Titanocene-Catalyzed Reductive Domino Epoxide Ring Opening/Defluorinative Cross-Coupling Reaction

Article abstract of DOI:10.1021/acs.orglett.0c00960

Herein, we report a method for efficient synthesis of gem-difluorobishomoallylic alcohols starting from trifluoromethyl-substituted alkenes and epoxides via a titanocene-catalyzed reductive domino reaction, which consists of a Ti(III)-mediated radical-type ring opening and the following allylic defluorinative cross-coupling reaction via sequential radical addition and β-F elimination. Notably, complete regioselectivity and high tolerance of functionalities can be achieved in this reaction. Furthermore, diverse 6-fluoro-3,4-dihydro-2H-pyrans have been prepared through derivatization of the cross-coupling products in one single step.

Full text of DOI:10.1021/acs.orglett.0c00960

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Letter
Titanocene-Catalyzed Reductive Domino Epoxide Ring Opening/
Defluorinative Cross-Coupling Reaction
Zhiyang Lin, Yun Lan, and Chuan Wang*
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ABSTRACT: Herein, we report a method for efficient synthesis of
gem-difluorobishomoallylic alcohols starting from trifluoromethyl-
substituted alkenes and epoxides via a titanocene-catalyzed
reductive domino reaction, which consists of a Ti(III)-mediated
radical-type ring opening and the following allylic defluorinative
cross-coupling reaction via sequential radical addition and β-F elimination. Notably, complete regioselectivity and high tolerance of
functionalities can be achieved in this reaction. Furthermore, diverse 6-fluoro-3,4-dihydro-2H-pyrans have been prepared through
derivatization of the cross-coupling products in one single step.
more, the cooperative catalysis of Ni and Ti allows the use of
aryl halides as the electrophiles in the ring opening reaction of
epoxides,7 while hydrogenation8 and isomerization9 of
epoxides involving Ti as a catalyst provide efficient access to
diverse alcohols.
ing opening of epoxides provides a powerful method to
Rapproach vicinal difunctionalized molecules. In compar-
ison to the well-established nucleophilic ring opening
reaction,1 the complementary electrophilic variant is distin-
guished by a unique reaction pathway and more desirable for
C−C bond formation due to the avoidance of using highly
reactive organometallics.2 Early contributions in this field
mainly focused on the use of stoichiometric transition metals
to realize the umpolung of the epoxides.3 In the last decades,
significant progress has been achieved in the titanocene-
catalyzed electrophilic radical-type ring opening of epoxides, in
which various Michael acceptors have been successfully
utilized as the coupling partners (Scheme 1A).4−6 Further-
gem-Difluoroalkenes are contained as a subunit in numerous
biologically active compounds and agrochemicals.10 Further-
more, as a metabolically more-stable bioisostere of carbonyl
groups, gem-difluoroalkenes promise superior phamaceutical
performance to their carbonyl analogues.11 In addition, gem-
difluoroalkenes can also serve as versatile building blocks for
synthesis of other fluorine-containing compounds.12 Therefore,
various strategies including functional-group conversion,13
nucleophilic addition to trifluoromethyl alkenes,14 and a
photocatalytic approach15 have been developed for synthesis
of gem-difluoroalkenes over the last decades. Recently,
transition-metal-catalyzed reductive allylic defluorinative
cross-coupling reactions of easily accessible trifluoromethyl
alkenes16 with various electrophiles including organohalides,17
acetals,18 N-hydroxyphthalimide (NHP) esters,19 and oxime
esters20 have emerged as a reliable method to prepare sterically
demanding and functional-group-rich gem-difluoroalkenes
(Scheme 1B). Herein, we envisage that the scope of this
reductive strategy could be extended to epoxides via engaing
titanocene catalysis, to enable the synthesis of gem-difluor-
obishomoallylic alcohols. The designed reaction consists of
two key elementary steps, which are the Ti(III)-mediated
Scheme 1. (A) Ti-Catalyzed Reductive Electrophilic Ring
Opening of Epoxides with Michael Acceptors; (B)
Reductive Electrophilic Allylic Defluorinative Cross-
Coupling of Trifluoromethyl Alkenes; (C) Domino
Electrophilic Ring Opening/Defluorinative Cross-Coupling
Reaction
Received: March 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00960
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
radical-type ring opening of epoxides and the following allylic
defluorinative cross-coupling via β-F elimination (Scheme 1C).
For optimization of the reaction conditions, the trifluor-
omethyl alkene 1a and the terminal epoxide 2a were selected
as the standard substrates (Table 1). Initially, the reaction was
Scheme 2. Evaluation of the Substrate Scope of the
Trifluoromethyl Alkenes
a b
,
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
solvent
T (°C)
yield 3aa (%)
yield 3aa′ (%)
1
2
3
4
5
THF
RT
RT
RT
60
58
15
42
76
55
39
30
0
19
43
0
3
0
0
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
c
d
6
RT
RT
RT
RT
85 (81)
c e
,
7
8
9
75
65
59
c f
,
c g
,
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the trifluoromethyl alkene 1a using 2.0 equiv of the epoxide
a
Unless otherwise specified, reactions were performed on a 0.4 mmol
scale of the trifluoromethyl alkenes 1a−q using 2.0 equiv of the
epoxide 2a, 20 mol % TiCp2Cl2, 1.0 equiv of NEt3·HCl, and 3.0 equiv
2a, 10 mol % TiCp2Cl2, 1.0 equiv of NEt3·HCl, and 3.0 equiv of Zn in
b
0.5 mL of solvent for 24 h. NMR yields are determined by 19F NMR
c
spectroscopy using 4-fluoroanisole as an internal standard. Reaction
b
d
of Zn in 1.0 mL of DMF at room temperature for 24 h. Yields are of
the isolated product after column chromatography. Reaction was
performed on a 0.2 mmol scale.
was performed with 20 mol % TiCp2Cl2. Yield of the isolated
c
e
product after column chromatography. Ti(indenyl)Cl3 was used
f
g
instead of TiCp2Cl2. Mn was used instead of Zn. Reaction was
performed without NEt3·HCl.
performed in THF at room temperature with TiCp2Cl2 (10
mol %) as a catalyst, NEt3·HCl as a proton donor, and Zn as a
reductant, affording an inseparable mixture of the desired gem-
difluoroalkene 3aa and the hydroalkylation product 3aa′ (entry
1). This ring opening reaction occurs exclusively on the more-
substituted site. A similar result was obtained when conducting
the reaction in toluene (entry 2). In contrast, the reaction in
DMF delivered compound 3aa as the only product in a
moderate yield (entry 3). In order to achieve higher conversion
of 1a, we carried out the reaction at 60 °C (entry 4) and 80 °C
(entry 5), respectively. However, it turned out that the
formation of the byproduct 3aa′ benefited from a higher
reaction temperature. Next, the catalyst loading was increased
to 20 mol % (entry 6). In this case, the product 3aa could be
obtained in a good yield (81%). Moreover, performing the
reaction with Ti(indenyl)Cl3 instead of TiCp2Cl2 resulted in a
slightly lower efficiency (entry 7). In addition, replacing Zn
with Mn as the reducing agent gave rise to an inferior result
(entry 8). In the absence of the proton donor NEt3·HCl, the
reaction could still proceed, albeit in a lower yield (entry 9).
The diminished efficiency is likely due to the relatively slow
liberation of the titanocene catalyst via Zn/Ti-cation exchange
in comparison to the protonation process.
aryl bromide (3ia), alcohol (3la), and ketone (3ma) were well-
tolerated in this reaction. Furthermore, heteroaryl trifluor-
omethyl alkenes 1n−p posed no problem, and the coupling
products 3na−pa were obtained in good efficiency. Our
method is also applicable for the reaction employing the
trifluoromethyl alkene 1q derived from estrone, providing
compound 3qa in a moderate yield. Unfortunately, the
reactions utilizing alkyl- or alkynyl-substituted trifluoromethyl
alkenes failed to deliver the desired products in analytically
pure form and are contaminated with inseparable hydro-
alkylation products. In the case of internal alkenes as
precursors, no conversion of the alkenes could be achieved.
Next, we continued to explore the versatility of this method
by varying the structure of the epoxides (Scheme 3). When
geminal disubstituted epoxides 2b−p were employed as
substrates, all the reactions afforded the products 3ab−ap in
moderate to good yields and perfect regioselectivities.
Functionalities including carbamate (3ae), ether (3af−ak),
silyl ether (3al), ester (3am and 3an), and imide (3ao) turned
out to be compatible under the standard reaction conditions.
In the case of the aliphatic monosubstituted epoxide 2p, the
couping reaction still occurred on the substituted carbon
exclusively, providing the corresponding primary bishomoal-
lylic alcohol 3ap as the single product. In addition, the reaction
using cyclohexane oxide 2q yielded two separable stereo-
isomers 3aq in a moderate diastereomeric ratio. However,
styrenyl oxide was found to be an unsuitable precursor in this
Ti-catalyzed reaction. When 1,2-disubstituted epoxides were
employed as substrates, the product was formed as a mixture of
four inseparable isomers concerning both regio- and stereo-
chemistry in low selectivities.
After establishing the optimal reaction conditions, we started
to evaluate the substrate scope of this titanocene-catalyzed
reaction (Scheme 2). First, diverse aryl trifluoromethyl alkenes
(1a−l) with electron-donating or electron-withdrawing sub-
stituents were reacted with the epoxide 2a. To our delight, all
these reactions proceeded smoothly, furnishing the corre-
sponding gem-difluorobishomoallylic alcohols 3aa−la in
moderate to good yields and complete regiocontrol. Notably,
B
https://dx.doi.org/10.1021/acs.orglett.0c00960
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Letter
Scheme 3. Evaluation of the Substrate Scope of the
Epoxides
Scheme 4. Derivatization of gem-Difluorobishomoallylic
a b
a b
,
,
Alcohols to 6-Fluoro-3,4-dihydro-2H-pyrans
a
Unless otherwise specified, reactions were performed on a 0.4 mmol
scale of the trifluoromethyl alkene 1a using 2.0 equiv of the epoxides
2b−q, 20 mol % TiCp2Cl2, 1.0 equiv of NEt3·HCl, and 3.0 equiv of
b
Zn in 1.0 mL of DMF at room temperature for 24 h. Yields are of the
c
isolated products after column chromatography. Reaction was
d
performed on a 1 mmol scale. Reactions were performed with 30
e
mol % TiCp2Cl2 at 40 °C. Determined by 1H NMR spectroscopy of
the crude product.
a
Unless otherwise specified, reactions were performed on a 0.15
mmol scale of the gem-difluorobishomoallylic alcohols 3 using 2.0
b
By taking advantage of the nucleophilic primary alcoholic
moiety contained in all the coupling products, various 6-fluoro-
3,4-dihydro-2H-pyrans 4 were readily synthesized in good to
excellent yields upon treatment of the gem-difluorobishomoal-
lylic alcohols 3 with NaH in THF (Scheme 4). It is noteworthy
that monofluorinated alkenes are bioisosteres of peptide bonds
in pharmaceutical research.21
equiv of the NaH in 1.0 mL of DMF for 2 h. Yields are of the
c
isolated products. Reaction was performed on a 1 mmol scale.
d
Reaction was performed on a 0.1 mmol scale of gem-difluoroalkenes.
e
Reaction time: 5 h.
Scheme 5. Reaction Employing the Enantioenriched
Epoxide 2g
To verify the radical reaction pathway of the ring opening
process, an enantioenriched epoxide 2g was subjected to the
standard reaction conditions. The defluorinative cross-coupling
product 3ag was obtained in racemic form, whereas the
enantiomeric excess of the recovered epoxide 2g remained
unchanged throughout the course of the reaction (Scheme 5).
A proposed reaction mechanism was depicted in Scheme 6.
Initially, Ti(III) is generated under reductive conditions and
subsequently carries out the reductive ring opening of epoxides
2 at the more-substituted site.4 The resultant carbon-centered
radical I performs radical addition to the trifluoromethyl
alkenes 1 to afford a CF3-substituted carbon radical II. It is
known that general alkyl radicals are able to perform oxidative
addition to Ti(III), which is known as an elementary step in
the Ti-mediated deoxygenation of epoxides.5b Therefore, we
believe that the more-electron-deficient CF3-substituted
carbon-radical II could be involved in a similar reaction with
Ti(III). The following Ti(IV)-mediated β-F elimination from
the generated complex III provides the intermediate IV, which
could stay in equilibrium with the zinc alkoxide V through ion
exchange between Zn(II) and Ti(IV). The protonation of
either the complex IV or V by NEt3·HCl leads to the formation
of the product 3. The reduction of Ti(IV) by Zn regenerates
Ti(III) for the next catalytic cycle.
Scheme 6. Proposed Reaction Mechanism
In summary, we successfully applied epoxides as the
electrophilic coupling partner in the reductive allylic
C
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Letter
(2) For a review on electrophilic ring opening of epoxides, see:
Wang, C. Electrophilic Ring Opening of Small Heterocycles. Synthesis
2017, 49, 5307−5319.
defluorinative coupling reaction with trifluoromethyl alkenes
under the catalysis of titanocene with the assistance of Zn as
the reducing agent. A reaction mechanism involving Ti-
mediated regioselective epoxide ring opening and β-F
elimination has been proposed. This protocol provides an
efficient entry to gem-difluorobishomoallylic alcohols, which
can be further converted into a series of 6-fluoro-3,4-dihydro-
2H-pyrans through a simple base-mediated nucleophilic
substitution reaction.
(3) (a) Hase, T.; Miyashita, A.; Nohira, H. Regioselective
Methylation of Epoxides Using Transition Metal Complexes. Chem.
Lett. 1988, 17, 219−222. (b) RajanBabu, T. V.; Nugent, W. A.
Intermolecular Addition of Epoxides to Activated Olefins. A New
Reaction. J. Am. Chem. Soc. 1989, 111, 4525−4527. (c) Fujimura, M.;
Takai, K.; Utimoto, K. Stereoselective Construction of Quaternary
Carbons by the Reaction of Aldehydes with Allylic Chromium
Reagents Prepared from l,3-Diene Monoepoxides and CrCl2. J. Org.
Chem. 1990, 55, 1705−1706. (d) Aurrecoechea, J. M.; Solay, M.
Stereoseleetive Samarium Diiodide-Promoted Intermoleeular Cou-
pling of Alkynyloxiranes with Ketones. Synthesis of 2,3-Pentadiene-
l,5-Diols. Tetrahedron Lett. 1995, 36, 2501−2504. (e) Aurrecoechea, J.
