Microwave-assisted aliphatic fluorine-chlorine exchange using triethylamine trihydrofluoride (TREAT-HF)

Article abstract of DOI:10.1016/j.tetlet.2009.03.103

Aliphatic fluorine-chlorine exchange reactions can be performed under microwave conditions using TREAT-HF as a mild and selective fluorination reagent. The highly polar TREAT-HF couples efficiently with microwave irradiation and reaction temperatures of 250 °C can be reached within 30 s. Under these conditions dichloromethyl- and trichloromethyl substrates can be converted into the corresponding fluoro analogs within 5 min. In order to prevent corrosion of borosilicate reaction vessel at high temperatures the use of sintered silicon carbide microwave vials is introduced.

Full text of DOI:10.1016/j.tetlet.2009.03.103

Tetrahedron Letters 50 (2009) 3665–3668
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted aliphatic fluorine–chlorine exchange using triethylamine
trihydrofluoride (TREAT-HF)
Jennifer M. Kremsner a, Michael Rack b, Christian Pilger b, C. Oliver Kappe a,
*
a Christian Doppler Laboratory for Microwave Chemistry (CDLMC), Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
b BASF SE, D-67056 Ludwigshafen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Aliphatic fluorine–chlorine exchange reactions can be performed under microwave conditions using
TREAT-HF as a mild and selective fluorination reagent. The highly polar TREAT-HF couples efficiently with
microwave irradiation and reaction temperatures of 250 °C can be reached within 30 s. Under these con-
ditions dichloromethyl- and trichloromethyl substrates can be converted into the corresponding fluoro
analogs within 5 min. In order to prevent corrosion of borosilicate reaction vessel at high temperatures
the use of sintered silicon carbide microwave vials is introduced.
Received 20 February 2009
Revised 11 March 2009
Accepted 16 March 2009
Available online 20 March 2009
Keywords:
gem-Difluoride
Fluorination
Ó 2009 Elsevier Ltd. All rights reserved.
Microwave irradiation
Pyrazole
Silicon carbide
The fluorination of biologically active molecules often results in
a profound modification of their biological activity.1 Fluorine
atoms incorporated into bioactive compounds can have major ef-
fects on bioavailability and metabolism caused by changes in the
lipophilicity and oxidative stability. In many cases the selective
installation of fluorine into a molecule leads to compounds with
improved binding affinity and/or enhanced physicochemical prop-
erties. In the area of agrochemistry the number of disclosed potent
crop protection agents containing one or more fluorine atoms is
steadily increasing (Fig. 1).
The most widely used technology for introducing fluorine into
organic molecules is fluorine–chlorine exchange.2 While aromatic
halogen exchange is commonly performed at elevated tempera-
tures by nucleophilic substitution using alkaline metal salts as a
fluoride source (Halex reaction),3 the most versatile industrial re-
agent for aliphatic fluorinations is anhydrous hydrogen fluoride.4
However, the low boiling point and high corrosivity of hydrogen
fluoride make it difficult to handle in the laboratory and its high
reactivity additionally causes undesired side reactions. Therefore,
a number of stable hydrogen fluoride-based reagents have been
introduced in recent years in order to overcome the hazards
involved in handling hydrogen fluoride.2 One of these mild fluorina-
tion reagents is triethylamine trihydrofluoride (TREAT-HF,
Et3NÁ3HF, Franz reagent) which has been widely used for introduc-
ing fluorine into organic molecules.5 TREAT-HF is a commercially
available colorless, hygroscopic liquid with a shelf life of at least
one year which has been reported not to corrode borosilicate glass-
ware.5 Although the nucleophilicity of the fluorine ion in TREAT-HF
is relatively low compared to other fluoride ion sources it is high
enough to permit substitution of activated leaving groups under
forcing conditions.5 In the context of our research on heterocyclic
crop protection agents containing gem-difluoromethyl groups
(e.g., Bixafen6 and Isopyrazam,7 Fig. 1) we became interested in
applying TREAT-HF as a thermally stable fluorination reagent in
microwave-assisted aliphatic fluorine–chlorine exchange reactions.
Not unlike ionic liquids,8 the distinctly polar properties of TREAT-
* Corresponding author. Tel: +43 316 3805352; fax: +43 316 3809840.
E-mail address: oliver.kappe@uni-graz.at (C. Oliver Kappe).
Figure 1. Selected fluorine-containing crop protection agents.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.103

3666
J. M. Kremsner et al. / Tetrahedron Letters 50 (2009) 3665–3668
HF appear to make it very suitable as a reagent (and/or solvent) in
microwave-heated transformations.9
Our initial model reaction to study the feasibility of microwave-
assisted aliphatic fluorine–chlorine exchange reactions using
TREAT-HF as the reagent involved the fluorination of dichloro-
methylbenzene (1) to difluoromethylbenzene (2) (Table 1). The
of conversion after 5 min (entry 4), but ultimately 200 °C (1–2 bar)
proved to be the optimum temperature for the difluorination of
dichloromethylbenzene (1) with TREAT-HF. After 5 min full con-
version was achieved with no dichloro starting material 1 or
monofluoro intermediate 3 being observable by HPLC (entry 6).
The selectivity for fluorination was close to 90%, the only remain-
ing product in the crude reaction mixture being benzaldehyde (4)
resulting from the inadvertent hydrolysis of dichloromethylben-
zene (1). Extending the reaction time to 10 min at 200 °C did not
significantly change the product ratio (entry 7) and a further in-
crease of reaction temperature to 220 °C showed no apparent
advantage (entry 8).13 Changing the substrate/reagent ratio did,
however, have a noticeable effect on the product distribution and
conversion. While doubling the concentration of 1 led to incom-
plete conversions, halving the amount of dichloromethylbenzene
(1) under otherwise identical conditions led to some improvement
(compare entries 9 and 10 with entry 4). Since in an industrial con-
text the minimization of reagents and solvents is of considerable
importance the chosen reagent/solvent ratio of 3.8/50 (mmol)
was not changed. For product isolation the reaction mixture was
poured on cold water and was extracted with diethyl ether. Subse-
quent washing of the organic phase with aqueous sodium carbon-
ate (10%) to remove benzoic acid (5) followed by aqueous sodium
bisulfite to remove benzaldehyde (4) provided pure difluorometh-
ylbenzene (2).14
As a second example for probing the efficiency of microwave-
assisted fluorine–chlorine exchange reactions with TREAT-HF the
fluorination of (trichloromethylthio)benzene (6) was investigated
(Table 2). In 2006, selective mono-, di-, or tri-chlorine–fluorine ex-
changes on trichloromethyl groups applying TREAT-HF and related
reagents were reported, with reaction times of several hours at ele-
vated temperatures not being uncommon.15 Our optimization
studies involving microwave-assisted fluorinations of 6 are sum-
marized in Table 2.
As can be seen from the data presented in Table 2, a careful
optimization of the reaction temperature—maintaining the reac-
tion time constant at 5 min—did allow the step-wise generation
of monofluoro- (7, 70 °C, entry 2), difluoro- (8, 160 °C, entry 5),
fluorination of
1
applying the more reactive pyridinium
poly(hydrogen fluoride) complex (Olah’s reagent) was reported in
1997 and required 14 h at room temperature providing a 70%
selectivity for difluorination.10 For the microwave-assisted fluori-
nations using TREAT-HF as reagent/solvent reactions were per-
formed applying controlled single-mode microwave heating in
sealed Pyrex vessels.11 During our optimization studies it became
immediately apparent that the hydrolysis12 1?4 can be a signifi-
cant side reaction to the desired fluorination pathway 1?3?2.
