Asymmetric Aza-Michael Reaction Mechanism
FULL PAPER
mixture was extracted with CH2Cl2 (3ꢁ100 mL), and the combined or-
ganic layers were washed with aq. NaHCO3 (3ꢁ50 mL), dried over
MgSO4, evaporated and purified by flash column chromatography. The
product was obtained as a white solid (1.64 g, 24%). Rf =0.35 (Et2O);
m.p. 92–938C; 1HNMR (270 MHz, CDCl 3): d = 8.44 (brs, 1H, NH),
5.80 (s, 1H; =CH2), 5.51 (s, 1H; =CH2), 3.70 (s, 3H; OCH3), 1.97 ppm (s,
3H; CH3); 13C NMR (100.6 MHz, CDCl3): d = 166.0 (s), 151.7 (s), 139.3
(s), 122.1 (s), 52.6 (s), 18.1 ppm (s); IR (KBr disc): n˜max =3286, 3108,
3002, 2958, 1773, 1687, 1636, 1458, 1225 cmꢀ1; MS (EI): m/z (%): 143 (45)
[M +ꢀH], 115 (14), 100 (24), 69 (82), 68 (48), 59 (26); elemental analysis
calcd (%) for C6H9NO3: C 50.35, H6.34, N 9.79, found: C 50.43, H6.24,
N 9.65.
(31); elemental analysis calcd (%) for C17H18N2O2: C 72.32, H6.43, N
9.92, found: C 72.21, H6.42, N 9.91.
(S)-(ꢀ)-N-[3-(4-Methoxylphenylamino)-2-methyl-propionyl]-benzamide
(16c): White solid; Rf =0.31 (EtOAc/pet. ether 40–60 1:1); m.p. 134–
1358C; chiral HPLC (Chiralpak AD, 254 nm, 10% IPA in hexane,
1 mLminꢀ1): tR
N
G
A
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A
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AHCTREUNG
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A
N
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3
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Similar procedures were used for the preparation of tigloyl derivatives 14
and 15.
(67.5 MHz, CDCl3): d=176.9 (s), 165.5 (s), 152.8 (s), 141.6 (s), 133.1 (s),
132.9 (s), 128.9 (s), 127.6 (s), 115.0 (s), 112.9 (s), 55.8 (s), 48.3 (s), 40.5
(s), 14.8 ppm (s); IR (KBr disc): n˜max =3368, 3273, 1728, 1673, 1600, 1485,
1234, 823 cmꢀ1; MS (EI): m/z (%): 312 (31) [M +ꢀH], 136 (100), 105
(38), 77 (25), 44 (35); elemental analysis calcd (%) for C18H20N2O3: C
69.21, H6.45, N 8.97, found: C 69.16, H6.37, N 8.86.
N-(2-Methylbut-2-enoyl)-benzamide (14):[14] The product was obtained as
a white solid in 40% yield. Rf =0.60 (Et2O); m.p. 103–1048C; 1HNMR
(400 MHz, CDCl3): d = 8.80 (brs, 1H; NH), 7.81 (d, 3J
ACHTREUNG
3
2H; ArH), 7.58 (t, 3J
(H,H)=7.4 Hz, 1H; ArH), 7.47 (t, J
ACHTREUNG
2H; ArH), 6.60 (q, 3J
C
3
(S)-(ꢀ)-[3-(4-Chlorophenylamino)-2-methylpropionyl]-carbamic
acid
1.85 ppm (d, J
A
methyl ester (17a): White solid; m.p. 124–1258C; Rf =0.67 (Et2O); chiral
d = 168.2 (s), 166.6 (s), 134.8 (s), 134.1 (s), 133.6 (s), 133.0 (s), 128.8 (s),
127.8 (s), 14.4 (s), 12.4 ppm (s); IR (KBr disc): n˜max =3270, 1692, 1674,
1600, 1481 cmꢀ1; MS (EI): m/z (%): 203 (32) [M +ꢀH], 188 (20), 105
(100), 83 (31), 55 (48).
