Glycerol as a biodegradable and reusable promoting medium for the catalyst-free one-pot three component synthesis of 4H-pyrans

Article abstract of DOI:10.1039/c2gc35135h

Glycerol is applied as a green, biodegradable and reusable promoting medium for one-pot three component synthesis of 4H-pyrans under catalyst-free conditions. A broad range of substrates including aromatic and heteroaromatic aldehydes, isatine derivatives

Full text of DOI:10.1039/c2gc35135h

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Green Chemistry
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PAPER
Glycerol as a biodegradable and reusable promoting medium for the
catalyst-free one-pot three component synthesis of 4H-pyrans
Hamid Reza Safaei,* Mohsen Shekouhy,* Sudabeh Rahmanpur and Athar Shirinfeshan
Received 28th January 2012, Accepted 15th March 2012
DOI: 10.1039/c2gc35135h
Glycerol is applied as a green, biodegradable and reusable promoting medium for one-pot three
component synthesis of 4H-pyrans under catalyst-free conditions. A broad range of substrates including
aromatic and heteroaromatic aldehydes, isatine derivatives, acenaphthenequinone and ninehydrine are
condensed with carbonyl compounds possessing a reactive α-methylene group and alkylmalonates.
All reactions are completed in short times, and the products are obtained in good to excellent yields.
The reaction medium could be recycled and reused several times without any loss of efficiency.
products to be removed by simple liquid–liquid phase extraction.
Moreover, glycerol is non-volatile under normal atmospheric
Introduction
It is well known that most organic reactions occur in a liquid
phase. The solvent not only allows a better contact between reac-
tants, stabilises or destabilises intermediates and/or transition
states but also determines the choice of work up procedures and
recycling or disposal strategies. Based on the principles of green
chemistry, a green solvent should meet numerous criteria such as
low toxicity, non-flammability, non-mutagenicity, non-volatility
and widespread availability among others. Moreover these green
solvents have to be cheap and easy to handle and recycle.1 In
the past decade, water,2 ionic liquids,3 polyethylene glycol,4
supercritical fluids5 (particularly supercritical carbon dioxide
(scCO2)6) and perfluorinated solvents7 have appeared as the
most promising options for current solvent innovation. Although
fascinating results have been reported, the use of these solvents
is still subject to strict limitations such as high cost equipment
for scCO2,8 or high prices and lack of data about the toxicity
and bio-compatibility for ionic liquids,9 or product separation
for aqueous-based processes.10 In other words, a universal green
solvent doesn’t exist and for this reason, the scientific commu-
nity is continuously searching for new sustainable media in
order to widen their use in catalytic and organic processes.
Glycerol is a green and biodegradable material produced as a
by-product in the biodiesel industry. In its pure form, glycerol is
a sweet-tasting, clear, colourless, odourless and viscous liquid.
Like polar solvents such as water, DMSO and DMF, glycerol is
able to facilitate the dissolution of inorganic salts, acids, bases,
enzymes and many transition metal complexes. Furthermore, it
also dissolves organic compounds that are poorly miscible in
water. Many hydrophobic solvents, such as ethers and hydro-
carbons, are immiscible in glycerol. This enables the reaction
pressure and has a high boiling point (290 °C), thus making dis-
tillation of the reaction products a feasible separation technique.
Reactions in glycerol can be carried out at high temperatures,
thus allowing acceleration of the reaction, or making possible
reactions that do not proceed in low boiling point solvents.
Besides, glycerol is a nontoxic (LD50 (oral rat) = 12 600 mg
kg−1), biodegradable and non-flammable solvent for which no
special handling precautions or storage is required. In particular,
the low toxicity of glycerol also allows its use as a solvent in the
synthesis of pharmaceutically active ingredients, in which the
toxicity and residue of solvents have to be carefully controlled.
Because of these unique properties, there is a large number of
reports on the application of glycerol as an efficient and con-
venient solvent in organic transformations.11 More recently Hei
et al. demonstrated that glycerol is an effective promoting
medium for electrophilic activation of aldehydes and they
showed that some reactions which have been conventionally
carried out using acid catalysts, can be performed under catalyst-
free conditions in the presence of glycerol as a reaction
medium.12
It is well known that pyrans are important core units in a
number of natural products13 and photochromic materials.14
Compounds with a pyran ring system have many pharmacologi-
cal properties and play important roles in biochemical pro-
cesses.14 Moreover, 4H-pyrans are useful intermediates for the
synthesis of various compounds, such as pyranopyridine deriva-
tives,15 polyazanaphthalenes,16 pyrano[2]pyrimidines,17 and
pyridin-2-ones.18 Therefore, preparation of this heterocyclic
nucleus has gained great importance in organic synthesis.
Recently, several methods have been reported for the synthesis
of pyran derivatives via a three component condensation of
β-dicarbonyl compounds with aldehydes and alkylmalonates.19
Various catalytic systems such as hexadecyltrimethyl ammonium
bromide (HMTAB),20 triethylbenzylammonium chloride
(TEBA),21 rare earth perfluorooctanoate (RE(PFO)3),22
Department of Applied Chemistry, Faculty of Science, Shiraz Branch,
Islamic Azad University, PO Box 71993-5, Shiraz, Iran.
E-mail: hrs@iaushiraz.net, m.shekouhy@gmail.com; Fax: +98(711)
6412488; Tel: +98(711)6402715
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(S)-proline,23 amino functionalized ionic liquids,24 MgO,25 SiO2
nanoparticles26 and silica bonded n-propyl-4-aza-1-azoniabicy-
clo[2.2.2]octane chloride (SB-DABCO)27 have been used for the
synthesis of 4H-pyrans so far. However, most of these methods
suffer from such drawbacks as low yields, long reaction times,
harsh reaction conditions, tedious work-up procedures, tedious
steps for the preparation of catalyst, application of toxic and
expensive catalysts, application of hazardous solvents for the
work up and lack of generality. Moreover, in most of the reported
methods, catalysts are not recyclable. Therefore, development
of an efficient, one-pot and chemoselective procedure for the
synthesis of 4H-pyrans is of considerable interest.
A survey of literature shows that the one-pot three component
synthesis of 4H-pyrans can be catalyzed in the presence of acidic
as well as basic catalysts. Indeed, to the best of our knowledge,
there are no reports on the diversity-oriented catalyst-free syn-
thesis of a library of this type of biologically active compounds.
Thus, based on the above facts and as a part of our research
program to develop selective, efficient and green catalyst-free
methods in organic synthesis28 we report herein the application
of glycerol as a green, biodegradable, reusable and efficient pro-
moting medium for the diversity-oriented synthesis of 4H-pyrans
via a one-pot three component condensation reaction between
carbonyl compounds 1, carbonyl compounds possessing a reac-
tive α-methylene group 2 and alkylmalonates 3 under catalyst-
free conditions (Scheme 1).
under catalyst-free conditions at various temperatures, and the
results are listed in Table 1 (Scheme 2).
Only a trace amount of products were detected in toluene,
DMF, DMSO, n-butyl acetate and in neat conditions (entries 1–4
and 14). While the reaction proceeded sluggishly in ethanol, a
huge improvement was observed in polyethylene glycol and
ethylene glycol (entries 5–7). Although water was proved to be
capable of promoting the reaction, in this case, a gummy solid
was obtained which makes the separation of products very hard
(entry 8). Inspired by the observed determinant effect of alco-
holic solvents on the reaction, we then investigated the efficiency
of glycerol as a solvent for this reaction. As we expected, the
reaction proceeded very well, and 93% yield was obtained under
identical conditions (entry 12). As shown in Table 1, the best
results were obtained at 80 °C in the presence of glycerol
(1 mL). Interestingly, all starting materials are soluble in gly-
cerol, so at the start of the reaction, a solution, which seemed to
be nearly transparent, was observed. All obtained products were
found to be insoluble in glycerol, so with progress of the reac-
tion, wrought products sediment slowly from the reaction
mixture.
Table 1 The catalyst-free condensation reaction between benzaldehyde
(1a, 1 mmol), dimedone (2b, 1 mmol) and malononitrile (3, 1 mmol)
under various conditions
Temp.
(°C)
Time
(min)
Yielda
(%)
Entry Solv. (1 mL)
1
2
3
4
5
6
7
8
Toluene
DMF
DMSO
n-Butyl acetate
Ethanol
Poly ethylene glycol 400
Ethylene glycol
Water
Glycerol
Glycerol
80
80
80
80
80
80
80
80
r.t.
50
60
80
100
80
360
360
360
360
360
90
<15
<15
<15
<15
48
83
80
71
23
76
89
Results and discussions
Initially, the reaction between benzaldehyde (1a), dimedone (2b)
and malononitrile (3a) was investigated in different solvents
90
130
360
360
190
60
60
360
9
10
11
12
13
14
Glycerol
Glycerol
Glycerol
—
93
93
<15
a Isolated yields.
Scheme 2 The catalyst-free condensation reaction between benzal-
dehyde (1a, 1 mmol), dimedone (2b, 1 mmol) and malononitrile (3a,
1 mmol).
Scheme 1 The catalyst-free one-pot three component synthesis of 4H-
pyrans in glycerol at 80 °C.
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It should be noted that the synthesis of 4H-pyran derivatives
via the one-pot three component condensation reaction between
carbonyl compounds, carbonyl compounds possessing a reactive
α-methylene group and alkylmalonates are generally carried out
in the presence of acids or bases, or metal-containing catalysts
with the aid of organic solvents or ionic liquids. Obviously,
these reported methods not only generate a lot of organic or inor-
ganic wastes during the work-up procedure, but also suffer from
the difficulty of removing trace amounts of residue metal species
from the product when it is applied in pharmaceutical synthesis.
Particularly, in the case of solid acids and solid bases, a large
amount of organic solvent has to be used for the separation and
recovery of the catalyst owing to the fact that both the catalyst
and the product are solid. Performing the model reaction in
glycerol not only offers a high reaction yield, but also avoids the
generation of toxic wastes, the use of large amount of organic
solvents or catalysts and tedious post-treatment. Therefore, our
system is an attractive strategy for the synthesis of the target
compound from the viewpoint of green synthesis.
With these results in hand, we then investigated the substrate
scopes and limitations of the synthesis of 4H-pyrans in glycerol
as a promoting medium, and the results are listed in Table 2. As
it is shown in Table 2, all reactions proceeded efficiently and the
desired products were produced in good to excellent yields in
relatively short reaction times without formation of any by-pro-
ducts. Aromatic aldehydes having electron withdrawing groups
(Table 2, entries 4ad, 4ai, 4at, 4aw, 4az, 4bk, 4bn, 4bo and
4bq) reacted at faster rates compared with those that substituted
with electron releasing groups (Table 2, entries 4al, 4ao, 4ap,
4au, 4ax, 4ba, 4bw and 4bx). Besides, our methodology has
been used successfully in order of acid and base sensitive
materials such as heteroaromatic aldehydes, and corresponding
4H-pyrans were obtained in excellent yields and without any by-
products (Table 2, entries 4aj, 4ak, 4as, 4aw, 4bb, 4bi, 4be). As
it is clear from the obtained results, the presented methodology
can be used in order of oxygen and sulfur containing heteroaro-
matic aldehydes. Due to the high hydrophilicity of glycerol, sep-
aration of the products from the reaction mixture could be
realized by adding water at 80 °C. This simple procedure allows
easy scale up of our methodology. In another study, to recognize
the applicability of our method at large scales, we examined
reactions in scales of 50 mmol and the results obtained are sum-
marized in Table 2. As shown in Table 2, the reactions were suc-
cessfully performed at large scales without significant loss of
yield.
spiro compounds containing pyrans have also been proved. They
also show good activity as hypertensive agents.36 They have
been the subject of great interest as potential novel analgesic
agents.37 Considering these facts, our methodology was applied
successfully for the synthesis of a broad range of spiro-4H-
pyrans (Table 3) via a one-pot three component reaction of
isatine derivatives 5(a–e), acenaphthenequinone 6 and/or ninhy-
drin 7 with carbonyl compounds possessing a reactive α-methyl-
ene group and alkylmalonates (Scheme 1).
It is well known that during the reaction of carbonyl com-
pounds with alkylmalonate derivatives, 3-cyanopyridine-2(1H)-
ones and 2,6-dicyanoanilines are two possible side products.
Moreover, hydrolysis of nitrile groups can occur.43 In our
attempts, we only obtained 4H-pyrans. The selectivity in the syn-
thesis of 4H-pyrans in the presence of glycerol can be explained
by the strict sequence of reactions in Scheme 3. We believe that
the presence of the reactive –OH groups in the structure of gly-
cerol plays a major role in its promoting activity for the
formation of olefin 9 which readily prepares in situ from
Knoevenagel condensation of aldehyde 1 with highly active CH-
acidic cyanoacetic ester derivative 3. Then, carbonyl compound
3 in the presence of glycerol converts to its corresponding
enolate form 10 and adds to the unsaturated nitrile 9 by Michael
reaction to produce intermediate 11, and enolate oxygen attacks
the nucleophilic nitrile group (Thorpe–Ziegler type reaction).
Finally, after the tautomeric proton shift, 4H-pyrans 4 are
formed.
It may be speculated that the polar amphoteric hydroxyl
groups of the glycerol facilitate the interaction of weak acidic
and basic components due to the stabilization of the correspond-
ing transition states and intermediates by hydrogen bonding.
This is noteworthy that there are two possible stereoisomers
(E amd Z) for intermediate 9 when ethyl or methyl cyanoacetate
is used instead of malononitrile. In another study, benazalde-
hyde, 4-nitrobenzaldehyde, 4-chlorobenzaldehyde and 4-
methoxybenzaldehyde were treated with ethyl cyanoacetate
under optimized conditions and the obtained products were
single diastereomers whose geometries were identified to be
E according to 1H NMR spectra of literature precedents.44
The possibility of recycling the glycerol was examined using
the reaction of benzaldehyde (1a) and dimedone (2b) with malo-
nonitrile (3a) under the optimized conditions. Upon completion,
water (5 mL) was added to the reaction mixture, shaked
thoroughly, and insoluble products separated by simple filtration
and recrystalized from EtOH. In order to recover the glycerol,
water was evaporated under reduced pressure at 100 °C. The
recovered glycerol was reused twenty times in the condensation
of benzaldehyde (1a) and dimedone (2b) with malononitrile (3a)
without any loss of activity.
It is well known that numerous medicinally active and natural
compounds with biological applications contain an indole
nucleus in their molecular structures.32 Besides, the spiro-
oxindole system is the core structure of many pharmacological
agents and natural alkaloids.33 For example, spirotryprostatin A,
a natural product isolated from the fermentation broth of Asper-
gillus fumigatus has been identified as a novel inhibitor of micro-
tubule assembly33 and pteropodine and isopteropodine have
been shown to modulate the function of muscarinic and seroto-
nin receptors.34 Spiro compounds represent an important class
of naturally occurring substances characterized by highly pro-
nounced biological properties. The spiro functionality has been
known for a long time to be present in phytochemicals such as
alkaloids, lactones and terpenoids.35 Biological activities of
Conclusions
In summary, we have reported a highly efficient, catalyst-free
and green method for the one-pot three-component synthesis of
4H-pyran derivatives using glycerol as an inexpensive, bio-
degradable, commercially available and reusable promoting
medium. This method not only offers substantial improvements
in the reaction rates and yields, but also avoids the use of
1698 | Green Chem., 2012, 14, 1696–1704
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Table 2 The glycerol promoted catalyst-free one-pot three component synthesis of 4H-pyran derivatives at 80 °C
1 mmol of Sub.
Time (min)
50 mmol of Sub.
Time (min)
Entry
Sub.
R
X
Yield (%)a
Yielda (%)
M.P.
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2a
2a
2a
2a
2a
2c
2c
2c
2c
2c
2c
2d
2d
2d
2d
2e
2e
2e
2f
Ph
4-Cl–Ph
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CN
CO2Me
CN
CN
CO2Me
CN
CN
CN
CN
CN
CN
CO2Me
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
60
60
80
35
70
50
80
100
90
80
70
90
90
110
75
80
60
70
65
50
90
80
50
80
70
45
95
85
70
70
75
110
120
150
110
180
130
70
100
50
50
93
95
91
96
91
93
90
92
93
92
92
90
93
91
93
92
92
90
93
91
90
92
95
93
94
94
92
91
93
95
92
90
94
91
92
90
93
91
91
95
92
90
94
93
91
93
92
92
90
93
90
100
110
80
110
90
130
150
150
110
110
120
150
140
110
150
100
110
100
90
130
120
90
110
110
70
120
120
110
110
110
160
160
180
130
250
150
110
130
90
89
88
89
92
84
91
85
83
81
85
86
88
88
84
89
84
89
89
89
91
84
86
90
87
82
89
88
83
85
90
85
89
89
84
88
84
86
87
85
89
87
88
90
85
88
85
82
86
83
87
224–226 (226–228)29
213–215 (213–215)29
230–232 (233–235)27
175–176 (175–177)29
257–258 (258–260)27
221–223
4-OEt–Ph
4-NO2–Ph
2-Naphthalene
Ph–CO–
3-OPh–Ph
2-Naphthalene
4-CF3–Ph
2-Thionyl
4-CN–Ph
4-C3H7–Ph
4-OEt–Ph
4-OEt–Ph
4-Me–Ph
3-OMe–Ph
3-Cl–Ph
195–196 (193–195)27
187–188 (188–190)27
153–155 (155–156)27
222–223 (220–222)27
182–183 (180–182)27
188–190
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
4as
4at
4au
4av
4aw
4ax
4ay
4az
4ba
4bb
4bc
4bd
4be
4bf
4bg
4bh
4bi
235–237
151–152 (149–150)27
233–235 (232–233)27
246–247
254–254 (254–255)27
208–210 (209–211)27
167–168 (168–169)27
183–185 (182–184)27
166–168
2-Cl–Ph
2-Thionyl
4-CF3–Ph
4-OEt–Ph
2-Naphthalene
4-CN–Ph
4-C3H7–Ph
Ph
4-NO2–Ph
4-OMe–Ph
2-Furyl
Ph
4-F–Ph
2-Furyl
Ph
4-Br–Ph
4-Me–Ph
2-Furyl
4-Cl–Ph
4-NO2–Ph
4-Cl–Ph
2-OMe–Ph
4-NO2–Ph
2-NO2–Ph
2-Cl–Ph
3-NO2–Ph
3-Cl–Ph
230–232
218–219 (217–219)27
159–161 (158–160)27
218–219 (216–217)30
242–244 (240–241)30
197–198 (195–196)30
171–172 (170–171)30
288–290 (287–288)30
230–232 (231–232)30
227–228 (226–227)30
255–257 (256–258)31
250–251 (252–254)31
255–256 (253–255)31
251–253 (251–252)31
191–193 (192–194)31
240–241 (241–243)31
263–265
2f
2f
2f
2f
4bj
4bk
4bl
2f
2g
2g
2g
2g
2g
2g
2g
2g
2g
2g
4bm
4bn
4bo
4bp
4bq
4br
4bs
4bt
4bu
4bv
4bw
4bx
231–232
262–263
264–266
228–229
264–265
266–268
>300
>300
278–279
283–282
297–298
>300
90
130
95
120
140
135
140
170
190
190
85
50
75
100
100
110
110
150
150
4-Cl–Ph
4-Cl–Ph
3-Cl–Ph
3-Cl–Ph
4-OMe–Ph
4-OMe–Ph
2g
2g
a Isolated yields.
