Contemporary development in sequential Knoevenagel, Michael addition multicomponent reaction for the synthesis of 4-Aryl-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile

Article abstract of DOI:10.1007/s11164-015-2187-y

An uncatalyzed efficient synthesis of bioactive pyridine derivatives has been investigated for the first time by a three-component sequential multicomponent reaction tackled with aromatic aldehydes, malononitrile, and 1,3-indandione via Knoevenagel condensation followed by Michael addition. The difference between the domino multicomponent and sequential multicomponent reaction is emphasized by this methodology. The reaction proceeds at ambient temperature without frequently useful N-source like ammonium salt for the construction of N-heterocycles, which makes this protocol a novel synthetic route for the preparation of the indenopyridine skeleton.

Full text of DOI:10.1007/s11164-015-2187-y

Res Chem Intermed
DOI 10.1007/s11164-015-2187-y
Contemporary development in sequential Knoevenagel,
Michael addition multicomponent reaction
for the synthesis of 4-Aryl-5-oxo-5H-indeno
[1,2-b]pyridine-3-carbonitrile
Ajinkya A. Patravale1 Anil H. Gore1
•
•
Dipti R. Patil1 Govind B. Kolekar1 Madhukar B. Deshmukh1
Prafulla B. Choudhari2 Manish S. Bhatia2
•
•
•
•
•
Prashant V. Anbhule1
Received: 19 March 2015 / Accepted: 17 July 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract An uncatalyzed efficient synthesis of bioactive pyridine derivatives has
been investigated for the first time by a three-component sequential multicomponent
reaction tackled with aromatic aldehydes, malononitrile, and 1,3-indandione via
Knoevenagel condensation followed by Michael addition. The difference between the
domino multicomponent and sequential multicomponent reaction is emphasized by
this methodology. The reaction proceeds at ambient temperature without frequently
useful N-source like ammonium salt for the construction of N-heterocycles, which
makes this protocol a novel synthetic route for the preparation of the indenopyridine
skeleton.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2187-
y) contains supplementary material, which is available to authorized users.
&
Prashant V. Anbhule
pvanbhule@gmail.com
1
2
Medicinal Chemistry Research Lab, Department of Chemistry, Shivaji University,
Kolhapur 416004, MS, India
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy,
Kolhapur 416013, MS, India
123

A. A. Patravale et al.
Graphical Abstract
Keywords Sequential multicomponent reaction Á Indenopyridine Á Domino
Knoevenagel–Michael addition
Introduction
In the current literature of synthetic chemistry, multicomponent reactions (MCRs)
gained an impressive position in the synthesis of a variety of organic compounds [1–
3]. The MCRs involve one-pot transformations and formation of new C–C or C–
hetero atom bonds, which are the structural backbone of heterocyclic molecules [4–
6]. It is noteworthy to mention that MCRs enhance molecular diversity and
complexity, reducing the reaction steps and time [7, 8]. Considering the recent
organic synthesis, MCRs are the major driving forces in the development of
chemistry, which helps to enhance our chemical knowledge and addressing the
several scientific parameters [9–11]. Literature revels that the domino, sequential,
and consecutive are the major three classes of multicomponent reactions (Fig. 1)
that are involved in synthesis of N-heterocyclic compounds [12–14].
Fig. 1 Types of multicomponent reaction
123

