Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes

Article abstract of DOI:10.1016/j.chempr.2018.07.003

gem-Difluoroalkenes have steric and electronic profiles similar to those of ketones, aldehydes, and esters, and consequently have been used widely as carbonyl isosteres in modern drug discovery. Although many attempts have been made to achieve gem-difluor

Full text of DOI:10.1016/j.chempr.2018.07.003

Article
Copper-Catalyzed Asymmetric
Defluoroborylation of 1-(Trifluoromethyl)Alkenes
Pan Gao, Chengkai Yuan, Yue
Zhao, Zhuangzhi Shi
shiz@nju.edu.cn
HIGHLIGHTS
The first asymmetric
defluoroborylation
Rapid access to optically active
gem-difluoroallylboronates
Cheap copper catalysis under
mild reaction conditions
Useful carbonyl mimic products
based on the diversity of boron
chemistry
A mild catalytic system has been established for the asymmetric
defluoroborylation of 1-(trifluoromethyl)alkenes via C-F activation. This route
employs a low-cost copper catalyst and can be used to generate chiral gem-
difluoroallylboronates with a broad substrate scope.
Gao et al., Chem 4, 1–11
September 13, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.07.003

Please cite this article in press as: Gao et al., Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes, Chem (2018),
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Article
Copper-Catalyzed Asymmetric
Defluoroborylation of 1-(Trifluoromethyl)Alkenes
Pan Gao, Chengkai Yuan, Yue Zhao, and Zhuangzhi Shi1,2,*
1
1
1
SUMMARY
The Bigger Picture
gem-Difluoroalkenes have steric and electronic profiles similar to those of ke-
tones, aldehydes, and esters, and consequently have been used widely as
carbonyl isosteres in modern drug discovery. Although many attempts have
been made to achieve gem-difluoroalkenes, the induction of enantioselectivity
at the a position of a gem-difluorovinyl group still remains a challenge. Herein,
an efficient method for the construction of gem-difluoroallylboronates with high
enantiomeric excess via a copper-catalyzed defluoroborylation of 1-(trifluoro-
Modern drug discovery relies on
advance in chemical synthesis to
address challenges from
designing new pharmaceutical
agents. Replacement of a
carbonyl with the corresponding
gem-difluoroalkene, a carbonyl
isostere, has been demonstrated
to provide bioactive substrates
still recognized by their target.
However, this potentially valuable
carbonyl mimic has not been more
extensively evaluated, possibly
because the conventional routes
to construct the gem-
2 2
methyl)alkenes with B pin is described. The reaction conditions were mild,
and a variety of common functional groups, such as ether, fluoride, chloride,
bromide, iodide, ester, cyano, sulfide, amino, and indoyl groups, were well
tolerated. Furthermore, we not only applied this developed system as a power-
ful synthetic tool for the late-stage modification of complex compounds but also
highlighted the utility of the formed compounds in synthesis.
INTRODUCTION
difluoroethylene motif involve a
functional-group interconversion
relying on highly reactive
gem-Difluorovinyl groups, important structural motifs in medicinal design, exhibit
steric and electronic profiles similar to those of the corresponding carbonyl substit-
1
uents, and consequently have been used widely as carbonyl isosteres. gem-Difluor-
intermediates, organometallic
reagents, or harsh reaction
oalkene mimics of bioactive ketones and esters have been prepared to improve
pharmaceutical properties such as bioactivity, target specificity, and metabolic sta-
2
–6
conditions. Our methodology
enables C-F activation of
bility of the mimics over those of their bioactive parent structures (Figure 1A).
Although impressive progress has been made in the synthesis of gem-difluoroal-
1
-(trifluoromethyl)alkenes via a
kenes in recent years, for example, the classical Wittig olefination and Julia-Kocien-
7
–18
defluoroborylation process to
produce a diverse array of
enantioenriched gem-
ski reaction, some issues remain unresolved.
First, most traditional approaches
require strong bases, which leads to a limited substrate scope and low efficiency;
second, the a position of a gem-difluorovinyl group in a drug candidate is usually
a chiral carbon center, and the induction of enantioselectivity at this position is still
difluoroallylboronates. We
anticipate that the strategy based
on the diversity of boron
chemistry will simplify the
synthesis and structural
1
9
challenging ; third, the rapid and efficient installation of a range of functional
groups such as hydroxyl, amino, and alkyl substituents to a position of a difluorovinyl
group is in high demand. On the other hand, a-chiral boronate-substituted
compounds are an important family of target molecules, because the C-B linkage
2
0–29
elaboration of gem-
provides an extremely useful stereogenic center.
They have been shown to
3
0,31
difluoroalkene targets in
chemistry, biology, and medicine.
participate in C-C coupling reactions with excellent enantioselectivity.
Further-
more, the formed chiral C-B bond may be readily converted into a C-O, C-N, and
other C-heteroatom bond with retention of the configuration, allowing access to a
3
2
wide array of functional groups that are common in valuable synthetic targets.
Therefore, to address the aforementioned challenges, an efficient method is to
construct a-chiral boronate-substituted gem-difluoroalkene building blocks.
Defluorinative functionalization of fluorine-containing compounds has shown prom-
3
3–40
ise as it confers synthetic versatility to inert C-F bonds.
Defluoroborylations of
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A Biological activity of chiral gem-difluoroalkenes:
NH2
CF2
N
Me
Me
O
O
F2C
OTDP
O
N
HO
S
COOH
O
F2C HO
OH
O
Me
H N
2
O
HO
CF2
TDP-6-deoxy-L-
lyxo-4-hexulose
isostere
Me
Artemisinin
isostere
Antitumor
agent
GABAAT
inactivator
B Known processes for defluoroborylation:
cat [Ni]
2
015
(equation 1)
(equation 2)
Ar
F
Ar Bpin
cat [Cu]
cat [Fe]
B pin
2 2
Bpin
Bpin
Ar
CF2
2017
Ar
R
-
FBpin
F
CF3
CF2
2017
(equation 3)
R
C Enantioselective defluoroborylation:
cat. [Cu]/L
Bpin
B pin
2
2
Downstream
Transformatiom
CF3
CF2
R
-
FBpin
R
Boron & Fluorine Chemistry
Figure 1. Development of a Protocol to Build Chiral gem-Difluoroallylboronates
unactivated fluoroarenes have been reported by several groups (Figure 1B, equa-
4
1–44
tion 1).
Recent progress has been made for the construction of Z-fluoro-alkenyl-
boronates by a Cu-catalyzed stereoselective monodefluoroborylation of gem-
4
5,46
47
48
difluoroalkenes (Figure 1B, equation 2).
Our group and Ito’s group have
also developed Cu-catalyzed stereoselective hydrodefluorinations of gem-difluor-
oalkenes to generate Z-fluoroalkenes, in which the Z-fluoro-alkenylboronates acted
as the key intermediates. Notably, Fe-catalyzed syntheses of gem-difluoroallylboro-
nates via the defluoroborylation of a-(trifluoromethyl)alkenes in the absence of
4
9
ligand have also been developed (Figure 1B, equation 3). Inspired by these results,
here we report a mild and operationally simple strategy for the construction of a-chi-
ral boronate-substituted gem-difluoroalkenes through a copper-catalyzed, enantio-
selective defluoroalkylation of 1-(trifluoromethyl)alkenes (Figures S35–S85) with
B
2
Pin
2
(Figure 1C). The challenge of this strategy was to cleave a stable C-F bond
group while simultaneously forming a readily transformable allylic C-B
in a CF
3
bond as part of a stereogenic center.
RESULTS AND DISCUSSION
1State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China
Initial studies of the catalytic reaction conditions identified Cu salts in conjunction
with an N-heterocyclic carbene (NHC) ligand as effective promoters of the addition
2Lead Contact
of B
2 2
pin to 1-(trifluoromethyl)alkene 1a (Table 1; see also Figures S35–S37). In the
t
presence of 10 mol % CuCl, 11 mol % ICy$HCl, 1.0 equiv NaO Bu, and 2.0 equiv
*Correspondence: shiz@nju.edu.cn
https://doi.org/10.1016/j.chempr.2018.07.003
ꢀ
3
MeOH at 45 C under an argon atmosphere in CH CN, we indeed observed the
2
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Table 1. Reaction Development
ꢀ
a
b
Entry
[M]
L*
Base (equiv)
Temp. ( C)
ee (%)
–
Yield of 4a (%)
t
1
2
3
4
5
6
7
8
9
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
FeCl2
ICy$HCl
ICy$HCl
ICy$HCl
L1
NaO Bu (1.0)
45
18
32
t
NaO Bu (1.0)
45
–
t
c
NaO Bu (2.0)
45
–
84 (58)
t
NaO Bu (2.0)
45
5
89
90
83
88
90
76
85
91
68
t
L2
NaO Bu (2.0)
45
21
54
82
88
75
84
89
92
92
–
t
L3
NaO Bu (2.0)
45
t
L4
NaO Bu (2.0)
45
t
L5
NaO Bu (2.0)
45
t
L6
NaO Bu (2.0)
45
t
10
11
12
13
14
15
16
L7
NaO Bu (2.0)
45
t
L5
NaO Bu (2.0)
RT
t
L5
NaO Bu (2.0)
0
t
c
L5
NaO Bu (2.0)
0–RT
0–RT
0–RT
0–RT
89 (65)
d
e
t
L5
NaO Bu (2.0)
trace
trace
0
L5
–
–
t
L5
NaO Bu (2.0)
–
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol) in CH
3
CN (2.0 mL), 12 hr, room temperature (RT), under Ar.
a
Enantiomeric excess values were determined by chiral high-performance liquid chromatography analysis.
b
Isolated yield after chromatography.
c
Isolated yield of 3a.
d
Without MeOH.
e
t
Without NaO Bu.
formation of defluoroborylation product 3a and isolated the corresponding alcohol
product 4a in 18% yield after Brown oxidation by NaBO
3
(entry 1). Other copper salts
t
such as CuI showed better yields (entry 2). The use of 2.0 equiv of NaO Bu resulted in
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10 mol% CuI
1
1 mol% L5
.0 equiv NaO Bu
Bpin
OH
t
NaBO3 4H O
2
2
CF3
CF2
OH
CF2
R
2.0 equiv MeOH
R
R
THF/H2O
o
CH3CN, 0 C~rt, 12h
B2pin2 (2a)
1
3
4
OH
OH
BnO
CF2
O
CF2
CF2
MeO
4
a
4b
78%, 94% ee
4c
8
9%, 92% ee
82%, 85% ee
OH
OH
CF2
O
CF2
O
MeO
Ph
4d
4e
83%, 91% ee
59%, 93% ee
CCDC 1821460
CF3
F
OH
OH
OH
CF2
CF2
Me
CF2
O
O
F3C
4
f
4g
92%, 93% ee
4h
6
7%, 88% ee
88%, 95% ee
OH
OH
OH
CF2
O
Cl
CF2
CF2
O
Br
Br
4j
4k
4i
76%, 91% ee
87%, 90% ee
83%, 85% ee
I
O
OH
OH
OH
CF2
CF2
O
CF2
Ph
O
TBSO
4l
4m
4n
76%, 90% ee
50%, 92% ee
63%, 83% ee
OH
Me OH
OH
CF2
O
N
CF2
Me
S
CF2
Ph
NC
4
o
4p
2%, 90% ee
4q
8
58%, 93% ee
7
2%, 87% ee
OH
O
OH
CF2
OH
O
CF2
H
H
N
N
CF2
H
O
O Me
4r
4s
4t
64%, 90% ee
82%, 89% ee
62%, 86% de
Me
Me
O
OH
Me
Ph
O
CF2
OH
CF2
Me
H
Me
CF3
S
CF3
H
H
Me
MeO
H
1x
4u
4v
1w
44%, 99% de
32%, dr = 3: 2
4
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Figure 2. Substrate Scope
t
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), CuI (10 mol % mmol), L5 (11 mol % mmol), NaO Bu (0.40 mmol), B
2
pin
2
(0.4 mmol), MeOH (0.40 mmol)
ꢀ
ꢀ
in CH
3
CN (2.0 mL), 12 hr, 0 C to room temperature (RT), under Ar, isolated yield after chromatography. For 4j and 4q, 0 C, 12 hr. For 4v,
diastereoselectivity was determined by high-performance liquid chromatography analysis.
8
4% isolated yield of 4a, despite precursor 3a being unstable on silica gel column
(
only 58% isolated yield, entry 3). To achieve an enantioselective variation, we first
evaluated chiral NHC ligands such as L1, which only afforded 5% enantiomeric
excess (ee) (entry 4). We found bidentate phosphine ligands such as (S)-SEGPHOS
(
entry 5) to be more effective, and we discovered that the JOSIPHOS family of li-
gands provided the best reactivity and enantioselectivity (entries 6–10). Among
t
p 3 2 2
them, the use of the (R, S )-L5, bearing P(4-CF Ph) and P Bu substituents, provided
the desired product 4a in 90% yield and 88% ee (entry 8). With the more active cata-
lyst system, it was found that reactions of 1a could be conducted at room tempera-
ꢀ
ture (RT) (entry 11) and even 0 C (entry 12), leading to a slight increase in enantiose-
lectivity. The greatest enhancement in reactivity (88%, 92% ee) was observed when
ꢀ
the reaction was slowly warmed from 0 C to RT (entry 13; see also Figures S8 and
t
S89–S91). Control experiments revealed that the absence of MeOH or NaO Bu
dramatically reduced the yield (entries 14 and 15). The choice of copper catalysis
4
9
2
was critical, while the reaction could not work in the presence of FeCl (entry 16).
With the optimized reaction conditions in hand, we then examined the scope of this
defluoroborylation reaction (Figure 2). The naphthyl group of substrate 1b (Figures
S38–S40) did not hinder the defluoroborylation process, and the reaction afforded
corresponding product 4b (Figures S9 and S92–S94) in 78% yield and 94% ee.
Asymmetric defluoroborylations of 1-(trifluoromethyl)alkenes with either ester (4c;
Figures S10 and S95–S97) or anisole (4d; Figures S11 and S98–S100) moieties on
a distal position proceeded smoothly. Biphenyl-containing substrate 1e was toler-
ated and gave product 4e (Figures S12 and S101–S103) in 93% ee. To determine
the absolute configuration of our products, we grew crystals of compound 4e and
subjected them to X-ray crystallographic analysis (Figure 2; see also Figure S6
and Tables S1, S2, S3, S4, and S5). A non-activated linear olefin could be trans-
formed successfully under the reaction conditions as well (4f; Figures S13 and
S104–S106). Reactions of 1g (Figures S47–S49) and 1h (Figures S50–S52), which
contain multiple sites for possible C-F borylation, showed extremely high selectivity
for C-F activation at the vinyl-fluoro functionality over the alkyl terminal position (4g-
4
h; Figures S14, S15, and S107–S112). It should be noted that the chemoselectivity
of the chiral copper catalyst was not affected by halo substituents such as Cl (4i;
Figures S16 and S113–S115), Br (4j-4k; Figures S17, S18, and S116–S121), and I
(
4l; Figures S19, and S122–S124) on the substrates, highlighting the potential of
this process in combination with subsequent conventional cross-coupling transfor-
mations. Adducts 4m (Figures S20 and S125–S127) and 4n (Figures S21 and
S128–S130) were formed by the coupling of the corresponding Bz- and TBS-pro-
2 2
tected alcohols with B pin , respectively. Substrate 1o (Figures S71–S73), with a
cyano group, was found to be compatible with the reaction conditions and
produced product 4o (Figures S22 and S131–S133) in 72% yield with 87% ee.
Notably, substrates with strong coordination abilities, such as those with amine
(
4p; Figures S23 and S134–S136), sulfide (4q; Figures S24 and S137–S139) and
O-phthalimide (4r; Figures S25 and S140–S142) moieties, still underwent the de-
fluoroborylation to afford the desired products in good yields. In addition, indole-
containing compound 1s (Figures S80–S82) was also accommodated with minimal
impact on yield or enantioselectivity (82% yield, 89% ee; see also Figures S26 and
S143–S145). Finally, having established an enantioselective defluoroborylation of
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Bpin
BnO
CF2
OH
CF2
5
6
6%, 90% ee
BnO
6
6
2
.0 mmol
3%, 90% ee
3
a
scale
5
5%, 91% ee
"
standard
OH
H
Bpin
CF2
R
CF conditions"
from 4a
3
R
BnO
(c)
F
B pin (2a)
2
2
1
7
3
8
(
9%, 87% ee
(
f)
E/Z = 95:5)
(
d)
OH
(
e)
OH
F
CF2
HO
( )7
BnO
H
F
1
0
8
OH
F
9
2%, 92% ee
F
95%, 91% ee
O
H
(only Z)
9
9
2%, 93% ee
Scheme 1. Enantioenriched gem-Difluoroallylboronates as Versatile Intermediates
t
Reagents and conditions: (a) 1a (0.20 mmol), 2a (0.40 mmol), NaO Bu (0.40 mmol), MeOH
ꢀ
(
(
(
0.40 mmol) in CH
3
CN (1.0 mL), 12 hr, 0 C to RT, under Ar; solvent was removed and CH
2
ICl
,4H
n
ꢀ
0.50 mmol) and BuLi (0.30 mmol) were added in THF (1.0 mL), 12 hr, 0 C; (b) then NaBO
3
2
O
2
0.40 mmol), THF/H O, 2 hr, RT, under Ar; (c) 4a (0.20 mmol), red Al (0.24 mmol), toluene, 12 hr,
ꢀ
t
8
0 C, under Ar; (d) 4a (0.20 mmol), CuTc (10 mol % mmol), Xantphos (10 mol % mmol), LiO Bu
ꢀ
(
(
(
0.60 mmol), B
0.20 mmol), Pd/C (10 mol % mmol), 1 atm H
2.0 mmol), MeOH/H O (20:1), 30 min, RT.
2
pin
2
(0.60 mmol), H
2
O (0.60 mmol), DMA (1.0 mL), 16 hr, 40 C, under Ar; (e) 4h
2
, THF (1.0 mL), 6 hr, RT; (f) 4m (0.20 mmol), NaOH
2
1
-(trifluoromethyl)alkenes with relatively simple molecules, we applied this strategy
to compounds derived from complex natural products. Substrate 1t, derived from
estrone, allowed the diastereoselective construction of product 4t (Figures S27
and S146–S148) in 62% yield with 86% diastereomeric excess. In addition, litho-
cholic acid derivative 1u (Figures S83–S85) was borylated with excellent diastereo-
selectivity. The reactivity was sensitive to substrate structure, and defluoroboryla-
tion of trifluoropropene substrate lv containing a secondary alkyl substituent only
afforded a mixture of diastereoisomers 4v (Figures S1 and S152–S154) in low con-
version. When b-(hetero)ary-containing 1-(trifluoromethyl)alkenes such as 1w and
1
x were subjected to the reaction, only a small amount of a-boronate addition prod-
ucts were generated at the current reaction conditions.
To showcase the practical utility of our copper-catalyzed asymmetric defluorobory-
lation process, we conducted a 2.0-mmol reaction and obtained gem-difluoroallyl-
boronate 3a (Figures S7 and S86–S88) in 55% yield and 92% ee following flash
column chromatography on silica gel (Scheme 1). As noted at the outset, enan-
tioenriched products bearing both boronate and gem-difluorovinyl groups are
extremely versatile intermediates in organic synthesis as they can be converted
to other important families of compounds with retention of the ee at the boron-
bound carbon. Several illustrative examples are provided. Boronate 5 (Figures
S155–S157), with an additional methylene unit, can be generated from substrate
6
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(
a, b)
CF3
10.0 mmol scale
1
1
1
2
1
7
.0 mmol scale
3%, 93% ee
(
c)
F
F
O
OH
Previous route
7 steps
NH2
COOH
Cbz
CF2
N
OEt
iPr
H
O
1
4
13
D-phenylalanine
Scheme 2. Application of Our Developed Method as a Key Step in the Synthesis of a
Ketodifluoromethylene Dipeptide Isostere
2 3 2 5 2
Reagents and conditions: (a) 11 (10.0 mmol), NaSO CF (30.0 mmol), I O (20.0 mmol), DCM/H O
ꢀ
(
4:1), 12 hr, 110 C; (B) DBU (20.0 mmol), DCM, 2 hr, RT; (C) 12 (1.0 mmol), CuI (10 mol %), L5 (11
t
ꢀ
mol %), NaO Bu (2.0 mmol), B
under Ar.
2 2 3
pin (2.0 mmol), MeOH (2.0 mmol), CH CN (10.0 mL), 12 hr, 0 C to RT,
1
a through a tandem homologation with the in situ-formed CH
2
ClLi reagent in 66%
5
0,51
yield and 90% ee.
This crude reaction mixture can be used to further generate
corresponding homoallylic gem-difluoroallyl alcohol 6 (Figures S29 and S158–S160)
in 63% yield and 90% ee. Reduction of 4a with red Al afforded E-fluoroalkene 7 (Fig-
ures S30 and S161–S163) in 89% yield and 87% ee (E/Z = 95:5). Alternatively, utiliz-
ing our recently developed method for copper-catalyzed hydrodefluorinations of
gem-difluoroalkenes with water could afford the Z-fluoroalkene 8 (Figures S31
4
7
and S164–S166) in 95% yield without loss of ee. The double bond in product
h could be hydrogenated to yield CF H-substituted alkane 9 (Figures S32
4
2
and S167–S169) in 92% yield and 92% ee. In addition, hydrolysis product 4m af-
forded access to diol 10 (Figures S33 and S170–S172) without erosion of the
enantiopurity.
The utility of our strategy can also be exemplified by its use in a key step in the asym-
metric synthesis of ketodifluoromethylene dipeptide isostere 14 (Scheme 2). Our
synthesis commenced with the preparation of 1-(trifluoromethyl)alkene 12 (Figures
S173–S175) from commercially available olefin 11. The reaction of 12 with B
2a) under the optimized conditions formed key intermediate 13 (Figures S34 and
S176–S178) in 73% yield and 94% ee, which was prepared from D-phenylalanine
2 2
pin
(
5
2
in seven steps in a previous route. We envisaged that this efficient method could
be used for the diversity-oriented synthesis of ketodifluoromethylene dipeptide iso-
steres for medicinal applications in the future.
How bidentate phosphine ligands induce high levels of enantioselectivity in the tran-
sition metal-catalyzed asymmetric reactions has been a topic of interest for some
time. Independent generation of the 1:1 CuI:L5 complex in CH
3
CN afforded a yellow
solid copper complex 15 (Figures S2–S4) confirmed by electrospray ionization mass
3
1
1
spectrometry and P- and H-nuclear magnetic resonance studies. However, cop-
per complex 15 did not prove to be a competent catalyst in the presence of 1-(tri-
2 2
fluoromethyl)alkene 1a and B pin (2a), identical to the CuI/L5 system in terms of
yield and enantioselectivity (Scheme 3A). This result indicates that complex 15 is
not a true catalyst for our reaction. To provide more insights into the mechanism
5
3
of the present catalytic system, we examined nonlinear effects (NLE) of the cop-
per-catalyzed asymmetric defluoroborylation of 1-(trifluoromethyl)alkenes using L5
with varying ee as the ligand under the optimized reaction conditions. A weak
Chem 4, 1–11, September 13, 2018
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A Investigation of a pregenerated copper complex 15
B Nonlinear relationship between enantiopurity of L5 and 4a
Me
I
t
P Bu2
F3C
Cu
t
P Bu2
rt, 2h, Ar
CH3CN
Fe
P
P
Fe
+
CuI
Me
CF3
F3C
mass = 782.1
calc. 782.1 (M-I)
yellow solid
CF3
+
L5
15
1
0 mol% 15
OH
t
NaBO3 4 H O
2
.0 equiv NaO Bu
2
BnO
CF2
BnO
CF3
2
.0 equiv MeOH
THF/H2O
1
a
o
4a
CH3CN, 0 C~rt, 12h
6
3%, 55% ee
B2pin2 (2a)
Scheme 3. Mechanistic Experiments
positive NLE was observed (Scheme 3B), indicating that the copper(I) species
involved in the catalysis should contain more than one bidentate phosphine ligand
5
4
within or at the periphery of the catalytic cycle.
From these experimental results and literature precedent, the proposed mechanism
of the Cu-catalyzed chiral gem-difluoroallylboronate formation is shown in Figure 3.
t
The reaction of the precatalyst (CuI), chiral ligand, and NaO Bu forms the catalyti-
cally active species (A). This complex can easily undergo transmetalation with the
5
5,56
anionic adduct of B
2
pin
2
(2a’)
to generate intermediate B. Reaction of 1-(trifluor-
omethyl)alkenes (1, R = alkyl), was found to afford only C-B bonds at the b position.
Such preferences were attributed to conjugate CF3 substituent (C). While using
1
-(trifluoromethyl)alkenes (1, R = (hetero)aryl) such as 1w-1x as substrates, C-Cu
bond formation may be electronically favored at the benzylic position stabilization
0
57–62
by the (hetero)aryl group (C ).
After further enantioselective formation of inter-
3
3–40,45–49
mediate D, cis b-F elimination
delivers the final product 3 and a CuF-like
t
species E, which can undergo anion exchange with NaO Bu to regenerate the cop-
per catalyst.
Conclusion
In summary, we have developed an efficient asymmetric copper-catalyzed system
that can activate the C-F bonds of 1-(trifluoromethyl)alkenes via a defluoroborylation
process to produce a diverse array of enantioenriched gem-difluoroallylboro-
6
3
nates. Given the ubiquity of the gem-difluorovinyl group and its precursors in
bioactive compounds, we anticipate that this strategy based on the diversity of bo-
ron chemistry will simplify the synthesis and structural elaboration of gem-difluoroal-
kene targets for research in chemistry, biology, and medicine.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND SOFTWARE AVAILABILITY
The crystallography data have been deposited at the Cambridge Crystallographic
Data Center (CCDC) under accession number CCDC: 1821460 (4e) and can be ob-
tained free of charge from www.ccdc.cam.ac.uk/getstructures.
8
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https://doi.org/10.1016/j.chempr.2018.07.003
CuI
L*
NaO Bu
Me
Me
t
O
O
MeO
Me
Me
Me
Me
O
MeOH
NaF
B2pin2
(2a)
B
B
t
tBuO CuLx*
Me
Me
NaO Bu
O
Na
t
A
NaO Bu
2a'
Bpin OMe
F
CuLx*
E
Bpin CuLx*
B
Bpin
CF2
R
3
CF3
R
Bpin
1
CuLx*
H
CF3
R
Me
Me Me
Me
Me
Me
H
Me
O
O
D
Me
B
CuLx*
CF3
VS
*LxCu
H
B
O
O
H
CF3
-
+
+
-
Alkyl
H
(hetero)Ar
H
R = Alkyl
R = (hetero)Aryl
C
C'
Figure 3. Proposed Catalytic Cycle
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 178
figures, 5 tables, and 1 data file and can be found with this article online at
https://doi.org/10.1016/j.chempr.2018.07.003.
ACKNOWLEDGMENTS
We thank the ‘‘1000-Youth Talents Plan’’ and the National Natural Science Founda-
tion of China (Grant 2167020084) for their financial support.
AUTHOR CONTRIBUTIONS
Z.S. conceived and designed the study and wrote the paper. P.G. and C.Y. per-
formed the experiments and mechanism study and analyzed the data. Y.Z. per-
formed the crystallographic studies.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: March 13, 2018
Revised: May 14, 2018
Accepted: July 6, 2018
Published: July 26, 2018
REFERENCES AND NOTES
1
. Uneyama, K. (2006). Hydrogen Bonding in
Organofluorine Compounds in Organofluorine
Chemistry (Blackwell Publishing), pp. 173–185.
3. Leriche, C., He, X., Chang, C.-W., and Liu,
H.-W. (2003). 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. 125, 6348–6349.
difluoro-substituted, conformationally rigid
vigabatrin analogue as a potent
g-aminobutyric acid aminotransferase
inhibitor. J. Med. Chem. 46, 5292–5293.
