Imidazo[1,5-a]pyridine-3-ylidenes - Pyridine derived N-heterocyclic carbene ligands

Article abstract of DOI:10.1016/j.tet.2005.03.115

The ready synthesis of differently substituted 2H-imidazo[1,5-a]pyridin-4- ium bromides is reported. These salts are precursors for a new class of N-heterocyclic carbene ligands. As a consequence of their bicyclic geometry, these ligands are capable of in

Full text of DOI:10.1016/j.tet.2005.03.115

Tetrahedron 61 (2005) 6207–6217
Imidazo[1,5-a]pyridine-3-ylidenes—pyridine derived
N-heterocyclic carbene ligands
†
Christian Burstein, Christian W. Lehmann and Frank Glorius
,†
*
¨ ¨
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
Received 4 December 2004; revised 26 January 2005; accepted 26 January 2005
Abstract—The ready synthesis of differently substituted 2H-imidazo[1,5-a]pyridin-4-ium bromides is reported. These salts are precursors
for a new class of N-heterocyclic carbene ligands. As a consequence of their bicyclic geometry, these ligands are capable of influencing the
coordination sphere of a carbene bound metal. The usefulness of these ligands was demonstrated in the palladium-catalyzed Suzuki–Miyaura
cross-coupling of sterically hindered aryl chlorides.
q 2005 Elsevier Ltd. All rights reserved.
In the last 10 years, N-heterocyclic carbenes (NHCs) have
become indispensable ligands for many areas of transition
metal catalysis.1 Many favorable characteristics render
NHC to be attractive ligands for catalysis. They are electron
rich donor ligands and generally form intriguingly stable
complexes with many metals. Moreover, the geometry of
NHC is different from other ligands, allowing the design of
new ligand geometries. Therefore, it is rather surprising that
most NHC ligands used in catalysis are 1,3-disubstituted
imidazolylidenes like IMes, IiPr or their saturated ana-
logues.2 These ligands influence the metal’s coordination
sphere only to some extent. Ligand 1, a hybrid between
IMes and the NHC derived from 2,3 is different. As a result
of its bicyclic structure the R substituent is placed in close
proximity to a carbene bound metal, thus allowing
significant shielding of the metal or, alternatively, stable
or hemilabile coordination to the metal. Here we report on
the flexible synthesis of pyridine derived imidazolium salts
of type 1 and their first application in catalysis.
1. Results and discussion
The synthesis of a range of differently substituted pyridine
derived NHC ligands started with pyridine carboxaldehydes
3 which are commercially available or easily prepared
following literature methods. Reaction of 3 with 2,4,6-
trimethyl aniline resulted in the smooth formation of
pyridine imines 4 in good yields (Table 1). The imidazolium
salt formation of 2 from bispyridine relied on the use of the
elaborated arsonium salt 6 as an alkylating agent, severely
reducing the attractivity of this ligand class.3 This might be
the reason why no successive reports on the use of this
particular carbene have appeared. On the other hand the
successful usage of a commercially available or easily
prepared alkylating agent would allow easy access to
pyridine-derived carbenes. Therefore, we were pleased to
find that a reagent formed from equal amounts of AgOTf
and chloromethyl pivalate4 resulted in the formation of the
desired imidazolium triflates, isolated as the corresponding
bromide 5 after anion exchange (Scheme 1). These bromide
salts crystallize more readily, significantly facilitating the
purification process. Overall, this route is efficient and
flexible and allows the formation of differently substituted
2H-imidazo[1,5-a]pyridin-4-ium salts 5 (RZH, Me, Ph,
OMe, Br).
Table 1. Yields for the synthesis of 5
Ligand
R
Yield of 4 (%)
Yield of 5 (%)
Keywords: Ligand design; N-heterocyclic carbene; Suzuki–Miyaura cross-
coupling.
a
b
c
d
e
H
Me
Ph
OMe
Br
90
90
99
89
88
53
52
47
22
54
*
Corresponding author. Tel.: C49 6421 2825562; fax C49 6421
2822021; e-mail: glorius@chemie.uni-marburg.de
† New address: University of Marburg, Fachbereich Chemie, Hans-
Meerwein-Strabe, 35032 Marburg, Germany.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.115

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C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
Scheme 1.
The structural identity of these compounds was unequi-
vocally determined by X-ray structure analysis of 5a and 5b
(Figs. 1 and 2).5,6 These two compounds have similar bond
lengths and angles. Most interestingly, on closer inspection
of the bond lengths in 5a and 5b both molecules show the
expected bond length alteration in the six-membered ring as
expected from the canonical forms shown in Scheme 2. The
˚
two formal double bonds are approximately 0.08 A shorter
than the single bond in between. These three bonds and the
bridging bond are identical within one s in 5a and 5b.
Interestingly, in 5c the 1H NMR signal of H–C(1) is shifted
upfield compared to the other imidazolium salts 5a and 5b
by more than 1 ppm This indicates that H–C(1) lies in the
anisotropic cone of the phenyl ring. A similar interaction is
envisioned to occur with a carbene bound metal.
Ligand precursors 5a–e can readily be synthesized.
However, in order to introduce a new substituent R the
whole sequence has to be repeated. A common synthetic
precursor that could be manipulated to yield differently
substituted products in one step would be highly desirable.
In general, organic halides enable a plethora of synthetic
transformations.7 Therefore, we investigated the derivatiza-
tion of bromide 5e. Transition metal catalyzed coupling
reactions seemed tempting, however, palladium catalyzed
transformations of aryl halides in the presence of
2-unsubstituted imidazolium salts can provide potential
pitfalls. Namely, deprotonation of the imidazolium salts
might occur, providing sensitive NHCs or the corresponding
palladium NHC complexes. Gratefully, after some optimi-
zation Suzuki cross-coupling of 5e with different boronic
acids or boronic acid esters provided the desired substituted
imidazolium salts 5f, 5g and 5h in good yields. This strategy
allows the synthesis of a variety of differently substituted
NHC-precursors in one step from 5e (Schemes 3 and 4).
Figure 1. Molecular structure of 5a which is situated on a crystallographic
2-fold axis. Atoms C2 and N2 share one position. Anisotropic displacement
˚
parameter ellipsoids are drawn at the 50% level. Selected bond lengths (A)
and angles (8): C1–N1 1.356(2), C1–C2 1.357(2), C2–N2i 1.403(3), C2–C3
1.412(2), C3–C4 1.351(3), C4–C4i 1.435(5), C5–N1 1.453(3), symmetry
code (i) KxC1/4, KyC5/4, z.
Compounds 5f and 5g can exist as atropisomers. Whereas
the two ortho-methyl groups of the mesitylene moiety of 5f
1
give only one signal in H and 13C NMR, in compound 5g
they result in two individual signals. This implies that
rotation of the 1-styryl moiety in 5f is fast relative to the
NMR time scale, whereas rotation of the phenanthrene unit
in 5g is slow. As a further indication for a relatively long life
time, capillary electrophoresis of 5g also results in two
discrete base line separated peaks with diffusion times of
15.8 and 16.2 min. However, separation of the two
atropisomers of 5g by HPLC on a chiral phase was not
successful.
Figure 2. Molecular structure of 5b. Anisotropic displacement parameter
˚
ellipsoids are drawn at the 50% level. Selected bond lengths (A) and angles
(8): N1–C1 1.3484(17), N1–C2 1.4044(18), N1–C6 1.4061(18), C1–N2
1.3359(17), N2–C7 1.3761(17), N2–C8 1.4475(18), C2–C3 1.355(2),
C3–C4 1.433(2), C4–C5 1.354(2), C5–C6 1.4222(19), C6–C7 1.3703(19).
Complexes of the NHCs derived from the ligand precursor 5
with RZH, Ph and C]C–Ph have also been characterized
by single crystal structure analysis in order to investigate
their coordinational behavior. The differently substituted
Scheme 2. Most important canonical forms of the imidazolium salts 5b.

C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
6209
Scheme 3. Suzuki–Miyaura cross-coupling of 5e.
Scheme 4. Retrosynthetic analysis and ligand features.
ligands behave differently and the stability of the complexes
formed depends strongly on the steric demand of the ligand.
