The Ugi-4CR is by far one of the most successful multicomponent reactions leading to high structural diversity and molecular complexity. However, the reaction mostly affords a linear peptide backbone, enabling post-Ugi transformations as the only solution to rigidify the Ugi-adduct into more drug like species. Not surprisingly, the development of these transformations, leading to new structural frameworks, has expanded rapidly over the last few years. As expected, palladium-catalyzed reactions have received the foremost attention, yet other metals, particularly gold complexes, are fast catching up. This tutorial review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects.

Gold-catalyzed carbocyclization and heteroannulation strategies have recently attracted much attention owing to the selective and efficient activation of the CC bond towards a wide range of nucleophiles that these methods provide.[1] Domino approaches involving gold-catalysis lead to complex heterocyclic compounds under exceedingly mild reaction conditions.[2] Although gold-catalyzed approaches are rising to prominence, they suffer in terms of diversity and procedural length. Multistep sequences are usually required for assembling the starting material for cyclization. We have recently reported a concise route to indoloazocines by a sequential Ugi/gold-catalyzed intramolecular hydroarylation approach.[3] Inspired by these findings and as a result of our continued synthetic interest in the indole core, [4] multicomponent reactions [5] and transition metal-catalysis, [6] we have developed a post-Ugi gold-catalyzed domino cyclization method to generate spiroindolines.The Ugi four-component reaction (4-CR) [7] of indole-3-carboxaldehyde (1 a) with p-methoxybenzyl amine (2 a), 2-butynoic acid (3 a) and tert-butyl isonitrile (4 a) in methanol at 50 8C gave Ugi-adduct 5 a in 71 % yield. When this was treated with 5 mol % of Au[PPh 3 ]OTf (OTf = trifluoromethanesulfonate) in CDCl 3 at RT, the expected outcome of the reaction was indoloazepinone 6 a' through an endo-dig cyclization [1m,n, 3] followed by rearrangement (Scheme 1). Surprisingly, an exo-dig cyclization followed by intramolecular trapping of the spiro intermediate occurred instead, resulting in the diastereoselective formation of tetracyclic spiroindoline 6 a in 61 % yield (Scheme 1).This observation was remarkable, as the attack on the a-position of an alkyne conjugated with an amide is rare, and trapping of the spiro intermediate by a sterically hindered tert-butyl amide is rather unexpected, as was the diastereoselectivity observed. Spiroindolines [8] are prominent molecular motifs that are frequently encountered among the large family of alkaloids; for example, it is present in communesines [8,9] and perophoramidines [8,10] (Figure 1), which display distinct pharmacological properties. [8][9][10] These fused polycyclic systems, which feature quaternary stereocenters, present a nontrivial challenge for organic chemists to develop synthetic approaches.

Pd-catalyzed domino Heck/borylation of acrylamides with B2pin2 is reported to generate synthetically useful indolinone-3-methyl boronic esters, via capturing σ-alkyl palladium with boron. Further functionalization of the obtained boronic ester qualify it as a new starting point for the functionalization of specific C(sp(3))-H bond. Moreover, the application of an Ugi-adduct as starting material or B2nep2 as an alternative boron source works equally well, making this a broadly applicable and robust method for the formation of a C-C and C-B bond in a single operation.

A regioselective approach for the synthesis of pyrrolopyridinones and pyrroloazepinones is reported employing an Ugi reaction followed by a gold(I) or platinum(II) catalyzed intramolecular hydroarylation.

A gold-catalyzed regioselective tandem cyclization of N-propynylbutynamide via Csp(3)-H functionalization has been described, providing a distinctive methodology for the architecture of cyclopentapyridinones as well as spirocyclopentapyridinones.

SummaryAn Ugi four-component reaction of propargylamine with 3-formylindole and various acids and isonitriles produces adducts which are subjected to a cationic gold-catalyzed diastereoselective domino cyclization to furnish diversely substituted spiroindolines. All the reactions run via an exo-dig attack in the hydroarylation step followed by an intramolecular diastereoselective trapping of the imminium ion. The whole sequence is atom economic and the application of a multicomponent reaction assures diversity.

A diversity‐oriented approach comprising a Ugi four‐component reaction and gold(I)‐catalyzed hydroarylation under very mild reaction conditions has been elaborated. This gives direct access to the synthesis of biologically important heterocycles such as pyrrolopyridines, pyridoindoles, and azepinoindoles in very good yields. The influence of the nucleophilicity of the heterocycle and the mode of ring closure are discussed.

The usual way to synthesize spiroindolinones is the application of isatin derivatives. Here, we report the first Pd‐catalyzed Buchwald–Hartwig addition–elimination strategy for the formation of the spiroindolinone–isoindolinone architecture. The application of the Ugi‐4‐component reaction (Ugi‐4CR) allows the facile introduction of diversity and increases the practicality of this protocol.