Organic Letters
Letter
Based on these results, we hypothesized an unexpected set of
mechanistic pathways (Scheme 5). For the Pummerer
cyclization and unearthed two new and/or underutilized
reaction pathways for acylated sulfoxides. These pathways
expand the tolerated functionalities on the aromatic ring system
as well as the substitution pattern near the sulfoxide moiety. The
discovery of the acyl oxonium ion pathway should provide the
synthetic community with access to a highly reactive electro-
philic moiety which will enable its further exploration. In the
following paper, we detail our application of these discoveries to
the efficient, enantioselective total synthesis of multiple
members of the abietane diterpenoids.20
Scheme 5. Plausible Explanation for Observed Products via
the Vinyl Sulfide and Acyl Oxonium Ion Pathways
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
Complete experimental details (PDF)
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Prof. Claudia Maier (OSU) and Jeff Morre (OSU) are
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acknowledged for mass spectra data. The authors are grateful
to Prof. Paul Ha-Yeon Cheong (OSU), Subir Goswami (OSU),
Maxson Richards (OSU), Michael Standen (Valliscor), and Dr.
Roger Hanselmann (Akebia Therapeutics) for their assistance
and helpful discussions. Financial support has been provided by
the National Science Foundation (CHE-1665246) and Oregon
State University.
cyclization that yields the tricyclic sulfide 9a, the acylated
sulfoxide fragmentation to a sulfonium ion is initially trapped as
the traditional Pummerer product 15a. This acetate 15a is
unstable due to the presence of β-hydrogens and undergoes
elimination to form the vinyl sulfide 8a. Upon addition of the
BF3·Et2O, the Lewis-enhanced Brønsted acidity regenerates the
thionium ion while sequestering the TFA counterion. This
combination of reagents enables formation of the key carbon−
carbon bond via electrophilic aromatic substitution. In contrast,
treatment of the traditional Pummerer product 15a with BF3·
Et2O prior to elimination to the vinyl sulfide 8a induces the
unexpected ionization of the sulfide moiety to generate the
highly reactive acylated oxonium ion 10. The preferential
ionization of the carbon−sulfur bond may be driven by initial
complexation of the Lewis acid with the more Lewis basic sulfur
lone pair, which sufficiently weakens the carbon−sulfur bond to
facilitate its cleavage. This acylated oxonium ion rapidly
undergoes electrophilic aromatic substitution to generate the
tricyclic trifluoroacetate 17a. Not surprisingly, the benzylic
trifluoroacetate 17a has a limited lifetime under the reaction
conditions and undergoes subsequent elimination to produce
the observed tricycle 11a. Overall, we have demonstrated that
careful control of reaction conditions can alter the fate of the
initial α-trifluoroacetoxy phenylsulfide 15a, enabling ultimate
cleavage of either (a) the C−OTFA bond to generate a thionium
ion (using Brønsted-acid-catalyzed elimination followed by
Lewis-enhanced Bronsted acid protonation of the vinyl sulfide
moiety) or (b) the C−SPh bond to generate to an acylated
oxonium ion (using Lewis acid complexation of the sulfur lone
pair).
REFERENCES
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(1) (a) Trost, B. M.; Rao, M. Angew. Chem., Int. Ed. 2015, 54, 5026−
5043. (b) Sipos, G.; Drinkel, E. E.; Dorta, R. Chem. Soc. Rev. 2015, 44,
3834−3860.
(2) (a) De Lucchi, O.; Miotti, U.; Modena, G. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1991; Vol. 40, pp 157−405.
(b) Feldman, K. S. Tetrahedron 2006, 62, 5003−5034.
(3) (a) Colomer, I.; Velado, M.; Fernandez de la Pradilla, R.; Viso, A.
Chem. Rev. 2017, 117, 14201−14243. (b) Xiao, X.; Zhao, Y.; Shu, P.;
Zhao, X.; Liu, Y.; Sun, J.; Zhang, Q.; Zeng, J.; Wan, Q. J. Am. Chem. Soc.
2016, 138, 13402−13407.
(4) (a) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002,
124, 766−767. (b) Grennberg, H.; Gogoll, A.; Backvall, J.-E. J. Org.
Chem. 1991, 56, 5808−5811.
(5) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346−
1347.
(6) For a recent review, see: Pulis, A. P.; Procter, D. J. Angew. Chem.,
Int. Ed. 2016, 55, 9842−9860.
(7) (a) Pummerer, R. Ber. Dtsch. Chem. Ges. 1909, 42, 2282−2291.
(b) Pummerer, R. Ber. Dtsch. Chem. Ges. 1910, 43, 1401−1412.
(8) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J. Angew.
Chem., Int. Ed. 2010, 49, 5832−5844.
(9) Selected examples of carbon−heteroatom bond formation in the
Pummerer reaction: (a) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104,
2401−2432. (b) Kobayashi, S.; Ishii, A.; Toyota, M. Synlett 2008, 2008,
1086−1090. (c) Feldman, K. S.; Fodor, M. D. J. Am. Chem. Soc. 2008,
130, 14964−14965. (d) Feldman, K. S.; Fodor, M. D. J. Org. Chem.
In summary, we have unearthed novel reaction parameters
which have both expanded the scope of the Pummerer
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