Aryl gem-Difluorovinyl Pinacolboronates: Synthesis and Utility for Suzuki-Miyaura Coupling Reaction

Article abstract of DOI:10.1246/CL.200621

The synthesis of unstable aryl difluorovinyl pinacolboronates was achieved by the dehydrofluorination of α-trifluoromethyl arylmethyl pinacolboronates with LDA. These aryl difluorovinyl pinacolboronates can be used for Suzuki-Miyaura coupling with various

Full text of DOI:10.1246/CL.200621

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Aryl gem-Difluorovinyl Pinacolboronates:
Synthesis and Utility for Suzuki-Miyaura Coupling Reaction
Jun Zhou, Bingyao Jiang, Ming Guo, Yuji Sumii, and Norio Shibata*
Advance Publication on the web September 11, 2020
doi:10.1246/cl.200621
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1
Aryl gem-Difluorovinyl Pinacolboronates:
Synthesis and Utility for Suzuki-Miyaura Coupling Reaction
Jun Zhou,1 Bingyao Jiang,1 Ming Guo,1 Yuji Sumii,1 and Norio Shibata*1,2
1 Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
2 Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China
*Correspondence: nozshiba@nitech.ac.jp
37 reaction,12 Julia-Kocienski cross-coupling,13 Horner-
38 Wadsworth-Emmons reactions,14 and others.15 Nowadays,
39 vast synthetic approaches for gem-difluorovinyl compounds
40 have emerged.16 Despite the tremendous methodologies for
41 synthesizing gem-difluorovinyl compounds,3,12-16 we noticed
42 that the Suzuki-Miyaura cross-coupling reaction of aryl gem-
43 difluorovinyl boronates (R2B(Ar)C=CF2) with aryl halides
44 has never appeared in the literature, except for Ichikawa's
45 seminal work in 1989.17 Ichikawa and co-workers reported
46 the synthesis of 2-alkyl-2-aryl-substituted gem-difluorovinyl
47 compounds by the coupling reaction of aryl bromides and
1
2
3
4
5
6
The synthesis of unstable aryl difluorovinyl pinacolboronates
was achieved by the dehydrofluorination of α-trifluoromethyl
arylmethyl pinacolboronates with LDA. These aryl
difluorovinyl pinacolboronates can be used for Suzuki-
Miyaura coupling with various aryl halides under Pd-
catalysis to furnish diaryl gem-difluorovinyl compounds.
7
8
Keywords: gem-difluorovinyl | pinacolboronates |
Suzuki-Miyaura coupling
9
In recent decades, organofluorine compounds have been
10 the subject of intense research activity because of their
11 pharmaceutical and agrochemical applications.1 The efficacy
12 of such molecules in these fields of study/research is
13 rigorously related to the remarkable physical and chemical
14 properties created by fluoro-functional groups such as
n
48 gem-difluorovinyl alkyl boranes (R2B(R)C=CF2, R = Bu,
49 sBu) generated in situ from 2,2,2-trifluoromethyl p-toluene
50 sulfonate with trialkyl boranes via a one-pot transformation
51 (Scheme 1a). Although this method is efficient, the gem-
52 difluorovinyl boranes are limited to alkyl-aryl-substituted
53 molecules (Ar(R)C=CF2). Thus, diaryl gem-difluorovinyl
54 molecules (Ar’(Ar)C=CF2) cannot be accessed.
15 trifluoromethyl
(CF3),
difluoromethyl
(CF2H),
16 trifluoromethylthio (SCF3), pentafluorosulfanyl (SF5) and
17 others in their structures.1,2 Among distinctly varying fluoro-
18 functional groups, the gem-difluorovinyl group (C=CF2) is
19 particularly attractive synthetically3-7 since the gem-
20 difluorovinyl moiety is exceptionally reactive towards
21 nucleophiles, allowing it to be efficiently transformed into
22 other fluorinated functional groups such as CF3,4 gem-
23 difluoromethylene (R-CF2R’),5 monofluoroalkene (C=CFR,
24 C=CFAr),6 and even non-fluorinated functional groups of
25 carboxylic acids and esters.7 The gem-difluorovinyl moiety is
26 also a known bioisostere for a carbonyl group.8 Moreover, the
27 high electrophilicity of the C=CF2 group is attractive for the
28 design of biologically active molecules, including enzyme
29 inhibitors,9 pesticides,10 and others11 (Figure 1).
Ichikawa
a)
(1989)
F
F
F
F
nBuLi
Ar-Br
CF3
equiv)
(2
TsO
cat.
cat., Pd
Cu
R
BR2
R
Ar
BR3
=
R
nBu, sBu
Hosoya
b) Ogoshi,
or
(2017)
equiv)
(Bpin)2 (1
F
F
F
F
tBu mol%)
(IPr)CuO
(5
examples
2
or
1,
F
2-Napth
2-Napth
21-50
1,
Bpin
THF, 100 °C, 20 h
%
Marder
c)
(2020)
F
F
pinB
Bpin
Bpin
Selectfluor
equiv)
(3
example
1
Bpin
30
p-MeOC6H4
p-MeOC6H4
O
NaHCO
3 (2.2 equiv)
CH3CN,
93%
F
F
F
Ph
O
rt, 6 h
HN
H
N
MeO
MeO
OH
F
work
N2
This
AcHN
S
N
d)
O
O
N
O
F
F
F
F
O
HO
F
Ar1
Ar2
CF3
LDA
-Br
-B(OH)2
OMe
F3C
F
Ar1
Ar1
Ar1
Ar2
OMe
Bpin
Bpin
pinacol
cat.
Pd
OH
·HCl
iso-combretastatin A-4
analogue
3
1
2
N
5-(2,2-difluorovinyl)-2'-
deoxyuridine
(antiviral
H2N
agent)
(anti-tubulin
unstable
unstable
SSR182289A
inhibitor)
examples
examples
10
5
F
agent)
(thrombin
55
56 Scheme 1. gem-Difluorovinyl boronates and their reaction. a)
57 Coupling reaction of alkyl gem-difluorovinyl boronates with aryl
58 bromides. b) First report of aryl gem-difluorovinyl boronates. c)
59 Second report of aryl gem-difluorovinyl boronates. d) The
60 preparation of aryl gem-difluorovinyl boronates and their
61 application for coupling reaction (this work).
F
F
F
F
F
N
Cl
S
F
S
NH2·HCl
O
O
HO
monoamine
fluensulfone
(pesticide)
oxidase inhibitor
monkey testicular
inhibitor
cymologous
C17(20) lyase
31
62
63
32 Figure 1. Examples of biologically active molecules with a gem-
33 difluorovinyl unit.
34
We envisaged that if the aryl gem-difluorovinyl boronates
64 (R2B(Ar)C=CF2) could be synthesized, then Ichikawa's
65 methodology would become a standard for the synthesis of
66 both alkyl-aryl and diaryl gem-difluorovinyl compounds by
35
The gem-difluorovinyl compounds have been traditionally
36 synthesized from carbonyl compounds by the Wittig

2
1
2
3
4
5
6
7
8
9
the Suzuki-Miyaura coupling reaction. When we started this
work in 2016,18 aryl gem-difluorovinyl boronates
(R2B(Ar)C=CF2) were completely unknown in the
SciFinder® database. In 2017, Ogoshi, Hosoya, and co-
workers reported the first preparation of gem-difluorovinyl
48 pinacolboronates
3
with
a
base should induce
49 dehydrofluorination triggered by negative hyperconjugation
50 of the CF3 group,22 resulting in the targeted aryl gem-
51 difluorovinyl pinacolboronates 1 (Table 1). Our study
52 commenced by optimizing the dehydrofluorination of α-
53 trifluoromethyl pinacolboronates 3. We selected α-
54 trifluoromethyl-p-methoxyphenylmethyl pinacolboronate 3a
55 as a model substrate. According to Molander's protocol, 3a
56 was prepared from CF3CH=N2 and p-MeOC6H4-B(OH)2.21
57 Using α-CF3-pinacolboronate 3a, we examined the base-
58 mediated dehydrofluorination of 3a to 1a. The results of a
59 brief screening of bases are summarized in Table 1. The use
pinacolboronates
having
a
naphthyl
group
(pinB(Napth)C=CF2)
by
regioselective
monodefluoroborylation of trifluoroalkenes under Cu-
catalysis, with 21-50% yield (two examples) (Scheme 1b).19
10 In 2020, Marder et al. disclosed a single example of the
11 synthesis of p-methoxyphenyl gem-difluorovinyl
12 pinacolboronate (pinB(p-MeOC6H4)C=CF2) by
n
13 difluorination of 1,1,2-triborylalkene by Selectfluor® with
14 93% yield (one example) (Scheme 1c).20 However, there is
15 no report of their use for any coupling reaction. Moreover,
16 their methods are limited (total 3 examples), and the
17 preparation of the corresponding starting materials requires
18 steps. Thus, the development of a novel synthetic method for
19 the aryl gem-difluorovinyl boronates remains a challenge.
20 Herein, we report the concise synthesis of aryl gem-
21 difluorovinyl pinacolboronates (pinB(Ar)C=CF2, 1) and their
22 application for the Suzuki-Miyaura cross-coupling reaction
23 to access the unsymmetrical diaryl gem-difluorovinyl
24 compounds (Ar’(Ar)C=CF2, 2). The key to preparing aryl
60 of BuLi at room temperature did not afford the desired
61 dehydrofluorination product 1a (entry 1). On the other hand,
62 LiHMDS or KHMDS gave the desired dehydrofluorinated
63 product 1a with low yield (entries 2 and 3). The use of LDA
64 at room temperature provided 1a in 30% yield (entry 4).
65 Yield improved to 62% when the reaction was performed at
66 −20 °C (entry 5). Starting material 3a is unstable, and a
67 couple of byproducts were observed in the reaction mixture,
68 but we could not identify them. While the dehydrofluorinated
69 product 1a could be isolated, 1a slowly decomposed during
70 the purification on silica-gel column chromatography.
71
Ar2
4
-Br
1) Ar1
(1
40 °C, 6 h
25 gem-difluorovinyl
pinacolboronates
1
is
the
B(OH)2
equiv)
LDA
equiv)
mol%)
DtBPF mol%)
Pd(OAc)2 (5
F
F
F
F
CF3
26 dehydrofluorination of unstable α-trifluoromethyl-α-
27 arylmethyl pinacolboronates 3 by treatment with LDA. While
28 the aryl gem-difluorovinyl pinacolboronates 1 were also
29 found to be unstable, the following Suzuki-Miyaura cross-
30 coupling reaction of 1 with aryl bromides 4 proceeded
31 smoothly to provide the desired diaryl-gem-difluorovinyl
32 compounds 2 in moderate overall yields. Our method for the
33 preparation of aryl gem-difluorovinyl pinacolboronates 1 is
34 very different form previous two approaches.19,20 Besides, in
35 our knowledge, this is the first example of Suzuki-Miyaura
36 cross-coupling reaction of aryl gem-difluorovinyl
37 pinacolboronates 1.
(1.1
(6
F3C
N2
−
Ar1
Ar1
4 (2
20
°C
2) pinacol
K3PO
Bpin
equiv)
Bpin
Ar1
Ar2
equiv)
(1
3a-f
THF, 2 h
2
H O
1a-f
equiv)
(7
2
unstable
unstable
examples
toluene, 60 °C, 12 h
examples
10
5
F
F
F
F
F
F
MeO
MeO
OMe MeO
NO2
MeO
CF3
2ab:
F
30%
2aa:
F
2ac:
39%
37%
F
F
F
F
Me
Me
MeO
CO2Me
MeO
2aeb
F
2af:
F
:
2ad:
F
23%
18%
36%
38
F
F
F
Cl
39 Table 1. Optimization of dehydrofluorination reaction
40 conditions of 3aa
PhO
OMe
OMe
Cl
OMe
2ba:
F
2ca:
2da:
33%
25%
34%
F
F
F
F
F
F
CF3
Bpin
Base
equiv)
(1.1
Bpin
Bpin
H
THF, Temp, 2 h
MeO
MeO
Ph
OMe
MeO
2ea: 21%
3a
1a
base
72
41
73 Scheme 2. Substrate scope of the Suzuki-Miyaura coupling
74 reaction of aryl gem-difluorovinyl pinacolboronates 1 with aryl
75 bromides 4a
Temp
Entry
Base
Yield (%)a
rt
rt
1
nBuLi
N.D.
7
2
LiHMDS
KHMDS
LDA
76 aIsolated yield was calculated according to aryl boronic acid (Ar1-
77 B(OH)2). See the details of experimental procedure for 2 in supporting
78 information (SI). bCommerical grade of 4-bromo-o-xylene (4e)
79 (contaminated with 3-bromo-o-xylene) was used.
80
rt
3
9
rt
4
30
62
−20 °C
5
LDA
42
43
44
a Isolated yield
81
With the desired 1a in hand, we examined the Suzuki-
82 Miyaura cross-coupling of 1a with aryl bromides. Since both
83 pinacolboronate 1a and precursor 3a are unstable, we decided
84 to examine the reaction from the start without purification in
85 each step (Scheme 2). After the initial screening of reaction
86 conditions focusing on the Suzuki-Miyaura coupling reaction,
Molander and co-workers reported the synthesis of α-
45 trifluoromethyl-α-arylmethyl pinacolboronates 3 from 2,2,2-
46 trifluorodiazoethane (CF3CH=N2) and aryl boronic acids
47 (Ar1-B(OH)2).21 We imagined that the treatment of

3
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
3
4
X. Zhang, S. Cao, Tetrahedron Lett. 2017, 58, 375.
1
2
3
4
5
6
7
8
9
we
found
that
Pd(OAc)2,
1,1'-bis(di-tert-
butylphosphino)ferrocene (DtBPF), K3PO4, and H2O in
toluene at 60 °C provided the desired coupling product 2aa
in 39% overall yield. With these optimized reaction
conditions, the substrate scope for aryl bromides 4 was
investigated. Taking into consideration the instability and
purification difficulty of pinacol boronates 1 and 3, a
stoichiometric amount of aryl boronic acid (Ar1-B(OH)2) was
used as starting material to proceed with the subsequent
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10 reactions to afford coupling products 2. When using 1a,
11 electron-donating and -withdrawing groups substituted aryl
12 bromides 4a-c were well-tolerated in the coupling reaction to
13 provide the corresponding diaryl gem-difluorovinyl products
14 2 in good yields (2aa–ac). Besides, 1-bromonaphthalene (4d)
15 with 1a also proceeded with the coupling reaction under
16 optimal reaction conditions to afford the corresponding
17 diaryl-gem-difluorovinyl-product (2ad: 23%). 4-Bromo-o-
18 xylene (4e) with 1a gave the desired product in lower yield
19 (2ae: 18%). The aryl bromide with a methyl ester moiety 4f
20 was also tolerated and accepted for the coupling reaction with
21 1a to furnish product 2af in 36% yield. We further examined
22 the substrate scope on gem-difluorovinyl boronates 1.
23 Electron-donating phenoxy-substituted gem-difluorovinyl
24 boronates 1b, electron-withdrawing chloro-substituted 1c, 1d,
25 and aryl-substituted 1e were transformed with p-
26 methoxyphenyl bromide (4a) into the corresponding
27 unsymmetrical diaryl gem-difluorovinyl compounds 2ba,
28 2ca, 2da and 2ea at an acceptable overall yield of 21-34%,
29 independent of the substitution of the Ar1 group of 2.
5
6
30
In summary, we report a feasible method for the
31 synthesis of aryl gem-difluorovinyl boronates 1, and
32 subsequent access to unsymmetrical diaryl gem-difluorovinyl
33 products 2 via the Pd-catalyzed Suzuki-Miyaura cross-
34 coupling reaction. While the aryl gem-difluorovinyl
35 pinacolboronates 1 were found to be unstable, they can be
36 straightforwardly synthesized from readily available 103
37 trifluorodiazoethane and aryl boronic acids followed by LDA
38 treatment. The wide synthetic application of aryl gem-
39 difluorovinyl boronates 1 for a variety of coupling reactions
40 is expected.
41
42 JSPS KAKENHI supported this work grants JP 18H02553
43 (KIBAN B).
44
45 Supporting
46 http://dx.doi.org/10.1246/cl.******.
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Information
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on
47 References and Notes
48
49
50
51
52
53
54
55
56
57
58
59
60
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4
1
2
8
9
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