H) are trans-coordinated to the palladium (Fig. 3).5 Both
aza-indolizinyl ligands are rotated almost perpendicular to
the coordination plane. The mesityl rings are oriented
perpendicular to the heterocycles and adopt a proximal
arrangement. The shortest non-bonding C/C distance is
Taking the unsubstituted 5a, the stable (NHC)2PdI2
complex 7 smoothly forms in 52% yield under standard
conditions (5a, Pd(OAc)2, NaI, KOtBu, THF).8 In the
distorted square planar complex 7 two carbene ligands (RZ
˚
3.537 A, formed between C12 and C30. The bond lengths of
the carbene ligand are all within three to four s to those in
5b, with the exception of the two carbene carbon–nitrogen
atom bonds. These are, after averaging over both ligands in
˚
7, 1.357(3) and 1.367(3) A long compared to 1.3359(19)
˚
and 1.3484(17) A in the aza-indolizinium salt.
The isolation of the corresponding (NHC)2PdI2 complex of
the sterically more demanding 5c failed under standard
conditions. However, sterically demanding 5c (RZPh) can
also form complexes. Stirring [Ir(COD)Cl]2 with
Figure 3. Molecular structure of 7. Anisotropic displacement parameter
˚
ellipsoids are drawn at the 50% level. Selected bond lengths (A) and angles
(8): Pd–C21 2.015(2), Pd–C1 2.033(2), Pd–I2 2.6062(2), Pd–I1 2.6289(2),
N1–C1 1.369(3), N1–C2 1.391(3), N1–C6 1.411(3), N2–C1 1.358(3),
N2–C7 1.381(3), N2–C8 1.446(3), N3–C21 1.364(3), N3–C22 1.393(3),
N3–C26 1.407(3), N4–C21 1.356(3), N4–C27 1.388(3), N4–C28 1.458(3),
C2–C3 1.345(4), C3–C4 1.436(4), C4–C5 1.347(4), C5–C6 1.428(3),
C6–C7 1.357(4), C22–C23 1.350(4), C23–C24 1.436(4), C24–C25
1.351(4), C25–C26 1.427(3), C26–C27 1.359(3), C21–Pd–C1 177.68(9),
C21–Pd–I2 88.45(6), C1–Pd–I2 92.45(7), C21–Pd–I1 87.41(6), C1–Pd–I1
92.30(6), I2–Pd–I1 163.418(10).
Scheme 5. Synthesis of complex 8.

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C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
of C21 (Fig. 5). The distances to the iridium atom are 3.183
˚
and 3.322 A for C26 and C21, respectively.
Secondary interactions, as observed in complex 8 between
the phenyl group and the metal, arguably play an important
role in catalysis.10 This might result in a stabilization or
activation of a catalytically active complex. This renders
ligands 5c, 5d, 5f, 5g and 5h especially valuable. It is
obvious that the electronic and steric character of the R
group can be fine tuned and also varied over a wide range.
We prepared palladium allyl complex 9 by stirring of the
NHC derived from 5f with palladium allyl chloride dimer.9
It is important to note that the bromo and not the chloro
complex is formed. The molecular structure is also distorted
pseudo-square planar (Fig. 6).5 The carbene ligand adopts a
conformation similar to the one in 8 and the bond lengths
follow the same trend as previously observed. The carbene
carbon–nitrogen bonds are even more elongated than in 7.
In addition, a short contact is observed between the metal
center and carbon atom C11 of the styrene substituent. With
Figure 4. Molecular structure of 8. Anisotropic displacement parameter
˚
ellipsoids are drawn at the 50% level. Selected bond lengths (A) and angles
(8): C1–N1 1.366(7), C1–N2 1.382(6), C1–Ir1 2.046(4), C2–C3 1.362(7),
C2–N1 1.370(7), C3–C4 1.407(7), C3–N2 1.438(6), C4–C5 1.343(8),
C5–C6 1.438(7), C6–C7 1.360(6), C7–N2 1.414(6), C8–Ir1 2.163(5),
C9–Ir1 2.190(4), C12–Ir1 2.099(5), C13–Ir1 2.106(5), C31–N1 1.470(6),
Br1–Ir1 2.4975(5), C1–Ir1–C12 87.43(19), C1–Ir1–C13 89.11(18),
C1–Ir1–C8 158.17(18), C12–Ir1–C8 97.2(2), C13–Ir1–C8 81.15(19),
C1–Ir1–C9 163.04(18), C12–Ir1–C9 80.9(2), C13–Ir1–C9 89.83(18),
C1–Ir1–Br1 96.58(12), C12–Ir1–Br1 153.83(16), C13–Ir1–Br1
164.88(13), C8–Ir1–Br1 88.62(15), C9–Ir1–Br1 88.73(13).
˚
3.081 A, the distance is shorter than the sum of the van der
Waals radii. A possible pyramidalisation of this carbon is
not detectable from the X-ray crystal structure, due to the
uncertainty of the hydrogen atom position. However, the
torsion angle C5–C11–C12–C13 deviates by 48 from
the ideal 1808, also indicating a weak interaction between
palladium and C11.
imidazolium salt 5c and KOtBu in THF results in the
formation of Ir(COD)5cBr (8) (Scheme 5).9 X-ray structural
analysis reveals interesting features of this complex
(Fig. 4, 5).5 The iridium center is coordinated in a distorted
pseudo-square planar arrangement. The carbene ligand and
the bromine are cis to each other and the two remaining
places of the co-ordination sphere are occupied by the
midpoints of the two carbon–carbon double bonds of the
cycloocta-1,4-diene. As expected, the phenyl-substituent of
the ligand shields one of the two faces of the coordination
plane of iridium. Most notable, there is an additional
intramolecular interaction between two of the phenyl carbon
atoms and the metal, resulting in a slight pyramidalization
Figure 6. Molecular structure of 9. Anisotropic displacement parameter
˚
ellipsoids are drawn at the 50% level. Selected bond lengths (A) and angles
(8): C1–C2 1.359(9), C1–Pd1 2.186(5), C2–C3 1.385(9), C2–Pd1 2.133(6),
C3–Pd1 2.123(6), C4–N2 1.360(5), C4–N1 1.377(5), C4–Pd1 2.059(4),
C5–C6 1.361(6), C5–N1 1.405(5), C6–C7 1.429(6), C7–C8 1.353(7),
C8–C9 1.420(6), C9–C10 1.369(6), C9–N1 1.412(5), C10–N2 1.375(6),
C19–N2 1.448(5), C4–Pd1–C3 99.86(19), C4–Pd1–C2 132.2(2), C4–Pd1–
C1 167.6(2), C3–Pd1–C1 67.7(2), C4–Pd1–Br1 98.08(11), C3–Pd1–Br1
161.81(16), C2–Pd1–Br1 126.6(2), C1–Pd1–Br1 94.31(16).
A more cationic metal with free coordination sites should
result in much stronger interactions. Treatment of a CH2Cl2
solution of complex 9 with AgSbF6 results in characteristic
1
changes in the H NMR spectrum, indicating a cationic
Figure 5. Molecular structure of 8. Intramolecular contact between the
palladium complex stabilized by double bond complexa-
tion. However, this complex decomposes on standing and
no crystals suitable for X-ray structural analysis could be
obtained.
˚
˚
iridium metal and carbon atom C21 (3.322 A) and C26 (3.183 A) shown as
thin dashed lines. Carbon atom C21 is slightly pyramidalized, the sum of all
bond angles for this atom is 359.59. The methyl groups of the mesityl ring
have been omitted for clarity.

C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
6211
Scheme 6.
2. Suzuki–Miyaura cross-coupling
catalytic activity has been reported, demonstrating the
usefulness of this exciting ligand class.
The Suzuki–Miyaura cross-coupling is one of the most
important method for the formation of unsymmetrical
biaryls, substructures of many important compounds.11 In
general, aryl bromides and aryl iodides are used as coupling
partner. However, the use of the cheaper but less reactive
aryl chlorides under mild conditions is of great academic
and practical interest and many research programs are
devoted to this.12 As a first test for the usefulness of this new
ligand system we chose the Suzuki–Miyaura cross-coupling
of sterically demanding aryl chlorides with aryl boronic
acids to give di- and tri-orthosubstituted biaryls (Scheme 6,
Table 2). Distinctive differences were found for the different
ligands. Employing 2.5 mol% catalyst, most ligand/palla-
dium combinations produced only low amounts of the
desired product. In contrast, ligands 5g and 5h lead to the
formation of di- and tri-orthosubstituted biaryls in respect-
able yields of up to 86% isolated yield.
