RSC Advances
Paper
CH2, m), 1.00 (3H, CH2CH3, t); 13C NMR (100 MHz, CDCl3): d
170.82, 125.19, 51.74, 22.76, 21.38, 9.62.
(S)-2d [99% ee value, [a]2D5 +11u (c = 10 mg mL21, methanol)].
The best yields of KR and DKR process were 34% and 68%
respectively.
For the substrate 1e, the solvent was evaporated and the
reaction crude purified by flash chromatography on silica gel
(50% EtOAc/petroleum ether) to give the corresponding amide
(S)-2e [93% ee value, [a]2D5 +93.2u (c = 2 mg mL21, methanol)].
The best yields of KR and DKR process were 26% and 60%
respectively.
N-(1,1,1-trifluoro-3-methylbutan-2-yl)acetamide (2c)
1H NMR (400 MHz, CDCl3): d 4.73–4.39 (1H, CHCF3, m), 2.16
(1H, CH(CH3)2, m), 2.11–2.04 (3H, COCH3, s), 1.71 (1H, NH, s),
1.02 (3H, CH(CH3)2, d), 0.98 (3H, CH(CH3)2, d); 13C NMR (100
MHz, CDCl3): d 170.36, 125.27, 54.42, 27.43, 23.00, 19.80,
17.06.
Hydrolysis of the optically active amide 2e to the amine 1e.
The optical amide 2e (92.4 mg, 0.4 mmol), 6 N HCl (1.5 mL)
and methanol (1.5 mL) were added to a round-bottomed flask
with a reflux condenser, and then agitated together at 80 uC for
15 h. When the reaction was complete, the mixture was
concentrated to remove methanol, and then neutralized with 4
N NaOH, and thereafter extracted with dichloromethane. The
organic layers were combined and the solvent was then
removed to give the amine 1e (75 mg, 0.396 mmol, 99% yield).
In order to gain the ee value of the amine 1e, acylation was
then carried out according to the above procedure. The
obtained product was measured regarding optical purity by
GC with a chiral column. The optical purity of the produced
(S)-amide 2e was maintained at the 93% ee value.
N-(2,2,2-trifluoro-1-phenylethyl)acetamide (2d)
1H NMR (400 MHz, CDCl3): d 7.43–7.18 (5H, aromatic protons,
m), 6.07 (1H, NH, d), 5.76–5.55 (1H, CHCF3, m), 2.10–1.90 (3H,
COCH3, s); 13C NMR (100 MHz, CDCl3): d 169.48, 132.84,
129.32, 129.02, 127.90, 125.91, 54.26, 23.15.
N-(1,1,1-trifluoro-3-phenylpropan-2-yl)acetamide (2e)
1H NMR (400 MHz, CDCl3): d 7.30–7.07 (5H, aromatic protons,
m), 5.63–5.32 (1H, NH, m), 4.93–4.84 (1H, CHCF3, m), 3.13
(1H, CH2Ph, dd), 2.70 (1H, CH2Ph, dd), 1.83 (3H, COCH3, s);
13C NMR (100 MHz, CDCl3): d 170.13, 134.91, 128.99, 128.72,
127.26, 125.04, 51.03, 34.26, 22.82.
Chemical synthesis of racemic amides (reference com-
pounds). Acetyl chloride (13 mmol) was added to a stirred
solution of amine (10 mmol) and triethylamine (11 mmol) in
dichloromethane (5 mL) at 0 uC. The reaction mixture was
allowed to stand at room temperature for 30 min. Cold water
was then added, and the organic layer was washed with dilute
hydrochloride acid to adjust the pH to 8. Aqueous layer was
extracted with dichloromethane and the organic layers were
combined. The solvents were then removed, and white crystals
of amide were obtained by recrystallization in n-hexane/EtOH.
Kinetic resolution or dynamic kinetic resolution of the
amines. Isopropyl acetate (0.5 mmol) and amine (0.1 mmol)
were dissolved in dry THF (1a, 1 mL) or toluene (1b to 1e, 1
mL), and 4 Å molecular sieves (100 mg) were added. The
kinetic resolution was started by addition of CALB (1a, 10 mg;
1b to 1e, 50 mg), or the dynamic kinetic resolution was
initiated by addition of CALB together with 5 mol% Pd/Al2O3
(20% w/w) at the required temperature. After the reaction was
terminated, the catalysts and molecular sieve were filtered off
and the samples were analyzed by GC.
For the substrate 1a, the solvent and residues were removed
by distillation and the corresponding amide (R)-2a [50% ee
value, [a]2D5 23.4u (c = 9 mg mL21, methanol)] was obtained.
The best yields of KR and DKR process in the solvent THF were
42% and 63% respectively.
For the substrate 1b, the solvent and residues were removed
by distillation in vacuum and the corresponding amide (S)-2b
(ee value ,5%) was obtained. The best yields of KR and DKR
process were 30% and 65% respectively.
Acknowledgements
The financial support from the National Natural Science
Foundation of China (No. 21072172, 21272208) and the
Zhejiang Provincial Natural Science Foundation (Project No.
2010-Z4090225) is gratefully acknowledged.
References
1 Y. Cheng, A. L. Guo and D. S. Guo, Curr. Org. Chem., 2010,
14, 977–999.
2 M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2005,
44, 214–231.
¨ ¨
3 B. Torok and G. K. S. Prakash, Adv. Synth. Catal., 2003, 345,
165–168.
4 W. R. Dolbier Jr, J. Fluorine Chem., 2005, 126, 157–163.
5 G. L. Grunewald, J. Lu, K. R. Criscione and C. O. Okoro,
Bioorg. Med. Chem. Lett., 2005, 15, 5319–5323.
6 I. J. Collins, J. C. Hannam, A. Madin and M. P. Ridgill,PCT
int. Appl. WO 2005/030731 A1.
7 S. Allen, S. S. Andrews, K. R. Condroski, J. Haas, L. Huang,
Y. Jiang, T. Kercher and J. Seo, PCT int. Appl. WO 2011/
006074 A1.
8 T. Siu, J. Young, M. Altman, A. Northrup, M. Katcher,
E. Sathyajith, E. Kozina, S. Peterson and M. Childers, PCT
int. Appl. WO 2009/035575 A1.
For the substrate 1c, the solvent and residues were removed
by distillation in vacuum and the corresponding amide (S)-2c
[88% ee value, [a]2D5 +26.8u (c = 2 mg mL21, methanol)] was
obtained. The best yields of KR and DKR process were 40%
and 80% respectively.
For the substrate 1d, the solvent was evaporated and the
reaction crude purified by flash chromatography on silica gel
(50% EtOAc/petroleum ether) to give the corresponding amide
9 Y. W. Wu and L. Deng, J. Am. Chem. Soc., 2012, 134,
14334–14337.
10 M. Liu, J. Li, X. Xiao, Y. Xie and Y. Shi, Chem. Commun.,
2013, 49, 1404–1406.
11 J. Liu and J. Hu, Future Med. Chem., 2009, 1, 875–888.
12 Z. Liu and J. Liu, Chem. Commun., 2008, 5233–5235.
13 A. Henseler, M. Kato, K. Mori and T. Akiyama, Angew.
Chem., Int. Ed., 2011, 50, 8180–8183.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 9820–9828 | 9827