Stereoselective Synthesis of Difluorinated 1,3-Dienes via Palladium-Catalyzed C-F Bond Activation of Tetrasubstituted gem-Difluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.1c01768

A highly diastereoselective Pd(0)-catalyzed synthesis of difluorinated 1,3-dienes is described. Symmetrical 1,3-dienes containing a vicinal difluoro moiety can be obtained as single diastereomers from tetrasubstituted gem-difluoroalkenes. The reaction presumably proceeds through a stereoselective twofold Pd-catalyzed Miyaura borylation/Suzuki-Miyaura cross-coupling of the C-F bond. Moreover, modular synthesis of unsymmetrical difluorinated 1,3-dienes is also achievable by the coupling between gem-difluoroalkenes and borylated monofluoroalkenes.

Full text of DOI:10.1021/acs.orglett.1c01768

pubs.acs.org/OrgLett
Letter
Stereoselective Synthesis of Difluorinated 1,3-Dienes via Palladium-
Catalyzed C−F Bond Activation of Tetrasubstituted gem-
Difluoroalkenes
Yanhui Wang,† Qiao Ma,† and Gavin Chit Tsui*
Cite This: Org. Lett. 2021, 23, 5241−5245
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A highly diastereoselective Pd(0)-catalyzed synthesis of difluori-
nated 1,3-dienes is described. Symmetrical 1,3-dienes containing a vicinal difluoro
moiety can be obtained as single diastereomers from tetrasubstituted gem-
difluoroalkenes. The reaction presumably proceeds through a stereoselective
twofold Pd-catalyzed Miyaura borylation/Suzuki−Miyaura cross-coupling of the
C−F bond. Moreover, modular synthesis of unsymmetrical difluorinated 1,3-
dienes is also achievable by the coupling between gem-difluoroalkenes and
borylated monofluoroalkenes.
onjugated 1,3-dienes are versatile building blocks that are
Cfrequently employed for the construction of carbo- and
heterocycles in Diels−Alder and pericyclic reactions toward
total synthesis.1,2 They are also important industrial feedstocks
for the production of polymers and are present in numerous
biologically active natural products and pharmaceutical
compounds. Less substituted 1,3-dienes can be synthesized
with stereocontrol via olefination and metathesis techniques.
However, with highly substituted 1,3-dienes, the synthetic
difficulty increases exponentially as the number of substituents
grows.3 Difluorinated 1,3-dienes with multiple substituents and
well-defined alkene geometry are extremely rare. Organo-
fluorine compounds play critical roles in drug discovery,
agrochemicals, and materials science.4 In particular, fluorinated
alkenes have the potential to act as amide bond isosteres and
enol mimics and therefore have found important applications
in pharmaceutical development and organic synthesis.5 Tradi-
tional methods for the synthesis of (Z,Z)- or (E,E)-difluoro-
1,3-dienes involved the stereospecific coupling of the C−Br
bond of (E/Z)-1-bromo-1-fluoroalkenes with bis(tributyltin)
or bis(pinacolato)diboron reagents.6 However, the preparation
of diastereomerically pure substrates was not trivial, and the
reactions could result in inseparable mixtures of E and Z
isomers.6a Also, the reactions were not completely selective,
generating small amounts of unavoidable (E,Z)-diene side
products.6b
assisted Pd(0)-catalyzed C−F bond functionalization of
tetrasubstituted gem-difluoroalkenes 1 for the synthesis of
stereodefined monofluoroalkenes (Scheme 1a).8 In the
presence of catalytic Pd(PPh3)4, cross-coupling between 1
and terminal alkynes,8a hydrosilanes,8b or boronic acids8c can
Scheme 1. Pd(0)-Catalyzed Stereoselective Synthesis of
Difluorinated 1,3-Dienes from Tetrasubstituted gem-
Difluoroalkenes via a Dual Catalytic Cycle
Selective cleavage and functionalization of C−F bonds of
abundant and inexpensive poly- or perfluorinated bulk
chemicals provides partially fluorinated products that might
be difficult or impossible to access by direct fluorination
methods. Therefore, the area of C−F bond activation has
attracted tremendous attention in recent years as a viable
strategy for obtaining valuable fluorinated molecules.7 Our
group recently discovered the highly stereoselective chelation-
Received: May 26, 2021
Published: June 11, 2021
https://doi.org/10.1021/acs.orglett.1c01768
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5241−5245
5241

Organic Letters
pubs.acs.org/OrgLett
Letter
take place selectively, affording (E)-monofluoroalkenes with
>99:1 diastereomeric ratio (d.r.). Herein we describe a novel
synthesis of symmetrical, fully substituted, vicinal difluoro-1,3-
dienes (E,E)-2 from 1 via a dual Pd catalytic cycle (Scheme
1b). The reaction design involves two Pd-catalyzed stereo-
selective C−F bond activation processes: (1) C−F bond
borylation to generate the borylated monofluoroalkene
intermediate as a coupling partner using a diboron reagent
[B−B] and (2) C−F bond cross-coupling of 1 with the in situ-
generated coupling partner. Both processes should be highly
selective, as otherwise a potentially inseparable mixture of
diastereomers, including (E,Z)-2 and (Z,Z)-2, would result.
Despite the enormous carbon−fluorine bond strength,
transition-metal-catalyzed aromatic C−F bond borylation has
been achieved for the synthesis of arylboronic esters from
fluoroarenes.7,9 With regard to alkenyl C−F bond borylation,
copper-catalyzed monodefluoroborylation of gem-difluoroal-
kenes has been most widely reported.10 The corresponding
borylated monofluoroalkenes could be obtained stereoselec-
tively, but no diene products were detected. We surmised that
a stereoselective twofold Pd-catalyzed Miyaura borylation
reaction11/Suzuki−Miyaura cross-coupling12 of gem-difluor-
oalkenes should be able to deliver the difluorinated 1,3-diene
products 2. To the best of our knowledge, Pd-catalyzed
borylation of gem-difluoroalkenes is unknown.13
(50 °C) caused a significant decrease in yield (Table 1, entries
1 and 2). A polar solvent such as DMF was less effective (57%
yield), while 1,4-dioxane gave comparable yield (85%). The
reaction did not occur in the absence of the Pd catalyst (Table
1, entry 3). Also, no product was obtained without the
borylation reagent B2pin2 (Table 1, entry 4). Using different
Pd catalysts such as PdII(OAc)2 or Pd0(dba)2 without the PPh3
ligand gave no conversion. However, adding PPh3 to these
catalysts (Pd:P = 1:4) restored the reactivity, thereby
highlighting the importance of the [Pd−PPh3] catalytic system
for this reaction (Table 1, entries 5−8). When the amount of
B2pin2 was increased, the yield was increased further (Table 1,
entry 9). Screening of borylation reagents revealed that
pinacolborane (HBpin)11b gave mostly hydrodefluorinated
products,8b while bis(catecholato)diboron (B2cat2) led to
decomposition (Table 1, entries 10 and 11). On the other
hand, bis(neopentylglycolato)diboron (B2nep2) was equally as
reactive as B2pin2 (Table 1, entry 12). In all cases, only one
product diastereomer, (E,E)-2a, was observed (d.r. > 99:1).
Next, a variety of tetrasubstituted gem-difluoroalkenes 115
containing (hetero)aryl substituent groups were subjected to
the developed conditions to explore the reaction scope
(Scheme 2). The corresponding symmetrical vicinal difluoro-
1,3-dienes 2a−i were successfully synthesized with excellent
diastereoselectivity (d.r. > 99:1 for E,E products). Electron-
neutral (2a, 2b) or -rich (2c) arenes provided reasonably good
We were delighted to find that in the presence of catalytic
Pd(PPh3)4 (10 mol %) and bis(pinacolato)diboron (B2pin2),
tetrasubstituted gem-difluoroalkene 1a afforded the 1,3-diene
product (E,E)-2a exclusively in good yield as a single
diastereomer (eq 1). Investigation of the reaction parameters
Scheme 2. Stereoselective Synthesis of Symmetrical
a
Difluorinated 1,3-Dienes
was subsequently carried out (Table 1).14 Lowering the
catalyst loading or running the reaction at a lower temperature
Table 1. Effects of Reaction Parameters on the Formation of
a
(E,E)-2a from 1a
Pd (x mol %)/ligand
(y mol %)
borylation reagent yield of (E,E)-2a
bc
,
entry
1
2
3
4
5
6
7
8
9
(equiv)
(%)
Pd(PPh3)4 (5)/−
Pd(PPh3)4 (10)/−
none
B2pin2 (1.5)
B2pin2 (1.5)
B2pin2 (1.5)
none
40
59
0
d
Pd(PPh3)4 (10)/−
Pd(OAc)2 (10)/−
Pd(OAc)2 (10)/PPh3 (40)
Pd(dba)2 (10)/−
Pd(dba)2 (10)/PPh3 (40)
Pd(PPh3)4 (10)/−
Pd(PPh3)4 (10)/−
Pd(PPh3)4 (10)/−
Pd(PPh3)4 (10)/−
0
B2pin2 (1.5)
B2pin2 (1.5)
B2pin2 (1.5)
B2pin2 (1.5)
B2pin2 (2.5)
HBpin (2.5)
B2cat2 (2.5)
B2nep2 (2.5)
0
85
0
82
90
0
10
11
12
0
91
a
Unless specified otherwise, reactions were carried out using 1a (0.1
mmol) in toluene (0.2 M) at 80 °C for 12 h under argon.
