Access to Unsymmetrical Ureas
Hexylurea (8): The title compound was prepared from hexylamine
(1.31 mL, 9.85 mmol) following procedure A to give 8 (1.32 g,
93%) as a white crystalline solid, m.p. 112 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 0.85 (t, J = 6.7 Hz, 3 H), 1.10–1.50 (m, 8 H), 2.93
(dt, app q, J = 6.5 Hz, 2 H), 5.42 (s, 2 H, NH2), 5.94 (t, J = 5.6 Hz,
1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 13.9 (CH3),
22.2 (CH2), 26.2 (CH2), 30.0 (CH2), 31.2 (CH2), 39.2 (CH2), 159.0
δ = 23.4 (CH3), 48.7 (CH), 125.9 (2 CH), 126.5 (CH), 128.3 (2 CH),
145.9 (Cq), 158.4 (Cq) ppm. IR (ATR): ν = 3418 (N–H), 3328 (N–
˜
H), 3208 (N–H), 2975, 1647 (C=O), 1593, 1533, 1494, 1450, 1372,
1279, 1148, 1021, 900, 749, 695 cm–1. MS (ESI+): m/z (%) = 187
(32) [M + Na]+, 351 (36) [2M + Na]+.
4-Methoxyphenylurea (14): The title compound was prepared from
p-anisidine (1.23 g, 10 mmol) following procedure A to give 14
(1.50 g, 90%) as a white crystalline solid, m.p. 78–79 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 3.68 (s, 3 H), 5.72 (s, 2 H, NH2), 6.80
(d, J = 8.7 Hz, 2 H, Ar-H), 7.29 (d, J = 8.7 Hz, 2 H, Ar-H), 8.31
(s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.1
(CH3), 113.9 (2 CH), 119.5 (2 CH), 133.7 (Cq), 154.0 (Cq), 156.3
(Cq) ppm. IR (ATR): ν = 3391 (N–H), 3197 (N–H), 2949, 2932,
˜
2867, 1655 (C=O), 1629, 1600, 1530, 1480, 1468, 1452, 1323, 1150,
780, 728 cm–1. MS (ESI+): m/z (%) = 145 (51) [M + H]+, 289 (100)
[2M + H]+.
Cyclohexylurea (9): The title compound was prepared from cyclo-
hexylamine (1.2 mL, 10.38 mmol) following procedure A to give 9
(1.29 g, 87%) as a white crystalline solid, m.p. 205 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 0.95–1.38 (m, 5 H), 1.40–1.88 (m, 5
H), 3.20–3.40 (m, 1 H), 5.28 (s, 2 H, NH2), 5.81 (d, J = 7.9 Hz, 1
H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 24.6 (2 CH2),
25.4 (CH2), 33.4 (2 CH2), 47.7 (CH), 158.3 (Cq) ppm. IR (ATR):
(Cq) ppm. IR (ATR): ν = 3350 (N–H), 3317 (N–H), 2958, 2928,
˜
2871, 2855, 1616 (C=O), 1574, 1519, 1478, 1454, 1289, 1249, 1226,
1066 cm–1. MS (ESI+): m/z (%) = 167 (43) [M + H]+, 189 (100) [M
+ Na]+, 205 (13) [M + K]+.
Procedure B, General Procedure for the Palladium-Catalysed Re-
ductive Alkylation of Primary Ureas: The monosubstituted urea
(1 mmol) and the aldehyde (3 mmol) were dissolved in dry meth-
anol (10 mL) in a stainless steel autoclave (50 mL), and then Pd
(5% on carbon; 53.2 mg, 2.5 mol-%) was added. The reactor was
tightly closed and purged three times, and then hydrogen (5 bar)
was introduced. The reactor was then placed in a graphite bath on
a magnetic stirrer, and the reaction mixture was stirred at 100 °C
for 15 h. After cooling to room temperature, the hydrogen pressure
was released. The palladium was removed by filtration under vac-
uum over a Millipore filter and thoroughly washed with methanol
several times. The filtrate was concentrated under reduced pressure.
