Synthesis of Benzofuran Derivatives via a DMAP-Mediated Tandem Cyclization Reaction Involving ortho-Hydroxy α-Aminosulfones

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields for the respective derivatives. This protocol demonstrates exceptional substrate versatility and robust scalability up to the Gram scale, establishing a stable platform for the synthesis of 3-aminobenzofuran derivative. The successful synthesis paves the way for further biological evaluations with potential implications in scientific research.

The 3-aminobenzofuran scaffold represents a significant subclass within the diverse family of benzofuran-based compounds, occupying a prominent position at the forefront of medical treatment advancements and innovations [12][13][14].Its unique structural features contribute to its promising potential in developing novel therapeutic agents [15][16][17] (Figure 1).Compound C exhibits potent antitumor properties by inducing cell cycle arrest and promoting apoptosis within cellular environments [18].Compound D stands as a crucial constituent in therapeutic agents aimed at alleviating the symptoms of Alzheimer's disease [19].
The 3-amino substitution enhances the biological activities of benzofuran derivatives, prompting research into innovative synthetic strategies to facilitate their clinical applications [20][21][22][23][24]. Recently, Helgren et al. introduced a microwave-facilitated, unprotected group synthesis of 3-amino-2,3-dihydrobenzofurans via chalcone precursors.This synthesis uses acid-catalyzed aldol condensation, reduction, and epoxidation reactions, facilitating C2, C3, and A-ring modifications [25].Wang and colleagues have developed a method for the synthesis of enantiomerically enriched 2,3-dihydrobenzofurans bearing quaternary carbon stereocenters in moderate to excellent yields (31-98%) through the copper/BOX complex-catalyzed reaction of 2-imino-substituted phenols with aryl diazoacetates.This reaction employs readily accessible catalysts and mild reaction conditions, demonstrating broad functional group tolerance, single diastereoisomer formation, and excellent enantioselectivity (88-97% ee).The reaction proceeds via a distinctive mechanism in which the copper catalyst exerts two distinct functions.Initially, it reacts with the diazo compound to generate a metallacarbene.Subsequently, it acts as a Lewis acid to activate the imine following the formation of an oxonium ylide [26].Panday and coworkers swiftly synthesized 3-amino-2-arylbenzofurans at room temperature via Cs 2 CO 3 -catalyzed route, advancing to Cu(II)-catalyzed N-arylation [27].Abtahi and coworkers achieved one-pot 3-aminobenzofuran synthesis using CuI in a deep eutectic solvent [28].The current synthetic methodologies for the construction of 3-aminobenzofuran frameworks, which encompass radical cyclization, coupling-cyclization, and Lewis acid/transition metal catalysis, are frequently impeded by complex purification procedures and rigorous reaction conditions.This hinders their practical applicability.
Molecules 2024, 29, x FOR PEER REVIEW 2 of 17 for the synthesis of enantiomerically enriched 2,3-dihydrobenzofurans bearing quaternary carbon stereocenters in moderate to excellent yields (31-98%) through the copper/BOX complex-catalyzed reaction of 2-imino-substituted phenols with aryl diazoacetates.This reaction employs readily accessible catalysts and mild reaction conditions, demonstrating broad functional group tolerance, single diastereoisomer formation, and excellent enantioselectivity (88-97% ee).The reaction proceeds via a distinctive mechanism in which the copper catalyst exerts two distinct functions.Initially, it reacts with the diazo compound to generate a metallacarbene.Subsequently, it acts as a Lewis acid to activate the imine following the formation of an oxonium ylide [26].Panday and coworkers swiftly synthesized 3-amino-2-arylbenzofurans at room temperature via Cs2CO3-catalyzed route, advancing to Cu(II)-catalyzed N-arylation [27].Abtahi and coworkers achieved one-pot 3-aminobenzofuran synthesis using CuI in a deep eutectic solvent [28].
The current synthetic methodologies for the construction of 3-aminobenzofuran frameworks, which encompass radical cyclization, coupling-cyclization, and Lewis acid/transition metal catalysis, are frequently impeded by complex purification procedures and rigorous reaction conditions.This hinders their practical applicability.Meanwhile, indanone and barbituric acid are prevalent in natural products and bioactive pharmaceutical molecules [29][30][31][32][33].The structures of 1,3-indanedione and 1,3-dimethylbarbituric acid, which serve as pivotal pharmacophore scaffolds, have garnered extensive research attention.The conventional utilization of 1,3-indandione [34] and 1,3-dimethylbarbituric acid [35,36] structures has been primarily focused on their benzylidene unsaturation moiety, offering a rich platform for chemical modifications and diverse functionalization.However, there is a scarcity of reports detailing their involvement in tandem cyclization reactions, highlighting an underexplored area with significant potential for further investigation and development [37][38][39][40].The combined pharmacophore strategy allows us to harness the potential of 1,3-indandione and 1,3-dimethylbarbituric acid to engage in tandem reactions with ortho-hydroxy α-amino sulfones, thereby constructing a series of target products featuring an aminobenzofuranospiroindanone and spirobarbiturate core skeleton.While devising a synthetic route, several unsuccessful attempts were made to utilize halogen-substituted N-succinimides as the primary halogen source (Scheme 1, path a).We then strategically shifted our focus to bromine-substituted 1,3-indandione as the substrate (Scheme 1, path b), a pivotal decision that ultimately led to the synthesis of a product structure with profound implications for the development of novel therapeutic agents.Meanwhile, indanone and barbituric acid are prevalent in natural products and bioactive pharmaceutical molecules [29][30][31][32][33].The structures of 1,3-indanedione and 1,3dimethylbarbituric acid, which serve as pivotal pharmacophore scaffolds, have garnered extensive research attention.The conventional utilization of 1,3-indandione [34] and 1,3dimethylbarbituric acid [35,36] structures has been primarily focused on their benzylidene unsaturation moiety, offering a rich platform for chemical modifications and diverse functionalization.However, there is a scarcity of reports detailing their involvement in tandem cyclization reactions, highlighting an underexplored area with significant potential for further investigation and development [37][38][39][40].The combined pharmacophore strategy allows us to harness the potential of 1,3-indandione and 1,3-dimethylbarbituric acid to engage in tandem reactions with ortho-hydroxy α-amino sulfones, thereby constructing a series of target products featuring an aminobenzofuranospiroindanone and spirobarbiturate core skeleton.While devising a synthetic route, several unsuccessful attempts were made to utilize halogen-substituted N-succinimides as the primary halogen source (Scheme 1, path a).We then strategically shifted our focus to bromine-substituted 1,3indandione as the substrate (Scheme 1, path b), a pivotal decision that ultimately led to the synthesis of a product structure with profound implications for the development of novel therapeutic agents.Scheme 1. Synthesis of 3-aminobenzofuran derivatives and our contributions.Scheme 1. Synthesis of 3-aminobenzofuran derivatives and our contributions.

Optimization of Reaction Conditions
To ascertain the optimal synthetic conditions for the benzofuran-spiroindenone derivative, we employed ortho-hydroxy α-aminosulfone 1a and 2-bromo-1,3-indandione 2a as the starting materials and stirred them in dichloromethane solvent at ambient temperature.This approach facilitated the identification of the most favorable experimental parameters.A preliminary investigation was conducted to assess the impact of various bases on the reaction efficiency (Table 1, entries 1-9).When using NaHCO 3 as the base, the desired product, namely 3aa, was obtained in 42% yield after 20 h reaction (Table 1, entry 1).Subsequently, Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 were subjected to screening.The results demonstrated that the effects of Na 2 CO 3 and K 2 CO 3 were comparable (Table 1, entries 2 and 3).However, when Cs 2 CO 3 was utilized, there was a considerable reduction in the yield (41%) (Table 1, entry 4).A selection of organic bases (Table 1, entries 5-9) was subjected to preliminary screening.When Et 3 N was used, there was no discernible improvement in the reaction yield, which remained at approximately 45% (Table 1, entry 5).Additionally, the other three organic bases, DABCO, DBU, and TMG, were also subjected to preliminary screening.When using these bases in the template reaction, there was no discernible alteration in the actual reaction outcome, with the yield fluctuating around 30% (Table 1, entries 6-8).It is noteworthy that when the organic base DMAP was subjected to evaluation (Table 1, entry 9), the reaction outcome exhibited a notable improvement, resulting in a yield increase of 70%.ature.This approach facilitated the identification of the most favorable experimental parameters.A preliminary investigation was conducted to assess the impact of various bases on the reaction efficiency (Table 1, entries 1-9).When using NaHCO₃ as the base, the desired product, namely 3aa, was obtained in 42% yield after 20 h reaction (Table 1, entry 1).Subsequently, Na2CO3, K2CO3, and Cs2CO3 were subjected to screening.The results demonstrated that the effects of Na2CO3 and K2CO3 were comparable (Table 1, entries 2 and 3).However, when Cs2CO3 was utilized, there was a considerable reduction in the yield (41%) (Table 1, entry 4).A selection of organic bases (Table 1, entries 5-9) was subjected to preliminary screening.When Et3N was used, there was no discernible improvement in the reaction yield, which remained at approximately 45% (Table 1, entry 5).Additionally, the other three organic bases, DABCO, DBU, and TMG, were also subjected to preliminary screening.When using these bases in the template reaction, there was no discernible alteration in the actual reaction outcome, with the yield fluctuating around 30% (Table 1, entries 6-8).It is noteworthy that when the organic base DMAP was subjected to evaluation (Table 1, entry 9), the reaction outcome exhibited a notable improvement, resulting in a yield increase of 70%.
Following the identification of the optimal base, a screening of solvents for the reaction was conducted, with the solvents listed in Table 1 (entries 10-15).When dichloroethane (DCE) was employed as the solvent (Table 1, entry 10), the yield was further augmented to 85%.In contrast, when the aromatic hydrocarbon solvent toluene was used, the yield of the reaction was not significantly enhanced (Table 1, 11).The large polar solvents, CH₃CN and EtOH, were also tested (Table 1, 12, and 14), but no improvement was observed in the reaction.Apart from exploring protic solvents, we also evaluated aprotic solvents, including THF (Table 1, entry 13) and MTBE (Table 1, entry 15).Nevertheless, the outcomes did not meet our initial expectations of significant enhancement.Through method optimization, it was established that the most favorable reaction conditions entailed utilizing DMAP as the base and DCE as the solvent, leading to a high yield of up to 85% for the desired product.a Unless otherwise specified, the reaction conditions are as follows: ortho-hydroxy α-aminosulfone 1a (0.15 mmol), 2-bromo-1,3-indandione 2a (0.1 mmol), and base (1.0 equiv.)were dissolved in a solvent (1.0 mL), and the reaction was stirred at room temperature.b The yield of silica gel column chromatography separation.
Following the identification of the optimal base, a screening of solvents for the reaction was conducted, with the solvents listed in Table 1 (entries 10-15).When dichloroethane (DCE) was employed as the solvent (Table 1, entry 10), the yield was further augmented to 85%.In contrast, when the aromatic hydrocarbon solvent toluene was used, the yield of the reaction was not significantly enhanced (Table 1, 11).The large polar solvents, CH 3 CN and EtOH, were also tested (Table 1, 12, and 14), but no improvement was observed in the reaction.Apart from exploring protic solvents, we also evaluated aprotic solvents, including THF (Table 1, entry 13) and MTBE (Table 1, entry 15).Nevertheless, the outcomes did not meet our initial expectations of significant enhancement.Through method optimization, it was established that the most favorable reaction conditions entailed utilizing DMAP as the base and DCE as the solvent, leading to a high yield of up to 85% for the desired product.

Substrate Scope
Once the optimal reaction conditions had been determined, a comprehensive investigation was conducted into the substrate scope of this reaction (Scheme 2).The examination of the 5-position substituents on ortho-hydroxy α-aminosulfone revealed that substitution with chlorine or fluorine at this position facilitated the synthesis of the target products 3ca and 3da with good to excellent yields.Unexpectedly, the substitution of the 5-position with bromine led to the synthesis of the desired product 3ba, albeit with a modest yield of merely 50%.It is noteworthy that the strategic substitution of the 5-position in ortho-hydroxy αaminosulfone with electron-rich groups, particularly methoxy and methyl groups, resulted in the successful synthesis of target compounds 3ea and 3fa, which exhibited good yields.Moreover, a comprehensive examination was undertaken to ascertain the impact of substituents at the 4-position on the physicochemical properties of these α-aminosulfones.The substitution of the 4-position with halogen atoms, such as chlorine or bromine, resulted in the successful acquisition of target products 3ga and 3ha with satisfactory yields.Subsequently, the substitution pattern at the 3-position of ortho-hydroxy α-aminosulfone was investigated.When the 3-position was substituted with the electron-donating methoxy group, the reaction failed to yield the desired target product.However, when the 3-position was substituted with halogen bromine or fluorine, the target products 3ia and 3ja were obtained with excellent yields of 90% and 95%, respectively.This highlights the superior reactivity of halogen-substituted ortho-hydroxy α-aminosulfones in comparison to those bearing electron-donating groups.Lastly, the reactivity of the 6-chloro-substituted orthohydroxy α-aminosulfone was evaluated, revealing a smooth reaction course that led to the formation of product 3ka with a good yield of 81%.These findings underscore the intricate interplay between substitution patterns and reactivity patterns in the synthesis of functionalized ortho-hydroxy α-aminosulfones.
Building upon the successful outcomes of the preceding experiment, the tandem cyclization reaction between ortho-hydroxy α-aminosulfone and bromo-substituted 1,3dimethylbarbituric acid was subjected to an extensive optimization process.This refinement effort revealed that the reaction, when conducted with DMAP serving as the base and DCE as the solvent, was capable of producing the target product 5aa in 80% yield.

Scaled-Up Synthesis
To demonstrate the practicality and stability of the DMAP-catalyzed tandem cyclization reaction involving ortho-hydroxy α-aminosulfone, an endeavor has also been made to conduct the reaction on a Gram-scale basis.As depicted in Scheme 4, the initial reaction scale was enlarged by approximately 55-fold.For the Gram-scale synthesis of ortho-hydroxy α-aminosulfone 1a with 2-bromo-1,3-indandione 2a, the target product 3aa was ultimately achieved with the same high yield (85%) as in previous smaller-scale reactions.Nevertheless, in the Gram-scale reaction involving ortho-hydroxy α-aminosulfone 1a and 5-bromo-1,3-dimethylbarbituric acid 4a, the yield decreased slightly but remained moderate (73%), enabling the successful isolation of the target product 5aa.This underscores the considerable potential of this methodology for the large-scale production of such compounds via tandem cyclization reactions.

Scaled-Up Synthesis
To demonstrate the practicality and stability of the DMAP-catalyzed tandem cy tion reaction involving ortho-hydroxy α-aminosulfone, an endeavor has also been m to conduct the reaction on a Gram-scale basis.As depicted in Scheme 4, the initial rea scale was enlarged by approximately 55-fold.For the Gram-scale synthesis of orth droxy α-aminosulfone 1a with 2-bromo-1,3-indandione 2a, the target product 3aa w timately achieved with the same high yield (85%) as in previous smaller-scale react Nevertheless, in the Gram-scale reaction involving ortho-hydroxy α-aminosulfone 1a 5-bromo-1,3-dimethylbarbituric acid 4a, the yield decreased slightly but remained erate (73%), enabling the successful isolation of the target product 5aa.This unders the considerable potential of this methodology for the large-scale production of such pounds via tandem cyclization reactions.

Asymmetric Catalytic Reaction Trials
Drawing upon our previous investigations into asymmetric catalysis [41][42][43], we have embarked on an extended exploration of this particular reaction, aiming for a more profound understanding.Consequently, catalysts C1-C4 with varying structural types were selected for in this asymmetric catalytic reaction (Scheme 6).Firstly, the reactions of cinchona alkaloid-derived squaramide catalysts (C1 and C2) catalyzed addition/cyclization of ortho-hydroxy-α-aminosulfone 1a with 2-bromo-1,3-indandione 2a showed relatively good catalytic performance, with catalyst C2 exhibiting the best performance.The catalytic product 3aa was obtained in 85% yield with 17% ee.When cinchona alkaloid and 1,2-diaminocyclohexane-derived thiourea catalysts (C3 and C4) were employed, the catalytic effect of the reactions was found to be even worse.Furthermore, catalyst C1 was used to catalyze the asymmetric tandem cyclization reaction of ortho-hydroxy α-aminosulfone 1a and 5-bromo-1,3-dimethylbarbituric acid 4a, yet the enantiomeric excess of the product was only 22% ee.Through analysis of the results, it can be seen that the multifunctional hydrogen bond-derived thiourea and squaramide catalysts exhibit generally poor asymmetric catalytic performance for this type of reaction.
ployed, the catalytic effect of the reactions was found to be even worse.Furthermore, catalyst C1 was used to catalyze the asymmetric tandem cyclization reaction of ortho-hydroxy α-aminosulfone 1a and 5-bromo-1,3-dimethylbarbituric acid 4a, yet the enantiomeric excess of the product was only 22% ee.Through analysis of the results, it can be seen that the multifunctional hydrogen bond-derived thiourea and squaramide catalysts exhibit generally poor asymmetric catalytic performance for this type of reaction.Scheme 6.Preliminary evaluation for asymmetric catalytic reaction.* The chiral carbon, absolute configuration not determined.

General Information
In the context of this study, commercially sourced reagents were utilized without undergoing any additional purification procedures.Commonly used solvents, including petroleum ether (boiling range 60-90 °C), ethyl acetate, dichloromethane, xylene, and methanol, as well as other analytical grade reagents, were produced by the Beijing Chemical Plant (Beijing, China).Column chromatography silica gel (200-300 mesh) and thinlayer chromatography silica gel plates were manufactured by Yantai Xinnuo New Materials Technology Co., Ltd.(Yantai, China) and Yantai Dexin Biotechnology Co., Ltd.(Yantai, China), respectively.The melting points were determined using an XT-4 melting point apparatus, and these values were reported without any correction.For nuclear magnetic resonance (NMR) analysis, 1 H NMR spectra were acquired on a Bruker Ascend 400 MHz spectrometer, with chemical shifts expressed in δ (ppm) units, utilizing tetramethylsilane (TMS) as the internal standard for calibration. 13C NMR spectra were recorded at 100 MHz on the same 400 MHz spectrometer, with chemical shifts also reported in ppm, referenced Scheme 6.Preliminary evaluation for asymmetric catalytic reaction.* The chiral carbon, absolute configuration not determined.

General Information
In the context of this study, commercially sourced reagents were utilized without undergoing any additional purification procedures.Commonly used solvents, including petroleum ether (boiling range 60-90 • C), ethyl acetate, dichloromethane, xylene, and methanol, as well as other analytical grade reagents, were produced by the Beijing Chemical Plant (Beijing, China).Column chromatography silica gel (200-300 mesh) and thin-layer chromatography silica gel plates were manufactured by Yantai Xinnuo New Materials Technology Co., Ltd.(Yantai, China) and Yantai Dexin Biotechnology Co., Ltd.(Yantai, China), respectively.The melting points were determined using an XT-4 melting point apparatus, and these values were reported without any correction.For nuclear magnetic resonance (NMR) analysis, 1 H NMR spectra were acquired on a Bruker Ascend 400 MHz spectrometer, with chemical shifts expressed in δ (ppm) units, utilizing tetramethylsilane (TMS) as the internal standard for calibration. 13C NMR spectra were recorded at 100 MHz on the same 400 MHz spectrometer, with chemical shifts also reported in ppm, referenced to TMS, and further calibrated against the solvent peak (CDCl 3 , δC = 77.00).For highresolution mass spectrometry, electron spray ionization (ESI) mass spectra were obtained using an Agilent 6520 Accurate-Mass Q-TOF MS system (Santa Clara, CA, USA), which was equipped with an ESI source and ensured precise and accurate mass measurements.

Experimental Materials for Tandem Reactions
The products 1a-1k were prepared according to the literature reported by Liu and coworkers [43,44].
The Gram-scale preparation method of 5aa is analogous to the aforementioned 3aa.

Conclusions
In summary, a comprehensive series of benzofuran-fused indanone and barbiturate derivatives were synthesized with remarkable success through tandem cyclization reactions, featuring 2-bromo-1,3-indenedione, 5-bromo-1,3-dimethylbarbituric acid, and orthohydroxy α-aminosulfones as pivotal reactants.By meticulously optimizing the reaction conditions with DMAP as the base catalyst, DCE as the solvent, and gentle stirring at room temperature, we achieved exceptional yields of up to 95% and 85% for benzofuran-fused indanone and barbiturate derivatives, respectively.The extension of the substrate scope and the successful execution of Gram-scale syntheses underscored the robustness and versatility of this methodology, significantly expanding the benzofuran derivative library and facilitating further biological evaluations.

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .