catalysts Article
9,10-Phenanthrenedione as Visible-Light Photoredox Catalyst: A Green Methodology for the Functionalization of 3,4-Dihydro-1,4-Benzoxazin-2Ones through a Friedel-Crafts Reaction Jaume Rostoll-Berenguer, Gonzalo Blay , José R. Pedro *
and Carlos Vila *
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot, València, Spain;
[email protected] (J.R.-B.);
[email protected] (G.B.) * Correspondence:
[email protected] (J.R.P.);
[email protected] (C.V.); Tel.: +34-9-6354-4329 (J.R.P.); +34-9-6354-3043 (C.V.) Received: 12 November 2018; Accepted: 6 December 2018; Published: 12 December 2018
Abstract: 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. Keywords: visible-light photocatalysis; organophotoredox catalysis; Friedel-Crafts reaction; indoles; 1,4-benzoxazin-2-ones
1. Introduction Visible-light (sunlight) is a safe, renewable, abundant, inexpensive, and non-polluting source of energy, which means that sunlight is the most “green” energy source that we can use. Therefore, the development of methodologies using visible-light has become one of the greatest challenges in the scientific community in the last century [1,2]. In this context, the development of methodologies to increase the use of visible-light to control chemical reactivity and achieve molecular complexity with higher levels of efficiency have become a hot topic in the last years and many challenging organic reactions have been described [3–9]. For this purpose, intensive research has been devoted to develop photoredox catalysts that are capable of absorbing visible light and transfer this energy to the organic molecules. Many elegant works on photocatalysis have been reported using transition metal ruthenium or iridium polypyridyl complexes as efficient photosensitizers [10–13]. However, these transition metals are expensive and they have potential toxicity that has limited their usefulness. Therefore, for the development of more sustainable visible-light photoredox methodologies the use of organic dyes is more convenient due to the low cost, high availability, and low toxicity that offer this kind of catalyst. However, some of the organophotoredox catalysts are expensive, such as pyrilium [14–18] or acridinium [19–24] salts (Figure 1). Organic dyes, such as Rose Bengal and Eosin Y, are more convenient due to their lower cost [25–31]. Nevertheless, the development of new methodologies using simpler organophotoredox catalysts that improve the sustainability of the “green” chemical Catalysts 2018, 8, 653; doi:10.3390/catal8120653
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methodologies using simpler organophotoredox catalysts that improve the sustainability of the process highly desirable. context, α-diketones represent a class of compounds that can exhibit “green”ischemical process Inisthis highly desirable. In this context, α-diketones represent a class of absorption bands in the visible range and that have been used for photochemical processes [32–34]. compounds that can exhibit absorption bands in the visible range and that have been used for For example, 9,10-phenanthrenedione an inexpensive organic compoundiswith very low molecular photochemical processes [32–34]. For isexample, 9,10-phenanthrenedione an inexpensive organic weight (Figure when with other organophotoredox catalysts. This α-diketone has compound with1) very low compared molecular weight (Figure 1) when compared with other organophotoredox absorption bands in the visible region (412 bands and 505 acetonitrile, for catalysts. This α-diketone has absorption innm thein visible region see (412Supplementary and 505 nm inMaterials acetonitrile, further details) and therefore could excited by visible-light. However, it has beenbyrarely used in 35, see supplementary materials for be further details) and therefore could be excited visible-light. visible-light photochemical processes [35–37]. However, it has been rarely used in visible-light photochemical processes [35–37].
commercially available common visible-light photoredox catalysts and 9,10Figure 1. 1. Comparison Comparisonofof commercially available common visible-light photoredox catalysts and 9,10-phenanthrenedione (source: Sigma-Aldrich (2018)). phenanthrenedione (source: Sigma-Aldrich (2018)).
On the other hand, tertiary amines represent an important class of compounds in organic synthesis, is ofisgreat interest for thefor chemical community, medicinal medicinal chemistry, synthesis, where wherefunctionalization functionalization of great interest the chemical community, pharmaceutical, and agrochemical industry. In industry. this context, visible-lightofcatalysis chemistry, pharmaceutical, and agrochemical In the thiscombination context, the of combination visibleand C-H bond functionalization adjacent to a tertiary amine has been successfully developed in light catalysis and C-H bond functionalization adjacent to a tertiary amine has been successfully 3 3 the last years Normally, thisNormally, sp -C-H functionalization involves the oxidation of the amine developed in [38–41]. the last years [38–41]. this sp -C-H functionalization involves the oxidation to iminium which can attacked variousbykind of nucleophiles. Nonetheless, the major of the amineion, to iminium ion, be which can beby attacked various kind of nucleophiles. Nonetheless, the number of examples are regarded to the functionalization of N-aryl tetrahydroisoquinolines [42–52], major number of examples are regarded to the functionalization of N-aryl tetrahydroisoquinolines N,N-dimethylanilines [53–57],[53–57], and N-aryl glycine derivatives [58–62]. Hence, [42–52], N,N-dimethylanilines and N-aryl glycine derivatives [58–62]. Hence,exploring exploring other substrates is highly desirable. In In this this context, context, 1,4-dibenzoxazinone 1,4-dibenzoxazinone skeleton skeleton is is present present in a wide number of compounds with biological activities and its functionalization could be significant and 3 interesting for medicinal chemistry [63–69]. Very recently, recently, Huo Huo described described the the iron iron catalyzed catalyzed sp sp3-C-H functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones [70,71] using as a terminal oxidant tert-Butyl hydroperoxide (DDQ) [71].[71]. We envisioned that hydroperoxide (TBHP) (TBHP)[70] [70]oror2,3-dichloro-5,6-dicyanobenzoquinone 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) We envisioned this could be achieved by a visible-light photochemical process. Herein, continuing that functionalization this functionalization could be achieved by a visible-light photochemical process. Herein, with our interest in interest the synthesis multisubstituted 1,4-dihydrobenzoxazin-2-ones [72] and [72] the continuing with our in the of synthesis of multisubstituted 1,4-dihydrobenzoxazin-2-ones Friedel-Crafts reactions with indoles [73–75], we [73–75], described thedescribed visible-light and the Friedel-Crafts reactions with indoles we thephotoredox visible-lightFriedel-Crafts photoredox reaction of indoles with benzoxazin-2-ones using as catalyst a simple and cheap diketone as Friedel-Crafts reaction of indoles with benzoxazin-2-ones using as catalyst a simple andsuch cheap the 9,10-phenanthrenedione, and oxygen as terminal oxidant. During our experimental work and diketone such as the 9,10-phenanthrenedione, and oxygen as terminal oxidant. During our the preparationwork of manuscript, a photoredox of 3,4-dihydro-1,4-benzoxazin-2-ones experimental and the preparation offunctionalization manuscript, a photoredox functionalization of 3,4was reported [76,77]. In both cases, the expensive Ru(bpy) Cl was used as photocatalyst. dihydro-1,4-benzoxazin-2-ones was reported [76,77]. In both the expensive Ru(bpy)2Besides, Cl2 was 2 cases, 2 unlike photoredox catalytic earlier [76], the results were obtained used asthe photocatalyst. Besides,system unlike described the photoredox catalytic systemthat described earlier with [76], our the method are were not affected bywith the steric hindrance around the C3 atom of the indole skeleton. results that obtained our method are not affected by carbon the steric hindrance around the C3 The second deals with the 3,4-dihydro-1,4-quinoxalin-2(1H)-one carbon atompaper of the [77] indole skeleton. Thefunctionalization second paper [77]ofdeals with the functionalization of 3,4skeleton and only one example skeleton of 3,4-dihydro-1,4-benzoxazin-2-ones was reported with low dihydro-1,4-quinoxalin-2(1H)-one and only one example of 3,4-dihydro-1,4-benzoxazin-2yield (44%). ones was reported with low yield (44%).
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%. In2018, view of the results, we decided to continue the optimization of the reaction conditions using Catalysts 8, 653 3 of 21 9,10-phenanthrenedione as a photocatalyst, due to its low molecular weight and its lower price in relation to the other photocatalysts tested. 2. Results In order to improve the yield of 3aa, we decided to investigate a dual catalytic protocol combining Brønsted or Lewis acid catalysisreaction and visible-light photoredox [58] (Table 2). For Initially, we choose the Friedel-Crafts between indole 1a andcatalysis 4-benzyl-3,4-dihydro-2H this purpose, different Brønsted acids, such as PhCO 2H or AcOH, were tested, however product 3aa -benzo[b][1,4]oxazin-2-one 2a in acetonitrile at room temperature under air atmosphere and the was obtained with lower and conditions, 3, respectively). Afterofwe decided to test salts as irradiation of white LEDsyield (5W).(entries Under 2these a survey photocatalyst wereZn screened, Lewis obtaining an improvement performance when we used 10 mol% of and theacid, results are summarized in Tableof1.the In catalytic a preliminary study of the photocatalyst (entries Zn(OTf) 2. In these conditions, the functionalized benzoxazinone 3aa was obtained in 76% after 9 h 1–6), Ru(bpy)2 Cl2 (A), Rose Bengal (B), Fukuzumi photocatalyst (E), and 9,10-phenanthrenedione (F) (entry 5).product Other Lewis acids, suchyields, as Fe(OTf) 2, Cu(OTf)2, and Sc(OTf)3 were evaluated (entries 6–8), afforded 3aa with similar around 30%, after 24 h. With these catalysts, we decided to obtaining lower yields for the corresponding The7–10). lowering theyield catalyst loading of change the molar ratio of 1a:2a from 0.15:0.1 toproduct 0.1:0.15 3aa. (entries The of best for compound Zn(OTf) 2 to 5 mol% did not influence in the yield of product 3aa (entry 10). Subsequently, different 3aa was obtained when Rose Bengal (B) and 9,10-phenanthrenedione (F) were used as photocatalyst solvents such as toluene, CHview 2Cl2, DMF, THF, or MeOH were screened (entries 11–14), obtaining the (53% yield in both cases). In of the good performance of the photocatalyst F, we decided to carry functionalized benzoxazinone with much lower yields.(G), Wehowever could diminish theofphotocatalyst and out the reaction using another 3aa α-diketone, such as benzyl the yield 3aa drop to only Lewis acid loadings maintaining the yield of product 3aa (entries 15 and 16). Finally, some control 15%. In view of the results, we decided to continue the optimization of the reaction conditions using experiments were carried Thus, indue theto absence of visible-light (entry 19) or 9,109,10-phenanthrenedione as a out. photocatalyst, its low molecular weight and its lower price in phenanthrenedione (entry 20), the product 3aa was not detected or the conversion was very low. relation to the other photocatalysts tested. Table 1. 1. Preliminary Preliminary optimization optimization of of the the reaction reactionconditions conditionsaa.. Table
Entry 1 2 3 4 5 6 7 8 9 10 11 a
Entry Photocatalyst (mol%) 1a (mmol) Photocatalyst (mol%) 1a (mmol) 1 A (1%)A (1%) 0.150.15 2 B (5%)B (5%) 0.150.15 3 C (5%)C (5%) 0.150.15 4 D (5%) 0.15 D (5%) 0.15 5 E (5%) 0.15 E (5%) 0.15 6 F (10%) 0.15 F (10%) 0.150.1 7 A (1%) A (1%)B (5%) 0.1 0.1 8 B (5%) 0.1 0.1 9 E (5%) E (5%) 0.1 0.1 10 F (10%) 11 G (10%) F (10%) 0.1 0.1 G (10%) 0.1
2a (mmol) 2a (mmol) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15
t (h) t (h) 24 24 27 27 46 46 48 48 48 48 25 25 24 24 24 24 48 48 24 24 24 24
Yield of 3aa (%) b b Yield of 3aa (%) 28 28 38 38 27 27 13 13 35 35 33 48 33 53 48 27 53 53 27 15 53 15
Reaction conditions: 1a, 2a, x mol% of photocatalyst in 1 mL of CH CN at rt under white LEDs 5W irradiation a Reaction conditions: 1a, 2a, x mol% of photocatalyst in 1 mL3 of CH3CN at rt under white LEDs 5W and air atmosphere. b Isolated yield of 3aa.
irradiation and air atmosphere. b Isolated yield of 3aa.
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 PhCO2 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, CH2 Cl2 , DMF, THF, or MeOH were screened (entries 11–14), 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
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were carried out. Thus, in the absence of visible-light (entry 19) or 9,10-phenanthrenedione (entry 20), Catalysts 2018, 8, x FOR PEER REVIEW 4 of 22 the product 3aa was not detected or the conversion was very low. Table 2. Optimization of the reaction conditions a. Table 2. Optimization of the reaction conditions a .
Entry Photocat. (mol%) Additive (mol%) Solvent t (h) Yield of 3aa (%) b Entry Photocat. (mol%) Additive (mol%) Solvent t (h) Yield of 3aa (%) b 1 F (10%) CH3 CN 53 53 1 F (10%) -CH3CN 24 24 2 F (10%) PhCO2H (10mol%) mol%) CH3 CN 36 36 2 H(10 2 F (10%) PhCO CH3CN 24 24 3 F (10%) AcOH (10 mol%) CH CN 24 26 26 3 CH3CN F (10%) AcOH (10 mol%) 24 3 4 F (10%) Zn(OAc)2 (10 mol%) CH3 CN 24 37 4 F (10%) Zn(OAc)2 (10 mol%) CH3CN 24 37 5 F (10%) Zn(OTf)2 (10 mol%) CH3 CN 9 76 F (10%) Zn(OTf)2 (10 mol%) CH3CN 9 76 5 6 F (10%) Fe(OTf)2 (10 mol%) CH3 CN 20 22 F (10%) Fe(OTf) CH3CN 17 20 6 7 F (10%) Cu(OTf)2 2(10 (10mol%) mol%) CH3 CN 19 22 7 F (10%) Cu(OTf) 2 (10 mol%) CH 3 CN 17 8 F (10%) Sc(OTf)3 (10 mol%) CH3 CN 19 16 19 F (10%) Sc(OTf) 3 (10 mol%) CH 3 CN 19 8 9 F (10%) Zn(OTf)2 (5 mol%) CH3 CN 9 74 16 10 F (10%) Zn(OTf)22(5(5mol%) mol%) Toluene 40 74 9 F (10%) Zn(OTf) CH3CN 8 9 11 F (10%) Zn(OTf)22(5(5mol%) mol%) CH2 Cl 20 30 40 F (10%) Zn(OTf) Toluene 8 10 2 12 F (10%) Zn(OTf)22(5(5mol%) mol%) DMFCH2Cl2 72 12 30 F (10%) Zn(OTf) 20 11 13 F (10%) Zn(OTf) (5 mol%) THF 9 34 12 2 12 F (10%) Zn(OTf)2 (5 mol%) DMF 72 14 F (10%) Zn(OTf)2 (5 mol%) MeOH 17 22 F (10%) Zn(OTf)2 (5 mol%) THF 9 34 13 15 F (5%) Zn(OTf)2 (5 mol%) CH3 CN 10 74 MeOH 17 22 14 F (10%) Zn(OTf)2 (5 mol%) 16 F (5%) Zn(OTf)2 (2.5 mol%) CH3 CN 10 75 15 F (5%) Zn(OTf) 2 (5 mol%) CH 3CN 10 74 17 B (5%) Zn(OTf)2 (2.5 mol%) CH3 CN 17 38 F (5%)F (5%) Zn(OTf) CH3CN 15 10 16 18 c Zn(OTf)22(2.5 (2.5mol%) mol%) CH3 CN 45 75 CH3CN 72 17 17 B (5%)F (5%) Zn(OTf) Zn(OTf)22(2.5 (2.5mol%) mol%) CH3 CN n.d. e 38 19 d 18 c F (5%) Zn(OTf) CH3CN 72 15 20 Zn(OTf)22(2.5 (2.5mol%) mol%) CH3 CN
