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theoretical yield of 2 equivalents, cyanate ions were detected
Keywords: amides · amines · peroxides · radicals ·
reaction mechanisms
in low yield (7.6%), whereas cyanide ions were formed in
high yield (84.8%; see the Supporting Information). On the
basis of these results, we further suggest that 13 cyclizes to
form the dioxirane intermediate 14, thus releasing the first
equivalent of cyanide, after which the second equivalent of
cyanide would be generated after amine addition to the
proposed acyl cyanide 16 to give the amide product 17
(Figure 2).
Next, to support the electrophilic dioxirane intermediate
14, intramolecular thioether-trapping experiments were per-
formed in O2-saturated CH3CN, such that the reaction of the
anion 11 with molecular O2 would be independent of the
concentration of 11 [Eq. (4)].[5b] In the event, the d-ethyl-
sulfenyl b-benzyl malononitrile 20 was prepared and reacted
under dilute conditions at À208C. This reaction gave the
oxidized sulfinyl amide 22 reliably in 5% yield. The direct
oxidation of 20 or the sulfide product 21 by O2 was excluded
by additional control experiments at room temperature for
over 48 hours (see the Supporting Information).
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In summary, we have presented a new powerful way to
construct challenging amide bonds between a-substituted
malononitriles and amines under O2. The oxidative amidation
proceeds under mild reaction conditions, is highly practical,
and simply employs cheap inorganic carbonate bases. Mech-
anistic studies support an initial SET pathway between the
anion 11 of the a-substituted malononitrile and O2 (via radical
12) to form the a-peroxide adduct 13 as a precursor to the
dioxirane 14, which generates acyl cyanide (16) via the
formation and fragmentation of bis(tetrahedral) adducts 15
(Figure 2). Notably, our method does not require the for-
mation of either congested pre-oxidized hydroxy malononi-
triles as masked acyl cyanides (MAC)[3c,d,6] or congested
halogenated nitroalkanes as precursors to activated
esters,[4c,5c,d] and therefore offers good substrate scope for
sterically hindered systems. It is thus reasoned that the SET
induced addition of O2 to 11 proceeds in a relatively
unencumbered way to generate the acyl cyanide 16, which is
known to react readily with amines (or alcohols) in a mild
manner.[13] This process compares favorably to either making
and reacting acid chlorides with metal cyanides or by
activating carboxylic acids with traditional reagents (e.g.
with phosphorocyanidates).[2,14] Lastly, we anticipate this
method to find wide synthetic use in difficult N-terminal
capping amidations and throughout the chemical scien-
ces.[1,2,15]
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Acknowledgments
We thank the School of Chemistry, University of Lincoln, UK
for funding to make this article open access.
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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