Iodine-catalyzed regioselective sulfenylation of imidazoheterocycles in PEG400

Article abstract of DOI:10.1039/c4gc01462f

An iodine-catalyzed sulfenylation of imidazo[1,2-a]-pyridines, -pyrimidines, and [1,2-b]pyridazines is herein described with various thiophenols using hydrogen peroxide as an oxidizing agent in PEG₄₀₀. The method enabled the formation of 3-arylthioimidazoheterocycles in moderate to excellent yields under metal-free conditions. Several functional groups were well tolerated under our optimized conditions. This journal is

Full text of DOI:10.1039/c4gc01462f

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Hiebel and S.
BERTEINA-RABOIN, Green Chem., 2014, DOI: 10.1039/C4GC01462F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Page 1 of 8
Green Chemistry
View Article Online
DOI: 10.1039/C4GC01462F
Ar
Ar
I2 (10 mol %)
H2O2 (1.1 equiv)
S
N
N
Ar / HetAr
+
Ar
ArSH
Ar / HetAr
N
N
PEG400
30 examples
up to 95 %
Formation of various 3-arylthioimidazoheterocycles using benign reagents and solvents with
harmless by-products

View Article Online
DOI: 10.1039/C4GC01462F
Green Chemistry
Page 2 of 8
Journal Name
RSCPublishing
ARTICLE
Iodine-catalyzed regioselective sulfenylation of
imidazoheterocycles in PEG400
Cite this: DOI: 10.1039/x0xx00000x
M.-A. Hiebel,*a and S. Berteina-Raboina
Received 00th January 2012,
Accepted 00th January 2012
An iodine-catalyzed sulfenylation of imidazo[1,2-a]-pyridines, -pyrimidines, and [1,2-b]pyridazines is
herein described with various thiophenols using hydrogen peroxide as oxidizing agent in PEG400. The
method enabled the formation of 3-arylthioimidazoheterocycles in moderate to excellent yields using
DOI: 10.1039/x0xx00000x
metal-free conditions. Several functional groups were well tolerated under our optimized conditions
.
www.rsc.org/
solvents. This medium has the advantage of being non-toxic,
odorless, neutral, nonvolatile, and non-irritating and is used in a
variety of pharmaceuticals and medications. Herein we report the
possible use of PEG400 as an efficient medium to introduce sulfenyl
groups under transition metal free conditions.
Introduction
Imidazo1,2-apyridines are recognized to exhibit a broad range of
biological activities.1 They are often used as building blocks in
pharmaceutical compounds, and count several commercially
available drugs such as the sedative Zolpidem, the anxiolytic
Alpidem or S aridipem, or the heart failure drug Olprinone (Fig 1).
Results and discussion
In order to achieve the optimized conditions, the sulfenylation of
6-methyl-2-phenylimidazo[1,2-a]pyridine
(1a)
with
4-
methylbenzenethiol (2a) was selected as the model reaction using
standard conditions such as iodine in catalytic amount12 with DMSO
as oxidant in PEG400 (Table 1).2d
Table 1. Optimization of the reaction conditions
Entry Catalyst
(equiv)
Oxidant
(equiv)
T
(°C)
t (h) Yield
(%)a
Fig 1. Examples of Imidazoheterocyclic-containing therapeutics.
1
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
KI (0.1)
NIS (0.1)
nBu4NI (0.1)
-
DMSO (3)
DMSO (3)
H2O2 (1.1)
H2O2 (1.1)
135
50
18
24
2
62b
In parallel, recent works exhibited the therapeutic value of
sulfenylated heterocycles such as indoles.2 Surprisingly, until lately,
few methods described the introduction of sulfenyl groups on
imidazo1,2-apyridines using copper,3 hypervalent iodine reagents,4
strong acidic conditions,5 ionic liquid,6 or silica-supported
CeCl3.7H2O/NaI.7 Next, Adimurthy et al.8 described the used of an
excess of N-chlorosuccinimide with thiophenols to form in situ
hypochlorothioite derivates,9 which were introduced in C3 position
of imidazo-1,2-apyridines and -2,1-bthiazoles. In our effort to
develop environmentally benign tools, we have continuously tried to
promote the use of non-toxic media. Therefore in our approach, we
focused on the potent combination of a non-toxic media, transition
metal free conditions with thiophenols or disulfide species.10
Recently, some polymer media started to be used as new solvents in
organic synthesis, in particular polyethylene glycol (PEG).11 PEG400
is a viscous sustainable liquid soluble in water and many organic
2
0
3
50
85
77
80
0c
3
RT
24
2
5
tBuOOH (1.1) 50
6
O2
50
50
50
50
50
50
50
2
7
K2S2O8 (1.1)
H2O2 (1.1)
H2O2 (1.1)
H2O2 (1.1)
H2O2 (1.1)
-
2
0c
8
2
25c
45c
20c
0
9
2
10
11
12
2
2
I2 (1)
24
0
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

View Article Online
DOI: 10.1039/C4GC01462F
Page 3 of 8
ARTICLE
Green Chemistry
Journal Name
aIsolated yield. bYield obtained with
thiocresol.cConversion estimated by 1H NMR.
2
equiv of 4-
The expected product 3a was isolated in 62 % yield after 18 hours
at 135 °C. Working at a lower temperature was desired however a
diminution to 50 °C inhibited completely the reaction (entries 1 and
2). Other oxidants were then investigated such as tertbutyl peroxide,
potassium persulfate, oxygen, and hydrogen peroxide was found to
be the most effective since 3a was isolated after 2 hours at 50 °C in
85 % yield. Unfortunately, at room temperature the reaction was less
efficient due to solubility issues of 1a in PEG400 (entry 4). Different
iodine sources were next investigated but 3a was only obtained in
low yields (entries 8-10). Both iodine and hydrogen peroxide are
necessary since only traces of 3a were observed when the reaction
was performed in their absence (entries 11 and 12). Surprisingly
even a stoichiometric amount of iodine did not provide the expected
product. Hence the optimized reaction conditions were chosen as
follows: 1a (1 equiv), 2a (1.1 equiv), hydrogen peroxide (1.1 equiv)
in PEG400 at 50 °C for 2 hours. It should be noted that working under
inert atmosphere did not improve the yield of the reaction.
aReaction performed on 5 mmol scale using 0.5 mol % I2, 5 h at 50
ºC. bAdditional introduction of iodine (10 mol %). cThe reaction was
d
performed in 3 mL of PEG400 at 60 °C. Additional introduction of
e
iodine (2 x 10 mol %). The reaction was performed in 3 mL of
PEG400 at 100 °C.
Scheme 1. Scope of substrates
In an endeavor to expand the scope of the methodology, the
reactivity of various imidazo[1,2-a]pyridines was investigated
(Scheme 1).
