A novel application of DDQ as electrophile in the Nenitzescu reaction U. Kucklaender a,⇑ , R. Bollig a , W. Frank b , A. Gratz a , J. Jose a a Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany b Institute of Inorganic and Structural Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany article info Article history: Received 29 October 2010 Revised 24 February 2011 Accepted 3 March 2011 Available online 10 March 2011 Keywords: Quinones Nenitzescu reaction DDQ addition Azaspiro[4,5]decatrienes 3-Amino-benzofurans Proteinkinase-CK2 inhibition Single electron transfer (SET) Radicalion pair abstract Reaction of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) with secondary enaminones yields surpris- ingly 2-aza-spiro[4,5]decatrienes. The reaction occurs via cyclisation of the primary Michael-adduct with the nitrile group. Reaction of DDQ with tertiary and also certain secondary enamines leads to 3-amino- benzo[b]furan derivatives. This is formed not by Michael-addition, but via geminate radical ion pair for- mation with subsequent generation of an oxygen–carbon bond to yield benzofurans. The new products are investigated with regards to inhibition of purified human proteinkinase CK2 and their general cyto- static activity. It turned out, that the most active compound is the 3-amino-5-hydroxy-benzofuran deriv- ative 11s with an IC 50 value of 0,2 lM for CK2. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction In continuation of our previous work studying the reaction of quinones and enamines in the Nenitzescu reaction in order to synthesize potential heterocyclic antitumour compounds, 1 we used completely substituted quinones (e.g., 1) as educt in the reaction with secondary enamines 2 leading to the indole 3 2 (Scheme 1). Furthermore, we investigated 2 the reaction of the activated qui- none 1 and tertiary enamines 2. This yielded indenes 4 by cyclisa- tion via enaminemethyl group due to participation of the methyl group in enamine tautomerization (Scheme 1). Our idea now was to use DDQ 5a as a completely substituted and activated quinone in the reaction with enamines. This seemed to be interesting since DDQ, which is normally used as oxidant, 3 is known to react with nucleophilic indoles and enols by C–C-bond formation via Michael-addition. 4,5 2. Chemical results and discussion 2.1. Secondary enamines We 6 investigated the reaction of DDQ 5a and also 2,3-dic- yanobenzoquinone 5b with enamines 2a–n derived from b-aminocrotonates or b-aminocinnamates, normally used in the Nenitzescu reaction as enamines to yield 5-hydroxy-indoles. 7 The first step should be a Michael-addition to intermediate 6. After cyc- lisation in the case of 5a we expected the formation of dihydro- indoles instead of aromatic indoles. Only reaction of quinone 5b can lead to an aromatic indole. The products of the reaction with 5a were isolated in high yield. The spectroscopic investigation showed unexpectedly sp 3 -singlets at 89–102 ppm in the 13 C NMR-spectra. The shift is in the typical range for a carbinolamine carbon. However, there is only one sp 3 -singlet in the 13 C NMR-spectra, which is not in agreement with the expected dihydroindole structure. We were able to acetylate the reaction products (7) from the quinones with 2a and 2h and obtained the corresponding acetyl derivatives to yield 8a,h. Some crystals from 8a were suitable for X-ray-analysis. The result ( Fig. 1) confirms the correct structure 8a. Thus, structures 7a–n are correct for all products, which is shown by the spectroscopic data accordingly. Thus, the reaction of quinones 5a,b involves in the first step a normal soft–soft reaction of the ß-carbon of enamine 2 in a nucle- ophilic 1,4-addition to position 2 of the quinone, to yield the inter- mediate 6 (Scheme 2). The following cyclisation happens by attack of the enamine nitrogen to the neighbouring nitrile group leading to the spirocompounds 7, being in perfect accordance with the cor- responding 13 C NMR-data. To our knowledge, this is the first time, that the formation of a 2-azaspiro[4,5]decatriene as final product of the Nenitzescu reac- tion has been observed. 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.03.006 ⇑ Corresponding author. Tel.: +49 1731884945. E-mail addresses: kucklaen@uni-duesseldorf.de (U. Kucklaender), Joachim.Jo- se@uni-duesseldorf.de (J. Jose). Bioorganic & Medicinal Chemistry 19 (2011) 2666–2674 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc