Building libraries of skeletally diverse scaffolds from novel heterocyclic active methylene compound through multi-component reactions

Article abstract of DOI:10.1016/j.tetlet.2012.04.013

Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,9-dimethyl-5-oxo-4-aryl-4,5,6,7- tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 2′-amino-7′,9′-dimethyl-2,5′-dioxo-6′, 7′-dihydro-5′H-spiro[indoline-3,4′-pyrano[2,3-d]pyrazolo[3, 4-b]pyridine]-3′-carbonitrile, and 5,5′-(arylmethylene)bis(4- hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have been synthesized through a multi-component reaction using novel heterocyclic active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.

Full text of DOI:10.1016/j.tetlet.2012.04.013

Tetrahedron Letters 53 (2012) 3044–3048
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Building libraries of skeletally diverse scaffolds from novel heterocyclic
active methylene compound through multi-component reactions
⇑
Ramasamy Jayarajan, Gnanasambandam Vasuki
Department of Chemistry, Pondicherry University, Puducherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 February 2012
Revised 3 April 2012
Accepted 4 April 2012
Available online 12 April 2012
Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,
9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 20-amino-
70,90-dimethyl-2,50-dioxo-60,70-dihydro-50H-spiro[indoline-3,40-pyrano[2,3-d]pyrazolo[3,4-b]pyridine]-30-car-
bonitrile, and 5,50-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have
been synthesized through a multi-component reaction using novel heterocyclic active methylene compound
4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol
can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Novel heterocyclic active methylene
compound
Diversity oriented synthesis
Multi-component reaction
Polycyclic heterocycles
Spiro heterocyclic scaffold
Diversity oriented synthesis (DOS),1 which aims at building
skeletally diverse scaffolds using readily available building blocks
is emerging as an important area of research in synthetic organic
chemistry to address the challenge posed by chemical genetics.2
In general, creating skeletal diversity through a multi-step reaction
involving up to five steps is accepted as a DOS protocol.3 Achieving
DOS through multi-component reactions (MCRs)4 is visualized as
an efficient and eco-friendly strategy. One of the important strate-
gies adopted in DOS is Build/Couple/Pair (BCP) strategy.3,5 MCR is
being used in couple phase6 of BCP to build a poly functional sub-
strate which is further manipulated to create skeletally diverse
scaffolds. But, creating skeletal diversity in the couple phase itself
can be considered as an innovation in achieving DOS. Our research
group is actively engaged in developing multi-component reaction
protocols for building libraries of skeletally diverse heterocyclic
scaffolds.7 Pyrazolopyridine scaffold is present in several inhibitors
viz., CDK1,8 protein kinases,9 human immunodeficiency virus (HIV)
reverse transcriptase,10 and cGMP degradation inhibitors,11 and
CCR1 antagonist.12 In addition this scaffold is reported to possess
herbicidal and fungicidal activities.11 Moreover, pyran skeleton is
another important core in a number of natural products13 and pho-
tochromic materials.14 Therefore a polycyclic heterocyclic scaffold
possessing both these skeletons can be an important scaffold to
explore biological pathways. Moreover, developing a spirocyclic
scaffold with pyrazolopyridine core is expected to improve the
biological properties shown by oxindole moiety.15
Designing novel building blocks which can be used in MCR to
achieve skeletal diversity is a challenging task. Active methylene
compounds are very important building blocks used in several
MCRs.16 Diverse and complex polycyclic heterocyclic scaffolds can
be accessed in one step through MCR by employing heterocyclic
compounds possessing an active methylene unit as a part of the ring.
4-Hydroxyquinolin-2(1H)-one17 and 4-hydroxy-2H-chromen-2-
one18 are a few such scaffolds used in several MCRs. Design and syn-
thesis of novel heterocyclic active methylene compounds and their
use in MCR to achieve skeletal diversity might significantly contrib-
ute in populating the chemical space. We herein report an
eco-friendly reaction protocol for the synthesis of novel heterocyclic
active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazol-
o[3,4-b]pyridine-6(7H)-one 3a, and demonstrated its use in MCR
for creating diverse heterocyclic scaffold libraries viz., 2-amino-
7,9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo
[3,4-b]pyridine-3-carbonitrile 6a–6q, 20-amino-70,90-dimethyl-2,
50-dioxo-60,70-dihydro-50H-spiro[indoline-3,40-pyrano[2,4-d]pyraz-
olo[3,4-b]pyridine]-30-carbonitrile 8a–8g, and 5,50-(aryl methy-
lene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6
(7H)-one) 9a–9f.
A solvent free two component reaction between 1,3-dimethyl-
1H-pyrazol-5-amine 1 and diethyl malonate 2 resulted in two
scaffolds viz., 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-
6(7H)-one 3a and N1,N3-bis(1,3-dimethyl-1H-pyrazol-5-yl)malona-
mide 3b in the ratio of 71:19 (yield 90%). But the reaction did not
occur in ethanol under reflux condition (Scheme 1).
A three-component reaction with heterocyclic active methylene
compound 3a, 4-methylbenzaldehyde 5d, and malononitrile 4 was
⇑
Corresponding author. Tel.: +91 413 2656740; fax: +91 413 2655987.
E-mail address: vasukig@gmail.com (G. Vasuki).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.013

R. Jayarajan, G. Vasuki / Tetrahedron Letters 53 (2012) 3044–3048
3045
Table 2
OH
Solvent optimization for three-component synthesis of 6da
Entry
Solvent
Temp (°C)
Time
Yieldb (%)
N
3a
O
N
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
iPrOH
tBuOH
DCM
CHCl3
DMSO
DMF
30
Reflux
30
30
30
30
30
30
30
8 h
1 h
79
80
77
72
81
85
70
90
85
99
N
H
O
O
Solvent free
120-140 C, 8h
10 min
15 min
30 min
10 min
20 min
15 min
8 min
5 min
+
N
o
NH2
O
+
N
O
O
O
HN
N
NH
1
2
3b
N
Ethanol
Water
N
N
10
30
a
The reactions were performed with 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-
Scheme 1. Solvent-free synthesis of novel building block.
b]pyridine-6(7H)-one (2 mmol), 4-methyl benzaldehyde (2 mmol), malononitrile
(2 mmol), piperidine (10 mol %), and solvent (10 mL).
b
Yields of isolated products.
performed in water at room temperature using different acid and
base catalysts (Table 1).
The reaction time and yield of the product were significantly
influenced by the nature of the catalyst (Table 1, entries 1–11).
The reaction was catalyzed only by bases. Base might activate
the nucleophile. The reaction was found to occur very fast with
excellent yield (99%) when piperidine (10 mol %) was used as
catalyst (Table 1, entry 11). The product was characterized to be
2-amino-7,9-dimethyl-5-oxo-4-p-tolyl-4,5,6,7-tetrahydropyrano
[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile scaffold 6d.
The reaction was also performed in several organic solvents
using piperidine (10 mol %) as catalyst (Table 2, entries 1–10).
Good to excellent yield (70–99%) of the product 6d was ob-
tained in all the solvents, but the reaction occurred very fast in
water (Table 2, entry 10). Therefore the three-component reaction
was performed in water using piperidine (10 mol %) as catalyst
with several aromatic and heteroaromatic aldehydes 5a–5q (Table
3, entries 1–17). The crystal structure19 of compound 6k is shown
in Figure 1.
Use of isatin derivatives 7a–7g as carbonyl component in the
three-component reaction (reaction 1) resulted in 20-amino-70,90-
dimethyl-2,50-dioxo-60,70-dihydro-50H-spiro[indoline-3,40-pyrano
[2,3-d]pyrazolo[3,4-b]pyridine]-30-carbonitrile scaffold 8a–8g in
Figure 1. Crystal structure of compound 6k DMSO solvate (the solvent molecule is
disordered).
Table 1
Optimization of three-component reaction conditiona
NH2
H
CN
O
OH
O
5d
Catalyst
Water, r.t.,
N
+
N
N
N
H
O
N
N
H
O
NC
CN
3a
4
6d
Entry
Catalyst (mol %)
Time
Yield of 6db (%)
1
2
3
4
5
6
7
8
9
TsOH (10)
FeCl3 (10)
ZnCl2 (10)
12 h
12 h
12 h
12 h
60 min
60 min
60 min
60 min
60 min
60 min
5 min
Trace
Trace
Trace
50
70
58
66
52
69
68
K2CO3 (10)
NH4OAc (10)
Et3N (10)
Et2NH (10)
DBU (10)
L-Proline (10)
Imidazole (10)
Piperidine (10)
10
11
99
a
The reactions were carried out with 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one (2 mmol),
4-methyl benzaldehyde (2 mmol), malononitrile (2 mmol), and water (10 mL) at 30 °C.
b
Yields of isolated products.

3046
R. Jayarajan, G. Vasuki / Tetrahedron Letters 53 (2012) 3044–3048
Table 3
Three-component synthesis of 6a–6q catalyzed by piperidine (reaction 1)a
O
NH2
OH
CN
R
H
R
O
5a-5q
N
+
Piperidine (10 mol %)
Water, r.t., 5-30 min
N
N
N
H
O
N
N
H
O
NC
CN
3a
6a-6q
4
Entry
R
Time (min)
Product 6
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5 5a
5
5
5
5
5
5
5
5
10
10
10
20
20
30
30
15
15
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
95
98
97
99
86
85
80
97
95
84
98
75
82
60
65
90
82
20-MeO-C6H4 5b
40-MeO-C6H4 5c
40-Me-C6H4 5d
40-NO2-C6H4 5e
40-Cl-C6H4 5f
30-Br-C6H4 5g
40-F-C6H4 5h
40-OH-C6H4 5i
30, 40-(OH)2-C6H3 5j
30-MeO,40-OH-C6H3 5k
20,30-(MeO)2-C6H3 5l
30,40-(MeO)2-C6H3 5m
20,40,50-(MeO)3-C6H2 5n
30,40,50-(MeO)3-C6H2 5o
20-Thiophenyl 5p
20-Furanyl 5q
a
The reactions were carried out with 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one (2 mmol), aldehyde
(2 mmol), malononitrile (2 mmol), piperidine (10 mol %), and water (10 mL) at 30 °C.
b
Yields of isolated products.
Table 4
Three-component synthesis of spiro[pyranopyrazolopyridine-indoline]dionesa 8a–8g
NH2
O
CN
O
3a
4
O
+
O
Piperidine (10 mol %)
NR1
N
Water, r.t.,
10-30 min
R2
N
O
N
H
N
R2
R1
7a-7g
8a-8g
Entry
R1
R2
Time (min)
Product 8
Yieldb (%)
1
2
3
4
5
6
7
H
H 7a
10
10
20
15
30
10
10
8a
8b
8c
8d
8e
8f
80
94
98
92
88
93
91
Methyl
Benzyl
Allyl
Propargyl
H
H 7b
H 7c
H 7d
H 7e
7-F 7f
H
5-NO2 7g
8g
a
Reaction condition: 4-Hydroxy-1,3-dimethyl-1H-pyrazolo [3,4-b]pyridine-6(7H)-one (2 mmol), isatin (2 mmol), malon-
onitrile (2 mmol), piperidine (10 mol %), and water (10 mL) at 30 °C.
b
Yields of isolated products.
good yields (80–98%) under the same reaction condition (Table 4).
The crystal structure19 of compound 8a is given in Figure 2.
The reaction is suggested to occur through the mechanism
shown in Scheme 2.
Then a pseudo three-component reaction was performed with
two equivalents of 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-
b]pyridine-6(7H)-one 3a and one equivalent of aldehyde in water
(5 mL) to obtain 5,50-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-
1H-pyrazolo[3,4-b]pyridin-6(7H)-one) 9 (reaction 2).
5, entries 1–6), the reaction did not occur when isatin was used as
carbonyl building block in this pseudo three-component reaction
(Table 5, entry 7). The observed difference in the reactivity of isatin
as compared to aldehydes in this pseudo three-component reac-
tion (reaction 2) can be ascribed to the inherent difference in the
reactivity of aldehyde and ketone. Moreover the active methylene
moiety of 3a is not sufficiently reactive to bring out Knoevenagel
condensation with isatin 7. The less reactivity of this moiety is also
reflected in the difference in the reaction time of three-component
reaction (reaction 1) and pseudo three-component reactions (reac-
tion 2). The crystal structure19 of compound 9d is given in Figure 3.
Though the reaction resulted from moderate to good yield of
the product 9 with aromatic and heteroaromatic aldehydes (Table

R. Jayarajan, G. Vasuki / Tetrahedron Letters 53 (2012) 3044–3048
3047
Figure 2. Crystal structure of 8a DMSO solvate (the solvent molecule is disordered).
CN
CN
CN
CN
O
R
R
HB
B
B
NC
CN
R
+
O
H
N
H
OH
N
O
Figure 3. Crystal structure of 9d DMSO solvate (the solvent molecule is disordered).
N
N
H
O
N
N
N
N
H
O
N
N
H
O
reactivity similar to active methylene compounds generally em-
ployed in MCRs.
B
NH2
NH
N
O
C
CN
R
Acknowledgment
CN
CN
O
O
R
R
G.V. thanks the University Grants Commission and Department
of Science and Technology (DST) for financial support. R.J. thanks
the UGC, New Delhi, India for the award of Rajiv Gandhi National
Fellowship.
N
H
O
N
N
N
N
N
H
N
H
O
N
H
O
Scheme 2. Plausible mechanism for the formation of 6.
Supplementary data
In conclusion, we have described the synthesis of a novel hetero-
cyclic active methylene compound under a solvent-free condition.
Use of this scaffold to develop skeletally diverse heterocyclic scaf-
folds through multi-component reaction in an eco-friendly syn-
thetic protocol has been demonstrated. The scaffold shows
Supplementary data (general experimental procedure, com-
plied spectroscopic data of new compounds and scanned copies
of spectra) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.013.
Table 5
Pseudo three-component reaction (reaction 2)a
O
OH
R3
NH
O
N
OH
N
N
N
H
R3
N
5
OH
O
H
(a)
(b)
R2
2
N
+
O
9a-9f
No reaction
N
N
H
3a
O
O
N
R1
7
Entry
R3
5
Time (h)
Product 9
Yieldb (%)
1
2
3
4
5
6
7
40-Me-C6H4
6
6
6
6
6
9a
9b
9c
9d
9e
9f
90
88
70
60
77
85
40-MeO-C6H4
20-MeO, 30-MeO-C6H3
30,40,50-(MeO)3-C6H2
20-Furanyl
20-Thiophenyl
Isatin 7
6
12
—
No reaction
a
(a) and (b): The reactions were carried out with 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one (2 mmol),
aldehyde/isatin (1 mmol), piperidine (10 mol %), and water (10 mL) at 30 °C.
b
Yields of isolated products.

3048
R. Jayarajan, G. Vasuki / Tetrahedron Letters 53 (2012) 3044–3048
12. Zhang, P.; Pennell, A. M. K.; Wright, J. J. K.; Chen, W.; Leleti, M. R.; Li, Y.; Li, L.;
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