The corresponding alkylated ureas were purified either by
recrystallization from diethyl ether or by column chromatography.
ν = 3421 (N–H), 3327 (N–H), 3196 (N–H), 2928, 2852, 1649
˜
(C=O), 1620, 1595, 1544, 1446, 1384, 1351, 1257, 1157, 892,
779 cm–1. MS (ESI+): m/z (%) = 143 (76) [M + H]+, 285 (100) [2M
+ H]+.
1-(Cyclohexylmethyl)urea (10): The title compound was prepared
from 1-(cyclohexylmethyl)amine (1.3 mL, 9.79 mmol) following
procedure A to give 10 (1.33 g, 87%) as a white crystalline powder,
1
m.p. 180–181 °C. H NMR (300 MHz, [D6]DMSO): δ = 0.70–0.96
(m, 2 H), 0.98–1.41 (m, 4 H), 1.50–1.78 (m, 5 H), 2.79 (dd, app t,
J = 6.3 Hz, 2 H), 5.32 (s, 2 H, NH2), 5.92 (t, J = 5.4 Hz, 1 H, NH)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 25.5 (2 CH2), 26.2
(CH2), 30.4 (2 CH2), 38.2 (CH), 45.5 (CH2), 158.9 (Cq) ppm. IR
(ATR): ν = 3384 (N–H), 3198 (N–H), 2920, 2851, 1651 (C=O),
˜
1-Benzyl-3-decylurea (16): The title compound was prepared from
benzylurea 12 (150 mg, 1 mmol) and decanal 15 (0.56 mL, 3 mmol)
according to procedure B. The residue was purified by recrystalli-
zation from Et2O to give 16 (250 mg, 86%) as a white powder, m.p.
1606, 1546, 1451, 1433, 1379, 1155, 959, 782 cm–1. MS (ESI+): m/z
(%) = 157 (61) [M + H]+, 313 (100) [2M + H]+.
Phenylethylurea (11): The title compound was prepared from 2-
phenylethylamine (1.25 mL, 9.84 mmol) following procedure A to
give 11 (1.13 g, 70%) as a white crystalline solid, m.p. 112–114 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 2.66 (t, J = 7.2 Hz, 2 H),
3.19 (dt, app q, J = 6.8 Hz, 2 H), 5.42 (s, 2 H, NH2), 5.90 (t, J =
5.4 Hz, 1 H, NH), 7.15–7.25 (m, 3 H, Ar-H), 7.25–7.35 (m, 2 H,
Ar-H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 36.2 (CH2), 40.9
(CH2), 126.0 (CH), 128.3 (2 CH), 128.7 (2 CH), 139.8 (Cq), 158.9
1
96 °C. H NMR (400 MHz, [D6]DMSO): δ = 0.86 (t, J = 6.8 Hz,
3 H), 1.18–1.31 (m, 14 H), 1.31–1.40 (m, 2 H), 2.98 (dt, app q, J
= 6.5 Hz, 2 H), 4.18 (d, J = 6.0 Hz, 2 H), 5.90 (t, J = 5.5 Hz, 1 H,
NH), 6.26 (t, J = 6.0 Hz, 1 H, NH), 7.17–7.27 (m, 3 H, Ar-H),
7.27–7.36 (m, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 14.0 (CH3), 22.1 (CH2), 26.4 (CH2), 28.7 (CH2), 28.8 (CH2),
29.0 (CH2), 29.1 (CH2), 30.0 (CH2), 31.3 (CH2), 39.3 (CH2), 42.9
(CH2), 126.5 (CH), 127.0 (2 CH), 128.2 (2 CH), 141.1 (Cq), 158.1
(Cq) ppm. IR (ATR): ν = 3420 (N–H), 3335 (N–H), 3213 (N–H),
˜
1650 (C=O), 1598, 1551, 1496, 1453, 1338, 1147, 774, 748,
697 cm–1. MS (ESI+): m/z (%) = 165 (100) [M + H]+, 187 (21) [M
+ Na]+, 329 (34) [2M + H]+, 351 (17) [2M + Na]+.
(Cq) ppm. IR (ATR): ν = 3320 (N–H), 2957, 2920, 2847, 1658
˜
(C=O), 1625, 1596, 1564, 1499, 1479, 1464, 1443, 1315, 1298, 1246,
1228 cm–1. MS (ESI+): m/z (%) = 291 (12) [M + H]+, 313 (100) [M
+
Na]+, 603 (23) [2M Na]+. HRMS (ESI+): calcd. for
+
Benzylurea (12): The title compound was prepared from benzyl-
amine (1.1 mL, 10.1 mmol) following procedure A to give 12
(1.37 g, 85%) as a white crystalline solid, m.p. 151 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 4.25 (d, J = 5.9 Hz, 2 H), 5.81 (s, 2
H, NH2), 6.63 (t, J = 5.9 Hz, 1 H, NH), 7.12–7.47 (m, 5 H, Ar-H)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 43.1 (CH2), 126.8
(CH), 127.2 (2 CH), 128.4 (2 CH), 141.0 (Cq), 159.4 (Cq) ppm. IR
C18H30N2NaO [M + Na]+ 313.2250; found 313.2249.
1-Decyl-3-hexylurea (17): The title compound was prepared from
hexyl urea 8 (144 mg, 1 mmol) and decanal 15 (0.56 mL, 3 mmol)
according to procedure B. The residue was purified by recrystalli-
zation from Et2O to give 17 (250 mg, 88%) as a white powder, m.p.
1
75 °C. H NMR (400 MHz, [D6]DMSO): δ = 0.85 (t, J = 6.4 Hz,
(ATR): ν = 3426 (N–H), 3328 (N–H), 1647 (C=O), 1597, 1556,
˜
6 H), 1.17–1.38 (m, 24 H), 2.94 (dt, app q, J = 6.2 Hz, 4 H), 5.73
(t, J = 5.4 Hz, 2 H, 2 NH) ppm. 13C NMR (100 MHz, CD3OD):
δ = 14.4 (CH3), 14.5 (CH3), 23.7 (CH2), 23.8 (CH2), 27.7 (CH2),
28.0 (CH2), 30.48 (CH2), 30.52 (CH2), 30.7 (CH2), 30.8 (CH2),
31.36 (CH2), 31.39 (CH2), 32.8 (CH2), 33.1 (CH2), 41.0 (2 CH2),
1467, 1455, 1386, 1328, 1309, 1142, 1107, 750, 694 cm–1. MS
(ESI+): m/z (%) = 151 (100) [M + H]+, 173 (29) [M + Na]+, 301
(48) [2M + H]+, 323 (24) [2M + Na]+.
1-(1-Phenylethyl)urea (13): The title compound was prepared from
1-phenylethylamine (1.3 mL, 10.1 mmol) following procedure A to
give 13 (1.42 g, 85%) as a white powder, m.p. 117 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 1.34 (d, J = 6.6 Hz, 3 H), 4.78 (t, J =
161.4 (Cq) ppm. IR (ATR): ν = 3326 (N–H), 2956, 2920, 2849,
˜
1610 (C=O), 1572, 1477, 1461, 1250, 1223, 725 cm–1. MS (ESI+):
m/z (%) = 285 (67) [M + H]+, 307 (100) [M + Na]+, 591 (73) [2M
6.8 Hz, 1 H), 5.62 (s, 2 H, NH2), 6.56 (d, J = 7.7 Hz, 1 H, NH), + Na]+. HRMS (ESI+): calcd. for C17H37N2O [M + H]+ 285.2900;
7.00–7.67 (m, 5 H, Ar-H) ppm. 13C NMR (75 MHz, [D6]DMSO):
found 285.2902.
Eur. J. Org. Chem. 2013, 5445–5454
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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