Synthesis of 4-alkynyl-1,2-dimethyl-5-nitro-1 H -imidazoles via microwave-assisted sonogashira cross-coupling reactions

Article abstract of DOI:10.1055/s-0032-1316907

A new, simple, rapid and moderate to high yielding synthesis of various 4-alkynyl-1,2-dimethyl-5-nitro-1H-imidazoles via Sonogashira palladium-catalyzed cross-coupling using microwave irradiation is described.

Full text of DOI:10.1055/s-0032-1316907

PAPER
▌1349
paper
Synthesis of 4-Alkynyl-1,2-dimethyl-5-nitro-1H-imidazoles via Microwave-
Assisted Sonogashira Cross-Coupling Reactions
Microwave-Assisted Sonogashira Cross-Coupling Reactions
Kevin Neildé, Maxime D. Crozet, Thierry Terme, Patrice Vanelle*
Aix-Marseille Université, UMR CNRS 7273: Institut de Chimie Radicalaire, Equipe Pharmaco-Chimie Radicalaire (LPCR),
Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS 30064, 13385 Marseille Cedex 5, France
Fax +33(4)86136822; E-mail: patrice.vanelle@univ-amu.fr
Received: 07.02.2013; Accepted after revision: 20.03.2013
ries of compounds. The 4-alkynylimidazole scaffold can
Abstract: A new, simple, rapid and moderate to high yielding syn-
be found in glutamate receptor antagonist molecules used
thesis of various 4-alkynyl-1,2-dimethyl-5-nitro-1H-imidazoles via
for the treatment of central nervous system diseases
Sonogashira palladium-catalyzed cross-coupling using microwave
irradiation is described.
(Alzheimer’s, Parkinson’s, Huntington’s).9 Moreover, 4-
alkynyl-5-nitroimidazoles are interesting substrates in or-
Key words: nitroimidazole, Sonogashira reaction, palladium,
ganic synthesis. Indeed, as Michael acceptors, they under-
go reactions with nucleophilic species,10 for example,
azides,11 and may represent good candidate substrates, in
particular, for Huisgen cycloaddition. Furthermore, they
might show potential as molecules able to react through
electron transfer reactions (e.g. SRN1),12 or via tetrakis(di-
methylamino)ethylene (TDAE) assisted methodology.13
cross-coupling, microwave irradiation
The 5-nitroimidazole moiety is well known for exhibiting
a wide spectrum of anti-infectious activity.1 Several 5-ni-
troimidazole-containing active principles are commonly
used in medicine such as metronidazole, secnidazole and
ornidazole. These chemotherapeutic agents inhibit the
growth of both anaerobic bacteria and some anaerobic
protozoa.2 Among the nitroimidazole family of drugs,
possibly the most important is metronidazole, which is
used extensively for the treatment of infections caused by
protozoa such as Trichomonas vaginalis, Entamœba his-
tolytica and Giardia intestinalis, and infections induced
by anaerobic bacteria. However, 5-nitroimidazoles have
been found to show high mutagenic activity in prokaryotic
microorganisms. Although a few hypotheses have been
published,3 active research in this area has not yet led to a
comprehensive mechanism for the mutagenic and thera-
peutic activities of these compounds in eukaryotic cells.
Thus, a nitroimidazole possessing good pharmacological
activity with no mutagenicity4 would be of significant in-
terest, not only from a safety point of view, but would also
provide a basis for further investigations of the mode of
action and mechanism of expression of mutagenicity.
Moreover, the emergence of metronidazole-resistant T.
vaginalis has resulted in decreased success of current ther-
apies.5,6 These refractory cases are usually treated with
higher doses of metronidazole, which leads to an increase
in the occurrence of side effects.6,7 Hence, alternative cu-
rative therapies are needed.
The Sonogashira reaction has proved to be extremely
versatile and has found extensive use in natural product14
and heterocycle synthesis.15 Only a few examples of
Sonogashira cross-coupling reactions of 4-bromoimid-
azoles have been reported in the literature.16 Moreover,
only one example of a Sonogashira reaction performed on
a nitrated imidazole ring has been described.9a Unfortu-
nately, these reaction conditions did not allow us to per-
form the Sonogashira cross-coupling between 4-bromo-
1,2-dimethyl-5-nitro-1H-imidazole (3) and propargyl al-
cohol, thus a more general method leading to a straightfor-
ward access to 4-alkynyl-5-nitroimidazoles was
investigated.
The required starting material for the Sonogashira cross-
coupling, 4-bromo-1,2-dimethyl-5-nitro-1H-imidazole
(3), was prepared in 22% overall yield by sequential bro-
mination of 2-methyl-5-nitro-1H-imidazole (1) with ele-
mental bromine, and methylation using dimethyl sulfate
in N,N-dimethylformamide (Scheme 1).17
Br
O2N
N
N
N
Br2
O2N
O2N
Br
N
N
Na2CO3
DMF, 70 °C
2 h
N
H
H
H
1
2 93%
In continuation of our research program centered on the
design and synthesis of novel molecules, we focused our
studies on the synthesis and evaluation of heterocyclic
compounds displaying diverse biological activities.8 We
report herein the preparation of new 5-nitroimidazoles
bearing alkynyl derivatives at the 4-position, in order to
extend the anti-infectious pharmacomodulation in this se-
O2N
Br
N
N
(MeO)2SO2
+
Br
O2N
N
N
DMF, 100 °C
2.5 h
Me
Me
4 23%
3 24%
Scheme 1 Preparation of starting material 3
SYNTHESIS 2013, 45, 1349–1356
Advanced online publication: 15.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316907; Art ID: SS-2013-Z0114-OP
© Georg Thieme Verlag Stuttgart · New York

1350
K. Neildé et al.
PAPER
All preliminary reaction trials were conducted with 4-bro- product (Table 1, entry 7). Concerning the base, aqueous
mo-1,2-dimethyl-5-nitro-1H-imidazole (3) and propargyl solutions of cesium or sodium carbonate led only to re-
alcohol, in a Biotage Initiator Microwave oven or by tra- covered starting materials (Table 1, entries 3 and 4). On
ditional heating.
the other hand, the use of cyclohexanamine or pyrrolidine
led to the formation of SNAr products (Table 1, entries 1
and 2). Only triethylamine (Table 1, entry 5) and tetrabu-
tylammonium acetate (Bu4NOAc) (Table 1, entries 8–16)
gave good cross-coupling product conversion rates. Opti-
mization of the reaction rate (to 1 h) was achieved by em-
ploying the alkyne substrate in excess (2.0 equiv), in the
presence of copper(I) iodide as the co-catalyst. Indeed, in
absence of copper(I) iodide, a significant decrease in the
yield was observed (Table 1, entry 16).22b Concerning the
heating method, cross-coupling occurred under both clas-
sical heating (Table 1, entry 8) and microwave irradiation
(Table 1, entries 9–16). Typically, a 10% increase in the
yield was observed using microwave irradiation over the
same reaction time.
The choice of the acetylene derivative was dictated by the
possible future use of the coupling product, which re-
quired a simple access to an sp3 C–Cl moiety, by way of
chlorination of a hydroxymethyl group. Indeed, based on
our studies on the reactivity of single electron transfer re-
actions,18 and as part of our program directed toward the
preparation of more complex heterocyclic structures of
pharmacological interest, we previously described the
first examples of a long-distance unimolecular radical nu-
cleophilic substitution (LD-SRN1) on a propargylic chlo-
ride,12 and via TDAE methodology.13
Based on earlier reports regarding the Sonogashira reac-
tion,9a,16,19–23 different cross-coupling reaction conditions
were tested focusing our attention on five parameters:
catalyst, co-catalyst, base, solvent and heating method.
Concerning the catalytic species, tetrakis(triphenylphos-
phine)palladium(0) [Pd(PPh3)4] and bis(triphenylphos-
phine)palladium(II) chloride [PdCl2(PPh3)2] were found
to be suitable sources of palladium for the cross-coupling,
whereas palladium(II) acetate [Pd(OAc)2] (with or with-
out the presence of CuI) favored homocoupling of the al-
As a result, microwave-assisted experimental conditions
were established, which permitted the synthesis of 3-(1,2-
dimethyl-5-nitro-1H-imidazol-4-yl)prop-2-yn-1-ol
(5,
see Table 2, entry 1) in 93% yield in one hour. The opti-
mized conditions were as follows: Pd(PPh3)4 (0.05 equiv),
copper(I) iodide (0.1 equiv), propargyl alcohol (2.0 equiv)
and tetrabutylammonium acetate (1.1 equiv) in acetoni-
trile under microwave irradiation (60 °C) for one hour
(Table 1, entry 9). The use of PdCl2(PPh3)2 as the palladi-
kyne.
