Periselectivity in the Aza-Diels-Alder Reaction of 1-Azadienes with α-Oxoketenes: A Combined Experimental and Theoretical Study.

Inversions in the periselectivity of formal aza-Diels-Alder cycloadditions between α-oxoketenes generated by a thermally-induced Wolff rearrangement and 1-azadienes were observed experimentally as a function of the α-oxoketene and the 1-azadiene, as well as the reaction temperature and time. Some unexpected inversion in the diastereoselectivity was observed, too. These variations in selectivities were fully rationalized by computational modeling using density functional theory (DFT) methods.

Diastereoselective access to polyoxygenated polycyclic spirolactones through a rhodium-catalyzed [3+2] cycloaddition reaction: experimental and theoretical studies.

The synthetic utility of γ-alkylidenebutenolides is demonstrated as highly competent dipolarophile partners in both intra- and intermolecular rhodium(II)-catalyzed 1,3-dipolar cycloaddition reactions. The strength of this approach lies in the formation of spiro[6,4]lactone moieties with the concomitant construction of quaternary spiro stereocenters. Typically, the construction of spirolactones involves an esterification step, which has often been reported as a "biosynthetic pathway", and often occurs either as or near to the final step of a total synthesis. Furthermore, a convergent and versatile route is reported for the formation of the (5,7) skeleton of molecules that were isolated from the Schisandra genus. Computational studies were performed to provide an overall picture of the mechanism of the intermolecular [3+2] cycloaddition between 2-diazo-1,3-ketoester and protoanemonin and to rationalize the empirical observations. In particular, we have demonstrated for the first time that the rhodium center plays an important role during the cyclization step itself and reacts with the dipolarophile as a complex with the ylide.

Temporary intramolecular generation of pyridine carbenes in metal-free three-component C-H bond functionalisation/aryl-transfer reactions.

Nucleophilic addition of pyridines to benzyne generates zwitterionic adducts that evolve by a rapid intramolecular proton shift to produce the corresponding pyridine carbenes, N-phenyl pyrid-2-ylidenes. In the presence of electrophilic ketones (isatin derivatives), the pyridylidenes can further react by an original bis-arylation reaction of the carbonyl compounds involving a formal pyridine C-H bond functionalisation. The overall transformation is an unprecedented three-component reaction featuring a carbene intermediate. The mechanism of this transformation was examined in detail by using both experimental and theoretical approaches. It was found that the generation of N-phenyl pyrid-2-ylidene from pyridine and benzyne is energetically favoured, and that the corresponding carbene dimer can also form easily. Under the three-component reaction conditions, the pyridylidene preferentially adds to the ketone group of the isatin derivative to produce a zwitterionic adduct amenable to an intramolecular aryl transfer reaction by a concerted nucleophilic aromatic substitution. This peculiar reactivity for a carbene was compared to possibly competitive known reactions of stable carbenes with carbonyl compounds, and the reaction was found to be under thermodynamic control. The reported method of generation of N-phenyl pyrid-2-ylidenes and their reactivity with carbonyl compounds unlock new perspectives in organic synthesis.

Divergent chemo-, regio-, and diastereoselective normal electron-demand Povarov-type reactions with α-oxo-ketene dienophiles.

The reactions between electron-rich 2-aza-dienes and α-oxo-ketenes derived from the Wolff rearrangement of 2-diazocycloalkane-1,3-diones chemo- and regioselectively produced spiro hydropyrid-4-ones with good to excellent diastereoselectivities. These reactions are likely to proceed via a domino Wolff/Friedel-Crafts/intramolecular Mannich process. Prolonged domino sequences also allowed the expeditious preparation of a series of pyrazolopyridine and pyridopyrimidine heterocycles.

Aluminium(III) trifluoromethanesulfonate as an efficient catalyst for the intramolecular hydroalkoxylation of unactivated olefins: experimental and theoretical approaches.

The Al(OTf)(3)-catalyzed cycloisomerization of unactivated unsaturated alcohols was studied from experimental and theoretical points of view. A series of cyclic ethers was obtained in excellent yields and regioselectivities. This catalyst system provides one of the most straightforward routes to cyclic ethers with Markovnikov-type regioselectivity under mild conditions. Theoretical and NMR studies were carried out in order to better determine the mechanism of this reaction. The NMR studies were in agreement with preferential complexation of Al(OTf)(3) to the oxygen atom of the unsaturated alcohol, but did not exclude complexation to the double bond of the alcohol. Theoretical calculations indicated strong acidification of the hydroxyl proton when Al(OTf)(3) was complexed to the alcohol oxygen atom. A plausible catalytic cycle for the Al(OTf)(3)-catalyzed intramolecular hydroalkoxylation of unactivated olefins is proposed.