Co-thermolysis: A one-pot synthetic method for novel 2-substituted-5- (trifluoromethoxy)thiophenes

Article abstract of DOI:10.1016/j.tetlet.2010.07.111

A new 'green' process to obtain trifluoromethoxylated compounds by a gas-phase method has been accomplished. Through it, new 2-substituted-5- (trifluoromethoxy)thiophenes have been obtained in moderate to good yields. Though the reaction occurs in the gas-phase and radicals are involved, an electron transfer mechanism is also postulated to explain the appearance of all detected products.

Full text of DOI:10.1016/j.tetlet.2010.07.111

Tetrahedron Letters 51 (2010) 5242–5245
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Co-thermolysis: a one-pot synthetic method for novel
2-substituted-5-(trifluoromethoxy)thiophenes
*
W. J. Peláez, G. A. Argüello
INFIQC—Departamento de Físico Química, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A new ‘green’ process to obtain trifluoromethoxylated compounds by a gas-phase method has been
accomplished. Through it, new 2-substituted-5-(trifluoromethoxy)thiophenes have been obtained in
moderate to good yields. Though the reaction occurs in the gas-phase and radicals are involved, an elec-
tron transfer mechanism is also postulated to explain the appearance of all detected products.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 June 2010
Accepted 20 July 2010
Available online 25 July 2010
Organic fluorine compounds often show unusual properties and
behavior in comparison with non-fluorinated parent compounds.1
The introduction of fluoroalkyl groups is not an easy task, since the
usual methods for alkylation cannot be applied due to the high
electronegativity of the fluorinated group. Especially, an explora-
tion of electrophilic perfluoroalkylating and perfluoromethoxylat-
ing agents is desired since reactions involving a perfluoroalkyl
cation as an intermediate are very limited.2
OCH3
OCCl3
OCF3
HF + BF3 or
a)
SbF3 + SbCl5
R
R
R
HF + C5H5N
b) RO-C(S)-SCH3
RO-CF2-SCH3
RO-CF3
Br
N
O
N
O
The chlorination/exchange sequence is routinely used for the
preparation of trifluoromethoxy-substituted arenes. The displace-
ment of the heavier halogen (Cl) by the lighter one (F) can be brought
about with anhydrous hydrogen fluoride in the presence of a cata-
lytic amount of boron trifluoride or with antimony trifluoride in
the presence of antimony pentachloride (Scheme 1a)3,4 and is com-
patible with substrates carrying electron-withdrawing groups. The
trifluoromethoxy arenes are obtained in yields ranging from 9% to
80%. Other method has been disclosed, when dithiocarbonates (xan-
thogenates) are exposed to a huge excess of hydrogen fluoride–pyr-
idine and 1,3-dibromo-5,5-dimethylhydantoine, Scheme 1b.5,6
Reagents containing fluorine bonded to a heteroatom (X–F) are
highly reactive because of the lone pair electron repulsion between
them; for that reason, they have been employed effectively to
introduce either X or F to target molecules. The relative electron-
withdrawing nature of X compared to F will determine which
one will be the reactant group. Typical fluorine-activated electro-
philic reagents are F–Cl, F–Br, F–I, and F–PhSe. On the other hand,
reactants that yield F-derivatives (electrophilic fluorinating re-
agents) are F–F, AcO–F, CF3CO2–F, R3N+–F, and Py+–F.
Br
OR
O
F
OR
OR
F
OR
O
OR
CF3OF
CF3OF
c)
Freon 11
-78°C
OR
OR
OR
Scheme 1. Synthesis of trifluoromethyl aryl/alkyl ethers and fluorinated aromatics
rings.
The reaction goes through the attack of the fluorine atom to the
aromatic ring through a typical electrophilic aromatic substitution,
Scheme 1c. This behavior is attributable to the strong electron-
withdrawing capacity of the trifluoromethoxy group which is, to-
gether with the FCO group, one of the very few moieties with more
electron-withdrawing capacity than the F atom.7
In this work, we present the direct synthesis of 2-substituted-
5-(trifluoromethoxy)thiophenes by
a co-thermolysis between
bistrifluoromethyl peroxide CF3OOCF3 (BTMP, 2) and 2-substi-
tuted-thiophenes. The pyrolysis of bistrifluoromethyl peroxide is a
complex reaction initiated by CF3O radicals. Descamps and Forst8 re-
ported that the overall rate constant involves at least three different
reaction steps, which are the initial fragmentation of BTMP into two
radicals, their recombination, and the disproportionation to CF2O
and CF3OF, Scheme 2.
The electrophilic addition of CF3OF to aromatic compounds has
been found to produce mono-fluorinated compounds instead of tri-
fluoromethoxylated derivatives.
Therefore, the purpose of this work is to scavenge CF3O radicals
with 2-substituted thiophenes, in order not to measure the kinetics
but to explore new synthetic ways to obtain perfluoromethoxylat-
* Corresponding author. Tel.: +54 351 433 4169; fax: +54 351 433 4188.
E-mail address: gaac@fcq.unc.edu.ar (G.A. Argüello).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.111

W. J. Peláez, G. A. Argüello / Tetrahedron Letters 51 (2010) 5242–5245
5243
k
k
k
for compound 3a, its concentration doubles at 15 min, as should be
expected for a simple reaction. Nevertheless, the increase in poly-
meric products is even greater, suggesting that they come from the
decomposition of 6 which is unstable at the reaction temperature,
(Table 1 and Scheme 3).
1
2
CF3OF
+ CF2O
CF3OOCF3
2 CF3O
k
-1
-2
1a, R = -H
1b,R = -CH3
-I
R
S
1c, R =
In the case of 2-iodo-thiophene 1c, the reaction yields even
more interesting compounds depending on the reaction time.
At short reaction times, the main products are the correspond-
ing trifluoromethoxy-thiophene 3c and 2,5-di-iodo-thiophene 11,
(Table 1 and Scheme 4).
CF3O
R
S
Scheme 2. Scavenge of CF3O radicals by co-thermolysis with thiophenes.
In order to verify that compound 11 is formed as a consequence
of 2 being present in the reaction, compound 1c was reacted with
and without iodine at 200 °C. In both cases only the unreacted
material was recovered, meaning that the formation of 11 occurs
only in the presence of bistrifluoromethyl peroxide 2 and that this
reaction competes with the formation of 3c.
All the reactions were performed with a 1:1 ratio of reagents
except the very last one. After 15 min, nearly 10% of 2-iodo-
thiophene 1c was recovered. The main products were 2-iodo-triflu-
oromethoxy-thiophene 3c and di-iodo-thiopene 11. The quantity
of 11 is almost the same as that at 10 min of reaction; but after
20 min, 11 goes down in concentration, while 3c increases (though
the amount of remaining reagent 1c is very low). Therefore, we
propose that 11 is reacting to afford 3c, as Figure 1 shows through
the increase in slope for its production after around 15 min.
Other interesting products start to appear, though in low yield,
after 15 min of reaction. Compounds 12 and 13 would be formed
through the same mechanism as for 11, and could be responsible
for the generation of 15 and 16. Besides, 14 affords a mixture of
17 and 18.
ed compounds in a direct one-pot gas-phase reaction, as opposed
to the many steps and reagents required in the reactions shown
in Scheme 1a and b that have been the benchmarks for CF3O rad-
ical insertion.
Co-thermolysis has been performed by heating the mixture of
BTMP 2 (CF3OOCF3) and the corresponding 2-substituted thio-
phenes (1a–c) at 200 °C. The reactions were performed at this tem-
perature because both reactants are in gas-phase; we previously
verified that compounds 1a–c stay unreacted at these conditions.
It is well known that the symmetric peroxide decomposes slowly
in CF3O radicals under heating.9 Nevertheless, when we carry out
the reactions, a pronounced acceleration was observed in the
decomposition of 2. Thus, 2-substituted-5-trifluoromethoxy-thio-
phenes were obtained in 10–67% yields as revealed by GC/MS anal-
yses carried out on the crude of the reactions after appropriate
solvent extraction.10
Particularly, the co-thermolysis reaction of thiophene 1a and
2-methyl-thiophene 1b yielded some undesired amounts of
polymers as well as other compounds, besides the trifluorometh-
oxy-thiopenes 3a,b (in 9% and 22% yields, respectively). There is
also an increase in the concentration of products with time. In fact,
The possible reaction mechanisms for the synthesis of the main
products are given in Scheme 5a. The path labeled A suggests a
Table 1
Reaction of thiophenes 1a–c with bistrifluoromethyl peroxide (BTMP) at 200 °C
Compd
Time (min)
Percentages obtained in the gas-phase reaction
1
3
4,5
6
7
8
9
10
11
12
13
14
15
16
17,18
a, H
5
15
10
5
10
15
20
15*
95.1
—
66.4
85.9
56.7
7.1
4.3
9.1
21.5
5.3
19.8
37.7
67.3
15.7
—
0.6
0.4
—
—
—
—
—
—
—
0.2
—
—
—
—
—
—
—
—
9.5
—
—
—
—
—
—
—
0.4
—
—
—
—
—
—
—
0.9
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0.3
1.3
0.4
1.4
3.5
2.9
1.2
b, CH3
c, I
8.4
22.0
21.9
6.3
—
—
—
—
—
—
4.0
2.9
—
10.2
3.0
0.6
4.0
0.4
0.7
3.5
8.4
—
3.2
5.2
—
5.0
2.4
—
1.7
46.7
35.1
*
Ratio of reactants 1c to 2 1:0.5.
OCF3
2
H
CF3O
H
OCF3
+
+
+
H
H
H
O
CF
3
CF3O
CF3O
S
S
S
S
S
7
1a
3a
4a
6
CF3O
OCF3
CH3
2
+
+
+
CH3
CH3
CH3
CH2OCF3
CF3O
S
1b
S
S
4b
S
5b
S
8
3b
S
CH3
+
H3C
S
CH2OCF3
F3CO
S
9
10
Scheme 3. Reaction of thiophene 1a,b with BTMP 2 at 200 °C.

5244
W. J. Peláez, G. A. Argüello / Tetrahedron Letters 51 (2010) 5242–5245
CF3O
I
OCF3
I
I
I
+
+
CF3O
S
I +
I
I
I
OCF3
18
CF3O
CF3O
S
S
S
S
S
3c
5c
4c
15
16
2
2
2
2
2
I
I
I
I
2
+
+
+
I
I
I
I
I
CF3O
17
S
S
S
S
S
S
1c
11
12
13
14
Scheme 4. Synthesis of trifluoromethoxy iodo thiophenes by co-thermolysis of 1c with BTMP 2.
Mechanism B is an electron transfer process from the substrate
to peroxide 2 to give a radical cation and a radical anion (19),
which decompose into trifluoromethoxyl radical and trifluorome-
thanolate, respectively. The trifluoromethoxyl radical should
recombine with the heterocyclic-radical cation to give trifluoro-
methoxylated compounds, as shown in Scheme 5. However, this
path could be thermodynamically unfavorable, because the reac-
tions are carried out in gas-phase. Nevertheless, gas-phase acyla-
tion of simple five-membered heteroarenes12 and reactions of
some peroxides with thiophene and furan via an electron transfer
process where acceleration was observed have been reported.13,14
MO calculations showed that the higher the electron-withdraw-
ing ability of the substituent, the lower the O–O antibonding en-
ergy level. Thus, the electron transfer (ET) should occur faster.12
In our case, due to the high electron-withdrawing ability of the
trifluoromethoxyl group, the ET process should be fast and the
reaction through path B should predominate over path A.
In addition, path B could explain the regioselectivity in the
formation of the main products; while in a free-radical reaction a
low regioselectivity is expected.13
Figure 1. Relative concentration of compounds 1c, 3c, and 11 against time at
200 °C.
On the other hand, if the reaction proceeds through a free-rad-
ical process, the rate-determining step should be the fragmenta-
tion of peroxide 2 in two CF3O radicals and its rate should not be
accelerated by the presence of thiophenes. In fact, the rate of
decomposition was accelerated by around one order of magnitude,
as it can be seen in Figure 2.
free-radical character for this reaction, initiated by the attack of the
CF3O radicals on 2-substituted thiophenes as expected. Neverthe-
less, another path could be postulated (B).
a)
- H
A
CF3O
R
H
S
R
S
CF3O
2 CF 3O
3a-c
-
CF3OH
R
S
CF3O
(CF3O)2
CF3OOCF3
1a-c
H
CF3O
19
R
S
CF3O
R
CF3O
B
S
20
R= I
I
b
b)
I
I+
a
2
S
b
OCF 3
+
CF3OI
21
S
18
CF3O
I
I
S
3c
a
S
14
CF3O
CF3O
+
CF3O
S
17
I
S
2
I
I
I
I
+
2
+
+
I
I
CF3O
CF3O
I
I
I
I
S
S
S
S
S
16
15
13
12
11
Scheme 5. Reaction mechanisms for the trifluoromethoxylation of thiophenes. The lower part applies only to 1c.

W. J. Peláez, G. A. Argüello / Tetrahedron Letters 51 (2010) 5242–5245
5245
In summary, we have been able to show that the gas-phase
reaction of fluorinated peroxides opens new synthetic paths to
the attainment of products that are either difficult to obtain
through more conventional and cumbersome fluorination methods
or completely new. There is, of course, a need for rigorous and
detailed study of the many possibilities about changing the reac-
tion’s conditions to improve the selectivity as well as the yield of
the desired products.
0
-1
-2
-3
-4
Ln(Ct/Co) vs t (s)
2 at 200°C
k= -(3.91+0.07)10-4s-1
Acknowledgments
Ln(Ct/Co) vs t (s)
2+1c at 200°C
The work at the Instituto de Fisicoquímica de Córdoba (INFIQC)
was supported by Consejo Nacional de Investigaciones Científicas y
Técnicas (CONICET), Fondo para la Investigación Científica y Tec-
nológica (FONCyT), and Secretaría de Ciencia y Tecnología (Se-
CyT—UNC).
k= -(1.96+0.03)10-3s-1
0
2
4
6
8
10
12
time (s, 10-2)
Figure 2. Temporal variation of concentration of 2 both in the absence and in the
presence of 1c as seen through gas-phase IR spectroscopy.11
Supplementary data
Supplementary data (experimental procedures and CG–MS
characterization of all compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2010.07.111.
Conclusive evidence in favor of path B is the experimental run
shown in the last row of Table 1. With a reagent’s ratio (1c to 2)
of 1:0.5, the starting material was recovered in amounts of 47%,
in contrast to the observed 7% for a 1:1 ratio. This can be rational-
ized only if the reaction proceeds through this particular process
with the CF3O radical being formed from the radical anion 19,
which is not equimolar to 1c. The trifluoromethanolate anion
immediately abstracts the H atom forming CF3OH and the system
recovers aromaticity. The CF3OH was not detected due to its fast
decomposition into CF2O and HF, both of them experimentally de-
tected in the reaction mixture. Had the reaction occurred exclu-
sively through path A, the CF3O radicals would equal the amount
of 1c molecules; thus, they should have reacted completely, giving
products 3, 4, and 5 with a low regioselectivity.
In order to explain the other compounds obtained from 1c, on
the basis of an ET mechanism, we propose that the counterpart
of 19, that is, the radical cation 20 decomposes into thienyl radical
and iodine cation, Scheme 5b. Recombinations of these species af-
ford CF3OI (21), 3c, and 14. The CF3OI is a powerful electrophilic
species, like CF3OF,7 and reacts with the available 1c to give 11,
12, and 13, through an electrophilic aromatic substitution. These
diiodinated derivatives react with 2 to yield the other fluorinated
compounds.
References and notes
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2000, 73, 471–484.
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a Shimadzu GC–MS-QP 5050
spectrometer equipped with a VF column, using helium as eluent at a flow
rate of 1.1 mL/min with a heating ramp of 15 °C/min from 50 °C to 280 °C.
11. Gas-phase Infrared spectra were recorded at room temperature with a Bruker
IFS-28 FT IR spectrometer.
12. Filippi, A.; Ochiucci, O.; Sprapani, C.; Speranza, M. Can. J. Chem. 1991, 69, 740–
748.
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