Organic Letters
Letter
intermediate, was also critically important. Substitution of
nitrosobenzene 9 instead of the tert-butyl hydroxycarbamate 2
did not yield any product but only resulted in slow
decomposition of the nitrosobenzene. Interestingly, use of
other hydroxylamines in lieu of 2 also did not lead to the
desired product (see the SI). The use of tert-butyl nitro-
soformate has been reported for the ene-type and Diels−Alder
reactions.8 The deuterated 1,2-dimethylindole 1c was synthe-
sized to examine the potential involvement of an ene process.
Under the standard reaction conditions, no loss of the
deuterium from the C2 methyl group was observed on the
basis of 1H NMR analysis, suggesting that an ene-type reaction
of the tert-butyl nitrosoformate is likely not involved in this
reaction. Furthermore, reaction of 1,3-dimethylindole 1d
under the same conditions also did not yield any product,
returning the starting material intact. The 1,2-disubstitution
pattern seems obligatory for the success of this reaction.
Based on the observations above, we propose a plausible
mechanism for oxindole formation, as depicted in Scheme 2.
Oxidation of tert-butyl hydroxycarbamate 2 to the correspond-
ing nitroso 2a in the presence of air and Cu(I) has been
reported previously.8a,9 Reaction of 1a and 4a with 2a leads to
the common intermediate I. Subsequent loss of a proton leads
to either intermediate II or VI, the point at which the
mechanism diverges. Intermediate II presumably can be
oxidized to the radical cation III through the intermediacy of
Cu(II). Intramolecular trap of the nitrogen-centered radical,
concomitant with a proton loss, could lead to intermediate IV.
Fragmentation of this intermediate along with one-electron
reduction, mediated through Cu(I), yields the final product 3a.
Alternatively, intramolecular closure of I to the oxazetidine V
(see dashed box), concomitant with deprotonation of C3, and
cleavage of the NO bond to deliver 3a cannot be excluded.10
Returning to the point of divergence, nucleophilic attack of VI
with hydroxylamine, either through the oxygen or nitrogen
atom, leads to the oxygenated or aminated products 5a or 5aa,
respectively. As discussed above, the ratio of oxygenated to
aminated product is influenced with the amount of water
added to the reaction. This is presumably as a result of the
change in the acidity of NH and OH in the presence or
absence of water, as has been discussed previously.11
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NIH
(GM110525). We also thank Dr. Richard J Staples (Depart-
ment of Chemistry, MSU) for help with X-ray crystallography
and Prof. William D Wulff (Department of Chemistry, MSU)
for valuable discussions.
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In conclusion, we have developed a mild, tunable Cu(I)-
catalyzed indole oxidation and a selective C−H functionaliza-
tion method. This methodology features a new route to oxidize
1,2-dialkyl indoles to form oxindole frameworks. Furthermore,
a new approach for the selective C−H functionalization of
1,2,3-trialkylindoles and cyclic indoles is disclosed.
ASSOCIATED CONTENT
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