Copper-Catalyzed Highly Enantioselective Difluoroalkylation of Secondary Propargyl Sulfonates with Difluoroenoxysilanes

Full text of DOI:10.1016/j.chempr.2019.09.012

Article
Copper-Catalyzed Highly Enantioselective
Difluoroalkylation of Secondary Propargyl
Sulfonates with Difluoroenoxysilanes
Xing Gao, Ran Cheng, Yu-Lan
Xiao, Xiao-Long Wan, Xingang
Zhang
xgzhang@mail.sioc.ac.cn
HIGHLIGHTS
Straightforward asymmetric
fluoroalkylation
High enantioselectivity and broad
substrate scope
Useful strategy for diverse
transformations
Transition-metal-catalyzed asymmetric fluoroalkylation remains a challenging
topic due to the lack of efficient enantioselective catalysts to facilitate the catalytic
cycle with fluoroalkylating reagents. In this article, Zhang and co-workers report a
copper-catalyzed highly enantioselective difluoroalkylation of secondary
propargyl sulfonates using difluoroenoxysilanes. The combination of copper with
PyBox shows a highly catalytic effect for the enantioselective synthesis of
propargylic a,a-difluoroketones that can serve as versatile building blocks for
diverse transformations.
Gao et al., Chem 5, 1–13
November 14, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.09.012

Please cite this article in press as: Gao et al., Copper-Catalyzed Highly Enantioselective Difluoroalkylation of Secondary Propargyl Sulfonates with
Difluoroenoxysilanes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.012
Article
Copper-Catalyzed Highly Enantioselective
Difluoroalkylation of Secondary Propargyl
Sulfonates with Difluoroenoxysilanes
Xing Gao, Ran Cheng, Yu-Lan Xiao, Xiao-Long Wan, and Xingang Zhang1,2,3,*
1
1
1
1
SUMMARY
The Bigger Picture
Despite the impressive progress recently made in transition-metal-catalyzed
fluoroalkylation, the related asymmetric fluoroalkylation remains a challenging
topic. Here, we report a copper-catalyzed highly enantioselective difluoroalky-
lation of secondary propargyl sulfonates using difluoroenoxysilanes. The
reaction proceeds under mild reaction conditions with Cu(I)/PyBox as the
catalyst. The advantages of this method include high efficiency, high enantio-
selectivity (enantiomeric ratio up to 99:1), and excellent functional-group
tolerance. The resulting chiral propargylic a,a-difluoroketones can be trans-
formed into enantiomerically enriched propargyl difluoromethylated com-
pounds, providing a good platform for accessing a wide range of chiral difluor-
omethylated compounds that are of great interest in medicinal chemistry and
materials science.
Fluorine-containing organic
compounds have paramount
applications in life and materials
sciences. The discovery of
advanced drugs and materials
requires precise site- and
stereoselective introduction of
fluoroalkyl groups into organic
molecules. Transition-metal-
catalyzed asymmetric
fluoroalkylation would be a
straightforward strategy for
accessing optically active
fluorinated compounds. However,
catalytic asymmetric
INTRODUCTION
fluoroalkylation is still
The site-selective fluoroalkylation for precise molecular engineering has become
an intensive research topic of synthetic organic chemistry because of the important
underdeveloped. In this article,
we describe a copper-catalyzed
highly enantioselective
1
–4
applications of fluorinated compounds in life and materials sciences.
Although
impressive achievements have been made in the fluoroalkylation over the
difluoroalkylation of secondary
propargyl sulfonates with
difluoroenoxysilanes. This
protocol provides a facile access
to diverse chiral difluoroalkylated
compounds that are of great
interest in medicinal chemistry.
This method should prompt
research for further transition-
metal-catalyzed asymmetric
fluoroalkylations.
5
past decade, the catalytic asymmetric fluoroalkylation remains underdeveloped
6
–8
and is still an elusive goal.
One of the major reasons for this challenge is
the lack of efficient enantioselective catalysis to facilitate the catalytic cycle with
fluoroalkylating reagents while suppressing the unfavorable side reactions, such
as decomposition or protonation of fluoroalkylating reagents, which restricts
the discovery of new chiral biological molecules for pharmaceuticals and
agrochemicals. In the area of asymmetric synthesis of fluorinated molecules, orga-
9
–13
14,15
nocatalysis
and Lewis acids
(R
have been employed to enantioselectively
f
, fluoroalkyl) bonds at stereogenic centers (Fig-
catalyze the formation of C–R
f
ure 1A). However, these developed methods are limited to the functionaliza-
tion of carbonyl substrates, thus limiting their widespread applications to
synthesize versatile organic compounds. Furthermore, compared to catalytic
9
–15
asymmetric trifluoromethylation,
strategies for catalytic asymmetric difluoroal-
1
6–23
kylation have been far less explored.
Given the unique properties of difluoro-
1
–4,24
2
methylene group (CF ),
some important pharmaceuticals used for the treat-
27
2
5,26
ment of cancer
and other diseases
contain a stereogenic center with
difluoroalkylated group (Figure 1C). Thus, developing new and efficient methods
to overcome the limitations in the catalytic asymmetric difluoroalkylation is highly
demanding.
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1

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Difluoroenoxysilanes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.012
RESULTS AND DISCUSSION
Research Design
2
8–30
Transition-metal-catalyzed asymmetric synthesis
would be a promising strategy to
construct diversified difluoroalkylated chiral center efficiently (Figure 1B). To date,
however, only rare examples of transition-metal-catalyzed asymmetric fluoroalkylation
3
1,32
have been reported.
These methods either are limited to enantiomerically en-
32
3
1
riched substrates or only have moderate enantioselectivity. To overcome these
33–37
limitations, we sought to use copper-catalyzed propargylic substitution reaction
to construct the difluoroalkylated stereogenic center (Figure 1B), because alkynes
are ubiquitous in numerous bioactive molecules and natural products, and more essen-
tially, carbon-carbon triple bond can serve as a versatile functional group for various
3
8
transformations. In this copper-catalyzed process, one crucial issue is how to facilitate
the difluoroalkyl anion, a hard nucleophile, to attack the in-situ-generated g-electro-
philic copper-allenylidene intermediate, a soft electrophile. Difluoroalkyl anions are
generally unstable presumably due to the repulsion between carbon anion and the
lone pair of fluorine atoms; on the other hand, the strong electron-withdrawing effect
of the fluorine atom makes the difluorocarbon anion an even harder nucleophile than
its nonfluorinated counterpart. As a consequence, difluoroalkyl anions encounter diffi-
39
culty to react with soft electrophiles, such as activated carbon-carbon double bonds.
To solve this problem, we envisioned that the a-aroylation of difluoromethyl anion
would provide a more stable difluoroenolate and make it a softer nucleophile through
a p-p conjugation between the lone pair of the oxygen and p-system of carbon-carbon
double bond and aromatic ring (Figure 1B).
Optimization Study
Accordingly, propargylic ester 1a and carbonate 1b, two common substrates used
for copper-catalyzed asymmetric propargylation, were examined to react with
f
phenyl-substituted difluoroenoxysilane 2a in the presence of CuOT (10 mol %)
and Ph-PyBox L1 (12 mol %) (Table 1, entries 1 and 2; Table S1). However, the start-
ing material 2a was recovered in 93%–97% recovery, and no desired product 3a was
obtained. Propargyl sulfonate 1c was then employed for the reaction with the pre-
sent difluoroalkyl anion, providing 3a in 60% yield with a 68:32 enantiomeric ratio
(
er) (Table 1, entry 3). In contrast, a-silyldifluoroacetate 2b and a-silyldifluoroaceta-
mide 2c were not applicable to the reaction (Table 1, entries 4 and 5; Table S1), and
0
0
only protonated difluoroacetate 2b and difluoroacetamide 2c were obtained.
When TMSCF H was used, only starting materials were recovered (Table S1). These
2
observations clearly demonstrate that the conjugated aryl group on compound 2
promotes the reaction. Encouraged by these results, a survey of a series of reaction
parameters, such as solvent (Table S2), ligand (Table S3), and reaction temperature
(
Table S4) was conducted. The choice of solvent is critical to this reaction. Among the
tested solvents, DCE was the best reaction medium; other solvents, such as THF,
CH CN, and DMF essentially showed no activity (Table S2). PyBox ligands with
3
different substituents were also examined (Table S3). iPr-PyBox (L2) showed compa-
rable reactivity with L1 (Table 1, entry 6). But ligands L3 (Cy-PyBox) and -L4
1Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
(
(
PhCH
2 2
CH -PyBox) led to no product (Table 1, entries 7 and 8). An increased er value
88:12) with 60% yield of 3a was obtained when L5 was used (Table 1, entry 9). How-
ever, further increasing the rigidity of the ligand and using L6 failed to improve the er
value (Table 1, entry 10). Increasing the steric hindrance of the difluoroenoxysilane
benefited the enantioselectivity. A higher er value of 92:8 with a lower yield (50%)
was obtained when difluoroenoxysilane 2d was used (Table 1, entry 11). The elec-
tronic nature of the aryl group on difluoroenoxysilane 2 also influenced the enantio-
2College of Chemistry, Henan Institute of
Advanced Techonology, Zhengzhou University,
Zhengzhou 450001, China
3Lead Contact
selectivity (Table S5). Aryl group bearing an electron-withdrawing substituent (CF
3
)
*Correspondence: xgzhang@mail.sioc.ac.cn
https://doi.org/10.1016/j.chempr.2019.09.012
at its para-position led to a decreased er value (85:15; Table 1, entry 12). On the
2
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Figure 1. Strategies for the Catalytic Enantioselective Fluoroalkylation and Representative Drugs Containing a Difluoroalkylated Stereogenic Center
(
(
(
A) Catalytic enantioselective fluoroalkylation by organocatalysis or Lewis acids.
B) Catalytic enantioselective fluoroalkylation by transition metal.
C) Representative drugs containing a difluoroalkylated stereogenic center.
basis of these results, difluoroenoxysilane 2d was then used for optimizing the reac-
tion conditions further. We found that increasing the steric hindrance of the leaving
group on propargyl sulfonate 1 could increase the er value of 3d to 95:5 (Table 1,
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Table 1. Representative Results for the Optimization of Copper-Catalyzed Enantioselective Difluoroalkylation of Propargyl Sulfonates
a
b
Entry
1
2, R
L
3, Yield (%), er
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1d
1e
1d
1d
1d
2a, Ph
2a, Ph
2a, Ph
2b, OEt
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
3a, 0, –
3a, 0, –
3a, 60, 68:32
3b, 0, –
2c, NEt
2a, Ph
2
3c, 0, –
3a, 56, 62:38
3a, trace, –
3a, 0, –
2a, Ph
2a, Ph
2a, Ph
3a, 60, 88:12
3a, 0, –
10
11
12
13
14
15
16
17
2a, Ph
2d, pMe-C
6
H
4
3d, 50, 92:8
3i, 56, 85:15
3d, 52, 95:5
3 6 4
2i, pCF -C H
2d, pMe-C
2d, pMe-C
2d, pMe-C
2d, pMe-C
6
H
4
H
4
H
4
H
4
6
6
6
3d, 72, 86.5:13.5
3d, 73, 95.5:4.5
c
c,d
c,e
3d, 88 (87), 95.5:4.5
3d, 91 (90), 95.5:4.5
6 4
2j, pMe-C H
Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv), 2 (0.45 mmol, 1.5 equiv), DCE (2 mL). Abbreviations: MS, molecular sieves; DIPEA,
N-ethyl-N-isopropylpropan-2-amine; DCE, 1,2-dichloroethane; Mes, 2,4,6-trimethylphenyl.
a
19
Determined by F NMR using fluorobenzene as an internal standard. The number given in parentheses is the isolated yield.
b
Determined by chiral HPLC analysis.
0 mol % Cu(CH CN) PF was used.
c
1
3
4
6
d
˚
1
d (0.6 mmol, 2.0 equiv), 2d (0.3 mmol, 1.0 equiv), LiF (1.0 equiv), 3A MS (50 mg), DCE (2 mL).
e
˚
1
d (0.6 mmol, 2.0 equiv), 2j (0.3 mmol, 1.0 equiv), LiF (1.0 equiv), 3A MS (50 mg), DCE (3 mL). 2j, ((2,2-difluoro-1-(p-tolyl)vinyl)oxy)triethylsilane.
entry 13; Table S6), but the yield of 3d was lower than that from benzenesulfonate 1e
Table 1, entry 14). A higher yield of 3d (73% yield) was obtained by using
Cu(CH CN) PF (10 mol %) as a catalyst (Table 1, entry 15). However, the yield could
not be improved further due to the decomposition of propargyl sulfonate 1d. To
(
3
4
6
˚
overcome this problem, 2.0 equiv of 1d and 3A MS were used, providing 3d in
˚
8
8% yield with 95.5:4.5 er value (Table 1, entry 16), in which the use of 3A MS could
suppress the protonation of 2d. Finally, the yield of 3d was improved to 91% (90%
yield upon isolation) by using TES protected difluoroenolate 2j as a coupling partner
(
Table 1, entry 17).
4
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Scheme 1. Copper-Catalyzed Enantioselective Difluoroalkylation of Propargyl Sulfonates 1 with Difluoroenoxysilane 2j
Reaction conditions (unless otherwise specified): 1 (0.6 mmol, 2.0 equiv), 2j (0.3 mmol, 1.0 equiv), and DCE (3 mL). All reported yields are isolated yields.
a
1
5 mol % Cu(CH
3
CN)
4 6
PF and 18 mol % L5 was used.
b
Gram-scale reaction.
Scope of the Investigation
Since the TES protected difluoroenolates are more stable than their TMS protected
counterparts, difluoroenoxytriethylsilanes 2 were then used to examine the sub-
strate scope. Generally, good to high yields with excellent enantioselectivities
were obtained when difluoroenoxysilane 2j was used to react with secondary
propargyl sulfonates 1 (Scheme 1; Figures S11–S43, S80–S146, and S262–S287).
The reaction exhibited high functional-group tolerance. The propargyl sulfonates
bearing nitro, vinyl, ester, cyano, and amide moieties underwent the reaction
smoothly (3j–3o and 3r). Even pyridyl-containing substrate showed the desired
reaction efficiency and enantioselectivity (3q). Importantly, the catalytic asymmetric
difluoroalkylation products (3p, 3s, and 3t) with bromide and alkyl sulfonate intact
provided good opportunities for further transformations. The generality of this cop-
per-catalyzed process was also demonstrated by the reaction of 2j with substrates
containing complex molecule. For instance, proline and estrone derivatives were
applicable to the reaction without erosion of er values (3u and 3v). Notably, in the
case of estrone-containing substrate, no aldol adduct between 2j and ketone was
observed (3v), thus demonstrating the advantages of this protocol. Furthermore,
the reaction was not restricted to the propargyl sulfonate with a linear chain, as sub-
strates bearing a cyclic chain were also competent coupling partners and provided
the corresponding products with er values as high as 99:1 (3w and 3x). Importantly,
the reaction can be readily scalable, as demonstrated by the gram-scale synthesis of
3
d without losing the reaction efficiency and enantioselectivity.
In addition to propargyl sulfonates, a variety of difluoroenoxysilanes 2 were inves-
tigated (Scheme 2; Figures S56–S79, S177–S224, and S288–S305). The aromatic
ring of compounds 2 bearing a bulky tert-butyl group or an electron-donating me-
thoxyl group at para-position did not interfere with the reaction efficiency and
enantioselectivity (4a–4d). Even 3,5-dimethoxy substituted phenyl containing
substrate still underwent the reaction efficiently with high er value (95.5:4.5) (4e).
The more sterically hindered 2, such as 2-naphthyl or o-toyl-substituted difluoroe-
noxysilanes, were also applicable to the reaction without losing enantioselectivity
(
3
4f–4h). Notably, compound 2o bearing an electron-withdrawing group CF was a
competent coupling partner, providing the corresponding product 4i in 89% yield
with high enantioselectivity (er = 96:4). It should be mentioned that the ketone
substrates bearing an electron-withdrawing group on the aromatic ring for the
preparation of difluoroenoxysilanes 2 are stable without the formation of stable hy-
0
drates. Furthermore, difluoroenoxytriethylsilane 2a bearing an unsubstituted
phenyl group underwent the reaction smoothly, providing 3a in 87% yield with
9
4:6 er value. These results demonstrate that the electronic nature and steric effect
of aryl group on the difluoroenoxysilane 2 are not critical factors for the reaction
efficiency and enantioselectivity under standard reaction conditions. Again, excel-
lent er values were obtained by using cyclic chain containing propargyl sulfonate
(
4j and 4k).
Transformation and Application
The resulting chiral difluoroalkylated alkynes can serve as versatile building blocks
for the diversity-oriented synthesis. As shown in Scheme 3A (Figures S225–S247),
Sonogashira reaction of 3d with heteroaryl iodides and reduction of the carbonyl
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Scheme 2. Copper-Catalyzed Enantioselective Difluoroalkylation of Propargyl Sulfonates 1 with Difluoroenoxysilanes 2
Reaction conditions (unless otherwise specified): 1 (0.6 mmol, 2.0 equiv), 2 (0.3 mmol, 1.0 equiv), and DCE (3 mL). All reported yields are isolated yields.
a
TMS protected compound 2 was used.
4
group with NaBH proceeded smoothly. The ketone can also be oxidized into
ester through Baeyer-Villiger oxidation of hydrogenated 3d, thus providing an
efficient way to access chiral difluoroacetylated compounds. The copper-catalyzed
click reaction of 3d with (azidomethyl)benzene provided [3 + 2] cycloaddition
products 5e in good yield, demonstrating the potential utility of the resulting
alkynes in the medicinal chemistry. Most remarkably, the p-Toyl acyl (pMe-
C
6
H
4
CO) group can be easily removed to access chiral difluoromethylated alkyne
d under mild reaction conditions without erosion of er value. To date, only two
examples of catalytic asymmetric difluoromethylation have been reported: one is
5
4
0,41
the chiral hypervalent iodide-catalyzed difluorinatation of styrenes,
and the
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Scheme 3. Transformations of Compounds 3d and 5d
(
(
A) Transformations of compound 3d.
B) Transformations of compound 5d.
All reported yields are isolated yields.
3
2
other is the copper-catalyzed asymmetric difluoromethylation of allylic halides.
But both reactions cannot access chiral difluoromethylated alkynes. The current
process can address this limitation and result in chiral difluoromethylated alkynes,
providing a good platform for diverse synthesis of a wide range of chiral difluoro-
methylated compounds that are difficult to access by conventional methods
(
Scheme 3B; Figures S248–S261). For instance, hydrogenation or partial hydroge-
nation of alkyne afforded the chiral difluoromethylated alkane 6a and alkene 6b
efficiently. Cross-coupling of 5d with 3-iodothiophene also proceeded smoothly.
Furthermore, compound 5d can be used for the construction of heterocycle 6d
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Scheme 4. Reaction of Internal Alkyne 1ze with Difluoroenoxysilane 2j
4
2
2
through [3 + 2] cyclization. Since CF H has been considered as a bioisostere of
4
3
44
hydroxyl and thiol group and also as a lipophilic hydrogen-bond donor, these
transformations provide efficient routes for applications in discovering interesting
new bioactive molecules for medicinal chemistry. The absolute configuration of
compounds 3 and 4 was assigned to be S-configured through the determination
4
5
of compound 5d by a chiroptical method, in which the electronic circular dichro-
ism (ECD) spectra for 5d was calculated by time-dependent density functional
4
6
theory (TD-DFT) to assign its absolute configuration. The simulated spectrum
is in good agreement with the experimental data (Figures S1–S3)
Mechanistic Studies
To gain mechanistic insights into the current reaction, several experiments
were conducted. Initially, an internal alkyne 1ze was used to react with difluoroe-
noxysilane 2j, but no desired product 7 was observed (Scheme 4). This result
demonstrates that terminal alkyne is essential in the promotion of the reaction; a di-
3
1
fluoroalkylcopper species via a redox catalytic cycle is less likely involved in the
reaction because both terminal and internal alkynes will generate the correspond-
ing ketones if a copper-redox catalytic cycle is the possible pathway. On the basis
4
7–49
of previous reports
and the crystallographic structure of Cu(CH
3 4 6
CN) PF /L1
4
7,48,50,51
(
Figure 3A),
a dinuclear copper complex may serve as the active species
to promote the reaction. This hypothesis was further supported by the nonlinear
relationship between the enantiopurity of ligand L5 and 3d in the reaction of 1d
with 2j (Figure 2; Table S7; Figure S4). Therefore, a plausible mechanism for the
4
7,52
observed stereochemistry on the basis of Maarseveen’s model
is proposed.
As illustrated in Figure 3B, a cooperative copper catalysis may be involved in the
reaction, in which one copper reacts with propargyl sulfonate 1 to generate the
copper-allenylidene complex, and the other binds to the difluoroenolate. Subse-
quently, nucleophilic attack of difluoroenolate copper to the Si-face of copper-alle-
nylidene via M1 produces the product in S configuration.
We also conducted a Hammett-type analysis of the reaction (Figure 4; Tables S8–
S17; Figures S5–S10). Plots of log(krel) versus s showed that both electron-donating
and electron-withdrawing substituents essentially have no effect on the reaction
efficiency, which is consistent with the results illustrated in Scheme 1B. The role of
the conjugated aryl group on the difluoroenoxysilane is probably to stablize the
difluoroenolate and facilitate the generation of a difluoroenolate copper species
for the reaction. Finally, to identify the effect of the aliphatic chain length on the
enantioselectivity, the proparyl sulfonates bearing different aliphatic chain were
examined (Scheme 5; Figures S44–S55 and S147–S176). We found that with
increasing the chain length of proparyl sulfonate, the enantioselectivity of the corre-
sponding product was increased, but until the chain spacer between the functional
group and leaving group was more than or equal to two carbons, the enantioselec-
tivity was not increased any more. The low yield of 3zb is because of the formation of
enyne byproduct. These results clearly demonstrate that the aliphatic chain length of
proparyl sulfonate is critical for the enantioselectivity and an aliphatic chain bearing
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Figure 2. Nonlinear Relationship: Plot of the ee Value of L5 and ee Value of 3d
at least two carbons between the functional group and leaving group is essential for
the high enantioselectivity.
Conclusion
In conclusion, we have developed the first example of copper-catalyzed highly enan-
tioselective difluoroalkylation of propargyl sulfonates with difluoroenoxysilanes. The
combination of copper(I) salts with PyBox shows a highly catalytic effect for the
enantioselective synthesis of propargylic a,a-difluoroketones. The aryl group on
the difluoroenoxysilanes plays an essential role in this copper-catalyzed process,
but its steric effect and electronic nature essentially do not interfere with the reaction
efficiency and enantioselectivity. Instead, the steric sulfonate leaving group and the
aliphatic chain length of propargyl sulfonate are critical factors for the reaction
enantioselectivity. The reaction proceeds smoothly under optimal reaction condi-
tions with high efficiency, high enantioselectivity (er up to 99:1), and excellent
functional-group tolerance. Most importantly, the resulting chiral propargylic
a,a-difluoroketones can be transformed into enantiomerically enriched propargyl
difluoromethylated compounds. These resulting chiral fluorinated structural motifs
are previously unknown and can serve as versatile building blocks for diversified
organic synthesis, thus offering a useful protocol for applications in medicinal
chemistry and materials science. Further studies to develop derivative reactions
are underway in our laboratory and will be reported in due course.
Figure 3. Proposed Reaction Mode for the Copper-Catalyzed Eantioselective Difluoroalkylation
of Secondary Propargyl Sulfonates with Difluoroenoxysilanes
(
(
A) Crystal structures of Cu/PyBox from Gamasa and Nishibayashi.
B) Maarseveen’s model for the reaction.
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Please cite this article in press as: Gao et al., Copper-Catalyzed Highly Enantioselective Difluoroalkylation of Secondary Propargyl Sulfonates with
Difluoroenoxysilanes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.012
Figure 4. Hammett Plot of Log(krel) versus s
EXPERIMENTAL PROCEDURES
To a 25 mL of Schlenk tube were added Cu(CH
3 4 6
CN) PF (11.2 mg, 0.03 mmol,
and10 mol %), L5 (18.8 mg, 0.036 mmol, and 12 mol %), LiF (7.8 mg, 0.3 mmol,
˚
and 1.0 equiv), and 3A MS (50 mg) in the glovebox. DIPEA (0.045 mmol, 15 mol
, and 0.0225 M in DCE) was then added. After the reaction mixture was stirred
at room temperature for 20 min, DCE (1.0 mL), propargyl sulfonate 1 (0.6 mmol,
.0 equiv), and difluoroenoxysilane 2 (0.3 mmol, 1.0 equiv) were added. The Schlenk
%
2
ꢀ
ꢀ
tube was sealed with a screw-cap and put into a cryogenic reactor (15 C –20 C).
After stirring for 12 h, the reaction mixture was worked up with ethyl acetate. The
1
9
yield was determined by F NMR using fluorobenzene as an internal standard.
The resulting mixture was filtered with a pad of celite. The filtrate was concentrated,
and the residue was purified with silica gel chromatography to give product 3. Full
experimental procedures are provided in the Supplemental Information.
Scheme 5. Investigation of Aliphatic Chain Length on the Enantioselectivity
All reported yields are isolated yields.
Chem 5, 1–13, November 14, 2019
11

Please cite this article in press as: Gao et al., Copper-Catalyzed Highly Enantioselective Difluoroalkylation of Secondary Propargyl Sulfonates with
Difluoroenoxysilanes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.012
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2
019.09.012.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of
China (nos. 21425208, 21790362, 21702225, and 21421002), the Strategic Priority
Research Program of the Chinese Academy of Sciences (no. XDB20000000), and
SIOC.
AUTHOR CONTRIBUTIONS
X.Z. and X.G. conceived and designed the experiments. X.Z. directed the project.
X.G. performed the experiments. R.C. prepared some starting materials. X.G. and
Y.-L.X. analyzed the data. X.-L.W. conducted chiral HPLC analysis. X.Z. wrote the
paper.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: May 17, 2019
Revised: August 6, 2019
Accepted: September 18, 2019
Published: October 14, 2019
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