Mechanistic Study of Suzuki–Miyaura Cross-Coupling Reactions of Amides Mediated by [Pd(NHC)(allyl)Cl] Precatalysts

Article abstract of DOI:10.1002/cctc.201800511

We report a combined experimental and computational investigation of the Suzuki–Miyaura cross-coupling of amides enabled by [Pd(NHC)(allyl)Cl] precatalysts. Most crucially, mechanistic details pertaining to the Pd⁰/NHC catalytic cycle were elucidated by computational methods. Mechanistic insights shed light on the role of each ligand about the metal. Sterics play a key role in the initial activation of the catalyst. As a key insight, we have shown that water participates in the activation of the Pd-NHC catalytic system. Easier activation has led to effect room temperature cross-coupling of a broad range of amides through selective N?C bond scission under the mildest conditions reported to date. The use of sterically hindered [Pd(IPr*)(cin)Cl] reported herein for the first time in the amide cross-coupling indicates that increasing flexible steric bulk of the isopropyl wingtip groups of the NHC ligand provides a modular scaffold for promoting amide cross-coupling in high yields. The precatalytic pathway involving both NHC ligands as well as the catalytic cycle beginning from the Pd⁰ species are discussed. The mechanistic details provide insight into the amide bond twist (distortion) that leads to N?C cross-coupling reactions and is required for the efficient N?C bond activation.

Full text of DOI:10.1002/cctc.201800511

Accepted Article
Title: Mechanistic Study of Suzuki-Miyaura Cross-Coupling Reactions
of Amides Mediated by [Pd(NHC)(allyl)Cl] Precatalysts
Authors: Steven Patrick Nolan, Michal Szostak, Albert Poater, Luigi
Cavallo, Guangchen Li, Peng Lei, and Eric Casals
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201800511
Link to VoR: http://dx.doi.org/10.1002/cctc.201800511
A Journal of
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ChemCatChem
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FULL PAPER
Mechanistic Study of Suzuki-Miyaura Cross-Coupling Reactions
of Amides Mediated by [Pd(NHC)(allyl)Cl] Precatalysts
[
a]
[a]
[a],
[b]
[b],
Guangchen Li, Peng Lei, Michal Szostak, * Eric Casals-Cruañas, Albert Poater, * Luigi
Cavallo, and Steven P. Nolan[d],[e]*
[c]
Abstract: We report a combined experimental and computational
investigation of the Suzuki-Miyaura cross-coupling of amides
enabled by [Pd(NHC)(allyl)Cl] precatalysts. Most crucially,
mechanistic details pertaining to the Pd(0)/NHC catalytic cycle were
elucidated by computational methods. Mechanistic insights shed
light on the role of each ligand about the metal. Sterics play a key
role in the initial activation of the catalyst. As a key insight, we have
shown that water participates in the activation of the Pd-NHC
catalytic system. Easier activation has led to effect room
temperature cross-coupling of a broad range of amides through
selective N-C bond scission under the mildest conditions reported to
date. The use of sterically-hindered [Pd(IPr*)(cin)Cl] reported herein
for the first time in the amide cross-coupling indicates that increasing
flexible steric bulk of the isopropyl wingtip groups of the NHC ligand
provides a modular scaffold for promoting amide cross-coupling in
high yields. The precatalytic pathway involving both NHC ligands as
well as the catalytic cycle beginning from the Pd(0) species are
discussed. The mechanistic details provide insight into the amide
bond twist (distortion) that leads to N-C cross-coupling reactions and
is required for the efficient N-C bond activation.
biaryl Suzuki-Miyaura cross-coupling is now the single most
widely implemented cross-coupling method within industrial and
academic research.4 The method has reached levels of
predictability and functional group tolerance to be considered, in
some cases, as a somewhat trivial process.1–4 In contrast to
these advances, cross-couplings involving amide substrates by
selective N–C insertion have been significantly more challenging
and therefore slower to develop.5 The key problem associated
with the cross-coupling of amides lies in overcoming the large
barrier to metal insertion imposed by amidic resonance
(n
N
→*C=O conjugation, barrier to rotation in planar amides of 15-
6
20 kcal/mol). As a consequence of the bio-relevance of the
amide linkage7 and the ubiquity of amides in pharmaceuticals,
agrochemicals, polymers, functional materials and synthetic
intermediates,8 amide bond activation by transition metals is a
very active area of research.9
–13
In 2017, Szostak et al. described the first method for the Pd-
NHC catalyzed cross-coupling of amides by highly selective N–
C insertion.14 Within this catalytic manifold, it is known that Pd-
NHC complexes provide the most active catalytic system
reported to date.15 Strong -donation by the ligand facilitates
oxidative addition and flexible steric bulk stabilizes the active
catalyst and promotes reductive elimination. The NHC ligand
properties have been discussed as affecting the key elementary
steps of the cross-coupling catalytic cycle.16–19 One of the most
appealing applications of the amide Suzuki-Miyaura acyl-cross-
coupling is as Weinreb amide equivalents but with a dramatically
improved substrate scope and in a highly attractive catalytic
manner.20 The further advancement of the Pd-catalyzed Suzuki-
Miyaura cross-coupling of amides will require detailed
elucidation of the catalytic cycle, which should form the basis for
the discovery and development of new and improved catalysts.
