A microwave-mediated catalyst- and solvent-free regioselective Biginelli reaction in the synthesis of highly functionalized novel tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2012.12.034

A series of novel ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4- tetrahydropyrimidine-5-carboxylates has been synthesized regioselectively by the Biginelli reaction of ethyl 3-oxo-4-(arylsulfonyl)butanoate, aromatic aldehyde and urea/thiourea under microwave irradiation and solvent- and catalyst-free conditions.

Full text of DOI:10.1016/j.tetlet.2012.12.034

Tetrahedron Letters 54 (2013) 1076–1079
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A microwave-mediated catalyst- and solvent-free regioselective Biginelli
reaction in the synthesis of highly functionalized novel tetrahydropyrimidines
Palani Sokkan Harikrishnan a, Stephen Michael Rajesh a, Subbu Perumal a, , Abdulrahman I. Almansour b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylates has been synthesized regioselectively by the Biginelli reaction of ethyl 3-oxo-4-(arylsulfonyl)but-
anoate, aromatic aldehyde and urea/thiourea under microwave irradiation and solvent- and catalyst-free
conditions.
Received 17 October 2012
Revised 6 December 2012
Accepted 8 December 2012
Available online 25 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Catalyst-free
Solvent-free
Green chemistry
Tetrahydropyrimidine
Dihydropyrimidinones (DHPMs) have received great attention
from synthetic and medicinal chemists due to their interesting bio-
logical applications.1 They exhibit a wide range of medicinal appli-
cations such as antiviral,2 antibacterial and antifungal,3 anticancer4
and calcium channel modulation.1a Monastrol (I), (Fig. 1) with the
pyrimidine-2-thione motif, specifically inhibits the motility of the
mitotic kinesin Eg5,5 while SQ 32926 (II)6 and Mon-97 (III)1a dis-
play antihypertensive and anticancer activities. In the present
work, we proposed to synthesize pyrimidines bearing the aryl-
sulfonylmethyl group, as several arylsulfone derivatives are known
to display antiviral7 and antitumour8 properties and act as Brady-
kinin B1 receptor antagonists9 for treatment of chronic pain. Aryl-
sulfone moiety is also prevalent in several biologically interesting
compounds that display antifungal, antibacterial or antitumour
activities10 and inhibit several enzymes, viz. cyclooxygenase-2
(COX-2)11 and HIV-1 reverse transcriptase.12
The three-component Biginelli reaction is a preferred method-
ology for the construction of structurally diverse DHPMs from sim-
ple starting materials, viz. aromatic aldehyde, diamide and keto
esters.13 In recent years, multicomponent reactions (MCRs)14 have
emerged as a versatile synthetic tool for the construction of biolog-
ically important new chemical entities with pot, atom and step
economies (PASE) in view of their green credentials such as con-
vergence, minimum waste generation and hence have carved a
niche in synthetic and medicinal chemistry arenas.15
The diversity of available methodologies for the Biginelli reac-
tion in the literature employs catalysts such as Fe3O4@ mesoporous
SBA-15(mesoporous nanocatalyst),16 [Gmim]Cl-Cu(II) complex in
neat condition,17 Mg–Al–CO3 and Ca–Al–CO3 hydrotalcite,18
SPINOL–phosphoric acid,19 poly(1-vinyl-3-(3-sulfopropyl) imi-
dazolium hydrogen sulfate) (poly(SIL)),20 chiral organocatalyst,21
1-methylimidazolium hydrogen sulfate in the presence of catalytic
amount of chlorotrimethylsilane ([Hmim]HSO4/TMSCl),22 5% per-
chloric acid doped silica (HClO4/SiO2),23 bioglycerol-based sulfonic
acid functionalized carbon catalyst24 and t-BuOK.25 These methods
suffer from one or more disadvantages such as use of corrosive/
expensive catalysts, inconsistent/moderate yields and organic sol-
vents. With this background in mind, we set out to establish a pro-
tocol for the efficient eco-friendly synthesis of novel medicinally
relevant tetrahydropyrimidines with arylsulfonylmethyl moiety
at the 6th position via three-component reaction employing sol-
vent- and catalyst-free reaction conditions. It is pertinent to note
that studies on the Biginelli reaction employing a solvent- and cat-
alyst-free green approach are meagre.26 The present study stems as
a part of our ongoing research programme on the exploration of
green transformations and domino/sequential multicomponent
reactions for the assembly of novel heterocycles of biological
importance.27
In the present investigation, a series of hitherto unreported no-
vel ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylates
4 has been synthesized by the
Biginelli reaction of ethyl 3-oxo-4-(arylsulfonyl)butanoate 1, aro-
matic aldehyde 2 and diamide (urea/thiourea) 3 under microwave
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.034

P. S. Harikrishnan et al. / Tetrahedron Letters 54 (2013) 1076–1079
1077
HO
HO
NO2
R
O
H
S
CO2Et
Me
H
S
COOEt
H2NOC
O
CO2Pr-i
N
HN
N
Ph
N
O2
S
N
H
Me
X
N
H
Ar
N
N
Me
Me
H
X = O, S
(I)
Monastrol
(II)
(III)
4
SQ 32926
Mon-97
Mitotic kinesin Eg5
Present work
Antihypertensive
agent
Anticancer drug
motor protein inhibitor
Figure 1. Biologically important DHPMs.
