A facile protocol for the synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5- dimethyldipyrazolo[3,4-b:4′,3′-e]pyridine derivatives by a Hantzsch-type reaction

Article abstract of DOI:10.1007/s00706-011-0565-8

A facile and efficient protocol is described for the synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4′,3′-e] pyridine derivatives in good yields by the condensation of 3-methyl-1H-pyrazol- 5(4H)-one, aromatic aldehydes, and ammonium a

Full text of DOI:10.1007/s00706-011-0565-8

Monatsh Chem (2011) 142:1169–1173
DOI 10.1007/s00706-011-0565-8
ORIGINAL PAPER
A facile protocol for the synthesis of 4-aryl-1,4,7,8-tetrahydro-
3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridine derivatives
by a Hantzsch-type reaction
•
Kun Zhao Min Lei Lei Ma Lihong Hu
•
•
Received: 17 January 2011 / Accepted: 26 June 2011 / Published online: 26 July 2011
Ó Springer-Verlag 2011
Abstract A facile and efficient protocol is described for
the synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyl-
dipyrazolo[3,4-b:40,30-e]pyridine derivatives in good yields
by the condensation of 3-methyl-1H-pyrazol-5(4H)-one,
aromatic aldehydes, and ammonium acetate under catalyst-
free conditions. The advantages of this protocol are oper-
ational simplicity, mild reaction conditions, high yields,
and little environmental impact.
and neuroprotective agents [10–12]. Furthermore, some 1,4-
dihydropyridine derivatives are well known as calcium
channel modulators and have emerged as one of the most
important classes of drugs for the treatment of hypertension
[13–16]. Because 1,4-dihydropyridines exhibit significant
biological activity, their synthesis has received a lot of
interest from organic and medicinal chemists.
In recent years, there have been several modifications of
the Hantzsch synthesis of 1,4-dihydropyridine derivatives,
e.g., the use of microwave irradiation [17, 18], ionic liquids
[19], TMSCl-NaI [20], metal triflates [21, 22], molecular
iodine [23, 24], SiO2-NaHSO4 [25], SiO2-HClO4 [26],
ceric ammonium nitrate [27], phenylboronic acid [28],
PTSA-SDS [29], and organocatalysts [30]. However, to the
best of our knowledge, there have been no reports of using
3-methyl-1H-pyrazol-5(4H)-one instead of b-dicarbonyl
compounds for the synthesis of 4-aryl-1,4,7,8-tetrahydro-
3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridine derivatives
by condensation of 3-methyl-1H-pyrazol-5(4H)-one, aro-
matic aldehydes, and ammonium acetate.
Keywords Hantzsch-type reaction ꢀ Aldehyde ꢀ
3-Methyl-1H-pyrazol-5(4H)-one ꢀ Catalyst-free
Introduction
The Hantzsch reaction is a well-known, simple, and
straightforward procedure for the synthesis of 1,4-dihydro-
pyridines by the three-component condensation of an
aldehyde, b-dicarbonyl compounds, and ammonium acetate
[1–4]. 1,4-Dihydropyridines are an important heterocyclic
motif in natural and synthetic organic chemistry owing to
their wide spectra of biological activities [5–9], e.g., they act
as vasodilator, bronchodilator, antitumor, hepatoprotective,
In connection with our ongoing research on the devel-
opment of simple and efficient syntheses of heterocyclic
compounds [31, 32], we carried out an investigation to
develop an efficient and practical method for the one-pot
synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyldipyraz-
olo[3,4-b:40,30-e]pyridine derivatives by the condensation of
3-methyl-1H-pyrazol-5(4H)-one, aromatic aldehydes, and
ammonium acetate under catalyst-free conditions.
K. Zhao ꢀ M. Lei (&) ꢀ L. Hu (&)
Shanghai Research Center for Modernization of Traditional
Chinese Medicine, Shanghai Institute of Materia Medica,
Shanghai 201203, People’s Republic of China
e-mail: mlei@mail.shcnc.ac.cn
L. Hu
e-mail: simmhulh@mail.shcnc.ac.cn
Results and discussion
L. Ma
Initially, we investigated the condensation reaction of
3-methyl-1H-pyrazol-5(4H)-one (1, 6 mmol), benzalde-
hyde (2a, 3.3 mmol), and ammonium acetate (4.5 mmol)
School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237,
People’s Republic of China
123

1170
K. Zhao et al.
Table 1 Optimization of reaction conditions
Table 2 Synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyldipyraz-
olo[3,4-b:40,30-e]pyridine derivatives
Entry Catalyst/mol%
Solvent Time/h Yield of 3a/%a
Entry ArCHO 2
Time/h Product 3 Yield/%a
1
ZnCl2 (10)
FeCl3 (10)
MgCl2 (10)
Yb(OTf)3 (5)
EtOH
EtOH
EtOH
EtOH
5
5
5
3
3
4
4
4
5
8
6
4
5
88
85
84
90
90
88
88
86
86
85
86
86b
83
1
C6H5CHO (2a)
5
5
3a
3b
3c
3d
3e
3f
86
92
93
84
90
88
86
90
94
92
88
85
2
2
4-MeC6H4CHO (2b)
4-ClC6H4CHO (2c)
3
3
4
4
4
3-NO2C6H4CHO (2d)
4-NO2C6H4CHO (2e)
4-CNC6H4CHO (2f)
2,4-Cl2C6H3CHO (2g)
4-FC6H4CHO (2h)
3
5
Cu(ClO4)2ꢀ6H2O (5) EtOH
5
2
6
Vitamin B1 (5)
TsOH (10)
NH2SO3H (10)
None
EtOH
EtOH
EtOH
EtOH
MeOH
THF
6
2
7
7
10
5
3g
3h
3i
8
8
9
9
4-(CH3)2NC6H4CHO (2i)
4-OH-3-CH3OC6H3CHO (2j)
4-OHC6H4CHO (2k)
4-CH3OC6H4CHO (2l)
3
10
11
12
13
None
10
11
12
a
3
3j
None
3
3k
3l
None
DMF
MeCN
6
None
Isolated yield
The reaction was carried out at reflux temperature
a
Isolated yields
b
The reaction was carried out at 100 °C
In conclusion, we have developed a simple and efficient
synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyldipy-
razolo[3,4-b:40,30-e]pyridine derivatives by
three-
a
under different reaction conditions. The results are sum-
marized in Table 1.
component reaction of 3-methyl-1H-pyrazol-5(4H)-one,
aromatic aldehydes, and ammonium acetate in EtOH under
catalyst-free conditions. This method has the advantages of
high yields, short reaction times, and simple manipulations,
which make it a useful process for the synthesis of these
heterocyclic compounds.
A series of catalysts and solvents were examined in the
condensation of 3-methyl-1H-pyrazol-5(4H)-one (1),
benzaldehyde (2a), and ammonium acetate under reflux
conditions. As shown in Table 1, this reaction was com-
plete in 3–5 h in the presence of different catalysts
(Table 1). It was interesting to note that this three-com-
ponent Hantzsch-type reaction could proceed smoothly
under catalyst-free conditions in high yields (Table 1,
entries 9–13). For economical and environmental reasons,
EtOH was chosen as the reaction medium for all further
reactions.
Experimental
Reagents and all solvents were analytically pure grade and
1
were used without further purification. H and 13C NMR
spectra were recorded on a Varian 400 MHz spectrometer
at 400 MHz and 100 MHz, with TMS as an internal stan-
dard. Chemical shifts (d) are given in parts per million
(ppm) relative to TMS, coupling constants (J) in hertz.
Melting points were determined with an X-4 apparatus and
are corrected. Mass spectra were measured with Thermo
Finnigan LCQ-Advantage. Elemental analyses (C, H, N, S)
were performed on Fisons EA 1110 CHNS elemental
analyzer, and their values were found to agree favorably
with the calculated ones.
To explore the scope of this method, the reaction con-
ditions were applied to a variety of aromatic aldehydes
(Table 2).
The results in Table 2 indicate that the reaction was
complete in 2–10 h and led to desired 1,4-dihydropyridines
3 in good yields (84–94%) (Scheme 1). Aromatic alde-
hydes carrying either electron-donating (2b, 2i, 2j, 2k, and
2l) or electron-withdrawing (2c, 2d, 2e, 2f, 2g, and
2 h) substituents all reacted very well, giving excellent
yields.
We propose a mechanism of the Hantzsch-type con-
densation as shown in Scheme 2. Initially, intermediate 4 is
formed by Knoevenagel condensation of 3-methyl-1H-
pyrazol-5(4H)-one (1) and aldehyde 2, and 5 is formed by
the condensation of 3-methyl-1H-pyrazol-5(4H)-one and
ammonium acetate. Then, Michael addition of intermediate
5 to 4 leads to the intermediate 6. Finally, intramolecular
cyclization and dehydration affords the 1,4-dihydropyri-
dine 3 (Scheme 2).
General procedure for the synthesis of compounds
3a–3l
A mixture of 3-methyl-1H-pyrazol-5(4H)-one (1, 6 mmol),
aromatic aldehyde (2a–2l, 3.3 mmol), and ammonium
acetate (4.5 mmol) in 5 cm3 EtOH was heated to reflux
under stirring for the given time (Table 2). After comple-
tion (by TLC), the reaction mixture was cooled to room
123

Synthesis of 4-aryl-1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridine derivatives
1171
Scheme 1
Ar
NH4OAc
+
2
Ar CHO
N
N
N
O
N
H
EtOH, reflux
N
H
N
H
N
H
1
2
3
Scheme 2
Ar
NH4OAc
+
Ar CHO
N
N
N
N
N
O
H2N
O
N
N
O
H
H
H
N
H
1
2
4
5
1
Ar
Ar
-H2O
N
HN
N
NH
N
N
N
N
N
O H2N
H
H
H
3
6
temperature, then 5 cm3 water was added to the mixture
and stirred for 5 min. The solid was filtered and recrys-
tallized from EtOH/H2O (3:1) to afford the pure products 3.
161.42 ppm; IR (KBr): vꢀ = 2,921.6, 1,602.6, 1,529.3,
1,488.8, 1,440.6, 1,093.4, 1,014.4, 844.7 cm-1
; MS
(ESI): m/z = 322, 324 ([M ? Na]?).
1,4,7,8-Tetrahydro-3,5-dimethyl-4-(3-nitrophenyl)-
dipyrazolo[3,4-b:40,30-e]pyridine (3d, C15H14N6O2)
1,4,7,8-Tetrahydro-3,5-dimethyl-4-phenyldipyrazolo-
[3,4-b:40,30-e]pyridine (3a, C15H15N5)
White solid, m.p.: 286–288 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.12 (s, 6H), 5.01 (s, 1H), 7.53 (t,
J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H),
8.02 (d, J = 7.8 Hz, 1H), 11.38 (brs, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 10.76, 33.02, 103.79, 121.20,
122.42, 129.70, 135.10, 140.25, 146.28, 148.05,
161.36 ppm; MS (ESI): m/z = 333 ([M ? Na]?).
White solid, m.p.: 240–242 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.07 (s, 6H), 4.82 (s, 1H), 7.10–7.20 (m,
5H), 11.29 (brs, 3H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 10.85, 33.22, 104.67, 125.85, 127.93, 128.17,
140.23, 143.83, 161.55 ppm; IR (KBr): vꢀ = 2,921.6,
1,602.6, 1,533.1, 1,490.7, 1,446.4, 1,218.8, 835.0,
709.7 cm-1; MS (ESI): m/z = 288 ([M ? Na]?).
1,4,7,8-Tetrahydro-3,5-dimethyl-4-(4-nitrophenyl)-
dipyrazolo[3,4-b:40,30-e]pyridine (3e, C15H14N6O2)
1,4,7,8-Tetrahydro-3,5-dimethyl-4-(4-methylphenyl)-
dipyrazolo[3,4-b:40,30-e]pyridine (3b, C16H17N5)
White solid, m.p.: 244–246 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.06 (s, 6H), 2.23 (s, 3H), 4.78 (s, 1H),
7.01 (s, 4H), 11.31 (brs, 3H) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 10.85, 20.98, 32.82, 104.83, 127.83,
128.74, 134.65, 140.14, 140.73, 161.53 ppm; MS (ESI):
m/z = 302 ([M ? Na]?).
1
White solid, m.p.: [300 °C; H NMR (400 MHz, DMSO-
d6): d = 2.10 (s, 6H), 4.98 (s, 1H), 7.39 (d, J = 8.4 Hz,
2H), 8.12 (d, J = 8.4 Hz, 2H), 11.38 (brs, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 10.77, 33.42, 103.73,
123.44, 129.26, 140.17, 146.05, 152.21, 161.31 ppm; IR
(KBr): vꢀ = 2,967.9, 2,750.6, 1,604.5, 1,510.0, 1,442.5,
1,346.1, 1,176.4, 728.9 cm-1; MS (ESI): m/z = 333
([M ? Na]?).
4-(4-Chlorophenyl)-1,4,7,8-tetrahydro-3,5-
dimethyldipyrazolo[3,4-b:40,30-e]pyridine
4-(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-
e]pyridin-4-yl)benzonitrile (3f, C16H14N6)
White solid, m.p.: 286–288 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.09 (s, 6H), 4.93 (s, 1H), 7.32 (d,
J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 11.39 (brs,
3H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.77,
(3c, C15H14ClN5)
White solid, m.p.: 254–256 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.08 (s, 6H), 4.83 (s, 1H), 7.14 (d,
J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 11.34 (brs,
3H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.79,
32.69, 104.32, 128.06, 129.84, 130.49, 140.15, 142.79,
123

1172
K. Zhao et al.
33.49, 103.76, 108.72, 119.61, 129.08, 132.19, 140.26,
149.91, 161.36 ppm; MS (ESI): m/z = 313 ([M ? Na]?).
1,4,7,8-Tetrahydro-4-(4-methoxyphenyl)-3,5-
dimethyldipyrazolo[3,4-b:40,30-e]pyridine
(3l, C16H17N5O)
4-(2,4-Dichlorophenyl)-1,4,7,8-tetrahydro-3,5-
dimethyldipyrazolo[3,4-b:40,30-e]pyridine
Yellow solid, m.p.: 185–187 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.07 (s, 6H), 3.69 (s, 6H), 4.77 (s, 1H),
6.77 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 11.16
(brs, 3H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 10.83, 32.41, 55.41, 104.98, 113.57, 128.86, 135.68,
140.10, 140.16, 157.64 ppm; MS (ESI): m/z = 318
([M ? Na]?).
(3g, C15H13Cl2N5)
Yellow solid, m.p.:[300 °C; 1H NMR (400 MHz, DMSO-
d6): d = 1.95 (s, 6H), 5.06 (s, 1H), 7.33 (dd, J1 = 2.1 Hz,
J2 = 8.4 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.49 (d,
J = 8.4 Hz, 1H), 11.08 (brs, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 15.62, 36.37, 107.01, 131.71,
133.56, 136.19, 137.10, 138.41, 143.80, 145.18,
165.75 ppm; IR (KBr): vꢀ = 2,746.1, 1,602.6, 1,571.7,
1,533.1, 1,469.5, 1,384.6, 790.6 cm-1; MS (ESI): m/z =
366, 368 ([M ? Na]?).
Acknowledgments This work was supported by the Chinese
National Science and Technology Major Project ‘Key New Drug
Creation and Manufacturing Program’ (Grants 2009ZX09301-001,
2009ZX09102-022), the National Natural Science Foundation of
China (Grants 21002027, 90713046, 30772638 and 30925040), and
CAS Foundation (Grant KSCX2-YW-R-179).
4-(4-Fluorophenyl)-1,4,7,8-tetrahydro-3,5-
dimethyldipyrazolo[3,4-b:40,30-e]pyridine
(3h, C15H14FN5)
White solid, m.p.: 258–260 °C; 1H NMR (400 MHz, DMSO-
d6): d = 2.08 (s, 6H), 4.83 (s, 1H), 7.03 (t, J = 8.9 Hz, 2H),
7.15 (dd, J1 = 5.9 Hz, J2 = 8.4 Hz, 2H), 11.35 (brs, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.79, 32.57,
104.61, 114.74 (J = 21 Hz), 129.67 (J = 7.9 Hz), 139.81
(J = 2.8 Hz), 140.10, 160.88 (J = 240 Hz), 161.44 ppm;
MS (ESI): m/z = 306 ([M ? Na]?).
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Red solid, m.p.: 240–242 °C; 1H NMR (400 MHz, DMSO-
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2-Methoxy-4-(1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo-
[3,4-b:40,30-e]pyridin-4-yl)phenol (3j, C16H17N5O2)
Yellow solid, m.p.: 262–264 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.06 (s, 6H), 3.65 (s, 3H), 4.76 (s, 1H), 6.56 (d,
J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 11.03
(brs, 4H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.89,
32.90, 56.09, 105.07, 112.80, 115.34, 120.41, 134.82, 140.00,
144.92, 147.44, 161.45 ppm; IR (KBr):vꢀ = 3,191.6, 2,503.1,
1,610.3, 1,585.2, 1,484.9, 1,259.3, 1,224.6, 1,130.1,
788.7 cm-1; MS (ESI): m/z = 334 ([M ? Na]?).
4-(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-
e]pyridin-4-yl)phenol (3k, C15H15N5O2)
White solid, m.p.: 268–270 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.06 (s, 6H), 4.73 (s, 1H), 6.61 (d,
J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 11.02 (brs,
4H) ppm; 13C NMR (100 MHz, DMSO-d6): d = 10.86,
32.42, 105.14, 114.96, 128.80, 133.90, 140.13, 155.58,
161.54 ppm; MS (ESI): m/z = 304 ([M ? Na]?).
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1173
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