Iodine-Catalyzed Cascade Annulation of 4-Hydroxycoumarins with Aurones: Access to Spirocyclic Benzofuran–Furocoumarins

An attractive approach for the preparation of spirocyclic benzofuran–furocoumarins has been developed through iodine-catalyzed cascade annulation of 4-hydroxycoumarins with aurones. The reaction involves Michael addition, iodination, and intramolecular nucleophilic substitution in a one-step process, and offers an efficient method for easy access to a series of valuable spirocyclic benzofuran–furocoumarins in good yields (up to 99%) with excellent stereoselectivity. Moreover, this unprecedented protocol provides several advantages, including readily available materials, an environmentally benign catalyst, a broad substrate scope, and a simple procedure.

In recent years, combining two rings to generate novel spiro-heterocycles has become an important approach to drug design [12,13].The design and synthesis of biologically active spiro-heterocycles have attracted the attention of many pharmacologists and chemists [14,15].In particular, the spiro-heterocycles that contain benzofuran have become one of the most interesting classes of molecules due to their notable biological activities [ [16][17][18].For example, griseofulvin A is one of the earliest spirocyclic drugs to exhibit antifungal activity [19], while spiro-benzofuran B, with isobenzofuranone and benzofuranone motifs, has been found to be a core chemical skeleton for antivirals against influenza viruses [20].(−)-Spiro-ganodermaine G, which is isolated from the Ganoderma species, displayed suppressive activity on the expression of TGF-β1-induced fibronectin and α-SMA, with a potential role in treating renal fibrosis (Figure 1) [21].Moreover, furocoumarins demonstrate a wide range of biological activities [22,23] as anticancer [24], antioxidant [25], antifungal [26] and antiproliferative [27].Therefore, there is great interest in exploring novel spiro-heterocycles between spiro-benzofurans and furocoumarins.Recently, Cui et al. [28] reported a novel procedure for spirocyclic benzofuran-furocoumarin synthesis, by Lewis acid-catalyzed [3+2]-cyclization of iodonium ylides with azadienes, in moderate yields with excellent stereoselectivity (Scheme 1a).Meanwhile, Yavari et al. [29] developed an electrochemical approach for accessibility to spirocyclic benzofuran-furocoumarin (Scheme 1b).Molecular iodine, as a very simple and efficient reagent, has drawn considerable attention from synthetic chemists, and has been widely used in various organic transformations [30,31].It is widely available, inexpensive, nontoxic, eco-friendly, and moisture resistant, and employed as a catalyst, resulting in the formation of new C-C [32,33], C-N [34,35], C-O [36], and C-S [37,38] bonds.In addition, molecular iodine has been recognized as a powerful tool for constructing the pharmacologically important heterocyclic rings [39][40][41].Currently, several approaches have also been disclosed for the synthesis of spiro-heterocycles through iodine-mediated cascade reactions [42][43][44].
Based on the above discussion and our interest in exploring novel synthetic strategies for the construction of spiro-heterocycles, we developed an iodine-catalyzed cascade reaction of 4-hydroxycoumarins with aurones to afford spirocyclic benzofuran-furocoumarins with high stereoselectivity.This transformation displayed favorable compatibility for developed an electrochemical approach for accessibility to spirocyclic benzofuran-furocoumarin (Scheme 1b).
Scheme 1. Strategies for the synthesis of spirocyclic benzofuran-furocoumarins.Molecular iodine, as a very simple and efficient reagent, has drawn considerable attention from synthetic chemists, and has been widely used in various organic transformations [30,31].It is widely available, inexpensive, nontoxic, eco-friendly, and moisture resistant, and employed as a catalyst, resulting in the formation of new C-C [32,33], C-N [34,35], C-O [36], and C-S [37,38] bonds.In addition, molecular iodine has been recognized as a powerful tool for constructing the pharmacologically important heterocyclic rings [39][40][41].Currently, several approaches have also been disclosed for the synthesis of spiro-heterocycles through iodine-mediated cascade reactions [42][43][44].
Based on the above discussion and our interest in exploring novel synthetic strategies for the construction of spiro-heterocycles, we developed an iodine-catalyzed cascade reaction of 4-hydroxycoumarins with aurones to afford spirocyclic benzofuran-furocoumarins with high stereoselectivity.This transformation displayed favorable compatibility for the preparation of various spirocyclic benzofuran-furocoumarins using I 2 as the efficient and green catalyst.

