Microwave-assisted double Suzuki-Miyaura cross-coupling in the 6,8-dibromoimidazo[1,2-a]pyridine series

Article abstract of DOI:10.1055/s-2007-990905

New, potentially bioactive, imidazopyridine derivatives were synthesized in a highly efficient synthesis in four steps from 2-amino-3,5-dibromopyridine using microwave-assisted double Suzuki-Miyaura cross-coupling methodology. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990905

PAPER
127
Microwave-Assisted Double Suzuki–Miyaura Cross-Coupling in the
6,8-Dibromoimidazo[1,2-a]pyridine Series
M
icrowave-Assis
é
te
d
D
ouble
m
Suzuki–Miyaura
C
i
ross-Couplin
S
g
zabo, Maxime D. Crozet, Patrice Vanelle*
Laboratoire de Chimie Organique Pharmaceutique, LCOP-UMR CNRS 6517, Faculté de Pharmacie, Université de la Méditerranée,
27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France
Fax +33(4)91794677; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Received 21 September 2007; revised 5 October 2007
tions in 2-[(arylsulfonyl)methyl]-6,8-dibromo-3-nitroimi-
Abstract: New, potentially bioactive, imidazopyridine derivatives
were synthesized in a highly efficient synthesis in four steps from
2-amino-3,5-dibromopyridine using microwave-assisted double
Suzuki–Miyaura cross-coupling methodology.
dazo[1,2-a]pyridines.13
Herein we report our work, starting from the condensation
of commercial 2-amino-3,5-dibromopyridine and 1,3-
Key words: double cross-coupling, microwaves, imidazo[1,2- dichloroacetone in ethanol to give 6,8-dibromo-2-(chlo-
a]pyridine, sulfones, spectroscopy
romethyl)imidazo[1,2-a]pyridine (1) (Scheme 1), which
was nitrated with 65% nitric acid at the 3-position to give
2 (Scheme 2).
Imidazo[1,2-a]pyridine derivatives are currently the ob-
ject of renewed interest in the pharmaceutical field.1 Re-
cently, many publications have reported their
pharmacological activities in various biological areas
such as antiviral,2 hypnotic,3 gastric antisecretory,4 and lo-
cal anesthetic5 properties. It is particularly in the field of
the central nervous system that the activity of this skeleton
appears to have currently the most importance, contribut-
ing in particular to a better comprehension of the mecha-
nism of action of psychotropic drugs.6
O
Br
Br
Cl
Cl
NH2
Cl
N
N
N
EtOH, heat
61%
Br
Br
1
Scheme 1
Br
Br
Cl
Cl
N
N
HNO3 (65%)
Over the last three decades, the use of sulfones in organic
chemistry and medicinal chemistry has increased dramat-
ically. Sulfones have been employed in many synthetic
methodologies as intermediates, enabling the preparation
of a great number of functionalized products, such as nat-
ural products and bioactive substances. The auxiliary sul-
fonyl group allows the deprotonation of a neighboring
carbon atom. The resulting carbanion can be involved in
various transformations after which the sulfonyl group
can be removed directly or through different methods in-
cluding reductive, oxidative, and alkylative desulfonyla-
tion.7
N
N
H2SO4
90%
Br
Br
NO2
1
2
Scheme 2
The resulting 6,8-dibromo-2-(chloromethyl)-3-nitroimi-
dazo[1,2-a]pyridine (2) reacted with sodium arylsulfi-
nates in dimethyl sulfoxide, probably following an SN2
mechanism, to give the corresponding sulfones 3 and 4
(Scheme 3).9,13
The Suzuki–Miyaura cross-coupling reaction is well
known to be an extremely efficient synthetic route for the
synthesis of functionalized heterocycles;8 several exam-
ples of 3-, 6-, and 8-arylimidazo[1,2-a]pyridines have
been described in the literature.9,10 In addition, this meth-
od is compatible with a large variety of functional
groups.11
Br
Br
Ar
O
ArSO2–Na+
DMSO
Cl
S
N
N
O
N
N
Br
Br
NO2
NO2
3
4
Ar = 4-MeC6H4 84%
Ar = Ph
94%
2
Only a few examples of double cross-coupling reactions
on heterocyclic systems have been reported and none of
them was performed on the imidazo[1,2-a]pyridine sys-
tem.12 In continuation of our previous work, we decided to
investigate double Suzuki–Miyaura cross-coupling reac-
Scheme 3
We decided to use initially the same conditions for the
double Suzuki–Miyaura cross-coupling reaction as were
used in the 2-(arylsulfonylmethyl)-6-bromo-3-nitroimid-
azo[1,2-a]pyridine series for mono-cross-coupling reac-
tions.13 C-Arylation was performed in aqueous medium
catalyzed by tetrakis(triphenylphosphine)palladium(0)
SYNTHESIS 2008, No. 1, pp 0127–0135
x
x
.
x
x
.2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990905; Art ID: Z22707SS
© Georg Thieme Verlag Stuttgart · New York

128
R. Szabo et al.
PAPER
and sodium carbonate. Indeed, water offers many advan-
tages, in addition to being readily available, it is inexpen-
sive, nontoxic, environmentally friendly, and
nonflammable.14 However, water has the drawback of be-
ing a bad solvent for most organic compounds. Conse-
quently, in order to facilitate solvation of the organic
reagents, a tetraalkylammonium salt was added as a
phase-transfer agent. As the Suzuki reaction involves
many ionic intermediates, tetrabutylammonium bromide
is appropriate. According to Leadbeater and co-workers,
the ammonium ion also plays a catalytic role activating
the boronic acid by the formation of a boronate complex
[ArB(OH)3]–[Bu4N]+.15
Furthermore, varying amounts of catalyst were evaluated
and the use of 5 mol% proved to be the most efficient.
Fewer byproducts were observed and, as a result, the de-
sired products were isolated more easily.
Using this methodology, unexpected products were ob-
served during trials involving excessive amounts of tet-
rakis(triphenylphosphine)palladium(0). Refluxing the
starting sulfones with 40 mol% tetrakis(triphenylphos-
phine)palladium(0) in water allowed complexes 5 and 6 to
be isolated with the palladium atom linked to C8 despite
the presence of boronic acid and sodium carbonate in the
medium. Such structures were elucidated by X-ray crys-
tallography (Figures 1 and 2).
