2,2-Difluoro-1,3-dimethylimidazolidine (DFI). A new fluorinating agent

Article abstract of DOI:10.1039/b204471d

2,2-Difluoro-1,3-dimethylimidazolidine (DFI) is a new deoxo-fluorinating agent that is useful for the conversion of alcohols to monofluorides, and aldehydes/ketones to gem-difluorides under mild conditions.

Full text of DOI:10.1039/b204471d

2,2-Difluoro-1,3-dimethylimidazolidine (DFI). A new fluorinating agent†
a
b
a
c
Hidetoshi Hayashi,* Hiroshi Sonoda, Kouki Fukumura and Teruyuki Nagata
a
Catalysis Science Laboratory, Mitsui Chemicals, Inc., 580-32 Nagaura, Sodegaura, Chiba 299-0265,
Japan. E-mail: Hidetoshi.Hayashi@mitsui-chem.co.jp Kouki.Fukumura@mitsui-chem.co.jp
Process Technology Laboratory, Mitsui Chemicals, Inc., 30 Asamuta-machi, Omuta, Fukuoka 836-8610,
Japan. E-mail: Hiroshi.Sonoda@mitsui-chem.co.jp
Process Technology Laboratory, Mitsui Chemicals, Inc, 580-32 Nagaura, Sodegaura, Chiba 299-0265,
Japan. E-mail: Teruyuki.Nagata@mitsui-chem.co.jp
b
c
Received (in Cambridge, UK) 9th May 2002, Accepted 10th June 2002
First published as an Advance Article on the web 1st July 2002
2,2-Difluoro-1,3-dimethylimidazolidine (DFI) is a new
Table 1 Chemical properties of DFI 1
deoxo-fluorinating agent that is useful for the conversion of
alcohols to monofluorides, and aldehydes/ketones to gem-
difluorides under mild conditions.
Appearance
Boiling Point
Melting Point
Density
Clear liquid
47 °C/37 mmHg
28.7 °C
1.096
Organofluorine compounds have received much attention due
to their unique physical/chemical properties that may give rise
to useful biological activities or novel characteristics. Deoxo-
fluorination is one of the practical methods to prepare fluorine
containing compounds; hydroxy groups can be converted to the
corresponding fluorides, e.g., alcohols to fluorides, carboxylic
acids to carbonyl fluoride, aldehydes/ketones to gem-di-
fluorides. In order to make it more useful, the fluorinating
reaction should be highly selective and the agents should be
easily handled. So far, in recent years, various deoxo-
fluorinating agents have been developed to cope with these
demands.
Flash Point
Exothermic starting point
(ARC)
40 °C
150.5 °C
filtration of the potassium chloride by-product and the po-
tassium fluoride (used in excess for the halogen exchange
reaction), DFI is easily isolated from the reaction mixture by
distillation. DFI can be also used for the fluorinating reaction,
without the need for isolation by distillation, in the solvent used
for its preparation. CDC is prepared by the reaction of DMI with
chlorinating reagents, such as phosgene, oxalyl chloride, in
2-Chloro-1,1,2-trifluoroethyldiethylamine
(Yarovenko
solvent.
6
1
2
agent), and hexafluoropropyldiethylamine (Ishikawa agent)
have been demonstrated to convert alcohols to fluorides and
carboxylic acids to carbonyl fluorides. However, these reagents
do not normally react with aldehydes and ketones, and do not
have enough stability on storage.
DFI can be stored, for example in PFA bottles at atmospheric
pressure under inert gas. The thermal decomposition profile of
DFI has been examined by accelerating rate calorimetry (ARC).
Thermal decomposition begins at 150 °C. DFI is much more
thermally stable than other typical deoxofluorinating agents,
such as DAST and Deoxo-Fluor.
DFI has broad applicability for the preparation of organo-
fluorine compounds. The fluorination of organic substrates with
DFI is summarized in Table 2.
DFI reacts with primary alcohols, secondary alcohols and
tertiary alcohols to afford alkyl fluorides in good yield under
mild conditions. In some cases, dehydrofluorinated products
are obtained. The hydroxy groups of substituted phenol can be
replaced with fluorine by DFI. For example, DFI reacts with
4-nitrophenol to afford 4-fluoronitrobenzene. However, fluor-
obenzene cannot be obtained by the reaction of DFI with
phenol. In this case, the formation of 1,3-dimethyl-2-phenox-
yimidazolinium hydrogenfluoride is observed.
DFI reacts with carboxylic acids to afford acyl fluorides
under mild conditions in good yield. Conversion of carboxy
group into a trifluoromethyl group is reported when benzoic
acid is heated with DAST in the presence of sodium fluoride at
80 °C for 20 h. However, the fluorination of benzoic acid with
DFI does not give trifluoromethylbenzene under the same
reaction conditions.
Reaction of aldehydes and ketones with DFI affords gem-
difluoro compounds in moderate to high yields under mild
Side reactions, the formation of alkyl vinyl
fluorides and alkyl acetylene, occur in the reaction of DFI with
Diethylaminosulfur trifluoride (DAST) is known as an
excellent fluorinating agent. It is easily handled compared with
3
other fluorinating agents such as HF and sulfur tetrafluoride,
and is useful for replacing hydroxy group and carbonyl oxygens
with fluorine under very mild conditions. However, the
preparation of DAST, the reaction of highly reactive sulfur
tetrafluorides with dimethylaminotrimethylsilane, requires spe-
cial care at a low temperature. Thus, a specific manufacturing
facility is required. As to safety, thermal decomposition has
been reported at about 90 °C with gas evolution.4 Bis(2-
7
TM 5
methoxyethyl)aminosulfur trifluoride(Deoxo-Fluor ) is re-
ported as a deoxofluorinating agent that is much more thermally
stable than DAST and very effective alternative to DAST.
These fluorinating agents developed so far are effective for
laboratory scale reactions but are not satisfactory for industrial
practices. A fluorinating agent for oxygen-containing functional
groups has not yet satisfactorily been developed for use in
industry from the point of view of the preparation process,
selectivity, yield, and economy.
3
Now, we report here a new fluorinating agent DFI that is
applicable for the practical transformation of oxygen-contain-
ing functional groups to the corresponding fluorides. The
fluorinating reaction requires no specific equipment or tech-
nique and can be carried out safely and with ease. The chemical
properties of DFI are summarized in Table 1.
8
conditions.
carbonyl compounds containing a-hydrogen. For example, DFI
2,2-Difluoro-1,3-dimethylimidazolidine (DFI) is prepared by
way of the halogen exchange reaction of 2-chloro-1,3-dimethy-
limidazolinium chloride (CDC) with spray-dried potassium
fluoride (sd KF) in solvent, such as 1,3-dimethyl-2-imidazolidi-
none (DMI), acetonitrile, at 80–90 °C (Scheme 1). After
†
Electronic supplementary information (ESI) available: experimental data.
See http://www.rsc.org/suppdata/cc/b2/b204471d/
Scheme 1 Preparation of DFI 1.
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Table 2 Fluorination of model compounds with DFI 1
by the halogen exchange reaction of CDC with spray dried KF.
If the same solvent is to be used for the preparation of DFI and
fluorination conducted by DFI, DFI need not to be isolated by
distillation from the reaction mixture. So the preparation
process of organofluorine compounds can become very simple.
Other fluorinating agents, such as PPDA, DAST, Deoxo-Fluor
cannot be recovered following the fluorinating reaction in the
form of their raw materials. So from the economical and
industrial point of view, fluorination by DFI is very useful for
the preparation of organofluorine compounds.
Yield
(%)
a
Entry Reactants
Conditions
(1.0 equiv.)
Products
1
Acetonitrile
1
2
25 °C, 1 h
87
1
(1.0 equiv.)
CH Cl 25 °C,
6 h
2
2
15 (A)
83 (B)
1
Several DFI analogues can be obtained by a synthetic method
similar to that for DFI. First step, the preparation of tetraalkyl-
chloroformamidinium chloride by the chlorinating reaction of
tetraalkylurea with chlorinating agent, and second step, the
preparation of bis(dialkylamino)difluoromethane which is a
DFI analogue, by the halogen exchange reaction of tetraalkyl-
chloroformamidinium chloride with spray dried KF. DFI
analogues which we have already synthesized are, for example,
bis(dimethylamino)difluoromethane (2), bis(di-n-butylamino)-
difluoromethane (3), 1,3-di-n-butyl-2,2-difluoroimidazolidine
1
(2.0 equiv.)
3
4
Acetonitrile
85 °C, 15 h
62
82
1(1.6 equiv.)
