Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

Summary N-Alkenyl ureas and N-alkenyl carbamates, like other N-acyl enamines, are typically nucleophilic at their β-carbon. However, by incorporating an α-aryl substituent, we show that they will also undergo attack at the β-carbon by organolithium nucleophiles, leading to the products of carbolithiation. The carbolithiation of E and Z N-alkenyl ureas is diastereospecific, and N-tert-butoxycarbonyl N-alkenyl carbamates give carbolithiation products that may be deprotected in situ to provide a new connective route to hindered amines.

To a solution of urea 3 in dry toluene (0.1 M) cooled at −40 °C, the desired organolithium reagent (2 equiv) is added slowly. After 1 hour, the reaction is quenched slowly with MeOH and NH 4 Cl. The crude is extracted with EtOAc, dried with MgSO 4 , concentrated under reduced pressure and purified by chromatography on silica gel (PE/EtOAc 9:1).
To a solution of urea 5 in dry tetrahydrofuran (0.1 M) cooled at −40 °C, the desired organolithium reagent (3 equiv) is added slowly. After 1 hour, the reaction is quenched slowly with MeOH and NH 4 Cl. The crude is extracted with EtOAc, dried with MgSO 4 , and concentrated under reduced pressure. The product was obtained without further purification.
To a solution of carbamate 9 in dry THF (0.1 M), cooled at −78 °C, the desired organolithium reagent (2 equiv) is added slowly. After 1 hour at −78 °C, the reaction is quenched by slow addition of MeOH.
The mixture is extracted with EtOAc and washed with NH 4 Cl. The organic phase is dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude is purified by flash chromatography on silica gel (PE/DCM 1:1).
Carbamate 10 is solubilised in dry THF (0.1 M) and the mixture is cooled to −40 °C. The desired alkyllithium reagent is added slowly and the reaction is stirred for 1 hour at −40 °C. The reaction is then quenched by slow addition of methanol. The solvent is removed under reduced pressure and the crude is solubilised in TFA. The reaction is stirred for 1 hour at r.t. The reaction mixture is diluted in DCM and washed with NaHCO 3 (1 M). The organic phase is dried (MgSO 4 ) and filtered, and the solvent is removed under reduce pressure. The corresponding amine is obtained without further purification.
Alternatively, the compound can be synthesised by treatment of the urea 6c with sodium hydride (2 equiv), in dry THF at 0 °C for 30 min, followed by addition of methyl iodide (2 equiv), at r.t. for 24 h. The reaction was diluted with Et 2 O and quenched with water. The mixture was extracted with EtOAc, dried (MgSO 4 ), and filtered, and the solvent was removed under reduced pressure. The desired compound was obtained in 60% yield after flash chromatography on silica gel (PE/EtOAc 9:1).
The solvent was removed under vacuum. The crude was solubilised in toluene and Boc 2 O was added (1 equiv) to the reaction mixture. The reaction mixture was stirred for 16 h under reflux. The crude was washed with H 2 O, the organic phases were combined and dried with MgSO 4 , and solvent was removed under reduced pressure. The desired compound was obtained without further purification in 80% yield (3.10 g) as an oil.
LDA (2 equiv) was added slowly and the reaction mixture was stirred for 2 h at this temperature. The reaction was quenched slowly with methanol, and the mixture was washed with NH 4 Cl and extracted with EtOAc. The organic phase was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude was purified by flash chromatography, and the desired compound was obtained in 90% yield (colourless oil).

tert-Butyl N-methyl-N-(1-phenylpentyl)carbamate (12a)
The compound was synthesised following the general procedure 3 starting from 50 mg (0.21 mmol) of vinyl carbamate 9. The desired product was obtained in 61% yield (40 mg) as a colourless oil. The NMR analysis shows the presence of two rotamers.

tert-Butyl N-methyl-N-(3-methyl-1-phenyl-butyl)carbamate (12b)
The compound was synthesised following the general procedure 3 starting from 40 mg (0.17 mmol) of carbamate 9. The desired product was obtained in 61% yield (29 mg) as a colourless oil. The NMR analysis shows the presence of two rotamers.