In general, the reactions were very clean and the expected products
were synthetized in moderate to excellent yields. The reaction
tolerates different aromatic thiols bearing electron-donating (Me,
OMe) and withdrawing groups (F, Br, CF3) in ortho, meta and para
positions (3a-i). Apart from 3b, 3e and 3f, which required an extra
addition of iodine (10 mol %) to consume 1a entirely, the
corresponding sulfenated product was smoothly obtained regardless
of the thiol used. Then different imidazo[1,2-a]pyridines substituted
in positions 6, 7 and 8 were examined. As observed by the yields of
3a and 3j-l, the reaction showed no electronic effect from the
substituent in position 6. However in position 7 for 3m-o, a
supplementary addition of iodine was required to achieve
completion. Furthermore, due to solubility issue, a dilution of the
medium and an increase of the temperature were necessary (3n and
3o). Finally, no steric hindrance was observed when a methyl group
was introduced in position 8 (3p). The influence of the substituents
on the phenyl ring of 2-phenylimidazo[1,2-a]pyridines was also
evaluated. Presence of moderate electron withdrawing (F, Cl) and
electron donating (OMe) groups did not prevent the smooth
formation of the expected products (3r-w) in high yields. Ortho and
meta substitutions did not affect the efficiency of the reaction.
Halides, esters, trifluoromethyls, cyanides substituents are well
tolerated under these mild conditions, which enable further
transformations. Nevertheless, nitro group gave poor results (3u)
probably due to a combined effect of the insolubility of the
corresponding starting material and its strong electron withdrawing
effect, which could deactivate the C3 position. Finally, on a larger
scale reaction (1 g of product), the catalyst loading could be lowered
to 0.5 mol % with similar results (3a).
Next, to demonstrate the generality of this methodology the
reaction conditions were applied to other imidazoheterocyclic
compounds (Scheme 2).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C4GC01462F
Green Chemistry
Page 4 of 8
Journal Name
ARTICLE
introduced, 3a was isolated along with dehalogenated product 1a.
The low efficiency of this pathway made us consider the possible
formation of disulfide intermediates. Indeed, iodine or hydrogen
peroxide is known to oxidize thiols into disulfides.14 1a and phenyl
disulfide was then submitted to our experimental conditions and 3i
was easily isolated after 4 h. No reaction occurred upon treatment of
1a and phenyl disulfide in the absence of I2 illustrating that the
transformation may not proceed via a radical pathway.15 The
reactivity was recovered when
1 equivalent of iodine was
introduced. The oxidative role of H2O2 was underlined when I2 was
introduced in a catalytic amount, as expected the reaction did not
reach completion.
Based on literature reports and our observations, a plausible
mechanism has been proposed (Scheme 4). Initially, phenyl disulfide
is generated from thiophenol in the presence of I2 or H2O2. Then the
electrophilic PhSI may be formed by interaction of the disulfide
derivates with I2.2e An electrophilic attack of PhSI on the C3 position
of 1a can occur leading to an imidazolenium intermediate. Releasing
hydroiodic acid forms 3i. Then, part of HI can be oxidized by H2O2
into hypoiodous acid.16 Reaction between another portion of HI and
HOI regenerates I2 with the formation of water.17
aThe reaction was performed at 80 °C in 2 mL of PEG400 for 24 h,
b
after 12 h, I2 (10 mol %) and H2O2 (1.1 equiv) were added. The
c
reaction was performed at 50 °C in 1 mL of PEG400 for 4 h. The
reaction was performed at 80 °C in 3 mL of PEG400 for 24 h, after 12
h, I2 (10 mol %) and H2O2 (1.1 equiv) were added.
Scheme 2. Extension to imidazo-pyrimidine and -pyridazine
compounds
First, imidazopyridazines were submitted to our experimental
conditions and we noticed that working at a higher temperature was
necessary to solubilize the starting material. Despite an increased
reaction time and an additional amount of iodine and hydrogen
peroxide, unreacted 6-chloro-2-phenylimidazo[1,2-b]pyridazine was
always recovered. Nonetheless the corresponding sulfenated
products (4a-c) were isolated in moderate to good yields with
thiophenols bearing electron withdrawing and donating groups. Then
the imidazopyrimidine scaffold was studied. Fortunately, without
any substituent on the pyrimidine ring, the reaction proceeded
smoothly under the optimal conditions. The desired products were
obtained in high yields (4d-f). However, for 6-chloro-2-
phenylimidazo[1,2-b]pyridazine, a loss of reactivity was observed
probably due to the insolubility of the compound in the reaction
medium. Increase of the temperature and of the dilution enabled to
obtain 4g in 51
% yield along with unreacted 6-chloro-2-
phenylimidazo[1,2-b]pyridazine.
Scheme 4. Plausible mechanism
To get some insight into the reaction mechanism, some control
experiments were performed (Scheme 3).
Conclusions
In summary, we have developed a simple, benign and efficient
method to introduce various aromatic thiols on imidazo[1,2-a]-
pyridines, -pyrimidines and [1,2-b]pyridazines, and without any
transition-metal catalysts in a non toxic medium which was able to
solubilize a large variety of substrates. After optimization, it was
found that iodine worked as a proficient catalyst easily regenerated
by hydrogen peroxide. Various functional groups were tolerated
under our conditions demonstrating the generality of our method.
Experimental section
General remarks
All reagents were purchased from commercial suppliers and were
used without further purification and imidazoheterocycles were
synthetized following the procedure reported in the literature.10a The
reactions were monitored by thin-layer chromatography (TLC)
analysis using silica gel (60 F254) plates. Compounds were
visualized by UV irradiation. Flash column chromatography was
Scheme 3. Control experiments
In the literature, iodination of the C3 position of imidazo[1,2-
a]pyridines are reported to be fast with high yields.13 In PEG400, the
reaction was not complete and 5 was only obtained in a moderate
yield after 24 h. Surprisingly, when p-thiocresol was next
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

View Article Online
DOI: 10.1039/C4GC01462F
Page 5 of 8
ARTICLE
Green Chemistry
Journal Name
performed on silica gel 60 (230-400 mesh, 0.040-0.063 mm). 148.0, 141.0, 138.5, 133.3, 128.9, 128.6, 128.4, 128.3 (q, J = 32.8
Melting points (mp [°C]) were taken on samples in open capillary Hz), 126.4 (q, J = 3.8 Hz), 125.3, 123.6, 121.9, 115.6, 116.2, 103.8,
21.6; 19F (235 MHz, CDCl3)  -65.7; IR (ATR, cm-1): 1645, 1602,
tubes and are uncorrected. The infrared spectra of compounds were
recorded on a Thermo Scientific Nicolet iS10. 1H and 13C NMR
spectra were recorded on a Bruker spectrometer at 250 MHz (13C,
62.9 MHz and 19F, 235 MHz). Chemical shifts are given in parts per
million from tetramethylsilane (TMS) as internal standard. All 19F
spectra are reported in ppm relative to hexafluorobenzene as internal
standard (-164.9 ppm). The following abbreviations are used for the
proton spectra multiplicities: b : broad, s: singlet, d: doublet, t:
triplet, q: quartet, p: pentuplet, m: multiplet. Coupling constants (J)
are reported in hertz (Hz). High-resolution mass spectra (HRMS
(ESI)) were performed on a Maxis Bruker 4G by the “Federation de
Recherche” ICOA/CBM (FR2708) platform and the monoisotopic
mass was given.
1495, 1012, 826, 774, 700, 689; HRMS (ESI): m/z [M+H]+ calc for
C21H16F3N2S 385.0981, found 385.0983.
3-((4-bromophenyl)thio)-6-methyl-2-phenylimidazo[1,2-
a]pyridine (3e) (PE/EA: 70:30) Beige solid (169 mg, 86 %); mp:
1
166.3-167.0 °C; H NMR (250 MHz, CDCl3)  8.19-8.12 (m, 2H),
8.10 (d, J = 7.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.47-7.35 (m, 3H), 7.35-
7.28 (m, 2H), 6.90-6.80 (m, 2H), 6.71 (dd, J = 6.9, 1.7 Hz, 1H), 2.44
(s, 3H); 13C NMR (62.9 MHz, CDCl3)  151., 147.8, 138.2, 135.0,
133.5, 132.6, 128.7, 128.6, 128.4, 127.2, 123.6, 119.8, 116.5, 116.0,
21.6; IR (ATR, cm-1): 3049, 2911, 1645, 1491, 1468, 807, 770, 687;
HRMS (ESI): m/z [M+H]+ calc for C20H16BrN2S 395.0212, found
395.0208.
3-((3-methoxyphenyl)thio)-6-methyl-2-phenylimidazo[1,2-
a]pyridine (3f) (PE/EA: 70:30) Yellow solid (135 mg, 78 %); mp:
106.7-107.5 °C; H NMR (250 MHz, CDCl3)  8.24-8.15 (m, 2H),
8.13 (d, J = 6.5 Hz, 1H), 7.54-7.30 (m, 4H), 7.11 (dd, J = 8.0, 7.9
Hz, 1H), 6.75-6.62 (m, 2H), 6.61-6.52 (m, 2H), 3.66 (s, 3H), 2.43 (s,
3H); 13C NMR (62.9 MHz, CDCl3)  160.5, 151.5, 147.7, 138.0,
137.1, 133.6, 130.4, 128.6, 128.6, 128.5, 123.8, 117.8, 116.3, 115.8,
111.7, 111.2, 105.5, 55.3, 21.5; IR (ATR, cm-1): 1644, 1589, 1575,
1483, 1463, 1251, 775, 750, 700, 684; HRMS (ESI): m/z [M+H]+
calc for C21H19N2OS 347.1213, found 347.1210.
General procedure for the sulfenylation of imidazoheterocycles.
Imidazoheterocycles (0.5 mmol), thiophenol (0.55 mmol) were
dissolved in PEG400 (1 mL). Hydrogen peroxide (0.55 mmol) with
iodine (13 mg, 0.05 mmol) were next added before heating up to 50
°C for the required time. After completion the reaction mixture was
diluted in EtOAc (20 mL). The organic phase was washed with a
saturated solution of sodium carbonate (3 x 10 mL) and sodium
thiosulfate (10 mL), dried with MgSO4 and concentrated under
reduced pressure. The crude material was purified by flash
chromatography on silica gel to provide the expected product.
1
3-((3-bromophenyl)thio)-6-methyl-2-phenylimidazo[1,2-
6-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3a)
a]pyridine (3g) (PE/EA: 70:30) Beige solid (159 mg, 81 %); mp:
(PE/EA: 70:30) Beige solid (140 mg, 85 %). mp: 130.5-131.9 °C;
1H NMR (250 MHz, CDCl3)  8.27-8.19 (m, 2H), 8.12 (d, J = 7.1
Hz, 1H), 7.52-7.31 (m, 4H), 7.00 (bd, J = 8.4 Hz, 2H), 6.90 (bd, J =
8.4 Hz, 2H), 6.64 (dd, J = 7.2, 2.2 Hz, 1H), 2.40 (s, 3H), 2.24 (s,
3H); 13C NMR (62.9 MHz, CDCl3)  151.1, 147.4, 137.8, 135.9,
133.6, 131.9, 130.2, 128.4, 128.4, 128.3, 125.7, 123.7, 116.2, 115.6,
106.0, 21.4, 20.9; IR (ATR, cm-1): 6054, 2915, 1643, 1488, 1440,
860, 701, 690; HRMS (ESI): m/z [M+H]+ calc for C21H19N2S,
331.1263 found 331.1262.
1
135.0-136.0 °C; H NMR (250 MHz, CDCl3)  8.18-8.13 (m, 2H),
8.11 (d, J = 6.9 Hz, 1H), 7.52-7.48 (m, 1H), 7.48-7.32 (m, 3H), 7.29-
7.22 (m, 1H), 7.18 (dd, J = 1.8, 1.8 Hz, 1H), 7.04 (dd, J = 8.0, 8.0
Hz, 1H), 6.84 (bd, J = 8.0 Hz, 1H), 6.72 (dd, J = 7.0, 1.6 Hz, 1H),
2.46 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  151.9, 147.8, 138.3,
138.2, 133.4, 130.8, 129.3, 128.7, 128.6, 128.5, 128.4, 128.1, 123.9,
123.6, 123.6, 116.5, 116.1, 21.6; IR (ATR, cm-1): 3066, 2920, 1647,
769, 745, 697; HRMS (ESI): m/z [M+H]+ calc for C20H16BrN2S
395.0212, found 395.0208.
3-((4-methoxyphenyl)thio)-6-methyl-2-phenylimidazo[1,2-
a]pyridine (3b) (PE/EA: 80:20) Beige solid (133 mg, 77 %); mp:
6-methyl-2-phenyl-3-(o-tolylthio)imidazo[1,2-a]pyridine
(3h)
(PE/EA: 75:25) White solid (129 mg, 78 %); mp: 165.5-166.1 °C;
1H NMR (250 MHz, CDCl3)  8.18-8.11 (m, 2H), 8.05 (d, J = 6.9
Hz, 1H), 7.50 (bs, 1H), 7.46-7.30 (m, 3H), 7.20 (bd, J = 7.5 Hz, 1H),
7.04 (ddd, J = 7.6, 7.3, 1.0 Hz, 1H), 6.91 (bdd, J = 7.8, 7.4 Hz, 1H),
6.68 (bd, J = 6.9 Hz, 1H), 6.43 (bd, J = 7.8 Hz, 1H), 2.52 (s, 3H),
2.44 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  151.8, 147.8, 137.9,
135.0, 134.6, 133.7, 130.8, 128.6, 128.5, 128.4, 127.0, 125.7, 124.2,
123.8, 116.4, 115.8, 105.8, 21.6, 19.9; IR (ATR, cm-1): 3043, 2914,
1646, 1463, 770, 752, 700. HRMS (ESI): m/z [M+H]+ calc for
C21H19N2S 331.1263, found 331.1263.
1
122.5-124.1 °C; H NMR (250 MHz, CDCl3)  8.26-8.20 (m, 2H),
8.17 (d, J = 7.0 Hz, 1H), 7.48-7.32 (m, 4H), 6.98 (ddd, J = 9.0, 3.1,
2.3 Hz, 2H), 6.75 (ddd, J = 9.0, 3.1, 2.3 Hz, 2H), 6.69 (dd, J = 7.0,
1.6 Hz, 1H), 3.72 (s, 3H), 2.43 (d, J = 0.8 Hz, 3H); 13C NMR (62.9
MHz, CDCl3)  158.6, 150.9, 147.4, 137.8, 128.5, 128.5, 128.5,
128.0, 123.8, 116.3, 115.7, 115.3, 107.0, 55.5, 21.5; IR (ATR, cm-1):
3057, 2952, 2832, 1646, 1488, 1463, 1239, 772, 702; HRMS (ESI):
m/z [M+H]+ calc for C21H19N2OS 347.1213, found 347.1216.