Contemporary development in sequential Knoevenagel…
The N-heterocycles, possessing the pyridine skeleton, are endowed with stringent
activities like antihistaminic [15–17], antioxidant [18], antitubercular [19, 20],
antiviral [21], Ca2? channel blocking [22–26], etc. Cerivastatin, an example of the
pyridine derivatives, is a well-known HMG-CoA reductase inhibitor [27, 28].
Among this class, indenopyridine, containing natural alkaloids (Fig. 2) such as
onychine (A), polyfothine (B), isoursuline (C), and cyathocaline (D), has great
privilege in medicinal chemistry [29–34].
Thus, inspired by these fascinating aspects and in continuation of our efforts [35–
39] to prepare vital heterocyclic molecules, herewith we put forth a highly
proficient, less toxic method by utilizing a 1,3-dicarbonyl compound in multicom-
ponent pattern.
From a historical standpoint, the synthesis of the pyridine motif has been
productively applied by Hantzsch in 1882 [40–42]. Recently, 1,3-dicarbonyl
compounds are most extensively used for the synthesis of bioactive molecules [43–
45]. It has been demonstrated that Knoevenagel [46–48] and Michael addition [49–
52] reactions are involved in the synthesis of bioactive pyridine nucleus [49–56]. A
number of homogeneous as well as heterogeneous catalysts [57–68] have been
employed for the preparation of pyridines, dihydropyridines, and its analogs in
diverse methods, e.g. acid [69, 70], base [71, 72], microwave synthesis [58], ionic
liquid [73, 74], etc., are cited in literature, but they have their own merits and
demerits. It has been evidenced that in most of the cases, the synthesis of the
N-containing skeleton is carried out by using ammonium salts as an N-source, but in
the absence of an ammonium salt, aromatic aldehyde, malononitrile, and 1,3-
diketone react to give a pyran derivative [75–77]. There are similar reactions
O
O
MeO
N
N
MeO
A = Onychine
B = Polyfothine
O
O
HO
MeO
N
N
MeO
OH
OH
C = Isoursuline
D = Cyathocaline
Fig. 2 Indenopyridine alkaloids A–D
123

A. A. Patravale et al.
observed in the literature [78–80] with its own merits and demerits. Hence, to outwit
these mentioned demerits of the previous reports herein, we successfully demon-
strate a novel method by engaging the intramolecular carbonitrile N-atom as the N-
source for the selective synthesis of the indenopyridine skeleton altering the
reported formation of indenopyran derivatives.
The aim of the present work is the synthesis of indenopyridine derivatives at
ambient temperature through a simple one-pot reaction of an aromatic aldehyde,
malononitrile, and 1,3-indandione (Scheme 1).
Results and discussion
Initially, 3-nitro benzaldehyde (1, 3 mmol) and malononitrile (2, 3 mmol) in 10 ml
of DMF were taken in a round-bottom flask as model reaction. The mixture was
stirred at room temperature until completion of the Knoevenagel condensation [46–
48], monitored by TLC. After formation of (3-nitrobenzylidene)propanedinitrile (5
Scheme 3), 1,3-indandione (3, 3 mmol) was added to the mixture maintaining the
sequence of the reaction as (1 ? 2 ? 3). The progress of the reaction was
monitored by TLC. After completion, the mixture was treated with cold water to
isolate the pure product 4a, which was obtained in excellent purity and there was no
need of further purification (Table 1, Entry 4a). The structure of the obtained
product was confirmed on the basis of the spectroscopic data.
Solvent effect on multicomponent reaction
To study the effect of solvent on the said multicomponent reaction, the same
reaction was carried out in a variety of solvents as discussed in Table 2, in case of
solvent reaction was monitored up to 6 h. It has been observed that polar protic
solvents without catalyst reaction proceed up to Knoevenagel condensation while in
polar aprotic solvents like acetonitrile, dioxane DMF, formamide, and DMSO
reaction give the desired product with a variable yield, as shown in Table 2.
O2N
O
O
O
CN
O
DMF / r.t
H
NC
+
+
or
1+3+2
1+2+3
CN
N
NO2
1
2
3
4a
Scheme 1 Synthesis of 4-(3,nitrophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4)
123

Contemporary development in sequential Knoevenagel…
Table 1 Synthesis of indenopyridine and indenopyran nucleolus and its derivatives
Entry
1
Aldehyde
O
Product
Time (h)
3
Yield
(%)
M.P. (°C)
244
4a*
86
85
88
H
O N
2
NO
2
O
NC
N
O
2
4b†
3
244
H
O N
2
NO
2
O
NC
N
O
3
6a‡
5
234
H
N
N
O
O
NC
H2N
*
4c
4
3.5
90
196
Cl
N
O
H
Cl
NC
O
Cl
Cl
O
5
4d*
3.5
90
165
H
Br
N
Br
O
NC
123

