Abstract
A novel organocatalytic reaction cascade between 3-cyano-4-styrylcoumarins and 2-mercaptoacetophenones is described. It is based on stereocontrolled functionalization of cyanocoumarins proceeding in a sequence of thia-Michael/aldol/annulation reactions. This highly diastereo- and enantioselective reaction is realized by employing enantioselective bifunctional catalysis and exhibits a broad substrate scope and excellent functional group tolerance. The synthetic application involves the transformation of the imidoester group, thus opening access to biologically relevant coumarin and δ-lactone-fused products.
Compounds bearing a poly(hetero)cyclic fused ring system are identified as an important group of molecules in the contemporary organic and medicinal chemistry. Due to their wide biological and synthetic relevance, they constitute an inspiration for the chemical community.1 Among various privileged heterocyclic structures, δ-lactone2 and coumarin3 rings are considered key units found in many optically active natural products that exhibit a large spectrum of biological activities (Scheme 1, top). Similarly, the substituted tetrahydrothiophene derivatives attract much attention owing to their significant value as building blocks and synthetic targets.4 Therefore, the combination of such biorelevant frameworks leads to new types of products with promising properties. In this context, the organocatalytic cascade reactions have been recognized as diverse strategies providing access to carbo- and heterocyclic scaffolds in an asymmetric fashion.5 2-Mercaptocarbonyl compounds constitute an interesting group of reactants in synthesis of tetrahydrothiophenes with the organocatalytic cascades involving these systems initiated by the thia-Michael addition followed by the intramolecular aldol reaction (Scheme 1, center).6 The formation of a nucleophilic tertiary alcohol in such a cascade allows for subsequent intramolecular reactions leading to the construction of unique poly(hetero)cyclic fused ring systems.7 However, such synthetic strategies still remain a challenge, particularly in the field of stereocontrolled remote functionalizations involving vinylogous Michael acceptors.8 In recent years, 4-methyl-3-cyanocoumarin and its derivatives have been recognized as highly attractive pronucleophilic vinylogous reactants in enantioselective reactions (Scheme 1, bottom).9 The incorporation of an olefin moiety in their structure provides access to a new class of vinylogous Michael acceptors that participate in the catalytic asymmetric remote γ,δ-functionalizations.
Scheme 1. Important Structural Motifs and Building Blocks in Organic Chemistry.
Notably, there are only a few examples of organocatalytic transformations involving these systems (Scheme 2, top). In 2019, the Yuan group described the enantioselective domino 1,6-addition/annulation reaction of 3-cyano-4-styrylcoumarins with isatin-derived Morita–Baylis–Hillman carbonates catalyzed by a chiral Brønsted base, in which the final product bears an additional cyclopentene framework.10 Moreover, Wang and Chen established an efficient NHC-catalyzed oxidative γ,δ-functionalization leading to the chiral derivatives containing a cyclohexanone unit.11 Very recently, we have demonstrated that 3-cyano-4-styrylcoumarins readily participate in the doubly vinylogous 1,6-addition with dienolates derived from 5-substituted-furan-2(3H)-ones.12 Despite these achievements, the remote transformations of this class of compounds remain limited.
Scheme 2. Remote Functionalization of 3-Cyano-4-Styrylcoumarins and the Synthetic Objectives of Our Study.
To the best of our knowledge, the reaction between coumarins 1 and 2-mercaptocarbonyl compounds 2 promoted by a modified cinchona alkaloid catalyst has never been achieved. As part of our continuing efforts on organocatalytic asymmetric construction of polycyclic frameworks containing δ-lactone and coumarin motifs,12,13 a new approach for the remote γ,δ-functionalization of 1 based on a stereocontrolled cascade involving thia-Michael/aldol/annulation reactions was devised (Scheme 2, bottom). As a consequence, the unique polycyclic chiral products 3 containing coumarin, 2H-pyran-2-imine and tetrahydrothiophene units were obtained. Furthermore, the efficient transformation of the imidoester group of 3 opened access to biologically important δ-lactone derivatives 4. At the outset of our studies, the reaction between 2-oxo-4-styryl-2H-chromene-3-carbonitrile 1a and 2-mercaptoacetophenone 2a was utilized as a model transformation. It was satisfying to find that the envisaged cascade was viable and chiral product 3a was afforded with variable amounts of thia-Michael reaction adduct 5a (Table 1, entries 1–3). In order to improve the enantioselectivity, a series of cinchona alkaloid catalysts 6 were screened, showing that 6c bearing a squaramide moiety was the best (Table 1, entry 3 vs 1–2). Moreover, extending the reaction time to 72 h allowed 3a to be obtained as the sole product of the cascade (Table 1, entry 3 vs 4) and the addition of molecular sieves limited the formation of the product of hydrolysis of 3a (Table 1, entry 4 vs 5). The evaluation of different solvents indicated that CDCl3 was superior in terms of chemoselectivity and yield of the cascade reaction (Table 1, entry 5 vs 6–8). Further optimization studies were focused on the evaluation of concentration effect (Table 1, entries 9–10) and reducing the catalyst loading to 5 mol % (Table 1, entry 11). Neither of these changes led to improvement of the results. Finally, modulating the molar ratio of the reactants led to a slightly higher yield of the process and the product 3a was obtained with excellent selectivity (Table 1, entry 12). Similar results of the reaction carried out in freshly distilled chloroform were observed (Table 1, entry 12 vs 13), and these conditions were found to be optimal.
Table 1. Stereocontrolled γ,δ-Functionalization of 3-Cyano-4-styrylcoumarins via Bifunctional Catalysis: Optimization Studiesa.
| Cat. | Solvent | Conv. (yield) [%]b | 3a:5ac | erd | |
|---|---|---|---|---|---|
| 1 | 6a | CDCl3 | >95 | 1:0.6 | 28:72 |
| 2 | 6b | CDCl3 | >95 | 1:0.6 | 52:48 |
| 3 | 6c | CDCl3 | >95 | 1:1.4 | 98:2 |
| 4e | 6c | CDCl3 | >95 (60) | 1:0 | 98:2 |
| 5e,f | 6c | CDCl3 | 88 (65) | 1:0 | 98:2 |
| 6e,f | 6c | CH2Cl2 | 83 | 1:0.9 | n.d. |
| 7e,f | 6c | CH3CN | 52 | 1:2.6 | n.d. |
| 8e,f | 6c | Toluene | 83 | 1:1.3 | n.d. |
| 9e,f,g | 6c | CDCl3 | >95 (70) | 1:0 | 98:2 |
| 10e,f,h | 6c | CDCl3 | 95 (70) | 1:0 | 97.5:2.5 |
| 11e,f,i | 6c | CDCl3 | >95 | 1:0.5 | n.d. |
| 12e,f,j | 6c | CDCl3 | >95 (76) | 1:0 | 98:2 |
| 13e,f,j,k | 6c | CHCl3 | >95 (76) | 1:0 | 98:2 |
Reactions performed on a 0.05 mmol scale using 1a (1 equiv) and 2a (2 equiv) in 0.1 mL of the solvent for 24 h.
Conversion as determined by 1H NMR of a crude reaction mixture. In parentheses yield of isolated product 3a after column chromatography is given.
Determined by 1H NMR of a crude reaction mixture.
Determined by a chiral stationary phase UPC2 for product 3a.
Reaction performed for 72 h.
Reaction performed with sieves 3A.
Reaction performed in 0.05 mL of the solvent.
Reaction performed in 0.2 mL of the solvent.
Reaction performed using 5 mol % of catalyst.
Reaction performed using 1a (1 equiv) and 2a (1.2 equiv).
Freshly distilled over P2O5 chloroform was used as a solvent.
Having identified the optimal conditions, the scope of the cascade was explored (Table 2). To our delight, various 2-mercaptocarbonyl compounds 2 with different steric and electronic character of substituents on the aromatic ring underwent an organocatalytic cascade smoothly. In almost all cases, substrates bearing electron-donating or electron-withdrawing groups on the phenyl ring provided optically active products 3b–g with good to high yields and excellent stereoselectivity (compare entries 3b–d vs 3e–g). The position of the substituents in 2 had no significant effect on the selectivity of the cascade. However, in the case of 3d,f,g, lower yields were observed. Additionally, the bulky 2-naphthyl-group in 2h was also well-tolerated. In the course of further scope studies, the possibility of modifying the structure of 2-oxo-4-styryl-2H-chromene-3-carbonitrile 1 was attempted as outlined in Table 2. In general, it was determined that the position and electron properties of the substituents at phenyl ring in 1b–h had no significant effect on both the enantioselectivity and the efficiency of the reaction leading to the corresponding 3i–o. Only in the reaction between 1g bearing a nitro group in the para-position of the phenyl ring and 2a, the product 3n was obtained in moderate yield. Notably, when 1i–j bearing electron-donating or electron-withdrawing groups on the chromene aromatic ring were tested, the products 3p–q were obtained with excellent enantioselectivities and moderate yields.
Table 2. Stereocontrolled γ,δ-Functionalization of 3-Cyano-4-styrylcoumarins via Bifunctional Catalysis: Substrate Scope for 3-Cyano-4-alkenyl-2H-chromen-2-ones 1 and 2-Mercaptocarbonyl Compounds 2a.
| 3 | R1 | R2 | R3 | Yield [%] | erb |
|---|---|---|---|---|---|
| 3a | H | Ph | Ph | 76 | 98:2 |
| 3b | H | Ph | 2-MeOC6H4 | 91 | 99:1 |
| 3c | H | Ph | 3-MeOC6H4 | 82 | 97:3 |
| 3d | H | Ph | 4-MeC6H4 | 59 | 99:1 |
| 3e | H | Ph | 2-FC6H4 | 83 | 97:3 |
| 3f | H | Ph | 4-FC6H4 | 74 | 96:4 |
| 3g | H | Ph | 4-CF3C6H4 | 62 | 97:3 |
| 3h | H | Ph | 2-Naphthyl | 51 | 98:2 |
| 3i | H | 4-MeOC6H4 | Ph | 84 | 99:1 |
| 3j | H | 3-MeC6H4 | Ph | 73 | 98:2 |
| 3k | H | 4-MeC6H4 | Ph | 76 | 98:2 |
| 3l | H | 3-ClC6H4 | Ph | 90 | 97:3 |
| 3m | H | 4-ClC6H4 | Ph | 80 | 99:1 |
| 3n | H | 4-NO2C6H4 | Ph | 46 | 99:1 |
| 3o | H | 4-CF3C6H4 | Ph | 89 | 95:5 |
| 3p | 9-MeO | Ph | Ph | 58 | 97:3 |
| 3q | 10-Br | Ph | Ph | 53 | 95:5 |
Reactions performed on a 0.1 mmol scale using 1a (1 equiv) and 2 (1.2 equiv) in 0.4 mL of the solvent for 20 h.
Determined by a chiral stationary phase UPC2.
To further demonstrate the synthetic utility of the developed cascade, the transformation of imidoester 3 into lactone 4 was performed (Table 3). Therefore, chiral compounds 3 were hydrolyzed to 4 under acidic conditions and the scope of the method was tested. It was found that all reactions proceeded with satisfactory results providing 4a–4h in moderate to high yields and with the preservation of optical purity introduced in the organocatalytic step. Subsequently, a 1 mmol scale experiment between 1a and 2a was carried out under the optimized conditions (Scheme 3). Moreover, the synthesis of compound 4a was performed in a one-pot fashion, obtaining the corresponding product with a very good outcome. Additionally, the tetrahydro-pyran-2-ylideneamine derivative 3 was subjected to selective Boc protection leading to N-protected product 7.
Table 3. Stereocontrolled γ,δ-Functionalization of 3-Cyano-4-styrylcoumarins via Bifunctional Catalysis: Derivatization of Products 3a.
| 4 | R1 | R2 | Yield [%] | erb |
|---|---|---|---|---|
| 4a | Ph | Ph | 70 | 98:2 |
| 4b | Ph | 2-MeOC6H4 | 90 | 99:1 |
| 4c | Ph | 3-MeOC6H4 | 74 | 97:3 |
| 4d | Ph | 2-FC6H4 | 88 | 97:3 |
| 4e | Ph | 4-CF3C6H4 | 76 | 97:3 |
| 4f | Ph | 2-Naphthyl | 84 | 97:3 |
| 4g | 4-MeOC6H4 | Ph | 57 | 99:1 |
| 4h | 3-MeC6H4 | Ph | 61 | 99:1 |
Reactions performed on a 0.1 mmol scale using 1a (1 equiv) and 2 (1.2 equiv) in 0.4 mL of the solvent for 24 h.
Determined by a chiral stationary phase UPC2.
Scheme 3. Stereocontrolled γ,δ-Functionalization of 3-Cyano-4-styrylcoumarins via Bifunctional Catalysis: Transformation of Product 3a.
The absolute configuration of product 4b was determined by the single-crystal X-ray analysis (see the Supporting Information for details). Because all products were synthesized under the catalysis of 6c, the absolute configurations of 3 and 4 were assigned by analogy. Based on the absolute stereochemistry of the final products 3 and 4, a plausible mechanism of a cascade was proposed (Scheme 4). The reaction is promoted by the bifunctional catalyst 6c, which is responsible for the independent activation of 2-oxo-4-styryl-2H-chromene-3-carbonitrile 1 and 2-mercaptocarbonyl compound 2. Such a recognition profile by H-bonding and ion-pairing interactions of both reaction partners allows the stereoselectivity of the cascade to be controlled. In the second stage of the cascade, an intramolecular vinylogous aldol reaction takes place, leading to the formation of chiral alkoxide anion 9, which reacts with the carbon atom of the nitrile group to give enantioenriched product 3.
Scheme 4. Stereocontrolled γ,δ-Functionalization of 3-Cyano-4-styrylcoumarins via Bifunctional Catalysis: Mechanistic Considerations.
In conclusion, the stereocontrolled γ,δ-functionalization of 2-oxo-4-styryl-2H-chromene-3-carbonitriles with 2-mercaptocarbonyl compounds was established employing bifunctional catalysis. Their reaction proceeded in a vinylogous fashion, providing polycyclic products in a sequence of reaction involving thia-Michael addition, followed by the intramolecular aldol and annulation. The developed cascade enables the introduction of 3,4-dihydrocoumarin, δ-lactone, and tetrahydrothiophene scaffolds in one structure, resulting in biologically important products in high yields and stereoselectivities with a broad scope.
Acknowledgments
This project was realized within the Sonata Bis programme (Grant Number: UMO-2015/18/E/ST5/00309) from the National Science Centre, Poland. Thanks are expressed to Dr. Lesław Sieroń (Lodz University of Technology) for the X-ray analysis.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.2c02836.
Experimental procedures, characterization of the products, NMR data, and HPLC traces (PDF)
Author Contributions
‡ M.R. and A.S. contributed equally.
The authors declare no competing financial interest.
Supplementary Material
References
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