Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions

Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 April 2025 V1 Latest version Share on Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions Authors : Shuhong Wang , Xinran Niu , Haojia Zhou , Jiatong Cao , Chenyang Guo , Junbiao Chang , and Bo Zhu 0000-0001-8231-5169 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174401291.17295524/v1 Published The Journal of Organic Chemistry Version of record Peer review timeline 185 views 140 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The acid-controlled single-component retro-aldol/Michael addition cascade reaction and [4+2] cycloaddition of benzofuran-derived azadienes (BDAs) are reported for the first time. Under the conditions of trifluoromethanesulfonic acid as the catalyst and with the addition of water, BDAs initiate the retro-aldol reaction, followed by a 1,4-Michael addition, yielding (arylmethylene)bis-(dibenzofuran) products with excellent yields and broad substrate applicability. This represents the first application of BDAs in a retro-aldol reaction. In contrast, in the absence of water and with boron trifluoride etherate as the catalyst, BDAs undergo a [4+2] cycloaddition reaction, constructing the spiro[benzofuran-2,3’-benzofuro[3,2-b]pyridine] framework with high yields and diastereoselectivity. The method features mild conditions, high atom economy, and provides a new approach for constructing benzofuran scaffold derivatives. Cite this paper: Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions Shuhong Wang, a , b Xinran Niu, b Haojia Zhou, b Jiatong Cao, b Chenyang Guo,* , a Junbiao Chang,* , a and Bo Zhu* , a a Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Schoof of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China. b College of Chemistry and Environmental Engineering, Anyang Institute of Technology, Anyang, Henan 455000, China. Acid-Regulated | BDAs | Benzofuran | Retro-Aldol Reaction | Cycloaddition Reaction Comprehensive Summary The acid-controlled single-component retro-aldol/Michael addition cascade reaction and [4+2] cycloaddition of benzofuran-derived azadienes (BDAs) are reported for the first time. Under the conditions of trifluoromethanesulfonic acid as the catalyst and with the addition of water, BDAs initiate the retro-aldol reaction, followed by a 1,4-Michael addition, yielding (arylmethylene)bis-(dibenzofuran) products with excellent yields and broad substrate applicability. This represents the first application of BDAs in a retro-aldol reaction. In contrast, in the absence of water and with boron trifluoride etherate as the catalyst, BDAs undergo a [4+2] cycloaddition reaction, constructing the spiro[benzofuran-2,3’-benzofuro[3,2-b]pyridine] framework with high yields and diastereoselectivity. The method features mild conditions, high atom economy, and provides a new approach for constructing benzofuran scaffold derivatives. Background and Originality Content Heterocycles are crucial components of many natural products and pharmaceuticals. Benzofuran and its derivatives serve as key heterocyclic scaffold and are widely found in drugs and biologically active molecules (Scheme 1A). 1-4 Ganodone , a naturally occurring benzofuran derivative, is recognized as a potential natural source of anticancer agents. 2 In addition, benzofuran-based drugs, such as Dronedarone and Amiodarone , are known for their ability to inhibit rapid heart rhythms. 3 Thus, the synthesis of benzofuran derivatives has attracted widespread attention in the field of organic synthesis. 4 Scheme 1. (A) Natural products and drug molecules containing benzofuran frameworks. (B) A summary of reactions of BDAs. (C) Acid-controlled cascade reaction and cycloaddition reaction of BDAs. The reaction of benzofuran-derived azadienes (BDAs) was first introduced by Zhao’s group in 2016. 5 After experiencing rapid development, BDAs-involving reactions have emerged as a powerful tool for the synthesis of benzofuran-containing heterocyclic compounds. Extensive research has been carried out on the application of BDAs as 4-atom synthons in [4+n] cycloaddition reactions to construct benzofuran-fused aza-heterocyclic structures (Scheme 1Ba). 