Synthesis of new 3-nitroimidazo[1,2-a]pyridine derivatives by S RN1 reactions

Article abstract of DOI:10.3987/COM-08-11396

6,8-Dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine was prepared and reacted under experimental conditions of S_RN1 reactions with different carbon and sulfur centered nucleophiles to determine the relative reactivities of the different typ

Full text of DOI:10.3987/COM-08-11396

HETEROCYCLES, Vol. 75, No. 9, 2008
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HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2263 - 2274. © The Japan Institute of Heterocyclic Chemistry
Received, 20th March, 2008, Accepted, 1st May, 2008, Published online, 8th May, 2008. COM-08-11396
SYNTHESIS OF NEW 3-NITROIMIDAZO[1,2-a]PYRIDINE
DERIVATIVES BY SRN1 REACTIONS
Rémi Szabo, Maxime D. Crozet, and Patrice Vanelle*
Universities of Aix-Marseille I, II, and III – CNRS, UMR 6264: Provence
Chemistry Laboratory, Radical Pharmaco-Chemistry Team (LPCR), Faculty of
Pharmacy, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France
Fax: 33 4 91 79 46 77; Email: patrice.vanelle@pharmacie.univ-mrs.fr
Abstract – 6,8-Dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine was
prepared and reacted under experimental conditions of SRN1 reactions with
different carbon and sulfur centered nucleophiles to determine the relative
reactivities of the different types of electrophile halides. Depending on the
nucleophile nature, the chloromethyl group and bromine atom in 8-position were
found to be reacting under these experimental conditions. An SRN1 reaction on
the pyridine part of the imidazo[1,2-a]pyridine is described for the first time.
INTRODUCTION
Imidazo[1,2-a]pyridine derivatives are currently the object of a renewed interest in the pharmacological
field.1,2 Many recent publications report their pharmacological activities in various biological areas. For
example, gastric antisecretory,3 local anesthetic,4 antiviral,5 hypnotic6,7 and anxiolytic8 properties have
been described. It is particularly in the field of the central nervous system that the activity of this skeleton
appears to have currently the most importance, contributing in particular to a better comprehension of the
mechanism of action of psychotropic drugs.9
Unimolecular radical nucleophilic substitution (SRN1) has been found to be an excellent method for many
types of aromatic, heterocyclic and aliphatic substrates with suitable leaving groups.10,11 In continuation
of our study of the reactivity in 2-chloromethyl-3-nitroimidazo[1,2-a]pyridine series in electron transfer
reactions12-13 and as part of a program directed to the preparation of more complex structures of
pharmacological interest,14-16 we have prepared 6,8-dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyri-
dine and studied their reactivity with different nucleophiles under SRN1 experimental conditions, in order
to determine the relative reactivity of the different electrophile halides.

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HETEROCYCLES, Vol. 75, No. 9, 2008
RESULTS AND DISCUSSION
The starting material 1 was easily obtained by condensation of commercial 2-amino-3,5-dibromopyridine
with 1,3-dichloroacetone in ethanol to give 6,8-dibromo-2-chloromethylimidazo[1,2-a]pyridine which was
nitrated with 65% nitric acid at the 3-position.16 In SRN1 experimental conditions, the nitronate, malonate
(Scheme 1, Table 1) and sulfinate (Scheme 2, Table 3) anions react only on the chloromethyl group at the
2-position of the 6,8-dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine (1) in DMSO under nitrogen
with photostimulation to give the corresponding products in moderate yields (30-94 %).
The reactions with C-centered nucleophile anions were performed using 3 equivalents of nitroalkane or
malonate derivatives in DMSO. In order to form the corresponding carbanions, we used 60% NaH in
DMSO.17
In agreement with previous works, photoinduced consumption of substrate (1) by various anions
increased in DMSO.18 Furthermore, solvation effects have been shown with dipolar aprotic solvents that
can exert a strong influence on formation and reactivity of radical anions.
