Domino processes have received great attention from the chemical community because they address fundamental principles of synthetic efficiency and reaction processing. 1 Over the last four years, we have been involved in a research program aimed at developing metal-free and diversity oriented domino-based syntheses of biologically relevant heterocyclic scaffolds. 2 Our design principle is based on the expected multiplicative effect on molecular complexity achieved by a chain of two or more coupled domino processes in the same reaction vessel. This approach requires a careful design of each of the participant domino processes. To be coupled in a chain manner, each domino process must generate a suitably functionalized molecule able to be simultaneously engaged in the subsequent complexity-generating domino process and so on. Additionally, the whole process would be performed in a format amenable for application in combinatorial chemistry. Experimentally, the transformation of this concept in a one synthetic step strategy is not a simple task due to the unattainable kinetic tuning of each of the numerous chemical reactions involved. A more feasible approach should consist in the transformation of this concept in a one-pot synthetic strategy. In this new scenario, the consecutive coupled domino processes should be performed one at a time and linked in a onepot operation. In a first experimental approach, we chose the simple model shown in eq 1, addressing the synthesis of polysubstituted pyrroles. The protocol combines two coupled domino processes: the trialkylamine-catalyzed synthesis of enolprotected propargylic alcohols 1 2 (domino I) and their sequential transformation into pyrroles 3 (domino II). The key for this transformation came from a serendipitously discovered spontaneous rearrangement of 1,3-oxazolidines 2 to pyrroles 3.Polysubstituted pyrroles are common pharmacophores of numerous natural antibiotics and alkaloids 3 and they have also found applications in the field of material chemistry. 4 These properties are of considerable interest in the development of new efficient syntheses of these heterocycles. Among the plethora of methods available for pyrrole construction, 3 metal-based strategies 5 and 1,3-dipolar cycloadditions 6 have concentrated the most attention. In contrast, the number of examples reported in the literature dealing with metal-free, modular and direct syntheses of these heterocycles is scarce. 7 Therefore, there is a clear demand for new metal-free, modular and direct synthetic protocols with atom-economy, easy reaction processing, general applicability and environmental care performance.1,3-Oxazolidines 2 are readily obtained in a one-pot manner by the ytterbium-catalyzed reaction 8 of the conjugated alkynoates 1 and primary amines (eq 2). Pure 1,3-oxazolidines 2 rearrange to pyrroles 3 when they are stored on the bench without solvent (eq 2). This rearrangement is very slow at room temperature and needs months to be completed. 9 While heating speeds up this process from months to ...

Abstract. The organocatalytic generation of a strong base by the action of a good nucleophile is the base for the in situ catalytic generation of conjugated acetylides in the presence of aldehydes or activated ketones. The method is affordable in a multicomponent domino format able to generate a chemically diverse set of multifunctionalized adducts that are very well suited for diversityoriented molecular construction. The domino process involves a nucleophile as catalyst and a terminal conjugated alkyne (H-CC-Z) and an aldehyde or activated ketone as building blocks. The chemical outcome of this process changes dramatically as a function of the nucleophile (tertiary amine or phosphine), temperature, stoichiometry and solvent. These multicomponent domino processes achieve molecular construction with good atom-economy and, very importantly, with an exquisite chemo-differentiating incorporation of identical starting units into the products (non-degenerated chemical output).These properties convert the H-CC-Z unit into a privileged diversity building block for diversity-oriented molecular construction. Applications to the modular and diversity-oriented synthesis of relevant heterocycles are discussed. A protocol involving two coupled domino processes linked in a one-pot manner will be discussed as an efficient synthetic manifold for the modular and diversity-oriented construction of multi-substituted nitrogen-containing heterocycles.