Organocatalytic application of ionic liquids: [bmim][MeSO4] as a recyclable organocatalyst in the multicomponent reaction for the preparation of dihydropyrimidinones and -thiones

Article abstract of DOI:10.1055/s-0030-1260067

The organocatalytic potential of 1-butyl-3-methylimidazolium-based room-temperature ionic liquids has been investigated for the synthesis of dihydropyrimidinones and -thiones by a one-pot multicomponent reaction involving an aldehyde, a -keto ester or -di

Full text of DOI:10.1055/s-0030-1260067

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Organocatalytic Application of Ionic Liquids:
[bmim][MeSO4] as a Recyclable Organocatalyst
in the Multicomponent Reaction for the
Preparation of Dihydropyrimidinones and -
thiones
ARTICLE in SYNTHESIS · JULY 2011
Impact Factor: 2.47 · DOI: 10.1055/s-0030-1260067
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SPECIAL TOPIC
2261
Organocatalytic Application of Ionic Liquids: [bmim][MeSO4] as a Recyclable
Organocatalyst in the Multicomponent Reaction for the Preparation of
Dihydropyrimidinones and -thiones
O
rganocatalyt
u
ic
A
pplicatio
d
n
of Ionic
L
i
i
quids pta Raha Roy, Pradeep S. Jadhavar, Kapileswar Seth, Kulin K. Sharma, Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67,
S. A. S. Nagar 160 062, Punjab, India
Fax +91(172)2214692; E-mail: akchakraborti@niper.ac.in
Received 28 April 2011
The major focus is on improving reaction media; volatile
Abstract: The organocatalytic potential of 1-butyl-3-methylimida-
zolium-based room-temperature ionic liquids has been investigated
for the synthesis of dihydropyrimidinones and -thiones by a one-pot
multicomponent reaction involving an aldehyde, a b-keto ester or b-
organic solvents amount to >85% of mass utilization in a
typical chemical manufacturing process, and, as recovery
efficiency is less than satisfactory, they are major contrib-
diketone, and urea or thiourea in excellent yields in short time. Fac- utors to environmental pollution.13 The use of alternative
tors that influence the efficiency of the ionic liquid as a catalyst
reaction media is a priority in the development of sustain-
were examined such as the anion and the imidazolium cation, par-
able chemistry, for which water and ionic liquids (ILs) are
ticularly the influence of C2 substitution in the latter. The ionic liq-
main contenders. There has been an upsurge of the use of
uid can be recovered and reused for five consecutive reactions
water as an alternative reaction medium in various organic
without significant loss of catalytic efficiency. The applicability of
reactions,14 however, its popularity has yet to reach its ze-
the methodology for large-scale reaction highlights its potential for
nith due to the poor aqueous solubility of organic com-
pounds; efforts being are made to overcome this problem
by using surfactants15 which may also play an unprece-
dented role in the reaction.16 Ionic liquids, on the other
hand, are hailed as the green solvents of the future.17
Therefore, the use of ionic liquids in multicomponent re-
actions has a perfect synergy in ecocompatible synthe-
sis.18 However, the innocuous behavior of ionic liquids is
under debate19 and their green image is under scrutiny20
on the grounds of combustibility,21 toxicity,22 and biode-
gradability.23 These have generated momentum in terms
of the non-solvent applications of ionic liquids.24
bulk synthesis.
Key words: ionic liquid, organocatalyst, multicomponent reaction,
dihydropyrimidinone, dihydropyrimidinethione
Multicomponent reactions (MCRs)1 have been recog-
nized as a new tool that provides timely synthetic support2
to medicinal chemists by the rapid construction of com-
plex structural frameworks in a convergent and atom-
economical fashion.
