Visible light-induced metal-free synthesis of quinoxalines using Rose Bengal as a photocatalyst

An efficient eco-friendly photocatalytic method was developed for the synthesis of pharmaceutically highly sought-after quinoxalines. This route is a simple condensation between o -phenylenediamine and an α -hydroxy ketone in methanol at room temperature in the presence of the organic dye Rose Bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) as a photocatalyst. Using this protocol, a library of examples with various o - phenyl enediamines and α -hydroxy ketones was prepared. This is a practically useful method for the development of quinoxaline derivatives of biological importance in good to excellent yields


Introduction
Heterocyclic compounds possess a highest priority in organic synthesis due to their diversified applications.Among them, quinoxalines is one of the most important classes of nitrogen-containing heterocyclic scaffolds which attracts researchers for their many activities.They are considered privileged scaffolds in the new drug discovery process. 1,2Quinoxaline derivatives are reported to have a varied range of biological properties, such as anticancer, 3 anti-malarial, anti-HIV, 4 antagonist and antibacterial properties. 5Some of the quinoxalinecontaining derivatives that exhibit biological activities are: NCGC55879-01 (I) (Figure 1) which acts as a BRCA1 inhibitor, 6 NSC-656889, XK 469 (II) is an antineoplastic agent 7 and other quinoxaline derivatives like quinacillin (III) is a semi-synthetic penicillin with antibacterial activity 8 and AG-1296 (IV), is a protein tyrosine kinase inhibitor. 9In addition to their medicinal importance they are also commonly used as an electron-acceptor unit, when combined with electron-donor units, these combined materials have efficient applications in photovoltaics, OLDED and dye-sensitized solar cells (DSSCs). 10Moreover, many quinoxaline derivatives have already found applications as organic semiconductors in thin film transistors. 11,12gure 1.Biologically important molecules containing a quinoxaline scaffold.
In view of their diverse utilization, several methods have been developed for the synthesis of quinoxalines. 13,14Previous approaches for the synthesis of quinoxalines make use o-phenylenediamines and αhydroxy ketones or diketones or diol compounds with various promoting agents such as CuCl2, 15 ceric ammonium nitrate (CAN), HgI2, 16 MnO2, 17 FeMPA, 18 TiO2, 19 [P4-VP]-PdNPs] 20 or Ru/N-C 21 and manganese octahedral molecular sieves 22 as well as microwave technology.However, these methods are associated with some drawbacks such as harsh reaction conditions, use of hazardous solvents, low yields, use of toxic and expensive reagents and longer reaction times (Table 1).Therefore, the development of eco-friendly methods for the synthesis of quinoxalines is greatly needed.
4][25] It is a powerful tool to accomplish novel organic chemical transformations via a single-electrontransfer pathway. 26,27Continuing our efforts towards the synthesis of heterocyclic scaffolds herein, we developed a visible-light-driven environmentally benign process for the synthesis of quinoxalines (Scheme 1) from readily available o-phenylenediamines and α-hydroxy ketones at room temperature under open air by using organic dye such as Rose Bengal as a photocatalyst Visible light-driven synthesis of quinoxaline derivatives.

