General Method for the Suzuki-Miyaura Cross-Coupling of Amides Using Commercially Available, Air- and Moisture-Stable Palladium/NHC (NHC = N-Heterocyclic Carbene) Complexes

Article abstract of DOI:10.1021/acscatal.6b03616

The direct Suzuki-Miyaura cross-coupling of amides catalyzed by Pd-NHC complexes is reported. Using a single protocol, commercially available, air- and moisture-stable (NHC)Pd(R-allyl)Cl complexes can effect Suzuki-Miyaura cross-coupling of a wide range of amides with arylboronic acids in very good yields. The studies described herein represent the use of versatile Pd-NHC complexes as catalysts for transition-metal-catalyzed cross-coupling of amides by N-C bond activation. The Pd-NHC catalysts provide a significant improvement over all current Pd-PR₃ systems employed for the amide N-C bond activation. Mechanistic studies provide strong support for the development of a unified reactivity scale of the amide bond for the generation of acyl-metal intermediates.

Full text of DOI:10.1021/acscatal.6b03616

Letter
pubs.acs.org/acscatalysis
General Method for the Suzuki−Miyaura Cross-Coupling of Amides
Using Commercially Available, Air- and Moisture-Stable Palladium/
NHC (NHC = N‑Heterocyclic Carbene) Complexes
Peng Lei,‡,† Guangrong Meng,‡ and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: The direct Suzuki−Miyaura cross-coupling of
amides catalyzed by Pd-NHC complexes is reported. Using a
single protocol, commercially available, air- and moisture-
stable (NHC)Pd(R-allyl)Cl complexes can effect Suzuki−
Miyaura cross-coupling of a wide range of amides with
arylboronic acids in very good yields. The studies described
herein represent the use of versatile Pd-NHC complexes as
catalysts for transition-metal-catalyzed cross-coupling of
amides by N−C bond activation. The Pd-NHC catalysts
provide a significant improvement over all current Pd-PR3
systems employed for the amide N−C bond activation. Mechanistic studies provide strong support for the development of a
unified reactivity scale of the amide bond for the generation of acyl-metal intermediates.
KEYWORDS: palladium, N-heterocyclic carbenes (NHCs), N−C activation, Suzuki−Miyaura cross-coupling, amides
remendous progress has been made in the past years in
Tthe area of transition-metal-catalyzed cross-coupling
Figure 2. Structures of carbene ligands and Pd-NHC catalysts. (Dipp
= 2,6-diisopropylphenyl; Mes = mesityl; Cy = cyclohexyl.)
Cross-coupling of aryl electrophiles, including activation of
C−O7 and C−N bonds,8 has been extensively studied.1−3
Figure 1. Amides as electrophiles in TM catalyzed C−C cross-
There has been an increasing effort to activate alternative
coupling: attractive alternative to stoichiometric Weinreb synthesis.
carboxylic acid cross-coupling partners under oxidant-free
conditions.9 In particular, amide bond cross-coupling benefits
reactions.1 Within palladium catalysis, typically, electron-rich
from the high bench stability of the amide precursors,
biomedical relevance of the amide bond, and the ability to
tertiary phosphines have been employed as ancillary ligands to
fine-tune the electrophilic reactivity by the tricoordinate N
enable cleavage of unreactive carbon−carbon or carbon−
center unavailable in other precursors.7,10 Following the
seminal report by Garg and co-workers on the C−O bond
formation from amides,11 we and others have sought to address
the challenges posed by amidic resonance (nN → πC*O barrier
to rotation of ca. 15−20 mol/kcal in planar amides).12−19
heteroatom bonds.2 Nucleophilic N-heterocyclic carbenes
(NHCs) have been developed as another dominant direction
in the cross-coupling arena.3 Specifically, the strong σ-donation
and variable steric bulk around the metal center facilitate
oxidative addition and reductive elimination steps enabling a
range of challenging cross-couplings.4,5 However, so far,
harnessing the reactivity of Pd-NHC complexes to enable
selective cross-coupling by activation of inert C−N bonds in
amides has not been used as a strategy for organic synthesis.6
Received: December 21, 2016
Revised: January 30, 2017
© XXXX American Chemical Society
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
amide
catalyst
ligand
base
temperature, T (°C)
yield (%)
1
2
1b
1b
1b
1c
1c
1c
1a
1a
1a
1b
1c