Result and Discussion
Initially, the reaction of 4-hydroxycoumarin 1a and aurone 2a was investigated to optimize the reaction conditions.The experimental results are summarized in Table 1.Fortunately, the desired spirocyclic benzofuran-furocoumarin 3a obtained a 54% yield from the reaction with 20 mol % of I 2 at 80 • C (Table 1, entry 1).The structure of 3a was determined based on their NMR spectroscopic similarities compared with the observed results [28,29].In order to improve the efficacy of the reaction, different temperatures were evaluated for the reaction, and it was found that the yield of 3a could be improved to 58% at 100 • C (Table 1, entry 2).Increasing the amount of I 2 did not yield better results (Table 1, entry 4).Subsequently, the effect of an additive was investigated, such as L-proline, TBAI, and TEBAC.It was found that TEBAC afforded the desired product 3a in better yields (Table 1, entries [5][6][7].Furthermore, increasing the amount of TEBAC loading to 40 mol % gave a higher yield of 3a at 68% (Table 1, entry 9).Notably, changing the ratio of 2a/1a from 1:1.3 to 1:1.5 (Table 1, entries [10][11][12] improved the yield of 3a to 82% within 16 h (Table 1, entry 12).Therefore, the optimized reaction conditions for 3a were 20 mol % of iodine as the catalyst, and 40 mol % of TEBAC as the additive, in DMSO at 100  the preparation of various spirocyclic benzofuran-furocoumarins using I2 as the efficient and green catalyst.

