NaNO2/I2-Mediated Regioselective Synthesis of Nitrosoimidazoheterocycles from Acetophenones by a Domino Process

Article abstract of DOI:10.1002/ejoc.201600553

A regioselective synthesis of nitrosoimidazoheterocycles from the reaction of 2-aminopyridines and acetophenones in the presence of NaNO₂and I₂is described. The reaction is suggested to proceed by a domino process involving sequentia

Full text of DOI:10.1002/ejoc.201600553

DOI: 10.1002/ejoc.201600553
Full Paper
Nitrogen Heterocycles
NaNO /I -Mediated Regioselective Synthesis of
2
2
Nitrosoimidazoheterocycles from Acetophenones by a Domino
Process[
‡]
[
a]
[a]
[a]
Sushobhan Mukhopadhyay, Shashikant U. Dighe, Shivalinga Kolle,
Praveen K. Shukla,[ and Sanjay Batra*
b,c]
[a,c]
Abstract: A regioselective synthesis of nitrosoimidazohetero- these 3-nitrosoimidazo[1,2-a]pyridines with aldehydes in the
cycles from the reaction of 2-aminopyridines and acetophen- presence of Fe/AcOH furnished 5-substituted pyrido
ones in the presence of NaNO and I is described. The reaction [2′,1′:2,3]imidazo[4,5-c]isoquinolines by reduction of the nitroso
2
2
is suggested to proceed by a domino process involving sequen- group followed by a Pictet–Spengler reaction in one pot. The
tial imine formation, iodination, iodide displacement by the synthesized compounds were assessed for their antibacterial
nitro group, and finally intramolecular cyclization. Reaction of and antifungal activities.
Introduction
Sc(OTf)3.[6e] Among differently substituted imidazo[1,2-a]pyr-
idines, the synthesis of 3-nitrosoimidazo[1,2-a]pyridines by in-
stallation of the nitroso group in the imidazo[1,2-a]pyridine
with tBuONO in MeCN under heating conditions was disclosed
recently. Notably, whereas Hajra et al. reported better yields
of products within 15 min of reaction, Yang et al. disclosed
that the identical reaction is complete within 18 h (Scheme 1).
Imidazo[1,2-a]pyridine, is a privileged scaffold prevalent in a va-
riety of drugs and other pharmacologically active compounds
[
1]
(
Figure 1). Compounds bearing this core structure also find
[7]
[
2]
utility in materials science. As a consequence, chemistries en-
abling the synthesis of this fundamental unit and installation of
functional groups on this core have received significant atten-
Previously, introductions of the nitroso group were typically
[
3,4]
tion.
The classical synthesis of imidazo[1,2-a]pyridine is gen-
[8]
achieved using NaNO under strongly acidic conditions. It is
2
erally considered to proceed by alkylation of the pyridine nitro-
gen atom by the bromo ketone followed by cyclodehydration
of the intermediate pyridinium ketone. Over the years it has
become apparent that the alkylative capacity of the electrophile
influences the formation of the imidazo[1,2-a]pyridine, and
therefore efforts to improve such syntheses have relied on im-
proving the alkylation efficiencies by installing facile leaving
noteworthy that, although direct syntheses of 3-nitro- or 3-
amino-substituted imidazo[1,2-a]pyridines from suitable start-
[9,10]
ing materials are known,
direct syntheses of 3-nitroso-sub-
stituted imidazo[1,2-a]pyridines remain elusive.
[
5]
groups. A complementary approach for the synthesis of this
core by an imine pathway exists, but only in a limited number
[
6]
of reports. Nonetheless, this approach was recently expanded
by McDonald and Pees wherein they treated electron-poor 2-
aminopyridines with a dimethylketal tosylate in the presence of
[
[
‡] CDRI Communication No. 9246. Part of this work was presented at the
INDIGO Conference” held between 21 and 24 February, 2016 at CBMR,
“
Lucknow.
a] Medicinal and Process Chemistry Division, CSIR – Central Drug Research
Institute, Sector 10, Jankipuram Extension,
Sitapur Road, Lucknow 226031, India
Figure 1. Representative drug or drug candidates containing imidazohetero-
cycles.
E-mail: s_batra@cdri.res.in
batra_san@yahoo.co.uk
http://www.cdriindia.org/sanjay.htm
In our ongoing efforts to investigate the utility of the NaNO /
I system for domino processes, we considered developing a
2
[
11]
2
[
[
b] Microbiology Division, CSIR-CDRI, Sector 10, Jankipuram Extension,
Sitapur Road, Lucknow 226031, India
c] Academy of Scientific and Innovative Research,
New Delhi 11025, India
direct and independent route to 3-nitrosoimidazo[1,2-a]pyr-
idines. We envisaged that treating 2-aminopyridine with aceto-
phenone would initially generate an imine capable of adding
iodine followed by substitution with a nitro group. The nitro
group would then tautomerize to the enolate form, which
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600553.
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Scheme 1. Synthesis of 3-nitrosoimidazo[1,2-a]pyridine as contrasted with the approach detailed herein.
might then undergo attack by the pyridine nitrogen atom with
concomitant dehydration leading to the title compound (fol-
lowing the imine pathway). Herein, we disclose the details of
our successful efforts related to this work.
Table 1. Results of reaction optimization efforts.[a]
Yield[b]
[%]
Results and Discussion
Entry
Reagent
equiv.)
Solvent
Temp
[°C]
Time
[h]
(
We initially probed the reaction between 2-aminopyridine (1a)
n.d.[c]
21
15
1
2
3
4
5
6
7
8
9
I
2
(0.3)
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
r.t.
100
100
100
100
100
100
80
80
80
80
80
12.0
8.0
8.0
8.0
8.0
and acetophenone (2a) in the presence of NaNO (1.1 equiv.)
2
I2 (0.3)
NIS (0.3)
NBS (0.3)
and I (0.3 equiv.) in DMSO (as the medium) at room tempera-
2
12
ture. This initial attempt failed and was thus repeated at a tem-
perature of 100 °C. Under these conditions we were pleased to
note that the reaction was completed in 8 h affording a mixture
of products from which the major compound was isolated in
c]
CuBr
2
(0.1)
n.d.[
c]
I
I
2
(0.3)
(0.3)
8.0
8.0
n.d.[
[c]
2
H
2
O
n.d.
I2 (0.3)
MeOH
EtOH
EtOH
EtOH
MeCN
12.0
12.0
12.0
12.0
12.0
41
56
67
80
21 % yield. The physical and spectroscopic data of the isolated
I
I
2
(0.3)
(0.5)
(0.5)
(0.5)
1
0
2
product are identical to those of 3-nitroso-2-phenylimidazo[1,2-
a]pyridine (3aa) as had been previously reported.[7] This result
prompted us to screen different conditions in order to optimize
the reaction (Table 1). In the first set of experiments, we
screened other halogenating reagents including NIS, NBS and
d]
1
1[
I
2
[c]
1
2
I
2
n.d.
[
a] All reactions were carried out using 1a (0.1 g, 1.06 mmol), acetophenone
2a (136 μL, 1.17 mmol), NaNO (0.81 g, 1.17 mmol), solvent (4 mL), air bal-
loon. [b] Isolated yields after column chromatography. [c] n.d. = no product
detected. [d] The reaction was performed using NaNO (0.11 g, 1.59 mmol).
2
2
CuBr for their effectiveness, but the yield of 3aa did not im-
2
prove (Table 1, Entry 2 versus Entries 3–5). Evaluation of reac-
tion efficiencies with different solvents revealed that the reac-
With the optimized conditions secured, the scope of the pro-
tion failed when using DMF or water as solvent (Table 1, En- tocol was tested with a variety of 2-aminopyridines 1a–f and
tries 6 and 7), whereas the use of methanol or ethanol led to acetophenones (substituted arylethanones) 2a–o; the results
improvement of the yields for 3aa to 41 % and 56 %, respec- are summarized in Scheme 2. In the first set of reactions differ-
tively (Table 1, Entries 8 and 9). Increasing the amount of iodine ent substituted phenylethanones 2b–j were treated with 2-
in the reaction to 0.5 equiv. further enhanced the yield of 3aa aminopyridine (1a). Notably, all reactions successfully afforded
to 67 % (Table 1, Entry 10). It was gratifying to discover that the corresponding 3-nitroso-substituted phenylimidazo[1,2-a]-
performing the reaction with 0.5 equiv. of iodine and 1.5 equiv. pyridines 3ab–3aj in 76–90 % yields (Scheme 2). More impor-
of NaNO furnished 3aa in 80 % yield (Table 1, Entry 11). Since tantly, no extensive workup was required for these reactions,
2
[
7]
earlier reports had used MeCN as the medium, we carried out and analytically pure products were isolated by simple filtra-
the reaction in MeCN; these conditions failed to yield 3aa tions of the separated solids in each reaction mixture. It was
(
Table 1, Entry 12). Thus, the optimized conditions identified observed that the presence of electron-donating or electron-
during our efforts involved heating of 1a with 1.1 equiv. of 2a, withdrawing groups on the phenyl ring in the substituted
.5 equiv. of NaNO and 0.5 equiv. of I in EtOH as the solvent phenylethanones does not influence product formation. We
1
2
2
at 80 °C for a period of 12 h.
next evaluated the scope of the protocol using substituted
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Scheme 2. Scope of the reaction with respect to 2-aminopyridines and substituted arylethanones.
heteroarylethanones 2k–o. Treatment of 2k–o with 1a under
the standardized conditions smoothly afforded the correspond-
ing products 3ak–3ao in good yields. In contrast to 3ab–3aj,
analytically pure products 3ak–3ao were readily isolated by col-
umn chromatography. In the second set of reactions, different
substituted 2-aminopyridines 1b–f were treated with differently
substituted arylethanones. Here, too, it was found that the elec-
tronic nature of the substitution present in the 2-aminopyridine
Scheme 3. Results of reactions of 2-aminobenzothiazole.
had no influence on the formation of the 3-nitrosoimidazo- then tautomerizes to the nitronate form D, which undergoes
1,2-a]pyridines (Scheme 2). Finally, the scope of the reaction intramolecular cyclization with concomitant dehydration to af-
[
was tested with 2-aminobenzothiazole derivatives 4a,b. Nota- ford 3-nitrosoimidazo[1,2-a]pyridine (3aa). To probe the sug-
bly, although 4a failed to react with 2a to afford the corre- gested reaction mechanism, a set of control experiments were
sponding product 5aa, substrate 4b afforded product 5ba in carried out (Scheme 5). Firstly, 1a was treated with phenacyl
6
8 % yield (Scheme 3). Review of the relevant literature re- iodide (6) and NaNO (1.5 equiv.) in EtOH in the absence of
2
vealed that this observation does, in fact, have literature prece- iodine. This reaction resulted in trace amounts of 3aa indicating
[
6e]
dence.
the essentiality of iodine for the reaction. Next, 1a was treated
A plausible mechanism for the formation of 3-nitrosoimid- with 6 under the standardized conditions in the presence of
azo[1,2-a]pyridine is depicted in Scheme 4. Initially 2-aminopyr- iodine resulting in the isolation of 3aa in only 26 % yield. This
idine (1a) reacts with acetophenone (2a) affording imine inter- result infers that the reaction probably does not proceed via a
mediate A. Next, in the presence of iodine, iodination takes phenacyl iodide intermediate. The reaction of 1a and 2a was
place at the α-C-H group of A to offer species B. Nucleophilic then performed under the optimized conditions in the pres-
displacement of the allylic iodide of B with the nitro group is ence of TEMPO; the inclusion of TEMPO had no impact on the
then envisioned to generate intermediate C. The nitro group reaction yield indicating that the reaction does not proceed by
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Scheme 4. Plausible mechanism for the generation of nitrosoimidazoheterocycles.
a radical mechanism. Conversely, the reaction of 2-phenylimid-
azo[1,2-a]pyridine (7) with I /NaNO under the standard reac-
2
2
tion conditions furnished 3aa in only 28 % yield indicating that
the reaction does not follow the classical route of heterocycle
formation followed by nitrosation.
Scheme 6. Transformation of 3aa into 5-substituted pyrido[2′,1′:2,3]imid-
azo[4,5-c]isoquinolines in one pot.
fungi. Whereas compound 3fh displayed potent antibacterial
activities, compounds 3aa and 3ah displayed potent antifungal
effects as compared to standard drugs used in the bioassays
(for results see Supporting Information).
Conclusions
We have developed a one-step synthesis of 3-nitrosoimid-
azo[1,2-a]pyridines using a NaNO /I -mediated domino reaction
2
2
Scheme 5. Control experiments.
between 2-aminopyridines and acetophenones. The reaction
furnishes 3-nitrosoimidazo[1,2-a]pyridines in good to excellent
yields and is proposed to proceed by an imine pathway. The
reaction has a broad substrate scope with respect to 2-amino-
pyridines and acetophenones. Moreover, the nitrosoimid-
azo[1,2-a]pyridine products can then be used to synthesize pyr-
ido[2′,1′:2,3]imidazo[4,5-c]isoquinolines by reduction of the
nitroso group and subsequent one-pot Pictet–Spengler reac-
tions.
To explore the synthetic utility of 3-nitrosoimidazo[1,2-a]pyr-
idines, a model reaction, in which the 3aa nitroso group was
reduced to the amine, was carried out using Fe/AcOH
(
Scheme 6); these reaction conditions furnished 3-aminoimid-
azo[1,2-a]pyridine (8) in 94 % yield. Additionally, it has been
reported that the Pictet–Spengler reaction of 8 with benzalde-
hydes in the presence of pTSA furnishes 5-substituted pyrido-
[
12]
[
2′,1′:2,3]imidazo[4,5-c]isoquinolines 10.
In our attempts to
make such a conversion a one-pot process, 3aa was treated
with benzaldehyde (9a) in the presence of Fe/AcOH. It was
pleasing to discover that the reaction afforded 10a in 78 %
yield after only 5 h. (Scheme 6). Repeating the reaction with 4-
bromobenzaldehyde (9b) also gave the corresponding cyclized
product 10b in 92 % yield.
Finally, several 3-nitrosoimidazopyridines generated during
the present study were examined for potential antibacterial and mination at 254 nm for UV-active materials. IR spectra were re-
antifungal activities against different strains of bacteria and corded using a Perkin–Elmer RX I FTIR spectrophotometer. H and
Experimental Section
General Methods: Melting points were determined in capillary tu-
bes with a Precision melting-point apparatus containing silicon oil
and are uncorrected. All experiments were monitored by analytical
thin layer chromatography (TLC). TLC was performed on pre-coated
silica gel plates. After elution, plates were visualized under UV illu-
1
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13C NMR spectra were recorded with 400 MHz spectrometers using
(hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 805, 1267, 1306, 1723,
max
–
1 1
CDCl3 or [D ]DMSO as solvent and TMS as an internal standard 2872, 3448 cm . H NMR (400 MHz, CDCl ): δ = 7.28–7.32 (m, 1 H),
6
3
(
chemical shifts in δ). Peak multiplicities of NMR signals were desig- 7.72 (d, J = 8.7 Hz, 2 H), 7.86–7.88 (m, 2 H), 8.60 (d, J = 8.7 Hz, 2 H),
nated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet),
9.94 (d, J = 9.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl ): δ = 117.7,
3
m (multiplet), etc. Coupling constants (J) are in Hz. The ESI-MS data
were recorded with a Thermo Finnigan LCQ Advantage, ion-trap (ESI ): m/z = 302.2. ESI-HRMS: calcd. for C H BrN O [M + H]
119.9, 126.6, 127.1, 130.6, 132.3, 136.3, 145.8, 153.4, 158.8 ppm. MS
+
+
13
8
3
mass spectrometer, and the HRMS data were recorded as EI-HRMS
using an Agilent 6520 Q-TOF, LC-MS/MS mass spectrometer. Column
chromatography was performed using silica gel (Spectrochem, par-
ticle size 100–200 mesh). Commercial-grade reagents and solvents
were used without further purification.
301.9929, found 301.9925.
2
-(4-Chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3af): Yield:
1 % (0.447 g from 0.2 g); green solid, m.p. 224–226 °C (ref.[ m.p.
7b]
8
2
1
7
24 °C); R = 0.52 (hexanes/EtOAc, 7:3, v/v). IR (neat): ν˜
= 695,
f
max
–
1 1
340, 1594, 1723, 2816, 3278 cm . H NMR (400 MHz, CDCl ): δ =
3
General Procedure for the Synthesis of Nitrosoimidazohetero-
cycles 3aa–3aj as Exemplified for 3aa: To a stirred solution of 2-
aminopyridine (1a) (0.2 g, 2.13 mmol) in ethanol (5 mL) were added
.29 (dd, J = 6.6, J = 4.0 Hz, 1 H), 7.54 (d, J = 8.56 Hz, 2 H), 7.86
1
2
(
d, J = 3.5 Hz, 2 H), 8.67 (d, J = 8.6 Hz, 2 H), 9.93 (d, J = 6.6 Hz, 1 H)
13
ppm. C NMR (100 MHz, CDCl ): δ = 117.7, 119.9, 126.6, 129.3,
3
acetophenone (2a) (272 μL, 2.34 mmol), NaNO (0.22 g, 3.19 mmol)
+
2
130.2, 132.1, 136.3, 138.4, 145.8, 153.4, 158.7 ppm. MS (ESI ): m/z =
258.1. ESI-HRMS: calcd. for C H ClN O [M + H] 258.0434, found
and I (0.269 g, 1.06 mmol) at room temperature. The flask contain-
+
2
13 8 3
ing the reaction mixture was kept under air using a balloon, and
the mixture was then heated at 80 °C for 12 h. After completion of
the reaction, the resulting solution was cooled to room tempera-
ture; a green solid residue separated. The solid was filtered off
through a sintered funnel. Further purification by recrystallization
from ethanol afforded the desired pure product 3aa (0.38 g, 80 %)
as a green solid.
2
58.0428.
2
-(4-Fluorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3ag): Yield:
4 % (0.430 g from 0.2 g); green solid, m.p. 120–122 °C (ref.[ m.p.
7a]
8
1
1
7
21 °C); R = 0.46 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 815,
f
max
–
1 1
287, 1364, 1500, 2805, 3392 cm . H NMR (400 MHz, CDCl ): δ =
3
.15 (dd, J = 19.6, J = 13.2 Hz, 3 H), 7.76 (d, J = 0.6 Hz, 2 H), 8.63
1
2
13
(t, J = 5.0 Hz, 2 H), 9.84 (d, J = 5.0 Hz, 1 H) ppm. C NMR (100 MHz,
3
-Nitroso-2-phenylimidazo[1,2-a]pyridine (3aa): Yield: 80 %
CDCl ): δ = 116.2 (d, J = 18 Hz), 117.6, 119.7, 126.7, 128.0 (d, J =
3
[7]
(0.38 g from 0.2 g); green solid, m.p. 164–166 °C (ref. m.p. 165 °C);
2
2
Hz), 133.1 (d, J = 7 Hz), 136.3, 145.9, 153.4, 158.9, 165.5 (d, J =
R = 0.45 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 790, 1348, 1462,
+
f
max
01 Hz) ppm. MS (ESI ): m/z = 242.2. ESI-HRMS: calcd. for C H FN O
1
3
8
3
–1 1
1
4
5
723, 2756, 3238 cm . H NMR (400 MHz, CDCl ): δ = 7.28 (d, J =
+
3
[
M + H] 242.0730, found 242.0734.
2-(4-Nitrophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3ah): Yield:
8 % (0.502 g from 0.2 g); green solid, m.p. 202–204 °C; R = 0.55
.8 Hz, 1 H), 7.52–7.61 (m, 3 H), 7.85 (d, J = 7.3 Hz, 2 H), 8.69 (d, J =
.4 Hz, 2 H), 9.95 (d, J = 4.96 Hz, 1 H) ppm. C NMR (100 MHz,
1
3
8
CDCl ): δ = 117.5, 119.5, 126.5, 128.2, 128.9, 130.1,130.8,131.6, 136.0,
f
3
+
(hexanes/EtOAc, 7:3, v/v). IR (KBr): ν
2806, 3358 cm . H NMR (400 MHz, CDCl ): δ = 7.37 (s, 1 H), 8.23–
= 767, 1345, 1430, 1713,
1
45.7, 153.4, 160.0 ppm. MS (ESI ): m/z = 224.1. ESI-HRMS: calcd. for
C H N O [M + H] 224.0824, found 224.0828.
3 9 3
˜
max
–
1 1
+
3
1
8.31 (m, 2 H), 8.36–8.42 (m. 2 H), 8.92 (d, J = 8.0 Hz, 2 H), 9.89 (d,
3
-Nitroso-2-(p-tolyl)imidazo[1,2-a]pyridine (3ab): Yield: 86 %
13
J = 6.3 Hz, 1 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 118.0,
[
7a]
6
(0.434 g from 0.2 g); green solid, m.p. 146–148 °C (ref.
m.p.
1
1
22.0, 124.8, 126.8, 131.2, 136.4, 138.4, 145.6, 148.6, 153.5,
56.2 ppm. MS (ESI ): m/z = 269.1. ESI-HRMS: calcd. for C H N O
1
1
2
46 °C); R = 0.48 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 785,
f
max
+
–1 1
13
8
4
3
256, 1453, 1568, 2876, 3398 cm . H NMR (400 MHz, CDCl ): δ =
3
+
[
M + H] 269.0675, found 269.0675.
.48 (s, 3 H), 7.23–7.28 (m, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.83–7.85
(
m, 2 H), 8.60 (d, J = 8.2 Hz, 2 H), 9.97 (d, J = 6.6 Hz, 1 H) ppm. 13
C
2-(2-Chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3ai): Yield:
NMR (100 MHz, CDCl ): δ = 21.4, 117.5, 119.4, 126.6, 128.9, 129.8, 76 % (0.416 g from 0.2 g); green solid, m.p. 178–180 °C; R
= 0.62
3
f
+
1
30.9, 136.2, 142.4, 145.9, 153.4, 160.2 ppm. MS (ESI ): m/z = 238.2. (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜max = 745, 1241, 1345, 1723,
+
–1 1
ESI-HRMS: calcd. for C H N O [M + H] 238.0980, found 238.0985.
2826, 3411 cm . H NMR (400 MHz, CDCl
3
): δ = 7.25 (t, J = 6.7 Hz,
1
4 11 3
1
1
H), 7.36–7.44 (m, 2 H), 7.53 (d, J = 7.0 Hz, 1 H), 7.78 (t, J = 7.6 Hz,
H), 7.80–7.87 (m, 2 H), 9.76 (d, J = 6.6 Hz, 1 H) ppm. C NMR
2
-(4-Methoxyphenyl)-3-nitrosoimidazo[1,2-a]pyridine
(3ac):
1
3
Yield: 78 % (0.42 g from 0.2 g); green solid, m.p. 188–190 °C; R =
f
(100 MHz, CDCl ): δ = 117.9, 120.1, 126.2, 126.8, 130.7, 130.9, 131.5,
3
0
2
.5 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 825, 1202, 1389, 1583,
max
+
–1
1
133.9, 134.3, 135.8, 142.2, 153.4, 161.0 ppm. MS (ESI ): m/z = 258.1.
ESI-HRMS: calcd. for C H ClN O [M + H] 258.0434, found 258.0435.
834, 3458 cm . H NMR (400 MHz, CDCl ): δ = 3.94 (s, 3 H), 7.09
3
+
13
8
3
(d, J = 8.9 Hz, 2 H), 7.21–7.25 (m, 1 H), 7.82–7.84 (m, 2 H), 8.69 (dd,
13
J = 7.0, J = 1.9 Hz, 2 H), 9.99 (d, J = 6.7 Hz, 1 H) ppm. C NMR
2-(3-Nitrophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3aj): Yield:
80 % (0.457 g from 0.2 g); green solid, m.p. 206–208 °C; R = 0.66
(hexanes/EtOAc, 7:3, v/v). IR (KBr): ν
1
2
(100 MHz, CDCl ): δ = 55.6, 114.6, 117.4, 119.1, 124.4, 126.8,
3
f
+
1
32.7,136.4, 146.3, 153.3, 159.9, 163.0 ppm. MS (ESI ): m/z = 254.2.
= 695, 1167, 1378, 1770,
˜
max
+
–1 1
ESI-HRMS: calcd. for C H N O [M + H] 254.0930, found 254.0937. 2826, 3423 cm . H NMR (400 MHz, [D ]DMSO): δ = 7.53–7.56 (m,
1
4
11
3
2
6
1
8
6
H), 7.86–7.90 (m, 1 H), 8.08 (dd, J = 15.0, J = 8.4 Hz, 2 H), 8.43–
2
-(1,1′-Biphenyl-4-yl)-3-nitrosoimidazo[1,2-a]pyridine
(3ad):
1 2
.46 (m, 1 H), 8.92 (d, J = 7.8 Hz, 1 H), 9.28 (s, 1 H), 9.74 (d, J =
Yield: 90 % (0.572 g from 0.2 g); green solid, m.p. 172–174 °C; R =
f
.6 Hz, 1 H) ppm. 13C NMR (100 MHz, [D ]DMSO): δ = 113.2, 117.3,
0
2
7
2
1
1
1
.49 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 745, 1278, 1672, 1873,
6
max
–1
1
120.2, 122.6, 126.1, 127.6, 130.8, 132.1, 136.2, 142.4, 145.5, 148.8,
907, 3345 cm . H NMR (400 MHz, CDCl ): δ = 7.26–7.29 (m, 1 H),
3
+
161.4 ppm. MS (ESI ): m/z = 269.1. ESI-HRMS: calcd. for C H N O
.42 (t, J = 7.2 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 2 H), 7.73 (d, J = 7.5 Hz,
H), 7.81–7.89 (m, 4 H), 8.79 (d, J = 8.3 Hz, 2 H), 9.98 (d, J = 6.6 Hz,
13 8 4 3
+
[
M + H] 269.0675, found 269.0671.
H) ppm. 13C NMR (100 MHz, CDCl ): δ = 117.6, 119.6, 126.7, 127.3,
3
General Procedure for the Synthesis of Nitrosoimidazohetero-
cycles 3ak–3fh, 5ba as Exemplified for 3ak: To a stirred solution
of 2-aminopyridine (1a) (0.2 g, 2.13 mmol) in ethanol (5 mL) were
added 3-acetylpyridine (2k) (257 μL, 2.34 mmol), NaNO2 (0.22 g,
27.6, 128.2, 129.1, 130.6, 131.4, 136.3, 140.3, 144.4, 145.9, 153.6,
59.7 ppm. MS (ESI ): m/z = 300.3. ESI-HRMS: calcd. for C H N O
+
1
9 13 3
+
[
M + H] 300.1137, found 300.1137.
2
-(4-Bromophenyl)-3-nitrosoimidazo[1,2-a]pyridine (3ae): Yield:
3.19 mmol), and I (0.269 g, 1.06 mmol) at room temperature. The
2
8
5 % (0.543 g from 0.2 g); green solid, m.p. 195–197 °C; R = 0.53
flask containing the reaction mixture kept under air using a balloon,
f
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and the mixture was then heated at 80 °C for 12 h. After completion
of the reaction, the resulting solution was cooled to room tempera- 1 H), 8.57–8.59 (m, 2 H), 9.78 (t, J = 0.8 Hz, 1 H) ppm. C NMR
7.53 (m, 3 H), 7.61 (dd, J = 8.9, J = 1.6 Hz, 1 H), 7.68 (d, J = 8.8 Hz,
1
2
1
3
ture, and the solvent was removed with the aid of a rotary evapora- (100 MHz, CDCl ): δ = 18.5, 116.8, 124.9, 128.9, 130.5, 130.9, 131.5,
3
+
tor. Thereafter, the reaction was quenched by the addition of 10 %
aqueous Na S O solution (10 mL) and the resulting mixture was
131.8, 138.7, 144.8, 153.4, 159.9 ppm. MS (ESI ): m/z = 238.1. ESI-
HRMS: calcd. for C H N O [M + H] 238.0980, found 238.0976.
+
2
2
3
14 11 3
extracted with EtOAc (3 × 20 mL). The combined organic fractions
were dried with Na SO , and the solvent was removed under vac-
uum. The crude product thus obtained was purified by column
chromatography on silica gel using hexanes/EtOAc (9.0:1.0, v/v) as
eluent to afford the desired product 3ak (0.424 g, 89 %) as a green
solid.
6
-Methyl-3-nitroso-2-(p-tolyl)imidazo[1,2-a]pyridine
(3bb):
2
4
Yield: 83 % (0.386 g from 0.2 g); green solid, m.p. 196–198 °C; R =
f
0
2
.44 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 775, 1248, 1464, 1623,
max
–
1 1
926, 3408 cm . H NMR (400 MHz, CDCl ): δ = 2.36 (s, 3 H), 2.38
3
(s, 3 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.58–7.61 (m, 1 H), 7.66 (d, J =
1
3
8.8 Hz, 1 H), 8.49 (d, J = 8.2 Hz, 2 H), 9.79 (s, 1 H) ppm. C NMR
3
-Nitroso-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (3ak): Yield:
(100 MHz, CDCl ): δ = 18.4, 21.8, 116.7, 125.0, 129.1, 129.8, 130.2,
3
+
8
9 % (0.424 g from 0.2 g); green solid, m.p. 138–140 °C; R = 0.32
130.8, 138.7, 142.2, 144.9, 153.3, 160.1 ppm. MS (ESI ): m/z = 252.1.
f
+
(
hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 785, 1263, 1560, 1679,
ESI-HRMS: calcd. for C H N O [M + H] 252.1137, found 252.1133.
max
15 13 3
–1 1
3
7
1
1
1
2
2
069, 3246 cm . H NMR (400 MHz, CDCl ): δ = 7.19–7.26 (m, 1 H),
3
2
-(4-Methoxyphenyl)-6-methyl-3-nitrosoimidazo[1,2-a]pyr-
.41–7.44 (m, 1 H), 7.80–7.81 (m, 2 H), 8.74 (dd, J = 3.2, J = 1.6 Hz,
1
2
idine (3bc): Yield: 77 % (0.38 g from 0.2 g); green solid, m.p. 188–
H), 8.88–8.91 (m, 1 H), 9.74 (d, J = 1.6 Hz, 1 H), 9.81 (d, J = 6.7 Hz,
1
1
2
90 °C; R = 0.42 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 836, 1258,
H) ppm. 13C NMR (100 MHz, CDCl ): δ = 117.7, 120.0, 123.6, 126.4,
f
max
3
–1 1
421, 1463, 1618, 2925, 3398 cm . H NMR (400 MHz, CDCl ): δ =
+
3
27.7, 136.2, 137.9, 145.6, 151.2, 151.9, 157.5 ppm. MS (ESI ): m/z =
25.2. ESI-HRMS: calcd. for C H N O [M + H] 225.0776, found
25.0779.
.36 (s, 3 H), 3.84 (s, 3 H), 6.99 (d, J = 8.9 Hz, 2 H), 7.58–7.65 (m, 2
+
1
2
8
4
13
H), 8.59 (d, J = 8.9 Hz, 2 H), 9.81 (s, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 18.4, 55.6, 114.5, 116.6, 124.5, 125.1, 129.9, 132.6, 138.8,
3
+
3
-Nitroso-2-(pyridin-4-yl)imidazo[1,2-a]pyridine (3al): Yield: 142.2, 153.2, 159.8, 162.9 ppm. MS (ESI ): m/z = 268.1. ESI-HRMS:
+
7
4 % (0.353 g from 0.2 g); green solid, m.p. 122–124 °C; R = 0.35
calcd. for C H N O [M + H] 268.1086, found 268.1082.
f
15 13 3 2
(
hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 756, 1358, 1664, 1923,
max
2
(
-(4-Bromophenyl)-6-methyl-3-nitrosoimidazo[1,2-a]pyridine
3be): Yield: 87 % (0.508 g from 0.2 g); green solid, m.p. 160–162 °C;
= 760, 1214, 1421,
–1 1
2
1
8
326, 3168 cm . H NMR (400 MHz, CDCl ): δ = 7.35 (t, J = 6.4 Hz,
3
H), 7.91 (dd, J = 18.0, J = 7.6 Hz, 2 H), 8.5 (d, J = 4.4 Hz, 2 H),
1
2
R = 0.55 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
13
f
max
.85 (d, J = 4.4 Hz, 2 H), 9.88 (d, J = 6.2 Hz, 1 H) ppm. C NMR
–
1 1
1
3
8
1
457, 1632, 3019, 3398 cm . H NMR (400 MHz, CDCl ): δ = 2.38 (s,
3
(100 MHz, CDCl ): δ = 118.1, 120.6, 124.3, 126.4, 136.3, 138.9, 145.4,
3
H), 7.62 (t, J = 4.7 Hz, 3 H), 7.68 (d, J = 8.7 Hz, 1 H), 8.48 (d, J =
+
1
50.6, 153.6, 156.9 ppm. MS (ESI ): m/z = 225.1. ESI-HRMS: calcd. for
.6 Hz, 2 H), 9.75 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl ): δ = 18.5,
+
3
C H N O [M + H] 225.0776, found 225.0775.
12 8 4
16.9, 124.9, 126.8, 130.7, 132.1, 132.2, 138.8, 144.7, 153.2,
+
2
-(Furan-2-yl)-3-nitrosoimidazo[1,2-a]pyridine (3am): Yield:
6 % (0.389 g from 0.2 g); green solid, m.p. 196–198 °C (ref.
158.5 ppm. MS (ESI ): m/z = 316.0. ESI-HRMS: calcd. for C H BrN O
14
10
3
[
7b]
+
8
1
1
6
9
1
m.p.
= 785,
max
[M + H] 316.0085, found 316.0081.
-Methyl-3-nitroso-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (3bk):
Yield: 80 % (0.405 g from 0.2 g); green solid, m.p. 120–122 °C; R =
95 °C); R = 0.44 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
6
–
1 1
165, 1563, 1690, 3189, 3546 cm . H NMR (400 MHz, CDCl ): δ =
3
f
.69 (t, J = 6.5 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.66–7.73 (m, 4 H),
0
3
7
1
.3 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 772, 1373, 1562, 1709,
1
3
max
.88 (d, J = 8.0 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 113.4,
3
–1 1
269, 3416 cm . H NMR (400 MHz, CDCl ): δ = 2.39 (s, 3 H), 7.19–
3
17.4, 118.0, 119.4, 125.6, 137.9, 142.0, 145.6, 149.6, 151.9 ppm. MS
.22 (m, 1 H), 7.39–7.43 (m, 1 H), 7.64–7.67 (m, 1 H), 7.71–7.76 (m,
+
+
(
1
ESI ): m/z = 185.1. ESI-HRMS: calcd. for C H N O [M + H]
11 8 2
13
H), 8.71–8.73 (m, 1 H), 8.86–8.89 (m, 1 H), 9.72 (s, 1 H) ppm.
C
85.0715, found 185.0715.
NMR (100 MHz, CDCl ): δ = 18.4, 116.9, 123.6, 124.7, 127.8, 130.9,
137.8, 138.7, 139.3, 146.2, 151.1, 151.7, 157.3 ppm. MS (ESI ): m/z =
239.1. ESI-HRMS: calcd. for C H N O [M + H] 239.0933, found
3
+
3
-Nitroso-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (3an): Yield:
0 % (0.438 g from 0.2 g); green solid, m.p. 202–204 °C (ref. m.p.
[
7a]
+
9
2
1
7
13 10 4
01 °C); R = 0.48 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 805, 239.0930.
f
max
–
1 1
193, 1460, 1679, 3179, 3506 cm . H NMR (400 MHz, CDCl ): δ =
3
7
-Methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3ca): Yield:
.18–7.24 (m, 2 H), 7.65–7.66 (m, 1 H), 7.69–7.73 (m, 2 H), 8.40–8.41
m, 1 H), 9.79 (d, J = 6.7 Hz, 1 H) ppm. C NMR (100 MHz, CDCl3):
2 % (0.359 g from 0.2 g); green solid, m.p. 200–202 °C (ref.[ m.p.
7a]
8
2
1
2
7
1
3
(
02 °C); R = 0.48 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 785,
f
max
δ = 117.3, 119.1, 127.7, 129.1, 132.1, 133.0, 134.2, 136.3, 146.8, 151.5,
1
[
–
1 1
241, 1506, 1687, 3265, 3562 cm . H NMR (400 MHz, CDCl ): δ =
+
3
55.0 ppm. MS (ESI ): m/z = 230.1. ESI-HRMS: calcd. for C H N OS
11 7 3
.46 (s, 3 H), 6.99 (d, J = 6.7 Hz, 1 H), 7.47–7.52 (m, 4 H), 8.58 (d, J =
+
M + H] 230.0388, found 230.0382.
.2 Hz, 2 H), 9.75 (d, J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
4
-Methyl-2-(3-nitrosoimidazo[1,2-a]pyridin-2-yl)thiazole (3ao): CDCl ): δ = 22.3, 116.5, 121.4, 126.1, 128.8, 130.8, 131.5, 146.4, 148.9,
3
+
Yield: 85 % (0.441 g from 0.2 g); yellow solid, m.p. 206–208 °C; R = 153.2, 160.3 ppm. MS (ESI ): m/z = 238.0. ESI-HRMS: calcd. for
f
+
0
3
6
.38 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 698, 1145, 1480, 1782,
C H N O [M + H] 238.0980, found 238.0983.
max
14 11 3
–1 1
269, 3486 cm . H NMR (400 MHz, CDCl ): δ = 2.50 (s, 3 H), 6.86–
3
2
-(4-Methoxyphenyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyr-
.90 (m, 2 H), 7.19–7.24 (m, 1 H), 7.56 (d, J = 9.0 Hz, 1 H), 8.18 (d,
idine (3cc): Yield: 74 % (0.365 g from 0.2 g); green solid, m.p. 208–
1
3
J = 6.9 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 17.4, 113.8,
3
[7b]
2
10 °C (ref.
m.p. 208 °C); R = 0.45 (hexanes/EtOAc, 7:3, v/v). IR
f
+
1
14.6, 117.9, 126.3, 126.7, 142.2, 147.8, 154.0, 160.8 ppm. MS (ESI ):
–
1 1
(
(
KBr): ν˜ = 758, 969, 1232, 1506, 1602, 1689, 3568 cm . H NMR
+
max
m/z = 245.2. ESI-HRMS: calcd. for C H N OS [M + H] 245.0497,
1
1 8 4
400 MHz, CDCl ): δ = 2.49 (s, 3 H), 3.78 (s, 3 H), 6.89 (d, J = 8.7 Hz,
3
found 245.0491.
-Methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3ba): Yield:
2 % (0.36 g from 0.2 g); green solid, m.p. 194–196 °C; R = 0.4
2
H), 7.78 (d, J = 8.9 Hz, 2 H), 8.52 (d, J = 8.6 Hz, 2 H), 9.59 (d, J =
13
6
8
8.9 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 22.6, 55.5, 114.2,
3
117.8, 125.4, 127.8, 132.6, 139.1, 144.4, 146.6, 152.7, 159.8,
f
+
(
2
hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 770, 1242, 1466, 1629,
163.1 ppm. MS (ESI ): m/z = 268.1. ESI-HRMS: calcd. for C H N O
max
15 13
3
2
–1
1
+
924, 3401 cm . H NMR (400 MHz, CDCl ): δ = 2.37 (s, 3 H), 7.54– [M + H] 268.1086, found 268.1080.
3
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
+
2
(
-(4-Bromophenyl)-7-methyl-3-nitrosoimidazo[1,2-a]pyridine
3ce): Yield: 89 % (0.521 g from 0.2 g); green solid, m.p. 212–214 °C;
R = 0.45 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν = 789, 1256, 1560,
(ESI ): m/z = 303.1. ESI-HRMS: calcd. for C13H ClN O [M + H]
7 4 3
303.0285, found 303.0280.
-Bromo-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3ea): Yield:
1 % (0.283 g from 0.2 g); green solid, m.p. 140–142 °C; R = 0.48
f
˜
max
6
–1 1
1
7
2
2
1
675, 3325, 3568 cm . H NMR (400 MHz, CDCl ): δ = 2.51 (s, 3 H),
.60 (d, J = 9.0 Hz, 2 H), 7.86 (d, J = 9.0 Hz, 2 H), 8.49 (d, J = 8.6 Hz,
3
8
f
(
hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 695, 1263, 1480, 1799,
max
1
3
H), 9.68 (d, J = 6.9 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ =
–1 1
3
3
7
2
1
269, 3440 cm . H NMR (400 MHz, CDCl ): δ = 7.46–7.53 (m, 3 H),
3
2.6, 118.1, 122.3, 125.6, 127.6, 128.4, 131.9, 132.2, 144.2, 145.6,
.65 (d, J = 9.2 Hz, 1 H), 7.80 (d, J = 9.1 Hz, 1 H), 8.58 (d, J = 7.8 Hz,
H), 10.01 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 113.9, 118.1,
+
58.6, 161.7 ppm. MS (ESI ): m/z = 316.1. ESI-HRMS: calcd. for
13
3
+
C H BrN O [M + H] 316.0085, found 316.0085.
14
10
3
26.4, 128.9, 130.8, 131.3, 131.8, 138.9, 143.9, 152.9, 159.6 ppm. MS
+
O [M + H]+
6
-Chloro-3-nitroso-2-phenylimidazo[1,2-a]pyridine (3da): Yield:
(ESI ): m/z = 302.1. ESI-HRMS: calcd. for C13
H
8
BrN
3
[
7b]
7
2
1
7
3 % (0.292 g from 0.2 g); green solid, m.p. 215–217 °C (ref.
m.p.
301.9929, found 301.9925.
16 °C); R = 0.5 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 789, 1206,
f
max
6
(
-Bromo-2-(4-methoxyphenyl)-3-nitrosoimidazo[1,2-a]pyridine
3ec): Yield: 84 % (0.322 g from 0.2 g); brown solid, m.p. 178–180 °C;
= 734, 1289, 1556,
–
1 1
589, 1689, 3256, 3514 cm . H NMR (400 MHz, CDCl ): δ = 7.47–
3
.53 (m, 3 H), 7.70 (d, J = 1.4 Hz, 2 H), 8.56–8.59 (m, 2 H), 9.92 (s, 1
R = 0.46 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
max
13
H) ppm. C NMR (100 MHz, CDCl ): δ = 117.7, 124.4, 126.0, 127.4,
–1 1
3
1
6
2
1
684, 3265, 3542 cm . H NMR (400 MHz, CDCl ): δ = 3.92 (s, 3 H),
3
+
1
2
2
28.9, 130.8, 131.8, 136.6, 143.8, 153.1, 159.7 ppm. MS (ESI ): m/z =
58.0. ESI-HRMS: calcd. for C H ClN O [M + H] 258.0434, found
58.0435.
-Chloro-3-nitroso-2-(p-tolyl)imidazo[1,2-a]pyridine (3db):
Yield: 72 % (0.304 g from 0.2 g); green solid, m.p. 160–162 °C; R =
.99 (d, J = 9.0 Hz, 2 H), 7.68 (d, J = 8.9 Hz, 2 H), 8.59 (d, J = 8.9 Hz,
H), 9.96 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 55.6, 113.4,
14.3, 125.4, 127.8, 130.6, 139.3, 144.4, 146.6, 153.7, 159.2,
163.2 ppm. MS (ESI ): m/z = 332.1. ESI-HRMS: calcd. for
+
1
3
8
3
13
3
+
6
+
C H10BrN O [M + H] 332.0035, found 332.0035.
14 3 2
f
0
2
.52 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 825, 1248, 1372, 1743,
max
8-Bromo-6-methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine
(3fa): Yield: 75 % (0.253 g from 0.2 g); green solid, m.p. 182–184 °C;
–1 1
836, 3438 cm . H NMR (400 MHz, CDCl ): δ = 2.39 (s, 3 H), 7.29
3
(d, J = 8.0 Hz, 2 H), 7.69 (s, 2 H), 8.49 (d, J = 8.2 Hz, 2 H), 9.95 (s, 1
R = 0.56 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν = 762, 1252, 1408,
f
˜
max
13
H) ppm. C NMR (100 MHz, CDCl ): δ = 22.7, 117.6, 124.4, 127.1,
1
m/z = 272.2. ESI-HRMS: calcd. for C H ClN O [M + H] 272.0591,
–1 1
3
1608, 2920, 3397 cm . H NMR (400 MHz, CDCl ): δ = 2.36 (s, 3 H),
3
+
28.5, 129.7, 130.7, 136.7, 142.6, 143.9, 153.1, 159.9 ppm. MS (ESI ):
7
.46–7.54 (m, 3 H), 7.85 (d, J = 1.0 Hz, 1 H), 8.62–8.64 (m, 2 H), 9.69
+
13
1
4
10
3
(s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 18.2, 111.8, 123.6,
3
found 272.0589.
-Chloro-2-(4-methoxyphenyl)-3-nitrosoimidazo[1,2-a]pyridine
3dc): Yield: 72 % (0.322 g from 0.2 g); green solid, m.p. 167–169 °C;
= 745, 1236, 1504,
1
28.9, 130.8, 131.1, 131.6, 131.8, 140.6, 142.8, 153.9, 159.8 ppm. MS
+
+
(ESI ): m/z = 316.01. ESI-HRMS: calcd. for C H BrN O [M + H]
6
(
14 10 3
316.0085, found 316.0082.
R = 0.48 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
max
8-Bromo-6-methyl-3-nitroso-2-(p-tolyl)imidazo[1,2-a]pyridine
(3fb): Yield: 78 % (0.276 g from 0.2 g); green solid, m.p. 166–168 °C;
–1 1
1
6
2
1
1
670, 3107, 3518 cm . H NMR (400 MHz, CDCl ): δ = 3.85 (s, 3 H),
3
.99 (d, J = 8.9 Hz, 2 H), 7.68 (d, J = 6.6 Hz, 2 H), 8.60 (d, J = 8.9 Hz,
R = 0.58 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 835, 1253, 1415,
1458, 1611, 2921, 3394 cm . H NMR (400 MHz, CDCl ): δ = 2.35 (s,
3
f
max
1
3
H), 9.98 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 55.5, 114.6,
–1 1
3
17.5, 123.9, 124.6, 126.8, 132.6, 136.7, 144.2, 152.9, 159.7,
3
8
H), 2.39 (s, 3 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.83 (s, 1 H), 8.54 (d, J =
+
63.1 ppm. MS (ESI ): m/z = 288.1. ESI-HRMS: calcd. for
13
.2 Hz, 2 H), 9.71 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ =
3
+
C H ClN O [M + H] 288.0540, found 288.0542.
14
10
3
2
18.2, 21.8, 111.6, 123.7, 128.9, 129.8, 130.5, 131.1, 140.6, 142.5, 142.9,
+
1
53.9, 159.9 ppm. MS (ESI ): m/z = 330.02. ESI-HRMS: calcd. for
2
-(4-Bromophenyl)-6-chloro-3-nitrosoimidazo[1,2-a]pyridine
3de): Yield: 84 % (0.440 g from 0.2 g); green solid, m.p. 188–190 °C;
R = 0.44 (hexanes/EtOAc, 6:4, v/v). IR (KBr): ν˜ = 757, 1215, 1522,
+
C H BrN O [M + H] 330.0242, found 330.0238.
(
15 12
3
f
max
8-Bromo-2-(4-bromophenyl)-6-methyl-3-nitrosoimidazo[1,2-a]-
pyridine (3fe): Yield: 82 % (0.346 g from 0.2 g); green solid, m.p.
–
1 1
1
588, 1673, 2401, 3553 cm . H NMR (400 MHz, CDCl ): δ = 7.48
3
(
d, J = 8.6 Hz, 2 H), 7.62 (d, J = 8.7 Hz, 2 H), 8.48 (d, J = 8.6 Hz, 2 144–146 °C; R = 0.53 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν
= 766,
f
˜
max
1
3
–1 1
H), 9.90 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 117.7, 124.3,
1219, 1413, 1625, 2923, 3397 cm . H NMR (400 MHz, CDCl ): δ =
3
3
+
1
26.3, 127.5, 131.9, 132.2, 136.7, 143.7, 152.9, 158.3 ppm. MS (ESI ): 2.37 (s, 3 H), 7.61 (d, J = 8.6 Hz, 2 H), 7.85 (d, J = 1.1 Hz, 1 H), 8.53
+
13
m/z = 336.1. ESI-HRMS: calcd. for C H BrClN O [M + H] 335.9539,
(d, J = 8.6 Hz, 2 H), 9.66 (s, 1 H) ppm. C NMR (100 MHz, CDCl3):
1
3
7
3
found 335.9536.
-Chloro-2-(4-fluorophenyl)-3-nitrosoimidazo[1,2-a]pyridine
3dg): Yield: 81 % (0.347 g from 0.2 g); red solid, m.p. 176–178 °C;
= 789, 1156, 1598,
δ = 18.3, 111.8, 123.6, 127.2, 130.5, 131.1, 132.2, 132.4, 140.7, 142.7,
+
1
53.7, 158.4 ppm. MS (ESI ): m/z = 394.0. ESI-HRMS: calcd. for
6
(
+
C H Br N O [M + H] 393.9191, found 393.9194.
14
9
2 3
R = 0.5 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
8-Bromo-6-methyl-2-(4-nitrophenyl)-3-nitrosoimidazo[1,2-a]-
pyridine (3fh): Yield: 84 % (0.324 g from 0.2 g); green solid, m.p.
max
–
1 1
1
7
690, 2456, 3369, 3506 cm . H NMR (400 MHz, CDCl ): δ = 7.03–
3
.08 (m, 2 H), 7.80–7.84 (m, 2 H), 8.60 (d, J = 8.3 Hz, 2 H), 9.88 (s, 1
156–158 °C; R = 0.65 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν
1217, 1426, 1461, 1639, 3022, 3391 cm . H NMR (400 MHz, CDCl ):
= 769,
f
˜
max
13
–1 1
H) ppm. C NMR (100 MHz, CDCl ): δ = 13.4, 116.1 (d, J = 22.2 Hz),
3
3
1
1
31.9, 133.3 29 (d, J = 9.7 Hz), 154.6, 166.5 29 (d, J = 257.3 Hz), δ = 2.40 (s, 3 H), 7.90 (s, 1 H), 8.32 (d, J = 8.9 Hz, 2 H), 8.85 (d, J =
+
13
85.1 ppm. MS (ESI ): m/z = 276.2. ESI-HRMS: calcd. for C H ClFN O
8.9 Hz, 2 H), 9.62 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 18.4,
1
3
7
3
3
+
[
M + H] 276.0340, found 276.0340.
112.2, 123.4, 123.9, 131.8, 132.0, 137.4, 140.9, 142.4, 149.7, 153.9,
+
1
[
56.5 ppm. MS (ESI ): m/z = 361.0. ESI-HRMS: calcd. for C H BrN O
14
9
4
3
6
-Chloro-2-(4-nitrophenyl)-3-nitrosoimidazo[1,2-a]pyridine
+
M + H] 360.9936, found 360.9937.
= 748, 1268, 8-Chloro-3-nitroso-2-phenylbenzo[d]imidazo[2,1-b]thiazole
max
(
3dh): Yield: 90 % (0.424 g from 0.2 g); yellow solid, m.p. 205–
2
07 °C; R = 0.62 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
–1 1
1
520, 1660, 3045, 3345 cm . H NMR (400 MHz, CDCl ): δ = 7.72
(5ba): Yield: 68 % (0.231 g from 0.2 g); yellow solid, m.p. 206–208 °C;
= 1348, 1460, 1758,
3
(
d, J = 9.6 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H), 8.82 (d, J = 8.9 Hz, 2 R = 0.35 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
f
max
1
3
–
1
1
H), 9.87 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 118.2, 121.4,
3102 cm . H NMR (400 MHz, CDCl ): δ = 7.28–7.35 (m, 1 H), 7.54–
3
3
1
3
1
23.6, 124.2, 126.5, 136.9, 139.7, 147.4, 152.9, 159.7, 163.1 ppm. MS
7.59 (m, 3 H), 7.72–7.82 (m, 2 H), 8.49 (d, J = 7.6 Hz, 2 H) ppm.
