Microwave-assisted one-pot synthesis of α-fluoro-α,β- unsaturated esters under solvent-free conditions

Article abstract of DOI:10.1055/s-2008-1078213

A microwave-assisted approach for the synthesis of α-fluoro-α, β-unsaturated esters from ethyl bromofluoroacetate, aldehydes, and triphenylphosphine in the presence of Zn-Cu under solvent-free conditions was achieved. The reaction was accomplished within

Full text of DOI:10.1055/s-2008-1078213

2376
LETTER
Microwave-Assisted One-Pot Synthesis of a-Fluoro-a,b-Unsaturated Esters
under Solvent-Free Conditions
Synthesis of
a
-Flu
i
oro-
a
,
b
s
-
Unsatura
h
tedEsters an Ren, Xiongjun Yang, Jing Hong, Xiaochun Yu*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325027, P. R. of China
Fax +86(577)88373013; E-mail: xiaochunyu@wzu.edu.cn
Received 26 April 2008
The synthesis of ethyl a-fluoro-a,b-unsaturated esters was
Abstract: A microwave-assisted approach for the synthesis of a-
fluoro-a,b-unsaturated esters from ethyl bromofluoroacetate, alde-
hydes, and triphenylphosphine in the presence of Zn–Cu under sol-
vent-free conditions was achieved. The reaction was accomplished
within five minutes with good product yields.
carried out using ethyl bromofluoroacetate, triphe-
nylphosphine, and aldehydes under microwave irradia-
tion. Initial studies were carried out using 4-
chlorobenzaldehyde (2b) as the model substrate to ex-
plore the reaction conditions (Scheme 1). We first exam-
ined the effect of different metallic reagents under the
one-pot conditions. The reaction was carried out at 110
°C, inside a 1000 W microwave oven using dry DMF as
solvent. The results are summarized in Table 1.
Key words: microwave irradiation, solvent-free, a-fluoro-a,b-un-
saturated ester
Microwave irradiation has been used in organic synthesis
since 19861 and is now accepted as a method for reducing
the reaction times for a large variety of reactions.2 It has
also been widely applied in the formation of carbon–car-
bon double bond, including Wittig,3 Heck,4 condensation
reactions,5 Knoevenagel reaction,6 or dehydration of aldol
compounds.7
Table 1 Results of Different Metallic Reagents with Ethyl Bromo-
fluoroacetate, Triphenylphosphine, and 4-Chlorobenzaldehyde
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Metallic reagent Time (min)
Yield (%)a
–
20
40
20
40
20
40
20
40
40
41
52
52
43
44
60
61
–
As many fluorinated compounds have biological activi-
ties,8 extensive studies on the preparation of fluorine-con-
taining analogues,9 particularly for the fluorine-
containing alkenes,10 have been carried out extensively in
recent years. There are already existing methods to con-
struct fluoro-substituted carbon–carbon double bond,11
and the reaction can be conducted in the presence of me-
tallic reagents, such as Et2Zn,12 Pd(PPh3)4,13 VOCl3,14
Mg(0).15 These methods are suitable for certain synthetic
Zn
Zn
Fe
Fe
Zn–Cu
Zn–Cu
conditions in many cases, however, some of these proce- DMF
dures are associated with one or more disadvantages such
a Isolated yield, product characterized by 1H NMR, IR, and MS.
as tedious process,16 long reaction time,13 expensive me-
tallic reagents, and difficult product separation,17 which
might limit the scale of an experiment. Thus, there is still
a necessity to find new methodologies that are fast and in-
expensive to carry out the reaction in a large scale. Herein,
we wish to report a microwave-assisted method for the
one-pot synthesis of ethyl a-fluoro-a,b-unsaturated esters
in the presence of Zn–Cu18 under solvent-free conditions.
As shown in Table 1, although the reaction could proceed
even without metallic reagents, addition of metallic re-
agents would improve the yield dramatically. We were
pleased to find that Zn–Cu was a good reagent for the one-
pot reaction. Similar yields were observed even if the re-
action time was extended to 40 minutes.
Then, we further investigated the solvent effect in the
presence of Zn–Cu under the microwave-irradiation con-
ditions. The results are summarized in Table 2.
O
Ph3P
Br
+
Cl
CHO
Cl
O
F
As shown in Table 2, the results indicated that the reaction
under solvent-free conditions afforded ethyl a-fluoro-a,b-
unsaturated ester in the best yield, thus solvent-free con-
ditions were chosen as our optimal conditions to examine
the reaction scope.
CH CFCO2Et
Scheme 1 Synthesis of a-fluoro-a,b-unsaturated ester
We further studied the effect at different temperatures and
powers of microwave in the presence of Zn–Cu under sol-
vent-free conditions. The results are summarized in
SYNLETT 2008, No. 15, pp 2376–2378
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078213; Art ID: W06908ST
1
5
.0
9
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a-Fluoro-a,b-Unsaturated Esters
Table 4 Results of Different Heating Methods
2377
Table 2 Results of Different Solvents with Ethyl Bromofluoroace-
tate, Triphenylphosphine, and 4-Chlorobenzaldehyde
Heating method
Metallic Time
reagent
Yield Z/Eb
(min) (%)a
Solvent
Metallic
reagent
Temp
(°C)
Time
(min)
Yield
(%)a
MW
Zn–Cu
5
5
83
60
75
69:31
–
Zn–Cu
Zn–Cu
Zn–Cu
Zn–Cu
Zn–Cu
Zn–Cu
Zn–Cu
110
110
80
20
20
20
20
20
20
20
73
60
53
59
50
51
40
Conventional heating method Zn–Cu
Conventional heating method Zn–Cu
65:35
72:28
DMF
60
MeCN
[Bmin]PF6
THF
a Isolated yield, products characterized by 1H NMR, IR, and MS.
b Ratio determined by 1H NMR (300 MHz, CDCl3) analysis.
110
60
Table 5 Synthesis of Ethyl a-Fluoro-a,b-Unsaturated Esters
CH2Cl2
40
O
Ph3P/Zn–Cu
MW
Br
C6H6
80
RHC CFCO2Et
+
RCHO
OEt
a Isolated yield.
F
1
2
3
Entry
R
Time
(min)
Product Yield
Z/Eb
Table 3. As shown in Table 3, the results indicated that
the yield was improved at 150 °C with a microwave power
of 1000 W. At the same time, we found the reaction time
could be reduced to five minutes with a stronger power
and at a higher temperature.
(%)a
78
83
84
67
60
66
69
81
70
1
2
3
4
5
6
7
8
9
4-O2NC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
5
5
5
5
5
5
5
5
5
3a
3b
3c
3d
3e
3f
68:32
69:31
61:39
70:30
100:0
57:43
58:42
60:40
62:38
Table 3 Results of Different Temperatures and Powers with Ethyl
Bromofluoroacetate, Triphenylphosphine, and 4-Chlorobenzalde-
hyde
4-Me2NC6H4
4-MeC6H4
2-O2NC6H4
2-MeOC6H4
Ph
Metallic reagent Power (W) Temp (°C) Time (min) Yield (%)a
Zn–Cu
500
700
90
90
20
20
20
20
20
20
20
5
48
53
56
57
66
73
75
83
3g
3h
3i
Zn–Cu
Zn–Cu
800
90
Zn–Cu
900
90
O
10
11
5
5
3j
70
44
60:40
86:14
Zn–Cu
1000
1000
1000
1000
90
O
Zn–Cu
110
120
150
3k
Zn–Cu
O
12
13
PhCH=CH
5
5
3l
56
–
68:32
Zn–Cu
a Isolated yield.
Pr
Pr
Pr
3m
3m
3m
–
–
–
20
40
–
Furthermore, we examined the effect of different heating
method in the presence of Zn–Cu under solvent-free con-
ditions. The results are summarized in Table 4. It can be
seen that the yield of the reaction was improved, and the
reaction time was shortened under microwave irradiation
as compared to the conventional heating method.
–
a Isolated yield, products characterized by 1H NMR, IR, and MS.
b Ratio determined by 1H NMR (300 MHz, CDCl3) analysis.
der the conventional heating method, the reaction time
was shortened from hours to five minutes with a slight im-
provement on stereoselectivity13 in the presence of Zn–Cu
under microwave irradiation.
To establish the generality of the methodology, various al-
dehydes were treated with ethyl bromofluoroacetate,
triphenylphosphine, and Zn–Cu under the optimized con-
ditions. The results are listed in Table 5.
1
The ratios of Z/E isomers were determined by H NMR
spectra. It was reported that the signals of vinyl and ethyl
protons of (Z)-a-fluoro-a,b-unsaturated esters were at a
lower field than those of the corresponding E compounds.
For example, the H NMR spectrum showed that the
chemical shifts of the vinyl proton and the methyl signal
It was notable that aliphatic aldehydes, except a,b-unsat-
urated aliphatic aldehydes, could not afford the prod-
ucts,19 even if the reaction time was increased to 40
minutes. Although a-fluoro-a,b-unsaturated esters could
be similarly synthesized in the presence of Pd(PPh3)4 un-
1
Synlett 2008, No. 15, 2376–2378 © Thieme Stuttgart · New York

2378
A. Ren et al.
LETTER
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In conclusion, we have developed a microwave-assisted
approach for the synthesis a-fluoro-a,b-unsaturated esters
from ethyl bromofluoroacetate, aldehyde, and triphe-
nylphosphine in the presence of Zn–Cu under solvent-free
conditions. The reaction does not require the use of any
volatile organic solvents as well as expensive metallic re-
agents. Thus, this is an economical and environmental
friendly method for the synthesis of a-fluoro-a,b-unsatur-
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Triphenylphosphine (1.2 mmol), ethyl bromofluoroacetate
(1.2 mmol), aldehyde (1.0 mmol), and Zn–Cu (0.1 g) were
added into an oven-dried round-bottom flask. The mixture
was stirred under microwave irradiation, which was set at
1000 W, 150 °C for 5 min. The product was purified by
chromatography on SiO2 with EtOAc and PE (60–90 °C).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the Natural Science Foundation of Zhejiang Pro-
vince (Y205540) for financial support.
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