Consecutive cross-coupling reactions of 2,2-difluoro-1-iodoethenyl tosylate with boronic acids: Efficient synthesis of 1,1-diaryl-2,2-difluoroethenes

Article abstract of DOI:10.3762/bjoc.9.286

The cross-coupling reactions of 2,2-difluoro-1-iodoethenyl tosylate (2) with 2 equiv of boronic acids in the presence of catalytic amounts of Pd(OAc)2 and Na2CO3 afforded the mono-coupled products 3 and 5 in high yields. The use of 4 equiv of boronic acid

Full text of DOI:10.3762/bjoc.9.286

Consecutive cross-coupling reactions of 2,2-difluoro-
1-iodoethenyl tosylate with boronic acids: efficient
synthesis of 1,1-diaryl-2,2-difluoroethenes
Ju Hee Kim, Su Jeong Choi and In Howa Jeong*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2470–2475.
Department of Chemistry & Medical Chemistry, Yonsei University,
1 Yonseidae-gil, Wonju, Gangwondo 220-710, Republic of Korea
doi:10.3762/bjoc.9.286
Received: 27 August 2013
Accepted: 22 October 2013
Published: 14 November 2013
Email:
In Howa Jeong* - jeongih@yonsei.ac.kr
* Corresponding author
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Keywords:
boronic acids; cross-coupling reaction; 1,1-diaryl-2,2-difluoroethene;
1,1-difluoro-1,3-dienes; 2,2-difluoro-1-iodoethenyl tosylate;
organo-fluorine
© 2013 Kim et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The cross-coupling reactions of 2,2-difluoro-1-iodoethenyl tosylate (2) with 2 equiv of boronic acids in the presence of catalytic
amounts of Pd(OAc)2 and Na2CO3 afforded the mono-coupled products 3 and 5 in high yields. The use of 4 equiv of boronic acids
in the presence of catalytic amount of Pd(PPh3)2Cl2 and Na2CO3 in this reaction resulted in the formation of symmetrical
di-coupled products 4 in high yields. Unsymmetrical di-coupled products 4 were obtained in high yields from the reactions of 3
with 2 equiv of boronic acids in the presence of catalytic amounts of Pd(OAc)2 and Na2CO3.
Introduction
The synthesis of 2,2-disubstituted-1,1-difluoroethenes have metal functional group, a halogen substituent or a tosylate group
received much attention to synthetic organofluorine chemists in at the vinyl carbon will provide a concise and efficient method
recent years because of their unique chemical reactivities for the synthesis of 2,2-disubstituted-1,1-difluoroethenes.
toward nucleophiles to produce monofluorinated organic com- Burton et al. reported a straightforward method for the prepar-
pounds [1-4], and their biological activity, such as mechanism- ation of 1,1-diaryl-2,2-difluoroethenes from the consecutive
based enzyme inhibitors, in the area of medicinal chemistry cross-coupling reaction of the 2,2-difluoro-1-bromoethenylzinc
[5-8]. The 1,1-difluoroethenylidene functionality in these com- reagent with aryl iodides, followed by arylboronic acids [17].
pounds is also known to act as a bioisostere for the carbonyl Recently, we also prepared 2,2-difluoro-1-tributylstan-
group of many biologically active compounds [9-12]. Although nylethenyl tosylate and (2,2-difluoroethenyl-idene)bis(tributyl-
numerous methods for the preparation of 2,2-disubstituted-1,1- stannane) which were utilized in the palladium-catalyzed
difluoroethenes have been reported in the previous literature consecutive cross-coupling reactions with electrophilic aryl
[13-22], a consecutive cross-coupling reaction of a proper iodides or nucleophilic arylstannane reagents to afford the
precursor such as a 1,1-difluoroethenylidene species bearing a corresponding 1,1-diaryl-2,2-difluoroethenes [20,21]. However,
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Beilstein J. Org. Chem. 2013, 9, 2470–2475.
these previous reagents still have some drawbacks such as the
existence of the toxic tributylstannyl group, thermal instability
of ethenylzinc reagents and the use of at least one nucleophilic
reactive site for the coupling partner. In contrast to these
reagents, the 1,1-difluoroethenylidene species bearing both an
electrophilic halogen substituent and a tosylate group at the
vinyl carbon have not been studied in the cross-coupling reac-
tion with stable and less toxic nucleophilic metal reagents such
Scheme 1: Preparation of 2,2-difluoro-1-iodoethenyl tosylate (2).
as aryl- and alkenylboronic acids. Herein, we report a prepar- reacted with 1 equiv of phenylboronic acid in the presence of
ation of 2,2-difluoro-1-iodoethenyl tosylate and its cross- 5 mol % of Pd(OAc)2 and Cs2CO3 (2 equiv) in methanol at
coupling reactions with aryl- and alkenylboronic acids to give room temperature for 15 h, mono- and di-coupled products 3a
the corresponding 1,1-difluoroalkenes.
and 4a were obtained in 21% and 10% yields, respectively,
along with a small amount of the self-coupled product (less than
5%) and reduced product. The use of 2 equiv of phenylboronic
Results and Discussion
Although the chemistry of the 2,2-difluoroethenylidene species acid in the same reaction increased the yield of 3a (38%) and 4a
as a building block has been well established in recent years, (19%). However, the use of high molecular amounts of Pd cata-
2,2-difluoro-1-iodoethenyl tosylate (2) was not previously lyst did not improve the yield of 3. The same reaction was
prepared. However, we easily synthesized the starting material performed with K2CO3 instead of Cs2CO3 as a base to give 3a
2 from the reaction of 2,2,2-trifluoroethyl tosylate (1) with and 4a in 56% and 16% yields. The use of K3PO4 in this reac-
2 equiv of LDA in THF at −78 °C, followed by treatment with tion provided similar results. Finally, the optimized reaction
1 equiv of iodine (Scheme 1).
condition was achieved by using Na2CO3 as a base, in which
only mono-coupled product 3a was obtained in 92% yield along
First, we attempted the consecutive palladium-catalyzed cross- with the self-coupled product derived from the excess boronic
coupling reaction of 2 with different arylboronic acids to afford acid. When the reaction was performed in the presence of 5%
unsymmetrical 1,1-diaryl-2,2-difluoroethenes. Since the use of Pd(PPh3)2Cl2 or Pd(CH3CN)2Cl2 instead of Pd(OAc)2,
a proper base in the Suzuki–Miyaura reaction is an important di-coupled product 4a was always formed in 6–13% yield. Opti-
factor to increase the yield of coupled product, we screened mization of the cross-coupling reaction of 2 with phenyl-
bases to get the optimized reaction conditions. When 2 was boronic acid is summarized in Table 1.
Table 1: Optimization of the cross-coupling reaction of 2 with phenylboronic acid.
Entry
Pd catalyst
X (equiv)
Y (mol %)
Base
Yield (%)a
3a
4a
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
1
2
3
2
2
2
2
2
2
5
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
21
38
18
30
56
54
92
78
55
10
19
40
24
16
17
–b
6
Pd(OAc)2
5
Pd(OAc)2
10
5
Pd(OAc)2
Pd(OAc)2
5
K3PO4
Pd(OAc)2
5
Na2CO3
Na2CO3
Na2CO3
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
5
5
13
aIsolated yield. bA trace amount of 4a was obtained.
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Beilstein J. Org. Chem. 2013, 9, 2470–2475.
After the successful coupling reaction of 2 with phenylboronic performed with K2CO3 or K3PO4 as a base under the same
acid under the optimized reaction conditions, the same reaction reaction conditions, the desired product 4a was obtained in up
was performed with other arylboronic acids bearing a proton, to 49–52% yield. The use of more soluble Cs2CO3 resulted in
fluoro, chloro, methyl, methoxy and trifluoromethyl on the the formation of 4a in 61% yield. Increasing the reaction
ortho-, meta- or para-position of the benzene ring. Reactions temperature did not improve the of yield of 4a. We also exam-
were successful with both electron-donating and electron-with- ined the effect of the palladium catalyst in this reaction. There-
drawing arylboronic acids to produce the corresponding 2,2- fore, the same reaction was performed in the presence of
difluoro-1-arylethenyl tosylates 3 in excellent isolated yields. 5 mol % of Pd(PPh3)2Cl2 instead of Pd(OAc)2, in which 4a was
Especially, the coupling reactions with arylboronic acids having obtained in 75% yield. Other palladium catalysts such as
an electron-donating group at the ortho-position of the benzene Pd(CH3CN)2Cl2 did not cause to improve the yield of 4a. Opti-
ring also provided the corresponding coupled products 3l–n in mization of the di-coupling reaction of 2 with phenylboronic
good yields. The cross-coupling reactions of 2 with arylboronic acid is summarized in Table 3.
acids are summarized in Table 2.
Diarylation reactions of 2 with arylboronic acids substituted by
Direct diarylation reactions of 2 with arylboronic acids were fluoro, chloro, methyl, methoxy, nitro and trifluoromethyl
also performed because di-coupled product 4a was formed in a substituent at the meta- or para-position of the benzene ring
mono-arylation reaction (Table 1) and also a recent work proceeded well under the optimized reaction conditions to give
showed a successful cross-coupling reaction of nonfluorinated the corresponding symmetrical di-coupled products 4b–k in
enol tosylates with a variety of arylboronic acids [23]. We 51–86% yield. However, coupling reactions with arylboronic
attempted a direct diarylation reaction of 2 with phenylboronic acids having a substituent such as chloro, methyl or a methoxy
acid to establish the optimized reaction conditions. Initial reac- group at the ortho-position of the benzene ring to produce the
tion of 2 with 3 equiv of phenylboronic acid in the presence of di-coupled products 4l–n were unsuccessful. This result prob-
5 mol % of Pd(OAc)2 and 2 equiv of Na2CO3 in MeOH at room ably indicates that the coupling process could be affected by
temperature for 22 h afforded the di-coupled product 4a in 30% steric hindrance in the second coupling reaction step. The
yield. The yield of 4a was increased to 39% using 4 equiv of di-coupling reactions of 2 with arylboronic acids are summa-
phenylboronic acid in this reaction. When the reaction was rized in Table 4.
Table 2: Preparation of 2,2-difluoro-1-arylethenyl tosylate 3.
Compound
R
t (h)
Yield (%)a
3a
3b
3c
3d
3e
3f
H
15
15
14
14
14
15
16
16
16
18
18
18
18
18
92
81
84
79
65
85
72
76
82
74
80
65
61
68
p-F
p-Cl
p-CH3
p-OCH3
p-CF3
m-F
3g
3h
3i
m-Cl
m-CH3
m-OCH3
m-CF3
o-CH3
o-OCH3
o-Cl
3j
3k
3l
3m
3n
aIsolated yield.
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Beilstein J. Org. Chem. 2013, 9, 2470–2475.
Table 3: Optimization of the di-coupling reaction of 2 with phenylboronic acid.
Entry
Pd catalyst
X (equiv)
Base
T (°C)
Yield (%)a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
3
4
4
4
4
4
4
4
Na2CO3
Na2CO3
K2CO3
rt
rt
30
39
52
49
61
58
75
21
Pd(OAc)2
rt
Pd(OAc)2
K3PO4
rt
Pd(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
rt
Pd(OAc)2
50
rt
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
rt
aIsolated yield of 4a.
Table 4: Preparation of symmetrical 1,1-diaryl-2,2-difluoroethenes 4.
Compound No
R
Yield (%)a
4a
4b
4c
4d
4e
4f
H
75
83
86
74
60
73
58
51
56
53
60
–b
–b
–b
p-F
p-Cl
p-CH3
p-OCH3
p-NO2
m-F
4g
4h
4i
m-Cl
m-CH3
m-OCH3
m-CF3
o-CH3
o-OCH3
o-Cl
4j
4k
4l
4m
4n
aIsolated yield. bA trace amount of product was obtained.
Unsymmetrical 1,1-diaryl-2,2-difluoroethenes can be prepared phenylboronic acid in the presence of 5 mol % Pd(PPh3)2Cl2
from the coupling reaction of mono-coupled tosylates 3 with and 2 equiv of Cs2CO3 in MeOH at room temperature for 12 h
arylboronic acids under similar reaction conditions. Therefore, afforded 1,1-diaryl-2,2-difluoroethene 4o in 89% yield. The
the cross-coupling reaction of 3a with 2 equiv of p-chloro- similar reactions of 3a with arylboronic acids having a
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Beilstein J. Org. Chem. 2013, 9, 2470–2475.
substituent such as fluoro, methyl, methoxy, and trifluoro- alkenylboronic acids. The same reaction conditions of the
methyl at the meta- or para-position of the benzene ring also mono-coupling reaction of 2 with arylboronic acid was applied
provided the corresponding 1,1-diaryl-2,2-difluoroethenes 4p–v to the alkenylation of 2. Therefore, the cross-coupling reaction
in 75–90% yields. The coupling reaction between 3c and of 2 with trans-2-phenylethenylboronic acid in the presence of
m-methylphenylboronic acid also resulted in the formation of 5 mol % of Pd(OAc)2 and 2 equiv of Na2CO3 in MeOH at room
4w in 79% yield. Similarly, 3k having an electron-withdrawing temperature for 15 h provided the cross-coupled product 5a in
group on the benzene ring was also reacted with p-methyl- 85% yield. The similar reaction of 2 with trans-oct-1-enyl-
phenylboronic acid to yield 4x in 70% yield. Table 5 summa- boronic acid afforded the cross-coupled product 5b in 81%
rizes the results of the coupling reactions of 3 with several aryl- yield. The cross-coupling reactions of 2 with alkenylboronic
boronic acids to give unsymmetrical 1,1-diaryl-2,2-difluoro- acids are summarized in Table 6.
ethenes.
Conclusion
The successful cross-coupling reaction of 2 with arylboronic In summary, we have successfully developed the consecutive
acids prompted us to examine similar coupling reactions with cross-coupling reactions of 2,2-difluoro-1-iodoethenyl tosylate
Table 5: Preparation of unsymmetrical 1,1-diaryl-2,2-difluoroethenes 4.
Compound No
R
R’
T (h)
Yield (%)a
4o
4p
4q
4r
H
H
p-Cl
p-F
12
12
12
14
18
12
14
14
12
12
89
90
81
79
82
81
77
75
79
70
H
p-CH3
p-OCH3
p-CF3
m-Cl
H
4s
4t
H
H
4u
4v
4w
4x
H
m-CH3
m-CF3
m-CH3
p-CH3
H
p-Cl
m-CF3
aIsolated yield.
Table 6: The cross-coupling reactions of 2 with alkenylboronic acids.
Compound No.
R
Yield (%)a
5a
5b
Ph
85
81
CH3(CH2)5
aIsolated yield.
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Supporting Information File 1
Experimental details, full spectroscopic data and spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-286-S1.pdf]
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Acknowledgements
This work was supported by a Basic Research Grant (2012-
0008411) funded by the National Research Foundation of
Korea.
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