Abstract
1-Azabicyclo[3.2.1]oct-3-ene were synthesized by the intramolecular carbocationic cyclization of 1-[2-hydroxy-2-(4-R-phenyl)ethyl]-1,2,3,6-tetrahydropyridines in a trifluoromethanesulfonic acid medium
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INTRODUCTION
The 1-azabicyclo[3.2.1]octane fragment is found in alkaloids isolated from some plants of the Amaryllidaceae family. These substances are known to exhibit a wide range of biological activities. For example, the alkaloids crinine and montanine (Fig. 1), as well as their derivatives, show antimalarial, antifungal, antitumor, antiviral, antibacterial, antihistamine, and cholinomimetic activity and some types of psychopharmacological activity [1–8].
Structure of alkaloids.
The synthesis of 1-azabicyclo[3.2.1]octane derivatives is much less documented than the synthesis of related bicyclic structures with the nitrogen atom in the bridging positions. The reported methods for constructing the 1-azabicyclo[3.2.1]octane core usually produce mixtures of products and involve a few stages, including intramolecular cyclizations initiated by radical or nucleophilic agents [9–17].
Taking into account that the generation and transformation of superelectrophilic intermediates is a dynamically developing area of organic chemistry [18], we consider 1,2,3,6-tetrahydropyridine systems containing at least two reaction centers as very promising objects for research in terms of the synthesis of new bi- and polycyclic compounds structurally similar to natural alkaloids and potentially having biological activity.
As known, treatment of 1-alkyl-1,2,3,6-tetrahydropyridines with TfOH gives a dicationic intermediate [19, 20], which enters inter- and intramolecular Friedel–Crafts reactions as an alkylating agent [21–23]. Furthermore, we showed that 1-[2-(adamantan-1-yl)-2-hydroxyethyl]-1,2,3,6-tetrahydropyridines undergo an intramolecular skeletal Wagner–Meerwein rearrangement under the action of TfOH, resulting in the formation of substituted 1-azabicyclo[3.3.1]non-3-enes annulated with the homoadamantane core [24]. Thus, depending on the nature of the substituent at the nitrogen atom of 1,2,3,6-tetrahydropyridine, the multiple bond can function either as a nucleophilic center or as a precursor of an electrophilic center in reactions in acidic media.
We realized the conversion of 1-[2-hydroxy-2-(4-R-phenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridines 2a–2f into 1-azabicyclo[3.2.1]oct-3-enes 3a–3f in a trifluoromethanesulfonic acid medium.
RESULTS AND DISCUSSION
The starting 1-[2-hydroxy-2-(4-R-phenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridines 2a–2f were prepared by the reduction of quaternary salts 1a–1f with sodium borohydride in methanol (Scheme 1) by the procedure described in [25, 26]. 4-Methylpyridinum salts 1a–1f were synthesized by the standard quaternization of 4-picoline with 4-R-phenacyl bromides [27–31].
1.
The 1H NMR spectra of compounds 2a–2f display the methylene proton signals of the 1,2,3,6-tetrahydropyridine and 2-hydroxyethyl fragments at 2.08–3.30 ppm and the OH proton signal as a broadened singlet at 4.05–4.23 ppm. The pyrimidine double bond proton signals are observed at 5.34–5.37 ppm, and the aromatic protons give signals at 6.80–8.20 ppm. The 13C NMR spectra of compounds 2a–2f all contain a signal of the tertiary carbon atom of the 2-hydroxyethyl group at 68.2–69.1 ppm and pyrimidine C4=C5 carbon signals at 118.0–118.8 and 132.9–137.8 ppm, respectively. The signals of the carbon atoms of the aromatic system are observed at 115.2–161.1 ppm. In the case of fluorine derivative 2d, the signals of aromatic carbons are split due to coupling with the 19F nuclei.
4-Methyl-1,2,3,6-tetrahydropyridines 2a–2f were then treated with TfOH to obtain cyclic intramolecular cationic cyclization products 1-azabicyclo[3.2.1]oct-3-enes 3a–3f in yields of 52–94% (Scheme 2). The reaction was carried out in an excess of TfOH at room temperature for 24 h (TLC monitoring, eluent i-PrOH). The products were isolated by column chromatography (eluent CH2Cl2–i-PrOH, 1 : 1). It is worth noting that the reactions with electron-acceptor-substituted tetrahydropyridines 2d–2f provide cyclization products in noticeably lower yields. Attempted cyclization in concentrated sulfuric acid was unsuccessful.
2.
The 1H NMR spectra of compounds 3a–3f, the signals of the protons of the bicyclic core are observed at 2.45–4.60 ppm, the signals of the double bond protons appear at 5.26–6.00 ppm, and aromatic protons give signals at 6.98–7.25 ppm. The presence in the 13C NMR spectra of products 3a–3f of two tertiary carbon signals in the range of 33.0–51.0 ppm provide evidence for the occurrence of intramolecular cyclization; the signals of the double bond C5 and C4 atoms of the bicycle appear at 111.5–114.8 and 138.0–147.5 ppm, respectively. The signals of the carbon atoms of the aromatic system are observed at 114.2–162.1 ppm. In the case of fluorine derivative 3d, the aromatic carbon signals are split due to coupling with the 19F nuclei.
The 1H and 13C NMR signals of compounds 3a–3f were assigned on the basis of the DEPT-135 13C NMR spectra ands and 2D HMBC 1H–13C and HETCOR 1H–13C experiments. The orientation of the aromatic substituent in compounds 3a–3f was determined using the 2D NOESY NMR experiment. The spectra of compounds 3a–3f contain cross-peaks indicative of the through-space interaction of the ortho protons of the benzene ring with the proton at C5, exo-oriented proton at C7, and anti-oriented proton at C8 (Fig. 2). This finding points to an exo orientation of the 4-R-phenyl substituent.
Through-space interactions of hydrogen atoms in compounds 3a–3f, detected by NOESY NMR analysis.
Let us consider the plausible reaction route, using the example of tetrahydropyridine 2a (Scheme 3). The initial protonation of both the tetrahydropyridine nitrogen atom and the hydroxyl group, followed by dehydration of the oxonium ion leads to the formation of dication A containing a benzyl-type cationic center, which further attacks the multiple bond of the tetrahydropyridine moiety. As a result, dication B is formed, whose subsequent deprotonation leads to 1-azabicyclo[3.2.1]oct-3-ene 3a. The fact that compound 4a formed by the Friedel–Crafts intramolecular alkylation involving the ortho positions of the phenyl ring was not detected can be explained by a hindered reaction of the aromatic system with the cationic center at the C4 atom of intermediate B because of the rigidly fixed configuration of the forming bicyclic core.
3.
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR Affinity-1 spectrometer in KBr pellets. The 1H and 13C NMR spectra were recorded on a JEOL NMR-ECX400 spectrometer at 400 and 100 MHz, respectively, using TMS as an internal standard. The melting points were determined by the capillary method on an SRS OptiMelt MPA 100 apparatus and are uncorrected. Thin-layer chromatography was performed on Sorbfil PSTH-AF-A-UV plates [layer 90–120 µm, UV indicator (254 nm)], spot visualization by exposure to iodine vapor. The elemental analyses were obtained on a EuroVector 3000 EA elemental analyzer using l-cystine as a standard.
Quaternary salts 1a–1f were prepared by a known procedure, and the melting points of the products are consistent with those reported in [27–31].
1-[2-Hydroxy-2-(4-R-phenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridines 2a–2f (general procedure). Sodium borohydride (0.2 g, 5.2 mmol) was added in portions with stirring to a cold (0°C) solution of 3.5 mmol of salt 1a–1f in 15 mL of MeOH over the course of 1 h. Then cooling was removed, and the reaction mixture was stirred for another 2 h, diluted with water (60 mL), and the product was extracte Na2SO4, the solvent was removed under reduced pressure, and the residue was purified by recrystallization from ethanol.
1-(2-Hydroxy-2-phenylethyl)-4-methyl-1,2,3,6-tetrahydropyridine (2a). Yield 0.68 g (90%), brick red powder, mp 74–75°C. IR spectrum, ν, cm–1: 3417, 2924, 2900, 2823, 2762, 1620, 1442, 1095, 1026, 702. 1H NMR spectrum (CDCl3), δ, ppm: 1.68 s (3H, CH3), 2.08 br.s (2H), 2.50–2.58 m (3H), 2.83 quintet (1H, 4J 5.7 Hz), 2.94 d (1H, 3J 15.6 Hz), 3.18 d (1H, 3J 15.6 Hz), 4.12 br.s (1H, CHOH), 4.75 d.d (1H, 4J 4.1, 3J 9.6 Hz), 5.34–5.35 m (1H, CH5), 7.21–7.26 m (1H), 7.29–7.37 m (4H). 13C NMR spectrum (CDCl3), δ, ppm: 23.0 (CH3), 30.7 (CH2), 50.2 (CH2), 52.6 (CH2), 66.0 (CH2), 69.1 (CHOH), 118.8 (CH), 125.9 (CHPh), 127.5 (CHPh), 128.4 (CHPh), 132.9 (Cquat), 142.4 (CPh). Found, %: C 77.44; H 8.86; N 6.38. C14H19NO. Calculated, %: C 77.38; H 8.81; N 6.45.
1-[2-Hydroxy-2-(4-methylphenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridine (2b). Yield 0.63 g (79%), brown powder, mp 67–70°C. IR spectrum, ν, cm–1: 3410, 2903, 2829, 1685, 1091, 1020, 708. 1H NMR spectrum (CDCl3), δ, ppm: 1.71 s (3H, CH3), 2.16 br.s (2H), 2.33 s (3H, CH3), 2.62–2.71 m (3H), 2.91–2.94 m (1H), 3.07 d (1H, 3J 8.0 Hz), 3.29 d (1H, 3J 8.0 Hz), 4.12 br.s (1H, CHOH), 4.84 t (1H, CHOH, 3J 8.0 Hz), 5.36 s (1H), 7.14 d (2H, 3J 8.0 Hz), 7.26 d (2H, 3J 8.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 21.2 (CH3), 22.9 (CH3), 30.0 (CH2), 50.2 (CH2), 52.4 (CH2), 65.7 (CH2), 68.8 (CHOH), 118.0 (CH), 125.9 (CHTol), 129.1 (CHTol), 133.1 (Cquat), 137.3 (CTol), 138.9 (CTol). Found, %: C 77.96; H 9.20; N 6.13. C15H21NO. Calculated, %: C 77.88; H 9.15; N 6.05.
1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridine (2c). Yield 0.76 g (88%), brown powder, mp 70–72°C. IR spectrum, ν, cm–1: 3390, 2900, 2825, 1670, 1250, 1014. 1H NMR spectrum (CDCl3), δ, ppm: 1.69 s (3H, CH3), 2.09 br.s (2H), 2.51–2.59 m (3H), 2.81–2.87 m (1H), 2.95 d (1H, 3J 16.0 Hz), 3.18 d (1H, 3J 16.0 Hz), 3.78 s (3H, OCH3), 4.23 br.s (1H, CHOH), 4.72 t (1H, CHOH, 3J 8.0 Hz), 5.36 s (1H, CH), 6.87 d (2H, 3J 8.0 Hz), 7.29 d (2H, 3J 8.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 23.0 (CH3), 30.7 (CH2), 50.2 (CH2), 52.6 (CH2), 55.3 (OCH3), 66.1 (CH2), 68.7 (CHOH), 113.8 (CHarom), 118.9 (CH), 127.2 (CHarom), 132.9 (Carom–CH–OCH3), 134.4 (Cquat), 159.1 (Carom–O). Found, %: C 72.77; H 5.54; N 5.73. C15H21NO2. Calculated, %: C 72.84; H 5.56; N 5.66.
1-[2-Hydroxy-2-(4-fluorophenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridine (2d). Yield 0.74 g (90%), brown powder, mp 101–103°C. IR spectrum, ν, cm–1: 3385, 2903, 2829, 1665, 1230, 1091. 1H NMR spectrum (CDCl3), δ, ppm: 1.70 s (3H, CH3), 2.14 br.s (2H), 2.54–2.70 m (2H), 2.88–2.94 m (1H), 3.05 d (1H, 3J 16.0 Hz), 3.27 d (1H, 3J 16.0 Hz), 3.67–3.72 m (1H), 4.25 br.s (1H, CHOH), 4.81–4.84 m (1H, CHOH), 5.36 br.s (1H, CH5), 6.99–7.03 m (2H), 7.25–7.36 m (2H). 13C NMR spectrum (CDCl3), δ, ppm: 22.9 (CH3), 30.1 (CH2), 50.2 (CH2), 52.4 (CH2), 65.6 (CH2), 68.4 (CHOH), 115.2 d (CHarom, 2JCF 21.0 Hz), 118.0 (CH), 127.6 d (CHarom, 3JCF 7.0 Hz), 133.1 (Carom), 137.8 (Cquat), 162.3 d (Carom–F, 1JCF 244.0 Hz). Found, %: C 71.38; H 7.74; N 6.02. C14H18FNO. Calculated, %: C 71.46; H 7.71; N 5.95.
