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DOI: 10.1055/a-2532-6077
One-Pot Pyridinium-Ylide-Assisted Tandem Reaction for the Diastereoselective Synthesis of trans-2,3-Dihydrofuran–Chromone Conjugates
S.P.D. thanks the University Grant Commission (UGC), for his fellowship (SRF). We also are grateful to CAS-V (UGC), Department of Chemistry, University of Calcutta, for funding as a departmental project.
Abstract
An efficient procedure for the preparation of novel fused 2,3-dihydrofuran–chromone conjugates was developed with the assistance of a pyridinium ylide generated in situ. Pyridine, a 3-formylchromone, a cyclohexane-1,3-dione, and a phenacyl bromide, with triethylamine acting as a catalyst, underwent a sequential, one-pot, two-step, tandem reaction that proceeded smoothly in aqueous media. 1H and 13C NMR spectroscopy and single-crystal analysis confirmed the diastereoselective synthesis of trans-2,3-dihydrofurans.
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Key words
metal-catalyst-free reaction - aqueous medium - dihydrofuran–chromone conjugates - gram-scale preparation - pyridinium ylides - one-pot reactionNumerous plant species contain significant quantities of heterocyclic compounds, which constitute a broad class of natural products.[1] Heterocyclic systems with five- or six-membered rings containing a heteroatom such as oxygen or nitrogen are of great interest because of their potential applications in biology and medicine.[2] Simple natural chromones and their derivatives are important oxygen-containing heterocycles that are essential for the synthesis and discovery of novel compounds with pharmacological and biological activities.[3] Numerous activities are noted in the biological profiles of molecules containing chromones, such as antiinflammatory,[4] antifungal, antibacterial,[5] antiviral,[6] antioxidant,[7] antitumor,[8] antianaphylactic,[9] [10] antiplatelet,[11] anticoagulant,[12] antiulcer, and biocidal[13] characteristics. They have also been found to be potential pigments, photoactive materials,[14] protein tyrosine phosphatases inhibitors, topoisomerases inhibitors, leukotriene receptor antagonists, phosphodiesterase inhibitors,[15] [16] and immune stimulators,[17] among other applications. Additionally, it is well known that chromones selectively block a number of processes, including the COX-1 and COX-2 cyclooxygenase and 5-lipoxygenase enzymes, NO generation, and protein kinase C and O2 – production in neutrophils triggered by phorbol myristate acetate or N-formylmethionyl-leucyl-phenylalanine.[15] [18] [19]
2,3-Dihydrofurans are common structural motifs found in a wide variety of natural products, biologically active substances, and drugs with notable biological effects, including antiinflammatory properties,[20] antifungal properties against Candida albicans,[21] tumor inhibition,[22] and antiatherosclerosis properties.[23] Also, dihydrofuran subunits form the basis of a number of bioactive compounds, including morphine (the most powerful analgesic), the antidepressant citalopram; and timber-derived (+)-conocarpan, which has antitrypanosomal, antifungal, antibacterial, and photoprotective properties (Figure [1]).[24] [25] Moreover, the synthetic chemistry community has shown an extensive interest in 2,3-dihydrofurans as functionalized furans that are important synthetic precursors and building blocks in organic synthesis.[26]
Because of their ease of use, catalyst-free processes, accessibility of starting materials, and tolerance toward functional groups, multicomponent reactions (MCRs) hold promise for addressing issues associated with conventional synthetic methodologies, including lengthy reaction times, alterations of reaction conditions, requirements for additional reagents, the isolation of intermediates, challenging purification processes, and sequential procedures.[27] [28] [29] [30] [31] The implementation of MCRs is a useful tactic in total synthesis, drug discovery, and bioconjugation, because such reactions permit various transformations of three or more substrates to yield a single product in a one-pot reaction.[32–35]
