894
V. Michaut et al. / Journal of Fluorine Chemistry 128 (2007) 889–895
1H (CD3OD): 2.88 (1H, dd, J = 8.7, J = 17.7), 3.05 (1H, dd,
J = 4.1, J = 17.7), 4.52 (1H, m), 5.25 (4H, b); NMR 13C
(CDCl3): 31.9, 50.7 (q, J = 32.5), 125.1 (q, J = 279.9), 171.2;
Anal. Calcd. for C4H7ClF3NO2: C, 24.82; H, 3.65; N, 7.24;
found: C, 24.84; H, 3.73; N, 7.18; optical rotation (c = 1.00,
anal. calcd. for C13H16F3NO2: C, 56.72; H, 5.86; N, 5.09;
found: C, 56.69; H, 5.68; N, 5.54; optical rotation (c = 1,
CHCl3, 25 8C): (R): [a]D = +22.6; [a]436 = +53.8; [a]546
+31.5; [a]578 = +27.6.
=
HCl 6N, 25 8C): (R): [a]D = +21.5; [a]365 = +65.7; [a]546
=
4.8. 1-Benzyl-4-(trifluoromethyl)azetidin-2-one (6)
+26.4; [a]578 = +23.5; (S) [a]D = À21.6; [a]365 = À60.0;
[a]546 = À24.1; [a]578 = À21.3.
Under inert atmosphere, at À12 8C, a freshly prepared
solution of methyl magnesium iodide in anhydrous diethyl
ether (1.3 mmol) was slowly added to a stirred solution of (R)
or (Rac.) ethyl 3-(benzylamino)-4,4,4-trifluorobutanoate 5
(0.170 g, 0.6 mmol) in anhydrous diethyl ether (2 mL). Once
the addition was finished, the reaction mixture was stirred at
À12 8C for 15 min more. Thereafter, the slurry was quenched
with saturated aqueous solution of NH4Cl and extracted 3 times
with diethyl ether. Organic phases were combined, washed with
aqueous NaHCO3, water and dried over Na2SO4. The filtered
solution was concentrated in vacuum. The residue was purified
by column chromatography with cyclohexane/ethyl acetate
(6/1) to yield desired product (0.112 g, 80%) as white solid.
C11H10F3NO, MW = 229.20, white solid, mp = 58–60 8C; IR
4.6. 3-Amino-4,4,4-trifluorobutan-1-ol (4)
To a suspension of LiAlH4 (0.205 g, 5.4 mmol) in dry THF
(17 mL), ethyl 3-amino-4,4,4-trifluorobutanoate 2 (0.5 g,
2.7 mmol) was added at À15 8C. Resulting mixture was stirred
for 2 h at À15 8C. Reaction was then quenched with iced water
and after stirring for 20 min at room temperature, mixture was
filtrated and extracted several times with diethyl ether. Solvent
was evaporated and crude product was purified on silica gel
column with a mixture of dichloromethane/methanol (97/3) as
eluent to afford desired product (0.251 g, 65%), as colourless
oil.
C4H8F3NO, MW = 143.11, colourless oil; NMR 19F
(CDCl3): À80.2 (3F, d, J = 6.9); NMR 1H (CDCl3): 1.61
(1H, m), 1.86 (1H, m), 2.30 (1H, b), 3.34 (1H, m), 3.82 (2H, m);
NMR 13C (CDCl3): 31.0, 53.8 (q, J = 29.7), 60.9, 126.2 (q,
J = 281.3); GC (BETA DEX 120, 15 m, 60 8C): (S): 12.6 min;
(R): 13.5 min; Anal. Calcd. for C4H8F3NO: C, 33.57; H, 5.63;
N, 9.79; found: C, 33.46; H, 5.79; N, 9.83; optical rotation
(c = 1.5, CHCl3, 25 8C): (R): [a]D = +44.0; [a]365 = +134.1;
[a]436 = +89.0; [a]546 = +53.7; [a]578 = +47.7.
(cmÀ1): 3033 (CHAro); 2940 (CH2); 1775 (COlactam); NMR 19
F
1
(CD3OD): À75.3 (d, J = 5.72); NMR H (CD3OD): 2.97 (1H,
dd, J = 15.1, J = 2.6), 3.05 (1H, dd, J = 15.1, J = 5.28), 3.75
(1H, m), 4.75 (1H, d, J = 15.1), 4.80 (1H, d, J = 15.1), 7.18–
7.33 (5H, m); NMR 13C (CD3OD): 38.7, 45.9, 49.8 (q,
J = 35.3), 124.6 (q, J = 279.0), 128.3, 128.6, 129.1, 134.7,
165.3; GC (Chiral DEX bDA, 40 m, 120 8C): (R): 14.0 min;
(S): 14.5 min; anal. calcd. for C11H10F3NO: C, 57.64; H, 4.40;
N, 6.11; found: C, 57.62; H, 4.44; N, 6.26; optical rotation
(c = 1, CHCl3, 25 8C): (R): [a]D = À108.7; [a]365 = À414.9;
[a]436 = À239.6; [a]546 = À131.5; [a]578 = À113.8.
4.7. (R)-Ethyl 3-(benzylamino)-4,4,4-trifluorobutanoate (5)
Freshly distilled benzaldehyde (329 mL, 3.24 mmol) was
added dropwise to a solution of (R)-ethyl 3-amino-4,4,4-
trifluorobutanoate 2 (0.4 g, 2.16 mmol) in a mixture of ethanol
(14 mL) and glacial acetic acid (3.5 mL). The resultant mixture
was stirred at room temperature for 1.5 h. After cooling to 0 8C,
sodium borohydride (0.144 g, 3.78 mmol) was added in
portions. After being stirred for an additional 15 min, the
reaction mixture was partitioned between saturated NaHCO3
and dichloromethane, the aqueous phase was twice extracted
with dichloromethane. Organic layers were combined, dried
over Na2SO4, and condensed in vacuum. The residue was
placed on silica gel column and eluted with a mixture of
cyclohexane/ethyl acetate (90/10) to afford desired product
(0.209 g, 76%) as colourless oil.
C13H16F3NO2, MW = 275.27, colourless oil; IR (cmÀ1):
3355 (NH); 3030 (CHAro); 2984 (CH3); 2937 (CH2); 1740
(CO); 1603 (dbAro); NMR 19F (CDCl3): À75.3 (3F, d, J = 6.8);
NMR 1H (CDCl3): 1.08 (3H, t, J = 7.2), 1.56 (1H, bs), 2.30 (1H,
dd, J = 9.8, J = 15.5), 2.52 (1H, dd, J = 4.1, J = 15.5), 3.50 (1H,
m), 3.70 (1H, d, J = 12.8), 3.80 (1H, d, J = 12.8), 4.05 (2H, m),
7.10 (5H, m); NMR 13C (CDCl3): 14.0, 35.0, 52.0, 56.2 (q,
J = 28.4), 61.0, 126.3 (q, J = 284.0), 127.3, 128.2, 128.4, 139.5,
170.0; GC (BPX5, 23 m, 40 8C (5 min), 8 8C/min, 280 8C):
16.1 min; GC–MS (EI): 91(100); 106(95); 188(9); 275(Mꢀ+);
4.9. N-[(Z)-Gly]-ethyl 3-amino 4,4,4-trifluorobutanoate (7)
To a stirred solution of Z-glycine (0.31 g, 1.48 mmol) in
distilled dichloromethane (20 mL), oxalyl dichloride (150 mL,
1.76 mmol) and a drop of distilled DMF were added dropwise
at 0 8C. After 2 h stirring at room temperature, ethyl 3-amino-
4,4,4-trifluorobutanoate 2 (0.3 g, 1.62 mmol) was first added
and then DIEA (0.84 mL, 4.8 mmol) was added dropwise at
0 8C. Once the addition was finished, the mixture was heated at
40 8C for 16 h. Thereafter, dichloromethane was added and the
mixture was washed twice with aqueous solution of NaHCO3
1 M, twice with aqueous solution of citric acid (5%) and finally
twice with distilled water. Organic phase was dried over MgSO4
and concentrated in vacuum. The residue was purified by
recrystallization (ethyl acetate/hexane) to yield the desired
product (0.41 g, 75%) as white solid.
C16H19F3N2O5, MW = 376.33, white solid, mp = 110 8C; IR
(cmÀ1): 3416 (NH); 3074 (CHAro); 2981 (CH2); 1728 (COester);
1695, 1682 (COamide); NMR 19F (CD3OD): À76.3 (3F, d,
1
J = 6.8); NMR H (CD3OD): 1.24 (3H, t, J = 7.2), 2.66 (2H,
2dd, J = 15.8, J = 7.2, J = 3.7), 3.91 (2H, d, J = 5.3), 4.15 (2H,
q, J = 7.2), 5.02 (1H, m), 5.12 (2H, s), 5.56 (1H, bs), 7.23 (1H,
bs), 7.34 (5H, m); NMR 13C (CD3OD): 14.1, 33.1, 44.7, 47.6 (q,
J = 31.8), 61.7, 67.5, 124.6 (q, J = 282.0), 128.2, 128.5, 128.7,