Figure 2 Ortep structure and structure of bromo{6-bromo-3-nitro-
2-(tosylmethyl)imidazo[1,2-a]pyridin-8-yl}bis(triphenylphosphine)-
palladium (6)
Figure 3 Ortep structure of 6,8-dibromo-3-nitro-2-[(phenylsulfo-
nyl)methyl]imidazo[1,2-a]pyridine (4)
regioselectivity had already been observed in 6,8-diha-
loimidazo[1,2-a]pyridine derivatives for nucleophilic ad-
ditions on aromatic structures involving alcoholate or
hydrogen sulfide but never in palladium-catalyzed reac-
tions.6a,16 In addition, the complex with the palladium
atom linked to the 6-position has not been observed under
any conditions that we have tried.
We then measured the C–Br bond lengths by X-ray dif-
fraction on a crystal of 6,8-dibromo-3-nitro-2-[(phenyl-
sulfonyl)methyl]imidazo[1,2-a]pyridine (4). The C11–
Br1 bond is shorter (1.8715 Å) than the C13–Br2 bond
(1.8945 Å) on the X-ray structure determination (Figure
3). Thus the 8-position appears more electropositive,
which could explain its greater affinity toward palladium
than the 6-position.
Figure 1 Ortep structure and structure of bromo{6-bromo-3-nitro-
2-[(phenylsulfonyl)methyl]imidazo[1,2-a]pyridin-8-yl}bis(triphenyl-
phosphine)palladium (5)
The complex 5 was also obtained by refluxing the sulfone
4 with 40 mol% tetrakis(triphenylphosphine)palladium(0)
in water in 72% yield.
In order to avoid the formation of the unreactive complex-
es 5 and 6 and because of the better solubility and stability
of palladium(II) acetate in water compared to tet-
rakis(triphenylphosphine)palladium(0), we decided to use
a palladium(II) acetate catalyst system for the continua-
tion of our studies.14
These structures first informed us about the kinetics of the
double cross-coupling reaction. Thus, the 8-position ap-
pears to react more vigorously than the 6-position. This
Synthesis 2008, No. 1, 127–135 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Double Suzuki–Miyaura Cross-Coupling
129
Br
R
more convenient to carry out the Suzuki reaction in a mi-
crowave reactor. The use of microwaves reduced the reac-
tion time to 20 minutes and the yields increased
significantly in some cases (Table 2). The reaction rate is
thus accelerated up to 50 times with a significant enhance-
ment of the process efficiency.
Ar
Ar
RB(OH)2
Na2CO3
O
O
S
S
N
N
O
O
N
Pd
N
Br
R
NO2
NO2
7a–h Ar = 4-MeC6H4
8a–h Ar = Ph
3
4
Ar = 4-MeC6H4
Ar = Ph
Table 2 Method 2 for Cross-Coupling Reactions of 6,8-Dibromo-
3-nitro-2-(tosylmethyl)imidazo[1,2-a]pyridine (3) with Arylboronic
Acids under Microwave Irradiation in Watera
Scheme 4
No organic solvents or cosolvents were used or investigat-
ed. Although the reaction mixtures were nonhomoge-
neous and aggregated, the yields were good overall (Table
1). Some yields appeared to suffer due to difficulties dur-
ing extractions in the workup. The aggregation, coupled
with the high surface tension of water, diminishes the con-
tact between hydrophobic species and water molecules.17
Entry
R
Product
7a
Time (min) Yield (%)
1
2
3
4
5
6
7
Ph
20
20
20
20
20
20
20
76
52
78
56
59
54
40
2-MeC6H4
4-MeOC6H4
4-FC6H4
3-F3CC6H4
2-naphthyl
1-naphthyl
7b
7c
7d
The mixture of the sulfone (1 equiv), boronic acid (2.8
equiv), palladium(II) acetate (20 mol%), tetrabutylammo-
nium bromide (1 equiv), and sodium carbonate (6 equiv)
was refluxed in water, until disappearance of starting ma-
terials, as monitored by TLC (Table 1). According to pre-
viously described methods of palladium-catalyzed
arylation of sulfonyl CH-acids, the use of a weak base
(Na2CO3) might be sufficient to enable the deprotonation
of this carbon atom, allowing cross-coupling reactions in
water.13
7e
7f
7g
a Conditions: Pd(OAc)2 (20 mol%), 3 (1 equiv), arylboronic acid (2.8
equiv), Na2CO3 (6 equiv), TBAB (1 equiv), H2O, 100 °C, 300 W.
In order to evaluate the influence of microwaves on this
cross-coupling reaction, we investigated the same proto-
col in an irradiation-transparent solvent.18 Hence, the mix-
ture without a phase-transfer agent was dissolved in 1,4-
dioxane and irradiated under the same conditions (Table
3). Under these conditions, the medium is homogenous, as
a result the use of a phase-transfer catalyst is no longer
necessary.
Table 1 Method 1 for Cross-Coupling Reactions of 6,8-Dibromo-
3-nitro-2-(tosylmethyl)imidazo[1,2-a]pyridine (3) with Arylboronic
Acids in Watera
Entry
R
Product
7a
Time (h) Yield (%)
1
2
3
4
5
6
7
Ph
30
24
40
24
26
44
63
72
61
40
94
30
38
32
2-MeC6H4
4-MeOC6H4
4-FC6H4
3-F3CC6H4
2-naphthyl
1-naphthyl
7b
Table 3 Method 3 for Cross-Coupling Reactions of 6,8-Dibromo-
3-nitro-2-(phenylsulfonyl)methyl]imidazo[1,2-a]pyridine (4) with
Arylboronic Acids under Microwave Irradiation in 1,4-Dioxane
Catalyzed by Palladium(II) Acetatea
7c
7d
Entry
R
Product
8a
Time (min) Yield (%)
7e
1
2
3
4
5
6
7
Ph
25
25
20
25
25
25
25
65
52
66
83
86
56
42
7f
2-MeC6H4
4-MeOC6H4
4-FC6H4
3-F3CC6H4
2-naphthyl
1-naphthyl
8b
7g
8c
a Conditions: Pd(OAc)2 (20 mol%), 3 (1 equiv), arylboronic acid (2.8
equiv), Na2CO3 (6 equiv), TBAB (1 equiv), H2O, 100 °C.
8d
8e
Under these conditions, we obtained double cross-cou-
pling products 7 in moderate to excellent yields. The best
result was obtained with boronic acids bearing an elec-
tron-withdrawing atom in the para position, such as 4-
fluorophenylboronic acid, which gives 7d in 94% yield
(Table 1).
8f
8g
a Conditions: Pd(OAc)2 (5 mol%), 4 (1 equiv), arylboronic acid (2.8
equiv), Na2CO3 (6 equiv), 1,4-dioxane, 100 °C, 300 W.
However, the reaction time often lasts for more than one
day. Hence we decided to investigate microwave irradia-
tion as a method to accelerate the transformation.18 The
same mixture was thus placed in a microwave oven and ir-
radiated with 300 W at 100 °C. As expected it proved
In order to validate the hypothesis about the solubility of
the catalyst in the medium, it was then interesting to ex-
plore the efficiency of tetrakis(triphenylphosphine)palla-
dium in 1,4-dioxane. The quantities of all reagents
Synthesis 2008, No. 1, 127–135 © Thieme Stuttgart · New York

130
R. Szabo et al.
PAPER
Table 4 Method 4 for Cross-Coupling Reactions of 2-[(Arylsulfo-
nyl)methyl]-6,8-dibromo-3-nitroimidazo[1,2-a]pyridines 3 and 4
with Arylboronic Acids under Microwave Irradiation in 1,4-Dioxane
Catalyzed by Tetrakis(triphenylphosphine)palladiuma
cross-coupling reactions that are readily applicable to or-
ganic synthesis in the laboratory.
In addition, the replacement of the bromine atom at the 6
or 8-positions by a less reactive leaving group (such as a
chlorine atom) will be investigated to invert the kinetics of
the regioselectivity during the cross-coupling process.
Entry
1
R
Compound Time (min) Yield (%)
Ph
7a
8a
30
20
63
62
Microwave-assisted reactions were performed in a multimode mi-
crowave oven Ethos Synth Lab Station (Ethos start, Milestone Inc.).
Melting points were determined with a B-540 Büchi melting point
2
3
4
5
6
7
8
2-MeC6H4
7b
8b
45
45
69
58
1
apparatus. 200 MHz H NMR (reference CHCl3 d = 7.26) and 50
4-MeOC6H4
4-FC6H4
7c
8c
20
15
71
64
MHz 13C NMR spectra (reference CHCl3 d = 76.9) were recorded
on a Bruker ARX 200 spectrometer in CDCl3 or DMSO-d6 soln at
the Faculté de Pharmacie de Marseille. ESI+ mass spectra were re-
corded on a double-focusing Finnigan MAT 95 instrumental with
BE geometry. Elemental analyses, MS, and X-ray crystal structure
analysis were carried out at the Spectropole, Faculté des Sciences et
Techniques de Saint-Jérôme. Column chromatography used silica
gel 60 (Merck, particle size 0.063–0.200 mm, 70–230 mesh
ASTM). TLC analyses were performed on 5 cm × 10 cm aluminum
plates coated with silica gel 60F-254 (Merck) in an appropriate sol-
vent. MS spectra were recorded on QStar Elite (Applied Biosystems
SCIEX) spectrometer. PEG was the matrix for HRMS.
7d
8d
25
20
72
87
3-F3CC6H4
2-naphthyl
1-naphthyl
3,4,5-(MeO)C6H2
7e
8e
35
25
77
73
7f
8f
45
30
71
66
7g
8g
45
35
52
67
The X-ray diffraction measurements were carried out on a Bruker-
Nonius KappaCCD diffractometer at 293(2) K. Structures were
solved using SIR92 and refinements calculations based on F2 were
performed using SHELXL-97. Compound 4 was crystallized from
slow evaporation of an i-PrOH soln to provide the desired single
crystals. Compounds 5 and 6 were crystallized from EtOH.20
7h
8h
35
30
70
66
a Conditions: Pd(PPh3)4 5 (mol%), 3 or 4 (1 equiv), arylboronic acid
(2.8 equiv), Na2CO3 (6 equiv), 1,4-dioxane, 100 °C, 300 W.
remained the same and the reactions were performed with
5 mol% tetrakis(triphenylphosphine)palladium (Scheme
4, Table 4).
6,8-Dibromo-2-(chloromethyl)imidazo[1,2-a]pyridine (1)
A mixture of 2-amino-3,5-dibromopyridine (2 g, 7.9 mmol) and
1,3-dichloroacetone (1.11 g, 8.7 mmol) was refluxed in EtOH (50
mL) for 30 h. The soln was cooled and evaporated under reduced
pressure. Cold H2O was added and the white precipitate that formed
was filtered and air-dried. The solid was washed with a small
amount of Et2O and recrystallized (i-PrOH) to give 1 (1.57 g, 61%)
as white needles; mp 152 °C.
The base, sodium carbonate, is added after 30 minutes of
stirring at room temperature as a 1 M solution in water.
This last protocol provides easier workup and purification
of the desired products. Double C-arylation products 7
and 8 are more readily available by performing the reac-
tion in 1,4-dioxane, catalyzed with tetrakis(triphenylphos-
1H NMR (200 MHz, CDCl3): d = 4.77 (s, 2 H), 7.55 (d, J = 1.6 Hz,
1 H), 7.69 (s, 1 H), 8.22 (d, J = 1.6 Hz, 1 H).
phine)palladium and heated under microwave irradiation. 13C NMR (50 MHz, CDCl3): d = 39.2, 106.3, 112.0, 112.8, 125.1,
130.4, 141.9, 144.9.
In this case, all the reagents are soluble in the medium and
resulting in a homogenous mixture.
Anal. Calcd for C8H5Br2ClN2: C, 29.62; H, 1.55; N, 8.64. Found: C,
29.75; H, 1.56; N, 8.74.
This method validates the compatibility of the cross-cou-
pling reaction with the functional groups, neither the sul-
fone nor the nitro group is altered. Furthermore, no
byproducts were observed from a possible cross-coupling
reaction with the neighboring carbon atom of the sul-
fone.19
6,8-Dibromo-2-(chloromethyl)-3-nitroimidazo[1,2-a]pyridine
(2)
To concd H2SO4 (40 mL) was added, with stirring, 1 (4.2 g, 12.9
mmol). The mixture was cooled to 0 °C in an ice bath and to the cold
stirred soln was added 65% HNO3 (4 mL). After returning to r.t., the
reaction was followed for 2 h. The soln was then poured into ice and
a yellow precipitate appeared. The solid was filtered and recrystal-
lized (i-PrOH) to give 2 (4.3 g, 90%) as olive-green needles; mp 172
In conclusion, we have developed an efficient method for
the synthesis of highly functionalized 6,8-diaryl-2-[(aryl-
sulfonyl)methyl]-3-nitroimidazo[1,2-a]pyridines 7 and 8 °C.
based on microwave-assisted Suzuki–Miyaura double
cross-coupling reaction. Comparison of the aqueous me-
dium versus ethereal solvent is the subject of our present
studies. We have shown that the choice of the catalyst is
related to the nature of the solvent.
