Copper-catalyzed defluorinative borylation and silylation of gem-difluoroallyl groups

Article abstract of DOI:10.1021/acs.orglett.0c02321

Stereodefined (Z)-fluoroalkenes are bioisosteres of amides and synthetic precursors to value-added fluorinated compounds, but their stereoselective synthesis remains challenging. Herein, we report a copper-catalyzed formal S_N2′ defluorinative borylation of 3-substituted 3,3-difluoropropenes to form 3-fluoroallylboronic esters in high yields with excellent Z/E ratios. The primary 3-fluoroallylboronic esters undergo several synthetic sequences involving S_E2 substitutions, S_N2 substitutions, and sigmatropic rearrangements to provide tertiary allylic fluorides.

Full text of DOI:10.1021/acs.orglett.0c02321

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Letter
Copper-Catalyzed Defluorinative Borylation and Silylation of gem-
Difluoroallyl Groups
Trevor W. Butcher,‡ Jonathan L. Yang,‡ and John F. Hartwig*
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ABSTRACT: Stereodefined (Z)-fluoroalkenes are bioisosteres of
amides and synthetic precursors to value-added fluorinated compounds,
but their stereoselective synthesis remains challenging. Herein, we report
a copper-catalyzed formal SN2′ defluorinative borylation of 3-substituted
3,3-difluoropropenes to form 3-fluoroallylboronic esters in high yields
with excellent Z/E ratios. The primary 3-fluoroallylboronic esters
undergo several synthetic sequences involving SE2′ substitutions, SN2′ substitutions, and sigmatropic rearrangements to provide
tertiary allylic fluorides.
everal fluorinated moieties are used to mimic common
functional groups found in bioactive molecules, while
elimination or oxidative addition of C−F bonds.29−35 Several
of these methods proceed with excellent stereoselectivity.
Prominent examples of such catalytic reactions include
formal SNV borylations and silylations of 1,1-difluoroalkenes
catalyzed by copper36−41 and formal SNV arylations of 1,1-
difluoroalkenes catalyzed by palladium (Scheme 1A).42 In
addition, formal SN2′ functionalizations of trifluoromethyl
alkenes to provide 1,1-difluoroalkenes have been catalyzed by
copper and iron (Scheme 1B).43−47 Recently, Hoveyda and Ito
reported the asymmetric formal SN2′ defluorinative borylation
of 1,3-disubstituted 3,3-difluoropropenes (Scheme 1C).14
These reactions provide access to secondary 3-fluoroallylbor-
onic esters but not to primary 3-fluoroallylboronic esters that
are useful for several reaction sequences involving allylic
substitutions or sigmatropic rearrangements.
Herein, we report the formal SN2′ defluorinative borylation
and analogous silylation of 3-substituted 3,3-difluoropropenes
to provide primary 3-fluoroallylboronic esters and 3-
fluoroallylsilanes in high yields with excellent Z/E selectivities
(Scheme 1D). The 3-fluoroallylboronic ester products are
sensitive to base-mediated decomposition; consequently, we
developed conditions under which sodium tert-butoxide serves
as a substoichiometric initiator, and fluoride, which is
eliminated over the course of the reaction, induces trans-
metalation of a Bpin group to copper. The primary 3-
fluoroallylboronic esters undergo reaction sequences that are
currently unknown for secondary 3-fluoroallylboronic esters.
