Microwave-Assisted Synthesis of N-Monosubstituted Urea Derivatives

Abstract

An easy and rapid procedure for the preparation of N-monosubstituted ureas via reaction between potassium cyanate and a wide range of amines is described. The procedure was performed under microwave irradiation using water as solvent. This methodology is particularly attractive since it provides ureas in high yield and purity.

Key words

urea - potassium cyanate - microwave - N-carbamoyl derivatives

References and Notes

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8

4-Nitrophenyl-N-benzylcarbamate was prepared by condensing benzylamine with 4-nitrophenyl-chloroformate.

15

Representative Procedure for the Synthesis of N -Alkylureas; 1-Phenethylurea (2f)
A stirred solution of 2-phenethylamine (2.3 mL, 18 mmol) in 1 N HCl (18 mL) and H₂O (9 mL) was treated with KOCN (7.3 g, 90 mmol) and then the mixture was irradiated to 80 ˚C for 1 h in a sealed tube (CEM designed 10-mL pressure-rated reaction vial) in a self-tuning single mode CEM Discover Focused synthesizer. The mixture was chilled rapidly to r.t., by passing compressed air through the microwave cavity for 3 min. After the cooling to r.t., the precipitate formed was filtered, and washed with hexane and Et₂O. The crude urea was dissolved in MeOH, the residue was filtered off. The desired 1-phenethylurea (2f) was isolated, by evaporating the solvent under reduced pressure, in a pure form and in high yield (2.3 g, 73%) as a crystalline white solid; mp 114-115 ˚C [lit.^¹6 115 ˚C]. ^¹H NMR (300 MHz, CDCl₃): δ = 2.64 (q, J = 6.6 Hz, 2 H), 3.17 (q, J = 6.4 Hz, 2 H), 5.43 (br s, 2 H), 5.94 (br s, 1 H), 7.23 (m, 5 H). ^¹³C NMR (75 MHz, DMSO): δ = 36.2, 40.8, 125.9, 128.3, 128.6, 139.8, 158.1. MS: m/z = 164 [M⁺]. Anal. Calcd for C₉H₁₂N₂O: C, 65.83; H, 7.37; N, 17.06. Found: C, 65.78; H, 7.32; N, 16.98.
Representative Procedure for the Synthesis of N -Aryl-ureas; 1- o -Tolylurea (2k): A stirred solution of o-toluidine (1.9 mL, 18 mmol) and AcOH (1.7 mL, 30 mmol) in H₂O (27 mL) was treated with KOCN (7.3 g, 90 mmol) and then was irradiated to 80 ˚C for 1 h in a sealed tube (CEM designed 10-mL pressure-rated reaction vial) in a self-tuning single mode CEM Discover Focused synthesizer. The mixture was chilled rapidly to r.t., by passing compressed air through the microwave cavity for 3 min. After the cooling to r.t., the precipitate formed was filtered, and washed with hexane and Et₂O. The crude urea was dissolved in MeOH, and the residue was filtered off. The desired 1-o-tolylurea (2k) was isolated by evaporating the solvent under reduced pressure in a pure form and in high yield (2.4 g, 88%) as a white solid; mp 186-188 ˚C (lit.^¹7 191 ˚C). ^¹H NMR (300 MHz, DMSO): δ = 2.18 (s, 3 H), 6.03 (br s, 2 H), 6.86 (m, 1 H), 7.09 (m, 2 H), 7.72 (br s, 1 H), 7.77 (d, J = 8.1 Hz, 1 H). ^¹³C NMR (75 MHz, DMSO): δ = 17.4, 120.4, 121.5, 125.5, 126.6, 129.5, 137.7, 155.7. MS: m/z = 150 [M⁺]. Anal. Calcd for C₈H₁₀N₂O: C, 63.98; H, 6.71; N, 18.65. Found: C, 63.76; H, 6.65; N, 18.66.
Representative Procedure for the Synthesis of N -Carbamoyl l -Amino Acids; N -Carbamoyl- l -phenyl-alanine (2q): A stirred solution of l-phenylalanine (3.0 g, 18 mmol) in H₂O (27 mL) was treated with KOCN (7.3 g, 90 mmol) and then was irradiated to 80 ˚C for 1 h in a sealed tube (CEM designed 10-mL pressure-rated reaction vial) in a self-tuning single mode CEM Discover Focused synthesizer. The mixture was chilled rapidly to r.t., by passing compressed air through the microwave cavity for 3 min. After the cooling to r.t., the mixture was acidified to pH 2 with 6 N HCl. The obtained solid was filtered and washed with cold H₂O (3 × 5 mL) and dried under vacuum to yield the N-carbamoyl-l-phenyl alanine (2q) in a pure form and in high yield (3.4 g, 90%) as a white solid; mp 192-194 ˚C (lit.^¹8 191-192 ˚C); [α]^²0 _D +38.7 (c = 1, MeOH).^{¹8 ¹}H NMR (300 MHz, DMSO): δ = 2.90 (m, 2 H), 4.32 (m, 1 H), 5.62 (br s, 2 H), 6.16 (br d, J = 8.4 Hz, 1 Η), 7.22 (m, 5 H).^{¹8 ¹³}C NMR (75 MHz, DMSO): δ = 37.6, 53.7, 126.3, 128.2, 129.2, 137.5, 158.1, 173.9.^¹8 MS: m/z = 208 [M⁺].^¹8 Anal. Calcd for C₁₀H₁₂N₂O₃: C, 57.68; H, 5.81; N, 13.45. Found: C, 57.71; H, 5.79; N, 13.44.