A solution of 25% wt sodium methoxide in methanol 3.0mL (12.8 mmol) was added dropwise to a solution of diethoxyacetonitrile 6.2g (48 mmol) in anh methanol 15mL with cooling on ambient water bath over 5 min period. The mixture was stirred at RT under Ar for 26 hours. [Note 1] To this solution containing (EtO)2CHC(OMe)=NH, solid p-bromobenzylamine hydrochloride 5.04g (22.65 mmol) was added followed by additional 25% NaOMe 3.0mL (12.8mmol). The mixture was refluxed under Ar at 70C on oil bath for 17 hours (overnight). The reaction mixture was evaporated, the residue was diluted with tert-BuOMe 50mL, the salts were removed by filtration (washed with additional TBME) and the filtrates were evaporated. The residue was dried on highvac (50C, 0.5Torr, 1 hour) to yield the crude amidine 7.64g as a dark brown honey.
The crude amidine was slowly added in a thin stream into vigorously stirred conc. sulfuric acid 50 mL with cooling on ice bath. The flask after amidine was rinsed with additional conc. sulfuric acid (2x10mL, then 4 mL) and these washings were also added to the reaction mixture. The cooling bath was removed and the dark mixture was stirred at RT under Ar for 1 day. The reaction mixture was poured onto ice (250 g) in a 1L beaker, the flask was washed with water and washings were added to the mixture. The mixture was made alkaline by careful addition of conc. aqueous ammonia (approx 220mL, exothermic!) with external cooling on water bath. When the mixture has cooled to RT the precipitated product was collected by filtration, washed with water and dried by suction. The obtained crude product was suspended in a mixture of ethanol 400mL and water 100mL. 6M HCl 4mL was added and the mixture was heated and sonicated until complete dissolution took place. Charcoal (3 spoons) was added, the mixture was heated to a brief reflux (2 min) then cooled to RT and filtered. The charcoal was washed with ethanol+water mixture (1:1, 1oomL). The filtrates were made basic by addition of conc. ammonia 3mL and gradually concentrated down to approx 125mL volume to remove ethanol. The precipitated product was collected by filtration, washed with water and dried by suction, then on highvac. Y=3.943g (78% overall) of a pure product as a light tan solid.
1H(d6-DMSO, 400MHz): 8.809(s, 1H), 7.793(app d, 1.8Hz, 1H), 7.730(d, 8.7Hz, 1H), 7.215(dd, 8.7Hz, 1.9Hz, 1H), 6.553(s, 1H), 6.112(br s, 2H); 13C(d6-DMSO, 100MHz): 157.12, 151.74, 139.61, 130.03, 125.90, 124.44, 124.17, 120.63, 95.85; LC/MS(+ESI): 223, 225 (M+1)
Note 1: The progress of methyl imidate formation from nitrile can be readily followed on NMR - by diluting samples of react mixture with CD3OD + TMS standard: (EtO)2CHC(OMe)=NH : 4.836(s, 1H), 3.760(s, 3H), 3.590(m, 4H), 1.213(t, 7.1Hz, 6H); (EtO)2CHCN: 5.490(s, 1H), 3.699(m, 4H), 1.239(t, 7.1Hz, 6H)
Note 2: A slightly more optimised version follows: 12 mL of 25% wt NaOMe in MeOH was added to a water-cooled solution of (EtO)2CHCN 11.81g in anh. MeOH 30mL over 10 min. After 12 hours at RT, solid p-bromobenzylamine hydrochloride 10.17g was added and the mix was refluxed under Ar at 70C for 14 hours, then evaporated. The residue was re-dissolved in TBME 50mL, filtered (salts washed with additional TBME) the filtrates were evaporated and the residue dried on highvac at 50C. The obtained crude amidine (15.19g) was slowly poured into ice-cooled conc. sulfuric acid 100mL, the flask was washed with additional H2SO4 (2×20 then 5mL) and the washings were combined with the reaction mixture. The mix was stired at RT for 11 hours, then poured on ice (0.5kg) and carefully alkalised with conc aq. ammonia 450mL (with cooling: exothermic). Upon cooling to RT, the precipitated crude product was collected by filtration, washed with water and dried by suction. The crude product was refluxed with EtOH 0.5L and water 0.25L mixture acidified with 6M HCl 8mL until complete dissolution took place (30min). The solution was cooled, charcoal 2.5g was added, the mix was brought to brief reflux again (5 min), cooled to RT and filtered, the charcoal washed with additional EtOH. The filtrates were concentrated to about half volume, made basic with conc. ammonia 8mL, concentrated slowly down to approx 220mL. The precipitated product was collected by filtration, washed with water, dried by suction and on highvac.
Y = 8.455g (83%) of a light tan solid (96% pure by HPLC, NMR)