Catalyst-Free Regioselective C-3 Nitrosation of Imidazopyridines with tert -Butyl Nitrite under Neutral Conditions

Article abstract of DOI:10.1055/s-0035-1560508

We have successfully developed a novel and efficient catalyst-free method for the synthesis of 3-nitroso-substituted imidazopyridines, from readily available imidazo[1,2-a]pyridines and tert-butyl nitrite, in good to excellent yields. Importantly, the use

Full text of DOI:10.1055/s-0035-1560508

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 122–130
paper
122
D. Yang et al.
Paper
Synthesis
Catalyst-Free Regioselective C-3 Nitrosation of Imidazopyridines
with tert-Butyl Nitrite under Neutral Conditions
Daoshan Yang
Kelu Yan
N
N
MeCN, air
80 °C
R1
R1
N
+
O
O
N
N
R2
Wei Wei
R2
catalyst-free
NO
H
Yao Liu
radical pathway
neutral conditions
easy operation
Mengqi Zhang
Caixia Zhao
Laijin Tian
Hua Wang*
Key Laboratory of Life-Organic Analysis and Key Laboratory of
Pharmaceutical Intermediates and Analysis of Natural Medicine,
School of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165, Shandong, P. R. of China
huawang_qfnu@126.com
Received: 05.08.2015
Accepted after revision: 25.09.2015
Published online: 30.10.2015
demonstrated a novel copper-catalyzed C-3 formylation of
imidazo[1,2-a]pyridines with dimethyl sulfoxide by using
dioxygen as the oxidant.14f In 2014, Adimurthy and co-
workers communicated an elegant N-chlorosuccinimide-
promoted regioselective sulfenylation of imidazo[1,2-
a]pyridines with thiophenols under mild conditions.14a In
2015, Hiebel’s group reported an iodine-catalyzed regiose-
lective sulfenylation of imidazoheterocycles in polyethylene
glycol 400 (PEG 400).14b In 2015, Atmakur and co-workers
reported a highly efficient iodine–dimethyl sulfoxide pro-
moted oxidative cross-coupling of imidazo[1,2-a]pyridines
with methyl ketones under mild conditions.14g Very recent-
ly, Li et al. described an efficient regioselective hydrazina-
tion of imidazo[1,2-a]pyridines with diethyl azodicarboxyl-
ate in neutral media under metal-free conditions.14h How-
ever, it still remains a challenging, but desirable task to
develop more efficient and practical methods to C-3 func-
tionalize the useful imidazo[1,2-a]pyridines.
DOI: 10.1055/s-0035-1560508; Art ID: ss-2015-h0466-op
Abstract We have successfully developed a novel and efficient cata-
lyst-free method for the synthesis of 3-nitroso-substituted imidazopyri-
dines, from readily available imidazo[1,2-a]pyridines and tert-butyl ni-
trite, in good to excellent yields. Importantly, the use of transition-
metal catalysts, stoichiometric amounts of acids, and toxic or potential-
ly dangerous oxidants is avoided. This easy and practical method com-
plements nitrosation reactions by expanding the scope and practicality,
and should attract much attention in synthetic and pharmaceutical
chemistry.
Key words metal-free, C–H functionalization, nitrosation, imidazopy-
ridines, heterocycles
Imidazoheterocycle motifs are extensively found in the
subunits of a variety of bioactive compounds,1 and they are
also widely used as privileged structures in pharmaceutical
compounds.2 It is worth noting that imidazo[1,2-a]pyridine
derivatives possess many excellent biological activities, in-
cluding antitumor,3 antibacterial,4 anti-inflammatory,5 an-
tiviral,6 antimicrobial,7 and antipyretic8 action. Importantly,
the imidazo[1,2-a]pyridine skeleton is the core structure in
many commercially available drugs, such as zolpidem (to
treat insomnia),2,9 zolimidine (to treat peptic ulcers),10 ol-
prinone (to treat heart failure),11 and minodronic acid (to
treat osteoporosis)12 (Figure 1). Consequently, many effi-
cient and useful methods for the synthesis of imidazo[1,2-
a]pyridine derivatives have been developed.13 Exploring
new methods for the C-3 functionalization of imidazo[1,2-
a]pyridines has attracted considerable attention, but, un-
fortunately, successful examples remain limited.14 In 2012,
Cao and Jiang published an efficient procedure for the C-3
arylation of substituted imidazo[1,2-a]pyridines by copper-
catalyzed C–H bond activation.14k In 2014, Cao et al.
Me2N
O
N
Me
N
SO2Me
Me
N
N
zolimidine
zolpidem
CN
Me
O
N
HN
PO(OH)2
OH
N
N
N
PO(OH)2
minodronic acid
olprinone
Figure 1 Popular drugs containing the imidazopyridine motif
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 122–130

123
D. Yang et al.
Paper
Synthesis
Nitroso compounds have been widely used as important
synthetic intermediates in organic transformations, such as
ene reactions,15 nitroso aldol reactions,16 and cycloaddi-
tions.17 Additionally, there are some biologically active aro-
matic nitroso compounds with proven special activity
against HIV-1 infectivity.18 As a consequence, the introduc-
tion of a nitroso group into an organic skeleton is an attrac-
tive synthetic goal. Unfortunately, synthetic methods for
the construction of nitroso compounds are rather limited.19
Classical methods for the synthesis of nitroso compounds
mainly focus on the oxidation of anilines to the correspond-
ing nitrosoarenes.20 Despite the various advantages of these
methods, wider application is limited by factors such as the
use of excess oxidants in these reactions and the formation
of undesired byproducts such as azo and azoxy compounds.
Some other methods have been developed for the nitrosa-
tion of organomercury,21 thallium,22 silicon,23 and electron-
rich arenes24 in the presence of nitrosyl chloride. Also, di-
rect nitrosation of imidazopyridines by using sodium ni-
trite–acetic acid has been a well-known and popular meth-
od for the synthesis of 3-nitrosoimidazopyridines.25 Never-
theless, these methods generally have some drawbacks,
such as the use of noncommercially available arylmetallics
or acid-oxidative conditions. In 2012, Molander and co-
workers reported a mild and selective method for the ipso-
nitrosation of organotrifluoroborates in the presence of ni-
trosonium tetrafluoroborate.26 However, it is still highly de-
sirable to discover new methods to prepare nitroso com-
pounds that utilize inexpensive nitroso reagents and pro-
ceed under non- or low-oxidative neutral conditions.
There have been several reports recently on the use of
tert-butyl nitrite as an excellent nitro source (NO2), such as
in nitro-carbocyclization of activated alkenes,27 direct C–H
nitration of arenes,28 nitration of quinoline N-oxides,29 ni-
tration of arylboronic acids,30 nitration of phenols,31 and ni-
tration/cyclization of 1,7-enynes.32 Nevertheless, to the best
of our knowledge, reports on the use of tert-butyl nitrite as
the nitroso source (NO) have been rare. In 2014, Jiao and co-
workers reported an efficient tetrabutylammonium bro-
mide catalyzed (10 mol%) dehydrogenative N-incorporation
of simple imines, with tert-butyl nitrite as the nitroso
source, leading to quinoxaline N-oxides.33 Herein, we report
a novel and direct, catalyst-free nitrosation of imidazopyri-
dines under neutral conditions, with simple and readily
available tert-butyl nitrite as the nitroso source.
absence of a catalyst (entry 5). These results confirm that a
catalyst-free nitrosation coupling reaction is possible. Addi-
tionally, different solvents were examined, showing that
acetonitrile was superior to the others (entries 5–10). Dif-
ferent reaction temperatures were also surveyed (entries
10–13), and the best result was obtained when the reaction
was conducted at 80 °C (entry 11).
Table 1 Optimization of the Reaction Conditionsa
N
N
N
+
O
O
N
N
H
1a
NO
3a
2
Entry
Catalyst
Solvent
Temp
Yield (%)b
1
2
Pd(OAc)2
PdCl2
Cu(OAc)2
FeCl2
DMF
DMF
DMF
DMF
DMF
90
90
90
90
90
90
90
90
90
90
80
70
60
71
66
72
72
75
71
44
70
78
81
81
74
63
3
4
5
none
6
none
DMSO
H2O
7
none
8
none
1,4-dioxane
DCE
9
none
10
11
12
13
none
MeCN
MeCN
MeCN
MeCN
none
none
none
a Reaction conditions: 2-phenylimidazo[1,2-a]pyridine (1a; 0.3 mmol),
t-BuONO (2; 0.6 mmol), solvent (2 mL), 18 h; under air.
b Isolated yield.
Having obtained the optimized reaction conditions
(MeCN as solvent, at 80 °C, under an air atmosphere), we
next turned our attention toward the scope and limitations
of the transformation, with the results summarized in
Scheme 1. Imidazo[1,2-a]pyridines carrying electron-
donating or electron-withdrawing aryl substituents per-
formed well in the reaction, with the corresponding 3-ni-
troso products obtained in good to excellent yields. Notably,
strongly electron-withdrawing groups such as trifluoro-
methyl and nitro were well tolerated in this transformation,
with 3x–z afforded in 77–81% yields. 2-(1-Naphthyl)imid-
azo[1,2-a]pyridine could also be employed in the reaction
to generate the desired product 3f in good yield. Notably, 2-
(2-furyl)imidazopyridines were also compatible with the
reaction conditions (3v and 3w). Although imidazopyri-
dines bearing aryl groups at the C-2 position performed
well in this reaction, unfortunately, 2-alkyl-substituted im-
idazopyridines were poor substrates, giving only traces of 4
(Scheme 1). The structure of 3n was unambiguously con-
firmed by X-ray crystallographic analysis (Figure 2) (see
As shown in Table 1, we started our studies by exploring
the reaction between 2-phenylimidazo[1,2-a]pyridine (1a)
with tert-butyl nitrite (2) to optimize the reaction condi-
tions. Initially, several transition-metal salts, such as palla-
dium(II) acetate, palladium(II) chloride, copper(II) acetate,
and iron(II) chloride (10 mol% catalytic amount relative to
1a) were tested in N,N-dimethylformamide at 90 °C under
an air atmosphere, but no obviously different activity was
observed (entries 1–4). To our delight, the desired nitrosat-
ed imidazopyridine (3a) was obtained in 75% yield in the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 122–130

