Synthesis of gem-Difluoroalkenes by Merging Ni-Catalyzed C-F and C-C Bond Activation in Cross-Electrophile Coupling

Article abstract of DOI:10.1021/acs.orglett.9b00692

By merging C-F and C-C bond activation in the cross-electrophile coupling, we developed an efficient cyanide-free synthesis of diverse functional-group-rich cyano-substituted gem-difluoroalkenes using cyclobutanone oxime esters and trifluoromethyl alkenes

Full text of DOI:10.1021/acs.orglett.9b00692

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of gem-Difluoroalkenes by Merging Ni-Catalyzed C−F and
C−C Bond Activation in Cross-Electrophile Coupling
Decai Ding,† Yun Lan,† Zhiyang Lin,† and Chuan Wang*,†
†Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular
Synthesis, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 20237, P. R. China
S
* Supporting Information
ABSTRACT: By merging C−F and C−C bond activation in the cross-
electrophile coupling, we developed an efficient cyanide-free synthesis of diverse
functional-group-rich cyano-substituted gem-difluoroalkenes using cyclobutanone
oxime esters and trifluoromethyl alkenes as precursors. Notably, this Ni-catalyzed
reaction is bestowed with broad substrate scope, low catalyst loading, complete
regioselectivities, and high tolerance of a wide range of sensitive functional
groups. Preliminary mechanistic studies indicate that an iminyl radical-initiated
C−C bond cleavage is involved in the reaction pathway.
n recent years, cross-electrophile coupling reactions have
emerged as a powerful method in organic synthesis toward
forming reactions, offering a new entry to synthesize nitriles
under cyanide-free conditions.14,15 Herein, we envisage that
both C−C16 and C−F17 bond activation could be merged in a
Ni-catalyzed cross-electrophile coupling reaction with trifluor-
omethyl alkenes and strained cyclobutanone oxime esters as
precursors, providing an efficient cyanide-free synthesis of
diverse cyano-substituted gem-difluoroalkenes as products
(Scheme 1).
I
C−C bond formation.1 In comparison with the classic
traditional cross-coupling reactions using stoichiometric
organometallics, cross-electrophile coupling is bestowed with
better step economy and higher functional group tolerance.
The tremendous advances in this realm focus on the cleavage
of relatively weak chemical bonds, such as C−I, C−Br,
activated C−Cl, and C−O bonds,2 whereas the activation of
stronger bonds, either C−F3 or C−C bonds,4 is rarely involved
in this field, let alone their combination.
Scheme 1. Synthesis of Cyano-Substituted gem-
Difluoroalkenes by Merging C−F and C−C Bond Cleavage
in the Ni-Catalyzed Cross-Electrophile Coupling
The synthesis of organofluorine compounds is one of the
most important research subjects in pharmaceutical and
agrochemical developments.5 Being the bioisostere of meta-
bolically vulnerable carbonyl compounds, gem-difluoroalkenes
are of particular interest in drug discovery due to their higher
stability in metabolism.6 Consequently, a number of bio-
logically active compounds containing a gem-difluoroalkene
moiety have been reported.7 Furthermore, gem-difluoroalkenes
are also versatile building blocks for the synthesis of fluorine-
containing moieties, such as monofluoromethylene, difluor-
ocyclopropane, and difluoromethyl group.8 Therefore, organic
chemists have made great efforts in the last decades to develop
simpler and more efficient methods for the synthesis of
structurally diverse gem-difluoroalkenes. Conventionally, two
successful strategies have been established to access this
structural motif. The first approach relies on the functional
group conversion, in which carbonyl or diazo compounds were
transformed into a difluoromethylene moiety.9,10 Furthermore,
in a convergent strategy, organometallics or strong-base-
mediated nucleophilic addition to trifluoromethyl alkenes,
followed by β−F elimination provides an alternative path to
gem-difluoroalkenes.11 Recently, both photocatalysis12 and Ni
catalysis3b−d,13 find applications in the synthesis of gem-
difluoroalkenes under mild reaction conditions. The C−C
bond cleavage of cycloketone oxime esters was successfully
employed in a series of C−C and C−heteroatom bond-
For optimization of the reaction conditions of this Ni-
catalyzed reaction, we used acetyl-substituted α-trifluorome-
thylstyrene 1a and α-benzyl cyclobutanone O-acetyl oxime 2a
as standard substrates (Table 1). Initially, we tested a series of
ligands using NiCl2·glyme as the catalyst and Zn as the
reductant in DMF at room temperature. When bipyridine and
terpyridine ligands L1−3 were employed, the reaction afforded
the cross-coupled product 3a in low to moderate yields
(entries 1−3). Notably, the cleavage of the C−C bond
occurred on the more-substituted site with complete
regiocontrol. In the case of the phenanthroline-based ligand
L4, no desired product was formed (entry 4). Next, several Ni
salts were investigated as catalysts, providing no better yield
Received: February 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00692
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Letter
Table 1. Optimization of the Reaction Conditions for the
Ni-Catalzyed Cross-Coupling Reaction
Scheme 2. Evaluation of the Substrate Scope by Variation of
the Structure of the Trifluoromethyl Alkenes
a
a b
,
b
entry
metal−salt
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
Ni(COD)2
NiBr2
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
THF
DMA
DMA
DMA
DMA
DMA
DMA
13
22
49
0
18
40
trace
25
16
56
0
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of α-trifluoromethylstyrenes 1 with 2 equiv α-benzyl cyclo-
butanone O-acetyl oxime 2a, 1 mol % NiCl2·glyme, 1 mol % ligand
L3, and 2 equiv Zn as the reductant in 2 mL of DMA at 60 °C for 40
Ni(acac)2
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
b
c
h. Yields of the isolated products. Determined by 13C NMR
spectroscopy.
c
11
d
12
e
trace
73
82
58
turned out to be suitable for this Ni-catalyzed reaction,
affording the product 3j in a good yield.
13
e f
,
14
Subsequently, we continued to explore the substrate
spectrum of this defluorinative reaction by varying the
structure of the cyclobutanone oxime esters (Scheme 3). In
the case of symmetrical cyclobutanone O-acetyl oximes, all of
the reactions proceeded smoothly under the optimal
conditions, affording the products 3k−t in moderate to high
yield. When unsymmetrical cyclic oxime esters were utilized as
precursors, all of the C−C bond cleavages occurred selectively
at the more substituted carbon center, furnishing the products
3u−aj in good to high yield. Remarkably, in the case of the cis-
bi-, and tri-cyclic oxime esters as substrates, only the formation
of trans-configurated products 3x−aj was observed, suggesting
a complete conversion of the stereochemistry of the newly
formed stereocenter. Furthermore, a 10 mmol scale reaction
was performed, providing the product 3k in a similar yield,
wherein the catalyst loading could be reduced to 0.5 mol %.
Unfortunately, the reactions using cyclopentanone- and
cyclohexanone-derived oxime esters as precursors failed to
yield the ring-opening products.
Next, we tested the application of our methodology in the
reactions involving some structurally complex trifluoromethyl
alkenes or cyclobutanone oxime esters, which derive from
gemfibrozil, estrone, stigmasterol, and vitamin E. To our
delight, all of the reactions afforded the desired products in
moderate to good yield (Scheme 4).
Furthermore, some derivatizations based on the conversion
of the cyano and gem-difluoroalkene moieties were carried out
(Scheme 5). The hydrolysis of 3k under basic conditions
delivered a carboxylic acid 4 and an amide 5 in good yield,
respectively. The diisobutylaluminum hydride (DIBAL-H)-
mediated reduction at −78 °C afforded an aldehyde 6 with
high efficiency. In addition, the difluoromethylene moiety was
successfully converted to a difluoromethyl group via a Pd/C-
catalyzed hydrogenation.
g
15
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of acetyl-substituted α-trifluoromethylstyrene 1a with 2 equiv α-
benzyl cyclobutanone O-acetyl oxime 2a, 5 mol % nickel-salt, 5 mol %
ligand, and 2 equiv Zn as the reductant in 2 mL of solvent at room
b
c
temperature for 40 h. Yields of the isolated product. Mn was used as
d
the reductant instead of Zn. Reaction was performed at 0 °C.
e
f
Reaction was performed at 60 °C. Reaction was performed with 1
g
mol % catalyst and 1 mol % ligand. Reaction was performed with 1
equiv α-benzyl cyclobutanone O-acetyl oxime 2a.
(entries 5−7). Moreover, a brief solvent screening was
undertaken, and an improved result was obtained in the case
of DMA as the solvent (entries 8−10). Replacing Zn by Mn as
the reducing agent resulted in a complete shutdown of the
studied reaction (entry 11). Furthermore, the temperature
impact on this Ni-catalyzed reaction was explored. At 0 °C, the
reaction became very sluggish, affording only a trace of product
(entry 12). In contrast, increasing the reaction temperature to
60 °C gave rise to a significantly improved efficiency (entry
13). Finally, the yield of the studied reaction was improved to a
high level, when the catalyst loading was lowered to 1 mol %
(entry 14). Reducing the amount of the oxime ester 2a to 1
equiv led to a decrease in the yield to 58%.
After establishing the optimal reaction conditions, we started
to evaluate the substrate scope of this Ni-catalyzed reductive
cross-coupling reaction (Scheme 2). First, we reacted α-benzyl
cyclobutanone O-acetyl oxime (2a) with a variety of aryl and
heteroaryl-substituted trifluoromethyl alkenes 1a−i. To our
delight, all of the reactions furnished the corresponding cyano-
substituted gem-difluoroalkenes 3a−i in moderate to good
yield. Notably, these reactions demonstrate good tolerance of
diverse functional moieties including ketones (3a), halides (3b
and 3c), amines (3d), hydroxyl group (3e), and amides (3f
and 3i). Furthermore, alkynyl trifluoromethyl alkene also
A series of control experiments were carried out to explore
the mechanism of this Ni-catalyzed reaction (Scheme 6). First,
a stoichiometric reaction of Ni(COD)2 with the trifluor-
B
DOI: 10.1021/acs.orglett.9b00692
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Organic Letters
Letter
a b
,
Scheme 3. Evaluation of the Substrate Scope by Variation of the Structure of the Cycloketone O-Acetyl Oximes18
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of trifluoromethyl alkenes 1 with 2 equiv cyclobutanone O-acetyl oximes
b
2, 1 mol % NiCl2·glyme, 1 mol % ligand L3, and 2 equiv Zn as the reductant in 2 mL of DMA at 60 °C for 40 h. Yields of the isolated products.
c
d
Reaction was performed on a 10 mmol scale using 0.5 mmol % catalyst loading. Determined by 13C NMR spectroscopy.
omethyl alkene 1a and the oxime ester 2a in the absence of a
reducing agent was carried out, providing the coupling product
3a in a moderate yield (Scheme 6A). This result indicates that
the Zn powder can serve as a terminal reductant in this
reaction. In our previous work, it was discovered that Ni(0)
species does not react with acyclic oxime esters.19 Thus we
wonder if strained cyclic oxime esters are also inert in the
presence of Ni(0) complex. To verify this, we performed the
stoichiometric reaction between Ni(COD)2 and the oxime
ester 2a (Scheme 6B). In contrast, a full consumption of 2a
was observed, and the ring opening product 5-phenyl-
pentanenitrile was afforded in a moderate yield after the
reaction was quenched with water. It is known that transition-
metal-promoted ring opening of cycloketone oxime esters can
proceed via either two-electron β-carbon elimination15a,b or
iminyl radical-initiated ring opening.15c−o To find out the
actual pathway of the studied reaction, we conducted the
stoichiometric reaction of the cyclic ketone ester 2n and
Ni(COD)2 with TEMPO as a radical scavenger (Scheme 6C).
In this case, the TEMPO adduct 8 was obtained in a moderate
yield, suggesting the formation of a carbon-centered radical in
the reaction mixture, which is generated through the iminyl
radical-initiated C−C bond cleavage. The aforementioned
results imply that the Ni(0) species is probably responsible for
the ring opening of cyclobutanone O-acetyl oximes. However,
we cannot exclude the possibility that an in situ generated
Ni(I) complex is the actual species inducing the radical-type
ring opening because the Ni(I) species is known to produce
alkyl radicals through interaction with alkyl halides.20
Next, a sequential stoichiometric reaction was conducted by
adding the trifluoromethyl alkene 1b to the premixed oxime
ester 2b, ligand L3, and Ni(COD)2 in DMA. However, the
cross-coupled product 3k was not formed in this case (Scheme
3D). The rapid H-radical abstraction of the carbon-centered
radical prior to the addition of 1b might account for this result.
Subsequently, we continued to explore the interaction between
the catalyst and the trifluoromethyl alkenes. According to our
previous work,3b,c Ni(0) species can likely form a complex with
trifluoromethyl alkenes using pyridine-based ligands, whereas
Ichikawa et al. discovered the formation of nickelacyclopro-
pane in the reaction between Ni(COD)2 and a trifluoromethyl
alkene using a phosphine ligand.13,21 Moreover, we wonder
how trifluoromethyl alkenes interact with the Ni(I) species,
which is probably also available in the reaction mixture under
the reductive conditions. Thus we performed the stoichio-
metric reaction employing trifluoromethylalkene 1b and NiCl2·
glyme with Zn as the reductant (Scheme 6E). In this case, the
hydrogenated product 9 was furnished in a moderate yield,
implying the formation of a nickelacyclopropane through the
interaction between an in situ generated Ni(I) species and the
C
DOI: 10.1021/acs.orglett.9b00692
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Organic Letters
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Scheme 4. Cross-Coupling Reaction Involving Structurally Complex Trifluoromethyl Alkenes or Cyclobutanone Oxime
a b
,
Esters
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of trifluoromethyl alkenes 1 with 2 equiv cyclobutanone O-acetyl oximes
b
2, 1 mol % NiCl2·glyme, 1 mol % ligand L3, and 2 equiv Zn as the reductant in 2 mL of DMA at 60 °C for 40 h. Yields of the isolated products.
c
Determined by 13C NMR spectroscopy.
Scheme 5. Derivatizations of a Ni-Catalyzed Defluorinative
Scheme 6. Control Experiments
Cross-Coupling Product
trifluoromethyl alkene 1b. When the oxime ester 2b was added
to the mixture instead of water, the desired product 3k was
provided in a moderate yield, revealing that a catalytic cycle
with the interaction between trifluoromethyl alkenes and Ni
catalyst as the initial step is feasible.
On the basis of the experimental results and previous
reports, we proposed two plausible mechanisms for this Ni-
catalyzed reaction (Scheme 7). The main difference between
them lies in the way the radicals add to the olefinic unit in the
C−C bond-forming step, which can proceed either off or on
the Ni catalyst. The first catalytic cycle is initiated by the
interaction of a Ni(0) species I with cyclobutanone oxime ester
2 (Scheme 4A). The generated iminyl radical II undergoes the
ring-opening reaction, providing a C-centered radical III. The
subsequent radical addition of III to trifluoromethyl alkene 1
without the participation of a Ni catalyst affords a relatively
electron-deficient α-trifluoromethyl carbon-radical IV, which
tends to perform the radical addition to the Ni(I) species V.
Next, the β-fluoro elimination on the resultant Ni(II)
intermediate VI provides the gem-difluoroalkene 3 as the
product and a Ni(II) species VII, which is reduced by Zn to
regenerate the Ni(0) species I for the next catalytic cycle. The
seminal work of Zhou and Molander revealed that alkyl
radicals are able to perform the addition to trifluoromethyl
alkenes in polar aprotic solvent in the absence of Ni, which
supports the mechanism mentioned above.12 Alternatively, the
reaction can start with the complexation of trifluoromethyl
alkene 1 with the Ni(0) species I (Scheme 4B). The afforded
Ni(0) complex VIII interacts with cyclobutanone oxime ester
D
DOI: 10.1021/acs.orglett.9b00692
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Scheme 7. Proposed Mechanisms of the Ni-Catalyzed
Reaction
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00692.
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chuanw@ustc.edu.cn.
ORCID
Chuan Wang: 0000-0002-9219-1785
Notes
The authors declare no competing financial interest.
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.
REFERENCES
■
(1) For reviews on cross-electrophile couplings, see: (a) Everson, D.
A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity
and Selectivity. J. Org. Chem. 2014, 79, 4793−4798. (b) Moragas, T.;
Correa, A.; Martin, R. Metal-Catalyzed Reductive Coupling Reactions
of Organic Halides with Carbonyl-Type Compounds. Chem. - Eur. J.
2014, 20, 8242−8258. (c) Gu, J.; Wang, X.; Xue, W.; Gong, H.
Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Other
Electrophiles: Concept and Mechanistic Considerations. Org. Chem.
Front. 2015, 2, 1411−1421. (d) Weix, D. J. Methods and Mechanisms
for Cross-Electrophile Coupling of Csp2 Halides with Alkyl
Electrophiles. Acc. Chem. Res. 2015, 48, 1767−1775. (e) Wang, X.;
Dai, Y.; Gong, H. Nickel-Catalyzed Reductive Couplings. Top. Curr.
Chem. 2016, 374, 43−72. (f) Richmond, E.; Moran, J. Recent
Advances in Nickel Catalysis Enabled by Stoichiometric Metallic
Reducing Agents. Synthesis 2018, 50, 499−513.
(2) For selected examples of cross-electrophile coupling involving
C−I, C−Br activated C−Cl, and C−O bonds, see: (a) Amatore, M.;
Gosmini, C. Angew. Chem., Int. Ed. 2008, 47, 2089−2092. (b) Everson,
D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-
Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010,
132, 920−921. (c) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H.
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl
Halides. Org. Lett. 2011, 13, 2138−2141. (d) Wotal, A. C.; Weix, D. J.
Synthesis of Functionalized Dialkyl Ketones from Carboxylic Acid
Derivatives and Alkyl Halides. Org. Lett. 2012, 14, 1476−1479.
(e) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Ketone Formation
via Mild Nickel-Catalyzed Reductive Coupling of Alkyl Halides with
Aryl Acid Chlorides. Org. Lett. 2012, 14, 3044−3047. (f) Everson, D.
A.; Jones, B. A.; Weix, D. J. Replacing Conventional Carbon
Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkyla-
tion of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134,
6146−6159. (g) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E.
Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of
Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc.
2013, 135, 7442−7445. (h) Correa, A.; Martin, R. Ni-Catalyzed
Direct Reductive Amidation via C−O Bond Cleavage. J. Am. Chem.
Soc. 2014, 136, 7253−7256. (i) Zhao, C.; Jia, X.; Wang, X.; Gong, H.
Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated
Tertiary Alkyl and Glycosyl Halides. J. Am. Chem. Soc. 2014, 136,
2 to initiate the radical-mediated C−C bond cleavage.
Meanwhile, the produced Ni(I) complex IX undergoes the
oxidative addition to form a nickelacyclopropane X. The
subsequent reductive ring opening of X leads to the formation
of the Ni(II) intermediate VI. The following β-fluoro
elimination furnishes the coupling product 3. In the final
step, Zn-mediated terminal reduction of VII regenerates the
Ni(0) species I.
In summary, a Ni-catalyzed cross-electrophile coupling of
cycloketone oxime esters with trifluoromethyl alkenes has been
accomplished through merging C−F and C−C bond
activation. This new method offers efficient access to prepare
various cyano-substituted gem-difluoroalkenes under cyanide-
free conditions, featuring a broad substrate scope, low catalyst
loading, complete regiocontrol, and high tolerance of a wide
range of sensitive functional moieties. Two different versions of
the reaction mechanism were proposed based on experimental
results and previous reports, and Ni-mediated generation of
iminyl radicals leading to the subsequent C−C bond cleavage
is involved in both cases.
