Lithiation and Substitution of N′-(ω-Phenylalkyl)-N,N-dimethylureas

Keith Smith, Gamal El-Hiti, Mohammed Alshammari
2012 Synthesis (Stuttgart)  
Lithiation of N′-phenethyl-N,N-dimethylurea with three equivalents of tert-butyllithium in anhydrous tetrahydrofuran at -78°C takes place on the nitrogen and on the side-chain of the CH 2 next to the phenyl ring (α-lithiation). The 2-lithio isomer can be obtained via bromine-lithium exchange of N′-2-(2-bromophenyl)ethyl-N,N-dimethylurea using methyllithium followed by tertbutyllithium in tetrahydrofuran at -78°C. The lithium reagents thus obtained react with various electrophiles to give the
more » ... iles to give the corresponding substituted derivatives in excellent yields. Lithiation of N′-(3-phenylpropyl)-N,N-dimethylurea takes place on the α-CH 2 with tert-butyllithium at 0 °C. On the other hand, lithiation of N′-(4phenylbutyl)-N,N-dimethylurea with tert-butyllithium at 0 °C takes place on one of the methyl groups of the urea unit. Substituted N′-Phenethyl-N,N-dimethylureas 5-11; General Procedure A solution of t-BuLi in pentane (4.51 mL, 1.9 M, 8.60 mmol) was added to a stirred solution of 2 (0.50 g, 2.60 mmol) at -78°C in anhyd THF (20 mL) under a N 2 atmosphere. The mixture was stirred at -78°C for 2 h and a solution of the electrophile (2.60 mmol), in anhyd THF (8 mL) if solid, neat otherwise, was added. The reaction mixture was stirred for 2 h at -78°C, and then allowed to warm to r.t. The mixture was quenched with a sat. aq NH 4 Cl (20 mL) and diluted with Et 2 O (20 mL). The organic layer was separated, washed with H 2 O (2 × 20 mL), dried (MgSO 4 ), and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel; Et 2 O-hexane, 1:3) to give the pure products 5-11. The yields obtained were in the range of 86-99% (Table 2) . Hydroxy-2,3-diphenylpropyl) -N,N-dimethylurea (5) Product 5 was a mixture of two racemic diastereoisomers in approximately equal proportions; yield: 0.75 g (97%); white solid; mp 180-184 °C. N′-(3-
doi:10.1055/s-0031-1291008 fatcat:wtymjdsacnhwtohtewto6ikd3e