Rapid room temperature buchwald-hartwig and suzuki-miyaura couplings of heteroaromatic compounds employing low catalyst loadings

Article abstract of DOI:10.1002/chem.200600283

The use of second-generation [(NHC)Pd(R-allyl)Cl] complexes for Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions involving heteroaromatic halides at room temperature is reported. The first examples of room temperature Suzuki-Miyaura cross-coupling of deactivated aryl chlorides with alkenyl boronic acids are also disclosed. Terminal substitution at the allyl moiety of the palladium complex facilitates its activation at room temperature leading to very active catalytic species enabling the present catalytic transformations to be performed rapidly using very mild reaction conditions. Catalyst loadings can be as low as 10 ppm for the Buchwald-Hartwig aryl amination and 50 ppm for the Suzuki-Miyaura reaction.

Full text of DOI:10.1002/chem.200600283

DOI: 10.1002/chem.200600283
Rapid Room Temperature Buchwald–Hartwigand Suzuki–Miyaura
Couplings of Heteroaromatic Compounds Employing Low Catalyst Loadings
Oscar Navarro, Nicolas Marion, Jianguo Mei, and Steven P. Nolan*[a]
Abstract: The use of second-generation
[(NHC)Pd(R-allyl)Cl] complexes for
are also disclosed. Terminal substitu-
tion at the allyl moiety of the palladi-
um complex facilitates its activation at
room temperature leading to very
active catalytic species enabling the
present catalytic transformations to be
performed rapidly using very mild re-
action conditions. Catalyst loadings can
be as low as 10 ppm for the Buchwald–
Hartwig aryl amination and 50 ppm for
the Suzuki–Miyaura reaction.
ACHTREUNG
Suzuki–Miyaura and Buchwald–Hart-
wig cross-coupling reactions involving
heteroaromatic halides at room tem-
perature is reported. The first examples
of room temperature Suzuki–Miyaura
cross-coupling of deactivated aryl
chlorides with alkenyl boronic acids
Keywords:
Buchwald–Hartwig
reaction · carbenes · cross-coupling ·
palladium
reaction
·
Suzuki–Miyaura
Introduction
Results and Discussion
Heteroaromatic compounds represent a recurring architec-
tural motif found in various areas of chemistry, ranging from
pharmaceutically active compounds[1,2] to polymers.[3] Al-
though the Suzuki–Miyaura[4] and Buchwald–Hartwig[5] re-
actions arguably are among the most powerful and widely
Aryl chlorides are very attractive halides due to their low
cost and wide diversity and availability. Historically, their
use in cross-coupling reactions has been somewhat limited
due to their poor reactivity, attributed to the strength of the
[10]
À
C Cl bond. Despite their importance, the coupling reac-
À
À
used methods to assemble C C or C N bonds, heterocyclic
compounds are usually not easily coupled in these important
reactions. These bond-making processes are achieved by
coupling an organic halide or pseudohalide with an organo-
boron reagent or an amine, respectively, in the presence of a
transition-metal catalyst.[6] It is well known that the ancillary
ligands on the metal center play a major role in dictating
the efficiency of a catalytic system.[5] Bulky, electron-rich
tions of most heteroaromatic chlorides remain a chal-
lenge,[11] especially at low temperatures and/or low catalyst
loadings. Although the poisoning effect of sulfur in some
palladium-catalyzed reactions is well known, it should also
be mentioned that such undesired effects have also been ob-
served with nitrogen containing substrates.[12]
Our group recently reported a general system involving
the use of palladacycle 1 for the room temperature Suzuki–
Miyaura cross-coupling of aryl chlorides in technical grade
isopropanol.[13] The system even allowed for the coupling of
sterically hindered unactivated aryl chlorides with sterically
hindered boronic acids under these mild conditions. Di- and
tri-ortho-substituted biaryls were isolated in high yields
using this simple protocol. In addition, the coupling of a
series of heteroaromatic (S- and N-containing) halides could
be carried out under these conditions in short reaction times
and high yields.[14] The only drawbacks associated with the
use of 1 are the harsh conditions required for the synthesis
of the complex and the associated low synthetic yield
(63%).[15] Furthermore, slow addition of the aryl chloride
was required when performing the coupling to avoid the un-
desired competing dehalogenation of the aryl halide. To fur-
ther explore and hopefully capitalize on ancillary ligand ef-
phosphines such as P
N
N
most utilized phosphorus-based ligands capable of stabiliz-
ing the active Pd0 species presumably responsible for activity
in these important bond-forming reactions.[7] The N-hetero-
cyclic carbenes[8] (NHC) represent an alternative class of li-
gands becoming increasingly popular to achieve these cou-
plings.[9]
[a] Dr. O. Navarro, N. Marion, J. Mei, Prof. Dr. S. P. Nolan
Department of Chemistry, University of New Orleans
2000 Lakeshore dr., New Orleans, LA 70148 (USA)
Fax : (+1)504-280-6860
E-mail: snolan@uno.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Chem. Eur. J. 2006, 12, 5142 – 5148

FULL PAPER
fects, the activation of complexes with the general formula
[(NHC)Pd(allyl)Cl] was recently examined {in Scheme 1,
[(IPr)Pd(allyl)Cl] (2) (IPr = (N,N’-bis(2,6-diisopropylphe-
nyl)imidazol)-2-ylidene)}. This was studied in order to deter-
mine how the architecture could be fine-tuned and lead to
an increase in the rate of activation of these catalyst precur-
sors at room temperature.
