Elia Matteucci

New entry to polycyclic fused indoles via gold(I)-catalyzed cascade reaction.

Polycyclic indoles are pivotal motifs in naturally occurring compounds, featuring a plethora of pharmacological and agrochemical applications. Large chemical decoration and nontrivial molecular scaffolds are common architectural patterns in indole-based alkaloids that still trigger organic chemists in developing chemically and economically efficient and sustainable methodologies for their preparation. Accordingly, efforts towards the synthesis of indole derivatives by means of metal as well as metal-free catalysis are growing exponentially. In this realm, N-fused indole alkaloids based on oxazinoACHTUNGTRENNUNG[4,3-a]indole and pyrazino ACHTUNGTRENNUNG[1,2-a]indole platforms have attracted growing attention due to their peculiar activity as ligands for 5-HT2C receptor, antidepressant, and 5-HT4 receptor antagonists. Very recently, the synthesis of densely functionalized oxazinoindoles has been addressed independently by the groups of Xiao and Gharpure through the N(1) or C(2) alkylation of the indole core with vinyl sulfonium salts and via Michael addition, respectively. Both of these elegant approaches required stoichiometric amounts of Lewis acid (i.e., (CH3)3SiOTf) or base (i.e. , KOH) along with the preformed indole nucleus, with inevitable repercussions on the availability of the acyclic precursors (Scheme 1 a, b). We recently entered a new scientific program addressing the simultaneous synthesis and functionalization of indole cores assisted by the same catalytic species. In particular, we documented the combined use of p-activated alcohols (i.e., propargylic alcohols) and gold catalysis as a powerful tool towards this goal. Tertiary propargylic alcohols, when allowed to react in the presence of mild metal bifunctional p/s acids, can act as electrophiles towards the C C triple bond, and the alcoholic group can exert either nucleophilic or electrophilic character, depending on the chemical surrounding. Based on this chemical flexibility, we envisioned an unprecedented synthesis of densely functionalized tricyclic oxazinoACHTUNGTRENNUNG[4,3-a]indoles 2 by means of simultaneous construction of the indole and the N(1)-C(2)-fused ring, starting from readily available aniline diols 1. The mechanistic plan would involve a cascade hydroamination/dehydrative synthetic sequence, delivering water as the only stoichiometric by-product of the entire process (Scheme 1 c). The choice of unprotected amine diol 1 as model substrate significantly restricted the class of potentially useful promoting agents. While Brønsted acids would presumably form the unreactive corresponding ammonium salts, conventional s Lewis acids could either be irreversibly deactivated by coordination to the hard heteroatoms or would lead to decomposition of the starting material if propargylic carbocations are formed before the hydroamination of the C C triple bond takes place. Consequently, p acid late-transitionmetal species appeared to be the promoters of choice for the titled transformation. In Table 1, we summarize some of the results obtained during the optimization of the catalytic system, choosing 1 a as the model substrate. As expected, organic Brønsted acids such as HNTf2 and pTsOH were not efficient, leading to rapid decomposition of 1 a (Table 1, entries 1,2). Similar chemical outcomes were recorded with In ACHTUNGTRENNUNG(OTf)3 (Table 1, [a] Dr. M. Chiarucci, E. Matteucci, G. Cera, Prof. M. Bandini Department of Chemistry “G. Ciamician”, Alma Mater Studiorum— University of Bologna via Selmi 2, 40138 Bologna (Italy) Fax: (+39) 051-2099456 E-mail : marco.bandini@unibo.it [b] Prof. G. Fabrizi Dipartimento di Chimica e Tecnologia del Farmaco Sapienza, Universit di Roma P.le A. Moro, 5, Rome (Italy) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201201249. Scheme 1. a,b) State of the art in the synthesis azepinoACHTUNGTRENNUNG[4,3-a]indoles. c) Synthetic approach of this work.

A Mesoionic Carbene as Neutral Ligand for Phosphorescent Cationic Ir(III) Complexes.

Two phosphorescent Ir(III) complexes bearing a mesoionic carbene ligand based on 1,2,3-triazolylidene are obtained for the first time. A silver-iridium transmetalation of the in situ-generated mesoionic carbene affords the cationic dichloro complex [Ir(trizpy)2Cl2](+) (3, trizpy = 1-benzyl-3-methyl-4-(pyridin-2-yl)-1H-1,2,3-triazolylidene) that reacts with a bis-tetrazolate (b-trz) dianionic ligand to give [Ir(trizpy)2(b-trz)](+) (5). The new compounds are fully characterized by NMR spectroscopy and mass spectrometry, and the X-ray structure of 3 is determined. The electrochemical behavior is somewhat different compared to most standard cationic iridium complexes. The first oxidation process is shifted to substantially higher potential in both 3 and 5, due to peculiar and different ligand-induced effects in the two cases, which stabilize the highest occupied molecular orbital; reduction processes are centered on the mesoionic carbene ligands. Both compounds exhibit a mostly ligand-centered luminescence band in the blue-green spectral region, substantially stronger in the case of 5 versus 3, both in CH3CN solution and in poly(methyl methacrylate) matrix at room temperature. Optimized geometries, orbital energies, spin densities, and electronic transitions are determined via density functional theory calculations, which support a full rationalization of the electrochemical and photophysical behavior. This work paves the way for the development of Ir-based emitters with neutral mesoionic carbene ligands and anionic ancillary ligands, a new concept in the area of cationic Ir(III) complexes.

Anionic Cyclometalated Iridium(III) Complexes with a Bis-Tetrazolate Ancillary Ligand for Light-Emitting Electrochemical Cells

A series of monoanionic Ir(III) complexes (2-4) of general formula [Ir(C^N)2(b-trz)](TBA) are presented, where C^N indicates three different cyclometallating ligands (Hppy = 2-phenylpyridine; Hdfppy = 2-(2,4-difluoro-phenyl)pyridine; Hpqu = 2-methyl-3-phenylquinoxaline), b-trz is a bis-tetrazolate anionic N^N chelator (H2b-trz = di(1H-tetrazol-5-yl)methane), and TBA = tetrabutylammonium. 2-4 are prepared in good yields by means of the reaction of the suitable b-trz bidentate ligand with the desired iridium(III) precursor. The chelating nature of the ancillary ligand, thanks to an optimized structure and geometry, improves the stability of the complexes, which have been fully characterized by NMR spectroscopy and high-resolution MS, while X-ray structure determination confirmed the binding mode of the b-trz ligand. Density functional theory calculations show that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are mainly localized on the metal center and the cyclometalating ligands, while the bis-tetrazolate unit does not contribute to the frontier orbitals. By comparison with selected classes of previously published cationic and anionic complexes with high ligand field and even identical cyclometallating moieties, it is shown that the HOMO-LUMO gap is similar, but the absolute energy of the frontier orbitals is remarkably higher for anionic vs cationic compounds, due to electrostatic effects. 2-4 exhibit reversible oxidation and reduction processes, which make them interesting candidates as active materials for light emitting electrochemical cells, along with red, green, and blue emission, thanks to the design of the C^N ligands. Photoluminescence quantum yields range from 28% (4, C^N = pqu, red emitter) to 83% (3, C^N = dfppy, blue emitter) in acetonitrile, with the latter compound reaching 95% in poly(methyl methacrylate) (PMMA) matrix. In thin films, the photoluminescence quantum yield decreases substantially probably due to the small intersite distance between the complexes and the presence of quenching sites. In spite of this, surprisingly stable electroluminescence was observed for devices employing complex 2, demonstrating the robustness of the anionic compounds.

Hybrid cholesterol-based nanocarriers containing phosphorescent Ir complexes: in vitro imaging on glioblastoma cell line

Recently the use of phosphorescent heavy-metal complexes in bioimaging techniques has been a promising research field and has been attracted increasing interest. Among these, phosphorescent iridium(III) complexes have shown many photophysical characteristics that made them promising candidates for fluorescence probes. In this study an innovative copolymer consisting of cholesterol, a natural component of biological membranes, and the well-known biocompatible Polyethylene (PEG), has been synthesized. Cholesterol–PEG amphiphilic copolymer has been used to form novel nanocarriers characterized by the incorporation and/or linkage of the phosphorescent iridium(III) derivatives through covalent or non-covalent interactions. Finally the nanocarriers surface has been functionalized with the peptide chlorotoxin (Cltx), a targeting agent selective for glioblastoma cells (U87MG). The so obtained targeted water soluble nanocarrier has been tested for in vitro imaging on the glioblastoma cell line and has shown no toxic effect on cells.

Phosphorescent iridium-containing nanomicelles: synthesis, characterization and preliminary applications in nanomedical imaging

Diagnostic nanomedicine constantly requires the development of novel contrast agents with intrinsic imaging capabilities. Phosphorescent Ir(III)-complexes represent good candidates when delivered through polymeric nanoparticles. In this work, we propose a biocompatible nanoparticle made from an intrinsically phosphorescent copolymer, synthesized directly with an imaging tag present on its backbone. Polymeric nanoparticles can be obtained with the exact amount of phosphorescent moieties needed to maximize their output signal. Complete characterization and ex vivo studies confirmed that this nanosystem is suitable as a future diagnostic tool.

Click-Derived Triazolylidenes as Chelating Ligands: Achievement of a Neutral and Luminescent Iridium(III)–Triazolide Complex

Versatility in the synthesis of triazole derivatives was exploited to obtain convenient mesoionic carbenes working as chelating or cyclometalating ligands for the preparation of cationic or neutral iridium(III) complexes. We present the synthesis and characterization of three new cationic cyclometalating iridium(III) complexes (1-3-BF4) and a neutral one (4), equipped with functionalized triazolylidene ligands. All the complexes are obtained in good yields, present irreversible or quasi-reversible oxidation and reduction processes, and display good photophysical stability. The complexes emit from 3MLCT or 3LC states, depending on the nature of the ancillary ligand. Compounds 1-3-BF4 display very low photoluminescence quantum yields (PLQY ≈ 1% in acetonitrile solution). Density functional theory calculations show that the luminescence of these three complexes is quenched by the presence of low-lying 3MC states, leading to a reversible detachment of the neutral ancillary ligands from the metal coordination sphere. On the contrary, this nonradiative deactivation pathway is not present in the case of the neutral complex 4, which in fact shows PLQYs above 10% and is the best emitter of the series. Moreover, complex 4 represents the first reported example of a photochemically and thermally stable neutral triazolide iridium(III) complex.