Synthesis and reactions of 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2- (3H)-ones Vytas Martynaitis a , Rasa Steponavi  ci  ut _ e a , Sonata Krik  stolaityt _ e a , Joana Solovjova b , Sven Mangelinckx c, y , Norbert De Kimpe c , Wolfgang Holzer d , Algirdas  Sa  ckus a, b, * a Department of Organic Chemistry, Kaunas University of Technology, LT-50270 Kaunas, Lithuania b Institute of Synthetic Chemistry, Kaunas University of Technology, LT-50270 Kaunas, Lithuania c Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Gent, Belgium d Department of Drug Synthesis, Faculty of Life Sciences, University of Vienna, Pharmaziezentrum, A-1090 Vienna, Austria article info Article history: Received 14 February 2011 Received in revised form 14 March 2011 Accepted 16 March 2011 Available online 23 March 2011 Keywords: Hydroxamic acids Indolium salts Imidazolidinones Ring opening abstract 1-Hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones, as a new type of azaheterocyclic hydroxa- mic acids, have been synthesized regioselectively from 1-carbamoylmethyl- or 1-(methoxycarbonyl) methyl-2,3,3-trimethyl-3H-indolium salts by reaction with hydroxylamine in the presence of a strong base. The alkylation and reduction with sodium borohydride of these novel heterocycles have been investigated. When treated with protic acids 1-hydroxy- or 1-alkoxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones underwent ring opening of the imidazolidine to afford 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-trimethyl- 3H-indolium salts. The structural assignments are based on extensive 1 H, 13 C and 15 N NMR spectroscopic studies and single crystal X-ray analyses. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction 1-Substituted 3H-indolium salts are important synthetic pre- cursors in the preparation of functionalized organic dyes with wide technical and biomedical applications. 1 Quaternisation of 2,3,3-tri- methyl-3H-indole with 2-haloacetamides affords reactive 1-carba- moylmethyl-2,3,3-trimethyl-3H-indolium salts, 2 possessing several reactive centres, which allow them to participate in various chemical transformations. The reaction of the latter with squaric acid afforded squaraine dyes, which have been investigated as non-covalent protein probes with high fluorescence quantum yield and good photostability. 3 When condensed with salicylic aldehydes, they underwent spirocyclization due to intramolecular addition of the phenolic oxygen atom across the carbon atom at the 2-position of the indole to give photochromic and thermochromic 1-carba- moylmethylindoline[2,2 0 ]spirobenzopyrans. 4 It is known also that 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride upon treatment with base undergoes cyclization to 9,9a-dihydro-1H- imidazo[1,2-a]indol-2(3H)-ones by nucleophilic addition of the amide nitrogen atom across the carbon atom at the 2-position of the indole. 2 Furthermore, 9a-styryl-9,9a-dihydro-1H-imidazo[1,2-a] indol-2(3H)-one derivatives were designed as colour formers for pressure- and heat-sensitive recording materials. 5 Finally, reaction of 1-carbamoylmethyl-3H-indolium chloride with hydrazine bishydrate selectively afforded 1-amino-9,9a-dihydro-1H-imidazo [1,2-a]indol-2(3H)-ones, possessing a cyclic hydrazide moiety, which was easily transformed to various heterocyclic structures. 6 In an effort to expand the chemical space of ring fused indoline derivatives bearing an annelated heterocycle at the N-1‒C-2 bond of the indole nucleus, the objective of this work was to investigate the reaction of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with hydroxylamine, and the structure of the indolyl hydroxamic acid derivatives obtained. The targeted heterocyclic compounds contain a 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)- one core (Fig. 1), which is, to the best of our knowledge, unreported in the literature. This new azaheterocyclic scaffold is however in- teresting in view of its similarity with the isomeric 1-hydroxy-9,9a- dihydro-1H-imidazo[1,2-a]indol-3(2H)-one core which is present in the natural hydroxylamine alkaloids tryptoquivaline, possessing tremorgenic activity, and asperlicin B, which is a competitive cho- lecystokinin (CCK) antagonist (Fig. 1). 7 Hydroxamic acids are ver- satile analytical reagents for the analysis and separation of metals 8 and possess also wide biomedical applications. 9 More specifically, 5-bromo-1H-indole-3-acetohydroxamic acid was recently identi- fied as a potent inhibitor of bacterial deformylases (Fig. 1), 10 while * Corresponding author. Fax: þ370 37 451432; e-mail address: algirdas.sackus@ ktu.lt (A.  Sa ckus). y Postdoctoral Fellow of the Research FoundationdFlanders (FWO), Belgium. Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.03.044 Tetrahedron 67 (2011) 3945e3953