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Catalysis Science & Technology
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ARTICLE
Journal Name
favoured to stabilize the metal sphere, before the release of Rutgers University and the NSF (CAREER CHE-1650766) are
DOI: 10.1039/C9CY02080B
KNPhCOOtBu, with a maximum kinetic cost of 15.5 kcal/mol. acknowledged for support. The 500 MHz spectrometer used in
The second substrate, i.e. the amine, then bonds to palladium this study was supported by the NSF-MRI grant (CHE-1229030).
and with a barrierless process a molecule of KHCO3 is lost to A. P. is a Serra Húnter Fellow, and thanks the Spanish MINECO
facilitate the final C-N bond formation that leads to the product. for a project PGC2018-097722-B-I00, and European Fund for
This last energy barrier has a reasonable kinetic cost that ranges Regional Development (FEDER) grant UNGI10-4E-801.
from 17.3 kcal/mol for the IMes system to 22.3 kcal/mol for
IPr*. To point out that all combinations were tested, involving
the three potential actors, i.e. the two substrates (amide and
Notes and references
amine), and the base. It was demonstrated that the lower the
sterical hindrance on the metal sphere the lower the kinetic
cost. This was checked comparing the transition state VII-VIII
that favours the release of KNPhCOOtBu with the potential
insertion of the amine previously. Even though the latter option
is thermodynamically favoured by 8.9 kcal/mol, kinetically is
disfavoured by more than 60 kcal/mol.
1
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Conclusions
3
(a) R. Marcia de Figueiredo, J. S. Suppo and J. M. Campagne,
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In summary, we have conducted a combined experimental and
computational study of the Buchwald-Hartwig cross-coupling of
amides (transamidation) using well-defined, air- and moisture-
stable [(Pd(NHC)allyl precatalysts. The two key insights drawn
from this study are (1) the comprehensive evaluation of a series
of distinct Pd(II)–NHC precatalysts featuring different NHC
scaffolds, and (2) elucidation the catalytic cycle by DFT methods
for a series of different Pd(II)–NHC precatalysts. These
transamidation reactions enable amide exchange under mild
conditions using carbonate base and non-nucleophilic anilines,
showing tolerance to sensitive functional groups that would be
difficult to accomplish using other transamidation methods. A
key practical feature is the use of bench-stable, commercially
available Pd(II)–NHC precatalysts that enable broad scope and
operational-simplicity. In a broader context, these reactions
enable access to medicinally relevant amides by selectivity
activating N–C(O) amide bonds by transition-metals. The
combination of experiments with calculations allowed the full
description of the reaction mechanism, locating the key barriers
that describe the feasibility of any palladium-allyl based catalyst
studied here. The larger the sterical hindrance of the allyl
moiety the better the catalytic performance, amazingly not for
the transition state but the reference intermediate to measure
the energy barrier.
4
5
(a) A. Mullard, Nat. Rev. Drug Discov., 2019, 18, 85; (b) L. M.
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6
Selected recent reports on amide bonds: (a) Y. Chen, A. Turlik
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,
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,
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8
L. Pauling, The Nature of the Chemical Bond, Oxford University
Press: 1940.
We expect that the facile access to NHC-supported acyl-
palladium(II) amido intermediates, the catalyst evaluation and
mechanistic details presented will enable the development of
improved catalyst systems and transamidation reactions of
bench-stable amide electrophiles by selective formation of acyl-
metals.
For selected reviews on amide activation, see: (a) S. Shi, S. P.
Nolan and M. Szostak, Acc. Chem. Res., 2018, 51, 2589; (b) G.
Meng and M. Szostak, Eur. J. Org. Chem., 2018, 20-21, 2352;
(c) R. Takise, K. Muto and J. Yamaguchi, Chem. Soc. Rev., 2017,
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For pertinent studies on ground-state-destabilization, see: (a)
R. Szostak, S. Shi, G. Meng, R. Lalancette and M. Szostak, J.
Org. Chem., 2016, 81, 8091; (b) G. Meng, S. Shi, R. Lalancette,
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Liu, S. Shi, Y. Liu, R. Liu, R. Lalancette, R. Szostak and M.
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Conflicts of interest
“There are no conflicts to declare”
10 For a review on acyl-Suzuki–Miyaura cross-coupling, see: J.
Buchspies and M. Szostak, Catalysts, 2019, , 53.
Acknowledgements
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6 | J. Name., 2012, 00, 1-3
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