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. 2019 May 17;21(10):3813-3816.
doi: 10.1021/acs.orglett.9b01258. Epub 2019 Apr 25.

Pd-Catalyzed Alkene Difunctionalization Reactions of Malonate Nucleophiles: Synthesis of Substituted Cyclopentanes via Alkene Aryl-Alkylation and Akenyl-Alkylation

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

Pd-Catalyzed Alkene Difunctionalization Reactions of Malonate Nucleophiles: Synthesis of Substituted Cyclopentanes via Alkene Aryl-Alkylation and Akenyl-Alkylation

Derick R White et al. Org Lett. .

Abstract

The Pd-catalyzed coupling of malonate nucleophiles with alkenes bearing tethered aryl or alkenyl triflates is described. These alkene difunctionalization reactions afford malonate-substituted cyclopentanes that contain fused aryl or cycloalkenyl rings. The transformations generate a five-membered ring, two C-C bonds, and provide products bearing up to three stereocenters with good chemical yield and generally high diastereoselectivity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Prior Studies
Scheme 2.
Scheme 2.. Reactions of Aryl Triflatesa,b,c
aConditions: 1.0 equiv 4, 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 3.
Scheme 3.. Reactions of Alkenyl Triflatesa,b,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. eThe reaction was conducted using 2.2 equiv of LiOtBu and 3.6 equiv of diethyl malonate, a substrate concentration of 0.8 M. fThe reaction was conducted using S-Phos as ligand. gThe reaction was conducted using Pd(acac)2 in place of Pd(OAc)2. hThe reaction was conducted in xylenes solvent at 110 °C.
Scheme 4.
Scheme 4.
Reactions of Other Activated Methylene Nucleophiles
Scheme 5.
Scheme 5.
Proposed Mechanism
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References

    1. For a review, see:

    2. Dhungana RK; KC S; Basnet P; Giri R Chem. Rec 2018, 18, 1314. - PubMed

    3. For selected recent examples, see

    4. KC S; Basnet P; Thapa S; Shrestha B; Giri R J. Org. Chem 2018, 83, 2920. - PubMed
    5. Kuang Y; Wang X; Anthony D; Diao T Chem. Commun 2018, 54, 2558. - PubMed
    6. Wang K; Ding Z; Zhou Z; Kong W J. Am. Chem. Soc 2018, 140, 12364. - PubMed
    7. Basnet P; Dhungana RK; Thapa S; Shrestha B; KC S; Sears JM; Giri R J. Am. Chem. Soc 2018, 140, 7782. - PubMed
    8. Derosa J; Tran VT; Boulous MN; Chen JS; Engle KM J. Am. Chem. Soc 2017, 139, 10657. - PubMed
    9. Derosa J; van der Puyl VA; Tran VT; Liu M; Engle KM Chem. Sci 2018, 9, 5278. - PMC - PubMed
    10. Liu Z; Zeng T; Yang KS; Engle KM J. Am. Chem. Soc 2016, 138, 15122. - PubMed
    11. Kirsch JK; Manske JL; Wolfe JP J. Org. Chem 2018, 83, 13568. - PMC - PubMed
    1. White DR; Hutt JT; Wolfe JP J. Am. Chem. Soc 2015, 137, 11246. - PMC - PubMed
    2. White DR; Wolfe JP Chem. Eur. J 2017, 23, 5419. - PubMed
    1. White DR; Herman MI; Wolfe JP Org. Lett 2017, 19, 4311. - PubMed
    1. Iwata C; Kubota H; Yamada M; Takemoto Y; Uchida S; Tanaka T; Imanishi T Tetrahedron Lett. 1984, 25, 3339.
    2. Iwata C; Takemoto Y; Kubota H Kuroda T; Imanishi T Tetrahedron Lett. 1985, 26, 3231.
    3. Muraoka M; Toshio N; Sugie A; Ono K; Yamamoto M US Patent 4,680,307, 1987.

    1. Related 2-cyclopentylacetic acid derivatives that would derive from saponification and decarboxylation of the products have also found utility as synthetic intermediates. For representative examples, see:

    2. Taber DF; Paquette CM; J. Org. Chem 2014, 79, 3410. - PubMed
    3. Srikrishna A; Beerahah B Tetrahedron Lett. 2007, 48, 2291.

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