Microreactors for the synthesis of fluorinated materials

Article abstract of DOI:10.1016/S0022-1139(03)00109-X

The utility of microreactor for the synthesis of α-fluoro-α, β-unsaturated esters, trifluoromethylation and Michael addition reaction, is described.

Full text of DOI:10.1016/S0022-1139(03)00109-X

Journal of Fluorine Chemistry 122 (2003) 243–246
Microreactors for the synthesis of fluorinated materials
*
Noriaki Miyake, Tomoya Kitazume
Graduate School of Bioscience & Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan
Received 29 January 2003; received in revised form 31 March 2003; accepted 5 April 2003
Abstract
The utility of microreactor for the synthesis of a-fluoro-a,b-unsaturated esters, trifluoromethylation and Michael addition reaction, is
described.
#
2003 Elsevier Science B.V. All rights reserved.
Keywords: Trifluoromethylation; Michael addition reaction; a-Fluoro-a,b-unsaturated ester; Microreactor
1
. Introduction
organometallics in polar organic solvents [1]. Especially,
the synthesis of a-fluoro-a,b-unsaturated esters from the
reaction of triethyl-2-fluoro-2-phosphonoacetate with
aldehydes was reported by several groups [8], however,
their procedures required NaH as a base at diethyl ether
reflux temperature or n-BuLi as a base at ꢀ78 8C in
tetrahydrofuran. To make clear the utility of microreactor
for the synthesis of a-fluoro-a,b-unsaturated esters, we
examined the reaction of triethyl-2-fluoro-2-phosphono-
acetate with aldehydes in the presence of 1,8-diazabicyclo-
[5,4,0]-7-undecene (DBU) at room temperature. The mix-
ture of aldehyde and triethyl-2-fluoro-2-phosphonoacetate
in 1,2-dimethoxyethane (DME) was injected via a syringe
and syringe-pump, while DBU in DME was also intro-
duced via another syringe controlled with the same syr-
inge-pump. The reaction was carried out in the
microreactors (channel width 100 mm, depth ca. 40 mm
The challenge in chemistry to develop new products,
practical processes, reaction media, conditions and/or utility
of materials based on the idea of green chemistry is having
one of the most important issues in scientific society [1–3].
Especially, in the fluorine chemistry, there is much interest in
the development of microreactors for chemical processing
[
4], because the benefits would include arithmetic scale-up
and problems of the safe handling and/or temperature con-
trol. However, except for direct fluorination with elemental
fluorine [5], no other examples of the introduction of a
fluorine atom and/or fluoroalkyl group onto the molecules
have been reported to our knowledge.
In this paper, we would like to describe the syntheses of
fluorinated materials via the Horner–Wadsworth–Emmons
reaction, trifluoromethylation and Michael addition reaction
in a microreactor.
ꢀ
1
and length 80 mm; flow rate 1 ml min ) shown in Fig. 1.
Products were trapped out in a flask containing 1N
HCl. The organic materials were extracted with diethyl
ether, and the ethereal layer was dried over MgSO4.
On removal of the solvent, yields were determined
by 19F NMR integral intensities using benzotrifluoride
as an internal standard. The structures were confirmed
by spectral data. The present reaction summarized in
Table 1.
2
. Results and discussion
2
.1. Fluorinated alkenes
While the Horner–Wadsworth–Emmons reactions [6,7],
are one of the important synthetic reactions especially in
the synthesis of fluorinated alkenes. Usually, fluorinated
alkenes are prepared from the addition-elimination of
polyfluoroethenes, chlorofluorocarbene, ethyl phenylsulfi-
nyl-fluoroacetate, triethyl-2-fluoro-2-phosphonoacetate and
1
The stereochemistry of products was confirmed by H
NMR coupling constants (JH–F) and chemical shifts of the
olefinic protons. It is well known that the coupling constant
(JH–F) of the Z-isomer is 25–45 Hz and that JH–F of the
E-isomer is 10–25 Hz. On the basis of the coupling constant
*
(
JH–F ¼ ꢁ35 Hz) and chemical shifts, the main products are
Corresponding author. Tel.: þ81-45-924-5754; fax: þ81-45-924-5780.
E-mail address: tkitazum@bio.titech.ac.jp (T. Kitazume).
E-isomers.
0022-1139/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00109-X

244
N. Miyake, T. Kitazume / Journal of Fluorine Chemistry 122 (2003) 243–246
Table 2
Trifluoromethylation
a
Yield (%)
Fig. 1. Microreactor chips with channel width 100 mm, depth ca. 40 mm
and length 80 nm.
Entry
Carbonyl compound
CHO
b
1
2
3
4
5
6
7
C
6
H
5
89 (76)
83 (97)
63
4-CF
4-MeOC
n-C 19CHO
(E)-PhCH¼CHCHO
PhCOCH
Cyclohexanone
3
C
6
H
4
CHO
Table 1
6 4
H CHO
Horner–Wadsworth–Emmons reaction
9
H
74
12
3
42
7
a
Yields were determined by 19F NMR.
b
In parentheses, yields are results of the reaction carried out in the
flask for 5 h.
a
Entry
R
C
Yield (%)
Z:E
which have basically similar characteristics at the reaction
site (b-position of a carbonyl moiety) on the basis of the pz
orbital coefficient of LUMO and electron density [10].
These results prompted us to employ ethyl-3-(trifluoro-
methyl)acrylate as a Michael acceptor for the synthesis of
fluorinated materials using the microreactor. As expected,
Michael addition reactions of these materials with 2-nitro-
propane in the presence of DBU proceeded smoothly to
afford the corresponding 1,4-adducts in the microreactors
(channel width 100 mm, depth ca. 40 mm and length 80 mm;
b
1
2
3
4
5
6
7
8
6
H
5
>99
70:30
77:23
64:36
68:32
76:24
74:26
64:36
64:36
c
78
b
4-CF
3
C
6
H
4
86
c
88
b
4-MeOC
6
H
4
>99
c
58
b
n-Nonyl
66
c
81
a
The ratios were determined by 19F NMR.
b
c
Isolated yields. Reactions were carried out in the flask for 30 min.
Reactions were carried out in the microreactor. Yields were
ꢀ
1
flow rate 1 ml min ) with 93% yield without any detectable
formation of polymeric products. The results using the
several types of donors are shown in Table 3.
determined by 19F NMR.
Using a microreactor, we have successfully carried out the
Horner–Wadsworth–Emmons reaction for the synthesis of
a-fluoro-a,b-unsaturated esters, however the E:Z ratio is not
different compared to the reaction in flask.
In conclusion, the successful application using a micro-
reactor is exciting and is likely to open the door to the
development of similar reaction systems for other important
organic reactions.
2
.2. Trifluoromethylation
3. Experimental
The trifluoromethylation has been achieved by several
methods until now [8,9]. To clarify the synthetic advantage
of trifluoromethylation in a microreactor, we have examined
the reaction of the mixture of a carbonyl compound and
trifluoromethyl(trimethyl)silane in THF with a mixture of
tetrabutylammonium fluoride in THF (channel width
3.1. General
All commercially available reagents were used without
1
further purification. Chemical shifts of H (300 MHz) and
1
1
00 mm, depth ca. 40 mm and length 80 mm; flow rate
ml min ), whereby the trifluoromethylated alcohol in
ꢀ
1
Table 3
its trifluoromethylated form is obtained upon the addition
of an appropriate nucleophilic initiator to the reaction
mixture. Trifluoromethylation in the microreactor (20 s)
proceeded quickly not to be compared with the same reac-
tion in the flask (5 h) (Table 2).
Michael addition reaction
a
Entry
R
1
R
2
Yield (%)
2
.3. Michael addition reaction
1
2
3
H
H
80 (90)
93 (92)
90 (99)
Me
H
Me
CO
We have previously reported the Michael addition reac-
tions of CF -containing acrylates such as ethyl-3-(trifluoro-
methyl)acrylate and/or benzyl-2-(trifluoromethyl)acrylate
2
Et
a
3
In parentheses, yields are results of the reaction carried out in the
flask for 30 min. Yields were determined by 19F NMR.