3. Experimental
3.1. General remarks
All reactions were conducted in dried glassware under an
atmosphere of argon. The solvents used were purified by
distillation over the drying agents indicated and were
transferred and stored under argon: tetrahydrofuran (THF)
(Na), CH2Cl2 (P4O10), toluene (Na/K). For flash chroma-
tography, Merck silica gel 60 (230–400 mesh) was used.
NMR spectra were recorded on a DPX 300 or AV 400
spectrometer (Bruker) in the solvents indicated; chemical
shifts (d) are given in parts per million relative to
tetramethylsilane, and coupling constants (J) are given in
Hertz. For IR, a Nicolet FT-7199 spectrometer or Perkin–
Elmer Fourier transform-IR Diamant Spectrum One (ATR)
was used; wavenumbers (n) are given in cmK1. For MS
(electron ionization (EI)), a FinniganMAT 8200 (70 eV)
was used, and for high-resolution MS (HRMS), a Finnigan
MAT 95 was used. All commercially available compounds
were used as received. K3PO4 was ground with a mortar and
flame dried.
Table 2. Suzuki–Miyaura cross-coupling of sterically hindered aryl
chlorides resulting in di- and triortho-substituted biarylsa
Entry
Ligand
Product
Yielda
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5f
5g
5h
5a
5b
5c
5d
5f
10
10
10
10
10
10
10
11
11
11
11
11
11
11
(!10)
(38)
(39)
(34)
(22)
86
(67)
!10
30 (28)
(27)
3.1.1. 2-Bromo-6-methoxypyridine. To a stirred solution
of 2,6-dibromopyridine (4.74 g, 20 mmol) in anhydrous
MeOH (20 ml) was added NaOMe (2.16 g, 40 mmol) in
anhydrous MeOH (8 ml) and the solution was refluxed for
24 h. The reaction mixture was poured into a cold aqueous
5% NaHCO3 solution (40 ml), and extracted with ether (5!
10 ml). The organic layer was washed with brine (15 ml)
and dried over Na2SO4. After evaporation of the solvent the
remaining residue was purified by Kugelrohr distillation
(2!10K2 mbar, 70 8C) to give the title compound (2.56 g,
68%) as a colorless liquid.
9
10
11
12
13
14
(!10)
(!10)
78
5g
5h
67 (69)
a Yield of isolated product; GC yield in brackets.
RfZ0.38 (hexane/EtOAc 9:1); IR (film) 2952, 1595, 1581,
1556, 1469, 1411, 1297, 1150, 1122, 1021, 855, 786; H
1
For Suzuki–Miyaura cross-couplings it is believed that a
monoligated Pd-species is the active catalyst.13 In order to
increase the life time of this species steric shielding or
hemilabile binding might be beneficial. Ligands derived
from 5g (RZphenanthryl) and 5h (RZ2,6-dimethoxy-
phenyl)14 are suitable for this kind of interaction. The
substituents R on the ligand shield the metal and in addition
they can bind to the metal possibly resulting in a stabilization
or activation of the catalytically active complex.
NMR (400 MHz, CDCl3) d 7.41–7.37 (m, 1H), 7.03 (d, JZ
7.5 Hz, 1H), 6.66 (d, JZ8.2 Hz, 1H), 3.92 (s, 3H); 13C
(100 MHz, CDCl3) d 163.7, 140.3, 138.6, 120.1, 109.3,
54.0; MS (EI) m/z (%) 189 (64), 188 (100), 187 (66), 186
(95), 160 (24), 159 (39), 158 (29), 157 (39), 108 (12), 93
(59), 78 (50), 76 (15), 65 (22), 64 (22), 53 (11), 76 (15), 65
(22), 64 (22), 53 (11), 51 (10), 50 (14), 39 (48), 38 (32), 37
(11); HRMS (ESI) calcd for C27H27N2:186.9633, found
186.9631.
In conclusion we have reported a facile synthetic route to a
new class of pyridine derived NHC ligands and transition
metal complexes thereof. The first investigation of their
3.1.2. 6-Methoxypyridine-2-carbaldehyde (3d). To a
solution of 2-bromo-6-methoxypyridine (2.56 g,

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C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
13.7 mmol) in anhydrous THF (50 ml) was added n-butyl
lithium (1.6 M in THF, 8.9 ml, 14.2 mmol) at K78 8C and
the solution was stirred for 1 h. DMF (1.18 ml, 15.2 mmol)
was added dropwise, and the solution was stirred for 30 min
at K78 8C. The cold solution was poured into an aqueous
solution of 5% NaHCO3 (130 ml) and extracted with ether
(3!50 ml). The organic layer was dried over Na2SO4. After
evaporation of the solvent the remaining residue was
purified by column chromatography (3!12 cm, hexane/
EtOAc 9:1) to give 3d (1.0 g, 54%) as a colorless liquid.
(100), 196 (9), 181 (6), 157 (20), 146 (36), 131 (17), 115 (6),
104 (8), 91 (18), 79 (20), 65 (8); HRMS (EI) calcd for
C15H16N2: 224.1313, found 224.1312.
3.1.5. (E)-2,4,6-Trimethyl-N-((6-methylpyridin-2-yl)-
methylene)benzenamine (4b). Aldehyde 3b (3.0 g,
24.8 mmol) and 2,4,6-trimethylaniline (3.5 ml, 24.8 mmol)
were dissolved in EtOH (40 ml) and heated to 90 8C for 2 h.
Evaporation of the solvent in vacuo, followed by Kugelrohr
distillation (2!10K2 mbar, 100–140 8C) of the remaining
residue resulted in 4b as a yellow solid (5.3 g, 90%).
RfZ0.68 (hexane/EtOAc 9:1); IR (film) 2986, 2954, 2828,
1720, 1702, 1599, 1473, 1331, 1274, 1219, 1028, 806, 779;
1H NMR (400 MHz, CDCl3) d 9.94 (m, 1H), 7.73–7.68 (m,
1H), 7.55–7.53 (m, 1H), 6.97–6.94 (m, 1H), 4.01 (s, 3H);
13C NMR (100 MHz, CDCl3) d 193.0, 164.4, 150.4, 139.0,
116.2, 115.4, 53.5; MS (EI) m/z (%) 137 (100), 136 (58),
108 (25), 107 (21), 94 (12), 93 (27), 80 (10), 79 (45), 78
(10), 66 (10), 65 (13), 52 (16), 51 (10), 39 (28), 38 (14);
HRMS (EI) calcd for C7H7NO2: 137.0478, found 137.0477.
RfZ0.58 (EtOAc); IR (KBr) 3063, 2967, 2912, 2855, 1640,
1590, 1572, 1480, 1458, 1380, 1208, 1144, 987, 856, 837,
807, 732; 1H NMR (400 MHz, CDCl3) d 8.31 (s, 1H), 8.10
(d, JZ7.8 Hz, 1H), 7.72 (t, JZ7.8 Hz, 1H), 7.26 (d, JZ
6.7 Hz, 1H), 6.90 (s, 2H), 2.65 (s, 3H), 2.31 (s, 3H), 2.15 (s,
6H); 13C NMR (100 MHz, CDCl3) d 163.7, 158.3, 154.0,
147.9, 136.8, 133.2, 128.7, 126.8, 124.8, 118.2, 24.3, 20.7,
18.2; MS (EI), m/z (%) 238 (100), 223 (45), 196 (7), 157
(14), 146 (35), 131 (15), 119 (12), 103 (7), 93 (41), 77 (13),
65 (11); HRMS (ESIpos, CH3OH and CH2Cl2) calcd for
C16H19N2CH: 239.1548, found 239.1550.
3.1.3. 2-Bromo-6-formylpyridine (3e). A solution of
n-butyl lithium (1.6 M in THF, 24.1 ml, 38.5 mmol) in
toluene (30 ml) was cooled to K10 8C and n-butyl
magnesiumbromide (2 M in THF, 10.95 ml, 21.9 mmol)
was added dropwise. To this mixture was added a solution
of 2,6-dibromopyridine (13 g, 55 mmol) in THF (40 ml).
After stirring for 4 h at K10 8C the reaction mixture was
poured into a solution of citric acid (21 g, 110 mmol) in
water (45 ml), and extracted with MTBE (4!25 ml). The
organic layer was dried over Na2SO4, and the solvent
removed in vacuo. The remaining residue was purified by
column chromatography (5!12 cm, hexane/EtOAc 10:1)
followed by crystallization from MTBE/hexane to give 3e
(6.05 g, 60%) as colorless crystals.
