Stereoselective Synthesis of Terminal Monofluoroalkenes from Trifluoromethylated Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c01701

Herein we report the hydrodefluorination reaction of trifluoromethylated alkenes to access terminal monofluoroalkenes. The use of LiAlH4 allowed the stereoselective synthesis of the terminal monofluoroalkenes in good to excellent yields with good to excel

Full text of DOI:10.1021/acs.orglett.0c01701

pubs.acs.org/OrgLett
Letter
Stereoselective Synthesis of Terminal Monofluoroalkenes from
Trifluoromethylated Alkenes
Pauline Poutrel, Xavier Pannecoucke, Philippe Jubault,* and Thomas Poisson*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01701
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein we report the hydrodefluorination reaction of
trifluoromethylated alkenes to access terminal monofluoroalkenes. The
use of LiAlH4 allowed the stereoselective synthesis of the terminal
monofluoroalkenes in good to excellent yields with good to excellent
diastereoselectivities. Mechanistic studies suggested a hydroalumina-
tion reaction followed by a stereoselective fluoride elimination.
Therefore, the development of straightforward methods to
access terminal monofluoroalkenes in a stereoselective manner
has attracted much interest (Figure 2).4 Among the reported
luorine is one of the most intriguing atoms in the periodic
Ftable. The intrinsic properties of the fluorine atom such as
its electronegativity and small radius, for instance, provide
specific physicochemical properties to organofluorine com-
pounds.1 Its introduction on a molecule can drastically change
the metabolic profile, the lipophilicity, the conformation, or the
hydrogen-bonding ability of a neighboring functional group,
for instance. These features readily explain its ubiquity in
pharmaceuticals and agrochemicals as well as the broad
portfolio of available fluorinated groups for the design of
bioactive molecules in discovery programs.2 As important
fluorinated motifs, it is worth mentioning the CF3, CF2H,
OCF3, or the SCF3 groups,3 for example. Among these
fluorinated groups, monofluoroalkenes are of high interest.4
The α-substituted monofluoroalkene motif is well recognized
as a bioisostere of the amide bond, whereas the terminal
monofluoroalkene motif is considered as a mimic of an
enol.2e,5
It is noteworthy that these terminal monofluoroalkenes are
found in a significant number of bioactive compounds, and the
stereoisomers often have different bioactivities (Figure 1).6
Figure 2. State of the art and present strategy.
methods to access this important motif, the olefination of
carbonyl derivatives is probably the most popular one, even
though it often suffers from a lack of stereoselectivity.7 Note
that Hu recently reported a stereoselective olefination protocol
affording the synthesis of terminal monofluoroalkenes with
high stereoselectivity.8 As alternative pathways, the nucleo-
philic fluorination of vinyl triflates or boronic acids using
Received: May 19, 2020
Figure 1. Bioactive molecules with terminal fluoroalkenes.
https://dx.doi.org/10.1021/acs.orglett.0c01701
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
AgOTf9a or a Pd catalyst, respectively,9b as well as the cross-
metathesis reaction,10 although restricted to disubstituted
monofluoroalkenes, were reported.
products, and the diastereosiomeric ratios were excellent,
except for the ortho-methyl-substituted styrene 2d (82:18). A
styrene derivative with a phenyl substituent at the para position
2f as well as the naphthyl derivative 2g were isolated in good
yields with good dr. The presence of strong electron-donating
groups at the para or meta position required an increase in the
reaction temperature from rt to 70 °C to obtain excellent yields
and a 95:5 dr (2h−j). Halogens and CF3 groups were also
tolerated, and the terminal monofluoroalkenes were obtained
in good yields with good dr (2k−n). In addition heterocyclic
derivatives were compatible under our standard conditions.
The thiophene derivative 1o was tested, and the corresponding
terminal monofluoroalkene 2o was isolated in moderate yield
with a moderate dr. The indole derivative 2p was obtained in
78% yield with an excellent dr, whereas the N-Ts-pyrrole-
substituted monofluoroalkene was isolated in 83% yield with a
88:12 dr. Then, β-substituted α-trifluoromethylstyrenes were
used in this hydrodefluorination reaction. A slight increase in
the LiAlH4 stoichiometry from 1 to 2 equiv was required to
ensure a complete conversion of the products into the
monofluoroalkenes. The presence of an alkyl chain did not
affect the reaction efficiency, and products 2r−t were isolated
in good to excellent yields. In all cases, the diastereoisomeric
ratio were excellent (>96:4). Unprotected alcohol 1t was
tested, and the product 2t was isolated in a decent 72% yield
with an 81:19 dr. Then, various protected alcohols were tested
to demonstrate the synthetic utility of our methodology.
Benzyl, MOM, and TBDMS protecting groups were well
tolerated, and the terminal monofluoroalkenes 2v−x were
isolated in good yields with excellent dr (up to 99:1). As part
of our interest in the use of β-trifluoromethyl acrylates as
versatile fluorinated building blocks,15 we sought to use them
to access the corresponding terminal monofluoroalkenes. A
slight increase in the LiAlH4 stoichiometry from 1 to 2.5 equiv
allowed the concomitant reduction of the ester group and the
hydrodefluorination process. A large panel of β-trifluoromethyl
acrylates was reduced into the terminal monofluoroalkenes in
good to excellent yields, whatever the substitution pattern. In
all cases, the diasteroisomeric ratio remained lower than those
obtained from the hydrodefluorination of α-trifluoromethyl-
styrenes (66:34 to 82:18 dr), and both diastereoisomers were
easily separable using silica gel flash chromatography. Finally,
the potential of this hydrodefluorination process was
demonstrated using the tetra-substituted trifluoromethylated
olefin 1ak. Using an extended reaction time, 1ak was readily
converted into the monofluoroalkene 2ak in a good 72% yield,
albeit with no diastereoselectivity. Unfortunately, some
substrates remained reluctant in our hand, highlighting the
limitation of the process. The β-alkyl-substituted β-trifluor-
omethylated acrylate and the β-trifluoromethylstyrene were
not reactive and showcased the need to have an aromatic
substituent on the trifluoromethylated alkenes. The β-
trifluoromethylated nitrostyrene and acrylonitrile were not
suitable substrates, and the hydrodefluorination product was
not observed.14 In the case of the phosphonate and sulfone
derivatives, the reaction proceeded, but the hydrodefluorinated
products were obtained in low yields (<30%).
The hydrodefluorination of gem-difluoroalkenes has also
been described using copper catalysts, for instance.11 Finally,
the halogen elimination on allyl fluorides has been widely
explored by the group of Paquin to build up monofluor-
oalkenes in the course of an allylic substitution reaction
(Figure 2).12 Surprisingly, no report has described the
synthesis of monofluoroalkenes from the corresponding
trifluoromethylated alkenes according to a controlled hydro-
defluorination strategy. As part of our research program
dedicated to the use of tri-, di-, and monofluorinated alkenes as
key building blocks to build up complex fluorinated
molecules,13 we sought to develop such an original approach
as a complementary strategy to the existing ones. Hence, we
report herein the stereoselective hydrodefluorination strategy
of trifluoromethylated alkenes to build up monofluoroalkenes.
After a careful examination of the reaction parameters using
the α,α,α-trifluoromethylstyrene 1a, we found that the use of 1
equiv of LiAlH4 in THF at room temperature allowed the
formation of the monofluoroalkene 2a in a very good 78%
NMR yield with a 95:5 diastereoisomeric ratio, and it was
isolated in a moderate 56% yield due to its high volatility
(Table 1, entry 1). The use of DIBAL did not afford the
a
Table 1. Synthesis of Monofluoroalkene 2a from 1a
bc
,
d
entry
change from the standard conditions
yield (%)
dr
1
2
3
4
5
none
78 (56)
0
62
NR
NR
95:5
DIBAL (4 equiv)
RedAl (2 equiv)
NaBH4
85:15
LiBH4
a
Reaction conditions: 1a (0.23 mmol), LiAlH4 (0.23 mmol), THF
b
(0.15 M), 21 h, rt. Yield determined by 19F NMR using 4-
c
nitrofluorobenzene as an internal standard. Isolated yield is reported.
d
Diasteroisomeric ratio (dr) was determined by 19F NMR on the
crude reaction mixture. NR = no reaction.
desired product but led to the gem-difluoromethylalkene I in
74% NMR yield (entry 2).14 The use of 2 equiv of RedAl as a
reductant allowed the formation of the desired terminal
monofluoroalkene 2a in 62% yield but with a lower 85:15
diasteroisomeric ratio (entry 3). Finally, the use of lithium or
sodium borohydride did not afford the expected product
(entries 4 and 5). Then, with these optimized conditions in
hand, we explored the scope of this transformation to showcase
the panel of accessible terminal monofluoroalkenes (Scheme
1).
Then, control experiments were carried out to get insight
into the mechanism of this hydrodefluorinative process
(Scheme 2). First, the influence of the olefin geometry was
evaluated with the E and Z isomers of β-trifluoromethyl
acrylate 1af. Regardless of the stereoisomer used, the
diastereoisomeric ratio and the yield remained unchanged,
First, the reaction was tested on α-trifluoromethylstyrene
derivatives. The reaction proceeded well with alkyl-substituted
aromatic rings whatever the position of the substituent at the
cost of an increase in the reaction temperature from room
temperature to 70 °C (2b−e). Isolated yields were somehow
lower than the NMR yields due to the high volatility of the
B
https://dx.doi.org/10.1021/acs.orglett.0c01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Scope of the Reaction
a
b
c
1 (0.3 mmol), LiAlH4 (0.3 mmol), THF (0.1 M), rt, 6−24 h. The major diastereoisomer is shown. 24 h reaction time. Yield determined by 19
F
d
e
f
NMR using 4-nitrofluorobenzene as an internal standard. Reaction was carried out at 70 °C for 24 h. 6 h reaction time. Reaction was performed
on a gram scale (4.1 mmol). 20 h reaction time. 17 h reaction time. 2 equiv of LiAlH4 was used. 2.5 equiv of LiAlH4 was used.
g
h
i
j
demonstrating that the olefin geometry has no influence on the
stereochemical outcome of the reaction. To understand the
reaction mechanism, the reaction was performed with the α-
difluoromethylstyrene derivative 3 to ascertain if this species
C
https://dx.doi.org/10.1021/acs.orglett.0c01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Mechanistic Studies
Scheme 3. Suggested Mechanism
monofluoroalkene 2 as a major product. The stereochemical
outcome of this fluoride elimination could be explained using a
Newman projection of the different conformers potentially
involved in the antiperiplanar elimination of the fluoride ion.
Indeed, the predictive model (TS-1) that leads to the minor Z
isomer clearly highlights an electronic repulsion between the
fluorine atom and the aromatic ring,16 in contrast with TS-2,
which predicts the formation of the E isomer.
In conclusion, we reported a simple and practical method for
the synthesis of terminal monofluoroalkenes from trifluor-
omethylated alkenes. The reaction proceeded well with α-
trifluoromethylstyrenes derivatives, β-trifluoromethyl acrylates,
and tetrasubstituted trifluoromethylated olefins. The terminal
monofluoroalkenes were obtained in good to excellent yields.
The reaction proved to be diastereoselective in favor of the E
isomer. Mechanistic studies supported the succession of two
hydroalumination reactions followed by a final stereoselective
fluoride elimination to explain the reaction outcome and the
diastereoselectivity of the process. We hope that this simple
and practical method will be useful to build up stereoselectively
more complex terminal monofluoroalkenes to access fluori-
nated molecules of interest.
a
Yield determined by 19F NMR using 4-nitrofluorobenzene as an
internal standard.
might be a reaction intermediate. The hydrodefluorination
proceeded well, giving the target terminal monofluoroalkene in
an excellent NMR yield but with a poor dr of 56:44. This result
precluded the involvement of this species as a reaction
intermediate. To get further insights, the reaction from 1h was
interrupted after 8 h, and we have been able to isolate the gem-
difluoroalkene 4. The latter was then submitted to the standard
reaction conditions, giving 2h in a similar yield with a similar
dr compared to the those observed starting from 1h,
demonstrating its possible role as a reaction intermediate.
