An Efficient Synthesis of Naphtho[2,3-b]furan-4,9-diones via Visible-Light-Mediated [3+2] Cycloaddition Reaction

Naphtho[2,3-b]furan-4,9-dione is an important privileged structural motif which is present in natural products, drugs, and drug candidates. Herein, visible-light-mediated [3+2] cycloaddition reaction for the synthesis of naphtho[2,3-b]furan-4,9-diones and dihydronaphtho[2,3-b]furan-4,9-diones has been developed. Under environmentally friendly conditions, a variety of title compounds were delivered in good yields. This new protocol shows excellent regioselectivity and remarkable functional group tolerance. This approach provides a powerful, green, efficient, and facile means to expand the structural diversity of naphtho[2,3-b]furan-4,9-diones and dihydronaph-tho[2,3-b]furan-4,9-diones as promising scaffolds for novel drug discovery.


Results and Discussion
In the pilot experiment, 2-hydroxy-1,4-naphthoquinone (1) was selected as the model substrate to react with phenylacetylene (2a) at ambient temperature under irradiation of blue LEDs (460 nm). Product 3a was obtained in 58% yield without any catalyst after 6 h irradiation in DCM (Table 1, entry 2). Furthermore, the use of different solvents, including acetone, THF, and toluene, failed to give better results than DCM (Table 1, entries 4-12, respectively). However, the yield was improved to 75% when a solvent of MeCN was used with irradiation for 6 h. (Table 1, entry 14). Consequently, the optimized reaction conditions turned out to be using MeCN as solvent under blue LEDs (460 nm) irradiation at ambient temperature for 6 h.

Results and Discussion
In the pilot experiment, 2-hydroxy-1,4-naphthoquinone (1) was selected as the model substrate to react with phenylacetylene (2a) at ambient temperature under irradiation of blue LEDs (460 nm). Product 3a was obtained in 58% yield without any catalyst after 6 h irradiation in DCM (Table 1, entry 2). Furthermore, the use of different solvents, including acetone, THF, and toluene, failed to give better results than DCM (Table 1, entries 4-12, respectively). However, the yield was improved to 75% when a solvent of MeCN was used with irradiation for 6 h. (Table 1, entry 14). Consequently, the optimized reaction conditions turned out to be using MeCN as solvent under blue LEDs (460 nm) irradiation at ambient temperature for 6 h. with enol ether, (d) transition-metal promoted thermal cyclization, (e) strong-base promoted thermal cyclization, (f) strong oxidantpromoted thermal cyclization.

Results and Discussion
In the pilot experiment, 2-hydroxy-1,4-naphthoquinone (1) was selected as the model substrate to react with phenylacetylene (2a) at ambient temperature under irradiation of blue LEDs (460 nm). Product 3a was obtained in 58% yield without any catalyst after 6 h irradiation in DCM (Table 1, entry 2). Furthermore, the use of different solvents, including acetone, THF, and toluene, failed to give better results than DCM (Table 1, entries 4-12, respectively). However, the yield was improved to 75% when a solvent of MeCN was used with irradiation for 6 h. (Table 1, entry 14). Consequently, the optimized reaction conditions turned out to be using MeCN as solvent under blue LEDs (460 nm) irradiation at ambient temperature for 6 h. The structure of product 3a was confirmed firstly by means of proton and carbon NMR spectra. It was noted that the naphtho[2,3-b]furan-4,9-dione 3a was obtained with complete regioselectivity, with only 2-phenylnaphtho[2,3-b]furan-4,9-dione was obtained and no isomer 3-phenylnaphtho[2,3-b]furan-4,9-dione being detectable or isolable (Scheme 3). Furthermore, the configuration of the main compound 3a was unambiguously established by single-crystal X-ray diffraction analysis (Figure 1), which indicated that the phenyl group is at a C-2 position (green) instead of a C-3 position. With the optimized conditions in hand (Table 1, entry 14), a series of substituted phenylacetylenes 2a−2k were evaluated (Scheme 4). It was noticed that the analogous reactions of formyl and various halogens substituted phenylacetylenes (2b-2e) with 2-hydroxy-1,4-naphthoquinone (1) successfully generated the corresponding products 3b-3e in moderate yields, respectively. Subsequently, we evaluated various alkyls substituted phenylacetylenes (2g-2j), such as Me, tBu, and cyclohexyl, all of which favourably delivered the corresponding products 3g-3j in good to very good yields, not showing significant differences in yield. Relatively speaking, an electron-donating group on the benzene ring, as in the case of 3j, is more favorable than the electron-withdrawing groups (CHO and halogens) of 3b-3e. Furthermore, other two phenylacetylene derivatives, diphenylacetylene and propargylamine (2k and 2l), were evaluated too, and corresponding naphtho[2,3-b]furan-4,9-diones 3k and 3l were obtained swimmingly, as predicted, in good yields.
14 MeCN 6 h 75% 15 MeCN 9 h 71% a The reactions were carried out on a 1 mmol scale in 20 mL of solvent at room temperature. b Isolate yields.
The structure of product 3a was confirmed firstly by means of proton and carbo NMR spectra. It was noted that the naphtho[2,3-b]furan-4,9-dione 3a was obtained wit complete regioselectivity, with only 2-phenylnaphtho[2,3-b]furan-4,9-dione was obtaine and no isomer 3-phenylnaphtho[2,3-b]furan-4,9-dione being detectable or isolabl (Scheme 3). Furthermore, the configuration of the main compound 3a was unambiguousl established by single-crystal X-ray diffraction analysis (Figure 1), which indicated that th phenyl group is at a C-2 position (green) instead of a C-3 position. With the optimize conditions in hand (Table 1, entry 14), a series of substituted phenylacetylenes 2a−2k wer evaluated (Scheme 4). It was noticed that the analogous reactions of formyl and variou halogens substituted phenylacetylenes (2b-2e) with 2-hydroxy-1,4-naphthoquinone (1 successfully generated the corresponding products 3b-3e in moderate yields, respectively Subsequently, we evaluated various alkyls substituted phenylacetylenes (2g-2j), such a Me, tBu, and cyclohexyl, all of which favourably delivered the corresponding product 3g-3j in good to very good yields, not showing significant differences in yield. Relativel speaking, an electron-donating group on the benzene ring, as in the case of 3j, is mor favorable than the electron-withdrawing groups (CHO and halogens) of 3b-3e. Further more, other two phenylacetylene derivatives, diphenylacetylene and propargylamine (2 and 2l), were evaluated too, and corresponding naphtho[2,3-b]furan-4,9-diones 3k and 3 were obtained swimmingly, as predicted, in good yields.  Next, to further examine the feasibility of this reaction, we examined the variation of the styrene component toward the formation of dihydronaphtho[2,3-b]furan-4,9-diones (5) (Scheme 5). With the above optimized conditions in hand (Table 1, entry 14), a series of substituted styrenes 4a-4h were evaluated (Scheme 5). It was observed that the analogous reactions of EDG or EWG substituted styrenes with 2-hydroxy-1,4-naphthoquinone (1) smoothly produced the corresponding products 5a-5h in moderate yields, respectively. Thereafter, we evaluated a heterocyclic olefin 2-vinylthiophene (4i), which was also found to be effective, as demonstrated in the successful installation of 5i with a 74% yield. Overall, different substituted phenylacetylene derivatives (2) and styrene derivatives (4)  To reveal the mechanism of this visible-light-mediated [3+2] cycloaddition reaction, several control experiments were performed (Scheme 6). As expected, no reaction occurs Next, to further examine the feasibility of this reaction, we examined the variation of the styrene component toward the formation of dihydronaphtho[2,3-b]furan-4,9-diones (5) (Scheme 5). With the above optimized conditions in hand (Table 1, entry 14), a series of substituted styrenes 4a-4h were evaluated (Scheme 5). It was observed that the analogous reactions of EDG or EWG substituted styrenes with 2-hydroxy-1,4-naphthoquinone (1) smoothly produced the corresponding products 5a-5h in moderate yields, respectively. Thereafter, we evaluated a heterocyclic olefin 2-vinylthiophene (4i), which was also found to be effective, as demonstrated in the successful installation of 5i with a 74% yield. Overall, different substituted phenylacetylene derivatives (2) and styrene derivatives (4)   Next, to further examine the feasibility of this reaction, we examined the variation of the styrene component toward the formation of dihydronaphtho[2,3-b]furan-4,9-diones (5) (Scheme 5). With the above optimized conditions in hand (Table 1, entry 14), a series of substituted styrenes 4a-4h were evaluated (Scheme 5). It was observed that the analogous reactions of EDG or EWG substituted styrenes with 2-hydroxy-1,4-naphthoquinone (1) smoothly produced the corresponding products 5a-5h in moderate yields, respectively. Thereafter, we evaluated a heterocyclic olefin 2-vinylthiophene (4i), which was also found to be effective, as demonstrated in the successful installation of 5i with a 74% yield. Overall, different substituted phenylacetylene derivatives (2) and styrene derivatives (4) reacted with 2-hydroxy-1,4-naphthoquinone (1) and generated corresponding cycloaddition products naphtho[2,3-b]furan-4,9-diones (3) and dihydronaphtho[2,3-b]furan-4,9-diones (5), not showing significant differences in yield. To reveal the mechanism of this visible-light-mediated [3+2] cycloaddition reaction, several control experiments were performed (Scheme 6). As expected, no reaction occurs To reveal the mechanism of this visible-light-mediated [3+2] cycloaddition reaction, several control experiments were performed (Scheme 6). As expected, no reaction occurs in the absence of light (Scheme 6b), which highlights the fact that the [3+2] cycloaddition reaction needs to be mediated by visible light. Furthermore, in reaction c of Scheme 6, TEMPO was added as a radical scavenger under standard conditions, and a trace amount of the target product 3a was observed. Based on the control experimental results and the

