New multicomponent domino reactions (MDRs) in water: Highly chemo-, regio- and stereoselective synthesis of spiro{[1,3]dioxanopyridine}-4,6-diones and pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1039/c0gc00073f

New multicomponent domino reactions (MDRs) have been established for the synthesis of spiro{pyrazolo[1,3]dioxanopyridine}-4,6-diones, spiro{isoxazolo[1,3]dioxanopyridine}-4,6-diones and pyrazolo[3,4-b]pyridines. The MDRs were conducted by reacting readily available and inexpensive starting materials in aqueous solution under microwave irradiation. A total of 26 examples were examined, and showed a broad substrate scope and high overall yields (76-93%). A new mechanism has been proposed to explain the reaction process and the resulting chemo-, regio- and stereoselectivity. The present green synthesis shows attractive characteristics such as the use of water as the reaction medium, one-pot conditions, short reaction periods (9-13 min), easy work-up/purification and reduced waste production without the use of any acids or metal promoters.

Full text of DOI:10.1039/c0gc00073f

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www.rsc.org/greenchem | Green Chemistry
New multicomponent domino reactions (MDRs) in water: highly chemo-,
regio- and stereoselective synthesis of spiro{[1,3]dioxanopyridine}-
4,6-diones and pyrazolo[3,4-b]pyridines†
Ning Ma,a Bo Jiang,a Ge Zhang,a Shu-Jiang Tu,*a Walter Weverb and Guigen Li*b
Received 3rd May 2010, Accepted 9th June 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c0gc00073f
New multicomponent domino reactions (MDRs) have
been established for the synthesis of spiro{pyrazolo[1,3]-
dioxanopyridine}-4,6-diones, spiro{isoxazolo[1,3]dioxano-
pyridine}-4,6-diones and pyrazolo[3,4-b]pyridines. The
MDRs were conducted by reacting readily available and
inexpensive starting materials in aqueous solution under
microwave irradiation. A total of 26 examples were exam-
ined, and showed a broad substrate scope and high overall
yields (76–93%). A new mechanism has been proposed
to explain the reaction process and the resulting chemo-,
regio- and stereoselectivity. The present green synthesis
shows attractive characteristics such as the use of water as
the reaction medium, one-pot conditions, short reaction
periods (9–13 min), easy work-up/purification and reduced
waste production without the use of any acids or metal
promoters.
performed by simply mixing readily available starting materials,
aromatic aldehydes, cyclopentanone and cyanoacetamide with
K2CO3 in ethylene glycol under microwave (MW) irradiation.
Recently, we have also found that when aliphatic aldehydes were
employed to replace their aromatic counterparts for the above
MDR reaction, the quinazoline derivatives were not generated.
Instead, the reaction was found to follow another pathway,
leading to multi-functionalized tricyclo[6.2.2.01,6]dodecanes.4b
As a continuation of our research devoted to the development
of multi-component domino reactions,4–6 we would like to report
a green chemo-, regio- and stereoselective MDR approach
to type III spiro[1,3]dioxanopyridine derivatives that are of
chemical and biomedical importance (Fig. 1). This reaction was
achieved by reacting aldehydes, pyrazolo-amines or isoxazolo-
amines, and Meldrum’s acid as starting materials in water with
microwave irradiation in the absence of any acid, metal catalyst,
or promoter (Scheme 1).
Multicomponent domino reactions (MDRs), particularly those
performed in aqueous media, have become increasingly useful
tools for the synthesis of chemically and biologically important
compounds because of their environmentally friendly atom-
economy and green characteristics.1–3 These reactions enable
multi-step synthesis to be conducted in a one-pot operation
to obtain a variety of invaluable products. Therefore, MDRs
can dramatically reduce the generation of chemical waste and
reduce the cost of the starting materials. One-pot MDRs often
shorten reaction periods, giving higher overall chemical yields
than multiple-step syntheses, and can therefore reduce the use
of energy and manpower.
Fig. 1 Structures of three types of spiro{[1,3]dioxanopyridine}-4,6-
diones.
In the past several years, we and others have developed various
multicomponent domino reactions that can provide easy access
to useful functionalized multiple ring structures of chemical and
pharmaceutical interest.4–7 For example, a new four-component
domino reaction was established to provide easy access to mul-
tifunctionalized quinazoline derivatives.4a The reaction is easily
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou, 221116, Jiangsu, P. R. China.
E-mail: laotu@xznu.edu.cn.; Fax: 86-516-83500065
Scheme 1
bDepartment of Chemistry and Biochemistry, Texas Tech University,
Lubbock, Texas, 79409-1061. E-mail: guigen.li@ttu.edu;
Fax: 806-742-3015
† Electronic supplementary information (ESI) available: Experimental
details and spectra. CCDC reference number 776624. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0gc00073f
Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione)8 and
its derivatives have been widely utilized in organic synthesis,
especially for multiple C–C bond formations9 due to its adequate
acidity (pKa 4.83), steric rigidity, and notable tendency to re-
generate acetone as an easily removed side-product. Spirocyclic
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Table 1 MDR synthesis of spiro{[1,3]dioxanopyridine}-4,6-diones (4)
compounds containing a Meldrum’s acid unit are very useful
building blocks for the total synthesis of natural products
and for medicinal research.10,11 For example, they serve as
precursors to exotic amino acids which are often used to enhance
biological activities of peptides, peptidomimetics and proteins.10
In 2003, Barbas III and coworkers established a new L-proline-
catalyzed multicomponent transformation of Meldrum’s acid
into type I unsymmetrical spiro[5.5]undecanes.9a Recently, the
synthesis of type II unsymmetrical spiroundecanes has been
achieved by Sapi and coworkers.12 To the best of our knowledge,
a successful approach to spirocyclic compounds of type III,
containing a Meldrum’s acid unit and the fused isoxazolo[5,4-
b]hydropyridine and pyrazolo[3,4-b]pyridine scaffolds, have not
been documented in the literature.
It has been reported that when arylidene-Meldrum’s acids
were subjected to reaction with 3-methyl-1-phenylpyrazol-5-
amine in refluxing toluene, isoxazolo[5,4-b]hydropyridines were
produced in good chemical yields.13 We have also found that
the MDR of Meldrum’s acid, aromatic aldehydes and 3-
methyl-1-phenylpyrazol-5-amine in glycol leads to pyrazolo[3,4-
b]pyridines in high yields.6 Surprisingly, when we conducted
MDR of the above three reactants by changing the ratio
of three reactants under microwave irradiation in the aque-
ous phase, we found that the product is not the antici-
pated pyrazolo[3,4-b]pyridine. Instead, the multifunctionalized
spiro{[1,3]dioxanopyridine}-4,6-dione 1a was generated with
high chemo-, regio- and stereoselectivity and good yield, as
shown in Scheme 1.
Entry
Product 4, Ar =
Time/min
Yield (%)
1
2
3
4
5
6
7
8
4a 4-ClC6H4
4b 4-NO2C6H4
4c C6H5
4d 3,4-(CH3O)2C6H3
4e 3,4,5-(CH3O)3C6H2
4f 4-HO,3-NO2C6H3
4g 4-FC6H4
4h 4-ClC6H4
4i 4-BrC6H4
4j 4-CH3OC6H4
4k 4-NO2C6H4
4l 2-ClC6H4
4m 3,4-(CH3O)2C6H3
4n C6H5
10
12
9
84
86
82
80
81
83
88
84
83
80
84
77
82
84
81
78
10
11
12
10
12
11
12
10
13
12
9
9
10
11
12
13
14
15
16
4o 3,4,5-(CH3O)3C6H2
4p Thien-2-yl
12
10
Table 2 MDR synthesis of pyrazolo[3,4-b]pyridines (5)
Interestingly, the N-phenyl-based spiro{pyrazolo[1,3]-
dioxanopyridine}-4,6-diones can only be generated in aqueous
solution. Other polar solvents, such as N,N-dimethylformamide
(DMF), glacial acetic acid (HOAc) and glycol resulted in
pyrazolo[3,4-b]pyridines as the major products. This outcome
was also found to be the case under solvent-free conditions.
Since water is an efficient absorber of microwave irradiation,
it often leads to the success of many organic reactions under
environmentally friendly conditions.14,15 Under this aqueous
system, the MDR of Meldrum’s acid (1), aromatic aldehydes
(2) and 3-methyl-1-phenylpyrazol-5-amine (3) in a molar ratio
of 1 : 2 : 1 resulted in spiro{pyrazolo[1,3]dioxanopyridine}-4,6-
dione (4a) and produced a chemical yield of 81%. The reaction
occurred rapidly at 100 ◦C, and was complete within a few
minutes.
The substrate scope of this reaction was investigated by
using various aryl aldehydes. As revealed in Table 1, aromatic
aldehydes bearing either electron-withdrawing or electron-
donating functional groups such as chloro, fluoro, bromo,
methyl or methoxy were all found to be suitable for the reaction
with Meldrum’s acid (1) and 3-methyl-1-phenylpyrazol-5-amine
(3a) to obtain spiro{pyrazolo[1,3]dioxanopyridine}-4,6-diones
(4a–f) in very good yields of 80–86% (Table 1, entries 1–6). We
also utilized 3-methylisoxazol-5-amine (3b) instead of 3-methyl-
1-phenylpyrazol-5-amine (3a) for this reaction, and that it can
react with Meldrum’s acid (1) and various aromatic aldehydes
bearing electron-withdrawing or electron-donating groups to af-
ford the corresponding spiro{isoxazolo [1,3]dioxanopyridine}-
4,6-diones (4g–o) within 9–13 min in very good yields
(77–88%) and excellent selectivities (Table 1, entries 7–16). Even
substrate (2p), which contains a 2-thienyl group, was proven
Entry
Product 5, Ar =
Time/min
Yield (%)
1
2
3
4
5
6
7
8
5a 4-ClC6H4
5b 4-BrC6H4
7
6
8
8
7
8
8
7
9
8
89
93
90
92
89
89
91
88
90
89
5c 4-CH3C6H4
5d 4-(CH3O)C6H4
5e 3-NO2C6H4
5f 2,3-(CH3O)2C6H3
5g 2,4-Cl2C6H3
5h 4-HO,3-NO2C6H3
5i C6H5
9
10
5j 4-ClC6H4
to be effective for this reaction and produced the 2-thienyl-
substituted spiro[1,3]dioxanopyridine (4p) in a yield of 78%.
In addition, it was found that the group on the N-1 po-
sition of 3-methyl-pyrazol-5-amine (3) played a crucial role
in controlling the chemoselectivity. Two N-H- and N-Me-
based pyrazol-5-amines, 3-methylpyrazol-5-amine (3c) and
3-methyl-1-methylpyrazol-5-amine (3d), resulted in the forma-
tion of pyrazolo[3,4-b]pyridines (5a–j) in good to excellent
yields of 84–93% without spiro{pyrazolo[1,3]dioxanopyridine}-
4,6-diones being formed, under the same aqueous phase
and microwave irradiation conditions (Table 2, Scheme 2).
It should be noticed that in our previous synthesis of
N-phenylpyrazolo[3,4-b]pyridines and 3-methylisoxazolo[5,4-
b]pyridines,6 a ratio of 1 : 1 : 1 for three reactants is required.
However, in the present system, the reactants in a ratio 1 : 2 : 1
also resulted in pyrazolo[3,4-b]pyridine products predominantly.
A similar broad substrate scope of aldehydes was observed for
this process.
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Scheme 2
All products were fully characterized by spectroscopic anal-
1
ysis, and the IR, H and 13C-NMR data were consistent with
their structures (for the spectra of all pure products, see the
ESI†). Furthermore, crystals of 4g were obtained by careful
recrystallization from a solution of DMF, and the structure was
unambiguously confirmed by X-ray crystallography (Fig. 2).
As expected, the two para-F-phenyl rings are parallel to the
two carbonyl groups, and these two aromatic rings are also ar-
ranged on equatorial positions of a six-membered hydropyridine
ring.
Scheme 3
methylisoxazol-5-amine (3b) are employed as the substrates, due
to the need of aldehyde for both the Knoevenagel reaction and
the condensation reaction. At the same time, this mechanism can
also explain why 3-methylpyrazol-5-amine (3c, X = NH) and
3-methyl-1-methylpyrazol-5-amine (3d, X = O) lead to the for-
mation of pyrazolo[3,4-b]pyridines and N-phenylpyrazolo[3,4-
b]pyridines (5); this is based on the fact that the amino group
(–NH2) in these substrates is more reactive and makes the
Michael addition and the carbonyl addition of intermediate (E)
occur at faster rates. It should be noted that the imine formation
is expected to be reversible in the aqueous phase; this favors the
second pathway in which the more reactive aromatic amine (3) is
consumed by intermediate A at a faster rate. This is in contrast to
the two former cases (X = O; N–Ph) in which the electron density
of the –NH2 group is ‘withdrawn’ by the stronger electronegative
oxygen or shared by the N-phenyl ring. These two factors make
the formation of imine B occur slowly.
In summary, new multicomponent domino reactions
(MDRs) have been established to afford spiro{pyrazolo[1,3]-
dioxanopyridine}-4,6-diones, spiro{isoxazolo[1,3]dioxanopyri-
dine}-4,6-diones, and pyrazolo[3,4-b]pyridines that serve as
versatile building blocks for both organic and medicinal re-
search. The reactions were conducted in aqueous solution with
microwave irradiation using readily available and inexpensive
starting materials. A new mechanism has been proposed to
explain the chemo-, regio- and stereoselectivity. This green
synthesis shows several attractive characteristics such as the
use of water as the reaction medium, simple conditions, short
Fig. 2 ORTEP diagram of 4g.
The mechanism of this MDR process is proposed as shown
in Scheme 3. The first two steps involve the Knoevenagel
reaction of Meldrum’s acid (1) with aldehyde (2) to form an
intermediate (A), and the condensation of aldehyde (2) with
aromatic amine (3) to form an imine (B). The next step is the
hetero-Diels–Alder reaction of the Knoevenagel adduct (A) with
the aromatic imine (B), resulting in pyridine ring formation
and intermediate (C), followed by proton transfer to obtain
the final spiro{[1,3]dioxanopyridine}-4,6-dione product (4). As
anticipated, the hetero-Diels–Alder reaction follows the endo
rule, providing the product with the two aromatic rings arranged
on the same side, as confirmed by X-ray structural analysis. The
regiochemistry is directed by the polarity of intermediates A
and B, in which the negatively charged a-position of the Kno-
evenagel adduct (A) attacks the positively charged imine carbon
center.
This mechanism explains well why two equivalents of alde-
hyde are necessary to form the spiro{[1,3]dioxanopyridine}-
4,6-dione (4) when 3-methyl-1-phenylpyrazol-5-amine (3) or 3-
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reaction periods, easy work-up, and reduced waste production
by the lack of any requirement for acids or metal promoters.
J1 = 7.2 Hz, J2 = 16.0 Hz, CH2), 2.53 (dd, 1H, J1 = 5.6 Hz,
J2 = 16.0 Hz, CH2), 1.84 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6) (d, ppm): 169.3, 148.7, 142.8, 141.4, 134.7, 131.1,
128.8, 128.5, 112.7, 106.8, 101.5, 33.3, 9.4. IR (KBr, n, cm-1):
3179, 3132, 3049, 2985, 2905, 1638, 1539, 1489, 1414, 1365,
1230, 1087, 1015, 926, 883, 827, 678. HRMS (ESI): m/z calcd
for: 262.0742 [M + H]+, found: 262.0760.
Experimental section
All microwave-assisted reactions were performed in
a
monomodal EmrysTM Creator from Personal Chemistry, Up-
psala, Sweden. Typically, in a 10 mL EmrysTM reaction vial,
Meldrum’s acid as a CH-acid, aldehydes and amine in water
(2 mL) were mixed and the vial then capped. The mixture
Acknowledgements
◦
was irradiated using microwaves at 200 W and 100 C for the
We are grateful for financial support from Qing Lan Project
(08QLT001) of the Jiangsu Education Committee, the Graduate
Foundation of Jiangsu Province (No. CX09S_043Z), the Gradu-
ate Foundation of Xuzhou Normal University (No. 09YLA005),
the Science Foundation in Interdisciplinary Major Research
Project of Xuzhou Normal University (No. 09XKXK01),
the Natural Science Foundation (09KJB150011), the Robert
A. Welch Foundation (D-1361), and NIH (R03DA026960) for
their generous support. We would like to thanks Parminder Kaur
and Gaurav Shakya for their assistance.
time specified. The automatic-mode stirring helped the mixing
and uniform heating of the reactants. Upon completion (as
monitored by TLC), the reaction mixture was cooled to room
temperature and filtered to obtain the crude products, which
were further purified by recrystallization from 95% EtOH.
General procedures for the synthesis of compounds 4 and 5
Preparation of compounds 4. In a 10 mL Emrys reaction vial,
the Meldrum’s acid (1, 1 mmol), aromatic aldehyde (2, 2 mmol),
3-methyl-1-phenylpyrazol-5-amine (3a) or 3-methylisoxazol-5-
amine (3b) (1.0 mmol) and water (2.0 mL) were mixed and the
vial ◦then capped. The mixture was heated for a given time at
100 C under microwave irradiation (initial power 100 W and
maximum power 200 W). Upon completion (as monitored by
TLC), the reaction mixture was cooled to room temperature and
then poured into cold water. The solid product was collected by
Bu¨chner filtration and subsequently recrystallized from EtOH
(95%) to give the pure products.
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the Meldrum’s acid (1, 1 mmol), aromatic aldehyde (2, 1 mmol),
3-methylpyrazol-5-amine (3c) or 3-methyl-1-methylpyrazol-5-
amine (3d) (1.0 mmol) and water (2.0 mL) were mixed and
the vial then capped. The mixture was heated for a given time
at 100 ◦C under microwave irradiation. Upon completion (as
monitored by TLC), the reaction mixture was cooled to room
temperature and then poured into cold water. The subsequent
work-up was the same as in the above reactions.
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