Direct Functionalization of C(sp2)–H Bond in Nonaromatic

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Article Cite This: ACS Omega 2019, 4, 825−834

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Direct Functionalization of C(sp2)−H Bond in Nonaromatic Azaheterocycles: Palladium-Catalyzed Cross-Dehydrogenative Coupling (CDC) of 2H‑Imidazole 1‑Oxides with Pyrroles and Thiophenes Alexey A. Akulov,† Mikhail V. Varaksin,†,‡ Valery N. Charushin,†,‡ and Oleg N. Chupakhin*,†,‡ †

Department of Organic & Biomolecular Chemistry, Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S. Kovalevskaya Street, 620041 Ekaterinburg, Russia

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‡

S Supporting Information *

ABSTRACT: The C(sp2)−H bond functionalization methodology was first applied to carry out the palladium-catalyzed oxidative C−H/C−H coupling reactions of 2H-imidazole 1oxides with pyrroles and thiophenes. As a result, a number of novel 5-heteroarylated 2H-imidazole 1-oxides, which are of particular interest in the design of bioactive molecules and advanced materials, have been synthesized in yields up to 78%. The detailed H/D-exchange experiments have also been performed to elucidate some mechanistic features of this crossdehydrogenative coupling process.

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INTRODUCTION Many organic compounds bearing the N-oxide structural motif are known as promising building blocks in the design of advanced materials, agrochemicals, cosmetics, and pharmaceuticals.1 The prevalence of the N-oxide scaffold in prospective organic compounds seems to be associated with the specific changes in properties of heterocyclic N-oxides relative to their parent compounds.2 Currently, this distinguishing feature of the N+−O− motif is often used in retrosynthetic schemes as an elegant tool to induce the desired physical and chemical properties, as well as pharmacological activities and other beneficial outcomes for the target compounds. In addition, the N-oxide function is generally considered as one of the privileged scaffolds in the structures of both intermediates and final products exhibiting a variety of therapeutic effects, such as antibacterial, antiviral, anticancer, antiprotozoal, antifungal, neuroprotective, and other activities.3 Among the known biologically active and medicinally important compounds bearing the N-oxide function, derivatives in which the −CN+−O− pharmacophore fragment is partly involved in a (hetero)aromatic ring (Figure 1) attract special attention. For instance, chlordiazepoxide I is a sedative and hypnotic medication of the benzodiazepine family, which is commonly used for the treatment of anxiety, insomnia, and to withdraw symptoms from alcohol and/or drug abuse.4 1,7Naphthyridine N-oxide II, the p38α mitogen-activated protein kinase inhibitor, is considered to be an efficient agent for therapy of autoimmune and inflammatory diseases.5 Indoline derivative III shows neuroprotective spin-trapping properties and prevents cell death under oxidative stress conditions.3j Furoxane IV, being a good nitric oxide donor, proved to possess an increased procognitive activity and cytotoxicity.6 © 2019 American Chemical Society

2,2′-Pyridylisatogen V is a good antioxidant agent with neuroprotective activity.7 It is worth noting that an overwhelming majority of practically interested organic compounds have turned out to be bi- and/or polyfunctional derivatives in which the structural subunits are linked to each other through the carbon−carbon bonds.8 In this respect, one of the key challenges for modern organic synthesis is the development of simple and convenient approaches to obtain the target organic ensembles containing various functional building blocks through the construction of the C−C bonds.9 The effectiveness and expediency of the methods used can be easily assessed, taking into account the compliance of the latter with the basic principles of green chemistry, such as atom and step economy.10 Currently, the green chemistry-oriented C−H functionalization methodology,11,12 which allows one to convert C(sp2)−H bonds of the starting materials into C−C bonds of the target products without any preliminary functionalization of the reactive partners, is considered to be a useful synthetic tool because it provides the environmental-friendly solutions in the design of bi- and/or polyfunctional organic compounds of various architectures. One of the most promising approaches based on the C(sp2)−H functionalization methodology suggests using the transition-metal-catalyzed oxidative C−H/C−H coupling reactions between (hetero)arenes.8a,b,12 These industrially important processes, being atom- and stage-efficient alternative to both C−X/C−Y and C−H/C−X(Y) coupling strategies [X Received: October 26, 2018 Accepted: December 26, 2018 Published: January 10, 2019 825

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Figure 1. Prospective N-oxide-based pharmaceuticals and drug candidates.

= (pseudo)halide, Y = metal], are actively used to functionalize aromatic and heteroaromatic (π-excessive and π-deficient) compounds, including azine N-oxides and other azineactivated forms. At the same time, the number of C−H/C− H coupling reactions studied in the chemistry of nonaromatic nitrogen-containing compounds has still rather been limited. Indeed, a few examples of the direct C−H functionalization of cyclic aldonitrones lacking an aromatic π-conjugated system are presented by the following reactions of 2H-imidazole 1oxides: uncatalyzed by transition metals (i) oxidative C−H/ C−Li coupling with organometallics,13 (ii) metalation followed by coupling with electrophiles,14 (iii) eliminative C−H/C−H coupling with azoles,15 and (iv) Pd(II)-catalyzed oxidative C− H/C−H coupling with indoles.15b It should be noted that in case of oxidative reactions (i, ii, and iv), the retention of the Noxide group in the coupling products is observed, whereas the eliminative process (iii) has been shown to result in the formation of 2H-imidazoles with the loss of the N-oxide function. This study is aimed at the development of a facile and effective synthetic approach for the direct C(sp2)−H bond functionalization of cyclic aldonitrones with fragments of pyrroles and thiophenes to obtain novel heterocyclic ensembles, 5-heteroaryl-substituted 2H-imidazole 1-oxides, in good yields.

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A special attention has been focused on the conditions optimization for these cross-coupling reactions by varying the basic parameters, such as molar ratio of the coupling partners 1 and 2, amounts of catalyst Pd(OAc)2 and oxidant Cu(OAc)2, and the reaction time. Initially, the conditions that had earlier been used for the direct C−H/C−H coupling of aldonitrones with indoles were checked.15b,16 The interaction of aldonitrone 1b with thiophene 2b proceeding in 1,4-dioxane at 120 °C in the presence of pyridine was chosen as the model reaction (Table 2). As a result of these experiments, the best yield (75%) of the coupling product 3g, 5-(5-acetylthiophen-2-yl)-2ethyl-2-methyl-4-phenyl-2H-imidazole 1-oxide, has been achieved after 24 h with the following ratio of reagents (Table 2, entry 9): 2H-imidazole 1b (1 mmol), thiophene 2b (2 mmol), palladium (0.1 mmol) and copper (1.5 mmol) acetates. In accordance with the modern concept for transition-metalcatalyzed cross-dehydrogenative coupling (CDC) reactions,17 the oxidative C−H/C−H coupling of 2H-imidazole 1-oxides with π-excessive heterocyclic compounds, such as pyrroles or thiophenes, seems to be a cyclic redox process. The organopalladium intermediates bearing the C−Pd bond are supposed to be formed, and the cyclic redox transformations of palladium catalyst Pd(II) → Pd(0) → Pd(II) take place in this case. It should also be mentioned that the data of mechanistic studies on these transition-metal-catalyzed cross-dehydrogenative coupling reactions suggest two plausible ways for palladium-induced activation of the C−H bond in (hetero)arenes, namely, electrophilic aromatic metalation and concerted metalation−deprotonation pathways.18 To gain insight into the CDC reaction mechanism and elucidate the competiveness for palladation of the reactive partners, the H/D exchange experiments have been performed (Scheme 1) using NMR spectroscopy. Herein, the previously described experimental protocol19 has been applied to perform a series of experiments separately with 2H-imidazole 1-oxide 1a and 2-acetylthiophene 2b by using the standard conditions: Pd(OAc)2, 0.1 mmol; Cu(OAc)2·H2O, 1.5 mmol; 1,4-dioxane, 5 mL; heating at 110−120 °C for 24 h, and D2O, 20 mmol, as

RESULTS AND DISCUSSION

The methodology for the direct nucleophilic C(sp2)−H bond functionalization in the series of nonaromatic 2H-imidazole 1oxides 1 has first been used as the main synthetic strategy to the family of novel C(5)-modified 2H-imidazole derivatives. In particular, the Pd(II)-mediated C−H/C−H cross-coupling reactions of cyclic nitrones 1a−c with a variety of π-excessive pyrroles and thiophenes 2a−g bearing both electron-donating and electron-withdrawing substituents have been carried out. The elaborated cross-dehydrogenative C−C coupling reactions have been shown to result in the formation of previously unknown biheterocyclic ensembles containing the N-oxide group in the imidazole ring in 40−78% yields (Table 1). 826

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Table 1. Scope and Yields for the Pd(II)-Mediated Oxidative Cross-Coupling Reaction of 2H-Imidazole 1-Oxides 1a−c with Pyrroles and Thiophenes 2a−ga,b

a Reaction conditions: 2H-imidazole 1-oxides 1a−c (1 mmol), pyrroles and thiophenes 2a−g (2 mmol), Pd(OAc)2 (0.1 mmol), Cu(OAc)2·H2O (1.5 mmol), and pyridine (1.5 mmol) in 1,4-dioxane (5 mL) at 110−120 °C for 24 h. bIsolated yields.

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Table 2. Optimization of Conditions for the Palladium(II)-Catalyzed Oxidative Cross-Coupling Reaction of 2H-Imidazole 1Oxide 1b with Thiophene 2b entry

1b (mmol)

2b (mmol)

Pd(OAc)2 (mmol)

Cu(OAc)2·H2O (mmol)

reaction time (h)

yield of 3g (%)

1 2 3 4 5 6 7 8 9 10 11 12

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

1.0 1.0 1.0 1.0 1.0 1.5 2.0 2.5 2.0 2.0 0.5 0.3

0.02 0.02 0.02 0.06 0.1 0.02 0.06 0.1 0.1 0.1 0.1 0.1

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.5 2.5 1.5 1.5

2 4 8 12 24 2 12 24 24 32 24 24

36 42 45 52 58 36 54 57 75 73 72 70

a deuterium source. The data of the 1H NMR experiments performed are summarized in Table 3. In the first instance, the role of pyridine in the process has been studied. The control experiments with compounds 1a and 2b carried out without pyridine have afforded no deuterated products (Table 3, entries 1 and 2), thus showing the crucial role of pyridine as a ligand in these transformations. Indeed, in analogous experiments proceeding in the presence of pyridine the hydrogen−deuterium exchange was shown to occur in case of 2-acetylthiophene 2b (Table 3, entries 3 and 4). Therefore, it has been suggested that the initial step of the cross-coupling process under discussion is the formation of the

Scheme 1. H/D Exchange Experiments for CrossDehydrogenative Coupling Partners 1a and 2b

Figure 2. Fragments of the 1H NMR spectra of the resulted reaction mixtures for H/D-exchange control experiments in case of 2-acetylthiophene 2b in the absence (a) (Table 3, entry 2) and the presence (b) of pyridine (Table 3, entry 4). 828

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Table 3. Conditions and Results of the H/D-Exchange Control Experimentsa conditions entry

1a (1.0 mmol)

2b (1.0 mmol)

Py (1.5 mmol)

Pd(OAc)2 (0.1 mmol)

Cu(OAc)2·H2O (1.5 mmol)

1a/1a-[D1] ratio

2b/2b-[D1] ratio

1 2 3 4 5 6

+ − + − − −

− + − + + +

− − + + + +

+ + + + − +

+ + + + + −

1.00:0 − 1.00:0 − − −

− 1.00:0 − 0.65:0.35 1.00:0 0.65:0.35

a

The resulted reaction mixtures were analyzed by 1H NMR spectroscopy in dimethyl sulfoxide (DMSO)-d6 at 295 K.

Scheme 2. Plausible Catalytic Cycle for the Cross-Dehydrogenative Coupling Reactions of 2H-Imidazole 1-Oxides 1a−c with Pyrroles and Thiophenes 2a−g

palladium intermediates A takes place at the first step due to the interaction of heteroaromatic compounds 2a−g with palladium(II) and pyridine molecules, which act as ligands (Ln) that stabilize the organometallic intermediates.18 Intermediates A seem to be coordinated with the oxygen center of 2H-imidazole 1-oxides 1a−c through the ligand-exchange mechanism to form intermediates B. The chelate-controlled functionalization of the nitrone C(1)−H bond through the concerted metalation/deprotonation transformations20b,21 appears to afford the intermediates C. Further reductive elimination has likely to form the desired biheterocyclic products 3a−r and Pd(0). The latter can be transformed into Pd(II) form via oxidation with copper(II) acetate, thus undergoing the recycling process.

organopalladium intermediate derived from heteroaromatic compound 2 (pyrrole or thiophene) rather than from nitrone 1. To confirm this hypothesis, attempts to deuterate 2acetylthiophene 2b in the absence of either palladium catalyst Pd(OAc)2 or oxidant Cu(OAc)2 have been undertaken. As expected, no hydrogen−deuterium exchange has been found to be occur in the absence of palladium acetate (Table 3, entry 5), whereas in the absence of copper acetate, compound 2b was deuterated up to 35% (Table 3, entry 6). These data appear to support the hypothesis that the covalent C−Pd bond is formed at the first step of the cross-coupling process deriving from the reaction of thiophene/pyrrole 2 with palladium acetate. In addition, the experimental data obtained have enabled us to refute the other versions of the hydrogen−deuterium exchange process associated with acid−base interactions of 2 with pyridine. as well as with the formation of organocopper intermediates. To illustrate it, the distinctive fragments of the 1 H NMR spectra of the reaction mixtures after furnishing the H/D-exchange control experiments with 2-acetylthiophene 2b are shown in Figure 2. On the basis of the experimental results and the analysis of the literature data,20,21 a plausible mechanism for the described cross-coupling reactions has been advanced (Scheme 2). It suggests that the formation of above-mentioned organo-

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CONCLUSIONS In summary, an original atom- and step-economical approach based on the palladium-mediated oxidative cross-dehydrogenative C−C coupling reactions (CDC) has successfully been applied for the synthesis of previously unknown biheterocyclic N-oxide ensembles. The mechanistic features of the C−H activation process have been highlighted, and the series of novel 5-heteroarylated 2H-imidazole 1-oxides, which are of particular interest in the design of bioactive molecules and 829

