First single electron transfer reaction on propargylic chloride in 5-nitroimidazole series

Article abstract of DOI:10.1016/j.tetlet.2014.04.100

We report here the first example of an S_RN1 reaction on propargylic chloride in heterocyclic series. The reaction of 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole with nitronate anions led to both the formation of the C-alkylated pr

Full text of DOI:10.1016/j.tetlet.2014.04.100

Accepted Manuscript
First Single Electron Transfer Reaction on Propargylic Chloride in 5-Nitroimi-
dazole Series
Kévin Neildé, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
PII:
S0040-4039(14)00737-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.100
TETL 44562
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 March 2014
24 April 2014
28 April 2014
Please cite this article as: Neildé, K., Crozet, M.D., Terme, T., Vanelle, P., First Single Electron Transfer Reaction
on Propargylic Chloride in 5-Nitroimidazole Series, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.04.100
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First Single Electron Transfer Reaction on Propargylic
Chloride in 5-Nitroimidazole Series.
Leave this area blank for abstract info.
Kévin Neildé, Maxime D. Crozet, Thierry Terme, Patrice Vanelle*
R1
R1
NO2
R2
R1
R2
NO2 (2.5 equiv.)
Cl
R2
NaH (2.5 equiv.)
N
N
N
+
O2N
O2N
DMSO
r.t., h, N2
O2N
N
N
N
(11-12 %)
2 examples
(24-86 %)
7 examples

1
Tetrahedron Letters
journal homepage: www.elsevier.com
First Single Electron Transfer Reaction on Propargylic Chloride in 5-Nitroimidazole
Series.
Kévin Neildé, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
Aix-Marseille Univ, 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.
ARTICLE INFO
ABSTRACT
Article history:
Received
We report here the first example of an SRN1 reaction on a propargylic chloride in heterocyclic
series. The reaction of 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole with
Received in revised form
Accepted
Available online
nitronate anions led to both the formation of the C-alkylated product through an SRN1
mechanism and the predominant ethylenic compound resulting from nitrous acid elimination on
the C-alkylated product. Interestingly, in contrast to our previous works on SRN1 reactivity, no
O-alkylated product was observed.
Keywords:
Nitroimidazole
2009 Elsevier Ltd. All rights reserved.
SRN1
Propargylic chloride
Light irradiation
Single-electron transfer
The 5-nitroimidazole scaffold is well known for its
to treat Trypasonoma cruzi (Chagas disease)8 or Mycobacterium
tuberculosis.9 Straightforward access to new derivatives
belonging to the biologically relevant 5-nitroimidazole scaffold is
therefore likely to be of interest to the scientific community.
Since Kornblum10 and Russell11 originally proposed the
radical chain mechanism to explain the C-alkylation of nitronate
anions by p-nitrobenzyl chloride, unimolecular radical
nucleophilic substitution12 (SRN1 as per Bunnett13) has been found
to be a good synthetic pathway for many types of aromatic14 or
heterocyclic substrates.15 SRN1 enables the formation of C-C
bonds between an alkyl halide and a nitronate in relatively mild
conditions avoiding the use of organometallic species. Moreover,
it can give access to tri or tetrasubstituted olefins through nitrous
acid elimination from the substitution product. However, the
SRN1 reaction requires substrates with a suitable leaving group
and with an electron-attracting group at an appropriate position.
The 5-nitroimidazole moiety was found to be an excellent
substrate to perform SRN1.16
major anti-infectious activities.1 Several
5 nitroimidazole-
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 Nowadays, the leading
drug in the nitroimidazole family is metronidazole used
extensively for the treatment of infections caused by protozoa
such as Trichomonas vaginalis, Entamœba histolytica, Giardia
intestinalis, as well as infections induced by anaerobic bacteria.
However, the 5-nitroimidazoles have been found to possess a
high mutagenic activity in prokaryotic microorganisms. While
several hypotheses have been put forward,3 active research in this
area has not yet revealed a comprehensive mechanism for the
mutagenic and therapeutic activities of these compounds in
eukaryotic cells. Access to a nitroimidazole possessing good
pharmacological activities but with no mutagenicity4 would,
therefore, be of great interest not only from a safety point of view
but also as a basis for further investigations of the mode of action
and mechanism of expression of mutagenicity. Moreover, the
emergence of metronidazole-resistant T. vaginalis is resulting in
decreased success with current therapies.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
Recently, small nitro-group-containing heterocyclic derivatives,
including 5-nitroimidazole series (fexinidazole), have been
(2.0 equiv)
OH
R
Cl
Bu4NOAc (1.1 equiv)
Pd(PPh3)4 (0.05 equiv)
CuI (0.1 equiv)
SOCl2 (1.5 equiv)
Br
O2N
N
N
N
MeCN
MW
60 °C, 1 h
DMF
0°C, 30 min
O2N
O2N
N
N
N
1
2
93%
3 90%
Scheme 1. Preparation of propargylic chloride 3
In continuation of our research program centered on the
design and synthesis of novel bioactive molecules,17 this work
focused on the 4-position of the 5-nitroimidazole ring because it
a—ttr—acti—ng attention in other biological applications, for instance
 Corresponding author. Tel.: +33-491-835-573; fax: +33-486-136-822; e-mail: patrice.vanelle@univ-amu.fr

2
Tetrahedron Letters
had proved to be key modifying in the structure-mutagenicity
C-alkylated products 4 + 5 in good yields (Table 1, entries 1-3).
Moreover, the C-alkylated products formed slowly and poorly in
the absence of luminous irradiation (Table 1, entry 4). DMSO
proved to be the best solvent to perform the C-alkylation reaction
(Table 1, entries 2, 5-7, 11). Trials with DMF led to poorer yields
for the same reaction time (Table 1, entries 10-11) while
methanol and HMPA did not yield any C-alkylated products 4 +
5. DMSO should promote solvation of counteranions in 2-
nitropropane anion sodium or lithium salt better than DMF,
inducing higher base strength in 2-nitropropane anion.20 Norris
transfer phase conditions21 led mainly to starting chloride 3 with
degradation products and with no or poor yield of C-alkylated
compounds 4 + 5 (Table 1, entries 8-9). Contrary to benzylic
series, the choice of the counter cation of the nitropropane salt
proved to be an important parameter (Table 1, entries 2, 10). The
best results were defined by in situ generation of the 2-
nitropropane anion using NaH (Table 1, entries 10-17).
Subsequently, reaction time, solvent and number of equivalents
of the 2-nitropropane anion were tested (Table 1, entries 10-17)
to identify optimal conditions. Thus, the best C-alkylation 4 + 5
yield was obtained using 2.5 equivalents of the 2-nitropropane
anion in DMSO after 30 min under light irradiation (Table 1,
entry 14). 22
relationships.1e,4 Moreover, previous studies had indicated the
influence of the planarity of the substrate in SRN1 reactions.16f,18
A lack of planeness greatly influences SRN1 reactivity, since the
electron withdrawing group effect decreases, which lowers the
reducibility of the system. Therefore, the choice of a planar
substituent as the propargylic chloride on the 4-position of the
imidazole ring met the dual goals of anti-infectious
pharmacomodulation and exploring SRN1 reactions.
The required starting material for the SRN1 reaction is 4-
(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole
3
which was prepared in two sequential steps from 4-bromo-1,2-
dimethyl-5-nitro-1H-imidazole 1 (scheme 1). The only example
of SRN1 reaction performed on a triple bond was described by
Roche14f on
the 1-(3-chloroprop-1-ynyl)-4-nitrobenzene.
However, the electron transfer is closely connected to the
intramolecular electron delocalization toward the nitro group
which is very substrate dependent. Thus, an entire SRN1 reactivity
study
imidazole 3 was needed.
First, optimization reactions were performed (Table 1)
to identify the best SRN1 conditions between 3 and the
commercially available 2-nitropropane. The SRN1 reaction led to
the two expected products, C-alkylated product 4 and ethylenic
compound 5 resulting from nitrous acid elimination on C-
alkylated product 4 (Scheme 2). The by-product generally
observed during studies of SRN1 reactivity is a product with
aldehyde function resulting from an O-alkylation according to an
SN2 mechanism.10,11,12 Surprisingly, however, this by-product was
never observed in our conditions has monitored by LC/MS.
Moreover, contrary to our previous study14f on the 1-(3-
chloroprop-1-ynyl)-4-nitrobenzene, no trace of the nitrobut-1-
enyl derivatives was observed.
of
4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-
Under the latter conditions, ethylenic product 523 was
formed exclusively. The formation of 424 was favored by shorter
reaction times and/or fewer equivalents of the 2-nitropropane
anion (Table 1, entries 12, 13, 16) which decreased the overall
yield of C-alkylated products.
Table 2 Inhibition of reaction between 3 and 2 nitropropane
anion
Entry
Scavenger
None
TEMPO 0.1 Equiv
TEMPO 1 Equiv
O2 (bubbling)
p-DNB 1 Equiv
4 + 5 (%)
1
2
3
4
5
86
13
0
0
39
NO2
Cl
hv, N2
N
N
+
NO2
N
+
O2N
O2N
O2N
M
N
Solvent
N
N
In order to confirm the single electron transfer
mechanism (Scheme 3), inhibition reactions were performed
(Table 2) by adding to the optimal reaction conditions (Table 1,
entry 14) amounts of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), O2 or para-dinitrobenzene (p-DNB), commonly used
as inhibitiors in the mechanistic study of SRN1 reactions.
Indeed, these species are well known to act as a radical trap
4
5
3
Scheme 2. Reactivity of propargylic chloride 3 with the 2-
nitropropane anion under SRN1 conditions
Under Kornblum conditions14a-c (Table 1, entries 1-5), 6
equivalents of 2-nitropropane lithium salt were required to obtain
25
Table 1 Reactivity study of 3 with 2-nitropropane anion
Entrya
M
Equiv. of anion
Solvent
DMSO
DMSO
DMSO
DMSO
DMF
Time (h)
0.5
0.5
0.5
20
Yield 4 (%)
Yield 5 (%)
Yield C-alk 4+5 (%)
1
2
Li
Li
2
3
0
11
0
12
21
69
19
16
0
12
32
69
19
28
0
3
4b
Li
6
Li
3
0
5
Li
3
2
11
0
6
Li
3
HMPA
MeOH
CH2Cl2/H2O
CH2Cl2/H2O
DMSO
DMF
20
7
Li
3
20
0
0
0
8c
NBu4
NBu4
Na
Na
Na
Na
Na
Na
Na
Na
3
48
0
0
0
9d
3
48
2
5
7
10e
11e
12e
13e
14e
15e
16e
17e
3
0.5
0.5
0.5
0.5
0.5
0.5
0.25
1
0
86
58
40
71
86
85
62
84
86
58
52
78
86
85
72
84
3
0
1.5
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
12
7
2.5
4
0
0
2.5
2.5
10
0
a All reactions were performed under nitrogen and irradiation with a 60W fluorescent lamp. All yields refer to chromatographically isolated pure products.
b without fluorescent lamp.
c Phase transfer conditions with NBu4Br in water.
d Phase transfer conditions with NBu4OH in water.
e 2-nitropropane salt was formed in situ using NaH in DMSO or DMF and 2-nitropropane.

3
Cl
Following optimization, the best conditions developed
during the study with the 2-nitropropane anion (Table 1, entry
14) were applied to six other nitronate anions (cycloalkane,
aromatic, heterocyclic nitronates and nitroester) (Scheme 4). The
original C-alkylated products resulting from SRN1 reaction were
fully characterized.27 The corresponding nitroalkanes were either
commercially available (formation of SRN1 product 6-8) or
synthesized in one step by oxidation of amine using MCPBA15d
(formation of SRN1 product 9-11) or by nitration of N-
methypyrrolidone15d (formation of SRN1 product 12). As observed
with the 2-nitropropane anion, these conditions led almost
exclusively to ethylenic products 6-8 and 10-12, in 24% to 84%
yield of isolated product. Compound 12 with the N-
methypyrrolidone substituent, which has been shown to enhance
antiparasitic activity in 5-nitroimidazole series,27 reacted poorly
with the optimized conditions described above (Table 1, entry
14). However, Norris phase transfer conditions were the best
experimental conditions (45% yield) when the 1-methyl-3-
nitropyrrolidin-2-one anion was used to synthesize compound 12.
This result could be explained by the poor solubility of the N-
methypyrrolidone anion in DMSO.28
N
+
NO2
O2N
N
Step 1 : Initiation
NO2
NO2
Cl
N
Step 4 : Single
electron transfer
O2N
N
Step 2 : Unimolecular
Dissociation
Cl
N
O2N
N
Cl-
N
O2N
N
TEMPO
TEMPO
N
N
NO2
O2N
O2N
N
N
N
O2N
N
Step 3 : Coupling
NO2
Scheme 3. SRN1 mechanism of 3 with 2-nitropropane anion
(TEMPO, O2) or as electron acceptor (p-DNB) disrupting the
SRN1 cyclic mechanism (Scheme 3) by coupling with the
propargyl radical (TEMPO, O2) or by competing with 3 in the
electron transfer from the nucleophile during the initiation step
(p-DNB). Inhibition for the synthesis of C-alkylation products (4
+ 5) was observed with TEMPO (Table 2, entries 2-3), O2 (Table
2, entry 4) and p-DNB (Table 2, entry 5). The effects of these
inhibitors on the reaction between 3 and the 2-nitropropane anion
provide good evidence of the SRN1 mechanism in the C-
alkylation.12,26
Figure 1. Ortep plot of 1,2-Dimethyl-4-(4-methylpent-3-en-1-
ynyl)-5-nitro-1H-imidazole 5
The structure of compound 5 was unambiguously
confirmed by X-ray structure analysis (Figure 1).29 Concerning
the stereochemistry of the alkenes 8, 10, 11 and 12 resulting from
nitrous acid elimination on the C-alkylation product, E-
stereoisomer was the only isomer observed as confirmed by X-
ray analysis of crystal of 10 (Figure 2).30 The other structures
were assigned by analogy and spectral comparison.
N
O2N
N
6
64 %a
N
O
NO2
NO2
N
N
O2N
O2N
N
N
Cl
7
12
12 %a / 45 %b
O
84 %a
O2N
N
N
EtOOC
O2N
N
NO2
COOEt
3
NO2
Figure 2. Ortep plot of (E)-1,2-Dimethyl-5-nitro-4-(4-
phenylpent-3-en-1-ynyl)-1H-imidazole 10
N
N
N
O2N
O2N
N
NO2
11
31 %a
8
In conclusion, we report here the first example of SRN1
on a propargylic chloride in heterocyclic chemistry. After
optimization between 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-
24 %a
NO2
nitro-1H-imidazole 3 and the 2-nitropropane anion, SRN
1
products 4 + 5 were obtained in 86% yield. The methodology
was extended to other nitronate anions, notably to substituents
possessing features of biological interest. Furthermore, 4-(3-
chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole is shown
to constitute an outstanding substrate for SRN1 reactivity because
of the absence of any O-alkylated compound. This substrate
could be a good starting material for further single electron
transfer studies.
N
N
N
+
O2N
O2N
N
9
10
57 %a
11 %a
a General conditions: Nitroalkane (2.5 equiv.), NaH (2.5 equiv.); DMSO, r.t., h, 30 min.
b Under Norris phase transfer conditions.
Scheme 4. Reaction of 3 with various nitroalkane anions

4
Tetrahedron
9643. (f) Crozet, M. P.; Gellis, A.; Pasquier, C.; Vanelle, P.; Aune,
J.-P. Tetrahedron Lett. 1995, 36, 525. (g) Gellis, A.; Vanelle, P.;
Kaafarani, M.; Benakli, K.; Crozet, M. P. Tetrahedron 1997, 53,
5471. (h) Vanelle, P.; Gellis, A.; Kaafarani, M.; Maldonado, J.;
Crozet, M. P. Tetrahedron Lett. 1999, 40, 4343. (i) Gellis, A.;
Njoya, Y.; Crozet, M. P.; Vanelle, P. Synth. Commun. 2001, 31,
1257. (j) Njoya, Y.; Boufatah, N.; Gellis, A.; Rathelot, P.; Crozet,
M. P.; Vanelle, P. Heterocycles 2002, 57, 1423. (k) Njoya, Y.;
Gellis, A.; Crozet, M. P.; Vanelle, P. Sulfur Lett. 2003, 26, 67. (l)
Gellis, A.; Boufatah, N.; Vanelle, P. Green Chem. 2006, 8, 483. (m)
Kabri, Y.; Gellis, A.; Vanelle, P. Green Chem. 2009, 11, 201.
16. (a) Vanelle, P. ; Crozet, M. P. Recent Res. Devel. Organic Chem.
1998, 2, 547. (b) Vanelle, P. ; Benakli, K. ; Maldonado, J. ; Crozet,
M. P. Heterocycles 1998, 48, 181. (c) Benakli, K.; Kaafarani, M.;
Crozet, M. P.; Vanelle, P. Heterocycles 1999, 51, 557. (d) Benakli,
K.; Terme, T.; Vanelle, P. Molecules 2002, 7, 382. (e) Benakli, K.;
Terme, T.; Maldonado, J.; Vanelle, P. Heterocycles 2002, 57, 1689.
(f) Zink, L.; Crozet, M. D.; Terme, T.; Vanelle, P. Tetrahedron
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Acknowledgment
This work is supported by the CNRS and the Aix-
Marseille University. The authors thank the Spectropole team for
elemental analysis, HRMS spectra recording and for X-ray
analysis. We express our thanks to V. Remusat for H and 13C
1
NMR spectra recording. K. Neildé is grateful to the French
ministry of higher education and research for a doctoral
fellowship.
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22. General procedure for the synthesis of compound 4-12 via SRN
1
reactions: In a 100 mL two-necked round flask, to NaH 60% (94
mg, 2.34 mmol; 2.5 equiv.) under N2 was added nitroalcane (2.34
mmol, 2.5 equiv.) in anhydrous DMSO (4 mL). The reaction
mixture was stirred at room temperature for 30 min, then 4-(3-
chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole 3 was added
in anhydrous DMSO under N2. The reaction mixture was stirred
under light irradiation until disappearance of the starting material as
monitored by TLC and LC-MS, diluted in cold water (10 mL) and
extracted with EtOAc (6 x 20 mL). The combined organic layers
were washed with brine (3 x 100 mL), dried under Na2SO4 and
concentrated under vacuum. The crude product was purified by
column chromatography on silica gel with the corresponding eluent
and recrystallized with the corresponding solvent to afford SRN
1
13. Bunnett, J. F.; Kim, J. K. J. Am. Chem. Soc. 1970, 92, 7463.
14. (a) Kornblum, N.; Pink, P.; Yorka, K. V. J. Am. Chem. Soc. 1961,
83, 2779. (b) Kornblum, N.; Pink, P. Tetrahedron 1963, 19(suppl.
1), 17. (c) Kornblum, N.; Davies, T. M.; Earl, G. W.; Holy, N. L.;
Kerber, R. C.; Musser, M. T.; Snow, D. H. J. Am. Chem. Soc. 1967,
89, 725. (d) Burt, B. L.; Freeman, D. J.; Gray, P. G.; Norris, R. K.;
Randles, D. Tetrahedron Lett. 1977, 3063. (e) Barker, S. D.; Norris,
R. K. Tetrahedron lett. 1979, 11, 973. (e) Benakli, K. ; Terme, T.;
Vanelle, P. Synthetic Commun. 2002, 32, 1859. (f) Roche, M.;
Terme, T.; Vanelle, P. Tetrahedron Lett. 2012, 53, 4184.
15. (a) Crozet, M. P.; Archaimbault, G.; Vanelle, P.; Nouguier, R.
Tetrahedron Lett. 1985, 26, 5133. (b) Vanelle, P.; Maldonado, J.;
Madadi, N.; Gueiffier, A.; Teulade, J.-C.; Chapat, J.-P.; Crozet, M.
P. Tetrahedron Lett. 1990, 31, 3013. (c) Crozet, M. P.; Giraud, L.;
Sabuco, J.-F.; Vanelle, P.; Barreau, M. Tetrahedron Lett. 1991, 32,
4125. (d) Vanelle, P.; Madadi, N.; Roubaud, C.; Maldonado, J.;
Crozet, M. P. Tetrahedron 1991, 28, 5173. (e) Roubaud, C.;
Vanelle, P.; Maldonado, J.; Crozet, M. P. Tetrahedron 1995, 51,
product 4-12. Microwave-assisted reactions were performed in a
Biotage Initiator Microwave oven using 0.5–2 mL sealed vials;
temperatures were measured with an IR-sensor and reaction times
are given as hold times.
Methods for the analytical data of compound 4-12: Melting points
were determined with a B-540 Büchi melting point apparatus. 200
1
MHz H NMR and 50 MHz 13C NMR spectra were recorded on a
Bruker ARX 200 spectrometer in CDCl3 or DMSO-d6 solution at
the Faculty of Pharmacy of Marseille. 1H and 13C NMR chemical
shifts () 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)]. Elemental analyses were carried out at the
Spectropole, Faculty of Sciences (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 x 10 cm aluminum plates coated with silica gel 60F-254
(Merck) in an appropriate eluting solvent. Visualization was made

5
with ultraviolet light (234 nm). Purity of synthesized compounds
was checked with LC-MS analyses which were realized 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 is a
Thermo Hypersil Gold® 50 × 2.1 mm (C18 bounded), with particles
of 1.9 μm diameter. The volume of sample injected on the column
was 1 μL. The chromatographic analysis, total duration of 8 min, is
3H),4.26 (q, J = 7.1 Hz, 2H), 6.86 (q, J = 1.4 Hz, 1H). 13C NMR
(50 MHz, CDCl3):  = 14.3 (CH3), 14.3 (CH3), 15.9 (CH3), 34.2
(CH3), 61.4 (CH2), 92.0 (C), 93.1 (C), 118.1 (CH), 125.9 (C),
142.5 (C), 149.5 (C), 166.8 (C). C-NO2 was not observed in this
experiment. LC-MS tr = 2.53 min; (ESI+) m/z 278 [M+H]+, 555
[2M+H]+. HRMS (ESI+): m/z [M+H]+ calcd. for C13H15N3O4:
278.1135; found: 278.1140.
1,2-Dimethyl-5-nitro-4-(4-nitro-4-phenylpent-1-ynyl)-1H-
imidazole (9): Compound 9 was isolated after purification by
column chromatography on silica gel (eluent: CH2Cl2–PE, 95:05)
and recrystallization from cyclohexane. Yield: 34 mg (11%);
made with the gradient of following solvents:
t = 0 min,
water/methanol 50/50; 0 < t < 4 min, linear increase in the
proportion of water to a ratio water/methanol 95/5; 4 < t < 6 min,
water/methanol 95/5; 6 < t < 7 min, linear decrease in the
proportion of water to return to a ratio 50/50 water/methanol; 6 < t
< 7 min, water/methanol 50/50. The water used was buffered with 5
mM ammonium acetate. The retention times (tr) of the molecules
analyzed are indicated in min.
1
beige powder; mp 139 °C. H NMR (200 MHz, CDCl3):  = 2.24
(s, 3H), 2.43 (s, 3H), 3.58 (dd, J1 = 51.5Hz , J2 = 17.2Hz, 2H),
3.85 (s, 3H), 7.36-7.49 (m, 5H). LC-MS tr = 2.58 min; (ESI+) m/z
329 [M+H]+, 657 [2M+H]+. HRMS (ESI+): m/z [M+H]+ calcd. for
C16H16N4O4: 329.1244; found: 329.1242.
23. 1,2-Dimethyl-4-(4-methylpent-3-en-1-ynyl)-5-nitro-1H-imidazole
(5): Compound 5 was isolated after purification by column
chromatography on silica gel (eluent: CH2Cl2–PE, 8:2) and
recrystallization from cyclohexane. Yield: 176 mg (86 %); yellow
powder; mp 159 °C. 1H NMR (200 MHz, CDCl3):  = 1.88 (s, 3H),
2.06 (s, 3H), 2.45 (s, 3H), 3.88 (s, 3H), 5.53 (s, 1H). 13C NMR (50
MHz, CDCl3):  = 14.3 (CH3), 21.7 (CH3), 25.4 (CH3), 34.1 (CH3),
83.9 (C), 96.3 (C), 104.9 (CH), 127.7 (C), 149.3 (C), 154.1 (C). C-
NO2 was not observed in this experiment. LC-MS tr = 2.20 min;
(ESI+) m/z 220 [M+H]+, 439 [2M+H]+. HRMS (ESI+): m/z [M+H]+
calcd. for C11H13N3O2: 220.1081; found: 220.1082.
24. 1,2-Dimethyl-4-(4-methyl-4-nitropent-1-ynyl)-5-nitro-1H-imidazole
(4): Compound 4 was isolated after purification by column
chromatography on silica gel (eluent: CHCl3–PE, 8:2 then 1:0) and
recrystallization from cyclohexane. Yield: 28 mg (12%); beige
solid; mp 132 °C.1H NMR (200 MHz, CDCl3):  = 1.77 (s, 6H),
2.45 (s, 3H), 3.16 (s, 2H), 3.88 (s, 3H). 13C NMR (50 MHz,
CDCl3):  = 14.2 (CH3), 25.7 (2 x CH3), 31.9 (CH2), 34.2 (CH3),
76.1 (C), 86.9 (C), 92.2 (C), 125.9 (C), 149.1 (C). LC-MS tr = 1.21
min; (ESI+) m/z 267 [M+H]+, 533 [2M+H]+. HRMS (ESI+): m/z
[M+H]+ calcd. for C11H14N4O4: 267.1088; found: 267.1087.
(E)-1,2-Dimethyl-5-nitro-4-(4-phenylpent-3-en-1-ynyl)-1H-
imidazole (10): Compound 10 was isolated after purification by
column chromatography on silica gel (eluent: CH2Cl2–PE, 8:2)
and recrystallization from cyclohexane. Yield: 120 mg (57%);
yellow powder; mp 154 °C. 1H NMR (200 MHz, CDCl3):  = 2.50
(m, 6H), 3.92 (s, 3H), 6.17 (s, 1H), 7.34-7.53 (m, 5H). 13C NMR
(50 MHz, CDCl3):  = 14.3 (CH3), 19.1 (CH3), 34.2 (CH3), 87.3
(C), 96.5 (C), 105.8 (CH), 125.8 (2 x CH), 127.4 (C), 128.6
(2xCH), 128.8 (CH), 140.5 (C), 149.5 (C), 152.6 (C). C-NO2 was
not observed in this experiment. LC-MS tr = 3.65 min; (ESI+) m/z
282 [M+H]+, 563 [2M+H]+. HRMS (ESI+): m/z [M+H]+ calcd. for
C16H15N3O2: 282.1237; Found: 282.1242. Anal. Calcd for
C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C,68.05; H,5.41;
N, 14.68.
(E)-4-[3-(3,4-Dihydronaphthalen-1(2H)-ylidene)prop-1-ynyl]-1,2-
dimethyl-5-nitro-1H-imidazole (11): Compound 11 was isolated
after purification by column chromatography on silica gel (eluent:
CH2Cl2–PE, 6:4) and recrystallization from cyclohexane. Yield:
1
103 mg (31%); yellow powder; mp 163 °C. H NMR (200 MHz,
CDCl3):  = 1.92 (qt, J = 6.3Hz, 2H), 2.52 (s, 3H), 2.84 (t, J =
6.2Hz, 2H), 2.99 (t, J = 6.3Hz, 2H), 3.93 (s, 3H), 6.32 (s, 1H),
7.12-7.26 (m, 3H), 7.63-7.67 (m, 1H). 13C NMR (50 MHz,
CDCl3):  = 14.4 (CH3), 23.0 (CH2), 30.0 (CH2), 30.7 (CH2), 34.2
(CH3), 88.4 (C), 97.0 (C), 101.5 (CH), 124.0 (CH), 126.4 (CH),
127.6 (C), 129.1 (CH), 129.5 (CH), 133.9 (C), 138.9 (C), 149.5
(C), 152.5 (C). C-NO2 was not observed in this experiment. LC-
MS tr = 4.15 min; (ESI+) m/z 308 [M+H]+, 615 [2M+H]+. HRMS
(ESI+): m/z [M+H]+ calcd. for C18H17N3O2: 308.1394; found:
308.1394.
25. Chanon, M.; Tobe, M. L. Angew. Chem. Int. Ed. Engl. 1982, 21, 1.
26. (a) Kerber, R.C.; Urry, G. W.; Kornblum, N. J. Am. Chem. Soc.
1965, 87, 4520. (b) Feuer, H.; Doty, J. K.; Kornblum, N. J.
Heterocycl. Chem. 1978, 15, 1419.
27. 4-(3-Cyclopentylideneprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-
imidazole (6): Compound 6 was isolated after purification by
column chromatography on silica gel (eluent: CH2Cl2–PE, 8:2) and
recrystallization from cyclohexane. Yield: 148 mg (64%); yellow
powder; mp 136 °C. 1H NMR (200 MHz, CDCl3):  = 1.74 (m,
4H), 2.46 (m, 2+3H), 2.63 (m, 2H), 3.89 (s, 3H), 5.66 (s, 1H). 13C
NMR (50 MHz, CDCl3):  = 14.3 (CH3), 26.2 (CH2), 26.7 (CH2),
33.0 (CH2), 34.1 (CH3), 34.5 (CH2), 84.4 (C), 96.8 (C), 99.8 (CH),
127.9 (C), 138.4 (C), 149.3 (C), 166.9 (C). LC-MS tr = 3.24 min;
(ESI+) m/z 246 [M+H]+, 491 [2M+H]+. HRMS (ESI+): m/z
[M+Na]+ calcd. for C13H16N3O2: 246.1237; found: 246.1236.
4-(3-Cyclohexylideneprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-
(E)-3-[3-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)prop-2-
ynylidene]-1-methylpyrrolidin-2-one (12): Compound 12 was
isolated after purification by column chromatography on silica gel
(eluent: CH2Cl2–MeOH, 98:2) and recrystallization from
1
cyclohexane. Yield: 90 mg (35%); yellow powder; mp 216 °C. H
NMR (200 MHz, DMSO-d6):  = 2.51 (s, 3H), 2.98 (s, 3H), 3.05
(td, J1 = 6.1Hz , J2 = 3.1Hz, 2H), 3.48 (t, J = 6.1Hz, 2H), 3.93 (s,
3H), 6.56 (t, J = 3.1Hz, 1H). 13C NMR (50 MHz, DMSO-d6):  =
14.3 (CH3), 24.5 (CH2), 30.5 (CH3), 34.3 (CH3), 46.7 (CH2), 89.5
(C), 96.2 (C), 108.6 (CH), 126.1 (C), 147.5 (C), 149.5 (C), 166.9
(C). C-NO2 was not observed in this experiment. LC-MS tr = 0.78
min; (ESI+) m/z 275 [M+H]+, 549 [2M+H]+. HRMS (ESI+): m/z
[M+H]+ calcd. for C13H15N4O3: 275.1139; found: 275.1141.
28. Jentzer, O.; Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M.
Eur. J. Med. Chem. 1991, 26, 687.
29. CCDC 980833 contains the supplementary crystallographicdata of
compound 5 for this paper. These data can be obtained free of
charge from The CambridgeCrystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
30. CCDC 980834 contains the supplementary crystallographicdata of
compound 10 for this paper. These data can be obtained free of
charge from The CambridgeCrystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
imidazole (7): Compound 7 was isolated after purification by
column chromatography on silica gel (eluent: CH2Cl2–PE, 8:2)
and recrystallization from cyclohexane. Yield: 205 mg (84%);
yellow powder; mp 111 °C. 1H NMR (200 MHz, CDCl3):  = 1.60
(s, 6H), 2.24 (m, 2H), 2.45 (s, 3H), 2.59 (m, 2H), 3.89 (s, 3H),
5.50 (s, 1H). 13C NMR (50 MHz, CDCl3):  = 14.3 (CH3), 26.3
(CH2), 27.8 (CH2), 28.4 (CH2), 32.2 (CH2), 34.1 (CH3), 36.4
(CH2), 83.7 (C), 96.2 (C), 101.4 (CH), 127.7 (C), 138.4 (C), 149.3
(C), 161.5 (C). LC-MS tr = 3.65 min; (ESI+) m/z 260 [M+H]+, 519
[2M+H]+. HRMS (ESI+): m/z [M+Na]+ calcd. for C14H18N3O2:
260.1394; found: 260.1390. Anal. Calcd for C14H17N3O2: C, 64.85;
H, 6.61; N, 16.20. Found: C,64.75; H,6.73; N, 15.84.
(E)-Ethyl 5-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)-2-methylpent-
2-en-4-ynoate (8): Compound 8 was isolated after purification by
column chromatography on silica gel (eluent: CH2Cl2) and
recrystallization from cyclohexane. Yield: 63 mg (24%); yellow
1
powder; mp 98 °C. H NMR (200 MHz, CDCl3):  = 1.32 (t, J =
7.1 Hz, 3H), 2.23 (d, J = 1.4 Hz, 3H), 2.51 (s, 3H), 3.93 (s,

NO2
Cl
h , N2
N
NO2
N
+
N
+
O2N
O2N
O2N
M
N
N
Solvent
N
4
5
3
Scheme 2