Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones

Abstract

Results and Discussion To validate our hypothesis we began to explore the process step by step. [...]α-chlorohydrazone derivative 1a [26,27,28,29,30] (2.0 mmol) dissolved in THF (9.0 mL) subjected to α-azidation using an ice-cooled aqueous solution of NaN3 [31] (2.0 mmol/1.0 mL) under magnetic stirring at room temperature. [...]our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a–k (53%–85%) is depicted in Scheme 5. [...]the implemented strategy broadens the substitution patterns at the amino-N1 and at C4 of the heterocycle skeleton with electron-withdrawing groups (5a–e) and tolerates the aromatic (amino-N1) and aliphatic (C4) groups, as for 5j [15,17,18] (Table 1). [...]the tautomerism thionoamide/thioloimide permits the introduction of a further element of diversity at the sulfur atom producing imidazole derivatives suitable to be combined with the useful 1-amino-Boc protected group [42] directly installed by this approach, as for 5a, 5c–f, 5k. [...]as an example, 5c,d,f (1.0 mmol) solved in acetone (10.0 mL), were reacted with 2-bromo-1-phenylethanone (6a) (1.0 mmol), 1-chloropropan-2-one) (6b) (1.0 mmol), and ethyl 2-bromoacetate (6c) (1.0 mmol), respectively, in the presence of K2CO3 (1.0 mmol).

1. Introduction

Imidazoles belong to an important class of heterocyclic compounds that play a crucial role in various biochemical processes [1]. A lot of imidazole-based molecules have been shown bioactivities, [2] such as antifungal, antiinflammatory, antihystamine, antihelmintic, analgesic, antineoplastic, antihypertensive activity [3,4,5,6,7].

Among imidazole derivatives, imidazole-2-thiones have been associated to a special class of biologically relevant thiourea derivatives [8] endowed with antithyroid [9], antiproliferative [10], matrix metalloproteinases (MPP) inhibitory [11] properties and can be used as building blocks for the synthesis of N-aminoimidazole with antiretroviral activity [12].

To date, the most widespread method used for the synthesis of N-substituted 1-amino-1H-imidazol-2(3H)-thiones can be referred to the Schantl’s protocol, which consists of reacting α-haloketones with potassium thiocyanate and monosubstituted arylhydrazines in weak acidic medium (Scheme 1) [13,14,15,16,17,18,19]. This multistep reaction is considered to proceed via the formation of conjugated azoalkenes, derived from α-thiocyanatohydrazones D (Scheme 2) and dipolarophile isothiocyanic acid intermediate that in turn undergo a [3+2] cycloaddition reaction providing substituted 1-arylamino-1H-imidazole-2(3H)-thione I scaffolds [20,21].

Even if this method appears robust, it seems to suffer of some limitations in terms of insertion of electron-withdrawing groups placed on the α-halohydrazone precursors of conjugated azoalkene intermediates. In this regard, for our research purposes, we tried to apply the Schantl’s method reacting 2-chloro-N,N-dimethyl-3-oxobutanamide (A), potassiun thiocyanate (B) and tert-butyl hydrazinecarboxylate (C) in acetic acid to obtain the corresponding N-substituted 1-amino-1H-imidazole-2(3H)-thione derivative I but without success. As shown in Scheme 2, instead of the cycloaddition, a 5-exo-dig cyclization reaction leading to 2-iminothiazole II took place. This evidence is in agreement with the result obtained by Lagoja and coworkers where a pathway involving the key α-thiocyanatohydrazone intermediate D is invoked [12].

The structure of the iminothiazoline II was confirmed by comparison of the spectral data of the same compound obtained by means of a different procedure previously described by some of us that foresees the conjugated hydrothiocyanation of the pertinent conjugated azoalkene in acidic medium followed by intramolecular cyclization [22].

Inspired by our previous experience [23], and in order to perform a complete regioselective-oriented method for the desired 1-amino-1H-imidazole-2(3H)-thiones I, we have planned a different strategy that avoids the use of bidentate-nucleophilic reagents such as the potassium thiocyanate. In the construction of I, three strategic disconnections between the N1-C2, C2-N3 and N3-C4 were hypothesized (Scheme 3).

We reasoned that the azidation process of the pertinent α-halohydrazone derivative followed by tandem Staudinger/aza-Wittig reaction with CS₂ could have been a successful route [24,25].

2. Results and Discussion

To validate our hypothesis we began to explore the process step by step. Thus, α-chlorohydrazone derivative 1a [26,27,28,29,30] (2.0 mmol) dissolved in THF (9.0 mL) subjected to α-azidation using an ice-cooled aqueous solution of NaN₃ [31] (2.0 mmol/1.0 mL) under magnetic stirring at room temperature. After the evaporation of the solvent and an appropriate extraction, the α-azidohydrazone derivative 2a was obtained in 70% yield. In the next step, the addition of a stoichiometric amount of PPh₃ to 2a (1.0 mmol) dissolved in CH₂Cl₂ (5.0 mL) furnished the iminophosphorane derivative 3a by precipitation from the reaction medium (66%). Then, 3a (0.65 mmol) was dissolved in 5.0 mL of THF/MeOH mixture (4:1) and treated with an excess of CS₂ at reflux to afford, after column chromatography purification, the corresponding N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivative 5a (53%) arising from intramolecular cyclization of the α-isothiocyanate hydrazone intermediate 4a (Scheme 4).

