Silver-Enabled General Radical Difluoromethylation Reaction with TMSCF2H

Article abstract of DOI:10.1002/anie.202014587

A silver-mediated oxidative difluoromethylation of styrenes and vinyl trifluoroborates with TMSCF₂H is reported for the first time. This method enables direct and facile access to CF₂H-alkenes from abundant alkenes with excellent functional-group compatibility. Moreover, this Ag/TMSCF₂H protocol could further enable a series of radical difluoromethylation reactions of a wide array of substrates, offering a generic and complementary platform for the construction of diversified C?CF₂H bonds.

Full text of DOI:10.1002/anie.202014587

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Silver-Enabled General Radical Difluoromethylation Reaction with
TMSCF2H
Authors: Jun YANG, Shengqing ZHU, Fang WANG, Feng-Ling QING,
and Lingling Chu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014587
Link to VoR: https://doi.org/10.1002/anie.202014587

10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
Silver-Enabled General Radical Difluoromethylation Reaction with
TMSCF2H**
Jun Yang,† Shengqing Zhu,† Fang Wang, Feng-Ling Qing, Lingling Chu*
[a]
J. Yang, Dr. S. Zhu, F. Wang, Dr. Prof. F.-L. Qing, Dr. Prof. L. Chu
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology,
Center for Advanced Low-Dimension Materials, Donghua University, Shanghai 201620, China
Email: lingling.chu1@dhu.edu.cn
J.Y. and S.Z. contributed equally to this work.
[**]
The authors are grateful for financial support provided by the National Natural Science Foundation of China (21991123, 21971036, 21901036), the
Shanghai Rising-Star Program (20QA1400200), the Shanghai Sailing Program (19YF1400300), and the Fundamental Research Funds for the Central
Universities.
Supporting information for this article is given via a link at the end of the document.
enabled oxidative difluoromethylation of styrenes and vinyl
trifluoroborates with TMSCF2H. By taking advantage of the
remarkable single-electron oxidation ability of silver salts,12 this
protocol has successfully explored TMSCF2H as a new CF2H
radical agent,13 providing an efficient protocol for selective
synthesis of a wide range of CF2H-alkenes, and eminently
Abstract: A silver-mediated oxidative difluoromethylation of styrenes
and vinyl trifluoroborates with TMSCF2H is reported for the first time.
This method enables direct and facile access to CF2H-alkenes from
abundant alkenes with excellent functional group compatibility.
Moreover, this Ag/TMSCF2H protocol could further enable a series of
radical difluoromethylation of a wide array of substrates, offering a
generic and complementary platform for the construction of diversified
C-CF2H bonds.
Introduction
Fluorine-containing moieties play pivotal roles in diverse areas
from medicinal chemistry to functional materials.1 Specifically, the
difluoromethyl group (CF2H) has drawn increasing attention in
drug discovery, since CF2H group could function as a unique
lipophilic bioisostere for alcohols, amides, and thiols that are
commonly found in lead compounds (Fig. 1A).2 Therefore, the
development of new and efficient synthetic methodologies for
incorporating the CF2H group into organic molecules is in great
demand.3 To date, radical difluoromethylation reaction with CF2H-
based agents has been one of the most employed approaches for
constructing CF2H-containing compounds,3 and a number of
CF2H-based reagents have been efficiently explored for
difluoromethylation of alkenes4,5 and (hetero)arenes6. Although
significant progress, rare examples of direct difluoromethylation
of alkenes for construction of vinyl-CF2H bonds have recently
been disclosed,7 with the scope limited to enamides and
acrylamides (Fig 1B).8 To the best of our knowledge, oxidative
difluoromethylation of simple styrenes, one of the most abundant
building blocks, has not been reported previously. Furthermore,
development of generic radical difluoromethylation protocol, that
is applicable to diverse substrates, with readily available and
stable CF2H radical agents remains highly desirable.
Difluoromethyltrimethylsilane (TMSCF2H) is
a
stable
nucleophilic difluoromethylating reagent frequently employed in
classical nucleophilic additions of carbonyl compounds.9 During
the last several years, exploration of TMSCF2H as an efficient
coupling agent in the transition metal-mediated CF2H-cross-
coupling reactions has been pursued by several research groups
including ours.10,11 Despite attractive, efficient and general
methods for the construction of CF2H-alkenes remain
underdeveloped. Herein, we report the first example of silver-
Fig 1. Generic Ag-mediated radical difluoromethylation of alkenes with
TMSCF2H.
