Poly(ethylene)glycol/AlCl3 as a new and efficient system for multicomponent Biginelli-type synthesis of pyrimidinone derivatives

Article abstract of DOI:10.1515/hc-2012-0157

Biginelli condensation of aldehydes, cyclopentanone and urea or thiourea in poly(ethylene)glycol 400, at 45°C in the presence of aluminum chloride as a highly efficient catalyst has been developed. The reaction is very fast, clean and environmentally beni

Full text of DOI:10.1515/hc-2012-0157

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0157ꢀ ꢀHeterocycl. Commun. 2013; 19(1): 69–73
APlioAmlyoo(zeadtehh,ySallemanneRa)hgmlaynic* aondl/FiAroulzCehl3Neamsatia new and efficient
system for multicomponent Biginelli-type
synthesis of pyrimidinone derivatives
Abstract: Biginelli condensation of aldehydes, cyclopen- [18], H2SO4 [19], BF3‧Et2O/CuCl [20], LaCl3‧7H2O in the pres-
tanone and urea or thiourea in poly(ethylene)glycol 400, ence of concentrated HCl [21], CeCl3‧7H2O [22], heteropolyac-
at 45°C in the presence of aluminum chloride as a highly ids [23], Cu(OTf)2 [24], TMSCl [25], LiClO4 [26], LiBr [27], InBr3
efficient catalyst has been developed. The reaction is very [28], FeCl3‧6H2O/HCl [29], TMSI [30], Brønsted acidic ionic
fast, clean and environmentally benign for the synthesis liquid [31], ionic liquid [32] and base catalyst [33]. They have
of a vast variety of pyrimidinone derivatives.
been used with success in ethanol, acetic acid, tetrahydro-
furan, acetonitrile or N,N-dimethylformamide.
Keywords: aluminum chloride; Biginelli condensation;
poly(ethylene)glycol; pyrimidinone.
Results and discussion
*Corresponding author: Salman Rahmani, Faculty of Chemistry,
Department of Organic Chemistry, Semnan University, 35195-363,
Semnan, Iran, e-mail: salmanrahmany@gmail.com
Ali Amoozadeh and Firouzeh Nemati: Faculty of Chemistry,
Department of Organic Chemistry, Semnan University, Semnan, Iran
In continuation of our studies on developing inexpensive
and environmentally benign methodologies for organic
reactions especially with the use of poly(ethylene)glycol
400 (PEG 400) as a green and reusable solvent [34–40],
we now report for the first time aluminum chloride cata-
lyzed Biginelli condensation reaction of cyclopentanone
with a vast variety of aldehydes with both urea or thiourea
using PEG 400 as the reaction medium (Equation 1). The
Introduction
Multicomponentreactions(MCRs)areimportanttransforma- versatility of aluminum chloride and the environmentally
tions in organic and medicinal chemistry [1–4]. These types benign nature of PEG encouraged us to couple them and
of condensation reactions provide a fast and easy access to study their utility for pyrimidinone synthesis reaction. To
a variety of polyheterocyclic compounds of therapeutic and the best of our knowledge, there are no literature reports
pharmacological properties [5–7]. The Biginelli reaction is a on Biginelli condensation under these conditions.
three-component reaction which is involves an α-ketoester,
Ar
O
an urea or thiourea, and an aldehyde to produce 3,4-dihy-
X
AlCl3 (0.3 mol)
PEG 400, rt
NH
(1)
dro-2(1H)-pyrimidinones [6]. Many of such compounds
show interesting bioactivity [8–11] or are used as substrates
to prepare heterocyclic products with pharmacological
properties [12]. These reasons have motivated researchers
to extend the scope of the method to other 1,3-dicarbonyl
compounds such as β-diamides [13], cyclic diketones [14]
and β-ketolactones [15]. Another modification has been
focused on the use of different acidic catalysts, mostly in the
ArCHO
H2N
NH2
N
H
X
Ar
1
2
3
4
4a: X = O; Ar = Ph
4h: X = S; Ar = Ph
4b: X = O; Ar = 2-Cl-C6H4
4c: X = O; Ar = 3-NO2-C6H4
4d: X = O; Ar = 4-Cl-C6H4
4e: X = O; Ar = 4-Br-C6H4
4f: X = O; Ar = 4-Me-C6H4
4g: X = O; Ar =4-OMe-C6H4
4i: X = S; Ar = 4-Cl-C6H4
4j: X = S; Ar = 3-NO2-C6H4
4k: X = S; Ar = 4-NO2-C6H4
4l: X = S; Ar = 4-OMe-C6H4
4m: X = S; Ar = 2-Naphtyl
4n: X = S; Ar =4-Br-C6H4
presence of a polar solvent. Formerly, the Biginelli reaction At the beginning, we studied the reaction under solvent-
suffered from the need of harsh conditions to afford accept- free conditions in the presence of 0–0.4 mmol AlCl3 as cat-
able yields. Recently, the development of mild Lewis acid [8, alyst. TLC analysis showed that the best quantity of AlCl3
9, 10, 16] and heteropolyacid [17] catalysts has considerably is 0.3 mmol. Owing to low yields (0–46%), we decided to
improved the yield of the reaction. In the presence of such perform the reaction in a solvent to potentially increase
catalysts, the reaction is relatively facile, leading to high the obtained yields. We tested CHCl3, CH2Cl2, Et2O, CH3CN,
yields of dihydropyrimidinones. These catalysts include EtOH, THF and PEG as solvents for Biginelli condensations
InCl3 [8], BiCl3 [10], phenylpyruvic acid [14], Al(NO3)3‧9H2O of cyclopentanone, benzaldehyde and urea in the presence