124
D. Yang et al.
Paper
Synthesis
N
N
N
MeCN, air
80 °C
R1
R1
N
+
R2
O
O
N
R2
NO
3
H
1
2
N
N
N
N
Me
N
N
NO
Me
NO
NO
3a (81%), (83%)a
3b (82%)
3c (86%)
Br
N
N
N
N
N
Cl
N
NO
NO
NO
3d (71%)
3e (73%)
3f (79%)
Me
Me
Me
N
Me
N
N
N
OMe
Cl
N
N
Br
NO
NO
NO
3g (76%)
3h (74%)
3i (71%)
Me
N
N
N
N
Me
Me
N
N
Me
NO
NO
3j (91%)
NO
3k (90%)
3l (85%)
Cl
Me
N
N
N
N
Cl
N
N
Me
Me
Me
NO
NO
N
NO
3m (81%)
3n (83%)
3o (74%)
Br
N
N
Br
N
N
N
Cl
Me
Me
NO
NO
NO
3p (74%)
3q (72%)
3r (68%)
Me
N
N
N
N
N
Cl
N
Br
Cl
Br
NO
NO
NO
3t (72%)
3s (69%)
3u (73%)
Me
Me
N
N
N
N
NO2
N
N
O
O
N
NO
NO
NO
3v (63%)
3x (77%)
3w (66%)
N
N
N
CF3
CF3
N
N
Me
NO
NO
NO
3y (74%)
4 (trace)
3z (81%)
Scheme 1 Direct C-3 nitrosation of different imidazopyridines 1. Reagents and conditions: imidazopyridine 1 (0.3 mmol), t-BuONO (2; 0.6 mmol),
MeCN (2 mL), 90 °C, 18 h; isolated yields of 3 are given. a Reaction carried out on 6 mmol scale.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 122–130

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D. Yang et al.
Paper
Synthesis
Me
Me
N
N
SnCl
(5 equiv)
2 2H2O
N
N
80 °C, EtOH, 2 h
93%
NO
NH2
further modification
3j
5
Scheme 2 Synthesis of 3-aminoimidazopyridine 5 by the present method
Supporting Information for details). Various other function-
al groups, such as methyl, methoxy, chloro, and bromo,
were found to be compatible with the present protocol. We
also investigated the synthetic applicability of the present
method by carrying out a gram-scale reaction between 1a
and 2 in the usual laboratory flask; 1.11 grams of 3a was
obtained in 83% yield without loss of efficiency (Scheme 1).
Thus, this protocol is expected to serve as a practical and
efficient access to 3-nitrosoimidazopyridines.
equiv), was added to the reaction system under the stan-
dard conditions; this led to inhibition of the reaction
(Scheme 3, a). This indicated that the reaction proceeds via
a radical pathway. Furthermore, when the reaction was car-
ried out under an oxygen atmosphere, the desired nitrosa-
tion product 3a was obtained in 80% yield, but no nitration
product 6 was observed (as determined by HPLC-MS); this
was quite different from the previous reports that the nitro-
so radical NO• could easily be oxidized to the nitro radical
NO2• under air or an oxygen atmosphere36 (Scheme 3, b).
As illustrated in Scheme 4, two possible mechanisms for
the direct transformation are proposed, on the basis of the
preliminary results described above and some previous re-
ports.14c,37 In path A, heating of tert-butyl nitrite leads to
the generation of the active nitroso radical I and the tert-
butoxy radical II. Subsequently, the nitroso radical reacts
with 2-phenylimidazo[1,2-a]pyridine (1a) to form the radi-
cal intermediate III. Then III is transformed into carboca-
tion intermediate IV via a single-electron transfer (SET)
process with the assistance of the tert-butoxy radical II. Fi-
nally, the desired product 3a is generated through the elim-
ination of a proton from intermediate IV. As a complemen-
tary mechanism (path B), heterolysis of tert-butyl nitrite
generates an electrophilic nitroso cation (V). Subsequently,
electrophilic addition of the electrophilic V to 1a also leads
to the intermediate carbocation IV.
Figure 2 X-ray crystal structure of compound 3n (CCDC 1412151)
We attempted the synthesis of 3-aminoimidazopyri-
dines by using the present method. As shown in Scheme 2,
3j was transformed into 5 in 92% yield in the presence of
tin(II) chloride in ethanol.34 Therefore, the present method
is a useful approach to 3-aminoimidazopyridine derivatives
from 3-H imidazopyridines.35
To gain a deeper understanding of the reaction mecha-
nism, a radical inhibitor, 2,6-di-tert-butyl-4-methylphenol
(BHT) or 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) (4
N
N
TEMPO or BHT
standard
N
(a)
+
O
O
N
N
conditions
2
NO
1a
3a
7% or 11%
N
N
N
NO
MeCN, O2
80 °C
3a
80%
N
(b)
+
O
O
N
N
N
1a
2
NO2
6
not detected
Scheme 3 Control experiments
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Synthesis
3-Nitroso-2-phenylimidazo[1,2-a]pyridine (3a)38
1a
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 54 mg
(81%); green solid; mp 163–165 °C (Lit.38 165 °C); Rf = 0.4 (PE–EtOAc,
2:1).
1H NMR (400 MHz, CDCl3): δ = 9.93 (d, J = 8.0 Hz, 1 H), 8.67 (d, J = 8.0
I
NO
heat
N
O
+
N
O
Hz, 2 H), 7.85–7.83 (m, 2 H), 7.60–7.54 (m, 3 H), 7.27–7.24 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 153.4, 145.7, 136.2, 131.6,
131.5, 130.8, 128.9, 126.5, 119.6, 117.5.
N
2
O
H
path A
III
ON
II
ESI-HRMS: m/z calcd for C13H10N3O [M + H]+: 224.0824; found:
224.0829.
3-Nitroso-2-p-tolylimidazo[1,2-a]pyridine (3b)
–O
HO
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 58 mg
N
N
(82%); green solid; mp 218–219 °C; Rf = 0.4 (PE–EtOAc, 2:1).
+
1H NMR (400 MHz, CDCl3): δ = 9.95 (d, J = 4.0 Hz, 1 H), 8.59 (d, J = 8.0
Hz, 2 H), 7.84–7.82 (m, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.26–7.24 (m, 1
H), 2.47(s, 3 H).
N
N
H
3a
NO
IV
ON
13C NMR (100 MHz, CDCl3): δ = 160.1, 153.3, 145.9, 142.3, 136.1,
130.8, 129.7, 128.8, 126.5, 119.3, 117.4, 21.6.
1a
ESI-HRMS: m/z calcd for C14H12N3O [M + H]+: 238.0980; found:
238.0987.
path B
heat
O–
+
N
NO+
V
O
O
3-Nitroso-2-m-tolylimidazo[1,2-a]pyridine (3c)
2
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 61 mg
(86%); green solid; mp 148–149 °C; Rf = 0.4 (PE–EtOAc, 2:1).
Scheme 4 Proposed mechanisms for the direct transformation
1H NMR (400 MHz, CDCl3): δ = 9.94 (d, J = 4.0 Hz, 1 H), 8.48 (m, 2 H),
7.85 (t, J = 8.0 Hz, 2 H), 7.47–7.40 (m, 2 H), 7.27–7.24 (m, 1 H), 2.49 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 160.3, 153.4, 145.7, 138.6, 136.1,
132.5, 131.4, 131.2, 128.8, 128.2, 126.5, 119.5, 117.5, 21.5.
In summary, a new catalyst-free system for the nitrosa-
tion of imidazopyridines was developed. The nitrosation re-
action proceeded well under neutral conditions to give the
3-nitrosoimidazopyridines in good to excellent yields. No-
tably, no metal catalysts, no acids, and no strong oxidants
were required in the transformation. The developed meth-
od provided an alternative and highly attractive route to
various potentially biologically active 3-nitrosoimidazopyr-
idines from easily available imidazo[1,2-a]pyridines and
tert-butyl nitrite.
ESI-HRMS: m/z calcd for C14H12N3O [M + H]+: 238.0980; found:
238.0981.
2-(4-Chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3d)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 55 mg
(71%); green solid; mp 223–225 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.12 (d, J = 8.0 Hz, 1 H), 8.65 (d, J = 8.0
Hz, 2 H), 7.91–7.80 (m, 2 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.30–7.27 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 158.6, 153.2, 145.6, 138.3, 136.2,
132.0, 130.0, 129.2, 126.5, 119.7, 117.5.
All commercially available reagents and chemicals were purchased
from chemical suppliers and used as received without further purifi-
cation. All the imidazopyridines were synthesized according to a pre-
viously reported method.13b Column chromatography was performed
on silica gel (200–300 mesh). MS and HRMS were carried out by ESI
on a TOF mass analyzer. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded of samples dissolved in CDCl3 with TMS as in-
ternal standard at room temperature.
ESI-HRMS: m/z calcd for
C13H9ClN3O [M +
H]+: 258.0434;
found:258.0434.
2-(2-Bromophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3e)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 66 mg
(73%); green solid; mp 143–145 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.86 (d, J = 4.0 Hz, 1 H), 7.98–7.87 (m, 3
H), 7.84–7.62 (m, 1 H), 7.54–7.44 (m, 2 H), 7.36 (t, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.2, 161.0, 153.4, 145.1, 135.7,
134.2, 133.9, 133.0, 131.4, 126.7, 119.9, 117.9.
ESI-HRMS: m/z calcd for C13H9BrN3O [M + H]+: 301.9929; found:
3-Nitrosoimidazo[1,2-a]pyridines 3; General Procedure
A 25 mL Schlenk tube equipped with a magnetic stirring bar was
charged with substituted imidazopyridine 1 (0.3 mmol), t-BuONO (2;
0.6 mmol), and MeCN (2 mL). The tube was sealed and then the mix-
ture was allowed to stir under an air atmosphere at 90 °C for 18 h. Af-
ter completion of the reaction, the resulting solution was cooled to
r.t., and the solvent was removed with the aid of a rotary evaporator.
The residue was purified by column chromatography (silica gel, PE–
EtOAc) to provide the desired product 3.
301.9931
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Synthesis
2-(1-Naphthyl)-3-nitrosoimidazo[1,2-a]pyridine (3f)39
8-Methyl-3-nitroso-2-p-tolylimidazo[1,2-a]pyridine (3k)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 65 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 68 mg
(79%); green solid; mp 206–207 °C; Rf = 0.4 (PE–EtOAc, 2:1).
(90%); green solid; mp 181–182 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.98 (d, J = 4.0 Hz, 1 H), 8.78 (d, J = 8.0
Hz, 1 H), 8.31 (d, J = 8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.00–7.89 (m,
3 H), 7.69–7.60 (m, 3 H), 7.34 (t, J = 8.0 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 9.73 (d, J = 8.0 Hz, 1 H), 8.56 (d, J = 8.0
Hz, 2 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.05 (t, J = 8.0
Hz, 1 H), 2.68 (s, 3 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.6, 154.3, 145.3, 135.9, 133.4,
13C NMR (100 MHz, CDCl3): δ = 159.2, 153.6, 145.6, 141.9, 135.4,
131.4, 128.6, 127.3, 126.3, 125.9, 125.1, 119.0, 117.7.
130.7, 129.5, 129.1, 127.7, 124.2, 119.1, 21.6, 16.5.
ESI-HRMS: m/z calcd for C17H12N3O [M + H]+: 274.0980; found:
ESI-HRMS: m/z calcd for C15H14N3O [M + H]+: 252.1137; found:
274.0977.
252.1130.
2-(4-Chlorophenyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine
6-Methyl-3-nitroso-2-p-tolylimidazo[1,2-a]pyridine (3l)
(3g)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 64 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 62 mg
(85%); green solid; mp 197–199 °C; Rf = 0.4 (PE–EtOAc, 2:1).
(76%); green solid; mp 213–214 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 9.54 (d, J = 8.0 Hz, 2 H),
7.70 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2
H), 2.45 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 153.2, 144.8, 142.0, 138.6,
130.6, 130.1, 129.6, 128.9, 124.8, 116.5, 21.6, 18.3.
1H NMR (400 MHz, CDCl3): δ = 9.81 (d, J = 8.0 Hz, 1 H), 8.64 (d, J = 8.0
Hz, 2 H), 7.60 (s, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H),
2.56(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 153.1, 149.0, 146.3, 138.2,
131.9, 130.1, 129.1, 126.1, 121.5, 116.5, 22.3.
ESI-HRMS: m/z calcd for C14H11ClN3O [M + H]+: 272.0591; found:
ESI-HRMS: m/z calcd for C15H14N3O [M + H]+: 252.1137; found:
252.1133.
272.0588.
6-Methyl-3-nitroso-2-o-tolylimidazo[1,2-a]pyridine (3m)
2-(3-Bromophenyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine
(3h)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 61 mg
(81%); green solid; mp 218–220 °C; Rf = 0.4 (PE–EtOAc, 2:1).
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 70 mg
(74%); green solid; mp 219–221 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J = 8.0 Hz, 1 H), 8.82 (s, 1 H),
8.65 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.61 (s, 1 H), 7.43 (t,
J = 8.0 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 2.57 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.4, 153.1, 149.0, 146.1, 134.3,
133.6, 133.2, 130.3, 129.4, 126.0, 122.9, 121.7, 116.6, 22.3.
ESI-HRMS: m/z calcd for C14H11BrN3O [M + H]+: 316.0085; found:
1H NMR (400 MHz, CDCl3): δ = 9.82 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H),
7.78 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.46–7.34 (m, 3 H),
2.62 (s, 3 H), 2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 153.7, 144.3, 138.4, 138.2,
133.1, 131.1, 130.3, 130.2, 125.6, 124.5, 116.8, 21.0, 18.3.
ESI-HRMS: m/z calcd for C15H14N3O [M + H]+: 252.1137; found:
252.1139.
316.0089.
6-Methyl-3-nitroso-2-(3-chlorophenyl)imidazo[1,2-a]pyridine
(3n)
2-(4-Methoxyphenyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 67 mg
(83%); green solid; mp 206–208 °C; Rf = 0.4 (PE–EtOAc, 2:1).
(3i)40
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 57 mg
(71%); green solid; mp 208–209 °C; Rf = 0.3 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.84 (d, J = 8.0 Hz, 1 H), 8.66 (d, J = 8.0
1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 8.65 (s, 1 H), 8.57 (d,
J = 8.0 Hz, 1 H), 7.76–7.69 (m, 2 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.48 (t,
J = 8.0 Hz, 1 H), 2.45 (s, 3 H).
