The Journal of Organic Chemistry
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CH2Cl2) gave 4 as a white solid (12.6 g, quantitative yield). Rf = 0.24
s, 1H), 4.79 (dd, J = 3.0, 3.0 Hz, 1H), 4.59 (br s, 1H), 4.28 (qd, J = 7.0,
3.0 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H), 2.46 (s, 3H), 1.16 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 141.7, 128.0, 127.4,
126.5, 77.7, 58.5, 31.7, 27.6, 13.1.
(4% MeOH/CH2Cl2); mp = 109−111 °C (lit.18 113−115 °C); H
1
NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 7.35 (t, J = 1.5 Hz, 1H),
7.09 (br s, 1H), 6.82 (br s, 1H), 3.02 (d, J = 4.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 149.6, 135.7, 130.0, 116.3, 27.4; IR (solid) νmax
3201, 3147, 3112, 3036, 1713, 1552, 1481, 1422, 1364, 1330, 1291,
1252, 1192, 1069, 1046, 910, 837, 807 720 cm−1; MS (ESI) m/z (rel
intensity) 148 (8), 126 (14), 69 (100); HRMS (ESI) m/z calcd for
C5H8N3O (MH+) 126.0661, found 126.0656.
1-(2-Bromobenzyl)-3-methylurea34 (5i). Ammonium HCl salt
used as starting material, with 2 equiv of Et3N (0.06 mL, 0.430 mmol);
48.1 mg, 99% yield; white solid; Rf = 0.30 (5% MeOH/CH2Cl2); mp =
151−153 °C (lit.34 154−155 °C); H NMR (400 MHz, CD3OD) δ
1
7.54 (dd, J = 8.0, 1.0 Hz, 1H), 7.37−7.29 (m, 2H), 7.15 (td, J = 8.0,
2.0 Hz, 1H), 4.85 (s, 2H), 2.72 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 161.8, 140.2, 133.8, 130.6, 129.9, 128.8, 124.1, 45.3, 27.2.
N-(N′-Methylurea)-L-proline Methyl Ester (5j). Ammonium
HCl salt used as starting material, with 2 equiv of Et3N (0.06 mL,
0.430 mmol); 30.2 mg, 81% yield; colorless oil; Rf = 0.35 (5% MeOH/
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.50 (br s, 1H), 4.44 (dd, J
= 8.0, 3.0 Hz, 1H), 3.74 (s, 3H), 3.49−3.44 (m, 1H), 3.37−3.31 (m,
1H), 2.81 (d, J = 5.0 Hz, 3H), 2.19−1.95 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 173.8, 157.2, 58.9, 52.1, 45.7, 29.7, 27.3, 24.5; IR (thin
film in CH2Cl2) νmax 3336, 2953, 2879, 1729, 1652, 1558, 1436, 1372,
1198, 1095, 1015, 769 cm−1; MS (ESI) m/z (rel intensity) 209 (63),
187 (81), 155 (16), 130 (100), 128 (49), 127 (22); HRMS (ESI) m/z
calcd for C8H15N2O3 (MH+) 187.1077, found 187.1084.
General Procedure for the Synthesis of N-Methyl Ureas 5a−
l. To a solution of carbamoylimidazole 4 (25.0 mg, 0.200 mmol, 1.0
equiv) and amine (0.200 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was
added Et3N (0.03 mL, 0.215 mmol, 1.1 equiv). The solution was
stirred for 18 h and concentrated under reduced pressure. Flash
chromatography yielded N-methylureas 5a−l.
N-Methylmorpholine-4-carboxamide29 (5a). 28.8 mg, quanti-
tative yield; white solid; Rf = 0.24 (8% MeOH/CH2Cl2); mp = 81−83
°C (lit.29 85−87 °C); 1H NMR (400 MHz, CDCl3) δ 5.05 (br s, 1H),
3.68−3.66 (m, 4H), 3.37−3.34 (m, 4H), 2.79 (d, J = 4.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 66.4, 43.8, 27.4.
1-(3,4-Dimethoxyphenethyl)-1,3-dimethylurea (5b). 44.4 mg,
1
88% yield; colorless oil; Rf = 0.36 (8% MeOH/CH2Cl2); H NMR
(400 MHz, CDCl3) δ 6.81−6.79 (m, 1H), 6.76−6.73 (m, 2H), 4.22
(br q, J = 4.5 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.47 (t, J = 7.5 Hz,
2H), 2.81 (s, 3H), 2.77 (t, J = 7.5 Hz, 2H), 2.76 (d, J = 4.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 158.7, 148.9, 147.5, 131.9, 120.7,
112.0, 111.3, 55.87, 55.86, 51.1, 34.7, 34.2, 27.6; IR (thin film in
CH2Cl2) νmax 3416, 3350, 2997, 2937, 2835, 1635, 1514, 1464, 1416,
1379, 1262, 1235, 1155, 1029, 807, 765 cm−1; MS (DART) m/z (rel
intensity) 254 (13), 253 (100); HRMS (DART) m/z calcd for
C13H21N2O3 (MH+) 253.1552, found 253.1548.
N-(N′-Methylurea)-L-leucine Methyl Ester (5k). Ammonium
HCl salt used as starting material, with 2 equiv each of 4 (50.0 mg,
0.400 mmol) and Et3N (0.06 mL, 0.430 mmol); 39.2 mg, 97% yield;
1
white solid; Rf = 0.29 (8% MeOH/CH2Cl2); mp = 85−87 °C; H
NMR (400 MHz, CDCl3) δ 5.35 (br d, J = 8.5 Hz, 1H), 5.05 (br q, J =
4.5 Hz, 1H), 4.48 (ddd, J = 8.5, 5.5, 5.5 Hz, 1H), 3.73 (s, 3H), 2.76 (d,
J = 4.5 Hz, 3H), 1.77−1.66 (m, 1H), 1.59 (ddd, J = 13.5, 8.5, 5.5 Hz,
1H), 1.48 (ddd, J = 13.5, 9.5, 5.5 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H),
0.93 (d, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.5, 158.6,
52.1, 51.6, 41.8, 27.0, 24.8, 22.8, 21.8; IR (solid) νmax 3324, 2957,
2873, 1742, 1630, 1583, 1435, 1341, 1273, 1227, 1193, 1141, 981
cm−1; MS (ESI) m/z (rel intensity) 225 (10), 203 (16), 146 (100);
HRMS (ESI) m/z calcd for C9H19N2O3 (MH+) 203.1390, found
203.1391.
1-Methyl-3-phenethylurea30 (5c). 35.6 mg, quantitative yield;
1
white solid; Rf = 0.21 (6% MeOH/CH2Cl2); mp = 75−77 °C; H
NMR (400 MHz, CDCl3) δ 7.31−7.26 (m, 2H), 7.23−7.17 (m, 3H),
4.69 (br t, J = 7.0 Hz, 1H), 4.64 (br s, 1H), 3.41 (td, J = 7.0, 7.0 Hz,
2H), 2.79 (t, J = 7.0 Hz, 2H), 2.70 (d, J = 5.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 159.0, 139.2, 128.8, 128.5, 126.3, 41.6, 36.4, 27.0.
1,1-Diethyl-3-methylurea31 (5d). 23.2 mg, 89% yield; colorless
N-(N′-Methylurea)-L-tryptophan (5l). Two equivalents each of 4
(50.0 mg, 0.400 mmol) and Et3N (0.06 mL, 0.430 mmol) were used.
The reaction was quenched with 0.5 M HCl in methanol prior to
concentrating under an air stream; 46.5 mg, 89% yield; white solid; Rf
1
oil; Rf = 0.26 (6% MeOH/CH2Cl2); H NMR (400 MHz, CDCl3) δ
4.30 (br s, 1H), 3.25 (q, J = 7.0 Hz, 4H), 2.81 (d, J = 4.5 Hz, 3H), 1.13
(t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.0, 41.2, 27.5,
13.8.
1
= 0.60 (80% EtOAc/hexanes); mp = 182−184 °C; H NMR (400
N-Methylpiperidine-1-carboxamide32 (5e). 25.9 mg, 91% yield;
MHz, CD3OD) δ 7.57 (dt, J = 8.0, 1.0 Hz, 1H), 7.31 (dt, J = 8.0, 1.0
Hz, 1H), 7.08 (s, 1H), 7.06 (td, J = 8.0, 1.0 Hz, 1H), 6.98 (td, J = 8.0,
1.0 Hz, 1H), 4.53 (dd, J = 6.5, 6.5 Hz, 1H), 3.29 (dd, J = 14.0, 6.5 Hz,
1H), 3.16 (dd, J = 14.0, 6.5 Hz, 1H), 2.64 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 178.6, 161.5, 138.1, 129.3, 124.5, 122.4, 119.8, 119.6,
112.3, 111.5, 56.2, 29.2, 27.0; IR (solid) νmax 3396, 2922, 2852, 1708,
1558, 1457, 1416, 1339, 1230, 1093, 1010, 740 cm−1; MS (ESI) m/z
(rel intensity) 284 (100), 262 (69), 256 (78), 205 (48), 188 (68), 149
(73); HRMS (ESI) m/z calcd for C13H16N3O3 (MH+) 262.1186,
found 262.1181.
white solid; Rf = 0.52 (7% MeOH/CH2Cl2); mp = 68−70 °C (lit.32
1
72−74 °C); H NMR (400 MHz, CDCl3) δ 4.54 (br s, 1H), 3.33−
3.30 (m, 4H), 2.80 (d, J = 4.5 Hz, 3H), 1.62−1.51 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 158.5, 44.8, 27.6, 25.6, 24.4.
1,1-Dibenzyl-3-methylurea (5f). 49.3 mg, 97% yield; white solid;
1
Rf = 0.36 (4% MeOH/CH2Cl2); mp = 75−76 °C; H NMR (400
MHz, CDCl3) δ 7.35−7.31 (m, 4H), 7.29−7.23 (m, 6H), 4.48 (s, 4H),
4.36 (br q, J = 4.5 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 159.2, 137.6, 128.7, 127.4, 127.1, 50.2, 27.8; IR
(solid) νmax 3505, 3355, 3028, 2918, 1602, 1550, 1493, 1395, 1266,
1156, 971, 949, 736, 692 cm−1; MS (DART) m/z (rel intensity) 256
(17), 255 (100); HRMS (DART) m/z calcd for C16H19N2O (MH+)
255.1497, found 255.1496.
General Procedure for the Synthesis of N-methyl Carba-
mates, Thiocarbamates and Aryl Ureas 6−10. Procedure A. To
a solution of carbamoylimidazole 4 (50.0 mg, 0.400 mmol, 2.0 equiv)
and a nucleophile (0.200 mmol, 1.0 equiv) dissolved in CH2Cl2 (1.0
mL) was added Et3N (55 μL, 0.395 mmol, 2.0 equiv). The solution
was stirred at room temperature for 18 h and concentrated under
reduced pressure. The products were isolated by flash chromatog-
raphy.
Procedure B. To a solution of carbamoylimidazole 4 (25.0 mg,
0.200 mmol, 1.0 equiv) and a nucleophile (0.200 mmol, 1.0 equiv)
dissolved in DMF (1.0 mL) was added 60% NaH in mineral oil (8.8
mg, 0.220 mmol, 1.1 equiv). The solution was stirred at room
temperature for 18 h and concentrated under an air stream. The
products were isolated by flash chromatography.
1-(2,4-Dimethoxybenzyl)-3-methylurea (5g). 44.8 mg, quanti-
tative yield; white solid; Rf = 0.30 (5% MeOH/CH2Cl2); mp = 145−
1
146 °C; H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.5 Hz, 1H),
6.43−6.40 (m, 2H), 5.01 (br t, J = 5.5 Hz, 1H), 4.66 (br q, J = 4.5 Hz,
1H), 4.24 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 2.72 (d, J =
4.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 159.0, 158.3,
130.0, 119.8, 103.9, 98.5, 55.34, 55.26, 39.7, 27.1; IR (solid) νmax 3325,
2940, 1742, 1616, 1580, 1509, 1206, 1155, 1131, 1034, 830 cm−1; MS
(ESI) m/z (rel intensity) 247 (13), 225 (5), 152 (9), 151 (100);
HRMS (ESI) m/z calcd for C11H17N2O3 (MH+) 225.1233, found
225.1227.
Procedure D. To a solution of carbamoylimidazole 4 (50.0 mg,
0.400 mmol, 2.0 equiv) and a nucleophile (0.200 mmol, 1.0 equiv)
dissolved in THF (1.0 mL) was added Et3N (55 μL, 0.395 mmol, 2.0
equiv). The solution was stirred at 65 °C for 18 h and concentrated
1-((1R,2S)-1-Hydroxy-1-phenylpropan-2-yl)-1,3-dimethylur-
ea33 (5h). 40.9 mg, 92% yield; colorless oil; Rf = 0.28 (5% MeOH/
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.36−7.23 (m, 5H), 4.87 (br
10366
dx.doi.org/10.1021/jo302084a | J. Org. Chem. 2012, 77, 10362−10368