E
DOI: 10.1021/acs.orglett.9b00692
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Letter
17645−17651. (j) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J.
Multimetallic Catalysed Cross-Coupling of Aryl Bromides with Aryl
Triflates. Nature 2015, 524, 454−457. (k) Ackerman, L. K. G.; Anka-
Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt Co-Catalysis for
Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates
and Aryl Halides. Chem. Sci. 2015, 6, 1115−1119. (l) Kadunce, N. T.;
Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling between Heteroaryl Iodides and α-Chloronitriles. J. Am.
Chem. Soc. 2015, 137, 10480−10483. (m) Wang, X.; Wang, S.; Xue,
W.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Bromides
with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2015, 137, 11562−
11565. (n) Arendt, K. M.; Doyle, A. G. Dialkyl Ether Formation by
Nickel-Catalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew.
Chem., Int. Ed. 2015, 54, 9876−9880. (o) Liu, J.; Ren, Q.; Zhang, X.;
Gong, H. Preparation of Vinyl Arenes by Nickel-Catalyzed Reductive
Coupling of Aryl Halides with Vinyl Bromides. Angew. Chem., Int. Ed.
Catalyzed Reductive Electrophilic Ring Opening of Cycloketone
Oxime Esters with Aroyl Chlorides. ACS Catal. 2018, 8, 11324−
11329.
(5) (a) Organofluorine Chemistry, Principles and Commercial
Applications. In Topics in Applied Chemistry; Banks, R. E., Smart, B. E.,
Tatlow, J. C., Eds.; Springer Press: New York, 1994. (b) Modern
Fluoroorganic Chemistry: Synthesis Reactivity, Applications; Kirsch, P.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004. (c) Muller, K.; Faeh,
̈
C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond
Intuition. Science 2007, 317, 1881−1886. (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem.
Soc. Rev. 2008, 37, 320−330. (e) Hagmann, W. K. The Many Roles
for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359−
4369. (f) Kirk, K. L. Fluorination in Medicinal Chemistry: Methods,
Strategies, and Recent Developments. Org. Process Res. Dev. 2008, 12,
305−321. (g) Fluorine in Medicinal Chemistry and Chemical Biology;
Ojima, I., Ed.; Wiley-Blackwell: Chichester, U.K., 2009. (h) Modern
Fluoroorganic Chemistry: Synthesis Reactivity, Applications, 2nd ed.;
Kirsch, P., Ed.; Wiley-VCH: Weinheim, Germany, 2013. (I) 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. (j) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.;
̈
2016, 55, 15544−15548. (p) Borjesson, M.; Moragas, T.; Martin, R.
Ni-Catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2.
J. Am. Chem. Soc. 2016, 138, 7504−7507. (q) Zhang, P.; Le, C.;
MacMillan, D. W. C. Silyl Radical Activation of Alkyl Halides in
Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electro-
phile Coupling. J. Am. Chem. Soc. 2016, 138, 8084−8087. (r) Hansen,
E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron,
S.; Weix, D. J. New Ligands for Nickel Catalysis from Diverse
Pharmaceutical Heterocycle Libraries. Nat. Chem. 2016, 8, 1126−
1130. (s) Cai, Y.; Benischke, A. D.; Knochel, P.; Gosmini, C. Chem. -
Eur. J. 2017, 23, 250−253. (t) Woods, B. P.; Orlandi, M.; Huang, C.-
Y.; Sigman, M. S.; Doyle, A. G. Nickel-Catalyzed Enantioselective
Reductive Cross-Coupling of Styrenyl Aziridines. J. Am. Chem. Soc.
2017, 139, 5688−5691. (u) Chen, F.; Chen, K.; Zhang, Y.; He, Y.;
Wang, Y.-M.; Zhu, S. Remote Migratory Cross-Electrophile Coupling
and Olefin Hydroarylation Reactions Enabled by in Situ Generation
of NiH. J. Am. Chem. Soc. 2017, 139, 13929−13935. (v) Ai, Y.; Ye, N.;
Wang, Q.; Yahata, K.; Kishi, Y. Zirconium/Nickel-Mediated One-Pot
Ketone Synthesis. Angew. Chem., Int. Ed. 2017, 56, 10791−10795.
(w) Peng, L.; Li, Z.; Yin, G. Photochemical Nickel-Catalyzed
Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl
Bromides. Org. Lett. 2018, 20, 1880−1883. (x) Hofstra, J. L.;
Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of
Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive
Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 139−142. (y) Yan,
X.-B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z. Reductive Coupling of
Benzyl Oxalates with highly Functionalized Alkyl Bromides by Nickel
Catalysis. Chem. Sci. 2018, 9, 4529−4534. (z) Heinz, C.; Lutz, J. P.;
Simmons, E. M.; Miller, M. M.; Ewing, W. R.; Doyle, A. G. J. Am.
Chem. Soc. 2018, 140, 2292−2300. (aa) Wang, X.; Ma, G.; Peng, Y.;
Pitsch, C. E.; Moll, B. J.; Ly, T. D.; Wang, X.; Gong, H. Ni-Catalyzed
Reductive Coupling of Electron-Rich Aryl Iodides with Tertiary Alkyl
Halides. J. Am. Chem. Soc. 2018, 140, 14490−14497.
Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of
̃
Fluorine-Containing Pharmaceuticals, Compounds Currently in
Phase II−III Clinical Trials of Major Pharmaceutical Companies:
New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116,
422−518. (k) Liu, Q.; Ni, C.; Hu, J. China’s Flourishing Synthetic
Organofluorine Chemistry: Innovations in the New Millennium. Natl.
Sci. Rev. 2017, 4, 303−325.
(6) (a) Bobek, M.; Kavai, I.; De Clercq, E. Synthesis and Biological
Activity of 5-(2,2-Difluorovinyl)-2’-deoxyuridine. 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.;
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 Agen. J. Med. Chem. 2009, 52, 4538−4542.
(7) (a) Meanwell, N. A. Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54,
́
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. (c) Leriche, C.; He, X.; Chang, C.-w.; Liu, H.-w. Reversal
of the Apparent Regiospecificity of NAD(P)H-Dependent Hydride
Transfer: The Properties of the Difluoromethylene Group, A
Carbonyl Mimic. J. Am. Chem. Soc. 2003, 125, 6348−6349.
(3) (a) Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-
J.; Xiao, B.; Fu, Y. Nickel-Catalyzed Defluorinative Reductive Cross-
Coupling of gem-Difluoroalkenes with Unactivated Secondary and
Tertiary Alkyl Halide. J. Am. Chem. Soc. 2017, 139, 12632−12637.
(b) Lan, Y.; Yang, F.; Wang, C. Synthesis of gem-Difluoroalkenes via
Nickel-Catalyzed Allylic Defluorinative Reductive Cross-Coupling.
ACS Catal. 2018, 8, 9245−9251. (c) 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, 775−780. (d) 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. (e) Zhou, L.; Zhu, C.; Bi, P.; Feng, C.
Ni-Catalyzed Migratory Fluoro-Alkenylation of Unactivated Alkyl
Bromides with gem-Difluoroalkenes. Chem. Sci. 2019, 10, 1144−1149.
(4) (a) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A.
M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.;
Ackerman, L. K. G.; Weix, D. J. Decarboxylative Cross-Electrophile
Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am.
Chem. Soc. 2016, 138, 5016−5019. (b) Ding, D.; Wang, C. Nickel-
(8) For reviews on the 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.
(9) For recent examples of the gem-difluoroolefination of carbonyl
compounds, see: (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
F
DOI: 10.1021/acs.orglett.9b00692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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 Difluoromethylene Phosphobe-
taine. 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) Li, Q.; Lin, J.-H.; Deng, Z. Y.;
Zheng, J.; Cai, J.; Xiao, J.-C. Wittig gem-Difluoroolefination of
Aldehydes with Difluoromethyltriphenylphosphonium Bromide. J.
Fluorine Chem. 2014, 163, 38−41. (g) 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.
(h) Wang, X.-P.; Lin, J.-H.; Xiao, J.-C.; Zheng, X. Decarboxylative
Julia−Kocienski gem-Difluoro-Olefination of 2-Pyridinyl Sulfonyldi-
fluoroacetate. Eur. J. Org. Chem. 2014, 2014, 928−932. (i) Aikawa, K.;
Toya, W.; Nakamura, Y.; Mikami, K. Development of
(Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and
Difluorocarbene Sources. Org. Lett. 2015, 17, 4996−4999. (j) 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. (k) Krishnamoorthy, S.; Kothandaraman,
J.; Saldana, J.; Prakash, G. K. S. Direct Difluoromethylenation of
Carbonyl Compounds by Using TMSCF3: The Right Conditions.
Eur. J. Org. 2016, 2016, 4965−4969.
(10) For selected examples of the gem-difluoroolefination of diazo
compounds, see: (a) 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. (b) 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
Precursor. J. Am. Chem. Soc. 2015, 137, 14496−14501. (c) 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. (d) 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.
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) Hayashi, T.; Huang, Y. H. Rhodium-Catalyzed Asymmetric
Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming
Enantioenriched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138,
12340−12343. (l) 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. (m) Dai, W.; Lin, Y.; Wan, Y.;
Cao, S. Cu-Catalyzed Tertiary Alkylation of α-(Trifluoromethyl)-
styrenes with Tertiary Alkylmagnesium Reagents. Org. Chem. Front.
2018, 5, 55−58. (n) 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. (o) 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.
(12) (a) Xiao, T.; Li, L.; Zhou, L. Synthesis of Functionalized gem-
Difluoroalkenes via a Photocatalytic Decarboxylative/Defluorinative
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 Mimic. Angew. Chem., Int. Ed. 2017, 56, 15073−15077.
(13) 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.
(14) For reviews on the use of oxime esters in the organic synthesis,
see: (a) Huang, H.; Cai, J.; Deng, G.-J. O-Acyl Oximes: Versatile
Building Blocks for N-Heterocycle Formation in Recent Transition
Metal Catalysis. Org. Biomol. Chem. 2016, 14, 1519−1530.
(b) Vessally, E.; Saeidian, H.; Hosseinian, A.; Edjlali, L.;
Bekhradnia, A. A Review on Synthetic Applications of Oxime Esters.
Curr. Org. Chem. 2016, 21, 249−271. (c) Race, N. J.; Hazelden, T. R.;
Faulkner, A.; Bower, J. F. Recent Developments in the Use of aza-
Heck Cyclizations for the Synthesis of Chiral N-Heterocycles. Chem.
Sci. 2017, 8, 5248−5260. (d) Davies, J.; Morcillo, S. P.; Douglas, J. J.;
Leonori, D. Hydroxylamine Derivatives as Nitrogen-Radical Pre-
cursors in Visible-Light Photochemistry. Chem. - Eur. J. 2018, 24,
12154−12163.
(15) For selected examples of C−C bond cleavage reactions
involving cycloketone oxime esters, see: (a) Nishimura, T.; Uemura,
S. Palladium(0)-Catalyzed Ring Cleavage of Cyclobutanone Oximes
Leading to Nitriles via β-Carbon Elimination. J. Am. Chem. Soc. 2000,
122, 12049−12050. (b) Nishimura, T.; Nishiguchi, Y.; Maeda, Y.;
Uemura, S. Palladium-Catalyzed Transformation of Cyclobutanone
O-Benzoyloximes to Nitriles via C−C Bond Cleavage. J. Org. Chem.
2004, 69, 5342−5347. (c) Nishimura, T.; Yoshinaka, T.; Nishiguchi,
Y.; Maeda, Y.; Uemura, S. Iridium-Catalyzed Ring Cleavage Reaction
of Cyclobutanone O-Benzoyloximes Providing Nitriles. Org. Lett.
2005, 7, 2425−2427. (d) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.-N.
Direct C−H Cyanoalkylation of Heteroaromatic N-Oxides and
Quinones via C−C Bond Cleavage of Cyclobutanone Oximes. Org.
Lett. 2017, 19, 5908−5911. (e) Yang, H.-B.; Selander, N. Divergent
Iron-Catalyzed Coupling of O-Acyloximes with Silyl Enol Ethers.
Chem. - Eur. J. 2017, 23, 1779−1783. (f) Zhao, B.; Shi, Z. Copper-
Catalyzed Intermolecular Heck-Like Coupling of Cyclobutanone
Oximes Initiated by Selective C−C Bond Cleavage. Angew. Chem., Int.
Ed. 2017, 56, 12727−12731. (g) Yang, H.-B.; Pathipati, S. R.;
Selander, N. Nickel-Catalyzed 1,2-Aminoarylation of Oxime Ester-
Tethered Alkenes with Boronic Acids. ACS Catal. 2017, 7, 8441−
8445. (h) Li, L.; Chen, H.; Mei, M.; Zhou, L. Visible-Light Promoted
(11) For selected examples of the synthesis of gem-difluoroalkenes
via organometallic- or strong-base-mediated nucleophilic addition to
trifluoromethyl alkenes involving β-F elimination, see: (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, 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. 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 CF2C−−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) Ichikawa, J.; Mori, T.; Iwai, Y. A New Class of Substrates for
the Nucleophilic 5-endo-trig Cyclization, 1-Trifluoromethylvinyl
Compounds: 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
G
DOI: 10.1021/acs.orglett.9b00692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
γ-Cyanoalkyl Radical Generation: Three-Component Cyanopropyla-
tion/Etherification of Unactivated Alkenes. Chem. Commun. 2017, 53,
11544−11547. (i) He, B.-Q.; Yu, X.-Y.; Wang, P.-Z.; Chen, J.-R.;
Xiao, W.-J. Photoredox Catalyzed Iminyl Radical-Triggered C-C Bond
Cleavage/Addition/Kornblum Oxidation Cascade of Oxime Esters
and Styrenes: Synthesis of Ketonitriles. Chem. Commun. 2018, 54,
12262−12265. (j) Ai, W.; Liu, Y.; Wang, Q.; Lu, Z.; Liu, Q. Cu-
Catalyzed Redox-Neutral Ring Cleavage of Cycloketone O-Acyl
Oximes: Chemodivergent Access to Distal Oxygenated Nitriles. Org.
Lett. 2018, 20, 409−412. (k) Yang, L.; Gao, P.; Duan, X.-H.; Gu, Y.-
R.; Guo, L.-N. Direct C−H Cyanoalkylation of Quinoxalin-2(1H)-
ones via Radical C−C Bond Cleavage. Org. Lett. 2018, 20, 1034−
1037. (l) Yu, X.-Y.; Chen, J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.;
Xiao, W.-J. A Visible-Light-Driven Iminyl Radical-Mediated C−C
Single Bond Cleavage/Radical Addition Cascade of Oxime Esters.
Angew. Chem., Int. Ed. 2018, 57, 738−743. (m) Dauncey, E. M.;
Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Photoinduced
Remote Functionalisations by Iminyl Radical Promoted C−C and C−
H Bond Cleavage Cascades. Angew. Chem., Int. Ed. 2018, 57, 744−
747. (n) Wu, J.; Zhang, J. Y.; Gao, P.; Xu, S.-L.; Guo, L.-N. Copper-
Catalyzed Redox-Neutral Cyanoalkylarylation of Activated Alkenes
with Cyclobutanone Oxime Esters. J. Org. Chem. 2018, 83, 1046−
1055. (o) Zhang, J.-J.; Duan, X.-H.; Wu, Y.; Yang, J.-C.; Guo, L.-N.
Transition-Metal Free C−C Bond Cleavage/Borylation of Cyclo-
ketone Oxime Esters. Chem. Sci. 2019, 10, 161−166.
B.; Katigbak, J.; Hu, C.; Diao, T. J. Am. Chem. Soc. 2019, 141, 1788−
1796.
(21) Ichitsuka, T.; Fujita, T.; Arita, T.; Ichikawa, J. Double C-F
Bond Activation through β-Fluorine Elimination: Nickel-Mediated [3
+ 2] Cycloaddition of 2-Trifluoromethyl-1-alkenes with Alkynes.
Angew. Chem., Int. Ed. 2014, 53, 7564−7568.
(16) For general reviews on the C−C bond cleavage reactions, see:
(a) C−C Bond Activation; Dong, G., Ed.; Topics in Current
Chemistry; Springer-Verlag: Berlin Heidelberg, Germany, 2014; p
346. (b) Marek, I.; Masarwa, A.; Delaye, P.-O.; Leibeling, M. Selective
Carbon−Carbon Bond Cleavage for the Stereoselective Synthesis of
Acyclic Systems. Angew. Chem., Int. Ed. 2015, 54, 414−429.
(c) Souillart, L.; Cramer, N. Catalytic C−C Bond Activations via
Oxidative Addition to Transition Metals. Chem. Rev. 2015, 115,
9410−9464. (d) Murakami, M.; Ishida, N. Potential of Metal-
Catalyzed C−C Single Bond Cleavage for Organic Synthesis. J. Am.
Chem. Soc. 2016, 138, 13759−13769. (e) Fumagalli, G.; Stanton, S.;
Bower, J.-F. Recent Methodologies That Exploit C−C Single-Bond
Cleavage of Strained Ring Systems by Transition Metal Complexes.
Chem. Rev. 2017, 117, 9404−9432. (f) Nairoukh, Z.; Cormier, M.;
Marek, I. Merging C−H and C−C bond cleavage in organic synthesis.
Nat. Chem. Rev. 2017, 1, 35.
(17) For reviews on C−F bond cleavage in the organic synthesis,
see: (a) Burdeniuc, J.; Jedicka, B.; Crabtree, R. H. Recent Advances in
C−F Bond Activation. Chem. Ber. 1997, 130, 145−154. (b) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119−2183. (c) Ahrens, T.;
Kohlmann, J.; Ahrens, M.; Braun, T. C−F Bond Activation in Organic
Synthesis. Functionalization of Fluorinated Molecules by Transition-
Metal-Mediated C−F Bond Activation To Access Fluorinated
Building Blocks. Chem. Rev. 2015, 115, 931−972. (d) Hamel, J.-D.;
Paquin, J.-F. Activation of C−F Bonds α to C−C Multiple Bonds.
Chem. Commun. 2018, 54, 10224−10239. (e) Fujita, T.; Fuchibe, K.;
Ichikawa, J. Transition Metal-Mediated and -Catalyzed C-F Bond
Activation via Fluorine Elimination. Angew. Chem., Int. Ed. 2019, 58,
390−402.
(18) The trans configuration of compounds 3ab and 8 was
confirmed by 2D-NOESY measurements (see the SI, pp 171−174).
The relative configurations of 3x−aa and 3ac−aj were assigned by
analogy, assuming a common reaction pathway.
(19) Wang, L.; Wang, C. Ni-Catalyzed 1,2-iminoacylation of alkenes
via a reductive strategy. Org. Chem. Front. 2018, 5, 3476−3482.
(20) (a) Anderson, T. J.; Jones, G. D.; Vicic, A. A. Evidence for a NiI
Active Species in the Catalytic Cross-Coupling of Alkyl Electrophiles.
J. Am. Chem. Soc. 2004, 126, 8100−8101. (b) Breitenfeld, J.; Ruiz, J.;
Wodrich, M. D.; Hu, X. Bimetallic Oxidative Addition Involving
Radical Intermediates in Nickel-Catalyzed Alkyl−Alkyl Kumada
Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004−12012.
(c) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-
Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl
Halides. J. Am. Chem. Soc. 2013, 135, 16192−16197. (d) Diccianni, J.
H
DOI: 10.1021/acs.orglett.9b00692
Org. Lett. XXXX, XXX, XXX−XXX