Organosulfur compounds have long played a vital role in organic chemistry and in the development of novel chemical structures and architectures. Prominent among these organosulfur compounds are those involving a sulfur(IV) center, which have been the subject of countless investigations over more than a hundred years. In addition to a long list of textbook sulfur-based reactions, there has been a sustained interest in the chemistry of organosulfur(IV) compounds in recent years. Of particular interest within organosulfur chemistry is the ease with which the synthetic chemist can effect a wide range of transformations through either bond formation or bond cleavage at sulfur. This review aims to cover the developments of the past decade in the chemistry of organic sulfur(IV) molecules and provide insight into both the wide range of reactions which critically rely on this versatile element and the diverse scaffolds that can thereby be synthesized.

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts.

Computational investigations of ligand-directed selectivities in Ullmann-type coupling reactions of methanol and methylamine with iodobenzene by β-diketone- and 1,10-phenanthroline-ligated CuI complexes are reported. Density functional theory calculations using several functionals were performed on both the nucleophile formation and aryl halide activation steps of these reactions. The origin of ligand-directed selectivities in N- versus O-arylation reactions as described in a previous publication (J. Am. Chem. Soc. 2007, 129, 3490−3491) were studied and explained. The selectivities observed experimentally are derived not from initial CuI(nucleophile) complex formation but from the subsequent steps involving aryl halide activation. The arylation may occur via single-electron transfer (SET) or iodine atom transfer (IAT), depending on the electron-donating abilities of the ligand and nucleophile. Mechanisms involving either oxidative addition/reductive elimination or σ-bond metathesis are disfavored. SET mec...

Computational Explorations of Mechanisms and Ligand-Directed Selectivities of Copper-Catalyzed Ullmann-Type Reactions

Recent advances in molecular rearrangements involving aryne intermediates

The hexadehydro-Diels–Alder (HDDA) reaction between an alkyne and a 1,3-diyne has recently become a rapidly growing area in the field of aryne chemistry. Both concerted and stepwise mechanisms for HDDA are energetically and geometrically feasible. The formation of a reactive benzyne intermediate under thermal conditions has been coupled with a wide variety of intra- and intermolecular trapping reactions to access highly functionalised aromatic compounds. With this in mind, reagents can be tailored to generate compounds for desired applications such as the synthesis of bioactive molecules or optoelectronic materials. This review presents a comprehensive overview of the HDDA reaction to date.

Methodology and applications of the hexadehydro-Diels–Alder (HDDA) reaction

An important question in organic chemistry concerns the extent to which benzynes-one of the classical reactive intermediates in organic chemistry-can react in discriminating fashion with trapping reagents. In particular, whether these species can react selectively with substrates containing multiple functional groups and possible sites of reactivity has remained unanswered. Natural products comprise a palette of multifunctional compounds with which to address this question. Here, we show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a preference for one among several pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products (some in as few as three steps) that enable subsequent and rapid access to structurally diverse polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity-a trait perhaps not broadly enough appreciated.

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Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

We report here reactions of alkyl sulfides with benzynes thermally generated by the hexadehydro-Diels–Alder (HDDA) cycloisomerization. The initially produced 1,3-betaine (o-sulfonium/aryl carbanion) undergoes intramolecular proton transfer to generate a more stable S-aryl sulfur ylide. This can react in various manners, including engaging weak acids (HA) in the reaction medium. This can produce transient ion pairs ArSR2+A– that proceed to the products ArSR + RA. When cyclic sulfides are used, A– opens the ring and is incorporated into the product, an outcome that constitutes a versatile, three-component coupling process.

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Reactions of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-Component Reactions

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (-)-daphlongamine H has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson-Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (-)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B.

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Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H.

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

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Vignesh Palani

Papers

Reactions of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-Component Reactions

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H.

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups.

Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (−)-Daphlongamine H

Reactions of Hexadehydro-Diels-Alder (HDDA)-Derived Benzynes with Thioamides: Synthesis of Dihydrobenzothiazino-Heterocyclics.