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Article

Synthesis and Selected Transformations of 2-Unsubstituted Imidazole N-Oxides Using a Ball-Milling Mechanochemical Approach †

by
Grzegorz Mlostoń
1,*,
Małgorzata Celeda
1,
Heinz Heimgartner
2,
Damian Duda
1,
Emilia Obijalska
1,* and
Marcin Jasiński
1,*
1
Department of Organic and Applied Chemistry, University of Lodz, Tamka 12, PL-91403 Łódź, Poland
2
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
*
Authors to whom correspondence should be addressed.
†
Dedicated to Professor Jacek Morzycki on the occasion of his 70th birthday.
Catalysts 2022, 12(6), 589; https://doi.org/10.3390/catal12060589
Submission received: 11 April 2022 / Revised: 17 May 2022 / Accepted: 25 May 2022 / Published: 28 May 2022
(This article belongs to the Special Issue Heteroaromatic N-oxides in Synthesis and Asymmetric Catalysis)
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Versions Notes

Abstract

Synthetically relevant 2-unsubstituted imidazole N-oxides were obtained by using the ball-milling mechanochemical method. The presented approach extended the scope of the known method and enabled the preparation of hitherto little known N(1)-aryl-substituted derivatives, which are of interest as starting materials for the synthesis of more complex imidazole-based organic materials, generally in good to excellent yields. In addition, selected one-pot mechanochemical transformations including N- and O-alkylations as well as sulfur transfer reactions based on either (3+2)-cycloaddition reaction with 2,2,4,4-tetramethylcyclobutane-1,3-dithione or sulfurization of the transient imidazol-2-ylidenes, generated from corresponding imidazolium salts, were studied. The reported results can be considered as a continuation of long-term studies focused on the synthesis and applications of 2-unsubstituted imidazole N-oxides.

Graphical Abstract

1. Introduction

The imidazole skeleton is well-known as a heterocycle motif widely spread in naturally occurring compounds as well as a key structural fragment of numerous practically useful synthetic organic compounds such as pharmaceuticals, agrochemicals, and materials with special properties [1,2,3,4,5,6,7,8,9]. In the last decade, 2-unsubstituted imidazole N-oxides 1 were demonstrated as versatile starting materials for the preparation of more complex imidazole derivatives, and the most important applications were summarized in recent reviews [10,11,12,13,14]. The most important transformations of compounds 1 are based on formal (3+2)-cycloadditions in which the N-oxide unit acts as ‘aldonitrone-like’ 1,3-dipole and the cycloaddition step is typically followed by cycloreversion or rearrangement of the initially formed, fused five-membered heterocycles driven by the re-aromatization of the imidazole ring (Scheme 1). For example, reactions with cycloaliphatic thioketones initiated by the 1,3-dipolar cycloaddition step leads to enolisable imidazole-2-thiones of type 2 via the so called ‘sulfur-transfer mechanism’ [15,16]. Similarly, reactions of 1 with β,β-difluorostyrenes open access to imidazole-functionalized arylacetates 3 [17], whereas cycloadditions with electron-deficient 2,2-bis(trifluoromethyl)ethene-1,1-dicarbonitrile (BTF) provides push–pull dicyanomethylidene-functionalized imidazoles 4 [18]. The latter reactions proceed via elimination of gaseous fluorinated by-products. A series of imidazol-2-ylacetates 5 was also prepared by using dimethyl acetylenedicarboxylate (DMAD) as a reactive dipolarophile [19]. More recently, other activated ethylenes were also applied for reactions with 1 to give imidazol-2-ylacetonitriles 6 formed via elimination of the acetone molecule from the initially formed (3+2)-cycloadducts [20] (Scheme 1).
The presence of the polarized N-oxide bond in 1 activates the C(2) and C(4) positions for formal cross-coupling reactions which occur either via Pd-catalyzed or Brönsted-acid-induced processes [21,22,23]. Imidazole N-oxides 1 easily undergo O-alkylation to provide 3-alkoxyimidazolium salts, which display properties of room-temperature ionic liquids (RTIL, m.p. < 100 °C) [24] as well as constitute a group of biologically active, alkoxy functionalized analogues of naturally occurring alkaloids of the lepidiline family [25]. In the latter context, smooth deoxygenation of 1 typically performed with Raney-nickel led to 1,4,5-trisubstituted imidazoles, which after quaternization at N(3) with benzyl chloride opened up an access to synthetic lepidilines A and C [26].
In addition, in a recent publication, imidazole N-oxides 1 were also demonstrated as highly useful starting materials for in situ-generation of alkoxy-functionalized imidazol-2-ylidenes (nucleophilic carbenes, NOHCs) as reactive intermediates that can be trapped by Au(I), Ag(I) and Cu(I) salts yielding the corresponding metal complexes [27] or by elemental chalcogens such as S and Se to give non-enolisable imidazole-2-thiones or imidazole-2-selones, respectively [28,29,30].
Taking into account the numerous applications of imidazole N-oxides 1, development of new reliable synthetic protocols for the preparation of this class of heterocycles is of current interest. The most often applied method for the synthesis of 1 is based on the condensation of α-hydroxyiminoketones 7 with formaldimines 8 in boiling ethanol (according to Scheme 2) [31,32,33,34,35]. However, this method cannot be applied for the preparation of N-aryl-substituted analogues due to the reduced nucleophilicity of the respective N-aryl formaldimines. This limitation can be partially overcome by using BF3·Et2O as a Lewis-acid catalyst at elevated temperatures [36].
In the last two decades of rapid development of synthetic procedures, applications based on a mechanochemical approach are reported, and especially important is the ball-milling method performed either without any liquid medium or in the presence of a small amount of so-called liquid-assisted grinding solvent (LAGs) [37,38,39,40]. These methods also offer a sustainable protocol and in some instances enable the synthesis of organic compounds inaccessible under standard conditions in solution using classic laboratory glass equipment. Mechanochemical methods are widely applied for the preparation of diverse heterocyclic compounds, but preparation of imidazole N-oxides 1 by mechanochemical procedures has scarcely been studied. To the best of our knowledge, the only published report relates to the synthesis of 2,4,5-trisubstituted imidazole N-oxides, starting with α-hydroxyiminoketones 7, aldehydes and amines, by standard milling in agar mortar with subsequent heating of the resulting mixture at 110–120 °C [41]. However, 2-unsubstituted analogues 1 cannot be accessed by this method due to their limited stability resulting from possible thermal isomerization into the respective imidazol-2-ones [32,42]. In our opinion, the experimental data given in ref. [41] (SI part) do not support the proposed structure of the expected 1-(4-chlorophenyl)-4,5-diphenylimidazole 3-oxide. For example, the 1H NMR spectrum does not reveal the presence of the diagnostic C(2)-H absorption appearing typically between 8.00 and 9.00 ppm; moreover, copies of the measured spectra are not presented.
Special attention deserve optically active imidazole N-oxides 1 prepared from enantiopure primary amines [28,35,43,44], 1,2-amino alcohols [33] or amino acid esters [45]. Some of them, derived from enantiopure trans-1,2-diaminocyclohexane (DACH), were demonstrated to act as useful organocatalysts in asymmetric allylation of aromatic aldehydes [46].
The goal of the present work was the elaboration of a general method useful for the synthesis of 2-unsubstituted N(1)-alkyl and N(1)-aryl imidazole N(3)-oxides of type 1 using the ball-milling mechanochemical approach. In addition, selected transformations of the imidazole N-oxides 1 performed under similar solvent-free conditions were also of interest (Scheme 2).

2. Results and Discussion

The first goal of the presented study was the comparison of methods for preparation of imidazole N-oxides 1 based on a typical protocol comprising condensation of α-hydroxyiminoketones 7 and formaldimines 8 performed either in acetic acid as a solvent (Method A) or via a mechanochemical approach. In the latter case, both two- (Method B) and three-component (Method C) variants were studied. In a test experiment, diacetyl monoxime (7a) was mixed with N-benzylformaldimine 8a (used as trimer 8a′) and, after addition of a small amount of AcOH as LAGs, the mixture was ball-milled for 20 min at room temperature (Scheme 3). After standard workup (see Experimental Part), the known 1-benzyl-4,5-dimethylimidazole N-oxide (1a) was isolated in the excellent yield of 92% (Table 1). Apparently, under these conditions, no isomerization into the respective imidazole-2-one takes place and the initially formed product remained unchanged. A similar result was achieved starting with the same formaldimine 8a and benzil monoxime (7b) to afford imidazole N-oxide 1b as an exclusive product isolated in 92% yield. In both cases, the expected products were obtained in significantly higher yields than in the standard protocol in solution (Table 1). Notably, the three-component mechanochemical reaction (Method C) also provided the desired imidazole N-oxides 1a and 1b, although in moderate yields comparable to those noticed for Method A.
Prompted by the results of the test experiments, a series of mechanochemical syntheses was performed using less reactive formaldimines 8b–8e derived from differently substituted anilines, and the obtained results are collected in Table 1. In all cases, the expected 1-aryl-substituted imidazole N-oxides were isolated in yields either higher or comparable to the classical wet procedure. It is worth underlining that there was no substantial influence of the electron-donating or electron-withdrawing character of the substituent present in the aryl ring on the chemical yield. In all the cases of N(1)-aryl-imidazole N(3)-oxides the 1H NMR spectra (taken in CDCl3 or CD3OD) revealed the presence of the diagnostic C(2)-H absorption (singlet) between 7.85–8.79 ppm, thereby confirming the postulated 2-unsubstituted structure of the imidazole core in products 1c–1i.
In addition to this series, the chiral formaldimine 8f (applied as trimer 8f′) derived from (R)-α-methylbenzylamine (9) was also tested [43]. Following the general devised protocol of Method B, after slightly extended reaction time (30 min), the desired products 1j and 1k were obtained in 62% and 44% yield, respectively (Scheme 4). In both cases, no racemization was observed and optically pure materials were isolated. Surprisingly, no expected products could be detected in a three-component approach using diacetyl monoxime (7a), (R)-α-methylbenzylamine and paraformaldehyde according to Method C. Furthermore, the attempted mechanochemical syntheses of bis-imidazole N-oxides 1l and 1m derived from (R,R)-1,2-diaminocyclohexane (10) were unsuccessful both in two- and three-component experiments. The product of the reaction of formaldehyde and diamine 10 exists as a stable dimeric tetraazaeicosane derivative 11, and very likely does not release the reactive monomeric form under the solvent-free conditions [44].
As shown in Scheme 1, one of the most widely applied transformation of 2-unsubstituted imidazole N-oxides of type 1 is the sulfur-transfer reaction based on initial (3+2)-cycloaddition with cycloaliphatic thioketones, such as 2,2,4,4-tetramethylcyclobutane-1,3-dithione (12) [15]. The conversions of N-aryl-imidazole N-oxides 1c–1i into the corresponding, little-known imidazole-2-thiones 13a–13d were also compared using the standard procedure (CH2Cl2, r.t., 10 min) and mechanochemical conditions (Scheme 5). In these experiments, LAGs-free ball-milling procedure (Method E) and the reaction carried out in solvent (Method D) led to comparable results, however, whereas the reactions in CH2Cl2 were finished after only 10 min, ball-milling required ca. 3 h to complete these conversions.
Imidazole N-oxides smoothly undergo O-benzylation reaction, leading to lesser known alkoxy-imidazolium salts [24]. In many cases, the obtained bromides or chlorides are oily materials, and the ion-exchange into hexafluorophosphate offers an easy access to crystalline derivatives. Notably, one of the most important applications of imidazolium salts relies on the exploration as precursors of nucleophilic heterocyclic carbenes (imidazol-2-ylidenes) [27,28,29,30]. In this context, the N-aryl N’-alkoxy-imidazolium bromides 14a–14f (not shown) were prepared based on known procedures by using benzyl bromide as suitable electrophile, and the subsequent ion-metathesis performed in aqueous ethanol provided crystalline hexafluorophosphates 14a[PF6]–14f[PF6] (Scheme 6, Method F). Alternatively, the same products were prepared by ball-milling (30 min, r.t.) in a one-pot procedure by using a mixture of the corresponding imidazole N-oxide 1, benzyl bromide and solid NH4PF6 without LAG additive (Scheme 2, Table 2, Method G). As expected, the characteristic strong low-field shift of the diagnostic absorption attributed to C(2)-H was observed in all the cases (9.83–10.37 ppm; spectra taken in DMSO-d6). The obtained N-benzyloxy-imidazolium salt 14c[PF6] (R1 = p-MeOC6H4, R2 = Me) was selected as model substrate for the sulfurization of the imidazole ring proceeding via the base-mediated in situ-generation of the corresponding carbene. Thus, reaction of hexafluorophosphate 14c[PF6] with elemental sulfur in pyridine/Et3N mixture (Method H) provided, after 16 h at room temperature, the expected non-enolisable imidazole-2-thione 15 (67%) as sole product. The alternative mechanochemical reaction with solid K2CO3 as a base (Method I) required 3 h of milling and afforded the same material isolated in 43% yield (Scheme 2, Table 2). These experiments demonstrate that imidazole-2-thiones are accessible in comparable yield using both procedures.
In a series of recent publications, smooth deoxygenation of imidazole N-oxides by treatment with freshly prepared Raney nickel leading to 1,4,5-trisubstituted imidazoles was reported [11,24,26,29]. These imidazole derivatives can be used for N-alkylation aimed at the preparation of corresponding 1,3,4,5-tetra-substituted imidazolium salts. This method was demonstrated as a straightforward procedure for the synthesis of naturally occurring imidazolium salts known as lepidilines [26]. In the present work, 1-aryl-substituted imidazole N-oxides 1d,e,f,i were deoxygenated yielding N-arylated imidazoles 16a–16d in fair yields of 58–79% (Scheme 7). As expected, the diagnostic signal attributed to C(2)-H in the 1H NMR spectra was found in remarkably higher-shifted field at 7.46–7.75 ppm (in CDCl3), what clearly evidences removal of the oxygen atom from the N(3) position. In contrast to the smooth O-benzylation of N-oxides 1, similar transformations of imidazoles 16 by using benzyl bromide required microwave irradiation (at 110 °C) to accomplish alkylation of the N(3) atom. As shown in Scheme 6, the obtained crude imidazolium bromides 17a–17d were subsequently transformed into hexafluorophosphates 17a[PF6]–17d[PF6] by ion-exchange with NH4PF6 in aqueous ethanol.
Following the known procedure, 1-benzyl-4,5-dimethyl-3-(4′-methoxyphenyl)-imidazolium hexafluorophosphate (17b[PF6]), which can be considered as a new type of lepidiline C analogues, was converted into the corresponding imidazole-2-thione 18 by sulfurization of the in situ-generated nucleophilic carbene (Scheme 8). The transformation was performed in pyridine solution (Method H) and in a ball-mill as well (Method I), and in both approaches yields of isolated final product were moderate.

3. Materials and Methods

3.1. Materials

Commercially available chemicals (solvents and reagents) were used as received. If not stated otherwise, sulfur transfer reactions were carried out under inert atmosphere of argon; subsequent manipulations were conducted in air. Mechanochemical reactions were performed by using Retsch Mixer Mill MM400. Products were purified by filtration through a short silica gel plug or by standard column chromatography (CC) on silica gel (230–400 mesh) by using freshly distilled solvents as eluents or by recrystallization from appropriate solvents. NMR spectra were measured on a Bruker AVIII (1H NMR (600 MHz); 13C NMR (151 MHz); 19F NMR (565 MHz)). Chemical shifts are given relative to residual undeuterated solvent peaks (for CDCl3: 1H NMR δ = 7.26 ppm, 13C NMR δ = 77.16 ppm; for DMSO-d6: 1H NMR δ = 2.50 ppm, 13C NMR δ = 39.52 ppm; for CD3OD: 1H NMR δ = 3.31 ppm) [47] or to CFCl3 (19F NMR δ = 0.00 ppm) used as external standard. Multiplicity of the signals in 13C NMR spectra were deduced based on supplementary 2D measurements (HMQC, HMBC). The IR spectra were measured with an Agilent Cary 630 FTIR spectrometer, in neat. Mass spectra were performed with a Varian 500-MS LC Ion Trap. Elemental analyses were obtained with a Vario EL III (Elementar Analysensysteme GmbH) instrument. Melting points were determined in capillaries with an Aldrich Melt-Temp II or with Stuart SMP30 apparatus and they are uncorrected.

