Site-Specific Alkene Hydromethylation via Protonolysis of Titanacyclobutanes.

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(m-Cl)(m-CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo-, regio-, and site-selective manner. The broad utility of this method is demonstrated across a series of mono- and di-substituted alkenes containing pendant alcohols, ethers, amides, carbamates and basic amines.

• Publication year

  2021

• Venue

  Angewandte Chemie

• Publication date

  2021-04-19

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1002/anie.202103278PMID 33871123PMCID PMC9169970
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cobalt-catalysed C–H methylation for late-stage drug diversification

  2020cited by this paper
• Divergent Synthesis of Antiviral Diterpenes Wickerols A and B.

  2020cited by this paper
• Photocatalytic Hydromethylation and Hydroalkylation of Olefins Enabled by Titanium Dioxide Mediated Decarboxylation.

  2020cited by this paper
• Late-stage oxidative C(sp3)–H methylation

  2020cited by this paper
• Catalytic protodeboronation of pinacol boronic esters: formal anti-Markovnikov hydromethylation of alkenes

  2019cited by this paper
• Hydroalkylation of Olefins To Form Quaternary Carbons.

  2019cited by this paper
• Modular access to functionalized 5–8–5 fused ring systems via a photoinduced cycloisomerization reaction

  2018cited by this paper
• Hydromethylation of Unactivated Olefins

  2015cited by this paper
• Ausgeprägte Methyleffekte in der Wirkstoff‐Forschung und der Bedarf an neuen C‐H‐Methylierungsreaktionen

  2013cited by this paper
• Profound methyl effects in drug discovery and a call for new C-H methylation reactions.

  2013cited by this paper
• Erzeugung sekundärer, tertiärer und quartärer Zentren durch geminale Disubstitution von Carbonyl‐Sauerstoffatomen

  2011cited by this paper
• Generation of secondary, tertiary, and quaternary centers by geminal disubstitution of carbonyl oxygens.

  2011cited by this paper
• Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with Grignard reagents.

  2005cited by this paper
• A quarter of a century of explorations in organozirconium chemistry.

  2005cited by this paper
• Control of Selectivity in the Hydromethylation of Olefins via Ligand Modification in Scandocene Catalysts

  2005cited by this paper
• Scope of palladium-catalyzed alkylative ring opening.

  2004cited by this paper
• A novel class of tunable zinc reagents (RXZnCH2Y) for efficient cyclopropanation of olefins.

  2004cited by this paper
• Katalytische Markownikow‐ und Anti‐Markownikow‐Funktionalisierung von Alkenen und Alkinen

  2004cited by this paper
• Catalytic Markovnikov and anti-Markovnikov functionalization of alkenes and alkynes: recent developments and trends.

  2004cited by this paper
• Iron-catalyzed regio- and stereoselective ring opening of [2.2.1]- and [3.2.1]oxabicyclic alkenes with a Grignard reagent.

  2003cited by this paper
• Copper phosphoramidite catalyzed enantioselective ring-opening of oxabicyclic alkenes: remarkable reversal of stereocontrol.

  2002cited by this paper
• Cascade radical cyclisations leading to polycyclic diterpenes. Total synthesis of (±)-spongian-16-one

  1998cited by this paper
• Olefin Metathesis in Cyclic Ether Formation. Direct Conversion of Olefinic Esters to Cyclic Enol Ethers with Tebbe-Type Reagents

  1996cited by this paper
• Synthesis of (.+-.)-.DELTA.9,12-capnellene using titanium reagents

  1986cited by this paper
• Stereoselective total synthesis of the complement inhibitor K-76

  1985cited by this paper
• In situ preparation of (.mu.-chloro)(.mu.-methylene)bis(cyclopentadienyl)(dimethylaluminum)titanium (Tebbe's reagent)

  1985cited by this paper
• An alternate path to reductive elimination for Group IVB metals: mechanism of cyclopropane formation from titanacyclobutanes

  1984cited by this paper
• A titanium vinylidene route to substituted allenes

  1983cited by this paper
• Cp2TiCH2 complexes in synthetic applications

  1983cited by this paper
• ESR study of a paramagnetic titanium methylene complex and of its reactions with olefins

  1982cited by this paper
• KINETICS AND STEREOCHEMISTRY OF THE TITANACYCLOBUTANE-TITANAETHYLENE INTERCONVERSION. INVESTIGATION OF A DEGENERATE OLEFIN METATHESIS REACTION

  1982cited by this paper
• 1,3-Dimetallacyclobutanes in metal-methylidene dimerization reactions

  1981cited by this paper
• Titanium-mediated methylene-transfer reactions. Direct conversion of esters into vinyl ethers

  1980cited by this paper
• Titanium metallacarbene-metallacyclobutane reactions: stepwise metathesis

  1980cited by this paper
• Alkyl groups migration from tetra-alkyl-silanes, -germanes, and -stannanes to carbenium ions, effected by Lewis acids: a novel method for synthesising hydrocarbons with a quaternary carbon atom

  1980cited by this paper
• Olefin homologation with titanium methylene compounds

  1978cited by this paper

• Direct ketone cyclopropanation enabled by Tebbe's reagent

  2026cites this paper
• Synthesis of the 3,3'-bipyrrole scaffold from diyne.

  2025cites this paper
• Enantioselective Total Synthesis of (+)-Fusicoccadiene via Photocatalytic Polyene Isomerization.

  2025cites this paper
• Non-enzymatic methylcyclization of alkenes

  2025cites this paper
• Access to 3-Azetidines via Halogenation of Titanacyclobutanes.

  2024cites this paper
• Chromium(III)-Catalyzed Desymmetrization of meso-Epoxides via Remote Stereocontrol: Synthesis of Chiral Fluorenes Bearing All-Carbon Quaternary Stereocenters.

  2024cites this paper
• Engaging Alkenes in Metallaphotoredox: A Triple Catalytic, Radical Sorting Approach to Olefin-Alcohol Cross-Coupling.

  2024cites this paper
• Regio- and Enantioselective Hydromethylation of 3-Pyrrolines and Glycals Enabled by Cobalt Catalysis

  2024cites this paper
• Practical and regioselective halonitrooxylation of olefins to access β-halonitrates

  2024cites this paper
• Constructing All-Carbon Quaternary Centers from Ketones via Titanacyclobutanes: Rapid Access to Azaspiro[3. n ]alkanes

  2023cites this paper
• Multigram synthesis of β-fluorinated saturated heterocyclic methanamines

  2023cites this paper
• Enantioselective Syntheses of Wickerols A and B

  2023cites this paper
• Enantioselective hydromethylation of unfunctionalized olefins with copper-hydride catalysis

  2022cites this paper
• Transition Metal–(μ-Cl)–Aluminum Bonding in α-Olefin and Diene Chemistry

  2022cites this paper
• Copper Hydride-Catalyzed Enantioselective Olefin Hydromethylation.

  2022cites this paper
• Halogen-atom and group transfer reactivity enabled by hydrogen tunneling

  2022cites this paper
• Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis

  2022cites this paper