Exploring the synthesis and the reactivity of 4-[4-(chloromethyl)styryl]-1, 2-dimethyl-5-nitro-1H-imidazole in TDAE strategy

Article abstract of DOI:10.1055/s-0033-1338572

We describe herein the preparation of 4-[4-(chloromethyl)styryl]-1,2- dimethyl-5-nitro-1H-imidazole via a Stille cross-coupling reaction. After determining the best reaction conditions, we investigated the reactivity of this activated chloromethyl compoun

Full text of DOI:10.1055/s-0033-1338572

348▌
PAPER
paper
Exploring the Synthesis and the Reactivity of 4-[4-(Chloromethyl)styryl]-1,2-
dimethyl-5-nitro-1H-imidazole in TDAE Strategy
4-(4-Substituted)styryl-5-nitro-1H-imidazoles
Nicolas Primas, Kévin Neildé, Youssef Kabri, Maxime D. Crozet, Thierry Terme, Patrice Vanelle*
Aix-Marseille Université, Institut de Chimie Radicalaire ICR, UMR CNRS 7273, Laboratoire de Pharmaco-Chimie Radicalaire,
Faculté de Pharmacie, 27 Boulevard Jean Moulin – CS 30064, 13385 Marseille Cedex 05, France
Fax +33(4)91794677; E-mail: patrice.vanelle@univ-amu.fr
Received: 10.10.2013; Accepted after revision: 19.11.2013
Tetrakis(dimethylamino)ethylene (TDAE) is an organic
Abstract: We describe herein the preparation of 4-[4-(chlorometh-
reducing agent that reacts with halogenated derivatives to
yl)styryl]-1,2-dimethyl-5-nitro-1H-imidazole via a Stille cross-
generate a carbanion under mild conditions.11 Since 2003,
we have undertaken a program directed toward the devel-
coupling reaction. After determining the best reaction conditions,
we investigated the reactivity of this activated chloromethyl com-
pound in a TDAE [tetrakis(dimethylamino)ethylene] strategy to- opment of original synthetic methods using TDAE meth-
odology in medicinal chemistry.12
ward 10 various electrophiles, obtaining 4-(4-substituted)styryl-
1,2-dimethyl-5-nitro-1H-imidazoles in moderate to good yields.
In continuation of our research program centered on the
Key words: nitroimidazole, Stille reaction, TDAE, carbanions,
design and synthesis of novel bioactive molecules using
cross-coupling
TDAE methodology12 or SRN1 reactions,13 we focused our
studies on the synthesis and evaluation of heterocyclic
compounds displaying notably antiparasitic activity.14 We
The discovery of the trichomonacide properties of azomy-
report herein the preparation of new 5-nitroimidazoles,
cin (2-nitroimidazole) in 19561 led to the development of
bearing a 4-substituted styryl group at the 4-position, in
the 5-nitroimidazole series, well known for their wide
order to extend the anti-infectious pharmacomodulation
spectrum of anti-infectious activity.2 The first-in-class
in this series of compounds. The 4-styrylimidazole scaf-
molecule is metronidazole (1961),3 which is widely used
fold can have applications in inhibitors of protein farne-
for the treatment of infections caused by protozoa such as
syltransferase,15 ligands of histamine H-3 receptors,16 or
Trichomonas vaginalis, Entamœba histolytica, and
antiparasitic agents.17,18 These derivatives have previous-
Giardia intestinalis, and infections induced by anaerobic
bacteria. Several 5-nitroimidazoles are also currently used
ly been prepared via Heck reaction,15 Horner–
Wadsworth–Emmons reaction,16 condensation between
in drugs, such as secnidazole or ornidazole. These chemo-
an aromatic aldehyde with the appropriate 4-methyl-5-ni-
therapeutic agents inhibit the growth of both anaerobic
troimidazole,17 or Suzuki–Miyaura reactions with the ap-
bacteria and some anaerobic protozoa.4 However, 5-nitro-
propriate styrylboronic acid, respectively.18 To the best of
imidazoles have been found to exhibit mutagenic activity
our knowledge, 4-(4-substituted)styryl-1,2-dimethyl-5-
nitro-1H-imidazoles are poorly represented in the litera-
ture and in order to prepare these derivatives, we first syn-
in prokaryotic microorganisms.5 Although mutagenicity
has not been demonstrated in eukaryotic cells, new nitro-
imidazole derivatives possessing good pharmacological
thesized the key intermediate 4-[4-(chloromethyl)styryl]-
activity with no mutagenicity6 would be of great interest
1,2-dimethyl-5-nitro-1H-imidazole (9) via a multistep
synthesis. Then, we used our knowledge of the reactivity
not only for patient care, but also to shed light on the mode
of action and the mechanism of expression of mutagenic-
of activated chloromethyl groups in TDAE methodolo-
ity. Moreover, the emergence of metronidazole-resistant
gies to investigate the reactivity of intermediate 9 under
similar conditions.
