Pictet-Spengler approach to PZQ: Cyclisation to Praziquanamin

27 Mar
Published by Michael Wolfle
1H_NMR_Praziquanamin.pdf81.68 KB
1H_NMR_Praziquanamin.dx111.8 KB

Reaction 1
The Pictet-Spengler cyclisation of the acetal 4 to the tetrahydroisoquinoline substructure 5 was conducted in concentrated sulfuric acid. The reaction showed a complete conversion to the tricycle in a very good yield and with high purity. The product was isolated by extraction from the basic aqueous solution, no further purification was needed. No side products were observed in the 1H NMR spectrum.

A mechanistic view of this cyclisation was published by Kim et al.; they postulated a N-acyliminium ion 6 as an intermediate species, which was formed after an acidic cleavage of the methoxy groups of the acetal 4.[1] The ring closure to the tetrahydroisoquinoline 7 occurred by a nucleophilic attack of the aromatic pi-electrons.


Proposed mechanism of the Pictet-Spengler cyclisation of 4.

To 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride 5 (500 mg, 1.65 mmol) cold sulfuric acid (1 mL) was added at 0°C. When the gas evolution had stopped the mixture was warmed to room temperature and stirred for 3 h. Then the solution was quenched with ice, made basic to pH 12 by adding 2 N aqueous NaOH solution and extracted with DCM. The organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, praziquanamine 5 was obtained as a colorless solid (314 mg, 1.55 mmol, 94%) in a high purity (lit. [1] 96%).
m.p. 118.1-119.2°C (lit. [1] 117-119°C). 1H NMR (CDCl3, 200 MHz): δ = 1.84 (bs, 1H), 2.70-3.10 (m, 4H), 3.60 (ABq, J = 17.2 Hz, Δν = 24 Hz, 2H), 3.69-3.78 (m, 1H), 4.76-4.92 (m, 2H), 7.11-7.28 (m, 4 H). C14H23ClN2O3 (202.3).

[1]     “Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel”, J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron, 1998, 54, 7395-7400.


MatTodd's picture

Great - looks like a simple reaction. This amine is the candidate for resolution, and of course is the same amine as you derived from hydrolysis of PZQ itself. So is it necessary in your view to purify this molecule further, by crystallization? Is it simple to crystallize this amine directly, or perhaps as the hydrochloride salt?
Yes, the mechanism of the ring closure is as you suggest. The intermediate will be in equilibrium with the other iminium ion (involving the other nitrogen atom) but there should be no ring closure that way since the orbital geometry is wrong - an example of Baldwin's rules (except here it's all probably reversible, so I imagine it's a question of final product stability).

Michael Wolfle's picture

The purity of the amine 5, obtained from the conversion of the aminoacetal hydrochloride 4 with sulfuric acid, is amazing. And I assume that the yield of this reaction could be still increased by reducing the reaction time or lowering the temperature. However, if a further purification is required, the free amine can be well crystallized from toluene.
For example, a subsequent purification is needed when the Pictet-Spengler cyclisation was conducted with the free aminoacetal of 4.

MatTodd's picture

OK, great. It's interesting that the temperature is kept low. Frequently for Pictet-Spengler reactions in the literature, there are electron-donating groups on the aromatic ring, presumably to increase the ring's nucleophilicity. Here you don't need them, but you're still in conc. acid. I also remember that in one of the papers you cite here, the (MeO)2 analog is made this way, which was always an interesting alternative since I think this analog of PZQ is approximately as active as PZQ itself.
In any case, it's promising you don't need to apply heat. This bodes well for the application of enantioselective catalysts for this reaction, where I imagine heat will not be great for generating high e.e.'s. We should assemble some papers detailing likely catalysts for this reaction, to see how synthetically accessible they are, and perhaps even to see if we can solicit donations from the relevant groups.