The 1,4-dihydropyrimidine moiety is a versatile pharma-
cophoric feature, as compounds with this structural frame-
work exhibit a broad range of biological activity, e.g.
calcium channel modulators, a1a-adrenergic receptor an-
tagonists, mitotic kinesin inhibitors, and antibacterial,
anti-inflammatory, fungicidal, and anticancer agents etc.3
Therefore, there has been continued interest from synthet-
ic organic and medicinal chemists in the development of
newer methodologies for this class of compounds that
comprise of a three-component reaction involving an al-
dehyde, a b-keto ester or b-diketone, and urea.4 Recent ef-
forts involve the use of a Brønsted acid5 or base,6 metal
Lewis acids,7 organocatalysts,8 and heterogeneous cata-
lysts,9 and nonconventional techniques, such as micro-
wave, ultrasound, high pressure, and grindstone
chemistry.10
In the pursuit of exploring the organocatalytic efficiency
of ionic liquids,25 we describe herein the potential of
room-temperature ionic liquids (RTILs) as organocata-
lysts for the synthesis of 1,4-dihydropyrimidinones and -
thiones in a one-pot, three-component reaction of an alde-
hyde, a b-keto ester or b-diketone, and urea or thiourea.
The use of ionic liquids in multicomponent reactions to
form 1,4-dihydropyridines has involved: (i) ionic-liquid-
phase organic synthesis (IoLiPOS), wherein one of the
substrates is supported on the ionic liquid,26 and (ii) the
use of ultrasound/microwave irradiation.27 There are few
reports on the use of ionic liquids, such as 1-butyl-3-
methylimidazolium tetrafluoroborate and 1-butyl-3-meth-
ylimidazolium chloroaluminate (10–40 mol%), as orga-
nocatalysts.28 However, the toxicity of 1-butyl-3-meth-
ylimidazolium-based ionic liquids is dependent on the
counteranion, and halide, tetrafluoroborate, and hexafluo-
rophosphate based ionic liquids are more toxic than alkyl
sulfate containing ionic liquids.29 Chloroaluminate anion
containing ionic liquids are susceptible to decomposition
in contact with moisture liberating corrosive HCl.
Recently there has been increasing concern centered
around the tight legislation on the maintenance of ‘green-
ness’ in synthetic pathways and processes.11 Green chem-
istry strongly influences chemical research, and there is an
insistence on the use of ‘greener’ reaction conditions.12
SYNTHESIS 2011, No. 14, pp 2261–2267
x
x.
x
x
.
2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260067; Art ID: C02111SS
© Georg Thieme Verlag Stuttgart · New York
Therefore, in order to identify a more ecocompatible ionic
liquid as an organocatalyst, a model reaction was exam-

2262
S. R. Roy et al.
SPECIAL TOPIC
ined comprising of a mixture of benzaldehyde (1a, 5 properties of the ionic liquid was observed which is in
mmol), ethyl acetoacetate (2a, 5 mmol), and urea (3a, 5 conformity with earlier observations.25 The poor catalytic
mmol) which was treated with various 1-butyl-3-meth- effect of sodium methyl sulfate (Table 1, entry 17)
ylimidazolium-based room-temperature ionic liquids (1 showed that the imidazolium-based cationic moiety is
mol%) (Scheme 1) at 100 °C for 30 minutes (Table 1).
also essential for the catalytic power of these ionic liquids.
However, the effect of the imidazolium-based cationic
moiety on the catalytic efficiency of the ionic liquid is in-
fluenced by the nature of substitution on the imidazole
ring. A 1,3-disubstituted imidazolium moiety is required
for better catalytic potency; the corresponding ionic liq-
uids derived from 1-methylimidazolium, 2-methylimida-
zolium, and 1,2-dimethylimidazolium cations are less
effective (entry 3 vs. entries 14–16). However, the C2 hy-
drogen of the 1,3-disubstituted imidazolium cation ap-
pears to be a crucial feature25 as [bmim]-based ionic
liquids devoid of the C2 hydrogen, such as [bdmim], ex-
hibited inferior catalytic efficiency (Table 2).
O
Ph
CHO
O
O
O
IL (1 mol%)
EtO
NH
+
+
H2N
NH
2 100 °C; neat,
OEt
N
H
O
30 min
1a
5 mmol
2a
5 mmol
3a
5 mmol
4a
Scheme 1 The synthesis of dihydropyrimidinone 4a catalyzed by
room-temperature ionic liquids
Table 1 The Catalytic Effect of Various Ionic Liquids in the Syn-
thesis of Dihydropyrimidinone 4a (see Scheme 1)a
Entry
1
Ionic liquidb
[bmim][Br]
Yieldc,d (%) of 4a
Table 2 Catalytic Efficiency of Various [bmim]-Based Ionic Liq-
uids Devoid of C2 Hydrogen of the Imidazole Moiety in Dihydro-
pyrimidinone 4a Formation (Scheme 1)a
70
55
80
90
72
79
67
71
73
55
75
65
68
70
50
45
41
trace
2
[bmim][PF6]
[bmim][BF4]
[bmim][MeSO4]
[bmim][MeSO3]
[bmim][HSO4]
[bmim][NTf2]
[bmim][NCN2]
[bmim][OH]
[bmim][HCO2]
[bmim][OAc]
[bmim][N3]
Entry
Ionic liquidb
Yieldc (%)
3
1
2
3
4
5
6
7
8
[bdmim][Br]
45
35
50
51
58
47
45
50
4
[bdmim][PF6]
[bdmim][BF4]
[bdmim][MeSO4]
[bdmim][HSO4]
[bdmim][NTf2]
[bdmim][NCN2]
[bdmim][OAc]
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a Reaction conditions: benzaldehyde (1a, 5 mmol), ethyl acetoacetate
(2a, 5 mmol), urea (3a, 5 mmol), RTIL (1 mol%), 100 °C (oil bath),
30 min.
[bmim][ClO4]
[Hmim][BF4]
[H-2-mim][BF4]
[H-1,2-dimim][BF4]
NaMeSO4
b [bdmim] = 1-butyl-2,3-dimethylimidazolium.
c Isolated yield of 4a (recrystallized from EtOAc).
To identify the optimum reactions conditions the
[bmim][MeSO4]-catalyzed three-component reaction of
benzaldehyde (1a), ethyl acetoacetate (2a), and urea (3a)
was performed under various conditions (Table 3).
–
The best result was obtained when the reaction was per-
formed using 1 mol% of the ionic liquid at 100 °C for 30
minutes, affording dihydropyrimidinone 4a in 90% yield
(Table 3, entry 2). The use of lower amounts (0.1 mol%)
of the ionic liquid required a longer time period to afford
comparable results (entry 1). No beneficial effect in terms
of reduction of the reaction time was observed when the
catalyst load was increased (entry 4). Decreasing the reac-
tion temperature had a detrimental effect on product yield
(entries 6–8). The use of larger amounts (5–10 mol%) of
the ionic liquid did not provide any beneficial effect in
terms of reducing the reaction time (entry 4) or reaction
temperature (entries 9 and 10).
a Reaction conditions: benzaldehyde (1a, 5 mmol), ethyl acetoacetate
(2a, 5 mmol), urea (3a, 5 mmol), ionic liquid (1 mol%), 100 °C (oil
bath), 30 min.
b [Hmim] = 1-methylimidazolium; [H-2-mim] = 2-methylimidazoli-
um; [H-1,2-dimim] = 1,2-dimethylimidazolium.
c Isolated yield of 4a (recrystallized from EtOAc).
d Wherever applicable the unreacted 2a was recovered.
