Synthesis of Mono and Poly-Heterocycles starting from 1,2-Diaza-1,3-Dienes (or precursors) as Building Blocks

Despite recent advances, robust strategies for producing libraries of chemical compounds that have a structural connection with biologically active natural-like molecules, especially around privileged structures, are still significant and needed. In particular, heterocycles are common structural units in marketed drugs and in medicinal chemistry due to the central role they play in modern drug design. Consequently, the search for new and efficient methods for the synthesis of heterocyclic systems, remains an important objective in organic chemistry. The usefulness of azoalkenes (also named 1,2-diaza-1,3-dienes (DDs)) as versatile “building blocks” for the construction of several and multiple five- and six-membered heterorings has been largely documented over the years. They not only reacted as Michael acceptors in conjugated 1,4 additions with nucleophiles but were also frequently applied in cycloaddition reactions with a wide variety of partners. Some uses and applications of this unique and fascinating class of compounds are discussed in this doctoral thesis. The first project was focused on the synthesis of new tetra-heterocyclic derivatives through the palladium-catalyzed intramolecular oxidative cross-coupling reaction (CDC), starting from indolethyl azoles (bi-eteroaromatic cycles), such as indole-imidazole, indole-pyrrole, indole-triazole which, in turn, are synthesized via azoalkene chemistry. In perspective to reduce environmental impact and to realize a “green” approach, an efficient TFApromoted dearomative cyclization of the same indole-tethered pyrroles giving access to a variety of challenging indoline-fused polycycles, including pyrido[1,2-a:3,4-b]-diindole core of homofascaplysin C alkaloid, has been developed. This protocol that avoids the use of metal catalysts, has advantages of mild reaction conditions, easily accessible starting materials, simple purification of the products and wide range of substrates and it offers the possibility to incorporate five, six and seven member rings between the bi-heterocyclic components through a complete regioselectivity and atom economy chemistry. Another project has regarded an umpolung α-(hetero)arylation strategy involving the Michaeltype reaction between electron-rich (hetero)aromatic substrates and azoalkenes. The reaction proceeded under very mild conditions at room temperature and in the presence of inexpensive, non-toxic ZnCl2 catalyst to provide access to otherwise inaccessible hydrazone structures. Subsequent hydrolysis of these latter to ketones as well as other valuable synthetic transformations to a variety of heterocyclic scaffolds demonstrated the usefulness of this protocol. On the basis of these results, a metal and oxidant free Brønsted acid-mediated cascade reaction to substituted benzofurans has been also realized. This annulation occurred between resorcinols or naphthol and DDs. A wide range of resorcinols was employed and the reaction exhibited a good functional group tolerance and scalability. The selection of the starting materials enabled the choice of up to five different variations in the architecture of the final products. The absence of metal catalysts and the easy work-up procedure together with the robustness, represent the key strength of this new approach to benzofurans. The structural complexity and diversity of polycyclic indoline skeletons, as well as their promising bioactivities, make this substructure a particularly important target to inspire methodology development. Intrigued by the synthetic potential of azoalkenes, a Zn(II)-catalyzed divergent synthesis of polycyclic indolines through formal [3+2] and [4+2] annulations of DDs with indoles has been realized. Taking advantage of the reciprocal reactivity/nature of substituents of the reagents, the same couple of reagents selectively furnished different types of highly functionalyzed poly-azaheterocycles embedding the indolinic skeleton as common privileged substructure. Strategically, the combination of indole and azoalkene partners as C2 and C2N2 synthons respectively, opened the way to two different classes of N-polyheterocyclic compounds. The selective oxidation of indoline to indole, hydrolysis of ester followed by decarboxylation and concomitant aromatization led to the tetracyclic fused indole-pyridazines. On the other hand, nonfused indole-pyrazol-5-one scaffold was easily prepared by treatment with TFA. Finally, a multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully carried out. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained, ensures post-modifications in view of Nbridgedheaded heterobicyclic structures. Starting material availability, functional group tolerance, mild conditions, efficiency and selectivity are relevant aspects of all these simple procedures.