Meta C-H Arylation of Electron-Rich Arenes: Reversing the Conventional Site Selectivity.
ABSTRACT: Controlling site selectivity of C-H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C-H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO2Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.
Project description:The catalytic 1,2-insertion polymerization of polar norbornenes (NBEs) leads to the formation of functional rigid macromolecules with exceptional thermal, optical and mechanical properties. However, this remarkable reaction is plagued by the low reactivity of the polar monomers, and most notably of those bearing a functional group in endo position. We have examined the polymerization mechanism of NBEs bearing one or two CO2Me groups either in exo or endo position catalyzed by the so-called naked allyl Pd+ SbF6- catalyst (1). Although endo dimethyl ester of 5-norbornene-2,3-dicarboxylic acid (NBE(CO2Me)2) is polymerized by 1, two endo units are never inserted consecutively along the polymer chain. Indeed, 1 is a tandem catalyst which not only catalyzes the insertion of the monomer but also the isomerization of endo and exo isomers. Thus, the polymerization of endo monomers proceeds via a novel mechanism, coined rectification-insertion mechanism, whereby half of the endo monomers are rectified into exo ones prior insertion, leading to the formation of an alternating endo-exo copolymer using an endo only feedstock. With this mechanism, the lack of reactivity of endo norbornenes is bypassed, and the polymerization of predominantly endo polar NBEs bearing a variety of functionalities such as esters, imides, acids, aldehydes, alcohols, anhydrides, or alkyl bromides proceeds with catalyst loadings as low as 0.002 mol%.
Project description:Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing poly substituted arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard substrates for Pd-catalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development of general approaches for aryl bromide-mediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Importantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility of these methods has been demonstrated in sequential cross coupling/ ortho functionalization reactions, consecutive Pd/NBE-catalyzed difunctionalization to construct penta-substituted aromatics and two-step meta functionalization reactions. Moreover, the origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic compounds.
Project description:Arenes with four different contiguous substituents, i.e. 1,2,3,4-tetrasubstituted arenes, are commonly found in bioactive compounds, but they are nontrivial to access via conventional methods. Through addressing the "<i>meta</i> constraint" in the palladium/norbornene (Pd/NBE) cooperative catalysis, which is the difficulty of tolerating a sizable <i>meta</i> substituent in aryl halide substrates, here a modular and regioselective approach is realized for preparing 1,2,3,4-tetrasubstituted arenes. One key is the use of a C2-amide-substituted NBE, and a combined experimental and computational study reveals its role in promoting the NBE insertion and the <i>ortho</i> C-H metalation steps. The scope is broad: a variety of electrophiles and nucleophiles could be introduced to the <i>ortho</i> and <i>ipso</i> positions, respectively, with 1,4-disubstituted aryl halides, leading to diverse unsymmetrical contiguous tetrasubstituted arenes. Application of this approach has been demonstrated in streamlined syntheses of several bioactive compounds.
Project description:The ?<sub>1</sub> receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to ?<sub>1</sub> with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed. Three compounds with the greatest affinity bind in the 2 nM <i>K</i> <sub>i</sub> range (?8.7 p<i>K</i> <sub>i</sub>). Furthermore, ligands with the (3<i>R</i>,4<i>R</i>) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater ?<sub>1</sub> versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects.
Project description:The meta-C-H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator. Both the modified norbornene and the mono-protected 3-amino-2-hydroxypyridine type ligand are crucial for this auxiliary-free meta-C-H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta-arylated products in high yields.
Project description:Conversion of chromane-6-triflate 5 to chromane-6-dehydroalanine 9 or 10 via its Bpin-derivative 6 followed by Suzuki coupling with protected dehydroalanine bromides 7 or 8 were reported (86%). Alternatively, a palladium-catalyzed stannation of 5 with Bu6Sn2 afforded the tributyltin derivative 11, and iodination (12) followed by coupling with 13 gave chromane-6-alanine 15 (75%). Either approach constitutes a conversion from chromane-6-triflate to the corresponding protected chromane-6-alanine or its dehydro analog.
Project description:Palladium(II)-catalyzed meta-C-H arylation and alkylation of benzylsulfonamide using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator are realized by using a newly developed electron-deficient directing group and isoquinoline as a ligand. This protocol features broad substrate scope and excellent functional-group tolerance. The meta-substituted benyzlsulfonamides can be readily transformed into sodium sulfonates, sulfonate esters, and sulfonamides, as well as styrenes by Julia-type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups.
Project description:Meta-C-H functionalization of benzylamines has been developed using a PdII /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO2 Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5?mol?% by using the optimal ligand.
Project description:The regiodivergent ring contraction of diastereomeric 2-silyl-5,6-dihydro-6-aryl-(2H)-pyrans via [1,2]- and [1,4]-Wittig rearrangements to the corresponding ?-silylcyclopentenols or (?-cyclopropyl)acylsilanes favor the [1,4]-pathway by ortho and para directing groups in the aromatic appendage and/or by sterically demanding silyl groups. The [1,2]-pathway is dominant with meta directing or electron-poor aromatic moieties. Exclusive [1,2]-Wittig rearrangements are observed when olefin substituents proximal to the silyl are present. cis and trans diastereomers exhibit different reactivities, but converge to a single [1,2]- or [1,4]-Wittig product with high diastereoselectivity and yield.
Project description:MicroRNAs (miRNAs) are non-coding but functional RNA molecules of 21-25 nucleotides in length. MiRNAs play significant regulatory roles in diverse plant biological processes. In order to decipher the relationship between nbe-miR1919c-5p and the accumulations of tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) DNAs, as well as viral symptom development, we investigated the function of nbe-miR1919c-5p during TbCSV and TbCSB co-infection in plants using a PVX-and a TRV-based short tandem target mimic (STTM) technology. Suppression of nbe-miR1919c-5p expression using these two technologies enhanced TbCSV and TbCSB co-infection-induced leaf curling symptoms in Nicotiana benthamiana plants. Furthermore, suppression of nbe-miR1919c-5p expression enhanced TbCSV and TbCSB DNA accumulations in the infected plants. Our results can advance our knowledge on the nbe-miR1919c-5p function during TbCSV and TbCSB co-infection.