Gianpiero Cera

Enantioselective Gold-Catalyzed Synthesis of Polycyclic Indolines

The synthesis of architecturally complex polycyclic fused indolines is achieved in a chemo-, regio-, and stereodefined manner, via an enantioselective gold-catalyzed cascade hydroindolination/iminium trapping synthetic sequence. Highly functionalized tetracyclic fused furoindolines (2) and dihydropyranylindolines (4) are synthesized in moderate to good yields and enantiomeric excesses of up to 87%.

Expedient Iron‐Catalyzed C−H Allylation/Alkylation by Triazole Assistance with Ample Scope

Triazole assistance set the stage for a unified strategy for the iron-catalyzed C-H allylation of arenes, heteroarenes, and alkenes with ample scope. The versatile catalyst also proved competent for site-selective methylation, benzylation, and alkylation with challenging primary and secondary halides. Triazole-assisted C-H activation proceeded chemo-, site-, and diastereo-selectively, and the modular TAM directing group was readily removed in a traceless fashion under exceedingly mild reaction conditions.

One-pot gold-catalyzed synthesis of azepino[1,2-a]indoles.

Indoles from scratch: A gold(I)/N-heterocyclic carbene complex (IPr=1,3-di(isopropylphenyl)imidazol-2-ylidene) was found to be particularly effective as a catalyst, enabling the one-pot synthesis of tricyclic azepinoindoles by an unprecedented cascade reaction. Readily available substrates, high chemoselectivity, good yields, and water as the only stoichiometric by-product are some of the main advantages of this method.

Taming Gold(I)–Counterion Interplay in the De-aromatization of Indoles with Allenamides

A careful interplay between the π electrophilicity of a cationic Au(I) center and the basicity of the corresponding counterion allowed for the chemo- and regioselective inter- as well as intramolecular de-aromatization of 2,3-disubstituted indoles with allenamides. The silver-free bifunctional Lewis acid/Brønsted base complex [{2,4-(tBu)2C6H3O}3PAuTFA] assisted the formation of a range of densely functionalized indolenines under mild conditions.

Gold meets enamine catalysis in the enantioselective α-allylic alkylation of aldehydes with alcohols

Synergetic gold(I)- and organo-catalysis proved to be efficient towards the intramolecular stereoselective α-allylic alkylation of aldehydes with simple primary and secondary alcohols. High diastereo- and enantioselectivity were recorded.

Iron-Catalyzed C-H Functionalization Processes.

Iron-catalyzed C–H activation has recently emerged as an increasingly powerful tool for the step-economical transformation of unreactive C–H bonds. Particularly, the recent development of low-valent iron catalysis has set the stage for novel C–H activation strategies via chelation assistance. The low-cost, natural abundance, and low toxicity of iron prompted its very recent application in organometallic C–H activation catalysis. An overview of the use of iron catalysis in C–H activation processes is summarized herein up to May 2016.

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.

Weak O-Assistance Outcompeting Strong N,N-Bidentate Directing Groups in Copper-Catalyzed C-H Chalcogenation.

A copper-mediated C-H chalcogenation of triazoles has been achieved by weak coordination. The user-friendly protocol showed high functional-group tolerance and ample substrate scope, yielding fully substituted 1,2,3-triazoles with complete positional site-selectivity. The C-H selenylation could likewise be achieved by means of copper catalysis. Our findings highlight for the first time that weak O-coordination can outcompete the strong N,N-bidentate coordination mode in C-H functionalization technology.

Iron-Catalyzed C-H Alkynylation through Triazole Assistance: Expedient Access to Bioactive Heterocycles

Triazole assistance enabled the first iron-catalyzed C-H alkynylation of arenes, heteroarenes, and alkenes. The modular TAM directing group set the stage for a sequential C-H alkynylation/annulation strategy with ample scope, enabling the iron-catalyzed assembly of isoquinolones, pyridones, pyrrolones, and isoindolinones with high levels of chemo-, site-, and regioselectivity.

MnCl2-Catalyzed C−H Alkylations with Alkyl Halides

C-H alkylations with challenging β-hydrogen-containing alkyl halides were accomplished with sustainable MnCl2 as the catalyst under phosphine-ligand-free conditions. The proximity-induced benzamide C-H activation occurred with ample substrate scope through rate-determining C-H metalation, also setting the stage for manganese-catalyzed oxidative C-H methylations.