3.1.6. (E)-2,4,6-Trimethyl-N-((6-phenylpyridin-2-yl)-
methylene)benzenamine (4c). 2-(6-Phenylpyridine)carb-
oxaldehyde (2.9 g, 16.0 mmol) and 2,4,6-trimethylaniline
(3.5 ml, 24.8 mmol) were dissolved in EtOH (25 ml) and
heated to 90 8C for 1 h. Evaporation of the solvent in vacuo,
followed by evaporation of the impurities by Kugelrohr
distillation (2!10K2 mbar, up to 80 8C) resulted in 4c as a
yellow solid (4.8 g, 99%).
RfZ0.64 (EtOAc/hexane 1:1); IR (KBr) 3064, 3010, 2971,
2940, 2916, 2857, 1635, 1587, 1578, 1566, 1476, 1460,
1448, 1207, 1143, 850, 760, 685, 635; 1H NMR (400 MHz,
CDCl3) d 8.45 (d, JZ0.3 Hz, 1H), 8.27 (dd, JZ1.1, 7.6 Hz,
1H), 8.10–8.08 (m, 2H), 7.91 (td, JZ0.6, 7.8 Hz, 1H), 7.84
(dd, JZ1.2, 7.8 Hz, 1H), 7.54–7.44 (m, 3H), 6.93 (s, 2H),
2.32 (s, 3H), 2.19 (s, 6H); 13C NMR (100 MHz, CDCl3) d
164.1, 157.3, 154.5, 148.0, 138.9, 137.3, 133.3, 129.2,
128.8, 128.8, 127.0, 126.8, 121.9, 119.2, 20.7, 18.2; MS
(EI), m/z (%) 300 (100), 285 (34), 155 (30), 144 (5), 131
(10), 91 (9), 77 (9); HRMS (EI) calcd for C21H20N2:
300.1626, found 300.1629.
RfZ0.45 (hexane/EtOAc 10:1); IR (KBr) 3040, 2872, 1732,
1574, 1436, 1413, 1291, 1213, 1120, 986, 856, 796; H
1
NMR (400 MHz, CDCl3) d 9.99–9.98 (m, 1H), 7.92–7.90
(m, 1H), 7.76–7.70 (m, 2H); 13C (100 MHz, CDCl3) d
191.6, 153.5, 142.6, 139.3, 132.6, 120.3; MS (EI) m/z (%)
187 (43), 185 (43), 159 (96), 158 (22), 157 (98), 156 (17), 78
(100), 77 (20), 76 (40), 75 (12), 52 (14), 51 (44), 50 (40), 29
(11); HRMS (ESI) calcd for C6H4BrO: 184.9476, found:
184.9474.
3.1.4. (E)-2,4,6-Trimethyl-N-((pyridin-2-yl)methylene)-
benzenamine (4a). 2-Pyridinecarboxaldehyde (3.57 ml,
37.3 mmol) and 2,4,6-trimethylaniline (5.2 ml, 37.3 mmol)
were dissolved in EtOH (50 ml) and heated to 90 8C for
30 min. Evaporation of the solvent in vacuo, followed by
Kugelrohr distillation (2!10K2 mbar, 100–150 8C) of the
remaining residue resulted in 4a as a yellowish solid (7.5 g,
90%).
3.1.7. (E)-N-((6-Methoxypyridin-2-yl)methylene)-2,4,6-
trimethylbenzenamine (4d). A solution of 2-methoxy-6-
formylpyridine (3d) (831 mg, 6.0 mmol) and 2,4,6-tri-
methyl aniline (847 ml, 6.0 mol) in EtOH (13 ml) were
refluxed for 4 h. The solvent was removed in vacuo and the
residue purified by Kugelrohr distillation, yielding 4d as
yellow solid (1.59 g, 89%).
RfZ0.89 (hexane/EtOAc 9:1C1% NEt3); IR (film) 3062,
3007, 2976, 2949, 2915, 2857, 1641, 1590, 1573, 1468,
1440, 1332, 1321, 1267, 1206, 1142, 1033, 987, 856, 841,
805, 731; 1H NMR (400 MHz, CDCl3) d 8.22–8.17 (m, 1H),
7.86–7.84 (m, 1H), 7.73–7.68 (m, 1H), 6.89 (s, 2H), 6.86–
6.83 (m, 1H), 3.99 (s, 3H), 2.29 (s, 3H), 2.14 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 164.0, 163.6, 152.1, 148.1,
138.8, 133.2, 128.7, 126.8, 114.0, 112.5, 53.4, 20.7, 18.1;
MS (EI) m/z (%) 255 (17), 254 (100), 253 (38), 238 (48),
RfZ0.60 (EtOAc); IR (KBr) 3051, 2974, 2946, 2911, 2854,
1640, 1585, 1566, 1482, 1468, 1435, 1202, 1143, 876, 862,
770, 739; 1H NMR (300 MHz, CDCl3) d 8.72 (m, 1H), 8.35
(s, 1H), 8.29 (dt, JZ1.0, 7.9 Hz, 1H), 7.84 (tdd, JZ0.6, 1.7,
7.6 Hz, 1H), 7.41 (ddd, JZ1.2, 4.9, 7.5 Hz, 1H), 6.91 (s,
2H), 2.31 (s, 3H), 2.18 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 163.4, 154.6, 149.6, 147.8, 136.7, 133.4, 128.8, 126.8,
125.2, 121.2, 20.7, 18.2; MS (EI), m/z (%) 224 (69), 209

C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
6213
196 (20), 195 (29), 146 (55), 145 (14),131 (18), 130 (11),
110 (18), 109 (25), 91 (16), 77 (12); HRMS (EI) calcd for
C16H18N2O: 254.1419, found 254.1421.
the resulting oil was chromatographed on silica gel (3!
10 cm, EtOAc/MeOH 10:1 to 5:1). The resulting oil was
dissolved in CH2Cl2 (90 mL), NBu4Br (10.8 g, 33.6 mmol)
was added and the solution was stirred. After 2 h the solvent
was removed in vacuo. Subsequent crystallisation from
EtOH/MTBE (1:4, 100 mL) gave 2.91 g (52%, 8.8 mmol)
of imidazolium triflate 5b as yellow/brown crystals.
3.1.8. N-((6-Bromopyridin-2-yl)methylene)-2,4,6-tri-
methylbenzenamine (4e). A solution of 2-bromo-6-formyl-
pyridine (2.96 g, 15.9 mmol) and 2,4,6-trimethyl aniline
(2.24 ml, 15.9 mmol) in EtOH (30 ml) was refluxed for 4 h.
The solvent was removed in vacuo and the residue purified
by Kugelrohr distillation (2!10K2 mbar, 70–90 8C), yield-
ing 4e as yellow oil which solidifies upon standing (6.97 g,
88%).
Rf (of 5b-OTf)Z0.57 (CH2Cl2/MeOH 10:1); IR (KBr)
3131, 3115, 3064, 2986, 2969, 2914, 1659, 1561, 1505,
1482, 1455, 1317, 1224, 1200, 1157, 1084, 1039, 860, 811,
772, 752; 1H NMR (400 MHz, CDCl3) d 10.72 (m, 1H), 7.89
(d, JZ1.7 Hz, 1H), 7.84 (d, JZ9.3 Hz, 1H), 7.23 (m, 1H),
6.98 (s, 2H), 6.93 (t, JZ0.9 Hz, 1H), 3.00 (s, 3H), 2.31 (s,
3H), 1.93 (s, 6H); 13C NMR (100 MHz, CDCl3) d 141.2,
134.4, 134.0, 131.2, 130.9, 129.7, 126.5, 125.9, 117.0,
116.1, 114.5, 21.0, 19.9, 17.7; MS (ESIpos, CH2Cl2), m/z
(%) 251 (100); HRMS (ESIpos, CH3OH and CH2Cl2) calcd
for C17H19N2 (cation): 251.1548, found 251.1550. Anal.
calcd For C17H20BrN2: C, 61.64; H, 5.78; N, 8.46. Found C,
61.52; H, 5.72; N, 8.41.
RfZ0.82 (hexane/EtOAc 9:1); IR (KBr) 3065, 2912, 2854,
1645, 1550, 1478, 1440, 1334, 1206, 1123, 985, 853, 810;
1H NMR (400 MHz, CDCl3) d 8.28 (s, 1H), 8.25 (dd, JZ
7.7, 0.8 Hz, 1H), 7.68 (dd, JZ7.8, 7.7 Hz, 1H), 7.59 (dd,
JZ7.8, 0.8 Hz, 1H), 6.90 (s, 2H), 2.29 (s, 3H), 2.13 (s, 6H);
13C NMR (100 MHz, CDCl3) d 161.8, 155.7, 147.3, 141.7,
138.8, 133.7, 129.5, 128.8, 126.7, 119.6, 20.7, 18.1; MS (EI)
m/z (%) 304 (30), 303 (16), 302 (30), 301 (12), 286 (3), 224
(18), 223 (100), 146 (66), 145 (14), 131 (20), 130 (11), 103
(9), 91 (13), 77 (11); HRMS (EI) calcd for C15H15BrN2:
302.0419, found 302.0420.
3.1.11. Imidazolium bromide 5c. To a suspension of
AgOTf (3.0 g, 11.7 mmol) in CH2Cl2 (30 mL) was added
chloromethyl pivalate (1.75 mL, 11.7 mmol) and the
resulting suspension was stirred for 45 min. After filtration
the filtrate was added to pyridine imine 4c (2.5 g, 8.3 mmol)
and the solution was stirred in a sealed tube in the dark at
40 8C for 14 h. After the solution was cooled to rt EtOH
(20 mL) was added, the solvent was removed in vacuo and
the resulting oil was chromatographed on silica gel (3.5!
10 cm, CH2Cl2 to CH2Cl2/MeOH 10:1). The resulting oil
was dissolved in CH2Cl2 (35 mL), NBu4Br (5.0 g,
15.5 mmol) was added and the solution was stirred. After
12 h, the solvent was removed in vacuo and the resulting oil
was chromatographed on silica gel (4!15 cm, EtOAc/
MeOH 10:1 to 4:1). Subsequent crystallisation from
CH2Cl2/MTBE (1:4, 100 mL) gave 1.52 g (47%,
3.9 mmol) of imidazolium triflate 5c as colorless crystals.
3.1.9. Imidazolium bromide 5a. To a suspension of AgOTf
(4.8 g, 18.7 mmol) in CH2Cl2 (50 mL) was added chloro-
methyl pivalate (2.78 mL, 18.7 mmol) and the resulting
suspension was stirred for 45 min. After filtration the filtrate
was added to pyridine imine 4a (3.0 g, 13.4 mmol) and the
solution was stirred in a sealed tube in the dark at 40 8C for
19 h. After the solution was cooled to rt MeOH (20 mL) was
added, the solvent was removed in vacuo and the resulting
oil was chromatographed on silica gel (2.5!10 cm,
CH2Cl2/MeOH 50:1 to 10:1). The resulting foam was
dissolved in CH2Cl2 (30 mL), NBu4Br (6 g, 18.6 mmol) was
added and the solution was stirred. After 2 h MTBE
(100 mL) was added and the crystals were collected by
filtration. Subsequent crystallisation from EtOH 2.75 g
(53%, 7.1 mmol) of imidazolium triflate 5a as colorless
crystals.
Rf (of 5c-OTf)Z0.68 (CH2Cl2/MeOH 10:1); IR (KBr)
3065, 3029, 2998, 2916, 1651, 1608, 1549, 1491, 1448,
1
1154, 851, 806, 763, 696; H NMR (400 MHz, CDCl3) d
Rf (of 5a-OTf)Z0.51 (CH2Cl2/MeOH 10:1); IR (KBr)
3070, 3045, 2992, 2917, 1649, 1607, 1537, 1497, 1449,
1212, 1158, 828, 763, 675; 1H NMR (400 MHz, D6-DMSO)
d 10.01 (d, JZ1.0 Hz, 1H), 8.62 (dd, JZ0.6, 7.1 Hz, 1H),
8.39 (s, 1H), 7.93 (d, JZ9.2 Hz, 1H), 7.38 (dd, JZ6.5,
8.8 Hz, 1H), 7.28 (td, JZ0.9, 7.1 Hz, 1H), 7.18 (s, 2H), 2.35
(s, 3H), 2.01 (s, 6H); 13C NMR (100 MHz, D6-DMSO) d
140.7, 134.3, 131.7, 129.9, 129.4, 127.8, 125.4, 124.8,
118.5, 118.1, 114.8, 20.8, 17.0; MS (EI), m/z (%) 236 (59),
221 (16), 206 (7), 158 (100), 144 (14), 115 (7), 103 (5), 91
(6), 80 (9); HRMS (ESIpos, CH3OH and CH2Cl2) calcd for
C16H17N2 (cation): 237.1391, found 237.1389.
8.86 (d, JZ1.1 Hz, 1H), 8.78 (d, JZ1.8 Hz, 1H), 8.48 (d,
JZ9.3 Hz, 1H), 7.73–7.70 (m, 2H), 7.61–7.57 (m, 3H), 7.43
(dd, JZ7.0, 9.3 Hz, 1H), 7.15 (dd, JZ0.9, 7.0 Hz, 1H), 6.99
(s, 2H), 2.31 (s, 3H), 2.05 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 141.6, 135.2, 133.9, 132.2, 131.3, 131.0, 130.6,
130.2, 129.7, 128.4, 125.8, 122.3, 119.6, 119.3, 117.6, 21.0,
17.7; MS (ESIpos, CH2Cl2), m/z (%) 313 (100); HRMS
(ESIpos, CH3OH and CH2Cl2) calcd for C22H21N2 (cation):
313.1704, found 313.1699.
3.1.12. Imidazolium bromide 5d. To a suspension of
AgOTf (2.06 g, 8 mmol) in CH2Cl2 (27 ml), chloromethyl
pivalate (1.24 g, 8 mmol) was added and stirred in the dark
for 45 min at rt. After filtration the filtrate was added to
imine 4d (1.46 g, 5.7 mmol) and stirred in the dark for 20 h
at 45 8C. The solution was cooled to room temperature and
quenched with EtOH (10 ml). The solvent was removed in
vacuo and the resulting residue was purified by column
chromatography (SiO2, 2.5!12 cm, EtOAc/MeOH 9:1).
Ion exchange with tetrabutylammonium bromide in CH2Cl2
3.1.10. Imidazolium bromide 5b. To a suspension of
AgOTf (6.0 g, 23.5 mmol) in CH2Cl2 (60 mL) was added
chloromethyl pivalate (3.5 mL, 23.5 mmol) and the result-
ing suspension was stirred for 45 min. After filtration the
filtrate was added to pyridine imine 4b (4.0 g, 16.8 mmol)
and the solution was stirred in a sealed tube in the dark at
40 8C for 24 h. After the solution was cooled to rt EtOH
(20 mL) was added, the solvent was removed in vacuo and

6214
C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
and recrystallization from CH2Cl2/THF yielded 5d (419 mg,
22%) as a greenish powder.
3.1.15. 2-(Phenanthren-10-yl)-1,3,2-dioxaborolane. Mag-
nesium turnings (1.94 g, 80 mmol) and a few crystals of
iodine were heated with a heatgun. After cooling, a solution
of 9-bromophenanthrene (12.8 g, 40 mmol) and ethyliodide
(6.24 g, 40 mmol) in THF (40 ml) was added dropwise.
After 1 h at room temperature this suspension was added
dropwise to a solution of trimethylborate (8.31 g, 80 mmol)
in THF (40 ml) at K78 8C. The reaction mixture was
warmed to room temperature and the solvent removed in
vacuo. To the resulting solid was added ethylene glycol
(6.7 ml, 120 mmol) and toluene (120 ml). After refluxing
overnight, toluene was removed in vacuo and the remaining
solid recrystalized from CH2Cl2/MTBE, yielding the title
compound as white crystals (7.01 g, 70%).
RfZ0.32 (EtOAc/MeOH 9:1); IR (KBr) 3058, 3031, 1656,
1555, 1374, 1281, 1200, 964, 854, 810, 772; 1H NMR
(400 MHz, CD2Cl2) d 9.65 (s, 1H), 8.17–8.07 (m, 1H), 7.69
(d, JZ9.3 Hz, 1H), 7.43 (dd, JZ7.6, 9.3 Hz, 1H), 7.10 (s,
2H), 6.59 (d, JZ7.6 Hz, 1H), 4.28 (s, 3H), 2.38 (s, 3H), 2.06
(s, 6H); 13C NMR (100 MHz, CD2Cl2) d 147.1, 141.7,
132.1, 131.2, 134.1, 127.9, 122.3, 115.0, 110.5, 93.2, 129.7,
58.1, 20.9, 17.3; MS (ESI) m/z 267; HRMS (ESI) calcd for
C17H19N2O: 267.1497, found 267.1489.
3.1.13. Imidazolium bromide 5e. To a suspension of
AgOTf (7.23 g, 28.14 mmol) in CH2Cl2 (100 ml) was added
chloromethyl pivalate (4.24 g, 28.14 mmol), and the
suspension was stirred in the dark for 45 min at rt. After
filtration, the filtrate was added to imine 4e (6.1 g,
20.1 mmol) and the solution was stirred in the dark for
17 h at 45 8C. The solution was cooled to room temperature
and quenched with EtOH (40 ml). The solvent was removed
in vacuo and the resulting residue was purified by column
chromatography (SiO2, 4.5!12 cm, CH2Cl2/MeOH 10:1).
Ion exchange with tetrabutylammonium bromide in CH2Cl2
and recrystallization from CH2Cl2/diethyl ether yielded 5e
(4.3 g, 54%) as brownish crystals.
RfZ0.95 (CH2Cl2/MeOH) IR (KBr) 3053, 2982, 2905,
1444, 1402, 1384, 1328, 1267, 1212, 1028, 770, 756; H
1
NMR (400 MHz, CDCl3) d 8.86–8.80 (m, 1H), 8.75–8.67
(m, 2H), 8,46 (s, 1H), 7.95 (d, JZ7.8 Hz, 1H), 7.75–7.57
(m, 4H), 4.51 (s, 4H); 13C NMR (100 MHz, CDCl3) d 138.5,
134.0, 131.7, 130.6, 129.6, 129.1, 128.6, 127.6, 126.4, 126.2,
125.9, 122.3, 122.2, 65.7; 11B NMR (128 MHz, CDCl3) d
?33.2; MS (EI), m/z (%) 248 (100), 247 (25), 218 (4), 217 (8),
204 (16), 203 (7), 191 (10), 178 (5), 177 (6), 176 (9), 151 (4),
124 (4); HRMS (EI) calcd for C16H13O2B: 248.1009, found
248.1011.
RfZ0.35 (CH2Cl2/MeOH 10:1); IR (KBr) 3053, 2974,
2914, 1646, 1523, 1307, 1297, 1184, 1154, 1037, 857, 812,
3.1.16. Imidazolium bromide 5g. A solution of imidazo-
lium salt 5e (300 mg, 0.756 mmol) and Pd(PPh3)4 (87.4 mg,
0.0756 mmol) in 1,2-dimethoxyethane (6 ml) was degassed
and stirred at room temperature for 30 min. To this
suspension was added a solution of Na2CO3 (84.2 mg,
0.794 mmol) in degassed H2O (1.5 ml) and 2-(phenanthren-
9-yl)-1,3,2-dioxaborolane (197 mg, 0.794 mmol). After 4 h
at 80 8C the reaction mixture was cooled to room
temperature and water (6 ml) was added. The mixture was
extracted with CH2Cl2 (4!10 ml), and the organic layer
was dried over Na2SO4. The solvent was removed in vacuo
and the resulting residue was purified by column chroma-
tography (SiO2, 2.5!12 cm, CH2Cl2/MeOH 20:1) to give
5g as a brownish solid foam (288 mg, 77%).
1
748, 648, 586; H NMR (400 MHz, CDCl3) d 9.94–9.91
(m, 1H), 8.76 (d, JZ1.8 Hz, 1H), 8.48 (d, JZ9.3 Hz, 1H),
7.47–7.45 (m, 1H), 7.24 (dd, JZ9.2 Hz, 9.3 Hz, 1H, with
CHCl3), 6.99 (s, 2H), 2.31 (s, 3H), 2.02 (s, 6H); 13C NMR
(100 MHz, CDCl3) d ?141.5, 133.8, 132.2, 130.8, 129.7,
126.1, 125.6, 123.1, 119.5, 118.4, 112.4, 21.0, 17.6; MS
(ESI) m/z 315; HRMS (ESI) calcd for C16H16N2: 315.0497,
found 315.0499.
3.1.14. Imidazolium bromide 5f. A solution of imidazo-
lium salt 5e (793 mg, 2 mmol) and Pd(PPh3)4 (92 mg,
0.08 mmol) in 1,2-dimethoxyethane (8 ml) was degassed
and stirred at room temperature for 30 min. To this
suspension was added a solution of Na2CO3 (222.6 mg,
2.1 mmol) in degassed H2O (2 ml) and 2-phenylvinylboro-
nic acid (310 mg, 2.1 mmol). After 2.5 h, the reaction
mixture was cooled to room temperature and water (10 ml)
was added. The mixture was extracted with CH2Cl2 (5!
15 ml), and the organic layer was dried over Na2SO4. The
solvent was removed in vacuo and the resulting residue was
purified by column chromatography (SiO2, 2.5!12 cm,
CH2Cl2/MeOH 20:1) to give 5f as a yellow solid (818 mg,
97%).
RfZ0.38 (DCM/MeOH 10:1) IR (KBr) 3382, 3145, 3056,
2955, 1653, 1553, 1450, 1311, 1187, 1153, 1039, 856, 809,
759, 729; 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1H), 8.96
(d, JZ9.3 Hz, 1H), 8.82 (d, JZ8.3 Hz, 1H), 8.74 (d, JZ
8.3 Hz, 1H), 8.16 (s, 1H), 8.03–7.99 (m, 1H), 7.85–7.68 (m,
4H), 7.60–7.50 (m, 2H), 4.45–4.43 (m, 1H), 7.22 (d, JZ
8.1 Hz, 1H), 6.90 (s, 2H), 2.25 (s, 3H), 1.96 (s, 3H), 1.88 (s,
3H); 13C NMR (100 MHz, CD2Cl2) d 141,8; 134,1; 134,0;
133,9; 132,1; 131,5; 131,4; 131,1; 131,0; 130,8; 129,7;
129,6; 129,6; 129,1; 128,1; 128,0; 127,9; 126,4; 126,0;
124,2; 124,2; 123,3; 122,9; 122,6; 120,9; 120,2; 118,0; 20,8;
17,3; 17,1; MS (ESI) m/z 413; HRMS (ESI) calcd for
C30H25N2: 413.2018, found 413.2019.
RfZ0.39 (CH2Cl2/MeOH); IR (KBr) 3400, 3030, 2919,
1647, 1623, 1535, 1497, 1449, 1198, 1155, 966, 852, 797,
753, 692; 1H NMR (400 MHz, CDCl3) d 11.39 (s, 1H), 8.40
(d, JZ15.8 Hz, 1H), 7.99–7.97 (m, 2H), 7.84–7.79 (m, 2H),
7.40–7.36 (m, 2H), 7.31–7.24 (m, 3H), 7.24–7.20 (m, 1H),
6.92 (s, 2H), 2.26 (s, 3H), 2.04 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 141.0, 138.3, 135.7, 135.0, 133.9, 131.1, 129.6,
129.5, 128.8, 128.6, 127.2, 125.9, 117.3, 116.2, 114.1,
113.1, 131.2, 21.0, 17.7; MS (ESI) m/z 339; HRMS (ESI)
calcd for C24H23N2: 339.1861, found 339.1865.
3.1.17. Imidazolium bromide 5h. A solution of imidazo-
lium salt 5e (595 mg, 1.5 mmol) and Pd(PPh3)4 (260 mg,
0.225 mmol) in 1,2-dimethoxyethane (12 ml) was degassed
and stirred at room temperature for 30 min. To this
suspension was added a solution of Na2CO3 (954 mg,
9 mmol) in degassed H2O (3 ml) and 2,6-dimethoxy-
phenylboronic acid (819 mg, 4.5 mmol). After 18 h at

C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
6215
80 8C, more Pd(PPh3)4 (120 mg, 0.1 mmol), 2,6-dimethoxy-
phenylboronic acid (546 mg, 3 mmol) and Na2CO3
(636 mg, 6 mmol) were added to the reaction mixture.
After heating for another 6 h at 80 8C, the reaction mixture
was cooled to room temperature and water (10 ml) was
added. The mixture was extracted with CH2Cl2 (5!15 ml),
and the organic layer was dried over Na2SO4. The solvent
was removed in vacuo and the resulting residue was purified
by column chromatography (SiO2, 2.5!12 cm, CH2Cl2/
MeOH 10:1) to give 5h as a brownish solid foam (462 mg,
68%).
room temperature. After addition of palladium allyl chloride
dimer (134 mg, 0.348 mmol) and LiBr (183 mg, 2.1 mmol)
the suspension was stirred for 3 h at room temperature. After
evaporation of the solvent the remaining solid was purified
by column chromatography (SiO2, 2.5!10 cm, CH2Cl2/
MeOH 95:5) to give 9 (326 mg, 83%) as a yellow solid.
RfZ0.95 (CH2Cl2/MeOH 10:1); IR (KBr) 3135, 3000,
2917, 1647, 1493, 1448, 1369, 1196, 1155, 956, 853, 782,
752, 694; 1H NMR (400 MHz, CDCl3) d 9.52 (d, JZ
15.7 Hz, 1H), 9.26 (d, JZ15.3 Hz, 1H), 7.74–7.65 (m, 4H),
7.41–7.24 (m, 10H), 7.08–6.71 (m, 10H), 4.80–4.66 (m,
1H), 4.66–4.52 (m, 1H), 4.04–3.91 (m, 2H), 3.52–3.38 (m,
2H), 2.88–2.79 (m, 1H), 2.70–2.60 (m, 1H), 2.38 (s, 3H),
2.33 (s, 6H), 2.24 (s, 3H), 2.17–2.11 (m, 1H), 2.03–1.96 (m,
1H), 1.85 (s, 6H); MS (ESI) m/z 485; HRMS (ESI) calcd for
C27H27N2Pd: 485.1208, found 485.1208.
RfZ0.25 (CH2Cl2/MeOH); IR (KBr) 3387, 3008, 2942,
2838, 1654, 1598, 1584, 1476, 1433, 1254, 1108, 783, 730;
1H NMR (400 MHz, CDCl3) d 8.75 (m, 1H), 8.50 (d, JZ
9.3 Hz, 1H), 8.36 (m, 1H), 7.51 (t, JZ8.5 Hz, 1H), 7.39 (dd,
JZ9.3, 9.3 Hz, 1H), 7.12–7.10 (m, 1H), 7.00 (s, 2H), 6.7 (d,
JZ8.5 Hz, 2H), 3.77 (s, 6H), 2.33 (s, 3H), 2.02 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 158.1, 141.4, 133.9, 133.5,
131.9, 131.1, 129.7, 128.7, 125.3, 123.0, 121.6, 119.4,
116.9, 107.1, 104.5, 56.0, 21.0, 17.3; MS (ESI) m/z 373;
HRMS (ESI) calcd for C24H25N2O2: 373.1916, found
373.1920.
3.1.21. Synthesis of a cationic complex from 9. A solution
of complex 9 (40 mg, 0.0767 mmol) in CH2Cl2 (1 ml) was
stirred with AgSbF6 (27.7 mg, 0.081 mmol) in the dark for
1 h. The resulting suspension was filtered and the filtrate
evaporated to dryness (40 mg, 73%).
3.1.18. Synthesis of complex 7. A mixture of imidazolium
triflate 5a (100 mg, 0.26 mmol), Pd(OAc)2 (23.2 mg,
0.10 mmol), NaI (62.2 mg, 0.41 mmol) and KOtBu
(31.4 mg, 0.28 mmol) in THF (7 ml) was stirred for 16 h
at room temperature. The solvent was evaporated in vacuo
and the remaining solid was purified by column chroma-
tography (SiO2, 1.5!15 cm, hexane/EtOAc 3:1) to give 7
(45 mg, 52%) as a yellow solid.
1H NMR (400 MHz, CD2Cl2) d 7.68–7.61 (m, 3H), 7.48–
7.35 (m, 5H), 7.12–7.03 (m, 4H), 6.85–6.84 (m, 1H), 5.34–
5.38 (m, 1H), 3.49–3.15 (m, 2H), 3.07–2.78 (m, 1H), 2.56–
2.53 (m, 1H), 2.36 (s, 3H), 1.95 (s, 3H), 1.90 (s, 3H);
MS(ESI) m/z 485.
3.2. General procedure for Suzuki–Miyaura cross-
coupling
RfZ0.62 (EtOAc/hexane 1:1); IR (KBr) 3137, 3111, 3006,
2957, 2916, 2854, 1752, 1736, 1651, 1608, 1525, 1484,
1464, 1366, 1333, 1241, 1196, 1034, 855, 847, 744, 681; 1H
NMR (400 MHz, CDCl3) d 8.98 (m, 2H), 7.26–7.21 (m,
2H), 7.11 (s, 2H), 6.87 (s, 4H), 6.87–6.84 (m, 2H), 6.72–
6.68 (m, 2H), 2.50 (s, 6H), 1.98 (s, 12H); 13C NMR
(100 MHz, CDCl3) d 157.3, 137.9, 135.5, 135.3, 131.3,
130.3, 129.1, 122.9, 116.8, 114.4, 111.8, 21.3, 20.8; MS
(EI), m/z (%) 837 (1), 836 (2), 835 (1), 834 (3), 833 (2), 832
(4), 831 (3), 830 (1), 705 (32), 577 (9), 237 (100); HRMS
(EI) calcd for C32H32I1N4: 705.0705, found 705.0704.
Preparation of the catalyst solution: in a glove box 5g
(24.7 mg, 0.025 mmol) and KOtBu (5.6 mg, 0.025 mmol)
were suspended in THF (0.6 ml) and stirred for 20 min.
[Pd(allyl)Cl]2 (9.7 mg, 0.0125 mmol) was added and the
mixture was stirred for another 20 min at room temperature
to give the catalyst solution.
To a vial containing the 2-methyl benzene boronic acid
(0.7 mmol) and K3PO4 (1.5 mmol) in degassed dioxane
(1.6 ml) was added the corresponding aryl halide
(0.5 mmol), followed by addition of one half of the catalyst
solution. After 16 h at 80 8C the solvent was removed in
vacuo and the residue chromatographed on silica with
hexane to give the biaryl product.
3.1.19. Synthesis of complex 8. [Ir(COD)Cl]2 (60 mg,
0.09 mmol) and KOtBu (25.3 mg, 0.23 mmol) were stirred
for 10 min in THF (6 ml). Imidazolium bromide 5c
(73.9 mg, 0.19 mmol) was added and the reaction mixture
was stirred for 1.5 h at room temperature. The solvent was
removed in vacuo and the remaining solid was purified by
column chromatography (SiO2, 1!12 cm, hexane/EtOAc
3:1) to give 8 (96 mg, 77%) as a yellow solid. This material
might contain a small amount of the corresponding chloro
complex.
Note added in proof
In parallel to this work, the investigation of imidazo[1,5-
a]pyridine derived NHCs has been reported by Lassaletta
and co-workers: Alcarazo, M.; Roseblade, S. L.; Cowley, A.
R.; Fernandez, R.; Brown, J. M.; Lassaletta, J. M. J. Am.
Chem. Soc. 2005, 127, 3290.
RfZ0.71 (EtOAc/hexane 1:3); IR (KBr) 3107, 3050, 2913,
2876, 2829, 1648, 1488, 1445, 1358, 1328, 1196, 1157,
1035, 780, 757, 710, 694.
Acknowledgements
3.1.20. Palladium complex 9. A solution of imidazolium
salt 5f (350 mg, 0.834 mmol) in THF (10 ml) was stirred
with potassium tert-butoxide (86 mg, 0.77 mmol) for 1 h at
We thank Professor A. Fu¨rstner for generous support, the
BMBF and Fonds der Chemischen Industrie (Liebig
scholarship to F.G.), Lilly Germany (Lilly Lecture Award)

6216
C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
0.08 mm, orthorhombic, Fddd [No. 70], aZ9.2195(2), bZ
as well as the Deutsche Forschungsgemeinschaft for
financial support. We thank H. Hinrichs and A. Deege for
executing capillary electrophoresis and HPLC measure-
ments. Valuable experimental contributions by S. Holle are
also gratefully acknowledged.
3
˚
˚
15.2969(4), cZ42.5886(11) A, VZ6006.3(3) A , ZZ16,
DcalcZ1.403 mg mK3, mZ2.726 mmK1, TZ100 K, 26,654
reflections collected, 1546 independent reflections, 1499
reflections with IO2s(I), qmaxZ26.43(, Gaussian absorption
correction (Tmin 0.79/Tmax 0.84), 91 refined parameters, RZ
0.019, RwZ0.086, SZ1.415, largest diff. peak and holeZ
0.4/K0.6 e AK3. Crystallographic data for 5b: C17H19BrN2,
˚
MrZ331.25 g molK1, colorless, crystal size 0.21!0.19!
