Synthetic application of 3,3-dichloro-1, 1, 1-trifluoroacetone (DCTFA) and 3,3,3-trichloro-1, 1, 1-trifluoroacetone (TCTFA) for trifluorolactic acid derivatives

Article abstract of DOI:10.1016/j.jfluchem.2003.11.030

Synthetic application of 3,3-dichloro-1,1,1-trifluoroacetone (DCTFA) and 3,3,3-trichloro-1,1,1-trifluoroacetone (TCTFA) for industrially important trifluorolactic acid derivatives is described. Trifluorolactic acid was obtained by hydrolysis of DCTFA unde

Full text of DOI:10.1016/j.jfluchem.2003.11.030

Journal of Fluorine Chemistry 125 (2004) 567–571
Synthetic application of 3,3-dichloro-1,1,1-trifluoroacetone (DCTFA)
and 3,3,3-trichloro-1,1,1-trifluoroacetone (TCTFA) for
trifluorolactic acid derivatives
*
Akihiro Ishii , Masatomi Kanai, Manabu Yasumoto, Kenjin Inomiya,
Yokusu Kuriyama, Yutaka Katsuhara
Chemical Research Center, Central Glass Co., Ltd., Kawagoe, Saitama 350-1151, Japan
Received 15 October 2003; accepted 17 November 2003
Abstract
Synthetic application of 3,3-dichloro-1,1,1-trifluoroacetone (DCTFA) and 3,3,3-trichloro-1,1,1-trifluoroacetone (TCTFA) for industrially
important trifluorolactic acid derivatives is described. Trifluorolactic acid was obtained by hydrolysis of DCTFA under basic conditions. On
the other hand, a-substituted trifluorolactic acid derivatives, such as a-methyltrifluorolactic acid and Mosher’s acid, were obtained by addition
reaction between TCTFA and carbon nucleophiles, followed by subsequent transformation of trichloromethyl group.
#
2004 Elsevier B.V. All rights reserved.
Keywords: Fluorinated synthons; 3,3-Dichloro-1,1,1-trifluoroacetone (DCTFA); 3,3,3-Trichloro-1,1,1-trifluoroacetone (TCTFA); Trifluorolactic acid;
a-Methyltrifluorolactic acid; Mosher’s acid
1
. Introduction
,3-Dichloro-1,1,1-trifluoroacetone (DCTFA) and 3,3,3-
2. Results and discussion
3
In non-fluorinated counterpart, transformation of 1,
1-dichloroacetone to lactic acid has been well-known [5].
If a similar reaction would proceed in the fluorinated
DCTFA, trifluorolactic acid could be directly produced in
a single step. After optimization of reaction conditions, the
expected trifluorolactic acid was obtained in a high yield
(Scheme 2). Critical reaction conditions were use of DCTFA
in a hydrate form and control of pH, in which more than 12
must be maintained always. In this reaction, an intramole-
cular redox reaction might occur, namely a reduction of
carbonyl group equivalent and an oxidation of dichloro-
methyl group. From this consideration, a tentative 1,2-
hydride transfer mechanism in in situ formed epoxide might
be proposed as shown in Fig. 1.
DCTFA was easily chlorinated by chlorine gas in the
presence of a catalytic amount of quinoline to produce
TCTFA in a high yield. Next, industrial synthetic methods
of a-substituted trifluorolactic acid derivatives using TCTFA
are described. Addition reaction between TCTFA and car-
bon nucleophile has never been reported to the best of our
knowledge. If an adduct product would be obtained, a
subsequent transformation of trichloromethyl group could
provide a-substituted trifluorolactic acid derivatives, such as
trichloro-1,1,1-trifluoroacetone (TCTFA) are regarded as
fluorinated synthons consisting of three carbons and having
a trifluoromethyl group. DCTFA is produced on an industrial
scale through a modified Swarts reaction from pentachloro-
acetone [1]. However, industrial synthetic application of
DCTFA has been quite limited. Only a hydrolysis of DCTFA
has been reported to produce a trifluoropyruvaldehyde
equivalent [2]. On the other hand, DCTFA is chlorinated
to produce TCTFA. TCTFA also has been used only as a
trifluoroacetylating agent of amino group [3].
Trifluorolactic acid derivatives are industrially important
intermediates in pharmaceutical chemistry and opto-elec-
tronic material science. Many synthetic researchers have
previously reported practical synthetic methods of these
derivatives, however, they are not necessarily effective from
an industrial point of view [4].