b
a
Determined by 19F NMR analysis using 4,4′-difluorobiphenyl as an
Isolated yields are shown. The diastereomeric ratios were
c
b
internal standard. The diastereomeric ratios were determined to be
determined to be >99:1 by 19F NMR analysis. Yield for the reaction
run on a 1.0 mmol scale.
d
>99:1 by 19F NMR analysis. The reaction was run at 50 °C.
5242
https://doi.org/10.1021/acs.orglett.1c01768
Org. Lett. 2021, 23, 5241−5245

Organic Letters
pubs.acs.org/OrgLett
Letter
yields. Electron-deficient arenes led to decreased yields due to
incomplete conversion (2d, 2e) and the formation of
hydrodefluorinated side products (2f).8b While fluoro (2e)
and chloro (2f) substituents were tolerated, the bromo
substrate gave no desired product. A heteroaromatic group
such as 3-thienyl (2g) was also compatible. Changing the ethyl
group of the ester moiety to benzyl provided the product in a
similar yield (2e vs 2h), but changing to a bulkier tert-butyl
group led to a very poor yield (ca. 11%). The biphenyl product
(2i) was obtained in good yield, and its X-ray crystal structure
unambiguously confirmed the (E,E)-diene configuration.
The reaction of benzyl-substituted gem-difluoroalkene 1j was
more sluggish under the standard conditions (53% 19F NMR
yield), but the use of a higher concentration (0.5 M) and
prolonged reaction time (24 h) led to a significantly improved
yield. The scope of benzylic difluorinated 1,3-dienes was
subsequently investigated under this set of conditions.
Naphthyl (2k) and biphenyl (2l) products were obtained
smoothly. Substituents at the para position of the benzene ring
were compatible, including sterically hindered tert-butyl (2m),
electron-donating methoxy (2n), and electron-withdrawing
trifluoromethyl (2o) groups. An aryl fluoride (2p) was
tolerated, showing a preference for the alkenyl C−F bond
activation of 1p over the aryl C−F bond activation. Sensitive
halogen groups such as aryl chloride (p-2q, o-2r) and bromide
(o-2s) remained intact, demonstrating the orthogonality of C−
F versus C−Br/Cl bond functionalization. The strong electron-
withdrawing nitro group (2t) at the meta position of the ring
gave a good yield. A dimethoxyarene (2u) and a difluoroarene
(2v) were compatible. The presence of a longer-chain alkyl
group (2w) or a benzyl ester substituent group (2x) did not
affect the reaction. Despite the varying electronic and steric
properties of the substituent groups, excellent diastereoselec-
tivities were obtained in all of the products (d.r. > 99:1). It is
noteworthy that the conjugated diester backbone of 2 belongs
to the family of muconic acid (MA) derivatives, which are
industrially important for the production of specialty
polymers.16
as (E,E)-3 could be obtained, albeit with poor efficiencies due
to the formation of competing homocoupling products.