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
enabling the expedient construction of diversified carbon-CF2H
bonds from a vast array of readily available substrates.
assume that a slow release of the unstable CF2H anion and
AgCF2H species could be possible in the presence of CsF and
nBu4NH2PO4 (See Table S1- S4 in SI for more optimization
studies).
With the optimal conditions in hand, we set out to explore the
scope of the alkenes that can be employed in this Ag-mediated
oxidative difluoromethylation protocol. As shown in Scheme 1, a
wide range of electron-rich and -poor styrenes smoothly
underwent the desired difluoromethylation reactions, delivering
(E)-CF2H-alkenes with moderate to high efficiency under the
optimal reaction conditions (Products A1–A21). No Z-isomers
were observed in all cases. Heteroaromatic styrenes, including
vinyl-indoles, -thiazoles, -pyridines, -quinolines, etc, were also
suitable alkene substrates (Products A22–A24 and A26–A27).
Pleasingly, many functional groups, including bromides, iodides,
and cyanides that were typically coupling handles for TM-
mediated difluoromethylation reactions, were found to be well
compatible under the mild conditions. The reaction of cyclic
alkenes such as acenaphthylene and 1,2-dihydronaphthalene
went on smoothly, yielding the corresponding trisubstituted CF2H-
alkenes with moderate efficiency (Products A28 and A29). Cyclic
and acyclic 1,1-disubstituted alkenes also works well (Products
A30–A32), nonetheless, CF2H-allylic product was obtained as a
major product in the case of A32. Pleasingly, this Ag-mediated
strategy was amenable to complex alkenes derived from natural
products and bioactive molecules. Styrenes incorporated with
coumarin, amino acids, borneol, glucose, sertraline, cholesterol,
and Vitamin E, were all suitable substrates, generating the
desired CF2H-alkene products with good efficiency and selectivity
(Products A33–A39).
Results and Discussion
We began our investigations into this oxidative
difluoromethylation protocol using styrene 1 as a model substrate
through extensive evaluations of reaction conditions (Table 1).
Pleasingly, we found that the combination of PivOAg, 1,10-
phenanthroline-5,6-dione (phendio) as an oxidant, and CsF as a
base could enable the reaction of 1 with TMSCF2H, generating
the desired (E)-CF2H-alkene product A1 in 80% yield (entry 1).
No (Z)-CF2H-alkene products or hydrodifluoromethylation
products were observed under this silver condition. Intriguingly,
phendio turned out to be the only effective oxidant for this
transformation, and other common oxidants from N-
fluorobenzenesulfonimide (NFSI) to quinones (DDQ, BQ) were
ineffective at all (entries 1–2). Several silver salts were capable to
promote the desired oxidative difluoromethylation, and PivOAg
proved to be the optimal (entries 3–4); nonetheless, neither
copper salts nor iron salts were competent (entry 5). Control
experiments suggested the necessary of silver salt and oxidant,
as no products were detected in the absence of neither of them
(entries 6–7). Use of CsF as the activator was found to be crucial
to the success of this transformation,
Table 1. Optimization of reaction conditions.[a]
PivOAg, phendio
CF2H
Potasium vinyltrifluoroborates are easy-handle coupling
partners frequently employed in catalytic cross-couplings,14 while
no examples of related difluoromethylation reactions have been
TMS CF2H
nBu4NH2PO4, CsF
DMF, 80 oC, 2h
Ph
Ph
styrene 1
CF2H-alkene A1
reported.
Gratifyingly,
silver-mediated
oxidative
difluoromethylation of potasium vinyltrifluoroborates with
TMSCF2H underwent smoothly under the oxidative conditions
(Scheme 1), regioselectively delivering linear vinyl-CF2H products
with moderate to high efficiency (Products A3, A40–A46). We
assumed that this transformation probably proceeds through a
CF2H radical addition followed by an elimination of the BF3K
group.15 Besides, alkenyl carboxylic acids, readily available
alkenyl materials, were also competent to undergo similar radical
difluoromethylation, furnishing CF2H-alkenes and -dienes with
moderate efficiency (Product A47) (Scheme 1).16
entry
variation from “standard conditions”
none
yield
80%
0%
1
2
3
NFSI, PhI(OAc)2, DDQ, or BQ instead of phendio
Ag2CO3 instead of PivOAg
60%
4
5
AgOAc instead of PivOAg
CuCN or Fe(acac)3 instead of PivOAg
w/o nBu4NH2PO4
28%
0%
6
60%
15%
0%
Inspired by the success of the above oxidative
difluoromethylation reactions, next, we further carried out the
extensive exploration of this AgOPiv/TMSCF2H protocol for
7
w/o CsF
8
w/o nBu4NH2PO4 + CsF
w/o [Ag]
9
0%
diverse
radical
difluoromethylation
reaction.
Radical
hydrodifluoromethylation of alkenes4 to forge C(sp3)-CF2H bond
was firstly investigated (Scheme 2). We gratifyingly found that a
wide range of unactivated alkenes underwent the silver-mediated
hydrodifluoromethylation reactions in the absence of phendio,
furnishing the corresponding CF2H-alkanes with moderate to
good efficiency and exclusive regioselectivity (Products B1–B8).
Functional groups such as esters, amides, and carbamates were
also well-tolerated.
10
w/o phendio
0%
[a]Reaction conditions: alkene 1 (0.1 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5
equiv.), CsF (2.0 equiv), phendio (1.5 equiv.), nBu4NH2PO4 (0.5 equiv.), DMF
[0.1 M], N2, 80 oC, 2 h. Yields determined by GC with an internal standard.
phendio = 1,10-phenanthroline-5,6-dione; NFSI = N-fluorobenzenesulfonimide;
DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; BQ = 1,4-benzoquinone.
and the addition of dihydrogenphosphate (nBu4NH2PO4)
dramatically improved the reaction efficiency (entries 8-10). We
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
O
N
O
N
PivOAg
phendio
BF3K
CF2H
R
R
+
TMS CF2H
R
CsF, n-Bu4NH2PO4
DMF, 80 oC, 2 h
alkenes
trifluoroborates
CF2H-alkenes
phendio
styrenes
R3
CF2H
CF2H
CF2H
R2
CF2H
CF2H
R1
A1 R1 = Ph
R4O
X
75%
A11 R3 = Cl 66%
A12 = Me 50%
A13 = CO2Me 58%
A5 R2 = Cl 75%
A6 = CF3 71%
A7 = CN 64%
A8 X = Cl 67%
A9 = Br 74%
A10 = I 61%
A14 R4 = Me 68%
A15 = Ph 70%
A2
A3
A4
= Me
= tBu
= CF3
75%
78%
85%
O
CF2H
CF2H
F
CF2H
Me
CF2H
N
CF2H
CF2H
HO2C
O2N
MeO
Br
O
A16 54%b
A17 50%
A18 56%
A19 64%
A20 60%
CF2H
CF2H
CF2H
CF2H
O
N
3
O
N
Boc
O
A21 68%
A22 62%
A23 49%
A24 45%
A25 56%
CF2H
CF2H
R4
Me
CF2H
CF2H
N
CF2H
N
S
CF2H
A30 R = Me 51%
A31 = Ph 55%
A28 56%b
A29 40%b
A32 56%
A26 52%
A27 68%
Me
O
O
Me
Me
O
BuO
N
CF2H
O
O
CF2H
NHBoc
A34 60%
O
A35 65%
Borneol derivative
CF2H
CF2H
Me
A33 56%
Coumarin derivative
Me
Amino acid derivative
A36 69%
Sertraline derivative
Me
O
O
O
CF2H
O
Me
Me
Cl
O
HMe
CF2H
Cl
O
O
A38 63%
Cholesterol derivative
H
H
CF2H
Me
Me
Me
O
O
O
A37 66%
Me
Me
Me
Me
Glucose derivative
Me
O
A39 61%
Me
O
Me
Me
Vitamin E derivative
Me
trifluoroborates
CF2H
CF2H
CF2H
CF2H
CF2H
MeO2C
F3CO
R
F
NC
A3 R = tBu, 75%c
A40 R = H, 70%c
A41 77%c
A42 72%c
carboxylic acids
CF2H
A43 71%c
A44 67%c
CF2H
CF2H
CF2H
CF2H
Ph
S
F3C
MeO
A45 62%c
A46 45%d
A47 52%e E/Z = 5/1
A14 69%e
A4 57%e
Scheme 1. Substrate Scope for oxidative difluoromethylation of styrenes. [a]alkene (0.2 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5 equiv.),
n
phendio (1.5 equiv.), Bu4NH2PO4 (0.5 equiv.), CsF (2.0 equiv.), DMF [0.1 M], N2, 80 oC, 2 h, isolated yields; [b]PivCl (1.0 equiv.) instead of
nBu4NH2PO4, phendio (2.5 equiv.); [c]trifluoroborates (0.2 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5 equiv.), phendio (2.5 equiv.), PivCl (1.0
o
equiv.), CsF (2.0 equiv.), DMF [0.1 M], N2, 80 C, 8 h, isolated yields; [d]19F NMR yield; [e] carboxylic acids (0.2 mmol), TMSCF2H (2.0 equiv.),
PivOAg (2.0 equiv.), phendio (2.5 equiv.), PivCl (1.0 equiv.), CsF (2.0 equiv.), DMF [0.067 M], N2, 80 oC, 8 h, isolated yields.
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
PivOAg
CF2H
TMS CF2H
+
R
R
PivCl, CsF
DMF, 80 oC, 2 h
unactivated alkenes
CF2H-alkanes
O
PhHN
CF2H
CF2H
CF2H
CF2H
7
CF2H
Me
HO
6
8
N
Ph
O
O
3
Boc
B1 77%
B2 74%
B3 81%
B4 59%
B5 65%
O
NC
Me
O
Me
Me
N
O
O
CF2H
6
Ph
O
CF2H
O
CF2H
O
8
S
N
6
R
O
Ph
B6 R = OMe
70%
71%
64%
B9 59%
B10 69%
B7
B8
CF3
Cl
Oxaprozin derivative
Febuxostat derivative
O
O
O
Me
CF2H
O
O
Me
5
8
CF2H
H
Me
H
Me
OMe
H
H
N
Cl
Me
Me
H
H
O
CF2H
6
O
B11 60%
O
B13 63%
Estrone derivative
B12 44%
Indometacin derivative
Boldenone derivative
Me
Me
H
CF2H
O
O
Ph
Si
CF2H
O
Ph
S
EWG
O
CF2H
Me Me
Ph
O
CF2H
CF2H
O
O
N
Me
Me
electron-deficient
alkene
B14 62%
B15 57%
B16 61%
B17 59%
B18 78%
Me
Me
CF2H
Me
CF2H
CF2H
CF2H
Me
CF2H
N
N
PG
Si
X
O
EtO2C CO2Et
Ph Ph
Ph
B22 PG = Ts, 81% (dr 5.5/1)
B23 PG = Boc, 60% (dr 11/1)
B19 72%b
B20 58% (dr 5/1)
B21 70% (dr 5/1)
B24 48% (dr >20/1)
1,5-diene
Scheme 2. Substrate Scope for Ag-mediated hydrodifluoromethylation. [a]alkene (0.2 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5 equiv.), PivCl
(1.0 equiv.), CsF (2.0 equiv.), DMF [0.1 M], N2, 80 oC, 2 h, isolated yields; [b]19F NMR yield.
difluoromethylation has drawn continuous research interest.6 This
silver protocol is feasibly applicable to heteroarenes to generate
Moreover, complex alkenes derived from biological-active
molecules also worked well with moderate efficiency, providing a
potential approach to install CF2H group for late-stage
modifications of structurally complex drugs (Products B9–B13).
1,1-Disubstituted alkenes worked with moderate efficiency
(Product B5), nonetheless, internal alkenes were incompetent
substrates. Furthermore, electron-deficient alkenes, including
acrylates, vinyl silanes, vinyl sulfones, and acrylamides, were
applicable in this transformation, forming the related b-CF2H
carbonyls and other compounds with moderate efficiency
(Products B14–B18). Additionally, 1,5-dienes reacted smoothly
with Ag/TMSCF2H to afford the radical cyclization products, and
several CF2H-incorporated five-membered carbon, nitrogen, and
the difluoromethylated heteroarenes. As depicted in Scheme 3,
the CF2H group could be directly and regioselectively installed
onto a series of substituted quinoxalin-2(1H)-ones with moderate
to high efficiency via this difluoromethylation system (Products
C1–C9). Other heteroaryl skeletons, exemplified by quinoxalines,
benzothiazoles, and benzofurans, were also competent
substrates, albeit with slightly decreased yields (Products C10–
C12). It should be noted that direct difluoromethylation of other
nitrogen heterocycles with AgOPiv/TMSCF2H failed, nonetheless,
employment of the related heterocycle N-oxides successfully
delivered the corresponding CF2H- pyridines, -quinolines, and –
isoquinolines with moderated efficiency (Products C13–C16).
Moreover, isonitriles were proved to be adequate substrates to
silicone cycles could be efficiently assembled (Products B19–B24) undergo the Ag-mediated radical difluoromethylation, generating
(see SI for more alkenes).
The facile assembly of heteroaryl-CF2H, important structural
motifs prevalent in drugs and drug candidates, via direct
diverse CF2H-heterocycles and providing complementary
reactivity to above-mentioned direct difluoromethylation of
heterocycles (Products C17–C24). Notably, subjection of
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
compound C25, a crucial intermediate for synthesizing an anti-
We regard this Ag/TMSCF2H radical difluoromethylation
Hepatitis
C
virus (HCV) inhibitbor, into this silver
protocol
could
complement
the
previously
known
difluoromethylation protocol delivered the corresponding CF2H
derivative C26 with moderate yield, further demonstrating the
synthetic merits of this methodology.
difluoromethylation methodologies, as shown in Scheme 4. An
unprecedent divergent difluoromethylation of 4-vinyl-1,1’-biphenyl
1 can be achieved via this Ag/TMSCF2H system (with or without
phendio), individually delivering the oxidative difluoromethylation
product A1 and hydrodifluoromethylation product B25 from the
CF2H
PivOAg
hetAr
hetAr
TMS CF2H
+
PivCl, CsF
DMF, 80 oC, 12 h
CF2H-hetAr
heteroarenes
heteroarenes
N
N
CF2H
N
CF2H
H
N
X
N
CF2H
R2
R2
N
CF2H
O
O
N
H
O
N
H
O
N
H
O
MeO
N
CF2H
n-C6H13
C3 X = Cl 84%
C4 = Br 82%
C5 R2 = Me 73%
C1 77%
C2 55%
C7 88%
C6
= F 78%
Me
O2N
N
CF2H
N
CF2H
N
N
CF2H
N
CF2H
CF2H
N
H
O
N
H
O
S
OC6H13
O
C11 49%b
C12 52%c
C8 60%
N-oxides
C9 55%
C10 37%
Me
Ph
N
N
CF2H
N
CF2H
C14 57%d
N
CF2H
N
CF2H
O
C13 51%d
C15 52%d
C16 68%d
isonitriles
R1
R2
Me
N
S
Ar
A
N
CF2H
N
CF2H
CF2H
N
CF2H
NC
C17 R1 = Me, 77%e
C18
C19 R1 = H, 60%e
C20
= F, 53%e
C21 76%e
C22 61%e
= OMe, 80%e
Ph
CO2Et
N
N3
Ph
Ph
CO2Et
NC
CF2H
N
N
H
NC
C24 58%e
C23 83%e
CF2H
■ Synthetic application
O
O
HN
Me
HN
N
CF2H
TMS CF2H
NH
H2N
Me
N
N
H2N
Me
N
Ph
S
N
PivOAg, PivCl, CsF
DMF, 80 oC, 12 h
N
N
NH
C26 40%d
HF2C
CF2H derivative
of HCV inhibitor
C25
(72% brsm)
O
Scheme 3. Substrate Scope for radical difluoromethylation. [a]heterocycle (0.2 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5 equiv.), PivCl (1.0
equiv.), CsF (2.0 equiv.), DMF [0.1 M], N2, 80 oC, 12 h, isolated yields; [b]Reaction with 2-chlorobenzo[d]thiazole (0.2 mmol); [c]PivOAg (2.5
equiv.), phendio (2.5 equiv.), PivCl (1.0 equiv.), DMF [0.067 M], N2, 80 oC, 12 h; [d] PivOAg (2.0 equiv.), PivCl (1.0 equiv.), DMF [0.067 M], N2,
80 oC, 12 h. [e]isonitriles (0.2 mmol), TMSCF2H (2.0 equiv.), PivOAg (1.5 equiv.), PivCl (1.0 equiv.), CsF (2.0 equiv.), DMF [0.1 M], N2, 80 oC, 12
h, isolated yields.
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10.1002/anie.202014587
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RESEARCH ARTICLE
same substrate in one system (Scheme 4A). Moreover, radical
difluoromethylation of vinyl benzoate 2 with Ag/TMSCF2H gave
the linear product 4, while the classic nucleophilic
difluoromethylation with TMSCF2H afforded the branched product
release the CF2H radical. The ligand-ligated [(SIPr)AgCF2H]
complex 13, a relatively stable AgCF2H compound that generally
participates in cross-couplings with halides in a two-electron
way,11 was prepared. Interestingly, reactions of complex 13 with
3, showing a distinct reactivity of our radical protocol (Scheme 4B). styrene or unactivated alkene failed to give any CF2H-alkene and
Furthermore, subjection of 5 and 8 containing a heteroarene and
a double bond into this Ag/TMSCF2H protocol or our previous
CuCN/TMSCF2H protocol10h led to exclusive selectivity toward
heteroarenes or alkenes (products 6 and 7, 9 and 10) (Scheme
4C).
