Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

Abstract

The cycloaddition of 1,3-dipoles at C=N bonds is a relatively rare process, in contrast to the widespread cycloaddition reactions at C=C, C≡C, and C=S bonds. In this study, we present the syntheses of novel hydantoin/1,2,4-oxadiazoline spiro-compounds using a 1,3-dipolar cycloaddition of nitrile oxides to C=N bonds of 5-iminohydantoins. The efficiency of the approach was demonstrated by varying the substituents at four positions of the resulting spirocyclic molecules. Cytotoxicity of the target hydantoin/1,2,4-oxadiazolines was shown to exceed previously known spiro-compounds bearing only hydantoins or 1,2,4-oxadiazolines (IC₅₀ values were 30-50 μM, HCT116 cell lines).

Keywords: 1,3-dipolar cycloaddition; Shiff bases; hydantoins; nitrile oxides; spiro-compounds.

Figure 1

Design and synthetic strategies for the target hydantoin/1,2,4-oxadiazoline spiro-compounds.

Scheme 1

Synthesis of dipolarophiles (5-iminohydantoins 2a–i).

Scheme 2

Preparation of the dipole precursors 4a–d.

Scheme 3

32CA reactions of nitrile oxides with 5-iminohydantoins (synthesis of spiro-compounds 5a–l). Isolated yields are shown. Unless otherwise noted dipolarophile 2 (0.15 mmol) and chloro oxime 4 (0.165 mmol) were used, and the product 5 was isolated via Et₂O trituration. ^aTriethylamine dropwise addition (1.2 equiv, 0.06 M CH₂Cl₂ solution, Ar, 0–5 °C); ^bdiffusion mixing technique (for details see Supporting Information File 1), ^cusing diffusion mixing N-(2-bromophenyl)formamide (6) was obtained with 80% yield; ^dproduct was isolated using column chromatography.

Scheme 4

Cycloaddition of nitrile oxide to 5-iminothiohydantoin 2j. ^aTriethylamine dropwise addition (2.4 equiv, 0.06 M CH₂Cl₂ solution, Ar, 0–5 °C); ^bdiffusion mixing technique.

Figure 2

Atropoisomerism of ortho-substituted spiro-compounds 5b and 5d.

Figure 3

Cytotoxicity investigation of hydantoin/1,2,4-oxadiazolines 5 (MTT test, HCT116 cell line) and selected examples of oxindole/1,2,4-oxadiazole [20] and hydantoin/1,2,4-triazoline [22] spiro-compounds.