HPLC (Chiralcel OD-H, 254 nm, 5% IPA in hexane, 1 mLminꢀ1): tR-
A
N
A
ACHTREUNG
N-(2-Methylbut-2-enoyl)-carbamic acid methyl ester (15): The product
was obtained as a white solid in 26% yield. Rf =0.32 (Et2O); m.p. 107–
1088C; 1HNMR (400 MHz, CDCl 3): d = 7.80 (brs, 1H; NH), 6.53 (q,
G
ACHTREUNG
AHCTREUNG
3J
1.83 ppm (d, J
(H,H)=6.8 Hz, 3H; CH3); 13C NMR (100.6 MHz, CDCl3):
A
151.9 (s), 146.3 (s), 129.1 (s), 122.3 (s), 114.1 (s), 53.2 (s), 46.8 (s), 39.3
(s), 15.2 ppm (s); IR (KBr disc): n˜max =3388, 3221, 1768, 1679, 1601, 1510,
1215, 812, 718 cmꢀ1; MS (EI): m/z (%): 272/271 (7/2) [M +ꢀH], 270 (17),
238 (18), 142 (41), 140 (100); elemental analysis calcd (%) for
C12H15ClN2O3: C 53.24, H5.58, N 10.35, found: C 53.34, H5.68, N 10.38.
3
d = 166.5 (s), 151.8 (s), 134.2 (s), 131.9 (s), 52.7 (s), 14.2 (s), 12.0 ppm
(s); IR (KBr disc): n˜max =3290, 1745, 1682, 1513, 1460, 1214 cmꢀ1; MS
(EI): m/z (%): 157 (72) [M +ꢀH], 129 (12), 83 (66), 82 (100), 55 (81), 54
(43); elemental analysis calcd (%) for C7H11NO3: C 53.49, H7.05, N 8.91,
found: C 53.33, H6.95, N 8.85.
(S)-(ꢀ)-N-(2-Methyl-3-phenylaminopropionyl)-carbamic acid methyl
ester (17b): White solid; m.p. 110–1118C; Rf =0.67 (Et2O); chiral HPLC
(Chiralpak AD, 254 nm, 2% IPA in hexane, 1 mLminꢀ1): tR
ACHTREUNG
(S)-(ꢀ)-N-[3-(4-Chlorophenylamino)-2-methylpropionyl]-benzamide
(16a): White solid. Rf =0.57 (EtOAc/pet. ether 40–60 1:1); m.p. 152–
1538C; chiral HPLC (Chiralcel AD, 254 nm, 10% isopropylalcohol (IPA)
37.1 min, tR
ACHTREUNG
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in hexane, 1 mLminꢀ1): tR
C
G
AHCTREUNG
AHCTREUNG
9.16 (brs, 1H; NH), 7.81 (d, 3J(H,H)=7.4 Hz, 2H; ArH), 7.58 (t, 3J-
A
3
2
ACHTREUNG
N
A
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A
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AHCTREUNG
113.1 (s), 53.1 (s), 46.9 (s), 39.6 (s), 15.1 ppm (s); IR (KBr disc): n˜max
=
3248, 3172, 1763, 1688, 1605, 1517, 787 cmꢀ1; MS (EI): m/z (%): 236 (12)
[M +ꢀH], 204 (10), 119 (10), 106 (100), 77 (11); elemental analysis calcd
(%) for C12H16N2O3: C 61.00, H6.83, N 11.86; found: C 61.00, H6.82, N
11.85.
A
N
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(67.5 MHz, CDCl3): d=178.0 (s), 165.5 (s), 146.3 (s), 133.3 (s), 132.6 (s),
129.1 (s), 128.9 (s), 127.7 (s), 122.2 (s), 114.1 (s), 47.0 (s), 40.2 (s),
15.0 ppm (s); IR (KBr): n˜max =3368, 3255, 1726, 1681, 1601, 1502, 819,
710 cmꢀ1; MS (EI): m/z (%): 318/317 (10/5) [M +ꢀH], 316 (23), 177 (46),
154 (100), 142 (28), 140 (100), 105 (98), 77 (54), 45 (47); elemental analy-
sis calcd (%) for C17H17ClN2O2: C 64.46, H5.41, N 8.84, found: C 64.36,
H5.37, N 8.77.
