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An electrochemical allylation/alkylation of cyclic/acyclic ethers is presented via a C(sp3)–H activation, proceeding under cathodic reduction. The reaction shows broad functional group tolerance and high yields.

The electrochemical carboxylation of Morita–Baylis–Hillman (MBH) acetates with CO2 is presented. The process proceeds in the absence of transition-metal catalysts and relies on the cathodic reduction of MBH acetates to generate nucleophilic anions that are able to trap low-pressure CO2. Valuable succinate derivatives are obtained (20 examples) in high yields (up to 90%) and with excellent functional group tolerance. A remarkable substrate-controlled (electronic nature) regioselectivity of the transformation is documented along with a mechanistic rationale based on control experiments.

A nickel-catalyzed reductive cross-electrophile coupling between the redox-active N-trifluoroeth-oxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2-Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α-hydroxy-α-trifluoromethyl C-centered radical for theC sp2Csp3 bond forming process.

Electrosynthesis is effectively employed in a general regio- and stereoselective alkylation of Morita−Baylis−Hillman compounds. The exposition of N-acyloxyphthalimides (redox-active esters) to galvanostatic electroreductive conditions, following the sacrificial-anode strategy, is proved an efficient and practical method to access densely functionalized cinnamate and oxindole derivatives. High yields (up to 80%) and wide functional group tolerance characterized the methodology. A tentative mechanistic sketch is proposed based on dedicated control experiments.

A dehydrogenative functionalization of styryl carbon-carbon double bonds with triflamide is described via dual visible-light photoredox/cobaloxime catalysis. A range of allylic triflamides (20 examples) were isolated in moderate to good yields (up to 88%) under stoichiometric acceptorless conditions. Dedicated labelling, as well as spectroscopic experiments, enabled to shed light on the concatenated photo- and chemo-catalytic cycles. (Figure presented.).

The tandem catalytic functionalization/carboxylation of double as well as triple carbon-carbon bonds with CO2 represent an emerging research area in synthetic organic methodology. In particular, the combination of mild reaction conditions, stoichiometric acceptor/donorless conditions (visible light photoredox catalysis) and chiral catalysts contributed to a rapid development of this intriguing research area capable of creating chemical diversity/ complexity from readily available unsaturated hydrocarbons and CO2 as a C1-buinding block. The most recent developments in the field have been collected in the present review article and organized, based on the different sets of π-systems/intermediates/reactive partners employed (i.e., nickelalactones, organo-halides) as well as synthetic strategies (i.e., visible-light photo redox catalysis).

A new [Au(I)] catalyzed intramolecular hydrocarboxylation of allenes is presented as a valuable synthetic route to oxazino-indolones. The use of 3,5-(CF3)2–C6H3–ImPyAuSbF6 as the optimal catalyst (5 mol%) was necessary to guarantee (i) wide tolerance of functional groups, (ii) mild reaction conditions (r.t., 16 h), and (iii) high yields (up to 90%). Preliminary attempts towards an enantioselective version (81 : 19 er) are also documented by means of a new family of chiral C1-symmetric ImPyAuCl complexes.

The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12π-components derived from 5H-benzo[a]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole) with excellent enantio- A nd diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2π-components relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo[a]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

We present an environmentally benign methodology for the covalent functionalization (arylation) of reduced graphene oxide (rGO) nanosheets with arylazo sulfones. A variety of tagged aryl units were conveniently accommodated at the rGO surface via visible light irradiation of suspensions of carbon nanostructured materials in aqueous media. Mild reaction conditions, absence of photosensitizers, functional group tolerance and high atomic fractions (XPS analysis) represent some of the salient features characterizing the present methodology. Control experiments for the mechanistic elucidation (Raman analysis) and chemical nanomanipulation of the tagged rGO surfaces are also reported.

A carboxylative Ni-catalyzed tandem C-C σ-bond activation of cyclobutanones followed by CO

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp

A carboxylative Ni-catalyzed tandem C-C σ-bond activation of cyclobutanones followed by CO2-electrophilic trapping is documented as a direct route to synthetically valuable 3-indanone-1-acetic acids. The protocol shows an adequate functional group tolerance and useful chemical outcomes (yield up to 76%) when AlCl3 is adopted as an additive. Manipulations of the targeted cyclic scaffolds and a mechanistic proposal based on experimental evidence complete the investigation.

The first stereoselective synthesis of enantioenriched axially chiral indole–quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unreported axially chiral indole–quinoline biaryls. The methodology is also implemented for the design and the preparation of challenging compounds exhibiting two stereogenic axes. DFT calculations shed light on the stereoselectivity of the central-to-axial chirality conversion, showing unconventional behavior.

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6π-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo- and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition.

An efficient and exceptionally stereoselective synthesis of chiral cycl[3.2.2]azines has been realized by means of the rational design and utilization of novel (E)-3-benzylidene-3H-pyrrolizines in iminium-ion-catalyzed [8+2] cycloaddition reactions. The presented protocol allows for the incorporation of diverse enals, including cinnamaldehydes, enolizable aldehydes, and substrates of extended conjugation. The obtained products contain both an electron-rich alkenyl pyrrole moiety and an electron-deficient carbaldehyde substituent, and both moieties can undergo selective transformations with retention of the stereochemical information established in the [8+2] cycloaddition.

A highly stereoselective 1,3-dipolar [6+4] cycloaddition towards bridged azabicyclo[4.3.1]decane scaffolds has been developed, reacting aldehydes, 2-aminomalonates and tropone under mild conditions in the presence of a chiral phosphoric acid catalyst. The scope is demonstrated for a series of aldehydes and 2-aminomalonates, and the reaction proceeds in high yields, >95:5 d.r. and up to 99 % ee. A series of transformations, as well as a mechanistic proposal, are presented.

In this work, a new chemodivergent domino approach for the preparation of various saturated heterocycles, based on phase-transfer catalysis (PTC), is presented. The versatile nature of doubly electrophilic substrates, showing both a Michael acceptor and a ketone, tethered by a heteroatom, enables three different domino reaction pathways. The nucleophile dictates the chemoselectivity of the reaction. Sulfa-Michael/aldol, cyanide addition/oxa-Michael and Michael/H-shift/aldol processes, along with the variation of the tethering heteroatom, results in the formation of six different classes of saturated heterocycles. DFT calculations account for the observed chemo- and diastereoselectivity of the two most productive processes. Moreover, an extensive investigation on the sulfa-Michael/aldol pathway was carried out, ultimately leading to the development of a new enantioselective domino approach to multi-substituted piperidines based on PTC. (Figure presented.).

Despite the broad interest in ferrocene containing compounds, ferrocenyl substrates have been employed in catalytic asymmetric settings only sporadically. Herein, catalytic asymmetric Povarov reactions with ferrocenecarbaldehyde-derived N-aryl imines are presented. This study demonstrates that the stereoelectronic properties of ferrocenyl imines do not preclude their engagement in enantioselective phosphoric acid catalysis: cycloadducts derived from benzyl N-vinylcarbamate were obtained in good yields and nearly enantiopure form using 0.1mol% of a standard Bronsted acid catalyst. Furthermore, it is shown that specific optimisation with some substrates allowed to lower the catalyst loading up to 10-20 parts-per-million, an unprecedented value for phosphoric acid catalysts. Such low loading protocol could be applied to a preparative scale reaction, and to imines derived from arylaldehydes.

The first peri- and stereoselective [10+4] cycloaddition between catalytically generated amino isobenzofulvenes and electron-deficient dienes is described. The highly stereoselective catalytic [10+4] cycloaddition exhibits a broad scope with high yields, reflecting a robust higher-order cycloaddition. Experimental and computational investigations support a kinetic distribution of intermediate rotamers dictating the enantioselectivity, which relies heavily on additive effects.

The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on N-acylpyridinium salts, give addition to the C-2/C-6 of the pyridine nucleus, rendering 1,2-/1,6-dihydropyridines. Herein, we present an alternative approach to this type of dearomatization reaction, employing activated N-benzylpyridinium salts in combination with a bifunctional organic catalyst. Optically active 1,4-dihydropyridines resulting from the addition of the nucleophile (indole) to the C-4 of the pyridine nucleus are obtained as major products, rendering this method for nucleophilic dearomatization of pyridines complementary to previous approaches.

A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 μm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.

Alkylideneindolenines are widely employed key electrophilic intermediates for the α-functionalization of the C-3 side chain of indoles. However, the reactivity of their extended (vinylogous) counterparts has not been carefully explored so far. These intermediates can undergo 1,4- or 1,6-addition with functionalization at α- or γ-position of the side chain, resulting in regioisomeric mixtures of products. This work demonstrates that a complete γ-regioselectivity can be achieved in the reaction of 3-indol-3-yl allylic alcohols with various nucleophiles. This process is catalysed by just 1 mol% zinc(II) triflate at room temperature and entails the 1,6-selective addition of the nucleophile to an extended protonated alkylideneindolenine generated in situ. Indoles, pyrroles, anilines and thiols can be efficiently used as nucleophilic partners for this reaction, delivering the corresponding 3-vinyl substituted, γ-functionalised indole products in moderate to good yields.

A new protocol for the enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of alpha-heteroarylated aldehydes.

Catalytic addition of chiral enamines to azinium salts is a powerful tool for the synthesis of enantioenriched heterocycles. An unprecedented asymmetric dearomative addition of aldehydes to activated N-alkylpyridinium salts is presented. The process exhibits complete C-4 regioselectivity along with high levels of diastereo- and enantiocontrol, achieving a high-yielding synthesis of a broad range of optically active 1,4-dihydropyridines. Moreover, the presented methodology enables the synthesis of functionalized octahydropyrrolo[2,3-c]pyridines, the core structure of anticancer peptidomimetics.

Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of - pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures.

In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,β-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a “side chain” characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15–60 μM for exposure time of 24–72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.