For example, the primary 3-fluoroallylboronic esters convert to
S
altering medicinally relevant properties, such as lipophilicity,
metabolic stability, conformation, and pKa.1 For example, −F,
−CF2H, and −CF2− groups can mimic −H, −OH, and
−C(O)− groups, respectively.2,3 A fluorinated motif of
particular interest is the (Z)-fluoroalkene because the geo-
metries and dipole orientations of these groups are similar to
those of amides. Because the hydrolytic stability and
lipophilicity of (Z)-fluoroalkenes are higher than those of
amides, they serve as bioisosteres for peptide bonds in
protease-resistant peptidomimetics.4 In addition to these
properties that are valuable for drug design, fluoroalkenes
serve as synthetic intermediates to secondary and tertiary alkyl
fluorides via hydrogenations,5−9 sigmatropic rearrange-
ments,10,11 allylic substitutions,12,13 nucleophilic allylations,14
Sigman−Heck reactions,15 and cycloadditions.16,17
The synthesis of fluoroalkenes in high isomeric purity is
important for several applications. For example, only the (Z)
isomers of fluoroalkenes serve as bioisosteres for amide bonds
(amides exist predominantly in their trans form), and
stereospecific reactions of fluoroalkenes require geometrically
pure olefins. Furthermore, the separation of geometric isomers
of olefins is often difficult, making high stereoselectivity an
important goal. Traditional methods to prepare fluoroalkenes,
such as Wittig and Horner−Wadsworth−Emmons olefina-
tions,18,19 Julia−Kocienski olefinations,20 Peterson olefina-
tions,21 Shapiro reactions,22 and alkyne hydrofluorinations,23,24
often provide the corresponding monofluoroalkenes with low
stereoselectivities. Improved reagents and catalysts for these
types of reactions are limited.25,26
Received: July 12, 2020
Due to these challenges and the wide availability of highly
fluorinated building blocks,27 new approaches to the synthesis
of fluoroalkenes based on the selective activation of C−F
bonds with transition-metal complexes have emerged.28 These
reactions typically proceed by sequences involving β-fluoride
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© XXXX American Chemical Society
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A

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nation product 3a (Table 1, entry 4). This result suggests that
the fluoride, which is eliminated over the course of this
reaction, promotes transmetalation of a Bpin group to copper.
Reactions conducted with Xantphos, IMes, and dppe occurred
in lower yields than did reactions conducted with PCy3 (Table
1, entries 6−8).
Scheme 1. Transition-Metal-Catalyzed Synthesis of
Fluoroalkenes by C−F Activation
With conditions identified for the formal SN2′ defluorinative
borylation of 2-(1,1-difluoroallyl)naphthalene, we investigated
the defluorinative borylation of a variety of analogous
electrophiles (Scheme 2). Due to the instability of the
Scheme 2. Investigation of the Scope of 3-Substituted 3,3-
Difluoropropenes That Undergo Defluorinative Borylation
tertiary allylic fluorides by oxidation and formal SN2′
substitutions catalyzed by copper or iridium12,13 or by
oxidation and tetramisole-catalyzed sigmatropic rearrange-
ments to provide tertiary allylic fluorides.
To initiate our investigation of the defluorinative borylation
of 3-substituted 3,3-difluoropropenes, we treated 2-(1,1-
difluoroallyl)naphthalene (1a)48 with bis(pinacolato)diboron
and a variety of bases in the presence of a copper catalyst.
Although 3-fluoroallylboronic ester 2a formed in moderate
yield, a significant quantity of the formal hydrodefluorination
product 3a also formed, and full conversion of the starting
material was observed (Table 1, entries 1−3).
We hypothesized that base-promoted protodeboronation of
allyl boronate 2a could be forming fluoroalkene 3a. Consistent
with this proposal, reactions conducted with substoichiometric
quantities of sodium tert-butoxide (0.4 equiv instead of 2.0
equiv) provided 3-fluoroallylboronic ester 2a in excellent yield
without concomitant formation of the formal hydrodefluori-
Table 1. Investigation of Reaction Conditions for
Defluorinative Borylation of 3-Substituted 3,3-
Difluoropropenes
a
a
entry
catalyst
base (equiv)
yield 2a (Z/E)
yield 3a
b
1
2
3
4
5
6
7
8
CuCl + PCy3
CuCl + PCy3
CuCl + PCy3
CuCl + PCy3
CuCl + PCy3
Cu(xantphos)Cl
Cu(IMes)Cl
LiOt-Bu (2.0)
NaOt-Bu (2.0)
KOt-Bu (2.0)
NaOt-Bu (0.4)
NaOt-Bu (0.2)
NaOt-Bu (0.4)
NaOt-Bu (0.4)
NaOt-Bu (0.4)
57% (94:6)
9%
34%
b
b
44% (>99:1)
b
4% (98:2)
0%
0%
0%
0%
allylboronic esters 2a−2k to chromatography, we determined
the yield and Z/E selectivity of the defluorinative borylation by
19F NMR spectroscopy and isolated the corresponding
alcohols 4a−4k after oxidation of the crude allylboronic esters.
Electrophiles bearing electron-neutral (1a, 1b), electron-rich
(1c, 1d), and electron-poor arenes (1e) underwent defluor-
inative borylation in good to excellent yields and in uniformly
high stereoselectivity.49 (1,1-Difluoroallyl)arenes bearing an
unprotected benzylic alcohol (1f), an aryl bromide (1g), or an
ortho substituent (1h) also underwent defluorinative boryla-
b
98% (99:1)
c
78% (>99:1)
74% (>99:1)
c
b
b
89% (99:1)
59% (99:1)
3%
c
CuCl + dppe
2%
a
Determined by 19F NMR with fluorobenzene as an internal standard.
b
c
Full conversion of 1a observed by 19F NMR. Remaining mass
balance corresponds to unconverted 1a. Ideal conditions used for
investigation of the scope are shown in bold.
B
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tions in high yields with excellent stereoselectivity. An aliphatic
tertiary alcohol bearing a gem-difluoroallyl group (1i) also
underwent defluorinative borylation in high yield and high
selectivity. Secondary alcohol 1j underwent defluorinative
borylation with only moderate Z/E selectivity with the catalyst
derived from CuCl and PCy3 (87:13 Z/E); however, reactions
of alcohol 1j conducted with catalytic Cu(xantphos)Cl
provided product 2j with excellent selectivity (>95:5 Z/E).
Lastly, 1H,1H,2H-perfluorooctene (1k) underwent defluor-
inative borylation to provide the corresponding highly
fluorinated allyl boronic ester 2k in excellent yield and
excellent stereoselectivity.50
considered that the SN2′ defluorinative silylation of 3-
substituted-3,3-difluoropropenes might occur under the
reaction conditions we developed for defluorinative borylation.
Indeed, the reaction of 2-(1,1-difluoroallyl)naphthalene (1a)
with a silylborane (PhMe2Si−Bpin) and NaOt-Bu in the
presence of copper chloride and tricyclohexylphosphine
afforded allyl silane 10a in excellent yield and stereoselectivity
(Scheme 4). While the chemistry of these products has not
been explored, this reaction shows a method to generate
allylsilanes containing fluorine.
Scheme 4. Defluorinative Silylation of 2-(1,1-
Difluoroallyl)naphthalene (1a)
The utility of the fluorinated allylic boronic esters as
synthetic intermediates is illustrated in Scheme 3. The boronic
Scheme 3. Synthetic Applications of 3-Fluoroallylboronic
Esters
In conclusion, we have developed a formal SN2′ defluor-
inative borylation and silylation of 3-substituted-3,3-difluor-
opropenes to provide primary 3-fluoroallylboronic esters and
3-fluoroallylsilanes in excellent stereoselectivity. The starting 3-
substituted-3,3-difluoropropenes are prepared in one step from
commercial compounds, and the products undergo reaction
sequences that lead to products that preserve the fluoroalkene
moiety or that convert the fluoroallyl unit to one containing a
tertiary allylic fluoride. Overall, the sequences initiated by the
new copper-catalyzed allylic substitutions of a boryl or silyl
group for one fluorine of a geminal difluoromethylene unit lead
to the conversion of readily available compounds containing a
difluoromethylene group to functionalized (Z)-fluoroalkenes
that serve as amide isosteres or chiral tertiary alkyl fluorides
that serve as fluorinated analogs of tertiary stereocenters.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02321.
■
esters converted to functionalized fluoroalkenes and tertiary
allylic fluorides. For example, 3-fluoroallylboronic esters 2a−2k
underwent oxidization with alkaline hydrogen peroxide to
provide the corresponding allylic alcohols 4a−4k in high yield
(Scheme 3, route a). These allylic alcohols convert to the
corresponding allylic esters, phosphates, or halides, and we
previously demonstrated that the resulting derivatives undergo
iridium-catalyzed allylic substitutions with soft nucleophiles to
provide enantioenriched tertiary allylic fluorides (Scheme 3,
route b).12,51 Konno, Ishihara, and co-workers have shown that
the corresponding phosphates undergo copper-mediated SN2′
reactions with organometallic reagents to provide racemic
tertiary allylic fluorides (Scheme 3, route c),13 and Smith and
co-workers have demonstrated that the corresponding
bromides undergo a two-step process involving a tetramisole-
catalyzed [2,3]-sigmatropic rearrangement to form enantioen-
riched α-amino-β-fluoro amides (Scheme 3, route d).10 We
demonstrated that boronic ester 2a also forms the correspond-
ing potassium trifluoroborate salt 5a in high yield under
standard conditions for conversions of boronic acids to
trifluoroborates (Scheme 3, route e),52 and we showed that
boronic ester 2a undergoes a formal SE2′ reaction with
benzaldehyde to form tertiary allylic fluoride 6a with high
diastereoselectivity (Scheme 3, route f).
sı
Experimental procedures, characterization data, and
NMR spectra for all novel compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
John F. Hartwig − Department of Chemistry, University of
California, California 94720, United States; orcid.org/
0000-0002-4157-468X; Email: jhartwig@berkeley.edu
Authors
Trevor W. Butcher − Department of Chemistry, University of
California, California 94720, United States; orcid.org/
0000-0001-5006-692X
Jonathan L. Yang − Department of Chemistry, University of
California, California 94720, United States; orcid.org/
0000-0003-3378-1379
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02321
Author Contributions
‡T.W.B. and J.L.Y. contributed equally.
Because copper-catalyzed silylation reactions are mechanis-
tically related to copper-catalyzed borylation reactions, we
C
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́
(16) McAlpine, I.; Tran-Dube, M.; Wang, F.; Scales, S.; Matthews,
J.; Collins, M. R.; Nair, S. K.; Nguyen, M.; Bian, J.; Alsina, L. M.; Sun,
J.; Zhong, J.; Warmus, J. S.; O’Neill, B. T. Synthesis of Small 3-Fluoro-
and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry. J.
Org. Chem. 2015, 80, 7266−7274.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) Mason, J. M.; Murkin, A. S.; Li, L.; Schramm, V. L.; Gainsford,
G. J.; Skelton, B. W. A β-Fluoroamine Inhibitor of Purine Nucleoside
Phosphorylase. J. Med. Chem. 2008, 51, 5880−5884.
We thank the NSF (CHE-1955635) for financial support.
T.W.B. gratefully acknowledges the National Science Founda-
tion for a predoctoral fellowship, and J.L.Y. gratefully
acknowledges the UC Berkeley Summer Undergraduate
Research Fellowship and the Rose Hills Foundation. We
thank the UC Berkeley College of Chemistry’s NMR facility
for resources provided and the staff for their assistance.
Instruments in the CoC-NMR facility are supported in part by
NIH S10OD024998.
́
(18) Depre, D.; Vermeulen, W. A. A.; Lang, Y.; Dubois, J.;
Vandevivere, J.; Vandermeersch, J.; Huang, L.; Robiette, R. Origin of
the E/Z Selectivity in the Synthesis of Tetrasubstituted Olefins by
Wittig Reaction of α-Fluorophosphonium Ylides: An Explanation for
the Low Stereoselectivity Observed in Reactions of α-Alkoxy
Aldehydes. Org. Lett. 2017, 19, 1414−1417.
(19) Zoute, L.; Dutheuil, G.; Quirion, J.-C.; Jubault, P.;
Pannecoucke, X. Efficient Synthesis of Fluoroalkenes via Dieth-
ylzinc-Promoted Wittig Reaction. Synthesis 2006, 2006, 3409−3418.
(20) Zajc, B.; Kumar, R. Synthesis of Fluoroolefins via Julia-
Kocienski Olefination. Synthesis 2010, 2010, 1822−1836.
REFERENCES
■
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in
Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
(2) Meanwell, N. A. Synopsis of Some Recent Tactical Application
of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529−2591.
(3) 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.
(21) Welch, J. T.; Herbert, R. W. The Stereoselective Construction
of (Z)-3-Aryl-2-fluoroalkenoates. J. Org. Chem. 1990, 55, 4782−4784.
(22) Yang, M.-H.; Matikonda, S. S.; Altman, R. A. Preparation of
Fluoroalkenes via the Shapiro Reaction: Direct Access to Fluorinated
Peptidomimetics. Org. Lett. 2013, 15, 3894−3897.
́
(23) Gorgues, A.; Stephan, D.; Cousseau, J. Mono-Hydrofluorina-
(4) Bartlett, P. A.; Otake, A. Fluoroalkenes as Peptide Isosteres:
Ground State Analog Inhibitors of Thermolysin. J. Org. Chem. 1995,
60, 3107−3111.
tion of Electrophilic Alkynes by the Liquid Biphasic CsF-H2O-DMF
system (DMF = N,N-dimethylformamide). J. Chem. Soc., Chem.
Commun. 1989, 1493−1494.
(24) Albert, P.; Cousseau, J. Tetrabutylammonium and Polymer-
Supported Dihydrogentrifluoride: New Hydrofluorinating Reagents
for Electrophilic Alkynes. J. Chem. Soc., Chem. Commun. 1985, 961−
962.
(25) O’Connor, T. J.; Toste, F. D. Gold-Catalyzed Hydro-
fluorination of Electron-Deficient Alkynes: Stereoselective Synthesis
of β-Fluoro Michael Acceptors. ACS Catal. 2018, 8, 5947−5951.
(26) 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.
(27) Feng, Z.; Xiao, Y.-L.; Zhang, X. Transition-Metal (Cu, Pd, Ni)-
Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl
Halides. Acc. Chem. Res. 2018, 51, 2264−2278.
(28) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Synthesis of
Monofluoroalkenes: A Leap Forward. Synthesis 2018, 50, 881−955.
(29) Hamel, J.-D.; Paquin, J.-F. Activation of C−F Bonds α to C−C
Multiple Bonds. Chem. Commun. 2018, 54, 10224−10239.
(30) 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.
(31) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Exploiting 3,3-
Difluoropropenes for the Synthesis of Monofluoroalkenes. Synlett
2016, 27, 821−830.
(32) Drouin, M.; Tremblay, S.; Paquin, J.-F. Palladium-Catalyzed
Synthesis of Monofluoroalkenes from 3,3-Difluoropropenes Using
Dimethylmalonate and Derivatives as Nucleophiles. Org. Biomol.
Chem. 2017, 15, 2376−2384.
(33) Bergeron, M.; Guyader, D.; Paquin, J.-F. SN2′ Reaction of
Allylic Difluorides with Lithium Amides and Thiolates. Org. Lett.
2012, 14, 5888−5891.
(5) Sedgwick, D. M.; Hammond, G. B. The History and Future
Challenges Associated with the Hydrogenation of Vinyl Fluorides. J.
Fluorine Chem. 2018, 207, 45−58.
(6) Ponra, S.; Yang, J.; Kerdphon, S.; Andersson, P. G. Asymmetric
Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins.
Angew. Chem. 2019, 131, 9383−9388.
(7) Krska, S. W.; Mitten, J. V.; Dormer, P. G.; Mowrey, D.;
Machrouhi, F.; Sun, Y.; Nelson, T. D. Enantioselective Synthesis of a
Chiral Fluoropiperidine via Asymmetric Hydrogenation of a Vinyl
Fluoride. Tetrahedron 2009, 65, 8987−8994.
(8) King, S. M.; Ma, X.; Herzon, S. B. A Method for the Selective
Hydrogenation of Alkenyl Halides to Alkyl Halides. J. Am. Chem. Soc.
2014, 136, 6884−6887.
(9) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P. G.
Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins
Using N,P-Ligands: A Struggle with Hydrogenolysis and Selectivity. J.
Am. Chem. Soc. 2007, 129, 4536−4537.
(10) Kasten, K.; Slawin, A. M. Z.; Smith, A. D. Enantioselective
Synthesis of β-Fluoro-β-aryl-α-aminopentenamides by Organocata-
lytic [2,3]-Sigmatropic Rearrangement. Org. Lett. 2017, 19, 5182−
5185.
(11) Kang, L.; Kim, E.; Choi, E. J.; Yoo, J. C.; Lee, W.; Hong, J. H.
Synthesis and Conformation of Novel 4′-Fluorinated 5′-Deoxythreo-
syl Phosphonic Acid Nucleosides as Antiviral Agents. Bull. Korean
Chem. Soc. 2012, 33, 4007−4014.
(12) Butcher, T. W.; Hartwig, J. F. Enantioselective Synthesis of
Tertiary Allylic Fluorides by Iridium-Catalyzed Allylic Fluoroalkyla-
tion. Angew. Chem., Int. Ed. 2018, 57, 13125−13129.
(13) Konno, T.; Ikemoto, A.; Ishihara, T. A New Entry to the
Construction of a Quaternary Carbon Center Having a Fluorine
Atom - SN2’ Reaction of gamma-Fluoroallylic Alcohol Derivatives
with Various Cyanocuprates. Org. Biomol. Chem. 2012, 10, 8154−
8163.
(14) Akiyama, S.; Kubota, K.; Mikus, M. S.; Paioti, P. H. S.; Romiti,
F.; Liu, Q.; Zhou, Y.; Hoveyda, A. H.; Ito, H. Catalytic
Enantioselective Synthesis of Allylic Boronates Bearing a Trisub-
stituted Alkenyl Fluoride and Related Derivatives. Angew. Chem., Int.
Ed. 2019, 58, 11998−12003.
(15) Liu, J.; Yuan, Q.; Toste, F. D.; Sigman, M. S. Enantioselective
Construction of Remote Tertiary Carbon−Fluorine Bonds. Nat.
Chem. 2019, 11, 710−715.
́
́
(34) Hamel, J.-D.; Drouin, M.; Paquin, J.-F. Synthesis of
Monofluoroalkenes using a Pt-Catalyzed Amination Reaction of
Cyclic 3,3-Difluoropropenes with Secondary Aliphatic Amines. J.
Fluorine Chem. 2015, 174, 81−87.
(35) Paquin, J. F. Synthesis of Monofluoroalkenes via the Activation
of Allylic C-F Bonds: A Novel Route to beta-Aminofluoroalkenes
Using Pd-Catalyzed Allylic Amination Reactions of 3,3-Difluoropro-
penes. Synlett 2011, 2011, 289−293.
D
https://dx.doi.org/10.1021/acs.orglett.0c02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(36) 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.
(37) 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.
(38) 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.
(39) Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Fluorinated Vinylsilanes
from the Copper-Catalyzed Defluorosilylation of Fluoroalkene
Feedstocks. Angew. Chem. 2018, 130, 334−338.
(40) 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.
(41) 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.
(42) Thornbury, R. T.; Toste, F. D. Palladium-Catalyzed
Defluorinative Coupling of 1-Aryl-2,2-Difluoroalkenes and Boronic
Acids: Stereoselective Synthesis of Monofluorostilbenes. Angew.
Chem., Int. Ed. 2016, 55, 11629−11632.
(43) Gao, P.; Yuan, C.; Zhao, Y.; Shi, Z. Copper-Catalyzed
Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes.
Chem. 2018, 4, 2201−2211.
(44) Zhao, X.; Li, C.; Wang, B.; Cao, S. Copper-Catalyzed Synthesis
of gem-Difluoroallylboronates from α-Trifluoromethyl Alkenes and
B2pin2. Tetrahedron Lett. 2019, 60, 129−132.
(45) Wang, M.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi, Z.
Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylbor-
onate-Activated Alkyl Grignard Reagents. J. Am. Chem. Soc. 2018, 140,
9061−9065.
(46) 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.
(47) Paioti, P. H. S.; del Pozo, J.; Mikus, M. S.; Lee, J.; Koh, M. J.;
Romiti, F.; Torker, S.; Hoveyda, A. H. Catalytic Enantioselective
Boryl and Silyl Substitution with Trifluoromethyl Alkenes: Scope,
Utility, and Mechanistic Nuances of Cu−F β-Elimination. J. Am.
Chem. Soc. 2019, 141, 19917−19934.
(48) Min, Q. Q.; Yin, Z. S.; Feng, Z.; Guo, W. H.; Zhang, X. G.
Highly Selective gem-Difluoroallylation of Organoborons with
Bromodifluoromethylated Alkenes Catalyzed by Palladium. J. Am.
Chem. Soc. 2014, 136, 1230−1233.
(49) The allylic alcohol derived from allylic boronic ester 2d was
unstable and could not be isolated. These allylic alcohols decompose
to form the corresponding aryl vinyl ketone, likely by SN1 allylic
transposition followed by loss of HF.
(50) Although the yield of the boronic ester was high, the isolated
yield of the corresponding alcohol was low due to volatility.
(51) Butcher, T. W.; Yang, J. L.; Amberg, W. M.; Watkins, N. B.;
Wilkinson, N. D.; Hartwig, J. F. Desymmetrization of difluoro-
methylene groups by C−F bond activation. Nature 2020, 583, 548−
553.
(52) Molander, G. A.; Sandrock, D. L. Potassium Trifluoroborate
Salts as Convenient, Stable Reagents for Difficult Alkyl Transfers.
Curr. Opin. Drug Discovery Dev. 2009, 12, 811−823.
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