In 2006, Chuang and Tsai reported the synthesis of 2,3-dihydrofurans from readily available enones and pyridinium salts (Scheme [1a]).[36] In 2017, Ullrich and co-workers developed a diastereo- and enantioselective synthesis of 2,3-dihydrofurans in the presence of chiral ammonium ylides (Scheme [1b]).[37] Inspired by these studies, we recently synthesized 6′,7′-dihydro-2H,2′H-spiro[acenaphthylene-1,3′-benzofuran]-2,4′(5′H)-dione scaffolds by using a pyridinium ylide as a key intermediate (Scheme [1c]).[38]
In 2022, Nousheen et al. synthesized 2,3-dihydrofuran–chromone conjugates in the presence of l-proline as a catalyst, with yields of 68–75%.[39] In our work (Scheme [1d]), we used triethylamine as a catalyst, resulting in an increase in the yield of the products to as high as 92%. According to the Nousheeen group, l-proline serves two functions: first, it helps to create a pyridinium ylide, and secondly, it aids in a Knoevenagel condensation. In our case, pyridine has three roles in the reaction. First, it acts as a tertiary amine to form a pyridinium salt. It then acts as a base to promote a Knoevenagel condensation between a cyclohexane-1,3-dione and a 3-formylchromone derivative. Lastly, it acts as a leaving group to complete the intramolecular substitution reaction. In our method, the reaction tolerates both electron-donating and electron-withdrawing groups at various positions on the 3-formylchromone and phenacyl bromide, opening a broad substrate scope, whereas the Nousheen group synthesized only compounds with substituents in the para-position of the phenacyl bromide.
The remarkable applications of derivatives of chromone and 2,3-dihydrobenzofuran prompted us to synthesize novel 2,3-dihydrobenzofuran derivative containing a chromone core (Scheme [1d]). Our aim was to develop a simple one-pot, catalyst-free, three-component synthesis of these derivatives, based on a pyridinium-ylide-assisted tandem reaction in an ecofriendly aqueous medium.
Chang and Tsai[36] and Ullrich and co-workers[37] have reported syntheses of 2,3-dihydrofurans from acyclic 1,3-diketones, pyridinium ylides, and aromatic aldehydes. Their intriguing findings prompted us to look into the possibility of a three-component tandem reaction for the effective synthesis of 2,3-dihydrofurans–chromone derivatives. First, phenacyl bromide (1 mmol), pyridine (3 mmol), 3-formylchromone (1 mmol), and acetylacetone (1mmole) were refluxed in water for two hours; this was followed by the addition of triethylamine (1 mmol), and the mixture was stirred for overnight. Surprisingly, TLC analysis indicated the formation of a pyridinium salt while the 3-formylchromone and acetylacetone remained in solution. This showed that, under these conditions, acetylacetone and 3-formylchromone do not condense, whereas the conditions favor the formation of a pyridinium salt. We then tested various acyclic 1,3-dicarbonyl compounds, such as ethyl acetoacetate and diethyl malonate, but no condensation occurred between the 3-formylchromone and the acyclic 1,3-dicarbonyl compound. These results suggested that pyridine and triethylamine are insufficiently basic to catalyze a Knoevenagel condensation reaction between 3-formylchromone and the acyclic 1,3-dicarbonyl compounds that were tested.
a Reaction conditions: 3-formylchromone (2a; 1 mmol), phenacyl bromide (1a; 1 mmol), dimedone (3a; 1 mmol), pyridine (1.5 mmol).
b Isolated yield.
