Synthesis of R,R-Disubstituted Amino Acid Derivatives
J . Org. Chem., Vol. 61, No. 21, 1996 7401
ration of solvent gave a colorless oil that solidified on standing.
It was purified by crystallization from ethyl acetate/hexane
to give 3 as colorless needles (43.8 g, 70%): mp 57-59 °C; 1H
NMR (CDCl3) δ 1.33 (t, 3H, J ) 7.3 Hz), 1.66 (s, 3H), 1.97 (s,
3H), 3.17 (d, 1H, J ) 13.5 Hz), 3.60 (d, 1H, J ) 13.5 Hz), 4.23
(m, 2H), 6.14 (bs, 1H), 6.73 - 6.91 (m, 3H), 7.19 (m, 1H); 13C
(CDCl3) δ 14.29, 23.64, 24.23, 40.48, 61.24, 62.17, 113.93 (J )
21.06 Hz), 116.83 (J ) 20.37 Hz), 125.69 (J ) 4.07 Hz), 129.72
(J ) 7.47 Hz), 139.36 (J ) 6.79 Hz), 162.78 ( J ) 245.20 Hz),
169.82, and 173.93; MS (CI) 268 (MH+). Anal. Calcd for
C14H18FNO3: C, 62.90; H, 6.78; N, 5.24. Found: C, 62.95; H,
6.66; N, 5.25.
En zym a tic Resolu tion of 3: (R)-2-(Acetyla m in o)-2-
m eth yl-3-(3-flu or op h en yl)p r op ion ic Acid Eth yl Ester (9)
a n d (S)-2-(Acetyla m in o)-2-m eth yl-3-(3-flu or op h en yl)p r o-
p ion ic Acid (10). To a stirring suspension of racemic ester
3 (42.7 g, 0.16 mol) in potassium phosphate buffer (0.2M, pH
6.0, 850 mL) were added t-BuOH (85 mL) and lipase L-10 (42.7
g), and the mixture was stirred at room temperature for 5 d,
keeping the pH of the reaction mixture constant by adding 2
N KOH solution as needed. Celite 545 (100 g) and reagent
alcohol (500 mL ) was added to the reaction mixture, which
was then stirred for 1 h and filtered. The pH of the filtrate
was adjusted to 8.8 with 2 N NaOH, and it was extracted with
ethyl acetate. The combined organic extracts were dried (Na2-
SO4 ) and concentrated. The residue was passed through a
small silica gel column using 1:1 ethyl acetate/hexane to give
pure ester 9 as an oil (20.2 g, 47.3%): 1H and 13C are same as
in 3; HRMS calcd for C14H18FNO3 268.1349, found 268.1352.
ee >99.9% as determined by chiral HPLC.
The pH of the aqueous layer was next adjusted to 7.0 with
2 N HCl and evaporated to dryness. The pure acid 10 was
isolated from a silica gel column using 1% acetic acid/ethyl
acetate as the eluant to afford a colorless solid (14 g, 36.7%):
mp 210-211 °C; 1H NMR (DMSO) δ 1.20 (s, 3H), 1.83 (s, 3H),
2.97 (d, 1H, J ) 13.5 Hz), 3.33 (d, 1H, J ) 13.5 Hz), 6.86-
6.95 (m, 2H), 7.05 (t, 1H, J ) 8.37 Hz), 7.33 (m, 1H), 7.85 (bs,
1H), and 12.46 (bs, 1H); 13C NMR (DMSO) δ 22.40, 22.65,
40.00, 58.06, 113.21 (J ) 20.68 Hz), 117.00 (J ) 20.68 Hz),
126.69 (J ) 2.38 Hz), 129.65 (J ) 7.84 Hz), 140.95 (J ) 7.84
Hz), 161.87 (J ) 243.03 Hz), 169.06, and 174.98; MS (CI) 240
(MH+). Anal. Calcd for C12H14FNO3: C, 60.24; H, 5.89; N,
5.85. Found: C, 60.38; H, 5.99; N, 5.75. ee ) 95.6%.
2-(Acetyla m in o)-2-m eth yl-3-(3-flu or op h en yl)p r op ion a -
m id e (14). Acetic anhydride (75 mL) was added to the acid
10 (8.00 g, 33.47 mmol), and the mixture was stirred at 140
°C for 0.25 h. After the reaction mixture was cooled to room
temperature, acetic anhydride was evaporated under reduced
pressure to give the oxazolinone 13 as light yellow oil (7.4 g,
99%): 1H NMR (CDCl3) δ 1.50 (s, 3H), 2.02 (s, 3H), 3.04 (s,
2H), 6.85-6.96 (m, 3H), 7.18-7.25 (m, 1H). It was used as
such without further purification in the next step.
chromatography, using 1:1 ethyl acetate/hexane, as a light
yellow solid (0.14 g, 75%): mp 135-137 °C; H NMR (CDCl3)
1
δ 1.64 (s, 3H), 2.01 (s, 3H), 3.26 (d, 1H, J ) 13.64 Hz), 3.38 (d,
1H, J ) 13.64 Hz), 5.48 (bs, 1H), 6.94-7.05 (m, 3H), and 7.28-
7.36 (m, 1H); 13C NMR (DMSO + CDCl3) δ 21.96, 23.20, 41.49,
49.01, 113.23 (J ) 20.88 Hz), 116.40 (J ) 20.94 Hz), 119.45,
125.56 (J ) 2.70 Hz), 128.77 (J ) 8.49 Hz), 135.81 (J ) 7.10
Hz), 161.32 (J ) 245.23 Hz), and 169.16; HRMS calcd for
C
12H13FN2O 221.1090, found 221.1098.
2-(Acet yla m in o)-2-m et h yl-3-(3-flu or op h en yl)t h iop r o-
p ion a m id e (15). H2S gas was passed through a solution of
nitrile 12 (0.061 g, 0.28 mmol) in ethyl alcohol (3 mL) and
ammonium hydroxide (1 mL) at -10 °C until the reaction
mixture was saturated. The flask was sealed, and the reaction
mixture was stirred at room temperature for 20 h. After
removal of excess H2S, the reaction mixture was diluted with
water and extracted with ethyl acetate. The combined extracts
were dried (Na2SO4), evaporated, and subjected to column
chromatography (elution with 1:1 ethyl acetate/hexane) to give
15 as a colorless viscous oil (0.064 g, 91%): 1H NMR (DMSO)
δ 1.32 (s, 3H), 1.84 (s, 3H), 3.47 (s, 2H), 6.85-6.94 (m, 2H),
7.02-7.09 (m, 1H), 7.28-7.36 (m, 1H), 7.77 (bs, 1H), 8.96 (bs,
1H), and 9.65 (bs, 1H); 13C NMR (CDCl3) δ 24.39, 25.87, 42.76,
64.84, 114.07 (J ) 20.88 Hz), 117.08 (J ) 21.07 Hz), 126.00 (J
) 2.58 Hz), 129.63 (J ) 8.30 Hz), 138.42 (J ) 7.67 Hz), 162.58
(J ) 245.67 Hz), 170.63, and 210.54; HRMS calcd for C12H15
FN2OS 255.0967, found 255.0945.
-
N-Acet yl-1-(3-flu or op h en yl)-2-m et h yl-2-(2-t h ia zolyl)-
eth yla m in e (16). To a solution of thioamide 15 (7.64 g, 27.33
mmol) in dry acetone (160 mL) was added bromoacetaldehyde
diethyl acetal (20.6 mL, 136.65 mmol) and HCl/dioxane (4 N,
0.3 mL). After the mixture was refluxed for 24 h, acetone was
evaporated and the residue was dissolved in CH2Cl2. It was
washed with water, dried (Na2SO4), and concentrated. The
pure product 16 was obtained by column chromatography on
silica gel using 1:1 ethyl acetate/hexane as eluant to afford a
light brown oil (5.70 g, 75%): 1H NMR (CDCl3) δ 1.90 (s, 3H),
2.01 (s, 3H), 3.35 (d, 1H, J ) 13.36 Hz), 3.77 (d, 1H, J ) 13.36
Hz), 6.50 (m, 1H), 6.61 (m, 1H), 6.71 (bs, 1H), 6.88 (m, 1H),
7.12 (m, 1H), 7.33 (d, 1H, J ) 3.24 Hz), and 7.61 (d, 1H, J )
3.24 Hz); 13C NMR (CDCl3) δ 24.30, 27.89, 45.37, 60.12, 113.62
(J ) 20.88 Hz), 116.94 (J ) 21.07 Hz), 119.40, 125.71 (J )
2.01 Hz), 129.19 (J ) 8.30 Hz), 138.73 (J ) 7.48 Hz), 141.13,
162.37 (J ) 245.17 Hz), 169.77, and 175.50; HRMS calcd for
C
14H15FN2OS 279.0967, found 279.0979.
1-(3-F lu o r o p h e n y l)-2-m e t h y l-2-(2-t h ia zo ly l)e t h y l-
a m in e (1). A mixture of 16 (4.70 g, 16.9 mmol) and 2 N HCl
(40 mL) was refluxed for 6.5 h. After the reaction mixture
was cooled, it was extracted with ethyl acetate. The organic
layer was discarded, the aqueous phase was made basic with
solid NaHCO3, and the crude product was extracted with CH2-
Cl2. The combined extracts were dried over Na2SO4, the
solvents were evaporated, and the amine 1 was obtained as a
light brown oil from a silica gel column using 1:1 ethyl acetate/
hexane as an eluant (3.23 g, 81%): 1H NMR (CDCl3) δ 1.59 (s,
3H), 1.78 (bs, 2H), 3.04 (d, 1H, J ) 13.09 Hz), 3.32 (d, 1H, J
) 13.09 Hz), 6.63-6.92 (m, 3H), 7.13-7.20 (m, 2H) and 7.76
(d, 1H, J ) 3.24 Hz); 13C NMR (CDCl3) δ 30.30, 50.07, 57.46,
113.76 (J ) 20.78 Hz), 117.26 (J ) 20.58 Hz), 118.96, 126.17
(3.73 Hz), 129.55 (J ) 8.62 Hz), 139.43 (J ) 7.33 Hz), 142.85,
Ammonia was bubbled through a solution of 13 (0.3 g, 1.34
mmol) in dry CHCl3 at -10 °C for 0.3 h. The tube was then
sealed, and the reaction mixture was stirred at room temper-
ature for 3 h. After the ammonia was evaporated, the reaction
mixture was filtered and the solid washed with CHCl3 and
dried to give 14 as a colorless solid (0.27 g, 83%): mp 223-
1
224 °C; H NMR (DMSO) δ 1.25 (s, 3H), 1.84 (s, 3H), 3.13 (d,
1H, J ) 13.23 Hz), 3.32 (d, 1H, J ) 13.23 Hz), 6.83-7.33 (m,
6H), and 7.53 (bs, 1H); 13C NMR (DMSO + CDCl3) δ 22.21,
22.31, 37.80, 58.31, 111.58 (J ) 20.85 Hz),115.31 (J ) 20.85
Hz), 124.67 (J ) 2.14 Hz), 127.77 (J ) 8.18 Hz), 138.71 (J )
7.11 Hz), 160.67 (J ) 243.97 Hz), 168.20, and 174.43; HRMS
calcd for C12H15FN2O3 239.1196, found 239.1198.
162.59 (J ) 245.28 Hz), and 180.62; HRMS calcd for C12H13
FN2S 237.0862, found 237.0867.
-
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spectra
for compounds 1, 4‚HCl, 9, 12, 14, 15, and 16 (7 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
2-(Acetyla m in o)-2-m eth yl-3-(3-flu or op h en yl)p r op ion i-
tr ile (12). Cyanuric chloride (0.1 g, 0.55 mmol) was added in
one portion to a stirring solution of amide 14 (0.2 g, 0.84 mmol)
in DMF at 0 °C. After the reaction mixture was stirred for 8
h at room temperature, it was quenched with ice-water and
extracted with CH2Cl2. The combined extracts were dried and
concentrated. The pure product 12 was obtained by column
J O9610671