Microwave assisted synthesis of novel 1, ω -bis(quinoxalin-2-yl)phenoxy)alkanes or arenes

A synthesis of a novel series of bis(quinoxaline) derivatives by the reaction of o -phenylenediamine with the appropriate bis( α -bromoketones) was reported. The reactions were performed under thermal as well as under microwave irradiation conditions. The reaction of bis( α -bromoketones) with 2,3-diaminopyridine proceeded to give two regioisomers of the corresponding bis{(pyrido[2,3-b ]pyrazinyl)phenoxy}methanes.

To find the optimal reaction conditions, the reaction was performed in EtOH using a variety of bases (DABCO, TEA, piperidine, pyridine and KOH) as outlined in Table 1.Compared with other bases, piperidine was found to achieve the best yields and the cleanest products in short reaction time (2 hr.) (entry 3, table 1).It is worthy to mention that prolonged reaction times (up to 7 hours) did not affect the yields of the target products.The reaction was also examined in different solvents (ethanol, dioxane, dichloromethane, acetonitrile, water and DMF) as well as under solvent free conditions.The reaction was found to proceed in most solvents but with different degrees of conversion and ethanol was proved to be the best solvent in terms of reaction time and yield as outlined in Table 2.Under solvent free conditions, the reaction also proceeded to give the target molecule 4 but in very low yield (entry 7, table 2).Moreover, attempts to synthesize 4 by direct reaction of 8 with 1 in water without catalyst according to the method described by Kumar et al. 49 were also unsuccessful (entry 5, table 2).To explore the scope of this transformation, o-phenylenediamine (1) was allowed to react with various bis(α-haloketones) under the optimized reaction conditions.Thus, bis(4,1-phenylene))bis(2-bromoethanones) 11 and 12 were prepared from the appropriate bis(acetophenones) 9 and 10 as previously reported by our group. 35Reaction of compounds 11 and 12 with o-phenylenediamine (1) afforded bis(quinoxalines) 13 and 14, respectively (Scheme 3).

Scheme 4. Synthesis of bis(quinoxalines) 21-23.
Using a similar approach, reaction of bis(bromoacetyl) arenes 26 and 27 with o-phenylenediamine (1) in the presence of piperidine in ethanol at reflux as well as under microwave reaction conditions afforded the corresponding bis(quinoxalines) 28 and 29, respectively.Compounds 26 and 27 were obtained from the corresponding bis(acetophenones) 24 and 25, respectively, upon treatment with N-bromosuccinimide (NBS) in the presence of p-toluenesulfonic acid in acetonitrile 50 (Scheme 5).

Scheme 5. Synthesis of bis(quinoxalines) 28 and 29.
The structure of the novel bis(quinoxalines) were confirmed by spectral tools as well as elemental analyses.Thus, compound 4 as a representative example showed the correct molecular ion peak at m/z 470 in its mass spectrum.The disappearance of peaks characteristic for CO and NH groups in the IR spectrum confirms the cyclization as well as the aromatization reactions.Furthermore, the IR of compound 4 revealed a peak at 1602 cm -1 characteristic for C=N stretching.Moreover, the 1 H NMR of compound 4 featured the methylene ether linkage OCH2 as a singlet signal at δ 4.50 ppm.The characteristic signal at δ 9.55 ppm is referring to quinoxaline-H3.All other protons were seen at the expected chemical shifts and integral values (See Experimental section and Supporting Information).
A plausible reaction mechanism for the formation of quinoxaline derivative 4 from o-phenylenediamine (1) and bis(bromoacetyl) 8 is illustrated in Scheme 6. Initially a nucleophilic substitution occurs on the phenacyl bromide to afford the intermediate I. Intermediate I was then cyclized to give 3-phenyl-1,2dihydroquinoxaline II.The latter compound underwent air oxidation to afford the aromatized bis(quinoxaline) 4 as the final product (Scheme 6).
It was noted that when symmetric diamine was used, the reaction proceeded smoothly in all the cases and resulted in the formation of the corresponding bis(quinoxalines) as sole products in good yields.On the other hand, when the reaction was further examined by employing the reaction of 2,3-diaminopyridine (30) as an unsymmetrical diamine with bis(4,1-phenylene))bis(2-bromoethanones) 8, 11 and 12, an inseparable mixture of two regioisomers were obtained with considerable difference in the isomer ratios (determined by 1 H NMR) depending on the structure of bis(2-bromoethanones).Thus, when 8 was used the two regioisomeric products 31 and 34 were obtained in a ratio of 4:1.On the other hand, the regioisomeric products 32 ∕ 35 and 33 ∕ 36 were obtained in ratios of 3:1 and 1:1, respectively, when 11 and 12 were used (Scheme 7).
The formation of the two regioisomers may be explained as a result of the difference in the reactivities of the two amino groups of compound 30.The pyridine nitrogen may deactivate the amino group at position 2 and thus, the other amino group participates firstly in the reaction and leads to intermediate I which then cyclized and oxidized affording the corresponding products 31-33.The reaction may also proceed through intermediate II that affords the regioisomers 34-36 upon cyclization and oxidation (Scheme 7).Carrying out these reactions under microwave irradiation did not provide a significant advantage in increasing the reaction yield or in changing the regioselective ratio of the products.It is noteworthy to mention that we examined the reaction by employing different substituted o-phenylene diamine but unfortunately, the reactions afforded in all cases inseparable mixture of regioisomeric products.

Conclusions
In conclusion, we synthesized a new series of bis(quinoxaline) derivatives by the reaction of ophenylenediamine or 2,3-diaminopyridine with the appropriate bis(α-bromoketones) under thermal heating as well as under microwave irradiation conditions.The reaction proceeded via initially substitution reaction followed by cyclization and subsequent aromatization in a one-pot process under basic conditions.

Table 2 .
The Solvent effect for synthesis of bis-quinoxalline 4