HFIP-catalyzed direct dehydroxydifluoroalkylation of benzylic and allylic alcohols with difluoroenoxysilanes

Article abstract of DOI:10.1039/d0cc06980a

Hexafluoroisopropanol (HFIP)-catalyzed direct dehydroxydifluoroalkylation of benzylic and allylic alcohols with difluoroenoxysilanes is developed. This procedure enables the synthesis of a broad range of α,α-difluoroketones, a class of highly valuable intermediates and building blocks in medicinal and organic chemistry. Here, we have demonstrated for the first time that HFIP could act as a powerful catalyst for fluorinated carbon-carbon bond formation. The application of this protocol in late-stage dehydroxydifluoroalkylation of potentially bioactive drugs and natural products has also been carried out.

Full text of DOI:10.1039/d0cc06980a

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DOI: 10.1039/D0CC06980A
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HFIP-Catalyzed Direct Dehydroxydifluoroalkylation of Benzylic
and Allylic Alcohols with Difluoroenoxysilanes
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
b
Jinshan Li, Wenxue Xi, Rong Zhong, Jianguo Yang,* Lei Wang, Hanfeng Ding and Zhiming
a
Wang*
DOI: 10.1039/x0xx00000x
A
hexafluoroisopropanol
(HFIP)-catalyzed
direct and coworkers designed a dendritic fluoroalcohol-based
dehydroxydifluoroalkylation of benzylic and allylic alcohols with catalyst for alkene epoxidation by immobilizing HFIP
3
a
difluoroenoxysilanes is developed. This procedure enables the monomers on hyperbranched polyglycerol. In their study, the
synthesis of a broad range of α,α-difluoroketones, a class of highly catalytic behaviour of HFIP itself was also tested and it was
valuable intermediates and building blocks in medicinal and found that catalytic activity is very low. In 2017, Peddinti and
organic chemistry. Here, we first demonstrated that HFIP could act coworkers investigated the catalytic behaviour of HFIP in the
3
b
as a powerful catalyst for the fluorinated carbon-carbon bond thiocarbonylation reaction with acyl halides and thiols. The
formation. Applications of this protocol in late-stage strong hydrogen-bonding of HFIP with the oxygen atom of acyl
-
dehydroxydifluoroalkylation of potentially bioactive drugs and halide and good leaving ability of Cl were believed to be the
natural products are also carried out.
key factors for this reaction. However, the real role of HCl
generated during the course of the reaction was unclear.
4
Over the past decade, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)
has been demonstrated as a remarkable polar organic solvent
or additive to achieve challenging chemical transformations.
Overall, the direct use of HFIP as a catalyst for is an issue that
remains to be addressed. Thus, developing efficient HFIP-
catalyzed reactions is highly demanding, especially given the
major drawback of the usage of the expensive HFIP as a
solvent for large-scale applications.
1
,2
Its particular physical and chemical properties (such as low
nucleophilicity, high ionizing power, strong hydrogen-bond
donor ability and cation stabilization) render HFIP an ideal
Considering the great potential of the C−F···H−O interactions
2
solvent in promoting various reactions under mild conditions.
between hydrogen and fluorine in various chemical
Despite these great advances, applications of HFIP as catalyst
in synthetic chemistry are rare (Figure 1). One of the main
obstacles for this challenge is the need to maintain a high local
concentration of HFIP (as in a solvent) to efficiently facilitate
the transformations. In the case of high local concentration,
the hydrogen-bond donor ability could be augmented through
the formation of H-bond network between multiple molecules
5
transformations, we focused on the synthesis of fluorine-
containing molecules via HFIP catalysis. As a class of valuable
fluorine-containing compounds, α,α-difluoroketones exhibit
unique physicochemical and biological properties and have
6,7
wide applications in medicinal chemistry. Therefore, the
development of efficient methods to for the construction of
structurally diverse α,α-difluoroketones with readily available
raw chemical materials under metal-free conditions is very
attractive and highly desirable.
1
h
of HFIP, which is a key feature for HFIP-mediated reactions.
To increase the local concentration of fluoroalcohol, Berkessel
Enhanced acidity
Although great efforts have been made toward the synthesis
of α,α-difluoroketone analogs over the past decade, the
convenient strategies for the synthesis of α,α-difluoroketones
H
O
Reduced nucleophilicity
F3C
CF3
HFIP
Strong hydrogen-bond donor ability
catalyst
HFIP
3
underdeveloped
more challenging
with different sp -based electrophiles have been far less
High polarity and redox stability
Cation stabilization
a popular solvent
or additive
explored. Due to the low electron density and poor
nucleophilicity of fluorinated enolates at C(α) caused by the
strong inductive effect of the two fluorine atoms, the direct
Figure 1 Key properties and applications of HFIP.
3
C(α)–C(sp ) bond forming reactions between nucleophilicα,α-
3
a. Advanced Research Institute and Department of Chemistry, Taizhou University,
139 Shifu Avenue, Taizhou 318000, P. R. China. E-mail: wzmmol@hotmail.com,
zhiming@tzc.edu.cn, yjg@tzc.edu.cn
Department of Chemistry, Zhejiang University, Hangzhou 310058, P. R. China.
Electronic supplementary information (ESI) available. See DOI: 10.1039/
difluoroketone enolates and C(sp ) electrophiles had difficulty
1
8
to deliver the desired α,α-difluoroketone products (Figure 2a).
b.
The direct alkylation of α,α-difluoroenolates with alkyl halides
could be proceeded,
†
x0xx00000x
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Journal Name
a) Difficulties in the direct construction of -difluoroketones with -difluoroketone
enolates with sp -based electrophiles
result of HFIP (entries 2−5). Only trace product was detected
with 1,1,1,3,3,3-hexafluoro-2-propyl-methyl ether (HFIPME) as
3
View Article Online
DOI: 10.1039/D0CC06980A
OM
R
3
sp
3
O
R3
R2
R1
R2
R1
F

R4
R4
+
the catalyst (entry 6), which indicated that the strong
hydrogen-bonding interaction of fluorinated alcohols plays
crucial roles in this reaction. Furthermore, the unique role of
the fluorine atoms in alcohols was demonstrated by the
inferior results when HFIP was replaced by isopropanol (entry
7). It should be noted that if HFIP was used as a solvent, the
reaction could be performed in less than 1 min at room
temperature (entry 8).
With the optimal reaction conditions in hand, we explored
the scope of this transformation, beginning with simple
monosubstituted primary benzylic alcohols. As exhibited in
Scheme 1, the reactions worked well with a range of
substituted primary, secondary, and tertiary benzylic alcohols
bearing either electron-donating or -withdrawing substituents
unfavorable
F
F F
strong inductive effect
low nucleophilicity
b) Limited strategies for direct synthesis of -difluoroketones
Strategy 1: Promoted with stoichiometric metals (Portella and Uneyama)
Me Me O
R1
OTMS
Ar
O
ZnI2 (5.0 equiv.)
Me
ZnBr2 (1.2 equiv.)
Me
F
F
F
R1
R1
Me
+
Me
O
F
F F
Ar
Br
Me
OAc
R1
Me
F
F
Strategy 2: Palladium-catalyzed decarboxylative alkylation (Altman)
R1
OH
+
O
O
O
BrCF2CO2Et
Pd (cat.)
R1
R2
R1
R2
+
O
O
90-140 o
C
O
F
F
LnPd
F F
15-36 h
R2
R1 = Aryl, allyl
R2
F F
H
(benzyloxy, methoxy, methyl, fluoro, chloro, and bromo),
c) New strategy: HFIP-catalyzed direct nucleophilic substitution reactions of alcohols
with fluorinated enolates
giving the desired α,α-difluoroketone products 3–5, 9–18 and
22–26 in moderate to good yields. Notably, alcohols containing
free phenolic hydroxyl group also proceeded smoothly,
delivering the desired products 6–8 in 62–71% yields. And
interestingly, α-cyclopropylbenzyl alcohol afforded the
H
F
O
H
HFIP
cat.
