Green catalysts: Solid-phase peptide carbene ligands in aqueous transition-metal catalysis

Article abstract of DOI:10.1002/ejoc.200800633

A series of functionalized imidazolium ions containing a pyridine moiety and carboxylic acid functionality has been synthesized in solution. These compounds serve as N-heterocyclic carbene precursors and were attached to a dipeptide on solid support by means of standard peptide coupling techniques. Treatment with base generated the corresponding carbenes, which were directly complexed to palladium(II) and subsequently studied by mass spectrometry and NMR spectroscopy. The supported monocarbene catalyst 7 was successfully applied in Sonogashira and Suzuki cross-coupling reactions, and the cross-coupling products were isolated in excellent yield. Bis(carbene) catalyst 8 was successfully applied in solution in high-yielding Suzuki cross-coupling reactions. Furthermore, the catalysts proved to be stable in aqueous media, which allowed the Suzuki cross-coupling reactions to be performed in water. No loss of catalytic activity was observed when supported catalyst 7 was recycled and subjected to repetitive cycles of Suzuki cross-coupling reactions in water. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800633

FULL PAPER
DOI: 10.1002/ejoc.200800633
Green Catalysts: Solid-Phase Peptide Carbene Ligands in Aqueous
Transition-Metal Catalysis
Kasper Worm-Leonhard[a] and Morten Meldal*[b]
Keywords: N-Heterocyclic carbenes / Palladium catalysts / Solid-phase synthesis / Pyridine ligands
A series of functionalized imidazolium ions containing a pyr-
idine moiety and carboxylic acid functionality has been syn-
in excellent yield. Bis(carbene) catalyst 8 was successfully
applied in solution in high-yielding Suzuki cross-coupling re-
thesized in solution. These compounds serve as N-heterocy- actions. Furthermore, the catalysts proved to be stable in
clic carbene precursors and were attached to a dipeptide on
solid support by means of standard peptide coupling tech-
niques. Treatment with base generated the corresponding
carbenes, which were directly complexed to palladium(II)
and subsequently studied by mass spectrometry and NMR
spectroscopy. The supported monocarbene catalyst 7 was
successfully applied in Sonogashira and Suzuki cross-coup-
ling reactions, and the cross-coupling products were isolated
aqueous media, which allowed the Suzuki cross-coupling re-
actions to be performed in water. No loss of catalytic activity
was observed when supported catalyst 7 was recycled and
subjected to repetitive cycles of Suzuki cross-coupling reac-
tions in water.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
late carbenes, a class of ligands where neighbouring hetero-
atom donor functionalities take part in the metal binding.
In particular, neighbouring N-heterocycles such as pyridine
have attracted attention, and promising results have been
obtained when they were applied in cross-coupling reac-
tions.[12,13] In recent years, the development of polymer-sup-
ported ligands has improved significantly.[14] The majority
of these ligands are phosphanes, but a few examples of
polymer-supported palladium-NHC catalysts have also
been reported.[15] When a catalyst is immobilized on solid
support, a number of advantages can be gained such as easy
recovery from reaction mixtures, no metal contamination
of reaction solutions, easy handling of minute catalyst
amount, and catalyst recycling. In addition, a combinato-
rial approach to catalyst design and optimization can be
applied if catalysts are attached to a solid support. We have
recently reported the first example of solid-phase-immobi-
lized, peptide-based NHC ligands and their complexation
to palladium.[16] Here we wish to extend the concept and
report the synthesis of new solid-supported pyridine-NHC
catalysts and their application in cross-coupling reactions.
Introduction
N-Heterocyclic carbenes (NHCs) have attracted increas-
ing attention since their emergence in the pioneering work
of Öfele and Wanzlick[1] and, subsequently, in the work of
Arduengo et al. on the isolation of a stable free carbene.[2]
Since then, NHCs have proven to be a versatile and efficient
class of ligands. They are easily synthesized, and the steric
bulk on the two nitrogens neighbouring the carbene–carbon
bond is easily modified. NHCs are often used as phosphane
mimics, but the carbenes are stronger σ-donor ligands and,
thus, provide a stronger metal binding site, which reduces
the tendency of metal dissociation.[3] Phosphane ligands
may suffer from degradation by phosphorus–carbon bond
cleavage during catalysis, which requires the presence of an
excess amount of ligand in the reaction.[4] Furthermore,
phosphane complexes are water- and air-sensitive, a disad-
vantage not shared by NHCs. Metal complexes of mono-
and polydentate NHCs have found widespread catalytic ap-
plication in a number of reactions such as cross-coupling,[5]
olefin metathesis,[6] hydrogenation,[7] hydroformylation,[8]
hydrosilylation,[9] and olefin polymerization.[10,11] Further
developments in this area have led to the generation of che-
Results and Discussion
[a] Centre for Solid Phase Organic Combinatorial Chemistry &
Molecular Recognition, Carlsberg Laboratory,
Gamle Carlsberg Vej 10, 2500 Valby, Denmark
[b] Centre for Solid Phase Organic Combinatorial Chemistry &
Molecular Recognition, Carlsberg Laboratory,
Gamle Carlsberg Vej 10, 2500 Valby, Denmark
Fax: +45-33274708
Imidazolium ions can be generated by several methods
comprising either one or several steps, depending on the
requirements for the N substituents.[17] In the present work,
we sought for a synthetic method that would give access to
unsymmetrical, N-substituted, imidazolium ions containing
a terminal, protected, carboxylic acid functionality.
E-mail: mpm@crc.dk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2008, 5244–5253

Solid-Phase Peptide Carbene Ligands
Such imidazolium ions would serve as N-heterocyclic
carbene precursors and would be well suited for incorpora-
tion onto the solid phase. By using commercially available
methyl or tert-butyl esters of different amino acids, four
amino-acid-derived imidazoles were synthesized in a modi-
fied, one-pot, Arduengo condensation reaction,[18] in which
the amino acid ester, glyoxal, formaldehyde, and aqueous
ammonia were reacted to generate the N-substituted imid-
azole ring (Scheme 1).
Scheme 2. Formation of pyridine-derivatized imidazolium salts.
In order to investigate the potential of the new imid-
azolium ion building blocks as N-heterocyclic carbene li-
gands on solid phase, two peptides were synthesized
(Scheme 4). The synthesis commenced with the attachment
of the acid-labile, Fmoc-protected, Rink-amide linker to
amino-functionalized PEGA resin[19] with the standard
Scheme 1. Synthesis of functionalized imidazoles by a four-compo-
nent condensation reaction.
Two of the imidazoles 1 were treated with commercially TBTU activation procedure.[20] This was followed by piperi-
available 2-(bromomethyl)pyridine with microwave (MW) dine/DMF-mediated Fmoc cleavage and TBTU coupling of
heating (Scheme 2). Nucleophilic displacement of the bro- Fmoc-Val-OH. After another Fmoc cleavage, Fmoc-Phe-
mide followed by TFA-mediated hydrolysis of the ester OH was attached, followed by Fmoc cleavage and attach-
functionality generated imidazoles 2a–b in good yield (80– ment of either imidazole 2a or 4b, thus generating the resin-
85%).
bound mono- and bis(imidazolium) ligands 5 and 6, respec-
In order to allow for the formation of bis(imidazolium) tively.
salts, commercially available 2,6-bis(bromomethyl)pyridine
The dipeptide (Phe-Val) was chosen as a tether between
was utilized (Scheme 3). Pyridines, symmetrically substi- the NHC and the solid support, thereby providing an
tuted with two imidazolium groups, were obtained by nucleo- anchorage point and a spacer toward the resin. The chiral
philic displacement of bromide upon the addition of 2 architecture is based on readily available amino acids and
equiv. of imidazole 1a, thus generating bis(imidazolium) their routine assembly, which allows for easy synthetic ma-
salt 3a. Unsymmetrically substituted salts were generated nipulation and variation at this position. A detailed study
by the sequential addition of 1-methylimidazole and imid- of the effects of substituting the tether has not been carried
azole 1a, which generated the bis(imidazolium) salt 3b. Sub- out, but different tethers have been applied previously.[16]
sequent TFA-mediated hydrolysis of the ester functionali- Although the chirality of the catalysts are not exploited in
ties afforded the corresponding carboxylic acids in excellent the present work, the ability to easily provide chiral environ-
yield (95%).
ment around the catalytic centre is obvious.
Scheme 3. Formation of pyridine-derivatized bis(imidazolium) salts.
Eur. J. Org. Chem. 2008, 5244–5253
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5245

K. Worm-Leonhard, M. Meldal
FULL PAPER
Scheme 4. Solid-phase synthesis of pyridine-derivatized mono- and bis(imidazolium) ligands.
With the resin-bound imidazolium ions in hand, carbene
The properties of resin-bound catalyst 7 were evaluated
formation and subsequent palladium complexation was in- in a series of Sonogashira cross-coupling reactions. Three
vestigated directly on the resin. Carbene formation was ac- different terminal alkynes (aromatic, aliphatic, and silyl)
complished by deprotonation of the imidazolium salt with and two different aromatic iodides were used as coupling
the base 2-tert-butylimino-2-diethylamino-1,3-dimethylper- partners (Table 1). The reactions were performed at 50 °C
hydro-1,3,2-diazaphosphorine (BEMP), directly followed in the presence of 2.5 mol-% catalyst and afforded the cross-
by trapping of the NHC with PdCl2COD[21] (Scheme 5). coupling products in excellent yield (87–95%). Less acti-
The optimized reaction conditions afforded a clean prepa- vated halides have not been subjected to the current cata-
ration of ligands 5 and 6 without any observation of palla- lytic system.
dium black precipitation. Upon release from the resin, it
The successful Sonogashira cross-couplings prompted us
was discovered by HRMS (ESI) analysis that a β-enolate to evaluate supported catalyst 7 in a series of Suzuki cross-
oxygen in compound 7 was coordinated to the palladium coupling reactions. Ten different boronic acids were selected
in addition to the carbene. This enolate was generated dur- and coupled to both iodobenzene and bromobenzene. All
ing the base treatment. Only a few examples of anionic li- the reactions were carried out in water and in the presence
gands derived from NHCs are known,[22] but the formation of 2.5 mol-% catalyst (Table 2). The ten reactions em-
of palladium-NHC-enolate complexes has been reported by ploying iodobenzene (Table 2, Entries 1a–4a and 6a–10a)
Waymouth et al.[23] These results emphasize the preference were performed at 50 °C and afforded the cross-coupling
for enolate formation when a carbonyl group is β to the products in excellent yield (90–96%). When the less reactive
carbene donor, thus enabling the formation of a stable six- bromobenzene was applied (Table 2, Entries 1b–4b and 6b–
membered chelate.
10b), the reactions were performed at 65 °C, which afforded
Scheme 5. Base-mediated mono- and bis(carbene) formation, followed by in situ complexation to palladium.
5246 Eur. J. Org. Chem. 2008, 5244–5253
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Solid-Phase Peptide Carbene Ligands
Table 1. Palladium-catalyzed Sonogashira cross-coupling reactions
utilizing resin-bound catalyst 7.
Table 2. Palladium-catalyzed Suzuki cross-coupling reactions utiliz-
ing catalysts 7 and 8.
[a] Isolated yield after flash column chromatography.
the cross-coupling products in good yield (79–88%). As ex-
pected, the most challenging (pentafluorophenyl)boronic
acid did not couple under any of the reaction conditions
employed (Table 2, Entries 5a–5d). The catalytic potential
of bis(carbene) catalyst 8 was evaluated in an equivalent
series of Suzuki cross-coupling reactions performed in
water. This time, the catalyst was released from the solid
support, purified, and employed in solution, while heating
of the reaction mixtures was performed by microwave irra-
diation. The reaction temperature was increased to 90 °C
and 100 °C for iodobenzene and bromobenzene, respec-
tively, while the catalyst amount was reduced to only
0.05 mol-%. The application of catalyst 8 under elevated
temperatures allowed for the cross-coupling reactions to
run to completion within 10 min. When iodobenzene was
applied (Table 2, Entries 1c–4c and 6c–10c), the cross-coup-
ling products could be isolated in excellent yield (92–96%),
and the application of bromobenzene (Table 2, Entries 1d–
4d and 6d–10d) furnished the cross-coupling products in
good yield (90–92%). No formation of cross-coupling prod-
uct could be observed when the reactions were performed
without a catalyst present. With respect to thermal stability,
MS analysis revealed that the catalyst was still intact after
the reactions had been performed at elevated temperatures
[a] Isolated yield after flash column chromatography. [b] Microwave
heating.
(100 °C). Further heating to higher temperatures was not after each cycle, the product was purified and quantified,
attempted. whereas the catalyst was washed and reused in the next re-
After performing the cross-coupling reactions, supported action (Table 3). After eight cycles, the catalyst was still
catalyst 7 was analyzed by MS (ESI) and showed no sign fully operational and showed no loss of activity. Overall,
of decomposition. Based on these results, an endurance test the combination of low catalyst amount, fast reaction times,
of the catalyst was set up, and the Suzuki cross-coupling high cross-coupling yields, and successful recycling of the
between 4-methylphenylboronic acid and iodobenzene was catalyst is very encouraging and illustrates that the catalyst
chosen. Repetitive cycles of cross-coupling reactions were system can rival existing systems both in solution and on
carried out with the same batch of supported catalyst 7, and solid support.[14]
Eur. J. Org. Chem. 2008, 5244–5253
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K. Worm-Leonhard, M. Meldal
FULL PAPER
toring was performed at 215 nm and 254 nm. Microwave reactions
were carried out with a Biotage Initiator microwave system. All
solvents were HPLC grade and stored over molecular sieves or dis-
tilled prior to use. Degassed solutions were obtained by bubbling
argon through them for 10 min. For reactions on solid phase,
PEGA800 resin (loading: 0.30–0.35 mmol/g, Versamatrix A/S) was
used. Prior to use, the resin was washed with methanol (5ϫ), aceto-
nitrile (5ϫ), DMF (5ϫ), and CH2Cl2 (5ϫ) and dried overnight
in vacuo. Solid-phase reactions were carried out in flat-bottomed
polyethylene syringes equipped with sintered Teflon filters (50 µm
pores), Teflon tubing, Teflon valves for flow control, and suction
to drain the syringes from below. For solid-phase reactions carried
out under argon, the syringes were equipped with a rubber septum
and an argon inlet. Resin loading was determined by Fmoc cleav-
age and measurement of the optical density at 290 nm. Loadings
were then calculated from a calibration curve. Starting materials
purchased from commercial suppliers were used without further
purification.
Table 3. Recycling experiment of resin-bound catalyst 7 in the pal-
ladium-catalyzed Suzuki cross-coupling reaction.
Run
1
2
3
4
5
6
7
8
%
94
96
93
95
92
96
93
94
Yield[a]
[a] Isolated yield after flash column chromatography.
General Procedure for Peptide Couplings: TBTU-mediated coup-
lings were performed by dissolving the carboxylic acid (3 equiv.)
in DMF, followed by the addition of N-ethylmorpholine (NEM,
4.0 equiv.) and (TBTU, 2.88 equiv.). The resulting solution was al-
lowed to react for 5 min and then added to the PEGA800 resin and
allowed to react for 2 h, followed by washing of the resin with
DMF (5ϫ) and CH2Cl2 (5ϫ). To verify that full conversion of the
free amine had taken place, the resin was checked by the Kaiser
test.
Conclusions
In summary, we have synthesized a series of function-
alized imidazolium-ion building blocks, containing a pyr-
idine moiety and carboxylic acid functionality. These com-
pounds, which serve as NHC precursors, were easily at-
tached to a dipeptide on solid support, with standard pep-
tide-coupling chemistry. Subsequent carbene formation was General Procedure for Linker Attachment on Solid Phase: Attach-
ment of the 4-[(2,4-dimethoxyphenyl)(Fmoc-amino)methyl]phen-
oxyacetic acid (Fmoc-Rink-amide) linker to the amino-function-
alized resin (PEGA800) was carried out by following the standard
amino acid coupling procedure (Fmoc-AA-OH, TBTU, NEM,
DMF). The linker (3.0 equiv.), NEM (4.0 equiv.), and TBTU
(2.88 equiv.) were mixed in DMF and allowed to react for 5 min.
The reaction mixture was added to the preswollen PEGA800 resin
and allowed to react for 2 h, followed by washing of the resin with
DMF (5ϫ) and CH2Cl2 (5ϫ).
accomplished by treatment with strong base, BEMP, fol-
lowed by complexation to palladium(II) on solid support.
These new and efficient palladium NHC catalysts were suc-
cessfully applied in Sonogashira and Suzuki cross-coupling
reactions. The catalysts proved stable toward TFA treat-
ment when released from the solid support and stable in
aqueous media, thus allowing for the Suzuki cross-coupling
reactions to be performed in water. No loss of catalytic ac-
tivity was observed when the catalyst was recycled and sub-
jected to repetitive cycles of cross-coupling reactions in
water.
General Procedure for Fmoc Deprotection: The Fmoc group was
removed by the addition of 20% piperidine in DMF for 2 min, and
the resin was washed with DMF (3ϫ), followed by the addition of
20% piperidine in DMF for 18 min. The resin was again washed
with DMF (5ϫ) and CH2Cl2 (5ϫ).
Experimental Section
General Procedure for Cleavage of Resin-Supported Peptides: Cleav-
age from the Rink-amide linker was achieved by treatment with
95% TFA (aqueous) for 2 h, followed by concentration in vacuo of
the solution phase.
General Remarks. 1H NMR (250 MHz, 600 MHz, or 800 MHz)
and 13C NMR (75 MHz, 150 MHz, or 200 MHz) were recorded
with a Bruker DRX250, Bruker DRX600, or Bruker Avance 800
spectrometer. Chemical shifts are reported in ppm relative to the
internal solvent peak (δ = 7.26 and 77.0 ppm, respectively, for
CDCl3). Coupling constants, J, are given in Hz. Multiplicities of
peaks are given as: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), and br (broad). MS (ESI) spectra were recorded with
a Bruker Esquire 3000plus mass spectrometer or a Micromass
QTOF Global Ultima instrument. TLC plates were Merck silica
gel 60 F254 on aluminum. Flash column chromatography was per-
formed with silica 60H (230–400 mesh). Analytical RP-HPLC was
performed with an HP1100 Series system, equipped with a Zorbax
300SB-C18 (3.5 µm, 4.6ϫ50 mm) column. A solvent gradient sys-
tem consisting of A (0.1% TFA in H2O) and B (0.1% TFA in
acetonitrile/H2O, 9:1) was used in a linear gradient (100% A Ǟ
100% B in 25 min). Preparative RP-HPLC was performed with a
Waters DeltaPrep system, equipped with a Waters 2487 detector
and a XTerra® Prep MSC18 cartridge (5 µm, 19ϫ10 mm). Moni-
tert-Butyl (Imidazol-1-yl)acetate (1a): Glyoxal (40 wt.-% solution in
H2O, 7.3 g, 50.0 mmol), and formaldehyde (37 wt.-% solution in
H2O, 4.1 g, 50.0 mmol) in iPrOH (50 mL) was added dropwise to a
stirred suspension of H-Gly-OtBu·HCl (8.4 g, 50 mmol), ammonia
(28 wt.-% solution in H2O, 55 mmol, 3.8 mL) and iPrOH (175 mL).
After complete addition, the reaction mixture was heated to 80 °C
and stirred for 6 h. The brownish solution was then cooled to 25 °C
and diluted with CH2Cl2 (125 mL). The organic layer was sepa-
rated, washed with NaOH (1.0 , 125 mL), dried with Na2SO4,
and concentrated in vacuo. Purification was performed by flash
chromatography and yielded the title compound as a yellow solid.
1
Yield 5.9 g (65%). H NMR (250 MHz, CDCl3): δ = 7.49 (s, 1 H),
7.09 (s, 1 H), 6.94 (s, 1 H), 4.58 (s, 2 H), 1.47 (s, 9 H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 166.4, 137.8, 129.4, 119.9, 83.2, 48.8,
27.9 ppm. M.p. 110–112 °C (ref.[24] 111–113 °C). HRMS (ESI):
calcd. for C9H15N2O2 [M + H]+ 183.1128; found 183.1136.
