Advanced Catalyst-Free Pseudo-Six-Component Synthesis of Tetrahydrodipyrazolopyridines in Water by Using Ammonium Carbonate as an Ecofriendly Source of Nitrogen

Article abstract of DOI:10.1055/s-0039-1691600

This work describes an improved environmentally friendly method for the synthesis of tetrahydrodipyrazolopyridines (THDPPs) in water through a catalyst-free pseudo-six-component reaction of alkyl acetoacetates, hydrazine hydrate, and ammonium carbonate wi

Full text of DOI:10.1055/s-0039-1691600

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
F. Tamaddon, A. Khorram
Letter
Synlett
Advanced Catalyst-Free Pseudo-Six-Component Synthesis of
Tetrahydrodipyrazolopyridines in Water by Using Ammonium
Carbonate as an Ecofriendly Source of Nitrogen
Fatemeh Tamaddon*
O
O
O
Ali Khorram
H3C Ar
N
CH3
N
H
*No catalyst
*No organic solvent
*One step
2
RO
CH3
Ar
+
H
H2O, r.t.
R = -Me, Et
Department of Chemistry, Faculty of Science, Yazd University,
Yazd 89195-741, Iran
ftamaddon@yazd.ac.ir
N
N
N
*Scalable
H
H
(NH4)2CO3
H
H N NH2⋅H2O
2
2
THDPPs, 10 examples
Ar = Ph, 4-HOC6H4,4-ClC6H4, 4-H3CC6H4,
3-O2NC6H4, 4-(H3C)2NC6H4, 4-O2NC6H4,
2-ClC6H4, 4-H3COC6H4, 4-BrC6H4
82–97% yield
khorramali58@gmail.com
Received: 16.10.2019
Accepted after revision: 04.01.2020
Published online: 04.02.2019
Multicomponent reactions (MCRs) permit atom-eco-
nomic and flexible assembly of more than two components
to give functionalized molecules such as pyrazolopyri-
dines.5b,7,8 In particular, MCRs are of interest for the synthe-
sis of heterocycles, which constitute 60% of all marketed
medicines.9 Moreover, a combination of MCRs with water-
based organic synthesis leads to synergistic environmental
advantages.10 In this context, we have developed water-
based organic transformations by MCRs under catalyst-free
conditions11 or by using biocompatible enzyme catalysts12
or surfactants.13
The 1,4-dihydropyridine (1,4-DHP) skeleton is an im-
portant pharmacophore in some coenzymes,14a clinical an-
tihypertensive drugs,14b and hexahydroquinolines.14c Gen-
erally, 1,4-DHPs are prepared by the conventional pseudo-
four-component Hantzsch reaction under various condi-
tions,14d so we developed a green version of this reaction by
using ammonium carbonate in water.11 Recently, the 1,4-
DHP ring has been conjugated to two pyrazole rings to give
the biologically active tetrahydrodipyrazolopyridines
(THDPPs) that contain both 1,4-DHP14b and pyrazole phar-
macophores.15 THDPPs are also the fused heterocycle prod-
ucts of a modified pseudo-six-component reaction of hy-
drazine and 1,3-dicarbonyl compounds with aldehydes and
ammonium acetate, and they are formed via a pyrazolone
intermediate produced in situ.15–20 In addition to the use of
various catalysts and organic solvents for the synthesis of
THDPPs, an ultrasound-assisted version of an MCR has also
recently been documented.15b However, there is still a need
for cleaner and more-efficient ecofriendly routes for large-
scale synthesis of THDPPS in water.
DOI: 10.1055/s-0039-1691600; Art ID: st-2019-k0447-l
Abstract This work describes an improved environmentally friendly
method for the synthesis of tetrahydrodipyrazolopyridines (THDPPs) in
water through a catalyst-free pseudo-six-component reaction of alkyl
acetoacetates, hydrazine hydrate, and ammonium carbonate with an
aldehyde in a mole ratio of 2:2:1:1 at room temperature. The ammoni-
um carbonate serves as a green source of nitrogen for the central 1,4-
dihydropyridine ring in the THDPPs. Methyl acetoacetate reacts faster
than either ethyl or propyl acetoacetate in this method. The product
precipitates during the reaction and is simply collected by filtration. Ad-
vantages of this environmentally benign method include no use of an
organic solvent, no hazardous waste, rapid clean reactions, and excel-
lent yields of products.
Keywords dipyrazolopyridines, water-based synthesis, catalyst-free
synthesis, multicomponent reaction, green chemistry, ammonium car-
bonate
The development of water-based procedures for the
synthesis of valuable biologically active compounds and
pharmaceuticals is an ecofriendly approach to green chem-
istry.1 The unique properties of water as a promising sus-
tainable solvent serve as the main impetus for developing
such reactions.2 Although aqueous organic transformations
profit from rate enhancement from the hydrophobic associ-
ation of organic materials,3 most catalysts and reagents
used in promoting reactions are water sensitive. Further-
more, surfactant catalysts used in improving aqueous or-
ganic reactions are usually nonrenewable and nonbiode-
gradable, creating further problems for water-based organ-
ic transformations. Therefore, catalyst-free organic
reactions in water4 that give filterable solid products would
be ideal for synthesis.5 Such safe reactions have attracted
growing interest for synthesis of designed multifunctional
organic materials with minimal chemical waste.6
To overcome the problems of dispersing organic compo-
nents in water and the moisture sensitivity of ammonium
acetate, we replaced this hygroscopic salt with ammonium
carbonate as a less-toxic nonhygroscopic and safer buffered
source of nitrogen for the synthesis of THDPPs in water.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. Tamaddon, A. Khorram
Letter
Synlett
Ammonium carbonate [(NH4)2CO3], is a sublimable solid
source of ammonia with a low melting point (58 °C) and an
LD50 of 1497 mg/kg that decomposes in water to give two
moles of ammonia at a buffered pH.11 Here, we report an
operationally simple, catalyst-free, water-based, room-
temperature synthesis of THDPPs by using ammonia
formed in situ from (NH4)2CO3 under completely safe condi-
tions (Scheme 1).
late (entry 10). The rapid reaction and the less-laborious
product isolation are additional advantages of this salt-
based method.
Table 1 NH3-Source Optimization for Catalyst-Free Synthesis of
THDPP1 in Water
Ph
H3C
N
CH3
N
Ammonium salt 2H2N NH2⋅H2O
H
r.t.
+
O
O
O
N
N
solvent
N
H
H
H
Ph
H
2
MeO
CH3
O
O
H
THDPP1
2H2N NH2⋅H2O
2
RO
CH3
+
Entry
Ammonium salt
Solvent
Time (h)
Yield (%)
O
(NH4)2CO3
Ar
1
2
NH4Cl
H2O
H2O
H2O
H2O
H2O
H2O
3
0
0
H2O r.t.
NH4NO3
3
3
NH4VO3
5
0
H3C Ar
N
CH3
N
H
4
NH4HCO3
NH4OC(O)H
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
[(NH4)OC(O)]2
[(NH4)OC(O)]2
1
78
81
96
89
90
65
65
76
THDPPs
N
N
N
5
1.5
0.25
1
H
H
H
6
Scheme 1 Environmentally friendly catalyst-free synthesis of THDPPs
in water
7
H2O–EtOH
8
EtOH
–
1
Initially, we attempted to synthesize 3,5-dimethyl-4-
phenyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridine
(THDPP1) as a model product by the catalyst-free room-
temperature reaction of methyl acetoacetate, hydrazine hy-
drate, and benzaldehyde in the presence of various ammo-
nium salts in a mole ratio of 2:2:1:1 (Table 1). Among the
ammonium salts screened, a maximum 96% yield of
THDPP1 was obtained by running the reaction in the pres-
ence of (NH4)2CO3 in water (Table 1, entry 6), and the prod-
uct could be isolated by simple filtration. The lower yield of
THDPP1 under solvent-free conditions was due to sublima-
tion of ammonium carbonate on stirring the reaction mix-
ture (entry 9). The mild buffered pH of the reaction medi-
um, hydrogen bonding, and the in situ release of NH3 from
(NH4)2CO3 in water are the reasons for the superiority of
this salt to other organic ammonium salts, including am-
monium formate (entry 5) and nonvolatile ammonium oxa-
9
2
10
11
H2O
–
2
2
To check the scale-up of this method, we performed the
model reaction on a 10 mmol scale of benzaldehyde under
the optimized conditions and we isolated the product
THDPP1 in 95% yield after 20 minutes.
To show the performance of (NH4)2CO3 in this method,
the result was compared with those of previous methods
for synthesis of THDPP1 (Table 2) and found to be superior
to earlier methods in terms of the reaction time, yield, and
conditions.
Because of the advantages of this metal- and catalyst-
free technique, the optimized conditions were extended to
the synthesis of other THDPPs by the pseudo-six compo-
Table 2 Performance of Syntheses of THDPP1 from Ammonium Carbonate
Entry
Conditions
N Source
Time (h)
Yielda (%)
1
2
3
4
5
6
7
H2O, r.t. (this work)
(NH4)2CO3
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
0.25
0.66
0.33
5
96
nano-CdZr4(PO4)6 (0.6 mol%), EtOH, reflux
CuFe2O4@HNTs (5 mg)b, EtOH, r.t
EtOH, reflux
9416
9617
8615a
9619
92
EtOH, reflux
5
FeNi3-ILs MNPsc (2 mg)b, EtOH, reflux
CuCr2O4 (4 mg)b, EtOH
0.70
0.75
93
a Isolated yield.
b Amount of catalyst per millimole of aldehyde.
c Ionic liquid immobilized on a FeNi3 nanocatalyst.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
F. Tamaddon, A. Khorram
Letter
Synlett
Table 3 The Scope of Catalyst-Free Synthesis of THDPPs from (NH4)2CO3 in Water
O
O
Ar
H3C
N
CH3
N
2NH2–NH2
CH3
H
RO
2
H2O, r.t.
+
O
N
N
N
H
H
H
(NH4)2CO3
Ar
H
THDPPs
Entry
Ar
Ph
R
Time (min)
Yield (%)
Mp (°C) (Lit.15,16
)
1
2
Et
15
10
20
25
18
15
25
18
17
18
10
10
12
30
20
30
97
98
92
94
88
92
91
93
97
97
94
95
86
82
90
83
235–237 (240–242)
239–241
Ph
Me
Et
3
4-HOC6H4
4-ClC6H4
4-Tol
265–267 (267–268)
254–256 (254–256)
244–246 (244–246)
243–245
4
Et
5
Et
6
4-Tol
Me
Et
7
3-O2NC6H4
3-O2NC6H4
4-Me2NC6H4
4-Me2NC6H4
4-O2NC6H4
4-O2NC6H4
2-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
285–286 (282–284)
283–285
8
Me
Et
9
242–244 (240–242)
243–244
10
11
12
13
14
15
16
Me
Et
333–335 (>300)
334–335
Me
Et
220–222 (164–165)
182–184 (185–187)
183–185
Et
Me
Et
165–167 (165–167)
nent reaction of several aryl aldehydes with hydrazine hy-
drate, ammonium carbonate, and various alkyl acetoace-
tates in water to afford the desired products (Table 3).21 Al-
though methyl acetoacetate reacted faster than ethyl
acetoacetate, this green method was compatible with vari-
ous substrates. The isolated products in each case were suf-
ficiently pure to show the expected characteristics. Howev-
er, the reaction with phenylhydrazine was ineffective under
our reaction conditions.
A probable reaction mechanism for the catalyst-free
synthesis of THPPs with ammonium carbonate as the
source of ammonia is shown in Scheme 2. We presumed
that the reaction begins with hydrazonation of ethyl aceto-
acetate, pyrazolone formation, and further condensation
with the other reaction components.
2:2:1:1. The advantages of this environmentally friendly
protocol are simple isolation of the product by filtration, no
use of any organic solvent, clean and rapid reactions, excel-
lent yields, and its ecofriendly nature.
THDPPs
H2O
Ar
H2N NH2
+
O
O
N
N
H2O
N
N
N
H
OEt
H
H
Ar
NNH2
O
N
HN
N
NH
O
N
EtO
H2O
H
+
CO2–
3
(NH4)2CO3
EtOH
O
2 NH3
Ar
HN
In summary, after evaluation of various organic and in-
organic ammonium salts as sources of nitrogen in a water-
based catalyst-free synthesis of the model compound
THDPP1 at room temperature, we selected ammonium car-
bonate as the optimal salt. This solid source of ammonia
was used in a catalyst-free and fully biocompatible synthe-
sis of THDPPs in water through a pseudo-six-component re-
action of alkyl acetoacetates, hydrazine hydrate, and am-
monium carbonate with an aldehyde in a mole ratio of
N
HN
N
N
NH
O
O
O
Ar
O
HN
N
Ar
H
O
H2O
N
NH
Scheme 2 Proposed mechanism for catalyst-free synthesis of THDPPs
in water
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
F. Tamaddon, A. Khorram
Letter
Synlett
Funding Information
(16) Safaei-Ghomi, J.; Shahbazi-Alavi, H.; Sadeghzadeh, R.; Ziarati, A.
Res. Chem. Intermed. 2016, 42, 8143.
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(18) Xu, H.; Li, L.; Wang, Z.; Xi, J.; Rong, L. Res. Chem. Intermed. 2018,
44, 3211.
We gratefully thank the Yazd University Research Council for financial
support.()
(19) MaGee, D. I.; Dabiri, M.; Salehi, P.; Koohshari, M.; Hajizadeh, Z.
ARKIVOC 2014, (iv), 204.
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(21) Tetrahydrodipyrazolopyridines; General Procedure
(NH4)2CO3 (2.0 mmol) was added to a stirred mixture of the
appropriate aldehyde (2.0 mmol), alkyl acetoacetate (4.0
mmol), and hydrazine hydrate (4.0 mmol) in H2O (1.0 mL), and
the mixture was stirred vigorously at r.t. for the appropriate
time (Table 3). The precipitated product was separated by
simple filtration.
4-(3,5-Dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-
e]pyridin-4-yl)phenol (Table 3, Entry 3)
White solid; yield: 244.1 mg (92%); mp 267–269 °C (Lit.15 267–
268 °C). FTIR (KBr): 3234 (overlapped NH and OH stretching),
2935 (CH stretching), 1600 cm–1 (C=N stretching). 1H NMR (400
MHz, DMSO-d6):  = 2.05 (s, 6 H, 2 CH3), 4.68 (s, 1 H, CH), 6.57
(d, J = 8 Hz, 2 H, Harom), 6.89 (d, J = 8 Hz, 2 H, ArH), 9.15 (s, OH),
11.52 (s, 3 H, 3 NH). 13C NMR (100 MHz, DMSO-d6):  = 10.35,
31.76, 104.51, 114.45, 128.25, 133.36, 139.75, 155.05, 161.05.
3,5-Dimethyl-4-(4-tolyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-
b:4′,3′-e]pyridine (Table 3, Entry 5)
White solid: 245.8 mg (88%); mp 244–246 °C (Lit.15 244–
246 °C). FTIR (KBr): 3170 (NH stretching), 2920 (CH stretching),
1610 (C=N stretching), 1520 (C=C aromatic), 1139 cm–1 (C–N
stretching). 1H NMR (400 MHz, DMSO-d6):  = 2.1 (s, 6 H, 2 CH3),
2.20 (s, 3 H, p-CH3), 4.78 (s, 1 H, CH), 6.99–7.00 (m, 4 H, Harom),
11.25 (s, 3 H, 3 NH). 13C NMR (100 MHz, DMSO-d6):  = 10.85,
20.98, 32.85, 104.85, 127.82, 128.83, 134.70, 140.20, 140.75,
161.50.
[4-(3,5-Dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-
e]pyridin-4-yl)phenyl]dimethylamine (Table 3, Entry 9)
Yellow-orange solid: 299.1mg (97%); mp 250–252 °C. FTIR
(KBr): 3514, 3168 (NH stretching), 2942 (CH stretching), 1608
(C=N stretching), 1520 (C=C arom), 1139 cm–1 (C–N stretching).
1H NMR (400 MHz, DMSO-d6):  = 2.26 (s, 6 H, 2 CH3), 2.91 (s, 6
H, 2 p-CH3), 4.9 (s, 1 H, CH), 6.75 (d, J = 8 Hz, 2 H, Harom), 7.3 (d,
J = 8 Hz, 2 H, Harom), 11.54 (s, 3 H, 3 NH).
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Med. Chem. 2013, 66, 415.
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F. Green Chem. 2009, 11, 1968. (d) Müller, T. J. J. Chem. Hetero-
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1187.
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of Biochemistry, 4th ed; W. H. Freeman: New York, 2005, 190.
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3, 8220.
3,5-Dimethyl-4-(4-nitrophenyl)-1,4,7,8-tetrahydrodipyra-
zolo[3,4-b:4′,3′-e]pyridine (Table 3, Entry 11)
Cream solid: 291.7 mg (94%); mp 333–335 °C (Lit.15 >300 °C).
FTIR (KBr): 3250 (NH stretching), 2985 (CH stretching), 1605
(C=N stretching), 1489 (overlapped asymm stretching NO2 with
C=C arom), 1352 (NO2 symm stretching), 753 cm–1 (out-of-plane
bending C–H, para-substituted). 1H NMR (400 MHz, DMSO-d6):
 = 2.1 (s, 6 H, 2 CH3), 4.95 (s, 1 H, CH), 7.35 (d, J = 8 Hz, 2 H,
H
arom), 8.1 (d, J = 8 Hz, 2 H, Harom), 11.20 (s, 3 H, 3 NH). 13C NMR
(100 MHz, DMSO-d6):  = 10.70, 33.40, 103.60, 123.40, 129.20,
140.20, 146.1, 152.25, 161.35.
(15) (a) Zhao, K.; Lei, M.; Ma, L.; Hu, L. Monatsh. Chem. 2011, 142,
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son. Sonochem. 2015, 27, 423.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D