(S)-(ꢀ)-N-[3-(4-Methoxylphenylamino)-2-methylpropionyl]-carbamic
acid methyl ester (17c): White solid; m.p. 102–1038C; Rf =0.53 (Et2O);
chiral HPLC (Chiralcel OD-H, 254 nm, 5% IPA in hexane, 1 mLminꢀ1):
tR
1.00 in CHCl3); 1HNMR (270 MHz, CDCl 3): d = 8.35 (brs, 1H; NH),
6.79 (d, 3J(H,H)=8.6 Hz, 2H; ArH), 6.75 (d, 3J
(H,H)=8.6 Hz, 2H;
A
N
(S)-(ꢀ)-N-(2-Methyl-3-phenylaminopropionyl)-benzamide (16b): White
solid; Rf =0.57 (EtOAc/pet. ether 40–60 1:1); m.p. 139–1408C; chiral
HPLC (Chiralpak AD, 254 nm, 10% IPA in hexane, 1 mLminꢀ1):
A
ACHTREUNG
ArH), 4.00 (brs, 1H; ArH), 3.74 (s, 6H; 2ꢁOCH3), 3.30–3.40 (m, 2H;
CH2N, CH), 3.18 (dd, 3J
C
G
3
1.22 ppm (d, J
A
tR
1.00 in CHCl3); 1HNMR (270 MHz, CDCl 3): d = 9.11 (brs, 1H; NH),
8.13 (d, 3J(H,H)=7.4 Hz, 2H; ArH), 7.81 (t, 3J
(H,H)=7.4 Hz, 1H;
ArH), 7.51 (t, J
ArH), 6.74 (t, 3J
2H; ArH), 3.79–3.86 (m, 1H; CH), 3.79 (brs, 1H; NH), 3.56 (dd, 3J-
(H,H)=8.6, 2J(H,H)=12.8 Hz, 1H; CH2), 3.33 (dd, 3J(H,H)=4.7, 2J-
(H,H)=12.8 Hz, 1H; CH2), 1.34 ppm (d, 3J
(H,H)=6.9 Hz, 3H; CH3);
A
G
d=175.9 (s), 165.7 (s), 152.8 (s), 141.7 (s), 116.5 (s), 114.8 (s), 55.8 (s),
53.0 (s), 48.2 (s), 39.8 (s), 15.0 ppm (s); IR (KBr disc): n˜max =3261, 3180,
1762, 1688, 1513, 1230, 816 cmꢀ1; MS (EI): m/z (%): 266 (15) [M +ꢀH],
234 (25), 143 (32), 136 (91), 123 (27), 108 (38), 69 (72); elemental analysis
calcd (%) for C13H18N2O4: C 58.63, H6.81, N 10.52, found: C 58.72H,
6.75, N 10.44.
A
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3
3
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A
A
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A
N
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(S)-(+)-3-Amino-2-methylpropionyl-benzamide [(S)-(+)-18]: A solution
of ceric ammonium nitrate (1.58 g, 2.88 mmol) in H2O (17 mL) was
added dropwise to a solution of (ꢀ)-16c (200 mg, 0.64 mmol, 45% ee) in
MeCN/H2O (22 mL:5 mL) at ꢀ108C. After 1 h, the reaction was
quenched by the addition of saturated sodium sulfite solution (15 mL),
13C NMR (67.5 MHz, CDCl3): d=177.8 (s), 166.0 (s), 147.5 (s), 133.7 (s),
132.8 (s), 129.4 (s), 128.9 (s), 127.7 (s), 118.1 (s), 113.2 (s), 47.1 (s), 40.4
(s), 15.0 ppm (s); IR (KBr disc): n˜max =3372, 3268, 1725, 1691, 1603, 1504,
805 cmꢀ1; MS (EI): m/z (%): 282 (19) [M +ꢀH], 120 (100), 105 (23), 77
Chem. Eur. J. 2007, 13, 4602 – 4613
ꢀ 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim
4611