Journal of the American Chemical Society
Article
Author Contributions
intramolecular Friedel−Crafts-type reaction. In our initial
studies, significant amounts of cyclized products were found at
low temperatures (cf. Scheme 3c; the higher temperature
involved in the reported protocol allowed for optimal yields).
To probe the possible intermediacy of α-OTf amide 10 in this
process, we prepared it independently from the corresponding
alcohol. (See the SI for details.) As shown in Scheme 3c, this
compound was not capable of undergoing cyclization at room
temperature, in contrast with the observations made before.
Similarly, heating triflate 10 under reaction conditions akin to
our original report but in the absence of base did not deliver any
product. Under these conditions, a significant amount of
cyclized product could be isolated only when 2-iodopyridine
was present. This suggested that the product might be formed by
the displacement of the α-OTf group first by 2-iodopyridine to
form a pyridinium intermediate (a transformation made possible
at high temperature, cf., the high barriers calculated by DFT
and Figure 5), which then undergoes Friedel−Crafts cyclization.
In situ triflated α-hydroxy amide 2o underwent rapid
substitution with external nucleophiles tetrabutylammonium
iodide and sodium Ts-methylamide to afford amides 1ac and 4a,
respectively (See the SI for details).
§These authors contributed equally.
Author Contributions
⊥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous support of this research by the Fundaca
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Ciencia e Tecnologia (SFRH/BD/141844/2018 FCT fellow-
ship to C.R.G.), the University of Vienna (uni:docs fellowship to
M.L.), the FWF (Fellowship M 2274 to C.J.T.; P 30226 to
N.M.), the ERC (CoG VINCAT 682002 to N.M.), and the
Austrian Academy of Sciences (DOC fellowship to D.K.) is
acknowledged. We acknowledge Dr. M. Riomet and Ing A.
Roller (both from U. Vienna) for proofreading and X-ray
crystallography measurements. Additionally we would like to
acknowledge Hugo Lisboa for graphical design support. Calcu-
lations were partially performed at the Vienna Scientific Cluster
(VSC). We are very grateful to the University of Vienna for
continued support of our research programs.
Taken together, these findings appear to paint a picture where,
in the case of an intramolecular nucleophile, no direct C−C
bond formation can occur without the formation of a reactive
intermediate; these experimental results are in complete
accordance with the proposed theoretical calculations. In the
case of intermolecular nucleophiles, the remarkable broadness of
species successfully employed (ranging from fluoride/halides to
alkoxides, amines and amides, and thiols and enolates) suggests
that, at least for some of these nucleophiles, the formation of an
α-OTf species is the pivotal event.
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CONCLUSIONS
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We have shown that the in situ umpolung of amides enables a
truly general platform for their α-functionalization under mild
conditions. Readily available nucleophilic reagents can thus be
used for the α-halogenation, -thiolation, -oxygenation, and
-amination of amides. We have demonstrated the unique
broadness and applicability of this method, and quantum
chemical calculations confirmed experimental evidence for an
unexpected pathway wherein the α-OTf amide is an
intermediate. This helps rationalize the vast range of different
nucleophiles that are effective in this methodology.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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Experimental procedures and characterization data for all
new compounds and computational details (PDF)
2-(Methylamino)-2-(4-nitrophenyl)-3-phenyl-1-(pyrroli-
din-1-yl)propan-1-one (CIF)
AUTHOR INFORMATION
Corresponding Author
ORCID
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Amides with Alkenes or Alkynes. Angew. Chem., Int. Ed. Engl. 1981, 20,
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(12) Charette, A. B.; Mathieu, S.; Martel, J. Electrophilic Activation of
Lactams with Tf2O and Pyridine: Expedient Synthesis of ( )-Tetra-
ponerine T4. Org. Lett. 2005, 7, 5401−5404.
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