2
. Lim, M.H., Kim, H.O., Moon, H.R., Chun, M.W.,
and Jeong, L.S. (2002). Synthesis of novel D-2’-
5. 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., et al.
(2004). SSR182289A, a selective and potent
0
0
deoxy-2 -C-difluoromethylene-4 -thiocytidine
as a potential antitumor agent. Org. Lett. 4,
4. Pan, Y., Qiu, J., and Silverman, R.B. (2003).
Design, synthesis, and biological activity of a
529–531.
Chem 4, 1–11, September 13, 2018
9

Please cite this article in press as: Gao et al., Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes, Chem (2018),
https://doi.org/10.1016/j.chempr.2018.07.003
orally active thrombin inhibitor. Bioorg. Med.
Chem. 12, 1713–1730.
20. Collins, B.S.L., Wilson, C.M., Myers, E.L., and
Aggarwal, V.K. (2017). Asymmetric synthesis of
secondary and tertiary boronic esters. Angew.
Chem. Int. Ed. 56, 11700–11733.
34. Ahrens, T., Kohlmann, J., Ahrens, M., and
Braun, T. (2015). Functionalization of
fluorinated molecules by transition-metal-
mediated C-F bond activation to access
fluorinated building blocks. Chem. Rev. 115,
6
. Magueur, G., Crousse, B., Our e´ vitch, M.,
Bonnet-Delpon, D., and B e´ gu e´ , J.P. (2006).
Fluoro-artemisinins: when a gem-
difluoroethylene replaces a carbonyl group.
J. Fluor. Chem. 127, 637–642.
21. Neeve, E.C., Geier, S.J., Mkhalid, I.A.I.,
Westcott, S.A., and Marder, T.B. (2016).
Diboron(4) compounds: from structural
curiosity to synthetic workhorse. Chem. Rev.
931–972.
35. Fuchibe, K., Mayumi, Y., Zhao, N., Watanabe,
S., Yokota, M., and Ichikawa, J. (2013). Domino
synthesis of fluorine-substituted polycyclic
aromatic hydrocarbons: 1,1-difluoroallenes as
synthetic platforms. Angew. Chem. Int. Ed. 52,
7825–7828.
7
. Chelucci, G. (2012). Synthesis and metal-
catalyzed reactions of gem-dihalovinyl
systems. Chem. Rev. 112, 1344–1462.
116, 9091–9161.
2
2
2
2. Xu, L., Zhang, S., and Li, P. (2015). Boron-
selective reactions as powerful tools for
modular synthesis of diverse complex
molecules. Chem. Soc. Rev. 44, 8848–8858.
8
. Liu, Y., Deng, M., Zhang, Z., Ding, X., Dai, Z.,
and Guan, J. (2012). Progress in preparation of
b,b-difluorovinyl compounds. Youji Huaxue 32,
36. Gao, B., Zhao, Y., and Hu, J. (2015). AgF-
mediated fluorinative cross-coupling of two
olefins: facile access to a-CF3 alkenes and
661–666.
3. Mlynarski, S.N., Schuster, C.H., and Morken,
J.P. (2014). Asymmetric synthesis from terminal
alkenes by cascades of diboration and cross-
coupling. Nature 505, 386–390.
b-CF
3
ketones. Angew. Chem. Int. Ed. 54,
9
. Prakash, G.K.S., Hu, J., Wang, Y., and Olah,
G.A. (2004). Difluoromethyl phenyl sulfone, a
difluoromethylidene equivalent: use in the
synthesis of 1,1-difluoro-1-alkenes. Angew.
Chem. Int. Ed. 43, 5203–5206.
638–642.
37. Xie, J., Yu, J., Rudolph, M., Rominger, F., and
Hashmi, A.S.K. (2016). Monofluoroalkenylation
of dimethylamino compounds through radical-
radical cross-coupling. Angew. Chem. Int. Ed.
4. Zhang, L., Lovinger, G.J., Edelstein, E.K.,
Szymaniak, A.A., Chierchia, M.P., and Morken,
J.P. (2016). Catalytic conjunctive cross-coupling
enabled by metal-induced metallate
1
1
1
0. Miura, T., Ito, Y., and Murakami, M. (2008).
Synthesis of gem-difluoroalkenes via b-fluoride
elimination of organorhodium(I). Chem. Lett.
55, 9416–9421.
rearrangement. Science 351, 70–74.
38. Thornbury, R.T., and Toste, F.D. (2016).
Palladium-catalyzed defluorinative coupling of
37, 1006–1007.
2
5. Schmidt, J., Choi, J., Liu, A.T., Slusarczyk, M.,
and Fu, G.C. (2016). A general, modular
method for the catalytic asymmetric synthesis
of alkylboronate esters. Science 354, 1265–
1269.
1-aryl-2,2-difluoroalkenes and boronic acids:
1. Zhao, Y., Huang, W., Zhu, L., and Hu, J. (2010).
Difluoromethyl 2-pyridyl sulfone: a new gem-
difluoroolefination reagent for aldehydes and
ketones. Org. Lett. 12, 1444–1447.
stereoselective synthesis of
monofluorostilbenes. Angew. Chem. Int. Ed.
55, 11629–11632.
3
9. Wu, J.-Q., Zhang, S.-S., Gao, H., Qi, Z., Zhou,
C.-J., Ji, W.-W., Liu, Y., Chen, Y., Li, Q., Li, X.,
and Wang, H. (2017). Experimental and
theoretical studies on rhodium-catalyzed
coupling of benzamides with 2,2-difluorovinyl
tosylate: diverse synthesis of fluorinated
heterocycles. J. Am. Chem. Soc. 139, 3537–
2. Zheng, J., Cai, J., Lin, J.-H., Guo, Y., and Xiao,
J.-C. (2013). Synthesis and decarboxylative
wittig reaction of difluoromethylene
26. He, J., Shao, Q., Wu, Q., and Yu, J.-Q. (2017).
3
Pd(II)-catalyzed enantioselective C(sp )-H
borylation. J. Am. Chem. Soc. 139, 3344–3347.
phosphobetaine. Chem. Commun. 49, 7513–
7515.
27. Smith, J.R., Collins, B.S.L., Hesse, M.J.,
Graham, M.A., Myers, E.L., and Aggarwal, V.K.
(2017). Enantioselective rhodium(III)-catalyzed
markovnikov hydroboration of unactivated
terminal alkenes. J. Am. Chem. Soc. 139, 9148–
9151.
1
3. Hu, M., He, Z., Gao, B., Li, L., Ni, C., and Hu, J.
2013). Copper-catalyzed gem-
difluoroolefination of diazo compounds with
TMSCF via C-F bond cleavage. J. Am. Chem.
3545.
(
4
0. Sakaguchi, H., Ohashi, M., and Ogoshi, S.
3
(
2018). Fluorinated vinylsilanes from the
Soc. 135, 17302–17305.
copper-catalyzed defluorosilylation of
fluoroalkene feedstocks. Angew. Chem. Int.
Ed. 57, 328–332.
28. Lee, J., Torker, S., and Hoveyda, A.H. (2017).
1
4. Gao, B., Zhao, Y., Hu, M., Ni, C., and Hu, J.
Versatile homoallylic boronates by chemo-,
(2014). gem-Difluoroolefination of diaryl
0
S
N
2 -, diastereo- and enantioselective catalytic
ketones and enolizable aldehydes with
difluoromethyl 2-pyridyl sulfone: new insights
into the Julia-Kocienski reaction. Chem. Eur. J.
41. Liu, X.-W., Echavarren, J., Zarate, C., and
Martin, R. (2015). Ni-catalyzed borylation of aryl
fluorides via C-F cleavage. J. Am. Chem. Soc.
137, 12470–12473.
sequence of Cu-H addition to vinyl-B(pin)/
allylic substitution. Angew. Chem. Int. Ed. 56,
821–826.
20, 7803–7810.
2
9. Cai, Y., Yang, X.-T., Zhang, S.-Q., Li, F., Li, Y.-Q.,
Ruan, L.-X., Hong, X., and Shi, S.-L. (2018).
Copper-catalyzed enantioselective
markovnikov protoboration of a-olefins
enabled by a buttressed N-heterocyclic
carbene ligand. Angew. Chem. Int. Ed. 57,
1
5. Hu, M., Ni, C., Li, L., Han, Y., and Hu, J. (2015).
gem-Difluoroolefination of diazo compounds
with TMSCF or TMSCF Br: transition-metal-
3 2
free cross-coupling of two carbene precursors.
42. Niwa, T., Ochiai, H., Watanabe, Y., and Hosoya,
T. (2015). Ni/Cu-catalyzed defluoroborylation
of fluoroarenes for diverse C-F bond
functionalizations. J. Am. Chem. Soc. 137,
14313–14318.
J. Am. Chem. Soc. 137, 14496–14501.
1
376–1380.
1
1
6. Gao, B., Zhao, Y., Hu, J., and Hu, J. (2015).
Difluoromethyl 2-pyridyl sulfone: a versatile
carbonyl gem-difluoroolefination reagent.
Org. Chem. Front. 2, 163–168.
43. Zhou, J., Kuntze-Fechner, M.W., Bertermann,
R., Paul, U.S.D., Berthel, J.H.J., Friedrich, A.,
Du, Z., Marder, T.B., and Radius, U. (2016).
Preparing (multi)fluoroarenes as building
blocks for synthesis: nickel-catalyzed borylation
of polyfluoroarenes via C-F bond cleavage.
J. Am. Chem. Soc. 138, 5250–5253.
3
3
0. Bigler, R., and Aggarwal, V.K. (2018). ortho-
Directing chromium arene complexes as
efficient mediators for enantiospecific C(sp )-
C(sp ) cross-coupling reactions. Angew. Chem.
2
3
7. Zhang, Z., Yu, W., Wu, C., Wang, C., Zhang, Y.,
and Wang, J. (2017). Reaction of diazo
compounds with difluorocarbene: an efficient
approach towards 1,1-difluoroolefins. Angew.
Chem. Int. Ed. 55, 273–277.
Int. Ed. 57, 1082–1086.
1. Wilson, C.M., Ganesh, V., Noble, A., and2
Aggarwal, V.K. (2017). Enantiospecific sp -sp
coupling of ortho- and para-phenols with
secondary and tertiary boronic esters. Angew.
Chem. Int. Ed. 56, 16318–16322.
44. Niwa, T., Ochiai, H., and Hosoya, T. (2017).
Copper-catalyzed ipso-borylation of
3
fluoroarenes. ACS Catal. 7, 4535–4541.
1
8. Fuchibe, K., Hatta, H., Oh, K., Oki, R., and
Ichikawa, J. (2017). Lewis acid promoted single
45. Zhang, J., Dai, W., Liu, Q., and Cao, S. (2017).
Cu-catalyzed stereoselective borylation of
0
C-F bond activation of the CF
type 3,3-difluoroallylation of arenes with
-trifluoromethyl-1-alkenes. Angew. Chem. Int.
3
group: S
N
1 -
32. Sandford, C., and Aggarwal, V.K. (2017).
Stereospecific functionalizations and
transformations of secondary and tertiary
boronic esters. Chem. Commun. 53, 5481–
5494.
2 2
gem-difluoroalkenes with B pin . Org. Lett. 19,
3283–3286.
2
Ed. 56, 5890–5893.
46. Sakaguchi, H., Uetake, Y., Ohashi, M., Niwa, T.,
Ogoshi, S., and Hosoya, T. (2017). Copper-
catalyzed regioselective
1
9. Huang, Y., and Hayashi, T. (2016). Rhodium-
catalyzed asymmetric arylation/defluorination
of 1-(trifluoromethyl)alkenes forming
33. Amii, H., and Uneyama, K. (2009). C-F bond
activation in organic synthesis. Chem. Rev. 109,
2119–2183.
monodefluoroborylation of polyfluoroalkenes
en route to diverse fluoroalkenes. J. Am. Chem.
Soc. 139, 12855–12862.
enantioenriched 1,1-difluoroalkenes. J. Am.
Chem. Soc. 138, 12340–12343.
10
Chem 4, 1–11, September 13, 2018

Please cite this article in press as: Gao et al., Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes, Chem (2018),
https://doi.org/10.1016/j.chempr.2018.07.003
4
4
4
5
5
7. Hu, J., Han, X., Yuan, Y., and Shi, Z. (2017).
Stereoselective synthesis of Z fluoroalkenes
through copper-catalyzed hydrodefluorination
of gem-difluoroalkenes with water. Angew.
Chem. Int. Ed. 56, 13342–13346.
53. Girard, C., and Kagan, H.B. (1998). Nonlinear
effects in asymmetric synthesis and
stereoselective reactions: ten years of
investigation. Angew. Chem. Int. Ed. 37, 2922–
2959.
catalyzed substitution reactions. J. Am. Chem.
Soc. 132, 10634–10637.
59. Lee, J.C.H., McDonald, R., and Hall, D.G.
(2011). Enantioselective preparation and
chemoselective cross-coupling of 1,1-diboron
compounds. Nat. Chem. 3, 894–899.
8. Kojima, R., Kubota, K., and Ito, H. (2017).
Stereodivergent hydrodefluorination of gem-
difluoroalkenes: selective synthesis of (Z)- and
54. Dong, K., Wang, Z., and Ding, K. (2012). Rh(I)-
catalyzed enantioselective hydrogenation of
a-substituted ethenylphosphonic acids. J. Am.
Chem. Soc. 134, 12474–12477.
60. Kobayashi, S., Xu, P., Endo, T., Ueno, M., and
Kitanosono, T. (2012). Chiral copper(II)-
catalyzed enantioselective boron conjugate
additions to a,b-unsaturated carbonyl
compounds in water. Angew. Chem. Int. Ed. 51,
12763–12766.
(
1
E)-monofluoroalkenes. Chem. Commun. 53,
0688–10691.
5
5. Dewhurst, R.D., Neeve, E.C., Braunschweig,
2 3
9. Liu, Y., Zhou, Y., Zhao, Y., and Qu, J. (2017).
Synthesis of gem-difluoroallylboronates via
FeCl -catalyzed boration/b-fluorine
2
elimination of trifluoromethyl alkenes. Org.
H., and Marder, T.B. (2015). Sp -sp
diboranes: astounding structural variability
and mild sources of nucleophilic boron for
organic synthesis. Chem. Commun. 51, 9594–
61. Check, C.T., Jang, K.P., Schwamb, C.B., Wong,
A.S., Wang, M.H., and Scheidt, K.A. (2015).
Ferrocene-based planar chiral
Lett. 19, 946–949.
9607.
0. Sadhu, K.M., and Matteson, D.S. (1985).
imidazopyridinium salts for catalysis. Angew.
Chem. Int. Ed. 54, 4264–4268.
5
6. Pietsch, S., Neeve, E.C., Apperley, D.C.,
Bertermann, R., Mo, F., Qiu, D., Cheung, M.S.,
Dang, L., Wang, J., Radius, U., et al. (2015).
Synthesis, structure, and reactivity of anionic
(Chloromethyl)lithium: efficient generation and
capture by boronic esters and a simple
preparation of diisopropyl (chloromethyl)
boronate. Organometallics 4, 1687–1689.
62. Kubota, K., Osaki, S., Jin, M., and Ito, H. (2017).
Copper(I)-catalyzed enantioselective
nucleophilic borylation of aliphatic ketones:
synthesis of enantioenriched chiral tertiary
a-hydroxyboronates. Angew. Chem. Int. Ed.
56, 6646–6650.
2
3
sp -sp diboron compounds: readily accessible
boryl nucleophiles. Chem. Eur. J. 21, 7082–
1. Sonawane, R.P., Jheengut, V., Rabalakos, C.,
Larouche-Gauthier, R., Scott, H.K., and
Aggarwal, V.K. (2011). Enantioselective
construction of quaternary stereogenic centers
from tertiary boronic esters: methodology and
applications. Angew. Chem. Int. Ed. 50, 3760–
7098.
5
7. Lee, J.-E., and Yun, J. (2008). Catalytic
asymmetric boration of acyclic a,b-unsaturated
esters and nitriles. Angew. Chem. Int. Ed. 47,
63. During the revision process for this manuscript,
Ito et al. reported a related paper: Kojima, R.,
Akiyama, S., and Ito, H. (2018). A copper(I)-
catalyzed enantioselective g-boryl substitution
of trifluoromethyl-substituted alkenes:
synthesis of enantioenriched g,g-gem-
difluoroallylboronates Angew. Chem. Int. Ed.
57, 7196–7199.
145–147.
3763.
5
2. Damon, D.B., and Hoover, D.J. (1990).
Synthesis of the ketodifluoromethylene
dipeptide isostere. J. Am. Chem. Soc. 112,
58. Guzman-Martinez, A., and Hoveyda, A.H.
(2010). Enantioselective synthesis of
allylboronates bearing a tertiary or quaternary
B-substituted stereogenic carbon by NHC-Cu-
6439–6442.
Chem 4, 1–11, September 13, 2018
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