Preparation of 2,2-difluoro-1-trialkylsilylethenylstannanes and their cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.12.071

Reaction of 2 with bis(tributyltin) in the presence of 3 mol % Pd ₂(dba)₃, 6 mol % XPhos, and 30 equiv of LiBr in wet and air bubbled THF at reflux for 8 h afforded the desired products 3 in 73-74% yields. The cross-coupling reaction

Full text of DOI:10.1016/j.tetlet.2013.12.071

Tetrahedron Letters 55 (2014) 1292–1295
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of 2,2-difluoro-1-trialkylsilylethenylstannanes and their
cross-coupling reactions
⇑
Jong Hee Jeon, Ju Hee Kim, Yeo Jin Jeong, In Howa Jeong
Department of Chemistry & Medical Chemistry, Yonsei University, Wonju, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 2 with bis(tributyltin) in the presence of 3 mol % Pd2(dba)3, 6 mol % XPhos, and 30 equiv of
LiBr in wet and air bubbled THF at reflux for 8 h afforded the desired products 3 in 73–74% yields. The
cross-coupling reaction of 3a with aryl iodides in the presence of 10 mol % Pd(PPh3)4 and 10 mol % CuI
afforded the coupled products 4a–p in 47–90% yields. The coupling reaction of 3b with various alkynyl
bromides having aryl-, alkyl, or trialkylsilyl group also afforded the corresponding 1,3-enynes 5a–g in
61–77% yields.
Received 22 August 2013
Revised 28 November 2013
Accepted 18 December 2013
Available online 25 December 2013
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
2,2-Difluoro-1-trialkylsilylethenylstannane
Cross-coupling reaction
1,1-Difluoro-2-trialkylsilyl-1,3-enynes
1,1-Difluoroalkenes are valuable fluoroorganic compounds
which exhibit chemical reactivities toward nucleophiles and thus
can be utilized as useful synthetic intermediates for the prepara-
tion of monofluorinated organic molecules.1–4 They are also poten-
tial mechanism-based inhibitors5,6 and have been known to
behave as a bioisostere for the carbonyl group.7 Therefore, the syn-
thesis of 1,1-difluoroalkenes is an important aspect of organofluo-
rine chemistry and thus numerous methods for the preparation of
1,1-difluoroalkenes have been reported in the previous litera-
tures.8–10 2,2-Difluoroethenylstannanes could be remarkable pre-
cursors of 1,1-difluoroalkenes because they can undergo the
Stille type of cross-coupling reaction with aryl, akenyl, and alkynyl
halides. Although several methods for the preparation of 2,2-diflu-
oroethenylstannane reagents having proton, bromine, alkoxy, and
phenyl groups at 1-position and their cross-coupling reactions
have been developed in last one decade,11–18 these types of re-
agents were utilized to introduce only one substituent at tributyl-
stannyl site via cross-coupling reaction. Recently, we developed
the method for the preparation of 2,2-difluoro-1-tributylstannyl-
ethenyl p-toluenesulfonate and (2,2-difluoroethenylidene)bis(trib-
utylstannane) which have two coupling partners such as the
nucleophilic tributylstannyl or electrophilic tosylate group at the
same carbon and underwent the cross-coupling reactions to give
1,1-difluoroalkenes.19,20 However, these two reagents still have
some drawbacks such as low reactivity of the tosylate group as a
coupling partner and low selectivity for the unsymmetrical cou-
pling reaction of bis(tributylstannane). In the course of our studies
on the preparation of new type of 2,2-difluoroethenylstannane to
overcome these drawbacks, we are interested in the preparation
of 2,2-difluoro-1-trialkylsilylethenylstannanes because the tribu-
tylstannyl group can be utilized for the cross-coupling reaction to
give 1-substituted 2,2-difluoroethenylsilanes which were known
to be valuable synthetic intermediates to give monofluoroalkenes
in recent years.21–25 Resultant 1-substituted 2,2-difluoroethenylsil-
anes will be also potential synthetic intermediates to provide the
variety of 1,1-difluoroalkenes via transformation of the trialkylsilyl
group. Herein, we report an efficient method for 2,2-difluoro-1-tri-
alkylsilylethenylstannanes and their cross-coupling reactions.
First of all, we synthesized 2,2-difluoro-1-trimethylsilylethenyl
p-toluenesulfonate (2a) in 95% yield from the reaction of 2,2,2-tri-
fluoroethyl p-toluenesulfonate (1) with LDA (2 equiv) in THF at
À78 °C, followed by treatment with trimethylsilyl chloride
(1 equiv). Similarly, 2,2-difluoro-1-triethylsilylethenyl p-toluene-
sulfonate (2b) was also prepared in 96% yield from the treatment
with triethylsilyl chloride.
1. LDA (2 equiv)/THF, -78 oC
F
F
OTs
SiR3
CF3CH2OTs
2. R3SiCl, THF, -78 o
C
rt
1
2a, R = Me (95%)
2b, R = Et (96%)
Although the direct cross-coupling reaction of 2a with phenylstann-
ane or phenylboronic acid was carried out in the catalytic condition,
the coupled product 3a was not obtained. Therefore, we attempted
the stannylation reaction of 2 with bis(tributyltin) in the presence
of Pd catalyst, ligand, and lithium salt to introduce a stannanyl
group at the tosylate site. When 2a was reacted with bis(tributyltin)
⇑
Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763 4323.
E-mail address: jeongih@yonsei.ac.kr (I.H. Jeong).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.071

J. H. Jeon et al. / Tetrahedron Letters 55 (2014) 1292–1295
1293
in the presence of 10 mol % Pd(PPh3)4 and 30 equiv of LiBr in dry
THF at reflux for 8 h, a trace amount of the desired product 3a
was observed in GC–MS spectrum. However, the use of wet and
air bubbled THF in the same reaction resulted in the formation of
3a in 24% yield (entry 2). The longer reaction time and the use of
low equiv of LiBr caused to decrease the yield of 3a (entries 3 and
4). The same reaction was performed in the presence of 10 mol %
Pd(PPh3)2Cl2 and 6 mol % XPhos26 as a ligand to give 3a in 35% yield
(entry 5). The use of Pd(CH3CN)2Cl2 instead of Pd(PPh3)2Cl2 in this
reaction caused to increase the yield of 3a up to 48% yield. When
this reaction was carried out in the presence of 10 mol % Pd2(dba)3
and 6 mol % XPhos under the same reaction condition, 3a was
obtained in 60% yield. After monitoring the reaction by changing
the mol % of Pd2(dba)3 and XPhos, we found that the use of
3 mol % Pd2(dba)3 and 6 mol % X-Phos in this reaction provided
the highest yield (73%) of 3a. Optimized reaction condition for the
stannylation of 2a is summarized in Table 1. Similarly, the
stannylation reaction of 2b with bis(tributyltin) in the presence of
3 mol % Pd2(dba)3, 6 mol % XPhos, and 30 equiv of LiBr in wet and
air bubbled THF at reflux for 8 h afforded the desired product 3b
in 74% yield.
We attempted the palladium-catalyzed cross-coupling reaction
of 3a with a variety of aryl iodides to introduce an aromatic group
at the stannane site. Initially, the coupling reaction between 3a
(1.0 equiv) and 4-iodobiphenyl (1.0 equiv) in the presence of
10 mol % Pd(PPh3)4 and 10 mol % CuI in DMF at 80 °C for 10 h
provided the coupled product 4a in 90% yield. When this reaction
was carried at room temperature, very slow reaction was occurred
and thus the reaction was not completed even after stirring for
24 h and gave the low yield (43%) of 4a based on the conversion
of starting material. The coupling reaction between 3a and iodobi-
phenyl did not occur without 10 mol % CuI under the same reaction
condition. The use of other solvents such as THF, ether, benzene,
and toluene in this coupling reaction did not provide the satisfied
result. The use of bromobiphenyl instead of iodobiphenyl as a
coupling partner under the same reaction condition did not
provide the desired product 4a at all. The coupling reactions of
3a with various aryl iodides having proton, fluoro, chloro, bromo,
methyl, methoxy, trifluoromethyl, and nitro on the meta or para-
position of the benzene ring afforded the coupled products 4b–p
in 47–90% yields which are summarized in Table 2. Aryl iodides
with electron-releasing and electron-withdrawing groups in the
para-position of the aromatic ring were coupled well under the
optimized reaction condition, whereas aryl iodides with electron-
releasing and electron-withdrawing groups in the meta-position
of the aromatic ring underwent the coupling reaction to produce
the corresponding cross-coupled product in relatively low yields.
