An Easy Access to Furan-Fused Polyheterocyclic Systems

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles.


Introduction
Benzo-and naphtho-fused furans and dihydrofurans are structural motifs abundantly distributed in natural products characterized by a wide spectrum of different biological activities [1]. For instance, Furomollugin and Rubicordifolin, isolated from the roots of Rubia Cordifolia, show activity against the hepatitis B virus and cytotoxicity against some tumoral cell lines [2]; Balsaminone A, isolated from the fruit of Impatiens balsamina L., is used for the treatment of articular rheumatism, bruises, and beriberi in Chinese traditional medicine [3], while Xylarianaphthol-1, isolated from a marine sponge-derived fungus of order Xylariales, is a p21 activator promoter and contributes to cancer prevention and treatment [4] (Figure 1).

Introduction
Benzo-and naphtho-fused furans and dihydrofurans are structural motifs abundantly distributed in natural products characterized by a wide spectrum of different biological activities [1]. For instance, Furomollugin and Rubicordifolin, isolated from the roots of Rubia Cordifolia, show activity against the hepatitis B virus and cytotoxicity against some tumoral cell lines [2]; Balsaminone A, isolated from the fruit of Impatiens balsamina L., is used for the treatment of articular rheumatism, bruises, and beriberi in Chinese traditional medicine [3], while Xylarianaphthol-1, isolated from a marine sponge-derived fungus of order Xylariales, is a p21 activator promoter and contributes to cancer prevention and treatment [4] (Figure 1). Although in nature naphtho [1,2-b]furans and 2,3-dihydronaphtho [1,2-b]furans, such as those in Figure 1, are more common, in synthetic pharmacologically-active compounds, naphtho-and 1,2-dihydronaphtho [2,1-b]furan derivatives are more diffuse and exhibit a broad spectrum of different biological properties, such as anticancer [5,6]; anti- Although in nature naphtho [1,2-b]furans and 2,3-dihydronaphtho [1,2-b]furans, such as those in Figure 1, are more common, in synthetic pharmacologically-active compounds, naphtho-and 1,2-dihydronaphtho [2,1-b]furan derivatives are more diffuse and exhibit a broad spectrum of different biological properties, such as anticancer [5,6]; anti-inflammatories [7] inflammatories [7] or antitubercular agents [8]; regulators of nuclear receptor HNF4-α [9]; and inhibitors of α-chymotrypsin, lipoxygenase, and C17,20 lyase [10][11][12] (Figure 2). Furthermore, the importance of these scaffolds is also due to the optical properties of some particular compounds, such as, for instance, vinylidene-naphthofurans, which show photochromism at room temperature in the solid state when adsorbed on silica gel or exposed to UV or sunlight [13], or NDFs (naphthodifurans) and ADFs (anthradifurans), which have been studied for their applications as hole-transporting materials and photosensitizers [14] (Figure 3). Due to their wide range of applications, many synthetic methods for the preparation of naphtho-and dihydronaphthofuran derivatives have been reported (Scheme 1)-the most common involving either the cyclization of a properly functionalized naphthol [15][16][17] or the two-step intermolecular reaction of a naphthol with a suitable reagent, followed by cyclization to give the final heterocyclic system. More often, basic conditions are employed to improve the reactivity of naphthol as double nucleophile, as, for instance, in the classical approach of the annulation of 2-naphthol with dihalo compounds [18]. However, the use of p-TSA [19,20] or of metal catalysis [21][22][23][24][25][26][27][28] has also been pursued. Furthermore, the importance of these scaffolds is also due to the optical properties of some particular compounds, such as, for instance, vinylidene-naphthofurans, which show photochromism at room temperature in the solid state when adsorbed on silica gel or exposed to UV or sunlight [13], or NDFs (naphthodifurans) and ADFs (anthradifurans), which have been studied for their applications as hole-transporting materials and photosensitizers [14] (Figure 3).
