Synthesis of Quinoxaline Analogues

Abstract

Substituted tricyclic or tetracyclic quinoxalines, tricyclic pyridoquinoxalines and bis-quinoxalines were synthesized in high yields starting from cyclic ketones by the a-bromination of cyclic ketones with N-bromosuccinimide (NBS) followed by condensation of the resulting a-bromo ketones with 1,2-diaminobenzene, 3,4-diaminopyridine, or 3,3¢-diaminobenzidine.Quinoxaline heterocycles are important benzoheterocycles in combinatorial drug discovery libraries. 1 There are a number of processes available to generate the structural skeleton of quinoxalines, but they are generally synthesized by the condensation of 1,2-dicarbonyls with 1,2-diamines in either acetic acid or ethanol heated to reflux. 2 Some recent reactions of 1,2-diaminobenzene with a-dicarbonyl equivalents are described as follows: (1) epoxides in the presence of Bi(0) and acid derivatives, 3 (2) ketones and potassium hydroxide in PEG 400, 4 (3) a-bromo ketones in an aqueous media system 5 or by use of solid phase chemistry, 6 (4) hydroxylimino ketones under microwave irradiation, 7 (5) a-hydroxyketones 8 by the use of iodine, 9 sulfamic acid, 10 nanoparticles, 11 metal complexmediated tandem oxidation process, 12 and other notable approaches. 13 Although a great number of quinoxalines and their derivatives with this specific substitution pattern have been developed, new methods for their preparation are needed. Since the above-mentioned procedures are almost all multi-step reactions, we wanted to explore a onepot methodology 14 for the preparation of tricyclic or tetracyclic quinoxaline skeletons by the a-bromination of cyclic ketones with N-bromosuccinimide (NBS) in acetic acid, followed by the addition of different aryl-1,2-diamines (e.g., 1,2-diaminobenzene; 3,4-diaminopyridine or 3,3¢-diaminobenzidine).Recently, Yao et al. reported that NBS (10 mol%) promoted the synthesis of 1,5-benzodiazepine 2 through the reaction of cyclohexanone (1a; 4.0 mmol) with 1,2-diaminobenzene (1.0 mmol) either at r.t. or at 40°C under solvent-free conditions. 15 Three components were added almost simultaneously for the one-pot reaction. However, our concise synthesis of quinoxaline 3a with the ordinal addition sequence was achieved from the reaction of cyclohexanone (1a; 1.0 mmol) with NBS (1.05 mmol) in acetic acid (5 mL), followed by the addition of the resulting a-bromo ketone with 1,2-diaminobenzene (1.1 mmol), as shown in Scheme 1. The major difference between the construction of the two frameworks of benzodiazepine 2 and quinoxaline 3a 8b is the sequence of addition of the reagents [NBS, cyclohexanone (1a), then 1,2-diaminobenzene].

A Green Synthesis of Quinoxalines and 2,3-Dihydropyrazines

“…5a-j, 6a,b,f,g,i, 7a,b,f,g,i, 11a-e, 12a, 13a agree with those reported in the literature. 37,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] For the NMR spectra of new compounds see the Supporting Information. 6c,d, 7c,d, 12b-e and 13b-e are reported together below with some spectral data of known compounds not yet reported in the literature.…”

Green Synthesis of Indeno[1,2-b]quinoxalines Using β-Cyclodextrin as Catalyst

“…The influence of the reaction time, catalyst dosage, temperature, and substrate dosage on the reaction was also investigated (Table 1, entries [13][14][15][16][17]. It can be seen that high temperatures were unfavorable to the reaction.…”

“…Therefore, a great deal of attention has been paid to the construction of indeno [1,2b]quinoxaline skeleton compounds [10]. Among these methods, the condensation of OPD with indan-1,2-diones or 1,2,3-indanetriones [11][12][13] (Scheme 1, Equation (i)) and the α-halogenation of 1-indanones with OPDs are the most commonly practiced [14,15] (Scheme 1, Equation (ii)). In addition to these strategies, other oxidation methods or ways of using other types of substrates have also been developed, such as the reaction between 2-indanone and OPD [16] (Scheme 1, Equation (iii)).…”

Heterocyclic chemistry

“…68 A transitionmetal free approach to quinoxalines was reported by Chang et al, using the in situ a-bromination of cyclic ketones followed by condensation of the a-bromo ketone intermediate with 1,2-diaminobenzene. 69 The latter condensation also occurs efficiently with 3,4-diaminopyridine or 3,3 0 -diaminobenzidine. Condensation of 1,2-diaminobenzenes with ninhydrin also gives quinoxalines, which can be further functionalised, as part of a one-pot four-component synthesis.…”