A facile and efficient procedure for one-pot four-component synthesis of polysubstituted spiro pyrano[2,3-: C] pyrazole and spiro 1,4-dihydropyridine catalyzed by a Dabco-based ionic liquid under mild conditions

Article abstract of DOI:10.1039/c7nj03967k

A simple and efficient synthetic protocol for the syntheses of spiro pyrano[2,3-c]pyrazole and spiro 1,4-dihydropyridine derivatives via a one pot four-component reaction catalyzed by Dabco-based ionic liquids has been successfully developed. Under the sa

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A facile and efficient procedure for one-pot four-component synthesis of polysubstituted spiro
pyrano[2,3-c]pyrazole and spiro 1,4-dihydropyridine catalyzed by Dabco-based ionic liquid under mild
condition
Tong Liu,a Yi-Huan Lai,a Ya-Qin Yub,* and Da-Zhen Xua,*
a.National Engineering Research Center of Pesticide (Tianjin), State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic
of China. Fax: +86 22 2350 5948; E-mail: xudazhen@nankai.edu.cn
b.Key Laboratory for Water Environment and Resources, Tianjin Normal University, Tianjin, 300387,
People’s Republic of China. Fax: +86 22 2376 6557; E-mail: yuyaqin@mail.tjnu.edu.cn
Keywords
one-pot synthesis, multi-component reaction, spiro compounds, activated alkynes
Abstract
A
simple and efficient synthetic protocol for the syntheses of spiro pyrano[2,3-c]pyrazole and spiro
1,4-dihydropyridine derivatives via a one pot four-component reaction catalyzed by Dabco-base ionic liquids has
been successfully developed. Under the same reaction conditions, when hydrazines were used as amine component
to react with isatins, active methylenes and dialkyl acetylenedicarboxylates, the reactions afford spiro
pyrano[2,3-c]pyrazoles in good to excellent yields (78-96%). While aromatic amines were used as amine
component in the same reaction, a completely different product scaffold of spiro 1,4-dihydropyridines was
obtained in moderate to good yields (52-93%). This synthetic protocol could be applicable to a wide range of
substrates. The desired products are easily separated and purified by simple crystallization. The catalyst could be
recycled five times. Plausible reaction mechanisms were proposed according to the experimental results.
Introduction
Spirocyclic compounds, widespread in pharmaceuticals and natural products, are considered as an important kind
of bioactive compounds in organic chemistry.[1] Among them, spirooxindole and its derivatives constitute the key
core of various natural products,[2] especially when their C-3 position fused to other heterocycles, that could highly
enhanced the biological activity.[3]
Heterocyclics are ubiquitously imperative structural units and constitute the largest diversity of organic molecules
of chemical, biomedical, and industrial significance.[4] Both functionalized pyrano[2,3-c]pyrazoles and
1,4-dihydropyridines are important classes of biologically active heterocycles. The pyrano[2,3-c]pyrazole moiety
is often present in bioactive drugs, which exhibit a wide range of biological activities such as antimicrobial,[5]
anticancer,[6] anti-inflammatory[7] and molluscicidal activities.[8] They are also potential inhibitors of human Chk1
kinase.[9] Similar to pyrano[2,3-c]pyrazole, 1,4-dihydropyridine derivatives are abundant in various natural
products as well as in synthetic pharmaceuticals. Substituted 1,4-dihydropyridine exhibit diverse biological
activities, such as antifungal,[10] antioxidant,[11] anticancer,[12] anticonvulsant,[13] and antiviral activity.[14]
Furthermore, 1,4-dihydropyridine could be used as hydrogen transfer reagents.[15] Due to their fascinating
biological activities, some simple and direct method for synthesis of the two kinds of spiroheterocyclics have been
developed by four-component reactions.[16][17] Although considerable progress has been made by these protocols,
many of them still suffer drawbacks, such as elevated temperature, special reaction conditions, using an unpleasant
smelly amine or unrecyclable catalysts. Especially, there is not a general procedure for prepared both of the two

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kinds heterocyclics. Therefore, the development of simple and efficient procedures for general synthesis of
important spiroheterocyclics is crucial in terms of synthetic technology.
The one-pot multi-component reactions (MCRs), involving the intrinsic generation of several new bonds via a
single synthetic operation without complicated purification steps, have proven to be a powerful tool for the rapid
synthesis of complex heterocyclic compounds in recent years.[18] The design of MCRs is also an effective way to
produce structural scaffolds or combinatorial libraries in modern drug discovery.[19] "Single reactant replacement",
involving the replacement of one reactant with a different reactant under the multi-component conditions, is the
most straightforward approach to design a new MCR.[20] By incorporating additional reactivity or functionality of
the new reactant, the resulting MCRs may be afforded a different product scaffold.
Ionic liquids (ILs) as environmentally friendly media have been employed in many chemical and biochemical
transformations.[21] But two serious drawbacks, low reactivity and high catalyst loading, limited their application in
chemical industry. Recently, we have reported a series of quaternary alkylammonium ILs based on the skeleton of
1,4-diazobicyclo [2.2.2] octane (DABCO), and they are shown to be very effective catalysts for many important
multi-component reactions.[22] Here, in continuation of our ongoing interest in ILs-mediated organic reactions, we
wish to disclose our study on using the Dabco-base ILs as highly efficient catalysts for the synthesis of spiro
pyrano[2,3-c]pyrazole and spiro 1,4-dihydropyridine derivatives respectively via one-pot four-component
reactions by using the method of "single reactant replacement". As shown in Scheme 1, under the same reaction
conditions, different amine components (hydrazine and aromatic amine) afford completely different product
scaffolds.
Scheme 1.
Results and discussion
Six kinds of Dabco-base IL catalysts were synthesized,[22] and they are shown in Figure 1. Then, the reaction
between isatin (1a), malononitrile (2a), dimethyl acetylenedicarboxylate (DMAD) (3a) and phenyl hydrazine (4a)
was chosen as the model reaction to screen different Dabco-base IL catalysts in ethanol as well as other classic
solvent in order to develop appropriate reaction conditions. The results are summarized in Table 1.
Figure 1. Structures of the Dabco-base ionic liquid catalysts.
Initially, different Dabco-base IL catalysts were tested in the reaction using ethanol as the solvent. It was found
that all the IL catalysts could drive the reaction, but the yields of 5a differed significantly with different IL
catalysts (Table 1, entries 1-6). When the reactions were performed in the presence of the ILs containing alkyl
substituents, the products were often obtained in poor yields (Table 1, entries 1 and 2). The reason could be

