Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

doi:10.26434/chemrxiv.12408839

Paper

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

Published Jun 3, 2020 · Antonin Clemenceau, Pierre Thesmar, Maxime Gicquel

Journal of the American Chemical Society

Q1 SJR score

29

Citations

0

Influential Citations

Full textSemantic Scholar

Abstract

Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds in a single step has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.

Study Snapshot

This study demonstrates a facile synthesis of cyclopropanes using gem-dialkyl groups and the 1,4-Pd shift mechanism, leading to diverse arylcyclopropanes and the anti-insomnia drug lemborexant.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

Sign up to use Study Snapshot

References

Diverse functionalization of strong alkyl C–H bonds by undirected borylation

The iridium catalyst ligated with 2-methylphenanthroline enables selective borylation of primary carbon-hydrogen bonds, enabling diverse functionalization of organic molecules at previously inaccessible positions.

Palladium-catalyzed oxidation of β-C(sp3)-H bond of primary alkylamines through a rare four-membered palladacycle intermediate.

Palladium-catalyzed oxidation of primary C-H bonds to nitrogen in an aliphatic amine occurs through a rare four-membered palladacycle intermediate, with cleavage of the C-H bond being rate-limiting and stabilization crucial.

Synthetic Approaches to Contemporary Drugs that Contain the Cyclopropyl Moiety

Synthetic approaches for incorporating the cyclopropyl moiety into various drugs have evolved over time, resulting in diverse and effective drugs.

Redox-Neutral Coupling between Two C(sp3)-H Bonds Enabled by 1,4-Palladium Shift for the Synthesis of Fused Heterocycles.

This study demonstrates a redox-neutral coupling between two C(sp3)-H bonds, enabling the synthesis of valuable fused heterocycles from readily accessible ortho-bromophenol and aniline precursors.

Highly Chemoselective, Transition-Metal-Free Transamidation of Unactivated Amides and Direct Amidation of Alkyl Esters by N-C/O-C Cleavage.

This study presents a mild, highly chemoselective method for transamidation of unactivated tertiary amides and direct amidation of alkyl esters, offering new opportunities for the synthesis of pivotal amide bonds in various chemical contexts.

Palladium-Catalyzed Intermolecular [4+1] Spiroannulation by C(sp3 )-H Activation and Naphthol Dearomatization.

This novel palladium-catalyzed method allows for rapid assembly of new spirocyclic molecules with broad functional-group tolerance, using a five-membered palladacycle as the key intermediate.

Pd-Catalyzed Enantioselective Ring Opening/Cross-Coupling and Cyclopropanation of Cyclobutanones.

This method provides chiral indanones with C3-quaternary stereocenters by enantioselective ring-opening/cross-coupling and intramolecular cyclopropanation, yielding chiral cyclopropane-fused-indanones

Palladium-Catalyzed Divergent Cyclopropanation by Regioselective Solvent-Driven C(sp3 )-H Bond Activation.

The tandem palladium-catalyzed Heck/regioselective C(sp3)-H activation reaction allows for the divergent synthesis of spiro- and fused-cyclopropanated indolines from N-methallylated 2-bromoarylamide

Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed Multiple C(sp3 )-H Activation Strategy.

This study developed a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes using a cobalt-catalyzed dual C(sp3 )-H activation strategy, with potential applications in organic synthesis.

Citations

Quaternary Carbon Editing Enabled by Sequential Palladium Migration.

Sequential palladium migration enables direct editing of quaternary carbons, enabling concurrent functionalization of primary, secondary, and quaternary carbons in nonstrained acyclic molecules.

1,4-Pd Migration-Enabled Synthesis of Fused 4-Membered Rings

This study presents a novel 1,4-Pd migration-catalyzed cyclobutanation method for producing fused cyclobutanes from cycloalkenyl (pseudo)halides, offering access to various substituted bicyclo[4,2,0]oc

Pd-Catalyzed Cascade Heck/C(sp3)-H Activation for Spirocyclopropyl Oxindoles.

Pd(0)-catalyzed Heck/C(sp3)-H activation cascade efficiently synthesizes spirocyclopropyl oxindoles in high yields from ortho-bromoacrylamides, offering a valuable approach for preparing alkaloids like ()

Rh(III)‐Catalyzed Annulative Coupling of Sulfoxonium Ylides with Allyl Acetates: Generation of Bicyclo[4.1.0]heptan‐2‐ones

Rhodium(III)-catalyzed annulative coupling efficiently generates bicyclo[4.1.0] heptan2ones from sulfoxonium ylides and allyl acetates under mild conditions, making it versatile for constructing cyclopropanes

Regioselective C-H Active Carbonylation via 1,4-Palladium Migration.

This study presents a highly regioselective three-component coupling reaction for synthesizing multisubstituted,-unsaturated amides using 1,4-palladium migration, C(sp2)-H activation, carbonylation, and amination

Palladium-catalyzed α-arylation of nitroalkanes with aryl triflates through the C(sp2)−C(sp3) bond coupling

This study presents a novel and environmentally friendly method for synthesis of -arylated nitroalkanes using palladium-catalyzed cross-coupling of nitroalkanes and phenol derivatives under mild conditions, yielding 50% to 90% of the desired product.