Result and Discussion
Initially, the reaction of 4-hydroxycoumarin 1a and aurone 2a was investigated to optimize the reaction conditions.The experimental results are summarized in Table 1.Fortunately, the desired spirocyclic benzofuran-furocoumarin 3a obtained a 54% yield from the reaction with 20 mol % of I2 at 80 °C (Table 1, entry 1).The structure of 3a was determined based on their NMR spectroscopic similarities compared with the observed results [28,29].In order to improve the efficacy of the reaction, different temperatures were evaluated for the reaction, and it was found that the yield of 3a could be improved to 58% at 100 °C (Table 1, entry 2).Increasing the amount of I2 did not yield better results (Table 1, entry 4).Subsequently, the effect of an additive was investigated, such as L-proline, TBAI, and TEBAC.It was found that TEBAC afforded the desired product 3a in better yields (Table 1, entries [5][6][7].Furthermore, increasing the amount of TEBAC loading to 40 mol % gave a higher yield of 3a at 68% (Table 1, entry 9).Notably, changing the ratio of 2a/1a from 1:1.3 to 1:1.5 (Table 1, entries [10][11][12] improved the yield of 3a to 82% within 16 h (Table 1, entry 12).Therefore, the optimized reaction conditions for 3a were 20 mol % of iodine as the catalyst, and 40 mol % of TEBAC as the additive, in DMSO at 100 °C for 16 h (Table 1, entry 12).With the optimal reaction conditions in hand, the substrate scope of 4-hydroxycoumarins and aurones were explored under standard reaction conditions.And the results are depicted in Scheme 2. The 4-hydroxycoumarins bearing electron withdrawing (F, Cl, Br, NO2) or electron donating groups (OMe, Me) on Ar 1 reacted smoothly, providing good yields of the corresponding spirocyclic benzofuran-furocoumarins, 3ab-3ah and 3bl.The reaction of 4-hydroxy-2H-benzo[h]chromen-2-one also proceeded smoothly and afforded an 86% yield of the spiro products 3ae.For the aurones, both the electron withdrawing (F, Cl, Br) and electron donating groups (OMe, OEt, Me) on Ar With the optimal reaction conditions in hand, the substrate scope of 4-hydroxycoumarins and aurones were explored under standard reaction conditions.And the results are depicted in Scheme 2. The 4-hydroxycoumarins bearing electron withdrawing (F, Cl, Br, NO 2 ) or electron donating groups (OMe, Me) on Ar 1 reacted smoothly, providing good yields of the corresponding spirocyclic benzofuran-furocoumarins, 3ab-3ah and 3bl.The reaction of 4-hydroxy-2H-benzo[h]chromen-2-one also proceeded smoothly and afforded an 86% yield of the spiro products 3ae.For the aurones, both the electron withdrawing (F, Cl, Br) and electron donating groups (OMe, OEt, Me) on Ar 2 of the benzofuranone moieties reacted with 4-hydroxycoumarin efficiently to afford 64−96% yields of the corresponding spiro products 3ai-3ao.However, when the substrate bore a NO 2 group on Ar 2 , the yield of the desired product 3bk decreased to 62%.Subsequently, the effects of the substituents on the phenyl ring of Ar 3 were evaluated.As the results reveal, the electron donating and electron withdrawing substituents of the phenyl ring on Ar 3 have a substantial impact on the efficacy of the reaction.Generally, an electron donating group displayed respectable suitability with good to excellent yields.The weak electron donating groups (CH 3 ) gave an 80% yield of 3ap.Notably, substrates bearing a strong electron donating group (OMe, t Bu) on Ar 3 showed excellent reactivity.The -o-OCH 3 , -p-OCH 3 , and -p-t Bu groups produced yields of 93%, 88%, and 94% for 3ar, 3as and 3aq, respectively, while the substrates bearing three substituent groups of OCH 3 gave the best results 3at with a 99% yield.Adversely, some electron withdrawing groups decreased in reaction efficiency to afford the desired spiro products.For the substrates bearing the strong electron withdrawing groups (-p-NO 2 , -o-F), no desired spiro products were detected due to the competitive elimination pathway affording the coupled products 4au and 4ax with yields of 78% and 77%, respectively.While the COOMe and CN groups were tolerated, they only gave diminished yields of 3az (51%) and 3ba (56%), and a slight amount of the coupled products 4az and 4ba were observed.Interestingly, electron withdrawing groups, such as -m-NO 2 , -m-F, -p-F, Cl, Br, I, -p-CF 3 and Ph, restored the activity and achieved good to excellent yields.Encouragingly, the heterocyclic furan and thiophene groups of Ar 3 are also compatible and effectively furnished 3bi and 3bj with yields of 69% and 84%.A naphthyl group of Ar 3 was also tolerated, and the desired spiro product 3bh was isolated with an 89% yield.
Just as Table 2 has shown, this approach for the synthesis of spirocyclic benzofuran-furocoumarins offers two advantages in terms of broad substrate scope and higher yields compared to reported methods.However, it still suffers from two drawbacks, including long reaction time and high temperature.Just as Table 2 has shown, this approach for the synthesis of spirocyclic benzofuranfurocoumarins offers two advantages in terms of broad substrate scope and higher yields compared to reported methods.However, it still suffers from two drawbacks, including long reaction time and high temperature.To improve the efficiency of this transformation, greener energy sources, including microwave and ultrasonic irradiation, were tested.As the results show, microwave irradiation displays obvious influence, which can improve the yield of 3a from 7% to 30% compared with traditional protocol.However, when ultrasonic irradiation with a Just as Table 2 has shown, this approach for the synthesis of spirocyclic benzofuranfurocoumarins offers two advantages in terms of broad substrate scope and higher yields compared to reported methods.However, it still suffers from two drawbacks, including long reaction time and high temperature.To improve the efficiency of this transformation, greener energy sources, including microwave and ultrasonic irradiation, were tested.As the results show, microwave irradiation displays obvious influence, which can improve the yield of 3a from 7% to 30% compared with traditional protocol.However, when ultrasonic irradiation with a Just as Table 2 has shown, this approach for the synthesis of spirocyclic benzofuranfurocoumarins offers two advantages in terms of broad substrate scope and higher yields compared to reported methods.However, it still suffers from two drawbacks, including long reaction time and high temperature.To improve the efficiency of this transformation, greener energy sources, including microwave and ultrasonic irradiation, were tested.As the results show, microwave irradiation displays obvious influence, which can improve the yield of 3a from 7% to 30% compared with traditional protocol.However, when ultrasonic irradiation with a

51-99%
16 h 100 To improve the efficiency of this transformation, greener energy sources, including microwave and ultrasonic irradiation, were tested.As the results show, microwave irradiation displays obvious influence, which can improve the yield of 3a from 7% to 30% compared with traditional protocol.However, when ultrasonic irradiation with a frequency of 35 KHz was used in the reaction, a 9% yield of 3a was obtained, with a large amount of still unreacted substrate (Table 3).4az and 4ba were observed.Interestingly, electron withdrawing groups, such as -m-NO2, -m-F, -p-F, Cl, Br, I, -p-CF3 and Ph, restored the activity and achieved good to excellent yields.Encouragingly, the heterocyclic furan and thiophene groups of Ar 3 are also compatible and effectively furnished 3bi and 3bj with yields of 69% and 84%.A naphthyl group of Ar 3 was also tolerated, and the desired spiro product 3bh was isolated with an 89% yield.Just as Table 2 has shown, this approach for the synthesis of spirocyclic benzofuranfurocoumarins offers two advantages in terms of broad substrate scope and higher yields compared to reported methods.However, it still suffers from two drawbacks, including long reaction time and high temperature.frequency of 35 KHz was used in the reaction, a 9% yield of 3a was obtained, with a large amount of still unreacted substrate (Table 3).Afterward, control experiments were conducted to investigate the mechanism of the formation of spirocyclic benzofuran-furocoumarins.First, the reaction of 1a and 2a was carried out without I2 under the optimum reaction conditions, and product 3a was not detected (Scheme 3a).Subsequently, substrates 1a and 2a were subjected to TsOH in DMSO at 100 °C, and no desired product was detected (Scheme 3b).Finally, replacement of the solvent with MeCN allowed for trace amounts of the desired product 3a (Scheme 3c).The above results indicate that the formation of 3 is based on the cooperative effect of I2 and DMSO.Afterward, control experiments were conducted to investigate the mechanism of the formation of spirocyclic benzofuran-furocoumarins.First, the reaction of 1a and 2a was carried out without I 2 under the optimum reaction conditions, and product 3a was not detected (Scheme 3a).Subsequently, substrates 1a and 2a were subjected to TsOH in DMSO at 100 • C, and no desired product was detected (Scheme 3b).Finally, replacement of the solvent with MeCN allowed for trace amounts of the desired product 3a (Scheme 3c).The above results indicate that the formation of 3 is based on the cooperative effect of I 2 and DMSO.
Molecules 2024, 29, x FOR PEER REVIEW 6 of 16 frequency of 35 KHz was used in the reaction, a 9% yield of 3a was obtained, with a large amount of still unreacted substrate (Table 3).Afterward, control experiments were conducted to investigate the mechanism of the formation of spirocyclic benzofuran-furocoumarins.First, the reaction of 1a and 2a was carried out without I2 under the optimum reaction conditions, and product 3a was not detected (Scheme 3a).Subsequently, substrates 1a and 2a were subjected to TsOH in DMSO at 100 °C, and no desired product was detected (Scheme 3b).Finally, replacement of the solvent with MeCN allowed for trace amounts of the desired product 3a (Scheme 3c).The above results indicate that the formation of 3 is based on the cooperative effect of I2 and DMSO.According to the experimental results above and the previous literature [45], a plausible pathway is proposed in Scheme 4. First, 4-hydroxycoumarin 1a and aurone 2a undergo Michael addition in the presence of I2 to generate intermediate 5, which captures the proton released from the 4-hydroxycoumarin, thus forming intermediate 6.In this process, TEBAC, as an effective catalyst following the addition of 4-hydroxycoumarin, is

