WONG ET AL.
3
were heated (60°C, 2 h) in 2 mL ethyl acetate. Upon
cooling, colorless plates of (S)‐[NH3CH(CH2OH)Ph](S)‐
[CF3CH(OH)COO] 5 (104 mg, Fw 281, 76% yield, 95%
ee) obtained by filtration. Single recrystallization gives
overall 70% yield with 99% ee. Combustion analysis for
5 C11H14F3NO4 calc. (found) C 46.98% (46.87) H 5.02%
(5.12) N 4.98% (5.51).
2.7 | Determination of % ee by chiral
chromatography
HPLC experiments were performed with a Thermo Scien-
tific Dionex UltiMate 3000 instrument fitted with
Phenomenex Lux 5 μm Amylose‐1 LC chiral column
(250 × 4.6 mm) running with normal phase 92 hexane:
8 i‐propanol: 0.2 trifluoroacetic acid at 5°C. Injection vol-
umes of 5 μL were used and run time 40 minutes. The
typical retention times of rac‐3,3,3‐trifluorolactic acid
were 21.4 and 23.1 minutes. These peaks were close but
clearly resolved with w1/2 ave of 1.0 minute (R = 1.6).
Peaks were detected from UV absorption at 210 nm.
The quantification of the racemate gave an acceptable
ratio of 50.2: 49.8% based on peak area.
Crystals of the diastereomeric salt
6
(S)‐
[NH3CH(CH2OH)Ph](R)‐[CF3CH(OH)COO] (86 mg, Fw
281, 63% yield) can be obtained by further addition of
(S)‐phenylglycinol (0.5 mmol. 70 mg) to the filtrate
solution, crystals obtained after crystallization at room
temperature for 8 hours. The product is contaminated
ith salt 5; therefore, its enantiomeric excess was not
determined.
The % ee in salts came from (R)/(S) peak integrations
after crude 3,3,3‐trifluorolactic acid was obtained from
dried organic extract, after salts treated with 50:50 ethyl
acetate: 1 M HCl soln. to remove cation to aqueous phase.
2.5 | Tandem resolution of rac‐3,3,3‐
trifluorolactic acid using (S)‐1‐phenylethyl‐
amine
Equimolar amount of rac‐3,3,3‐trifluorolactic acid (7.0 g,
48.5 mmol) and (S)‐1‐phenylethylamine (6.4 mL, 50
mmol,) in 90 mL dry ethyl acetate (3 Å UOP molecular
sieves) were refluxed for 2 hours under N2 with flow
extractor charged with freshly calcined 3 Å UOP molecu-
lar sieves for removal the traces of water. Solution was
slowly cooled to 0°C in ice bath and left for 3 hours.
Resulting colorless block crystals of 1 were filtered off
(5.40 g, 84% yield, 92% ee).
A total of 7 mL of water was added to the filtrate,
heated to full dissolution of precipitate, and slowly
cooled down to ambient temperature. The platy white
crystals of 2 settle out after 3 hours (2.91 g) and a further
crop (2.65 g) overnight. Combined yield of salt 2
(S)‐[NH3CHMePh] (R)‐[CF3CH(OH)COO]·H2O) was
5.56 g, 81% yield (96% ee).
3 | RESULTS
3.1 | Resolution 1: Reinvestigation using
1‐phenylethylamine
In the previous report for the resolution of rac‐3,3,3‐
trifluorolactic acid, an equimolar requivalent of (S)‐1‐
phenylethylamine was added to a 9:1 ethyl acetate:
hexane solution of the acid.12 This was then heated at
60°C for 30 minutes and upon cooling afforded a solid
in 75% yield with 68% ee. Three crystallizations were
required to obtain a reasonably enantiopure sample. To
examine the system in more detail, the reaction was
duplicated on a mmol scale reaction in ethyl acetate.
Solids collected were in ca. 70% yield, and these were
ground and a powder X‐ray pattern was recorded of the
product mixture.
A
single crystal structure determination of
a
2.6 | Tandem resolution of rac‐3,3,3‐
specimen from the solid mixture showed the structure
to be the (S)‐(S) salt 1, (S)‐[NH3CHMePh]
(S)‐[CF3CH(OH)COO]. Details of this and other single
crystal structure determinations are given in Table 1.
The structure of an ion pair in 1 is shown in Figure 2.
Crystals of 1 are monoclinic, space group P21 and have
two ion pairs per cell (Z′ = 1, Z = 2) and a cell volume of
652.2Å3 at 100 K. The structure refined to acceptably low
(R)‐indices and Flack parameter with a clean final elec-
tron density map (no difference peaks or holes >0.2
e−Å−3) consistent with a clean (S)‐(S) cation‐anion stereo-
chemistry for the salt in the single crystal specimen. The
structure itself was thus consistent with a more optimal
resolution; hence, the phase purity of the solid product
trifluorolactic acid by sequential use of (S)‐
phenylglycinol and (S)‐1‐phenylethylamine
Rac‐3,3,3‐trifluorolactic acid (10.31 mmol, 1.485 g), (S)‐
phenylglycinol (5.4 mmol, 0.739 g) were heated (60°C, 2
hours) in 5.5 mL ethyl acetate. Upon cooling, colorless
plates of 5 (S)‐[NH3CH(CH2OH)Ph] (S)‐[CF3CH(OH)
COO] (1.102 g, 76% yield, 94 % ee) were obtained by fil-
tration. Then water (0.6 mL) and (S)‐1‐phenylethylamine
(5.4 mmol, 0.657 g) were added to the mother liquor
and crystals of 2 (S)‐[NH3CHMePh](R)‐[CF3CH(OH)
COO]·H2O (0.835 g, 58% yield, 95 % ee) after 5 hours
and a further crop (170 mg) collected overnight to give
a total yield of 69%.