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Article

Different Behavior of 2-Substituted 3-Nitro-2H-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters

by
Ivan A. Kochnev
,
Alexey Y. Barkov
,
Nikita S. Simonov
,
Maria V. Ulitko
,
Nikolay S. Zimnitskiy
,
Vladislav Y. Korotaev
* and
Vyacheslav Y. Sosnovskikh
*
Institute of Natural Sciences and Mathematics, Ural Federal University, 51 Lenina Ave., 620000 Ekaterinburg, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(24), 8983; https://doi.org/10.3390/molecules27248983
Submission received: 28 November 2022 / Revised: 9 December 2022 / Accepted: 13 December 2022 / Published: 16 December 2022
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2H-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo’ isomers of the corresponding chromeno[3,4-c]pyrrolidines in a ratio of 2.0–2.3:1 in 85–93% total yields as a result of a Michael addition/Mannich reaction sequence. In a similar reaction involving 2-trifluoromethyl-3-nitro-2H-chromenes, only endo chromeno[3,4-c]pyrrolidines are formed in 85–94% yields. 3-Nitro-2-(trichloromethyl)-2H-chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti-isomers with the cis,trans-configuration of the chromane ring in 40–67% yields. Some 4-CF3-substituted chromano[3,4-c]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.

Graphical Abstract

1. Introduction

The chromeno[3,4-c]pyrrolidine scaffold is the main structural element of a number of bioactive molecules with important pharmaceutical properties. For example, the trans-chromeno[3,4-c]pyrrolidine derivative S33138 is a dopamine D3 receptor antagonist and a potential drug for the treatment of CNS disorders such as schizophrenia and Parkinson’s disease [1], while its cis-derivative, fiduxosin, is an α1-adrenoceptor antagonist and a promising drug for the treatment of benign prostatic hyperplasia [2] (Figure 1). It was recently reported that spirooxindole derivatives of chromenopyrroli(zi)dines 1 and 2 show high antitumor activity against human cervical carcinoma and human rhabdomyosarcoma cancer cells along with low cytotoxicity against normal human dermal fibroblast [3,4,5]. Fused prolinates 3 have been successfully tested as antimycobacterial agents against the M. tuberculosis H37Rv strain [6]. Therefore, the development of regio- and stereoselective methods for the synthesis of novel Δ3-fused chromenopyrrolidine derivatives is an urgent task.
A convenient one-pot atom-economical method for the synthesis of functionalized pyrrolidines is based on the reaction of electron-deficient alkenes with stabilized azomethine ylides generated in situ from Schiff bases [7,8,9,10,11,12]. Due to the high regio- and stereoselectivity of reactions involving these ylides, this approach is an indispensable tool in the synthesis of complex heterocyclic molecules containing up to four new chiral centers with the required arrangement and spatial orientation of substituents from relatively simple and commercially available precursors. When amino acid esters are used as the amino component of the Schiff base, prolinates are formed as reaction products. These reactions are usually carried out in the presence of catalytic amounts of a Brønsted base and transition metal or lithium salt as a Lewis acid. Lewis acids increase the stereoselectivity of the process by stabilizing the W-conformation of the ylide [13,14].
Being readily available and highly reactive substrates, conjugate nitroalkenes are widely used as dipolarophiles for the stereoselective synthesis of nitroprolinates [15,16,17,18]. In the reactions of trans-nitrostyrene with iminoesters, four diastereomers can be formed, classified as endo, exo, endo’ and exo’ isomers (Scheme 1).
Depending on the type of catalyst, endo [19,20,21,22], exo [23,24] or exo’ [25] isomers can be obtained as a result of a diastereo- and enantioselective concerted 1,3-dipolar cycloaddition or of a Michael addition/Mannich reaction sequence. Heating without a Lewis acid and a base gave the mixtures of endo, exo, endo’ [26] or endo and exo [27] isomers.
Due to the presence of a β-nitrostyrene moiety, 3-nitro-2H-chromenes can also react with azomethine ylides to form chromenopyrroli(zi)dine derivatives [28,29,30]. There are only four reports on the reactions of nitrochromenes with stabilized azomethine ylides based on amino acid esters and arylaldehydes [6,31,32,33] (Scheme 2). It was reported that the reaction between 2-aryl-substituted nitrochromenes 4 and Schiff bases 5 in the presence of DBU and LiBr resulted in adducts exo-3 [6], while the same reaction in the presence of Et3N and AgOAc led to products 6 as individual endo isomers [31]. If the ylide from methyl sarcosinate and benzaldehyde was used as a reagent, only adducts endo’-7 were obtained [31]. In the works [32,33], the synthesis of products endo-6 (Ar2 = Ph, R1 = Et, R2 = CO2Et) from chromenes 4 and the corresponding iminoester 5 in the presence of a chiral base [32] or by a three-component reaction involving 3-nitro-2-phenyl-2H-chromene, diethyl 2-aminomalonate and benzaldehyde without a catalyst [33] has been described.
Our group’s science research is focused on the development of methods for Δ3-carbo- and heteroannulation of 2-trifluoromethyl-substituted 3-nitro-2H-chromenes using available ambiphilic reagents [3,4,5,34,35]. The introduction of the electron-withdrawing CF3-group in position 2 of 3-nitro-2H-chromene not only activates the double bond but also increases the stereoselectivity of their reactions with nucleophiles and ambiphiles. Furthermore, the replacement of the methyl group by the trifluoromethyl one in the bioactive molecule can lead to an increase in pharmacological properties due to enhanced lipophilicity and metabolic stability [36,37,38].
In this work, the behavior of 2-phenyl- and 2-trifluoro(trichloro)methyl-substituted 3-nitro-2H-chromenes 4 in the reaction with stabilized azomethine ylides generated from α-iminoesters 5 in the presence of Et3N and AgOAc have been compared and cytotoxic activity of some 4-phenyl- and 4-trifluoromethyl-substituted chromeno[3,4-c]pyrrolidine derivatives has been studied.

