Copper-Catalyzed Regioselective Monodefluoroborylation of Polyfluoroalkenes en Route to Diverse Fluoroalkenes

Article abstract of DOI:10.1021/jacs.7b08343

Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions via copper catalysis. The method has shown an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroethylene (TFE), (

Full text of DOI:10.1021/jacs.7b08343

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Article
Copper-Catalyzed Regioselective Monodefluoroborylation
of Polyfluoroalkenes En Route to Diverse Fluoroalkenes
Hironobu Sakaguchi, Yuta Uetake, Masato Ohashi, Takashi Niwa, Sensuke Ogoshi, and Takamitsu Hosoya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08343 • Publication Date (Web): 29 Aug 2017
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Copper-Catalyzed Regioselective Monodefluoroborylation of
Polyfluoroalkenes en Route to Diverse Fluoroalkenes
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Hironobu Sakaguchi,†,§ Yuta Uetake,‡,§ Masato Ohashi,† Takashi Niwa,*,‡ Sensuke Ogoshi,*,† and
Takamitsu Hosoya*,‡,¶
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, 2ꢀ1 Yamadaꢀoka, Suita, Osaka 565ꢀ0871,
Japan
‡Chemical Biology Team, Division of BioꢀFunction Dynamic Imaging, RIKEN Center for Life Science Technologies
(CLST), 6ꢀ7ꢀ3 Minatojimaꢀminamimachi, Chuoꢀku, Kobe 650ꢀ0047, Japan
¶Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
(TMDU), 2ꢀ3ꢀ10 KandaꢀSurugadai, Chiyodaꢀku, Tokyo 101ꢀ0062, Japan
ABSTRACT: Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions
via copper catalysis. The method has showed an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroꢀ
ethylene (TFE), (trifluorovinyl)arenes, and trifluoromethylated monofluoroalkenes. The choice of boron source was important for
the efficient transformation of (difluorovinyl)arenes; (Bpin)2 was suitable for substrates with an electronꢀdeficient aryl group and
(Bnep)2 for those with an electronꢀrich aryl group. Derivatization of the (fluoroalkenyl)boronic acid esters to the corresponding
potassium trifluoroborate salts has rendered the products easily isolable, which greatly improved the synthetic practicality of the
monodefluoroborylation reaction. Stoichiometric experiments indicate that the fate of the regioselectivity depends on the mode of
β
ꢀfluorine elimination, which depends on the substrate. Further transformation of the boryl group has allowed facile preparation of
fluoroalkene derivatives as exemplified by the synthesis of a fluoroalkene mimic of atorvastatin, which potently inhibited the enꢀ
zyme activity of HMGꢀCoA reductase.
■
INTRODUCTION
Scheme 1. Synthesis of Fluoroalkenes from Polyfluoroalꢀ
kenes
Organofluorine molecules have been widely applied in variꢀ
ous research fields because of the unique properties of fluorine
atoms.1 In particular, fluoroalkenes have attracted considerable
interest from medicinal chemists because fluoroalkene units
are structurally similar to amide bonds. Fluoroalkene mimics
of bioactive amides have been prepared to improve the pharꢀ
maceutical properties such as bioactivity, target specificity,
and metabolic stability of the bioactive amides.2 Highly fluoriꢀ
nated alkenes are also gaining much attention as promising
monomers for preparing fluorineꢀcontaining polymers.3 Nevꢀ
ertheless, only a limited range of fluoroalkenes can be preꢀ
pared by the conventional methods,4 and thus, a novel method
that allows for the synthesis of diverse fluoroalkene derivaꢀ
tives is eagerly anticipated.
A
Derivatization of polyfluoroalkenes via C–F bond cleavage
Alkyl
Ar
m
Fn
m–R
F
β
-fluorine
F
elimination
Fn
Fn
1,2-addition
R
easily
available
Fn
boron chemistry
[B]
B
This work
cat. Cu
(B(OR)2)2
R
F
F
Fn
Fn
Fn
Monodefluoro-
borylation
F
F
F
F
Ar
F
F
F
F
etc.
F3C
F
R
One of the most efficient approaches to fabricate fluoroalꢀ
kenes is functionalization of highly fluorinated alkenes via C–
F bond cleavage (Scheme 1A). This type of transformation has
been achieved via 1,2ꢀaddition of organometallic species folꢀ
lithium salt, enhances the βꢀfluorine elimination step, which
enables alkylative C–F bond cleavage of tetrafluoroethylene
(TFE) with relatively weak nucleophiles such as organozinc
reagents, expanding the scope of this approach.6 To achieve
global diversification from polyfluoroalkenes, we assumed
that transition metalꢀcatalyzed monodefluoroborylation would
suit our purpose;7,8 the resulting borylated fluoroalkenes9 were
lowed by βꢀfluorine elimination of the resulting fluoroethyl
metal intermediates. For this purpose, strong nucleophiles
such as organolithium or organomagnesium reagents have
been used, largely limiting the scope of the substrate.5 In this
context, we recently found that a hard Lewis acid, such as a
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expected to serve as useful synthetic intermediates that take
Table 1. Optimization of Ligand and Copper Sourcea
Page 2 of 10
1
2
3
4
5
6
7
8
advantage of reliable transformations based on versatile orꢀ
ganoboron chemistries (Scheme 1B). In this context, during
our investigation on the transformation using TFE,10 we found
that weak copper(I) nucleophiles, such as arylcopper(I) reaꢀ
gents, were available for 1,2ꢀaddition to TFE under mild conꢀ
ditions; subsequent treatment of the products of carbocupraꢀ
yield recovered
(%)b 1a (%)b
tion with a Lewis acid prompted the βꢀfluorine elimination to
entry [Cu] (x mol %)
ligand (y mol %)
afford the corresponding trifluoroalkene derivatives.11 Based
on these previous studies, we conceived the idea of using
borylcopper(I) to achieve borylative cleavage of polyfluoroalꢀ
kenes via an addition–elimination mechanism. During preparaꢀ
tion of this manuscript, Cao and coꢀworkers reported a similar
monodefluoroborylation reaction of gemꢀdifluoroalkenes cataꢀ
lyzed by a (xantphos)Cu(I) complex (xantphos: 4,5ꢀbis(diꢀ
1
2
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
(IPr)CuCl (5)
CuBr (5)
CuI (5)
PCy3 (10)
P(nꢀBu)3 (10)
PCy2Ph (10)
95
93
92
0
0
9
10
11
12
13
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3
8
4
CyJohnPhos (10) 65
28
68
10
9
5
PPh3 (10)
dcpm (5)
25
83
61
57
65
68
86
phenylphosphino)ꢀ9,9ꢀdimethylxanthene)
to
afford
boryl(fluoro)alkenes.12 Although they clearly demonstrated the
synthetic utility of boryl(fluoro)alkenes, yields for
monodefluoroborylation reactions were typically moderate and
the scope of substrate was limited to gemꢀdifluoroalkenes bearꢀ
ing a neutral or electronꢀrich aryl group. Herein, we describe a
6
7
dcpe (5)
8
dcpp (5)
25
29
32
0
9
dppf (5)
10
11
12
13
14
15
16
17
18
19
20
21
xantphos (5)
1,10ꢀphen (5)
practical synthetic method for
a
diverse range of
boryl(fluoro)alkenes, which has been achieved based on the
copperꢀcatalyzed regioselective borylative cleavage of C–F
bond of various (poly)fluoroalkenes.13
2,2'ꢀbipyridine (5) 22
67
54
0
–
40
92
66
94
75
96
4
PCy3 (10)
■
RESULTS AND DISCUSSIONS
PCy3 (10)
24
0
Optimization of the Reaction Conditions for
Monodefluoroborylation of 2ꢀ(2,2ꢀDifluorovinyl)arenes.
From an extensive screen of conditions using 2ꢀ(2,2ꢀ
difluorovinyl)naphthalene (1a) as a model substrate, we found
a copper catalyst that efficiently promoted transꢀselective
monodefluoroborylation under mild conditions to give
CuOAc (5)
CuCN (5)
CuCl2 (5)
CuCl (5)
–
PCy3 (10)
PCy3 (10)
19
0
PCy3 (10)
–
89
83
0
boryl(fluoro)alkene 3a; heating
a
mixture of 1a,
PCy3 (10)
3
bis(pinacolato)diboron (2a, (Bpin)2, 1.5 equiv), copper(I) chloꢀ
ride (CuCl, 5 mol %), tricyclohexylphosphine (PCy3, 10 mol
%), and cesium fluoride (CsF, 1.2 equiv) in tetrahydrofuran
(THF) at 40 °C for 24 h afforded borylated fluoroalkene 3a in
an excellent yield as a single stereoisomer (Table 1, entry 1).
Among examined ligands (entries 1–13), electronꢀdonating
trialkylphosphines such as PCy3 and tri(nꢀbutyl)phosphine (P(nꢀ
Bu)3) gave excellent results (entries 1 and 2). Several copper(I)
sources other than CuCl were applicable for this transforꢀ
mation (entries 14–18). Reactions without either of the copper
complex or ligand were totally impractical (entries 19 and 20).
Preꢀcoordinated copper complexes, such as (Cy3P)2CuCl and
[(Cy3P)CuCl]2, which are airꢀstable and storable without speꢀ
cial care, were available, thus enhancing the convenience of
the method (entries 21 and 22). Furthermore, the amount of
copper complex could be reduced to 1 mol % without a deꢀ
crease in the yield of 3a (entries 23–25).
