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. 2025 Aug 22;90(33):11910-11922.
doi: 10.1021/acs.joc.5c01392. Epub 2025 Aug 7.

Deconstructing α-Amidoalkyl Sulfones as Dual d-Sulfonyl/ a-Azomethine Synthons: Synthesis of 3-Sulfonylmethylindole Aminals

Guillermo Domínguez  1 , Anje Mujika  1 , Iker Hernández  1 , Vadim A Soloshonok  1   2 , Aitor Landa  1 , Mikel Oiarbide  1
Affiliations

Deconstructing α-Amidoalkyl Sulfones as Dual d-Sulfonyl/ a-Azomethine Synthons: Synthesis of 3-Sulfonylmethylindole Aminals

Guillermo Domínguez et al. J Org Chem. .

Abstract

α-Amido sulfones (1) are widely applied as electrophilic aminoalkylation reagents. However, nonproductive sulfinate species are formed alongside. Here, we report that ethyl propiolate-promoted coupling of 1 and gramines provides 3-sulfonylmethylindole aminals II smoothly, thus establishing α-amido sulfones as dual donor/acceptor reagents with full atom incorporation on the target molecule. Simple adjustment of reactants loading allows one to revert the reaction outcome, leading to exclusive formation of 3-sulfonylmethylindoles I instead.

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Figures

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1
α-Amido sulfones as ambifunctional reagents.
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1. Scope of the Reaction Leading to 3-Arenesulfonylmethyl (aza)­indoles 13/16
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2. α-Amido Sulfones as Dual Donor/Acceptor Reagents
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3. Control Experiments
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2
Variation of 1H NMR NH peaks as a function of temperature for (a) gramine 8a alone, (b) sulfone 13aa alone, and (c) equimolar admix of 8a and 13aa (taken in DMSO-d 6; ΔT intervals = 5 K). Equations of δ (ppm) vs ΔT straight lines: (a) δ = 11.98–0.003721ΔT; (b) δ = 11.99–0.002936ΔT; and (c) δ1 = 12.09–0.00289296ΔT, δ2 = 12.67–0.00243207ΔT.
4
4. Plausible Reaction Pathway
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References

    1. Engberts J. B. F. N., Strating J.. The Mannich condensation of sulfinic acids, aldehyde, and ethyl carbamate II: The use of higher aldehydes. Recl. Trav. Chim. Pays-Bas. 1965;84:942–950. doi: 10.1002/recl.19650840714. - DOI
    2. Pearson W. H., Lindbeck A. C., Kampf J. W.. Configurational stability of chiral, nonconjugated nitrogen-substituted organolithium compounds generated by tin-lithium exchange of N-[(1-tri-n-butylstannyl)­alkyl]­imidazolidin-2-ones and -oxazolidin-2-ones. J. Am. Chem. Soc. 1993;115:2622–2636. doi: 10.1021/ja00060a011. - DOI
    3. Kanazawa A. M., Denis J.-N., Greene A. E.. Highly Stereocontrolled and Efficient Preparation of the Protected, Esterification-Ready Docetaxel (Taxotere) Side Chain. J. Org. Chem. 1994;59:1238–1240. doi: 10.1021/jo00085a004. - DOI
    1. Petrini M.. α-Amido Sulfones as Stable Precursors of Reactive N-Acylimino Derivatives. Chem. Rev. 2005;105:3949–3977. doi: 10.1021/cr050528s. - DOI - PubMed
    2. Marcantoni E., Palmieri A., Petrini M.. Recent synthetic applications of α-amido sulfones as precursors of N-acylimino derivatives. Org. Chem. Front. 2019;6:2142–2182. doi: 10.1039/C9QO00196D. - DOI

    1. Selected examples:

    2. Blay G., Girón R. M., Montesinos-Magraner M., Pedro J. R.. Leaving Group and Regioselectivity Switches in the Aminoalkylation Reaction of Indoles and Related Heterocycles with α-Amido Sulfones. Eur. J. Org. Chem. 2013;2013:3885–3895. doi: 10.1002/ejoc.201300369. - DOI
    3. Monleón A., Montesinos-Magraner M., Sanz-Marco A., Blay G., Pedro J. R.. Three-Component Synthesis of α-Aminoperoxides Using Primary and Secondary Dialkylzinc Reagents with O2 and α-Amido Sulfones. Org. Lett. 2020;22:5380–5384. doi: 10.1021/acs.orglett.0c01692. - DOI - PubMed
    4. Gbubele J. D., Misiaszek T., Siczek M., Olszewski T. K.. α-Amido sulphones as useful intermediates in the preparation of C-chiral α-aminophosphonates and α-aminophosphonic acids. Org. Biomol. Chem. 2023;21:6180–6191. doi: 10.1039/D3OB00924F. - DOI - PubMed

    1. Catalytic asymmetric variants (selected examples):

    2. Gomez-Bengoa E., Linden A., López R., Múgica-Mendiola I., Oiarbide M., Palomo C.. Asymmetric Aza-Henry Reaction Under Phase Transfer Catalysis: An Experimental and Theoretical Study. J. Am. Chem. Soc. 2008;130:7955–7966. doi: 10.1021/ja800253z. - DOI - PubMed
    3. Park S. Y., Liu Y., Oh J. S., Kweon Y. K., Jeong Y. B., Duan M., Tan Y., Lee J.-W., Yan H., Song C. E.. Asymmetric Aminalization via Cation-Binding Catalysis. Chem. - Eur. J. 2018;24:1020–1025. doi: 10.1002/chem.201703800. - DOI - PubMed
    4. Serusi L., Palombi L., Pierri G., Di Mola A., Massa A.. Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)­isoindolin-1-ones from α-Amido Sulfones. J. Org. Chem. 2022;87:8420–8428. doi: 10.1021/acs.joc.2c00518. - DOI - PMC - PubMed
    1. Ballini R., Palmieri A., Petrini P., Torregiani E.. Solventless Clay-Promoted Friedel-Crafts Reaction of Indoles with α-Amido Sulfones: Unexpected Synthesis of 3-(1-Arylsulfonylalkyl) Indoles. Org. Lett. 2006;8:4093–4096. doi: 10.1021/ol061604w. - DOI - PubMed

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