Technical Field
[0001 ] The present invention relates to a process for producing
α-trifluoromethyl-α,|3-unsaturated esters, which are important as intermediates for
pharmaceutical and agricultuial chemicals
Background Art
[0002 ] It is known that α-trifluoromethyl-α,β-unsaturated esters are important
as intermediates for pharmaceutical and agricultural chemicals There have been
reported, as conventional production techniques relevant to the present invention,
dehydration processes that use thionyl chloride (SOC12), diphosphorus pentaoxide
(P2O5), acetic anhydride [(CH3CO)2O] and trifluoromethanesulfonic acid
anhydride [(CF3SO2)2O] as dehydrating agents (see Non-Patent Documents 1 to 6
and Patent Document 1) Among others, the process using the
trifluoromethanesulfonic acid anhydride is applicable to even raw substrates in
which the acidity of the β-position proton is low (whereby the desired reaction is
unlikely to proceed) and is thus regarded as one most superior process
[0003 ] Further, the present applicant has disclosed a process of
dehydroxyfluorination of an alcohol with the combined use of sulfuryl fluoride
(SO2F2) and an organic base (see Patent Document 2)
Prior Art Documents
Patent Documents
[0004 ] Patent Document 1 U S Patent Application Publication No
2006/0004195
Patent Document 2 Japanese Laid-Open Patent Publication No
2006-290870
Non-Patent Documents
[0005 ] Non-Patent Document 1 Mendeleev Communications (Russia), 2006, P
175-177
Non-Patent Document 2 Izvestiya Akademi Nauk, Senya
Khimicheskaya (Russia), 1992, P 2617-2623
Non-Patent Document 3 Journal of Fluorine Chemistry (Netherlands),
1991, Vol 51, P 323-334

Non-Patent Document 4 Zhurnal Organicheskor Khimn (Russia), 1989,
Vol 25, P 2523-2527
Non-Patent Document 5 Journal of Fluorine Chemistry (Netherlands),
1982, Vol 21, P 377-384
Non-Patent Document 6 Journal of the Chemical Society (UK), 1961,
P 4519-4521
Disclosure of the Invention
[0006 ] It is an object of the present invention to provide a practical production
process of an α-trifluoromethyl-α, β-unsaturated ester In order to achieve the
object of the present invention, it is necessary to solve problems in the prior art
techniques
[0007 ] The processes of Non-Patent Documents 1 to 6 aie limited to
applications where the P-proton of the raw substrate is high in acidity due to the
presence of a neighboring electron attracting group, and a leaving group of the
reaction intermediate (derived from a hydroxyl group of the raw substrate) can be
readily eliminated by the electron pushing effect of the conjugated system The
applicable substrate ranges of the processes of Non-Patent Documents 1 to 6 are
very narrow
[0008 ] On the other hand, it is said that the process of Patent Document 1 has a
wide applicable substiate range There is however no disclosure in Patent
Document 1 about the specific reaction conditions and yield in the case of using
α-trifluoromethyl-α-hydroxyesters as raw substrates as in the case of the present
invention (It is merely stated in this patent document that the reaction is
performed under conditions similar to those specified for typical reaction
schemes ) Follow-up experiment has hence been conducted on the dehydration of
the target substrate of the present invention, α-trifluoromethyl-α-hydroxyesters,
under the suitable reaction conditions of Patent Document 1 (dehydrating agent
trifiuoromethanesulfonic acid anhydride, base pyridine, reaction solvent
methylene chloride, temperature range 0 to 35°C) The results of the follow-up
experiment however show that the yield of the reaction is very low (see the
after-mentioned Comparative Example 1 of TABLE 1 and Comparative Example 4

of TABLE 2) The cause for such a low yield is a very slow rate of elimination
from the reaction intermediate to the target product (see Scheme 1) Thus, it can
hardly be said that the process of Patent Document 1 is practical for production of
α-trifluoromethyl-α,β-unsaturated esters
[0009] [Chem 1]
Scheme 1

[0010 ] Further, although the trifluoromethanesulfonic acid anhydride has two
trifluoromethanesulfonyl (CF3SO2) groups, only one of these
trifluoromethanesulfonyl groups is used for conversion to the leaving group of the
reaction intermediate It cannot be thus said that trifluoromethanesulfonic acid
anhydride is a preferred dehydrating agent in view of the atom economy etc It
cannot also be said that the process using the trifluoromethanesulfonic acid
anhydride is suitable for large-scale production of the target product as there occur
as a by-product two molecules of trifluoromethanesulfonic acid (CF3SO3H), which
is difficult to decompose and causes a problem in waste treatment, per 1 molecule
of the target compound
[0011 ] As mentioned above, there has been a demand for a practical production
process applicable to a wide range of substrate materials and capable of producing
an α-trifluoromethyl-α,β-unsaturated ester with high yield in a short time (1 e with
high productivity) and with high reactant atom economy but without causing a
problem in waste treatment
[0012 ] The present inventors have made extensive researches in view of the
above problems and, as a result, have found that it is possible to produce an
α-trifluoromethyl-α,β-unsaturated ester by reacting an

