Green and Efficient Construction of Chromeno[3,4-c]pyrrole Core via Barton–Zard Reaction from 3-Nitro-2H-chromenes and Ethyl Isocyanoacetate

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4-c]pyrroles in 63–94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2H-chromenes and ethyl isocyanoacetate through the Barton–Zard reaction in ethanol at reflux for 0.5 h, using K2CO3 as a base, has been developed.

The Barton-Zard reaction is an efficient one-pot method for the synthesis of 5-unsubstituted pyrroles from readily available conjugated nitroalkenes and alkyl isocyanoacetates [27][28][29][30][31]. From this point of view, 3-nitro-2H-chromenes are suitable substrates for the design of a chromeno [3,4-c]pyrrole scaffold. Indeed, due to the presence of a β-nitrostyrene fragment in the molecule, 3-nitro-2H-chromenes are widely used in the synthesis of fused polyheterocyclic systems [32][33][34]. The introduction of a trifluoromethyl group into a drug molecule often leads to an increase in its physiological activity because of improvements to the transport characteristics of the drug and an increase in its metabolic stability [35,36]. We have recently developed methods for the synthesis of trifluoromethyl-substituted chromenopyrroli(zi)dines with pronounced cytotoxic activity against HeLa and RD cancer cells [37][38][39]. In this work, we report an eco-friendly and efficient approach to the synthesis of 2,4dihydrochromeno [3,4-c]pyrroles 12 from 2-mono-and 2,2-disubsituted 3-nitrochromenes 10 and ethyl isocyanoacetate 11 via the Barton-Zard reaction (Scheme 1). The Barton-Zard reaction is an efficient one-pot method for the synthesis of 5-unsubstituted pyrroles from readily available conjugated nitroalkenes and alkyl isocyanoacetates [27][28][29][30][31]. From this point of view, 3-nitro-2H-chromenes are suitable substrates for the design of a chromeno [3,4-c]pyrrole scaffold. Indeed, due to the presence of a β-nitrostyrene fragment in the molecule, 3-nitro-2H-chromenes are widely used in the synthesis of fused polyheterocyclic systems [32][33][34]. The introduction of a trifluoromethyl group into a drug molecule often leads to an increase in its physiological activity because of improvements to the transport characteristics of the drug and an increase in its metabolic stability [35,36]. We have recently developed methods for the synthesis of trifluoromethyl-substituted chromenopyrroli(zi)dines with pronounced cytotoxic activity against HeLa and RD cancer cells [37][38][39]. In this work, we report an eco-friendly and efficient approach to the

Scheme 2.
Reaction of 3-nitro-2H-chromenes 10aa with ethyl isocyanoacetate 11. The reaction was carried out at room temperature (method A) or at reflux (method B). Three bases (DBU, DABCO and K2CO3) and three solvents (THF, MeCN and EtOH) were tested. It was found that regardless of the base used, the starting chromene 10aa was absent in the reaction mixture after 1 h or 0.5 h under the conditions of method A or B, respectively (monitoring by TLC). In ethanol, all three bases were effective both at room temperature and at boiling (entries 7-9). In MeCN, the yields of the product increased noticeably with a rise in the temperature (entries 4-6). In contrast, if THF was used as the solvent, the yields decreased at reflux when DBU or DABCO were used as bases (entries 1-2). The best yield of 12aa (94%) was achieved when the reaction was carried out in ethanol at reflux using 1.5 equiv. K2CO3 (entry 10). A further increase in the amount of base did not significantly affect the yield of product (entries 11-12).
Next, under optimized conditions, the substrate scope for the synthesis of chromeno[3,4-c]pyrroles 12 were examined by varying the substituents R 1 -R 4 in nitrochromenes 10 (Scheme 3).   (29 mg, 0.26 mmol, 1.3 equiv.) in 1 mL of a solvent was added to a mixture of 10aa (49 mg, 0.20 mmol, 1.0 equiv.) and the corresponding base in 2 mL of a solvent, and the reaction mixture was stirred at room temperature for 1 h (method A) or under reflux for 0.5 h (method B). b Isolated yield.
The reaction was carried out at room temperature (method A) or at reflux (method B). Three bases (DBU, DABCO and K 2 CO 3 ) and three solvents (THF, MeCN and EtOH) were tested. It was found that regardless of the base used, the starting chromene 10aa was absent in the reaction mixture after 1 h or 0.5 h under the conditions of method A or B, respectively (monitoring by TLC). In ethanol, all three bases were effective both at room temperature and at boiling (entries 7-9). In MeCN, the yields of the product increased noticeably with a rise in the temperature (entries 4-6). In contrast, if THF was used as the solvent, the yields decreased at reflux when DBU or DABCO were used as bases (entries 1-2). The best yield of 12aa (94%) was achieved when the reaction was carried out in ethanol at reflux using 1.5 equiv. K 2 CO 3 (entry 10). A further increase in the amount of base did not significantly affect the yield of product (entries 11-12).
The substituents at the 2-position of chromene 10 had a notable effect on the yields of the products 12 (Scheme 3). The highest yields (83-94%) were observed in the reactions of isonitrile 11 with 2-trifluoromethyl-and 2-phenyl-substituted chromenes 10aa-ag and 10ba-bg. The yields of 2-trichloromethyl-substituted pyrroles 12ca-cg decreased by 7-14% compared to 2-trifluoromethyl-substituted analogs 12aa-ag. Lower yields in the reactions involving chromenes 12ca-cg were probably associated with the formation of 2-(dichloromethylidene)chromenes as a result of the elimination of HCl under the action of the base. We have already observed a similar process earlier in the reactions of these chromenes with sodium azide [40]. The introduction of a second substituent at the 2-position of chromenes 10aa-ag or 10ba-bg (Ph or CF 3 group, respectively) reduced the yields of products 12da-dg to 63-76% due to additional steric hindrances for attacking the double bond by the reagent. At the same time, the yields of pyrroles 12 were almost independent from the donor-acceptor properties of substituents R 3 and R 4 . Replacement of the hydrogen atoms at the positions 6 and 8 of the starting chromenes 10 with the donor MeO or EtO groups only slightly reduced the yields of compounds 12. To test the scalability of the procedure for the synthesis of 4-substituted 2,4dihydrochromeno[3,4-c]pyrroles 12, the gram-scale reaction of chromene 10aa (1.00 g) with isonitrile 11 (0.60 g) was carried out under the standard condition to obtain the target product 12aa (1.20 g) in 94% yield (Scheme 4). ent from the donor-acceptor properties of substituents R and R . Replacement of the hydrogen atoms at the positions 6 and 8 of the starting chromenes 10 with the donor MeO or EtO groups only slightly reduced the yields of compounds 12.
To test the scalability of the procedure for the synthesis of 4-substituted 2,4-dihydrochromeno[3,4-c]pyrroles 12, the gram-scale reaction of chromene 10aa (1.00 g) with isonitrile 11 (0.60 g) was carried out under the standard condition to obtain the target product 12aa (1.20 g) in 94% yield (Scheme 4).      To assess the possibility of using pyrroles 12 in organic synthesis, some transformations of the pyrrole ring were carried out (Scheme 6). It was found that chromenopyrrole 12aa was methylated at the nitrogen atom to form the N-methyl derivative 13 in 76% yield.
Treatment of compound 12aa with phenylboronic acid by the Chan-Evans-Lahm coupling reaction led to the corresponding N-phenylpyrrole 14 in 45% yield. 3-Bromo derivative 15 was obtained in 55% yield by bromination of compound 15 with N-bromosuccinimide.
the spectra of compounds 12da-dg this group manifested as a singlet in the range of 84.3-85.2 ppm. The 13 C NMR spectra of these compounds contained quartets of the CF3 group and the С-4 atom in the range of 122.9-124.1 and 71.0-82.2 ppm with coupling constants 283.1-284. respectively. To assess the possibility of using pyrroles 12 in organic synthesis, some transformations of the pyrrole ring were carried out (Scheme 6). It was found that chromenopyrrole 12aa was methylated at the nitrogen atom to form the N-methyl derivative 13 in 76% yield. Treatment of compound 12aa with phenylboronic acid by the Chan-Evans-Lahm coupling reaction led to the corresponding N-phenylpyrrole 14 in 45% yield. 3-Bromo derivative 15 was obtained in 55% yield by bromination of compound 15 with Nbromosuccinimide. Scheme 6. Some transformations of the pyrrole ring of compound 12aa.
In summary, a green and efficient regioselective method for the synthesis of 4-substituted 2,4-dihydrochromeno [3,4-c]pyrroles has been developed by the Barton-Zard reaction, using K2CO3 as a base and ethanol as a solvent. The availability of the starting 3nitro-2H-chromenes, operational simplicity and scalability, as well as the possibility of further functionalization of the products, open up prospects for the synthesis of libraries of compounds bearing a chromeno [3,4-c]pyrrole framework, which are of undoubted interest for medicinal chemistry, especially due to the presence of the CF3 group.

General
IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer using an attenuated total reflectance (ATR) unit (FTIR mode, ZnSe crystal); the absorbance maxima (ν) are reported in cm -1 . NMR spectra (See Supplementary Materials) were recorded on Bruker Scheme 6. Some transformations of the pyrrole ring of compound 12aa.
In summary, a green and efficient regioselective method for the synthesis of 4-substituted 2,4-dihydrochromeno [3,4-c]pyrroles has been developed by the Barton-Zard reaction, using K 2 CO 3 as a base and ethanol as a solvent. The availability of the starting 3-nitro-2H-chromenes, operational simplicity and scalability, as well as the possibility of further functionalization of the products, open up prospects for the synthesis of libraries of compounds bearing a chromeno [3,4-c]pyrrole framework, which are of undoubted interest for medicinal chemistry, especially due to the presence of the CF 3 group.

General
IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer using an attenuated total reflectance (ATR) unit (FTIR mode, ZnSe crystal); the absorbance maxima (ν) are reported in cm -1 . NMR spectra (See Supplementary Materials) were recorded on Bruker Avance III-500 ( 1 H, 500 MHz; 19 F, 471 MHz; 13 C, 126 MHz) and Bruker DRX-400 ( 1 H, 400 MHz; 19 F, 376 MHz) spectrometers in CDCl 3 . The chemical shifts (δ) are reported in ppm relative to the internal standard TMS ( 1 H NMR), C 6 F 6 ( 19 F NMR), and residual signal of the solvent ( 13 C NMR). The HRMS spectra were obtained using the UHR-QqTOF maXis Impact HD (Bruker Daltonics, Billerica, MA, USA) mass spectrometer. Melting points were determined on an SMP40 apparatus. Monitoring of the reaction progress and assessment of the purity of synthesized compounds were carried out by TLC on Sorbfil PTSKh-AF-A-UF plates (eluent EtOAc-hexane, 1:3). All solvents used were dried and distilled by standard procedures. The starting chromenes 10 were prepared according to described procedures [41][42][43]. Compounds 13-15 were obtained according to the procedures analogous to those described in [44][45][46].

Synthesis of Compounds 12aa-dg
General procedure. To a mixture of the appropriate 3-nitro-2H-chromene 10 (0.5 mmol) and K 2 CO 3 (104 mg, 0.75 mmol) in EtOH (4 mL), a solution of ethyl isocyanoacetate 11 (74 mg, 0.65 mmol) in EtOH (2 mL) was added dropwise with stirring. Then, the mixture was refluxed for 0.5 h with stirring (TLC control, EtOAc-hexane (1:3)). After completion of the reaction, 1 mL of 5% hydrochloric acid was added and the reaction mixture was evaporated under reduced pressure. Then, water (25 mL) was added to the residue, the precipitate was filtered, dried at 75 • C and recrystallized from a dichloromethane-hexane (2:1) system to give products 12 as beige powders.