3-Nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes: synthesis and reactions with nucleophiles

A method is proposed for the synthesis of 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes by tandem condensation of salicylic aldehydes with (E)-3,3,3-trifluoro-1-nitro-2-phenylprop-1-ene in the presence of triethylamine. The example of 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromene was used to demonstrate conjugated addition reactions with enamines, nitromethane, and aniline, which are characteristic for this class of compounds. The structure of the obtained products was confirmed by X-ray structural analysis.

3-Nitro-2H-chromenes represent an important class of organic compounds, the properties of which have been intensively studied in recent years.1 The interest toward these heterocycles as starting substrates for the preparation of more complex bioactive molecules is linked to their availability and high reactivity, as well as the common occurrence of many derivatives of chromene and chromane (3,4-dihydro-2H-1-benzopyran) in plants. Such compounds show promise as pesticides and potential drug molecules.2

The reactivity of 3-nitro-2H-chromenes is mostly determined by the nitroalkene moiety, although the substituent at position 2 can also substantially affect the rate and direction of some reactions, even though it is bonded to sp ³-hybridized carbon atom. For example, we recently studied 3-nitro-2-(trifluoromethyl)-2H-chromenes

1 (Fig. 1), the reactivity of which toward nucleophiles significantly exceeded1 the previously known 3-nitro-2-phenyl-2H-chromenes 2, due to the presence of a CF₃ group providing an additional strong negative inductive effect, thus activating the double bond in pyran ring. Besides that, the addition reactions involving 2-(trifluoromethyl) chromenes 1 were found to be more stereoselective, compared to the analogous reactions of 2-phenylchromenes 2, allowing us to obtain a wide range of new 2,3,4-trisubstituted chromanes as individual diastereomers, the structures of which were reliably established by X-ray structural analysis.3

Figure 1

2-Substituted 3-nitro-2H-chromenes 1–3.

The introduction of a bulky phenyl substituent along with the CF₃ group at position 2 of chromenes 1 was clearly of interest, as it allowed to obtain 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes 3 that represented a combination of chromenes 1 and 2 (Fig. 1). The structural features of compounds 3 can not only increase the stereoselectivity of addition reactions involving these compounds and to expand the range of stereochemically different 2,2,3,4-tetrasubstituted chromanes, but also lead to the emergence of new, useful properties of chromenes themselves, as well as in products obtained from them.

The most common method that has been used for obtaining 3-nitro-2H-chromenes is based on the reaction of salicylic aldehydes with conjugated nitroalkenes in the presence of bases, due to the wide availability of these starting materials.1 The process represented a nucleophilic addition of the respective phenolate anion to nitroalkene molecule, followed by intramolecular Henry reaction and led to the formation of 4-hydroxy-3-nitrochromane, dehydration of which provided the desired product (Scheme 1). This approach can be used for the synthesis of a wide range of nitrochromenes containing various substituents both at position 2 of the pyran system and in the aromatic ring.

Scheme 1

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In a continuation of our efforts directed toward the synthesis4 and understanding of the chemical properties5 of 3-nitro-2-(trifluoromethyl)-2H-chromenes 1, in the current work we propose a method for the preparation of previously unknown 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes 3 and describe representative reactions of Nand C-nucleophiles with a compound of this class, which lacks substituents in the benzene ring.

Nitrochromenes 3a–g were synthesized from the corresponding salicylic aldehydes and (E)-3,3,3-trifluoro-1-nitro-2-phenylprop-1-ene, obtained by Henry reaction from trifluoroacetophenone and nitromethane, followed by dehydration of the formed nitro alcohol with thionyl chloride in the presence of pyridine.6 The synthesis of chromenes 3a,d–g was performed in dichloromethane at room temperature for 3 h, using triethylamine as base. The formation of 4-hydroxy-3-nitrochromane intermediate was not observed, and the yields of chromenes 3a,d–g reached 80–96% (Scheme 1, Table 1). Additional refluxing for 3 min was required for obtaining chromenes 3b,c from 5-chloro- and 5-bromosalicylic aldehydes, while their yields were lower (64–69%).

Table 1 Yields of nitrochromenes 3a–g

Chromenes 3a–g were isolated as yellow fine crystalline powders. ¹H NMR spectra of these compounds contained a characteristic singlet of 4-CH proton in the range of 8.07–8.24 ppm. The diastereotopic methylene protons in 8-ethoxychromene 3g were observed as two double quartets at 4.07 and 4.11 ppm, pointing to the presence of asymmetric carbon atom in the molecule. The trifluoromethyl group bonded to sp ³ carbon atom was observed in ¹⁹ F NMR spectra of chromenes 3a–g as a singlet at 88.8–89.5 ppm, which was shifted downfield compared to chromenes 1 (83.9–84.3 ppm),^3a−c,4a,5b due to the deshielding effect of 2-phenyl substituent. ¹³C NMR spectra of compounds 3a–g featured quartets of the CF₃ group and the C-2 atom in the ranges of 123.2−123.7 and 82.4−83.7 ppm, respectively, with the spin-spin coupling constants of ¹ J _CF = 289.4−290.6 and ² J _CF = 30.8−31.3 Hz, as well as a quartet or broadened singlet of the C _ipso atom in the phenyl substituent at 127.2−127.4 ppm (³ J _CF = 1.0−1.5 Hz). IR spectra of the obtained compounds contained absorption bands due to the stretching vibrations of double bond at 1631−1641 cm^–1 and the olefinic nitro group at 1519−1528 and 1289−1342 cm^–1. The structure of nitrochromene 3a was confirmed by X-ray structural analysis (Fig. 2).

Figure 2

The molecular structure of compound 3a with atoms represented by thermal vibration ellipsoids of 30% probability.

We further studied the interaction of 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromene (3a) with primary and tertiary push-pull enamines, which were synthesized from acetoacetic ester and acetylacetone. It was found that ethyl (Z)-3-aminocrotonate (4), similarly as in the case of 3-nitro-2-(trifluoromethyl)-2H-chromenes 1,7 added with its most nucleophilic α-carbon atom at position 4 of chromene 3a that was activated by nitro group, forming 2,2,3,4-tetrasubstituted chromane 5 in 74% yield as an individual trans,trans -diastereomer tt-5 with (Z)-configuration of the enaminoester moiety, stabilized by intramolecular hydrogen bond. The reaction was performed by brief heating in anhydrous acetonitrile, followed by maintaining at room temperature for 3 days (Scheme 2).

Scheme 2

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The trans-diequatorial configuration of nitro group and enaminoester moiety was identified from the large value of spin-spin coupling constant between 3-CH and 4-CH protons (J _3,4 = 11.7 Hz), observed in¹H NMR spectrum of compound 5 in CDCl₃ solution. The presence of intramolecular hydrogen bond both in solution and solid state, associated with the (Z)-configuration of double bond, was evident from the broadened singlet of NH proton in the downfield region (8.94 ppm) and from the presence of ν(NH) absorption band at 3490 cm^–1 in the IR spectrum of chromane 5. The CF₃ group was observed as a singlet in ¹⁹F NMR spectrum of this compound at 85.6 ppm.

The validity of conclusions about the structure of compound 5 that were reached from the examination of spectral data, as well as the relative configuration of substituents at the C-2 atom were confirmed by monocrystal X-ray structural analysis of this chromane, proving its trans,trans configuration at C-2, C-3, and C-4 atoms (tt-isomer). As shown in Figure 3, all three bulky substituents in the heterocycle (CF₃, NO₂, and the enaminoester group) occupied equatorial positions, while the planar phenyl substituent at the C-2 carbon atom and the 3,4-CH hydrogen atoms were axially oriented. The unfavorable steric interactions between the bulky substituents caused the pyran ring to assume a twisted halfchair conformation. The planarity of enaminoester moiety was caused by the presence of an intramolecular hydrogen bond between the hydrogen atom of amino group and the carbonyl oxygen atom, with the interatomic distances N(2)–H(2A) 0.90(2), H(2A)···O(5) 1.96(2), N(2)···O(5) 2.660(3) Å, and the angle N(2)–H(2A)···O(5) 133(2)°. The plane of enaminoester moiety was nearly orthogonal to the aromatic ring plane (the dihedral angle between these planes was equal to 85.8(2)°).

Figure 3

The molecular structure of compound tt- 5 with atoms represented by thermal vibration ellipsoids of 30% probability.

It should be noted that chromane tt- 5 both in crystalline state (Fig. 3) and in solution phase (as indicated by the presence of one set of signals in ¹H and ¹⁹F NMR spectra) existed in the form of the energetically favored atropoisomer with anti configuration of the 4-CH atom and the CO₂Et group, due to the hindered rotation around the C(4)–C(2') bond (Scheme 2).7

In contrast to the primary (Z)-enaminoester 4, the interaction of chromene 3a with tertiary (E)-enamino ketone 6 under analogous conditions occurred with the participation of vinylogous β-methyl group and led to the formation of cis,trans-chromane 7 in 49% yield. The reaction time could be shortened to 5 h, if the process was performed at 60°C (Scheme 3). Chromenes 1 reacted with enamino ketone 6 in analogous way.^3c

Scheme 3

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¹H NMR spectrum of compound 7 contained two double doublets of diastereotopic methylene protons at 3.19 and 3.71 ppm, with spin-spin coupling constants of ² J = 13.1 Hz; ³ J = 3.0 and 2.5 Hz, respectively, a singlet of the =CH proton (6.00 ppm) and a broadened singlet of the 3-CH proton (5.26 ppm); the signal of the 4-CH proton overlapped with the signals of morpholine CH₂OCH₂ protons. The similar chemical shifts of 3-CH proton and spin-spin coupling constant J _3,4 ≈ 0 Hz were earlier observed in the case of cis,trans-2,3,4-trisubstituted 2-CX3-chromanes 8 (X = F, Cl), the structure of which has been definitely proved by X-ray structural analysis.^3c Based on this, we can propose that the same cis,trans configuration and preferred conformation with cis configuration of equatorial CF₃ group and trans configuration of pseudoaxial aminoenone moiety relative to the axial nitro group also existed in the molecule of chromane ct- 7, with the only difference that the axial position was occupied by phenyl substituent instead of the 2-CH proton (Scheme 4). The CF₃ group in the ¹⁹F NMR spectrum of compound ct- 7 was manifested as a singlet at 85.1 ppm.

Scheme 4

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Chromene 3a readily reacted with α-morpholinostyrene (9) in acetonitrile solution, giving a good yield of the respective 2,2,3,4-tetrasubstituted chromane 10. It is interesting to note that the spatial structure of this product substantially depended on the temperature regime. For example, when the reaction was performed at room temperature for 1 day, a 3:1 mixture of stereoisomeric chromanes 10a and 10b was formed in 96% yield, from which the major isomer 10a could be isolated as pure sample by simple recrystallization from a mixture of dichloromethane–hexane (2:1). At the same time, the chromane 10b was formed in 71% yield by heating a mixture of chromene 3a and enamine 9 for 4 h in acetonitrile at 60°C (Scheme 5). It is logical to assume that the isomer 10a resulted from kinetic control, and was transformed upon heating via a retro-Michael reaction to the thermodynamically more stable isomer 10b. We have previously identified and studied a similar transformation in the series of 3-nitro-2-(trihalomethyl)-2H-chromenes.^3e

Scheme 5

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The spatial structure of compounds 10a,b was established by X-ray structural analysis. The structure of diastereomer tc- 10a is presented in Figure 4, and it is obvious that the bulkiest enamine moiety of the molecule occupies an equatorial position, while the CF₃ and NO₂ groups are arranged in a trans-diaxial configuration (trans,cis-isomer). The pyran ring, similarly as in chromane tt- 5, exists in a twisted half-chair conformation. A similar conformation of heterocycles was identified also in chromane cc- 10b, and in that case both of the bulky substituents (CF₃ and enamine group) occupied equatorial positions (cis,cis-isomer) (Fig. 5). The phenyl substituent in enamine group deviated by 80.7(3)° from the plane of double bond in isomer tc- 10a and by −67.7(3)° in the isomer cc- 10b, while the nitrogen atom of morpholine ring in both molecules only slightly deviated from this plane, as indicated by the 3(1)° value of the torsion angle N(2)–C(18)–C(17)–H(17) in chromane 10a and −7(2)° value of the torsion angle N(1)–C(18)–C(17)–H(18) in chromane 10b. The planes of chromane system benzene ring and the enamine moiety in compounds 10a,b were rotated one relative to the other by −74.3(3) and 78.5(3)°, respectively.

Figure 4

The molecular structure of compound tc- 10a with atoms represented by thermal vibration ellipsoids of 30% probability.

Figure 5

The molecular structure of compound cc- 10b with atoms represented by thermal vibration ellipsoids of 30% probability.

The diastereomers tc- 10a and cc- 10b were characterized by similar chemical shift values of the 3-CH proton (5.40 and 5.32 ppm, respectively) and the spin-spin coupling constant J _3,4 (5.6 and 5.4 Hz, respectively), while the signal of the 4-CH proton in the spectrum of chromane tc- 10a was observed at lower field (4.07 ppm), compared to the spectrum of chromane cc- 10b (3.39 ppm). This fact can be explained by the preferred existence of compound tc- 10a as conformer with axial CF₃ group both in solid state (Fig. 4) and in solution phase, while the same group preferred an equatorial position in isomer cc- 10b both in crystal structure (Fig. 5) and in solution. For this reason, the pseudoaxial 4-CH proton in the isomer cc-10b was located in the region shielded by axial phenyl substituent, resulting in an upfield shift of its ¹H NMR signal. ¹⁹F NMR signals of CF₃ group in the stereoisomeric products tc- 10a and cc- 10b were observed as singlets at 87.2 and 84.2 ppm, respectively (Scheme 6, Table 2).

Scheme 6

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Table 2 The characteristic signals in ¹H and ¹⁹F NMR spectra of compounds 5, 7, 10a,b, 11a–c, 12a–c

In contract to the diastereoselective reactions of enamines described above, the interaction of nitrochromene 3a with nitromethane in the presence of K₂CO₃ at room temperature without solvent after 2 days led to the formation of a mixture of three out of the four possible stereoisomers of 3-nitro-4-(nitromethyl)-2-phenyl-2-(trifluoromethyl)chromane (11) in the ratio of ct- 11a : cc- 11b : tc- 11c = 44:38:18, and 77% yield. Analogous diastereomers of 2,2,3,4-tetrasubstituted chromanes were obtained in a total yield of 37% by reacting chromene 3a with aniline at 100°C for 2 h, albeit at a different isomer ratio of ct- 12a : cc- 12b : tc- 12c = 9:36:55 (Scheme 7).

Scheme 7

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The relative molecular configurations of products 11a–c and 12a–c were successfully established by NMR spectroscopy, based on the results obtained for the individual stereoisomers ct- 7, tc- 10a, and cc- 10b. For example, ¹H NMR spectra of ct-isomers 11a and 12a contained the signal of 3-CH proton as only slightly broadened singlet (5.94 ppm, J _3,4 ≈ 0). The pairs of compounds tc-11c, tc- 12c and cc-11b, cc- 12b showed close values of spin-spin coupling constants (J _3,4 = 4.9–5.6 Hz), but different ¹⁹F NMR chemical shifts of CF₃ group (87.8–88.0 ppm in tc-isomers and 84.2–84.6 ppm in cc-isomers) (Table 2).

It should be noted that the chemical shifts of 3,4-CH protons and CF₃ group along with the vicinal spin-spin coupling constant J _3,4 had a diagnostic value and could be useful for establishing the relative configurations of stereoisomeric chromanes via NMR spectroscopy. The 4-CH proton in cc-isomers of chromanes 11 and 12 was shielded by the phenyl substituent and its signal was shifted upfield relative to the analogous signal of tc-isomer (Δδ = 0.73–0.77 ppm). As expected, the largest spin-spin coupling constant J _3,4 = 11.7 Hz was observed for chromane tt- 5 with trans-diaxially oriented 3-CH and 4-CH protons. The moderate values of J _3,4 = 4.9–5.6 Hz were characteristic for the tc- and cc-isomers with axiallyequatorial hydrogen atoms, while J _3,4 ≈ 0 Hz in ct-isomers, where the 3-CH and 4-CH protons were oriented transdiequatorially. The axial CF₃ group in tc-isomer was deshieded by the phenyl ring, resulting in a downfield shift of its ¹⁹F NMR signal by 2.8–3.8 ppm, compared to the other isomers. This feature enabled rapid detection of tc-isomer in the reaction mixture by ¹⁹F NMR spectroscopy. The situation changed to the opposite in cc-isomers, where the equatorial CF₃ group was shielded by the phenyl substituent. In that case, its signal was slightly (by 0.4 ppm) shifted upfield relative to the signal of ct-isomer (Table 2).

Thus, 3-nitro-2-phenyl-2-(trifluoromethyl)-2H-chromenes served as readily available and highly reactive substrates in a series of reactions with C- and N-nucleophiles, which allowed us to demonstrate the utility of such substrates for diastereoselective synthesis of new 2,2,3,4-tetrasubstituted chromanes.

Experimental

IR spectra were recorded on a Bruker Alpha spectrometer with ATR accessory (ZnSe crystal). ¹H and ¹⁹F NMR spectra were acquired on a Bruker DRX-400 spectrometer (400 and 376 MHz, respectively) in CDCl₃, using TMS and C₆F₆ as internal standards. ¹³C NMR spectra were acquired on a Bruker Avance 500 spectrometer (126 MHz) in CDCl₃ with TMS as internal standard. Elemental analysis was performed on a PE 2400 automatic analyzer. Melting points were determined on an SMP40 apparatus.

The starting (E)-3,3,3-trifluoro-1-nitro-2-phenylprop-1-ene was synthesized according to a published procedure.6

Synthesis of nitrochromenes 3a–g (General method). Anhydrous Et₃N (0.014 ml, 0.1 mmol) was added to a solution of the appropriate salicylic aldehyde (1.0 mmol) and (E)-3,3,3-trifluoro-1-nitro-2-phenylprop-1-ene (0.24 g, 1.1 mmol) in anhydrous CH₂Cl₂ (3 ml), and the mixture was maintained at room temperature for 3 h. In the case of 5-chloro- and 5-bromosalicylic aldehydes, the mixture after addition of Et₃N was at first refluxed for 3 min, then left for 3 h at room temperature. After the reaction was complete, the solvent was removed at reduced pressure, the residue was recrystallized from MeOH (compound 3d) or from ethanol (the rest of the compounds), and the target compounds were isolated as yellow powders.

3-Nitro-2-phenyl-2-(trifluoromethyl)-2 H -chromene (3a). Yield 0.31 g (96%), mp 141–142°C. IR spectrum, ν, cm⁻¹: 1640, 1608, 1570, 1519, 1483, 1455, 1330, 1314. ¹H NMR spectrum, δ, ppm (J, Hz): 6.99 (1H, br. d, J = 8.2, H-8); 7.09 (1H, td, J = 7.5, J = 1.0, H-6); 7.37 (1H, dd, J = 7.6, J = 1.6, H-5); 7.40–7.43 (3H, m, H-3,4,5 Ph); 7.44 (1H, ddd, J = 8.2, J = 7.4, J = 1.6, H-7); 7.60–7.67 (2H, m, H-2,6 Ph); 8.24 (1H, s, 4-CH). ¹³C NMR spectrum, δ, ppm (J, Hz): 82.4 (q, J = 30.9, C-2); 116.2; 116.3; 123.4; 123.7 (q, J = 290.6, CF₃); 127.2 (q, J = 1.4); 128.5; 129.6; 130.5; 133.7; 135.2; 135.3; 138.8; 152.6. ¹⁹F NMR spectrum, δ, ppm: 88.8 (s, CF₃). Found, %: C 59.80; H 3.12; N 4.30. C₁₆H₁₀F₃NO₃. Calculated, %: C 59.82; H 3.14; N 4.36.

6-Chloro-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H chromene (3b). Yield 0.23 g (64%), mp 77–78°C. IR spectrum, ν, cm⁻¹: 1634, 1566, 1525, 1474, 1451, 1420, 1332. ¹H NMR spectrum, δ, ppm (J, Hz): 6.95 (1H, d, J = 8.3, H-8); 7.35 (1H, d, J = 2.3, H-5); 7.38 (1H, dd, J = 8.3, J = 2.3, H-7); 7.40–7.46 (3H, m, H Ph); 7.57–7.64 (2H, m, H Ph); 8.14 (1H, s, 4-CH). ¹⁹F NMR spectrum, δ, ppm: 89.0 (s, CF₃). Found, %: C 54.08; H 2.37; N 3.96. C₁₆H₉ClF₃NO₃. Calculated, %: C 54.03; H 2.55; N 3.94.

6-Bromo-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H chromene (3c). Yield 0.28 g (69%), mp 74–75°C. IR spectrum, ν, cm⁻¹: 1632, 1560, 1525, 1472, 1415, 1331. ¹H NMR spectrum, δ, ppm (J, Hz): 6.90 (1H, d, J = 8.6, H-8); 7.38–7.46 (3H, m, H Ph); 7.49 (1H, d, J = 2.4, H-5); 7.52 (1H, dd, J = 8.6, J = 2.4, H-7); 7.56–7.65 (2H, m, H Ph); 8.14 (1H, s, 4-CH). ¹³C NMR spectrum, δ, ppm (J, Hz): 82.6 (q, J = 30.8, C-2); 115.4; 118.0; 118.2; 123.5 (q, J = 290.2, CF₃); 127.2 (q, J = 1.5); 128.6; 129.9; 132.1; 132.4; 134.6; 137.6; 139.8; 151.5. ¹⁹F NMR spectrum, δ, ppm: 89.0 (s, CF₃). Found, %: C 48.09; H 2.14; N 3.48. C₁₆H₉BrF₃NO₃. Calculated, %: C 48.03; H 2.27; N 3.50.

6,8-Dibromo-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H -chromene (3d). Yield 0.46 g (95%), mp 151–152°C. IR spectrum, ν, cm⁻¹: 1635, 1550, 1527, 1407, 1289. ¹H NMR spectrum, δ, ppm (J, Hz): 7.26 (1H, d, J = 2.1, H-5(7)); 7.36–7.48 (3H, m, H Ph); 7.57–7.66 (2H, m, H Ph); 7.76 (1H, d, J = 2.1, H-7(5)); 8.07 (1H, s, 4-CH). ¹³C NMR spectrum, δ, ppm (J, Hz): 83.7 (q, J = 31.3, C-2); 111.6; 115.6; 119.4; 123.2 (q, J = 289.4, CF₃); 127.3 (br. s); 128.6; 130.2; 131.3; 131.4; 133.6; 139.9; 141.1; 148.4. ¹⁹F NMR spectrum, δ, ppm: 89.5 (s, CF₃). Found, %: C 40.20; H 1.64; N 2.89. C₁₆H₈Br₂F₃NO₃. Calculated, %: C 40.12; H 1.68; N 2.92.

6-Methyl-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H chromene (3e). Yield 0.27 g (80%), mp 96–97°C. IR spectrum, ν, cm⁻¹: 1634, 1575, 1522, 1487, 1422, 1332. ¹H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s, CH₃); 6.88 (1H, d, J = 8.3, H-8); 7.14 (1H, br. d, J = 1.6, H-5); 7.23 (1H, dd, J = 8.3, J = 1.6, H-7); 7.34–7.46 (3H, m, H Ph); 7.55–7.69 (2H, m, H Ph); 8.19 (1H, s, 4-CH). ¹⁹F NMR spectrum, δ, ppm: 88.9 (s, CF₃). Found, %: C 61.23; H 3.55; N 4.18. C₁₇H₁₂F₃NO₃. Calculated, %: C 60.90; H 3.61; N 4.18.

6-Methoxy-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H chromene (3f). Yield 0.33 g (95%), mp 101–102°C. IR spectrum, ν, cm⁻¹: 1641, 1576, 1525, 1487, 1454, 1429, 1332, 1308. ¹H NMR spectrum, δ, ppm (J, Hz): 3.81 (3H, s, OCH₃); 6.84 (1H, d, J = 2.9, H-5); 6.93 (1H, d, J = 8.9, H-8); 6.99 (1H, dd, J = 8.9, J = 2.9, H-5); 7.37–7.45 (3H, m, H-3,4,5 Ph); 7.58–7.66 (2H, m, H-2,6 Ph); 8.18 (1H, s, 4-CH). ¹³C NMR spectrum, δ, ppm (J, Hz): 55.8; 82.4 (q, J = 30.9, C-2); 113.7; 116.8; 117.1; 121.4; 123.7 (q, J = 290.6, CF₃); 127.2 (br. s); 128.4; 129.6; 133.7; 135.1; 139.6; 146.6; 155.3. ¹⁹F NMR spectrum, δ, ppm: 89.1 (s, CF₃). Found, %: C 57.91; H 3.59; N 3.93. C₁₇H₁₂F₃NO₄. Calculated, %: C 58.13; H 3.44; N 3.99.

8-Ethoxy-3-nitro-2-phenyl-2-(trifluoromethyl)-2 H chromene (3g). Yield 0.33 g (89%), mp 90–91°C. IR spectrum, ν, cm⁻¹: 1631, 1606, 1574, 1528, 1473, 1396, 1342, 1323. ¹H NMR spectrum, δ, ppm (J, Hz): 1.38 (3H, t, J = 7.0, OCH₂CH ₃); 4.07 (1H, dq, J = 9.8, J = 7.0) and 4.11 (1H, dq, J = 9.8, J = 7.0, OCH ₂CH₃); 6.94 (1H, dd, J = 7.5, J = 1.6, H-7); 6.99 (1H, t, J = 7.8, H-6); 7.05 (1H, dd, J = 8.0, J = 1.6, H-7); 7.36–7.44 (3H, m, H-3,4,5 Ph); 7.61–7.69 (2H, m, H-2,6 Ph); 8.17 (1H, s, 4-CH). ¹³C NMR spectrum, δ, ppm (J, Hz): 14.7; 65.5; 82.7 (q, J = 31.0, C-2); 117.7; 120.4; 122.2; 123.4; 123.6 (q, J = 289.7, CF₃); 127.4 (q, J = 1.0); 128.4; 129.6; 133.7; 134.8; 139.7; 142.3; 147.3. ¹⁹F NMR spectrum, δ, ppm: 89.2 (s, CF₃). Found, %: C 59.34; H 3.86; N 3.87. C₁₈H₁₄F₃NO₄. Calculated, %: C 59.18; H 3.86; N 3.83.

Ethyl ( Z )-3-amino-2-[(2 S *,3 S *,4 S *)-3-nitro-2-phenyl-2-(trifluoromethyl)chroman-4-yl]but-2-enoate ( tt- 5). A mixture of chromene 3a (0.32 g, 1.0 mmol) and ethyl (Z)-3-aminocrotonate (4) (0.13 g, 1.0 mmol) in anhydrous MeCN (1 ml) was heated until dissolution at 50°C (3 min) and then maintained at room temperature for 3 days. The obtained solid product was filtered off and recrystallized from a system of CH₂Cl₂–hexane, 1:2. Yield 0.33 g (74%), white powder, mp 165–166°C. IR spectrum, ν, cm⁻¹: 3490, 3319, 1659, 1613, 1585, 1556, 1512, 1485, 1454, 1369. ¹H NMR spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 7.1, OCH₂CH ₃); 1.91 (3H, s, CH₃); 3.85 (1H, dq, J = 10.7,

J = 7.1) and 3.96 (1H, dq, J = 10.7, J = 7.1, OCH ₂CH₃); 4.12 (1H, d, J = 11.7, 4-CH); 4.78 (1H, br. s, NH); 6.18 (1H, d, J = 11.7, 3-CH); 6.91–6.98 (2H, m, H-6,8); 7.11 (1H, d, J = 8.1, H-5); 7.21–7.23 (1H, m, H-7); 7.34 (2H, t, J = 7.6, H-3,5 Ph); 7.40 (1H, tt, J = 7.3, J = 1.2, H-4 Ph); 7.50 (2H, d, J = 7.9, H-2,6 Ph); 8.94 (1H, br. s, NH). ¹³C NMR spectrum, δ, ppm (J, Hz): 13.7; 21.3; 37.6; 59.0; 81.4 (q, J = 29.7, C-2); 85.5; 87.7; 116.2; 122.6; 123.5 (q, J = 286.1, CF₃); 124.2; 127.0; 127.7 (q, J = 1.6); 128.3; 129.8; 130.9; 151.0; 162.1; 168.7 (one carbon atom was not observed). ¹⁹F NMR spectrum, δ, ppm: 85.6 (s, CF₃). Found, %: C 58.66; H 4.60; N 6.21. C₂₂H₂₁F₃N₂O₅. Calculated, %: C 58.67; H 4.70; N 6.22.

( E )-4-Morpholino-5-[(2 S *,3 R *,4 S *)-3-nitro-2-phenyl-2-(trifluoromethyl)chroman-4-yl]pent-3-en-2-one ( ct- 7). A mixture of chromene 3a (0.32 g, 1.0 mmol) and (E)-4-morpholinopent-3-en-2-one (6) (0.17 g, 1.0 mmol) in anhydrous MeCN (0.5 ml) was maintained for 5 h at 60°C. The mixture was then cooled to room temperature, the

solvent was removed at reduced pressure, the residue was treated with anhydrous Et₂O (5 ml). The precipitate formed was filtered off and washed with hexane (3×0.5 ml). Yield 0.24 g (49%), white powder, mp 202–203°C (decomp.). IR spectrum, ν, cm⁻¹: 1658, 1636, 1563, 1535, 1490, 1446, 1367, 1321. ¹H NMR spectrum, δ, ppm (J, Hz): 2.10 (3H, s, CH₃); 2.62 (4H, br. s, CH₂NCH₂); 3.19 (1H, dd, J = 13.1, J = 3.0) and 3.71 (1H, dd, J = 13.1, J = 2.5, CH ₂CH); 3.23–3.40 (5H, m, 4-CH, CH₂OCH₂); 5.26 (1H, br. s, 3-CH); 6.00 (1H, s, =CH–COMe); 6.89 (1H, d, J = 7.7, H-8); 6.94 (1H, t, J = 7.7, H-6); 7.25 (1H, d, J = 7.9, H-5); 7.32 (1H, t, J = 7.6, H-7); 7.37–7.45 (3H, m, H-3,4,5 Ph); 7.61 (2H, d, J = 7.6, H-2,6 Ph). ¹³C NMR spectrum, δ, ppm (J, Hz): 31.8; 35.0; 38.2; 46.5; 65.6; 79.6 (q, J = 30.7, C-2); 84.2; 96.5; 117.2; 119.9; 122.1; 122.7 (q, J = 286.0, CF₃); 127.4; 129.1; 129.2; 129.6; 130.2; 132.7; 150.3; 161.8; 194.7. ¹⁹F NMR spectrum, δ, ppm: 85.1 (s, CF₃). Found, %: C 61.06; H 5.27; N 5.63. C₂₅H₂₅F₃N₂O₅. Calculated, %: C 61.22; H 5.14; N 5.71.

4-{( E )-2-(2 S *,3 S *,4 S *)-[3-Nitro-2-phenyl-2-(trifluoromethyl) chroman-4-yl]-1-phenylvinyl}morpholine ( tc- 10a). A mixture of chromene 3a (0.32 g, 1.0 mmol) and α-morpholinostyrene (9) (0.19 g, 1.0 mmol) was dissolved in anhydrous MeCN (0.5 ml) and maintained at room temperature for 1 day. The obtained solid product was filtered off and washed with hexane, providing chromane tc- 10a as a 3:1 mixture with isomer cc- 10b. Yield of the isomer mixture was 0.47 g (96%), beige powder, mp 202–203°C (decomp.). Recrystallization from a system of CH₂Cl₂–hexane, 2:1, gave the individual isomer tc- 10a. Yield 0.33 g (67%), light-yellow powder, mp 204–205°C. IR spectrum, ν, cm⁻¹: 1616, 1584, 1485, 1453, 1382, 1360. ¹H NMR spectrum, δ, ppm (J, Hz): 2.77–2.90 (4H, m, CH₂NCH₂); 3.66–3.75 (4H, m, CH₂OCH₂); 4.07 (1H, dd, J = 9.4, J = 5.6, 4-CH); 4.20 (1H, d, J = 9.4, =CH–CPh); 5.40 (1H, d, J = 5.6, 3-CH); 7.06 (1H, td, J = 7.5, J = 1.1, H-6); 7.14 (1H, dd, J = 8.2, J = 1.1, H-8); 7.28 (1H, dddd, J = 8.2, J = 7.8, J = 1.5, J = 1.0, H-7); 7.31–8.01 (11H, m, H-5, H Ph). ¹³C NMR spectrum, δ, ppm (J, Hz): 35.6 (q, J = 1.7); 49.0; 66.7; 78.7 (q, J = 28.8, C-2); 85.8; 96.9; 116.0; 120.5; 122.2; 123.4 (q, J = 290.1, CF₃); 127.7; 128.5; 128.7; 128.8; 128.9; 129.7; 132.4; 136.1; 152.0; 156.2 (two carbon atoms were not observed). ¹⁹F NMR spectrum, δ, ppm: 87.2 (s, CF3). Found, %: C 65.97; H 4.89; N 5.45. C₂₈H₂₅F₃N₂O₄. Calculated, %: C 65.88; H 4.94; N 5.49.

4-{( E )-2-(2 S *,3 R *,4 R *)-[3-Nitro-2-phenyl-2-(trifluoromethyl) chroman-4-yl]-1-phenylvinyl}morpholine ( cc- 10b). A mixture of chromene 3a (0.32 g, 1.0 mmol) and α-morpholinostyrene (9) (0.19 g, 1.0 mmol) in anhydrous MeCN (1.0 ml) was maintained for 4 h at 60°C. The obtained solid product was filtered off and recrystallized from a system of CH₂Cl₂–hexane, 1:3. Yield 0.36 g (71%), white powder, mp 265–266°C (decomp.). IR spectrum, ν, cm⁻¹: 1616, 1587, 1486, 1455, 1361. ¹H NMR spectrum, δ, ppm (J, Hz): 2.69–2.87 (4H, m, CH₂NCH₂); 3.39 (1H, dd, J = 8.9, J = 5.4, 4-CH); 3.63–3.73 (4H, m, CH₂OCH₂); 4.27 (1H, d, J = 8.9, =CH–CPh); 5.32 (1H, d, J = 5.4, 3-CH); 7.00 (1H, td, J = 7.7, J = 1.0, H-6); 7.01–7.44 (13H, m, H-5,7,8, H Ph). ¹³C NMR spectrum, δ, ppm (J, Hz): 35.5; 48.8; 66.7; 80.0 (q, J = 30.8, C-2); 83.5; 96.8; 116.6; 122.1; 122.4 (q, J = 285.3, CF3); 122.6; 128.0; 128.5; 128.6; 128.8; 128.9; 129.0; 129.4; 132.5; 136.3; 151.0; 156.3 (one carbon atom was not observed). ¹⁹F NMR spectrum, δ, ppm: 84.2 (s, CF₃). Found, %: C 65.72; H 4.80; N 5.56. C₂₈H₂₅F₃N₂O₄. Calculated, %: C 65.88; H 4.94; N 5.49.

3-Nitro-4-nitromethyl-2-phenyl-2-(trifluoromethyl)chromane (11). A solution of chromene 3a (0.32 g, 1.0 mmol) in CH₃NO₂ (1 ml) in the presence of K₂CO₃ (15 mg, 0.1 mmol) was stirred for 2 days at room temperature, then treated with 10% HCl (5 ml), extracted with CH₂Cl₂ (2×1 ml), and the organic phase was dried over Na₂SO₄. The solvent was removed and the residue was recrystallized from a system of CH₂Cl₂–hexane, 1:3, giving a mixture of isomers ct-11a, cc-11b, and tc-11c in 44:38:18 ratio. Yield 0.29 g (77%), white powder, mp 125–126°C. IR spectrum, ν, cm⁻¹: 1557, 1493, 1453, 1373. Isomer ct -11a. ¹H NMR spectrum, δ, ppm (J, Hz): 3.16 (1H, dd, J = 14.7, J = 10.8) and 4.08 (1H, dd, J = 14.7, J = 4.8, CH₂); 4.12 (1H, dd, J = 10.8, J = 4.8, 4-CH); 5.94 (1H, s, 3-CH); 7.05 (1H, br. d, J = 8.1, H-8); 7.11 (1H, td, J = 7.9, J = 1.1, H-6); 7.33 (1H, dd, J = 8.3, J = 0.7, H-5); 7.38 (1H, br. t, J = 7.9, H-7); 7.41–7.52 (5H, m, H Ph). ¹⁹F NMR spectrum, δ, ppm: 85.0 (s, CF₃). Isomer cc -11b. ¹H NMR spectrum, δ, ppm (J, Hz): 3.85 (1H, dt, J = 9.7, J = 4.7, 4-CH); 4.42 (1H, dd, J = 15.4, J = 9.7) and 4.99 (1H, dd, J = 15.4, J = 4.5, CH₂); 6.06 (1H, d, J = 4.9, 3-CH); 6.92 (1H, br. d, J = 8.0, H-8); 7.04 (1H, td, J = 7.9, J = 1.1, H-6); 7.30 (1H, dd, J = 8.2, J = 1.0, H-5); 7.41–7.52 (5H, m, H Ph); the signal of H-7 proton overlapped with the corresponding signal of the major isomer. ¹⁹F NMR spectrum, δ, ppm: 84.6 (s, CF₃). Isomer tc -11c. ¹H NMR spectrum, δ, ppm (J, Hz): 4.48 (1H, dd, J = 15.4, J = 9.0) and 5.14 (1H, dd, J = 15.4, J = 5.0, CH₂); 4.58 (1H, dt, J = 9.0, J = 5.1, 4-CH); 6.04 (1H, d, J = 5.1, 3-CH); 7.07 (1H, br. d, J = 7.9, H-8); 7.10 (1H, br. t, J = 7.9, H-6); 7.29 (1H, dd, J = 8.2, J = 1.0, H-5); 7.41–7.52 (5H, m, H Ph); the signal of H-7 proton overlapped with the corresponding signal of the major isomer. ¹⁹F NMR spectrum, δ, ppm: 88.0 (s, CF₃). Found, %: C 53.39; H 3.52; N 7.30. C₁₇H₁₃F₃N₂O₅. Calculated, %: C 53.41; H 3.43; N 7.33.

(2 S *,3 R *,4 R *)-3-Nitro- N ,2-diphenyl-2-(trifluoromethyl) chroman-4-amine (12). A mixture of chromene 3a (0.32 g, 1.0 mmol) and aniline (0.47 g, 5.0 mmol) was maintained for 2 h at 100°C, then cooled to room temperature. The excess of aniline was removed at reduced pressure, the residue was washed with water (2×5 ml) and dried. Recrystallization from a system of CH₂Cl₂–hexane, 1:3, provided a mixture of isomers ct-12a, cc-12b, and tc-12c in 9:36:55 ratio. Yield 0.15 g (37%), white powder, mp 129–130°C. IR spectrum, ν, cm⁻¹: 3388, 1604, 1591, 1562, 1513, 1491, 1453, 1364, 1330. Isomer ct -12a. ¹H NMR spectrum, δ, ppm (J, Hz): 4.69 (1H, d, J = 10.4, 4-CH); 4.95 (1H, d, J = 10.4, NH); 5.94 (1H, s, 3-CH); 6.31 (2H, d, J = 8.0, H-2,6 Ph aniline); the aromatic proton signals overlapped with the corresponding signals of the major isomer. ¹⁹F NMR spectrum, δ, ppm: 84.6 (s, CF₃). Isomer cc -12b. ¹H NMR spectrum, δ, ppm (J, Hz): 3.82 (1H, d, J = 9.9, NH); 4.72 (1H, dd, J = 9.9, J = 5.2, 4-CH); 6.08 (1H, d, J = 5.2, 3-CH); 6.54 (2H, d, J = 8.0, H-2,6 Ph aniline); 6.85 (1H, t, J = 7.4, H-6); 7.04 (1H, t, J = 7.4, H-7); 7.20–7.27 (3H, m, H-5,8, H-4 Ph aniline); 7.36 (2H, d, J = 7.6, H-2,6 Ph); 7.45–7.60 (5H, m, H-3,4,5 Ph, H-3,5 Ph aniline). ¹⁹F NMR spectrum, δ, ppm: 84.2 (s, CF3). Isomer tc -12c. ¹H NMR spectrum, δ, ppm (J, Hz): 3.83 (1H, d, J = 9.9, NH); 5.49 (1H, dd, J = 9.9, J = 5.6, 4-CH); 6.12 (1H, d, J = 5.6, 3-CH); 6.78 (2H, d, J = 7.9, H-2,6 Ph aniline); 6.91 (1H, t, J = 7.4, H-6); 7.11 (1H, t, J = 7.4, H-7); 7.24–7.34 (3H, m, H-5,8, H-4 aniline); 7.38 (2H, d, J = 7.6, H-2,6 Ph); 7.39–7.90 (5H, m, H-3,4,5 Ph, H-3,5 Ph aniline). ¹⁹F NMR spectrum, δ, ppm: 87.8 (s, CF₃). Found, %: C 63.56; H 3.98; N 6.88. C₂₂H₁₇F₃N₂O₃. Calculated, %: C 63.77; H 4.14; N 6.76.

X-ray structural study of compounds 3a, 5, and 10a,b. Crystals suitable for X-ray structural analysis were obtained by slow evaporation of MeCN solutions of compounds 3a, 5, and 10a,b. The X-ray structural analysis was performed on an Xcalibur Eos diffractometer with CCD-detector according to the standard procedure (MoKα radiation, graphite monochromator, ω-scanning, 2θ_max 56.44°) at 22°C. The structures were solved by direct method using the SHELX97 software suite.8 The positions of non-hydrogen atoms were independently refined in anisotropic approximation, while hydrogen atoms were placed in geometrically calculated positions and included in the refinement according to "rider" model with dependent thermal parameters. The complete X-ray structural data set for compounds 3a, 5, and 10a,b was deposited at the Cambridge Crystallographic Data Center (deposits CCDC 1499968, CCDC 1499970, CCDC 1499971, and CCDC 1499969, respectively).