10.1002/chem.202101439
Chemistry - A European Journal
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Next, we investigated the scope of the cyclohexanones using
1a as a coupling partner (Scheme 3). Cyclohexanones bearing a
methyl or phenyl group gave 3ab–3ad bearing the
corresponding aryl group in good to high yields. Polar functional
groups were also tolerated; N-arylated amino acid esters 3ae–
3ag bearing an ester, amide, or ether moiety were successfully
synthesized in high yields. These cyclohexanones, except 2-
methylcyclohexanone (2c) and 2-methoxycyclohexanone (2g),
which are sterically hindered around the carbonyl group, showed
extremely high enantiopurity (96–99% ee). While the steric
hindrance of the bulky cyclohexanones inhibited the desired
dehydrogenation step, it likely did not affect the competing
racemization reactions from the unreacted 1 or the intermediary
4 (Figure 2a), resulting in a decrease in the enantiopurity of 3.
It is noteworthy that the developed flow method could also
supply fused aryl and heteroaryl groups to the amino acid esters.
2-Tetralone reacted to afford the desired N-naphthyl product
(3ah) in high yield with 99% ee. Furthermore, N-benzylated 4-
and 3-piperidones 2i and 2j produced the 4- and 3-pyridine
derivatives 3ai and 3aj, respectively.[14] In this interesting
transformation, it is assumed that the N-pyridyl group is
introduced via consecutive condensation and dehydrogenative
aromatization involving N-debenzylation by the Pd catalyst.
Almost all the examples afforded a high yield of up to 90%, good
to excellent enantiopurity of 84–99% ee, a TOF of up to 9.7 h–1,
and an STY of up to 135 g L−1 h−1.
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Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from the New Energy and Industrial Technology
Development Organization (NEDO) project, Japan.
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Keywords: amino acids • N-arylation • continuous-flow
synthesis • cyclohexanones • heterogeneous catalysis
5
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