N-heterocycle carbene (NHC)-ligated cyclopalladated N,N- dimethylbenzylamine: A highly active, practical and versatile catalyst for the Heck-Mizoroki reaction

Article abstract of DOI:10.1039/b821892g

The wide dissemination of catalytic protocols in academic and industrial laboratories is facilitated by the development of catalysts that are not only highly active but also user-friendly, stable to moisture, air and long term storage and easy to prepare on a large scale. Herein we describe a protocol for the Heck-Mizoroki reaction mediated by cyclopalladN-dimethylbenzylamine (dmba) ligated ne, 1,3-bdot;HCl in refluxing acetonitrile in air in the presence of K₂CO in iates the H bromides in reagent grade NMP at the 0.1-2 mol% range without the need for rigorous anhydrous techniques or a glovebox, and is active even in air. The catalyst is capable of achieving very high levels of catalytic activity (TON of up to 5.22 × 10⁵) for the coupling of a deactivated arylbromide, p-bromoanisole, with tBu acrylate as a benchmark substrate pair. A wide range of aryl bromides, iodides and, for the first time with a NHC-Pd catalyst, a triflate was coupled with diverse acrylate derivatives (nitrile, tert-butyl ester and amides) and styrene derivatives. The use of excess (>2 equiv.) of the aryl bromide and tert-butyl acrylate leads to mixture of tert-butyl β,β-diarylacrylate and tert-butyl cinnamate derivatives depending on the substitution pattern of the aryl bromide. Electron rich m- and p-substituted arylbromides give the diarylated products exclusively, whereas electron-poor aryl bromides give predominantly mono-arylated products. For o-substituted aryl bromides, no doubly arylated products could be obtained under any conditions. Overall, the active catalyst (IMes-Pd) shows higher activity with electron-rich aryl halides, a marked difference compared with the more commonly used phosphane-Pd or non-ligated Pd catalysts.

Full text of DOI:10.1039/b821892g

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Volume 7 | Number 10 | 21 May 2009 | Pages 1989–2224
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FULL PAPER
2WT\XRP[ꢀBRXT]RT
Guang-Rong Peh et al.
(NHC)-ligated cyclopalladated
N,N-dimethylbenzylamine: a catalyst
for the Heck–Mizoroki reaction
In this issue...
1477-0520(2009)7:10;1-H

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
N-heterocycle carbene (NHC)-ligated cyclopalladated
N,N-dimethylbenzylamine: a highly active, practical and versatile catalyst for
the Heck–Mizoroki reaction†
Guang-Rong Peh, Eric Assen B. Kantchev,*‡ Chi Zhang and Jackie Y. Ying*
Received 5th December 2008, Accepted 13th February 2009
First published as an Advance Article on the web 26th March 2009
DOI: 10.1039/b821892g
The wide dissemination of catalytic protocols in academic and industrial laboratories is facilitated by
the development of catalysts that are not only highly active but also user-friendly, stable to moisture, air
and long term storage and easy to prepare on a large scale. Herein we describe a protocol for the
Heck–Mizoroki reaction mediated by cyclopalladated N,N-dimethylbenzylamine (dmba) ligated with a
N-heterocyclic carbene, 1,3-bis(mesityl)imidazol-2-ylidene (IMes), that fulfils these criteria. The
precatalyst can be synthesized on ~100 g scale by a tri-component, sequential, one-pot reaction of
N,N-dimethylbenzylamine, PdCl2 and IMes·HCl in refluxing acetonitrile in air in the presence of
K2CO3. This single component catalyst is stable to air, moisture and long term storage and can be
conveniently dispensed as a stock solution in NMP. It mediates the Heck–Mizoroki reaction of a range
of aryl- and heteroaryl bromides in reagent grade NMP at the 0.1–2 mol% range without the need for
rigorous anhydrous techniques or a glovebox, and is active even in air. The catalyst is capable of
achieving very high levels of catalytic activity (TON of up to 5.22 ¥ 105) for the coupling of a
deactivated arylbromide, p-bromoanisole, with tBu acrylate as a benchmark substrate pair. A wide
range of aryl bromides, iodides and, for the first time with a NHC-Pd catalyst, a triflate was coupled
with diverse acrylate derivatives (nitrile, tert-butyl ester and amides) and styrene derivatives. The use of
excess (>2 equiv.) of the aryl bromide and tert-butyl acrylate leads to mixture of tert-butyl
b,b-diarylacrylate and tert-butyl cinnamate derivatives depending on the substitution pattern of the
aryl bromide. Electron rich m- and p-substituted arylbromides give the diarylated products exclusively,
whereas electron-poor aryl bromides give predominantly mono-arylated products. For o-substituted
aryl bromides, no doubly arylated products could be obtained under any conditions. Overall, the active
catalyst (IMes-Pd) shows higher activity with electron-rich aryl halides, a marked difference compared
with the more commonly used phosphane-Pd or non-ligated Pd catalysts.
the Heck–Mizoroki reaction is also a key transformation of
Introduction
strategic importance in natural product synthesis.5 The generally
accepted mechanism6 for the Heck–Mizoroki reaction is shown
in Scheme 1. The first step, oxidative addition of the arylhalide
into the active Pd(0) catalyst is common for all Pd-mediated
It is difficult to imagine organic synthetic chemistry today without
cross-coupling reactions, a family of transformations that allow
two organic moieties to be joined by a single bond by means of a
transition metal catalyst,1 most often Pd.2 Within the family, the
Heck–Mizoroki reaction3 has become one of the most prominent.