On the other hand, the cross-coupling between 1a and (Z)-
5a, which was synthesized by stereoseletive Cu-catalyzed
monodefluoroborylation of β,β-difluorostyrenes,10,14 occurred
smoothly under the Pd catalytic conditions to afford the
unsymmetrical difluorinated 1,3-diene (E,Z)-6a in high yield as
a single diastereomer [(eq 2]. The geometries of the two
double bonds were confirmed by 19F−1H HOESY NMR
experiments.14 The excellent diastereoselectivity of the
reaction relied on two key criteria: stereoselective C−F bond
activation of 1a (selecting the C−F bond syn to the ester
moiety) and stereospecific cross-coupling of (Z)-5a (retaining
the Z alkene geometry).
By this strategy, a series of unsymmetrical difluorinated 1,3-
dienes (E,Z)-6 were successfully prepared (Scheme 4).
Borylated monofluoroalkenes 5 bearing different aromatic
substituent groups were coupled with difluoroalkene 1a in
moderate to good yields to give 6b−d.
Scheme 4. Stereoselective Synthesis of Unsymmetrical
a
Difluorinated 1,3-Dienes
Crossover experiments were carried out by mixing the
phenyl-sustituted substrate 1a with benzyl-substituted 1j (1:5
molar ratio) under the standard conditions (Scheme 3). The
Scheme 3. Crossover Experiments
a
Isolated yields are shown. Diastereomeric ratios (d.r.) were
b
determined by 19F NMR analysis. The reaction was run for 36 h.
unsymmetrical 1,3-diene (E,E)-3a was thus obtained in 32%
yield (22% isolated yield, d.r. > 99:1) along with smaller
amounts of unavoidable homocoupled products (E,E)-2a
(14%) and (E,E)-2j (20%). Optimization studies showed
that the yield of 3a increased as the amount of 1j increased but
reached a maximum at 5.0 equiv of 1j.14 Similarly, a mixture of
1a and 1c (1:1 molar ratio) afforded (E,E)-3b in 31% yield
(30% isolated yield, d.r. > 99:1) in almost equal proportion as
the homocoupled products (E,E)-2a (37%) and (E,E)-2c
(30%). Therefore, unsymmetrical difluorinated 1,3-dienes such
The structure of the product and the diene configuration
were verified by X-ray crystallography of compound 6d. A
modular approach was possible to synthesize compounds with
two electron-rich arenes (6e) or an electron-rich and an
electron-deficient arene (6f), which should be useful for SAR
studies in medicinal chemistry. Similarly, products containing a
benzyl group and an aryl group were obtainable (6g−i),
although longer reaction times were required. Excellent
diastereoselectivities were observed from the reactions, but
some of the arylated compounds (6d, 6e, 6f) underwent
5243
https://doi.org/10.1021/acs.orglett.1c01768
Org. Lett. 2021, 23, 5241−5245

Organic Letters
pubs.acs.org/OrgLett
Letter
alkene isomerization upon isolation.17 In comparison, the
alkene configuration was more stable in dienes 6g−i and 2.
Further studies were conducted to shed light on the reaction
mechanism (Scheme 5). Other [M−M] (M = Si, Sn) reagents,
5f).8a Adding B2pin2 to this complex led to the direct
formation of 1,3-diene product (E,E)-2a. Therefore, a
vinylpalladium(II) species analogous to Int-1 should be a
viable intermediate for the Miyaura borylation step in the
catalytic cycle.18
In conclusion, we have developed a Pd(0)-catalyzed
synthesis of difluorinated 1,3-dienes with excellent diaster-
eoselectivities. A variety of densely functionalized symmetrical
1,3-dienes containing a vicinal difluoro motif can be obtained
from tetrasubstituted β,β-difluoroacrylates via a stereoselective
twofold Miyaura borylation/Suzuki−Miyaura cross-coupling of
the C−F bond. Furthermore, unsymmetrical difluorinated 1,3-
dienes are also accessible through diastereoselective Pd-
catalyzed cross-coupling between tetrasubstituted gem-difluor-
oalkenes and borylated monofluoroalkenes.