pyridine were found to react very efficiently with a range of
amines. Reactions with cyclic dialkylamines reached comple-
tion within five minutes (Tables 1 and 2, entries 1 and 2) and
are quantitative; leading, in the case of entry 1 to a workup
that simply required filtration through Celite without purifi-
cation by column chromatography. As expected, the more
sterically demanding dibutyl- and diallylamine required a
longer reaction time to provide
ACHTREUNG
ACHTREUNG
in almost quantitative yield the
corresponding 2-pyridyl deriv-
atives (Table 2, entries 3 and
4). It is noteworthy that this is
the first example, to the best
of our knowledge, of chloro-
pyridines coupled with amines
under such mild conditions
Scheme 1. Complexes 1–4.
and in such short reaction
times.[20,11a] The same trend
was observed with N-methyl-
These complexes and this frameworkwere selected since
their synthesis is very straightforward and proceed in high
yields, even in multigram preparations.[16] By decreasing the
stability of the h3 bond by control of electronic and steric ef-
fects, we reasoned that terminal substitution (alkyl or aryl)
at the allyl moiety would facilitate the activation of the com-
plexes at room temperature[16a,17] leading to the postulated
active catalytic species, [(NHC)Pd0]. To test our hypothesis,
we prepared a series of complexes with general formula
aniline which produced diaryl compounds within 15 minutes
(Table 1, entry 3 and Table 2, entry 5). Surprisingly, coupling
reactions with 3-chloro- and 3-bromopyridine, strongly unac-
tivated compared with 2-pyridyl halides,[21] proceeded rapid-
ly. This allowed for the formation of 3-pyridylamino com-
pounds at room temperature in no more than 45 minutes.
More strikingly, when 3-bromopyridine was added to re-
action mixtures containing morpholine or piperidine, an in-
tense exotherm was observed and these reactions reached
completion within five minutes (Table 1, entries 4 and 5).
Encouraged by the reactivity of 3-halopyridines, we carried
[(NHC)Pd(R-allyl)Cl], and examined their reaction profiles
A
for the Suzuki–Miyaura and the Buchwald–Hartwig reac-
tions with aryl chlorides. These
trials provided excellent re-
sults.[18] Herein, we report on
Table 1. Buchwald–Hartwig reactions with N-containing heteroaromatic bromides.
the use of two of those substi-
tuted-allyl palladium com-
plexes, [(IPr)Pd
(3) (cinnamyl = 3-phenylallyl)
and [(SIPr)Pd(cinnamyl)Cl] (4)
(SIPr = (N,N’-bis(2,6-diisopro-
pylphenyl)-4,5-dihydroimida-
zol)-2-ylidene) for specific
trials with heteroaromatic hal-
ides as substrates.
A
Entry
1
Bromide
Amine
Product
t [min]
Yield [%][a]
94
ACHTREUNG
1
2
3
2
96
92
10
Buchwald–Hartwigreactions
:
As we[16a] and others[19] have
reported the use of the SIPr
carbene leading to a better cat-
alyst performance than the IPr
carbene in this reaction, we
tested the activity of 4 in a
series of reactions involving
the coupling of N-containing
heteroaromatic halides with
primary and secondary amines
at room temperature (Tables 1
and 2). 2-Bromo- and 2-chloro-
4
5
5
5
90
72
6
7
90
40
92
87
Reaction conditions: 1 mmol aryl bromide; 1.1 mmol amine; 1 mol% 4; 1.1 mmol KOtBu; 1 mL DME. [a] Iso-
lated yields, average of two runs.
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S. P. Nolan et al.
Table 2. Buchwald–Hartwig Reactions with N-containing heteroaromatic chlorides.
dine and 3-bromoquinoline
with boronic acids did not take
place under these conditions,
while 2-bromo- and 2-chloro-
pyridine coupled smoothly in
high yields (Table 3, entries 1,
Entry
1
Chloride
Amine
Product
t [min]
Yield [%][a]
89
2
2) using
3 in as low as
0.05 mol% (or 500 ppm). We
have not found precedents in
the literature for the room
temperature Suzuki–Miyaura
coupling of 2-chlorobenzimida-
zole (Table 3, entry 3) or
5-chloro-1,3-benzodioxole
2
3
4
5
15
60
98
94
92
(Table 3, entry 4). 2-Substitut-
ed benzimidazoles are a ubiq-
uitous moiety in heteroaromat-
ic chemistry and can be found
in applications ranging from
anticancer drugs[24] to conduct-
ing polymers.[3] As an addition-
al practical advantage, for all
Suzuki–Miyaura couplings re-
ported here, catalyst solutions
5
15
92
6
7
15
45
86
82
Reaction conditions: 1 mmol aryl chloride; 1.1 mmol amine; 1 mol% 4; 1.1 mmol KOtBu; 1 mL DME. [a] Iso-
lated yields, average of two runs.
out reactions with 3-bromoquinoline. N-Methylaniline and
piperidine yielded the corresponding 3-aminoquinolines
(Table 1, entries 6 and 7). Considering the mild reaction
conditions employed, this is a considerable advance since
few reports on aryl amination involve haloquinolines.[22]
where prepared with technical grade isopropanol (IPA) and
injected in the sample vials through a septum cap. From a
practical point of view, these conditions are very appealing,
especially since it makes use of an inexpensive and environ-
mentally friendly solvent (IPA) without the need for pre-
drying or purification.
Suzuki–Miyaura reactions: In earlier work, we identified
(IPr)-bearing palladium complexes as the most effective for
Suzuki–Miyaura coupling reactions,[16,18] the following ex-
periments were carried out using 3 as pre-catalyst. As for
the Buchwald–Hartwig reaction, attempts to couple sulfur-
containing heteroaromatic halides (2- or 3-bromo- or chloro-
thiophenes and 2-chlorobenzothiazole) with boronic acids at
room temperature invariably failed but reactions carried out
at 608C proceeded smoothly. The Suzuki–Miyaura coupling
of chlorothiophenes at room
We then proceeded to examine whether this system could
facilitate the coupling of heteroaromatic halides with alke-
nylboronic acids, another significant challenge (Table 4).
Mild temperatures are often mandatory for the coupling of
aryl bromides with vinylboronic acids, this to favor desired
high E/Z selectivity. Buchwald and co-workers recently re-
ported on a very efficient system to couple aryl bromides
and a variety of alkenylboronic acids.[25]
temperature has been report-
ed.[14,23] However, in the pres-
ent system since the high thio-
philicity of PdII may cause the
heteroaromatic substrate to in-
teract with the pre-catalyst and
thereby inhibit activation, our
results suggest that the forma-
tion of the [(NHC)Pd0] species
is not immediate under these
conditions. Interestingly, unlike
the Buchwald–Hartwig reac-
tion, the position of the nitro-
gen in the ring has a major
effect in the Suzuki–Miyaura
coupling: the couplings of 3-
bromopyridine, 3-chloropyri-
Table 3. Suzuki–Miyaura couplings of heteroaryl halides.
Entry
1
Ar-X
Boronic acid
Product
t [h]
Yield [%][a]
94
3.5
2
3
15
15
96
95
Reaction conditions: 1 mmol aryl halide; 1.05 mmol boronic acid; 0.05 mol% 3; 1.1 mmol KOtBu; 1 mL tech-
nical grade isopropanol. [a] Isolated yields, average of two runs.
