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Article

Lepidiline-Derived Imidazole-2(3H)-Thiones: (3+2)-Cycloadditions vs. Nucleophilic Additions in Reactions with Fluorinated Nitrile Imines

by
Wiktor K. Poper
1,2,
Kamil Świątek
1,2,
Katarzyna Urbaniak
1,
Barbara Olszewska
1 and
Marcin Jasiński
1,*
1
Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, 91403 Łódź, Poland
2
Doctoral School of Exact and Natural Sciences, The University of Lodz, 90237 Łódź, Poland
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(19), 3851; https://doi.org/10.3390/molecules30193851
Submission received: 10 August 2025 / Revised: 8 September 2025 / Accepted: 18 September 2025 / Published: 23 September 2025
(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 3rd Edition)
Browse Figures
Versions Notes

Abstract

Two series of imidazole-2(3H)-thiones inspired by naturally occurring lepidiline alkaloids, bearing either one or two benzyl-type substituents located at the N(1)/N(3) atoms, respectively, were prepared and examined in reactions with in situ generated C-trifluoromethyl-N-aryl nitrile imines. N,N-Dibenzylated imidazole-2-thiones served exclusively as C=S dipolarophiles to afford hitherto unknown CF3-functionalized spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives formed through the (3+2)-cycloaddition pathway. In contrast, the enolizable N-monobenzylated imidazole-2-thiones provided acyclic products, i.e., hydrazonothioates, resulting from nucleophilic addition of the respective en(thio)late onto the C-termini of the 1,3-dipole. The presented results extend the scope of both fluorinated products available via trapping of the in situ generated CF3-nitrile imines as well as synthetic analogues of lepidilines. In addition, spectroscopic analysis of the obtained products and the known related systems revealed 13C NMR chemical shifts attributed to the C-(CF3) atom as useful probes to differentiate the open-chain hydrazonothioates (δ = 112–120), 2,2-diaryl/dialkyl-2,3-dihydro-1,3,4-thiadiazoles (δ = 130–145), and more strained spiro-1,3,4-thiadiazole derivatives (δ = 166–170) reported herein.

Graphical Abstract

1. Introduction

There is increasing interest in the chemistry of imidazole alkaloids recognized as compounds of various structures and numerous roles in biological processes, and in certain cases, they are applied for medicinal needs [1,2,3,4]. Although the majority of known imidazole alkaloids originate from marine organisms, terrestrial flora also offer a variety of imidazole-based materials. For example, a lactone-functionalized imidazole alkaloid pilocarpine (1), first isolated from north Brazilian plant Maranham Jaborandi (Pilocarpus microphyllus), is an effective agent for treatment of so-called ‘dry mouth’ (xerostomia) as well as medication to treat glaucoma in order to reduce intraocular pressure (pressure inside the eye) (Figure 1) [5]. Lepidium genome, widely distributed in South America, is considered another valuable source of imidazole-based alkaloids. Thus, non-ionic dimeric structures such as lepidine (2) as well as monomeric lepidinoside A (3a, R = H) and lepidinoside B (3b, R = OMe) functionalized with β-d-galactopyranose moiety were identified as secondary metabolites in annual herb called garden cress (Lepidium sativum) [6,7]. On the other hand, several ionic N,N-dibenzylated imidazolium alkaloids such as lepidiline A and lepidiline C (4a,b; R = H or OMe, respectively) were identified in Maca root (Lepidium meyenii) [8,9,10], a known nutrient food rich in vitamins, minerals, and proteins [11,12].
Notably, natural lepidilines exhibit promising anticancer properties [8], and for this reason, modification of their structures is considered an attractive strategy for the preparation of new bioactive compounds with desired bioactivity profiles. For example, in a series of independent work by Tacke, Kerr, and Tóth groups, lepidiline A demonstrated a suitable starting material for preparation of N-heterocyclic carbene (NHC) complexes with several metal ions, of which silver(I) and gold(I) complexes were demonstrated to be remarkably cytotoxic against ovarian and uterine, as well as breast cancer cells (Figure 1) [13,14,15]. Furthermore, our work demonstrated that introduction of the fluorine atom or fluorinated groups such as CF3 and OCF3 at meta position of the peripheral benzylic substituents in lepidiline [16], as well as functionalization of the central imidazole ring with the SCF3 moiety [17], remarkably amplifies anticancer activity of the parent alkaloid. Hence, further study towards fluorinated lepidilines of various substitution patterns is of general interest.
In a series of recent work, the CF3-functionalized nitrile imines of type 9, formally derived from trifluoroacetonitrile, were demonstrated to be highly useful building blocks to access various fluorinated heterocyclic systems of general importance for pharmaceutical and agrochemical applications (Scheme 1) [18,19,20,21,22]. The mentioned 1,3-dipoles 9 can be easily generated in situ through base-mediated dehydrohalogenation of the respective hydrazonoyl precursors such as bromides 10 [23], and in the presence of suitable dipolarophile, they smoothly undergo Huisgen cycloaddition reactions to give five-membered products. For instance, highly chemo- and regioselective (3+2)-cycloadditions using the C=C (or C≡C), C=N, and the C=S dipolarophilic reaction partners were developed to afford valuable CF3-functionalized pyrazoles [24,25,26,27], 1,2,4-triazoles [28,29,30], and 1,3,4-thiadiazole derivatives [31,32,33], respectively.
Taking into account the unusually high reactivity of the C=S group in 1,3-dipolar cycloaddition reactions (for this reason, thiocarbonyls are often called as superdipolarophiles [34,35]), in continuation of our quest towards fluorinated lepidilines and related imidazole derivatives [36,37,38], the thioxo-functionalized analogues, i.e., enolizable and non-enolizable imidazole-2(3H)-thiones 7 and 8 (Figure 1), respectively, were prepared and examined in reactions with in situ-generated CF3-nitrile imines 9. Here we report different reaction outcomes observed for reactions of the selected imidazole-2-thiones; whereas enolizable substrates of type 7 provided exclusively acyclic products (i.e., hydrazonothioates) formed by nucleophilic addition of the respective thiolates onto the C-termini of the 1,3-dipole, the non-enolizable 1,3-dibenzyl-imidazole-2-thiones 8 afforded solely the expected spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives resulting from the (3+2)-cycloaddition of the 1,3-dipole and the C=S group of dipolarophile 8. The scope and limitations of both developed reactions was also checked.

2. Results and Discussion

The required imidazole-2-thiones 7 and 8 are readily available building blocks that can be prepared using the corresponding nitrone-like 2-unsubstitutied imidazole N-oxides 11 recognized as convenient precursors for various imidazole-based systems [39,40,41]. Following the general protocol depicted in Scheme 2, two selected enolizable imidazole derivatives bearing benzyl (7a) or 3-methoxybenzyl (7b) substituent located at the N(1) of the imidazole ring were prepared through the one-pot telescopic approach starting from the respective benzylamines 12 (see, Supporting Information in Supplementary File S1), by treatment of 12 with solid paraformaldehyde under reflux, followed by acid-induced (in glacial AcOH [36]) condensation of the first formed formaldimines 13 with diacetyl monoxime to give N-oxides 11a and 11b. Sulfur-transfer with 2,2,4,4-tetramethylcyclobutane-1,3-dithione [42] provided the desired enolizable imidazole-2-thiones 7a and 7b, which were isolated in fair overall yield of 53% and 51% (for 3 steps), respectively. With two intermediate imidazole N-oxides 11a and 11b in hand, the non-enolizable series of imidazole-2-thiones 8a–8c was synthesized in a one-pot manner starting with deoxygenation of 11 with Raney-nickel, in MeOH, at room temperature, followed by microwave-activated N-benzylation of the imidazole ring with selected benzyl chlorides (R′ = H or OMe) to give the corresponding imidazolium chlorides 15. Subsequent sulphuration of the in situ-generated N-heterocyclic carbenes derived from salts 15 with elemental sulfur in pyridine afforded desired products of type 8. Also, in this case the overall yield of isolated products 8a, 8b, and 8c was satisfactory (42%, 71%, and 66%, respectively; for three steps from imidazole N-oxides 11).
A series of CF3-nitrile imine precursors, i.e., hydrazonoyl bromides 10, was prepared following the general literature protocols by NBS-mediated bromination [31] of the azomethine group in trifluoroacetaldehyde arylhydrazones [43]. Based on our experience in base-induced in situ generation of nitrile imines 9 and their trapping with dipolarophiles [24,25,26,44,45] as well as other bifunctional reagents in solution [46,47], but also under solvent-free mechanochemical conditions [48,49], the initial experiments were carried out using slight excess imidazole-2-thione 7a (1.2 equiv.), and N-tolyl-functionalized bromide 10a (1.0 mmol) selected as a model precursor, in dry THF solution, in the presence of three-fold excess Et3N (Scheme 3). To our delight, slow consumption of the starting imidazole-2-thione was observed at room temperature, and after overnight stirring, the reaction was complete. Whereas increasing excess of triethylamine to 5 equiv. slightly accelerated the studied transformation, replacement of THF by toluene or by dichloromethane showed no positive effects on the reaction progress. Also, increase in the reaction temperature (THF, up to 65 °C) provided more complex reaction mixtures, presumably due to decomposition of the first formed product. Removal of the solid triethylammonium bromide by filtration followed by purification of the crude products on chromatography column provided solid material, which was recrystallized from petroleum ether/dichloromethane mixture to give colorless crystalline 16a in 52% yield. Whereas the ESI-MS measurements supplemented by combustion analysis confirmed the expected molecular formula as C21H21F3N4S, analysis of spectroscopic data of the isolated material suggested the open-chain structure of 16a (i.e., the respective hydrazonothioate resulting from nucleophilic addition) rather than the isomeric (3+2)-cycloaddition product formed by the attack onto the C=S bond. In particular, in the 13C NMR spectrum of 16a the diagnostic quartet (2JC-F = 37.6 Hz) attributed to the C-(CF3) atom was found at a remarkably higher field of δ = 113.2 in comparison to absorptions observed for typical 2,2-(hetero)diaryl- and 2,2-dialkyl-2,3-dihydro-1,3,4-thiadiazole derivatives, usually between δ = 130–145 [31,32,33].
An analogous result was observed for the reaction of m-methoxybenzyl-functionalized derivative 7b with the model CF3-nitrile imine 9a; also in that case, the corresponding hydrazonothioate 16b was formed as a single product, which was isolated as an analytically pure oil in comparable yield of 55% (Scheme 3). Next, a series of hydrazonoyl bromides 10b–10h was involved into the study and examined in reactions with imidazole-2-thione 7a under standard reaction conditions. In all the experiments, the exclusive thiophilic addition of 7a onto positively charged C atom of the nitrile imine 9 was observed to afford hydrazonothioates 10c–10i in moderate yield (51–63%), irrespectively of the electronic nature of the substituent located at the para position of the N-phenyl group in hydrazonoyl bromide 10.
In continuation of the study, 1,3-dibenzyl-4,5-dimethylimidazole-2-thione (8a) was examined in reaction with model CF3-nitrile imine 9a under the analogous reaction conditions. The consumption of starting materials along with the formation of a single product was observed within 6 h (by TLC monitoring), and after removal of the solvents followed by standard column chromatography, the expected (3+2)-cycloadduct 17a (74%) was isolated as a colorless solid (Scheme 4). The structure of 17a was confirmed on the basis of spectroscopic analysis; for example, in the 1H NMR spectrum, a set of characteristic signals attributed to the C2-symmetric imidazole unit was located at δ = 2.06 (6H, 2 Me) and δ = 5.08 (4H, 2 CH2Ph), while absorptions found at δ = 2.16 (3H, Me) and between δ = 6.55–7.11 (14H) revealed the presence of all three aromatic substituents. More importantly, in the 13C NMR spectrum the diagnostic absorption attributed to the C(2) atom of the 1,3,4-thadiazole ring was found at δ = 167.2 (2JC-F = 33.3 Hz), indicating the formation of a strained system, while absorption at δ = −66.5 in the 19F NMR spectrum denoted the presence of a single CF3 group. Further tests including ESI-MS measurements and combustion analysis confirmed the molecular formula of 17a as C28H27F3N4S and the analytical purity of the sample.
Imidazole-2-thiones bearing one (8b) or two m-methoxybenzyl (8c) groups were also reacted with CF3-nitrile imine 9a to afford (3+2)-cycloadducts rac-17b and 17c, albeit partial decomposition of these products was observed during purification on column, and the spectroscopically pure samples were isolated in lower yield (54% and 50%, respectively). Finally, a series of variously substituted nitrile imines were examined, and in all of the cases the expected spiro products were formed. Notably, the presence of such synthetically useful substituents and functional groups as methoxy, halogens (Cl and Br), ester (OCOPh), as well as strongly electron-withdrawing cyano and nitro moieties were tolerated, and the desired materials 17d–17j were isolated in fair 50–74% yield (Scheme 4).
Some time ago, a series of thiocarbonyl compounds was examined in reactions with CF3-nitrile imines of type 9. Thus, (cyclo)aliphatic [31] and (hetero)aromatic thioketones [32], monomeric thiochalcones [33] as well as perfluorinated secondary thioamides [50] provided the expected 5-membered products, namely 2,2-disubstituted 2,3-dihydro-1,3,4-thiadiazoles, which were fully characterized by spectroscopic methods. In all of these cases, in the 13C NMR spectra the diagnostic absorption attributed to the C(5) atom (q, 2JC-F ≈ 37–43 Hz) linked with the CF3 group was found between δ = 130–145 (Figure 2).
In the present work, the thiourea-type lepidiline analogues 7 and 8 provided different products depending on the substitution pattern; whereas enolizable substrates afforded hydrazonothioates 16, the non-enolizable starting materials yielded solely the corresponding spiro products 17. These structural differences can be observed in the 13C NMR spectra as the analogous quartet signal is either remarkably high-field (unhindered adducts) or down-field shifted (more strained spiro[imidazo-1,3,4-thiadiazoles]), respectively (Figure 2). Thus the 13C NMR absorption of the C(CF3) atom can be considered a useful probe to easily differentiate the type of products formed in reactions between thiocarbonyl compounds and the CF3-nitrile imines.
The formation of hydrazonothioates 16 and spiro (3+2)-cycloadducts 17 also deserve a brief comment; in the former case, the starting enolizable imidazole-2-thione 7 presumably suffer deprotonation under the applied reaction conditions to give highly nucleophilic en(thio)late intermediate A (Scheme 5). The formed anion smoothly adds to the C-termini of the nitrile imine 9 to give B. Subsequent protonation of the negatively charged N atom in nicely stabilized B leads to sterically unhindered product 16. In the case of non-enolizable imidazole-2-thiones 8, no corresponding thiolate anion operates; taking into account known remarkable polarization of the carbon–sulfur bond in imidazole-2-thiones [51], we tentatively propose that the reaction initiates thiophilic addition of nitrile imine onto 8′, leading to zwitterionic intermediate of type C. This first formed adduct undergoes 1,5-ring closure to afford final sterically demanding (3+2)-cycloadduct 17 in a fully regioselective manner.