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01768.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 2047492 and 2074260 contain 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, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Gavin Chit Tsui − Department of Chemistry, The Chinese
University of Hong Kong, Shatin, New Territories, Hong
Kong SAR, China; orcid.org/0000-0003-4824-8745;
Email: gctsui@cuhk.edu.hk
Authors
including hexamethyldisilane and bis(tributyltin), were inferior
compared with B2pin2, causing poor conversion and the
formation of side products, including α-CF3 and hydro-
defluorinated products (Scheme 5a).14 The β,β-difluorostyrene
(trisubstituted) derivative 4a afforded the monodefluorobory-
lated product in good yield using Cu(OAc)/Xantphos as the
catalyst and B2pin2,10b but no such product was generated from
tetrasubstituted gem-difluoroalkene 1a under identical con-
ditions (also no 1,3-diene product 2a), possibly because of
decomposition of the starting material under the basic
conditions (Scheme 5b). Two control experiments demon-
strated the importance of the vinylic ester moiety for C−F
bond activation: compound 4a was unreactive under the
standard Pd conditions (Scheme 5c), and cross-coupling
between 4a and (Z)-5a also did not take place (Scheme 5d).
A competition experiment using 1a with both vinyl Bpin
compound (Z)-5a and B2pin2 was carried out (Scheme 5e).
The cross-coupled product (E,Z)-6a was obtained predom-
inantly, with only a trace amount of the diene product (E,E)-
2a. This suggested that the Suzuki−Miyarura cross-coupling
occurs much faster than the Miyaura borylation under the
standard conditions. The stoichiometric reaction between 1a
and Pd(PPh3)4 yielded the monofluorovinylpalladium(II)
iodide complex Int-1, which was stable and isolable (Scheme
Yanhui Wang − Department of Chemistry, The Chinese
University of Hong Kong, Shatin, New Territories, Hong
Kong SAR, China
Qiao Ma − Department of Chemistry, The Chinese University
of Hong Kong, Shatin, New Territories, Hong Kong SAR,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01768
Author Contributions
†Y.W. and Q.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council of
Hong Kong (N_CUHK403/20) and the Chinese University of
Hong Kong (Faculty of Science - Direct Grant for Research).
We are also thankful for funding from the Key Laboratory of
Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
5244
https://doi.org/10.1021/acs.orglett.1c01768
Org. Lett. 2021, 23, 5241−5245

Organic Letters
pubs.acs.org/OrgLett
Letter
Soc. 2017, 139, 12855−12862. (b) Zhang, J.; Dai, W.; Liu, Q.; Cao, S.
Cu-Catalyzed Stereoselective Borylation of gem-Difluoroalkenes with
B2pin2. Org. Lett. 2017, 19, 3283−3286. (c) Tan, D.-H.; Lin, E.; Ji,
W.-W.; Zeng, Y.-F.; Fan, W.-X.; Li, Q.; Gao, H.; Wang, H. Copper-
Catalyzed Stereoselective Defluorinative Borylation and Silylation of
gem-Difluoroalkenes. Adv. Synth. Catal. 2018, 360, 1032−1037.
(d) Ito, H.; Seo, T.; Kojima, R.; Kubota, K. Copper(I)-Catalyzed
Stereoselective Defluoroborylation of Aliphatic gem-Difluoroalkenes.
Chem. Lett. 2018, 47, 1330−1332. (e) Kojima, R.; Kubota, K.; Ito, H.
Stereodivergent Hydrodefluorination of gem-Difluoroalkenes: Selec-
tive Synthesis of (Z)- and (E)-Monofluoroalkenes. Chem. Commun.
2017, 53, 10688−10691. (f) Hu, J.; Han, X.; Yuan, Y.; Shi, Z.
Stereoselective Synthesis of Z Fluoroalkenes Through Copper-
Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water.
Angew. Chem., Int. Ed. 2017, 56, 13342−13346. (g) Hu, J.; Zhao, Y.;
Shi, Z. Highly Tunable Multi-Borylation of gem-Difluoroalkenes via
Copper Catalysis. Nat. Catal. 2018, 1, 860−869. (h) Yan, S.-S.; Wu,
D.-S.; Ye, J.-H.; Gong, L.; Zeng, X.; Ran, C.-K.; Gui, Y.-Y.; Li, J.; Yu,
D.-G. Copper-Catalyzed Carboxylation of C-F Bonds with CO2. ACS
Catal. 2019, 9, 6987−6992.
(11) (a) Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-
Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloar-
enes: A Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995,
60, 7508−7510. (b) Murata, M.; Watanabe, S.; Masuda, Y. Novel
Palladium(0)-Catalyzed Coupling Reaction of Dialkoxyborane with
Aryl Halides: Convenient Synthetic Route to Arylboronates. J. Org.
