Pictet-Spengler route to Praziquantel

 

START: 12/03/12
FINISH: 13/03/12

==========================================
Summary and Conclusion
The reaction proceeded as expected with an isolated product yield of 81%. Proton NMR of the product showed trace amounts of solvent and the phenethylamine starting material. Failed recrystallisation attempt from diethyl ether and hexane. Product deemed adequate for use in further reactions.
==========================================

Background
See synaptic leap post: here.




Hazard and Risk Assessment


Following Experiments
Synthesis of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-1)
AgOTf catalysed synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-1)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-3)

Chemical Information
2-Phenethylamine (1) - SMILES: c1ccc(cc1)CCN, InChI: InChI=1S/C8H11N/c9-7-6-8-4-2-1-3-5-8/h1-5H,6-7,9H2, InChIKey: BHHGXPLMPWCGHP-UHFFFAOYSA-N.
Benzaldehyde (2)- SMILES: c1ccc(cc1)C=O, InChI: InChI=1S/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H, InChIKey: HUMNYLRZRPPJDN-UHFFFAOYSA-N.
N-Benzylidene-N-phenethylamine (3, KAB18-1) - SMILES: N(=C/c1ccccc1)\CCc2ccccc2, InChI: InChI=1S/C15H15N/c1-3-7-14(8-4-1)11-12-16-13-15-9-5-2-6-10-15/h1-10,13H,11-12H2/b16-13+, InChIKey: OOBAKFDIGIHHOM-DTQAZKPQSA-N

Procedure
Benzaldehyde (1.6 mL, 16 mmol, 1 eq) was added slowly to a stirring mixture of diethyl ether (4 mL) and 2-phenethylamine (2 mL, 16 mmol, 1 eq). The reaction was left to stir at rt from 08:36.
After 4 hours of stirring, the reaction mixture was dried over magnesium sulfate, filtered then concentrated to give a yellow liquid, which crystallised on standing (2.7 g, 81%). Confirmed by H-NMR.


Attempted recrystallisation from Et₂O/hexane. Starting mass: 736 mg.

13/03/12 - Recrystallisation failed. No further purification attempts.

Summary and Conclusion
The reaction proceeded as expected with an isolated product yield of 81%. Proton NMR of the product showed trace amounts of solvent and the phenethylamine starting material. Failed recrystallisation attempt from diethyl ether and hexane. Product deemed adequate for use in further reactions.

-----------------------------------------------------------------------------
NOTES 12/03/12
- Flask: 19.4842 g
- UPLOAD NMR
- Still working out a way to assay the rxn progress. Two possibilities so far: Product has same R_f as benzaldehyde or has an R_f smaller than phenethylamine. Last attempt was in MeOH/EtOAc, 1:5, v/v. Phenethylamine moved, but suspected product spot was still on the base line. Doesn't make sense. Will attempt DCM/MeOH mixture.
- Sample may also contain some benzaldehyde.

NOTES 13/03/12
- ReXST failed. Wary of heating solution during reXST - product may hydrolyse to starting materials.
- Trace starting materials in product weren't removed, again because hydrolysis of the imine might occur.
-----------------------------------------------------------------------------