Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Aug 16;23(8):1610-1630.
doi: 10.1021/acs.oprd.9b00248. Epub 2019 Jul 30.

Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for the Synthesis of Substituted Bicyclic Cyclopentanes

Evan C Bornowski  1 , Elsa M Hinds  1 , Derick R White  1 , Yusuke Nakamura  1 , John P Wolfe  1
Affiliations

Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for the Synthesis of Substituted Bicyclic Cyclopentanes

Evan C Bornowski et al. Org Process Res Dev. .

Abstract

Palladium-catalyzed alkene difunctionalization reactions between alkenes bearing tethered aryl or alkenyl triflates and enolate nucleophiles are described. The transformations form two C-C bonds, a ring, and up to two stereocenters, while producing substituted cyclopentane derivatives that contain appended carbonyl functionality. Products are formed with up to >20:1 diastereoselectivity, and formation of sterically congested bonds between quaternary carbon atoms is feasible.

Keywords: Alkene Difunctionalization; Cross-Coupling; Palladium; Stereoselective.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Scheme 1.
Scheme 1.. Prior Studies
Scheme 2.
Scheme 2.. Reactions of Aryl Triflates with Malonatesa–c
aConditions: 1.0 equiv 1, 1.2 equiv diethyl malonate, 1.4 equiv LiOtBu, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1–0.25 mmol scale. bDiastereomeric ratios were determined by 1H NMR analysis. Diastereomeric ratios were identical for crude reaction mixtures and isolated compounds unless otherwise noted. cYields are average isolated yields of two or more experiments. dThe reaction was conducted using RuPhos as ligand.
Scheme 3.
Scheme 3.. Reactions of Alkenyl Triflates Bearing Terminal Alkenes with Malonatesa–c
aConditions: 1.0 equiv 5, 1.2 equiv diethyl malonate, 1.4 equiv LiOtBu, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1–0.25 mmol scale. bDiastereomeric ratios were determined by 1H NMR analysis. Diastereomeric ratios were identical for crude reaction mixtures and isolated compounds unless otherwise noted. cYields are average isolated yields of two or more experiments. dThe reaction was conducted using (BrettPhos)Pd(allyl)(Cl) in place of Pd(OAc)2. eThe reaction was conducted using 2.2 equiv of LiOtBu and 3.6 equiv of diethyl malonate, a substrate concentration of 0.8 M, and a reaction temperature of 65 °C.
Scheme 4.
Scheme 4.. Optimization of the Reaction Between 1l and Diethyl Malonatea
aConditions: 1.0 equiv 1l, 2.0 equiv diethyl malonate, 4 mol% Pd, 6 mol % ligand, 2.2 equiv LiOtBu, toluene (0.8 M), 95 °C, 14 h. bIsolated yield (average of two or more experiments). cDiastereomeric ratios were determined by 1H NMR analysis. dLiHMDS was used as a base instead of LiOtBu. eThe yield was determined by 1H NMR analysis of the crude reaction mixture using phenanthrene as an internal standard.
Scheme 5.
Scheme 5.. Reactions of Alkenyl Triflates Bearing Internal Alkenes with Malonatesa–c
aConditions: 1.0 equiv 1, 3.6 equiv diethyl malonate, 2.2 equiv LiOtBu, 4 mol % Pd(acac)2, 6 mol % SPhos, toluene (0.8 M), 95 °C, 14 h. Reactions were conducted on a 0.2 mmol scale. bDiastereomeric ratios were determined by 1H NMR analysis. Diastereomeric ratios were identical for crude reaction mixtures and isolated compounds unless otherwise noted. cYields are average isolated yields of two or more experiments. dThe reaction was conducted in xylenes solvent at 110 °C.
Scheme 6.
Scheme 6.. Reactions of Other Doubly Activated Nucleophiles a–c
Scheme 7.
Scheme 7.. Reactions of Ester Nucleophilesa–c
aConditions: 1.0 equiv triflate substrate, 1.2 equiv ester, 2.2 equiv LiHMDS, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1–0.25 mmol scale. bDiastereomeric ratios were determined by 1H NMR analysis. Diastereomeric ratios were identical for crude reaction mixtures and isolated compounds unless otherwise noted. cYields are average isolated yields of two or more experiments. dRuPhos was used in place of BrettPhos as the ligand.
Scheme 8.
Scheme 8.. Reactions of Ketone Nucleophilesa
aConditions: 1.0 equiv triflate substrate, 1.2 equiv ketone, 1.4 equiv LiHMDS, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1–0.25 mmol scale. bDiastereomeric ratios were determined by 1H NMR analysis. Diastereomeric ratios were identical for crude reaction mixtures and isolated compounds unless otherwise noted. cYields are average isolated yields of two or more experiments. dThe reaction was conducted with 2.6 equiv of the ketone.
Scheme 9.
Scheme 9.. Mechanism and Relative Stereochemistry
See this image and copyright information in PMC

References

    1. For recent reviews, see:

    2. Dhungana RK; KC S; Basnet P; Giri R Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins. Chem. Rec 2018, 18, 1314. - PubMed
    3. Garlets ZJ; White DR; Wolfe JP Recent Developments in Pd0-Catalyzed Alkene Carboheterofunctionalization Reactions. Asian. J. Org. Chem 2017, 6, 636. - PMC - PubMed
    4. Kaur N; Wu F; Alom N-E; Ariyarathna JP; Saluga SJ; Li W Intermolecular Alkene Difunctionalizations for the Synthesis of Saturated Heterocycles. Org. Biomol. Chem 2019, 17, 1643. - PubMed
    5. Chemler SR; Karyakarte SD; Khoder ZM Stereoselective and Regioselective Synthesis of Heterocycles via Copper-Catalyzed Additions of Amine Derivatives and Alcohols to Alkenes. J. Org. Chem 2017, 82, 11311. - PMC - PubMed
    6. Yin G; Mu X; Liu G Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond Forming at a High-Valent Palladium Center. Acc. Chem. Res 2016, 49, 2413. - PubMed
    7. Muniz K; Martinez C Development of Intramolecular Vicinal Diamination of Alkenes: From Palladium to Bromine Catalysis. J. Org. Chem 2013, 78, 2168. - PubMed
    8. Balme G; Bouyssi D; Monteiro N Palladium-Mediated Cascade or Multicomponent Reactions: A New Route to Carbo- and Heterocyclic Compounds. Pure. Appl. Chem 2006, 78, 231.

    1. For selected recent examples that form two C–C bonds, see:

    2. KC S; Basnet P; Thapa S; Shrestha B; Giri R Ni-Catalyzed Regioselective Dicarbofunctionalization of Unactivated Olefins by Tandem Cyclization/Cross-Coupling and Application to the Concise Synthesis of Lignan Natural Products. J. Org. Chem 2018, 83, 2920. - PubMed
    3. Kuang Y; Wang X; Anthony D; Diao T Ni-Catalyzed two-Component Reductive Dicarbofunctionalization of Alkenes via Radical Cyclization. Chem. Commun 2018, 54, 2558. - PubMed
    4. Wang K; Ding Z; Zhou Z; Kong W Ni-Catalyzed Enantioselective Reductive Diarylation of Activated Alkenes by Domino Cyclization/Cross-Coupling. J. Am. Chem. Soc 2018, 140, 12364. - PubMed
    5. Basnet P; Dhungana RK; Thapa S; Shrestha B; KC S; Sears JM; Giri R Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones. J. Am. Chem. Soc 2018, 140, 7782. - PubMed
    6. Derosa J; Tran VT; Boulous MN; Chen JS; Engle KM Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling. J. Am. Chem. Soc 2017, 139, 10657. - PubMed
    7. Derosa J; van der Puyl VA; Tran VT; Liu M; Engle KM Direct Nickel-Catalyzed 1,2-Dialkylation of Alkenyl Carbonyl Compounds Chem. Sci 2018, 9, 5278. - PMC - PubMed
    8. Liu Z; Zeng T; Yang KS; Engle KM β,γ-Vicinal Dicarbofunctionalization of Alkenyl Compounds via Directed Nucleopalladation. J. Am. Chem. Soc 2016, 138, 15122. - PubMed

    9. For related transformations between aryl halide and malonates bearing tethered alkenes, see:

    10. Balme G; Bouyssi D; Faure R; Gore J; Van Hemelryck B Formation de Cyclopentans a Partier de Malonates δ-Ethyeniques par un Processus Catalytique en Palladium(0) Stereochemie et Mecanisme. Tetrahedron 1992, 48, 3891.
    1. White DR; Hutt JT; Wolfe JP Asymmetric Pd-Catalyzed Alkene Carboamination Reactions for the Synthesis of 2-Aminoindane Derivatives. J. Am. Chem. Soc 2015, 137, 11246. - PMC - PubMed
    2. White DR; Wolfe JP Stereocontrolled Synthesis of Amino-Substituted Carbocycles by Pd-Catalyzed Alkene Carboamination Reactions. Chem. Eur. J 2017, 23, 5419. - PubMed
    1. White DR; Herman MI; Wolfe JP Palladium-Catalyzed Alkene Carboalkoxylation Reactions of Phenols and Alcohols for the Synthesis of Carbocycles. Org. Lett 2017, 19, 4311. - PubMed
    1. Kirsch JK; Manske JL; Wolfe JP Pd-Catalyzed Alkene Carboheteroarylation Reactions for the Synthesis of 3-Cyclopentylindole Derivatives. J. Org. Chem 2018, 83, 13568. - PMC - PubMed

LinkOut - more resources