sphere (balloon), and a high degree of isotope incorporation
into the amide product was observed (Δ þ 83; Table 1, entry 6).
This is suggestive of an aerobic pathway that diverts from
Scheme 1, 7, and the intermediate peroxide (Scheme 1, 9) can
fragment to amide and the elements of bromonium nitrate.
Together, each pathway explains why water is not necessarily re-
quired as a reagent but may be a helpful additive by promoting
nitrite hydrolysis (anaerobic) or formation of nitrate or (potas-
sium) hypobromite (aerobic).
Conclusions
In summary, we have identified two pathways to amide product
from the putative tetrahedral intermediate formed in UmAS. The
pathway is highly dependent on the nature of the atmosphere
above the solution. When degassed and stirred under argon, the
nitro oxygen serves as the primary source of oxygen in the amide
product. If the solution is instead stirred under an atmosphere of
oxygen, nearly all of the amide oxygen can result from gaseous
oxygen. This mechanistic picture also rationalizes our earlier
observation that amide is still produced when measures are taken
to use anhydrous conditions for UmAS. In this case, particularly
with the anaerobic variant, the isomerization to nitrite can still
occur, and amine (or carbonate) can serve the role of nitrosyl
acceptor. Aside from the clearer picture this study provides for
further reaction optimization and development, we have demon-
strated that 18O-labeled amides can be prepared conveniently
using UmAS by the straightforward supply of 18O2 as an atmo-
sphere during an otherwise standard coupling with amine.
In an effort to devise a direct preparation of 18O-labeled
amides, we developed an experimental preparation that favors
the aerobic pathway to amide. Two key modifications were made:
1) solutions of the reactants were degassed by freeze-pump-thaw
cycles, and 2) the final cycle was finished by drawing 18O2 into the
head space of the vial. To minimize overall cost, a vial was used to
maintain a small volume without unduly limiting the solution’s
contact with the labeled oxygen atmosphere. (The SI Appendix
provides a description of the experiment as well as a picture
of the experimental setup.) Application of this protocol to a series
of couplings provided labeled amides (Table 2, 11a–f) with a high
degree of enrichment (65–93%; Table 2), as well as site-selectivity
(Table 2, entries 4–6). Although it is likely that higher levels
of incorporation could be achieved using techniques to further
enrich the solvent with labeled oxygen, or a vessel pressurized by
oxygen, our goal was to establish the efficiency of incorporation
using an inexpensive, easily reproduced experimental setup.
ACKNOWLEDGMENTS. We would like to thank Libin Xu and Ned Porter
(Vanderbilt University) for helpful discussions and Ahmad Al-Mestarihi and
Brian Bachmann for initial access to 18O2. We are grateful to Amgen for
financial support of this work. Chiral nonracemic nitroalkane donors
were prepared with the support of the National Institutes of Health (GM
084333). J.P.S. was supported by a National Science Foundation Predoctoral
Fellowship.
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