A. A. Patravale et al.
Table 1 continued
Entry
6
Aldehyde
O
Product
Time (h)
Yield
(%)
M.P. (°C)
125
H
4e*
3
85
O
NC
N
O
7
4f*
3.5
93
150
H
N
N
O
NC
N
O
8
4g*
3
90
198
H
CN
NC
O
NC
N
O
9
4h*
3
94
198
O
O
H
O
O
O
NC
N
123

Contemporary development in sequential Knoevenagel…
Table 1 continued
Entry
Aldehyde
Product
Time (h)
Yield
(%)
M.P. (°C)
222
O
10
4i*
3.5
93
H
OH
HO
H CO
3
OCH
3
O
NC
N
11
H
O
4j*
3
92
184
S
S
O
NC
N
O
12
4k*
4
95
158
H
OCH
H CO
3
3
O
NC
N
O
13
4l*
4
94
214
H
OCH3
H3CO
H3CO
NC
OCH
3
O
N
123

A. A. Patravale et al.
Table 1 continued
Entry
14
Aldehyde
Product
Time (h)
3.5
Yield
(%)
M.P. (°C)
228
O
4m*
96
H3CO
H3CO
H
OCH3
OCH3
H3CO
NC
OCH
3
O
N
O
15
4n*
4
92
208
H3CO
H
OH
HO
H CO
OCH
O
OCH
3
3
3
NC
N
16
No reaction
24
–
–
O
H
* Sequential addition: 3-nitro aldehyde 1 ? malononitrile 2 ? 1,3-indandione 3
Sequential addition: 3-nitro aldehyde 1 ? 1,3-indandione 3 ? malononitrile 2
à
Domino addition: All components are initially added (N,N dimethyl benzaldehyde 1, malononitrile 2,
1,3-indandione 3)
Table 2 Effect of solvent in multicomponent synthesis of indenopyridine derivatives (4a)
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Water
6
6
6
6
6
6
6
6
Knoevenagel
Ethanol
Acetonitrile
Dioxane
DMF
Knoevenagel
27
31
86
Formamide
DMSO
42
38
Toluene
Knoevenagel
Sequence-selective study of multicomponent reaction
The unexpected formation of the pyridine skeleton raised many questions about the
formation of pyran derivatives. As a number of analogous methods have been
123

Contemporary development in sequential Knoevenagel…
N
O
O
O
O
O
CN
CN
DMF / r.t
3.5h
H
NC
+
+
N
H2N
6a (88%)
3
2
1
Scheme 2 Synthesis of 2-amino-4-[4-(dimethylamino)phenyl]-5-oxo-4,5-dihydroindeno[1,2-b]pyran-3-
carbonitrile 6a [Domino process]
mentioned for the formation of pyran derivatives [75–77], we focused our efforts on
the sequential studies consisting of the alteration in the addition sequence of the
reactants. We tried the same reaction in an alternating way, e.g. 3-nitro
benzaldehyde (1, 3 mmol) reacts with 1,3-indandione (3, 3 mmol) in a Knoevenagel
condensation monitored by TLC, and then the malononitrile was added (2, 3 mmol).
Astonishingly, we obtained again the corresponding pyridine derivative 4a (Table 1,
entry 4n) instead of the expected pyran.
However, a literature study [75–77] reveals that the one-pot domino reaction
between aromatic aldehyde, malononitrile, and 1,3-dicarbonyl compounds like
cyclohexane-1,3-dione [75] or dimedone [76, 77] exclusively give the correspond-
ing pyran. Thus, we performed a one-pot domino reaction (Scheme 2) between
4-(dimethylamino)benzaldehyde (1), malononitrile (2), and 1,3-indandione (3) in
which, as expected, we obtained the pyran 2-amino-4-[4-(dimethylamino)phenyl]-5-
oxo-4,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (6a), which confirmed by the
spectroscopic techniques.
Hence, the selective formation of pyridine or pyran derivatives is based on the
sequential or domino reaction pathways, respectively. Thus, the addition sequence
of substrates plays a key role in this reaction for the synthesis of N- or O-containing
derivatives. Again, to check the scope and synthetic efficiency, the method was
further screened with a variety of aromatic aldehydes. Regardless of their functional
groups, products 4a were obtained in good yields favoring our protocol. However,
the method was not suitable for aliphatic aldehydes as the reaction failed to give any
N- or O-containing derivatives.
Mechanism
The formation of products 4a may be explained on the basis of the mechanism as
shown in Scheme 3. Initially, aryl aldehyde (1) and malononitrile (2) undergo a
Knoevenagel condensation to form a Knoevenagel adduct (3-nitrobenzylidene)
propanedinitrile (5), which acts as a Michael acceptor in the addition of the enol
form of 1,3-indandione (3) to form an intermediate (7). Further, the intermediates
(7) on rearrangements to give keto imine derivatives (8) which tautomerize to
123

A. A. Patravale et al.
..
O2N
HO
O
O
H
CN
CN
2
CN
CN
H
3
Knovenagel
condensation
O
C
+
Michael addition
O
N
HN
NO2
NO2
1
7
5
O2N
O2N
O2N
O
O
CN
H
O
CN
NC
CH
-H2O
CH
O
OH
:
H
N
HN
N
9
8
4a
Scheme 3 Mechanistic pathway of the reaction
reactive species enol imine derivatives (9). Finally, the reactive enol imine
derivative undergoes intramolecular cyclization to afford a respective pyridine
derivative (4a).
Conclusions
In conclusion, we have successfully established a novel synthesis of indeno[1,2-
b]pyridine-3-carbonitrile derivatives at ambient temperature via sequential multi-
component reaction avoiding the usual necessity of an external N-source. This
methodology is bestowed with the significance of sequential addition of substrates,
convenient work-up procedure, and compatibility of the protocol on a large scale.
Spectroscopic data of the synthesized compounds
4-(3-Nitrophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4a)
Addition sequence
3-Nitro aldehyde 1 ? malononitrile 2 ? 1,3-indandione 3 yellow solid, Yield:
0.84 mg (86 %). M. P. 244 °C IR (KBr) (Vmax, Cm-1): 1347, 1516 (NO2), 1603,
1
1673 (Ar), 1695 (CO), 2195 (CN). H-NMR (CDCl3 300 MHz): d 7.70–7.76 (m,
123