(Cy3P)2CuCl (5)
–
–
–
–
–
96
99
98
97
93
22 [(Cy3P)CuCl]2 (2.5)
0
23
24
(Cy3P)2CuCl (2)
(Cy3P)2CuCl (1)
0
0
25 (Cy3P)2CuCl (0.5)
4
aCyJohnPhos = 2ꢀdicyclohexylphosphinobiphenyl; dcpm =
bis(dicyclohexylphosphino)methane; dcpe = 1,2ꢀ
bis(dicyclohexylphosphino)ethane; dcpp = 1,3ꢀ
bis(dicyclohexylphosphino)propane; dppf = 1,1'ꢀ
bis(diphenylphosphino)ferrocene; 1,10ꢀphen = 1,10ꢀ
phenanthroline; IPr = 1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazoleꢀ2ꢀ
ylidene. bYields were determined by 1H NMR analysis.
The amount of potassium acetate could be reduced to 0.2
equiv by performing the reaction at a higher temperature
(80 °C), whereas the reaction did not proceed without adding a
base (Table 3, entries 1–3). These results suggest that only a
catalytic amount of base is essential for this catalytic transꢀ
formation. Indeed, the reaction using 1 mol % of copper(I)
acetate with 2 mol % of PCy3 at 80 °C (entry 4) gave a compaꢀ
rable result to that using 1 mol % of (Cy3P)2CuCl with 0.2
equiv of potassium acetate (entry 2).
Further screening of a base using (Cy3P)2CuCl as the copper
source showed that other bases are also employable (Table 2).
In particular, an excellent result was obtained using potassium
acetate instead of CsF that rendered the reaction conditions
milder (entry 7). Lowering the reaction temperature to 30 °C
slightly slowed the rate of the reaction (entry 11). In contrast
to the Cao’s report,12 the use of a relatively strong base, such
as tertꢀbutoxide, was less efficient for our case (entries 5 and
8).
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Scheme 2. Monodefluoroborylation Using (Bnep)2 (2b)
Table 2. Optimization of Base
1
2
3
4
5
6
7
8
entry
1
base
CsF
yield (%)a
recovered 1a (%)a
97
58
95
24
57
16
96
75
10
2
0
0
Isolation of Boryl(fluoro)alkenes. Boronic pinacol ester 3a
was difficult to purify without loss by using typical chromatoꢀ
graphic techniques because of its high affinity to silicaꢀgel.
TLC analysis of 3b, which is a phenyl analogue of 3a, and
2
Cs2CO3
CsOAc
KF
9
3
0
10
11
12
13
14
15
16
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19
20
21
22
23
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25
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4
67
0
protodefluorinated analogue of 3b, transꢀβꢀstyrylboronic acid
5
KOtBu
K2CO3
KOAc
NaOtBu
Na2CO3
NaOAc
KOAc
pinacol ester (3bꢀdeF), indicated that the fluoro group was
responsible for this behavior (Figure S1). Thus, to improve the
synthetic practicality of the monodefluoroborylation reaction,
we looked for an easy method to treat the borylated product
before examining the scope of substrates. After extensive exꢀ
aminations, we found that sequential transformation of 3a to
the corresponding potassium trifluoroborate 4a suited our purꢀ
pose (Scheme 3); treatment of the crude reaction mixture conꢀ
taining 3a with aqueous KHF2 efficiently afforded 4a as an
airꢀstable solid even when the reaction was conducted using
1a in gramꢀscale.14 Subsequent defluorogenative hydrolysis of
4a with a small amount of silicaꢀgel gave the corresponding
boronic acid 5a. Using this scheme, borylated fluoroalkenes
4a and 5a were obtained in pure form using only a simple
filtering procedure.
6
9
7
0
8
0
9
79
91
24
10
11b
72
aYields were determined by 1H NMR analysis. bReaction was
performed at 30 °C.
Table 3. Reactions with Reduced Amount of KOAc
Scheme 3. Isolation of Borylated Fluoroalkenes
entry
[Cu] (mol %)
(Cy3P)2CuCl (1)
(Cy3P)2CuCl (1)
(Cy3P)2CuCl (1)
CuOAc (1) + PCy3 (2)
x (equiv) temp (°C) yield (%)a
1
2
3
4
0.2
0.2
0
40
80
80
80
29
77
0
0
62
aYields were determined by 1H NMR analysis.
A wide range of solvents were employable for this reaction.
In particular, ethereal solvents such as THF, 1,4ꢀdioxane, and
cyclopentyl methyl ether (CPME) gave efficient results (Table
S1). Although no reaction proceeded when tetrahydroxy diboꢀ
ron was used instead of (Bpin)2 (2a) probably because of poor
solubility in THF, the use of bis(neopentyl glycolato)diboron
(2b, (Bnep)2) gave a comparable result to 2a (Scheme 2). By
Substrate Scope for Monodefluoroborylation of 2ꢀ(2,2ꢀ
Difluorovinyl)arenes. The optimized conditions for
monodefluoroborylation (Table 2, entry 7) and the isolation
procedure (Scheme 3) were applicable to transformation of a
wide range of 2ꢀ(2,2ꢀdifluorovinyl)arenes 1 to the correspondꢀ
ing boryl(fluoro)alkenes
3
and
4
(Table 4).
