2020 Publications

Su, Y.-L.; Tram, L.; Wherritt, D.; Arman, H.; Griffith, W. P.; Doyle, M. P.* α-Amino Radical-Mediated Diverse Difunctionalization of Alkenes: Construction of C-C, C-N and C-S Bonds. ACS Catal. 2020, 10, 13682−13687. doi: 10.1021/acscatal.0c04243


A general catalytic methodology for 1,2-RF/Y-difunctionalization of conjugated alkenes is reported. Diverse functionalized carbon radicals (RF•), which are generated through copper(I)-initiated selective halogen atom abstraction via a tert-butyl hydroperoxide-induced α-amino radical process, undergo regiocontrolled addition to carbon-carbon double bonds. The newly formed carbon radicals combine with Y = CN, N3, or NCS from TMSY in a copper(I)-promoted process to form a broad spectrum of α-cyano-, α-azido- and α-thiocyano-β-substituted products with additional functionalities in RF in high yields. Conversion of the reaction products to functionalized cyclopropane, amide, amine, triazole, thiol, and tetrazole highlights the potential utility of this method.

Su, Y.-L.;† Liu, G.-X.;† Liu, J.-W.; Tram, L.; Qiu, H.;* Doyle, M. P.* Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds. J. Am. Chem. Soc. 2020, 142, 13846-13855. doi: 10.1021/jacs.0c05183

One of the most common reactions of diazo compounds with alkenes is cyclopropanation that occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2=CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes delivering new carbon radical species, then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Wang, R.; Marichev, K. O.; Dong, K.; Jensen, J. A.; Doyle, M. P. Chiral 3‑Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions. J. Org. Chem. 2020, 85, 9475–9490. doi: 10.1021/acs.joc.0c01176


A nucleophilic retro-Claisen ring-opening of donor−acceptor cyclobutenes, formed with high stereocontrol by [3 + 1]-cycloaddition of TIPS-protected enoldiazoacetates with αacyl sulfur ylides, has been developed. Removal of the TIPS group to form the isolable β-keto ester precedes the strain-induced ringopening. Various amines, alcohols, thiols, and amino acid derivatives are effective nucleophiles, and their products are formed in very high yields via stoichiometric reactions. The chirality of the reactant donor−acceptor cyclobutenes is fully retained in the ring-opening reactions. The 3-acylglutaric acid products are converted to various valuable structures, including
amido-diols, γ-aminobutyric acid (GABA) derivatives, and heterocycles. 

Su, Y.-L.; De Angelis, L.; Tram, L.; Yu, Y.; Doyle, M. P. Catalytic Oxidative Cleavage Reactions of Arylalkenes by tert-Butyl Hydroperoxide – A Mechanistic Assessment. J. Org. Chem. 2020, 85, 3728–3741. doi: 10.1021/acs.joc.9b03346


Oxidative cleavage reactions of aryl-alkenes by tert-butyl hydroperoxide that occur by free radical processes provide access to carboxylic acid or ketone products. However, the pathway to these cleavage products is complex, initiated by regioselective oxygen radical addition to the carbon-carbon double bond. Subsequent reactions of the initially formed benzyl radical lead eventually to carbon-carbon cleavage. Thorough investigations of these reactions have identified numerous reaction intermediates that are on the pathways to final product formation, and they have identified a new synthetic methodology for the synthesis of peroxy radical addition induced hydroperoxide formation.


Zheng, H.; Dong, K.; Wherritt, D.; Arman, H.; Doyle, M. P. Brønsted Acid Catalyzed Friedel-Crafts-type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds. Angew. Chem. Int. Ed. 2020, 59, 13613- 13617. doi.org/10.1002/anie.202004328


The direct Friedel-Crafts-type coupling and denitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal-free strategy are described. This acid-catalyzed methodology is efficient for the formation of α-diazo β-carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β-unsaturated esters, β-indole-substituted diazo esters, and dienes  are obtained in good to high yields and selectivities. Futhermore, experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3- or 1,4- hydride transfer processes as well as fragmentation.


 Dong, K.; Xu, X.; Doyle, M. P. Copper(I)-catalyzed highly enantioselective [3+3]-cycloaddition of γ-alkyl enoldiazoacetates with nitrones. Org. Chem. Front. 2020, 7, 1653-1657. doi: 10.1039/D0QO00539H


Chiral copper(I) catalysts are preferred over chiral dirhodium(II) catalysts for [3 + 3]-cycloaddition reactions of γ-alkyl-substituted enoldiazoacetates compounds with nitrones. Using the In-SaBox ligand these reactions effectively produce cis-3,6-dihydro-1,2-oxazine derivatives under mild conditions in high yield and with exceptional stereocontrol, and enantioselectivity increases with the size of the γ-substituent. Mechanistic studies show that cycloaddition occurs solely through the formation of (Z)-γ-substituted metallo-enolcarbene intermediates that are catalytically gennerated from both (Z)- and (E)-γ-substituted enoldiazoactates via donor-acceptor cyclopropene intermediates.