Multiple Multicomponent Reactions: Unexplored Substrates, Selective Processes, and Versatile Chemotypes in Biomedicine

Abstract

Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner.

The Groebke‐Blackburn‐Bienaymé Reaction

“…Difficulties in predicting reactivity were found with some combinations of starting materials and cannot always be attributed to electronic factors, as steric effects have a significant effect as well, illustrated in Figure 2. [35] Aliphatic aldehydes give good yields when aromatic isocyanides are used, however, when both aldehyde and isocyanide are both electron rich, a reduction in yield was described recently. [34] Although such findings are valuable starting point for better understanding the GBB-3CR, we've tried to illustrate the scope and limitations in a broader sense, including the effect of substituents on each of the reported starting materials.…”

“…Using bis‐ ( 19–20 ) or tris amidines in the GBB‐3CR allows for multiple MCRs in a single transformation as demonstrated by Lavilla et al The position of each amidine when applying asymmetric bis‐amidine 19 determines the reactivity and therefore the selectivity of the first GBB‐3CR and enables introduction of different aldehyde and isocyanide components in the second GBB‐3CR. This regioselectivity is also seen in symmetric bis‐amidines, but require stoichiometric amounts of the aldehyde and isocyanide components.…”

“…In the general scope and limitation of the GBB‐3CR it was found that the reaction is best performed at room temperature in MeOH, with a concentration ranging between 0.3–1.0 m , using arylaldehydes, 2‐aminopyridines, and aliphatic isocyanides in stoichiometric amounts, in the presence of a catalytic amount of 10 mol‐% Sc(OTf) 3 . Difficulties in predicting reactivity were found with some combinations of starting materials and cannot always be attributed to electronic factors, as steric effects have a significant effect as well, illustrated in Figure …”

Diaminoimidazopyrimidines: Access via the Groebke–Blackburn–Bienaymé Reaction and Structural Data Mining

“…Despite the usefulness of this MCR reaction in providing in a single step drug‐like heterocycles, diaminoimidazopyrimidines have not been previously thoroughly studied. One exception includes the work of Lavilla et al where the 2,4‐diaminopyrimidine 1 is used without protection in a GBB‐3CR, leading selectively to the substituted imidazo[1,2‐ a ]pyrimidin‐7‐amine derivatives 2 (Scheme ). That work served as inspiration for us since the use of this diamine 1 could potentially lead also to the scaffold of imidazo[1,2‐ c ]pyrimidin‐5‐amine 3 , which is our targeted scaffold (Scheme ).…”

Selectivity in multiple multicomponent reactions: types and synthetic applications

“…Interestingly, the protocol allows control of the respective localization of all reactant inputs. Thus, inverting the order of the MCRs leads to the complementary disposition of the residues in the final MCR adduct [31].…”