Chem. 1997, 62, 6458−6459. Review: (c) Chow, W. K.; Yuen, O. Y.;
Choy, P. Y.; So, C. M.; Lau, C. P.; Wong, W. T.; Kwong, F. Y. A
Decade Advancement of Transition Metal-Catalyzed Borylation of
Aryl Halides and Sulfonates. RSC Adv. 2013, 3, 12518−12539.
(12) Reviews: (a) Miyaura, N.; Suzuki, A. Palladium-Catalyzed
Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev.
1995, 95, 2457−2483. (b) Suzuki, A. Cross-Coupling Reactions of
Organoboranes: An Easy Way to Construct C-C Bonds (Nobel
Lecture). Angew. Chem., Int. Ed. 2011, 50, 6722−6737.
REFERENCES
■
(1) (a) De Paolis, M.; Chataigner, I.; Maddaluno, J. Recent
Advances in Stereoselective Synthesis of 1,3-Dienes. Top. Curr. Chem.
2012, 327, 87−146. (b) Mehta, G.; Prakash, H. S. R. Synthesis of
Conjugated Dienes and Polyenes. In Patai’s Chemistry of Functional
Groups; Rappoport, Z., Ed.; Wiley: Chichester, U.K., 1997. (c) Hubert,
P.; Seibel, E.; Beemelmanns, C.; Campagne, J.-M.; de Figueiredo, R.
M. Stereoselective Construction of (E,Z)-1,3-Dienes and Its
Application in Natural Product Synthesis. Adv. Synth. Catal. 2020,
362, 5532−5575.
(2) Houk, K. N. Frontier Molecular Orbital Theory of Cycloaddition
Reactions. Acc. Chem. Res. 1975, 8, 361−369.
(3) For recent breakthroughs on the stereoselective synthesis of
highly substituted 1,3-dienes, see: (a) Zhou, Z.; Chen, J.; Chen, H.;
Kong, W. Stereoselective Synthesis of Pentasubstituted 1,3-Dienes via
Ni-Catalyzed Reductive Coupling of Unsymmetrical Internal Alkynes.
Chem. Sci. 2020, 11, 10204−10211. (b) Liu, J.; Yang, J.; Baumann,
W.; Jackstell, R.; Beller, M. Stereoselective Synthesis of Highly
Substituted Conjugated Dienes via Pd-Catalyzed Carbonylation of
1,3-Diynes. Angew. Chem., Int. Ed. 2019, 58, 10683−10687.
(4) (a) In 2019, more than a quarter of all drugs approved by the
U.S. Food and Drug Administration (14 out of 48) contained
fluorine. See: de la Torre, B. G.; Albericio, F. The Pharmaceutical
Industry in 2019. An Analysis of FDA Drug Approvals from the
Perspective of Molecules. Molecules 2020, 25, 745−757. (b) Ojima, I.
Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell:
Chichester, U.K., 2009. (c) Tsui, G. C.; Hu, J.-B. Organofluorine
Chemistry. Asian J. Org. Chem. 2019, 8, 566−567.
(5) Selected reviews: (a) Drouin, M.; Hamel, J.-D.; Paquin, J.-F.
Synthesis of Monofluoroalkenes: A Leap Forward. Synthesis 2018, 50,
881−955. (b) Yanai, H.; Taguchi, T. Synthetic Methods for
Fluorinated Olefins. Eur. J. Org. Chem. 2011, 2011, 5939−5954.
(6) Seminal reports: (a) Xu, J.; Burton, D. J. Stereospecific
Preparation of Symmetrical (1Z,3Z) 2,3-Difluoro-1,4-Disubstituted-
Buta-1,3-Dienes by the Coupling Reaction Between Bis(tributyltin)
and High E/Z 1-Bromo-1-Fluoroalkenes. Tetrahedron Lett. 2002, 43,
4565−4567. (b) Eddarir, S.; Rolando, C. J. Regiospecific Synthesis of
Symmetrical (1E,3E) 2,3-Difluoro-1,4-Diphenyl-Buta-1,3-Dienes via
Palladium-Catalyzed Cross-Coupling of (Z) 2-Bromo-2-Fluoroethe-
nylbenzenes in Presence of Bis(pinacolato)diboron. J. Fluorine Chem.
2004, 125, 377−380.
(7) Selected reviews: (a) Amii, H.; Uneyama, K. C-F Bond
Activation in Organic Synthesis. Chem. Rev. 2009, 109, 2119−2183.
