Pyrrolo quinoxalines preparations

Condensed quinoxalines have been synthesized using 2-chloro-3-alkynylquinoxalines as common intermediates. 2-Chloro-3-phenylethynylquinoxaline 98 was prepared from 2,3-dichloroquinoxaline (97). Action of methylamine on 98 gave 1,2-disubstituted pyrrolo[2,3-fcjquinoxaline 99. Similarly, 2-phenylthieno[2,3-fc]quinoxaline 100 was synthesized by treating 98 with ethanolic sodium sulfide. 

Inspired by the bioorganometallic approach, two series of ferrocenyl pyrrolo[ 1,2-a] quinoxalines were designed and prepared (Fig. 17). The derivatives were tested in vitro against three different strains of P. falciparum F32, FcBl, and PFB [107]. The best results (IC50 between 30 and 70 nM in comparison to CQ IC5o = 225 nM) were observed in the first series with a bis(3-aminopropyl)piperazine as a linker. These compounds were tested for then ability to inhibit p-hematin formation. For all but one case, the derivatives did not interfere with hemozoin formation... 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

Routes via o-aminophenylpyrroles present the most convenient syntheses of a wide variety of pyrrolo[l,2-a]quinoxalines. Thus reaction of the amino compound 6 with acetic anhydride in acetic acid gave the acetamido derivative which was cyclized with phosphoryl chloride to give the 4-methyl compound 7 (R = Me) in 56% yield. The 4-phenyl compound 7 (R = Ph) has been prepared similarly. An even more convenient synthesis of 4-aryl compounds is achieved by reaction of compound 6 with aromatic aldehydes to give the 4,5-dihydro derivatives These are readily oxidized to 4-arylpyrrolo[l,2-a]quinoxalines 9 with manganese dioxide. This approach may be carried out in one step by reaction of compound 6 with aromatic aldehydes (e.g., benzaldehyde) in the presence of cupric acetate. Reaction of the aminophenylpyrrole 6 with 90% formic acid gave pyrrolo[l,2-a]quinoxaline (7, R = H) directly in 98% yield. Pyrrolo[l,2-a]quinoxalines substituted in the l-position and the 7-position have also been prepared from appropriately substituted... 

Cyclization of the quinoxaline chloride 50 to prepare pyrrolo[2,3-f ]quinoxaline under usual conditions is slow and the yield is low, because the aminoquinoxa-lines are strong chelating agents and poison Pd catalysts. However, the locked Pd catalyst is released and the reaction proceeds smoothly under Jeffery s ligandless conditions to give the pyrrolo[2,3- ]quinoxaline 51 in 67 % yield [38]. 

Another often encountered substructure for intramolecular 5- xo-Mizoroki-Heck reactions is allyl side chain containing vinyl halide D (Figure 6.3) [73, 74], Based on this substrate structure, a series of 3-substituted pyrrolo[2,3-b]quinoxalines have been prepared via intramolecular Mizoroki-Heck reaction under Jeffery s ligand-free conditions in moderate to excellent yields (Scheme 6.25) [75]. 

Cheeseman GWH, Roy PD (1968) The preparation and rearrangement of bromo- and iodo-pyrrolo [l,2-a]quinoxalines. J Chem Soc C 2848-2852. doi 10.1039/J39680002848 Cheeseman GWH, Roy PD (1969) Preparation and reactions of pyrrolo[l,2-a]quinoxalinesul-phonic acids J Chem Soc C 5 856-860. doi 10.1039/J39690000856 Cheeseman GWH, Tuck B (1965a) A new synthesis of pyrrolo[l,2-a]quinoxalines. Chem Ind 31 1382-1385... 

Molina P, Alajarin M, Vidal A (1990) New methodology for the preparation of pyrrole and indole derivatives via iminophosphoranes synthesis of pyrrolo[l,2-fl]quinoxalines, indolo[3,2-c] quinolines and indolo[l,2-c]quinazolines. Tetrahedron 46(3) 1063-1078. doi 10.1016/80040-4020(01)81384-3... 

Sypchenko VV, Potikha LM, Kovtunenko VA, Baumer VN, Shishkin OV (2012) Preparation of isoindolo[2,l-a]quinoxalines based on JV-(2-aminophenyl)isoindole derivatives. Chem Heterocyclic Compd 48(7) 1033-1042. doi 10.1007/sl0593-012-1096-x Szabo G, Kiss R, Payer-Lengyel D, Vukics K, Szikra J, Baki A, Molnar L, Fischer J, Keseru GM (2009) Hit-to-lead optimization of pyrrolo[l,2-a]quinoxalines as novel cannabinoid type 1 receptor antagonists. Bioorg Med Chem Lett 19(13) 3471-3475. doi 10.1016/j.bmcl.2009.05. 010... 

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