Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

Abstract

Hydantoin and its analogues such as thiohydantoin and iminohydantoin have received substantial attention from both a chemical and a biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, and herbicidal properties that have led, in some cases, to clinical applications. Because of these broad-spectrum activities, intensive research efforts have been dedicated in industry and academia to the synthesis and structural modifications of hydantoin and its derivatives. Realizing the importance of hydantoin in organic and medicinal chemistry, we also initiated a research program that successfully designed and developed new routes and methods for the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at various positions, particularly at the N-1 position without following a protection–deprotection strategy. Because combinations of two or more pharmacophoric groups can lead to hybrid molecules that display a mixed mechanism of action on biological targets, we extended our developed strategy to the syntheses of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, or phosphate scaffold as a second pharmacophore to exploit their diverse biological functions.

1 Introduction

2 Chemistry and Properties

2.1 Physical Properties

2.2 Chemical Properties

2.3 Biological Properties

3 General Synthetic Methods

4 Synthesis of Diversely Substituted Hydantoins

5 Synthesis of Diversely Substituted Thiohydantoins

6 Synthesis of Diversely Substituted Iminohydantoins

7 Fused or Bicyclic (Thio)hydantoins

8 Di- or Multivalent (Thio)hydantoins

9 Hydantoin-Based Hybrid Molecules

9.1 Hydantoin–Isooxazoline Hybrids

9.2 Hydantoin–Triazole Hybrids

9.3 Hydantoin–Phosphate Hybrids: Phosphorylated Hydantoins

10 Summary and Outlook

Key words

hydantoins - thiohydantoins - iminohydantoins - hybrid molecules - pharmaceutical chemistry

Publication History

Received: 05 April 2021

Accepted after revision: 12 April 2021

Accepted Manuscript online:
12 April 2021

Article published online:
25 June 2021

• References and Notes

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• 139 Dimethyl (3-Methyl-2,5-dioxoimidazolidin-1-yl)phosphonate (121; R = Me)1-Methylhydantoin (1 g, 8.77 mmol) was dissolved in anhyd THF (25 mL). To this solution, was added a 60% oil suspension of NaH (0.3 g) in three portions at 0 °C. The mixture was stirred for 0 °C for 1 h, refluxed for 2 h, and then cooled to 0 °C. A solution of dimethyl chlorophosphate (1.6 g) in anhyd THF (10 mL) was added and the mixture was stirred for 4 h at 0 °C until the reaction was complete (TLC). The mixture was filtered and the solvent was evaporated to one-fourth of its original volume. Et₂O (30 mL) was added, and a viscous yellow oily liquid settled out as impurities after 20 min. The solution was decanted and kept for 2 h in a refrigerator to give white crystals; yield: 1700 mg (88%); mp 214–216 °C.
• 140 The ¹H NMR spectrum for 121 (R = Me) showed a singlet at δ = 2.92 for N–CH₃ and a singlet at δ = 3.94 for –CH₂. The two methyl groups attached to the phosphorus atom appeared as a doublet (J _PH = 11 Hz) at δ = 3.92. The ¹³C NMR peaks for the N–CH₃, OCH₃, –NCH₂–, C=O (C-2), and C=O (C-4) groups appeared at δ = 29.5, 52.3–52.4, 55.60, 153.9–154.0, and 168.5 respectively. The ³¹P-decoupled NMR showed a singlet at δ = –6.44.