The coupling reaction with aryl iodides having a substituent such
as methoxy or chloro group in the ortho-position of the benzene
ring resulted in a complex reaction mixture and failed to produce
the desired product. Similarly, the cross-coupling reaction of 3b
with iodobiphenyl as a standard coupling partner under the
optimized reaction condition also afforded the corresponding
cross-coupled product 4s in 88% yield. In spite of synthetically
useful compound in recent years,22–24 synthesis of the coupled
products 4 has been quite limited in the previous literature27,28
except for a recent report, in which 4 were prepared from the
Suzuki–Miyaura reactions of 2,2-difluoro-1-iodoethenyltrialkylsi-
lane, synthesized from 2,2,2-trifluoroethyl iodide, with arylboronic
acids.25
We also attempted the palladium-catalyzed cross-coupling reac-
tion of 3b with alkynyl iodides to produce 1,1-difluoro-2-triethylsi-
lyl-1,3-enynes 5. When 3b was reacted with phenylethynyl iodide
in the presence of 10 mol % of Pd(PPh3)4 and 10 mol % of CuI in
DMF at 80 °C for 1 h, the starting material 3b was completely con-
sumed, but only dimerized product of phenylethynyl iodide, 1,4-di-
phenyl-1,3-butadiyne, was obtained in 85% yield and no desired
product 5a was observed. The reaction was also carried out at room
temperature and 50 °C, but the dimerized product was always ob-
tained. This result indicated that palladium-catalyzed dimerization
process of alkynyl iodide was much faster than palladium-catalyzed
cross-coupling reaction of 3b with alkynyl iodide. To establish a
method for the preparation of 1,1-difluoro-2-triethylsilyl-1,3-eny-
nes 5, we attempted the palladium-catalyzed cross-coupling reac-
tion of 3b with phenylethynyl bromide which may be less reactive
than phenylethynyl iodide in the catalytic process of the dimeriza-
tion reaction. The coupling reaction between 3b and phenylethynyl
bromide in the presence of 10 mol % of Pd(PPh3)4 and 10 mol % of
Table 2
Cross-coupling reaction of 3a with aryl iodides
R
SnBu3
SiMe3
R
F
F
F
F
Pd(PPh3)4 (10 mol %)/CuI (10 mol %)
+
I
DMF, 80 oC,
t
h
SiMe3
Table 1
(1 equiv)
3a
4
Optimization reaction condition for the stannylation of 2a
SnBu3
SiMe3
F
F
OTs
F
F
Compound no.
R
t (h)
Yielda (%)
Pd catalyst (X mol %)/XPhos (Y mol %)
LiBr (Z equiv), THF, reflux,
+
(Bu3Sn)2
(1.0 equiv)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
p-C6H5
H
p-F
p-Cl
p-Br
p-OCH3
p-CH3
p-NO2
p-CF3
m-F
10
16
16
14
16
20
20
14
16
16
14
16
20
20
14
16
20
14
90
70
78
86
79
72
71
89
85
50
54
57
51
47
60
53
t
h
SiMe3
2a
3a
Entry Pd catalyst
X
Y
Z
t
Yielda,b
(%)
(mol %)
(mol %)
(equiv)
(h)
1c
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
10
10
10
10
10
0
0
0
0
6
6
6
6
6
30
30
10
30
30
30
30
30
30
8
8
8
24
8
8
8
8
8
Trace
24
10
5
m-Cl
35
48
60
68
73
m-Br
m-OCH3
m-CH3
m-NO2
m-CF3
o-OCH3
o-Cl
Pd(CH3CN)2Cl2 10
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
10
6
3
b
—
—
a
b
Isolated yield.
b
The reactions were performed in wet (0.025 mg of H2O in 1 mL THF) air bubbled
a
THF.
Isolated yield.
No product was obtained.
c
b
The reactions were carried in dry THF.

