5-(2-Methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one

Abstract

An amino acid-derived 2-thiohydantoin, 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one, obtained from l-methionine, was synthesized in a two-step reaction protocol with allyl isothiocyanate. The compound was obtained in an 82% yield and was fully structurally characterized by NMR and IR spectroscopy. The crystal structure, molecular packing, and intermolecular interactions were characterized by X-ray diffraction analysis.

1. Introduction

2-Thiohydantoins, as part of the broader hydantoin family, are considered to be valuable and privileged scaffolds in the fields of medicinal chemistry and pharmacology, as well as in material sciences [1]. Hydantoins are known for their applications as clinically approved drugs as anticonvulsants, antiandrogens, muscle relaxants, and antibiotics [2], as well as for their use in various branches of industry as pesticides, preservatives, corrosion inhibitors, and more [3].

The hydantoin scaffold is synthetically available through various possible synthetic strategies and starting substrates, but one of the more convenient routes is synthesis from amino acids [4]. The advantages of this route include mild reaction conditions, high yields, simple reaction workup, and the availability of a large number of substituted and functionalized structures. Hydantoins and amino acids are, in this sense, interchangeable, because not only can hydantoins be synthesized from amino acids, but amino acids can be synthesized from hydantoins. In fact, highly functionalized and structurally complex amino acids can be obtained from hydantoins via hydrolysis, which are often very difficult or even impossible to obtain otherwise [5].

Amino acid-derived 2-thiohydantoins exhibit a variety of biological activities, such as antimicrobial [6], antiviral [7], anticancer [8], antimutagenic [9], and neurotropic [10], and are the subject of numerous preclinical investigations. The body of work conducted so far highlights the significance of these compounds in the effort to obtain novel bioactive compounds and therapeutics. Since hydantoins exhibit a plethora of biological activities and preclinical biological testing consumes a lot of time and resources, it is difficult to screen for the full spectrum of their bioactive potential. It is, therefore, highly beneficial to have published libraries of small molecules that are readily available for in vitro, in vivo, or even in silico screening. For this reason, in this study, we report the synthesis and structural characterization of an l-methionine-derived 2-thiohydantoin derivative, 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one. The structure of the compound is fully characterized by NMR and IR spectroscopy, as well as X-ray diffraction analysis.

2. Results and Discussion

2.1. Synthesis and Spectral Characterization

Synthesis of the amino acid-derived 2-thiohydantoin, 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one is depicted in Scheme 1. The first synthetic step is a conversion of l-methionine 1 to its methyl ester 2 using a methanolic HCl protocol. The reaction of acetyl chloride with methanol generates HCl, and in this acidic methanol environment, amino acids are easily converted to their corresponding methyl ester hydrochlorides. l-Methionine was converted to its methyl ester because methyl esters undergo cyclization to 2-thiohydantoins more easily than amino acids due to the methoxy group being a better leaving group than hydroxyl in the applied reaction conditions.

The second step is the reaction of the methyl ester with allyl isothiocyanate. l-Methionine methyl ester hydrochloride 2 is first relieved of HCl with the addition of Et₃N, because the amino group needs to be deprotonated and free for the nucleophilic addition reaction. l-Methionine methyl ester then undergoes an addition and cyclization reaction to form the 2-thiohydantoin product, 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one 3. It is obtained in a high 82% yield.

The 2-thiohydantoin product 3 is expected to be obtained as a perfect racemate, as racemization is known to occur in these types of reaction systems under basic conditions. This is supported by the crystallographic data. A recemization of this type is reported in a paper by Haslak et al., where they examined a reaction of l-alanine methyl ester and aryl isothiocyanates in the presence of triethylamine [11]. They proposed that racemization occurs with triethylamine, after cyclization, as cyclic ureides are known to undergo a ring-opening racemization process in basic conditions.

5-(2-Methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one was structurally characterized by NMR and IR spectroscopy. The spectra can be found in the Supplementary Material. In the ¹H NMR spectrum, all expected signals can be observed. The broad singlet of the NH proton of the 2-thiohydantoin ring can be observed at 7.81 ppm. For the sake of clarity, this discussion follows the numbering scheme depicted in Figure 1. At 5.86 ppm, a complex doublet of doublet of triplets from the CH proton of the allyl group double bond (C8) can be observed. The complexity of this signal originates from the coupling of the proton with three chemically distinct neighboring protons in its environment. The triplets in this signal result from coupling with two chemically identical protons from the allyl methylene group C7 (the value of the coupling constant is J = 5.8 Hz and is characteristic for vicinal aliphatic coupling), while further splitting of the signal results from coupling with two chemically inequivalent protons from the terminal allyl double bond CH₂ group C9. The coupling constant for the proton that is in the cis position is 10.2 Hz, while the coupling constant for the proton in the trans position is expectedly higher and is 17.2 Hz. A multiplet of the terminal allyl double bond CH₂ group C9 can be observed at 5.18–5.32 ppm. The signal is very complex and cannot be fully characterized, but can, for the sake of discussion, be considered as two doublets of doublets for each of the protons. The signal of the C9 proton in the trans position to the proton at C8 is expectedly shifted further downfield at 5.24–5.32 ppm and is more split, while the signal of the cis proton is slightly less shifted at 5.18–5.23 ppm and is less split. Signal of the allyl methylene protons C7 is at 4.43 ppm, seemingly in the form of a doublet, with a coupling constant of J = 6.0 Hz. Upon closer look, it can be observed that the signal is actually a doublet of triplets, due to allylic coupling. The signal of the 2-thiohydantoin ring proton C3 can be observed at 4.28 ppm in the form of a doublet of doublet of doublets, with coupling constants J = 1.2, 4.2, and 7.4 Hz. The proton from the rigid ring system interacts differently with vicinal protons from the C4 methylene group, and thus, the coupling constants are different (4.2 and 7.4 Hz), while the third coupling constant of 1.2 Hz originates from long-range coupling with C5 methylene protons. Other signals in the spectrum originate from the protons from the side chain attached to the C3 carbon of the 2-thiohydantoin ring. The triplet at 2.68 ppm is from the C5 methylene protons, the multiplets at 2.18–2.34 ppm and 1.89–2.10 ppm are from the C4 methylene protons, and the singlet at 2.12 ppm is from the C6 methyl group attached to the sulfur atom.

In the ¹³C NMR spectrum, all expected signals can be observed. The signals of thiocarbonyl and carbonyl carbons from the 2-thiohydantoin ring are at 183.54 and 173.42 ppm. The allyl double bond carbons C8 and C9 are at 130.50 and 118.58 ppm. 2-Thiohydantoin ring carbon C3 and allyl methylene carbon C7 are at 55.52 and 43.34 ppm, side branch methylene carbons C4 and C5 are at 30.42 and 30.30 ppm, and the C6 methyl carbon is at 15.30 ppm.

2.2. Molecular and Crystal Structure Description

Molecular structure of 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one is depicted in Figure 1. All bond lengths, valence, and torsion angles are within the expected range, as found by comparison with structures available in the Cambridge structural database that have similar structural fragments, using methodology implemented in Mogul [12]. The five-membered 2-thiohydantoin ring is planar, with allyl substituent oriented perpendicular to the ring plane (torsion angle C1–N1–C7–C8 equals −88.7(2)°).

Hirshfeld surface analysis (Figure 2) reveals that most intermolecular contacts are found between hydrogen atoms (51%), followed by S∙∙∙H (26%), O∙∙∙H (12%), and C∙∙∙H (7%). Calculation of enrichment ratios [13] shows that, except H∙∙∙H contacts (E_HH = 0.9), all other mentioned are favored in the crystal structure (E_OH = 5.8, E_SH = 1.2, E_CH = 1.2). For the largest proportion of the Hirshfeld surface, it is found that d_norm ≥ 0 holds, meaning that crystal packing does not involve many short intermolecular contacts. The exception is N2–H2∙∙∙S1ⁱ hydrogen bond (symmetry operation (i) −x + 2, −y + 1, −z + 1), which shows prominent red patches (d_norm < 0) on the Hirshfeld surface in the proximity of donor and acceptor atoms (Figure 3). In the fingerprint plot, this interaction is visualized as a very sharp pair of spikes. Geometrical parameters of this interaction are N2–H2 = 0.81(2) Å, H2···S1i = 2.56(2) Å, N2···S1ⁱ = 3.3696(18) Å, N2–H2···S1ⁱ = 174(2)°. Less prominent are red patches corresponding to short contacts C3–H3∙∙∙S1ⁱⁱ (symmetry operation (ii) −x + 1, −y + 1, −z + 1).

