Elsevier

Tetrahedron Letters

Volume 57, Issue 18, 4 May 2016, Pages 1953-1957
Tetrahedron Letters

Synthetic study on the T3P®-promoted one-pot preparation of 1-substituted-3,4-dihydro-β-carbolines by the reaction of tryptamine with carboxylic acids

https://doi.org/10.1016/j.tetlet.2016.03.067Get rights and content

Highlights

  • Novel one-pot method for β-carboline synthesis from tryptamine.

  • Beneficial synergy of the MW irradiation with a green reagent.

  • Efficient synthesis of harmalan and dihydro-eudistomin U.

  • Experimental proof for the water scavenging mechanism of T3P®.

Abstract

A novel and efficient one-pot method has been developed for the synthesis of 1-substituted-3,4-dihydro-β-carbolines from tryptamine and a wide variety of carboxylic acids. The reaction was successfully applied to the synthesis of an important alkaloid harmalan as well as dihydro-eudistomin-U. This represents the first case in which 1-propanephosphonic acid cyclic anhydride (T3P®) has been used in the Bischler–Napieralski reaction. Unexpectedly it was observed that less than two equivalents of the T3P® reagent were sufficient for the two consecutive reactions.

Introduction

β-Carbolines, incorporating a tricyclic pyrido[3,4-b]indole scaffold, form a prominent group of alkaloids.1 β-Carbolines and their reduced analogs, such as dihydro- and tetrahydro-β-carbolines can be found in various plants, mammalian and marine invertebrates.2 Both simple and complex β-carboline derivatives possess a broad spectrum of biological and pharmacological activities including antimicrobial,3 antimalarial,4 antithrombotic,5 parasiticidal,6 anti-HIV,7 anti-Alzheimer,8 and antifungal effects.9 An important member of the tetrahydro-β-carboline family is tadalafil, a commercially available drug for the treatment of erectile dysfunction.10 Furthermore, simple β-carbolines have been used as starting materials in the preparation of many indole alkaloids and other physiologically active compounds.11

Various methodologies have been reported in the literature for the construction of the β-carboline skeleton.12 Among these, the Bischler–Napieralski reaction, described in 1893 by August Bischler and Bernard Napieralski, is one of the most important procedures for the synthesis of 3,4-dihydro-β-carbolines from tryptamine.13 In general, this cyclization reaction requires harsh reagents, for example treatment of the amide formed from tryptamine with POCl314 or P2O515 in solvents with high boiling points, such as toluene or xylenes. In the last decades, milder reaction conditions have also been described such as the use of polyphosphoric acid (PPA) or ester (PPE) in dichloromethane,16 Ph3P in tetrachloromethane,17 Tf2O/DMAP,18 (COCl)2/FeCl3,19 and (PhO)3P·Cl2 in dichloromethane.20

Recently, we reported the application of 1-propanephosphonic acid cyclic anhydride (T3P®) in the synthesis of α-aminophosphonates,21 phosphinic esters22 and amides.23 The T3P® reagent is a versatile promoter of a wide range of transformations, including condensation, oxidation, rearrangement, and various other functional group transformations, therefore its application in synthesis is swiftly increasing.24 Herein, we report a one-pot procedure for the synthesis of 1-substituted-3,4-dihydro-β-carbolines from tryptamine and the corresponding carboxylic acids using T3P® as the condensation reagent. To the best of our knowledge, this reagent has not yet been applied in the Bischler–Napieralski reaction.

Section snippets

Results and discussion

First, the reaction of tryptamine (1) and benzoic acid (2a) was investigated. Heating the two components in a microwave (MW) reactor at 150 °C for 30 min without solvent or in toluene resulted in the formation of the tryptamine benzoate salt (3a). However, when the T3P® reagent (solution in ethyl acetate) was also added under MW conditions, acylation took place giving rise to the formation of Nb-benzoyltryptamine (4a), which underwent subsequent Bischler–Napieralski cyclization in a consecutive

Conclusions

A new one-pot method has been developed for the cascade acylation between tryptamine and aliphatic or (hetero)aromatic carboxylic acids. The primarily formed amide undergoes subsequent Bischler–Napieralski ring closure to afford 3,4-dihydro-β-carbolines containing various substituents at position 1. The application of T3P® under MW irradiation was beneficial to attain high yields. Additionally, natural products, 1-methyl-3,4-dihydro-β-carboline (harmalan) and dihydro-eudistomin-U have been

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