Photoinduced Atom Transfer Radical Addition/Cyclization Reaction between Alkynes or Alkenes with Unsaturated α-Halogenated Carbonyls

We have developed a photochemical ATRA/ATRC reaction that is mediated by halogen bonding interactions. This reaction is caused by the reaction of malonic acid ester derivatives containing bromine or iodine with unsaturated compounds such as alkenes and alkynes in the presence of diisopropylethylamine under visible light irradiation. As a result of various control experiments, it was found that the formation of complexes between amines and halogens by halogen-bonding interaction occurs in the reaction system, followed by the cleavage of the carbon–halogen bonds by visible light, resulting in the formation of carbon radicals. In this reaction, a variety of substrates can be used, and the products, cyclopentenes and cyclopentanes, were obtained by intermolecular addition and intramolecular cyclization.

Preparation of Antiproliferative Terpene-Alkaloid Hybrids by Free Radical-Mediated Modification of ent-Kauranic Derivatives

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C–C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.

Ni–Catalyzed Difunctionalization of Alkynyl Bromides with Thiosulfonates and N-Arylthio Succinimides: A Convenient Synthesis of 1,2-Thiosulfonylethenes and 1,1-Dithioethenes

An efficient Ni-catalyzed vicinal thiosulfonylation of 1-bromoalkynes with thiosulfonates in the presence of cesium carbonate has been described. An operationally simple and highly regioselective atom transfer radical addition (ATRA) of alkynyl bromides provided a wide range of (E)-1,2-thiosulfonylethenes (alpha-aryl-beta-thioarylvinyl sulfones) in moderate to high yields. The immense substrate scope of both alkynyl bromides and thiosulfonates were explored with a broad range of functional groups. Also, the indole derived 1,1-bromoalkenes were also successfully sightseen in 1,2-thiosulfonylation process. Moreover, the Ni-catalyzed geminal-dithiolation of alkynyl bromides with N-arylthio succinimides, thus providing 1,1-dithioalkenes in high yields. The present protocol is reliable at gram-scale, and a sequential one-pot bromination and thiosulfonylation of phenylacetylene have also been achieved in scale-up synthesis. A plausible mechanism is proposed to rationalize the experimental outcome and control experiments for the vicinal thiosulfonylation.

Forskolin Editing via Radical Iodo- and Hydroalkylation

The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- and reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl­catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

Atom-transfer radical addition of fluoroalkyl bromides to alkenes via a photoredox/copper catalytic system

A method for the addition of fluorinated alkyl bromides to alkenes is described.