There are 14 molecules in the first coordination sphere of 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one, associated with 11 unique intermolecular interactions. Their energies are summarized in

Table 1. Summary of intermolecular interaction energies of the unique molecular pairs constituting the first coordination sphere for 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one calculated using the CE-B3LYP model energy.

N	Symmetry Operation	R/Å	E/kJ mol−1
			Eele	Epol	Edis	Erep	Etot
1	−x, −y, −z	6.13	−71.4	−14.3	−23.7	90.8	−50.6
1	−x, −y, −z	6.39	−17.0	−5.6	−28.7	15.1	−37.8
2	x, y, z	5.32	−11.4	−5.8	−34.1	24.0	−31.2
1	−x, −y, −z	4.94	−15.5	−4.0	−30.6	30.5	−27.2
1	−x, −y, −z	9.78	−14.0	−2.9	−17.3	18.7	−20.4
1	−x, −y, −z	6.58	1.2	−2.0	−22.0	9.7	−13.4
1	−x, −y, −z	12.13	−4.2	−0.7	−7.6	6.4	−7.6
2	x, y, z	10.93	−0.0	−0.3	−5.5	3.3	−2.9
2	x, y, z	11.16	0.1	−0.1	−2.3	0.3	−1.8
1	−x, −y, −z	10.77	1.9	−0.2	−4.1	0.3	−1.5
1	−x, −y, −z	12.95	2.0	−0.4	−3.2	1.9	0.2

N is the number of interactions; R is the distance between molecular centroids. The relevant space group symmetry operation is reported without translation. Total interaction energy is calculated by the addition of scaled individual components: E_tot = k_eleE_ele + k_polE_pol + k_disE_dis + k_repErep, where k_ele = 1.057, k_pol = 0.740, k_dis = 0.871, and k_rep = 0.618 [14].

. Dissection of the molecular packing on the energetic basis reveals that this crystal structure is of a layered type. Schematically, this is visualized in the energy framework shown in Figure 4.

Every molecule is surrounded by six closest neighbors in the crystallographic ab plane. The strongest interaction (–51 kJ mol⁻¹) is mediated through the mentioned N2–H2···S1ⁱ hydrogen bond formed between inversion-related molecules. The high electrostatic contribution to the stabilizing energy of this interaction is expected due to strong electrostatic complementarity between molecules, as visualized by Hirshfeld surfaces of the neighboring molecules decorated with electrostatic potential (Figure 5). Other interactions in this plane have significantly higher dispersion than the electrostatic component, but they can hardly be ascribed to some specific atom–atom interaction type. Their energies are in the range of –13 to −38 kJ mol⁻¹. There is only one interaction between layers that has comparable energy (−20 kJ mol⁻¹) to those found within the layer. This interaction has a similar contribution of electrostatic and dispersion terms.

The compound crystallizes in the centrosymmetric space group, which implies that the solid phase is obtained as a racemate containing equimolar amounts of both enantiomers.

3. Materials and Methods

3.1. Chemicals

All the reagents used in this study were analytical grade or higher purity, obtained from Sigma–Aldrich (St. Louis, MO, USA) and Merck (Darmstadt, Germany).

3.2. Instrumentations

The ¹H NMR spectra were acquired on a Varian Gemini-2000 spectrometer (Palo Alto, CA, USA) at 200 MHz. All chemical shifts are referenced to the solvent dimethylsulfoxide-d6 (DMSO-d₆), and downfield shifts were recorded as positive numbers. IR data were obtained using PerkinElmer^® Spectrum One FTIR spectrometer (Shelton, CT, USA). Diffraction measurements were performed on a Gemini S (Oxford Diffraction) single crystal X-ray diffractometer (Yarnton, England, UK).

3.3. Synthetic Protocols

3.3.1. General Procedure for the Preparation of l-Methionine Methyl Ester

Amino acid methyl esters were prepared according to a well-known methanolic HCl method. A total of 5 mL of methanol was added to a round-bottom flask and cooled to 0 °C. Acetyl chloride (2 mL) was added slowly to the stirred solution and then stirred for another 20 min at 0 °C to generate methanolic HCl. An amino acid (5 mmol) was added in one portion, and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo, and solid amino acid methyl ester hydrochloride was used without further purification. Ester purity was confirmed by ¹H NMR spectroscopy.

3.3.2. General Procedure for the Preparation of 5-(2-Methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one

5-(2-Methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one was synthesized by following a lightly modified published protocol [15]. A mixture of 5 mmol of l-methionine methyl ester, 5 mmol Et₃N, and 15 mL of CH₂Cl₂ was stirred for about 20 min at room temperature until all of the ester was dissolved. Allyl isothiocyanate (5 mmol) was added dropwise, and the reaction mixture was heated under reflux for 7 h. The solution was cooled at room temperature, and the solvent was evaporated. The residue was dissolved in CH₂Cl₂, washed with water and brine, and dried over anhydrous Na₂SO₄. The solvent was once again evaporated, leaving a crude solid product that was recrystallized from CH₂Cl₂/hexane.

3.3.3. Compound Data of 5-(2-Methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one

Light orange needle crystals; Yield 82%; m.p. = 119–120 °C; IR (KBr) ν_max: 3169, 3002, 2921, 1741, 1646, 1531, 1432, 1346, 1255, 1165, 923, 650 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.81 (bs, 1H), 5.86 (ddt, J = 5.8, 10.2, 17.2 Hz, 1H), 5.18–5.32 (m, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.28 (ddd, J = 1.2, 4.2 and 7.4 Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.18–2.34 (m, 1H), 2.12 (s, 3H), 2.01 (septet, J = 6.8 Hz, 1H) ppm. ¹³C NMR (50 MHz, CDCl₃) δ 183.54, 173.42, 130.50, 118.58, 58.52, 43.34, 30.42, 30.30, 15.30 ppm.

3.4. Crystal Structure Determinations

The monochromatic Mo Kα X-radiation was used as a probe, with the diffractometer operating in a ω-scan mode. Instrument control and data reduction were performed with the CrysAlisPRO [16]. Structure was solved with SHELXT [17] and refined with SHELXL [18]. A summary of crystallographic and refinement details is listed in

Table 2. Crystallographic and refinement details of 5-(2-methylsulfanylethyl)-3-prop-2-enyl-2-sulfanylideneimidazolidin-4-one.

Crystal Data
Chemical formula	C9H14N2OS2
Mr	230.34
Crystal system	Triclinic
Space group	P$\overline{1}$
Temperature, K	295
a/Å	5.3161 (4)
b/Å	10.4776 (7)
c/Å	10.9253 (9)
α/°	100.211 (6)
β/°	101.448 (7)
γ/°	95.476 (6)
V/Å3	581.58 (8)
Z	2
Radiation type	Mo Kα
µ/mm−1	0.43
Crystal size, mm	0.77 × 0.38 × 0.24
Data collection
Diffractometer	Gemini S (Oxford Diffraction)
Absorption correction	Analytical
Tmin, Tmax	0.787, 0.924
No. of measured reflections	8315
No. of independent reflections	2721
No. of observed [I > 2σ(I)] reflections	2229
Rint	0.027
(sin θ/λ)max/Å−1	0.683
Refinement
R[F2 > 2σ(F2)]	0.046
wR(F2)	0.134
S	1.020
No. of reflections	2721
No. of parameters	132
H-atom treatment	Mixed
Δρmax, Δρmin/e Å−3	0.60 −0.53

. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 2474856). Hirshfeld surface analysis and assessment of intermolecular interaction energies were performed with CrystalExplorer [19], using TONTO [20] as the backend program for quantum chemistry calculations.