R3
O
R3
OTMS
O
F3C
CF3
CF3
R2
R1
R2
R1
n
F
R3
R4
R4
R2
R1
+
F3C
OH
o
F
F
F
HFIP activates alcohol/
fluorinated nucleophile
1o, 2 , 3 and naturally occuring alcohols
o
Figure 2 Strategies for the construction of α,α-difluoroketones with alkylated product of difluoroenoxysilane in good yield, without
3
different sp -based electrophiles.
the formation of rearrangement product (13). Deactivated
alcohols with strong electron-withdrawing groups such as
trifluoromethyl and ester can be difluoroalkylated by
increasing the loading of HFIP (19 and 20). With particular
substrate containing both primary and secondary benzylic
alcohols, only the secondary alcohol reacted under reaction
conditions to exclusively yield the monosubstituted product
but stoichiometric amounts of metal reagents must be
required (Figure 2b, strategy 1). Altman and co-workers
developed a palladium-catalyzed decarboxylative strategy for
accessing α,α-difluoroketones with in-situ formed α,α-
difluoroenolates (Figure 2b, strategy 2). The reactions
tolerate a broad spectrum of functional groups and provide an
efficient way to access various functionalized α,α-
difluoroketone derivatives. However, the α,α-difluorinated
esters are not easily accessible and have to be prepared by a
multi-step procedure from primary alcohols, ethyl
9
1
0
2
1, with the primary alcohol still in place.
The scope of the allylation reaction was next explored.
Chalcols bearing electron-donating or electron-withdrawing
groups on the aromatic ring were all found to be suitable
substrates, affording the desired products in 53‒92% yields
bromodifluoroacetate, aldehyde.
Given the ubiquity of
(
27–33). Cinnamyl alcohol substrate undergoes the
alcohols11 and the high activation ability of HFIP with OH-
1
f
containing substrates, we envisioned that the H-bond
Table 1 Screening of Conditionsa
O
networks of HFIP could activate the hydroxyl group and
OTMS
OH
catalyst (10 mol %)
solvent, rt
Ph
difluoroenoxysilane1
2,13
in a cooperative manner via a dual
+
F
Ph
F
F
BnO
F
BnO
F
activation mode to give the α,α-difluoroketones efficiently.
Herein, we describe our efforts for the development of HFIP-
catalyzed direct dehydroxydifluoroalkylation of alcohols with
difluoroenoxysilanes to access various α,α-difluoroketones and
its potential applications for the late-stage modification of
drugs and natural products (Figure 2c).
1
2
3
Catalyst:
OH
CF3
HFIP
F
HO Me
F3C CF3
HO Ph
F3C CF3
OMe
HO
F3C
OH
OH
F3C
F3C
HFIPME
CF3
F
F
TFE
HFMIP
HFPIP
TFBD
Entry
Catalyst
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
HFIP
Time
3 h
Yield (%)b
We initially investigated the reactions of (4-
(benzyloxy)phenyl)methanol 1 and difluoroenoxysilane 2 with
1
2
3
4
5
6
7
HFIP
TFE
HFMIP
HFPIP
TFBD
HFIPME
87
48
39
31
6
Trace
0
89
different polyfluorinated alcohols as catalysts (Table 1).
Interestingly, the reaction proceeded smoothly to afford the
desired product 3 in good yield in the presence of 10 mol %
HFIP in dichloromethane (DCM) at room temperature (entry
6 h
12 h
12 h
12 h
12 h
12 h
1
). Other fluorinated alcohols, such as 2,2,2-trifluoroethanol
i
(TFE), 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol (HFMIP),
PrOH
−
c
1
2
,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol
,2,3,3-tetrafluorobutane-1,4-diol (TFBD) could also work,
(HFPIP)
and
8
< 1 min
a
Reaction conditions : alcohol 1 (1.0 mmol), difluoroenoxysilane 2
1.05 mmol), and catalyst (10 mol %) in solvent (3.0 mL) at room
(
although the yields were relatively low compared with the
b
c
temperature. Isolated yield. HFIP was used as solvent.
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
OTMS
R4
R3
F
O
R3
R2
R1
group containing secondary alcohol to selectively afford the
difluoroketone 37 in 83% yield. Both isomers were obtained
R2
R1
F
HFIP (cat.)
View Article Online
DOI: 10.1039/D0CC06980A
+
R4
DCM, rt, 2-12 h
OH
F
F
benzylic derivatives
when cyclic allyl alcohol was employed, giving the
corresponding inseparable products (38/38’ = 1:1) in 93%
yield. Notably , 2-cyclohexen-1-ol provided the desired product
O
O
O
O
Ph
Ph
Ph
Ph
Ph
F
F
F
F
Fe
F
F
F F
BnO
MeO
HO
3
, 87%
4, 83%
5, 61%
6, 63%
3
9 in 64% yield with increasing the loading of HFIP. In addition,
O
O
Me
O
Me
O
tBu
HO
MeO
HO
propargylic alcohols were also found to be compatible in these
reactions (40 and 41).
Ph
Ph
Ph
F
F
F F
F
F
F
F
Me
7
, 62%
tBu 8, 71%
9, 83%
10, 87%
The high site selectivity of benzylic and allylic alcohol and wide
functional-group compatibility make possible the late-stage
functionalization. To demonstrate this potential, a number of
drugs, natural products and related bioactive molecules with
alcoholic hydroxyl group were examined. For example,
gastrodin, a main constituent of a Chinese herbal medicine
Tianma, was converted into its difluoroketone analogue 42 in
good yield. Fenofibrate (cholesterol-lowering drug),
chlorfenethol (acaricide), stiripentol (anticonvulsant drug), key
intermediate of ipragliflozin (antidiabetic drug) and 4-
androstenediol (steroid hormones) were also successfully
functionalized (43–47). To further illustrate the practicability of
our strategy in the synthesis of functionalized fluorine-
containing compounds, a gram-scale reaction was conducted
with stiripentol (3 mmol) and afforded 45 in 92% yield.
Substituted difluoroenoxysilanes also gave corresponding
products in good yields (48–52).
F
O
Me
O
Me
O
O
F
Ph
Ph
Ph
Ph
F
F
F
F
F F
Cl
R'
Br
1
1, 80%
12, 78%
13, 87%
14, 72%
O
15, R' = R'' = H, 96%
6, R' = R'' = F, 67%
7, R' = R'' = Cl, 69%
8, R' =H, R'' = Br, 70%
9, R' =H, R'' = CF3, 87%a
0, R' =H, R'' = CO2Me, 63%a
O
O
F
F
F
F
1
1
1
1
2
Ph
F
Ph
Ph
F
OH
R''
O
21, 85%
22, 77%
O
O
F
F
F
F
O
O
Ph
Ph
Ph
F
F
F
Ph
F
S
Me
2
3, 84%
24, 81%
25, 39%
allylic derivatives
Ph
26, 78%
O
F
Ph
O
Me
O
F
F
Ph
O
F
Ph
Ph Ph
Ph
Ph
Ar1
Ar2
F
F
F
F
7, Ar1 = Ar2 = C6H5, 82%
2
2
2
3
3
3
3
35, 79%
36, 78%
8, Ar1 = Ar2 = 4-MeC6H4, 92%
34
+
O
F
9, Ar1 = Ar2 = 4-MeOC6H4, 89%
O
F
0, Ar1 = Ar2 = 4-FC6H4, 78%
Ph
A series of experiments were carried out to reveal the
mechanism (Scheme 2). First, (R)-1-phenylethanol (> 98% ee) was
treated with 2 under standard condition, which afforded 9 in
racemic form (Scheme 2a). The reaction of 2 in the presence of a
catalytic amount of HFIP smoothly gave 2,2-difluoroacetophenone
and self-aldol product 53 (Scheme 2b). This phenomenon indicated
that HFIP has the potential to activate difluoroenoxysilane. Next,
the necessity of fluorine atom on the silyl enol ether was fully
proved by using difluorinated, monofluorinated, non-fluorinated
analogues and dichloroenoxysilane (Scheme 2c). Further NMR
studies showed the potential interactions between HFIP and
alcohols or difluoroenoxysilanes (see the Supporting Information
for details).
1, Ar1 = Ar2 = 4-ClC6H4, 82%
F
F
Me
Me
2, Ar1 = Ar2 = 4-BrC6H4, 86%
34'
Cl
3, Ar1 = Ar2 = 2-naphthyl, 51%
83% (34:34' = 1.3:1)
37, 83%
O
F
O
O
F
O
O
F
Ph
Ph
Ph
F
F
F
F
F
Ph
F
Ph
F
+
Ph
Ph
Ph
38
93% (38:38' = 1:1) 38'
39, 64%a
40, 52%
41, 87%
Late-stage functionalization of bioactive molecules
Ph
F
O
F
O
O
O
Ph
F
O
F
Ph
HO
HO
F
Me Me
OH
Me
F
OiPr
OH
2, 65%
Cl
O
O
Cl
O
Cl
4
43, 60%
From fenofibrate
44, 74%
From chlorfenethol
From gastrodin
OH
O
F
Me
Br
F
Ph
Me
H
F
According to these experiment results and previous work,14
a possible catalytic cycle is proposed (Scheme 3). The overall
O
O
Me
Me
F
H
H
S
Ph
Me
F
Ph
F
F
4
5, 98%
O
47, 71%a
From 4-androstenediol
reaction pathway would be in agreement with an SN1
From stiripentol
.0 mmol, 1.03 g, 92%
46, 87%
3
From key intermediate of ipragliflozin
nucleophilic substitution mechanism. Alcohol is protonated by
Substrate Scope of Difluoroenoxysilanes
O
O
O
HFIP, producing a stabilized carbocation intermediate via
hydrogen bonding interaction. The intrinsic propensity of
fluorinated alcohols to form the multiple H-bond networks
greatly increases the acidity of HFIP and accelerates the catalytic
MeO
F
Ar
Ar
Ar
F
F F
5
1, Ar = 4-MeC6H4, 91%
52, Ar = 4-FC6H4, 83%
F
F
BnO
HO
4
5
9, Ar = 4-MeC6H4, 74%
0, Ar = 4-FC6H4, 71%
4
8, Ar = 4-MeOC6H4, 86%
Scheme
1
Substrate
scope
of
HFIP-catalyzed
direct
5,14
reaction. On the other hand, the C–F···H–O interactions between
dehydroxydifluoroalkylation of alcohols. Standard reaction conditions:
alcohol (0.5 mmol), difluoroenoxysilane (1.05 equiv.), HFIP (10 mol %) in
DCM (3.0 mL) at room temperature. The yields are isolated yields.
difluoroenoxysilane and the H-bond networks of HFIP may
efficiently improve the reactivity of fluorinated enolates. Then, the
direct reaction of fluorinated enolates with carbocation
intermediate smoothly affords the desired difluoroketones.
a
DCM/HFIP 2.5:1 (~10.0 equiv. of HFIP was used).
substitution reaction to give both branched and linear α-allyl-
In summary, we have successfully developed a general
α,α-difluoroketones (34 and 34’, generally 1.3:1). For tertiary method to prepare α,α-difluoroketones through HFIP-
alcohols having a vinyl group attached to the 3° carbon center, catalyzed direct dehydroxydifluoroalkylation of benzylic and
migration of the double bond took place to deliver the linear allylic alcohols with difluoroenoxysilanes that allows efficient
difluoroketones 35 and 36 in 81% and 78% yields. Similar late-stage functionalization of a variety of known drugs and
migration of the double bond was also observed for the vinyl natural products. The reaction conditions developed are mild
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
a) HFIP-catalyzed direct alkylation of -difluoroenoxysilane with (R)-1-phenylethanol
Catal., 2020, 10, 6023; (e) S.-D. Wang, G. Force,ViRew. GAruticilleloOtn,liJn.e-
O
F
F. Carpentier, Y. Sarazin, C. Bour, V. Gandon and D. Leboeuf,
OTMS
DOI: 10.1039/D0CC06980A
OH
F
Ph
HFIP (10 mol %)
DCM, rt, 3 h
ACS Catal., 2020, 10, 10794.
F
Ph
Me
+
Ph
Ph
Me
F
9, 84%, 0% ee
3
(a) A. Berkessel, J. Krämer, F. Mummy, J. M. Neudörfl and R.
Haag, Angew. Chem., Int. Ed., 2013, 52, 739; (b) P. Singh and
R. K. Peddinti, Tetrahedron Lett., 2017, 58, 1875.
H. F. Motiwala, R. H. Vekariya and J. Aubé, Org. Lett., 2015,
>
98% ee
2
b) Control experiment
OTMS
O
Ph OH
HF2C
O
HFIP (10 mol %)
DCM, rt, 2 h
F
F
+
+
side products
Ph
Ph
Ph
F
F
F
4
5
2
F
3, 67% determined by HRMS and 1H NMR
5
1
7, 5484.
c) Exploration the fluorine effect of HFIP-catalyzed direct alkylation reaction
O
For selected examples on C−F⋯H−O Interactions, see: (a) D.
Cahard and V. Bizet, Chem. Soc. Rev., 2014, 43, 135; (b) P. A.
Champagne, J. Desroches and J.-F. Paquin, Synthesis, 2015,
1
5
0 (X = Y = F), ca. 2 h, 89%
4 (X =H, Y = F), ca. 8 h, 61%
OH
OTMS
HFIP
(10 mol %)
DCM, rt
X
X
Y
Ph
Ar
Me
+
Ph
55 (X = Y = H), ca. 24 h, no desired product
Me 56 (X = Y = Cl), ca. 24 h, no desired product
Y
Ar
Ar = 4-MeC6H5
3
06; (c) C. Ni and J. Hu, Chem. Soc. Rev., 2016, 45, 5441; (d)
Scheme 2 Mechanistic studies.
Y.-J. Hao, J.-S. Yu, Y. Zhou, X. Wang and J. Zhou, Acta Chim.
Sinica., 2018, 76, 925; (e) P. A. Champagne, Y. Benhassine, J.
Desroches and J.-F. Paquin, Angew. Chem., Int. Ed., 2014, 53,
13835; (f) K. A. Lee, D. L. Silverio, S. Torker, D. W. Robbins, F.
Haeffner, F. W. van der Mei and A. Hoveyda, Nat. Chem.,
2016, 8, 768.
H
O
OH
R2
H
O
F
F3C
CF3
CF3
H
R1
R3
CF3
O
H
Ph
F
R1
R3
H
R2
H
CF3
CF3
O
6
7
(a) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur,
Chem. Soc. Rev., 2008, 37, 320; (b) E. P. Gillis, K. J. Eastman,
M. D. Hill, D. J. Donnelly and N. A. Meanwell, J. Med. Chem.,
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5822; (d) B. M. Johnson, Y.-Z. Shu, X. Zhuo and N. A.
Meanwell, J. Med. Chem., 2020, 63, 6315.
For selected reviews on α,α-Difluoroketones, see: (a) G.
Pattison, Eur. J. Org. Chem., 2018, 3520; (b) X.-S. Hu, J.-S. Yu
and J. Zhou, Chem. Commun., 2019, 55, 13638; (c) S.
Sadhukhan, J. Santhi and B. Baire, Chem. - Eur. J., 2020, 26,
7145.
OTMS
F
-TMS
H-bond network
catalyst
F3C
F3C
H
O
Ph
H
F
R1
O
H
F3C
F3C
O
H
R2
H
R3
O
H
H
H
H
O
O
H
O
R1
CF3
F3C
F3C
R3
H
F3
C
H
H
R2
F3C
CF3
F3C
CF3
-H2O
Scheme 3 Plausible mechanism.
and proved to be compatible with sensitive functional groups.
Mechanistic experiments reveal that the hydrogen-bond
interactions of HFIP play a crucial role in promoting the
difluoroalkylation reactions. We envision that this HFIP-
catalyzed strategy would bring new opportunities to access
structurally diverse fluorinated molecules, especially for the
late-stage functionalization of complex bioactive molecules.
This work was supported by the Leading Innovative and
Entrepreneur Team Introduction Program of Zhejiang (No.
8
9
(a) K. Uneyama, Organofluorine Chemistry; Blackwell:
Oxford, 2006: p 10; (b) C.-P. Qian, T. Nakai, D. A. Dixon and B.
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547.
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0 (a) M.-H. Yang, D. L. Orsi and R. A. Altman, Angew. Chem.,
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During the submission of this manuscript, Zhou and Yu
2
(
019R01005), Natural Science foundation of Zhejiang Province
Nos. LY18B020002 and LQ20B020005).
3
reported a Fe(OTf) -catalyzed nuclephilic substitution of
cyclic or acyclic tertiary with difluoroenoxysilanes to
construct α,α-difluoroketones bearing a quaternary carbon
center. Y.-J. Hao, Y. Gong, Y. Zhou, J. Zhou and J.-S. Yu, Org.
Lett., 2020, DOI: 10.1021/acs.orglett.0c03123.
Conflicts of interest
There are no conflicts to declare.
1
1 Selected examples on the transformations with alcohols, (a)
W. Zhang, J. Chen, J.-H. Lin, J.-C. Xiao and Y.-C. Gu, iScience,
Notes and references
2
018, 5, 110; (b) W. Zhang, J.-H. Lin, W. Wu, Y.-C. Cao and J.-
1
For selected reviews on HFIP, see: (a) J.-P. Bégué, D. Bonnet-
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1
1
2
015, 5, 17269; (d) J. Wencel-Delord and F. Colobert, Org.
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(
a) F.-M. Liao, Z.-Y. Cao, J.-S. Yu and J. Zhou, Angew. Chem.,
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7
747; (e) X. Jiang, D. Meyer, D. Baran, M. A. C. González and
2
For selected examples of HFIP as solvent or additive playing
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4 J.-S. Yu, Y.-L. Liu, J. Tang, X. Wang and J. Zhou, Angew. Chem.,
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| J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC06980A
HFIP-Catalyzed Direct Dehydroxydifluoroalkylation of Benzylic and Allylic Alcohols with
Difluoroenoxysilanes
Jinshan Li,a Wenxue Xi,a Rong Zhong, Jianguo Yang,* Lei Wang, Hanfeng Ding and Zhiming
a
a
a
b
Wang*a
HFIP
cat.
R3
F
O
OTMS
R4
R2
R1
R3
R2
R1
F
R4
+
OH
DCM, rt
F
F
5
0 examples
Substrate scope
1o, 2 , 3 and naturally occuring alcohols
o
o
Metal-free catalysis Mild reaction conditions
Late-stage functionalization