Al2O3/MeSO3H: A novel and recyclable catalyst for one-pot synthesis of 3,4-dihydropyrimidinones or their sulfur derivatives in Biginelli condensation

Article abstract of DOI:10.1080/00397910802444258

Al2O3/CH3SO3H (AMA) is an efficient catalyst for the three-component condensation reaction of aldehyde, 1,3-dicarbonyl compound, and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2-(1H)-ones in high isolated yield via this procedure, w

Full text of DOI:10.1080/00397910802444258

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Al2O3/MeSO3H: A Novel and
Recyclable Catalyst for
One-Pot Synthesis of 3,4-
Dihydropyrimidinones or Their
Sulfur Derivatives in Biginelli
Condensation
Hashem Sharghi a & Mahboubeh Jokar a
a Department of Chemistry, Shiraz University, Shiraz,
Iran
Version of record first published: 24 Feb 2009.
To cite this article: Hashem Sharghi & Mahboubeh Jokar (2009): Al2O3/MeSO3H: A
Novel and Recyclable Catalyst for One-Pot Synthesis of 3,4-Dihydropyrimidinones
or Their Sulfur Derivatives in Biginelli Condensation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:6,
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Synthetic Communications1, 39: 958–979, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802444258
Al2O3/MeSO3H: A Novel and Recyclable
Catalyst for One-Pot Synthesis of
3,4-Dihydropyrimidinones or Their Sulfur
Derivatives in Biginelli Condensation
Hashem Sharghi and Mahboubeh Jokar
Department of Chemistry, Shiraz University, Shiraz, Iran
Abstract: Al2O3=CH3SO3H (AMA) is an efficient catalyst for the three-component
condensation reaction of aldehyde, 1,3-dicarbonyl compound, and urea or thiourea
to afford the corresponding 3,4-dihydropyrimidin-2-(1H)-ones in high isolated
yield via this procedure, which works very effectively regardless of the electronic
nature of the substituent on the ring, although electron-donating groups precipitate
the rate of reaction. The catalyst is recyclable and stable at room temperature, and
the reaction protocol is simple, is cost-effective, and gives good isolated yield with
high purity.
Keywords: AMA, Biginelli, dihydropyrimidinones, methansulfonic acid, recycl-
able catalysis
INTRODUCTION
Multicomponent reactions (MCRs) occupy an outstanding position in
organic and medicinal chemistry for their high degree of atom economy,
applications in combinatorial chemistry, and diversity-oriented synthesis.[1]
The Biginelli reaction,[2] one of the most useful multicomponent reactions,
offers an efficient way to access multifunctionalized 3,4-dihydropyrimidin-
2-(1H)-ones (DHPMs) and related heterocyclic compounds.[3] Such
Received August 12, 2008.
Address correspondence to Hashem Sharghi, Department of Chemistry,
Shiraz University, Shiraz 71454, Iran. E-mail: shashem@chem.susc.ac.ir,
hsashemsharghi@gmail.com
958

One-Pot Synthesis of 3,4-Dihydropyrimidinones
959
heterocycles (Scheme 1) show a wide scope of pharmacological properties
including antiviral, antitumor, antibacterial, and anti-inflammatory activ-
ities.[4] Recently, appropriately functionalized DHPM analogs have
emerged as orally active antihypertensive agents (1,2)[5] and a1a adrenocep-
tor-selective antagonists (3).[6] Another highlight in this context has been
the identification of the structurally rather simple DHPM monastrol (4)
as a novel cell-permeable molecule that blocks normal bipolar spindle
assembly in mammalian cells, causing cell cycle arrest.[7]
Thus the synthesis of these heterocyclic compounds is of much current
importance. The search for more suitable preparation of dihydropyrimidi-
nones continues today. The first protocol to prepare the compounds of
this type was presented by Biginelli in 1893 and involved a three-compo-
nent, one-pot condensation.[2] A major drawback to Biginelli’s original
reactions, however, was poor to moderate yields.[8] Recently, many
improved procedures have been reported using InBr3,[9] InCl3,[10]
LiClO4,[11] FeCl3 ꢀ 6H2O or NiCl2 ꢀ 6H2O,[12] p-TsOH,[13] LaCl3 ꢀ 7H2O,[14]
Bi(OTf)3,[15] La(OTf)3,[16] BF3 ꢀ OEt2,[17] ionic liquids (BMIm ꢀ PF6
and BMIm ꢀ BF4),[18] natural HEU type zeolite, [19] I2,[20] N-bromosuccini-
[22]
mide (NBS),[21] polyaniline–bismoclite complex
and other Lewis
acids,[23] heteropoly acid,[24] sulfated zirconia,[25] Sr(NO3)2,[26] and cova-
lently anchored sulfonic acid onto silica.[27] However, some of the newer
reported methods also suffer from drawbacks such as unsatisfactory
Scheme 1. Four of these related heterocyclic compounds 3,4-dihydropyrimidin-2-
(1H)-ones (DHPMs) that have pharmacological properties are illustrated above.

