Efficient microwave-assisted palladium-catalyzed suzuki-miyaura cross-coupling reactions in 5-nitroimidazole series

Article abstract of DOI:10.1055/s-0029-1216905

A new simple, rapid and high yielding synthesis (mean yield = 83%) of various 4-aryl, 4-heteroaryl, and 4-styryl-1,2-dimethyl-5-nitro-1H-imidazoles by palladium-catalyzed Suzuki-Miyaura cross-coupling reactions using microwave irradiation is described.

Full text of DOI:10.1055/s-0029-1216905

3150
PAPER
Efficient Microwave-Assisted Palladium-Catalyzed Suzuki–Miyaura
Cross-Coupling Reactions in 5-Nitroimidazole Series
P
alladium-Catalyze
d
C
a
r
oss-Coupl
x
ing Reaction
i
s
of 5-
m
N
itroimidazoles e D. Crozet, Laura Zink, Vincent Remusat, Christophe Curti, Patrice Vanelle*
Laboratoire de Pharmaco-Chimie Radicalaire, LPCR, Faculté de Pharmacie, Universités d’Aix-Marseille I, II, III – CNRS, UMR 6264:
Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Fax +33(4)91794677; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Received 6 May 2009; revised 15 May 2009
Suzuki–Miyaura cross-coupling reactions in 2-haloimida-
Abstract: A new simple, rapid and high yielding synthesis (mean
zole,9 2,4-dihaloimidazole9a–9c,10 and 4-haloimidazole10,11
series are reported in the literature. Moreover, no example
of Suzuki–Miyaura reaction performed on a nitrated imi-
dazole ring was described to our knowledge.
yield = 83%) of various 4-aryl, 4-heteroaryl, and 4-styryl-1,2-di-
methyl-5-nitro-1H-imidazoles by palladium-catalyzed Suzuki–
Miyaura cross-coupling reactions using microwave irradiation is
described.
Key words: cross-coupling, 5-nitroimidazoles, palladium, Suzuki
reaction, arylations
We have recently reported an efficient microwave-assist-
ed Suzuki cross-coupling reaction of imidazo[1,2-a]py-
ridines.12 The method, which was tested to carry out cross-
coupling reaction, used 10 mol% Pd(PPh3)4 as a catalyst,
5 equivalents of Na2CO3 as the base, 1.3 equivalents of an
arylboronic derivative, and 1 equivalent of tetrabutylam-
monium bromide (TBAB) in water, heating being provid-
ed with microwave irradiation.
The 5-nitroimidazole scaffold is well known for exhibit-
ing major anti-infectious activities.1 Several 5-nitroimida-
zole-containing active principles are commonly used in
medecine such as metronidazole, secnidazole, and ornida-
zole. These chemotherapeutic agents inhibit the growth of
both anaerobic bacteria and some anaerobic protozoa.2
Nowadays, the most clinically used drug-compound for
the treatment of both infections caused by protozoa such
as Trichomonas vaginalis, Entamoeba histolytica, Giar-
dia intestinalis, and infections induced by anaerobic bac-
teria is metronidazole. However, the 5-nitroimidazoles
have been found to possess a high mutagenic activity in
prokaryotic microorganisms. A nitroimidazole possessing
good pharmacological activities with no mutagenicity3
would be of great interest, not only from a safety point of
view, but would also provide a basis for further investiga-
tions on the mechanism involved in their mutagenicity.
Moreover, emergence of metronidazole-resistant Tri-
chomonas vaginalis results in decreasing the success of
current therapies.4,5 These refractory cases are usually
treated with higher doses of metronidazole, which lead to
an increase in the occurrence of side effects.5,6 Thus, alter-
native curative therapies are needed.
In continuation of our studies, we focused our research on
the interest of microwave heating in Suzuki–Miyaura
cross-coupling reaction. The required starting material for
the Suzuki cross-coupling reaction is the 4-bromo-1,2-
dimethyl-5-nitro-1H-imidazole (3). Unfortunately, it is
impossible to obtain the compound 3 in good yield, direct-
ly from the nonhalogenated immediate precursor (i.e.,
dimetridazole or 1,2-dimethyl-5-nitro-1H-imidazole).
