A new synthetic approach for novel 4-substituted-5-nitroimidazoles

Article abstract of DOI:10.1016/S0040-4039(02)00767-0

A new synthetic approach, involving an S_RN1 reaction of the anion of 1-methyl-4-phenylsulfonyl-methyl-5-nitro-1H-imidazole with 2,2-dinitropropane and a radical anion or a concerted radical reductive elimination of sulfonyl and nitro groups affords an original 5-nitroimidazole bearing a trisubstituted ethylenic double bond at 4-position.

Full text of DOI:10.1016/S0040-4039(02)00767-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4127–4129
A new synthetic approach for novel
4-substituted-5-nitroimidazoles†
Maxime D. Crozet,a,b Patricia Perfetti,a Mustapha Kaafarani,a Patrice Vanellea,b,* and
Michel P. Crozeta
aLCMO, UMR 6517, Avenue Escadrille Normandie-Niemen, BP 562, 13997 Marseille Cedex 20, France
bLaboratoire de Chimie Organique, Faculte´ de Pharmacie, 27 Bd J. Moulin, 13385 Marseille Cedex 05, France
Received 17 April 2002; accepted 19 April 2002
Abstract—A new synthetic approach, involving an SRN1 reaction of the anion of 1-methyl-4-phenylsulfonyl-methyl-5-nitro-1H-
imidazole with 2,2-dinitropropane and a radical anion or a concerted radical reductive elimination of sulfonyl and nitro groups
affords an original 5-nitroimidazole bearing a trisubstituted ethylenic double bond at 4-position. © 2002 Elsevier Science Ltd. All
rights reserved.
The SRN1 reaction of 1-methyl-2-chloromethyl-5-nitro-
1H-imidazole with the lithium salt of a secondary
nitroalkane followed by nitrous acid elimination has
been shown to be a good method for the preparation of
Then, the VNS reaction is a powerful method to pre-
pare a phenylsulfone bearing 1-methyl-4-substituted-5-
nitro-1H-imidazole, which after removal of a proton by
a strong base to give the stabilized carbanion 2− could
be used as nucleophile for SRN1 reactions with various
nitro electrophiles. Indeed, Ono et al. have shown that
carbanions bearing a sulfonyl group and an electron-
withdrawing group (cyano, ethyl ester) are able to react
by SRN1 reaction with gem-dinitroalkanes.5
various 1-methyl-5-nitro-1H-imidazoles bearing
a
trisubstituted double bond in the 2 position.1 By this
method, very active compounds against anaerobic bac-
teria have been prepared.2 Because, 1-methyl-4-
chloromethyl-5-nitro-1H-imidazole is unknown and its
precursor, 1-methyl-4-hydroxymethyl-5-nitro-1H-imi-
dazole, is relatively difficult to synthesize,3 another
approach was necessary to prepare various 1-methyl-5-
nitro-1H-imidazoles bearing a trisubstituted double
bond in 4-position in order to compare their biological
activities with the 2-substituted isomers. The vicarious
nucleophilic substitution of hydrogen (VNS) in
nitroarenes with carbanions bearing leaving groups X
at the anion center is a process of general character and
significant practical value for organic synthesis. In 1-
methyl-5-nitro-1H-imidazole series, Makosza et al.
have been prepared by VNS reaction, 1-methyl-4-
phenylsulfonylmethyl-5-nitro-1H-imidazole 2 in 63%
yield from chloromethyl phenyl sulfone and the easily
available 1-methyl-5-nitro-1H-imidazole 1.4
On the other hand, a-nitrosulfones are useful synthetic
intermediates. For example, the lithium or sodium salts
of (phenylsulfonyl)nitromethane gave predominant C-
alkylation when treated with methyl iodide, primary
alkyl iodides, and benzylic bromides or iodides.6 This is
in sharp contrast to typical nitronates which give pre-
dominant O-alkylation under these conditions. So, the
study of the reactivity in SRN1 reaction of a carbanion
bearing a phenylsulfonyl group and a nitroheterocyclic
group with a gem-dinitroalkane to give 3 became an
interesting problem concerning scope and limitations of
SRN1 reaction. Finally, to complete the synthesis of
1-methyl-5-nitro-1H-imidazoles bearing a trisubstituted
double bond, it was of interest to examine the ease with
which the secondary sulfonyl group and the tertiary
nitro group could be eliminated in a radical anion7 or a
concerted radical reductive elimination8 from the b-
nitrosulfone 3. In this paper, we would like to report
that the stabilized carbanion 2− is able to react by the
SRN1 mechanism with different nitro electrophiles9 and
that 1-methyl-5-nitro-1H-imidazole bearing a trisubsti-
tuted double bond in 4 position as 4 can be prepared
according to the following scheme:
Keywords: SRN1 reaction; sulfonyl carbanion; C-alkylation; desul-
fonylation; 5-nitroimidazole.
* Corresponding author. Fax: 33
4
91 79 46 77; e-mail:
patrice.vanelle@pharmacie.univ-mrs.fr
This paper is dedicated to the late Professor Jean-Marie Surzur.
Deceased on January 24, 2002.
†
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00767-0

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M. D. Crozet et al. / Tetrahedron Letters 43 (2002) 4127–4129
Na2S, 9 H2O (1.5 equiv.) in DMF at room temperature
under argon with photostimulation to give after purifica-
tion by column chromatography (silica gel, ethyl acetate)
4 in 28% yield and 3% in 16% yield. A higher yield in 4
(55%) after column chromatography (silica gel, CHCl3/
Et2O: 6/4) was obtained with modification of the exper-
imental conditions described8 for reductive elimination
induced by tin radical (Bu3SnH, 2.5 equiv., AIBN, 0.9
equiv., 22 h).
First and foremost, it has been shown that the sodium
salt of 2 reacted with p-nitrobenzyl chloride, the classical
nitro electrophile to study a substitution reaction which
proceeds via radical anion intermediates,10 and that the
stabilized carbanion 2− reacted with p-nitrobenzyl chlo-
ride either by the SN2 mechanism, the SRN1 mechanism
or by the two mechanisms.
The sodium salt of 2 has been prepared from 2 in DMSO
under argon at room temperature by reaction of sodium
hydride (60% dispersion in mineral oil) and reacted with
p-nitrobenzyl chloride during 24 h under photostimula-
tion. After work-up and purification, the product 3a has
been obtained in 70% yield. The same reaction in presence
of p-dinitrobenzene11 (5% molar) gave 3a in 75% yield
showing no inhibition. To confirm that 2− is able to react
by SN2 mechanism with different primary alkyl halides,
the C-alkylation of 2− has been studied under the same
experimental conditions with benzyl bromide and methyl
iodide. The corresponding secondary sulfones 3b and 3c
have been obtained in, respectively, 81% and 84% yields.
The same yields of 3a–c are approximately obtained under
spontaneous initiation.
In conclusion, a new synthetic approach, involving an
SRN1 reaction of the stabilized anion formed from
1-methyl-4-phenylsulfonyl-methyl-5-nitro-1H-imidazole
with 2,2-dinitropropane and a radical anion or a con-
certed radical reductive elimination of sulfonyl and nitro
groups affords an original 5-nitroimidazole bearing a
trisubstituted ethylenic double bond at 4-position. The
extension of this direct and rapid radical approach to new
4-substituted-5-nitroimidazoles to more complex nitro
electrophiles and other nitroheterocyclic sulfones is in
progress in our laboratories.
References
1. Crozet, M. P.; Surzur, J.-M.; Vanelle, P.; Ghiglione, C.;
Maldonado, J. Tetrahedron Lett. 1985, 26, 1023–1026.
2. (a) Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau,
M. Eur. J. Med. Chem. 1991, 26, 167–178; (b) Jentzer, O.;
Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M.
Eur. J. Med. Chem. 1991, 26, 687–697; (c) Vanelle, P.;
Crozet, M. P. Recent Res. Dev. Org. Chem. 1998, 2,
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Pol. J. Chem. 1985, 55, 1055–1061; (b) Baker, D. C.; Putt,
S. R.; Showalter, H. D. H. J. Heterocycl. Chem. 1983, 20,
629–634.
Under photostimulation, a,p-dinitrocumene gave traces
of 3d and p,p%-dinitrobicumyl12 in 22% yield. By addition
of p-dinitrobenzene (5% molar), the formation of 3d
significantly increased (12% yield) showing that the SRN1
C-alkylation of 2− by a nitro electrophile at a tertiary
carbon atom is possible and p-dinitrobenzene with a
relatively slow electron-transfer chain reaction speeds up
the reaction.12
Under the experimental conditions (sodium salt, DMSO,
photostimulation, RT, argon, 24 h), 2,2-dinitropropane
(1 equiv.) gave after column chromatography (silica gel,
ethyl acetate) the desired compound 3 in 27% yield and
a mixture of 2 and 3% resulting from nitrous acid
elimination from 3. With a small excess (1.1 equiv.) of
2,2-dinitropropane or 2-bromo-2-nitropropane and
entrainment10 by the lithium salt of 2-nitropropane, 3 was
obtained in 38% yield with a mixture of 40% of 2 and
15% of 3% as calculated from 1H NMR spectra. To prepare
the alkene 4, first the experimental conditions for reduc-
tive elimination reaction induced by a reducing agent such
as Na2S were used. The b-nitrosulfone 3 was treated with
4. Makosza, M.; Kwast, E. Bull. Pol. Acc.: Chem. 1987, 35,
287–292.
5. Ono, N.; Tamura, R.; Nakatsuka, T.; Hayami, J.; Kaji,
A. Bull. Chem. Soc. Jpn. 1980, 53, 3295–3300.
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Morrow, S. D.; Hardinger, S. A.; Saft, M. S. J. Org.
Chem. 1981, 46, 765–770.
7. Kornblum, N.; Boyd, S. D.; Pinnick, H. W.; Smith, R. G.
J. Am. Chem. Soc. 1971, 93, 4316–4318.
8. Ono, N.; Kamimura, A.; Kaji, A. J. Org. Chem. 1987, 52,
5111–5116.

M. D. Crozet et al. / Tetrahedron Letters 43 (2002) 4127–4129
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1
9. 4-[1-Benzenesulfonyl-2-(4-nitrophenyl)-ethyl]-1-methyl-5-
nitro-1H-imidazole 3a: Yellow solid, mp 175°C (ethanol),
1H NMR 300 MHz (CDCl3) l 3.63 (dd, J=3.6 Hz,
J=13.8 Hz, 1H); 3.80–4.00 (m, 4H); 5.60 (dd, J=3.8 Hz,
J=11.7 Hz, 1H); 7.24–8.04 (m, 10H). 13C NMR 75 MHz
(CDCl3) l 32.4 (CH2); 36.1 (CH3); 63.9 (CH); 123.8
(CH); 128.9 (CH); 129.1 (CH); 129.9 (CH); 134.3 (CH);
135.8 (C); 137.1 (C); 139.9 (CH); 144.1 (C); 146.9 (C).
Anal. Calcd for C18H16N4O6S (416.41): C, 51.92; H, 3.87;
N, 13.45. Found: C, 52.12; H, 3.88; N, 13.50. 4-[1-Ben-
zenesulfonyl-2-phenyl-ethyl]-1-methyl-5-nitro-1H-imida-
mp 189–191°C (acetone/petroleum spirit 60–80: 3/5). H
NMR 300 MHz (CDCl3) l 1.67 (s, 3 H); 2.34 (s, 3 H);
3.88 (s, 3 H); 6.56 (s, 1 H); 7.42–7.66 (m, 6H). 13C NMR
75 MHz (CDCl3) l 23.9 (CH3); 27.1 (CH3); 36.2 (NCH3);
65.9 (CH); 89.5 (C); 128.3 (2CH); 129.2 (2CH); 133.8 (C);
134.5 (CH); 138.3 (C); 140.1 (CH); (C-NO2 not observed
under the conditions of this experiment). Anal. Calcd for
C14H16N4O6S (368.37): C, 45.65; H, 4.38; N, 15.21.
Found: C, 45.38; H, 4.38; N, 15.38. The structure of 3
was further confirmed by single crystal X-ray diffraction.
Crozet, M. D. Thesis, University of Aix-Marseille, in
preparation. 4-(1-Benzenesulfonyl-2-methyl-propenyl)-1-
methyl-5-nitro-1H-imidazole 3%: Pale yellow solid, mp
1
zole 3b: White solid, mp 163°C (ethanol). H NMR 300
MHz (CDCl3) l 3.52 (dd, J=3.6 Hz, J=13.6 Hz, 1H);
3.66–3.76 (m, 1H); 3.82 (s, 3H); 5.62 (dd, J=3.6 Hz,
J=11.7 Hz, 1H); 7.02–7.83 (m, 11H). 13C NMR 75 MHz
(CDCl3) l 33.14 (CH2); 36.4 (CH3); 64.9 (CH); 127.2
(CH); 128.9 (CH); 129.3 (CH); 129.4 (CH); 134.5 (CH);
136.7 (C); 137.1 (C); 138.0 (C); 138.2 (C); 140.4 (CH).
Anal. Calcd for C18H17N3O4S (371.41): C, 58.21; H, 4.61;
N, 11.31. Found: C, 57.91; H, 4.59; N, 11.35. 4-[1-Ben-
1
135–136°C (ethanol). H NMR 300 MHz (CDCl3) l 1.74
(s, 3H); 2.21 (s, 3H); 4.00 (s, 3H); 7.44–7.60 (m, 4H);
7.88–8.00 (m, 2H). 13C NMR 75 MHz (CDCl3) l 21.6
(CH3); 25.2 (CH3); 35.9 (NCH3); 127.5 (CH); 128.8 (CH);
131.0 (C); 132.9 (CH); 137.0 (C); 137.8 (C); 139.9 (CH);
142.4 (C); 155.7 (CH). Anal. Calcd for C14H15N3O4S
(321.35): C, 52.33; H, 4.70; N, 13.08. Found: C, 52.27; H,
4.71; N, 13.08. 4-(2-Methylpropenyl)-1-methyl-5-nitro-
1H-imidazole 4: Yellow solid, mp 106–107°C (hexane).
1H NMR 300 MHz (CDCl3) l 2.00 (s, 3H); 2.19 (s, 3H);
3.96 (s, 3H); 6.77 (s, 1H); 7.46 (s, 1H). 13C NMR 75 MHz
(CDCl3) l 20.7 (CH3); 27.9 (CH3); 35.9 (NCH3); 115.0
(CH); 139.9 (CH); 144.3 (C); 146.9 (C); (C-NO2 not
observed under the conditions of this experiment). Anal.
Calcd for C8H11N3O2 (181.19): C, 53.03; H, 6.12; N,
23.19. Found: C, 53.07; H, 6.06; N, 22.84.
zenesulfonyl-ethyl]-1-methyl-5-nitro-1H-imidazole
3c:
White solid, mp 156°C (ethanol). 1H NMR 300 MHz
(CDCl3) l 1.72 (d, J=7.0 Hz, 3H); 3.91 (s, 3H); 5.34 (q,
J=7.0 Hz, 1H); 7.46–7.80 (m, 6H). 13C NMR 75 MHz
(CDCl3) l 12.8 (CH3); 36.0 (CH3); 58.4 (CH); 128.9
(CH); 133.9 (CH); 137.3 (C); 138.1 (C); 140.0 (CH). Anal.
Calcd for C12H13N3O4S (295.32): C, 48.80; H, 4.44; N,
14.23. Found: C, 48.88; H, 4.44; N, 14.14. 4-[1-Benzene-
sulfonyl-2-methyl-2-(4-nitro-phenyl)-propyl]-1-methyl-5-
nitro-1H-imidazole 3d: Yellow solid, mp 225°C (ethanol),
1H NMR 300 MHz (CDCl3) l 1.67 (s, 3H); 2.07 (s, 3H);
3.77 (s, 3H); 5.95 (s, 1H); 7.30–8.04 (m, 10H). 13C NMR
75 MHz (CDCl3) l 26.3 (CH3); 27.6 (CH3); 36.1 (CH3);
43.7 (C); 69.7 (CH); 123.2 (CH); 127.2 (CH); 127.8 (CH);
128.7 (CH); 133.5 (CH); 137.6 (C); 139.8 (CH); 140.0 (C);
146.4 (C); 154.2 (C). Anal. Calcd for C20H20N4O6S
(444.46): C, 54.05; H, 4.54; N, 12.61. Found: C, 54.03; H,
4.58; N, 12.43. 4-(1-Benzenesulfonyl-2-methyl-2-nitro-
propyl)-1-methyl-5-nitro-1H-imidazole 3: White solid,
10. Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14,
734–745.
11. Chanon, M.; Tobe, M. L. Angew. Chem., Int. Ed. Engl.
1982, 21, 1–23.
12. Kornblum, N.; Cheng, L.; Davies, T. M.; Earl, G. W.;
Holy, N. L.; Kerber, R. C.; Kester, M. M.; Manthey, J.
W.; Musser, M. T.; Pinnick, H. W.; Snow, D. H.;
Stuchal, F. W.; Swiger, R. T. J. Org. Chem. 1987, 52,
196–204.