Molecules 2022, 27, x FOR PEER REVIEW 2 of 17 inflammatories [7] or antitubercular agents [8]; regulators of nuclear receptor HNF4-α [9]; and inhibitors of α-chymotrypsin, lipoxygenase, and C17,20 lyase [10][11][12] (Figure 2). Furthermore, the importance of these scaffolds is also due to the optical properties of some particular compounds, such as, for instance, vinylidene-naphthofurans, which show photochromism at room temperature in the solid state when adsorbed on silica gel or exposed to UV or sunlight [13], or NDFs (naphthodifurans) and ADFs (anthradifurans), which have been studied for their applications as hole-transporting materials and photosensitizers [14] (Figure 3). Due to their wide range of applications, many synthetic methods for the preparation of naphtho-and dihydronaphthofuran derivatives have been reported (Scheme 1)-the most common involving either the cyclization of a properly functionalized naphthol [15][16][17] or the two-step intermolecular reaction of a naphthol with a suitable reagent, followed by cyclization to give the final heterocyclic system. More often, basic conditions are employed to improve the reactivity of naphthol as double nucleophile, as, for instance, in the classical approach of the annulation of 2-naphthol with dihalo compounds [18]. However, the use of p-TSA [19,20] or of metal catalysis [21][22][23][24][25][26][27][28] has also been pursued. Due to their wide range of applications, many synthetic methods for the preparation of naphtho-and dihydronaphthofuran derivatives have been reported (Scheme 1)-the most common involving either the cyclization of a properly functionalized naphthol [15][16][17] or the two-step intermolecular reaction of a naphthol with a suitable reagent, followed by cyclization to give the final heterocyclic system. More often, basic conditions are employed to improve the reactivity of naphthol as double nucleophile, as, for instance, in the classical approach of the annulation of 2-naphthol with dihalo compounds [18]. However, the use of p-TSA [19,20] or of metal catalysis [21][22][23][24][25][26][27][28] has also been pursued.
However, since most of the protocols reported in the literature [29,30] suffer from some limitations, such as, for instance, the substrate scope and the possibility to obtain differently functionalized products, the development of more versatile methods is still a topic of interest. In this context, nitrostyrenes have been considered as useful annulation reagents in the reaction with naphthols, because of their ability to react as double electrophiles with the bidentate naphthol enolate, generated in situ under basic conditions. Particular functionalization of the nitro-compound, as, for example, in Morita-Baylis-Hillman [31], together with different reaction conditions, could lead to naphthodihydrofuran or to naphthofuran derivatives, in this case, occasionally with the help of an increase of temperature. However, since most of the protocols reported in the literature [29,30] suffer from some limitations, such as, for instance, the substrate scope and the possibility to obtain differently functionalized products, the development of more versatile methods is still a topic of interest. In this context, nitrostyrenes have been considered as useful annulation reagents in the reaction with naphthols, because of their ability to react as double electrophiles with the bidentate naphthol enolate, generated in situ under basic conditions. Particular functionalization of the nitro-compound, as, for example, in Morita-Baylis-Hillman [31], together with different reaction conditions, could lead to naphthodihydrofuran or to naphthofuran derivatives, in this case, occasionally with the help of an increase of temperature. Scheme 1. Literature-reported methods [15,[17][18][19]21] (a), (b) and the approach of the present work (c).
As a matter of fact, starting from a pioneering report [32], during our previous studies, while exploring the reactivity of different nucleophiles towards nitrobutadienes generated by an initial ring-opening of nitrothiophenes [33][34][35], we obtained a great variety of nitrogen-containing heterocycles, such as methyleneazetidines [36], pyrroles [37], pyrazoles [38], carbazoles [39], imidazo[1,2-a]pyridines [40], and nitroindoles [41]. However, the involvement of nucleophiles able to generate O-heterocycles, as, for instance, enols, has not been investigated so far. In order to fill the gap and to obtain furan-fused derivatives, the reaction between nitrobutadienic building blocks and aromatic enolates has been now thoroughly investigated and relevant results are reported hereinafter.

