Programmable Deuteration of Indoles via Reverse Deuterium Exchange

Methods for selective deuterium incorporation into drug-like molecules have become extremely valuable due to the commercial, mechanistic, and biological importance of deuterated compounds. Herein, we report a programmable labeling platform that allows access to C2, C3, or C2- and C3-deuterated indoles under mild, user-friendly conditions. The C2-deuterated indoles are accessed using a reverse hydrogen isotope exchange strategy which represents the first non-directed C2-deuteration of indoles

Controlling the crystal structure of precisely spaced polyethylene-like polyphosphoesters

Understanding polymer crystallization is important for polyethylene-like materials. A small fraction of monomers with functional groups within the polyethylene chain can act as crystallization “defects”. Such defects can be used to control the crystallization behavior in bulk and to generate functional anisotropic polymer crystals if crystallized from a dilute solution. Due to their geometry, phosphate groups cannot be incorporated in the polyethylene lamellae and thus control chain folding and crystal morphology. Herein, the synthesis and crystallization behavior for three different long-chain polyphosphates with a precise spacing of 20, 30, and 40 CH2-groups between each phosphate group are reported. Monomers were prepared by esterification of ethyl dichlorophosphate with respective tailor-made unsaturated alcohols. Acyclic diene metathesis (ADMET) polymerization and subsequent hydrogenation were used to receive polyethylene-like polyphosphoesters with molecular weights up 23 100 g mol−1. Polymer crystallization was studied from the melt and dilute solution. Samples were characterized by differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). A change in crystal structure from pseudo-hexagonal to orthorhombic was observed from the “C20” to the “C40” polymer. Melting points and lamellar thicknesses increased with the length of the aliphatic spacer from 51 °C (“C20”) to 62 °C (“C30”) and 91 °C (“C40”). Values for the long periods in bulk (3.1 nm for C20, 4.8 nm for C30, and 7.2 nm for C40) obtained by SAXS and TEM are in qualitative agreement. The thickness of the crystalline part obtained by AFM and TEM increased from about 1.0 nm (C20) to 2.0 nm (C30) to 2.9 nm (C40). Our systematic library of long-chain polyphosphates will allow designing anisotropic polymer colloids by crystallization from solution as functional and versatile colloid platform

Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization

Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd­(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle

Palladium(II)-Catalyzed Directed <i>anti-</i>Hydrochlorination of Unactivated Alkynes with HCl

A regio­selective <i>anti</i>-hydrochlorination of unactivated alkynes is reported. The reaction utilizes <i>in situ</i> generated HCl as the source of both the Cl^– and H⁺ and is catalyzed by palladium­(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-aminoquinoline bidentate directing groups are used to control the regio­selectivity of the chloropalladation step and stabilize the resulting alkenylpalladium­(II) intermediate for subsequent protodepalladation. This method provides access to a broad array of substituted alkenyl chlorides in excellent yields and with high regio­selectivity. The products from this transformation were successfully derivatized via Stille coupling to a variety of trisubstituted alkene products. Reaction progress kinetic analysis was performed, shedding light on a possible mechanism for this catalytic process

Copper-Catalyzed Chan–Lam Cyclopropylation of Phenols and Azaheterocycles

Small molecules containing cyclopropane–heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan–Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects <i>O</i>-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about <i>N</i>-cyclopropylation. The transformation is catalyzed by Cu­(OAc)₂ and 1,10-phenanthroline and employs 1 atm of O₂ as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups

Trifluoromethylation of Allylsilanes under Photoredox Catalysis

A new catalytic method to access allylic secondary CF₃ products is described. These reactions use the visible light excited Ru(bpy)₃Cl₂·6H₂O catalyst and the Togni or Umemoto reagent as the CF₃ source. The photoredox catalytic manifold delivers enantioenriched allylic trifluoromethylated products not accessible under Cu(I) catalysis