6,7 Meanwhile, several reports have elaborated on the construction of spiro- benzofuran frameworks via [2+n] cycloaddition reactions, in which BDAs act as 2-atom synthons (Scheme 1Bb). 8 Additionally, the utilization of BDAs as Michael acceptors in 1,4-addition reactions with diverse nucleophiles has also witnessed rapid development (Scheme 1Bc). 9 Despite the significant contributions of these studies, the importance of the benzofuran structure makes exploring new cycloaddition and addition reactions of BDAs highly desirable. Moreover, to date, no reports have been made on single-component cycloaddition reactions involving BDAs, in which BDAs act as both 4-atom synthons and 2-carbon synthons. The retro-aldol reaction, an efficient method for C−C bond cleavage, has been widely studied and applied in various cascade conversion processes, total synthesis, and kinetic resolution. 10 However, no reports have been published on the retro-aldol reactions of BDAs. Here, we report unprecedented single-component reactions with BDAs, where the retro-aldol/Michael addition cascade reaction and [4+2] cycloaddition reaction can be selectively controlled by the addition of different acids and are precisely orchestrated to occur in a 1:1 ratio, affording two distinct benzofuran derivatives with good to excellent yields and chemical selectivity (Scheme 1C). This work not only provides two novel benzofuran scaffolds but also represents the first example of a single-component reaction involving BDAs. Results and Discussion Our investigations began with the retro-aldol/Michael addition cascade reaction of 1a in the presence of an acid catalyst in CHCl 3 at room temperature. Table 1 Optimization of the retro-aldol / Michael addition cascade and [4+2] cycloaddition reactions. 1 HCOOH CHCl 3 rt nd - 2 CH 3 COOH CHCl 3 rt nd 3 HBF 4 (48w%, H 2 O) CHCl 3 rt trace - 4 CF 3 COOH CHCl 3 rt trace - 5 CF 3 SO 3 H CHCl 3 rt 51 29 6 BF 3 ·Et 2 O CHCl 3 rt 35 47 7 InCl 3 CHCl 3 rt 19 23 8 CF 3 SO 3 H CHCl 3 40 41 42 9 CF 3 SO 3 H CHCl 3 0 48 21 10 d CF 3 SO 3 H CHCl 3 rt 82 13 11 e CF 3 SO 3 H CHCl 3 rt 78 trace 12 d,f CF 3 SO 3 H CHCl 3 :EA (3:1) rt 90 - 13 BF 3 ·Et 2 O EA rt - nd 14 BF 3 ·Et 2 O Tol rt - trace 15 BF 3 ·Et 2 O DCM rt - 79 16 BF 3 ·Et 2 O Acetone rt - 25 17 BF 3 ·Et 2 O MeCN rt - 22 18 BF 3 ·Et 2 O THF rt - nd 19 g BF 3 ·Et 2 O DCM rt - 85 20 h BF 3 ·Et 2 O DCM rt - 85 21 g BF 3 ·Et 2 O DCM 40 - 92 22 g BF 3 ·Et 2 O DCM 50 - 92 a Unless otherwise stated, the reactions were carried out at the 0.2 mmol scale in a solvent (2 mL) for 3 h. b Isolated yield. c The dr value was determined by crude 1 H NMR and dr > 20:1. d 0.5 equiv of H 2 O was added. e 0.75 equiv of H 2 O was added. f The reaction time is 4 h. g 15 mol% of BF 3 ·Et 2 O was used. h 20 mol% of BF 3 ·Et 2 O was used. HCOOH and CH 3 COOH were found to be unsuitable for catalyzing this reaction, and no related product was detected (entries 1-2). When HBF 4 (48 wt%, in H₂O) and CF 3 COOH were applied to the reaction, only trace amounts of the product were observed (entries 3-4). However, when CF 3 SO 3 H was added to the reaction system, the product 2a was obtained with a yield of 51%. Additionally, we were surprised to observe the formation of a novel [4+2] cycloaddition product 3a under this condition, with a yield of 29% and excellent diastereoselectivity (dr > 20:1) (entry 5). The structures of 2a and 3a were determined via single-crystal X-ray analyses, respectively. Encouraged by these promising results, we continued to optimize various acid catalysts, including HCl (12 M), H 2 SO 4 (12 M), HNO 3 (12 M) and BF 3 ·Et 2 O, InCl 3 . However, the results showed that inorganic acids had almost no catalytic effect on the cascade reaction (see Supporting Information), while both of the Lewis acids led to lower yields of 2a (entries 6-7). In contrast, BF 3 ·Et 2 O performed better in the formation of 3a , achieving a yield of 47% (entry 6). Different solvents were also examined, but no enhancement was