Rational exploration of N-Heterocyclic carbene (NHC) palladacycle diversity: A highly active and versatile precatalyst for suzuki-miyaura coupling reactions of deactivated aryl and alkyl substrates

Article abstract of DOI:10.1002/chem.200902842

As less attention has been focussed on the design of highly efficient palladium precatalysts to ensure the smooth formation of the active catalyst for metal-mediated cross coupling reactions, we herein demonstrate that combining the bulky N-heterocyclic carbene (NHC) 1,3-bis(2,6-diisopropylphenyl)imidazol-2- ylidene (IPr) with cyclopalladated acetanilide as the optimal palladium precatalyst leads to superior catalytic activity compared with the state-of-the-art NHC-Pd catalysts. The complex was discovered through the evaluation of a small, rationally designed library of NHC-palladacycles prepared by a novel, practical and atom-economic method, the direct reaction of IPrHCl with palladacycle acetate dimers.

Full text of DOI:10.1002/chem.200902842

DOI: 10.1002/chem.200902842
Rational Exploration of N-Heterocyclic Carbene (NHC) Palladacycle
Diversity: A Highly Active and Versatile Precatalyst for Suzuki–Miyaura
Coupling Reactions of Deactivated Aryl and Alkyl Substrates
Guang-Rong Peh, Eric Assen B. Kantchev,* Jun-Cheng Er, and Jackie Y. Ying*[a]
Abstract: As less attention has been fo-
cussed on the design of highly efficient
palladium precatalysts to ensure the
smooth formation of the active catalyst
for metal-mediated cross coupling reac-
tions, we herein demonstrate that com-
bining the bulky N-heterocyclic car-
bene (NHC) 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene (IPr) with
cyclopalladated acetanilide as the opti-
mal palladium precatalyst leads to su-
perior catalytic activity compared with
the state-of-the-art NHC–Pd catalysts.
The complex was discovered through
the evaluation of a small, rationally de-
signed library of NHC–palladacycles
prepared by a novel, practical and
atom-economic method, the direct re-
action of IPr·HCl with palladacycle
acetate dimers.
Keywords: carbenes · chemical li-
brary · cross-coupling · heterocy-
cles · palladium
Introduction
and further developed as a process of major academic and
industrial significance over the next decade. Aryl chlorides
are another challenging but important class of substrates be-
cause they are more readily available and cheaper, but
much less active than the traditional aryl bromides and io-
dides.[15,16] Today, palladium complexes of N-heterocyclic
carbenes (NHC),[17–21] in particular, the bulky 1,3-bis(2,6-di-
A revolutionary development in organic synthesis took
place in 1972–1977:[1] the discovery of nickel[2–4] and palladi-
um[4–8] catalysts that allowed for the first time organic moie-
ACHTUNGTRENNUNGties in aryl or vinyl halides and aryl or vinyl organometallic
derivatives to be joined by a single bond, a transformation
that had been generally considered impossible. Palladium-
mediated cross-coupling reactions[9,10] have since become a
strategic class of transformations in modern organic synthe-
sis, allowing an astonishing variety of complex molecules[11]
to be prepared in a highly efficient manner. In the pharma-
ceutical industry, palladium-mediated coupling reactions are
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
allow the coupling reactions of chloroarenes to proceed in
high yields under mild conditions, even at room tempera-
ture. Similarly, the cross-coupling of alkyl halides is ham-
pered by their low reactivity (relative to unsaturated sub-
strates) and competition by b-hydride elimination.[27–29]
These obstacles notwithstanding, the coupling of unactivated
alkyl halides with palladium complexes of bulky trialkyl-
phosphanes[30–38] or NHCs[39–48] has been successfully devel-
oped.
The nature of the palladium precatalyst, which is responsi-
ble for the smooth introduction of the active catalyst into
the cycle, is as important as the nature of the spectator
ligand for the success of a coupling reaction. A strong de-
pendency on the palladium source has often been observed
in many palladium-mediated cross-coupling reactions. How-
ever, the design of easy-to-activate palladium precatalysts
lags behind spectator ligand design or discovery. Recently,
Buchwald and co-workers elegantly showed that a six-mem-
bered palladacycle that was activated by a well-understood
mechanism led to a significant improvement in the efficien-
À
the single most employed C C bond-forming reaction in the
large-scale synthesis of drug candidates.[12] Since the 1970s
the expansion of the scope of cross-coupling reactions to
new classes of substrates has continued unabated. This has
been enabled by the discovery of ever more active and spe-
cialised spectator ligands. In the mid 1990s amine cross-cou-
pling (Buchwald–Hartwig amination) was discovered[13,14]
[a] G.-R. Peh, Dr. E. A. B. Kantchev, J.-C. Er, Prof. J. Y. Ying
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos, Singapore 138669 (Singapore)
Fax : (+65)-6478-9020
E-mail: ekantchev@gmail.com
jyying@ibn.a-star.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.20090902842.
4010
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4010 – 4017

FULL PAPER
process of catalyst activation has become the dominant
strategy in NHC–Pd catalyst development.[17,20] Nolan and
co-workers showed that introducing a methyl or phenyl sub-
stituent at C-1 of the allyl moiety of [(IPr)PdACHTNUTRGNE(NUG p-allyl)Cl]
complexes led to much faster activation in isopropanol/
tBuOK.[57] Also, an IPr-ligated six-membered palladacycle
(3; Scheme 1) was activated by this protocol highly efficient-
ly.[51,58] Although NHC–palladacycles have been known
since 1978,[59] the effect of the cyclometallated ligand on cat-
alyst activation in the search for highly active catalysts has
not been explored to date in a systematic manner, despite
the promise of this class of complexes. Herein we present a
highly active and easily prepared NHC–palladacycle catalyst
for use in the Suzuki–Miyaura coupling reaction of aryl
chlorides discovered through the exploration of a small, ra-
tionally designed NHC–palladacycle library prepared by a
novel synthetic method.
Results and Discussion
Library design and synthesis—a new method for NHC–pal-
ladacycle preparation: Since the seminal work by the groups
of Herrmann,[60] Beller[61] and Hartwig,[62] palladacycles[63]
have become mainstream precatalysts[64,65] for cross-coupling
reactions. In the presence of the nucleophilic coupling part-
ner or a base, palladacycles release atomic Pd0 by a s-bond
metathesis/reductive elimination sequence.[62,66] The corre-
sponding hybrid NHC– (such as IPr, 1; Scheme 1) or phos-
phane–palladacycles analogously form mono-ligated ligand–
Pd species.[67] The highest catalytic activity is generally at-
tained at a ligand/Pd ratio of 1:1 when the spectator ligand
Scheme 1. Rationally diverse library of NHC–palladacycles (a) prepared
by a novel, atom-economic method (b).
cy of Buchwald–Hartwig amination when ligated with S-
is either an NHC or a bulky trialkylphosphane or dialkylACHTUNGTRENNUNG(2-
Phos compared with a similar catalyst prepared in situ from
biaryl)phosphane.[68] Furthermore, the availability of a large
number of diverse cyclopalladated compounds and spectator
ligands opens the doors to the generation of a combinatorial
library in the search for the most active precatalyst.[69] To ex-
plore the ability of various palladacycles to release Pd0
under mild conditions, we considered a small palladacycle li-
brary that was rationally diverse with respect to the donor
[Pd2ACHTUNGTRENNUNG
(dba)3] (dba: 1,3-dibenzylideneacetone).[49] The precata-
lyst allowed amination of non-activated aryl chlorides to be
performed at temperatures as low as À108C. Another im-
pressive report by Fairlamb et al. showed that the use of the
more electron-rich 3,3’,5,5’-tetramethoxy analogue of dba
(dmdba) instead of dba in the popular precatalyst [PdACTHNUTRGNEUNG(dba)2]
facilitated the departure of disposable ligands, which result-
ed in an overall improvement in catalytic efficiency in the
Suzuki–Miyaura reaction.[50] The importance of both discov-
eries is underscored by the fact that these catalysts were
made commercially available within a very short time after
publication. The problem of precatalyst design is especially
acute in the field of NHC–Pd catalysis as a consequence of
the non-trivial complexation of NHC to palladium. On one
hand, in situ catalyst preparations are generally unsatisfacto-
ry, and on the other hand, well-defined precatalysts undergo
activation at very different rates.[17,51,52] There is a similar de-
pendence of the activation profile of NHC–Ru metathesis
catalysts on the nature of the disposable ligand situated anti
to the NHC,[53–56] which implies that this phenomenon might
be general for NHC ligands. For this reason, the high-yield-
ing synthesis, under optimised conditions, of well-defined
complexes carrying additional ligands that are shed in the
atom (NACHTUGNTRENNUG ACHTUNGTRENNUNG
(sp3), N(sp2), P(phosphane), P(phosphite), S or O)
and ring size (five or six) (Scheme 1a), carrying the highly
active bulky carbene IPr and a chloride as the charge-bal-
ance anion. The current methods[67,70–72] for preparing NHC–
palladacycles have not been deployed for combinatorial li-
brary generation due to the practical limitations associated
with the handling of highly air-sensitive free NHCs, low
yields and/or narrow substrate scope. Therefore, we sought
a more “combinatorially friendly” NHC–palladacycle prepa-
ration protocol that could yield a wide range of NHC–palla-
dacycles in an air- and moisture-tolerant manner, relying on
easily accessible NHC precursors (imidazolium salts). His-
torically, the reaction of PdACHTNUTRGNENG(U OAc)2 and imidazolium salts to
form NHC–PdII halide complexes has paved the way for the
current surge in NHC catalysis.[60] We surmised that pallada-
cycle-bound acetates would retain this reactivity. This was
proven to be the case: heating IPr·HCl (1)[22] with pre-
Chem. Eur. J. 2010, 16, 4010 – 4017
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4011

J. Y. Ying, E. A. B. Kantchev et al.
formed palladacycle acetates (easily prepared by o-pallada-
paring IPr–Pd complexes from IPr·HCl (1) and PdACTHUNGTERNNU(G OAc)2 in
tion of the required heteroatom-containing aromatic com-
a 1:1 ratio only resulted in decomposition.
pounds with PdACHTUNGTRENNUNG(OAc)2) in dimethyl sulfoxide (DMSO) led
to the expedient formation of IPr-ligated palladacycles (2–
11) in yields of 53–82% (Scheme 1b) with a success rate of
80% (attempts at the synthesis of compounds 7 and 8
failed). The reaction has a wide scope, affording the first ex-
amples of NHC-ligated k2C,S-palladacycles 9 and 10 and a
k2C,O-palladacycle 11 in good yields (60–76%). Compounds
9 and 11 exhibit the same structural pattern as observed in
known C,P- and C,N-palladacycles,[67,70–72] that is, a slightly
distorted square-planar PdII centre with the planes of the
imidazole and palladacycle rings almost, but not exactly, per-
pendicular and the carbene carbon and the neutral donor
ligand mutually trans (Figure 1). For comparison, when
Catalytic activity evaluation: Palladacycles release Pd0 in a
manner that is dependent on temperature, co-reactant and
the nature of the cyclometallated framework.[62,66,69] High
temperatures or strongly basic/nucleophilic co-reactants are
generally necessary. We sought cyclopalladated ligand(s)
that would allow the active IPr–Pd catalyst to be released
efficiently at room temperature under mild, non-basic condi-
tions. To achieve this, a model Suzuki–Miyaura reaction
with a deactivated aryl chloride (12) was performed with the
exact amount of NaOH necessary to neutralise the boronic
acid before the injection of the precatalyst stock solution,
creating only a mildly basic medium (Scheme 2). We dis-
IPr·HCl (1) reacts with PdACHTNUGRTNEUNG(OAc)2 in a 2:1 ratio, a PdCl2
complex containing one IPr ligand bound to palladium
through C1 (normal mode) and one through C4 (abnormal
mode) is formed.[52] Our repeated experiments aimed at pre-
Scheme 2. Cross-coupling reaction of a deactivated substrate, p-chloroa-
nisole (12), and pre-activated phenylboronic acid under non-basic condi-
tions at room temperature mediated by the IPr-Pd precatalyst with vari-
ous disposable ligands.
AHCTUNGTREGcNNUN overed that acetanilide-derived palladacycle 11 (O-6) was
highly active under these conditions (yield of 86% after
30 min; Figure 2). None of the other NHC–palladacycles
screened was active under these conditions.[73] Complex 11
also outperformed the other known IPr–Pd precatalysts car-
rying other precatalyst-stabilising disposable ligands: ace-
AHCTUNGTRENNUNG
tylacetonate (14),[74] p-allyl (15),[75] p-cinnamyl (16),[57] 3-
chloropyridine (PEPPSI-IPr, 17)[42] and naphthoquinone
(18).[76] Only precatalysts 16 and 17 led to moderate cross-
coupling yields (yields of 8.5% for 16 and 40% for 17 vs.
88% for 11 after 2 h; Figure 2).
A calorimetric experiment using the preformed sodium
phenyltrihydroxyborate (a commercial, convenient and
active Suzuki–Miyaura substrate[77]) and p-chloroanisole (12;
Scheme 3) revealed that the activation of the catalyst was
fast at room temperature, resulting in a very short induction
time (~1.5 min, Figure 3). Thereupon a highly exothermic
reaction ensued, with the temperature of the reaction mix-
ture reaching 38.08C within 7.5 min, and the reaction was
complete within 20–25 min. Notably, this experiment was
performed by dispensing a solution of 11 in methanol in air
without the use of anhydrous and air-free solvents, which
Figure 1. ORTEP representation of the single-crystal X-ray structures of
complexes 9 (upper) and 11 (lower). The thermal ellipsoids were drawn
at the 30% probability level and the hydrogen atoms and co-crystallising
solvent molecules (for complex 11) have been omitted for clarity.
Scheme 3. Cross-coupling reaction of a deactivated substrate, p-chloroa-
nisole (12), and sodium phenyltrihydroxyborate mediated by complex 11
in air.
4012
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4010 – 4017

N-Heterocyclic Carbene Palladacycle Diversity
FULL PAPER
Table 1. Cross-coupling reaction of a deactivated substrate, p-chloroani-
sole (12), and pre-activated phenylboronic acid under non-basic condi-
tions at 08C mediated by 11.
11 [mol%]
time [h]
yield of 13 [%]
2
2
5
0.5
2
4
0.46
23
97
strates, complex 11 was resynthesised on a gram scale by a
modified method as we found that the method for cyclopal-
ladation of acetanilide we originally employed[79] during the
palladacycle library synthesis did not work reproducibly on
a large scale in our hands. Cyclopalladation in the presence
of trifluoroacetic acid (TFA) furnished the corresponding
TFA–palladacycle.[80] Considering TFA to be insufficiently
basic to deprotonate an imidazolium salt, we converted it
into a chloride and introduced the carbene by a method re-
cently developed in our laboratory (K2CO3 in acetonitrile at
Figure 2. Evaluation of the catalytic activity of the NHC–palladacycle li-
brary (upper panel) and comparison of the catalytic activity of IPr-cyclo-
palladated acetanilide complex 11 with popular, commercially available
IPr-Pd precatalysts (lower panel) in the model reaction (Scheme 2).
reflux, yield of 77% from Pd
ACHTUNGRTEN(NNUG OAc)2 on a 1.5 g scale;
Scheme 4).[70]
Scheme 4. Preparative synthesis of 11 on a 1.5 g scale.
We next investigated the coupling reactions of aryl and
vinyl chlorides and aryl- and vinylboronic acids (Scheme 5)
under the conditions of our screening protocol. Complex 11
(2 mol%) mediated the Suzuki–Miyaura reaction of an
array of electron-poor (activated), electron-rich, doubly
ortho-substituted and heterocyclic (all deactivated) aryl and
vinyl chlorides with electron-rich or non-hindered arylbo-
Figure 3. Thermal profile of the reaction of p-chloroanisole (12) and
sodium phenyltrihydroxyborate in air mediated by complex 11
(Scheme 3).
demonstrates the potential of this complex for practical
Suzuki–Miyaura coupling reactions in the context of auto-
mated parallel synthesis.[78]
Moreover, the active catalyst from 11 was produced at
08C, even though the Suzuki–Miyaura coupling was consid-
erably slower at that temperature. At 2 mol% and 30 min
reaction time, almost no product was obtained at 08C. A
longer reaction time (4 h) and higher catalyst loading
ACHTUNGTRENrNUGN onic acids in good to excellent yields at room temperature.
The reaction took place under practically non-basic condi-
tions, which allowed base-sensitive substrates to be used.
For instance, the coupling of methyl 4-chlorobenzoate
(product 19, 100%) proceeded in quantitative yield without
any competing ester hydrolysis. Generally we found that the
performance of the catalyst was much more sensitive to the
substituents in the boronic acids than in the aryl chlorides;
hindered or electron-poor arylboronic acids only activated
the catalyst reliably at 708C. At room temperature, only low
yields were observed for these more challenging coupling
partners. Whether this difference in performance is due to
(5 mol%) resulted in
a practically quantitative yield
(Table 1). To the best of our knowledge, this is the first ex-
ample of a palladium-catalysed Suzuki–Miyaura coupling re-
action below room temperature.
IPr-cyclopalladated acetanilide complex as
a practical
Suzuki–Miyaura precatalyst: To explore the scope of sub-
Chem. Eur. J. 2010, 16, 4010 – 4017
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4013

J. Y. Ying, E. A. B. Kantchev et al.
Scheme 5. Cross-coupling reactions of aryl and vinyl chlorides with aryl-
and vinylboronic acids, pinacol esters and potassium trifluoroborates
under non-basic conditions mediated by 11. The yields are of isolated
chromatographically homogeneous materials (average from two runs),
non-optimised for time and catalyst loading.
the inability of the less active boronic acids to activate the
precatalyst at room temperature or the active catalyst (IPr–
Pd0) did not attain sufficiently high turnover is unclear at
this point. Synthetically important congeners of arylboronic
acid, pinacol boronic esters or potassium trifluoroborates,
also reacted under these conditions (products 21 and 29 pre-
pared in yields of 100 and 58%, respectively).
Scheme 6. Cross-coupling reactions of aryl and alkyl chlorides and bro-
mides with alkyl bromides and arylboronic acids, esters and potassium
trifluoroborates in various possible combinations mediated by 11. The
yields are of isolated chromatographically homogeneous materials (aver-
age from two runs), non-optimised for time and catalyst loading. Condi-
tions: A) 4 mol% 11, K3PO4·H2O, dioxane; B) 4 mol% 11, K3PO4, THF/
H2O; C) 4 mol% 11, tBuOK, dioxane/MeOH; D) 5 mol% 11, K3PO4, di-
oxane/H2O; E) 2 mol% 11, K3PO4, dioxane/H2O.
IPr–Pd0 (the active catalyst released upon activation of
11) has been shown to mediate cross-coupling reactions of
the much more challenging sp3 carbon centres[40,42–47] in addi-
tion to the more traditional sp2 centres. In the case of or-
edge) reaction of alkyl halides and arylboronic acids mediat-
ed by NHC–Pd complexes required the use of tert-BuOK
(37 and 38 in yields of 92 and 83%, respectively), which
also demonstrates the coupling reactions of sp3 and sp2
carbon centres in various possible combinations with IPr–Pd
in the case of organoboron nucleophiles. In this case, K3PO4
and NaOH were ineffective. We further endeavoured to test
the limits of the catalytic activity of complex 11 by employ-
ing a very sterically hindered aryl chloride, 2-chloro-1,3-di-
ACHTUNGTRENNUNGganozinc reagents (Negishi coupling), coupling reactions for
various possible combinations have been demonstrated.[43]
The scope of the Suzuki–Miyaura coupling reactions mediat-
ed by complex 11 was significantly expanded to include
alkyl halides and alkyl boron reagents when K3PO4 or tert-
BuOK were used as the base at room temperature and up
to 1008C (Scheme 6). Gratifyingly, complex 11 was also
readily activated under conditions suitable for the coupling
of these more challenging substrate combinations even
though each combination required a specific solvent, base
and temperature to take place. 9-Alkyl-9-BBN (9-alkyl-9-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
good yields (39 and 40 in yields of 64 and 72%, respective-
ly) in the presence of K3PO4 at 5 mol% 11. Remarkably, nu-
merous attempts to couple phenylboronic acids to this aryl
chloride with or without additional substituents were unsat-
isfactory, generally producing low yields and inseparable
mixtures. Therefore, we believe this substrate can serve as a
suitable ꢁbenchmarkꢂ for future catalyst development in the
borabicycloACHTUNGTRENNUNG[2.2.1]nonane) derivatives reacted smoothly with
alkyl bromides (products 33 and 34 in yields of 81 and 72%,
respectively) and aryl halides (halide=Br, Cl; 35 and 36 in
yields of 72 and 100%, respectively) with K3PO4 as the
base. On the other hand, the first (to the best of our knowl-
4014
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4010 – 4017

N-Heterocyclic Carbene Palladacycle Diversity
FULL PAPER
filtered into a 100 mL pear-shaped flask. Silica gel (3–5 g) was added and
the solvent was removed under reduced pressure. The free-flowing
powder was transferred into an empty CombiFlash solid-loading car-
tridge and the product was purified by flash chromatography (Combi-
Flash 12 g cartridge, gradient (% B, time): 0 to 60, 30 min); 9 (176 mg,
74%) was isolated as an off-white solid. 1H NMR ([D6]DMSO,
400 MHz): d=7.80 (s, 2H), 7.42 (t, J=7.9 Hz, 2H), 7.29 (dd, J=7.6,
1.2 Hz, 2H), 7.21 (brs, 2H), 6.85 (dd, J=7.2, 1.2 Hz, 1H), 6.77 (td, J=
7.2, 1.2 Hz, 1H), 6.75 (td, J=7.6, 1.4 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H),
3.98–3.44 (brs, 2H), 3.35–2.90 (brs, 4H), 1.33 (d, J=6.4 Hz, 6H), 1.11 (d,
J=6.4 Hz, 6H), 0.97 (d, J=6.4 Hz, 6H), 0.89–0.42 ppm (brs, 6H);
13C NMR ([D6]DMSO, 100 MHz): d=178.8, 151.2, 149.7, 147.6, 145.2,
138.7, 137.3, 136.5, 130.0, 126.3, 125.7, 124.1, 123.7, 123.4, 46.8, 28.8, 28.6,
26.7, 23.5, 21.2, 20.9 ppm; elemental analysis calcd. (%) for
C35H45ClN2PdS (667.68): C 62.96, H 6.79, N 4.20; found: C 62.72, H 6.63,
N 3.94.
field of cross-coupling reactions. Finally, the coupling reac-
tions of boronic esters and potassium trifluoroborates (41
and 42 in yields of 86 and 96%, respectively) were demon-
strated to proceed well in the presence of K3PO4 at a lower
catalyst loading (2 mol%).
Conclusion
We have discovered a novel, highly active precatalyst for
the coupling of deactivated aryl chlorides and phenylboronic
acid at room temperature under very mild, weakly basic
conditions through the evaluation of a small, rationally di-
verse library of NHC–palladacycles. The NHC–palladacycles
were synthesised by a novel method involving the heating of
easily accessible palladacycle acetates with an imidazolium
salt. NHC-ligated o-palladated acetanilide mediated the sp2
(electrophile)–sp2 (organoboron compound), sp2–sp3, sp3–sp2
and sp3–sp3 Suzuki–Miyaura coupling reactions of challeng-
ing substrates in good-to-excellent yields. As a case in point,
the coupling reactions of an extremely sterically hindered
aryl chloride, 1-chloro-2,6-diisopropylbenzene, were con-
ducted for the first time. Representatives of all major classes
of organoboron compounds (boronic acids and esters, potas-
sium trifluoroborates and 9-BBN derivatives) were found to
be suitable. Remarkably, this catalyst also allowed the first
palladium-mediated Suzuki–Miyaura coupling at 08C to be
achieved. The precatalyst could be synthesised in air on a
gram scale in good yields. The Suzuki–Miyaura reactions
can also be performed by using non-anhydrous solvents in
air.
Chloro
no)phenyl-C1,O]palladium(II) (11): A 100 mL round-bottomed flask was
charged with Pd(OAc)2 (674 mg, 3 mmol), acetanilide (810 mg, 6 mmol)
ACHTUNGTNER[NUNG 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][2-(N-acetylami-
AHCTUNGTRENNUNG
and an egg-shaped magnetic stirrer bar in air. Anhydrous dioxane
(12 mL) and TFA (1.2 mL, 16 mmol) were added with stirring. The reac-
tion mixture was heated at 708C for 2.5 h. While hot, the greenish-yellow
solution was diluted with brine (50 mL) and stirred for 30 min. The pre-
cipitate formed was filtered and washed sequentially with H2O (50 mL),
Et2O (25 mL) and CH2Cl2 (25 mL). After drying, cyclopalladated acetani-
lide chloride (713 mg, 2.58 mmol) was obtained as a canary yellow solid.
IPr·HCl (1; 1.15 g, 2.71 mmol), K2CO3 (430 mg, 3.10 mmol) and an egg-
shaped magnetic stirrer bar were added to this solid in a 50 mL round-
bottomed flask in air. CH3CN (13 mL) was added and the reaction mix-
ture was heated at reflux with vigorous stirring for 2.5 h. The mixture
was cooled to room temperature and filtered through a pad of Celite
with copious amounts of CH2Cl2. Complex 11 (1.53 g, 77% from Pd-
AHCTUNRTGEG(NUNN OAc)2) was obtained as an off-white solid after flash chromatography
(CombiFlash 24 g cartridge; solvent A: hexane/CH2Cl2 (1:1, v/v); solvent
B: ethyl acetate; gradient (% B, time): 0 to 5, 30 min). 1H NMR (CDCl3,
400 MHz): d=9.72 (brs, 1H), 7.33 (t, J=7.7 Hz, 2H), 7.20 (brs, 2H),
7.09–7.14 (m, 4H), 6.77–6.85 (m, 2H), 6.54–6.58 (m, 1H), 6.35 (brd, J=
7.5 Hz, 1H), 3.26 (quint., J=6.4 Hz, 2H), 3.06 (quint., J=6.4 Hz, 2H),
2.01 (brs, 3H), 1.39 (d, J=6.5 Hz, 6H), 1.10 (d, J=6.7 Hz, 6H), 0.97 (d,
J=6.8 Hz, 6H), 0.58 ppm (d, J=6.6 Hz, 6H); 13C NMR (CDCl3,
100 MHz): d=175.5, 166.9, 165.4, 147.8, 145.1, 141.6, 140.1, 136.0, 134.8,
130.0, 127.4, 125.1, 124.2, 124.1, 124.1, 122.8, 117.8, 29.0, 28.5, 26.7, 26.2,
23.1, 22.9, 21.9 ppm; HRMS (FAB): calcd. for C35H44ON3106Pd [MÀCl]+:
628.2514; found: 628.2526 (d=1.96 ppm); C35H44ON3108Pd [MÀCl]+:
630.2518; found: 630.2517 (d=À0.09 ppm).
Experimental Section
General: All reagents, catalysts and solvents were purchased from com-
mercial sources and used without further purification, unless otherwise
indicated. Deuterated solvents were purchased from Sigma–Aldrich.
TLC plates and reaction vials (screw-cap threaded, caps attached, 17 ꢃ
60 mm) were purchased from VWR. 1H and 13C NMR data were ac-
quired at 258C on a Bruker AV400 spectrometer. The elemental analyses
were performed at the National University of Singapore. Prior to the
analysis, the samples were dissolved in CH2Cl2 and filtered; the solvent
was removed under reduced pressure, and the neat compounds were
dried at 568C, 5 torr over P2O5 for 18 h. HRMS (FAB and EI) were per-
formed at the National University of Singapore. Flash chromatography
was conducted on a CombiFlash Rx16 or CombiFlash Companion by
using normal-phase silica-gel cartridges with hexane (solvent A)/ethyl
acetate (solvent B) gradients, unless otherwise specified. All preparative
Suzuki–Miyaura cross-coupling reaction runs were performed in dupli-
cate and combined before purification; the amounts and yields indicated
below were for a single run.
N-[4-(o-Tolyl)phenyl]-N’,N’-dimethylurea (23)
Stock solution A: Complex 11 (111 mgmLÀ1) was placed in a pear-shaped
flask, which was capped with a rubber septum, and the flask was backfil-
led with Ar (3ꢃ). The complex was then dissolved in the desired volume
of dry, oxygen-free THF (Note: The stock solution could be stored for at
least 2 weeks without loss of activity).
Stock solution B: NaOH (40 mgmLÀ1) was gently shaken in MeOH until
complete dissolution and then degassed by bubbling a gentle stream of
Ar for at least 15 min.
Reaction procedure: A Pyrex glass tube was charged with a magnetic stir-
rer bar, N-(4-chlorophenyl)-N’,N’-dimethylurea (199 mg, 1 mmol) and o-
tolylboronic acid (163 mg, 1.2 mmol). The tube was sealed with a septum
and backfilled with Ar (3ꢃ). An aliquot (1.2 mL) of the stock solution A
(13.3 mg 11, 2 mol%) was then added and the mixture was stirred for
5 min. Next an aliquot (1.2 mL) of the stock solution B (48 mg NaOH,
1.2 mmol) was added and the reaction mixture was stirred at the desired
temperature for 18 h. The reactions were carried out in duplicate and the
mixtures were then combined by quantitative transfer (CH2Cl2) to a
100 mL pear-shaped flask. Silica gel (1.5–2.5 g) was added and the solvent
was removed in vacuo. The free-flowing powder was transferred into an
empty CombiFlash solid-loading cartridge and 23 (188 mg, 74%) was ob-
tained as a white solid after flash chromatography (CombiFlash 12 g car-
tridge; gradient (% B, time): 0 to 10, 1 min; 10 to 50, 20 min). 1H NMR
ChloroACHTUNGTRENNUNG[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][2-(methylthio-
methyl)phenyl-C1,S)palladium(II) (9): Cyclopalladated benzyl methyl thi-
oether acetate (151 mg, 0.5 mmol) and IPr·HCl[22] (1; 213 mg, 0.5 mmol)
were dissolved in DMSO (2.5 mL) in a Radley carousel tube and heated
at 1208C with stirring for 1 h. After cooling, H2O (25 mL) was added and
the off-white or grey precipitate was filtered through a pad of Celite and
washed with copious amounts of water. After removing most of the
water by air suction for 10 min, the filter cake was dissolved completely
in CH2Cl2 (20–50 mL) and the product solution was dried (MgSO4) and
Chem. Eur. J. 2010, 16, 4010 – 4017
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4015

J. Y. Ying, E. A. B. Kantchev et al.
(CDCl3, 400 MHz): d=7.43 (d, J=8.6 Hz, 2H), 7.23–7.28 (m, 6H), 3.07
(s, 6H), 2.29 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d=155.8, 141.5,
137.9, 136.6, 135.5, 130.3, 129.9, 129.7, 127.1, 125.8, 119.5, 36.5, 20.6 ppm;
HRMS (FAB): calcd. for C16H19N2O [M+H]+: 255.1497; found: 255.1492
(d=2.19 ppm).
tative transfer (CH2Cl2) to a 100 mL pear-shaped flask. Silica gel (2.5–
4 g) was added and the solvent was removed under reduced pressure on
a rotary evaporator equipped with a bump trap fitted with a glass filter.
The free-flowing powder was transferred quantitatively into an empty
CombiFlash solid-loading cartridge and 37 (201 mg, 92%) was obtained
after flash chromatography (CombiFlash 12 g cartridge; gradient (% B,
time): 0 to 20, 25 min). 1H NMR (CDCl3, 400 MHz): d=8.02 (dd, J=1.9,
5.1 Hz, 1H), 7.37 (dd, J=1.9, 7.2 Hz, 1H), 6.82 (dd, J=5.0, 7.1 Hz, 1H),
6.82 (dd, J=5.0, 7.1 Hz, 1H), 3.95 (s, 3H), 2.56–2.60 (m, 2H), 2.35 (t, J=
7.1 Hz, 1H), 1.66–1.75 (m, 2H), 1.58–1.65 (m, 2H), 1.46–1.55 ppm (m,
2H); 13C NMR (CDCl3, 100 MHz): d=162.1, 144.3, 137.6, 124.5, 119.8,
116.7, 53.3, 29.6, 28.4, 28.2, 25.2, 17.1 ppm; HRMS (FAB): calcd. for
C12H17N2O [M+H]+: 205.1335; found: 205.1341 (d=2.55 ppm).
9-(4-Methoxyphenyl)-2,2-dimethylnonanenitrile (33)
Hydroboration of 4-allylanisole in dioxane: A 50 mL round-bottomed
flask equipped with a magnetic stirrer bar was charged with 9-BBN
dimer (1.74 g, 7.15 mmol) in a glove box. The flask was capped with a
rubber septum and removed from the glove box. Anhydrous 1,4-dioxane
(5 mL) was added followed by 4-allylanisole (2.0 mL, 1.93 g, 13 mmol).
Additional anhydrous dioxane (5 mL) was added to give a final concen-
tration of 1.3m based on 4-allylanisole. The reaction was stirred overnight
at room temperature to give a clear homogeneous 9-[3-(4-methoxyphe-
nyl)propyl]-9-BBN solution.
2-(2,6-Diisopropylphenyl)furan (39): A 10 mL reaction vial was charged
with 11 (0.02 mmol, 14 mg), furan-2-boronic acid (244 mg, 2.0 mmol),
finely ground K3PO4 (2.0 mmol, 425 mg) and a magnetic stirrer bar. It
was sealed with a rubber septum and purged with Ar (3ꢃ). 2-Chloro-1,3-
diisopropylbenzene (197 mg, 1.0 mmol) was added through a preweighed
syringe and 1,4-dioxane (2.5 mL) and H2O (1.0 mL) were injected in suc-
cession with vigorous stirring. The reaction was carried out in duplicate
and stirred overnight at 1008C, after which time the reactions were com-
bined, diluted with H2O (10 mL) and extracted with CH2Cl2 (3ꢃ10 mL).
The combined organic layers were dried (MgSO4), filtered through a
Celite pad and quantitatively transferred into a 100 mL pear-shaped
flask. Silica gel (2–3 g) was added and the solvent was removed in vacuo.
The free-flowing powder was transferred into an empty CombiFlash
solid-loading cartridge and 39 (147 mg, 64%) was obtained after flash
chromatography (CombiFlash 12 g cartridge; gradient (% B, time): 0,
30 min). 1H NMR (CDCl3, 400 MHz): d=7.56 (brs, 1H), 7.42–7.46 (m,
1H), 7.24–7.27 (m, 2H), 6.53–6.54 (m, 1H), 6.31–6.33 (m, 1H), 2.71–2.78
(m, 2H), 1.20 ppm (dd, J=6.9, 1.6 Hz, 12H); 13C NMR (CDCl3,
100 MHz): d=151.8, 141.6, 129.7, 129.1, 122.6, 110.3, 109.3, 30.8,
24.3 ppm; HRMS (EI): calcd. for C16H20O [M]+: 228.1514; found:
228.1509 (d=À2.22 ppm).
Reaction procedure:
A 10 mL vial was charged with 11 (27 mg,
0.04 mmol), finely ground K3PO4·H2O (369 mg, 1.6 mmol) and a magnetic
stirrer bar. The vial was sealed with a rubber septum and backfilled with
Ar (3ꢃ). 6-Bromo-2,2-dimethylhexanenitrile (170 mL, 204 mg, 1.0 mmol)
was added through a syringe followed by a solution of 9-[3-(4-methoxy-
phenyl)propyl]-9-BBN (1.3m in dioxane; 1.25 mL, 1.6 mmol). The reac-
tion was carried out in duplicate and after 18 h, the reaction mixtures
were combined by quantitative transfer (CH2Cl2) to a 100 mL pear-
shaped flask. Silica gel (1.5–2.5 g) was added and the solvent was re-
moved in vacuo. The free-flowing powder was transferred into an empty
CombiFlash solid-loading cartridge and 33 (220 mg, 81%) was obtained
after flash chromatography (CombiFlash 12 g cartridge; gradient (% B,
time): 0 to 5, 20 min). 1H NMR (CDCl3, 400 MHz): d=7.11 (d, J=
8.6 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.54–2.58 (m, 2H),
1.58–1.67 (m, 3H), 1.42–1.55 (m, 4H), 1.34 ppm (brs, 12H); 13C NMR
(CDCl3, 100 MHz): d=157.6, 134.9, 129.3, 125.3, 113.6, 55.2, 41.1, 35.0,
32.4, 31.7, 29.5, 29.3, 29.1, 26.7, 25.3; HRMS (EI): calcd. for C18H27NO
[M]+: 273.2087; found: 273.2096 (d=3.22 ppm).
1,2,3-Trimethoxy-5-(3-(4-methoxyphenyl)propyl)benzene (35)
Hydroboration of 4-allylanisole in THF: A solution of 9-BBN (0.5m in
THF, 39 mL, 19.5 mmol) followed by 4-allylanisole (2.0 mL, 1.93 g,
13 mmol) was injected into an oven-dried 100 mL round-bottomed flask
equipped with a magnetic stirrer bar. The reaction was stirred overnight
at room temperature and the 9-[3-(4-methoxyphenyl)propyl]-9-BBN so-
lution formed (0.32m in THF) was used directly.
Acknowledgements
This work was funded by the Institute of Bioengineering and Nanotech-
nology (Biomedical Research Council, Agency for Science, Technology
and Research, Singapore). We thank G.-K. Tan (National University of
Singapore X-Ray Facility) for structural analysis of complexes 9 and 11,
Prof. M. G. Organ (York University, Canada) for the generous gift of
PEPPSI-IPr and Dr. Hartmut Schedel (Tokyo Chemical Industries) for
assistance with the commercialisation of complex 11 and related NHC–
palladacycles and the experimental results depicted in Figure 3.
Reaction procedure:
A 10 mL vial was charged with 11 (27 mg,
0.04 mmol) followed by finely ground anhydrous K3PO4 (340 mg,
1.6 mmol) and a magnetic stirrer bar. The vial was sealed with a rubber
septum and backfilled with Ar (3ꢃ). 5-Bromo-1,2,3-trimethoxybenzene
(340 mg, 1.0 mmol) was added and 9-[3-(4-methoxyphenyl)propyl]-9-
BBN solution (0.32m in THF, 5.0 mL, 1.6 mmol) and H2O (1.0 mL) were
injected through a syringe in succession with vigorous stirring. The reac-
tion was carried out in duplicate and after 18 h, the reaction mixtures
were combined by quantitative transfer (CH2Cl2) to a 100 mL pear-
shaped flask. Silica gel (1.5–2.5 g) was added and the solvent was re-
moved in vacuo. The free-flowing powder was transferred into an empty
CombiFlash solid-loading cartridge and 35 (229 mg, 72%) was obtained
after flash chromatography (CombiFlash 12 g cartridge; gradient (% B,
time): 0 to 20, 25 min). 1H NMR (CDCl3, 400 MHz): d=7.13 (d, J=
8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 6.42 (s, 2H), 3.86 (s, 6H), 3.85 (s,
3H), 3.81 (s, 1H), 2.59–2.65 (m, 4H), 1.90–2.00 ppm (m, 2H); 13C NMR
(CDCl3, 100 MHz): d=157.7, 153.0, 138.2, 134.2, 129.4, 113.7, 105.2, 60.9,
56.0, 55.3, 35.8, 34.6, 33.3 ppm; HRMS (EI): calcd. for C19H24O4 [M]+:
316.1669; found: 316.1670 (d=0.40 ppm).
[1] E. Negishi, J. Organomet. Chem. 2002, 653, 34.
[2] K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94,
4374.
[3] R. J. P. Corriu, J. P. Masse, Chem. Commun. 1972, 144.
[4] L. Cassar, J. Organomet. Chem. 1975, 93, 253.
[5] E. Negishi, S. Baba, Chem. Commun. 1976, 596.
[6] S. Baba, E. Negishi, J. Am. Chem. Soc. 1976, 98, 6729.
[7] A. O. King, N. Okukado, E. Negishi, Chem. Commun. 1977, 683.
[8] E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821.
[9] A. De Meijere, F. Diederich, Metal-catalyzed Cross-coupling Reac-
tions, 2nd ed., Wiley, New York, 2004, and references therein.
[10] E. Negishi, Handbook of Organopalladium Chemistry for Organic
Synthesis, Wiley, New York, 2002, and references therein.
[11] For a review, see: K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew.
Chem. 2005, 117, 4516; Angew. Chem. Int. Ed. 2005, 44, 4442.
[12] For a review, see: J. S. Carey, D. Laffan, C. Thomson, M. T. Williams,
Org. Biomol. Chem. 2006, 4, 2337.
6-(2-Methoxypyridin-3-yl)hexanenitrile (37): A 10 mL vial was charged
with 11 (27 mg, 0.04 mmol), 2-methoxy-3-pyridineboronic acid (230 mg,
1.5 mmol), tBuOK (168 mg, 1.5 mmol) and a magnetic stirrer bar. The
vial was sealed with a rubber septum and backfilled with Ar (3ꢃ). Anhy-
drous dioxane (1.2 mL) and anhydrous methanol (1.2 mL) were added in
succession through a syringe. After stirring for 15 s, 3-bromohexanenitrile
(140 mL, 176 mg, 1.0 mmol) was added through a syringe. The reaction
mixture was stirred at room temperature. The reaction was carried out in
duplicate and after 18 h, the reaction mixtures were combined by quanti-
[13] A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem. 1995,
107, 1456; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.
4016
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4010 – 4017

N-Heterocyclic Carbene Palladacycle Diversity
FULL PAPER
[14] J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609.
[15] For a review, see: R. B. Bedford, C. S. J. Cazin, D. Holder, Coord.
Chem. Rev. 2004, 248, 2283.
[16] For a review, see: A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114,
4350; Angew. Chem. Int. Ed. 2002, 41, 4176.
[49] M. R. Biscoe, B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc. 2008,
130, 6686.
[50] I. J. S. Fairlamb, A. R. Kapdi, A. F. Lee, Org. Lett. 2004, 6, 4435.
[51] O. Navarro, Y. Oonishi, R. A. Kelly III, E. D. Stevens, O. Briel, S. P.
Nolan, J. Organomet. Chem. 2004, 689, 3722.
[52] L.-C. Campeau, P. Thansandote, K. Fagnou, Org. Lett. 2005, 7, 1857.
[53] J. A. Love, M. S. Sanford, M. W. Day, R. H. Grubbs, J. Am. Chem.
Soc. 2003, 125, 10103.
[54] J. A. Love, J. P. Morgan, T. M. Trnka, R. H. Grubbs, Angew. Chem.
2002, 114, 4207; Angew. Chem. Int. Ed. 2002, 41, 4035.
[55] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168.
[56] T. Weskamp, F. J. Kohl, W. Hieringer, D. Gleich, W. A. Herrmann,
Angew. Chem. 1999, 111, 2573; Angew. Chem. Int. Ed. 1999, 38,
2416.
[57] N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott, S. P.
Nolan, J. Am. Chem. Soc. 2006, 128, 4101.
[58] O. Navarro, N. Marion, Y. Oonishi, R. A. Kelly III, S. P. Nolan, J.
Org. Chem. 2006, 71, 685.
[59] K. Hiraki, M. Onishi, K. Sewaki, K. Sugino, Bull. Chem. Soc. Jpn.
1978, 51, 2548.
[60] W. A. Herrmann, C. Brossmer, K. ꢆfele, C.-P. Reisinger, T. Prierme-
ier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1844.
[61] M. Beller, H. Fischer, W. A. Herrmann, K. ꢆfele, C. Brossmer,
Angew. Chem. 1995, 107, 1992; Angew. Chem. Int. Ed. Engl. 1995,
34, 1848.
[62] J. Louie, J. F. Hartwig, Angew. Chem. 1996, 108, 2531; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2359.
[63] For a review, see: J. Dupont, C. S. Consorti, J. Spencer, Chem. Rev.
2005, 105, 2527.
[64] For a review, see: I. P. Beletskaya, A. V. Cheprakov, J. Organomet.
Chem. 2004, 689, 4055.
[65] For a review, see: J. Dupont, M. Pfeffer, J. Spencer, Eur. J. Inorg.
Chem. 2001, 1917.
[66] I. P. Beletskaya, A. N. Kashin, N. B. Karlstedt, A. V. Mitin, A. V.
Cheprakov, G. M. Kazankov, J. Organomet. Chem. 2001, 622, 89.
[67] M. S. Viciu, R. A. Kelly III, E. D. Stevens, F. Naud, M. Studer, S. P.
Nolan, Org. Lett. 2003, 5, 1479.
[68] For a review, see: U. Christmann, R. Vilar, Angew. Chem. 2005, 117,
370; Angew. Chem. Int. Ed. 2005, 44, 366.
[69] A. Schnyder, A. F. Ingolese, M. Studer, H.-U. Blaser, Angew. Chem.
2002, 114, 3820; Angew. Chem. Int. Ed. 2002, 41, 3668.
[70] E. A. B. Kantchev, J. Y. Ying, Organometallics 2009, 28, 289.
[71] R. B. Bedford, M. Betham, M. E. Blake, R. M. Frost, P. N. Horton,
M. B. Hursthouse, R.-M. Lꢇpez-Nicolꢄs, Dalton Trans. 2005, 2774.
[72] G. D. Frey, J. Schꢅtz, W. A. Herrmann, J. Organomet. Chem. 2006,
691, 2403.
[73] Preliminary studies indicated that complex 11 was activated smooth-
ly and rapidly under strong basic conditions (tBuOK/iPrOH). The
only other library member that was activated under these conditions
was 3 (see Ref.[67]).
[17] For a review, see: N. Marion, E. M. Nolan, Acc. Chem. Res. 2008,
41, 1440.
[18] F. Glorius, N-Heterocyclic Carbenes in Transition-Metal Catalysis,
Springer, Berlin, 2007, and references therein.
[19] S. P. Nolan, N-Heterocyclic Carbenes in Synthesis, Wiley-VCH,
Weinheim, 2006, and references therein.
[20] For a review, see: E. A. B. Kantchev, C. J. OꢂBrien, M. G. Organ,
Angew. Chem. 2007, 119, 2824; Angew. Chem. Int. Ed. 2007, 46,
2768.
[21] For a review, see: W. A. Herrmann, Angew. Chem. 2002, 114, 1342;
Angew. Chem. Int. Ed. 2002, 41, 1290.
[22] A. J. Arduengo III, R. Krafczyk, R. Schmutzler, Tetrahedron 1999,
55, 14523.
[23] For a review, see: G. C. Fu, Acc. Chem. Res. 2008, 41, 1555.
[24] For a review, see: D. S. Surry, S. L. Buchwald, Angew. Chem. 2008,
120, 6438; Angew. Chem. Int. Ed. 2008, 47, 6338.
[25] For a review, see: R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008,
41, 1461.
[26] For a review, see: C. C. Mauger, G. A. Mignani, Aldrichimica Acta
2006, 39, 17.
[27] For a review, see: A. C. Frisch, M. Beller, Angew. Chem. 2005, 117,
680; Angew. Chem. Int. Ed. 2005, 44, 674.
[28] For a review, see: D. J. Cꢄrdenas, Angew. Chem. 2003, 115, 398;
Angew. Chem. Int. Ed. 2003, 42, 384.
[29] For a review, see: T.-Y. Luh, M.-K. Leung, K.-T. Wong, Chem. Rev.
2000, 100, 3187.
[30] T. Brenstrum, D. A. Gerristma, G. M. Adjabeng, C. S. Frampton, J.
Britten, A. J. Robertson, J. McNulty, A. Capretta, J. Org. Chem.
2004, 69, 7635.
[31] S. L. Wiskur, A. Korte, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 82.
[32] K. Menzel, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 3718.
[33] J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 12527.
[34] H. Tang, K. Menzel, G. C. Fu, Angew. Chem. 2003, 115, 5233;
Angew. Chem. Int. Ed. 2003, 42, 5079.
[35] M. R. Netherton, G. C. Fu, Angew. Chem. 2002, 114, 4066; Angew.
Chem. Int. Ed. 2002, 41, 3910.
[36] J. H. Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. 2002, 114, 2025;
Angew. Chem. Int. Ed. 2002, 41, 1945.
[37] J. H. Kirchhoff, M. R. Netherton, I. D. Hills, G. C. Fu, J. Am. Chem.
Soc. 2002, 124, 13662.
[38] M. R. Netherton, C. Dai, K. Neuschꢅtz, G. C. Fu, J. Am. Chem. Soc.
2001, 123, 10099.
[39] L. Firmansjah, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 11340.
[40] C. Valente, S. Baglione, D. Candito, C. J. OꢂBrien, M. G. Organ,
Chem. Commun. 2008, 735.
[41] G. Altenhoff, S. Wꢅrtz, F. Glorius, Tetrahedron Lett. 2006, 47, 2925.
[42] C. J. OꢂBrien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass,
A. Lough, A. C. Hopkinson, M. G. Organ, Chem. Eur. J. 2006, 12,
4743.
[43] M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev,
C. J. OꢂBrien, C. Valente, Chem. Eur. J. 2006, 12, 4749.
[44] N. Hadei, E. A. B. Kantchev, C. J. OꢂBrien, M. G. Organ, Org. Lett.
2005, 7, 3805.
[45] N. Hadei, E. A. B. Kantchev, C. J. OꢂBrien, M. G. Organ, J. Org.
Chem. 2005, 70, 8503.
[46] C. J. OꢂBrien, E. A. B. Kantchev, G. A. Chass, N. Hadei, A. C. Hop-
kinson, M. G. Organ, D. H. Setiadi, T.-H. Tang, D.-C. Fang, Tetrahe-
dron 2005, 61, 9723.
[74] N. Marion, E. C. Ecarnot, O. Navarro, D. Amoroso, A. Bell, S. P.
Nolan, J. Org. Chem. 2006, 71, 3816.
[75] M. S. Viciu, R. F. Germaneau, S. P. Nolan, Org. Lett. 2002, 4, 4053.
[76] K. Selvakumar, A. Zapf, A. Spannenberg, M. Beller, Chem. Eur. J.
2002, 8, 3901.
[77] A. N. Cammidge, V. H. M. Goddard, H. Gopee, N. L. Harrison,
D. L. Hughes, C. J. Schubert, B. M. Slutton, G. L. Watts, A. J. White-
head, Org. Lett. 2006, 8, 4071.
[78] Complex 11 will be commercially available from Tokyo Chemical
Industries under the trademark SingaCycle.
[79] H. Horino, N. Inoue, Tetrahedron Lett. 1979, 20, 2403.
[80] W. Mossi, A. J. Klaus, P. Rys, Helv. Chim. Acta 1992, 75, 2531.
[47] K. Arentsen, S. Caddick, F. G. N. Cloke, A. P. Herring, P. B. Hitch-
cock, Tetrahedron Lett. 2004, 45, 3511.
Received: October 15, 2009
[48] M. Eckhardt, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 13642.
Published online: February 19, 2010
Chem. Eur. J. 2010, 16, 4010 – 4017
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4017