To shed some light on the possible reaction pathway, we
have conducted a series of mechanistic studies (Scheme 5).
Addition of TEMPO only afforded the formation of CF2H-TEMPO
adducts with no observations of vinyl-CF2H in this Ag/TMSCF2H
system (Scheme 5A). Moreover, the reaction of cyclopropyl
alkene 11 with TMSCF2H under the oxidative difluoromethylation
conditions afforded the allylic-CF2H product 12,
CF2H-alkane products under similar conditions (Scheme 5C),
suggesting a distinct reactivity difference in the well-ligated
complex 13 and the “ligandless” AgCF2H species that shows
innate propensity to undergo homolytic cleavage to give CF2H
radical.13 Further studies are still ongoing in our lab to elucidate a
detailed reaction pathway.
A)
CF2H
TMS CF2H
TEMPO (2.0 equiv.)
Me
Me
Me
Me
N
O
standard condition
shown in entry x
HF2C
64%
CF2H
Ph
Ph
not observed
A) Divergent reactivity regarding styrenes
CF2H
conditions
B)
C)
TMS CF2H
in Scheme 1
Ph
Ph
AgOPiv
standard condition
shown in entry x
A1 75% (E only)
CF2H
TMSCF2H
conditions
11
12 33%
Ph
in Scheme 2
styrene
CF2H
B25 50%
13
iPr
iPr
B) Complementary regioselectivity to nucleophilic difluoromethylation
phendio, CsF
DMF
N
Ph
O
Ph
AgOPiv
TMSCF2H
no [Ag]
O
CF2H
Me
Ag CF2H
O
N
A1 not observed
CF2H
CF2H
Ph
O
TMSCF2H
Ph
O
Ph
O
iPr
iPr
13
2
3 45%
4 37%
Me
Me
6
6
CsF, DMF
B1 not observed
(SIPr)AgCF2H 13
C) Complementary chemoselectivity to Cu-mediated dlfluoromethylation
S
CuCN
HF2C
Scheme 5. Mechanistic studies. I) Reaction in the presence of TEMPO; II)
Reaction with cyclopropyl alkene; III) Reactions with isolated
(SIPr)AgCF2H.
N
TMSCF2H
6 68%
N
S
N
S
AgOPiv
5
Conclusion
TMSCF2H
CF2H
7 66%
In conclusion, we report
a
general Ag-mediated
O
CuCN
difluoromethylation protocol by utilizing commercially available
and stable TMSCF2H as an efficient radical CF2H agent, and
develop the first example of silver-mediated oxidative
difluoromethyation of styrenes and vinyl trifluoroborates to access
CF2H-alkene compounds. This protocol is also applicable to
diversified substrates including vinyl carboxylic acids, alkenes,
dienes, heteroarenes, and isonitriles, providing an efficient and
valuable alternative to forge diverse C-CF2H bonds from ready
available materials. We expect this broadly applicable radical
difluoromethylation protocol would find potential applications in
pharmaceuticals and agrochemicals.
N
O
O
6
HF2C
TMSCF2H
N
9 58%
O
O
AgOPiv
N
O
O
CF2H
8
6
TMSCF2H
10 55%
Scheme 4. Complementary reactivity between this Ag/TMSCF2H protocol
and previously reported difluoromethylation protocol.
probably generated via a radical addition/ring-opening/cyclization
pathway, in 33% yield (Scheme 5B), further indicating a radical
pathway. Based on the fact that no strong coordinating ligands
were required in this silver protocol, we assumed that an in-situ
generated, unstable AgCF2H species13 might be involved to
Keywords: difluoromethylation • silver • alkenes • heteroarenes
• radical fluoroalkylation
Reference
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
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10.1002/anie.202014587
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Silver-Enabled General Radical Difluoromethylation Reaction with TMSCF2H
CF2H
CF2H
R
R
CF2H-alkene
CF2H-alkane
TMS CF2H
AgOPiv
CF2H
CF2H
BF3K
R
> 100
examples
CF2H-diene
A silver-mediated oxidative difluoromethylation of styrenes and vinyltrifluoroborates with TMSCF2H to construct vinyl-CF2H bonds has
been achieved for the first time. This protocol also provides a generic platform for radical difluoromethylation of a broad array of
substrates including diverse alkenes, carboxylic acids, heteroarenes, and isonitriles, enabling expedient construction of diversified
carbon-CF2H bonds.
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