NiH-Catalyzed Migratory Defluorinative Olefin Cross-Coupling: Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form gem-Difluoroalkenes

Article abstract of DOI:10.1002/anie.201915840

We report a NiH-catalyzed migratory defluorinative coupling between two electronically differentiated olefins. A broad range of unactivated donor olefins can be joined directly to acceptor olefins containing an electron-deficient trifluoromethyl substituent in both intra- and intermolecular fashion to form gem-difluoroalkenes. This migratory coupling shows both site- and chemoselectivity under mild conditions, with the formation of a tertiary or quaternary carbon center.

Full text of DOI:10.1002/anie.201915840

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: NiH-Catalyzed Migratory Defluorinative Cross Olefin-Coupling:
Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form
gem-Difluoroalkenes
Authors: Fenglin Chen, Xianfeng Xu, Yuli He, Genping Huang, and
Shaolin Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915840
Angew. Chem. 10.1002/ange.201915840
Link to VoR: http://dx.doi.org/10.1002/anie.201915840
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10.1002/anie.201915840
Angewandte Chemie International Edition
COMMUNICATION
NiH-Catalyzed Migratory Defluorinative Cross Olefin-Coupling:
Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form
gem-Difluoroalkenes
Fenglin Chen, Xianfeng Xu, Yuli He, Genping Huang, and Shaolin Zhu*
Abstract: We report
a
nickel hydride-catalyzed migratory
defluorinative coupling between two electronically-differentiated
olefins. A broad scope of unactivated donor olefins can be joined
directly to acceptor olefins containing an electron-deficient trifluoro-
methyl-substituent in both intra- and intermolecular fashions to form
gem-difluoroalkenes. This migratory coupling has both site- and
chemoselectivity under mild conditions, with the formation of a
tertiary or quaternary carbon center.
a
Representative application of gem-difluoroalkenes in pharmaceuticals
O
O
O
bioisostere of
carbonyl group
O
artemisinin
(antimalarial)
IC50 = 8.9 nM
artemisinin analogue
(improved activity)
IC50 = 4.6 nM
O
O
O
O
CF2
Ichikawa’s work: gem-difluoroalkene via Ni-catalyzed defluorinative reductive cycloaddition
O
b
c
L
NiII
via:
R1
R2
L
Ni0
CF3
R3
R2
R2
R1
CF3
R3
H
[2+2+1]
+
CF3
R2
cat. Ni(0)
Et3SiH
CF2
R3
metallacycle
R3
R1
R1
gem-Difluoroalkenes are versatile precursors to a broad
variety of organofluorine compounds which are widely used in
agrochemicals, pharmaceuticals, and materials science.[1] Owing
to their enhanced metabolic stability, such compounds are also
ideal carbonyl bioisosteres useful in modern drug discovery due
to their steric and electronic similarity to ketones, aldehydes, and
esters (Figure 1a).[2] Consequently, considerable effort has been
made towards their synthesis.[3] The gem-difluoromethylenation
of carbonyl or diazo precursors is the direct approach for their
construction,[4] but, as an alternative, catalytic defluorinative
alkylation, sequential introduction of an alkyl group into the
readily prepared CF3-substituted alkene and β-fluorine-
elimination, offers another promising approach.[5] This latter
process usually requires the pregenerated organometallic
reagents used in a metal-catalyzed SN2'-type transformation or
This work: NiH-catalyzed migratory defluorinative reductive cross olefin-coupling
cross olefin-coupling
donor olefin
R1
R2
R2
CF2
()n
R1 ≠ Ar, N, O
R1
R3
R3
()n
Ar
^_^
R4
easily accessible
H
gem-difluoroalkene
(formal defluoroalkylation)
NiH
Ni
acceptor olefin
migratory olefin-coupling
ˇ^ˇ
R2 R1
CF3
CF2
R1 = Ar, N, O
R4
R3
Ar
()n
Ar
R4
CF3-substituted
H
ꢀ site- & chemoselective
ꢀ form 3o or 4o carbon center
ꢀ mild/broad scope
d
Envisioned catalytic cycle
O
L
NiCl2·dme (cat.)
R3SiH
N
()4
R3SiCl
O
R3SiF
1a
LNiIH
the prefunctionalized alkyl radical precursor used in
a
I
R3SiH
CF2
NiH species
regeneration
hydrometallation
photocatalytic process. However, the requirement for
pregenerated organometallic reagent or prefunctionalized alkyl
radical precursor is less than ideal from the standpoints of step-
and atom-economy, and the coupling is limited to the site of
preinstalled reactive coupling groups.
FG
()4
PMP
NiI
H
NiI
chainwalking
LNiIF VI
FG
II
FG
()4
3a
olefin cross-coupling
()4
H
CF3
PMP
2a
olefin
coordination
β-F elimination
Nickel
NiI
FG
()4
FG
V
III
I CF
Ni
CF3
3
()4
PMP
IV
PMP
FG
Giese addition
()4
FG
NiII
Ni0 CF3
PMP
()4
CF3
oxidative
cyclization
PMP
[*]
F. Chen, X. Xu, Y. He, Prof. S. Zhu
Regioselectivity depend on the stability of radical: tertiary (3o) > secondary (2o) > primary (1o)
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, Chemistry and
Biomedicine Innovation Center (ChemBIC), School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, 210093,
(China)
Figure 1. Site- and chemoselective (migratory) hydro-γ,γ-difluoroallylation of
olefins.
E-mail: shaolinzhu@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/slzhu/
Prof. G. Huang
Synergistic combination of chainwalking and cross-
coupling, remote functionalization[6–10] has emerged as a general
strategy with which to achieve inert sp3 C–H bond
functionalization not readily accessible via classical directing
group pathways or harsh and potentially unselective non-
directed C–H activation conditions. Recently, the abundant
Department of Chemistry, School of Science, Tianjin University, and
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin, 300072, (China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915840
Angewandte Chemie International Edition
COMMUNICATION
10 mol% NiCl2·dme
12 mol% L1
O
O
CF2
PMP
nickel-catalyzed remote functionalization of olefins has attracted
considerable interest.[10] In this process, easily accessible and
bench-stable unsaturated hydrocarbons are used as latent
nucleophile equivalents, obviating the need for multistep
prefunctionalization. Cross-couplings happen selectively at
remote sp3 C–H bonds with traditional coupling partners.
Although the NiH-catalyzed migratory olefin polymerization is a
well-known industrial process,[11] a site- and chemoselective
catalytic system for the migratory coupling between a donor
olefin and an acceptor olefin remains elusive.[12] Stimulated by
Ichikawa’s pioneering studies on Ni-catalyzed defluorinative
reductive cycloaddition of trifluromethyl alkenes with alkynes
CF3
PMP
+
N
()4
N
()4
2.5 equiv (EtO)3SiH
40 mol% LiF, DMSO (0.40 M)
60 °C, 24 h
O
O
2a
3a
gem-difluoroalkene
1a
(2.0 equiv)
(1.0 equiv)
"cross olefin-coupling"
Entry
1
Variation from standard conditions
none
Yield (%)[a]
rr[b]
80(73)
64
<5
0
>99:1
>99:1
–
2
3
NiBr2 instead of NiCl2·dme
bpy instead of L1
L3–L5 instead of L1
L2 instead of L1
4
–
5
6
29
56
70
4
>99:1
>99:1
>99:1
–
L6 instead of L1
7
8
DEMS instead of (EtO)3SiH
w/o LiF
(Figure 1b),[5f] we propose
a
NiH-catalyzed[13] migratory
9
Li2CO3 instead of LiF
DMA instead of DMSO
25 °C
65
18
12
77
80
>99:1
>99:1
>99:1
>99:1
>99:1
10
11
12
13
defluorinative coupling process between unactivated donor
olefins and CF3-substituted acceptor olefins to rapidly introduce
a gem-difluoroalkene unit into targets (Figure 1c).
under air in a closed vial
1.0 equiv water added
Our proposed mechanism is outlined in Figure 1d. A NiH
species, generated in situ, would selectively initiate a rapid
chainwalking process along the hydrocarbon chain of a donor
alkene (1a), accessing various alkylnickel(I) species (II) as latent
radical equivalents, with which an electron-deficient CF3-
substituted olefin (2a) could act both as a ligand to stabilize the
alkylnickel(I) species (II) and as a competent radical acceptor.
The more stable alkyl radical, the radical cage pair (IV)
generated by a single electron transfer of complex III will be
selectively captured by the Ni(0)/2a complex to generate the
nickel(I) species (V) which is expected to rapidly undergo β-
fluorine elimination to deliver the desired product (3a). With a
stoichiometric hydrosilane, the NiH species (I) is regenerated
from NiF (VI) to complete the catalytic cycle.
L1 R = Me
L2 R = nBu
O
Me
N
N
N
L3 R = OMe
L4 R = CF3
N
N
R
R
N
L5
L6
[a] Yields determined by GC using n-tetradecane as the internal standard, the
yield in parentheses is the isolated yield. [b] Regioselectivities (rr) determined
by GC and GCMS analysis. DMSO=dimethylsulfoxide.
With the optimal conditions in hand, we examined the
scope of the donor alkene partner (Table 2). As anticipated, 1,1-
disubstituted alkenes bearing a wide variety of substituents (1a–
1j) underwent this transformation smoothly to form quaternary
carbon compounds with excellent branch regioselectivity,[14] and
a number of monosubstituted terminal alkenes (1k–1t) are
compatible. In general, coupling occurs at the most accessible
steric branch position and the formal defluorinated olefin-
coupling product is formed. Both activated terminal and internal
alkenes, such as styrenes (1s–1a') and alkenyl boronic esters
(1r, 1b'–1f'), selectively couple at the benzylic position and α-
carbon of the boronate, respectively. In addition, heteroatom
substituted cyclic olefins, 2,3-dihydrofuran (1g') and N-Boc-3-
pyrroline (1h') couple at the carbon α to the heteroatom.
Coupling of simple cyclic olefins (1i'–1l') is equally useful.
Notably, a diverse spectrum of functional groups, including
silanes (1e, 1o, and 1p), a silyl ether (1f), esters (1g, 1n, and
1x), phthalimides (1h, 1e'), boronic esters (1j, 1r, 1s, and 1a'–
1f'), phosphate esters (1q, 1y), a ketone (1t), a nitrile (1w),
carbamates (1z, 1h'), and an ether (1g'), are compatible.
As shown in Table 3a, in unactivated terminal (4a–4k) or
internal (4l–4n) alkenes with a remote aryl group on the alkyl
chain, migration toward the aryl group and subsequent benzylic
coupling is preferred. To get better yields, Li2CO3 is used as
base and DMA is chosen as solvent in most cases. As
anticipated, a variety of substituents on the remote aryl ring,
including electron donating (4c, 4d) and electron withdrawing
(4f–4h) substituents, are well tolerated. Notably, the reaction is
orthogonal to tosylate (4e), aryl chloride (4h), and aryl fluoride
(4k) which are potential coupling motifs that could be used for
further derivatization. This method is also applicable to late-
stage functionalization of a variety of structurally complex olefin
intermediates, such as a (-)-camphanic acid (4i) derivative and a
glucoside derivative (4j). Moreover, in remote alkenes with a
On the basis of our previously developed NiH-catalyzed
migratory hydrofunctionalization of olefins with electrophilic
coupling partners,[10e,h,i,m–o,r] we first examined the proposed
migratory defluorinative cross olefin-coupling of
a
1,1-
disubstituted alkene (1a) with a trifluoromethyl alkene (2a).
Systematic manipulation of the reaction parameters revealed
conditions under which the desired gem-difluoroalkene product
(3a) was obtained in 73% isolated yield as a single regioisomer
(Table 1, entry 1). Lower yield was obtained when using NiBr2 as
precatalyst (entry 2). The alkyl groups of L1 were found to be
critical and use of a parent pyridine compound, a 6,6'-dimethoxy
derivative, or a 6,6'-ditrifluoromethyl derivative delivered little or
no desired product (entries 3, 4). Replacement of L1 with a C6-
substituted pyrox ligand (L5) also gave no desired product (entry
4). Inferior results were achieved by other 6,6'-dialkylsubstituted
pyridine-based ligands (L2, L6, entries 5, 6), and use of
diethoxy(methyl)silane (DEMS) also resulted in decreased yield
(entry 7). Control experiments revealed that base was critical
(entry 8), and use of Li2CO3 was less efficient (entry 9). N,N-
dimethylacetamide (DMA) was shown to be an unsuitable
solvent (entry 10) and conduction of the reaction at 25 °C led to
a poor yield (entry 11). In addition, the reaction is compatible
with air and moisture; comparable yields were obtained when
conducting the reaction under air in a closed vial and with 1.0
equiv water, respectively (entries 12, 13).
Table 1: Variation of reaction parameters.
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10.1002/anie.201915840
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COMMUNICATION
heteroatomic substituent at the terminus of the hydrocarbon
chain, migratory coupling selectively happens at the carbon α to
the heteroatom (4o–4q, Table 3b).
Table 2: Cross olefin-coupling: scope of alkene component.[a,b]
10 mol% NiCl2·dme
12 mol% L1
R3
R1
R1
CF3
ꢀ Form quaternary/tertiary carbon center
CF2
PMP
+
R3
R2
ꢀ Predictable branch (Markovnikov) selective
ꢀ Air and moisture compatible
PMP
2a
2.5 equiv (EtO)3SiH
40 mol% LiF
DMSO (0.40 M), 60 °C, 24 h
R2
1
3
donor alkene
acceptor alkene
defluorinative olefin-coupling
(a) from 1,1-disubstituted alkenes
CF2
PMP
CF2
CF2
PMP
CF2
CF2
PMP PhthN
CF2
PMP
CF2
PMP
R
TBDPSO
MeO2C
nBu
PMP
()2
PMP
()4
R
3d R = tBu, 48% yield, 80:1 rr
3e R = TMS, 50% yield, 22:1 rr
3i R = Ph, 70% yield, >99:1 rr
3j R = Bpin, 86% yield, 54:1 rr
3b 94% yield, 23:1 rr
3c 62% yield, >99:1 rr
3f 69% yield, >99:1 rr
3g 67% yield, >99:1 rr
3h 71% yield, 52:1 rr
(b) from terminal alkenes
CF2
CF2
CF2
PMP
PMP
MeO2C
MeO2C
CF2
CF2
CF2
PMP
CF2
H
H
EtO
EtO
O
R
PMP
R3Si
PMP
P
Bpin
PMP
PMP
H
Bpin
3k R = Me, 56% yield, 27:1 rr
3l R = Cy, 94% yield, 30:1 rr
Estrone derivative
3t 74% yield, >20:1 rr
3o R = Me, 84% yield, 45:1 rr
O
3m R = tBu, 92% yield, 25:1 rr 3n 88% yield, 26:1 rr 3p R = Ph, 84% yield, >99:1 rr 3q 77% yield, >99:1 rr 3r 85% yield, >99:1 rr 3s 63% yield, >99:1 rr
(c) from internal alkenes
MeO2C
CF2
PMP
CF2
PMP
N
CF2
PMP
Bpin
Ph
iBuO2C
Ph
CF2
PMP
CF2
PMP
(EtO)2OP
Ph
CF2
PMP
CF2
PMP
NC
PMP
3u[c] 92% yield, >99:1 rr
3v[c] 74% yield, >99:1 rr
3w[c] 61% yield, >99:1 r.r. 3x[c] 59% yield, >99:1 rr
3y[c] 67% yield, >99:1 rr
3z[c] 73% yield, >99:1 rr 3a' 89% yield, >99:1 rr
nHex
CF2
nBu
Bdan
()3
()4
CF2
PMP
CF2
R
CF2
PMP
PhthN
CF2
PMP
CF2
PMP
CF2
PMP
()n
PMP
X
Bpin
Bpin
Bpin
PMP
3j' n = 1, 61% yield
3k' n = 2, 66% yield
3l' n = 4, 91% yield
3b' R = Ph, 77% yield, 23:1 rr
3c' R = Cl, 81% yield, >99:1 rr 3d' 74% yield, >99:1 rr
3g' X = O, 92% yield, 19:1 rr
3h' X = NBoc, 53% yield, 26:1 rr 3i' 74% yield, >99:1 rr
3e' 76% yield, >99:1 rr
3f' 96% yield, >99:1 rr
[a] Isolated yields on 0.20 mmol scale (average of two runs). [b] Rr determined by GC and GCMS analysis, ratios reported as >20:1 determined by crude 1H NMR
analysis. [c] 10 mol% NiBr2·3H2O, 12 mol% L1, 5 mol% PPh3, 2.5 equiv (EtO)3SiH, 40 mol% LiF, 20 mol% TBAB, DMA (0.40 M), 60 °C, 24 h.
TBAB=tetrabutylammonium bromide.
Table 3: Migratory olefin-coupling: scope of alkene component.[a]
10 mol% NiI2
12 mol% L1
R'
CF3
PMP
()n
CF2
PMP
ꢀ Migratory cross olefin-coupling
ꢀ Allylic defluorinative alkylation
ꢀ No dissociation of NiH from olefin
R'
+
()n
R
2.5 equiv (EtO)3SiH
20 mol% Li2CO3
DMA (0.40 M), 50 °C, 24 h
R
4
2a
5
donor alkene
acceptor alkene
migratory defluorinative olefin-coupling
(a) migrated to benzylic position
CF2
CF2
CF2
PMP
CF2
CF2
MeO
CF2
PMP
MeO
TsO
PMP
PMPH2
CF3
2-Nap
PMP
Ph
PMP
MeO
MeO
5c 79% yield, 82:1 rr
OMe
5a[b] 85% yield, 29:1 rr
5b 56% yield, 38:1 rr
5d[b] 86% yield, 78:1 rr
5e 70% yield, >99:1 rr
5f 65% yield, 38:1 rr
OAc
CF2
CF2
PMP
O
CF2
O
CF2
CF2
AcO
O
MeO2C
Cl
PMP
N
O
O
PMP
PMP
PMP
AcO
O
O
O
F
OAc
OMe
OMe
5g 82% yield, 51:1 rr
5h 62% yield, 46:1 rr
5i 63% yield, >99:1 rr
5j 74% yield, >20:1 rr
5k 69% yield, >99:1 rr
(b) migrated to α-carbon adjacent to heteroatom
Ph CF2
)
Z
CF2
CF2
PMP
CF2
E/
CF2
PMP
1
:
PMP
Ph
(8
CF2
PMP
5l[b,c] 71% yield, 22:1 rr
PMP
(3
N
PMP
N
:
O
1
Boc
E/
Z
Ph
)
5m[b,c] 65% yield, >99:1 rr
5n[b] 73% yield, >99:1 rr
5o[b] 76% yield, 20:1 rr
5p[d] 89% yield, 18:1 rr
5q[d] 84% yield, >99:1 rr
[a] Yield and rr are as defined in Table 2. [b] 10 mol% NiBr2·3H2O, 12 mol% L1, 5 mol% PPh3, 2.5 equiv (EtO)3SiH, 40 mol% LiF, 20 mol% TBAB, DMA (0.40 M),
60 °C, 24 h. [c] 1.0 equiv LiF used. [d] 10 mol% NiCl2·dme, 12 mol% L1, 2.5 equiv (EtO)3SiH, 40 mol% LiF, DMSO (0.40 M), 60 °C, 24 h.
The optimized conditions also prove to be efficient for
various aryl and heteroaryl substituted trifluoromethyl alkenes
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10.1002/anie.201915840
Angewandte Chemie International Edition
COMMUNICATION
(Table 4). In terms of electronic properties, substrates with
along the hydrocarbon chain of donor alkene. This is consistent
with the hypothesis that NiH-catalyzed chainwalking selectively
occurs with a donor alkene (1o) over the acceptor alkene (2a).
Moreover, that no deuterium scrambling occurred when a
deuterated trifluoromethyl olefin (2a-D) was used further
supports that there is no chainwalking along the acceptor olefin
(2a). Finally, a crossover reaction was carried out with equimolar
amounts of deuterated olefin (1a-D) and undeuterated olefin
(4g). Interestingly, 5a-D and 5g were obtained as the only
products and no crossover product 5g-D was observed. This
observation indicates that chainwalking occurs without
dissociation of NiH/NiD from the donor olefin, which stands in
contrast to our previously studied processes.[10e,h,i,m–o,r]
electron-rich
(2c–2e)
or
electron-withdrawing
(2g–2o)
substituents on the aryl ring couple efficiently. Under these mild
conditions, not only ethers (2c–2g), esters (2l and 2m), and a
nitrile (2p), are tolerated, even normally easy reduced functional
groups like a sulfone (2j), a ketone (2k), and aldehydes (2n, 2o)
remain intact. Additionally, heterocycles such as a dibenzofuran
(2q), a carbazole (2r), a benzothiophene (2s), a quinoline (2t),
and a pyridine (2u) are also compatible. Unfortunately, alkyl-
substituted trifluoromethyl alkenes are inactive under current
conditions.
Table 4: Scope of the trifluoromethyl alkene component.[a]
10 mol% NiI2
CF3
nPr CF2
Ar
a
Intramolecular reactions
12 mol% L1
Ph
+
CF3
F
Ar
Ph
2.5 equiv (EtO)3SiH
20 mol% Li2CO3
MeO2C
MeO2C
standard
3a
2
6
Ph
MeO2C
F
conditions
donor alkene
acceptor alkene
DMA (0.40 M), 50 °C, 24 h
(gem-difluoroalkene)
CO2Me
Ph
nPr CF2
8a 75% yield, 3:1 dr, >99:1 rr
7a
nPr CF2
nPr CF2
O
O
F
F
Ph
standard
Ph
Ph
Ph
conditions
O
CF3
R
O
Ph
6d[b] R = OPh, 71% yield, 22:1 rr
6e[b] R = OBn, 64% yield, >99:1 rr
6f[b] R = SMe 73% yield, 20:1 rr
8b 50% yield, 2:1 dr, >99:1 rr
7b
Large-scale experiment
MeO2C
6b 91% yield, >99:1 rr
6c[b] 68% yield, 42:1 rr
b
nPr CF2
10 mol% NiI2
12 mol% L1
nPr CF2
nPr CF2
nPr CF2
Ph
+
Ph
2.5 equiv (EtO)3SiH
20 mol% Li2CO3
DMA (0.40 M), 50 °C, 24 h
O
Ph
Ph
Ph
CF3
CO2Me
3a
2m
6m
O
5 mmol-scale
(2.0 equiv)
88% yield, 92:1 rr
R
6h[b] R = Ph, 75% yield, 22:1 rr
6i R = CF3, 75% yield, 29:1 rr
SO2Me
c
Deuterated experiments
6g 60% yield, 28:1 rr
6j 72% yield, >99:1 rr
(0.76 D)
(0.18 D)
CF2
10 mol% NiCl2·dme
12 mol% L1
CF3
nPr CF2
nPr CF2
nPr CF2
+
Me3Si
Me3Si
2.5 equiv DBpin
40 mol% LiF
DMSO (0.40 M), 60 °C, 24 h
PMP
PMP
Ph
Ph
Ph
(0.06 D)
CO2Me
CHO
2a (2.0 equiv)
3o-D 60% yield, 30:1 rr
1o
O
10 mol% NiCl2·dme
12 mol% L1
CF3
CF2
(0.89 D)
6l m-CO2Me 62% yield, >99:1 rr 6n m-CHO 57% yield, >99:1 rr
D
6k 82% yield, 92:1 rr
6m p-CO2Me 78% yield, 81:1 rr
6o p-CHO 69% yield, >99:1 rr
Me3Si
+
Me3Si
PMP
PMP
2.5 equiv (EtO)3SiH
40 mol% LiF
DMSO (0.40 M), 60 °C, 24 h
D
D
D
(0.89 D)
(0.88 D) (0.90 D)
3o-D 85% yield, 46:1 rr
nPr CF2
nPr CF2
O
F2C
2a-D (2.0 equiv)
1o
(0.86 D)
CN
nPr
Ph
N
Ph
Ph
(0.85 D) (1.26 D)
(0.86 D)
D
D
D
(0.32 D)
CF2
Ph
(0.84 D)
10 mol% NiI2
12 mol% L1
2.5 equiv (EtO)3SiH
6q[b] 76% yield, 22:1 rr
6r[b] 59% yield, >99:1 rr
(0.84 D)
Ph
(0.87 D)
PMP
D
6p 61% yield, >99:1 rr
CF3
1a-D (1.0 equiv)
nPr CF2
5a-D 49% yield
nPr CF2
nPr CF2
nPr CF2
+
+
20 mol% Li2CO3
DMA (0.40 M), 50 °C, 24 h
PMP
S
Ph
MeO2C
Ph
Ph
N
2a
PMP
45% yield
5g (no D-incorporated)
N
N
MeO2C
4g (1.0 equiv)
()2
6s 70% yield, 32:1 rr
6t 62% yield, 33:1 rr
6u 76% yield, 26:1 rr
[a] Yield and rr are as defined in Table 2. [b] 10 mol% NiBr2·3H2O, 12 mol%
L1, 5 mol% PPh3, 2.5 equiv (EtO)3SiH, 40 mol% LiF, 20 mol% TBAB, DMA
(0.40 M), 60 °C, 24 h.
Scheme 1. Intramolecular, large-scale, and deuterated experiments.
In summary, we have developed a NiH-catalyzed migratory
defluorinative olefin-coupling of unactivated donor olefins with
CF3-substituted acceptor olefins, both intra- and intermolecularly
to form gem-difluoroalkenes. This mild process is compatible
with air and moisture and has broad substrate scope. Excellent
chemo- and regioselectivity are observed with the formation of a
tertiary or quaternary carbon center. Further development and
application of this reaction as well as mechanistic investigation is
currently in progress.
This process also proceeds well in an intramolecular
version (Scheme 1a). Under the standard conditions, reductive
defluorinative cyclization products (8a, 8b) are obtained as
single regioisomers. The robustness and applicability of this
process was further demonstrated by the large-scale synthesis
of 6m (Scheme 1b).
As shown in Scheme 1c, a series of isotope labeling
experiments were conducted in an effort to understand the
behavior of NiH. A reaction of allyltrimethylsilane (1o) with a
trifluoromethyl olefin (2a) using a deuterated pinacolborane
(DBpin) as the hydride source was first carried out. The
corresponding product 3o-D was obtained with deuterium
scrambling and deuterium incorporation only at all positions
Acknowledgements
Support was provided by NSFC (21772087, 21822105), and
Fundamental Research Funds for the Central Universities
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10.1002/anie.201915840
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(020514380182).
Keywords: C–H activation • cross-coupling • isomerization •
nickel • regioselectivity
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Fenglin Chen, Xianfeng Xu, Yuli He,
Genping Huang, and Shaolin Zhu*
R2 R1
H
CF2
Ar
R1
ꢀꢁQ
CF3
Ar
ꢀ migratory cross olefin-coupling
ꢀ chainwalking along donor olefin
ꢀ no dissociation of NiH from olefin
ꢀ site- & chemoselective
+
NiH
R3
R4
R3
ꢀꢁQꢂꢃ
R2
Page No. – Page No.
R4
CF3-substituted
acceptor olefin
easily accessible
donor olefin
gem-difluoroalkene
carbonyl mimic
(isostere)
NiH-Catalyzed Migratory
ꢀ air & moisture compatible
ꢀ mild/broad scope
"
☹
Defluorinative Cross Olefin-Coupling:
Trifluoromethyl-Substituted Alkenes
as Acceptor Olefins to Form gem-
Difluoroalkenes
NiH
gem-Difluoroalkenes, a carbonyl bioisostere in modern drug discovery, were
obtained through a practical migratory defluorinative cross olefin-coupling process
between donor olefin and trifluoromethyl-substituted acceptor olefin. During this
mild process, chainwalking occurs only along the hydrocarbon chain of the donor
olefin with no dissociation of NiH.
This article is protected by copyright. All rights reserved.