Motivated by this result, we aimed to develop a one-pot sequential multicomponent reaction (MCR) [32,33,34,35] as alternative method for regioselective synthesis of a new series of imidazole-2-thione-containing structures as suitable precursors for drug-like compounds [36].

Hence, our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a–k (53%–85%) is depicted in Scheme 5. The whole process that permits the formation of the desired heterocycle can be easily checked by the complete disappearance of the pertinent α-azidohydrazone derivative and by the observation of Ph₃P=S as byproduct (thin-layer chromatography (TLC) check, see Experimental Section). It is to be noted that for 5a, the efficiency of the reaction benefits by this latter protocol increasing the overall yield from 25% (obtained employing the step-by-step procedure) to 79% (Table 1). Moreover, the implemented strategy broadens the substitution patterns at the amino-N1 and at C4 of the heterocycle skeleton with electron-withdrawing groups (5a–e) and tolerates the aromatic (amino-N1) and aliphatic (C4) groups, as for 5j [15,17,18] (Table 1).

These results not only lie in the wide scenario of the heterocyclic scaffolds obtainable through tandem Staudinger/aza-Wittig sequence [24,25,37,38,39,40,41], but the concurrent presence of reactive functionalities in the target compounds 5a–k ensures post-modifications in view of heterobicyclic structures. In fact, the tautomerism thionoamide/thioloimide permits the introduction of a further element of diversity at the sulfur atom producing imidazole derivatives suitable to be combined with the useful 1-amino-Boc protected group [42] directly installed by this approach, as for 5a, 5c–f, 5k. Thus, as an example, 5c,d,f (1.0 mmol) solved in acetone (10.0 mL), were reacted with 2-bromo-1-phenylethanone (6a) (1.0 mmol), 1-chloropropan-2-one) (6b) (1.0 mmol), and ethyl 2-bromoacetate (6c) (1.0 mmol), respectively, in the presence of K₂CO₃ (1.0 mmol). After the removal of solvent followed by extraction, the corresponding α-(imidazol-2-ylthio) carbonyl compounds 7a–c were obtained as solid after column chromatography purification (84%–93%) (Scheme 6). The subsequent cleavage of the Boc-protecting group under homogeneous [43] or heterogeneous acidic conditions [44] was able to produce free amino function available to interact with the carbonyl appendage in 2-position of the ring, affording new 2H-imidazo [2,1-b][1,3,4]thiadiazine derivatives 8a,b by condensation or 2H-imidazo[2,1-b][1,3,4]thiadiazinone derivative 8c by acylic nucleophilic substitution process (Scheme 6, Table 2).

It is worthwhile to note that the proposed synthetic pathway can offer an alternative method for obtaining 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives 8 with respect to the ring transformation of α-(oxazol-2-ylthio) ketones 9 on treatment with hydrazine hydrate 10 [45], together with the possibility of wide diversification of the substituents at the different positions of the N-bridgeheaded heterobicyclic structures. As depicted in Scheme 7, a different disconnection for the assembly of the 2H-imidazo[2,1-b][1,3,4]thiadiazine scaffold can be envisaged.

3. Experimental Section 3.1. General

All the commercially available reagents and solvents were used without further purification. α-Halohydrazones 1a–k were synthesized by known procedures [26,27,28,29,30]. Chromatographic purification of compounds was carried out on silica gel (60–200 μm). Thin-layer chromatography (TLC) analysis was performed on pre-loaded (0.25 mm) glass supported silica gel plates (Silica gel 60, F254, Merck; Darmstadt, Germany); compounds were visualized by exposure to UV light. Melting points (Mp) were determined in open capillary tubes and are uncorrected.

All ¹H NMR and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively at 25 °C on a Bruker Ultrashield 400 spectrometer (Bruker, Billerica, MA, USA). Proton and carbon spectra were referenced internally to residual solvent signals as follows: δ = 2.50 ppm for proton (middle peak) and δ = 39.50 ppm for carbon (middle peak) in DMSO-d₆ and δ = 7.27 ppm for proton and δ = 77.00 ppm for carbon (middle peak) in CDCl₃. The following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet and br = broad signal. All coupling constants (J) are given in Hz. Copies of ¹H-NMR and ¹³C-NMR spectra of compounds II, 2a, 3a, 5a–k, 7a–c, and 8a–c are in Supplementary Materials. FT-IR spectra were measured as Nujol mulls using a Nicolet Impact 400 (Thermo Scientific, Madison, WI, USA). Mass spectra were obtained by ESI-MS analyses performed on Thermo Scientific LCQ Fleet Ion Trap LC/MS and Xcalibur data System. High-resolution mass spectra (HRMS) were determined with ESI resource on a Waters Micromass QTOF instrument (Waters, Milford, MA, USA). Elemental analyses were within ±0.4 of the theoretical values (C, H, N).

