Project description:A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift. Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Brønsted acids, albeit less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full mechanistic details, as well as the scope of this transformation, are discussed.
Project description:Multisubstituted furans were prepared from dialkyl 2-(aziridin-2-ylmethylene)malonate and/or 1,3-dione through aziridine ring opening by the internal carbonyl oxygen with the assistance of BF3·OEt2, followed by aromatization. This synthetic method is free from any metal and is atom-economical with all of the atoms in the starting material retained in the final product.
Project description:An N,N'-dioxide/scandium(III) complex catalyzed, highly efficient conjugate addition of malonic esters to enynes is described. A range of trisubstituted 1,2-allenyl ketones were obtained in high yields (up to 99 %) with good d.r. (up to 95/5) and excellent ee values (97 %-99 %). Moreover, the products could be easily transformed into chiral furan and 5-hydroxypyrazoline derivatives, both of which are important skeletons of many biologically active compounds and pharmacologicals.
Project description:Benzimidazolone constitutes the core structure of numerous pharmaceuticals, agrochemicals, inhibitors, pigments, herbicides, and fine chemicals. Amination of hydrocarbons is an attractive tool for the creation of nitrogen-containing products. However, the multiple steps, harsh conditions, and low atom efficiencies often present in these reactions remain challenging. We present a multicomponent synthesis of functional benzimidazolones from arylamines, dialkylamines, and alcohols, acting via the sequence of copper-catalyzed oxidative tandem C-H aminations and alkyl deconstructive carbofunctionalization. The catalytic transformation forms multiple bonds in one single operation, uses readily available feedstocks and a naturally abundant Cu/O2 catalyst system, has broad substrate scope, avoids pre-installation of aminating agents and directing groups, and provides high chemo- and regioselectivity, resulting in direct functionalization of inert C-H and C-C bonds via single-electron oxidation-induced activation mode. This platform can be expected to provide structurally diverse products with interesting biological, chemical, and physical properties.
Project description:Various γ-acyloxyalkynyl ketones were efficiently converted into highly substituted furans with 2.5 mol % of triflimide (triphenylphosphine)gold(I) as a catalyst in dichloroethane at 70 °C.
Project description:Herein, direct alkylation of the C-H bond at the α-position of furans catalyzed by palladium catalyst is reported. This protocol targets α-alkylfurans, achieving moderate to good yields under very practical reaction conditions. With a broad scope of substrates and good functional group tolerance, this method will has promising utility in medicinal chemistry.
Project description:The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3)-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer's disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery.
Project description:A one-pot three-step sequence involving Rh-catalyzed alkene hydroacylation, sulfide elimination and Rh-catalyzed aryl boronic acid conjugate addition gave products of traceless chelation-controlled hydroacylation employing alkyl aldehydes. The stereodefined β-aryl ketones were obtained in good yields with excellent control of enantioselectivity. Good variation of all three reaction components is possible.
Project description:Herein, we report the development of a catalytic enantioselective addition of N-substituted allyl equivalents to ketone electrophiles through use of Cu-catalyzed reductive coupling to access important chiral 1,2-aminoalcohol synthons in high levels of regio-, diastereo-, and enantioselectivity. Factors affecting enantioinduction are discussed including the identification of a reversible ketone allylation step that has not been previously reported in Cu-catalyzed reductive coupling.