960
H. Sharghi and M. Jokar
Scheme 2. One-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and thiones
using Al2O3=CH3SO3H (AMA).
yields, cumbersome product isolation procedures, and environmental pol-
lution.[9,10,14,16,17] Moreover, the main disadvantage of almost all existing
methods is that the catalysts are destroyed in the workup procedure and
cannot be recovered or reused. Therefore, still there is need for versatile,
simple, and environmentally friendly processes whereby DHPMs may
be formed under milder and practical conditions.
Solid-supported reagents are unique acid catalysts that have become
popular over the past two decades. The activity and selectivity of a
reagent dispersed on the surface of a support are improved as the effec-
tive surface area of the reagent is increased significantly, and hence they
are expected to perform more effectively than the individual reagents.[28]
Low toxicity, air tolerance, low prices, and moisture resistance are other
common features that cause the use of solid-supported reagents to be more
attractive than alternatives of conventional Lewis acids or metal triflates.
In our last work, it was reported that a mixture of Al2O3=CH3SO3H
(AMA) is an inexpensive and effective reagent for Fries rearrange-
ment,[29] Beckmann rearrangements,[30] direct conversions of aromatic
aldehydes to the corresponding glycol monoesters,[31] hydration of
nitriles into amides,[32] syntheses of macrocyclic polyether-diesters,[33]
syntheses of new hydroxythioxanthone derivatives,[34] direct sulfonyltion
of phenloes with p-toluensulfonic acid,[35] and synthesis of coumarin deri-
vatives,[36] in excellent yields and with high selectivity. Here we report the
ability of this reagent as reusable catalyst for the one-pot synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones and thiones in high yields (Scheme 2).
RESULTS AND DISCUSSION
To exploit simple and suitable conditions for synthesis of 3,4-dihydro-
pyrimidin-2-(1H)-ones, the reaction of benzaldehyde 5a, urea 6a, and

One-Pot Synthesis of 3,4-Dihydropyrimidinones
961
ethyl acetoacetate 7a was chosen as a model to afford the DHPM 8a
(R1 ¼ Ph, R2 ¼ Me, R3 ¼ OEt, X ¼ O), and its behavior was studied under
1
a variety of conditions via thin-layer chromatography (TLC) and H
NMR and 13C NMR spectroscopy (Table 1).
A summary of obtained results is provided in Table 1. At room
temperature, the reaction rate was found to be slow and was
increased with increase in temperature. At 60 ꢁC, the reaction rate
was found to be maximal, and further increase in temperature did
not show any enhancement (Table 1, entries 6 and 7). Entries 1–6
show the effect of various solvents on the yield of reaction. Although
toluene, acetonitrile, and dimethyl formamide afforded the product in
high yields, we chose ethanol for its low cost and environmental
acceptability. Our results show that the reaction does not proceed if
no catalyst is employed (Table 1, entry 8), whereas the yield of Bigi-
nelli product is increased to 98% with the addition of AMA (0.1 g,
equal to 0.5 mmol Hþ). Entry 6 described the yields of five consecu-
tive condensations leading to 8a. In these experiments, the product
was isolated by filtration and washing the solid residues with ethyl
acetate. Thus the remaining catalyst, which always works the same,
begins reloading with fresh reagents for further runs. We did not
observe any large decrease in the yield, demonstrating the efficiency
of alumina methansulfonic acid (AMA) as a catalyst in Biginelli
Table 1. Reaction of benzaldehyde 5a (1 mmol), ethyl acetoacetate 7a (1 mmol),
and urea 6a (1.2 mmol) under various reaction conditions
Time
(h)
Entry
Conditions
Catalysta
Yield (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2=Refꢁluxed
CH3CN=60 C
AMA
AMA
AMA
AMA
AMA
AMA
AMA
None
Al2O3
10
10
10
10
10
1
3
24
10
45
90
70
75
ꢁ
THF=60 C ꢁ
Toluene=60 C
DMF=60 C ꢁ
ꢁ
80
98, 97, 96, 95, 95c
C2H5OH=60 C
C2H5OH=rt
C2 H5 OH/Refluxed
53
25
0
ꢁ
C2H5OH=60 C
a0.1 g, equal to 0.5 mmol Hþ.
bIsolated yield.
cThe same catalyst was used for each of five runs.

