Well-Defined, Air-Stable, and Readily Available Precatalysts for Suzuki and Buchwald-Hartwig Cross-coupling (Transamidation) of Amides and Esters by N-C/O-C Activation

Article abstract of DOI:10.1021/acs.orglett.9b01053

A general class of well-defined, air-stable, and readily available Pd(II)-NHC precatalysts (NHC = N-heterocyclic carbene) for Suzuki and Buchwald-Hartwig cross-coupling of amides (transamidation) and esters by selective N-C/O-C cleavage is reported. Since these precatalysts are highly active and the easiest to synthesize, the study clearly suggests that [Pd(NHC)(acac)Cl] should be routinely included during the development of new cross-coupling methods. An assay for in situ screening of NHC salts in this cross-coupling manifold is presented.

Full text of DOI:10.1021/acs.orglett.9b01053

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
[Pd(NHC)(acac)Cl]: Well-Defined, Air-Stable, and Readily Available
Precatalysts for Suzuki and Buchwald−Hartwig Cross-coupling
(Transamidation) of Amides and Esters by N−C/O−C Activation
Tongliang Zhou,‡ Guangchen Li,‡ Steven P. Nolan,§ and Michal Szostak*,†,‡
†College of Chemistry and Chemical Engineering and Key Laboratory of Auxiliary Chemistry and Technology for Chemical
Industry, Ministry of Education, Shaanxi University of Science and Technology, Xi’an 710021, China
‡Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
§Department of Chemistry and Center for Sustainable Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium
S
* Supporting Information
ABSTRACT: A general class of well-defined, air-stable, and
readily available Pd(II)-NHC precatalysts (NHC = N-
heterocyclic carbene) for Suzuki and Buchwald−Hartwig
cross-coupling of amides (transamidation) and esters by
selective N−C/O−C cleavage is reported. Since these
precatalysts are highly active and the easiest to synthesize, the
study clearly suggests that [Pd(NHC)(acac)Cl] should be
routinely included during the development of new cross-
coupling methods. An assay for in situ screening of NHC salts
in this cross-coupling manifold is presented.
ligand facilitates insertion of the metal into challenging
ransition-metal-catalyzed cross-coupling of amides by N−
TC activation has emerged as a powerful method for C(acyl)−X bonds.15 The flexible steric bulk of the NHC ligand
promoting the reductive elimination step as well as mild reaction
conditions in the absence of strong bases have played a central
role in the production of high value structural motifs by N−C
and O−C activations.16 To date, two general classes of Pd(II)−
NHC precatalysts have been developed for the cross-coupling of
C(acyl)−X bonds, namely, [Pd(NHC)(allyl)Cl] complexes,
bearing an allyl-type throw-away ligand,17 and Pd−PEPPSI-type
complexes,18 bearing N-heterocycles as the throw-away ligand.
Herein, we report the third class of Pd(II)−NHC precatalysts
for the cross-coupling of amides and esters (Figure 1B). Since
these precatalysts are highly active, general, and among the
easiest to synthesize from the corresponding NHC salts, the
study clearly suggests that [Pd(NHC)(acac)Cl] should be
routinely included during the development of new cross-
coupling methods of bench-stable amide and ester electrophiles.
We demonstrate that these well-defined, air-stable, and readily
available [Pd(NHC)(acac)Cl] precatalysts promote Suzuki4,11
and Buchwald−Hartwig19,20 cross-coupling of amides (trans-
amidation) and esters with exquisite selectivity at the C(acyl)−
X (X = N, O) bond. A broad range of CO electrophiles as well
as functional groups and sterically hindered amines are tolerated
in this process. Crucially, we present an assay for in situ screening
of NHC salts in this cross-coupling manifold,21 which should
significantly facilitate the development of improved catalysts for
N−C/O−C cross-coupling. Overall, the study should lead to
functionalization of the classically considered inert amide bonds
of key significance in pharmaceuticals and natural products
(Figure 1A).1−10 Studies have demonstrated close similarities of
the amide and ester cross-coupling manifolds initiated by an
oxidative addition of a low-valent metal into C(acyl)−X (X = N,
O) bond, permitting to generalize the cross-coupling plat-
form.11,12
The key advance in the area was identification of strongly σ-
donating Pd-NHC precatalysts,13,14 wherein the NHC ancillary
Figure 1. (a) Amides as new electrophiles in cross-coupling reactions.
(b) This work: [Pd(NHC)(acac)Cl] general catalysts for N−C/O−C
activation.
Received: March 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01053
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Letter
further advances in important N−C/O−C cross-coupling
reactions of unconventional amide and ester electrophiles.
Notable features of our study include: (1) the present class of
catalysts is the easiest to synthesize from the corresponding
NHC salts, and (2) the use of acac throw-away ligand permits to
in situ screen NHC salts in this cross-coupling manifold, which is
not possible with any other throw-away ligands. Given that these
catalysts are highly active, robust, and air-stable, these
precatalysts should be routinely included in screening of the
best catalysts for amide and ester cross-coupling.
Scheme 1. Scope of the [Pd(IPr)(acac)Cl]-catalyzed Suzuki−
a b
,
Miyaura Cross-coupling of Amides
In the context of amide bond activation, our laboratory has
introduced strategies that allow for the direct functional group
interconversion of amides enabled by selective metal insertion
into the N−C bond.2−4 Guided by the rational design of Pd-
NHC catalysts, we hypothesized that the use of [Pd(NHC)-
(acac)Cl] precatalysts in conjunction with the facile synthesis of
these complexes might allow for the general access to acyl-Pd
intermediates by C(acyl)−X (X = N, O) bond activation. Since
the synthesis of [Pd(NHC)(acac)Cl] proceeds in a single, high-
yielding, scalable, and operationally convenient step (Figure
2),22a,b,c these catalysts offer a key practical advantage, cf. other
Figure 2. Facile synthesis of well-defined, air-stable [Pd(NHC)(acac)-
Cl].
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (3.0 equiv), [Pd] (3
Pd(II)−NHCs. The very simple synthesis of [Pd(NHC)(acac)-
Cl] results from a facile displacement of a κ2-O,O-bound acac
from the Pd(acac)2 precursor (routinely, >90−95% yield).
After extensive optimization, we found that the Suzuki−
Miyaura cross-coupling of a model N-Ph/Boc amide 1a
activated by the N-carbamate group (RE = 7.2 kcal/mol, τ =
29.1°, χN = 8.4°; RE = resonance energy; τ = twist angle, χN =
nitrogen pyramidalization angle)23 occurs in 89% yield using
[Pd(IPr)(acac)Cl] (3 mol %) as a precatalyst (K2CO3, 3 equiv,
THF, 110 °C) (eq 1).
b
mol %), K2CO3 (3.0 equiv), THF (0.25 M), 110 °C, 16 h. Isolated
yields. See Supporting Information (SI) for details.
(3a), electron-rich (3b−c), and electronically deactivated
boronic acids (3d). Furthermore, steric-hindrance (3e), meta-
substitution (3f), and boronic acids bearing electrophilic groups
(3g) that would not be easily tolerated in the classic Weinreb
ketone synthesis are tolerated. Moreover, fluorinated boronic
acids (3h−i) and heterocyclic boronic acids (3j) serve as
competent partners in this cross-coupling. The scope of the
amide component is similarly broad and includes electronically
diverse (3c′−d′), sterically hindered (3e′), heterocyclic amides
(3k), and amides bearing electrophilic groups (3g′). At present,
halides are not compatible with the Pd-NHC catalysis. Studies
are in progress to develop new classes of catalysts that allow
cross-coupling in the presence of halides.
We were pleased to find that this readily available precatalyst
is compatible with a broad range of amide precursors (Scheme 2,
1g−k).14 The generality of the coupling bodes well for its future
applications in organic synthesis.
To further expand the potential utility of [Pd(IPr)(acac)Cl]
precatalyst, we examined its utility in the acyl-Buchwald−
Hartwig coupling by N−C bond activation (transamidation)
(Scheme 3).20 The rich variety of amides in medicinal chemistry
and natural products has made the development of trans-
amidation methods an intense research area.24 Acyl Buchwald−
Hartwig cross-coupling provides a powerful and unconventional
approach to amide transamidation,25 employing challenging less
nucleophilic amines. We found that [Pd(IPr)(acac)Cl] is a
highly effective precatalyst for this reaction (Scheme 3). As
Importantly, the cleavage of the N-activating group was not
observed, consistent with the mild reaction conditions and the
high reactivity of the [Pd(IPr)(acac)Cl] precatalyst. It should be
noted that Pd-phosphane catalysts are not compatible with the
direct activation of the amide bond in the synthetically useful N-
Boc amides,13 which effectively serve as 2° amide equivalents.
Optimization revealed increase of the reaction yield with
increasing the amount of base and boronic acid, consistent
with the rate-limiting transmetalation. Note that the base and
boronic acid are soluble under the reaction conditions. Other
bases, including Na2CO3 and K3PO4, were less effective.
With the optimum conditions in hand, the scope of the
Suzuki−Miyaura cross-coupling was next evaluated (Scheme 1).
As shown, the reaction is compatible with a broad range of
electronically diverse boronic acids, including electron-neutral
B
DOI: 10.1021/acs.orglett.9b01053
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Letter
variety of amides (Scheme 4, 1g−k), attesting to the generality
of the coupling.
Scheme 2. Amide Scope in the [Pd(IPr)(acac)Cl]-catalyzed
Cross-coupling
a
Scheme 4. Amide Scope in the [Pd(IPr)(acac)Cl]-catalyzed
a
Buchwald−Hartwig Cross-coupling of Amides
a
See Scheme 1.
Scheme 3. Scope of the [Pd(IPr)(acac)Cl]-catalyzed
Buchwald−Hartwig Cross-coupling of Amides
a b
,
a
See Scheme 2.
To further explore the utility of [Pd(IPr)(acac)Cl], we
investigated the Suzuki and Buchwald−Hartwig cross-coupling
of a representative phenolic ester (Scheme 5).11,12,20 We were
pleased to find that this catalyst can also be used for a catalytic
ester to ketone and ester to amide interconversion.
Scheme 5. Suzuki−Miyaura and Buchwald−Hartwig Cross-
Coupling of Esters using [Pd(IPr)(acac)Cl]
Kinetic profiling studies were performed to assess the
performance of [Pd(IPr)(acac)Cl] in the Suzuki and
Buchwald−Hartwig cross-coupling of amides (Scheme 6).
Studies demonstrated facile activation under the developed
conditions in both reactions (Suzuki: 10 min, 60% yield; 30 min,
75% yield; Buchwald-Hartwig: 30 min, 72% yield; 60 min, 77%
yield). Turnover numbers (TON) of 570 and 410 were
determined for the cross-coupling of amide 1a in the Suzuki
a
Conditions: amide (1.0 equiv), amine (2.0 equiv), [Pd] (3 mol %),
b
K2CO3 (3.0 equiv), DME (0.25 M), 110 °C, 16 h. Isolated yields.
shown, this precatalyst demonstrates broad compatibility.
Electronically diverse (5a−c) and sterically hindered anilines
(5d−f), including the extremely bulky 2,6-disubstituted aniline
(5e) as well as N,N-disubstituted anilines (5f) and bulky
primary amines (5g) readily participate in the coupling.
Furthermore, the reaction is compatible with biologically
relevant carbazoles (5h), sulfonamides (5i), and 2-amino-
biphenyls (5j). As a distinguishing feature of the mild Pd-NHC
catalysis platform, electrophilic functional groups such as esters
and sulfonamides are compatible. It is worth noting that the
coupling of both electronically deactivated (5k) and amides
bearing electrophilic functional groups (5l) is achieved by this
method.
Scheme 6. Determination of TON in the Cross-Coupling
using [Pd(IPr)(acac)Cl]
Pleasingly, the survey of amide precursors revealed that
[Pd(IPr)(acac)Cl] effectively promotes the amidation of a
C
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(4-MeO-C6H4-B(OH)2, [Pd(IPr)(acac)Cl], 0.10 mol %) and
Buchwald−Hartwig (4-anisidine, [Pd(IPr)(acac)Cl], 0.10 mol
%) reactions under the standard conditions, indicating high
reactivity of the complex. This reactivity can be compared with
allyl-type precatalysts [(Pd(IPr)(cin)Cl] (Suzuki: 10 min, 79%;
30 min, 92%; Buchwald-Hartwig: 30 min, 79%; 60 min, 87%).
While the higher temperature is needed for precatalyst
activation, these conditions employ mild carbonate base and
are carried out in the absence of water, which does not lead to
the formation of hydroxides in the reaction.17g
Scheme 8. In Situ Screening of NHC Salts in Buchwald−
Hartwig Coupling of Amides Using [Pd(NHC)(acac)Cl]
A key advantage of [Pd(NHC)(acac)Cl] precatalysts hinges
upon their facile synthesis (Figure 2). Accordingly, we
hypothesized that the acac precatalyst platform might be
deployed to rapidly evaluate the influence of the NHC by use
of their salt precursors in the acyl cross-coupling without
preforming of Pd(II)−NHC precatalysts in a separate step.22 As
shown, rapid evaluation of a small subset of NHC salts revealed
that IPr and IMes are the preferred NHC ligands for the Suzuki
cross-coupling (Scheme 7), while saturated SIPr, aliphatic ItBu,
ICy, and bulky IPr* are less preferred.
of NHC salts, which should significantly facilitate the develop-
ment of optimized cross-coupling protocols of acyl electrophiles.
The study vividly demonstrates that the class of [Pd(NHC)-
(acac)Cl] catalysts should be routinely considered in the
development of C(acyl)−X cross-coupling reactions.
Scheme 7. In Situ Screening of NHC Salts in Suzuki−Miyaura
Coupling of Amides Using [Pd(NHC)(acac)Cl]
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01053.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Steven P. Nolan: 0000-0001-9024-2035
Michal Szostak: 0000-0002-9650-9690
Notes
Likewise, IPr, IMes, and SIPr were identified as the most
effective NHC ligands in the Buchwald−Hartwig cross-coupling
(Scheme 8) with ItBu, ICy, and IPr* resulting in diminished
yields. Note that control experiments against well-defined
[Pd(IPr)(acac)Cl] (91% yield, Suzuki-Miyaura; 86% yield,
amination) demonstrate that the difference in catalytic perform-
ance is very small. Allyl-based precatalysts cannot be used for in
situ screening due to less efficient Pd-NHC formation.17 We
believe this rapid screening assay should significantly facilitate
the development of ligands and improved protocols for C−X
acyl bond activation.
In summary, we have reported a general class of well-defined,
air-stable, and readily synthesized [Pd(NHC)(acac)Cl] pre-
catalysts for Suzuki−Miyaura and Buchwald−Hartwig cross-
coupling of amides (transamidation) and esters by selective N−
C/O−C cleavage. These Pd(II)−NHC precatalysts are highly
reactive and among the easiest to synthesize from the
corresponding NHC salts. A broad range of amides, boronic
acids, and anilines, including those with electrophilic groups,
were coupled in high yields and with high cleavage selectivity.
Crucially, we have developed an in situ assay for rapid screening
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz
spectrometer was supported by the NSF-MRI grant (CHE-
1229030). For work performed in Ghent, VLAIO (SBO project
CO2PERATE) is gratefully acknowledged for partial support.
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F
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