556
J. Escorihuela et al. / Tetrahedron 69 (2013) 551e558
mixture was stirred at 50e60 ꢀC for 8 h. The white solid formed was
filtered and washed with cold basic water (3ꢂ10 mL) and then with
cold water. The solid was dried under reduced pressure (60e70 ꢀC)
for 24 h.
6H, CH3) 1.58e1.61 (m, 2H, CH2), 1.87e1.96 (m, 1H, CH), 3.73 (d,
1H, J¼5.4 Hz, CH*), 4.34e4.50 (dd, 2H, J¼14.4 Hz, NHCH2Ph),
7.28e7.33 (m, 5H, AreH); 13C NMR (125 MHz, CDCl3) dC: 10.5,
14.0, 24.3, 36.9, 43.1, 57.9, 127.4, 128.3, 128.5, 138.5, 168.1; Anal.
Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C, 70.98;
H, 9.19; N, 12.78.
4.4. General procedure for the deprotection of N-Cbz-
amides 6aeh10e12
L-amino
4.4.6. (S)-N-Benzylpyrrolidine-2-carboxamide
(6f). Yield¼89%;
The N-Cbz-amino amide was treated with a solution of HBr/
AcOH (33%) and the mixture was stirred at room temperature until
CO2 evolution ceased. At this point, dry diethyl ether was added to
the clear solution, which led to the deposition of a precipitate. This
was filtered and washed with additional ether and dissolved in
distilled water; the resulting solution was extracted with chloro-
form (3ꢂ10 mL). Solid NaOH was then added up to a pH value of 12
and the resulting solution was saturated with NaCl and extracted
with chloroform (3ꢂ10 mL). The organic phase was dried over
anhydrous MgSO4 and evaporated under vacuum to obtain a white
solid.
mp¼125.1e126.7 ꢀC; [
a
]
20 þ13.6 (c 0.1, MeOH); ESI-MS m/z¼205.3
D
(MþHþ); IR (KBr) nmax: 3312, 2895, 1962, 1669, 1544, 1255 cmꢁ1
;
1H NMR (500 MHz, CDCl3) dH: 1.49e1.63 (m, 2H, CH2), 1.77e2.05
(m, 2H, CH2), 2.74e2.89 (m, 2H, CH2), 3.62e3.68 (m, 1H, CH*), 4.51
(m, 1H, NHCH2Ph), 6.85e6.90 (m, 3H, AreH), 7e23e7.28 (m, 3H,
AreH), 7.32e7.35 (m, 2H); 13C NMR (125 MHz, CDCl3) dC: 23.6,
29.8, 43.2, 47.6, 60.9, 126.4, 127.3, 128.1, 136.2, 170.1; Anal. Calcd for
C
12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.89; H, 7.84; N,
13.61.
4.4.7. (S)-2-Amino-N-benzyl-3-(1H-indol-3-yl)propanamide (6g).
Yield¼89%; mp¼189.1e190.9 ꢀC; [
a]
20 þ10.8 (c 0.1, MeOH); ESI-MS
D
4.4.1. (S)-2-Amino-N-benzyl-3-phenylpropanamide (6a). Yield¼63%;
m/z¼294.7 (MþHþ); IR (KBr) nmax: 3325, 2897, 1963, 1667, 1540,
20
mp¼179.1e180.4 ꢀC; [
a]
D
þ21.1 (c 0.1, MeOH); ESI-MS m/z¼255.3
1258 cmꢁ1 1H NMR (500 MHz, CDCl3) dH: 3.14e3.38 (ddd, 2H,
;
(MþHþ), 277.3 (MþNaþ); IR (KBr) nmax: 3320, 2895,1953,1667,1542,
1257 cmꢁ1; 1H NMR (500 MHz, CDCl3) dH: 2.74e2.82 (dd, 1H, J¼8.7,
13.7 Hz, CH2Ph), 3.26e3.32 (dd,1H, J¼7.0,12.6 Hz, CH2Ph) 3.66e3.70
(m, 2H, NHCH2Ph, CH*), 4.43e4.45 (d, 1H, J¼6.5 Hz, NHCH2Ph),
6.85e6.88 (m, 2H, AreH), 6.87e6.98 (m, 2H, AreH), 7.11e7.14 (m,
6H, AreH), 7.57 (s, 1H, NH); 13C NMR (125 MHz, CDCl3) dC: 41.0, 43.2,
56.5, 126.8, 127.0, 127.4, 127.8, 128.7, 129.4, 137.8, 138.4, 174.0; Anal.
Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C, 75.49; H,
7.27; N, 11.22.
J¼6.8, 11.8 Hz, CH2Ind), 4.20e4.34 (dd, 2H, J¼8.9 Hz, NHCH2Ph), 4.51
(m, 1H, CH*), 6.85e6.90 (m, 3H, AreH), 7e10e7.40 (m, 5H, AreH),
7.70 (br, 1H, AreH), 8.01 (br, 1H, AreH); 13C NMR (125 MHz, CDCl3)
dC: 43.7, 55.2,107.2,112.1,118.5,120.5,125.0,127.1,127.3,127.5,128.5,
128.8, 131.3, 135.2, 136.6, 169.7; Anal. Calcd for C18H19N3O: C, 73.69;
H, 6.53; N, 14.32. Found: C, 73.89; H, 6.64; N, 14.21.
4.4.8. (S)-2-Amino-N-benzyl-2-phenylacetamide (6h). Yield¼84%;
20
mp¼173e175 ꢀC; [
a
]
þ34.8 (c 0.1, MeOH); ESI-MS m/z¼240.3
D
(MþHþ); IR (KBr) nmax: 3332, 2893, 1962, 1669, 1545, 1258 cmꢁ1; 1H
NMR (500 MHz, CDCl3) dH: 4.20 (d, 2H, J¼8.9 Hz, NHCH2Ph), 4.81 (s,
4.4.2. (S)-2-Amino-N-benzyl-3-methylbutanamide (6b). Yield¼87%;
20
mp¼115.1e116.0 ꢀC; [
a
]
þ37.4 (c 0.1, MeOH); ESI-MS m/z¼207.1
1H, CH*), 6.88e6.94 (m, 4H, AreH), 7e13e7.35 (m, 6H, AreH); 13
C
D
(MþHþ); IR (KBr) nmax: 3320, 2895, 1953, 1667, 1542, 1257 cmꢁ1; 1H
NMR (500 MHz, CDCl3) dH: 1.01e1.04 (dd, 6H, J¼6.9 Hz, CH3), 2.18
(m, 1H, CH(CH3)2), 3.68 (d, 1H, J¼5.7 Hz, CH*), 4.36e4.50 (dd, 2H,
J¼14.7, 27.0 Hz, NHCH2Ph), 7.26e7.34 (m, 10H, AreH); 13C NMR
(125 MHz, CDCl3) dC: 16.8 (CH3), 17.7, 30.4, 43.2, 58.7, 127.4, 128.3,
128.5, 138.2, 168.3; Anal. Calcd for C12H18N2O: C, 69.87; H, 8.80; N,
13.58. Found: C, 70.01; H, 8.89; N, 13.42.
NMR (125 MHz, CDCl3) dC: 43.7, 55.2, 126.6, 127.0, 127.8, 128.5,
128.6, 130.3, 133.2, 136.3, 169.7; Anal. Calcd for C18H19N3O: C, 80.20;
H, 7.02; N, 8.13. Found: C, 80.29; H, 7.18; N, 8.08.
4.5. General procedure for the preparation of 2:1 Ni
complexes
An appropriate amount of a-amino amide (1 mmol) dissolved in
4.4.3. (S)-2-Amino-N-benzyl-4-methylpentanamide (6c). Yield¼83%;
methanol was allowed to reflux under an inert atmosphere with
Ni(OAc)2$4H2O (0.5 mmol) in the presence of KOH (1 mmol) for
30 min. The solution was filtered and concentrated to dryness. The
resulting residue was washed in dichloromethane, recrystallized
from ethanol, and dried in vacuum.
20
mp¼189.1e190.4 ꢀC; [
a]
þ27.9 (c 0.1, MeOH); ESI-MS m/z¼221.3
D
(MþHþ); IR (KBr) nmax: 3310, 2955, 1979, 1655, 1522, 1252 cmꢁ1; 1H
NMR (500 MHz, CDCl3) dH: 0.90e0.95 (d, 6H, J¼6.6 Hz, CH3),
1.34e1.58 (m, 2H, CH2CH(CH3)2), 1.61e1.72 (m, 1H, CH(CH3)2),
3.33e3.36 (d, 1H, J¼7.3 Hz, CH*), 4.37 (d, 2H, J¼7.2 Hz, NHCH2Ph),
7.27e7.31 (m, 5H, AreH); 13C NMR (125 MHz, CDCl3) dC: 22.8, 23.5,
26.1, 44.2, 45.9, 54.8, 128.5, 128.8, 129.7, 140.1, 178.1; Anal. Calcd for
4.5.1. 2:1 Ni complex of (S)-2-amino-N-benzyl-3-phenylpropanamide
(7a). Yield: 79%; FTIR (KBr): 3442, 3046, 2951, 1590 (C]O), 1455,
C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C, 71.04; H, 9.22; N,
1261 cmꢁ1; UVevis absorption (MeOH): (ε, Mꢁ1 cmꢁ1) 351 nm
l
12.82.
(260); ESI-MS (negative) m/z 599.2 [MþCl]ꢁ; Anal. Calcd for
C16H16N2ONi: C, 67.99; H, 6.06; N, 9.91. Found: C, 67.82; H, 6.25; N,
4.4.4. (S)-2-Amino-N-benzylpropanamide(6d). Yield¼92%; mp¼179.0
9.96.
20
e180.5 ꢀC; [
a]
þ2.1 (c 0.1, MeOH); ESI-MS m/z¼179.3 (MþHþ); IR
D
(KBr) nmax: 3294, 2937, 1955, 1682, 1534, 1260 cmꢁ1
;
1H NMR
4.5.2. 2:1 Ni complex of (S)-2-amino-N-benzyl-3-methylbutanamide
(500 MHz, CDCl3) dH: 1.31e1.34 (d, 3H, J¼7.2 Hz, CH3), 3.86e3.92 (dd,
1H, J¼6.9 Hz, CH*), 4.15e4.30 (dd, 2H, J¼15.3 Hz, NHCH2Ph), 7.11e7.21
(m, 5H, AreH); 13C NMR (125 MHz, CDCl3) dC: 19.1, 45.7, 51.7, 129.9,
130.3, 131.5, 138.3, 172.7; Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92;
N, 15.72. Found: C, 67.31; H, 7.97; N, 17.87.
(7b). Yield: 72%; FTIR (KBr): 3438, 3045, 2959, 1582 (C]O), 1465,
1259 cmꢁ1; UVevis absorption (MeOH):
l
(ε, Mꢁ1 cmꢁ1) 438 nm
(245); ESI-MS (negative) m/z 503.2 [MþCl]ꢁ; Anal. Calcd for
C12H16N2ONi: C, 61.43; H, 7.30; N, 11.94. Found: C, 70.01; H, 8.89; N,
13.42.
4.4.5. (2S,3S)-2-Amino-N-benzyl-3-methylpentanamide
(6e).
4.5.3. 2:1 Ni complex of (S)-2-amino-N-benzyl-4-methylpentanamide
20
Yield¼88%; mp¼164.1e166.0 ꢀC; [
a
]
þ7.2 (c 0.1, MeOH); ESI-
(7c). Yield: 70%; FTIR (KBr): 3440, 3049, 2933, 1589 (C]O), 1459,
D
MS m/z¼221.1 (MþHþ); IR (KBr) nmax: 3290, 2935, 1953, 1684,
1260 cmꢁ1; UVevis absorption (MeOH): (ε, Mꢁ1 cmꢁ1) 452 nm
l
1532, 1257 cmꢁ1
;
1H NMR (500 MHz, CDCl3) dH: 0.92e1.01 (m,
(210); ESI-MS (negative) m/z 531.2 [MþCl]ꢁ; Anal. Calcd for