Hz, 2 H), 7.53 (s, 1 H), 7.06–7.01 (m, 3 H), 3.91 (s, 3 H), 2.92 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.8, 160.1, 153.0, 149.0, 146.8,
13C NMR (100 MHz, CDCl3): δ = 157.9, 153.1, 144.4, 138.6, 134.9,
133.4, 131.2, 130.8, 130.3, 130.0, 128.8, 124.7, 116.8, 18.4.
132.6, 126.3, 124.3, 120.8, 116.2, 114.4, 55.5, 22.3.
ESI-HRMS: m/z calcd for C15H14N3O2 [M + H]+: 268.1086; found:
ESI-HRMS: m/z calcd for C14H11ClN3O [M + H]+: 272.0591; found:
272.0595.
268.1081.
6-Methyl-3-nitroso-2-(4-chlorophenyl)imidazo[1,2-a]pyridine
(3o)
8-Methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3j)25d
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 65 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 60 mg
(91%); green solid; mp 140–141 °C; Rf = 0.4 (PE–EtOAc, 2:1).
(74%); green solid; mp 212–213 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.78 (d, J = 8.0 Hz, 1 H), 8.69 (d, J = 8.0
Hz, 2 H), 7.62–7.53 (m, 3 H), 7.13 (t, J = 8.0 Hz, 1 H), 2.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.2, 153.8, 145.6, 135.4, 131.9,
1H NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 8.62 (d, J = 8.0 Hz, 2 H),
7.74 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 2
H), 2.45 (s, 3 H).
131.3, 130.8, 128.7, 127.9, 124.2, 119.4, 16.5.
13C NMR (100 MHz, CDCl3): δ = 158.3, 153.1, 144.5, 138.6, 138.0,
131.8, 130.6, 130.2, 129.1, 127.4, 116.7, 29.7.
ESI-HRMS: m/z calcd for C14H11ClN3O [M + H]+: 272.0591; found:
ESI-HRMS: m/z calcd for C14H12N3O [M + H]+: 238.0980; found:
238.0981.
272.0597.
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2-(4-Bromophenyl)-6-methyl-3-nitrosoimidazo[1,2-a]pyridine
6-Bromo-3-nitroso-2-m-tolylimidazo[1,2-a]pyridine (3u)
(3p)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 69 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 70 mg
(73%); green solid; mp 225–226 °C; Rf = 0.4 (PE–EtOAc, 2:1).
(74%); green solid; mp 176–178 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.77 (s, 1 H), 8.52 (d, J = 8.0 Hz, 2 H),
1H NMR (400 MHz, CDCl3): δ = 10.09 (s, 1 H), 8.46 (s, 2 H), 7.88 (d,
J = 8.0 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.45–7.43 (m, 2 H), 2.49 (s, 3
7.72–7.64 (m, 4 H), 2.43 (s, 3 H).
H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 153.1, 144.5, 138.6, 132.0,
13C NMR (100 MHz, CDCl3): δ = 159.8, 153.0, 143.9, 138.9, 138.7,
131.9, 131.7, 130.6, 130.5, 127.4, 126.6, 124.7, 116.7, 18.4.
132.7, 131.2, 131.1, 128.9, 128.1, 126.4, 118.0, 113.8, 21.5.
ESI-HRMS: m/z calcd for C14H11BrN3O [M + H]+: 316.0085; found:
ESI-HRMS: m/z calcd for C14H11BrN3O [M + H]+: 316.0085; found:
316.0078.
316.0081.
2-(3-Bromophenyl)-6-methyl-3-nitrosoimidazo[1,2-a]pyridine
2-(2-Furyl)-3-nitrosoimidazo[1,2-a]pyridine (3v)41
(3q)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 40 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 68 mg
(63%); green solid; mp 195–197 °C; Rf = 0.3 (PE–EtOAc, 2:1).
(72%); green solid; mp 186–187 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 9.89 (d, J = 8.0 Hz, 1 H), 7.88–7.84 (m, 4
H), 7.27 (s, 1 H), 6.72 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 151.2, 147.2, 146.7, 146.5, 136.4,
126.5, 119.4, 118.9, 117.6, 113.4.
ESI-HRMS: m/z calcd for C11H8N3O2[M + H]+: 214.0617; found:
214.0610.
1H NMR (400 MHz, CDCl3): δ = 9.80 (s, 1 H), 9.81 (d, J = 8.0 Hz, 2 H),
8.63 (d, J = 8.0 Hz, 1 H), 7.77–7.69 (m, 3 H), 7.42 (t, J = 8.0 Hz, 1 H),
2.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.2, 153.1, 144.5, 138.6, 132.0,
131.9, 131.7, 130.6, 130.5, 127.4, 126.6, 124.7, 116.7, 18.4.
ESI-HRMS: m/z calcd for C14H11BrN3O [M + H]+: 316.0085; found:
2-(2-Furyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine (3w)25d
316.0081.
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 45 mg
(66%); green solid; mp 221–222 °C; Rf = 0.3 (PE–EtOAc, 2:1).
6-Chloro-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3r)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 52 mg
(68%); green solid; mp 214–216 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 10.00 (s, 1 H), 8.64 (d, J = 8.0 Hz, 2 H),
7.78 (s, 2 H), 7.63–7.54 (m, 3 H), 7.42 (t, J = 8.0 Hz, 1 H), 2.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 153.1, 143.8, 136.6, 131.8,
131.3, 130.8, 128.9, 127.4, 124.4, 117.8.
ESI-HRMS: m/z calcd for C13H9ClN3O [M + H]+: 258.0434; found:
1H NMR (400 MHz, CDCl3): δ = 9.77 (s, 1 H), 7.85–7.81 (m, 2 H), 7.58
(s, 1 H), 7.07 (s, 1 H), 6.69 (s, 1 H), 2.54 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.4, 149.2, 147.0, 146.7, 130.9,
128.8, 126.0, 121.2, 118.7, 116.5, 113.3, 22.3.
ESI-HRMS: m/z calcd for C12H10N3O2 [M + H]+: 228.0773; found:
228.0779.
258.0436.
7-Methyl-2-(4-nitrophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3x)
Column chromatography (silica gel, PE–EtOAc, 4:1); yield: 60 mg
(77%); green solid; mp 212–213 °C; Rf = 0.3 (PE–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): δ = 9.77 (d, J = 8.0 Hz, 1 H), 8.62 (d, J = 8.0
Hz, 2 H), 7.56 (s, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 1 H),
2.54 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.8, 153.1, 149.0, 146.2, 138.1,
131.9, 130.1, 129.0, 126.0, 121.5, 116.5, 22.3.
ESI-HRMS: m/z calcd for C14H11N4O3 [M + H]+: 283.0831; found:
283.0827.
6-Chloro-2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine
(3s)
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 60 mg
(69%); green solid; mp 225–227 °C; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 10.01 (s, 1 H), 8.66 (d, J = 8.0 Hz, 2 H),
7.82 (m, 2 H), 7.55 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.7, 153.1, 143.7, 138.6, 136.8,
131.9, 129.8, 129.3, 127.7, 124.4, 117.8.
ESI-HRMS: m/z calcd for C13H8Cl2N3O [M + H]+: 292.0044; found:
292.0048.
3-Nitroso-2-[4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridine
(3y)
6-Bromo-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3t)
Column chromatography (silica gel, PE–EtOAc, 4:1); yield: 65 mg
Column chromatography (silica gel, PE–EtOAc, 3:1); yield: 65 mg
(74%); green solid; mp 170–172 °C; Rf = 0.3 (PE–EtOAc, 3:1).
(72%); green solid; Rf = 0.4 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 10.11 (s, 1 H), 8.67 (d, J = 8.0 Hz, 2 H),
7.90 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.63–7.56 (m, 3 H).
1H NMR (400 MHz, CDCl3): δ = 9.90 (d, J = 4.0 Hz, 1 H), 8.82 (d, J = 8.0
Hz, 2 H), 7.91–7.85 (m, 2 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.84–7.30 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 159.6, 153.0, 144.0, 138.9, 131.8,
131.3, 130.8, 128.9, 126.4, 118.1, 113.9.
ESI-HRMS: m/z calcd for C13H9BrN3O [M + H]+: 301.9929; found:
301.9931.
13C NMR (100 MHz, CDCl3): δ = 153.4, 145.4, 136.1, 134.9, 133.0 (q,
J = 34.3 Hz), 131.0, 126.4, 126.7 (q, J = 271.2 Hz), 125.6 (q, J = 4.2 Hz),
120.7, 117.7.
ESI-HRMS: m/z calcd for C14H9F3N3O [M + H]+: 292.0698; found:
292.0664.
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6-Methyl-3-nitroso-2-[4-(trifluoromethyl)phenyl]imidazo[1,2-
a]pyridine (3z)
(3) Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei,
G.; Chavignon, O.; Teulade, J. C.; Kerbal, A.; Essassi, E. M.;
Debouzy, J. C.; Witvrouw, M.; Blache, Y.; Balzarini, J.; De Clercq,
E.; Chapat, J. P. J. Med. Chem. 1996, 39, 2856.
(4) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40,
1170.
(5) (a) Abignente, E. Actual. Chim. Ther. 1991, 18, 193. (b) Rupert, K.
C.; Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.;
Olini, G. C.; Fahmy, B.; Siekierka, J. Bioorg. Med. Chem. Lett. 2003,
13, 347.
(6) Hamdouchi, C.; Blas, J.; Prado, M.; Gruber, J.; Heinz, B. A.; Vance,
L. J. Med. Chem. 1999, 42, 50.
Column chromatography (silica gel, PE–EtOAc, 4:1); yield: 78 mg
(81%); green solid; mp 205–207 °C; Rf = 0.4 (PE–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): δ = 9.76 (s, 1 H), 8.76 (d, J = 8.0 Hz, 2 H),
7.79–7.68 (m, 4 H), 2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.5, 153.2, 144.3, 138.6, 135.0,
132.5 (q, J = 32.2 Hz), 131.0, 130.8, 126.7 (q, J = 271.2 Hz), 125.5 (q,
J = 4.2 Hz), 124.5, 122.7, 116.9, 18.3.
ESI-HRMS: m/z calcd for C15H11F3N3O [M + H]+: 306.0854; found:
306.0843.
(7) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888.
(8) Denora, N.; Laquintana, V.; Lopedota, A.; Serra, M.; Dazzi, L.;
Biggio, G.; Pal, D.; Mitra, A. K.; Latrofa, A.; Trapani, G.; Liso, G.
Pharm. Res. 2007, 24, 1309.
(9) Swainston, H. T.; Keating, G. M. CNS Drugs 2005, 19, 65.
(10) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.;
Biancotti, A.; Gamba, A.; Murmann, W. J. Med. Chem. 1965, 8,
305.
(11) Ueda, T.; Mizushige, K. Curr. Vasc. Pharmacol. 2006, 4, 1.
(12) Sorbera, L. A.; Castaner, J.; Leeson, P. A. Drugs Future 2002, 27,
935.
(13) For selected examples, see: (a) Nair, D. K.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Lett. 2012, 14, 4580. (b) Yan, R. L.; Yan,
H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Huang, G. S.; Liang, Y. M. J. Org.
Chem. 2012, 77, 2024. (c) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.;
Han, J.; Lei, A. Chem. Commun. 2012, 48, 11073. (d) Wang, H.;
Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem. Int.
Ed. 2011, 50, 5678. (e) Monir, K.; Bagdi, A.; Mishra, S.; Majee, A.;
Hajra, A. Adv. Synth. Catal. 2014, 356, 1105. (f) Mohan, D. C.;
Donthiri, R. R.; Rao, S. N.; Adimurthy, S. Adv. Synth. Catal. 2013,
355, 2217. (g) Chernyak, N.; Gevorgyan, V. Angew. Chem. Int. Ed.
2010, 49, 274. (h) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem.
Commun. 2011, 47, 11333. (i) Yu, J.; Jin, Y.; Zhang, H.; Yang, X.;
Fu, H. Chem. Eur. J. 2013, 19, 16804.
(14) (a) Ravi, C.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2014, 16,
2978. (b) Hiebel, M.-A.; Berteina-Raboin, S. Green Chem. 2015,
17, 937. (c) Monir, K.; Kumar Bagdi, A.; Ghosh, M.; Hajra, A.
J. Org. Chem. 2015, 80, 1332. (d) Ghosh, M.; Naskar, A.; Mitra, S.;
Hajra, A. Eur. J. Org. Chem. 2015, 715. (e) Marhadour, S.; Bazin,
M.-A.; Marchand, P. Tetrahedron Lett. 2012, 53, 297. (f) Cao, H.;
Lei, S.; Li, N.; Chen, L.; Liu, J.; Cai, H.; Qiu, S.; Tan, J. Chem.
Commun. 2015, 51, 1823. (g) Chennapuram, M.; Emmadi, N. R.;
Bingi, C.; Atmakur, K. RSC Adv. 2015, 5, 19418. (h) Wang, Y.;
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2958. (i) Gao, Z.; Zhu, X.; Zhang, R. RSC Adv. 2014, 4, 19891.
(j) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv.
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Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C.
Angew. Chem. Int. Ed. 2011, 50, 1896.
8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-amine (5)
Nitroso compound 3j (94 mg, 0.4 mmol) was added to a solution of
SnCl2·H2O (5 equiv) in EtOH (2 mL). After the mixture had stirred at
80 °C for 2 h, the suspension was cooled to r.t. The precipitate that
formed was filtered, washed extensively with EtOH (10 mL), and the
solvent was removed with the aid of a rotary evaporator. The residue
was purified by column chromatography (silica gel, EtOAc); this pro-
vided the desired product 5.
Yield: 83 mg (93%); mp 209–211 °C; Rf = 0.7 (EtOAc).
1H NMR (400 MHz, DMSO-d6): δ = 8.51 (s, 1 H), 7.90 (d, J = 8.0 Hz, 2
H), 7.57–7.54 (m, 3 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H),
5.90 (br, 2 H), 2.58 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 136.9, 130.3, 129.2, 128.2, 128.1,
128.0, 127.9, 127.6, 123.8, 122.0, 114.9, 16.5.
ESI-HRMS: m/z calcd for C14H14N3 [M + H]+: 224.1188; found:
224.1185.
Acknowledgment
The authors gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Nos. 21302110,
21302109 and 21375075), the Taishan Scholar Foundation of Shan-
dong Province, the Natural Science Foundation of Shandong Province
(ZR2013BQ017 and ZR2013BM007), the Project of Shandong Province
Higher Educational Science and Technology Program (J13LD14), and
the Scientific Research Foundation of Qufu Normal University (BSQD
2012021). We thank Pengfei Sun in this group for reproducing the re-
sults of 3a and 3q.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560508.
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p
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