Catalyzing the Hydrodefluorination of CF3-Substituted Alkenes by PhSiH3. H?Transfer from a Nickel Hydride

Article abstract of DOI:10.1021/jacs.9b13757

The hydrodefluorination of CF₃-substituted alkenes can be catalyzed by a nickel(II) hydride bearing a pincer ligand. The catalyst loading can be as low as 1 mol%. gem-Difluoroalkenes containing a number of functional groups can be formed in goo

Full text of DOI:10.1021/jacs.9b13757

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Article
Catalyzing the Hydrodefluorination of CF3-substituted
Alkenes by PhSiH3. H• Transfer from a Nickel Hydride
Chengbo Yao, Shuai Wang, Jack R. Norton, and Matthew Hammond
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Jan 2020
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R2
R2
F
2.5 mol% 1b
2 eq Me2NHBH3
F
eq 3
F
5
6
toluene, 80 oC
R1
R1
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H3C
H
H3C
H
H
H
CH3
O
CH3
O
O
O
O
O
O
O
CF2
O
H
H
H3C
H3C
9
gem-difluoromethylene
artemisinin
IC50 = 4.6 nM
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artemisinin
IC50 = 8.9 nM
H3C
O
OTDP
O
H3C
F2C
OTDP
O
HO
HO
OH
OH
recognized by TDP L-rhamnose synthase,
overrides conventional reduction
(TDP = thymidine diphosphate)
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F3C
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H
B
CF3
CF3
CF3
F3C
F3C
F3C
CH2Ph
CH2Ph
N
N
N
N
N
N
N Zr
O
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F3C
H3C
Pt
CH3
CH3
7
8
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2
a. function group interconversion
3
4
Julia(-Kocienski)
O
CF2
5
6
Wittig or Horner-Wadsworth-Emmons
reaction
R1
R2
R1
R2
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9
N2
CF2 carbene precursor
CF2
R2
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R1
R2
R
R1
Mg
F3C
F2C
R
reduction / elimination
X
b. SN2’ type
CF2
Nu = RMgX, RLi, R2NLi etc.
Nu
CF3
R
+
Nu
R
c. photocatalysis
4CzIPN, Ru or Ir complex
R RP
CF2
CF3
+
R
R
R
R
-
radical precursor RP = Si(OR)4 , BF3K, CO2H
d. Ni catalysis
CF2
CF3
+
cata. Ni
R RP
Zn
R
R
RP = X, OR, CO2NPhth etc.
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CH3
1
2
3
4
5
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7
N
Ni
F
C6D6, 50oC
N
Ni
H
F
+
eq 1
+
CF3
O
N
N
O
O
N
N
O
F
Ph
Ph
Ph
Ph
1b
2b
1a
2a
8
9
PhSiH3
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C6D6, 50oC
CH3
F
5 mol% 1a
F
eq 2
CF3
1 equiv PhSiH3
C6D6, rt, 24h
2a
2b
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Fluorine Atom Abstration Initiation
3
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CH3
F
F
F
3a
9
F
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4
Ni(Ⅰ)
1c
Ni(II)H
CF3
1a
2a
F
Ni(II)F
F
PhSiH3
1b
4
Hydrogen Atom Transfer Initiation
CF3
CF3
5
2a
Ni(Ⅰ)
1c
Ni(II)H
CF3
1a
5
F
Ni(II)F
1b
F
PhSiH3
3a
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F
5 mol% 1a
a)
b)
F
1 equiv PhSiH3
C6D6, 70oC, 24h
CF3
F
F
CF3
5 mol% 1a
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1 equiv PhSiH3
C6D6, 70oC, 24h
C2H5
5 mol% 1a
F
CF3
1 equiv PhSiH3
C6D6, 95oC, 10 days
F
c)
N
H3C
5 mol% 1a
O
+
CF3
1 equiv PhSiH3
C6D6, rt, 24h
73%
CF3
N
O
(3 eq)
6
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R
R
5 mol% 1a
1
2
3
4
F
1 equiv PhSiH3
C6D6, rt, 24h
Ar
Ar
2a-q
CF3
F
3a-q
5
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9
CH3
F
CH3
F
CH3
F
F
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F
F
MeS
3a, 88%
3c, 92%
3b, 91%
CH3
F
CH3
CH3
F
MeO
F
F
MeHN
F
F
HO2C
O
OMe
3d, 92%
CH3
3e, 96%
3f, 82%
F
F
CH3
F
F
F
N
(E/Z = 2:1)
3i, 77%c
CH3
3h, 75%b
CH3
3g, 90%
CH3
F
F
F
F
F
F
F
MeO2C
NC
3j, 80%
3k, 90%
3l, 86%
CH3
CH3
CH3
F
F
F
F
H
O
F
F
Me2N
O
3m, 86%
3n, 53%
3o, 50%
CH3
H2C
CH3
CH3
F
F
F
BnO2C
F
F
N
F
H3C
3r, 91%d
3p, 85%
3q, 85%
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CH3
F
5 mol% 1a
CF3
1 equiv PhSiH3
C6D6, rt, 24h
F
5
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2a
2b
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Catalyzing the Hydrodefluorination of CF3-substituted Alkenes by
PhSiH3. H• Transfer from a Nickel Hydride
Chengbo Yao1, Shuai Wang1†, Jack Norton1*, Matthew Hammond1
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1Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, United States.
ABSTRACT: The hydrodefluorination of CF3-substituted alkenes can be catalyzed by a nickel(II) hydride bearing a pincer
ligand. The catalyst loading can be as low as 1 mol%. gem-Difluoroalkenes containing a number of functional groups can be
formed in good to excellent yields, by a radical mechanism initiated by H• transfer from the nickel hydride. The relative reac-
tivity of various substrates supports the proposed mechanism, as does a TEMPO trapping experiment.
INTRODUCTION
carbonyl or diazo compounds (Scheme 1a).16-17 However,
these functional-group interconversion strategies typically
involve highly reactive intermediates or harsh reaction con-
ditions, limiting their substrate scope.
Fluorine chemistry is gaining increasing attention be-
cause of the importance of fluorine-containing compounds
in medicinal chemistry and agrochemistry.1-6 Among fluo-
rine-containing functional groups, gem-difluoroalkenes are
intriguing, contained in a series of biologically active com-
pounds,7-10 and well established as a bioisostere of car-
bonyl compounds with increased metabolic stability and
thus improved pharmaceutical performance.11-14 In the case
of artemisinin, the replacement of a carbonyl with a gem-
difluoralkene gives enhanced antimalarial activity. In some
cases, the gem-difluoroalkene moiety reverses the regiose-
lectivity of enzyme-catalyzed hydride reduction. (Figure 1)
gem-Difluoroalkenes can also serve as versatile building
blocks for the synthesis of other fluorine-containing mole-
cules.15-20
There are several ways in which gem difluoroalkenes can
be prepared from the readily available21-25 trifluoromethyl-
substituted alkenes. In one convergent approach, nucleo-
philic attack on a CF3 can lead to fluoride loss, but an SN2’
reaction with strong nucleophiles, such as Grignard rea-
gents or organolithium reagents, will suffer from poor func-
tional group tolerance (Scheme 1b). Recently, radical chem-
istry has been used for the synthesis of gem-difluoroal-
kenes, with defluorination of CF3 by either photocatalysis or
Ni catalysis (Scheme 1c, d).26-36
Figure 1. Representative applications of gem-difluoroalkenes.
The growing interest in the gem-difluoroalkene moiety
has led to a number of strategies for its preparation
(Scheme 1). The conventional approach relies on functional
group interconversion, i.e., the difluoromethylenation of
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Scheme 1. Typical synthetic routes to gem-difluoroalkenes.
1
2
3
Typical Ni-catalyzed defluorinations of trifluoromethyl
alkenes for the synthesis of gem-difluoroalkenes begin with
single electron transfer from the nickel to an alkyl radical
precursor. The resulting alkyl radical adds to another CF3
alkene, producing a new radical which is then quenched by
the formation of a Ni-C bond; β-F elimination gives the final
product. Other routes to functionalized gem-difluoroal-
kenes, such as alkenylation,37 arylation,38 and borylation,39
have also been reported.
4
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Scheme 2. Hydrodefluorination by PhSiH3 of ⍺-CF3 styrene
2a by isoPmBox Ni(II)-H 1a in a stoichiometric and a catalytic
manner.
In general C-F bond activation provides an easy approach
to the synthesis of partially fluorinated compounds from
40-41
readily available polyfluorinated species.15,
The sim-
Table 1 displays the scope of our reaction. Various sub-
stituents, either electron-donating or electron-withdraw-
ing, and different substitution patterns on the aromatic ring
are well tolerated. All the substrates give yields ranging
from good to near quantitative. No substantial amount of
hydrogenation products was observed for any of the sub-
strates, demonstrating a satisfying chemoselectivity. A thi-
oether 3c, an ether 3d, a tertiary amine 3m, and the het-
eroaromatic rings in 3g and 3p remain intact. Even the
acidic protons of an amide 3e or the carboxylic acid 3f do
not interfere with the reaction. An exocyclic gem-difluoro-
alkene 3h, and the 2,2-difluorostyrene 3r, can be obtained
from trisubstituted alkenes bearing a CF3 substituent, alt-
hough an elevated temperature is required. Interestingly,
only the E isomer of the starting material gives product,
with elevated temperature and extended reaction time,
while the Z isomer remains unreacted.53 A monofluoroal-
kene 3i can be obtained from an alkene bearing a difluoro-
methyl substituent. Nitrile 3j, ester 3k, ketone 3n, and alde-
hyde 3o, which are not compatible with Wittig or Julia-type
olefinations or with strong nucleophiles in SN2’-type reac-
tions, are all well tolerated by our method. Product 3l shows
that our reaction can achieve chemoselective activation of
the C-F bonds in trifluoromethyl alkenes without attacking
an aryl fluoride C–F bond. Other radical stabilizing groups,
like a carboalkoxy substituent, can also facilitate the reac-
tion, as shown by the formation of product 3q. Unfortu-
nately, the reaction does not work on CF3 alkenes with ali-
phatic substituents, even at elevated temperatures — a re-
sult that is to be expected from the mechanism we propose
below.
plest transformation of this sort, hydrodefluorination, has
attracted much attention and features a unique mechanistic
diversity.42-45 However, most hydrodefluorination reactions
promoted by transition metals are limited to aromatic or
olefinic C-F bonds and show little selectivity among such
bonds. The Hisaeda group has reported a (Co)B12-TiO2 hy-
brid catalyst for the photochemical hydrodefluorination of
substituted ⍺-CF3 styrenes,46 although a hydrogenation by-
product is always generated along with the gem-difluoroal-
kene. Zhang and his coworkers reported a copper-catalyzed
reductive defluorination of β-trifluoromethylated enones.47
However, the use of Grignard reagents limited its functional
group tolerance. Herein, we report that the iso-PmBox
Ni(II) hydride 1a can catalyze the synthesis of gem-difluoro-
alkenes by the hydrodefluorination of trifluoromethyl-sub-
stituted alkenes with silanes.
RESULTS AND DISCUSSION
The iso-PmBox nickel hydride system 1a was developed
by, and has been studied by, the Gade group.48 It is well es-
tablished that the Ni(II) hydride is in dynamic equilibrium
with Ni(I) metalloradical. The Ni(I) can abstract halides
from organic compounds and make Ni(II) halides, from
which Ni(II)-H can be regenerated with silanes and boron
hydrides.49-52
While investigating hydrogen atom transfer (HAT) from
1a, we found that it carried out the hydrodefluorination of
⍺-CF3 styrene 2a (Scheme 2). During that reaction the char-
acteristic 19F NMR resonance of the Ni(II)-F complex 1b was
observed at  –444.3.49 Moreover, the disappearance of 2a
(a 19F singlet at  –64.50) was accompanied by the appear-
ance of an ABX3 pattern centered at  –90.69 (2JF,F = 44.1Hz,
4JH,F = 3.3 Hz) belonging to the gem-difluoroalkene 3a. After
the addition of PhSiH3, the 19F peak of 1b disappeared and
the 1H NMR peak of 1a reappeared. (Et3SiH did not regener-
ate 1a.) Indeed, 1a was able to catalyze, in quantitative yield
(as determined by 19F NMR) at room temperature, the de-
hydrofluorination of 2a with a stoichiometric amount of
PhSiH3.
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Table 1. Substrate scope of the nickel-hydride-cata-
Page 16 of 20
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2
lyzed hydrodefluorination of trifluoromethyl-substi-
Table 2. Control Experiments
tuted alkenes.a
3
4
5
6
7
8
9
Entry
Deviation from “Standard Yielda
Condition”
10
11
12
13
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20
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1
2
3
None
>95%
< 5%
No 1a
20 mol% HCpCr(CO)3, or 20 < 5%
mol% HV(CO)4(dppe) in-
stead of 1a
4
5
1 mol% 1a, 72h
>95%
>95%
0.4 equiv PhSiH3
All reactions are performed on 0.5 mmol scale. aDetermined
by 19F-NMR
Two mechanisms for this reaction seem worth consider-
ing. One (shown in the top of Scheme 3) is similar to Gade’s
proposal for the hydrodefluorination (eq 3) of geminal
difluorocyclopropanes.49 The Ni(I) (complex 1c) may ab-
stract an F atom from the substrate 2a to form the Ni(II) flu-
oride 1b and the organic radical 4; H• transfer from the
Ni(II) hydride 1a will then give the product 3a and regener-
ate 1c, while the silane will reduce the fluoride 1b back to
the hydride 1a. The other possible mechanism (shown at
the bottom of Scheme 3) involves the sort of H• transfer to
olefins that we have used to generate radicals for cyclization
and isomerization.55-58 Transfer to the methylene of 2a from
the hydride 1a is expected,59-60 generating the organic radi-
cal 5 while leaving the Ni(I) complex 1c. Abstraction of an F
atom from 5 by 1c gives the product 3a and yields the Ni
fluoride 1b,61 which can be reduced by the silane back to
1a.
aIsolated yields, unless otherwise noted. b70 oC; c50 oC; d95
oC, 10 days, only from the E isomer of starting material. The
yield is determined by 19F NMR.
The control experiment in Table 2 (entry 2) shows that
the nickel hydride 1a is required for the reaction. Attempts
at replacing 1a with metal hydrides previously used in our
lab (entry 3), such as HCpCr(CO)3 and HV(CO)4(dppe) (dppe
= 1,2-bis(diphenylphosphino)ethane), have been unsuc-
cessful,54 so the reactivity of 1a is unique. The catalyst load-
ing can be reduced (entry 4) to 1 mol% without diminishing
the yield, although a longer reaction time is necessary. The
number of equivalents of PhSiH3 can be reduced without af-
fecting the yield (entry 5), which suggests that all three
silane hydrides can be used.
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The structure of 6 has been confirmed by single-
crystal X-ray diffraction (Figure 2).
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3
4
5
6
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9
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14
15
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17
Scheme 3. Two possible mechanisms initiated by fluorine
atom abstraction and hydrogen atom transfer respectively
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19
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27
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Figure 2. Molecular structure of TEMPO-adduct 6. Hydrogen
atoms are omitted for clarity.
The second mechanism is supported by several lines of
evidence. First, it explains why aliphatic alkenes do not
work (Scheme 4a), even at an elevated temperature. The
aryl group is essential for stabilizing the organic radical re-
sulting from HAT, given that CF3 is a radical destabilizing
group;62-63 however, the fluorine atom abstraction in the
first mechanism would not require an aryl substituent. Sec-
ond, the slow reaction of trisubstituted alkenes (in Scheme
4b) is more easily explained by the second mechanism —
using the established60, 64 effects of olefin substitution on the
rate of HAT to an olefin from a metal hydride. A methyl sub-
stituent on the carbon receiving the H• (in the second mech-
anism) is known to slow HAT by about three orders of mag-
nitude, while the rate of fluorine atom abstraction (in the
first mechanism) should not change much with the extra
substituent on carbon. Third, and the most conclusive, is the
successful trapping of the radical 5 by TEMPO (TEMPO,
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (Scheme 4c). The
addition of 3 equiv of TEMPO to the reaction results in the
formation of the TEMPO adduct 6 in 73% isolated yield.
CONCLUSION
gem-Difluoroalkenes with a variety of functional groups
can be generated by the nickel-hydride-catalyzed hydro-
defluorination of CF3 alkenes. The reaction is initiated by H•
transfer from Ni to the substrate. Trapping of the radical 5
with TEMPO demonstrates a new mechanism for the previ-
ously reported48 NNN-pincer nickel(I/II) system.
EXPERIMENTAL SECTION
General Procedures. All manipulations were carried out
in an inert atmosphere box (O2 < 1 ppm) or under Ar by
standard Schlenk techniques unless otherwise noted. Glass-
ware was oven-dried or flame-dried prior to use. All com-
mercial reagents were used as received without further pu-
rification unless specified. Deuterated benzene (C6D6) was
distilled from molten potassium & benzophenone ketyl.
Benzene (C6H6) and tetrahydrofuran (THF) were distilled
from sodium-benzophenone ketyl. isoPmbox-Ni(II)-H 1a48,
67
CpCr(CO)3H65, HV(CO)4(dppe)66 and Co(dmgBF2)2(THF)2
were synthesized according to the literature procedures and
stored in an argon atmosphere glovebox (O < 1 ppm). 1H NMR,
2
13C NMR and 19F NMR spectra were recorded using a Bruker
500 Ascend, DRX 500, DRX 400, or DRX 300 spectrometer.
Peaks are referenced relative to solvent residual peaks in
benzene-d6, THF-d8, CD3CN and CDCl3. The data are reported
as follows: chemical shift in parts per million from internal tet-
ramethylsilane on the δ scale, integration, multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
m = multiplet), and coupling constants (Hz). High-resolution
mass spectra were acquired on a Waters XEVO G2-XS QToF
mass spectrometer equipped with a UPC2 SFC inlet and a
LockSpray source with one of three probes: electrospray
ionization (ESI) probe, atmospheric pressure chemical ion-
ization (APCI) probe, or atmospheric pressure solids analy-
sis probe (ASAP). X- ray diffraction data were collected on a
Bruker Apex II diffractometer. Crystal data, data collection
and refinement parameters are summarized in Table S1.
Scheme 4. Evidences in favor of HAT-initiating mechanism
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Page 18 of 20
Corresponding Author
The structure was solved using direct methods and stand-
ard difference map techniques, and was refined by full-ma-
1
2
3
jrn11@columbia.edu (J. N.)
2
trix least-squares procedures on F with SHELXTL (Version
Present Addresses
2013/4). 68-70
4
5
6
7
8
9
†Shuai Wang: Department of Chemistry and Biochemis-
try, University of California, San Diego 9500 Gil-
man Drive Pacific Hall 4500, La Jolla, CA 92093
General Procedure of NiH Catalyzed Hydrodefluori-
nation. In an inert atmosphere glovebox, CF3 substituted al-
kenes (0.25 mmol or 0.5 mmol), PhSiH3 (1 equiv), and isoP-
mbox Ni(II)-H 1a (0.05 equiv) were weighed in a glass vial
and transferred to a J-Young tube using 1ml of dry and de-
gassed C6D6. The reaction was carried out at room temper-
ature for 24 hours unless otherwise noted. The crude reac-
tion mixture was directly subjected to flash column chroma-
tography for purification. Spectroscopic details of all the re-
action products can be found in the Supporting Information.
Orcid ID
Chengbo Yao: 0000-0003-4470-7414
Shuai Wang: 0000-0001-9464-6758
Jack Norton: 0000-0003-1563-9555
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Notes
The authors declare no competing financial interests.
Reaction with other metal hydrides. In an inert atmos-
phere glovebox, (1,1-difluoroprop-1-en-2-yl)benzene 2a
(0.25 mmol), PhSiH3 (0.25 mmol, 1 equiv), and HCpCr(CO)3
(10 mg, 0.05 mmol, 0.2 equiv), Co(dmgBF2)2(THF)2 (27 mg,
0.05 mmol, 0.2 equiv), or HV(CO)4(dppe) (28 mg, 0.05
mmol, 0.2 equiv) were weighed in a glass vial and trans-
ferred to a J-Young tube using 1ml of dry and degassed C6D6.
The reaction was carried out at room temperature for 24
ACKNOWLEDGEMENT
We thank Rebecca Wiles and Gary Molander for provid-
ing some of the CF3 alkenes (2b-2h in Table 1). Lutz Gade
and Chris Lorenc are acknowledged for helpful discus-
sions. Research reported in this publication was sup-
ported by the National Institute of General Medical Sci-
ences of the National Institutes of Health under Award
R01GM124295.
1
hours. Crude H NMR and 19F NMR were taken directly or
after silica plug.
TEMPO trapping experiment. In an inert atmosphere
glovebox, (1,1-difluoroprop-1-en-2-yl)benzene 2a (0.5
mmol), PhSiH3 (0.5 mmol, 1 equiv), TEMPO (1.5 mmol, 3
equiv) and isoPmbox Ni(II)-H 1a (0.025 mmol, 0.05 equiv)
were weighed in a glass vial and transferred to a J-Young
tube using 1ml of dry and degassed C6D6. The reaction was
carried out at room temperature for 144 hours. The reac-
tion conversion was 56%, 77% and 89% at 3 hours, 17
hours and 144 hours. The crude reaction mixture was di-
rectly subjected to flash column chromatography for purifi-
cation. Flash column chromatography was done using pure
hexane. Product was obtained with 73% yield.
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