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Cross-Coupling Reactions
FULL PAPER
Table 4. Suzuki–Miyaura couplings of trans-2-phenylvinylboronic acid.
Miyaura cross coupling of un-
activated aryl chlorides with an
alkenylboronic acid performed
in such yields and reasonable
reaction times at room temper-
ature.
Entry
1
Ar-X
Product
t [h]
Yield [%][a]
94
0.5
Buchwald–Hartwigand
Suzuki–Miyaura reactions at
low catalyst loadings: Decreas-
ing the amount of palladium
necessary to catalyze a process
is desirable not only because
of cost, but also in order to fa-
cilitate metal removal once the
reaction is complete. This is es-
pecially important in industrial
settings where concerns of
product purity, toxicity associ-
ated with residual metal and
general environmental issues
have significant health and
2
3
1
94
92
1.5
4
5
1
1
92
95
6
7
2
1
61
78[b]
economical
consequences.[26]
The very rapid reactions ob-
served for a wide array of sub-
strates naturally led us to ex-
amine the effect of reducing
the catalyst loading.
7
1
94
Reaction conditions: 1 mmol aryl halide; 1.05 mmol boronic acid; 1.0 mol% 3; 1.1 mmol KOtBu; 1 mL techni-
cal grade isopropanol. [a] Isolated yields. >99:1 trans:cis isomers. [b] 2 mol% catalyst loading.
For the Buchwald–Hartwig
reaction, the use of 4 allowed
While substrates without ortho-substituents coupled at
room temperature, electron-rich and ortho-substituted bro-
mides required a reaction temperature of 408C. Higher tem-
peratures were required to couple the analogous chlorides,
leading to the undesired E/Z alkene isomerization. In the
present NHC-based system, re-
for the use of as low as 10 parts per million (ppm) pre-cata-
lyst if the temperature was raised to 808C. The reaction be-
tween morpholine and 2-bromopyridine (Table 5, entry 1)
can be conducted at room temperature with a catalyst load-
ing of only 0.1 mol%; the reaction reached completion in
actions proceeded smoothly at
Table 5. Buchwald–Hartwig reactions at room temperature and low catalyst loadings.
room
temperature
using
1 mol% of 3 in very short re-
action times and high yields
for the coupling of 2,4,6-trime-
thylphenyl bromide, 2,6-dime-
thylphenyl bromide, 4-bromo-
biphenyl and 2-bromopyridine.
Longer reaction times were re-
quired for the coupling of anal-
ogous aryl chlorides, and the
electron-rich, sterically de-
Entry
1
Aryl halide
Amine
Cat. loading [mol%]
1
t
Yield [%][a]
99
1 min
0.1
0.001
0.001
2 min
50 h
12 h
93
97
91[b]
2
3
1
1 min
100
0.1
0.001
0.001
5 min
48 h
20 h
93
95
manding
2,6-dimethylphenyl
chloride did not reach comple-
tion despite using a higher cat-
alyst loading (2 mol%) and a
longer reaction time. In all
cases, E/Z alkene isomeriza-
tion was negligible. To the best
of our knowledge, these are
the first examples of Suzuki–
94[b]
1
15 min
98
0.1
0.001
0.001
1 h
50 h
40 h
99
73
93[b]
Reaction conditions: 1 mmol halopyridine; 1.1 mmol amine; 1.1 mmol KOtBu; 1 mL DME. [a] GC yields
(hexamethylbenzene as internal standard) average of two runs. [b] T=808C.
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5145

S. P. Nolan et al.
two minutes, corresponding to a turnover frequency (TOF)
of 27900 hÀ1. Moreover, with a 10 ppm catalyst loading the
reaction reached completion at room temperature but re-
cies in solution. We have presented examples of couplings of
heteroaryl bromides and chlorides with boronic acids or
amines at room temperature proceeding in extremely short
reaction times. When the temperature is increased, catalyst
loadings as low as 50 ppm of 2 or 3 can be used for the
Suzuki–Miyaura reaction, and as low as 10 ppm of 4 for the
Buchwald–Hartwig reaction. We have also reported the first
examples of room temperature Suzuki–Miyaura coupling of
unactivated aryl chlorides with alkenyl boronic acids. Addi-
tionally, complexes 2–4 are air- and moisture-stable and can
be prepared on multigram scale in high yields. Complex 2 is
commercially available and congeners will also shortly be
offered.[30] Studies aimed at exploring the reaction chemistry
of these latter generation palladium catalysts in related
cross-coupling reactions are currently ongoing in our labora-
tories.
quired 50 h, providing
a turnover number (TON) of
97000.[11a] Remarkably, the reaction time could be reduced
by a factor of 4 if the temperature was raised to 808C.
2-Chloropyridine also reacted very rapidly with morpho-
line with 0.1 mol% catalyst (TOF = 11160 hÀ1). A TON of
95000 was obtain when 10 ppm catalyst used (Table 5,
entry 2). This TON value is very similar to the one recently
reported by Hartwig.[11a] Finally, we carried out the reaction
between 2-chloropyridine and dibutylamine. Strikingly, even
with a sterically demanding amine, high TON values were
obtained at room temperature and at 808C (73000 and
93000, respectively). It is of note that a literature search re-
vealed that this particular coupling was carried out with the
corresponding bromide prior to the present study and re-
quired elevated temperatures (808C) and high catalyst load-
ing (2–3 mol%).[27]
Experimental Section
For the Suzuki–Miyaura reaction, when the temperature
is increased to 808C, the catalyst loading can be reduced to
50 ppm with no loss of yield and proceeds in even shorter
reaction times.
General information: All aryl halides, amines and boronic acids were
used as received (Aldrich, Acros). Technical grade isopropanol was used
to carry out catalytic reactions (Mallinckrodt Chemicals). Potassium tert-
butoxide (Acros) was stored under argon in an M. Braun glovebox. Com-
plexes 2–4 were prepared according to the literature.[16b,18] Flash chroma-
tography was performed on silica gel (230–400 mesh, Silicycle). 1H and
13C nuclear magnetic resonance spectra were recorded on a Varian-300
or Varian-400 MHz spectrometer at ambient temperature in CDCl3, C6D6
or [D6]DMSO (Cambridge Isotope Laboratories, Inc). Elemental analy-
ses were performed at Robertson Microlit Laboratories, Inc., Madison,
NJ.
As expected, the use of the commercially available
[(IPr)Pd(allyl)Cl] (2) at high temperature provides the same
N
results as when 3 is used (Table 6, entry 1),[18,28] highlighting
again the significant role of the higher terminal substitution
at the allyl moiety in activating the catalyst at lower temper-
atures. This effect is in contrast to our observations for the
Buchwald–Hartwig reaction where terminal allylic substitu-
tion has a profound influence on activation regardless of
temperature.
Buchwald–Hartwigcross-couplingreactions
General procedure: In a glovebox, 4 (1 mol%, 6.5 mg), potassium tert-
butoxide (1.1 mmol, 124 mg) and anhydrous 1,2-dimethoxyethane
(DME) (1 mL) were added in turn to
a vial equipped with a magnetic bar,
and sealed with a screw cap fitted
Table 6. Suzuki–Miyaura reactions at low catalyst loading.
with a septum. Outside the drybox,
the amine (1.1 mmol) and the aryl
halide (1 mmol) were injected in turn
through the septum. (If one of the
two starting materials was a solid, it
Entry
1
Ar-X
Boronic acid
Product
[Pd]
t [h]
Yield [%][a]
was added to the vial inside the glo-
vebox, and DME and the second
starting material were added outside
the drybox through the septum.) The
3
2
3
3
93
92
vial was then stirred on
a stirring
plate at room temperature unless oth-
erwise indicated. The reaction was
monitored by gas chromatography.
When the reaction reached comple-
tion, or no further conversion could
be observed, water was added to the
reaction mixture, the organic layer
was extracted with tert-butyl methyl
ether (MTBE), dried over magnesi-
2
2
3
91
Reaction conditions: 1 mmol aryl chloride; 1.05 mmol boronic acid; 1.1 mmol KOtBu; 1 mL technical grade
isopropanol. [a] Isolated yields, average of two runs.
Conclusion
um sulfate and the solvent was evaporated in vacuo. When necessary, the
product was purified by flash chromatography on silica gel. The reported
yields are the average of at least two runs.
N-(3-Pyridyl)piperidine (Table 1, entry 5):[31] The general procedure
yielded, after flash chromatography on silica gel (pentane/MTBE 80:20),
the title compound (117 mg, 72%). 1H NMR (300 MHz, CDCl3): d =
8.30 (s, 1H, HAr), 8.05 (d, J=4.5 Hz, 1H, HAr), 7.19–7.10 (m, 2H, HAr),
3.18 (t, J=5.1 Hz, 4H, CH2-N), 1.75–1.67 (m, 4H, CH2-CH2-N), 1.63–1.57
In summary, we have demonstrated how simple modifica-
tions to the ancillary ligands surrounding palladium allow
for dramatic changes in catalytic performance.[29] This effect
is attributed to a facile activation step leading to the effi-
cient generation of a catalytically active palladium(0) spe-
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Cross-Coupling Reactions
FULL PAPER
(m, 2H, CH2
CAr), 140.2 (CH, CAr), 139.1 (CH, CAr), 123.5 (CH, CAr), 122.7 (CH, CAr),
50.0 (CH2, CH2-N), 25.7 (CH2, CH2-CH2-N), 24.2 (CH2, CH2(CH2)2-N).
A
septum. Outside the glovebox, technical grade isopropanol (1 mL) was
injected through the septum and the mixture was stirred on a stirring
plate at room temperature for 15 min. Aryl halide (1 mmol) was then in-
jected and the reaction was monitored by gas chromatography. When the
reaction reached completion, or no further conversion could be observed,
water was added to the reaction mixture, the organic layer was extracted
with diethyl ether, dried over magnesium sulfate and the solvent was
evaporated in vacuo. When necessary the product was purified by flash
chromatography on silica gel using mixtures hexanes/EtOAc 95:5.
N-(3-Quinolinyl)piperidine (Table 1, entry 7):[32] The general procedure
yielded, after flash chromatography on silica gel (pentane/MTBE 70:30),
the title compound (185 mg, 87%). 1H NMR (300 MHz, CDCl3): d =
8.78 (d, J=2.7 Hz, 1H, HAr), 7.97 (d, J=7.8 Hz, 1H, HAr), 7.63 (d, J=
9.3 Hz, 1H, HAr), 7.49–7.38 (m, 2H, HAr), 7.28 (d, J=2.7 Hz, 1H, HAr),
3.21 (t, J=5.1 Hz, 4H, CH2-N), 1.77–1.70 (m, 4H, CH2-CH2-N), 1.62–1.55
(m, 2H, CH2
(CH2)2-N); 13C NMR (75 MHz, CDCl3): d = 145.6 (CH, N-
E
Suzuki–Miyaura cross-couplingof heteroaryl chlorides with boronic acids
at low catalyst loadings
CHAr), 142.7 (C, CAr), 129.1 (C, CAr), 128.9 (CH, CAr), 127.8 (C, CAr),
126.8 (CH, CAr), 126.5 (CH, CAr), 126.0 (CH, CAr), 116.6 (CH, CAr), 50.6
General procedure: In a glovebox, potassium tert-butoxide (1.1 mmol,
124 mg), boronic acid (1.05 mmol) and aryl chloride (if solid, otherwise
see below) were added in turn to a vial equipped with a magnetic bar,
and closed with a screw cap with a septum. Outside the glovebox, the re-
quired amount of catalyst solution (catalyst loading 0.005 mol%, 20 mL)
was injected through septum, followed by technical grade isopropanol
(1 mL). The reaction mixture was placed in an oil bath at 808C over a
magnetic stirring plate. After 15 min the aryl halide (1 mmol) was inject-
ed (if liquid) and the reaction was monitored by gas chromatography.
When the reaction reached completion, or no further conversion could
be observed, water was added to the reaction mixture, the organic layer
was extracted with MTBE, dried over magnesium sulfate and the solvent
was evaporated in vacuo. When necessary, the product was purified by
flash chromatography on silica gel using mixtures pentane/MTBE 95:5.
(CH2, CH2-N), 25.7 (CH2, CH2-CH2-N), 24.1 (CH2, CH2(CH2)2-N).
N
N,N-Diallyl-N-(2-pyridyl)amine (Table 2, entry 4):[33] The general proce-
dure yielded, after flash chromatography on silica gel (pentane/MTBE
90:10), the title compound (159 mg, 98%). 1H NMR (300 MHz, CDCl3):
d = 8.15 (d, J=3.3 Hz, 1H, HAr), 7.43–7.37 (m, 1H, HAr), 6.55–6.51 (m,
1H, HAr), 6.47 (d, J=8.7 Hz, 1H, HAr), 5.91–5.82 (m, 2H, -CH=CH2),
5.17–5.12 (m, 4H, -CH=CH2), 4.11 (d, J=5.1 Hz, 4H, CH2-N); 13C NMR
(75 MHz, CDCl3): d 158.9 (C, N-CAr), 148.1 (CH, CAr), 137.3 (CH, CH=
CH2), 134.2 (CH, CAr), 116.2 (CH2, -CH=CH2), 115.1 (CH, CAr), 106.3
(CH, CAr), 50.3 (CH2, CH2-N).
Buchwald–Hartwigcross-couplingat low catalyst loading
Preparation of catalyst solutions: In a glovebox, in a scintillation vial,
[(SIPr)Pd(cinnamyl)Cl] (4) (6.5 mg, 0.01 mmol) was dissolved in DME
A
(10 mL), providing solution A. In another vial, DME (9 mL) was added
to solution A (1 mL), providing solution B. A third vial containing solu-
tion B (1 mL) and DME (9 mL) provided solution C.
General procedure: In a glovebox, potassium tert-butoxide (1.1 mmol,
124 mg), hexamethylbenzene (1 mmol, 153 mL) and catalyst solution
(1 mL solution A for 0.1 mol% of 4, solution C for 0.001 mol% of 4)
were added in turn to a vial equipped with a magnetic bar, and sealed
with a screw cap fitted with a septum. Outside the glovebox, the amine
(1.1 mmol) and the aryl halide (1 mmol) were injected in turn through
the septum. The reaction mixture was then stirred at room temperature
unless otherwise indicated. The reaction was monitored by gas chroma-
tography and the yields given using hexamethylbenzene as internal stand-
ard.
Acknowledgements
The National Science Foundation is gratefully acknowledged for financial
support of this work. Promerus LLC, Umicore AG, Lonza and Eli Lilly
and Co. are gratefully acknowledged for their gifts of materials. We
thankBoeringer-Ingelheim Pharmaceuticals Inc. for an unrestricted grant
and are indebted to the University of Ottawa and Boston College for
their hospitality while UNO recovers from Hurricane Katrina. Dr. Mihai
S. Viciu is acknowledged for very helpful discussions.
Suzuki–Miyaura cross-couplingreactions
Preparation of the catalyst solutions: In
a glovebox, 3 (6.5 mg,
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with a screw cap with a septum. Outside the glovebox, technical grade
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Suzuki–Miyaura cross-couplingof heteroaryl chlorides or bromides with
boronic acids at room temperature
General procedure: In a glovebox, potassium tert-butoxide (1.1 mmol,
124 mg), boronic acid (1.05 mmol) and aryl halide (if solid, otherwise see
below) were added in turn to a vial equipped with a magnetic bar, and
closed with a screw cap with a septum. Outside the glovebox, the re-
quired amount of catalyst
3 solution (catalyst loading 0.05 mol%,
200 mL) was injected through the septum, followed by technical grade
isopropanol to a final volume of 1 mL. The mixture was stirred on a stir-
ring plate at room temperature for 15 min. Aryl halide (1 mmol) was
then injected (if liquid) and the reaction was monitored by gas chroma-
tography. When the reaction reached completion, or no further conver-
sion could be observed, water was added to the reaction mixture, the or-
ganic layer was extracted with MTBE, dried over magnesium sulfate and
the solvent was evaporated in vacuo. When necessary the product was
purified by flash chromatography on silica gel using mixtures pentane/
MTBE 95:5.
Suzuki–Miyaura cross-couplingof aryl and heteroaryl halides with trans-
2-phenylvinylboronic acid at room temperature
General procedure: In a glovebox, 3 (6.5 mg), potassium tert-butoxide
(1.1 mmol, 124 mg), boronic acid (1.05 mmol) were added in turn to a
vial equipped with a magnetic bar, and closed with a screw cap with a
Chem. Eur. J. 2006, 12, 5142 – 5148
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5147

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Received: March 1, 2006
Published online: April 21, 2006
5148
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 5142 – 5148