Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media
Pyrimido[4,5-d]pyrimidine derivatives were synthesized by using an efficient, facile and solvent-free procedure. Here, a non-conventional synthetic procedure has been developed where solid support of alumina is used as energy transfer medium under microwave irradiation (MWI) which devoids hazards of...
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irk-123456789-73682010-03-30T12:02:15Z Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media Kategaonkar, A.H. Sadaphal, S.A. Shelke, K.F. Shingate, B.B. Shingare, M.S. Pyrimido[4,5-d]pyrimidine derivatives were synthesized by using an efficient, facile and solvent-free procedure. Here, a non-conventional synthetic procedure has been developed where solid support of alumina is used as energy transfer medium under microwave irradiation (MWI) which devoids hazards of solution phase reactions. The reaction time has been brought down from minutes to seconds with improved yield as compared to reported method. Похідні піримідо[4,5-d]піримідину синтезовано за допомогою простого й ефективного методу без застосування розчинника. Розроблено нетрадиційний спосіб синтезу, за якого нерухому підкладку із оксиду алюмінію використано як середовище для передачі енергії при мікрохвильовому випромінюванні, що запобігає негативним ефектам, які обумовлюють реакції у фазі розчинника. Новий метод дає змогу скоротити час реакції від декількох хвилин до кількох секунд і покращити її вихід. 2009 Article Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media / A.H. Kategaonkar, S.A. Sadaphal, K.F. Shelke, B.B. Shingate, M.S. Shingare // Ukrainica Bioorganica Acta. — 2009. — Т. 7, № 1. — С. 3-7. — Бібліогр.: 19 назв. — англ. 1814-9758 http://dspace.nbuv.gov.ua/handle/123456789/7368 en Інститут молекулярної біології і генетики НАН України |
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Pyrimido[4,5-d]pyrimidine derivatives were synthesized by using an efficient, facile and solvent-free procedure. Here, a non-conventional synthetic procedure has been developed where solid support of alumina is used as energy transfer medium under microwave irradiation (MWI) which devoids hazards of solution phase reactions. The reaction time has been brought down from minutes to seconds with improved yield as compared to reported method. |
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Kategaonkar, A.H. Sadaphal, S.A. Shelke, K.F. Shingate, B.B. Shingare, M.S. |
| spellingShingle |
Kategaonkar, A.H. Sadaphal, S.A. Shelke, K.F. Shingate, B.B. Shingare, M.S. Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| author_facet |
Kategaonkar, A.H. Sadaphal, S.A. Shelke, K.F. Shingate, B.B. Shingare, M.S. |
| author_sort |
Kategaonkar, A.H. |
| title |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| title_short |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| title_full |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| title_fullStr |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| title_full_unstemmed |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
| title_sort |
microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media |
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Інститут молекулярної біології і генетики НАН України |
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2009 |
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http://dspace.nbuv.gov.ua/handle/123456789/7368 |
| citation_txt |
Microwave assisted synthesis of pyrimido[4,5-d]pyrimidine derivatives in dry media / A.H. Kategaonkar, S.A. Sadaphal, K.F. Shelke, B.B. Shingate, M.S. Shingare // Ukrainica Bioorganica Acta. — 2009. — Т. 7, № 1. — С. 3-7. — Бібліогр.: 19 назв. — англ. |
| work_keys_str_mv |
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| first_indexed |
2025-07-02T10:11:44Z |
| last_indexed |
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1836529593836634112 |
| fulltext |
3
Introduction. Combinatorial chemistry is
playing an increasingly important role as one of
the tool of modern medicinal chemistry for the
rapid discovery of new leads [1]. The prepara�
tion of libraries of small organic molecules is a
rapidly evolving area of research [2]. Pyrimido
pyrimidines are annelated uracils that have
attracted considerable interest in recent years.
Derivatives of pyrimido pyrimidine are known
to display a wide range of pharmacological
activities, and their potent inhibitory properties
regarding the tyrosine kinase domain of epider�
mal growth factor receptor [3], 5�phosphoribo�
syl�1�pyrophosphate synthetase [4] and dihyd�
rofolate reductase [5] have been fully demon�
strated. Numerous reports delineate the antitu�
mour [6], antiviral [7], antioxidant [8], antifungal
and heptatoprotective activities.
