Sachin G. Modha

A Diversity‐Oriented Approach to Spiroindolines: Post‐Ugi Gold‐Catalyzed Diastereoselective Domino Cyclization

Gold-catalyzed carbocyclization and heteroannulation strategies have recently attracted much attention owing to the selective and efficient activation of the C C bond towards a wide range of nucleophiles that these methods provide. Domino approaches involving gold-catalysis lead to complex heterocyclic compounds under exceedingly mild reaction conditions. 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. Inspired by these findings and as a result of our continued synthetic interest in the indole core, multicomponent reactions and transition metal-catalysis, we have developed a post-Ugi gold-catalyzed domino cyclization method to generate spiroindolines. The Ugi four-component reaction (4-CR) of indole-3carboxaldehyde (1a) with p-methoxybenzyl amine (2a), 2-butynoic acid (3a) and tert-butyl isonitrile (4a) in methanol at 50 8C gave Ugi-adduct 5a in 71% yield. When this was treated with 5 mol% of Au[PPh3]OTf (OTf= trifluoromethanesulfonate) in CDCl3 at RT, the expected outcome of the reaction was indoloazepinone 6a’ through an endo-dig cyclization 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 6a 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 are prominent molecular motifs that are frequently encountered among the large family of alkaloids; for example, it is present in communesines and perophoramidines (Figure 1), which display distinct pharmacological properties. These fused polycyclic systems, which feature quaternary stereocenters, present a nontrivial challenge for organic chemists to develop synthetic approaches.

Gold(I) and platinum(II) switch: a post-Ugi intramolecular hydroarylation to pyrrolopyridinones and pyrroloazepinones.

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 Microwave-Assisted Diastereoselective Multicomponent Reaction To Access Dibenzo[c,e]azepinones: Synthesis and Biological Evaluation

An unprecedented microwave-assisted multicomponent strategy has been elaborated for the fast, efficient, and diastereoselective generation of the dibenzo[c,e]azepinone scaffold. The generated compounds were evaluated for their bioactivity.

An expeditious route toward pyrazine-containing nucleoside analogues.

An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been demonstrated.

Microwave-assisted palladium-catalyzed phosphonium coupling of 2(1H)-pyrazinones.

An expedient route for the synthesis of differently substituted 2(1H)-pyrazinones applying a microwave-assisted palladium-catalyzed phosphonium coupling procedure is reported. The method has also been successfully extended to some other tautomerizable heterocycles for efficient C-C cross-coupling.

Mild room-temperature palladium-catalyzed C3-arylation of 2(1H)-pyrazinones via a desulfitative Kumada-type cross-coupling reaction.

An efficient desulfitative Kumada-type cross-coupling protocol is reported for the C3-arylation of 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones. The method has also been successfully extended to the arylation of some (hetero)aryl thioethers and thioesters.

Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines

Summary An 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.

Microwave-assisted synthesis of a novel class of imidazolylthiazolidin-4-ones and evaluation of its biological activities

The synthesis and biological activity of a hitherto unknown class of compounds, the imidazolylthiazolidin-4-ones, are described. A two-step procedure has been elaborated starting from our previously described 2-aminoimidazoles. The application of microwave irradiation has been proven to be beneficial for the condensation of the imine with mercaptoacetic acid leading to the formation of imidazolylthiazolidin-4-ones. None of the compounds showed antiviral activity at subtoxic concentrations. Several compounds displayed a moderate cytostatic activity. These data form the basis for further improvement of the potential antiproliferative activity of this class of compounds.

Diversity-Oriented Synthesis of Substituted Furo[2,3-b]pyrazines

A highly efficient method for the synthesis of diversely substituted furo[2,3-b]pyrazines has been elaborated. The Ag+- or iodine-mediated electrophilic cyclization of readily generated 5-chloro-3-substituted ethynyl-1-(4-methoxybenzyl)-pyrazin-2(1H)-ones affords substituted furo[2,3-b]pyrazines, which undergo various palladium catalyzed reactions to generate a library of difficult to attain diversely substituted furo[2,3-b]pyrazines.

Synthesis of Triarylamines via Sequential C–N Bond Formation

A one-pot domino N-arylation protocol is described using diaryliodonium reagents under copper catalysis. The reaction uses both aryl groups of the diaryliodonium reagent to generate triarylamines starting from simple anilines, representing an atom-economical preparation of an important class of organic material building blocks.