3.2. Methods

3.2.1. Synthesis of Imidazole N-Oxides 1a–1m

Method A: α-Hydroxyiminoketone 7a or 7b (1.1 mmol) and formaldimine 8 (1.0 mmol) were dissolved in glacial acetic acid (3 mL) and the mixture was stirred for 12 h at room temperature. After the concentrated aq. HCl (0.5 mL) was added dropwise, the solvent was evaporated under reduced pressure and the residue was dissolved in MeOH (5 mL). Then, excess solid NaHCO3 (1.0 g) was added and stirring was continued for 30 min. In order to remove NaCl the mixture was diluted with CH2Cl2 (10 mL), filtered, and the solvents were removed. Crude products 1c–1i were filtered through a short silica gel plug (AcOEt gradient AcOEt/MeOH 1:1). If not stated otherwise, the resulting product was triturated with Et2O, the precipitated imidazole N-oxide 1 was filtered, washed with additional portions of Et2O (2 × 5 mL) and air-dried.
Method B: α-Hydroxyiminoketone 7a or 7b (1.1 mmol), formaldimine 8 (1.0 mmol), a small amount of glacial acetic acid (0.1 mL, 0.175 mmol), and a zirconium ball (∅ 5.0 mm) were placed in the zirconium mechanochemical vial, and the mixture was ball-milled for 0.5 h at 25 Hz. The resulting material was dissolved in MeOH (5 mL), concentrated aq. HCl (0.5 mL) was added followed by solid NaHCO3 (1.0 g) and the mixture was magnetically stirred for 20 min. After the mixture was diluted with CH2Cl2 (10 mL) and filtered, the solvents were removed in vacuo. Crude N(1)-aryl imidazole N(3)-oxides 1c–1i were filtered through a short silica gel plug (AcOEt gradient AcOEt/MeOH 1:1). If not stated otherwise, the resulting material was triturated with Et2O, the precipitated imidazole N-oxide 1 was filtered and washed with additional portions of Et2O (2 × 5 mL).
Method C: α-Hydroxyiminoketone 7a or 7b (1.1 mmol), paraformaldehyde (30 mg, 1.2 mmol), the appropriate amine (1.0 mmol), glacial acetic acid (0.1 mL, 0.175 mmol), and a zirconium ball (∅ 5.0 mm) were placed in the zirconium mechanochemical vial and the mixture was ball-milled for 45 min at 25 Hz. Product 1 was isolated following the general work-up described for Method B.
1-Benzyl-4,5-dimethylimidazole 3-oxide (1a): Method A, 131 mg (65%), colorless crystals, m.p. 192−195 °C (ref. [32], m.p. 199−201 °C); Method B, 186 mg (92%); Method C, 133 mg (68%). 1H NMR (600 MHz, CDCl3): δ 2.03, 2.14 (2 s, 6 H, 2 Me), 4.93 (s, 2 H, CH2), 7.02–7.05, 7.26–7.33 (2 m, 2 H, 3 H), 7.74 (s, 1 H, C(2)H).
1-Benzyl-4,5-diphenylimidazole 3-oxide (1b): Method A, 202 mg (62%), colorless crystals, m.p. 183−185 °C (ref. [32], m.p. 176−178 °C); Method B, 300 mg (92%); Method C, 270 mg (83%). 1H NMR (600 MHz, CDCl3): δ 4.98 (s, 2 H, CH2), 7.08–7.10, 7.21–7.25, 7.28–7.32, 7.34–7.37, 7.38–7.42, 7.43–7.46, 7.56–7.59 (7 m, 2 H, 2 H, 3 H, 3 H, 2 H, 1 H, 2 H), 8.01 (s, 1 H, C(2)H).
1-Phenyl-4,5-dimethylimidazole 3-oxide (1c): Method A, 171 mg (91%), colorless crystals, m.p. 183−185 °C (CH2Cl2/i-Pr2O); Method B, 148 mg (79%); Method C, 132 mg (70%). 1H NMR (600 MHz, CDCl3): δ 2.09, 2.25 (2 s, 3 H each, 2 Me), 7.23–7.26, 7.45–7.51 (2 m, 2 H, 3 H), 7.91 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 7.5, 9.6, 121.7, 124.5, 126.0*, 127.7, 129.4, 130.0*, 135.2; *higher intensity. IR (neat): ν 3049, 2929, 1595, 1491, 1379, 1350, 1330, 1200, 816, 764, 697 cm–1. ESI-MS (m/z): 211 (20, [M+Na]+), 189 (100, [M+H]+). Elemental analysis for C11H12N2O (188.2): calculated, C 70.19, H 6.43, N 14.88; found, C 70.19, H 6.38, N 15.04.
1,4,5-Triphenylimidazole 3-oxide (1d): Method A, 299 mg (96%), colorless crystals, m.p. 208−210 °C (CH2Cl2/i-Pr2O); Method B, 298 mg (96%); Method C, 243 mg (78%). 1H NMR (600 MHz, CDCl3): δ 6.98–7.01, 7.09–7.12, 7.15–7.19, 7.23–7.36, 7.52–7.55 (5 m, 2 H, 2 H, 2 H, 7 H, 2 H), 8.27 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 125.9, 126.4, 126.6, 126.9, 127.1, 128.3, 128.6, 128.7, 129.0, 129.1, 129.7, 130.2, 130.6, 131.3, 134.9. IR (neat): ν 3071, 1506, 1364, 1223, 1163, 842, 760, 697 cm–1. ESI-MS (m/z): 335 (50, [M+Na]+), 313 (100, [M+H]+). Elemental analysis for C21H16N2O · 1.3H2O (336.1): calculated, C 74.98, H 5.59, N 8.33; found, C 75.12, H 5.35, N 8.68.
1-(4-Methoxyphenyl)-4,5-dimethylimidazole 3-oxide (1e): Method A, 107 mg (49%), colorless crystals, m.p. 82−84 °C (CH2Cl2/i-Pr2O); Method B, 124 mg (57%); Method C, 172 mg (79%). 1H NMR (600 MHz, CDCl3): δ 1.98, 2.16 (2 s, 3 H each, 2 Me), 3.78 (s, 3 H, OMe), 6.90–6.93, 7.10–7.12 (2 m, 2 H each), 7.85 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 7.4, 9.3, 55.6, 114.9, 122.1, 124.7, 127.0, 127.3, 127.5, 160.1. IR (neat): ν 3269, 3116, 3053, 2967, 2930, 2840, 1510, 1297, 1252, 1178, 1111, 1029, 846, cm–1. ESI-MS (m/z): 219 (100, [M+H]+). Elemental analysis for C12H14N2O2 · 2H2O (254.1): calculated, C 56.68, H 7.14, N 11.02; found, C 56.21, H 6.87, N 11.48.
1-(4-Methoxyphenyl)-4,5-diphenylimidazole 3-oxide (1f): Method A, 233 mg (68%), colorless crystals, m.p. 165−167 °C (CH2Cl2/i-Pr2O); Method B, 202 mg (59%); Method C, 239 mg (70%). 1H NMR (600 MHz, CDCl3): δ 3.78 (s, 3 H, Ome), 6.82–6.85, 6.99–7.06, 7.18–7.22, 7.24–7.32, 7.55–7.57 (5 m, 2 H, 4 H, 2 H, 4 H, 2 H), 8.16 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 55.6, 126.5, 114.7, 127.3, 128.2, 128.4, 128.6, 128.9, 130.1, 130.6, 126.8, 127.0, 127.3, 127.7, 131.1, 159.8. IR (neat): ν 3049, 2937, 1505, 1439, 1368, 1293, 1215, 1025, 835, 760, 693 cm–1. ESI-MS (m/z): 365 (15, [M+Na]+), 343 (100, [M+H]+). Elemental analysis for C22H18N2O2 · 1.5H2O (369.2): calculated, C 71.53, H 5.73, N 7.58; found, C 71.16, H 5.42, N 7.46.
1-(4-Bromophenyl)-4,5-dimethylimidazole 3-oxide (1g): Method A, 164 mg (42%), colorless crystals, m.p. 166−168 °C (CH2Cl2/i-Pr2O); Method B, 152 mg (39%); Method C, 250 mg (64%). 1H NMR (600 MHz, CDCl3): δ 2.07, 2.22 (2 s, 3 H each, 2 Me), 7.11–7.13, 7.61–7.63 (2 m, 2 H each), 7.88 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 7.4, 9.5, 121.8, 123.4, 125.3, 127.5, 127.6, 133.1, 133.8. IR (neat): v 3100, 2926, 1485, 1381, 1351, 1202, 1073, 941, 840, 807 cm–1. ESI-MS (m/z): 291 (95, [M{81Br}+Na]+), 289 (49, [M{79Br}+Na]+), 269 (95, [M{81Br}+H]+), 267 (100, [M{79Br}+H]+). Elemental analysis for C11H11BrN2O · 0.75H2O (279.5): calculated, C 47.08, H 4.49, N 9.98; found, C 47.00, H 4.11, N 10.37.
1-(4-Fluorophenyl)-4,5-dimethylimidazole 3-oxide (1h): Thick brown oil; Method A, 169 mg (82%); Method B, 161 mg (78%); Method C, 179 mg (87%). 1H NMR (600 MHz, CDCl3): δ 2.07, 2.25 (2 s, 3 H each, 2 Me), 7.17–7.22, 7.29–7.32 (2 m, 2 H each), 8.26 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 7.5, 9.5, 117.1 (d, 2JC–F = 23.3 Hz), 122.2, 125.6, 127.4, 128.1 (d, 3JC–F = 8.9 Hz), 130.8 (d, 4JC–F = 3.2 Hz), 162.9 (d, 1JC–F = 250.8 Hz). 19F NMR (565 MHz, CDCl3): δ −110.6 (mc). IR (neat): ν 3058, 3071, 2930, 1677, 1506, 1387, 1223, 1160, 1101, 831 cm–1. ESI-MS (m/z): 207 (100, [M+H]+). Elemental analysis for C11H11FN2O (206.1): calculated, C 64.07, H 5.38, N 13.58; found, C 64.09, H 5.40, N 13.52.
1-(4-Fluorophenyl)-4,5-diphenylimidazole 3-oxide (1i): Method A, 112 mg (34%), colorless crystals, m.p. 252−254 °C (Et2O); Method B, 191 mg (58%); Method C, 224 mg (68%). 1H NMR (600 MHz, CD3OD): δ 7.13–7.19, 7.25–7.28, 7.31–7.39, 7.49–7.51 (4 m, 4 H, 2 H, 6 H, 2 H), 8.79* (s, 1 H, C(2)H); *lower intensity due to partial H/D exchange. 13C NMR (151 MHz, CDCl3): δ 117.5 (d, 2JC–F = 23.6 Hz), 129.3, 129.5, 129.8, 130.0, 130.1*, 130.5, 131.5, 131.9, 132.1, 132.2 (d, 4JC–F = 3.2 Hz), 146.2 (d, 1JC–F = 248.8 Hz); *broadened absorption attributed to two ortho-CH groups of the N(1)-substituent; the 3JC-F cannot be determined. 19F NMR (565 MHz, CDCl3): δ −114.0 (mc). IR (neat): ν 3071, 1506, 1485, 1398, 1364, 1295, 1223, 1162, 1110, 1005, 842, 775, 760, 693 cm–1. ESI-MS (m/z): 331 (100, [M+H]+). Elemental analysis for C21H15FN2O (330.1): calculated C 76.35, H 4.58, N 8.48; found, C 76.38, H 4.61, N 8.59.
(R)-1-(1-Phenyl)ethyl-4,5-dimethylimidazole 3-oxide (1j): Method A, 204 mg (93%), colorless crystals, m.p. 230−232 °C (Et2O) (ref. [43], m.p. 224 °C (decomp.)), [α]D20−149.1 (c = 0.16, CHCl3) (ref. [43], [α]D20 = −138.5 (c = 1.00, MeOH)); Method B, 134 mg (62%), [α]D20 = −166.0 (c = 0.20, CHCl3). 1H NMR (600 MHz, CDCl3): δ 1.76 (d, J = 7.1 Hz, 3 H, Me), 1.98, 2.16 (2 s, 3 H each, 2 Me), 5.20 (q, J = 7.1 Hz, 1 H, CHMe), 7.04–7.06, 7.27–7.34 (2 m, 2 H, 3 H), 7.89 (s, 1 H, C(2)H).
(R)-1-(1-Phenyl)ethyl-4,5-diphenylimidazole 3-oxide (1k): Method A, 218 mg (64%), colorless crystals, m.p. 189−191 °C (Et2O) (ref. [43], m.p. 217 °C (decomp.)), [α]D20 +57.6 (c = 0.22, CHCl3) (ref. [43], [α]D20 = +30.0 (c = 1.00, MeOH)); Method B, 150 mg (44%), [α]D20 +63.9 (c = 0.42, CHCl3); Method C, 122 mg (29%), [α]D20 +57.7 (c = 0.20, CHCl3). 1H NMR (600 MHz, CDCl3): δ 1.77 (d, J = 7.1 Hz, 3 H, Me), 5.24 (q, J = 7.1 Hz, 1 H, CHMe), 7.05–7.07, 7.13–7.15, 7.21–7.25, 7.29–7.36, 7.39–7.42, 7.53–7.55 (6 m, 2 H, 2 H, 3 H, 5 H, 1 H, 2 H), 8.12 (s, 1 H, C(2)H).
(R,R)-trans-1,1-(Cyclohexane-1,2-diyl)bis(4,5-dimethylimidazole)-3,3′-dioxide (1l): Reactions were carried out according to general protocols using 1.1 mmol of 7a and 0.25 mmol of 11 (Methods A and B) or 0.5 mmol of 10 (Method C). Method A, 182 mg (60%), colorless crystals, m.p. 208−211 °C (Et2O) (ref. [44], m.p. 210 °C (decomp.)), [α]D20 = −241.9 (c = 0.42, CHCl3) (ref. [44], [α]D20−267.6 (c = 1.00, MeOH)); Methods B and C: no formation of 1l was observed. 1H NMR (600 MHz, CDCl3): δ 1.52–1.58 (m, 2 H), 1.82–1.96 (m, 4 H), 1.94, 2.03 (2 s, 6 H each, 4 Me), 2.09–2.14 (m, 2 H), 4.31 (mc, 2 H), 8.56 (s, 2 H, 2 C(2)H).
(R,R)-trans-1,1-(Cyclohexane-1,2-diyl)bis(4,5-diphenylimidazole)-3,3′-dioxide (1m): Following the general protocols 1.1 mmol of 7b and 0.25 mmol of 11 (Methods A and B) or 0.5 mmol of diamine 10 (Method C) were used. Method A, 265 mg (48%), colorless crystals, m.p. 210−212 °C (Et2O) (ref. [44], m.p. 209 °C (decomp.)), [α]D20 = −21.0 (c = 0.40, CHCl3) (ref. [44], [α]D20 = +6.0 (c = 1.02, MeOH)). Methods B and C: no formation of 1m was observed. 1H NMR (600 MHz, CDCl3): δ 1.28–2.48 (m, 8 H), 4.04 (mc, 2 H), 7.05–7.41, 7.48–7.56 (2 m, 14 H, 6 H), 8.23 (s, 2 H, 2 C(2)H).

3.2.2. Synthesis of Enolizable Imidazole 2-Thiones 13a–13d

Method D: To a stirred solution of imidazole N-oxide 1 (0.5 mmol) in CH2Cl2 (2 mL), a solution of 2,2,4,4-tetramethylcyclobutane-1,3-dithione (12, 0.26 mmol) in CH2Cl2 (2 mL) was added at room temperature, and stirring was continued until the red color of the thioketone faded (typically ca. 10 min). After the solvent was removed in vacuo, the residue was triturated with petroleum ether (10 mL), and the crystalline imidazole-2-thione 13 was filtered and washed with additional portions of petroleum ether (2 × 3 mL) to give spectroscopically pure product.
Method E: A mixture of imidazole N-oxide 1 (0.5 mmol), dithione 12 (0.26 mmol), and a zirconium ball (∅ 5.0 mm) were placed in the zirconium mechanochemical vial and the mixture was ball-milled for 3 h at 25 Hz. The resulting material was triturated with petroleum ether (10 mL), and the crystalline precipitate of product 13 was filtered and washed with two portions of petroleum ether (2 × 3 mL).
4,5-Dimethyl-1-phenyl-1H-imidazole-2(3H)-thione (13a): Method D, 170 mg (91%), colorless solid, m.p. 225−227 °C (decomp.); Method E, 179 mg (96%). 1H NMR (600 MHz, DMSO-d6): δ 1.78, 2.03 (2 s, 3 H each, 2 Me), 7.28–7.30, 7.42–7.52 (2 m, 2 H, 3 H), 12.08 (s, 1 H, NH). 13C NMR (150 MHz, DMSO-d6): δ 8.9, 9.4, 119.6, 121.3, 128.4, 128.5, 129.0, 136.6, 160.7. IR (neat): v 3164, 3053, 2922, 2706, 1662, 1593, 1495, 1435, 1383, 1353, 1215, 1032, 805, 756 cm–1. ESI-MS (m/z): 227 (100, [M+H2O+Na]+).
1,4,5-Triphenyl-1H-imidazole-2(3H)-thione (13b): Method D, 312 mg (95%), colorless solid, m.p. 240−242 °C (decomp.); Method E, 262 mg (80%). 1H NMR (600 MHz, DMSO-d6): δ 7.15–7.39 (m, 15 H, 3 Ph), 13.04 (s, 1 H, NH). 13C NMR (150 MHz, DMSO-d6): δ 125.0, 126.7*, 127.4, 127.8, 128.1, 128.2, 128.53, 128.55, 128.6, 128.7, 128.8, 129.2, 130.9, 136.3, 163.0; *higher intensity. IR (neat): v 3041, 2915, 2732, 1595, 1491, 1371, 1260, 1178, 1070, 1025, 917, 831, 764 cm–1. ESI-MS (m/z): 351 (82, [M+Na]+), 329 (100, [M+H]+).
1-(4-Methoxyphenyl)-4,5-dimethyl-1H-imidazole-2(3H)-thione (13c): Method E, 108 mg (46%), colorless solid, m.p. 227−229 °C (decomp.). 1H NMR (600 MHz, DMSO-d6): δ 1.77, 2.02 (2 s, 3 H each, 2 Me), 3.80 (s, 3 H, OMe), 7.02–7.04, 7.17–7.19 (2 m, 2 H each), 12.02 (s, 1 H, NH). 13C NMR (150 MHz, DMSO-d6): δ 8.8, 9.4, 55.4, 114.1, 119.3, 121.6, 129.2, 129.6, 158.8, 160.8. IR (neat): v 1513, 1439, 1387, 1337, 1301, 1242, 1226, 1170, 1103, 1029, 999 cm–1. ESI-MS (m/z): 257 (58, [M+Na]+), 235 (100, [M+H]+), 203 (98).
1-(4-Fluorophenyl)-4,5-dimethyl-1H-imidazole-2(3H)-thione (13d): Method E, 100 mg (45%), colorless solid, m.p. 251−254 °C (decomp.). 1H NMR (600 MHz, DMSO-d6): δ 1.79, 2.03 (2 s, 3 H each, 2 Me), 7.32–7.37 (m, 4 H), 12.11 (s, 1 H, NH). 13C NMR (150 MHz, DMSO-d6): δ 8.8, 9.3, 115.9 (d, 2JC-F = 23.0 Hz), 119.6, 121.4, 130.7 (d, 3JC-F = 8.8 Hz), 132.8 (d, 4JC-F = 3.0 Hz), 160.9, 161.5 (d, 1JC-F = 245.3 Hz). 19F NMR (565 MHz, DMSO-d6): δ −113.3 (mc). IR (neat): v 3168, 3060, 2922, 2713, 1666, 1506, 1397, 1357, 1244, 1222, 1148, 1088, 1006, 846, 782 cm–1. ESI-MS (m/z): 245 (55, [M+Na]+), 223 (100, [M+H]+).

3.2.3. Synthesis of N-benzyloxy-imidazolium Salts 14a[PF6]–14d[PF6]

Method F: A solution of imidazole N-oxide 1 (1.0 mmol) and benzyl bromide (205 mg, 1.2 mmol) in CHCl3 (1 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was washed with few portions of Et2O (3 × 5 mL). The resulting crude imidazolium bromide was dissolved in EtOH (2 mL) and a solution of NH4PF6 (196 mg, 1.2 mmol) in distilled water (1 mL) was added dropwise under vigorous stirring. After 5 min, the crystalline product 14[PF6] was filtered and dried under reduced pressure.
Method G: Imidazole N-oxide 1 (1.0 mmol), benzyl bromide (205.2 mg, 1.2 mmol), solid NH4PF6 (196 mg, 1.2 mmol), and a zirconium ball (∅ 5.0 mm) were placed in a mechanochemical vial and the mixture was ball-milled for 0.5 h at 25 Hz. The resulting material was dissolved in CH2Cl2 (5 mL), filtered, the solvent was removed, and the product 14[PF6] was washed with Et2O (4 × 5 mL) followed by drying under reduced pressure.
3-Benzyloxy-4,5-dimethyl-1-phenylimidazolium hexafluorophosphate (14a[PF6]): Method F, 322 mg (76%), colorless crystals, m.p. 160−163 °C (EtOH/H2O); Method G, 305 mg (72%). 1H NMR (600 MHz, DMSO-d6): δ 2.14, 2.26 (2 s, 3 H each, 2 Me), 5.52 (s, 2 H, Bn), 7.48–7.52, 7.56–7.58, 7.62–7.70 (3 m, 3 H, 2 H, 5 H), 9.96 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 6.8, 8.7, 83.6, 124.5, 124.9, 126.2, 128.9, 130.1, 130.2, 130.5, 130.7, 132.1 (br)*, 132.2, 133.2; *broadened absorption of C(2). IR (neat): ν 3161, 1607, 1539, 1498, 1461, 1424, 1372, 1331, 1208, 1111, 824, 760, 697 cm–1. ESI-MS (m/z): 279 (100, [M−PF6]+). Elemental analysis for C18H19F6N2OP (424.11): calculated C 50.95, H 4.51, N 6.60; found, C 50.67, H 4.53, N 6.74.
3-Benzyloxy-1,4,5-triphenylimidazolium hexafluorophosphate (14b[PF6]). Method F, 520 mg (95%), colorless crystals, m.p. 219−221 °C (EtOH/H2O); Method G, 356 mg (65%). 1H NMR (600 MHz, DMSO-d6): δ 5.35 (s, 2 H, Bn), 7.22–7.27, 7.33–7.46, 7.49–7.59 (3 m, 4 H, 11 H, 5 H), 10.41 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 84.1, 123.1, 124.4, 128.1, 128.9, 129.0, 129.2, 129.2, 129.4, 129.7, 130.09, 130.12, 130.25, 130.29, 130.5, 131.0, 131.6, 133.8 (br), 133.9. IR (neat): ν 3153, 1539, 1510, 1450, 1372, 1238, 1159, 891, 764, 697 cm–1. ESI-MS (m/z): 421 (100, [M+H2O−PF6]+).
3-Benzyloxy-1-(4-methoxyphenyl)-4,5-dimethylimidazolium hexafluorophosphate (14c[PF6]): Method F, 286 mg (63%), colorless crystals, m.p. 172−173 °C (EtOH/H2O); Method G, 285 mg (65%). 1H NMR (600 MHz, DMSO-d6): δ 2.11, 2.25 (2 s, 3 H each, 2 Me), 3.85 (s, 3 H, OMe), 5.49 (s, 2 H, Bn), 7.18–7.21, 7.48–7.57 (2 m, 2 H, 7 H) 9.83 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 6.8, 8.6, 55.8, 83.6, 115.0, 124.2, 125.2, 125.8, 127.7, 128.9, 130.2, 130.5, 132.1 (br), 132.2, 160.6. IR (neat): ν 3165, 1539, 1510, 1454, 1379, 1305, 1249, 1208, 1174, 1036, 951, 913, 828 cm–1. ESI–MS (m/z): 309 (100, [M−PF6]+). Elemental analysis for C19H21F6N2O2P (454.1): calculated, C 50.23, H 4.66, N 6.17; found, C 50.06, H 4.66, N 6.39.
3-Benzyloxy-1-(4-methoxyphenyl)-4,5-diphenylimidazolium hexafluorophosphate (14d[PF6]): Method F, 491 mg (85%), colorless crystals, m.p. 223−225 °C (EtOH/H2O); Method G, 474 mg (82%). 1H NMR (600 MHz, DMSO-d6): δ 3.78 (s, 3 H, OMe), 5.32 (s, 2 H, Bn), 7.05–7.08, 7.21–7.26, 7.33–7.35, 7.37–7.46, 7.49–7.55 (5 m, 2 H, 4 H, 2 H, 8 H, 3 H), 10.28 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 56.7, 84.0, 114.7, 123.2, 124.6, 125.9, 127.99, 128.02, 128.8, 128.9, 129.0, 129.4, 130.06, 130.13, 130.2, 130.3, 130.5, 131.0, 131.6, 133.6 (br), 160.4. IR (neat): ν 3159, 1513, 1446, 1383, 1301, 1252, 1215, 1174, 1067, 960, 828, 764, 697 cm–1. ESI–MS (m/z): 433 (100, [M−PF6]+). Elemental analysis for C29H25F6N2O2P (578.2): calculated, C 60.21, H 4.36, N 4.84; found, C 60,21, H 4.39, N 4.99.
3-Benzyloxy-1-(4-fluorophenyl)-4,5-dimethylimidazolium hexafluorophosphate (14e[PF6]): Method F, 349 mg (79%), colorless crystals, m.p. 178−180 °C (EtOH/H2O); Method G, 367 mg (83%). 1H NMR (600 MHz, DMSO-d6): δ 2.13, 2.26 (2 s, 3 H each, 2 Me), 5.50 (s, 2 H, Bn), 7.48–7.58, 7.70–7.73 (2 m, 7 H, 2 H), 9.91 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 6.7, 8.6, 83.7, 117.0 (d, 2JC–F = 23.4 Hz), 124.4, 125.2, 128.9 (d, 3JC–F = 9.4 Hz), 129.0, 129.5 (d, 4JC–F = 3.0 Hz), 130.2, 130.5, 132.2, 132.4 (br), 162.9 (d, 1JC–F = 248.4 Hz). 19F NMR (565 MHz, CDCl3): δ−70.1 (d, 1JP–F = 711.0 Hz, PF6),−109.9 (mc, C-F). IR (neat): ν 3166, 1547, 1510, 1372, 1238, 1215, 1160, 1103, 947, 910, 828, 757, 701 cm–1. ESI–MS (m/z): 297 (100, [M−PF6]+). Elemental analysis for C18H18F7N2OP (442.1): calculated, C 48.88, H 4.10, N 6.33; found, C 48.66, H 4.11, N 6.56.
3-Benzyloxy-1-(4-fluorophenyl)-4,5-diphenylimidazolium hexafluorophosphate (14f[PF6]): Method F, 402 mg (71%), colorless crystals, m.p. 225−227 °C (EtOH/H2O); Method G, 379 mg (67%). 1H NMR (600 MHz, DMSO-d6): δ 5.33 (s, 2 H, Bn), 7.21–7.27, 7.33–7.36, 7.38–7.46, 7.49–7.57 (4 m, 4 H, 2 H, 8 H, 5 H), 10.37 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 84.1, 116.8 (d, 2JC-F = 23.6 Hz), 123.1, 124.4, 128.1, 128.86, 128.88, 129.1, 129.2 (d, 3JC–F = 9.4 Hz), 129.3, 129.6 (d, 4JC-F = 2.8 Hz), 130.0, 130.1, 130.2, 130.3, 130.5, 131.0, 131.5, 133.9 (br), 162.6 (d, 1JC–F = 248.8 Hz). 19F NMR (565 MHz, CDCl3): δ−70.1 (d, 1JP–F = 711.6 Hz, PF6), −109.8 (mc, C–F). IR (neat): ν 3153, 1543, 1510, 1449, 1238, 1159, 831, 764, 701 cm–1. ESI–MS (m/z): 421 (100, [M−PF6]+). Elemental analysis for C28H22F7N2OP (566.1): calculated, C 59.37, H 3.91, N 4.95; found, C 59.28, H 3.98, N 5.22.

3.2.4. Synthesis of Non-Enolizable Imidazole-2-thiones 15 and 18 via Sulfurization of an Intermediate Carbene

Method H: To a solution of imidazolium salt 14c[PF6] or 17b[PF6] (1.0 mmol), elemental sulfur (70.4 mg, 2.4 mmol) in anhydrous pyridine (3 mL), Et3N (0.15 mL, 1.1 mmol) was added dropwise and the mixture was stirred overnight under inert atmosphere of Ar. After solvents were removed in vacuo, the resulting material was purified by preparative thin-layer chromatography (PLC: SiO2, CH2Cl2/MeOH 98:2) to give non-enolizable imidazole-2-thione 15 or 18, respectively.
MethodI: Imidazolium salt 14c[PF6] or 17b[PF6] (1.0 mmol), elemental sulfur (70.4 mg, 2.4 mmol), solid K2CO3 (415 mg, 3.0 mmol), and a zirconium ball (∅ 5.0 mm) were placed in a mechanochemical vial and the mixture was ball-milled for 3 h at 25 Hz. The resulting crude product 15 or 18, respectively, was purified on PLC as described for Method H.
1-Benzyloxy-3-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole-2(3H)-thione (15). Method H, 228 mg (67%), colorless oil; Method I, 146 mg (43%). 1H NMR (600 MHz, CDCl3): δ 1.80, 1.87 (2 s, 3 H each, 2 Me), 3.83 (s, 3 H, OMe), 5.46 (s, 2 H, Bn), 6.98–7.01, 7.19–7.22, 7.37–7.39, 7.51–7.53 (4 m, 2 H, 2 H, 3 H, 2 H). 13C NMR (151 MHz, CDCl3): δ 7.7, 9.8, 55.5, 78.1, 114.7, 118.5, 120.0, 128.63, 128.65, 129.3, 129.6, 130.4, 134.1, 158.3, 159.8. IR (neat): ν 2933, 2836, 1673, 1606, 1550, 1510, 1442, 1410, 1297, 1245, 1170, 1110, 1021, 831 cm–1. ESI–MS (m/z): 341 (100, [M+H]+).
1-Benzyl-3-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole-2(3H)-thione (18). Method H, 91 mg (28%), colorless oil; Method I, 176 mg (54%). 1H NMR (600 MHz, CDCl3): δ 1.86, 2.01 (2 s, 3 H each, 2 Me), 3.84 (s, 3 H, OMe), 5.43 (s, 2 H, Bn), 7.00–7.03, 7.23–7.27, 7.30–7.35 (3 m, 2 H, 3 H, 4 H). 13C NMR (151 MHz, CDCl3): δ 9.6, 9.8, 48.8, 55.5, 114.7, 121.5, 122.2, 127.3, 127.6, 128.7, 129.5, 129.9, 136.6, 159.7, 163.6. IR (neat): ν 1517, 1442, 1387, 1342, 1301, 1252, 1167, 1099, 1029, 995 cm–1. ESI-MS (m/z): 347 (100, [M+Na]+), 325 (26, [M+H]+).

3.2.5. Synthesis of 1,4,5-trisubstituted Imidazoles 16

To a solution of imidazole N-oxide 1 (1.0 mmol) in MeOH (2 mL) was added excess freshly prepared Raney nickel at room temperature and the vigorous stirring was continued until the starting N-oxide was fully consumed (typically ca. 30 min; TLC monitoring: SiO2, AcOEt/MeOH 1:1). The resulting mixture was filtered through a short pad of Celite® and the solvent was removed under reduced pressure to give spectroscopically pure imidazole 16. Solid products were recrystallized from a hexane/Et2O mixture.
1,4,5-Triphenyl-1H-imidazole (16a): 129 mg (64%); colorless crystals, m.p. 175–178 °C (Et2O/hexane). 1H NMR (600 MHz, CDCl3): δ 7.10–7.21, 7.24–7.29, 7.31–7.34, 7.53–7.55 (4 m, 5 H, 5 H, 3 H, 2 H), 7.78 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 126.0, 126.8, 127.4, 128.1, 128.25, 128.33, 128.7, 128.8, 129.4, 130.3, 131.0, 134.6, 136.6, 137.5, 139.1. IR (neat): ν 3112, 3056, 1599, 1502, 1442, 1371, 1271, 1245, 1129, 1074, 1025, 951, 913 cm–1. ESI-MS (m/z): 297 (100, [M+H]+).
1-(4-Methoxyphenyl)-4,5-dimethyl-1H-imidazole (16b): 145 mg (72%); brown oil. 1H NMR (600 MHz, CDCl3): δ 2.04, 2.21 (2 s, 3 H each, 2 Me), 3.84 (s, 3 H, OMe), 6.95–6.98, 7.15–7.17 (2 m, 2 H each), 7.46 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 9.1, 12.8, 55.7, 114.6, 123.4, 127.1, 129.9, 133.8, 135.3, 159.4. IR (neat): ν 2922, 2840, 1707, 1610, 1513, 1446, 1297, 1245, 1170, 1107, 1029, 943, 835, 801, 716, 671 cm–1. ESI-MS (m/z): 203 (100, [M+H]+).
1-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (16c): 326 mg (58%); colorless crystals, m.p. 182–184 °C (Et2O/hexane). 1H NMR (600 MHz, CDCl3): δ 3.79 (s, 3 H, OMe), 6.81–6.84, 7.03–7.05, 7.14–7.20, 7.23–7.29, 7.52–7.54 (5 m, 2 H, 2 H, 3 H, 5 H, 2 H), 7.73 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ 55.6, 114.4, 126.7, 127.26, 127.32, 128.2, 128.3, 128.7, 129.1, 129.5, 130.3, 130.9, 134.6, 137.7, 138.7, 159.2. IR (neat): ν 3041, 2956, 2904, 2836, 1886, 1599, 1530, 1439, 1301, 1249, 1174, 1111, 1070, 1029, 925, 917, 839, 772, 719 cm–1. ESI-MS (m/z): 327 (100, [M+H]+). Elemental analysis for C22H18N2O (326.1): calculated, C 80.96, H 5.56, N 8.58; found, C 80.75, H 5.76, N 8.41.
1-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole (16d): 314 (79%); colorless crystals, m.p. 172–173 °C (Et2O/hexane). 1H NMR (600 MHz, CDCl3): δ 7.00–7.04, 7.08–7.11, 7.13–7.15, 7.19–7.21, 7.24–7.31, 7.52–7.54 (6 m, 2 H, 2 H, 2 H, 1 H, 5 H, 2 H), 7.75 (s, 1 H, C(2)H). 13C NMR (151 MHz, CDCl3): δ116.4 (d, 2JC–F = 23.0 Hz), 126.9, 127.3, 127.7 (d, 3JC–F = 8.7 Hz), 128.36, 128.40, 128.8, 128.9, 130.0, 130.9, 132.7 (d, 4JC–F = 3.3 Hz), 134.4, 137.5, 139.1, 162.0 (d, 1JC–F = 248.5 Hz). 19F NMR (565 MHz, CDCl3): δ −113.0 (mc). IR (neat): ν 3064, 1599, 1510, 1485, 1372, 1219, 1185, 1101, 1066, 1025, 980, 910, 835, 809, 764, 695 cm–1. ESI-MS (m/z): 315 (110, [M+H]+). Elemental analysis for C21H15FN2 (314.1): calculated, C 80.24, H 4.81, N 8.91; found, C 80.14, H 4.79, N 8.94.

3.2.6. Synthesis of N-benzyl-imidazolium Salts 17a[PF6]–17d[PF6]

A mixture of imidazole 16 (1.0 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) in MeCN (2 mL) was placed in a closed vessel and heated in a microwave reactor at 110 °C for 3 h. The mixture was cooled to room temperature, the solvent was removed and the resulting material was washed with Et2O (4 × 5 mL). The obtained crude imidazolium bromide was dissolved in EtOH (2 mL) and a solution of NH4PF6 (196 mg, 1.2 mmol) in distilled water (1 mL) was added dropwise under vigorous stirring. After 5 min, the precipitate of 17[PF6] was filtered and dried under reduced pressure.
1-Benzyl-3,4,5-triphenylimidazolium hexafluorophosphate (17a[PF6]): 425 mg (80%); colorless crystals, m.p. 224–227 °C (EtOH/H2O). 1H NMR (600 MHz, DMSO-d6): δ 5.45 (s, 2 H, Bn), 7.13–7.20, 7.22–7.34, 7.39–7.58 (3 m, 4 H, 8 H, 8 H), 9.97 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 50.7, 124.9, 125.0, 126.5, 127.9, 128.49, 128.51, 128.7, 128.9, 129.7, 129.8, 130.35, 130.36, 130.7, 130.9, 131.4, 132.0, 133.70, 133.73, 137.1 (br). IR (neat): ν 1595, 1558, 1498, 1450, 1353, 1219, 1170, 1081, 1025, 924, 831, 764, 705 cm–1. ESI-MS (m/z): 387 (100, [M−PF6]+).
1-Benzyl-3-(4-methoxyphenyl)-4,5-dimethylimidazolium hexafluorophosphate (17b[PF6]): 399 mg (91%); colorless crystals, m.p. 170–171 °C (EtOH/H2O). 1H NMR (600 MHz, DMSO-d6): δ 2.11, 2.19 (2 s, 3 H each, 2 Me), 3.85 (s, 3 H, OMe), 5.47 (s, 2 H, Bn), 7.18–7.21, 7.39–7.46, 7.58–7.61 (3 m, 2 H, 5 H, 2 H), 9.49 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 8.2, 8.6, 49.9, 55.8, 115.0, 126.2, 126.6, 127.7, 127.9, 128.0, 128.6, 129.1, 134.1, 135.7 (br), 160.5. IR (neat): ν 3168, 1562, 1517, 1454, 1359, 1305, 1256, 1236, 1197, 1167, 1109, 1033, 831, 749, 711 cm–1. ESI-MS (m/z): 293 (100, [M−PF6]+).
1-Benzyl-3-(4-methoxyphenyl)-4,5-diphenylimidazolium hexafluorophosphate (17c[PF6]): 444 mg (79%); colorless crystals, m.p. 173–175 °C (EtOH/H2O). 1H NMR (600 MHz, DMSO-d6): δ 3.78 (s, 3 H, OMe), 5.44 (s, 2 H, Bn), 7.04–7.07, 7.14–7.17, 7.23–7.32, 7.38–7.48 (4 m, 2 H, 4 H, 8 H, 5 H), 9.90 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 50.7, 55.7, 114.8, 125.0, 125.2, 126.4, 127.9, 128.0, 128.5, 128.6, 128.8, 129.0, 129.8, 130.4, 130.8, 131.0, 131.3, 132.3, 133.9, 137.1 (br), 160.3. IR (neat): ν 316, 1554, 1513, 1454, 1223, 1182, 1161, 1077, 1018, 941, 824, 760, 697 cm–1. ESI-MS (m/z): 417 (100, [M−PF6]+).
1-Benzyl-3-(4-fluorophenyl)-4,5-diphenylimidazolium hexafluorophosphate (17d[PF6]): 500 mg (91%); colorless oil (EtOH/H2O). 1H NMR (600 MHz, DMSO-d6): δ 5.44 (s, 2 H, Bn), 7.12–7.18, 7.22–7.25, 7.28–7.32, 7.36–7.40, 7.44–7.46, 7.58–7.62 (6 m, 4 H, 2 H, 6 H, 4 H, 1 H, 2 H), 9.90 (s, 1 H, C(2)H). 13C NMR (151 MHz, DMSO-d6): δ 51.1, 116.9 (d, 2JC–F = 23.4 Hz), 125.09, 125.11, 126.8, 128.2, 128.4, 128.8, 129.0, 129.2, 129.4 (d, 3JC–F = 9.3 Hz), 130.2, 130.3 (d, 4JC–F = 3.0 Hz), 130.7, 131.1, 131.2, 131.7, 132.6, 133.9, 137.4 (br), 162.8 (d, 1JC–F = 248.5 Hz). IR (neat): ν 3023, 2255, 2125, 1715, 1551, 1513, 1446, 1223, 1159, 1051, 1025, 962, 839, 760, 701 cm–1. ESI-MS (m/z): 405 (100, [M−PF6]+).

4. Conclusions

The presented results demonstrate that 2-unsubstituted imidazole N-oxides, including less known 1-aryl derivatives, are accessible by a mechanochemical approach, and their syntheses can be carried out as two- or three-component reactions. Both methods led to the expected products, but higher yields were achieved starting with formaldimines and α-hydroxyiminoketones (two-component reaction). Remarkably, in none of the cases was undesired isomerization of the N-oxide function into imidazol-2-one group observed. The obtained 1-arylimidazole N-oxides are versatile building blocks and undergo typical reactions characteristic for this class of imidazole derivatives. For example, they can be converted into enolisable imidazole-2-thiones via sulfur-transfer reaction as well as into non-enolisable imidazole-2-thiones by sulfurization of in situ-generated imidazol-2-ylidenes. The latter reaction can be successfully performed both in pyridine-Et3N solution and by ball-milling in the presence of solid K2CO3 as a base. Taking into account the wide applicability of 2-unsubstituted imidazole N-oxides, the devised solvent-free mechanochemical approach offers an alternative method for their environmentally friendly preparation.

Author Contributions

Conceptualization and methodology, G.M., H.H. and E.O.; software, E.O. and M.J.; investigation, M.C., D.D. and E.O.; writing—original draft preparation, G.M. and M.J.; writing—review and editing, G.M., H.H. and M.J.; supervision, G.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Science Centre (Cracow, Poland) in the framework of a Beethoven-2 project (G.M.; grant no. 2016/23/G/ST5/04115/1).

Data Availability Statement

All the digital experimental data and samples of new materials are available from the authors.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 00589 sch001
Scheme 1. Exemplary transformations of 2-unsubstituted imidazole N-oxides 1 proceeding via initial (3+2)-cycloadditions and leading to imidazole-2-thiones 2 [15], aryl(imidazol-2-yl)acetates 3 [17], 2-(dicyanomethylidene)imidazoles 4 [18], (imidazol-2-yl)acetates 5 [19] and (imidazol-2-ylidene)acetonitriles 6 [20] as final products.
Scheme 1. Exemplary transformations of 2-unsubstituted imidazole N-oxides 1 proceeding via initial (3+2)-cycloadditions and leading to imidazole-2-thiones 2 [15], aryl(imidazol-2-yl)acetates 3 [17], 2-(dicyanomethylidene)imidazoles 4 [18], (imidazol-2-yl)acetates 5 [19] and (imidazol-2-ylidene)acetonitriles 6 [20] as final products.
Catalysts 12 00589 sch001
Catalysts 12 00589 sch002
Scheme 2. Synthesis of N(1)-alkyl and N(1)-aryl-functionalized 2-unsubstituted imidazole N(3)-oxides 1 and some selected transformations under ball-milling mechanochemical conditions reported herein.
Scheme 2. Synthesis of N(1)-alkyl and N(1)-aryl-functionalized 2-unsubstituted imidazole N(3)-oxides 1 and some selected transformations under ball-milling mechanochemical conditions reported herein.
Catalysts 12 00589 sch002
Catalysts 12 00589 sch003
Scheme 3. Two- and three-component syntheses of 2-unsubstituted imidazole N-oxides 1a–1i in solution (Method A) and under mechanochemical activation (Methods B and C).
Scheme 3. Two- and three-component syntheses of 2-unsubstituted imidazole N-oxides 1a–1i in solution (Method A) and under mechanochemical activation (Methods B and C).
Catalysts 12 00589 sch003
Catalysts 12 00589 sch004
Scheme 4. Attempted mechanochemical syntheses of chiral imidazole N-oxides 1j–1m derived from (R)-α-methylbenzylamine (9) and (R,R)-1,2-diaminocyclohexane (10) in two- and three-component experiments.
Scheme 4. Attempted mechanochemical syntheses of chiral imidazole N-oxides 1j–1m derived from (R)-α-methylbenzylamine (9) and (R,R)-1,2-diaminocyclohexane (10) in two- and three-component experiments.
Catalysts 12 00589 sch004
Catalysts 12 00589 sch005
Scheme 5. Application of selected N-aryl imidazole N-oxides 1c–e,h in wet (Method D) and solvent-free mechanochemical (Method E) sulfur-transfer reaction, respectively, leading to imidazole-2-thiones 13a–13d.
Scheme 5. Application of selected N-aryl imidazole N-oxides 1c–e,h in wet (Method D) and solvent-free mechanochemical (Method E) sulfur-transfer reaction, respectively, leading to imidazole-2-thiones 13a–13d.
Catalysts 12 00589 sch005
Catalysts 12 00589 sch006
Scheme 6. O-Benzylation of N(1)-arylated imidazole N(3)-oxides 1 with benzyl bromide, subsequent ion-exchange in resulting bromides using NH4PF6, and sulfurization of the imidazole ring in hexafluorophosphate 14c[PF6] leading to non-enolisable imidazole-2-thione 15.
Scheme 6. O-Benzylation of N(1)-arylated imidazole N(3)-oxides 1 with benzyl bromide, subsequent ion-exchange in resulting bromides using NH4PF6, and sulfurization of the imidazole ring in hexafluorophosphate 14c[PF6] leading to non-enolisable imidazole-2-thione 15.
Catalysts 12 00589 sch006
Catalysts 12 00589 sch007
Scheme 7. Three-step synthesis of imidazolium salts 17[PF6] via deoxygenation of imidazole N-oxides 1 with Raney-Ni and subsequent N-benzylation of the resulting imidazoles 16 followed by the ion-exchange in bromides 17.
Scheme 7. Three-step synthesis of imidazolium salts 17[PF6] via deoxygenation of imidazole N-oxides 1 with Raney-Ni and subsequent N-benzylation of the resulting imidazoles 16 followed by the ion-exchange in bromides 17.
Catalysts 12 00589 sch007
Catalysts 12 00589 sch008
Scheme 8. Sulfurization of the intermediate imidazol-2-ylidene derived from imidazolium salt 17b[PF6] leading to imidazole-2-thione 18.
Scheme 8. Sulfurization of the intermediate imidazol-2-ylidene derived from imidazolium salt 17b[PF6] leading to imidazole-2-thione 18.
Catalysts 12 00589 sch008
Table 1. Synthesis of imidazole N-oxides 1a–1i by using Methods A-C: Scope of substrates a.
Table 1. Synthesis of imidazole N-oxides 1a–1i by using Methods A-C: Scope of substrates a.
ProductR1R2Method (Yield [%])
1aBnMeA (65)
B (92)
C (66)
1bBnPhA (62)
B (92)
C (83)
1cPhMeA (91)
B (79)
C (70)
1dPhPhA (96)
B (96)
C (78)
1ep-MeOC6H4MeA (49)
B (57)
C (79)
1fp-MeOC6H4PhA (68)
B (59)
C (70)
1gp-BrC6H4MeA (42)
B (39)
C (64) b
1hp-FC6H4MeA (82)
B (78)
C (87)
1ip-FC6H4PhA (34)
B (58)
C (87)
a Reaction conditions–Method A: α-hydroxyiminoketone 7 (1.1 mmol), formaldimine 8 (1.0 mmol), AcOH (3.0 mL), r.t., 12 h; Method B: α-hydroxyiminoketone 7 (1.1 mmol), formaldimine 8 (1.0 mmol), AcOH (0.1 mL), ball-milling (25 Hz), r.t., 20 min; Method C: α-hydroxyiminoketone 7 (1.1 mmol), amine (1.0 mmol), paraformaldehyde (1.2 mmol), AcOH (0.1 mL), ball-milling (25 Hz), r.t., 45 min. b Reaction time 30 min.
Table 2. Synthesis of alkoxy-imidazolium salts of type 14[PF6] and the sulfurization of 14c[PF6]; comparison of mechanochemical (Methods G and I) approaches with reactions in solution (Methods F and H) a.
Table 2. Synthesis of alkoxy-imidazolium salts of type 14[PF6] and the sulfurization of 14c[PF6]; comparison of mechanochemical (Methods G and I) approaches with reactions in solution (Methods F and H) a.
ProductR1R2Method (Yield [%])
14a[PF6]PhMeF (76)
G (72)
14b[PF6]PhPhF (95)
G (65)
14c[PF6]p-MeOC6H4MeF (63)
G (65)
14d[PF6]p-MeOC6H4PhF (85)
G (82)
14e[PF6]p-FC6H4MeF (79)
G (83)
14f[PF6]p-FC6H4PhF (71)
G (67)
15p-MeOC6H4MeH (67)
I (43)
a Reaction conditions–Method F: (i) imidazole N-oxide 1 (1.0 mmol), BnBr (1.2 mmol), CHCl3 (1.0 mL), r.t., overnight; (ii) NH4PF6 (1.2 mmol), EtOH/H2O 2:1 (3.0 mL), r.t., 5 min; Method G: imidazole N-oxide 1 (1.0 mmol), BnBr (1.2 mmol), NH4PF6 (1.2 mmol), ball-milling (25 Hz), r.t., 30 min; Method H: imidazolium salt 14 (1.0 mmol), S8 (2.4 mmol), py (3.0 mL), Et3N (0.15 mL), r.t., 16 h; Method I: imidazolium salt 14 (1.0 mmol), S8 (2.4 mmol), K2CO3 (3.0 mmol), ball-milling (25 Hz), 3 h.
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Mlostoń, G.; Celeda, M.; Heimgartner, H.; Duda, D.; Obijalska, E.; Jasiński, M. Synthesis and Selected Transformations of 2-Unsubstituted Imidazole N-Oxides Using a Ball-Milling Mechanochemical Approach. Catalysts 2022, 12, 589. https://doi.org/10.3390/catal12060589

AMA Style

Mlostoń G, Celeda M, Heimgartner H, Duda D, Obijalska E, Jasiński M. Synthesis and Selected Transformations of 2-Unsubstituted Imidazole N-Oxides Using a Ball-Milling Mechanochemical Approach. Catalysts. 2022; 12(6):589. https://doi.org/10.3390/catal12060589

Chicago/Turabian Style

Mlostoń, Grzegorz, Małgorzata Celeda, Heinz Heimgartner, Damian Duda, Emilia Obijalska, and Marcin Jasiński. 2022. "Synthesis and Selected Transformations of 2-Unsubstituted Imidazole N-Oxides Using a Ball-Milling Mechanochemical Approach" Catalysts 12, no. 6: 589. https://doi.org/10.3390/catal12060589

APA Style

Mlostoń, G., Celeda, M., Heimgartner, H., Duda, D., Obijalska, E., & Jasiński, M. (2022). Synthesis and Selected Transformations of 2-Unsubstituted Imidazole N-Oxides Using a Ball-Milling Mechanochemical Approach. Catalysts, 12(6), 589. https://doi.org/10.3390/catal12060589

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