O
O
Ar'
irradiation and solvent- and catalyst-free conditions (Scheme 1).
The efficiency of this method has also been compared with reac-
tions carried out in the presence of acid catalysts, viz. acetic acid,
aluminium chloride, stannous chloride, cerium(III) chlorideꢀ7H2O,
ferric chloride and cupric acetate (Scheme 1) and solvents viz. eth-
anol, methanol, dimethyl formamide and acetonitrile taking the
model reaction of ethyl 3-oxo-4-(p-chlorophenylsulfonyl)butano-
ate, 4-methoxybenzaldehyde and urea leading to 4a (Table 1).
The results disclose that a maximum yield of 4a was obtained
when the reaction was performed in the absence of any catalyst
and solvent.
The reaction under microwave irradiation affording 4a was also
examined at temperatures ranging from 100 to 150 °C with an
increment of 10 °C. The results show that the yield of 4a reaches
a maximum at 150 °C and that the reaction is completed in
10 min. Performing the reaction at 180 °C did not significantly alter
the yield. Consequently, all subsequent reactions under micro-
wave-irradiation were performed under solvent- and catalyst-free
conditions at 150 °C (Table 2).28,29
In addition, the reactions for synthesizing 4 were also per-
formed under the classical thermal method in ethanol at reflux.
The results reveal that the yield of the reaction under microwave
irradiation (74–93%) is significantly more than that realized under
conventional heating conditions, 45–58% (Table 2). The reaction
under microwave irradiation could also be completed more rapidly
in minutes than under traditional heating conditions, albeit differ-
ent temperatures employed render the two protocols incompara-
ble with respect to the reaction time.
OEt
H2N
Ar'
COOEt
MW, 5-10 min
HN
+
O2
S
+
NH2
X = O, S
X
O
H
X
N
H
Ar
O2S Ar
1
2
3
4
Scheme 1. Synthesis of ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4-tet-
rahydropyrimidine-5-carboxylates 4.
Table 1
Solvent-, catalyst- and temperature optimization for the synthesis of 4a under
microwave irradiation
Entry
Catalysta
Solventb
Time (min)
Temp (°C)
Yield of 4a (%)
1
2
3
4
5
6
7
8
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
10
10
10
10
10
10
10
15
15
20
15
10
10
10
10
10
10
100
110
120
130
140
150
180
150
150
150
150
150
150
150
150
150
150
65
68
72
75
83
88
86
60
58
40
62
78
72
75
68
75
70
EtOH
MeOH
DMF
CH3CN
—
9
—
—
—
10
11
12
13
14
15
16
17
CH3COOH
AlCl3
SnCl2
CeCl3ꢀ7H2O
FeCl3
—
—
—
—
Cu(OAc)2
—
a,b
No solvent or catalyst employed unless specified.
Table 2
Synthesis of tetrahydropyrimidines 4 under thermal and microwave irradiation
Compd
Ar
Ar0
X
Reaction time
Refluxa (h) (80 °C) MWb (min) (150 °C)
Yield (%)
Refluxc
Mp (°C)
MW
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
O
O
O
O
O
O
O
O
S
S
S
S
S
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
45
52
48
55
45
50
58
52
44
56
48
48
56
52
56
45
88
86
90
80
93
89
78
91
78
92
75
93
86
74
85
92
222–223
218–219
215–216
209–210
226–227
220–221
217–218
207–208
211–212
212–213
201–202
198–199
219–220
229–230
224–225
204–205
p-FC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-FC6H4
p-MeOC6H4
p-MeC6H4
p-Cl-C6H4
p-F-C6H4
p-MeOC6H4
p-MeC6H4
p-Cl-C6H4
p-F-C6H4
S
S
S
a
Refluxed in ethanol.
b
c
Irradiation was programmed at 150 °C, 53 W and 2 bar pressure with high absorption level.
Isolated yield after purification.

1078
P. S. Harikrishnan et al. / Tetrahedron Letters 54 (2013) 1076–1079
OCH3
106.6 ppm. The ethyl hydrogens of the ester function appear as a
quartet and triplet at 3.88 and 1.08 ppm (J = 7.1 Hz) respectively,
the former shows HMBC with ester carbonyl at 164.1 ppm and
CH3 carbon at 13.9 ppm. The carbonyl carbon C-2 appearing at
152.5 ppm shows HMBC with H-4 at 5.29 ppm, while the methoxy
hydrogens occur as a singlet at 3.80 ppm.
4'
O
H
O
H
H3C
H
3
4
NH
5
H
2
6
N
H
O
A plurality of mechanisms28,29 proceeding via intermediates
such as Knovenagel condensation product, enamine, iminium ion
etc for the Biginelli reaction in presence of catalysts has been pos-
tulated. Since the present transformation has been effected in the
absence of any catalyst and solvent, the mechanistic investigation
of this Biginelli transformation is worthy of investigation. That this
H
6'
SO2
1
Cl
Figure 2. Selected HMBCs of 4a.
transformation does not occur through the intermediacy of
a,b-
3.80, s, 3H
55.3
unsaturated ketosulfonyl ester 9 is evident from the fact that it is
not formed in the reaction of 1 with 4-methoxybenzaldehyde un-
der microwave irradiation. The reaction of 1 with urea/thiourea re-
quired microwave irradiation for a much longer time than that
needed for the completion of the overall three-component reaction
of 1 with aldehyde and amide affording 4, as evident from the fact
that even after microwave irradiation of a mixture of 1 and dia-
mide for 15 min, the reaction was not complete. Thus, the transfor-
mation via enamine intermediate is also unlikely under the
reaction conditions.
OCH3
159.4
164.1
3.88, q, 2H
O
60.7
H
5.29, s, 1H
1.08, t, J = 7.1 Hz, 3H
106.6
54.7
152.5
13.9 H3C
O
NH
H
4.55, d, 1H, J = 13.8 Hz
5.14, d, 1H, J = 13.8 Hz
55.6
N
O
H
H
SO2
Cl
Consequently, the formation of ethyl 2-oxo/thio-4-aryl-6-(aryl-
sulfonylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates 4 is
visualized to involve the formation of (i) N-arylideneurea interme-
diate 6 generated by the dehydration of intermediate 5, which, in
turn, is formed from the reaction of aldehyde 2 and urea/thiourea
3 (Scheme 2). Presumably, subsequent reaction of N-arylideneurea
6 with the enol form of ethyl 3-oxo-4-(arylsulfonyl)butanoate 1
produces an open-chain ureide 7, which undergoes condensative
annulation to afford 4. This mechanism is further supported by
the fact that the reaction of 4-methoxybenzaldehyde with urea/
thiourea conducted separately under microwave irradiation for
5 min afforded the corresponding imine, which upon further
Figure 3. Selected NMR data of 4a.
The structure of these ethyl 2-oxo/thio-4-aryl-6-(arylsulfo-
nylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates 4 is in ac-
cord with elemental analyses and 1H, 13C and 2D NMR
spectroscopic data as illustrated for a representative example 4a.
In the 1H NMR spectrum of 4a, H-4 appears as a singlet at
5.29 ppm, which shows HMBCs with C-5 at 106.6 ppm and C-40
at 127.7.3 ppm (Figs. 2 and 3). The methylenic hydrogens at the
6th position appear as doublets at 4.55 and 5.14 ppm
(J = 13.8 Hz), which show HMBCs with C-6 at 114.0 and C-5 at
Ar'
Ar'
Ar'
H
O
CO2Et
..
Aldol-type
reaction
H
X
-H2O
N
OH
2
N
..
1
HO
NH2
NH2
X
NH2
SO2
6
Ar
X
NH2
5
3
Ar'
Ar'
Ar'
H
CO2Et
O
H
X
CO2Et
H
N
CO2Et
N
N
-H2O
Annulation
O
S 2
X
Ar
NH2
S
N
X
N
Ar
OH
O2
SO2
H
H
7
8
Ar
4
X = O/S
Ar'
EtO2C
O
Ar
SO2
1
+ 2
X
9
Ar'
O
S2
H
X
O
Ar'
S2
Ar
EtO2C
N
Ar
N
X
N
..
HO
H
H2N
X
6
4'
CO2Et
1
Not f ormed
Scheme 2. Plausible mechanistic pathway for the formation of 4.

P. S. Harikrishnan et al. / Tetrahedron Letters 54 (2013) 1076–1079
1079
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Organmet. Chem. 2012, 723, 154.
reaction with 1 under microwave irradiation for 5 min furnished
product 4. These reactions together require 10 min microwave
irradiation for completion similar to the three-component overall
reaction leading to 4 which was also completed in 10 min.
This reaction proceeds regioselectively as the product is formed
by the reaction of the methylene group flanked by the keto and es-
ter functions of 1 resulting in the exclusive formation of regioisom-
er 4, while the other regioisomer 40, formed by the involvement of
the methylene adjacent to the arylsulfonyl group is not detected
even in traces. The absence of formation of regioisomer 40 is pre-
sumably ascribable to the steric interaction between the arylsulfo-
nyl group in the enol of 1 and the aryl ring of the imine 5 impeding
the formation of 40 (Scheme 2).
18. Lal, J.; Sharma, M.; Guptab, S.; Parashara, P.; Sahua, P.; Agarwala, D. D. J. Mol.
Catal. A. Chem. 2012, 352, 31.
19. Xu, F.; Huang, D.; Lin, X.; Wang, Y. Org. Biomol. Chem. 2012, 10, 4467.
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21. Saha, S.; Moorthy, J. N. J. Org. Chem. 2011, 76, 396.
In conclusion, an expedient and environment-friendly proce-
dure for the synthesis of ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylm-
ethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates
4
in high
22. Kefayati, H.; Asghari, F.; Khanjanian, R. J. Mol. Liq. 2012, 172, 147.
23. Narahari, S. R.; Reguri, B. R.; Gudaparthi, O.; Mukkanti, K. Tetrahedron Lett.
2012, 53, 1543.
yields in the absence of catalyst under solvent-free microwave
irradiation is described in this Letter.
24. Konkala, K.; Sabbavarapu, N. M.; Katla, R.; Durga, N. Y. V. Vijai Kumar Reddy, T.;
Prabhavathi Devi, B.L.A.; Prasad, R.B.N Tetrahedron Lett. 2012, 53, 1968.
25. Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J. Org. Chem. 2010, 75, 1162–1167.
26. (a) Ranu, B. C.; Hajra, A.; Dey, S. S. Org. Process Res. Dev. 2002, 6, 817; (b) Wang,
R.; Liu, Z.-Q. J. Org. Chem. 2012, 77, 3952.
27. (a) Indumathi, S.; Perumal, S.; Anbananthan, N. Green Chem. 2012, 14, 3361.;
(b) Devi Bala, B.; Michael Rajesh, M.; Perumal, S. Green Chem. 2012, 14, 2484;
(c) Gunasekaran, P.; Balamurugan, K.; Sivakumar, S.; Perumal, S.; Menendez, J.
C.; Almansour, A. I. Green Chem. 2012, 14, 750; (d) Michael Rajesh, S.; Bala, B.
D.; Perumal, S.; Menéndez, J. C. Green Chem. 2011, 13, 3248; (e) Prasanna, P.;
Balamurugan, K.; Perumal, S.; Menéndez, J. C. Green Chem. 2011, 13, 2123; (f)
Michael Rajesh, S.; Perumal, S.; Menéndez, J. C.; Pandian, S.; Murugesan, R.
Tetrahedron 2012, 68, 5631; (g) Indumathi, S.; Perumal, S.; Menendez, J. C. J.
Org. Chem. 2010, 75, 472.
Acknowledgement
S.P. and A.I.M. gratefully acknowledge the Deanship of Scientific
Research at King Saud University for funding through the research
Grant RGP-VPP-026.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
034.
28. General Procedure Conventional method:
A
mixture of ethyl 3-oxo-4-
(1 mmol)
(arylsulfonyl)butanoate (1 mmol), (4-methoxybenzaldehyde)
1
2
and diamide 3 (1 mol) was heated to reflux in ethanol for the time given in
Table 2. After completion of the reaction as indicated by TLC, the reaction
mixture was concentrated and poured into ice water with stirring. The product
was filtered, washed with water (2 ꢁ 10 ml), dried and purified by passing
through a short column of silica gel employing ethyl acetate/petroleum ether
(1:4 v/v) as eluent to obtain pure product 4a.
References and notes
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2. Hurst, E. W.; Hull, R. J. Med. Pharm. Chem. 1961, 3, 215.
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Mitchison, T. J. Science 1999, 286, 971.
6. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;
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Chem. Lett. 2008, 18, 4764.
Under
microwave
irradiation:
A
mixture
of
ethyl
3-oxo-4-
2 (1 mmol)
(arylsulfonyl)butanoate
1
(1 mmol), (4-methoxybenzaldehyde)
and diamide 3 (1 mol) was taken in a 10 ml quartz vial, sealed and placed in a
Biotage microwave oven. The vial was subjected to microwave irradiation,
programmed at 150 °C, 53 W, 2 bar pressure and very high absorption level for
the time given in Table 2. After a period of 1–2 min, the temperature reached a
plateau, 150 °C, and remained constant. After gas jet cooling to room
temperature (3 min), the reaction mixture was extracted with CH2Cl2
(2 ꢁ 5 mL), dried over MgSO4 and concentrated in vacuo to obtain the crude
product which was purified as done for the thermal reaction. The yield,
analytical and spectroscopic data for a representative compound are given
below:
Ethyl
6-((4-chlorophenylsulfonyl)methyl)-4-(4-methoxyphenyl)-2-oxo-1,2,3,4-
tetra hydropyrimidine-5-carboxylate (4a)
Pale yellow solid; yield 88%; mp 222–223 °C, 1H NMR (300 MHz, CDCl3) dH:
1.08 (t, 3H, J = 7.2 Hz, CH3), 3.79 (s, 3H, –OCH3), 3.90 (q, 2H, J = 7.2 Hz, –CH2),
4.54 (d, 1H, J = 13.8 Hz), 5.13 (d, 1H, J = 13.8 Hz), 5.28 (s, 1H), 5.99 (s. 1H, –NH),
6.81 (d, 2H, J = 8.7 Hz, Ar-H), 7.07 (d, 2H, J = 8.7 Hz, Ar-H), 7.33 (d, 2H,
J = 8.7 Hz, Ar-H), 7.75 (d, 2H, J = 8.7 Hz, Ar-H), 8.24 (s, 1H, –NH); 13C NMR
(75 MHz, CDCl3) dC: 13.9, 54.8, 55.3, 55.7, 60.7, 106.7, 114.0, 127.7, 129.1,
130.3, 134.7, 135.8, 136.2, 140.8, 152.5, 159.4, 164.1. Anal. Calcd for
10. (a) Sun, Z. Y.; Botros, E.; Su, A. D.; Kim, Y.; Wang, E.; Baturay, N. Z.; Kwon, C. H. J.
Med. Chem. 2000, 43, 4160; (b) Otzen, T.; Wempe, E. G.; Kunz, B.; Bartels, R.;
Lehwark-Yvetot, G.; Hansel, W.; Schaper, K.-J.; Seydel, J. K. J. Med. Chem. 2004,
47, 240.
C21H21ClN2O6S: C, 54.25; H, 4.55; N, 6.03. Found C, 54.32; H, 4.47; N, 6.13.
29. Suresh, A.; Sandhu, J. S. ARKIVOC 2012, i, 66.