1H NMR (200 MHz, DMSO-d6): d = 5.13 (s, 2 H), 8.49 (d, J = 1.5
Hz, 1 H), 9.40 (d, J = 1.5 Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): d = 38.9, 110.7, 112.6, 127.6,
130.1, 136.2, 140.8, 146.7.
Anal. Calcd for C8H4Br2ClN3O2: C, 26.01; H, 1.09; N, 11.38.
Found: C, 26.35; H, 1.08; N, 11.47.
This methodology gives access to a large variety of ana-
logues, considering the numerous palladium-catalyzed
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Microwave-Assisted Double Suzuki–Miyaura Cross-Coupling
131
6,8-Dibromo-3-nitro-2-(tosylmethyl)imidazo[1,2-a]pyridine (3)
To a soln of sodium 4-toluenesulfinate (1.44 g, 8.1 mmol) in DMSO
under N2, was added 2 (1 g, 2.7 mmol); the soln was stirred at r.t.
for 2 h. After the disappearance of 2 (TLC), the mixture was poured
into cold H2O (300 mL). The precipitated solid was filtered, air-
dried, and recrystallized (i-PrOH) to give 4 (1.11 g, 84%) as beige
needles; mp 222 °C.
1H NMR (200 MHz, CDCl3): d = 2.46 (s, 3 H), 5.12 (s, 2 H), 7.34
(d, J = 8.3 Hz, 2 H), 7.74 (d, J = 8.3 Hz, 2 H), 7.99 (d, J = 1.2 Hz, 1
H), 9.52 (d, J = 1.3 Hz, 1 H).
Bromo[6-bromo-3-nitro-2-(tosylmethyl)imidazo[1,2-a]pyridin-
8-yl)bis(triphenylphosphine)palladium (6)
Cross-coupling reaction of 4-methoxyphenylboronic acid with 3,
Pd(PPh3)4 catalyst (40%), and base with purification by column
chromatography (silica gel, CH2Cl2) and recrystallization (EtOH)
gave 6 as yellow crystals; mp 262 °C.
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H), 4.93 (s, 2 H), 7.14–
7.15 (m, 1 H), 7.22–7.30 (m, 18 H), 7.61–7.74 (m, 16 H), 8.33–8.34
(m, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 56.8, 111.9, 121.5, 127.7,
127.8, 127.9, 128.1, 129.7, 130.2, 130.3, 130.7, 134.5, 134.6, 134.7,
136.9, 138.3, 139.6, 139.7, 139.7, 144.8, 145.2, 145.2, 158.6, 158.7,
158.8.
13C NMR (50 MHz, CDCl3): d = 21.7, 56.7, 111.4, 113.3, 126.7,
128.5, 129.8, 136.0, 136.2, 139.7, 141.2, 145.3.
Anal. Calcd for C15H11Br2N3O4S: C, 36.83; H, 2.27; N, 8.59; S,
6.56. Found: C, 36.87; H, 2.34; N, 8.52; S, 6.52.
Crystal Data for 6: C51H41Br2N3O4P2PdS, M = 1120.13, pale yel-
low prisms, crystal dimensions 0.15 × 0.1 × 0.1 mm. Monoclinic,
space group P21/c (T = 293 K) with a = 18.5377(1) Å,
b = 12.9038(1) Å, c = 26.7430(3) Å, a = 90.00°, b = 111.3411(3)°,
g = 90.00°, V = 5958.46(9) Å3, Z = 4, m = 1.779 mm–1,
F(000) = 2220, index ranges –20 £ h £ 26, –18 £ k £ 15, –35 £ l £
38. The q range = 1.97–30.97°, 577 variables and 0 restraints, were
refined for 11815 independent reflections with I ≥ 2 sI to
R = 0.0538, wR2 = 0.1439, GoF = 1.082.
6,8-Dibromo-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-
a]pyridine (4)
To a soln of sodium benzenesulfinate (0.14 g, 0.8 mmol) in DMSO
under N2, was added 2 (0.1 g, 0.27 mmol); the soln was stirred at r.t.
for 2 h. After the disappearance of 2 (TLC), the mixture was poured
into cold H2O (150 mL). The precipitated solid was filtered, air-
dried, and recrystallized (i-PrOH) to give 3 (0.122 g, 94%) as beige
needles; mp 205 °C.
6,8-Diaryl-2-[(arylsulfonyl)methyl]-3-nitroimidazo[1,2-a]py-
ridines 7 and 8; General Procedures
1H NMR (200 MHz, CDCl3): d = 5.15 (s, 2 H), 7.51–7.72 (m, 3 H),
7.84–7.91 (m, 2 H), 8.00 (d, J = 1.6 Hz, 1 H), 9.53 (d, J = 1.6 Hz, 1
Method 1 (Table 1): A soln of 3 (250 mg, 0.5 mmol), boronic acid
(1.4 mmol), Pd(OAc)2 (0.1 mmol), TBAB (0.5 mmol), and Na2CO3
(3 mmol) in H2O (20 mL) was refluxed at 100 °C until disappear-
ance of the starting material (TLC). After cooling, the solvent was
evaporated and the residue dissolved in EtOAc. The organic layer
was washed with H2O (1 ×) and brine (2 ×), dried (Na2SO4), and
concentrated under vacuum. Flash chromatography (silica gel,
CHCl3–EtOAc, CHCl3–Et2O, or EtOAc, 95:5 or 9:1) provided the
desired compound.
H).
13C NMR (50 MHz, CDCl3): d = 56.7, 111.5, 113.4, 126.7, 128.5,
129.2, 134.2, 136.1, 139.1, 139.5, 141.2.
Anal. Calcd for C14H9Br2N3O4S: C, 35.39; H, 1.91; N, 8.84; S, 6.75.
Found: C, 35.52; H, 1.95; N, 8.70; S, 6.80.
Crystal Data for 4: C14H9Br2N3O4S, M = 475.12, colorless prisms,
crystal dimensions 0.3 × 0.075 × 0.025 mm. Monoclinic, space
group P21/c (T = 293 K) with a = 15.2598(4) Å, b = 5.1839(1) Å,
c = 20.7550(6) Å, a = 90.00°, b = 101.9752(8)°, g = 90.00°,
V = 1606.10(7) Å3, Z = 4, m = 5.202 mm–1, F(000) = 928, index
ranges –21 £ h £ 21, 0 £ k £ 7, 0 £ l £ 29. The q range = 1.36–30.89°,
217 variables and 0 restraints, were refined for 2538 independent re-
flections with I ≥ 2sI to R = 0.0392, wR2 = 0.0889, GoF = 0.834.
Method 2 (Table 2): A soln of 3 (250 mg, 0.5 mmol), boronic acid
(1.4 mmol), Pd(OAc)2 (0.1 mmol), TBAB (0.5 mmol), and Na2CO3
(3 mmol) in H2O (20 mL) was irradiated by microwaves (300 W) at
100 °C for 20 min. After cooling, the solvent was evaporated and
the residue dissolved in EtOAc. The organic layer was washed with
H2O (1 ×) and brine (2 ×), dried (Na2SO4), and concentrated under
vacuum. Flash chromatography (silica gel, CHCl3–EtOAc, CHCl3–
Et2O, or EtOAc, 95:5 or 9:1) provided, after recrystallization with
an appropriate solvent, the desired compound.
Bromo{6-bromo-3-nitro-2-[(phenylsulfonyl)methyl]imida-
zo[1,2-a]pyridin-8-yl}bis(triphenylphosphine)palladium (5)
Cross-coupling reaction of 4-methoxyphenylboronic acid with 4,
Pd(PPh3)4 catalyst (40%), and base, with purification by column
chromatography (silica gel, CH2Cl2) and recrystallization (EtOH)
gave 5 as yellow crystals; mp 251 °C.
1H NMR (200 MHz, CDCl3): d = 4.95 (s, 2 H), 7.14–7.15 (m, 1 H),
7.29–7.31 (m, 15 H), 7.45–7.48 (m, 2 H), 7.60–7.69 (m, 16 H),
7.83–7.87 (m, 2 H), 8.33–8.34 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.7, 112.0, 121.5, 127.7, 127.8,
127.9, 128.0, 128.1, 129.0, 129.1, 129.4, 129.8, 129.9, 130.3, 130.7,
133.9, 134.4, 134.5, 134.6, 134.7, 138.2, 138.2, 139.6, 139.7, 139.7,
139.8, 145.1, 145.2, 145.3, 156.7, 158.6, 158.7, 158.8.
Method 3 (Table 3): A soln of 4 (250 mg, 0.5 mmol), boronic acid
(1.4 mmol), and Pd(OAc)2 (0.025 mmol) in 1,4-dioxane (20 mL)
was stirred at r.t. for 30 min. Then, 1 M Na2CO3 (3 mL, 3 mmol)
was added to the mixture. This soln was irradiated by microwaves
(300 W) at 100 °C until disappearance of the starting material
(TLC). After cooling, the solvent was evaporated and the residue
dissolved in EtOAc. The organic layer was washed with H2O (1 ×)
and brine (2 ×), dried (Na2SO4), and concentrated under vacuum.
Flash chromatography (silica gel, CHCl3–EtOAc, CHCl3–Et2O, or
EtOAc, 95:5 or 9:1) provided, after recrystallization with an appro-
priate solvent, the desired compound.
Crystal Data for 5: C50H39Br2N3O4P2PdS, M = 1106.10, pale yel-
low prisms, crystal dimensions 0.7 × 0.25 × 0.15 mm. Monoclinic,
space group P21/c (T = 293 K) with a = 19.6557(2) Å,
b = 11.7184(2) Å, c = 22.2449(3) Å, a = 90.00°, b = 111.1486(6)°,
g = 90.00°, V = 4778.65(11) Å3, Z = 4, m = 2.184 mm–1,
F(000) = 2156, index ranges –27 £ h £ 25, 0 £ k £ 15, 0 £ l £ 31. The
q range = 2.56–30.00°, 563 variables and 0 restraints, were refined
for 8002 independent reflections with I ≥ 2sI to R = 0.0453,
wR2 = 0.1128, GoF = 0.869.
Method 4 (Table 4): A soln of 3 or 4 (250 mg, 0.5 mmol), boronic
acid (1.4 mmol), and Pd(PPh3)4 (0.025 mmol) in 1,4-dioxane (20
mL) was stirred at r.t. for 30 min. Then, 1 M Na2CO3 (3 mL, 3
mmol) was added to the mixture. This soln was irradiated by micro-
waves (300 W) at 100 °C until disappearance of the starting material
(TLC). After cooling, the solvent was evaporated and the residue
dissolved in EtOAc. The organic layer was washed with H2O (1 ×)
and brine (2 ×), dried (Na2SO4), and concentrated under vacuum.
Flash chromatography (silica gel, CHCl3–EtOAc, CHCl3–Et2O, or
EtOAc, 95:5 or 9:1) provided, after recrystallization with an appro-
priate solvent, the desired compound.
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132
R. Szabo et al.
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3-Nitro-6,8-diphenyl-2-(tosylmethyl)imidazo[1,2-a]pyridine
(7a)
131.4, 132.0, 132.0, 136.5, 139.8, 142.3, 145.0, 160.9, 161.0, 165.9,
166.0.
Cross-coupling reaction of phenylboronic acid followed by purifi-
cation by column chromatography (silica gel, CHCl3–Et2O, 9:1)
and recrystallization (i-PrOH) gave 7a as a yellow powder; mp 190
°C.
MS (ESI+): m/z = 520 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C27H20F2N3O4S: 520.1137; found:
520.1131.
1H NMR (200 MHz, CDCl3): d = 2.48 (s, 3 H), 5.21 (s, 2 H), 7.32–
7.36 (m, 2 H), 7.44–7.61 (m, 6 H), 7.66–7.71 (m, 2 H), 7.75–7.79
(m, 4 H), 7.97 (d, J = 1.7 Hz, 1 H), 9.61 (d, J = 1.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 56.8, 123.7, 127.4, 128.7,
128.7, 129.1, 129.4, 129.5, 129.7, 129.8, 131.1, 132.0, 134.1, 136.0,
136.5, 139.9, 142.59, 144.9.
3-Nitro-2-(tosylmethyl)-6,8-bis[3-(trifluoromethyl)phenyl]imi-
dazo[1,2-a]pyridine (7e)
Cross-coupling reaction of 3-(trifluoromethyl)phenylboronic acid
followed by purification by column chromatography (silica gel,
CHCl3–Et2O, 9:1) and recrystallization (i-PrOH) gave 7e as shiny
green plates; mp 213 °C.
MS (ESI+): m/z = 484 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C27H22N3O4S: 484.1325; found:
1H NMR (200 MHz, CDCl3): d = 2.44 (s, 3 H), 5.19 (s, 2 H), 7.29–
7.33 (m, 2 H), 7.58–7.90 (m, 8 H), 7.95 (d, J = 1.7 Hz, 1 H), 8.05–
8.07 (m, 2 H), 9.66 (d, J = 1.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 56.9, 123.7, 123.8, 124.3,
124.6, 125.9, 126.2, 128.5, 129.2, 129.5, 129.8, 130.1, 130.2, 130.8,
130.9, 132.1, 132.1, 133.0, 134.7, 136.5, 136.7, 140.2, 142.3, 145.1.
484.1322.
3-Nitro-6,8-di-2-tolyl-2-(tosylmethyl)imidazo[1,2-a]pyridine
(7b)
Cross-coupling reaction of 2-tolylboronic acid followed by purifi-
cation by column chromatography (silica gel, CHCl3–Et2O, 9:1)
and recrystallization (i-PrOH) gave 7b as a yellow powder; mp 214
°C.
1H NMR (200 MHz, CDCl3): d = 2.24 (s, 3 H), 2.37 (s, 3 H), 2.45
(s, 3 H), 5.16 (s, 2 H), 7.27–7.44 (m, 10 H), 7.56 (d, J = 1.5 Hz, 1
H), 7.74 (s, 1 H), 7.78 (s, 1 H), 9.41 (d, J = 1.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.4, 20.5, 21.7, 56.9, 125.6,
125.9, 126.5, 128.5, 129.1, 129.2, 129.7, 130.1, 130.4, 130.7, 131.0,
131.5, 131.9, 133.6, 134.1, 135.8, 135.9, 136.7, 136.8, 140.0, 142.7,
144.9.
Anal. Calcd for C29H19F6N3O4S: C, 56.22; H, 3.09; N, 6.78; S, 5.18.
Found: C, 55.77; H, 3.33; N, 6.73; S, 4.97.
6,8-Dinaphthalen-2-yl-3-nitro-2-(tosylmethyl)imidazo[1,2-
a]pyridine (7f)
Cross-coupling reaction of naphthalen-2-ylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–Et2O,
95:5) and recrystallization (i-PrOH) gave 7f as a yellow powder; mp
122 °C.
1H NMR (200 MHz, CDCl3): d = 2.40 (s, 3 H), 5.21 (s, 2 H), 7.27–
7.31 (m, 2 H), 7.52–7.60 (m, 4 H), 7.76 (m, 2 H), 7.80 (m, 2 H),
7.85–8.04 (m, 6 H), 8.13–8.14 (m, 1 H), 8.18 (d, J = 1.6 Hz, 1 H),
8.35 (s, 1 H), 9.63 (d, J = 1.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.6, 56.9, 123.8, 124.7, 126.5,
126.5, 126.7, 127.0, 127.6, 127.8, 128.2, 128.3, 128.6, 128.6,
129.2, 129.4, 129.7, 130.0, 130.9, 131.3, 131.5, 131.8, 133.1, 133.2,
133.2, 133.4, 133.5, 136.6, 139.9, 142.6, 145.0.
MS (ESI+): m/z = 512 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C29H26N3O4S: 512.1638; found:
512.1637.
6,8-Bis(4-methoxyphenyl)-3-nitro-2-(tosylmethyl)imidazo[1,2-
a]pyridine (7c)
Cross-coupling reaction of 4-methoxyphenylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–Et2O,
95:5) and recrystallization (toluene) gave 7c as a brick red powder;
mp 228 °C.
MS (ESI+): m/z = 584 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C35H26N3O4S: 584.1638; found:
584.1637.
1H NMR (200 MHz, CDCl3): d = 2.48 (s, 3 H), 3.89 (s, 3 H), 3.89
(s, 3 H), 5.20 (s, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 7.06 (d, J = 8.8 Hz,
2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.72 (d,
J = 6.1 Hz, 2 H), 7.77 (d, J = 5.6 Hz, 2 H), 7.88 (d, J = 1.7 Hz, 1 H),
9.49 (d, J = 1.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 55.4, 55.5, 56.8, 114.2,
114.9, 122.5, 126.5, 128.3, 128.5, 128.6, 128.8, 129.7, 130.6, 130.6,
131.7, 136.5, 139.6, 142.4, 144.8, 160.4, 160.5.
6,8-Dinaphthalen-1-yl-3-nitro-2-(tosylmethyl)imidazo[1,2-
a]pyridine (7g)
Cross-coupling reaction of naphthalen-1-ylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–Et2O,
9:1) and recrystallization (i-PrOH) gave 7g as a pale green powder;
mp 157 °C.
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 3 H), 5.15 (s, 2 H), 7.14
(m, 2 H), 7.59–7.98 (m, 17 H), 9.67 (s, 1 H).
Anal. Calcd for C29H25N3O6S: C, 64.08; H, 4.64; N, 7.73; S, 5.90.
Found: C, 64.40; H, 4.77; N, 7.62; S, 5.73.
13C NMR (50 MHz, CDCl3): d = 21.6, 25.4, 56.9, 124.7, 125.0,
125.2, 125.4, 126.2, 126.4, 126.5, 126.8, 127.2, 128.1, 128.5, 128.7,
128.8, 129.6, 129.6, 130.0, 130.8, 131.4, 131.4, 131.5, 131.6, 131.7,
133.9, 135.2, 136.7, 140.3, 144.7.
MS (ESI+): m/z = 584 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C35H26N3O4S: 584.1638; found:
6,8-Bis(4-fluorophenyl)-3-nitro-2-(tosylmethyl)imidazo[1,2-
a]pyridine (7d)
Cross-coupling reaction of 4-fluorophenylboronic acid followed by
purification by column chromatography (silica gel, CHCl3–Et2O,
9:1) and recrystallization (i-PrOH) gave 7d as yellow needles; mp
231 °C.
1H NMR (200 MHz, CDCl3): d = 2.48 (s, 3 H), 5.19 (s, 2 H), 7.12–
7.20 (m, 3 H), 7.29–7.35 (m, 3 H), 7.62–7.68 (m, 2 H), 7.75–7.83
(m, 4 H), 7.88 (s, 1 H), 9.56 (s, 1 H).
584.1634.
3-Nitro-2-(tosylmethyl)-6,8-bis(3,4,5-trimethoxyphenyl)imida-
zo[1,2-a]pyridine (7h)
Cross-coupling reaction of 3,4,5-trimethoxyphenylboronic acid fol-
lowed by purification by column chromatography (silica gel,
CHCl3–Et2O, 9:1) and recrystallization (i-PrOH) gave 7h as an or-
ange powder; mp 107 °C.
13C NMR (50 MHz, CDCl3): d = 21.7, 56.8, 115.6, 116.0, 116.4,
116.8, 123.6, 128.6, 129.2, 129.3, 129.8, 130.0, 130.0, 131.1, 131.2,
Synthesis 2008, No. 1, 127–135 © Thieme Stuttgart · New York

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Microwave-Assisted Double Suzuki–Miyaura Cross-Coupling
133
1H NMR (200 MHz, CDCl3): d = 2.45 (s, 3 H), 3.96–3.98 (m, 18 H),
5.18 (s, 2 H), 6.83 (s, 2 H), 7.27–7.34 (m, 4 H), 7.76 (d, J = 8.1 Hz,
2 H), 7.92 (d, J = 1.5 Hz, 1 H), 9.53 (d, J = 1.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 56.5, 56.5, 56.9, 60.9, 61.0,
105.1, 107.1, 123.4, 128.3, 129.3, 129.4, 129.8, 131.1, 131.8, 132.3,
136.7, 139.2, 139.5, 139.6, 142.7, 145.2, 153.5, 154.1.
MS (ESI+): m/z = 664 ([M + H]+)
HRMS: m/z [M + H]+ calcd for C33H34N3O10S: 664.1959; found:
6,8-Bis(4-fluorophenyl)-3-nitro-2-[(phenylsulfonyl)methyl]imi-
dazo[1,2-a]pyridine (8d)
Cross-coupling reaction of 4-fluorophenylboronic acid followed by
purification by column chromatography (silica gel, CHCl3–EtOAc,
9:1) and recrystallization (i-PrOH) gave 8d as yellow needles; mp
218 °C.
1H NMR (200 MHz, CDCl3): d = 5.21 (s, 2 H), 7.11–7.97 (m, 14 H),
9.55 (d, J = 1.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.7, 56.7, 115.6, 116.0, 116.4,
116.8, 123.5, 125.9, 128.0, 128.2, 128.3, 128.4, 128.5, 129.1, 129.2,
129.3, 129.4, 129.9, 130.0, 130.1, 130.1, 131.1, 131.3, 131.9, 132.0,
133.9, 139.4, 139.6, 142.3, 161.0, 161.0, 165.9, 165.9.
664.1948.
3-Nitro-6,8-diphenyl-2-[(phenylsulfonyl)methyl]imidazo[1,2-
a]pyridine (8a)
Cross-coupling reaction of phenylboronic acid followed by purifi-
cation by column chromatography (silica gel, CHCl3–EtOAc, 95:5)
and recrystallization (i-PrOH) gave 8a as a yellow powder; mp
203–204 °C.
MS (ESI+): m/z = 506 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C26H18F2N3O4S: 506.0980; found:
506.0978.
1H NMR (200 MHz, CDCl3): d = 5.23 (s, 2 H), 7.47–7.58 (m, 8 H),
7.66–7.81 (m, 5 H), 7.89–7.97 (m, 3 H), 9.60 (s, 1 H).
3-Nitro-2-[(phenylsulfonyl)methyl]-6,8-bis[3-(trifluorometh-
yl)phenyl]imidazo[1,2-a]pyridine (8e)
Cross-coupling reaction of 3-(trifluoromethyl)phenylboronic acid
followed by purification by column chromatography (silica gel,
CHCl3–EtOAc, 95:5) and recrystallization (i-PrOH) gave 8e as
shiny green plates; mp 194 °C.
1H NMR (200 MHz, CDCl3): d = 5.12 (s, 2 H), 7.49–7.58 (m, 3 H),
7.63 (m, 1 H), 7.67 (s, 1 H), 7.71–7.81 (m, 3 H), 7.86 (m, 2 H), 7.90
(s, 1 H), 7.95 (d, J = 1.5 Hz, 1 H), 8.00–8.04 (m, 2 H), 9.65 (d,
J = 1.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.8, 123.4, 123.7, 124.6, 128.4,
129.1, 129.2, 129.5, 130.1, 130.2, 130.7, 130.8, 130.9, 131.4, 132.1,
132.9, 133.0, 134.0, 134.6, 136.6, 139.3, 140.0, 142.3.
MS (ESI+): m/z = 606 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C28H18F6N3O4S: 606.0916; found:
13C NMR (50 MHz, CDCl3): d = 56.8, 123.6, 127.4, 128.6, 128.7,
129.0, 129.1, 129.3, 129.4, 129.8, 131.1, 132.0, 133.8, 134.0, 135.9,
139.4, 139.7, 142.5.
MS (ESI+): m/z = 470 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C26H20N3O4S: 470.1169; found:
470.1161.
3-Nitro-2-[(phenylsulfonyl)methyl]-6,8-di-2-tolylimidazo[1,2-
a]pyridine (8b)
Cross-coupling reaction of 2-tolylboronic acid followed by purifi-
cation by column chromatography (silica gel, CHCl3–EtOAc, 95:5)
and recrystallization (PrOH) gave 8b as a golden powder; mp 153
°C.
1H NMR (200 MHz, CDCl3): d = 2.24 (s, 3 H), 2.37 (s, 3 H), 5.18
(s, 2 H), 7.23–7.69 (m, 12 H), 7.87–7.93 (m, 2 H), 9.41 (d, J = 1.6
Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.4, 20.5, 56.8, 125.5, 125.9,
126.5, 128.5, 129.1, 129.2, 130.0, 130.3, 130.7, 131.0, 131.5, 131.9,
133.6, 133.9, 134.0, 135.8, 135.9, 136.8, 139.6, 139.8, 142.7.
606.0915.
6,8-Dinaphthalen-2-yl-3-nitro-2-[(phenylsulfonyl)methyl]imi-
dazo[1,2-a]pyridine (8f)
Cross-coupling reaction of naphthalen-2-ylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–
EtOAc, 95:5) and recrystallization (i-PrOH) gave 8f as a yellow
powder; mp 151 °C.