1-[2-Hydroxy-2-(4-chlorophenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridine (2e). Yield 0.72 g (82%), light-brown powder, mp 80–83°C. IR spectrum, ν, cm–1: 3315, 3015, 2902, 1260, 1020, 830. 1H NMR spectrum (CDCl3), δ, ppm: 1.69 s (3H, CH3), 2.10 br.s (2H), 2.44–2.48 m (1H), 2.53–2.57 m (2H), 2.82–2.85 m (1H), 2.95 d (1H, 3J 16.0 Hz), 3.15 d (1H, 3J 16.0 Hz), 4.05 br.s (1H, CHOH), 4.71–4.75 m (1H, CHOH), 5.36 s (1H, CH5), 7.30 s (4H). 13C NMR spectrum (CDCl3), δ, ppm: 22.9 (CH3), 30.6 (CH2), 50.2 (CH2), 52.6 (CH2), 65.8 (CH2), 68.4 (CHOH), 118.7 (CH), 127.3 (CHarom), 128.5 (CHarom), 132.9 (Cquat), 133.1 (Carom–Cl), 140.9 (Carom). Found, %: C 66.73; H 7.24; N 5.63. C14H18ClNO. Calculated, %: C 66.79; H 7.21; N 5.56.
1-[2-Hydroxy-2-(4-nirophenyl)ethyl]-4-methyl-1,2,3,6-tetrahydropyridine (2f). Yield 0.90 g (98%), red-brown powder, mp 94–97°C. IR spectrum, ν, cm–1: 3410, 2903, 2829, 1685, 1510, 1350, 1310, 1111, 760. 1H NMR spectrum (CDCl3), δ, ppm: 1.71 s (3H, CH3), 2.16 br.s (2H), 2.52–2.60 m (1H), 2.69–2.73 m (2H), 2.91–2.97 m (1H), 3.07 d (1H, 3J 16.0 Hz), 3.29 d (1H, 3J 16.0 Hz), 4.94–4.97 m (1H, CHOH), 5.37 s (1H, CH5), 7.25 s (1H, CHOH), 7.56 d (2H, 3J 8.0 Hz), 8.20 d (2H, 3J 8.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 22.9 (CH3), 30.0 (CH2), 50.2 (CH2), 52.3 (CH2), 65.1 (CH2), 68.2 (CHOH), 117.8 (CH), 123.7 (CHarom), 126.6 (CHarom), 133.2 (Cquat), 147.4 (Carom), 149.7 (Carom–NO2). Found, %: C 64.20; H 6.96; N 10.61. C14H18N2O3. Calculated, %: C 64.11; H 6.92; N 10.68.
Synthesis of compounds 3a–3f (general procedure). Trifluoromethanesulfonic acid, 4.4 mL (50 mmol), was added in portions over the course of 3 h to a solution of 0.5 g of tetrahydropyridine 2a–2f in 1.5 mL of anhydrous CH2Cl2, cooled to 0°C. Then cooling was removed, and the reaction mixture was stirred for 24 h, poured onto ice, adjusted to pH 12–13 with 20% NaOH solution, and the product was extracted with CH2Cl2 (3 × 20 mL). The extract was washed with saturated NaCl solution, and the combined organic extracts were dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was separated by column chromatography (eluent CH2Cl2–i-PrOH, 1 : 1).
4-Methyl-6-phenyl-1-azabicyclo[3.2.1]oct-3-ene (3a). Yield 0.38 g (83%), beige crystals, mp 93–95°C. IR spectrum, ν, cm–1: 2989, 2935, 1604, 1504, 1454, 1384, 1056, 833, 771, 748, 698. 1H NMR spectrum (CDCl3), δ, ppm: 1.38 s (3H, CH3), 2.24 br.s (1H), 2.69–3.46 m (5H), 3.99–4.23 m (2H), 5.78–5.96 m (1H), 7.06–7.25 m (5H). 13C NMR spectrum (CDCl3), δ, ppm: 26.5 (CH3), 44.7 (CH), 50.9 (CH), 59.7 (CH2), 64.7 (CH2), 69.7 (CH2), 112.4 (CH), 123.0 (CHPh), 128.6 (CHPh), 129.0 (CHPh), 142.3 (Cquat), 147.4 (CPh). Found, %: C 84.43; H 8.62; N 6.95. C14H17N. Calculated, %: C 84.37; H 8.60; N 7.03.
4-Methyl-6-(p-tolyl)-1-azabicyclo[3.2.1]oct-3-ene (3b). Yield 0.43 g (94%), beige crystals, mp 91–92°C. IR spectrum, ν, cm–1: 3076, 2979, 2930, 1614, 1050, 832. 1H NMR spectrum (CDCl3), δ, ppm: 1.41 c (3H, CH3), 2.27 c (3H, CH3), 2.75–3.61 m (8H), 5.89–5.91 m (1H), 6.98–7.08 m (4H). 13C NMR spectrum (CDCl3), δ, ppm: 21.4 (CH3), 26.4 (CH3), 33.4 (CH), 44.3 (CH), 51.2 (CH2), 58.3 (CH2), 59.6 (CH2), 113.5 (CH), 124.1 (CHTol), 129.5 (CHTol), 138.9 (CTol), 139.3 (CTol), 147.5 (Cquat). Found, %: C 84.37; H 8.97; N 6.66. C15H19N. Calculated, %: C 84.46; H 8.98; N 6.57.
6-(4-Methoxyphenyl)-4-methyl-1-azabicyclo[3.2.1]oct-3-ene (3c). Yield 0.43 g (93%), beige crystals, mp 83–84°C. IR spectrum, ν, cm–1: 3050, 2900, 2825, 1670, 1250, 1014. 1H NMR spectrum (CDCl3), δ, ppm: 1.21 s (3H, CH3), 2.46–3.69 m (8H), 3.76 s (3H, OCH3), 5.34–5.40 m (1H), 7.17–7.25 m (4H). 13C NMR spectrum (CDCl3), δ, ppm: 18.4 (CH3), 45.9 (CH), 50.3 (CH), 55.3 (CH2), 58.3 (CH3), 63.6 (CH2), 68.8 (CH2), 114.2 (CHarom), 114.8 (CH), 128.8 (CHarom), 139.0 (Carom), 140.4 (Cquat), 159.3 (COCH3). Found, %: C 78.63; H 8.41; N 6.90. C15H19NO. Calculated, %: C 78.56; H 8.35; N 6.98.
4-Methyl-6-(4-fluorophenyl)-1-azabicyclo[3.2.1]oct-3-ene (3d). Yield 0.30 g (65%), white powder, mp 97–99°C. IR spectrum, ν, cm–1: 3075, 2903, 2829, 1665, 1230, 1178, 1091. 1H NMR spectrum (CDCl3), δ, ppm: 1.14 s (3H, CH3), 1.20–1.32 m (1H), 2.52 s (1H), 3.25–3.28 m (1H), 3.59–3.76 m (3H), 4.08–4.21 m (2H), 5.26–5.34 m (1H), 7.02 d (2H, 3J 8.0 Hz), 7.23 d (2H, 3J 8.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 22.0 (CH3), 46.4 (CH), 50.6 (CH), 52.8 (CH2), 55.7 (CH2), 58.9 (CH2), 111.5 (CH), 116.3 d (CHarom, 2JCF 22.0 Hz), 128.4 d (CHarom, 3JCF 8.0 Hz), 135.8 (Carom–CH), 145.1 (Cquat), 162.1 d (Carom–F, 1JCF 246.0 Hz). Found, %: C 77.31; H 7.39; N 6.54. C14H16FN. Calculated, %: C 77.39; H 7.42; N 6.45.
6-(4-Chlorophenyl)-4-methyl-1-azabicyclo[3.2.1]oct-3-ene (3e). Yield 0.38 g (83%), gray powder, mp 91–94°C. IR spectrum, ν, cm–1: 3080, 2979, 2930, 1504, 1020, 693. 1H NMR spectrum (CDCl3), δ, ppm: 1.67 s (3H, CH3), 3.76–3.85 m (2H), 4.20–4.34 m (5H), 4.49–4.53 m (1H), 5.95–6.00 m (1H), 7.04–7.15 m (4H). 13C NMR spectrum (CDCl3), δ, ppm: 22.8 (CH3), 45.6 (CH), 50.1 (CH), 63.6 (CH2), 64.7 (CH2), 68.6 (CH2), 113.4 (CH), 128.3 (CHarom), 129.2 (CHarom), 133.5 (Carom–Cl), 138.0 (Carom), 140.0 (Cquat). Found, %: C 71.99; H 6.97; N 5.92. C14H16ClN. Calculated, %: C 71.94; H 6.90; N 5.99.
3-Methyl-6-(4-nirophenyl)-1-azabicyclo[3.2.1]oct-3-ene (3f). Yield 0.24 g (52%), yellow powder, mp 81–83°C. IR spectrum, ν, cm–1: 3065, 2900, 2830, 1675, 1520, 1350, 1310, 1111, 760. 1H NMR spectrum (CDCl3), δ, ppm: 1.19 s (3H, CH3), 2.98–4.69 m (8H), 5.38–5.46 m (1H), 7.78–7.55 m (2H), 8.12–8.17 m (2H). 13C NMR spectrum (CDCl3), δ, ppm: 22.9 (CH3), 45.8 (CH), 50.7 (CH), 58.2 (CH2), 63.5 (CH2), 64.9 (CH2), 113.9 (CH), 123.9 (CHarom), 129.0 (CHarom), 138.0 (Cquat), 142.4 (Carom), 147.5 (Carom). Found, %: C 68.90; H 6.64; N 11.40. C14H16N2O2. Calculated, %: C 68.83; H 6.60; N 11.47.
CONCLUSIONS
A series of novel 4-methyl-6-exo-(4-R-phenyl)-1-azabicyclo[3.2.1]oct-3-enes was synthesized by the one-step intramolecular carbocationic cyclization of 1-[2-hydroxy-2-(4-R-phenyl)ethyl]-1,2,3,6-tetrahydropyridines in trifluoromethanesulfonic acid. It was shown that the cyclization products of tetrahydropyridines 2d–2f which contain electron-acceptor substituents in the benzene ring are formed in noticeably lower yields. The cyclization of 1,2,3,6-tetrahydropyridine 2a in concentrated sulfuric acid did not occur. The resulting data serve as a basis for further research on the stereochemical features of the reaction and the biological activity of the synthesized cyclic structures.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
Jin, Z. and Xu, X.-H., in Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes, Ramawat, K.G. and Mérillon, J.M., Eds., Berlin, Heidelberg: Springer-Verlag, 2013, p. 479. https://doi.org/10.1007/978-3-642-22144-6_18
Nair, J.J. and van Staden, J., Fitoterapia, 2019, vol. 134, p. 305. https://doi.org/10.1016/j.fitote.2019.02.009
Nair, J.J., Wilhelm, A., Bonnet, S.L., and van Staden, J., Bioorg. Med. Chem. Lett., 2017, vol. 22, p. 4943. https://doi.org/10.1016/j.bmcl.2017.09.052
Nair, J.J. and van Staden, J., Fitomedicine, 2020, vol. 73, p. 152753. https://doi.org/10.1016/j.phymed.2018.11.013
Tram, N.T.N., Titorenkova, Tz.V., Bankova, V.St., Handjieva, N.V., and Popov, S.S., Fitoterapia, 2002, vol. 73, p. 183. https://doi.org/10.1016/S0367-326X(02)00068-0
Chahal, S., Lekhak, M.M., Kaur, H., Shekhawat, M.S., Dey, A., Jha, P., Kumar, Pandey, D., and Kumar, V., S. Afr. J. Bot., 2021, vol. 136, p. 7. https://doi.org/10.1016/j.sajb.2020.04.029
Maafi, N., Pidaný, F., Maříková, J., Korábečný, J., Hulcová, D., Kučera, T., Schmidt, M., Al, Shammari, L., Špulák, M., Catapano, M.C., Mecava, M., Prchal, L., Kuneš, J., Janoušek, J., Kohelová, E., Jenčo, J., Nováková, L., and Cahlíková, L., Bioorg. Med. Chem. Lett., 2021, vol. 51, p. 127374. https://doi.org/10.1016/j.bmcl.2021.128374
Schürmann, da, Silva, A.F., de, Andrade, J.P., Bevilaqua, L.R.M., Maria, de, Souza, M., Izquierdo, I., Henriques, A.T., and Zuanazzi, J.Â.S., Pharmacol. Biochem. Behav., 2006, vol. 85, p. 148. https://doi.org/10.1016/j.pbb.2006.07.027
Puriņš, M., Kumpiņš, V., Skomorokhov, M., Mishnev, A., and Turks, M., Tetrahedron Lett., 2020, vol. 61, p. 151405. https://doi.org/10.1016/j.tetlet.2019.151405
Orlek, B.S., Blaney, F.E., Brown, F., Clark, M.S.G., Hadley, M.S., Hatcher, J., Riley, G.J., Rosenberg, H.E., Wadsworth, H.J., and Wyman, P., J. Med. Chem., 1991, vol. 34, p. 2726. https://doi.org/10.1021/jm00113a009
Della, E.W. and Knill, A.M., J. Org. Chem., 1996, vol. 61, p. 7529. https://doi.org/10.1021/jo960886i
Della, E.W. and Smith, P.A., J. Chem. Soc., Trans. 1, 2001, vol. 24, p. 445. https://doi.org/10.1039/B006691P
Pandey, G., Gupta, N.R., and Gadre, S.R., Eur. J. Org. Chem., 2011, vol. 2011, p. 740. https://doi.org/10.1002/ejoc.201001263
Tamiz, A.P., Smith, M.P., Enyedy, I., Flippen-Anderson, J., Zhang, M., Johnson, K.M., and Kozikowski, A.P., Bioorg. Med. Chem. Lett., 2000, vol. 10, p. 1681. https://doi.org/10.1016/S0960-894X(00)00308-5
Thill, B.P. and Aaron, H.S., J. Org. Chem., 1968, vol. 33, p. 4376. https://doi.org/10.1021/jo01276a014
Bhatti, B.S., Strachan, J., Breining, S.R., Miller, C.H., Tahiri, P., Crooks, P.A., Deo, N., Day, C.S., and Caldwell, W.S., J. Org. Chem., 2008, vol. 73, p. 3497. https://doi.org/10.1021/jo800028q
Walker, D.P., Acker, B.A., Jacobsen, E.J., and Wishka, D.G., J. Heterocycl. Chem., 2008, vol. 45, p. 247. https://doi.org/10.1002/jhet.5570450131
Konovalov, A.I., Antipin, I.S., Burilov, V.A., Madzhidov, T.I., Kurbangalieva, A.R., Nemtarev, A.V., Solovieva, S.E., Stoikov, I.I., Mamedov, V.A., Zakharova, L.Ya., Gavrilova, E.L., Sinyashin, O.G., Balova, I.A., Vasilyev, A.V., Zenkevich, I.G., Krasavin, M. Yu., Kuznetsov, M.A., Molchanov, A.P., Novikov, M.S., Nikolaev, V.A., Rodina, L.L., Khlebnikov, A.F., Beletskaya, I.P., Vatsadze, S.Z., Gromov, S.P., Zyk, N.V., Lebedev, A.T., Lemenovskii, D.A., Petrosyan, V.S., Nenaidenko, V.G., Negrebetskii, V.V., Baukov, Yu. I., Shmigol’, T.A., Korlyukov, A.A., Tikhomirov, A.S., Shchekotikhin, A.E., Traven’, V.F., Voskresenskii, L.G., Zubkov, F.I., Golubchikov, O.A., Semeikin, A.S., Berezin, D.B., Stuzhin, P.A., Filimonov, V.D., Krasnokutskaya, E.A., Fedorov, A. Yu., Nyuchev, A.V., Orlov, V.Yu., Begunov, R.S., Rusakov, A.I., Kolobov, A.V., Kofanov, E.R., Fedotova, O.V., Egorova, A.Yu., Charushin, V.N., Chupakhin, O.N., Klimochkin, Yu.N., Osyanin, V.A., Reznikov, A.N., and Fisyuk, A.S., Russ. J. Org. Chem., 2018, vol. 54, p. 157. https://doi.org/10.1134/S107042801802001X
Klumpp, D.A., Beauchamp, P.S., Sanchez, Jr. G.V., Aguirre, S., and de Leon, S., Tetrahedron Lett., 2001, vol. 42, p. 5821. https://doi.org/10.1016/S0040-4039(01)01130-3
Olah, G.A. and Klumpp, D.A., Superelectrophiles and their Chemistry, Hoboken: Wiley-Intersciense, 2008.
Shadrikova, V.A., Golovin, E.V., Shiryaev, V.A., Baymuratov, M.R., Rybakov, V.B., and Klimochkin, Yu.N., Chem. Heterocycl. Compd., 2015, vol. 51, p. 891. https://doi.org/10.1007/s10593-015-1792-4
Shadrikova, V.A., Golovin, E.V., Kuznetsova, E.A., Rostova, M.Yu., and Klimochkin, Yu.N., Russ. J. Org. Chem., 2016, vol. 52, p. 1452. https://doi.org/10.1134/S1070428016100146
Shadrikova, V.A., Popov, A.S., Termelyova, M.V., Baymuratov, M.R., and Klimochkin, Yu.N., Chem. Heterocycl. Compd., 2020, vol. 56, p. 909. https://doi.org/10.1007/s10593-020-02748-8
Shadrikova, V.A., Golovin, E.V., Rybakov, V.B., and Klimochkin, Yu.N., Chem. Heterocycl. Compd., 2015, vol. 56, p. 898. https://doi.org/10.1007/s10593-020-02747-9
Grierson, D.S., Harris, M., and Husson, H.P., J. Am. Chem. Soc., 1980, vol. 102, p. 1064. https://doi.org/10.1021/ja00523a026
Wichitnithad, W., O’Callaghan, J.P., Miller, D.B., Train, B.C., and Callery, P.S., Bioorg. Med. Chem., 2011, vol. 19, p. 7482. https://doi.org/10.1016/j.bmc.2011.10.038
Szwajca, A., Łęska, B., Schroeder, G., and Szafran, M., J. Mol. Struct., 2004, vol. 708, p. 87. https://doi.org/10.1016/j.molstruc.2004.01.073
Sato, K., Nakajima, K., Arai, S., and Yamagishi, T., Liebigs Ann., 1996, vol. 4, p. 439. https://doi.org/10.1002/jlac.199619960404
Koh, H.J., Han, K.L., Lee, H.W., and Lee, I., J. Org. Chem., 2000, vol. 65, p. 4076. https://doi.org/10.1021/jo000411y
Bahner, C.T., Easley, W., Walden, B.G., Lyons, H., and Biggerstaff, G., J. Am. Chem. Soc., 1952, vol. 74, p. 3960. https://doi.org/10.1021/ja01135a600
Phillips, W.G. and Ratts, K.W., J. Org. Chem., 1970, vol. 35, p. 3144. https://doi.org/10.1021/jo00834a064
ACKNOWLEDGMENTS
The work was carried out using the equipment of the “Study of the Physical and Chemical Properties of Substances and Materials” Center for Collective Use, Samara State Technical University.
Funding
Synthesis was perfomed under financial support of the Russian Foundation for Basic Research (project no. 20-53-04035, competition type Bel_mol_a). The spectral characteristics were studied under financial support of the Ministry of Science and Higher Education of the Russian Federation (topic no. FSSE-2023-0003) in the core of the state assignment for the Samara State Technical University.
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Translated from Zhurnal Organicheskoi Khimii, 2023, Vol. 59, No. 8, pp. 1057–1064 https://doi.org/10.31857/S0514749223080074.
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Shadrikova, V.A., Shumkova, A.A., Shiryaev, V.A. et al. Synthesis of 4-Methyl-6-N-(4-R-phenyl)-1-azabicyclo[3.2.1]octane-3-enes. Russ J Org Chem 59, 1335–1341 (2023). https://doi.org/10.1134/S1070428023080079
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DOI: https://doi.org/10.1134/S1070428023080079