Contemporary development in sequential Knoevenagel…
1H, Ar–H), 7.87–7.91 (m, 3H, Ar–H), 8.07–8.11 (m, 3H, Ar–H), 8.39–8.40 (d,
J = 6.0, 1H, Ar–H), 8.68–8.70 (d, J = 6.0, 1H, Ar–H). 13C-NMR (CDCl3
75 MHz): d 123.40, 123.62, 123.70, 123.74, 123.79, 130.04, 132.25, 134.26,
135.92, 136.02, 138.43, 140.29, 141.17, 142.63, 142.67, 197.60. HRMS
(M ? H) ? 328.0723 Anal. calc. for C19H9N3O3 (327.29): C 69.72, H 2.77, N
12.84 found: C 69.65, H 2.70, N 12.80.
4-(3-Nitrophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4b)
Addition sequence
3-Nitro aldehyde 1 ? 1,3-indandione 3 ? malononitrile 2, Yield: 0.82 mg (85 %).
M. P. 244 °C IR (KBr) (Vmax, Cm-1): 1312, 1507 (NO2) 1649 (Ar), 1702(CO), 2232
1
(CN). H-NMR (CDCl3 300 MHz): d 7.69–7.73 (m, 1H, Ar–H), 7.87–7.91 (m, 3H,
Ar–H), 8.08–8.12 (m, 3H, Ar–H), 8.38–8.40 (m, 1H, Ar–H), 8.66–8.68 (d, J = 6.0,
1H, Ar–H). 13C-NMR (CDCl3 75 MHz): d 123.39, 123.68, 123.81, 126.75, 127.98,
134.26, 129.75, 131.62, 134.25, 135.82, 135.95, 138.92, 140.26, 142.58, 143.02,
148.43, 188.59. Anal. calc. for C19H9N3O3 (327.29): calculated: C 69.72, H 02.77,
N 12.84 found: C 69.43, H 02.61, N 12.60.
2-Amino-4-[4-(dimethylamino)phenyl]-5-oxo-4,5-dihydroindeno[1,2-
b]pyran-3-carbonitrile (6a)
Domino addition
All components are initially added (N,N dimethyl benzaldehyde 1, malononitrile 2,
1,3-indandione 3). Yellow solid, Yield: .89 mg (88 %). M. P. 234° IR (KBr) (Vmax
,
Cm-1): 1556, 1659 (Ar), 1713 (CO), 2209 (CN). 1H-NMR (CDCl3 300 MHz): 3.16
(s, 6H, –NCH3), 4.18 (s, 1H, –CH), 6.74–6.76 (d, J = 8.4 Hz, 2H, Ar–H), 7.74
(br.s, 2H, –NH2) 7.79 (s, 1H, Ar–H), 7.92–7.98 (m, 3H, Ar–H), 8.53–8.56 (d,
J = 8.4 Hz, 2H, Ar–H). 13C-NMR (CDCl3 75 MHz): 40.05, 43.40, 111.37, 121.96,
122.44, 123.36, 123.43, 125.81, 131.70, 134.07, 134.35, 135.29, 137.97, 141.21,
141.61, 142.19, 147.43, 153.91, 155.27, 158.04, 189.90. Anal. Calc. for
C21H17N3O2 (343.37): C 73.45, H 04.99, N 12.24 found: C 73.57, H 05.05, N 12.29.
4-(2,4-Dichlorophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4c)
Addition sequence
2,4-Dichlo aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid, Yield:
0.95 mg (90 %). M. P. 196 °C (decompose). IR (KBr) (Vmax, Cm-1): 733 (C–Cl),
1579, 1694 (Ar), 1730 (CO), 2203 (CN).1H-NMR (CDCl3 300 MHz): 7.39–7.42
(dd, J = 2.1 Hz, J = 10.5 Hz 1H, Ar–H), 7.53–7.54 (d, J = 2.1 Hz, 1H, Ar–H), 7.
85–7.89 (m, 2H, Ar–H), 8.00–8.07 (m, 2H, Ar–H) 8.26 (s, 1H, Ar–H), 8.74–8.77 (d,
J = 9.0 Hz, 1H, Ar–H). 13C-NMR (CDCl3 75 MHz): 123.55, 123.57, 127.14,
129.20, 129.78, 130.76, 134.51, 135.66, 135.70, 138.21, 139.00, 140.26, 140.47,
123

