Exploration of uracils: Pot and step economic production of pyridine core containing templates by multicomponent aza-Diels-Alder reaction

Article abstract of DOI:10.1039/c4ra02273d

An efficient pot and step economic protocol for synthesis of pyrido[2,3-d]pyrimidine derivatives from a multicomponent aza-Diels-Alder reaction of uracil analogues, aromatic aldehydes and acetophenones in the presence of Na₂CO₃ in DMF was developed. The key step of the reaction is in situ generation of the reactive dienophile from aldehyde and acetophenone and their subsequent reaction with diene to give the desired product.

Full text of DOI:10.1039/c4ra02273d

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Exploration of uracils: pot and step economic
production of pyridine core containing templates
by multicomponent aza-Diels–Alder reaction†
Cite this: RSC Adv., 2014, 4, 22955
Received 15th March 2014
Accepted 1st May 2014
*
Manas M. Sarmah and Dipak Prajapati
DOI: 10.1039/c4ra02273d
www.rsc.org/advances
An efficient pot and step economic protocol for synthesis of pyrido- known to act as potent inhibitor of dihydrofolate reductase
[2,3-d]pyrimidine derivatives from a multicomponent aza-Diels–Alder (DHFR);4c,d a target site in most of the parasitic diseases. In
ˇ
reaction of uracil analogues, aromatic aldehydes and acetophenones 2012, Skedelj's group showed that 6-arylpyrido[2,3-d]pyrimi-
in the presence of Na2CO3 in DMF was developed. The key step of the dines had notable action as ATP-competitive inhibitor of
reaction is in situ generation of the reactive dienophile from aldehyde bacterial D-alanine: D-alanine ligase (Ddl).4e These discoveries
and acetophenone and their subsequent reaction with diene to give have stimulated considerable interest in the synthesis of pyri-
the desired product.
dine containing carbocycles through new and efficient routes.
Uracil or pyrimidine-2,4-dione is one of the four essential
components in the nucleic acid of RNA. A wide range of works
on uracil are reported by synthetic chemists5 as well as biolo-
gists.6 General methods for the synthesis of uracil derivatives
involve the annulation reactions starting from suitably
substituted uracils and related systems.7 We have recently
synthesized a series of iminoquinazolinedione derivative from
vinyl uracils without using any solvent or catalyst.7f We also
developed efficient methodologies for syntheses of some
complex tetrahydroquinazolinedione and dihydropyrido[2,3-d]-
pyrimidine derivatives7g and, method for the formation of a
library of dihydropyrido[4,3-d]pyrimidines was also well-docu-
mented by applying vinyl uracils in a microwave-assisted
multicomponent reaction.7h,i 6-(Morpholinomethyleneamino)-
1,3-dimethyluracil 1a is a reactive diene for [4 + 2]-cycloaddition
reactions and a diverse array of potential products can be
obtained by its synthetic manipulation. The molecule can
simply be synthesized within two hours from N,N-dimethyl-6-
aminouracil, morpholine and triethyl orthoformate under
reux conditions and subsequent recrystallization of the crude
solid from ethanol.8 In continuation to our studies on uracil
molecules,7f–n we describe in this paper an efficient three-
component aza-Diels–Alder procedure for the synthesis of
various pyrido[2,3-d]pyrimidine derivatives from the equimolar
reaction mixture of 6-(morpholinomethyleneamino)-1,3-di-
methyluracil, aromatic aldehydes and acetophenones in DMF
(Scheme 1). To the best of our knowledge, only one report was
available in the literature for the synthesis of uracil derivatives
using 6-(morpholinomethyleneamino)-1,3-dimethyluracil as
one of the starting reactants7i and thus we believe, our work will
be able to draw considerable attention of organic chemists to
Introduction
Multicomponent reactions (MCRs) are one pot synthetic oper-
ations where concurrent combination of more than two
common and convenient reactants furnishes a single product
containing signicant portions of all reacting counterparts.
Spectacular results have been obtained by synthetic organic
chemists for construction of complex and structurally diverse
molecules by using MCRs with advantages such as high degree
of synthetic efficiency, molecular diversity and step-economy.1
The concept of aza-Diels–Alder reaction strategy is successfully
applied in numerous multicomponent reactions for construc-
tion of electrifying molecules.2
Over the years, pyridine containing molecules has attracted
much attention due to its extensive availability throughout
nature. The eld of pyridine and its derivatives is a promising
area of research as this structural motif appears in a large
number of pharmaceutical agents and natural products.3 Very
recently, Saikia et al. developed a convenient method to
synthesize pyrido[2,3-d]pyrimidines which were found to
possess remarkable activities against microorganisms such as
B. subtilis, S. aureus, K. pneumonia and E. coli.4a PD180970
(a novel pyrido[2,3-d]pyrimidine derivative), was successfully
applied to inhibit Bcr-Abl and induce apoptosis in Bcr-Abl
expressing leukemic cells.4b Pyrido[2,3-d]pyrimidine is also
Medicinal Chemistry Division, CSIR-North-East Institute of Science and Technology,
Jorhat, Assam 785006, India. E-mail: dr_dprajapati2003@yahoo.co.uk; Fax: +91
376 2370011
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02273d
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solvent systems, and the results obtained are indicated in
Table 1. The reaction did not occur in dry condition and the
starting materials were recovered quantitatively. It was observed
that all solvent systems showed ‘no progress with no base’ in
either reux or stirring conditions (entries 2–11, Table 1). We
were excited to notice that presence of catalytic amount of an
organic base (e.g., morpholine, piperidine and pyrrolidine)
could initiate the reaction but only in solvents with high boiling
points, particularly in DMF. However, the percentage of
Scheme 1 Synthesis of pyrido[2,3-d]pyrimidines.
explore the diene properties of 6-(morpholinomethylene- conversion into product was very less (entries 12–16, Table 1).
amino)-1,3-dimethyluracil.
We then changed our methodology and planned to carry out a
series of reactions at the boiling point of all solvents with
moderately stronger bases. It was observed that good to better
results were obtained when the reaction was carried out in
presence of catalytic amount of inorganic bases (entries 19–24,
Table 1). Because of easy handling and availability we preferred
Na2CO3 (ref. 9) over other bases and the model reaction was
screened in presence of Na2CO3 at various concentrations. We
found that more than 80% of the product, 6-benzoyl-5-(4-
methoxyphenyl)-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione
4a could be obtained within 6 hours, when the reaction mixture
with Na2CO3 (10 mol%) was vigorously stirred in DMF at its
boiling point. The yield of the product was unaffected by a
further increase in the loading of the catalyst but a lower yield of
the product was obtained from the reaction with 20 mol% of
Na2CO3. By considering the side effects associated with the use
of dimethyl sulfoxide (DMSO) for example, sedation, headache,
nausea, dizziness, burning eyes, constipation etc. DMF was
considered as better solvent for the cycloaddition. We have also
taken aim to reduce the time of the reaction for formation of the
Results and discussion
Our initial effort was to develop an appropriate solvent system
and reaction condition to perform the proposed reaction. The
model reaction of 6-(morpholinomethyleneamino)-1,3-di-
methyluracil (1a, 1 mmol), p-anisaldehyde (2a, 1 mmol) and
acetophenone (3a, 1 mmol) was investigated under different
Table 1 Optimization studies for synthesis of pyrido[2,3-d]pyrimidine
4aa
Entry
Solvent
Base
Yieldd (%) product by application of microwaves but very poor conversion
into product was observed under microwave conditions. Using
1
Neat
—
—
—
—
—
—
—
—
NRb
the optimized reaction conditions, the feasibility of the reaction
NRb
2
3
4
Water
Chloroform
DCM
NRb
NRb
NRb
NRb
NRb
NRb
NRb
NRb
NRb
NR
scheme was studied in detail by varying the uracils, aldehydes
and acetophenones and the results obtained are summarized
in Fig. 1.
5
DCE
6
7
MeOH
EtOH
During our generalization studies we were satised to nd
that the reaction was effective with aldehydes and acetophe-
nones bearing electron-withdrawing and, -donating substitu-
ents on the aromatic ring. In all cases, regiospecic formation
of the aromatic pyrido[2,3-d]pyrimidine templates were
observed in excellent yields together with trace amounts of
corresponding a,b-unsaturated ketones arising from aromatic
aldehydes and acetophenones as byproduct which were
removed during column chromatography. It can be mentioned
here that yields of the products were better with aldehydes and
acetophenones bearing electron withdrawing groups on both
and/or on either sides of the aromatic rings. A lower yield of
product was observed when heteroaromatic and conjugated
aromatic aldehydes were employed (relative to the reaction with
6-(morpholinomethyleneamino)-1,3-dimethyluracil, benzalde-
hyde and acetophenone). It was observed that 6-(morpholino-
methyleneamino)-1,3-dimethyluracil 1a was more reactive than
6-(piperidinylmethyleneamino)-1,3-dimethyluracil 1b, 6-(pyrroli-
dinylmethyleneamino)-1,3-dimethyluracil 1c, and vinyl uracils
prepared from N,N-diethyl-6-aminouracil (1d–1f); leading to
better yields of pyrido[2,3-d]pyrimidines. However, the reaction
8
9
Acetonitrile
Toluene
DMF
DMSO
EtOH
Acetonitrile
Water
DMF
DMSO
o-Xylene
DMF
DMF
DMF
DMF
DMSO
DMF
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Morpholine
Piperidine
Piperidine
Morpholine
Pyrrolidine
Na2CO3, 10 mol%
Na2CO3, 5 mol%
Na2CO3, 10 mol%
Na2CO3, 15 mol%
Na2CO3, 20 mol%
Na2CO3, 10 mol%
K2CO3, 10 mol%
Cs2CO3, 10 mol%
Et3N
NR
NR
Trace
Trace
Trace
40c
85c
85c
70c
72c
70c
DMF
DMF
70c
12c
a
Reaction conditions: a mixture of 6-(morpholinomethyleneamino)-
mmol), p-anisaldehyde (2a, mmol),
1,3-dimethyluracil (1a,
1
1
b
acetophenone (3a, 1 mmol) was reuxed/stirred for 10 h without
c
base; vigorously stirred in presence of a base at the boiling point
points of solvents till the completion of reaction. d Isolated yield.
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Scheme 2 Plausible mechanism for the formation of 4a.
Scheme 3 Synthesis of pyrido[2,3-d]pyrimidine 4a by two-compo-
nent reaction.
Fig.
1 Synthesis of pyrido[2,3-d]pyrimidine derivatives. Reaction
Fig. 2 Comparison between reported and present work.
conditions: a mixture of vinyl uracil (1, 1 mmol), substituted aldehyde
(2, 1 mmol), substituted acetophenone (3, 1 mmol), and Na2CO3 (10
mol%) was vigorously stirred in DMF (5 ml) at 153 ꢀC till the completion
of reaction (as indicated by TLC).
Rf value 0.75 (ethyl acetate–hexane 1 : 2) within less than two
hours. Aer two hours we stopped the reaction and isolated the
compound responsible for the spot whose NMR spectra corre-
sponded to A. These consequences showed that the experi-
mental results were highly consistent with the proposed
mechanism. Earlier we reported a two-component reaction of
uracil amidine 1g with a,b-unsaturated compound B in ethanol
to generate very limited numbers of pyrido[2,3-d]pyrimidines
40in 6 h.10 But it is noteworthy that the multicomponent reaction
with 10 mol% Na2CO3 in alcoholic medium was reluctant to
undergo transformation despite long reaction time (Fig. 2).
The step and pot economy principle (pre-functionalization of
a,b-unsaturated ketone was not required) together with good
yields associated with our new methodology make the approach
more economical and useful over previous scheme to synthesize
pyrido[2,3-d]pyrimidines.
failed when aliphatic aldehydes and ketones were employed
and only the condensation product between the aldehyde and
ketone was formed. An attempt to perform the reaction with
aliphatic aldehydes and ketones at high temperatures led to the
decomposition of the starting materials. All of the products
obtained were characterized by different methods such as, IR
and NMR spectroscopy, mass spectrometry and elemental
analysis.
A plausible mechanism for the formation of the pyrido[2,3-d]-
pyrimidine is shown in Scheme 2. It is believed that the base
promotes the formation of a,b-unsaturated ketone A between
p-anisaldehyde 2a and acetophenone 3a which then undergoes a
cycloaddition reaction with the diene system of uracil 1, followed
by elimination of the amine moiety to generate dihydropyrido-
[2,3-d]pyrimidine derivative B. Oxidative aromatisation of B
under the reaction conditions then leads to the formation of
pyrido[2,3-d]pyrimidines 4a.
Conclusions
To verify our proposed mechanism, a two component reac- In summary, we have demonstrated an aza-Diels–Alder reaction
tion was carried out between a pre-formed unsaturated ketone A which efficiently leads to the synthesis of a diverse range of
and 6-(morpholinomethyleneamino)-1,3-dimethyluracil 1a pyrido[2,3-d]pyrimidine derivatives.
A
wide variety of
under the same reaction conditions (Scheme 3). As expected, substituted aromatic aldehydes, cinnamaldehyde, hetero-
the derivative 4a was obtained in comparable yield (82%). We aromatic aldehydes, and substituted acetophenones were
further conrmed our mechanistic postulate by monitoring the shown to undergo the reaction with different uracil molecules
model reaction at different time intervals (by thin layer chro- to give exclusive amount of desired products. Overall, our
matography) and observed that an intense spot appeared with developed methodology requires simple and easily available
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starting materials and we consider that this reaction will create
interest among chemists to investigate the diene behavior of
some uracil derivatives.
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We are grateful to CSIR, New Delhi for nancial support to this
work. We also thank the Director, CSIR-NEIST, Jorhat for his
keen interest and constant encouragement.
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