9,10-Phenanthrenedione as Visible-Light Photoredox Catalyst: A Green Methodology for the Functionalization of 3,4-Dihydro-1,4-Benzoxazin-2- Ones through a Friedel-Crafts Reaction

A visible-light photoredox functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones through a Friedel-Crafts reaction with indoles using an inexpensive organophotoredox catalyst is described. The reaction uses a dual catalytic system that is formed by a photocatalyst simple and cheap, 9,10-phenanthrenedione, and a Lewis acid, Zn(OTf)2. 5W white LEDs are used as visible-light source and oxygen from air as a terminal oxidant, obtaining the corresponding products with good yields. The reaction can be extended to other electron-rich arenes. Our methodology represents one of the most valuable and sustainable approach for the functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones, as compared to the reported procedures. Furthermore, several transformations were carried out, such as the synthesis of the natural product cephalandole A and a tryptophol derivative.


Results
Initially, we choose the Friedel-Crafts reaction between indole 1a and 4-benzyl-3,4-dihydro-2H -benzo[b] [1,4]oxazin-2-one 2a in acetonitrile at room temperature under air atmosphere and the irradiation of white LEDs (5W). Under these conditions, a survey of photocatalyst were screened, and the results are summarized in Table 1. In a preliminary study of the photocatalyst (entries 1-6), Ru(bpy) 2 Cl 2 (A), Rose Bengal (B), Fukuzumi photocatalyst (E), and 9,10-phenanthrenedione (F) afforded product 3aa with similar yields, around 30%, after 24 h. With these catalysts, we decided to change the molar ratio of 1a:2a from 0.15:0.1 to 0.1:0.15 (entries 7-10). The best yield for compound 3aa was obtained when Rose Bengal (B) and 9,10-phenanthrenedione (F) were used as photocatalyst (53% yield in both cases). In view of the good performance of the photocatalyst F, we decided to carry out the reaction using another α-diketone, such as benzyl (G), however the yield of 3aa drop to only 15%. In view of the results, we decided to continue the optimization of the reaction conditions using 9,10-phenanthrenedione as a photocatalyst, due to its low molecular weight and its lower price in relation to the other photocatalysts tested. change the molar ratio of 1a:2a from 0.15:0.1 to 0.1:0.15 (entries 7-10). The best yield for compound 3aa was obtained when Rose Bengal (B) and 9,10-phenanthrenedione (F) were used as photocatalyst (53% yield in both cases). In view of the good performance of the photocatalyst F, we decided to carry out the reaction using another α-diketone, such as benzyl (G), however the yield of 3aa drop to only 15%. In view of the results, we decided to continue the optimization of the reaction conditions using 9,10-phenanthrenedione as a photocatalyst, due to its low molecular weight and its lower price in relation to the other photocatalysts tested.
In order to improve the yield of 3aa, we decided to investigate a dual catalytic protocol combining Brønsted or Lewis acid catalysis and visible-light photoredox catalysis [58] (Table 2). For this purpose, different Brønsted acids, such as PhCO2H or AcOH, were tested, however product 3aa was obtained with lower yield (entries 2 and 3, respectively). After we decided to test Zn salts as Lewis acid, obtaining an improvement of the catalytic performance when we used 10 mol% of Zn(OTf)2. In these conditions, the functionalized benzoxazinone 3aa was obtained in 76% after 9 h (entry 5). Other Lewis acids, such as Fe(OTf)2, Cu(OTf)2, and Sc(OTf)3 were evaluated (entries 6-8), obtaining lower yields for the corresponding product 3aa. The lowering of the catalyst loading of Zn(OTf)2 to 5 mol% did not influence in the yield of product 3aa (entry 10). Subsequently, different solvents such as toluene, CH2Cl2, DMF, THF, or MeOH were screened (entries [11][12][13][14], obtaining the functionalized benzoxazinone 3aa with much lower yields. We could diminish the photocatalyst and Lewis acid loadings maintaining the yield of product 3aa (entries 15 and 16). Finally, some control experiments were carried out. Thus, in the absence of visible-light (entry 19) or 9,10phenanthrenedione (entry 20), the product 3aa was not detected or the conversion was very low. In order to improve the yield of 3aa, we decided to investigate a dual catalytic protocol combining Brønsted or Lewis acid catalysis and visible-light photoredox catalysis [58] (Table 2). For this purpose, different Brønsted acids, such as PhCO 2 H or AcOH, were tested, however product 3aa was obtained with lower yield (entries 2 and 3, respectively). After we decided to test Zn salts as Lewis acid, obtaining an improvement of the catalytic performance when we used 10 mol% of Zn(OTf) 2 . In these conditions, the functionalized benzoxazinone 3aa was obtained in 76% after 9 h (entry 5). Other Lewis acids, such as Fe(OTf) 2 , Cu(OTf) 2 , and Sc(OTf) 3 were evaluated (entries 6-8), obtaining lower yields for the corresponding product 3aa. The lowering of the catalyst loading of Zn(OTf) 2 to 5 mol% did not influence in the yield of product 3aa (entry 10). Subsequently, different solvents such as toluene, CH 2 Cl 2 , DMF, THF, or MeOH were screened (entries [11][12][13][14], obtaining the functionalized benzoxazinone 3aa with much lower yields. We could diminish the photocatalyst and Lewis acid loadings maintaining the yield of product 3aa (entries 15 and 16). Finally, some control experiments With the optimized reaction conditions in hand (entry 13, Table 2), the scope of the Friedel-Crafts reaction was explored with a range of indoles 1 with several substituents in different positions (Scheme 1). Indoles bearing electron-donating (Me, Ph, OMe, OH) or electron-withdrawing (F, Cl, Br) groups furnished the corresponding functionalized benzoxazinones 3 in 54-80% yield, independently of the position or the electronic character of the substituents. Moreover, disubstituted indoles, such as 1n-1p, afforded the corresponding products 3na-3pa, with high yields (up to 77%). It is interesting to note the good results that were obtained with 2-and 4-substituted indoles, despite the steric hindrance around the reactive carbon atom. Thus, for example, 2-methyl-and 4methylindol gave the corresponding reaction products with yields of 58% and 64%, respectively (versus 13% and 26% described in the literature [76]). Also 2-phenyl-, 4-fluoro-, and 1,2dimethylindole give yields of 80%, 79%, and 70%, respectively.
Afterwards, we examined the scope of the Friedel-Crafts alkylation with a range of 3,4-dihydro-1,4-benzoxazin-2-ones 2 using indole 1a as nucleophile (Scheme 2). An assortment of derivatives with different groups on the benzyl moiety reacted smoothly in the optimized reaction conditions, obtaining the corresponding products 3ab-3ad with good yields (56-88%). A thienylmethyl group on the nitrogen of the benzoxazinone 1e could be used in the Friedel-Crafts reaction obtaining the corresponding product 3ae with a high yield (77%). Additionally, 3,4-dihydro-1,4-benzoxazin-2-ones 1g and 1h, with methyl substituents at 6 and 7 positions worked well in this Friedel-Crafts reaction. With the optimized reaction conditions in hand (entry 13, Table 2), the scope of the Friedel-Crafts reaction was explored with a range of indoles 1 with several substituents in different positions (Scheme 1). Indoles bearing electron-donating (Me, Ph, OMe, OH) or electron-withdrawing (F, Cl, Br) groups furnished the corresponding functionalized benzoxazinones 3 in 54-80% yield, independently of the position or the electronic character of the substituents. Moreover, disubstituted indoles, such as 1n-1p, afforded the corresponding products 3na-3pa, with high yields (up to 77%). It is interesting to note the good results that were obtained with 2-and 4-substituted indoles, despite the steric hindrance around the reactive carbon atom. Thus, for example, 2-methyl-and 4-methylindol gave the corresponding reaction products with yields of 58% and 64%, respectively (versus 13% and 26% described in the literature [76]). Also 2-phenyl-, 4-fluoro-, and 1,2-dimethylindole give yields of 80%, 79%, and 70%, respectively.
Based on previous literature reports [3,70] and control experiments (see supplementary materials for further details) a possible mechanism for the reaction is proposed in Scheme 5. Initially, under visible-light irradiation, 9,10-phenanthrenedione F is excited to F*. Subsequently, this excited state, by a single-electron transfer (SET), transforms 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2one 2a into a nitrogen radical cation I, with the consequent reduction of F* to the radical anion F .-, which can be oxidized by molecular oxygen (O2) regenerating the photocatalyst F. On the other hand, deprotonation of the nitrogen radical cation I can generate the α-amino radical II, which can be further oxidized to the iminium ion III. After the nucleophilic attack of indole 1a to the iminium ion III, product 3aa is obtained. The radical mechanism was confirmed by an experiment control using a radical scavenger (TEMPO). Under these conditions, a trace amount of product 3aa was observed by 1 H NMR of the crude reaction mixture and the corresponding adduct formed from radical II and TEMPO was detected by HRMS. In this mechanism, the O2 is the terminal oxidant that is reduced in H2O2. The role of molecular oxygen was also studied in a control experiment. When we performed the photocatalyzed Friedel-Crafts reaction under argon atmosphere, the conversion to product 3aa was very low (12%). However, the role of Zn(OTf)2 is not clear, with this Lewis acid, the reaction is accelerated, activating either the electrophile or the nucleophile, or both.
Based on previous literature reports [3,70] and control experiments (see Supplementary Materials for further details) a possible mechanism for the reaction is proposed in Scheme 5. Initially, under visible-light irradiation, 9,10-phenanthrenedione F is excited to F*. Subsequently, this excited state, by a single-electron transfer (SET), transforms 4-benzyl-3,4-dihydro-2H -benzo[b][1,4]oxazin-2-one 2a into a nitrogen radical cation I, with the consequent reduction of F* to the radical anion F .-, which can be oxidized by molecular oxygen (O 2 ) regenerating the photocatalyst F. On the other hand, deprotonation of the nitrogen radical cation I can generate the α-amino radical II, which can be further oxidized to the iminium ion III. After the nucleophilic attack of indole 1a to the iminium ion III, product 3aa is obtained. The radical mechanism was confirmed by an experiment control using a radical scavenger (TEMPO). Under these conditions, a trace amount of product 3aa was observed by 1 H NMR of the crude reaction mixture and the corresponding adduct formed from radical II and TEMPO was detected by HRMS. In this mechanism, the O 2 is the terminal oxidant that is reduced in H 2 O 2 . The role of molecular oxygen was also studied in a control experiment. When we performed the photocatalyzed Friedel-Crafts reaction under argon atmosphere, the conversion to product 3aa was very low (12%). However, the role of Zn(OTf) 2 is not clear, with this Lewis acid, the reaction is accelerated, activating either the electrophile or the nucleophile, or both.
To showcase the utility of our catalytic protocol, we performed several synthetic transformations (Scheme 6). Compound 3aa was catalytically deprotected using H 2 and 10% Pd/C in THF/EtOH, and then the addition of 1 equivalent of DDQ for 1 h, allowed us to obtain the natural product cephalandole A [78] (8) in 91% yield in a one-pot reaction. Moreover, compounds 3 can be used to prepare tryptophol derivatives by a reduction of the carbonyl group of the benzoxazin-2-one. Tryptophols are a class of indoles bearing a 3-(hydroxyethyl) side chain. These class of compounds have been isolated from a variety of natural sources, and some of them possess biological activity [79][80][81][82].
Therefore, compound 3aa has been reduced with LiAlH 4 affording tryptophol derivative 9 with 57% yield. To showcase the utility of our catalytic protocol, we performed several synthetic transformations (Scheme 6). Compound 3aa was catalytically deprotected using H2 and 10% Pd/C in THF/EtOH, and then the addition of 1 equivalent of DDQ for 1 h, allowed us to obtain the natural product cephalandole A [78] (8) in 91% yield in a one-pot reaction. Moreover, compounds 3 can be used to prepare tryptophol derivatives by a reduction of the carbonyl group of the benzoxazin-2-one. Tryptophols are a class of indoles bearing a 3-(hydroxyethyl) side chain. These class of compounds have been isolated from a variety of natural sources, and some of them possess biological activity [79][80][81][82]. Therefore, compound 3aa has been reduced with LiAlH4 affording tryptophol derivative 9 with 57% yield. Scheme 6. Synthetic transformations. Isolated yields after column chromatography.

General Information
Reactions were carried out in 5 mL vials under air, unless otherwise indicated. Commercial reagents were used as purchased. Reactions were monitored by thin-layer chromatography (TLC) analysis using Merck Silica Gel 60 F-254 (Sigma-Aldrich, St. Louis, MO, USA) thin layer plates and these are visualized using both an UV lamp (254 nm) and then a CAM solution (an aqueous solution of ceric ammonium molybdate). Flash column chromatography was performed on Merck Silica Gel 60 (Sigma-Aldrich, St. Louis, MO, USA), 0.040-0.063 mm. NMR (Nuclear Magnetic Resonance) spectra were run in a Bruker DPX300 spectrometer (Bruker, Billerica, MA, USA) at 300 MHz for 1 H and 75 MHz for 13 C using residual nondeuterated solvent as internal standard (CHCl3: δ 7.26 and δ 77.00 ppm, respectively, MeOH: δ 3.34 ppm and δ 49.87 ppm, respectively, Acetone: δ 2.05 ppm and δ 29.84 ppm, respectively). Chemical shifts are given in ppm. The carbon multiplicity was established by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. High resolution mass spectra (HRMS-ESI) were recorded on a TRIPLETOF T 5600 spectrometer (AB Sciex, Warrington, UK), equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI). To showcase the utility of our catalytic protocol, we performed several synthetic transformations (Scheme 6). Compound 3aa was catalytically deprotected using H2 and 10% Pd/C in THF/EtOH, and then the addition of 1 equivalent of DDQ for 1 h, allowed us to obtain the natural product cephalandole A [78] (8) in 91% yield in a one-pot reaction. Moreover, compounds 3 can be used to prepare tryptophol derivatives by a reduction of the carbonyl group of the benzoxazin-2-one. Tryptophols are a class of indoles bearing a 3-(hydroxyethyl) side chain. These class of compounds have been isolated from a variety of natural sources, and some of them possess biological activity [79][80][81][82]. Therefore, compound 3aa has been reduced with LiAlH4 affording tryptophol derivative 9 with 57% yield. Scheme 6. Synthetic transformations. Isolated yields after column chromatography.

General Information
Reactions were carried out in 5 mL vials under air, unless otherwise indicated. Commercial reagents were used as purchased. Reactions were monitored by thin-layer chromatography (TLC) analysis using Merck Silica Gel 60 F-254 (Sigma-Aldrich, St. Louis, MO, USA) thin layer plates and these are visualized using both an UV lamp (254 nm) and then a CAM solution (an aqueous solution of ceric ammonium molybdate). Flash column chromatography was performed on Merck Silica Gel 60 (Sigma-Aldrich, St. Louis, MO, USA), 0.040-0.063 mm. NMR (Nuclear Magnetic Resonance) spectra were run in a Bruker DPX300 spectrometer (Bruker, Billerica, MA, USA) at 300 MHz for 1 H and 75 MHz for 13 C using residual nondeuterated solvent as internal standard (CHCl3: δ 7.26 and δ 77.00 ppm, respectively, MeOH: δ 3.34 ppm and δ 49.87 ppm, respectively, Acetone: δ 2.05 ppm and δ 29.84 ppm, respectively). Chemical shifts are given in ppm. The carbon multiplicity was established by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. High resolution mass spectra (HRMS-ESI) were recorded on a TRIPLETOF T 5600 spectrometer (AB Sciex, Warrington, UK), equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI). Scheme 6. Synthetic transformations. Isolated yields after column chromatography.

General Information
Reactions were carried out in 5 mL vials under air, unless otherwise indicated. Commercial reagents were used as purchased. Reactions were monitored by thin-layer chromatography (TLC) analysis using Merck Silica Gel 60 F-254 (Sigma-Aldrich, St. Louis, MO, USA) thin layer plates and these are visualized using both an UV lamp (254 nm) and then a CAM solution (an aqueous solution of ceric ammonium molybdate). Flash column chromatography was performed on Merck Silica Gel 60 (Sigma-Aldrich, St. Louis, MO, USA), 0.040-0.063 mm. NMR (Nuclear Magnetic Resonance) spectra were run in a Bruker DPX300 spectrometer (Bruker, Billerica, MA, USA) at 300 MHz for 1 H and 75 MHz for 13 C using residual nondeuterated solvent as internal standard (CHCl 3 : δ 7.26 and δ 77.00 ppm, respectively, MeOH: δ 3.34 ppm and δ 49.87 ppm, respectively, Acetone: δ 2.05 ppm and δ 29.84 ppm, respectively). Chemical shifts are given in ppm. The carbon multiplicity was established by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. High resolution mass spectra (HRMS-ESI) were recorded on a TRIPLETOF T 5600 spectrometer (AB Sciex, Warrington, UK), equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI).

Characterization Data for Compounds 3, 6 and 7
All photocatalysts, indoles, and related arenes were commercially available. 3,4-dihydrobenzoxazin-2-ones derivatives 2a, 2b, and 2c were synthesized according to a procedure that was published in the literature and the spectroscopic data ( 1 H-NMR and 13 C-NMR) match with those reported. 3,4-dihydro-benzoxazin-2-ones derivatives 2d, 2e, 2f, 2g, and 2h were synthesized according to the same procedure and were characterized by 1 H-NMR, 13 C-NMR, and HRMS (see supplementary materials for further details).

Synthesis and Characterization of Compound 9
In a 10 mL round bottomed flask was placed compound 3aa (15.5 mg, 0.044 mmol) and it was purgued with N2. Afterwards, dry THF (1 mL) was added via syringe and the resulted solution was cooled down to 0 °C. After 5 min, LiAlH4 (0.08 mL 1 M in THF, 0.087 mmol, two equivalents) was added via syringe and the mixture was stirred for 1.5 h at 0 °C. Subsequently, the reaction was stopped with the addition of saturated aqueous NH4Cl solution (1 mL) and saturated aqueous Rochelle Salt solution (5 mL). The resulting mixture was extracted with EtOAc (three times), washed with brine, and dried over anhydrous MgSO4. The solvent was removed by reduced pressure and the resulting residue was purified by column chromatography using hexane: EtOAc mixtures as eluent (from 90:10 to 60:40) to afford compound 9 (9.0 mg, 0.025 mmol, 57% yield) as a colourless oil. (

Conclusions
In summary, we have described a visible-light functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones with indoles and other electron-rich arenes using a dual catalytic system that was formed by a Lewis acid (Zn(OTf)2) and 9,10-phenanthrenedione as photocatalyst. Under our reaction conditions, the corresponding products are obtained with good yields. Unlike the photoredox catalytic system described earlier [76], the results that were obtained with our method are not affected by the steric hindrance around the reactive carbon atom. Thus, 2-and 4-substituted indoles and 1,3,5trimethoxybenzene give the corresponding reaction products with good yields. Besides our method uses one of the cheapest, simple, and commercially available organophotocatalyst (9,10-

Synthesis and Characterization of Compound 9
In a 10 mL round bottomed flask was placed compound 3aa (15.5 mg, 0.044 mmol) and it was purgued with N 2 . Afterwards, dry THF (1 mL) was added via syringe and the resulted solution was cooled down to 0 • C. After 5 min, LiAlH 4 (0.08 mL 1 M in THF, 0.087 mmol, two equivalents) was added via syringe and the mixture was stirred for 1.5 h at 0 • C. Subsequently, the reaction was stopped with the addition of saturated aqueous NH 4 Cl solution (1 mL) and saturated aqueous Rochelle Salt solution (5 mL). The resulting mixture was extracted with EtOAc (three times), washed with brine, and dried over anhydrous MgSO 4 . The solvent was removed by reduced pressure and the resulting residue was purified by column chromatography using hexane: EtOAc mixtures as eluent (from 90:10 to 60:40) to afford compound 9 (9.0 mg, 0.025 mmol, 57% yield) as a colourless oil. 3aa was consumed, DDQ (19.3 mg, 0.085 mmol) was added directly to the reaction mixture. After 1 h, the reaction mixture was filtered through a pad of Celite, the solvents were removed by reduced pressure and the resulting residue was purified by column chromatography using a hexane:EtOAc 95:5 mixture as eluent to afford Cephalandole A, 8 (20.3 mg, 0.077 mmol, 92% yield) as a bright yellow solid.
Supplementary Materials: The following materials are available online at http://www.mdpi.com/2073-4344/8/ 12/653/s1, Complete experimental procedures and characterization of new products, 1 H and 13 C NMR spectra for all compounds.
Author Contributions: C.V. and J.R.-B. conceived and designed the experiments; J.R.-B. performed the experiments; J.R.-B. and C.V. analyzed the data; G.B. contributed reagents/materials/analysis tools; C.V. and J.R.P. wrote the paper. All authors read, revised and approved the final manuscript.