Streamlined access to 2,3-dihydropyrazino[1,2-a]indole-1,4-diones via Ugi reaction followed by microwave-assisted cyclization Sergey Tsirulnikov a , Mikhail Nikulnikov a , Volodymyr Kysil b , Alexandre Ivachtchenko b , Mikhail Krasavin a, * a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg. 141400, Russia b ChemDiv, Inc., 6605 Nancy Ridge Dr., San Diego, CA 92121, USA article info Article history: Received 7 June 2009 Revised 10 July 2009 Accepted 17 July 2009 Available online 22 July 2009 Keywords: Isocyanide-based multi-component reactions Post-Ugi modifications Microwave-assisted synthesis Combinatorial chemistry abstract An efficient method is developed to construct drug-like 2,3-dihydropyrazino[1,2-a]indole-1,4-diones from 1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and primary amines via a one-pot, two-step procedure involving Ugi reaction and microwave-assisted cyclization. Ó 2009 Elsevier Ltd. All rights reserved. The Ugi multi-component reaction (U-MCR) 1 is an efficient pro- cedure for coupling reaction components from four different func- tional classes in a single condensation product. While it may have initially seemed that such striking atom economy would be tar- nished by the redundancy of dipeptoid motifs present in the prod- ucts of the U-MCR, the potential of the latter as a source of almost infinite scaffold diversity is uncovered by intelligent design of post-Ugi events. From the earlier work of Hulme on the ‘Ugi-depro- tect-cyclize’ (UDC) strategy 2 to skillful functionalization of the U- MCR product with appendages capable of reacting in a second, orthogonal event (such as Mitsbunobu, 3 Heck, 4 Diels–Alder, 5 or photocycloaddition 6 processes)—it has become clear that U-MCR can be utilized for the formation of a wide range of heterocyclic molecular frameworks. Numerous reports on post-Ugi chemistry in the last decade (thoroughly reviewed by Akritopoulou-Zanze 7 ) have promoted further activity in this area as witnessed in the re- cent literature. 8 We recently reported that the products 1 of U-MCR of 1H-pyr- azole-3-carboxylic acids in combination with tert-butyl isocyanide undergo microwave-assisted cyclization giving rise to medic- inally important 5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2 (Scheme 1). 9 In this cyclization process, the unsubstituted pyrazole nitrogen acts as an internal nucleophile to displace tert-butylamine from the terminal amide functionality. This view was supported by our later finding that other isocyanide-derived amide termini in scaffolds such as 1 can also cyclize onto the pyrazole moiety (albeit less effectively) and that replacement of the pyrazole with less reactive indole leads to significantly diminished yields. 10 Herein we report that the products 3 of U-MCR of 1H-indole-2- carboxylic acids and ethyl pyruvate with various amines and isocy- anides undergo high yielding microwave-assisted cyclization into 2,3-dihydropyrazino[1,2-a]indole-1,4-diones 4 (Scheme 2). Com- pounds containing such motifs have been reported to possess cyto- toxic, 11 melatoninergic, 12 antiviral 13 , and antifungal 14 activities. This broad medicinal relevance and the constrained peptidomi- metic character of 4 make these new compounds attractive addi- tions to any diversity set for biological screening. The cyclization precursors 3 were prepared on 3 mmol scale as follows: Equimolar amounts of the amine and ethyl pyruvate were dissolved in methanol (10 mL) in a microwave reactor tube and heated at 50 °C for one hour to ensure complete imine formation. 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.07.096 * Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780. E-mail address: myk@chemdiv.com (M. Krasavin). N H O N R 1 R 2 O NH N R 3 AcOH MW, 20 min, 180 o C N N N O R 2 R 1 O R 3 1 2 Scheme 1. Cyclization of Ugi reaction products 1 derived from t-BuNC and 5- substituted-1H-pyrazole-3-carboxylic acids. 9 Tetrahedron Letters 50 (2009) 5529–5531 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet