General methodology for the chemoselective N-alkylation of (2,2,6,6)-tetramethylpiperidin-4-ol: Contribution of microwave irradiation

Highlights

• Alkylation of sterically hindered amines.

• N-Alkylation versus O-Alkylation.

• Microwave irradiation used to decrease reaction time.

• Microwave irradiation improves the yields.

Abstract

A convenient method to access a broad variety of N-alkyl-(2,2,6,6)-tetramethylpiperidin-4-ol compounds is reported. The thermal treatment of a mixture of (2,2,6,6)-tetramethylpiperidin-4-ol and allyl or benzyl bromide derivatives gave the corresponding N–alkylated compounds in good yields while leaving the hydroxyl functional group intact. Whereas 40 h were needed to reach complete conversion, microwave irradiation allowed the reaction time to be reduced (20 min) and improved the yields in most cases.

Introduction

Sterically Hindered Amine (SHA) is a term coined by Sartori and Savage in 1983 to define any primary or secondary amine derivatives in which the amino group is bonded to a tertiary carbon atom and a secondary or tertiary carbon atom, respectively [1]. They have long been known for their performance in carbon dioxide removal for gas steaming in industrial chemical processes [2], [3], [4]. (2,2,6,6)-Tetramethylpiperidin-4-ol derivatives 1 belong to this compound class and have added an extra-dimension to applications over the last two decades. Indeed, 1 is a synthetic precursor of TEMPOL [5] which is a well-known nitroxyl radical of major interest in organic synthesis [6], as well as polymer chemistry [7]. TEMPOL exhibits not only a higher oxidation potential than its TEMPO analogue [8], but also represents a low cost alternative [6]. In this context, Rychnovsky and co-workers showed that the catalytic activity of TEMPOL could be three times higher than that of TEMPO when grafted to a polymeric carrier via the OH moeity [9]. Using N-allyl (2,2,6,6)-tetramethylpiperidin-4-ol as a precursor of TEMPOL was essential to achieve the grafting procedure. In another context, 1–derived N-alkylated compounds are also useful for commercial polymeric material stabilization [10], [11]. In particular, N-alkyl substitution enables significant modulation of the photosensibilizing effects of 1 in polypropylene [10]. For at least these two reasons, the N-alkylation reaction of 1 has been well studied, but the development of an efficient protocol remains desirable as the literature precedent is scarce in this regard [12]. Whiten and co-workers carried out the synthesis of N-ethyl, N-methyl and N-hydroxymethylanthra-none-(2,2,6,6)-tetramethyl-piperidin-4-ol from 1 in moderated to good yields, using classical S_N2 reaction conditions (Scheme 1, a) [13].

Banert and co-workers thereafter capitalized on this contribution to reinvestigate the synthesis of triacetonamine derivatives, without however studying neither the scope nor alternatives to reduce the reaction time [14]. Alternatively, Novelli and co-workers proposed a double Michael addition-based approach for the synthesis of N-benzyl-(2,2,6,6)-tetramethylpiperidin-4-one from phorone and benzylamine (Scheme 1, b) [15]. Although this method provides the expected compound in a good yield, multiple purification steps by column chromatography strongly limits its attractiveness. Later, Rychnovsky’s group reported the synthesis of three N-allyl-(2,2,6,6)-tetramethyl-piperidin-4-ol compounds in good yields [9]. The reaction was conducted in a sealed tube using two equivalents of (2,2,6,6)-tetramethylpiperidin-4-ol 1 with regard to the electrophile (Scheme 1, c). Herein, we report that this method is convenient for the preparation of N-benzyl and N-allyl-(2,2,6,6)-tetramethylpiperidin-4-ol in good to high yields, including on gram-scale when performed in an autoclave. The scope was examined and the effect of microwave irradiation on the process was also investigated to optimize its effectiveness.