The ionic liquid 1-butyl-3-methylimidazolium methyl
sulfate {[bmim][MeSO4]} containing the less toxic alkyl
sulfate anion proved to be the most effective. However,
apart from the toxic effect of the associated anion, signif-
icant influence by the counteranion on the organocatalytic
Synthesis 2011, No. 14, 2261–2267 © Thieme Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Application of Ionic Liquids
2263
Table 3 Optimization of Various Reaction Parameters for
[bmim][MeSO4]-Catalyzed Dihydropyrimidinone 4a Formationa
Table 4 The [bmim][MeSO4]-Catalyzed Synthesis of Dihydropyri-
midinones and -thionesa–c
O
R1
Entry
[bmim][MeSO4] Time (min) Temp (°C) Yieldb (%)
(mol%)
O
R2
NH
X
R2
100 °C, neat
R1CHO
89c
90
+
+
1
2
0.1
1
45
30
30
15
30
30
60
30
30
30
100
100
100
100
100
60
[bmim][MeSO4]
(1 mol %)
R3
N
H
4a–t
X
H2N
NH2
R3
O
1a–o
1 equiv
2a–c
1 equiv
3a,b
1 equiv
3
5
92
Entry R1
R2
R3
X
Time Prod- Yieldd
(min) uct
4
10
60d
95
(%)
90
88
83
87
82
82
85
90
90
91
85
86
89
88
80
80
84
90
85
82
5
10
1
1
2
Ph
Ph
Ph
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
O
S
30
40
25
30
30
25
30
30
25
30
30
45
35
30
70
65
20
40
40
20
4a
4b
4c
4d
4e
4f
6
traced
81
7
1
80
3
Me
8
1
80
51d
traced
62d
4
4-MeOC6H4
4-MeOC6H4
OEt
OEt
OEt
O
S
9
5
60
5
10
5
80
6
4-Me2NC6H4
O
O
O
S
a Reaction conditions: benzaldehyde (1a, 5 mmol), ethyl acetoacetate
(2a, 5 mmol), urea (3a, 5 mmol), [bmim][MeSO4].
b Isolated yield of 4a (recrystallized from EtOAc).
c Reaction was carried out on a 25-mmol scale for ease of handling of
the ionic liquid.
7
2,4,6-Me3C6H2 OEt
4g
4h
4i
8
4-HOC6H4
3-HOC6H4
4-AcC6H4
4-NCC6H4
4-F3CC6H4
4-F3CC6H4
3-O2NC6H4
Ph
OEt
Me
9
d Unreacted 2a was recovered.
10
11
12
13
14
15
16
17
18
19
20
OEt
OEt
OEt
OEt
OEt
(CH2)3
(CH2)3
OEt
Me
O
O
O
S
4j
To establish the scope and generality of [bmim][MeSO4]
as an organocatalyst for the synthesis of dihydropyrimid-
inones and -thiones 4a–t, various aryl, heteroaryl, and al-
iphatic aldehydes 1a–o were treated with urea or thiourea
3a,b and 1,3-dicarbonyl compounds 2a–c and the results
are summarized in Table 4.
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
O
S
In all cases, the reaction proceeded smoothly to afford the
corresponding dihydropyrimidinones and -thiones 4a–t in
excellent yields (80–91%) in short reaction times (25–45
min). The reaction is compatible with a variety of func-
tional groups such as alkoxy, hydroxy, dimethylamino, ni-
tro, acetyl, and nitrile as well as with acid-sensitive
substrates (entries 18 and 19). The b-keto esters 2a and b-
diketones (acyclic or cyclic) 2b,c react smoothly with
urea or thiourea 3a,b and aldehydes 1a–o to give the cor-
responding dihydropyrimidinone and -thione derivatives.
Thiourea (3b) exhibited greater reactivity than urea (3a)
(Table 4, cf. entry 2 vs. 3 and 12 vs. 13). The b-keto ester
2a exhibited greater reactivity over the b-diketone 2b (en-
try 1 vs. 2) and cyclic b-diketone 2c reacted relatively
sluggishly compared to the acyclic b-diketone 2b (entry 3
vs. 15).
4-i-PrC6H4
1-naphthyl
2-thienyl
2-furyl
S
Me
Me
Me
Me
O
S
Me
S
Cy
OEt
O
a Reaction conditions: aldehyde (5 mmol), b-dicarbonyl compound (5
mmol), urea/thiourea (5 mmol), [bmim][MeSO4] (1 mol%), 100 °C
(oil bath).
b R2 = OEt, R3 = Me 2a, R2 = R3 = Me 2b, R2,R3= (CH2)3 2c.
c X = O 3a; X = S 3b.
d Isolated yield of the corresponding dihydropyrimidinone and -thione
4 (recrystallized from EtOAc). All compounds have been character-
ized by IR and NMR spectroscopy and MS spectrometry. The spectral
data of known compounds are available in the Supporting Information.
