Iodine catalyzed mild 4CR protocol for synthesis of Tetrahydroimidazo[1,2-a]pyridines: Cascade construction of multiple C-C and C-Hetero bonds

Article abstract of DOI:10.1016/j.tet.2015.05.062

A highly convergent and straight forward synthesis of N-fused heterocycles, including 1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acids is successfully achieved via a one-pot four-component cascade reaction utilizing pyruvic acid, aldehydes, dia

Full text of DOI:10.1016/j.tet.2015.05.062

Accepted Manuscript
Iodine Catalyzed Mild 4CR Protocol for Synthesis of
Tetrahydroimidazo[1,2-a]pyridines: Cascade Construction of Multiple C−C and C
−Hetero Bonds
Atieh Rezvanian
PII:
S0040-4020(15)00733-4
10.1016/j.tet.2015.05.062
TET 26780
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 April 2015
Revised Date: 6 May 2015
Accepted Date: 18 May 2015
Please cite this article as: Rezvanian A, Iodine Catalyzed Mild 4CR Protocol for Synthesis of
Tetrahydroimidazo[1,2-a]pyridines: Cascade Construction of Multiple C−C and C−Hetero Bonds,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.05.062.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Leave this area blank for abstract info.
Iodine Catalyzed Mild 4CR Protocol for Synthesis of
Tetrahydroimidazo[1,2-a]pyridines: Cascade
Construction of Multiple C−C and C−Hetero Bonds
Atieh Rezvanian*
Department of Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran
O
OH
NO2
H
O
Ar
N
NH2
H
NO2
SMe
I2 (10%)
R
Cascade
N
SN /Michael/
Knoevenagel/
N-cyclization
reaction
R
CH3CN, 5 h
MeS
NH2
HO
O
Ar-CHO
up to 94%

ACCEPTED MANUSCRIPT
2
Iodine Catalyzed Mild 4CR Protocol for Synthesis of
Tetrahydroimidazo[1,2-a]pyridines: Cascade Construction of
Multiple C−C and C−Hetero Bonds
Atieh Rezvanian*
Department of Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran
Abstract—A highly convergent and straightforward synthesis of N-fused heterocycles,
including 1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acids is successfully achieved
via a one-pot four-component cascade reaction utilizing pyruvic acid, aldehydes, diamines and
1,1-bis(methylthio)-2-nitroethylene (BMTNE) in the presence of a catalytic amount of molecular
iodine in acetonitrile. The new efficient domino protocol generates two rings by the concomitant
formation of C–N (three) and C–C (two) multiple bonds presumably involving a sequence of
N,N-acetal formation, Knoevenagel reaction, aza–ene reaction, imine–enamine/keto–enol
tautomerization, and N-cyclization as key steps. The merit of this protocol is highlighted by its
easily available and economical starting materials, operational simplicity, efficient utilization of
all the reactants, clean reaction profile, simple workup procedure, and tolerance of a wide variety
of functional groups.
1. Introduction
The central theme of organic synthesis is the construction and cleavage of bonds in organic
molecules. Modern synthesis involves the design of efficient synthetic protocol that minimizes
Keywords: Molecular iodine, Pyruvic acid, Imidazo[1,2-a]pyridine-5-carboxylic acid, Four-component reaction
Corresponding author, Tel.: +98 21 88042510; fax: +98 21 88041344; e-mail: Rezvaniana@alzahra.ac.ir

ACCEPTED MANUSCRIPT
3
the number of synthetic steps for the rapid generation of functionalized molecules with
interesting properties. One approach to achieve this goal involves the development of
ecocompatible, multicomponent procedures. Multicomponent reactions (MCRs) offer a wide
range of possibilities for the construction of pre-defined highly complex molecules in a single
step with high atom economy, minimum time, labor, cost, and straight forward experimental
procedures.1 These benefits are highlights for multicomponent cascade reactions, which involve
in situ production of an intermediate with a strategic reactive site for subsequent
transformations.2 In the past decade, a lot of multicomponent reactions have been reported,3,4 yet
developing novel MCRs that meet almost all of advantages above is still in the burgeoning
phase.
In recent times, the use of molecular iodine has received considerable attention as an
inexpensive, nontoxic, readily available catalyst for various organic transformations to afford the
corresponding products in excellent yields with high selectivity.5 The mild Lewis acidity
associated with iodine enhanced its usage in organic synthesis to realize several organic
transformations using stoichiometric levels to catalytic amounts. Owing to numerous advantages
associated with this eco-friendly element, iodine has been explored as a powerful catalyst for
various organic transformations.6 So the development of a reaction that uses catalytic amounts of
non toxic and readily available iodine should greatly contribute to the creation of
environmentally benign processes. Interestingly, to some extent, the reactions promoted by
iodine usually afford unexpected results.7
Nitro ketene aminals (NKA) and related compounds possessing the conjugated system N-C=C-
EWG are important versatile synthetic intermediates in synthetic chemistry and they have
received increasing attention recently.8 Their usage for constructing a variety of nitrogen

ACCEPTED MANUSCRIPT
4
containing heterocycles or fused heterocyclic compounds that are hardly accessible by other
synthetic methods has been extensively studied.9 The notable feature of NKA is the highly
polarized ethylene systems with electro-donating amino group and electro-withdrawing
substituent at both ends. This unique structural feature makes them serve as bis-nucleophiles
reacting with various bis-electrophiles.
Our research goal during the past few years has been the synthesis of a library of
pharmacologically relevant fused polyheterocyclic systems employing enamines and aminals.10
Recently, we have become interested in the application of nitro ketene aminal intermediates
resulting from the reaction of 1,1-bis(methylthio)-2-nitroethylene (BMTNE) and diamines or
primary amines for the synthesis of interesting heterocycles in one-pot processes. During a
previous investigation, we succeeded in developing a novel class of oxa-aza[3.3.3]propellane
fused derivatives based on reaction of NKA and Knoevenagel adduct from ninhydrin and
malononitrile (Scheme 1).10b
R
CH2(CN)2
O
R
O
N
NH
R
O
O
NH2
NO2
EtOH
+
NH2
r.t. 12 h
O
CN
MeS
MeS
H
NO2
Scheme 1. Synthesis of fused oxa-aza[3.3.3]propellanes via one-pot, four-component reaction
2. Results and discussion
Encouraged by this successful effort, I decided to perform the reaction of heterocyclic ketene
aminals (HKAs) and the Knoevenagel adduct generated in situ from of pyruvic acid and
benzaldehyde, to evaluate the construction of useful fused azaheterocycle molecules under mild
reaction conditions. Reactions of pyruvic acid derivatives with bisnucleophiles have been applied

ACCEPTED MANUSCRIPT
5
for the synthesis of various types of heterocycles since the beginning of the last century. On the
other hand, multicomponent reactions of pyruvic acid leading to heterocycles have rarely been
investigated.
During the course of our studies, molecular iodine was discovered which can be applied as a
good catalyst for the activation of the carbonyl group of benzaldehyde11 and the iodine catalyzed
Michael reactions are well known.12 Accordingly, at first, the reaction of pyruvic acid and 4-
chlorobenzaldehyde under different conditions was evaluated that afforded the expected
Knoevenagel adduct intermediate. Initially, the reaction was carried out in ethanol at room
temperature. Whether the catalyst was added or not, the target compound 4a was not obtained
after 24 h (Table 1, entries 1 and 2). However, when the reaction was heated at reflux and the
molecular iodine was added, I found that the reaction was complete and the desirable
Knoevenagel adduct was obtained in an isolated yield of 27% within 24 h (Table 1, entry 3).
Subsequently, reaction conditions was optimized by screening several solvents, and of those
examined, acetonitrile was the most suitable. With molecular iodine as good promoter in hand,
next I intended to optimize its loading, and it was found that the use of 10 mol% of I2 provided
the best result. Reducing the mol% of I2 in the reaction increased the reaction time and lowered
the yield, and increasing the catalyst loading did not show any improvement (Table 1, entries 6
and 7). Therefore, the best reaction conditions were achieved by employing with molecular
iodine (0.1 mmol) in acetonitrile under reflux for 2 h (Table 1, entry 8).
Next, to verify the possibility to perform a “classic” one-pot four-component reaction, the
reaction was carried out by sequential addition of reagents ethylenediamine, nitro ketene
dithioacetal (BMTNE), pyruvic acid and 4-chlorobenzaldehyde in one flask under the same
reaction conditions. This manner avoids the isolation of the intermediates and should save time

ACCEPTED MANUSCRIPT
6
Table 1. Screening Optimum Reaction Conditions for the Formation of Intermediate
Knoevenagel Condensation Product
Catalyst
(mol%)
Temp
Entry
Solvent
Time (h)
Yielda %
(°C)
1
2
3
4
5
6
7
-
EtOH
EtOH
EtOH
MeOH
THF
rt
24
24
24
24
10
5
nrb
nr
-
rt
I2 (10)
I2 (10)
I2 (10)
I2 (5)
I2 (20)
I2 (10)
70
65
70
80
80
80
27
14
30
44
92
94
MeCN
MeCN
MeCN
2
8
2
a Isolated yield
b No reaction
of execution and solvent amounts, and afford better yields. Thus, in a pilot reaction,
ethylenediamine and BMTNE in acetonitrile, was combined. The resultant reaction mixture was
stirred to complete the SN reaction as monitored by thin-layer chromatography (TLC). After the
formation of HKA 5, pyruvic acid and 4-chlorobenzaldehyde with catalytic amount of I2 (10
mol%) were introduced and the reaction was heated at reflux in an oil bath until completion
(monitored by TLC). The desired product was isolated, filtered, and washed with cold ethanol to
afford the pure product 4a. The resultant pure compound was identified on the basis of
spectroscopic data. Because of the existence of two stereogenic centers in the products 4d-f,
mixture of two diastereomers was expected. For 4d and 4f products, two diastereomers were
1
13
formed (Fig. 1). But, the H and C NMR spectral data of 4e clearly indicated that only one of
the two possible diastereomers was obtained for this product.
With the optimal reaction conditions, we then investigated the use of different starting materials
in order to determine the reactivity domain of the cascade reaction (Table 2). For
ethylenediamines and aromatic aldehydes 2, the substituents, whether with electron-withdrawing,

ACCEPTED MANUSCRIPT
7
or electron-releasing groups on the aromatic ring, afforded corresponding products in excellent
yields. Application of other diamines such as 1,3-propylenediamines and 1,4-butanediamine lead
to a complex mixture which was difficult to purify and characterize (Table 2).
Product
Ratio of two
diastereomers
-
Entry
Ar
Diamine
3
Total yield %
4
4a
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Ethylenediamine
Ethylenediamine
94
85
88
90
84
87
-
1
2
3
4
5
6
7
8
-
4b
4c
4d
4e
4f
Ethylenediamine
-
1,2-Propanediamine
1,2-Propanediamine
1,2-Propanediamine
1,3-Propylenediamine
1,4-Butanediamine
91:9
-
83:17
-
-
4g
4h
-
Table 2. One-Pot Synthesis of Tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acids 4a-f via
Domino SN/Knoevenagel condensation/Michael Addition/Cyclization Reaction
1
The molecular structure of products 4a-f was elucidated from elemental analysis, IR, and H
13
NMR and C NMR spectra. The mass spectrum of 4b displayed the molecular ion peak at m/z
301, which is in agreement with the proposed structure. The IR spectrum of this compound
showed an absorption band due to the NH stretching frequency at 3352 cm-1. Absorption bands
1
at 1727, 1651 cm–1 are due to the C=O and NC=C groups stretching frequencies. The H NMR

ACCEPTED MANUSCRIPT
8
spectrum of 4b showed one sharp singlet for the methyl group (δ = 2.23 ppm), three multiplets
for two CH2 groups, because these protons are diastereotopic (δ = 3.68-3.74, 4.06-4.16 and 4.24-
4.32 ppm), two doublets for CH groups (δ = 4.80 and 6.06 ppm, 3JHH = 5.6 Hz), and two singlets
for NH and OH groups (δ = 9.32 and 13.17 ppm). Also, four aromatic hydrogens gave rise to
characteristic signals in the aromatic region of the spectrum. Observation of 13 distinct signals in
1
the H-decoupled 13C NMR spectrum of 4b is in agreement with the proposed structure. The
most important region of the spectrum is related to resonances due to, CNO2, CCO and CO
which appear at δ = 119.0, 127.0 and 163.2 ppm.
NO2
NO2
H
H
H
H
7
7
N
N
H
Me
Ar
Ar
N
O
N
2
Me
2
H
OH
HO
O
2S, 7R
2R, 7S
2R, 7R
2S, 7S
Figure 1. Expected mixture of two diastereomers of 4d-f
Although no detailed mechanistic studies have been carried out at this point, a rational
mechanism for this one-pot procedure is outlined in Scheme 2. This mechanism is proposed
knowing the chemical behavior of pyruvic acid, benzaldehyde, and ketene aminal intermediate
HKA. Based on this mechanism, HKA 5 readily prepared in situ from the addition of
ethylenediamine and BMTNE via a SN2 reaction followed by loss of 2 equiv of MeSH. Next, the
formation of second key intermediate 6 occurs through Knoevenagel condensation of
benzaldehyde 2 with enol form pyruvic acid in the presence of iodine. With a strong electron-
withdrawing nitro group at the α-position and electron-donating diamino groups on the
diazaheterocycle of HKA, HKA 5 can serve as a nucleophilic component with the electrophilic
arylidene pyruvic acid 6 in a Michael-type addition to produce an open chain azaketene type

