Highly γ-Selective Arylation and Carbonylative Arylation of 3-Bromo-3,3-difluoropropene via Nickel Catalysis

Article abstract of DOI:10.1002/anie.202015921

A nickel-catalyzed highly γ-regioselective arylation and carbonylative arylation of 3-bromo-3,3-difluoropropene has been developed. The reaction proceeds under mild reaction conditions, providing the gem-difluoroalkenes with high efficiency and good functional group tolerance. The resulting gem-difluoroalkenes can serve as versatile building blocks for diversified synthesis. Preliminary mechanistic studies and density functional theory calculations reveal that both non-radical and radical pathways are possible for the reaction, and the radical pathway is more likely. The high γ-regioselectivity results from the β-bromide elimination of alkylnickel(II) species or from the reductive elimination of nickel(III) species [(aryl)(CF₂=CHCH₂)Ni^III(L_n)X]. The γ-selective carbonylation of 3-bromo-3,3-difluoropropene under 1 atm CO gas also provides a new way for nickel-catalyzed carbonylation.

Full text of DOI:10.1002/anie.202015921

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Homogeneous Catalysis
Hot Paper
Highly g-Selective Arylation and Carbonylative Arylation of 3-Bromo-
3,3-difluoropropene via Nickel Catalysis
Ran Cheng, Yueqian Sang, Xing Gao, Shu Zhang, Xiao-Song Xue,* and Xingang Zhang*
Abstract: A nickel-catalyzed highly g-regioselective arylation
and carbonylative arylation of 3-bromo-3,3-difluoropropene
has been developed. The reaction proceeds under mild reaction
conditions, providing the gem-difluoroalkenes with high
efficiency and good functional group tolerance. The resulting
gem-difluoroalkenes can serve as versatile building blocks for
diversified synthesis. Preliminary mechanistic studies and
density functional theory calculations reveal that both non-
radical and radical pathways are possible for the reaction, and
the radical pathway is more likely. The high g-regioselectivity
results from the b-bromide elimination of alkylnickel(II)
been reported scarcely. One of the possible reasons is the lack
of efficient catalytic systems and suitable fluoroalkylating
reagents to discriminate one reaction site among the multiple
functional bonds.
3-Bromo-3,3-difluoropropene (BDFP)[5] is a useful build-
À
ing block owing to the synthetic versatility of its carbon
carbon double bond and tunable reaction sites. Efficient
methods that enable the highly selective substitution on both
a- and g-sites of BDFP would provide structural diversified
fluorinated compounds of great interest in medicinal chemis-
try and advanced functional materials. Recently, we devel-
oped an efficient method for the highly a-selective arylation
of BDFP with arylboronic acids using a palladium catalyst,
representing the first example of catalytic synthesis of gem-
difluoroallylated arenes with BDFP (Scheme 1a).[6] Consid-
ering that the nature of the palladium catalyst is critical for
the high a-substitution selectivity of BDFP, we envisioned
that using a different transition-metal catalyst to modulate the
reactivity of arylboronic acids towards BDFP would make it
possible to access gem-difluoroalkenes, g-substituted BDFP
products (Scheme 1b), a versatile structural motif that has
species or from the reductive elimination of nickel(III) species
III
=
[(aryl)(CF2 CHCH2)Ni (Ln)X]. The g-selective carbonyla-
tion of 3-bromo-3,3-difluoropropene under 1 atm CO gas also
provides a new way for nickel-catalyzed carbonylation.
I
ntroduction of one or more fluorine atoms into organic
molecules can dramatically change their physical, chemical,
and biological properties.[1] Specifically, the binding of
fluorinated groups at different sites in the same organic
molecule can also lead to different properties. Therefore,
extensive efforts have been made to develop general and
efficient methods for controllable incorporation of fluori-
nated groups into organic compounds.[2] In addition to the
traditional fluoroalkylating reactions,[3] recently, transition-
metal-catalyzed fluoroalkylations have emerged as an attrac-
[2a–c,4]
À
tive strategy to construct C Rf bonds (Rf = fluoroalkyl).