α-trifluoromethyl-α-hydroxy ester with sulfuryl fluoride in the presence of an
organic base The present inventors have also found that it is preferable that the
α-trifluoromethyl-α-hydroxy ester used as the raw substrate has a hydrogen atom
as one β-position substituent group and either an alkyl group, a substituted alkyl
group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a
substituted aromatic ring group as the other β-position substituent group and is
more preferable that an ester moiety of the α-trifluoromethyl-α-hydroxy ester is an
alkyl ester The above raw substrate is readily available Further, the use of the
above raw substrate is advantageous in that the desired reaction proceeds
favorably, and the resulting α-trifluoromethyl-α,β-unsaturated ester is particularly
important as a pharmaceutical and agricultural intermediate The present
inventors have further found that it is preferable to use either
l,5-diazabicyclo[4 3 O]non-5-ene (DBN) or l,8-diazabicyclo[5 4 O]undec-7-ene
(DBU) as the organic base The use of the above organic base is advantageous in
that the desired reaction proceeds more favorably
[0013 ] The reaction conditions of the present invention are similar to the
dehydroxyfluormation conditions of Patent Document 2 In fact, there could
occur a fluoride by-product by replacement of an α-position hydroxyl group of the
raw substrate with a fluorine atom (see Scheme-1, Example 1) It has however
been shown that the α-trifluoromethyl-α,β-unsaturated ester can be obtained
selectively as the dehydration product by the use of the
α-trifluoromethyl-α-hydroxy ester as the raw substrate in the present invention

[0015 ] It has also been shown that, although trifluoromethanesulfonyl fluoride

(CF3SO2F) and sulfuryl fluoride are expected to have the same effects as the
reactant, the use of sulfuryl fluoride leads to a far superior conversion rate and GC
purity to those by the use of trifluoromethanesulfonyl fluoride (see comparisons of
Example 2 and Comparative Example 2 and of Example 3 and Comparative
Example 3 in TABLE 1)
[0016 ] It has further been shown that, although the desired reaction proceeds
favorably even with the use of triethylamine as the organic base, the use of
l,8-diazabicyclo[5 4 O]undec-7-ene leads to a superior GG purity to that by the use
of triethylamine (see comparison of Examples 2 and 3 in TABLE 1 and
comparison of Examples 4 and 5 in TABLE 2), and it is particularly preferable to
use the organic base stronger in basicity than triethylamine (more specifically, not
only l,8-diazabicyclo[5 4 O]undec-7-ene, but also 4-dimethylaminopyndine
(DMAP), l,5-diazabicyclo[4 3 O]non-5-ene (DBN),
N,N,N',N',N"-pentamethylguanidine, l,5,7-triazabicyclo[4 4 O]dec-5-ene (TBD),
or phosphazene base such as BEMP or t-Bu-P4)
[0017] [TABLE 1]


a Gas chromatographic purity at the time of determination of conversion rate
The term inside parentheses E Z isomer ratio
b l,8-Diazabicyclo[5 4 O]undec-7-ene
c Fluoride < 5%


[0019 ] In this way, the present inventors have found the particularly useful
techniques for production of the α-trifluoromethyl-α,β-unsaturated ester The
present invention is based on these findings
[0020 ] Namely, the present invention provides a practical process for
producing an α-trifluoromethyl-α,β-unsaturated ester as defined as follows by
Inventive Aspects 1 to 3
[0021] [Inventive Aspect 1]
A process for producing an α-trifluoromethyl-α,β-unsaturated ester of
the general formula [2], comprising reacting an α-trifluoromethyl-α-hydroxy ester
of the general formula [1] with sulfuryl fluoride (SO2F2) in the presence of an
organic base
[Chem 3]


where R and R each independently represent a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl
group, a substituted alkynyl group, an aromatic ring group, a substituted aromatic
ring group, an alkylcarbonyl group, a substituted alkylcarbonyl group, an
alkoxycarbonyl group, a substituted alkoxycarbonyl group, an arylcarbonyl group,
a substituted arylcarbonyl group, a cyano group or a nitro group, R3 represents an
alkyl group or a substituted alkyl group, and the wavy line in the general formula
(2) indicates that the double bond is in an E-isomer configuration, a Z-isomer
configuration or a mixture thereof
[0022 ] [Inventive Aspect 2]
A process for producing an α-trifluoromethyl-α,β-unsaturated ester of
the general formula [4], comprising reacting an α-trifiuoromethyl-α-hydroxy ester
of the general formula [3] with sulfuryl fluoride (SO2F2) in the presence of an
organic base



where R4 represents an alkyl group, a substituted alkyl group, an alkenyl group, a
substituted alkenyl group, an aromatic ring group or a substituted aromatic ring
group, R5 represents an alkyl group, the wavy line in the general formula [4]
indicates that the double bond is in an E-isomer configuration, a Z-isomer
configuration or a mixture thereof
[0023 ] [Inventive Aspect 3]
The process for producing the α-trifluoromethyl-α,β-unsaturated ester
according to Inventive Aspect 1 or 2, wherein the organic base is either
l,5-diazabicyclo[4 3 O]non-5-ene (DBN) or l,8-diazabicyclo[5 4 O]undec-7-ene
(DBU)
Detailed Description
[0024 ] The advantages of the present invention over the prior art techniques
will be explained below
[0025 ] The production process of the present invention is applicable to a wide
range of substrate materials Further, it is possible by the pioduction process of
the present invention that the target compound can be obtained with high
productivity and high yield It is also possible that the target compound can be
obtained with high chemical purity as there occurs almost no difficult-to-separate
by-product The sulfuryl fluoride used in the present invention has high atom
economy and can be easily processed into inorganic salts e g fluorite (CaF2) and
calcium sulfate (CaSCU) that do not raise particular problems In addition, the
sulfuryl fluoride is widely used as a fumigant and available in a large quantity at
low cost as compared to the other dehydrating agents such as
trifluoromethanesulfonic acid anhydride and fluorosulfunc acid anhydride
((FSO2)20) as disclosed in Patent Document 1
[0026 ] As mentioned above, the production process of the present invention

