Pictet-Spengler route to Praziquantel

 

NMR-monitored experiments - testing various intermediates of PZQ (derivatives) with a strong achiral Bronstedt-acid as pretests for chiral derivatives of the catalyst





Hazard and Risk Assessment:
Reaction Class: 2
Hazards: T Toxic, X Irritant, C Corrosive
Risk rating: U = Unlikely

Start time: 6:15 PM 02/07/2010
End time: 4:00 PM 08/07/2010

General Procedure:
Each of the compound MW7, MW29-4, MW14, MW40-1 (75.0 µmol) shown in Table1 was solved in CDCl3 (~0.5 mL) in a NMR tube and MW39-2 (1.8 mg, 4.0 µmol, 5 mol%) was added.
- after 3 days at r.t no conversion was monitored (by 1H NMR)
- heated to 60°C for further 3 days -> no conversion of the starting material

MW41-1A – MW41-4A
-> addition of MeSO3H (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%) as a Broensted-acidic co-catalyst [reaction index A]
-> reference experiments: MeSO3H (5.2 µL of a 5% solution in CDCl3, 384 µg, 4.0 µmol, 5 mol%). [reaction index B]



Start time: 5:30 PM 08/07/2010
End time: 4:00 PM 12/07/2010

After 16.5 h at r.t. - no conversion monitored by NMR
-> heated to 60°C for 3 d

Results:
MW41-1A/MW41-1B and MW41-3A/MW41-3B:
No conversion of the starting material monitored

MW41-2A/MW41-2B
About 50% conversion in both trials, no significant difference to the reference experiment

MW41-4A/MW41-4B
Nearly complete conversion of the starting material, but the reference experiment showed a better consumption!


Summary:
The BINOL-N-triflyl phosphoramide catalyst MW39-1 showed no activity (for 5 mol% catalyst loading) for an acid-catalysed Pictet-Spengler reaction of the tested compounds. An additional strong Broenstedt-acid MeSO3H, intended as a co-catalyst, didn’t influence the catalytic activity of the phosphoramide MW39-1. The conversion of MW29-4 and MW40-1 (experiments MW41-2A/MW41-2B and MW41-4A/MW41-4B) was caused by the added MeSO3H, but only the N-cyclohexanoyl-protected amines showed a consumption of the starting material, the free amines MW7 and MW14.