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N-demethylation of N,N-dimethylanilines promoted by [(N4Py)FeIVO]2+ occurs by an electron transfer-proton transfer (ET-PT) mechanism with a rate determining PT step. From the bell-shaped curve of the KDIE profile it has been estimated that the pKa of [(N4Py)FeIII-OH]2+ is 9.7.

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Nitrimines have been identified as impressive starting points for the syntheses of otherwise inaccessible, sterically encumbered enamines. The activation of nitrimines with urea catalysts for reaction with a variety of amines enables the formation of highly substituted enamines in high yield. The reactions benefit from mild, metal-free conditions, high functional group tolerance, and straightforward scale up.

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Multicomponent reactions are employed extensively in many areas of organic chemistry. Despite significant progress, the discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free reaction-discovery platform that can be used in the identification of new multicomponent transformations. Our approach is based on parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers. This strategy enabled the identification of a simple organic phosphine that can catalyse a previously unknown condensation of siloxyalkynes, aldehydes and amines to produce 3-hydroxyamides with high efficiency and diastereoselectivity. The reaction was further optimized using solution-phase methods.

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A C-O bond-formation reaction that proceeds through C-H functionalization of N,N-dialkylanilines at the ortho-position is presented. The iron-catalyzed selective ortho-benzoyloxylation follows a polar Friedel-Crafts-like mechanism and is sensitive to the nucleophilicity of the anilines. The benzoyl-oxylation of a variety of N,N-disubstituted anilines and Nphenyl heterocycles is carried out under extremely mild conditions. Furthermore, the methodology has been successfully employed for the generation of 1,4-benzoxazepines and oaminophenols.

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A copper-catalyzed functionalization of inert cyclic ethers was developed to provide alpha-aminonitriles via a cascade oxidation/amination/ring-opening/cyanation reaction. A series of highly versatile alpha-aminonitriles were obtained from primary or secondary anilines, and heterocyclic and aliphatic amines with high yields. This process features excellent functional group tolerance, a broad substrate scope, and high activity under ambient conditions.

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The Chan-Lam reaction remains a highly utilized transformation for C-N bond formation. However, anilines remain problematic substrates due to their lower nucleophilicity. To address this problem, we developed an electrochemically mediated Chan-Lam coupling of aryl boronic acids and amines utilizing a dual copper anode/cathode system. The mild conditions identified have enabled the preparation of a wide range of functionalized biarylanilines in good yields and chemoselectivities.

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4-Aminocyclopentenones were synthesized from readily available glycals and secondary anilines, with the aid of a Lewis acid-surfactant-combined catalyst. The reactions proceeded via a 4pi conrotatory electrocyclization, affording the corresponding 4-aminocyclopentenones in good yields with excellent diastereoselectivities.

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An original synthetic protocol has been developed for the preparation of highly functionalized tryptamines from 2-hydroxycyclobutanone and secondary arylamines via a solvent-free Br°nsted acid catalysed two-step reaction sequence.

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An efficient method for the synthesis of tertiary amines through a gold(I)-catalyzed tandem reaction of alkynes with secondary amines has been developed. In the presence of ethyl Hantzsch ester and [{(tBu) 2(o-biphenyl)P}AuCl]/AgBF4 (2 mol %), a variety of secondary amines bearing electron-deficient and electron-rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron-deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99 % yield. For indolines bearing a preexisting chiral center, their reactions with alkynes in the presence of ethyl Hantzsch ester catalyzed by [{(tBu)2(o-biphenyl)P}AuCl]/AgBF 4 (2 mol %) afforded tertiary amines in excellent yields and with good to excellent diastereoselectivity. All of these organic transformations can be conducted as a one-pot reaction from simple and readily available starting materials without the need of isolation of air/moisture-sensitive enamine intermediates, and under mild reaction conditions (mostly room temperature and mild reducing agents). Mechanistic studies by NMR spectroscopy, ESI-MS, isotope labeling studies, and DFT calculations on this gold(I)-catalyzed tandem reaction reveal that the first step involving a monomeric cationic gold(I)-alkyne intermediate is more likely than a gold(I)-amine intermediate, a three-coordinate gold(I) intermediate, or a dinuclear gold(I)-alkyne intermediate. These studies also support the proposed reaction pathway, which involves a gold(I)-coordinated enamine complex as a key intermediate for the subsequent transfer hydrogenation with a hydride source, and reveal the intrinsic stereospecific nature of these transformations observed in the experiments. Producing tertiary amines: The AuI-catalyzed tandem reaction of alkynes with secondary amines provides simple and efficient access to highly substituted tertiary amines with excellent yields and good to excellent diastereoselectivity. Mechanistic studies confirm that a possible reaction pathway involves intermolecular hydroamination via a monomeric cationic gold(I)-alkyne intermediate and subsequent transfer hydrogenation via a gold(I)-coordinated enamine intermediate. Copyright

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Purpose: To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. Methods: Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel. Results: Pyrrolo[3,2-d] pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI50) inhibitor of 8 tumor cell lines. Conclusion: We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.

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