A. A. Patravale et al.
142.44, 188.55. Anal. calc. for C19H8ClN2O (351.18): C 64.98, H 2.30, N 7.98
found: C 65.04, H 2.23, N 7.90.
4-(4-Bromophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4d)
Addition sequence
4-Bromo aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid, Yield:
0.98 mg (90 %). M. P 165° C IR (KBr) (Vmax, Cm-1): 735 (C–Br), 1613, 1687 (Ar),
1764 (CO), 2199 (CN).1H-NMR (CDCl3 300 MHz): 7.65–7.68 (d, J = 8.7 Hz, 2H,
Ar–H), 7.81–7.86 (m, 3H, Ar–H), 8.02–8.04 (m, 2H, Ar–H), 8.35–8.38 (d,
J = 8.4 Hz, 2H, Ar–H). 13C-NMR (CDCl3 75 MHz): 110.49, 115.62, 123.01,
123.06, 126.46, 127.03, 131.23, 134.58, 134.72, 140.03, 142.50, 147.30, 148.95,
153.95, 190.11. Anal calc for C19H9BrN2O (361.19) : C 63.18, H 2.51, N 7.76
found: C 63.30, H 2.58, N 7.88.
4-(Anthracen-9-yl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4e)
Addition sequence
Anthracen-9-aldehyde ? malononitrile 2 ? 1,3-indandione 3, Brown solid, Yield:
0.95 mg (85 %). M. P. 125° C IR (KBr) (Vmax, Cm-1): 1250, 1567, 1686 (Ar), 1718
(CO), 2230 (CN). 1H-NMR (CDCl3 300 MHz): 7.53–7.58 (m, 2H, Ar–H), 7.67–7.70
(m, 2H, Ar–H), 7.71–7.88 (m, 3H, Ar–H), 7.95–8.05 (m, 2H, Ar–H), 8.08 (s, 1H,
Ar–H), 8.70 (s, 1H, Ar–H) 8.99–9.02 (dd, J = 0.6 Hz, J = 9.6 Hz, 2H, Ar–H),
9.68–9.70 (d, J = 7.8 Hz, 1H, Ar–H). 13C-NMR (CDCl3 75 MHz): 123.38, 123.62,
125.61, 128.97, 129.17, 131.04, 132.06, 134.96, 135.07, 192.38. Anal. calc. for
C27H14N2O (382.41): C 84.80, H 3.69, N 7.33 found: C 84.76, H 3.64, N 7.32.
4-[4-(Dimethylamino)phenyl]-5-oxo-5H-indeno[1,2-b]pyridine-3-
carbonitrile (4f)
Addition sequence
N,N-Dimethyl aldehyde ? malononitrile 2 ? 1,3-indandione 3, Red solid; Yield:
0.90 mg (93 %). M. P. 150° C (decompose) IR (KBr) (Vmax, Cm-1): 1517, 1667
(Ar), 1767 (CO), 2211 (CN). H-NMR (CDCl3 300 MHz): 3.15 (s, 6H, –NMe),
1
6.73–6.75 (d, J = 6.6 Hz, 2H, Ar–H), 7.71–7.73 (m, 2H, Ar–H), 7.79 (s, 1H, Ar–H)
7.92 (s, 2H, Ar–H) 8.52–8.55 (d, J = 6.6 Hz, 2H, Ar–H). 13C-NMR (CDCl3
75 MHz): 39.94, 111.28, 121.90, 122.35, 122.86, 133.98, 134.26, 137.89, 139.77,
142.13, 147.36, 153.83, 191.60. Anal. calc. for C21H15N3O (325.36):C 77.52, H
4.65, N 12.91 found: C 77.45, H 4.54, N 12.80.
123

Contemporary development in sequential Knoevenagel…
4-(4-Cyanophenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4 g)
Addition sequence
4-Cyno aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid; Yield:
0.83 mg (90 %). M. P 198 °C (decompose) IR (KBr) (Vmax, Cm-1): 1375, 1674
(Ar), 1693 (CO), 2195 (CN), 2234 (CN). H-NMR (CDCl3 300 MHz): 7.80–7.91
1
(m, 5H, Ar–H), 8.05–8.08 (m, 2H, Ar–H), 8.51–8.54 (d, J = 8.4 Hz, 2H, Ar–
H).13C-NMR (CDCl3 75 MHz): 115.46, 123.69, 123.74, 128.72, 132.21, 132.64,
133.74, 135.66, 135.76, 143.24, 188.89. Anal. calc for C20H9N3O (307.30) C 78.17,
H 2.95, N 13.67 found: C 78.30, H 3.02, N 13.80.
4-(1,3-Benzodioxol-5-yl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile
(4 h)
Addition sequence
1,3-benzodioxole-5-carbaldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow
solid, Yield: 0.91 mg (93 %). M. P. 198° C (decompose) IR (KBr) (Vmax, Cm-1):
1578, 1690 (Ar), 1720 (CO), 2223 (CN), 1H-NMR (CDCl3 300 MHz): 6.12 (s, 2H, -
CH2), 6.93–6.96 (d, J = 8.1 Hz, 1H, Ar–H), 7.81–7.82 (s, 4H, Ar–H), 7.98–8.02 (m,
2H, Ar–H), 8.54 (s, 1H, Ar–H). 13C-NMR (CDCl3 75 MHz): 102.15, 108.60,
112.82, 123.10, 123.14, 126.81, 128.12, 132.97, 133.26, 134.93, 135.15, 139.92,
142.40, 146.95, 148.21, 152.50, 158.71, 190.63. HRMS (M ? H) ? 327.1296 Anal.
calc. for C20H10N2O3 (326.30): C 73.62, H 3.09, N 8.59 found: C 73.68, H 3.15, N
8.70.
4-(4-Hydroxy-3-methoxyphenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-
carbonitrile (4i)
Addition sequence
4-Hydroxy-3-methoxy aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow
solid, Yield: 0.92 mg (92 %). M. P. 222° C IR (KBr) (Vmax, Cm-1): 1565, 1672
(Ar), 1714 (CO), 2166 (CN), 3500 (OH), 1H-NMR (CDCl3 300 MHz): 4.14 (s, 3H,
–MeO), 6.29 (s, 1H, Ar–H), 7.00–7.03 (d, J = 8.4 Hz, 1H, Ar–H), 7.61–7.64 (dd,
J = 1.8 Hz, J = 10.2 Hz 1H, Ar–H), 7.79–7.83 (m, 3H, Ar–H), 7.98–8.01 (m, 2H,
Ar–H), 9.02 (s, 1H, –OH). 13C-NMR (CDCl3 75 MHz): 55.86, 110.63, 110.93,
113.25, 113.97, 114.58, 115.17, 122.95, 123.07, 124.35, 127.93, 132.21, 133.67,
134.62, 147.60, 149.70, 154.80, 158.43. 188.82. Anal. calc. for C20H12N2O3
(328.32): C 73.16, H 03.68, N 8.53 found: C 73.16, H 3.65, N 8.60.
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A. A. Patravale et al.
5-Oxo-4-(thiophen-2-yl)-5H-indeno[1,2-b]pyridine-3-carbonitrile (4j)
Addition sequence
Thiophen-2-aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid; Yield:
0.79 mg (92 %). M. P 184° C IR (KBr) (Vmax, Cm-1): 1584, 1683 (Ar), 1723 (CO),
2322 (CN). H-NMR (CDCl3 300 MHz): 7.24–7.28 (m, 1H, Ar–H), 7.79–7.83 (m,
1
2H, Ar–H), 7.86–7.89 (m, 1H, Ar–H), 7.96–8.03 (m, 3H, Ar–H) 8.09 -8.11 (dd,
J = 0.6 Hz, J = 4.2 Hz, 1H, Ar–H). 13C-NMR (CDCl3 75 MHz): 123.03, 123.14,
124.97, 128.46, 134.63, 134.84, 135.95, 137.61, 137.78, 140.52, 141.17, 142.22,
189.59. Anal. calc. for C17H8N2OS (288.32): C 70.82, H 2.80, N 9.72 found: C
70.75, H 2.80, N 9.63.
4-(4-Methoxyphenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4 k)
Addition sequence
