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Article

Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles

by
Pavel S. Gribanov
1,*,
Anna N. Philippova
1,
Alexander F. Smol’yakov
1,
Diana N. Tukhvatullina
1,2,
Viktoria A. Vlasova
1,2,
Maxim A. Topchiy
3,
Andrey F. Asachenko
3 and
Sergey N. Osipov
1,*
1
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28/1 Vavilova Str., 119334 Moscow, Russia
2
D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya pl., 125047 Moscow, Russia
3
A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Leninskiy Prospect 29, 119991 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(7), 1401; https://doi.org/10.3390/molecules30071401
Submission received: 26 February 2025 / Revised: 13 March 2025 / Accepted: 20 March 2025 / Published: 21 March 2025
(This article belongs to the Special Issue Synthesis and Functionalization of Nitrogen Heterocycles)
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Abstract

:
An efficient access to novel 2-substituted 1H-imidazole derivatives was developed based on acid-mediated denitrogenative transformation of 5-amino-1,2,3-triazole derivatives available through dipolar azide−nitrile cycloaddition (DCR). The proposed approach includes intramolecular cyclization of 5-amino-4-aryl-1-(2,2-diethoxyethyl) 1,2,3-triazoles followed by triazole ring opening and insertion of in situ formed carbene intermediate into the O-H bond of different alcohols under acidic conditions.

Graphical Abstract

1. Introduction

Nitrogen-containing compounds, particularly imidazoles, are highly significant in heterocyclic chemistry due to their diverse chemical properties and applications in agriculture and pharmacology [1,2] as well as in functional materials [3,4,5]. The imidazole core is an essential structural element of many compounds whose derivatives are widely used in organic synthesis [6,7,8], e.g., as directing groups in transition metal-catalyzed C-H activation reactions [9,10] and as NHC ligands in homogeneous catalysis [11,12,13].
The transition metal-catalyzed ring opening of easily accessible 1,2,3-triazoles is well-known for the generation of metallocarbene intermediates, and they undergo a wide range of synthetically useful transformations like cycloadditions, ring expansions, ylide formation and so forth to access different heterocyclic compounds [14,15,16,17,18,19,20], including imidazoles [2,21,22,23]. However, such reactions require the use of precious Rh-, Co-, or Ni-complexes as the catalysts. Therefore, the development of alternative strategies, especially cheap metal-free methods of the 1,2,3-triazole ring opening to afford important heterocyclic derivatives, is highly desirable.
It is known that the stability of the 1,2,3-triazole core is considerably affected by the electronic nature of the substituents at the N1, C4 and C5 atoms [23]. The presence of a donor amino group at position C5 [24] and acceptor substituents (e.g., sulfonyl, perfluoroalkyl or carbonyl groups) at position N1 [21,25,26,27] significantly increases the polarity of the N-N bond, as a result of which this 1,2,3-triazole can exist in equilibrium with the corresponding tautomeric diazoamidine. It is also known that some conjugated 1,2,3-triazole-containing heterocyclic systems, such as pyridotriazoles [17,28,29] or in situ generated triazolobenzoxazoles [29,30], have a high potential for electrocyclic ring opening. The formation of systems based on the corresponding diazo intermediates opens up possibilities for their further modification via transannulation to afford a new nitrogen-containing heterocyclic ring by trapping these intermediates with different reagents [20,28,31,32,33].
Based on the above-mentioned concepts and our own studies in the synthesis of functional 5-amino-1,2,3-triazoles through a combination of the azide-nitrile dipolar cycloaddition (DCR) reaction with the Dimroth rearrangement (Scheme 1a) [34,35,36], here we report on a novel efficient approach to biologically relevant 2-substituted imidazole derivatives via acid-mediated denitrogenative transformation of the 5-amino-1,2,3-triazole ring followed by O-H carbene insertion (Scheme 1b). To the best of our knowledge, this type of transformation has not been previously investigated for 5-amino-1,2,3-triazole derivatives.

2. Results

Synthesis

At the beginning of our study, a new series of starting 5-amino-1-(2,2-diethoxyethyl) 1,2,3-triazoles 3 has been prepared via dipolar [3+2] cycloaddition (DCR) of a wide range of aromatic and heteroaromatic acetonitriles 1 with diethyl 2-azidoacetaldehyde diethyl acetal 2 according to an efficient and simple protocol developed in our previous works [34,36]. The method allowed us to easily obtain a number of corresponding 5-amino-1,2,3-triazole derivatives 3a–n with different substituents at the C4 position (Scheme 2). For the reaction of liquid R-CH2CN (for the synthesis of 3a–c, 3g–i and 3k), solvent-free conditions were used [34]; for solid nitriles insoluble in the azide 2, we used DMSO as a solvent to afford the corresponding products 3d–f, 3j and 3l–n [36].
The molecules containing vicinal functionalities such as amino- and protected acetal groups are often used in synthetic organic chemistry to furnish nitrogen-containing heterocyclic compounds, in particular pyrrole and indole derivatives, through intermolecular cyclization under acidic conditions [37,38,39,40]. Following this strategy and literature precedent concerning acid hydrolysis of α-(1,2,3-triazole)-substituted acetals [41], 5-amino-1-(2,2-diethoxyethyl)-4-phenyl-1H-1,2,3-triazole 3a was initially hydrolyzed by heating in conc. HCl to determine what would happen after deprotection of the aldehyde function. As a result, it was revealed that the reaction smoothly occurs at 90°C and goes to completion for 3 h to afford (1H-imidazol-2-yl)(phenyl)methanol 4a in 89% yield as a transannulation product (Scheme 3). It should be noted that the compound 4a has been previously described by Yus’s group [42] via an isoprene-mediated lithiation of protected imidazole derivatives to use as a ligand in a palladium-catalyzed Hiyama reaction [6].
The strategy tested for the preparation of 4a was further used to react other starting 5-amino-substituted 1,2,3-triazole acetals 3. After an initial screening of reaction conditions, we found that the best yield of the desired product 4 can be achieved by refluxing of acetals 3 alcohol solutions (for MeOH, EtOH, i-PrOH, n-BuOH and t-BuOH) in the presence of 0.5 mL conc. HCl (see Section 3.4.3). As a result, we have prepared various 2-(alkoxy(hetaryl)methyl) 1H-imidazole derivatives 4a–z in good to excellent yields (Scheme 3). The steric and electronic nature of the substituents and their location in the phenyl ring at position C4 do not have a significant effect on the outcome of the reaction. The examples of 4u and 4v demonstrate the possibility of incorporating the imidazole core into the benzothiadiazole-based (BTD) luminophores, which are important units of innovative optoelectronic devices [36,43,44].
All compounds obtained were fully characterized by standard physicochemical methods. In 1H NMR spectra of imidazole derivatives 4, the following characteristic signals were observed: the corresponding singlets in the 11.0–12.0 ppm region (1H of the N-H group), 6.5–7.0 ppm (2H at the imidazole double bond) and 5.0–6.0 ppm (1H at the quaternary carbon atom). In addition, the structure of 4d was unambiguously confirmed by X-ray analysis. Compound 4d crystallizes in a crystal as two independent molecules (z = 8). Both molecules are in a common position. The formation of a strong intermolecular N(5B)-H(5B)…N(2A) interaction is observed in the crystal (Figure 1).
A plausible mechanism for the reaction involves an initial hydrolysis of the starting 5-amino-1,2,3-triazoloacetal 3 to the corresponding aldehyde A, which can further undergo intramolecular cyclization to imidazotriazole B existing in equilibrium with its tautomeric form C. The diazo compound C then eliminates nitrogen and undergoes the carbene insertion into the O-H bond of the corresponding alcohol to afford the final 2-substituted imidazole 4 (Scheme 4).
An interesting exception has been found in the case of 4-(pyridin-2-yl)-substituted 1,2,3-triazole 3k that transforms into the corresponding extremely stable 3-(1H-imidazol-2-yl)-[1,2,3]triazolo[1,5-a]pyridine 5a under standard conditions in good yield (Scheme 5). The formation of the expected imidazole-containing ether 5a’ as a result of carbene insertion into the ethanol O-H bond was not detected. It is not excluded that the pyridine ring stabilized diazo intermediate A hampers nitrogen elimination due to more favorable intermolecular N-N bond formation. It is worth noting that compounds with a 1,2,3-triazolo-[1,5-a]-pyridine framework can be used in organic and medicinal chemistry for the preparation of biologically relevant molecules [31,45,46].

3. Materials and Methods

3.1. General Information

All reagents were used as purchased from Sigma-Aldrich. Starting with 2-(4-bromophenyl)acetonitrile [47], 2-(pyridin-2-yl)acetonitrile [48], 2-(4-((trimethylsilyl) ethynyl)phenyl)acetonitrile [49], 2-(4′-methyl-[1,1′-biphenyl]-4-yl)acetonitrile [50], 2-(4-(7-(4-methoxyphenyl)benzo[c][1,2,5]thiadiazol-4-yl)phenyl)acetonitrile [36], 2-(2-(p-tolylethynyl)phenyl)acetonitrile [51], 2,2′-(1,4-phenylene)diacetonitrile [52] and (aNHC)CuCl [53] were synthesized according to published procedures. Analytical data were in accordance with the literature data. Analytical TLC was performed with Merck silica gel 60 F 254 plates (Darmstadt, Germany); visualization was accomplished with UV light or iodine vapors. Chromatography was carried out using Merck silica gel (Kieselgel 60, 0.063–0.200 mm) and petroleum ether/ethyl acetate as an eluent. The 1H and 13C NMR spectra were recorded on a Varian Inova 400 spectrometer operating at 400 and 101 MHz, respectively. Chemical shifts are given in ppm using residual solvent signals as internal standards. High-resolution mass spectrometry spectra were obtained using an AB Sciex Triple TOF 5600+ (Framingham, MA, USA), which supported different ionization sources. The melting points were determined on a Stuart SMP 10 melting point apparatus (Wertheim, Germany) and are uncorrected.