M.; Iztueta, E. Regio- and Stereoselective Samarium Diiodide-
Promoted Intermolecular Coupling between Vinyloxiranes and
Ketones. Synthesis of 2-Alken-l,5-Diols. Tetrahedron Lett. 1995, 36,
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00960.
Representative experimental procedures and necessary
characterization data for all new compounds are
provided (PDF)
́
7129−7132. (f) Fernandez-Mateos, A.; de la Nava, E. M.; Coca, G. P.;
́
Ramos Silva, A.; Rubio Gonzalez, R. Radicals from Epoxides.
Intramolecular Addition to Aldehyde and Ketone Carbonyls. Org.
Lett. 1999, 1, 607−610. (g) Ruano, G.; Grande, M.; Anaya, J.
AUTHOR INFORMATION
Corresponding Author
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̂
Stereospecific Synthesis of Highly Functionalized Tricyclic a-Lactams
by Radical Cyclizations Using Titanocene Monochloride. J. Org.
́
̃
Chem. 2002, 67, 8243−8246. (h) Ruano, G.; Martianez, J.; Grande,
M.; Anaya, J. Stereospecific Synthesis of Polyfunctionalized
Chuan Wang − Hefei National Laboratory for Physical Science
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China; Center for Excellence in Molecular Synthesis of CAS,
Hefei, Anhui 230026, P. R. China; orcid.org/0000-0002-
9219-1785; Email: chuanw@ustc.edu.cn
Carbacephams Induced by Titanocene(III) Chloride. J. Org. Chem.
́
́
2003, 68, 2024−2027. (i) Fernandez-Mateos, A.; Mateos Buron, L.;
́
Rabanedo Clemente, R.; Ramos Silvo, A. I.; Rubio Gonzalez, R.
Radical Cyclization of Epoxynitriles Mediated by Titanocene
Chloride. Synlett 2004, 2004, 1011−1014.
Authors
(4) For a review on Ti catalysis of radical type, see: McCallum, T.;
Wu, X.; Lin, S. Recent Advances in Titanium Radical Redox Catalysis.
J. Org. Chem. 2019, 84, 14369−14380.
Zhiyang Lin − Hefei National Laboratory for Physical Science at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
(5) For selected examples on titanocene-catalyzed electrophilic ring
̈
opening of epoxides, see: (a) Gansauer, A.; Pierobon, M.; Bluhm, H.
Yun Lan − Hefei National Laboratory for Physical Science at the
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei, Anhui 230026, P. R. China
Catalytic, Highly Regio- and Chemoselective Generation of Radicals
from Epoxides: Titanocene Dichloride as an Electron Transfer
Catalyst in Transition Metal Catalyzed Radical Reactions. Angew.
̈
Chem., Int. Ed. 1998, 37, 101−103. (b) Gansauer, A.; Bluhm, H.;
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00960
Pierobon, M. Emergence of a Novel Catalytic Radical Reaction:
Titanocene-Catalyzed Reductive Opening of Epoxides. J. Am. Chem.
̈
Soc. 1998, 120, 12849−12859. (c) Gansauer, A.; Pierobon, M.;
Notes
Bluhm, H. Stereoselective Synthesis of Tri- and Tetrasubstituted
Olefins by Tandem Cyclization Addition Reactions Featuring Vinyl
The authors declare no competing financial interest.
̈
Radicals. Angew. Chem., Int. Ed. 2002, 41, 3206−3208. (d) Gansauer,
A.; Bluhm, H.; Rinker, B.; Narayan, S.; Schick, M.; Lauterbach, T.;
Pierobon, M. Reagent-Controlled Stereoselectivity in Titanocene-
Catalyzed Epoxide Openings: Reductions and Intermolecular
Additions to α,β-Unsaturated Carbonyl Compounds. Chem. - Eur. J.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (Grant No. 21772183), the Fundamental
Research Funds for the Central Universities
(WK2060190086), “1000-Youth Talents Plan” start-up fund-
ing, as well as the University of Science and Technology of
China.
̈
2003, 9, 531−542. (e) Gansauer, A.; Lauterbach, T.; Geich-Gimbel,
D. Polarity Matching of Radical Trapping: High Yielding 3-exo and 4-
exo Cyclizations. Chem. - Eur. J. 2004, 10, 4983−4990. (f) Friedrich,
J.; Walczak, K.; Dolg, M.; Piestert, F.; Lauterbach, T.; Worgull, D.;
̈
Gansauer, A. Titanocene Catalyzed 4-exo Cyclizations: Mechanism,
REFERENCES
Experiment, Catalyst Design. J. Am. Chem. Soc. 2008, 130, 1788−
■
̈
1796. (g) Gansauer, A.; Worgull, D.; Knebel, K.; Huth, I.;
(1) For reviews on nucleophilic ring opening reactions of epoxides,
see: (a) Jacobsen, E. Asymmetric Catalysis of Epoxide Ring-Opening
Reactions. Acc. Chem. Res. 2000, 33, 421−431. (b) Pastor, M. I.; Yus,
M. Asymmetric Ring Opening of Epoxides. Curr. Org. Chem. 2005, 9,
1−29. (c) Schneider, C. Synthesis of 1,2-Difunctionalized Fine
Chemicals through Catalytic, Enantioselective Ring-Opening Reac-
tions of Epoxides. Synthesis 2006, 2006, 3919−3944. (d) Wang, C.;
Luo, L.; Yamamoto, H. Metal-Catalyzed Directed Regio- and
Enantioselective Ring-Opening of Epoxides. Acc. Chem. Res. 2016,
49, 193−204. (e) Meninno, S.; Lattanzi, A. Organocatalytic
Asymmetric Reactions of Epoxides: Recent Progress. Chem. - Eur. J.
2016, 22, 3632−3642.
Schnakenburg, G. 4-exo Cyclizations by Template Catalysis. Angew.
Chem., Int. Ed. 2009, 48, 8882−8885.
(6) For a review on the radical-type coupling reactions with Michael
̈
acceptors, see: Streuff, J.; Gansauer, A. Metal-Catalyzed β-
Functionalization of Michael Acceptors through Reductive Radical
Addition Reactions. Angew. Chem., Int. Ed. 2015, 54, 14232−14242.
(7) (a) Zhao, Y.; Weix, D. J. Nickel-Catalyzed Regiodivergent
Opening of Epoxides with Aryl Halides: Co-Catalysis Controls
Regioselectivity. J. Am. Chem. Soc. 2014, 136, 48−51. (b) Zhao, Y.;
Weix, D. J. Enantioselective Cross-Coupling of meso-Epoxides with
Aryl Halides. J. Am. Chem. Soc. 2015, 137, 3237−3240.
D
https://dx.doi.org/10.1021/acs.orglett.0c00960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
̈
hlhaus, F.; Gansauer, A. General, Highly
̈
Anion and Difluorocarbene Sources. Org. Lett. 2015, 17, 4996−4999.
(k) Gao, B.; Zhao, Y.; Hu, J.; Hu, J. Difluoromethyl 2-Pyridyl Sulfone:
a Versatile Carbonyl gem-Difluoroolefination Reagent. Org. Chem.
Front. 2015, 2, 163−168. (l) 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. (m) 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. (n) Zhang, Z.; Yu, W.; Wu, C.;
Wang, C.; Zhang, Y.; Wang, J. Reaction of Diazo Compounds with
Difluorocarbene: An Efficient Approach towards 1,1-Difluoroolefins.
Angew. Chem., Int. Ed. 2016, 55, 273−277. (o) Krishnamoorthy, S.;
Kothandaraman, J.; Saldana, J.; Prakash, G. K. S. Direct Difluor-
omethylenation of Carbonyl Compounds by Using TMSCF3: The
Right Conditions. Eur. J. Org. Chem. 2016, 2016, 4965−4969. (p) Ma,
Y.; Reddy, B. R. P.; Bi, X. Coupling of Trifluoroacetaldehyde N-
Triftosylhydrazone with Organoboronic Acids for the Synthesis of
gem-Difluoroalkenes. Org. Lett. 2019, 21, 9860−9863.
(8) (a) Funken, N.; Mu
Selective Synthesis of 1,3- and 1,4-Difunctionalized Building Blocks
by Regiodivergent Epoxide Opening. Angew. Chem., Int. Ed. 2016, 55,
̈
12030−12034. (b) Yao, C.; Dahmen, T.; Gansauer, A.; Norton, J.
Anti-Markovnikov Alcohols via Epoxide Hydrogenation through
Cooperative Catalysis. Science 2019, 364, 764−767.
(9) Ye, K.-Y.; McCallum, T.; Lin, S. Bimetallic Radical Redox-Relay
Catalysis for the Isomerization of Epoxides to Allylic Alcohols. J. Am.
Chem. Soc. 2019, 141, 9548−9554.
(10) (a) Bobek, M.; Kavai, I.; De Clercq, E. Synthesis and Biological
Activity of 5-(2,2-Difluorovinyl)-2-deoxyuridinet. J. Med. Chem. 1987,
30, 1494−1497. (b) Pan, Y.; Qiu, J.; Silverman, R. B. Design,
Synthesis, and Biological Activity of a Difluoro-Substituted,
Conformationally Rigid Vigabatrin Analogue as a Potent γ-Amino-
butyric Acid Aminotransferase Inhibitor. J. Med. Chem. 2003, 46,
5292−5293. (c) Altenburger, J.-M.; Lassalle, G. Y.; Matrougui, M.;
Galtier, D.; Jetha, J.-C.; Bocskei, Z.; Berry, C. N.; Lunven, C.; Lorrain,
J.; Herault, J.-P.; Schaeffer, P.; O’Connor, S. E.; Herbert, J.-M.
SSR182289A, a Selective and Potent Orally Active Thrombin
Inhibitor. Bioorg. Med. Chem. 2004, 12, 1713−1730. (d) Messaoudi,
́
S.; Treguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J. R.;
(14) (a) Hiyama, T.; Obayashi, M.; Sawahata, M. Preparation and
Carbonyl Addition of γ,γ-Difluoroallylsilanes. Tetrahedron Lett. 1983,
24, 4113−4116. (b) Fuchikami, T.; Shibata, Y.; Suzuki, Y. Facile
Syntheses of Fluorine-containing α,β-Unsaturated Acids and Esters
from 2-Trifluoromethylacrylic Acid. Tetrahedron Lett. 1986, 27,
Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. Isocombretastatins A versus Combretastatins
A: The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic
and Antitubulin Agent. J. Med. Chem. 2009, 52, 4538−4542.
(11) (a) Meanwell, N. A. Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54,
́
́
3173−3176. (c) Begue, J.-P.; Bonnet-Delpon, D.; Rock, M. H. A
Concise Synthesis of Functionalised gem-Difluoroalkenes, via the
Addition of Organolithium Reagents to α-Trifluoromethylstyrene.
́
2529−2591. (b) Magueur, G.; Crousse, B.; Ourevitch, M.; Bonnet-
́
́
́
́
Delpon, D.; Begue, J.-P. Fluoro-artemisinins: When a gem-Difluoro-
ethylene Replaces a Carbonyl Group. J. Fluorine Chem. 2006, 127,
637−642.
Tetrahedron Lett. 1995, 36, 5003−5006. (d) Begue, J.-P.; Bonnet-
Delpon, D.; Rock, M. H. Addition of Organolithium Reagents to α-
(Trifluoromethyl)styrene: Concise Synthesis of Functionalised gem-
Difluoroalkenes. J. Chem. Soc., Perkin Trans. 1 1996, 1, 1409−1413.
(e) Ichikawa, J.; Fukui, H.; Ishibashi, Y. 1-Trifluoromethylvinylsilane
as a CF2C−-CH2+ Synthon: Synthesis of Functionalized 1,1-Difluoro-
1-alkenes via Isolable 2,2-Difluorovinylsilanes. J. Org. Chem. 2003, 68,
7800−7805. (f) Ichikawa, J.; Ishibashi, Y.; Fukui, H. A Novel
Synthesis of Functionalized 1,1-Difluoro-1-alkenes via Isolable 2,2-
Difluorovinylsilanes. Tetrahedron Lett. 2003, 44, 707−710. (g) Ichika-
wa, J.; Mori, T.; Iwai, Y. A New Class of Substrates for the
Nucleophilic 5-endo-trig Cyclization, 1-Trifluoromethylvinyl Com-
pounds: Syntheses of Indoline and Pyrrolidine Derivatives. Chem.
Lett. 2004, 33, 1354−1355. (h) Miura, T.; Ito, Y.; Murakami, M.
Synthesis of gem-Difluoroalkenes via β-Fluoride Elimination of
Organorhodium(I). Chem. Lett. 2008, 37, 1006−1007. (i) Ichikawa,
J.; Iwai, Y.; Nadano, R.; Mori, T.; Ikeda, M. A New Class of Substrates
for Nucleophilic 5-endo-trig Cyclization, 2-Trifluoromethyl-1-alkenes:
Synthesis of Five-Membered Hetero- and Carbocycles That Bear
Fluorinated One-Carbon Units. Chem. - Asian J. 2008, 3, 393−406.
(j) Fuchibe, K.; Takahashi, M.; Ichikawa, J. Substitution of Two
Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis
of 3-Fluoropyrazoles. Angew. Chem., Int. Ed. 2012, 51, 12059−12062.
(k) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J.
Cu(I)-Catalyzed Cross-Coupling of Terminal Alkynes with Trifluor-
omethyl Ketone N-Tosylhydrazones: Access to 1,1-Difluoro-1,3-
enynes. Org. Lett. 2015, 17, 2474−2477. (l) Ichitsuka, T.; Fujita,
T.; Ichikawa, J. Nickel-Catalyzed Allylic C(sp3)−F Bond Activation of
Trifluoromethyl Groups via β-Fluorine Elimination: Synthesis of
Difluoro-1,4-dienes. ACS Catal. 2015, 5, 5947−5950. (m) Hayashi,
T.; Huang, Y. H. Rhodium-Catalyzed Asymmetric Arylation/
Defluorination of 1-(Trifluoromethyl)alkenes Forming Enantioen-
riched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138, 12340−
12343. (n) Liu, Y.; Zhou, Y.; Zhao, Y.; Qu, J. Synthesis of gem-
Difluoroallylboronates via FeCl2-Catalyzed Boration/β-Fluorine
Elimination of Trifluoromethyl Alkenes. Org. Lett. 2017, 19, 946−
949. (o) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J.
Divergent Synthesis from Reactions of 2-Trifluoromethyl-1,3-
conjugated Enynes with N-Acetylated 2-Aminomalonates. Org.
Biomol. Chem. 2017, 15, 2253−2258. (p) Dai, W.; Lin, Y.; Wan, Y.;
Cao, S. Cu-Catalyzed Tertiary Alkylation of α-(Trifluoromethyl)-
(12) For reviews on synthesis of gem-difluoroalkenes and their
applications in organic synthesis, see: (a) Ichikawa, J. Gem-
Difluoroolefin Synthesis: General Methods via Thermostable
Difluorovinylmetals Starting from 2,2,2-Trifluoroethanol Derivatives.
J. Fluorine Chem. 2000, 105, 257−263. (b) Chelucci, G. Synthesis and
Metal-Catalyzed Reactions of gem-Dihalovinyl Systems. Chem. Rev.
2012, 112, 1344−1462. (c) Zhang, X.; Cao, S. Recent Advances in
the Synthesis and C-F Functionalization of gem-Difluoroalkenes.
Tetrahedron Lett. 2017, 58, 375−392.
(13) (a) Nowak, R.; Robins, M. J. New Methodology for the
Deoxygenative Difluoromethylenation of Aldehydes and Ketones;
Unexpected Formation of Tetrafluorocyclopropanes. Org. Lett. 2005,
7, 721−724. (b) Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Difluoromethyl
2-Pyridyl Sulfone: A New gem-Difluoroolefination Reagent for
Aldehydes and Ketones. Org. Lett. 2010, 12, 1444−1447.
(c) Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Conversion between
Difluorocarbene and Difluoromethylene Ylide. Chem. - Eur. J. 2013,
19, 15261−15266. (d) Zheng, J.; Cai, J.; Lin, J.-H.; Guo, Y.; Xiao, J.-
C. Synthesis and Decarboxylative Wittig Reaction of Difluoro-
methylene Phosphobetaine. Chem. Commun. 2013, 49, 7513−7515.
(e) Thomoson, C. S.; Martinez, H.; Dolbier, W. R., Jr. The Use of
Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate as the Difluorocarbene
Source to Generate an in situ Source of Difluoromethylene
Triphenylphosphonium Ylide. J. Fluorine Chem. 2013, 150, 53−59.
(f) Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. Copper-Catalyzed
gem-Difluoroolefination of Diazo Compounds with TMSCF3 via C-F
Bond Cleavage. J. Am. Chem. Soc. 2013, 135, 17302−17305. (g) Li,
Q.; Lin, J.-H.; Deng, Z.-Y.; Zheng, J.; Cai, J.; Xiao, J.-C. Wittig gem-
Difluoroolefination of Aldehydes with Difluoromethyltriphenylphos-
phonium Bromide. J. Fluorine Chem. 2014, 163, 38−41. (h) Gao, B.;
Zhao, Y.; Hu, M.; Ni, C.; Hu, J. gem-Difluoroolefination of Diaryl
Ketones and Enolizable Aldehydes with Difluoromethyl 2-Pyridyl
Sulfone: New Insights into the Julia−Kocienski Reaction. Chem. - Eur.
J. 2014, 20, 7803−7810. (i) Wang, X.-P.; Lin, J.-H.; Xiao, J.-C.;
Zheng, X. Decarboxylative Julia-Kocienski gem-Difluoro-Olefination
of 2-Pyridinyl Sulfonyldifluoroacetate. Eur. J. Org. Chem. 2014, 2014,
928−932. (j) Aikawa, K.; Toya, W.; Nakamura, Y.; Mikami, K.
Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl
E
https://dx.doi.org/10.1021/acs.orglett.0c00960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
styrenes with Tertiary Alkylmagnesium Reagents. Org. Chem. Front.
2018, 5, 55−58. (q) Wu, X.; Xie, F.; Gridnev, I. D.; Zhang, W. A
Copper-Catalyzed Reductive Defluorination of β-Trifluoromethylated
Enones via Oxidative Homocoupling of Grignard Reagents. Org. Lett.
2018, 20, 1638−1642. (r) Wang, P.; Pu, X.; Zhao, Y.; Wang, P.; Li,
Z.; Zhu, C.; Shi, Z. Enantioselective Copper-Catalyzed Defluor-
oalkylation Using Arylboronate-Activated Alkyl Grignard Reagents. J.
Am. Chem. Soc. 2018, 140, 9061−9065.
Sakaguchi, K. Fluoroalkene Modification of Mercaptoacetamide-
Based Histone Deacetylase Inhibitors. Bioorg. Med. Chem. 2010, 18,
605−611. (g) Meanwell, N. A. Fluorine and Fluorinated Motifs in the
Design and Application of Bioisosteres for Drug Design. J. Med. Chem.
2018, 61, 5822−5880.
(15) (a) Xiao, T.; Li, L.; Zhou, L. Synthesis of Functionalized gem-
Difluoroalkenes via a Photocatalytic Decarboxylative/Defluorina-tive
Reaction. J. Org. Chem. 2016, 81, 7908−7916. (b) Lang, S.; Wiles, R.
J.; Kelly, C. B.; Molander, G. A. Photoredox Generation of Carbon
Centered Radicals Enables the Construction of 1,1-Difluoroalkene
Carbonyl Mimics. Angew. Chem., Int. Ed. 2017, 56, 15073−15077.
(c) Phelan, J. P.; Lang, S. B.; Sim, J.; Berritt, S.; Peat, A. J.; Billings, K.;
Fan, L.; Molander, G. A. Open-Air Alkylation Reactions in
Photoredox-Catalyzed DNA-Encoded Library Synthesis. J. Am.
Chem. Soc. 2019, 141, 3723−3732. (d) Xia, P.-J.; Ye, Z.-P.; Hu, Y.-
Z.; Song, D.; Xiang, H.-Y.; Chen, X.-Q.; Yang, H. Photocatalytic,
Phosphoranyl Radical-Mediated N−O Cleavage of Strained Cyclo-
ketone Oximes. Org. Lett. 2019, 21, 2658−2662. (e) He, Y.; Anand,
D.; Sun, Z.; Zhou, L. Visible-Light-Promoted Redox Neutral γ,γ-
Difluoroallylation of Cycloketone Oxime Ethers with Trifluoromethyl
Alkenes via C−C and C−F Bond Cleavage. Org. Lett. 2019, 21,
3769−3773. (f) Wiles, R. J.; Phelan, J. P.; Molander, J. A. Metal-Free
Defluorinative Arylation of Trifluoromethyl Alkenes via Photoredox
Catalysis. Chem. Commun. 2019, 55, 7599−7602. (g) Guo, Y.-Q.;
Wang, R.; Song, H.; Liu, Y.; Wang, Q. Visible-Light-Induced
Deoxygenation/Defluorination Protocol for Synthesis of γ,γ-Difluor-
oallylic Ketones. Org. Lett. 2020, 22, 709−713.
(16) Tian, F.; Yan, G.; Yu, J. Recent Advance in the Synthesis and
Applications of α-(Trifluoromethyl)styrenes in Organic Synthesis.
Chem. Commun. 2019, 55, 13486−13505.
(17) (a) Lan, Y.; Yang, F.; Wang, C. Synthesis of gem-
Difluoroalkenes via Nickel-Catalyzed Allylic Defluorinative Reductive
Cross-Coupling. ACS Catal. 2018, 8, 9245−9251. (b) Lin, Z.; Lan, Y.;
Wang, C. Reductive Allylic Defluorinative Cross-Coupling Enabled by
Ni/Ti Cooperative Catalysis. Org. Lett. 2019, 21, 8316−8322.
(18) Lin, Z.; Lan, Y.; Wang, C. Synthesis of gem-Difluoroalkenes via
Nickel-Catalyzed Reductive C−F and C−O Bond Cleavage. ACS
Catal. 2019, 9, 775−781.
(19) Lu, X.; Wang, X.-X.; Gong, T.-J.; Pi, J.-J.; He, S.-J.; Fu, Y.
Nickel-Catalyzed Allylic Defluorinative Alkylation of Trifluoromethyl
Alkenes with Reductive Decarboxylation of Redox-Active Esters.
Chem. Sci. 2019, 10, 809−814.
(20) (a) Ichikawa, J.; Nadano, R.; Ito, N. 5-endo Heck-Type
Cyclization of 2-(Trifluoromethyl)allyl Ketone Oximes: Synthesis of
4-Difluoromethylene-Substituted 1-Pyrrolines. Chem. Commun. 2006,
42, 4425−4427. (b) Ding, D.; Lan, Y.; Lin, Z.; Wang, C. Synthesis of
gem-Difluoroalkenes by Merging Ni-Catalyzed C−F and C−C Bond
Activation in Cross-Electrophile Coupling. Org. Lett. 2019, 21, 2723−
2730.
̀
(21) (a) Van der Veken, P.; Senten, K.; Kertesz, I.; De Meester, I.;
́
Lambeir, A.-M.; Maes, M.-B.; Scharpe, S.; Haemers, A.; Augustyns, K.
Fluoro-Olefins as Peptidomimetic Inhibitors of Dipeptidyl Peptidases.
J. Med. Chem. 2005, 48, 1768−1780. (b) Niida, A.; Tomita, K.;
Mizumoto, M.; Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.; Inui, K.;
Fujii, N. Unequivocal Synthesis of (Z)-Alkene and (E)-Fluoroalkene
Dipeptide Isosteres To Probe Structural Requirements of the Peptide
Transporter PEPT1. Org. Lett. 2006, 8, 613−616. (c) Couve-
Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral Dipeptide Mimics
Possessing a Fuoroolefin Moiety: a Relevant Tool for Conformational
and Medicinal Studies. Org. Biomol. Chem. 2007, 5, 1151−1157.
(d) Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.;
Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel,
R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry,
N. A.; Weber, A. E. Fluoroolefins as Amide bond Mimics in dipeptidyl
Peptidase IV Inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2409−
2413. (e) Osada, S.; Sano, S.; Ueyama, M.; Chuman, Y.; Kodama, H.;
F
https://dx.doi.org/10.1021/acs.orglett.0c00960
Org. Lett. XXXX, XXX, XXX−XXX