We realized that the advantages of using of ionic liquids
as organocatalysts over conventional organocatalysts
would lie in the feasibility of their reuse. Hence we decid-
ed to study the reuse of [bmim][MeSO4] in the three-
component reaction to give dihydropyrimidinone 4a
(Table 5). In each case [bmim][MeSO4] was recovered af-
ter product isolation and the recovered ionic liquid was re-
used for the next four consecutive reactions. The desired
dihydropyrimidinone 4a was obtained in very good yields
without significant loss of catalytic activity of
[bmim][MeSO4].
The feasibility of large-scale synthesis was next demon-
strated by the reaction of benzaldehyde (1a, 25 mmol)
with equimolar amounts of ethyl acetoacetate (2a) and
urea (3a) performed in the presence of 1 mol% of
[bmim][MeSO4] to afford dihydropyrimidinone 4a in
90% yield.
Synthesis 2011, No. 14, 2261–2267 © Thieme Stuttgart · New York

2264
S. R. Roy et al.
SPECIAL TOPIC
zaldehyde (1a) and urea (3a) were heated at 100 °C in the
presence and absence of [bmim][MeSO4].
Table 5 Reuse of [bmim][MeSO4] for Synthesis of Dihydropyrim-
idinone 4aa
In the case of reactions under options (a) and (b) the start-
ing materials remained unchanged (TLC) even after main-
taining the reaction mixture at 100 °C for 3–6 hours.
These eliminate the possibility of the reaction following
the Knovenagel and enaminone routes. However, in case
of the option (c) a white solid precipitated within a short
period of time (~2 min) even in the absence of the ionic
liquid and complete consumption of the starting materials
took place (TLC). This suggests that the reaction proceeds
through the initial formation of the imine 5 which, howev-
er, need not require any catalytic assistance although the
solid product formation occurs almost immediately (<1
min) in the presence of the ionic liquid (Scheme 2). The
solid product 5a was next treated with ethyl acetoacetate
(2a) in the presence and absence of [bmim][MeSO4];
treatment of the solid product 5a [obtained in the absence
of catalyst] with ethyl acetoacetate (2a) at 100 °C in the
absence of catalyst for 30 minutes gave no dihydropyrim-
idinone 4a, but treatment of 5a with ethyl acetoacetate
(2a) in the presence of [bmim][MeSO4] (1 mol%) at 100
°C for 25 minutes afforded dihydropyrimidinone 4a in
83% yield. Therefore, the ionic liquid exhibits its distinct
and indispensable role during the reaction of the active
methylene carbon of ethyl acetoacetate (2a) (presumably
through its enol form) with the imine 5a and in the subse-
quent cyclodehydration step. However, the reaction of the
white solid 5a with ethyl acetoacetate (2a) at 100 °C for
25 minutes in the presence of [bdmim][MeSO4] produced
dihydropyrimidinone 4a in a lower yield (40%) and high-
lighted the important contribution of the C2 hydrogen of
the 1,3-dialkylimidazolium moiety in the activation pro-
cess.
Entry
Use
1st
Yieldb,c (%)
1
2
3
4
5
90
88
84
82
79
2nd
3rd
4th
5th
a Reaction conditions: benzaldehyde (1a, 5 mmol), ethyl acetoacetate
(2a, 5 mmol), urea (3a, 5 mmol), [bmim][MeSO4] (1 mol%), 100 °C
(oil bath), 30 min.
b After each experiment the ionic liquid was recovered and the recov-
ered ionic liquid was used as the organocatalyst for the subsequent
batch/entry of reaction.
c Isolated yield of dihydropyrimidinone 4a (recrystallized from
EtOAc).
We next attempted to understand the mechanistic course
of the reaction under the catalytic influence of the ionic
liquid. The three-component reaction of an aldehyde, a b-
dicarbonyl compound and urea has been proposed to pro-
ceed by three distinctive routes: (i) intermediate formation
the imine or iminium salt of the aldehyde and the urea
which undergoes subsequent nucleophilic attack by the
active methylene carbon of the b-dicarbonyl compound
through its enol form followed by intramolecular cyclo-
condensation, (ii) formation of the Knovenagel adduct of
the b-dicarbonyl compound and the aldehyde and subse-
quent aza-Michael reaction with urea followed by in-
tramolecular cyclodehydration, and (iii) formation of
enaminone through aza-Michael reaction of urea with the
enol form of the b-dicarbonyl compound and subsequent
aldol-type reaction of its enamine moiety with the alde- Endeavors to synthesize 1,4-dihydropyrimidinones are
hyde followed by cyclodehydration.30 To understand the mostly driven by their known biological importance. One
role of the ionic liquid in the course of the reaction the fol- of these biologically important classes is mitotic kinesin
lowing sets of experiments were performed: equimolar Eg5 inhibitors and the first report of monastrol (6)31 in
mixtures of (a) benzaldehyde (1a) and ethyl acetoacetate 1999 stimulated the synthesis of dihydropyrimidinones
(2a), (b) urea (3a) and ethyl acetoacetate (2a), and (c) ben- and dihydropyrimidinethiones to establish structure–
2a (5 mmol)
O
O
O
2 min, 100 °C
no catalyst
100 °C, 25 min
no reaction
+
Ph
H
H2N
NH2
Ph
N
NH2
no catalyst
1a
5 mmol
3a
5 mmol
5a; white solid
O
Ph
2a (5 mmol)
O
O
O
EtO
NH
100 °C, 25 min
2 min, 100 °C
no catalyst
+
Ph
H
H2N
NH2
[bmim][MeSO4]
(1 mol%)
Ph
N
NH2
N
H
O
1a
5 mmol
3a
5 mmol
5a; white solid
4a; yellow solid (83%)
O
Ph
2a (5 mmol)
O
O
O
100 °C, 25 min
2 min, 100 °C
no catalyst
EtO
NH
+
Ph
H
H2N
NH2
[bdmim][MeSO4]
(1 mol%)
Ph
N
NH2
N
H
O
1a
5 mmol
3a
5 mmol
5a; white solid
4a; yellow solid (41%)
Scheme 2 Assessment of the role of [bmim][MeSO4] in the course of dihydropyrimidinone 4a formation during the three-component reaction
Synthesis 2011, No. 14, 2261–2267 © Thieme Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Application of Ionic Liquids
2265
OH
CHO
O
S
O
O
100 °C, neat, 45 min
EtO
NH
+
+
H2N
NH2
OEt
[bmim][MeSO4]
(1 mol%)
yield = 85%
HO
N
S
1f
1 equiv
2a
1 equiv
3b
1 equiv
H
6 monastrol
OH
CHO
O
O
S
100 °C, neat, 90 min
+
NH
+
H2N
NH2
[bmim][MeSO4]
(1 mol%)
yield = 80%
HO
O
N
H
S
1f
1 equiv
2c
1 equiv
3b
1 equiv
7 enastron
Scheme 3 Synthesis of bioactive dihydropyrimidinones 6 and 7 catalyzed by [bmim][MeSO4]
ence of [bmim][MeSO4] (0.125 g, 1 mol%) for 30 min to afford 4a
(11.7 g, 90%) after usual workup and purification.
activity relationships to generate more effective mitotic
kinesin Eg5 inhibitors as well as generating novel leads in
diverse therapeutic areas. This has led to the discovery of
enastron (7) as a more potent mitotic kinesin Eg5 inhibi-
tor.32 Hence we extended our methodology to the synthe-
sis of monastrol (6) and its analogue enastron (7), both
these molecules were formed in excellent yields in a short
reaction time (Scheme 3).
Ethyl 4-Mesityl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (4g)
Mp 262 °C.
IR (KBr): 3430, 2926, 2855, 1698, 1642, 1598, 1456, 1231, 1094
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.88 (t, J = 8.0 Hz, 3 H, CH3),
2.12 (s, 3 H, CH3), 2.16 (s, 3 H, CH3), 2.29 (s, 6 H, CH3), 3.78 (q,
J = 6.5 Hz, 2 H, CH2), 5.76 (s, 1 H, CH), 6.75 (s, 2 H, ArCH), 7.27
(br s, 1 H, NH), 9.02 (br s, 1 H, NH).
1
The H and 13C NMR spectra were recorded on a Bruker Avance
400 MHz NMR spectrometer in DMSO with residual undeuterated
solvent (DMSO; 2.54 ppm for 1H NMR, 40.45 ppm for 13C NMR)
using Me4Si as an internal standard. Chemical shifts (d) are given in
ppm and J values are given in Hz. The melting points were mea-
sured in Perkin-Elmer Micro DSC. The IR spectra were recorded on
KBr pellets in a Nicolet Impact 410 FTIR spectrophotometer. Mass
spectra were recorded on advance Bruker Daltonics® MALDI-
TOF-TOF mass spectrometer [for MALDI] and HRMS on Bruker
Maxis®. Solvent evaporation was performed under reduced pres-
sure (Buchi rotary evaporator). Chemicals were purchased from Al-
drich, Lancaster and Fluka Chemicals and used as received.
13C NMR (100 MHz, DMSO-d6): d = 14.15, 17.97, 20.79, 51.29,
59.31, 97.37, 136.02, 136.98, 137.47, 146.82, 151.20, 166.01.
HRMS: m/z = 302.1620 (M + 1).
1-[4-(3-Hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-yl]ethanone (4i)
Mp 250 °C.
IR (KBr): 3434,2347, 1620, 1443, 1320, 1180 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.13 (s, 3 H, COCH3), 2.30 (s,
3 H, CH3), 5.20 (d, J = 3.6 Hz, 1 H, CH), 6.63–6.66 (m, 3 H, ArCH),
7.11 (t, J = 8.0 Hz, 1 H, ArCH), 9.45 (s, 1 H, NH), 9.69 (s, 1 H, OH),
10.23 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 18.65, 30.76, 54.27, 110.80,
113.87, 115.14, 117.64, 130.05, 144.75, 157.97, 174.39, 195.33.
Characterization data for new compounds are provided below;
those for known compounds in the Supporting Information.
Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (4a); Typical Procedure
A mixture of benzaldehyde (1a, 0.61 g, 5 mmol), ethyl acetoacetate
(2a, 0.65 g, 5 mmol, 1 equiv), and urea (3a, 0.38 g, 5 mmol, 1 equiv)
was stirred magnetically at 100 °C in the presence of
[bmim][MeSO4] (0.012 g, 1 mol%). After completion of the reac-
tion (30 min, TLC) the mixture was diluted with H2O (1 mL) and
EtOAc (5 mL). The organic layer was separated and the crude prod-
uct was recrystallized (EtOAc) to afford 4a (1.17 g, 90%). The
aqueous layer containing the ionic liquid was subjected to rotary
evaporation at 80 °C under reduced pressure for 20 min to afford the
recovered ionic liquid which was used/reused for 5 subsequent fresh
batches of reaction of 1a (0.534 g, 5 mmol), 2a (0.65 g, 5 mmol, 1
equiv), and 3a (0.3 g, 5 mmol, 1 equiv) to afford 4a in 90, 88, 84,
82, and 79% yields, respectively, after usual workup and purifica-
tion.
HRMS: m/z = 285.0650 (M + Na+).
Ethyl 4-(4-Acetylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropy-
rimidine-5-carboxylate (4j)
Mp 202 °C.
IR (KBr): 3435, 1770, 1641, 1227, 1092 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.09 (t, J = 6.8 Hz, 3 H, CH3),
2.25 (s, 3 H, CH3), 3.31 (s, 3 H, COCH3), 3.97 (q, J = 6.8 Hz, 2 H,
CH2), 5.20 (s, 1 H, CH), 7.36 (d, J = 7.6 Hz, 2 H, ArCH), 7.79 (br
s, 1 H, NH), 7.91 (d, J = 7.6 Hz, 2 H, ArCH), 9.24 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 14.52, 18.20, 27.18, 54.12,
59.75, 99.08, 126.97, 129.01, 136.37, 149.24, 150.17, 152.38,
165.63, 197.94.
On a large-scale operation, the reaction of benzaldehyde (1a, 5.34
g, 50 mmol), ethyl acetoacetate (2a, 6.5 g, 50 mmol, 1 equiv), and
urea (3a, 3.0 g, 50 mmol, 1 equiv) was stirred at 100 °C in the pres-
HRMS: m/z = 325.1142 (M + Na+).
Synthesis 2011, No. 14, 2261–2267 © Thieme Stuttgart · New York

2266
S. R. Roy et al.
SPECIAL TOPIC
Ethyl 6-Methyl-2-thioxo-4-[4-(trifluoromethyl)phenyl]-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4m)
Mp 218 °C.
R (KBr): 3429, 2920, 1652, 1577, 1456, 1325, 1111 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.08 (t, 3 H, J = 7.2 Hz, CH3),
3.33 (s, 3 H, CH3), 4.00 (q, 2 H, J = 6.8 Hz, CH2), 5.25 (s, 1 H, CH),
7.42 (d, 2 H, J = 8.0 Hz, ArCH), 7.73 (d, 2 H, J = 8.0 Hz, ArCH),
9.72 (br s, 1 H, NH), 10.44 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 14.42, 17.59, 54.08, 60.18,
100.46, 123.26, 226.08, 126.11, 127.59, 127.74, 128.57, 128.89,
129.20, 146.01, 146.14, 148.24, 165.39, 174.75.
(3) (a) Kappe, C. O. Molecules 1998, 3, 1. (b) Kappe, C. O.
Eur. J. Med. Chem. 2000, 35, 1043. (c) Yarim, M.; Saraç,
S.; Kiliç, F. S.; Erol, K. Farmaco 2003, 58, 17. (d) Kidwai,
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Chem. 2005, 40, 816. (e) Kumar, P.; Sankar, B. R.; Nasir,
G.; Baig, R. B.; Chandrashekaran, S. Eur. J. Med. Chem.
2009, 44, 4192.
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HRMS: m/z = 367.0710 (M + Na+).
4-(4-Isopropylphenyl)-2-thioxo-1,2,3,4,7,8-hexahydroquinazo-
lin-5(6H)-one (4p)
Mp 217 °C.
(e) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2007,
48, 7343. (f) Yu, Y.; Liu, C.; Luo, G. Bioorg. Med. Chem.
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IR (KBr): 3427, 3246, 2956, 1624, 1454, 1373, 1180 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.81–1.96 (m, 4 H, CH2CH3),
2.19–2.31 (m, 4 H, CH2CH3), 2.49–2.70 (m, 4 H, CH2), 2.77–2.86
(m, 1 H, CH), 5.14 (d, J = 2.8 Hz, 1 H, CH), 7.05–7.19 (m, 4 H,
ArCH), 9.64 (br s, 1 H, NH), 10.55 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 20.32, 24.30, 26.90, 33.41,
36.78, 52.10, 109.56, 126.84, 126.87, 128.33, 141.24, 146.44,
151.09, 196.74.
HRMS: m/z = 323.1202 (M + Na+).
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Monastrol (6)
A mixture of 3-hydroxybenzaldehyde (1f, 0.534 g, 5 mmol), ethyl
acetoacetate (2a, 0.65 g, 5 mmol, 1 equiv), and thiourea (3b, 0.3 g,
5 mmol, 1 equiv) was stirred magnetically at 100 °C in the presence
of [bmim][MeSO4] (0.012 g, 1 mol%). After completion of the re-
action (45 min, TLC) the mixture was diluted with H2O (1 mL) and
EtOAc (5 mL). The organic layer was separated and the crude prod-
uct was recrystallized (EtOAc) to afford 6 (1.24 g, 85%).31
Enastron (7)
A mixture of 3-hydroxybenzaldehyde (1f, 0.534 g, 5 mmol), cyclo-
hexane-1,3-dione (2c, 0.56 g, 5 mmol, 1 equiv), and thiourea (3b,
0.3 g, 5 mmol, 1 equiv) was stirred magnetically at 100 °C in the
presence of [bmim][MeSO4] (0.012 g, 1 mol%). After completion
of the reaction (90 min, TLC) the mixture was diluted with H2O (1
mL) and EtOAc (5 mL). The organic layer was separated and the
crude product was recrystallized (EtOAc) to afford 7 (1.09 g,
80%).32
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
S.R.R. and K.S. thank CSIR, New Delhi, India for SRF.
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Organocatalytic Application of Ionic Liquids
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