Results
Within this context, we considered of particular interest the hypothesizable outcome of the double nucleophilic attack of β-naphthol on 4a (Ar = p-tol). This particular substrate actually is not exactly a nitrobutadiene, but rather a nitrostilbene, deriving from the initial ring-opening of 3-nitrobenzo[b]thiophene with pyrrolidine [42] (Scheme 2). From the ringopening product 2, sulfane 3a (Ar = p-tol) originates by reaction with p-tolyl magnesium bromide; the following oxidation at sulfur with MCPBA produces sulfone 4a. Therefore, the nitrobutadienes 3a and 4a retain the reactivity of the nitrovinyl moiety, gaining at the same time stability, thanks to the inclusion of the conjugated double bond within a benzene ring.
razoles [38], carbazoles [39], imidazo[1,2-a]pyridines [40], and nitroindoles [41]. However, the involvement of nucleophiles able to generate O-heterocycles, as, for instance, enols, has not been investigated so far. In order to fill the gap and to obtain furan-fused derivatives, the reaction between nitrobutadienic building blocks and aromatic enolates has been now thoroughly investigated and relevant results are reported hereinafter.

Results
Within this context, we considered of particular interest the hypothesizable outcome of the double nucleophilic attack of β-naphthol on 4a (Ar = p-tol). This particular substrate actually is not exactly a nitrobutadiene, but rather a nitrostilbene, deriving from the initial ring-opening of 3-nitrobenzo[b]thiophene with pyrrolidine [42] (Scheme 2). From the ring-opening product 2, sulfane 3a (Ar = p-tol) originates by reaction with p-tolyl magnesium bromide; the following oxidation at sulfur with MCPBA produces sulfone 4a. Therefore, the nitrobutadienes 3a and 4a retain the reactivity of the nitrovinyl moiety, gaining at the same time stability, thanks to the inclusion of the conjugated double bond within a benzene ring. Quite rewardingly, a TLC analysis of the reaction mixture obtained after 18 h in the conditions of Scheme 2 showed the absence of the substrate and the presence of a single product as a white solid. Spectroscopic analysis ( 1 H and 13 C NMR, MS) revealed the structure of 5a (Scheme 3, Ar = p-tol), isolated in excellent yields as a single diastereoisomer, without need of purification by column chromatography. We thus considered it worthwhile to investigate the scope of this reaction as to the Ar moiety, introducing groups with different electronic or steric features. Sulfanes 3b-f and sulfones 4b-f were prepared according to Scheme 1, and the latter were initially reacted with β-naphthol (Scheme 3). The obtained results, reported in Table 1, show a generally very good behaviour of 4, whatever the aryl substituent. In each case, the obtained diastereoisomer revealed at the 1 HNMR analysis a J of about 5-7 Hz for the dihydrofuran moiety, corresponding presumably to the anti-configuration, as expected on the grounds of a process under thermodynamic control. In order to ascertain without any doubt the Quite rewardingly, a TLC analysis of the reaction mixture obtained after 18 h in the conditions of Scheme 2 showed the absence of the substrate and the presence of a single product as a white solid. Spectroscopic analysis ( 1 H and 13 C NMR, MS) revealed the structure of 5a (Scheme 3, Ar = p-tol), isolated in excellent yields as a single diastereoisomer, without need of purification by column chromatography. razoles [38], carbazoles [39], imidazo[1,2-a]pyridines [40], and nitroindoles [41]. However, the involvement of nucleophiles able to generate O-heterocycles, as, for instance, enols, has not been investigated so far. In order to fill the gap and to obtain furan-fused derivatives, the reaction between nitrobutadienic building blocks and aromatic enolates has been now thoroughly investigated and relevant results are reported hereinafter.