Among these catalytic methodologies, however, the control-
lable site-selective fluoroalkylation by the same fluoroalky-
lating reagent to access different fluorinated isomers has only
[*] R. Cheng, X. Gao, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
Y. Sang, Prof. Dr. X.-S. Xue
College of Chemistry, Nankai University
Tianjin 300071 (P. R. China)
E-mail: xuexs@nankai.edu.cn
Prof. Dr. S. Zhang
School of Materials and Energy
University of Electronic Science and Technology of China
2006 Xiyuan Avenue, West High-Tech Zone, Chengdu, Sichuan
611731 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015921.
Scheme 1. Transition-metal-catalyzed regioselective substitution of 3-
bromo-3,3-difluoropropene.
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important applications in medicinal chemistry and advanced
functional materials.[7]
Cs2CO3 could also afford 3a in comparable yields (see the
Supporting Information), thus providing complementary
reaction conditions. Finally, an 84% isolated yield of 3a
with almost single g-selectivity was obtained by prolonging
the reaction time to 24 h (Table 1, entry 5). Under these
reaction conditions, good repeatability of the reaction could
be obtained. No product was observed in the absence of
nickel catalyst (Table 1, entry 6) and only 6% yield of 3a was
obtained without ligand (Table 1, entry 7), thus demonstrat-
ing the essential role of [Ni/L] in promoting the reaction.
With viable reaction conditions in hand, we next exam-
ined the reaction of BDFP 1 with a variety of arylboronic
acids (Table 2). Overall, good to high yields of gem-difluor-
oalkenes 3 with excellent g-selectivity (g/a = 30:1 to > 99:1)
were obtained. Arylboronic acids bearing an electron-donat-
ing or an electron-withdrawing substituent showed reliable
reaction efficiency. The nickel-catalyzed process exhibited
good functional group tolerance. Versatile functional groups,
such as trimethylsilyl, thioether, enolizable ketone, formyl,
ester, and cyano moieties, were compatible with the reaction
conditions (3d–3 f, 3j–3m). Importantly, an aryl-bromide-
containing substrate was also a competent coupling partner
and provided the corresponding product 3i in 78% yield, thus
offering opportunities for subsequent derivatization. The
steric effect of the arylboronic acid slightly influenced the
reaction efficiency, but moderate yield was still obtained (3c).
The common methods to synthesize gem-difluoroalkenes
rely on the difluoromethylenation of aldehydes and ketones[8]
or b-F elimination of trifluoromethylated compounds.[8a,9]
Following our studies on the nickel-catalyzed fluoroalkylation
reactions,[10] we hypothesized that the g-selective substitution
of BDFP could be obtained by choosing an appropriate nickel
catalyst, which can facilitate the transmetalation of nickel
with arylboronic acid,[11] followed by insertion of the resulting
À
arylnickel complex [Ar-Ni] (A) into the carbon carbon
double bond and b-bromide elimination (Scheme 1c,
path I). Furthermore, this strategy could also be extended to
the g-selective carbonylation of BDFP (Scheme 1b), as we
recently found that the [Ar(CO)NiII(Ln)X] complex (D)
II
[11]
À
could be easily formed between [Ar Ni ] species and CO,
which may benefit the g-selective carbonylation of BDFP
through a similar pathway as mentioned above (Scheme 1d).
One crucial issue to be addressed in this strategy is how to
suppress the competitive a-substitution of the BDFP reaction
(Scheme 1c, path II). We carried out a systematic investiga-
tion to resolve this challenge. Herein, we describe a nickel-
catalyzed, highly g-selective arylation and carbonylation of
BDFP, providing an efficient access to gem-difluoroalkenes.
