Selective C(sp2)−H Halogenation of "click" 4-Aryl-1,2,3-triazoles

Selective bromination reactions of “click compounds” are described. Electron-neutral and electron-deficient arenes selectively undergo unprecedented Pd-catalyzed C–H ortho-halogenations assisted by simple triazoles as modular directing groups, whereas electron-rich arenes are regioselectively halogenated following an electrophilic aromatic substitution reaction pathway. These C–H halogenation procedures exhibit a wide group tolerance, complement existing bromination procedures, and represent versatile synthetic tools of utmost importance for the late-stage diversification of “click compounds”. The characterization of a triazole-containing palladacycle and density functional theory studies supported the mechanism proposal.We are grateful to Gobierno Vasco (ELKARTEK_KK-2015/0000101; IT_1033-16) and UPV/EHU (GIU15/31) for financial support. A. C. thanks MINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action is also acknowledged

Heterocycle-based bifunctional organocatalysts in asymmetric synthesis

Different chiral bifunctional organocatalysts derived from trans-cyclohexane-1,2-diamine bearing different types of guanidine units able to form-hydrogen bonding activation have been designed. Conformational rigid 2-aminobenzimidazoles bearing a tertiary amino group have been used in enantioselective Michael type reactions of activated methylene compounds to nitroalkenes. The C2 symmetric bis(2-aminobenzimidazole) derivatives the appropriate organocatalyst for the conjugate addition of 1,3-dicarbonyl compounds to maleimides as well as for the SN1 reaction of benzylic alcohols with carbon nucleophiles. 2-Aminobenzimidazoles bearing a primary amino group have shown excellent catalytic activity in the Michael reaction of aldehydes to maleimides and nitroalkenes. Diastereomeric 2-aminopyrimidines bearing a prolinamide unit have been incorporated in the trans-cyclohexane-1,2-diamine scaffold and have been used for the inter- and intra-molecular direct aldol reaction under solvent-free conditions. For the Michael reaction of aldehydes with maleimides the primary amine 2-aminopyrimidine has shown excellent efficiency as organocatalyst. The bifunctional character of these organocatalysts has been demonstrated by means of DFT calculations.The Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), FEDER, the Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017), the Basque Government (GV Grant IT-291-07), the FP7 Marie Curie Actions of the European Commission via the ITN ECHONET network (MCITN-2012-316379) and the Universities of Alicante and Basque Country are gratefully acknowledged for financial support. We also thank for technical and human support provided by IZO-SGI SGIker of UPV-EHU and European funding (ERDF and ESF)

Enantioselective Synthesis of Succinimides by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-aminobenzimidazole) Organocatalyst

A wide variety of chiral succinimides have been prepared in high yields and enantioselectivities by asymmetric conjugate addition of 1,3-dicarbonyl compounds to maleimides under very mild reaction conditions using a bifunctional benzimidazole-derived organocatalyst. Computational and NMR studies support the hydrogen-bonding activation role of the catalyst and the origin of the stereoselectivity of the process.Financial support from the Ministerio de Educación y Ciencia (MEC) (project numbers CTQ2007-62771/BQU, CTQ2010-20387), from Consolider INGENIO 2010 (grant number CSD2007-00006), from the Generalitat Valenciana (PROMETEO/2009/038), from Fondos Europeos para el Desarrollo Regional (FEDER), from the University of Alicante, and from the European Union (EU) (ORCA Action CM0905) is acknowledged

Four-Step Synthesis of (−)-4-epi-Presilphiperfolan-8α-ol by Intramolecular Iron Hydride Atom Transfer-Mediated Ketone-Alkene Coupling and Studies to Access trans-Hydrindanols with a Botryane Scaffold

From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (−)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent FeIII-mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds.Financial support for this research was provided by the Grants PID2019-104188GB-I00 and PID2019-110008GB-I00 funded by MCIN/AEI/10.13039/501100011033. We also thank SGIker (UPV/EHU) for providing human and computational resources. B.B. acknowledges the Serra Hunter program (Generalitat de Catalunya)

Enantioselective Synthesis of Succinimides by Michael Addition of Aldehydes to Maleimides Organocatalyzed by Chiral Primary Amine-Guanidines

The monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine affords chiral primary amine-guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α-disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N-dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen-bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine-guanidines versus primary amine-thioureas as the organocatalysts.The authors thank the Spanish Ministerio de Economía y Competitividad (MEC) (projects CTQ2010-20387, CTQ2010-21263-C02, and Consolider Ingenio 2010, CSD2007-00006), the Fondos Europeos para el Desarrollo Regional (FEDER), the COST Action CM0905 “Organocatalysis”, the Generalitat Valenciana (Prometeo/2009/039), the Basque Government (GV grant IT-291-07), the University of Alicante, and the University of the Basque Country for the financial support

Conformational Flexibility as a Tool for Enabling Site-Selective Functionalization of Unactivated sp(3) C-O Bonds in Cyclic Acetals

A dual catalytic manifold that enables site-selective functionalization of unactivated sp(3) C-O bonds in cyclic acetals with aryl and alkyl halides is reported. The reaction is triggered by an appropriate sigma*-p orbital overlap prior to sp(3) C-O cleavage, thus highlighting the importance of conformational flexibility in both reactivity and site selectivity. The protocol is characterized by its excellent chemoselectivity profile, thus offering new vistas for activating strong sigma sp(3) C-O linkages.We thank ICIQ, FEDER/MCI-AEI/PGC2018-096839-B-I00, MCIN-PID2019-110008GB-I00, European Research Council (ERC) under European Union's Horizon 2020 research and innovation program (Grant Agreement No. 883756) for financial support. E.G.-B. thanks SGIker (UPV/EHU) for providing human and computational resources. C.R. thanks the European Union's Horizon 2020 and innovation program under the Marie Sklodowska-Curie grant agreement (839980)

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

N-Tosyl-(S a)-binam-l-prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.This work was financially supported by the Ministerio de Economia y Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (Prometeo/2009/039), the University of Alicante, and the EU (ORCA action CM0905)

Zinc Iodide Catalyzed Synthesis of Trisubstituted Allenes from Terminal Alkynes and Ketones

A straightforward, user-friendly, efficient protocol for the one pot, ZnI2-catalyzed allenylation of terminal alkynes with pyrrolidine and ketones, toward trisubstituted allenes, is described. Trisubstituted allenes can be obtained under either conventional heating or microwave irradiation conditions, which significantly reduces the reaction time. A sustainable, widely available, and low-cost metal salt catalyst is employed, and the reactions are carried out under solvent-free conditions. Among others, synthetically valuable allenes bearing functionalities such as amide, hydroxyl, or phthalimide can be efficiently prepared. Mechanistic experiments, including kinetic isotope effect measurements and density functional theory (DFT) calculations, suggest a rate-determining [1,5]hydride transfer during the transformation of the intermediate propargylamine to the final allene.The research project was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "1st Call for H.F.R.I. Research Projects to support Faculty Members & Researchers and the procurement of high-cost research equipment grant" (Project Number: 16.Acronym: SUSTAIN). We thank Professor Thomas Mavromoustakos for his advice and support concerning the calculation of the relaxation delay times for the NMR analysis related to the kinetic isotope effect measurements. We also acknowledge the contribution of COST Action CA15106 (C-H Activation in Organic Synthesis.CHAOS). We also thank the Spanish Ministerio de Ciencia e Innovacion (PID2019-110008GB-I00) and IZO-SGI SGIker of UPV/EHU for financial and human support. The Special Account for Research Grants of the National and Kapodistrian University of Athens is also gratefully acknowledged for funding (research program 70/4/17454)

Organocatalytic Enantioselective α-Nitrogenation of α,α-Disubstituted Aldehydes in the Absence of a Solvent

A highly efficient enantioselective α-nitrogenation method of α,α-disubstituted aldehydes with azodicarboxylates promoted by a chiral carbamate-monoprotected cyclohexa-1,2-diamine as organocatalyst has been developed. The process was carried out without any solvent, and the corresponding α,α-disubstituted α-nitrogenated aldehydes were obtained with excellent yields and enantioselectivities up to 99% ee. The sustainability of the procedure was established through the calculation of green metrics, such as EcoScale and E-factor. In addition, theoretical calculations have been used to justify the obtained enantioselectivity sense.This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (PGC2018-096616-B-I00), the Spanish Ministry of Science and Innovation (PID2019-110008GB-I00), and the University of Alicante (VIGROB-173). We also thank SGIker (UPV/EHU) for providing human and computational resources

Amidosilylcyclopentadienyl monoalkyl zirconium compounds: evidence\ud of a N-assisted 1,3-proton shift olefin isomerization mechanism

New η5-cyclopentadienyl-η1-amido monoalkyl zirconium compounds of the type [ZrR(η5-\ud C5H4SiMe2-η1-NtBu)(η5-C5H4R0)] (R = Me, Bn; R0 =H, SiMe3, SiMe2CH2CHdCH2) have been\ud synthesized and fully characterized. Allyldimethylsilylcyclopentadienyl derivatives [ZrR(η5-C5H4SiMe2-η1-NtBu)(η5-C5H4SiMe2CH2CHdCH2)] isomerize the allyl fragment bound to the\ud cyclopentadienyl ring to give the corresponding [ZrR(η5-C5H4SiMe2-η1-NtBu)(η5-C5H4SiMe2CHdCHCH3)] compounds (R=Me, Bn). Experimental as well as DFT computational studies support an isomerization mechanism based on a N-assisted 1,3-proton shift