3-((4-fluorophenyl)thio)-6-methyl-2-phenylimidazo[1,2-
a]pyridine (3c) (PE/EA: 70:30) Beige solid (142 mg, 85 %); mp:
6-methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine
(3i)8
1
178.8-179.6 °C; H NMR (250 MHz, CDCl3)  8.22-8.16 (m, 2H),
(PE/EA: 70:30) White solid (130 mg, 82 %); mp: 173.3-174.1 °C;
1H NMR (250 MHz, CDCl3)  8.12-8.06 (m, 2H), 8.04 (d, J = 7.0
Hz, 1H), 7.41-7.37 (m, 1H), 7.37-7.21 (m, 3H), 7.15-6.98 (m, 3H),
6.93-6.86 (m, 2H), 6.74 (dd, J = 7.2, 1.6 Hz, 1H), 2.36 (s, 3H); 13C
NMR (62.9 MHz, CDCl3)  151.5, 147.7, 138.0, 135.7, 133.7, 129.5,
128.6, 128.5, 128.4, 126.1, 125.6, 123.8, 116.4, 115.8, 105.6, 21.6;
IR (ATR, cm-1): 1643, 1492, 1476, 1466, 855, 745, 687; HRMS
(ESI): m/z [M+H]+ calc for C20H17N2S 317.1107, found 317.1110.
8.14 (d, J = 6.9 Hz, 1H), 7.51-7.46 (m, 1H), 7.45-7.42 (m, 1H), 7.42-
7.32 (m, 2H), 7.02-6.85 (m, 4H), 6.71 (dd, J = 7.0, 1.7 Hz, 1H), 2.46
(s, 3H); 13C NMR (62.9 MHz, CDCl3)  161.7 (d, J = 245 Hz),
151.4, 147.7, 138.1, 133.6, 130.6, 130.6, 128.7, 128.6, 128.4, 127.7,
127.6, 123.6, 116.9, 116.5, 116.4, 115.9, 105.9, 21.6; 19F (235 MHz,
CDCl3)  -119.4; IR (ATR, cm-1): 3062, 2917, 1646, 1589, 1484,
1007, 840, 770, 690; HRMS (ESI): m/z [M+H]+ calc for
C20H16FN2S 335.1013, found 335.1010.
6-bromo-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3j)
6-methyl-2-phenyl-3-((4-
(PE/EA: 90:10) White solid (140 mg, 71 %); mp: 173.4-174.0 °C;
1H NMR (250 MHz, CDCl3)  8.43 (dd, J = 1.9, 0.8 Hz, 1H), 8.25-
8.16 (m, 2H), 7.61 (dd, J = 9.4, 0.9 Hz, 1H), 7.52-7.32 (m, 4H), 7.05
(d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.3 Hz, 2H), 2.28 (s, 3H); 13C NMR
(62.9 MHz, CDCl3)  151.9, 145.6, 136.5, 133.1, 131.1, 130.5,
130.2, 129.0, 128.6, 128.5, 126.1, 124.8, 118.4, 108.1, 107.8, 21.1;
IR (ATR, cm-1): 3047, 2921, 1519, 1490, 771 695, 684; HRMS
(trifluoromethyl)phenyl)thio)imidazo[1,2-a]pyridine
(3d)
(PE/EA: 80:20) White solid (142 mg, 75 %); mp: 153.2-154.1 °C;
1H NMR (250 MHz, CDCl3)  8.17-8.11 (m, 2H), 8.09 (bd, J = 6.8
Hz, 1H), 7.54-7.49 (m, 1H), 7.49-7.45 (m, 1H), 7.45-7.42 (m, 2H),
7.41-7.33 (m, 2H), 7.10-7.02 (m, 2H), 6.74 (dd, J = 7.0, 1.6 Hz, 1H),
2.46 (d, J = 0.8 Hz, 3H); 13C NMR (62.9 MHz, CDCl3)  152.1,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C4GC01462F
Green Chemistry
Page 6 of 8
Journal Name
ARTICLE
(ESI): m/z [M+H]+ calc for C20H16BrN2S 395.0212, found
395.0208.
2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3q)7 (PE/EA:
50:50) Beige solid (147 mg, 93 %); mp: 140.9-141.8 °C (lit: 145-147
1
methyl
2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine-6-
°C); H NMR (250 MHz, CDCl3)  8.28 (dt, J = 6.9, 1.2 Hz, 1H),
carboxylate (3k) (PE/EA: 70:30) White solid (145 mg, 78 %); mp:
153.5-154.3 °C; 1H NMR (250 MHz, CDCl3)  9.06 (dd, J = 1.7, 0.9
Hz, 1H), 8.29-8.21 (m, 2H), 7.92-7.84 (m, 1H), 7.71 (dd, J = 9.4, 0.9
Hz, 1H), 7.52-7.34 (m, 3H), 7.03 (bd, J = 8.0 Hz, 2H), 6.94 (bd, J =
8.3 Hz, 2H), 3.93 (s, 3H), 2.26 (s, 3H); 13C NMR (62.9 MHz,
CDCl3)  165.3, 152.8, 147.7, 136.6, 133.0, 131.2, 130.5, 129.1,
128.6, 128.6, 126.4, 126.3, 120.1, 117.2, 117.1, 108.9, 52.6, 21.0; IR
(ATR, cm-1): 3057, 3028, 2957, 1717, 1629, 1436, 1295, 805, 765,
695; HRMS (ESI): m/z [M+H]+ calc for C22H19N2O2S 375.1162,
found 375.1161.
8.25-8.19 (m, 2H), 7.72 (dt, J = 9.0, 1.1 Hz, 1H), 7.50-7.28 (m, 4H),
7.02 (d, J = 8.2 Hz, 2H), 6.91 (bd, J = 8.3 Hz, 2H), 6.85 (dd, J = 6.8,
1.2 Hz, 1H), 2.26 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  151.4,
147.2, 136.2, 133.6, 131.7, 130.3, 128.7, 128.5, 128.5, 126.7, 126.0,
124.7, 117.8, 113.1, 107.0, 21.0; IR (ATR, cm-1): 3063, 3035, 2915,
1648, 1631, 1489, 1465, 806, 742, 699, 688, 682; HRMS (ESI): m/z
[M+H]+ calc for C20H17N2S 317.1107, found 317.1104.
2-(2-methoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3r)
1
(PE/EA: 70:30) Yellow gum (164 mg, 95 %); H NMR (250 MHz,
CDCl3) 8.16 (dt, J = 6.9, 1.2 Hz, 1H), 7.73 (dt, J = 9.0, 1.2 Hz, 1H),
7.52 (dd, J = 7.5, 1.8, Hz 1H), 7.44-7.26 (m, 2H), 7.07-6.65 (m, 4H),
6.90-6.80 (m, 3H), 3.67 (s, 3H), 2.26 (s, 3H); 13C NMR (62.9 MHz,
CDCl3)  157.6, 150.5, 147.1, 135.7, 132.1, 132.1, 130.1, 130.0,
126.2, 126.0, 124.6, 123.0, 120.5, 118.0, 113.0, 111.1, 109.5, 55.5,
21.0; IR (ATR, cm-1): 1630, 1604, 1581, 1490, 1480, 1246, 751,
738; HRMS (ESI): m/z [M+H]+ calc for C21H19N2OS 347.1213,
found 347.1209.
2-phenyl-3-(p-tolylthio)-6-(trifluoromethyl)imidazo[1,2-
a]pyridine (3l) (PE/EA: 70:30) Beige solid (152 mg, 79 %); mp:
1
161.0-162.0 °C; H NMR (250 MHz, CDCl3)  8.66 (s, 1H), 8.32-
8.17 (m, 2H), 7.80 (d, J = 9.3 Hz, 2H), 7.56-7.38 (m, 3H), 7.05 (bd,
J = 8.1 Hz, 2H), 6.94 (bd, J = 8.3 Hz, 2H), 2.27 (s, 3H); 13C NMR
(62.9 MHz, CDCl3)  152.8, 146.9, 136.8, 132.8, 130.6, 129.2,
128.7, 128.5, 126.4, 125.7, 123.6 (q, J = 5.7 Hz), 122.6 (q, J = 2.9
Hz), 121.4, 118.5, 117.5 (q, J = 34.4 Hz), 109.4, 21.0; 19F (235
MHz, CDCl3)  -65.2; IR (ATR, cm-1): 3044, 1649, 1490, 1467,
1059, 800, 694, 681; HRMS (ESI): m/z [M+H]+ calc for
C21H16F3N2S 385.0981, found 385.0978.
2-(3-methoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3s)
PE/EA: 70:30) Light yellow solid (165 mg, 95 %); mp: 72.4-74.0
1
°C; H NMR (250 MHz, CDCl3)  8.19 (dt, J = 6.9, 1.2 Hz, 1H),
7.77-7.67 (m, 2H), 7.62 (dt, J = 9.0, 1.2 Hz, 1H), 7.307.17 (m, 2H),
6.91 (d, J = 8.1 Hz, 2H), 6.86-6.71 (m, 4H), 3.71 (s, 3H), 2.15 (s,
3H); 13C NMR (62.9 MHz, CDCl3)  159.7, 151.0, 147.0, 136.2,
134.8, 131.6, 130.3, 129.5, 126.7, 126.0, 124.6, 121.0, 117.7, 115.1,
113.3, 113.2, 107.2, 56.4, 21.0; IR (ATR, cm-1): 1631, 1602, 1578,
1490, 1478, 1461, 1341, 884, 802, 755, 737, 688; HRMS (ESI): m/z
[M+H]+ calc for C21H19N2OS 347.1213, found 347.1210.
7-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3m)
(PE/EA: 70:30) White solid (142 mg, 86 %); mp: 131.6-133.0 °C;1H
NMR (250 MHz, CDCl3)  8.21 (d, J = 7.5 Hz, 2H), 8.13 (d, J = 7.0
Hz, 1H), 7.58-7.30 (m, 4H), 7.01 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 7.9
Hz, 2H), 6.67 (d, J = 7.0 Hz, 1H), 2.42 (s, 3H), 2.25 (s, 3H); 13C
NMR (62.9 MHz, CDCl3)  151.2, 147.6, 137.9, 136.0, 133.7, 132.0,
130.3, 128.5, 128.5, 128.4, 125.8, 123.8, 116.3, 115.7, 106.1, 21.5,
21.0; IR (ATR, cm-1): 3049, 2915, 1645, 1489, 800, 770, 689;
HRMS (ESI): m/z [M+H]+ calc for C21H19N2S 331.1263, found
331.1261.
2-(4-methoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3t)
(PE/EA: 60:40) Beige solid (131 mg, 85 %); mp: 161.7-162.5 °C; 1H
NMR (250 MHz, CDCl3)  8.25 (d, J = 6.9 Hz, 1H), 8.18 (d, J = 8.4
Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.36-7.23 (m, 1H), 7.07-6.76 (m,
7H), 3.83 (s, 3H), 2.25 (s, 3H); 13C NMR (62.9 MHz, CDCl3) 
160.1, 151.2, 147.1, 136.1, 131.8, 130.3, 129.8, 126.5, 126.2, 125.9,
124.6, 117.5, 114.0, 112.9, 106.0, 55.4, 21.0; IR (ATR, cm-1): 2949,
2831, 1610, 1247, 833, 756, 743; HRMS (ESI): m/z [M+H]+ calc for
C21H19N2OS 347.1213, found 347.1210.
2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine-7-carbonitrile
(3n) PE/EA: 70:30) White solid (128 mg, 75 %); mp: 218.0-219.0
1
°C; H NMR (250 MHz, CDCl3)  8.35 (dd, J = 7.0, 0.9 Hz, 1H),
8.23 (dd, J = 7.9, 1.8 Hz, 2H), 8.08 (bs, 1H), 7.55-7.37 (m, 3H),
7.09-6.97 (m, 3H), 6.90 (d, J = 8.2 Hz, 2H), 2.27 (s, 3H); 13C NMR
(62.9 MHz, CDCl3)  153.5, 144.9, 137.0, 132.5, 130.6, 130.0,
129.8, 128.8, 128.6, 126.5, 125.5, 123.5, 117.5, 113.3, 110.8, 109.3,
21.1; IR (ATR, cm-1): 3094, 3051, 2230, 801; HRMS (ESI): m/z
[M+H]+ calc for C21H16N3S 342.1059, found 342.1056.
2-(4-nitrophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3u)
(PE/EA: 70:30) Yellow solid (57 mg, 32 %); mp: 214.8-215.2 °C;
1H NMR (250 MHz, CDCl3)  8.50-8.42 (m, 2H), 8.37-8.24 (m, 3H),
7.74 (d, J = 9.0 Hz, 1H), 7.45-7.32 (m, 1H), 7.04 (d, J = 8.0 Hz, 2H),
6.98-6.84 (m, 3H), 2.26 (s, 3H); 13C NMR (62.9 MHz, CDCl3) 
148.4, 147.7, 147.3, 140.0, 136.8, 130.7, 130.6, 129.0, 127.4, 126.1,
124.8, 123.8, 118.1, 113.8, 109.1, 21.0; IR (ATR, cm-1): 1634, 1595,
1510, 1491, 1337, 855, 755, 705; HRMS (ESI): m/z [M+H]+ calc for
C20H16N3O2S 362.0958, found 362.0954.
7-bromo-2-(4-chlorophenyl)-3-(p-tolylthio)imidazo[1,2-
a]pyridine (3o) (PE/EA: 90:10) White solid (190 mg, 91 %). mp:
1
178.2-178.8 °C; H NMR (250 MHz, CDCl3)  8.17 (d, J = 8.4 Hz,
2H), 8.13 (d, J = 8.1 Hz, 1H), 7.88 (bs, 1H), 7.40 (d, J = 8.3 Hz, 2H),
7.03 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 7.9
Hz, 2H), 2.27 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  150.6, 147.1,
136.7, 135.0, 131.6, 130.7, 130.5, 129.7, 128.8, 126.1, 124.9, 121.0,
120.0, 117.2, 107.9, 21.0; IR (ATR, cm-1): 1621, 1512, 1490, 1459,
838, 808, 790, 779, 728; HRMS (ESI): m/z [M+H]+ calc for
C20H15BrClN2S 428.9822, found 428.9820.
2-(4-fluorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3v)
(PE/EA: 70:30) Beige solid (168 mg, 98 %); mp: 103.5-104.8°C; 1H
NMR (250 MHz, CDCl3)  8.33-8.15 (m, 3H), 7.70 (d, J = 9.0 Hz,
1H), 7.32 (dd, J = 8.2, 7.5 Hz, 1H), 7.12 (dd, J = 8.8, 8.7 Hz, 2H),
7.02 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 7.0
Hz, 1H), 2.25 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  165.1, 161.2,
150.4, 147.1, 136.3, 131.4, 130.4, 130.3, 130.2, 129.8, 129.7, 126.8,
125.9, 124.6, 117.7, 115.6, 115.3, 113.2, 106.7, 21.0; 19F (235 MHz,
CDCl3)  -116.3; IR (ATR, cm-1): 1632, 1474, 1220, 1014, 797, 754,
742; HRMS (ESI): m/z [M+H]+ calc for C20H16FN2S 335.1013,
found 335.1010.
8-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3p)
(PE/EA: 70:30) White solid (154 mg, 93 %); mp: 106.7-107.3 °C;
1H NMR (250 MHz, CDCl3)  8.25-8.18 (m, 2H), 8.15 (bdd, J = 6.8,
1.1 Hz, 1H), 7.50-7.31 (m, 3H), 7.11 (ddd, J = 7.0, 1.3, 1.1 Hz, 1H),
7.02 (bd, J = 8.0 Hz, 2H), 6.91 (bd, J = 8.0 Hz, 2H), 6.77 (ddd, J =
6.9, 6.7, 1 Hz, 1H), 2.71 (bs, 3H), 2.26 (bs, 3H); 13C NMR (62.9
MHz, CDCl3)  151.0, 147.5, 136.0, 133.9, 132.0, 130.3, 128.6,
128.5, 128.5, 127.8, 125.9, 125.4, 122.5, 113.1, 107.1, 21.0, 16.9; IR
(ATR, cm-1): 3029, 2918, 1622, 1489, 1466, 804, 749, 702; HRMS
(ESI): m/z [M+H]+ calc for C21H19N2S 331.1263, found 331.1261.
2-(4-chlorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3w)
PE/EA: 50:50) Beige solid (152 mg, 90 %); mp: 132.5-133.4 °C; 1H
NMR (250 MHz, CDCl3)  8.27 (d, J = 6.8 Hz, 1H), 8.19 (d, J = 8.4
Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.36-7.24
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

View Article Online
DOI: 10.1039/C4GC01462F
Page 7 of 8
ARTICLE
Green Chemistry
Journal Name
(m, 1H), 7.01 (d, J = 7.9 Hz, 2H), 6.93-6.81 (m, 3H), 2.25 (s, 3H);
13C NMR (62.9 MHz, CDCl3)  150.1, 147.1, 136.4, 134.6, 132.1,
6-chloro-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyrimidine (4g)
DCM) Pale Yellow solid (90 mg, 51 %); mp: 213.5-214.5 °C. H
131.3, 130.4, 129.7, 128.7, 126.9, 126.0, 124.6, 117.8, 113.3, 107.2, NMR (250 MHz, CDCl3)  8.54 (s, 2H), 8.38-8.30 (m, 2H), 7.51-
1
21.0; IR (ATR, cm-1): 3030, 3029, 1630, 1489, 1462, 827, 800, 756, 7.36 (m, 3H), 7.05 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 2.27
743; HRMS (ESI): m/z [M+H]+ calc for C20H16ClN2S 351.0717,
found 351.0714.
(s, 3H); 13C NMR (62.9 MHz, CDCl3)  153.6, 150.8, 148.3, 137.0,
132.5, 130.6, 130.0, 129.6, 129.5, 128.7, 128.7, 126.4, 119.0, 106.9,
21.0; IR (ATR, cm-1): 3078, 3051, 1519, 1476, 1440, 800, 699;
HRMS (ESI): m/z [M+H]+ calc for C19H15ClN3S 352.0670, found
6-chloro-2-phenyl-3-(p-tolylthio)imidazo[1,2-b]pyridazine
(DCM) Pale Yellow solid (93 mg, 53 %); mp: 175.2-175.8 °C; H
(4a)
1
NMR (250 MHz, CDCl3)  8.30-8.23 (m, 2H), 7.92 (d, J = 9.3 Hz, 352.0669.
1H), 7.57-7.33 (m, 3H), 7.16-7.07 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 3-iodo-6-methyl-2-phenylimidazo[1,2-a]pyridine (5) (PE/EA:
1
2.25 (s, 3H); 13C NMR (62.9 MHz, CDCl3)  150.7, 147.4, 139.4,
80:20) Beige solid (77 mg, 46 %); mp: 159.9-160.2 °C; H NMR
136.8, 132.9, 131.0, 130.1, 129.1, 128.6, 128.4, 128.1, 126.7, 120.7, (250 MHz, CDCl3)  8.15-8.00 (m, 3H), 7.53-7.33 (m, 4H), 6.76 (dd,
115.2, 21.1; IR (ATR, cm-1): 2919, 2850, 1524, 1491, 1465, 1100,
799, 703; HRMS (ESI): m/z [M+H]+ calc for C19H15ClN3S
352.0670, found 352.0669.
J = 7.0, 1.7 Hz, 1H), 2.45 (s, 3H); 13C NMR (62.9 MHz, CDCl3) 
148.5, 147.9, 136.8, 133.8, 128.6, 128.4, 128.3, 125.8, 116.2, 115.9,
58.3, 21.4; IR (ATR, cm-1): 3059, 2919, 1646, 1494, 1464, 1439,
767, 695; HRMS (ESI): m/z [M+H]+ calc for C14H12 IN2 335.0040,
found 335.0040.
6-chloro-3-((4-fluorophenyl)thio)-2-phenylimidazo[1,2-
b]pyridazine (4b) (DCM) Pale pink solid (110 mg, 62 %); mp:
1
212.2-213.2 °C; H NMR (250 MHz, CDCl3)  8.30-8.21 (m, 2H),
Notes and references
7.95 (d, J = 9.4 Hz, 1H), 7.54-7.40 (m, 3H), 7.25-7.14 (m, 3H), 6.92
(bdd, J = 8.7, 8.7 Hz, 2H); 13C NMR (62.9 MHz, CDCl3)  164.1,
160.2, 150.6, 147.6, 139.5, 132.8, 130.6, 130.5, 129.5, 129.5, 129.3,
128.7, 128.5, 126.8, 126.5, 120.9, 116.7, 116.3; 19F (235 MHz,
CDCl3)  -118.0; IR (ATR, cm-1): 3093, 3062, 1526, 1488, 1465,
1219, 1099, 831, 805, 702, 690; HRMS (ESI): m/z [M+H]+ calc for
C18H12ClFN3S 356.0419, found 356.0417.
a
Institut de Chimie Organique et Analytique (ICOA) Université
d’Orléans UMR-CNRS 7311, BP 6759, rue de Chartres 45067 Orléans
cedex 2 (France)
Electronic Supplementary Information (ESI) available: [Experimental
procedures, spectral characterization, and coppies of 1H, 13C, and 19F
spectra for all compounds.]. See DOI: 10.1039/c000000x/
1
(a) K. S. Gudmundsson, S. D. Boggs, J. G. Catalano, A. Svolto, A.
Spaltenstein, M. Thomson, P. Wheelan and S. Jenkinson. Bioorg. Med.
Chem. Lett., 2009, 19, 6399; (b) Y. Sato, Y. Onozaki, T. Sugimoto, H.
Kurihara, K. Kamijo, C. Kadowaki, T. Tsujino, A. Watanabe, S. Otsuki,
M. Mitsuya, M. Iida, K. Haze, T. Machida, Y. Nakatsuru, H. Komatani,
H. Kotani and Y. Iwasawa Bioorg. Med. Chem. Lett., 2009, 19, 4673; (c)
C. Enguehard-Gueiffier and A. Gueiffier Mini-Rev. Med. Chem., 2007,
7, 888 (and the references therein).
6-chloro-3-((4-methoxyphenyl)thio)-2-phenylimidazo[1,2-
b]pyridazine (4c) (DCM) White solid (118 mg, 64 %); mp: 160.5-
161.6 °C; 1H NMR (250 MHz, CDCl3)  8.34-8.25 (m, 2H), 7.91 (d,
J = 9.3 Hz, 1H), 7.56-7.36 (m, 3H), 7.32-7.22 (m, 2H), 7.13 (d, J =
9.3 Hz, 1H), 6.81-6.71 (m, 2H), 3.73 (s, 3H); 13C NMR (62.9 MHz,
CDCl3)  159.4, 150.1, 147.3, 139.2, 133.0, 131.4, 129.1, 128.6,
128.6, 126.7, 124.7, 120.6, 116.5, 115.0, 55.4; IR (ATR, cm-1):
3094, 3062, 2837, 1592, 1526, 1490, 1464, 1438, 1217, 1099, 807,
728, 689; HRMS (ESI): m/z [M+H]+ calc for C19H15ClN3OS
368.0619, found 368.0617.
2
Recent articles on this subject: (a) X. Zhou and X. Li, RSC Adv., 2014,
4, 1241; (b) P. Katrun, C. Mueangkaew, M. Pohmakotr, V. Reutrakul, T.
Jaipetch, D. Soorukram and C. Kuhakarn, J. Org. Chem., 2014, 79,
1778; (c) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang, and G.-L. Deng,
Org. Lett., 2014, 16, 50; (d) F. Xiao, H. Xie, S. Liu and G.-J. Deng, Adv.
Synth. Catal., 2014, 356, 364; (e) J. B. Azeredo, M. Godoi, G. M.
Martins, C. C. Silveira and A. L. Braga, J. Org. Chem., 2014, 79, 4125;
(f) X. Zhang, X. Zhou, H. Xiao and X. Li, RSC Adv., 2013, 3, 22280; (g)
C. D. Prasad, S. Kumar, M. Sattar, A. Adhikary and S. Kumar, Org.
Biomol. Chem., 2013, 11, 8036; (h) M. Klečka, R. Pohl, J. Čejka and M.
Hocek, Org. Biomol. Chem. 2013, 11, 5189; (i) T. Hamashima, Y. Mori,
K. Sawada, Y. Kasahara, D. Murayama, Y. Kamei, H. Okuno, Y.
Yokoyama and H. Suzuki, Chem. Pharm. Bull., 2013, 61, 292; (j) P.
Sang, Z. Chen, J. Zou and Y. Zhang, Green Chem., 2013, 15, 2096; (k)
F.-L. Yang and S.-K. Tian, Angew.Chem. Int. Ed., 2013, 52, 4929; (l) C.
C. Silveira, S. R. Mendes, L. Wolf, G. M. Martins and L. von Mühlen,
Tetrahedon, 2012, 68, 10464; (m) M. Chen, Z.-T. Huang and Q.-Y.
Zheng, Chem. Commun., 2012, 48, 11686; (n) W. Ge and Y. Wei, Green
Chem., 2012, 14, 2066; (o) D. Huang, J. Chen, W. Dan, J. Ding, M. Liu
and H. Wu, Adv. Synth. Catal., 2012, 354, 2123; (p) M. Tudge, M.
Tamiya, C. Savarin and G. R. Humphrey, Org. Lett., 2006, 8, 565; (q) K.
M. Schlosser, A. P. Krasutsky, H. W. Hamilton, J. E. Reed and K.
Sexton, K. Org. Lett., 2004, 6, 819.
2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyrimidine
(4d)
(EA/MeOH: 99:1) Beige solid (136 mg, 86 %); mp: 139.5-140.0 °C;
1H NMR (250 MHz, CDCl3)  8.68-8.60 (m, 1H), 8.51 (dd, J = 6.7,
2.1 Hz, 1H), 8.40-8.31 (m, 2H), 7.49-7.35 (m, 3H), 7.02 (d, J = 8.0
Hz, 2H),6.97-6.87 (m, 3H), 2.25 (s, 3H); 13C NMR (62.9 MHz,
CDCl3)  151.6, 151.6, 150.1, 136.7, 132.9, 132.2, 130.6, 130.5,
129.2, 128.7, 128.6, 126.2, 109.4, 106.1, 21.0; IR (ATR, cm-1):
3060, 1604, 1488, 1341, 1212, 798, 769, 683; HRMS (ESI): m/z
[M+H]+ calc for C19H16N3S 318.1059, found 318.1059.
2-phenyl
-((4-fluorophenyl)thio)-2-phenylimidazo[1,2-
a]pyrimidine (4e) (EA/MeOH: 99:1) Beige solid (141 mg, 88 %);
1
mp: 153.5-154.4 °C; H NMR (250 MHz, CDCl3)  8.66 (dd, J =
4.2, 2.0 Hz, 1H), 8.53 (dd, J = 6.8, 2.0 Hz, 1H), 8.39-8.30 (m, 2H),
7.52-7.36 (m, 3H), 7.06-6.86 (m, 5H); 13C NMR (62.9 MHz, CDCl3)
 163.8, 159.9, 152.9, 151.8, 150.1, 132.8, 132.1, 129.4, 129.3,
129.3, 128.7, 128.7, 128.2, 128.0, 117.1, 116.8, 109.6, 105.8; 19F
(235 MHz, CDCl3)  -118.4; IR (ATR, cm-1): 3087, 3061, 1613,
1486, 1218, 833, 760, 714, 689; HRMS (ESI): m/z [M+H]+ calc for
C18H13FN3S 322.0809, found 322.0809.
3
(a) D. C. Mohan, S. N. Rao, C. Ravi and S. Adimurthy, Asian J. Org.
Chem., 2014, 3, 609; (b) Z. Li, J. Hong and X. Zhou, Tetrahedron, 2011,
67, 3690; (c) C. Hamdouchi, J. de Blas and J. Ezquerra, Tetrahedron,
1999, 55, 541.
C. Hamdouchi, C. Sanchez and J. Ezquerra, Synthesis, 1998, 867.
S. M. Patil, S. Kulkarni, M. Mascarenhas, R. Sharma, S. M. Roopan and
A. Roychowdhury, Tetrahedron, 2013, 69, 8255.
3-((4-methoxyphenyl)thio)-2-phenylimidazo[1,2-a]pyrimidine
(4f) (EA) Yellow solid (153 mg, 92 %); mp: 147.5-148.0 °C; H
1
4
5
NMR (250 MHz, CDCl3)  8.62 (dd, J = 4.2, 2.0 Hz, 1H), 8.55 (dd,
J = 6.8, 2.0 Hz, 1H), 8.42-8.35 (m, 2H), 7.52-7.36 (m, 3H), 7.05-
6.97 (m, 2H), 6.92 (dd, J = 6.8, 4.2 Hz, 1H), 6.81-6.72 (m, 2H), 3.72
(s, 3H); 13C NMR (62.9 MHz, CDCl3)  159.0, 152.3, 151.5, 149.9,
133.0, 132.1, 129.2, 128.8, 128.6, 128.5, 124.5, 115.4, 109.4, 107.0,
55.5; IR (ATR, cm-1): 3057, 2839, 1611, 1589, 1488, 1233, 841,
810, 762, 700, 689; HRMS (ESI): m/z [M+H]+ calc for C19H16N3OS
334.1009, found 334.1007.
6
7
8
9
Z. Gao, X. Zhu and R. Zhang, RSC Adv., 2014, 4, 19891.
W. Ge, X. Zhu and Y. Wei, Y. Eur. J. Org. Chem., 2013, 6015.
C. Ravi, D. C. Mohan and S. Adimurthy, S. Org. Lett., 2014, 16, 2978.
R. J. Bochis, L. E. Olen, M. H. Fisher, and R. A. Reamer, J. Med. Chem.,
1981, 24, 1483.
10 (a) M.-A. Hiebel, Y. Fall, M.-C. Scherrmann and S. Berteina- Raboin,
Eur. J. Org. Chem., 2014, 4643; (b) N. Fresneau, M.-A. Hiebel, L. A.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C4GC01462F
Green Chemistry
Page 8 of 8
Journal Name
ARTICLE
Agrofoglio and S. Berteina-Raboin, Tetrahedron Lett., 2012, 53, 1760;
(c) N. Fresneau, M.-A. Hiebel, L. A. Agrofoglio and S. Berteina-Raboin,
Molecules, 2012, 68, 4409.
11 (a) M. S. Rao, M. Haritha, N. Chandrasekhar, M. V. B. Rao and M. Pal,
Tetrahedron lett., 2014, 55, 1660; (b) N. Mangarao, G. M. Basha, T.
Ramu, R. Srinuvasarao, S. Prasanthi and V. Siddaiah, Tetrahedron Lett.,
2014, 55, 177; (c) R. Turgis, I. Billault, S. Acherar, J. Augé and M.-C.
Scherrmann, Green Chem., 2013, 15, 1016; (d) L. Ning, L. Chun, R.
Xiaofeng and J. Zilin, Advances in Chemistry Research, 2012, 16, 125.
Publisher (Nova Science Publishers, Inc); (e) E. Colacino, J. Martinez, F.
Lamaty, L. S. Patrikeeva, L. L. Khemchyan, V. P. Ananikov and I. P.
Beletskaya, Coordin. Chem. Rev., 2012, 256, 2893; (f) U. P. Singh,
Synlett, 2012, 2721; (g) M. Huang, L. Wang, X. Zhu, Z. Mao, D. Kuang
and Y. Wan, Eur. J. Org. Chem., 2012, 4897; (h) G. Chen, J. Weng, Z.
Zheng, X. Zhu, Y. Cai, J. Cai and Y. Wan, Y. Eur. J. Org. Chem., 2008,
3524; (i) D. E. Bergbreiter, Chem. Rev., 2002, 102, 3345; (j) T. J.
Dickerson, N. N. Reed and K. D. Janda, Chem. Rev., 2002, 102, 3325.
12 (a) F. C. Küpper, M. C. Feiters, B. Olofsson, T. Kaiho, S. Yanagid, M.
B. Zimmermann, L. J. Carpenter, G. W. Luther III, Z. Lu, M. Jonsson
and L. Kloo, Angew. Chem. Int. Ed., 2011, 50, 11598; (b) M. Jered, D.
Vražič and M. Zupan, Tetrahedron, 2011, 67, 1355.
13 (a) S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib and G. Guillaumet,
Lett. Org. Chem., 2012, 9, 118; (b) C.-P. Zhang, Z. L. Wang, Q.-Y.
Chen, C.-T. Zhang, Y.-C. Gu and J. C. Xiao, Angew. Chem. Int. Ed.,
2011, 50, 1896; (c) S.-Y. Takizawa, J.-I. Nishida, T. Tsuzuki, S. Tokito
and Y. Yamashita, Inorg. Chem., 2007, 46, 4306; (d) Z.-P. Zhuang, M-P.
Kung, A. Wilson, C.-W. Lee, K. Plössl, C. Hou, D.-M. Holtzman and H.
F. Kung, J. Med. Chem., 2003, 46, 237.
14 Recent articles using iodine for the formation of disulfide: (a) F. S.
Teplyakov, T. G. Vasileva, M. L. Petrov and D. A. Androsov, Org. Lett.,
2013, 15, 4038; (b) M. T. Rubino, M. Agamennone, C. Campestre, P.
Campiglia, V. Cremasco, R. Faccio; A. Laghezza, F. Loiodice, D.
Maggi, E. Panza, A. Rossello and P. Tortorella, ChemMedChem, 2011,
6, 1258; (c) L. Wang and D. L. J. Clive, Org. Lett., 2011, 13, 1734; (d)
A. Spurg, G. Schnakenburg and S. R. Waldvogel, Chem. Eur. J., 2009,
15, 13313. Recent articles using hydrogen peroxide for the formation of
disulfide: (e) K. A. Mazzio, K. Okamoto, Z. Li, S. Gutmann; E. Strein,
D. S. Ginger, R. Schlaf and C. K. Luscombe, Chem. Comm., 2013, 49,
1321; (f) T. Nabeshima, D. Nishida and T. Saiki, Tetrahedron, 2003, 59,
639; (g) V. Kesavan, D. Bonnet-Delpon and J.-P. Begue, Synthesis,
2000, 223.
15 J. Zhao, H. Fang, J. Han, Y. Pan and G. Li, Adv. synth. Catal., DOI:
10.1002/adsc.201400032
16 Å. M. L. Øuiestad, A. C. Petersen, V. Bakken, J. Vedde and E. Uggerud,
Angew. Chem. Int. Ed., 2001, 40, 1305.
17 J. Barluenga, M. Marco-Arias, F. González-Bobes, A. Ballesteros
and J. M. González, Chem. Eur. J., 2004, 10, 1677.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7