Under SRN1 experimental conditions (inert atmosphere, photostimulation), the reaction with nitroalkane
anions gave the ethylenic derivatives (2-6) resulting from the consecutive C-alkylation and nitrous acid
elimination from C-alkylated product.
Scheme 1
R1
Br
R1
2
3
4
5
6
R1=R2=Me
94%
83%
59%
91%
30%
O2N
R1=H, R2=Me
R1,R2= -(CH2)4-
R1,R2= -(CH2)5-
R1=R2=CO2Et
R2
N
R2
N
Br
Br
NO2
NaH
DMSO
Cl
N
N
CO2R'
CO2R'
hν / N2
Br
R
Br
NO2
R
64%
57%
61%
67%
7
8
9
R=H, R'=Me
R=H, R'=Et
R=Me, R'=Et
CO2R'
CO2R'
N
1
10 R=Ph, R'=Et
N
Br
NO2
In order to confirm the single electron transfer in the reaction of 1 with 2-nitropropane or diethyl
phenylmalonate sodium salts, we added classical inhibitors19 (TEMPO and CuCl2) and we have compared
the reaction rates (Table 2). For a coherent comparison, reaction times were identical for inhibition study
and corresponded to the optimized conditions without inhibitor. These reactions are strongly inhibited in
presence of TEMPO, a classical free radical scavenger used in the mechanism studies of SRN1 reaction.19

HETEROCYCLES, Vol. 75, No. 9, 2008
2265
Table 1. Reaction with various C-centered anions
Entry
1
Anions
Time
Yield (%)
94
Product
Me
Me
Me
NO2
20 min
2
2
3
35 min
15 min
83
59
3
4
NO2
NO2
NO2
4
5
20 min
28 h
91
30
5
6
EtO2C
EtO2C
NO2
MeO2C
6
7
8
9
10 min
15 min
15 min
15 min
64
57
61
67
7
8
MeO2C
EtO2C
EtO2C
EtO2C
Me
9
EtO2C
EtO2C
EtO2C
10
Furthermore, ligand transfer oxidation by cupric salts with radical suppressed carbon alkylation.
As an understanding of the relationship between the nucleophile and the substrate in single electron
transfer is useful in order to increase the selectivity and the yield of the reaction,20 we have investigated
the reactivity of 1 with other conventional nucleophiles as for example S-centered anions21 (Table 3). The
reaction between the sodium salt of arylsulfinic acids (Entries 14-16) or 2-sulfanylbenzothiazole
(BzTh-SH, entry 18) in DMSO gave the required products in good to excellent yields (75-94 %, Scheme
2, Table 3) only by replacement of chlorine atom.
In order to identify the main mechanism of the reaction, we have studied the reactivity of this last reaction
by addition of cupric chloride as inhibitor (Table 3, entry 16).22 When this last inhibitor is added in
catalytic quantity to the reaction mixture, the yield of 12 strongly decreased. This indicates that the rate of
reaction is retarded and the reaction does not stop.

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HETEROCYCLES, Vol. 75, No. 9, 2008
Table 2. Reaction with various C-centered anions
Entry
Anions
Inhibitor
Time
Yield (%)
10
Product
Me
NO2
NO2
10
CuCl2
20 min
2
Me
Me
11
12
13
TEMPO
CuCl2
20 min
15 min
15 min
0
13
0
2
Me
EtO2C
10
10
EtO2C
EtO2C
TEMPO
EtO2C
Furthermore, the reaction does not follow free radical chain mechanism exclusively, rather, both the
mechanisms with free radical chain and nucleophilic substitution displacement reaction are operative.
Scheme 2
Br
O
-
Ar-SO2 Na+
S Ar
O
N
11 Ar=Ph
12 Ar=p-Me-C6H4
13 Ar=p-Cl-C6H4
94%
84%
75%
Br
N
DMSO / hν / N2
Br
Cl
N
NO2
N
Br
Br
DMSO / NaH / hν
N
S
NO2
N2
S
N
1
14
90%
N
N
Br
SH
S
NO2
Table 3. Reaction with various S-centered anions
Entry
14
Anions
Conditions
DMSO
Time
Yield (%) Product
-
Ph-SO2 Na+
2 h
94
11
-
-
15
p-Me-C6H4-SO2
Na+
DMSO
2 h
84
12
16
17
18
p-Me-C6H4-SO2
Na+
DMSO / 10% CuCl2
2 h
57
12
-
p-Cl-C6H4-SO2
Na+
DMSO
2 h
75
90
13
14
BzTh-SH
DMSO / NaH
20 min

HETEROCYCLES, Vol. 75, No. 9, 2008
2267
Moreover, thiophenol presented noteworthy reactivity (Scheme 3 and Table 4, entry 19). Actually,
treating 1 with 2.2 or even 1.2 equivalents of thiophenol and equimolar amount of NaH in DMSO resulted
in
6-bromo-3-nitro-8-phenylsulfanyl-2-phenylsulfanylmethylimidazo[1,2-a]pyridine
(15),
from
concomitant replacement of bromine atom at the 8-position and chlorine atom on the chloromethyl group
at the 2-position, as main product. The structure of 15 was confirmed by X-ray analysis (Figure 1).
Scheme 3
S
DMSO / NaH
S
N
Br
N
Br
Cl
N
SH
hν / N2
15
16
NO2
N
Br
NO2
Br
S
N
1
toluene / TBAOH
N
Br
or
NO2
DMSO / NaH / CuCl2
Figure 1. ORTEP plot of the 6-bromo-3-nitro-8-phenylsulfanyl-2-phenylsulfanylmethylimidazo[1,2-a]-
pyridine (15).
Table 4. Reaction with thiophenol
Entry
19
Anion
Ph-SH
Ph-SH
Ph-SH
Conditions
DMSO / NaH
Time
25 min
4 h
Yield (%)
Product
15
71
63
67
20
toluene / TBAOH
DMSO / NaH / 10% CuCl2
16
21
25 min
16

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HETEROCYCLES, Vol. 75, No. 9, 2008
As already described, the 8-position of imidazo[1,2-a]pyridine could react with alcoholate, thiolate anions
or hydrogen sulfide but the mechanism was not clearly established.7,23 Indeed, the reaction may be
thought to proceed through either of the two mechanisms (i) a simple nucleophilic aromatic substitution
(SNAr) or (ii) a free radical chain mechanism (SRN1). However, mechanism in benzene, naphthalene or
heterocyclic (pyridine, quinoline, thiophene) series was clearly studied with brominated or iodinated
compounds and followed single electron transfer reaction.24 In order to identify the main mechanism of
the reaction, we have studied the reactivity by addition of CuCl2 as inhibitor.
The constatations observed with sulfinate anions are applicable to the reactivity between compound 1 and
phenylthiolate anion but only with the chloromethyl group at 2-position (Scheme 3). Indeed, when the
inhibitor is added to the reaction mixture, only the reactivity at 8-position is stopped. By contrast, the
reaction of the chloromethyl group is slightly retarded when inhibitor was added. These observations
could suggest that the 8-position reacts only via free radical chain reaction, and the chloromethyl group at
2-position could follow a borderline mechanism, between SN2 and SRN1.
In conclusion, the 6,8-dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine reacts with different carbon
and sulfinate centered anions only by substitution of chloromethyl group. The reaction is very probably
mediated by an SRN1 mechanism. Furthermore, with phenylthiolate anion we found a double reactivity at
the 8-position and chloromethyl group. The reaction at the 8-position followed very certainly an electron
transfer process on the other hand the chloromethyl group could not follow free radical chain mechanism
exclusively.
This regioselectivity in imidazo[1,2-a]pyridine series is described for the first time in the literature and
could be used for the preparation of more complexe structures of pharmacological interest. Work is under
progress to prepare new derivatives by SRN1 reaction on the pyridine moiety.
EXPERIMENTAL
General Methods. Melting points were determined with a B-540 Büchi melting point apparatus. 200
1
13
MHz H NMR and 50 MHz C NMR spectra were recorded on a Bruker ARX 200 spectrometer in
CDCl3 or DMSO-d6 solution at the Faculté de Pharmacie de Marseille. 1H and 13C NMR chemical shifts
(δ) are reported in ppm with respect to CHCl3 7.26 ppm (1H) and 77.16 ppm (13C) and to DMSO-d6 2.50
ppm (1H) and 39.70 ppm (13C). Elemental analyses were carried out at Spectropole, University of
Aix-Marseille III.
Compounds 1, 11 and 12 were already described.16
General Procedure for SRN1 reaction with nitronate and malonate anions. A solution of 60% NaH (3
eq.) in DMSO under N2 was treated with appropriate nitroalkane (3 eq.) and stirred at rt for 20 min. A
solution of 6,8-dibromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine 1 (1 eq.) in DMSO was then

HETEROCYCLES, Vol. 75, No. 9, 2008
2269
added and the mixture was irradiated with a 60 W tungsten lamp and stirred until disappearance of
starting material as monitored by TLC. At this time, the mixture was poured into cold water. The aqueous
solution was extracted with CH2Cl2. The organic layers were washed with brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was purified by chromatography on a silica
gel column. Wanted products were recrystallized from i-PrOH, s-BuOH or cyclohexane.
Inhibitions were performed using the same protocol adding 10 mol% TEMPO or CuCl2 with 1
simultaneously.
6,8-Dibromo-2-(2-methylprop-1-enyl)-3-nitroimidazo[1,2-a]pyridine (2).
Recrystallization from i-PrOH gave pink needles, yielding 94%. mp 149 °C. 1H NMR (CDCl3) δ 2.10 (d,
J = 1.0 Hz, 3H, CH3); 2.39 (d, J = 1.0 Hz, 3H, CH3); 7.06-7.07 (m, 1H, CH); 7.92 (d, J = 1.6 Hz, 1H,
CH); 9.58 (d, J = 1.6 Hz, 1H, CH). 13C NMR (CDCl3) δ 21.3 (CH3); 28.5 (CH3); 109.4 (C); 112.5 (CH);
114.8 (CH); 127.0 (CH); 135.6 (CH); 141.5 (C); 148.7 (C); 152.8 (C), the C-NO2 was not observed under
these experimental conditions. Anal. Calcd for C11H9Br2N3O2: C, 35.23; H, 2.42; N, 11.20. Found: C,
35.47; H, 2.41; N, 11.33.
E-6,8-Dibromo-2-(but-1-enyl)-3-nitroimidazo[1,2-a]pyridine (3).
Recrystallization from i-PrOH gave pink needles, yielding 83%. mp 138 °C. 1H NMR (CDCl3) δ 1.19 (t, J
= 7.5 Hz, 3H, CH3); 2.34-2.53 (m, 2H, CH2); 7.29 (dt, J = 15.6 Hz, J = 1.4 Hz, 1H, CH); 7.48 (dt, J =
13
15.6 Hz, J = 6.1 Hz, 1H, CH); 7.92 (d, J = 1.7 Hz, 1H, CH); 9.55 (d, J = 1.7 Hz, 1H, CH). C NMR
(CDCl3) δ 12.7 (CH3); 26.5 (CH2); 109.3 (C); 112.3 (C); 118.7 (CH); 127.0 (C); 135.9 (CH); 141.8 (C);
147.9 (CH); 148.1 (C), the C-NO2 was not observed under these experimental conditions. Anal. Calcd for
C11H9Br2N3O2: C, 35.23; H, 2.42; N, 11.20. Found: C, 35.21; H, 2.40; N, 11.13.
6,8-Dibromo-2-(cyclopentylidenemethyl)-3-nitroimidazo[1,2-a]pyridine (4).
1
Recrystallization from s-BuOH gave brown crystals, yielding 59%. mp 156 °C. H NMR (CDCl3) δ
1.67-1.92 (m, 4H, 2xCH2); 2.63-2.70 (m, 2H, CH2); 3.00-3.06 (m, 2H, CH2); 7.27-7.32 (m, 1H, CH); 7.90
(d, J = 1.6 Hz, 1H, CH); 9.57 (d, J = 1.6 Hz, 1H, CH). 13C NMR (CDCl3) δ 25.7 (CH2); 26.9 (CH2); 34.0
(CH2); 37.3 (CH2); 109.1 (C); 110.4 (CH); 112.4 (C); 127.1 (CH); 135.5 (CH); 141.7 (C); 142.4 (C);
149.2 (C); 166.6 (C). Anal. Calcd for C13H11Br2N3O2: C, 38.93; H, 2.76; N, 10.48. Found: C, 39.03; H,
2.87; N, 10.46.
6,8-Dibromo-2-(cyclohexylidenemethyl)-3-nitroimidazo[1,2-a]pyridine (5).
Recrystallization from i-PrOH gave beige solid, yielding 91%. mp 159 °C. 1H NMR (CDCl3) δ 1.63-1.78
(m, 6H, 3 CH2); 2.40-2.46 (m, 2H, CH2); 3.03-3.09 (m, 2H, CH2); 6.96 (s, 1H, CH); 7.92 (d, J = 1.6 Hz,
13
1H, CH); 9.58 (d, J = 1.6 Hz, 1H, CH). C NMR (CDCl3) δ 26.4 (CH2); 27.9 (CH2); 28.9 (CH2); 30.9

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HETEROCYCLES, Vol. 75, No. 9, 2008
(CH2); 39.0 (CH2); 109.4 (C); 112.0 (CH); 112.4 (C); 127.0 (CH); 135.5 (CH); 141.5 (C); 148.8 (C);
160.1 (C), the C-NO2 was not observed under these experimental conditions. Anal. Calcd for
C14H13Br2N3O2: C, 40.51; H, 3.16; N, 10.12. Found: C, 40.01; H, 3.07; N, 9.78.
Diethyl 2-[(6,8-dibromo-3-nitroimidazo[1,2-a]pyridin-2-yl)methylene]malonate (6).
Recrystallization from i-PrOH gave yellow powder, yielding 30%. mp 179 °C. 1H NMR (CDCl3) δ 1.37 (t,
J = 7.2 Hz, 3H, CH3); 1.37 (t, J = 7.1 Hz, 3H, CH3); 4.36 (q, J = 7.2 Hz, 2H, CH2); 4.50 (q, J = 7.1 Hz,
13
2H, CH2); 7.98 (d, J = 1.7 Hz, 1H, CH); 8.39 (s, 1H, CH); 9.54 (d, J = 1.7 Hz, 1H, CH). C NMR
(CDCl3) δ 14.0 (CH3); 14.1 (CH3); 62.1 (CH2); 62.3 (CH2); 111.3 (C); 113.6 (C); 126.6 (CH); 127.9
(CH); 134.9 (C); 136.3 (CH); 141.3 (C); 141.8 (C); 163.1 (C=O); 165.3 (C=O). the C-NO2 was not
observed under these experimental conditions. Anal. Calcd for C15H13Br2N3O6: C, 36.69; H, 2.67; N, 8.56.
Found: C, 36.86; H, 2.63; N, 8.51.
Dimethyl 2-[(6,8-dibromo-3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]malonate (7).
Recrystallization from i-PrOH gave brown needles, yielding 64%. mp 172 °C. 1H NMR (CDCl3) δ 3.79 (s,
6H, 2xCH3); 3.86 (d, J = 7.5 Hz, 2H, CH2); 4.26 (t, J = 7.5 Hz, 1H, CH); 7.94 (d, J = 1.6 Hz, 1H, CH);
9.55 (d, J = 1.6 Hz, 1H, CH). 13C NMR (CDCl3) δ 29.4 (CH2); 49.1 (CH); 52.8 (2xCH3); 110.5 (C); 112.9
(C); 126.7 (CH); 135.6 (CH); 141.1 (C); 150.3 (C); 169.0 (2xC=O), the C-NO2 was not observed under
these experimental conditions. Anal. Calcd for C15H15Br2N3O6: C, 33.57; H, 2.38; N, 9.04. Found: C,
32.97; H, 2.30; N, 8.64.
Diethyl 2-[(6,8-dibromo-3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]malonate (8).
Recrystallization from i-PrOH gave golden needles, yielding 57%. mp 136 °C. 1H NMR (CDCl3) δ 1.29 (t,
J = 7.2 Hz, 6H, 2xCH3); 3.84 (d, J = 7.6 Hz, 2H, CH2); 4.23 (q, J = 7.2 Hz, 4H, 2xCH2); 4.24 (t, J = 7.6
13
Hz, 1H, CH); 7.93 (d, J = 1.6 Hz, 1H, CH); 9.54 (d, J = 1.6 Hz, 1H, CH). C NMR (CDCl3) δ 14.1
(2xCH3); 29.3 (CH2); 49.4 (CH); 61.7 (2xCH2); 110.4 (C); 112.8 (C); 126.7 (CH); 135.6 (CH); 141.1 (C);
150.6 (C); 168.6 (2xC=O), the C-NO2 was not observed under these experimental conditions. Anal. Calcd
for C15H15Br2N3O6: C, 36.54; H, 3.07; N, 8.52. Found: C, 36.73; H, 3.12; N, 8.78.
Diethyl 2-[(6,8-dibromo-3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]-2-methylmalonate (9).
1
Recrystallization from cyclohexane gave brown powder, yielding 61%. mp 122 °C. H NMR (CDCl3) δ
1.28 (t, J = 7.2 Hz, 6H, 2xCH3); 1.53 (s, 3H, CH3); 3.90 (s, 2H, CH2); 4.25 (q, J = 7.2 Hz, 4H, 2xCH2);
13
7.92 (d, J = 1.7 Hz, 1H, CH); 9.52 (d, J = 1.7 Hz, 1H, CH). C NMR (CDCl3) δ 14.0 (2xCH3); 20.1
(CH3); 35.0 (CH2); 53.6 (2xCH2); 61.7 (C); 110.3 (C); 112.9 (C); 126.8 (CH); 131.3 (C); 135.5 (CH);
140.9 (C); 149.5 (C); 171.3 (2xC=O). Anal. Calcd for C16H17Br2N3O6: C, 37.89; H, 3.38; N, 8.29. Found:
C, 37.89; H, 3.38; N, 8.25.

HETEROCYCLES, Vol. 75, No. 9, 2008
2271
Diethyl 2-[(6,8-dibromo-3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]-2-phenylmalonate (10).
1
Recrystallization from i-PrOH gave yellow needles, yielding 67%. mp 149 °C. H NMR (DMSO-d6) δ
1.17 (t, J = 7.0 Hz, 6H, 2xCH3); 4.12 (s, 2H, CH2); 4.16-4.34 (m, 4H, 2xCH2); 7.24-7.31 (m, 5H, 5xCH);
8.42 (d, J = 1.6 Hz, 1H, CH); 9.35 (d, J = 1.6 Hz, 1H, CH). 13C NMR (DMSO-d6) δ 14.2 (2xCH3); 36.4
(CH2); 61.8 (C); 62.0 (2xCH2); 110.3 (C); 112.2 (C); 127.7 (CH); 128.0 (CH); 128.1 (2xCH); 128.5
(2xCH); 131.5 (C); 136.2 (CH); 137.2 (C); 140.8 (C); 149.0 (C); 169.5 (2xC=O). Anal. Calcd for
C21H19Br2N3O6: C, 44.31; H, 3.36; N, 7.38. Found: C, 44.39; H, 3.39; N, 7.41.
6,8-Dibromo-2-[(4-chlorophenylsulfonyl)methyl]-3-nitroimidazo[1,2-a]pyridine (13).
To a solution of sodium 4-chlorophenylsulfinate (300 mg, 1.51 mmol) in DMSO under N2, was added 1
(300 mg, 0.812 mmol). The solution was stirred at rt for 2 h. After disappearance of 1 (as monitored by
TLC), the mixture was poured into 200 mL of cold water. Precipitated solid was filtered and air dried to
give after recrystallization from s-BuOH, 310 mg (75 %) of 11 as shiny pale yellow plates. mp 194 °C. 1H
NMR (DMSO-d6) δ 5.29 (s, 2H, CH2); 7.65 (d, J = 8.7 Hz, 2H, 2xCH); 7.78 (d, J = 8.7 Hz, 2H, 2xCH);
8.45 (d, J = 1.5 Hz, 1H, CH); 9.38 (d, J = 1.5 Hz, 1H, CH). 13C NMR (DMSO-d6) δ 55.9 (CH2); 79.3 (C);
110.7 (C); 112.4 (C); 127.5 (CH); 129.5 (2xCH); 130.6 (2xCH); 131.7 (C); 136.3 (CH); 137.5 (C); 139.5
(C); 141.0 (C). HRMS m/z Calcd for C14H9Br2ClN3O4S: 509.8342. Found: 509.8346.
2-[(6,8-Dibromo-3-nitroimidazo[1,2-a]pyridine-2-yl)methylsulfanyl]benzo[d]thiazole (14).
To a solution of 60% NaH (32 mg, 0.812 mmol, 1.2 eq.) in DMSO under N2, was added
2-sulfanylbenzothiazole (136 mg, 0.812 mmol, 1.2 eq.). The solution was stirred for 20 min at rt and
added 1 (250 mg, 0.678 mmol, 1 eq.) and additional stirring was allowed for 20 min. At this time, starting
material had disappeared as monitored by TLC (eluted with CHCl3/petroleum ether, 7/3). The solution
was then poured into 200 mL of cold water and the precipitated solid was filtered and air dried to give,
1
after recrystallization from s-BuOH, 305 mg (90%) of 14 as beige crystals. mp 254 °C. H NMR
(DMF-d7) δ 5.27 (s, 2H, CH2); 7.36-7.55 (m, 2H, 2xCH); 7.86-7.90 (m, 1H, CH); 8.03-8.07 (m, 1H, CH);
8.43 (m, 1H, CH); 9.53 (d, J = 1.6 Hz, 1H, CH). Anal. Calcd for C15H8Br2N4O2S2: C, 36.02; H, 1.61; N,
11.20; S, 12.82. Found: C, 35.24; H, 1.60; N, 11.87; S, 12.25. HRMS m/z Calcd for C15H8Br2N4O2S2:
500.8508. Found: 500.8513.
6-Bromo-3-nitro-8-phenylsulfanyl-2-phenylsulfanylmethylimidazo[1,2-a]pyridine (15).
To a solution of 60% sodium hydride (71 mg, 1.786 mmol, 2.2 eq.) in DMSO under N2, was added
thiophenol (0.18 mL, 1.786 mmol, 2.2 eq.). The solution was stirred for 10 min and added 1 (300 mg,
0.812 mmol, 1 eq.) and additional stirring was allowed for 25 min. At this time, starting material had
disappeared as monitored by TLC (eluted with CHCl3/petroleum ether, 7/3). The solution was then
poured into 200 mL of cold water and extracted with EtOAc (3 x 30 mL). Combined organic layers were

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HETEROCYCLES, Vol. 75, No. 9, 2008
washed with brine (5 x 20 mL), dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. The oily residue was precipitated from petroleum ether and recrystallization from
1
i-PrOH gave 272 mg of 15 (71% yield) as yellow crystals. mp 171 °C. H NMR (CDCl3) δ 4.67 (s, 2H,
CH2); 6.82 (d, J = 1.7 Hz, 1H, CH); 7.17-7.33 (m, 3H, 3xCH); 7.47-7.66 (m, 7H, 7xCH); 9.26 (d, J = 1.7
13
Hz, 1H, CH). C NMR (CDCl3) δ 33.2 (CH2); 111.7 (C); 123.6 (CH); 126.9 (CH); 127.7 (C); 127.9
(CH); 128.9 (2xCH); 130.4 (2xCH); 130.5 (CH); 130.6 (2xCH); 133.2 (C); 135.1 (C); 135.7 (2xCH);
139.9 (C); 149.2 (C), the C-NO2 was not observed under these conditions. Anal. Calcd for
C20H14BrN3O2S2: C, 50.85; H, 2.99; N, 8.90; S, 13.58. Found: C, 50.87; H, 3.01; N, 8.92; S, 13.85.
Same conditions with additional 10 mol% CuCl2 provided 16 (described below) yielding 67%.
6,8-Dibromo-3-nitro-2-phenylsulfanylmethylimidazo[1,2-a]pyridine (16).
Under a nitrogen atmosphere, a solution of tetrabutylammonium hydroxide (40% in water) was treated
with thiophenol (0.649 mmol) for 20 min. A solution of 1 (0.541 mmol) in toluene was then added and
the mixture was irradiated with a 60 W tungsten lamp and stirred at rt for 4 h. At this time, the mixture
was poured into cold water (150 mL). The aqueous solution was extracted with CH2Cl2 (3 x 30 mL). The
combined organic layers were washed with water (6 x 15 mL), dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column.
Recrystallization from i-PrOH gave 151 mg of 16, yielding 63%. mp 140 °C. 1H NMR (CDCl3) δ 4.66 (s,
2H, CH2); 7.21-7.32 (m, 3H, 3xCH); 7.43-7.50 (m, 2H, 2xCH); 7.96 (d, J = 1.6 Hz, 1H, CH); 9.54 (d, J =
1.6 Hz, 1H, CH). 13C NMR (CDCl3) δ 33.3 (CH2); 110.7 (C); 113.0 (C); 126.8 (CH); 127.2 (CH); 128.9
(2xCH); 130.9 (2xCH); 134.7 (C); 135.8 (CH); 141.0 (C); 150.2 (C), the C-NO2 was not observed under
these conditions. Anal. Calcd for C14H9Br2N3O2S: C, 37.95; H, 2.05; N, 9.48; S, 7.24. Found: C, 37.99; H,
2.06; N, 9.45; S, 7.19.
X-Ray structure determination
Data were measured on a Bruker-Nonius KappaCCD diffractometer with a graphite-monochromated
Mo-Kα radiation at 293 (2) K.
Crystal data of 15: Dark yellow prism, C20H14BrN3O2S2, crystal dimensions 0.2 x 0.15 x 0.15 mm.
M=472.37, orthorhombic, space group P 21 21 21, a=8.5520(1), b=13.4949(2), c=17.4150(4) Å,
α=90.00°, β=90.00°, γ=90.00°, V=2009.84(6) Å3, Z=4, µ = 2.274 mm-1, F(000) = 952, index ranges 0 ≤ h
≤ 11, 0 ≤ k ≤ 18, -23 ≤ l ≤ 23. 253 variables and 0 restraints, were refined for 3405 reflections collected
with I ≥ 2σI to R = 0.0392, wR2 = 0.0963, GoF = 1.006.

HETEROCYCLES, Vol. 75, No. 9, 2008
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ACKNOWLEDGEMENTS
This work is supported by the CNRS and the Universities of Aix-Marseille. The authors thank V.
Remusat, G. Herbette and F. Ziarelli for the 1H and 13C NMR spectra recording, M. Giorgi for the X-ray
diffraction and structure analysis, V. Monnier for the mass spectra recording and Chahrazad Boujerah for
technical support.
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