Paper
Having established a successful dehydrative N-benzyla-
RSC Advances
Notes and references
tion strategy, we compared the catalytic activity of our p-
benzylpalladium catalyst system with other efficient systems
(Scheme 8). While the Pd(0)/TPPMS-catalyzed reaction in
heptane proceeded to completion within 4 h (see Table 1), the
previous borrowing hydrogen protocols10c,20 resulted in no
reaction. Furthermore, the Pd-catalyzed reaction in water
(our previous work)7b was not effective (only 40% yield),
clearly demonstrating the superiority of the present catalytic
strategy using heptane.
To highlight the synthetic utility, we performed the N-ben-
zylation on a gram scale (see ESI†). N-Benzylated product 3a
(1.56 g) was facilely isolated in 88% yield from pyridine
substrate 1a with alcohol 2a. The developed simple operations
also avoided the use of column chromatography for a gram
scale reaction.
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Conclusions
In summary, we report an efficient palladium-catalyzed dehydrative
N-benzylation in heptane via the borrowing hydrogen methodology.
The strategy provides an efficient method for the facile synthesis of
benzylaminopyridines, which are found in a wide variety of phar-
maceuticals. Notably, the use of a Pd(0)/TPPMS catalyst in a non-
polar heptane solvent with a trace amount of water is critical for
our catalytic system. Water molecules assist in the aggregation of
polar substrates followed by the formation of an active p-benzyl-
palladium catalyst system in heptane, which signicantly boosts the
borrowing hydrogen reaction. We expect that this study will aid in
the design of new catalytic systems using non-polar solvents, and
will serve as an entry point for reaction discovery.
Experimental
General procedure
To a sealed tube were added 2-aminopyridines 1 (1 mmol), Pd
catalyst (0.05 mmol), phosphine ligand (0.1 mmol), alcohols 2 (5
mmol) and heptane (4 mL). The resulting reaction mixture was
heated at 120 ꢀC for 17 h under air. Aer completion of the
reaction, the mixture was cooled to room temperature. The
reaction mixture was diluted with water, and then extracted
with EtOAc. The combined organic phases were washed with
brine, dried over MgSO4, and ltered and concentrated to
dryness under reduced pressure. The resulting residue was
puried by ash column chromatography on silica gel (eluent:
n-hexane/EtOAc) to obtain desired products 3.
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
AcknowledgementsThis work was supported by JSPS KAKENHI
grant number 19K07003.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 23144–23150 | 23149