962
H. Sharghi and M. Jokar
condensations. Therefore, the solid insoluble MeSO3H=Al2O3 is a
truly heterogeneous efficient catalyst for this transformation.
The previously mentioned results show the advantages of this
method as a new and more suitable way to DHPM synthesis.
Results of the Biginelli reaction catalyzed by AMA are presented in
Table 2. Alumina methansulfonic acid (AMA) works for the
condensation of a series of aldehydes, 1,3-dicarbonyl compounds, and
urea or thiourea. It is an environmentally, friendly catalyst that works
at 60 ꢁdeg;C in short reaction times (20 min-3 h). This catalyst works
regardless of structural variations in the aldehydes or b-ketoesters.
Besides, the b-ketoester, b-diketone (Table 2, entries 14, 15, 16, and
21) can also be employed without any decrease in yields. Under these
conditions, the yields were significantly better in comparison with
classical Biginelli procedure. Thus, several pharmacologically relevant
substituent patterns could be introduced with high efficiency under the
present conditions.
A variety of heterocyclic, aliphatic, and aromatic aldehydes
were reacted with urea and b-dicarbonyl compound to afford 3,4-
dihydropyrimidin-2-(1H)-ones in high yields using catalytic amounts of
AMA (0.1 g, equal to 0.5 mmol Hþ) under similar reaction conditions.
Various types of substituted benzaldehydes containing either
electron-withdrawing or electron-donating substitutions successfully
afforded the Biginelli products in high yields (Table 2, entries 1–28).
An important feature of this procedure is the survival of a variety of func-
tional groups such as ethers, nitro, hydroxyl, halides, cyanide, etc. under
the reaction conditions. Acid-sensitive substrates such as 4-cyano benzal-
dehyde are also reacted in high yields without the formation of any side
products (Table 2, entry 11).
Although aromatic aldehydes having either electron-donating or
electron-withdrawing substituents reacted efficiently to afford excellent
yields of 3,4-dihydropyrimidin-2-(1H)-ones, the aliphatic aldehydes,
which are known to be less reactive under conventional Biginelli reaction
conditions, also reacted smoothly to afford very high yields (Table 2,
entries 26 and 27).
Thiourea was used as one of the substrates to provide the corre-
sponding DHPMs in reasonable yields (Table 2, entries 21–24, 27, and
28). Most important, many of the pharmacologically relevant sub-
stitution patterns on the aromatic ring could be introduced without
any interruption in efficiency.
To access the feasibility of applying this method in a preparative
scale, we carried out the one-pot, three-component Biginelli condensation
of benzaldehyde with ethyl acetoacetate and urea on a 100-mmol scale
(Table 2, entry 29). As expected, the reaction proceeded similarly to the

963

964

One-Pot Synthesis of 3,4-Dihydropyrimidinones
965
case in a smallerly scale (Table 2, entry 1), and the desired 3,4-dihydro-
pyrimidinone was obtained in 98% isolated yield in 25 min.
The merits of the present method are reflected from the fact that it
provides better yields of various substituted 3,4-dihydropyrimidinones
in shorter reaction times as compared to the recently known methods
using heterogeneous catalysts.
The generally accepted Biginelli reaction mechanism[17,44,45a]
(Scheme 3) involves the formation of C¼N bond from the parent alde-
hyde (I) and urea followed by (protic or Lewis) acid-catalyzed addition
of acetoacetate ester (II) to the aryl (or alkyl)idene–urea (Ia) and
cyclodehydration (via Ib), yielding dihydropyrimidinones (III). AMA
might promote the reaction by accelerating the formation C¼N bond
in the rate-determining step.[45b]
In conclusion, the present procedure provides an efficient and
improved modification of Biginelli reactions. Mild reaction condition,
ease of workup, high yields, stability and recyclability of the catalyst,
large-scale synthesis, and simple procedure are features of this new pro-
cedure. Moreover, this method has the ability to tolerate a wide variety
of substituents in all three components. When we compare our results
(time, yield, reaction conditions) with some results obtained by other
groups, as can be seen, our method is simpler, is more efficient, and
uses no toxic solvents, and the catalyst could be readily recovered
and reused for the one-pot formation of DHPMs. Hence, we believe
that this method will find wide application in organic synthesis as well
as industry.
Scheme 3. Suggested Biginelli reaction mechanism.

966
H. Sharghi and M. Jokar
EXPERIMENTAL
General Information
NMR spectra were recorded on a Bruker Avance DPX-250 (1H NMR
250 MHz and 13C NMR 62.9 MHz) spectrometer in pure deuterated sol-
vents with tetramethylsilane (TMS) as an internal standard. Chemical
shifts (d) are reported in parts per million (ppm), and coupling
constants (J) are in hertz (Hz). The following abbreviations were used
to explain the multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, and m ¼ multiplet. IR spectra were obtained using a
Shimadzu Fourier transform infrared (FT-IR) 8300 spectrophotometer.
Mass spectra were determined on a Shimadzu GCMS-QP 1000 EX
instrument at 70 or 20 ev. Melting points were determined in open capil-
lary tubes in a Buchi-535 circulating-oil melting-point apparatus. The
¨
purity determination of the substrates and reaction monitoring were
accomplished by thin-layer chromatography (TLC) on silica-gel Poly-
Gram SILG=UV 254 plates. Chemical materials were purchased from
Fluka, Aldrich and Merck companies. Acidic alumina (Al2O3) type
540 C was purchased from Fluka.
Preparation of AMA
Methansulfonic acid (16.52 mL, 255 mmol) was added dropwise over a
period of 90 min at 40 ꢁC to a mixture of alumina (51 g, 510 mmol)
in dichloromethane (30 mL). After the addition was complete, the mix-
ture was stirred for 2 h, and then the solvent was evaporated under
reduced pressure. After removal of CH2Cl2 in a rotary evaporator,
ꢁ
the solid powder was kept at 120 C for 72 h. A white solid of 68.0 g
was obtained.
General Procedure for Synthesis of DHPMs
A mixture of the aldehyde (1 mmol), b-dicarbonyl compound (1 mmol),
urea or thiourea (1.2 mmol), and alumina-methansulfonic acid (0.1 g,
þ
ꢁ
equal to 0.5 mmol H ) in ethanol (5 mL) was heated at 60 C for the
appropriate time (Table 2). After completion of the reaction as indicated
by TLC, the reaction mixture was cooled to room temperature and was
filtered through a sinter funnel. The solid residue was washed with
ꢁ
20 mL hot ethanol (50 C). The remaining catalyst was reloaded with
fresh reagents for further runs. The filtrate was concentrated, and the

