Multicomponent one-pot solvent-free synthesis of functionalized unsymmetrical dihydro-1H-indeno[1,2-b]pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.10.022

A simple and efficient synthesis of 4-aryl-4,5-dihydro-1H-indeno[1,2-b]pyridine derivatives has been achieved via a four-component cyclocondensation of 1,3-indanedione, aromatic aldehydes, β-ketoesters and ammonium acetate in one-pot in the absence of cat

Full text of DOI:10.1016/j.tetlet.2009.10.022

Tetrahedron Letters 50 (2009) 7096–7098
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Multicomponent one-pot solvent-free synthesis of functionalized
unsymmetrical dihydro-1H-indeno[1,2-b]pyridines
*
Subhasis Samai, Ganesh Chandra Nandi, Ram Kumar, M. S. Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of 4-aryl-4,5-dihydro-1H-indeno[1,2-b]pyridine derivatives has been
achieved via a four-component cyclocondensation of 1,3-indanedione, aromatic aldehydes, b-ketoesters
and ammonium acetate in one-pot in the absence of catalyst and solvent at room temperature on grind-
ing. The present approach offers several advantages such as shorter reaction times, higher yields, low
cost, simple work-up and easy purification.
Received 12 September 2009
Revised 29 September 2009
Accepted 3 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
One-pot synthesis
Indenopyridine
Hantzsch reaction
Solvent-free
The developing of new multicomponent reactions (MCRs) and
improving the known MCRs are an area of considerable current
interest. However, if the one-pot MCRs could be carried out under
solvent- and catalyst-free conditions, it would be most efficient
synthetic methods of organic synthesis. As opposed to the classi-
cal way to synthesize complex molecules by sequential synthesis,
MCRs allow the assembly of complex molecules in one-pot and
show a facile execution, high atom-economy and high selectiv-
ity.1 As a one-pot reaction, MCRs generally afford good yields
and are fundamentally different from two-component and step-
wise reactions in several aspects2 and permitted a rapid access
to combinatorial libraries of complex organic molecules for an
efficient lead structure identification and optimization in drug
discovery.
Dihydropyridine derivatives possess a variety of biological
activities3 and drugs such as nifedipine, nicardipine and amlodip-
ine are effective cardiovascular agents for the treatment of hyper-
tension.3d,e In particular, indenopyridines (azafluorenes) are one of
the most important privileged medicinal scaffolds, which were
developed initially as antihistamines4a but shown inadvertently
to cause antispermatogenic effects4b,c in various species and are
useful inhibitors of spermatogenesis in animals,5 and showed a
fungicidal activity.6 Compounds with this motif show a wide range
of pharmacological activities. Hydrogenated indenopyridines have
valuable therapeutic uses.7 They lower serum lipids, in particular
the triglycerides, and are used for the therapy of primary hyperlip-
idemias and certain other hyperlipidemias. They also have poten-
tial antidepressant activity.8
Indeno[1,2-b]pyridines have been synthesized in good yields by
two-component (under reflux in high boiling solvents such as
toluene, xylene and dioxane in the presence of acid or base
catalysts),9–11 three-component (at 70 °C)12a and four-component
reactions (under solvent-free MW irradiation).12b,c 5-Oxo-1H-4,5-
dihydroindeno[1,2-b]pyridines have been synthesized by the
condensation of 2-arylideneindane-1,3-diones with b-aminocroto-
nates in refluxing acetic acid.13 4-Aryl-2-oxo-2,5-dihydro-1H-inde-
no[1,2-b]pyridines were synthesized by three-component reaction
in the presence of sodium hydroxide under solvent-free condi-
tion.14 A green method for the synthesis of indeno[2,1-c]pyridines
in ionic liquid catalyzed by malononitrile has been developed.15
Recently, a MCR of indane-1,3-dione, an aldehyde and an amine-
containing aromatic compound leading to the formation of indeno-
pyridine-based heterocyclic medicinal scaffolds has been investi-
gated.16 However, the use of high temperatures, expensive
catalysts and longer reaction times limits the use of these methods.
Therefore, the search for a better method for the synthesis of
dihydroindenopyridines is of prime importance.
In recent days the progress of solvent- and catalyst-free syn-
thesis has attracted the attention of chemists as they are envi-
ronmentally benign processes. There are many reactions
(Grignard,17 Aldol condensation,18 Reformatsky reaction,19 Dieck-
mann condensation,20 Knoevenagel condensation21 and polyhy-
droquinoline synthesis22), which have been reported under
solvent-free condition at room temperature on grinding. As part
of our continued interest23 in the development of facile multi-
* Corresponding author. Tel.: +91 542 6702502; fax: +91 542 2368127.
E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.022

S. Samai et al. / Tetrahedron Letters 50 (2009) 7096–7098
7097
R
CHO
O
O
O
O
O
Grinding, RT
Solvent-free
+
NH OAc
4
+
+
1
OR
O
R
HN
1
OR
4
2
3
Me
1
R
R
CHO
O
O
O
O
Knoevenagel
condensation
Michael
addition
1
+
OR
1
H
OR
-H O
2
R
O
O
+
O
O
2
3
HN
H N
2
A
C
B
Intramolecular
condensation
R
R
O
O
H
O
O
H O
2
1
HO
N
OR
1
HN
OR
H
D
1
Scheme 1. Synthesis of 4-aryl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridines.
Table 1
component reaction, herein we report a very simple and highly
efficient one-pot method for the synthesis of unsymmetrical
dihydro-1H-indeno[1,2-b]pyridine derivatives via a multicompo-
nent process under solvent- and catalyst-free conditions (Scheme
1).
Synthesis of indeno[1,2-b]pyridines (1a–o)
Entry
R
R1
Product
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
p-NO2
p-Cl
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
12
5
79
87
86
73
67
71
71
74
72
75
69
77
85
83
73
15
17
20
20
18
15
20
12
20
10
7
4-Aryl-4,5-dihydro-1H-indeno[1,2-b]pyridines have been syn-
thesized via four-component cyclocondensation of 1,3-indanedi-
one (1.0 mmol), aldehyde (1.0 mmol), b-ketoester (1.0 mmol) and
ammonium acetate (1.5 mmol) in a mortar at room temperature
on grinding.24 From a mechanistic point of view, the first step is
the formation of Knoevenagel product A. The second key interme-
diate is ester enamine B, produced by the condensation of b-keto-
ester with ammonia. Condensation of these two fragments gives
the acyclic Michael adduct intermediate C, which undergoes intra-
molecular cyclization with participation of the amino function and
one of the indanedione carbonyl group to form the dihydroindeno-
pyridine 1. A mechanistic rationale portraying the probable se-
quence of events for the formation of 4-aryl-4,5-dihydro-1H-
indeno[1,2-b]pyridines is given in Scheme 1. All the synthesized
compounds have been characterized by elemental and spectral
(IR, 1H, 13C NMR and mass) studies (Table 1).
Investigations of the reaction scope revealed that various aro-
matic aldehydes (bearing electron-withdrawing and electron-
donating groups) and esters can be utilized in this protocol (Table
1). It has been observed that better yields are obtained with sub-
strates having electron-withdrawing groups. In the case of ortho-
substituted aldehydes the yields are slightly lower (probably due
to steric hindrance) than para-substituted ones. A possible expla-
nation for the better yield in solvent-free conditions is that the eu-
tectic mixture having uniform distribution of the reactants brings
the reacting species in close proximity to react than in solvent. It
may be considered that the environment of the reaction system
without solvent is different from that in the solutions, resulting
in a higher concentration of local reaction sites, and improving
the global efficiency.
p-OH
o-OMe
p-OMe
p-CH3
2,4-Cl2
o-Cl
o-NO2
m-NO2
H
p-NO2
p-Cl
p- CH3
12
15
a
Isolated yield.
In conclusion, we have developed a facile and efficient one-pot,
four-component synthesis of 1H-indeno[1,2-b]-pyridines under
solvent- and catalyst-free conditions at room temperature in high
yields. The key step in our synthetic sequence is the intramolecular
condensation with participation of the amino function and one of
the indanedione carbonyl group in the acyclic intermediate result-
ing in ring closure to form the 1H-indeno[1,2-b]pyridines. The
milder conditions, shorter reaction times, low costs, easy work-
up and high yields make this process attractive over the other
available methods.
Acknowledgement
S.S. and G.C.N. are thankful to the Council for Scientific and
Industrial Research (CSIR), New Delhi, for financial assistance in
the form of Senior Research Fellowship.

7098
S. Samai et al. / Tetrahedron Letters 50 (2009) 7096–7098
12. (a) Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134; (b) Hatamjafari, F.
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a typical reaction procedure 1,3-indanedione (1.0 mmol), aldehyde
(1.0 mmol), ethyl acetoacetate or methyl acetoacetate (1.0 mmol) and
ammonium acetate (1.5 mmol) were thoroughly mixed in a mortar followed
by grinding till the completion of reaction (monitored by TLC). The resultant
solid material was washed thoroughly with water to remove any unreacted
ammonium acetate and was air-dried overnight, which was purified by silica
gel column chromatography using ethyl acetate and n-hexane as eluent.
2-Methyl-4-(4-nitrophenyl)-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]pyridine-3-car-
boxylic acid ethyl ester (1b): mp 216–217 °C; FT-IR (KBr, cmÀ1): 3294, 1702,
1653, 1599; 1H NMR (300 MHz, CDCl3): d 8.13 (d, J = 8.7 Hz, 2H), 7.52 (d,
J = 6.9 Hz, 2H), 7.39–7.29 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 7.2 Hz,
1H), 6.52 (s, 1H, NH, D2O exchangeable), 5.13 (s, 1H), 4.07 (q, J = 7.5 Hz, 2H),
2.57 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 191.8, 166.7,
153.1, 152.9, 146.5, 144.6, 135.6, 133.5, 131.5, 130.5, 128.7, 123.6, 121.7, 117.2,
109.3, 106.8, 60.3, 37.7, 20.0, 14.0; ESI MS (m/z): 390.12 (M++1). Anal. Calcd for
C22H18N2O5: C, 67.69; H, 4.65; N, 7.18. Found: C, 67.58; H, 4.53; N, 7.32.
4-(4-Chlorophenyl)-2-methyl-5-oxo-4,5-dihydro-1H-indeno-[1,2-b]pyridine-3-car-
boxylic acid methyl ester (1n): mp 228–229 °C; FT-IR (KBr, cmÀ1): 3275, 1707,
1639; 1H NMR (300 MHz, DMSO-d6): d 10.22 (s, 1H, NH, D2O exchangeable), 7.59–
7.20 (m, 8H), 4.78 (s, 1H), 3.15 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d
190.8, 167.1, 153.8, 145.5, 145.3, 136.0, 133.3, 131.7, 130.7, 130.1, 129.3, 128.1,
120.5,119.3,108.1,105.7,50.9,36.5,18.6;ESIMS(m/z):366.16(M++1).Anal. Calcd
for C21H16NO3Cl: C, 68.95; H, 4.41; N, 3.83. Found: C, 68.90; H, 4.38; N, 3.72.
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