Tritylamine as an Ammonia Surrogate in the Ugi Reaction Provides Access to Unprecedented 5-Sulfamido Oxazoles Using Burgess-type Reagents.

Irene Preet Bhela,Marta Serafini,Erika Del Grosso,Gian Cesare Tron,Tracey Pirali

doi:10.1021/acs.orglett.1c01002

Irene Preet Bhela, Marta Serafini + Show 3 more

Open Access

https://doi.org/10.1021/acs.orglett.1c01002

Copy DOI

Abstract

Starting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position. The synthetic procedure employs readily available starting materials and proceeds smoothly under mild reaction conditions with good tolerance for a variety of functional groups, coming to fill a gap in the field of oxazole compounds.

Highlights

Starting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position
Letter trifluoroethanol followed by cyclization in the presence of trifluoroacetic acid (TFA)/trifluoroacetic anhydride (TFAA) to give 5-(trifluoroacetamido)-oxazoles (Figure 1).[9]
From our experience in the field of multicomponent reaction (MCR),[15] we assumed that the simplest procedure to afford the required diamide substructures was represented by the Ugi 4-component reaction. When this MCR is conducted in the presence of ammonia it is known that yields are poor, especially when formaldehyde is used as an oxo reactive partner, due to the formation of side products.[16]. This limitation was evident when, during a medicinal chemistry campaign aimed at identifying novel IDO1 inhibitors,[17] two compounds, 1o and 1p (Scheme 2), bearing a diamide substructure were required for our structure−activity relationship study

Summary

Introduction

Starting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position. We disclose a reaction in which the use of Burgesstype reagents[13] leads to the simultaneous formation of the oxazole ring and insertion of a sulfamide group on the heterocyclic system.

Results

Conclusion