C
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+
NMR (100 MHz, CDCl ): δ = 120.3, 125.3, 126.6, 126.9, 128.9, 131.7,
131.7, 132.1, 139.3, 167.1 ppm. MS (ESI ): m/z = 374.2. ESI-HRMS:
3
+
+
1
3
3
32.5, 133.9, 135.5, 137.6, 145.9, 157.1, 158.9 ppm. MS (ESI ): m/z =
calcd. for C H BrN [M + H] 374.0293, found 374.0292.
20
12
3
+
14.1. ESI-HRMS: calcd. for C H ClN OS [M + H] 314.0155, found
1
5
8
3
14.0155.
Acknowledgments
General Procedure for the Synthesis of 2-Phenylimidazo[1,2-
a]pyridin-3-amine (8): To a stirred solution of 3aa (0.1 g,
S. M. and S. U. D. acknowledge the Council of Scientific and
Industrial Research (CSIR), New Delhi, and S. K. acknowledges
0
.45 mmol) in glacial acetic acid (2 mL) was added iron powder
(
0.075 g, 1.35 mmol). The resulting suspension was stirred at 100 °C the University Grants Commission (UGC), New Delhi) for finan-
for 3 h. After completion of the reaction (as determined by TLC), cial support in the form of fellowships. The authors acknowl-
the reaction mixture was filtered through a bed of Celite to remove edge the SAIF Division of CDRI for providing spectroscopic data.
the iron residue, which was washed with ethyl acetate (30 mL). The
Financial assistance to S. B. from the CSIR Network project HOPE
is also acknowledged (grant BSC 0014).
filtrate was partitioned with 2
M KOH, and the basic layer was fur-
ther extracted with ethyl acetate (3 × 25 mL). The combined organic
extracts were washed with brine (35 mL), dried with anhydrous
Na SO , and concentrated under reduced pressure. The crude resi- Keywords: Nitrogen heterocycles · Imidazo[1,2-a]pyridines ·
2
4
due was purified by column chromatography on silica gel using Iodine · Sodium nitrite · Domino reactions · Pictet-Spengler
hexanes/EtOAc (6.0:4.0, v/v) as eluent to afford the desired product reaction
8
(0.088 g, 94 %) as a yellow solid.
2
-Phenylimidazo[1,2-a]pyridin-3-amine (8): Yield: 94 % (0.088 g
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from 0.1 g); yellow solid, m.p. 118–120 °C; R = 0.2 (hexanes/EtOAc,
f
7
3
:3, v/v). IR (KBr): ν˜
= 869, 1410, 1626, 1964, 2339, 3222,
max
–
1 1
431 cm . H NMR (400 MHz, CDCl ): δ = 3.43 (br. s, 2 H), 6.82 (t,
3
J = 7.2 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 7.28–7.35 (m, 1 H), 7.45–
1
3
7
.56 (m, 3 H), 7.97–8.02 (m, 3 H) ppm. C NMR (100 MHz, CDCl3):
δ = 112.1, 117.1, 122.1, 123.8, 127.3, 127.4, 128.9, 134.0, 140.8 ppm.
MS (ESI ): m/z = 210.1. ESI-HRMS: calcd. for C13H11N [M + H]
+
+
3
3
72; e) R. Garamvolgyi, J. Dobos, A. Sipos, S. Boros, E. Illyès, F. Baska, L.
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2
10.1031, found 210.1030.
1
General Procedure for the Synthesis of Pyrido[2′,1′:2,3]imid-
azo[4,5-c]isoquinolines as Exemplified for 10a: To a stirred solu-
tion of 3aa (0.1 g, 0.45 mmol) in glacial acetic acid (2 mL) was
added benzaldehyde (9a) (49 μL, 0.49 mmol) and iron powder
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0.075 g, 1.35 mmol). The resulting reaction mixture was then
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Celite to remove the iron residue, which was washed with ethyl
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acetate (30 mL). The filtrate was partitioned with 2
M
KOH, and the
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combined organic extracts were washed with brine (35 mL), dried
with anhydrous Na SO , and concentrated under reduced pressure.
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2
4
The crude residue was purified by column chromatography on silica
gel using hexanes/EtOAc (7.0:3.0, v/v) as eluent to afford the desired
product 10a (0.103 g, 78 %) as a white solid.
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-Phenylpyrido[2′,1′:2,3]imidazo[4,5-c]isoquinoline (10a): Yield:
7
8 % (0.103 g from 0.1 g); white solid, m.p. 172–174 °C; R = 0.3
f
(
hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 972, 1342, 1560, 1848,
409 cm . H NMR (400 MHz, CDCl ): δ = 6.79 (t, J = 6.8 Hz, 1 H),
max
3
314–3320; e) X.-H. Huang, S.-C. Wang, B.-W. Li, X. Wang, Z.-M. Ge, R.-T.
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3
6
7
3
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.90 (d, J = 8.6 Hz, 2 H), 7.12–7.19 (m, 1 H), 7.38 (t, J = 2.1 Hz, 3 H),
.49 (d, J = 8.9 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 2 H), 7.76 (dd, J = 7.4,
1
1
3
J2 = 3.7 Hz, 2 H), 8.36 (d, J = 6.7 Hz, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 112.3, 114.3, 117.3, 123.2, 124.9, 127.3, 128.3, 128.4,
3
+
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2
2
28.8, 129.7, 131.2, 134.1, 136.6, 143.0, 159.5 ppm. MS (ESI ): m/z =
+
96.2. ESI-HRMS: calcd. for C20H13N [M + H] 296.1188, found
3
96.1189.
5
-(4-Bromophenyl)pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinoline
(
10b): Yield: 92 % (0.154 g from 0.1 g); yellow solid, m.p. 194–
1
1
6
8
96 °C; R = 0.3 (hexanes/EtOAc, 7:3, v/v). IR (KBr): ν˜
= 980, 1389,
f
max
–
1 1
506, 1918, 3519 cm . H NMR (400 MHz, [D ]DMSO): δ = 6.82–
6
.86 (m, 1 H), 7.05–7.09 (m, 1 H), 7.39–7.46 (m, 3 H), 7.70 (d, J =
.5 Hz, 2 H), 7.88 (t, J = 1.7 Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 8.25
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3
(d, J = 6.9 Hz, 1 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 111.5,
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17.0, 122.8, 123.1, 126.7, 127.2, 127.3, 128.2, 128.7, 130.5, 130.7,
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[
Received: May 4, 2016
Published Online: ■
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Full Paper
Nitrogen Heterocycles
S. Mukhopadhyay, S. U. Dighe,
S. Kolle, P. K. Shukla, S. Batra* .... 1–10
NaNO /I -Mediated Regioselective
2
2
Synthesis of Nitrosoimidazohetero-
cycles from Acetophenones by a
A domino reaction between 2-amino- direct and efficient synthesis of nitro-
pyridines and acetophenones in the soimidazoheterocycles.
presence of NaNO2 and I2 enables
Domino Process[
‡]
DOI: 10.1002/ejoc.201600553
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim