Site-Selective Alkoxylation of Benzylic C-H Bonds by Photoredox Catalysis.
ABSTRACT: Methods that enable the direct C-H alkoxylation of complex organic molecules are significantly underdeveloped, particularly in comparison to analogous strategies for C-N and C-C bond formation. In particular, almost all methods for the incorporation of alcohols by C-H oxidation require the use of the alcohol component as a solvent or co-solvent. This condition limits the practical scope of these reactions to simple, inexpensive alcohols. Reported here is a photocatalytic protocol for the functionalization of benzylic C-H bonds with a wide range of oxygen nucleophiles. This strategy merges the photoredox activation of arenes with copper(II)-mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C-O bonds with high site selectivity, chemoselectivity, and functional-group tolerance using only two equivalents of the alcohol coupling partner. This method enables the late-stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential applications in synthesis and medicinal chemistry.
Project description:A 1:1 mixture of [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgClO(4) catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio- and stereospecific with preferential addition of the alcohol nucleophile at the ?-position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor ? regioisomer is formed predominantly through a secondary reaction manifold involving regioselective ?-alkoxylation of the initially formed allylic ether rather than by the direct ?-alkoxylation of the allylic alcohol.
Project description:A practical, chemoselective oxidation of alcohols employing catalytic quantities of DDQ as the oxidant and Mn(OAc)(3) as the co-oxidant is described. Electron-rich benzylic alcohols are oxidized efficiently to their corresponding carbonyls, but less electron-rich benzylic alcohols remain unchanged. Allylic alcohols are rapidly oxidized to their corresponding aldehyde or ketone counterparts in high yields. This protocol is operationally simple, employs an inexpensive source of Mn(OAc)(3), has short reaction times, and exhibits a significant chemoselectivity favoring allylic alcohols over benzylic alcohols. This procedure also avoids the use of very large excesses of reagents and sometimes poor reproducibility that characterize previously developed reagents such as MnO(2).
Project description:The selective oxidation of benzylic alcohols was performed by using commercially available aluminum oxy-hydroxide-supported palladium (Pd/AlO(OH)) nanoparticles (0.5 wt.% Pd, about 3?nm size) under mild conditions. The oxidation method comprises the oxidation of benzyl alcohols catalyzed by aluminum oxy-hydroxide-supported palladium under ultrasonic and solvent-free conditions and a continuous stream of O<sub>2</sub>. The characterization of aluminum oxy-hydroxide-supported palladium nanocatalyst was conducted by several advanced analytical techniques including scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), and elemental analysis by ICP-OES. The oxidation of a variety of benzyl alcohol compounds were tested by the aluminum oxy-hydroxide-supported palladium nanoparticles, and all expected oxidation products were obtained by the high conversion yields within 3?hours. The reaction progress was monitored by TLC (Thin-layer chromatography), and the yields of the products were determined by <sup>1</sup>H-NMR and <sup>13</sup>C NMR analysis.
Project description:Homogeneous Cu/TEMPO catalyst systems (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) have emerged as some of the most versatile and practical catalysts for aerobic alcohol oxidation. Recently, we disclosed a (bpy)Cu(I)/TEMPO/NMI catalyst system (NMI = N-methylimidazole) that exhibits fast rates and high selectivities, even with unactivated aliphatic alcohols. Here, we present a mechanistic investigation of this catalyst system, in which we compare the reactivity of benzylic and aliphatic alcohols. This work includes analysis of catalytic rates by gas-uptake and in situ IR kinetic methods and characterization of the catalyst speciation during the reaction by EPR and UV-visible spectroscopic methods. The data support a two-stage catalytic mechanism consisting of (1) "catalyst oxidation" in which Cu(I) and TEMPO-H are oxidized by O(2) via a binuclear Cu(2)O(2) intermediate and (2) "substrate oxidation" mediated by Cu(II) and the nitroxyl radical of TEMPO via a Cu(II)-alkoxide intermediate. Catalytic rate laws, kinetic isotope effects, and spectroscopic data show that reactions of benzylic and aliphatic alcohols have different turnover-limiting steps. Catalyst oxidation by O(2) is turnover limiting with benzylic alcohols, while numerous steps contribute to the turnover rate in the oxidation of aliphatic alcohols.
Project description:Ru(OH) x /Al2O3 is among the more versatile catalysts for aerobic alcohol oxidation and dehydrogenation of nitrogen heterocycles. Here, we describe the translation of batch reactions to a continuous-flow method that enables high steady-state conversion and single-pass yields in the oxidation of benzylic alcohols and dehydrogenation of indoline. A dilute source of O2 (8% in N2) was used to ensure that the reaction mixture, which employs toluene as the solvent, is nonflammable throughout the process. A packed bed reactor was operated isothermally in an up-flow orientation, allowing good liquid-solid contact. Deactivation of the catalyst during the reaction was modeled empirically, and this model was used to achieve high conversion and yield during extended operation in the aerobic oxidation of 2-thiophene methanol (99+% continuous yield over 72 h).
Project description:8-Membered cyclic ethers are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed intramolecular dehydrative alkoxylation of ?-hydroxy allylic alcohols was explored to stereoselectively construct ?,?'-cis-oxocenes and further applied in a formal synthesis of (+)-laurencin. The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative method for the synthesis of molecular building blocks and natural products that contain highly functionalized 8-membered cyclic ethers.
Project description:Selective methylene C-H oxidation for the synthesis of alcohols with a broad scope and functional group tolerance is challenging due to the high proclivity for further oxidation of alcohols to ketones. Here, we report the selective synthesis of benzylic alcohols employing bis(methanesulfonyl) peroxide as an oxidant. We attempt to provide a rationale for the selectivity for monooxygenation, which is distinct from previous work; a proton-coupled electron transfer mechanism (PCET) may account for the difference in reactivity. We envision that our method will be useful for applications in the discovery of drugs and agrochemicals.
Project description:A simple cobalt(ii)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.
Project description:Aerobic oxidation reactions have been the focus of considerable attention, but their use in mainstream organic chemistry has been constrained by limitations in their synthetic scope and by practical factors, such as the use of pure O(2) as the oxidant or complex catalyst synthesis. Here, we report a new (bpy)Cu(I)/TEMPO catalyst system that enables efficient and selective aerobic oxidation of a broad range of primary alcohols, including allylic, benzylic, and aliphatic derivatives, to the corresponding aldehydes using readily available reagents, at room temperature with ambient air as the oxidant. The catalyst system is compatible with a wide range of functional groups and the high selectivity for 1° alcohols enables selective oxidation of diols that lack protecting groups.
Project description:In this study, a new heterobimetallic Mo(VI)-V(V) organosilicon Schiff base complex has been prepared and characterized by different techniques, such as FTIR, Raman, MS, ICP-AES, TGA, and XPS. The bimetallic nanocomplex, revealed by TEM images, showed high oxidation stability and desired activity in the aerobic oxidation of a structurally diverse set of benzylic alcohols in ethanol as a safe solvent. Further, oxidation of benzylic hydrocarbons successfully occurred, producing the target compounds in high yields and excellent selectivities. Our results demonstrated a cooperative effect between Mo(VI) and V(V) as redox active sites in an organosilicon Schiff base framework. A facile and practical reusability of the solid catalyst at the end of the reaction was observed.