Mn doped ZrO2 as a green, efficient and reusable heterogeneous catalyst for the multicomponent synthesis of pyrano[2,3-d]-pyrimidine derivatives

Article abstract of DOI:10.1039/c5ra06373f

A simple and an efficient method has been developed for the one-pot multicomponent synthesis of pyrano[2,3-d]-pyrimidine derivatives. This was achieved through the condensation reaction between dimethylbarbituric acid, aromatic aldehyde and malononitrile

Full text of DOI:10.1039/c5ra06373f

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Mn doped ZrO2 as a green, efficient and reusable heterogeneous catalyst for
the multicomponent synthesis of pyrano[2,3-d]-pyrimidine derivatives
Surya Narayana Maddila, Suresh Maddila, Werner E. van Zyl*, Sreekantha B. Jonnalagadda*
*School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban-4000, South Africa.
Graphical Abstract:
R
O
CHO
O
N
CN
Mn/ZrO2
N
CN
CN
N
r.t., EtOH:H2O
O
N
O
NH2
O
O
R
4(a-k)
1(a-k)
3
2

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COMMUNICATION
Mn doped ZrO2 as a green, efficient and reusable heterogeneous catalyst
for the multicomponent synthesis of pyrano[2,3-d]-pyrimidine
derivatives
Surya Narayana Maddila, Suresh Maddila, Werner E. van Zyl*, Sreekantha B. Jonnalagadda*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
ZrO2 has good redox and chemical stability and is an acid–based
biꢀfunctional catalyst, which is stable in alkaline or acidic
50 solutions.11 ZrO2 in combination with metals (cermets) have been
used in organic synthesis12 and manganese has previously been
used as dopant in zirconia. The crystalline structure of ZrO2 is
one of the key factors affecting the structureꢀactivity relationships
of Mnꢀbased catalysts.13 The Mn/ZrO2 solid material possesses
55 both Bronsted and Lewis acids centers.
A simple and an efficient method has been developed for the
one-pot multicomponent synthesis of pyrano[2,3-d]-
pyrimidine derivatives. This was achieved through the
10 condensation reaction between dimethylbarbituric acid,
aromatic aldehyde and malononitrile in the presence of a
Mn/ZrO2 heterogeneous catalyst with ethanol/water mixture
as solvent over only 1 hour. Further advantages to this
synthesis methodology include excellent yields, mild reaction
15 conditions, atom economy, environment friendly, reusable
catalyst and no need for chromatographic separations.
Pyranes and pyrimidine derivatives are an important class of
heterocyclic compounds that feature in
a
number of
pharmaceutical drugs and natural products of medicinal interest.
This class of compounds exhibit a range of sought after features
Multicomponent reactions (MCRs) have emerged as an
exciting field of research where three or more reactants are all
added together in a singleꢀstep to afford pure products in high
20 yield. MCRs are mostly used in organic synthesis, biological
discovery, combinatorial library and agrochemical synthesis.1ꢀ4
The simple protocols, inexpensive reactants and green principles
involved make MCRs and attractive field of study.4 Well planned
MCRs afford higher chemical yields than multipleꢀstep syntheses,
25 resulting in conservation of energy and manpower and are often
complete in relatively short reaction times5 making it an
environmentally benign and elegant process.1,6,7
60 including
antimicrobial,14
antioxidant,15
antiꢀtumor,16
antimalarial,17 antimetabolite,17 antileishmanial,18 antiviral,19
antihypertensive,20 antiꢀconvulsant,21 and antiꢀinflammatory
activities.22 The computational chemistry of many of pyrimidine
derivatives has also been documented.23
65
Literature search shows several described methods for
synthesis of various pyrano[2,3ꢀd]pyrimidine derivatives. Such
protocols
employed
[ChꢀOSO3H]3W12PO40,24
diammoniunhydrogenphosphate25 microwave irradiation,26,27
DABCO,28 electrolysis,29,30 γꢀFe2O3@HApꢀSi(CH2)3SO3H,31 Lꢀ
70 proline,32 NaHCO333 and urea34 etc. as catalysts. In general terms,
many of these approaches face few or more of the limitations
such as using toxic reagents, strong acidic or basic conditions,
costly reagents and catalysts, strict reaction conditions, tedious
steps, and low product yields or long reaction times, which limit
75 their use in practical applications. Thus, researchers are
compelled to find new and improved approaches for
environmental friendly synthesis of these heterocyclic molecules
with impressive yields. The best of our knowledge there are no
reports on the multicomponent facile oneꢀpot synthesis of
80 pyrano[2,3ꢀd]pyrimidine derivatives and with EtOH/water
mixture as solvent system. In this manuscript we report the
synthesis of pyrano[2,3ꢀd]ꢀpyrimidine derivatives by using
Mn/ZrO2 as a catalyst in the presence of equal ratio of
EtOH:water for the first time. We report a novel protocol for the
85 synthesis of those derivatives using an inexpensive and robust
catalyst which accomplishes the reactions in short reaction times.
Reactions were carried out during preliminary investigations to
screen for various catalysts and under catalystꢀfree conditions and
varying solvents. Reactions with 1,3ꢀdimethylbarbituric acid (1
The use of heterogeneous catalysts with recyclability and
reusability potential add value to the oneꢀpot reactions involving
30 MCRs.8 The use of heterogeneous catalysts has gained
prominence in the field of heterocyclic synthesis because of
simple workꢀup, cost effectiveness, mild reaction conditions,
atom economy, good activity, easy recyclability and scope to
modify the surface properties.9,10 Heterogeneous materials are
35 used as green reaction media due to their distinct chemical and
physical properties such as nonꢀvolatility, thermal stability, nonꢀ
inflammability, controlled miscibility10 and playing a vital role as
catalysts in the MCRs. Metal oxides are good contenders in this
regard as they have a proven track record as catalysts and
40 supports. Thermal calcination of such materials at 773 K, lead to
the formation of acidic/basic mixed metallic oxides with
moderate surfaceꢀarea and can act as catalysts for various
condensation reactions.
Zirconia (ZrO2) is an interesting support material where a
45 particular zirconia phase (cubic, tetragonal etc.) can be stabilized
down to room temperature by the amount of dopant added and
this can promote the activity of the supported metal catalysts.
This journal is © The Royal Society of Chemistry [year]
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mmol), substituted aldehyde (1 mmol) and malononitrile (1.1
2.5% Mn loading was found optimal with 90 % yield in 1 h
mmol) and water or ethanol as solvent and no catalyst showed no 30 (Table 1, entry 16). A further increase of metal (5%) loading led
reaction at RT even after 12 h under reflux conditions, (Table 1,
entries 1ꢀ4). To obtain the most efficient catalytic conditions, the
title reaction was investigated in the presence of different catalyst
materials such as alumina, silica, MnCl2, and ZnCl2 and in the
to a slight decreased yield (88%) (Table 1, entry 17).
In an effort to find the optimal reaction conditions, the reaction
was carried out using various amounts of catalyst at RT. It was
found that 30 mg catalyst gave a maximum yield of 90% in 1 h.
5
presence of EtOH and water (50:50 v/v). The obtained results are 35 Using more than 30 mg of catalyst for the reaction had no
summarized in (Table 1, entries 5ꢀ8) and indicate that the reaction
did not occur in the presence of alumina or silica, and the yield
10 obtained was very low with MnCl2 or ZnCl2. Further, we tested
the scope of reaction in the presence of ionic liquids such as Lꢀ
proline, (Bmim)BF4 and (Bmim)OH, but yields were low (Table
1, entry 9ꢀ11).
The reactions were also investigated using 30 mg of CuO,
15 MnO2, ZrO2, as catalysts under room temperature conditions in
1:1 ethanol/water mixture. The CuO, MnO2 and ZrO2 gave yields
significant improvement on the yield or the reaction time.
However, the decrease in amount of the catalyst to 20 and 10 mg,
decreased the product yield to 89%, 87%, 73% and 67%,
respectively (Table 1, entries 18ꢀ21).
An interrogation of the experimental results and the effect of
various polar and nonꢀpolar solvents on the three component
reaction clearly indicate that the EtOH/water solvent system plays
a vital role in facilitating the reaction (Table 1), comparatively
less polar solvents like CH3CN, DMF afforded poor yields (Table
40
of 42%, 53% and 48%, respectively (Table 1 entry 12ꢀ14). The 45 1, entries 22,23). The protic polar (ethanol, water) solvents on
reaction was repeated under similar conditions using Mn/ZrO2
which gave an excellent yield of 90% in 1 h once optimum
20 dopant percentage had been established. The impact of Mn
loading on zirconia in tuning its catalytic efficiency was further
their own failed to produce the anticipated high yield (Table 1,
entry 24, 25) but interestingly, the miscible mixture of EtOH:H2O
(50:50 v/v) gave a high 90% yield. This effect can be explained
by
a simple acidꢀbase biꢀfunctional catalysis mechanism
investigated. To find the ideal loading of Mn on ZrO2 on catalyst 50 facilitated by the strong hydrogen bond interaction at the
activity, reactions with 1%, 2% and 5% Mn doped ZrO2 were
carried out under otherwise comparable conditions. The
25 percentage of Mn loading was found to have an influence on the
reaction yield as well as reaction time (Table 1, entries 15ꢀ17).
organic–aqueous ethanol interface which stabilizes the reaction
intermediate. A highlyꢀpolar solvent which dissipates heat faster
possibly provide optimum conditions for the formation of
intermediates, and their conversion to final products on the
Using 1% Mn/ZrO2 catalyst yielded 76% product in 3 h under 55 catalyst surface.
EtOH/water mixture solvent conditions (Table 1, entry 15). A
Table 1. Optimization of reaction conditions of the threeꢀcomponent synthesis.a
Entry
Catalyst
Solvent
Condition
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
No catalyst
No catalyst
No catalyst
No catalyst
Al2O3
SiO2
MnCl2
ZnCl2
Lꢀproline
(Bmim)BF4
Bmim)OH
CuO (30 mg)
MnO (30 mg)
H2O
EtOH
H2O
EtOH
R.T
R.T
Reflux
Reflux
R.T
R.T
R.T
R.T
Reflux
Reflux
Reflux
R.T
R.T
R.T
R.T
R.T
R.T
R.T
24
24
12
12
10
10
5
8
3
4
3.5
6
3.5
4
3
1
1
1
1.5
2
2
3.5
4
ꢀꢀ
ꢀꢀ
Trace
Trace
ꢀꢀ
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
CH3CN
ꢀꢀ
28
18
48
44
51
42
53
48
76
90
88
89
87
73
67
46
35
74
69
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ZrO2 (30 mg)
1% Mn/ZrO2 (30 mg)
2.5% Mn/ZrO2 (30 mg)
5% Mn/ZrO2 (30 mg)
2.5% Mn/ZrO2 (40 mg)
2.5% Mn/ZrO2 (50 mg)
2.5% Mn/ZrO2 (20 mg)
2.5% Mn/ZrO2 (10 mg)
2.5% Mn/ZrO2 (40 mg)
2.5% Mn/ZrO2 (40 mg)
2.5% Mn/ZrO2 (30 mg)
2.5% Mn/ZrO2 (30 mg)
R.T
R.T
R.T
R.T
R.T
R.T
R.T
DMF
EtOH
H2O
3
3.5
aReaction conditions: dimethylbarbituric acid (1 mmol),
substituted aldehyde (1 mmol) and malononitrile (1.1 mmol) and
60 EtOH:water (1:1 v/v, 10 mL), R.T.
ꢀꢀ No reaction
bIsolated yields;
65
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45 demonstrated in Figure 2. The high intensity of the peaks
suggested that all the prepared catalysts are polycrystalline in
nature. The dꢀspacing’s at 2 theta angles of 25.3, 34.9, 38.9, and
55.3 for Mn2O3 respectively. This is in good agreement with the
ICDD PDF No. 65ꢀ7467. From the XRD diffractograms it is
50 evidenced that Mn2O3 is the major phase in all the catalysts.
There is a formation of additional phase i.e Mn3O4 is observed.
The dꢀspacing’s at a 2 theta angles of 32.5, 54.6 and 63.1 for
Mn3O4 which is correspond to the ICDD PDF No. 39ꢀ1218 for
Mn3O4 phase. The ZrO2 showed the sharp peaks corresponding to
55 tetragonal ZrO2 (ICDD PDF No. 88ꢀ1007, 2θ = 25.7, 38.2, 49.8,
and 55.7.
Table 2. Synthesis of pyrano[2,3ꢀd]ꢀpyrimidines derivatives
catalyzed by Mn/ZrO2 catalyst.
Entry
R
Product Yield
(%)
Mp °C
Lit Mp °C
1
2
4ꢀMeOꢀPh
2,3ꢀ(MeO)2ꢀ
Ph
4a
4b
85
86
225ꢀ226
216ꢀ218
225ꢀ227 [29,30
ꢀꢀ
3
2,5ꢀ(MeO)2ꢀ
Ph
4c
85
231–233
ꢀꢀ
4
5
6
7
8
9
10
11
2ꢀBrꢀPh
4ꢀBrꢀPh
2ꢀClꢀPh
3ꢀNO2ꢀPh
3ꢀOHꢀPh
Ph
4d
4e
4f
4g
4h
4i
84
79
78
83
79
84
90
84
202ꢀ203
210ꢀ211
235ꢀ237 237ꢀ238 [29]
221ꢀ223
196ꢀ198
219ꢀ220 219ꢀ222 [29]
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
Mn/ZrO2 Adsorption
Mn/ZrO2 Desorption
2ꢀFꢀPh
3ꢀFꢀPh
4j
4k
237ꢀ238
214ꢀ215
ꢀꢀ
ꢀꢀ
60
aReaction conditions: 1,3ꢀdimethylbarbituric acid (1 mmol),
substituted aldehyde (1 mmol) and malononitrile (1.1 mmol) and
EtOH:water (1:1 v/v, 10 mL), R.T.
5
bAll synthesized compounds are identified and their structures
65
1
were conformed with IR, HNMR, 13C NMR spectral data and
melting points as compared with literature values.
10 ꢀꢀ New compounds/no literature available.
0.0
0.2
0.4
0.6
0.8
1.0
Using the optimised reaction conditions, the applicability of the
protocol was evaluated for the synthesis of other pyrano[2,3ꢀ
d]pyrimidine derivatives with various aromatic aldehydes. The
15 Mn/ZrO2 heterogeneous catalyst proved to be an ideal material
to catalyse the facile oneꢀpot synthesis of pyrano[2,3ꢀd]ꢀ
pyrimidine derivatives with good to excellent yields. All the
reaction products with other details are depicted in Table 2.
Interestingly, the substrates used and reaction yields obtained
20 suggest that irrespective of electronꢀwithdrawing and electron
donating groups in ortho, meta and para positions of the
aromatic ring, using Mn/ZrO2 as catalyst, all the substrates gave
good to excellent yields of desired pyrano[2,3ꢀd]ꢀpyrimidine
derivatives (Table 2). The plausible reaction pathway is shown
25 in Mechanism 1. All the resultant products were characterized
and molecular structures were confirmed by FTIR, 1H NMR,
13C NMR and 15N NMR (GHSQC) spectral analysis (Electronic
Supplementary Information).
70
75
80
85
90
Relative Pressure (P/Po)
Figure 1: BET surface of Mn/ZrO2 catalyst
♦
•
♦
•
ZrO2
Μ
n3O4
# Μn2O3
♦
•
♦
#
#
♦
#
•
•
#
20
30
40
50
60
70
80
90
2θ
30 BET surface and ICP analysis:
Figure. 2. Powder Xꢀray diffractogram spectra of Mn/ZrO2
catalyst
Figure 1 illustrates the N2 adsorption–desorption isotherms and
pore size distribution curves for the Mn doped ZrO2. The catalyst
displays the characteristic hysteresis loop of a Type IV isotherm
(IUPAC) lying in the p/po range of 0.6ꢀ0.95 typical for
35 mesoporous materials. The pore size distribution and specific
area was calculated from the BarrettꢀJoynerꢀHalenda (BJH
adsorption) and BrunauerꢀEmmettꢀTeller methods respectively.
The BET surface area of Mn/ZrO2 was confirmed to be 188.47
m2/g with an average pore size and volume of 11.9 nm and 0.567
40 cm3/g respectively. The metal wt % obtained from ICP is in
correlation with the nominal weight loading.
Infrared-spectra (FT-IR):
Figure 3 displays FTꢀIR spectra of mesoporous Mn on ZrO2
catalyst exhibited characteristic absorption band at 3368.6 cmꢀ1,
1655.4 cmꢀ1 and 1368.3 cmꢀ1 corresponding to the vibration of
95 hydroxyl group, which involve the OꢀH vibrating mode of traces
of adsorbed water. Absorption band at 749.8 cmꢀ1 and 492.3 cmꢀ1
was due to stretching peaks of MnꢀOꢀMn and MnꢀO vibrations,
respectively in accord with literature values.35
A strong
absorption band was observed at 1136.3 cmꢀ1 for the asymmetric
100 stretching of Zr–O group, supporting the formation of ZrO2
groups on their surfaces. No organic groups were found to be
surface adsorbed based on IR results.
Powder X-ray diffractogram (XRD) analysis:
The XRD patterns of the calcined 2% Mn on ZrO2 catalyst are
This journal is © The Royal Society of Chemistry [year]
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Reusability of Mn/ZrO2
To test reusability, a recycling experiment was employed using
60 a model reaction. Thus, after completion of reaction, the catalyst
was recovered by filtration, washed with ethanol and dried under
vacuum. The recovered catalyst was reꢀused for six times with a
slight loss in catalytic activity (Figure 6). The minor loss
perceived in the catalytic activity after 6th run could be due to
65 poisoning by organic impurities.
5
10
15
Mn/ZrO
2
100
80
70
4000 3500 3000 2500 2000 1500 1000 500
Wavelength (cm-1)
60
Figure 3. FTꢀIR image of Mn/ZrO2 catalyst
40
SEM & TEM analysis:
75
20
The SEM image of the prepared catalyst is shown in Figure 4.
20 The catalyst was crystalline in nature but with a coarse surface
morphology. The manganese oxide particles were observed as
hexagonalꢀshaped particles which were dispersed on the surface
0
1
2
3
4
5
6
Catalytic Cycles
of the zirconia. The manganese oxide particles are shown in a red 80 Figure 6. Recyclability of Mn/ZrO2 catalyst
colour circles in Figure 4. These observations are also in
25 agreement with literature.36 The TEM images showed that the
zirconia particles are irregular and ovalꢀshaped. The red circles in
Figure 5 shows the manganese oxide particles which might be
agglomerated on the surface of zirconia.
Conclusions
In conclusion, we report an environmentally benign and an
efficient oneꢀpot multicomponent green synthesis of pyranoꢀ[2,3ꢀ
85 d]ꢀpyrimidine derivatives using Mn/ZrO2 as catalyst in green
solvent media and with good atom efficiency. This simple and
recyclable heterogeneous catalyst, Mn/ZrO2 shows high catalytic
activity for multicomponent reactions. The current method deals
several advantages such as short reaction time, costꢀeffectiveness,
90 purity of products, excellent yields, use of small amount of
inexpensive catalyst and environmentally benign green solvent.
30
35
Acknowledgements
Authors are grateful to the National Research Foundation of
95 South Africa for financial support and University of KwaZuluꢀ
Natal for the research facilities.
40
Notes and references
Figure 4. SEM image of Mn/ZrO2 catalyst
School of Chemistry & Physics, University of KwaZulu-Natal, Westville
100 Campus, Chiltern Hills, Durban-4000, South Africa. Fax: +27 31 260
3091; Tel: +27 31 260 7325/3090; E-mail: jonnalagaddas@ukzn.ac.za
45
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
105
50
Catalyst Preparation
Mn doped ZrO2 of various wt.% was prepared by a wet impregnation
technique as described in our earlier reports.37,38 5.0 g of zirconium oxide
powder (Alfa Aesar Chemical) was suspended in 250 mL of double
110 distilled water and mixed with the desired masses of MnCl2 (Manganese
(II) chloride tetrahydrate, Aldrich) based on the weight percentages of
interest. The mixture was stirred for 4 h using a magnetic stirrer at room
temperature (RT) and then heated to 90 °C for 4 h. The precipitate was
dried in an air oven at 110ꢀ120 °C for 12 h, followed by calcination at 450
55
Figure 5. TEM image of Mn/ZrO2 catalyst
4
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°C for 5 h to afford the 1%, 2.5% & 5% w/w of the Mn/ZrO2 catalysts.
General Procedure for the synthesis of pyrano[2,3-d]-pyrimidines:
A solution containing dimethylbarbituric acid (1 mmol), substituted
aldehyde (1 mmol), malononitrile (1.1 mmol) and Mn/ZrO2 (30 mg) in
mixture of EtOH:H2O (1:1 v/v, 10 mL) was continuously stirred for 1.0 h
at RT using a magnetic stirrer (Scheme 1). The progress and completion
DMSOꢀd6) δ 7.22 (s, 2H, NH2); IR (KBr, cmꢀ1): 3317, 2937, 2188, 1681,
35 1645, 1474; HRMS of [C18H18N4O5 + Na] (m/z): 393.1166; Calcd.:
393.1175..
7-Amino-5-(2,5-dimethoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-
tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4c): 1H NMR
(400 MHz, DMSOꢀd6) δ = 3.07 (s, 3H, NCH3), 3.38 (s, 3H, NCH3), 3.65
5
of the reaction was monitored by TLC. The reaction mixture was then 40 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 4.58 (s, 1H, CH), 6.64 (d, J = 3.02
filtered, and the filtrate was subsequently evaporated under reduced
pressure to obtain the crude product which was recrystallized with ethanol
Hz, 1H, ArH), 6.74 (dd, J = 8.9, 3 Hz, 1H, ArH), 6.89 (d, J = 8.9 Hz, 1H,
ArH), 7.15 (s, 2H, NH2); 13C NMR (100 MHz, DMSOꢀd6): δ 27.59, 29.00,
31.32, 55.22, 56.34, 57.63, 88.05, 111.51, 112.76, 115.37, 119.02, 130.99,
150.00, 150.23, 151.52, 153.15, 158.15, 160.34; 15N NMR (40.55 MHz,
45 DMSOꢀd6) δ 7.15 (s, 2H, NH2); IR (KBr, cmꢀ1): 3302, 3175, 2934, 2194,
1715, 1683, 1634, 1599, 1487; HRMS of [C18H18N4O5 ─ H] (m/z):
369.0389; Calcd.: 371.0395.
10 to afford pure product (4aꢀk). The recovered catalyst was subjected to
washing with ethanol, dried and reꢀused for up to six cycles.
R
O
7-Amino-5-(2-bromophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4d): 1H NMR (400 MHz,
50 DMSOꢀd6) δ = 3.05 (s, 3H, NCH3), 3.36 (s, 3H, NCH3), 4.86 (s, 1H, CH),
7.11ꢀ7.15 (m, 1H, ArH), 7.28 (d, J = 4.2 Hz, 2H, ArH), 7.33 (s, 2H, NH2),
7.53 (d, J = 8.00 Hz, 1H, ArH); 13C NMR (100 MHz, DMSOꢀd6): δ 27.58,
29.12, 35.80, 57.36, 88.23, 118.42, 122.77, 128.07, 128.64, 130.25,
132.45, 149.97, 151.47, 157.64, 160.28; 15N NMR (40.55 MHz, DMSOꢀ
55 d6) δ 7.33 (s, 2H, NH2); IR (KBr, cmꢀ1): 3310, 2930, 2913, 1684, 1637,
1470; HRMS of [C16H13BrN4O3 ─ H] (m/z): 387.0103; Calcd.: 387.0093..
7-Amino-5-(4-bromophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4e): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.07 (s, 3H, NCH3), 3.34 (s, 3H, NCH3), 4.32 (s, 1H, CH),
60 7.21 (d, J = 8.00 Hz, 2H, ArH), 7.35 (s, 2H, NH2), 7.47 (d, J = 8.00 Hz,
2H, ArH); 13C NMR (100 MHz, DMSOꢀd6): δ 27.62, 29.09, 36.04, 58.03,
88.22, 118.85, 119.80, 129.67, 131.07, 143.54, 149.95, 151.15, 157.57,
160.43; 15N NMR (40.55 MHz, DMSOꢀd6) δ 7.35 (s, 2H, NH2); IR (KBr,
cmꢀ1): 3426, 3299, 2930, 2189, 1683, 1633, 1487.
CHO
O
N
CN
Mn/ZrO2
N
CN
CN
N
r.t., EtOH:H2O
O
N
O
NH2
O
O
R
4(a-k)
1(a-k)
3
2
Scheme 1: Synthesis of pyrano[2,3-d]-pyrimidine derivatives
H
CN
O
CN
O
H
N
H
HO
NC
N
N
C
CN
O
NC
NC
N
O
Catalyst
Catalyst
Knoevenagel
Condensation
Dehydration
R
R
O
N
R
R
N
O
O
R
R
65 7-Amino-5-(2-chlorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4f): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.06 (s, 3H, NCH3), 3.36 (s, 3H, NCH3), 4.86 (s, 1H, CH),
7.23ꢀ7.36 (m, 6H, ArH, NH2); 13C NMR (100 MHz, DMSOꢀd6): δ 27.59,
29.11, 33.52, 57.18, 87.97, 118.52, 127.46, 128.37, 129.24, 132.17,
70 141.08, 149.97, 151.50, 157.76, 160.28; 15N NMR (40.55 MHz, DMSOꢀ
d6) δ 7.30 (s, 2H, NH2); IR (KBr, cmꢀ1): 3382, 3310, 3193, 2959, 2193,
1703, 1684, 1638, 1474; HRMS of [C16H13ClN4O3 ─ H] (m/z): 343.0992;
O
N
O
H
CN
CN
N
Cyclization
N
C
NH
O
O
N
O
NH2
O
Mechanism 1. Plausible reaction mechanism for the formation of
pyrano[2,3-d]-pyrimidine derivatives
15
Calcd.: 343.1008.
7-Amino-5-(3-nitrophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
75 1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4g): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.01 (s, 3H, NCH3), 3.34 (s, 3H, NCH3), 5.12 (s, 1H, CH),
7.43 (d, J = 8.00 Hz, 1H, ArH), 7.48 (s, 2H, NH2), 7.51 (s, 1H, ArH), 7.64
(t, J = 8.00, 1H, ArH), 7.83 (d, J = 8.00 Hz, 1H, ArH); 13C NMR (100
MHz, DMSOꢀd6): δ 27.57, 29.11, 30.77, 56.62, 88.33, 118.40, 123.63,
80 128.02, 130.73, 133.42, 138.38, 149.05, 149.87, 151.82, 158.31, 160.50;
15N NMR (40.55 MHz, DMSOꢀd6) δ 7.48 (s, 2H, NH2); IR (KBr, cmꢀ1):
3373, 3306, 3184, 2957, 2196, 1706, 1683, 1632, 1522, 1490; HRMS of
[C16H13N5O5 ─ H] (m/z): 354.0844; Calcd.: 354.0838.
7-Amino-5-(3-hydroxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-
85 tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4h): 1H NMR
(400 MHz, DMSOꢀd6) δ = 3.09 (s, 3H, NCH3), 3.35 (s, 3H, NCH3), 4.21
(s, 1H, CH), 6.58ꢀ6.66 (m, 3H, ArH), 7.06 (t, J = 8.00 Hz, 1H, ArH), 7.29
(s, 2H, NH2), 8.42 (s, 1H, OH); 13C NMR (100 MHz, DMSOꢀd6): δ 27.65,
29.05, 36.35, 58.62, 88.98, 113.76, 114.15, 117.92, 119.05, 129.19,
90 145.48, 149.94, 150.96, 157.22, 160.43, 165.86; 15N NMR (40.55 MHz,
DMSOꢀd6) δ 7.29 (s, 2H, NH2); IR (KBr, cmꢀ1): 3370, 3303, 3199, 2965,
2197, 1783, 1636, 1598, 1484; HRMS of [C16H14N4O4 ─ H] (m/z):
325.0894; Calcd.: 325.0900.
7-Amino-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-
tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4a): 1H NMR
(400 MHz, DMSOꢀd6) δ = 3.07 (s, 3H, NCH3), 3.36 (s, 3H, NCH3), 3.72
(s, 3H, OCH3), 4.31 (s, 1H, CH), 6.83 (d, J = 8.2 Hz, 2H, ArH), 7.14 (d, J
20 = 8.04 Hz, 2H, ArH), 7.29 (s, 2H, NH2); 13C NMR (100 MHz, DMSOꢀd6):
δ 27.64, 29.74, 35.81, 55.02, 58.55, 89.09, 113.64, 119.17, 128.18,
136.81, 149.95, 150.87, 157.88, 158.38, 160.45; 15N NMR (40.55 MHz,
DMSOꢀd6) δ 7.29 (s, 2H, NH2); IR (KBr, cmꢀ1): 3368, 3307, 3181, 2965,
2188, 1682, 1680, 1605, 1508; HRMS of [C17H16N4O4 ─ H] (m/z):
25 339.2011; Calcd.: 339.2021.
7-Amino-5-(2,3-dimethoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-
tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4b): 1H NMR
(400 MHz, DMSOꢀd6) δ = 3.06 (s, 3H, NCH3), 3.36 (s, 3H, NCH3), 3.75
(s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.61 (s, 1H, CH), 6.71 (d, J = 7.04
30 Hz, 1H, ArH), 6.87 (d, J = 8.00, 1H, ArH), 6.94 (t, J = 7.96, 1H, ArH),
7.22 (s, 2H, NH2); 13C NMR (100 MHz, DMSOꢀd6): δ 27.59, 29.07,
31.06, 55.49, 58.15, 59.90, 83.77, 111.29, 119.07, 120.70, 123.60, 136.99,
146.32, 149.94, 151.28, 152.24, 157.85, 160.37; 15N NMR (40.55 MHz,
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DOI: 10.1039/C5RA06373F
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7-Amino-1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]-pyrimidine-6-carbonitrile (4i): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.07 (s, 3H, NCH3), 3.35 (s, 3H, NCH3), 4.31 (s, 1H, CH),
7.18ꢀ7.28 (m, 5H, ArH), 7.30 (s, 2H, NH2); 13C NMR (100 MHz, DMSOꢀ
d6): δ 27.63, 29.07, 36.47, 58.63, 88.78, 119.01, 126.73, 127.28, 129.49,
130.44, 144.08, 149.97, 151.09, 157.63, 160.45; 15N NMR (40.55 MHz,
DMSOꢀd6) δ 7.30 (s, 2H, NH2); IR (KBr, cmꢀ1): 3380, 3307, 3193, 2866,
2196, 1703, 1682, 1639, 1607, 1493; HRMS of [C16H14N4O3 ─ H] (m/z):
309.0984; Calcd.: 309.0988.
65
20
21
22
23
5
70
10 7-Amino-5-(2-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4j): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.06 (s, 3H, NCH3), 3.35 (s, 3H, NCH3), 4.61 (s, 1H, CH),
7.11 (t, J = 7.68 Hz, 2H, ArH), 7.24ꢀ7.27 (m, 2H, ArH), 7.35 (s, 2H,
NH2); 13C NMR (100 MHz, DMSOꢀd6): δ 27.60, 29.07, 30.42, 57.16,
15 87.59, 115.36, 118.74, 124.43, 128.70, 128.78, 129.69, 149.95, 151.43,
157.93, 158.78, 160.75; 15N NMR (40.55 MHz, DMSOꢀd6) δ 7.35 (s, 2H,
NH2); IR (KBr, cmꢀ1): 3384, 3311, 3194, 2962, 2195, 1683, 1637, 1509,
1488; HRMS of [C16H13FN4O3 ─ H] (m/z): 327.0889; Calcd.: 327.0893.
7-Amino-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-
20 1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4k): 1H NMR (400 MHz,
DMSOꢀd6) δ = 3.07 (s, 3H, NCH3), 3.34 (s, 3H, NCH3), 4.36 (s, 1H, CH),
7.02ꢀ7.10 (m, 3H, ArH), 7.32ꢀ7.34 (m, 3H, ArH, NH2); 13C NMR (100
MHz, DMSOꢀd6): δ 27.62, 29.08, 36.20, 58.10, 88.11, 113.89, 114.50,
118.85, 123.45, 130.05, 147.01, 147.07, 149.99, 151.29, 157.62, 160.51;
25 15N NMR (40.55 MHz, DMSOꢀd6) δ 7.32 (s, 2H, NH2); IR (KBr, cmꢀ1):
3382, 3305, 3192, 2194, 1711, 1683, 1635, 1613, 1490.
75 24
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