solves all of the prior art problems and can be applied for industiial uses So far
as the present inventors know, there has been no report about organic synthesis
example using, as a dehydrating agent, sulfuryl fluoride that is widely known and
used as the fumigant
[0027 ] The production process of the α-trifluoromethyl-α,β-unsaturated ester
according to the present invention will be described in detail below
[0028 ] According to the present invention, an
α-trifluoromethyl-α,|3-unsaturated ester of the general formula [2] is produced by
reaction of an α-trifluoromethyl-α-hydroxy ester of the general formula [1] with
sulfuryl fluoride in the presence of an organic base
[0029 ] In the α-trifluoromethyl-α-hydroxy ester of the general formula [1], R1
and R each independently represents a hydrogen atom, an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl
group, a substituted alkynyl group, an aromatic ring group, a substituted aromatic
ring group, an alkylcarbonyl group, a substituted alkylcarbonyl group, an
alkoxycarbonyl group, a substituted alkoxycarbonyl group, an arylcarbonyl group,
a substituted arylcarbonyl group, a cyano group or a nitro group Among others,
a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a
substituted alkenyl group, an aromatic ring group and a substituted aromatic ring
group are preferred as R and R It is more preferred that one of R and R is a
hydrogen atom and the other of R and R is either an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group
or a substituted aromatic ring group
[0030 ] Herein, the alkyl group generally has 1 to 18 carbon atoms and can be in
the form of a linear or branched structure, or a cyclic structure (in the case of 3 or
more carbon atoms) The alkenyl group refers to that in which any number of
single bonds between any two adjacent carbon atoms of the above alkyl group has
been replaced with a double bond In this case, the double bond can be in an
E-isomer configuration, a Z-isomer configuration or a mixture thereof The
alkynyl group refeis to that in which any number of single bonds between any two
adjacent carbon atoms of the above alkyl group has been replaced with a triple

bond The aromatic ring group generally has 1 to 18 carbon atoms and can be an
aromatic hydrocarbon group such as phenyl, naphthyl or anthryl, or an aromatic
heterocyclic group containing a hetero atom e g a nitrogen atom, an oxygen atom
or a sulfur atom, such as pyrrolyl, furyl, thienyl, indolyl, benzofuryl or
benzothienyl The alkyl moiety (R) of the alkylcarbonyl group (-COR) is the
same as the above alkyl group The alkyl moiety (R) of the alkoxycarbonyl group
(-CO2R) is also the same as the above alkyl group The aryl moiety (Ar) of the
arylcarbonyl group (-COAr) is the same as the above aromatic ring group
[0031 ] Any of the carbon atoms of the alkyl group, the alkenyl group, the
alkynyl group, the aromatic ring group, the alkylcarbonyl group, the
alkoxycarbonyl group and the arylcarbonyl group may be replaced with any
number of and any combination of substituents (which correspond to the
substituted alkyl group, the substituted alkenyl group, the substituted alkynyl group,
the substituted aromatic ring group, the substituted alkylcarbonyl group, the
substituted alkoxycarbonyl group and the substituted arylcarbonyl group,
respectively) Examples of such substituents are halogen atoms such as fluorine,
chlorine, bromine and iodine, azide group, nitro group, lower alkyl groups such as
methyl, ethyl and propyl, lower haloalkyl groups such as fluoromethyl,
chloromethyl and bromomethyl, lower alkoxy groups such as methoxy, ethoxy and
propoxy, lower haloalkoxy groups such as fluoromethoxy, chloromethoxy and
bromomethoxy, lower alkylamino groups such as dimethylamino, diethylamino
and dipropylamino, lower alkylthio groups such as methylthio, ethylthio and
propylthio, cyano group, lower alkoxycarbonyl groups such as methoxycarbonyl,
ethoxycarbonyl and propoxycarbonyl, aminocarbonyl (CONH2), lower
alkylaminocarbonyl groups such as dimethylaminocarbonyl, diethylaminocarbonyl
and dipropylaminocarbonyl, unsaturated groups such as alkenyl groups and
alkynyl groups, aromatic ring groups such as phenyl, naphthyl, pyrrolyl, furyl and
thienyl, aromatic ring oxy groups such as phenoxy, naphthoxy, pyrrolyloxy,
furyloxy and thienyloxy, aliphatic heterocyclic groups such as pipendyl, pipendino
and morphohnyl, hydroxyl group, protected hydroxyl groups, amino group
(including amino acids and peptide residues), protected amino groups, thiol group,

protected thiol groups, aldehyde group, protected aldehyde groups, carboxyl
group, and protected carboxyl groups
[0032 ] The following terms are herein defined by the following meanings in
the present specification The term "lower" means that the group to which the
term is attached has 1 to 6 carbon atoms in the form of a linear structure, a
branched structure or a cyclic structure (in the case of 3 carbons or more) It
means that, when the "unsaturated group" is a double bond (alkenyl group), the
double bond can be in an E-isomer configuration, a Z-isomer configuration or a
mixture thereof It means that the "protected hydroxyl, ammo, thiol, aldehyde
and carboxyl groups" may be those having protecting groups as described in
"Protective Groups in Organic Synthesis", Third Edition, 1999, John Wiley & Sons,
Inc (In this case, two or more functional groups may be protected with one
protecting group ) Further, the "unsaturated group", "aromatic ring group",
"aromatic ring oxy group" and "aliphatic heterocyclic group" may be substituted
with halogen atoms, azide group, nitro group, lower alkyl groups, lower haloalkyl
groups, lower alkoxy groups, lower haloalkoxy groups, lower alkylamino groups,
lower alkylthio groups, cyano group, lower alkoxycarbonyl groups, aminocarbonyl
group, lower aminocarbonyl groups, hydroxyl group, protected hydroxyl groups,
amino group, protected amino groups, thiol group, protected thiol groups, aldehyde
group, protected aldehyde groups, carboxyl group or protected carboxyl groups
Although some of these substituent groups could react with sulfuryl fluoride in the
presence of the organic base, the desired reaction can be promoted favorably by
adoption of the suitable reaction conditions
[0033 ] In the α-trifluoromethyl-α-hydroxy ester of the general formula [1], R3
represents an alkyl group or a substituted alkyl group Among others, an alkyl
group is preferred as R3 Particularly preferred as R3 is a lower alkyl group
[0034 ] Examples of the alkyl group and substituted alkyl group usable as R
are the same as those mentioned above as R1 and R2
[0035 ] The α-trifluoromethyl-α-hydroxy ester of the general formula [1] can
be prepared with reference to, for example, Tetrahedron (U K ), 2002, Vol 58, P
8565-8571 or Tetrahedron Letters (U K ), 2004, Vol 45, P 183-185

