Long distance-SRN1 in nitroimidazole series favored by temperature

Article abstract of DOI:10.1016/j.tetlet.2011.10.096

New reductive alkylating agents in 4- and 5-nitroimidazole series produce exclusively O-alkylation with nitronate anions under classical S_RN1 conditions at room temperature. Electron-transfer C-alkylation is observed under microwave irradiation

Full text of DOI:10.1016/j.tetlet.2011.10.096

Tetrahedron Letters 52 (2011) 6991–6996
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Long distance-SRN1 in nitroimidazole series favored by temperature
⇑
Laura Zink, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
Aix-Marseille Univ., Laboratoire de Pharmaco-Chimie Radicalaire, LPCR, Faculté de Pharmacie, CNRS, UMR 6264: Laboratoire Chimie Provence, 27 Bd Jean Moulin,
13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
New reductive alkylating agents in 4- and 5-nitroimidazole series produce exclusively O-alkylation with
nitronate anions under classical SRN1 conditions at room temperature. Electron-transfer C-alkylation is
observed under microwave irradiation or under conventional heating. Furthermore, X-ray spectroscopy
shows that the dihedral angles between the phenyl and imidazole rings for the two series are different,
which could greatly influence reactivity in 4- and 5-nitroimidazole series.
Received 12 September 2011
Revised 11 October 2011
Accepted 17 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Single-electron transfer
LD-SRN
1
Microwave heating
Nitroimidazole
X-ray spectroscopy
5-nitroimidazole scaffold is known to display major anti-infec-
tious activities.1 Several 5-nitroimidazole-containing active princi-
ples are commonly used in medicine. These chemotherapeutic
agents inhibit the growth of anaerobic bacteria and of some anaer-
obic protozoa.2 Nowadays, 2-(2-methyl-5-nitro-1H-imidazol-1-
yl)ethanol (metronidazole) is the drug compound most frequently
used clinically for the treatment of infections caused both by pro-
tozoa such as Trichomonas vaginalis, Entamœba histolytica, Giardia
intestinalis, and by anaerobic bacteria.
this reaction at sp3 carbon have been studied extensively.13 These
studies showed that ambident nitronate anion reacted by O-alkyl-
ation with benzylic halides. For example, benzyl chloride led to
benzaldehyde only by O-alkylation with the 2-nitropropane anion
from an SN2 mechanism. In contrast, p-nitrobenzyle chloride re-
acted by C-alkylation with the 2-nitropropane anion, leading to
the C-alkylated product.
Our previous study investigated a new SRN1 reaction on (E)-2-[4-
(chloromethyl)styryl]-1-methyl-5-nitro-1H-imidazole, involving a
long distance (10 bonds) between the electron-withdrawing and
leaving groups (LD-SRN1). Unfortunately, when the chloride reacted
with 2-nitropropane anion under various suitable conditions for the
However, 5-nitroimidazoles have been found to possess high
mutagenic activity in prokaryotic micro-organisms.3 Moreover,
the emergence of metronidazole-resistant T. vaginalis is currently
affecting therapeutic success.4,5 These refractory cases are usually
treated with higher doses of metronidazole, which leads to
increased side effects.5,6 A nitroimidazole offering good pharmaco-
logical activities against metronidazole-resistant T. vaginalis and
G. intestinalis, with no mutagenicity, would be of great interest.1b,e,7,8
Unimolecular radical nucleophilic substitution (SRN1) has been
found to be an excellent synthetic pathway for many types of aro-
matic, heterocyclic, or aliphatic substrates with suitable leaving
groups,9 requiring substrates substituted with an electron-attract-
ing group at the appropriate position.
S
RN1 reaction (inert atmosphere, light), it only led to the aldehyde
derivative through an SN2 process (Scheme 1).14
These reactions are usually performed in DMSO at room
temperature under inert atmosphere and photostimulation in or-
der to initiate the SRN1, but the influence of temperature on the
competition between SN2 and SRN1 has never been evaluated.
Moreover, Geske showed in 1964 that the planarity of the nitro-
benzyl group has an influence on this competition.15 Indeed, o-nitro-
benzyl chloride was more difficult to reduce than p-nitrobenzyl
chloride, and provided 52% of o-nitrobenzaldehyde by O-alkylation.
This has been established via the steric hindrance between the nitro
group and the chloromethyl group on the phenyl ring in the ortho
isomer, which decreased the coplanarity in the molecule. The
system became less reducible by tending electronically to isolate
the nitro group from the ring.
Since Kornblum10 and Russell11 originally proposed the radical
chain mechanism to explain the C-alkylation of nitronate anions
by p-nitrobenzyl chloride, later designated as SRN1 (unimolecular
radical nucleophilic substitution) by Bunnett,12 the extensions of
To further our work on SRN1 (LD-SRN1) reactivity and its limits
in 5-nitroimidazole series and as part of a program aimed at the
preparation of new and potentially safer nitroimidazoles, we
⇑
Corresponding author. Tel.: +33 4 91835573; fax: +33 4 86136822.
E-mail addresses:
patrice.vanelle@univmed.fr,
patrice.vanelle@pharmacie.
univ-mrs.fr (P. Vanelle).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.096

6992
L. Zink et al. / Tetrahedron Letters 52 (2011) 6991–6996
N
O
90%
0%
O2N
N
N
NO2
H
X
O2N
N
N
O2N
O2N
N
Scheme 1. (E)-2-[4-(Chloromethyl)styryl]-1-methyl-5-nitro-1H-imidazole reactivity with 2-nitropropane anion.
Br
O2N
O2N
Br
Br
O2N
N
N
N
N
Br2
O2N
DMS
N
H
1
N
H
N
H
2 90%
N
NaHCO3
DMF, 70 ºC
DMF 100 ºC,
2.5h
3 24% (5-NO2 series)
4 23% (4-NO2 series)
2h
Pd(PPh3)4
DME, EtOH
Na2CO3
HO
OH
OH
Cl
HO
B
MW 150 W
N
N
SOCl2
O2N
O2N
r.t., 16 h
N
N
5 87% (5-NO2 series)
5' 54% (4-NO2 series)
6 100% (5-NO2 series)
6' 100% (4-NO2 series)
Scheme 2. Preparation of LD-SRN1 precursors 6 and 60.
prepared 4(5)-[4-(chloromethyl)phenyl]-1,2-dimethyl-5(4)-nitro-
1H-imidazoles and studied their reactivities with different nucleo-
philes, under SRN1 experimental conditions (LD-SRN1), in order to
determine the reactivity of both isomers.
The starting material was obtained by the bromination of
commercial 2-methyl-4(5)-nitro-1H-imidazole 1 with elemental
bromine in DMF, methylation of 2 by dimethylsulfate to obtain 3,
which was then subjected to a Suzuki–Miyaura cross-coupling
reaction to synthesize [4-(1,2-dimethyl-5-nitro-1H-imidazol-
4-yl)phenyl]methanol 5.16 Chlorination of 5 with thionyl chloride
The first result in Table 1 shows that 6 reacts with the 2-nitro-
propane anion to give exclusively 1018 (entries 2, 6) resulting from
an SN2 O-alkylation with good yields under the usual SRN1 condi-
tions described by Kornblum (65% in DMSO–72% in DMF) at room
temperature. Different SRN1 reaction conditions were therefore
examined, in order to study their influence on reactivity. Under
conventional heating (oil-bath heating) in DMSO at 170 °C, a mix-
ture of the expected C-alkylated products 8 (36%) and 9 (43%)
resulting from the consecutive SRN1 C-alkylation and base-pro-
moted nitrous acid elimination were obtained (entry 8) without
aldehyde 10. In DMF at 140 °C, the reaction gave 8 (57%) and 10
(12%) (entry 4), but no trace of compound 9. DMSO should solvate
counterion in 2-nitropropane anion sodium salt better than DMF,
inducing higher base strength in 2-nitropropane anion.19
With these encouraging results and on the basis of our previous
studies,20 we decided to evaluate the influence of microwave irra-
diation on the LD-SRN1 reaction. The best microwave-assisted
experimental conditions were defined, yielding in DMF a mixture
of 821 (60%), 10 (22%), and the appearance of 921 (10%) (Table 1, en-
try 5). In DMSO, these conditions allowed the formation of 9 in 60%
yields (entry 9).
provided
4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-
imidazole 6,17 which appeared to be a good candidate to investigate
LD-SRN1 (six bonds) (Scheme 2).
Furthermore, as alkylammonium chlorides are known to be
poor leaving groups in SN2 reactions,9 we decided to synthesize
and study the reactivity of N-[4-(1,2-dimethyl-5-nitro-1H-imida-
zol-4-yl)benzyl]-N,N-diethylethanaminium chloride 7. N,N,N-Tri-
ethylethanaminium chloride derivative 7 was prepared in 94%
yield from 6 with triethylamine (2 equiv) in anhydrous acetone
at 44 °C for 24 h (Scheme 3).
Thus, no ‘specific effect’ (non-thermal effect)22 from microwave
irradiation was found and thermal effect alone appears sufficient
to affect the main reaction from SN2 to SRN1.
As shown in entry 11 (Table 1), the use of the best experimental
conditions cited above (Table 1, entry 5) with compound 7 gave a
mixture of expected products 8 (44%) and 9 (32%). Moreover, no
trace of aldehyde derivative was observed. These results suggest
that both substrates 6 and 7 formed C-alkylated product by LD-
Cl-
Cl
N+
anhydrous acetone
N
44 ºC, 24 h
N
N
2 equiv
O2N
N
O2N
SRN1.
N
In order to confirm the single-electron transfer mechanism,
inhibition reactions were performed (Table 2) by adding to the
reaction mixture catalytic amounts (10 mol %) of cupric chloride
(CuCl2) or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), which
6
7 94%
Scheme 3. Preparation of 7.

L. Zink et al. / Tetrahedron Letters 52 (2011) 6991–6996
6993
Table 1
Reactivity study of 6 and 7 through LD-SRN
1
O2N
R
H
O
NO2
N
N
N
N
O2N
+
O2N
+
O2N
O2N
N
N
N
N
6 R = Cl
9
7 R = (Et)3N+Cl-
8
10
Entry
Substrate
Equiv anion
Solvent
Time (h)
Conditions
N2, dark, rt
8 (%)
9 (%)
10 (%)
1
2
3
4
5
6
7
8
6
6
6
6
6
6
6
6
6
7
7
6
6
6
6
6
3
6
6
6
3
6
DMF
DMF
DMF
DMF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
48
—
—
—
—
—
—
10
—
33
43
60
—
73
72
—
12
22
62
Traces
—
N2, h
m
, rt
N2, dark, 140 °C
140 °C
MW 140 °C
N2, hm, rt
N2, dark, 170 °C
170 °C
56
57
60
—
28
36
—
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
9
10
11
MW 170 °C
—
22
—
N2, h
m
, rt
—
44
0.5
MW 140 °C
32
The reactivity of 6 was investigated with the nitrocyclopentane
Table 2
Inhibition reactions with 2-nitropropane aniona
anion. As a result, formation of the expected C-alkylation products
was observed under microwave heating in 19–22% overall yield
(Table 3, entries 4 and 5). Under SRN1 classical conditions, aldehyde
10 was formed with up to 98% yield (Table 3, entry 3).
The nature of the nucleophile is crucial for SRN1 reactions and
necessitates an understanding of the relationship between the
nucleophile and the substrate in single-electron transfer
reactions.13b
Entry
Inhibitor (0.1 equiv)
8 (%)
9 (%)
10 (%)
1
2
3
—
60
25
8
10
14
10
22
22
27
CuCl2
TEMPO
a
All reactions performed using 1 equiv of 6, 6 equiv of 2-nitropropane anion in
DMF under microwave irradiation, at 140 °C, for 0.5 h.
In order to extend the reaction to a variety of nucleophiles, the
study next explored the S-centered anion (Scheme 4).23 The reac-
tion between 4-methylbenzenesulfinic acid sodium salt and 6 in
DMSO at 100 °C under microwave irradiation gave the required
S-alkylated product 1324 in good yield (79%).
To identify the main mechanism of the reaction, the reactivity
of this latter reaction was studied by adding an inhibitor (Table
4, entries 2 and 3). The reaction rate decrease is less significant
than with 2-nitropropane anion, indicating that the reaction could
possibly result from a combination of SN2 and SRN1 mechanisms.
are commonly employed inhibitors used to provide mechanistic
study of SRN1 reactions.9h,13a The reaction times were identical
for the inhibition study and corresponded to the conditions in Ta-
ble 1, entry 5 without an inhibitor.
Inhibition for the production of 8 was observed with TEMPO
and CuCl2. The effects of classical inhibitors13a on the reaction of
6 with the 2-nitropropane anion leading to 8 and 9 provide good
evidence for assigning the SRN1 mechanism for the C-alkylation.
Table 3
Reactivity of 6 with the nitrocyclopentane anion
O2N
Cl
H
O
NO2
6 equiv
N
N
N
N
O2N
O2N
NaH
O2N
O2N
N
N
N
N
12
10
11
6
Entry
Solvent
Conditions
Time (h)
10 (%)
11 (%)
12 (%)
1
DMF
N2, h
N2, h
N2, h
MW 170 °C
MW 140 °C
m
m
m
, rt
, rt
, rt
3
65
50
98
—
—
—
—
22
4
—
—
—
—
15
2
DMFb
DMSO
DMSO
DMF
24
0.3
0.2
0.5
3a
4
5
43
a
The reaction was induced by adding a catalytic amount of nitropropane anion.
DMF distilled.
b

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L. Zink et al. / Tetrahedron Letters 52 (2011) 6991–6996
Cl
O
S
O
O
O
S
N
2 equiv
O2N
N
N
6
DMSO MW 100 ºC
0.5 h
13 79%
O2N
N
Scheme 4. Reactivity of 6 with 4-methylbenzenesulfinic acid sodium salt.
Figure 1. Ortep plot of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-
imidazole 6.
Table 4
Inhibition reactions with 4-methylbenzenesulfinic acid sodium salt
a
Entry
Inhibitor (0.1 equiv)
13 (%)
1
2
3
—
79
55
46
CuCl2
TEMPO
a
All reactions performed using 1 equiv of 6, 2 equiv of 4-methylbenzenesulfinic
acid sodium salt, in DMSO under microwave irradiation, at 100 °C, for 0.5 h.
In order to compare the influence of the 4- versus 5-position of
the nitro group on the imidazole ring through LD-SRN1, the 5-[4-
(chloromethyl)phenyl]-1,2-dimethyl-4-nitro-1H-imidazole 60 was
synthesized through the same synthesis pathway as 6 from 4
and the reactivity with C-centered and S-centered anions was stud-
ied24 (Table 5).
The reaction of 60 with 2-nitropropane anion under experimen-
tal conditions as defined in Table 1 (entry 5) provides the expected
product 90 in 49% yield. However, the C-alkylation products in 5-
nitroimidazole series were obtained in 70% overall yield. Although,
thermal effect was required to observe an SRN1 reactivity, yields
obtained in 4-nitroimidazole series were generally lower than in
5-nitroimidazole series. This surprising result encouraged us to
study the structure by X-ray analysis of a crystal of 625 and 60.26
We observed that the dihedral angles between the two planes
formed by the phenyl and imidazole rings (N1–C1–C6–C11) were,
Figure 2. Ortep plot of 5-[4-(chloromethyl)phenyl]-1,2-dimethyl-4-nitro-1H-imid-
azole 60.
respectively 39.8° (6) and 55.2° (60) (Fig. 1 and 2). These different
dihedral angle values may greatly affect reactivity in 4- and 5-
nitroimidazole series.
Table 5
Reactivity of 60 through LD-SRN
1
O
O
O2N
O2N
S
N
N
O
Cl
N
S
R
N
DMF r.t. 24 h
O
6'
13' 93%
O2N
O2N
O2N
N
N
N
R
nitronate
anion
R
N
R
N
O
N
O2N
H
8' R = CH3
10'
9' R = CH3
12' R = -(CH2)3-
11' R = -(CH2)3-
Entry
Anion 6 equiv
Conditions
N2, h , rt
140 °C
Time (h)
80 (%)
90 (%)
100 (%)
110 (%)
120 (%)
1
2
2-Nitropropanea
m
48
0.5
0.5
3
—
17
—
—
—
—
—
49
—
—
98
18
—
98
—
—
—
—
—
—
—
—
—
—
3
MW 140 °C
4c
5
Nitrocyclopentaneb
N2, h
m, rt
MW 170 °C
0.2
Traces
a
b
c
2-Nitropropane anion was dissolved in DMF.
Nitrocyclopentane anion was formed in situ using NaH in DMSO.
The reaction was induced by adding a catalytic amount of 2-nitropropane anion.

L. Zink et al. / Tetrahedron Letters 52 (2011) 6991–6996
6995
17. Juspin, T.; Zink, L.; Crozet, M. D.; Terme, T.; Vanelle, P. Molecules 2011, 16,
6883–6893.
The different yields observed could be explained by a lower elec-
tronic conjugated system between the phenyl and imidazole rings.
Indeed, it has been established that a lack of planeness greatly influ-
ences SRN1 reactivity,15 since the electron-withdrawing group does
not function properly, which lowers the reducibility of the system.
In conclusion, we have shown in this Letter that 4-[4-(chloro-
18. General procedure of classical conditions: 2-Nitropropane anion (6 equiv) was
added to a solution of 6 or 60 (1 equiv) in DMF or DMSO (25 mL) in a nitrogen-
flushed flask. The mixture was irradiated with a 60 W tungsten lamp and
stirred for 0.5 h. Then, the mixture was poured into cold H2O. The aqueous
solution was extracted with CHCl3. The organic layers were washed with brine,
dried (Na2SO4) and evaporated under reduced pressure. The product was
purified by chromatography column on SiO2 (ethyl acetate). 4-(1,2-Dimethyl-5-
nitro-1H-imidazol-4-yl)benzaldehyde (10): Yellow crystals, mp 190 °C (toluene).
1H NMR (200 MHz, CDCl3): d 2.54 (s, 3H), 3.94 (s, 3H), 7.93 (s, 4H), 10.06 (s, 1H).
13C NMR (50 MHz, CDCl3): d 14.1 (CH3), 34.2 (CH3), 129.3 (2ꢀCH), 130.1
(2ꢀCH), 136.5 (C), 137.6 (C), 141.6 (C), 148.5 (C), 191.78 (CHO). Anal. Calcd for
methyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole
6 and 5-[4-
(chloromethyl)phenyl]-1,2-dimethyl-4-nitro-1H-imidazole 60 react
with various carbon- and sulfur-centered anions by substitution at
the chloromethyl group. The reaction with C-centered nucleophiles
is very probably mediated by the SRN1 mechanism and is greatly
influenced by thermal effect. Heating leads to a major inversion of
rate between SN2 and SRN1 processes. These results constitute the
first example of a specific LD-SRN1 reactivity promoted by the ther-
mal effect. Investigations with other nitronate anions and antipara-
sitic evaluation of synthesized compounds are currently in progress.
C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 59.34; H, 4.70; N, 16.90.
19. Reichardt, C. In Solvents and Solvent Effects in Organic Chemistry, Second ed.;
VCH Verlagsgesellschaft: Weinheim, 1988; pp 5–50.
20. (a) Vanelle, P.; Gellis, A.; Kaafarani, M.; Maldonado, J.; Crozet, M. P. Tetrahedron
Lett. 1999, 40, 4343–4346; (b) Gellis, A.; Njoya, Y.; Crozet, M. P.; Vanelle, P.
Synth. Commun. 2001, 31, 1257–1262; (c) Njoya, Y.; Boufatah, N.; Gellis, A.;
Rathelot, P.; Crozet, M. P.; Vanelle, P. Heterocycles 2002, 57, 1423–1432; (d)
Njoya, Y.; Gellis, A.; Crozet, M. P.; Vanelle, P. Sulfur Lett. 2003, 26, 67–75; (e)
Gellis, A.; Boufatah, N.; Vanelle, P. Green Chem. 2006, 8, 483–487; (f) Kabri, Y.;
Gellis, A.; Vanelle, P. Green Chem. 2009, 11, 201–208.
Acknowledgments
21. General procedure of conventional heating: 2-Nitropropane anion (6 equiv) was
added to a solution of 6 or 60 (1 equiv) in DMF or DMSO (25 mL) in a nitrogen-
flushed flask. The mixture is placed in an oil-bath previously heated to 140 °C
(DMF) or (170 °C) and stirred for 0.5 h. After cooling, the mixture was poured
into cold H2O. The aqueous solution was extracted with CHCl3. The organic
layers were washed with brine, dried (Na2SO4) and evaporated under reduced
pressure. The product was purified by chromatography column on SiO2 (ethyl
acetate/chloroform mixtures). General procedure of microwave experimental
conditions: 2-nitropropane anion (6 equiv) was added to a solution of 6 or 60
(1 equiv) in DMF or DMSO (25 mL) and then heated to 140 °C (DMF) or 170 °C
(DMSO) for 0.5 h under microwave irradiation (200 W). After cooling, the
mixture was poured into cold H2O. The aqueous solution was extracted with
CHCl3. The organic layers were washed with brine, dried (Na2SO4) and
evaporated under reduced pressure. The product was purified by
chromatography column on SiO2. Microwave-assisted reactions were
performed in a multimode ETHOS Synth Lab station and MicroSYNTH Lab
terminal 1024 (Ethos start, Milestone Inc.) ovens. 1,2-Dimethyl-4-[4-(2-methyl-
2-nitropropyl)phenyl]-5-nitro-1H-imidazole (8): Brown oil, 1H NMR (200 MHz,
CDCl3): d 1.58 (s, 6H), 2.53 (s, 3H), 3.25 (s, 2H), 3.91 (s, 3H), 7.17 (d, J = 8.3 Hz,
2H), 7.70 (d, J = 8.3 Hz, 2H). 13C NMR (50 MHz, CDCl3): d 13.9 (CH3), 25.6
(2ꢀCH3), 34.3 (CH3), 46.4 (CH2), 88.5 (C), 129.7 (2ꢀCH), 129.9 (2ꢀCH), 130.3
This Letter is supported by the CNRS and the Universities of Aix-
Marseille. The authors thank the Spectropole team for various ana-
lytical measurements, and M. Giorgi for the X-ray crystal-structure
determinations. We express our thanks to V. Remusat for 1H and
13C NMR spectra recording.
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(C), 136.6 (C), 142.2 (C), 148.2 (C). HRMS calcd for
C
15H18N4O4 [M+H]+:
319.1401, found: 319.1400. 1,2-Dimethyl-4-[4-(2-methylprop-1-enyl)phenyl]-5-
nitro-1H-imidazole (9): Yellow crystal, mp 108 °C (i-PrOH). 1H NMR (200 MHz,
CDCl3): d 1.89 (d, J = 1.2 Hz, 3H), 1.90 (d, J = 1.2 Hz, 3H), 2.52 (s, 3H), 3.90 (s,
3H), 6.29 (br s, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H). 13C NMR
(50 MHz, CDCl3): d 14.1 (CH3), 19.5 (CH3), 27.0 (CH3), 34.1 (CH3), 124.8 (CH),
128.4 (2ꢀCH), 128.8 (C), 129.2 (2ꢀCH), 136.7 (C), 140.0 (C), 143.4 (C), 148.2 (C).
HRMS calcd for C15H17N3O2 [M+H]+: 272.1394, found: 272.1400.
22. Kappe, C. O.; Stadler, A. In Microwaves in Organic and Medicinal Chemistry;
Mannhold, R., Kubinyi, H., Folkers, G., Eds.; WILEY-VCH GmbH & Co. KGaA:
Weinheim, 2005; Vol. 25,.
23. (a) Kornblum, N.; Kestner, M. M.; Boyd, S. D.; Cattran, L. C. J. Am. Chem. Soc.
1973, 95, 3356–3361; (b) Norris, R. K.; Wright, T. A. Aust. J. Chem. 1985, 38,
1107–1116; (c) Palacios, S. M.; Alonso, R. A.; Rossi, R. A. Tetrahedron 1985, 41,
4147–4156; (d) Miyake, H.; Yamamura, K. Bull. Chem. Soc. Jpn. 1986, 59, 89–91.
24. 1,2-Dimethyl-5-nitro-4-[4-(tosylmethyl)phenyl]-1H-imidazole
(13):
Yellow
neddle, mp 198 °C (i-PrOH). 1H NMR (200 MHz, CDCl3): d 2.40 s, 3H), 2.52 (s,
3H), 3.90 (s, 3H), 4.33 (s, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H),
7.50 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H). 13C NMR (50 MHz, CDCl3): d 14.0
(CH3), 21.6 (CH3), 34.2 (CH3), 62.8 (CH2), 128.7 (2ꢀCH), 129.6 (2ꢀCH), 129.7
(2ꢀCH), 130.5 (2ꢀCH), 131.8 (C), 134.8 (2ꢀC), 142.1 (C), 144.8 (2ꢀC), 148.2 (C).
Anal. Calcd for C19H19N3O4S: C, 59.21; H, 4.97; N, 10.90; S, 8.32. Found: C,
59.25; H, 5.03; N, 10.98; S, 8.35. 1,2-Dimethyl-5-[4-(2-methylprop-1-
enyl)phenyl]-4-nitro-1H-imidazole (90): Yellow oil, 1H NMR (200 MHz, CDCl3):
d 1.92 (d, J = 1.0 Hz, 3H), 1.94 (d, J = 1.0 Hz, 3H), 2.50 (s, 3H), 3.41 (s, 3H), 6.30
(br s, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H). 13C NMR (50 MHz,
CDCl3): d 13.6 (CH3), 19.6 (CH3), 27.1 (CH3), 31.9 (CH3), 124.3 (CH), 124.3 (C),
129.0 (2ꢀCH), 129.9 (2ꢀCH), 132.9 (C), 137.5 (C), 140.5 (C), 143.8 (C). HRMS
calcd for C15H17N3O2 [M+H]+: 272.1394, found: 272.1395. 4-(1,2-Dimethyl-4-
nitro-1H-imidazol-5-yl)benzaldehyde (100): White powder, mp 163 °C (i-PrOH).
1H NMR (200 MHz, CDCl3): d 2.50 (s, 3H), 3.42 (s, 3H), 7.57 (d, J = 8.2 Hz, 2H),
8.03 (d, J = 8.2 Hz, 2H), 10.10 (s, 1H). 13C NMR (50 MHz, CDCl3): d 13.4 (CH3),
31.9 (CH3), 127.0 (C), 129.8 (2ꢀCH), 131.0 (2ꢀCH), 133.1 (C), 136.9 (C), 143.0
(C), 144.6 (C), 191.3 (CHO). Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N,
17.13. Found: C, 58.87; H, 4.64; N, 16.87. 1,2-Dimethyl-4-nitro-5-[4-
(tosylmethyl)phenyl]-1H-imidazole (130): Yellow neddle, mp 224 °C (i-PrOH).
1H NMR (200 MHz, CDCl3): d 2.43 (s, 3H), 2.51 (s, 3H), 3.40 (s, 3H), 4.35 (s, 2H),
7.30 (s, 6H), 7.56 (d, J = 8.3 Hz, 2H). 13C NMR (50 MHz, CDCl3): d 13.5 (CH3),
21.6 (CH3), 31.9 (CH3), 62.6 (CH2), 127.8 (C), 128.5 (2ꢀCH), 129.7 (2ꢀCH), 130.3
(C), 130.3 (2ꢀCH), 131.3 (2ꢀCH), 131.8 (C), 134.8 (C), 143.0 (C), 144.1 (C), 145.1
(C). Anal. Calcd for C19H19N3O4S: C, 59.21; H, 4.97; N, 10.90; S, 8.32. Found: C,
59.36; H, 5.08; N, 10.84; S, 8.30.
9. (a) Kornblum, N.; Pink, P.; Yorka, K. V. J. Am. Chem. Soc. 1961, 83, 2779–2780;
(b) Crozet, M. P.; Archaimbault, G.; Vanelle, P.; Nouguier, R. Tetrahedron Lett.
1985, 26, 5133–5134; (c) Vanelle, P.; Maldonado, J.; Madadi, N.; Gueiffier, A.;
Teulade, J.-C.; Chapat, J.-P.; Crozet, M. P. Tetrahedron Lett. 1990, 31, 3013–3016;
(d) Crozet, M. P.; Giraud, L.; Sabuco, J.-F.; Vanelle, P.; Barreau, M. Tetrahedron
Lett. 1991, 32, 4125–4128; (e) Roubaud, C.; Vanelle, P.; Maldonado, J.; Crozet,
M. P. Tetrahedron 1995, 51, 9643–9656; (f) Crozet, M. P.; Gellis, A.; Pasquier, C.;
Vanelle, P.; Aune, J.-P. Tetrahedron Lett. 1995, 36, 525–528; (g) Gellis, A.;
Vanelle, P.; Kaafarani, M.; Benakli, K.; Crozet, M. P. Tetrahedron 1997, 53, 5471–
5484; (h) Rossi, R. A.; Pierini, A. B.; Peñéñori, A. B. Chem. Rev. 2003, 103, 71–167.
10. Kornblum, N.; Michel, R. E.; Kerber, R. C. J. Am. Chem. Soc. 1966, 88, 5660–5662.
11. Russell, G. A.; Danen, W. C. J. Am. Chem. Soc. 1966, 88, 5663–5665.
12. Bunnett, J. F.; Kim, J. K. J. Am. Chem. Soc. 1970, 92, 7463–7464.
13. (a) Chanon, M.; Tobe, M. L. Angew. Chem., Int. Ed. 1982, 21, 1–86; (b) Russell, G.
A. Adv. Phys. Org. Chem. 1987, 23, 271–322; (c) Bowman, W. R. In Photoinduced
Electron Transfer: Photoinduced Nucleophilic Substitution at sp3-Carbon, Part C;
Fox, M. A., Chanon, M., Eds.; Elsevier: Amsterdam, 1988; pp 487–552. Chap.
4.8; (d) Kornblum, N. Aldrichim. Acta 1990, 23, 71–78; (e) Savéant, J.-M. Adv.
Phys. Org. Chem. 1990, 26, 1–130.
14. Benakli, K.; Kaafarani, M.; Crozet, M. P.; Vanelle, P. Heterocycles 1999, 51, 557–
565.
15. (a) Geske, D. H.; Ragle, J. L.; Bambenek, M. A.; Balch, A. L. J. Am. Chem. Soc. 1964,
86, 987–1002; (b) Kerber, R. C.; Urry, G. W.; Kornblum, N. J. Am. Chem. Soc.
1965, 87, 4520–4528.
16. Crozet, M. D.; Zink, L.; Rémusat, V.; Curti, C.; Vanelle, P. Synthesis 2009, 3150–
3156.

6996
L. Zink et al. / Tetrahedron Letters 52 (2011) 6991–6996
25. Crystal
data
for
compound
6:
C12H12ClN3O2,
yellow
prisms
26. Crystal
Data
for
compound
MW = 265.70,
60:
C12H12ClN3O2,
orthorhombic,
brown
space
prisms,
group,
(0.22 ꢀ 0.14 ꢀ 0.12 mm3), MW = 265.70, orthorhombic, space group,
(0.22 ꢀ 0.18 ꢀ 0.1 mm3),
P2(1)2(1)2(1) (T = 293 K), a = 7.4952(2) Å, b = 12.8330(3) Å, c = 13.1171(5) Å,
P2(1)2(1)2(1) (T = 293 K) a = 7.7310(2) Å, b = 10.1625(2) Å, c = 15.9718(5) Å,
a
l
= 90°, b = 90°,
c
= 90°; V = 1261.68(7) Å3, Z = 4, Dcalc = 13.99 g cmꢁ1
,
a
l
= 90°, b = 90°,
c
= 90°; V = 1254.85(6) Å3, Z = 4, Dcalc = 14.06 g cmꢁ1
F(000) = 552, index ranges 0 6 h 6 10, 0 6 k 6 13,
,
= 0.3 mmꢁ1, F(000) = 552, index ranges 0 6 h 6 9, 0 6 k 6 17, 0 6 l 6 17; h
= 0.302 mmꢁ1
,
range = 3.13–28.73°, 163 variables and 0 restraints, were refined for 1310
0 6 l 6 21; h range = 2.38–28.71°, 165 variables and 0 restraints, were refined
for 1388 reflections with I P 2 I to R1 = 0.0589, wR2 = 0.1898, GooF = 1.155.
reflections with I P 2 to R1 = 0.0702, wR2 = 0.1656, GooF = 1.077. CCDC
rI
r
825743 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
data_request/cif of from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; email:
deposit@ccdc.cam.ac.uk.
CCDC 825744 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
data_request/cif of from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; email:
deposit@ccdc.cam.ac.uk.