On the basis of the above hypothesis, we began this study
by choosing (4-(tert-butyl)phenyl)boronic acid 2a as a model
substrate (Table 1). We found that the combination of
NiCl2·DME (5 mol%) with 1,10-phenathroline (phen,
5 mol%) in the presence of K2CO3 in dioxane at 808C
could provide the g-selective product 3a in 48% yield, with
only trace amounts of a-selective product 4a observed
(Table 1, entry 1). Further examination of different ligands
(for details, see the Supporting Information) showed that 2,2’-
bypyridine (bpy) performed better than others, providing 3a
in 86% yield with excellent g-selectivity (g/a = 86:1, Table 1,
entry 2), but no product was observed with tripyridine (tpy) as
the ligand (Table 1, entry 3). The reaction was also sensitive to
the nickel sources. NiCl2·DME turned out to be the optimal
one in terms of yield and regioselectivity (see the Supporting
Information). Among the tested solvents and bases, THF and
Table 2: Ni-catalyzed g-selective arylation of gem-difluoropropene bro-
mide with arylboronic acids.[a]
Table 1: Representative results for the optimization of Ni-catalyzed 3,3-
difluoroallylation of arylboronic acids.[a]
entry
[Ni]
Ligand
3a/4a, yield [%][b]
1
2
3
4
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiBr2·DME
NiCl2·DME
none
Phen
Bpy
Tpy
Bpy
Bpy
Bpy
none
48/traces
86/1
nd/nd
30/traces
86 (84)/trace
nd/nd
5[c]
6
7
NiCl2·DME
6/1
[a] Reaction conditions (unless otherwise specified): 2a (0.9 mmol,
1.50 equiv), 1 (0.6 mmol, 1.0 equiv), dioxane (4 mL), 8 h. [b] Determined
by 19F NMR using fluorobenzene as an internal standard, the number in
parentheses is the isolated yield; nd=not detected. [c] Reaction run for
24 h.
[a] Reaction conditions (unless otherwise specified): 2 (0.9 mmol,
1.5 equiv), 1 or 1’ (0.6 mmol, 1 equiv), K2CO3 (2.0 equiv), dioxane
(4 mL). [b] Reaction run for 48 h. [c] 2 equiv of Cs2CO3 were used as base.
[d] 2.0 equiv of CsF were used. [e] 0.5 equiv of H2O was used. [f] THF was
used as solvent. [g] Gram-scale reaction.
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The reaction can be readily scaled up, as demonstrated by the
gram-scale synthesis of 3a without erosion of the reaction
efficiency. Branch-substituted BDFP was also applicable to
the reaction, providing the corresponding product 3o in 39%
yield without observation of the b-H elimination side product.
The high efficiency and excellent g-selectivity of this
nickel-catalyzed process encouraged us to evaluate the g-
selective carbonylation of BDFP. We found that the g-
selective carbonylation of BDFP could be obtained with
high efficiency and moderate to excellent regioselectivity
(g/a = 6.7:1–99:1) under 1 atm of CO using NiCl2·DME as the
catalyst and phen as the ligand (Table 3). An even higher
yield was obtained on gram-scale synthesis of the carbonyl
compound (5a). These result suggests that the current
catalytic system is highly compatible with the nickel-catalyzed
carbonylation reaction using inexpensive CO gas, which
remains challenging because of the easy formation of highly
toxic and unreactive Ni(CO)4 species.[12–14] Both electron-rich
and electron-deficient arylboronic acids were applicable to
the reaction, and good functional group tolerance was
observed in such a transformation (5 f–5l). However, for the
electron-deficient substrates, moderate g-selectivity was
observed (5g–5i).
Scheme 2. Transformations of compounds 3a and 5a.
À
ization of the carbon carbon double bond in 3a with TMSN3
and I2 provided the azide-substituted difluoroalkylated com-
pound 6 in synthetically useful yield. To the best of our
knowledge, such a transformation has not been reported yet.
The introduced azide and iodide moieties offer additional
opportunities for downstream transformations. Bromination
of 3a efficiently produced difluoroalkyl bromide 7, which
could be employed as a good coupling partner for transition-
metal-catalyzed cross-coupling reactions. The transformation
of carbonyl compound 5a was also conducted. Selective
reduction of 5a with NaBH4 afforded alcohol 8 in 83% yield,
while hydrogenation of 5a over a short time (3 h) could
provide difluoromethylated alkane 9 with the carbonyl intact.
The resulting gem-difluoroalkenes 3 and 5 can serve as
a versatile building block for the diversified synthesis of
fluorinated compounds. As shown in Scheme 2, difunctional-
Table 3: Ni-catalyzed g-selective carbonylation of gem-difluoropropene
bromide with arylboronic acids under 1 atm of CO.[a]
À
Prolonging the reaction time, both carbon carbon double
bond and carbonyl group in 5a were reduced, providing
difluoromethylated alcohol 10 in moderate yield. The nucle-
ophilic addition of vinylmagnesium bromide to ketone 5a also
proceeded smoothly and furnished allylic alcohol 11 in 71%
yield.
To identify whether a radical pathway was involved in the
reaction, we conducted radical clock experiments (Scheme 3).
Treatment of a-cyclopropyl styrene 12 with the reaction
mixture of arylboronic acid 2a and BDFP 1 under standard
reaction conditions did not lead to the ring-opening expan-
sion product 13 (Scheme 3a). We also prepared an arylnickel-
(II) complex (A1)[10c,15] and an arylacylnickel(II) complex
(D1).[11] Stoichiometric reaction of A1 or D1 with 12 in the
presence of BDFP 1 did not provide 13 either (Scheme 3b).
Instead, the gem-difluoroalkene 3a and 5a were obtained in
54% and 35% yield, respectively. However, density func-
tional theory (DFT) calculations showed that trapping of
gem-difluoroallyl radical with 12 is kinetically disfavored over
the combination of the gem-difluoroallyl radical with nickel
complex D1 (see Supporting Information, Figures S9 and
S11), indicating that the pathway involving a radical cannot be
excluded. We also conducted radical inhibition experiments
and found that the yield of 3a was dramatically decreased for
[a] Reaction conditions (unless otherwise specified): 2 (0.9 mmol,
1.5 equiv), 1 (0.6 mmol, 1 equiv), K2CO3 (2.0 equiv), dioxane (4 mL).
[b] Reaction run for 12 h. [c] Reaction run for 48 h. [d] Using 4,7-
dimethoxy-1,10-phenanthroline as the ligand. [e] Gram-scale reaction.
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Scheme 3. Radical trapping experiments.
Scheme 4. Stoichiometric reactions using A1 and D1 as the catalysts.
the reaction of arylboronic acid 2a with 1 in the presence of
an electron transfer inhibitor, 1,4-dinitrobenzene 14, or
a radical scavenger, a-phenyl styrene 15, under standard
reaction conditions (Scheme 3d). In addition, the addition of
TEMPO to the reaction totally inhibited the reaction, and an
adduct 16 was observed in 5% yield (Scheme 3e). These
results suggested that a radical pathway is likely involved in
the reaction.
To gain more detailed mechanistic insight into the
reaction, we conducted a stoichiometric reaction of A1 with
BDFP 1, leading to 3a in almost quantitative yield (98%,
Scheme 4a). Kinetic studies showed that this stoichiometric
reaction is faster than the standard catalytic reaction with 4,4’-
ditBubpy as the ligand (Figures S1 and S2). The reaction of
complex D1 with BDFP 1 could also provide corresponding
carbonylated gem-difluoroalkene 5a (60% yield, g/a = 8:1,
Scheme 4b), and it is also faster than the standard catalytic
carbonyl reaction.
complex or arylacylnickel(II) complex may be the key
intermediate in the current nickel-catalyzed process.
Finally, we conducted DFT calculations to shed further
light on the reaction mechanism (for details, see the
Supporting Information, Figures S4–S12). Interestingly, both
the non-radical and radical pathways are possible for the
reaction (Scheme 5). The key steps of these two pathways
require a similar free energy of activation from arylnickel(II)
II
À
[Ar Ni (Ln)X] complex A. For the non-radical pathway
(Scheme 5, Path I), the insertion of arylnickel(II) complex A
À
into the carbon carbon double bond of BDFP 1 requires
II
27.1 kcalmolÀ1 from [Ph Ni (Ln)X] A2 via transition state
À
3TS1a (Figures 1a, S4, and S5). A similar free energy barrier is
also found for the key step in the radical pathway (Scheme 5,
Path II), in which the formation of a gem-difluoroallyl radical
III
3
À
I-1 and [Ph Ni (Ln)X2] E1 via transition state TS1b from A
Additionally, nickel(II) complexes A1 and D1 could also
serve as the catalysts to produce the gem-difluoroalkenes
(Scheme 4c,d).[16] Kinetic studies showed that the reaction
rate of the A1-catalyzed reaction is similar to the standard
reaction using 4,4’-ditBubpy as the ligand (Figures S2 and S3).
Furthermore, in addition to the formation of desired product
3m, the reaction of arylboronic acid 2m with 1 catalyzed by
A1 led to a small amount of 3a (Scheme 4e), and with
increasing the loading amount of A1 from 5 mol% to
10 mol%, the formation of 3a increased from 3% to 6%
yield. Thereby, these results indicated that the arylnickel(II)
Scheme 5. Proposed mechanism.
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possible for the current reaction, but the radical pathway is
more likely.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21931013, 21790362, and
21933004), the Strategic Priority Research Program of the
Chinese Academy of Sciences (No. XDB20000000).
Figure 1. DFT-calculated transition states for a) the rate-determining
step of the non-radical pathway (3TS1a: the insertion of arylnickel(II)
complex A into the double bond of BDFP 1) and the radical pathway
(3TS1b: bromine abstraction from 1 by A); b) the reductive elimination
process in the radical pathway.
Conflict of interest
The authors declare no conflict of interest.
and BDFP requires 27.0 kcalmolÀ1 (Figures 1a and S9).
Additionally, in path I, after the formation of key intermedi-
ate alkylnickel(II) B, b-bromide elimination is faster than the
b-H elimination step (Figure S8); as a result, a g-selective
gem-difluoroalkene is produced. DFT calculations also show
that the possibility of an SN2’ pathway through attack of A2 to
BDFP is thermodynamically disfavored, as the dissociation of
a bromide anion from BDFP requires a very high free energy
barrier (51.7 kcalmolÀ1, Figure S6). For Path II, the g-selec-
Keywords: 3-bromo-3,3-difluoropropene · arylboronic acids ·
carbonylation · gem-difluoroalkenes · nickel catalysis
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III
=
elimination of key intermediate [(aryl)(CF2 CHCH2)Ni -
(Ln)X] C1 is the kinetically favorable pathway, as a higher free
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À
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III
À
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1. Recombination of the resulting radical with another A
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III
=
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highly g-selective arylation and carbonylation of BDFP via
nickel catalysis. The reaction exhibited good functional group
tolerance and provided the gem-difluoroalkenes with high
efficiency and regioselectivity. The resulting products can
serve as versatile building blocks for diversified synthesis.
Preliminary mechanistic studies and DFT calculations
revealed that the reaction starts with the transmetalation of
nickel(II) with arylboronic acids to form an arylnickel(II)
complex, and both non-radical and radical pathways are
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[16] The lower yield of 3a compared to the standard reaction
conditions is because of using 4,4’-ditBuBpy as the ligand.
Replacing bpy with 4,4’-ditBuBpy under standard reactions led
to 3a in 57% yield, see the Supporting Information.
[11] a) H.-Y. Zhao, X. Gao, S. Zhang, X. Zhang, Org. Lett. 2019, 21,
1031; b) M.-Q. Zhou, H.-Y. Zhao, S. Zhang, Y.-X. Zhang, X.
Zhang, J. Am. Chem. Soc. 2020, 142, 18191.
[12] a) L. Kollar, Modern Carbonylation Methods, Wiley-VCH,
Weinheim, 2008; b) M. Beller, X.-F. Wu, Transition Metal
Catalyzed Carbonylation Reactions: Carbonylative Activation
of C-X Bonds, Springer, Amsterdam, 2013; c) X.-F. Wu, H.
Manuscript received: November 29, 2020
Revised manuscript received: February 27, 2021
Accepted manuscript online: March 18, 2021
Version of record online: && &&, &&&&
6
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ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Homogeneous Catalysis
R. Cheng, Y. Sang, X. Gao, S. Zhang,
X.-S. Xue,* X. Zhang*
&&&& — &&&&
Highly g-Selective Arylation and
Carbonylative Arylation of 3-Bromo-3,3-
difluoropropene via Nickel Catalysis
A nickel-catalyzed highly g-regioselective
arylation and carbonylation of 3-bromo-
3,3-difluoropropene has been developed.
The reaction provides a variety of gem-
difluoroalkenes with good functional
group tolerance and high efficiency. Pre-
liminary mechanistic studies and DFT
calculations revealed that both non-radi-
cal and radical pathways are possible for
the reaction.
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
7
These are not the final page numbers!