[0036 ] It suffices to use the sulfuryl fluoride in an amount of 0 7 mol or more
per 1 mol of the α-trifluoromethyl-α-hydroxy ester of the general formula [1]
The amount of the sulfuryl fluoride used is generally preferably 0 8 to 10 mol,
more preferably 0 9 to 5 mol, per 1 mol of the α-trifluoromethyl-α-hydroxy ester
of the general formula [1]
[0037 ] Examples of the organic base are triethylamine, dnsopropylethylamine,
tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, pyridine, 2,3-lutidine,
2,4-lutidine, 2,6-lutidme, 3,4-lutidine, 3,5-lutidine, 2,4,6-colhdine, 3,5,6-colhdine,
4-dimethylaminopyndine, l,5-diazabicyclo[4 3 O]non-5-ene,
l,8-diazabicyclo[5 4 O]undec-7-ene, N,N,N',N',N"-pentamethylguanidine,
l,5,7-triazabicyclo[4 4 O]dec-5-ene, and phosphazene bases such as BEMP and
t-Bu-P4 Among others, triethylamine, dnsopropylethylamine, tri-n-butylamine,
pyridine, 2,6-lutidine, 2,4,6-colhdine, 4-dimethylaminopyndine,
l,5-diazabicyclo[4 3 O]non-5-ene and l,8-diazabicyclo[5 4 O]undec-7-ene are
preferred as the organic base Particularly preferred as the organic base are
triethylamine, dnsopropylethylamine, l,5-diazabicyclo[4 3 O]non-5-ene and
l,8-diazabicyclo[5 4 O]undec-7-ene The above organic bases can be used solely
or in combination thereof
[0038 ] It suffices to use the organic base in an amount of 0 7 mol or more per 1
mol of the α-trifluoromethyl-α-hydroxy ester of the general formula [1] The
amount of the organic base used is generally preferably 0 8 to 10 mol, more
preferably 0 9 to 5 mol, per 1 mol of the α-trifluoromethyl-α-hydroxy ester of the
general formula [1] In the case of using two or more kinds of organic base
materials in combination, the amount of the organic base used refers to the total
amount of the organic base materials Either one of the organic base materials
stronger in basicity may be used in a catalytic amount (sec Examples 5 to 7)
[0039 ] Examples of the reaction solvent are aliphatic hydrocarbon solvents
such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbon solvents such
as benzene, toluene and xylene, halogenated hydrocarbon solvents such as
methylene chloride, chloroform and 1,2-dichloroethane, ether solvents such as
diethyl ether, tetrahydrofuran, dnsopropyl ether and tert-butyl methyl ether, ester

solvents such as ethyl acetate and n-butyl acetate, nitrile solvents such as
acetonitrile and propionitrile, amide solvents such as N,N-dimethylformamide,
N,N-dimethylacetoamide and l,3-dimethyl-2-imidazohdinone, and dimethyl
sulfoxide Among others, n-hexane, n-heptane, toluene, xylene, methylene
chloride, tetrahydrofuran, dnsopropyl ether, tert-butyl methyl ether, ethyl acetate,
acetonitrile, propionitrile, N,N-dimethylformamide and dimethyl sulfoxide are
preferred as the reaction solvent Particularly preferred as the reaction solvent are
n-heptane, toluene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether,
ethyl acetate, acetonitrile and N,N-dimethylformamide The above reaction
solvents can be used solely or in combination thereof In the present invention,
the reaction may alternatively be conducted in the absence of the reaction solvent
[0040 ] It suffices to use the reaction solvent in an amount of 0 01 L (liter) or
more per 1 mol of the α-trifluoromethyl-α-hydroxy ester of the general formula [1]
The amount of the reaction solvent used is generally preferably 0 03 to 30 L, more
preferably 0 05 to 20 L, per 1 mol of the α-trifluoromethyl-α-hydroxy ester of the
general formula [1]
[0041 ] It suffices that the reaction temperature is in the range of-30 to +150°C
The reaction temperature is generally preferably -20 to +140°C, more preferably
-10to+130°C
[0042 ] Further, it suffices that the reaction time is 24 hours or less As the
reaction time depends on the raw substrate and the reaction conditions, it is
preferable to determine the time at which the raw substrate has almost disappeared
as the end of the reaction while monitoring the progress of the reaction by any
analytical means such as gas chromatography, liquid chromatography or nuclear
magnetic resonance
[0043 ] The α-trifluoromethyl-α,β-unsaturated ester of the general formula [2]
can be obtained as a crude product by post treatment of the reaction terminated
liquid As one example of post treatment operation, it is feasible to dilute the
reaction terminated liquid (if necessary, after concentrating the reaction terminated
liquid by evaporation of the reaction solvent) with an organic solvent (such as
n-hexane, n-heptane, toluene, xylene, methylene chloride, dnsopropyl ether,

tert-butyl methyl ether or ethyl acetate), wash the diluted liquid with water or an
aqueous solution of an alkali metal inorganic base (such as sodium
hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium
carbonate) (and, if necessary, dry the organic phase with a drying agent such as
anhydrous sodium sulfate or anhydrous magnesium sulfate), and then, concentrate
the recovered organic phase The crude product can also be obtained by directly
subjecting the reaction terminated liquid to distillation under reduced pressure for
simplification of the post tieatment operation Further, the crude product can be
purified to a high chemical purity, as needed, by purification operation such as
activated carbon treatment, distillation, recrystalhzation or column chromatography
Herein, the wavy line in the general formula (2) indicates that the double bond of
the α-trifluoromethyl-α,β-unsaturated ester is in an E-isomer configuration, a
Z-isomer configuration or a mixture thereof, and the stereochemistry of the target
product vanes depending on the raw substrate and the reaction conditions
[0044 ] As described above, the α-trifluoromethyl-α,β-unsaturated ester is
produced by reaction of the α-trifluoromethyl-α-hydroxy ester with sulfuryl
fluoride in the presence of the organic base (Inventive Aspect 1)
[0045 ] In Inventive Aspect 1, it is preferable to use the raw substrate having a
hydrogen atom as one β-position substituent group and either an alkyl group, a
substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic
ring group or a substituted aromatic ring group as the other β-position substituent
group and whose ester moiety is an alkyl ester (Inventive Aspect 2) This
preferred raw substrate is readily available Further, the use of this preferred raw
substrate is advantageous in that the desired reaction proceeds favorably, and the
resulting α-trifluoromethyl-α,β-unsaturated ester is particularly important as a
pharmaceutical and agricultural intermediate
[0046 ] It is further preferable in Inventive Aspects 1 and 2 to use either
l,5-diazabicyclo[4 3 O]non-5-ene (DBN) or l,8-diazabicyclo[5 4 O]undec-7-ene
(DBU) as the organic base (Inventive Aspect 3) The desired reaction can be
promoted more favorably by the use of this preferred organic base
[0047 ] [Examples]

The present invention will be described in more detail below by way of
the following examples It should be noted that these examples are illustrative
and are not intended to limit the present invention thereto
[0048 ] [Example 1]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 2 00 g (10 75 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

5 4 mL (1 99 M) of acetonitrile and 2 17 g (21 44 mmol, 1 99 eq) of triethylamine
The reaction vessel was immersed in a cooling bath of-78°C, followed by
blowing 2 19 g (21 46 mmol, 2 00 eq) of sulfuryl fluoride (SO2F2) from a cylinder
into the reaction vessel The resulting liquid was stirred for one night at room
temperature
[0049 ] It was determined by l9F-NMR of the reaction terminated liquid that
the conversion rate of the reaction was 86% It was also confirmed from the
1 F-NMR results for determination of the reaction conversion rate that the
generation ratio of α-trifluoromethyl-α,β-unsaturated ester of the following
formula

to a fluoride of the following formula
[Chem 9]


was 70 30 No post treatment was performed on the reaction terminated liquid
The 'H-NMR and 19F-NMR data of the product are indicated below
[0050 ] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 5
ppm, α-trifluoromethyl-α,β-unsaturated ester /1 35 (t, 7 1Hz, 3H), 4 32 (q, 7 1Hz,
2H), 6 42 (s, 1H), 6 72 (s, 1H), fluoride /1 25-1 45 (t, 3H), 2 75-3 50 (m, 3H),
4 25-4 50 (q, 2H)
l9F-NMR [reference material C6F6, deuterium solvent CDCI3] 8 ppm,
α-trifluoromethyl-α,β-unsaturated ester / 96 06 (s, 3F), fluoride / 31 88 (s, IF),
83 73 (s, 3F)
[0051] [Example 2]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 1 00 g (4 38 mmol, 1 00 eq) of ot-trifluoromethyl-α-hydroxy ester of the
following formula

5 0 mL (0 88 M) of acetomtrile and 1 30 g (12 85 mmol, 2 93 eq) of triethylamine
The reaction vessel was immersed in a cooling bath of -78°C, followed by
blowing 0 89 g (8 72 mmol, 1 99 eq) of sulfuryl fluoride (SO2F2) from a cylinder
into the reaction vessel The resulting liquid was stirred for one night at room
temperature
[0052 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 92% It was also confirmed
that the reaction product had a gas chromatographic purity of 80 7% (intermediate
[LG, leaving group (OSO2F)] 10 1%, fluoride < 5%) and a E Z isomer ratio of
40 60 at the time of determination of the reaction conversion rate The reaction

terminated liquid was diluted with 30 mL of ethyl acetate, washed with 30 mL of
an aqueous saturated potassium carbonate solution, further washed with 30 mL of
water, and then, dried with anhydrous magnesium sulfate The recovered organic
phase was subjected to concentration under reduced pressure and purified by short
column chromatography (silica gel, ethyl acetate-n-hexane system) With this,
0 63 g of α-trifluoromethyl-α,β-unsaturated ester of the following formula

was obtained as the purified product It was confirmed that the yield of the
product was 68%, the gas chromatographic purity of the product was 74 7%, and
the E Z isomer ratio of the product was 34 66 The 'H-NMR and 19F-NMR data
of the product are indicated below
[0053 ] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 8
ppm, E isomer /1 05-1 15 (d, 6H), 1 25-1 40 (t, 3H), 3 29 (m, 1H), 4 20-4 35 (q,
2H), 6 56 (d, 10 2Hz, 1H), Z isomer / 1 05-1 15 (d, 6H), 1 25-1 40 (t, 3H), 3 08 (m,
1H), 4 20-4 35 (q, 2H), 6 97 (d, 11 0Hz, 1H)
19F-NMR [reference material C6F6, deuterium solvent CDCI3] 8 ppm,
E isomer / 97 80 (s, 3F), Z isomer /103 05 (s, 3F)
[0054 ] [Example 3]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 1 00 g (4 38 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

5 0 mL (0 88 M) of acetonitrile and 1 97 g (12 94 mmol, 2 95 eq) of
l,8-diazabicyclo[5 4 O]undec-7-ene (DBU) The reaction vessel was immersed in

a cooling bath of-78°C, followed by blowing 0 90 g (8 82 mmol, 2 01 eq) of
sulfuryl fluoride (SO2F2) from a cylinder into the reaction vessel The resulting
liquid was stirred for one night at 50°C
[0055 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 100% It was also confirmed
that the reaction product had a gas chromatographic purity of 96 9% (as corrected
by subtracting the peak of the DBU) (intermediate [LG, leaving group (OSO2F)]
1 2%, fluoride < 5%) and an E Z isomer ratio of 37 63 at the time of
determination of the reaction conversion rate The reaction terminated liquid was
diluted with 30 mL of ethyl acetate, washed with 30 mL of an aqueous saturated
potassium carbonate solution, further washed with 30 mL of water, and then, dried
with anhydrous magnesium sulfate The recovered organic phase was subjected
to concentration under reduced pressure and purified by short column
chromatography (silica gel, ethyl acetate-n-hexane system) With this, 0 74 g of
α-trifluoromethyl-α,β-unsaturated ester of the following formula

was obtained as the purified product It was confirmed that the yield of the
product was 80%, the gas chromatographic purity of the product was 98 4%, and
the E Z isomer ratio of the product was 42 58 The 'H-NMR and l9F-NMR data
of the product were equivalent to those of Example 2
[0056 ] [Example 4]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 2 00 g (7 63 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula
[Chem 14]


10 0 mL (0 76 M) of acetomtrile and 3 48 g (22 86 mmol, 3 00 eq) of
l,8-diazabicyclo[5 4 O]undec-7-ene (DBU) The reaction vessel was immersed in
a cooling bath of-78°C, followed by blowing 1 56 g (15 29 mmol, 2 00 eq) of
sulfuryl fluoride (SO2F2) from a cylinder into the reaction vessel The resulting
liquid was stirred for one night at 50°C
[0057 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 95% It was also confirmed
that the reaction product had a gas chromatographic purity of 90 6% (as corrected
by subtracting the peaks of the DBU and substrate-derived impurities) (fluoride <
5%) and an E Z isomer ratio of 90 10 at the time of determination of the reaction
conversion rate The reaction terminated liquid was diluted with 30 mL of ethyl
acetate, washed with 30 mL of an aqueous saturated potassium carbonate solution,
further washed with 30 mL of water, and then, dried with anhydrous magnesium
sulfate The recovered organic phase was subjected to concentration under
reduced pressure and purified by short column chromatography (silica gel, ethyl
acetate-n-hexane system) With this, 1 69 g of α-trifluoromethyl-α,β-unsaturated
ester of the following formula

was obtained as the purified product It was confirmed that the yield of the
product was 91%, the gas chromatographic purity of the product was 90 5% (as
corrected by subtracting the peaks of the substrate-derived impurities), and the E Z
isomer ratio of the product was 87 13 The 'H-NMR and 19F-NMR data of the

J
product are indicated below
[0058 ] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 5
ppm, E isomer /1 20 (t, 7 2Hz, 3H), 4 26 (q, 7 2Hz, 2H), 7 15-7 45 (Ar-H, 5H+s,
1H), Z isomer / 1 15-1 45 (t, 3H), 4 05-4 45 (q, 2H), 7 15-7 45 (Ar-H, 5H), 8 09 (s,
1H)
19F-NMR [reference material CeF6, deuterium solvent CDCI3] 8 ppm,
E isomer / 97 85 (s, 3F), Z isomer /103 81 (s, 3F)
[0059 ] [Example 5]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 1 00 g (3 81 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

5 0 mL (0 76 M) of acetomtrile, 0 29 g (1 90 mmol, 0 50 eq) of
l,8-diazabicyclo[5 4 O]undec-7-ene (DBU) and 0 77 g (7 61 mmol, 2 OOeq) of
triethylamine The reaction vessel was immersed in a cooling bath of-78°C,
followed by blowing 0 78 g (7 64 mmol, 2 01 eq) of sulfuryl fluoride (SO2F2) from
a cylinder into the reaction vessel The resulting liquid was stirred for one night
at 50°C
[0060 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 95% It was also confirmed
that the reaction product had a gas chromatographic purity of 80 2% (as corrected
by subtracting the peaks of the DBU and substrate-derived impurities) (fluoride <
5%) and an E Z isomer ratio of 90 10 at the time of determination of the reaction
conversion rate The reaction terminated liquid was diluted with 20 mL of ethyl
acetate, washed with 20 mL of an aqueous saturated potassium carbonate solution,
further washed with 20 mL of water, and then, dried with anhydrous sodium sulfate
The recovered organic phase was subjected to concentration under reduced

pressure and then to vacuum drying With this, 0 92 g of
α-trifluoromethyl-α,β-unsaturated ester of the following formula

was obtained as the crude product It was confirmed that the yield of the product
was 99%, the gas chromatographic purity of the product was 83 6% (as corrected
by subtracting the peaks of the substrate-derived impurities), and the E Z isomer
ratio of the product was 75 25 The 'H-NMR and l9F-NMR data of the product
were equivalent to those of Example 4
[0061] [Example 6]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 3 00 g (13 26 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

10 0 mL (1 33 M) of acetonitrile, 1 00 g (6 57 mmol, 0 50 eq) of
l,8-diazabicyclo[5 4 O]undec-7-ene (DBU) and 2 68 g (26 48 mmol, 2 OOeq) of
triethylamine The reaction vessel was immersed in a cooling bath of -78°C,
followed by blowing 4 06 g (39 78 mmol, 3 00 eq) of sulfuryl fluoride (SO2F2)
from a cylinder into the reaction vessel The resulting liquid was stirred for one
night at 50°C
[0062 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 100% It was also confirmed
that the reaction product had a gas chromatographic purity of 96 1 % (fluoride <
5%) and an E Z isomer ratio of 92 8 at the time of determination of the reaction

conversion rate The reaction terminated liquid was diluted with 30 mL of ethyl
acetate, washed with 30 mL of an aqueous saturated potassium carbonate solution,
further washed twice with 30 mL of water, and then, dried with anhydrous
magnesium sulfate The recovered organic phase was subjected to concentration
under reduced pressure and then to vacuum drying
[0063 ] With this, 2 62 g of α-trifluoromethyl-α,β-unsaturated ester of the
following formula

was obtained as the crude product It was confirmed that the yield of the product
was 95%, the gas chromatographic purity of the product was 97 9%, and the E Z
isomer ratio of the product was 92 8 The ' H-NMR and ' 9F-NMR data of the
product are indicated below
[0064 ] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 5
ppm, E isomer /1 33 (t, 7 2Hz, 3H), 1 90 (s, 3H), 4 30 (q, 7 2Hz, 2H), 5 31 (s, 1H),
5 33 (s, 1H), 6 83 (s, 1H), Z isomer /1 33 (t, 7 2Hz, 3H), 1 93 (s, 3H), 4 30 (q,
7 2Hz, 2H), 5 11 (s, 1H), 5 21 (s, 1H), 7 50 (s, 1H)
1 F-NMR [reference material CeF6, deuterium solvent CDCI3] 8 ppm,
E isomer / 98 05 (s, 3F), Z isomer /103 85 (s, 3F)
[0065 ] [Example 7]
Into a pressure-proof reaction vessel of stainless steel (SUS) were
placed 50 00 g (249 80 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

83 0 mL(3 01 M) of acetonitrile, 19 00 g (124 80 mmol, 0 50 eq) of

l,8-diazabicyclo[5 4 O]undec-7-ene (DBU) and 63 20 g (624 57 mmol, 2 50eq) of
triethylamine The reaction vessel was immersed in a cooling bath of -78°C,
followed by blowing 51 00 g (499 71 mmol, 2 00 eq) of sulfuryl fluoride (SO2F2)
from a cylinder into the reaction vessel The resulting liquid was stirred for one
night at room temperature
[0066 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 99% It was also confirmed
that the reaction product had a gas chromatographic purity of 82 1 % (fluoride
9 0%) and an E Z isomer ratio of 78 22 at the time of determination of the reaction
conversion rate The reaction terminated liquid was directly subjected to
evaporation under reduced pressure (boiling point 52 to 58°C, vacuum degree
5000 Pa) With this, 17 21 g of α-trifluoromethyl-α,β-unsaturated ester of the
following formula

was obtained as the crude product It was confirmed that the yield of the product
was 38%, the gas chromatographic purity of the product was 82 8% (fluoride
10 5%), and the E Z isomer ratio of the product was 79 21 The'H-NMRand
19F-NMR data of the product are indicated below
[0067] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 5
ppm, E isomer /1 34 (t, 7 2Hz, 3H), 2 17 (dq, 7 3Hz, 2 2Hz, 3H), 4 31 (q, 7 2Hz,
2H), 6 95 (q, 7 3Hz, 1H), Z isomer /1 25-1 40 (t, 3H), 2 09 (dq, 7 6Hz, 2 8Hz, 3H),
4 20-4 45 (q, 2H), 7 33 (q, 7 6Hz, 1H)
19F-NMR [reference material C6F6, deuterium solvent CDCI3] 8 ppm,
E isomer / 97 64 (s, 3F)5 Z isomer /103 00 (s, 3F)
[0068 ] Further, the ' H-NMR and l9F-NMR data of the fluoride of the
following formula
[Chem 22]


are indicated below
[0069 ] 'H-NMR [reference material (CH3)4Si, deuterium solvent CDC13] 8
ppm, 1 25-1 40 (t, 3H+m, 3H), 3 65-3 85 (m, 1H), 3 85-4 00 (m, 1H), 4 20-4 45 (q,
2H)
19F-NMR [reference material CeF6, deuterium solvent CDCI3] 5 ppm,
30 08 (s, IF), 80 39 (s, 3F)
[007O] [Comparative Example 1]
To a methylene chloride solution (usage amount 5 0 mL, 0 26 M)
containing 0 30 g (1 31 mmol, 1 00 eq) of α-trifluoromethyl-α-hydroxy ester of the
following formula

0 58 g (2 06 mmol, 1 57 eq) of trifluoromethanesulfonic acid anhydride
((CF3SO2)20) was added under ice cooling The resulting liquid was stirred for
10 minutes, followed by adding 0 26 g (3 29 mmol, 2 51 eq) of pyridine to the
liquid while maintaining the liquid at the same temperature The liquid was then
further stirred for 1 hour After that, the liquid was heated to room temperature
and stirred for one night
[0071 ] It was determined by gas chromatography of the reaction terminated
liquid that the conversion rate of the reaction was 86% It was also confirmed
from the gas chromatography measurement for determination of the reaction
conversion rate that α-trifluoromethyl-α,β-unsaturated ester of the following
formula
[Chem 24]


was obtained with a gas chromatographic purity of 0 7% (intermediate (LG
leaving group (OSO2CF3)) 83 8%) and an E Z isomer ratio of 60 40 No post
treatment was performed on the reaction terminated liquid
[0072 ] As shown in TABLE 1, Comparative Example 2 was carried out in the
same manner as in Example 2 except for replacing the leactant Similarly,
Comparative Example 3 was carried out in the same manner as in Example 3
except for replacing the reactant as shown in TABLE 1 Further, Comparative
Example 4 was carried out in the same manner as in Comparative Example 1
except for replacing the raw substrate (see reaction schemes of TABLES 1 and 2)

WE CLAIM:
1 A process for producing an α-trifluoromethyl-α,β-unsaturated ester of the general
formula [2],
comprising reacting an α-trifluoromethyl-α-hydroxy ester of the general
formula [1] with sulfuryl fluoride (SO2F2) in the presence of at least one kind of
organic base selected from the group consisting of triethylamine,
dnsopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine,
pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-
colhdine, 3,5,6-colhdine, 4-dimethylaminopyndine, l,5-diazabicyclo[4 3 O]non-5-ene,
l,8-diazabicyclo[5 4 O]undec-7-ene, N,N,N',N',N"-pentamethylguanidine, 1,5,7-
triazabicyclo[4 4 O]dec-5-ene and phosphazene bases

where R and R each independently represent a hydrogen atom, an alkyl group of 1 to
18 carbon atoms, an alkenyl group of 1 to 18 carbon atoms, an alkynyl group of 1 to 18
carbon atoms, an aromatic ring group of 1 to 18 carbon atoms, an alkylcarbonyl group
having an alkyl moiety of 1 to 18 carbon atoms, an alkoxycarbonyl group having an
alkyl moiety of 1 to 18 carbon atoms, an arylcarbonyl group having an aryl moiety of 1
to 18 carbon atoms, a cyano group or a nitro group, R represents an alkyl group of 1 to
18 carbon atoms, each of the alkyl group, the alkenyl group, the alkynyl group, the
aromatic ring group, the alkylcarbonyl group, the alkoxycarbonyl group and the
arylcarbonyl group as R1, R2 and the alkyl group as R3 may have any number of and
any combination of substituents selected from halogen atoms, azide group, nitro group,
C1-C6 linear or branched or C3-C6 cyclic alkyl groups, C1-C6 linear or branched or C3-
C6 cyclic haloalkyl groups, C1-C6 linear or branched or C3-C6 cyclic alkoxy groups, C1-

C6 linear or branched or C3-C6 cyclic haloalkoxy groups, C1-C6 linear or branched or
C3-C6 cyclic alkylamino groups, C1-C6 linear or branched or C3-C6 cyclic alkylthio
groups, cyano group, C1-C6 linear or branched or C3-C6 cyclic alkoxycarbonyl groups,
C1-C6 linear or branched or C3-C6 cyclic aminocarbonyl groups, unsaturated groups,
aromatic ring groups, aromatic ring oxy groups, aliphatic heterocyclic groups, hydroxyl
group, protected hydroxyl groups, amino group, protected amino groups, thiol group,
protected thiol groups, aldehyde group, protected aldehyde groups, carboxyl group and
protected carboxyl groups, and the wavy line in the general formula (2) indicates that
the double bond is in an E-isomer configuration, a Z-isomer configuration or a mixture
thereof
2 The process for producing the α-trifluoromethyl-α,β-unsaturated ester as claimed in
claim 1, wherein the α-trifluoromethyl-α,β-unsaturated ester is an α-trifluoromethyl-
α,β-unsaturated ester of the general formula [4], and wherein the α-trifluoromethyl-α-

hydroxy ester is an α-trifluoromethyl-α-hydroxy ester of the general formula [3]

where R4 represents an alkyl group of 1 to 18 carbon atoms, an alkenyl group of 1 to 18
carbon atoms or an aromatic ring group of 1 to 18 carbon atoms, each of the alkyl
group, the alkenyl group and the aromatic ring group as R4 may have any number of
and any combination of substituents selected from halogen atoms, azide group, nitro
group, C1-C6 linear or branched or C3-C6 cyclic alkyl groups, C1-C6 linear or branched
or C3-C6 cyclic haloalkyl groups, C1-C6 linear or branched or C3-C6 cyclic alkoxy
groups, C1-C6 linear or branched or C3-C6 cyclic haloalkoxy groups, C1-C6 linear or

branched or C3-C6 cyclic alkylamino groups, C1-C6 linear or branched or C3-C6 cyclic
alkylthio groups, cyano group, C1-C6 linear or branched or C3-C6 cyclic alkoxycarbonyl
groups, C1-C6 linear or branched or C3-C6 cyclic aminocarbonyl groups, unsaturated
groups, aromatic ring groups, aromatic ring oxy groups, aliphatic heterocyclic groups,
hydroxyl group, protected hydroxyl groups, amino group, protected amino groups, thiol
group, protected thiol groups, aldehyde group, protected aldehyde groups, carboxyl
group and protected carboxyl groups, R5 represents an alkyl group of 1 to 18 carbon
atoms, the wavy line in the general formula [4] indicates that the double bond is in an
E-isomer configuration, a Z-isomer configuration or a mixture thereof
3 The process for producing the α-trifluoromethyl-α,β-unsaturated ester as claimed in
claim 1 or 2, wherein the organic base is either l,5-diazabicyclo[4 3 O]non-5-ene
(DBN) or l,8-diazabicyclo[5 4 O]undec-7-ene (DBU)

ABSTRACT

TITLE PROCESS FOR PRODUCING
α-TRIFLUOROMETHYL-α,β-UNSATURATED ESTER
An α-trifluoromethyl-α,β-unsaturated ester can be produced by reacting
an α-trifluoromethyl-α-hydroxy ester with sulfuryl fluoride (SO2F2) in the
presence of an organic base. It is preferable that the raw substrate has a hydrogen
atom as one β-position substituent group and either an alkyl group, a substituted
alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group
or a substituted aromatic ring group as the other β-position substituent group. It
is more preferable that an ester moiety of the raw substrate is an alkyl ester. This
raw substrate is readily available. Further, the desired reaction can proceed
favorably with the use of this raw substrate. It is also preferable to use either
l,5-diazabicyclo[4 3 O]non-5-ene (DBN) or l,8-diazabicyclo[5 4 O]undec-7-ene
(DBU) as the organic base. The desired reaction can proceed more favorably
with the use of this organic base.