Mild and efficient cyanuric chloride catalyzed Pictet-Spengler reaction

Abstract

A practical, mild and efficient protocol for the Pictet-Spengler reaction catalyzed by cyanuric chloride (trichloro-1,3,5-triazine, TCT) is described. The 6-endo cyclization of tryptophan/tryptamine and modified Pictet-Spengler substrates with both electron-withdrawing and electron-donating aldehydes was carried out by using a catalytic amount of TCT (10 mol %) in DMSO under a nitrogen atmosphere. TCT catalyzed the Pictet-Spengler reaction involving electron-donating aldehydes in excellent yield. Thus, it has a distinct advantage over the existing methodologies where electron-donating aldehydes failed to undergo 6-endo cyclization. Our methodology provided broad substrate scope and diversity. This is indeed the first report of the use of TCT as a catalyst for the Pictet-Spengler reaction.

Keywords: 6-endo cyclization; Pictet–Spengler; TCT; cyanuric chloride; β-carboline.

Scheme 1

The Pictet–Spengler reaction of tryptamine with 4-tolualdehyde.

Figure 1

The two Pictet–Spengler substrates employed in the TCT catalyzed cyclization.

Scheme 2

Synthesis of the Pictet–Spengler substrate 4. Reaction conditions: (a) K₂CO₃, DMF, 80 °C, 3 h; (b) Zn, AcOH-EtOH, 60 °C, 4 h.