1294
J. H. Jeon et al. / Tetrahedron Letters 55 (2014) 1292–1295
Table 3
In summary, we have developed a method for the novel 1,
Cross-coupling reaction of 3b with alkynyl bromides
1-difluoro-2-trialkylsilylethenylstannane 3 as a new type of 2,2-
difluoroethenylstannane reagent by the stannylation of 2,2-di-
fluoro-1-trialkylsilylethenyl p-toluenesulfonate 2. Novel stannane
reagent 3 underwent the palladium-catalyzed cross-coupling reac-
tion with aryl iodides to give 2,2-difluoro-1-arylethenylsilane 4.
Similarly, alkynylation reaction of 3 with alkynyl bromides under
the same reaction condition also provided the coupled products,
2,2-difluoro-1,3-enynes 5. Alternatively, 2,2-difluoro-1,3-enynes 5
was also prepared from the palladium-catalyzed cross-coupling
reaction between 2,2-difluoro-1-trialkylsilylethenyl iodide 6 and
alkynyltributylstannane reagents. The further synthetic utilities of
3 and 5 will be described in the future Letters.
R
SnBu3
F
F
F
Pd(PPh3)4 (10 mol %)/CuI (10 mol %)
THF, reflux, t (h)
+
Br
R
(1 equiv)
SiEt3
3b
SiEt3
F
5
Compound No.
R
t (h)
Yielda (%)
5a
5b
5c
5d
5e
5f
C6H5
3
3
3
3
3
5
5
61
64
65
77
74
70
73
p-CH3C6H5
p-ClC6H5
n-C4H9
n-C6H13
Si(CH3)3
Si(i-C3H7)3
5g
Acknowledgements
a
Isolated yield.
This work was supported by a Basic Research Grant (2011-
0022295) funded by the National Research Foundation of Korea.
CuI in DMF at 80 °C for 3 h afforded the coupled product 5a in 47%
yield along with the dimerized product of alkynyl bromide. This
result indicated that phenylethynylpalladium (II) bromide interme-
diate formed from the oxidative addition process between phenyl-
ethynyl bromide and Pd(PPh3)4 underwent the transmetallation
with 3b much faster than the dimerization with phenylethynyl bro-
mide. When this reaction was performed in THF instead of DMF, the
coupled product 5a was obtained in 61% yield. Aryl-, alkyl-, and tri-
alkylsilyl-substituted ethynyl bromides also underwent coupling
reactions with 3b under a similar condition to give the coupled
products 5b–g in good yields which are summarized in Table 3.
Supplementary data
Supplementary data (experimental procedures and 1H, 13C and
19F NMR spectra for 2a–b, 3a–b, 4a–p, 5a–g) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.12.071.
C6H5
C6H5
85%
SnBu3
SiEt3
F
F
Pd(PPh3)4 (10 mol %)/CuI (10 mol %)
DMF, 80 oC, 1 h
+
I
C6H5
C6H5
SiEt3
(1 equiv)
F
F
3b
5a
In order to examine the cross-coupling reaction via reverse reac-
tive counterpart, we prepared 2,2-difluoro-1-trialkylsilylethenyl io-
dides 6a–b in 70–73% yields from the reaction of 3 with iodine
(2 equiv) in THF at À30 °C followed by warming to room tempera-
ture. Recently, Paquin et al. also prepared 6a–b via an one-pot two
step reaction from the 2,2,2-trifluoroethyl iodide.25 The palladium-
catalyzed cross-coupling reaction of 6b with phenylethynyltribu-
tylstannane in the presence of 10 mol % of Pd(PPh3)4 and 10 mol %
of CuI in THF at reflux for 2 h provided the desired product 5a in
85% yield and no dimerized product was observed. Similarly, the
reaction of 6b with n-butyl- or trimethylsilyl-substituted ethynyl-
tributylstannane also afforded the corresponding 1,3-enynes 5d
or 5f in 95% and 75% yields, respectively. We also performed the
Sonogashira reaction of 6b with phenylethyne in the presence of
PdCl2(PPh3)2, CuI, and triethylamine in DMF at 80 °C for 3 h, but
the desired product 5a was isolated in only 31% yield.
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5a (85%)
(R = C6H5, -C4H9, SiMe3)
n
5d (95%)
5f (75%)

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