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. 2023 Apr 10;14(21):5650-5655.
doi: 10.1039/d3sc01072d. eCollection 2023 May 31.

Synthesis of spirooxindoles via formal acetylene insertion into a common palladacycle intermediate

Xavier Abel-Snape  1 , Colton E Johnson  1 , Bianca Imbriaco  1 , Mark Lautens  1
Affiliations

Synthesis of spirooxindoles via formal acetylene insertion into a common palladacycle intermediate

Xavier Abel-Snape et al. Chem Sci. .

Abstract

A palladium-catalyzed spirocyclization reaction is reported, which is proposed to arise via insertion of an oxabicycle into a palladacycle, formed from carbocyclization and a C-H functionalization sequence. Mechanistic studies suggest the insertion is diastereoselective and a post-catalytic retro-Diels-Alder step furnishes an alkene, wherein the oxibicycle has served as an acetylene surrogate. Aryl iodides and carbamoyl chlorides were compatible as starting materials under the same reaction conditions, enabling the convergent and complementary synthesis of spirooxindoles, as well as other azacycles. These spirooxindoles allowed further transformations that were previously unaccessible.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. (I) Palladium-catalyzed spirocyclizations via remote C–H activation. (II) Palladium-catalyzed synthesis of indenes and benzofulvenes using an oxabicycle as an acetylene surrogate.
Scheme 2
Scheme 2. Spirooxindoles synthesized from aryl iodides. Reactions were performed on a 0.2 mmol scale; isolated yields are shown. aReaction was performed on a 1 mmol scale.
Scheme 3
Scheme 3. Spirooxindoles synthesized from carbamoyl chlorides. Reactions were performed on a 0.2 mmol scale; isolated yields are shown.
Scheme 4
Scheme 4. Synthesis of analogous azacycles. (I) Spirocyclic pyrroline. (II) Dihydrobenzoindolone. (III) Indolo[2,1-a]isoquinolinone. Reactions were performed on a 0.2 mmol scale; isolated yields are shown.
Scheme 5
Scheme 5. Mechanistic studies. (I) Isolation of pre-retro-Diels–Alder intermediates 3a* and 3g*. (II) Confirmation of 3a* as a precursor to 3a. (III) Insertion of an oxabicycle that cannot undergo a retro-Diels–Alder step. (IV) Palladacycle 3i-Pd as a competent intermediate in the catalytic cycle. (V) KIE experiment. Reactions were performed on a 0.2 mmol scale; isolated yields are shown. aYield was determined by 1H NMR spectroscopic analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard. bReaction was performed on a 0.1 mmol scale.
Scheme 6
Scheme 6. Proposed mechanism.
Scheme 7
Scheme 7. Derivatizations. (I) Ketene [2 + 2] cycloaddition then dehalogenation. (II) Epoxidation. (III) Epoxide ring opening with sodium azide. (IV) Hydrogenation. (V) Iron-catalyzed Wacker oxidation. Reactions were performed on a 0.15 mmol scale; isolated yields are shown. aReaction was performed on a 0.029 mmol scale.
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References

    1. For select reviews on transition-metal catalyzed C–H functionalization methodologies see:

    2. Alberico D. Scott M. E. Lautens M. Chem. Rev. 2007;107:174. doi: 10.1021/cr0509760. - DOI - PubMed
    3. Thansandote P. Lautens M. Chem. - Eur. J. 2009;15:5874. doi: 10.1002/chem.200900281. - DOI - PubMed
    4. McMurray L. O'Hara F. Gaunt M. J. Chem. Soc. Rev. 2011;40:1885. doi: 10.1039/C1CS15013H. - DOI - PubMed
    5. Baudoin O. Chem. Soc. Rev. 2011;40:4902. doi: 10.1039/C1CS15058H. - DOI - PubMed
    6. Liu C. Yuan J. Gao M. Tang S. Li W. Shi R. Lei A. Chem. Rev. 2015;115:12138. doi: 10.1021/cr500431s. - DOI - PubMed
    7. Hartwig J. F. J. Am. Chem. Soc. 2016;138:2. doi: 10.1021/jacs.5b08707. - DOI - PMC - PubMed
    8. Xue X.-S. Ji P. Zhou B. Cheng J.-P. Chem. Rev. 2017;117:8622. doi: 10.1021/acs.chemrev.6b00664. - DOI - PubMed
    9. Font M. Gulías M. Mascareñas J. L. Angew. Chem., Int. Ed. 2022;61:e202112848. doi: 10.1002/anie.202112848. - DOI - PMC - PubMed
    10. Dutta S. Chatterjee S. Al-Thabaiti S. A. Bawaked S. Mokhtar M. Maiti D. Chem Catal. 2022;2:1046. doi: 10.1016/j.checat.2022.03.027. - DOI
    11. Lu M.-Z., Goh J., Maraswami M., Jia Z., Tian J.-S. and Loh T.-P., Chem. Rev., 2022, 122, 17479. - PubMed

    1. For select reviews on palladium-catalyzed C–H activation methodologies see:

    2. Chen X. Engle K. M. Wang D.-H. Yu J.-Q. Angew. Chem., Int. Ed. 2009;48:5094. doi: 10.1002/anie.200806273. - DOI - PMC - PubMed
    3. Lyons T. W. Sanford M. S. Chem. Rev. 2010;110:1147. doi: 10.1021/cr900184e. - DOI - PMC - PubMed
    4. Shaikkh T. M. Hong F.-E. J. Organomet. Chem. 2016;801:139. doi: 10.1016/j.jorganchem.2015.10.022. - DOI
    5. Wang J. Dong G. Chem. Rev. 2019;119:7478. doi: 10.1021/acs.chemrev.9b00079. - DOI - PMC - PubMed

    1. For reports of Pd catalyzed domino-Heck syntheses of spirocycles resulting from direct C–C reductive elimination see:

    2. Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Nat. Chem. 2017;9:361. doi: 10.1038/nchem.2631. - DOI - PubMed
    3. Marchese A. D. Durant A. G. Lautens M. Org. Lett. 2022;24:95. doi: 10.1021/acs.orglett.1c03682. - DOI - PubMed
    4. Xu B. Ji D. Wu L. Zhou L. Liu Y. Zhang Z.-M. Zhang J. Chem. 2022;8:836. doi: 10.1016/j.chempr.2021.12.019. - DOI

    1. For reports of Pd catalyzed domino-Heck syntheses of spirocycles resulting from insertion of an external reagent into a palladacycle intermediate see:

    2. Zheng H. Zhu Y. Shi Y. Angew. Chem., Int. Ed. 2014;53:11280. doi: 10.1002/anie.201405365. - DOI - PMC - PubMed
    3. Pérez-Gómez M. García-López J.-A. Angew. Chem., Int. Ed. 2016;55:14389. doi: 10.1002/anie.201607976. - DOI - PubMed
    4. Yoon H. Lossouarn A. Landau F. Lautens M. Org. Lett. 2016;18:6324. doi: 10.1021/acs.orglett.6b03213. - DOI - PubMed
    5. Pérez-Gómez M. Hernández-Ponte S. Bautista D. García-López J.-A. Chem. Commun. 2017;53:2842. doi: 10.1039/C7CC00065K. - DOI - PubMed
    6. Shao C. Wu Z. Ji X. Zhou B. Zhang Y. Chem. Commun. 2017;53:10429. doi: 10.1039/C7CC06196J. - DOI - PubMed
    7. Yoon H. Rölz M. Landau F. Lautens M. Angew. Chem., Int. Ed. 2017;56:10920. doi: 10.1002/anie.201706325. - DOI - PubMed
    8. Xiao G. Chen L. Deng G. Liu J. Liang Y. Tetrahedron Lett. 2018;59:1836. doi: 10.1016/j.tetlet.2018.03.086. - DOI
    9. Ye F. Ge Y. Spannenberg A. Neumann H. Beller M. Nat. Commun. 2020;11:5383. doi: 10.1038/s41467-020-19110-3. - DOI - PMC - PubMed
    10. Ma J. Liu T.-X. Zhang P. Zhang C. Zhang G. Chem. Commun. 2021;57:49. doi: 10.1039/D0CC07143A. - DOI - PubMed
    11. Xu Y. Xu W. Chen X. Luo X. Lu H. Zhang M. Yang X. Deng G. Liang Y. Yang Y. Chem. Sci. 2021;12:11756. doi: 10.1039/D1SC03487A. - DOI - PMC - PubMed
    1. Franzoni I. Yoon H. García-López J.-A. Poblador-Bahamonde A. I. Lautens M. Chem. Sci. 2018;9:1496. doi: 10.1039/C7SC04709F. - DOI - PMC - PubMed