Results
Within this context, we considered of particular interest the hypothesizable outcome of the double nucleophilic attack of β-naphthol on 4a (Ar = p-tol). This particular substrate actually is not exactly a nitrobutadiene, but rather a nitrostilbene, deriving from the initial ring-opening of 3-nitrobenzo[b]thiophene with pyrrolidine [42] (Scheme 2). From the ring-opening product 2, sulfane 3a (Ar = p-tol) originates by reaction with p-tolyl magnesium bromide; the following oxidation at sulfur with MCPBA produces sulfone 4a. Therefore, the nitrobutadienes 3a and 4a retain the reactivity of the nitrovinyl moiety, gaining at the same time stability, thanks to the inclusion of the conjugated double bond within a benzene ring. Quite rewardingly, a TLC analysis of the reaction mixture obtained after 18 h in the conditions of Scheme 2 showed the absence of the substrate and the presence of a single product as a white solid. Spectroscopic analysis ( 1 H and 13 C NMR, MS) revealed the structure of 5a (Scheme 3, Ar = p-tol), isolated in excellent yields as a single diastereoisomer, without need of purification by column chromatography.

Scheme 3. Reaction conditions to obtain naphthodihydrofurans 5a-f.
We thus considered it worthwhile to investigate the scope of this reaction as to the Ar moiety, introducing groups with different electronic or steric features. Sulfanes 3b-f and sulfones 4b-f were prepared according to Scheme 1, and the latter were initially reacted with β-naphthol (Scheme 3). The obtained results, reported in Table 1, show a generally very good behaviour of 4, whatever the aryl substituent. In each case, the obtained diastereoisomer revealed at the 1 HNMR analysis a J of about 5-7 Hz for the dihydrofuran moiety, corresponding presumably to the anti-configuration, as expected on the grounds of a process under thermodynamic control. In order to ascertain without any doubt the Scheme 3. Reaction conditions to obtain naphthodihydrofurans 5a-f.
We thus considered it worthwhile to investigate the scope of this reaction as to the Ar moiety, introducing groups with different electronic or steric features. Sulfanes 3b-f and sulfones 4b-f were prepared according to Scheme 1, and the latter were initially reacted with β-naphthol (Scheme 3). The obtained results, reported in Table 1, show a generally very good behaviour of 4, whatever the aryl substituent. In each case, the obtained diastereoisomer revealed at the 1 HNMR analysis a J of about 5-7 Hz for the dihydrofuran moiety, corresponding presumably to the anti-configuration, as expected on the grounds of a process under thermodynamic control. In order to ascertain without any doubt the configuration of the isolated diastereoisomer, the structure of compound 5a was confirmed by X-ray analysis ( Figure 4). configuration of the isolated diastereoisomer, the structure of compound 5a was confirmed by X-ray analysis ( Figure 4).  Having these (2,3)-diaryl substituted naphthodihydrofurans in hand, we thought it could be of interest to attempt their oxidative aromatization to the corresponding naphthofurans, with the aim of extending the conjugated system, in search of better optical properties. The aromatization to 6a-f proceeded very easily with 3 mol eq. of DDQ in toluene at 50 °C, and furnished generally, after chromatographic separation, rather satisfying yields (Scheme 4). As hoped, after the extension of the conjugated system, we actually observed the appearance of optical properties for the aromatized compounds. The model 6a revealed a good fluorescence when irradiated under the UV lamp ( Figure 5), which encourages a Having these (2,3)-diaryl substituted naphthodihydrofurans in hand, we thought it could be of interest to attempt their oxidative aromatization to the corresponding naphthofurans, with the aim of extending the conjugated system, in search of better optical properties. The aromatization to 6a-f proceeded very easily with 3 mol eq. of DDQ in toluene at 50 • C, and furnished generally, after chromatographic separation, rather satisfying yields (Scheme 4).  