Results and Discussion
With the aim to develop an efficient new photocatalytic method for the synthesis of quinoxalines from ophenylenediamines and α-hydroxy ketones, our initial attempt at the Rhodamine B (2 mol%) catalysed reaction of o-phenylenediamine (1) with α-hydroxy ketone (2) using 15 W LED bulb at room temperature for 6 hours resulted in the production of desired quinoxaline 3 was obtained in a 74% yield (Table 2, entry 1).
To investigate more reaction conditions, various photocatalysts like Rose Bengal, Eosin-y, methylene blue, Ru-and Ir-complexes were screened (Table 2, entries 2-6).Among these, Rose Bengal was found to be the most effective.In addition, the reaction was checked in different solvents such as water, acetone, dichloroethane (DCE), methanol, ethanol, chloroform, 2-propanol, acetonitrile, hexane, ethyl acetate and Page 4 of 13 © AUTHOR(S) dichloromethane (DCM) (Table 2, entries 7-22) with 2 mol % of photocatalyst in the presence of white LED bulb (15 W) in which, Rose Bengal in methanol was found to be the best conditions, resulting in a 90% yield of 3 in a reaction time of 6 hours (Table 2, entry 6).Once Rose Bengal has been identified as the best photocatalyst for promoting this reaction, we turned our consideration towards optimization of the amount of photocatalyst essential for obtaining a high yield of quinoxaline.A series of trials were conducted using different quantities of Rose Bengal wherein it was observed that the use of 2 mol % catalyst gave the best result.Reducing the amount of catalyst resulted in a poorer yield.Moreover, the advantage of the Rose Bengal is its reusability, 33 the catalyst can be reused for up to three cycles with the almost same results, as shown in Figure 2. Furthermore, we studied the reaction conditions by conducting control experiments, including the effect of photocatalyst, light and atmospheric oxygen.In these experiments, reaction in the absence of a photocatalyst, light (Table 2, entries 23-26) and switch on-off trials, revealed that both the catalyst and light were essential.Poor yields were obtained under inert conditions (Table 2, entry 27).
Having established optimal reaction conditions in hand, we extended the scope of the present photocatalytic method using various substituted o-phenylenediamines and α-hydroxy ketones for the synthesis of corresponding products.The reaction was successful with various o-phenylenediamines (e.g.substituted with H, Cl, Br, Me, F, NO2, I, dimethyl, and dichloro) and α-hydroxy-1,2-diphenylmethane in moderate to good yields (Figure 3, 70-90 %).Moreover, the optimized conditions were also successfully applied to heteroaryl α-hydroxy ketones which generated the corresponding heterocycle-substituted products in moderate yields (Figure 3).Notably, aliphatic and unsymmetrical α-hydroxy ketones also worked smoothly under the current conditions to afford the desired quinoxalines.
Various o-phenylenediamines, with different aromatic substituents, both electron-withdrawing and electron-donating, afforded the substituted quinoxalines 3 in good to excellent yields.The electronic effects of the substituents did not show much effect on the yield of the products.After separation of the product, Rose Bengal was eluted by using a polar solvent mixture (chloroform/methanol) that allows the catalyst to be reused subsequent to evaporation of the solvent under vacuum.A plausible pathway for the synthesis of quinoxaline from o-phenylenediamine and α-hydroxy ketones is depicted in Figure 4. Initially, the reaction between the o-phenylenediamine (1) and α-hydroxy ketone (2) gives the imine A, which on single-electron extraction by the visible-light-excited Rose Bengal (RB*) via an SET process results in the formation of Rose Bengal radical anion (RB•−) and radical cation B. Transfer of an electron to O2 to form the superoxide radical anion, and regeneration of Rose Bengal completes the photoredox cycle.Finally, the abstraction of hydrogen by hydroxyl radical (HOO•) from C results in the formation of the desired quinoxaline product (3).The elimination of hydrogen peroxide (H2O2) was identified by starch iodide paper, an observation that provides support to the above mechanism. 26

Conclusions
We have disclosed a new, one-pot protocol for the synthesis of quinoxalines (3a-z) by employing α-hydroxy ketone and o-phenylenediamine as the starting materials.This protocol utilizes visible light as an inexpensive, green and eco-sustainable energy source, cheap and commercially available starting materials, Rose Bengal as a metal-free photoredox catalyst and molecular oxygen (open-air) as an oxidant at ambient temperature.This protocol tolerates a wide variety of substrates such as aromatic, aliphatic and unsymmetrical α-hydroxy ketones and various substituted o-phenylenediamines.It is expected that this procedure will offer wide practical utility.

Experimental Section
General.All chemicals, reagents and photocatalysts were purchased from commercial sources and were used without further purification.Reactions were monitored by TLC on a silica gel glass plate containing 60 GF-254, and visualization was done by UV light and iodine vapor. 1 H and 13 C NMR spectra were recorded on Bruker UXNMR/XWIN-NMR (300 MHz) or InovaVarian-VXR-unity (400, 500 MHz) instruments.Chemical shifts were expressed in parts per million ( in ppm) downfield from TMS expressed as internal standard and coupling constants are expressed in Hz. 1 H NMR spectral data were reported in the following order: multiplicity (s, singlet; brs, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet), coupling constants in Hz, and the number of protons.ESI mass spectra were recorded on a Micromass Quattro LC using ESI+ software with a capillary voltage 3.98 kV and an ESI mode positive ion trap detector.High-resolution mass spectra were recorded on a QSTAR XL Hybrid MS-MS mass spectrometer.Melting points were determined with an electrothermal digital melting point apparatus IA9100 and are uncorrected.All reactions were conducted in glass vials and using the following procedure and and an LED bulb (15W) reaction set-up.

Figure 2 .
Figure 2. Graph representing reusability of the catalyst.

Figure 3 .
Figure 3. Scope of the substrates.

.
Comparison of the new method with existing methods for synthesis of quinoxalines

Table 2 .
Optimization of photocatalytic synthesis of quinoxalines a a Reaction conditions: 1a (1 equiv.),2a(1equiv.),solvent(12mL) and a 15 W white LED bulb kept at a distance of 10 cm (approx.)from the reaction vessel.bYields of the isolated products after column chromatography.cAbsence of the photocatalyst.dThereaction was run in the dark.eInertcondition, ND = the desired product was not detected on TLC.Page 6 of 13© AUTHOR(S)