Indeed, as observed by Sunjic et al.13 the direct bromina-
tion reaction of 1-alkyl-2-methyl-5-nitro-1H-imidazole is
not possible because of the poor reactivity of the 4-posi-
tion toward electrophilic substitution reactions. We decid-
ed to brominate the 2-methyl-4(5)-nitro-1H-imidazole (1)
as proposed by Bhujanga Rao et al.14 with elemental bro-
mine (1.1 equiv) in DMF (Scheme 1). Then, the 4(5)-bro-
mo-2-methyl-5(4)-nitro-1H-imidazole was methylated by
O2N
Br
N
In continuation of our research program on the reactivity
of 5-nitroimidazoles and in order to prepare new safe 5-ni-
troimidazoles as effective drugs against metronidazole-
resistant Trichomonas vaginalis and Giardia intestina-
lis,1b,e,7 we were interested in the preparation of new 5-ni-
troimidazoles bearing an aryl, heteroaryl, or styryl group
in the 4-position.
N
Br2
N
O2N
Me
Me
Br
N
H
O2N
Me
Na2CO3
DMF, 70 °C
2 h
N
N
H
H
1
2 93%
Br
O2N
The Suzuki–Miyaura reaction has proved to be extremely
versatile and has found extensive use in natural products
and heterocyclic synthesis.8 Only few examples of
N
N
DMS
+
O2N
Me
N
Me
Me
Br
N
DMF, 100 °C
2.5 h
Me
3 24%
SYNTHESIS 2009, No. 18, pp 3150–3156
x
x.
x
x
.
2
0
0
9
4 23%
Advanced online publication: 14.07.2009
DOI: 10.1055/s-0029-1216905; Art ID: Z08809SS
Scheme 1 Preparation of starting material 3
© Georg Thieme Verlag Stuttgart · New York

PAPER
Palladium-Catalyzed Cross-Coupling Reactions of 5-Nitroimidazoles
3151
Table 1 Microwave-Mediated Suzuki–Miyaura Coupling Reac-
tions of Imidazole 3 with Aryl, Heteroaryl, or Styrylboronic Acids
Using Pd(PPh3)4
dimethyl sulfate (DMS) following the procedure pro-
posed by Sunjic et al.13 (Scheme 1).
a
First attempt of cross-coupling reaction was tested with
experimental conditions cited above. Unfortunately, these
previous conditions did not work on 4-bromo-1,2-dimeth-
yl-5-nitro-1H-imidazole. Different cross-coupling reac-
tion conditions were therefore examined, in order to study
their influence on the reactivity.
Br
R
RB(OH)2
Pd(PPh3)4 (3.4 mol%)
N
N
Me
Me
O2N
O2N
Na2CO3
MW 150 W
DME–EtOH
N
N
Me
Me
3
5–22
All reaction trials were conducted with 4-bromo-1,2-di-
methyl-5-nitro-1H-imidazole (3) and phenylboronic acid,
in a synthesis multimode microwave oven (ETHOS Synth
Lab station) or by classical heating method.
En- Boronic acid
try
Product
TimeYield
(h) (%)
OH
Six reaction parameters were tested (equivalent of arylbo-
ronic acid, solvent, base, catalyst, phase transfer agent,
heating method). Finally, the best microwave-assisted ex-
perimental conditions were defined, permitting the syn-
thesis of 1,2-dimethyl-5-nitro-4-phenyl-1H-imidazole (5)
in 93% yield in one hour. To prepare compound 5, the 4-
bromo-1,2-dimethyl-5-nitro-1H-imidazole (3) and 0.034
equivalent of Pd(PPh3)4 were dissolved in 1,2-dimethoxy-
ethane (DME) and the mixture stirred for one hour. A so-
lution of phenylboronic acid in ethanol and 3 equivalents
of Na2CO3 were added. Finally, the mixture was irradiated
under microwave (150 W).15 To evaluate the scope and
the limitations of this procedure, we performed coupling
reactions with 18 variously substituted boronic acid deriv-
atives. The results show that this coupling reaction is ap-
plicable to all aryl, heteroaryl, and styryl boronic acids
used in our study (Table 1).
B
1
5
6
1
1
93
93
N
OH
O2N
N
F
OH
B
2
3
OH
N
F
O2N
N
Cl
OH
B
7
1
71
OH
N
Cl
O2N
N
These experimental conditions allowed us to synthesize
compounds 20–22, by reaction of 3 with (E)-styrylboronic
acid, (E)-4-(trifluoromethyl)styrylboronic acid, and (E)-
4-methylstyrylboronic acid, in good to excellent yields
(Table 1, entries 16–18), which constitutes an interesting
alternative to the Heck reaction. Indeed, there is only one
described example, which deals with the Heck reaction on
3.16 The reaction was 100% stereoselective. X-ray struc-
ture analysis of a crystal of compounds 20 and 21 con-
firmed the presence of E-isomer exclusively (Figures 1
and 2).
OH
B
F3C
OH
4
5
8
9
1
3
68
80
N
O2N
N
CF3
OH
B
O2N
OH
N
O2N
N
NO2
CF3
OH
F3C
B
F3C
OH
6
7
10
2
1
98
89
N
O2N
CF3
N
MeO
OH
B
11
OH
N
Figure 1 Ortep structure of (E)-1,2-dimethyl-5-nitro-4-styryl-1H-
imidazole (20)
MeO
O2N
N
Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York

3152
M. D. Crozet et al.
PAPER
Table 1 Microwave-Mediated Suzuki–Miyaura Coupling Reac-
tions of Imidazole 3 with Aryl, Heteroaryl, or Styrylboronic Acids
Using Pd(PPh3)4a (continued)
Table 1 Microwave-Mediated Suzuki–Miyaura Coupling Reac-
tions of Imidazole 3 with Aryl, Heteroaryl, or Styrylboronic Acids
Using Pd(PPh3)4a (continued)
Br
R
Br
R
RB(OH)2
Pd(PPh3)4 (3.4 mol%)
RB(OH)2
Pd(PPh3)4 (3.4 mol%)
N
N
N
N
Me
Me
Me
Me
O2N
O2N
O2N
O2N
Na2CO3
MW 150 W
DME–EtOH
Na2CO3
MW 150 W
DME–EtOH
N
N
N
N
Me
Me
Me
Me
3
5–22
3
5–22
En- Boronic acid
try
Product
TimeYield
(h) (%)
En- Boronic acid
try
Product
TimeYield
(h) (%)
OMe
MeO
OH
B
O
OH
MeO
14
15
18
2
2
87
60
B
N
MeO
OH
OH
O
8
12
1
91
OH
O2N
N
N
MeO
OMe
O2N
N
S
OH
19
20
N
B
S
OH
OH
O2N
N
B
9
13
14
1
1
87
95
OH
N
HO
O2N
N
OH
B
16
1
63
OH
N
OH
O2N
N
B
10
N
OH
O2N
N
F3C
OH
B
17
21
1
95
OH
OH
11
15
1
78
F3C
N
B
OH
O2N
N
N
O2N
N
OH
B
OH
18
22
1
91
OH
B
12
13
16
17
2
2
86
66
N
OH
N
O2N
N
O2N
N
a Conditions: Pd(PPh3)4 (3.4 mol%), 3 (1 equiv), arylboronic acid
(1.03 equiv) or heteroarylboronic acid (1.03 equiv) or (E)-styrylbo-
ronic acid (1.03 equiv), Na2CO3 (3 equiv), DME–EtOH (6 mL:2 mL).
An initial microwave irradiation of 150 W was used, the temperature
being ramped from r.t. to 75 °C, then held for the time indicated.
HO
OH
B
N
O2N
N
Furthermore, the X-ray structure analysis reveals a static
disorder at the level of the CF3 substituent. The fluorine
atoms were refined on several sites with partial occupan-
cies (Figure 2).
Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Cross-Coupling Reactions of 5-Nitroimidazoles
3153
with H2O (3 × 30 mL) and brine (3 × 30 mL), dried (Na2SO4), and
concentrated under vacuum. Purification of the residue by column
chromatography on silica gel and recrystallization afforded the cor-
responding 4-aryl-1,2-dimethyl-5-nitro-1H-imidazoles 5–17, or 4-
heteroaryl-1,2-dimethyl-5-nitro-1H-imidazoles 18,19, or 1,2-di-
methyl-5-nitro-4-styryl-1H-imidazoles 20–22.
1,2-Dimethyl-5-nitro-4-phenyl-1H-imidazole (5)
Compound 5 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–PE–EtOAc, 50:25:25) and re-
crystallization from cyclohexane; yield: 93%; yellow powder; mp
93 °C.
1H NMR (200 MHz, CDCl3): d = 2.59 (s, 3 H, CH3), 3.94 (s, 3 H,
Figure 2 Ortep structure of (E)-1,2-dimethyl-5-nitro-4-[4-(trifluo-
romethyl)styryl]-1H-imidazole (21)
CH3), 7.43–7.46 (m, 3 H, 3 CH), 7.74–7.79 (m, 2 H, 2 CH).
13C NMR (50 MHz, CDCl3): d = 13.9, 34.2, 128.2, 129.6, 129.7,
130.9, 142.7, 148.0.
In summary, we have developed a general operating pro-
cedure for the rapid and efficient synthesis of new 4-aryl-,
4-heteroaryl-, or 4-styryl-dimetridazole derivatives from
the microwave-assisted palladium-mediated coupling re-
actions of aryl, heteroaryl, and styryl boronic acids with 4-
bromo-1,2-dimethyl-5-nitro-1H-imidazole (3). Finally, a
wide array of electron-withdrawing and electron-donating
Anal. Calcd for C11H11N3O5: C, 60.82; H, 5.10; N, 19.34. Found: C,
61.09; H, 5.16; N, 19.37.
4-(4-Fluorophenyl)-1,2-dimethyl-5-nitro-1H-imidazole (6)
Compound 6 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–EtOAc, 8:2) and recrystalliza-
tion from butan-2-ol; yield: 93%; yellow powder; mp 161 °C.
groups has shown to be well tolerated under these micro- 1H NMR (200 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.92 (s, 3 H,
CH3), 7.07–7.16 (m, 2 H, 2 CH), 7.74–7.81 (m, 2 H, 2 CH).
wave-assisted conditions. The extension of this approach
to other palladium-catalyzed coupling reactions involving
other bioactive compounds is in progress in our laborato-
ry.
13C NMR (50 MHz, CDCl3): d = 14.5, 34.5, 115.2 (d, J = 22.0 Hz),
127.6 (d, J = 3.3 Hz), 131.8 (d, J = 8.4 Hz), 142.5, 148.3, 163.6 (d,
J = 249.9 Hz).
Anal. Calcd for C11H10FN3O2: C, 56.17; H, 4.29; N, 17.86. Found:
C, 56.20; H, 4.42; N, 18.10.
Microwave assisted reactions were done in a multimode microwave
oven ETHOS Synth Lab Station (Ethos start, Milestone Inc.). Melt-
ing points were determined with a B-540 Büchi melting point appa-
4-(4-Chlorophenyl)-1,2-dimethyl-5-nitro-1H-imidazole (7)
Compound 7 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–PE–EtOAc, 50:25:25) and re-
crystallization from i-PrOH; yield: 71%; pale orange powder; mp
151 °C (Lit.15 mp 145–147 °C).
1H NMR (200 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.91 (s, 3 H,
CH3), 7.40 (d, J = 8.7 Hz, 2 H, 2 CH), 7.72 (d, J = 8.7 Hz, 2 H, 2
CH).
1
ratus. 200 MHz H NMR and 50 MHz 13C NMR spectra were
recorded on a Bruker ARX 200 spectrometer in CDCl3 or DMSO-
1
d6 solution at the Faculté de Pharmacie de Marseille. H and 13C
NMR chemical shifts (d) are reported in ppm with respect to CHCl3
[7.26 ppm (1H) and 76.9 ppm (13C)]. Elemental analyses and X-ray
crystal structure analyses were carried out at the Spectropole,
Faculté des Sciences et Techniques de Saint-Jérôme. Silica gel 60
(Merck, particle size 0.063–0.200 mm, 70–230 mesh ASTM) was
used for column chromatography. TLC analyses were performed on
5 cm × 10 cm aluminum plates coated with silica gel 60F-254
(Merck) in an appropriate eluting solvent.
13C NMR (50 MHz, CDCl3): d = 14.1, 34.2, 128.4, 130.0, 130.9,
135.6, 142.0, 148.31.
Anal. Calcd for C11H10ClN3O2: C, 52.50; H, 4.01; N, 16.70. Found:
C, 52.82; H, 4.15; N, 16.96.
Crystal-Structure Analysis
1,2-Dimethyl-5-nitro-4-[3-(trifluoromethyl)phenyl]-1H-imida-
zole (8)
Compound 8 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–PE–EtOAc, 50:25:25) and re-
crystallization from cyclohexane; yield: 68%; white cream powder;
mp 78 °C.
1H NMR (200 MHz, CDCl3): d = 2.56 (s, 3 H, CH3), 3.95 (s, 3 H,
CH3), 7.52–7.70 (m, 2 H, 2 CH), 7.93–8.03 (m, 2 H, 2 CH).
13C NMR (50 MHz, CDCl3): d = 13.9, 34.0, 123.9 (q, J = 272.6 Hz),
125.8 (q, J = 3.7 Hz), 126.4 (q, J = 4.0 Hz), 128.4, 130.4 (q,
J = 32.6 Hz), 132.7, 132.8, 134.8, 141.6, 148.5.
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. The compounds 20 and 21 were
crystallized by slow evaporation of an i-PrOH solution to provide
desired single crystals.
Compounds 5–22 via Suzuki Cross-Coupling Reactions; Gener-
al Procedure
In a 250 mL two-necked flask, 4-bromo-1,2-dimethyl-5-nitro-1H-
imidazole (3; 0.91 mmol, 1 equiv) and Pd(PPh3)4 (0.031 mmol,
0.034 equiv) were dissolved in DME (6 mL), and the solution was
stirred under N2 for 1 h. A solution of the corresponding arylboronic
acid or styrylboronic acid (1.03 equiv) in absolute EtOH (2 mL) and
aq 1 M Na2CO3 (6 mL) was added to the flask. The reaction mixture
was heated in a microwave oven and irradiated with 150 W until the
disappearance of the starting material as monitored by TLC. Sol-
vents were removed under reduced pressure and the crude residue
was dissolved in CHCl3 (50 mL). The organic layer was washed
Anal. Calcd for C12H10F3N3O2: C, 50.53; H, 3.53; N, 14.73. Found:
C, 50.24; H, 3.74; N, 14.66.
1,2-Dimethyl-5-nitro-4-(3-nitrophenyl)-1H-imidazole (9)
Compound 9 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and recrystallization from i-
PrOH; yield: 80%; yellow powder; mp 159 °C.
Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York

3154
M. D. Crozet et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 2.56 (s, 3 H, CH3), 3.96 (s, 3 H,
CH3), 7.58–7.66 (m, 1 H, CH), 8.08–8.14 (m, 1 H, CH), 8.25–8.31
(m, 1 H, CH), 8.65–8.68 (m, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 14.1, 34.4, 124.1, 124.8, 129.0,
133.3, 135.5, 140.5, 147.4, 148.0, 148.6.
was washed with Et2O (25 mL); yield: 95%; white powder; mp
74 °C.
1H NMR (200 MHz, CDCl3): d = 2.20 (s, 3 H, CH3), 2.50 (s, 3 H,
CH3), 3.92 (s, 3 H, CH3), 7.20–7.33 (m, 4 H, 4 CH).
13C NMR (50 MHz, CDCl3): d = 13.8, 19.3, 33.7, 125.1, 128.6,
129.2, 129.6, 132.0, 135.2, 136.9, 143.6, 148.2.
Anal. Calcd for C11H10N4O4: C, 50.38; H, 3.84; N, 21.37. Found: C,
50.16; H, 3.85; N, 21.17.
Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C,
62.26; H, 5.77; N, 18.38.
4-[3,5-Bis(trifluoromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-
imidazole (10)
Compound 10 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and recrystallization from cyclo-
hexane; yield: 98%; white powder; mp 88 °C.
1H NMR (200 MHz, CDCl3): d = 2.56 (s, 3 H, CH3), 3.96 (s, 3 H,
CH3), 7.92 (s, 1 H, CH), 8.26 (s, 2 H, CH).
13C NMR (50 MHz, CDCl3): d = 14.1, 34.3, 122.9 (sept, J = 3.7
Hz), 123.2 (q, J = 272.6 Hz), 129.8 (q, J = 2.7 Hz), 137.4 (q,
J = 33.4 Hz), 133.9, 135.2, 140.1, 148.8.
4-(Biphenyl-4-yl)-1,2-dimethyl-5-nitro-1H-imidazole (15)
Compound 15 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CH2Cl2–EtOAc, 9:1) and recrystalliza-
tion from i-PrOH; yield: 78%; yellow powder; mp 144 °C.
1H NMR (200 MHz, CDCl3): d = 2.56 (s, 3 H, CH3), 3.94 (s, 3 H,
CH3), 7.33–7.56 (m, 3 H, 3 CH), 7.62–7.69 (m, 4 H, 4 CH), 7.87 (d,
J = 8.3 Hz, 2 H, 2 CH).
13C NMR (50 MHz, CDCl3): d = 14.2, 34.2, 126.8, 127.2, 127.6,
128.8, 130.0, 130.5, 140.6, 142.2, 143.1, 148.3.
Anal. Calcd for C13H9F6N3O2: C, 44.20; H, 2.57; N, 11.90. Found:
C, 44.38; H, 2.53; N, 11.89.
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C,
69.47; H, 5.21; N, 14.31.
4-(4-Methoxyphenyl)-1,2-dimethyl-5-nitro-1H-imidazole (11)
Compound 11 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–PE–EtOAc, 50:25:25) and re-
crystallization from butan-2-ol; yield: 89%; brown powder; mp
118 °C.
1H NMR (200 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.85 (s, 3 H,
CH3), 3.90 (s, 3 H, CH3), 6.96 (d, J = 8.9 Hz, 2 H, 2 CH), 7.77 (d,
J = 8.9 Hz, 2 H, 2 CH).
1,2-Dimethyl-4-(naphthalen-2-yl)-5-nitro-1H-imidazole (16)
Compound 16 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and recrystallization from i-
PrOH; yellow powder; yield: 86%; mp 141 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.49 (s, 3 H, CH3), 3.86 (s, 3
H, CH3), 7.51–8.02 (m, 6 H, CH), 8.27 (s, 1 H, CH).
13C NMR (50 MHz, DMSO-d6): d = 13.9, 34.3, 126.6, 126.8, 127.2,
127.4, 127.7, 128.6, 128.9, 129.6, 132.5, 133.1, 134.9, 142.0, 149.4.
13C NMR (50 MHz, CDCl3): d = 14.0, 34.2, 55.3, 113.6, 123.6,
131.2, 143.3, 148.2, 160.8.
Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C,
67.49; H, 5.19; N, 15.67.
Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 16.99. Found:
C, 58.40; H, 5.43; N, 17.02.
1,2-Dimethyl-4-(naphthalen-1-yl)-5-nitro-1H-imidazole (17)
Compound 17 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and recrystallization from i-
PrOH; yield: 66%; yellow powder; mp 146 °C.
1H NMR (200 MHz, CDCl3): d = 2.55 (s, 3 H, CH3), 3.97 (s, 3 H,
CH3), 7.39–7.71 (m, 5 H, 5 CH), 7.88–7.96 (m, 2 H, 2 CH).
1,2-Dimethyl-4-(3,4,5-trimethoxyphenyl)-5-nitro-1H-imida-
zole (12)
Compound 12 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–EtOAc, 5:5) and recrystalliza-
tion from cyclohexane; yield: 91%; yellow powder; mp 115 °C.
1H NMR (200 MHz, CDCl3): d = 2.60 (s, 3 H, CH3), 3.90 (s, 3 H,
CH3), 3.91 (s, 6 H, 2 CH3), 3.93 (s, 3 H, CH3), 7.11 (s, 2 H, 2 CH).
13C NMR (50 MHz, CDCl3): d = 14.2, 34.1, 125.0, 125.9, 126.5,
128.1, 128.5, 129.7, 129.9, 131.3, 133.4, 140.0, 142.7, 148.4.
13C NMR (50 MHz, CDCl3): d = 14.1, 34.2, 56.2, 60.9, 107.1,
126.7, 134.8, 139.4, 143.0, 148.1, 152.8.
Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C,
67.24; H, 4.94; N, 15.64.
Anal. Calcd for C14H17N3O5: C, 54.72; H, 5.58; N, 13.67. Found: C,
55.14; H, 5.67; N, 13.66.
4-(Furan-2-yl)-1,2-dimethyl-5-nitro-1H-imidazole (18)
Compound 18 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc–CHCl3, 8:2) and recrystalliza-
tion from cyclohexane; yield: 87%; yellow powder; mp 132 °C.
1H NMR (200 MHz, CDCl3): d = 2.55 (s, 3 H, CH3), 3.93 (s, 3 H,
CH3), 6.57 (dd, J = 3.6, 1.8 Hz, 1 H, CH), 7.59 (d, J = 3.6 Hz, 1 H,
CH), 7.62 (d, J = 1.8 Hz, 1 H, CH).
[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]methanol
(13)
Compound 13 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–MeCN, 6:4) and recrystallization
from toluene; yield: 87%; yellow powder; mp 187 °C.
1H NMR (200 MHz, CDCl3): d = 1.75 (s, 1 H, OH), 2.52 (s, 3 H,
CH3), 3.91 (s, 3 H, CH3), 4.74 (s, 2 H, CH2), 7.42 (d, J = 8.0 Hz, 2
H, 2 CH), 7.75 (d, J = 8.1 Hz, 2 H, 2 CH).
13C NMR (50 MHz, CDCl3): d = 14.2, 34.2, 112.1, 115.7, 134.4,
144.7, 145.6, 149.3.
Anal. Calcd for C9H9N3O3: C, 52.17; H, 4.38; N, 20.28. Found: C,
51.95; H, 5.38; N, 19.95.
13C NMR (50 MHz, CDCl3): d = 14.1, 34.1, 65.0, 126.5, 129.7,
131.1, 142.2, 143.3, 148.3.
1,2-Dimethyl-4-(5-methylthiophen-2-yl)-5-nitro-1H-imidazole
(19)
Compound 19 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–PE–EtOAc, 50:25:25) and re-
crystallization from cyclohexane; yield: 60%; yellow powder; mp
143 °C.
Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 16.99. Found: C,
58.25; H, 5.41; N, 16.10.
1,2-Dimethyl-4-(2-methylphenyl)-5-nitro-1H-imidazole (14)
Compound 14 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and the solid product obtained
Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Cross-Coupling Reactions of 5-Nitroimidazoles
3155
1H NMR (200 MHz, CDCl3): d = 2.50 (s, 3 H, CH3), 2.53 (s, 3 H,
CH3), 3.89 (s, 3 H, CH3), 6.82 (d, J = 3.7 Hz, 1 H, CH), 8.01 (d,
J = 3.7 Hz, 1 H, CH).
13C NMR (50 MHz, CDCl3): d = 14.7, 15.4, 34.8, 126.5, 131.5,
138.3, 145.1, 148.8.
13C NMR (50 MHz, CDCl3): d = 14.1, 21.4, 34.0, 116.5, 127.5,
129.5, 133.5, 137.1, 139.3, 142.4, 149.1.
Anal. Calcd for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C,
65.30 H, 5.94; N, 16.29.
Anal. Calcd for C10H11N3O2S: C, 50.62; H, 4.67; N, 17.71. Found:
C, 50.56; H, 4.72; N, 17.28.
Acknowledgment
This work was supported by the CNRS and the University of Aix-
Marseille. The authors thank Michel Giorgi for the X-ray diffrac-
tion and structure analysis, Rémi Szabo, Kamille Belahreche, and
Walid El-Azab for technical support.
(E)-1,2-Dimethyl-5-nitro-4-styryl-1H-imidazole (20)
Compound 20 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CHCl3–EtOAc, 6:4) and recrystalliza-
tion from i-PrOH; yield: 63%; yellow powder; mp 144 °C (Lit.17 mp
140 °C).
1H NMR (200 MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 3.90 (s, 3 H,
CH3), 7.33–7.45 (m, 3 H, 3 CH), 7.61 (d, J = 8.0 Hz, 2 H, 2 CH),
7.77 (s, 2 H, 2 CH).
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13C NMR (50 MHz, CDCl3): d = 14.1, 34.0, 117.5, 127.5, 128.8,
129.0, 136.3, 137.0, 142.1, 149.1.
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64.60; H, 5.50; N, 17.45.
Crystallographic Data18
M = 243.26, yellow prisms, crystal dimensions, 0.2 × 0.1 × 0.1 mm.
Monoclinic, Space group, P21/c (T = 293 K) with a = 9.6330(2) Å,
b = 9.9793(2) Å, c = 13.0384(3) Å, a = 90.00°, b = 108.2640(10)°,
g = 90.00°, V = 1190.25(4) Å3, Z = 4, m = 0.095 mm–1,
F(000) = 512, index ranges 0 £ h £ 12, 0 £ k £ 13, –17 £ l £ 16. The
q range = 2.23–28.25°, 165 variables and 0 restraints, were refined
for 1962 independent reflections with I ≥ 2 sI to R = 0.0565,
wR2 = 0.1664, GOF = 1.242.
(E)-1,2-Dimethyl-5-nitro-4-[4-(trifluoromethyl)styryl]-1H-imi-
dazole (21)
Compound 21 was isolated after purification by column chromatog-
raphy on silica gel (eluent: EtOAc) and recrystallization from i-
PrOH; yield: 95%; yellow powder; mp 164 °C.
1H NMR (200 MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 3.91 (s, 3 H,
CH3), 7.59–7.88 (m, 6 H, 6 CH).
13C NMR (50 MHz, CDCl3): d = 14.2, 34.0, 120.2, 126.8 (q,
J = 271.9 Hz), 125.7 (q, J = 3.7 Hz), 127.5, 130.3 (q, J = 32.4 Hz),
134.7, 139.7, 139.8, 141.3, 149.2.
Anal. Calcd for C14H12F3N3O2: C, 54.02; H, 3.89; N, 13.50. Found:
C, 54.19; H, 4.18; N, 13.56.
Crystallographic Data18
M = 311.27, colorless prisms, crystal dimensions, 0.25 × 0.2 × 0.15
mm. Triclinic, Space group, P1 (T = 293 K) with a = 6.396 Å,
b = 10.529 Å, c = 11.69 Å, a = 110.83°, b = 93.69°, g = 106.29°,
V = 694.3 Å3, Z = 2, m = 0.129 mm–1, F(000) = 320, index ranges 0
£ h £ 8, –14 £ k £ 13, –15 £ l £ 15. The q range = 1.9–28.73°, 253
variables and 0 restraints, were refined for 2507 independent reflec-
tions with I ≥ 2 sI to R = 0.0583, wR2 = 0.161, GOF = 1.135.
(E)-1,2-Dimethyl-4-(4-methylstyryl)-5-nitro-1H-imidazole (22)
Compound 22 was isolated after purification by column chromatog-
raphy on silica gel (eluent: CH2Cl2–EtOAc, 9:1) and recrystalliza-
tion from i-PrOH; yield: 91%; green powder; mp 203–204 °C.
1H NMR (200 MHz, CDCl3): d = 2.37 (s, 3 H, CH3), 2.51 (s, 3 H,
CH3), 3.89 (s, 3 H, CH3), 7.18 (d, J = 8.1 Hz, 2 H, 2 CH), 7.51 (d,
J = 8.1 Hz, 2 H, 2 CH), 7.73 (s, 2 H, 2 CH).
Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York

3156
M. D. Crozet et al.
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Synthesis 2009, No. 18, 3150–3156 © Thieme Stuttgart · New York