β,βꢀ
Difluorostyrene (1b) and its derivatives with an electronꢀ
withdrawing group at paraꢀposition of the phenyl group, such
as 1c–j, were smoothly borylated to give the desired products
4b–j in good to excellent yields (Table 4A). Notably, our
method was applicable to the substrates with a strong electronꢀ
withdrawing group such as cyanoꢀsubstituted 1i, which was
reported unsuitable for the defluoroborylation under Cao’s
conditions.12 Transformations of several boronates bearing an
electronꢀwithdrawing group, such as 3f, 3h, and 3i, into the
corresponding trifluoroborates 4f, 4h, and 4i, respectively,
required gentle heating (50 °C), probably due to their slow
dissociation of pinacol from 3.
using
a
similar catalyst, we recently achieved the
defluoroborylation of fluoroarenes, wherein formation of a
small amount of defluoroprotonated product was detected
depending on the substrates.7e However, such protonation was
not observed through this study. Moreover, neither a cisꢀisomer
of boryl(fluoro)alkenes nor a diborylated byproduct via succesꢀ
sive cleavage of two C–F bonds was observed, demonstrating
that clean transformation proceeded under the optimized condiꢀ
tions.
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Table 4. transꢀSelective Monodefluoroborylation of Various (Difluorovinyl)arenes
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aThe reactions with aqueous KHF2 were performed at 50 °C. b2 equiv of 2a was used. cIsolated yields as boronic esters 3 or 3′ in parentheꢀ
ses. dTwo times the reagents were used. eThe reaction was performed for 48 h. f2.5 equiv of 2b was used.
A variety of substituents on the aromatic ring were toleratꢀ
ed; these include further transformable groups such as (pseuꢀ
do)halogeno (1d, 1e, and 1j), cyano (1i),15 and methylthio
(1y)16 groups. Notably, substrates having an unprotected pheꢀ
nolic hydroxy group, such as 1k, were also applicable to afꢀ
ford the desired products in high yields. In the case of 1k,
whereas an acceptable result was obtained from the reaction
conducted under the standard conditions (Table 5, entry 1),
using an increased amount of 2a (2.0 or 2.5 equiv) significantꢀ
ly improved the yield of 3k (entries 4 and 5). The reactions of
difluoroalkenes containing aromatic systems other than benꢀ
zene, such as naphthalene (1m), indole (1n), benzofuran (1o),
benzothiophene (1p), and quinoline (1q), as well as vinyloꢀ
gous gemꢀdifluoroꢀ1,3ꢀbutadienylbenzene (1r) proceeded uneꢀ
ventfully to afford the borylated products 4m–r in high yields.
Double defluoroborylation of 1,4ꢀbis(difluorovinyl)benzene
(1s) also efficiently took place using double the amounts of
reagents to afford bisborylated 3s, which was isolable as a
bisboronate form.
improvement was obtained by using (Bnep)2 (2b) instead of 2a
(entry 5). The same tendency was observed for paraꢀmethoxy
substituted substrate 1t (Table 7, entries 1 and 2). This finding
allowed for efficient monodefluoroborylation of a wide range
of other substrates bearing an electronꢀrich aryl group, such as
1t–ac, affording the corresponding borylated products 3' and 4
in high yields (Table 4B). Furthermore, fully substituted gemꢀ
difluoroalkene 1ad was also monoborylated using 2b to afford
trisubstituted vinylboronate 3ad', although extending the reacꢀ
tion time to 48 h was needed to obtain the desired product in
reasonable yield. In this case, the reaction also proceeded in a
regioselective manner, where the fluorine atom at transꢀ
position of the biaryl group was replaced with a boron atom
(see the Supporting Information for structure determination of
3ad'). Conversely, the use of (Bnep)2 (2b) was less effective
for the reaction of substrates bearing an electronꢀwithdrawing
group. For example, the borylation of paraꢀmethoxycarbonylꢀ
substituted 1f with 2b resulted in a lower conversion than that
with 2a (Table 7, entries 3 and 4). These results indicated that
there is a matched and mismatched combination between subꢀ
strates and diborons. While this method demonstrated a broad
scope for (difluorovinyl)arenes, the reactions of (difluoroviꢀ
nyl)alkane and (dichlorovinyl)arene resulted in no conversion
(Figure S3).
Substrates bearing an electronꢀdonating group resulted in
low conversion under the standard conditions using (Bpin)2
(2a) as the boron source. For example, paraꢀbenzyloxyꢀ
substituted substrate 1v was monodefluoroborylated with 2a to
afford 3v in a moderate yield (Table 6, entry 1). Whereas inꢀ
creasing the amount of reagents or prolongation of the reaction
time did not improve the yield of 3v (entries 2–4), significant
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Table 5. Monodefluoroborylation of 1k Bearing a Hydroxy
Group
nyl)arenes 1 did not provide the desired monoborylated prodꢀ
1
2
3
4
5
6
7
8
uct 7a (Table 8, entry 1), we rescreened the reaction condiꢀ
tions. Although simple elevation of the reaction temperature to
100 °C was not effective (entry 2), using CsF as a base affordꢀ
ed a small amount of 7a (entry 3). Further screening revealed
that the use of a copper(I) tertꢀbutoxide complex significantly
improved the yield (entry 4). Conclusively, the use of
(IPr)CuOtBu (10 mol %) gave the best result affording 7a
quantitatively (entry 5). Using the preꢀsynthesized complex
was important to achieve an efficient conversion; significant
decrease of the yield of 7a was observed when a mixture of
(IPr)CuCl and sodium tertꢀbutoxide was used (entries 6 and
7). The amount of the catalyst could be reduced to 5 mol %,
which still afforded 7a in an excellent yield (entry 8). Moreoꢀ
ver, the reaction could be conducted at lower temperatures by
extending the reaction time, which afforded 7a in acceptable
yields (entries 9–11).
entry
(B(OR)2)2 (x equiv) y (equiv) 3 or 3' yield (%)a
9
1
2
3
4
5
(Bpin)2 (2a, 1.5)
(Bnep)2 (2b, 1.5)
(Bpin)2 (2a, 1.5)
(Bpin)2 (2a, 2.0)
(Bpin)2 (2a, 2.5)
1.2
1.2
2.2
1.2
1.2
78
77
78
91
90
3k
3k'
3k
3k
3k
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aYields were determined by 1H NMR analysis.
Table 8. Screen of Conditions for Monodefluoroborylation
of TFE (6a)
Table 6. Monodefluoroborylation of ElectronꢀRich Subꢀ
strate 1v
temp
(°C)
entry [Cu] (x mol %)
base (y equiv)
yield (%)a
entry (B(OR)2)2 (x equiv) y (mol %) time (h) 3 or 3' yield (%)a
1
2
(Cy3P)2CuCl (10)
(Cy3P)2CuCl (10)
(Cy3P)2CuCl (10)
CuOtBu (10)b
KOAc (1.2)
40
0
0
1
2
3
4
5
(Bpin)2 (2a, 1.5)
(Bpin)2 (2a, 2.0)
(Bpin)2 (2a, 1.5)
(Bpin)2 (2a, 1.5)
(Bnep)2 (2b, 1.5)
1
1
5
1
1
24
24
24
48
24
42
45
50
65
91
3v
3v
3v
3v
3v'
KOAc (1.2)
100
100
100
100
100
100
100
80
3
CsF (1.2)
8
4
–
69
5
(IPr)CuOtBu (10)
–
>99
37
6
(IPr)CuCl (10)
NaOtBu (0.1)
NaOtBu (1)
aYields were determined by 1H NMR analysis.
7
(IPr)CuCl (10)
16
8
(IPr)CuOtBu (5)
(IPr)CuOtBu (5)
(IPr)CuOtBu (5)
(IPr)CuOtBu (5)
–
–
–
–
93
Table 7. Comparison of Monodefluoroborylation Using
Different Diboron Reagents
9
77 (90)c
59 (89)d
22 (69)d
10
11
60
40
aYields were determined by 19F NMR analysis. bThe reaction was
performed in the presence of xantphos (10 mol %). cYield of 7a
when the reaction was performed for 80 h in parentheses. dYields
of 7a when the reaction was performed for 240 h in parentheses.
3 or
3'
recovery
entry
R′
(B(OR)2)2
yield (%)a
of 1 (%)a
1
2
3
4
OMe (1t)
OMe (1t)
(Bpin)2 (2a)
(Bnep)2 (2b)
35
90
94
79b
48
2
3t
Substrate Scope for Monodefluoroborylation of
Polyfluoroalkenes.
The
optimized
conditions
for
3t'
3f
monodefluoroborylation of TFE (6a) (Table 8, entry 5) could
be applied to monodefluoroborylation of several polyfluoroalꢀ
kenes, including (trifluorovinyl)arenes and trifluoromethylated
monofluoroalkenes (Table 9). Due to water sensitivity of the
products, structure identification and determination of the
yields of products other than 7c were conducted by 19F NMR
analysis (see the Supporting Information for details). The reacꢀ
tions of 1ꢀ and 2ꢀ(trifluorovinyl)naphthalene (6b and 6c) proꢀ
ceeded selectively at the geminal position with respect to the
aryl group to give 7b and 7c (entries 1 and 2). The reaction
with heptafluoropropyl trifluorovinyl ether (6d) afforded only
a trace amount of the desired product 7d, and trifluorovinylꢀ
borane 7a was obtained in 7% yield (entry 3). This result indiꢀ
CO2Me (1f) (Bpin)2 (2a)
CO2Me (1f) (Bnep)2 (2b)
0
11
3f'
aYields were determined by 1H NMR analysis. bFormation of a
trace amount of (Z)ꢀmonofluoroalkene (<2% yield) in the reaction
mixture was observed by 1H NMR analysis (Figure S2).
Optimization of the Reaction Conditions for
Monodefluoroborylation of TFE. Next, we examined to
expand the method to monodefluoroborylation of polyfluoroꢀ
alkenes. Since the reaction of TFE (6a) under the conditions
similar to that for the monodefluoroborylation of (difluoroviꢀ
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using stoichiometric amounts of (Cy3P)2CuCl and KOAc at
cated that
with the desired
β
ꢀalkoxy elimination preferably occurred compared
ꢀfluorine elimination. In this case, the deꢀ
1
2
3
4
5
6
7
8
40 °C directly gave boryl(fluoro)alkene 3a in 75% yield withꢀ
out observation of the corresponding vinylcopper(I) complex
in the mixture (Scheme 4C).
β
sired 7d was obtained in moderate yield using xantphos as the
ligand. In addition to these polyfluoroalkenes, trifluoromethylꢀ
ated monofluoroalkenes 8a and 8b, which have fluorine atoms
at the vinyl and allyl positions, respectively, were
monodefluoroborylated selectively at the C(sp2)–F bond moieꢀ
ty to afford borylated products 9a and 9b in high yields (enꢀ
tries 4 and 5).
Scheme 4. Stoichiometric Reactions
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 9. Regioselective Monodefluoroborylation of Various
Triꢀ and Monofluoroalkenes
entry
1b
substrate
product
yield (%)a
21
6b
7b
2b
50 (42)c
6c
7c
1 (+ 7a 7%)
(37%)e
3d
6d
7d
4f
65
87
8a
8b
9a
9b
5e,f
aYields were determined by 19F NMR analysis. b1 equiv of 6b or
6c and 1.5 equiv of 2a were used. cIsolated yield in the parentheꢀ
ses. d1.5 equiv of 6d was used. eCuOtBu (5 mol %) and xantphos
(5 mol %) were used instead of (IPr)CuOtBu. fExcess amount of
8a or 8b were used. See the Supporting Information for details.
Figure 1. ORTEP drawing of 10 with thermal ellipsoids at the
30% probability level (H atoms have been omitted for clarity).
Selected bond lengths (Å) and angles (deg): C1–C2 1.276(9), Cu–
C2 1.902(6), Cu–C3 1.887(6), C2–Cu–C3 169.3(2), Cu–C2–C1
125.8(5), Cu–C2–F3 121.5(4), C1–C2–F3 111.9(5).
Stoichiometric Reactions. Several stoichiometric reactions
offered an insight into the reaction mechanism (Scheme 4).
The reaction of the structurally characterized borylcopper(I)
complex (IPr)CuBpin,17 which was prepared by mixing
(IPr)CuOtBu and diboron 2a in situ, with an excess amount of
TFE (6a) in THF at room temperature afforded a trifluoroviꢀ
nylcopper(I) complex 10 in 91% yield (Scheme 4A). The
structure of 10 was unambiguously determined by Xꢀray difꢀ
fraction analysis (Figure 1). In this reaction, generation of
fluoroboronate (FBpin) was also observed, indicating that 10
was formed via 1,2ꢀaddition of the borylcopper(I) complex to
TFE (6a) followed by elimination of FBpin, which was proꢀ
moted by the thermodynamically favored B–F bond formation.
The reaction of isolated 10 with diboron 2a in the presence of
8a, which was used as a borylcopper scavenger, proceeded at
100 °C to afford trifluorovinylboronate 7a in 60% yield
(Scheme 4B). In this reaction, formation of the borylated
product 9a was also observed, indicating that the borylcopper
species was regenerated during the reaction. Conversely, the
reaction of (difluorovinyl)arene 1a with one equivalent of 2a
Scheme 5. Effects of Additives
Effects of Additives. In our previous work on ipsoꢀ
borylation of fluoroarenes that was achieved by means of a
similar combination of (Cy3P)2CuCl and (Bpin)2 (2a), the adꢀ
dition of electronꢀdeficient arenes inhibited the reaction, which
indicated the involvement of single electronꢀtransfer (SET)
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process from an electronꢀrich borylcopper(I) species.7e To
afforded monofluorinated transꢀstilbene derivatives 11b and
11c, respectively, in excellent yields.
1
2
3
4
5
6
7
8
check whether SET process or a radical species is involved in
the monodefluoroborylation of 1a, we examined the reaction
in the presence of several additives, such as 1,4ꢀ
bis(trifluoromethyl)benzene or radical scavengers (Scheme 5).
In all cases, the reaction proceeded uneventfully to provide the
desired 3a in high yields, suggesting that the
monodefluoroborylation does involve neither a SET process
nor generation of free radical species as an intermediate.
Scheme 7. CrossꢀCoupling with Boryl(fluoro)alkenes
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Plausible Mechanism. On the basis of experimental results,
we currently consider that the monodefluoroborylation proꢀ
ceeds via additionꢀelimination pathway, and the regioselectiviꢀ
ty originates in the mode of the βꢀfluorine elimination step,
which depends on the substrates. In the case of TFE or triꢀ
fluoroalkenes 6, the reaction starts from 1,2ꢀaddition of the
borylcopper(I) complex to form the C–B bond at the more
electroꢀpositive olefinic carbon in 6, affording the alkylꢀ
copper(I) species I (Scheme 6A). Subsequent elimination of
FBpin affords vinylcopper(I) complex II, which then reacts
with 2a under heating conditions to afford 7 with regeneration
of the borylcopper(I) complex. Selective formation of 7b and
7c (R = 1ꢀ or 2ꢀnaphthyl) indicates faster elimination of FBpin
than that of copper(I) fluoride, which affords isomer 7' that
was not observed in this study. In contrast, the reaction of the
borylcopper(I) complex with gemꢀdifluoroalkene 1 gives an
alkylcopper(I) species III that has no fluorine atom at the viciꢀ
nal position with respect to the introduced boron atom
(Scheme 6B). Thus, in this case, elimination of copper(I) fluoꢀ
ride occurs to provide 3, which could be accelerated by
KOAc.11 This mechanism, wherein the borylation proceeds
without the formation of a vinylcopper(I) intermediate, is conꢀ
sistent with the fact that the reaction proceeded at a low temꢀ
perature (40 °C).
Finally, we demonstrated the utility of the method by the
synthesis of a fluoroalkene mimic of a widelyꢀused antihyperꢀ
lipidemic drug, atorvastatin (Figure 2).18 Suzuki–Miyaura
crossꢀcoupling of a boryl(fluoro)styrene unit 5b with broꢀ
mopyrrole 12 proceeded by using SPhosPdG3 as a precatalyst
to give 13 in high yield (Figure 2A). Subsequent deprotections
of isopropylidene acetal and tertꢀbutyl ester moieties under
standard acidic and basic conditions, respectively, afforded the
desired fluoroalkene mimic 14. Evaluation of the HMGꢀCoA
reductase inhibitory effect of the mimic 14 using a commercial
assay kit demonstrated that the replacement of amide moiety
of atorvastatin to fluoroethylene structure did not significantly
affect the activity the original compound; the mimic 14
showed a similar level of inhibition activity to that of atorvasꢀ
tatin (Figure 2B). This result indicates that replacing the amide
moiety of the drug candidates would provide another promisꢀ
ing candidate with favorable characters such as increased hyꢀ
drophobicity and improved metabolic stability.19
Scheme 6. Plausible Mechanisms Depending on the Subꢀ
strates
■
CONCLUSION
We have developed a practical synthetic method for borylated
fluoroalkenes via copperꢀcatalyzed monodefluoroborylation of
polyfluoroalkenes. The method has been successfully applied to
a broad range of substrates, including (difluorovinyl)arenes,
tetrafluoroethylene (TFE), (trifluorovinyl)arenes, and trifluoroꢀ
Synthetic Application of Monodefluoroborylated Comꢀ
pounds. The borylated products served as useful synthetic
units for introduction of fluoroalkene moieties (Scheme 7 and
Figure 2). For example, copperꢀmediated crossꢀcoupling reacꢀ
tion of trifluorovinylborane 7a with 4ꢀiodobenzotrifluoride
proceeded smoothly to give a trifluorostyrene derivative 11a
(Scheme 7A). The crossꢀcoupling reaction of borylated monoꢀ
fluoroalkenes also took place efficiently (Scheme 7B); Suzuꢀ
ki–Miyaura coupling of boronic acid 5a with aryl halides such
as (4ꢀethoxycarbonyl)phenyl bromide and 4ꢀbromoanisole
methylated monofluoroalkenes. The mode of the βꢀelimination
step, which occurs after the addition of borylcopper(I) species to
the polyfluoroalkene, influences the fate of the regioselectivity
depending on the substrates. Various fluoroalkenyl molecules,
including a bioactive fluoroalkene mimic of an amide groupꢀ
containing commercial drug, have become easily available by
this method, which would facilitate the development of useful
functional molecules in a broad fields, including drug discovery
and materials science.
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Page 8 of 10
B(OH)2
A
B
F
F
1
F
2
3
4
5
5b (2.5 equiv)
O
O
O
O
SPhosPdG3 (5 mol %)
CsF (3 equiv)
CO2t-Bu
CO2t-Bu
N
N
Br
DMF, H2O
80 °C, 12 h
12
13 95%
F
6
7
F
F
8
9
0.1 M aq
NaOH
2 M aq HCl
OH OH
OH OH
CO2Na
CO2H
H
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
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34
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49
50
51
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53
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55
56
57
58
59
60
THF, rt, 16 h
THF, rt, 5 h
N
14 88%
(atorvastatin mimic)
atorvastatin
F
O
Figure 2. (A) Synthesis of a fluoroalkene mimic of atorvastatin 14 and evaluation of its HMGꢀCoA reductase inhibitory effect. (B) Doseꢀ
response curves with Hill slopes (252 sec after treatment of HMGꢀCoA reductase), showing that atorvastatin and 14 inhibited HMGꢀCoA
reductase activity with IC50 values of 162 nM and 655 nM, respectively. See the Supporting Information for details.
317, 1881–1886. (c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelꢀ
ly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315–8359, and
■
ASSOCIATED CONTENT
references cited therein.
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omol. Chem. 2007, 5, 1151–1157. (b) Taguchi, T.; Yanai, H. In Fluo-
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cotteꢀSavard, M.ꢀO.; Paquin, J.ꢀF. Chem. Soc. Rev. 2011, 40, 2867–
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(c) Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58, 375–392.
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1487.
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J. Org. Chem. 2008, 73, 522–528. (b) Ohashi, M.; Kamura, R.; Doi,
R.; Ogoshi, S. Chem. Lett. 2013, 42, 933–935.
(7) For ipsoꢀborylation via aromatic C–F bond cleavage, see: (a)
Liu, X.ꢀW.; Echavarren, J.; Zarate, C.; Martin, R. J. Am. Chem. Soc.
2015, 137, 12470−12473. (b) Niwa, T.; Ochiai, H.; Watanabe, Y.;
Hosoya, T. J. Am. Chem. Soc. 2015, 137, 14313–14318. (c) Mfuh, A.
M.; Doyle, J. D.; Chhetri, B.; Arman, H. D.; Larionov, O. V. J. Am.
Chem. Soc. 2016, 138, 2985–2988. (d) Zhou, J.; KuntzeꢀFechner, M.
W.; Bertermann, R.; Paul, U. S. D.; Berthel, J. H. J.; Friedrich, A.; Du,
Z.; Marder, T. B.; Radius, U. J. Am. Chem. Soc. 2016, 138, 5250−
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4541.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization for new compounds,
including copies of NMR spectra.
■
AUTHOR INFORMATION
Corresponding Authors
*takashi.niwa@riken.jp
*ogoshi@chem.eng.osakaꢀu.ac.jp
*takamitsu.hosoya@riken.jp
Author Contribution
§H.S. and Y.U. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors thank Dr. Isao Kii, Ms. Rie Sonamoto, and Ms.
Harumi Ito at RIKEN CLST for their kind support on the
HMGꢀCoA reductase inhibition assay. This research was supꢀ
ported by the Platform Project for Supporting Drug Discovery
and Life Science Research funded by Japan Agency for Mediꢀ
cal Research and Development (AMED) (T.H. and T.N.);
JSPS KAKENHI Grant Numbers 17H03057 and 16KT0057
(M.O.), 15H03118 (T.H. and T.N), 16H01133 (Middle Molecꢀ
ular Strategy; T.H.), 15K05509 (T.N.), 16H02276 (S.O.); the
Cooperative Research Project of Research Center for Biomedꢀ
ical Engineering (T.H.); the Sasakawa Scientific Research
Grant from The Japan Science Society (Y.U.). H.S. is grateful
for support as a JSPS Research Fellow.
(8) For metalative C(sp2)–F bond cleavage, see: (a) Braun, T.;
Noveski, D.; Neumann, B.; Stammler, H.ꢀG. Angew. Chem., Int. Ed.
2002, 41, 2745–2748. (b) Yamada, S.; Takahashi, T. Konno T.; Ishiꢀ
hara, T. Chem. Commun. 2007, 3679–3681. (c) Brisdon, A. K.;
Pritchard, R. G.; Thomas, A. Organometallics 2012, 31, 1341–1348.
(d) Ohashi, M.; Shibata, M.; Saijo, H.; Kambara, T.; Ogoshi, S. Or-
ganometallics 2013, 32, 3631–3639. (e) Ohashi, M.; Saijo, H.; Shibata,
M.; Ogoshi, S. Eur. J. Org. Chem. 2013, 443–447.
(9) For synthesis of metalated fluoroalkenes, see ref 8 and: (a)
McCarthy, J. R.; Huber, E. W.; Le, T.ꢀB.; Laskovics, F. M.; Matꢀ
thews, D. P. Tetrahedron 1996, 52, 45–58. (b) Wnuk, S. F.; Garcia, P.
I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047–2049. (c) Wang, Z.; Gonzaꢀ
lez, A.; Wnuk, S. F. Tetrahedron Lett. 2005, 46, 5313–5316.
(10) For recent reviews, see: (a) Ohashi, M.; Ogoshi, S. Top. Or-
ganomet. Chem. 2015, 52, 197–215. (b) Ohashi, M.; Ogoshi, S. J.
Synth. Org. Chem. Jpn. 2016, 74, 1047–1057.
■
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8
(13) This work was presented at the 97th CSJ Annual Meeting,
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and coꢀworkers described copperꢀcatalyzed transformations that inꢀ
volved related defluoroborylation reactions of gemꢀdifluoroalkenes.
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reported as the major pathway for metabolic excretion of atorvastatin.
See, Black, A. E.; Hayes, R. N.; Roth, B. D.; Woo, P.; Woolf, T. F.
Drug Metab. Dispos. 1999, 27, 916–923.
9
10
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Table of Contents (TOC) graphic
1
2
3
4
cat. Cu
(B(OR)2)2
F
B(OR)2
R
Fn
Fn
Fn
5
6
7
8
9
F
F
B
Monodefluoroborylation
via addition–elimination
Ar
B
B
F
F
etc.
F
F
Ar
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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