Herein, we report a combined experimental and computational
investigation of the Suzuki-Miyaura cross-coupling of amides
enabled by [Pd(NHC)(allyl)Cl] precatalysts. This class of highly
Introduction
The Pd-catalyzed Suzuki-Miyaura cross-coupling represents
one of the most important developments in synthetic chemistry
in the last four decades.1,2 Extensive studies have enabled
tremendous advances in the cross-coupling of aryl electrophiles
in the formation of C–C bonds.3 In particular, the Pd-catalyzed
[
[
a]
b]
Guangchen Li, Peng Lei, Prof. Dr. Michal Szostak
Department of Chemistry, Rutgers University, 73 Warren Street,
Newark, New Jersey 07102, United States
Email: ms2223@newark.rutgers.edu
Eric Casals-Cruañas and Dr. Albert Poater
Institut de Química Computacional i Catàlisi and Departament de
Química, Universitat de Girona, Campus Montilivi, 17003 Girona,
Catalonia, Spain
practical Pd(II)-NHC precatalysts, introduced and extensively
developed by one of us (SPN),21 allows activation to the
monoligated Pd(0)-NHC under mild conditions.22 In this study,
mechanistic details pertaining to the Pd(0)/NHC catalytic cycle
were elucidated by computational methods. Mechanistic insights
offer explanations of the role of each ligand on the metal
together with the role of the mandatory base used to activate
the [Pd(NHC)(cin)Cl] precatalysts, where NHC = N-heterocyclic
carbene; cin = cinnamyl. The role of the steric hindrance on the
NHC ligand was explored by substituting IPr with the more
sterically demanding IPr* (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-
4-methylphenyl)imidazol-2-ylidene).17 As a key insight, we show
that water helps to activate the Pd-NHC catalytic system, which
can then enable room temperature cross-coupling of a broad
Email: albert.poater@udg.edu
[
[
c]
d]
Prof Dr Luigi Cavallo
King Abdullah University of Science & Technology, KAUST
Catalysis Center (KCC), 23955-6900 Thuwal, Saudi Arabia
Prof. Dr. Steven P. Nolan
Department of Chemistry and Center for Sustainable Chemistry,
Ghent University, Krijgslaan 281, S-3, B-9000 Ghent, Belgium
Email: Steven.Nolan@ugent.be
[
d]
Prof. Dr. Steven P. Nolan
Department of Chemistry, College of Science, King Saud University,
P. O. Box 2455, Riyadh 11451, Saudi Arabia
Supporting information for this article is given via a link at the end of
the document.
range of amides through selective N–C bond scission under the
mildest conditions reported to date.9
–14
The use of sterically-
1
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ChemCatChem
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FULL PAPER
hindered [Pd(IPr*)(cin)Cl] reported herein for the first time in the
amide cross-coupling indicates that increasing flexible steric bulk
of the isopropyl wingtip groups of the NHC ligand15 provides a
modular scaffold for promoting the amide cross-coupling in high
yields. In light of the past experiments where it was
demonstrated that terminal substitution of the allyl scaffold in
three evacuation/back filling cycles under high vacuum. Solvent
(0.25 M) and H
stirring at room temperature. After the indicated time, the
reaction mixture was diluted with CH Cl (10 mL), filtered, and
concentrated. The sample was analyzed by 1H NMR (CDCl
2
O (typically, 5.0 equiv) were added with vigorous
2
2
3
,
500 MHz) and GC-MS to obtain conversion, selectivity and yield
using internal standard and comparison with authentic samples.
Analytical sample was purified by chromatography on silica gel
(EtOAc/hexanes) for characterization purposes.9g,14a
[
Pd(NHC)(allyl)Cl] complexes results in a more facile activation
14,21
of the complex to afford the catalytic species,
the precatalytic
pathway of both NHC ligands as well as the catalytic pathway
that starts from the Pd(0) species are discussed. The
mechanistic details provide the basis to understand the amide
bond twist (distortion) that leads to N–C cross-coupling
reactions6,9–13 and that is required for the efficient N–C bond
activation. We fully expect this study will lead to the discovery of
even more effective agents for catalytic functionalization of
amides. The specific goals of our investigation were to (1)
provide insights into the Suzuki-Miyaura cross-coupling
reactions of amide substrates, and (2) explore the catalytic
pathway by Density Functional Theory (DFT) calculations. In this
manuscript we report the following new findings:
Computational Details: All DFT static calculations were
performed at the GGA level with the Gaussian09 set of
programs,23 using the BP86 functional of Becke and Perdew.24
The electronic configuration of the molecular systems was
described with the standard split-valence basis set with a
polarization function of Ahlrichs and co-workers for H, C, B, N, O
and Cl (SVP keyword in Gaussian)25 and Def2-QZVPP for K.26
For Pd we used the quasi-relativistic Stuttgart/Dresden effective
core potential,27 with an associated valence basis set (standard
SDD keywords in Gaussian09). Geometry optimizations were
carried out without symmetry constraints, and the
characterization of the stationary points was performed by
analytical frequency calculations. These frequencies were used
to calculate unscaled zero-point energies (ZPEs) as well as
thermal corrections and entropy effects at 298 K and 1 atm by
using the standard statistical mechanics relationships for an
ideal gas. Moreover, we also included the D3 Grimme pairwise
scheme to account for dispersion corrections in the geometry
optimizations.28 Energies were obtained via single-point
calculations on the BP86-optimized geometries using the M06
functional.29 In these single-point energy calculations, H, C, B,
N, O and Cl were described by using the Def2-TZVP basis set
that includes polarization functions,30 Def2-QZVPP for K,
whereas for the metal (Pd), the SDD basis set has been
employed. On top of the M06/Def2-TZVP∼sdd//BP86-
D3/SVP∼sdd energies, we added the ZPEs thermal and entropy
corrections obtained at the BP86-D3/SVP∼sdd level. In addition,
to calculate the reported Gibbs energies, we included solvent
effects of THF solution estimated with the polarizable continuous
solvation model (PCM) as implemented in Gaussian09.31
(
1) For the first time we demonstrate that water is critical for
the Suzuki-Miyaura cross-coupling of amides using Pd-
NHCs. This is a fundamental observation that will greatly
help the community to perform the amide bond cross-
coupling reactions.
(
2) For the first time, we demonstrate that sterically-bulky Pd-
NHC catalysts show similar or in some cases even higher
reactivity than Pd-IPr-type catalysts. This is a fundamental
observation that could lead to the development of even
more active precatalysts for amide bond cross-coupling
reactions.
(
3) For the first time we propose, by computational methods, a
detailed mechanism for the Suzuki-Miyaura cross-coupling
of amides using Pd-NHCs. This is a fundamental finding as
the computed mechanism helps to explain experimental
observations and will be used as a springboard to develop
even more efficient cross-coupling reactions of the amide
bond.
Furthermore, it should be clearly noted that although the initial
research focused on Pd-phosphines, Pd(II)-NHC complexes
have been shown to be the most reactive and by far the most
user-friendly catalysts in amide bond cross-coupling. Specifically,
the use of Pd(II)-NHCs permits for (i) broad generality of the
coupling; (ii) cross-coupling at low catalyst loading; (iii) reduction
of cost because 1:1 ratio of Pd:ligand is used; (iv) operational
simplicity because the catalysts are air- and moisture-stable and,
as such, can be readily applied by organic chemists.
Results and Discussion
Optimization of the Suzuki-Miyaura cross-coupling of various
amides (Table 1, 1a, N,N = glutarimide; 1b, N,N = Ph,Ts; 1c,
N,N = Ph,Boc) using [Pd(IPr)(cin)Cl] (IPr = 1,3-bis (2,6-di-iso-
propylphenyl)imiazol-2-ylidene) and [Pd(IPr*)(cin)Cl] under
anhydrous conditions demonstrated that (1) [Pd(IPr)(cin)Cl] is an
effective catalyst for the cross-coupling at 60 °C, but negligible
conversions were achieved at room temperature and (2)
Methodology
[
Pd(IPr*)(cin)Cl] is much less effective than [Pd(IPr)(cin)Cl]
under these conditions for all three standard amides examined.
It is worthwhile to note that from amides 1a-1c, most
synthetically-useful are amides 1c (N,N = Ph,Boc) due to ease
General Procedure for the Suzuki-Miyaura Cross-Coupling:
An oven-dried vial equipped with a stir bar was charged with an
amide substrate (1.0 equiv, 0.10 mmol), base (3.0 equiv, 0.30
mmol), boronic acid (2.0 equiv, 0.20 mmol), [Pd] (3 mol%),
placed under a positive pressure of argon, and subjected to
of preparation from secondary benzamides in
a single,
operationally-simple and high-yielding step. The observed order
2
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ChemCatChem
10.1002/cctc.201800511
FULL PAPER
of reactivity with [Pd(IPr*)(cin)Cl] (1a>1c>1b) follows the
reactivity order determined earlier using [Pd(IPr)(cin)Cl], albeit
at much lower conversions.
Having demonstrated proof-of-concept that sterically-
hindered [Pd(IPr*)(cin)Cl] could promote the Suzuki-Miyaura
cross-coupling of amides, extensive optimization of the reaction
conditions was carried out using amide 1c (N,N = Boc, Ph) as a
model substrate (Table 2).
[Pd(IPr)(cin)Cl], and therefore is the preferred catalyst for cross-
coupling of amides under these conditions.
Table 2. Selected optimization results in the Suzuki-Miyaura
cross-coupling of amide 1c using [Pd(IPr*)(cin)Cl].a
1
4
On the basis of optimization studies (Table 2, Table SI1 and
Tables 2-3), we have identified three catalytic systems that can
effectively promote the Suzuki-Miyaura cross-coupling of amide
entry
T (°C) base
solvent
yield (%)
<2 (<2)a
<2
1
2
3
4
5
6
7
8
9
23
23
K
K
3
PO
CO
4
toluene
toluene
toluene
toluene
DME
DME
DME
DME
2
3
1c using [Pd(IPr*)(cin)Cl] precatalyst: (1) K
2 3 2
CO /THF/H O; (2)
23 KOtBu
23 KF
23 KOtBu
23 KOH
<2
K
3
PO /toluene/H O; (3) KF/toluene/H O. The following additional
4
2
2
8 (9)a
<2
points were noted during the optimization studies: (1) water is
critical to achieve high reactivity using [Pd(IPr*)(cin)Cl] with
7
<2
<2
<2
<2
<2
10
<2
optimum conversions observed at 5.0 equiv of H
to the amide at 0.25 M concentration (vide infra); (2) the
KF/toluene/H O system was found to be the most general for the
2
O with respect
23 Cs
2
CO
3
23 CO
K
2
3
2
23 KOH
23 KOH
dioxane
toluene
dioxane
Suzuki-Miyaura cross-coupling using [Pd(IPr*)(cin)Cl].
10
Table 1. Reactivity of amides 1a-1c using [Pd(IPr)(cin)Cl] and
11
12
23
23
23
K
3
K
3
K
3
PO
PO
PO
4
4
4
[
Pd(IPr*)(cin)Cl] under anhydrous conditions.a
CH
2
Cl
2
13
14
15
16
17
THF
THF
23 KF
23 Na
<2
<2
2
CO
CO
PO
23 KF
3
toluene
toluene
toluene
23 Cs
23
2
3
<2
86 (>95)
95 (90)a
b
a
K
3
4
18
tolueneb
yield(1a)
%)
yield (1b)
yield (1c)
[
Pd]
T (°C)
a
(
(%)
(%)
[Pd] = [Pd(IPr*)(cin)Cl]. Conditions: amide (1.0 equiv), 4-Tol-
B(OH) (2.0 equiv), [Pd] (3 mol%), base (3.0 equiv), solvent
2
0.25 M), 23 °C, 15 h. IPr instead of IPr*. toluene:H O = 40:1.
2
IPr
IPr
IPr*
IPr*
23
60
23
60
25
>98
14
13
92
<2
33
a
<2
94
<2
48
a
b
(
Table 3. Suzuki-Miyaura cross-coupling of amides using
Pd(IPr)(cin)Cl] and [Pd(IPr*)(cin)Cl]: boronic acid scope.a
57
[
IPr = [Pd(IPr)(cin)Cl]. IPr* = [Pd(IPr*)(cin)Cl]. Conditions: amide
(
1.0 equiv), 4-Tol-B(OH)
2
(2.0 equiv), [Pd] (3 mol%), K
2
CO
3
(3.0
Boronic Acid Scope
O
[
Pd] (3 mol%)
O
equiv), THF (0.25 M), T, 15 h. Entries IPr* at 60 °C, Ph-B(OH)
2
.
KF (3.0 equiv)
Ph
B(OH)2
H2O (5.0 equiv)
N
+
R’
R’
Boc
toluene, 23 °C
1
2
3
O
O
O
Generality of the cross-coupling of amides using [Pd(IPr*)(cin)Cl]
was evaluated (Tables 3-4). For comparison, all reactions were
conducted using [Pd(IPr*)(cin)Cl] and [Pd(IPr)(cin)Cl] in side-by-
side experiments. The reaction scope was studied by
comprehensively examining neutral, electron-rich, electron-
withdrawing and sterically-hindered (ortho-substituted) boronic
acids (Table 3). Likewise, the reactivity of neutral, electron-rich,
electron-withdrawing and sterically-hindered amides was
systematically evaluated (Table 4). On the basis of the reactivity
results (see the SI for additional results), we conclude that (1)
both catalysts, [Pd(IPr*)(cin)Cl] and [Pd(IPr)(cin)Cl], are highly
effective for the cross-coupling of a wide range of amides and
boronic acids under very mild room temperature conditions; (2)
with the exception of sterically-demanding substrates,
OMe
CF3
51%b
[
Pd-IPr*]
95%
97%
[
Pd-IPr]
95%
85%
86%b
O
Me
O
O
CO2Me
Me
[Pd-IPr*]
82%
67%
95%
90%
[
Pd(IPr*)(cin)Cl] shows generally higher reactivity and is less
95%c
90%c
[
Pd-IPr]
a
sensitive to experimental set-up (i.e. oxygen, vide infra) than
Conditions: amide (1.0 equiv), [Pd] (3 mol%), ArB(OH) (2.0 equiv), KF
3.0 equiv), H O (5.0 equiv), toluene (0.25 M), 23 °C, 18 h. K PO (3.0
2 3 4
2
b
(
3
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ChemCatChem
10.1002/cctc.201800511
FULL PAPER
c
equiv). K
[
2
CO
3
(3.0 equiv), THF (0.25 M). [Pd-IPr*] = [Pd(IPr*)(cin)Cl].
water on the cross-coupling is consistent with the role of water
solubilizing the base under the reaction conditions.
Pd-IPr] = [Pd(IPr)(cin)Cl].
Table 4. Suzuki-Miyaura cross-coupling of amides using
Pd(IPr)(cin)Cl] and [Pd(IPr*)(cin)Cl]: amide scope.a
[
Furthermore, TONs were calculated using [Pd(IPr*)(cin)Cl]
and [Pd(IPr)(cin)Cl] (Table 5). The results demonstrate that (1)
TON in excess of 1,000 can be achieved using [Pd(IPr)(cin)Cl];
Amide Scope
[
Pd] (3 mol%)
O
O
KF (3.0 equiv)
Ph
B(OH)2
H2O (5.0 equiv)
N
and (2) [Pd(IPr)(cin)Cl] gives
a
comparable TON to
R’
+
R’
Boc
toluene, 23 °C
[
Pd(IPr*)(cin)Cl] at 0.25 mol% catalyst loading, while at lower
1
2
3
catalyst loading (0.05-0.10 mol%), [Pd(IPr)(cin)Cl] gives higher
TON than [Pd(IPr*)(cin)Cl].
Me
O
O
O
MeO
F3C
[
Pd-IPr*] 71%b
85%
96%
[Pd-IPr]
82%b
86%
94%
Kinetic profile of the Suzuki coupling of 1c using
[Pd(IPr)(cin)Cl] and [Pr(IPr*)(cin)Cl]
O
O
O
100
O
MeO2C
Ph
8
0
0
[
Pd-IPr*] 95%
94%
82%
93%
6
[
[
Pd(IPr)(cin)Cl]
Pd(IPr*)(cin)Cl]
96%c
40
20
0
[Pd-IPr]
82%
a
Conditions: amide (1.0 equiv), [Pd] (3 mol%), ArB(OH)
3.0 equiv), H O (5.0 equiv), toluene (0.25 M), 23 °C, 18 h. K
(3.0 equiv), THF (0.25 M). [Pd-IPr*]= [Pd(IPr*)(cin)Cl].
2
(2.0 equiv), KF
b
(
2
3 4
PO (3.0
c
2 3
equiv). K CO
[
Pd-IPr] = [Pd(IPr)(cin)Cl].
0
50
100
150
200
250
300
time (min)
Figure 1. Kinetic profile of the Suzuki-Miyaura cross-coupling of
amide 1c with 4-tolylboronic acid catalyzed by [Pd(IPr)(cin)Cl]
and [Pd(IPr*)(cin)Cl]. Conditions: amide (1.0 equiv), [Pd] (3
To gain further insight into the relative reactivity of
Pd(IPr*)(cin)Cl] versus [Pd(IPr)(cin)Cl], kinetic profiles of the
model reaction using amide 1c and 4-tolylboronic acid were
constructed (Figure 1). The results demonstrate that under these
conditions (1) the reactions are complete within 300 min; (2) IPr
leads to a comparable initiation and conversion than for IPr*.
[
2 2
mol%), 4-Tol-B(OH) (2.0 equiv), KF (3.0 equiv), H O (5.0 equiv),
toluene (0.25 M), 23 °C, 0-300 min.
Kinetic profile of the Suzuki coupling of 1c using
Pd(IPr)(cin)Cl]
[
Kinetic profiles in the model reaction using [Pd(IPr)(cin)Cl] and
100
[
(
Pd(IPr*)(cin)Cl] with varying amounts of water were obtained
Figures 1-2). The data demonstrate that (1) increasing the
8
6
4
2
0
0
0
0
0
amount of water results in faster initiation and conversion for
both catalysts; and (2) 1.0 equiv of water suffices to achieve
>95% conversion with both [Pd(IPr)(cin)Cl] and [Pd(IPr*)(cin)Cl].
(
Pd(IPr)(cin)Cl, 5.0 equiv)
Note that no reaction is observed in the absence of water under
otherwise identical conditions, which rules out the effect of
adventitious water contamination.
(Pd(IPr)(cin)Cl, 1.0 equiv)
To further validate the effect of water, the model reaction was
conducted with varying equivalents of water (Figure 3). The
results clearly show that (1) the optimal reactivity is obtained
with 1-5 equiv of water for both [Pd(IPr*)(cin)Cl] and
0
2
4
6
8
10
12
14
16
18
20
time (h)
[
Pd(IPr)(cin)Cl]; and (2) [Pd(IPr*)(cin)Cl], bearing bulky aromatic
groups, allows for a valuable broader reactivity window, in
agreement with synthetic scope studies. The observed effect of
Figure 2. Kinetic profile of the Suzuki-Miyaura cross-coupling
of amide 1c with 4-tolylboronic acid catalyzed by [Pd(IPr)(cin)Cl].
4
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ChemCatChem
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2
Conditions: amide (1.0 equiv), [Pd] (3 mol%), 4-Tol-B(OH) (2.0
equiv), KF (3.0 equiv), H
C, 0-18 h.
2
O (1.0-5.0 equiv), toluene (0.25 M), 23
°
Effect of water on the Suzuki coupling of 1c using
Pd(IPr)(cin)Cl] and [Pd(IPr*)(cin)Cl]
[
100
80
60
40
20
0
[
[
Pd(IPr)(cin)Cl]
Pd(IPr*)(cin)Cl]
0
5
10
15
20
25
30
water (equiv)
Figure 3. Effect of water on the Suzuki-Miyaura cross-coupling
of amide 1c with 4-tolylboronic acid catalyzed by [Pd(IPr)(cin)Cl]
and [Pd(IPr*)(cin)Cl]. Conditions: amide (1.0 equiv), [Pd] (3
2 2
mol%), 4-Tol-B(OH) (2.0 equiv), KF (3.0 equiv), H O (0-25
equiv), toluene (0.25 M), 23 °C, 18 h.
Table 5. Determination of TON using [Pd(IPr)(cin)Cl] and
Figure 4. Energetic profile of the plausible pathways for the
activation of the precatalyst [Pd(IPr)(cin)Cl]. Gibbs energies in
solvent are in kcal/mol.
a
[
Pd(IPr*)(cin)Cl].
The external pathway consists of a nucleophilic intermolecular
attack of the potassium carbonate onto the allyl moiety that
leads to intermediate I2, which is 5.5 kcal/mol more stable than
the precatalyst (Pre). First, adduct intermediate I1 is achieved
and the energy barrier TS1 that links I1 with I2 is 31.9 kcal/mol.
Then, molecules of allylcarbonate and KCl are released to
obtain the active catalytic species IPr-Pd(0). In the internal
pathway, at least two steps are required, starting from the
[
Pd]
TON
[Pd-IPr]
TON
[Pd-IPr*]
time
(h)
T (°C)
(
mol%)
0
0
0
0
.25
.25
.10
.05
23
288
372
970
280
276
690
560
15
0.5
0.5
15
-
shared intermediate I1. First, there is a ligand substitution of Cl
110
110
110
-
by KCO
3
by means of K
2
CO
3
leading to intermediate I3, which is
1360
15.6 kcal/mol lower in energy than the precatalyst Pre. Second,
the allyl moiety undergoes a nucleophilic intramolecular attack
by the carbonate to obtain intermediate I4, which is 6.4 kcal/mol
less stable than the previous intermediate overcoming an energy
barrier of 27.1 kcal/mol, and consequently of 30.3 kcal/mol from
I1. Finally, to complete the precatalyst activation, a release of an
allylcarbonate molecule to achieve the desired active catalyst
Pd-IPr takes place. Both mechanisms have the same rate-
determining step, namely the formation of the corresponding
alkene coordination intermediates I2 and I4, which for the
external pathway is less favored by 1.6 kcal/mol than the internal
a
[
Pd-IPr] = [Pd(IPr)(cin)Cl]. [Pd-IPr*] = [Pd(IPr*)(cin)Cl]. Conditions:
(2.0 equiv), [Pd] (x mol%), KF (3.0
O (5.0 equiv), toluene (0.25 M).
amide (1.0 equiv), 4-Tol-B(OH)
equiv), H
2
2
To better understand the reaction between N-acyl-tert-butyl-
carbamates and arylboronic acids in the presence of K CO
meditated by [Pd(NHC)(cin)Cl]-based catalysts DFT calculations
were conducted. Since the catalytic cycle initiates with the
formation of a Pd(0) species, it was necessary to examine the
2
3
3
2
activation step from the Pd(II) precatalyst.
As recently
3
3
postulated by Poater and co-workers , there are two main
pathways to obtain the catalytic species, an external or an
internal pathway where the base first binds to the allyl moiety
and secondly releases the latter organic moiety leading to the
Pd(0) species. Both plausible pathways have been studied and
their energetic profiles are presented in Figure 4.
mechanism. Moreover, for this pre-activation mechanism it is
necessary to point out that Nova and coworkers34 have shown,
computationally, that the replacement of a chloride by an
isopropoxide ligand is facile, requiring to overcome an energy
barrier of some 10 kcal/mol. Thus, the cost of ligand exchange in
I1I3 is meaningless with respect to the energy barrier of the
rate determining step described here as TS2 (Figure 5). Overall,
the pre-activation step requires 30.3 kcal/mol.
5
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This clearly indicates that the catalyst which bears the IPr*
ligand may more easily achieve the active species with respect
to the IPr, according to its preactivation.
Structurally, the Pd–C bond distance to be cleaved in I3,
before the transition state TS2 is longer in the IPr* complex,
which suggests that the activation of the bond that will be broken
in the next C–O bond formation is somewhat more facile.
Further, the energy differences between the transition states
bearing IPr (Figure 5a) and IPr* (Figure 5b) confirm that the
formation of the C–O bond is easier for the more sterically
hindered IPr* as the cleaved Pd–C bond with the allyl moiety
and the C···O distance that will link the former allyl and
carbonate moieties are longer in the transition state bearing IPr*.
Figure 5. DFT optimized geometries of TS2 for the
[
(
Pd(NHC)(cin)Cl]-based catalysts, where NHC = (left) IPr and
right) IPr* (main distances given in Å; hydrogens are omitted for
Having examined the activation of the Pd(II) center, we next
focused on the catalytic cycle of the Suzuki-Miyaura coupling of
amides in order to explore the possible mechanism and the role
of the base. To have a better overview of the catalytic cycle, we
divided the study into the three main steps of a cross-coupling
clarity).
catalytic
cycle:
(1)
oxidative
addition,
(2)
transmetalation/nucleophilic attack and (3) reductive elimination.
First, we describe the reaction pathway for the catalyst
bearing IPr. The first step in this cycle (Figure 7) is the oxidative
addition of the Pd(0) active species with the N-acyl-tert-butyl-
carbamate to give intermediate I5, which is located 4.1 kcal/mol
higher in energy. Then, via a concerted transition state TS3 with
an associated energy barrier of 11.0 kcal/mol the cleavage of
the N–C(O) bond of I5 leads to the formation of the intermediate
I6, which shows the oxidative addition step to be exoergonic by
3.0 kcal/mol, and kinetically only 15.1 kcal/mol are required.
Thus, both these energy values indicate that the C(O)–N bond
cleavage is thermodynamically and kinetically favorable.
A structural analysis of the oxidative addition has been
performed by observing the distances of the most relevant
structures for this process in which the palladium is inserted in
the C(O)–N bond, which is rather weakened in I5 (Figure 8).
Initially, the C(O) –N bond distance is 1.505 Å and the distances
between Pd and ketone carbon and nitrogen atoms are 2.282
and 2.132 Å, respectively. However, once the oxidative addition
takes place and I6 is formed, these distances become 1.970 and
Figure 6. Energetic profile of the plausible pathways for the
activation of the [Pd(IPr*)(cin)Cl] precatalyst. Gibbs energies in
solvent are given in kcal/mol.
2.092 Å, respectively. After the cleavage of the C(O)–N bond
this distance turns out to be 3.103 Å.
Moreover, a comparison between the two NHC ligands, IPr
and IPr* has been performed with the aim to determine which
would provide an easier activation of the precatalyst. Each
ligand has been compared with its analogue undergoing the
same pathway (see Figure 6). A general observation is that for
both pathways it can be observed that the IPr* ligand generates
lower energy barriers than the IPr ligand. Particularly, the energy
difference in the TS2 of the internal mechanism is more
favoured by 2.3 kcal/mol than the external one, but overall the
internal mechanism requires 7.6 kcal/mol less than the IPr ligand.
The transition state TS3 consists of a concerted mechanism
that involves three centers (see Figure 8a). The distances Pd–C,
Pd–N and C(O)–N are 2.113, 2.124 and 1.770 Å, respectively.
6
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ChemCatChem
10.1002/cctc.201800511
FULL PAPER
Figure 7. Free energy profile (in kcal/mol) of the overall catalytic cycle of the SMC of amides in THF as referred to Pd(NHC)(0), NHC
=
IPr (in black) and IPr* (in red).
Next, we turned our attention to the transmetalation step. Of
potassium acts as a countercation, otherwise the reaction would
not readily proceed.
the entire catalytic cycle, this step is the least-known
mechanistically-speaking. What is known about transmetalation
is that there are two plausible pathways, the boronate pathway
and the oxopalladium pathway and both require the presence of
a base. However, recent computational studies have shown that
the more plausible pathway is the boronate one. Therefore, in
this study, we have only focused in the boronate pathway using
potassium carbonate as a base in THF, conditions employed by
The next stage of the transmetalation step is based on its own
definition, leading to the formation of intermediate I10 from I8.
To form I10, first, intermediate I8 needs to overcome an energy
barrier of 15.7 kcal/mol, and 23.8 kcal/mol with respect to I7,
becoming TS5, the transition state that defines the rate
determining step of the transmetalation step, and also of the
catalytic pathway. This step consists of a concerted mechanism,
wherein the phenyl group of the boronic compound migrates
towards the metal. The next intermediate I9 lies 2.6 kcal/mol
above intermediate I8, and as such still 10.7 kcal/mol above I7.
Finally, intermediate I9 releases the boronic potassium salt and
intermediate I10 is located 4.0 kcal/mol below I9. Overall the
transmetalation process is exoergonic by 35.6 kcal/mol.
1
4
the Szostak group , and potassium carbonate as a base in a
mixture of protic solvent in THF (Figure 7). The
a
transmetalation begins from intermediate I6 and the
organoboronate compound. The latter species is formed by the
reaction between K CO and the organoboronic acid. The
2 3
transmetalation process can be divided into two stages, the first
one would be until intermediate I8 and the second that leads to
intermediate I10. The first stage starts with the reaction of the
organoboronate species with I6 to give intermediate I7, which
lies 42.3 kcal/mol below the previous intermediate I6. Next, there
is a replacement of the boronic acid for the amino moiety
generating unstable intermediate I8 after release of the amino
moiety. I8 is only 8.1 kcal/mol higher in energy than I7, but
kinetically requires to overcome a barrier of 22.2 kcal/mol. Here,
In terms of bond distances, the transmetalation step is like a
rollercoaster because several bonds are formed and cleaved.
From the beginning of the process in the carbonate pathway, the
distance of the bond to be broken, Pd–N is 2.445 Å, whereas the
distances between other pairs of atoms, such as Pd–C(Ph) or
B–C(Ph) change substantially as transmetalation evolves.
7
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ChemCatChem
10.1002/cctc.201800511
FULL PAPER
Initially, these distances were 4.868 and 1.640 Å, respectively.
In TS5, the phenyl migration towards Pd results in changes in
several distances such as 2.158 Å for B–C(Ph) bond or 2.146 Å
for the Pd–C(Ph) bond (see Figure 8b).
elimination (5.3 kcal/mol). However, the preactivation energy
barrier is still 4.3 kcal/mol higher in energy.
In addition, Figure 7 also includes the catalytic pathway from
the Pd-IPr* precatalyst to determine the effects of the two
different NHC ligands. From examination of the energetic profile,
one can notice that the two pathways maintain a similar profile.
This general observation confirms that both ancillary ligands
have a similar influence on the reaction. Despite this high
similarity between both energy profiles, some differences
emerge upon closer examination. The energy barrier of the
oxidative addition is 15.1 kcal/mol for both NHC type ligands.
However, the next transmetallation shows an energy barrier of
26.5 kcal/mol for the IPr* system, thus 2.7 kcal/mol higher than
for the IPr system, whereas the final reductive elimination is 3.4
kcal/mol more facile for IPr. Therefore, although the two ligands
give similar energies in the cross-coupling, IPr* tends to be less
favourable, with a lower energy requirement of 2.7 kcal/mol for
the rate-determining step defined by TS5. The reason for this is
found in the elongation of the bond with potassium that holds
one hydroxyl group on boron atom with IPr (2.574 Å), which is
absent for IPr* (3.025 Å), see Figure 8.
a)
The main goal of the geometrical modification of the NHC
ligand was to unravel how the modified steric properties of IPr*
affected the reactivity in comparison with IPr. To analyse the
steric influence of the ligand, we have used topographic steric
maps. The points in space defining the steric map were located
with the SambVca package developed by Cavallo and
coworkers.35 This program basically analyses the first
coordination sphere around the metal, which is the location
where catalysis occurs.36 It is normally used to calculate the
buried volume of a given ligand , which is a number that
quantifies the amount of the first coordination sphere of the
metal occupied by this ligand. SambVca also allows the user to
perform a more detailed analysis by the %VBur in the individual
quadrants around the Pd center, as well as the steric map of the
NHC ligand in Pd-systems. Splitting the total %VBur into quadrant
contributions quantifies any asymmetry in the way the ligand
wraps around the metal and allows to understand how changing
the ligand from IPr to IPr* modifies the shape of the reactive
pocket. In this study, the steric maps were calculated for both
NHC ligands that bear the Pd(0) complexes in the absence of
other ligands around the metal, and working without symmetry
constraints.
b)
c)
3
7
Figure 8. DFT-optimized a) TS3, b) TS5 and c) TS6 for the Pd-
IPr and Pd-IPr* catalysts in the SMC of amides (main distances
given in Å; hydrogens are omitted for clarity).
The last step of the catalytic cycle is the reductive elimination.
This step consists of the facile formation of the C–C bond with
an energy barrier of 5.2 kcal/mol and a highly exoergonic step of
24.8 kcal/mol. Similar to the oxidative addition, the
transformation of I10 to I11 is via a three-centre transition state
TS6 (see Figure 8c). Finally, from I11, the release of the desired
product and the regeneration of the palladium active species IPr-
Pd(0) closes the catalytic cycle.
To summarize, the overall catalytic cycle depicted in Figure 7
is comprised of three main steps (oxidative addition,
transmetalation, and reductive elimination). The rate-determining
transition state is TS5 with the free energy of 23.8 kcal/mol. The
energy barrier of the transmetalation step (rate-determining
step) is 23.8 kcal/mol (relative to I7), which is much higher than
those for the oxidative addition (15.1 kcal/mol) and reductive
Figure 9. Topographic steric maps of the free (left) IPr and
(right) IPr* NHC ligands. The isocontour curves of the steric
maps are in Å. The xz plane is the mean plane of the NHC ring,
8
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ChemCatChem
10.1002/cctc.201800511
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whereas the yz plane is the plane orthogonal to the mean plane
of the NHC ring, and passing through the carbene C atom of the
NHC ring.
kcal/mol higher in energy than for K PO . Furthermore, the
3
4
mechanism that involves boron-based anionic species using a
strong base, such as KOH, that involves coordination of a
hydroxyl group to the boron center, was examined (Figure 10).
For IPr the alternative mechanism from I6 to I10 was further
studied. We found that the upper barrier described by TS7 has
an energy barrier of 26.4 and 29.1 kcal/mol for IPr and IPr*,
respectively, and is thus similar to the values found with a mild
The maps of the NHC ligands reported in Figure 9 show
clearly that IPr* is slightly more sterically demanding than IPr.
The %VBur is 49.5 % for IPr*, whereas a value of 49.0 % is found
for IPr (see Table 6). Examining in more detail the steric maps in
Figure 9, the IPr map shows two quadrants slightly more
hindered, but this asymmetry is negligible compared to the
asymmetry in the IPr* map, where the distribution of the steric
bulk around the metal is remarkably different and the hindrance
is much more localized into two quadrants (top left and bottom
right quadrants). Thus, bearing in mind that the topographic
maps characterize the ligand surface offered to the substrate, it
is clear that IPr* has an intrinsic strong steric hindrance that after
binding to the metal precludes coordination of sterically-
demanding substrates. In these systems, even though IPr*
creates higher steric constraints than IPr, again, IPr* adopts a
quite asymmetric folding, creating a groove into which the
substrate can coordinate. In contrast, the IPr ligand adopts a
quite flat surface to accommodate the incoming substrate,
bound to the palladium trans to the NHC ligand. Overall, IPr* can
be seen also as a ligand that is able to exert steric pressure to
repel the incoming substrate, i.e. the ligand can retract away to
make space for other ligands. This analysis highlights the
intrinsic dynamic behavior of IPr*, indicating that the interaction
between the complex and the substrate requires a conformation
rearrangement of the complex, which is more consistent with an
2 3
base K CO .
“
induced-fit” model rather than with a “lock-and-key” model.
Table 6. Total %VBur and quadrant %VBur (numbers in brackets)
values for the NHC ligands (IPr and IPr*) for the Pd(0) complexes.
%
V
Bur
IPr
IPr*
49.5
39.0
61.5
42.8
54.6
Total
49.0
47.0
50.9
47.0
50.9
Figure 10. Free energy profile (in kcal/mol) of the I6I10
alternative pathway by KOH, corresponding to the SMC of
amides in THF as referred to Pd(NHC)(0), NHC = IPr (in black)
or IPr* (in red).
Quadrant Bottom-Left
Quadrant Top-Left
Quadrant Top-Right
Quadrant Bottom-Right
Conclusion
We have elucidated mechanistic details pertaining to the
Suzuki-Miyaura cross-coupling of amides via the Pd(0)/NHC
catalytic cycle. The study provides extensive insights into the
activation of amides by the practical Pd-NHC catalysis using
readily accessible, air- and moisture-stable Pd(II) precatalysts.
The role of the steric hindrance on the NHC ligand was
examined by substituting IPr with the more sterically demanding
IPr*, playing a key role in this initial activation of the catalyst.
Furthermore, we have demonstrated for the first time that
increasing steric bulk of the Pd-NHC catalyst leads to selective
N–C insertion/cross-coupling of the amide bond. The developed
catalytic system operates under the mildest conditions reported
to date and promotes cross-coupling of a wide range of amides
The role of the base was further studied. Focusing on the rate
4
determining step, i.e. TS5, using a mild phosphate base, K PO ,
the barrier is 29.1 and 25.3 kcal/mol, for IPr and IPr*,
respectively. Structurally, the transition state strongly resembles
3
the transition state determined for K
2 3
CO for both NHC ligands
(
see SI). However, for KF the story changes completely and the
barrier decreases to only 9.9 and 20.0 kcal/mol relative to
intermediate I7, for IPr and IPr*, respectively. With respect to the
Pd(0) initial active catalytic species, the determined barriers are
2
6.1 and 29.3 kcal/mol, respectively. Thus, the performance of
the three bases is similar in terms of energy barriers. Using IPr*
as the NHC ligand with K CO and KF the barrier is 1.2 and 4.0
2
3
9
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ChemCatChem
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FULL PAPER
and boronic acids. Using DFT calculations, we have studied the
precatalyst activation mechanism for [Pd(NHC)(cin)Cl] catalysts,
followed by the complete description of the Suzuki−Miyaura
cross-coupling cycle for the catalytically active NHC-Pd(0)
species using model N-acyl-tert-butyl-carbamate and boronic
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442-4489. (f)
Hruszkewycz, D. P.; Balcells, D.; Guard, L. M.; Hazari, N.; Tilset, M. J.
Am. Chem. Soc. 2014, 136, 7300-7316. (g) Hruszkewycz, D. P.; Tilset,
M.; Guard, L. M.; Balcells, D.; Feldman, N.; Hazari, N. Organometallics
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R.; Nelson, D. J. Beilstein J. Org. Chem. 2015, 11, 2171-2178. (i) (h)
Hazari, N.; Hruszkewycz, D. P. Chem. Soc. Rev. 2016, 45, 2871-2899.
(a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451-3674.
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See, refs. 3a-d.
2 3
acid in the presence of K CO and KF for the rate determining
steps of both (1) the precatalyst activation; and (2) catalytic
pathways. Our theoretical results suggest that the rate-
determining step of the catalytic process is (1) the activation of
the precatalyst by formation of the C–O bond between the cin
moiety and the carbonate moieties for [Pd(IPr)(cin)Cl]; and (2)
the transmetallation in the catalytic cycle for [Pd(IPr*)(cin)Cl],
respectively. The exchange of the IPr* ancillary ligand by IPr
improves catalytic performance by decreasing the upper energy
barrier of the catalytic pathway. However, the increased steric
bulk of the IPr* ligand promotes catalysis by facilitating
precatalyst activation. Thus, the preactivation step to generate
the active Pd(0)-NHC active species is energetically less
expensive for [Pd(IPr*)(cin)Cl]. In a broader context, this study
shows that Pd-NHC catalysts bearing a very significant flexible-
bulk promote N–C activation with high reactivity, and that
experimentally water is critical in this cross-coupling manifold.
Computational studies to address the role of water in the cross-
coupling are currently underway. Given the rich portfolio of
extremely-sterically bulky NHC ligands and the importance of
Suzuki-Miyaura cross-couplings, we fully expect that this study
will lead to the discovery of even more efficient systems for
catalytic functionalization of amides. Studies to isolate reaction
intermediates are in progress and will be reported in due course.
[4]
[
[
5]
6]
(a) Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev. 2017, 46,
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[
9]
For representative acyl coupling, see: (a) Hie, L.; Nathel, N. F. F.; Shah,
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Acknowledgements
A.P. thanks the Spanish MINECO for a project CTQ2014-59832-
JIN, and EU for a FEDER fund (UNGI08-4E-003). Rutgers
University and the NSF (CAREER CHE-1650766) are gratefully
acknowledged for support (M.S.). The Bruker 500 MHz
spectrometer was supported by the NSF-MRI grant (CHE-
4
364. (c) Meng, G.;Shi, S.; Szostak, M. ACS Catal. 2016, 6, 7335-
339. (d) Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2017, 19, 2158. (e)
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Amani, J.; Alam, R.; Badir, S.; Molander, G. A. Org. Lett. 2017, 19,
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Szostak, M. Chem. Sci. 2017, 8, 6525 and references cited therein.
fellowship (No. 201606350069). SPN thanks the ERC, King
Saud University and King Abdullah University of Science and
Technology (Award No. OSR-2015-CCF-1974-03) for support.
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10] For representative decarbonylative coupling, see: (a) Meng, G.;
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3095-3098 and references cited therein.
Keywords: dorta
[
1]
For monographs on cross-coupling, see: (a) Metal-Catalyzed Cross-
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Eds.; Wiley: New York, 2014. (b) Science of Synthesis: Cross-Coupling
and Heck-Type Reactions, Molander, G. A.; Wolfe, J. P.; Larhed, M.,
Eds.; Thieme: Stuttgart, 2013.
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L.; Humke, J. N.; Stanley, L. M. J. Am. Chem. Soc. 2017, 139, 10228-
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[
[
2]
3]
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Entry for the Table of Contents
Layout 1:
FULL PAPER
Suzuki Cross-Coupling of Amides via N-C Activation
A mechanistic study of the
palladium-catalyzed
Suzuki-Miyaura cross
coupling of amides is
described.
Guangchen Li, Peng Lei,
O
B(OH)2
O
Michal Szostak,* Eric Casals-
Cruañas, Albert Poater,* Luigi
Cavallo and Steven P. Nolan *
R'
[Pd(NHC)(cin)Cl]
N
Ar1
+
Ar2
Ar1
Ar2
R''
Me
Me
Me
Me
Me
Me
N
N
Page No. – Page No.
Pd
Me
Me
Cl
Mechanistic Study of Suzuki-
Miyaura Cross-Coupling
Reactions of Amides
Mediated by
Ph
full mechanistic details
RT cross-coupling
bulky NHC catalyst
[
Pd(NHC)(allyl)Cl]
Precatalysts
1
2
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