Easily prepared air- and moisture-stable Pd-NHC (NHC = N-heterocyclic carbene) complexes: A reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction

Article abstract of DOI:10.1002/chem.200600251

The synthesis of NHC-PdCl₂-3-chloropyridine (NHC = N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.

Full text of DOI:10.1002/chem.200600251

FULL PAPER
DOI: 10.1002/chem.200600251
Easily Prepared Air- and Moisture-Stable Pd–NHC (NHC=N-Heterocyclic
Carbene) Complexes: A Reliable, User-Friendly, Highly Active Palladium
Precatalyst for the Suzuki–Miyaura Reaction
Christopher J. OꢀBrien,[a] Eric Assen B. Kantchev,[a] Cory Valente,[a] Niloufar Hadei,[a]
Gregory A. Chass,[a] Alan Lough,[b] Alan C. Hopkinson,[a] and Michael G. Organ*[a]
Abstract: The synthesis of NHC-PdCl2-
3-chloropyridine (NHC=N-heterocy-
clic carbene) complexes from readily
available starting materials in air is de-
scribed. The 2,6-diisopropylphenyl de-
rivative was found to be highly catalyti-
cally active in alkyl–alkyl Suzuki and
Negishi cross-coupling reactions. The
synthesis, ease-of-use, and activity of
this complex are substantial improve-
ments over in situ catalyst generation
and all current Pd–NHC complexes.
The utilization of complex 4 led to the
development of a reliable, easily em-
ployed Suzuki–Miyama protocol. Em-
ploying various reaction conditions al-
lowed a large array of hindered biaryl
and drug-like heteroaromatic com-
pounds to be synthesized without diffi-
culty.
À
Keywords: alkanes · C C coupling ·
heterocycles · palladium
The use of N-heterocyclic carbenes (NHCs) as ligands has
led to an array of exciting developments in Pd-catalyzed
cross-coupling reactions.[1] The high sensitivity of isolated
NHCs[2] necessitates handling under rigorously anhydrous
conditions. In situ preparation of active Pd–NHC catalysts
has been the dominant strategy to circumvent this prob-
lem.[3,4] Recently, we disclosed the first Negishi alkyl–alkyl
cross-coupling protocol with a Pd–NHC catalyst prepared
from the imidazolium salt 1 and common Pd sources, and
proposed that the active catalyst is a monoligated Pd–NHC
complex.[5] However, the uncertainty surrounding the stoi-
chiometry and composition of the active species is a major
drawback in mechanistic interpretation of the results.[6]
Moreover, the rate and efficiency of catalyst formation is
difficult to control under these conditions, possibly leading
to waste of precious Pd metal and ligand precursor. The de-
velopment of stable, easy-to-prepare-and-handle Pd–NHC
complexes that are readily activated under the reaction con-
ditions would increase the use of Pd–NHC catalysts in aca-
demic and industrial laboratories. Recently, the groups of
Herrmann,[7] Nolan,[8] Beller,[9] and Sigman[10] have publish-
ed an array of monoligated Pd–NHC complexes that show
high levels of activity in Pd-catalyzed reactions. However,
these catalysts were all prepared under rigorous anhydrous
conditions even when the isolated carbene was not used. A
major step forward, then, would be to develop a process for
the preparation of Pd–NHC precatalysts in air, using readily
available starting materials on a large scale. We envisioned
stable, PdII species bearing one NHC ligand, two anionic li-
gands (e.g., Cl, Br, OAc) and a fourth, “throw-away” ligand.
Even though a number of Pd complexes of NHC–pyridine
bidentate chelating ligands have been prepared,[7a,11] ana-
logues containing monodentate NHC and pyridine ligands
are virtually unknown.[12] Hence, analogous to Grubbs
et al.,[13a] we concluded that a suitably substituted pyridine
would be an excellent candidate for the role of the throw-
away ligand. Gratifyingly, heating of imidazolium salts 1, 2,
or 3 with PdCl2, and K2CO3 in neat 3-chloropyridine, in air
[a] Dr. C. J. OꢀBrien, Dr. E. A. B. Kantchev, C. Valente, N. Hadei,
Dr. G. A. Chass, Prof. A. C. Hopkinson, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON M3J 1P3 (Canada)
Fax : (+1)416-736-5956
E-mail: organ@yorku.ca
[b] Dr. A. Lough
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON M5S 3H6 (Canada)
(Scheme 1) led to the corresponding complexes 4–6
[13b]
À
(Figure 1) in excellent yields by direct C H insertion.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It contains the
preparation, characterization data, X-ray crystallography data for 4
and general procedures for all cross-coupling reactions.
When we submitted complex 4 (1 mol%) to alkyl–alkyl
Suzuki and Negishi cross-coupling reactions, rapid (Suzuki
5 minutes, Negishi 30 minutes) quantitative formation of 7
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4743

Scheme 1. Synthesis of NHC-PdCl2-3-chloropyridine complexes.
Figure 2. Rate studies with precatalysts 4 and 5 in the alkyl–alkyl cross-
coupling reactions: a) Suzuki reaction; b) Negishi reaction. Yields deter-
mined by GC/MS against a calibrated internal standard (undecane).
Figure 1. ORTEP representation of the crystal structure of 4. The crucial
role of the auxiliary pyridine ligand is highlighted.
was observed at room temperature (Table 1). Not only were
the yields with the diethyl analogue 5 moderate (31–34%),
the rate of the reaction was also much slower than with
Table 1. Catalytic activity of the Pd–NHC catalysts 4–6 in alkyl–alkyl
cross-coupling reactions.
Scheme 2. Activation and use of complex 4.
[a,b]
Entry
M
Yield of n-heptylbenzene (7) [ %]
4
5
6
1
2
ZnBr[c]
BBu2
100
100
34
31
8.0
6.5
analyzed the reaction mixture by GC/MS. From this analysis
we observed the formation of n-tetradecane and liberation
of 3-chloropyridine.[15] Additionally, preliminary computa-
tional studies further collaborate our proposed activation
mechanism.[15b] Thus, after palladium reduction the pyridine
dissociates, analogous to the loss of a phosphine group. A
significant increase in rate was observed when catalysis with
[d]
[a] GC yield (internal standard-undecane) after 24 h at RT; all reactions
in duplicate. [b] Control experiments with no catalyst showed no conver-
sion in all cases. [c] n-Butylzinc bromide (1.3 equiv), THF/NMP=2:1.
[d] Tri-n-butylborane (1.2 equiv), tBuOK (1.3 equiv), iPrOH.
complex 4 (Table 1, Figure 2). These results imply that bulky
NHC ligands lead to fast reductive elimination, which sup-
presses undesired side reactions or catalyst decomposition in
a manner analogous with bulkyphosphines.[14] It is unlikely
that pyridine dissociation initiates catalyst activation consid-
ering the high stability of complex 4.[13c] Rather, rapid reduc-
tion facilitated by the organometallic reagent takes place
followed by pyridine dissociation from the generated Pd0
species (Scheme 2). To support this rationale we treated
complex 4 with two equivalents of n-heptylzinc bromide and
precatalyst 4 at 1 mol% was compared to the [Pd2(dba)3]/1
A
(dba=dibenzylideneacetone) in situ protocol at 4 mol%
(Figure 3a). Extremely fast rates at 1 mol% of 4 made it dif-
ficult to reliably measure the reaction rate, therefore a load-
ing of 0.1 mol% was used (Figure 3b). Interestingly, after
one hour there was a considerable difference in turnover
frequency (TOF, Figure 3b) when the isolated complex and
in situ processes were compared. If we assume that the
same active catalyst is generated in solution when either
protocol is employed and that turnover number (TON) and
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Chem. Eur. J. 2006, 12, 4743 – 4748

Cross-Coupling Reactions
FULL PAPER
into a variety of Suzuki–Miyaura reaction conditions with
no anhydrous precautions taken (Table 2). We were delight-
ed to find that all complexes functioned as excellent cata-
lysts at 808C (Table 2, entries 1, 2 and 4).
Table 2. Optimization of Suzuki–Miyaura conditions for boronic acids.
Entry
Catalyst
(mol%)
Solvent
Base
(equiv)
T
[8C]
Yield
G
A
[%][a,b]
1
2
3
4
5
6
7
8
6 (2)
5 (2)
5 (2)
4 (2)
4 (2)
4 (2)
4 (2)
4 (2)
4 (2)
4 (2)
4 (1)
4 (1)
dioxane
dioxane
DME
dioxane
dioxane
DME
dioxane
dioxane
dioxane
dioxane
dioxane
iPrOH
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K3PO4 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
tBuOK
80
80
80
80
80
80
80
80
60
RT
80
RT
74
95
54
48
92
77
80
95
97
86
74
97
9
10
11
12
Figure 3. In situ catalyst versus NHC-PdCl2-3-chloropyridine complexes
in the alkyl–alkyl Negishi reaction: a) rate comparison with [Pd2
A
and 4; b) TON comparison between [Pd2(dba)3]/1 and 4 after 1 h.
AHCTREUNG
[a] GC yield (internal standard, undecane) after 2 h at RT; all reactions
in duplicate. [b] Control experiments with no catalyst showed no conver-
sion.
TOF are inherent properties of a compound it appears that
only ~0.1 mol% of active catalyst is actually formed when
utilizing the in situ protocol, even though 4 mol% of the
precursors are used. The fact that most published protocols
make use of in situ catalyst formation, with the inherent
problems detailed above, may account for the limited use
and capricious nature of Pd–NHC-based methodology.
To further demonstrate the utility of compounds 4–6, we
decided to evaluate the complexes in a highly industrial ap-
plicable process, the Suzuki–Miyaura reaction. The palladi-
um-catalyzed Suzuki–Miyaura reaction is the most readily
However, under closer scrutiny we found that complex 4
was superior as it was possible to conduct reactions in both
dioxane and iPrOH at room temperature with a judicious
choice of base (Table 2, entries, 10 and 12).
Expansion of the protocol to potassium trifluoroboroates
was accomplished by simply changing the solvent to metha-
nol (Table 3, entries 2 and 5–8). The employment of a varie-
ty of reaction conditions allowed a large array of hindered
biaryls and drug-like heteroaromatics to be easily synthe-
sized (Scheme 3). A notable result is the synthesis of 19
À
utilized C C cross-coupling protocol due to boronic acid
availability and stability, substrate compatibility, ease-of-use,
and waste disposal. In recent years there have been signifi-
cant advances in palladium–phosphine-based Suzuki–
Miyaura methodology.[16] Fu and co-workers detailed the
employment of alkyl halides and toylates with alkylboranes,
a variety of boronic acids, and in one instance an alkyl bor-
onic acid.[17] The coupling of hindered aromatic halides with
aryl and vinyl boronic acids was disclosed by Buchwald and
co-workers.[18] Additionally, Capretta et al.[19] successfully
coupled secondary bromides with aryl boronic acids. In con-
trast to phosphine-ligated processes, the development of
NHC-based protocols has been less successful. Indeed, pal-
ladium–NHC catalysts lack the substrate scope and ease-of-
use of their phosphine cousins.[1] Progress has been made,
but either the cross-coupling reaction or catalyst synthesis
must be carried out in a rigorously dry and inert environ-
ment, typically employing a glove box.[3,20] Furthermore,
most NHC methodology relies on in situ formation of the
active catalyst, which leads to irreproducibility and wide
yield variations.[5] We therefore submitted complexes 4–6
Table 3. Optimization of Suzuki–Miyaura conditions for potassium tri-
fluoroborates.
Entry
Solvent
Base (equiv)
T [8C]
Yield [%][a,b]
1
2
3
4
5
6
7
8
dioxane
MeOH
EtOH
iPrOH
MeOH
MeOH
MeOH
MeOH
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
CsF
60
60
60
60
RT
60
60
60
0
90
30
27
86
0
KOH
K3PO4
91
84
[a] GC yield (internal standard, undecane) after 24 h at RT; all reactions
in duplicate. [b] Control experiments with no catalyst showed no conver-
sion.
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4745

M. G. Organ et al.
of 4, easily reduced to a highly active Pd0–NHC species. We
believe the pyridine ligand plays a pivotal role in the facile
preparation and stabilization of the PdII complex, while
readily dissociating upon catalyst activation. We have coined
the term PEPPSI (pyridine-enhanced precatalyst, prepara-
tion, stabilization, and initiation) to describe this effect. Ad-
ditionally the method of preparation of complex 4 is a sub-
stantial improvement over previously reported Pd–NHC
complexes and allows easy synthesis on
a kilogram
scale.[13b,22] The high activity of complex 4 (PEPPSI-IPr;
IPr=diisopropylphenylimidazolium derivative) in alkyl–
alkyl couplings with Zn and B derivatives (arguably the
most challenging case) holds great promise that 4 will be
generally applicable to a wide variety of cross-coupling pro-
tocols. To this end we demonstrated the utility of 4 in the
Suzuki–Miyaura reaction. The employment of various reac-
tion conditions allowed a large array of hindered biaryl and
drug-like heteroaromatic compounds to be synthesized with-
out difficulty. In one case a highly active MBA catalyst was
readily produced in one step. We believe that complex 4
with all of the advantages stated above will be widely adopt-
ed in industrial and academic research laboratories world
wide.[22,23]
Experimental Section
Below are representative procedures for the formation of the PEPPSI
complexes and the Suzuki–Miyaura cross-coupling reactions. A detailed
account of reaction conditions and characterization of products can be
found in the Supporting Information.
Synthesis of the NHC-PdCl2-3-chloropyridine complexes: In air, a vial
was charged with PdCl2 (177 mg, 1.0 mmol), NHC·HCl (1.1 mmol),
K2CO3 (691 mg, 5.0 mmol) and a stirrer bar. 3-Chloropyridine (4.0 mL)
was added, the vial was capped with a Teflonꢂ-lined screw cap and
heated with vigorous stirring for 16 h at 808C. After cooling to RT, the
reaction mixture was diluted with CH2Cl2 and passed through a short pad
of silica gel covered with a pad of Celite eluting with CH2Cl2 until the
product was completely recovered. Most of the CH2Cl2 was removed
(rotary evaporator) at RT, and the 3-chloropyridine was then vacuum-dis-
tilled (water aspirator vacuum) and saved for reuse. The pure complexes
4–6 were isolated after triturating with pentane, decanting of the super-
natant and drying in high vacuum.
Scheme 3. Sp2–sp2 substrate scope. All reactions were performed by using
standard laboratory techniques. Method A: (1 mol%), KtOBu
(1.3 equiv), reagent grade isopropanol, RT. Method B: 4 (2 mol%), diox-
ane, 608C . Method C: 4 (2 mol%), K2CO3 (3.0 equiv), methanol, 608C.
Method D: 4 (2 mol%), KOHs (3.0 equiv), dioxane, RT. Compound 11
was isolated in 70% yield after 12 h at RT. Compound 19 was prepared
4
Data for complex 4: Using the above method NHC·HCl (468 mg,
1.1 mmol) gave complex 4 (677 mg, 97%) as a yellow solid. M.p. 2408C
(decomp); 1H NMR (400 MHz, CDCl3): d=8.62 (d, J=1.6 Hz, 1H), 8.54
(d, J=5.6 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.37
(d, J=7.7 Hz, 4H), 7.16 (s, 2H), 7.09 (dd, J=8.0 Hz, 5.7 Hz, 1H), 3.18
(m, 4H), 1.50 (d, J=6.7 Hz, 12H), 1.14 ppm (d, J=6.8 Hz, 12H);
13C NMR (100 MHz, CDCl3): d=153.5, 150.5, 149.4, 146.7, 137.4, 135.0,
132.0, 130.3, 125.1, 124.3, 124.1, 28.7, 26.3, 23.2 ppm; elemental analysis
calcd (%) for C32H40Cl3N3Pd: C 56.57, H 5.93, N 6.18; found: C 56.90, H
5.99, N 6.52.
from 4 (4 mol%) K2CO3 (6.0 equiv), and RB(OH2) (2.4 equiv); this prod-
G
uct has been made on a 10 g scale with a yield of 80%.
(Scheme 3), which when used in combination with triethyl-
phosphine has been demonstrated to form a highly effective
asymmetric Morita–Baylis–Hillman (MBA) catalyst.[21]
Use of isopropanol/tBuOK (Method A) allowed for rapid
cross-coupling at room temperature, whereas more sensitive
coupling partners were effectively coupled utilizing K2CO3
in dioxane (Method B) or methanol in the case of potassium
trifluoroborates (Method C).
In conclusion we have developed a series of NHC-PdCl2-
3-chloropyridine complexes that are: 1) readily prepared in
air on a large-scale from cheap starting materials, 2) handled
and stored in air—no glove box necessary, and 3) in the case
Procedure for method A: In air, a vial was charged with potassium tert-
butoxide (154 mg, 1.30 mmol) and complex 4 (6.8 mg, 0.01 mmol), and
the vial was sealed and purged with argon (3”). Technical grade isopro-
panol (1.0 mL) was added and the contents were stirred at room temper-
ature until a color change from yellow to red/brown was observed
(~10 min). Under a cone of argon, the boronic acid (1.20 mmol) was added,
the vial was resealed with a septum, and the organohalide (1.00 mmol)
was injected with a microliter syringe. Alternatively, if the boronic acid
was soluble in isopropanol, it can be added as a solution (1.0 mL). The
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Cross-Coupling Reactions
FULL PAPER
solution was stirred at room temperature for the indicated period of
time. The reaction was then diluted with diethyl ether (2 mL) and trans-
ferred to a round-bottomed flask. The reaction vial was rinsed with addi-
tional diethyl ether (2 mL) and combined with the previous dilution.
Each reaction was performed in duplicate and the contents were com-
bined, concentrated onto silica gel, and purified by flash chromatography.
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Procedure for method B: In air, a vial was charged with complex 4
(6.8 mg, 0.01 mmol), potassium carbonate (207 mg, 1.50 mmol), the bor-
onic acid (0.6 mmol), and the organohalide (0.5 mmol). The vial was
sealed with a septum and purged with argon (3”). Dioxane (2.0 mL) was
added and the contents were stirred at 608C for the specified period of
time. The reaction was then diluted with diethyl ether (2 mL) and trans-
ferred to a round-bottomed flask. The reaction vial was rinsed with addi-
tional diethyl ether (2 mL) and combined with the previous dilution.
Each reaction was performed in duplicate and the contents were com-
bined, concentrated onto silica gel, and purified by flash chromatography.
Procedure for method C: In air, a vial was charged with complex 4
(6.8 mg, 0.01 mmol), potassium carbonate (207 mg, 1.50 mmol), the potas-
sium trifluoroborate (0.55 mmol), and the organohalide (0.5 mmol). The
vial was sealed with a septum and purged with argon (3”). Technical
grade methanol (2.0 mL) was added and the contents stirred at 608C for
the specified period of time. The reaction was then diluted with diethyl
ether (2 mL) and transferred to a round-bottomed flask. The reaction
vial was rinsed with additional diethyl ether (2 mL) and combined with
the previous dilution. Each reaction was performed in duplicate and the
contents were combined, concentrated onto silica gel, and purified by
flash chromatography.
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[12] Independently, while this work was in progress, preparation of
chiral, N-ferrocenyl-substituted NHC-PdI2-pyridine complexes was
published: A. Bertogg, F. Campanovo, A. Togni, Eur. J. Inorg.
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Procedure for method D: Method B was followed; however, in the place
of solid potassium carbonate, solid KOH (84 mg, 1.50 mmol) was utilized.
Additionally, the reaction was carried out at room temperature instead of
608C.
Acknowledgement
[13] a) Analogous to Grubbs type-III catalyst: J. A. Love, J. P. Morgan,
T. M. Trnka, R. H. Grubbs, Angew. Chem. 2002, 114, 4207–4209;
Angew. Chem. Int. Ed. 2002, 41, 4035–4037; b) complex 4 was pre-
pared on 35 g scale, 93% yield by using Cs2CO3; c) complexes 4–6
are air and water tolerant and do not decompose upon standing.
We thank ORDCF and NSERC Canada for financial support.
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Heating 4 at 1008C in [ D]DMSO for 24 h led to no visable decom-
6
position (by H and 13C NMR spectroscopic analysis).
1
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[15] a) Prior to GC/MS analysis, the crude mixture was passed through a
plug of silica to prevent the catalyst from entering the GC column
(see the Supporting Information); b) DFT calculations at the
B3LYP/DZVP level showed that the binding enthalpy of 3-chloro-
pyridine to NHC-ligated PdII is 4.5 kcalmolÀ1 higher than to Pd0.
Also the dissociation energy of PH3 is 16.5 kcalmolÀ1 compared to
19.4 kcalmolÀ1 for the 3-chloropyridine; c) one reviewer suggested
an NMR experiment would pinpoint whether the 3-chloropyridine
dissociated from a Pd0 or a PdII center. However, this would not be
the case, since the production of free 3-chloropyridine and the ho-
mocoupled product would be seen; in both cases simply the order of
events would be reversed upon catalyst activation.
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Received: February 22, 2006
Published online: March 28, 2006
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