Synthesis of new 2-substituted 3-amino-4-hydroxymethylthiophenes through intramolecular nitrile oxide cycloaddition processes and N,O-bond cleavage

Venerando Pistarà,Maria A Chiacchio,Graziella Greco,Paolo Quadrelli,Antonino Corsaro,Jacques Royer

doi:10.3998/ark.5550190.0012.618

Venerando Pistarà, Maria A Chiacchio + Show 4 more

Open Access

https://doi.org/10.3998/ark.5550190.0012.618

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Abstract

A synthesis of new 2-substituted 3-amino-4-hydroxymethylthiophenes 7 is reported as a useful alternative to the long known oximation of oxothiophenes 8, followed by treatment with gaseous hydrochloric acid in a polar solvent. The synthesis consists of an INOC process of unsaturated sulfide nitrile oxides, obtained from the condensation of corresponding nitroalkenes and allylmercaptan and then dehydration, which leads to tetrahydrothieno(3,4-c)isoxazoline 4. N,O- Bond cleavage of 4 upon hydride reduction affords to thiophenes 7 of biological interest.

Highlights

Intramolecular nitrile oxide-olefin cycloaddition processes (INOC)[1] have been of considerable synthetic and mechanistic interest, especially, as far as it concerns the resulting isoxazoline ring which can serve as a precursor of different functionalities stereoselectively produced by cleavage of the N,O-bond (Scheme 1)
These INOC reactions are useful in the field of the functionalization of heterocycles as they lead to isoxazoline-fused heterocycles, which, after selective scission of the isoxazoline nucleus, afford to heterocycles containing two functional groups which are otherwise difficult to introduce into the heterocycle, but, generally, manipulable.[2]
In this paper we have extended the scope of the above reaction sequence to other derivatives 7b-i with several groups, such as ethyl, benzyl, and phenyl group, and some sugar groups, linked to the 2 position of the ring, because 2-substituted-4-hydroxymethyl-3-aminotiophenes 7 are useful as intermediates in the synthesis of thiophene derivatives of pharmaceuticals and agrochemicals.[10]

Summary

Introduction

Intramolecular nitrile oxide-olefin cycloaddition processes (INOC)[1] have been of considerable synthetic and mechanistic interest, especially, as far as it concerns the resulting isoxazoline ring which can serve as a precursor of different functionalities (hydroxyketone, aminoalcohol and other functional groups) stereoselectively produced by cleavage of the N,O-bond (Scheme 1). After evaporation of the solvent under reduced pressure, the oily residue was chromatographed on silica gel (eluant: cyclohexane:ether = 10:l) to give a diastereomeric mixture of β-nitroalkyl sulfides 2f, 2g, 2h and 2i, in the ratios 1.2:8.8, 1.4:8.6, 2.2:7.8 and 1.6:8.4, respectively, as it appeared from the integrations of the CH-S proton signals of the 1H NMR spectra performed on the corresponding crude reaction mixtures.

Results

Conclusion