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Article

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

by
Ivan A. Kochnev
,
Alexey Y. Barkov
,
Nikolay S. Zimnitskiy
,
Vladislav Y. Korotaev
* and
Vyacheslav Y. Sosnovskikh
*
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(23), 8456; https://doi.org/10.3390/molecules27238456
Submission received: 11 November 2022 / Revised: 25 November 2022 / Accepted: 27 November 2022 / Published: 2 December 2022
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates)
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Abstract

:
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.

1. Introduction

The chromenopyrrole moiety is present in a wide range of natural and synthetic compounds with a number of important useful properties [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. Thus, chromeno[3,4-b]pyrrole scaffold is the basis of the skeleton of type I lamellarin alkaloids isolated from marine mollusks, tunicates and sponges [1,2] (Figure 1). Some of them have shown anticancer activity [3,4], including against multidrug-resistant cancer cell lines [5], as well as anti-HIV-1 activity at noncytotoxic concentration [6]. Synthetic chromeno[3,4-b]pyrrole derivatives 1 exhibited antibacterial activity against Staphylococcus aureus and Escherichia coli comparable to that of gentamicin [7]. Significant pharmacological activity was also found in chromeno[4,3-b]- and chromeno[3,4-c]pyrrole derivatives. For example, 1,3-diaryl-substituted pyrrolo[3,2-c]coumarin 2 is a benzodiazepine receptor ligand [8], while pyrrolo[3,4-c]coumarin-1-carboxylic acid 3 has shown high antibacterial activity against Gram-positive and Gram-negative bacteria [9] (Figure 1). Pericyclic pyrrolo[3,4-c]coumarin 4 emits blue light and may be tested as blue-light emitters with an electron-transporting ability [10] (Figure 1). In view of the above, the development of methods for the synthesis of these classes of compounds is being carried out by various scientific groups, and the search for new effective approaches to the design of chromenopyrrole scaffolds continues [11,12,13,14,15].
There are several strategies for the synthesis of the chromeno[3,4-c]pyrrole core. The most important ones are shown in Scheme 1. Wang et al. developed an efficient method for the synthesis of pyrrolo[3,4-c]coumarins 5 via FeCl3-promoted three-component reaction between 2-hydroxy-β-nitrostyrenes, dimethyl acetylenedicarboxylate and amines [16]. Fused pyrroles 6 were obtained by Khavasi et al. [17] and Alizadeh et al. [18] from 3-acylcoumarins or salicylaldehydes and β-keto esters through a two- or three-component reaction using the Van Leusen protocol. Samanta et al. reported the synthesis of 2-(2,4-dihydrochromeno[3,4-c]pyrrol-1-yl)acetates 8 from 3-(3-formyl-2H-chromen-4-yl)acrylates 7 by treatment with hydroxylamine hydrochloride, amino alcohols or sodium azide [19,20]. Recently, a metal-free method for the synthesis of chromeno[3,4-c]pyrroles 9 based on nitrative cyclization of the corresponding 1,7-diynes with tert-butyl nitrite in the presence of water has been developed [21].
There are also reports on the synthesis of 1,3-diphenylpyrrole[3,4-c]coumarin by cycloaddition of the azomethine ylide generated from benzaldehyde and phenylglycine to 4-phenylsulfinylcoumarin [22], 2-benzyl-1-(pyridin-2-ylmethyl)-2,4-dihydrochromeno[3,4-c]pyrrole from 4-bromo-2H-chromene-3-carbaldehyde, benzylamine and 2-ethynylpyridine via the palladium-catalyzed one-pot Sonogashira reaction [23], and 2-benzyl-3-methyl-1-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole from the corresponding 1,7-diyne through intramolecular [3+2] cycloaddition [24]. However, these methods are represented by single examples. Pyrrolocoumarin 4 was synthesized from 4-hydroxycoumarin, triethyl orthoformate and glycine in two steps in an overall yield of 81% [6]. A similar approach has been used to obtain 4,4-dialkyl-2-acetyl-2,4-dihydrochromeno[3,4-c]pyrroles from 2,2-dialkyl-4-oxochromane-3-carbaldehydes [25]. More recently, a copper-catalyzed [1,2]-Stevens-type asymmetric cascade cyclization/rearrangement of OTBS-substituted N-propargyl ynamides to form chromeno[3,4-c]pyrroles bearing a chiral C-4 stereocenter has been reported [26].
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 2,4-dihydrochromeno[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).

2. Results and Discussion

In order to obtain chromeno[3,4-c]pyrroles 12, we optimized conditions for the reaction of 2-trifluoromethyl-substituted chromene 10aa with ethyl isocyanoacetate 11 to form chromeno[3,4-c]pyrrole 12aa (Scheme 2, Table 1).
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 R1–R4 in nitrochromenes 10 (Scheme 3).
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 CF3 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 R3 and R4. 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).
The probable reaction mechanism includes the Michael addition of isonitrile 11 to chromene 10, intramolecular cyclization of the nitronate anion A into pyrroline B, protonation of anion B, elimination of nitrous acid in pyrroline C, and 1,3-H shift in 3H-pyrrole D to form chromeno[3,4-c]pyrrole 12 (Scheme 5) [27].
The 1H NMR spectra of chromeno[3,4-c]pyrroles 12 contained a slightly broadened singlet of the 2-NH proton in the range of 9.08–9.53 ppm. The H-3 proton manifested as a doublet, or as a doublet of doublets at 6.36–7.16 ppm, with a coupling constants 3JH3,H2 = 2.6–3.1 Hz and 4JH3,H4 = 0.7 Hz in the spectra of 2-monosubstituted chromenopyrroles 12aa–cg, and as a doublet of quartets at 7.16–7.23 ppm with coupling constants 3JH3,H2 =2.6–2.8 Hz, 5JH,F = 1.4–1.5 Hz in the spectra of 2,2-disubstituted chromenopyrroles 12da–dg. The signal of the H-9 proton was unshielded with respect to the other protons of the benzene ring and resonated at 8.10–8.89 ppm. The 19F NMR spectra of products 12aa–ag featured a doublet of the trifluoromethyl group at 82.6–83.0 ppm with 3JF,H = 6.6–6.8 Hz, while in the spectra of compounds 12da–dg this group manifested as a singlet in the range of 84.3–85.2 ppm. The 13C NMR spectra of these compounds contained quartets of the CF3 group and the C-4 atom in the range of 122.9–124.1 and 71.0–82.2 ppm with coupling constants 283.1–284.3 and 30.8–34.8 Hz, 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 N-bromosuccinimide.
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 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 CF3 group.

3. Materials and Methods

3.1. 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 (1H, 500 MHz; 19F, 471 MHz; 13C, 126 MHz) and Bruker DRX-400 (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). 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].

3.2. Synthesis of Compounds 12aa–dg

General procedure. To a mixture of the appropriate 3-nitro-2H-chromene 10 (0.5 mmol) and K2CO3 (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.
Ethyl 4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12aa). Yield 146 mg (94%), mp 109–110 °C. IR (ATR) ν 3286 (NH), 1667 (C=O). 1H NMR (500 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.1 Hz), 4.42 (q, 2H, J = 7.1 Hz), 5.57 (q, 1H, J = 6.6 Hz), 6.92 (d, 1H, J = 3.0 Hz), 7.04 (dd, 1H, J = 8.0, 1.4 Hz), 7.06 (td, 1H, J = 8.0, 1.4 Hz), 7.22 (td, 1H, J = 8.0, 1.5 Hz), 8.68 (dd, 1H, J = 8.0, 1.5 Hz), 9.29 (s, 1H); 19F NMR (471 MHz, CDCl3) δ 82.9 (d, J = 6.6 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.0, 71.0 (q, 2JCF = 34.2 Hz), 112.2, 116.9, 117.5, 117.8 (2C), 121.0, 122.5, 123.4 (q, 1JCF = 283.8 Hz), 127.6, 129.2, 151.7, 160.1. HRMS (ESI) m/z: [M + H]+ calcd for C15H13F3NO3 312.0843, found 312.0846.
Ethyl 8-methoxy-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ab). Yield 145 mg (85%), mp 120–123 °C. IR (ATR) ν 3275 (NH), 1676 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J = 7.1 Hz), 4.42 (q, 2H, J = 7.1 Hz), 5.52 (qd, 1H, J = 6.7, 0.4 Hz), 6.78 (dd, 1H, J = 8.8, 3.1 Hz), 6.91 (d, 1H, J = 3.1 Hz), 6.96 (d, 1H, J = 8.8 Hz), 8.37 (d, 1H, J = 3.1 Hz), 9.29 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 83.0 (d, J = 6.7 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 14.5, 55.7, 61.0, 70.9 (q, 2JCF = 33.9 Hz), 112.1, 112.5, 115.4, 117.4, 117.5, 117.7, 118.3, 121.4, 123.4 (d, 1JCF = 283.6 Hz), 145.7, 154.8, 160.0. HRMS (ESI) m/z: [M + H]+ calcd for C16H15F3NO4 342.0948, found 342.0953.
Ethyl 6-ethoxy-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ac). Yield 147 mg (83%), mp 115–117 °C. IR (ATR) ν 3393, 1698, 1567, 1470, 1455, 1414, 1351, 1311. 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J = 7.1 Hz), 1.44 (t, 3H, J = 7.0 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.41 (q, 2H, J = 7.1 Hz), 5.66 (q, 1H, J = 6.8 Hz), 6.90 (dd, 1H, J = 8.0, 1.4 Hz), 6.93 (d, 1H, J = 3.1 Hz), 6.98 (t, 1H, J = 8.0 Hz), 8.30 (dd, 1H, J = 8.0, 1.5 Hz), 9.33 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 82.9 (d, J = 6.8 Hz); 13C NMR (126 MHz, CDCl3) δ 14.4, 14.9, 61.0, 65.4, 70.9 (q, 2JCF = 34.3 Hz), 112.3, 115.0, 117.6, 117.9, 118.8, 120.1, 121.0, 121.9, 123.4 (q, 1JCF = 284.3 Hz), 141.8, 147.8, 160.1. HRMS (ESI) m/z: [M + H]+ calcd for C17H17F3NO4 356.1105, found 356.1111.
Ethyl 8-chloro-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ad). Yield 154 mg (89%), mp 169–170 °C. IR (ATR) ν 3279 (NH), 1667 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.44 (q, 2H, J = 7.1 Hz), 5.57 (q, 1H, J = 6.6 Hz), 6.94 (d, 1H, J = 3.1 Hz), 6.97 (d, 1H, J = 8.7 Hz), 7.16 (dd, 1H, J = 8.7, 2.6 Hz), 8.70 (d, 1H, J = 2.6 Hz), 9.47 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 82.8 (d, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ 14.3, 61.4, 71.0 (q, 2JCF = 34.5 Hz), 112.0, 117.9, 118.1 (2C), 119.1, 119.5, 123.2 (q, 1JCF = 283.9 Hz), 127.3, 127.4, 128.8, 150.2, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C15H12ClF3NO3 346.0454, found 346.0455.
Ethyl 8-bromo-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ae). Yield 176 mg (90%), mp 177–178 °C. IR (ATR) ν 3281 (NH), 1666 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.49 (t, 3H, J = 7.1 Hz), 4.45 (q, 2H, J = 7.1 Hz), 5.57 (q, 1H, J = 6.6 Hz), 6.92 (d, 1H, J = 8.7 Hz), 6.94 (d, 1H, J = 3.1 Hz), 7.30 (dd, 1H, J = 8.6, 2.4 Hz), 8.84 (d, 1H, J = 2.5 Hz), 9.39 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 82.8 (d, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 71.0 (q, 2JCF = 34.0 Hz), 112.0, 114.9, 117.9, 118.1, 118.6, 119.3, 119.6, 123.2 (q, 1JCF = 283.7 Hz), 130.2, 131.7, 150.7, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C15H12BrF3NO3 389.9947, found 389.9948.
Ethyl 6,8-dichloro-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12af). Yield 167 mg (88%), mp 187–190 °C. IR (ATR): ν 3278 (NH), 1671 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.43 (dq, 1H, J = 10.3, 7.1 Hz), 4.47 (dq, 1H, J = 10.3, 7.1 Hz), 5.68 (q, 1H, J = 6.6 Hz), 6.97 (d, 1H, J = 3.1 Hz), 7.29 (d, 1H, J = 2.5 Hz), 8.68 (d, 1H, J = 2.5 Hz), 9.44 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 82.6 (d, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 71.4 (q, 2JCF = 34.8 Hz), 111.9, 118.1, 118.3, 119.0, 120.3, 122.8, 122.9 (q, 1JCF = 283.6 Hz), 125.9, 127.3, 129.1, 146.1, 159.9. HRMS (ESI) m/z: [M + H]+ calcd for C15H11Cl2F3NO3 380.0063, found 380.0059.
Ethyl 6,8-dibromo-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ag). Yield 213 mg (91%), mp 187–188 °C. IR (ATR): ν 3278 (NH), 1668 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.42 (dq, 1H, J = 11.0, 7.1 Hz), 4.46 (dq, 1H, J = 11.0, 7.1 Hz), 5.68 (q, 1H, J = 6.5 Hz), 6.97 (d, 1H, J = 3.1 Hz), 7.58 (d, 1H, J = 2.3 Hz), 8.84 (d, 1H, J = 2.3 Hz), 9.46 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 82.6 (d, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.6, 71.4 (q, 2JCF = 34.7 Hz), 111.8, 112.0, 114.8, 118.1, 118.3, 118.8, 120.8, 122.9 (d, 1JCF = 284.1 Hz), 129.4, 134.6, 147.5, 159.9. HRMS (ESI) m/z: [M + H]+ calcd for C15H11Br2F3NO3 467.9051, found 467.9051.
Ethyl 4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ba). Yield 136 mg (85%), mp 91–93 °C. IR (ATR) ν 3298 (NH), 1660 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.40 (t, 3H, J = 7.1 Hz,), 4.38 (dq, 1H, J = 10.9, 7.1 Hz), 4.44 (dq, 1H, J = 10.9, 7.1 Hz), 6.05 (s, 1H), 6.36 (d, 1H, J = 2.9 Hz), 7.01 (dd, 1H, J = 8.0, 1.1 Hz), 7.04 (td, 1H, J = 8.0, 1.1 Hz), 7.18 (td, 1H, J = 8.0, 1.5 Hz), 7.33–7.41 (m, 3H), 7.44–7.49 (m, 2H), 8.59 (dd, 1H, J = 8.0, 1.5 Hz), 9.18 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.5, 60.7, 76.0, 117.1, 117.6, 119.8, 121.5, 121.8, 123.4, 125.6, 127.6 (2C), 127.6, 128.5 (2C), 128.5, 128.8, 139.9, 153.9, 160.7. HRMS (ESI) m/z: [M + H]+ calcd for C20H18NO3 320.1281, found 320.1286.
Ethyl 8-methoxy-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12bb). Yield 145 mg (83%), mp 140–142 °C. IR (ATR) ν 3281 (NH), 1673 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J = 7.1 Hz), 3.86 (s, 3H), 4.40 (dq, 1H, J = 10.8, 7.1 Hz), 4.43 (dq, 1H, J = 10.8, 7.1 Hz), 6.01 (s, 1H), 6.38 (dd, 1H, J = 2.9, 0.7 Hz), 6.77 (dd, 1H, J = 8.8, 3.1 Hz), 6.94 (d, 1H, J = 8.8 Hz), 7.34–7.42 (m, 3H), 7.45–7.50 (m, 2H), 8.28 (d, 1H, J = 3.1 Hz), 9.08 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.6, 55.8, 60.7, 75.9, 112.1, 115.0, 117.0, 117.1, 118.0, 120.3, 121.9, 123.6, 127.6, 128.4 (2C), 128.5 (2C), 139.9, 147.9, 154.4, 160.5. HRMS (ESI) m/z: [M + H]+ calcd for C21H20NO4 350.1387, found 350.1392.
Ethyl 6-ethoxy-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12bc). Yield 156 mg (86%), mp 85–87 °C. IR (ATR) ν 3323 (NH), 1701 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.37 (t, 3H, J = 7.0 Hz), 1.40 (t, 3H, J = 7.1 Hz), 4.06 (dq, 1H, J = 9.8, 7.0 Hz), 4.09 (dq, 1H, J = 9.8, 7.0 Hz), 4.37 (dq, 1H, J = 11.0, 7.1 Hz), 4.40 (dq, 1H, J = 11.0, 7.1 Hz), 6.16 (s, 1H), 6.49 (dd, 1H, J = 2.8 Hz), 6.85 (dd, 1H, J = 8.0, 1.5 Hz), 6.95 (t, 1H, J = 8.0 Hz), 7.28–7.36 (m, 3H), 7.43–7.48 (m, 2H), 8.20 (dd, 1H, J = 8.0, 1.5 Hz), 9.19 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 14.9, 60.7, 65.1, 75.4, 114.5, 117.0, 117.2, 120.2, 120.9, 121.1, 121.4, 123.0, 127.3 (2C), 128.1, 128.3 (2C), 140.0, 143.7, 148.3, 160.6. HRMS (ESI) m/z: [M + H]+ calcd for C22H22NO4 364.1543, found 364.1550.
Ethyl 8-chloro-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12bd). Yield 154 mg (87%), mp 145–146 °C. IR (ATR) ν 3303 (NH), 1668 (C=O). 1H NMR (500 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.9, 7.1 Hz), 4.44 (dq, 1H, J = 10.9, 7.1 Hz), 6.06 (s, 1H), 6.42 (d, 1H, J = 2.6 Hz), 6.93 (d, 1H, J = 8.6 Hz), 7.12 (dd, 1H, J = 8.6, 2.6 Hz), 7.35–7.41 (m, 3H), 7.43–7.46 (m, 2H), 8.60 (d, 1H, J = 2.6 Hz), 9.20 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.2, 76.1, 117.3, 117.5, 118.8, 120.1, 121.1, 123.1, 126.7, 127.3, 127.6 (2C), 128.4, 128.6 (2C), 128.7, 139.5, 152.4, 160.7. HRMS (ESI) m/z: [M + H]+ calcd for C20H17ClNO3 354.0891 found 354.0895.
Ethyl 8-bromo-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12be). Yield 177 mg (89%), mp 141–143 °C. IR (ATR) ν 3298 (NH), 1665 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.48 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.8, 7.1 Hz), 4.47 (dq, 1H, J = 10.8, 7.1 Hz), 6.06 (s, 1H), 6.42 (d, 1H, J = 2.9 Hz), 6.88 (d, 1H, J = 8.6 Hz), 7.31–7.42 (m, 3H), 7.42–7.48 (m, 2H), 8.73 (d, 1H, J = 2.5 Hz), 9.21 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.2, 76.1, 114.2, 117.3, 117.5, 119.3, 119.8, 121.7, 123.0, 127.6 (2C), 128.6 (2C), 128.7, 130.1, 131.3, 139.5, 152.9, 160.7. HRMS (ESI) m/z: [M + H]+ calcd for C20H17BrNO3 398.0386, found 398.0394.
Ethyl 6,8-dichloro-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12bf). Yield 163 mg (84%), mp 138–140 °C. IR (ATR) ν 3317 (NH), 1662 (C=O). 1H NMR (500 MHz, CDCl3) δ 1.46 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.8, 7.1 Hz), 4.44 (dq, 1H, J = 10.8, 7.1 Hz), 6.22 (s, 1H), 6.57 (d, 1H, J = 2.9 Hz), 7.24 (d, 1H, J = 2.5 Hz), 7.34–7.39 (m, 3H), 7.41–7.45 (m, 2H), 8.53 (d, 1H, J = 2.5 Hz), 9.30 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.3, 76.1, 117.3, 117.8, 119.4, 122.3, 122.5, 123.4, 125.8, 126.3, 127.3 (2C), 128.5 (2C), 128.6, 128.6, 139.0, 148.1, 160.5. HRMS (ESI) m/z: [M + H]+ calcd for C20H16Cl2NO3 388.0502, found 388.0505.
Ethyl 6,8-dibromo-4-phenyl-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12bg). Yield 205 mg (86%), mp 185–187 °C. IR (ATR) ν 3265 (NH), 1667 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.42 (dq, 1H, J = 10.8, 7.1 Hz), 4.44 (dq, 1H, J = 10.8, 7.1 Hz), 6.24 (s, 1H), 6.58 (d, 1H, J = 2.9 Hz), 7.30–7.40 (m, 3H), 7.40–7.46 (m, 2H), 7.53 (d, 1H, J = 2.5 Hz), 8.70 (d, 1H, J = 2.5 Hz), 9.26 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.3, 76.0, 112.6, 113.9, 117.2, 117.9, 119.2, 122.4, 122.7, 127.2 (2C), 128.5 (2C), 128.6, 129.3, 134.0, 139.0, 149.5, 160.4. HRMS (ESI) m/z: [M + H]+ calcd for C20H16Br2NO3 475.9491, found 475.9496.
Ethyl 4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ca). Yield 144 mg (80%), mp 135–137 °C. IR (ATR) ν 3278 (NH), 1644 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.1 Hz), 4.43 (q, 2H, J = 7.1 Hz), 5.76 (s, 1H), 7.04 (dd, 1H, J = 8.0, 1.3 Hz), 7.06 (td, 1H, J = 8.0, 1.3 Hz), 7.12 (d, 1H, J = 3.1 Hz), 7.23 (td, 1H, J = 8.0, 1.6 Hz), 8.72 (dd, 1H, J = 8.0, 1.6 Hz), 9.37 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.5, 61.0, 81.9, 101.5, 113.8, 116.8, 116.9, 117.9, 120.4, 121.7, 122.1, 127.4, 129.3, 152.0, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C15H13Cl3NO3 359.9956, found 359.9960.
Ethyl 8-methoxy-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12cb). Yield 152 mg (78%), mp 155–157 °C. IR (ATR) ν 3301 (NH), 1683 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.1 Hz), 3.85 (s, 3H), 4.43 (q, 2H, J = 7.1 Hz), 5.70 (s, 1H), 6.79 (dd, 1H, J = 8.8, 3.1 Hz), 6.99 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J = 3.1 Hz), 8.41 (d, 1H, J = 3.1 Hz), 9.37 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.5, 55.7, 60.9, 81.9, 101.5, 111.8, 114.0, 115.5, 116.9, 117.3, 118.3, 120.4, 122.1, 146.0, 154.5, 160.1. HRMS (ESI) m/z: [M + H]+ calcd for C16H15Cl3NO4 390.0062, found 390.0067.
Ethyl 6-ethoxy-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12cc). Yield 152 mg (75%), mp 135–137 °C. IR (ATR) ν 3305 (NH), 1682 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J = 7.1 Hz), 1.46 (t, 3H, J = 7.0 Hz), 4.11 (dq, 1H, J = 9.7, 7.1 Hz), 4.18 (dq, 1H, J = 9.7, 7.1 Hz), 4.42 (q, 2H, J = 7.1 Hz), 5.86 (s, 1H), 6.90 (dd, 1H, J = 8.0, 1.6 Hz), 6.97 (t, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 3.1 Hz), 8.34 (dd, 1H, J = 8.0, 1.6 Hz), 9.38 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 15.0, 60.9, 65.4, 81.9, 101.4, 113.8, 114.8, 117.0, 118.9, 119.7, 120.4, 121.5, 121.7, 142.1, 147.7, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C17H17Cl3NO4 404.021, found 404.0219.
Ethyl 8-chloro-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12cd) Yield 156 mg (79%), mp 195–197 °C. IR (ATR) ν 3278 (NH), 1664 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.48 (t, 3H, J = 7.1 Hz), 4.40 (dq, 1H, J = 10.8, 7.1 Hz), 4.47 (dq, 1H, J = 10.8, 7.1 Hz), 5.75 (s, 1H), 7.00 (d, 1H, J = 8.6 Hz), 7.14 (d, 1H, J = 3.0 Hz), 7.17 (dd, 1H, J = 8.6, 2.6 Hz), 8.75 (d, 1H, J = 2.6 Hz), 9.44 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.4, 82.0, 101.3, 113.7, 117.3, 118.0, 119.2, 120.3, 120.5, 127.1, 127.1, 128.9, 150.5, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C15H12Cl4NO3 393.9566, found 393.9569.
Ethyl 8-bromo-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12ce). Yield 176 mg (80%), mp 180–181 °C. IR (ATR) ν 3277 (NH), 1664 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.49 (t, 3H, J = 7.1 Hz), 4.44 (dq, 1H, J = 10.8, 7.1 Hz), 4.47 (dq, 1H, J = 10.8, 7.1 Hz), 5.75 (s, 1H), 6.95 (d, 1H, J = 8.6 Hz), 7.14 (d, 1H, J = 3.1 Hz), 7.31 (dd, 1H, J = 8.6, 2.4 Hz), 8.87 (d, 1H, J = 2.4 Hz), 9.47 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 81.9, 101.3, 113.6, 114.5, 117.3, 118.5, 119.8, 120.0, 120.6, 129.9, 131.8, 151.0, 160.3. HRMS (ESI) m/z: [M + H]+ calcd for C15H12BrCl3NO3 437.9061, found 437.9067.
Ethyl 6,8-dichloro-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12cf). Yield 174 mg (81%), mp 143–144 °C. IR (ATR) ν 3282 (NH), 1668 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.43 (dq, 1H, J = 10.8, 7.1 Hz), 4.46 (dq, 1H, J = 10.8, 7.1 Hz), 5.86 (s, 1H), 7.16 (d, 1H, J = 3.0 Hz), 7.29 (d, 1H, J = 2.5 Hz), 8.71 (d, 1H, J = 2.5 Hz), 9.53 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 82.3, 100.8, 113.7, 117.6, 119.7, 120.5, 120.6, 122.7, 125.6, 126.9, 129.1, 146.5, 160.0. HRMS (ESI) m/z: [M + H]+ calcd for C15H11Cl5NO3 427.9176, found 427.9174.
Ethyl 6,8-dibromo-4-(trichloromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12cg). Yield 207 mg (80%), mp 175–178 °C. IR (ATR) ν 3284 (NH), 1664 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.48 (t, 3H, J = 7.1 Hz), 4.43 (dq, 1H, J = 10.8, 7.1 Hz), 4.47 (dq, 1H, J = 10.8, 7.1 Hz), 5.87 (s, 1H), 7.16 (d, 1H, J = 3.1 Hz), 7.59 (d, 1H, J = 2.3 Hz), 8.89 (d, 1H, J = 2.3 Hz), 9.52 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 82.5, 100.7, 111.6, 113.7, 114.5, 117.6, 119.6, 120.5, 120.9, 129.1, 134.6, 148.0, 160.0. HRMS (ESI) m/z: [M + H]+ calcd for C15H11Br2Cl3NO3 515.8166, found 515.8174.
Ethyl 4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12da). Yield 141 mg (73%), mp 100–102 °C. IR (ATR) ν 3366 (NH), 1707 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J = 7.1 Hz), 4.40 (dq, 1H, J = 10.8, 7.1 Hz), 4.43 (dq, 1H, J = 10.8, 7.1 Hz), 7.00 (ddd, 1H, J = 8.0, 7.6, 1.9 Hz), 7.14–7.22 (m, 3H), 7.24–7.31 (m, 3H), 7.48–7.54 (m, 2H), 8.53 (dd, 1H, J = 7.9, 1.2 Hz), 9.37 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 85.2 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.0, 80.7 (q, J = 30.8 Hz), 117.0, 117.5, 117.9, 118.1, 118.7, 121.0, 122.5, 124.1 (q, 1JCF = 283.7 Hz), 127.7, 128.0 (2C), 128.1 (2C), 129.0, 129.2, 135.4, 150.7, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C21H17F3NO3 388.1155, found 388.1153.
Ethyl 8-methoxy-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12db). Yield 136 mg (65%), mp 105–107 °C. IR (ATR) ν 3346 (NH), 1714 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.41 (t, 3H, J = 7.1 Hz), 3.78 (s, 3H), 4.39 (dq, 1H, J = 10.9, 7.1 Hz), 4.42 (dq, 1H, J = 10.9, 7.1 Hz), 6.76 (dd, 1H, J = 8.8, 3.1 Hz), 7.08 (d, 1H, J = 8.8 Hz), 7.16 (dq, 1H, J = 2.6, 1.4 Hz), 7.24–7.30 (m, 3H), 7.46–7.52 (m, 2H), 8.21 (d, 1H, J = 3.1 Hz), 9.45 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.5, 55.6, 61.0, 80.6 (q, 2JCF = 30.8 Hz), 112.1, 115.4, 117.2, 117.5, 117.8, 118.7, 119.2, 121.3, 124.1 (q, 1JCF = 283.6 Hz), 127.9 (2C), 128.2 (2C), 129.0, 135.3, 144.6, 154.8, 160.1. HRMS (ESI) m/z: [M + H]+ calcd for C22H19F3NO4 418.1261, found 418.1259.
Ethyl 6-ethoxy-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12dc). Yield 136 mg (63%), mp 137–138 °C. IR (ATR) ν 3291 (NH), 1668 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.41 (t, 3H, J = 7.1 Hz), 1.53 (t, 3H, J = 7.0 Hz), 4.13 (dq, 1H, J = 9.5, 7.0 Hz), 4.23 (dq, 1H, J = 9.5, 7.0 Hz), 4.38 (dq, 1H, J = 11.0, 7.1 Hz), 4.42 (dq, 1H, J = 11.0, 7.1 Hz), 6.83 (dd, 1H, J = 8.0, 1.4 Hz), 6.91 (t, 1H, J = 8.0 Hz), 7.21 (dq, 1H, J = 2.8, 1.4 Hz), 7.23–7.28 (m, 3H), 7.56–7.63 (m, 2H), 8.10 (dd, 1H, J = 8.0, 1.4 Hz), 9.39 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 15.0, 60.9, 65.0, 81.2 (q, 2JCF = 31.1 Hz), 114.3, 117.5, 117.6, 117.7, 119.8, 120.1, 121.1, 122.2, 124.1 (q, 1JCF = 283.1 Hz), 127.9 (2C), 128.0 (2C), 129.0, 135.0, 140.6, 148.5, 160.2. HRMS (ESI) m/z: [M + H]+ calcd for C23H21F3NO4 432.1417, found 432.1421.
Ethyl 8-chloro-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12dd). Yield 160 mg (76%), mp 158–160 °C. IR (ATR) ν 3457 (NH), 1720 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.9, 7.1 Hz), 4.46 (dq, 1H, J = 10.9, 7.1 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.19 (dq, 1H, J = 2.6, 1.4 Hz), 7.27–7.31 (m, 4H), 7.43–7.49 (m, 2H), 8.68 (d, 1H, J = 2.4 Hz), 9.50 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3. (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 80.9 (q, 2JCF = 31.2 Hz), 115.1, 116.9, 118.0, 118.1, 119.3, 119.8, 120.6, 123.9 (q, 1JCF = 283.6 Hz), 128.1 (4C), 129.3, 130.2, 131.7, 134.9, 149.8, 160.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H16ClF3NO3 411.0765, found 422.0760.
Ethyl 8-bromo-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12de). Yield 168 mg (72%), mp 153–155 °C. IR (ATR) ν 3283 (NH), 1670 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.9, 7.1 Hz), 4.46 (dq, 1H, J = 10.9, 7.1 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.19 (dq, 1H, J = 2.8, 1.5 Hz), 7.27–7.31 (m, 4H), 7.43–7.50 (m, 2H), 8.68 (d, 1H, J = 2.4 Hz), 9.47 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 80.9 (q, 2JCF = 31.2 Hz), 115.1, 116.9, 118.0, 118.1, 119.3, 119.8, 120.6, 123.9 (q, J = 283.6 Hz), 128.1 (4C), 129.2, 130.2, 131.7, 134.9, 149.8, 160.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H16BrF3NO3 466.0260, found 466.0262.
Ethyl 6,8-dichloro-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (12df). Yield 155 mg (68%), mp 172–173 °C. IR (ATR) ν 3291 (NH), 1687 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.45 (t, 3H, J = 7.1 Hz), 4.40 (dq, 1H, J = 10.9, 7.1 Hz), 4.46 (dq, 1H, J = 10.9, 7.1 Hz), 7.23 (dq, 1H, J = 2.8, 1.5 Hz), 7.25 (d, 1H, J = 2.5 Hz), 7.28–7.34 (m, 3H), 7.51–7.57 (m, 2H), 8.49 (d, 1H, J = 2.5 Hz), 9.50 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.3, 61.5, 82.0 (q, 2JCF = 31.6 Hz), 117.1, 117.9, 118.4, 119.0, 121.4, 123.7 (q, 1JCF = 283.6 Hz), 123.8, 126.0, 127.5, 128.0 (2C), 128.2 (2C), 129.0, 129.5, 134.2, 145.3, 159.9. HRMS (ESI) m/z: [M + H]+ calcd for C21H15Cl2F3NO3 456.0376, found 456.0374.
Ethyl 6,8-dibromo-4-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (10dg). Yield 191 mg (70%), mp 181–183 °C. IR (ATR) ν 3246 (NH), 1683 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.46 (t, 3H, J = 7.1 Hz), 4.41 (dq, 1H, J = 10.8, 7.1 Hz), 4.46 (dq, 1H, J = 10.8, 7.1 Hz), 7.22 (dq, 1H, J = 2.8, 1.5 Hz), 7.28–7.35 (m, 3H), 7.52–7.60 (m, 3H), 8.67 (d, J = 2.3 Hz, 1H), 9.52 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 84.3 (s, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.5, 82.2 (q, 2JCF = 31.7 Hz), 112.8, 115.0, 117.0, 117.9, 118.4, 118.9, 121.8, 123.7 (q, 1JCF = 283.6 Hz), 128.1 (2C), 128.2 (2C), 129.4, 129.5, 134.2, 134.5, 146.8, 160.0. HRMS (ESI) m/z: [M + H]+ calcd for C21H15Br2F3NO3 543.9365, found 543.9365.

3.3. Synthesis of Compounds 13–15

Ethyl 2-methyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (13). A mixture of 2,4-dihydrochromeno[3,4-c]pyrrole 12aa (156 mg, 0.5 mmol), iodomethane (106 mg, 1.5 mmol) and K2CO3 (138 mg, 1.0 mmol) in acetone (3 mL) was heated at 40 °C for 18 h with stirring. Upon completion of the reaction, the mixture was poured into ice water (25 mL) and the precipitate was filtered and washed with water (10 × 5 mL). Yield 124 mg (76%), white powder, mp 68–70 °C. IR (ATR) ν 1690 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.1 Hz), 3.91 (s, 3H), 4.42 (q, 2H, J = 7.1 Hz), 5.47 (q, 1H, J = 6.7 Hz), 6.76 (s, 1H), 6.99–7.06 (m, 2H), 7.15–7.21 (ddd, 1H, J = 8.1, 7.8, 1.4 Hz), 8.28 (dd, 1H, J = 7.8, 1.4 Hz); 19F NMR (376 MHz, CDCl3) δ 83.2 (d, J = 6.7 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 14.2, 38.5, 60.8, 70.9 (q, 2JCF = 34.0 Hz), 110.2, 117.1, 118.6, 118.7, 121.7, 122.2, 123.4 (q, 1JCF = 283.6 Hz), 124.2, 127.0, 128.6, 151.8, 161.4. HRMS (ESI) m/z: [M + H]+ calcd for C16H15F3NO3 326.0999, found 326.1004.
Ethyl 2-phenyl-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (14). A mixture of chromene 10aa (138 mg, 0,5 mmol), phenylboronic acid (122 mg, 1.0 mmol), Et3N (139 μL, 101 mg 1.0 mmol) and Cu(OAc)2 (91 mg, 0.5 mmol) in 1,2-dichloroethane (3 mL) was refluxed with stirring for 20 h. 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)). Yield 87 mg (45%), white powder, mp 115–116 °C. IR (ATR) ν 1682 (C=O). 1H NMR (400 MHz, CDCl3) δ 0.92 (t, 3H, J = 7.1 Hz), 4.08 (q, 2H, J = 7.1 Hz), 5.57 (qd, 1H, J = 6.6, 0.5 Hz), 6.92 (s, 1H), 7.03–7.09 (m, 2H), 7.22 (ddd, 1H, J = 8.1, 7.5, 1.6 Hz), 7.29–7.34 (m, 2H), 7.39–7.48 (m, 3H), 8.39–8.43 (m, 1H); 19F NMR (376 MHz, CDCl3) δ 83.3 (d, J = 6.6 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 13.5, 60.7, 70.9 (q, 2JCF = 34.1 Hz), 111.2, 117.1, 118.0, 119.6, 122.0, 122.5, 123.4 (q, 1JCF = 283.6 Hz), 123.5, 125.6 (2C), 126.8, 128.0, 129.0 (2C), 129.1, 141.0, 151.7, 161.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H17F3NO3 388.1155, found 388.1160.
Ethyl 3-bromo-4-(trifluoromethyl)-2,4-dihydrochromeno[3,4-c]pyrrole-1-carboxylate (15). To a solution of pyrrole 3aa (0.5 mmol) cooled to 0–5 °C in CHCl3 (5 mL), NBS (98 mg, 0.55 mmol) was added portionwise within 25 min with stirring. Then, the reaction mixture was stirred overnight and the precipitate was filtered and washed with CHCl3 (1 mL). The solution was evaporated under reduced pressure to complete dryness, washed with water (3 × 5 mL), and recrystallized from 70% ethanol. Yield 107 mg (55%), white powder, mp 165–167 °C. IR (ATR) ν 3225 (NH), 1665 (C=O). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, 3H, J = 7.1 Hz), 4.42 (dq, 1H, J = 11.6, 7.1 Hz), 4.45 (dq, 1H, J = 11.6, 7.1 Hz), 5.44 (q, 1H, J = 6.7 Hz), 7.03–7.09 (m, 2H), 7.24 (td, 1H, J = 7.8, 1.5 Hz), 8.62 (dd, 1H, J = 7.8, 1.5 Hz), 9.42 (s, 1H); 19F NMR (376 MHz, CDCl3) δ 83. 8 (d, J = 6.7 Hz, CF3); 13C NMR (126 MHz, CDCl3) δ 14.4, 61.3, 69.8 (q, 2JCF = 34.1 Hz), 102.4, 112.1, 117.0, 117.1, 118.5, 122.6 (2C), 123.5 (q, 1JCF = 286.7 Hz), 127.8, 129.8, 151.8, 159.3. HRMS (ESI) m/z: [M + H]+ calcd for C15H12BrF3NO3 389.9947, found 389.9955.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238456/s1, S2–S32: NMR spectra of compounds 12–15.

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., 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 are 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).

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 08456 g001 550
Figure 1. Representative natural and synthetic chromenopyrroles.
Figure 1. Representative natural and synthetic chromenopyrroles.
Molecules 27 08456 g001
Molecules 27 08456 sch001 550
Scheme 1. Strategies for the synthesis of the chromeno[3,4-c]pyrroles framework.
Scheme 1. Strategies for the synthesis of the chromeno[3,4-c]pyrroles framework.
Molecules 27 08456 sch001
Molecules 27 08456 sch002 550
Scheme 2. Reaction of 3-nitro-2H-chromenes 10aa with ethyl isocyanoacetate 11.
Scheme 2. Reaction of 3-nitro-2H-chromenes 10aa with ethyl isocyanoacetate 11.
Molecules 27 08456 sch002
Molecules 27 08456 sch003 550
Scheme 3. Synthesis of 2,4-dihydrochromeno[3,4-c]pyrroles 12.
Scheme 3. Synthesis of 2,4-dihydrochromeno[3,4-c]pyrroles 12.
Molecules 27 08456 sch003
Molecules 27 08456 sch004 550
Scheme 4. Gram-scale synthesis of 2,4-dihydrochromeno[3,4-c]pyrrole 12aa.
Scheme 4. Gram-scale synthesis of 2,4-dihydrochromeno[3,4-c]pyrrole 12aa.
Molecules 27 08456 sch004
Molecules 27 08456 sch005 550
Scheme 5. Probable mechanism for the reaction leading to chromeno[3,4-c]pyrroles 12.
Scheme 5. Probable mechanism for the reaction leading to chromeno[3,4-c]pyrroles 12.
Molecules 27 08456 sch005
Molecules 27 08456 sch006 550
Scheme 6. Some transformations of the pyrrole ring of compound 12aa.
Scheme 6. Some transformations of the pyrrole ring of compound 12aa.
Molecules 27 08456 sch006
Table
Table 1. Condition optimization for the reaction of 10aa with 11 a.
Table 1. Condition optimization for the reaction of 10aa with 11 a.
EntryBaseEquiv.SolventYield b, %
Method AMethod B
1DBU1.1THF8671
2DABCO1.1THF5844
3K2CO31.1THF6167
4DBU1.1MeCN5785
5DABCO1.1MeCN6572
6K2CO31.1MeCN4460
7DBU1.1EtOH7285
8DABCO1.1EtOH8983
9K2CO31.1EtOH8586
10K2CO31.5EtOH8994
11K2CO32.0EtOH9594
12K2CO33.0EtOH9395
a A solution of 11 (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.
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Kochnev, I.A.; Barkov, A.Y.; Zimnitskiy, N.S.; Korotaev, V.Y.; Sosnovskikh, V.Y. Green and Efficient Construction of Chromeno[3,4-c]pyrrole Core via Barton–Zard Reaction from 3-Nitro-2H-chromenes and Ethyl Isocyanoacetate. Molecules 2022, 27, 8456. https://doi.org/10.3390/molecules27238456

AMA Style

Kochnev IA, Barkov AY, Zimnitskiy NS, Korotaev VY, Sosnovskikh VY. Green and Efficient Construction of Chromeno[3,4-c]pyrrole Core via Barton–Zard Reaction from 3-Nitro-2H-chromenes and Ethyl Isocyanoacetate. Molecules. 2022; 27(23):8456. https://doi.org/10.3390/molecules27238456

Chicago/Turabian Style

Kochnev, Ivan A., Alexey Y. Barkov, Nikolay S. Zimnitskiy, Vladislav Y. Korotaev, and Vyacheslav Y. Sosnovskikh. 2022. "Green and Efficient Construction of Chromeno[3,4-c]pyrrole Core via Barton–Zard Reaction from 3-Nitro-2H-chromenes and Ethyl Isocyanoacetate" Molecules 27, no. 23: 8456. https://doi.org/10.3390/molecules27238456

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