hazardous catalysts or solvents. The promising points for the pre-
sented methodology are efficiency, generality, high yield, short
reaction time, cleaner reaction profile, ease of product isolation,
simplicity, potential for recycling of the reaction medium, and
finally, agreement with green chemistry protocols, making it a
useful and attractive process for the synthesis of 4H-pyran
derivatives. Moreover, the presented method can be used in large
scale synthesis. Compared with previously reported systems
composed of acid or base catalysts and organic solvents, appli-
cation of glycerol as a solvent not only makes the product separ-
ation much easier, but also shows higher environmental
compatibility and sustainability due to the avoidance of a
quenching step, reduced reliance on toxic organic solvents, and
minimization of waste.
Experimental
Reagents and solvents were purchased from Merck, Fluka or
Aldrich. Melting points were determined in capillary tubes in an
electro-thermal C14500 apparatus. The progress of the reaction
and the purity of compounds were monitored by TLC analytical
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Table 3 Glycerol-promoted catalyst-free one-pot three component synthesis of spiro-4H-pyrans at 80 °C
Entry
Subs./X
Carbonyl compound
Time (min)
Yielda (%)
M.P.
8aa
8ab
8ac
8ad
8ae
8af
8ag
8ah
8ai
2b/CN
2a/CN
2c/CN
2d/CN
2e/CN
2d/CO2Et
2c/CN
2f/CN
2f/CN
5a
5a
5a
5a
5a
5a
5a
5a
5c
5e
5a
5a
5e
5d
5d
5d
5b
5b
5b
5e
6
60
75
65
75
70
80
85
80
80
85
80
95
75
70
75
95
75
90
85
70
120
90
90
90
120
120
135
130
130
91
91
93
91
90
92
92
91
93
91
91
90
93
92
92
90
93
91
92
91
93
93
91
93
90
92
92
91
92
291–293 (290–292)38
297–298 (298–299)38
249–250 (248)39
220–222 (222)39
233–235 (236)39
227–228 (229)40
206–208 (208)39
281–282 (283–285)40
>300 (>300)40
>300 (>300)40
226–227
8aj
8ak
8al
2f/CN
2c/CO2Me
2b/CO2Et
2b/CN
2a/CN
2c/CN
2a/CO2Et
2b/CN
2f/CN
2a/CO2Me
2a/CN
2f/CO2Et
2c/CN
2g/CN
2g/CN
2g/CO2Et
2g/CO2Me
2g/CO2Et
2g/CO2Me
2g/CO2Et
238–239
8am
8an
8ao
8ap
8aq
8ar
8as
8at
8au
8av
8aw
8ax
8ay
8az
8ba
8bb
8bc
277–278 (278–280)41
281–282
241 (dec.)
270–272 (273–274)42
>300 (>300)41
279–281 (278–280)41
274 (dec.)
280–281
240–242
197–198
296–298
191–193
228–230
242–244
225–227
6
5a
7
5a
5a
7
7
5c
259–261
272–274
a Isolated yields.
General procedure for the large scale synthesis of 4H-pyran
derivatives
silica gel plates (Merck 60 F250). All known compounds were
1
identified by comparison of their melting points and H NMR
1
data with those in the authentic samples. The H NMR (500 and
To a mixture of carbonyl compound (50 mmol), carbonyl com-
pound possessing a reactive α-methylene group (50 mmol) and
alkylmalonate (50 mmol) in a 200 mL round-bottomed, two-
necked flask fitted with an efficient mechanical stirrer and a
reflux condenser, was added glycerol (50 mL), and the resulting
mixture was stirred in an oil-bath (80 °C). The progress of the
reaction was monitored by TLC using EtOAc–n-hexane (1 : 4) as
an eluent. After completion of the reaction, warm water (50 mL)
was added. Glycerol dissolved in the water and the insoluble
crude products were isolated by simple filtration. The crude pro-
ducts were dissolved in warm EtOH or aqueous EtOH (60 mL)
and were allowed to stand at room temperature for 24 h.
The crystalline solids were collected, washed with ethanol
(3 × 10 mL) and dried. The filtrate containing glycerol was
extracted with methyl tert-butyl ether (2 × 50 mL) to remove
any organic compounds dissolved in the aqueous phase. The
aqueous layer was separated and the water was evaporated under
reduced pressure at 100 °C to give pure glycerol which was used
for the next run under similar reaction conditions.
400 MHz) and 13C NMR (125 and 100 MHz) were run on a
Bruker Avance DPX-250, FT-NMR spectrometer. Chemical
shifts are given as δ values against tetramethylsylane as the
internal standard and J values are given in Hz. Microanalysis
was performed on a Perkin-Elmer 240-B microanalyzer.
General procedure for the synthesis of 4H-pyran derivatives
To a mixture of carbonyl compound (1 mmol), carbonyl com-
pound possessing a reactive α-methylene group (1 mmol) and
alkylmalonate (1 mmol) in a 10 mL round-bottomed flask con-
nected to a reflux condenser, was added glycerol (1 mL), and the
resulting mixture was stirred in an oil-bath (80 °C). The progress
of the reaction was monitored by TLC using EtOAc–n-hexane
(1 : 4) as an eluent. After completion of the reaction, warm water
(5 mL) was added. Glycerol dissolved in the water and the inso-
luble crude products were isolated by simple filtration. The crude
products were dissolved in warm EtOH or aqueous EtOH (6 mL)
and were allowed to stand at room temperature for 5–6 h. The
crystalline solids were collected and dried. The filtrate containing
glycerol was extracted with methyl tert-butyl ether (2 × 5 mL) to
remove any organic compounds dissolved in the aqueous phase.
The aqueous layer was separated and the water was evaporated
under reduced pressure at 100 °C to give pure glycerol which
was used for the next run under similar reaction conditions.
Selected spectral data
2-Amino-4-benzoyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (compound 4af). White powder, 1H
NMR (DMSO-d6, 500 MHz): δ 1.05 (s, 3H), 1.07 (s, 3H), 2.12
1700 | Green Chem., 2012, 14, 1696–1704
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Scheme 3 The proposed mechanism for the synthesis of 4H-pyrans in the presence of glycerol as a promoting media.
(AB System, J = 16.0 Hz, 1H), 2.34 (AB System, J = 16.0 Hz,
1H), 2.41 (AB System, J = 17.5 Hz, 1H), 2.61 (AB System, J =
17.5 Hz, 1H), 4.98 (s, 1H), 7.23 (s, 2H), 7.55 (t, J = 7.75 Hz,
2H), 7.68 (t, J = 7.5 Hz, 1H), 8.05(d, J = 7.5 Hz, 2H). 13C NMR
(DMSO-d6, 125 MHz): δ 27.2, 29.5, 33.2, 36.7, 50.4, 53.0,
111.5, 119.9, 129.5, 129.7, 134.4, 136.6, 160.9, 164.8, 196.8,
199.4. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69.
Found: C, 70.83; H, 5.62; N, 8.72.
(m, 2H), 2.58–2.63 (m, 2H), 3.72 (s, 3H), 4.16 (s, 1H),
6.67–6.77 (m, 3H), 6.97 (s, 2H), 7.20 (t, J = 8.0 Hz, 1H). 13C
NMR (DMSO-d6, 125 MHz): δ 20.6, 27.3, 36.1, 37.1, 55.7,
58.9, 112.2, 114.1, 114.5, 120.1, 120.6, 130.3, 147.2, 159.3,
160.0, 165.3, 196.6. Anal. Calcd for C17H16N2O3: C, 68.91; H,
5.44; N, 9.45;. Found: C, 69.01; H, 5.45; N, 9.49.
6-Amino-3-methyl-4-(naphthalen-2-yl)-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (compound 4av). White
1
2-Amino-4-(4-isopropylphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
powder, H NMR (DMSO-d6, 500 MHz): δ 1.75 (s, 3H), 4.86
hydro-4H-chromene-3-carbonitrile
(compound
4al). White
(s, 1H), 7.26 (s, 2H), 7.31–7.37 (m, 2H), 7.48–7.51 (m, 4H),
7.80–7.93 (6H). 13C NMR (DMSO-d6, 125 MHz): δ 13.4, 37.8,
58.9, 99.2, 120.8, 126.7, 126.8, 127.0, 127.1, 128.4, 128.6,
129.3, 130.2, 133.1, 133.7, 138.4, 141.7, 144.8, 146.2, 160.3.
Anal. Calcd for C24H18N4O: C, 76.17; H, 4.79; N, 14.81.
Found: C, 76.21; H, 4.81; N, 14.85.
1
powder, H NMR (DMSO-d6, 500 MHz): δ 0.97 (s, 3H), 1.03
(s, 3H), 1.16 (s, 6H), 2.11 (AB system, J = 16.0 Hz, 1H), 2.24
(AB system, J = 16.o Hz, 1H), 2.49–2.51 (Distorted AB system,
2H), 2.81–2.86 (m, 1H), 4.13 (s, 1H), 6.95 (s, 2H), 7.04 (d, J =
8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H). 13C NMR (DMSO-d6,
125 MHz): δ 24.6, 24.7, 27.7, 29.2, 32.6, 33.8, 36.0, 50.8, 59.4,
113.7, 120.6, 127.1, 127.8, 143.0, 147.3, 159.3, 163.3, 196.5.
Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33; Found:
C, 74.91; H, 7.22; N, 8.19.
7-Amino-5-(4-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carbonitrile (compound 4bl). White
1
powder, H NMR (DMSO-d6, 500 MHz): δ 4.37 (s, 1H), 6.97
(s, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 9.2
(s, 1H), 11.1 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 35.8,
59.3, 80.1, 119.1, 127.9, 130.0, 131.1, 142.6, 150.4, 159.3,
160.3, 163.1. Anal. Calcd for C14H9ClN4O3: C, 53.09; H, 2.86;
N, 17.69. Found: C, 53.14; H, 2.92; N, 17.77.
2-Amino-4-(4-ethoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (compound 4am). White powder, 1H
NMR (DMSO-d6, 500 MHz): δ 1.29 (t, J = 7.0 Hz, 3H),
1.85–1.94 (m, 2H), 2.23–2.29 (m, 2H), 2.49–2.60 (m, 2H),
3.94–3.99 (m, 2H), 4.14 (s, 1H), 6.80–6.83 (m, 2H), 6.93
(s, 2H), 7.04–7.06 (m, 2H). 13C NMR (DMSO-d6, 125 MHz): δ
14.1, 21.3, 28.9, 36.6, 38.9, 58.2, 64.5, 113.1, 114.5, 119.0,
129.3, 135.3, 155.0, 156.7, 159.1, 198.5. Anal. Calcd for
C18H18N2O3: C, 69.66; H, 5.85; N, 9.03;. Found: C, 69.71; H,
5.88; N, 9.12.
7-Amino-5-(2-methoxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (compound 4bm).
1
White powder, H NMR (DMSO-d6, 500 MHz): δ 3.64 (s, 3H),
4.29 (s, 1H), 6.84–6.88 (m, 2H), 6.87–6.89 (m, 3H), 7.13 (d, J =
8.0 Hz, 1H), 9.01 (s, 1H), 10.88 (s, 1H). 13C NMR (DMSO-d6,
125 MHz): δ 29.1, 54.3, 58.8, 78.9, 112.1, 119.0, 120.6, 121.3,
125.9, 130.0, 151.4, 158.8, 159.3, 160.0, 163.5. Anal. Calcd for
C15H12N4O4: C, 57.69; H, 3.87; N, 17.94. Found: C, 57.62; H,
3.82; N, 7.98.
2-Amino-4-(3-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
1
chromene-3-carbonitrile (compound 4ap). White powder, H
NMR (DMSO-d6, 500 MHz): δ 1.87–1.96 (m, 2H), 2.27–2.31
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7-Amino-5-(4-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carbonitrile (compound 4bn).
White powder, H NMR (DMSO-d6, 500 MHz): δ 3.29 (s, 1H),
7.08 (s, 2H), 7.49 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H),
9.41 (s, 1H), 10.93 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ
35.4, 58.2, 79.9, 119.3, 123.5, 125.9, 143.8, 150.5, 150.8, 159.0,
160.1, 163.8. Anal. Calcd for C14H9N5O5: C, 51.38; H, 2.77; N,
21.40. Found: C, 51.45; H, 2.84; N, 21.49.
4.94 (s, 1H), 7.05 (s, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.35 (d, J =
8.0 Hz, 2H), 9.09 (s, 1H), 11.01 (s, 1H). 13C NMR (DMSO-d6,
125 MHz): δ 35.4, 61.5, 76.4, 80.3, 127.8, 130.0, 131.3, 142.1,
143.6, 160.5, 162.5, 163.7, 167.4. Anal. Calcd for
C15H12ClN3O5: C, 51.51; H, 3.46; N, 12.02. Found: C, 51.61;
H, 3.48; N, 12.11.
1
Methyl 7-amino-5-(3-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]pyrimidine-6-carboxylate
(compound
4bu).
1
7-Amino-5-(2-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
White powder, H NMR (DMSO-d6, 500 MHz): 3.83 (s, 3H),
4.06 (s, 1H), 6.98 (s, 2H), 7.10–7.21 (m, 2H), 7.29 (d, J = 8.1
Hz, 1H), 7.36 (s, 1H), 9.12 (s, 1H), 10.98 (s, 1H). 13C NMR
(DMSO-d6, 125 MHz): δ 35.8, 52.6, 76.9, 78.8, 124.9, 125.0,
127.7, 129.6, 133.3, 143.1, 150.0, 160.1, 160.4, 163.3, 167.1.
Anal. Calcd for C15H12ClN3O5: C, 51.51; H, 3.46; N, 12.02.
Found: C, 51.54; H, 3.41; N, 12.08.
pyrano[2,3-d]pyrimidine-6-carbonitrile
(compound
4bo).
1
White powder, H NMR (DMSO-d6, 500 MHz): δ 4.48 (s, 1H),
7.04 (s, 2H), 7.49–7.56 (m, 2H), 7.74 (d, J = 8.0 Hz, 2H), 8.01
(d, J = 8.5 Hz, 1H), 9.08 (s, 1H), 10.89 (s, 1H). 13C NMR
(DMSO-d6, 125 MHz): δ 31.6, 59.2, 79.5, 119.3, 123.9, 126.9,
129.8, 130.9, 133.7, 147.1, 150.6, 159.0, 160.6, 163.3. Anal.
Calcd for C14H9N5O5: C, 51.38; H, 2.77; N, 21.40. Found: C,
51.46; H, 2.71; N, 21.49.
Ethyl 7-amino-5-(3-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]pyrimidine-6-carboxylate
(compound
4bv).
1
7-Amino-5-(2-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
White powder, H NMR (DMSO-d6, 500 MHz): 0.99 (t, J = 7.5
Hz, 3H), 3.83 (m, 2H), 4.11 (s, 1H), 6.99 (s, 2H), 7.11–7.25
(m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 9.10 (s, 1H),
11.01 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 13.6, 35.7,
52.8, 76.9, 78.8, 124.8, 125.0, 127.9, 129.6, 133.5, 143.0,
150.2, 160.1, 160.3, 163.2, 167.2. Anal. Calcd for C16H14-
ClN3O5: C, 52.83; H, 3.88; N, 11.55. Found: C, 52.90; H,
3.3.84; N, 11.61.
pyrano[2,3-d]pyrimidine-6-carbonitrile
(compound
4bp).
1
White powder, H NMR (DMSO-d6, 500 MHz): δ 4.31 (s, 1H),
6.98 (s, 2H), 7.16–7.34 (m, 3H), 7.58 (d, J = 8.1 Hz, 1H), 9.12
(s, 1H), 11.08 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 30.9,
58.4, 80.1, 119.0, 126.7, 126.9, 127.6, 128.8, 131.5, 142.9,
149.6, 157.5, 160.4, 163.4. Anal. Calcd for C14H9ClN4O3: C,
53.09; H, 2.86; N, 17.69. Found: C, 53.17; H, 2.81; N, 17.72.
7-Amino-5-(3-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carbonitrile (compound 4bq). Yel-
lowish powder, H NMR (DMSO-d6, 500 MHz): δ 4.33 (s, 1H),
7.03 (s, 2H), 7.56–7.63 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 8.16
(s, 1H), 9.15 (s, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6,
125 MHz): δ 34.9, 58.0, 79.9, 119.2, 120.8, 121.5, 132.9, 133.6,
143.1, 145.6, 150.0, 158.5, 160.6, 163.7. Anal. Calcd for
C14H9N5O5: C, 51.38; H, 2.77; N, 21.40. Found: C, 51.32; H,
2.81; N, 21.49.
Ethyl 7-amino-5-(4-methoxyphenyl)-2,4-dioxo-2,3,4,5-tetrahy-
dro-1H-pyrano[2,3-d]pyrimidine-6-carboxylate (compound 4bw).
Yellow powder, 1H NMR (DMSO-d6, 500 MHz): 1.01 (t, J = 7.3
H, 3H), 3.84–3.89 (m, 5H), 4.86 (s, 1H), 6.84 (d, J = 8.0 Hz,
2H), 7.03 (s, 2H), 7.13 (d, J = 8.0 Hz, 2H), 9.09 (s, 1H), 11.0 (s,
1H). 13C NMR (DMSO-d6, 125 MHz): δ 14.3, 36.9, 56.2, 61.3,
76.4, 79.5, 114.1, 130.0, 135.5, 136.9, 150.5, 156.3, 160.9,
162.3, 163.3, 167.6. Anal. Calcd for C17H17N3O6: C, 56.82; H,
4.77; N, 11.69. Found: C, 56.89; H, 4.82; N, 11.75.
1
7-Amino-5-(3-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carbonitrile (compound 4br). White
powder, H NMR (DMSO-d6, 500 MHz): δ 4.59 (s, 1H), 7.06
(s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.24–7.33 (m, 2H), 7.41
(s, 1H), 9.11 (s, 1H), 10.91 (s, 1H). 13C NMR (DMSO-d6,
125 MHz): δ 35.9, 59.1, 80.1, 119.0, 124.9, 125.7, 127.9, 130.1,
133.8, 142.9, 150.6, 158.8, 160.4, 163.9. Anal. Calcd for
C14H9ClN4O3: C, 53.09; H, 2.86; N, 17.69. Found: C, 53.18; H,
2.80; N, 17.75.
Methyl 7-amino-5-(4-methoxyphenyl)-2,4-dioxo-2,3,4,5-tetra-
hydro-1H-pyrano[2,3-d]pyrimidine-6-carboxylate
(compound
1
4bx). Yellow powder, 1H NMR (DMSO-d6, 500 MHz): 3.42
(3, 3H), 3.76 (s, 3H), 4.91 (s, 1H), 6.81 (d, J = 8.2 Hz, 2H),
7.01 (s, 2H), 7.15 (d, J = 8.2 Hz, 2H), 9.06 (s, 1H), 10.99
(s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 36.6, 56.1, 61.2,
76.6, 79.4, 114.0, 130.2, 135.6, 136.7, 150.6, 156.1, 160.0,
162.4, 163.5, 167.9. Anal. Calcd for C16H15N3O6: C, 55.65; H,
4.38; N, 12.17. Found: C, 55.71; H, 4.31; N, 12.20.
Ethyl 7-amino-5-(4-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-
Methyl 2-amino-5′-bromo-2′,5-dioxo-5,6,7,8-tetrahydrospiro-
[chromene-4,3′-indoline]-3-carboxylate (compound 8as). White
powder, H NMR (DMSO-d6, 500 MHz): 1.86–1.88 (m, 2H),
1H-pyrano[2,3-d]pyrimidine-6-carboxylate (compound 4bs).
1
1
White powder, H NMR (DMSO-d6, 500 MHz): δ 0.98 (t, J =
7.5 Hz, 3H), 3.98 (m, 2H), 4.91 (s, 1H), 7.06 (s, 2H), 7.19
(d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 9.11 (s, 1H), 10.98
(s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 13.6, 35.5, 61.3,
76.4, 80.4, 127.8, 130.1, 131.2, 142.0, 143.3, 160.7, 162.3,
163.7, 167.9. Anal. Calcd for C16H14ClN3O5: C, 52.83; H, 3.88;
N, 11.55. Found: C, 52.88; H, 3.91; N, 11.59.
2.17–2.21 (m, 2H), 2.62–2.64 (m, 2H), 3.27 (s, 3H), 6.62 (d, J =
8.0 Hz, 1H), 7.02 (s, 1H), 7.19 (dd, J = 2.0, 8.0 Hz, 1H), 7.87
(s, 1H), 10.29 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 20.4,
27.8, 37.8, 47.9, 51.0, 76.9, 110.7, 112.9, 114.4, 126.1, 130.7,
139.3, 144.1, 159.8, 165.7, 168.3, 180.4, 195.8. Anal. Calcd for
C18H15BrN2O5: C, 51.57; H, 3.61; N, 6.68; found C, 51.60; H,
3.62; N, 6.65.
Methyl 7-amino-5-(4-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahy-
dro-1H-pyrano[2,3-d]pyrimidine-6-carboxylate (compound 4bt).
White powder, H NMR (DMSO-d6, 500 MHz): 3.54 (s, 3H),
2-Amino-5′-methyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-
4,3′-indoline]-3-carbonitrile (compound 8at). White powder, 1H
1
1702 | Green Chem., 2012, 14, 1696–1704
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Methyl 7′-amino-2,2′,4′-trioxo-1′,2′,3′,4′-tetrahydrospiro-
NMR (DMSO-d6, 500 MHz): 1.76–1.78 (m, 2H), 2.18 (s, 3H),
2.21–2.23 (m, 2H), 2.41–2.44 (m, 2H), 6.68 (d, J = 7.0 Hz, 1H),
6.76 (s, 1H), 6.96 (d, J = 7.75 Hz, 1H), 7.16 (s, 2H), 10.28
(s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 20.4, 27.8,
37.8, 47.9, 51.0, 76.9, 110.7, 112.9, 114.4, 126.1, 130.7, 139.3,
144.1, 159.8, 165.7, 168.3, 177.4, 195.8. Anal. Calcd for
C18H15N3O3: C, 67.28; H, 4.71; N, 13.08; found C, 67.35; H,
4.77; N, 13.15.
[indoline-3,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate
(com-
pound 8az). White powder, 1H NMR (DMSO-d6, 500 MHz):
3.92 (S, 3H), 7.01 (s, 2H), 7.11 (m, 1H), 7.21–7.29 (m, 3H),
9.10 (s, 1H), 9.71 (s, 1H), 11.01 (s, 1H). 13C NMR (DMSO-d6,
125 MHz): δ 53.2, 61.7, 79.5, 80.0, 114.2, 123.6, 127.62,
127.67, 129.1, 140.8, 149.8, 160.3, 162.3, 163.7, 167.1, 168.6.
Anal. Calcd for C16H12N4O6: C, 53.94; H, 3.39; N, 15.73; found
C, 53.98; H, 3.33; N, 15.80.
Ethyl 2′-amino-2,5′-dioxo-2H,5′H-spiro[acenaphthylene-1,4′-
pyrano[2,3-b]chromene]-3′-carboxylate (compound 8au). Yel-
lowish powder, 1H NMR (DMSO-d6, 500 MHz): 1.22 (t, J = 7.0
Hz, 3H), 3.32–3.37 (m, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.52–7.57
(m, 2H), 7.72–7.79 (m, 2H), 7.67 (d, J = 7.5 Hz, 2H), 8.08
(d, J = 7.5 Hz, 1H), 8.17–8.20 (m, 3H). 13C NMR (DMSO-d6,
125 MHz): δ 13.1, 52.1, 59.5, 77.3, 105.8, 113.4, 117.3, 120.8,
120.9, 123.6, 123.7, 125.2, 125.7, 128.8, 129.2, 130.1, 131.1,
134.3, 135.8, 142.2, 144.7, 152.7, 154.9, 159.6, 159.7, 167.8,
205.6. Anal. Calcd for C26H17NO6: C, 71.07; H, 3.90; N, 3.19;
found C, 71.14; H, 3.96; N, 3.22.
Ethyl 7′-amino-1,2′,3,4′-tetraoxo-1,1′,2′,3,3′,4′-hexahydrospiro
[indene-2,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate
(com-
pound 8ba). Yellowish powder, 1H NMR (DMSO-d6,
500 MHz): 1.06 (t, J = 7.6 Hz, 3H), 3.95 (m, 2H), 7.03 (S, 2H),
8.06 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, H), 9.11 (s, 1H),
10.96 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 14.1, 61.3,
63.9, 78.8, 79.3, 125.1, 132.9, 141.0, 152.3, 159.8, 161.9,
162.3, 163.8, 167.6, 196.8. Anal. Calcd for C18H13N3O7: C,
56.40; H, 3.42; N, 10.96; found C, 56.46; H, 3.45; N, 10.91.
Methyl 7′-amino-1,2′,3,4′-tetraoxo-1,1′,2′,3,3′,4′-hexahydros-
piro[indene-2,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate (com-
pound 8bb). Yellowish powder, 1H NMR (DMSO-d6,
500 MHz): 3.93 (s, 3H), 7.01 (S, 2H), 8.04 (d, J = 8.5 Hz, 2H),
8.15 (d, J = 8.5 Hz, H), 9.08 (s, 1H), 10.98 (s, 1H). 13C NMR
(DMSO-d6, 125 MHz): δ 59.9, 63.7, 78.5, 79.2, 125.0, 132.9,
141.0, 152.3, 159.6, 161.9, 162.7, 163.8, 167.5, 196.6. Anal.
Calcd for C17H11N3O7: C, 55.29; H, 3.00; N, 11.38; found C,
5.33; H, 3.07; N, 11.32.
6′-Amino-3′-methyl-2-oxo-1′-phenyl-1′H,2H-spiro[acenaphthylene-
1,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile (compound 8av). Yellow-
ish powder, 1H NMR (DMSO-d6, 500 MHz): 1.06 (s, 3H),
7.35–7.37 (m, 1H), 7.51–7.54 (m, 2H), 7.59–7.64 (m, 3H),
7.78–7.82 (m, 3H), 7.92–7.95 (m, 1H), 8.08–8.11 (m, 2H), 8.42
(d, J = 8.0 Hz, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 12.9,
53.6, 58.6, 116.5, 118.9, 121.1, 122.5, 124.6, 125.3, 125.6,
126.8, 128.9, 129.7, 129.9, 130.8, 131.4, 132.7, 136.2, 141.9,
152.5, 177.3, 197.8. Anal. Calcd for C25H16N4O2: C, 74.25; H,
3.99; N, 13.85; found C, 74.31; H, 4.05; N, 13.90.
Ethyl 7′-amino-5-chloro-2,2′,4′-trioxo-1′,2′,3′,4′-tetrahydros-
piro[indoline-3,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate (com-
1
pound 8bc). White powder, H NMR (DMSO-d6, 500 MHz):
1.09 (t, J = 7.3 Hz, 3H), 3.84 (m, 2H), 6.98 (s, 2H), 7.21
(m, 1H), 7.38 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 9.12 (s, 1H),
9.76 (s, 1H), 11.10 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ
14.3, 46.9, 61.7, 78.9, 111.6, 126.9, 128.9, 129.3, 131.0, 138.9,
150.7, 160.1, 162.1, 163.9, 167.0, 168.3. Anal. Calcd for
C17H13ClN4O6: C, 50.45; H, 3.24; N, 13.84; found C, 50.48; H,
3.26; N, 13.87.
7′-Amino-2,2′,4′-trioxo-1′,2′,3′,4′-tetrahydrospiro[indoline-3,5′-
pyrano[2,3-d]pyrimidine]-6′-carbonitrile
(compound
8aw).
1
White powder, H NMR (DMSO-d6, 500 MHz): 6.95 (s, 2H),
7.05 (t, J = 8.3 Hz, 1H), 7.21–7.30 (m, 3H), 9.03 (s, 1H), 9.66
(s, 1H), 11.03 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 47.6,
58.2, 79.8, 114.5, 117.1, 123.9, 127.81, 127.86, 129.3, 140.9,
150.4, 158.6, 159.9, 163.9, 168.8. Anal. Calcd for C15H9N5O4:
C, 55.73; H, 2.81; N, 21.66; found C, 55.78; H, 2.85; N, 21.72.
Acknowledgements
7′-Amino-1,2′,3,4′-tetraoxo-1,1′,2′,3,3′,4′-hexahydrospiro[indene-
2,5′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile (compound 8ax).
White powder, H NMR (DMSO-d6, 500 MHz): 7.01 (s, 2H),
The authors thank the Research Committee of Islamic Azad Uni-
versity (Shiraz Branch) for financial support of this work.
1
8.01 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 9.08 (s, 1H),
11.03 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 58.1, 64.2,
80.0, 116.5, 124.6, 131.3, 140.9, 151.1, 158.9, 160.8, 162.3,
196.4. Anal. Calcd for C16H8N4O5: C, 57.15; H, 2.40; N, 16.66;
found C, 57.21; H, 2.44; N, 16.72.
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This journal is © The Royal Society of Chemistry 2012
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