The
use
of
tris(dibenzylideneacetone)-
dipalladium(0) [Pd2(dba)3] did not afford any coupling
Table 1 Optimization of the Sonogashira Coupling Reaction of Imidazole 3 with Propargyl Alcohola
Entry
Base (equiv)
Pd (equiv)
Temp (°C)b
Time (h)
Yield of 5 (%)
1
2
cyclohexanamine (2.0 equiv)
pyrrolidine (1.5 equiv)
Cs2CO3 (2.0 equiv)
PdCl2(PPh3) (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.1 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(OAc)2 (0.05 equiv)
Pd2(dba)3 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
PdCl2(PPh3) (0.05 equiv)
Pd(PPh3)4 (0.07 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
60
0.5
1
0
0
60
3
MW 60
MW 60
MW 60
60
1
0
4
Na2CO3 (2.0 equiv)
1
0
5
Et3N (2.0 equiv)
1
40
0
6
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
Bu4NOAc (1.1 equiv)
24
24
1
7
60
0
8
60
83
93
93
93
72
81
81
90
35c
9
MW 60
MW 60
MW 60
MW 40
MW 80
MW 60
MW 60
MW 60
1
10
11
12
13
14
15
16
1
1
1
1
0.5
1.5
1
a CuI (0.1 equiv), propargyl alcohol (2.0 equiv), MeCN.
b MW = microwave heating at the specified temperature.
c CuI was omitted.
Synthesis 2013, 45, 1349–1356
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Sonogashira Cross-Coupling Reactions
1351
Table 2 Microwave-Assisted Sonogashira Coupling Reactions of
Imidazole 3 with Terminal Alkynesa (continued)
um source and N,N-dimethylformamide as the solvent
gave similar results. When triethylamine was employed as
the base the cross-coupling proceeded in only a moderate
40% yield (Table 1, entry 5). At present, the reason behind
the beneficial effect of tetrabutylammonium acetate in
these reactions is not clear. Undoubtedly, tetrabutylam-
monium acetate acts as a mild base deprotonating the
most acidic hydrogen of the alkyne, but according to
Urgaonkar,23 the acetate anion in combination with a
bulky cation could also play an essential role by providing
a naked, more reactive acetate anion, or by stabilization of
the oxidative addition adduct [ArPd(II)X].
R
R
(2.0 equiv)
Bu4NOAc (1.1 equiv)
Pd(PPh3)4 (0.05 equiv)
CuI (0.1 equiv)
Br
N
N
O2N
O2N
MeCN
MW
60 °C, 1 h
N
N
Me
Me
5–25
3
R = Alk, Ar
Entry
6
Alkyne
Product
Yield (%)
To evaluate the scope and limitations of this procedure,
we examined the Sonogashira cross-coupling reaction of
imidazole 3 with 24 different terminal alkynes (Table 2).
Initially, alkynes which might lead to promising candi-
dates to effect later SRN1 studies (by further chlorination
of the hydroxymethyl group next to the triple bond) were
reacted under the optimized conditions to afford the cor-
responding coupled products in moderate to excellent
yields (Table 2, entries 1–8).
10
84
OH
7
8
9
11
12
13
98
98
87
OH
Table 2 Microwave-Assisted Sonogashira Coupling Reactions of
Imidazole 3 with Terminal Alkynesa
OH
R
R
(2.0 equiv)
Bu4NOAc (1.1 equiv)
Pd(PPh3)4 (0.05 equiv)
CuI (0.1 equiv)
Br
HO
N
N
O2N
O2N
MeCN
MW
60 °C, 1 h
N
N
Me
Me
10
11
14
15
79
54
5–25
3
HO
R = Alk, Ar
Entry
1
Alkyne
Product
Yield (%)
5
93
OH
12
13
16
17
72
98
OH
2
3
4
5
6
7
8
9
87
72
52
80
HO
OH
14
15
18
19
78
93
HO
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1349–1356

1352
K. Neildé et al.
PAPER
Table 2 Microwave-Assisted Sonogashira Coupling Reactions of
Imidazole 3 with Terminal Alkynesa (continued)
alkynes: 1-phenylprop-2-yn-1-ol, prop-2-ynylbenzene
and phenyl(prop-2-ynyl)sulfane. The stability of these al-
kynes in basic medium was examined and no side-product
formation was observed, which is detrimental to the
Sonogashira cross-coupling. Attempts to prove that for-
mation of the desired Sonogashira cross-coupling prod-
ucts had occurred were unsuccessful under our conditions,
and only led to intractable tar-like materials, which can be
explained by the possible formation of highly reactive
allene24 or enone25 species, as previously described in the
literature.
R
R
(2.0 equiv)
Bu4NOAc (1.1 equiv)
Pd(PPh3)4 (0.05 equiv)
CuI (0.1 equiv)
Br
N
N
O2N
O2N
MeCN
MW
60 °C, 1 h
N
N
Me
Me
5–25
3
R = Alk, Ar
Entry
16
Alkyne
Product
Yield (%)
In summary, we have developed a general procedure for
the rapid and efficient synthesis of new 4-arylacetylene or
4-alkylacetylene-1,2-dimethyl-5-nitro-1H-imidazole de-
rivatives via the microwave-assisted palladium-mediated
coupling reactions of arylacetylenes or alkylacetylenes
with 4-bromo-1,2-dimethyl-5-nitro-1H-imidazole (3). A
wide range of substituted acetylene derivatives was
shown to tolerate these microwave-assisted conditions.
Furthermore, we have synthesized promising candidates
for subsequent SRN1 reactions (via chlorination of the hy-
droxymethyl group adjacent to the triple bond), the prod-
ucts of which may show potential as new anti-infectious
5-nitroimidazole-containing agents. Pharmacological
evaluation of all the synthesized compounds is under way.
20
80
94
17
21
OMe
18
19
22
23
75
70
OMe
Commercial reagents were used as received without additional pu-
rification. Microwave-assisted reactions were performed in 0.5–2
mL sealed vials using a Biotage Initiator Microwave oven; temper-
atures were measured with an IR-sensor and reaction times are giv-
en as hold times. TLC analyses were performed on 5 cm × 10 cm
aluminum plates coated with silica gel 60F-254 (Merck) in an ap-
propriate eluting solvent; samples were made visual with UV light
(234 nm). Silica gel 60 (Merck, particle size 0.063–0.200 mm, 70–
230 mesh ASTM) was used for column chromatography. Melting
points were determined with a B-540 Büchi melting point appara-
tus. 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra were re-
corded on a Bruker ARX 200 spectrometer in CDCl3 or DMSO-d6
at the Faculty of Pharmacy of Marseille. 1H and 13C NMR chemical
shifts (δ) are reported in ppm with respect to reference CHCl3 [7.26
ppm (1H) and 77.0 ppm (13C)] and DMSO-d6 [2.50 ppm (1H) and
39.5 ppm (13C)]. urity of the synthesized compounds was deter-
mined by LC–MS analyses, which were carried out at the Faculty of
Pharmacy of Marseille using a Thermo Scientific Accela High
Speed LC System® coupled with a single quadrupole mass spec-
trometer (Thermo MSQ Plus ®). The RP-HPLC column used was a
Thermo Hypersil Gold ® 50 × 2.1 mm (C18 bound), with particles
of 1.9 μm diameter. The volume of sample injected into the column
was 1 μL. Chromatographic analysis (total duration of 8 min), was
accomplished with the following solvent gradients: t = 0 min, H2O–
MeOH (50:50); 0 < t < 4 min, linear increase in the proportion of
H2O to a ratio of H2O–MeOH (95:5); 4 < t < 6 min, H2O–MeOH
(95:5); 6 < t < 7 min, linear decrease in the proportion of H2O to re-
turn to a ratio H2O–MeOH (50:50); 6 < t < 7 min, H2O–MeOH
(50:50). The H2O used was buffered with NH4OAc (5 mM). The re-
tention times (tR) of the molecules analyzed are given in minutes.
F
Me2N
20
21
24
25
40
98
H2N
a Reaction conditions: Pd(PPh3)4 (0.05 equiv), CuI (0.1 equiv), alkyne
(2.0 equiv), Bu4NOAc (1.1 equiv), MeCN, microwave irradiation
(60 °C).
In an effort to further expand the scope of this Sonogashira
reaction, we next investigated the reaction of compound 3 HRMS spectra were recorded on a MicrOTOF Q (Bruker) spec-
trometer. An equimolar mixture of sodium formiate and sodium
acetate was used as the matrix for HRMS. The experimental exact
mass was given for the ion which had the maximum isotopic abun-
dance. Elemental analyses were carried out at Spectropole, Faculty
with a series of other acetylenic alcohols (Table 2, entries
9 and 10), aliphatic terminal alkynes (Table 2, entries 11
and 12) and aryl acetylenes (Table 2, entries 13–21). De-
spite numerous efforts, no combination of the above pa-
of Sciences (Saint-Jérôme).
rameters was successful with the following three terminal
Synthesis 2013, 45, 1349–1356
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Sonogashira Cross-Coupling Reactions
1353
Sonogashira Cross-Coupling; General Procedure
1H NMR (200 MHz, CDCl3): δ = 1.06 (d, J = 6.7 Hz, 3 H), 1.09 (d,
J = 6.7 Hz, 3 H), 1.89–2.12 (m, 1 H), 2.45 (s, 3 H), 2.84 (br s, 1 H),
3.87 (s, 3 H), 4.43 (d, J = 5.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 14.0, 17.5, 18.1, 34.0, 34.4, 68.2,
77.2, 97.3, 125.9, 149.0.
LC–MS (ESI+): tR = 1.20 min; m/z = 238 [M + H]+, 475 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H15N3O3Na: 260.1006;
To a soln of 4-bromo-1,2-dimethyl-5-nitro-1H imidazole (3) (150
mg, 0.68 mmol, 1.0 equiv) in MeCN (2 mL) were added Pd(PPh3)4
(39 mg, 0.034 mmol, 0.05 equiv), CuI (7 mg, 0.068 mmol, 0.1
equiv), Bu4NOAc (225 mg, 0.75 mmol, 1.1 equiv) and the alkyne
(1.36 mmol, 2.0 equiv). The mixture was heated in a microwave
oven at 60 °C until the starting material had been consumed (moni-
tored by TLC and LC–MS). The solvent was removed under re-
duced pressure and the crude residue was purified by column
chromatography on silica gel and recrystallized from an appropriate
solvent (or solvent mixture) to afford 4-alkylacetylene-1,2-dimeth-
yl-5-nitro-1H-imidazoles 5–16, or 4-arylacetylene-1,2-dimethyl-5-
nitro-1H-imidazoles 17–25.
found: 260.1005.
4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)-2-phenylbut-3-yn-2-
ol (9)
Compound 9 was isolated after purification by column chromatog-
raphy on silica gel (CHCl3) and recrystallization from cyclohexane–
PrOH (1:1).
3-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)prop-2-yn-1-ol (5)
Compound 5 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from H2O.
Yield: 156 mg (80%); beige powder; mp 149 °C.
1H NMR (200 MHz, CDCl3): δ = 1.88 (s, 3 H), 2.39 (s, 3 H), 3.35
(s, 1 H), 3.87 (s, 3 H), 7.28–7.42 (m, 3 H), 7.72–7.79 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 14.0, 32.9, 34.0, 70.3, 76.7, 100.1,
125.1, 125.9, 127.8, 128.3, 144.9, 149.1.
LC–MS (ESI+): tR = 2.07 min; m/z = 286 [M + H]+, 571 [2 M + H]+.
Yield: 124 mg (93%); beige powder; mp 183 °C.
1H NMR (200 MHz, DMSO-d6): δ = 2.39 (s, 3 H), 3.79 (s, 3 H), 4.34
(d, J = 6.2 Hz, 2 H), 5.48 (t, J = 6.2 Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 13.7, 33.8, 49.5, 76.4, 96.0,
124.8, 138.9, 149.9.
HRMS (ESI+): m/z [M + Na]+ calcd for C15H15N3O3Na: 308.1006;
found: 308.1005.
LC–MS (ESI+): tR = 0.60 min; m/z = 196 [M + H]+, 218 [M + Na]+,
391 [2 M + H]+, 413 [2 M + Na]+.
Anal. Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C,
63.16; H, 5.26; N, 14.76.
HRMS (ESI+): m/z [M + Na]+ calcd for C8H9N3O3Na: 218.0536;
found: 218.0535.
3-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)-1,1-diphenylprop-2-
yn-1-ol (10)
Compound 10 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (1:1).
4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)but-3-yn-2-ol (6)
Compound 6 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (1:1).
Yield: 200 mg (84%); beige powder; mp 180 °C.
1H NMR (200 MHz, CDCl3): δ = 1.67 (s, 1 H), 2.33 (s, 3 H), 3.85
(s, 3 H), 7.21–7.39 (m, 6 H), 7.67–7.72 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 13.9, 34.0, 74.8, 78.8, 99.2, 125.9,
126.2, 127.7, 128.3, 144.4, 149.2.
LC–MS (ESI+): tR = 3.14 min; m/z = 348 [M + H]+.
Yield: 124 mg (87%); yellow powder; mp 105 °C (dec.).
1H NMR (200 MHz, DMSO-d6): δ = 1.39 (d, J = 6.5 Hz, 3 H), 2.39
(s, 3 H), 3.79 (s, 3 H), 4.64 (quin, J = 6.5 Hz, 1 H), 5.60 (d, J = 5.5
Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 13.7, 24.2, 33.8, 56.7, 75.1,
99.4, 124.9, 139.0, 149.9.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H17N3O3Na: 370.1162;
found: 370.1163.
LC–MS (ESI+): tR = 0.52 min; m/z = 210 [M + H]+, 419 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C9H11N3O3Na: 232.0693;
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C,
69.15; H, 4.92; N, 12.09.
found: 232.0693.
4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)-2-methylbut-3-yn-2-
ol (7)
Compound 7 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (8:2).
1-[(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)ethynyl]cyclopenta-
nol (11)
Compound 11 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (8:2).
Yield: 110 mg (72%); beige powder; mp 115 °C.
1H NMR (200 MHz, CDCl3): δ = 1.62 (s, 6 H), 2.44 (s, 3 H), 3.12
(br s, 1 H), 3.87 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 14.0, 30.9, 33.9, 65.4, 74.0, 101.7,
126.0, 149.0; the C-NO2 carbon was not observed under these ex-
perimental conditions.
Yield: 166 mg (98%); beige powder; mp 119 °C.
1H NMR (200 MHz, CDCl3): δ = 1.70–2.14 (m, 8 H), 2.43 (s, 3 H),
3.21 (br s, 1 H), 3.85 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 14.0, 23.4 (2 C), 33.9, 42.1 (2 C),
74.5, 74.8, 101.3, 126.1, 138.9, 149.0.
LC–MS (ESI+): tR = 0.96 min; m/z = 250 [M + H]+, 272 [M + Na]+,
LC–MS (ESI+): tR = 0.82 min; m/z = 224 [M + H]+, 447 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C10H13N3O3Na: 246.0849;
499 [2 M + H]+, 521 [2 M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H15N3O3Na: 272.1006;
found: 272.1008.
found: 218.0847.
1-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)-4-methylpent-1-yn-
3-ol (8)
Compound 8 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 97:3) and recrystallization
from cyclohexane–PrOH (8:2).
1-[(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)ethynyl]cyclohexa-
nol (12)
Compound 12 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (8:2).
Yield: 84 mg (52%); beige powder; mp 111 °C.
Yield: 176 mg (98%); beige powder; mp 129 °C.
© Georg Thieme Verlag Stuttgart · New York
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1H NMR (200 MHz, CDCl3): δ = 1.07–2.11 (m, 10 H), 2.41 (s, 3 H),
3.82 (s, 3 H), 3.94 (br s, 1 H).
HRMS (ESI+): m/z [M + Na]+ calcd for C12H15N3O2Na: 256.1056;
found: 256.1055.
13C NMR (50 MHz, CDCl3): δ = 13.8, 23.0, 25.0, 33.9, 39.4, 68.8,
75.8, 101.3, 125.9, 138.9, 149.0.
1,2-Dimethyl-5-nitro-4-(p-tolylethynyl)-1H-imidazole (17)
Compound 17 was isolated after purification by column chromatog-
raphy on silica gel (CHCl3–acetone, 98:2) and recrystallization
from cyclohexane.
LC–MS (ESI+): tR = 1.50 min; m/z = 264 [M + H]+, 286 [M + Na]+,
527 [2 M + H]+, 549 [2 M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C13H17N3O3Na: 286.1162;
Yield: 170 mg (98%); yellow powder; mp 182 °C.
1H NMR (200 MHz, CDCl3): δ = 2.36 (s, 3 H), 2.46 (s, 3 H), 3.89
(s, 3 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 14.1, 21.6, 34.0, 81.0, 97.1, 118.8,
126.8, 129.2, 132.1, 139.8, 149.2.
LC–MS (ESI+): tR = 3.30 min; m/z = 256 [M + H]+, 511 [2 M + H]+.
found: 286.1160.
4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)but-3-yn-1-ol (13)
Compound 13 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (1:1).
Yield: 123 mg (87%); beige powder; mp 158 °C.
1H NMR (200 MHz, DMSO-d6): δ = 2.38 (s, 3 H), 2.62 (t, J = 6.8
Hz, 2 H), 3.58 (t, J = 6.8 Hz, 2 H), 3.78 (s, 3 H), 4.93 (br s, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 13.6, 23.5, 33.8, 59.4, 74.1,
95.7, 125.6, 149.8.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H13N3O2Na: 278.0900;
found: 278.0900.
1,2-Dimethyl-5-nitro-4-(o-tolylethynyl)-1H-imidazole (18)
Compound 18 was isolated after purification by column chromatog-
raphy on silica gel (CHCl3–acetone, 98:2) and recrystallization
from cyclohexane.
LC–MS (ESI+): tR = 0.49 min; m/z = 210 [M + H]+, 232 [M + Na]+,
419 [2 M + H]+, 441 [2 M + Na]+.
Yield: 136 mg (78%); yellow powder; mp 160 °C.
1H NMR (200 MHz, CDCl3): δ = 2.49 (s, 3 H), 2.58 (s, 3 H), 3.92
(s, 3 H), 7.13–7.33 (m, 3 H), 7.57–7.61 (m, 1 H).
HRMS (ESI+): m/z [M + Na]+ calcd for C9H11N3O3Na: 232.0693;
found: 232.0694.
13C NMR (50 MHz, CDCl3): δ = 14.1, 20.7, 34.0, 85.2, 96.0, 121.7,
125.6, 126.9, 129.5, 129.6, 132.6, 141.4, 149.2.
LC–MS (ESI+): tR = 3.31 min; m/z = 256 [M + H]+, 511 [2 M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C14H14N3O2: 256.1081;
6-(1,2-Dimethyl-5-nitroimidazol-4-yl)hex-5-yn-3-ol (14)
Compound 14 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (1:1).
Yield: 128 mg (79%); beige powder; mp 113 °C.
found: 256.1080.
1H NMR (200 MHz, DMSO-d6): δ = 0.89 (t, J = 7.5 Hz, 3 H), 1.30–
1.71 (m, 2 H), 2.38 (s, 3 H), 2.55–2.59 (m, 2 H), 3.53–3.67 (m, 1 H),
3.78 (s, 3 H), 4.85 (d, J = 4.9 Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 9.8, 13.6, 27.6, 28.7, 33.8, 69.8,
74.5, 95.6, 125.7, 138.9, 149.8.
1,2-Dimethyl-5-nitro-4-[(2,4,5-trimethylphenyl)ethynyl]-1H-
imidazole (19)
Compound 19 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (8:2).
LC–MS (ESI+): tR = 0.78 min; m/z = 238 [M + H]+, 260 [M + Na]+,
Yield: 179 mg (93%); yellow powder; mp 176 °C.
1H NMR (200 MHz, CDCl3): δ = 2.21 (s, 3 H), 2.25 (s, 3 H), 2.51
(s, 3 H), 2.52 (s, 3 H), 3.94 (s, 3 H), 7.02 (s, 1 H), 7.38 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 14.1, 19.0, 19.8, 20.1, 34.1, 84.2,
475 [2 M + H]+, 497 [2 M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H15N3O3Na: 260.1006;
found: 260.1008.
97.2, 118.8, 127.1, 131.0, 133.6, 133.9, 138.8, 138.9, 149.1.
LC–MS (ESI+): tR = 4.23 min; m/z = 284 [M + H]+, 567 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H17N3O2Na: 306.1213;
found: 306.1210.
4-(Cyclopropylethynyl)-1,2-dimethyl-5-nitro-1H-imidazole
(15)
Compound 15 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane.
Yield: 75 mg (54%); beige powder; mp 130 °C (dec.).
1H NMR (200 MHz, CDCl3): δ = 0.89–0.95 (m, 4 H), 1.44–1.57 (m,
1 H), 2.40 (s, 3 H), 3.84 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 0.6, 9.2, 14.0, 33.9, 68.1, 102.7,
127.2, 138.8, 148.9.
LC–MS (ESI+): tR = 1.41 min; m/z = 206 [M + H]+, 411 [2 M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C10H12N3O2: 206.0924;
found: 206.0925.
4-[(4-tert-Butylphenyl)ethynyl]-1,2-dimethyl-5-nitro-1H-imid-
azole (20)
Compound 20 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane.
Yield: 162 mg (80%); brown powder; mp 116 °C.
1H NMR (200 MHz, CDCl3): δ = 1.31 (s, 9 H), 2.46 (s, 3 H), 3.89
(s, 3 H), 7.37 (d, J = 8.6 Hz, 2 H), 7.55 (d, J = 8.6 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 14.1, 31.0, 34.0, 34.9, 81.0, 97.1,
118.9, 125.4, 126.8, 131.9, 138.9, 149.2, 152.9.
LC–MS (ESI+): tR = 3.98 min; m/z = 298 [M + H]+, 595 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H19N3O2Na: 320.1370;
found: 320.1367.
4-(Cyclopentylethynyl)-1,2-dimethyl-5-nitro-1H-imidazole (16)
Compound 16 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane.
Yield: 114 mg (72%); yellow powder; mp 82 °C.
1H NMR (200 MHz, CDCl3): δ = 1.52–2.06 (m, 7 H), 2.39 (s, 3 H),
2.80–2.94 (m, 1 H), 3.83 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 14.0, 25.0, 30.8, 33.4, 33.8, 72.4,
103.5, 127.2, 138.7, 148.8.
4-[(3-Methoxyphenyl)ethynyl]-1,2-dimethyl-5-nitro-1H-imid-
azole (21)
Compound 21 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane–PrOH (8:2).
LC–MS (ESI+): tR = 3.13 min; m/z = 234 [M + H]+, 467 [2 M + H]+.
Synthesis 2013, 45, 1349–1356
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Sonogashira Cross-Coupling Reactions
1355
Yield: 173 mg (94%); yellow powder; mp 167 °C.
1H NMR (200 MHz, CDCl3): δ = 2.49 (s, 3 H), 3.82 (s, 3 H), 3.93
(s, 3 H), 6.93–7.36 (m, 4 H).
13C NMR (50 MHz, DMSO-d6): δ = 13.7, 33.8, 80.6, 98.3, 106.7,
113.6, 126.6, 133.2, 150.3, 150.6.
LC–MS (ESI+): tR = 0.92 min; m/z = 256 [M + H]+, 512 [2 M + H]+;
under our basic conditions, we observed a loss of 1 Da.
HRMS (ESI+): m/z [M + Na]+ calcd for C13H12N4O2Na: 279.0852;
13C NMR (50 MHz, CDCl3): δ = 14.1, 34.1, 55.3, 81.3, 96.6, 116.3,
116.5, 122.9, 124.7, 126.6, 129.5, 139.0, 159.3.
found: 279.0853.
LC–MS (ESI+): tR = 2.85 min; m/z = 272 [M + H]+, 543 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H13N3O3Na: 294.0849;
found: 294.0852.
Acknowledgment
This work was supported by the CNRS and Aix-Marseille Univer-
sity. The authors thank the Spectropole team for elemental analysis.
4-[(2-Methoxyphenyl)ethynyl]-1,2-dimethyl-5-nitro-1H-imid-
azole (22)
Compound 22 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane.
1
We express our thanks to V. Remusat for recording H and 13C
NMR spectra and to T. Schembri and D. Lafitte (Marseille Protéo-
mique - PIT2) for HRMS spectra. K. Neildé is grateful to the French
ministry of higher education and research for a doctoral fellowship.
Yield: 139 mg (75%); brown powder; mp 135 °C.
1H NMR (200 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.89 (s, 3 H), 3.92
(s, 3 H), 6.87–6.98 (m, 2 H), 7.30–7.38 (m, 1 H), 7.51–7.58 (m, 1
H).
References
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13C NMR (50 MHz, CDCl3): δ = 14.1, 34.0, 55.9, 85.4, 93.6, 110.8,
111.2, 120.4, 126.9, 131.0, 134.0, 149.2, 160.7.
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4-[(3-Fluorophenyl)ethynyl]-1,2-dimethyl-5-nitro-1H-imidaz-
ole (23)
Compound 23 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 98:2) and recrystallization
from cyclohexane.
Yield: 123 mg (70%); yellow powder; mp 165 °C.
1H NMR (200 MHz, CDCl3): δ = 2.47 (s, 3 H), 3.91 (s, 3 H), 7.03–
7.13 (m, 1 H), 7.26–7.41 (m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 14.1, 34.0, 82.1, 95.0 (d, J = 3.7
Hz), 116.8 (d, J = 21.2 Hz), 118.8 (d, J = 23.1 Hz), 123.7 (d, J = 9.5
Hz), 126.0, 128.0 (d, J = 3.3 Hz), 130.0 (d, J = 8.4 Hz), 149.2, 162.2
(d, J = 247.3 Hz).
LC–MS (ESI+): tR = 2.94 min; m/z = 260 [M + H]+, 519 [2 M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C13H10FN3O2Na: 282.0649;
found: 282.0650.
4-[(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)ethynyl]-N,N-di-
methylbenzenamine (24)
Compound 24 was isolated after purification by column chromatog-
raphy on silica gel (CHCl3–acetone, 98:2) and recrystallization
from cyclohexane–PrOH (1:1).
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Yield: 76 mg (40%); red powder; mp 189 °C (dec.).
1H NMR (200 MHz, CDCl3): δ = 2.47 (s, 3 H), 3.01 (s, 6 H), 3.91
(s, 3 H), 6.64 (d, J = 8.6 Hz, 2 H), 7.51 (d, J = 8.6 Hz, 2 H).
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found: 307.1166.
4-[(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)ethynyl]benzen-
amine (25)
Compound 25 was isolated after purification by column chromatog-
raphy on silica gel (CH2Cl2–MeOH, 99:1) and recrystallization
from cyclohexane–PrOH (1:1).
Yield: 171 mg (98%); red powder; mp 191 °C (dec.).
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(br s, 2 H), 6.58 (d, J = 8.6 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York
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1356
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PAPER
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Synthesis 2013, 45, 1349–1356
© Georg Thieme Verlag Stuttgart · New York