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Solid-Phase Peptide Carbene Ligands
tert-Butyl 3-(Imidazol-1-yl)propionate (1b): A solution of glyoxal
(40 wt.-% solution in H2O, 1.5 g, 10.0 mmol) and formaldehyde 84.5 mg (85%). H NMR (250 MHz, CD3OD): δ = 9.18 (s, 1 H),
tive RP-HPLC to yield the title compound as a yellow oil. Yield
1
(37 wt.-% solution in H2O, 811.9 mg, 10.0 mmol) in iPrOH (10 mL)
was added dropwise to a stirred suspension of H-β-Ala-OtBu·HCl
(1.8 g, 10 mmol), ammonia (28 wt.-% solution in H2O, 11 mmol,
0.8 mL), and iPrOH (35 mL). After complete addition, the reaction
mixture was heated to 80 °C and stirred for 6 h. The slightly yellow
solution was then cooled to 25 °C and diluted with CH2Cl2
(25 mL). The organic layer was separated, washed with NaOH
(1.0 , 25 mL), dried with Na2SO4, and concentrated in vacuo. Pu-
rification was performed by kugelrohr distillation and yielded the
title compound as a yellow oil. Yield 0.7 g (36%). 1H NMR
(250 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.02 (s, 1 H), 6.92 (s, 1 H),
4.20 (t, J = 6.6 Hz, 2 H), 2.67 (t, J = 6.6 Hz, 2 H), 1.40 (s, 9 H)
ppm. 13C NMR (63 MHz, CDCl3): δ = 169.7, 137.2, 129.4, 118.8,
81.6, 42.5, 37.1, 28.0 ppm. HRMS (ESI): calcd. for C10H17N2O2
[M + H]+ 197.1285; found 197.1293.
8.58 (ddd, J = 0.8, 1.5, 4.9 Hz, 1 H), 7.90 (dt, J = 1.7, 7.7 Hz, 1
H), 7.68 (td, J = 1.8, 11.2 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 1 H) 7.42
(ddd, J = 1.0, 4.9, 7.7 Hz, 1 H), 5.59 (s, 2 H), 5.15 (s, 2 H) ppm.
13C NMR (63 MHz, CD3OD): δ = 169.0, 151.1 (2 C), 139.5, 139.3,
125.4, 125.3, 124.2, 124.0, 55.0, 50.9 ppm. HRMS (ESI): calcd. for
C11H12N3O2 [M – CF3COO–]+ 218.0924; found 218.0936.
3-[(S)-1-Carboxy-2-methylpropyl]-1-[(pyridin-2-yl)methyl]-3H-imid-
azol-1-ium Trifluoroacetate (2b): To a solution of imidazole 1c
(54.7 mg, 0.3 mmol) in DMF (1.5 mL) was added 2-(bromomethyl)-
pyridine hydrobromide (75.9 mg, 0.3 mmol), and the solution was
heated to 150 °C for 25 min under microwave irradiation. The sol-
vent was removed in vacuo and the crude product was dissolved in
CH2Cl2/TFA (1:1) and stirred for 4 h, after which time the solvent
and TFA were removed in vacuo. Purification was performed by
preparative RP-HPLC to yield the title compound as a brown oil.
1
Yield 89.6 mg (80%). H NMR (250 MHz, [D6]DMSO): δ = 9.47
Methyl 2-[(S)-2-Imidazol-1-yl]-3-methylbutyrate (1c): A solution of
glyoxal (40 wt.-% solution in H2O, 1.5 g, 10.0 mmol) and formalde-
hyde (37 wt.-% solution in H2O, 811.9 mg, 10.0 mmol) in iPrOH
(10 mL) was added dropwise to a stirred suspension of H-Val-
OMe·HCl (1.7 g, 10 mmol), ammonia (28 wt.-% solution in H2O,
11 mmol, 0.8 mL), and iPrOH (35 mL). After complete addition,
the reaction mixture was heated to 80 °C and stirred for 6 h. The
brownish solution was then cooled to 25 °C and diluted with
CH2Cl2 (25 mL). The organic layer was separated, washed with
NaOH (1.0 , 25 mL), dried with Na2SO4, and concentrated in
vacuo. Purification was performed by preparative HPLC and
yielded the title compound as a slightly yellow oil. Yield 1.1 g
(s, 1 H), 8.53 (ddd, J = 0.9, 1.6, 4.8 Hz, 1 H), 7.91 (dd, J = 1.8,
7.7 Hz, 1 H), 7.85 (td, J = 1.7, 7.3 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 1
H), 7.40 (ddd, J = 1.0, 4.9, 7.6 Hz, 1 H), 5.63 (s, 2 H), 5.17 (d, J
= 7.4 Hz, 1 H), 2.51–2.49 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.86
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ =
169.1, 153.3, 149.5, 137.6, 137.4, 123.6, 122.9, 122.7, 122.3, 66.9,
53.1, 30.8, 18.7, 17.8 ppm. HRMS (ESI): calcd. for C14H18N3O2
[M – CF3COO–]+ 260.1394; found 260.1399.
3,3Ј-(Pyridine-2,6-diyldimethanediyl)bis[1-(2-tert-butoxycarbonyl-
methyl)-1H-imidazol-3-ium] Dibromide (3a): To a solution of imid-
azole 1a (136.7 mg, 0.75 mmol) in DMF (2.0 mL) was added 2,6-
bis(bromomethyl)pyridine (79.5 mg, 0.3 mmol), and the solution
was heated to 110 °C for 10 min under microwave irradiation. The
solvent was removed in vacuo, and the crude product was purified
by preparative RP-HPLC to yield the title compound as a colour-
1
(60%). H NMR (250 MHz, CDCl3): δ = 8.91 (s, 1 H), 7.41 (s, 1
H), 7.40 (s, 1 H), 4.75 (d, J = 8.6 Hz, 1 H), 3.83 (s, 3 H), 2.53–2.39
(m, 1 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR (63 MHz, CDCl3): δ = 168.4, 135.9, 121.1, 120.5, 67.5,
53.3, 32.4, 18.9, 18.3 ppm. HRMS (ESI): calcd. for C9H15N2O2 [M
+ H]+ 183.1128; found 183.1133.
1
less oil. Yield 162.4 mg (86%). H NMR (250 MHz, [D6]DMSO):
δ = 9.21 (s, 2 H), 7.99 (t, J = 7.8 Hz, 1 H), 7.75 (d, J = 1.6 Hz, 1
H), 7.74 (d, J = 1.6 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 7.67 (d, J
= 1.6 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 2 H), 5.62 (s, 4 H), 5.19 (s, 4
H), 1.46 (s, 18 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ =
165.8, 153.4, 138.8, 137.9, 123.6, 122.9, 121.9, 83.0, 52.6, 50.0, 27.5
ppm. MS (ESI): calcd. for C25H35N5O4 [M – 2Br–]2+ 234.6; found
234.6.
tert-Butyl 2-[(S)-2-Imidazol-1-yl]-4-methylpentanoate (1d): A solu-
tion of glyoxal (40 wt.-% solution in H2O, 1.5 g, 10.0 mmol) and
formaldehyde (37 wt.-% solution in H2O, 811.9 mg, 10.0 mmol) in
iPrOH (10 mL) was added dropwise to a stirred suspension of H-
Leu-OtBu·HCl (2.2 g, 10 mmol), ammonia (28 wt.-% solution in
H2O, 11 mmol, 0.8 mL), and iPrOH (35 mL). After complete ad-
dition, the reaction mixture was heated to 80 °C and stirred for 6 h.
The brownish solution was then cooled to 25 °C and diluted with
CH2Cl2 (25 mL). The organic layer was separated, washed with
NaOH (1.0 , 25 mL), dried with Na2SO4, and concentrated in
vacuo. Purification was performed by flash chromatography and
yielded the title compound as a slightly yellow oil. Yield 1.3 g
1-(2-tert-Butoxycarbonylmethyl)-3-({6-[(1-methyl-1H-imidazol-3-
ium-3-yl)methyl]pyridin-2-yl}methyl)-1H-imidazol-3-ium Dibromide
(3b): To a solution of 1-methylimidazole (24.6 mg, 0.3 mmol) in
DMF (2.0 mL) was added 2,6-bis(bromomethyl)pyridine (79.5 mg,
0.3 mmol), and the solution heated to 110 °C for 10 min under mi-
crowave irradiation. Imidazole 1a (54.7 mg, 0.3 mmol) was then
added, and the solution was heated to 110 °C for an additional
10 min under microwave irradiation. The solvent was removed in
vacuo, and the crude product was purified by preparative RP-
HPLC to yield the title compound as a yellow oil. Yield 119.1 mg
(75%). 1H NMR (250 MHz, [D6]DMSO): δ = 9.29 (s, 1 H), 9.18
(s, 1 H), 7.97 (t, J = 7.7 Hz, 1 H), 7.80–7.67 (m, 4 H), 7.48 (d, J =
7.7 Hz, 2 H), 5.64 (s, 2 H), 5.54 (s, 2 H), 5.23 (s, 2 H), 3.89 (s, 3
H), 1.46 (s, 9 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 165.8,
153.5, 153.4, 138.7, 138.0, 137.1, 123.5, 123.4, 123.0, 122.9, 122.0,
121.9, 83.0, 52.6, 52.4, 50.0, 35.7, 27.5 ppm. MS (ESI): calcd. for
C20H27N5O2 [M – 2Br–]2+ 184.6; found 184.6.
1
(56%). H NMR (250 MHz, CDCl3): δ = 7.53 (s, 1 H), 7.05 (s, 1
H), 7.00 (s, 1 H), 4.62 (t, J = 7.9 Hz, 1 H), 2.41–2.32 (m, 1 H), 1.88
(dd, J = 7.8, 7.2 Hz, 2 H), 1.42 (s, 9 H), 0.92 (d, J = 4.1 Hz, 3 H),
0.89 (d, J = 4.2 Hz, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ =
169.1, 136.8, 129.3, 117.3, 82.7, 59.0, 41.5, 27.8, 24.5, 22.6, 21.5
ppm. HRMS (ESI): calcd. for C13H23N2O2 [M + H]+ 239.1754;
found 239.1757.
3-(Carboxymethyl)-1-[(pyridin-2-yl)methyl]-3H-imidazol-1-ium Tri-
fluoroacetate (2a): To
a solution of imidazole 1a (54.7 mg,
0.3 mmol) in DMF (1.5 mL) was added 2-(bromomethyl)pyridine
hydrobromide (75.9 mg, 0.3 mmol), and the solution was heated to
150 °C for 25 min under microwave irradiation. The solvent was
removed in vacuo, and the crude product was dissolved in CH2Cl2/
3,3Ј-(Pyridine-2,6-diyldimethanediyl)bis[1-(carboxymethyl)-1H-imid-
azol-3-ium] Bis(trifluoroacetate) (4a): The tert-butyl ester 3a
TFA (1:1) and stirred for 1 h, after which time the reaction mixture (126.0 mg, 0.2 mmol) was dissolved in CH2Cl2/TFA (1:1) and
was concentrated in vacuo. Purification was performed by prepara- stirred for 4 h, after which time the solvent and TFA were removed
Eur. J. Org. Chem. 2008, 5244–5253
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5249

K. Worm-Leonhard, M. Meldal
FULL PAPER
in vacuo, and the crude product was purified by preparative RP-
HPLC to yield the title compound as a slightly yellow oil. Yield
110.8 mg (95%). H NMR (800 MHz, [D6]DMSO): δ = 9.17 (s, 2
H), 7.98 (t, J = 7.7 Hz, 1 H), 7.73 (s, 2 H), 7.66 (s, 2 H), 7.49 (d,
J = 7.7 Hz, 2 H), 5.61 (s, 4 H), 5.17 (s, 4 H) ppm. 13C NMR
(201 MHz, [D6]DMSO): δ = 168.2, 153.5, 138.8, 137.7, 123.7,
122.8, 122.0, 52.5, 49.8 ppm. HRMS (ESI): calcd. for C17H19N5O4
[M – 2 CF3COO–]2+ 178.5713; found 178.5710.
treatment with 95% TFA (aqueous). After purification by prepara-
tive RP-HPLC (purity Ͼ 95%), the title compound was obtained
as a white powder. Yield 24.1 mg (41%) obtained from 300 mg of
1
1
PEGA800 resin (loading: 0.25 mmol/g). H NMR (250 MHz, [D6]-
DMSO): δ = 9.15 (s, 1 H), 9.09 (s, 1 H), 8.87 (d, J = 8.1 Hz, 1 H),
8.12 (d, J = 8.9 Hz, 1 H), 7.96 (t, J = 7.7 Hz, 1 H), 7.66–7.58 (m,
4 H), 7.48 (t, J = 7.0 Hz, 2 H), 7.38 (br. s, 1 H), 7.28–7.20 (m, 5
H), 7.06 (br. s, 1 H), 5.58 (s, 2 H), 5.51 (s, 2 H), 5.04 (d, J = 5.7 Hz,
2 H), 4.71 (dt, J = 4.5, 8.9 Hz, 1 H), 4.13 (dd, J = 6.7, 8.8 Hz, 1
H), 3.84 (s, 3 H), 3.07 (dd, J = 4.4, 13.8 Hz, 1 H), 2.82 (dd, J =
9.4, 13.8 Hz, 1 H), 1.96 (qd, J = 6.7 Hz, 1 H), 0.85 (d, J = 6.5 Hz,
3 H), 0.82 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (63 MHz, [D6]-
DMSO): δ = 172.6, 170.3, 164.6, 153.5, 153.4, 138.7, 138.0, 137.3,
137.0, 129.2 (2 C), 128.0 (2 C), 126.2, 123.4 (2 C), 123.0, 122.6,
122.0, 121.9, 57.5, 54.2, 52.4 (2 C), 50.5, 37.7, 35.7, 30.3, 19.2, 17.9
ppm. HRMS (ESI): calcd. for C30H38N8O3 [M – 2 CF3COO–]2+
279.1528; found 279.1528.
1-(Carboxymethyl)-3-({6-[(1-methyl-1H-imidazol-3-ium-3-yl)meth-
yl]pyridin-2-yl}methyl)-1H-imidazol-3-ium Bis(trifluoroacetate) (4b):
The tert-butyl ester 3b (119.0 mg, 0.2 mmol) was dissolved in
CH2Cl2/TFA (1:1) and stirred for 4 h, after which time the solvent
and TFA were removed in vacuo, and the crude product was puri-
fied by preparative RP-HPLC to yield the title compound as a
slightly yellow oil. Yield 102.5 mg (95%). 1H NMR (250 MHz, [D6]-
DMSO): δ = 9.20 (s, 1 H), 9.10 (s, 1 H), 7.98 (t, J = 7.7 Hz, 1 H),
7.77–7.65 (m, 4 H), 7.48 (d, J = 7.7 Hz, 2 H), 5.62 (s, 2 H), 5.52
(s, 2 H), 5.19 (s, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (63 MHz, [D6]-
DMSO): δ = 168.0, 153.5, 153.4, 138.7, 137.8, 137.0, 123.5, 123.4,
123.0, 122.8, 122.0, 121.9, 52.5, 52.4, 49.8, 35.7 ppm. HRMS (ESI):
calcd. for C16H19N5O2 [M – 2 CF3COO–]2+ 156.5764; found
156.5750.
Pd Complex 7: Resin-bound 5 was swelled in MeCN and treated
with BEMP (2.0 equiv.) for 15 min under an argon atmosphere fol-
lowed by the addition of PdCl2COD (1.5 equiv.). The reaction was
left for 5 h and then washed with MeCN (5ϫ) and CH2Cl2 (5ϫ).
The final complex was released from the resin by a 2 h treatment
with 95% TFA (aqueous). After purification by preparative RP-
HPLC (purity Ͼ 95%), the title compound was obtained as a white
powder. Yield 14.9 mg (35%) obtained from 250 mg of PEGA800
N-{[3-(Pyridin-2-ylmethyl)-1H-imidazol-3-ium-1-yl]acetyl}-
L-phen-
ylalanyl- -valine Trifluoroacetate (5): Attachment of the Fmoc-
L
1
Rink-amide linker followed the standard amino acid coupling pro-
cedure (Fmoc-Aa-OH, TBTU, NEM, DMF). The Fmoc-protecting
group was removed under standard conditions by two successive
additions of 20% piperidine in DMF. The amino acids Fmoc-Val-
OH and Fmoc-Phe-OH were coupled to the resin with the above-
mentioned standard coupling procedure with the standard Fmoc-
deprotection steps in between. Imidazolium salt 2a was then at-
tached to the resin with the standard amino acid coupling pro-
cedure, and the final product was released from the resin by a 2 h
treatment with 95% TFA (aqueous). After purification by prepara-
tive RP-HPLC (purity Ͼ 95%), the title compound was obtained
as a white powder. Yield 22.5 mg (45%) obtained from 350 mg of
resin (loading: 0.25 mmol/g). H NMR (800 MHz, [D6]DMSO): δ
= 10.02 (d, J = 8.3 Hz, 1 H), 8.56 (d, J = 5.6 Hz, 1 H), 8.20 (dt, J
= 1.4, 7.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.71 (s, 1 H), 7.63
(t, J = 6.5 Hz, 1 H), 7.58 (d, J = 1.9 Hz, 1 H), 7.56 (d, J = 1.9 Hz,
1 H), 7.38, (s, 1 H), 7.10–7.09 (m, 2 H), 6.99–6.98 (m, 1 H), 5.66
(d, J = 16.3 Hz, 1 H), 5.45 (dd, J = 4.0, 5.2 Hz, 1 H), 5.05 (d, J =
16.2 Hz, 1 H), 4.79 (d, J = 16.9 Hz, 1 H), 4.68 (d, J = 16.9 Hz, 1
H), 4.23 (t, J = 7.8 Hz, 1 H), 3.12 (dd, J = 5.5, 13.5 Hz, 1 H), 3.02
(dd, J = 3.7, 13.5 Hz, 1 H), 2.11 (qd, J = 6.8, 13.8 Hz, 1 H), 0.98
(d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(151 MHz, [D6]DMSO): δ = 182.2, 171.7, 164.7, 154.0, 151.6,
147.4, 141.6, 141.2, 138.4, 138.0, 136.5, 130.9, 127.9, 126.7, 126.2,
126.1, 122.9, 122.1, 66.4, 59.7, 53.4, 40.1, 30.5, 19.7, 18.6 ppm.
1
PEGA800 resin (loading: 0.25 mmol/g). H NMR (800 MHz, [D6]-
HRMS (ESI): calcd. for C25H29N6O3Pd [M
567.1336; found 567.1337.
–
CF3COO–]+
DMSO): δ = 9.20 (s, 1 H), 8.74 (d, J = 8.2 Hz, 1 H), 8.10 (d, J =
9.0 Hz, 1 H), 7.88 (dt, J = 1.6, 7.6 Hz, 1 H), 7.75 (t, J = 1.5 Hz, 1
H), 7.56 (t, J = 1.5 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.40 (dd,
J = 5.2, 7.2 Hz, 1 H), 7.35 (s, 1 H), 7.25–7.24 (m, 5 H), 7.19–7.17
(m, 1 H), 7.08 (s, 1 H), 5.58 (s, 2 H), 5.02 (d, J = 16.5 Hz, 1 H),
4.96 (d, J = 16.5 Hz, 1 H), 4.69 (dt, J = 4.6, 8.8 Hz, 1 H), 4.12 (dd,
J = 6.7, 8.9 Hz, 1 H), 3.04 (dd, J = 4.5, 13.9 Hz, 1 H), 2.79 (dd, J
= 9.4, 13.9 Hz, 1 H), 1.95 (qd, J = 6.8, 13.6 Hz, 1 H), 0.85 (d, J =
6.8 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (201 MHz,
[D6]DMSO): δ = 173.2, 171.0, 165.0, 154.1, 150.1, 138.4, 138.1,
137.9, 129.8, 129.7, 128.6, 128.5, 126.9, 124.3, 124.2, 123.1, 123.0,
58.1, 54.6, 53.6, 51.1, 38.4, 31.0, 19.8, 18.6 ppm. HRMS (ESI):
calcd. for C25H31N6O3 [M – CF3COO–]+ 463.2452; found 463.2458.
Pd Complex 8: Resin-bound 6 was swelled in MeCN and treated
with BEMP (3.0 equiv.) for 15 min under an argon atmosphere,
followed by the addition of PdCl2COD (1.5 equiv.). The reaction
was left for 5 h and then washed with MeCN (5ϫ) and CH2Cl2
(5ϫ). The final complex was released from the resin by 2 h treat-
ment with 95% TFA (aqueous). After purification by preparative
RP-HPLC (purity Ͼ 95%), the title compound was obtained as a
white powder. Yield 10.5 mg (26%) obtained from 200 mg of
1
PEGA800 resin (loading: 0.25 mmol/g). H NMR (600 MHz, [D6]-
DMSO): δ = 10.08 (d, J = 7.2 Hz, 1 H), 9.18 (s, 1 H), 9.04 (s, 1
H), 8.01 (t, J = 7.6 Hz, 1 H), 7.73–7.72 (m, 1 H), 7.67 (s, 1 H),
7.49–7.46 (2 H), 7.38 (s, 1 H), 7.15 (m, 2 H), 6.95–6.93 (m, 3 H),
6.82 (d, J = 6.9 Hz, 2 H), 5.55 (s, 2 H), 5.48 (s, 2 H), 4.78–4.68 (m,
3 H), 4.00 (t, J = 7.7 Hz, 1 H), 3.90 (s, 3 H), 3.01 (m, 1 H), 2.91
(dd, J = 4.7, 13.1 Hz, 1 H), 2.03 (qd, J = 7.3, 13.9 Hz, 1 H), 0.92
(d, J = 6.0 Hz, 3 H), 0.91 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(151 MHz, [D6]DMSO): δ = 182.1, 182.0, 171.4, 171 ppm. 0, 164.5,
154.4, 153.8, 139.1, 137.2, 135.8, 130.5, 130.4, 127.6, 127.1, 126.6,
123.7, 123.2, 123.0, 122.3, 122.2, 64.8, 59.6, 54.7, 52.8, 52.5, 36.0,
29.7, 25.8, 19.1, 18.5 ppm. HRMS (ESI): calcd. for
C30H36ClN8O3Pd [M – CF3COO–]+ 697.1634; found 697.1644.
N-{[3-({6-[(1-Methyl-1H-imidazol-3-ium-3-yl)methyl]pyridin-2-
yl}methyl)-1H-imidazol-3-ium-1-yl]acetyl}-L-phenylalanylvaline Bis-
(trifluoroacetate) (6): Attachment of the Fmoc-Rink-amide linker
was performed following the standard amino acid coupling pro-
cedure (Fmoc-Aa-OH, TBTU, NEM, DMF). The Fmoc-protecting
group was removed under standard conditions by two successive
additions of 20% piperidine in DMF. The amino acids Fmoc-Val-
OH and Fmoc-Phe-OH were coupled to the resin with the above-
mentioned standard coupling procedure with the standard Fmoc-
deprotection steps in between. Imidazolium salt 4b was then at-
tached to the resin with the standard amino acid coupling pro-
cedure, and the final product was released from the resin by a 2 h
General Procedure for Sonogashira Cross-Coupling Reactions: To a
Nunc vial containing the solid-phase-immobilized palladium cata-
5250
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5244–5253

Solid-Phase Peptide Carbene Ligands
lyst (2.5 mol-%) was added the aryl iodide (0.2 mmol, 1.0 equiv.),
alkyne (0.6 mmol, 3.0 equiv.), Et3N (1.0 mmol, 5.0 equiv.), CuI
then cooled to room temp. The aqueous phase was decanted off,
and the beads were transferred to a polyethylene syringe, equipped
(0.01 mmol, 0.05 equiv.), and DMF (1.0 mL). The solution was with a sintered Teflon® filter, and washed with EtOAc (50 mL) to
heated to 50 °C for 6 h and then cooled to room temp. and transfer-
red to a polyethylene syringe, equipped with a sintered Teflon filter.
The beads were washed with EtOAc (5ϫ5 mL) to extract the prod-
uct. The organic phase was concentrated in vacuo and purified by
flash column chromatography on silica gel (EtOAc/hexane, 1:9).
extract the product. The organic phase was concentrated in vacuo
and purified by flash column chromatography on silica gel (EtOAc/
hexane, 1:9). Yields for the cross-coupling reactions performed with
iodobenzene are given below, whereas yields from the cross-coup-
lings with bromobenzene are given in Table 2. When catalyst 8 was
applied, it was added in solution (0.05 mol-%), and the additional
compounds were added as described above. Heating was performed
by microwave irradiation for 10 min, and the reaction mixture was
extracted with EtOAc (5ϫ 1 mL), followed by purification of the
concentrated extract by flash column chromatography on silica gel
(EtOAc/hexane, 1:9). Yields are given in Table 2.
1-Nitro-2-(phenylethynyl)benzene (9): The reaction was carried out
as described in the general procedure for Sonogashira cross-coup-
ling reactions. The product obtained was an orange oil. Yield
1
42 mg (94%). H NMR (250 MHz, CDCl3): δ = 8.07 (dd, J = 1.3,
8.2 Hz, 1 H), 7.72 (dd, J = 1.5, 7.8 Hz, 1 H), 7.62–7.56 (m, 3 H),
7.45 (dd, J = 1.5, 7.8 Hz, 1 H), 7.36–7.41 (m, 3 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 149.6, 134.5, 132.7, 132.0, 129.2, 128.5, 4-Methylbiphenyl (15): The reaction was carried out as described
128.4, 124.7, 122.4, 118.7, 97.1, 84.7 ppm.
in the general procedure for Suzuki cross-coupling reactions. The
product obtained was a white solid. Yield 16 mg (96%). H NMR
1
4-(Phenylethynyl)benzaldehyde (10): The reaction was carried out as
described in the general procedure for Sonogashira cross-coupling
reactions. The product obtained was a yellow solid. Yield 37 mg
(250 MHz, CDCl3): δ = 7.61–7.57 (m, 2 H), 7.51 (d, J = 8.2 Hz, 2
H), 7.43 (t, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.26 (d, J
= 7.8 Hz, 2 H), 2.41 (s, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ
= 141.2, 138.4, 137.0, 129.5, 128.7, 127.0, 126.8, 21.1 ppm. M.p.
48–49 °C (ref.[27] 49–50 °C).
1
(90%). H NMR (250 MHz, CDCl3): δ = 10.02 (s, 1 H), 7.88–7.85
(m, 2 H), 7.69–7.66 (m, 2 H), 7.58–7.54 (m, 2 H), 7.40–7.35 (m, 3
H) ppm. 13C NMR (63 MHz, CDCl3): δ = 191.3, 135.4, 132.1,
131.8, 129.5, 128.9, 128.4, 122.5, 93.4, 88.5 ppm. M.p. 98–99 °C
(ref.[25] 98–100 °C).
3,5-Dimethoxybiphenyl (16): The reaction was carried out as de-
scribed in the general procedure for Suzuki cross-coupling reac-
tions. The product obtained was a colourless oil. Yield 20 mg
(93%). 1H NMR (250 MHz, CDCl3): δ = 7.61–7.56 (m, 2 H), 7.48–
7.33 (m, 3 H), 6.75 (d, J = 2.3 Hz, 2 H), 6.49 (t, J = 2.3 Hz, 1 H),
3.86 (s, 6 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 161.0, 143.5,
141.2, 128.7, 127.5, 127.2, 105.5, 99.3, 55.4 ppm.
Trimethyl(2-nitrophenylethynyl)silane (11): The reaction was carried
out as described in the general procedure for Sonogashira cross-
coupling reactions. Product obtained as a slightly yellow oil. Yield
1
40 mg (91%). H NMR (250 MHz, CDCl3): δ = 8.00 (dd, J = 1.3,
8.1 Hz, 1 H), 7.65 (dd, J = 1.5, 7.7 Hz, 1 H), 7.54 (dt, J = 1.4,
7.5 Hz, 1 H), 7.44 (ddd, J = 1.6, 7.4, 8.1 Hz, 1 H), 0.28 (s, 9 H)
ppm. 13C NMR (63 MHz, CDCl3): δ = 150.2, 135.1, 132.6, 128.8,
124.4, 118.4, 103.7, 99.3, –0.4 ppm.
2-Methoxy-5-phenylpyridine (17): The reaction was carried out as
described in the general procedure for Suzuki cross-coupling reac-
tions. The product obtained was a colourless oil. Yield 17 mg
(92%). 1H NMR (250 MHz, CDCl3): δ = 8.40 (dd, J = 0.6, 2.5 Hz,
1 H), 7.79 (dd, J = 2.6, 8.6 Hz, 1 H), 7.55–7.32 (m, 5 H), 6.82 (dd,
J = 0.7, 8.6 Hz, 1 H), 3.99 (s, 3 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 163.6, 145.0, 137.9, 137.5, 130.1, 129.0, 127.3, 126.7,
110.8, 53.5 ppm.
4-[(Trimethylsilanyl)ethynyl]benzaldehyde (12): The reaction was
carried out as described in the general procedure for Sonogashira
cross-coupling reactions. The product obtained was a white solid.
Yield 38 mg (93%). 1H NMR (250 MHz, CDCl3): δ = 9.99 (s, 1
H), 7.81 (d, J = 8.4 Hz, 2 H), 7.59 (d, J = 8.3 Hz, 2 H), 0.26 (s, 9
H) ppm. 13C NMR (63 MHz, CDCl3): δ = 191.3, 135.6, 132.4,
129.4, 103.8, 99.0, –0.2 ppm. M.p. 67–68 °C (ref.[26] 66–67 °C).
3-(Trifluoromethyl)biphenyl (18): The reaction was carried out as
described in the general procedure for Suzuki cross-coupling reac-
tions. The product obtained was a yellow oil. Yield 20 mg (90%).
1H NMR (250 MHz, CDCl3): δ = 7.84–7.76 (m, 2 H), 7.62–7.37
(m, 7 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 142.0, 139.8,
130.4, 129.2, 129.0, 128.0, 127.2, 124.0, 123.9, 123.8 ppm.
1-(Hex-1-ynyl)-2-nitrobenzene (13): The reaction was carried out as
described in the general procedure for Sonogashira cross-coupling
reactions. The product obtained was a slightly yellow oil. Yield
1
35 mg (87%). H NMR (250 MHz, CDCl3): δ = 7.95 (dd, J = 1.2,
8.2 Hz, 1 H), 7.57 (dd, J = 1.8, 7.7 Hz, 1 H), 7.50 (dt, J = 1.3, 3,4-Dichlorobiphenyl (20): The reaction was carried out as de-
7.4 Hz, 1 H), 7.38 (dt, J = 1.8, 8.3 Hz, 1 H), 2.48 (t, J = 6.9 Hz, 2 scribed in the general procedure for Suzuki cross-coupling reac-
H), 1.68–1.42 (m, 4 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR tions. The product obtained was a white solid. Yield 20 mg (90%).
(63 MHz, CDCl3): δ = 150.1, 134.7, 132.4, 127.8, 124.3, 119.3, 99.4,
30.4, 21.9, 19.5, 13.6 ppm.
1H NMR (250 MHz, CDCl3): δ = 7.68–7.38 (m, 8 H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 141.2, 138.8, 137.5, 130.7, 129.0,
128.1, 127.0, 126.3 ppm. M.p. 47–48 °C (ref.[28] 48–49 °C).
4-(Hex-1-ynyl)benzaldehyde (14): The reaction was carried out as
described in the general procedure for Sonogashira cross-coupling
reactions. The product obtained was a yellow oil. Yield 35 mg
4-Fluorobiphenyl (21): The reaction was carried out as described
in the general procedure for Suzuki cross-coupling reactions. The
1
1
(95%). H NMR (250 MHz, CDCl3): δ = 9.97 (s, 1 H), 7.78 (d, J
product obtained was a white solid. Yield 16 mg (93%). H NMR
= 8.4 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H), 2.44 (t, J = 6.9 Hz, 2 H),
(250 MHz, CDCl3): δ = 7.59–7.52 (m, 4 H), 7.44 (t, J = 7.3 Hz, 2
1.67–1.43 (m, 4 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR H), 7.35 (t, J = 7.2 Hz, 1 H), 7.13 (t, J = 8.7 Hz, 2 H) ppm. 13C
(63 MHz, CDCl3): δ = 191.4, 134.9, 132.0, 130.6, 129.4, 95.2, 80.1,
30.6, 22.0, 19.2, 13.6 ppm.
NMR (63 MHz, CDCl3): δ = 162.5 (d, J = 246.3 Hz), 140.3, 137.4,
128.8, 128.7, 128.6, 127.2, 127.0, 115.6 (d, J = 21.4 Hz) ppm. M.p.
72–73 °C (ref.[29] 71–72 °C).
General Procedure for Suzuki Cross-Coupling Reactions: To a Nunc
vial containing the solid-phase-immobilized palladium catalyst 7
(2.5 mol-%) was added the aryl halide (0.1 mmol, 1.0 equiv.), bo-
ronic acid (0.2 mmol, 2.0 equiv.), Cs2CO3 (0.2 mmol, 2.0 equiv.),
and H2O (1.0 mL). The solution was heated to 50 °C for 6 h and
3-Nitrobiphenyl (22): The reaction was carried out as described in
the general procedure for Suzuki cross-coupling reactions. The
product obtained was a yellow solid. Yield 18 mg (90%). 1H NMR
(250 MHz, CDCl3): δ = 8.46 (t, J = 2.0 Hz, 1 H), 8.20 (ddd, J =
Eur. J. Org. Chem. 2008, 5244–5253
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5251

K. Worm-Leonhard, M. Meldal
FULL PAPER
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1.0, 2.3, 8.2 Hz, 1 H), 7.92 (ddd, J = 1.1, 1.7, 7.8 Hz, 1 H), 7.65–
7.40 (m, 6 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 148.8, 142.9,
138.7, 133.0, 129.7, 129.2, 128.5, 127.2, 122.0, 121.9 ppm. M.p. 59–
60 °C (ref.[30] 60–61 °C).
[7]
[8]
[9]
3-Chloro-4-methoxybiphenyl (23): The reaction was carried out as
described in the general procedure for Suzuki cross-coupling reac-
tions. The product obtained was a white solid. Yield 20 mg (91%).
1H NMR (250 MHz, CDCl3): δ = 7.63–7.30 (m, 7 H), 7.00 (d, J =
8.5 Hz, 1 H), 3.95 (s, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ =
154.4, 139.5, 134.7, 128.8, 127.2, 126.7, 126.2, 122.8, 112.3, 56.2
ppm. M.p. 91–92 °C (ref.[31] 93 °C).
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1
product obtained was a yellow oil. Yield 18 mg (93%). H NMR
(250 MHz, CDCl3): δ = 8.15 (br. s, 1 H), 7.89 (s, 1 H), 7.68 (dd, J
= 1.3, 8.3 Hz, 2 H), 7.49–7.43 (m, 4 H), 7.36–7.33 (m, 1 H), 7.24
(m, 1 H), 6.64–6.62 (m, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ
= 142.5, 135.3, 133.4, 129.0, 128.6, 127.4, 126.3, 124.8, 121.9, 119.2,
111.2, 103.0 ppm.
Supporting Information (see also the footnote on the first page of
1
this article): H, 13C and HPLC spectra of compounds 1–24.
Acknowledgments
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Published Online: September 25, 2008
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5253