2. Results and Discussion

To obtain 4-phenyl-substituted chromeno[3,4-c]pyrrolidines 8, we used the Nyerges group’s method [31], but the amount of AgOAc was reduced from 150 to 10 mol%. The reaction between chromene 4a and imine ester 5b (Ar = 4-MeOC6H4) in the presence of Et3N and AgOAc in toluene at room temperature for 5 h led to the mixture of endo-8b and endo’-8b isomers in a ratio of 2.1:1 in 60% total yield (Scheme 3, Table 1, entry 1). It motivated us to optimize the conditions for this reaction. Replacing toluene with acetonitrile or tetrahydrofuran led to an increase in the yield of the target product to 91–92% (Table 1, entries 2–3). The best yield of adduct 8b (93%) was achieved when the reaction was carried out in dichloromethane (DCM) (Table 1, entry 4). The use of CuI as a catalyst proved to be less efficient (Table 1, entries 5–8). Regardless of the nature of the catalyst and solvent, the ratio of stereoisomers remained unchanged.
Under optimized conditions, chromeno[3,4-c]pyrrolidines 8a−g were obtained as mixtures of endo and endo’ isomers in a 2.0–2.3:1 ratio with 85–93% total yields (Scheme 4, Table 2). The donor-acceptor properties of substituents in chromene 4 and in the aryl fragment of the α-iminoester 5 had no significant effect on the yields of products 8 and the diastereoselectivity of the reaction. Individual isomers endo-8a−g and endo’-8a−g in 54–61% and 20–27% yields, respectively, were prepared after the purification of crude products by column chromatography.
Next, we examined 2-trifluoromethyl-substituted chromenes 4d−i in the reaction with iminoesters 5a−e. It was found that under the same conditions, adducts endo-9a−j are formed in 85–94% yields as the only reaction products (Scheme 5, Table 3). Other isomers were not detected in the reaction mixtures by 19F NMR spectroscopy. The product yields also did not depend on the nature of the substituents in the starting chromenes 4 and Schiff bases 5.
3-Nitro-2-(trichloromethyl)-2H-chromenes 4j−n under the same conditions react with iminoesters 5a,b,e to give the corresponding Michael adducts 10a−g in 40–67% yields as individual anti isomers with the cis,trans configuration of the chromane ring (Scheme 6, Table 4). The lowest yield (40%) was observed in the reaction involving nitrochromene 4n with the MeO group in position 6. The isomers syn-10 were not observed in the reaction mixtures.
To understand the reason for such different stereoselectivity of the reactions involving 2-Ph- and 2-CF3-substituted chromenes 4, additional experiments have been performed. If the reaction between chromene 4d and iminoesters 5b was carried out at −20 °C, the mixture of the products endo-9b, endo’-9b and exo-9b was obtained in a ratio of 65:27:8, respectively (Scheme 7). When this process was carried out at room temperature without AgOAc, the content of the isomer endo’-9b increased to 38% (endo-9b:endo’-9b:exo-9b = 51:38:11), and the total yield decreased to 42%. If the crude mixture of compounds endo-8b endo’-8b was heated in toluene for 12 h, the content of the endo’ isomer was reduced to 11%.
Thus, chromeno[3,4-c]pyrrolidines endo-8,9 and exo-9 are formed as a result of the Michael addition of W-shaped ylides to chromenes 4 followed by Mannich cyclization through intermediates A and C. (Scheme 8). A similar process involving S-shaped ylides leads to minor products endo’-8,9 through intermediate B. Apparently, S-ylides are formed in the presence of a slight excess of Et3N relative to AgOAc in the reaction mixture. If chromene 4 contains a trichloromethyl group at position 2, closing the pyrrolidine ring is impossible due to steric repulsions between the CCl3 and Ar substituents. In this case, the end products of the reaction are Michael adducts anti-10.
The addition of azomethine ylides to chromenes 4 occurs reversibly. The isomers endo’-8,9 and exo-9 are kinetic control products (KC) and convert into the thermodynamically more stable isomers endo-8,9 at higher temperatures (TC). In the case of more reactive 2-CF3-chromenes 4, the reverse reaction proceeds even at room temperature under the reaction conditions.
The structure and relative configuration of compounds 8–10 were confirmed by 1D and 2D NMR spectroscopy and X-ray single-crystal analysis. In the 1H NMR spectra of chromeno[3,4-c]pyrrolidines 8 and 9, signals of the H-1, H-3, H-4 and H-9b characteristic protons are observed (Figure 2). In the spectra of isomers, endo-8a−g and endo-9a−j acquired in CDCl3, the signal of the H-1 proton manifested as a doublet or a doublet of doublets at 4.00–4.15 ppm with the spin-spin coupling constant 3J1,9b = 3.0–3.9 Hz. A doublet of the H-9b proton in these isomers manifested in the range of 4.49–4.79 ppm. In the spectra of isomers endo’-8a−g and endo’-9b, both of these protons are observed as doublets in the range of 4.83–5.00 and 4.90–5.10 ppm, respectively, with the coupling constant 3J, = 9.3–9.8 Hz. In the spectra of endo isomers, the signal of the H-3 proton manifested at 4.73–4.97 ppm, while in the spectra of endo’ isomers, this proton is deshielded and is observed at 5.29–5.42 ppm. The signal of the H-4 proton manifested as a singlet in the range of 5.50–5.68 ppm in the spectra of adducts endo-8a−g and endo’-8a−g or as a quartet at 5.03–5.18 ppm with the coupling constant 3JH,F = 6.8–7.0 Hz in the spectra of adducts endo-9a−j and endo’-9b. In the 1H NMR spectrum of isomer exo-9b, signals of the H-1, H-3, H-4 and H-9b characteristic protons are observed at 4.40, 4.51, 4.38 and 4.67 ppm, respectively. The coupling constant 3J1,9b is 5.8 Hz. The 19F NMR spectra of isomers endo-9a−j, endo’-9b and exo-9b contain doublets of CF3-group at 96.6–97.0, 98.0 and 95.8 ppm with coupling constants 6.8–7.0, 7.0 and 7.2 Hz, respectively.
In the 2D 1H−1H NOESY spectrum of compound endo-8b, the cross-peaks H-1↔H-3, H-1↔H-4, H-3↔H-4 and H-9b↔Ho Ph are observed, which indicate the cis arrangement of the H-1, H-3 and H-4 hydrogen atoms relative to the fused tricyclic system (Figure 3). The 2D 1H−1H NOESY spectrum of compound endo’-8b has shown the cross-peak H-1↔H-2,6 4-MeOC6H4 along with the cross-peaks H-3↔H-4 and H-9b↔Ho Ph, which indicate the trans arrangement of the H-1 and H-3 atoms and the cis arrangement of the H-3 and H-4 atoms. The cross-peak H-9b↔H-3 is not observed in the spectra of both isomers.
The relative configuration of endo chromeno[3,4-c]pyrrolidines 8 and 9 was unambiguously confirmed by single crystal X-ray diffraction analysis of compounds endo-8b and endo-9a (Figure 4 and Figure 5). In both molecules, the H-1, H-3, and H-4 atoms are located on one side of the condensed tricyclic system, with the 4-Ph or 4-CF3-group occupying the axial position, while the nitro group is in the equatorial positions. The pyran and pyrrolidine rings have half-chair and twist conformations, respectively.
In the 1H NMR spectra of 2-CCl3-substituted chromanes 10a−g, the signals of the H-2’, H-3’ and H-4’ protons of the chromane ring in the range of 5.18–5.30, 6.25–6.29 and 4.08–4.14 ppm, respectively, with spin-spin coupling constants 3J2’,3’ ≈ 3J3’,4’ ≈ 1.0–1.8 Hz, and a singlet of the vinylic proton at 7.87–7.99 ppm are observed (see Supplementary Materials for NMR spectra).
The structure and relative configuration of chromane 10c was unambiguously confirmed by single crystal X-ray diffraction analysis (Figure 6). In this molecule, the nitro and CF3 groups are located on the same side of the pyran ring, with the latter occupying the equatorial position. The iminoester fragment and the nitro group are arranged trans-diaxially. The pyran ring has a distorted half-chair conformation.
For representative chromeno[3,4-c]pyrrolidines endo-8b,e−g and endo-9e,f−j, their in vitro cytotoxic activity against HeLa cervical cancer and human dermal fibroblast cells (HDF) was evaluated. The known cytotoxin camptothecin [39] was used for comparison (Table 5). Of all the tested 2-Ph-substituted chromeno[3,4-c]pyrrolidines 8, only endo-8e bearing a benzo[d][1,3]dioxol-5-yl substituent at position 3 showed noticeable cytotoxic activity against HeLa cells. Compound endo-9j with a p-methoxyphenyl substituent at position 3 and the EtO group at position 6 is cytotoxic to HeLa and HDF cells. Compound endo-9b with a p-methoxyphenyl group at position 3 exhibited a high antitumor activity along with low toxicity and is a promising drug candidate.
In summary, it has been found that the addition of azomethine ylides derived from α-iminoesters to 2-Ph- and 2-CF3-substituted 3-nitro-2H-chromenes proceeds as a reversible Michael addition/Mannich reaction sequence. The reaction of these ylides with 2-CCl3-chromenes stops at the Michael addition step. The stereochemistry of chromenoprolinates can be controlled by varying the temperature and solvent. One-pot stereoselective approaches to the synthesis of 4-(trifluoromethyl)-substituted chromeno[3,4-c]pyrrolidines and methyl 2-(arylideneamino)-2-(2-(trichloromethyl)chroman-4-yl)acetates from available reagents have been developed. Some 4-CF3-substituted chromeno[3,4-c]pyrrolidine derivatives have shown high antitumor activity and are of undoubted interest in medicinal chemistry.

3. Materials and Methods

3.1. General

IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer (Shimadzu Corp., Kyoto, Japan) using an attenuated total reflectance (ATR) unit (FTIR mode, diamond prism), and the absorbance maxima (ν) are reported in cm–1. NMR spectra were recorded on Bruker Avance III-500 (work frequencies: 1H—500 MHz, 19F—471 MHz, 13C—126 MHz) and Bruker DRX-400 (Bruker BioSpin GmbH, Ettlingen, Germany, work frequencies: 1H—400 MHz; 19F—376 MHz) spectrometers in CDCl3. The chemical shifts (δ) are reported in ppm relative to the internal standard TMS (1H NMR), C6F6 (19F NMR), and residual signal of the solvent (13C NMR). 2D NMR spectra were acquired on Bruker AVANCE NEO (600 MHz) and Bruker AVANCE 400 spectrometers. The HRMS spectra were obtained using the UHR-QqTOF maXis Impact HD mass spectrometer. Melting points were determined on an SMP40 apparatus. Column chromatography was performed on silica gel (Merck 60, 70–230 mesh, Darmstadt, Germany). All solvents used were dried and distilled by standard procedures. The starting chromenes 4a−c and 4d−n were prepared according to described procedures [40,41]. Schiff bases 5 were obtained according to the described procedure [42].

3.2. Synthesis of Compounds 8a–g

General procedure. A mixture of the appropriate 3-nitro-2-phenyl-2H-chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (7 μL, 5 mg, 0.05 mmol) and AgOAc (5.8 mg, 0.05 mmol) was stirred in dichloromethane (2 mL) for 5 h at room temperature (TLC control, EtOAc−hexane (1:2)). Upon completion of the reaction, the residue was evaporated under reduced pressure to complete dryness. The residue was purified by silica gel column chromatography (eluent−EtOAc−hexane (1:2)) to give products endo-8 and exo’-8.
Methyl(1S*,3S*,3aS*,4R*,9bR*)-3a-nitro-3,4-diphenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8a). Yield 120 mg (56%), white powder, mp 183–185 °C. IR (ATR) ν 3381 (NH), 1748 (C=O), 1547, 1340 (NO2). 1H NMR (500 MHz) δ 3.14 (dd, 1H, J = 10.8, 7.8 Hz, NH), 4.02 (s, 3H, MeO2C), 4.15 (dd, J = 7.8, 3.8 Hz, 1H, H-1), 4.79 (d, J = 3.8 Hz, 1H, H-9b), 4.97 (d, J = 10.8 Hz, 1H, H-3), 5.58 (s, 1H, H-4), 6.82 (d, J = 8.2 Hz, 1H, H-6), 7.07 (t, J = 7.6 Hz, 1H, H-8), 7.11–7.21 (m, 6H, H-7, H Ph), 7.35–7.45 (m, 2H, H Ph), 7.55 (d, J = 7.6 Hz, 1H, H-9); 13C NMR (126 MHz) δ 46.0, 53.0, 68.6, 70.5, 75.5, 96.7, 118.3, 123.3, 125.1, 126.9 (2C), 128.3 (2C), 128.5 (2C), 128.8, 128.88, 128.90, 129.0 (2C), 129.6, 133.9, 135.1, 149.9, 172.4. HRMS (ESI) m/z: [M + H]+ calcd for C25H23N2O5 431.1601, found 431.1595.
Methyl(1R*,3S*,3aS*,4R*,9bR*)-3a-nitro-3,4-diphenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8a). Yield 50 mg (23%), beige powder, mp 90–92 °C. IR (ATR) ν 3350 (NH), 1735 (C=O), 1542, 1355 (NO2). 1H NMR (500 MHz) δ 2.78 (br. s, 1H, NH), 3.36 (s, 3H, MeO2C), 5.00 (d, J = 9.8 Hz, 1H, H-1), 5.06 (d, J = 9.8 Hz, 1H, H-9b), 5.38 (s, 1H, H-3), 5.68 (s, 1H, H-4), 6.81 (d, J = 8.2, 1.2 Hz, 1H, H-6), 6.96 (td, J = 7.6, 1.2 Hz, 1H, H-8), 7.11 (ddd, J = 8.2, 7.8, 1.4 Hz, 1H, H-7), 7.22–7.34 (m, 11H, H-9, H Ph); 13C NMR (126 MHz) δ 45.2, 51.7, 64.3, 68.6, 77.5, 97.8, 118.1, 120.6, 121.9, 127.3 (2C), 128.2 (2C), 128.4 (2C), 128.7 (2C), 128.87, 128.92, 129.0, 129.7, 134.8, 136.7, 152.6, 173.3. HRMS (ESI) m/z: [M + H]+ calcd for C25H23N2O5 431.1601, found 431.1604.
Methyl(1S*,3S*,3aS*,4R*,9bR*)-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8b). Yield 145 mg (63%), white powder, mp 159–161 °C. IR (ATR) ν 3323 (NH), 1745 (C=O), 1536, 1361 (NO2). 1H NMR (600 MHz) δ 3.09 (br. s, 1H, NH), 3.83 (s, 3H, MeO), 4.02 (s, 3H, MeO2C), 4.13 (br. s, 1H, H-1), 4.77 (d, J = 3.7 Hz, 1H, H-9b), 4.93 (d, J = 4.9 Hz, 1H, H-3), 5.53 (s, 1H, H-4), 6.81 (d, J = 8.1 Hz, 1H, H-6), 6.95 (d, J = 8.6 Hz, 2H, H-3,5 4-MeOC6H4), 7.06 (td, J = 7.5, 0.9 Hz, 1H, H-8), 7.12–7.20 (m, 6H, H-7, H Ph), 7.30 (d, J = 8.6 Hz, 2H, H-2,6 4-MeOC6H4), 7.55 (d, J = 7.6 Hz, 1H, H-9); 13C NMR (151 MHz) δ 45.9 (C-9b), 53.2 (MeO2C), 55.3 (MeO), 68.4 (C-1), 70.1 (C-3), 75.5 (C-4), 96.4 (C-3a), 114.4 (C-3,5 4-MeOC6H4), 118.4 (C-6), 123.3 (C-8), 124.9 (C-9a), 125.3 (C-7), 128.1 (C-2,6 4-MeOC6H4), 128.3 (C-2,6 Ph), 128.5 (C-3,5 Ph), 128.7 (C-9), 128.9 (C-4 Ph, C-1 4-MeOC6H4), 135.0 (C-1 Ph), 149.8 (C-5a), 160.6 (C-4 4-MeOC6H4), 172.3 (C=O). HRMS (ESI) m/z: [M + H]+ calcd for C26H25N2O6 461.1707, found 461.1710.
Methyl(1R*,3S*,3aS*,4R*,9bR*)-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8b). Yield 48 mg (21%), beige powder, mp 132–133 °C. IR (ATR) ν 3356 (NH), 1732 (C=O), 1543, 1351 (NO2). 1H NMR (600 MHz) δ 2.74 (br. s, 1H, NH), 3.35 (s, 3H, MeO2C), 3.78 (s, 3H, MeO), 4.98 (d, J = 9.8 Hz, 1H, H-1), 5.04 (d, J = 9.8 Hz, 1H, H-9b), 5.35 (s, 1H, H-3), 5.64 (s, 1H, H-4), 6.80 (dd, J = 8.2, 1.0 Hz, 1H, H-6), 6.85 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 6.95 (td, J = 7.6, 1.0 Hz, 1H, H-8), 7.10 (ddd, J = 8.2, 7.6, 1.0 Hz, 1H, H-7), 7.21 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.23 (d, J = 8.0 Hz, 1H, H-9), 7.25–7.28 (m, 5H, H Ph); 13C NMR (151 MHz) δ 45.2, 51.9, 55.3, 64.4, 68.6, 77.5, 97.9, 114.2 (2C), 118.3, 120.9, 122.1, 128.3 (2C), 128.36, 128.40, 128.5 (2C), 128.6 (2C), 129.0, 129.8, 134.9, 152.6, 160.3, 173.4. HRMS (ESI) m/z: [M + H]+ calcd for C26H25N2O6 461.1707, found 461.1706.
Methyl(1S*,3S*,3aS*,4R*,9bR*)-3-(3,4-dimethoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8c). Yield 132 mg (54%), white powder, mp 191–193 °C. IR (ATR) ν 3327 (NH), 1732 (C=O), 1535, 1341 (NO2). 1H NMR (500 MHz) δ 3.12 (br. s, 1H, NH), 3.90 (s, 3H, MeO), 3.91 (s, 3H, MeO), 4.02 (s, 3H, MeO2C), 4.14 (d, J = 3.8 Hz, 1H, H-1), 4.77 (d, J = 3.8 Hz, 1H, H-9b), 4.92 (c, 1H, H-3), 5.55 (s, 1H, H-4), 6.81 (dd, J = 7.5, 1.0 Hz, 1H, H-6), 6.85 (d, J = 1.8 Hz, 1H, H-2 (MeO)2C6H3), 6.90 (d, J = 8.3 Hz, 1H, H-5 (MeO)2C6H3), 6.95 (dd, J = 8.3, 1.8 Hz, 1H, H-6 (MeO)2C6H3), 7.06 (td, J = 7.5, 1.0 Hz, 1H, H-8), 7.12–7.21 (m, 6H, H-7, H Ph), 7.54 (d, J = 7.5 Hz, 1H, H-9); 13C NMR (126 MHz) δ 45.9, 53.0, 55.9, 56.1, 68.4, 70.5, 75.7, 96.4, 109.8, 111.3, 118.3, 119.6, 123.2, 125.1, 126.3, 128.3 (2C), 128.5 (2C), 128.8, 128.9 (2C), 135.1, 149.3, 149.9, 150.1, 172.5. HRMS (ESI) m/z: [M + H]+ calcd for C27H27N2O6 491.1813, found 491.1814.
Methyl (1R*,3S*,3aS*,4R*,9bR*)-3-(3,4-dimethoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8c). Yield 66 mg (27%), beige powder, mp 113–115 °C. IR (ATR) ν 3338 (NH), 1732 (C=O), 1536, 1340 (NO2). 1H NMR (500 MHz) δ 2.73 (br. s, 1H, NH), 3.36 (s, 3H, MeO2C), 3.80 (s, 3H, MeO), 3.85 (s, 3H, MeO), 4.96 (d, J = 9.5 Hz, 1H, H-1), 5.07 (d, J = 9.5 Hz, 1H, H-9b), 5.40 (s, 1H, H-3), 5.59 (s, 1H, H-4), 6.71 (d, J = 1.8 Hz, 1H, H-2 (MeO)2C6H3), 6.78–6.83 (m, 2H, H-6, H-5 (MeO)2C6H3), 6.90 (dd, J = 8.0, 1.8 Hz, 1H, H-6 (MeO)2C6H3), 6.96 (t, J = 7.6 Hz, 1H, H-8), 7.10 (t, J = 7.8 Hz, 1H, H-7), 7.23–7.31 (m, 6H, H-9, H Ph); 13C NMR (126 MHz) δ 45.4, 51.7, 55.8, 56.0, 64.0, 68.4, 77.8, 97.9, 110.5, 111.0, 118.2, 119.7, 122.0, 127.9, 128.1 (2C), 128.3, 128.6 (2C), 128.9 (2C), 129.7, 134.9, 149.0, 149.6, 152.6, 173.5. HRMS (ESI) m/z: [M + H]+ calcd for C27H27N2O6 491.1813, found 491.1806.
Methyl (1S*,3S*,3aS*,4R*,9bR*)-3a-nitro-4-phenyl-3-(3,4,5-trimethoxyphenyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8d). Yield 143 mg (55%), white powder, mp 200–202 °C. IR (ATR) ν 3356 (NH), 1735 (C=O), 1537, 1332 (NO2). 1H NMR (500 MHz) δ 3.02 (br. s, 1H, NH), 3.87 (s, 3H, MeO), 3.89 (s, 6H, MeO), 4.02 (s, 3H, MeO2C), 4.13 (d, J = 3.8 Hz, 1H, H-1), 4.80 (d, J = 3.8 Hz, 1H, H-9b), 4.89 (c, 1H, H-3), 5.59 (s, 1H, H-4), 6.58 (s, 2H, H-2,6 3,4,5-(MeO)3C6H2), 6.82 (d, J = 8.1 Hz, 1H, H-6), 7.07 (t, J = 7.6 Hz, 1H, H-8), 7.13–7.24 (m, 6H, H-7, H Ph), 7.53 (d, J = 7.6 Hz, 1H, H-9); 13C NMR (126 MHz) δ 45.8, 52.9 (3C), 56.3, 68.1, 70.2, 75.7, 96.3, 104.1 (2C), 118.1, 123.1, 124.7, 128.1 (2C), 128.3 (2C), 128.6, 128.77, 128.80, 129.8, 134.9, 138.9, 149.9, 153.4 (2C), 172.4. HRMS (ESI) m/z: [M + H]+ calcd for C28H29N2O8 521.1918, found 521.1921.
Methyl (1R*,3S*,3aS*,4R*,9bR*)-3a-nitro-4-phenyl-3-(3,4,5-trimethoxyphenyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8d). This product was not isolated in pure form. 1H NMR (400 MHz) δ 3.02 (br. s, 1H, NH), 3.39 (s, 3H, MeO2C), 3.77 (s, 6H, MeO), 3.81 (s, 3H, MeO), 4.94 (d, J = 9.3 Hz, 1H, H-1), 5.10 (d, J = 9.3 Hz, 1H, H-9b), 5.42 (c, 1H, H-3), 5.54 (s, 1H, H-4), 6.46 (s, 2H, H-2,6 3,4,5-(MeO)3C6H2), 6.79 (d, J = 8.2 Hz, 1H, H-6), 6.98 (td, J = 7.6, 1.1 Hz, 1H, H-8), 7.10 (t, J = 8.1 Hz, 1H, H-7), 7.21–7.37 (m, 6H, H-9, H Ph).
Methyl (1S*,3S*,3aS*,4R*,9bR*)-3-(benzo[d][1,3]dioxol-5-yl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8e). Yield 133 mg (56%), white powder, mp 177–179 °C. IR (ATR) ν 3328 (NH), 1744 (C=O), 1536, 1346 (NO2). 1H NMR (500 MHz) δ 3.00 (dd, J = 10.2, 7.7 Hz, 1H, NH), 4.01 (s, 3H, MeO2C), 4.11 (dd, J = 7.7, 3.8 Hz, 1H, H-1), 4.77 (d, J = 3.8 Hz, 1H, H-9b), 4.89 (d, J = 10.2 Hz, 1H, H-3), 5.57 (s, 1H, H-4), 5.99 (d, J = 1.4 Hz, 1H, OCH2O), 6.00 (d, J = 1.4 Hz, 1H, OCH2O), 6.80 (dd, J = 8.1, 1.1 Hz, 1H, H-6), 6.85 (d, J = 8.0 Hz, 1H, H-7 benzo[d][1,3]dioxol-5-yl), 6.86 (d, J = 1.6 Hz, 1H, H-4 benzo[d][1,3]dioxol-5-yl), 6.88 (dd, J = 8.1, 1.6 Hz, 1H, H-6 benzo[d][1,3]dioxol-5-yl), 7.06 (td, J = 7.6, 1.1 Hz, 1H, H-8), 7.11–7.22 (m, 6H, H-7, H Ph), 7.53 (d, J = 7.6 Hz, 1H, H-9); 13C NMR (126 MHz) δ 45.8, 53.0, 68.3, 70.2, 75.5, 96.3, 101.4, 107.0, 108.6, 118.3, 120.8, 123.2, 125.1, 127.6, 128.3 (2C), 128.5 (2C), 128.8, 128.9 (2C), 135.1, 148.3, 148.7, 149.9, 172.4. HRMS (ESI) m/z: [M + H]+ calcd for C26H23N2O7 475.1500, found 475.1486.
Methyl (1R*,3S*,3aS*,4R*,9bR*)-3-(benzo[d][1,3]dioxol-5-yl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8e). Yield 47 mg (20%), beige powder, mp 111–113 °C. IR (ATR) ν 3362 (NH), 1731 (C=O), 1543, 1340 (NO2). 1H NMR (500 MHz) δ 2.69 (br. s, 1H, NH), 3.36 (s, 3H, MeO2C), 4.95 (d, J = 9.7 Hz, 1H, H-1), 5.04 (d, J = 9.7 Hz, 1H, H-9b), 5.32 (br. s, 1H, H-3), 5.64 (s, 1H, H-4), 5.94 (d, J = 1.3 Hz, 1H, OCH2O), 5.95 (d, J = 1.3 Hz, 1H, OCH2O), 6.73–6.82 (m, 4H, H-6, H-4,6,7 benzo[d][1,3]dioxol-5-yl), 6.96 (td, J = 7.5, 1.0 Hz, 1H, H-8), 7.10 (td, J = 7.6, 1.2 Hz, 1H, H-8), 7.22 (dd, J = 7.6, 1.2 Hz, 1H, H-9), 7.25–7.29 (m, 5H, H Ph); 13C NMR (126 MHz) δ 45.0, 51.7, 64.1, 68.4, 77.5, 97.6, 101.2, 107.5, 108.3, 118.2, 120.7, 121.2, 121.9, 128.2 (2C), 128.4 (2C), 128.87, 128.92, 129.7, 130.4, 134.7, 147.9, 148.2, 152.5, 173.4. HRMS (ESI) m/z: [M + H]+ calcd for C26H23N2O7 475.1500, found 475.1503.
Methyl(1S*,3S*,3aS*,4R*,9bR*)-8-bromo-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8f). Yield 164 mg (61%), white powder, mp 208–210 °C. IR (ATR) ν 3359 (NH), 1755 (C=O), 1547, 1362 (NO2). 1H NMR (500 MHz) δ 3.07 (dd, J = 10.6, 7.7 Hz, 1H, NH), 3.82 (s, 3H, MeO), 4.03 (s, 3H, MeO2C), 4.10 (dd, J = 7.7, 3.8 Hz, 1H, H-1), 4.74 (d, J = 3.8 Hz, 1H, H-9b), 4.88 (d, J = 10.6 Hz, 1H, H-3), 5.53 (s, 1H, H-4), 6.69 (d, J = 8.7 Hz, 1H, H-6), 6.94 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.11–7.15 (m, 2H, H Ph), 7.16–7.22 (m, 3H, H Ph), 7.24 (dd, J = 8.7, 2.5 Hz, 1H, H-7), 7.28 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.67 (d, J = 2.5 Hz, 1H, H-9); 13C NMR (126 MHz) δ 45.8, 53.2, 55.3, 68.3, 70.3, 75.7, 96.0, 114.4 (2C), 115.4, 120.2, 125.4, 127.3, 128.0 (2C), 128.2 (2C), 128.6 (2C), 129.0, 131.4, 131.9, 134.7, 149.1, 160.6, 172.1. HRMS (ESI) m/z: [M + H]+ calcd for C26H24BrN2O6 539.0812, found 539.0809.
Methyl(1R*,3S*,3aS*,4R*,9bR*)-8-bromo-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8f). Yield 57 mg (21%), beige powder, mp 188–190 °C. IR (ATR) ν 3382 (NH), 1715 (C=O), 1546, 1362 (NO2). 1H NMR (500 MHz) δ 2.72 (br. s, 1H, NH), 3.47 (s, 3H, MeO2C), 3.78 (s, 3H, MeO), 4.96 (d, J = 9.8 Hz, 1H, H-1), 4.99 (d, J = 9.8 Hz, 1H, H-9b), 5.29 (s, 1H, H-3), 5.63 (s, 1H, H-4), 6.70 (d, J = 8.7 Hz, 1H, H-6), 6.85 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.21 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.23–7.29 (m, 7H, H-7,9, Ph); 13C NMR (126 MHz) δ 44.7, 51.9, 55.2, 63.9, 68.3, 77.5, 97.2, 114.1 (2C), 120.0, 122.9, 124.3, 128.26 (2C), 128.32 (2C), 128.5 (2C), 129.0, 131.6, 131.8, 132.3, 134.4, 151.2, 160.0, 170.4. HRMS (ESI) m/z: [M + H]+ calcd for C26H24BrN2O6 539.0812, found 539.0810.
Methyl (1S*,3S*,3aS*,4R*,9bR*)-8-methoxy-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-8g). Yield 140 mg (57%), white powder, mp 173–175 °C. IR (ATR) ν 3364 (NH), 1752 (C=O), 1544, 1365 (NO2). 1H NMR (400 MHz) δ 3.09 (t, J = 8.7 Hz, 1H, NH), 3.79 (s, 3H, MeO), 3.82 (s, 3H, MeO), 4.02 (s, 3H, MeO2C), 4.12 (dd, J = 6.7, 3.9 Hz, 1H, H-1), 4.72 (d, J = 3.9 Hz, 1H, H-9b), 4.93 (d, J = 10.4 Hz, 1H, H-3), 5.50 (s, 1H, H-4), 6.69 (dd, J = 8.8, 2.5 Hz, 1H, H-7), 6.72 (d, J = 8.8 Hz, 1H, H-6), 6.94 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.07 (d, J = 2.5 Hz, 1H, H-9), 7.11–7.21 (m, 5H, H Ph), 7.29 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4); 13C NMR (126 MHz) δ 46.4, 53.0, 55.2, 55.6, 68.4, 70.3, 75.7, 96.7, 113.1, 114.4 (2C), 114.7, 119.1, 125.6, 126.0, 128.0 (2C), 128.3 (2C), 128.4 (2C), 128.8, 135.1, 143.6, 155.3, 160.6, 172.3. HRMS (ESI) m/z: [M + H]+ calcd for C27H27N2O7 491.1813, found 491.1812.
Methyl (1R*,3S*,3aS*,4R*,9bR*)-8-methoxy-3-(4-methoxyphenyl)-3a-nitro-4-phenyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-8g). Yield 54 mg (22%), beige powder, mp 95–97 °C. IR (ATR) ν 3344 (NH), 1733 (C=O), 1542, 1358 (NO2). 1H NMR (500 MHz) δ 2.73 (br. s, 1H, NH), 3.40 (s, 3H, MeO2C), 3.76 (s, 3H, MeO), 3.79 (s, 3H, MeO), 4.97 (d, J = 9.7 Hz, 1H, H-1), 5.01 (d, J = 9.7 Hz, 1H, H-9b), 5.36 (s, 1H, H-3), 5.59 (s, 1H, H-4), 6.66 (dd, J = 8.8, 2.8 Hz, 1H, H-7), 6.71 (d, J = 8.8 Hz, 1H, H-6), 6.75 (d, J = 2.8 Hz, 1H, H-9), 6.86 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.20–7.26 (m, 7H, H-2,6 4-MeOC6H4, H Ph); 13C NMR (126 MHz) δ 45.5, 51.7, 55.2, 55.7, 64.3, 68.6, 77.4, 98.0, 114.0, 114.1 (2C), 115.0, 118.9, 121.6, 128.2 (2C), 128.36 (2C), 128.44 (2C), 128.8, 130.1, 134.9, 146.2, 154.4, 160.2, 173.2. HRMS (ESI) m/z: [M + H]+ calcd for C27H27N2O7 491.1813, found 491.1811.

3.3. Synthesis of Compounds 9a–j

General procedure. A mixture of the appropriate 3-nitro-2-(trifluoromethyl)-2H-chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (7 μL, 5 mg, 0.05 mmol) and AgOAc (5.8 mg, 0.05 mmol) was stirred in dichloromethane (2 mL) for 5 h at room temperature (TLC control, EtOAc−hexane (1:3)). Upon completion of the reaction, the residue was evaporated under reduced pressure to complete dryness. The residue was purified by silica gel column chromatography (eluent−EtOAc−hexane (1:3)) to give products endo-9.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-3a-nitro-3-phenyl-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9a). Yield 190 mg (90%), beige powder, mp 125–127 °C. IR (ATR) ν 3320 (NH), 1743 (C=O), 1546, 1361 (NO2). 1H NMR (500 MHz) δ 3.13 (dd, J = 11.3, 7.5 Hz, 1H, NH), 4.02 (s, 3H, MeO2C), 4.09 (dd, J = 7.5, 3.1 Hz, 1H, H-1), 4.57 (d, J = 3.1 Hz, 1H, H-9b), 4.83 (d, J = 11.3 Hz, 1H, H-3), 5.11 (q, J = 7.0 Hz, 1H, H-4), 7.07 (dd, J = 8.2, 1.0 Hz, 1H, H-6), 7.18 (ddd, J = 8.2, 7.6, 1.0 Hz, 1H, H-8), 7.23–7.32 (m, 3H, H-7, H Ph), 7.43–7.47 (m, 3H, H Ph), 7.52 (d, J = 7.7 Hz, 1H, H-9); 19F NMR (471 MHz) δ 96.6 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.6, 53.1, 68.4, 70.2, 72.3 (q, 2JCF = 31.8 Hz, C-4), 93.6, 117.6, 123.3 (q, 1JCF = 288.9 Hz, CF3), 124.0, 124.4, 126.5 (2C), 129.09, 129.14, 129.2 (2C), 130.0, 132.6, 149.0, 171.9. HRMS (ESI) m/z: [M + H]+ calcd for C20H18F3N2O5 423.1162, found 423.1160.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-3-(4-methoxyphenyl)-3a-nitro-3-phenyl-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9b). Yield 208 mg (92%), white powder, mp 163–165 °C. IR (ATR): ν 3321 (NH), 1742 (C=O), 1547, 1362 (NO2). 1H NMR (500 MHz) δ 3.07 (dd, J = 11.2, 7.6 Hz, 1H, NH), 3.83 (s, 3H, MeO), 4.02 (s, 3H, MeO2C), 4.07 (dd, J = 7.6, 3.0 Hz, 1H, H-1), 4.54 (d, J = 3.0 Hz, 1H, H-9b), 4.79 (d, J = 11.2 Hz, 1H, H-3), 5.07 (q, J = 7.0 Hz, 1H, H-4), 6.95 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.06 (dd, J = 8.1, 1.0 Hz, 1H, H-6), 7.15 (td, J = 7.6, 1.0 Hz, 1H, H-8), 7.22 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.28 (td, J = 8.1, 1.0 Hz, 1H, H-7), 7.51 (dd, J = 7.6, 1.0 Hz, 1H, H-9); 19F NMR (471 MHz) δ 96.7 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.5, 53.1, 55.3, 68.4, 70.0, 72.4 (q, 2JCF = 31.4 Hz, C-4), 93.5, 114.6 (2C), 117.5, 123.4 (q, 1JCF = 288.7 Hz, CF3), 124.0, 124.4 (2C), 127.7 (2C), 129.1 (2C), 149.0, 160.9, 172.0. HRMS (ESI) m/z: [M + H]+ calcd for C21H20F3N2O6 453.1268, found 453.1272.
Methyl (1R*,3S*,3aS*,4S*,9bR*)-3-(4-methoxyphenyl)-3a-nitro-3-phenyl-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo’-9b). This product was obtained according to the general procedure at −20 °C for 5 h and was not isolated in pure form. 1H NMR (400 MHz) δ 2.67 (br. s, 1H), 3.36 (s, 3H, MeO2C), 3.83 (s, 3H, MeO), 4.83 (d, J = 9.0 Hz, 1H, H-1), 4.90 (d, J = 9.0 Hz, 1H, H-9b), 5.13 (q, J = 7.0 Hz, 1H, H-4), 5.30 (s, 1H, H-3), 6.94 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 6.98 (dd, J = 8.0, 1.0 Hz, 1H, H-6), 7.02–7.08 (m, 2H, H-7,8), 7.15 (dd, J = 7.6, 1.4 Hz, 1H, H-9), 7.27 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4); 19F NMR (376 MHz) δ 98.0 (d, J = 7.0 Hz, CF3).
Methyl (1R*,3R*,3aS*,4S*,9bR*)-3-(4-methoxyphenyl)-3a-nitro-3-phenyl-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (exo-9b). This product was obtained according to the general procedure without AgOAc and was not isolated in pure form. 1H NMR (400 MHz) δ 3.02 (dd, J = 10.8, 10.0 Hz, 1H, NH), 3.74 (s, 3H, CO2Me), 3.87 (s, 3H, MeO), 4.07 (dd, J = 10.0, 5.8 Hz, 1H, H-1), 4.38 (d, J = 5.8 Hz, 1H, H-9b), 4.51 (d, J = 10.8 Hz, 1H, H-3), 4.67 (q, J = 7.2 Hz, 1H, H-4) (other signals overlapped with signals of major isomers). 19F NMR (471 MHz) δ 95.8 (d, J = 7.2 Hz, CF3).
Methyl (1S*,3S*,3aS*,4S*,9bR*)-3-(3,4-dimethoxyphenyl)-3a-nitro-3-phenyl-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9c). Yield 222 mg (92%), white powder, mp 150–152 °C. IR (ATR) ν 3386 (NH), 1745 (C=O), 1547, 1363 (NO2). 1H NMR (400 MHz) δ 3.07 (dd, J = 10.8, 7.5 Hz, 1H, NH), 3.83 (s, 6H, 2MeO), 4.03 (s, 3H, MeO2C), 4.07 (dd, J = 7.5, 3.0 Hz, 1H, H-1), 4.55 (d, J = 3.0 Hz, 1H, H-9b), 4.78 (d, J = 10.8 Hz, 1H, H-3), 5.10 (q, J = 7.0 Hz, 1H, H-4), 6.76 (d, J = 1.8 Hz, 1H, H-2 3,4-(MeO)2C6H3), 6.87 (dd, J = 8.3, 1.8 Hz, 1H, H-6 3,4-(MeO)2C6H3), 6.91 (d, J = 8.3 Hz, H-5 3,4-(MeO)2C6H3), 7.06 (dd, J = 8.2, 1.0 Hz, 1H, H-6), 7.17 (td, J = 7.6, 1.0 Hz, 1H, H-8), 7.28 (td, J = 8.2, 1.0 Hz, 1H, H-7), 7.51 (dd, J = 7.6, 1.0 Hz, 1H, H-9); 19F NMR (376 MHz) δ 96.9 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.4, 53.1, 55.9, 56.1, 68.3, 70.3, 72.4 (q, 2JCF = 31.5 Hz, C-4), 93.4, 109.3, 111.5, 117.6, 119.3, 123.4 (q, 1JCF = 288.9 Hz, CF3), 124.0, 124.4, 124.9, 129.08, 129.11, 149.0, 149.6, 150.4, 172.0. HRMS (ESI) m/z: [M + H]+ calcd for C22H22F3N2O7 483.1374, found 483.1374.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-3a-nitro-4-(trifluoromethyl)-3-(3,4,5-trimethoxyphenyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9d). Yield 218 mg (85%), white powder, mp 115–117 °C. IR (ATR) ν 3326 (NH), 1747 (C=O), 1549, 1334 (NO2). 1H NMR (400 MHz) δ 3.01 (dd, J = 10.4, 7.2 Hz, 1H, NH), 3.88 (s, 3H, MeO), 3.89 (s, 6H, 2MeO), 4.03 (s, 3H, MeO2C), 4.07 (dd, J = 7.2, 3.1 Hz, 1H, H-1), 4.56 (d, J = 3.1 Hz, 1H, H-9b), 4.75 (d, J = 10.4 Hz, 1H, H-3), 5.13 (q, J = 7.0 Hz, 1H, H-4), 6.50 (s, 2H, H-2,6 3,4,5-(MeO)2C6H2), 7.07 (dd, J = 8.2, 1.2 Hz, 1H, H-6), 7.18 (td, J = 7.7, 1.2 Hz, 1H, H-8), 7.29 (td, J = 8.2, 1.0 Hz, 1H, H-7), 7.51 (dd, J = 7.7, 1.0 Hz, 1H, H-9); 19F NMR (376 MHz) δ 96.9 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.3, 53.1, 56.4 (2C), 60.9, 68.3, 70.5, 72.5 (q, 2JCF = 31.6 Hz, C-4), 93.3, 103.8 (2C), 117.6, 123.3 (q, 1JCF = 288.8 Hz, CF3), 124.0, 124.5, 128.2, 129.1, 129.2, 149.0, 153.8 (3C), 172.0. HRMS (ESI) m/z: [M + H]+ calcd for C23H24F3N2O8 513.1479, found 513.1472.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-3-(benzo[d][1,3]dioxol-5-yl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9e). Yield 203 mg (87%), white powder, mp 168–170 °C. IR (ATR) ν 3336 (NH), 1736 (C=O), 1544, 1362 (NO2). 1H NMR (400 MHz) δ 2.97 (dd, J = 10.7, 7.6 Hz, 1H, NH), 4.01 (s, 3H, MeO2C), 4.05 (dd, J = 7.6, 3.0 Hz, 1H, H-1), 4.55 (d, J = 3.0 Hz, 1H, H-9b), 4.75 (d, J = 10.7 Hz, 1H, H-3), 5.11 (q, J = 7.0 Hz, 1H, H-4), 6.01 (d, J = 1.4 Hz, 1H, OCH2O), 6.02 (d, J = 1.4 Hz, 1H, OCH2O), 6.76–6.82 (m, 2H, H-4,7 benzo[d][1,3]dioxol-5-yl), 6.85 (d, J = 7.9 Hz, 1H, H-6 benzo[d][1,3]dioxol-5-yl), 7.05 (dd, J = 8.2, 1.1 Hz, 1H, H-6), 7.17 (td, J = 7.7, 1.1 Hz, 1H, H-8), 7.27 (td, J = 8.2, 1.1 Hz, 1H, H-7), 7.50 (d, J = 7.7, 1.1 Hz, 1H, H-9); 19F NMR (376 MHz) δ 96.7 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.3, 53.1, 68.2, 70.0, 72.3 (q, 2JCF = 31.4 Hz, C-4), 93.3, 101.6, 106.6, 108.8, 117.6, 120.5, 123.4 (q, 1JCF = 289.0 Hz, CF3), 124.0, 124.4, 126.3, 129.09, 129.13, 148.5, 148.99, 149.02, 171.9. HRMS (ESI) m/z: [M + H]+ calcd for C21H18F3N2O7 467.1061, found 467.1064.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-8-chloro-3-(4-methoxyphenyl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9f). Yield 219 mg (90%), white powder, mp 191–193 °C. IR (ATR) ν 3316 (NH), 1745 (C=O), 1547, 1360 (NO2). 1H NMR (500 MHz) δ 3.06 (dd, J = 11.0, 7.7 Hz, 1H, NH), 3.83 (s, 3H, MeO), 4.01–4.05 (m, 4H, MeO2C, H-1), 4.50 (d, J = 3.3 Hz, 1H, H-9b), 4.74 (d, J = 11.0 Hz, 1H, H-3), 5.07 (q, J = 6.9 Hz, 1H, H-4), 6.95 (d, J = 8.6 Hz, 2H, H-3,5 4-MeOC6H4), 7.01 (d, J = 8.7 Hz, 1H, H-6), 7.20 (d, J = 8.6 Hz, 2H, H-2,6 4-MeOC6H4), 7.24 (dd, J = 8.7, 2.3 Hz, 1H, H-7), 7.49 (d, J = 2.3 Hz, 1H, H-9); 19F NMR (471 MHz) δ 96.8 (d, J = 6.9 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 45.3, 53.3, 55.3, 68.1, 70.1, 72.5 (q, 2JCF = 31.7 Hz, C-4), 93.1, 114.7 (2C), 119.1, 123.2 (q, 1JCF = 288.9 Hz, CF3), 124.1, 125.8, 127.7 (2C), 128.7, 129.4, 129.5, 147.7, 161.0, 171.6. HRMS (ESI) m/z: [M + H]+ calcd for C21H19ClF3N2O6 487.0878, found 487.0879.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-8-bromo-3-(4-methoxyphenyl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9g). Yield 250 mg (94%), white powder, mp 191–192 °C. IR (ATR) ν 3315 (NH), 1746 (C=O), 1546, 1361 (NO2). 1H NMR (500 MHz) δ 3.06 (br. s, 1H, NH), 3.83 (s, 3H, MeO), 4.01–4.05 (m, 4H, MeO2C, H-1), 4.50 (d, J = 3.3 Hz, 1H, H-9b), 4.73 (s, 1H, H-3), 5.07 (q, J = 6.9 Hz, 1H, H-4), 6.94 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 6.97 (d, J = 8.8 Hz, 1H, H-6), 7.20 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.38 (dd, J = 8.8, 2.2 Hz, 1H, H-7), 7.63 (d, J = 2.2 Hz, 1H, H-9); 19F NMR (471 MHz) δ 96.8 (d, J = 6.9 Hz, CF3); 13C NMR (126 MHz) δ 45.2, 53.3, 55.3, 68.1, 70.1, 72.4 (q, 2JCF = 31.7 Hz, C-4), 93.0, 114.6 (2C), 116.8, 119.4, 123.2 (q, 1JCF = 288.9 Hz, CF3), 124.0, 126.2, 127.7 (2C), 131.7, 132.3, 148.2, 160.9, 171.6. HRMS (ESI) m/z: [M + H]+ calcd for C21H19BrF3N2O6 531.0373, found 531.0374.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-6,8-dibromo-3-(4-methoxyphenyl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9h). Yield 284 mg (93%), white powder, mp 189–191 °C. IR (ATR) ν 3321 (NH), 1750 (C=O), 1547, 1362 (NO2). 1H NMR (400 MHz) δ 3.07 (dd, J = 10.8, 7.7 Hz, 1H, NH), 3.80 (s, 3H, MeO), 4.00 (dd, J = 7.7, 3.2 Hz, 1H, H-1), 4.03 (s, 3H, MeO2C), 4.53 (d, J = 3.2 Hz, 1H, H-9b), 4.72 (d, J = 10.8 Hz, 1H, H-3), 5.18 (q, J = 6.8 Hz, 1H, H-4), 6.96 (d, J = 8.6 Hz, 2H, H-3,5 4-MeOC6H4), 7.22 (d, J = 8.6 Hz, 2H, H-2,6 4-MeOC6H4), 7.61 (d, J = 1.9 Hz, 1H, H-9), 7.67 (d, J = 1.9 Hz, 1H, H-7); 19F NMR (376 MH) δ 97.0 (d, J = 6.8 Hz, CF3); 13C NMR (126 MHz) δ 45.5, 53.5, 55.3, 68.1, 70.3, 73.1 (q, 2JCF = 32.2 Hz, C-4), 93.2, 112.9 114.8 (2C), 116.9, 122.9 (q, 1JCF = 288.5 Hz, CF3), 123.8, 127.5, 127.7 (2C), 130.9, 135.3, 145.5, 161.1, 171.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H18Br2F3N2O6 608.9478, found 608.9475.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-8-methoxy-3-(4-methoxyphenyl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9i). Yield 215 mg (89%), white powder, mp 125–127 °C. IR (ATR) ν 3368 (NH), 1744 (C=O), 1547, 1348 (NO2). 1H NMR (400 MHz) δ 3.07 (dd, J = 11.3, 7.8 Hz, 1H, NH), 3.82 (s, 3H, MeO), 3.83 (s, 3H, MeO), 4.02 (s, 3H, MeO2C), 4.07 (dd, J = 7.8, 3.2 Hz, 1H, H-1), 4.49 (d, J = 3.2 Hz, 1H, H-9b), 4.78 (d, J = 11.3 Hz, 1H, H-3), 5.03 (q, J = 7.0 Hz, 1H, H-4), 6.83 (dd, J = 9.0, 2.8 Hz, 1H, H-7), 6.95 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 6.98 (d, J = 9.0 Hz, 1H, H-6), 7.01 (d, J = 2.2 Hz, 1H, H-9), 7.21 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4); 19F NMR (376 MHz) δ 97.0 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 45.9, 53.1, 55.3, 55.7, 68.3, 70.1, 72.6 (q, 2JCF = 31.4 Hz, C-4), 93.8, 113.1, 114.6 (2C), 115.2, 118.4, 123.4 (q, 1JCF = 289.2 Hz, CF3), 124.4, 124.8, 127.7 (2C), 142.8, 156.2, 160.9, 171.9. HRMS (ESI) m/z: [M + H]+ calcd for C22H22F3N2O7 483.1374, found 483.1374.
Methyl (1S*,3S*,3aS*,4S*,9bR*)-6-ethoxy-3-(4-methoxyphenyl)-3a-nitro-4-(trifluoromethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-1-carboxylate (endo-9j). Yield 216 mg (87%), white powder, mp 123–125 °C. IR (ATR) ν 3348 (NH), 1752 (C=O), 1557, 1361 (NO2). 1H NMR (400 MHz) δ 1.48 (t, J = 7.0 Hz, Me), 3.06 (dd, J = 10.9, 7.6 Hz, 1H, NH), 3.83 (s, 3H, MeO), 4.01 (s, 3H, MeO2C), 4.05 (dd, J = 7.6, 3.2 Hz, 1H, H-1), 4.17 (d, J = 7.0 Hz, OCH2), 4.52 (d, J = 3.2 Hz, 1H, H-9b), 4.81 (d, J = 10.9 Hz, 1H, H-3), 5.19 (q, J = 7.0 Hz, 1H, H-4), 6.82–6.89 (m, 1H, H-8), 6.94 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.06–7.10 (m, 2H, H-7,9), 7.25 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4); 19F NMR (376 MHz) δ 97.1 (d, J = 7.0 Hz, CF3); 13C NMR (126 MHz) δ 14.7, 45.7, 53.1, 55.3, 64.7, 68.4, 70.2, 72.7 (q, 2JCF = 31.5 Hz, C-4), 94.0, 112.3, 114.6 (2C), 120.1, 123.3 (q, 1JCF = 288.8 Hz, CF3), 124.3, 124.4, 125.3, 127.8 (2C), 139.1, 148.1, 160.9, 172.0. HRMS (ESI) m/z: [M + H]+ calcd for C23H23F3N2NaO7 519.1350, found 519.1347.

3.4. Synthesis of Compounds 10a–g

General procedure. A mixture of the appropriate 3-nitro-2-(trichloromethyl)-2H-chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (7 μL, 5 mg, 0.05 mmol) and AgOAc (5.8 mg, 0.05 mmol) was stirred in dichloromethane (2 mL) for 5 h at room temperature (TLC control, EtOAc−hexane (1:3)). Upon completion of the reaction, the residue was evaporated under reduced pressure to complete dryness. The residue was purified by by silica gel column chromatography using (eluent−EtOAc−hexane (1:3)) to give products 10 as white powders.
Methyl (S)-2-[((E)-benzylidene)amino]-2-((2S*,3R*,4R*)-3-nitro-2-(trichloromethyl)chroman-4-yl)acetate (10a). Yield 101 mg (43%), mp 225–227 °C. IR (ATR) ν 1737 (C=O), 1552, 1311 (NO2). 1H NMR (400 MHz) δ 3.86 (s, 3H, MeO2C), 4.14 (br. d, J = 2.3 Hz, 1H, H-4’), 4.53 (d, J = 2.3 Hz, 1H, H-2), 5.22 (d, J = 1.4 Hz, 1H, H-2’), 6.29 (br. d, J = 1.4 Hz, 1H, H-3’), 7.04 (d, J = 8.0 Hz, 1H, H-8’), 7.09 (t, J = 7.5 Hz, 1H, H-6’), 7.20–7.29 (m, 2H, H-5’,7’), 7.39 (t, J = 7.3 Hz, 2H, H Ph), 7.46 (tt, J = 7.3, 1.3 Hz, 1H, H Ph), 7.63 (dd, J = 7.3, 1.3 Hz, 2H, H Ph), 8.02 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.7, 53.2, 76.1, 78.8, 82.7, 95.5, 117.6, 118.4, 123.1, 127.8, 128.7 (2C), 128.8, 128.9 (2C), 132.1, 134.5, 153.8, 166.6, 169.9. HRMS (ESI) m/z: [M + H]+ calcd for C20H18Cl3N2O5 471.0276, found 471.0276.
Methyl (S)-2-[((E)-4-methoxybenzylidene)amino]-2-((2S*,3R*,4R*)-3-nitro-2-(trichloromethyl)chroman-4-yl)acetate (10b). Yield 170 mg (66%), mp 155–157 °C. IR (ATR) ν 1737 (C=O), 1553, 1310 (NO2). 1H NMR (500 MHz) δ 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO2C), 4.11 (br. s, 1H, H-4’), 4.48 (d, J = 2.3 Hz, 1H, H-2), 5.25 (d, J = 1.6 Hz, 1H, H-2’), 6.29 (br. d, J = 1.6 Hz, 1H, H-3’), 6.89 (d, J = 8.7 Hz, 2H, H-3,5 4-MeOC6H4), 7.03 (d, J = 8.0 Hz, 1H, H-8’), 7.09 (t, J = 7.5 Hz, 1H, H-6’), 7.20–7.27 (m, 2H, H-5’,7’), 7.54 (d, J = 8.7 Hz, 2H, H-2,6 4-MeOC6H4), 7.92 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.7 (C-4’), 53.1 (MeO), 55.4 (MeO), 76.0 (C-2), 78.7 (C-3’), 82.6 (C-2’), 95.6 (CCl3), 114.2 (C-3,5 4-MeOC6H4), 117.5 (C-5’), 118.6 (C-4a’), 123.0 (C-6’), 127.5 (C-1 4-MeOC6H4), 127.8 (C-8’), 128.7 (C-7’), 130.4 (C-2,6 4-MeOC6H4), 153.8 (C-8a’), 162.8 (C-4 4-MeOC6H4), 165.7 (C=N), 170.2 (C=O). HRMS (ESI) m/z: [M + H]+ calcd for C21H20Cl3N2O6 501.0381, found 501.0372.
Methyl (S)-2-[((E)-benzo[d][1,3]dioxol-5-ylmethylene)amino]-2-((2S*,3R*,4R*)-3-nitro-2-(trichloromethyl)chroman-4-yl)acetate (10c). Yield 146 mg (55%), mp 189–191 °C. IR (ATR) ν 1732 (C=O), 1552, 1339 (NO2). 1H NMR (500 MHz) δ 3.85 (s, 3H, MeO2C), 4.11 (br. d, J = 2.4 Hz, 1H, H-4’), 4.48 (d, J = 2.4 Hz, 1H, H-2), 5.21 (d, J = 1.8 Hz, 1H, H-2’), 6.00 (s, 2H, OCH2O), 6.26 (dd, J = 1.8, 1.0 Hz, 1H, H-3’), 6.78 (d, J = 8.0 Hz, 1H, H-7 benzo[d][1,3]dioxol-5-yl), 7.01 (dd, J = 8.0, 1.5 Hz, 1H, H-6 benzo[d][1,3]dioxol-5-yl), 7.05 (dd, J = 8.3, 1.1 Hz, 1H, H-8’), 7.09 (dd, J = 7.6, 1.1 Hz, 1H, H-6’), 7.20 (d, J = 1.5 Hz, 1H, H-4 benzo[d][1,3]dioxol-5-yl), 7.21–7.27 (m, 2H, H-5’,7’), 7.87 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.6, 53.1, 75.9, 78.7, 82.6, 95.5, 101.7, 106.5, 108.2, 117.6, 118.5, 123.1, 125.9, 127.8, 128.8, 129.3, 148.5, 151.1, 153.8, 165.5, 170.1. HRMS (ESI) m/z: [M + H]+ calcd for C21H18Cl3N2O7 515.0174, found 515.0181.
Methyl (S)-2-((2S*,3R*,4R*)-6-chloro-3-nitro-2-(trichloromethyl)chroman-4-yl)-2-[((E)-4-methoxybenzylidene)amino]acetate (10d). Yield 161 mg (60%), mp 127–129 °C. IR (ATR) ν 1743 (C=O), 1556, 1337 (NO2). 1H NMR (500 MHz) δ 3.83 (s, 3H, MeO), 3.85 (s, 3H, MeO2C), 4.08 (br. s, 1H, H-4’), 4.44 (d, J = 1.8 Hz, 1H, H-2), 5.29 (d, J = 1.3 Hz, 1H, H-2’), 6.26 (br. s, 1H, H-3’), 6.90 (d, J = 8.6 Hz, 2H, H-3,5 4-MeOC6H4), 6.98 (d, J = 8.8 Hz, 1H, H-8’), 7.19 (dd, J = 8.8, 2.1 Hz, 1H, H-7’), 7.59 (d, J = 2.1 Hz, 1H, H-5’), 7.59 (d, J = 8.6 Hz, 2H, H-2,6 4-MeOC6H4), 7.99 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.5, 53.2, 55.5, 75.7, 78.3, 82.8, 95.3, 114.3 (2C), 119.0, 120.4, 127.4, 127.5, 127.9, 129.0, 130.5 (2C), 152.4, 162.9, 166.1, 169.8. HRMS (ESI) m/z: [M + H]+ calcd for C21H19Cl4N2O6 534.9992, found 534.9993.
Methyl (S)-2-((2S*,3R*,4R*)-6-bromo-3-nitro-2-(trichloromethyl)chroman-4-yl)-2-[((E)-4-methoxybenzylidene)amino]acetate (10e). Yield 194 mg (67%), mp 158–160 °C. IR (ATR) ν 1743 (C=O), 1557, 1337 (NO2). 1H NMR (500 MHz) δ 3.83 (s, 3H, MeO), 3.85 (s, 3H, MeO2C), 4.08 (s, 1H, H-4’), 4.44 (s, 1H, H-2), 5.30 (s, 1H, H-2’), 6.26 (s, 1H, H-3’), 6.90 (d, J = 8.3 Hz, 2H, H-3,5 4-MeOC6H4), 6.93 (d, J = 8.8 Hz, 1H, H-8’), 7.32 (d, J = 8.8 Hz, 1H, H-7’), 7.39 (s, 1H, H-5’), 7.59 (d, J = 8.3 Hz, 2H, H-2,6 4-MeOC6H4), 7.99 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.4, 53.2, 55.5, 75.7, 78.3, 82.7, 95.3, 114.3 (2C), 115.2, 119.4, 120.9, 127.4, 130.50 (2C), 130.53, 131.8, 152.9, 162.9, 166.1, 169.8. HRMS (ESI) m/z: [M + H]+ calcd for C21H19BrCl3N2O6 578.9487, found 578.9486.
Methyl (S)-2-((2S*,3R*,4R*)-6,8-dibromo-3-nitro-2-(trichloromethyl)chroman-4-yl)-2-[((E)-4-methoxybenzylidene)amino]acetate (10f). Yield 165 mg (50%), mp 112–115 °C. IR (ATR) ν 1735 (C=O), 1561, 1341 (NO2). 1H NMR (500 MHz) δ 3.81 (s, 3H, MeO), 3.84 (s, 3H, MeO2C), 4.11 (br. s, 1H, H-4’), 4.43 (d, J = 1.8 Hz, 1H, H-2), 5.35 (d, J = 1.6 Hz, 1H, H-2’), 6.25 (br. s, J = 1.5 Hz, 1H, H-3’), 6.92 (d, J = 8.6 Hz, 2H, H-3,5 4-MeOC6H4), 7.35 (d, J = 1.6 Hz, 1H, H-5’), 7.60 (d, J = 8.6 Hz, 2H, H-2,6 4-MeOC6H4), 7.62 (d, J = 1.6 Hz, 1H, H-7’), 8.03 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.6, 53.3, 55.5, 75.5, 78.3, 83.2, 94.8, 114.4 (2C), 115.0, 122.9, 127.3, 128.1, 129.7, 130.6 (2C), 134.9, 149.8, 163.0, 166.5, 169.6. HRMS (ESI) m/z: [M + H]+ calcd for C21H18Br2Cl3N2O6 656.8592, found 656.8590.
Methyl (S)-2-((2S*,3R*,4R*)-6-methoxy-3-nitro-2-(trichloromethyl)chroman-4-yl)-2-[((E)-4-methoxybenzylidene)amino]acetate (10g). Yield 106 mg (40%), mp 168–170 °C. IR (ATR) ν 1746 (C=O), 1562, 1326 (NO2). 1H NMR (500 MHz) δ 3.80 (s, 3H, MeO), 3.83 (s, 3H, MeO), 3.85 (s, 3H, MeO2C), 4.08 (dd, J = 2.3, 1.7 Hz, 1H, H-4’), 4.46 (d, J = 2.3 Hz, 1H, H-2), 5.18 (d, J = 1.7 Hz, 1H, H-2’), 6.25 (dd, J = 1.7, 1.0 Hz, 1H, H-3’), 6.89 (d, J = 8.8 Hz, 2H, H-3,5 4-MeOC6H4), 6.75 (d, J = 2.9 Hz, 1H, H-5’), 6.79 (dd, J = 8.9, 2.9 Hz, 1H, H-7’), 6.90 (d, J = 8.9 Hz, 1H, H-8’), 7.59 (d, J = 8.8 Hz, 2H, H-2,6 4-MeOC6H4), 7.95 (s, 1H, =CH); 13C NMR (126 MHz) δ 42.9, 53.1, 55.4, 75.8, 75.9, 78.6, 82.9, 95.6, 112.3, 114.2 (2C), 114.6, 118.3, 119.2, 127.5, 130.4 (2C), 147.9, 155.2, 162.8, 165.6, 170.2. HRMS (ESI) m/z: [M + H]+ calcd for C22H22Cl3N2O7 531.0487, found 531.9486.

3.5. Biology

3.5.1. Cell Cultures

The human cervical carcinoma (HeLa) cell line was purchased from the Bank of Cell Cultures of the Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, Russia. The normal human dermal fibroblasts (HDF) cell line was obtained from the Institute of Medical Cell Technologies, Ekaterinburg, Russia.

3.5.2. Assessment of In Vitro Cytotoxic Activity

The cells were seeded in 96-well microplates at a seeding density of 2 × 105 cells per mL and cultured for 24 h in DMEM medium with glutamine (1%) in the presence of 10% fetal bovine serum and gentamicin (50 mg/L) at 37 °C in a humidified atmosphere containing 5% CO2. Then the tested compounds were added to the wells in various concentrations (10−7 M, 10−6 M, 10−5 M, 10−4 M). Cells with compounds were incubated for 72 h, after which cell viability was assessed using the standard MTT test [43] based on the reduction of the yellow tetrazole salt by living cell mitochondrial dehydrogenases to formazan crystals, soluble in DMSO. Experiments were performed in triplicates with negative control (culture medium), positive control (camptothecin, 3 mM) and solvent control (DMSO). The results of the MTT test were evaluated by comparing the optical density of the formazan solution measured on a flatbed scanner Tecan Infinite M200 PRO (Tecan Austria GmbH, Austria) at a wavelength of 570 nm in the experimental and control wells and control wells and calculating the cytotoxicity index (IC). The cytotoxicity index was determined for each concentration of the studied substances by AAT Bioquest-calculator: https://www.aatbio.com/tools/ic50-calculator (accessed on 15 November 2022). The parameters of the arithmetic mean value and the standard error were calculated. The differences in the average values according to the Mann-Whitney U test with p < 0.05 were considered reliable. For the statistical analysis, Microsoft Excel 2019 (Microsoft corp., Redmond, DC, USA) and Statistika 13.3 (Tibco, Palo Alto, CA, USA) were used.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27248983/s1: X-ray diffraction experiments; NMR spectra of compounds 8–10 [44,45].

Author Contributions

Conceptualization and methodology were provided by A.Y.B. and V.Y.K. A.Y.B., I.A.K., and V.Y.K. conceived and designed the experiments. A.Y.B., I.A.K., N.S.Z. and V.Y.K. analyzed the results. The experimental work was conducted by I.A.K., N.S.S. (chemistry) and M.V.U. (biology). V.Y.K. and V.Y.S. wrote the paper. Project administration and funding acquisition were carried out by V.Y.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Foundation for Basic Research (project 20-03-00716) and the Ministry of Science and Higher Education of the Russian Federation (project FEUZ-2020-0052).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article and Supplementary Material.

Acknowledgments

Analytical studies were carried out using equipment at the Center for Joint Use ‘Spectroscopy and Analysis of Organic Compounds’ at the Postovsky Institute of Organic Synthesis of the Russian Academy of Sciences (Ural Branch) and the Laboratory of Complex Investigations and Expert Evaluation of Organic Materials of the Center for Joint Use at the Ural Federal University.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 27 08983 g001 550
Figure 1. Some bioactive chromenopyrroli(zi)dines.
Figure 1. Some bioactive chromenopyrroli(zi)dines.
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Molecules 27 08983 sch001 550
Scheme 1. Possible diastereomers generated from α-iminoesters and trans-nitrostyrenes.
Scheme 1. Possible diastereomers generated from α-iminoesters and trans-nitrostyrenes.
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Molecules 27 08983 sch002 550
Scheme 2. Reactions of 2-aryl-substituted 3-nitro-2H-chromenes 4 with azomethine ylides generated from amino acid esters and arylaldehydes [6,31].
Scheme 2. Reactions of 2-aryl-substituted 3-nitro-2H-chromenes 4 with azomethine ylides generated from amino acid esters and arylaldehydes [6,31].
Molecules 27 08983 sch002
Molecules 27 08983 sch003 550
Scheme 3. The reaction of nitrochromene 4a with azomethine 5b.
Scheme 3. The reaction of nitrochromene 4a with azomethine 5b.
Molecules 27 08983 sch003
Molecules 27 08983 sch004 550
Scheme 4. Synthesis of 4-Ph-substituted chromeno[3,4-c]pyrrolidines 8.
Scheme 4. Synthesis of 4-Ph-substituted chromeno[3,4-c]pyrrolidines 8.
Molecules 27 08983 sch004
Molecules 27 08983 sch005 550
Scheme 5. Synthesis of 4-CF3-substituted chromeno[3,4-c]pyrrolidines 9.
Scheme 5. Synthesis of 4-CF3-substituted chromeno[3,4-c]pyrrolidines 9.
Molecules 27 08983 sch005
Molecules 27 08983 sch006 550
Scheme 6. Synthesis of 2-CCl3-substituted chromanes 10.
Scheme 6. Synthesis of 2-CCl3-substituted chromanes 10.
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Molecules 27 08983 sch007 550
Scheme 7. Control experiments.
Scheme 7. Control experiments.
Molecules 27 08983 sch007
Molecules 27 08983 sch008 550
Scheme 8. Proposed mechanism for the AgOAc-catalyzed reaction of chromenes 4 with iminoesters 5.
Scheme 8. Proposed mechanism for the AgOAc-catalyzed reaction of chromenes 4 with iminoesters 5.
Molecules 27 08983 sch008
Molecules 27 08983 g002 550
Figure 2. Characteristic chemical shifts of stereoisomeric chromeno[3,4-c]pyrrolidines 8 and 9 in 1H (in blue) and 19F (in magenta) NMR spectra in CDCl3.
Figure 2. Characteristic chemical shifts of stereoisomeric chromeno[3,4-c]pyrrolidines 8 and 9 in 1H (in blue) and 19F (in magenta) NMR spectra in CDCl3.
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Molecules 27 08983 g003 550
Figure 3. The main correlations in the 2D 1H−1H NOESY spectra of endo-8b and endo’-8b.
Figure 3. The main correlations in the 2D 1H−1H NOESY spectra of endo-8b and endo’-8b.
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Molecules 27 08983 g004 550
Figure 4. Molecular structure of endo-8b (ORTEP drawing, 50% probability level).
Figure 4. Molecular structure of endo-8b (ORTEP drawing, 50% probability level).
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Molecules 27 08983 g005 550
Figure 5. Molecular structure of endo-9a (ORTEP drawing, 50% probability level).
Figure 5. Molecular structure of endo-9a (ORTEP drawing, 50% probability level).
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Molecules 27 08983 g006 550
Figure 6. Molecular structure of 10c (ORTEP drawing, 30% probability level).
Figure 6. Molecular structure of 10c (ORTEP drawing, 30% probability level).
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Table
Table 1. Condition optimization for the reaction of 4a with 5b a.
Table 1. Condition optimization for the reaction of 4a with 5b a.
EntryCatalystSolventTotal Yield b, %Ratio c of endo:endo’
1AgOAcPhMe602.1:1
2AgOAcMeCN912.1:1
3AgOAcTHF922.1:1
4AgOAcDCM932.1:1
5CuIPhMe402.1:1
6CuIMeCN702.1:1
7CuITHF702.1:1
8CuIDCM782.1:1
a Conditions: a mixture of 4a (63 mg, 0.25 mmol) and 5b (58 mg, 0.28 mmol) was stirred at room temperature in 1 mL of the corresponding solvent for 5 h in the presence of Et3N (2.9 mg, 0.025 mmol) and the corresponding catalyst (0.025 mmol). b Isolated yield. c Determined by 1H NMR spectroscopy of the reaction mixtures.
Table
Table 2. Scope of the synthesis of 4-Ph-substituted chromeno[3,4-c]pyrrolidines 8 a.
Table 2. Scope of the synthesis of 4-Ph-substituted chromeno[3,4-c]pyrrolidines 8 a.
Chromene 4R1Imine
5		ArProductTotal yield b, %Yield b endo-8, %Yield b endo’-8, %Ratio c of
endo:endo’
aHaPh8a8756232.0:1
aHb4-MeOC6H48b9363212.1:1
aHc3,4-(MeO)2C6H38c9054272.2:1
aHd2,3,4-(MeO)3C6H28d8755− d2.3:1
aHebenzo[d][1,3]dioxol-5-yl8e8556202.3:1
bBrb4-MeOC6H48f9261212.2:1
cMeOb4-MeOC6H48g8857222.2:1
a Conditions: a mixture of the appropriate chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (5 mg, 0.05 mmol) and AgOAc (5.8 mg, 0.05 mmol) was stirred at room temperature in DCM (2 mL) for 5 h. b Isolated yield. c Determined by 1H NMR spectroscopy of the reaction mixtures. d This isomer was not isolated from the reaction mixture.
Table
Table 3. Scope of the synthesis of 4-CF3-substituted chromeno[3,4-c]pyrrolidines 9 a.
Table 3. Scope of the synthesis of 4-CF3-substituted chromeno[3,4-c]pyrrolidines 9 a.
Chromene 4R1R2Imine 5ArProductYield b, %
dHHaPhendo-9a90
dHHb4-MeOC6H4endo-9b92
dHHc3,4-(MeO)2C6H3endo-9c92
dHHd2,3,4-(MeO)3C6H2endo-9d85
dHHebenzo[d][1,3]dioxol-5-ylendo-9e87
eClHb4-MeOC6H4endo-9f90
fBrHb4-MeOC6H4endo-9g94
gBrBrb4-MeOC6H4endo-9h93
hMeOHb4-MeOC6H4endo-9i89
iHEtOb4-MeOC6H4endo-9j87
a Conditions: a mixture of the appropriate chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (5 mg, 0.05 mmol) and AgOAc (5.8 mg, 0.05 mmol) was stirred at room temperature in DCM (2 mL) for 5 h. b Isolated yield.
Table
Table 4. Scope of the synthesis of 2-CCl3-substituted chromanes 10 a.
Table 4. Scope of the synthesis of 2-CCl3-substituted chromanes 10 a.
Chromene 4R1Imine 5ArProductYield b, %
jHaPh10a43
jHb4-MeOC6H410b66
jHebenzo[d][1,3]dioxol-5-yl10c55
kClb4-MeOC6H410d60
lBrb4-MeOC6H410e67
mBrb4-MeOC6H410f50
nMeOb4-MeOC6H410g40
a Conditions: a mixture of the appropriate chromene 4 (0.5 mmol), azomethine 5 (0.55 mmol), Et3N (5 mg, 0.05 mmol,) and AgOAc (5.8 mg, 0.05 mmol) was stirred at room temperature in DCM (2 mL) for 5 h. b Isolated yield.
Table
Table 5. Cytotoxic activity (IC50) of compounds endo-8b,e−g and endo-9b,e−j against HeLa and HDF cell lines.
Table 5. Cytotoxic activity (IC50) of compounds endo-8b,e−g and endo-9b,e−j against HeLa and HDF cell lines.
CompoundIC50, μM
HeLaHDF
endo-8b5300 ± 120.033.23 ± 1.65
endo-8e44.98 ± 2.15806.00 ± 41.54
endo-8f5610 ± 37.0745.0 ± 16.40
endo-8g5220 ± 117.0781.0 ± 17.50
endo-9b0.55 ± 0.01− a
endo-9e108 ± 15.8185 ± 14.2
endo-9f50.22 ± 3.401750.00 ± 120.0
endo-9g3100.0 ± 84.8225.00 ± 47.20
endo-9h4400.0 ± 90.18750.0 ± 647.0
endo-9i12.17 ± 1.37213.00 ± 51.25
endo-9j4.19 ± 0.050.74 ± 0.05
Camptothecin1.66 ± 0.97323.27 ± 28.93
a This compound is not cytotoxic in the concentration range from 10−7 M to 10−4 M.
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Kochnev, I.A.; Barkov, A.Y.; Simonov, N.S.; Ulitko, M.V.; Zimnitskiy, N.S.; Korotaev, V.Y.; Sosnovskikh, V.Y. Different Behavior of 2-Substituted 3-Nitro-2H-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters. Molecules 2022, 27, 8983. https://doi.org/10.3390/molecules27248983

AMA Style

Kochnev IA, Barkov AY, Simonov NS, Ulitko MV, Zimnitskiy NS, Korotaev VY, Sosnovskikh VY. Different Behavior of 2-Substituted 3-Nitro-2H-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters. Molecules. 2022; 27(24):8983. https://doi.org/10.3390/molecules27248983

Chicago/Turabian Style

Kochnev, Ivan A., Alexey Y. Barkov, Nikita S. Simonov, Maria V. Ulitko, Nikolay S. Zimnitskiy, Vladislav Y. Korotaev, and Vyacheslav Y. Sosnovskikh. 2022. "Different Behavior of 2-Substituted 3-Nitro-2H-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters" Molecules 27, no. 24: 8983. https://doi.org/10.3390/molecules27248983

APA Style

Kochnev, I. A., Barkov, A. Y., Simonov, N. S., Ulitko, M. V., Zimnitskiy, N. S., Korotaev, V. Y., & Sosnovskikh, V. Y. (2022). Different Behavior of 2-Substituted 3-Nitro-2H-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters. Molecules, 27(24), 8983. https://doi.org/10.3390/molecules27248983

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