Having these (2,3)-diaryl substituted naphthodihydrofurans in hand, we thought it could be of interest to attempt their oxidative aromatization to the corresponding naphthofurans, with the aim of extending the conjugated system, in search of better optical properties. The aromatization to 6a-f proceeded very easily with 3 mol eq. of DDQ in toluene at 50 °C, and furnished generally, after chromatographic separation, rather satisfying yields (Scheme 4). As hoped, after the extension of the conjugated system, we actually observed the appearance of optical properties for the aromatized compounds. The model 6a revealed a good fluorescence when irradiated under the UV lamp ( Figure 5), which encourages a As hoped, after the extension of the conjugated system, we actually observed the appearance of optical properties for the aromatized compounds. The model 6a revealed a good fluorescence when irradiated under the UV lamp ( Figure 5), which encourages a deeper study in the future of the fluorescence properties of these new naphthofuran derivatives.  Encouraged to proceed in our study, we changed the aromatic enol moving to a quinoline derivative, so as to introduce a further heteroatom in the system. 8-Hydroxyquinoline was our next choice as promising reagent to obtain angular dihydrofuro-and furo[3,2h]quinolines, a kind of fusion not so often reported in the literature. Under the same conditions employed for 2-naphthol, the reactions proceeded faster, but yields in the desired product were generally lower (Scheme 5; cf. yields in Table 1), due to the presence in the Encouraged to proceed in our study, we changed the aromatic enol moving to a quinoline derivative, so as to introduce a further heteroatom in the system. 8-Hydroxyquinoline was our next choice as promising reagent to obtain angular dihydrofuro-and furo [3,2-h]quinolines, a kind of fusion not so often reported in the literature. Under the same conditions employed for 2-naphthol, the reactions proceeded faster, but yields in the desired product were generally lower (Scheme 5; cf. yields in Table 1), due to the presence in the final mixture of minor components that were necessary to remove by chromatographic purification. product were generally lower (Scheme 5; cf. yields in Table 1), due to the presence in the final mixture of minor components that were necessary to remove by chromatographic purification.
When trying to aromatize the obtained dihydrofuroquinoline 7a according to the conditions reported in Scheme 4, the reaction proceeded quickly, but a TLC analysis of the final reaction mixture revealed an extensive decomposition. Such failure could probably be attributed to the presence of the oxidizable aza group. A search for adequate conditions compatible with the presence of the N-heterocycle brought us to use only 2 mol eq. of the same oxidant DDQ, in a different solvent (CHCl3), at room temperature; the desired furoquinoline was thus obtained within 24 h after chromatography in 91% yields. These successful conditions were then applied to dihydrofuroquinoline 7d, furnishing in this case only a lower yield of 8d (Scheme 5). It is interesting to note that both dihydrofuroquinoline 7a and furoquinoline 8a show fluorescent properties under UV light, at a different wavelength compared to the naphthofuran derivative 6a ( Figure 6). We intend to develop the study of fluorescence for derivatives 7 and 8 in the future. When trying to aromatize the obtained dihydrofuroquinoline 7a according to the conditions reported in Scheme 4, the reaction proceeded quickly, but a TLC analysis of the final reaction mixture revealed an extensive decomposition. Such failure could probably be attributed to the presence of the oxidizable aza group. A search for adequate conditions compatible with the presence of the N-heterocycle brought us to use only 2 mol eq. of the same oxidant DDQ, in a different solvent (CHCl 3 ), at room temperature; the desired furoquinoline was thus obtained within 24 h after chromatography in 91% yields. These successful conditions were then applied to dihydrofuroquinoline 7d, furnishing in this case only a lower yield of 8d (Scheme 5).
It is interesting to note that both dihydrofuroquinoline 7a and furoquinoline 8a show fluorescent properties under UV light, at a different wavelength compared to the naphthofuran derivative 6a ( Figure 6). We intend to develop the study of fluorescence for derivatives 7 and 8 in the future. In order to obtain a different polyheterocyclic system, we turned our attention to another phenolic nucleophile, e.g., 4-hydroxycoumarin, whose behaviour was studied with the model nitrostilbene 4a. Under the usual reaction conditions (K2CO3 in DMSO) the process proved to be very slow, and the desired product was not present in the final reaction mixture, probably due to the prevalence of alternative pathways, such as, for instance, the hydrolysis of the coumarin ring. Searching for a suitable system, we performed the reaction in the presence of an organic base (DABCO) in a less polar solvent (CHCl3), observing in this case the dihydro-4H-furochromenone derivative 9a in a complex reaction mixture, containing also unreacted starting material (13%); the reaction is still under investigation in order to optimize the conditions and effectively improve the yield (Scheme 6). In order to obtain a different polyheterocyclic system, we turned our attention to another phenolic nucleophile, e.g., 4-hydroxycoumarin, whose behaviour was studied with the model nitrostilbene 4a. Under the usual reaction conditions (K 2 CO 3 in DMSO) the process proved to be very slow, and the desired product was not present in the final reaction mixture, probably due to the prevalence of alternative pathways, such as, for instance, the hydrolysis of the coumarin ring. Searching for a suitable system, we performed the reaction in the presence of an organic base (DABCO) in a less polar solvent (CHCl 3 ), observing in this case the dihydro-4H-furochromenone derivative 9a in a complex reaction mixture, containing also unreacted starting material (13%); the reaction is still under investigation in order to optimize the conditions and effectively improve the yield (Scheme 6). cess proved to be very slow, and the desired product was not present in the final reaction mixture, probably due to the prevalence of alternative pathways, such as, for instance, the hydrolysis of the coumarin ring. Searching for a suitable system, we performed the reaction in the presence of an organic base (DABCO) in a less polar solvent (CHCl3), observing in this case the dihydro-4H-furochromenone derivative 9a in a complex reaction mixture, containing also unreacted starting material (13%); the reaction is still under investigation in order to optimize the conditions and effectively improve the yield (Scheme 6). Scheme 6. Reaction of compound 4a with 4-hydroxycoumarin (42% yield on the reacted substrate).
As a further evolution for naphthofurans 6a-f and furoquinolines 8a,d we devised an electrocyclization process in order to increase the complexity of our polyheterocycles systems. To undergo the pericyclic reaction, the 6π-conjugated system includes three "aromatic" double bonds, e.g., that of the furan ring, and those of the 3-aryl and the 2-(2methylsulfonyl)phenyl substituents. Due to the presence of two non-equivalent ortho positions in the sulfonylated ring, two different electrocyclization products could in principle be expected (10a and 10′a) (Scheme 7), from which two aromatized systems (11a and 11′a) could in turn originate, via methanesulfinic acid elimination or rather by dehydrogenation, respectively. Both processes seemed to be of potential interest, so we proceeded to find the adequate conditions. Scheme 7. Hypothesizable electrocyclized products 10a and 10′a from 6a, and their following evolution to aromatized 11a and 11′a. Scheme 6. Reaction of compound 4a with 4-hydroxycoumarin (42% yield on the reacted substrate).
As a further evolution for naphthofurans 6a-f and furoquinolines 8a,d we devised an electrocyclization process in order to increase the complexity of our polyheterocycles systems. To undergo the pericyclic reaction, the 6π-conjugated system includes three "aromatic" double bonds, e.g., that of the furan ring, and those of the 3-aryl and the 2-(2-methylsulfonyl)phenyl substituents. Due to the presence of two non-equivalent ortho positions in the sulfonylated ring, two different electrocyclization products could in principle be expected (10a and 10 a) (Scheme 7), from which two aromatized systems (11a and 11 a) could in turn originate, via methanesulfinic acid elimination or rather by dehydrogenation, respectively. Both processes seemed to be of potential interest, so we proceeded to find the adequate conditions. mixture, probably due to the prevalence of alternative pathways, such as, for instance, the hydrolysis of the coumarin ring. Searching for a suitable system, we performed the reaction in the presence of an organic base (DABCO) in a less polar solvent (CHCl3), observing in this case the dihydro-4H-furochromenone derivative 9a in a complex reaction mixture, containing also unreacted starting material (13%); the reaction is still under investigation in order to optimize the conditions and effectively improve the yield (Scheme 6). Scheme 6. Reaction of compound 4a with 4-hydroxycoumarin (42% yield on the reacted substrate).
As a further evolution for naphthofurans 6a-f and furoquinolines 8a,d we devised an electrocyclization process in order to increase the complexity of our polyheterocycles systems. To undergo the pericyclic reaction, the 6π-conjugated system includes three "aromatic" double bonds, e.g., that of the furan ring, and those of the 3-aryl and the 2-(2methylsulfonyl)phenyl substituents. Due to the presence of two non-equivalent ortho positions in the sulfonylated ring, two different electrocyclization products could in principle be expected (10a and 10′a) (Scheme 7), from which two aromatized systems (11a and 11′a) could in turn originate, via methanesulfinic acid elimination or rather by dehydrogenation, respectively. Both processes seemed to be of potential interest, so we proceeded to find the adequate conditions. Scheme 7. Hypothesizable electrocyclized products 10a and 10′a from 6a, and their following evolution to aromatized 11a and 11′a. Scheme 7. Hypothesizable electrocyclized products 10a and 10 a from 6a, and their following evolution to aromatized 11a and 11 a.
A thermic approach on the model substrate 6a, treated in xylene at reflux, after 24 h, revealed by TLC that only starting material was present; evidently, the attainable temperature (140 • C) was not sufficient to induce the pericyclic process. We thus turned to the alternative photoinduction and, on the grounds of our previous experience and of literature data, we dissolved 6a in acetone and introduced the sample in a Rayonet reactor (λ = 300 nm): under these conditions, the pericyclic process went straight on, and, thanks to MeSO 2 H elimination, the aromatized polyheterocycle 11a was directly generated in satisfactory yield (63%) within the same (24 h) period of time (Scheme 8).

Molecules 2022, 27, x FOR PEER REVIEW 8 of 17
A thermic approach on the model substrate 6a, treated in xylene at reflux, after 24 h, revealed by TLC that only starting material was present; evidently, the attainable temperature (140 °C) was not sufficient to induce the pericyclic process. We thus turned to the alternative photoinduction and, on the grounds of our previous experience and of literature data, we dissolved 6a in acetone and introduced the sample in a Rayonet reactor (λ = 300 nm): under these conditions, the pericyclic process went straight on, and, thanks to MeSO2H elimination, the aromatized polyheterocycle 11a was directly generated in satisfactory yield (63%) within the same (24 h) period of time (Scheme 8).
Scheme 8. First attempts to obtain electrocyclization products from 6a by a thermally or a photochemically induced reaction.
The photoinduced process was then extended to the whole 6b-f series, obtaining in each case (but for 6b) good yields in the aromatized products 11c-f (Figure 7), without isolation of the alternative polycycles 11′c-f or of the corresponding cyclohexadiene inter-Scheme 8. First attempts to obtain electrocyclization products from 6a by a thermally or a photochemically induced reaction. The photoinduced process was then extended to the whole 6b-f series, obtaining in each case (but for 6b) good yields in the aromatized products 11c-f (Figure 7), without isolation of the alternative polycycles 11 c-f or of the corresponding cyclohexadiene intermediates 10 or 10 . Scheme 8. First attempts to obtain electrocyclization products from 6a by a thermally or a photochemically induced reaction.
The photoinduced process was then extended to the whole 6b-f series, obtaining in each case (but for 6b) good yields in the aromatized products 11c-f (Figure 7), without isolation of the alternative polycycles 11′c-f or of the corresponding cyclohexadiene intermediates 10 or 10′. In order to test the role of the methylsulfonyl group of 6 in the electrocyclization, we prepared the corresponding sulfane derivative 13a by applying to 3a the procedure of Scheme 3 and aromatizing the resulting 12a. Interestingly enough, when we applied the photoinduced process to 13a, the product isolated was identical to that isolated from 6a, e.g., the full aromatic polycycle 11a (Scheme 9). In order to test the role of the methylsulfonyl group of 6 in the electrocyclization, we prepared the corresponding sulfane derivative 13a by applying to 3a the procedure of Scheme 3 and aromatizing the resulting 12a. Interestingly enough, when we applied the photoinduced process to 13a, the product isolated was identical to that isolated from 6a, e.g., the full aromatic polycycle 11a (Scheme 9).

Materials and Methods
1 H NMR and 13 C NMR spectra were recorded with a JEOL JNM-ECZR 400 spectrometer, at 400 and 100 MHz, respectively; chemical shifts (TMS as internal reference) are reported as δ values (ppm). Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; tt, triplet of triplets; m, multiplet; and br, broad. Gas chromatography-mass spectrometry (GC-MS) was performed on HP 5890/5971 (EI 70 eV) system equipped with a HP-1 MS capillary column (12 m × 0.2 mm i.d × 0.33 μm). High-resolution mass spectra (HRMS) were obtained with an Agilent MSD TOF mass spectrometer and recorded in positive ion mode with an electrospray (ESI) source. IR spectra were recorded on a Perkin Elmer Spectrum 65 FT-IR and wave numbers are reported in cm −1 . Melting points were determined with a Büchi 535 apparatus and are uncorrected. Petroleum ether and light petroleum refer to the fractions with bp 40-60 °C and 80-100 °C, respectively. Silica gel 230-400 mesh or neutral alluminium oxide Acros Organics (50-200 μm), were used for column chromatography. TLC analysis were performed on commercially prepared 60 F254 silica gel plates and visualized by UV irradiation (eluant: petroleum ether-ethyl acetate). All commercially available reagents were used as received. The 3-nitrobenzothiophene 1 [43], (E)-1-(2-(2-(methylthio)phenyl)-2-nitrovinyl) pyrrolidine 2 [42], nitrovinyl derivatives 3a, b, d-f and 4a, b, df were obtained usually in high yields, as already reported [44]. Compounds 3c and 4c were prepared following the same procedure.

Materials and Methods
1 H NMR and 13 C NMR spectra were recorded with a JEOL JNM-ECZR 400 spectrometer, at 400 and 100 MHz, respectively; chemical shifts (TMS as internal reference) are reported as δ values (ppm). Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; tt, triplet of triplets; m, multiplet; and br, broad. Gas chromatography-mass spectrometry (GC-MS) was performed on HP 5890/5971 (EI 70 eV) system equipped with a HP-1 MS capillary column (12 m × 0.2 mm i.d × 0.33 µm). High-resolution mass spectra (HRMS) were obtained with an Agilent MSD TOF mass spectrometer and recorded in positive ion mode with an electrospray (ESI) source. IR spectra were recorded on a Perkin Elmer Spectrum 65 FT-IR and wave numbers are reported in cm −1 . Melting points were determined with a Büchi 535 apparatus and are uncorrected. Petroleum ether and light petroleum refer to the fractions with bp 40-60 • C and 80-100 • C, respectively. Silica gel 230-400 mesh or neutral alluminium oxide Acros Organics (50-200 µm), were used for column chromatography. TLC analysis were performed on commercially prepared 60 F254 silica gel plates and visualized by UV irradiation (eluant: petroleum ether-ethyl acetate). All commercially available reagents were used as received. The 3-nitrobenzothiophene 1 [43], (E)-1-(2-(2-(methylthio)phenyl)-2-nitrovinyl) pyrrolidine 2 [42], nitrovinyl derivatives 3a, b, d-f and  4a, b, d-f were obtained usually in high yields, as already reported [44]. Compounds 3c and 4c were prepared following the same procedure.

General Procedure for the Oxidative Aromatization Reaction of Dihydronaphthofurans 5a-f
to Naphthofurans 6a-f The relevant dihydrofuran 5 (0.17 mmol) was dissolved in toluene (3.0 mL) and DDQ (0.51 mmol, 116 mg) was added. The reaction was stirred at 50 • C in an oil bath and monitored by TLC. After the disappearance of the starting material (24 h), the mixture was filtered, and then the filtrate was washed with dichloromethane and toluene, and then with saturated Na 2 CO 3 (2 × 5 mL), water (1 × 5 mL) and brine (1 × 5 mL). The organic phase was dried with anhydrous Na 2 SO 4 and the solvent evaporated to give the crude 7, which was purified by column chromatography (petroleum ether/ethyl acetate 1:1 to 1:2).