Mono N-alkylation
To a stirred suspension of Cs2CO3 (0.006 mol) in 3 mL DMF was added the representative primary amine (0.006 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Then a solution of alkyl bromide (0.002 mol) in 2 mL DMF was added over a period of 5 minutes. The resulting mixture was stirred at room temperature for overnight (12 h). The reaction mixture was filtered and the filtrate was diluted with 25 mL ethyl acetate, washed with 50 mL brine, 50 mL water and dried (Na2SO4), evaporated to give the corresponding secondary amine which was purified by silica gel chromatography using a gradient of hexane and ethyl acetate (colorless oil, 15%).
First why using only around 0.5 Eq of the bromide abd the get a very bad 15% yield? The origiginal paper in JOC (67, 674) states over 1 Eq of the bromide. Cesium effect for mono alkylation of primary amines is a great concept on paper but did’nt work well in my hands, but I know poeple who used this methodology with succes.
gilgerto
April 1, 2008 at 7:03 pm
There is a typo – we took one eq. of bromide. The yield is variable with our substrates. Sometimes we improved the yields to 40-50% by adding 1 eq. sodium iodide or tetrabutylammionium iodide (TBAI) to the reaction mixture. With activated halides (benzylic chlorides/sodium iodide system) we obtained the products of mono N-alkylation in excellent yields.
pmgb
April 1, 2008 at 7:58 pm
iodo is better leaving group the rxn could just be run longer in the case of hindered bromides.
the reason yeilds are low is water in inhibiting the sn2 reaction.
also noted the higher dielectric constant aprotic solvents give better yeilds and selectivity
condidered dimethyl sulfone?
ian
January 21, 2009 at 3:02 am