0.05 mm, monoclinic, P21/n [No. 14], aZ9.49180(10),
Supplementary data
˚
bZ12.3577(2), cZ13.2973(2) A, bZ94.8220(10)8, VZ
Capillary electrophoresis plot for 5g together with UV–vis
spectra of the two atropisomers (peaks).
3
1554.21(4) A , ZZ4, DcalcZ1.416 mg mK3, mZ2.637 mmK1
,
˚
TZ100 K, 43,271 reflections collected, 5929 independent
reflections, 5048 reflections with IO2s(I), qmaxZ33.28,
Gaussian absorption correction (Tmin 0.61/Tmax 0.88), 185
refined parameters, RZ0.031, RwZ0.095, SZ0.967, largest
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.03.
115
diff. peak and holeZ0.5/K0.5 e AK3. Crystallographic data
˚
for 7: C32H32I2N4Pd, MrZ832.82 g molK1, yellow, crystal
size 0.30!0.09!0.05 mm, orthorhombic, Pbca [No. 61],
˚
aZ15.40640(10), bZ14.49290(10), cZ27.6507(2) A, VZ
3
6173.94(7) A , ZZ8, DcalcZ1.792 mg mK3, mZ2.629 mmK1
,
˚
References and notes
TZ100 K, 72,369 reflections collected, 7659 independent
reflections, 6531 reflections with IO2s(I), qmaxZ28.308,
Gaussian absorption correction (Tmin 0.51/Tmax 0.88), 358
refined parameters, RZ0.024, RwZ0.056, SZ1.003, largest
1. For excellent reviews on the use of NHC ligands in catalysis,
see: (a) Herrmann, W. A. Angew. Chem. Int., Ed. 2002, 41,
diff. peak and holeZ0.7/K0.6 e AK3. Crystallographic data
˚
¨
1290. (b) Herrmann, W. A.; Kocher, C. Angew. Chem. Int., Ed.
1997, 36, 2162. See also, (c) Arduengo, A. J., III; Krafczyk, R.
Chem. Unserer Zeit 1998, 32, 6. (d) Bourissou, D.; Guerret, O.;
for 8: C30H32BrIrN2, MrZ692.69 g molK1, orange, crystal
size 0.16!0.14!0.14 mm, orthorhombic, Pbca [No. 61],
˚
aZ12.78330(10), bZ17.9798(2), cZ21.8389(2) A, VZ
¨
Gabbaı, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39.
3
5019.48(8) A , ZZ8, DcalcZ1.833 mg mK3, mZ6.934 mmK1
,
˚
(e) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang,
C.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69–82.
2. For some applications of sterically demanding NHC ligands,
TZ100 K, 50,356 reflections collected, 5765 independent
reflections, 4604 reflections with IO2s(I), qmaxZ27.508,
Gaussian absorption correction (Tmin 0.46/Tmax 0.53), 307
refined parameters, RZ0.032, RwZ0.149, SZ1.139, largest
¨
¨
see: (a) Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.;
Grosche, M.; Herrmann, W. A. Angew. Chem. Int., Ed. 2002,
41, 1363. (b) Eckhardt, M.; Fu, G. J. Am. Chem. Soc. 2003,
125, 13642. (c) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.; Wang,
Y.; Liu, X.; Andrus, M. B. Org. Lett. 2003, 5, 3317.
(d) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F.
Angew. Chem. Int., Ed. 2003, 42, 3690. (e) Altenhoff, G.;
Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc.
2004, 126, 15195.
diff. peak and holeZ1.4/K1.7 e AK3. Crystallographic data
˚
for 9: C27H27BrN2Pd, MrZ565.82 g molK1, yellow, crystal
size 0.13!0.09!0.06 mm, monoclinic, P21/n [No. 14],
˚
aZ7.76490(10), bZ19.3896(2), cZ15.7751(2) A, bZ
3
93.0000(10)8, VZ2371.82(5) A , ZZ4, DcalcZ1.585 mg mK3
,
˚
mZ2.484 mmK1, TZ100 K, 54,264 reflections collected,
5442 independent reflections, 5119 reflections with IO2s(I),
qmaxZ27.508, Gaussian absorption correction (Tmin 0.88/Tmax
0.95), 280 refined parameters, RZ0.052, RwZ0.175, SZ
3. Weiss, R.; Reichel, S.; Handke, M.; Hampel, F. Angew. Chem.
Int., Ed. 1998, 37, 344.
1.147, largest diff. peak and holeZ2.2/K3.5 e AK3. Crystal-
˚
4. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem.
Commun. 2002, 2704.
lographic data (excluding structure factors) for the structures
in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 256664 (7), CCDC 256665 (5b), CCDC
256666 (8), CCDC 256667 (5a), CCDC 256668 (9). Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: 144-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
5. Suitable crystals were obtained by recrystallization from
methylenchloride/hexane (5a, 7 and 9), ethanol/MTBE (5b)
and MTBE/hexane (8). Data were recorded using an Enraf–
Nonius KappaCCD diffractometer with graphite-monochro-
˚
mated Mo Ka-radiation (lZ0.71073 A) and a rotating anode
(FR 591) from the same manufacturer. The crystal was
mounted on the tip of a glass fibre using viscous perfluoro-
polyether (Lancaster) and cooled in a stream of cold nitrogen
gas. The structures were solved by direct methods (SHELXS-
97; G.M. Sheldrick, Program for the determination of crystal
6. Worth mentioning is the strict crystallographic two-fold
symmetry of 5a, while the molecule itself possesses only Cs
symmetry resulting in the mutual disorder of the bridging
carbon and nitrogen atom. This disorder was taken into
account in the structure refinement, by equivalencing the
shared C/N position and displacement parameter with a 1:1
site occupation.
¨
structures, University of Gottingen, Germany, 1997) and
refined by full-matrix least-squares techniques against F2
(SHELXL-97; G.M. Sheldrick, Program for least-squares
¨
refinement of crystal structures, University of Gottingen,
Germany, 1997). Hydrogen atoms were inserted from
geometry consideration using the HFIX option of the program.
Crystallographic data for 5a: C16H17BrN2, MrZ
7. Metal-catalyzed Cross-coupling Reactions; Diederich, F., de
Meijere, A., Eds.; Wiley: New York, 2004.
¨
8. (a) Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.;
Artus, G. R. J. Angew. Chem. Int., Ed. Engl. 1995, 34, 2371.
317.23 g molK1
,
colorless, crystal size 0.10!0.09!

C. Burstein et al. / Tetrahedron 61 (2005) 6207–6217
6217
(b) Enders, D.; Gielen, H. J. Organomet. Chem. 2001, 70,
617–618. The triflate salt of 5a was employed for this reaction.
9. Because of their sensitivity and lability, the iridium complex 8
and the palladium complex 9 were not fully characterized. In
the case of 8, the formation of a small amount of the
corresponding chloro complex can not be excluded.
chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int.,
Ed. 2002, 41, 4176. See also: (b) Miura, M. Angew. Chem. Int.,
Ed. 2004, 43, 2201.
13. The importance of monoligated Pd(0) complexes as cata-
lytically active species in Suzuki–Miyaura cross-coupling has
been proposed. See, for example: (a) Littke, A. F.; Dai, C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 4020. (b) Stambuli, J. P.;
Kuwano, R.; Hartwig, J. F. Angew. Chem. Int., Ed. 2002, 41,
4746. (c) Hu, Q.-S.; Lu, Y.; Tang, Z.-Y.; Yu, H.-B. J. Am.
Chem. Soc. 2003, 125, 2856.
10. (a) Glorius, F. Angew. Chem. Int., Ed. 2004, 43, 3364.
(b) Slone, C. S.; Weinberger, D. A.; Mirkin, C. A. Prog. Inorg.
Chem. 1999, 48, 233.
11. (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359. (b) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457. (d) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147. (e) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11.
14. The 2,6-dimethoxyphenyl group was also used in an
exceptionally practical and general catalyst system for the
Suzuki–Miyaura cross-coupling: Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem. Int., Ed. 2004,
43, 1871.
12. For a review on Pd-catalyzed cross-coupling reactions of aryl