(b) Fujita, T.; Fuchibe, K.; Ichikawa, J. Transition-Metal-Mediated
and -Catalyzed C-F Bond Activation by Fluorine Elimination. Angew.
Chem., Int. Ed. 2019, 58, 390−402. (c) Zhang, X.; Cao, S. Recent
Advances in the Synthesis and C-F Functionalization of gem-
Difluoroalkenes. Tetrahedron Lett. 2017, 58, 375−392.
(13) For a rare example of Pd-catalyzed borylation of aryl C−F
bonds, see: Zhao, X.; Wu, M.; Liu, Y.; Cao, S. LiHMDS-Promoted
Palladium or Iron-Catalyzed ipso-Defluoroborylation of Aryl Fluo-
rides. Org. Lett. 2018, 20, 5564−5568.
(14) See the Supporting Information for full details.
(15) (a) Hu, M.; Ni, C.; Li, L.; Han, Y.; Hu, J. gem-
Difluoroolefination of Diazo Compounds with TMSCF3 or
TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene
Precursors. J. Am. Chem. Soc. 2015, 137, 14496−14501. (b) Zheng, J.;
Lin, J.-H.; Yu, L.-Y.; Wei, Y.; Zheng, X.; Xiao, J.-C. Cross-Coupling
between Difluorocarbene and Carbene-Derived Intermediates Gen-
erated from Diazocompounds for the Synthesis of gem-Difluoroole-
fins. Org. Lett. 2015, 17, 6150−6153.
(16) Khalil, I.; Quintens, G.; Junkers, T.; Dusselier, M. Muconic
Acid Isomers as Platform Chemicals and Monomers in the Biobased
Economy. Green Chem. 2020, 22, 1517−1541.
(17) We observed that (E,Z)-6a was prone to alkene isomerization
after prolonged storage at room temperature, possibly to the (E,E)
isomer. The isomerization can be promoted by light, presumably via a
radical mechanism. See the Supporting Information for 19F NMR
studies of the isomerization of (E,Z)-6a.
(8) (a) Ma, Q.; Wang, Y.; Tsui, G. C. Stereoselective Palladium-
Catalyzed C-F Bond Alkynylation of Tetrasubstituted gem-Difluor-
oalkenes. Angew. Chem., Int. Ed. 2020, 59, 11293−11297. (b) Ma, Q.;
Liu, C.; Tsui, G. C. Palladium-Catalyzed Stereoselective Hydro-
defluorination of Tetrasubstituted gem-Difluoroalkenes. Org. Lett.
2020, 22, 5193−5197. (c) Wang, Y.; Qi, X.; Ma, Q.; Liu, P.; Tsui, G.
C. Stereoselective Palladium-Catalyzed Base-Free Suzuki-Miyaura
Cross-Coupling of Tetrasubstituted gem-Difluoroalkenes: An Exper-
imental and Computational Study. ACS Catal. 2021, 11, 4799−4809.
(9) Representative examples: (a) Liu, X. W.; Echavarren, J.; Zarate,
C.; Martin, R. Ni-Catalyzed Borylation of Aryl Fluorides via C-F
Cleavage. J. Am. Chem. Soc. 2015, 137, 12470−12473. (b) Niwa, T.;
Ochiai, H.; Watanabe, Y.; Hosoya, T. Ni/Cu-Catalyzed Defluorobor-
ylation of Fluoroarenes for Diverse C-F Bond Functionalizations. J.
Am. Chem. Soc. 2015, 137, 14313−14318. (c) Guo, W.-H.; Min, Q.-
Q.; Gu, J.-W.; Zhang, X.-G. Rhodium-Catalyzed ortho-Selective C-F
Bond Borylation of Polyfluoroarenes with Bpin-Bpin. Angew. Chem.,
Int. Ed. 2015, 54, 9075−9078.
(18) See the Supporting Information for detailed discussion of the
dual Pd catalytic cycle.
(10) (a) Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.;
Hosoya, T. Copper-Catalyzed Regioselective Monodefluoroborylation
of Polyfluoroalkenes en Route to Diverse Fluoroalkenes. J. Am. Chem.
5245
https://doi.org/10.1021/acs.orglett.1c01768
Org. Lett. 2021, 23, 5241−5245