A Pd(0)/blue light catalyzed carboiodination reaction is reported. A simple, air-stable catalytic system, utilizing [Pd(allyl)Cl] 2 and DPEPhos, generated a variety of iodinated hetero-and carbocycles including oxindoles, dihydrobenzofurans, indolines, a chromane, and a tetrahydronaphthalene. This protocol was tolerant of sensitive functional groups including free carboxylic acids, phenols, and anilines, as well as pyridines, while delivering products in up to 94% yield. Support for a reversible C−I bond formation via a single electron mechanism was obtained using a deuterium labeled substrate and a stoichiometric neopentylpalladium species.T ransition-metal catalyzed halogenation protocols have often hinged on gaining a deeper understanding of the reversibility of carbon−halogen bond forming events. One powerful synthetic strategy that implements reversible C−X bond formation is the palladium-catalyzed carboiodination reaction, wherein halogenated heterocycles can be built from the intramolecular transfer of a C(sp 2 )−X group across a tethered π-system. 1−4 Traditionally, palladium catalyzed carboiodination reactions involve a 2-electron mechanistic cycle and are initiated by a ground-state Pd(0) catalyst undergoing an oxidative addition with an aryl halide. 1,2,4 Recently, the use of blue light in conjunction with palladium catalysis has offered a convenient route to access excited-state palladium species. 5−10 Unlike their thermal counterparts, photochemical reactions involving excited-state Pd(0) are typically thought to involve tandem palladium/radical intermediates. These reactions can mimic the reactivity of ground state palladium species, via a single electron mechanism in domino reactions. 6,8,10−13 Though the presence of radical intermediates has been well established, 5,6,14 a mechanism involving both discrete Pd(II) intermediates and alkyl radical/Pd(I) species has not been broadly explored.Thermally initiated carboiodination reactions typically employ a palladium catalyst bearing bulky electron-rich phosphines, or a nickel catalyst and a PPh 3 , P(OR) 3 or an N,N-ligand. 1,15−20 These reaction mechanism initiate via an oxidative addition to the C−I bond, followed by a migratory insertion across the π-system, and terminate with a ligandmediated 3-center 2-electron, 18 or an H-bonding initiated S N 2type reductive elimination. 21 The most successful conditions for the palladium carboiodination reactions utilize high temperatures and QPhos or t-Bu 3 P, costly and air-sensitive bulky phosphines (Scheme 1a). Often times, bulky 3°-amine
The palladium-catalyzed synthesis of bis-heterocyclic spirocycles containing both pyrroline and indoline motifs is reported. Di-tert-butyldiaziridinone is used to functionalize palladacycles generated in situ via domino Narasaka−Heck/C−H activation reactions. The reaction is readily scalable, and the spirocyclic products can undergo deprotection, reduction, and (3 + 2) cycloadditions, highlighting their synthetic utility. Additionally, kinetic isotope effect experiments support a turnover-limiting C−H functionalization step in the catalytic cycle.
A palladium-catalyzed epimerization reaction of stereogenic alkyl iodides is reported. This transformation involves use of an air-stable precatalyst that efficiently epimerizes the C−I bond from the exo to the endo face of [2.2.1] bicyclic compounds. Mechanistic experiments support the stereoinversion of the C−I bond via reversible bond formation to generate the antiproduct bearing an endo iodide. Density functional theory studies were conducted to support a thermodynamically driven epimerization. Stoichiometric experiments suggested that irradiation of isolable alkyl−Pd(II) complexes promoted the C−I reductive elimination, which could even be applied to C−Br bond formation.
Inverse design of short single-stranded RNA and DNA sequences (aptamers) is the task of finding sequences that satisfy a set of desired criteria. Relevant criteria may be, for example, the presence of specific folding motifs, binding to molecular ligands, sensing properties, and so on. Most practical approaches to aptamer design identify a small set of promising candidate sequences using high-throughput experiments (e.g., SELEX) and then optimize performance by introducing only minor modifications to the empirically found candidates. Sequences that possess the desired properties but differ drastically in chemical composition will add diversity to the search space and facilitate the discovery of useful nucleic acid aptamers. Systematic diversification protocols are needed. Here we propose to use an unsupervised machine learning model known as the Potts model to discover new, useful sequences with controllable sequence diversity. We start by training a Potts model using the maximum entropy principle on a small set of empirically identified sequences unified by a common feature. To generate new candidate sequences with a controllable degree of diversity, we take advantage of the model's spectral feature: an "energy" bandgap separating sequences that are similar to the training set from those that are distinct. By controlling the Potts energy range that is sampled, we generate sequences that are distinct from the training set yet still likely to have the encoded features. To demonstrate performance, we apply our approach to design diverse pools of sequences with specified secondary structure motifs in 30-mer RNA and DNA aptamers.
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