Proline is a non‐toxic and inexpensive natural amino acid that is readily available in both enantiomeric forms and was one of the very first compounds to be studied as an organocatalyst. Proline can engage in several modes of organocatalysis, as it can behave both as a Brønsted acid or a Brønsted base, and it can also easily generate the iminium or enamine intermediates that are typical of covalent organocatalysis. In view of the importance of diminishing the generation of residues formed by volatile organic solvents, the development of synthetically useful reactions that can be performed in aqueous environments is of increasing significance. The synergic combination of the advantages of water as a reaction medium with the efficiency associated to reactions that are able to generate several bonds in one operation is particularly relevant from the point of view of sustainable chemistry. In this review we critically summarize the use of proline and proline derivatives as catalysts of multi‐component reactions performed in aqueous media and leading to synthetically and biologically relevant heterocycles, a very important class of compounds that constitutes over 60% of drugs and agrochemicals.

A palladium catalyzed cascade process involving synchloropalladation, intramolecular olefin insertion, and oxidative C− Cl bond formation reactions was demonstrated for the synthesis of dichlorinated tetrahydroquinolines in high yields (up to 93%). The N-propargyl arylamines having a tethered α,β-unsaturated carbonyl moiety underwent a regioselective syn-chloropalladation followed by a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The rare insertion of the second chlorine atom was rationalized comprising a Pd II/IV catalytic cycle and oxidative cleavage of the C−Pd II bond.

Synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine under metal-free green conditions.

An efficient Pd(II)-catalyzed cascade approach was established for the synthesis of 9-chloro-1H-benzo[b]furo-[3,4-e]azepin-1-ones starting from N-propargyl arylamines having a pendant α,β-unsaturated ester scaffold. The mechanism of this sequential process involved intramolecular syn-oxypalladation followed by olefin insertion and ortho sp 2 -C−Cl bond formation reactions. This high atom-and step-economical cascade sequence generated two heterocycle rings and three new bonds in a single synthetic operation.