For the pharmaceutical industry in particular, a recent survey
of the chemical reactions employed by major pharmaceutical
companies for the preparation of drug candidates in process R
& D found that among all C–C bond-forming reactions, Pd-
catalyzed processes were the single most employed reaction class
(22%), with the Suzuki–Miyaura and Heck–Mizoroki reactions
claiming the lion’s share (11% and 7%, respectively).4 In addition,
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way #04-01
The Nanos, Singapore 138669
† Electronic supplementary information (ESI) available: Synthetic proce-
dures and characterization data for compounds 1, 7–66. CCDC reference
number 674228. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b821892g
‡ Current address: Forma Therapeutics Singapore Pte. Ltd, Nanyang
Technological University, SPMS-CBC-04/05, 21 Nanyang Link Singapore
637371
Scheme 1 The generally accepted mechanism of the Heck–Mizoroki
reaction.
2110 | Org. Biomol. Chem., 2009, 7, 2110–2119
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cross-coupling reactions. Upon binding of the olefin to the resul-
tant Ar-Pd(II)-X intermediate, syn-migratory insertion followed
by s-bond rotation and syn-b-hydride elimination ensue, resulting
in the formation of the Heck–Mizoroki product and H-Pd(II)-X
adduct. Base-promoted reductive elimination of HX completes
the cycle and regenerates the catalyst. Ligandless Pd7 was the
catalyst in the initial reports of this reaction by the groups of
Heck8 and Mizoroki9 and even today it remains one of the top
choices owing to low cost and high activity. Pd(OAc)2 alone7,10 or in
the presence of tetraalkyl ammonium salts (Jeffery conditions),7,11
PdCl2 and its soluble bis(nitrile) adducts12 or preformed Pd
nanoparticles13 have all been explored as readily available lig-
andless Pd precatalysts. The first use of the cyclopalladated
tri(o-tolyl)phosphane (Herrmann-Beller palladacycle) a catalyst
for the Heck–Mizoroki14 and Suzuki–Miyaura15 reactions was
published in 1995. As there are a plethora of stable, o-palladated
aromatic compounds possessing O, N, P or S atoms,16 this finding
caused a surge of enthusiasm with the expectation for asymmetric
induction and Pd(II)/Pd(IV) catalytic cycle17 if the palladacycle
framework were retained in the coordination sphere of the Pd
atom during catalysis. Subsequent investigation, however, showed
that under cross-coupling conditions palladacycles are not stable,
but degrade rapidly to give colloidal Pd(0).18,19 Today, pallada-
cycles are popular, highly active precatalysts for the ligandless
Heck–Mizoroki reaction.20
As a result of numerous studies throughout the years, it
has become clear that high-yield couplings of aryliodides and
activated bromides can be achieved with virtually any Pd source.21
However, arylhalides derived from more complex, highly sub-
stituted aryl and heteroaryl halides usually require the addition
of a spectator ligand (L, Scheme 1). The nature of the ligand
plays a paramount role for the success of challenging cross-
couplings. Triarylphosphanes, for example triphenylphosphane
and tri(o-tolyl)phosphane are excellent ligands for Heck–Mizoroki
couplings of iodo- and, especially, bromoarenes with an ex-
tended range of olefins.22 Bulky, electron-rich trialkyl phos-
phanes such as tri(tert-butyl)phosphane and tricyclohexylphos-
phane are required for coupling the more inert, but cheaper
and more widely-available chloroarenes23,24 or room temperature
Heck–Mizoroki reactions.24,25 Finally, P, C -palladacycles derived
from suitably substituted triarylphosphanes have shown high
catalytic activity at comparatively lower catalyst loadings, even
towards arylchlorides.15 When P, C -palladacycles are activated,
highly active mono-ligated phosphane-Pd(0) complexes are
produced.26 However, phosphane ligands suffer from numer-
ous drawbacks. Pd-bound phosphanes are degraded at high
temperatures,27 leading to highly colored by-products that could be
difficult to remove from the cross-coupling product. In addition,
triarylphosphanes readily dissociate from Pd and are usually em-
ployed in excess in order to suppress the formation of catalytically
inactive Pd-black. On the other hand, trialkylphosphanes, which
can be used at 1:1 stoichiometry to Pd, are expensive and air-
sensitive, some even pyrophoric. In recent years, N-heterocyclic
carbenes (NHCs)28,29 have emerged as powerful ligands and
catalysts in general,30 and as an alternative to phosphane ligands in
Pd-mediated reactions in particular.31 NHC-Pd complexes exhibit
higher stability32 compared to their phosphane counterparts at
the high temperatures often employed during cross-couplings,
even at 1:1 Pd/NHC stoichiometry. In addition, the strong
s-donicity of NHCs facilitates the oxidative addition.33 Start-
ing with the seminal publication by Herrmann et al.,32 the
Heck–Mizoroki reaction of simple arylbromides or iodides with
acrylates or styrene has become a favorite benchmark for assessing
the catalytic potential of new NHC ligands.34,35 Even though
these studies have firmly established that NHCs are an excellent
choice as ligands for the Heck reaction,34,35 less common but more
synthetically relevant substrates have not been hitherto explored in
a systematic manner. Recently, we communicated our preliminary
results on the preparation and use of a well-defined, stable NHC-
palladacyclic complex (1; Fig. 1) in the Heck–Mizoroki reaction of
challenging substrates. Complex 1 showed levels of activity equal
to or exceeding other highly active Heck–Mizoroki catalysts.36
Herein we report the full account of the design and development
of 1 as a practical, highly active, versatile and user-friendly
Heck–Mizoroki catalyst.
Results and discussion
Catalyst design and large scale preparation
Pd-complexes of a bulky carbene, 1,3-bis(mesityl)imidazolyl-2-
ylidene (IMes; Fig. 1) mediate the Heck–Mizoroki reaction of
simple aryl bromides and diazonium salts with simple acrylates
and styrene.37–39 An unsymmetrical NHC ligand carrying one
N-Mes substituent and one chelating phosphane N-substituent
has also shown high levels of activity.35 Therefore, we focused on
IMes as a privileged ligand for the development of a practical,
widely applicable NHC-mediated Heck–Mizoroki reaction. How-
ever, the nature of the Pd precatalyst responsible for the smooth
delivery of Pd from the initial precatalyst into the catalytic cycle
also plays an important role in the success of the catalytic process
as a whole.40,41 As NHCs are highly air- and moisture-sensitive,
they are usually generated in-situ42 from stable precursors, e.g.,
imidazolium salts43 and then captured with common Pd sources.
