A catalyst free, multicomponent-tandem, facile synthesis of pyrido[2,3-d]pyrimidines using glycerol as a recyclable promoting medium

Article abstract of DOI:10.1039/c5nj01938a

A clean and efficient, multicomponent-tandem strategy for the synthesis of pyrido[2,3-d]pyrimidines is reported in glycerol, a biodegradable and reusable promoting medium. The advantages of the present methodology includes a one-pot catalyst free environm

Full text of DOI:10.1039/c5nj01938a

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DOI: 10.1039/C5NJ01938A
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LETTER
Catalyst Free, Multicomponent-Tandem Facile
Synthesis of Pyrido [2, 3-d] pyrimidines Using Glycerol
as a Recyclable Promoting Media
Cite this: DOI: 10.1039/c3nj00000x
Swastika Singh,a Mohammad Saquib,a Mandavi Singh,a Jyoti Tiwari,a Fatima Tufail,a
Jaya Singh,b Jagdamba Singha*
Received 00thXXXXX 2013,
Accepted 00thXXXXX 2013
DOI: 10.1039/c3nj00000x
www.rsc.org/njc
OH
HO
HN
O
Abstract A clean and efficient, multicomponent tandem
OH
HN
N
OH
strategy for synthesis of pyrido [2, 3-
d] pyrimidines is
O
OH
N
N
N
O
N
N
O
HO
HN
reported in glycerol, biodegradable and reusable
a
N
HN
NH
N
N
O
promoting media. Advantages of the present methodology
includes a one pot catalyst free environment friendly
approach, 100 % atom economy, cost effectiveness, broad
substrate scope, operational simplicity, short reaction times,
easy workup procedure and high yields.
H2N
N
H
PDꢀ06989616
RTK inhibitors
Folic acid14
Riboflavin15
O
Cl
O
N
O
N
N
NH2
O
N
NH2
OH
N
N
O
N
N
NH
N
N
N
N
N
Multicomponent reactions have recently been recognized as a major
new expansion in synthetic organic chemistry. They allow the
assembly of complex molecules in one pot, thus maximizing
synthetic efficiency and reducing costs. In the last few decades there
has been a growing emphasis on sustainable chemistry due to the
global push to improve green credential.1 Utilization of
multicomponent reactions for sustainable synthesis holds great
promise in organic synthesis however this area still remains underꢀ
utilised. One major thrust area in green chemistry is the replacement
of the toxic organic solvents with sustainable and green solvents. 2
Cdk4 inhibition18
IC50 = 0.004 mM
Antiꢀtumor activity17
eEFꢀ2K inhibitors19
(IC50 = 420 mM)
µ
IC50 = 3.74 g/mL; MCF7
Figure 1. Some examples of biologically relevant compounds having pyrido
[2, 3ꢀ d]pyrimidine skeleton
A large number of methods for synthesis of pyrido[2,3ꢀ
d]pyrimidines have already been reported in literature20ꢀ22 such as
by using nanoꢀcrystalline MgO as catalyst,22b using sulfonic acid
functionalized SBAꢀ15,20a using HApꢀencapsulatedꢀ ꢀFe2O3
supported sulfonic acid nanocatalyst,22a using Vitamin B1, in
20b
In this context perfluorinatedsolvents3, water4, ionic liquids5,
polyethylene glycol6, and supercritical fluids (particularly
supercritical carbon dioxide ꢀ scCO2)7etc. have been used as
potential alternatives to conventional organic solvents. But their use
involves many limitations, forcing the scientific community to look
for alternative green solvents. In this backdrop glycerol has emerged
as an attractive solvent. It possesses the benefits of both water and
ionic liquids like low toxicity, relatively low vapour pressure, easy
availability, reusability, inexpensiveness, renewability, high boiling
point and ability to dissolve a wide range of organic and inorganic
ionic liquid,22c using ZrO2 Nanoparticles,20d using diammonium
hydrogen phosphate (DAHP),20c using TBAB (tetraꢀbutyl
ammonium bromide),20f using TEBAC (triethylbenzylammonium
chloride),20e using KF–Alumina,21d and using palladium 1994.21e
.
However, in spite of their potential usefulness, many of these
reported methods suffer from drawbacks such as the use of
environmentally harmful organic solvents, expensive catalysts,
harsh reaction conditions, difficult workꢀup, nonꢀrecyclability of
solvents, commercial unavailability and low yields.22Therefore,
the development of newer more efficient and greener methods for
synthesis of pyrido[2,3ꢀd]pyrimidines remains a highly active
research field, as evidenced by the increasing number of reports
compounds.8 9 Development of catalyst free reactions is another area
’
that has attracted much attention in green chemistry due to the
inherent advantages involved in terms of cost and environment.10, 11
on the synthesis of pyridopyrimidines in the last ten years.13aꢀm,20
.
Pyrimidines represent one of the most biologically, and
pharmaceutically active class of compounds.12 When this pyrimidine
moiety is fused with different heterocycles, it results in hybrid
scaffolds with improved activity. Pyrido [2, 3ꢀd] pyrimidine is one
such pyrimidine based hybrid scaffold which has attracted
considerable attention due to their broad biological and medicinal
applications.13
To the best of our knowledge, catalyst free synthesis of pyrido [2,
3ꢀ d] pyrimidine has still not been reported. Consequently, in
continuation of our ongoing research programon the development
of green synthetic routes to important heterocyclic molecules23, we
herein report a new, catalyst free, clean and efficient oneꢀpot
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 1-3 | 1

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VJieowuArrtnicalelONnlainme e
COMMUNICATION
DOI: 10.1039/C5NJ01938A
7
9
Ethanol
PEGꢀ400
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
None
None
None
None
None
None
None
60 °C
80 °C
80 °C
60 °C
40 °C
RT
6 h
4 h
1.5 h
3h
4 h
6 h
60
63
94
86
80
76
94
O
N
O
10.
11.
12.
13.
14.
HN
CN
CHO
CN
HN
O
NH2
CN
O
N
N
4
NH2
CH3
3
CH3
100 °C
1.5 h
2
1
a All reactions were carried out with 1 (1 mmol), 2 (1mmol), 3 (1mmol) in 5
mL of solvent under air.b Isolated yieldsc. M.P. of compound 4 was found to
be 303 ꢀ 306 °C (Reported >300 °C)20b
Scheme 1. General synthetic strategy
synthesis of
pyrido[2,3ꢀd]pyrimidines using glycerol as a
promoting media.
Once ideal conditions for conducting the reaction had been
identified, the scope and limitations of the developed synthetic
protocol was explored under the optimized reaction conditions with
aldehydes having different substituents (Table 2). In all the cases the
desired product wasobtained in high yield and short reaction times
(Table 2). It was observed that when an electron withdrawing group
was present on the aldehyde, the reaction proceeded faster and the
product was formed in higher yield, while the presence of an
electron donating group slowed down the reaction and led to reduced
yield of the product (Table 2).
In our initial endeavour we conducted a model reaction using
benzaldehyde (1, 1mmol), and malononitrile (2, 1 mmol) in water at
room temperature (RT). A clear solution was obtained after 30
minutes with the disappearance of the starting material spots and
formation of a new spot on TLC, indicating the formation of the
cyanoꢀolefin intermediate. To the reaction mixture containing the
cyanoꢀolefin was added6ꢀaminoꢀ1ꢀmethyl uracil (3, 1mmol).
However no further reaction was observed even after 12 h of stirring
(Table 1). We further performed the same experiment at 60 °C and
then under reflux, but in both cases the product was formed only in
traces (Table 1). The experiment was also performed in presence of
CTAB and SDS respectively at RT as well as under reflux but with
little success and product was formed only in trace amount even
after 12 h of stirring. Now in order to improve the yield we decided
to screen different solvents. The reaction was first performed in
ethanol at 60°C without using any catalyst. To our delight the
reaction occurred in this case leading to the formation of solid
product in moderate yield (60 %), which was identified as product 4,
after about 5 h 30 min of addition of the third compound (6ꢀaminoꢀ1ꢀ
methyluracil,3) to the reaction mixture. The reaction was now reꢀ
conducted at reflux but no improvement in yield was observed
though reaction time got marginally reduced (5 h). In our effort to
further improve the yield, the experiment was carried out using
PEGꢀ400 at 75 °C but with little success as there was only a
marginal increase in yield in this case (63 %). However use of
glycerol in place of PEG led to a remarkable enhancement in yield
(94%) and considerable reduction in reaction time (1.5 h). The
experiment was now repeated at lower temperatures; 60 °C, 40 °C
and RT (Table 1). However it was noticed that there was a decrease
in yield and increase in reaction time with decreasing temperature.
Table 2. Substrate scopea
R1
O
R3
O
R3
Glycerol, 80 o
60 - 90 min
C
CHO
N
CN
CN
CN
R1
N
O
N
NH2
O
N
N
NH2
R2
6-16
2
3 R2 = CH3; R3 = H
5 R2 = R3 = H
R2
17-28
Entry
Aromatic
aldehydes
Pyrido[2,3ꢀ
d]pyrimidines
Tim
(min)
Yiel
d
M.P. (oC)
(%)b
NO2
CHO
O
300ꢀ302
CN
1
2
60
94
94
(>300)20b
HN
NO2
O
N
CH3
N
NH2
6
17
NO2
CHO
O
N
CN
298ꢀ300
HN
70
90
(>300)20b
NO2
O
N
NH2
We now also put up the same reaction at a higher temperature (100
°C), but no increase in yield or reduction in reaction time was
observed. From the above experiments it was inferred that use of
glycerol at 80 °C gave the best result. An improvement in yield and
shortening of reaction time was observed on increasing the reaction
temperature, but raising the reaction temperature beyond 80 °C did
not lead to any further increase in yield or rate of reaction.
CH3
7
18
300ꢀ303
3
90
(>300)20d
8
9
19
O
O
OH
HN
CN
CHO
Solvent, Additive
Temp, Time
CN
CN
HN
O
N
O
N
NH2
O
N
N
NH2
CN
295ꢀ298
HN
CH3
4
5
90
80
90
93
(>300)20b
CH3
1
2
O
N
NH2
3
4
CH3
Table1.Effect of solvent and temp. on yield of pyrido[2,3ꢀd]pyrimidine 4a
20
Yield(%)b,c
Entry Solvent
Additive Temperature Time
CHO
Cl
1
2
3
3
4
5
6
Water
Water
Water
Water
Water
Water
Ethanol
None
None
CTAB
CTAB
SDS
RT
reflux
RT
reflux
RT
12 h
12 h
12 h
12 h
12 h
12 h
5 h
NR
NR
O
Cl
CN
298ꢀ300
HN
Trace
Trace
Trace
Trace
60
(>300)20b
O
N
N
NH2
CH3
10
SDS
None
reflux
reflux
21
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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COMMUNICATION
DOI: 10.1039/C5NJ01938A
dihydropyridine type intermediate III which undergoes air oxidation
to finally give the pyrido [2, 3ꢀd] pyrimidine 4 (Scheme 2).
Cl
N
CHO
O
300ꢀ304
Once the methodology for the synthesis of pyrido [2, 3ꢀd]
pyrimidine had been perfected and its generality had been amply
demonstrated we turned our attention towards examining the
reusability of glycerol. Glycerol was dissolved in hot water while the
product remained insoluble in water. The crude product was
obtained by simple filtration and filtrate containing glycerol was
again used for the reaction. The findings of this study are shown in
figure2. It was observed that the products were obtained in excellent
to good yield even after reusing the glycerol four times, amply
demonstrating the recyclability of glycerol.
CN
HN
6
7
80
70
93
94
(>300)
21b
O
N
CH3
NH2
Cl
11
22
CHO
300ꢀ302
(>300)21b
F
12
In conclusion we have disclosed a rapid and an efficient one pot
synthesis of pyrido[2, 3ꢀd]pyrimidine ꢀ a biologically significant
hybrid scaffold in compliance with green chemistry principles.
Highlights of the present methodology are the use of nonꢀhazardous
reaction conditions, use of cheap starting materials, isolation of pure
product through simple filtration thereby avoiding the need for
column chromatography, very high yields and 100% atom economy.
One key feature of the present work is the use of glycerol as a
recyclable promoting media amply highlighting the growing
potential of glycerol in organic synthesis.
23
25
303ꢀ305
9
90
80
86
93
(>300) 20a
14
15
303ꢀ306
(>300)20a
10
26
300ꢀ302
11
80
93
(>300)20b
16
27
NO2
CHO
O
12.
80
94
>300
CN
HN
NO2
O
N
H
N
NH2
Figure 2. Recyclability of glycerol
28
6
a All reactions were carried out using benzaldehydes 6ꢀ16 (1 mmol), 2
(1mmol), 3 or 5 (1mmol) in 5 mL of glycerol under air.b Isolated yields.
Experimental
OH
To around bottom flask containing 5 ml glycerol was added the
respective benzaldehyde (1 mmol) and malononitrile (1 mmol) under
stirring and the temperature of the reaction was set at 80 ºC. After
formation of the cyanoꢀolefin, the respective 6ꢀaminoꢀ1ꢀmethyluracil
(1 mmol) was added to the reaction mixture and it was allowed to
stir till completion (TLC). Warm water was now added to the
reaction mixture whence glycerol got dissolved and the insoluble
solid crude product was separated by simple filtration which was as
good as the pure compound (1H NMR). The filtrate containing
glycerol was extracted with methyl tꢀbutyl ether (4 × 25 mL) to
remove any organic compounds dissolved in the aqueous phase. The
aqueous layer was separated and evaporated in vacuo to give pure
glycerol which was used for the next cycle.
OH
OH HO
OH
HO
OH
H
O
CN
CN
CN
CN
CN
H
CH
CN
HN
I
O
1
2
O
N
NH2
O
CN
CH3
HN
3
O
N
N
NH2
CH3
OH
4
Air oxidation
ꢀ2H
HO
HO
N
C
NC
H
O
O
N
CN
CN
HN
HN
C
Acknowledgements
NH
O
N
N
H
NH2
NH2
O
NH
CH3
CH3
III
II
The authors are thankful to SAIF, PU, Chandigarh and SAIF, CDRI,
Lucknow for spectral data. The authors also acknowledge the
financial support from UGC, New Delhi in form of fellowships for
SS, FT, MS and major research project (Project No. 42ꢀ263/2013
(SR)). Dr. Saquib specifically thanks UGC, New Delhi for Dr. D.S.
Kothari Postdoctoral Fellowship (Award No. F.4ꢀ2/2006 (BSR)/13ꢀ
Scheme 2. Plausible mechanism
Formation of desired compound seemed to be initiating by
Knovenagel condensation of aldehyde and malononitrile to give
cyanoꢀolefin I followed by Michael type addition between uracil 3
and cyanoꢀolefin I to give the unstable intermediate II which
undergoes concomitant cyclization affording the subsequent
This journal is © The Royal Society of Chemistry 2012
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DOI: 10.1039/C5NJ01938A
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Research Fellowship.
Notes and references
a
Environmentally Benign Synthesis Lab, Department of Chemistry,
University of Allahabad, Allahabadꢀ211002 (India). Tel: +919415218507; Eꢀ
mail: dr.jdsau@gmail.com
b
Department of Chemistry, LRPG College, Sahibabad, Ghaziabadꢀ201005
(India).
†
Electronic Supplementary Information (ESI) available: [Experimental
1
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New Journal of Chemistry
An efficient and green, one-pot synthesis of pyrido[2,3d]pyrimidines, a biologically important
heterocyclic scaffold, using glycerol as a promoter cum solvent