On-DNA Synthesis of Multisubstituted Indoles.

The increasing role of the DNA-encoded library technology in early phase drug discovery represents a significant demand for DNA-compatible synthetic methods for therapeutically relevant heterocycles. Herein, we report the first on-DNA synthesis of multisubstituted indoles via a cascade reaction of Sonogashira coupling and intramolecular ring closure. Further functionalization by Suzuki coupling at the third position exploits a diverse chemical space. The high fidelity of the method also enabled the construction of an indole-based mock library.

A stepwise one-pot synthesis of aliphatic thiols and their derivatives from acrylamides and sulfur.

Elemental sulfur enables the convenient formation of C-S bonds and the direct incoporation of S-S bonds. The reactivity of easily accessible electron deficient alkenes towards sulfur, however, is barely disclosed. Herein, we investigated the reactivity of acrylamides with sulfur and eventually developed a new pseudo-multicomponent reaction for the preparation of polysulfides. Sequential one-pot reduction led to diversely substituted thiols. Additional third stage one-pot modifications provided thioethers, unsymmetric disulfide and thioester.

Continuous-Flow Synthesis of Thioureas, Enabled by Aqueous Polysulfide Solution.

We have developed the continuous-flow synthesis of thioureas in a multicomponent reaction starting from isocyanides, amidines, or amines and sulfur. The aqueous polysulfide solution enabled the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration after the removal of the co-solvent, and the sulfur retained in the mother liquid. Presenting a wide range of thioureas synthesized by this procedure confirms the utility of the convenient continuous-flow application of sulfur.

Chromatography-Free Multicomponent Synthesis of Thioureas Enabled by Aqueous Solution of Elemental Sulfur.

The development of a new three-component chromatography-free reaction of isocyanides, amines and elemental sulfur allowed us the straightforward synthesis of thioureas in water. Considering a large pool of organic and inorganic bases, we first optimized the preparation of aqueous polysulfide solution from elemental sulfur. Using polysulfide solution, we were able to omit the otherwise mandatory chromatography, and to isolate the crystalline products directly from the reaction mixture by a simple filtration, retaining the sulfur in the solution phase. A wide range of thioureas synthesized in this way confirmed the reasonable substrate and functional group tolerance of our protocol.