This process is difficult to control; hence, the amounts and
composition of the active species produced are uncertain.37,44,45
The development of stable, well-defined NHC-Pd complexes that
can be activated under the reaction conditions can mitigate
the above drawbacks. Today, a number of such complexes have
been prepared38,44,46 and some are now commercially available.
Palladacycles decompose in a controlled manner to yield atomic
Pd(0) and the corresponding Heck–Mizoroki product at the pal-
ladated carbon47 (Fig. 1) under the conditions of the reaction.18,26
Therefore, palladacycles ligated with a single phosphane41,48,49 or
carbene ligand48,50–52 serve as stable precursors to mono-ligated53
catalytically active bulky phosphane/carbene-Pd(0) species. We
reasoned that a complex (1, Fig. 1) comprised of IMes
and the widely-used o-cyclopalladated N,N-dimethylbenzylamine
(2)54 had the potential to be an excellent precatalyst for the
Heck–Mizoroki reaction of challenging arylhalides by virtue
of combining the powerful carbene ligand with palladacycle-
controlled active catalyst release. Furthermore, wide adoption of
the catalytic protocols is facilitated when a number of practical
considerations besides the intrinsic activity of the catalyst—large
scale availability, cost, stability, tolerance to impurities, oxygen and
moisture, avoidance of highly toxic, difficult to remove reagents
and ease-of-use, among others—are met. A survey of the existing
methods for preparation of NHC-ligated palladacycles revealed
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Fig. 1 NHC-Palladacycle 1 as a catalyst for the Heck–Mizoroki reaction: design principles.
that treatment of dimeric palladacycles (e.g., 2) with isolated
carbenes in a glovebox is the most common.29,52 On the other
hand, alternative methods that employ moisture- and air-tolerant
carbene surrogates proceed only in moderate to low yields or are
limited in scope.50,55 Considering the above, we sought a general,
practical, scalable NHC-palladacycle synthesis that would employ
stable, easy to handle NHC precursors (imidazolium salts) and
in-situ prepared palladacycles without the need for anhydrous
techniques or a glove-box.56 We discovered that heating PdCl2
and the amine 4 in HPLC-grade acetonitrile in air in the presence
of K2CO3 followed by addition of the imidazolium salt IMes·HCl
(3) led to near quantitative yield of complex 1. Under optimized
conditions, multi-gram quantities of 1 (Scheme 2; 95 g, 90%)
were obtained after simple crystallization (CH3CN). The single
crystal X-ray structural analysis†§ confirmed the desired product,
revealing a characteristic, slightly distorted square-planar Pd(II)
centre with the NHC and the dimethylamino ligands mutually
trans (Fig. 2; bond angle C(carbene)–Pd–N(NMe2) = 169.9 ◦).
The Pd–C bond lengths are as expected for single bonds, 1.98 and
Fig. 2 ORTEP representation of the single crystal X-ray structure
of IMes-Pd(dmba)Cl (1). The thermal ellipsoids are shown at 30%
probability. The asymmetric unit has two molecules of the Pd com-
plex and a water molecule, which has been assigned 0.5 occupancy.
Only one of the Pd complexes is shown. Selected bond distances
˚
(A): N1-C1: 1.360(3); N2-C1: 1.369(3); Pd1-C1: 1.980(2); Pd1-C22:
1.997(2); Pd1-N3: 2.1365(18); Pd1-Cl1: 2.4025(7). Selected bond angles
(◦): N1-C1-N2: 104.08(18); C1-Pd1-C22: 91.48(9); C1-Pd1-N3: 169.87(8);
C22-Pd–N3: 82.09(8); C1-Pd1-Cl1: 94.41(6); C22-Pd1-Cl1: 173.63(7);
N3-Pd–Cl1: 91.74(6). Selected dihedral angles (◦): N1-C2-C3-N2: -0.04;
C1-N1-C4-C9: 88.44; C1-N2-C13-C14: 64.30; N1-C1-Pd–C22: -100.82;
C22-C27-C28-N3: -26.28.
˚
2.00 A for Pd-C(carbene) and Pd-C(o-phenyl), respectively. The
position of the imidazole ring relative to the puckered palladacycle
ring is close to perpendicular (dihedral angle N1(imidazole)–
C(carbene)–Pd-C(o-phenyl) = -100.8◦).
§ Crystal data for 1: Empirical formula: C30H36.50ClN3O0.25Pd; Formula
˚
weight: 584.97; Temperature: 243(2) K; Wavelength: 0.71073 A; Crys-
tal system: Triclinic; Space ◦group: P-1; Unit cell dimensions: a =
◦
˚
˚
˚
13.5773(6) A a= 87.2240(10) , b = 13.5923(6) A b= 71.8720(10) , c =
◦
3
˚
15.9863(7) A g = 84.4660(10) ; Volume: 2790.2(2) A ; Z: 4; Density
(calculated): 1.393 Mg/m3; Absorption coefficient: 0.785 mm-1; F(000):
1210; Crystal size: 0.30 ¥ 0.20 ¥ 0.16 mm3; Theta range for data
collection: 1.34 to 27.50◦; Index ranges: -17<=h<= 17, -17<=k<=
17, -20<=l<= 20; Reflections collected: 35633; Independent reflections:
12801 [R(int) = 0.0277]; Completeness to theta = 27.50◦: 99.9%; Absorp-
tion correction: Sadabs, (Sheldrick 2001); Max. and min. transmission:
0.8847 and 0.7987; Refinement method: Full-matrix least-squares on F2;
Data/restraints/parameters: 12801/3/662; Goodness-of-fit on F2: 1.024;
Final R indices [I>2s(I)]: R1 = 0.0346, wR2 = 0.0829; R indices (all data):
R1 = 0.0427, wR2 = 0.0866; Largest diff. peak and hole: 0.577 and -0.252
Scheme 2 One-pot, three-component synthesis of IMes-Pd(dmba)Cl (1;
2
dmba = k N,C-N,N-dimethylbenzylamine).
Initial evaluation of the activity of IMes-Pd(dmba)Cl in the
Heck–Mizoroki reaction and couplings of simple bromoarenes
The initial assessment of the catalytic activity of 1 was conducted at
catalyst loadings of 0.1–10-5 mol% on the arylation of tBu acrylate
(6) with a deactivated arylbromide, p-bromoanisole (5) (Table 1),
-3
˚
e.A
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Table 1 Evaluation of complex 1 at low catalyst loadings (0.1–1 ¥
10-5 mol%) in the benchmark reactions of a deactivated substrate,
p-bromoanisole (5)
Entry
Mol% 1
Time, h
7/5, %a
TONb
1
2
3
4
5
6
2.0
0.10
0.010
0.0010
1 ¥ 10-4
1 ¥ 10-5
18
24
72
72
168
168
100c/0
86/6
59/32
54/40
11/81
5.2/74
–
–
–
–
1.14 ¥ 105
5.22 ¥ 105
a The reactions (1.0M 5, 2.0M 6, 0.7 mmol scale) were performed in
duplicate and averaged product yield and starting material recovery
(+/-4%) were determined by quantitative 1H NMR spectroscopy (internal
standard: DMF). b TON = mmol 7/mmol 1. c Isolated yield.
a substrate that was recently suggested as a benchmark for testing
of new Pd-catalysis.16 The colorless solution of precatalyst 1 and
the substrates in NMP turned orange within 1–5 min of heating,
indicative of palladacycle decomposition and the formation of
catalytically active IMes-Pd(0) species. The solution retained this
color throughout the reaction, implying little or no formation of
Pd-black in accord with the established notion of the excellent
thermal stability of NHC-Pd complexes. The catalyst showed
excellent productivity, reaching a maximum TON of 5.22 ¥ 105
for arylbromide 5. Notably, a 54% yield for the product 7 was
obtained even when precatalyst 1 was employed at 10 ppm, a
concentration comparable with the FDA-established limit for Pd
in active pharmaceutical ingredients. Under the standard condi-
tions, a variety of simple bromoarenes underwent Heck–Mizoroki
coupling with tert-butyl acrylate (6) (Scheme 3). Heck–Mizoroki
couplings of the three bromotoluene isomers (o-, m- and p-),
2-bromonaphthalene and the double coupling of p-dibromoben-
zene proceeded in excellent yields (81–96%) in the presence of
2 equiv. of K2CO3 (products 8–12). Similarly, electron-deficient
fluorinated bromobenzene derivatives were excellent substrates
(products 13 and 14). The coupling of other electron-deficient
bromobenzenes was less effective under these conditions (A)—
even though the starting materials were completely consumed,
the yields of the corresponding tBu cinnamate derivatives (15 and
16) were moderate (60 and 36%, respectively). The appearance
of an intense dark brown–black color suggested that the most
likely reason for the low yields would be either product or starting
material degradation. A change to milder conditions (2 equiv.
of iPr2NEt, 120◦C, B) led to much higher yields. Electron-rich
substrates coupled well under standard conditions (A) (18: 91%
and 19: 94%), and so did simple heteroaryl bromides (20: 87%
and 21: 91%). Extensive attempts at Heck–Mizoroki couplings
of deactivated aryl chlorides (p-chloroanisole or p-chlorotoluene)
were unsuccessful. It should be noted that unlike the facile
Suzuki–Miyaura coupling or Buchwald–Hartwig amination of
deactivated aryl chlorides, Heck–Mizoroki reaction for these
substrates mediated by NHC-Pd catalysts has been a long standing
and as yet unsolved problem.31
Scheme 3 Preparative Heck–Mizoroki couplings of simple aryl bromides
mediated by IMes-Pd(dmba)Cl (1) (0.5 mol%). Conditions A: K2CO3
(2 equiv.), 140 ◦C. Conditions B: iPr2NEt (2 equiv.), 120 ◦C. The
reaction times were not minimized. The yields shown are for chromato-
graphically homogeneous materials, average of two runs.
Heck–Mizoroki reaction of functionalized bromo- and iodoarenes
with acrylate and styrene derivatives
Encouraged by these results, we explored preparative Heck–
Mizoroki couplings of a wider range of more challenging,
functionalized and heterocyclic aryl bromides (Schemes
4
and 6) and iodides (Schemes 5 and 6) with a wider range of
acrylate (Schemes 4 and 5) and styrene (Scheme 6) derivatives.
Electron-deficient substrates coupled well (44: 81%, 47: 95%).
Particularly, the coupling of an iodobenzene derivative carrying
the pharmaceutically important p-sulphonylamido functionality
was facile (35: 76%). Couplings of p-chloroiodobenzene (36: 88%
and 37: 95%) and p-chlorostyrene (46: 74%) proceeded in high
yields indicating that the IMes-Pd catalyst is tolerant to aryl
chlorides. Importantly, couplings of deactivated arylhalides with
two o-alkyl substituents (22 and 23: 72%), free anilines (26: 88%,
40: 79% and 42: 63%), phenols (25: 77% and 46: 74%), or highly
electron-rich substrates with multiple methoxy substituents (27:
91%, 28: 98%, 29: 45%, with 55% starting bromide recovered, 30:
84%, 39: 78%, 43: 91%) all proceeded in good to excellent yields.
