The Journal of Organic Chemistry
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Hz), 3.85 (3H, s), 3.08 (1H, dd, J = 13.9 and 5.2 Hz), 2.96 (1H, dd, J
= 13.9 and 7.1 Hz); 13C NMR (50 MHz, CDCl3) δ 175.1, 154.3,
140.0, 135.6, 131.6 (q, J = 33.2 Hz), 129.1, 128.8, 127.4, 122.9 (q, J =
272.7 Hz), 117.9 (m), 115.6 (m), 53.9, 52.9, 37.6; 19F NMR (188
MHz, CDCl3) δ −8.22 (3F, s); MS 435 (M + H+, 100).
(S)-Methyl 2-(3-tert-Butylureido)-3-phenylpropanoate
(3k).23 Utilizing 9 equiv of amine, reaction time 20 h. Yellow low
melting solid; 66 mg, 79% yield; [α]D = +66.1 (c = 1.0, CHCl3); IR
(film) 3352, 2962, 1745, 1637, 1558, 1453, 1218; 1H NMR (200 MHz,
CDCl3) δ 7.27−7.14 (3H, m), 7.12−7.05 (2H, m), 5.12 (1H, br s),
4.69 (1H, t, J = 5.8 Hz), 4.40 (1H, br s), 3.65 (3H, s), 3.01(1H, dd, J =
13.9 and 5.8 Hz), 2.91 (1H, dd, J = 13.9 and 5.8 Hz), 1.25 (9H, s); 13C
NMR (50 MHz, CDCl3) δ 173.7, 156.6, 136.3, 129.3, 128.3, 126.8,
53.7, 52.0, 50.2, 38.6, 29.3; MS 279 (M + H+, 100).
(S)-1-Benzyl 4-Methyl 2-(3-benzylureido)succinate (4b).
Utilizing 6 equiv of Et3N and 3 equiv of amine, reaction time 1 h.
Yellow solid; 100 mg, 90% yield; mp 64−66 °C; [α]D = +16.3 (c = 1.0,
CHCl3); IR (film) 3356, 3319, 2348, 1732, 1627, 1219, 772; 1H NMR
(200 MHz, CDCl3) δ 7.35−7.12 (10H, m), 5.86 (1H, d, J = 8.3 Hz),
5.56 (1H, t, J = 5.5 Hz), 5.09 (1H, d, J = 12.3 Hz), 5.02 (1H, d, J =
12.3 Hz), 4.80 (1H, dt, J = 8.3 and 4.7 Hz), 4.35−4.25 (2H, m), 3.50
(3H, s), 2.96 (1H, dd, J = 17.1 and 4.7 Hz), 2.79 (1H, dd, J = 17.1 and
4.7 Hz); 13C NMR (50 MHz, CDCl3) δ 171.9, 171.8, 157.5, 139.0,
135.2, 128.5, 128.3, 128.1, 127.4, 127.2, 127.1, 67.3, 51.8, 49.5, 44.2,
36.9; MS 371 (M + H+, 100); HRMS exact mass calculated for [M +
+
H] (C20H23O5N2) requires m/z 371.1601, found m/z 371.1605.
Methyl 2-(3-Benzylureido)acetate (4c). Utilizing 6 equiv of
Et3N and 3 equiv of amine, reaction time 1 h. Yellow oil; 50 mg, 75%
1
(S)-Methyl 2-(3,3-Dibenzylureido)-3-phenylpropanoate (3l).
Utilizing 6 equiv of Et3N and 3 equiv of amine, reaction time 1 h.
Yellow solid; 99 mg, 82% yield; mp 84−86 °C; [α]D = +29.6 (c = 1.0,
yield; IR (film) 3338, 2347, 1743, 1619, 1433, 1219; H NMR (200
MHz, CDCl3) δ 7.27−7.15 (5H, m), 5.77 (2H, br s), 4.35−4.20 (2H,
m), 3.90−3.80 (2H, m), 3.60 (3H, s); 13C NMR (50 MHz, CDCl3) δ
171.9, 158.5, 139.2, 128.4, 127.1, 127.0, 52.0, 44.0, 41.9; MS 223 (M +
H+, 100); HRMS exact mass calculated for [M + H]+ (C11H15O3N2)
requires m/z 223.1077, found m/z 223.1076.
1
CHCl3); IR (film) 3353, 2964, 1746, 1633, 1560, 1454, 1218; H
NMR (200 MHz, CDCl3) δ 7.39−7.24 (6H, m), 7.24−7.13 (7H, m),
7.02−6.94 (2H, m), 4.99−4.77 (2H, m), 4.49 (2H, d, J = 16.4 Hz),
4.39 (2H, d, J = 16.4 Hz), 3.68 (3H, s), 3.10 (1H, dd, J = 13.8 and 5.2
Hz), 3.00 (1H, dd, J = 13.8 and 6.0 Hz); 13C NMR (50 MHz, CDCl3)
δ: 172.7, 157.4, 137.0, 135.9, 128.9, 128.6, 128.3, 127.3, 127.0, 126.7,
54.3, 52.0, 50.0, 38.0; MS 417 (M + H+, 100); HRMS exact mass
Methyl 4-(3-Benzylureido)butanoate (4d). Utilizing 6 equiv of
Et3N and 3 equiv of amine, reaction time 1 h. Yellow solid, 53 mg, 70%
yield; mp 62−66 °C; IR (film) 3346, 2347, 1733, 1634, 1568, 1437,
1219, 1030; 1H NMR (200 MHz, CDCl3) δ 7.36−7.09 (5H, m), 5.59
(1H, br s), 5.31 (1H, br s), 4.23 (2H, s), 3.62 (3H, s), 3.06 (2H, t, J =
6.2 Hz), 2.24 (2H, t, J = 7.2 Hz), 1.79−1.62 (2H, m); 13C NMR (50
MHz, CDCl3) δ 174.1, 158.8, 139.4, 128.4, 127.1, 127.0, 51.6, 44.0,
39.4, 31.1, 25.2; MS 251 (M + H+, 100); HRMS exact mass calculated
for [M + H]+ (C13H19O3N2) requires m/z 251.1390, found m/z
251.1390.
+
calculated for [M + Na] (C25H26O3N2Na) requires m/z 425.1836,
found m/z 425.1855.
(S)-Methyl 3-Phenyl-2-(piperidine-1-carboxamido)-
propanoate (3m). Utilizing 9 equiv of amine, reaction time 20 h.
Yellow solid; 62 mg, 71% yield; mp 78−82 °C; [α]D = +45.4 (c = 1.0,
CHCl3); IR (film) 3416, 2936, 1745, 1629, 1537, 1218; 1H NMR (200
MHz, CDCl3) δ 7.30−7.15 (3H, m), 7.14−7.05 (2H, m), 4.88 (1H, d,
J = 7.5), 4.78−4.69 (1H, m), 3.68 (3H, s), 3.36−3.16 (4H, m), 3.11
(1H, dd, J = 14.2 and 5.3 Hz), 3.04 (1H, dd, J = 14.2 and 5.4 Hz),
1.64−1.38 (6H, m); 13C NMR (50 MHz, CDCl3) δ 173.2, 156.4,
136.3, 129.2, 128.3, 126.8, 54.3, 52.0, 44.7, 38.2, 25.4, 24.2; MS 291
1,3-Dibenzylurea (4e).25 Utilizing 6 equiv of Et3N and 3 equiv of
amine, reaction time 1 h. White solid; 55 mg, 76% yield; mp 152−156
°C {lit. mp 166−169 °C}24b; IR (film) 3317, 2970, 5921, 2371, 1625,
1
1577, 1262, 1054, 1032, 1012; H NMR (200 MHz, CDCl3) δ 7.35−
7.11 (10H, m), 5.40−4.50 (2H, br s), 4.27 (4H, s); 13C NMR (50
MHz, CDCl3) δ 158.2, 138.9, 128.6, 127.3, 127.2, 44.5; MS 241 (M +
H+, 100).
+
(M + H+, 100); HRMS exact mass calculated for [M + H]
(C16H23O3N2) requires m/z 291.1703, found m/z 291.1708.
(S)-Methyl 2-(Morpholine-4-carboxamido)-3-phenylpropa-
noate (3n).24 Utilizing 9 equiv of amine, reaction time 20 h. Low
melting point colorless solid; 79 mg, 90% yield; [α]D = +60.3 (c = 1.0,
CHCl3); IR (film) 3180, 2924, 1744, 1632, 1533, 1454, 1263, 1218,
1116; 1H NMR (200 MHz, CDCl3) δ 7.39−7.16 (3H, m), 7.16−6.91
(2H, m), 4.97 (1H, d, J = 7.4 Hz), 4.84−4.63 (1H, m), 3.68 (3H, s),
3.65−3.52 (4H, m), 3.32−3.21 (4H, m), 3.12−3.02 (2H, m); 13C
NMR (50 MHz, CDCl3) δ 173.0, 156.6, 136.0, 129.1, 128.4, 126.9,
66.3, 54.2, 52.2, 43.7, 38.1; MS 293 (M + H+, 100).
1-Allyl-3-benzylurea (4f).26 Utilizing 6 equiv of Et3N and 3 equiv
of amine, reaction time 1 h. White solid; 40 mg, 70% yield; mp 90−93
°C {lit. mp 91 °C};26 IR (film) 3319, 2351, 1621, 1555, 1217, 921; 1H
NMR (200 MHz, CDCl3) δ 7.35−7.08 (5H, m), 5.89−5.62 (1H, m),
5.52 (1H, br s), 5.33 (1H, br s), 5.17−4.94 (2H, m), 4.23 (2H, s),
3.76−3.58 (2H, m); 13C NMR (50 MHz, CDCl3) δ 158.7, 139.3,
135.4, 128.4, 127.2, 127.0, 115.3, 44.1, 42.7; MS 191 (M + H+, 100).
1-Benzyl-3-cyclohexylurea (4g).27 Utilizing 6 equiv of Et3N and
3 equiv of amine, reaction time 1 h. Colorless solid, 50 mg, 72% yield;
mp 151−154 °C {lit. mp 150−153 °C};27b IR (film) 3330, 2928, 2851,
(S)-Benzyl 1-{[(S)-1-Methoxy-1-oxo-3-phenylpropan-2-yl]-
carbamoyl}pyrrolidine-2-carboxylate (3o). Utilizing 9 equiv of
amine, reaction time 20 h. Yellow oil; 108 mg, 88% yield; [α]D = +5.4
(c = 1.0, CHCl3); IR (film) 3440, 2951, 1741, 1738, 1649, 1520, 1454,
1392, 1217, 1171; 1H NMR (200 MHz, CDCl3) δ 7.37−7.27 (5H, m),
7.27−7.15 (3H, m), 7.14−7.04 (2H, m), 5.20 (1H, d, J = 12.3 Hz),
5.10 (1H, d, J = 12.3 Hz), 4.88 (1H, br d, J = 7.8 Hz), 4.81−4.71 (1H,
m), 4.48−3.38 (1H, m), 3.67 (3H, s), 3.42−3.20 (2H, m), 3.11 (1H,
dd, J = 12.3 and 5.5 Hz), 3.06 (1H, dd, J = 12.3 and 5.5 Hz), 2.24−
1.86 (4H, m); 13C NMR (50 MHz, CDCl3) δ 172.7, 172.6, 155.3,
135.9, 135.5, 129.2, 128.4, 128.3, 128.1, 127.9, 126.8, 66.6, 58.9, 54.0,
52.0, 45.5, 38.0, 29.4, 24.2; MS 411 (M + H+, 100); HRMS exact mass
calculated for [M + H] + (C23H27O5N2) requires m/z 411.1914, found
m/z 411.1931.
1
1625, 1576, 1454, 1219; H NMR (200 MHz, CDCl3) δ 7.45−7.19
(5H, m), 5.05 (1H, br s), 4.65 (1H, br s), 4.27 (2H, s), 3.56−3.29
(1H, m), 1.95−1.77 (2H, m), 1.72−1.43 (3H, m), 1.39−0.90 (5H, m);
13C NMR (50 MHz, CDCl3) δ 157.5, 139.2, 128.6, 127.4, 127.3, 49.2,
44.5, 33.8, 25.5, 24.8; MS 233 (M + H+, 100).
N-Benzylpiperidine-1-carboxamide (4h).25b,28 Utilizing 9
equiv of amine, reaction time 20 h. Colorless solid, 43 mg, 66%
yield; mp 101−104 °C {lit. mp 103−105 °C};28 IR (film) 3328, 2933,
1
2851, 1620, 1538, 1219; H NMR (200 MHz, CDCl3) δ 7.43−7.10
(5H, m), 4.82 (1H, br s), 4.42−4.36 (2H, m), 3.35−3.25 (4H, m),
1.65−1.42 (6H, m); 13C NMR (50 MHz, CDCl3) δ 157.5, 139.6,
128.5, 127.7, 127.1, 45.0, 44.9, 25.5, 24.3; MS 219 (M + H+, 100).
4-(3-Benzylureido)butyl 4-(trifluoromethyl)benzoate (4i).
Utilizing 9 equiv of amine, reaction time 20 h. White solid; 85 mg,
72% yield; mp 128−130 °C; IR (film) 3323, 2348, 1729, 1621, 1328,
(S)-Methyl 2-(3-Benzylureido)-3-methylbutanoate (4a).19
Utilizing 6 equiv of Et3N and 3 equiv of amine, reaction time 1 h.
White solid; 70 mg, 88% yield; mp 83−85 °C {lit. mp 82−84 °C};19a
[α]D = +16.8 (c = 1.0, CHCl3) {lit. [α]D = +16.0 (c = 1.0, CHCl3 )};
1
1218, 1121, 772; H NMR (200 MHz, CDCl3) δ 8.10 (2H, d, J = 8.2
Hz), 7.67 (2H, d, J = 8.2 Hz), 7.35−7.15 (5H, m), 4.35−4.25 (4H, m),
3.25−3.15 (2H, t, J = 6.7 Hz), 1.80−1.52 (4H, m); 13C NMR (50
MHz, CDCl3) δ 165.4, 158.3, 138.9, 134.4 (q, J = 32.6 Hz), 133.4,
129.9, 128.6, 127.4, 127.3, 125.4 (q, J = 3.5 Hz), 123.6 (q, J = 272.7
Hz), 65.1, 44.5, 40.0, 26.7, 26.0; 19F NMR (188 MHz, CDCl3) δ −8.08
(3F, s); MS 395 (M + H+, 100); HRMS exact mass calculated for [M
+ H]+ (C20H22F3O3N2) requires m/z 395.1577, found m/z 395.1591.
19b
1
IR (film) 3316, 2964, 2365, 1743, 1635, 1559, 1218, 1134; H
NMR (200 MHz, CDCl3) δ 7.53−6.85 (5H, m), 5.95−5.59 (2H, m),
4.42−4.14 (3H, m), 3.57 (3H, s), 2.12−1.88 (1H, m), 0.86 (3H, d, J =
6.8 Hz), 0.79 (3H, d, J = 6.9 Hz); 13C NMR (50 MHz, CDCl3) δ
174.1, 158.2, 139.2, 128.4, 127.2, 127.0, 57.9, 51.8, 44.1, 31.2, 18.9,
17.6; MS 265 (M + H+, 100).
4481
dx.doi.org/10.1021/jo500492x | J. Org. Chem. 2014, 79, 4477−4483