1H NMR (200 MHz, CDCl3): d = 5.25 (s, 2 H), 7.49–7.70 (m, 7 H),
7.78–8.06 (m, 10 H), 8.17 (s, 1 H), 8.21 (d, J = 1.4 Hz, 1 H), 8.36
(s, 1 H), 9.72 (d, J = 1.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.9, 123.9, 124.7, 126.5, 126.6,
126.8, 127.1, 127.1, 127.7, 127.8, 128.3, 128.3, 128.6, 129.2, 129.2,
129.5, 130.1, 131.2, 131.5, 132.0, 133.1, 133.3, 133.3, 133.5, 133.9,
139.5, 139.8, 142.7.
MS (ESI+): m/z = 498 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C28H24N3O4S: 498.1482; found:
498.1483.
6,8-Bis(4-methoxyphenyl)-3-nitro-2-[(phenylsulfonyl)meth-
yl]imidazo[1,2-a]pyridine (8c)
Cross-coupling reaction of 4-methoxyphenylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–
EtOAc, 95:5) and recrystallization (i-PrOH) gave 8c as a brick red
powder; mp 126 °C.
MS (ESI+): m/z = 570 ([M + H]+).
1H NMR (200 MHz, CDCl3): d = 3.89 (s, 6 H), 5.22 (s, 2 H), 6.98
(d, J = 8.7 Hz, 2 H), 7.06 (d, J = 8.7 Hz, 2 H), 7.52–7.62 (m, 4 H),
7.67–7.75 (m, 3 H), 7.88–7.92 (m, 3 H), 9.50 (d, J = 1.7 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C34H24N3O4S: 570.1482; found:
570.1483.
6,8-Dinaphthalen-1-yl-3-nitro-2-[(phenylsulfonyl)methyl]imi-
dazo[1,2-a]pyridine (8g)
Cross-coupling reaction of naphthalen-1-ylboronic acid followed
by purification by column chromatography (silica gel, CHCl3–
EtOAc, 95:5) and recrystallization (i-PrOH) gave 8g as a pale green
powder; mp 174 °C.
13C NMR (50 MHz, CDCl3): d = 55.4, 55.5, 56.8, 114.2, 114.9,
122.5, 126.5, 128.3, 128.5, 128.6, 128.9, 129.1, 130.6, 131.8, 133.8,
139.4, 139.5, 142.5, 160.5, 160.6.
MS (ESI+): m/z = 530 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C28H24N3O6S: 530.1380; found:
1H NMR (200 MHz, CDCl3): d = 5.18 (s, 2 H), 7.32–8.02 (m, 20 H),
9.67 (d, J = 1.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.8, 124.7, 125.0, 125.2, 125.4,
126.2, 126.4, 126.5, 126.8, 127.2, 128.1, 128.5, 128.7, 128.8, 128.9,
129.6, 129.7, 130.1, 130.9, 131.4, 131.5, 131.7, 133.7, 133.9, 133.9,
135.2, 139.6, 140.1, 143.6.
530.1378.
Anal. Calcd for C28H23N3O6S: C, 63.51; H, 4.38; N, 7.93; S, 6.05.
Found: C, 62.96; H, 4.63; N, 7.42; S, 5.80.
Synthesis 2008, No. 1, 127–135 © Thieme Stuttgart · New York

134
R. Szabo et al.
PAPER
FR 2599368, 1987; Chem. Abstr. 1987, 109, 170422.
MS (ESI+): m/z = 570 ([M + H]+).
(f) George, P.; Giron, C. EP 172096, 1986; Chem. Abstr.
1986, 105, 97458. (g) Kaplan, J.-P.; George, P. EP 92458,
1983; Chem. Abstr. 1983, 100, 103345. (h) Kaplan, J.-P.;
George, P.; Bernardon, J. M. EP 92459, 1983; Chem. Abstr.
1983, 100, 139102.
HRMS: m/z [M + H]+ calcd for C34H24N3O4S: 570.1482; found:
570.1481.
3-Nitro-2-[(phenylsulfonyl)methyl]-6,8-bis(3,4,5-trimethoxy-
phenyl)imidazo[1,2-a]pyridine (8h)
Cross-coupling reaction of 3,4,5-trimethoxyphenylboronic acid fol-
lowed by purification by column chromatography (silica gel,
CHCl3–EtOAc, 9:1) and recrystallization (i-PrOH) gave 8h as an
orange powder; mp 103 °C.
1H NMR (200 MHz, CDCl3): d = 3.93–3.97 (m, 18 H), 5.19 (s, 2 H),
6.81 (s, 2 H), 7.24 (s, 2 H), 7.49–7.69 (m, 3 H), 7.91–7.95 (m, 3 H),
9.51 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.5, 56.9, 60.9, 61.0, 105.2,
107.2, 123.4, 128.3, 129.2, 129.3, 129.5, 131.1, 131.8, 132.4, 134.1,
139.3, 139.4, 139.5, 139.6, 142.7, 153.5, 154.1.
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2006, 45, 1282.
(9) Crozet, M. D.; Castera, C.; Kaafarani, M.; Crozet, M. P.;
Vanelle, P. ARKIVOC 2003, (x), 273.
(10) (a) Enguehard, C.; Renou, J.-L.; Collot, V.; Hervet, M.;
Rault, S.; Gueiffier, A. J. Org. Chem. 2000, 65, 6572.
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Anal. Calcd for : C, 59.16; H, 4.81; N, 6.47; S, 4.94. Found: C,
58.63; H, 4.88; N, 6.37; S, 4.76.
MS (ESI+): m/z = 650 ([M + H]+).
HRMS: m/z [M + H]+ calcd for C32H32N3O10S: 650.1802; found:
650.1789.
(11) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
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Acknowledgement
This work is supported by the CNRS and the Universities of Aix-
Marseille. The authors thank V. Rémusat, M. Noailly and G.
Giuglio-Tonolo for recording the NMR spectra, V. Monnier for re-
cording mass spectra, M. Giorgi for the X-ray crystal structure de-
terminations and G. Herbette for his help.
(13) Castera, C.; Crozet, M. D.; Crozet, M. P.; Vanelle, P.
Heterocycles 2005, 65, 337.
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(19) Kashin, A. N.; Mitin, A. V.; Mitin, A. V.; Beletskaya, I. P.;
Wife, R. Tetrahedron Lett. 2002, 43, 2539.
(20) Detailed X-ray crystallographic data are available from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2, 1EZ, UK (for compound 4, CCDC
659668; 5, CCDC 659669; 6, CCDC 659670). These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synthesis 2008, No. 1, 127–135 © Thieme Stuttgart · New York