Pd-PEPPSI: Water-Assisted Suzuki?Miyaura Cross-Coupling of Aryl Esters at Room Temperature using a Practical Palladium-NHC (NHC=N-Heterocyclic Carbene) Precatalyst

Article abstract of DOI:10.1002/adsc.201701563

A Pd-PEPPSI-catalyzed (Pd=Palladium, PEPPSI=pyridine-enhanced precatalyst preparation stabilization and initiation) Suzuki-Miyaura cross-coupling of aryl esters via selective C?O cleavage at room temperature is reported. The developed catalyst system displays broad substrate scope with respect to both components under practical ambient reaction conditions using readily-available, cheap, modular, air- and moisture-stable Pd-NHC precatalyst (NHC=N-heterocyclic carbene). The use of water proved crucial for achieving high reactivity in this coupling. The catalyst system represents the mildest conditions for the Suzuki?Miyaura cross-coupling of aryl esters reported to date. The protocol also allowed for achieving TON >1,000 (TON=turnover number) in the Suzuki?Miyaura ester coupling for the first time. (Figure presented.).

Full text of DOI:10.1002/adsc.201701563

Title: Pd-PEPPSI: Water-Assisted Suzuki–Miyaura Cross-Coupling of
Aryl Esters at Room Temperature using a Practical Palladium-
NHC (NHC = N-Heterocyclic Carbene) Precatalyst
Authors: Guangchen Li, Shicheng Shi, Peng Lei, and Michal Szostak
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701563
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10.1002/adsc.201701563
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pd-PEPPSI: Water-Assisted Suzuki–Miyaura Cross-Coupling
of Aryl Esters at Room Temperature using a Practical
Palladium-NHC (NHC = N-Heterocyclic Carbene) Precatalyst
Guangchen Li,a Shicheng Shi,a Peng Lei,a,b and Michal Szostaka*
a
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, United States
Fax: (+1)-973-353-1264; phone: (+1)-973-353-5329; e-mail: michal.szostak@rutgers.edu
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
the cross-coupling of esters have been realized,[13,14]
Abstract.
PEPPSI
A Pd-PEPPSI-catalyzed (Pd = Palladium,
= pyridine-enhanced precatalyst preparation the development of general, robust, widely-available
stabilization and initiation) Suzuki-Miyaura cross-coupling
of aryl esters via selective C–O cleavage at room
temperature is reported. The developed catalyst system
displays broad substrate scope with respect to both
components under practical ambient reaction conditions
using readily-available, cheap, modular, air- and moisture-
and operationally-convenient catalytic systems that
operate under practical ambient conditions has
remained a major challenge.
In 2017, our laboratory introduced a new catalytic
method for the Suzuki-Miyaura cross-coupling of
aryl esters[15] using widely-available Pd-PEPPSI
precatalysts (Pd = Palladium, PEPPSI = pyridine-
enhanced precatalyst preparation stabilization and
initiation).[16] In this initial disclosure, high
temperatures (80 °C), high catalyst loading (3.0
mol%), amount of base (4.5 equiv) and boronic acid
(3.0 equiv) were required. Through ever-increasing
effort to improve the practicality, cost and
operational-simplicity of the coupling,[17–20] we
identified a greatly improved catalyst system that
permits for the first time to perform the Suzuki-
Miyaura cross-coupling of aryl esters using readily-
available, cheap and modular Pd-NHC (NHC = N-
heterocyclic carbene) precatalyst under practical
ambient conditions (Figure 1). The developed catalyst
system represents the mildest conditions for the
Suzuki-Miyaura cross-coupling of aryl esters reported
to date.[21]
stable Pd-NHC precatalyst (NHC
= N-heterocyclic
carbene). The use of water proved crucial for achieving
high reactivity in this coupling. The catalyst system
represents the mildest conditions for the Suzuki-Miyaura
cross-coupling of aryl esters reported to date. The protocol
also allowed for achieving TON >1,000 (TON = turnover
number) in the Suzuki-Miyaura ester coupling for the first
time.
Keywords: Suzuki–Miyaura; aryl esters; cross-coupling;
C–O activation; Pd-PEPPSI
Introduction
The development of general catalytic systems for
palladium-catalyzed cross-coupling reactions has
revolutionized the field of organic synthesis with a
long-lasting impact on various fields of chemistry.[1–3]
While these transformations typically utilize aryl
halides or pseudohalides,[4,5] arguably, one of the
most important developments involves cross-
coupling
of
bench-stable
carboxylic
acid
derivatives.[6,7] These reactions involve oxidative
addition of a metal to acyl electrophile, a step which
needs to overcome low reactivity of the acyl C–X
bond (X = O, N), resulting from nX→*C=O
conjugation.[8]
Figure 1. Pd-PEPPSI-Catalyzed Cross-Coupling of Aryl
Esters at Room Temperature.
Transition-metal-catalyzed cross-couplings of aryl
esters by acyl cleavage[9,10] are of significant synthetic
interest due to the ubiquity of esters as common
intermediates in organic synthesis and their potential
to serve as Weinreb amide equivalents with
dramatically improved substrate scope under catalytic
reaction conditions.[11,12] While several methods for
Results and Discussion
Experimentally, cross-coupling of aryl ester 1
proceeds at 80 °C in 84% yield (Table 1, entry 1,
<10% conversion at 23 °C).[15] We were delighted to
1
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10.1002/adsc.201701563
Advanced Synthesis & Catalysis
find that the addition of water (5.0 equiv) provided
the desired diaryl ketone in excellent yield at room
temperature (entry 2). Moreover, the catalyst loading
could be decreased to 1.0 mol% while retaining high
reaction efficiency (entry 3). Control experiments
established the essential role of water concentration
we were delighted to find that a broad range of
electronically
(3c’-e’)
and
sterically
(3f’)
differentiated aryl esters can participate as coupling
partners in this mild room temperature protocol.
Particularly notable is the functional group tolerance
toward alkyl ester (3e’), which is a problematic
substrate using strong bases, such as KOH or KO-
tBu,[13,14] highlighting another advantage of our
protocol. Electron-deficient polyfluorinated (3j) and
electron-rich 5-memebered heterocycles substituted
at the deactivating 2-position (3k) are well-tolerated.
Finally, we determined that while the cross-coupling
of a challenging aliphatic ester (3l) was sluggish at
room temperature, this new aqueous protocol permits
Table 1. Optimization of the Reaction Conditions.[a,b]
Entry Pd-PEPPSI
[mol%]
H2O
[equiv]
T
[°C]
Yield
[%]
Table 2. Pd-PEPPSI-Catalyzed Suzuki–Miyaura Cross-
1[c,d]
2
3
4
5
6
7
8
3.0
3.0
1.0
1.0
1.0
1.0
0.50
0.25
-
80
23
23
23
23
23
23
23
84
94
95
36
93
<2
85
60
Coupling of Aryl Esters at Room Temperature.[a,b]
5.0
5.0
3.0
10.0
-
5.0
5.0
[a]Conditions: ester (1.0 equiv), Ar-B(OH)2 (2.0 equiv), Pd-
PEPPSI (x mol%), K2CO3 (3.0 equiv), H2O (y equiv), THF
(0.25 M), 23 °C, 18 h. [b]GC/1H NMR yields. [c]Ar-B(OH)2
(3.0 equiv), K2CO3 (4.5 equiv), 80 °C. [d]Ref. 15.
(entries 4-5), with marginal conversion observed in
the absence of water under these conditions (entry 6).
Furthermore, the catalyst loading could be further
decreased to 0.50 mol% (entry 7) and even 0.25
mol% (entry 8), while maintaining high reactivity
(vide infra). It should be noted that the developed
conditions (Pd-PEPPSI, 1.0 mol%, K2CO3, 3.0 equiv,
Ar-B(OH)2, 2.0 equiv, 23 °C) are superior to previous
catalytic systems[13,14] in terms of reactant loading,
low price and availability of Pd-NHC precatalyst.
The dramatic enhancement in efficiency upon
addition of water is discussed in the section below.
In most cases, we observed recovery of the PhOH
group after the reaction. No reaction was observed in
the absence of the catalyst. We hypothesize that the
bulky ligand facilitates reductive elimination of the
product.[16a] The mechanism likely involves reduction
to Pd(0)-NHC, oxidative addition of the acyl C–OPh
bond, transmetallation and reductive elimination.[6a]
Under the developed conditions, the reaction
exhibits broad scope with respect to both the boronic
acid and aryl ester coupling partners (Table 2). As
shown, a range of electronically-diverse boronic acids
undergo efficient cross-coupling (3a-e). This includes
electronically-deactivated 4-CF3-substituted phenyl
boronic acid (3d), which is a challenging nucleophile
in this coupling manifold.[13,14] Full selectivity in the
cross-coupling of 4-CO2Me ester was observed (3e),
attesting to the high chemoselectivity of the
method.[22] In addition, steric hindrance was readily
tolerated at the boronic acid component (3f-g).
Furthermore, heterocyclic boronic acids (3h-i) can be
readily incorporated to generate diaryl ketones in
excellent yields. With respect to the ester component,
[a]Conditions: ester (1.0 equiv), Ar-B(OH)2 (2.0 equiv), Pd-
PEPPSI (1.0 mol%), K2CO3 (3.0 equiv), H2O (5.0 equiv),
THF (0.25 M), 23 °C, 18 h. [b]Isolated yields. [c]80 °C
Table 3. Cross-coupling using various Pd-NHCs.[a]
Entry
Pd-NHC
[mol%]
H2O
[equiv]
T
[°C]
Yield
[%]
1
2
3
1.0, 4
1.0, 4
1.0, 5
-
5.0
-
23
23
23
<2
95
<5
2
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10.1002/adsc.201701563
Advanced Synthesis & Catalysis
4
5
6
1.0, 5
1.0, 6
1.0, 6
5.0
-
5.0
23
23
23
73
<2
94
pioneered by Nolan and co-workers.[23] More recently,
the substituted indenyl-type ligand was reported,
[Pd(IPr)(ind)Cl] (6),[24] however, while there appear
to be some advantages of this precatalyst, it remains
to be seen if it will find wide applications in catalysis
due to high commercial price, lengthy route to the
throw-away ligand and the lack of clear benefits in
the majority of cross-couplings to date. As shown in
Table 3, the addition of water activates all three
catalysts towards highly efficient coupling at ambient
conditions (entries 1 vs. 2, 3 vs. 4, 5 vs. 6). Since the
majority of modern ligand development efforts are
directed at the synthesis of cheap, easily assembled,
[a]Conditions: ester (1.0 equiv), Ar-B(OH)2 (2.0 equiv), Pd-
NHC (1.0 mol%), K2CO3 (3.0 equiv), H2O (0-5.0 equiv),
THF (0.25 M), 23 °C, 18 h.
and
generally-available
precatalysts,[2–4]
our
Scheme 1. Pd-NHC Catalysts for Room Temperature
Suzuki-Miyaura Cross-Coupling of Aryl Esters.
observations highlight the potential of Pd-PEPPSI to
promote elementary steps[6] in Pd-catalysis of bench-
stable acyl-electrophiles with high efficiency.
Scheme 3. Synthesis of [Pd(-OH)Cl(IPr)]2 from Pd-
PEPPSI-IPr. Dipp = 2,6-diisopropylphenyl.
Plot of conversion vs. time for aryl ester 1a
100
80
60
(PEPPSI-IPr-A)
Scheme 2. Determination of TON in the Cross-Coupling
of Aryl Esters at Room Temperature. Note: the following
TON was observed at 60 °C: Pd-PEPPSI: TON = 1440;
[Pd(IPr)(cin)Cl]: TON = 1640; [Pd(IPr)(ind)Cl]: TON =
1520. 4-Tol = 4-tolyl.
(PEPPSI-IPr-B)
(PEPPSI-IPr-C)
40
20
0
0
2
4
6
8
10
12
14
16
to significantly decrease catalyst loading (from 6.0
mol%[15] to 1.0 mol%) in the cross-coupling. Overall,
this new catalytic system constitutes a major
improvement over other available methods for the
Suzuki-Miyaura cross-coupling of esters.[13,14] The
method enables efficient catalysis at ambient
conditions, using cheap, readily available Pd-PEPPSI
catalyst[16–20] at low catalytic loading and employing a
mild carbonate base under operationally-simple
reaction conditions.
In order to further demonstrate the utility of this
aqueous cross-coupling method, cross-coupling of
aryl ester 1 in the absence and presence of water was
tested using various Pd-NHC precatalysts (Table 3,
Scheme 1). Generally speaking, two major classes of
throw-away ligands in the Suzuki-Miyaura cross-
coupling using Pd-NHC precatalysts have been
developed:[16] PEPPSI-type heterocyclic ligands (4)
and allyl-type ligands, such as [Pd(IPr)(cin)Cl] (5),
time (h)
Figure 2. Kinetic profile of 1a. Conditions: A) 1a, 4-Tol-
B(OH)2 (2.0 equiv), K2CO3 (3.0 equiv), Pd-PEPPSI (3.0
mol%), H2O (5.0 equiv), 23 °C; B) 1a, 4-Tol-B(OH)2 (2.0
equiv), K2CO3 (3.0 equiv), Pd-PEPPSI (3.0 mol%), 23 °C;
C) 1a, 4-Tol-B(OH)2 (2.0 equiv), K2CO3 (3.0 equiv),
[Pd(-OH)Cl(IPr)]2 (1.5 mol%), H2O (5.0 equiv), 23 °C.
It is noteworthy that we observe high TON (TON
= turnover number) value of 600 for the room
temperature Suzuki-Miyaura cross-coupling using
Pd-PEPPSI (Scheme 2). This can be compared with
TON of 570 and 680 using allyl-type catalysts (5) and
(6), and with TON of 1440 (4), 1640 (5) and 1520 (6)
at 60 °C. Note that these conditions utilize close to
stoichiometric amounts of both the base (1.2 equiv)
and boronic acid (1.2 equiv). To our knowledge, this
3
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10.1002/adsc.201701563
Advanced Synthesis & Catalysis
is by far the mildest conditions for the Suzuki-
Miyaura cross-coupling of esters reported to Conclusions
date.[13,14]
Experiments were performed to establish the role
of water in the cross-coupling. Pietraszuk et al.[25] and
Nolan et al.[26] independently reported the synthesis
of Pd(II)-NHC hydroxide dimers,[27] and their high
activity in the Suzuki-Miyaura cross-coupling of aryl
halides. Subjecting the Pd-PEPPSI precatalyst to our
standard cross-coupling conditions (K2CO3, H2O)
produces the hydroxide dimer, [Pd(-OH)Cl(IPr)]2
(7) in appreciable 32% yield at ambient conditions
(H2O, 50 mmol) and close to quantitative yield at
65 °C (Scheme 3). Kinetic studies demonstrate that
the cross-coupling using [Pd(-OH)Cl(IPr)]2 (7)
proceeds at a faster rate than with Pd-PEPPSI (4)
(Figure 2, conditions A-B). Note that negligible
conversion is observed in the absence of water
(Figure 2, conditions C). Thus, formation of the
hydroxide dimer may be taking place prior to
In summary, in this Update article, we have shown
the first Pd-PEPPSI-catalyzed Suzuki-Miyaura cross-
coupling of aryl esters via selective C–O cleavage at
room temperature. The developed catalytic system
employs cheap, readily-available, air-stable and
easily-assembled Pd-PEPPSI precatalyst, which
shows major advantages over other Pd-NHC
complexes. This new methodology has been
successfully applied to the cross-coupling of a wide
range of electronically- and sterically-varied aryl
esters and boronic acids generating biaryl ketones in
good to excellent yields under operationally-practical
reaction conditions. We have shown that the
activating effect of water is general, and includes
PEPPSI-type and allyl-type Pd-NHC precatalysts.
This protocol has also allowed for the first time to
achieve TON >1,000 in the Suzuki-Miyaura cross-
coupling of aryl esters. Mechanistic studies
demonstrated that Pd(II)-NHC hydroxide dimer is
formed under the reaction conditions, and that this
species shows high catalytic activity in the cross-
coupling of esters. We anticipate that the findings
reported in this manuscript will have broad
implications for the development of general cross-
coupling methods using Pd-NHC catalysis.
Scheme 4. Large Scale Suzuki–Miyaura Cross-Coupling at
Room Temperature.
reduction to the active Pd(0)-NHC species.[28] Studies
on the catalytic cycle are ongoing and will be
reported separately.
The scalability of this new cross-coupling protocol
has been evaluated. We were pleased to find that the
cross-coupling of 1a could be conveniently carried
out on a gram scale and gave the desired ketone
product in 95% isolated yield (Scheme 4), attesting to
the synthetic utility of the method.
Experimental Section
General Information. General methods have been
published.[12]
General Procedure for the Suzuki-Miyaura Cross-
Coupling of Esters at RT. An oven-dried vial equipped
with a stir bar was charged with an ester substrate (neat,
1.0 equiv), potassium carbonate (typically, 3.0 equiv),
boronic acid (typically, 2.0 equiv), PEPPSI-IPr (typically,
1.0 mol%), placed under a positive pressure of argon, and
subjected to three evacuation/backfilling cycles under high
vacuum. THF (typically, 0.25 M) and H2O (typically, 5.0
equiv) were added with vigorous stirring at room
temperature. After the indicated time, the reaction mixture
was diluted with CH2Cl2 (10 mL), filtered, and
concentrated. The sample was analyzed by 1H NMR
(CDCl3, 500 MHz) and GC-MS to obtain conversion,
selectivity and yield using internal standard and
comparison with authentic samples. Purification by
chromatography on silica gel (EtOAc/hexanes) afforded
the title product.
Finally, it is important to point out advantages of
using ester electrophiles in the cross-coupling.[6a] (1)
Bench-stable ester electrophiles represent prevalent
precursors in organic synthesis as well as products of
many synthetic reactions, which renders them unique
over alternative acyl cross-coupling precursors. (2)
Moreover, the high stability of bench-stable esters
provides opportunities for orthogonal cross-coupling
strategies in the presence of other electrophiles. (3)
Furthermore, esters are easy to prepare, while their
cross-coupling is operationally-simple without taking
special precautions to exclude moisture or air, which
makes them attractive for practical industrial and
academic applications.[3a] (4) Lastly, using easily-
accessible ester precursors allows to reduce the
amount of toxic waste generated during the cross-
coupling manifolds. It is further interesting that the
current catalytic system shows exquisite selectivity
for the cross-coupling of aryl esters in the presence of
their alkyl counterparts. This is due to much higher
barrier to isomerization around the C–O bond in alkyl
esters (C–OPh, 9.3 kcal/mol; C–OMe, 12.8 kcal/mol),
which renders oxidative addition selective for the
OPh electrophiles.[13c]
Representative Cross-Coupling Procedure at RT (1.0 g
scale). An oven-dried vial equipped with a stir bar was
charged with phenyl benzoate (neat, 5.05 mmol, 1.00 g, 1.0
equiv), potassium carbonate (15.2 mmol, 2.10 g, 3.0 equiv),
p-tolylboronic acid (10.1 mmol, 1.38 mg, 2.0 equiv),
PEPPSI-IPr (1.0 mol%, 34.0 mg), placed under a positive
pressure
of
argon,
and
subjected
to
three
evacuation/backfilling cycles under high vacuum. THF
(0.25 M) and H2O (25.25 mmol, 0.45 mL, 5.0 equiv) were
added with vigorous stirring at room temperature, and the
reaction mixture was stirred for 36 h at room temperature.
After the indicated time, the reaction mixture was diluted
with CH2Cl2 (80 mL), filtered, and concentrated. The
1
sample was analyzed by H NMR (CDCl3, 500 MHz) and
GC-MS to obtain conversion, selectivity and yield using
internal standard and comparison with authentic samples.
4
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10.1002/adsc.201701563
Advanced Synthesis & Catalysis
Purification by chromatography on silica gel
(EtOAc/hexanes) afforded the title product; 95% (0.941 g).
[10] For a review on acylmetal intermediates, see: L. J.
Gooßen, N. Rodriguez, K. Gooßen, Angew. Chem. Int.
Ed. 2008, 47, 3100-3120; Angew. Chem. 2008, 120,
3144-3164.
Acknowledgements
[11] For representative decarbonylative coupling of
amides, see: a) G. Meng, M. Szostak, Angew. Chem. Int.
Ed. 2015, 54, 14518-14522; Angew. Chem. 2015, 127,
14726-14730; b) S. Shi, G. Meng, M. Szostak, Angew.
Chem. Int. Ed. 2016, 55, 6959-6963; Angew. Chem.
2016, 128, 7073-7077; c) C. Liu, M. Szostak, Angew.
Chem. Int. Ed. 2017, 56, 12718-12722; Angew. Chem.
2017, 129, 12892-12896 and references cited therein.
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz
spectrometer used in this study was supported by the NSF-MRI
grant (CHE-1229030). P.L. thanks the China Scholarship
Council (No. 201606350069) for a fellowship.
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UPDATE
Pd-PEPPSI: Water-Assisted Suzuki–Miyaura
Cross-Coupling of Aryl Esters at Room
Temperature using a Practical Palladium-NHC
(NHC = N-Heterocyclic Carbene) Precatalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Guangchen Li, Shicheng Shi, Peng Lei, Michal
Szostak*
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