N. Miyake, T. Kitazume / Journal of Fluorine Chemistry 122 (2003) 243–246
245
1
3
C NMR (75 MHz) spectra were recorded in ppm (d)
d ¼ 98.8 (s), d ¼ 83.3 (d, J ¼ 6:89 Hz) ppm from internal
downfield from the following internal standard (Me Si,
C F .
6 6
4
d ¼ 0.00) in CDCl . The 19F (282 MHz) NMR spectra were
ꢂ 1-{4-(Methoxy)phenyl}-2,2,2-trifluoroethanol [11]
3
1
recorded in ppm downfield from internal standard C F in
6
H NMR (CDCl ): d ¼ 2.40 (OH, br), d ¼ 3.90 (Ome),
6
3
CDCl using a VXR 300 instrument.
3
d ¼ 4.95 (1H, q, J ¼ 6:87 Hz), d ¼ 7.25–7.85 (Ar–H).
1
9
F NMR (CDCl ): d ¼ 83.2 (d, J ¼ 6:89 Hz) ppm from
3
3.2. Horner–Wadsworth–Emmons reaction: typical
procedure is as follows
internal C F .
6 6
3.4. Michael addition reaction: typical procedure
is as follows
ꢂ Ethyl-2-fluoro-3-phenyl propenoate [7]
The mixture of benzaldehyde (106 mg, 1 mmol) and
triethyl-2-fluoro-2-phosphonoacetate (363 mg, 1.5 mmol)
in DME (0.59 ml) was injected via a syringe and syringe-
pump, while 8-ethyl-1,8-diazabicyclo[5,4,0]-7-undecene
ꢂ Ethyl-4-nitro-3-trifluoromethylbutanoate [10]
In the above procedure, the mixture of 2-nitropropane
(134 mg, 1.5 mmol) and (E)-ethyl 4,4,4-trifluorocroto-
nate (168 mg, 1 mmol) in CH CN (0.72 ml) was injected
(
228 mg, 1.5 mmol) in DME (0.77 ml)was also introduced
3
via another syringe controlled with the same syringe-
pump. The reaction was carried out in the microreactors
via a syringe and syringe-pump, while 8-ethyl-1,8-dia-
zabicyclo[5,4,0]-7-undecene (228 mg, 1.5 mmol) in
CH CN (0.77 ml) was also introduced via another syringe
(
channel width 100 mm, depth ca. 40 mm and length
0 mm; flow rate 1 ml min ). The reaction mixture was
3
ꢀ
1
8
introduced into 1N HCl directly, andthen organic materials
controlled with the same syringe-pump. The reaction was
1
worked up similarly. H NMR (CDCl ): d ¼ 1.29 (3H, t,
3
were extracted with diethyl ether (three times, 2 ml), and
the extract was dried over anhydrous MgSO and on
J ¼ 7:16 Hz), 2.60 (1H, dd, J ¼ 8:63, 17.1 Hz), d ¼ 2.82
(1 H, dd, J ¼ 4:97, 17.1 Hz), d ¼ 3.55–3.80 (1H, m),
d ¼ 4.21 (2H, q, J ¼ 7:14 Hz), d ¼ 4.62 (1H, dd, J ¼
4
removal of the solvent. The yield and E:Z ratio were
determined by the 19F NMR integral intensities using
5:55, 14.1 Hz), d ¼ 4.71 (1H, dd, J ¼ 6:39, 14.1 Hz),
1
13
benzotrifluoride as an internal standard. E-isomer: H
NMR (CDCl ): d ¼ 1.24 (3H, t, J ¼ 7:08 Hz), d ¼ 4.25
C (CDCl ): d ¼ 14.030, 30.659 (q, J ¼ 2:33 Hz),
3
d ¼ 38.907 (q, J ¼ 28:6 Hz), d ¼ 61.798, 72.277,
3
1
9
(
(
2H, q), d ¼ 6.92 (1H, d, J ¼ 21:4 Hz), d ¼ 7.34–7.48
125.57 (q, J ¼ 280 Hz), d ¼ 169.27. F NMR (CDCl ):
3
1
9
Ar–H). F NMR (CDCl ): d ¼ 44.4 (d, J ¼ 21:4 Hz)
d ¼ 95.8 (d, J ¼ 9:48 Hz) ppm from internal C F .
6 6
3
1
ꢀ1
from C F . Z-isomer: H NMR (CDCl ): d ¼ 1.39 (3H, t,
