still produced the desired gem-
difluorovinyl arenes in good yields (3n−p). Various electron-
poor substrates were also examined. Aryl bromides containing
ester (3q−u) or ketone functionalities (3v) led to high yields,
while a decrease in yield was observed for a substate containing
an aldehyde group (3w).14 Further examination of electron-
deficient substrates revealed that both sulfonyl- and cyano-
groups are also tolerated (3x−y). Notably, the developed cross-
electrophile coupling reaction is compatible with a range of
heterocycles as demonstrated by the high yields obtained for
substrates containing quinazolinyl (3z−aa), indolyl (3ab),
benzothiophenyl (3ac), dibenzofuryl (3ad), lactone (3ae),
and pyridyl moieties (3af).
With the optimized reaction conditions in hand, the substrate
scope with regard to aryl bromides was investigated (Scheme 2).
Initially, electron-neutral aryl bromides were examined.
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Under modified reaction conditions, substrates bearing two
aryl bromide moieties were found to undergo double gem-
difluorovinylation in high yields, as demonstrated with the
biphenyl and naphthyl products (3ag−aj, see modified
conditions in Scheme 2). Also, the use of a BINOL-derivative
led to facile double gem-difluorovinylation thus affording a
product (3ai), which have potential for applications in ligand
development for asymmetric catalysis.15 An electron-deficient
2,3,4,5-tetraphenylsilole containing two 1,1-difluorovinyl
groups was synthesized in an excellent yield utilizing our
method (3aj). This product might have potential applications in
material science, such as OLED devices16 and sensors for
explosive compounds.17 Finally, the developed cross-electro-
phile coupling methodology was applied for the installation of
gem-difluorovinyl moieties on drug-like scaffolds such as steroid,
amino acid, vitamin, and sugar molecules (3ak−ao). These
results show the great potential of this method for late-stage
derivatization of pharmaceuticals.
Next, we investigated the possibility for using other types of
aryl electrophiles than aryl bromides (Scheme 3a). The use of an
aryl iodide as substrate for this cross-electrophile coupling
reaction afforded the desired product in 80% yield. Homocou-
pling of the aryl iodide was found to be a significant side reaction.
Aryl chlorides showed less reactivity, and after 16 h, most of the
starting material remained unreacted. An aryl tosylate and
triflate did not react under the standard reaction conditions. The
robustness and potential for scale-up of the nickel-catalyzed
cross-electrophile coupling reaction was demonstrated by a
successful reaction on gram-scale (Scheme 3b). Unfortunately,
2-substituted-1,1-difluorovinyl tosylates failed to couple with
aryl bromides.18
suggest that Ni(0) is likely responsible for initiating the reaction,
that Zn(II) promotes the reaction, and that Zn is necessary for
catalytic turnover.
In order to investigate the role of Zn in the nickel-catalyzed
cross-coupling reactions, a reaction with vinyl tosylate 2 under
the standard conditions, but in the absence of aryl bromide, was
set up. Quenching the reaction mixture with I2 led to 56% yield
of 1,1-difluoro-2-iodoethene 5 (Scheme 5-1). In addition, when
zinc reagent 6 was employed instead of vinyl tosylate 2 under the
standard catalytic conditions, 3q was formed in 95% yield
(Scheme 5-2). These results strongly indicate that a 1,1-
difluorovinyl zinc reagent is formed during the cross-coupling
reaction.
To further support the hypothesis that a Ni(0) species
initiates a catalytic cycle by oxidative addition to the aryl
bromide, complex 7 was synthesized.9g The use of a catalytic
amount of 7, instead of NiCl2/L1, afforded 89% yield of the
expected product 3q, indicating that complex 7 is catalytically
competent (Scheme 5-3). Furthermore, we found that complex
7 can react directly with 2,2-difluorovinyl tosylate (2) producing
3q in similar yields in the presence and absence of Zn (Scheme
5-4). The moderate yields are likely due to the high nickel
concentration which was previously found to decrease the yield
in the stoichiometric experiments (Scheme 4-3). Closer
inspection of the reaction mixture for the reaction performed
in the absence of Zn revealed a small amount of homocoupling
product 8. The formation of 8 suggests that a Ni(0) species is
formed which could potentially initiate the reaction by oxidative
addition into the C−OTs bond. Accordingly, it is not necessarily
the nickel(II) complex 7 that initiates the reaction by directly
activating the 2,2-difluorovinyl tosylate (2).