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131.5 (C); 133.5 (C); 165.2 (C) ppm. IR (DRA): ν 1478, 1446, 1420, 1384, 1367, 1354, 1318, 1244, 1228, 1194, 1155, 765, 742, 727, 697, 646 cm−1. MS (EI): m/z 270 [M]+. Anal. calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; O, 5.92; S, 11.86. Found: C, 66.62; H, 5.13; N, 9.91. 2,2-Dimethyl-5-(1-methyl-1H-pyrrol-2-yl)-4-phenyl-2Himidazole 1-Oxide (3c). Yield: 208 mg (78%), mp = 97−102 °C. Rf 0.1 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.59 (s, 6H); 3.49 (s, 3H); 6.01−6.02 (m, 1H); 6.10−6.12 (m, 1H); 7.00−7.01 (m, 1H); 7.39−7.43 (m, 2H); 7.48−7.55 (m, 3H) ppm. 13C NMR (DMSO-d6): δ 24.4 (CH3); 34.7 (CH3); 99.0 (C); 108.1 (CH); 112.5 (CH); 118.4 (C); 125.3 (CH); 127.8 (CH); 128.2 (CH); 130.0 (C); 130.9 (CH); 131.9 (C); 165.1 (C) ppm. IR (DRA): ν 1544, 1502, 1444, 1429, 1386, 1345, 1329, 1245, 1227, 1182, 1155, 1094, 1059, 1028, 946, 775, 733, 695, 665, 654 cm−1. MS (EI): m/z 267 [M]+. Anal. calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72; O, 5.98. Found: C, 71.72; H, 6.60; N, 15.68. 2,2-Dimethyl-4-phenyl-5-(1H-pyrrol-2-yl)-2H-imidazole 1Oxide (3d). Yield: 170 mg (67%), mp = 99−104 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.57 (s, 6H); 5.81−5.83 (m, 1H); 6.09−6.11 (m, 1H); 7.01−7.03 (m, 1H); 7.53−7.65 (m, 5H); 12.07 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 24.0 (CH3); 98.4 (C); 109.4 (CH); 111.6 (CH); 119.4 (C); 121.6 (CH); 128.76 (CH); 128.82 (CH); 129.7 (C); 130.9 (CH); 134.0 (C); 166.1 (C) ppm. IR (DRA): ν 1553, 1479, 1438, 1421, 1390, 1365, 1330, 1194, 1166, 1112, 1067, 1040, 967, 776, 731, 700, 663, 648, 595 cm−1. MS (EI): m/z 253 [M]+. Anal. calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59; O, 6.32. Found: C, 71.30; H, 6.00; N, 16.54. 2,2-Dimethyl-4-phenyl-5-(5-phenyl-1H-pyrrol-2-yl)-2Himidazole 1-Oxide (3e). Yield: 197 mg (60%), mp = 125−130 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.62 (s, 6H); 5.98−6.00 (m, 1H); 6.68 (t, 1H, J = 3.36); 7.28 (t, 1H, J = 7.36); 7.42 (t, 2H, J = 7.72); 7.56−7.71 (m, 7H); 12.30 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 24.0 (CH3); 98.3 (C); 107.6 (CH); 112.9 (CH); 120.5 (C); 123.9 (CH); 127.1 (CH); 128.1 (CH); 128.2 (CH); 128.9 (CH); 129.0 (C); 130.5 (CH); 130.8 (C); 132.6 (C); 133.0 (C); 164.8 (C) ppm. IR (DRA): ν 3256, 3168, 3146, 3115, 2974, 2933, 1601, 1579, 1519, 1418, 1120, 1042, 931, 736, 696 cm−1. MS (EI): m/z 329 [M]+. Anal. calcd for C21H19N3O: C, 76.57; H, 5.81; N, 12.76; O, 4.86. Found: C, 76.64; H, 5.76; N, 12.80. 2,2-Dimethyl-4-phenyl-5-(4,5,6,7-tetrahydro-1H-indol-2yl)-2H-imidazole 1-Oxide (3f). Yield: 129 mg (42%), mp = 141−146 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSOd6 + CCl4): δ 1.56 (d, 6H, J = 6.12); 1.59−1.61 (m, 2H); 1.68−1.70 (m, 2H); 2.30 (t, 2H, J = 5.82); 2.60 (t, 2H, J = 6.00); 5.58 (d, 1H, J = 2.04); 7.54−7.63 (m, 5H); 11.60 (s, 1H) ppm. 13C NMR (DMSO-d6): 22.2 (CH2); 22.51 (CH2); 22.54 (CH2); 23.0 (CH2); 24.0 (CH3); 97.4 (C); 110.0 (CH); 117.2 (C); 117.9 (C); 128.0 (CH); 128.1 (CH); 128.9 (C); 130.2 (CH); 130.4 (C); 133.5 (C); 165.3 (C) ppm. IR (DRA): ν 2932, 1522, 1489, 1443, 1407, 1320, 1303, 1260, 1237, 1170, 1144, 1092, 1073, 1003, 975, 922, 803, 772, 696, 655 cm−1. MS (EI): m/z 307 [M]+. Anal. calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67; O, 5.20. Found: C, 74.10; H, 7.00; N, 13.76. 5-(5-Acetylthiophen-2-yl)-2-ethyl-2-methyl-4-phenyl-2Himidazole 1-Oxide (3g). Yield: 245 mg (75%), mp = 121−126 °C. Rf 0.1 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.59 (t, 3H, J = 7.32); 1.61 (s, 3H); 1.95−2.00 (m,

advanced materials, has been obtained and fully characterized. The developed methodology proved to be an efficient synthetic tool to provide C(sp2)−H/C(sp2)−H cross-coupling of 2H-imidazole 1-oxides with π-excessive heterocyclic compounds, such as pyrroles or thiophenes, affording the target products in yields up to 78%.

