A Practical Approach to New (5Z) 2-Alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one Derivatives

A practical protocol for the preparation of (5Z)-2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives is reported. The new compounds were obtained in good yield and stereoselectivity in two steps, namely a solvent-free Knoevenagel condensation under microwave irradiation, followed by an S-alkylation reaction with various halogenoalkanes.

Due to the biological activity associated with the imidazolone moiety, we embarked on a project to investigate possible bioactive molecules based on 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives of the imidazolone core. Herein, we report our results concerning the synthesis of these new 2-alkylthio-5-arylmethylene derivatives based on the 1-methyl-2-thiohydantoin scaffold and their biological evaluation as protein kinase inhibitors. The protein kinases of the human kinome represent a wide family of disease relevant targets for identification, preparation and optimization of potential therapeutic agents in structure-activity relationship (SAR) studies [15].
For this project, the needed 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one can be built from sarcosine and a thiocyanate as precursors of the 1-methyl-2-thiohydantoin scaffold, aldehydes and halogenoalkanes, to introduce diversity at the C-5 position and on the sulfur atom at the C-2 position respectively, by Knoevenagel condensation and S-alkylation reactions ( Figure 2).   Complete conversion according to the modified procedure of Kenyon et al. [21,22] was observed after 19 hours at 140 °C, affording the desired starting compound 1 in 90% yield. In the second step, for the Knoevenagel condensations from aryl aldehydes and thiohydantoins, several methods have been employed in the literature. Many of these methods suffer from one or more limitations such as requiring harsh reaction conditions, producing low to moderate yields, relatively long reaction times and cumbersome experimental processes. Among these reported methods, the Knoevenagel reaction has been performed in the presence of mineral or organic bases with various solvents: ethanolamine in absolute ethanol [23], potassium hydroxide in anhydrous ethanol [24], sodium hydride in anhydrous acetonitrile [25]. The utility of microwave irradiation (μω) to carry out organic reaction has now become a regular feature. The main benefits of performing the reaction under microwave conditions are the higher product yields and the significant rate-enhancements that can be observed. It's clear that application of microwave technology to the rapid synthesis of potential biological molecules is a useful tool for the medicinal chemistry community, for whom reaction speed is of great importance [26,27]. Moreover, when a reaction is carried out in a microwave reactor, the use of solvent can be avoided [28,29], allowing eco-friendly synthesis and offering several advantages, such as reduced risk of explosions and easier work-up. In this context, we have examined two experimental protocols for the synthesis of 5-arylmethylene-1-methyl-2-thiohydantoins 4.
The results of the two methods investigated for the preparation of Knoevenagel products 4 are presented in Table 1. In Method A, 1-methyl-2-thiohydantoin (1) was coupled with commercial aryl aldehydes 2(a-e) in the presence of two equivalents of propylamine at 80 °C under microwave irradiation (in a Synthewave® 402 reactor [30]) for a reaction time ranging from 40 to 60 minutes. In Method B, an equimolecular mixture of the starting hydantoin 1 and arylaldimine 3 was heated at 80 °C under microwave irradiation for the same reaction time. The arylaldimines 3 were prepared in good yields according to a solvent-free microwave protocol developed in our laboratory [31]. The reactions of both methods were conveniently monitored by 1 H-NMR or by TLC on precoated plates of silica gel with an appropriate eluant. As can be seen from inspection of the data presented in Table 1, the 5-arylmethylene-1-methyl-2-thioxo-imidazolidin-4-ones 4(a-e) were prepared in better yields (86-98%) using the microwave irradiation reaction conditions (Method A). It is noteworthy that for safety reasons, a 4-min. heating ramp was performed before the temperature was maintained at the selected maximum of 80 °C (power 80 W). The structure of the new compounds 4(a-e) were substantiated by 1 H-, 13 C-NMR and HRMS. In all cases, compounds 4 were obtained in a stereospecific way and the geometry of the double bond was attributed as being Z by the shielding effect of the carbonyl group C-4 on the olefinic proton H-5 (δ H-5 = 6.34-6.85 ppm) [32,33]. Table 1. Results for the solvent-less preparation of 5-arylmethylene-1-methyl-2-thioxo imidazolin-4-ones 4(a-e) under microwave from aldehydes 2(a-e) (Method A) or aldimines 3(a-e) (Method B).

Product Method A Method B Starting reagent
Yield a of 4 (%) Starting reagent Yield a of 4 (%) 4a 2a a Yield of isolated product after purification by recrystallization; b The reaction failed under microwave and also in an oil bath using the same reaction conditions. With the 5-arylmethylene-1-methyl-2-thioxo imidazolin-4-one derivatives 4 in hand, we designed an experimental strategy for the preparation of the 2-alkylthio-1,5-dihydro-4H-imidazol-4-ones 6. For this study, a set of different halogeno compounds 5 represents the second point of diversity in this scaffold by using commercial products [ethyl iodide (5a), allyl bromide (5b), propyl bromide (5c), chloroacetonitrile (5d), ethyl bromoacetate (5e) and 3-bromopropanol (5f)]. Owing to the lesser reactivity of the chloro and bromo alkanes 5(b-f), one equivalent of potassium iodide was added in the reaction mixtures and the reagents were covered with dry acetonitrile. After work-up (elimination of the salts and solvent), all the crude products were purified easily by recrystallization in ethanol. The reaction conditions listed in Table 2 showed that the S-alkylations could be carried out at various reaction temperatures (60-81 °C) with a reaction time ranging from 14 to 51 hours. As seen from the results, it can be observed that these S-alkylations gave moderate to good yields (42-68%). The structural assignment of the new 2-alkylthio-5-arylmethylene-1-methyl 1,5-dihydro-4H-imidazol-4ones 6(a-g) is based on spectroscopic data ( 1 H-, 13 C-NMR, HRMS). It should be noted that this alkylation step gave regioselective S-alkylation with retention of the (5Z)-stereochemistry (δ H-5 = 6.83-7.21 ppm).

General
Melting points were determined on a Kofler melting point apparatus and are uncorrected. Thin-layer chromatography (TLC) was accomplished on 0.2-mm precoated plates of silica gel 60 F-254 (Merck) and visualization was made with ultraviolet light (254 and 312 nm) or with a fluorescent indicator. 1 H-and 13 C-NMR spectra were recorded on a Bruker AC 300 P spectrometer at 300 MHz and 75 MHz, respectively. Chemical shifts are expressed in parts per million downfield from tetramethylsilane as an internal standard. Data are given in the following order: d value, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), number of protons, coupling constants J is given in Hertz. The mass spectra (HRMS) were taken respectively on a Varian MAT 311 at an ionizing potential of 70 eV in the Centre Régional de Mesures Physiques de l'Ouest (CRMPO, Rennes, France). Reactions under microwave irradiations were realized in the Synthewave® 402 apparatus (Merck Eurolab, Div. Prolabo, France). The microwave instrument consists of a continuous focused microwave power output from 0 to 300W. All the experiments were performed using stirring option. The target temperature was reached with a ramp of 4 minutes and the chosen microwave power stay constant to hold the mixture at this temperature. The reaction temperature is monitored using calibrated infrared sensor and the reaction time includes the ramp period. Acetonitrile was distilled over calcium chloride after standing overnight and stored over molecular sieves (3Å). Solvents were evaporated with a Büchi rotary evaporator. All reagents were purchased from Acros, Aldrich Chimie, Fluka France and used without further purification. (1): This starting compound was prepared in a 50 mL twonecked round-bottomed flask, equipped with a magnetic stirrer and reflux condenser by the fusion of commercial sarcosine (4 g, 44.9 mmol) with ammonium thiocyanate NH 4 SCN (10.26 g, 134.7 mmol, 3 equiv.) at 140 °C under a slow stream of nitrogen. After 19 hr of heating under vigorous stirring, the dark red solution was cooled. The solid cake which formed was broken up and washed with 20 mL of water onto a filter. The crystals were then washed successively with deionized water (three 15 mL portions), 95% ethanol (one 20 mL portion) and hexane (one 20 mL portion). The precipitated product was further dried under high vacuum (10 −2 Torr) at 30 °C for 2 hours, to give the desired 1-methyl-2thioxoimidazolidin-4-one (1) as a powder that was used without further purification. Yield = 90%. Mp = 230-232 °C. 1