T. vaginalis has resulted in decreased success of current
therapies.7 These refractory cases are usually treated with
Starting from 4-bromobenzyl alcohol (1), Sonogashira
higher doses of metronidazole, which increases the occur-
cross-coupling reaction with (trimethylsilyl)acetylene
afforded the TMS-protected alkyne 2 which was deprot-
ected to give 4-alkynylbenzyl alcohol 3 using tetrabutyl-
ammonium fluoride in tetrahydrofuran (Scheme 1).19
Protection of benzyl alcohol 3 using 3,4-dihydro-2H-py-
ran afforded the O-THP alcohol 4.20 We first tried to pre-
pare the corresponding styrylboronic acid pinacol ester 5′′
by hydroboration of the alkyne using catecholborane in
tetrahydrofuran.21 Unfortunately, although this type of re-
action was clearly reported in the literature, all attempts
failed in our hands and this suitable compound was not
isolated. To overcome this problem, we chose to perform
an analogous procedure using tin chemistry instead of
boron chemistry. Thus, radical hydrostannylation of the
rence of side effects.8 Recently, small nitro-group-
containing heterocyclic derivatives, including 5-nitro-
imidazole series (fexinidazole), have gained attention in
other biological applications such as Trypanosoma cruzi
(Chagas disease)9 or Mycobacterium tuberculosis.10
Straightforward access to new derivatives belonging to
the biologically relevant 5-nitroimidazole scaffold is
therefore likely to be of interest to the scientific commu-
nity.
SYNTHESIS 2014, 46, 0348–0356
Advanced online publication: 02.12.2013
0
0
3
9
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7
8
8
1
1
4
3
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DOI: 10.1055/s-0033-1338572; Art ID: SS-2013-T0672-OP
© Georg Thieme Verlag Stuttgart · New York

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4-(4-Substituted)styryl-5-nitro-1H-imidazoles
349
TMS
Br
i
ii
HO
HO
HO
1
3
2
iv
iii
SnBu3
iv
3
THPO
5 R = THP
5' R = H
RO
4
Bpin
v
x
THPO
5''
Br
O2N
N
Me
Cl
vii, viii
THPO
N
Me
6
N
N
Me
Me
5
vi
N
N
O2N
O2N
Me
Me
7
9
Scheme 1 Preparation of key intermediate 9. Reagents and conditions: (i) (trimethylsilyl)acetylene, PdCl2(PPh3)2, Et3N, 70 °C, 36 h, 93%; (ii)
1 M TBAF in THF, r.t., 12 h, 95%; (iii) 3,4-dihydro-2H-pyran, PTSA, CH2Cl2, 12 h, 96%; (iv) Bu3SnH, AIBN, toluene, 80 °C, 12 h, 5: 65%,
5′: 14%; (v) 1 M catecholborane in THF, 70 °C, 5′′ not obtained; (vi) PdCl2(PPh3)2, CuI, PEG-400, MW 150 °C, 1 h, 91%; (vii) PTSA, MeOH,
r.t., 12 h, 8: 98%; (viii) SOCl2, r.t., 12 h, 96%.
terminal alkyne of 4 in presence of 2,2′-azobis(isobutyro- action appeared to us crucial to improve the reaction yield.
nitrile) provided (E)-styrylstannane 5 in good yield.22 It In order to avoid the thermal decomposition of dimethyl-
must be pointed out that radical hydrostannylation of al- formamide, we chose PEG-400 as solvent.27 Using 3% of
cohol 3 provided the corresponding compound 5′ in only catalyst and microwave heating at 150 °C for 1.5 hours,
14% yield.23 Then, stannane 5 was engaged in a micro- the target compound was obtained in 70% yield (entry 3).
wave-assisted Stille cross-coupling reaction24 with 4-bro- Addition of copper(I) iodide as co-catalyst slightly im-
mo-1,2-dimethyl-5-nitro-1H-imidazole25 (6) affording proved the yield (entry 4). With 3 mol% of catalyst in-
the O-THP protected compound 7, which was further de- stead of 2 mol%, the reaction yield reached 86% (entry 5).
protected in presence of 4-toluenesulfonic acid, leading to The use of lithium chloride as co-catalyst24 decreased the
compound 8. Finally, chlorination of benzyl alcohol 8 was yield (entry 6), whereas the use of tetrakis(triphenylphos-
performed in thionyl chloride at room temperature to give phine)palladium(0) as catalyst was disappointing (entry
to the expected key intermediate 9 in 47% overall yield in 7). In the end, the best reaction conditions were obtained
seven steps. The assignment of the alkene configuration by using 4 mol% of dichlorobis(triphenylphosphine)pal-
was made by X-ray structural radiocrystallography.26
ladium(II) in presence of 4 mol% of copper(I) iodide in
PEG-400 at 150 °C under microwave heating for one hour
(entry 8).
Table 1 summarizes the optimization of the Stille cou-
pling reaction between styrylstannane 5 and 4-bromo-5-
nitroimidazole 6.
Having secured a good access to the key intermediate 4-
[4-(chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-imid-
azole (9), we next investigated its reactivity with TDAE
methodology.
Our first attempt to perform the Stille reaction was under
typical conditions in dimethylformamide using dichloro-
bis(triphenylphosphine)palladium(II) (2 mol%) as the
palladium source and without any base or co-catalyst un- The first attempt was made using three equivalents of N-
der microwave heating in a sealed vial. Under these con- tosylbenzylimine28 as electrophile in presence of one
ditions, starting from stannane 5′ the yield was promising equivalent of TDAE in anhydrous dimethylformamide at
(Table 1, entry 1). Since 5′ was obtained in a very low –20 °C for one hour followed by stirring at room temper-
yield, further experiments were based on the more acces- ature for 1.5 hours. The expected addition compound 10a
sible stannane 5. Under the same conditions, the yield was was isolated in 47% yield (Table 2, entry 1). If the amount
only 46% (entry 2). Increasing the temperature of the re- of TDAE was increased to 1.3 equivalents, the yield of
© Georg Thieme Verlag Stuttgart · New York
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N. Primas et al.
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Table 1 Optimization of the Stille Coupling Reaction of Styrylstannane 5 and 5′ with 4-Bromo-5-nitroimidazole 6
Br
N
O2N
Me
N
RO
SnBu3
6
Me
N
Me
RO
catalyst, Cu
solvent
N
1.3 equiv
O2N
Me
MW, time
5 R = THP
5' R = H
7 R = THP
8 R = H
Entry
Catalyst (mol%)
Co-catalyst (mol%) Solvent
Tempa (°C)
Time (h)
Yield (%) of 7
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (2)
PdCl2(PPh3)2 (2)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (2)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (3)
Pd(PPh3)4 (3)
–
DMF
100
100
150
150
150
150
150
150
1
79b
46
70
75
86
71
57
91
–
DMF
1
–
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
1.5
1
CuI (4)
CuI (4)
LiCl (6)
–
1
1
1.5
1
PdCl2(PPh3)2 (4)
CuI (4)
a Microwave heating at the specified temperature.
b Starting from unprotected styrylstannane 5′ to afford 8.
10a was slightly enhanced (entry 2). Electron-donating bromobenzaldehyde (entry 12). It must be pointed out that
groups such as the methoxy group afforded 10b with a this same experiment conducted in tetrahydrofuran in-
slightly lower yield than previously, even though the reac- stead of dimethylformamide was unsuccessful: no trace of
tion time was considerably increased. Under the same the target compound 10g was observed by LC-MS analy-
conditions, a similar yield of 10c was obtained with N-to- sis. We therefore investigated other substrates bearing
syl-4-fluorobenzylimine (entry 4). Using aldehydes as carbonyl function, and found that diethyl oxomalonate af-
electrophiles, the yield of 10d increased using a longer re- forded the expected derivative 10h in 55% yield at room
action time (entry 6), and also by heating the reaction mix- temperature in only one hour (entry 13). However, when
ture (entry 7). The structure of this compound was ethyl pyruvate was used, the reaction mixture had to be
confirmed by X-ray structural analysis (Figure 1). The heated to improve the reaction yield from 31% to 71% of
resolution of the structure gives an average picture of the 10i (entries 14 and 15), while ethyl glyoxylate only led to
crystal showing two enantiomers based on chiral carbon the target derivative 10j in 37% yield (entry 16). The
C13. The major enantiomer is the structure containing the global observed yields remained slightly lower when us-
oxygen O3A and hydrogen H3A representing an abun- ing 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-
dance of about 80% of (S)-10d in the crystal.26 In the case imidazole as the starting material probably due to the
of 4-formylbenzonitrile, heating the reaction mixture at 70 greater number of bonds between the nitro electron-with-
°C resulted in a lower yield of 10e than the same reaction drawing group and the chlorine atom which plays the role
conducted at room temperature (entries 8 and 9). Strong of leaving group in the formation of the benzylic anion.29
electron-withdrawing groups such as the nitro group did Globally in these reactions, byproducts observed by LC-
not improve the yield of this reaction, leading to only 42% MS analysis were mainly due to the reduction of com-
yield of 10f after 24 hours at room temperature. The reac- pound 9.
tion also worked with ortho-substituted substrates like 2-
Synthesis 2014, 46, 348–356
© Georg Thieme Verlag Stuttgart · New York

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4-(4-Substituted)styryl-5-nitro-1H-imidazoles
351
Table 2 Addition of Chloromethyl 9 with Various Electrophiles Using TDAE Strategy
Cl
E
TDAE (1.3 equiv)
N
N
Me
electrophile
(3 equiv)
Me
N
DMF
N
O2N
9 (1 equiv)
O2N
Me
Me
temp, time
10a–j
Entry
Electrophile
Temp
Time (h)
Product
Yield (%) of 10
TsHN
N
Ts
1
2
r.t.
r.t.
1.5
1.5
47a
54
N
Me
N
O2N
Me
10a
TsHN
N
Ts
Me
N
3
4
r.t.
r.t.
