In search for the acid-catalyzed Pictet-Spengler cyclisation using organic Brønsted acids

19 Apr
Published by Michael Wolfle


Previously, we showed the acid-mediated Pictet-Spengler cyclisation of 4 to racemic praziquanamin 5 by concentrated sulfuric acid. The route to the enantioselective synthesis to (R)-PZQ, we investigated an organocatalyzed Pictet-Spengler reaction using phenylphosphinic acid 10 and p-toluenesulfonic acid as Brønsted acids.
Akiyma and Terada in 2004, developed a new class of chiral phosphoric Brønsted acids 12, which catalyzed the asymmetric addition of nucleophiles to imines 11 and their analogues successfully.[1,2]

Scheme 2. Asymmetric addition of nucleophiles to imines with chiral phosphoric Brønsted acids.

The first asymmetric Pictet-Spengler cyclisation using chiral phosphoric Brønsted acids were performed by List et al. in which electron rich tryptamines 14 converted to tetrahydro-b-carbolines 16 in high yields and ee's up to 96%.[3]

Scheme 3. Catalytic asymmetric Pictet-Spengler reaction by List et al.

Antilla and co-workers found that phenylphosphonic acid 10 as an efficacious promoter for imine amidations, which also prompted the development of chiral phosphoric acids.[4,5]

Scheme 4. Phenylphosphonic acid-catalyzed imine amidation by Antilla et al.
The Pictet-Spengler cyclisation was tested with catalytic amounts of phenylphosphinic acid 10 (20 mol%, entry 1-3, Table 1) initially. Since starting material was recovered, a slight excess of Brønsted acid was used (1.2 eq., entry 4-6) and the reaction was attempted at room temperature. However, even reflux temperatures and a change of the solvent from toluene to DCE also showed no conversion to the heterocycle 5 and either the starting material or decomposition products were observed using 1H NMR. p-Toluenesulfonic acid was used to test whether a stronger acid to this reaction could promote ring closure.
In result, all attempts to an organoacid-mediated Pictet-Spengler showed no conversion. Possible reasons for the unsuccessful conversion to the heterocycle could be the less nucleophilicity of the arene and the less strength of the used acids.

Table 1. Reaction conditions for the attempts to the Bronsted acid-mediated Pictet-Spengler cyclisation.

To 5 (100 mg, 330 µmol) was added the Brønsted acid phenylphosphinic acid (8.61 mg, 60.6 µmol for 0.2 eq.; 56.3 mg, 396 µmol for 1.2 eq.) or p-toluenesulfonic acid (69.2 mg, 396 µmol, 1.2 eq.), dissolved in toluene (5 mL) or DCE (5 mL) and heated to reflux. After the reaction time specified in Table 1 the mixture was quenched with water and made basic to pH 12 by adding 2 N aqueous NaOH solution. After extraction with ethyl acetate the organic layer was washed with brine and dried over Na2SO4. The concentrated residue was analyzed by 1H NMR and monitored by TLC (silica gel on aluminium, EtOAc:MeOH:Et3N = 1:1:0.01).
[1]    “Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted Acid”, T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 12, 1566-1568; DOI: 10.1002/anie.200353240.
 [2]    “Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation” D.  Uraguchi and Masahiro Terada, J. Am. Chem. Soc. 2004, 126, 17, 5356–5357; DOI: 10.1021/ja0491533.
 [3]    “Catalytic Asymmetric Pictet-Spengler Reaction”, J. Seayad, A. M. Seayad and B. List, J. Am. Chem. Soc. 2006, 128, 1086-1087.
 [4]     “Chiral Phosphoric Acids: Powerful Organocatalysts for Asymmetric Addition Reactions to Imines”, S. J. Connon, Angew. Chem. Int. Ed. 2006, 45, 3909-3912.
 [5]    “Brønsted Acid-Catalyzed Imine Amidation”, G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadhavuni, Y. Wang, and J. C. Antilla,  J. Am. Chem. Soc. 2005, 127, 45, 15696–15697; DOI: 10.1021/ja0533085.