Acetonitrile
85°C, 8 h
1
(2.0 equiv.)
5
6
glyme 85 °C,
6
21 (A)
72 (B)
h
(
4) (Scheme 3). These DFI analogues are expected to have
different chemical properties, such as reactivity, selectivity in
the fluorinating reaction and thermal stability, in comparison
with DFI. The fluorinating reaction of oxygen-containing
functional groups conducted by these DFI analogues are now
under investigation. We are now attempting to synthesize
another DFI analogue and to investigate chemical properties.
1(2.4 equiv.)
Acetonitrile
15 (A)
85 (B)
85 °C, 8 h
1
(2.0 equiv.)
7
Acetonitrile
5 °C, 7 h
Determined by gas chromatography.
8
96
a
Scheme 3 DFI analogues.
reacts with cyclohexanone to afford 1,1-difluorocyclohexanone
and 1-fluorocyclohexene in the ratio of 23+77. If the desired
products are gem-difluoro compounds, hydrogen fluoride is
added to the reaction mixture to afford gem-difluoro compounds
exclusively. DFI reacts with 4-alkoxyacetophenone to afford a-
fluoro-4-methoxystyrene and 4-methoxyphenylacetylene in the
ratio of 15+85. The mechanism of the formation of alkyl
acetylene and alkyl vinyl fluorides has not yet been deter-
mined.
DFI can be recovered after the fluorinating reaction in the
form of DMI, and this DMI can be reused for the raw materials
of DFI. DMI can be recycled in the fluorinating reaction
conducted by DFI. The recycling system of DMI in the
fluorinating reaction by DFI is shown in Scheme 2. After the
fluorinating reaction, DFI turns into DMI. Then CDC is
prepared by the chlorinating reaction of DMI with a chlorinat-
ing agent, such as phosgene. And after that, DFI can be obtained
In summary, we have developed a new fluorinating agent,
DFI which is very effective for deoxo-fluorination reactions,
much more thermally stable than other deoxo-fluorinating
agents, and can be easily prepared and used in industry. Detailed
studies of reactivity are now in progress.
Notes and references
† Electronic supplementary information (ESI) available: experimental data.
See http://www.rsc.org/suppdata/cc/b2/b204471d/
1
2
3
N. N. Yarovenko and M. A. Raksha, Zh. Obshch. Khim., 1959, 29,
159.
A. Takaoka, H. Iwakiri and N. Ishikawa, Bull. Chem. Soc. Jpn., 1978, 51,
267.
W. J. Middleton, J. Org. Chem., 1975, 40, 574; L. N. Markovskij, V. E.
Pashinnik and A. V. Kirsanov, Synthesis, 1973, 787; M. Hudlicky, Org.
React., 1988, 35, 513.
2
1
4
5
P. A. Messina, K. C. Mange and W. J. Middleton, J. Fluorine. Chem.,
1
989, 42, 137.
G. S. Lal, G. P. Pez, R. J. Pesaresi and F. M. Prozonic, Chem.Commun.,
999, 215; G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic and H.
1
Cheng, J. Org. Chem., 1999, 64, 7048; G. S. Lal, E. Lobach and A. Evans,
J. Org. Chem., 2000, 65, 4830; R. P. Singh, U. Majumber and J. M.
Shreeve, J. Org. Chem., 2001, 66, 6263.
T. Mukaiyama, T. Isobe, M. Kato, M. Miyagaki and S. Kogo, Jpn. Kokai
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6
7
1
999, 64, 6984.
Typical procedure: DFI was added slowly to a solution of alcohol in an
inert solvent in a nitrogen atmosphere at temperatures and for times
indicated. The fluorinated products were isolated by pouring the reaction
mixture into an aqueous solution of sodium carbonate, and then
separating, drying, and distilling the organic layer.
8
Typical procedure is similar to that of fluorination of alcohols which is
mentioned above. DFI was added slowly to a solution of carbonyl
compounds in an inert solvent in a nitrogen atmosphere at temperatures
and for times indicated. The fluorinated products were isolated by
pouring the reaction mixture into an aqueous solution of sodium
carbonate, and then separating, drying, and distilling the organic the
organic layer.
Scheme 2 The recycling of DMI in the fluorinating reaction by DFI.
CHEM. COMMUN., 2002, 1618–1619
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