Palladium-Catalyzed Stereoselective Hydrodefluorination of Tetrasubstituted gem-Difluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.0c01813

A highly stereoselective palladium(0)-catalyzed hydrodefluorination (HDF) of tetrasubstituted gem-difluoroalkenes is developed. By using catalytic Pd(PPh3)4 (2.5-5 mol percent) and hydrosilane Me2PhSiH, various trisubstituted terminal (E)-monofluoroalkenes can be synthesized with excellent E/Z selectivity (>99:1) and good functional group tolerability. The key stereocontrol should be exerted by an ester-directed C-F bond oxidative addition step in the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.0c01813

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Stereoselective Hydrodefluorination of
Tetrasubstituted gem-Difluoroalkenes
Qiao Ma, Caroline Liu, and Gavin Chit Tsui*
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ABSTRACT: A highly stereoselective palladium(0)-catalyzed hydrodefluori-
nation (HDF) of tetrasubstituted gem-difluoroalkenes is developed. By using
catalytic Pd(PPh3)4 (2.5−5 mol %) and hydrosilane Me2PhSiH, various
trisubstituted terminal (E)-monofluoroalkenes can be synthesized with
excellent E/Z selectivity (>99:1) and good functional group tolerability. The
key stereocontrol should be exerted by an ester-directed C−F bond oxidative
addition step in the catalytic cycle.
Scheme 1. Stereoselective Hydrodefluorination (HDF) of
Trisubstituted versus Tetrasubstituted gem-Difluoroalkenes
he growing demand for introducing fluorine into new
materials, pharmaceuticals, and agrochemicals has inspired
T
the development of diverse synthetic strategies.1 To achieve the
goal of efficient synthesis of fluorinated molecules, a dichotomy
of approaches can be found: (1) formation of C−F bonds and
(2) selective cleavage and functionalization of C−F bonds. The
former approach has received tremendous attention culminating
in the successful development of various electrophilic,
nucleophilic, and radical fluorination techniques.2 The latter
approach, C−F bond activation, however, is considered a major
challenge in organic synthesis.3 Poly- or perfluorinated bulk
chemicals are readily available on an industrial scale, and
selective C−F bond functionalization can provide partially
fluorinated products that may be difficult to obtain by direct
fluorination methods.
Hydrodefluorination (HDF), the conversion of a C−F bond
into a C−H bond, is the simplest form of C−F bond activation
yet with unique mechanistic diversity.4 While transition-metal-
catalyzed HDF of polyfluoroarenes has been well-established
with detailed mechanistic investigations, the corresponding
HDF of gem-difluoroalkenes, which can provide valuable
terminal monofluoroalkenes, has been much less explored. A
key application of monofluoroalkenes is their potential as
peptide bond isosteres in drug discovery.1b,5 Literature reports
have dealt with HDF of trisubstituted gem-difluoroalkenes6 to
address the important issue of stereoselectivity for obtaining
either (E)- or (Z)-1,2-disubstituted monofluoroalkenes
(Scheme 1).7 In the transition-metal-free example, Red-Al has
been employed as a hydride source to undergo an addition/
elimination pathway with gem-difluoroalkenes resulting in the
(E)-product (Scheme 1a).7a,b,8 Examples of transition-metal-
catalyzed HDF of gem-difluoroalkenes are very rare; Ito et al. and
Shi et al. independently reported the copper(I)-catalyzed HDF
for obtaining the (Z)-product (Scheme 1b).7c,d The reaction
relies on the migratory insertion of double bond to the Cu−B
bond followed by β-F elimination to give the (Z)-vinylboron
intermediate. Analogously, insertion of a double bond in the
Cu−H bond (H from hydrosilane) followed by β-F elimination
affords the (E)-product directly, as reported by Ito et al.
(Scheme 1c).7c The crucial stereocontrol in the β-F elimination
step is based on either the electronic repulsion between the F and
R group or the steric repulsion between Bpin and the R group.9
Received: May 29, 2020
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© XXXX American Chemical Society
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Despite the high carbon−fluorine bond dissociation energy
The reaction scope was subsequently investigated using alkyl-
substituted substrates 1a−t under standard conditions (Scheme
2). In all cases, only the (E)-product was obtained as a single
(BDE) of approximately 500
50 kJ/mol,10 palladium-
catalyzed HDF of polyfluoroarenes through oxidative addition
of the C−F bond is known.4,11 On the contrary, no report of Pd-
catalyzed HDF of gem-difluoroalkenes exists in the literature to
date. Zhang et al. described an intriguing ortho-selective Pd-
catalyzed HDF of polyfluoroarenes using N-heterocycles as
directing groups (DGs).11a We envisioned that a chelation-
assisted C−F bond oxidative addition could be applied to
tetrasubstituted gem-difluoroalkenes creating a stereodifferen-
tiation in the two C−F bonds that would be difficult to achieve
by electronic or steric repulsion (Scheme 1b).12 We herein
report the first Pd-catalyzed stereoselective HDF of tetrasub-
stituted gem-difluoroalkenes based on this hypothesis.
Scheme 2. Hydrodefluorination of Alkyl-Substituted gem-
a
Difluoroalkenes
The tetrasubstituted gem-difluoroalkene 1a containing a
vinylic ester group as a potential directing group was
conveniently synthesized from the corresponding diazo
precursor.13 By using dimethylphenylsilane as the “H source”
with only 5 mol % of tetrakis(triphenylphosphine)palladium(0)
catalyst upon heating at 80 °C, we were able to observe full
conversion of 1a to the hydrodefluorinated product 2a as a
single (E)-isomer (Table 1, entry 1). The reaction parameters
Table 1. Effects of Reaction Parameters
a
yield
entry
variation from the “standard” conditions
(%)
b
1
2
3
4
5
6
7
8
9
none
99
a
Ph2MeSiH or Et2SiH2, instead of Me2PhSiH
Ph3SiH, instead of Me2PhSiH
Et3SiH, instead of Me2PhSiH
HBpin, instead of Me2PhSiH
2.5 mol % of Pd(PPh3)4
50 °C
99
94
83
General conditions: 1 (0.2 mmol), Me2PhSiH (0.4 mmol), toluene
(0.8 mL), under argon. Isolated yields. E/Z > 99:1 as determined by
b
c
GC−MS and 19F NMR analyses. 2.4 mmol scale. Reaction was run
d
c
at 120 °C in DMF. 48 h.
57
86
10
77
0
diastereomer. The (E)-alkene geometry of compound 2b was
further confirmed by 19F−1H HOESY NMR experiments.14
Benzyl-substituted products 2c−m displayed excellent func-
tional group tolerability. Substituents at the para position of the
benzene ring including bulky tert-butyl (2c), electron-donating
methoxy (2d), and electron-withdrawing trifluoromethyl (2e),
fluoro (2f), and chloro (2g) were compatible. Other functional
groups such as nitro (2i) and cyano (2j) at the meta position and
ester (2k) at the ortho position were also shown to be
compatible. Disubstituted aryl (2l and 2m) and naphthyl (2n)
systems gave good yields. Variations of the vinylic ester
substituent group, including tert-butyl (2o) and benzyl (2p),
did not lead to drastic changes in yield and E/Z selectivity.
Longer chain linear alkyl-substituted products 2q−s were also
obtained; some required a higher reaction temperature in DMF
(2r−s). The lower yield for product 2r was due to its lower
boiling point. Reaction at a larger scale (2.4 mmol) also provided
product 2a (0.44 g) in good yield. X-ray crystallography
unambiguously confirmed the structure and (E)-alkene
configuration of the biphenyl-containing product 2t.
1.2 equiv of Me2PhSiH
no Pd(PPh3)4
10
[PdCl(allyl)]2 (2.5 mol %), Pd(OAc)2 (5 mol %), or Pd(dba)2
(5 mol %), instead of Pd(PPh3)4
[PdCl(allyl)]2 (2.5 mol %)/PPh3 (20 mol %), Pd(OAc)2
(5 mol %)/PPh3 (20 mol %), or Pd(dba)2 (5 mol %)/PPh3
(20 mol %), instead of Pd(PPh3)4
0
11
99
a
b
GC yield. E/Z > 99:1 as determined by GC−MS and 19F NMR
analyses. E/Z = 33:1.
c
were carefully screened, and some important trends are
highlighted in Table 1.14 Among the tested hydrosilanes,
Ph2MeSiH and Et2SiH2 were equally effective while Ph3SiH and
Et3SiH were less reactive (Table 1, entries 2−4). On the other
hand, using HBpin11e led to a significant decrease in yield (Table
1, entry 5). Lower catalyst loading, lower reaction temperature,
and lower equivalents of hydrosilane all caused a decrease in
yield (Table 1, entries 6−8). No reaction occurred without the
Pd catalyst (Table 1, entry 9). Other Pd catalysts including
Pd(II) complexes such as [PdCl(allyl)]2 and Pd(OAc)2 or a
Pd(0) complex such as Pd(dba)2 were completely unreactive
(Table 1, entry 10). However, adding PPh3 ligand to the above
catalysts (Pd/P = 1:4) increased the reactivity dramatically
(Table 1, entry 11). Apart from the result of using HBpin (Table
1, entry 5), we did not detect the formation of (Z)-isomer during
the optimization studies.14
When the previous “standard” conditions were applied to the
phenyl-substituted substrate 1u, we only observed 58% GC yield
of the desired product (E)-2u, along with unreacted starting
materials and inseparable “over-reduced” side products 2u′ and
2u″ (Scheme 3). Extensive screenings of reaction parameters
were subsequently carried out to reoptimize the conditions for
improving the yield of 2u while minimizing side-product
B
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Scheme 3. Yield-Enhancing Effect of Adding Catalytic TsN3
Scheme 5. Further Studies
at Room Temperature
formation.14 We found that the reactions gave significant
amounts of over-reduction products at higher temperatures, yet
the conversions were very poor at lower temperatures (e.g., 5%
yield at 23 °C). The solution to this dilemma was narrowed
down to the use of additives, in particular, an organic azide TsN3
in catalytic amounts. A unique combination of as low as 2.5 mol
% Pd(PPh3)4 and 5 mol % TsN3 at room temperature allowed
full conversion of 1u to product 2u as a single (E)-isomer with a
clean reaction profile.
With the new set of conditions in hand, a variety of
(hetero)aryl-substituted hydrodefluorinated products were
successfully synthesized in good to excellent yields (Scheme
4). Electron-rich (2v) or -poor (2z) aryl substituents, biphenyl
stereocontrol by tetrasubstituted gem-difluoroalkenes 1 based
on electronic/steric repulsion7a,b,8 is not sufficient compared to
the stereocontrol exerted by the Pd-catalyzed pathway (E/Z >
99:1). Reported copper-catalyzed conditions7c were not
applicable to 1a, resulting in poor yields and inferior
stereoselectivity (Scheme 5b,c). We suspect that the tetrasub-
stituted alkenes 1 are less reactive toward migratory insertion of
Cu−B/H and the use of base might cause substrate
decomposition. Using Me2PhSiD led to deuterated (E)-2a,
proving that hydrosilane is the H source (Scheme 5d).
Scheme 4. Hydrodefluorination of (Hetero)aryl-Substituted
a
gem-Difluoroalkenes
Through NMR studies, we observed the formation of Pd(II)
intermediate Int-1 (19F NMR: −25.34 ppm, broad triplet, J =
16.9 Hz; 31P NMR: 19.55 ppm, doublet, J = 16.6 Hz) as a single
diastereomer from the stoichiometric reaction between 1a and
Pd(PPh3)4 in the presence of NaI (eq 1).14,15 Adding Me2PhSiH
to Int-1 followed by heating at 80 °C provided full conversion to
product (E)-2a (eq 2). Furthermore, we separately prepared a
well-characterized Pd(II) complex Int-212 and added
Me2PhSiH to it, affording product (E)-2u in 90% yield (eq 3).
These results show that a Pd(II) complex similar to Int-1/Int-2,
which should be formed upon stereoselective C−F bond
oxidative addition, is a viable intermediate for the product.
a
General conditions: 1 (0.2 mmol), Me2PhSiH (0.4 mmol), toluene
(0.8 mL), under argon. Isolated yields. E/Z > 99:1 as determined by
GC−MS and 19F NMR analyses.
(2ad), naphthyl (2ae), and thienyl (2af) groups were tolerated.
The results from products 2v−x showed that the ester
substituent group, including a sterically encumbering isopropyl
group (2x), did not significantly affect the yield and E/Z
selectivity. There was no sign of aryl C−F bond activation in 2z
(versus vinyl C−F bond). Furthermore, aryl bromide (2ac), a
well-known cross-coupling partner in Pd(0) catalysis, remained
intact, underscoring the orthogonal C(vinyl)−F bond vs
C(aryl)−Br bond functionalization. The (E)-alkene geometry
of compound 2u was confirmed by 19F−1H HOESY NMR
experiments.14
A series of experiments were conducted to shed light on
mechanistic understanding of the Pd-catalyzed HDF reaction of
1 (Scheme 5). Under the Pd-free conditions using NaBH4 as the
hydride source (Scheme 5a), a mixture of E/Z products was
obtained in 4:1 ratio. This result indicates that the intrinsic
On the basis of the above studies and literature reports, the
following plausible catalytic cycle for Pd-catalyzed stereo-
selective HDF of tetrasubstituted gem-difluoroalkene 1 is
proposed (Scheme 6). The ester functionality of difluoroalkene
1 serves as a directing group (DG) by chelation to the Pd center
(species A).16 Stereodifferentiating C−F bond oxidative
C
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Scheme 6. Proposed Catalytic Cycle
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01813.
Experimental procedures, detailed mechanistic studies,
characterization data, crystallographic data, 1H NMR, 13C
NMR, and 19F NMR spectra for all new products (PDF)
Accession Codes
CCDC 1994409 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
addition to Pd(0) affords the monofluorovinylpalladium(II)
fluoride intermediate B as a single diastereomer.12 The existence
of B is supported by the above NMR and complex studies (cf.
eqs 1−3). Reaction of B with hydrosilane, a fluorophilic
reductant, generates the Pd(II) hydrido complex C.11a The
formation of thermostable Si−F bond provides the key driving
force,17 which also streamlines the reaction since no external
bases are needed to activate the hydrosilane.18 Finally, reductive
elimination of C releases the monofluoroalkene product 2 in an
E-configuration as well as regenerates the Pd(0) catalyst.
The yield-enhancing effect of adding an organic azide was
worth investigating since it has been rarely described in Pd
catalysis (cf. Schemes 3 and 4). We monitored the interaction
between Pd(PPh3)4 and TsN3 (Pd/azide = 1:2) by 31P NMR
over time (see the Supporting Information). The reaction
quickly produced the N-tosyl iminophosphorane (TsN =
PPh3),19a,b presumably via a Staudinger-type reaction19c
between TsN3 and the ligand PPh3 of Pd(PPh3)4. A new Pd−
P signal was also observed, which was believed to be
bis(triphenylphosphine)palladium(0) “Pd(PPh3)2”.20 The
two-coordinate Pd(PPh3)2 was very reactive toward oxidative
addition with iodobenzene to afford PhPd(PPh3)2I quantita-
tively. It also reacted with gem-difluoroalkene 1u to produce a
characteristic side product α-trifluoromethyl ester, via C−F
bond oxidative addition intermediate B (cf. Scheme 6). This
evidence supported that, at room temperature, azide reacts with
the triphenylphosphine ligand of Pd(PPh3)4 to create a
coordinatively unsaturated Pd(PPh3)2, which is the active
species for the C−F bond oxidative addition step. Such
“activation” of Pd catalyst is important for (hetero)aryl-
substituted substrates 1u−af since at higher temperature (e.g.,
80 °C) over-reduction products started to appear. On the other
hand, alkyl-substituted substrates 1a−t (cf. Scheme 2) were not
prone to over-reduction at 80 °C, and Pd(PPh3)4 might be in
equilibrium with Pd(PPh3)2 at this temperature, thus making
azide additive unnecessary.
AUTHOR INFORMATION
Corresponding Author
■
Gavin Chit Tsui − Department of Chemistry, The Chinese
University of Hong Kong, New Territories, Hong Kong SAR;
orcid.org/0000-0003-4824-8745; Email: gctsui@
cuhk.edu.hk
Authors
Qiao Ma − Department of Chemistry, The Chinese University of
Hong Kong, New Territories, Hong Kong SAR
Caroline Liu − Department of Chemistry, The Chinese University
of Hong Kong, New Territories, Hong Kong SAR
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01813
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council of
Hong Kong (CUHK 24301217) and the Chinese University of
Hong Kong (the Faculty Strategic Fund for Research from the
Faculty of Science and the Direct Grant for Research). We also
thank the Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, for funding.
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