One-Pot Synthesis of 3,4-Dihydropyrimidinones
967
solid product was recrystallized from ethyl acetate=n-hexane (1=3) or
ethanol.
All produced DHPMs were characterized in detailed structural data
1
by IR, H NMR, 13C NMR, and elemental analysis as given next.
Data
Unknown compounds or compounds for which incomplete physical data
were reported in the literature were characterized by FTIR, NMR
(1H, 13C), and elemental analysis.
Ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-5-pyrimidine-
carboxylate (8a)
Compound 8a was obtained in 98% yield. Mp 204–206 ꢁC (lit. 202–
1
204 C)[37]; H NMR (250 MHz, CDCl3): 1.19 (t, J ¼ 7.1 Hz, 3H), 2.33
ꢁ
(s, 3H), 4.01 (q, J ¼ 7.2 Hz, 2H), 5.31 (s, 1H), 5.90 (s, 1H), 7.10–7.35
(m, 5H), 8.30 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 14.1, 18.6, 55.7,
60.0, 101.3, 126.5, 127.0, 128.0, 143.0, 146.2.
Ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8b)
Compound 8b was obtained in 91% yield. Mp 209–211 ꢁC, (lit. 209–
1
211 C) [37]; H NMR (250 MHz, DMSO): 1.04 (t, J ¼ 7.0 Hz, 3H), 2.24
ꢁ
(s, 3H), 3.86 (q, J ¼ 7.0 Hz, 2H), 5.25 (s, 1H), 7.50 (d, J ¼ 7.3 Hz, 2H),
7.85 (s, 1H), 8.20 (d, J ¼ 7.2 Hz, 2H), 8.54 (s, 1H); 13C NMR
(62.9 MHz, DMSO): 13.9, 17.8, 53.6, 59.3, 98.1, 123.7, 127.6, 146.6,
149.3, 151.7, 151.9, 165.0.
Ethyl-4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8c)
Compound 8c was obtained in 95% yield. Mp 212–214 ꢁC, (lit. 213–
1
215 C)[37]; H NMR (250 MHz, CDCl3): 1.18 (t, J ¼ 7.2 Hz, 3H), 2.31
ꢁ
(s, 3H), 4.06 (q, J ¼ 7.2 Hz, 2H), 5.35 (s, 1H), 6.80 (s, 1H), 7.22–7.28
(m, 4H), 8.37 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 14.1, 18.6, 55.0,
60.1, 101.1, 127.9, 128.8, 133.7, 142.2, 146.5, 153.6, 165.4.

968
H. Sharghi and M. Jokar
Ethyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxylate (8d)
ꢁ
Compound 8d was obtained in 96% yield. Mp 203–205 C, (lit. 201–
1
203 C)[37]; H NMR (250 MHz, DMSO): 1.10 (t, J ¼ 7.0 Hz, 3H), 2.23
ꢁ
(s, 3H), 3.70 (s, 3H), 3.96 (q, J ¼ 7.0 Hz, 2H), 5.10 (s, 1H), 6.88 (d,
J ¼ 8.8 Hz, 2H), 7.15 (d, J ¼ 8.6 Hz, 2H), 7.65 (s, 1H), 9.14 (s, 1H); 13C
NMR (62.9 MHz, DMSO): 14.5, 18.1, 53.7, 55.4, 59.5, 100.1, 114.1,
127.8, 137.4, 148.4, 152.6, 158.8, 165.8.
Ethyl-4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8e)
ꢁ
Compound 8e was obtained in 90% yield. Mp 190–192 C, (lit. 190–
1
193 C)[38]; H NMR (250 MHz, CDCl3): 1.20 (t, J ¼ 7.2 Hz, 3H), 2.34
ꢁ
(s, 3H), 4.06 (q, J ¼ 7.2 Hz, 2H), 5.37 (s, 1H), 6.15 (s, 1H), 7.16–7.40
(m, 4H), 8.37 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 14.11, 18.61,
55.25, 60.19, 100.0, 124.0, 126.0, 128.0, 130.0, 134.0, 145.0, 146.0,
153.0, 165.0.
Ethyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8f)
Compound 8f was obtained in 92% yield. Mp 227–229 ꢁC, (lit. 226–
1
227 C)[37]; H NMR (250 MHz, DMSO): 1.07 (t, J ¼ 7.2 Hz, 3H), 2.25
ꢁ
(s, 3H), 3.96 (q, J ¼ 7.2 Hz, 2H), 7.61–7.70 (m, 2H), 7.87 (s, 1H), 8.07–
8.36 (m, 2H), 9.34 (s, 1H); 13C NMR (62.9 MHz, DMSO): 13.9, 17.8,
53.6, 59.3, 98.3, 120.9, 122.3, 130.1, 132.9, 146.9, 147.7, 149.4, 151.7,
164.0.
Ethyl-4-(2-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8g)
ꢁ
Compound 8g was obtained in 88% yield. Mp ¼ 216–217 C, (lit. 215–
[9]
1
ꢁ
218 C) ; H NMR (250 MHz, CDCl3): 1.13 (t, J ¼ 7.2 Hz, 3H), 2.41
(s, 3H), 3.90 (q, J ¼ 7.0 Hz, 2H), 5.77 (s, 1H), 5.87 (s, 1H), 7.05–7.26
(m, 3H), 7.34–7.51 (m, 1H), 8.69 (s, 1H); 13C NMR (62.9 MHz, CDCl3):
13.9, 18.3, 55.1, 59.9, 98.8, 127.5, 128.0, 129.3, 129.8, 132.6, 139.5, 148.4,
153.1, 165.3.

One-Pot Synthesis of 3,4-Dihydropyrimidinones
969
Ethyl-6-methyl-2-oxo-4-(2-thienyl)-1,2,3,4-tetrahydro-5-
pyrimidinecarboxylate (8h)
ꢁ
Compound 8h was obtained in 95% yield. Mp ¼ 209–210 C, (lit. 209–
210 C)[39]; H NMR (250 MHz, CDCl3): 1.29 (t, J ¼ 7.0 Hz, 3H), 2.27
1
ꢁ
(s, 3H), 4.13 (q, J ¼ 7.2 Hz, 2H), 5.68 (s, 1H), 6.35 (s, 1H), 6.87–6.95
(m, 2H), 7.17 (d, J ¼ 5.0 Hz, 1H), 8.51 (s, 1H); 13C NMR (62.9 MHz,
CDCl3): 14.2, 18.5, 50.6, 60.2, 101.6, 123.9, 124.8, 126.7, 146.8, 147.3,
153.9, 165.4.
Ethyl-6-methyl-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8i)
Compound 8i was obtained in 96% yield. Mp 169–171 ꢁC, (lit. 169–
171 ꢁC)[11]
;
1H NMR (250 MHz, CDCl3): 1.10 (t, J ¼ 7.2 Hz, 3H),
2.31 (s, 6H), 4.06 (q, J ¼ 7.2 Hz, 2H), 5.34 (s, 1H), 5.86 (s, 1H),
7.02–7.42 (4H, m), 8.25 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 14.1,
18.6, 21.0, 55.3, 59.9, 101.5, 126.5, 129.3, 137.6, 140.8, 146.2, 153.5,
165.7.
Ethyl-4-(2,4-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8j)
ꢁ
Compound 8j was obtained in 95% yield. Mp ¼ 157–159 C, (lit. 158–
40
1
ꢁ
160 C) ; H NMR (250 MHz, CDCl3): 1.10 (t, J ¼ 7.0 Hz, 3H), 2.26
(s, 3H), 3.71 (s, 3H), 3.76 (s, 3H), 4.04 (q, J ¼ 7.0 Hz, 2H), 5.67 (s,
1H), 5.84 (s, 1H), 6.75 (d, J ¼ 2.7 Hz, 1H), 6.70–6.88 (m, 2H), 8.59 (s,
1H); 13C NMR (62.9 MHz, CDCl3): 14.2, 18.5, 49.9, 55.6, 55.7, 59.9,
98.1, 111.2, 112.1, 113.8, 130.9, 148.5, 150.9, 153.5, 153.7, 165.7.
Ethyl-4-(4-cyanophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8k)
ꢁ
Compound 8k was obtained in 85% yield. Mp 219–221 C, (lit. 219–
1
222 C)[38]; H NMR (250 MHz, CDCl3): 1.14 (t, J ¼ 7.0 Hz, 3H), 2.33
ꢁ
(s, 3H), 4.01 (q, J ¼ 7.2 Hz, 2H), 5.45 (s, 1H), 6.11 (s, 1H), 7.37 (d,
J ¼ 8.2 Hz, 2H), 7.62 (d, J ¼ 8.1 Hz, 2H), 8.52 (s, 1H); 13C NMR
(62.9 MHz, CDCl3): 14.2, 18.8, 55.3, 60.3, 100.4, 111.9, 118.5, 127.4,
132.6, 147.1, 148.5, 153.2, 165.2.

970
H. Sharghi and M. Jokar
Ethyl-4-(2,6-dichlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8l)
Compound 8l was obtained in 88% yield. Mp ¼ 280–283 ꢁC, (lit.
1
226ꢁC)[23e]; H NMR (250 MHz, DMSO): 0.87 (t, J ¼ 7.1 Hz, 3H), 2.15
(s, 3H), 3.80 (q, J ¼ 7.2 Hz, 2H), 6.1 (s, 1H), 7.25 (t, J ¼ 8.67 Hz, 1H),
7.35 (d, J ¼ 7.7 Hz, 2H), 7.69 (s, 1H), 9.25 (s, 1H); 13C NMR
(62.9 MHz, DMSO): 13.6, 17.8, 52.1, 58.7, 94.0, 129.3, 135.1, 137.5,
149.7, 150.5, 164.8.
Ethyl-4-(4-isopropylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8m)
ꢁ
Compound 8m was obtained in 90% yield. Mp 140–142 C; IR (KBr),
1
t (cmꢂ1): 3247, 3120, 2962, 2931, 1705, 1651, 1288, 1096, 775, 663; H
NMR (250 MHz, CDCl3) 1.08–1.21 (m, 9H), 2.29 (s, 3H), 2.73 (m, 1H),
3.98 (q, J ¼ 7.2 Hz, 2H), 5.28 (s, 1H), 6.00 (s, 1H), 7.06 (d, J ¼ 8.2 Hz,
2H), 7.15 (d, J ¼ 8.2 Hz, 2H), 8.64 (s, 1H); 13C NMR (62.9 MHz, CDCl3):
14.1, 18.5, 23.9, 33.7, 55.2, 59.9, 101.4, 126.5, 126.7, 129.8, 141.2, 146.4,
148.4, 153.9, 165.8. C17H22N2O3 (302.371): calc. C, 67.53%; H, 7.33%;
N, 9.26%, found C, 67.59%; H, 7.26%, N, 9.20%.
5-Acetyl-6-methyl-4-(4-methylphenyl)-3,4-dihydro-2(1H)-
pyrimidinone (8n)
ꢁ
Compound 8n was obtained in 93% yield. Mp 204–206 C; IR (KBr),
1
t (cmꢂ1): 3288, 3120, 2920, 1699, 1616, 1236, 1139, 765, 561; H NMR
(250 MHz, CDCl3) 2.07 (s, 3H), 2.30 (s, 6H), 5.42 (s, 1H), 6.29 (s, 1H),
7.01–7.22 (m, 4H), 8.59 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 19.5,
21.1, 30.8, 55.9, 110.5, 126.5, 129.7, 137.9, 139.9, 146.1, 153.5, 195.4.
C14H16N2O2 (244.292): calc. C, 68.83%; H, 6.60%; N 1.47%, found C,
68.89%; H, 6.50%, N 1.51%.
5-Acetyl-4-(3-chlorophenyl)-6-methyl-3,4-dihydro-2(1H)-
pyrimidinone (8o)
ꢁ
Compound 8o was obtained in 86% yield. Mp 280–281 C; IR (KBr),
t (cmꢂ1): 3290, 3105, 3915, 1706, 1676, 1614, 1362, 1234, 1190, 917,
763, 628; H NMR (250 MHz, DMSO): 2.1 (s, 3H), 2.28 (s, 1H), 5.25
1
13
(s, 1H), 7.16–7.45 (m, 4H), 7.87 (s, 1H), 9.24 (s,1H); C NMR
(62.9 MHz, DMSO): 18.9, 30.4, 53.1, 109.3, 124.9, 126.8, 127.2, 130.4,

One-Pot Synthesis of 3,4-Dihydropyrimidinones
971
133.0, 146.6, 148.7, 152.0, 194.0 C13H13ClN2O2 (264.710): calc. C,
58.99%; H, 4.95%; N, 10.56%, found C, 58.89%, H, 5.00%; N, 10. 61%.
5-Acetyl-6-methyl-4-phenyl-3,4-dihydro-2(1H)-pyrimidinone (8p)
ꢁ
Compound 8p was obtained in 89% yield. Mp ¼ 229–230 C, (lit. 233–
1
236 ꢁC)[16]; H NMR (250 MHz, DMSO): 2.16 (s, 1H), 2.27 (s, 1H),
5.24 (s, 1H), 7.25–7.35 (m, 5H), 7.80 (s, 1H), 9.16 (s,1H); 13C NMR
(62.9 MHz, DMSO): 18.8, 30.3, 53.7, 109.5, 126.4, 127.5, 128.17, 144.2,
148.1, 152.1, 194.2.
Ethyl-6-(chloromethyl)-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8q)
ꢁ
Compound 8q was obtained in 90% yield. Mp 164–166 C; IR (KBr),
t (cmꢂ1): 3363, 3232, 3124, 2927, 2866, 1704, 1654, 1434, 1099, 1018,
1
771. H NMR (250 MHz, CDCl3): 1.20 (t, J ¼ 7.0 Hz, 3H), 2.29 (s. 3H),
4.08 (q, J ¼ 7.0 Hz, 2H), 4.75 (d, J ¼ 13.0 Hz, 1H), 4.83 (d, J ¼ 13.0 Hz,
2H), 5.39 (s, 1H), 6.56 (s, 1H), 7.09–7.026 (m, 4H), 8.01 (s, 1H); 13C
NMR (62.9 MHz, CDCl3): 14.0, 21.1, 55.1, 60.6, 103.5, 126.5, 129.1,
129.4, 129.9, 137.8, 140.1, 143.8, 153.9, 164.6. C16H17ClN2O3 (308.736):
calc. C, 58.35%; H, 5.55%, 9.07%, found C, 58.40%; H 5.45%, N, 9.00%.
Ethyl-6-(chloromethyl)-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8r)
ꢁ
Compound 8r was obtained in 87% yield. Mp 162–164 C; IR (KBr),
t (cmꢂ1): 3355, 3232, 3132, 2869, 1704, 1635, 1099, 1022, 914, 732, 455;
1H NMR (250 MHz, DMSO): 1.06 (t, J ¼ 7.0 Hz, 3H), 4.01 (q, J ¼ 7.2 Hz,
2H), 4.57 (dd, J1 ¼ 10.7 Hz J2 ¼ 3.2 Hz, 1H), 4.61 (dd, J1 ¼ 10.2 Hz,
J2 ¼ 3.5 Hz, 1H), 5.35 (s, 1H), 7.60–7.71 (m, 2H), 8.0–8.12 (m, 3H),
9.68 (s, 1H); 13C NMR (62.9 MHz, DMSO): 13.6, 53.3, 60.1, 100.8,
121.1, 122.5, 130.2, 132.9, 145.9, 146.5, 146.9, 147.7, 151.9, 163.8.
C14H14ClN3O5 (339.733): calc. C, 49.50%, H, 4.15%; N, 12.37%, found
C, 49.60%; H 4.10%, N 12.0%.
Ethyl-6-(chloromethyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8s)
ꢁ
Compound 8s was obtained in 87% yield. Mp 174–176 C; IR (KBr),
t (cmꢂ1): 3355, 3228, 3124, 2974, 1693, 1647, 1307, 1230, 1099, 1022,

972
H. Sharghi and M. Jokar
1
756, 694; H NMR (250 MHz, CDCl3): 1.13 (t, J ¼ 7.0 Hz, 3H), 4.03
(q, J ¼ 7.0 Hz, 2H), 4.71 (d, J ¼ 13.2 Hz, 1H), 4.84 (d, J ¼ 13.1 Hz,
1H), 5.35 (s, 1H), 5.78 (s, 1H), 7.14–7.81 (m, 5H), 7.98 (s, 1H); 13C
NMR (62.9 MHz, CDCl3): 14.0, 39.7, 55.8, 60.7, 67.9, 126.6, 127.8,
128.3, 128.9, 142.7, 143.1, 147.0, 148.9, 164. C14H15ClN2O3
(294.736): calc. C, 57.05%: H, 5.13%; N, 9.50%, found C, 57.15%;
H, 5.10%; N, 9.45%.
Ethyl-6-methyl-4-(2-naphthyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidine-
carboxylate (8t)
ꢁ
Compound 8t was obtained in 91% yield. Mp 196–198 C; IR (KBr), t
(cmꢂ1): 3222, 3095, 2929, 1703, 1651, 1429, 1284, 1085, 1020, 779, 682,
478; 1H NMR (250 MHz, CDCl3): 1.14 (t, J ¼ 7.2 Hz, 3H), 2.33 (s,
3H), 4.05 (q, J ¼ 7.2 Hz, 2H), 5.52 (s, 1H), 6.24 (s, 1H), 7.35–7.48
(m, 3H), 7.62 (s, 1H), 7.70–7.80 (m, 3H), 8.64 (s, 1H); 13C NMR
(62.9 MHz, CDCl3): 14.0, 18.3, 52.1, 60.0, 98.8, 127.1, 127.9, 129.3,
129.8, 132.6, 139.5, 148.4, 153.1, 165.3. C18H18N2O3 (310.351): calc.
C, 69.66%; H, 5.85%; N, 9.03%; found C, 69.78%; H, 5.80%; N,
9.10%.
1-(6-Methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)
ethanone (8u)
Compound 8u was obtained in 89% yield. Mp 183ꢁC (decomposed) (lit.
;
185ꢁC decomposed)[42] 1H NMR (250 MHz, DMSO): 2.16 (s, 3H),
2.37 (s, 3H), 5.28 (s, 1H), 7.26–7.59 (m, 5H), 9.89 (s, 1H), 10.37 (s,
1H); 13C NMR (62.9 MHz, DMSO): 18.2, 30.4, 53.7, 110.4, 126.5,
127.46, 128.6, 142.8, 144.5, 168.0, 174.0, 194.7.
Ethyl-6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecar-
boxylate (8v)
Compound 8v was obtained in 85% yield. Mp 209–211 ꢁC (lit. 208–
[9]
1
ꢁ
211 C) ; H NMR (250 MHz, CDCl3): 1.19 (t, J ¼ 7.1 Hz, 3H), 2.35
(s, 3H), 4.10 (q, J ¼ 7.1 Hz, 2H), 5.38 (s, 1H), 7.20–7.35 (m, 5H), 7.48
(s, 1H), 8.12 (s, 1H); 13C NMR (62.9 MHz, CDCl3): 14.1, 18.3, 56.2,
60.4, 102.9, 126.8, 128.4, 128.9, 142.3, 142.7, 165.2, 174.5.

One-Pot Synthesis of 3,4-Dihydropyrimidinones
973
Ethyl-4-(3-nitrophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8w)
Compound 8w was obtained in 88% yield. Mp 206–208 ꢁC (lit. 206–
1
207 C)[23a]; H NMR (250 MHz, CDCl3): 1.08 (t, J ¼ 7.2 Hz, 3H), 2.29
ꢁ
(s, 3H), 4.05 (q, J ¼ 7.2 Hz, 2H), 5.30 (s, 1H), 7.63–7.67 (m, 2H), 8.04
(s, 1H), 8.14 (dd, J1 ¼ 6.2 Hz, J2 ¼ 2.2 Hz, 1H), 9.74 (s, 1H), 10.48 (s,
1H); 13C NMR (62.9 MHz, DMSO): 13.9, 17.8, 53.4, 59.7, 99.8, 121.1,
122.7, 130.4, 133.0, 145.4, 145.9, 147.7, 164.8, 174.4.
Ethyl-4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8x)
Compound 8x was obtained in 87% yield. Mp 183–184 ꢁC (lit. 184–
1
186 C)[43]; H NMR (250 MHz, DMSO): 1.06 (t, J ¼ 7.2 Hz, 3H), 2.26
ꢁ
(s, 3H), 4.01 (q, J ¼ 7.0 Hz, 2H), 5.08 (s, 1H), 7.63 (m, 3H), 7.20 (t,
J ¼ 8.7 Hz, 1H), 9.40 (s, 1H), 9.56 (s, 1H), 10.41 (s, 1H); 13C NMR
(62.9 MHz, DMSO): 13.9, 17.1, 53.9, 59.5, 100.7, 113.2, 114.5, 116.9,
129.4, 144.7, 144.8, 157.4, 165.1, 174.1.
Ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
5-pyrimidinecarboxylate (8y)
Compound 8y was obtained in 94% yield. Mp 163–164ꢁC (lit. 163–165
ꢁC)9; 1H NMR (250 MHz, DMSO):1.10 (t, J ¼ 7.0 Hz, 3H), 2.22
(s, 3H), 4.05 (q, J ¼ 7.0 Hz, 2H), 5.04 (s, 1H), 6.58–6.66 (m, 3H), 7.07
(t, J ¼ 8.1 Hz, 1H), 7.66 (s, 1H), 9.32 (s, 1H), 9.34 (s, 1H); 13C NMR
(62.9 MHz, DMSO): 14.0, 17.7, 53.7, 59.1, 99.3, 113.0, 114.1, 116.8,
129.2, 146.1, 148.0, 152.0, 157.3, 165.3.
Ethyl-6-methyl-2-oxo-4-pentyl-1,2,3,4-tetrahydro-5-pyrimidine-
carboxylate (8z)
ꢁ
Compound 8z was obtained in 85% yield. Mp 151–154 C; IR (KBr), t
(cmꢂ1): 3263, 3101, 2939, 3862, 1728, 1651, 1465, 1226, 1087, 1026,
1
779; H NMR (250 MHz, DMSO): 0.80 (t, J ¼ 6.5 Hz, 3H), 1.08–120
(m, 11H), 1.92 (s, 3H), 4.80 (q, J ¼ 6.7 Hz, 2H), 8.09 (s, 1H), 8.19 (s,
1H); 13C NMR (62.9 MHz, DMSO): 13.7, 14.1, 18.0, 21.9, 23.3, 30.9,
36.6, 49.9, 58.9, 99.8, 148.2, 152.4, 165.4; C13H22N2O3 (254.325): calc.
C, 61.39%, H, 8.72%, N, 11.01%, found C, 61.45%, H, 8.67%, N,
11.10%.

974
H. Sharghi and M. Jokar
Ethyl-4-butyl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarbox-
ylate (8a0)
ꢁ
Compound 8a0 was obtained in 83% yield. Mp 138–140 C; IR (KBr), t
(cmꢂ1): 3186, 2927, 2856, 1710, 1651, 1596, 1434, 1184, 1095, 752, 644,
1
528; H NMR (250 MHz, DMSO): 0.81 (t, J ¼ 6.5 Hz, 3H), 1.1–1.2 (m,
9H), 2.18 (s, 3H), 3.98–4.18 (m, 3H), 9.34 (s, 1H), 10.24 (s, 1H); 13C
NMR (62.9 MHz, DMSO): 13.6, 14.1, 17.0, 21.8, 25.5, 35.8, 50.3, 59.4,
100.6, 145.1, 165.1, 174.9; C12H20N2O2S (256.365): calc. C 56.22%; H,
7.86%; N, 10.93%; S, 12.51%, found C, 56.31%; H, 7.81%; N, 10.87%;
S, 12.59%.
Benzyl-6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxylate (8b0)
Compound 8b0 was obtained in 83% yield. Mp 157–159 ꢁC (lit.156–
1
157 C)[46]; H NMR (250 MHz, DMSO): 2.30 (s, 3H), 4.99 (d, J ¼ 12.7
ꢁ
Hz, 1H), 5.10 (d, J ¼ 12.7 Hz, 1H), 5.19 (s, 1H), 7.10–7.31 (m, 10H),
9.66 (s, 1H), 10.38 (s, 1H); 13C NMR (62.9 MHz, DMSO): 17.2, 54.0,
65.1, 100.1, 126.4, 127.5, 127.7, 127.7, 128.2, 128.5, 136.2, 143.2, 145.8,
164.8, 174.1.
ACKNOWLEDGMENT
We gratefully acknowledge the support of this work by the Shiraz
University Research Council and Shiraz Faculty of Pharmacy. We are
also grateful to Mr. H. Sajedian Fard for helpful cooperation.
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