Multi�component reactions (MCRs) [9] are
masterpieces of synthetic efficiency and reac�
tion design. Therefore, mastering unusual com�
binations and sequences of elementary organic
reactions under similar conditions is the major
conceptual challenge in engineering novel types
of MCR. Most advantageously and practically,
MCR can often be extended into combinatorial
[10] and solid phase syntheses promising mani�
fold opportunities for developing novel lead
structures of active agents, catalysts and even
novel molecule based materials. Inevitably,
many classical heterocyclic syntheses are MCR
that are based upon carbonyl group condensa�
tions. Hence, medicinal chemistry is largely
found on these easily accessible heterocyclic
frameworks. The use of multicomponent reac�
tions (MCRs) to generate interesting and novel,
drug�like scaffolds is replete in the recent che�
mical literature [11]. For novel Biginelli�like
scaffold synthesis, the use of the common open
chain в�dicarbonyl compounds in Biginelli reac�
tions has been extended to the use of cyclic β�
diketones [12], β�ketolactones [13], cyclic β�
diesters or β�diamides, benzocyclic ketones and
α�keto acids. All of these reactions were per�
formed using conventional heating and reaction
times were long.
Microwave promoted solvent�free reactions
[14] are well known as environmentally benign
methods that also usually provide improved
selectivity, enhanced reaction rates, cleaner
products and manipulative simplicity [15].
Ukrainica Bioorganica Acta 1 (2009) 3—7
www.bioorganica.org.ua
*Corresponding author.
Tel.: +910240�2403311, fax: +91240�2400491
E�mail address: prof_msshingare@rediffmail.com
© A.H. Kategaonkar, S.A. Sadaphal, K.F. Shelke, B.B. Shingate,
M.S. Shingare, 2009
Microwave assisted synthesis of pyrimido[4,5�d]pyrimidine
derivatives in dry media
A.H. Kategaonkar, S.A. Sadaphal, K.F. Shelke, B.B. Shingate, M.S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University
Aurangabad (M.S.) 431004, India
Summary. Pyrimido[4,5�d]pyrimidine derivatives were synthesized by using an efficient, facile and solvent�
free procedure. Here, a non�conventional synthetic procedure has been developed where solid support of alumi�
na is used as energy transfer medium under microwave irradiation (MWI) which devoids hazards of solution
phase reactions. The reaction time has been brought down from minutes to seconds with improved yield as com�
pared to reported method.
Keywords: solvent�free, alumina, barbituric acid, pyrimido[4,5�d]pyrimidines, microwave irradiation.
However, these procedures are practically limi�
ted as the solvents in microwave oven at eleva�
ted temperatures create high pressures, which
may cause explosion. To circumvent these prob�
lems, there is a need for the development of
newer methods which proceed under mild and
solvent free condition. Solvents are often used to
pre�absorb the substrates on to, and wash the
products off the solid support. Benefits from
using solvent�free approaches include improved
safety by avoiding low�boiling solvents that
would otherwise cause undesirable pressure
increases during heating. For the transition of
microwaves to the reactants, the solid support is
the best option. Moreover they also provide an
opportunity to work with open vessels and an
enhanced possibility of upscalling the reactions
on a preparative scale [16].
Nowadays solvent�free synthesized reactions
much importance because of the absence of sol�
vents coupled with the high yields and short
reaction times often associated with reactions of
this type make these procedures very attractive
for organic synthesis. Earlier reported proce�
dures for the synthesis of pyrimido[4,5�d]pyri�
midines typically involved longer reaction time
and less yield [17]. In the present communica�
tion, we would like to describe the advantages of
dry reaction techniques coupled with microwa�
ve activation and their applications to organic
synthesis using solid supports [18].
Result and discussion. In view of the above
mentioned limitations of the reported method,
pharmacological importance of heterocycles and
our ongoing endeavors to conduct organic syn�
thesis under solvent free conditions [19], we
describe a expeditious solventless microwave
accelerated approach for the rapid assembly of
pyrimido[4,5�d]pyrimidines. Aromatic aldehydes
(2a�m, 0.01 mmol) on reaction with barbituric
acid (1, 0.01 mmol) and urea/thiourea (3a�b,
0.01mmol) using dry conditions yielded corre�
sponding pyrimido[4,5�d]pyrimidines (Scheme 1).
As far as our interest in investigating the
facile, rapid and expeditious solventless metho�
dology for pyrimido[4,5�d]pyrimidine, we tried
the reaction of benzaldehyde (2a, 0.01 mmol),
with barbituric acid (1, 0.01 mmol) and urea (3a,
0.01 mmol) with two different approaches to
observe the effect of solid support. We carried
out the reaction in absence of neutral alumina
and in presence of neutral alumina. Here we
observe the considerable changes as reaction
rate enhancement occurred by bringing down
the reaction time from minutes to seconds with
improved yield as compared to reported method.
The optimization was done by varying microwa�
ve power from 150 watts to 600 watts.
All results during this optimization were
summarized in Table 1. Firstly, we observe wi�
thout neutral alumina yield was very poor when
power was 150 and 300 watts (Table 1, 10�15 %)
and above 600 watts there is no appreciable
change in yield (Table 1, 30�50 %) With neutral
alumina it was observed that by increase in
power up to 600 watts, there was increase in
yield and shortened reaction time with solid
support of neutral alumina. Beyond the 600 watts
there was no significant change in reaction time
and yield.
Thus a microwave power 600 watts was cho�
A.H. Kategaonkar et al.
4 Ukrainica Bioorganica Acta 1 (2009)
HN
N
H
OO
O
+ R-CHO +
H2N NH2
X
1 2(a-p) 3(a-b)
MWI
HN
N
H
N
H
NH
O
O X
R
4(a-p)
X
3a=Urea
3b=Thiourea
Scheme 1
Synthesis of pyrimido[4, 5�d]pyrimidine deriva�
tives using alumina under solvent�free condition
Table 1
Optimization of time for benzaldehyde
Yield (%)a
Entry
Power
(watts)
Time With
Al2O3
Without
Al2O3
1 150 7 min 50 10
2 300 4.50 min 60 15
3 450 3 min 75 30
4 600 30 sec 95 35
5 750 30 sec 95 50
aIsolated Yields.
sen as the optimal one with solid support of neu�
tral alumina under MWI. Under these optimized
reaction conditions the expected pyrimido[4,5�
d]pyrimidine (Table 2, entry 4a) was obtained
with 95 % yield within 30 seconds. Hence all the
derivatives of pyrimido[4,5�d]pyrimidines were
prepared by microwave power 600 watts with
neutral alumina (Table 2).
Typical experimental procedure. A mixture
of barbituric acid (0.01 mmol), an aromatic alde�
hyde (0.01 mmol), urea or thiourea (0.01 mmol)
and 1 gm of neutral alumina (Al2O3) irradiated in
a microwave oven operating medium power
(600 watts) for appropriate time (Table 2). Prog�
ress of reaction was monitored by thin layer
chromatography using ethyl acetate: hexane
(2:8) solvent system.
After completion of reaction, the reaction
mixture was cooled to room temperature and
poured on crushed ice. Recrystallization was
done in dimethyl formamide and the neutral
alumina is recovered by simple filtration.
Melting points were determined in open capil�
laries and are uncorrected. The completion of
reactions was monitored by thin layer chro�
matography (TLC) on Merck silica gel plates. IR
spectra were recorded on a matrix of KBr with
Perkin�Elmer 1430 spectrometer. 1HNMR spec�
tra were recorded on Varian NMR spectrome�
ter, Model Mercury Plus (400 MHz), Mass spec�
tra [ES�MS] were recorded on a Water�Micro
mass Quattro�II spectrophotometer. For the
microwave irradiation experiments described
below, a microwave oven equipped with a
turntable was used (LG Smart Chef MS�255R
operating at 2450 MHz having maximum output
of 900 W) for reaction.
55,,66��ddiihhyyddrroo��55��pp��ttoollyyllppyyrriimmiiddoo[[44,,55��dd]]ppyyrriimmii��
ddiinnee��22,,44,,77((11HH,,33HH,,88HH))��ttrriioonnee ((44ee)).. IR (KBr, cm�1):
3490, 3250, 3125, 2867, 1697, 1616, 1468. 1H NMR
(DMSO�d6, 400 MHz, δ ppm): 10.93 (s, 2H, NH),
10.03 (s, 1H, NH), 7.94 (s, 1H, NH), 6.97�6.86 (m,
4H, Harom), 5.89 (s, 1H, 5�H), 2.88 (s, 3H, CH3).
Mass (ES/MS): m/z 273 [M+H]+.
55,,66��ddiihhyyddrroo��55��((44��hhyyddrrooxxyypphheennyyll))ppyyrriimmii��
ddoo[[44,,55��dd]]ppyyrriimmiiddiinnee��22,,44,,77((11HH,,33HH,,88HH))��ttrriioonnee
((44ff)).. IR (KBr, cm�1): 3478, 3265, 3193, 3118, 1711,
1608, 1526. 1H NMR (DMSO�d6, 400 MHz, δ
ppm): 11.30 (s, 1H, NH), 11.02 (s, 2H, NH), 8.40 (s,
1H, NH), 7.1�7.14 (m, 4H, Harom), 4.9 (s, 5�H). Mass
(ES/MS): m/z 275 [M+H]+.
55��((44��((ddiimmeetthhyyllaammiinnoo))pphheennyyll))��55,,66��ddiihhyydd��
rrooppyyrriimmiiddoo[[44,,55��dd]]ppyyrriimmiiddiinnee��22,,44,,77((11HH,,33HH,,88HH))��
ttrriioonnee ((44gg)).. IR (KBr, cm�1): 3181, 3041, 2842,
1650, 1520. 1H NMR (DMSO�d6, 400 MHz, δ
ppm): 11.20 (s, 1H, NH), 10.98 (s, 2H, NH), 8.20 (s,
1H, NH), 6.6�6.8 (m, 4H, Harom), 5.58 (s, 1H, 5�H),
2.89 (s, 6H, CH3). Mass(ES/MS): m/z 302 [M+H]+.
55,,66��ddiihhyyddrroo��55��((44��hhyyddrrooxxyy��33��mmeetthhooxxyypphhee��
nnyyll))ppyyrriimmiiddoo[[44,,55��dd]]ppyyrriimmiiddiinnee��22,,44,,77((11HH,,33HH,,
88HH))��ttrriioonnee ((44hh)).. IR (KBR, cm�1): 3279, 3070, 2866,
1667, 1501. 1H NMR (DMSO�d6, 400 MHz, δ
Microwave assisted synthesis of pyrimido[4,5�d]pyrimidine derivatives in dry media
5www.bioorganica.org.ua
Table 2
Microwave assisted solvent�free solid neutral alumina supported synthesis
of pyrimido[4,5�d]pyrimidine derivatives (power=600 watts)
Time Yield(%)b M. P.(oC)
Entry R X Found
(sec.)
Reported
(min.)
Found Reported Found Reported
4a C6H5 O 30 2.3 95 87 247�250 244�246
4b 2�OH C6H4 O 35 3.3 96 82 218�220 220�222
4c 4�Cl C6H4l O 30 3.0 96 86 294�295 296�298
4d 4�OMe C6H4 O 35 2.0 97 85 285�287 284�286
4e 4�CH3 C6H4 O 35 – 96 – 248�250c –
4f 4� OH C6H4 O 35 – 87 – 210�212c –
4g 4�N(CH3)2 C6H4 O 35 – 88 – 255�257c –
4h 4�OH, 3�OMe C6H4 O 25 – 85 – 275�277c –
4i 4�NO2 C6H4 O 30 – 70 – 202�204c –
4j 4�Br C6H4 O 30 – 87 – 210�212c –
4k 2�Cl�3�Quinolinyl O 40 3.3 95 87 282�284 280
4l Piperonyl O 40 2.0 94 85 294(d) >300(d)
4m C6H5 S 30 2.3 95 90 294�295 290�292
4n 2�OH C6H4 S 35 3.0 94 80 198�200 200�202
4o 4�Cl C6H4l S 25 3.0 98 92 280(d) 278(d)
4p 4�OMe C6H4 S 40 2.3 96 88 >300(d) >300
Reported data [17] b Isolated yields based upon starting aldehyde. c Newly synthesized compounds.
ppm): 11.25 (s, 2H, NH), 10.80 (s, 1H, NH), 8.45 (s,
1H, NH), 6.80�7.20 (m, 4H, Harom), 5.89 (s, 1H, 5�
H), 3.40 (s, 3H, OCH3). Mass (ES/MS): m/z 305
[M+H]+.
55,,66��ddiihhyyddrroo��55��((44��nniittrroopphheennyyll))ppyyrriimmiiddoo[[44,,55��
dd]]ppyyrriimmiiddiinnee��22,,44,,77((11HH,,33HH,,88HH))��ttrriioonnee ((44ii)).. IR
(KBR, cm�1): 3382, 3191, 3087, 2965, 2856, 1650,
1515. 1H NMR (DMSO�d6, 400 MHz, δ ppm): 11.40
(s, 1H, NH), 11.20 (s, 2H, NH), 10.18 (s, 1H, NH),
8.20�8.40 (m, 4H, Harom), 5.46 (s, 1H, 5�H). Mass
(ES/MS): m/z 304 [M+H]+.
55��((44��bbrroommoopphheennyyll))��55,,66��ddiihhyyddrrooppyyrriimmii��
ddoo[[44,,55��dd]]ppyyrriimmiiddiinnee��22,,44,,77((11HH,,33HH,,88HH))��ttrriioonnee
((44jj)).. IR (KBR, cm�1): 3200, 3044, 2837, 1620, 548.
1H NMR (DMSO�d6, 400 MHz, δ ppm): 11.30 (s,
2H, NH), 10.01 (s, 1H, NH), 8.6 (s, 1H, NH), 7.20�
7.43 (m, 4H, Harom), 5.59 (s, 1H, 5�H). Mass
(ES/MS): m/z 336 [M+H]+.
Conclusion. We have described an improved,
efficient and one pot synthesis of pyrimido[4,5�
d]pyrimidine derivatives via a three�component
cycloaddition reaction. Another advantage of
this method is excellent yields in shorter reac�
tion time with high purity of the products.
AAcckknnoowwlleeddggeemmeennttss.. The authors are thankful to
the Head, Department of Chemistry, Dr. Babasa�
heb Ambedkar Marathwada University, Auranga�
bad�431 004, India for providing laboratory facil�
ities. AHK is grateful to University Grants Com�
mission, New Delhi for the award of fellowship.
Надійшла в редакцію 29.07.2008 р.
A.H. Kategaonkar et al.
6 Ukrainica Bioorganica Acta 1 (2009)
Синтез похідних піримідо[4,5�d]піримідинів у сухому середовищі
за допомогою мікрохвильового випромінювання
А.Х. Категаонкар, С.A. Садапхал, К.Ф. Шелке, Б.Б. Шингате, М.С. Шингаре
Університет ім. Доктора Бабасахеба Амбедкара Марасвади
м. Аурангабад, Індія
Резюме. Похідні піримідо[4,5�d]піримідину синтезовано за допомогою простого й ефективного методу без за�
стосування розчинника. Розроблено нетрадиційний спосіб синтезу, за якого нерухому підкладку із оксиду алюмі�
нію використано як середовище для передачі енергії при мікрохвильовому випромінюванні, що запобігає негатив�
ним ефектам, які обумовлюють реакції у фазі розчинника. Новий метод дає змогу скоротити час реакції від декіль�
кох хвилин до кількох секунд і покращити її вихід.
Ключові слова: метод без використання розчинника, оксид алюмінію, барбітурова кислота, піримідо[4,5�d]пі�
римідини, мікрохвильове випромінювання.
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