Carbodiimides-Mediated Multi Component Synthesis of Biologically Relevant Structures

Abstract

Multi-component reactions are very popular because they offer a wealth of products, while requiring only a minimum effort combining many elements of an ideal synthesis, such as operational simplicity, atom economy, bond-forming efficiency, and the access to molecular complexity from simple starting materials. As such, multi-component reactions have become the cornerstones of both combinatorial chemistry and diversity-oriented synthesis and thus playing a central role in the development of modern synthetic methodology for pharmaceutical and drug discovery research. In this Insight we will highlight the development of novel multi-component reactions based on the reactivity of carbodiimides, paying particular attention on their mechanistic features. We will address our attention on the process developed by us and others groups, in these last years, for the synthesis of biologically relevant structures such as, for example, heterocycles and glyco-conjugates.

Accessing Heteroannular Benzoxazole and Benzimidazole Scaffolds via Carbodiimides Using Azide–Isocyanide Cross-Coupling as Catalyzed by Mesoionic Singlet Palladium Carbene Complexes Derived from a Phenothiazine Moiety

“…As expected, the molecular structure of 4 (Figure 2 and Supporting Information, Table S1), as determined by the single crystal X-ray diffraction study, exhibited a nonplanar butterfly structure with the S and N heteroatoms occupying the 1,4 apical positions, while the two aromatic rings are pointed outward from the (2,3) and (5,6) positions of a boat confirmation, consistent with commonly observed conformation of a phenothiazine moiety. 42 In agreement with the d 8 35 (Supporting Information, Table S2).…”

“…A careful scrutiny of the substrate scope study brings out an interesting trend of the catalyst reactivity observed along the line, 4 > 5 ∼ 6 > 7, thereby implying that the pyridine bound Pd complex (4) is the most effective, while the PPh 3 bound Pd complex (7) is the least effective of all the ten substrates studied for the azide−isocyanide coupling reaction. The other two precatalysts, i.e., the isocyanide bound Pd complex (5) and the bis-mesoionic 1,2,3-triazole based NHC complex (6), lie in between the highly active (4) and the least active (7) precatalysts, and are comparable to each other in terms of the catalysis product yield. We are not aware of any other structurally characterized molecular palladium catalysts reported for the azide-iscocyanide coupling barring [Pd(PPh 3 ) 4 ].…”

“…Carbodiimides have long evoked interest for over half a century now, primarily for their diverse range of applications varying from peptide synthesis to phosphorylation reactions to dehydration reactions. − Their biocompatibility and nontoxicity make them well-suited for peptide synthesis as cross-linkers providing “zero-length” amide linkages between carboxylic and amine groups . In organic synthesis, carbodiimides, belonging to the heterocumulene family of compounds and containing two adjacent CN bonds, are also of sustained interest as they provide a unique opportunity for synthesizing N-heterocycles, which are known for their pharmaceutical properties. , The N-heterocycles constitute common fragments in marketed drugs and medicinal chemistry targets as a part of the drug discovery initiatives . Hence, convenient access routes to these important carbodiimide class of compounds are in demand, and catalytically achieving that remains a challenging objective.…”

“…4 In organic synthesis, carbodiimides, belonging to the heterocumulene family of compounds and containing two adjacent C�N bonds, are also of sustained interest as they provide a unique opportunity for synthesizing Nheterocycles, which are known for their pharmaceutical properties. 5,6 The N-heterocycles constitute common fragments in marketed drugs and medicinal chemistry targets as a part of the drug discovery initiatives. 1 Hence, convenient access routes to these important carbodiimide class of compounds are in demand, 7 and catalytically achieving that remains a challenging objective.…”