3. Materials and Methods

3.1. Chemical Synthesis General Methods

Experimental procedures: Solvents and chemicals were purchased and used as received. Products were purified by standard column chromatography (CC) on silica gel (230–400 mesh). Melting points were determined in capillaries with a MEL-TEMP II apparatus (Laboratory Devices, Holliston, MA, USA) or with a Stuart SMP30 apparatus (Bibby Scientific Ltd., Stone, Staffordshire, UK) with automatic temperature monitoring, and are uncorrected. The NMR spectra were taken on a Bruker AVIII instrument (1H at 600 MHz, 13C at 151 MHz, and 19F at 565 MHz) (Bruker BioSpin AG, Fällanden, Switzerland). Chemical shifts are reported relative to solvent residual peaks; for CDCl3: 1H NMR: δ = 7.26, 13C NMR: δ = 77.16 or to CFCl3 (19F NMR: δ = 0.00) used as external standard. The IR spectra were measured with an Agilent Cary 630 FTIR spectrometer (Agilent Technologies, Santa Clara, CA, USA), in neat. MS (ESI) were taken with a Varian 500-MS LC Ion Trap (Varian, Inc., Walnut Creek, CA, USA), and high resolution MS (ESI-TOF) measurements were taken with a Waters Synapt G2-Si mass spectrometer (Waters Corporation, Milford, MA, USA). Combustion analyses were performed with a Vario EL III (Elementar Analysensysteme GmbH, Langenselbold, Germany) instrument.
Starting materials: Hydrazonoyl bromides 10 were prepared by reaction of the corresponding trifluoroacetaldehyde arylhydrazones with NBS, according to general protocol [31], while the required fluoral hydrazones were obtained by condensation of aqueous fluoral hydrate (~75% in H2O) with commercial arylhydrazines [43]. The intermediate imidazole N-oxides 11 were prepared by AcOH-catalyzed condensation of formaldimines with diacetyl monoxime, as described [36]. Sulphuration of the latter imidazole N-oxides was carried out using cyclobutane-derived thioketone according to general report [42].

