Pyridine-based, microwave-assisted one-pot synthetic protocol for the synthesis of ethyl 3-substituted-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates

Article abstract of DOI:10.1007/s11164-015-2270-4

Pyridine has been used for one-pot, two-component synthesis of ethyl 3-substituted-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives in moderate to good yields by condensing N-substituted thioureas with diethyl ethoxymalonate under microwave irradiation.

Full text of DOI:10.1007/s11164-015-2270-4

Res Chem Intermed
DOI 10.1007/s11164-015-2270-4
Pyridine-based, microwave-assisted one-pot synthetic
protocol for the synthesis of ethyl 3-substituted-4-oxo-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
Sourabh Mundra1 Radhakrishnan Mahesh1
•
Received: 11 May 2015 / Accepted: 8 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Pyridine has been used for one-pot, two-component synthesis of ethyl
3-substituted-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate deriva-
tives in moderate to good yields by condensing N-substituted thioureas with diethyl
ethoxymalonate under microwave irradiation.
Keywords 5-Carboethoxy-2-thiouracil Á Thiourea Á Pyrimidine Á Microwave
irradiation Á Synthesis
Introduction
Microwave technology has been widely used in the field of drug discovery and in
the development synthesising organic compounds/library of compounds to develop
lead candidates. The reaction acceleration, simplicity in handling, improvement of
product yield, efficient source of energy and the ability to unambiguously control
reaction conditions (temperature and pressure, etc.) make this technique versatile.
In the past few years, intensive studies have been carried out for the synthesis and
structural elucidation of 6-carboxyuracil (2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-
carboxylic acid) due to its remarkable role in the formation of nucleic acid [1, 2].
Therefore, 6-carboxyuracil and its derivatives have remained an area of research
focus for medicinal chemists [3, 4]. Meanwhile, 5-carboxyuracil (2,4-dioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid) and its analogues that possess a wide
spectrum of biological activities, viz. anti-hypertensive, antibacterial, antitumor,
antiviral and anticancer, are comparatively less explored [5, 6]. It is worth noting
&
Sourabh Mundra
sourabh_mundra@yahoo.co.in
1
Department of Pharmacy, FD-III, Birla Institute of Technology and Science, Pilani,
Pilani, Rajasthan 333031, India
123

S. Mundra, R. Mahesh
OH
NO2
O
O
O
NH
O
NH
N
H
S
N
H
S
Monastrol
LaSOM-65
Fig. 1 Pharmacologically active 3,4-dihydropyrimidin-2-(1H)-thiones (DHPMs)
that a very limited number of reports are available for thiolated-5-carboxyuracil (4-
oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid) [7, 8] and its ester
derivatives (Monastrol [9] and LaSOM-65 [10]; Fig. 1), despite their promising
biological results [4, 11]. Keeping all these aspects in mind, it was thought
worthwhile to explore and develop a new methodology for the synthesis of
5-carbethoxy-2-thiouracil and its analogues in our laboratory.
According to Ulbricht and Price experiment [12], condensation of thiourea and
ethyl ethoxymethylene cyanoacetate generated 5-cyano-2-thiouracil as a minor
product and 5-carbethoxy-2-thiocytosine as a major product. However, by replacing
ethyl ethoxymethylene cyanoacetate with ethyl phenylmethylene cyanoacetate, the
products obtained were 2-thiouracils instead of 5-carbethoxy-2-thiocytosines [11].
Later, Whitehead and Traverso reported one-pot synthesis of 5-carbethoxy-2-
thiouracil and its analogues, using conventional protocol by reacting thiourea and di-
ethyl ethoxymalonate [13]. Beside this, the classical Pietro Biginelli method has been
attracting various scientific groups worldwide in recent years, for the generation of
tetrahydropyrimidine/di-hydropyrimidine ring. This method represented a simple
and efficient synthesis of complex molecules based upon one-pot, multi-component
condensation reaction between thiourea/urea, appropriate aldehydes and b-ketoesters
under strong acidic conditions [14, 15]. Further, several new improved procedures
for the classical method using Lewis acids, such as combination of aluminium
chloride and hydrochloric acid (HCl) [16], BF3ÁOEt2 [17], low-melting tartaric acid-
urea mixtures [9], metal triflates [18, 19], zeolites [20], strong protic acids like HCl
[21, 22] and sulfuric acid (H2SO4 ) [21] have been developed; also, microwave- [23]
and ultrasonic-assisted methods [24] have been developed. Moreover, Friot et al.
[25] reported that S-methylthioimines or its iodide salts reacted with acrylic
dienophiles or ketenes in the presence of triethylamine to give methylthiodihy-
dropyrimidines/methylthiotetrahydropyrimidines with good yields.
In several studies, phase-transfer-catalysed (PTC) reaction conditions were used
as a general alkylation protocol to carry out alkylation of synthesized tetrahydropy-
rimidine/di-hydropyrimidine rings [26–29]. However, alkylation of tetrahydropy-
rimidine/di-hydropyrimidine rings using PTC conditions generated S-monoalkylated
(2nd position-alkylated derivatives) and/or simultaneous S- and N-dialkylated
products (2nd and 3rd position-alkylated derivatives) [29]. Additionally, an attempt
of selective N-alkylation (3rd position) of an S-benzylated intermediate yielded both
123

Pyridine-based, microwave-assisted one-pot synthetic protocol…
N- and O-dialkylated products (3rd and 4th positions), simultaneously [30].
Furthermore, it has been reported that treatment of methylthiodihydropyrimidines/
methylthiotetrahydropyrimidines with hydrogen sulfide (H2S) afforded the corre-
sponding thiouracil derivatives with selective substitution at the 3rd position, i.e.,
thiooxotetrahydroprimidinones [25]. Moreover, a recent report by Botsi and
Tsolomitis demonstrated the acid-mediated preparation of 5-carbethoxy-2-thiour-
acils via one or two steps [31].
Overall, most of the aforementioned routes (Fig. 2), for the synthesis of a
tetrahydropyrimidine/di-hydropyrimidine ring and its substituted 3rd-position ana-
logues were associated with limitations, such as being a multistep synthesis, a long
reaction time, harsh conditions and expensive reagents, thereby limiting their
application in sustainable (‘‘green’’) chemistry. Thus, the drawbacks associated with
the existing routes for the development of tetrahydropyrimidine/di-hydropyrimidine
rings, and motivated by the success of the pyridine-based, three-component conden-
sation reactions for other scaffolds [32–35], as well as continuous synthetic interests in
heterocyclic rings [36–38], here, we report a novel, pyridine-based, microwave-assisted
one-pot synthetic route for the synthesis of ethyl 3-substituted-4-oxo-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate derivatives in quantitative yields.
Fig. 2 Some reported methods for the synthesis 5-carbethoxy-2-thiouracil and its analogues
123

S. Mundra, R. Mahesh
Experimental
Chemistry
All reagents and solvents were purchased from commercial sources and used without
further purification. Reactions were monitored by thin layer chromatography (TLC,
silica gel-60 F254), using a solvent system of ethyl acetate/hexane and methanol/
dichloromethane (in suitable proportions). The scientific multimode CATA-R
(140–700 W, Catalyst Systems, Pune, India) microwave synthesizer model equipped
with glass vial extension by a condenser was used for performing the reaction. The
microwave was equipped with a temperature control system (external probe) but
without a pressure control system. Reactions were performed in 5 mL of unclosed
microwave vials. Open capillary tubes on a Precision Buchi B530 melting point
instrument containing silicon oil were used to compute melting points (uncorrected).
1
Proton nuclear magnetic resonance ( H NMR) and carbon-13 ( 13C) NMR spectra
were recorded on a Bruker DPX-400 NMR spectrometer using trimethylsilane (TMS)
as an internal standard. A WatersTM 3100 mass detector using an electrospray
ionization (ESI, ?ve) mode was used to record mass spectra. A WatersTM binary
gradient module liquid chromatography–mass spectrometry (LC–MS) system suited
with a photodiode array detector was used to evaluate the purity of the representative
compounds. Prior to use in high-performance liquid chromatography (HPLC), all
solvents were passed through filters (water membrane: Pall Corporation, 47-mm GH
Polypro, 0.45 lm). Two methods were used to determine the purity. Method A: 10-%
methanol (MeOH) in H2O (1 mL/min, isocratic) and Method B: 15-% MeOH in H2O
(1 mL/min, isocratic). Elemental analysis was performed on an Elementar, Vario Pyro
Cube (Germany); the C, H and N analyses were repeated twice.
General procedure
A mixture of compound 1 (12.0 mmol) or (4a–k), diethyl (ethoxymethylene)
malonate
2 (12.0 mmol), potassium carbonate (24.0 mmol) and pyridine
(48.0 mmol) were stirred together in anhydrous N,N0-dimethylformamide (20 mL)
under 120-°C microwave heating (300 W). Completion of the reaction was
confirmed by TLC. The solvent was evaporated under vacuum and the residue was
dissolved in ethyl acetate. The solution was washed with HCl (1 N), dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was
purified by column chromatography to give pure solid compound 3 or (5a–k).
All compounds are known [13, 25, 29, 31, 39] except 5j and 5k, which are novel.
Analytical data for some representative compounds are as mentioned below.
Ethyl 3-benzyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3)
Off white solid, purity 97.51 % (method A); 1H NMR [400 MHz, deuterated
dimethylsulfoxide (DMSO-d6)]: d 13.12 (s, 1H, NH), 8.03 (s, 1H, pyrimidine),
7.33–7.21 (m, 5H, phenyl), 5.50 (s, 2H, NCH2), 4.18 (q, J = 7.06, 2H, ester), 1.24
(t, J = 7.06 Hz, 3H, ester); 13C NMR (101 MHz, DMSO-d6): d 177.24 (C2), 162.19
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Pyridine-based, microwave-assisted one-pot synthetic protocol…
(C4), 156.50 (CO ester), 145.91 (C6), 127.03–135.84 (Ph-C), 106.00 (C5), 60.47
(OCH2), 48.79 (NCH2), 14.07 (CH3); MS (ESI): m/z 291.02 (M?1)?; Anal. calcd
for C14H14N2O3S C, 57.92; H, 4.86; N, 9.65; found C, 57.94; H, 4.87; N, 9.63.
Ethyl 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5a)
1
Orange solid, purity 100 % (method A); H NMR (400 MHz, DMSO-d6): d 12.78
(s, 1H, NH), 12.72 (s, 1H, NH), 7.96 (s, 1H, pyrimidine), 4.17 (q, J = 7.1 Hz, 2H,
ester), 1.24 (t, J = 7.1 Hz, 3H, ester); 13C NMR (101 MHz, DMSO-d6): d 176.48
(C2), 162.18 (C4), 157.14 (CO ester), 147.38 (C6), 107.04 (C5), 60.34 (OCH2), 14.12
(CH3); MS (ESI): m/z 200.9 (M?1)?; Anal. calcd for C7H8N2O3S C, 41.99; H, 4.03;
N, 13.99; found C, 41.97; H, 4.05; N, 13.98.
Ethyl 3-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5b)
Yellow solid, purity 100 % (method A); 1H NMR (400 MHz, DMSO-d6): d 8.10 (s,
1H, pyrimidine), 4.10 (q, J = 7.1 Hz, 2H, ester), 3.52 (s, 3H, methyl), 1.21 (t,
J = 7.1 Hz, 3H, ester); 13C NMR (101 MHz, DMSO-d6): d 185.92 (C2), 165.23
(C4), 160.06 (CO ester), 156.51 (C6), 102.63 (C5), 58.63 (OCH2), 33.52 (NCH3),
14.31(CH3); MS (ESI): m/z 215.0 (M?1)?; Anal. calcd for C8H10N2O3S C, 44.85;
H, 4.70; N, 13.08; found C, 44.83; H, 4.72; N, 13.09.
Ethyl 3-allyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5e)
1
Yellow solid, purity 98.76 % (method A); H NMR (400 MHz, DMSO-d6): d 8.15
(s, 1H, pyrimidine), 5.86 (m, 1H, vinyl CHD), 5.05 (m, 1HC), 5.03 (m, 1HB), 5.01
(m, 2H, NCH2A), 4.10 (q, J = 7.1 Hz, 2H, ester), 1.22 (t, J = 7.1 Hz, 3H, ester);
13C NMR (101 MHz, DMSO-d6): d 185.74 (C2), 165.30 (C4), 159.45 (CO ester),
156.82 (C6), 133.38 (CH2, allyl), 116.10 (CH, vinyl), 103.09 (C5), 58.69 (OCH2),
47.53 (NCH2), 14.39 (CH3, ester); MS (ESI): m/z 241.1 (M?1)?; Anal. calcd for
C10H12N2O3S C, 49.99; H, 5.03; N, 11.66; found C, 49.98; H, 5.02; N, 11.68.
Ethyl 3-ethyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5f)
Yellow solid, purity 100 % (method A); 1H NMR (400 MHz, DMSO-d6): d 8.11 (s, 1H,
pyrimidine), 4.39 (q, J = 6.9 Hz, 2H, NCH2), 4.10 (q, J = 7.1 Hz, 2H, ester), 1.21 (t,
J = 7.1 Hz, 3H, ester), 1.12 (t, J = 6.9 Hz, 3H, CH3); 13C NMR (101 MHz, DMSO-d6):
d 185.48 (C2), 165.56 (C4), 160.30 (CO ester), 156.65 (C6), 102.71 (C5), 58.97 (OCH2),
40.70 (NCH2), 14.36 (CH3, ester), 11.84 (CH3); MS (ESI): m/z 229.1 (M?1)?; Anal.
calcd for C9H12N2O3S C, 47.35; H, 5.30; N, 12.27; found C, 47.37; H, 5.31; N, 12.29.
Ethyl 3-(2-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(5j)
1
White solid, purity 99.08 % (method B); H NMR (400 MHz, CDCl3 ? DMSO-
d6): d 8.20 (s, 1H, pyrimidine), 7.31 (m, 1H, phenyl), 7.17-7.05 (m, 3H, phenyl),
123

S. Mundra, R. Mahesh
4.20 (q, J = 7.2 Hz, 2H, ester), 3.78 (s, 3H, methoxy), 1.29 (t, J = 7.2 Hz, 3H,
ester); 13C NMR (101 MHz, CDCl3 ? DMSO-d6): d 177.48 (C2), 164.56 (C4),
159.30 (CO ester), 157.30 (C–O, benzene ring), 146.65 (C6), 117.03-131.84 (Ph–C),
104.40 (C5), 60.97 (OCH2), 56.97 (OCH3), 14.31 (CH3, ester); MS (ESI): m/z 307.1
(M?1)?; Anal. calcd for C14H14N2O3S C, 54.89; H, 4.61; N, 9.14; found C, 54.91;
H, 4.60; N, 9.16.
Ethyl 3-(4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(5k)
Off white solid, purity 95.31 % (method B); 1H NMR (400 MHz, CDCl3 ? DMSO-
d6): d 8.24 (s, 1H, pyrimidine), 7.36 (m, 2H, phenyl), 7.06–6.91 (m, 2H, phenyl),
4.19 (q, J = 7.2 Hz, 2H, ester), 3.80 (s, 3H, methoxy), 1.25 (t, J = 7.2 Hz, 3H,
ester); 13C NMR (101 MHz, CDCl3 ? DMSO-d6): d 177.80 (C2), 164.70 (C4),
159.68 (CO ester), 156.99 (C–O, benzene ring), 146.61 (C6), 115.03-129.84 (Ph–C),
103.99 (C5), 60.91 (OCH2), 56.91 (OCH3), 14.31 (CH3, ester); MS (ESI): m/z 307.1
(M?1)?; Anal. calcd for C14H14N2O4S C, 54.89; H, 4.61; N, 9.14; found C, 54.90;
H, 4.62; N, 9.13.
Results and discussion
Initially, the investigation was started with the synthesis of compound 3 (entry no. 1;
Table 1), adopting a classical synthetic protocol in which benzyl thiourea (1) was
condensed with diethyl ethoxymalonate (2), along with sodium ethoxide/EtOH at
room temperature stirring for 3 days [13]. The crude compound was purified by
column chromatography and the structure of isolated pure compound 3 was
assigned on the basis of 1H NMR, 13C NMR and mass spectral data. Considering the
importance of this scaffold and to expedite the faster synthesis for the target
compound 3, various conventional and microwave-assisted syntheses using different
methodologies were explored. The details of various trial conditions to optimize the
model reaction (Scheme 1) are summarized in Table 1.
In order to discover suitable reaction conditions to synthesize compound 3,
conventional heating was initially attempted at 100 °C for 5 h. The reaction was
monitored by TLC; no new spot was detected after 5 h (entry no. 2; Table 1). By
extending the heating time for further 5 h, one new spot was observed with less
intensity via TLC; the formed spot was subjected to flash chromatography which
afforded 20 % of the desired product (entry no. 3; Table 1). When the same reaction
was attempted by switching the reaction solvent from ethanol to a DMF/ethanol
mixture (1:1), no significant conversion was noticed upon heating at 100 °C for
10 h. However, heating the reaction mixture at 120 °C for 28 h pushed the reaction
further and 70 % of desired product was isolated (entry no. 4; Table 1). Further, no
significant improvement in the yield was observed (72 %) when the reaction was
conducted using DMF as the solvent at 120 °C for 28 h (entry no. 5; Table 1).
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Pyridine-based, microwave-assisted one-pot synthetic protocol…
Table 1 Optimization of the model reaction (Scheme 1) to obtain target compound 3 using various
methodologies
Sr. no. Solvent
Base
Temp (°C) Timea % Yieldb
Method
1
EtOH
EtOH
EtOH
NaOEt
NaOEt
NaOEt
rt
72
5
75
Classical
2
100
100
120
120
rt
No reaction
20
Conventional
Conventional
Conventional
Conventional
Conventional
Conventional
Microwave
3
10
28
28
5
4
EtOH/DMF NaOEt
70
5
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
EtOH
DMF
DMF
DMF
DMF
DMF
DMF
NaOEt
K2CO3
TEA
72
6
No reaction
No reaction
No reaction
20c
7
rt
5
8
K2CO3
K2CO3
K2CO3
NaOEt
NaOEt
130
130
130
130
130
15
45
60
30
40
40
50
60
40
40
50
9
Microwave
10
11
12
13
14
15
16
17
18
a
Mutiple spots Microwave
45c
42d
40c
41c
40d
65c
65c
63d
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
K2CO3/pyridine (0.5 eq) 130
K2CO3/pyridine (0.5 eq) 130
K2CO3/pyridine (0.5 eq) 130
K2CO3/pyridine (2.0 eq) 130
K2CO3/pyridine (3.0 eq) 130
K2CO3/pyridine (3.0 eq) 140
Time in h (Entries 1–7) and in min (Entries 8–18)
Yields refer to isolated pure compounds
Starting material recovered
b
c
d
Yield of isolated product from multiple spots
EtOH ethanol, DMF dimethylformamide
Classical Protocol
O
O
O
O
H
O
O
N
NH2
N
Conventional Approach
Microwave approach
+
O
O
S
S
N
H
1
2
3
Scheme 1 Various strategies to synthesize target compound 3
Moreover, no fruitful results were obtained by performing the reaction at room
temperature using a variety of bases (entry nos. 6, 7; Table 1).
The above-mentioned observations prompted us to carry out the model reaction
under microwave irradiation utilizing different reaction conditions. Among them,
the first reaction was performed in a 5-mL microwave vial (open) using DMF as the
solvent and potassium carbonate (2 mol equivalent) as a base at 130 °C (entry no. 8;
Table 1). TLC revealed no new spot after 15 min; enhancing the duration additional
15 min resulted in one new spot being observed with faint intensity via TLC.
123

S. Mundra, R. Mahesh
Further microwave irradiation for 15 min and addition of more base potassium
carbonate (1 mol equivalent) to this reaction did not show any improvement in the
intensity of the spot. Therefore, the solvent was evaporated under vacuum, and the
crude mixture was purified by column chromatography to obtain the pure compound
at a 20-% yield (entry no. 9; Table 1). Interestingly, by increasing the reaction time
to 60 min under similar reaction conditions, multiple spots were observed via TLC
(entry no. 10; Table 1).
Next, a new strategy was planned to try the reaction using ethanol as the solvent
and sodium ethoxide (1 mol equivalent) as a base at 130 °C under microwave
irradiation for 15 min. TLC affirmed one new spot with low intensity. Subsequently,
by extending the heating time an extra 15 min, improvement was observed in the
intensity of the spot. The spot was subjected to column chromatography and
afforded the desired product 3 at a 45-% yield (entry no. 11; Table 1). By
prolonging the reaction an additional 10 min, multiple spots were detected via TLC
(entry no. 12; Table 1).
On the contrary, when the reaction was carried out with a potassium carbonate/
pyridine (1:0.25 mol equivalents) combination as the base at 130 °C, an intense spot
was observed via TLC after 40 min. The spot was isolated as compound 3 at a 40-%
yield (entry no. 13; Table 1), signifying the additive role of pyridine in our
condensation reaction because the reaction proceeded sluggishly when potassium
carbonate was used alone. Further, to improve the product yield as well as reaction
rate, we optimized the above reaction conditions. In this context, the reaction was
performed with similar conditions for 50 min. Interestingly, no significant
improvement in product yield was observed (entry no. 14; Table 1). However,
conducting the reaction for 60 min, under similar conditions, multiple spots were
observed via TLC (entry no. 15; Table 1). Then, our attention was turned to
standardizing the amount of pyridine, whereby reactions were performed with
varying concentrations of pyridine, viz. 1, 1.5, 2 and 3 mol equivalents at different
time intervals. 2 mol equivalent of pyridine was found to be sufficient for the
efficient transformation of this reaction in 40 min (entry no. 16; Table 1), since
increasing the amount of pyridine with enhancement of time and temperature did
not improve the yield (entry nos. 17, 18; Table 1). Moreover, it is worth mentioning
that we observed 300-W microwave irradiation to be the most favourable with the
aforementioned conditions.
Thus, in the present study (prototype; Scheme 1; Table 1), optimized
microwave conditions were found to be more superior than conventional heating
procedures for the synthesis of target compound (3). Therefore, choosing the
optimized reaction conditions and to evaluate the scope of the substrate, various
N-substituted thioureas (4a–k) were condensed with diethyl ethoxymalonate (2),
as depicted in Scheme 2, which afforded the final ethyl 3-substituted-4-oxo-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives (5a–k) with moder-
ate to good yields.
Overall, we have optimized the reaction conditions involving a straightforward
approach for the successful preparation of various 5-carbethoxy-2-thiouracil
derivatives. Further, to compare the scope and limitations of this reaction with
123

Pyridine-based, microwave-assisted one-pot synthetic protocol…
O
O
O
H
R
S
O
O
N
NH2
N
O
K2CO3/Pyridine/DMF
130 °C/ 40-60 min
R
+
O
O
S
N
H
(4a-k)
(5a-k)
2
Scheme 2 Optimized microwave-assisted synthetic route conditions for the synthesis of compounds
(5a–k)
other protocols, it has been found that some reported conditions [13, 31] were
efficacious in terms of yield. However, short reaction time, simple setup and
inexpensive reagents in collation to the established methods [13, 25, 31] made this
route a useful alternative for the synthesis of valuable ethyl 3-substituted-4-oxo-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives.
All the synthesized compounds were isolated, purified and subjected to
physicochemical characterization (Table 2). The structural features of some
1
representative compounds (5a, 5b, 5e, 5f, 5j and 5k) were assigned by H NMR,
13C NMR, mass spectroscopy and elemental analysis. The characteristic spectral
data of the compounds are in accordance with the proposed structures. For
1
example, H NMR signals for the ester linkage in the target compounds were
observed in their expected region at d (4.10–4.20, CH2 protons) and d (1.21–1.29,
CH3 protons). The pyrimidine moiety containing one aromatic proton (6th position)
appeared in the region d (7.96–8.24). The shielding of this proton due to strong
electron-donating groups (methyl, ethyl, allyl, and methoxyphenyl), were observed
as compared to a weak electron-donating group (benzylene) in compound 3. To
understand the allylic system of compound 5e, the hydrogens are represented as A–
D (Table 1). The hydrogen atom characterized by A is the easiest multiplet on the
spectrum to recognize in the region at d 5.01. The proton B has a smaller pattern as
per NMR in the region at d 5.03, as compared to proton C, because it has a cis
coupling to proton D, whereas proton C underwent trans coupling to proton D;
thus, in NMR it showed a wider pattern in the region at d 5.05. The hydrogen atom
labelled as D (vinyl proton) appeared as the broadest and most complicated pattern
in the region at d 5.86. However, the exact interpretation requires various coupling
constants (Jcd trans and Jbd cis). Unfortunately, due to merging of the sub-peaks of
the allylic protons, the well separation of multiplets did not occur. Apart from this,
depending upon the position and type of substitution present on the N3 position,
corresponding peaks were observed in the 1H NMR spectra. Further, all these
compounds (5a, 5b, 5e 5f, 5j and 5k) were characterized with 13C NMR, which
gave corresponding peaks. The purity of the representative compounds, as assessed
by LC-MS, was [95 %. Mass spectra (ESI) of the compounds exhibited a
molecular ion as (M?1)?. The elemental compositions determined using Elemen-
tar, Vario Pyro Cube demonstrated that experimental values were in agreement
with computed ones.
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S. Mundra, R. Mahesh
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Pyridine-based, microwave-assisted one-pot synthetic protocol…
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S. Mundra, R. Mahesh
Conclusion
In summation, we have reported that by using pyridine the total reaction time for the
synthesis of ethyl 3-substituted-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-car-
boxylate derivatives under microwave irradiation could be shortened from a few
days to a few/couple of minutes. To the best of our knowledge, synthesis of such
compounds by this method is novel and not previously reported elsewhere.
Moreover, pyridine, in combination with potassium carbonate, made this protocol
simple, convergent and attractive for the construction of biologically important
tetrahydropyrimidines and notably similar molecules, compared to the existing
methods, which could possibly be tested with other compounds. Further study to
explore the mechanistic path of this condensation reaction is currently undergoing in
our laboratory.
Acknowledgments The authors gratefully acknowledge the financial support from the Department of
Biotechnology (BT/IN/Canada/22/AM/2009), New Delhi, India as a part of the ISTP Canada-DBT
Collaborative R&D Program. Authors are also thankful to the Birla Institute of Technology & Science
(BITS), Pilani, India, and SAIF, Panjab University, Chandigarh, India, for providing the infrastructure
facilities and analytical facilities, respectively. The authors are grateful to Dr. L.P. Kotra (University
Health Network, Toronto, Canada), Dr. Sai Kumar Chakka (Encycle Therapeutics, Toronto-Canada) and
Dr. Asif Mohmmed (ICGEB, Delhi, India) for their valuable suggestions.
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