Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence.

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.

Tandem Synthesis of Polycyclic Isoindoles.

We report an easy multicomponent synthesis of polycyclic isoindoles from cyclic 1,3-dicarbonyls, aldehydes, isocyanides, and maleimides. The key step consists of the one-pot Diels-Alder trapping of a reactive 2-aminofuran intermediate, formed by a sequence of a Knoevenagel condensation and a [4+1] cycloaddition. Moreover, a further microwave-promoted dehydrogenative N-C bond forming reaction allows the straightforward synthesis of a natural product like isoindolocarbazole, validating the utility of our methodology to obtain isoindoles as useful intermediates for the synthesis of complex polycyclic molecules.

Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction.

Aminoxanthones constitute a group of therapeutically promising compounds that so far have been synthetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonylchromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cycloaddition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aromatization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-determining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straightforward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process has also been applied to the synthesis of biologically important chromenophenantridines and secalonic acid related xanthone dimers.

Regioselective Tandem [4 + 1]-[4 + 2] Synthesis of Amino-Substituted Dihydroxanthones and Xanthones.

A highly convergent and operationally simple approach to mycotoxin-related 4-amino-substituted 1-hydroxydihydroxanthones is described. The target compounds are obtained in one pot by the multicomponent reaction of 3-carbonylchromones, isocyanides, and nonsymmetric dienophiles. The reaction, which involves a tandem [4 + 1]-[4 + 2] cycloaddition, efficiently affords a variety of both monomeric and dimeric polysubstituted dihydroxanthones structurally similar to bioactive ergochromes. Further aromatization to the corresponding xanthones is readily achieved by treatment with DBU under microwave irradiation.

Elusive 2-aminofuran Diels-Alder substrates for a straightforward synthesis of polysubstituted anilines.

The first multicomponent coupling of isocyanides, α,ß-unsaturated carbonylic compounds and dienophiles, based on the trapping of unstable intermediate 2-aminofurans, is described. This novel tandem [4 + 1]-[4 + 2] cycloaddition is efficiently catalysed by yttrium triflate and constitutes an operationally simple and highly convergent approach to a variety of polysubstituted anilines. Moreover, this methodology permits the use of tert-butylisocyanide as a convertible isocyanide to yield directly N-unprotected anilines in the same pot.