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EXPERIMENTAL SECTION General Experimental Methods. The NMR (1H, 400 MHz and 13C, 100 MHz) spectra were recorded on a Bruker AVANCE II spectrometer in DMSO-d6 using tetramethylsilane as an internal standard. The 13C NMR spectra were recorded in a mode of attached proton test with full proton decoupling. The mass spectra (EI) were obtained by means of a SHIMADZU GCMS-QP2010 Ultra mass spectrometer. The infrared spectra were recorded on a Bruker Alpha FT-IR spectrometer. The elemental analysis was fulfilled on a CHNS/ O analyzer. The reactions course was monitored by thin-layer chromatography (0.25 mm silica gel plates, Merck 60F 254). Column chromatography was carried out on 220−440 mesh silica gel (60, 0.035−0.070 mm). General Procedure for the Synthesis of 3a−r. In a similar manner to the previously described procedure,15b a mixture of aldonitrone 1a−c (1 mmol), pyrrole or thiophene 2a−g (2 mmol), palladium(II) acetate (22.5 mg, 0.1 mmol), copper(II) acetate monohydrate (300 mg, 1.5 mmol), and pyridine (0.12 mL, 1.5 mmol) in 1,4-dioxane (5 mL) was refluxed at 110−120 °C for 24 h. The cooled to ambient temperature reaction mass was then subjected to flash chromatography on neutral Al2O3 using ethyl acetate as an eluent. The resulted eluate was concentrated in vacuo to dryness. The formed residue was chromatographed using silica gel column technique with the EtOAc−hexane gradient elution. The obtained eluate was finally concentrated in vacuo. 2,2-Dimethyl-4-phenyl-2H-imidazole 1-oxide 1a, 3-phenyl1,4-diazaspiro[4.5]deca-1,3-diene 1-oxide 1c,22 and 2-ethyl-2methyl-4-phenyl-2H-imidazole 1-oxide 1b15b were prepared according to the published procedures. Thiophene 2a, 2acetylthiophene 2b, pyrrole 2c, 1-methylpyrrole 2d, 2-acetyl1H-pyrrole 2e, 2-phenyl-1H-pyrrole 2f, 4,5,6,7-tetrahydro-1Hindole 2g, palladium(II) acetate, copper(II) acetate monohydrate, pyridine, and 1,4-dioxane were purchased from commercial sources. Characterization Data for All Products (3a−r). 5-(5Acetylthiophen-2-yl)-2,2-dimethyl-4-phenyl-2H-imidazole 1Oxide (3a). Yield: 200 mg (64%), mp = 137−142 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.61 (s, 6H); 2.53 (s, 3H); 6.96 (d, 1H, J = 4.16); 7.57−7.70 (m, 5H); 7.81 (d, 1H, J = 4.12) ppm. 13C NMR (DMSO-d6): δ 24.0 (CH3); 26.8 (CH3); 99.5 (C); 127.9 (CH); 128.2 (CH); 128.5 (CH); 130.5 (CH); 131.4 (C); 132.0 (CH); 133.0 (C); 133.9 (C); 142.2 (C); 164.5 (C); 191.3 (C) ppm. IR (DRA): ν 3850, 3243, 3188, 3167, 3141, 2978, 1602, 1579, 1519, 1442, 1133, 917, 735, 696, 580 cm−1. MS (EI): m/z 312 [M]+. Anal. calcd for C17H16N2O2S: C, 65.36; H, 5.16; N, 8.97; O, 10.24; S, 10.26. Found: C, 64.89; H, 4.81; N, 7.82. 2,2-Dimethyl-4-phenyl-5-(thiophen-2-yl)-2H-imidazole 1Oxide (3b). Yield: 151 mg (56%), mp = 107−112 °C. Rf 0.3 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.59 (s, 6H); 6.99 (d, 1H, J = 3.12); 7.08 (t, 1H, J = 4.08); 7.58− 7.68 (m, 5H); 7.74 (d, 1H, J = 4.64) ppm. 13C NMR (DMSOd6): δ 24.1 (CH3); 98.6 (C); 126.5 (CH); 127.4 (CH); 127.6 (C); 128.2 (CH); 128.3 (CH); 128.5 (CH); 130.5 (CH); 830

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ν 3449, 2927, 2847, 1601, 1572, 1535, 1487, 1443, 1269, 955, 752, 690, 646, 565 cm−1. MS (EI): m/z 343 [M]+. Anal. calcd for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; O, 4.66. Found: C, 74.66; H, 6.15; N, 11.74. 5-(5-Acetyl-1H-pyrrol-2-yl)-2-ethyl-2-methyl-4-phenyl-2Himidazole 1-Oxide (3l). Yield: 167 mg (54%), mp = 157−162 °C. Rf 0.1 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.58 (t, 3H, J = 7.28); 1.55 (s, 3H); 1.91−1.96 (m, 1H); 2.08−2.13 (m, 1H); 2.25 (s, 3H); 7.05 (s, 1H); 7.56− 7.64 (m, 6H); 12.27 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 6.7 (CH3); 23.3 (CH3); 25.5 (CH3); 30.1 (CH2); 100.8 (C); 110.8 (C); 114.5 (CH); 125.7 (CH); 128.2 (CH); 128.5 (CH); 130.5 (CH); 131.5 (C); 131.9 (C); 133.5 (C); 167.2 (C); 187.2 (C) ppm. IR (DRA): ν 3131, 2970, 1658, 1569, 1445, 1360, 1339, 1306, 1186, 1135, 1083, 952, 940, 838, 766, 701, 629 cm−1. MS (EI): m/z 309 [M]+. Anal. calcd for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58; O, 10.34. Found: C, 69.63; H, 6.27; N, 13.36. 2-(5-Acetylthiophen-2-yl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene 1-Oxide (3m). Yield: 246 mg (70%), mp = 163−168 °C. Rf 0.3 (heptane/EtOAc, 6:4). 1H NMR (DMSOd6 + CCl4): δ 1.40−1.43 (m, 1H); 1.56 (d, 2H, J = 12.36); 1.72−1.89 (m, 5H); 2.03−2.10 (m, 2H); 2.52 (s, 3H); 6.96 (d, 1H, J = 4.24); 7.58−7.70 (m, 5H); 7.81 (d, 1H, J = 4.28) ppm. 13 C NMR (DMSO-d6): δ 22.7 (CH2); 24.2 (CH2); 26.8 (CH3); 34.4 (CH2); 101.8 (C); 127.8 (CH); 128.3 (CH); 128.5 (CH); 130.4 (CH); 131.6 (C); 132.0 (CH); 133.3 (C); 133.9 (C); 142.1 (C); 164.7 (C); 191.3 (C) ppm. IR (DRA): ν 2933, 2921, 2860, 1650, 1560, 1446, 1383, 1363, 1309, 1273, 1196, 959, 818, 773, 707, 695, 657 cm−1. MS (EI): m/z 352 [M]+. Anal. calcd for C20H20N2O2S: C, 68.16; H, 5.72; N, 7.95; O, 9.08; S, 9.10. Found: C, 68.15; H, 5.66; N, 7.56. 3-Phenyl-2-(thiophen-2-yl)-1,4-diazaspiro[4.5]deca-1,3diene 1-Oxide (3n). Yield: 202 mg (65%), mp = 179−184 °C. Rf 0.4 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.44−1.52 (m, 3H); 1.80−1.88 (m, 5H); 7.04 (d, 2H, J = 3.24); 7.56−7.67 (m, 6H) ppm. 13C NMR (DMSO-d6): δ 22.5 (CH2); 24.1 (CH2); 34.4 (CH2); 100.7 (C); 126.1 (CH); 127.1 (CH); 127.3 (C); 127.8 (CH); 128.0 (CH); 128.2 (CH); 130.0 (CH); 131.3 (C); 133.5 (C); 165.1 (C) ppm. IR (DRA): ν 3063, 2933, 2860, 1566, 1496, 1477, 1444, 1422, 1383, 1359, 1339, 1324, 1292, 959, 770, 735, 702, 659, 629 cm−1. MS (EI): m/z 310 [M]+. Anal. calcd for C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; O, 5.15; S, 10.33. Found: C, 68.87; H, 5.69; N, 8.71. 2-(1-Methyl-1H-pyrrol-2-yl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene 1-Oxide (3o). Yield: 184 mg (60%), mp = 157−162 °C. Rf 0.3 (heptane/EtOAc, 6:4). 1H NMR (DMSOd6 + CCl4): δ 1.40−1.52 (m, 3H); 1.83−1.88 (m, 5H); 2.02− 2.09 (m, 2H); 3.46 (s, 3H); 6.00−6.02 (m, 1H); 6.10−6.11 (m, 1H); 7.00 (t, 1H, J = 2.06); 7.41 (t, 2H, J = 7.44); 7.49− 7.54 (m, 3H) ppm. 13C NMR (DMSO-d6): δ 22.6 (CH2); 24.3 (CH2); 34.5 (CH3); 34.8 (CH2); 101.2 (C); 107.9 (CH); 112.2 (CH); 118.3 (C); 125.0 (CH); 127.6 (CH); 128.0 (CH); 130.0 (C); 130.6 (CH); 132.1 (C); 165.3 (C) ppm. IR (DRA): ν 2941, 2927, 1544, 1503, 1487, 1443, 1377, 1350, 1329, 1278, 1167, 961, 728, 688, 675, 658, 609 cm−1. MS (EI): m/z 307 [M]+. Anal. calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67; O, 5.20. Found: C, 74.26; H, 7.00; N, 13.60. 3-Phenyl-2-(1H-pyrrol-2-yl)-1,4-diazaspiro[4.5]deca-1,3diene 1-Oxide (3p). Yield: 135 mg (46%), mp = 195−200 °C. Rf 0.4 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.38−1.49 (m, 3H); 1.75−1.88 (m, 5H); 2.10 (t, 2H, J =

1H); 2.14−2.19 (m, 1H); 2.53 (s, 3H); 6.97 (d, 1H, J = 4.24); 7.58−7.70 (m, 5H); 7.82 (d, 1H, J = 4.28) ppm. 13C NMR (DMSO-d6): 6.7 (CH3); 23.0 (CH3); 26.9 (CH3); 30.3 (CH2); 102.0 (C); 128.0 (CH); 128.3 (CH); 128.7 (CH); 130.7 (CH); 132.2 (CH); 132.6 (C); 133.1 (C); 133.6 (C); 142.3 (C); 165.6 (C); 191.5 (C) ppm. IR (DRA): ν 1659, 1611, 1575, 1499, 1447, 1381, 1368, 1349, 1306, 1266, 1197, 1148, 944, 812 cm−1. MS (EI): m/z 326 [M]+. Anal. calcd for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58; O, 9.80; S, 9.82. Found: C, 65.93; H, 5.36; N, 7.95. 2-Ethyl-2-methyl-4-phenyl-5-(thiophen-2-yl)-2H-imidazole 1-Oxide (3h). Yield: 170 mg (60%), mp = 83−88 °C. Rf 0.3 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.58 (t, 3H, J = 7.28); 1.59 (s, 3H); 1.94−2.01 (m, 1H); 2.10− 2.17 (m, 1H); 7.01 (d, 1H, J = 3.52); 7.09 (t, 1H, J = 4.48); 7.57−7.67 (m, 5H); 7.74 (d, 1H, J = 4.8 ppm). 13C NMR (DMSO-d6): 6.7 (CH3); 23.1 (CH3); 30.1 (CH2); 101.0 (C); 126.6 (CH); 127.2 (C); 127.4 (CH); 128.2 (CH); 128.3 (CH); 128.6 (CH); 130.5 (CH); 132.6 (C); 133.4 (C); 166.2 (C) ppm. IR (DRA): ν 3330, 3274, 3213, 3180, 2968, 2855, 1641, 1603, 1537, 1443, 1372, 1180, 1143, 941, 694 cm−1. MS (EI): m/z 284 [M]+. Anal. calcd for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85; O, 5.63; S, 11.28. Found: C, 67.02; H, 5.43; N, 9.64. 2-Ethyl-2-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4-phenyl2H-imidazole 1-Oxide (3i). Yield: 197 mg (70%), mp = 79− 84 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.63 (t, 3H, J = 7.32); 1.58 (s, 3H); 1.92−1.98 (m, 1H); 2.12−2.17 (m, 1H); 3.49 (s, 3H); 5.98−5.99 (m, 1H); 6.10−6.12 (m, 1H); 7.02 (t, 1H, J = 2.12); 7.40−7.43 (m, 2H); 7.49−7.53 (m, 3H) ppm. 13C NMR (DMSO-d6): δ 6.8 (CH3); 23.8 (CH3); 30.2 (CH2); 35.0 (CH3); 101.5 (C); 108.2 (CH); 112.5 (CH); 118.4 (C); 125.5 (CH); 127.8 (CH); 128.3 (CH); 131.0 (CH); 131.3 (C); 131.9 (C); 166.2 (C) ppm. IR (DRA): ν 1545, 1505, 1487, 1461, 1447, 1433, 1379, 1350, 1331, 1281, 1179, 954, 721, 693, 660 cm−1. MS (EI): m/z 281 [M]+. Anal. calcd for C17H19N3O: C, 72.57; H, 6.81; N, 14.94; O, 5.69. Found: C, 72.00; H, 6.86; N, 14.53. 2-Ethyl-2-methyl-4-phenyl-5-(1H-pyrrol-2-yl)-2H-imidazole 1-Oxide (3j). Yield: 134 mg (50%), mp = 89−94 °C. Rf 0.2 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.60 (t, 3H, J = 7.24); 1.57 (s, 3H); 1.94−1.99 (m, 1H); 2.09− 2.14 (m, 1H); 5.82 (s, 1H); 6.10 (d, 1H, J = 2.64); 7.02 (s, 1H); 7.54−7.64 (m, 5H); 12.08 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 6.8 (CH3); 23.2 (CH3); 29.9 (CH2); 100.4 (C); 109.0 (CH); 111.2 (CH); 118.6 (C); 121.1 (CH); 128.2 (CH); 128.4 (CH); 130.3 (C); 130.4 (CH); 133.4 (C); 166.4 (C) ppm. IR (DRA): ν 3293, 1557, 1446, 1409, 1391, 1362, 1325, 1196, 1114, 1070, 1043, 824, 760, 734, 701, 659, 599 cm−1. MS (EI): m/z 267 [M]+. Anal. calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72; O, 5.98. Found: C, 71.12; H, 6.66; N, 14.67. 2-Ethyl-2-methyl-4-phenyl-5-(5-phenyl-1H-pyrrol-2-yl)2H-imidazole 1-Oxide (3k). Yield: 199 mg (58%), mp = 75− 80 °C. Rf 0.3 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 0.64 (t, 3H, J = 7.30); 1.61 (s, 3H); 1.98−2.03 (m, 1H); 2.14−2.19 (m, 1H); 5.99−6.00 (m, 1H); 6.68 (t, 1H, J = 3.36); 7.29 (t, 1H, J = 7.36); 7.42 (t, 2H, J = 7.72); 7.58−7.70 (m, 7H); 12.28 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 6.8 (CH3); 23.2 (CH3); 30.0 (CH2); 100.8 (C); 107.8 (CH); 113.1 (CH); 120.2 (C); 124.0 (CH); 127.2 (CH); 128.2 (CH); 128.5 (CH); 129.1 (CH); 130.2 (C); 130.7 (CH); 130.9 (C); 132.8 (C); 133.0 (C); 165.9 (C) ppm. IR (DRA): 831

DOI: 10.1021/acsomega.8b02916 ACS Omega 2019, 4, 825−834

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11.64); 5.81 (s, 1H); 6.09 (d, 1H, J = 2.76); 7.01 (s, 1H); 7.53−7.64 (m, 5H); 12.07 (s, 1H) ppm. 13C NMR (DMSOd6): δ 22.9 (CH2); 24.4 (CH2); 34.4 (CH2); 100.2 (C); 108.9 (CH); 111.1 (CH); 118.9 (C); 121.0 (CH); 128.26 (CH); 128.28 (CH); 129.3 (C); 130.3 (CH); 133.7 (C); 165.6 (C) ppm. IR (DRA): ν 3284, 2943, 2922, 2851, 1498, 1441, 1408, 1392, 1373, 1332, 1113, 1088, 1058, 996, 729, 696 cm−1. MS (EI): m/z 293 [M]+. Anal. calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32; O, 5.45. Found: C, 73.54; H, 6.55; N, 14.27. 3-Phenyl-2-(4,5,6,7-tetrahydro-1H-indol-2-yl)-1,4diazaspiro[4.5]deca-1,3-diene 1-Oxide (3q). Yield: 132 mg (40%), mp = 167−172 °C. Rf 0.4 (heptane/EtOAc, 6:4). 1H NMR (DMSO-d6 + CCl4): δ 1.43 (d, 2H, J = 12.64); 1.59− 1.84 (m, 10H); 2.06−2.12 (m, 2H); 2.29 (d, 2H, J = 5.56); 2.58 (d, 2H, J = 5.8); 5.55 (d, 1H, J = 1.16); 7.53−7.62 (m, 5H); 11.62 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 22.1 (CH2); 22.5 (CH2); 22.6 (CH2); 23.0 (CH2); 24.3 (CH2); 34.3 (CH2); 99.5 (C); 109.8 (CH); 117.2 (C); 117.8 (C); 128.0 (CH); 129.0 (C); 130.0 (CH); 130.2 (C); 133.7 (C); 165.5 (C) ppm. IR (DRA): ν 2924, 2851, 1601, 1538, 1489, 1442, 1336, 1267, 1233, 1184, 1009, 971, 954, 698, 566 cm−1. MS (EI): m/z 347 [M]+. Anal. calcd for C22H25N3O: C, 76.05; H, 7.25; N, 12.09; O, 4.60. Found: C, 76.14; H, 7.30; N, 12.11. 2-(5-Acetyl-1H-pyrrol-2-yl)-3-phenyl-1,4-diazaspiro[4.5]deca-1,3-diene 1-Oxide (3r). Yield: 147 mg (44%), mp = 195−200 °C. Rf 0.1 (heptane/EtOAc, 6:4). 1H NMR (DMSOd6 + CCl4): δ 1.42 (d, 2H, J = 12.16); 1.79 (t, 6H, J = 14.58); 2.06 (t, 2H, J = 11.16); 2.24 (s, 3H); 7.04 (s, 1H); 7.56−7.64 (m, 6H); 12.24 (s, 1H) ppm. 13C NMR (DMSO-d6): δ 22.9 (CH2); 24.5 (CH2); 25.5 (CH3); 34.6 (CH2); 100.7 (C); 111.1 (C); 114.6 (CH); 125.8 (CH); 128.3 (CH); 128.4 (CH); 130.4 (CH); 130.9 (C); 131.4 (C); 133.8 (C); 166.4 (C); 187.2 (C) ppm. IR (DRA): ν 3236, 2938, 1647, 1561, 1442, 1367, 1331, 1300, 1236, 1065, 1002, 831, 786, 773, 710 cm−1. MS (EI): m/z 335 [M]+. Anal. calcd for C20H21N3O2: C, 71.62; H, 6.31; N, 12.53; O, 9.54. Found: C, 70.00; H, 6.53; N, 11.59. General Procedure for the H/D Exchange Control Experiments. The hydrogen−deuterium exchange control experiments were carried out according to the literature procedure.19 The deuteration reactions of either 2H-imidazole 1-oxide 1a or 2-acetylthiophene 2b separately carried out using the conditions noted in Table 3. Heavy water D2O (20.0 mmol) was used as a deuterium source. All reaction mixtures were refluxed at 110−120 °C for 24 h in 1,4-dioxane (5 mL). Then, the mixture was cooled to room temperature, filtered through neutral alumina, and concentrated in vacuo. The obtained residues were individually analyzed by means of 1H NMR spectroscopy.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alexey A. Akulov: 0000-0003-3966-3728 Mikhail V. Varaksin: 0000-0002-7997-3686 Oleg N. Chupakhin: 0000-0002-1672-2476 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The research was financially supported by the Russian Science Foundation (Project no. 18-73-00088). REFERENCES

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02916. 1 H and 13C NMR spectra of 3a−r; 1H−13C heteronuclear single quantum coherence, 1H−13C heteronuclear multiple bond correlation, and 1H−1H nuclear Overhauser effect spectroscopy 2D NMR spectra of 3c; 1 H NMR spectra of reaction mixtures, isolated during the H/D exchange control experiments (PDF)

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DOI: 10.1021/acsomega.8b02916 ACS Omega 2019, 4, 825−834

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