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1a
1b
1c
1a
1b
1c
1a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
IMesHCl
IPrHCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
KF
110
110
110
110
110
110
110
110
110
60
<5
15
<5
9
3
ICyHBF4
IMesHCl
IPrHCl
4
5
16
12
61
67
57
92
94
>98
90
82
92
67
<2
<2
64
<2
<2
94
94
94
71
<5
<5
51
92
91
>98
66
92
82
6
ICyHBF4
IMesHCl
IPrHCl
7
8
9
ICyHBF4
10
11
12
13
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(allyl)Cl
60
60
80
c
14
d
80
15
80
16
17
18
19
20
80
80
80
KOH
80
NaOt-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
80
e
21
80
f
22
80
g
23
h
80
24
80
i
25
80
26
27
28
29
30
31
32
33
34
80
(IPr)Pd(allyl)Cl
80
(IPr)Pd(allyl)Cl
80
(SIPr)Pd(cinnamyl)Cl
(SIPr)Pd(cinnamyl)Cl
(SIPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
80
60
60
40
40
40
a
Conditions: amide (1.0 equiv), R-B(OH)2 (2.0 equiv), catalyst (3 mol %), K2CO3 (3.0 equiv), THF (0.25 M), T, 15 h. Entries 1−9: ligand (6
b
c
d
e
f
g
h
i
mol %), dioxane. GC/1H NMR yields. Dioxane. Toluene. Without K2CO3. K2CO3 (1.0 equiv). K2CO3 (2.0 equiv). K2CO3 (5.0 equiv). R-
B(OH)2 (1.2 equiv). 1a (N-glutarimide); 1b (N-Ts/Ph); 1c (N-Boc/Ph).
To date, three major classes of amides have emerged as
promising precursors for the development of highly selective
amide N−C bond activation reactions: N-glutarimide amides
introduced by us,13 and N-acyl-tert-butyl-carbamates (Boc) and
N-acyl-tosylamides (Ts) designed by Garg11,12 and Zou14 and
subsequently employed by others (Figure 1). Typically, the
Suzuki−Miyaura cross-coupling has been employed as a proof-
of-concept reaction to study the effects of catalyst systems,
amide precursors and reaction mechanisms to enable further
developments.20 The use of Suzuki−Miyaura cross-coupling as
a test reaction is long established;1−3 the Suzuki−Miyaura
cross-coupling ranks as an extremely powerful tool in organic
synthesis. For example, the ketone products of the acyl Suzuki−
Miyaura variant constitute a key feature of myriad of
medicinally relevant scaffolds, important natural products, and
organic materials.21 Principally, once a specific substrate/
catalyst combination has been demonstrated and the rationale
for the fundamental steps in N−C activation outlined, a large
variety of cross-coupling reactions via a given generic acyl-metal
intermediate can be expected.
Herein, we report the first direct Suzuki−Miyaura cross-
coupling of amides catalyzed by Pd-NHC complexes. Notable
features of our study include (i) the development of a single
generic catalyst system to enable cross-coupling of a wide range
of amides; (ii) the use commercially available, air- and
moisture-stable (NHC)Pd(R-allyl)Cl complexes in a single
operationally simple protocol; (iii) the first use of versatile Pd-
NHC complexes as catalysts for transition-metal-catalyzed
cross-coupling of amides by N−C bond activation; and (iv)
the development of a unified reactivity scale of the amide bond
for the generation of acyl-metal intermediates. Most
importantly, the present study demonstrates, as a “proof-of-
concept”, that Pd-NHC catalysts provide a significant improve-
ment in catalytic efficiency over all current Pd-PR3 systems
employed for the amide N−C bond activation to date,
including (i) N−C activation/cross-coupling of generic types
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Table 2. Pd-NHC-Catalyzed Suzuki−Miyaura Cross-
Table 3. Pd-NHC-Catalyzed Suzuki−Miyaura Cross-
a b
,
a b
,
Coupling of Amides: Scope of Boronic Acids
Coupling of Amides: Scope of Amides
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (2.0 equiv), [Pd] (3
mol %), K2CO3 (3.0 equiv), 60 °C, 15 h. Entries 6−10: 80 °C.
b
Isolated yields.
of amides under one set of conditions that enables kinetic
studies to correlate the reactivity of amides with geometric and
energetic properties of the amide bond; (ii) cross-coupling
under mild conditions; and (iii) high turnover numbers across
different types of amides. Given the versatility of Pd-NHC
catalysts,3−5 we expect that this study will enable the
development of a wide range of novel C−C bond cross-
coupling reactions and lead to significant improvements in
catalytic efficiency of amide bond activation platform. We
envision the use of Pd-NHC as generic catalysts in amide N−C
bond activation manifolds.
Recently, in parallel with studies by others, our laboratory
introduced new protocols for the direct activation of
amides,11−17 exploiting ground-state destabilization18,19 to
achieve synthetically valuable cross-coupling selectivity.7
Seeking to advance the concept, we recognized the limitations
of Pd/PR3 catalyst systems.3−5 Our initial efforts focused on the
use of in situ-generated Pd-NHC complexes.3−5 Three major
types of amidesnamely, N-glutarimide (1a), N-acyl-Ts (1b),
a
Conditions: amide (1.0 equiv), Ar−B(OH)2 (2.0 equiv), [Pd] (3
b
mol %), K2CO3 (3.0 equiv),T, 15 h. Isolated yields. c110 °C. d[Pd] (6
mol %). 60 °C.
e
and N-acyl-Boc (1c) amideswere selected for the study to
probe the effects of electronic destabilization18a,b on the
reactivity. Note that, to date, the selected amides are the only
types of acyclic amides that undergo successful Suzuki cross-
coupling with organometallics by N−C bond cleavage;22 our
group reported a Pd/PCy3 system for cross-coupling of amides
(1a),13a,b the Garg group reported a Ni/NHC system for the
cross-coupling of N-Boc/R amides (1c),12a while Zou reported
a Pd/PCy3 system at 110 °C for the cross-coupling of N-Ts/R
amides (1b).14 The initial screening validated our hypothesis
that Pd-NHC complexes (Figure 2) can be employed as
catalysts for amide N−C cross-coupling (Table 1, entries 1−9);
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further improvement in the catalytic efficiency of the system.
One equivalent of base is sufficient to achieve good coupling
efficiency (Table 1, entries 21−24). Moreover, the use of an
almost-stoichiometric amount of boronic acid leads to efficient
coupling, providing an entry point for further reaction
development (entry 25). Interestingly, (IPr)Pd(allyl)Cl pro-
vided inferior results (Table 1, entries 26−28), which is
consistent with the importance of a more-facile activation of the
precatalyst.23a As anticipated, (SIPr)Pd(cinnamyl)Cl showed
similar reactivity to (IPr)Pd(cinnamyl)Cl in the reaction (Table
1, entries 29−31).23a,b Finally, good to excellent efficiency was
observed at 40 °C with all three amide substrates (Table 1,
entries 32−34). Overall, these results provide a strong entry
point to the development of the N−C amide bond activation at
room temperature. Note that, under the optimized conditions,
cleavage of the alternative σ(C−N) bond25 was not observed in
any of the three substrates.
Figure 3. Kinetic profile of amides 1a−1c in the Suzuki−Miyaura
cross-coupling with 4-tolylboronic acid catalyzed by (IPr)Pd-
(cinnamyl)Cl (3 mol %) at 60 °C.
The high activity of the Pd-NHC is unprecedented in the
amide N−C bond cross-coupling.11−18 We have previously
attempted cross-coupling of amide (1b) at 60 °C using our
optimized Pd/PCy3 system, leading to quantitative recovery of
the amide.13 Moreover, attempted cross-coupling of amide (1c)
using Pd/PCy3 at 60 °C resulted in amide recovery.
Scheme 1. Generalized Reactivity Scale of Amides for TM-
Catalyzed N−C Metal Insertion
a
Next, the scope of the reaction was systematically
investigated with the focus on electronic and steric properties
of the boronic acid (Table 2) and amide cross-coupling
partners (Table 3). Generally, excellent yields of the cross-
coupling products were obtained for electron-neutral, sterically
demanding, electron-rich, and electron-deficient arylboronic
acids across all amides examined (Table 2, entries 1−15). As
shown, the reaction was exceptionally tolerant of the
substitution on the amide component (see Table 3). The
electronic nature of the amide was found to have minimal
impact on the reaction efficiency, tolerating both strongly
electron-donating (3d, 3h) and strongly electron-withdrawing
substrates (3f, 3g). Ortho-steric substitution was well-
accommodated (3b, 3i). As a testament to the high efficiency
of the catalytic system, strongly electron-donating five-
membered heterocycles, such as thiophene (3j) and furan
(3k), substituted at the conjugating 2-position, were well-
tolerated. The reactions of electronically deactivated amides
were conducted at 110 °C to obtain optimum results.
Moreover, the reaction provided high yields for the cross-
coupling of N-alkyl/Ts and N-alkyl/Boc-substituted amides,
further demonstrating generality of the catalyst system. Prior to
this work, these substrates were found unreactive using Pd
systems.13,14
Kinetic studies were performed to evaluate the relative
reactivity of amides 1a−1c undergoing the cross-coupling
(Figure 3). The reaction of amide (1a) gave full conversion
after ∼30 min. By contrast, using amide (1a) under our
optimized Pd/PR3 conditions resulted in a ca. 50% conversion
after 2 h at 60 °C.13 Initial rates revealed the following order of
reactivity of amides 1a−1c: (1a) (νinitial = 4.0 × 10−1 mM s−1) >
(1c) (νinitial = 7.5 × 10−2 mM s−1) > (1b) (νinitial = 4.0 × 10−2
mM s−1).
a
Note that N-Boc/alkyl and N-Ts-alkyl amides are unreactive using
Pd-PR3 systems thus far. Er = resonance energy.
however, the observed efficiency was inadequate. The beneficial
selectivity using IPr vs IMes was noted (Table 1, entries 1, 2, 4,
and 5). We then turned our attention to (NHC)Pd(R-allyl)Cl
complexes developed by Nolan and co-workers.23 These well-
defined, commercially available Pd-NHC precatalysts allow to
use a strict 1:1 Pd/NHC ratio, are moisture- and air-stable, and
can be activated to give the monoligated Pd(0) under mild
conditions.24 The improved reactivity of (NHC)Pd(R-allyl)Cl
complexes, compared to alternative complexes, results from the
ease of activation to give an active Pd(0) species and
maintaining a strict 1:1 ligand:metal ratio.23a
We were delighted to find, after extensive optimization of the
reaction conditions, that the use of (IPr)Pd(cinnamyl)Cl
afforded the desired cross-coupling product with excellent
efficiency, using all three amide precursors at temperatures as
low as 60 °C (Table 1, entries 10−12). Several results in the
optimization studies are worth noting. The reaction showed
strong dependence on the base used, with K2CO3, Cs2CO3, and
KOH providing the best results, while KF, K3PO4, and NaOt-
Bu were completely ineffective (Table 1, entries 16−20).
Screening with amide (1b) was routinely performed at 80 °C.
This temperature leads to slight improvement in the catalytic
efficiency. The amide bond activation in (1b) is more
challenging than in (1a) and (1c)18a (vide infra, mechanistic
studies). The ability to employ different bases may allow for
Turnover numbers (TON) of 870, 740, and 850 were
determined for the cross-coupling of amides 1a−1c ((IPr)Pd-
(cinnamyl)Cl, 0.10 mol %, 110 °C). This is, by far, the highest
TON determined for Pd-catalyzed amide N−C activation
reported to date.11−18 Overall, these results clearly demonstrate
that Pd-NHC complexes might enable a range of practical
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In summary, we have described the first direct Suzuki−
Miyaura cross-coupling of amides catalyzed by Pd-NHC
complexes. The cross-coupling of different classes of amides
is promoted by a single, commercially available, air- and
moisture-stable (NHC)Pd(R-allyl)Cl precatalyst. The versatile
method shows broad scope, with respect to both the boronic
acid and amide components. The Pd-NHC catalysts described
show a substantial improvement over Pd-PR3 systems
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properties of Pd-NHC complexes render them attractive
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scale of the amide bond for the generation of acyl-metal
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b03616.
■
S
Procedures and analytical data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Guangrong Meng: 0000-0002-3023-0654
Michal Szostak: 0000-0002-9650-9690
■
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Rev. 2016, 45, 1257−1272. (c) See ref 6.
Present Address
†Department of Applied Chemistry, College of Science, China
Agricultural University, Beijing 100193, PRC.
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Author Contributions
‡Both authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The 500
MHz spectrometer used in this study was supported by the
NSF-MRI (Grant No. CHE-1229030). P.L. thanks the China
Scholarship Council (No. 201606350069) for a fellowship.
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