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Synlett 2009(14): 2273-2276  
DOI: 10.1055/s-0029-1217807
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel Domino Approach to Fluorescent Pyrimido[1,6-a]indolones

Diego Facoettia, Giorgio Abbiatia, Laura d’Avolioa, Lutz Ackermannb, Elisabetta Rossi*a
a DISMAB, Sezione di Chimica Organica ‘Alessandro Marchesini’, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Fax: +39(02)50314476; e-Mail: elisabetta.rossi@unimi.it;
b Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Goettingen, Tammannstr. 2, 37077 Goettingen, Germany
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Publication History

Received 21 May 2009
Publication Date:
07 August 2009 (online)

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Abstract

Easily accessible N-ethoxycarbonyl-2-alkynylindoles undergo, in the presence of primary aryl amines and under TiCl4/t-BuNH2 catalysis, domino hydroamination-annulation reactions giving rise to pyrimido[1,6-a]indolones in good to excellent yields. The reaction involves an initial highly regio- and chemoselective hydroamination reaction. The obtained compounds show interesting fluorescence properties and could represent a new class of useful markers for bioanalytical purpose.

Key words

alkynes - titanium - hydroaminations - domino reactions - heterocycles - fluorescence

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Representative Procedure - Synthesis of 3a
In a 25 mL Schlenk tube, a solution of t-BuNH2 (49.83 mg, 71.6 µL, 0.673 mmol) in dry toluene (3 mL) was stirred at 0 ˚C under nitrogen. To the cooled solution TiCl4 (25.53 mg, 14.76 µL, 0.135 mmol) was added dropwise via syringe. The obtained mixture was stirred at 0 ˚C for 15 min, and then a solution of 2a (194.5 mg, 0.673 mmol) and 4-methylaniline (86.5 mg, 0.808 mmol) in dry toluene (3 mL) was slowly added via cannula under a nitrogen atmosphere. The reaction mixture was warmed at 105 ˚C and stirred overnight. After cooling the reaction mixture was poured in 0.1 N HCl (20 mL), the organic layer was separated and the aqueous phase extracted with EtOAc (3 × 20 mL). The collected organic phases were dried over Na2SO4 and concentrated at reduced pressure. The resulting crude material was purified by flash chromatography on SiO2 (EtOAc-hexane, 1:9) to afford 210 mg (89% yield) of pyrimido[1,6-a]indol-1-one 3a. White solid; mp 199-200 ˚C. IR (KBr): 3366, 1692, 1634, 1390, 1366, 781, 754 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 8.69 (dd, J = 0.7, 7.0 Hz, 1 H), 7.65-7.71 (m, 1 H), 7.31-7.44 (m, 2 H), 7.21 (s, 5 H), 7.10 (s, 4 H), 6.61 (s, 1 H), 6.54 (s, 1 H), 2.30 (s, 3 H). ¹³C NMR (50.3 MHz, APT, CDCl3): δ = 149.3 (Cq), 140.9 (Cq), 138.0 (Cq), 135.7 (Cq), 135.5 (Cq), 134.5 (Cq), 133.7 (Cq), 131.1 (Cq), 129.7 (CH), 129.6 (CH), 129.2 (CH), 128.5 (CH), 128.2 (CH), 124.2 (CH), 123.0 (CH), 120.0 (CH), 116.6 (CH), 101.3 (CH), 98.8 (CH), 21.4 (CH3). ESI-MS: m/z (%) = 351 (100) [MH+]. ESI-MS/MS: m/z (%) = 351 (64) [MH+], 259 (100). Anal. Calcd for C24H18N2O: C, 82.26; H, 5.18; N, 7.99. Found: C, 82.24; H, 5.14; N, 8.03.

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UV and fluorescence spectra were recorded at 25 ˚C in MeOH. As an example both absorption and emission spectra of compound 3c are reported in Figure 3.

Figure 3