The coupling of a thioether-substituted arylbromide (24, 75%
yield) and an aryliodide containing a nitro and methoxy group
(38, 68%) were also facile. Notably, for some substrates, good
yields were observed even at 100 ◦C (31: 63% and 36: 88%). The
couplings of substituted thiophenes (34: 59% and 41: 78%) and a
relatively simple quinoline substrate (31: 83%) proceeded well. The
success of the Heck–Mizoroki coupling of heterocycles containing
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Scheme 6 Preparative Heck–Mizoroki couplings of aryl bromides and io-
dides with styrene derivatives and analogs mediated by IMes-Pd(dmba)Cl
(1) (2 mol%). Conditions A: K2CO3 (2 equiv.), 140 ◦C. Conditions B:
iPr2NEt (2 equiv.), 120 ◦C. The reaction times were not minimized. The
yields shown are for chromatographically homogeneous materials, average
of two runs.
two N-atoms was dependent on the nature of the heterocycle.
Whereas high yields were observed for the couplings of pyrimidine
(30: 84% and 42: 63%) and imidazole (32: 82%) derivatives,
4-bromo-1,3,5-trimethylpyrazole,
a
very difficult substrate,57
yielded product 33 in 32% yield and 49% of the starting bromide
was recovered. With respect to the Heck acceptors, acrylate
esters,58 amides and acrylonitrile and various styrene derivatives
(Scheme 6; 43–46: 74–91%) were all suitable. In particular, the
first Heck–Mizoroki couplings of vinylferrocene (47: 95%) and
4-vinylpyridine (48: 92%) with NHC-Pd catalyst are noteworthy.
The Heck–Mizoroki protocol mediated by IMes-Pd(dmba)Cl
can be carried out in aerobic conditions without a significant
decrease in yields (22: 44 vs 72%; 26: 81 vs 88%; 27: 92 vs 91%; 39:
92 vs 78%; 46: 78 vs 74% for aerobic and anaerobic conditions,
respectively)
Scheme 4 Preparative Heck–Mizoroki couplings of more challenging
aryl bromides with acrylate derivatives mediated by IMes-Pd(dmba)Cl
(1) (2 mol%). The reaction times were not minimized. The yields shown
are for chromatographically homogeneous materials, average of two
runs.
Heck–Mizoroki reaction of aryltriflates with acrylate
and styrene derivatives
Aryltriflates are highly active substrates; however, no examples of
the Heck–Mizoroki reaction of aryltriflates mediated by NHC-Pd
catalysts have been reported to date. We explored the coupling of
triflate 49 with a variety of Heck–Mizoroki acceptors (Table 2).
Under standard conditions (A), complete degradation of the
triflate with no product formation was observed in the presence of
a number of common bases. The use of halide additives proved to
be more promising—whereas 1 equiv. of Bu4NCl and Bu4NI gave
approx. 15% yield of 50, 69% was achieved with Bu4NBr (TBAB).
˚
The addition of 4 A molecular sieves to suppress base-promoted
hydrolysis of the triflate by adventitious moisture led to a further
increase of the yield to 93% (quantitative 1H NMR spectroscopy;
79% isolated yield). However, decreasing the amount of TBAB
to 0.1 equiv. was detrimental, resulting in only 37% of 50,
with the remaining starting material recovered. Under optimized
conditions, triflate 49 underwent Heck–Mizoroki couplings with
Scheme 5 Preparative Heck–Mizoroki couplings of aryl iodides with
acrylate derivatives mediated by IMes-Pd(dmba)Cl (1) (2 mol%). The
reaction times were not minimized. The yields shown are for chromato-
graphically homogeneous materials, average of two runs.
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Table 2 Heck–Mizoroki couplings of aryl triflate 49 with styrene and
acrylate derivatives mediated by IMes-Pd(dmba)Cl (1) (2 mol%). The
reaction times were not minimized. The yields shown are the average of
two runs
Table 3 Double Heck–Mizoroki arylation of electron-rich and electron-
deficient aryl bromides with tert-butyl acrylate (6). The reaction times were
not minimized. The yields shown are the average of two runs
Entry
R
Additive
Yield, %
Entry Ar–Br
Di-/mono-arylation, %
o- m-
< 3a,b
13b (50)
69b
p-
1
2
3
4
5
6
7
8
9
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
CONiPr2
4-MeOC6H4-
4-ClC6H4-
None
Bu4NCl (1 equiv.)
Bu4NBr (1 equiv.)
Bu4NI (1 equiv.)
Bu4NBr (1 equiv.), 4 A MS
Bu4NBr (0.1 equiv.), 4 A MS
Bu4NBr (1 equiv.), 4 A MS
Bu4NBr (1 equiv.), 4 A MS
Bu4NBr (1 equiv.), 4 A MS
1
0/100 (54) 92(55)/0
91(56)/0
19b
93b/79c
37b
˚
˚
64c (51)
73c (52)
56c (53)
˚
˚
˚
2
3
4
0/86 (10)
0/62 (59)
81(57)/0
84 (58)/0
a Na2CO3, Cs2CO3, NaOAc, iPr2NEt, (nC8H17)3N, Cy2NMe (Cy = cyclo-
hexyl) and DBU (1,4-diazabicyclo[3.2.0]undecane) were also ineffective.
b The yield (+/-4%) was determined by quantitative 1H NMR spec-
troscopy (internal standard DMF). c Isolated yields of analytically pure
materials after column chromatography.
24 (60)/41 (61)a 21 (62)/59 (13)a
0/89 (63)b 6 (64)/63 (17)b 6 (65)/55 (66)b
N,N-diisopropylacrylamide (51: 64%) 4-methoxystyrene (52:
73%) and 4-chlorostyrene (53: 56%).
a The mono-and diarylated products were obtained as unseparable mix-
tures. The yields were determined by 1H NMR spectroscopy. b In the
presence of 4 A molecular sieves.
˚
Double Heck–Mizoroki reactions
When more than 2 equiv. of aryl halide are used, the cin-
namate initially formed undergoes a second Heck–Mizoroki
reaction to yield a b,b-diarylacrylate. Isolated cases of Heck–
Mizoroki diarylations of acrylates and styrene mediated by
NHC-Pd catalysts are known.35,59 However, there have not been
complete studies on how the steric and electronic properties of
the substituent on the aryl halide can affect the outcome of
the double arylation reaction mediated by NHC-Pd catalysts.
We undertook a systematic evaluation of the efficiency of the
double Heck–Mizoroki reaction (4 mol% of 1) between tert-
butyl acrylate (6) and o-, m- and p-isomers of bromoanisole and
bromotoluene as representative electron-rich aryl bromides, and
bromobenzotrifluoride and methyl bromobenzoate as electron-
deficient, respectively. All o-substituted aryl bromides, (Table 3)
gave exclusively monoarylated products (10, 54, 59, 63; 62–100%
yields). For electron-rich m- and p-substituted aryl bromides, b,b-
diarylacrylates (55–58; 81–92% yields) were obtained exclusively.60
On the other hand, electron-deficient m- and p-substituted aryl
bromides generally gave mixtures of mono- (13, 17, 61, 66; 41–
63% yields) and diarylated products (60, 62, 64, 65; 6–24% yields)
with the mono-arylated products (cinnamates) being major the
major ones. These results imply that both electronic and steric
effects affect the product distribution considering that methyl and
trifluoromethyl substituents are virtually identical in size. We fur-
ther attempted to obtain diarylated product from o-bromoanisole
(54) with different Pd-catalysts (Scheme 7 and Table 4). Complex
1 (100%) was the best catalyst of all complexes tested, supporting
our choice of IMes as a privileged ligand for Heck–Mizoroki reac-
tion (Fig. 1). Cyclopalladated N,N-dimethylbenzylamine (dmba)
ligated with other 1,3-diarylimidazol-2-ylidenes (68 and 70),
1,3-diaryl-4,5-dihydroimidazol-2-ylidenes (67 and 69) and simple
1,3-diisopropylimidazol-2-ylidene (71), recently synthesized in
our group,56 all gave lower yields (31–76%). The corresponding
tricyclohexylphosphine complex (73)41 and the parent dimeric
palladacycle (2)54 also gave high yields of 66 (73 and 63%, respec-
tively). In comparison, the Herrmann-Beller palladacycle (73)14,15
performed rather poorly. A high yield (86%) was also observed
with [Pd(PPh3)4]. Disappointingly, no catalyst yielded even a
trace of the desired diarylated product, revealing an important
limitation in the current scope of the Heck–Mizoroki catalysts.61
Importantly, the results of our double Heck–Mizoroki reaction
experiments demonstrate that, unlike phosphane-Pd and ligand-
less Pd catalysts, which show higher activity for electron-deficient
(hence known as “activated”) aryl halides, IMes-Pd shows higher
activity for electron-rich or “deactivated” arylbromides. Recent
comparative computational studies on the complete cycle of the
Heck–Mizoroki reaction mediated by phosphane-Pd and NHC-
Pd catalysts by Lee et al. have shown that for NHC-Pd catalysts
the olefin binding-migratory insertion step (Scheme 1) proceeding
from a cationic NHC-Pd species is the rate-limiting step, whereas
for phosphane-Pd catalysts, the oxidative addition is the rate-
limiting step.62 Our results are consistent with such a mechanism.
Oxidation of the arylbromide to the monoligated NHC-Pd(0)
species, the active catalyst (Fig. 1), yields a new NHC-Pd(II)-Br
moiety s-bonded to an aryl substituent. Conceivably, the more
electron rich the aryl group, the higher the electron density on the
Pd atom and the higher the propensity of the bromide ion to leave
the coordination sphere of Pd during the olefin binding/migratory
insertion step.
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Table 4 Effect of the catalyst structure on the outcome of the double
Heck–Mizoroki reaction between o-bromoanisole (2.2 equiv.) and tert-
butyl acrylate (6) (Scheme 7). The yields shown are the average of two
runs
PdCl2 dissolved completely (approx. 25 min). Finely powdered
K2CO3 (62.9 g, 455 mmol) was added in one portion and the
mixture was stirred under reflux until the solution changed color
to bright canary yellow (approx. 5 min). IMes·HCl (3) (65.1 g,
191 mmol) was added in one portion and the reflux continued
for another 30 min. After cooling, the mixture was diluted with
CH2Cl2, filtered and the volatiles removed under vacuum. IMes-
Pd(dmba)Cl (1) (95.2 g, 90% yield, white crystalline solid) was
crystallized from CH3CN (30 mL), filtered and dried under high
vacuum; mp 225–230 ◦C (with decomposition); 1H NMR (CDCl3,
400 MHz): d 7.10 (s, 2H), 6.99 (s, 2H), 6.83–6.76 (m, 4H), 6.70 (td,
J = 7.6, 1.2 Hz, 1H), 6.58 (dd, J = 7.2, 1.2 Hz, 1H), 3.53 (s, 2H),
2.45 (s, 6H), 2.44 (s, 6H), 2.29 (s, 6H), 2.23 (s, 6H); 13C NMR
(CDCl3, 100 MHz): d 175.6, 149.3, 147.6, 138.3, 138.3, 137.4,
136.2, 133.9, 129.4, 128.7, 123.9, 123.2, 123.0, 121.2, 72.2, 50.0,
21.1, 20.2, 19.8; Anal. calcd for C30H36ClN3Pd (580.50): C, 62.07;
H, 6.25; N, 7.24. Found: C, 62.02; H, 6.37; N, 7.40.
Entry
Catalyst (4 mol%)a
Mono-/di-arylation, %b
1
2
3
4
5
6
7
8
IMes-Pd(dmba)Cl (1)
SIMes-Pd(dmba)Cl (67)
IPr-Pd(dmba)Cl (68)
SIPr-Pd(dmba)Cl (69)
IPrp-Pd(dmba)Cl (70)
iPr2Im-Pd(dmba)Cl (71)
Cy3P-Pd(dmba)Cl (72)c
Herrmann-Beller
100/0
76/0
41/0
73/0
31/0
58/0
73/0
21/0
palladacycle (73)
[Pd(PPh3)4]
[Pd(dmba)Cl]2 (2)
9
10
86/0
63/0
a Relative to the limiting reagent, tert-butyl acrylate (6). b The re-
maining unreacted o-bromoanisole was recovered. In some cases, 2,2¢-
dimethoxybiphenyl arising from homocoupling of o-bromoanisole was
isolated as a minor product (<10%). c Cy = cyclohexyl.
Stock solution of the catalyst
The required amount of IMes-Pd(dmba)Cl (1) (7.26 mg/mL for
0.5 mol% or 29.03 mg/mL for 2 mol%) was dissolved in reagent
grade NMP and the solution degassed by purging with Ar for
10–20 min.
General procedure for Heck–Mizoroki reaction (A)
To a vial with a magnetic stirrer bar, the arylbromide (1 mmol),
the olefin (1.5 mmol at 0.5 mol% or 1.2 mmol at 2 mol% 1) were
weighed in (if solids) or added via syringe (if liquids), followed by
addition of K2CO3 (276 mg, 2.0 mmol). Stock solution of IMes-
Pd(dmba)Cl (1) (400 mL) was added and the atmosphere above
the reaction mixture was purged with Ar over 30 sec. The vial was
closed with a screw cap and heated at 140 ◦C with vigorous stirring
over 18 h. Two reactions were done side by side. After cooling,
the combined reaction mixtures were filtered with CH2Cl2 (total
20 mL). The crude product was loaded directly over a short pad of
silica gel and purified by flash chromatography. For experiments
conducted in-air, the same procedure was followed except the
purging of precatalyst stock solution and reaction vial with Ar
was omitted.
(E)-3-(4-(Methylthio)phenyl)-1-(morpholine-1¢-yl)-prop-2-en-1-
one (24)
Scheme 7 Double Heck–Mizoroki reaction between o-bromoanisole and
tert-butyl acrylate (6) mediated by various Pd catalysts. The reaction times
were not minimized.
Following procedure A (2 mol% 1), 4-bromothioanisole (203 mg)
and N-acryloyl morpholine (150 mL, 169 mg) were used. The
reactions were cooled and combined after filtration (CH2Cl2, total
of 30 mL), washed with water (5 ¥ 20 mL), dried (MgSO4),
and the volatiles removed under reduced pressure. Product 24
(169 mg, 75%) was obtained as a white solid after column
chromatography on silica gel (ethyl acetate gradient in hexane-
CH2Cl2 (5:1, vol/vol): 0 to 25%, 25 min); mp 113–119 C; H
NMR (CDCl3, 400 MHz): d 7.66 (d, J = 15.4 Hz, 1H), 7.44
(m, 2H), 7.22 (m, 2H), 6.80 (d, J = 15.4 Hz, 1H), 3.73 (m, 8H),
2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 165.7, 142.7, 141.1,
131.7, 128.2, 126.1, 115.4, 66.9, 15.3; Anal. calcd for C14H17NO2S
(263.36): C, 63.85; H, 6.51; N, 5.32. Found: C, 64.03; H, 6.51; N,
5.20.
Experimental section
Large scale synthesis of IMes-Pd(dmba)Cl
◦
1
A two necked flask (1 L) was charged with a large, egg-shaped
magnetic stirrer bar, PdCl2 (32.3 g, 182 mmol), CH3CN (370 mL;
HPLC grade) and N,N-dimethylbenzylamine (4) (29 mL, 25.8 g,
191 mmol). One of the necks was equipped with a reflux condenser
and the other was closed with a glass stopper. The mixture was
heated at reflux until a clear, dark orange solution was formed and
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©

General procedure for Heck–Mizoroki reaction (B)
2.0 mmol) were weighed in (if solids) or added via syringe (if
liquids). Stock solution of IMes-Pd(dmba)Cl (1) (4 mol%; 800 mL)
was added and the atmosphere above the reaction mixture was
purged with Ar over 30 sec. The vial was closed with a screw
To a vial with a magnetic stirrer bar, the arylbromide (1 mmol),
the olefin (1.5 mmol at 0.5 mol% or 1.2 mmol at 2 mol% 1)
were weighed in (if solids) or added via syringe (if liquids).
iPr2NEt (350 mL, 258 mg, 2.0 mmol) and stock solution of IMes-
Pd(dmba)Cl (1) (400 mL) were added and the atmosphere above
the reaction mixture was purged with Ar over 30 sec. The vial was
closed with a screw cap and heated at 120 ◦C with vigorous stirring
over 18 h. Two reactions were done side by side. After cooling,
the combined reaction mixtures were filtered under dilution with
CH2Cl2 (total 20 mL). The crude product was loaded directly over
a short pad of silica gel and purified by flash chromatography.
◦
cap and heated at 140 C with vigorous stirring over 18 h. Two
reactions were done side by side. After cooling, the combined
reaction mixtures were filtered under dilution with CH2Cl2 (total
20 mL), washed with water (5 ¥ 20 mL), dried (MgSO4), and the
volatiles removed under reduced pressure. The crude product was
loaded directly over a short pad of silica gel and purified by flash
chromatography.
tert-Butyl 3,3-bis(3-methoxyphenyl)acrylate (55)
2-(2,5-Dimethylstyryl)benzonitrile (44)
Following procedure D (4 mol% 1), from 3-bromoanisole (275 mL,
412 mg), 55 (313 mg, 92%) was obtained as a colorless oil after
column chromatography on silica gel (ethyl acetate gradient in
Following procedure B (2 mol% 1), from 2-bromobenzonitrile
(182 mg) and 2,5-dimethylstyrene (175 mL, 159 mg), 44 (188 mg,
81%) was obtained as white solid after column chromatography
on silica gel (ethyl acetate gradient in hexane: 0%, 10 min, then 0 to
10%, 10 min); mp 72–76◦C; 1H NMR (CDCl3, 400 MHz): d 7.80 (d,
J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H),
7.55–7.50 (m, 2H), 7.37 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.13–7.07
(m, 2H), 2.37 (s, 3H); 13C NMR (CDCl3, 400 MHz): d 141.0, 135.9,
135.0, 133.4, 133.2, 132.8, 131.4, 130.5, 129.5, 127.5, 126.4, 125.5,
125.0, 118.2, 111.1, 21.1, 19.5; Anal. calcd for C17H15N (233.31):
C, 87.52; H, 6.48; N, 6.00. Found: C, 87.38; H, 6.66; N, 5.91.
1
hexane: 0%, 5 min, then 0 to 20%, 20 min); H NMR (CDCl3,
400 MHz): d 7.31–7.21 (m, 2H), 6.93–6.75 (m, 6H), 6.28 (s, 1H),
3.80 (s, 3H), 3.78 (s, 3H), 9.55(s, 9H); 13C NMR (CDCl3, 400 MHz):
d 165.8, 159.2, 153.8, 140.7, 129.3, 129.0, 121.7, 120.8, 120.1, 114.6,
114.5, 113.8, 113.6, 80.4, 55.3, 55.2, 27.8; Anal. calcd for C21H24O4
(340.41): C, 74.09; H, 7.11. Found: C, 74.12; H, 7.12.
Conclusion
General procedure for Heck–Mizoroki reaction of aryltriflates (C)
In conclusion, we have developed a novel NHC-palladacycle as a
rationally designed precatalyst (1) with respect to both catalytic
performance and practicality. Complex 1 is available in high
yield in multi-gram amounts from inexpensive starting materials
by virtue of a one-pot, three-component NHC-palladacycle
synthesis, and is stable to air, moisture (even tolerating aqueous
workup) and long-term shelf storage (>3 years). The catalyst
can be either weighed in as a solid or dispensed as a stock
solution in NMP, which can be stored for at least a week without
losing its activity. The reactions are performed without any special
techniques or glovebox—after addition of the coupling partners,
the base and the catalyst stock solution in air, the atmosphere
above the solution is simply purged with Ar. Moreover, the catalyst
can be used in air without significant loss of activity (Tables 3–5).
The small amount of NMP used (0.4 mL/mmol arylbromide)
allows for direct isolation of the products by flash chromatography
(Rf permitting) without the cumbersome, difficult-to-automate
aqueous extractive workup step. In summary, these features render
catalyst 1 particularly suitable for deployment in automated
parallel synthesis workstations. Taken together, the results in this
work validate the design principle (Fig. 1) that both a powerful
ligand (in this case IMes) and suitable disposable ligands, which
deliver the active catalyst smoothly and efficiently into the catalytic
cycle, are necessary for high catalytic activity across a wide
range of substrates. Importantly, this work has revealed that
IMes-Pd is more active for electron rich, “deactivated” arylbro-
mides as opposed to phosphane-Pd and ligandless Pd catalysts
that show higher activity for electron-deficient, “activated” aryl
bromides. The design and exploration of later generations of
NHC-palladacycle precatalysts for other important Pd-mediated
reactions based on this paradigm are underway.
A vial was charged with a magnetic stirrer bar, 3,5-dimethylphenyl
trifluoromethanesulfonate (49) (190 mL, 254 mg, 1 mmol), the
olefin (1.2 mmol), TBAB (322 mg, 1 mmol), K2CO3 (276 mg,
˚
2.0 mmol) and powdered molecular sieves (4 A; approx. 500 mg).
Stock solution of IMes-Pd(dmba)Cl (2 mol% 1; 400 mL) was added
and the atmosphere above the reaction mixture was purged with
Ar over 30 sec. The vial was closed with a screw cap and heated
at 140 ◦C with vigorous stirring over 18 h. Two reactions were
done side by side. After cooling, the reactions were combined
after filtration (CH2Cl2, total of 30 mL), washed with water (5 ¥
20 mL), dried (MgSO4), and the volatiles removed under reduced
pressure. The crude product was loaded directly onto a short pad
of silica gel and purified by flash chromatography.
1-(4-Chlorostyryl)-3,5-dimethylbenzene (53)
Following procedure C (2 mol% 1), from 4-chlorostyrene (145 mL,
167 mg), 53 (136 mg, 56%) was obtained as a white solid after
column chromatography on silica gel (ethyl acetate gradient in
◦
1
hexane: 0%, 10 min, then 0 to 15%, 20 min); mp 54–58 C.; H
NMR (CDCl3, 400 MHz): d 7.44 (m, 2H), 7.33 (m, 2H), 7.15 (s,
2H), 7.05 (s, 2H), 6.95 (s, 1H), 2.36 (s, 6H); 13C NMR (CDCl3,
100 MHz): d 138.2, 136.9, 133.0, 129.7, 129.5, 128.8, 127.6, 127.6,
127.0, 124.5, 21.3; Anal. calcd for C16H15Cl (242.09): C, 79.17; H,
6.23. Found: C, 79.59; H, 6.29.
General procedure for the double Heck–Mizoroki arylation
reaction (D)
To a vial with a magnetic stirrer bar, the arylbromide (2.2 mmol),
tert-butyl acrylate (6) (145 mL, 128 mg, 1.0 mmol), K2CO3 (276 mg,
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Org. Biomol. Chem., 2009, 7, 2110–2119 | 2117
©

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Acknowledgements
This work was funded by the Institute of Bioengineering and Nan-
otechnology (IBN) and Biomedical Research Council (BMRC) of
the Agency for Science, Technology and Research (A*STAR), Sin-
gapore. X-Ray crystallography was performed at the Department
of Chemistry, National University of Singapore. We thank
G.-K. Tan for assistance with the structure determination of com-
plex 1.
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The Royal Society of Chemistry 2009
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