10.1002/chem.201904717
Chemistry - A European Journal
COMMUNICATION
Based on the experimental results, a plausible mechanism is
proposed in Scheme 3 (eq 4). The -ketoacid and the amine
couple to afford iminoacid intermediate A, before the addition of
TBHP to the highly electrophilic imino group occurs. The
resulting tetrahedral intermediate B could then be converted into
the desired amide under concomitant release of carbon dioxide
and t-butyl alcohol.
Keywords: peroxides • decarboxylation • α-ketoacids • amides •
peptides
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In summary, we have described a novel decarboxylative
acylation reaction for aliphatic and aromatic amines, which
employs -ketoacids as acylating agents. The formation of the
amide bond proceeds, in contrast to previously reported
acylation reactions, under mild conditions and exhibits unique
chemoselectivity. Taking advantage of these characteristic
features allowed efficiently synthesizing complex amides
including peptides and amide analogues of bioactive molecules.
The obtained results demonstrate the synthetic potential of this
approach for the chemoselective late-stage amidation of
complex amines in total synthesis and the chemical ligation of
peptides. We are currently exploring further applications of this
strategy and investigating mechanistic details of the
transformation.
In previous reports on the photo-induced decarboxylative amidation of
aliphatic amines, low yields were observed despite the use of a large
excess (5–10 equiv.) of aliphatic amines; for details, see refs. 8a and 8b.
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[11] In contrast to the TBHP-mediated acylation conditions, photo-mediated
decarboxylative amidations are inhibited by the addition of
stoichiometric amount of TEMPO; for details, see: ref. 8b.
a
[12] The addition of 1 equiv. of AcOH did not have influence on the control
experiment. This results could exclude the possibility that an acid
accelerates the oxidation of amines. See Supporting Information for
details.
[13] KAHA ligation was reported to proceed effectively at approximately 40
ºC. Conversely, the TBHP-mediated acylation proceeds even at 0 ºC.
This result corroborates that the amidation does not proceed via an
amine oxidation followed by KAHA ligation.
Acknowledgements
This work was supported by JSPS KAKENHI grants
JP16H06384 and JP18K14865. The authors gratefully
acknowledge the Japan Science Society for a Sasakawa
Scientific Research Grant.
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