4-Methoxy aldehyde ? malononitrile 2 ? 1,3-indandione 3, Light yellow solid,
Yield: 0.8 mg (95 %). M. P 158° C IR (KBr) (Vmax, Cm-1): 1580, 1683 (Ar), 1718
(CO), 2154 (CN). 1H-NMR (CDCl3 300 MHz): 3.93 (s, 3H, -MeO), 6.99–7.04 (dd,
J = 3.0 Hz, J = 14.7 Hz, 2H, Ar–H), 7.78–7.83 (m, 3H, Ar–H), 7.97–8.01 (m, 2H,
Ar–H), 8.53–8.58 (dd, J = 2.7 Hz, J = 14.4 Hz, 2H, Ar–H). 13C-NMR (CDCl3
75 MHz): 55.31, 114.26, 123.03, 123.06, 126.56, 126.60, 134.51, 134.70, 137.16,
140.05, 142.48, 146.60, 163.88, 190.13 Anal. calc. for C20H12N2O2 (312.32): C
76.91, H 3.87, N 8.97; found: C 76.99, H 3.91, N 8.92.
4-(3,4-Dimethoxyphenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile (4 l)
Addition sequence
3,4-Dimethoxy aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid,
Yield: 0.96 mg (94 %). M. P 214 °C (decompose). IR (KBr) (Vmax, Cm-1): 1564,
1673 (Ar), 1712 (CO), 2220 (CN).1H-NMR (CDCl3 300 MHz): 3.97 (s, 3H, –MeO),
4.07 (s, 3H, –MeO); 6.90–6.93 (d, J = 8.4 Hz, 1H, Ar–H), 7.66–7.69 (dd,
J = 1.8 Hz, J = 9.9 Hz, 1H, Ar–H), 7.76–7.78 (t, J = 4.8 Hz 3H, Ar–H),
7.94–7.97 (m, 2H, Ar–H), 8.85 (s, 1H, Ar–H). 13C-NMR (CDCl3 75 MHz) :
55.82, 55.93, 110.47, 115.60, 123.01, 123.07, 126.45, 127.03, 131.24, 134.58,
134.72, 140.03, 142.50, 147.31, 148.94, 153.95, 190.10. Anal. calc. for C21H14N2O3
(342.34): C 73.6, H 04.12, N 08.18; found: C 73.72, H 04.05, N 08.20.
5-Oxo-4-(3,4,5-trimethoxyphenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile (4 m)
Addition sequence
3,4,5-Triimethoxy aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow solid,
Yield: 1.06 mg (96 %). M. P. 228° C (decompose) IR (KBr) (Vmax, Cm-1): 1678
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Contemporary development in sequential Knoevenagel…
1
(Ar), 1715 (CO), H NMR (CDCl3 300 MHz): 4.0 (s, 3H, –MeO), 4.02 (s, 6H, –
MeO), 7.81–7.84 (m, 3H, Ar–H), 7.98–8.02 (m, 4H, Ar–H), 13C-NMR (CDCl3
75 MHz): 56.34, 61.10, 112.07, 123.16, 123.20, 127.80, 128.51, 135.10, 135.46,
139.93, 140.02, 142.52, 143.17, 147.39, 152.87, 190.46 Anal. calc. for C22H16N2O4
(372.37) : C 70.96, H 4.33, N 7.52 found: C 70.77, H 4.05, N 7.32.
4-(4-Hydroxy-3,5-dimethoxyphenyl)-5-oxo-5H-indeno[1,2-b]pyridine-3-
carbonitrile (4n)
Addition sequence
3,5-Dimethoxy-4-hydroxy aldehyde ? malononitrile 2 ? 1,3-indandione 3, Yellow
solid, Yield: .98 mg (92 %) M. P. 208 °C (decompose) IR (KBr) (Vmax, Cm-1):
1673, (Ar), 1695 (CO), 2195 (CN), 3364 (OH) 1H-NMR (CDCl3 300 MHz): 4.06 (s,
6H, –MeO), 6.28 (s, 1H, –OH), 7.80 (s, 3H, Ar–H), 7.99–8.32 (m, 4H, Ar–H) 13C-
NMR (CDCl3 75 MHz): 56.52, 112.07, 123.00, 123.11, 125.28, 125.53, 126.58,
134.94, 135.13, 139.86, 140.62, 141.05, 142.41, 146.85, 147.93, 190.62 Anal. calc.
for C21H14N2O4 (358.34): C 70.39, H 3.94, N 7.82 found: C 70.17, H 4.10, N 7.96.
Acknowledgments The author PVA gratefully acknowledges UGC New Delhi for a major research
project and [F. No.39 -786/2010(SR)]. Author AAP acknowledges DST-PURSE for a fellowship.
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