12
12
49
52
N
O2N
MeO
Me
OMe
10b
TsHN
N
Ts
Me
N
N
O2N
F
Me
F
10c
HO
N
N
N
CHO
5
6
7
r.t.
r.t.
70 °C
1.5
12
4
21
33
38
Me
N
O2N
Cl
Me
Cl
10d
HO
CHO
Me
8
9
r.t.
70 °C
12
4
52
34
N
O2N
NC
Me
CN
10e
HO
CHO
Me
10
11
r.t.
r.t.
2
24
36
42
N
O2N
O2N
Me
NO2
10f
HO
Br
N
N
CHO
Br
Me
12
r.t.
12
33b
O2N
Me
10g
© Georg Thieme Verlag Stuttgart · New York
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N. Primas et al.
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Table 2 Addition of Chloromethyl 9 with Various Electrophiles Using TDAE Strategy (continued)
Cl
E
TDAE (1.3 equiv)
N
N
Me
electrophile
(3 equiv)
Me
N
DMF
N
O2N
9 (1 equiv)
O2N
Me
Me
temp, time
10a–j
Entry
13
Electrophile
Temp
Time (h)
Product
Yield (%) of 10
OH
EtO2C
O
O
EtO2C
N
Me
r.t.
1
55
EtO
OEt
N
O
O2N
Me
10h
OH
Me
O
EtO2C
N
14
15
r.t.
70 °C
3
4
31
71
Me
Me
EtO
N
O
O2N
Me
10i
HO
O
EtO2C
N
Me
H
16
r.t.
3
37
EtO
N
O2N
O
Me
10j
a Using 1 equiv of TDAE.
b In THF, no trace of product 10g was observed by LC-MS analysis.
that are of biological interest, notably as anti-infectious
agents. It is noteworthy that intermediate 9 could also be
an appropriate substrate for long-distance-SRN1 reac-
tions,30 and further research is in progress and will be re-
ported in due time.
Commercial reagents were used as received without additional pu-
rification. Melting points were determined on a Kofler bench and
are uncorrected. Elemental analysis and HRMS were carried out at
the Spectropole, Faculté des Sciences et Techniques de Saint-
Jérôme, Marseille, France. NMR spectra were recorded on a Bruker
ARX 200 spectrometer at the Faculté de Pharmacie de Marseille
(200 MHz 1H NMR: reference CHCl3 δ = 7.26, DMSO-d6 δ = 2.50
and 50 MHz 13C: reference CDCl3 δ = 76.9, DMSO-d6 δ = 39.5).
Solvents were dried by conventional methods. The following adsor-
bent was used for column chromatography: silica gel 60 (Merck,
particle size 0.063–0.200 mm, 70–230 mesh ASTM). TLC was per-
Figure 1 X-ray crystal structure of compound 10d; major enantio-
mer (S)-10d ca. 80% in the crystal
In conclusion, we have prepared the previously unreport- formed on 5 cm × 10 cm aluminum plates coated with silica gel
60F-254 (Merck) in an appropriate eluent. Visualization was made
with UV light (234 nm). HRMS spectra were recorded on QStar
Elite (Applied Biosystems SCIEX) spectrometer with a PEG ma-
trix. The experimental exact mass is given for the ion that has the
ed 4-[4-(chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-
imidazole (9) using a Stille cross-coupling reaction after
establishing the best experimental reaction conditions.
This new chloromethylated substrate was reacted toward
maximum isotopic abundance. Purity of synthesized compounds
various electrophiles in the presence of TDAE, affording
moderate to good yields of original 4-(4-substitut-
ed)styryl-1,2-dimethyl-5-nitro-1H-imidazole derivatives
was checked with LC-MS analyses performed at the Faculty of
Pharmacy of Marseille with a Thermo Scientific Accela High Speed
LC System® coupled with a single quadrupole mass spectrometer
Thermo MSQ Plus®. The RP-HPLC column used was a Thermo
Synthesis 2014, 46, 348–356
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4-(4-Substituted)styryl-5-nitro-1H-imidazoles
353
Hypersil Gold® 50 × 2.1 mm (C18 bonded) with particle size: 1.9
μm diameter. The volume of sample injected on the column was 1
μL. The chromatographic analysis, total duration of 8 min, was
made with following solvent gradient: t = 0 min, H2O–MeOH
50:50; 0 < t < 4 min, linear increase in the proportion of H2O to a
ratio H2O–MeOH 95:5; 4 < t < 6 min, H2O–MeOH 95:5; 6 < t < 7
min, linear decrease in the proportion of H2O to return to a ratio
H2O–MeOH 50:50; 6 < t < 7 min, H2O–MeOH 50:50. The H2O used
was buffered with 5 mM NH4OAc. Microwave reactions were per-
formed using a Biotage Initiator Microwave oven using 10–20-mL
sealed vials; temperatures were measured with an IR sensor and re-
action times given as hold times. The preparation of compounds 2,19
3,19 4,20 and 618 was achieved as described in the literature.
(silica gel, CH2Cl2–acetone, 10:0 then 9:1) provided 7 as a yellow
solid; yield: 1.98 g (91%); mp 135 °C.
1H NMR (200 MHz, CDCl3): δ = 7.75 (s, 2 H, CH=CH), 7.60 (d,
J = 7.3 Hz, 2 H), 7.38 (d, J = 7.3 Hz, 2 H), 4.91–4.64 (m, 2 H), 4.52
(d, J = 12.4 Hz, 1 H), 3.98–3.89 (m, 4 H), 3.66–3.41 (m, 1 H), 2.49
(s, 3 H), 1.95–1.38 (m, 6 H).
13C NMR (50 MHz, CDCl3): δ = 149.4, 142.6, 139.5, 136.5, 135.8,
128.3, 127.7, 117.9, 97.9, 68.6, 62.3, 34.2, 30.7, 25.6, 19.5, 14.4;
CNO2 not visible under these conditions.
LC-MS (ESI+): tR = 3.55 min; m/z = 358.24 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O4: 358.1761; found:
358.1762.
Crystal-Structure Analysis
(E)-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vinyl]phe-
nyl}methanol (8)26
The X-ray diffraction measurements were carried out on a Bruker-
Nonius KappaCCD diffractometer at 293 K. Structures were solved
using SIR92 and refinements calculations based on F2 were per-
formed using SHELXL-97. The compounds 8 and 10d were crys-
tallized by slow evaporation of an MeCN solution to provide
desired single crystals.
To a soln of THP-protected alcohol 7 (1.98 g, 5.54 mmol) in MeOH
(80 mL) was added a catalytic amount of PTSA (a spatula tip) under
an argon atmosphere. The mixture was stirred overnight at r.t. The
volatiles were removed under vacuum and the resulting mixture was
triturated (minimal amount of Et2O and a drop of CH2Cl2). Filtra-
tion of the suspension led to 8 as a yellow solid; yield: 1.48 g (98%);
mp 177 °C.
(E)-{4-[2-(Tributylstannyl)vinyl]phenyl}methanol (5′)23
A 50-mL round-bottomed single-neck flask equipped with a con-
denser, an argon gas inlet, and a magnetic stir bar was charged with
(4-ethynylphenyl)methanol (3, 661 mg, 5.0 mmol), Bu3SnH (1.35
mL, 5.0 mmol), AIBN (25 mg), and toluene (10 mL). The flask was
heated to 80 °C overnight. The mixture was then cooled to r.t., and
all volatiles were removed under reduced pressure to give a crude
product that was purified by column chromatography (PE–EtOAc,
7:3) to give 5′ as a colorless oil; yield: 290 mg (14%).
1H NMR (200 MHz, CDCl3): δ = 7.75 (s, 2 H, CH=CH), 7.60 (d,
J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 4.71 (s, 2 H), 3.90 (s, 3
H), 2.49 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 149.4, 142.5, 141.9, 136.4, 135.9,
127.9, 127.5, 118.0, 65.2, 34.2, 14.4; CNO2 not visible under these
conditions.
LC-MS (ESI+): tR = 1.17 min; m/z = 274.30 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H16N3O3: 274.1186; found:
1H NMR (200 MHz, CDCl3), 7.42 (d, J = 8.2 Hz, 2 H), 7.32 (d,
J = 8.2 Hz, 2 H), 6.88 (s, 2 H, CH=CH), 4.66 (s, 2 H), 1.66–0.75 (m,
27 H, SnBu3).
274.1185.
13C NMR (50 MHz, CDCl3): δ = 145.7, 140.2, 138.4, 129.9, 127.3,
126.3, 65.2, 29.2, 27.4, 13.8, 9.7.
(E)-4-[4-(Chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-imid-
azole (9)
To a 100-mL dry round-bottomed single-neck flask equipped with
a condenser was introduced alcohol 8 (1.52 g, 5.55 mmol) and
freshly distilled SOCl2 (15 mL) under an argon atmosphere. The
yellow mixture was vigorously stirred overnight at r.t. The excess
SOCl2 was distilled off. The crude product was triturated (PE–
CH2Cl2 and a drop of MeOH), filtered, and thoroughly washed with
PE leading to chloride 9 as a yellow solid; yield: 1.55 g (96%); mp
199 °C.
1H NMR (200 MHz, CDCl3): δ = 7.62 (s, 2 H, CH=CH), 7.46 (d,
J = 8.1 Hz, 2 H), 7.27 (d, J = 8.1 Hz, 2 H), 4.48 (s, 2 H), 3.77 (s, 3
H), 2.41 (s, 3 H).
(E)-Tributyl(4-{[(tetrahydro-2H-pyran-2-yl)oxy]meth-
yl}styryl)stannane (5)
A 100-mL round-bottomed single-neck flask equipped with a con-
denser, an argon gas inlet, and a magnetic stir bar was charged with
2-[(4-ethynylbenzyl)oxy]tetrahydro-2H-pyran (4, 4.0 g, 18.5
mmol), Bu3SnH (4.98 mL, 18.5 mmol), AIBN (121 mg), and tolu-
ene (45 mL). The flask was heated to 80 °C overnight under argon.
The mixture was then cooled to r.t., and all volatiles were removed
under reduced pressure to give a crude product that was purified by
column chromatography (PE then PE–EtOAc,9:1) to give 5 as a col-
orless oil; yield: 6.1 g (65%).
13C NMR (50 MHz, CDCl3): δ = 149.3, 141.6, 138.3, 136.5, 136.3,
129.1, 127.9, 118.0, 46.0, 34.2, 14.2; CNO2 not visible under these
conditions.
LC-MS (ESI+): tR = 3.60 min; m/z = 292.06 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H15N3O2Cl: 292.0847;
1H NMR (200 MHz, CDCl3): δ = 7.42 (d, J = 8.3 Hz, 2 H), 7.34 (d,
J = 8.3 Hz, 2 H), 6.88 (s, 2 H, CH=CH), 4.88–4.66 (m, 2 H), 4.51
(d, J = 12.2 Hz, 1 H), 4.02–3.86 (m, 1 H), 3.63–3.49 (m, 1 H), 1.96–
1.22 (m, 19 H), 1.03–0.88 (m, 14 H).
13C NMR (50 MHz, CDCl3): δ = 145.8, 138.3, 137.7, 129.6, 128.2,
126.1, 97.7, 68.6, 62.2, 30.7, 29.2, 27.4, 25.6, 19.5, 13.8, 9.7.
found: 292.0848.
(E)-1,2-Dimethyl-5-nitro-4-(4-{[(tetrahydro-2H-pyran-2-
yl)oxy]methyl}styryl)-1H-imidazole (7)
(E)-4-(4-Substituted)styryl-1,2-dimethyl-5-nitro-1H-imidazoles
10a–j; General Procedure
To a PEG-400 (15 mL) soln of 4-bromo-1,2-dimethyl-5-nitro-1H-
imidazole (6, 1.34 g, 6.08 mmol, 1 equiv) and styrylstannane 5 (4.01
g, 7.9 mmol, 1.3 equiv) was added PdCl2(PPh3)2 (171 mg, 0.24
mmol, 4 mol%) and CuI (46 mg, 0.24 mmol, 4 mol%) in a micro-
wave vial. The mixture was degassed with argon for 15 min and the
vial was sealed with a septum. Then, the mixture was heated in a mi-
crowave oven at 150 °C for 1 h. After cooling, the mixture was
quenched with sat. aq NaHCO3. The mixture was extracted with
EtOAc and the organic layer was washed with 5% KF solution and
brine. The organic layer was dried (Na2SO4) and the volatiles were
removed under vacuum. The crude was column chromatographed
A Schlenk tube equipped with a septum was charged with (E)-4-[4-
(chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-imidazole (9, 120
mg, 0.41 mmol,1 equiv) and electrophile (1.23 mmol, 3 equiv). The
tube was purged and filled with argon gas, and then anhydrous DMF
(6 mL) was added. The solution was stirred at –20 °C and TDAE
(125 μ L, 0.53 mmol, 1.3 equiv) was added dropwise via a syringe
and the mixture was kept at this temperature for 1 h under vigorous
stirring. The solution was then warmed to the required temperature
and for the required time (see Table 2); TLC analysis showed the to-
tal consumption of 9. The mixture was quenched with H2O (5 mL)
and EtOAc (15 mL) was added. The organic layer was washed with
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 348–356

354
N. Primas et al.
PAPER
H2O (3 × 15 mL), dried (Na2SO4), and finally concentrated under
vacuum. Purification of the crude product by column chromatogra-
phy (silica gel, CH2Cl2–acetone, 10:0 then 9:1) gave the corre-
sponding compound 10.
(E)-4-(2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-1-hydroxyethyl)benzonitrile (10e)
Yellow solid; yield: 83 mg (52%); mp 227 °C.
1H NMR (200 MHz, DMSO-d6): δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.62
(s, 2 H), 7.51 (d, J = 6.9 Hz, 4 H), 7.20 (d, J = 8.0 Hz, 2 H), 5.59 (d,
J = 4.7 Hz, OH), 4.88 (dd, J = 11.3, 6.1 Hz, 1 H), 3.80 (s, 3 H), 2.91
(d, J = 6.5 Hz, 2 H), 2.44 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 151.3, 150.3, 141.3, 139.7,
135.5, 134.5, 133.8, 131.9, 130.2, 127.0, 126.9, 119.0, 117.2, 109.5,
72.8, 44.9, 33.8, 13.8.
(E)-N-(2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-1-phenylethyl)-4-methylbenzenesulfonamide (10a)
Yellow solid; yield: 114 mg (54%); mp 232 °C.
1H NMR (200 MHz, DMSO-d6): δ = 8.30 (d, J = 7.2 Hz, 1 H, NH),
7.61 (s, 2 Halkene), 7.39 (d, J = 8.1 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2
H), 7.19–7.15 (m, 5 H), 7.13–7.00 (m, 4 H), 4.43 (d, J = 7.4 Hz, 1
H), 3.81 (s, 3 H), 2.83 (d, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.24 (s, 3
H).
13C NMR (50 MHz, DMSO-d6): δ = 150.3, 142.2, 141.7, 141.3,
139.0, 138.5, 135.5, 134.5, 134.0, 129.8, 129.0, 128.0, 126.9, 126.8,
126.6, 126.1, 117.2, 59.1, 43.1, 33.8, 20.9, 13.8.
LC-MS (ESI+): tR = 2.97 min; m/z = 389.10 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H21N4O3: 389.1608; found:
389.1610.
(E)-2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vinyl]phe-
nyl}-1-(4-nitrophenyl)ethanol (10f)
Yellow solid; yield: 70 mg (42%); mp 238 °C.
LC-MS (ESI+): tR = 4.06 min; m/z = 517.17 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H29N4O4S: 517.1904;
1H NMR (200 MHz, DMSO-d6): δ = 8.17 (d, J = 8.7 Hz, 2 H), 7.64–
7.48 (m, 6 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.67 (d, J = 4.7 Hz, OH),
4.95 (dd, J = 11.7, 6.4 Hz, 1 H), 3.80 (s, 3 H), 2.94 (d, J = 6.2 Hz, 2
H), 2.43 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 153.5, 150.3, 146.4, 141.3,
139.5, 135.5, 134.5, 133.9, 130.2, 127.2, 126.9, 123.1, 117.2, 72.6,
44.9, 33.8, 13.8.
found: 517.1903.
(E)-N-(2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-1-{4-methoxyphenyl}ethyl)-4-methylbenzenesul-
fonamide (10b)
Yellow solid; yield: 110 mg (49%); mp 235 °C.
1H NMR (200 MHz, DMSO-d6): δ = 8.19 (d, J = 8.7 Hz, 1 H, NH),
7.60 (s, 2 H), 7.35 (dd, J = 16.4, 7.9 Hz, 4 H), 7.21–6.91 (m, 6 H),
6.71 (d, J = 8.3 Hz, 2 H), 4.38 (dd, J = 15.7, 7.6 Hz, 1 H), 3.80 (s, 3
H), 3.68 (s, 3 H), 2.83 (d, J = 7.2 Hz, 2 H), 2.43 (s, 3 H), 2.25 (s, 3
H).
LC-MS (ESI+): tR = 3.39 min; m/z = 409.01 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H21N4O5: 409.1506; found:
409.1503.
13C NMR (50 MHz, DMSO-d6): δ = 158.1, 150.3, 141.6, 141.3,
139.1, 138.6, 135.5, 134.5, 134.0, 133.9, 129.8, 129.0, 127.8, 126.9,
126.1, 117.2, 113.3, 58.6, 55.0, 43.1, 33.8, 20.9, 13.8.
(E)-1-(2-Bromophenyl)-2-{4-[2-(1,2-dimethyl-5-nitro-1H-imid-
azol-4-yl)vinyl]phenyl}ethanol (10g)
Yellow solid; yield: 60 mg (33%); mp 198 °C.
1H NMR (200 MHz, CDCl3): δ = 7.72 (s, 2 H), 7.61 (dd, J = 7.7, 1.5
Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.40–7.24 (m, 4 H), 7.14 (td,
J = 7.7, 1.6 Hz, 1 H), 5.25 (dd, J = 9.3, 3.0 Hz, 1 H), 3.86 (s, 3 H),
3.17 (dd, J = 13.8, 3.0 Hz, 1 H), 2.76 (dd, J = 13.8, 9.3 Hz, 1 H),
2.43 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 149.3, 143.1, 142.4, 142.4, 139.7,
136.9, 134.9, 132.7, 130.1, 129.0, 127.9, 127.8, 127.5, 121.8, 117.3,
73.9, 44.2, 34.2, 14.2.
LC-MS (ESI+): tR = 3.90 min; m/z = 546.43 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H31N4O5S: 547.2010;
found: 547.2010.
(E)-N-(2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-1-{4-fluorophenyl}ethyl)-4-methylbenzenesulfon-
amide (10c)
Yellow solid; yield: 115 mg (52%); mp 240 °C.
1H NMR (200 MHz, DMSO-d6): δ = 8.30 (d, J = 8.8 Hz, 1 H), 7.60
(s, 2 H), 7.43–6.91 (m, 12 H), 4.46 (dd, J = 16.0, 7.6 Hz, 1 H), 3.79
(s, 3 H), 2.83 (d, J = 7.4 Hz, 2 H), 2.43 (s, 3 H), 2.24 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 161.1 (d, J = 242.6 Hz), 150.3,
141.9, 141.3, 138.8, 138.4, 138.2 (d, J = 3.0 Hz), 135.5, 134.5,
134.0, 129.8, 129.0, 128.6 (d, J = 8.2 Hz), 126.9, 126.1, 117.3,
114.6 (d, J = 21.3 Hz), 58.4, 43.1, 33.8, 20.9, 13.8.
LC-MS (ESI+): tR = 4.11 min; m/z = 441.93 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H21N3O3Br: 442.0761;
found: 442.0760.
Diethyl (E)-2-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]benzyl}-2-hydroxymalonate (10h)
Yellow solid; yield: 97 mg (55%); mp 153 °C.
1H NMR (200 MHz, CDCl3): δ = 7.70 (d, J = 1.4 Hz, 2 H), 7.50 (d,
J = 8.2 Hz, 2 H), 7.25 (d, J = 7.9 Hz, 2 H), 4.24 (q, J = 7.1 Hz, 4 H),
3.87 (s, 3 H), 3.34 (s, 2 H), 2.47 (s, 3 H), 1.28 (t, J = 7.1 Hz, 6 H).
13C NMR (50 MHz, CDCl3): δ = 170.0, 149.4, 142.5, 136.5, 135.8,
135.4, 130.9, 127.4, 117.8, 79.3, 62.8, 40.4, 34.1, 14.3, 14.1; CNO2
not visible under these conditions.
LC-MS (ESI+): tR = 3.35 min; m/z = 432.06 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H26N3O7: 432.1765; found:
LC-MS (ESI+): tR = 4.12 min; m/z = 534.96 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H28N4O4SF: 535.1810;
found: 535.1810.
(E)-1-(4-Chlorophenyl)-2-{4-[2-(1,2-dimethyl-5-nitro-1H-imid-
azol-4-yl)vinyl]phenyl}ethanol (10d)26
Yellow solid; yield: 78 mg (38%); mp 192 °C.
1H NMR (200 MHz, DMSO-d6): δ = 7.61 (s, 2 H), 7.50 (d, J = 8.1
Hz, 2 H), 7.33 (s, 4 H), 7.18 (d, J = 8.0 Hz, 2 H), 5.42 (d, J = 4.6 Hz,
OH), 4.78 (dd, J = 11.3, 6.1 Hz, 1 H), 3.78 (s, 3 H), 2.89 (d, J = 6.4
Hz, 2 H), 2.42 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 150.3, 144.5, 141.3, 140.0,
135.6, 134.4, 133.7, 131.2, 130.2, 127.9, 127.8, 126.8, 117.1, 72.8,
45.2, 33.8, 13.8.
432.1764.
Ethyl (E)-3-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-2-hydroxy-2-methylpropanoate (10i)
Yellow solid; yield: 109 mg (71%); mp 142 °C.
1H NMR (200 MHz, CDCl3): δ = 7.71 (s, 2 H), 7.51 (d, J = 8.2 Hz,
2 H), 7.20 (d, J = 8.1 Hz, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 3.87 (s, 3
H), 3.13 (s, 1 H, OH), 3.00 (dd, J = 31.5, 13.5 Hz, 2 H), 2.48 (s, 3
H), 1.49 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H).
LC-MS (ESI+): tR = 3.99 min; m/z = 398.05 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H21N3O3Cl: 398.1266;
found: 398.1268.
Synthesis 2014, 46, 348–356
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-(4-Substituted)styryl-5-nitro-1H-imidazoles
355
13C NMR (50 MHz, CDCl3): δ = 176.2, 149.4, 142.5, 137.3, 136.6,
135.1, 130.7, 127.4, 117.6, 75.2, 62.1, 46.2, 34.1, 26.1, 14.4, 14.3;
CNO2 not visible under these conditions.
LC-MS (ESI+): tR = 3.15 min; m/z = 374.14 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O5: 374.1710; found:
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374.1710.
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Ethyl (E)-3-{4-[2-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)vi-
nyl]phenyl}-2-hydroxypropanoate (10j)
Yellow solid; yield: 55 mg (37%); mp 112 °C.
1H NMR (200 MHz, CDCl3): δ = 7.71 (d, J = 1.3 Hz, 2 H), 7.53 (d,
J = 8.1 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 2 H), 4.43 (s, 1 H, OH), 4.22
(q, J = 7.1 Hz, 2 H), 3.87 (s, 3 H), 3.13 (dd, J = 13.9, 4.5 Hz, 1 H),
3.04–2.85 (m, 2 H), 2.47 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (50 MHz, CDCl3): δ = 174.2, 149.4, 142.6, 137.6, 136.5,
135.1, 130.1, 127.6, 117.7, 71.2, 61.9, 40.5, 34.1, 14.4, 14.3; CNO2
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HRMS (ESI): m/z [M + H]+ calcd for C18H22N3O5: 360.1554; found:
360.1555.
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Acknowledgment
This work was supported by the CNRS and Aix-Marseille Univer-
sity. The authors thank Michel Giorgi for the X-ray diffraction and
structure analysis. We warmly thank V. Remusat for recording 1H
and 13C NMR spectra and T. Schembri and D. Lafitte (Marseille
Protéomique - PIT2) for HRMS spectra. We thank also O. Khoume-
ri for providing the N-tosylimine derivatives.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York