Advances in Green Catalysis for the Synthesis of Medicinally Relevant N-Heterocycles

A Sofia Santos,Nuno Viduedo,M Manuel B Marques,Artur M S Silva,José C Cunha,Daniel Raydan

doi:10.3390/catal11091108

A Sofia Santos, Nuno Viduedo + Show 4 more

Open Access

https://doi.org/10.3390/catal11091108

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Journal: Catalysts	Publication Date: Sep 15, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Universidade Nova de Lisboa, University of Aveiro

Abstract

N-heterocycles, both saturated and unsaturated, are ubiquitous biologically active molecules that are extremely appealing scaffolds in drug discovery programs. Although classical synthetic methods have been developed to access many relevant N-heterocyclic scaffolds, representing well-established and reliable routes, some do not meet the needs of sustainability. In this context, several advances have been made towards the sustainable synthesis of N-heterocycles. This review focuses on the most recent examples from the last five years of catalytic synthesis of several heterocyclic compounds of medicinal relevance. Thus, the synthesis of isoindoloquinazolines, quinazolines and azaindoles, among others, are covered. The synthetic methods selected include the use of homogeneous and heterogeneous catalysts and the use of alternative and sustainable methods such as, for example, metal-catalyzed acceptorless coupling and one-pot reactions. The green aspects of the individual synthetic approaches are highlighted, and the scope of each methodology is described.

Highlights

Antonella AronicaN-containing heterocycles are among the most relevant structural components of pharmaceuticals, and according to an analysis from the U.S FDA, 59% of unique smallmolecule drugs contain a nitrogen heterocycle [1].Both saturated and unsaturated N-heterocycles are prevalent in biologically active molecules and constitute increasingly attractive scaffolds for the development of new medicines (Figure 1)
Catalysts 2021, 11, 1108 of 21 named reactions have been developed to address the synthesis of N-heterocycles2 [12]
The previous methodology reported by the team involved a palladium-catalyzed cascade C–N cross-coupling/Heck reaction that allowed for a straightforward synthesis of substituted 4, 5, 6- and 7-azaindoles but did not work when applied to N-aryl amino-o-bromopyridines

Summary

Introduction

N-containing heterocycles are among the most relevant structural components of pharmaceuticals, and according to an analysis from the U.S FDA, 59% of unique smallmolecule drugs contain a nitrogen heterocycle [1] Both saturated and unsaturated N-heterocycles are prevalent in biologically active molecules and constitute increasingly attractive scaffolds for the development of new medicines (Figure 1). Catalysts 2021, 11, 1108 of 21 named reactions have been developed to address the synthesis of N-heterocycles2 [12]. Examples of the use of green heterogeneous catalysts and recyclable catalysts combined with non-traditional activation reagents and atom-efficient methods such as one-pot reactions and acceptorless coupling methods such as microwave (MW). N-heterocycles of medicinal relevance improved and green reagents and atom-efficient as one-pot reactions and using acceptorless coupling approaches are reviewed (Figure 2). The synthesis of N-heterocycles of medicinal relevance using improved and green approaches are reviewed (Figure 2).

Green Catalytic

Structure some of the catalysts

Naphthopyranopyrimidine-based

Lactic acidcatalyzed catalyzedone-pot one-pot synthesis

Hydrogenation

Findings

Conclusions