To gain more insight into the reaction mechanism, some
additional experiments were performed (Scheme 4). When the
radical scavenger TEMPO was added to the standard
conditions, the expected product 3q was not detected (Scheme
4-1, entry 1). Considering the poisonous effect that TEMPO can
have on a nickel catalyst, this finding is not conclusive evidence
for a radical process.19 In contrast, the reactions proceeded
cleanly in the presence of other radical scavengers, such as BHT
and 1,1′-diphenylethylene, and 3q was produced in 86% and
90% yield, respectively (Scheme 4-1, entries 2−3). These results
indicate that radicals are not involved in the product-forming
pathways.
Under the standard reaction conditions, methyl 4-bromo-
benzoate (1q) afforded the product 3q in 90% yield, but in the
absence of Zn, no product was observed (Scheme 4-2). This
result suggests that the catalytic cycle does not start from Ni(II)
and that Zn plays a role as a reductant for initiating the reaction.
Notably, the use of a Ni(0) source, Ni(COD)2, instead of NiCl2
led to 5% yield of 3q in the absence of Zn, thus demonstrating
that product formation can start from Ni(0). The use of
Ni(COD)2 in the presence of zinc led to 65% yield of 3q
(Scheme 4-3-i, entry 1). Increasing the catalyst loading to 50%
and even 100%, led to the formation of 3q in 8% and 17% yield,
respectively. (Scheme 4-3-i, entries 2 and 3) Interestingly, the
addition of ZnBr2 (20 mol %) in the stoichiometric reaction in
the absence of Zn improved the yield (Scheme 4-3-i, entry 3).
Notably, the use of a large excess of Zn inhibited the reaction
(Scheme 4-3-i, entries 2 and 3). Finally, the discrete nickel(0)
complex 420 was applied in the reaction leading to reaction
outcomes consistent with the results obtained for Ni(COD)2
(Scheme 4-3-ii). Pleasingly, the yield of 3q reached 91% in the
presence of Zn (Scheme 4-3-ii, entry 1). Overall, these results
Based on the experiments above and literature,21 we propose
two plausible Ni(0)/Ni(II) catalytic cycles with and without Zn
involved in the transmetalation process (Figure 1). First, the
Ni(0) complex formed from reduction of the Ni(II) source
undergoes oxidative addition into both the C−Br and the C−
OTs bond, affording Ar−Ni(II)−Br (A) and (F2CCH)−
Ni(II)−OTs(B), respectively. The subsequent transmetalation
between these two Ni(II) complexes gives Br−Ni(II)−OTs (C)
and (F2CCH)−Ni(II)−Ar (D). Alternatively, the complexes
C and D can be generated via an indirect way by two sequential
transmetalation steps between Ni and Zn species (B + ZnX2 →
C + E, A + E → D + ZnX2) as shown in pathway II.22 Finally, the
reductive elimination from Ni(II) intermediate D generates the
desired gem-difluorovinyl arene product and Ni(0). Meanwhile,
complex C is reduced by Zn to Ni(0). Both of these two Ni(0)
species can take part in the next catalytic cycle.