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explained by the transition state M-1 in proposed mechanism in Scheme 4. The hydrogen bonds play an important
role in the double-activation. Among different catalysts, the [Dabco-H][AcO] could afford 4a with a better yield of
95 % in shorter time (Table 1, entry 5). Then, it was taken as the catalyst of choice for the reaction and evaluated
in other solvents, such as H2O, DCE, THF and 1,4-dioxane, and neat conditions (Table 1, entries 7-11). However,
no better results were obtained. Different catalyst loadings were also tested, when using 5 mol% of the catalyst, the
reaction could afford 5a in a good yield of 83% (Table 1, entry 12). While increased the catalyst loading more than
10 mol%, nearly the same results were obtained as using 10 mol% of the catalyst (Table 1, entry 13). Other kinds
of ILs, such as [Bu4N]OH and [bmIm]OH, were also tested in the reaction, but only moderate yields were obtained
(Table 1, entries 14 and 15).
Table 1. Optimization of reaction conditions[a]
Entry
Cat (10 mol%)
Solvent(mL) Time (min)
Yield
(%)[b]
62
1
[Dabco-C4]Cl
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
H2O
60
2
[Dabco-C3OH]Cl
[Dabco-H]Cl
60
14
3
60
92
4
[Dabco-H][HSO4]
[Dabco-H][AcO]
[Dabco-H][BF4]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Dabco-H][AcO]
[Bu4N]OH
60
90
5
40
95
6
60
81
7
100
40
35
8
DCE
93
9
THF
100
100
200
60
69
10
11
12[c]
13[d]
14
15
1,4-dioxane
neat
51
39
ethanol
ethanol
ethanol
ethanol
83
40
95
40
82
[bmIm]OH
40
64
[a] Reaction conditions: isatin (1a, 1 mmol), malononitrile (2a, 1.05 mmol), dimethyl acetylenedicarboxylate
(DMAD) (3a, 1.05 mmol) and phenyl hydrazine (4a, 1 mmol), catalyst (10 mol%) and solvent (1.0 mL), under
40 °C.
[b] Isolated yield.
[c] Catalyst 5 mol%.
[d] Catalyst 15 mol%.
Under the optimized conditions, we then examined the scope of various isatins (1), active methylenes (2), dialkyl
acetylenedicarboxylates (3) and hydrazines (4) for the synthesis of structurally diverse spiro
pyrano[2,3-c]pyrazoles (5) via one-pot four-component reactions in the presence of 10 mol% the IL catalyst

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[Dabco-H][AcO] in ethanol. The results are listed in Table 2. As Table 2 indicates, all isatins containing
electron-withdrawing or -donating groups were successfully reacted in the reaction and afforded the corresponding
products 5a-e in good to excellent yields (78-95%) within 40-360 minutes (Table 2, entries 1-5). However, a
longer reaction time was needed when the isatin contained an electron-donating group of Me (Table 2, entry 5).
When hydrazine hydrate (4b) was used instead of phenyl hydrazine (4a) to react with the same substrates, we
found that the intermediate pyrazolone A (Scheme 4) could be formed very quickly because of the low steric
hindrance, so the reactions with hydrazine hydrate (4b) could afford the corresponding products in excellent yields
within shorter reaction times (Table 2, entries 6 vs 1, 7 vs 2, 8 vs 3). Other substrates, such as ethyl cyanoacetate
(2b) and diethyl acetylenedicarboxylate (DEAD, 3b) were also studied in this one-pot four-component reaction.
They all worked well under the optimal reaction conditions. Compared to malononitrile (2a), ethyl cyanoacetate
(2b) is a less reactive substrate. Because the electron-withdrawing ability of the carboxylic group is weaker than
that of the CN group, the methylene group of malononitrile is more activated in the reaction. Therefore, the
reaction with ethyl cyanoacetate (2b) needed a longer reaction time to get high yields (Table 2, entries 9 vs 1,10 vs
6). We also found that the yields decreased with the increase of the chain R2 length of substrates 3 (Table 2, entries
11 vs 1,12 vs 6).
Table 2. One-pot synthesis of derivatives of spiro pyrano[2,3-c]pyrazoles from hydrazines.
Entry
isatin
X
R2
R3
5
Time
Yield
(min) (%)
1
H
CN
CN
CN
Me Ph
Me Ph
Me Ph
Me Ph
Me Ph
5a
5b
5c
5d
5e
5f
40
95
83
93
91
78
96
96
94
88
93
81
90
2
5-Cl
5-F
120
120
120
360
30
3
4
5-OMe CN
5
1-Me
H
CN
CN
CN
CN
6
Me
Me
Me
H
H
H
7
5-Cl
5-F
H
5g
5h
5i
60
8
90
9
CO2Et Me Ph
300
300
120
40
10
11
12
H
CO2Et Me
H
5j
H
CN
CN
Et
Et
Ph
H
5k
5l
H
[a] Reaction conditions: isatin (1, 1 mmol), active methylene (2, 1.05 mmol), dialkyl acetylenedicarboxylate (3,
1.05 mmol) and hydrazine (4, 1 mmol), [Dabco-H][AcO] (10 mol%) and ethanol (1.0 mL), under 40 °C.
[b] Isolated yield.
To further broaden the scope of the reaction, isatins were replaced by acenaphthenequinone under the optimal
reaction conditions. As expected, the reaction proceeded well to afford the corresponding

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spiro[acenaphthylene-1,4’-pyrano[2,3-c]pyrazoles] 7a-b in excellent yields without observing any side reactions.
The results are shown in Scheme 2.
Scheme 2. Synthesis of spiro[acenaphthylene-1,4’-pyrano[2,3-c]pyrazoles].
Moreover, the scope of carbonyls for the present protocol was investigated using ninhydrin, producing the desired
spiro products 9a-b in high yields. The results are summarized in Scheme 3. All the results indicate that this is a
general and efficient protocol for one-pot synthesis of a broad range of spiro pyrano[2,3-c]pyrazole derivatives
under mild conditions.
Scheme 3. Synthesis of spiro[indene-2,4’-pyrano[2,3-c]pyrazoles].
By using the method of "single reactant replacement", we tried to use aromatic amines as a new amine components
to replace hydrazines in the four-component reaction with isatins, active methylenes and dialkyl
acetylenedicarboxylates. Encouraging results were obtained, another MCR was obtained and afforded a different
scaffold. It was found that a series of spiro 1,4-dihydropyridines have been prepared in moderate to good yields
without changing the optimized conditions. The results are shown in Table 3. Isatins with electron withdrawing
groups often afforded good yields. Dialkyl acetylenedicarboxylates and aromatic amines with electron
withdrawing or donating groups have not shown much effect on the formation of final products.
Table 3. One-pot synthesis of derivatives spiro 1,4-dihydropyridines from amines.

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Entry
R1
R2
R4
11
Time
Yield
(%)
81
(h)
4
1
H
Me
Me
Me
Me
Me
Me
Et
4-OMe
4-Br
11a
11b
11c
11d
11e
11f
2
H
4
86
3
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Br
5-Br
5-Br
5-Me
4-OMe
4-Br
8
85
4
7
89
5
4-Me
4-F
8
92
6
6
83
7
4-F
11g
11h
11i
6
93
8
Me
Me
Et
4-OMe
4-Br
5
91
9
6
88
10
11
4-Me
4-OMe
11j
6
85
Me
11k
8
52
[a] Reaction conditions: isatin (1, 1 mmol), malononitrile (2a, 1.05 mmol), dialkyl acetylenedicarboxylate (3, 1.05
mmol) and amine (10, 1 mmol), [Dabco-H][AcO] (10 mol%) and ethanol (1.0 mL), under 40 °C.
[b] Isolated yield.
The reusability of the catalyst was also examined for prepared of 5a on a 6-mmol scale. The results are listed in
Table 4. The catalyst [Dabco-H][AcO] could be recovered and reused in the four-component for five times.
Table 4. Recycling of the catalyst [Dabco-H][AcO] in the synthesis of 5a.
Run
1
2
3
4
5
Yield (%)
95
94
91
90
87
The plausible mechanisms for the formation of spiro pyrano[2,3-c]pyrazoles and spiro 1,4-dihydropyridines were
proposed using the present protocol and they are shown in Scheme 4 and 5 respectively. In Scheme 4, initially, a
condensation occurs between dialkyl acetylenedicarboxylate and hydrazine, forming pyrazolone intermediate A,
which reacts with the Knoevenagel product B formed from isatin and malononitrile. After the Michael addition of
A with B, the key intermediate M-1 undergoes enolization and intramolecular cyclization to form C. Finally, after
the tautomeric proton shift, C transforms into the desired product.

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Scheme 4. Plausible mechanism for synthesis of spiro pyrano[2,3-c]pyrazoles.
In Scheme 5, with the activation of the catalyst [Dabco-H][AcO], the aromatic amine adds on to dialkyl
acetylenedicarboxylate to afford the zwitterionic intermediate D which undergoes Michael addition with
Knoevenagel product B to form intermediate E. After the intermediate M-2 formed through the migration of
hydrogen atom, an intramolecular cyclization occurs to afford F. Finally, after the tautomeric proton shift, the
desired products are formed.
O
CN
O
+
N
H
CN
NH
O
CN
NC
R2O2
R2O2
C
CN
C
NH
NH
2 N
O
Ar
(E)
N
H
O
R2O2
C
C
CN
(B)
R2O2
N
H
N
(M-2)
H2
N
Ar
H
N
R2O2
C
Ar
N
CO2R2
D
(
)
AcO
NH
NH
AcO
N
Ar-NH2
H
N
N
O
CN
H
N
O
CN
R2O2C
R2O2C
R2O2
C
O
O
AcO
O
R2O2
C
N
NH2
N
NH
O
R2O
OR2
Ar
(F)
Ar
R2O
OR2
Scheme 5. Plausible mechanism for synthesis of spiro 1,4-dihydropyridines.
Conclusion
In conclusion, the present study deals with the development of an efficient synthetic strategy to construct complex
spiro pyrano[2,3-c]pyrazoles and spiro 1,4-dihydropyridines catalyzed by a reusable Dabco-base ionic liquid under
mild conditions. The two different products could be obtained just by the method "single reactant replacement".
The procedure offers several significant advantages, such as simple separation, purified by crystallization, easily
available starting materials, low cost and cleaner reaction profiles. To the best of our knowledge, such an efficient
synthetic protocol for the synthesis of two important kinds of spirocyclic compounds is reported for the first time.
Experimental
General experimental information. All chemicals were purchased from commercial suppliers and were used
without further purification. Melting points were determined with an X-4 apparatus and are uncorrected. 1H NMR

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and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer with DMSO-d6 as the solvent. Chemical
1
shifts are reported relative to TMS as internal standard. The H NMR data are reported as the chemical shift in
parts per million, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet), coupling constant in hertz, and number
of protons.
General procedure for the synthesis of spiro pyrano[2,3-c]pyrazoles and spiro 1,4-dihydropyridines. A
10-mL round bottomed flask was charged with hydrazine (aromatic amine) (1 mmol), dialkyl
acetylenedicarboxylate (1.05 mmol), [Dabco-H][AcO] (10 mol%) and ethanol (1 mL). After stirring for 5 min at
40 °C, isatin (1 mmol) and malononitrile (1.05 mmol) were added to the reaction mixture, and the reaction was
continued for the appropriate time. The formation of the products was monitored by TLC. After completion of the
reaction, cold water (2 mL) was added, the mixture was solidified in the round bottomed flask, filtered and washed
with cold water to remove the catalyst. The purification of the crude products by recrystallization from ethanol
provided pure products without column purification. After removing solvent under vacuum and extracting with
ether, the catalyst [Dabco-H][AcO] could be reused for the next run of the same reaction.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (NSFC) (No.
21302101), and National Training Programs of Innovation and Entrepreneurship for Undergraduates (No.
201610055092, 201610055085). We also thank the Nankai University State Key Laboratory of Elemento-Organic
Chemistry for support.
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New Journal of Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C7NJ03967K
A facile and efficient procedure for one-pot four-component synthesis of
polysubstituted spiro pyrano[2,3-c]pyrazole and spiro 1,4-dihydropyridine
catalyzed by Dabco-based ionic liquid under mild condition
Tong Liu, Yi-Huan Lai, Ya-Qin Yu and Da-Zhen Xu
Spiro pyrano[2,3-c]pyrazoles and spiro 1,4-dihydropyridines were obtained in high yields from different amine
components under Dabco-based ionic liquid catalysis.