10.1002/anie.201907366
Angewandte Chemie International Edition
COMMUNICATION
Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem.
Rev. 2019, 119, 2192–2452.
a naphthalene amide (26s) was converted in high selectivity to
the ortho borylated product when using the BAIPy-Ir catalyst.
Next a peptide based aromatic amide 27s was converted with
high selectivity (conversion 85%, ortho product >94%).
Importantly, these results demonstrate the potential of this
protocol for late state functionalization of valuable peptide based
aromatic compounds.
[2]
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Finally, N-benzylthiophenecarboxamide 28s as a particular
challenging substrate was explored. Generally CH borylation is
directed to the position C5-H because of steric and electronic
effects, and the inert C3-H bond is not borylated.[13] Using the
BAIPy-Ir as catalyst we surprisingly formed 67% of the C4
borylated product, which is usually not formed at all, along with
some diborylated product in which both the C4 and C3 positions
are functionalized. Importantly, the most activated C5-H bond
remains untouched (Table 1b). The wide substrate scope
demonstrates the generality of the supramolecular approach for
ortho-selective CH borylation of aromatic amides.
We performed a gram scale CH borylation reaction using 0.4-3
mol% iridium at 60 oC (Scheme S3), forming the ortho-CH
borylated compound 1so and 12so with up to 85% isolated yield
and 123 TON. The boron functionality allows easy follow-up
chemistry to introduce various groups[2], and as one typical
example 1so was transformed into a hydroxyl group via an
oxidation-hydrolysis sequence with quantitative yield using H2O2.
Thus, this readily available supramolecular iridium catalyst is
feasible for large scale application to directly install the versatile
boron moiety on the aromatic amides.
In summary, we report a readily accessible supramolecular
iridium catalyst for ortho-selective CH borylation of valuable
secondary aromatic amides which operate via substrate pre-
organization via hydrogen bonding. Catalytic experiments with N-
methylbenzamides and aromatic amides (>26 examples)
including peptide based analogues demonstrate that this
supramolecular catalyst converts a variety of secondary aromatic
amides with a variety of functional groups at different positions on
the aromatic ring, making the strategy very general. The
supramolecular iridium catalyst has been applied at gram scale
with high conversion and selectivity at elevated temperature.
These experiments show that supramolecular substrate
orientation is a powerful approach to control the regioselectivity in
challenging CH borylation reactions.
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Acknowledgements
We acknowledge Dr. Vivek Sinha and Pim R. Linnebank for fruitful
discussions. S. Bai thanks the China Scholarship Council for a
PhD fellowship (CSC201506010269) and the RPA sustainable
chemistry of the University of Amsterdam for financial support.
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Keywords: CH Activation • Iridium catalyzed borylation • Supramolecular
substrate preorganization • secondary aromatic amides • hydrogen
bonds
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