Materials and Methods
Unless otherwise specified, the starting materials and reagents used in the reactions were commercially available and used without further purification.Aurones 2 was prepared by the published procedures [47,48]. 1 H (400 MHz), 13 C (100 MHz), DEPT 135 (100 MHz) and DEPT 90 (100 MHz).NMR spectra were recorded on a Bruker Avance 400 spectrometer in CDCl3 or .HRMS were performed with an AB QSTAR Pulsar mass spectrometer.Melting points were tested on an XT-4A melting-point apparatus without correction.The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254.For column chromatography, silica gel (200-300 mesh) was also employed.
The 1 H NMR and 13 C NMR spectral of the products are given in Supplementary Materials.

Materials and Methods
Unless otherwise specified, the starting materials and reagents used in the reactions were commercially available and used without further purification.Aurones 2 was prepared by the published procedures [47,48]. 1 H (400 MHz), 13 C (100 MHz), DEPT 135 (100 MHz) and DEPT 90 (100 MHz).NMR spectra were recorded on a Bruker Avance 400 spectrometer in CDCl 3 or DMSO-d 6 .HRMS were performed with an AB QSTAR Pulsar mass spectrometer.Melting points were tested on an XT-4A melting-point apparatus without correction.The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254.For column chromatography, silica gel (200-300 mesh) was also employed.
The 1 H NMR and 13 C NMR spectral of the products are given in Supplementary Materials.

Figure 1 .Scheme 1 .
Figure 1.Example of biologically active spiro-benzofuran and furocoumarin derivatives.Molecular iodine, as a very simple and efficient reagent, has drawn considerable attention from synthetic chemists, and has been widely used in various organic transformations[30,31].It is widely available, inexpensive, nontoxic, eco-friendly, and moisture resistant, and employed as a catalyst, resulting in the formation of new C-C[32,33], C-N

Scheme 3 .a
Scheme 3. Control experiments (a-c).According to the experimental results above and the previous literature[45], a plausible pathway is proposed in Scheme 4. First, 4-hydroxycoumarin 1a and aurone 2a undergo Michael addition in the presence of I2 to generate intermediate 5, which captures the proton released from the 4-hydroxycoumarin, thus forming intermediate 6.In this process, TEBAC, as an effective catalyst following the addition of4-hydroxycoumarin, is

Scheme 3 .Scheme 4 .
Scheme 3. Control experiments (a-c).According to the experimental results above and the previous literature [45], a plausible pathway is proposed in Scheme 4. First, 4-hydroxycoumarin 1a and aurone 2a undergo Michael addition in the presence of I 2 to generate intermediate 5, which captures the proton released from the 4-hydroxycoumarin, thus forming intermediate 6.In this process, TEBAC, as an effective catalyst following the addition of 4-hydroxycoumarin, is used to improve the efficiency of the Michael addition reaction [46].Subsequently, intermediate 6 automerizes into its enol-form-intermediate 7. Further electrophilic substitution between intermediate 7 and I 2 is probably activated by DMSO and affords intermediate 8 immediately.

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .

Table 2 .
Comparison between reported methods and this method.

Table 2 .
Comparison between reported methods and this method.

Table 2 .
Comparison between reported methods and this method.

Table 2 .
Comparison between reported methods and this method.

Table 2 .
Comparison between reported methods and this method.

Table 3 .
Comparison between green energy sources and traditional protocol a .

Table 3 .
Comparison between green energy sources and traditional protocol a .

Table 3 .
Comparison between green energy sources and traditional protocol a .