Organic Letters
Letter
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subjected to the reaction conditions. The increased acidity of 26
appears to be responsible for the decomposition: deprotonation
of 26 with NaH resulted in amination to form the deacylated
indole 27.25 While deprotonation rescued the reactivity of 26,
deprotonation of 4-pyridyl 12d did not result in N-heterocycle
formation using palladium and CO. Since the use of an α-4-
pyridyl group should not preclude an ene-reaction, we interpret
this data as evidence that sp3-C−N bond formation does not
occur through an ene-reaction and that a bidentate chelation of
the pyridyl group and the carboxylate to the metal ion (or
proton) is critical for bond formation.
In conclusion, we have developed a palladium-catalyzed
reductive cyclization of nitroarenes that converts a sp3-C−H
bond to a sp3-C−N bond. By constructing the C−N bond
through nucleophile attack onto a nitrosoarene catalytic
intermediate, this reaction is mechanistically distinct from C−
H bond amination reactions to enable synthesis of a variety of
ring sizes and N-heterocycles by simply changing the identity of
the nucleophile and tether length. Our future investigations will
further probe the synthetic potential of each class of initially
explored nucleophiles to define the fundamental electrophilicity
of the nitrosoarene intermediate.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
Ruck-Braun, K. J. Org. Chem. 2005, 70, 2350.
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Experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
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Corresponding Author
ORCID
Author Contributions
(9) (a) Cenini, S.; Ragaini, F.; Tollari, S.; Paone, D. J. Am. Chem. Soc.
1996, 118, 11964. (b) Srivastava, R. S.; Nicholas, K. M. Chem. Commun.
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S.; Brignoli, D.; Gasperini, M.; Gallo, E. J. Org. Chem. 2003, 68, 460.
(e) Formenti, D.; Ferretti, F.; Ragaini, F. ChemCatChem 2018, 10, 148.
(10) (a) Jana, N.; Zhou, F.; Driver, T. G. J. Am. Chem. Soc. 2015, 137,
6738. (b) Shevlin, M.; Guan, X.; Driver, T. G. ACS Catal. 2017, 7, 5518.
(c) Zhou, F.; Wang, D.-S.; Guan, X.; Driver, T. G. Angew. Chem., Int. Ed.
2017, 56, 4530.
The manuscript was written through the contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(11) Åkerbladh, L.; Odell, L. R.; Larhed, M. Synlett 2019, 30, 141.
(12) Wehman, P.; Borst, L.; Kamer, P. C. J.; Leeuwen, P. W. N. M. V.
Chem. Ber. 1997, 130, 13.
(13) In ref 12, van Leeuwen and co-workers reported that the TOF of
(phen)2Pd(OTf)2 diminished from 241 mol/mol h to 47 mol/mol h
when the F3C group was moved from the para-position to the ortho-
position.
(14) In contrast, exposure of α-cyano- or α-nitro-substituted
carboxylates to reaction conditions resulted in decomposition.
(15) For a discussion of the scope and limitations of SnCl2-mediated
reductive cyclization of difuryl-substituted nitroarenes, see: Uchuskin,
M. G.; Molodtsova, N. V.; Abaev, V. T.; Trushkov, I. V.; Butin, A. V.
Tetrahedron 2012, 68, 4252.
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Chem., Int. Ed. Engl. 1993, 32, 1638. (b) Paul, F.; Fischer, J.;
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We are grateful to the National Science Foundation (No. CHE-
1564959) for their generous financial support. I.A. thanks the
DAAD scholarship program for support. We thank Mr. Furong
Sun (UIUC) for HRMS data.
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