3.2. Crystal Structure Determination

Single-crystal X-ray diffraction experiments were carried out with a Bruker SMART APEX CCD area detector diffractometer (Bruker, Billerica, MA, USA). The crystal was kept at 120 K during data collection. Using Olex2 [54], the structure was solved with the SHELXT [55] structure solution program using intrinsic phasing and refined with the XL [56] refinement package using least squares minimisation.
Crystal Data for 4d C13H16N2O (M = 216.28 g/mol): monoclinic, space group P21/n (no. 14), a = 9.9055(7) Å, b = 18.8699(14) Å, c = 12.9213(10) Å, β = 92.299(3), V = 2413.3(3) Å3, Z = 2, T = 120 K, μ(MoKα) = 0.077 mm−1, Dcalc = 1.191 g/cm3, 33,287 reflections measured (3.822 ≤ 2Θ ≤ 51.996), 4736 unique (Rint = 0.0486, Rsigma = 0.0390), which were used in all calculations. The final R1 was 0.0674 (I > 2σ(I)) and wR2 was 0.1841.
Crystal Data for 5a C9H7N5 (M = 185.20 g/mol): monoclinic, space group P21/n (no. 14), a = 4.1391(3) Å, b = 16.4192(14) Å, c = 12.1450(9) Å, β = 98.262(4), V = 816.82(11) Å3, Z = 4, T = 120 K, μ(MoKα) = 0.101 mm−1, Dcalc = 1.506 g/cm3, 8267 reflections measured (4.2 ≤ 2Θ ≤ 51.984), 1584 unique (Rint = 0.0338, Rsigma = 0.0324), which were used in all calculations. The final R1 was 0.0339 (I > 2σ(I)) and wR2 was 0.0859.
Deposition numbers 2426762 (for 4d) and 2426763 (for 5a), respectively, contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre service www.ccdc.cam.ac.uk/structures (accessed on 11 March 2025).

3.3. Preparation and Characterization of Starting Acetonitrile Derivatives

2-(4′-methoxy-[1,1′-biphenyl]-2-yl)acetonitrile
The title compound was synthesized according to literature procedure [36] from 2-(2-bromophenyl)acetonitrile and (4-methoxyphenyl)boronic acid as a light-yellow solid (44% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.56–7.49 (m, 1H, HAr), 7.41–7.36 (m, 2H, HAr), 7.32–7.27 (m, 1H, HAr), 7.22 (d, J = 8.6 Hz, 2H, HAr), 6.99 (d, J = 8.6 Hz, 2H, HAr), 3.87 (s, 3H, ArOCH3), 3.64 (s, 2H, CH2CN). 13C NMR (101 MHz, Chloroform-d) δ 159.3, 141.7, 132.3, 130.7, 130.2, 129.0, 128.3, 128.0, 118.5, 116.1, 114.2, 55.4, 22.2. HRMS (ESI) C15H14NO, m/z: calc. for [M+H]+: 224.1070; found: 224.1070.
2-(2-((trimethylsilyl)ethynyl)phenyl)acetonitrile
The title compound was synthesized from 2-(2-bromophenyl)acetonitrile according to literature procedures [57,58] as a light yellow oil (yield 92%). 1H NMR (400 MHz, Chloroform-d) δ 7.49 (t, J = 7.3 Hz, 2H, HAr), 7.37 (d, J = 7.0 Hz, 1H, HAr), 7.29 (t, J = 7.4 Hz, 1H, HAr), 3.90 (s, 2H, CH2CN), 0.28 (s, 9H, Si(CH3)3). 13C NMR (101 MHz, Chloroform-d) δ 132.7, 132.3, 129.4, 128.2, 128.1, 122.8, 101.7, 101.5, 22.8, 0.0. HRMS (APPI) C13H16NSi, m/z: calc. for [M+H]+: 214.1047; found: 214.1046.
2-(2-ethynylphenyl)acetonitrile
The title compound was synthesized from 2-(2-((trimethylsilyl)ethynyl)phenyl) acetonitrile according to literature procedures [57] as a light yellow oil (yield 87%). Analytical data were in accordance with the literature [59]. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 7.6 Hz, 1H, HAr), 7.49 (d, J = 7.7 Hz, 1H, HAr), 7.39 (t, J = 7.6 Hz, 1H, HAr), 7.31 (d, J = 7.5 Hz, 1H, HAr), 3.91 (s, 2H, CH2CN), 3.40 (s, 1H, Ar-CCH). 13C NMR (101 MHz, Chloroform-d) δ 133.1, 132.5, 129.7, 128.2, 128.2, 121.7, 117.4, 83.6, 80.5, 22.7.
2-(4-ethynylphenyl)acetonitrile
The title compound was synthesized from 2-(4-((trimethylsilyl)ethynyl)phenyl) acetonitrile according to literature procedures [57] as a light yellow oil (yield 96%). Analytical data were in accordance with the literature [49]. 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 8.2 Hz, 2H, HAr), 7.29 (d, J = 8.0 Hz, 2H, HAr), 3.75 (s, 2H, CH2CN), 3.11 (s, 1H, Ar-CCH). 13C NMR (101 MHz, Chloroform-d) δ 132.9, 130.6, 128.0, 122.2, 117.4, 82.8, 78.2, 23.7.
2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)acetonitrile
The title compound was synthesized according to literature procedure [60]. A screw-cap vial equipped with a magnetic stir bar was charged with 2-(2-ethynylphenyl)acetonitrile (0.75 mmol), benzyl azide (1.5 equiv.) and 1 mol% (aNHC)CuCl. The reaction mixture was stirred for 24 h at 40 °C. After 24 h, the reaction mixture was dissolved in dichloromethane and evaporated to dryness in vacuo. Purification by chromatography (eluent—hexane: ethyl acetate 2:1) yielded an analytically pure product as a yellow solid (yield 62%). M.p. 99–101 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H, Htrz), 7.56 (d, J = 7.5 Hz, 1H, HAr), 7.43–7.31 (m, 8H, HAr), 5.59 (s, 2H, ArCH2), 4.21 (s, 2H, CH2CN). 13C NMR (101 MHz, Chloroform-d) δ 147.2, 134.5, 129.8, 129.5, 129.4, 129.3, 129.0, 129.0, 128.5, 128.4, 128.2, 121.9, 118.4, 54.4, 22.9. HRMS (ESI) C17H15N4, m/z: calc. for [M+H]+: 275.1291; found: 275.1293.
2-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)acetonitrile
The title compound was synthesized according to literature procedure [60]. A screw-cap vial equipped with a magnetic stir bar was charged with 2-(4-ethynylphenyl)acetonitrile (0.75 mmol), benzyl azide (1.5 equiv.) and 1 mol% (aNHC)CuCl. The reaction mixture was stirred for 24 h at 40 °C. After 24 h, the reaction mixture was dissolved in dichloromethane and evaporated to dryness in vacuo. Purification by chromatography (eluent—hexane: ethyl acetate 2:1) yielded an analytically pure product as a light yellow solid (yield 57%). M.p. 166–167 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.2 Hz, 2H, HAr), 7.68 (s, 1H, Htrz), 7.41–7.31 (m, 7H, HAr), 5.58 (s, 2H, ArCH2), 3.77 (s, 2H, CH2CN). 13C NMR (101 MHz, Chloroform-d) δ 147.4, 134.7, 130.6, 129.7, 129.3, 129.0, 128.5, 128.2, 126.5, 119.8, 117.8, 54.4, 23.5. HRMS (ESI) C17H15N4, m/z: calc. for [M+H]+: 275.1291; found: 275.1297.

3.4. Preparation and Characterization of Novel Compounds

3.4.1. General Procedure A for Solvent-Free Preparation of 5-Amino-1-(2,2-Diethoxyethyl)-1,2,3-Triazoles 3 via Dipolar Azide−Nitrile Cycloaddition (DCR)

A 25 mL round-bottom flask equipped with a magnetic stir bar was charged with 0.5 mmol of acetonitrile derivative 1 and 1.1 equiv. of diethyl 2-azidoacetaldehyde diethyl acetal 2. The resulting mixture was placed into a water bath (room temperature), and 0.1 equiv. of powdered potassium tert-butoxide was added portionwise. The reaction mixture was allowed to stir for 3 h at room temperature. After 3 h, the reaction mixture was dissolved in an EtOAc/H2O mixture (1:1, 10 mL); the organic phase was separated and the aqueous mixture was extracted with ethyl acetate (3 × 5 mL). The organic extract was evaporated to dryness in vacuo. Purification by chromatography (eluent—hexane: ethyl acetate 2:1) yielded an analytically pure product.

3.4.2. General Procedure B for Preparation of 5-Amino-1-(2,2-Diethoxyethyl)-1,2,3-Triazoles 3 via Dipolar Azide−Nitrile Cycloaddition (DCR) in DMSO

A 25 mL round-bottom flask equipped with a magnetic stir bar was charged with 0.5 mmol of acetonitrile derivative 1, 3.0 equiv. of diethyl 2-azidoacetaldehyde diethyl acetal 2 and DMSO (8 mL). The resulting mixture was placed into a water bath (room temperature), and 0.5 equiv. of powdered potassium tert-butoxide was added portionwise. The reaction mixture was allowed to stir for 3 h at 70 °C. On completion, the mixture was poured into water and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography (eluent—hexane: ethyl acetate 2:1) yielded an analytically pure product.

3.4.3. General Procedure C for Preparation of 1H-Imidazole Derivatives 4

A 25 mL round-bottomed flask, equipped with a magnetic stir bar and reflux condenser, was charged with a mixture of 0.5 mmol of 5-amino-1-(2,2-diethoxyethyl)-1,2,3-triazole 3a-n, corresponding ROH (10 mL) and 0.5 mL of conc. HCl. The resulting mixture was refluxed for 3 h. On completion, the mixture was neutralized by a water solution of NaOH and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography (ethyl acetate) yielded an analytically pure product.

3.4.4. General Procedure D for CuAAC Synthesis of 4y and 4z

To a solution of 3g or 3i (0.3 mmol) in anhydrous toluene (2 mL), the corresponding amount of benzyl azide (2 equiv.) and CuTC (copper (I) thiophene-2-carboxylate) (5 mol.%) was added. The reaction mixture was stirred at room temperature for 4 h at 50 °C. Upon the completion of the reaction (monitored by TLC), the mixed solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate), yielding an analytically pure product.
1-(2,2-diethoxyethyl)-4-phenyl-1H-1,2,3-triazol-5-amine (3a)
Compound 3a was synthesized according to general procedure A (yield 92%) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.5 Hz, 2H, HAr), 7.41 (t, J = 7.6 Hz, 2H, HAr), 7.29–7.24 (m, 1H, HAr), 4.76 (t, J = 5.3 Hz, 1H, CH(OEt)2), 4.39 (s, 2H, NH2), 4.33 (d, J = 5.3 Hz, 2H, CH2CH), 3.80–3.72 (m, 2H, OCH2CH3), 3.57–3.49 (m, 2H, OCH2CH3), 1.17 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.0, 132.0, 130.5, 129.0, 126.9, 125.8, 102.5, 64.5, 50.0, 15.3. HRMS (ESI) C14H21N4O2, m/z: calc. for [M+H]+: 277.1659; found: 277.1665.
4-(2-bromophenyl)-1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine (3b)
Compound 3b was synthesized according to general procedure A (yield 98%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.0 Hz, 1H, HAr), 7.50 (d, J = 7.6 Hz, 1H, HAr), 7.35 (t, J = 7.5 Hz, 1H, HAr), 7.20 (t, J = 7.7 Hz, 1H, HAr), 4.79 (t, J = 5.4 Hz, 1H, CH(OEt)2), 4.33 (d, J = 5.4 Hz, 2H, CH2CH), 4.23 (s, 2H, NH2), 3.80–3.73 (m, 2H, OCH2CH3), 3.57–3.50 (m, 2H, OCH2CH3), 1.18 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.5, 133.0, 132.6, 132.5, 130.9, 129.7, 127.7, 122.7, 102.5, 64.5, 49.9, 15.3. HRMS (ESI) C14H20BrN4O2, m/z: calc. for [M+H]+: 355.0764; found: 355.0770.
4-(2-chlorophenyl)-1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine (3c)
Compound 3c was synthesized according to general procedure A (yield 98%) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.61–7.57 (m, 1H, HAr), 7.43 (d, J = 7.6 Hz, 1H, HAr), 7.37–7.28 (m, 2H, HAr), 4.80 (t, J = 5.4 Hz, 1H, CH(OEt)2), 4.35 (d, J = 5.4 Hz, 2H, CH2CH), 4.28 (s, 2H, NH2), 3.81–3.74 (m, 2H, OCH2CH3), 3.58–3.52 (m, 2H, OCH2CH3), 1.19 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.9, 132.2, 132.2, 130.5, 129.8, 129.3, 129.3, 127.2, 102.6, 64.6, 49.9, 15.3. HRMS (ESI) C14H20ClN4O2, m/z: calc. for [M+H]+: 311.1269; found: 355. 311.1274.
1-(2,2-diethoxyethyl)-4-(4′-methoxy-[1,1′-biphenyl]-2-yl)-1H-1,2,3-triazol-5-amine (3d)
Compound 3d was synthesized according to general procedure B (yield 78%) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.68–7.63 (m, 1H, HAr), 7.40–7.34 (m, 3H, HAr), 7.23 (d, J = 9.2 Hz, 2H, HAr), 6.82 (d, J = 8.7 Hz, 2H, HAr), 4.66 (t, J = 5.2 Hz, 1H, CH(OEt)2), 4.17 (d, J = 5.2 Hz, 2H, CH2CH), 3.77 (s, 3H, ArOCH3), 3.70–3.62 (m, 2H, OCH2CH3), 3.48–3.40 (m, 4H, NH2 and OCH2CH3), 1.09 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 158.9, 139.4, 139.0, 133.7, 131.5, 130.2, 130.1, 129.8, 128.3, 127.5, 114.1, 102.3, 64.0, 55.2, 50.1, 15.3. HRMS (ESI) C21H27N4O3, m/z: calc. for [M+H]+: 383.2078; found: 383.2077.
4-(4-bromophenyl)-1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine (3e)
Compound 3e was synthesized according to general procedure A (yield 76%) as a yellow solid. M.p. 101–102 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 4H, HAr), 4.76 (td, J = 5.2, 1.0 Hz, 1H, CH(OEt)2), 4.43 (s, 2H, NH2), 4.33 (d, J = 5.2 Hz, 2H, CH2CH), 3.81–3.73 (m, 2H, OCH2CH3), 3.58–3.50 (m, 2H, OCH2CH3), 1.19 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.1, 132.1, 130.9, 129.5, 127.2, 120.6, 102.4, 64.5, 50.1, 15.3. HRMS (ESI) C14H20BrN4O2, m/z: calc. for [M+H]+: 355.0764; found: 355.0770.
1-(2,2-diethoxyethyl)-4-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazol-5-amine (3f)
Compound 3f was synthesized according to general procedure B (yield 83%) as a yellow solid. M.p. 140–142 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 8.3 Hz, 2H, HAr), 7.65 (d, J = 8.1 Hz, 2H, HAr), 7.51 (d, J = 8.0 Hz, 2H, HAr), 7.24 (d, J = 7.9 Hz, 2H, HAr), 4.78 (t, J = 5.3 Hz, 1H, CH(OEt)2), 4.43 (s, 2H, NH2), 4.36 (d, J = 5.3 Hz, 2H, CH2CH), 3.82–3.74 (m, 2H, OCH2CH3), 3.59–3.51 (m, 2H, OCH2CH3), 2.38 (s, 3H, ArCH3), 1.20 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.6, 139.1, 137.9, 137.2, 130.7, 129.7, 128.9, 127.5, 126.9, 126.1, 105.2, 64.6, 50.1, 21.2, 15.4. HRMS (ESI) C21H27N4O2, m/z: calc. for [M+H]+: 367.2129; found: 367.2135.
1-(2,2-diethoxyethyl)-4-(4-ethynylphenyl)-1H-1,2,3-triazol-5-amine (3g)
Compound 3g was synthesized according to general procedure A (yield 63%) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J = 8.1 Hz, 2H, HAr), 7.51 (d, J = 8.0 Hz, 2H, HAr), 4.75 (t, J = 5.2 Hz, 1H, CH(OEt)2), 4.47 (s, 2H, NH2), 4.32 (d, J = 5.1 Hz, 2H, CH2CH), 3.80–3.72 (m, 2H, OCH2CH3), 3.57–3.49 (m, 2H, OCH2CH3), 3.09 (s, 1H, Ar-CCH), 1.18 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.4, 132.7, 132.5, 129.6, 125.2, 120.3, 102.3, 83.7, 77.6, 64.5, 50.0, 15.3. HRMS (ESI) C16H21N4O2, m/z: calc. for [M+H]+: 301.1666; found: 301.1664.
1-(2,2-diethoxyethyl)-4-(2-ethynylphenyl)-1H-1,2,3-triazol-5-amine (3h)
Compound 3h was synthesized according to general procedure A (yield 53%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 7.9 Hz, 1H, HAr), 7.59 (d, J = 7.6 Hz, 1H, HAr), 7.45 (t, J = 7.6 Hz, 1H, HAr), 7.31 (t, J = 7.6 Hz, 1H, HAr), 4.81 (t, J = 5.4 Hz, 1H, CH(OEt)2), 4.42 (s, 2H, NH2), 4.37 (d, J = 5.4 Hz, 2H, CH2CH), 3.78 (dd, J = 9.2, 7.1 Hz, 2H, OCH2CH3), 3.56 (dd, J = 9.2, 7.1 Hz, 2H, OCH2CH3), 3.22 (s, 1H, Ar-CCH), 1.20 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.8, 134.6, 133.7, 130.6, 130.3, 129.5, 127.5, 119.3, 102.5, 83.3, 81.0, 64.4, 50.0, 15.4. HRMS (ESI) C16H21N4O2, m/z: calc. for [M+H]+: 301.1666; found: 301.1659.
1-(2,2-diethoxyethyl)-4-(2-(p-tolylethynyl)phenyl)-1H-1,2,3-triazol-5-amine (3i)
Compound 3i was synthesized according to general procedure A (yield 93%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 7.8 Hz, 1H, HAr), 7.61 (d, J = 7.7 Hz, 1H, HAr), 7.42 (t, J = 7.6 Hz, 1H, HAr), 7.37 (d, J = 8.0 Hz, 2H, HAr), 7.33 (t, J = 7.7 Hz, 1H, HAr), 7.12 (d, J = 7.8 Hz, 2H, HAr), 4.82 (t, J = 5.2 Hz, 1H, 1H, CH(OEt)2), 4.56 (s, 2H, NH2), 4.39 (d, J = 5.3 Hz, 2H, CH2CH), 3.75 (dd, J = 9.0, 7.2 Hz, 2H, OCH2CH3), 3.53 (dd, J = 9.0, 7.1 Hz, 2H, OCH2CH3), 2.35 (s, 3H, ArCH3), 1.13 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.9, 138.8, 133.9, 132.9, 131.5, 130.9, 130.2, 129.2, 128.7, 127.4, 120.6, 119.9, 102.4, 93.5, 88.2, 64.4, 50.0, 21.6, 15.2. HRMS (ESI) C23H27N4O2, m/z: calc. for [M+H]+: 391.2129; found: 391.2132.
4,4′-(1,4-phenylene)bis(1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine) (3j)
Compound 3j was synthesized according to general procedure B (yield 51%) as a pale yellow solid. M.p. 177–179 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.70 (s, 4H, HAr), 4.77 (t, J = 5.3 Hz, 2H, CH(OEt)2), 4.47 (s, 4H, NH2), 4.34 (d, J = 5.2 Hz, 4H, CH2CH), 3.81–3.74 (m, 4H, OCH2CH3), 3.58–3.51 (m, 4H, OCH2CH3), 1.19 (t, J = 7.0 Hz, 12H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 139.1, 130.4, 130.2, 126.1, 102.4, 64.5, 50.0, 15.3. HRMS (ESI) C22H35N8O4, m/z: calc. for [M+H]+: 475.2776; found: 475.2780.
1-(2,2-diethoxyethyl)-4-(pyridin-2-yl)-1H-1,2,3-triazol-5-amine (3k)
Compound 3k was synthesized according to general procedure A (yield 87%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 4.9 Hz, 1H, HAr), 8.08 (d, J = 8.1 Hz, 1H, HAr), 7.70 (td, J = 8.0, 1.7 Hz, 1H, HAr), 7.09–7.04 (m, 1H, HAr), 5.86 (s, 2H, NH2), 4.78 (t, J = 5.3 Hz, 1H, CH(OEt)2), 4.34 (d, J = 5.3 Hz, 2H, CH2CH), 3.82–3.75 (m, 2H, OCH2CH3), 3.59–3.53 (m, 2H, OCH2CH3), 1.21 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 153.0, 148.3, 142.8, 136.4, 127.8, 120.2, 118.3, 102.2, 64.2, 49.7, 15.2. HRMS (ESI) C13H20N5O2, m/z: calc. for [M+H]+: 278.1612; found: 278.1617.
1-(2,2-diethoxyethyl)-4-(4-(7-(4-methoxyphenyl)benzo[c][1,2,5]thiadiazol-4-yl)phenyl)-1H-1,2,3-triazol-5-amine (3l)
Compound 3l was synthesized according to general procedure B (yield 46%) as a red solid. M.p. 156–158 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 8.3 Hz, 2H, HAr), 7.92 (d, J = 8.7 Hz, 2H, HAr), 7.84 (d, J = 8.2 Hz, 2H, HAr), 7.78 (d, J = 7.3 Hz, 1H, HBTD), 7.72 (d, J = 7.3 Hz, 1H, HBTD), 7.07 (d, J = 8.6 Hz, 2H, HAr), 4.81 (t, J = 5.3 Hz, 1H, CH(OEt)2), 4.52 (s, 2H, NH2), 4.39 (d, J = 5.3 Hz, 2H, CH2CH), 3.89 (s, 3H, ArOCH3), 3.84–3.77 (m, 2H, OCH2CH3), 3.61–3.54 (m, 2H, OCH2CH3), 1.22 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 160.0, 154.3, 154.2, 139.4, 135.9, 133.0, 132.2, 131.9, 130.5, 130.1, 129.9, 129.8, 128.1, 127.4, 125.8, 114.2, 102.6, 64.6, 55.5, 50.1, 15.4. HRMS (ESI) C27H29N6O3S, m/z: calc. for [M+H]+: 517.2016; found: 517.2018.
4-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)-1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine (3m)
Compound 3m was synthesized according to general procedure B (yield 73%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 7.5 Hz, 1H, HAr), 7.50–7.42 (m, 3H, HAr), 7.35–7.31 (m, 3H, HAr), 7.22–7.18 (m, 3H, HAr), 5.45 (s, 2H, CH2Ar), 4.68 (t, J = 5.2 Hz, 1H, CH(OEt)2), 4.12 (d, J = 5.2 Hz, 2H, CH2CH), 3.81 (s, 2H, NH2), 3.74–3.68 (m, 2H, OCH2CH3), 3.51–3.45 (m, 2H, OCH2CH3), 1.13 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 146.7, 139.4, 134.8, 131.2, 130.4, 130.3, 129.6, 129.2, 129.1, 128.7, 128.7, 128.7, 128.0, 122.8, 102.3, 64.4, 54.1, 49.8, 15.3. HRMS (ESI) C23H28N7O2, m/z: calc. for [M+H]+: 434.2299; found: 434.2297.
4-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)-1-(2,2-diethoxyethyl)-1H-1,2,3-triazol-5-amine (3n)
Compound 3n was synthesized according to general procedure B (yield 84%) as a light brown oil. 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.2 Hz, 2H, HAr), 7.70 (d, J = 8.1 Hz, 3H, HAr), 7.40–7.36 (m, 3H, HAr), 7.33–7.30 (m, 2H, HAr), 5.57 (s, 2H, CH2Ar), 4.78 (t, J = 5.2 Hz, 1H, CH(OEt)2), 4.46 (s, 2H, NH2), 4.36 (d, J = 5.2 Hz, 2H, CH2CH), 3.79 (dd, J = 9.2, 7.0 Hz, 2H, OCH2CH3), 3.56 (dd, J = 9.2, 7.1 Hz, 2H, OCH2CH3), 1.21 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 148.0, 139.2, 134.8, 131.8, 130.1, 129.3, 129.1, 128.9, 128.2, 126.3, 126.0, 119.6, 102.5, 64.6, 54.4, 50.1, 15.4. HRMS (ESI) C23H28N7O2, m/z: calc. for [M+H]+: 434.2299; found: 434.2304.
(1H-imidazol-2-yl)(phenyl)methanol (4a) [6]
Compound 4a was synthesized from 3a according to general procedure C via boiling in conc. HCl (white solid yield 89%). M.p. 196–198 °C (lit.: 192–194 °C [42]). 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H, NH), 7.39 (d, J = 7.6 Hz, 2H, HAr), 7.30 (t, J = 7.5 Hz, 2H, HAr), 7.21 (t, J = 7.2 Hz, 1H, HAr), 6.97 (s, 1H, -HC=CH-), 6.75 (s, 1H, -HC=CH-), 6.22 (d, J = 4.5 Hz, 1H, OH), 5.71 (d, J = 4.4 Hz, 1H, CHOH). 13C NMR (101 MHz, DMSO-d6) δ 150.2, 143.4, 128.0, 127.0, 126.4, 115.9, 69.6. HRMS (ESI) C10H11N2O, m/z: calc. for [M+H]+: 175.0866; found: 157.0869.
2-(methoxy(phenyl)methyl)-1H-imidazole (4b)
Compound 4b was synthesized according to general procedure C (yield 75%) from 3a and MeOH as a pale yellow solid. M.p. 99–100 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H, NH), 7.40–7.32 (m, 4H, HAr), 7.30–7.25 (m, 1H, HAr), 6.93 (s, 2H, -HC=CH-), 5.38 (s, 1H, CHOR), 3.26 (s, 3H, OCH3). 1H NMR (400 MHz, Chloroform-d) δ 7.37–7.29 (m, 5H, HAr), 6.98 (s, 2H, -HC=CH-), 5.44 (s, 1H, CHOR), 3.40 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6) δ 147.2, 140.0, 128.2, 127.7, 126.9, 109.6, 79.3, 56.5. HRMS (ESI) C11H13N2O, m/z: calc. for [M+H]+: 189.1022; found: 189.1022.
2-(ethoxy(phenyl)methyl)-1H-imidazole (4c)
Compound 4c was synthesized according to general procedure C (yield 57%) from 3a and EtOH as a white solid. M.p. 127–129 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H, NH), 7.38 (t, J = 8.8 Hz, 2H, HAr), 7.33 (d, J = 7.6 Hz, 2H, HAr), 7.29–7.24 (m, 1H, HAr), 6.92 (s, 2H, -HC=CH-), 5.48 (s, 1H, CHOR), 3.46–3.38 (m, 2H), 1.16 (t, J = 7.0 Hz, 3H, CH3). 1H NMR (400 MHz, Chloroform-d) δ 7.38–7.33 (m, 4H, HAr), 7.32–7.29 (m, 1H, HAr), 6.98 (s, 2H, -HC=CH-), 5.54 (s, 1H, CHOR), 3.60–3.52 (m, 2H, OCH2CH3), 1.25 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, DMSO-d6) δ 147.6, 140.4, 128.2, 127.5, 126.8, 77.4, 64.0, 15.1. HRMS (ESI) C12H15N2O, m/z: calc. for [M+H]+: 203.1179; found: 203.1166.
2-(isopropoxy(phenyl)methyl)-1H-imidazole (4d)
Compound 4d was synthesized according to general procedure C (yield 48%) from 3a and i-PrOH as a white solid. M.p. 83–85 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H, NH), 7.38 (d, J = 7.2 Hz, 2H, HAr), 7.32 (t, J = 7.4 Hz, 2H, HAr), 7.25 (t, J = 7.1 Hz, 1H, HAr), 6.91 (s, 2H, -HC=CH-), 5.58 (s, 1H, CHOR), 3.55 (p, J = 6.1 Hz, 1H, OCH(CH3)2), 1.14 (d, J = 6.0 Hz, 3H, OCH(CH3)2), 1.11 (d, J = 6.1 Hz, 3H, OCH(CH3)2). 1H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 7.3 Hz, 2H, HAr), 7.30 (d, J = 7.0 Hz, 2H, HAr), 7.26–7.23 (m, 1H, HAr), 6.93 (s, 2H, -HC=CH-), 5.66 (s, 1H, CHOR), 3.73–3.66 (m, 1H, OCH(CH3)2), 1.18 (d, J = 6.2 Hz, 3H, OCH(CH3)2), 1.16 (d, J = 6.2 Hz, 3H, OCH(CH3)2). 13C NMR (101 MHz, DMSO-d6) δ 148.0, 140.9, 128.1, 127.4, 126.8, 74.8, 69.1, 22.1. HRMS (ESI) C13H17N2O, m/z: calc. for [M+H]+: 217.1335; found: 217.1333.
2-(butoxy(phenyl)methyl)-1H-imidazole (4e)
Compound 4e was synthesized according to general procedure C (yield 51%) from 3a and n-BuOH as a light yellow solid. M.p. 93–95 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H, NH), 7.40–7.31 (m, 4H, HAr), 7.28–7.24 (m, 1H, HAr), 6.92 (s, 2H, -HC=CH-), 5.45 (s, 1H, CHOR), 3.39–3.33 (m, 2H, O(CH2)3CH3), 1.57–1.48 (m, 2H, O(CH2)3CH3), 1.38–1.30 (m, 2H, O(CH2)3CH3), 0.85 (t, J = 7.1 Hz, 3H, O(CH2)3CH3). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (t, J = 8.2 Hz, 4H, HAr), 7.29 (d, J = 7.2 Hz, 1H, HAr), 6.98 (s, 2H, -HC=CH-), 5.54 (s, 1H, CHOR), 3.54–3.46 (m, 2H, O(CH2)3CH3), 1.65–1.58 (m, 2H, O(CH2)3CH3), 1.43–1.36 (m, 2H, O(CH2)3CH3), 0.90 (t, J = 7.4 Hz, 3H, O(CH2)3CH3). 13C NMR (101 MHz, DMSO-d6) δ 147.5, 140.4, 128.2, 127.5, 126.8, 77.6, 68.2, 31.3, 18.9, 13.8. HRMS (ESI) C14H19N2O, m/z: calc. for [M+H]+: 231.1492; found: 231.1493.
2-(tert-butoxy(phenyl)methyl)-1H-imidazole (4f)
Compound 4f was synthesized according to general procedure C (yield 35%) from 3a and t-BuOH as a white solid. M.p. 129–131 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.39 (d, J = 7.6 Hz, 2H, HAr), 7.30 (t, J = 7.4 Hz, 2H, HAr), 7.22 (t, J = 7.3 Hz, 1H, HAr), 6.96 (s, 2H, -HC=CH-), 5.82 (s, 1H, CHOR), 1.23 (s, 9H, OC(CH3)3). 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 7.35 (d, J = 7.7 Hz, 2H, HAr), 7.29 (t, J = 7.4 Hz, 2H, HAr), 7.21 (t, J = 7.1 Hz, 1H, HAr), 6.88 (s, 2H, -HC=CH-), 5.72 (s, 1H, CHOR), 1.15 (s, 9H, OC(CH3)3). 13C NMR (101 MHz, Chloroform-d) δ 150.5, 142.0, 128.7, 128.5, 127.6, 126.8, 126.4, 76.0, 70.7, 28.5. HRMS (ESI) C14H19N2O, m/z: calc. for [M+H]+: 231.1492; found: 231.1495.
2-((2-bromophenyl)(methoxy)methyl)-1H-imidazole (4g)
Compound 4g was synthesized according to general procedure C (yield 62%) from 3b and MeOH as a white solid. M.p. 159–160 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 8.0 Hz, 1H, HAr), 7.41 (d, J = 7.7 Hz, 1H, HAr), 7.30 (t, J = 7.5 Hz, 1H, HAr), 7.16 (t, J = 7.6 Hz, 1H, HAr), 6.98 (s, 2H, -HC=CH-), 5.81 (s, 1H, CHOR), 3.41 (s, 3H, OCH3). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H, NH), 7.60 (d, J = 8.0 Hz, 1H, HAr), 7.54 (d, J = 7.7 Hz, 1H, HAr), 7.42 (t, J = 7.5 Hz, 1H, HAr), 7.26 (t, J = 7.7 Hz, 1H, HAr), 6.95 (s, 2H, -HC=CH-), 5.64 (s, 1H, CHOR), 3.28 (s, 3H, OCH3). 13C NMR (101 MHz, Chloroform-d) δ 146.7, 138.2, 133.2, 129.9, 128.8, 128.0, 123.9, 122.3, 78.6, 57.5. HRMS (ESI) C11H12BrN2O, m/z: calc. for [M+H]+: 267.0128; found: 267.0132.
2-((2-bromophenyl)(ethoxy)methyl)-1H-imidazole (4h)
Compound 4h was synthesized according to general procedure C (yield 70%) from 3b and EtOH as a light brown solid. M.p. 147–149 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 8.0 Hz, 1H, HAr), 7.41 (d, J = 7.8 Hz, 1H, HAr), 7.32 (t, J = 7.5 Hz, 1H, HAr), 7.17 (t, J = 7.5 Hz, 1H, HAr), 7.01 (s, 2H, -HC=CH-), 5.94 (s, 1H, CHOR), 3.60 (q, J = 7.0 Hz, 2H, OCH2CH3), 1.27 (t, J = 7.0 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H, NH), 7.58 (t, J = 7.6 Hz, 2H, HAr), 7.42 (t, J = 7.5 Hz, 1H, HAr), 7.25 (t, J = 7.6 Hz, 1H, HAr), 7.07 (s, 1H, -HC=CH-), 6.80 (s, 1H, =CH), 5.73 (s, 1H, CHOR), 3.45 (q, J = 7.0 Hz, 2H, OCH2CH3), 1.15 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.0, 138.7, 133.1, 129.7, 128.9, 127.9, 123.8, 122.2, 76.8, 65.2, 15.3. HRMS (ESI) C12H14BrN2O, m/z: calc. for [M+H]+: 281.0284; found: 281.0290.
2-((2-chlorophenyl)(ethoxy)methyl)-1H-imidazole (4i)
Compound 4i was synthesized according to general procedure C (yield 50%) from 3c and EtOH as a white solid. M.p. 148–149 °C. 1H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H, NH), 7.40 (dd, J = 7.3, 1.9 Hz, 1H, HAr), 7.36 (dd, J = 7.5, 1.6 Hz, 1H, HAr), 7.26–7.22 (m, 2H, HAr), 7.07–6.92 (m, 2H, -HC=CH-), 5.95 (s, 1H, CHOR), 3.58 (q, J = 7.0 Hz, 2H, OCH2CH3), 1.24 (t, J = 7.0 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H, NH), 7.60 (d, J = 7.1 Hz, 1H, HAr), 7.44–7.36 (m, 2H, HAr), 7.35–7.30 (m, 1H, HAr), 6.93 (s, 2H, -HC=CH-), 5.78 (s, 1H, CHOR), 3.45 (q, J = 7.0 Hz, 2H, OCH2CH3), 1.15 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.1, 137.1, 133.6, 129.7, 129.4, 128.7, 127.2, 122.2, 74.6, 65.2, 15.3. HRMS (ESI) C12H14ClN2O, m/z: calc. for [M+H]+: 237.0789; found: 281.0795.
2-(ethoxy(4′-methoxy-[1,1′-biphenyl]-2-yl)methyl)-1H-imidazole (4j)
Compound 4j was synthesized according to general procedure C (yield 70%) from 3d and EtOH as a pale yellow solid. M.p. 158–159 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.38–7.35 (m, 1H, HAr), 7.31–7.23 (m, 5H, HAr), 6.92 (s, 2H, -HC=CH-), 6.89 (d, J = 8.4 Hz, 2H, HAr), 5.59 (s, 1H, CHOR), 3.80 (s, 3H, ArOCH3), 3.25 (p, J = 7.3 Hz, 2H, OCH2CH), 1.04 (t, J = 7.0 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H, NH), 7.56 (d, J = 7.1 Hz, 1H, HAr), 7.33 (d, J = 8.7 Hz, 4H, HAr), 7.22–7.18 (m, 1H, HAr), 7.00 (d, J = 8.6 Hz, 2H, HAr), 6.92 (s, 2H, -HC=CH-), 5.48 (s, 1H, CHOR), 3.82 (s, 3H, ArOCH3), 3.25–3.19 (m, 2H, OCH2CH3), 1.02 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 158.9, 148.8, 142.2, 137.2, 133.0, 130.7, 130.4, 128.0, 127.7, 127.7, 113.6, 74.8, 64.4, 55.4, 15.3. HRMS (ESI) C19H21N2O2, m/z: calc. for [M+H]+: 309.1598; found: 309.1604.
2-(isopropoxy(4′-methoxy-[1,1′-biphenyl]-2-yl)methyl)-1H-imidazole (4k)
Compound 4k was synthesized according to general procedure C (yield 77%) from 3d and i-PrOH as a white solid. M.p. 167–169 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.43–7.39 (m, 1H, HAr), 7.37 (d, J = 8.6 Hz, 2H, HAr), 7.33–7.29 (m, 2H, HAr), 7.26–7.23 (m, 1H, HAr), 6.96 (s, 2H, -HC=CH-), 6.92 (d, J = 8.6 Hz, 2H, HAr), 5.76 (s, 1H, CHOR), 3.83 (s, 3H, ArOCH3), 3.42 (h, J = 6.0 Hz, 1H, OCH(CH3)2), 0.97 (d, J = 6.2 Hz, 3H, OCH(CH3)2), 0.91 (d, J = 6.0 Hz, 3H, OCH(CH3)2). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 7.60 (d, J = 7.6 Hz, 1H, HAr), 7.38 (d, J = 8.4 Hz, 2H, HAr), 7.36–7.28 (m, 2H, HAr), 7.19 (d, J = 7.4 Hz, 1H, HAr), 7.05 (s, 1H, -HC=CH-), 7.01 (d, J = 8.3 Hz, 2H, HAr), 6.81 (s, 1H, -HC=CH-), 5.62 (s, 1H, CHOR), 3.80 (s, 3H, ArOCH3), 3.32–3.25 (m, 1H, OCH(CH3)2), 0.91–0.87 (m, 6H, OCH(CH3)2). 13C NMR (101 MHz, Chloroform-d) δ 158.9, 149.4, 142.0, 137.7, 133.0, 130.9, 130.3, 127.9, 127.7, 113.6, 71.9, 69.3, 55.4, 22.9, 21.5. HRMS (ESI) C20H23N2O2, m/z: calc. for [M+H]+: 323.1754; found: 323.1761.
2-((4-bromophenyl)(ethoxy)methyl)-1H-imidazole (4l)
Compound 4l was synthesized according to general procedure C (yield 86%) from 3e and EtOH as a pale yellow solid. M.p. 153–154 °C. 1H NMR (400 MHz, Chloroform-d) δ 9.34 (s, 1H, NH), 7.47 (d, J = 8.4 Hz, 2H, HAr), 7.26–7.23 (d, J = 8.3 Hz, 2H, HAr), 6.99 (s, 2H, -HC=CH-), 5.49 (s, 1H, CHOR), 3.59–3.52 (m, 2H, OCH2CH3), 1.25 (t, J = 7.0 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H, NH), 7.54 (d, J = 8.3 Hz, 2H, HAr), 7.33 (d, J = 8.2 Hz, 2H, HAr), 7.05 (s, 1H, -HC=CH-), 6.80 (s, 1H, -HC=CH-), 5.48 (s, 1H, CHOR), 3.43 (q, J = 7.0 Hz, 2H, OCH2CH3), 1.16 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 148.0, 138.7, 131.8, 128.6, 122.1, 77.4, 65.2, 15.3. HRMS (ESI) C12H14BrN2O, m/z: calc. for [M+H]+: 281.0284; found: 281.0290.
2-(methoxy(4′-methyl-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole (4m)
Compound 4m was synthesized according to general procedure C (yield 45%) from 3f and MeOH as a light brown solid. M.p. 147–149 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H, NH), 7.61 (d, J = 8.0 Hz, 2H, HAr), 7.54 (d, J = 7.9 Hz, 2H, HAr), 7.44 (d, J = 8.1 Hz, 2H, HAr), 7.26 (d, J = 7.9 Hz, 2H, HAr), 6.94 (s, 2H, -HC=CH-), 5.42 (s, 1H, CHOR), 3.29 (s, 3H, ArCH3), 2.33 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO-d6) δ 147.2, 139.4, 138.8, 136.9, 136.7, 129.5, 128.9, 127.4, 126.4, 126.2, 125.0, 78.9, 56.5, 20.6. HRMS (ESI) C18H19N2O, m/z: calc. for [M+H]+: 279.1492; found: 279.1496.
2-(ethoxy(4′-methyl-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole (4n)
Compound 4n was synthesized according to general procedure C (yield 71%) from 3f and EtOH as a light brown solid. M.p. 136–138 °C. 1H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H, NH), 7.56 (d, J = 8.1 Hz, 2H, HAr), 7.47–7.42 (m, 4H, HAr), 7.24 (d, J = 8.0 Hz, 2H, HAr), 7.02 (s, 2H, -HC=CH-), 5.59 (s, 1H, CHOR), 3.61 (dq, J = 14.3, 7.3 Hz, 2H, OCH2CH3), 2.39 (s, 3H, ArCH3), 1.28 (t, J = 7.0 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H, NH), 7.60 (d, J = 8.1 Hz, 2H, HAr), 7.54 (d, J = 7.9 Hz, 2H, HAr), 7.45 (d, J = 8.0 Hz, 2H, HAr), 7.26 (d, J = 7.8 Hz, 2H, HAr), 6.93 (s, 2H, -HC=CH-), 5.52 (s, 1H, CHOR), 3.49–3.42 (m, 2H, OCH2CH3), 2.33 (s, 3H, ArCH3), 1.18 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 148.6, 141.0, 138.3, 138.0, 137.2, 129.6, 128.9, 127.5, 127.3, 127.2, 127.0, 77.8, 65.1, 21.2, 15.4. HRMS (ESI) C19H21N2O, m/z: calc. for [M+H]+: 293.1648; found: 293.1648.
2-(isopropoxy(4′-methyl-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole (4o)
Compound 4o was synthesized according to general procedure C (yield 62%) from 3f and i-PrOH as a yellow solid. M.p. 174–175 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.1 Hz, 2H, HAr), 7.46–7.42 (m, 4H, HAr), 7.23 (d, J = 7.8 Hz, 2H, HAr), 7.01 (s, 2H, -HC=CH-), 5.72 (s, 1H, CHOR), 3.80–3.74 (m, 1H, OCH(CH3)2), 2.39 (s, 3H, ArCH3), 1.24 (d, J = 6.3 Hz, 3H, OCH(CH3)2), 1.22 (d, J = 6.1 Hz, 3H, OCH(CH3)2). 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H, NH), 7.59 (d, J = 8.0 Hz, 2H, HAr), 7.53 (d, J = 7.8 Hz, 2H, HAr), 7.44 (d, J = 8.1 Hz, 2H, HAr), 7.26 (d, J = 7.8 Hz, 2H, HAr), 6.93 (s, 2H, -HC=CH-), 5.63 (s, 1H, CHOR), 3.62–3.56 (m, 1H, OCH(CH3)2), 2.33 (s, 3H, ArCH3), 1.16 (d, J = 6.1 Hz, 3H, OCH(CH3)2), 1.13 (d, J = 6.0 Hz, 3H, OCH(CH3)2). 13C NMR (101 MHz, Chloroform-d) δ 149.0, 140.8, 138.9, 137.9, 137.1, 129.5, 128.8, 127.2, 127.1, 127.0, 75.1, 70.2, 22.6, 22.1, 21.2. HRMS (ESI) C20H23N2O, m/z: calc. for [M+H]+: 307.1805; found: 307.1809.
2-(butoxy(4′-methyl-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole (4p)
Compound 4p was synthesized according to general procedure C (yield 84%) from 3f and n-BuOH as a white solid. M.p. 138–140 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.1 Hz, 2H, HAr), 7.47–7.41 (m, 4H, HAr), 7.23 (d, J = 8.0 Hz, 2H, HAr), 7.01 (s, 2H, -HC=CH-), 5.57 (s, 1H, CHOR), 3.59–3.49 (m, 2H, O(CH2)3CH3), 2.39 (s, 3H, ArCH3), 1.66–1.60 (m, 2H, O(CH2)3CH3), 1.46–1.39 (m, 2H, O(CH2)3CH3), 0.92 (t, J = 7.4 Hz, 3H, O(CH2)3CH3). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H, NH), 7.60 (d, J = 8.2 Hz, 2H, HAr), 7.53 (d, J = 8.1 Hz, 2H, HAr), 7.44 (d, J = 8.2 Hz, 2H, HAr), 7.25 (d, J = 8.0 Hz, 2H, HAr), 7.04 (s, 1H, -HC=CH-), 6.81 (s, 1H, -HC=CH-), 5.49 (s, 1H, CHOR), 3.43–3.38 (m, 2H, O(CH2)3CH3), 2.33 (s, 3H, ArCH3), 1.57–1.52 (m, 2H, O(CH2)3CH3), 1.39–1.33 (m, 2H, O(CH2)3CH3), 0.86 (t, J = 7.4 Hz, 3H, O(CH2)3CH3). 13C NMR (101 MHz, Chloroform-d) δ 148.7, 141.1, 138.3, 138.0, 137.3, 129.6, 128.9, 127.5, 127.3, 127.3, 127.1, 78.0, 69.5, 32.0, 21.2, 19.5, 14.0. HRMS (ESI) C21H25N2O, m/z: calc. for [M+H]+: 321.1961; found: 321.1968.
(1H-imidazol-2-yl)(4′-methyl-[1,1′-biphenyl]-4-yl)methanol (4q)
Compound 4q was synthesized from 3f according to general procedure C via boiling in conc. HCl (light brown solid, yield 85%). M.p. 148–149 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.1 Hz, 2H, HAr), 7.53 (d, J = 8.0 Hz, 2H, HAr), 7.45 (d, J = 8.3 Hz, 2H, HAr), 7.25 (d, J = 8.0 Hz, 2H, HAr), 6.92 (s, 2H, -HC=CH-), 6.22 (s, 1H, OH), 5.77 (s, 1H, CHOH), 2.33 (s, 3H, ArCH3). 13C NMR (101 MHz, DMSO-d6) δ 150.0, 142.0, 138.9, 137.1, 136.6, 129.5, 128.9, 126.9, 126.4, 126.0, 69.2, 20.6. HRMS (ESI) C17H17N2O, m/z: calc. for [M+H]+: 265.1335; found: 265.1342.
2-(ethoxy(2-(p-tolylethynyl)phenyl)methyl)-1H-imidazole (4r)
Compound 4r was synthesized according to general procedure C (yield 53%) from 3i and EtOH as a white solid. M.p. 137–139 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 7.1 Hz, 1H, HAr), 7.40 (t, J = 8.2 Hz, 3H, HAr), 7.35–7.29 (m, 2H, HAr), 7.15 (d, J = 7.8 Hz, 2H, HAr), 7.00 (s, 2H, -HC=CH-), 6.08 (s, 1H, CHOR), 3.68–3.61 (m, 2H, OCH2CH3), 2.36 (s, 3H, ArCH3), 1.26 (t, J = 7.0 Hz, 1H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H, NH), 7.57 (d, J = 7.9 Hz, 1H, HAr), 7.51 (d, J = 7.5 Hz, 1H, HAr), 7.47 (d, J = 8.0 Hz, 2H, HAr), 7.44–7.39 (m, 1H, HAr), 7.34 (t, J = 7.6 Hz, 1H, HAr), 7.25 (d, J = 8.2 Hz, 2H, HAr), 6.95 (s, 2H, =CH), 5.94 (s, 1H, CHOR), 3.49 (q, J = 7.1 Hz, 2H, OCH2CH3), 2.34 (s, 3H, ArCH3), 1.16 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.9, 140.9, 138.8, 133.2, 132.7, 131.6, 129.8, 129.3, 128.8, 128.2, 127.9, 127.4, 123.0, 120.1, 94.6, 86.6, 76.1, 65.2, 21.6, 15.4. HRMS (ESI) C26H25N4O2S, m/z: calc. for [M+H]+: 317.1648; found: 317.1655.
2-(ethoxy(2-ethynylphenyl)methyl)-1H-imidazole (4s)
Compound 4s was synthesized according to general procedure C (yield 91%) from 3h and EtOH as a light brown solid. M.p. 148–150 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 7.8 Hz, 1H, HAr), 7.37 (dd, J = 11.2, 7.4 Hz, 2H, HAr), 7.28 (d, J = 1.0 Hz, 1H, HAr), 7.00 (s, 2H, -HC=CH-), 6.04 (s, 1H, CHOR), 3.63–3.57 (m, 2H, OCH2CH3), 3.32 (s, 1H, Ar-CCH), 1.28–1.25 (m, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H, NH), 7.53 (d, J = 8.0 Hz, 1H, HAr), 7.46 (d, J = 7.7 Hz, 1H, HAr), 7.42 (t, J = 7.5 Hz, 1H, HAr), 7.31 (t, J = 7.6 Hz, 1H, HAr), 6.93 (s, 2H, -HC=CH-), 5.87 (s, 1H, CHOR), 4.41 (s, 1H, Ar-CCH), 3.46–3.40 (m, 2H, OCH2CH3), 1.14 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.8, 141.8, 133.3, 129.5, 128.1, 127.1, 121.7, 82.4, 81.4, 75.8, 65.1, 29.8. HRMS (ESI) C14H15N2O, m/z: calc. for [M+H]+: 227.1179; found: 227.1183.
2-(ethoxy(4-ethynylphenyl)methyl)-1H-imidazole (4t)
Compound 4t was synthesized according to general procedure C (yield 76%) from 3g and EtOH as a white solid. M.p. 155–157 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H, NH), 7.44 (d, J = 8.1 Hz, 2H, HAr), 7.38 (d, J = 8.0 Hz, 2H, HAr), 7.06–6.75 (m, 2H, -HC=CH-), 5.50 (s, 1H, CHOR), 4.08 (s, 1H, Ar-CCH), 3.49–3.43 (m, 2H, OCH2CH3), 1.17 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 148.0, 140.4, 132.3, 126.8, 122.2, 121.8, 112.9, 83.4, 77.5, 77.5, 65.1, 15.3. HRMS (ESI) C14H15N2O, m/z: calc. for [M+H]+: 227.1179; found: 227.1181.
4-(4-(ethoxy(1H-imidazol-2-yl)methyl)phenyl)-7-(4-methoxyphenyl)benzo[c][1,2,5]thiadiazole (4u)
Compound 4u was synthesized according to general procedure C (yield 86%) from 3l and EtOH as a yellow solid. M.p. 164–166 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.96–7.91 (m, 4H, HAr), 7.73 (s, 2H, HAr), 7.57 (d, J = 8.2 Hz, 2H, HAr), 7.08 (d, J = 8.7 Hz, 2H, HAr), 7.03 (s, 2H, -HC=CH-), 5.67 (s, 1H, CHOR), 3.90 (s, 3H, ArOCH3), 3.71–3.60 (m, 2H, OCH2CH3), 1.31 (d, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 160.0, 154.2, 148.5, 139.6, 137.5, 133.2, 132.3, 130.6, 130.0, 129.6, 128.4, 127.4, 127.1, 114.3, 77.8, 65.3, 55.6, 15.4. HRMS (ESI) C25H23N4O2S, m/z: calc. for [M+H]+: 443.1536; found: 443.1541.
4-(4-((1H-imidazol-2-yl)(isopropoxy)methyl)phenyl)-7-(4-methoxyphenyl)benzo[c][1,2,5]thiadiazole (4v)
Compound 4v was synthesized according to general procedure C (yield 76%) from 3l and i-PrOH as a yellow solid. M.p. 175–177 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 8.2, 5.1 Hz, 4H, HAr), 7.71 (s, 2H, HAr), 7.57 (d, J = 8.0 Hz, 2H, HAr), 7.08 (d, J = 8.3 Hz, 2H, HAr), 7.02 (s, 2H, -HC=CH-), 5.79 (s, 1H, CHOR), 3.89 (s, 3H, ArOCH3), 3.85–3.80 (m, 1H, OCH(CH3)2), 1.27 (d, J = 6.3 Hz, 3H, OCH(CH3)2), 1.24 (d, J = 6.0 Hz, 3H, OCH(CH3)2). 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H, NH), 8.00 (d, J = 8.7 Hz, 2H, HAr), 7.97 (d, J = 8.1 Hz, 2H, HAr), 7.90 (s, 2H), 7.56 (d, J = 8.0 Hz, 2H, HAr), 7.12 (d, J = 8.5 Hz, 2H, HAr), 7.04 (s, 1H, -HC=CH-), 6.84 (s, 1H, -HC=CH-), 5.69 (s, 1H, CHOR), 3.86 (s, 3H, ArOCH3), 3.72–3.66 (m, 1H, OCH(CH3)2), 1.21 (d, J = 6.0 Hz, 3H, OCH(CH3)2), 1.17 (d, J = 6.0 Hz, 3H, OCH(CH3)2). 13C NMR (101 MHz, Chloroform-d) δ 160.0, 154.3, 149.0, 140.2, 137.3, 133.2, 132.3, 130.6, 130.0, 129.5, 128.4, 127.4, 127.1, 114.3, 75.1, 70.5, 55.5, 22.8, 22.1. HRMS (ESI) C26H25N4O2S, m/z: calc. for [M+H]+: 457.1693; found: 457.1696.
1,4-bis(ethoxy(1H-imidazol-2-yl)methyl)benzene (4w)
Compound 4w was synthesized according to general procedure C (yield 44%) from 3j and EtOH as a white solid. M.p. 196–198 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 2H, NH), 7.35 (s, 4H, HAr), 6.90 (s, 4H, -HC=CH-), 5.45 (s, 2H, CHOR), 3.43–3.38 (m, 4H, OCH2CH3), 1.14 (t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, DMSO-d6) δ 147.4, 139.6, 126.6, 126.6, 77.1, 63.9, 15.1. HRMS (ESI) C18H23N4O2, m/z: calc. for [M+H]+: 327.1816; found: 327.1820.
1,4-bis((1H-imidazol-2-yl)(isopropoxy)methyl)benzene (4x)
Compound 4x was synthesized according to general procedure C (yield 76%) from 3j and i-PrOH as a white solid. M.p. 206–207 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 2H, NH), 7.33 (s, 4H, HAr), 7.00 (s, 2H, -HC=CH-), 6.76 (s, 2H, -HC=CH-), 5.55 (s, 2H, CHOR), 3.56–3.50 (m, 2H, OCH(CH3)2), 1.12 (d, J = 6.1 Hz, 6H, OCH(CH3)2), 1.09 (d, J = 6.1 Hz, 6H, OCH(CH3)2). 13C NMR (101 MHz, DMSO-d6) δ 147.9, 140.0, 126.5, 126.5, 116.5, 74.6, 69.0, 22.0. HRMS (ESI) C20H27N4O2, m/z: calc. for [M+H]+: 355.2129; found: 355.2136.
1-benzyl-4-(2-(ethoxy(1H-imidazol-2-yl)methyl)phenyl)-1H-1,2,3-triazole (4y)
Compound 4y was synthesized according to general procedure C from 3m and EtOH (yield 66%) or general procedure D from 3i (yield 98%) as a white solid. M.p. 147–149 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.85–7.81 (m, 2H, HAr), 7.41–7.35 (m, 7H, HAr), 7.31 (d, J = 7.5 Hz, 1H, HAr), 7.03 (s, 2H, -HC=CH-), 6.00 (s, 1H, CHOR), 5.63 (s, 2H, ArCH2), 3.46–3.35 (m, 2H, OCH2CH3), 1.06 (t, J = 6.8 Hz, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H, NH), 7.64–7.58 (m, 2H, HAr), 7.44–7.40 (m, 3H, HAr), 7.38 (s, 1H, HAr), 7.36–7.34 (m, 3H, HAr), 7.09 (s, 2H, -HC=CH-), 6.07 (s, 1H, CHOR), 5.69 (s, 2H, ArCH2), 3.35 (dd, J = 6.9, 3.0 Hz, 2H, OCH2CH3), 1.05 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, DMSO-d6) δ 145.2, 137.3, 135.9, 133.1, 129.6, 129.1, 128.8, 128.1, 127.9, 127.8, 127.6, 124.2, 73.6, 63.9, 53.0, 15.0. HRMS (ESI) C21H22N5O, m/z: calc. for [M+H]+: 360.1819; found: 360.1824.
1-benzyl-4-(4-(ethoxy(1H-imidazol-2-yl)methyl)phenyl)-1H-1,2,3-triazole (4z)
Compound 4z was synthesized according to general procedure C from 3n and EtOH (yield 75%) and general procedure D from 3g (yield 92%) as a white solid. M.p. 167–169 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 8.1 Hz, 2H, HAr), 7.64 (s, 1H, HAr), 7.42–7.37 (m, 5H, HAr), 7.31–7.28 (m, 2H, HAr), 7.00 (s, 2H, -HC=CH-), 5.58 (s, 1H, CHOR), 5.57 (s, 2H, ArCH2), 3.60–3.54 (m, 2H, OCH2CH3), 1.26–1.24 (m, 3H, OCH2CH3). 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H, NH), 8.61 (s, 1H, HAr), 7.81 (d, J = 8.2 Hz, 2H, HAr), 7.44 (d, J = 8.2 Hz, 2H, HAr), 7.36 (q, J = 6.8 Hz, 5H, HAr), 6.93 (s, 2H, -HC=CH-), 5.64 (s, 2H, ArCH2), 5.50 (s, 1H, CHOR), 3.46–3.41 (m, 2H, OCH2CH3), 1.17 (t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.9, 139.4, 134.8, 130.4, 129.3, 128.9, 128.2, 127.4, 126.0, 119.8, 65.1, 54.3, 15.3. HRMS (ESI) C21H22N5O, m/z: calc. for [M+H]+: 360.1819; found: 360.1823.
3-(1H-imidazol-2-yl)-[1,2,3]triazolo [1,5-a]pyridine (5a)
Compound 5a was synthesized according to general procedure C (yield 78%) from 3k in EtOH as a white solid. M.p. 210–212 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H, NH), 9.12 (d, J = 7.0 Hz, 1H, HAr), 8.38 (d, J = 8.8 Hz, 1H, HAr), 7.56–7.51 (m, 1H, HAr), 7.27 (t, J = 6.9 Hz, 1H, HAr), 7.24 (s, 1H, -HC=CH-), 7.11 (s, 1H, -HC=CH-). 13C NMR (101 MHz, DMSO-d6) δ 139.4, 130.3, 130.2, 129.0, 127.0, 125.8, 119.1, 117.1, 116.7. HRMS (ESI) C9H8N5, m/z: calc. for [M+H]+: 186.0774; found: 186.0774.

4. Conclusions

In summary, we elaborated on a highly efficient transition metal-free access to new functionalized 1H-imidazole derivatives. The method is based on the acid-mediated denitrogenative transformation of 5-amino-4-aryl-1-(2,2-diethoxyethyl)-1,2,3-triazole derivatives involving intramolecular cyclization of 5-amino-1,2,3-triazole acetals followed by triazole ring opening and insertion of in situ formed carbene intermediate into the O-H bond of different alcohols to afford the previously inaccessible 2-substituted imidazoles in good to excellent yields with a broad substrate scope. To the best of our knowledge, this type of transformation has not been previously investigated for 5-amino-1,2,3-triazole derivatives.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30071401/s1: The following are available in File S1: copies of the 1H and 13C NMR spectra for all novel compounds as well as the crystallography data for 4d and 5a.

Author Contributions

Conceptualization: P.S.G. and S.N.O.; methodology: P.S.G.; investigation: P.S.G. (synthesis, NMR spectra registering and characterization), A.N.P., D.N.T. and V.A.V. (synthesis), A.F.A. and M.A.T. (synthesis of (aNHC)CuCl), A.F.S. (X-ray investigation); writing—original draft preparation: P.S.G. and S.N.O.; writing—review and editing: P.S.G. and S.N.O.; supervision: P.S.G.; project administration: P.S.G.; funding acquisition: P.S.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Russian Science Foundation (grant RSF. No. 23-73-01029).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

Spectral characterization, NMR and X-ray diffraction studies were performed using the equipment of the Center for Collective Use of INEOS RAS with the support from the Ministry of Science and Higher Education of the Russian Federation.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 01401 sch001
Scheme 1. Synthetic approaches to (a) 5-amino-1,2,3-triazole derivatives and (b) 1H-imidazoles.
Scheme 1. Synthetic approaches to (a) 5-amino-1,2,3-triazole derivatives and (b) 1H-imidazoles.
Molecules 30 01401 sch001
Molecules 30 01401 sch002
Scheme 2. Synthesis of 5-amino-1-(2,2-diethoxyethyl)-1,2,3-triazole derivatives 3a–n. Reaction conditions: 1 1 (0.5 mmol), 2 (1.1 equiv.), KOtBu (0.1 equiv.), neat, 25 °C, 3 h; 2 1 (0.5 mmol), 2 (3.0 equiv.), KOtBu (0.5 equiv.), DMSO, 70 °C, 3 h.
Scheme 2. Synthesis of 5-amino-1-(2,2-diethoxyethyl)-1,2,3-triazole derivatives 3a–n. Reaction conditions: 1 1 (0.5 mmol), 2 (1.1 equiv.), KOtBu (0.1 equiv.), neat, 25 °C, 3 h; 2 1 (0.5 mmol), 2 (3.0 equiv.), KOtBu (0.5 equiv.), DMSO, 70 °C, 3 h.
Molecules 30 01401 sch002
Molecules 30 01401 sch003
Scheme 3. Synthesis of 1H-imidazole derivatives 4a–z. Reaction conditions: 3 (0.5 mmol), ROH (10 mL), conc. HCl (0.5 mmol), reflux, 3 h.
Scheme 3. Synthesis of 1H-imidazole derivatives 4a–z. Reaction conditions: 3 (0.5 mmol), ROH (10 mL), conc. HCl (0.5 mmol), reflux, 3 h.
Molecules 30 01401 sch003
Molecules 30 01401 g001
Figure 1. Crystal structure of 4d (CCDC 2426762) demonstrating intermolecular interactions N2A…N5B of 2.8327(2) and N2A…H5B of 2.0100 A°. Doted line is the standard designation in cristallography for intermolecular contacts.
Figure 1. Crystal structure of 4d (CCDC 2426762) demonstrating intermolecular interactions N2A…N5B of 2.8327(2) and N2A…H5B of 2.0100 A°. Doted line is the standard designation in cristallography for intermolecular contacts.
Molecules 30 01401 g001
Molecules 30 01401 sch004
Scheme 4. Proposed mechanism of imidazole formation.
Scheme 4. Proposed mechanism of imidazole formation.
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Molecules 30 01401 sch005
Scheme 5. Synthesis of [1,2,3]triazolo[1,5-a]pyridine derivative 5a (CCDC 2426763).
Scheme 5. Synthesis of [1,2,3]triazolo[1,5-a]pyridine derivative 5a (CCDC 2426763).
Molecules 30 01401 sch005
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Gribanov, P.S.; Philippova, A.N.; Smol’yakov, A.F.; Tukhvatullina, D.N.; Vlasova, V.A.; Topchiy, M.A.; Asachenko, A.F.; Osipov, S.N. Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles. Molecules 2025, 30, 1401. https://doi.org/10.3390/molecules30071401

AMA Style

Gribanov PS, Philippova AN, Smol’yakov AF, Tukhvatullina DN, Vlasova VA, Topchiy MA, Asachenko AF, Osipov SN. Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles. Molecules. 2025; 30(7):1401. https://doi.org/10.3390/molecules30071401

Chicago/Turabian Style

Gribanov, Pavel S., Anna N. Philippova, Alexander F. Smol’yakov, Diana N. Tukhvatullina, Viktoria A. Vlasova, Maxim A. Topchiy, Andrey F. Asachenko, and Sergey N. Osipov. 2025. "Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles" Molecules 30, no. 7: 1401. https://doi.org/10.3390/molecules30071401

APA Style

Gribanov, P. S., Philippova, A. N., Smol’yakov, A. F., Tukhvatullina, D. N., Vlasova, V. A., Topchiy, M. A., Asachenko, A. F., & Osipov, S. N. (2025). Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles. Molecules, 30(7), 1401. https://doi.org/10.3390/molecules30071401

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