Enantioselective Hydrogenation of dehydro-PZQ and derivatives

 

Synthesis of PZQ enamide by oxidation of PZQ with molten sulfur. See related experiments on rac-PZQ: Sulfur melt data smogasbord



Hazard and Risk Assessment:


Optimization of the reaction time:
Start time: 9:50 AM 19/04/2011

MW60-1:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 10 min.
- yellow coloured solution in ethyl acetate

MW60-2:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 20 min.
- orange coloured solution in ethyl acetate

MW60-3:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 40 min.
- dark red coloured solution in ethyl acetate

TLC (ethyl acetate, stain: Ceric ammonium molybdate, KMnO4)


-> best result for a reaction time between 20 and 40 min: 30 min - good conversion , less starting material


Scale-up:
Start time: 1:15 PM 19/04/2011

MW60-4:
rac-benzoyl-PZQ (2.00 g, 6.41 mmol, M.W. 312 g/mol) and sulfur (412 mg, 12.8 mmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 45 min under argon atmosphere.
- yellow solid after mixture cooled down, orange solution in ethyl acetate
Work-up:
- dissolved in ethyl acetate and evaporated with silica gel
- column chromatography (hexane:ethyl acetate, 3:1)
Rf = 0.18

Yield: 600 mg (1.94 mmol, 30%) [M.W. 310.4 g/mol]
Reisolated PZQ: 1.22 g (61%)



-> Reaction wasn't completed after 45 min at 180°C

see Repetition: Oxidation of PZQ with sulfur (MW60-5)

Analytical data: see Characterization of PZQ-enamide

References:
[1] Spectral and Chemical Properties of Pyrazino-[2,1-a]-isoquinolin-4-one Derivatives, K. Kiec'-Kononowicz, Arch. Pharm. 1989, 322,795-799. DOI: 10.1002/ardp.19893221104.