General Information
All starting materials were purchased from available commercial suppliers and used without further purification. Thin layer chromatography (TLC) was performed on silica gel GF254 plates. Melting points were obtained by using an XT-5A digital melting-point apparatus and were uncorrected. The NMR spectra were recorded on a Bruker Avance 400 spectrometer at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR). HRMS analyses were carried out on a Thermo Fisher Q-Exactive mass spectrometer, which was operated in electrospray ionization (ESI) mode.

General Procedure for the Synthesis of Naphtho[2,3-b]furan-4,9-diones (3)
In a 25 mL tube, 2-hydroxy-1,4-naphthoquinone 1 (1.0 mmol) and alkyne 2 (1.0 mmol) were dissolved in 20 mL of acetonitrile. The reaction mixture was under irradiation of visible blue LEDs (460 nm) for 6.0 h. After completion (by TLC), the reaction mixture was evaporated to dryness in a vacuo. The residue was purified by medium-pressure chromatography (silica gel) using a mixed solvent of hexane and ethyl acetate (10-50% EA). The products were characterized by 1 H NMR, 13 C NMR, and HRMS spectroscopy.    In a 25 mL tube, 2-hydroxy-1,4-naphthoquinone 1 (1.0 mmol) and alkenes 4 (1.0 mmol) were dissolved in 20 mL of acetonitrile. The reaction mixture was under irradiation of visible blue LEDs (460 nm) for 6.0 h. After completion (by TLC), the reaction mixture was evaporated to dryness in vacuo. The residue was purified by medium-pressure chromatography (silica gel) using a mixed solvent of hexane and ethyl acetate (10-50% EA). The products were characterized by 1 H NMR, 13 C NMR, and HRMS spectroscopy. The results of the X-ray diffraction analysis for compounds 3a and 5d were deposited with the Cambridge Crystallographic Data Centre (CCDC 2264554 and 2264555).