Reactivity of 2-Thiohydantoins Towards Various Electrophilic Reagents: Applications to the Synthesis of New 2-Ylidene-3,5-dihydro-4H-imidazol-4-ones.

Abstract

A new route to 5-(imidazolidin-2-ylidene)-2-methylsulfanyl-3,5-dihydro-imidazol-4-ones 4a-c using ketene dithioacetal intermediates 3a-c is described. The reactivity of thiohydantoin derivatives 2a-c towards N,N-dimethylformamide diethylacetal (DMF-DEA) was also explored using solvent-free technique under microwave irradiation (μω). The ¹H- and ¹³C-NMR spectra of some representative products are discussed.

Introduction

There has been much interest in the synthesis and properties of 2-thiohydantoin derivatives that are useful synthetic intermediates with a wide range of applications as therapeutics [1] as well as fungicides and herbicides [2]. Furthermore, several 5-arylidene-3-aryl-2-thiohydantoins and their S-glucosylated derivatives [3] show potent activity against the herpes simplex virus (HSV) [4] and the human immunodeficiency virus (HIV) [5].

A series of S-alkylated 4-ylidene thiohydantoins has been developed in our laboratory as precursors for the preparation of marine alkaloid 2-aminoimidazolones [6] with protein kinase inhibition activities [7]. As part of our program directed towards new, simple and efficient procedures for the synthesis of new 2-thiohydantoin derivatives to study their biological activities, the linking of ylidene thiohydantoins to hydrophilic imidazolidines was considered. We report in this contribution our results on the preparation of 5-imidazolidin-2-yliden-3,5-dihydro-4H-imidazol-4-ones via ketene dithioacetals and the reactivity of S-alkylated thiohydantoins towards N,N-dimethylformamide diethylacetal (DMF-DEA) under microwave irradiation (μω).

Results and Discussion

The 3-substituted-2-thioxo-imidazolin-4-ones starting materials 1a-c [8] used in Scheme 1 were easily prepared in good yields (96%) on a large scale (up to 20 g) by addition of commercial isothiocyanates to methyl glycinate hydrochloride in a basic medium. With the 2-thiohydantoins 1a-c in hand, regioselective S-alkylation with 1.5 equiv. of methyl iodide and 0.5 equiv. of potassium carbonate gave the 2-methylsulfanyl-3,5-dihydro-imidazol-4-ones 2a-c in yields ranging from 90 to 96%.

Scheme 1.

Scheme 1.

Reagents and reaction conditions: (i) MeI 1.5 equiv., K₂CO₃ 0.5 equiv., MeCN, 40 °C, 14 h.; (ii) CS₂ 1.1 equiv., K₂CO₃ 2.1 equiv., MeI 2.5 equiv., MeCN, 40 °C, 16 h.; (iii) (CH₂NH₂)₂ 10 equiv. or o-C₆H₄(NH₂)₂ 1.1 equiv., CHCl₃, 70 °C, 8 days; (iv) DMF-DEA 1 equiv., μω at 70 °C, 1 h.

Originally synthesized by Freund in 1919 [9], ketene dithioacetals have become established intermediates in synthetic organic methodology. The sulphur atom exercises a stabilizing effect on neighboring positive as well as negative charges. This makes the double bond in ketene dithioacetals responsive towards both nucleophilic as well as electrophilic attack, an extremely useful feature for organic synthetic purposes [10].

The desired ketene dithioacetals 3a-c are readily prepared by a one-pot reaction of 2a-c with carbon disulfide (1.1 equiv.) in the presence of potassium carbonate in MeCN, followed by alkylation with methyl iodide (2.5 equiv.). After moderate heating at 40 °C during 16 hours, the ketene dithioacetals 3a-c are obtained in moderate to good yields (60-70%). The ketene dithioacetals 3a-c were next reacted with a large excess of dry ethylenediamine in chloroform to afford the desired N,N-acetals 4a-c in moderate yields (41-54%) after recrystallization from acetone. The reaction took place smoothly under mild conditions (70 °C, 8 days) and was easily monitored by the evolution of methane thiol. On the other hand, when ortho-phenylenediamine was employed, no reaction occurred at 70 °C in CHCl3 and only the decomposition of the starting materials was observed when more forcing reaction conditions were used (neat conditions, 15 days). These results indicate that the N,N-acetal formation seems to be influenced by the electronic effects of the primary amine.

The chemical structures of the reaction products 4a-c were determined on the basis of their spectroscopic data (¹H-, ¹³C-NMR) and HRMS analysis. In the ¹H-NMR spectra of 4a-c, the absence of the methylene proton signal (I = 1H) and the observation of nitrogen proton signals of two protons exclude the amidine tautomer 4'. In the ¹³C-NMR spectra of 4c, the C-5,Cβ bond revealed a strong polarization (δ_C-5 100 and δ_Cβ 164.2 ppm) that is attributed to the exocyclic "push-pull" double bound structure [11].

In the course of identifying new chemical structures derived from 2-thiohydantoins for their biological activities [12], we were interested in evaluating the chemical reactivity of C-5 methylene protons. We have investigated the reactivities of 2-methylsulfanyl-3,5-dihydro-imidazol-4-ones 2a-c with N,N-dimethylformamide diethylacetal [13] using solvent-free conditions under microwave dielectric heating (μω) [14]. The microwave reactor (Synthewave^® 402 [15]) comprises a single-mode microwave cavity that operates at a frequency of 2.45 GHz with continuous microwave irradiation power from 0 to 300 W. The reaction vial is a cylindrical quartz reactor (Ø = 4 cm) which was introduced into the Synthewave^® 402 microwave reactor. Inside the microwave cavity, the vial was exposed to microwave irradiation. The temperature was measured with an IR captor [16] (infrared thermometry). The software algorithm regulates the microwave output power so that the preselected maximum temperature is maintained for the desired reaction/irradiation time. After the irradiation period, the reaction vial is cooled rapidly to ambient temperature by compressed air (gas jet cooling). The compounds 2a-c were converted with DMF-DEA (1.05 equiv.) into the corresponding 5-dimethyl-aminomethylidene-2-methylsulfanyl-3,5-dihydro-imidazol-4-ones 6a-c [17] in yields ranging from 80 to 86% after a reaction time of 1 hour at 70 °C under microwave irradiation. The products 6a-c can exist in (5Z) and/or (5E) isomeric forms with respect to the exocyclic C=C double bond. In all cases, the compounds 6a-c exist as single isomers, as shown by the presence of only one set of signals in each of ¹H- and ¹³C-NMR, but differentiation between (Z)- and (E)- form is not possible on the basis of chemical shifts. However, the two isomeric forms are easily be differentiated on the basis of the magnitude of the long range heteronuclear ¹³C-¹H coupling constants, ³J_CH which have been used for determination of configuration in various systems [18]. Generally, the magnitude of coupling constant for cis-configuration around the C=C double bond is smaller (2-6 Hz) than that observed for trans-oriented nuclei (8-12 Hz). In the case of compound 6a (R¹ = Me), the magnitude of coupling constant ³J_CH = 3.4 Hz showed that 6a exists in the (Z) form. Similar coupling constants have also been observed in some oxazolones derivatives with an analogous structural element [19].

Conclusions

In summary, the major significance of these results is the development of a versatile and practical route of N,N-acetal derivatives of 2-methylsulfanyl-3,4-dihydro-imidazol-4-ones via ketene dithioacetals. The extension of this strategy to other aliphatic primary diamines with these ketene dithioacetals is presently in progress and may complement those existing in the literature. Work is also in progress to study the protein kinase C inhibition activities of these new imidazolones [20]. The results of these pharmacological studies will be reported elsewhere in due course.