In this paper, we report industrial synthetic methods of
trifluorolactic acid derivatives using DCTFA and TCTFA
(
Scheme 1).
*
Corresponding author.
E-mail address: aishii@cgco.co.jp (A. Ishii).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.030

568
A. Ishii et al. / Journal of Fluorine Chemistry 125 (2004) 567–571
O
OH
CF3
CHCl2
CF3
CO H
2
H
DCTFA
trifluorolactic acid
Cl2
O
OH
OCH3
CF3
CCl3
CF3
CO H
CF3
CO H
2
2
CH3
C H
6 5
TCTFA
α-methyltrifluorolactic acid
Mosher's acid
Scheme 1. Industrial synthetic methods of trifluorolactic acid derivatives using DCTFA and TCTFA.
OH
adduct product was obtained in a high yield in a usual
HO
OH
3
0% NaOH aq. (4 eq.)
(pH > 12)
manner. Methanolysis of the obtained adduct product under
a basic condition, followed by hydrolysis of in situ formed
methyl ester produced a-methyltrifluorolactic acid methyl
ether in a good yield. Subsequent demethylation of methyl
ether proceeded smoothly in a quantitative yield using an
excess amount of hydrobromic acid.
2
H O
2
CF3
CHCl2
CF3
CO H
2
<
25 ˚C, 1 h
H
200 g scale
yield 92%
Scheme 2. Industrial synthetic method of trifluorolactic acid using
DCTFA.
Friedel–Crafts reaction between TCTFA and benzene was
alsoexamined.AfterscreeningofLewisacid, onlyaluminium
chloride was found to be effective. In this Friedel–Crafts
reaction, reaction temperature was critical (Table 1). In more
than ꢀ25 8C, trityl type by-product greatly increased, so in
ordertoobtaina reasonableyield, ꢀ30 8C mustbe maintained
for a relatively long reaction time. Under the optimized
reaction temperature, an industrial synthetic method of
Mosher’s acid was examined (Scheme 4). The trityl type
by-product could be easily removed by a fractional distilla-
tion. A similar methanolysis could be applied to the further
transformation. The expected Mosher’s acid was obtained in a
high yield.
RO
CF3
O
Cl
H
R = H or Na
Fig. 1. 1,2-Hydride transfer mechanism.
a-methyltrifluorolactic acid and Mosher’s acid. The former
compound is a very important intermediate in the develop-
ment of therapeutic agent for urinary incontinence [6].
Grignard reaction between TCTFA and methylmagne-
sium chloride was examined (Scheme 3). The expected
In both methanolyses, the ring opening reaction of in situ
formed epoxide occurred regioselectively on the carbon
attached to a trifluoromethyl group (Fig. 2).
O
OH
CH MgCl (1eq.)
CH OK (4eq.) KOH aq. (1eq.)
3
3
CF3
CCl3
0 kg scale
CF3
CCl3
THF
CH OH
25 ˚C, 1 h
CH3
3
5
-
10 ˚C, 3 h
45 ˚C, 7 h
yield 87%
OCH3
OH
4
8% HBr (7eq.)
10 ˚C, 12 h
CF3
CO H
CF3
CO H
2
2
1
CH3
CH3
yield 63%
quantitative yield
Scheme 3. Industrial synthetic method of a-methyltrifluorolactic acid using TCTFA.
Scheme 4. Industrial synthetic method of Mosher’s acid using TCTFA.

A. Ishii et al. / Journal of Fluorine Chemistry 125 (2004) 567–571
569
Table 1
Friedel–Crafts reaction between TCTFA and benzene
a
b
c
d
run
temp.
conv.
yield
expected pro. : by-pro.
1
2
3
ꢀ20 8C
ꢀ30 8C
ꢀ40 8C
>90%
80%
20%
55%
60%
1:1
3:1
6:1
75%
a
b
c
d
Temperature.
Coversion.
Isolated yield of expected product after fractional distillation.
Expected product : by-product.
500 ml and concentration under a reduced pressure gave a
O
crude product. Heptane 270 ml was added to the crude
product. After stirring for 12 h at room temperature, the
precipitated crystal was filtered to give the expected trifluor-
Cl
CF3
R
olactic acid [4b] 133 g (92% yield).
1
-
Cl
R = CH3, C6H5
OCH3
H NMR (CD OD), d 4.53 (q, 7.6 Hz, 1H); Hydroxy
3
group and carboxyl group could not be assigned.
1
Fig. 2. Regioselective ring opening.
3
C NMR (CD OD), d 70.9 (q, 31.7 Hz), 124.4 (q,
3
2
81.4 Hz), 169.5.
1
9
F NMR (CD OD), d þ87.75 (d, 7.6 Hz, 3F).
3
In summary, the industrial synthetic methods of trifluoro-
lactic acid derivatives, such as trifluorolactic acid, a-methyl-
trifluorolactic acid and Mosher’s acid using DCTFA and
TCTFA have been developed. These are alternative syn-
thetic methods that do not demand the use of troublesome
alkali cyanide.
3.3. Synthesis of TCTFA by chlorination of DCTFA
Chlorine gas 0.716 kg (10.1 mol, 1.01 eq.) bubbled into
anhydrous DCTFA 1.809 kg (10.0 mol, 1 eq.) containing
quinoline 0.018 kg (1 wt.% of DCTFA) at 70 8C. Sequential
direct fractional distillation gave the purified TCTFA [3]
2.046 kg in 95% yield. Boiling point; 79 8C/atmospheric
3
. Experimental
pressure.
1
3
C NMR (CDCl ), d 89.6, 115.2 (q, 291.6 Hz), 172.7
3
3
.1. General
(q, 37.2 Hz).
1
9
F NMR (CDCl ), d þ95.16 (s, 3F).
3
1H NMR (400 MHz) or 13C NMR (100 MHz) spectra
were measured with a JEOL a-400 FT-NMR spectrometer in
3.4. Industrial synthetic method of a-methyltrifluorolactic
acid using TCTFA
CDCl or CD OD solutions with (CH ) Si as internal stan-
3
3
3 4
dard. 19F NMR (376 MHz) spectra were measured with a
JEOL a-400 FT-NMR spectrometer in CDCl or CD OD
Two moles per kilogram methylmagnesium chloride in
tetrahydrofuran solution 116.1 kg (232.1 mol, 1.0 eq.) was
added to anhydrous TCTFA 50.0 kg (232.1 mol, 1 eq.) at
less than ꢀ10 8C under nitrogen atmosphere. After stirring
for 3 h at the same temperature, 10 wt.% hydrochloric acid
93.1 kg (255.3 mol, 1.1 eq.) was added to the reaction
mixture. After stirring for 1 h at room temperature, the
organic layer was recovered. Sequential direct fractional
distillation gave the tetrahydrofuran solution of adduct
product. Quantitative analysis (internal reference method,
C F , 19F NMR) indicated that the expected adduct product
3
3
solutions with C F as internal standard. High-resolution
mass spectra were obtained with a Hitachi M-2500.
6
6
3.2. Industrial synthetic method of trifluorolactic acid
using DCTFA
DCTFA trihydrate 235 g (1 mol, 1 eq.) was added to
0 wt.% NaOH aqueous solution 533 g (4 mol, 4 eq.) at less
3
than 25 8C. After stirring for 1 h at the same temperature,
3
1
7 wt.% hydrochloric acid 197 g (2 mol, 2 eq.) and water
80 g were added to the reaction mixture. Extraction with
6
6
[7] 46.7 kg was contained in the tetrahydrofuran solution
(87% yield).
ethyl acetate 500 ml (twice), washing with saturated brine

570
A. Ishii et al. / Journal of Fluorine Chemistry 125 (2004) 567–571
1
H NMR (CDCl ), d 1.83 (q, 1.5 Hz, 3H); hydroxy group
and dichloromethane 65 kg at less than ꢀ30 8C. After
stirring for 48 h at the same temperature, the reaction
mixture was added to water 75 l. Extraction with dichlor-
omethane 75 l, washing with 10% brine 75 l and concentra-
tion under a reduced pressure gave a crude product.
Fractional distillation gave the purified adduct product [7]
3
could not be assigned.
1
3
C NMR (CDCl ), d 19.7 (q, 1.7 Hz), 82.3 (q, 27.6 Hz),
3
1
01.3, 123.9 (q, 287.7 Hz).
1
9
F NMR (CDCl ), d þ 89:43 (s, 3F). HRMS (EI), cal-
3
culated for C H Cl F O (M ꢀ Cl) 194.9591, found
4
4
2 3
1
94.9586.
The total amount of adduct product 46.7 kg (201.9 mol,
39.5 kg (55% yield).
1
H NMR (CDCl ), d 3.90 (br, 1H), 7.38–7.49 (Ar–H, 3H),
3
1
1
7
3
eq.) was added to 32% CH OK in methanol solution
3
7.88–7.94 (Ar–H, 2H).
3
1
77.0 kg (807.6 mol, 4.0 eq.) at 45 8C. After stirring for
h at the same temperature, 30 wt.% KOH aqueous solution
7.8 kg (201.9 mol, 1.0 eq.) was added to the reaction
C NMR (CDCl ), d 84.2 (q, 28.2 Hz), 100.9, 123.6 (q,
3
288.5 Hz), 127.7, 128.3, 129.9, 131.3.
1
9
F NMR (CDCl ), d þ93.81 (s, 3F). HRMS (EI), calcu-
3
mixture at less than 30 8C. After stirring for 1 h at
5 8C, the precipitated inorganic salt was filtered off.
lated for C H Cl F O (M) 291.9436, found 291.9149.
9 6 3 3
2
The total amount of adduct product 39.5 kg (127.7 mol,
1 eq.) was added to 32% CH OK in methanol solution
The filtrate was concentrated under a reduced pressure,
and then water 55 l and toluene 55 l were added to the
residue. After stirring for 1 h, the aqueous layer was recov-
ered. 37 wt.% hydrochloric acid 37.8 kg (383.6 mol,
3
111.9 kg (510.8 mol, 4.0 eq.) at 45 8C. After stirring for
20 h at the same temperature, 25 wt.% KOH methanol
solution 28.7 kg (127.7 mol, 1.0 eq.) was added to the
reaction mixture at less than 30 8C. After stirring for 3 h
at 25 8C, the precipitated inorganic salt was filtered off. The
filtrate was concentrated under a reduced pressure, and then
water 50 l and 37% hydrochloric acid 25.2 kg (255.4 mol,
2.0 eq.) were added to the residue. Extraction with ethyl
acetate 70 l (twice), washing with 10% brine 50 l and con-
centration under a reduced pressure gave a crude product.
Quantitative analysis by a similar method indicated that the
expected Mosher’s acid [9] 26.3 kg was contained in the
crude product (88% yield). The crude product was contami-
nated by benzoic acid (ca. 10%). Further purification was
carried out through a distillation of the corresponding acid
1
.9 eq.) was added to the aqueous layer. Extraction with
ethyl acetate 50 l (twice), washing with 10% brine 50 l
and concentration under a reduced pressure gave a crude
product. Quantitative analysis by a similar method
indicated that the expected a-methyltrifluorolactic acid
methyl ether [8] 21.9 kg was contained in the crude product
(
63% yield).
1
H NMR (CDCl ), d 1.67 (q, 1.2 Hz, 3H), 3.52 (q, 0.8 Hz,
3
3
H), 7.75 (br, 1H).
1
3
C NMR (CDCl ), d 16.6 (q, 1.6 Hz), 53.8, 80.3
3
(
q, 28.7 Hz), 123.3 (q, 286.0 Hz), 172.7.
9
1
F NMR (CDCl ), d þ 85:28 (s, 3F). HRMS (EI), cal-
3
culated for C H F O (M ꢀ CH O) 142.0242, found
chloride (ca. 80% total purification recovery yield).
1
4
5
3
2
2
1
42.0233.
Forty-eight percent HBr 150.2 kg (891.1 mol, 7.0 eq.)
H NMR (CDCl ), d 3.56 (q, 1.2 Hz, 3H), 7.40–7.47
3
(Ar–H, 3H), 7.55–7.62 (Ar–H, 2H), 9.10 (br, 1H).
3
1
was added to the total amount of a-methyltrifluorolactic
acid methyl ether 21.9 kg (127.3 mol, 1 eq.). The reaction
mixture was stirred at 110 8C for 12 h. After cooling,
4
5
C NMR (CDCl ), d 55.5, 84.4 (q, 28.2 Hz), 123.0
3
(q, 287.4 Hz), 127.3, 128.6, 129.9, 131.0, 171.3.
1
9
F NMR (CDCl ), d þ90.55 (s, 3F).
3
8 wt.% NaOH aqueous solution 53.0 kg (636.5 mol,
.0 eq.) was added to the reaction mixture. Extraction with
ethyl acetate 35 l (twice), washing with 10% brine 35 l and
concentration under a reduced pressure gave a crude pro-
duct. Heptane 60 l was added to the crude product. After
stirring for 12 h at room temperature, the precipitated crystal
was filtered to give the expected a-methyltrifluorolactic acid
Acknowledgements
We thank Prof. Tamejiro Hiyama (Kyoto University) for
fruitful discussions.
[
6c] 20.1 kg (quantitative yield).
1
References
H NMR (CD OD), d 1.53 (q, 0.8 Hz, 3H); hydroxy group
3
and carboxyl group could not be assigned.
1
3
[1] (a) Y. Goto, M. Watanabe, T. Sakaya, R. Nadano, JP Patent
C NMR (CD OD), d 20.3 (q, 1.7 Hz), 75.9 (q, 29.2 Hz),
3
2
000247923 (2000) [CAN 133:222325];
b) R. Nadano, T. Sakaya, M. Watanabe, Y. Goto, T. Nakamichi, S.
Suenaga, JP Patent 2000143575 (2000) [CAN 132:334213];
c) M. Kanai, T. Sakaya, M. Watanabe, Y. Goto, R. Nadano, EP Patent
872468 (1998) [CAN 129:289881];
1
25.6 (q, 284.1 Hz), 172.2.
9
(
1
F NMR (CD OD), d þ84.12 (s, 3F).
3
(
3.5. Industrial synthetic method of Mosher’s acid using
TCTFA
(
d) M. Kanai, T. Sakaya, M. Watanabe, Y. Goto, JP Patent 10287609
1998) [CAN 129:330468].
(
[
2] (a) Y. Oda, M. Yanakawa, JP Patent 2000063306 (2000) [CAN
32:180281];
A mixture of TCTFA 50.0 kg (232.1 mol, 1 eq.) and
benzene 45.3 kg (580.3 mol, 2.5 eq.) was added to a solution
containing aluminium chloride 15.5 kg (116.1 mol, 0.5 eq.)
1
(b) M. Cushman, H. Patel, A. McKenzie, J. Org. Chem. 53 (1988)
5088.

A. Ishii et al. / Journal of Fluorine Chemistry 125 (2004) 567–571
571
[
[
3] C.A. Panetta, T.G. Casanova, J. Org. Chem. 35 (1970)
275.
4] (a) T. Katagiri, F. Obara, S. Toda, K. Furuhashi, Synlett (1994)
07;
(b) G.R. Bebernitz, T.D. Aicher, J.L. Stanton, J. Gao, S.S. Shetty, D.C.
Knorr, R.J. Strohschein, J. Tan, L.J. Brand, C. Liu, W.H. Wang, C.C.
Vinluan, E.L. Kaplan, C.J. Dragland, D. DelGrande, A. Islam,R.J. Lozito,
X. Liu, W.M. Maniara, W.R. Mann, J. Med. Chem. 43 (2000) 2248;
(c) C.J. Ohnmacht, K. Russell, J.R. Empfield, C.A. Frank, K.H.
Gibson, D.R. Mayhugh, F.M. McLaren, H.S. Shapiro, F.J. Brown, D.A.
Trainor, C. Ceccarelli, M.M. Lin, B.B. Masek, J.M. Forst, R.J. Harris,
J.M. Hulsizer, J.J. Lewis, S.M. Silverman, R.W. Smith, P.J. Warwick,
S.T. Kau, A.L. Chun, T.L. Grant, B.B. Howe, J.H. Li, S. Trivedi, T.J.
Halterman, C. Yochim, M.C. Dyroff, M. Kirkland, K.L. Neilson, J.
Med. Chem. 39 (1996) 4592.
4
5
(
(
(
(
(
b) C. Bussche-Hunnefeld, C. Cescato, D. Seebach, Chem. Ber. 125
1992) 2795;
c) T. Kubota, T. Tanaka, M. Iijima, N. Iijima, JP Patent 03148249
1991) [CAN 115:255644];
d) T. Kubota, Y. Kondoh, T. Ohyama, T. Tanaka, Nippon Kagaku
Kaishi (1989) 1576;
(e) J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem. 34 (1969) 2543;
(f) R.A. Darrall, F. Smith, M. Stacey, J.C. Tatlow, J. Chem. Soc.
(1951) 2329.
[7] Y.V. Zeifman, Izvestiya Akademi Nauk, Seriya Khimicheskaya (1992)
464.
[
[
5] T. Tanaka, T. Kuroda, H. Kishimoto, S. Kamimori, Yukagaku 28
1979) 501.
[8] C. Pareja, E. Martin-Zamora, R. Fernandez, J.M. Lassaletta, J. Org.
Chem. 64 (1999) 8846.
(
6] (a) S.-H. Lu, T. Yamagata, K. Atsuki, L. Sun, C.P. Smith, N.
Yoshimura, M.B. Chancellor, W.C. Groat, Brain Res. 946 (2002) 72;
[9] F.J.A. Hundscheid, V.K. Tandon, P.H.F.M. Rouwette, A.M. Leusen,
Tetrahedron 43 (1987) 5073.