Over the last two decades, radical chemistry of propargyl systems was developed into a potent synthetic field providing access to classes of organic compounds that are otherwise hardly accessible. The levels of diastereoselection thus achieved (up to 100%) are unprecedented for free propargyl radicals, as well as for organic radicals π-bonded to transition metals. These advances were enabled by the coordination of the triple bond to a Co2(CO)6 core that precluded an acetylene-allene rearrangement, stabilized requisite propargyl cations, created conformational constraints at the carbon-carbon bond formation site, configurationally altered the acetylenic moiety allowing for 1,3-steric induction upon the newly formed stereocenters, increased bulkiness of propargyl triads thus controlling the spatial orientation of converging radicals, and allowed for α-to-γ projection of the reaction site and alteration of the transiency of radical intermediates. In the course of these studies, a number of popular "beliefs" were proven to be untrue. First, cobalt-complexed propargyl cations, which have long been considered to be thermally labile species, were engaged in synthetically meaningful transformation at temperatures as high as 147 °C. Second, in radical dimerization reactions, higher reaction temperatures did not adversely impact the yields and levels of d,l-diastereoselectivity. Third, π-bonded organometallic radicals, deemed unruly, were effectively controlled with complementary mechanistic tools, thus achieving the highest levels of stereoselectivity (up to 100%) in inter- and intramolecular reactions. Fourth, meso stereoisomers, being thermally labile and kinetically disfavored, were discovered to be major products in intramolecular cyclizations induced by cobaltocene. Fifth, propargyl cations were synthesized in the absence of strong acids, thus increasing the functional tolerance and achieving a long sought after compatibility with acid-sensitive functionalities. A concept of sequestered propargyl radicals was introduced to explain disparity in diastereoselectivity data: heterogeneous reducing agents allegedly produce "free" radicals, while homogeneous reductants generate "sequestered" radicals associated with reductant-derived oxidized species. Among mechanistic tools, a 1,3-steric induction was found to be most efficient for controlling the stereoselectivity of radical reactions (up to 100% d,l). In intramolecular reactions, a d,l-to-meso reversal of stereoselectivity was discovered with zinc being replaced with cobaltocene as a reductant. Among efficient tools for controlling the stereoselectivity in intramolecular cyclizations is a rigidity of the carbon tether that provides for an exclusive formation of d,l-diastereomers. Two novel reactions that belong to a new field of unorthodox organometallic radical chemistry were discovered: the spontaneous conversion of cobalt-complexed propargyl cations to radicals and the THF-mediated process wherein a THF molecule assumes a new role of an initiator in radical reactions. A multistep mechanism involves a THF-induced alteration of propargyl cations that facilitates a redox process between metal clusters. Novel stereoselective methods provide access to topologically and functionally diverse 3,4-diaryl and 3,4-dialkyl-1,5-alkadiynes, 3,4-disubstituted 1,5-cycloalkadiynes (C8-C12), 3,4-dialkoxy-1,5-(cyclo)alkadiynes, and 3,7-diene-1,9-alkadiynes, which can be used in targeted syntheses of organic assemblies of relevance to medicinal chemistry, materials science, and natural product syntheses. Novel mechanistic tools and methodologies for controlling stereoselectivity in radical reactions can be expanded toward new types of π-bonded unsaturated units (dienes, arenes, diynes, and enynes) and transition metals other than cobalt (Fe, Cr, Mo, W, and Mn).
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http://dx.doi.org/10.1021/ar500365v | DOI Listing |
Org Lett
December 2024
Departamento de Química Orgánica e Inorgánica e Instituto Universitario de Química Organometálica "Enrique Moles", Unidad Asociada al C.S.I.C., Universidad de Oviedo, C/Julián Clavería 8, 33006 Oviedo, Spain.
Herein, we report a gold-catalyzed propargylation of chromone derivatives by propargylsilanes. Chromones are synergistically activated by the silylium cation resulting from the gold activation of the propargylsilane. The reaction exclusively occurs at the C2-position of the chromone, and a single diastereoisomer is formed.
View Article and Find Full Text PDFOrg Lett
November 2024
School of Chemistry, University of Hyderabad, Gachibowli 500046, Telangana, India.
Allyl amines are vital components in various biologically important molecules and play a significant role in their function. Presently, most methods are geared toward the preparation of di- and trisubstituted allyl amines, leaving a gap for the development of more versatile approaches. We herein describe an approach to yield tetrasubstituted allyl amines through palladium (Pd)-catalyzed regioselective dicarbofunctionalization of masked N-phthalimide-protected propargyl amines.
View Article and Find Full Text PDFNat Commun
October 2024
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
The asymmetric Büchner reaction and related arene cyclopropanations represent one type of the powerful methods for enantioselective dearomatization. However, examples of asymmetric Büchner reactions via a non-diazo approach are quite scarce, and the related arene cyclopropanation based on alkynes has not been reported. Herein, we disclose an asymmetric Büchner reaction and the related arene cyclopropanation by copper-catalyzed controllable cyclization of N-propargyl ynamides via vinyl cation intermediates, leading to chiral tricycle-fused cycloheptatrienes and benzonorcaradienes in high yields and enantioselectivities.
View Article and Find Full Text PDFChem Commun (Camb)
November 2024
Department of Applied Chemistry and Bioscience, Chitose Institute of Science and Technology, Chitose, 066-8655, Japan.
The reaction of -stannylated propargyl esters in the presence of a cationic gold(I) catalyst affords vinylidenecyclopropane derivatives as a mixture of diastereomers. The -geometry of the alkenes is almost entirely retained in the product. DFT calculations suggest the involvement of the gold(I)-stabilized propargyl cation as a resonance form of gold(I)-coordinated allenylidene species.
View Article and Find Full Text PDFOrg Biomol Chem
October 2024
Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica "A. Marchesini", Università degli Studi di Milano, Via Golgi, 19, 20133 Milano, Italy.
In this study, we explored and optimized a MW-enhanced divergent approach for the synthesis of 2-substituted benzofurans and chromenes, starting from seventeen substituted -propargylphenols characterized by a monoaryl substitution on the propargylic sp carbon. Firstly, we developed a robust platform for the preparation of a library of -propargylphenols. Under basic conditions, -propargylphenols reacted regioselectively to yield benzofurans in yields ranging from 43% to 100%.
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