Chemical Modification of Oxidized Polyethylene Enables Access to Functional Polyethylenes with Greater Reuse.

Polyethylene is a commodity material that is widely used because of its low cost and valuable properties. However, the lack of functional groups in polyethylene limits its use in applications that include adhesives, gas barriers, and plastic blends. The inertness of polyethylene makes it difficult to install groups that would enhance its properties and enable programmed chemical decomposition. To overcome these deficiencies, the installation of pendent functional groups that imbue polyethylene with enhanced properties is an attractive strategy to overcome its inherent limitations. Here, we describe strategies to derivatize oxidized polyethylene that contains both ketones and alcohols to monofunctional variants with bulk properties superior to those of unmodified polyethylene. Iridium-catalyzed transfer dehydrogenation with acetone furnished polyethylenes with only ketones, and ruthenium-catalyzed hydrogenation with hydrogen furnished polyethylenes with only alcohols. We demonstrate that the ratio of these functional groups can be controlled by reduction with stoichiometric hydride-containing reagents. The ketones and alcohols serve as sites to introduce esters and oximes onto the polymer, thereby improving surface and bulk properties over those of polyethylene. These esters and oximes were removed by hydrolysis to regenerate the original oxygenated polyethylenes, showing how functionalization can lead to materials with circularity. Waste polyethylenes were equally amenable to oxidative functionalization and derivatization of the oxidized material, showing that this low- or negative-value feedstock can be used to prepare materials of higher value. Finally, the derivatized polymers with distinct solubilities were separated from mechanically mixed plastic blends by selective dissolution, demonstrating that functionalization can lead to novel approaches for distinguishing and separating polymers from a mixture.

The Buchwald-Hartwig Amination After 25†Years.

The Pd-catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp2 )-N bonds. The pioneering reports from Migita and subsequently Buchwald and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin-free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald-Hartwig amination. This Minireview summarizes the evolution of this cross-coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well-established methodology.

Palladium-Catalyzed Methylation of Aryl, Heteroaryl, and Vinyl Boronate Esters.

A method for the direct methylation of aryl, heteroaryl, and vinyl boronate esters is reported, involving the reaction of iodomethane with aryl-, heteroaryl-, and vinylboronate esters catalyzed by palladium and PtBu2Me. This transformation occurs with a remarkably broad scope and is suitable for late-stage derivatization of biologically active compounds via the boronate esters. The unique capabilities of this method are demonstrated by combining carbon-boron bond-forming reactions with palladium-catalyzed methylation in a tandem transformation.

Palladium- and Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles.

A complementing Pd- and Rh-catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N-allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as certified drugs and potential drug candidates. The new methods feature high chemo-, regio- and enantioselectivities aside from displaying a broad substrate scope and functional group compatibility. A mechanistic rational accounting for allene racemization and trans-alkene selectivity is discussed.

Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters.

A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C-H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C-H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether.

Alkynes as Electrophilic or Nucleophilic Allylmetal Precursors in Transition-Metal Catalysis.

Diverse late transition metal catalysts convert terminal or internal alkynes into transient allylmetal species that display electrophilic or nucleophilic properties. Whereas classical methods for the generation of allylmetal species often form stoichiometric by-products, the recent use of alkynes as allylmetal precursors enables completely atom-efficient catalytic processes to be carried out, including enantioselective transformations.

The Total Synthesis of Epothilone†D as a Yardstick for Probing New Methodologies.

Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron-magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the ß-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.

Rhodium-Catalyzed Diastereoselective Cyclization of Allenyl-Sulfonylcarbamates: A Stereodivergent Approach to 1,3-Aminoalcohol Derivatives.

A diastereoselective and stereodivergent rhodium-catalyzed intramolecular coupling of sulfonylcarbamates with terminal allenes is described and it provides selective access to 1,3-aminoalcohol derivatives, scaffolds found in bioactive compounds. The reaction is compatible with a large range of different functional groups, thus furnishing products with high diastereoselectivities and yields. Moreover, multigram scale reactions, as well as the application of suitable product transformations were demonstrated.

Stereodivergent and Protecting-Group-Free Synthesis of the Helicascolide Family: A Rhodium-Catalyzed Atom-Economical Lactonization Strategy.

Natural products of polyketide origin, in particular small-sized lactones often possess a very broad range of impressive biological activities. An efficient way to demonstrate the concise access to six-membered lactones was emphasized as part of a stereodivergent and protecting-group-free synthesis of all three representatives of the helicascolide family. This strategy features an atom-economical and highly diastereoselective rhodium-catalyzed "head-to-tail" lactonization by an intramolecular addition of ω-allenyl-substituted carboxylic acids to terminal allenes, including the selective construction of a new stereocenter in the newly formed core structures. The excellent selectivities with which the helicascolide precursors were obtained are remarkable, thus resulting in an expeditious and highly efficient natural product synthesis.

Regioconvergent and Enantioselective Rhodium-Catalyzed Hydroamination of Internal and Terminal Alkynes: A Highly Flexible Access to Chiral Pyrazoles.

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with internal and terminal alkynes features an utmost chemo-, regio-, and enantioselective access to enantiopure allylic pyrazoles, readily available for incorporation in small-molecule pharmaceuticals. This methodology is distinguished by a broad substrate scope, resulting in a remarkable compatability with a variety of different functional groups. It furthermore exhibits an intriguing case of regio-, position-, and enantioselectivity in just one step, underscoring the sole synthesis of just one out of up to six possible products in a highly flexible approach to allylated pyrazoles by emanating from various internal and terminal alkynes.

Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide†A and Late-Stage Modification.

Natural products of polyketide origin with a high level of symmetry, in particular C2 -symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important structural motif was developed as part of a concise and highly convergent synthesis of clavosolide A. This strategy features an atom-economic "head-to-tail" dimerization by the stereoselective rhodium-catalyzed addition of carboxylic acids to terminal allenes with the simultaneous construction of two new stereocenters. The excellent efficiency and selectivity with which the C2 -symmetric core structures were obtained are remarkable considering the outcome under classical dimerization conditions. Furthermore, this approach facilitates late-stage modification and provides ready access to potential new lead structures.

Regio- and enantioselective synthesis of N-substituted pyrazoles by rhodium-catalyzed asymmetric addition to allenes.

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.