Metal‐Free Radical 5‐exo‐dig Cyclizations of Phenol‐Linked 1,6‐Enynes for the Synthesis of Carbonylated Benzofurans

A new metal‐free radical 5‐exo‐dig cyclization of phenol‐linked 1,6‐enynes with O₂, 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO), and tBuONO is described. With this general method, carbonylated benzofurans can be accessed through incorporation of two oxygen atoms into the product from O₂ and TEMPO through dioxygen activation and oxidative cleavage of the N? O bond, respectively.     

5‐exo versus 6‐endo Thiyl‐Radical Cyclizations in Organic Synthesis

Since the discovery of the radical mediated thiol‐ene and thiol‐yne reactions, these reactions have been employed in an intramolecular manner for the synthesis of sulfur‐containing heterocycles. Although closely related on a mechanistic basis, the thiol‐ene and thiol‐yne cyclization can differ greatly in regioselectivity and product distribution, with the thiol‐ene process being more predictable and thus attracting greater utilization. Herein, we review intramolecular thiyl‐radical addition reactions and the factors leading to the observed regioselectivity in examples in which both the 5‐exo and 6‐endo mode of cyclization are feasible. We highlight the applications of these important reactions for organic synthesis in the recent literature.     

gem‐Dihalocyclopropanes as Building Blocks in Natural‐Product Synthesis: Enantioselective Total Syntheses of ent‐Erythramine and 3‐epi‐Erythramine

ent‐Erythramine ((?)‐ 1 ), the enantiomer of the alkaloid erythramine, was prepared in 15 steps from known compounds. The first of three pivotal bond‐forming steps in the synthesis was a Suzuki–Miyaura cross‐coupling reaction of the starting materials to give a bis‐silyl ether. The second involved silver(I)‐induced electrocyclic ring opening of the gem‐dichlorocyclopropane formed in the next step and trapping of the ensuing π‐allyl cation by the tethered nitrogen atom to give, following cleavage of the allyloxycarbonyl protecting group, an approximately 5:6 mixture of the chromatographically separable diastereoisomeric spirocyclic products. In the third critical bond‐forming reaction, the iodide formed from one of the diastereoisomers underwent a radical‐addition/elimination reaction sequence that led to (?)‐ 1 in 89 % yield. The application of the same sequence of transformations to the other diastereoisomer afforded 3‐epi‐(+)‐erythramine (3‐epi‐(+)‐ 1 ).     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo selectivity.     

Heteroacene Synthesis through C−S Cross‐Coupling/5‐endo‐dig Cyclization

Highly efficient, one‐step synthesis of sulfur‐containing heteroacenes was achieved through palladium‐catalyzed C?S cross‐coupling of bis‐alkynes with thioacetate as hydrogen sulfide surrogate. Heteroacenes consisting of three, five, and seven fused aromatic rings were obtained in a single catalytic step by four‐, six‐, and eightfold C?S bond formation.     

Radical Cyclization/ipso‐1,4‐Aryl Migration Cascade: Asymmetric Synthesis of 3,3‐Difluoro‐2‐propanoylbicyclo[3.3.0]octanes

A novel method for the asymmetric synthesis of 3,3‐difluoro‐2‐propanoylbicyclo‐[3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso‐1,4‐aryl migration cascade.     

Design of Leaving Groups in Radical CC Fragmentations: Through‐Bond 2c–3e Interactions in Self‐Terminating Radical Cascades

Radical cascades terminated by β‐scission of exocyclic C?C bonds allow for the formation of aromatic products. Whereas β‐scission is common for weaker bonds, achieving this reactivity for carbon–carbon bonds requires careful design of radical leaving groups. It has now been found that the energetic penalty for breaking a strong σ‐bond can be compensated by the gain of aromaticity in the product and by the stabilizing two‐center, three‐electron “half‐bond” present in the radical fragment. Furthermore, through‐bond communication of a radical and a lone pair accelerates the fragmentation by selectively stabilizing the transition state. The stereoelectronic design of radical leaving groups leads to a new, convenient route to Sn‐functionalized aromatics.     

Tandem Radical Cyclization for the Construction of Difluoro‐Containing Oxindoles and Quinoline‐2,4‐diones

Cu‐catalyzed direct difluoromethylation of activated alkenes through a difluoromethyl radical addition/cyclization to afford difluorinated oxindoles and quinoline‐2,4‐diones has been developed. This method provides convenient access to a variety of oxindoles and quinoline‐2,4‐diones under mild conditions via a proposed tandem radical cyclization process, while tolerating various functional groups well. Moreover, a facile method to construct diverse difluorinated quinoline‐2,4‐diones by visible‐light photoredox catalysis under mild conditions was presented.     

Titanocene(III)‐Catalyzed 6‐exo Versus 7‐endo Cyclizations of Epoxypolyprenes: Efficient Control and Synthesis of Versatile Terpenic Building Blocks

In this article, a complete study on the selectivity of titanocene(III) cyclization of epoxypolyprenes is presented. The requirements for the formation of six‐ or seven‐membered rings during these cyclizations are determined, taking into account the different substitution pattern in the epoxypolyprene precursor. Thus, a complete selectivity to 6‐exo or 7‐endo cyclization process has been achieved, yielding mono‐, bi‐, and even tricyclic compounds, constituting a new and efficient access to this type of derivative. Additionally, this procedure opens the possibility to prepare excellent building blocks for the synthesis of polycyclic compounds with a trisubstituted oxygenated function, which is present in several natural terpenes.