observed compared to CHCl 3 (see Supporting Information). Increasing the temperature is more conducive to the formation of 3a , while the yield of 2a is lower (entry 8). Lowering the temperature is unfavorable for the formation of both products (entry 9). Subsequently, we found that adding 0.5 equiv of H 2 O to the reaction system significantly increased the yield of 2a to 82% (entry 10). We speculated that the addition of water promotes the retro-aldol reaction. When the amount of H 2 O was increased to 0.75 equiv, the yield of 2a dropped to 78% (entry 11). This is presumably due to the excess water weakening the catalytic performance of the catalyst and reducing the reaction efficiency. To further diminish the formation of 3a and enhance the yield of 2a , we tried utilizing a mixed solvent with CHCl 3 : EA= 3:1 (v:v), and pleasingly, the yield of 2a climbed to 90% (entry 12). Meanwhile, the product 3a possesses an unprecedented and valuable spiro[benzofuran-2,3’-benzofuro[3,2- b ]pyridin] skeleton structure. Given the potential utility of spiro-benzofuran scaffolds, 11 after achieving a yield of 47% with BF 3 ·Et 2 O as the catalyst, we continued to optimize the reaction conditions for 3a with respect to solvent (entries 13-18), catalyst equivalent (entries 19-20) and temperature (entries 21-22). Ultimately, we achieved the optimal reaction conditions with a yield of 92% and excellent diastereoselectivity (dr > 20:1) (entry 21). Scheme 2. Substrate scope of the retro-aldol / Michael addition cascade reaction. Reaction conditions: BDAs (0.2 mmol), CF 3 SO 3 H (10 mmol%, 1.8 μL), H 2 O (0.5 eq), CHCl 3 /EA (V:V = 3:1, 2mL), at room temperature. Subsequently, a variety of BDAs substrates were examined under the optimal reaction conditions (entry 12, Table 1). A series of substrates 1 with different substituents at the ortho , meta , and para positions of the phenyl ring attached to the alkenyl groups can all yield the target product 2 in moderate to excellent yield (70-98%). Among these, obvious electronic effects were found in p -substituted BDAs. Substrates with electron-withdrawing groups ( 2e - 2g ) offered higher yields than those with -donating groups ( 2b - 2d ). Functional groups such as chloro- ( 2f and 2k ) and bromo- ( 2l ) exhibited good reactivity, and broadening the potential applications in synthesis. Perhaps due to the large steric hindrance, the reaction time for 1m needed to be extended to 47 hours. Increasing the number of substituents on the benzene ring to two, regardless of whether they occupied the 3,4-positions ( 2o , 2p ) or the 3,5-positions ( 2q , 2r ), had no effect on product formation. Substrates with bulky substituents, such as 1-naphthyl ( 1s ) and 2-naphthyl ( 1t ), can also yield the corresponding products in 91% and 88%, respectively. However, it is important to note that the reaction time for 1s needs to be prolonged to 28 hours to achieve high efficiency. To further investigate the influence of substituents on the imine nitrogen atom, a wide array of substituents present on the sulfonamide portion of BDAs was evaluated. The results indicated that the substituents on the sulfonamide moiety had no detrimental effects on the reaction, yielding excellent productivities ranging from 80% to 98% ( 2u - 2ab ) . Scheme 3. Substrate scope of the Diels-Alder cycloaddition. Reaction conditions: BDAs (0.2 mmol), BF 3 •Et 2 O (15 mmol%, 3.8 μL), DCM (2mL), at 40 ℃. The dr values of all products from 3a to 3ad are greater than 20:1. After determining the substrates scope of the retro-aldol/Michael addition cascade reaction, we then investigated the generality for the synthesis of spiro-benzofuran frameworks 3. The electronic and steric effects of the aryl substituents attached to the alkene were not significant. BDAs with different electronic properties, including those with meta - (3b-3f) and para -substituents (3g-3o), all undergo smooth [4+2] cycloaddition reactions, yielding a series of spiro-benzofuran products with yields ranging from 75% to 92%. Furthermore, both augmenting the number of substituents on the benzyl phenyl ring (3p-3s) and substituting it with a bulky naphthalene group (3t) exhibited good to excellent reaction tolerance. We found that the functional groups on benzofuran core affected the reaction efficiency. For example, the methoxy-substituted substrate required 90 hours of reaction time to obtain the corresponding product 3u with a yield of 70% due probably to electronic effects of the methoxy units which deactivate the dienophile in the Diels-Alder reaction. Additionally, substrates bearing diverse sulfonamide substituents efficiently produced the corresponding products in high yields. Notably, the chloro- (3z, 3aa) and bromo-substituted products (3ab) offer possibilities for further transformations and applications. Even the nitro group, a strong electron-withdrawing substituent, led to the formation of product 3ad with a satisfactory yield. To demonstrate the potential utility of the Diels-Alder cycloaddition and the retro-aldol/1,4-addition cascade reaction, scaled-up syntheses were subsequently carried out under standard reaction conditions, affording the corresponding products 2a and 3a in 78% and 73% isolated yields, respectively (Scheme 4a). Furthermore, we performed several synthetic transformations of the spiro-product 3f (Scheme 4b). First, 3f was treated with potassium carbonate to yield a benzofuro[3,2- b ] pyridine product 4 , whose structure was confirmed by single-crystal X-ray diffraction analysis. Second, after reacting 3f with potassium carbonate, the addition of H 2 O to the reaction mixture and extension of the stirring time led to the formation of product 5 with an 85% yield. Additionally, compound 3f was converted into product 6 with a 90% yield and >20:1 dr via a coupling reaction. Scheme 4. Scale-up reactions and further transformations of 3f . Based on the experimental evidence that equal amounts of aromatic aldehydes were generated when forming product 2 , and supported by relevant literature, 7,12 a plausible mechanism was proposed in Scheme 5. After acid catalysis and the addition of water, 1a first forms intermediate B , which then undergoes isomerization and a retro-aldol reaction to yield the benzofuran intermediate C , along with the elimination of one molecule of benzaldehyde. Intermediate C then undergoes a Michael addition with activated A to generate the target product 2a . Under anhydrous conditions, 1a , activated by a Lewis acid, undergoes a [4+2] cycloaddition reaction to generate the spiro-benzofuran product 3a. Scheme 5. Proposed mechanism for the cascade reaction and [4+2] cycloaddition. Conclusions In summary, we have successfully developed a novel reaction methodology, using acid catalysis to achieve the first-ever single-component retro-aldol/Michael addition cascade reaction and [4+2] cycloaddition of BDAs with excellent chemical selectivity. This method offers several advantages, including good to excellent yields, metal-free conditions, a broad substrate scope, and mild reaction conditions. Notably, the [4+2] cycloaddition reaction also demonstrates excellent diastereoselectivity. Two novel benzofuran frameworks were otained through this method, which have potential value in natural product synthesis and drug discovery. Experimental General pcocedure for the retro-aldol/Michael addition cascade reaction . A dried tube with a magnetic stir bar was charged with benzofuran-derived azadiene 1 (0.2 mmol, 1.0 equiv ), CHCl 3 (1.5 mL), ethyl acetate (EA, 0.5 mL), followed by the addition of H 2 O (1.8 μL ) and trifluoromethanesulfonic acid ( CF 3 SO 3 H, 1.8 μL , 0.1 equiv ). The reaction mixture was stirred for 4-48 h at room temperature . After the reaction was confirmed complete via TLC analysis, it was quenched by the addition of 2 drops saturated sodium bicarbonate solution. Subsequently, the mixture was dried over anhydrous Na₂SO₄ and filtered, then the combined organic solution was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel, using petroleum ether/ethyl acetate (12:1-6:1, v/v) with 1% glacial acetic acid as the eluent to get white solid 2 . General pcocedure for the [4+2] cycloaddition reaction. To a dried 25 mL schlenk tube equipped with a magnetic stir bar, benzofuran-derived azadiene 1 (0.2 mmol, 1.0 equiv ), dichloromethane (DCM, 2 mL), and boron trifluoride diethyl etherate (BF 3 ·Et 2 O, 3.8 μL , 0.15 equiv ) were added in sequence. The reaction mixture was stirred at 40 ℃ for 3-96 h . After the completion of the reaction monitored by TLC, the reaction was quenched with 2 drops saturated sodium bicarbonate solution, Then the mixture was dried over anhydrous Na₂SO₄ and filtered. The solvent of the combined organic phase was removed under reduced pressure and the residue was purified by flash chromatography over silica gel, using petroleum ether/ethyl acetate (12:1-6:1, v/v) with 1% triethylamine as the eluent to get white solid 3 . Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.202400xxx. Acknowledgement This work was supported by the National Natural Science Foundation of China (82473767 and 82130103), the Research Project from Pingyuan Laboratory (2023PY-ZZ-0204), and the Central Plains Scholars and Scientists Studio Fund (2018002). We also acknowledge financial support from the Henan Key Laboratory of Organic Functional Molecules and Drug Innovation. References [1] (a) Abbas, A. A.; Dawood, K. M. Benzofuran as a Promising Scaffold for the Synthesis of Novel Antimicrobial Agents. Expert Opin. Drug Discov. 2022 , 17, 1357-1376; ( b) Chand, K.; Rajeshwari; Hiremathad, A.; Singh, M.; Santos, M. A.; Keri, R. S. A Review on Antioxidant Potential of Bioactive Heterocycle Benzofuran: Natural and Synthetic Derivatives. Pharmacol. Rep. 2017 , 69, 281-295; (c) Dawood, K. M. An Update on Benzofuran Inhibitors: A Patent Review. Expert Opin. 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NHC-Catalysed Retro-Aldol/Aldol Cascade Reaction Enabling Solvent-Controlled Stereodivergent Synthesis of Spirooxindoles. Chin. Chem. Lett. 2021, 32 , 2567-2571; (b) Nan, J.; Chen, P.; Zhang, Y.; Yin, Y.; Wang, B.; Ma, Y. Metal-Free Synthesis of 2-Substituted Quinolines via High Chemoselective Domino Condensation/Aza-Prins Cyclization/Retro-Aldol between 2-Alkenylanilines with β-Ketoesters. J. Org. Chem. 2020, 85, 14042-14054. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Left to Right: (Top) Shuhong Wang, Xinran Niu, Haojia Zhou, Jiatong Cao, (Bottom) Chenyang Guo, Junbiao Chang, Bo Zhu Entry for the Table of Contents Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions Shuhong Wang, Xinran Niu, Haojia Zhou, Jiatong Cao, Chenyang Guo,* Junbiao Chang,* and Bo Zhu* Chin. J. Chem. 2024 , 42 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX The acid-controlled single-component retro-aldol/Michael addition cascade reaction and [4+2] cycloaddition of BDAs are reported for the first time. Both reactions exhibit excellent yields, moreover, the [4+2] cycloaddition reaction also demonstrates high diastereoselectivity (dr >20:1). Information & Authors Information Version history V1 Version 1 07 April 2025 Peer review timeline Published The Journal of Organic Chemistry Version of Record 20 May 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords acid-regulated bdas benzofuran cycloaddition reaction retro-aldol reaction Authors Affiliations Shuhong Wang Henan Normal University View all articles by this author Xinran Niu Anyang Institute of Technology View all articles by this author Haojia Zhou Anyang Institute of Technology View all articles by this author Jiatong Cao Anyang Institute of Technology View all articles by this author Chenyang Guo Henan Normal University View all articles by this author Junbiao Chang Henan Normal University View all articles by this author Bo Zhu 0000-0001-8231-5169 [email protected] Henan Normal University View all articles by this author Metrics & Citations Metrics Article Usage 185 views 140 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shuhong Wang, Xinran Niu, Haojia Zhou, et al. Acid-Regulated Selective Synthesis of Benzofuran Derivatives via Single-Component BDAs Retro-Aldol/Michael Addition Cascade and [4+2] Cycloaddition Reactions. 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