Microwave-assisted and traceless synthesis of imidazoquinoxalinones.

To discover lead compounds of significant pharmacological activity, it is necessary to screen a large number of compounds within a short period of time. Combinatorial chemistry along with high-throughput screening has been able to generate vast molecular libraries to meet this demand for diversified chemical compounds.1 Although solid-phase library synthesis offers a practical method with the advantages of fast purification,2 it is hampered by the heterogeneous conditions and requires a large excess of reagents to drive it to completion. The introduction of soluble polymer supports3 to combinatorial synthesis has resulted in an alternative method that enables standard solution-based chemistry to be performed with favorable reaction kinetics and product purification similar to solid phase reactions. Furthermore, monitoring progress of reactions on the support is significantly simplified by using conventional analytical methods.4 Despite numerous advances in high-throughput synthesis methods, a more practical approach in fast library preparation is emerging. Many polymer-supported reactions require hours or days to complete conversion with conventional heating. Same reactions only take a few minutes to complete with microwave irradiation. Several papers that have applied microwave irradiation in solidor solution-phase synthesis are now widely reported,5 and their results demonstrate higher yields and shorter reaction times compared to that of conventional thermal heating. The development of microwaveassisted traceless library synthesis provides rapid access to the targeted compounds without requiring cleavage of the polymer support. To better meet the need of enhancing druglike library synthesis, we report the rapid synthesis of biologically interesting imidazoquinoxalinones by the application of microwave technique and traceless approach. The heterocyclic systems containing quinoxaline rings were largely investigated and were effective in pharmacological and agrochemical herbicides. For example, pyrazoloquinoxaline showed a relatively high antibacterial activity, wherein the minimum inhibitory concentration (MIC) was 25 μg/mL against Bacillus Licheniformis and Celllulomaonas Sp.6-10 The tricyclic fused scaffold incorporating pyrazine and imidazole with a benzene spacer moiety resulted in compounds with promising biological activation (Figure 1). For example, AGL 2043 blocked PDGFR kinase with inhibitory effects on the related Flt-3 and c-Kit receptors.11-15 Lin-benzoadenine has been studied with respect to the exhibition of strong enzyme binding, activation, and action as cofactor in enzymatic reactions.16 Tricyclic quinoxalinones (TQXs) are reported as selective AMPA receptor antagonists.17 In continuation of our interest in soluble polymersupported synthesis of benzimidazoles and quinoxalinones, the present investigation develops an efficient one-pot traceless synthesis of imidazolo[4,5-g]-quinoxalinone on a soluble polymer support under microwave irradiation. The microwave-assisted multistep synthetic route to the targeted imidazoquinoxalinones is described in Scheme 1. The synthesis starts with esterification of the commercially available Fmoc-protected amino acids with poly(ethylene glycol) (PEG-OH, MW ≈ 5000) under microwave conditions for 15 min to obtain the Fmoc-protected amino ester conjugates (1). The same coupling reaction was done in 8 h by conventional reflux heating. The regeneration of the free amino group was achieved by treating 1 with 10% piperidine in dichloromethane at room temperature which left the polymer support intact leading to the polymer-bound amines (2). The next step in the synthesis is the ipso-fluoro displacement reaction with highly electrophilic dinitrodifluorobenzene inside the microwave cavity. The reaction proceeds to completion in 7 min resulting in the formation of polymer-bound dinitrofluoro amines (3). It should be noted that under harsh microwave heating, no disubstituted species were observed after cleavage of 3. This could be that immobilized substrate 3 is less reactive than difluoronitrobenzene once one fluoro was first replaced by polymerbound amino esters 2. Difluoronitrobenzene has been utilized as a bifunctional cross-linker since it contains two fluoro groups which could be successively substituted by different nucleophiles.18 The use of this symmetric scaffold for the construction of fused heterocycles by solid-phase synthesis has been published.18d However, the acidolysis of acylamidoquinoxaline to cleave the polystyrene support is necessary. The second point of molecular diversity was introduced by another SNAr reaction of various alkyl aromatic amines giving rise to the PEG-immobilized dinitro diamines (4) under microwave irradiation in 10 min. In contrast, conventional heating for this transformation required 7 h of reflux in EtOH to go to completion. Simultaneous quantitative reduction of the aromatic m-dinitro group to the corresponding aniline derivatives was then studied in various conditions. We found that by using either Zn in HCOONH4 or tin(II) * To whom correspondence should be addressed. Fax: +(886)-35736007. E-mail: [email protected]. 455 J. Comb. Chem. 2006, 8, 455-458