It is well known that cyclic 1,3-diketones are much more reactive than their acyclic counterparts. We therefore shifted our interest toward cyclic 1,3-diketones. Phenacyl bromide (2a; 1 mmol), pyridine (1.5 mmol), 3-formylchromone (1a; 1 mmol), and dimedone (3a; 1 mmol) were refluxed in ethanol for two hours. This was followed by the addition of DBU (1 mmol), and the resulting mixture was refluxed for three hours. We were pleased to discover that derivative 4a was obtained in 40% yield (Table [1], entry 1). In an attempt to increase the yield of the reaction, we varied such reaction parameters as the base, the time, the solvent, and the temperature, using phenacyl bromide (2a; 1 mmol), pyridine (1.5 mmol), 3-formylchromone (1a; 1 mmol), and dimedone (3a; 1 mmol) as model reactants. Out of curiosity, we initially carried out the reaction without a base at 50 °C in EtOH as a solvent (Table [1], entry 2), but none of the required product was obtained. From this, we concluded that a base is necessary for the reaction, so we screened several bases (K2CO3, DBN, DABCO, and Et3N) (entries 3–6), among which Et3N (entry 6) gave compound 4a in the highest yield (50%). Inspired by this result, we performed a model reaction in EtOH in the presence of triethylamine for two hours, but there was no further increase in the yield (entry 7). To maximize the yield, we then screened various solvents (MeCN, THF, and DMF), but these produced only a slight increase in yield of 4a (50–58%) (entries 8–10). However, a marked increase in the yield of 4a was observed when water was used as the solvent (entry 11). A further examination of various reaction temperatures (80 to 100 °C) showed that the yield increased with increasing temperature (entries 12–14). The highest yield was obtained when the reaction was carried out for three hours at 100 °C in a refluxing aqueous medium containing one equivalent of Et3N. Finally, we tried the reaction for an extended time of 12 hours, but no increase in the yield of product 4a was observed.
After identifying the most suitable reaction condition, we turned our attention to the scope of the reaction by using various phenacyl bromides, cyclohexane-1,3-diones, and 3-formylchromones (Scheme [2]). To our satisfaction, under the optimal conditions, a variety of aryl-substituted phenacyl bromides were suitable for this reaction. The reaction of 3-formylchromone (1a), phenacyl bromide (2a), and dimedone (3a) gave the expected 3-[(2S,3S)-2-benzoyl-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-1-benzofuran-3-yl]-4H-chromen-4-one (4a) in an excellent yield (91%). Reactants bearing an electron-donating p-methyl or o-methoxy groups gave the corresponding products 4b (88%) and 4c (89%).
The structure of 4b was confirmed by single-crystal X-ray crystallography.[40] Next, to our delight, substitutions of the phenacyl bromide with electron-withdrawing groups (-Cl, -Br, -CF3, -NO2) at the para- or meta-position of the benzene ring were well tolerated and provided the corresponding products (4d–h) in excellent yields (85–89%). We also found that sterically hindered 2,4-dichlorophenacyl bromides gave product 4i in 89% yield. To demonstrate the practicality of our new reaction system, a gram-scale (1 g) experiment was conducted, yielding an 81% yield of product 4a.
To further demonstrate the broad scope of our method, a variety of cyclic 1,3-diketones (5-methylcyclohexane-1,3-dione, cyclohexane-1,3-dione, and 4,4-dimethylcyclohexane-1,3-dione) and phenacyl bromide derivatives with various functional groups (methyl, methoxy, chloro, bromo, nitro, and trifluoromethyl) at various positions were found to be tolerated, undergoing the required transformation to yield the desired products. However, when we used 5-methylcyclohexa-1,3-dione or 4,4-dimethylcyclohexa-1,3-dione, the yields of the corresponding products decreased. With 4,4-dimethylcyclohexane-1,3-dione or methylcyclohexane-1,3-dione, phenacyl bromides bearing either electron-donating or electron-accepting substituents gave the corresponding products 4j–m in moderate yields (70–74%). Furthermore, there was no increase in yield when cyclohexane-1,3-dione was used: phenacyl bromides with either an electron-withdrawing group (-CF3, -Cl) or an electron-donating group (-OCH3) in various position were readily transformed into the corresponding products 4n–r in good yields (85, 85, 88, 84, and 84%, respectively). Finally, we were interested in scrutinizing the effect of various substituents on the 3-formylchromone. 3-Formylchromones bearing either an electron-donating or an electron-withdrawing group in the 6-position (methyl, isopropyl, nitro, or chloro) reacted with various cyclic 1,3-diketones to afford the corresponding products 4s–z in excellent yields (82–90%). The structure of product 4w was confirmed by single-crystal X-ray analysis.[40] Of the 28 compounds in Scheme [2], only 4a, 4b, 4d, 4e, and 4f were previously reported by Nousheen and co-workers.[39]
To understand the exact mechanism, we carried some control experiments (Scheme [3]). Initially, we carried out a control experiment between 3-formylchromone (1a) and dimedone (3a) in the presence of pyridine to produce intermediate II (Scheme [3a]). The structure of intermediate II was confirmed by mass spectrometry and NMR studies. Next, the reaction of intermediate II with phenacyl bromide (2a) and pyridine in the presence of Et3N proceeded smoothly to furnish 4a in 91% yield (Scheme [3b]). In addition, when the reaction of 1a, 2a, and 3a was carried out in the absence of pyridine, none of the desired compound 4a was obtained, but a trace amount of intermediate II was formed (Scheme [3c]).
On the basis of these results, we can state that the tandem reaction proceeds in a straightforward manner. A plausible reaction course to explain the mechanism of this one-pot multicomponent reaction is shown in Scheme [4]. The first step is the formation of two intermediates. A pyridinium salt (intermediate Ι) is formed by the addition of phenacyl bromide (2a) with pyridine, and intermediate II is formed by a pyridine-catalyzed Knoevenagel condensation of 3-formylchromone (1a) with dimedone (3a). The second step is a Michael addition of the pyridinium ylide 5, formed by deprotonation of the zwitterionic pyridinium salt intermediate I by triethylamine. On heating, the zwitterionic species can follow two different pathways to produce two different products. In Pathway 1, the formation of cyclopropane 6 (which was not seen here) occurs when the carbanion is substituted intramolecularly on the pyridine moiety. In Pathway 2, the carbanion converts into a resonance-stabilized enolate through a keto–enol tautomerization process. The final step is an intramolecular SN 2 attack of the resonance-stabilized carbanion on the carbon bearing the pyridine moiety to give the 2,3-dihydrofuran–chromone derivative 4a. For the SN 2 reaction to occur, the electrophilic carbon atom with the leaving pyridyl group must undergo a nucleophilic enolate attack from its back side. Because of steric hindrance in the carbanion (intermediate III) and the transition state, the bulky phenacyl group and the 3-formylchromone group adopt stereochemically opposite positions. The formation of the key intermediate was further confirmed by a mass spectrometric analysis of the crude reaction mixture. Consequently, the trans-2,3-dihydrofuran is produced as the exclusive product. Here pyridine plays a crucial role. In the proposed mechanism, pyridine has a triple role in the reaction. First, it acts as a tertiary amine to form the pyridinium salt. Secondly, it acts as a base in promoting the Knoevenagel condensation between the cyclic 1,3-diketone and the 3-formylchromone derivative. Finally, it acts as a leaving group to complete the intramolecular substitution reaction.
In conclusion, we have developed an efficient one-pot, tandem, three-component coupling reaction for the synthesis of biologically interesting functionalized dihydrobenzofuran–chromone conjugates from readily available reagents. Under the optimized conditions, the reaction takes place through a Michael addition and an intramolecular cyclization of a pyridinium ylide formed in situ. We believe that this is an efficient synthetic methodology for the construction of 2,3-dihydrofuran–chromone derivative in a stereoselective fashion. Based on steric hindrance in the cyclization step, a mechanism for this diastereoselective formation of trans-2,3-dihydrofuran derivatives was proposed.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2532-6077.
- Supporting Information
- CIF File
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References and Notes
- 1 Machado NF. L, Marques MP. M. Curr. Bioact. Compd. 2010; 6: 76
- 2 Ostrowska K, Grzeszczuk D, Maciejewska D, Młynarczuk-Biały I, Czajkowska A, Sztokfisz A, Dobrzycki Ł, Kruszewska H. Monatsh. Chem. 2016; 147: 1615
- 3 Ellis GP. In Chromenes, Chromanones, and Chromones . Ellis GP. Wiley; New York: 2009. 1
- 4 Gábor M. Prog. Clin. Biol. Res. 1986; 213: 471
- 5 Rival Y, Grassy G, Taudou A, Ecalle R. Eur. J. Med. Chem. 1991; 26: 13
- 6 Teimouri MB, Akbari-Moghaddam P, Golbaghi G. ACS Comb. Sci. 2011; 13: 659
- 7 Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa SM, Khalifa TI. Planta Med. 2002; 68: 957
- 8 Gonzalez AG, Darias V, Estevez E, Vivas JM. Planta Med. 1983; 47: 56
- 9 Teimouri MB, Asnaashari B, Moayedi M, Naderi S. Synlett 2015; 101
- 10 Teimouri MB, Mashayekhi F, Alishaei E. J. Iran. Chem. Soc. 2016; 13: 583
- 11 Mazzei M, Balbi A, Roma G, Di Braccio M, Leoncini G, Buzzi E, Maresca M. Eur. J. Med. Chem. 1988; 23: 237
- 12a Zghab I, Trimeche B, Mansour MB, Hassine M, Touboul D, Jannet HB. Arabian J. Chem. 2017; 10: S2651
- 12b Dey S, Lo H.-J, Wong C.-H. J. Am. Chem. Soc. 2019; 141: 10309
- 12c Dey S, Lo H.-J, Wong C.-H. Org. Lett. 2020; 22: 4638
- 13 Teimouri MB, Zolfaghari F, Naderi S. Tetrahedron 2017; 73: 262
- 14 Teimouri MB, Eskandari M. J. Chem. Res. 2011; 35: 500
- 15 Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F. Chem. Rev. 2014; 114: 4960
- 16a Reis J, Gaspar A, Milhazes N, Borges F. J. Med. Chem. 2017; 60: 7941
- 16b Tawfik HA, Ewies EF, El-Hamouly WS. Int. J. Res. Pharm. Chem. 2014; 4: 1046
- 16c Gobbi S, Hu Q, Zimmer C, Engel M, Belluti F, Rampa A, Hartmann RW, Bisi A. J. Med. Chem 2016; 59: 2468
- 16d Carradori S, Silvestri R. J. Med. Chem 2015; 58: 6717
- 16e Reis J, Manzella N, Cagide F, Mialet-Perez J, Uriarte E, Parini A, Borges F, Binda C. J. Med. Chem. 2018; 61: 4203
- 17 Gamal-Eldeen AM, Djemgou PC, Tchuendem M, Ngadjui BT, Tane P, Toshifumi H. Z. Naturforsch., C 2007; 62: 331
- 18 Gautam R, Jachak SM, Kumar V, Mohan CG. Bioorg. Med. Chem. Lett. 2011; 21: 1612
- 19 Subbareddy CV, Sumathi S. New J. Chem. 2017; 41: 9388
- 20 Yuan R, Huang L, Du L.-J, Feng J.-F, Li J, Luo Y.-Y, Xu Q.-M, Yang S, Gao H, Feng Y.-L. Pharmacol. Res. 2019; 142: 102
- 21 Fukuda T, Shimoyama K, Nagamitsu T, Tomoda H. J. Antibiot. 2014; 67: 445
- 22 Li Y, Hale KJ. Org. Lett. 2007; 9: 1267
- 23 Jung J.-K, Johnson BR, Duong T, Decaire M, Gharbaoui T, Boatman PD, Sage CR, Chen R, Richman JG, Connolly DT, Semple G. J. Med. Chem. 2007; 50: 1445
- 24 Zheng S.-L, Yu W.-Y, Xu M.-X, Che C.-M. Tetrahedron Lett. 2003; 44: 1445
- 25 Clive DL. J, Stoffman EJ. L. Org. Biomol. Chem. 2008; 6: 1831
- 27a Cheng C.-W, Zhou Y, Pan W.-H, Dey S, Wu C.-Y, Hsu W.-L, Wong C. Nat. Commun. 2018; 9: 5202
- 27b Bagley MC, Dale JW, Bower J. Chem. Commun. 2002; 1682
- 28 Akritopoulou-Zanze I. Curr. Opin. Chem. Biol. 2008; 12: 324
- 29 Ivachtchenko AV, Ivanenkov YA, Kysil VM, Krasavin MY, Ilyin AP. Russ. Chem. Rev. 2010; 79: 787
- 30 Teimouri MB, Mansouri F. J. Chem. Res. 2010; 34: 330
- 31 Cano PA, Islas-Jácome A, González-Marrero J, Yépez-Mulia L, Calzada F, Gámez-Montaño R. Bioorg. Med. Chem. 2014; 22: 1370
- 32 Teimouri MB, Bazhrang R, Eslamimanesh V, Nouri A. Tetrahedron 2006; 62: 3016
- 33 Dömling A. Curr. Opin. Chem. Biol. 2002; 6: 306
- 34 Shaabani A, Maleki A, Rezayan AH, Sarvary A. Mol. Diversity 2011; 15: 41
- 35 Ruijter E, Scheffelaar R, Orru RV. A. Angew. Chem. Int. Ed. 2011; 50: 6234
- 36 Chuang C.-P, Tsai A.-I. Synthesis 2006; 675
- 37 Worgull D, Öhler L, Strache JP, Friedrichs T, Ullrich P. Eur. J. Org. Chem. 2017; 6077
- 38 Das S, Basu S, Halder S, Mukhopadhyay C. Tetrahedron 2024; 160: 134041
- 39 Nousheen A, Chandrakanth M, Sagar BK, Somarapu VL. J. Mol. Struct. 2022; 1261: 132899
- 40 CCDC 2403331 and 2403329 contain the supplementary crystallographic data for compounds 4b and 4w. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
- 41 2-[(2S*,3S*)-2-Benzoyl-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-1-benzofuran-3-yl]-4H-chromen-4-one (4a); Typical Procedure 3-Formylchromone (1a; 1 mmol, 0.174 g), phenacyl bromide (2a; 1 mmol, 0.199 g), dimedone (3a; 0.140 g, 1 mmol), and pyridine (0.118 g, 1.5 mmol) were added to H2O (2 mL) in a 10 mL round-bottomed flask equipped with a reflux condenser. The mixture was refluxed in the open atmosphere at 100 °C (oil bath) for 2 h. Et3N (1 mmol, 0.101g) was then added, and the resulting mixture was refluxed for another 3 h until the reaction was complete (TLC). The resulting mixture was then cooled to r.t. and the crude product was extracted with EtOAc (2 × 10 mL) using a separatory funnel. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel (100–200 mesh), PE–EtOAc] to give a white solid; yield: 380 mg (91%); mp 200–202 °C; Rf = 0.4 (20% EtOAc–PE). 1H NMR (300 MHz, CDCl3): δ = 8.19–8.16 (m, 1 H), 8.01–7.98 (m, 2 H), 7.85 (s, 1 H), 7.70–7.59 (m, 2 H), 7.51–7.37 (m, 4 H), 6.10 (d, J = 5.4 Hz, 1 H), 4.56 (d, J = 5.7 Hz, 1 H), 2.49 (ABq, J = 16.8 Hz, 2 H), 2.23 (s, 2 H), 1.15 (s, 3 H), 1.12 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 194.5, 193.0, 177.6, 177.4, 156.5, 154.5, 134.3, 134.2, 133.9, 129.5, 128.9, 125.8, 125.4, 124.4, 121.7, 118.3, 111.2, 87.6, 51.4, 41.4, 37.9, 34.4, 29.2, 28.5. HRMS (ESI/TOF-Q): m/z [M + H]+ calcd C26H23O5: 415.1545; found: 415.1540
Corresponding Author
Publication History
Received: 27 December 2024
Accepted after revision: 04 February 2025
Accepted Manuscript online:
04 February 2025
Article published online:
17 March 2025
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References and Notes
- 1 Machado NF. L, Marques MP. M. Curr. Bioact. Compd. 2010; 6: 76
- 2 Ostrowska K, Grzeszczuk D, Maciejewska D, Młynarczuk-Biały I, Czajkowska A, Sztokfisz A, Dobrzycki Ł, Kruszewska H. Monatsh. Chem. 2016; 147: 1615
- 3 Ellis GP. In Chromenes, Chromanones, and Chromones . Ellis GP. Wiley; New York: 2009. 1
- 4 Gábor M. Prog. Clin. Biol. Res. 1986; 213: 471
- 5 Rival Y, Grassy G, Taudou A, Ecalle R. Eur. J. Med. Chem. 1991; 26: 13
- 6 Teimouri MB, Akbari-Moghaddam P, Golbaghi G. ACS Comb. Sci. 2011; 13: 659
- 7 Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa SM, Khalifa TI. Planta Med. 2002; 68: 957
- 8 Gonzalez AG, Darias V, Estevez E, Vivas JM. Planta Med. 1983; 47: 56
- 9 Teimouri MB, Asnaashari B, Moayedi M, Naderi S. Synlett 2015; 101
- 10 Teimouri MB, Mashayekhi F, Alishaei E. J. Iran. Chem. Soc. 2016; 13: 583
- 11 Mazzei M, Balbi A, Roma G, Di Braccio M, Leoncini G, Buzzi E, Maresca M. Eur. J. Med. Chem. 1988; 23: 237
- 12a Zghab I, Trimeche B, Mansour MB, Hassine M, Touboul D, Jannet HB. Arabian J. Chem. 2017; 10: S2651
- 12b Dey S, Lo H.-J, Wong C.-H. J. Am. Chem. Soc. 2019; 141: 10309
- 12c Dey S, Lo H.-J, Wong C.-H. Org. Lett. 2020; 22: 4638
- 13 Teimouri MB, Zolfaghari F, Naderi S. Tetrahedron 2017; 73: 262
- 14 Teimouri MB, Eskandari M. J. Chem. Res. 2011; 35: 500
- 15 Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F. Chem. Rev. 2014; 114: 4960
- 16a Reis J, Gaspar A, Milhazes N, Borges F. J. Med. Chem. 2017; 60: 7941
- 16b Tawfik HA, Ewies EF, El-Hamouly WS. Int. J. Res. Pharm. Chem. 2014; 4: 1046
- 16c Gobbi S, Hu Q, Zimmer C, Engel M, Belluti F, Rampa A, Hartmann RW, Bisi A. J. Med. Chem 2016; 59: 2468
- 16d Carradori S, Silvestri R. J. Med. Chem 2015; 58: 6717
- 16e Reis J, Manzella N, Cagide F, Mialet-Perez J, Uriarte E, Parini A, Borges F, Binda C. J. Med. Chem. 2018; 61: 4203
- 17 Gamal-Eldeen AM, Djemgou PC, Tchuendem M, Ngadjui BT, Tane P, Toshifumi H. Z. Naturforsch., C 2007; 62: 331
- 18 Gautam R, Jachak SM, Kumar V, Mohan CG. Bioorg. Med. Chem. Lett. 2011; 21: 1612
- 19 Subbareddy CV, Sumathi S. New J. Chem. 2017; 41: 9388
- 20 Yuan R, Huang L, Du L.-J, Feng J.-F, Li J, Luo Y.-Y, Xu Q.-M, Yang S, Gao H, Feng Y.-L. Pharmacol. Res. 2019; 142: 102
- 21 Fukuda T, Shimoyama K, Nagamitsu T, Tomoda H. J. Antibiot. 2014; 67: 445
- 22 Li Y, Hale KJ. Org. Lett. 2007; 9: 1267
- 23 Jung J.-K, Johnson BR, Duong T, Decaire M, Gharbaoui T, Boatman PD, Sage CR, Chen R, Richman JG, Connolly DT, Semple G. J. Med. Chem. 2007; 50: 1445
- 24 Zheng S.-L, Yu W.-Y, Xu M.-X, Che C.-M. Tetrahedron Lett. 2003; 44: 1445
- 25 Clive DL. J, Stoffman EJ. L. Org. Biomol. Chem. 2008; 6: 1831
- 27a Cheng C.-W, Zhou Y, Pan W.-H, Dey S, Wu C.-Y, Hsu W.-L, Wong C. Nat. Commun. 2018; 9: 5202
- 27b Bagley MC, Dale JW, Bower J. Chem. Commun. 2002; 1682
- 28 Akritopoulou-Zanze I. Curr. Opin. Chem. Biol. 2008; 12: 324
- 29 Ivachtchenko AV, Ivanenkov YA, Kysil VM, Krasavin MY, Ilyin AP. Russ. Chem. Rev. 2010; 79: 787
- 30 Teimouri MB, Mansouri F. J. Chem. Res. 2010; 34: 330
- 31 Cano PA, Islas-Jácome A, González-Marrero J, Yépez-Mulia L, Calzada F, Gámez-Montaño R. Bioorg. Med. Chem. 2014; 22: 1370
- 32 Teimouri MB, Bazhrang R, Eslamimanesh V, Nouri A. Tetrahedron 2006; 62: 3016
- 33 Dömling A. Curr. Opin. Chem. Biol. 2002; 6: 306
- 34 Shaabani A, Maleki A, Rezayan AH, Sarvary A. Mol. Diversity 2011; 15: 41
- 35 Ruijter E, Scheffelaar R, Orru RV. A. Angew. Chem. Int. Ed. 2011; 50: 6234
- 36 Chuang C.-P, Tsai A.-I. Synthesis 2006; 675
- 37 Worgull D, Öhler L, Strache JP, Friedrichs T, Ullrich P. Eur. J. Org. Chem. 2017; 6077
- 38 Das S, Basu S, Halder S, Mukhopadhyay C. Tetrahedron 2024; 160: 134041
- 39 Nousheen A, Chandrakanth M, Sagar BK, Somarapu VL. J. Mol. Struct. 2022; 1261: 132899
- 40 CCDC 2403331 and 2403329 contain the supplementary crystallographic data for compounds 4b and 4w. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
- 41 2-[(2S*,3S*)-2-Benzoyl-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-1-benzofuran-3-yl]-4H-chromen-4-one (4a); Typical Procedure 3-Formylchromone (1a; 1 mmol, 0.174 g), phenacyl bromide (2a; 1 mmol, 0.199 g), dimedone (3a; 0.140 g, 1 mmol), and pyridine (0.118 g, 1.5 mmol) were added to H2O (2 mL) in a 10 mL round-bottomed flask equipped with a reflux condenser. The mixture was refluxed in the open atmosphere at 100 °C (oil bath) for 2 h. Et3N (1 mmol, 0.101g) was then added, and the resulting mixture was refluxed for another 3 h until the reaction was complete (TLC). The resulting mixture was then cooled to r.t. and the crude product was extracted with EtOAc (2 × 10 mL) using a separatory funnel. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel (100–200 mesh), PE–EtOAc] to give a white solid; yield: 380 mg (91%); mp 200–202 °C; Rf = 0.4 (20% EtOAc–PE). 1H NMR (300 MHz, CDCl3): δ = 8.19–8.16 (m, 1 H), 8.01–7.98 (m, 2 H), 7.85 (s, 1 H), 7.70–7.59 (m, 2 H), 7.51–7.37 (m, 4 H), 6.10 (d, J = 5.4 Hz, 1 H), 4.56 (d, J = 5.7 Hz, 1 H), 2.49 (ABq, J = 16.8 Hz, 2 H), 2.23 (s, 2 H), 1.15 (s, 3 H), 1.12 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 194.5, 193.0, 177.6, 177.4, 156.5, 154.5, 134.3, 134.2, 133.9, 129.5, 128.9, 125.8, 125.4, 124.4, 121.7, 118.3, 111.2, 87.6, 51.4, 41.4, 37.9, 34.4, 29.2, 28.5. HRMS (ESI/TOF-Q): m/z [M + H]+ calcd C26H23O5: 415.1545; found: 415.1540