Control experiments established that difluoromethylbenzene (2)
is stable toward hydrolysis under the reaction conditions and that
therefore the formation of benzaldehyde (4) together with trace
amounts benzoic acid (5) is likely to arise from the hydrolysis of
dichloromethylbenzene (1), as a consequence of adventitious
amounts of water being present in the reaction mixture. This
hypothesis was substantiated by deliberately adding excess water
(7 equiv) to the reaction mixture before microwave irradiation. As
expected, under these conditions benzaldehyde (4) was the main
reaction product. Removal of water from commercial TREAT-HF
by azeotropic distillation prior to use with toluene led to signifi-
cant improvements, in particular for samples of TREAT-HF which
had been stored for a long time.
Screening of reaction conditions for the fluorination process
next focused on variations in reaction time and temperature and
the substrate/reagent ratio. The optimum selectivity for fluorina-
tion (vs hydrolysis) was obtained by rapidly heating the reaction
mixture to temperatures between 180 and 200 °C. At 150 °C the
fluorination was incomplete even after 30 min, with significant
amounts of starting material 1 and monofluorination product 3
still being present in the reaction mixture (entries 1 and 2).
Increasing the reaction temperature to 180 °C led to a high degree
Table 1
Optimization of the fluorination of dichloromethylbenzene (1) with TREAT-HF
(50 mmol) under controlled microwave conditions.a
Table 2
Optimization of the fluorination of (trichloromethylthio)benzene (6) with TREAT-HF
(50 mmol) under controlled microwave conditionsa
F
Z
O
H
Cl
Cl
O
OH
TREAT-HF (neat)
S
Cl
Cl
+
S
X
Z
+
TREAT-HF (neat)
S
MW, 150-220 °C, 2-30 min
+
S
Cl
F
2; Z = F
3; Z = Cl
MW, 70-250 °C, 5-15 min
1
4
5
6
7; X = Z = Cl
8; X = F, Z = Cl
9; X = Z = F
10
Entry
1 (mmol)
Temperature (°C)
Time (min)
Product distributionb (%)
1/2/3/4/5
Entry
6 (mmol)
Temperature (°C)
Time (min)
Product distributionb (%)
6/7/8/9/10
1
2
3
4
5
6
7
8
9
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
7.6
1.9
150
150
180
180
200
200
200
220
180
180
10
30
2
5
3
5
10
3
5
5
50/13/32/3/2
13/44/27/13/2
6/60/28/4/2
1/77/9/9/4
2/82/5/9/2
0/89/0/11/0
0/88/0/9/3
1/85/1/10/3
12/41/23/22/2
1/84/4/8/2
1
2
3
4
5
6
7
8
3.7
3.7
3.7
3.7
3.7
3.7
3.7
3.7
70
5
5
5
5
5
5
5
5
51/48/0/0/1
1/94/3/0/2
0/69/28/0/3
0/0/75/17/8
0/1/90/3/6
0/0/51/39/10
0/0/5/82/13
0/0/0/91/9
100
130
180
160
200
230
250
10
a
a
Reaction conditions: single-mode microwave irradiation (Biotage Initiator 8
EXP 2.0, power setting: very high absorbing = 90 W max Power), 2–5 mL sealed
Pyrex microwave vial, 3 mL TREAT-HF (50 mmol), magnetic stirring, external IR
temperature monitoring, reaction time refers to fixed hold time at the set tem-
perature, excluding a ramp time of ca. 1 min.
Reaction conditions: single-mode microwave irradiation (Biotage Initiator 8
EXP 2.0, power setting: very high absorbing = 90 W max Power), 2–5 mL sealed
Pyrex microwave vial, 3 mL TREAT-HF (50 mmol), magnetic stirring, external IR
temperature monitoring, reaction time refers to fixed hold time at the set tem-
perature, excluding a ramp time of ca. 1 min.
b
b
Product distribution refers to relative peak area (%) ratios of crude HPLC–UV
Product distribution refers to relative peak area (%) ratios of crude HPLC–UV
(215 nm) traces. The identity of products 2–5 was established by GC–MS analysis.
(215 nm) traces. The identity of products 7–10 was confirmed by GC–MS analysis.

J. M. Kremsner et al. / Tetrahedron Letters 50 (2009) 3665–3668
3667
and (trifluoromethylthio)benzene (9, 250 °C, entry 8) in remark-
ably high selectivity.14 As expected, an increase in reaction temper-
ature led to a higher degree of fluorination. Diphenyl disulfide (10)
was always present as a by-product in small quantities (1–13%) as
a result of hydrolysis of the perchlorinated thioanisoles to thiophe-
nol followed by subsequent oxidation. Similar to the results de-
scribed in Table 1, (trifluoromethylthio)benzene (9) proved to be
stable under the reaction conditions and did not undergo hydroly-
sis once formed.
During the TREAT-HF mediated fluorination of chloro
derivatives 1 and 6 at high temperatures (>200 °C), we did notice
an apparent corrosion of the Pyrex microwave reaction vials in
the vapor space above the liquid’s surface. Although generally
considered non-corrosive,5,16 TREAT-HF can release hydrogen
fluoride at elevated temperatures and will therefore attack borosil-
icate glass to some extent. In a control study measuring the weight
loss of unused fresh microwave reaction vessels (weight ca. 16.5 g)
after exposure to TREAT-HF under microwave conditions we have
discovered that corrosion occurs even at comparatively low
temperatures (100 °C) and is highly dependent on reaction
temperature and time. While at 100 °C the weight loss after
5 min is already measurable but comparatively small (20 mg),
significant loss of glass was encountered after a 30 min exposure
at 250 °C (500 mg).17 Hydrogen fluoride-mediated vessel corrosion
at these temperatures leads to the formation of gel-type materials,
making an extractive work-up of the reaction mixture
troublesome. In addition, it became apparent that the undesired
hydrolysis phenomena in the fluorinations described above
(see Tables 1 and 2) are likely the result of water being formed
during the corrosion process (SiO2 + 4HF?SiF4 + 2H2O and
SiO2 + 6HF?H2[SiF6] + 2H2O).
We have therefore repeated the fluorination 1?2 in a custom-
made microwave vial made out of sintered silicon carbide
(SiC).18,19 Silicon carbide is not only completely resistant to
TREAT-HF even at 250 °C for prolonged periods of time, but is also
a strong microwave absorber which makes it ideal for performing
microwave chemistry.18 Employing our optimized fluorination
conditions (Table 1, entry 6) the degree of hydrolysis 1?4 could in-
deed be reduced from 11% (Pyrex) to 5% (SiC).
Having access to an extensive data set on microwave-assisted
controlled fluorine–chlorine exchange reaction using TREAT-HF
as comparatively mild fluorination reagent, we subsequently ap-
plied this expertise to the preparation of our desired target struc-
ture, ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate
(12) (Scheme 1). This difluoromethyl-substituted heterocycle is a
key precursor in the preparation of pyrazolyl-carboxamides such
as Bixafen and Isopyrazam which are known to be active fungicidal
ingredients (Fig. 1).6,7 The preparation of 12 by fluorination of the
corresponding dichloro derivative 1120 with TREAT-HF in an auto-
clave at 145 °C (8 h) was recently disclosed in the patent litera-
ture.21 Using microwave irradiation the conditions were rapidly
optimized on a 2.5 mmol scale (2 mL TREAT-HF) to provide the de-
sired difluoromethyl structure 12 within only 5 min reaction time.
At 150 °C (5 min) the crude mixture was still mainly composed of
unreacted starting material 11 while at 200 °C (5 min) both the
starting material and the monofluoro intermediate where present.
Ultimately, reaction temperatures between 230 and 250 °C proved
well suited for the efficient generation of the desired difluoro ana-
log 12. After 5 min full conversion was obtained with minor
amounts (ca. 10%) of ester hydrolysis product 13 being identified
as the only byproduct by HPLC and GC–MS analysis. From a pre-
parative experiment on a 13.5 mmol scale using a 20 mL micro-
wave vial a 69% isolated yield of 12 was obtained.22
Along similar lines, the fluorination of 3-dichloromethylpyraz-
ole 14 to the corresponding difluoro derivative 15 was investigated
(Scheme 1). A recent patent discloses this TREAT-HF mediated fluo-
rination under autoclave conditions (160 °C, 1 h) and the subse-
quent conversion of pyrazole 15 to pyrazolyl-4-carboxamides
using bromination/aminocarbonylation chemistry.23 Applying
sealed vessel microwave heating, optimum conditions for the fluo-
rination 14?15 utilized 170 °C for 5 min, with only trace amounts
of the corresponding aldehyde hydrolysis product being formed.24
In conclusion we have demonstrated that TREAT-HF is a suit-
able reagent for performing efficient aliphatic fluorine–chlorine ex-
change reactions under high-temperature microwave conditions.
Due to the polar and ionic nature of this ionic liquid-like fluorina-
tion reagent high reaction temperatures can be attained rapidly on
exposure to microwave irradiation. This allows a selective step-
wise fluorine–chlorine exchange under highly controlled reaction
conditions. Fluorinations that conventionally require many hours
have been performed in less than 5 min reaction time under micro-
wave conditions. For fluorination processes involving exposure to
TREAT-HF for prolonged time periods at high temperatures micro-
wave reaction vessels made from highly resistant silicon carbide
are a practical alternative.
Supplementary data
Supplementary data (Experimental procedures) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.103.
References and notes
1. (a) Welch, J. T. Tetrahedron 1987, 43, 3123–3197; (b) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; John Wiley & Sons: New
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3. (a) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225–231; (b) Pleschke, A.;
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Chicester, 2005; (b) McClinton, M. A. Aldrichim. Acta 1995, 28, 31–35; (c) Haufe,
G. J. Prakt. Chem. 1996, 338, 99–113.
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6285.
Cl
F
F
Cl
CO2Et
F
F
TREAT-HF (neat)
MW, 250 °C, 5 min
N
N
N
N
CO2Et
+
CO2H
N
N
Me
Me
Me
12
13
11
Cl
F
Cl
F
TREAT-HF (neat)
MW, 170 °C, 5 min
N
N
N
N
Me
Me
15
14
9. We are not aware of any publications describing microwave-assisted fluorine-
halogen exchange reactions using TREAT-HF. For previous reports on the use of
Scheme 1. Fluorination of ethyl 3-(dichloromethyl)-1-methyl-1H-pyrazole-4-car-
boxylate (11) and 3-(dichloromethyl)-1-methyl-1H-pyrazole (14).

3668
J. M. Kremsner et al. / Tetrahedron Letters 50 (2009) 3665–3668
microwave irradiation in conjunction with this reagent for epoxide ring-
opening and C@O to CHCF2 exchange, see: (a) Yu, H-W.; Nakano, Y.; Fukuhara,
pressures (e.g., ca. 10 bar at 250 °C) or repeated vial usage must therefore be
strictly avoided.
T.; Hara, S. J. Fluorine Chem. 2005, 126, 962–966; (b) Akiyama, Y.; Hiramatsu, C.;
Fukuhara, T.; Hara, S. J. Fluorine Chem. 2006, 127, 920–923; (c) Furuya, T.;
Fukuhara, T.; Hara, S. J. Fluorine Chem. 2005, 126, 721–725; (d) Inagaki, T.;
Fukuhara, T.; Hara, S. Synthesis 2003, 1157–1159.
18. (a) Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651–4658; (b)
Kremsner, J. M.; Stadler, A.; Kappe, C. O. J. Comb. Chem. 2007, 9, 285–291.
19. Microwave experiments in SiC vessels closely simulate oil bath experiments
since the penetration of the electromagnetic field into the inner part of the vial
is small. Due to the high thermal conductivity of SiC, rapid heating of the
reaction mixture can nevertheless be obtained, similar to a standard microwave
chemistry experiment. Further details on SiC reaction vessels for use in single-
mode microwave reactors will be reported in subsequent publications.
20. Lantzsch, R.; Jörges, W.; Pazenok, S. PCT Int. Appl. 2005, WO 2005/042468
(Bayer Cropscience AG); Chem. Abstr. 2005, 142, 409463.
10. Saint Jalmes, L. PCT Int. Appl. 1997, WO 9743231 (Rhone-Poulenc Chimie SA,
Fr.) (Chem. Abstr. 1997, 128, 34573).
11. For a recent review with 930 references and a tabular survey of ca. 200
microwave chemistry review articles, books and book chapters, see: Kappe, C.
O.; Dallinger, D. Mol. Diversity 2009(13). doi:10.1007/s11030-009-9138-8.
12. (a) Seper, K. W. In Kirk-Othmer Encyclopedia of Chemical Technology; John Wiley
& Sons: Chicester, 2001; (b) Martin, G. J.; Heck, G.; Djamaris-Zainal, R.; Martin,
M. L. J. Agric. Food Chem. 2006, 54, 10120–10128.
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(Bayer Cropscience AG); Chem. Abstr. 2005, 142, 482038.
13. It should be noted, however, that extremely rapid fluorinations with similar
high selectivities can be achieved by irradiating the reaction mixture with
22. Representative experimental procedure: In a 20 mL sealed Biotage microwave
vial dichloromethyl–pyrazole 1120 (3.200 g, 13.5 mmol) and TREAT-HF (13.9 g,
86 mmol, 14 mL) were heated with stirring to 250 °C for 5 min. After cooling,
the content of the reaction vessel was poured on water and the aqueous
mixture was extracted with MTBE. The organic phase was washed with water,
1 N HCl, and saturated aqueous NaCl solution and dried over MgSO4. Removal
of the solvent provided 1.90 g (69%) of difluoromethyl–pyrazole 12 as a light
brown powder (>90% purity by HPLC at 215 nm). 1H NMR (CDCl3, 360 MHz): d
1.37 (t, J = 7.1 Hz, 3H), 3.98 (s, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.12 (t, J = 54.0 Hz,
1H), 7.91 (s, 1H), MS (EI, 70 eV): m/z = 204, mp = 58–59 °C.
constant 300 W of microwave power for 30 s. This leads to
a maximum
monitored reaction temperature of 250 °C as a result of the high microwave
absorptivity of the polar TREAT-HF reagent/solvent (Refs. 8,9).
14. Isolated yields on experiments carried out on a comparatively small scale were
only moderate (50–60%) as
a consequence of the high volatility of the
fluorinated product. See also: (a) Kitazume, T.; Ebata, T. J. Fluorine Chem. 2004,
125, 1509–1511 (compound 2); (b) Pooput, C.; Dolbier, W. R., Jr.; Medebielle,
M. J. Org. Chem. 2006, 71, 3564–3568 (compound 9).
15. Saint-Jalmes, L. J. Fluorine Chem. 2006, 127, 85–90.
16. Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.; Izawa, K. Tetrahedron
Lett. 2001, 42, 2321–2324.
23. Zierke, T.; Reinheimer, J.; Rack, M.; Smid, S. P.; Altenhoff, A. G.; Schmidt-
Leithoff, J.; Challand, N. PCT Int. Appl. 2008, WO 2005/145740 (BASF SE); Chem.
Abstr. 2008, 150, 1454365.
17. CAUTION! Corrosion of microwave vials during usage represents a serious
safety risk as the pressure rating of the heavy-walled vials (20 bar) will not be
maintained. Prolonged exposure of TREAT-HF at high temperatures and
24. The fluorination was performed on an unseparable mixture of the 3-
dichloromethyl pyrazole 14 and its 5-dichloromethyl isomer. See
Supplementary data for more details.