INTRODUCTION

2-Amino-3-cyano-4H-pyran derivatives are known to exhibit pronounced biological activity; in particular, they inhibit SARS-CoV-2 [1], cholinesterase [2], Staphylococcus aureus [3, 4], tumors [5–7], acetyl­cholinesterase [8], and M. tuberculosis [9]. They also show antioxidant [10–12] and anti-inflammatory [13–15] activities.

RESULTS AND DISCUSSION

Taking into account practical importance of sub­stituted 2-amino-3-cyano-4H-pyrans, we continued our research in the field of chemistry of these organic compounds [16–20] and studied three-component condensation of dimedone (1), malononitrile (2) and benzaldehyde (3a) or 3-phenylpropanal (3b) in 2-aminoethanol at 20°C. As a result, tetrahydro­chromene derivatives 4a and 4b were obtained. A probable reaction mechanism (Scheme 1) involves Knoevenagel condensation of aldehyde 3 and malono­nitrile (2) with the formation of intermediate A, fol­lowed by Michael addition of dimedone (1). Intra­molecular cyclization of adduct B yields 81–88% of final product 4. In this reaction, 2-aminoethanol is likely to act as a base catalyst. Compounds 4 were synthesized previously in the presence of piperidine [21] or morpholine [22].

Scheme
scheme 1

1.

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Treatment of pyran 4a with bromine in methanol under irradiation with a 500-W lamp led to the formation of benzofuran derivative 5 in 45% yield. Presumably, in the first stage conjugate addition of bromine and methanol to the double C4a=C8a bond gives intermediate C, and next follows bromination of the second double C=C bond to produces 3,4a-dibromo derivative D. Opening of the pyran ring in D leads to intermediate E which undergoes cyclization to final structure 5 with elimination of ammonium bromide (Scheme 1). It should be noted that pyran derivatives structurally related to 4 reacted with bromine in methanol through opening of the heteroring to give methyl 2-cyano-3-(4,4-dimethyl-2,6-dioxo­cyclohexyl)-3-(4-hydroxyphenyl)prop-2-enoate [23], 3-aryl-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)­propionic acids were obtained by the action of sulfuric acid and boiling formic acid [24], and their oxidation with 1-chloropyrrolidine-2,5-dione, iodine, sodium chlorate, or sodium hypochlorite produced alkyl 3-aryl-6,6-dimethyl-4-oxooctahydrobenzofuran-2-carbox­ylates [25].

A similar three-component condensation of dime­done (1), 4-chlorobenzaldehyde (6), and methyl 3-amino-3-selanylidenepropanoate (7) afforded chromene 8. The reaction was carried out in anhydrous ethanol at 20°C under argon in the presence of an equi­molar amount of N-methylmorpholine. Assumingly, the first stage of this process is Knoevenagel conden­sation of 6 and 7 to form intermediate F, which is followed by Michael addition of CH acid 1. Chemo­selective cyclization of adduct G thus formed with elimination of hydrogen selenide yields final product 8 (Scheme 2).

Scheme
scheme 2

2.

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Unexpected result was obtained in the three-com­ponent condensation of dimedone (1), cyanothio­acet­amide (9), and cyclohex-3-ene-1-carbaldehyde (10) in 2-aminoethanol at 20°C. The product of this reaction was 4H-thiopyran derivative 11. This may be explained assuming that the Michael addition stage involves the second molecule of CH acid 9 instead of dimedone (1); the subsequent chemoselective intramolecular cycliza­tion of intermediate H gives thiopyran 11. The maxi­mum yield of 11 was achieved using reactants 9 and 10 at a ratio of 2:1, which confirmed the proposed scheme (Scheme 3). Compound 11 was synthesized by us previously by the reaction of malononitrile (2) with cyanothioacetamide (9) and aldehyde 10 in ethanol in the presence of morpholine [26].

Scheme
scheme 3

3.

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The structure of compounds 4a, 4b, 5, 8, and 11 was confirmed by their spectral characteristics. The IR spectra of 4a, 4b, 5, 8, and 11 showed absorption bands typical of stretching vibrations of functional groups present in their molecules, and their 1H and 13C NMR spectra were consistent with the assigned structures (see Experimental). Furthermore, the molecular and crystal structures of compounds 4b, 5, 8, and 11 were determined by X-ray analysis.

Figure 1 shows the molecular and crystal structure of compound 4b. The 4H-pyran ring of the bicyclic chromene fragment of molecule 4b adopts a strongly flattened boat conformation with the O1 and C4 atoms deviating by 0.092(2) and 0.208(2) Å, respectively, from the basal plane passing through the other ring carbon atoms. The cyclohexene ring of the chromene fragment has an unsymmetrical half-boat conformation with the C7 and C8 atoms deviating by 0.752(3) and 0.187(3) Å, respectively, from the basal plane passing through the other ring carbon atoms. The ethylene bridge connecting the benzene and pyran rings has trans configuration with the torsion angle C4C9C10C11 equal to –169.47(13)°, and it occupies less sterically favorable pseudo-axial position with a dihedral angle of 63.41(7)° between the benzene ring plane and basal plane of the pyran ring. The N2 atom has trigonal–planar configuration with the sum of the bond angles equal to 359(5)°.

Fig. 1.
figure 1

(a) Molecular structure of compound 4b and (b) packing of its molecules in crystal with the formation of H-bonded bands along the [10] direction. Intermolecular hydrogen bonds are shown with dashed lines.

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Molecule 4b possesses an asymmetric carbon atom (C4), and compound 4b crystallizes as a racemate. Molecules 4b in crystal are linked through fairly strong intermolecular N–H···N and N–H···O bonds (Table 1, Fig. 2) to form bands along the b crystallographic axis. The bands are located at van der Waals distances from each other.

Fig. 2.
figure 2

Hydrogen-bonded band formed by molecules 4b in crystal. Intermolecular hydrogen bonds are shown with dashed lines.

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Table 1. Hydrogen bonds in the crystal structures of compounds 4b, 5, 8, and 11
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The molecular structure of compound 5 with atom numbering is shown in Fig. 3. The cyclohexane and tetrahydrofuran rings of the central octahydrobenzo­furan fragment appear as typical slightly distorted chair (basal plane C4C5C7C8) and envelope conforma­tions (basal plane O1C2C3C4), respectively. The six- and five-membered rings are cis-fused with a dihedral angle of 70.60(2)° between the corresponding basal planes. Molecule 5 possesses four asymmetric carbon atoms, C2, C3, C4, and C9, and compound 5 in crystal is a racemate with 2SR,3SR,4RS,9RS relative configura­tion of the chiral centers. Molecules 5 in crystal are linked through weak intermolecular hydrogen bonds C–H···O (Table 1) and noncovalent interactions Br1···N1 [0.5 – x, 0.5 + y, 0.5 – z; 3.097(3) Å] (Fig. 3b) to form puckered layers parallel to the (001) plane and arranged at van der Waals distances from each other (Fig. 4).

Fig. 3.
figure 3

(a) Molecular structure of compound 5 represented by anisotropic displacement ellipsoids for non-hydrogen atoms with a probability of 50% and (b) puckered layer formed by molecules 5 in crystal. Intermolecular hydrogen bonds C–H···O and non­covalent interactions Br···N are shown with dashed lines.

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Fig. 4.
figure 4

Crystal structure of compound 5 represented by puckered layers parallel to the (001) plane. Intermolecular hydrogen bonds C–H···O and noncovalent interactions Br···N are shown with dashed lines.

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Figure 5a shows the molecular structure of com­pound 8 with atom numbering. Its structure is very similar to the structure of 4b. The pyran ring of the chromene fragment adopts a strongly flattened boat conformation with the O1 and C4 atoms deviating by 0.089(2) and 0.181(2) Å, respectively, from the basal plane passing through the other ring carbon atoms. The cyclohexene ring has an unsymmetrical half-boat conformation in which the C7 and C8 atoms deviate by 0.706(3) and 0.121(3) Å, respectively, from the basal plane formed by the other ring atoms. The 4-chloro­phenyl substituent appears in the less sterically favor­able pseudo-axial orientation and is turned through a dihedral angle of 77.45(5)° with respect to the basal plane of the pyran ring. The acetyl group is almost coplanar to the basal plane of the pyran ring [the corresponding dihedral angle is 6.50(13)°], and its orientation is stabilized by the intramolecular hydrogen bond N–H···O (Table 1). The N1 atom has trigonal–planar configuration with the sum of the bond angles equal to 359(4)°. Like molecule 4b, the C4 atom of 8 is asymmetric, and crystalline compound 8 is a racemate. However, unlike 4b, molecules 8 in crystal are linked through intermolecular hydrogen bonds N–H···Cl, N–H···O, and C–H···O to form double-deck layers parallel to the (001) plane (Table 1, Fig. 5b). The layers give rise to a three-dimensional network through Cl···Cl noncovalent interactions with a distance of 3.4432(7) Å.

Fig. 5.
figure 5

(a) Molecular structure of compound 8 represented by anisotropic displacement ellipsoids for non-hydrogen atoms with a probability of 50% and (b) double-deck layer parallel to the (001) plane in the crystal structure of 8. Intermolecular hydrogen bonds and Cl···Cl noncovalent interactions are shown with dashed lines.

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The molecular structure of 4H-thiopyran derivative 11 is shown in Fig. 6a. The central 4H-thiopyran ring has a boat conformation with the S1 and C4 atoms deviating by 0.435(4) and 0.505(4) Å, respectively, from the basal plane passed through the other ring atoms. The cyclohexenyl substituent occupies less sterically favorable axial position. The N1 amino nitrogen atom has trigonal–planar configuration with the sum of the bond angles equal to 359.3°, whereas the N4 atom is trigonal–pyramidal (sum of the bond angles 352.6°). The C4 atom is asymmetric, and compound 11 in crystal is a racemate. Molecules 11 in crystal are linked through intermolecular hydrogen bonds N–H···N to form layers parallel to the (101) plane (Table 1, Fig. 6b). The layers appear at van der Waals distances from each other and form a zipper type packing (Fig. 6c).

Fig. 6.
figure 6

(a) Molecular structure of compound 11 represented by anisotropic displacement ellipsoids for non-hydrogen atoms with a probability of 50%; alternative position of the disordered cyclohexenyl substituent is shown with dashed lines; (b) structure of a layer formed by molecules 11 in crystal; (c) zipper packing of hydrogen-bonded layers parallel to the (101) plane in the crystal structure of 11. Intermolecular hydrogen bonds N–H···N are shown with dashed lines.

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EXPERIMENTAL

The IR spectra were recorded on a Varian Vertex 70 spectrometer from samples prepared as KBr discs. The 1H and 13C NMR spectra were recorded on a Varian VXR–400 spectrometer at 399.97 and 100 MHz, respec­tively, using DMSO-d6 as solvent and tetra­methylsilane as internal standard. The mass spectra were obtained with an Orbitrap Elite high-resolution mass spectrometer; samples were dissolved in 1 mL of DMSO, and the solution was diluted with 100 volumes of 1% formic acid in acetonitrile and introduced into electrospray ionization source at a flow rate of 40 μL/min using a syringe pump; the source gas supply was turned off; needle voltage 3.5 kV, capillary temperature 275°C; positive and negative ions were detected using an orbital trap with a resolution of 480000. [2DMSO + H]+ (m/z 157.03515) and dodecyl sulfate anion (m/z 265.14789) were used as internal calibrants for positive and negative ions, respectively. Elemental analysis was performed with a Perkin Elmer CHN analyzer. The melting point were measured using a Kofler hot stage. The progress of reactions and the purity of the isolated compounds were monitored by TLC on Silufol UV-254 plates using acetone–hexane (3:5) as eluent; visualization was done by treatment with iodine vapor and under UV light.

The unit cell parameters and X-ray reflection inten­sities for single crystals of compounds 4b, 8, and 11 were determined on a Bruker D8 QUEST PHOTON-III CCD diffractometer (graphite monochromator, φ- and ω-scanning). The data were processed using SAINT [27]. A correction for absorption was applied by SADABS [28]. The X-ray diffraction data for com­pound 5 were obtained at the “Kurchatov Institute” National Research Center on an RSA synchrotron station equipped with a two-coordinate Rayonix SX165 CCD detector (φ-scanning with a step of 1.0°). The data were processed using iMOSFLM program implemented in CCP4 software package [29]. Ab­sorption of X-ray radiation was taken into account using SCALA program [30]. The principal crystal­lo­graphic data and refinement parameters are collected in Table 2.

Table 2. Crystallographic data for compounds 4b, 5, 8, and 11
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The structures were determined by direct methods and were refined against F2 by the full-matrix least-squares method in anisotropic approximation for non-hydrogen atoms. The cyclohexene ring in molecule 11 was disordered by two positions with different populations. Hydrogen atoms of the amino groups of 4b and 8 were localized objectively by difference Fourier syntheses and were refined isotropically with fixed thermal displacement parameters [Uiso(H) = 1.2Ueq(N)]. Hydrogen atoms of the amino groups of 11 were localized objectively by difference Fourier syntheses and were refined with fixed positional parameters (riding model) and isotropic thermal dis­placement parameters [Uiso(H) = 1.2Ueq(N)]. The positions of the other hydrogens were calculated geometrically and refined with fixed positional param­eters (riding model) and isotropic thermal displacement parameters [Uiso(H) = 1.5Ueq(C) for methyl groups and 1.2Ueq(C) for other groups]. All calculations were performed using SHELXTL [31]. The tabulated coordinates of atoms, bond lengths, bond and torsion angles, and anisotropic displacement parameters for compounds 4b, 5, 8, and 11 were deposited to the Cambridge Crystallographic Data Centre (CCDC entry nos. 2143982, 2143983, 2143984, and 2143985, respectively).

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a). A mix­ture of 1.0 mL (10 mmol) of benzaldehyde (3a) and 0.66 g (10 mmol) of malononitrile (2) in 15 mL of 2-aminoetanol was stirred at 20°C for 25 min, 1.4 g (10 mmol) of dimedone (1) was added, and the mixture was stirred for 25 min and left to stand for 48 h. The mixture was diluted with an equal volume of water, and the precipitate was filtered off and washed with water, ethanol, and hexane. Yield 3.6 g (88%), colorless crystals, mp 238–240°C (from EtOH); published data [21]: mp 237–238°C.

2-Amino-7,7-dimethyl-5-oxo-4-(2-phenylethyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4b) was synthesized in a similar from 1.34 g of 3-phenylpropanal (3b). Yield 2.6 g (81%), colorless crystals, mp 197–198°C (from EtOH); published data [22]: mp 199–200°C. 13C NMR spectrum, δC, ppm: 23.2, 24.5, 25.5, 26.8, 27.9, 32.3, 46.3, 51.2, 108.5, 116.3, 121.9 (2C), 124.4 (2C), 124.6 (2C), 137.9, 156.2, 159.5, 192.6. Mass spectrum (ESI): m/z 323.1759 [M + H]+. C20H22N2O2. Calculated: M + H 323.1681.

Methyl 3a-bromo-2,7a-dimethoxy-6,6-dimethyl-4-oxo-3-phenyloctahydro-1-benzofuran-2-carbox­ylate (5). Molecular bromine, 0.51 mL (10 mmol), was added dropwise at room temperature to a mixture of 2.94 g (10 mmol) of pyran 4a and 30 mL under stirring on a magnetic stirrer and irradiation with a 500-W lamp. The rate of the addition was maintained so that the reaction mixture retained pink color (~15 min). The mixture was then stirred for 60 min and left to stand in a refrigerator. After 24 h, the mixture was diluted with an equal volume of water and left to stand further for 24 h at room temperature. The colorless needles were filtered off and successively washed with water, methanol, and hexane. Yield 1.9 g (45%), mp 208–210°C. IR spectrum, ν, cm–1: 2245 (C≡N), 1715 (C=O), 1702 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.01 s (3H, Me), 1.12 s (3H, Me), 2.06 d (1H, CH2, 2J = 14.8 Hz), 2.25 d (1H, CH2, 2J = 14.8 Hz), 3.21 d (1H, CH2, 2J = 17.8 Hz), 3.27 d (1H, CH2, 2J = 17.8 Hz), 3.50 s (3H, MeO), 3.84 s (3H, OMe), 4.95 s (1H, 3-H), 7.28–7.41 m (3H, Harom), 7.53–7.62 m (2H, Harom). 13C NMR spectrum, δC, ppm: 26.1, 32.2, 32.7, 48.5, 50.2, 54.3, 55.1, 66.2, 80.04, 111.6, 115.5, 128.4 (2C), 129.2, 133.0 (2C), 135.2, 165.4, 199.2, 207.5. Mass spectrum (ESI): m/z 437.0681 [M + H]+. C20H22BrNO5. Calculated: M + H 437.0597.

Methyl 2-amino-4-(4-chlorophenyl)-7,7-di­methyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (8). To a mixture of 1.4 g (10 mmol) of 4-chlorobenzaldehyde (6) and 20 mL of anhydrous ethanol we added with stirring at 20°C under argon 1.81 g (10 mmol) of CH acid 7 and 1.1 mL (10 mmol) of N-methylmorpholine. The mixture was stirred for 30 min, 1.4 g (10 mmol) of dimedone (1) was added, and the mixture was stirred for 1 h and left to stand for 24 h. The precipitate was filtered off and washed with ethanol and hexane. Yield 2.8 g (78%), colorless cubic crystals, mp 173–175°C (from EtOH). IR spectrum, ν, cm–1: 3408, 3345, 3241 (NH2), 1696, 1713 (C=O), 1649 (δNH2). 1H NMR spectrum, δ, ppm (J, Hz): 0.85 s (3H, Me), 1.00 s (3H, Me), 2.03 d (1H, CH2, 2J = 16.1 Hz), 2.23 d (1H, CH2, 2J = 16.1 Hz), 2.45 d (1H, CH2, 2J = 17.6 Hz), 2.47 d (1H, CH2, 2J = 17.6 Hz), 3.47 s (3H, MeO), 4.48 s (1H, 4-H), 7.10 d (2H, Harom, J = 8.4 Hz), 7.23 d (2H, Harom, J = 8.4 Hz), 7.59 br.s (2H, NH2). 13C NMR spectrum, δC, ppm: 26.9, 29.1, 32.3, 33.3, 50.3, 51.0, 77.6, 115.6, 128.2 (2C), 128.6, 129.8, 130.8 (2C), 145.8, 159.7, 162.7, 168.6, 196.2. Mass spectrum (ESI): m/z 362.1162 [M + H]+. C19H20ClNO4. Calculated: M + H 362.1081.

2,6-Diamino-4-(cyclohex-3-en-1-yl)-4H-thio­pyran-3,5-dicarbonitrile (11). Cyanothioacetamide (9, 2.0 g, 20 mmol) was added with stirring at 20°C to a solution of 0.94 mL (10 mmol) of aldehyde 10 in 15 mL of 2-aminoethanol, and the mixture was stirred for 2 h and left to stand for 24 h. The mixture was diluted with an equal volume of water, and the precipitate was successively washed with water, ethanol, and hexane. Yield 1.83 g (71%), yellow crystals, mp 199–201°C (from AcOH) [26]. 13C NMR spectrum, δC, ppm: 25.1, 26.3, 29.0, 44.5, 70.7, 71.1, 120.2, 126.2 (2C), 127.1 (2C), 153.2, 153.3. Mass spectrum (ESI): m/z 259.1012 [M + H]+. C13H14N4S. Calculated: M + H 259.0939.

CONCLUSIONS

The condensation of dimedone, malononitrile, and aldehydes in 2-aminoethanol afforded pyran derivatives whose molecular and crystal structures were deter­mined by X-ray analysis. Radical bromination of 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetra­hydro-4H-chromene-3-carbonitrile in methanol was accompanied by pyran ring contraction with the formation of benzofuran derivative.