3.2. General Procedure for Synthesis of Cycloadducts 16 and 17

In a round-bottomed flask equipped with a stirring bar, an imidazole-2-thione 7 or 8 (1.2 mmol) was dissolved in dry THF (5 mL), the hydrazonoyl bromide 10 (1.0 mmol) was added followed by triethylamine (505 mg, 0.7 mL, 5.0 mmol), the flask was covered with a stopper, and the solution was stirred at ambient temperature until the starting hydrazonoyl bromide was fully consumed (TLC monitoring; typically 6 h for reactions of imidazole-thiones 7, and 4 h for symmetric analogues 8). The solvents were removed in vacuo, and the product was isolated via a standard column chromatography (CC) on silica gel (gradient petroleum ether to petroleum ether/CH2Cl2 1:3 for hydrazonothioates 16; gradient hexane to hexane/AcOEt 2:3 for spiro-products 17), and recrystallized from a petroleum ether/dichloromethane mixture (in the case of products 16).
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-tolyl)-ethanehydrazonothioate (16a): colorless crystals, 218 mg (52%), mp 105–106 °C. 1H NMR (600 MHz, CDCl3) δ 1.98, 2.19, 2.32 (3s, 3H each), 5.29 (s, 2H), 6.93–6.95 (m, 2H), 7.12–7.17 (m, 4H), 7.27–7.33 (m, 3H), 11.37 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.6, 12.8, 20.9, 48.4, 113.2 (q, 2JC-F = 37.6 Hz), 114.2, 121.2 (q, 1JC-F = 271.5 Hz, CF3), 126.2, 127.5, 127.9, 129.0, 129.90, 129.92, 132.1, 136.00, 136.01, 140.6. 19F NMR (565 MHz, CDCl3) δ −65.32 (s, CF3). ESI-MS (m/z) 419.5 (100, [M+H]+). IR (neat) v 1569, 1513, 1349, 1256, 1156, 1081 cm−1. Anal. Calcd for C21H21F3N4S (418.5): C 60.27, H 5.06, N 13.39, S 7.66; found: C 60.11, H 5.19, N 13.34, S 7.69.
1-(3-Methoxybenzyl)-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-tolyl)-ethanehydrazonothioate (16b): thick yellow oil, 247 mg (55%). 1H NMR (600 MHz, CDCl3) δ 1.99, 2.19, 2.32, 3.74 (4s, 3H each), 5.26 (s, 2H), 6.47 (mc, 1H), 6.52–6.54 (m, 1H), 6.81–6.83 (m, 1H), 7.12–7.17 (m, 4H), 7.22–7.25 (m, 1H), 11.36 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.6, 12.8, 20.8, 48.3, 55.3, 111.9, 113.19 (q, 2JC-F = 37.6 Hz), 113.21, 114.2, 118.4, 121.1 (q, 1JC-F = 271.6 Hz, CF3), 127.5, 129.8, 129.89, 130.08, 132.1, 136.0, 137.6, 140.6, 160.2. 19F NMR (565 MHz, CDCl3) δ −65.27 (s, CF3). ESI-MS (m/z) 449.4 (100, [M+H]+). IR (neat) v 1599, 1566, 1506, 1446, 1264, 1174, 1122, 1029 cm−1. Anal. Calcd for C22H23F3N4SO (448.5): C 58.92, H 5.17, N 12.49, S 7.15; found: C 58.95, H 5.17, N 12.41, S 7.34.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-metoxyphenyl)-ethanehydrazonothioate (16c): beige crystals, 274 mg (63%), mp 90–92 °C. 1H NMR (600 MHz, CDCl3) δ 1.98, 2.18, 3.79 (3s, 3H each), 5.28 (s, 2H), 6.87–6.89 (m, 2H), 6.93–6.95 (m, 2H), 7.17–7.19 (m, 2H), 7.26–7.33 (m, 3H), 11.33 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.4, 55.8, 112.6 (q, 2JC-F = 37.7 Hz), 114.8, 115.4, 121.2 (q, 1JC-F = 271.4 Hz, CF3), 126.2, 127.4, 128.0, 129.0, 130.0, 135.9, 136.0, 136.8, 155.6. 19F NMR (565 MHz, CDCl3) δ −65.19 (s, CF3). ESI-MS (m/z) 435.3 (100, [M+H]+). IR (neat) v 1562, 1506, 1407, 1331, 1234, 1141, 1096, 1036, 969 cm−1. Anal. Calcd for C21H21F3N4SO (434.5): C 58.05, H 4.87, N 12.90, S 7.38; found: C 58.00, H 4.79, N 12.77, S 7.57.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-phenyl-ethanehydrazonothioate (16d): cream solid, 210 mg (52%), mp 89-91 °C. 1H NMR (600 MHz, CDCl3) δ 1.99, 2.20 (2s, 3H each), 5.29 (s, 2H), 6.93–6.95 (m, 2H), 7.00–7.02 (m, 1H), 7.24–7.27 (m, 2H), 7.28–7.34 (m, 5H), 11.45 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.4, 114.1 (q, 2JC-F = 37.6 Hz), 114.3, 121.1 (q, 1JC-F = 271.8 Hz, CF3), 122.6, 126.2, 127.6, 128.0, 129.1, 129.4, 129.8, 136.0, 136.1, 142.9. 19F NMR (565 MHz, CDCl3) δ −65.53 (s, CF3). ESI-MS (m/z) 405.3 (100, [M+H]+). IR (neat) v 1621, 1547, 1491, 1457, 1402, 1338, 1252, 1148, 1096, 1077 cm−1. Anal. Calcd for C20H19F3N4S (404.5): C 59.39, H 4.74, N 13.85, S 7.93; found: C 59.38, H 4.74, N 13.79, S 8.01.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-chlorophenyl)-ethanehydrazonothioate (16e): colorless solid, 264 mg (60%), mp 114–116 °C (decomp.). 1H NMR (600 MHz, CDCl3) δ 1.99, 2.18 (2s, 3H each), 5.27 (s, 2H), 6.92–6.94 (m, 2H), 7.16–7.19 (m, 2H), 7.27–7.33 (m, 5H), 11.57 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.5, 115.0 (q, 2JC-F = 37.7 Hz), 115.5, 120.9 (q, 1JC-F = 271.9 Hz, CF3), 126.2, 127.5, 127.6, 128.0, 129.1, 129.4, 129.6, 135.9, 136.1, 141.6. 19F NMR (565 MHz, CDCl3) δ −65.76 (s, CF3). (−)-ESI-MS (m/z) 438.9 (35, [M{37Cl}-H]−), 437.0 (100, [M{35Cl}-H]−). IR (neat) v 1558, 1487, 1405, 1327, 1159, 1107, 973 cm−1. Anal. Calcd for C20H18ClF3N4S (438.9): C 54.73, H 4.13, N 12.77, S 7.30; found: C 54.72, H 4.08, N 12.80, S 7.44.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-bromophenyl)-ethanehydrazonothioate (16f): beige solid, 261 mg (54%), mp 108–110 °C. 1H NMR (600 MHz, CDCl3) δ 1.99, 2.17 (2s, 3H each), 5.27 (s, 2H), 6.92–6.94 (m, 2H), 7.11–7.13 (m, 2H), 7.26–7.33 (m, 3H), 7.40–7.43 (m, 2H), 11.58 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.5, 114.9, 115.2 (q, 2JC-F = 37.8 Hz), 115.9, 120.9 (q, 1JC-F = 271.8 Hz, CF3), 126.2, 127.7, 128.0, 129.1, 129.6, 132.3, 135.9, 136.1, 142.1. 19F NMR (565 MHz, CDCl3) δ −65.80 (s, CF3). (−)-ESI-MS (m/z) 483.1 (97, [M{81Br}-H]−), 482.1 (100, [M{79Br}-H]−). IR (neat) v 1558, 1484, 1406, 1327, 1141, 1159, 1100, 973 cm−1. Anal. Calcd for C20H18BrF3N4S (483.4): C 49.70, H 3.75, N 11.59, S 6.63; found: C 49.78, H 3.85, N 11.65, S 6.86.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-benzoyloxyphenyl)-ethanehydrazonothioate (16g): beige crystals, 319 mg (61%), mp 125–128 °C (decomp.). 1H NMR (600 MHz, CDCl3) δ 1.99, 2.19 (2s, 3H each), 5.29 (s, 2H), 6.93–6.94 (m, 2H), 7.17–7.19 (m, 2H), 7.27–7.33 (m, 5H), 7.50–7.53 (m, 2H), 7.62–7.65 (m, 1H), 8.20–8.22 (m, 2H), 11.53 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.5, 114.5 (q, 2JC-F = 37.4 Hz), 115.0, 121.0 (q, 1JC-F = 271.9 Hz, CF3), 122.7, 126.2, 127.7, 128.0, 128.7, 129.1, 129.7, 129.8, 130.3, 133.7, 135.9, 136.1, 140.8, 146.2, 165.6. 19F NMR (565 MHz, CDCl3) δ −65.62 (s, CF3). ESI-MS (m/z) 525.3 (100, [M+H]+). IR (neat) v 1737, 1558, 1502, 1331, 1245, 1193, 1144, 1111, 1062, 1025, 977 cm−1. Anal. Calcd for C27H23F3N4SO2 (524.6): C 61.82, H 4.42, N 10.68, S 6.11; found: C 61.60, H 4.27, N 10.41, S 6.09.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-cyanophenyl)-ethanehydrazonothioate (16h): beige crystals, 218 mg (51%), mp 118–120 °C (decomp.). 1H NMR (600 MHz, CDCl3) δ 2.00, 2.18 (2s, 3H each), 5.27 (s, 2H), 6.92–6.93 (m, 2H), 7.28–7.34 (m, 5H), 7.58–7.61 (m, 2H), 12.02 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.5, 105.1, 114.5, 118.4 (q, 2JC-F = 37.8 Hz), 119.5, 120.5 (q, 1JC-F = 272.7 Hz, CF3), 126.1, 127.9, 128.1, 129.08, 129.13, 133.8, 135.7, 136.2, 146.4. 19F NMR (565 MHz, CDCl3) δ −66.39 (s, CF3). (−)-ESI-MS (m/z) 428.0 (100, [M-H]−). IR (neat) v 2215, 1602, 1551, 1502, 1413, 1338, 1297, 1249, 1129, 977 cm−1. Anal. Calcd for C21H18F3N5S (429.5): C 58.73, H 4.22, N 16.31, S 7.47; found: C 58.71, H 4.27, N 16.27, S 7.62.
1-Benzyl-4,5-dimethylimidazol-2-yl 2,2,2-trifluoro-N′-(4-nitrophenyl)-ethanehydrazonothioate (16i): yellow crystals, 260 mg (58%), mp 108–111 °C (decomp.). 1H NMR (600 MHz, CDCl3) δ 2.01, 2.19 (2s, 3H each), 5.28 (s, 2H), 6.93–6.94 (m, 2H), 7.28–7.34 (m, 5H), 8.20–8.24 (m, 2H), 12.22 (sbr, 1H). 13C NMR (151 MHz, CDCl3) δ 9.7, 12.9, 48.5, 113.8, 119.4 (q, 2JC-F = 37.9 Hz), 120.5 (q, 1JC-F = 272.9 Hz, CF3), 125.9, 126.1, 128.0, 128.2, 129.9, 129.2, 135.6, 136.2, 142.6, 148.2. 19F NMR (565 MHz, CDCl3) δ −66.53 (s, CF3). ESI-MS (m/z) 450.3 (100, [M+H]+). IR (neat) v 1580, 1551, 1495, 1331, 1252, 1148, 1107 cm−1. Anal. Calcd for C20H18F3N5O2S (449.5): C 53.45, H 4.04, N 15.58, S 7.13; found: C 53.37, H 4.10, N 15.43, S 7.21.
1′,3′-Dibenzyl-4′,5′-dimethyl-4-(4-tolyl)-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17a): colorless solid, 376 mg (74%), mp 143–144 °C. 1H NMR (600 MHz, CDCl3) δ 2.06 (s, 6H), 2.16 (s, 3H), 5.08 (s, 4H), 6.55–6.57 (m, 2H), 6.80–6.82 (m, 2H), 7.11–7.14 (m, 4H), 7.19–7.21 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 9.9, 20.6, 50.3, 117.5, 121.0 (q, 1JC-F = 277.0 Hz, CF3), 124.6, 127.9, 128.3, 128.9, 129.4, 133.0, 133.1, 142.5, 142.9, 167.2 (q, 2JC-F = 33.3 Hz). 19F NMR (565 MHz, CDCl3) δ −66.46 (s, CF3). ESI-MS (m/z) 509.3 (100, [M+H]+). IR (neat) v 1498, 1450, 1297, 1238, 1156, 1111, 1077, 991 cm−1. Anal. Calcd for C28H27F3N4S (508.6): C 66.12, H 5.35, N 11.02, S 6.30; found: C 66.21, H 5.32, N 10.88, S 6.43.
1′-Benzyl-3′-(3-methoxybenzyl)-4′,5′-dimethyl-4-(4-tolyl)-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17b): colorless solid, 290 mg (54%), mp 137–139 °C. 1H NMR (600 MHz, CDCl3) δ 2.08, 2.09, 2.18, 3.67 (4s, 3H each), 5.06, 5.10 (2s, 2H each), 6.56–6.59 (m, 2H), 6.71–6.76 (m, 3H), 6.81–6.84 (m, 2H), 7.13–7.15 (m, 3H), 7.20–7.23 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 9.96, 9.97, 20.7, 50.44, 50.47, 55.5, 113.6, 114.3, 117.6, 120.2, 121.0 (q, 1JC-F = 276.9 Hz, CF3), 124.6, 124.7, 128.0, 128.4, 129.0, 129.5, 129.9, 133.1, 133.2, 134.7, 142.7, 143.1, 160.1, 167.3 (q, 2JC-F = 33.2 Hz). 19F NMR (565 MHz, CDCl3) δ −66.56 (s, CF3). IR (neat) v 1498, 1439, 1298, 1286, 1238, 1166, 1111, 1077 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C29H30F3N4OS 539.2092, found 539.2098.
1′,3′-Bis(3-methoxybenzyl)-4′,5′-dimethyl-4-(4-tolyl)-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17c): colorless solid, 284 mg (50%), mp 124–126 °C. 1H NMR (600 MHz, CDCl3) δ 2.09 (s, 6H), 2.18 (s, 3H), 3.66 (s, 6H), 5.05 (s, 4H), 6.56–6.58 (m, 2H), 6.71–6.75 (m, 6H), 6.82–6.84 (m, 2H), 7.12–7.15 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 9.9, 20.7, 50.4, 55.5, 113.6, 114.4, 117.5, 120.1, 121.1 (q, 1JC-F = 276.9 Hz, CF3), 124.7, 129.5, 129.9, 133.0, 134.6, 142.7, 143.0, 160.1, 167.1 (q, 2JC-F = 32.1 Hz). 19F NMR (565 MHz, CDCl3) δ −66.54 (s, CF3). IR (neat) v 1603, 1491, 1439, 1260, 1159, 1115, 980 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C30H32F3N4O2S 569.2198, found 569.2198.
1′,3′-Dibenzyl-4′,5′-dimethyl-4-(4-methoxyphenyl)-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17d): pale yellow solid, 225 mg (43%), mp 49–51 °C. 1H NMR (600 MHz, CDCl3) δ 2.10 (s, 6H), 3.66 (s, 3H), 5.09 (s, 4H), 6.52–6.57 (m, 4H), 7.10–7.13 (m, 4H), 7.20–7.23 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 9.9, 50.3, 56.7, 114.3, 119.7, 121.0 (q, 1JC-F = 276.9 Hz, CF3), 124.4, 127.9, 128.4, 129.0, 133.3, 138.3, 143.3, 156.3, 167.8 (q, 2JC-F = 32.5 Hz). 19F NMR (565 MHz, CDCl3) δ −66.46 (s, CF3). IR (neat) v 1498, 1443, 1290, 1230, 1167, 1115, 1073, 1028, 991 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C28H28F3N4OS 525.1936, found 525.1938.
1′,3′-Dibenzyl-4′,5′-dimethyl-4-phenyl-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17e): pale yellow solid, 257 mg (52%), mp 57–59 °C. 1H NMR (600 MHz, CDCl3) δ 2.10 (s, 6H), 5.11 (s, 4H), 6.65–6.67 (m, 2H), 6.84–6.86 (m, 1H), 7.00–7.03 (m, 2H), 7.12–7.15 (m, 4H), 7.19–7.21 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.5, 117.2, 121.0 (q, 1JC-F = 277.0 Hz, CF3), 123.3, 124.9, 127.1, 128.0, 128.5, 128.9, 129.0, 133.0, 142.8, 144.9, 167.4 (q, 2JC-F = 32.4 Hz). 19F NMR (565 MHz, CDCl3) δ −66.57 (s, CF3). IR (neat) v 1595, 1491, 1454, 1290, 1230, 1167, 1118, 1059, 988 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H26F3N4S 495.1830, found 495.1835.
4-(4-Chlorophenyl)-1′,3′-dibenzyl-4′,5′-dimethyl-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17f): colorless solid, 391 mg (74%), mp 63–65 °C. 1H NMR (600 MHz, CDCl3) δ 2.17 (s, 6H), 5.10 (s, 4H), 6.46–6.48 (m, 2H), 6.86–6.88 (m, 2H), 7.09–7.10 (m, 4H), 7.18–7.24 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.4, 118.2, 120.9 (q, 1JC-F = 277.2 Hz, CF3), 124.9, 128.0, 128.2, 128.56, 128.64, 129.0, 132.8, 142.3, 143.4, 168.2 (q, 2JC-F = 32.4 Hz). 19F NMR (565 MHz, CDCl3) δ −66.58 (s, CF3). IR (neat) v 1484, 1454,1286, 1234, 1170, 1118,1006, 988 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H25ClF3N4S 529.1441, found 529.1447.
4-(4-Bromophenyl)-1′,3′-dibenzyl-4′,5′-dimethyl-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17g): colorless solid, 400 mg (70%), mp 69–71 °C. 1H NMR (600 MHz, CDCl3) δ 2.17 (s, 6H), 5.09 (s, 4H), 6.40–6.42 (m, 2H), 7.00–7.02 (m, 2H), 7.08–7.10 (m, 4H), 7.18–7.24 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.4, 115.8, 118.5, 120.9 (q, 1JC-F = 277.1 Hz, CF3), 125.0, 128.0, 128.6, 129.0, 131.5, 132.7, 142.1, 143.9, 168.2 (q, 2JC-F = 32.5 Hz). 19F NMR (565 MHz, CDCl3) δ −66.57 (s, CF3). IR (neat) v 1484, 1454, 1286, 1234, 1170, 1118, 1066, 1006, 987 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H25BrF3N4S 573.0935, found 573.0941.
4-(4-Benzoyloxyphenyl)-1′,3′-dibenzyl-4′,5′-dimethyl-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17h): colorless solid, 331 mg (54%), mp 149–150 °C. 1H NMR (600 MHz, CDCl3) δ 2.15 (s, 6H), 5.14 (s, 4H), 6.64–6.67 (m, 2H), 6.86–6.89 (m, 2H), 7.14–7.17 (m, 4H), 7.23–7.25 (m, 6H), 7.49–7.51 (m, 2H), 7.61–7.64 (m, 1H), 8.15–8.17 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.6, 117.9, 121.0 (q, 1JC-F = 277.1 Hz, CF3), 122.0, 124.9, 128.1, 128.67, 128.70, 129.1, 129.7, 130.2, 132.9, 133.7, 142.7, 142.8, 146.7, 165.0, 167.5 (q, 2JC-F = 32.6 Hz). 19F NMR (565 MHz, CDCl3) δ −66.61 (s, CF3). IR (neat) v 1737, 1498, 1454, 1356, 1282, 1200, 1192, 1107, 1059, 1006, 988 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C34H30F3N4O2S 615.2042, found 615.2037.
4-(4-Cyanophenyl)-1′,3′-dibenzyl-4′,5′-dimethyl-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17i): pale yellow solid, 312 mg (60%), mp 67–69 °C. 1H NMR (600 MHz, CDCl3) δ 2.27 (s, 6H), 5.08, 5.14 (2sbr, 2H each), 6.45–6.48 (m, 2H), 7.05–7.09 (m, 6H), 7.13–7.20 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.5, 105.1, 116.1, 119.1, 120.8 (q, 1JC-F = 277.4 Hz, CF3), 125.5, 128.1, 128.8, 129.1, 132.3, 132.5, 141.1, 148.1, 168.9 (q, 2JC-F = 32.5 Hz). 19F NMR (565 MHz, CDCl3) δ −66.67 (s, CF3). IR (neat) v 2222, 1603, 1498, 1454, 1238, 1170, 1170, 1118, 1080, 1010, 988 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C28H25F3N5S 520.1783, found 520.1787.
1′,3′-Dibenzyl-4′,5′-dimethyl-4-(4-nitrophenyl)-2-trifluoromethylspiro [1,3,4-thiadiazole-5,2′-imidazole] (17j): light red solid, 216 mg (40%), mp 53–55 °C. 1H NMR (600 MHz, CDCl3) δ 2.30 (s, 6H), 5.08, 5.16 (2sbr, 2H each), 6.44–6.48 (m, 2H), 7.06–7.09 (m, 4H), 7.11–7.16 (m, 6H), 7.66–7.68 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 10.0, 50.6, 115.3, 120.8 (q, 1JC-F = 277.5 Hz, CF3), 124.4, 125.6, 128.0, 128.8, 129.1, 132.2, 140.9, 142.1, 149.7, 169.3 (q, 2JC-F = 32.6 Hz). 19F NMR (565 MHz, CDCl3) δ −66.67 (s, CF3). IR (neat) v 1592, 1495, 1454, 1334, 1271, 1238, 1170, 1107 cm−1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H25F3N5O2S 540.1681, found 540.1691.

4. Conclusions

In summary, two series of lepidiline-inspired imidazole-2(3H)-thiones were examined in reactions with in situ-generated trifluoromethylated nitrile imines. Enolizable imidazole-2-thiones solely provided the respective hydrazonothioates formed through nucleophilic S-addition onto the 1,3-dipole, whereas the N,N-disubstituted non-enolizable analogues afforded the corresponding (3+2)-cycloadducts in high yield. The latter products belong to a hitherto very little-known spiro [1,3,4-thiadiazole-5,2′-imidazole] family [52] and are the first examples of non-ionic spiro-analogues of naturally occurring lepidiline alkaloids as well as new fluorinated imidazole-thiadiazole hybrids of potential interest in medicine, agrochemistry, and material sciences [53,54,55]. The present work further expands the scope of products available by trapping of CF3-nitrile imines with thiocarbonyl substrates and reveals absorptions of the C-(CF3) atom in the 13C NMR spectrum as a useful probe for the differentiation of the open-chain, monocyclic, and spiro-cyclic products in the series. Furthermore, the presented results nicely supplement a more recent study on (chemo)selectivity problems in reactions of enolizable azaheterocyclic thiones [56,57].

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30193851/s1: Supplementary File S1. Copies of 1H, 13C, and 19F NMR spectra of all new compounds.

Author Contributions

Conceptualization and methodology, M.J. and W.K.P.; investigation, W.K.P., K.Ś., K.U. and B.O.; writing—original draft preparation, M.J.; writing—review and editing, M.J. and W.K.P.; supervision, M.J.; project administration, M.J.; funding acquisition, W.K.P. and M.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the University of Lodz in the framework of IDUB grants (W.K.P.; #5/ODW/DGB/2022, and M.J.; #14/IGB/2024).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

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

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Molecules 30 03851 g001
Figure 1. Structures of pilocarpine (1) and selected imidazole-based alkaloids 2–4 found in Lepidium species, synthetic bioactive lepidiline analogues 5 and 6, and the enolizable and non-enolizable thio-lepidilines 7 and 8, respectively, studied herein.
Figure 1. Structures of pilocarpine (1) and selected imidazole-based alkaloids 2–4 found in Lepidium species, synthetic bioactive lepidiline analogues 5 and 6, and the enolizable and non-enolizable thio-lepidilines 7 and 8, respectively, studied herein.
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Molecules 30 03851 sch001
Scheme 1. Generation of CF3-nitrile imines 9 through base-induced dehydrohalogenation of hydrazonoyl bromides 10, and exemplary 1,3-dipolar cycloadditions of 9 with selected C=C, C=N, and C=S dipolarophiles leading to pyrazoles, 1,2,4-triazoles, and 1,3,4-thiadiazoles, respectively.
Scheme 1. Generation of CF3-nitrile imines 9 through base-induced dehydrohalogenation of hydrazonoyl bromides 10, and exemplary 1,3-dipolar cycloadditions of 9 with selected C=C, C=N, and C=S dipolarophiles leading to pyrazoles, 1,2,4-triazoles, and 1,3,4-thiadiazoles, respectively.
Molecules 30 03851 sch001
Molecules 30 03851 sch002
Scheme 2. Synthesis of imidazole-2-thiones 7a,b and 8a–8c employing imidazole N-oxides 11 as key intermediates: a overall yield for 3 steps.
Scheme 2. Synthesis of imidazole-2-thiones 7a,b and 8a–8c employing imidazole N-oxides 11 as key intermediates: a overall yield for 3 steps.
Molecules 30 03851 sch002
Molecules 30 03851 sch003
Scheme 3. Synthesis of hydrazonothioates 16a–16i derived from enolizable imidazole-2-thiones 7a and 7b: scope of hydrazonoyl bromides 10.
Scheme 3. Synthesis of hydrazonothioates 16a–16i derived from enolizable imidazole-2-thiones 7a and 7b: scope of hydrazonoyl bromides 10.
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Molecules 30 03851 sch004
Scheme 4. Synthesis of spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives 17a–16j derived from non-enolizable imidazole-2-thiones 8a–8c: scope of hydrazonoyl bromides 10.
Scheme 4. Synthesis of spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives 17a–16j derived from non-enolizable imidazole-2-thiones 8a–8c: scope of hydrazonoyl bromides 10.
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Molecules 30 03851 g002
Figure 2. The diagnostic 13C NMR chemical shifts attributed to the C-(CF3) atom in known CF3-functionalized 2,2-dialkyl/diaryl-2,3-dihydro-1,3,4-thiadiazoles [31,32,33,50], lepidiline-derived hydrazonothioates 16 and spiro-1,3,4-thiadiazole derivatives 17 reported in this work.
Figure 2. The diagnostic 13C NMR chemical shifts attributed to the C-(CF3) atom in known CF3-functionalized 2,2-dialkyl/diaryl-2,3-dihydro-1,3,4-thiadiazoles [31,32,33,50], lepidiline-derived hydrazonothioates 16 and spiro-1,3,4-thiadiazole derivatives 17 reported in this work.
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Molecules 30 03851 sch005
Scheme 5. The proposed mechanisms for the formation of hydrazonothioates 16 and (3+2)-cycloadducts 17.
Scheme 5. The proposed mechanisms for the formation of hydrazonothioates 16 and (3+2)-cycloadducts 17.
Molecules 30 03851 sch005
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Poper, W.K.; Świątek, K.; Urbaniak, K.; Olszewska, B.; Jasiński, M. Lepidiline-Derived Imidazole-2(3H)-Thiones: (3+2)-Cycloadditions vs. Nucleophilic Additions in Reactions with Fluorinated Nitrile Imines. Molecules 2025, 30, 3851. https://doi.org/10.3390/molecules30193851

AMA Style

Poper WK, Świątek K, Urbaniak K, Olszewska B, Jasiński M. Lepidiline-Derived Imidazole-2(3H)-Thiones: (3+2)-Cycloadditions vs. Nucleophilic Additions in Reactions with Fluorinated Nitrile Imines. Molecules. 2025; 30(19):3851. https://doi.org/10.3390/molecules30193851

Chicago/Turabian Style

Poper, Wiktor K., Kamil Świątek, Katarzyna Urbaniak, Barbara Olszewska, and Marcin Jasiński. 2025. "Lepidiline-Derived Imidazole-2(3H)-Thiones: (3+2)-Cycloadditions vs. Nucleophilic Additions in Reactions with Fluorinated Nitrile Imines" Molecules 30, no. 19: 3851. https://doi.org/10.3390/molecules30193851

APA Style

Poper, W. K., Świątek, K., Urbaniak, K., Olszewska, B., & Jasiński, M. (2025). Lepidiline-Derived Imidazole-2(3H)-Thiones: (3+2)-Cycloadditions vs. Nucleophilic Additions in Reactions with Fluorinated Nitrile Imines. Molecules, 30(19), 3851. https://doi.org/10.3390/molecules30193851

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