Synthesis of aminomethyl derivatives of 5-substituted-3-(prop-2-ynyl)dihydrofuran-2(3H)-ones

1 Introduction

Along with many other structures, γ-butyrolactones serve as important scaffolds for natural compounds [1, 2]. Structures bearing this fragment are widespread in nature, and a number of such molecules have been isolated so far [3–5]. Several compounds that may be of practical interest in pharmacology and medicine have been obtained from Gloiopeltis furcata, Aspergillus ustus, Gardenia sootepensis, Sinularia maxima, Salvia miltiorrhiza, and others [6–10]. Other examples include biologically important muricatacin [11], tornabeatins [12], and matairesinol [13] (Fig. 1).

Fig. 1:

Selected examples of natural products and pharmaceuticals based on the dihydrofuran-2(3H)-one scaffold.

Research on butanolide-containing structures is focused not only on isolation of natural compounds, but also on accessing the appropriate synthetic analogs [14–17]. Considerable interest in these compounds is explained by substantial biological activities that different dihydrofuran-2(3H)-one-based molecules possess including cytotoxic and antimicrobial activities [1, 3, 6–13, 18–20].

Moreover, there are several known experimental and approved drugs bearing a γ-butyrolactone fragment [21, 22] (Fig. 1). Considering all those mentioned above, it is obvious that the development of new methods for the synthesis of lactone-containing compounds is of a distinct interest.

Previously, we carried out numerous elaborations of the methods to get different functionally substituted dihydrofuran-2(3H)-ones [23]. Additionally, follow-up biological investigations of the latter have also been performed to reveal antibacterial activity of the synthesized compounds [24].

Mannich aminomethylation reactions are known to be widely used in fine organic synthesis [25, 26], but there are not many reports on the application of this method in the chemistry of lactones [27–29].

2 Results and discussion

To expand the library of potentially bioactive dihydrofuran-2(3H)-ones and to develop new methods for the synthesis of polyfunctionalized butanolides, we chose 5-substituted-3-(prop-2-ynyl)dihydrofuran-2(3H)-ones as an object for research and studied the aminomethylation of the terminal alkyne group by the Mannich reaction. At first, appropriate starting materials 1 were synthesized according to a known procedure [23]. Afterward, syntheses of target compounds 3a–l were carried out and optimal conditions providing high yields of products were determined (Scheme 1). The interaction of propynylbutanolides 1 with various secondary amines (e.g. dialkylamines, morpholine, piperidine) and paraformaldehyde in the presence of catalytic amounts of CuCl₂ leads to the introduction of the aminomethyl fragment (Table 1).

Scheme 1:

Synthesis of 3a–l. (i) 1 (1.0 equiv.), amine (1.5 equiv.), paraformaldehyde (1.4 equiv.), CuCl₂ (8.5 mol%), dioxane, 95 °C, 8 h.

Table 1

Synthesis of 3a–l.

^aYields of isolated products.

Moreover, it was established that the reaction of aminomethylation proceeds selectively at the triple bond and, irrespective of the nature of the used amine, provides high yields of the target products.

3 Conclusion

In conclusion, a general method for the synthesis of new dihydrofuran-2(3H)-ones has been elaborated. To transform initial γ-butyrolactones bearing an ethynyl group in the side chain, the Mannich aminomethylation method was used. As a result, a new functional group was successfully introduced into the molecule, with the triple bond remaining unchanged. All compounds were synthesized, with good to very good yields. Our future studies will be directed toward investigations on the biological activity of the synthesized compounds.

4 Experimental section