Finally, experiments with LiAlD4 were performed with 1g and
1u′ to understand the mechanism of the hydrodefluorination
reaction. The reaction of 1g with LiAlD4 clearly demonstrated
the incorporation of a deuterium atom on the terminal position
of the alkene and a single D atom at the allylic position of 2g.
Similarly, the reaction with 1u′ led to a similar incorporation of
deuterium on the monofluoroalkene and at the allylic position.
These results pointed out the two different sites of hydride
incorporation. Hence, with all of these data in hand, we
suggested the following mechanism (Scheme 3).
First, the hydroalumination of the α-trifluoromethylstyrene
1 led to the hydro-aluminated derivative A. A first fluoride
elimination afforded the gem-difluoromethylalkene B, which
has been isolated from the reaction mixture (vide supra). The
regioselectivity of the hydride incorporation was supported by
the deuteration experiment carried out with 1g (Scheme 2).
Then, a second hydroalumination occurred, providing a
transient Al-species C, which was then involved in a
stereoselective fluoride elimination to provide the (E)-
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01701.
Experimental procedures, compound characterization
1
data, and H and 13C spectra of the products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
Philippe Jubault − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France; orcid.org/0000-0002-3295-9326;
Email: philippe.jubault@insa-rouen.fr
́
Thomas Poisson − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France; Institut Universitaire de France, 75231 Paris, France;
orcid.org/0000-0002-0503-9620;
Email: thomas.poisson@insa-rouen.fr
D
https://dx.doi.org/10.1021/acs.orglett.0c01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
pounds: 10 Years of Innovation. Chem. Rev. 2015, 115, 9073−9174.
(c) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F.
Synthetic Approaches to Monofluoroalkenes. Chem. Soc. Rev. 2011,
40, 2867. (d) Pfund, E.; Lequeux, T.; Gueyrard, D. Synthesis of
Fluorinated and Trifluoromethyl-Substituted Alkenes Through the
Modified Julia Olefination: an Update. Synthesis 2015, 47, 1534−
1546. (e) Yanai, H.; Taguchi, T. Synthetic Methods for Fluorinated
Olefins. Eur. J. Org. Chem. 2011, 2011, 5939−5954. For a recent
example, see: (f) Liao, F.-M.; Cao, Z.-Y.; Yu, J.-S.; Zhou, J. Highly
Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and
Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes. Angew.
Chem., Int. Ed. 2017, 56, 2459−2463.
́
Pauline Poutrel − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France
Xavier Pannecoucke − Normandie Universite, INSA Rouen,
UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen,
France
́
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01701
Notes
(5) For reviews, see: (a) Couve-Bonnaire, S.; Cahard, D.;
Pannecoucke, X. Chiral Dipeptide Mimics Possessing a Fluoroolefin
Moiety: a Relevant Tool for Conformational and Medicinal Studies.
Org. Biomol. Chem. 2007, 5, 1151−1157. (b) Drouin, M.; Paquin, J.-F.
Recent Progress in the Racemic and Enantioselective Synthesis of
Monofluoroalkene-Based Dipeptide Isosteres. Beilstein J. Org. Chem.
2017, 13, 2637−2658. For selected recent examples, see:
(c) Hohlfeld, K.; Wegner, J. K.; Kesteleyn, B.; Linclau, B.; Unge, J.
Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal
HIV-1 Protease Inhibitors (II). J. Med. Chem. 2015, 58, 4029−4038.
(d) Nadon, J.-F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partially supported by Normandie Universite
■
́
́
(NU), the Region Normandie, the Centre National de la
́
Recherche Scientifique (CNRS), Universite de Rouen
Normandie (URN), INSA Rouen Normandie, Labex SynOrg
(ANR-11-LABX-0029), and Innovation Chimie Carnot (I2C).
́
P.P. thanks the Region Normandie (RIN 100% program) for a
doctoral fellowship. T.P. thanks the Institut Universitaire de
France (IUF) for support.
́
H.; Blais, V.; Guerin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-
Ψ[(Z)CFCH]-Phe, a Fluoroalkene Dipeptide Isostere, and Its
Incorporation Into a Leu-Enkephalin Peptidomimetic. ACS Chem.
Neurosci. 2017, 8, 40−49. (e) Choi, W. J.; Chung, H.-J.; Chandra, G.;
Alexander, V.; Zhao, L. X.; Lee, H. W.; Nayak, A.; Majik, M. S.; Kim,
H. O.; Kim, J.-H.; Lee, Y. B.; Ahn, C. H.; Lee, S. K.; Jeong, L. S.
Fluorocyclopentenyl-Cytosine with Broad Spectrum and Potent
Antitumor Activity. J. Med. Chem. 2012, 55, 4521−4525. (f) Chang,
W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P.
A.; Otto, M. J.; Sofia, M. J. Bioorg. Med. Chem. Lett. 2012, 22, 2938−
2942. (g) Pierry, C.; Couve-Bonnaire, S.; Guilhaudis, L.; Neveu, C.;
REFERENCES
■
(1) O’Hagan, D. Understanding Organofluorine Chemistry. An
Introduction to the C−F Bond. Chem. Soc. Rev. 2008, 37, 308−319.
(2) (a) Modern Synthesis Processes and Reactivity of Fluorinated
Compounds, 1st ed.; Groult, H., Leroux, F., Tressaud, A., Eds.;
Elsevier, 2017. (b) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-
Mining for Sulfur and Fluorine: an Evaluation of Pharmaceuticals to
Reveal Opportunities for Drug Design and Discovery. J. Med. Chem.
́
́
2014, 57, 2832−2842. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.;
̃
́
Marotte, A.; Lefranc, B.; Cahard, D.; Segalas-Milazzo, I.; Leprince, J.;
del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu,
H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs
Introduced to the Market in the Last Decade (2001−2011). Chem.
Rev. 2014, 114, 2432−2506. (d) Mei, H.; Han, J.; Fustero, S.; Medio
Simon, M.; Sedgwick, D. M.; Santi, C.; Ruzziconi, R.; Soloshonok, V.
A. Fluorine-Containing Drugs Approved by the FDA in 2018. Chem. -
Eur. J. 2019, 25, 11797−11819. (e) Meanwell, N. A. Fluorine and
Fluorinated Motifs in the Design and Application of Bioisosteres for
Drug Design. J. Med. Chem. 2018, 61, 5822−5880. (f) Gillis, E. P.;
Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A.
Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015,
58, 8315−8359. (g) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev.
2008, 37, 320−330.
Pannecoucke, X. Fluorinated Pseudopeptide Analogues of the
Neuropeptide 26RFa: Synthesis, Biological, and Structural Studies.
ChemBioChem 2013, 14, 1620−1633. (h) Drouin, M.; Wadhwani, P.;
Grage, S. L.; Bu
C.; Staub, A.; Paquin, J.-F.; Ulrich, A. S. Monofluoroalkene-Isostere as
19F NMR Label for the Peptide Backbone: Synthesis and Evaluation
̈
rck, J.; Reichert, J.; Tremblay, S.; Mayer, M. S.; Diel,
a
in Membrane-Bound PGLa and (KIGAKI)3. Chem. - Eur. J. 2020, 26,
1511−1517. (i) Drouin, M.; Laxio Arenas, J.; Paquin, J.-F. Evaluating
the Impact on the Local Hydrophobicity of the Incorporation of
Monofluoroalkene in the Backbone of Short Peptides. ChemBioChem
2019, 20, 1817−1826.
(6) (a) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber,
E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S.
Stereospecific Method to E and Z. Terminal Fluoro Olefins and Its
Application to the Synthesis of 2’-Deoxy-2’-Fluoromethylene Nucleo-
sides as Potential Inhibitors of Ribonucleoside Diphosphate
Reductase. J. Am. Chem. Soc. 1991, 113, 7439−7440. (b) Asahina,
Y.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. Synthesis and
Antibacterial Activity of 1-(2-Fluorovinyl)-7-Substituted-4-Quino-
lone-3-Carboxylic Acid Derivatives, Conformationally Restricted
Analogues of Fleroxacin. J. Med. Chem. 2005, 48, 3194−3202.
(c) Shimizu, M.; Ohno, A.; Yamada, S. (10Z)- and (10E)-19-Fluoro-
1alpha,25-Dihydroxyvitamin D3: an Improved Synthesis via 19-nor-
10-Oxo-Vitamin D. Chem. Pharm. Bull. 2001, 49, 312−317.
(d) Ohno, A.; Shimizu, M.; Yamada, S. Fluorinated Vitamin D
Analogs to Probe the Conformation of Vitamin D in Its Receptor
Complex: 19F-NMR Studies and Biological Activity. Chem. Pharm.
Bull. 2002, 50, 475−483.
(3) For selected reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter,
T. Introduction of Fluorine and Fluorine-Containing Functional
Groups. Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (b) Charpentier,
J.; Fruh, N.; Togni, A. Electrophilic Trifluoromethylation by Use of
̈
Hypervalent Iodine Reagents. Chem. Rev. 2015, 115, 650−682.
(c) Besset, T.; Jubault, P.; Pannecoucke, X.; Poisson, T. New Entries
Toward the Synthesis of OCF3-Containing Molecules. Org. Chem.
Front. 2016, 3, 1004−1010. (d) Belhomme, M.-C.; Besset, T.;
Poisson, T.; Pannecoucke, X. Recent Progress Toward the
Introduction of Functionalized Difluoromethylated Building Blocks
Onto C(Sp2) and C(Sp) Centers. Chem. - Eur. J. 2015, 21, 12836−
12865. (e) Tlili, A.; Toulgoat, F.; Billard, T. Synthetic Approaches to
Trifluoromethoxy-Substituted Compounds. Angew. Chem., Int. Ed.
2016, 55, 11726−11735. (f) Toulgoat, F.; Alazet, S.; Billard, T. Direct
Trifluoromethylthiolation Reactions: the “Renaissance” of an Old
Concept. Eur. J. Org. Chem. 2014, 2014, 2415−2428.
(7) For selected examples, see: (a) Prakash, G. K. S.; Shakhmin, A.;
Zibinsky, M.; Ledneczki, I.; Chacko, S.; Olah, G. A. J. Fluorine Chem.
2010, 131, 1192−1197. (b) Zhu, L.; Ni, C.; Zhao, Y.; Hu, J.
Tetrahedron 2010, 66, 5089−5100. (c) Cox, D. G.; Gurusamy, N.;
Burton, D. J. J. Am. Chem. Soc. 1985, 107, 2811−2812. (d) Boys, M.
(4) For selected reviews, see: (a) Drouin, M.; Hamel, J.-D.; Paquin,
J.-F. Synthesis of Monofluoroalkenes: a Leap Forward. Synthesis 2018,
50, 881−955. (b) Champagne, P. A.; Desroches, J.; Hamel, J.-D.;
Vandamme, M.; Paquin, J.-F. Monofluorination of Organic Com-
E
https://dx.doi.org/10.1021/acs.orglett.0c01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
L.; Collington, E. W.; Finch, H.; Swanson, S.; Whitehead, J. F.
Tetrahedron Lett. 1988, 29, 3365−3368.
(c) Schlinquer, C.; Huang, W.-S.; Chen, L.; Poisson, T.;
Pannecoucke, X.; Charette, A. B.; Jubault, P. Rhodium Catalysed
Enantioselective Synthesis of Mono-(Halo)-Methyl-Cyclopropanes.
Org. Biomol. Chem. 2019, 17, 472−476. (d) Huang, W.-S.; Schlinquer,
C.; Poisson, T.; Pannecoucke, X.; Charette, A. B.; Jubault, P. General
Catalytic Enantioselective Access to Monohalomethyl and Trifluor-
omethyl Cyclopropanes. Chem. - Eur. J. 2018, 24, 10339−10343.
(e) Bos, M.; Huang, W.-S.; Poisson, T.; Pannecoucke, X.; Charette, A.
B.; Jubault, P. Catalytic Enantioselective Synthesis of Highly
Functionalized Difluoromethylated Cyclopropanes. Angew. Chem.,
Int. Ed. 2017, 56, 13319−13323. (f) Zhao, Q.; Tognetti, V.; Joubert,
L.; Besset, T.; Pannecoucke, X.; Bouillon, J.-P.; Poisson, T. Palladium-
Catalyzed Synthesis of 3-Trifluoromethyl-Substituted 1,3-Butadienes
by Means of Directed C−H Bond Functionalization. Org. Lett. 2017,
19, 2106−2109. (g) Pons, A.; Ivashkin, P.; Poisson, T.; Charette, A.
B.; Pannecoucke, X.; Jubault, P. Catalytic Enantioselective Synthesis
of Halocyclopropanes. Chem. - Eur. J. 2016, 22, 6239−6242. (h) Pons,
A.; Beucher, H.; Ivashkin, P.; Lemonnier, G.; Poisson, T.; Charette, A.
B.; Jubault, P.; Pannecoucke, X. Rhodium-Catalyzed Cyclopropana-
tion of Fluorinated Olefins: a Straightforward Route to Highly
Functionalized Fluorocyclopropanes. Org. Lett. 2015, 17, 1790−1793.
(14) See the Supporting Information for details.
(15) Poutrel, P.; Ivanova, M. V.; Pannecoucke, X.; Jubault, P.;
Poisson, T. Copper-Catalyzed Enantioselective Formation of C−CF3
Centers From β-CF3-Substituted Acrylates and Acrylonitriles. Chem. -
Eur. J. 2019, 25, 15262−15266.
(16) (a) Jin, G.; Zhang, J.; Wu, W.; Cao, S. Stereoselective Synthesis
of β-Fluoroenyne by the Reaction of gem-Difluoroalkenes with
Terminal Alkynes. J. Fluorine Chem. 2014, 168, 240−246. (b) Wu, J.;
Xiao, J.; Dai, W.; Cao, S. Synthesis of Monofluoroalkenes Through
Selective Hydrodefluorination of gem-Difluoroalkenes with Red-Al®.
RSC Adv. 2015, 5, 34498−34501. (c) Xie, S.-L.; Cui, X.-Y.; Gao, X.-
T.; Zhou, F.; Wu, H.-H.; Zhou, J. Stereoselective Defluorinative
Carboxylation of gem-Difluoroalkenes with Carbon Dioxide. Org.
Chem. Front. 2019, 6, 3678−3682.
(8) Liu, Q.; Shen, X.; Ni, C.; Hu, J. Stereoselective Carbonyl
Olefination with Fluorosulfoximines: Facile Access to Z or E Terminal
Monofluoroalkenes. Angew. Chem., Int. Ed. 2017, 56, 619−623.
(9) (a) Furuya, T.; Ritter, T. Fluorination of Boronic Acids
Mediated by Silver(I) Triflate. Org. Lett. 2009, 11, 2860−2863.
(b) Ye, Y.; Takada, T.; Buchwald, S. L. Palladium-Catalyzed
Fluorination of Cyclic Vinyl Triflates: Effect of TESCF3 as an
Additive. Angew. Chem., Int. Ed. 2016, 55, 15559−15563.
(10) (a) Koh, M. J.; Nguyen, T. T.; Zhang, H.; Schrock, R. R.;
Hoveyda, A. H. Direct Synthesis of Z-Alkenyl Halides Through
Catalytic Cross-Metathesis. Nature 2016, 531, 459−465. (b) Nguyen,
T. T.; Koh, M. J.; Shen, X.; Romiti, F.; Schrock, R. R.; Hoveyda, A. H.
Kinetically Controlled E-Selective Catalytic Olefin Metathesis. Science
2016, 352, 569−575.
(11) For selected examples, see: (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. Soc. 2017, 139,
12855−12862. (b) Hu, J.; Han, X.; Yuan, Y.; Shi, Z. Stereoselective
Synthesis of Z Fluoroalkenes Through Copper-Catalyzed Hydro-
defluorination of gem-Difluoroalkenes with Water. Angew. Chem., Int.
Ed. 2017, 56, 13342−13346. (c) Andrella, N. O.; Xu, N.; Gabidullin,
B. M.; Ehm, C.; Baker, R. T. Selective Copper Complex-Catalyzed
Hydrodefluorination of Fluoroalkenes and Allyl Fluorides: a Tale of
Two Mechanisms. J. Am. Chem. Soc. 2019, 141, 11506−11521.
(d) Kojima, R.; Kubota, K.; Ito, H. Stereodivergent Hydro-
defluorination of gem-Difluoroalkenes: Selective Synthesis of (Z)-
and (E)-Monofluoroalkenes. Chem. Commun. 2017, 53, 10688−
10691. (e) Landelle, G.; Turcotte-Savard, M.-O.; Marterer, J.;
Champagne, P. A.; Paquin, J.-F. Stereocontrolled Access to Unsym-
metrical 1,1-Diaryl-2-Fluoroethenes. Org. Lett. 2009, 11, 5406−5409.
(f) Landelle, G.; Turcotte-Savard, M.-O.; Angers, L.; Paquin, J.-F.
Stereoselective Synthesis of Both Stereoisomers of β-Fluorostyrene
Derivatives From a Common Intermediate. Org. Lett. 2011, 13,
1568−1571. (g) Phillips, N.; Coates, G.; White, A.; Crimmin, M. R.
Defluoroalkylation of Sp3 C-F Bonds of Industrially Relevant
Hydrofluoroolefins. Chem. - Eur. J. 2020, 26, 5365. (h) Tian, H.;
Shimakoshi, H.; Imamura, K.; Shiota, Y.; Yoshizawa, K.; Hisaeda, Y.
Photocatalytic Alkene Reduction by a B12−TiO2 hybrid Catalyst
Coupled with C−F Bond Cleavage for gem-Difluoroolefin Synthesis.
Chem. Commun. 2017, 53, 9478−9481.
(12) (a) Hamel, J.-D.; Cloutier, M.; Paquin, J.-F. Exploiting a
Difference in Leaving Group Ability: an Approach to β-Substituted
Monofluoroalkenes Using gem-Chlorofluoropropenes. Org. Lett. 2016,
18, 1852−1855. (b) Bergeron, M.; Johnson, T.; Paquin, J.-F. The Use
of Fluoride as a Leaving Group: SN2′ Displacement of a C-F Bond on
3,3-Difluoropropenes with Organolithium Reagents to Give Direct
Access to Monofluoroalkenes. Angew. Chem., Int. Ed. 2011, 50,
11112−11116. (c) Drouin, M.; Tremblay, S.; Paquin, J.-F. Palladium-
Catalyzed Synthesis of Monofluoroalkenes From 3,3-Difluoropro-
penes Using Dimethylmalonate and Derivatives as Nucleophiles. Org.
Biomol. Chem. 2017, 15, 2376−2384. (d) Bergeron, M.; Guyader, D.;
Paquin, J.-F. SN2’ Reaction of Allylic Difluorides with Lithium Amides
and Thiolates. Org. Lett. 2012, 14, 5888−5891. (e) Pigeon, X.;
́
́
Bergeron, M.; Barabe, F.; Dube, P.; Frost, H. N.; Paquin, J.-F.
Activation of Allylic C-F Bonds: Palladium-Catalyzed Allylic
Amination of 3,3-Difluoropropenes. Angew. Chem., Int. Ed. 2010,
49, 1123−1127. (f) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Exploiting
3,3-Difluoropropenes for the Synthesis of Monofluoroalkenes. Synlett
2016, 27, 821−830.
(13) (a) Huang, W.-S.; Delcourt, M.-L.; Pannecoucke, X.; Charette,
A. B.; Poisson, T.; Jubault, P. Catalytic Asymmetric Synthesis of α,α-
Difluoromethylated and α-Fluoromethylated Tertiary Alcohols. Org.
Lett. 2019, 21, 7509−7513. (b) Pons, A.; Tognetti, V.; Joubert, L.;
Poisson, T.; Pannecoucke, X.; Charette, A. B.; Jubault, P. Catalytic
Enantioselective Cyclopropanation of α-Fluoroacrylates: an Exper-
imental and Theoretical Study. ACS Catal. 2019, 9, 2594−2598.
F
https://dx.doi.org/10.1021/acs.orglett.0c01701
Org. Lett. XXXX, XXX, XXX−XXX