IR (neat): 1740, 1570 cm
.
6
6
3
J ¼ 7:08 Hz), d ¼ 4.36 (2H, q), d ¼ 6.93 (1H, d,
ꢂ Ethyl-4-nitro-4-methyl-3-trifluoromethylpentanoate
19
1
J ¼ 35:1 Hz), d ¼ 7.34–7.48 (Ar–H). F NMR (CDCl ):
H NMR (CDCl ): d ¼ 1.29 (3H, t, J ¼ 7:20 Hz),
3
3
d ¼ 36.3 (d, J ¼ 35:1 Hz) ppm from internal C F .
d ¼ 1.61 (3H, s), d ¼ 1.70 (3H, s), d ¼ 2.38 (1H, dd,
J ¼ 5:25, 17.25 Hz), d ¼ 2.68 (1H, dd, J ¼ 6:60, 17.40
Hz), d ¼ 4.04 (1H, ddq, J ¼ 5:10, 6.60, 9.30 Hz),
6
6
3
.3. Trifluoromethylation : typical procedure
is as follows
1
3
d ¼ 4.21 (2H, q, J ¼ 7:20 Hz). C NMR (CDCl ):
3
d ¼ 14.04, 23.26, 24.66, 30.86, 46.39 (q, J ¼ 26:34
Hz), d ¼ 61.66, 87.78, 125.68 (q, J ¼ 280:88 Hz),
ꢂ 1-Phenyl-2,2,2-trifluoroethanol [9]
1
9
The mixture of benzaldehyde (106 mg, 1 mmol) and
trifluoromethyl(trimethyl)silane (213 mg, 1.5 mmol) in
THF (0.67 ml) was injected via a syringe and syringe-
pump, while tetrabutylammonium fluoride (1 M solution
in THF, 1 ml) was also introduced via another syringe
controlled with the same syringe-pump. The reaction was
carried out in the microreactors (channel width 100 mm,
d ¼ 169.45. F (CDCl ): d ¼ 67.1 (d, J ¼ 9:30 Hz)
3
ppm from internal C F .
6
6
ꢀ
1
IR (neat): 1741, 1553 cm
C H NO F : C, 42.03; H, 5.49; N, 5.45. Found: C,
. Anal. calcd. for
9
14
2 3
41.68; H, 5.61; N, 5.34.
ꢂ Ethyl-4-ethoxycarbonyl-4-nitro-3-trifluoromethyl
butanoate
ꢀ
1
1
depth ca. 40 mm and length 80 mm; flow rate 1 ml min ).
The reaction mixture was introduced into 1N HCl
directly, and then organic materials were extracted with
diethyl ether (three times, 2 ml), and the extract was
Diastereomeric mixture. H NMR (CDCl ): d ¼ 1.28
3
(3H, td, J ¼ 7:15, 0.82 Hz), d ¼ 1.32 (3H, td, J ¼ 7:14,
1.37 Hz), d ¼ 2.78–2.93 (2H, m), d ¼ 3.86–3.95 (1H, m),
d ¼ 4.00–4.09 (1H, m), d ¼ 4.24 (2H, qd, J ¼ 9:62,
1
3
dried over anhydrous MgSO and on removal of the
4
4.67 Hz), d ¼ 4.34 (2H, m).
C NMR (CDCl ):
3
solvent.
1
d ¼ 13.780(d,J ¼ 5:44 Hz),d ¼ 14.042(d,J ¼ 8:88 Hz),
d ¼ 29.602, 29.780, 41.072 (q, J ¼ 28:37 Hz), d ¼ 41.169
(q, J ¼ 28:63 Hz), d ¼ 61.719, 63.248, 63.889, 64.158,
84.352 (m), d ¼ 124.994 (q, J ¼ 279:99 Hz), d ¼ 125.043
H NMR (CDCl ): d ¼ 2.70 (OH, br), d ¼ 5.03 (1H, q,
3
19
J ¼ 6:87 Hz), d ¼ 7.20–7.65 (Ar–H). F NMR (CDCl ):
3
d ¼ 83.3 (d, J ¼ 6:89 Hz) ppm from internal C F .
6
6
ꢂ 1-{4-(Trifluoromethyl)phenyl}-2,2,2-trifluoroethanol [11]
(q, J ¼ 279:99 Hz), d ¼ 161.671, 161.755, 169.118,
1
19
H NMR (CDCl ): d ¼ 2.40 (OH, br), d ¼ 5.12 (1H, q,
169.327.
d ¼ 92.1 (d, J ¼ 7:76 Hz) ppm from internal C F .
F (CDCl ): d ¼ 91.8 (d, J ¼ 8:62 Hz),
6 6
3
3
19
J ¼ 6:87 Hz), d ¼ 7.40–7.60 (Ar–H). F NMR (CDCl ):
3

246
N. Miyake, T. Kitazume / Journal of Fluorine Chemistry 122 (2003) 243–246
[
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