ACCEPTED MANUSCRIPT
9
intermediate which transformed to intermediate 8 through imine-enamine tautomerization.
Subsequently, in the presence of active ketonic carbonyl in intermediate 8, nucleophilic addition
of the secondary amino group to the acidic carbonyl group followed by loss of 1 equiv of H2O
affords product 4.
Ar
O
O
I2 (10%)
CHO
Ar
+
CO2H
Knoevenagel
condensation
NO2
O
OH
O
H
6
N
O
OH
R
O2N
N
R
NH2
H
H
NO2
SN reaction
-2 MeSH
+
Ar
NH
HN
R
MeS
SMe
NH2
Michael
addition
5
NO2
O2N
Ar
H
Ar
O2N
H
N
imine-enamine
tautomerizatiom
Ar
O
O
N-cyclization
-H2O
R
HN
HN
N
OH
OH
NH
N
R
R
O
O
HO
O
7
8
Scheme 2. Mechanistic Rationalization for the Formation of 4
3. Conclusion
In summary, we have successfully developed a simple and highly efficient synthesis of 1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid frameworks through four-component
coupling of ketene-N,N-acetals, aldehydes, and pyruvic acid in the presence of 10 mol% of I2
under metal-free conditions. This atom economic domino protocol involves SN
reaction/Knoevenagel condensation/Michael addition/cyclization sequence forming three new
bonds (two C–C and three C–N), and two heterocycles in a single operation with all reactants
efficiently being utilized. The method involves the use of readily available commercial reagents

ACCEPTED MANUSCRIPT
10
and operationally simple synthetic protocols and does not require advanced intermediates or
anhydrous solvents. Significantly, the presence of an acidic group at the 9 position on
imidazo[1,2-a]pyridines make these compounds excellent entrants as precursors for further
synthetic renovations to meet the need for diverse useful purposes. The isolation and purification
of compounds by simple filtration and ethanol washing makes the process very simple avoiding
conventional chromatographic separation. I hope this clean and simple four-component coupling
protocol maybe of value for both synthetic and medicinal chemists for academic research and
practical applications.
4. Experimental
The diamines, l,l-bis(methylthio)-2-nitroethene, aldehydes, and pyruvic acid were obtained from
Merck (Germany) and Fluka (Switzerland) and were used without further purification. Elemental
analyses for C, H and N were performed using a Heraeus CHN–O–Rapid analyzer. Mass spectra
were recorded on a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization
potential of 70 eV. 1H NMR (300 and 400 MHz) and 13C NMR (75 MHz) spectra were obtained
using Bruker DRX-300 AVANCE and Bruker DRX-400 AVANCE spectrometers. IR spectra were
recorded as KBr pellets on a NICOLET FT-IR 100 spectrometer, absorbencies are reported in
cm-1.
4.1. Typical synthesis procedure: (for example 4a)
To a magnetically stirred 10 mL flask containing 1,1-bis(thiomethyl)-2-nitroethylene (0.16 g, 1
mmol) in acetonitrile (3 mL) was added ethylenediamine (0.06 g, 1 mmol). After 3 h, pyruvic
acid (0.08 g, 1 mmol), 4-chlorobenzaldehyde (0.14 g, 1 mmol) and iodine (0.12 g, 0.1 mmol)
were added to the reaction mixture, and stirring was allowed to continue at for 2 h at reflux.

ACCEPTED MANUSCRIPT
11
After the completion of the reaction, the precipitated product was filtered and washed with cold
ethanol to afford the pure product 4a.
4.1.1.
7-(4-Chlorophenyl)-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic
acid (4a). Yellow powder, mp = 178-180 °C (decomp), 0.30 g, yield: 94%. IR (KBr) (νmax, cm-
1): 3349 (NH), 1728 (C=O), 1652 (NC=C) cm−1. Anal. Calcd for C14H12ClN3O4: C, 52.27; H,
3.76; N, 13.06. Found C, 52.23; H, 3.77 N, 13.09. δH (500 MHz, DMSO-d6): 3.67-3.71 (m, 2 H,
NCH2), 4.09-4.11 (m, 1 H, NCH2), 4.23-4.25 (m, 1 H, NCH2), 4.84 (d, 3JHH = 5.5 Hz, 1 H, CH ),
3
3
6.04 (d, 3JHH = 5.5 Hz, 1 H, CH), 7.20 (d, JHH = 8.4 Hz, 2 CH of Ar), 7.30 (d, JHH = 8.4 Hz, 2
CH of Ar), 9.31 (s, 1 H, NH), 13.17 (br, 1 H, OH). δC (100 MHz, DMSO-d6): 40.9 (CH), 43.4
(CH2N), 47.5 (CHN), 104.5 (CH), 118.3 (C-NO2), 127.1 (CCO), 128.4 (CH of Ar), 129.2 (CH of
Ar), 131.2 (Cipso-Ar), 142.4 (Cipso-Ar), 153.8 (NCN), 162.9 (CO);
4.1.2.
7-(4-Methylphenyl)-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic
acid (4b). Yellow powder, mp = 172-174 °C (decomp), 0.26 g, yield: 85%. IR (KBr) (νmax, cm-
1): 3352 (NH), 1727 (C=O), 1651 (C=N), cm−1. Anal. Calcd for C15H15N3O4: C, 59.80; H, 5.02;
N, 13.95. Found C, 59.76; H, 5.04; N, 13.98. MS (EI, 70 eV): m/z (%) = 301 (M+, 2), 290 (10),
270 (10), 255 (90), 224 (21), 209 (100), 181 (42), 115 (37). δH (300 MHz, DMSO-d6): 2.23 (s, 3
H, CH3), 3.71 (m, 2 H, CH2), 4.11 (m, 1 H, NCH2), 4.27 ( m, 1 H, NCH2), 4.80 (d, 3JHH = 5.6 Hz,
1 H, CH ), 6.06 (d, 3JHH = 5.6 Hz, 1 H, CH), 7.08 (br, 4 CH of Ar), 9.32 (s, 1 H, NH), 13.10 (br,
1 H, OH). δC (75 MHz, DMSO-d6): 20.7 (CH3), 41.0 (CH), 43.3 (CH2N), 47.5 (CH2N), 104.8
(CH), 119.0 (C-NO2), 127.0 (CCO), 127.3 (CH of Ar), 129.0 (CH of Ar), 135.7 (Cipso-Ar), 140.5
(Cipso-Ar), 153.9 (NCN), 163.2 (CO).
4.1.3. 7-(4-Methoxyylphenyl)-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic
acid (4c). Yellow powder, mp = 175-177 °C (decomp), 0.28 g, yield: 88%. IR (KBr) (νmax, cm-1):

ACCEPTED MANUSCRIPT
12
3353 (NH), 1723 (C=O), 1652 (NC=C) cm−1. Anal. Calcd for C15H15N3O5: C, 56.78; H, 4.76; N,
13.24. Found C, 56.84; H, 4.73; N, 13.20. δH (300 MHz, DMSO-d6): 3.68 (s, 3 H, OCH3), 3.71-
3.74 (m, 2 H, NCH2), 4.07-4.17 ( m, 1 H, NCH2), 4.23-4.32 (m, 1 H, NCH2), 4.78 (d, 3JHH = 5.4
3
3
Hz, 1 H, CH), 6.08 (d, JHH = 5.5 Hz, 1 H, CH), 6.82 (d, JHH = 8.2 Hz, 2 CH of Ar), 7.11 (d,
3JHH = 8.2 Hz, 2 CH of Ar), 9.29 (s, 1 H, NH), 13.08 (br, 1 H, OH). δC (75 MHz, DMSO-d6):
40.6 (CH), 43.3 (CH2N), 47.6 (CH2N), 55.1 (OCH3), 105.1 (CH), 113.8 (CH of Ar), 119.2 (C-
NO2), 126.8 (CCO), 128.5 (CH of Ar), 135.5 (Cipso-Ar), 153.9 (NCN), 158.2 (Cipso-Ar), 163.2
(CO).
4.1.4.
7-(4-Chlorophenyl)-2-methyl-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-
carboxylic acid (4d). Yellow powder, mp = 179-181 °C (decomp), 0.30 g, yield: 90%. IR (KBr)
(νmax, cm-1): 3347 (NH), 1729 (C=O), 1650 (NC=C) cm−1. Anal. Calcd for C15H14ClN3O4: C,
53.66; H, 4.20; N, 12.52. Found C, 53.62; H, 4.21 N, 12.56. Major isomer 4d: δH (300 MHz,
3
DMSO-d6): 1.31 (d, JHH = 5.6 Hz, 3 H, CH3), 3.83-3.88 (m, 1 H, NCH2), 4.10-4.18 (m, 1 H,
NCH2), 4.25-4.32 (m, 1 H, NCH), 4.87 (d, 3JHH = 5.4 Hz, 1 H, CH), 6.05 (d, 3JHH = 5.1 Hz, 1 H,
CH), 7.25 (d, 3JHH = 8.3 Hz, 2 CH of Ar), 7.32 (d, 3JHH = 8.3 Hz, 2 CH of Ar), 9.47 (s, 1 H, NH),
13.17 (br, 1 H, OH). δC (75 MHz, DMSO-d6): 20.5 (CH3), 40.8 (CH), 51.1 (CH2N), 54.0 (CHN),
104.0 (CH), 118.0 (C-NO2), 127.1 (CCO), 128.3 (CH of Ar), 129.1 (CH of Ar), 131.1 (Cipso-Ar),
142.4 (Cipso-Ar), 152.9 (NCN), 162.9 (CO). Minor isomer 4d: δH (300 MHz, DMSO-d6): 1.19 (d,
3JHH = 6.1 Hz, 3 H, CH3), 3.39-3.46 (m, 1 H, NCH2), 3.68-3.74 (m, 1 H, NCH2), 4.37-4.33 (m, 1
H, NCH), 4.91 (d, 3JHH = 5.2 Hz, 1 H, CH ), 6.12 (d, 3JHH = 5.1 Hz, 1 H, CH), 7.25 (d, 3JHH = 8.4
Hz, 2 CH of Ar), 7.32 (d, 3JHH = 8.3 Hz, 2 CH of Ar), 9.42 (s, 1 H, NH), 13.09 (br, 1 H, OH). δC
(75 MHz, DMSO-d6): 20.1 (CH3), 40.3 (CH), 51.3 (CH2N), 54.2 (CHN), 104.1 (CH), 118.2 (C-

ACCEPTED MANUSCRIPT
13
NO2), 127.2 (CCO), 128.3 (CH of Ar), 129.1 (CH of Ar), 131.1 (Cipso-Ar), 142.4 (Cipso-Ar),
153.1 (NCN), 162.9 (CO).
4.1.5.
2-Methyl-7-(4-methylphenyl)-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-
carboxylic acid (4e). Yellow powder, mp = 174-176 °C (decomp), 0.26 g, yield: 84%. IR (KBr)
(νmax, cm-1): 3349 (NH), 1778 (C=O), 1658 (NC=C) cm−1. Anal. Calcd for C16H17N3O4: C,
60.95; H, 5.43; N, 13.33. Found C, 60.91; H, 5.46; N, 13.36. δH (300 MHz, DMSO-d6):1.30 (d,
3JHH = 5.6 Hz, 3 H, CH3), 2.23 (s, 3 H, CH3), 3.66-3.72 (m, 1 H, NCH2), 4.13-4.15 (m, 1 H,
NCH2), 4.37-4.43 (m, 1 H, NCH), 4.80 (d, 3JHH = 5.3 Hz, 1 H, CH), 6.07 (d, 3JHH = 5.4 Hz, 1 H,
CH), 7.07 (br, 4 CH of Ar), 9.41 (s, 1 H, NH), 13.12 (br, 1 H, OH). δC (75 MHz, DMSO-d6):
20.2 (CH3), 20.7 (CH3), 41.0 (CH), 51.3 (CH2N), 54.3 (CHN), 104.5 (CH), 119.2 (C-NO2), 126.8
(CCO), 127.3 (CH of Ar), 129.0 (CH of Ar), 135.8 (Cipso-Ar), 140.5 (Cipso-Ar), 153.3 (NCN),
163.1 (CO).
4.1.6. 7-(4-Methoxylphenyl)-2-methyl-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-
carboxylic acid (4f). ). Yellow powder, mp = 176-178 °C (decomp), 0.29 g, yield: 87%. IR
(KBr) (νmax, cm-1): 3345 (NH), 1733 (C=O), 1666 (NC=C) cm−1. Anal. Calcd for C16H17N3O5: C,
58.0; H, 5.17; N, 12.68. Found C, 58.04; H, 5.15; N, 12.65. Major isomer 4f: δH (300 MHz,
DMSO-d6): 1.30 (d, J = 5.6 Hz, 3 H, CH3), 3.69 (s, 3 H, OCH3), 3.85-3.86 (m, 1 H, NCH2), 4.13-
4.15 ( m, 1 H, NCH2), 4.24-4.30 ( m, 1 H, NCH2), 4.79 (d, 3JHH = 4.7 Hz, 1 H, CH), 6.09 (d, 3JHH
3
3
= 6.3 Hz, 1 H, CH), 6.83 (d, JHH = 6.3 Hz, 2 CH of Ar), 7.11 (d, JHH = 7.3 Hz, 2 CH of Ar),
9.39 (s, 1 H, NH), 13.16 (br, 1 H, OH). δC (75 MHz, DMSO-d6): 20.2 (CH3), 40.3 (CH), 51.1
(CH2N), 54.1 (CHN), 55.1 (OCH3), 104.7 (CH), 113.9 (CH of Ar), 119.3 (C-NO2), 126.5 (CCO),
128.4 (CH of Ar), 135.4 (Cipso-Ar), 153.0 (NCN), 158.1 (Cipso-Ar), 163.1 (CO). Minor isomer 4f:
δH (300 MHz, DMSO-d6): 1.29 (d, 3JHH = 6.1 Hz, 3 H, CH3), 3.73 (s, 3 H, OCH3), 3.88-3.92 (m,

ACCEPTED MANUSCRIPT
14
3
1 H, NCH2), 4.13-4.15 (m, 1 H, NCH2), 4.24-4.27 (m, 1 H, NCH), 4.81 (d, JHH = 4.7 Hz, 1 H,
CH), 6.15 (d, 3JHH = 6.04 Hz, 1 H, CH), 6.82-7.12 (m, 4 CH of Ar), 9.44 (s, 1 H, NH), 13.16 (br,
1 H, OH). δC (75 MHz, DMSO-d6): 20.7 (CH3), 40.5 (CH), 51.3 (CH2N), 54.3 (CHN), 55.1
(OCH3), 104.8 (CH), 113.9 (CH of Ar), 119.5 (C-NO2), 126.6 (CCO), 128.5 (CH of Ar), 135.5
(Cipso-Ar), 153.2 (NCN), 158.1 (Cipso-Ar), 163.1 (CO).
Acknowledgements
Financial support of this research from Alzahra University, Iran is gratefully acknowledged.
References
1. (a) Zhu, J.; Bienaymé, H. Multicomponent reactions; John Wiley & Sons: Weinheim,
Germany, 2005. (b) Weber, L. Curr. Med. Chem. 2002, 9, 2085. (c) Hulme, C.; Gore, V.
Curr. Med. Chem. 2003, 10, 51. (d) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15,
1300. (e) Dömling, A. Chem. Rev. 2005, 106, 17.
2. (a) Schreiber, S. L. Science, 2000, 287, 1964. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
3. (a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259. (b) Noyori, R. Nat. Chem. 2009, 1, 5.
(c) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (d)
Posner, G. H. Chem. Rev. 1986, 86, 831. (e) Boger, D. L.; Desharnais, G.; Capps, K. Angew.
Chem., Int. Ed. 2003, 42, 4138. (f) Ugi, I.; Werner, B.; Dömling, A. In Targets in
Heterocycles Systems, Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Italian
Society of Chemistry: Rome, 2000; Vol. 4, pp 1. (g) Ugi, I. Pure Appl. Chem. 2001, 73, 187.
(h) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (i) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.

ACCEPTED MANUSCRIPT
15
4. (a) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427. (b) Shestopalov, A. M.;
Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans,
D. H. Org. Lett. 2002, 4, 423. (c) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002,
4, 3147. (d) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4, 3309. (e) Bora, U.; Saikia, A.;
Boruah, R. C. Org. Lett. 2003, 5, 435. (f) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org.
Lett. 2003, 5, 1205.
5. (a) Togo, H.; Iida, S. Synlett 2006, 14, 2159. (b) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org.
Chem. 2006, 71, 8283. (c) Lin, C.; Fang, H.; Tu, Z.; Liu, J.; Yao, C. J. Org. Chem. 2006, 71,
6588. (d) Gao, S.; Zeng, T. T.; Sastry, M. N. V.;Chu, C.; Liu, J.; Lin, C.; Yao, C.
Tetrahedron Lett. 2006, 47, 1889.
6. (a) Lucas, R.; Vergnaud, J.; Teste, K.; Zerrouki, R.; Sol, V.; Krausz, P. Tetrahedron Lett.
2008, 49, 5537. (b) Wang, X. S.; Li, Q.; Yao, C. S.; Tu, S. J. Eur. J. Org. Chem. 2008, 20,
3513. (c) Wang, J.; Xu, F. X.; Lin, X. F.; Wang, Y. G. Tetrahedron Lett. 2008, 49, 5208.
(d) Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Yadav, J. S. Synlett 2008, 7, 1045. (e) Zhao, P.
C.; Li, J.; Jia, X. S. Synlett 2008, 6, 932. (f) List, B.; Castello, C. Synlett 2001, 11, 1687.
7. Wang, G. W.; Gao, J. Org. Lett. 2009, 11, 2385.
8. (a) Yan, S. J.; Niu, Y. F.; Huang, R.; Lin, J. Synlett 2009, 2821. (b) Muhammd, Y.; Yu, C.
Y.; Jia, Y. M.; Huang, Z. T. Synlett 2008, 9, 1357. (c) Li, M.; Zhou, Z. M.; Wen, L. R.;
Qiu, Z. X. J. Org. Chem. 2011, 76, 3054. (d) Wen, L. R.; Liu, C.; Li, M.; Wang, L. J. J.
Org. Chem. 2010, 75, 7605.
9. (a) Zeng, C. C.; Liu, F. J.; Ping, D. W. J. Org.Chem. 2009, 74, 6386. (b) Yu, C. Y.; Yang, P.
H.; Zhao, M. X.; Huang, Z. T. Synlett 2006, 12, 1835. (c) Huang, Z. T.; Wang, M. X.; J.
Org. Chem. 1992, 57,184. (d) Liao, J. P.; Zhang, T.; Yu, C.Y.; Huang, Z. T. Synlett 2007, 5,

ACCEPTED MANUSCRIPT
16
0761. (e) Wen, L. R.; Jiang, C. Y.; Li, M.; Wang, L. J. Tetrahedron 2011, 67, 293. (f)
Huang, Z.; Wang, M. Heterocycles 1994, 37, 1233. (g) Sharon, A.; Maulik, P. R.; Roy, R.;
Ram, V. J. Tetrahedron Lett. 2004, 45, 5815. (h) Jones, R. C. F.; Patel, P.; Hirst, S. C.;
Turner, I. Tetrahedron 1997, 53, 11781. (i) Huang, Z. T.; Liu, Z. R. Heterocycles 1986, 24,
2247. (j) Jones, R. C. F.; Smallridge, M. J. Tetrahedron Lett. 1988, 29, 5005. (k) Jones, R.
C. F.; Patel, P.; Hirst, S. C.; Smallridge, M. J. Tetrahedron 1998, 54, 6191. (l) Zhao, M. X.;
Wang, M. X.; Huang, Z. T. Tetrahedron 2002, 58, 1309. (m) Nie, X. P.; Wang, M. X.;
Huang, Z. T. Synthesis 2000, 1439.
10. (a) Alizadeh, A.; Rezvanian, A.; Zhu, L. G. J. Org. Chem. 2012, 77, 4385. (b) Rezvanian,
A.; Alizadeh, A. Tetrahedron, 2012, 68, 10164. (c) Rezvanian, A.; Alizadeh, A.; Zhu, L. G.
Synlett 2012, 2526. (d) Alizadeh, A.; Rezvanian, A. Comptes Rendus Chimie, 2014, 17, 103.
(e) Alizadeh, A.; Rezvanian, A. Synlett 2011, 8, 1105. (f) Alizadeh A.; Rezvanian, A.
Mokhtari, J. Synthesis 2011, 21, 3491. (g) Alizadeh, A.; Zarei, A.; Rezvanian, A. Synthesis
2011, 3, 497. (h) Alizadeh, A.; Rezvanian, A.; Yuan, D. Tetrahedron 2010, 66, 9933. (i)
Alizadeh, A.; Firuzyar, T.; Mikaeili, A. J. Heterocycl. Chem. 2013, 676. (j) Alizadeh, A.;
Firuzyar, T.; Mikaeili, A. Synthesis 2010, 22, 3913. (k) Alizadeh, A.; Mokhtari, J.; Ahmadi,
M. Tetrahedron 2012, 68, 319.
11. Ren, Y. M.; Cai, C.; Yang, R. C. RSC Adv. 2013, 3, 7182.
12. (a) Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Pal, M. RSC Adv. 2012, 2,
3387. (b) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005, 46, 1751. (c)
Zhang, Z.-H.; Lin, J. Synth. Commun. 2007, 37, 209. (d) Zeng, X.-F.; Ji, S.-J.; Su, X.-M.
Chin. J. Chem. 2008, 26, 413. (e) Hazra, A.; Paira, P.; Sahu, K. B. Banerjee, S.; Mondal, N.
B. Catal. Commun. 2008, 9, 1681.

ACCEPTED MANUSCRIPT
Table 1. Screening Optimum Reaction Conditions for the Formation of Intermediate
Knoevenagel Condensation Product
Catalyst
(mol%)
Temp
Entry
Solvent
Time (h)
Yielda %
(°C)
1
2
3
4
5
6
7
-
EtOH
EtOH
EtOH
MeOH
THF
rt
24
24
24
24
10
5
nrb
nr
-
rt
I2 (10)
I2 (10)
I2 (10)
I2 (5)
I2 (20)
I2 (10)
70
65
70
80
80
80
27
14
30
44
92
94
MeCN
MeCN
MeCN
2
8
2
a Isolated yield
b No reaction
Product
Ratio of two
diastereomers
Entry
Ar
Diamine
3
Total yield %
4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ethylenediamine
Ethylenediamine
Ethylenediamine
-
94
85
88
90
84
87
-
1
2
3
4
5
6
7
8
4a
-
4b
4c
4d
4e
4f
-
1,2-Propanediamine
1,2-Propanediamine
1,2-Propanediamine
1,3-Propylenediamine
1,4-Butanediamine
91:9
4-MeC6H4
4-MeOC6H4
4-ClC6H4
-
83:17
-
-
4g
4h
4-ClC6H4
-
Table 2. One-Pot Synthesis of Tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acids 4a-f via
Domino SN/Knoevenagel condensation/Michael Addition/Cyclization Reaction