1732
P.D. Bailey et al. / Tetrahedron 65 (2009) 1724–1736
compound as a white solid (0.078 g, 45%). Rf 0.24 both isomers
(diethyl ether); mp (S,S) isomer 142–145 ꢀC; (S,R) isomer 113–
(22 mg, 95%, 100% d.e.) as a colourless, viscous oil. Rf 0.60 for both
isomers [(2:1) hexane–ethyl acetate]; dH (CDCl3, 90 MHz) 7.37–7.27
(5H, m, Ph), 6.60 (1H, br s, NH), 5.69 [5.51] (1H, d, JHF 55.5, CHF), 5.13
(1H, quin, Jw7.0, CHMe), 1.54 (3H, d, J 6.8, CHMe); dC (CDCl3,
22.5 MHz) 162.6 (d, JCF 25.6, C]O) (s), 141.8 (s, ArC), 128.8 (d, ArC),
127.8 (d, ArC), 126.3 (d, ArC), 96.0 (d, JCF 224.0, CHF) (d), 49.1 (d,
CHMe), 21.4 [21.5] (q, Me); nmax (CHCl3)/cmꢁ1 3430, 2930, 2120
(N3), 1690, 1500, 1310, 1005; m/z no Mþ, 174 (50%), 159 (59), 132
(58), 104 (74), 77 (100), 51 (72), 42 (39).
117 ꢀC (dichloromethane–hexane); (S,S) isomer [
a
] ꢁ167.1 (c 0.35,
CHCl3); (S,R) isomer [
a
] ꢁ52.9 (c 0.73, CHCl3); found: Mþ 292.1216.
C15H17FN2O3 requires 292.1223; dH (CDCl3, 200 MHz) 7.38–7.28 (5H,
m, Ph), 6.72 [6.65] (1H, d, JHF 47.8, CHF), 6.62 (1H, br s, NH) 5.15 (1H,
quin, Jw6.7, CHMe), 2.72 [2.75] (4H, t, J 6.5, CH2CH2CH2), 2.00 [2.04]
(2H, quin, J 6.5, CH2CH2CH2), 1.58 [1.59] (3H, d, J 6.9, CHMe); dC
(CDCl3, 100 MHz) 171.3 [171.5] (s, C]O), 164.4 (d, JCF 24.1, C]O) (s),
142.1 [142.4] (s, ArC), 128.8 (d, ArC), 127.5 [127.6] (d, ArC), 126.3 (d,
ArC), 85.2 (d, JCF 218.3, CHF) (d), 48.9 [49.1] (d, CHMe), 32.6 (t,
COCH2), 21.6 [21.2] (q, Me), 16.5 [16.6] (t, CH2); dF (CDCl3, 376 MHz)
ꢁ163.71 [ꢁ163.38] (d, JFH 47.8, CHF); nmax (KBr)/cmꢁ1 3313, 3287,
1750, 1705, 1672, 1539, 1347, 1239, 1172, 1126, 1050, 1013; m/z 292
(Mþ, 2%), 144 (21), 120 (100), 105 (100), 55 (99).
6.15. (S/R)-N-[(S)-1-Phenylethyl]-2-cyano-2-fluoro-
ethanamide, 14a,b
Fluoroethanamide 3a,b (122 mg, 0.40 mmol) and potassium
cyanide (25 mg, 0.40 mmol) were dissolved in DMF (4 cm3) under
an argon atmosphere. The mixture was stirred at ambient tem-
perature for 2 h, and then the solvent was removed in vacuo. The
residue was purified via silica flash chromatography (dichloro-
methane) to yield the title compound as a colourless oil [35 mg, 42%
yield or 65% after correction for recovered starting material (43 mg,
35%)]. Rf 0.48 (both isomers, CH2Cl2); found: Mþ 206.0855.
C11H11FN2O requires 206.0855; dH (CDCl3, 90 MHz) 7.38–7.28 (5H,
m, Ph), 6.60 (1H, br s, NH), 5.48 {5.41} (1H, d, JHF 47.0, CHF), 5.16 (1H,
quin, Jw7.0, CHMe), 1.59 {1.57} (3H, d, J 7.0, CHMe); dC (CDCl3,
22.5 MHz) 159.3 (d, JCF 19.5, C]O) (s), 141.3 (s, ArC), 128.9 (d, ArC),
128.1 (d, ArC), 126.2 (d, ArC), 76.7 (d, JCF 201.0, CHF) (d), 49.7 (d,
CHMe), 21.2 (q, Me), CN signal not observed; dF (CDCl3, 84.5 MHz)
ꢁ190.5 (both isomers) (d, JFH 47.0); nmax (CHCl3)/cmꢁ1 3420, 3020,
1705, 1520, 1450, 1070, 700; m/z 206 (Mþ, 95%), 191 (100), 180 (34),
148 (34), 105 (92), 77 (48), 51 (52).
6.12. (S/R)-N-Benzyl-2-(2,5-dioxo-1-pyrrolidinyl)-2-
fluoroethanamide, 11
Ethanamide 11 was prepared according to the method described
for 9a using
4 (117 mg, 0.40 mmol), succinimide (44 mg,
0.44 mmol) and sodium hydride (13.3 mg, 0.44 mmol) in a total of
7 cm3 of DMF. This yielded the title compound (88 mg, 83%) as
a white solid. Rf 0.37 [(1:1) chloroform–ethyl acetate]; mp 123–
126 ꢀC [(1:6) chloroform–diethyl ether]; found: Mþ 264.0919.
C13H13FN2O3 requires 264.0910; dH (CDCl3, 300 MHz) 7.65 (1H, br s,
NH), 7.35–7.25 (5H, m, Ph), 6.12 (1H, d, JHF 48.7, CHF), 4.49 (2H, ABX,
JAB 14.9, JAX 6.4 and JBX 5.5, CH2), 2.81 [4H, s, (CH2)2]; dC (CDCl3,
22.5 MHz) 175.1 (s, C]O), 163.6 (d, JCF 26, C]O) (s), 137.1 (s, ArC),
128.5 (d, ArC), 127.4 (d, ArC), 127.6 (d, ArC), 83.6 (d, JCF 217, CHF) (d),
43.2 (t, CH2N), 27.9 (t, CH2); nmax (CHCl3)/cmꢁ1 3440, 3020, 1795,
1735, 1700, 1535, 1380, 1255, 1180, 1050, 700; m/z 264 (Mþ, 9%) 166
(20), 106 (100), 91 (94), 65 (20), 55 (35).
6.16. (E)-3-Amino-3-cyano-2-fluoro-N-[(S)-1-phenylethyl]-
acrylamide, 15
6.13. (S/R)-N-Benzyl-2-(2,6-dioxo-1-piperidinyl)-2-
fluoroethanamide, 12
Fluoroiodoethanamide 3a,b (126 mg, 0.41 mmol) and potassium
cyanide (60 mg, 0.92 mmol) were dissolved in DMF (5 cm3) under
an argon atmosphere, and stirred at ambient temperature for 20 h.
After removal of the solvent in vacuo, the residue was purified via
silica flash chromatography (diethyl ether) to yield the title com-
pound (85 mg, 89%) as a dark red oil. Rf 0.18 (CH2Cl2); found: Mþ
233.0964. C12H12FN3O requires 233.0964; dH (CDCl3, 90 MHz) 7.38–
7.28 (5H, m, Ph), 5.44 (1H, q, J 7.2, CHMe), 4.56 (1H, br s, OH), 1.71
(3H, d, J 7.2, CHMe) (no other signals clearly observed); dC (CDCl3,
22.5 MHz) 139.6 (s, ArC),128.8 (d, ArC),127.8 (d, ArC),126.5 (d, ArC),
47.8 (d, CHMe), 17.3 (q, Me) from the auxiliary, plus four weak
signals at 164.5, 163.4, 154.0 and 153.5, all of which are singlets in
the off-resonance spectrum; nmax (CHCl3)/cmꢁ1 3500, 3390, 3310,
3000, 1750, 1715, 1655, 1585, 1420, 1390, 1265, 1190, 1135, 905, 860,
700; m/z 233 (Mþ, 22%), 129 (73), 105 (100), 77 (19).
Ethanamide 12 was prepared according to the procedure de-
scribed above for 10a,b, using glutarimide (2.819 g, 24.9 mmol),
sodium bis(trimethylsilyl)amide (1.0 M in THF, 19.9 cm3,
19.9 mmol) and ethanamide 4 (1.459 g, 4.98 mmol) in anhydrous
THF (100 cm3) yielding the title compound as a white crystalline
solid (0.601 g, 54%). Rf 0.24 (diethyl ether); mp 164–167 ꢀC (diethyl
ether–hexane); found: Mþ 278.1058. C14H15FN2O3 requires
278.1067; found: C, 60.41; H, 5.54; N, 9.91%. C14H15FN2O requires C,
60.43; H, 5.43; N, 10.07%; dH (CDCl3, 200 MHz) 7.38–7.28 (5H, m,
Ph), 6.70 (1H, br s, NH), 6.69 (1H, d, JHF 50.0, CHF), 4.58 (1H, ABX, J
14.8 and 5.7, PhCHHNH) and 4.48 (1H, ABX, J 14.8 and 5.7,
PhCHHNH), 2.71 (4H, t, J 6.5, CH2CH2CH2), 2.02 (2H, quin, J 6.5,
CH2CH2CH2); dC (CDCl3, 75 MHz) 171.4 (s, C]O), 165.2 (d, JCF 24.8,
C]O) (s), 137.3 (s, ArC), 128.8 (d, ArC), 127.9 (d, ArC), 127.7 (d, ArC),
85.2 (d, JCF 218.0, CHF) (d), 43.5 (t, CH2N), 32.6 (t, COCH2), 16.5 (t,
CH2); dF (CDCl3, 188 MHz) ꢁ165.6 (dd, JFH 50.0 and 3.5); nmax (KBr)/
cmꢁ1 3324, 1747, 1704, 1674, 1552, 1345, 1174, 1120, 1042, 743, 701;
m/z 278 (Mþ, 8%), 106 (100), 91 (65).
6.17. (S)-N-[(S)-1-Phenylethyl]-a-fluorobetainamide, 16a
Ethanamide 3a (100 mg 0.33 mmol) was dissolved in distilled
acetone (3 cm3), then cooled to 0 ꢀC. To this was added a 4.5 M
solution of trimethylamine in acetone (75 mL, 0.34 mmol) and the
mixture was stirred at ambient temperature for 3 h. The solvent
and excess amine were then removed in vacuo to yield the title
compound (117 mg, 98%, 100% d.e.) as a white solid. Mp>300 ꢀC; dH
(DMSO-d6, 300 MHz) 9.62 (1H, br s, NH), 7.38–7.24 (5H, m, Ph), 6.04
[6.03] (1H, d, JHF 45.0, CHF), 5.03 (1H, quin, Jw7.2, CHMe), 3.24
[3.22] (9H, d, JHF 1.3, NMe3), 1.48 [1.47] (3H, d, J 6.8, CHMe); dC
(DMSO-d6, 22.5 MHz) 162.4 (d, JCF 22, C]O) (s), 146.4 [146.5] (s,
ArC), 132.5 (d, ArC), 131.2 (d, ArC), 130.1 (d, ArC), 102.4 (d, JCF 232,
CHF) (d), 54.0 (q, NMe3), 52.8 (d, CHMe), 25.4 (q, Me); dF (DMSO-d6,
84.5 MHz) ꢁ167.4 (both isomers) (d, JFH 45.0); nmax (Nujol)/cmꢁ1
3280,1700,1540,1470,1400,1380,1250,1220,1155,1105,1090, 960,
6.14. (S)-N-[(S)-1-Phenylethyl]-2-azido-2-fluoro-
ethanamide, 13a
Sodium azide (108 mg, 1.67 mmol) and 3a (32 mg, 0.10 mmol)
were dissolved in DMF (5 cm3) and then stirred at ambient tem-
perature for 3 h. Next DMF was removed in vacuo to leave a white
solid, which was triturated thoroughly with diethyl ether
(2ꢂ20 cm3), then filtered. The ether was removed from the filtrate
to leave a residue, which was purified via silica flash chromato-
graphy [(3:1) hexane–ethyl acetate] to yield the title compound