Density functional theory (DFT) calculations23 were then
conducted to assess the feasibility of the two proposed reaction
mechanisms. The reduction of Ni(II) by Zn is thermodynami-
cally favorable (ΔG = −13.2 kcal/mol, Scheme S1), supporting
the role of Zn in the reduction of Ni(II) to Ni(0). As shown in
Figure 2 and Figure S1, the activation barriers for the ensuing
oxidative addition of the Ni(0) complex to 2,2-difluorovinyl
tosylate (2) and methyl 4-bromobenzoate (1q) substrates are
23.7 (TSB0−B) and 14.7 (TS1A0‑A) kcal/mol, respectively. Then,
the direct transmetalation between the two Ni(II) species A and
B to form C and D is calculated to have an activation barrier of
28.8 kcal/mol (TSB‑D, path I in orange). In addition, our
calculations unveiled an energetically more favorable path I’
which involves two consecutive transmetalation steps (TSB−F
and TSF‑D). The first transmetalation step (TSB−F) exchanges
the Br and OTs groups between the two Ni atoms to form F and
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the second one (TSF‑D) transfers the OTs and difluorovinyl
groups to afford D. The calculated barriers for the two
transmetalation steps of path I’ are 16.5 and 27.5 kcal/mol,
respectively, and thus, path I’ is more favorable than path I by 1.3
kcal/mol. Furthermore, the Zn-involved transmetalation proc-
ess (pathway II in black) only needs to overcome a barrier of
26.7 kcal/mol (B → TSE‑D) to form D. The barrier for the final
reductive elimination of D, which leads to the gem-difluorovinyl
arene product, is 26.5 kcal/mol. All the barriers listed above can
be overcome under the reaction temperature. Therefore, the
computational results suggest that both non-Zn assisted
pathways (path I and I’) and Zn-mediated pathway (path II)
are energetically feasible. Path II is more favorable than path I’
by 0.8 kcal/mol in line with the experimental observation that
ZnBr2 promotes the Ni(COD)2 catalyzed cross-coupling
reaction (Scheme 4-3-i, entry 3).
Finally, we conducted kinetic experiments to evaluate the
validity of the conclusions from the DFT calculations.23
Notably, a second-order dependency on the concentration of
nickel was observed. In addition, the reaction profile displayed
overall zero-order kinetics for the entire reaction progress. These
observations are consistent with both the nonzinc-assisted and
the zinc-assisted pathways, assuming that reduction of C is fast
and irreversible.24 Importantly, the results would be inconsistent
with a catalytic cycle involving only one nickel species.
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
Ting Wang − Warshel Institute for Computational Biology,
Shenzhen Key Laboratory of Steroid Drug Development,
School of Life and Health Sciences, The Chinese University of
Hong Kong (Shenzhen), Shenzhen 518172, China;
orcid.org/0000-0002-6871-470X
Haotian Sun − Department of Dermatology, State Key
Laboratory of Bio-therapy and Cancer Center, West China
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
Yue Li − Department of Dermatology, State Key Laboratory of
Bio-therapy and Cancer Center, West China Hospital and
West China School of Pharmacy, Sichuan University, Chengdu
610041, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c03993
Author Contributions
⊥B.X. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science Foundation
(21901168), “1000-Youth Talents Plan” and Sichuan Univer-
sity. (Z.L.) S.K. thanks the Lundbeck Foundation (R250-2017-
1292) and the Technical University of Denmark for generous
financial support. G.J. thanks the National Natural Science
Foundation (21803047) and the Natural Science Foundation of
Guangdong Province (no. 2019A1515011865).
In summary, we have developed a nickel-catalyzed cross-
electrophile coupling reaction between (hetero)aryl bromides
and 2,2-difluorovinyl tosylate. The method provides easy access
to gem-difluorovinyl arenes in excellent yields. The mild
reactions conditions allow for very broad functional group
tolerance. Finally, mechanistic experiments and DFT studies are
indicative of a Zn(II)-promoted Ni(0)/Ni(II) catalytic cycle,
which therefore differs from the current mechanistic hypothesis
for C(sp2)−C(sp2) cross-electrophile coupling reactions.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedures, compounds’ characterization,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Søren Kramer − Department of Chemistry, Technical
University of Denmark, 2800 Kgs. Lyngby, Denmark;
orcid.org/0000-0001-6075-9615; Email: sokr@
kemi.dtu.dk
́
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Gui-Juan Cheng − Warshel Institute for Computational
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China; Email: chengguijuan@cuhk.edu.cn
Zhong Lian − Department of Dermatology, State Key
Laboratory of Bio-therapy and Cancer Center, West China
Hospital and West China School of Pharmacy, Sichuan
University, Chengdu 610041, China; orcid.org/0000-
0003-2533-3066; Email: lianzhong@scu.edu.cn
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Baojian Xiong − Department of Dermatology, State Key
Laboratory of Bio-therapy and Cancer Center, West China
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ACS Catalysis
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