Acidic task-specific ionic liquid as catalyst of microwave-assisted solvent-free Biginelli reaction

Article abstract of DOI:10.1134/S1070428007070202

A simple and effective synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine-2(1H)-thione derivatives has been developed on the basis of three-component condensation of substituted aromatic and heterocyclic aldehydes, methyl acetoacetate,

Full text of DOI:10.1134/S1070428007070202

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 7, pp. 1058–1064. © Pleiades Publishing, Ltd., 2007.
Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 7, pp. 1063–1070.
Acidic Task-Specific Ionic Liquid as Catalyst
of Microwave-Assisted Solvent-Free Biginelli Reaction*
A. Arfan, L. Paquin, and J. P. Bazureau
Universite de Rennes 1, Laboratoire Sciences Chimiques de Rennes.
UMR CNRS 6510 Groupe lngenierie Chimique & Molecules pour le Vivant (ICMV).
Bat. 10A, Campus de Beaulieu, Avenue du General Leclerc, CS 74205, 35042 Rennes Cedex, France
e-mail: jean-pierre.bazureau@univ-rennes1.fr
Received August 31, 2006
Abstract—A simple and effective synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine-
2(1H)-thione derivatives has been developed on the basis of three-component condensation of substituted
aromatic and heterocyclic aldehydes, methyl acetoacetate, and urea or thiourea in the presence of 10% of
an acidic task-specific ionic liquid ([C4mim][HSO4]) as catalyst under microwave irradiation in the absence of
a solvent. The proposed procedure ensures short reaction times (4.4–8 min) and good yields after purification
by recrystallization.
DOI: 10.1134/S1070428007070202
Mullticomponent reactions [1] have become an in-
creasingly important method for developing new po-
tential biologically active substances. Multicomponent
condensations involve three or more compounds react-
ing in a single event, but consecutively to form a new
product, which contains the essential parts of all the
starting materials. In 1893, Italian chemist Pietro
Biginelli anticipated intuitively the synthetic potential
of multicomponent reactions [2] by combining in
a single flask the reactants of two different reactions
leading to the same product. The original Biginelli
protocol for the preparation of 3,4-dihydropyrimidin-
2(1H)-ones implied heating a mixture of three com-
ponents (a1dehyde I, β-keto ester II and urea III) in
ethanol containing a catalytic amount of HCl
(Scheme 1). The major drawback associated with this
protocol is the low yields, particularly for substituted
aromatic and aliphatic aldehydes [3]. This has led to
the development of multistep synthetic strategies [4].
In the past 10 years, interest in the three-component
Biginelli reaction has increased rapidly because of the
diverse range of pharmaceutical properties [5] exhib-
ited by dihydropyrimidine derivatives. They have
emerged as integral backbones of several calcium
channel blockers [6], vasorelaxants [7], α1a-adrenergic
receptor antagonists [8], neuropeptide Y (NPY) antag-
onists [9] and antimitotic agents [10]. In addition,
several marine alkaloids containing a dihydropyrimi-
dine-5-carboxylate moiety also showed interesting bio-
logical activity [11].
Scheme 1.
O
O
X
R3CHO
+
+
Due to importance of the Biginelli reaction prod-
ucts, much work on improving the yield and reaction
conditions has been actively pursued in several dec-
ades. The improved synthetic methods involved the
use of simple metal (and ammonium) salts with nucle-
ophilic anions, e.g., LiBr [12], NH4Cl [13], FeCl3 [14]
as active catalysts. The catalytic effect of metal cations
is even more pronounced in methods based on metal
salts with non-nucleophilic anions, such as LiClO4
[15], Zn(OTf)2 [16], Al(HSO4)3 [17], and various lan-
thanide trifluoromethanesulfonates Ln(OTf)3 (Ln =
Yb, Sc, La) [18]. In other cases, effective Biginelli
R1
OR2
H2N
R3
NH2
I
II
III
O
HCl, EtOH
reflux
R2O
NH
R1
N
X
H
IV
X = O, S.
* The text was submitted by the authors in English.
1058

ACIDIC TASK-SPECIFIC IONIC LIQUID AS CATALYST
1059
Table 1. Catalytic effect of ionic liquid [C4mim][HSO4] in
model Biginelli reactiona
reaction conditions employed stoichiometric reagents
like BF3·OEt2 and AcOH/CuCl catalyst in boiling THF
[19], KHSO4 in glycol [20], H3BO3 in glacial AcOH
[21]. In addition, the Biginelli reaction can be accom-
plished with moderate rate enhancement in 1-butyl-3-
methylimidazolium tetrafluoroborate ([bmim][BF4])
that has a nonacidic counterion [22]. In the present
work we showed that this ionic liquid is not very ef-
ficient. The use of l-butyl-3-methyl-imidazolium hy-
drogen sulfate ([bmim][HSO4]) was also reported for
the synthesis of coumarins [23]. In contrast to simple
catalytic methods, those employing suitable dehydrat-
ing agents proved to be more effective, even in syn-
theses of more complex dihydropyrimidinones. Thus
Kappe and co-workers [24] further improved the
Biginelli reaction using microwave irradiation in the
presence of ethyl polyphosphate (PPE) to give higher
chemical yields of dihydropyrimidinones. In 2002,
Ranu et al. reported a noncatalytic Biginelli synthesis
[25]; however, our substrates failed to react under
these conditions. It should be noted that, despite nu-
merous papers appeared since 2002 in the field of the
Biginelli reaction, no noncatalytic conditions were
reported again.
O
O
O
p-MeOC6H4CHO
+
+
Me
OMe
O
H2N
NH2
Ia
II
IIIa
C6H4OMe-p
NH
MeO
[C4mim][HSO4], MW
R1
N
O
H
IVa
Amounts of reactants
[C4mim][HSO4], mol % IIIa, equiv
Tempera-
ture, °C
Yield,b %
05
10
20
10
10
10
3.0
3.0
3.0
1.5
2.5
3.0
140
140
140
140
140
120
55
c98c
98
72
88
62
a
b
c
Reaction time 4.4 min; the progress was monitored by 1H NMR
(200 MHz) in CDCl3 using TMS as internal reference.
The reaction was carried out until disappearance of initial com-
pound Ia or II.
Under conventional heating (on a bath preliminarily heated to the
same temperature), the reaction was complete in 16.3 min.
Task-specific ionic liquids (TSIL) are those incor-
porating functional groups designed to exhibit partic-
ular properties or reactivities; in the recent years TSILs
have attracted considerable attention [26, 27]. Davis
et al. reported on TSILs in which the cations were both
intrinsically Brønsted acidic and nonvolatile. This was
done by covalently tethering an alkanesulfonic acid
group to the IL cation [28]. Such sulfonic acid-based
TSILs were used simultaneously as solvent and cata-
lyst for Fischer esterification [29], dehydrodimeriza-
tion of alcohols [27], pinacol–benzopinacol rearrange-
ments [30], and electrophilic substitution of indoles
with aldehydes [31].
significant rate enhancement and higher yields. A large
number of review articles and several books provide
extensive coverage of the subject [35]. While perform-
ing our research program on the use of microwave
dielectric heating in TSIL-catalyzed reactions [36], we
presumed that 1-butyl-3-methyl-imidazolium hydrogen
sulfate ([C4mim][HSO4]) as an acidic TSIL is a poten-
tial catalyst for the Biginelli synthesis of 3,4-dihydro-
pyrimidin-2(1H)-ones.
Another approach developed by our group for the
acidic TSILs is to introduce the latent acidity into the
anion by anion metathesis from hydrogen sulfate with
the corresponding imidazolium [32] or pyridinium
halides [33]. These acidic TSILs were used as catalysts
for esterification reactions; the resulting esters were
insoluble in the TSILs and were isolated in high yields
with high purity. In the same manner, Jiang and Han
investigated their catalytic activity in Mannich reac-
tions [34].
The catalyst [C4mim][HSO4] was synthesized ac-
cording to the new two-step process developed in our
laboratory [33]. The first step is solvent-free quaterni-
zation of commercial 1-methylimidazole with chloro-
butane under microwave irradiation [37],** followed
by anion metathesis. For anion exchange, the corre-
sponding coordinating anion was HSO4– from commer-
cially available sodium hydrogen sulfate. The anion
metathesis reaction was carried out in dry acetonitrile
by stirring at room temperature under nitrogen for
The utility of microwave irradiation (MW) to carry
out organic reactions has now become a regular
feature. The main benefits of performing reactions are
** Other syntheses of ionic liquids using a commercial multimode
microwave reactor were described in [38].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

ARFAN et al.
1060
Scheme 2.
O
Ar
[C4mim][HSO4]
MW, 140°C
O
O
X
MeO
NH
ArCHO
+
+
Me
OMe
H2N
NH2
Me
N
H
X
Ia–Ik
II
IIIa, IIIb
IVa–IVn
I, Ar = 4-MeOC6H4 (a), Ph (b), 4-ClC6H4 (c), 4-O2NC6H4 (d), pyridin-3-yl (e), 4-BrC6H4 (f), 2-BrC6H4 (g), 4-HOCOC6H4 (h),
3,4-OCH2OC6H3 (i), 4-HOC6H4 (j), 3-FC6H4 (k); III, X = O (a), S (b); IV, Ar = 4-MeOC6H4, X = O (a); Ar = Ph, X = O (b); Ar =
4-ClC6H4, X = S (c); Ar = 4-O2NC6H4, X = S (d); Ar = 4-MeOC6H4, X = S (e); Ar = 4-O2NC6H4, X = O (f); Ar = pyridin-3-yl,
X = O (g); Ar = 4-BrC6H4, X = O (h); Ar = 2-BrC6H4, X = O (i); Ar = 4-HOCOC6H4, X = O (j); Ar = 4-ClC6H4, X = O (k); Ar =
3,4-OCH2OC6H3, X = O (l); Ar = 4-HOC6H4, X = O (m); Ar = 3-FC6H4, X = O (n).
3 days (97%). After removal of insoluble NaCl by
filtration, the exchange efficiency was determined by
measuring the concentration of HSO4– ion in a solution
of [C4mim][HSO4] by volumetric titration with com-
mercial NaOH solution and phenolphthalein as indica-
tor [33]. The structure of the liquid [C4mim][HSO4]
was also confirmed by conventional techniques
(1H and 13C NMR and HRMS).
tion at 120 and 140°C. The resu1ts are presented in
Table 1.
The data in Table 1 show that increase in the
amount of [C4mim][HSO4] at 140°C raises the yield
(run nos. 1–3). A slight excess of urea also favors the
process (run nos. 4, 5). The yield increases from 62%
at 120°C to 98% at 140°C, other conditions being
equal. The best yield (98%) and the shortest reaction
time (4.4 min) were attained at a Ia–II–IIIa–[C4mim]·
[HSO4] ratio of 1:1:3:0.1 at 140°C under microwave
irradiation (power level 50%, 150 W). No by-products
were detected in the crude reaction mixture by 1H NMR
spectroscopy.
With the desired [C4mim][HSO4] catalyst in hand,
we started to examine the effect of the amount of
[C4mim][HSO4] on the reaction of 4-methoxybenzal-
dehyde (Ia, 1 equiv) with methyl acetoacetate (II,
1 equiv) and urea (IIIa, 1.5–3 equiv) as model process
using solvent-free technique under microwave irradia-
On the basis of our results, we focused on the
application of [C4mim][HSO4] as catalyst in different
Biginelli reactions with a variety of substituted aromat-
ic aldehydes. The results are summarized in Table 2.
We used aromatic and heterocyclic aldehydes Ia–Ij
having either electron-donating or electron-withdraw-
ing substituents, which afforded good yields (from 75
to 87% after purification by recrystallization) of the
corresponding 3,4-dihydropyrimidin-2(1H)-ones and
-thiones IVa–IVn (Scheme 2). It is seen that all micro-
wave-assisted reactions required a short time. This
suggests that microwaves enhance the catalytic activity
of [C4mim]·[HSO4] in the Biginelli reaction. The gen-
erally accepted Biginelli reaction mechanism [39]
(Scheme 3) involves the formation of C=N bond from
initial aldehyde I and urea III, followed by protic acid-
catalyzed addition of acetoacetate II to the protonated
arylmethylideneurea V and cyclodehydration of inter-
mediate A to dihydropyrimidone B which is tautomer-
ic to IV. Presumably, microwave irradiation acceler-
ates the formation of C=N bond as the rate-determin-
ing step.
Table 2. Microwave-assisted solvent-free Biginelli reactions
catalyzed by [C4mim][HSO4]
Product no.
Reaction time,a min
Yield,b %
4.4
5.0
5.1
5.5
5.1
5.4
5.1
4.9
6.0
8.0
5.4
4.5
5.1
5.1
85
80
80
79
82
82
76
87
72
75
87
82
83
80
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
IVj
IVk
IVl
IVm
IVn
a
The reactions were performed at 140°C (150 W) until initial
Under the same reaction conditions, aromatic alde-
hydes reacted with thiourea (IIIb) to give the corre-
sponding 3,4-dihydropyrimidine-2(1H)-thiones which
compound I or II disappeared (TLC).
After recrystallization; according to the H NMR spectra of the
b
1
crude reaction mixtures, the yield was 98% (with respect to 4-H).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

ACIDIC TASK-SPECIFIC IONIC LIQUID AS CATALYST
1061
Scheme 3.
Ar
O
X
X
[C4mim][HSO4]
–H2O
II
HN
OMe
ArCHO
+
H2N
NH2
H2N
N
Ar
COMe
NH2
X
I
IIIa, IIIb
V
A
Ar
N
O
Ar
O
HN
OMe
HN
OMe
–H2O
X
Me
X
N
H
Me
B
IV
are also interesting from the viewpoint of their biolog-
ical activity [40]. Thus the ionic liquid [C4mim][HSO4]
also exhibits a significant catalytic effect under micro-
wave irradiation in the Biginelli synthesis of dihydro-
pyrimidine-2-thione derivatives with short reaction
times (5.1 min for IVc and IVe and 5.5 min for IVd)
and the same stoichiometry.
(the reaction time included the temperature ramp
period).
Solvents were removed on a Buchi rotary evapora-
tor. The melting points were determined on a Kofler
hot stage and were not corrected. Thin-layer chroma-
tography was performed on 0.2-mm precoated plates
of silica gel 60F-254 (Merck) or neutral aluminum
oxide 60F-254 (Merck). Spots were visualized under
UV light (λ 254 or 365 nm) or using a fluorescent
indicator.
To conclude, we have developed an efficient proce-
dure for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones from aromatic and heterocyclic aldehydes under
solvent-free microwave-assisted conditions with short
reaction times (<10 min). The process involves
an acidic TSIL, [C4mim][HSO4], as a readily available
catalyst which was used for the first time in hetero-
cyclic chemistry and ensured good to high yields of
pure dihydropyrimidinone derivatives. To our knowl-
edge, this rapid and simple procedure [41] has not
been reported previously, and it may supplement the
existing methods [42].
All reagents were commercial products purchased
from Acros, Aldrich, and Fluka and were used without
additional purification.
General procedure for the synthesis of 3,4-di-
hydropyrimidin-2-ones(thiones) IVa–IVn under
microwave irradiation. A cylindrical quartz reactor
(1.8 cm in diameter) was charged with a mixture of
3 mmol of aromatic aldehyde I, 3 mmol of methyl
acetoacetate II, 9 mmol of urea or thiourea IIIa or
IIIb, and 0.3 mmol of [C4mim][HSO4], and the reactor
was placed in a microwave oven. The mixture was
stirred under microwave irradiation at 140°C (150 W)
for a time indicated in Table 2 and cooled to room tem-
perature, an ice–water mixture (5:1 by volume) was
added, and the mixture was thoroughly stirred to dis-
solve the catalyst and remove excess urea III. The
light yellow precipitate was stirred with 10 ml of ice
water for 10 min, filtered off, dried in a high vacuum,
and recrystallized from ethanol.
EXPERIMENTAL
The IR spectra were recorded on a Biorad FTS
175C spectrometer. The 1H and 13C NMR spectra were
measured from solutions in DMSO-d6 on a Bruker AC
1
300P spectrometer (300 MHz for H and 75 MHz for
13C). The high-resolution mass spectra (electron im-
pact, 70 eV) were obtained on a Varian MAT-311 mass
spectrometer at CRMPQ (Rennes, France).
Microwave-assisted reactions were carried out in
a Synthewave® 402 apparatus [43] (Prolabo Merck-
Eurolab, France [44]) with variable power output (0 to
300 W). All experiments were performed in an open
quartz reactor equipped with a reflux condenser and
a stirrer. The required temperature was attained in
3 min, and the irradiation power was held constant to
maintain that temperature. The temperature was meas-
ured using a Prolabo calibrated infrared sensor [45]
Methyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVa).
mp 194–196°C; published data [45]: mp 192–194°C.
IR spectrum (KBr), ν, cm–1: 3250, 3100, 2951, 2837,
1
1717, 1655, 1587, 1514. H NMR spectrum, δ, ppm:
2.26 s (3H, CH3), 3.54 s (3H, CO2CH3), 3.72 s (3H,
OCH3), 5.12 d (1H, 4-H, J = 3.2 Hz), 6.88 d (2H, 3′-H,
5′-H, J = 8.6 Hz), 7.14 d (2H, 2′-H, 6′-H, J = 8.6 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

ARFAN et al.
1062
7.72 br.s (1H, NH), 9.22 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 17.8 (CH3), 50.7 (CO2CH3), 53.2 (C4),
55.0 (OCH3), 99.3 (C5), 113.7 (C3′, C5′), 127.3 (C2′,
C6′), 136.8 (C1′), 148.3 (C6), 152.2 C2), 158.4 (C4′),
165.8 (CO2CH3). Found: M+ 276.1118. C14H16N2O4.
Calculated: M 276.1110.
6.70 d (2H, 2′-H, 6′-H, J = 7.9 Hz), 7.12 d (2H, 3′-H,
5′-H, J = 7.9 Hz), 9.62 br.s (1H, NH), 10.32 br.s (1H,
13
NH). C NMR spectrum, δC, ppm: 17.7 (CH3), 51.5
(CO2CH3), 53.8 (C4), 55.5 (OCH3), 101.1 (C5), 114.4
(C3′, C5′), 128.0 (C2′, C6′), 136.0 (C1′), 145.5 (C6),
159.2 (CO2CH3), 166.1 (C4′), 174.5 (C2). Found:
M+ 292.0886. C14H16N2O3S. Calculated: M 292.0882.
Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (IVb). mp 211–212°C;
published data [46]: mp 210–212°C. IR spectrum
(KBr), ν, cm–1: 3158, 3024, 2949, 2902, 1713, 1645,
Methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (IVf). mp 236–
238°C; published data [43]: mp 237–238°C. IR spec-
trum (KBr), ν, cm–1: 3209, 3113, 2967, 2949, 1715,
1
1433. H NMR spectrum, δ, ppm: 2.25 s (3H, CH3),
1
3.53 s (3H, CO2CH3), 5.14 d (1H, 4-H, J = 3 Hz),
1693, 1517. H NMR spectrum, δ, ppm: 2.27 s (3H,
7.22–7.35 m (5H, Ph), 7.77 br.s (1H, NH), 9.23 br.s
CH3), 3.54 s (3H, CO2CH3), 5.27 d (1H, 4-H, J =
3.1 Hz), 7.50 d (2H, 3′-H, 5′-H, J = 8.6 Hz), 7.91 br.s
(1H, NH), 8.21 d (2H, 2′-H, 6′-H, J = 8.6 Hz), 9.38 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 18.4 (CH3),
51.3 (CO2CH3), 54.0 (C4), 98.5 (C5), 124.3 (C3′, C5′),
128.0 (C2′, C6′), 147.2 (C4′), 150.1 (C1′), 152.3 (C6′),
152.3 (C2), 166.0 (CO2CH3). Found: M+ 291.0846.
C13H13N3O5. Calculated: M 291.0855.
13
(1H, NH). C NMR spectrum, δC, ppm: 18.3 (CH3),
51.3 (CO2CH3), 54.3 (C4), 99.1 (C5), 126.6 (C3′, C5′),
128.0 (C4′), 128.9 (C2′, C6′), 145.1 (C1′), 149.1 (C6),
152.7 (C2), 166.3 (CO2CH3). Found: M+ 246.1014.
C13H14N2O3. Calculated: M 246.1011.
Methyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVc).
mp 136–138°C. IR spectrum (KBr), ν, cm–1: 3272,
Methyl 6-methyl-2-oxo-4-(pyridin-3-yl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (IVg). mp 236–
238°C. IR spectrum (KBr), ν, cm–1: 3181, 3081, 2946,
1
3175, 2998, 2953, 1699, 1572, 1186. H NMR spec-
trum, δ, ppm: 2.29 s (3H, CH3), 3.56 s (3H, CO2CH3),
5.17 d (1H, 4-H, J = 3.5 Hz), 7.23 d (2H, 2′-H, 6′-H,
J = 8.4 Hz), 7.42 d (2H, 3′-H, 5′-H, J = 8.4 Hz),
9.70 br.s (1H, NH), 10.42 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 17.71 (CH3), 51.6 (CO2CH3), 53.8
(C4), 100.5 (C5), 128.7 (C2′, C6′), 129.1 (C3′, C5′), 132.8
(C4′), 142.6 (C1′), 146.1 (C6′), 166.0 (CO2CH3), 174.7
(C2). Found: M+ 296.0391. C13H13ClN2O2S. Calculat-
ed: M 296.0386.
1
2912, 1706, 1675, 1507. H NMR spectrum, δ, ppm:
2.27 s (3H, CH3), 3.53 s (3H, CO2CH3), 5.19 s (1H,
4-H), 7.25–7.62 m (2H, 4′-H, 5′-H), 7.84 br.s (1H,
NH), 8.32–8.45 m (2H, 2′-H, 6′-H), 9.35 br.s (1H,
13
NH). C NMR spectrum, δC, ppm: 18.3 (CH3); 51.3
(CO2CH3); 53.8 (C4); 99.0 (C5); 113.4 (C3′); 114.6,
122.6, 131.0, 148.0 (C2′, C4′, C5′, C6′); 149.7 (C6);
152.6 (C2); 166.2 (CO2CH3). Found: M+ 247.0934.
C12H13N3O3. Calculated: M 247.0957.
Methyl 6-methyl-4-(4-nitrophenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVd).
mp 122–124°C. IR spectrum (KBr), ν, cm–1: 3178,
Methyl 4-(4-bromophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVh).
mp 210–212°C. IR spectrum (KBr), ν, cm–1: 3207,
1
3105, 2997, 2952, 1693, 1567, 1516. H NMR spec-
1
trum, δ, ppm: 2.31 s (3H, CH3), 3.56 s (3H, CO2CH3),
5.30 d (1H, 4-H, J = 2.1 Hz), 7.48 d (2H, 3′-H, 5′-H,
J = 8.2 Hz), 8.23 d (2H, 2′-H, 6′-H, J = 8.2 Hz),
9.79 br.s (1H, NH), 10.53 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 17.8 (CH3), 51.7 (CO2CH3), 54.0
(C4), 99.9 (C5), 124.5 (C3′, C5′), 128.2 (C2′, C6′), 146.7
(C4′), 147.4 (Cl′), 150.6 (C6′), 165.8 (CO2CH3), 175.0
(C2). Found: M+ 307.0622. C13H13N3O4S. Calculated:
M 307.0627.
3105, 2975, 2946, 1715, 1693, 1520. H NMR spec-
trum, δ, ppm: 2.24 s (3H, CH3), 3.53 s (3H, CO2CH3),
5.12 d (1H, 4-H, J = 3.1 Hz), 7.18 d (2H, 2′-H, 6′-H,
J = 8.3 Hz), 7.52 d (2H, 3′-H, 5′-H, J = 8.3 Hz),
7.79 br.s (1H, NH), 9.28 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 18.3 (CH3), 51.3 (CO2CH3), 53.8 (C4),
99.0 (C5), 120.8 (C4′), 129.0 (Ar, C2′, C6′), 131.8 (C3′,
C5′), 144.5 (C1′), 149.5 (C6), 152.5 (C2), 166.2
(CO2CH3). Found: M+ 324.0130. C13H13BrN2O3. Cal-
culated: M 324.0109.
Methyl 4-(4-methoxyphenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVe).
mp 172–174°C. IR spectrum (KBr), ν, cm–1: 3322,
3287, 3179, 2969, 2934, 1670, 1610, 1560, 1508.
1H NMR spectrum, δ, ppm: 2.29 s (3H, CH3), 3.55 s
(3H, CO2CH3), 3.72 s (3H, OCH3), 5.12 s (1H, 4-H),
Methyl 4-(2-bromophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVi).
mp 220–222°C. IR spectrum (KBr), ν, cm–1: 3249,
1
3210, 3099, 2952, 1706, 1650, 1459. H NMR spec-
trum, δ, ppm: 2.29 s (3H, CH3), 3.45 s (3H, CO2CH3),
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ACIDIC TASK-SPECIFIC IONIC LIQUID AS CATALYST
1063
mp 232–234°C. IR spectrum (KBr), ν, cm–1: 3418,
3239, 3044, 2926, 2849, 1786, 1620, 1556. 1H NMR
spectrum, δ, ppm: 2.23 s (3H, CH3), 3.52 s (3H,
CO2CH3), 5.03 d (1H, 4-H, J = 3.2 Hz), 6.68 d (2H,
3′-H, 5′-H, J = 8.3 Hz), 7.01 d (2H, 2′-H, 6′-H, J =
8.3 Hz), 7.64 br.s (1H, NH), 9.15 br.s (1H, OH),
9.34 br.s (1H, NH). 13C NMR spectrum, δC, ppm: 18.3
(CH3), 51.2 (CO2CH3), 53.7 (C4), 100.0 (C5), 115.5
(C3′, C5′), 127.8 (C2′, C6′), 135.7 (C1′), 148.5 (C6), 152.8
(C2), 157.0 (C4′), 166.4 (CO2CH3). Found:
M+ 262.0975. C13H14N2O4. Calculated: M 262.0954.
5.58 d (1H, 4-H, J = 2.8 Hz), 7.17–7.21 m (1H, 6′-H),
7.29–7.37 m (2H, 4′-H, 5′-H), 7.57 d (1H, 3′-H, J =
7.8 Hz,), 7.71 br.s (1H, NH), 9.32 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 18.2 (CH3), 51.2
(CO2CH3), 54.4 (C4), 98.6 (C5), 122.7 (C2′), 129.0
(C5′), 129.2 (C6′), 129.9 (C4′), 133.2 (C3′), 143.8 (C1′),
149.9 (C6), 151.9 (C2), 165.9 (CO2CH3). Found:
M+ 324.0980. C13H13BrN2O3. Calculated: M 324.0110.
4-(5-Methoxycarbonyl-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-4-yl)benzoic acid (IVj).
mp 230–232°C. IR spectrum (KBr), ν, cm–1: 3297,
1
3210, 3147, 2956, 2912, 1712, 1671, 1506. H NMR
Methyl 4-(2-fluorophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVn).
mp 220–222°C. IR spectrum (KBr), ν, cm–1: 3339,
spectrum, δ, ppm: 2.25 s (3H, CH3), 3.53 s (3H,
CO2CH3), 5.20 s (1H, 4-H), 7.34 d (2H, 2′-H, 6′-H, J =
6.9 Hz), 7.83 br.s (1H, NH), 7.90 d (2H, 3′-H, 5′-H, J =
7 Hz), 9.29 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 18.3 (CH3), 51.3 (CO2CH3), 54.2 (C4), 98.9 (C5),
126.7 (C2′, C6′), 130.1 (C3′, C5′), 131.5 (C4′), 149.3
(C1′), 149.5 (C6), 152.6 (C2), 166.2 (CO2CH3), 167.9
(CO2H). Found: M+ 290.0902. C14H14N2O5. Calculat-
ed: M 290.0903.
1
3295, 3148, 3055, 2953, 1715, 1670, 1587. H NMR
spectrum, δ, ppm: 2.26 s (3H, CH3), 3.54 s (3H,
CO2CH3), 5.16 d (1H, 4-H, J = 3.3 Hz), 6.98–7.09 m
(3H, 4′-H, 5′-H, 6′-H), 7.37–7.39 m (1H, 3′-H),
7.82 br.s (1H, NH), 9.29 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 18.3 (CH3), 51.3 (CO2CH3), 53.8 (C4),
99.0 (C5), 113.4 d (C4′, J = 20.8 Hz), 114.6 d (C2′, J =
20.8 Hz), 122.6 d (C6′, J = 2.6 Hz), 131.0 d (C5′, J =
8.1 Hz), 147.9 d (C1′, J = 5.8 Hz), 149.7 (C6), 152.6
(C2), 162.6 d (C3′, J = 244 Hz), 166.2 (CO2CH3).
Found: M+ 264.0915. C13H13FN2O3. Calculated:
M 264.0910.
Methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IVk).
mp 204–206°C; published data [43]: mp 206–208°C.
IR spectrum (KBr), ν, cm–1: 3211, 3109, 2974, 2948,
1
1716, 1690, 1490. H NMR spectrum, δ, ppm: 2.25 s
(3H, CH3), 3.53 s (3H, CO2CH3), 5.14 s (1H, 4-H),
7.24 d (2H, 3′-H, 5′-H, J = 7.7 Hz), 7.39 d (2H, 2′-H,
6′-H, J = 7.7 Hz), 7.80 br.s (1H, NH), 9.28 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 18.3 (CH3), 51.3
(CO2CH3), 53.7 (C4), 99.1 (C5), 128.6 (C2′, C6′), 128.9
(C3′, C5′), 132.3 (C4′), 144.1 (C1′), 149.5 (C6), 152.5
(C2), 166.2 (CO2CH3). Found: M+ 280.0604.
C13H13ClN2O3. Calculated: M 280.0615.
The authors thank Emeritus Prof. J. Hamelin for
fruitful discussions, Dr. P. Guenot (CRMPQ) for the
mass spectrometry measurements, and Merck Eurolab
Prolabo (France) for providing the Synthewave 402®
apparatus.
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