P2O5 Mediated an Efficient Synthesis and Biological Evaluation of Heterocyclic-fused Pyrimidine Derivatives as an Antitubercular Agent

Article abstract of DOI:10.1002/jhet.3018

An efficient P₂O₅ mediated protocol for the synthesis of pyrido[2,3-d:6,5-d]dipyrimidines has been developed through one-pot three-component condensation of aromatic aldehydes, barbituric acid/thiobarbituric acid, and 1,3-dimethyl-6-

Full text of DOI:10.1002/jhet.3018

Month 2017
P2O5 Mediated an Efficient Synthesis and Biological Evaluation of
Heterocyclic-fused Pyrimidine Derivatives as an Antitubercular Agent
Kirti T. Patil,a Poojali P. Warekar,a Priyanka T. Patil,a Santosh S. Undare,b Govind B. Kolekar,b and
b
*
Prashant V. Anbhule
aDepartment of Agrochemicals and Pest Management, Shivaji University, Kolhapur, India
bMedicinal Chemistry Research Lab, Department of Chemistry, Shivaji University, Kolhapur, India
*E-mail: pvanbhule@gmail.com
Received March 2, 2017
DOI 10.1002/jhet.3018
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
An efficient P2O5 mediated protocol for the synthesis of pyrido[2,3-d:6,5-d]dipyrimidines has been
developed through one-pot three-component condensation of aromatic aldehydes, barbituric
acid/thiobarbituric acid, and 1,3-dimethyl-6-amino-uracil in ethanol. All the synthesized products were
screened for their in vitro antitubercular activity, and results reveal that most of the compounds exhibited
moderate to good activity against Mycobacterium tuberculosis H37RV strain.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
[3]. With delight, it has been recognized that several first-
line drugs like isoniazid, rifampicin, pyrazinamide, and
ethambutol are playing crucial role for treatment for TB.
However, appearance and spread of multidrug-resistant
TB and extensively drug-resistant TB with additional
resistance to a fluoroquinolone and antibiotics like
kanamycin, amikacin, or capreomycin have become a new
defy for the prevention and treatment of this lethal disease
[4,5]. In this context, the World Health Organization
reported that, in 2015, about 480,000 recent cases with
multidrug-resistant TB, and an extra 100,000 cases of
rifampicin-resistant TB were found [3]. The another
reality is that the susceptibility of people infected with the
acquired immune deficiency syndrome, which improves
the risk of developing TB in 100 times more and
increasing resistance to exiting drugs [6]. Owing to these
facts, there is an imperative need for novel and effective
Tuberculosis (TB) is a most common disease and serious
global health problem caused by Mycobacterium
tuberculosis and is the major reason of morbidity and
mortality worldwide especially in developing countries
[1]. In recent literature, it has been accounted that about
one third population of the world is infected by means of
this most hazardous microorganism and remains
uncontrollable in several developing countries [2]. The
World Health Organization estimated that, in 2015, 10.4
million new TB cases were reported, of which 5.9 million
were among men, 3.5 million among women, and 1.0
million among children. Moreover, the recent
documentation discloses that, in 2015, there were an
estimated 1.4 million deaths caused because of TB and an
extra 0.4 million TB deaths among HIV infected people
© 2017 Wiley Periodicals, Inc.

K. T. Patil, P. P. Warekar, P. T. Patil, S. S. Undare, G. B. Kolekar, and P. V. Anbhule
Vol 000
antitubercular agents with improved properties like
RESULT AND DISCUSSION
enhanced activity against multidrug-resistant strain [7].
Pyrimidine and their fused analogues are important class
of heterocycles, which exhibits a broad spectrum of
pharmaceutical and biological activities [8]. These are the
important heterocyclic compounds present in many natural
products and are building blocks of nucleic acids like
DNA and RNA, which are generally found in all living
organisms [9]. Among the fused pyrimidines,
Till today, synthesis of fused pyrimidine derivatives
generally involves dimedone, 1,3-Indanedione, ethyl
acetoacetate, and malanonitrile as active methylene
compounds [35–37]. These pyrimidine derivatives were
reported with various acid and base catalysts such as MgO
[38], p-dodecylbenzenesulfonic acid [39], and (SBA-Pr-
SO3H) [40]. However, we successfully explored use of
P2O5 in our previous work [41] and decided to continue it
for the synthesis of 5-(3-chlorophenyl)-1,3-dimethyl-5,10-
dihydropyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-
2,4,6,8(1H,3H,7H,9H)-tetrone derivatives.
In the pilot experiment, 3-chlorobenzlaldehyde
(1 mmole), barbituric acid (1 mmole), and 1, 3-dimethyl-
6-amino-uracil (1 mmole) were stirred in ethanol (10 ml)
at reflux temperature using P2O5 as a catalyst (Scheme 1).
The reaction progress was monitored by using thin layer
chromatography (TLC). After 2 h heating at reflux
condition, the desired product was obtained. To check the
catalytic activity, same reaction was extended with
different acid–base catalysts shown in Table 1. P2O5 is
proficient mediator for the synthesis of the reaction. It acts
as an acid and increases the acidic condition in the
reaction that leads for shorter reaction time.
furopyrimidines
[10],
pyrazolopyrimidines
[11],
pyrrolopyrimidines [12], pyridopyrazolopyrimidines [13],
and pyrazolotriazolopyrimidines [14] have exhibited
significant biological activities and are found to be used in
pharmaceutical industries. Pyridopyrimidines are nitrogen-
bearing heterocyclic compounds that possess various
medicinal applications such as antitumor [15], antiviral
[16], and antioxidant [17]. Moreover, in the field of drug
designing, these pyridopyrimidine scaffolds and their oxo
and thioxo derivatives were frequently used and are known
as pharmacophores [18]. These pharmacophores are the
group of annelated uracils with biological significance as
their connection with purine pteridine system [19].
Multicomponent reactions (MCRs) are powerful and
efficient tools for the designing of novel and structurally
complex molecules with a less reaction steps, simple
workup procedures, and less reaction time, and facile
execution are important tactics in combinatorial chemistry
[20–22]. Moreover, MCRs have come into sight as a vital
methodology in synthesis of many medicinally important
N-based heterocyclic skeletons. In consequence of the
various advantages, a noteworthy attempt has been
committed for the improvement of MCRs [23–26].
To observe appropriate quantity of P2O5, the same
reaction has been carried out in varying the amount of
P2O5 (Table 2). The 80 mg of P2O5 is sufficient quantity
for the said reaction to get maximum yield of the
product. On excess addition of catalyst, there is no any
change in the yield or time of the reaction.
Phosphorus pentoxide (P2O5) is an inexpensive acidic
catalyst that shows great synthetic potential in organic
conversion like in Beckmann rearrangement [27], olefin
dimerization [28], tetrahydropyranylation of alcohols
[29], and formation of 1,1-diacetate[30].
According to the recent reports of pyrimidine-fused
heterocycles [31,32] and with continuation of our recent
success [33,34], we have developed a new methodology
for the synthesis of pyrido[2,3-d:6,5-d]dipyrimidines
through one-pot three-component reaction of aromatic
aldehydes, barbituric/thiobarbituric acid, and 1,3-dimethyl-
6-amino-uracil in ethanol at reflux temperature using P2O5
as mediator with good to excellent yield of desired
products in shorter reaction time.
Table 1
Optimization of catalyst.a
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
Acetic acid
Without catalyst
Triethylamine
DABCO
5
12
7
6.5
2
65
45
55
60
90
P2O5
DABCO, 1,4-diazabicyclo[2.2.2]octane; P2O5, phosphorus pentoxide.
aReaction Condition: Mixture of 3-chlorobenzaldehyde (1 mmol),
barbituric acid (1 mmol), and 1,3-dimethyl-6-amino-uracil (1 mmol) was
refluxed in ethanol.
bIsolated yield of product.
The bold entries indicates optimized reaction condition.
Scheme 1. One-pot three-component synthesis of pyrido[2,3-d:6,5-d]dipyrimidines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
P2O5 Mediated an Efficient Synthesis and Biological Evaluation
Table 2
Table 4
Optimization of P2O5 quantity.a
Synthesis of pyrido[2,3-d:6,5-d]dipyrimidines using phosphorus
pentoxide mediator.a
Quantity of P2O5
Entry
Product
R
X
Time
Yieldb (%)
Entry
mg
Mol (%)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
3-ClC6H4
O
O
O
S
S
O
S
S
S
S
O
2
1.5
2
2
1.30
2
82
84
88
80
84
80
82
88
84
82
80
1
2
3
4
20
40
60
80
141
283
425
567
709
7
6.5
4
2–3
2–3
50
65
60
90
90
4-CNC6H4
2-NO2C6H4
3-Cl C6H4
3-NO2C6H4
2-Cl C6H4
2-Cl C6H4
4-NO2C6H4
2-NO2C6H4
4-Cl C6H4
4-Cl C6H4
5
100
2
P2O5, phosphorus pentoxide.
1.5
1.5
2.0
2.5
aReaction Condition: Mixture of 3-chlorobenzaldehyde (1 mmol),
barbituric acid (1 mmol), and 1,3-dimethyl-6-amino-uracil (1 mmol) and
P2O5 was refluxed in ethanol.
9
10
11
4j
4k
bIsolated yield of product
The bold entries indicates optimized reaction condition.
aReaction Condition: Mixture of aromatic aldehyde (1 mmol), barbituric/
thiobarbituric acid (1 mmol), 1,3-dimethyl-6-amino-uracil (1 mmol) and
P2O5 was refluxed in ethanol.
bIsolated yield of product
To study the effect of solvent, the same reaction was
carried out in various protic and aprotic solvents. It has
been found that ethanol is better solvent for this organic
transformation in good to excellent yield of the desired
product (Table 3).
spectroscopic data were found to be in good agreement with
proposed structure. The structure of the said compound is
also confirmed from the 13C NMR spectral data and mass
spectra along with elemental analysis.
To expand this approach, various electron rich and
electron deficient aromatic aldehydes were used to
construct
a
series of 1,3-dimethylꢀ5-phenyl-9,10-
Possible mechanism.
The possible mechanism for
dihydropyrido[2,3-d:6,5-d]dipyrimidine- 2,4,6,8(1H, 3H,
5H, 7H)-tetraone derivatives. It was delightful to observe
that most of aldehydes exhibited satisfactory reactivity
profile (Table 4). The IR spectrum of 5-(3-chlorophenyl)-
1,3-dimethyl-5,10-dihydropyrimido [50,40:5,6]pyrido[2,3-
d]pyrimidine-2,4,6,8 (1H, 3H, 7H, 9H)-tetrone (Table-4,
entry 1) shows absorption at 3448, 3350, 3174 and
synthesis of pyrido[2,3-d:6,5-d]dipyrimidines derivatives is
shown in Scheme 2. The cyclization looks to precede the
acid mediated Knoevenagel condensation and Michael type
addition reaction. Barbituric acid/thiobarbituric acid 1
reacts with aromatic aldehydes 2 to form standard
Knoevenagel condensation product 3. The subsequent
Michael-type addition of the 1,3-dimethyl uracil 4 with
Knoevenagel product 3 followed by cyclization affords the
intermediate 5 which on dehydration gives desired product 6.
1698 cmꢀ1. In the H NMR spectrum of same compound,
1
two singlets appearing between δ 3.21 and δ 3.46 show
protons of two methyl groups. The singlet appears at δ
5.43 because of methine proton, which indicates complete
cyclization of compound. The four aromatic protons are
exhibited as multiplet between δ 7.10 and δ 7.26, while
protons of three-NH groups appear as a three broad singlet
at δ 7.42, δ 10.92, and δ 11.25–11.28. The obtained
Antituberculosis activity. All the compounds prepared
herein were subjected for their antiTB activity against M.
tuberculosis H37Rv strain using Alamar blue assay. In this
methodology, thermally stable reagents were used and
showed good correlation with proportional and BACTEC
radiometric method.
5-(phenyl)-1,3-dimethyl-5,10-dihydropyrimido[50,40:5,
6]pyrido[2,3-d]pyrimidine-2,4,6,8 (1H,3H,7H,9H)-tetrone
and 5-(phenyl)-1,3-dimethyl-8-thioxo-5,8,9,10-tetrahydro
pyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,
7H)-trione derivatives were screened for their
antitubercular activities against M. tuberculosis H37Rv
strain using Alamar blue assay by reported method. The
results are shown in Table 5.
The synthesized compounds were screened for
antimycobacterial activity at concentration of 0.8, 1.6, 3.12,
6.25, 12.5, 25, 50, and 100 μg/mL by using standard drugs
such as pyrazinamide, ciprofloxacin, and streptomycin for
comparison purpose. The results were shown that all the
compounds demonstrated activity at 50 μg/mL.
Table 3
Optimization of solvent.a
Entry
Solvent
Time (h)
Yieldb(%)
1
2
3
4
5
Ethanol
Acetonitrile
DMSO
DMF
2
5
90
60
65
60
55
6–6.5
4
10
Water
DMSO, dimethyl sulfoxide; DMF, dimethylformamide.
aReaction Condition: Mixture of 3-chlorobenzaldehyde (1 mmol),
barbituric acid (1 mmol), 1,3-dimethyl-6-amino-uracil (1 mmol) and P2O5
was refluxed in different solvents.
bIsolated yield of product
The bold entries indicates optimized reaction condition.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. T. Patil, P. P. Warekar, P. T. Patil, S. S. Undare, G. B. Kolekar, and P. V. Anbhule
Vol 000
Scheme 2. Mechanistic pathway of the reaction.
Table 5
Antituberculosis activity of the synthesized compounds against Mycobacterium tuberculosis.
Compound code
100 μg/mL 50 μg/mL 25 μg/mL 12.5 μg/mL 6.25 μg/mL 3.12 μg/mL 1.6 μg/mL 0.8 μg/mL
4a
4b
4c
4d
4e
4f
4g
4h
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
4i
4j
4k
S
S
S
R
R
R
Minimum inhibitory
concentration
Pyrazinamide
Streptomycin
Ciprofloxacin
3.125 μg/mL
6.25 μg/mL
3.125 μg/mL
S, susceptible; R; resistant.
EXPERIMENTAL
automatic system for detection of mycobacterial growth
and drug susceptibility testing of M. tuberculosis [43]. It
is successful to detect mycobacterium growth more
rapidly than culturing method [44]. A modification to the
BACTEC 460TB susceptibility method was developed
using a modified 7H12 radiometric medium [45].
This method involves only one medium in detection of
growth in a specimen having a positive direct smear for
acid–base bacilli. Pyrazinamide, streptomycin, and
ciprofloxacin were taken, and stock solutions were
prepared in deionized water. Two hundred microliters of
sterile deionized water was added to all outer perimeter
wells of sterile 96 wells plate to minimize evaporation of
medium in the test wells during incubation. The 96 wells
plate received 100 μL of the Middlebrook 7H9 broth, and
serial dilution of compounds were made directly on plate.
All commercially available chemicals were obtained from
commercial sources. Melting points were taken in an open
capillary and are found to be uncorrected. IR spectra were
1
recorded on a PerkinElmer FT-IR Spectrum. The H NMR
and 13C NMR spectra obtained (DMSO-d6) on a Bruker
(300 MHz) using tetramethylslane as an internal standard.
The progress of reaction was checked by TLC using silica
gel G (laboratory reagent).
Antituberculosis activity using Alamar blue assay. The
BACTEC instrument (Becton, Dickinson and Company,
Franklin Lakes, NJ) is radiometric technique produced by
Becton Dickinson and is specially designed to
accumulate Mycobacteria Growth Indicator Tube (MGIT)
[42]. BACTEC MGIT 960 (MGIT 960) is the fully
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
P2O5 Mediated an Efficient Synthesis and Biological Evaluation
The final drug concentrations tested were 100 to
0.2 μg/mL. The plates were covered and sealed with
parafilm and incubated at 37°C for 5 days. After this
time, 25 μL of freshly prepared 1:1 mixture of Almar
blue reagent, and 10% tween 80% was added to the plate
and incubated for 24 h. A blue color in the well was
interpreted as no bacterial growth, and pink color was
scored as growth. The minimum inhibitory concentration
was defined as the lowest drug concentration, which
prevented the color change from blue to pink.
3.73.; N, 22.21%. Found: C, 57.12.; H, 3.70.; N,
22.24%.
1,3-dimethyl-5-(2-nitrophenyl)-5,10-dihydropyrimido[50,40:5,
6]pyrido[2,3-d]pyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone (4c)
(Table-4 Entry-3). White solid; Yield 88%; mp. >300°C,
1
IR: νmax = 3372, 3178, 3099, 2877, and 1677 cmꢀ1, H
NMR (300 MHz, DMSO): δ = 3.05 (s, 3H,–CH3), 3.34
(s, 3H, ꢀCH3) 5.79 (s, 1H,–CH), 7.36–7.48 (m, 4H,
Ar-H), 8.00 (s, 1H, ꢀNH), and 10.95 (s, 1H, ꢀNH) ppm.
13C NMR (75 MHz, DMSO): δ = 18.46, 28.41, 29.50,
30.71, 30.87, 56.94, 89.07, 89.35, 123.81, 124.34,
127.38, 129.22, 131.51, 132.99, 149.77, 150.22, 150.36,
155.44, 162.40, and 164.21 ppm Mass: Mass calculated
for [C18H14N6O4] = m/z 398.330; Obs. Mass = 398.33
[m/z]. Anal. Calcd for C17H14N6O6: C, 51.26.; H, 3.54.;
N 21.10%. Found = C, 51.24.; H, 3.52.; N, 21.11%.
General procedure for synthesis of 5-(3-chlorophenyl)-1,3-
dimethyl-5,10-dihydropyrimido[50,40:5,6]-2,4,6,8 (1H,3H,7H,
9H)-tetrone (4a).
In 50 mL round bottom flask, 3-
chlorobenzaldehyde (1 mmole), barbituric acid
(1 mmole), 1,3-dimethyl-6-amino-uracil (1 mmole), and
80 mg of P2O5 were added in 10 mL ethanol, and
resulting mixture was refluxed for 2 h. The reaction
progress was monitored by TLC (Petroleum ether: Ethyl
acetate). After completion of reaction, the product formed
was simply filtered and washed with hot ethanol and
petroleum ether. The precipitate was recrystalized by
using hot ethanol to afford pure product and confirmed
by spectral analysis. The P2O5 is reacted with water to
form phosphoric acid. So during the use of it, care must
be taken by wearing gloves and laboratory goggle to
5-(3-chlorophenyl)-1,3-dimethyl-8-thioxo-5,8,9,10-tetrahyd
ropyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,7H)-
trione (4d) (Table-4 Entry-4). White solid; Yield 80%; mp.
>300°C, IR: νmax = 3449, 3351, 3056, 2884, and
1
1693 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.13 (s,
3H,–CH3), 3.38 (s, 3H, ꢀCH3) 5.36 (s, 1H,–CH),
7.07–7.15 (m, 3H, Ar-H), 7.18 (s, 1H, Ar-H), 7.36 (s,
1H, ꢀNH), 12.18 (s, 1H, ꢀNH), and 12.50 (s, 1H,
ꢀNH) ppm. 13C NMR (75 MHz, DMSO): δ = 28.58,
30.77, 33.49, 88.45, 95.61, 125.18, 126.03, 126.53,
129.78, 133.74, 150.34, 155.66, 164.58, and
avoid skin and eye contact of P2O5.
5-(3-chlorophenyl)-1,3-dimethyl-5,10-dihydropyrimido[50,
40:5,6] -2,4,6,8 (1H,3H,7H,9H)-tetrone (4a) (Table 4 Entry-
173.85
ppm.
Mass:
Mass
calculated
for
1).
White solid; Yield 82%; mp. >300°C, IR:
[C17H14ClN5O3S] = m/z 403.842; Obs. Mass = 403.840
[m/z]. Anal. Calcd for C17H14ClN5O3S: C, 50.56.; H,
3.49.; N, 17.34%. Found: C, 50.53.; H 3.45.; N,
17.31%.
νmax = 3448, 3350, 3174, 2885, and 1698 cmꢀ1 1H
,
NMR (300 MHz, DMSO): δ = 3.21 (s, 3H,–CH3), 3.46
(s, 3H, ꢀCH3), 5.43 (s, 1H,–CH), 7.10–7.26 (m, 4H, Ar-
H), 7.42 (s, 1H, ꢀNH), 10.92 (s, 1H, ꢀNH), and 11.25–
11.28 (s, 1H, ꢀNH) ppm. 13C NMR (75 MHz, DMSO):
δ = 14.13, 18.40, 22.55, 89.21, 90.58, 124.96, 125.31,
125.91, 126.49, 126.67, 129.15, 129.50, 133.83, 141.82,
150.46, 150.51, 151.03, 155.38, 162.02, 164.48 and 167.82
ppm. Mass: Mass calculated for [C17H14ClN5O4] = m/z
387.377; Obs. Mass = 387.770 [m/z]. Anal. Calcd for
C17H14ClN5O4: C, 52.65; H, 3.14.; N, 18.06%. Found: C,
1,3-dimethyl-5-(3-nitrophenyl)-8-thioxo-5,8,9,10-tetrahydro
pyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,7H)-
trione (4e) (Table-4 Entry-5).
White solid; Yield 84%;
mp. >300°C, IR: νmax = 3478, 3423, 3073, 2879, and
1
1604 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.14 (s,
3H,–CH3), 3.40 (s, 3H, ꢀCH3) 5.48 (s, 1H,–CH),
7.48–7.58 (m, 2H, Ar-H), 7.81–7.89 (m, 2H, Ar-H),
7.99 (s, 1H, ꢀNH), 11.61 (s, 1H, ꢀNH), and 12.60 (s,
1H, ꢀNH) ppm. 13C NMR (75 MHz, DMSO):
δ = 28.57, 30.73, 33.67, 88.27, 95.35, 121.10, 121.48,
129.32, 133.22, 148.40, 150.32, 155.75, 164.60, 165.78,
and 173.99 ppm. Mass: Mass calculated for
[C17H14N6O5S] = m/z 414.395; Obs. Mass: 414.392
[m/z]. Anal. Calcd for C17H14N6O5S: C, 49.27.; H,
3.41.; N, 20.28%. Found: C, 49.25.; H, 3.38.; N 20.24%.
52.68.; H, 3.10.; N, 18.09%.
4-(1,3-dimethyl-2,4,6,8-tetraoxo-1,2,3,4,5,6,7,8,9,10-decahy
dropyrimido[50,40:5,6]pyrido[2,3-d]pyrimidin-5-yl)benzonitrile
(4b) (Table-4 Entry-2).
Yellow solid; Yield 84%; mp.
>300°C, IR: νmax = 3325, 3073, 2972, 2223, and
1689 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.20 (s,
1
3H,–CH3), 3.46 (s, 3H, ꢀCH3) 5.48 (s, 1H,–CH),
7.35–7.37 (d, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.59–7.61
(s, 2H, Ar-H), 7.86–7.94 (s, 1H, ꢀNH), 10.96 (s, 1H,
ꢀNH), and 11.28 (s, 1H, ꢀNH) ppm. 13C NMR
(75 MHz, DMSO): δ =28.50, 30.72, 34.10, 90.21,
109.10, 119.15, 127.80, 132.00, 146.17, 150.28,
150.40, and 155.61 ppm. Mass: Mass calculated for
[C18H14N6O4] = m/z 378.341; Obs. Mass = 378.340
[m/z]. Anal. Calcd for C18H14N6O4: C, 57.14.; H,
5-(2-chlorophenyl)-1,3-dimethyl-5,10-dihydropyrimido[50,
40:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone
(4f) (Table-4 Entry-6).
White solid; Yield 80%; mp.
>300°C, IR: νmax = 3326, 2946, 2778, and 1672 cmꢀ1
,
1H NMR (300 MHz, DMSO): δ = 3.05 (s, 3H,–CH3),
3.35 (s, 3H,–CH3) 5.79 (s, 1H,–CH), 7.33–7.41 (m, 4H,
Ar-H), 7.46 (s, 1H, ꢀNH), 10.93 (s, 1H, ꢀNH), and
11.25 (s, 1H, ꢀNH) ppm. 13C NMR (75 MHz DMSO):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. T. Patil, P. P. Warekar, P. T. Patil, S. S. Undare, G. B. Kolekar, and P. V. Anbhule
Vol 000
δ = 18.67, 28.41, 30.67, 32.94, 90.09, 126.43, 127.69,
129.65, 130.09, 132.23, 133.14, 137.86, 150.26, 150.34,
155.01, and 164.19 ppm. Anal. Calcd for C17H14ClN5O4:
C, 52.65.; H, 3.73.; N, 22.21%. Found: C, 52.67.; H,
3.71.; N, 22.18%.
5-(4-chlorophenyl)-1,3-dimethyl-5,10-dihydropyrimido[50,
40:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8(1H,3H,7H,9H)-tetrone
(4k) (Table-4 Entry-11).
White solid; Yield 80%; mp.
>300°C, IR: νmax = 3446, 3163, 2945, and 1692 cmꢀ1
,
1H NMR (300 MHz, DMSO): δ = 3.14 (s, 3H,–CH3),
3.39 (s, 3H, ꢀCH3), 5.35 (s, 1H, ꢀCH), 7.04–7.14 (m,
3H, Ar-H), 7.27(d, 1H, Ar-H), 10.63 (s, 1H, ꢀNH),
11.04 (s, 1H, ꢀNH), and 13.92(s, 1H, ꢀNH) ppm. Anal.
Calcd for C17H14ClN5O4: C, 52.65.; H, 3.14.; N, 18.06%.
Found: C, 52.59.; H, 3.11.; N, 18.04%.
5-(2-chlorophenyl)-1,3-dimethyl-8-thioxo-5,8,9,10-tetrahyd
ropyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,
7H)-trione (4g) (Table-4 Entry-7).
White solid; Yield
82%; mp. >300°C, IR: νmax = 3352, 3056, 2885, and
1
1693 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.13 (s,
3H,–CH3), 3.38 (s, 3H, ꢀCH3) 5.35 (s, 1H,–CH), 7.01–
7.15 (m, 3H, Ar-H), 7.38 (s, 1H, Ar-H), 7.93 (s, 1H,
ꢀNH), 12.23 (s, 1H, ꢀNH), and 12.56 (s, 1H,
ꢀNH) ppm. 13C NMR (75 MHz, DMSO): δ = 28.57,
30.13, 30.68, 33.21, 35.28, 88.71, 95.84, 127.15,
128.17, 128.48, 131.18, 150.40, 151.01, 155.53, 164.53,
165.77, and 173.72 ppm. Anal. Calcd for
C17H14ClN5O3S: C, 50.56.; H, 3.49.; N, 17.34%. Found:
C, 50.52.; H, 3.46.; N, 17.30%.
CONCLUSION
In conclusion, we have demonstrated a mild and
efficient P2O5 mediated synthesis of pyrido[2,3-d:6,5-d]
dipyrimidines using one-potthree-component reaction of
aromatic aldehydes, barbituric acid/thiobarbituric acid,
and 1, 3-dimethyl-6-amino-uracil. The advantages of the
present protocol are simple experimental procedure,
shorter reaction time, avoidance of tedious work-up, and
good yields of desired products. All the synthesized
products were screened for their antituberculosis activity
activities using Alamar blue assay, and results reveal that
most of the compounds exhibited moderate to good
activity against M. tuberculosis H37RV strain.
1,3-dimethyl-5-(4-nitrophenyl)-8-thioxo-5,8,9,10-tetrahydro
pyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,7H)-
trione (4h) (Table-4 Entry-8).
White solid; Yield 88%;
mp. >300°C, IR: νmax = 3422, 3090, 2944, and
1
1689 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.05 (s,
3H,–CH3), 3.35 (s, 3H, ꢀCH3) 5.80 (s, 1H,–CH),
7.31–7.51 (m, 4H, Ar-H), 7.96 (s, 1H, ꢀNH), 12.31 (s,
1H, ꢀNH), and 12.62 (s, 1H, ꢀNH) ppm. 13C NMR
(75 MHz DMSO): δ = 28.50, 30.81, 30.93, 88.61,
94.25, 123.94, 127.60, 129.19, 131.62, 132.32, 149.73,
150.10, 155.65, 164.32, and 173.84 ppm. Anal. Calcd
for C17H14N6O5S: C, 49.27.; H, 3.41.; N, 20.28%.
Found C, 49.20.; H, 3.35.; N, 20.21%.
Acknowledgments. One of the authors (K.T.P.) is thankful to
Shivaji University, Kolhapur for providing financial support in
the form of DRF.
1,3-dimethyl-5-(2-nitrophenyl)-8-thioxo-5,8,9,10-tetrahydro
pyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,7H)-
trione (4i) (Table-4 Entry-9). White solid; Yield 84%; mp.
REFERENCES AND NOTES
>300°C, IR: νmax = 3189, 3100, 2887, and 1689 cmꢀ1
.
[1] Godfrey, C.; Andersen, J.; Mngqibisa, R.; Scott, L. E.;
Conradie, F. Lancet 2016, 387, 1157.
[2] Konstantinos, A. Australian Prescriber 2010, 33, 12.
[3] World Health Organization Global Tuberculosis Report, 2015.
1–115
1H NMR (300 MHz, DMSO): δ = 3.06 (s, 3H,–CH3),
3.36 (s, 3H, ꢀCH3) 5.81 (s, 1H,–CH), 7.37–7.44 (m,
4H, Ar-H), 7.50 (s, 1H, ꢀNH), 12.32 (s, 1H, ꢀNH),
and 12.59 (s, 1H, ꢀNH) ppm.13C NMR (75 MHz
DMSO): δ = 28.50, 30.81, 30.90, 88.62, 94.22, 123.94,
127.53, 129.18, 131.61, 132.33, 149.70, 150.10, 155.64,
164.30, and 173.83 ppm. Anal. Calcd for C17H14N6O5S: C,
49.27.; H, 3.41.; N, 20.28%. Found C, 49.23.; H, 3.44.; N,
20.25%.
[4] Gandhi, N. R.; Nunn, P.; Dheda, K.; Schaaf, H. S.; Zignol, M.;
Soolingen, D. Lancet 2010, 375, 1830.
[5] Chang, K. C.; Yew, W. W. Respirology 2013, 18, 8.
[6] (a) Bloom, B. R.; Murray, C. J. L. Science 1992, 257, 1055; (b)
Snider, D. E. J.; Roper, W. L. N. Engl J Med 1992, 326, 703.
[7] (a) Lugo, M. T.; Bewley, C. A. J Med Chem 2008, 51, 2606;
(b) Janin, Y. L. Bioorg Med Chem 2007, 15, 2479.
[8] (a) Sharma, P.; Rane, N.; Gurram, V. K. Bioorg Med Chem
Lett 2004, 14, 4185; (b) Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie,
G. F. Adv Heterocycl Chem 1984, 41, 319; (c) Suzuki, N. Chem Pharm
Bull 1980, 28, 761.
5-(4-chlorophenyl)-1,3-dimethyl-8-thioxo-5,8,9,10-tetrahyd
ropyrimido[50,40:5,6]pyrido[2,3-d]pyrimidine-2,4,6(1H,3H,
7H)-trione (4j) (Table-4 Entry-10).
White solid; Yield
[9] (a) Lagoja, I. M. Chem Biodivers 2015, 2, 1; (b) Huang, R.;
Chen, Y.; Zeng, Z.; Gao, C.; Su, X.; Peng, Y. Mar Drugs 2014, 12, 5817.
[10] Petricci, E.; Radi, M.; Corelli, F.; Botta, M. Tetrahedron Lett
2003, 44, 9181.
[11] Makarov, V. A.; Riabova, O. B.; Granik, V. G.; Dahse, H. M.;
Stelzner, A.; Wutzlerc, P.; Schmidtke, M. Bioorg Med Chem Lett 2005,
15, 37.
82%; mp. >300°C, IR: νmax = 3355, 3060, 2967, and
1
1693 cmꢀ1, H NMR (300 MHz, DMSO): δ = 3.14 (s,
3H,–CH3), 3.39 (s, 3H, ꢀCH3) 5.36 (s, 1H,–CH), 7.07–
7.18 (m, 3H, Ar-H), 7.37 (d, 1H, Ar-H), 7.95 (s, 1H,
ꢀNH), 12.23 (s, 1H, ꢀNH), and 12.52 (s, 1H, ꢀNH)
ppm. Anal. Calcd for C17H14ClN5O3S: C, 50.56.; H,
3.49.; N, 17.34%. Found: C, 50.53.; H, 3.47.; N, 17.32%.
[12] Matsumoto, N. N.; Takahashi, M. Tetrahedron Lett 2005, 46,
5551.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
P2O5 Mediated an Efficient Synthesis and Biological Evaluation
[13] Alberti, M. J.; Auten, E. P.; Lackey, K. E.; McDonald, O. B.;
Wood, E. R.; Preugschat, F.; Cutler, G. J.; Kane-Carson, L.; Liu, W.; Jung,
D. K. Bioorg Med Chem Lett 2005, 15, 3778.
[14] Baraldi, P. G.; El-Kashef, H.; Farghaly, A. R.; Vanellec, P.;
Fruttaroloa, F. Tetrahedron 2004, 60, 5093.
[15] Sanghhvi, Y. S.; Larson, S. B.; Matsumoto, S. S.; Nord, L. D.;
Smee, D. F.; Willis, R. C.; Avery, T. H.; Robins, R. K.; Revankar, G. R. J
Med Chem 1989, 32, 629.
[16] Tenser, R. B.; Gaydos, A.; Hay, K. A. Antimicrob Agents
Chemother 2001, 45, 3657.
[17] De la Cruz, J. P.; Carrasco, T.; Ortega, G.; Sanchez De la
Cuesta, F. Lipid 1992, 27(1), 92.
[18] (a) Blankley, C. J.; Bennett, L. R.; Fleming, R. W.; Smith,
R. D.; Tessman, D. K.; Kaplan, H. R. J Med Chem 1983, 26, 403;
(b) Alajarine, R.; Alvbarez-Builla, J.; Vaquero, J. J.; Sunkel, C.;
Fau, J.; Statkow, P.; Sanz, J. Tetrahedron Asymmetry 1993, 4, 617;
(c) Gangjee, A.; Zhu, Y.; Queener, S. F. J Med Chem 1998, 41,
4533.
[32] Mosslemin, M. H.; Nateghi, M. R. Ultrason Sonochem 2010,
17, 162.
[33] (a) Valekar, N. J.; Patil, P. P.; Gore, A. H.; Kolekar, G. B.;
Deshmukh, M. B.; Anbhule, P. V. Heterocycl Chem 2015, 52, 1669; (b)
Patil, K. T.; Walekar, L. S.; Undare, S. S.; Kolekar, G. B.; Deshmukh,
M. B.; Choudhari, P. B.; Anbhule, P. V. Indian J Chem 2016, 55B, 1151.
[34] (a) Patravale, A. A.; Gore, A. H.; Patil, D. R.; Kolekar, G. B.;
Deshmukh, M. B.; Anbhule, P. V. Ind Eng Chem Res 2014, 53, 16568; (b)
Undare, S. S.; Valekar, N. J.; Patravale, A. A.; Jamale, D. K.; Vibhute, S.
S.; Walekar, L. S.; Kolekar, G. B.; Deshmukh, M. B.; Anbhule, P. V. Res
Chem Intermediate 2016, 42, 4373.
[35] Nemati, F.; Saeedirad, R. Chin Chem Lett 2013, 24, 370.
[36] Kidwai, M.; Jain, A.; Bhardwaj, S. Mol Divers 2012, 16, 121.
[37] Sabour, B.; Peyrovi, M. H.; Hajimohammadi, M. Res Chem
Intermed 2015, 41, 1343.
[38] Sheibani, H.; Seifi, M.; Bazgir, A. Syncom 2009, 39, 1055.
[39] Sapkal, B. M.; More, D. H. Der Pharma Chemica 2015, 7(3),
167.
[40] Ziarani, G. M.; Nasab, N. H.; Rahimifard, M.; Soorki, A. A. J
Saudi Chem Soc 2015, 19, 676.
[41] (a) Deshmukh, M. B.; Anbhule, P. V.; Jadhav, S. D.; Mali, A.
R.; Jagtap, S. S.; Deshmukh, S. A. Indian J Chem 2007, 46B, 1545; (b)
Warekar, P. P.; Kolekar, G. B.; Deshmukh, M. B.; Anbhule, P. V. Synthetic
Commun 2014, 44, 3594.
[42] Tortoli, E.; Cichero, P.; Piersimoni, C.; Simonetti, M. T.; Gesu,
G.; Nista, D. J Clin Microbiol 1999, 37, 3578.
[43] Apers, L.; Mutsvangwa, J.; Magwenzi, J. Int J Tuberc Lung
Dis 2003, 7, 376.
[19] (a) Clercq, E. D.; Beraaerts, R. J Biol Chem 1987, 262, 14905;
(b) Lunt, E. In Comprehensive Organic Chemistry, 4Barton, D.; Ollis,
W. D. Eds.; Pergamon Press: Oxford, 1974, p. 493.
[20] Gu, Y. L. Green Chem 2012, 14, 2091.
[21] Parajapati, D.; Thakur, A. J Tetrahedron Lett 2005, 46, 1433.
[22] Mironov, M. A. QSAR Comb Sci 2006, 25, 423.
[23] Domling, A. Chem Rev 2006, 106, 17.
[24] Lancaster, M. Green Chemistry: An Introductory Text; Royal
Society of Chemistry: Cambridge, 2002.
[25] Dolle, R. E.; Bourdonnec, B. L.; Morales, G. A.; Moriarty, K. J.;
Salvino, J. M. J Comb Chem 2006, 8, 597.
[44] Vincke, G. 0; Yegers, H.; Vanachter, P.A.; Butzler, J. P. J
Antimicrob Chemother 1982, 10, 351.
[45] Salfinger, M.; Relier, L. B.; Demehlk, B.; Johnson, Z. T. Res
Microbiol 1989, 140, 31.
[26] Ganesan, A. Comb Chem 2002, 7, 47.
[27] Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett 2001, 42, 8441.
[28] Hamamatsu, T.; Kimura, N.; Takashima, T.; Morikita, T. Patent
USPTO Appln. No. 20090099400—Class: 585529.
[29] Eshghi, H.; Shafieyoon, P. Phosphorous, Sulfur Silicon Relat.
Elem. 2004, 179, 2149.
[30] Eshghi, H.; Gordi, Z. Phosphorous, Sulfur Silicon Relat Elem
2004, 179, 134.
[31] Bazgir, A.; Khanaposhtani, M. M.; Ghahremanzadeh, R.;
Soorki, A. A.; Chimie, C. R 2009, 12, 1287.
SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet