Wittig gem-difluoroolefination of aldehydes with difluoromethyltriphenylphosphonium bromide

Article abstract of DOI:10.1016/j.jfluchem.2014.04.011

Wittig reaction of aldehydes with difluoromethyltriphenylphosphonium bromide leading to gem-difluoroolefins in moderate yields is described. The reaction displays a good substrate scope including aryl, heteroaryl and α,β-unsaturated aldehydes. Difluoromethyltriphenylphosphonium bromide could be easily prepared and stored for a long time under air atmosphere. The salt exhibits high thermal stability demonstrated by thermogravimetric analysis. Its structure was confirmed by NMR spectroscopy and single crystal X-ray analysis.

Full text of DOI:10.1016/j.jfluchem.2014.04.011

Journal of Fluorine Chemistry 163 (2014) 38–41
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Wittig gem-difluoroolefination of aldehydes with
difluoromethyltriphenylphosphonium bromide
Qiang Li, Jin-Hong Lin, Zu-Yong Deng, Jian Zheng, Ji Cai, Ji-Chang Xiao *
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Wittig reaction of aldehydes with difluoromethyltriphenylphosphonium bromide leading to gem-
Received 25 March 2014
Received in revised form 14 April 2014
Accepted 17 April 2014
Available online 28 April 2014
difluoroolefins in moderate yields is described. The reaction displays a good substrate scope including
aryl, heteroaryl and
a,b-unsaturated aldehydes. Difluoromethyltriphenylphosphonium bromide could
be easily prepared and stored for a long time under air atmosphere. The salt exhibits high thermal
stability demonstrated by thermogravimetric analysis. Its structure was confirmed by NMR
spectroscopy and single crystal X-ray analysis.
Keywords:
ß 2014 Elsevier B.V. All rights reserved.
Wittig reaction
gem-Difluoroolefination
Aldehydes
Difluoromethyltriphenylphosphine
bromide
1
. Introduction
part of our continuing research interest in ylide chemistry
[23,24,29], we have now investigated the Wittig gem-difluoroo-
The introduction of fluorine or fluorine-containing functional
lefination of aldehydes with difluoromethyltriphenylphospho-
nium bromide in the presence of base.
groups usually furnishes the target molecules with unique
physical, chemical and biological properties [1–4]. As an important
class of fluorinated compounds, gem-difluoroolefins have been
widely used in a variety of research areas, such as medical and
agricultural chemistry and material sciences [5–10]. Due to their
versatility, intense research efforts have been directed toward the
exploration of applicable protocols for the construction of gem-
2. Results and discussion
Difluoromethyltriphenylphosphonium bromide was easily
prepared via a quaternization reaction of triphenylphosphine with
trimethylsilyl bromodifluoroacetate, which could be synthesized
on a large scale from bromodifluoroacetate in a 2-step sequence,
and the subsequent desilylation and decarboxylation in the
presence of TBAF (tetra-n-butylammonium fluoride) (Scheme 1).
The structure of the salt was confirmed by NMR spectroscopy and
single crystal X-ray analysis [30]. Difluoromethyltriphenylpho-
sphonium bromide is stable to air and water, and exhibits high
thermal stability demonstrated by thermogravimetric analysis
2
difluorovinylidene moiety (CF 55 C) [11–22]. Previously, we have
shown that decarboxylative Witting reaction and Julia–Kocienski
reaction are quite efficient for the synthesis of gem-difluoroolefins
under mild conditions [23,24]. In the study on the decarboxylative
Wittig reaction, we found difluoromethylene phosphonium ylide
could be generated in situ from the decarboxylation of difluor-
omethylene phosphobetaine without the presence of base [23]. We
speculated that deprotonation of difluoromethyltriphenylpho-
sphonium salt might also lead to the in situ formation of
difluoromethylene phosphonium ylide, which could undergo
Wittig reaction with carbonyl compounds. Even though the
synthesis of difluoromethyltriphenylphosphonium salt has been
reported [25–28], its reactivity has been largely unexplored. As
(
T
d
= 223 8C).
With the stable salt in hand, we then investigated its
application as an ylide precursor in Wittig gem-difluoroolefina-
tion with 4-phenylbenzaldehyde. The desired reaction performed
at rt in DMF by employing DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene) (2 equiv.) as the base was observed, even though the yield
was quite low (entry 1, Table 1). Other bases including organic
bases and inorganic bases were not effective for this reaction
(entries 2–7). Elevating the reaction temperature to 50 8C
*
Corresponding author. Tel.: +86 21 5492 5340; fax: +86 21 6416 6128.
E-mail addresses: jchxiao@sioc.ac.cn, jchxiao@gmail.com (J.-C. Xiao).
http://dx.doi.org/10.1016/j.jfluchem.2014.04.011
022-1139/ß 2014 Elsevier B.V. All rights reserved.
0

Q. Li et al. / Journal of Fluorine Chemistry 163 (2014) 38–41
39
low yield was obtained (2k). The reaction is not applicable for
ketone.
3. Conclusion
In conclusion, we have described the Wittig gem-difluoroole-
fination of aldehydes with difluoromethyltriphenylphosphonium
bromide in the presence of DBU, giving the corresponding products
in moderate yields. Difluoromethyltriphenylphosphonium bro-
mide could be easily prepared and exhibits high thermal stability.
Further studies on the reactivity of difluoromethyltriphenylpho-
sphonium bromide are currently underway.
Scheme 1. The preparation of difluoromethyltriphenylphosphonium bromide.
improved the yield significantly (entry 8), but further elevation of
temperature resulted in inferior results (entries 9 and 10). The
examination of solvent effect revealed that solvent is quite
important for the reaction (entries 11–16). The reactions in DMF
and in DMSO gave the same result (entry 8 and 11). The yield was
increased with the increasing of molar ratio of 1:base:aldehyde to
4. Experimental
4.1. The procedure for the synthesis of
difluoromethyltriphenylphosphonium bromide (1)
3
:3:1 (entry 17). Shortening the reaction time from 12 h to 4 h did
Into the solution of KOH (56 g, 1 mol) in methanol (500 mL) was
slowly added BrCF CO Et (203 g, 1 mol) at room temperature. The
not influence the yield (entry 18 vs. 17). The effect of molar ratio
of 1:base:aldehyde on the reaction proceeding for 4 h was further
examined (entries 19–22). It was found that the ratio of 3:3:1 was
quite efficient for the desired conversion (entry 18).
2
2
resulting mixture was stirred at the same temperature until
BrCF CO Et was completely consumed. The solvent was removed
2
2
by concentration to give BrCF CO K as a solid (202 g, 95%).
2
2
Then a variety of carbonyl compounds were tested for their
suitability for use in this gem-difluoroolefination under the
optimal reaction conditions (entry 18, Table 1). As shown in
Scheme 2, the reaction displayed a good tolerance toward different
electron-donating and -withdrawing groups on the aryl ring,
giving the desired difluoroolefinated products in moderate yields
2 2
The mixture of BrCF CO K (21.3 g, 100 mmol) and TMSCl
(44 mL, 500 mmol) was refluxed until BrCF CO K was completely
2
2
consumed. Distillation gave BrCF CO SiMe as a liquid (22.1 g,
2
2
3
1
19
90%). H NMR (300 MHz, CDCl3)
(282 MHz, CDCl3)
d 0.40 (s, 9H) ppm; F NMR
d
ꢀ62.36 (s, 2F).
Into the solution of PPh (3.93 g, 15 mmol) in THF (30 mL) was
3
(
2a–2h). The reaction proceeded equally well for heteroaromatic
added BrCF CO SiMe (2.47 g, 10 mmol) in 1 h at 0 8C under N2.
2
2
3
substrates (2i–2j). In the case of
a
,b
-unsaturated aldehyde, only
The mixture was stirred for another 1 h. The solution of TBAF
Table 1
a
Optimization of reaction conditions for gem-difluoroolefination.
b
Entry
Base
Solvent
Temp. (8C)
Time (h)
2a (%)
1
2
3
4
5
6
7
8
9
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMAc
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
80
100
50
50
50
50
50
50
50
50
50
50
50
50
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
4
13
ND
ND
ND
8
i-
2
Pr NH
Et
Et
3
N
2
NH
t-BuOK
KOH
ND
ND
60
50
46
60
N.R.
11
20
15
20
84
84
38
68
60
ND
2 3
K CO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
1
1
1
1
1
1
1
0
1
2
3
4
5
DCE
Toluene
Xylene
DMF
DMF
DMF
DMF
DMF
DMF
6
c
1
7
c
1
8
d
e
1
2
2
9
4
0
4
f
1
4
g
2
2
4
a
b
c
d
e
f
Reaction conditions: 4-phenylbenzaldehyde (0.2 mmol), 1 (0.4 mmol) and base (0.4 mmol) in solvent (2 mL).
19
Determined by F NMR.
0
.6 mmol of 1 and 0.6 mmol of base were used.
.2 mmol of 1 and 0.2 mmol of base were used.
.8 mmol of 1 and 0.8 mmol of base were used.
.6 mmol of 1 and 0.3 mmol of base were used.
.6 mmol of 1 and 1.2 mmol of base were used.
0
0
0
g
0

4
0
Q. Li et al. / Journal of Fluorine Chemistry 163 (2014) 38–41
F
1
O
1
-Bromo-4-(2,2-difluorovinyl)benzene (2e): 70% yield; H NMR
300 MHz, CDCl 7.46 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H),
5.23 (dd, J = 26.0, 3.4 Hz, 1H). F NMR (282 MHz, CDCl
(dd, J = 29.1, 26.0 Hz, 1F), ꢀ83.05 (dd, J = 29.1, 3.4 Hz, 1F).
-(2,2-Difluorovinyl)-3-(trifluoromethyl)benzene (2f): 65% yield;
H NMR (300 MHz, CDCl 7.56 (s, 1H), 7.54–7.39 (m, 3H), 5.31 (dd,
J = 25.6, 3.3 Hz, 1H). F NMR (282 MHz, CDCl
ꢀ63.02 (s, 3F),
80.43 to ꢀ80.73 (m, 1F), ꢀ82.30 (dd, J = 27.2, 3.3 Hz, 1F).
-(2,2-Difluorovinyl)benzonitrile (2g): 40% yield; 1H NMR
(400 MHz, CDCl 7.61 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz,
2H), 5.33 (dd, J = 25.5, 3.3 Hz, 1H). F NMR (376 MHz, CDCl
ꢀ77.89 (dd, J = 25.5, 20.6 Hz, 1F), ꢀ79.54 (dd, J = 20.6, 3.3 Hz, 1F).
DBU, DMF
[
Ph
3
2
PCF H
]
Br-
(
3
) d
R
H
0 o
5
C
R
F
1
9
1
2
3
)
d
ꢀ81.20
F
F
F
F
1
F
F
F
1
F
3
) d
Ph
Cl
Me
MeO
19
3
) d
2
a, 79%
2b, 70%
2c, 56%
ꢀ
F
4
F
F
F
3
) d
Br
1
9
CF
3
3
) d
2
d, 69%
2e, 70%
2f, 65
F
F
1
2
-(2,2-Difluorovinyl)naphthalene (2h); 78% yield; H NMR
300 MHz, CDCl 7.85–7.70 (m, 4H), 7.54–7.40 (m, 3H), 5.42 (dd,
J = 26.4, 3.6 Hz, 1H). F NMR (282 MHz, CDCl
J = 30.7, 26.4 Hz, 1F), ꢀ83.59 (dd, J = 30.7, 3.6 Hz, 1F).
F
F
F
(
3
) d
F
F
19
3
)
d
ꢀ81.86 (dd,
NC
S
1
2
g, 40%
2h, 78%
2k, 30%
2i, 55%
3-(2,2-Difluorovinyl)benzo[b]thiophene (2i): 55% yield;
NMR (300 MHz, CDCl
J = 7.8 Hz, 1H), 7.51–7.33 (m, 3H), 5.60 (dd, J = 25.8, 1.7 Hz, 1H).
H
F
3
) d 7.87 (d, J = 7.6 Hz, 1H), 7.71 (d,
F
F
19
N
F NMR (282 MHz, CDCl
J = 25.8, 1.7 Hz, 1F).
3
) d
ꢀ80.67 (t, J = 25.8 Hz, 1F), ꢀ84.51 (dd,
2
j, 59%
1
3
-(2,2-Difluorovinyl)quinolone (2j): 59% yield;
(400 MHz, CDCl
H), 8.07 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 (ddd,
J = 8.4, 6.9, 1.4 Hz, 1H), 7.57–7.52 (m, 1H), 5.45 (dd, J = 26.2, 3.0 Hz,
H NMR
Scheme 2. gem-Difluoroolefination of aldehydes. Reaction conditions: aldehyde
0.2 mmol), salt 1 (0.6 mmol) and DBU (0.6 mmol) (molar ratio of aldehyde:1:DBU
was 1:3:3) in DMF (2 mL) at 50 8C for 4 h. Isolated yields.
3
) d 8.83 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz,
(
1
1
9
1
(
H). F NMR (376 MHz, CDCl
dd, J = 25.3, 3.0 Hz).
(E)-(4,4-Difluorobuta-1,3-dien-1-yl)benzene (2k): 30% yield;
H NMR (300 MHz, CDCl 7.42–7.27 (m, 5H), 6.66 (dd, J = 15.9,
3
)
d
ꢀ79.60 (t, J = 25.8 Hz), ꢀ80.96
(
tetra-n-butylammonium fluoride, 10 mL, 1 M) was added. The
resulting mixture was refluxed for 1 h. The crude product
precipitated as a solid. After filtration, the solid was washed with
1
3
) d
10.8 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 5.14 (dd, J = 24.1, 10.8 Hz,
1
9
THF (40 mL) and Et
solid (3.34 g, 85%). M.P. = 184 8C; T
DMF) 9.50 (td, J = 46.6, 29.6 Hz, 1H), 8.16–8.06 (m, 9H), 7.99–7.90
2
O (40 mL) to give the pure product as a white
1H). F NMR (282 MHz, CDCl
(d, J = 26.4 Hz, 1F).
3
)
d
ꢀ85.13 to ꢀ85.37 (m, 1F), ꢀ86.97
1
d
= 223 8C; H NMR (400 MHz,
d
1
9
(
2
m, 6H). F NMR (376 MHz, DMF)
d
ꢀ127.78 (dd, J = 77.9, 46.6 Hz,
Acknowledgements
31
F). P NMR (162 MHz, DMF) d 19.29 (t, J = 77.9 Hz, 1P).
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21032006, 21172240), the 973
Program of China (grant number 2012CBA01200), and the Chinese
Academy of Sciences for financial support.
4
.2. Typical procedure for gem-difluoroolefination
Into the mixture of difluoromethyltriphenylphosphonium
bromide (236 mg, 0.6 mmol), aldehyde (0.2 mmol) and DBU
90 L, 0.6 mmol) was added DMF (2 mL) under N . The resulting
mixture was stirred at 50 8C for 4 h. After being cooled to room
temperature, the solution was diluted with CH Cl (10 mL) and
washed with water (5 mL ꢁ 2). The organic phase was dried over
sodium sulfate. The solvent was removed by concentration and the
residue was subjected to column chromatography to give the pure
product.
(
m
2
Appendix A. Supplementary data
2
2
Supplementarydataassociatedwiththisarticlecanbefound, inthe
online version, at http://dx.doi.org/10.1016/j.jfluchem.2014.04.011.
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0
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4
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J = 26.3, 3.6 Hz, 1H). F NMR (282 MHz, CDCl
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