3.2. Step-By-Step Synthetic Method for 5a

3.2.1. Synthesis of tert-butyl 2-(3-azido-4-(dimethylamino)-4-oxobutan-2-ylidene)hydrazinecarboxylate (2a)

To the α-halohydrazone 1a (555.5 mg, 2.0 mmol) solved in THF (9.0 mL), an ice-cooled aqueous solution (1.0 mL, T = 4 °C) of NaN₃ (2.0 mmol, 130.02 mg) was added. The reaction mixture was stirred at room temperature until the disappearance of the starting 1a (TLC check). THF was removed under reduced pressure and the residue was diluted with water and extracted with CH₂Cl₂ (3 × 15.0 mL). The combined organic layers were dried over anhydrous NaSO₄ and concentrated under reduced pressure. The crude reaction was purified by crystallization from Et₂O affording the α-azido derivative 2a. Yield 70.0% (398.0 mg) as a white solid; Mp 120–124 °C (dec); ¹H-NMR, 400 MHz, DMSO-d₆) δ 1.44 (s, 9H, OBu^t), 1.84 (s, 3H, CH₃), 2.86 (s, 3H, NCH₃), 2.92 (s, 3H, NCH₃), 4.99 (s, 1H, CH), 9.82 (br s, 1H, NH, D₂O exch.); ¹³C-NMR (100 MHz, DMSO-d₆) δ 13.8, 28.0, 35.5, 36.6, 64.6, 79.5, 146.2, 152.9, 166.5; IR (Nujol, ν, cm⁻¹): 3239, 3150, 2982, 2172, 2098, 1706, 1686, 1664; MS m/z (ESI): 285.07 (M + H)⁺; anal. calcd. for C₁₁H₂₀N₆O₃ (284.31): 46.47; H, 7.09; N, 29.56; found: C, 46.36; H, 7.15; N, 29.65.

3.2.2. Synthesis of tert-butyl 2-(4-(dimethylamino)-4-oxo-3-((triphenylphosphoranylidene)amino)butan-2-ylidene)hydrazinecarboxylate (3a)

1.0 Mmol of 2a (284.31 mg) was solved in CH₂Cl₂ (5.0 mL). The reaction flask was then immersed in an ice bath (T = 0 °C), and a cooled solution of PPh₃ (262.3 mg, 1.0 mmol) in CH₂Cl₂ (1.0 mL) was added dropwise. The reaction was brought back to room temperature and stirred until the disappearance of organic azide 2a (monitored by TLC). The formation of phosphazene 3a was accompanied by the development of N₂. After partial removal of the solvent under reduced pressure, 3a was isolated by precipitation from a solution of CH₂Cl₂/EtOAc as white powder; yield 66% (342.3 mg); Mp 127–131 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.42 (s, 9H, OBu^t), 1.81 (s, 3H, CH₃), 2.59 (s, 3H, NCH₃), 2.73 (s, 3H, NCH₃), 4.62 (t, J_H-P = 9.2 Hz, 1H, CH), 7.57–7.90 (m, 15H, Ar), 9.64 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 13.0, 28.0, 35.6, 36.1, 59.3, 79.5, 120.9 (¹J_C-P = 102.0 Hz), 129.7 (²J_C-P = 14.0 Hz), 133.7 (³J_C-P = 11.0 Hz), 133.8 (³J-_CP = 12.0 Hz), 134.9 (⁴J_C-P = 2.0 Hz), 150.7, 167.0 ppm; IR (Nujol, ν, cm⁻¹): 3543, 3377, 3211, 1722, 1664; MS m/z (ESI): 519.31 (M + H)⁺; anal. calcd. for C₂₉H₃₅N₄O₃P (518.59): C, 67.17; H, 6.80; N, 10.80; found: C, 67.31; H, 6.86; N, 10.72.

3.2.3. Synthesis of tert-butyl (4-(dimethylcarbamoyl)-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5a)

0.65 Mmol of 3a (337.0 mg,) was solved in a mixture of THF:MeOH (4:1, 5.0 mL) heating. Then, 0.5 mL of CS₂ was added and the reaction was refluxed. The end of the reaction was defined (4.0 h) by the disappearance of 3a together with the formation of Ph₃P=S as byproduct (monitored by TLC). After removal of the reaction solvents under reduced pressure, a first crop of 5a was obtained as white powder from a solution of THF/light petroleum ether. A further amount was be gained by column chromatography eluting with CH₂Cl₂/EtOAc mixtures. White powder from THF/light petroleum ether; yield 53% (103.4 mg); Mp 172–173 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆,) δ 1.32 and 1.45 (2 s, 9H, OBu^t), 1.99 (s, 3H, CH₃), 2.94 [s, 6H, N(CH₃)₂], 9.69 and 10.15 (2 br s, 1H, NH, D₂O exch.), 12.50 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 8.9, 27.6, 27.8, 35.9, 80.8, 116.2, 128.2, 153.8, 160.2, 162.9 ppm; IR (Nujol, ν, cm⁻¹): 3188, 3115, 1741, 1645, 1607; MS m/z (ESI): 301.15 (M + H)⁺; calcd. for C₁₂H₂₀N₄O₃S (300.38): C, 47.98; H, 6.71; N, 18.65; found: C, 48.11; H, 6.63; N, 18.57. The partition of some signals here, as well as in the following cases, is due to the N1-amide rotameric effect [46].

3.3. Typical MCR Procedure for the Synthesis of N-Substituted 1-Amino-1H-Imidazole-2(3H)-Thione Derivatives 5a–k

To a round flask equipped with a magnetic stirring bar containing ice-cooled solution of NaN₃ (1.0 mmol, 65.01 mg) dissolved in 0.5 mL of H₂O, the corresponding α-halohydrazone 1a–k (1.0 mmol) dissolved in THF (4.5 mL) was added. The mixture was stirred at room temperature until the disappearance of 1 (monitored by TLC). Upon completion, Na₂SO₄ (0.5 g)_, a solution of PPh₃ (1.1 mmol, 288.5 mg) in THF (1.0 mL) and CS₂ (1.0 mL) were added in sequence, and the mixture was refluxed for the appropriate reaction time (3.0–20.0 h). The formation of the final products 5a–k was revealed by the complete disappearance of the spot corresponding to the α-azidohydrazone 2a–k as well as the detection of the byproduct Ph₃P=S. The Na₂SO₄ was filtered in vacuo and washed with THF (10.0 mL). The filtrate was concentrated under reduced pressure and the residue was purified by crystallization and/or by chromatography eluting with cyclohexane:EtOAc or CH₂Cl₂:EtOAc mixtures. The resulting products 5a–k were isolated by crystallization from the specific solvents (see below). According to this procedure, 5a was obtained in 79% (237.3 mg).

N,N,5-trimethyl-1-(3-phenylureido)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxamide (5b): Yield 53% (169.3 mg), pink powder from CH₂Cl₂/Et₂O; Mp 247–248 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 2.06 (s, 3H, CH₃), 2.97 [s, 6H, N(CH₃)₂], 7.01 (t, J = 8.0 Hz, 1H, Ar), 7.29 (t, J = 8.0 Hz, 2H, Ar), 7.46 (d, J = 8.0 Hz, 2H, Ar), 9.00 (s, 1H, NH, D₂O exch.), 9.33 (br s, 1H, NH, D₂O exch.), 12.56 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 9.3, 36.8, 116.1, 118.3, 122.3, 128.7, 129.0, 139.1, 153.6, 160.3, 162.6 ppm; IR (Nujol, ν, cm⁻¹): 3323, 3248, 3195, 3136, 1713, 1638, 1605; MS m/z (ESI): 320.40 (M + H)⁺; calcd. for; C₁₄H₁₇N₅O₂S (319.38): C, 52.65; H, 5.37; N, 21.93; calcd. for; C₁₄H₁₇N₅O₂S (319.38): C, 52.65; H, 5.37; N, 21.93; found: C, 52.79; H, 5.44; N, 21.84.

tert-Butyl (4-(diethylcarbamoyl)-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5c): Yield 72% (236.3 mg), white powder from EtOAc/THF/light petroleum ether; Mp 168–169 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.06–1.10 (m, 6H, 2xNCH₂CH₃), 1.32 and 1.45 (2s, 9H, OBu^t), 1.94 and 1.97 (2s, 3H, CH₃), 3.26–3.37 (m, 4H, 2xNCH₂CH₃), 9.68 and 10.07 (2 br s, 1H, NH, D₂O exch.), 12.49 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 8.6, 13.4, 27.5, 27.8, 34.8, 80.6, 117.0, 126.6, 153.8, 159.8, 162.7 ppm; IR (Nujol, ν, cm⁻¹): 3169, 3120, 1748, 1642, 1634; MS m/z (ESI): 329.23 (M + H)⁺;calcd. for C₁₄H₂₄N₄O₃S (328.16): C, 51.20; H, 7.37; N, 17.06; found: C, 51.09; H, 7.42; N, 16.95.

tert-Butyl (5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5d): Yield 69% (158.1 mg), white powder from EtOAc/THF/light petroleum ether; Mp 168–169 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.32 and 1.45 (2s, 9H, OBu^t), 1.93 (s, 3H, CH₃), 6.60 (s, 1H, CH), 9.51 and 9.94 (2 br s, 1H, NH, D₂O exch.), 11.97 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 8.9, 27.9, 80.5, 108.9, 126.9, 153.9, 162.4 ppm; IR (Nujol, ν, cm⁻¹): 3271, 3144, 3098, 1744, 1732, 1640; MS m/z (ESI): 229.96 (M + H)⁺; calcd. for C₉H₁₅N₃O₂S (229.09): C, 47.14; H, 6.59; N, 18.33; found: C, 47.01; H, 6.65; N, 18.41.

