Microwave-assisted preparation of trifluoroacetaldehyde (fluoral): isolation and applications

Article abstract of DOI:10.1016/j.tetlet.2007.06.170

A novel method for the preparation of trifluoroacetaldehyde (fluoral, TFAc, CF₃CHO) from commercially available trifluoroacetaldehyde ethylhemiacetal (TFAE) by microwave irradiation is described. The isolation, characterization and reaction of fluoral with various nucleophiles were studied to verify the diverse applicability of this new method.

Full text of DOI:10.1016/j.tetlet.2007.06.170

Tetrahedron Letters 48 (2007) 6372–6376
Microwave-assisted preparation of trifluoroacetaldehyde
(fluoral): isolation and applications
*
´
Shainaz M. Landge, Dmitry A. Borkin and Bela To¨ro¨k
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA
Received 5 June 2007; revised 28 June 2007; accepted 30 June 2007
Abstract—A novel method for the preparation of trifluoroacetaldehyde (fluoral, TFAc, CF3CHO) from commercially available tri-
fluoroacetaldehyde ethylhemiacetal (TFAE) by microwave irradiation is described. The isolation, characterization and reaction of
fluoral with various nucleophiles were studied to verify the diverse applicability of this new method.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
oxidation of trifluoroethanol;14 oxidative nitration of
trifluoropropane;15 and reduction of trifluoroacetyl
chloride.16 Most of these methods required high temper-
atures (ꢀ400–450 °C)17 and were carried out in the va-
por phase. Considering the synthetic importance of
TFAc, developing a low temperature, rapid, and easy
to handle method is highly desirable.
The synthesis of organofluorine compounds has at-
tracted extensive attention over the years.1,2 Their
unique properties make them invaluable in life and
material sciences. Their importance is especially obser-
vable in the pharmaceutical sector, approximately 20%
of all drugs contain at least one fluorine atom. Indeed,
three of the current top 10 best sellers are organofluorine
products.3 The synthesis of these compounds, however,
often raises unexpected difficulties.4
A new synthetic tool, microwave-assisted organic syn-
thesis,18 appears to be a useful synthetic method to reach
the above goal.
Trifluoroacetaldehyde (TFAc, fluoral) is one of the most
important synthons from which compounds containing
trifluoromethyl group can be prepared.5 TFAc is also
frequently utilized in asymmetric synthesis of trifluoro-
methylated compounds.6 Synthetic methodologies using
TFAc have considerable limitations2a due to its trouble-
some handling, harsh preparation conditions, and low
boiling point (À18.8 °C to À17.5 °C).7 Trifluoroacetal-
dehyde ethylhemiacetal (TFAE) is often used as a pre-
cursor for TFAc, though, only in limited applications.8
Continuing our efforts in the field of microwave-assisted
reactions19 and organofluorine chemistry,20 herein, we
report an effective and convenient method for the prep-
aration of TFAc using microwave irradiation. The effi-
ciency of the TFAc generation is also demonstrated in
several reactions.
2. Results and discussion
Preparation of fluoral (TFAc) from trifluoroacetalde-
hyde ethylhemiacetal (Scheme 1) was carried out in a
simple apparatus illustrated in Figure 1. TFAE was
mixed with concd H2SO4, then the reaction vessel was
placed into the microwave reactor and irradiated at
Over the years, several methods were reported for the
preparation of TFAc from TFAE: (i) H3PO4/polyphos-
phoric acid (PPA);9 (ii) P2O5;10 (iii) H2SO4.11 Other ap-
proaches involved the reduction of trifluoroacetic acid
or its esters;12 fluorination of trichloroacetaldehyde;13
OH
OEt
O
conc. H2SO4
Keywords: Trifluoroacetaldehyde; Fluoral; Microwave irradiation;
Trifluoromethylated alcohols.
MW /100 and 150 oC
F3C
F3C
H
*
Corresponding author. Tel.: +1 617 287 6159; fax: +1 617 287
6030; e-mail: bela.torok@umb.edu
Scheme 1. Synthesis of trifluoroacetaldehyde from its ethyl hemiacetal.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.170

S. M. Landge et al. / Tetrahedron Letters 48 (2007) 6372–6376
6373
ture on the formation of TFAc from TFAE. The results
are summarized in Table 1.
The data indicated that gradual increase in temperature
provided the best yield. Using this temperature pro-
gram, we studied the effect of pyrrole/TFAE (used for
TFAc generation) ratios on the probe reaction (Table
2). The results showed that 1:2 ratio provided the best
performance, although, the 1:1, 1:3 and 1:4 ratios also
gave very similar yields. As a result, this ratio was cho-
sen for further reactions. It is worth noting that the 92%
yield obtained at 1:1 ratio indicates that the yield of
TFAc generation is close to quantitative.
Figure 1. Schematic representation of the apparatus used for the
preparation of TFAc and its immediate reaction with nucleophiles.
After optimization of the experimental conditions for
the TFAc generation, we tested our method by carrying
out reactions of TFAc with various nucleophiles. The
above optimized conditions (gradual microwave heat-
ing, and 1:2 nucleophile–TFAE ratio) were applied.
The results are summarized in Table 3.
100 °C and 150 °C for 5 min each to produce the gas-
eous TFAc. To ensure that all TFAc produced was
transferred to another vessel for isolation or further
reaction, dry N2 gas was continuously passed through
the system.
The inert atmosphere protected TFAc from moisture
and hydrate formation. TFAc was condensed and iso-
lated at À78 °C. It was characterized as CF3CHO by
NMR spectroscopy. Both 1H and 19F NMR spectra
indicated the presence of the underivatized trifluoroacet-
aldehyde. The expected quartet was observed for the
formyl H, while a doublet appeared for the CF3 in the
19F NMR spectrum (see Section 4). Our method made
possible the exact determination of the NMR data of
unprotected TFAc that hitherto was known only from
mixtures.21
Further reactions involved Friedel–Crafts hydroxyalkyl-
ation with activated heteroaromatics, couplings with
Grignard reagent, Wittig phosphonium salts, ethyl dia-
zoacetate, and hydroxyalkylation of anilines. The reac-
tions provided excellent yields in most cases. In few
cases the yields were only moderate due to significant
side reactions. The conversion of the starting material,
however, was always excellent indicating that the origi-
nal attempt of producing free TFAc was successful.
Table 1. Effect of temperature on generation of TFAc probed by its
reaction with pyrrolea
We also intended to verify our TFAc preparation meth-
od via chemical reactions. The TFAc/N2 gas mixture
obtained during the irradiation was directly passed into
the adjacent reaction vessel containing a nucleophilic
substrate (Fig. 1). Several nucleophilic substrates were
chosen for these reactions (Scheme 2). The Friedel–
Crafts hydroxyalkylation of pyrrole was selected as a
test reaction. First, we studied the effect of the tempera-
N
H
OH
OEt
O
conc. H2SO4
MW
CF3
OH
N
H
F3C
RT
F3C
H
Entry
Temperature (°C)
Yield (%)b
1
2
3
4
5
70
100
130
150
23
68
70
83
94c
O
O
CF3
OH
O
70–100–130–150
F3C
O
CF3
a TFAE (2.0 mmol), H2SO4 = 2 ml, CH2Cl2 = 1 ml, t = 5 min, MW
power = 200 W; Reaction conditions: pyrrole (1.0 mmol),
CH2Cl2 = 1 ml, rt.
N2CHCOOEt
PhMgBr
b Based on pyrrole, GC yield.
c Gradual increase of temperature in 2 min increments.
CF3
OH
O
CF3
OH
Ar-H
Ar
Ph
F3C
H
Table 2. Effect of pyrrole–TFAE initial molar ratios on the yield of the
hydroxyalkylation reaction of pyrrolea
R'-CH2-PPh3
N
H
Entry
Pyrrole–TFAE
Yield (%)b
1
2
3
4
1:1
1:2
1:3
1:4
92
94
92
91
CF3
R'
N
F3C
OH
a Reaction conditions: pyrrole (1.0 mmol), H2SO4 = 2 ml, CH2Cl2 =
1 ml, T = 70–100–130–150 °C, t = 2 min each step, MW power =
200 W.
Ar = pyrrol-2-yl, 1-methyl-pyrrol-2-yl, indol-3-yl
R' = 4-CF3-C6H4, 4-NO2-C6H4
b Based on pyrrole, determined by GC–MS.
Scheme 2. Reaction of trifluoroacetaldehyde with various nucleophiles.

6374
S. M. Landge et al. / Tetrahedron Letters 48 (2007) 6372–6376
Table 3. Microwave-assisted generation of TFAc and its reaction with nucleophilesa
Substrate
T (°C)(solvent)
Yield (%)b
94
Product
OH
1
2
rt (CH2Cl2)
N
H
N
CF3
H
OH
rt (CH2Cl2)
rt (CH2Cl2)
98
33
N
N
CF3
HO
CF3
3
4
N
H
N
H
CF3
MgBr
rt (Ether)
51
OH
CF3
OH
5
0 °C (CH3NO2) ZnCl2
91c (56:35)
+
O
CF3
CF3
PPh3
PPh3
6
7
8
9
rt (CH2Cl2)
rt (CH2Cl2)
rt (CH2Cl2)
À10 °C (THF)
35d (60:40)e
55d (75:25)e
15f (81% conv)g
60h
F3C
O2N
F3C
F3C
O2N
CF3
O
O
O
N2
O
O
N
N
H
F3C OH
a TFAc generation: TFAE (2.0 mmol), H2SO4 = 2 ml, T = 70–100–130–150 °C (gradual), t = 2 min each, MW power = 200 W; Reaction conditions:
substrate (1.0 mmol), solvent = 1 ml.
b GC yield.
c 56% Trifluoromethylated alcohol, 35% Diels–Alder adduct.
d NaH was added to the benzyltriphenylphosphonium salt and stirred for 1 h prior to reaction with TFAc.
e E:Z ratio.
f Determined by 19F NMR and GC–MS.
g Mixtures of products are formed.
h Determined by 19F NMR.
3. Conclusion
sel technique. The temperature was measured and
increased gradually using an infrared temperature detec-
tor/controller.
In conclusion, a novel microwave-assisted protocol is
developed for the preparation of trifluoroacetaldehyde.
The method produces TFAc efficiently and rapidly,
while it is convenient, easy to handle and operate, and
reproducible. The TFAc generated may be utilized for
the preparation of a wide array of trifluoromethylated
compounds.
Trifluoroacetaldehyde
ethylhemiacetal
(TFAE)
(2 mmol) and 2 ml of concd H2SO4 were added to a
nitrogen flushed vial. The vial was sealed with a plastic
septum and inserted into the microwave cavity, where
it was continuously stirred during the irradiation. The
vial was equipped with an inlet to pass nitrogen gas
through and an outlet for TFAc/N2 gas mixture
(Fig. 1). The outlet was connected to an adjacent reac-
tion vessel containing a nucleophile. The reaction vessel
was equipped with a N2 outlet to avoid pressure build-
up. The TFAE/H2SO4 mixture was then heated gradu-
ally from 70–100–130–150 °C, (power 200 W) for
2 min each. The flowing N2 carried the TFAc gas pro-
duced, directly into the adjacent reaction vessel.
4. General procedures
4.1. Preparation of trifluoroacetaldehyde (TFAc)—gen-
eral procedure
The reactions were carried out in a focused CEM Dis-
cover Benchmate microwave reactor, using the open ves-

S. M. Landge et al. / Tetrahedron Letters 48 (2007) 6372–6376
6375
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The isolation of TFAc was carried out using 3 mmol
TFAE and 2 ml of concd H2SO4. The mixture was irra-
diated at a specified temperature (90 and 150 °C) for
5 min each. The colorless gas produced was passed
through drying agent and condensed directly into an
NMR tube at À78 °C. The isolated TFAc was immedi-
ately mixed with CDCl3, and sealed under N2 flow.
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1
NMR spectra were recorded without delay. H NMR
(300.126 MHz, CDCl3), d (ppm) 9.39 (q, JH–F
=
3.0 Hz, 1H, CH). 19F NMR(282.401 MHz, CFCl3), d
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procedure
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solvent were placed into a 10 ml round-bottomed flask
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produced was passed into the vessel and was further stir-
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nitrogen flow. The progress of the reaction was moni-
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Acknowledgment
Financial support provided by University of Massachu-
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acknowledged.
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