Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H- pyrrole-2-carboxamides. Evidence of a Smiles rearrangement Georgios Rotas, Athanasios Kimbaris and George Varvounis * Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece Received 16 July 2004; revised 25 August 2004; accepted 16 September 2004 Available online 2 October 2004 Abstract—An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a–g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a–c and 7a–c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction Pyrrolo[1,2-a]quinoxalines are best known as high-affinity and selective agonists of the 5-HT 3 receptors. 1–3 More recently, several bispyrrolo[1,2-a]quinoxaline derivatives were found to have significant antimalarial activity 4 whereas certain pyrrolo[1,2-a]quinoxalin-4(5H)-ones have shown promising antiviral 5 and antiallergic 6 properties. 5-Alkylpyrrolo[1,2-a]quinoxalin-4(5H)-ones may be formed by first synthesising the lactam derivatives 1–3,7 followed by alkylation. 5 Other routes include the use of benzimidazolium N-ylides in 1,3-dipolar cycloadditions with alkenes 6,8 and alkynes 9 or reaction with 2,2-dihydro- poly(per)fluoroalkanoates, 10 and by reductive ring-opening/ ring-closure of pyridazinoquinoxalinones. 11 2. Results and discussion Following our previous interest in the synthesis of pyrrolo[1,2-a]quinoxalines 12 we now wish to report our findings that lead to the synthesis of 5-alkyl(or aryl)- pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2- carboxamides. Carboxamides 3a–c were prepared by reacting appropriate 2-trichloroacetylpyrroles 2a–b, derived by treating 1-arylpyrroles 1a–b with trichloroacetyl chloride, with diethylamine or cyclohexylamine in 1,4-dioxane for 1.5 h (Scheme 1). In contrast, the preparation of aromatic carboxamides 7a–e required first hydrolysis of trichloroacetyl derivative 2a to the carboxylic acid 4, conversion of the latter with thionyl chloride into acid chloride 5 and then, without isolation, treatment of 5 with aromatic amines 6a–e for 2 days in a 1:1 pyridine–toluene mixture (Scheme 2). Attempts to react 4-chloro-2-nitroaniline or 2-trifluoromethylaniline with acid chloride failed. This is probably due to a combination of steric and electronic reasons which is reflected in the low yield (45%) of 7b. Railey and Johnson have previously prepared a large number of N-alkyl(or aryl)-4,5-dihalo-1H- pyrrole-2-carboxamides, as potential antibacterial agents, in a similar manner. 13 Upon treating carboxamides 3a,c or 7a–c,e with NaH in DMF for 4.5 or 2 h, pyrroloquinoxalinones 8a–f were obtained in excellent yields (77–95%). The work-up involved adding to water and neutralising with 2 N HCl. This led to hydrolysis of the initially formed ester 8e to the carboxylic acid 8d. The ester 8e was isolated when the 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.09.048 Tetrahedron 60 (2004) 10825–10832 Keywords: Pyrroles; Pyrroloquinoxalinones; Denitrocyclisation; Defluoro- cyclisation; Smiles rearrangement. * Corresponding author. Tel.: C30 26510 98382; fax: C30 26510 98799; e-mail: gvarvoun@cc.uoi.gr