tert-Butyl (4-carbamoyl-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5e): Yield 58% (157.8 mg), white powder from CH₂Cl_2/light petroleum ether; Mp 270 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.32 and 1.45 (2s, 9H, OBu^t), 2.23 and 2.26 (2s, 3H, CH₃), 7.23 and 7.53 (2 br s, 2H, NH₂, D₂O exch.), 9.71 and 10.17 (2s, 1H, NH, D₂O exch.), 12.42 (s, 1H, NH, D₂O exch.) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 8.9, 10.1, 27.6, 27.8, 80.9, 115.8, 133.1, 153.7, 159.6, 162.9 ppm; IR (Nujol, ν, cm⁻¹): 3395, 3354, 3182, 3137, 1754, 1717, 1676, 1594; MS m/z (ESI): 273.04 (M + H)⁺; calcd. for C₁₀H₁₆N₄O₃S (272.09): C, 44.10; H, 5.92; N, 20.57; found: C, 44.23; H, 5.96; N, 20.45.

tert-Butyl (5-methyl-4-(phenylcarbamoyl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5f): Yield 67% (233.2 mg), white powder from EtOAc; Mp 170–171 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.34 and 1.46 (2s, 9H, OBu^t), 2.28 (s, 3H, CH₃), 7.11 (t, J = 8.0 Hz, 1H, Ar), 7.35 (t, J = 8.0 Hz, 2H, Ar), 7.65 (d, J = 8.0 Hz, 2H, Ar), 9.68 (s, 1H, NH, D₂O exch.), 10.28 (s, 1H, NH, D₂O exch.), 12.69 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 9.2, 27.8, 81.0, 116.0, 119.7, 123.8, 128.8, 133.9, 138.4, 153.7, 156.3, 163.2 ppm; IR (Nujol, ν, cm⁻¹): 3375, 3243, 3066, 1752, 1659, 1630, 1598, 1545; MS m/z (ESI): 349.22 (M + H)⁺; calcd. for C₁₆H₂₀N₄O₃S (348.13): C, 55.16; H, 5.79; N, 16.08; found: C, 55.01; H, 5.72; N, 16.16.

1-(5-Methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)-3-phenylurea (5g): Yield 82% (203.4 mg), white powder from THF/EtOAc; Mp 245–248 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 2.01 (s, 3H, CH₃), 6.64 (s, 1H, CH), 6.99 (t, J = 8.0 Hz, 1H, Ar), 7.28 (t, J = 8.0 Hz, 2H, Ar), 7.46 (d, J = 8.0 Hz, 2H, Ar), 8.91 (s, 1H, NH, D₂O exch.), 9.25 (s, 1H, NH, D₂O exch.), 12.05 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 9.1, 108.8, 118.3, 122.3, 127.6, 128.8, 139,1, 153.8, 161.9 ppm; IR (Nujol, ν, cm⁻¹): 3305, 3154, 3119, 3097, 1714, 1681, 1637, 1602; MS m/z (ESI): 249.07 (M + H)⁺; calcd. for C₁₁H₁₂N₄OS (248.07): C, 53.21; H, 4.87; N, 22.56; found: C, 53.08; H, 4.94; N, 22.65.

N-(5-methyl-2-thioxoimidazolidin-1-yl)benzamide (5h): Yield 59% (137.6 mg) white powder from MeOH; Mp 240–242 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.97 (s, 3H, CH₃), 6.72 (s, 1H, CH), 7.56 (t, J = 8.0 Hz, 2H, Ar), 7.65 (t, J = 8.0 Hz, 1H, Ar), 7.99 (d, J = 8.0 Hz, 2H, Ar), 11.44 (s, 1H, NH, D₂O exch.), 12.15 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 8.9, 109.3, 127.0, 127.7, 128.6, 131.5, 132.5, 162.0, 165.4 ppm; IR (Nujol, ν, cm⁻¹): 3168, 3106, 1666, 1631; MS m/z (ESI): 234.04 (M + H)⁺; calcd. for C₁₁H₁₁N₃OS (233.29): C, 56.63; H, 4.75; N, 18.01; found: C, 56.76; H, 4.82; N, 17.89.

1-(4,5-Dimethyl-2.thioxo-2,3-dihydro-1H-imidazol-1-yl)-3-phenylurea (5i): Yield 85% (223.0 mg), white powder from THF/Et₂O; Mp 245–250 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.94 (s, 3H, CH₃), 1.99 (s, 3H, CH₃), 6.99 (t, J = 8.0 Hz, 2H, Ar), 7.28 (t, J = 8.0 Hz, 1H, Ar), 7.46 (d, J = 8.0 Hz, 2H, Ar), 8.89 (s, 1H, NH, D₂O exch.), 9.19 (s, 1H, NH, D₂O exch.), 12.00 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 7.8, 8.9, 116.6, 118.3, 122.2, 122.5, 128.7, 139.1, 153.9, 160.7 ppm; IR (Nujol, ν, cm⁻¹): 3271, 3172, 3095, 1719, 1691, 1665, 1603; MS m/z (ESI): 263.11 (M + H)⁺; calcd. for C₁₂H₁₄N₄OS (262.33): C, 54.94; H, 5.38; N, 21.36; found: C, 54.87; H, 5.46; N, 21.23.

4,5-Dimethyl-1-[(4-nitrophenyl)amino]-1H-imidazole-2(3H)-thione (5j): Yield 84% (222.0 mg), beige powder from THF/EtOAc/Et₂O; Mp 279–282 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.90 (s, 3H, CH₃), 2.03 (s, 3H, CH₃), 6.59 (d, J = 8.0 Hz, 2H, Ar), 8.10 (d, J = 8.0 Hz, 2H, Ar), 10.09 (s, 1H, NH, D₂O exch.), 12.19 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 7.6, 9.0, 111.3, 117.8, 121.7, 125.8, 139.3, 153.0, 160.8 ppm; IR (Nujol, ν, cm⁻¹): 3199, 3094, 1673, 1594; HRMS m/z calcd. for [M + H]⁺ C₁₁H₁₃N₄O₂S 265.0759; found 265.0774.

tert-Butyl (5-phenyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5k): Yield 66% (192.3 mg), light yellow powder from THF/EtOAc/light petroleum ether; Mp 172–174 °C (dec.); ¹H-NMR (400 MHz, DMSO-d₆) δ 1.17 and 1.39 (2s, 9H, OBu^t), 7.18 (s, 1H, CH), 7.35–7.49 (m, 5H, Ar), 9.79 and 10.12 (2s, 1H, NH, D₂O exch.), 12.51 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ 27.5, 27.9, 80.2, 80.5, 110.7, 110.8, 126.9, 127.0, 127.7, 127.9, 128.1, 128.5, 130.6, 130.8, 153.2, 153.9, 162.0, 164.2 ppm; IR (Nujol, ν, cm⁻¹): 3275, 3120, 3093, 1726, 1618, 1600; MS m/z (ESI): 292.18 (M + H)⁺; calcd. for C₁₄H₁₇N₃O₂S (291.37); C, 57.71; H, 5.88; N, 14.42; found: C, 57.83; H, 5.82; N, 14.37.

3.4. General Procedure for the Synthesis of α-(Imidazol-2-Ylthio) Carbonyl Compounds 7a–c.

To a suspension of the N-Boc-protected 1-amino-1H-imidazole-2(3H)-thione derivatives 5c,d,f (1.0 mmol) and K₂CO₃ (1.0 mmol, 138 mg) in 10.0 mL of acetone, the corresponding α-halocarbonyl derivative 6a–c (1.0 mmol) was added. The reaction mixture was kept under magnetic stirring at room temperature. Upon completion (monitored by TLC) the solvent was removed, and the crude reaction mixture was quenched to neutrality with a solution of HCl 1N and extracted with EtOAc (30.0 mL). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was removed in vacuum and the crude extract was purified by crystallization or by column chromatography eluting with cyclohexane:ethyl acetate mixtures to furnish 7a–c derivatives in good yields (84%–93%).

tert-Butyl (4-(diethylcarbamoyl)-5-methyl-2-((2-oxo-2-phenylethyl)thio)-1H-imidazol-1-yl)carbamate (7a): Yield 84% (375.1 mg); white solid from Et₂O; Mp 123–126 °C; ¹H-NMR (400 MHz, CDCl₃) δ 1.14–1.23 (m, 6H, 2xNCH₂CH₃), 1.48 (s, 9H, OBu^t), 1.98 (s, 3H, CH₃), 3.37–3.64 (m, 4H, 2xNCH₂CH₃), 4.50 (br s, 1H, SCH_aH_b), 4.69 (br s, 1H, SCH_aH_b), 7.46 (t, J = 8.0 Hz, 2H, Ar), 7.58 (t, J = 8.0 Hz, 1H, Ar), 7.97 (d, J = 8.0 Hz, 2H, Ar), 9.45 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, CDCl₃) δ 8.7, 12.9, 14.5, 28.0, 40.6, 41.6, 43.4, 82.5, 128.4, 128.5, 128.7, 130.9, 133.7, 135.3, 135.4, 139.9, 153.8, 164.5, 193.7 ppm; IR (Nujol, ν, cm⁻¹): 3114, 3059, 1741, 1726, 1700, 1681, 1597, 1584; MS m/z (ESI): 447.35 (M + H)⁺; calcd. for C₂₂H₃₀N₄O₄S (446.56): C, 59.17; H, 6.77; N, 12.55; found: C, 59.02; H, 6.84; N, 11.67.

tert-Butyl (5-methyl-2-((2-oxopropyl)thio)-1H-imidazol-1-yl)carbamate (7b): Yield 93% (265.4 mg); ocher solid from EtOAc/cyclohexane; Mp 103–104 °C; ¹H-NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H, OBu^t), 2.14 (s, 3H, CH₃), 2.24 (s, 3H, COCH₃), 3.81 (br s, 1H, SCH_aH_b), 3.94 (br s, 1H, SCH_aH_b), 6.77 (s, 1H, CH), 8.26 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, CDCl₃) δ 8.9, 28.0, 28.8, 44.8, 82.8, 125.1, 131.5, 139.5, 154.1, 203.5 ppm; IR (Nujol, ν, cm⁻¹): 3125, 1725, 1714; MS m/z (ESI): 286.17 (M + H)⁺; calcd. for C₁₂H₁₉N₃O₃S (285.36): C, 50.51; H, 6.71; N, 14.73; found: C, 50.40; H, 6.78; N, 14.86.

Ethyl 2-((1-((tert-Butoxycarbonyl)amino)-5-methyl-4-(phenylcarbamoyl)-1H-imidazol-2-yl)thio)acetate (7c): Yield 92% (399.7 mg), white solid from EtOAc/cyclohexane; Mp 134–136 °C; ¹H-NMR (400 MHz, CDCl₃) δ 1.27 (t, J = 8.0 Hz, 3H, OCH₂CH₃), 1.51 (s, 9H, OBu^t), 2.55 (s, 3H, CH₃), 3.66 (d, J = 16.0 Hz, 1H, SCH_aH_b), 3.90 (d, J = 16.0 Hz, 1H, SCH_aH_b), 4.17–4.24 (m, 2H, OCH₂CH₃), 7.10 (t, J = 8.0 Hz, 1H, Ar), 7.34 (t, J = 8.0 Hz, 2H, Ar), 7.67 (d, J = 8.0 Hz, 2H, Ar), 8.18 (br s, 1H, NH, D₂O exch.), 8.96 (s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, CDCl₃): δ 9.4, 14.0, 28.0, 36.7, 62.7, 83.4, 119.5, 123.8, 128.9, 129.9, 137.3, 138.0, 139.0, 153.6, 160.6, 169.9 ppm; IR (Nujol, ν, cm⁻¹): 3315, 3182, 1733, 1647, 1601; MS m/z (ESI): 435.20 (M + H)⁺; calcd. for C₂₀H₂₆N₄O₅S (434.51): C, 55.28; H, 6.03; N, 12.89; found: C, 55.39; H, 5.97; N, 12.81.

3.5. General Procedure for the Synthesis of N-Bridgeheaded Heterobicyclic Derivatives 8a–c.

Derivative 7a,b (1.0 mmol) was solved in 5.0 mL of a solution of trifluoroacetic acid (TFA) and CH₂Cl₂ (1:1). The reaction mixture was left at room temperature until the disappearance of the starting 7a,b (TLC check). Then, the solvent was removed under reduced pressure and the crude reaction mixture was quenched to neutrality with a saturated solution of Na₂CO₃ and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After the removal of the solvent, the crude extract was purified by crystallization or by column chromatography eluting with cyclohexane/ethyl acetate mixtures to furnish 8a,b derivatives. For obtaining 8c, the best condition found was to treat 7c (1.0 mmol) with Amberlyst 15H (500 mg) in refluxing dioxane (15.0 mL) for 12.0 h. Upon completion (monitored by TLC) the resin was filtered off in vacuo and washed with THF (20.0 mL). The filtrate was evaporated under reduced pressure and the crude reaction mixture was purified by crystallization.

N,N-diethyl-6-methyl-3-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazine-7-carboxamide (8a): Yield 82% (269.3 mg) white powder from EtOAc/cyclohexane; Mp 125–127 °C; ¹H-NMR (400 MHz, CDCl₃) δ 1.22 (t, J = 8.0 Hz, 6H, 2xNCH₂CH₃), 2.56 (s, 3H, CH₃), 3.53 (br s, 2H, NCH₂CH₃), 3.74 (br s, 2H, NCH₂CH₃), 3.97 (s, 2H, SCH₂), 7.50–7.52 (m, 3H, Ar), 7.90 (d, J = 8.0 Hz, 2H, Ar) ppm; ¹³C-NMR (100 MHz, CDCl₃) δ 9.7, 13.0, 14.5, 23.9, 40.3, 43.0, 127.0, 128.9, 129.7, 131.1, 131.3, 133.5, 134.2, 150.8, 164.1 ppm; IR (Nujol, ν, cm⁻¹): 1611, 1574, 1562, 1557; MS m/z (ESI): 329.28 (M + H)⁺; calcd. for C₁₇H₂₀N₄OS (328.43): C, 62.17; H, 6.14; N, 17.06; found: C, 62.04; H, 6.19; N, 17.15.

3,6-Dimethyl-2H-imidazo[2,1-b][1,3,4]thiadiazine (8b): Yield 65% (108.7 mg); white needles from CHCl₃/cyclohexane; Mp 57–58 °C; ¹H-NMR (400 MHz, CDCl₃) δ 2.26 (s, 3H, CH₃), 2.32 (s, 3H, CH₃), 3.42 (s, 2H, SCH₂), 6.70 (s, 1H, CH), ppm; ¹³C-NMR (100 MHz, CDCl₃) δ 8.8, 23.5, 26.1, 123.7, 128.6, 130.1, 152.0 ppm; IR (Nujol, ν, cm⁻¹): 1640. 1582; MS m/z (ESI): 168.06 (M + H)⁺; calcd. for C₇H₉N₃S (167.23): C, 50.27; H, 5.42; N, 25.13; found: C, 50.39; H, 5.39 N, 25.06.

6-Methyl-3-oxo-N-phenyl-3,4-dihydro-2H-imidazo[2,1-b][1,3,4]thiadiazine-7-carboxamide (8c): Yield 74% (213.3 mg), light yellow powder from EtOAc/light petroleum ether; Mp 229–232 °C; ¹H-NMR (400 MHz, DMSO-d₆) δ 2.53 (s, 3H, CH₃), 3.81 (s, 2H, SCH₂), 7.04 (t, J = 8.0 Hz, 1H, Ar), 7.29 (t, J = 8.0 Hz, 2H, Ar), 7.81 (d, J = 8.0 Hz, 2H, Ar), 9.80 (s, 1H, NH, D₂O exch.), 12.27 (br s, 1H, NH, D₂O exch.) ppm; ¹³C-NMR (100 MHz, DMSO-d₆): δ 9.2, 29.7, 119.8, 123.0, 128.3, 128.4, 130.6, 132.2, 138.8, 160.8, 164.6 ppm; IR (Nujol, ν, cm⁻¹): 1679, 1666, 1595, 1582; MS m/z (ESI): 288.97 (M + H)⁺; calcd. for C₁₃H₁₂N₄O₂S (288.32): C, 54.15; H, 4.20; N, 19.43; found: C, 54.08; H, 4.27; N, 19.31.

4. Conclusions

In conclusion, combining sequential azidation, Staudinger, and aza-Wittig reactions with CS₂ on α-halohydrazones in a one-pot protocol, variously substituted 1-amino-1H-imidazole-2(3H)-thiones are directly accessible in good yields and with complete control of regioselectivity. The method is particularly attractive and advantageous for its mild conditions, operational simplicity, and its efficiency as well as its robustness (wide substrate scope and tolerance of various functional groups) and reliability. The concurrent presence of reactive appendages on the obtained scaffolds ensures post-modifications toward N-bridgeheaded heterobicyclic structures.

Supplementary Materials

The following are available online: procedure followed for obtaining II; copies of 1H-NMR and 13C-NMR spectra of II [22]; copies of 1H-NMR and 13C-MNR spectra of all newly synthesized compounds; copies of HMQC of compound 5a and 8c.

Author Contributions

C.C. performed all synthetic work in laboratory; G.M. designed the experiments; G.F.; supervised the project, F.M. funding acquisition; L.D.C. validation; S.S.* conceived the synthetic route and wrote the paper.

Funding

The authors declare no competing financial interest.

Acknowledgments

The authors gratefully thank Anna Maria Gioacchini and Samuele Lillini who competently performed the mass spectra and the Department of Biomolecular Science of the University of Urbino for the economical support.

Conflicts of Interest

There are no conflicts to declare.

Scheme 1.Schantl's protocol for the synthesis of N-substituted 1-amino-1H-imidazole-2(3H)-thione derivatives I.

Scheme 1.Schantl's protocol for the synthesis of N-substituted 1-amino-1H-imidazole-2(3H)-thione derivatives I.

Scheme 2.Pathway for the formation of 2-iminothiazoline heterocycle II.

Scheme 2.Pathway for the formation of 2-iminothiazoline heterocycle II.

Scheme 3.Our hypothesized disconnection of 1-amino-1H-imidazole-2(3H)-thione I derivatives.

Scheme 3.Our hypothesized disconnection of 1-amino-1H-imidazole-2(3H)-thione I derivatives.

Scheme 4.Step-by-step synthetic pathway for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivative 5a.

Scheme 4.Step-by-step synthetic pathway for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivative 5a.

Scheme 5.New multicomponent reaction (MCR) method for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivatives 5a-k.

Scheme 5.New multicomponent reaction (MCR) method for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivatives 5a-k.

Scheme 6.Synthetic approach to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.

Scheme 6.Synthetic approach to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.

Scheme 7.Different synthetic approaches to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.

Scheme 7.Different synthetic approaches to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.

Table 1.Substrate scope of the MCR synthetic pathway for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivatives 5a-k.

[ Table omitted. See PDF. ]

a Overall yield of isolated product 5a from the step-by-step reaction based on 1a; b Overall yield of isolated products 5a-k from one-pot MCR based on 1a-k.

Table

Table 2.Substrate scope of the reaction between 1-amino-2,3-dihydro-1H-imidazole-2-thione derivatives 5 with α-haloketones 6a,b or α-haloester 6c.

[ Table omitted. See PDF. ]

a Yield of isolated product 7a-c based on 6a-c; b Yield of isolated product 8a-c based on 7a-c.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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