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ꢁꢁꢁꢂ
70ꢀ ꢀA. Amoozadeh et al.: Multicomponent Biginelli-type synthesis of pyrimidinone derivatives
of 0.3 mmol AlCl3 as catalyst. The results showed that this
reaction is highly solvent-dependent. It does not work at
all in ethanol. It seems that alcohols with low molecular
weight are not suitable choices as solvents for the reac-
tions catalyzed by AlCl3 because they can react readily with
Lewis acid. In addition, the reaction does not work well in
chloroform, dichloromethane, diethyl ether or tetrahydro-
furan (yields in the range of 25–65%). Fortunately, in the
case of PEG 400 as solvent, the yield is excellent (91%).
The Biginelli condensation of cyclopentanone, benza-
ldehyde and urea in PEG 400 as solvent in the presence
of different amounts of AlCl3 as catalyst (0.0–0.4 mmol) at
room temperature was performed. Similarly to the solvent-
free conditions, the amount of 0.3 mmol of AlCl3 as catalyst
is optimal to give yield of 91%. The effect of temperature on
Conclusion
Efficient conditions for the synthesis of pyrimidinone
derivatives using Biginelli reaction by condensation of
cyclopentanone with different aldehydes and urea and/or
thiourea in the presence of AlCl3, in PEG as a green and
reusable solvent are reported. This protocol is a low cost
procedure that is also user and environmentally friendly.
Experimental
General
Chemicals were purchased from Merck and Aldrich chemical com-
the Biginelli condensation of cyclopentanone, benzalde- panies. Thin layer chromatography (TLC) on commercial aluminum
backed plates of silica gel 60 F254 was used to monitor the progress
hyde and urea in presence of 0.3 mmol AlCl3 in PEG 400 as
of reactions. Melting points were recorded on a Thermo Scientific
solvent was studied. Reaction was performed at 45°C, 60°C
9100 apparatus. The FT-IR spectra were taken on a Perkin-Elmer,
and 80°C. With increases in the temperature up to 45°C,
1
model 783, spectrophotometer in KBr pellets. The H NMR spectra
the yield was also increased up to yield 94%. However, a
(300 MHz) and 13C NMR spectra (75 MHz) were recorded in DMSO-
further rise in temperature to 80°C caused a decrease in
d6 on a Bruker AMX-300 spectrometer. Elemental analyses were per-
yield, from 89% at 60°C to 84% at 80°C. In summary, the formed on a Perkin-Elmer CHN analyzer, 2400 series II.
optimal temperature for this reaction is 45°C.
The reaction works easily for a vast variety of alde-
hydes with both electron-donating and electron-withdraw-
General procedure for preparation
ing groups with both urea and thiourea to give correspond-
of pyrimidinones 4a–n
ing pyrimidinone derivatives in good to excellent yields.
1
A mixture of aldehyde (1 mmol), ketone (1 mmol), urea or thiourea
(1.2 mmol) and AlCl3 (0.3 mmol) in PEG (2 mL) was stirred at 45°C for
a period of time indicated below. Afer completion of the reaction, as
monitored by TLC, distilled water (4 mL) was added. The solid precip-
itate was filtered and washed with absolute ethanol or ethyl acetate
(3 mL) and acetone (2 mL) and dried in air.
As an alternative work-up procedure, the reaction mixture was
cooled in a dry ice-acetone bath to precipitate the PEG 400 and or-
ganic products were extracted with ether. The ether layer was washed
with water (2 mL) and dried over MgSO4. The organic solvent was re-
moved under reduced pressure to give the crude product 4a–n. The
product was crystallized from ethanol.
The new compounds characterized by FT-IR, H NMR, 13C
NMR and CHN analysis (Experimental section). However,
it should be noted that the reaction time for aldehydes
with electron-withdrawing groups is considerably longer
(4b– 4e vs. 4f, 4g). High yields for the reaction of electron-
rich aldehydes have been noted [41]. In their proposed
mechanism, Zhang et al. [41] have suggested aldol conden-
sation between cyclopentanone and aldehyde to produce
corresponding α,α′-bis(substituted benzylidene)cyclopen-
tanone 5. Then this intermediate product would react with
urea or thiourea to produce desired pyrimidinone 4a,h
[41] (Equation 2). Concerning this proposed mechanism,
we expected that compound 5 would also undergo reac-
tion with urea or thiourea under our conditions to produce
pyrimidinone 4. However, compound 4 was not found in
the reaction mixture, which suggests that the mechanism
of this transformation requires additional studies.
(7E)-7-Benzylidene-3,4,6,7-tetrahydro-4-phenyl-1H-cyclo-
penta[d]pyrimidin-2(5H)-one (4a)ꢀYellow solid; yield 94%; mp
238–240°C; (lit mp 236–239°C [25]); reaction time 2.5 h.
(7E)-7-(2-Chlorobenzylidene)-4-(2-chlorophenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4b)ꢀYellow solid;
yield 86%; mp 228–231°C; (lit mp 232–234°C [25]); reaction time 5.5 h.
X
X
H2N
NH2
H2N
NH2
O
AlCl3, PEG 400
YbCl3
Ph
4a, h
Ph
No reaction
(2)
5
X = O, S
X = O, S
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ꢂꢁꢁꢁ
A. Amoozadeh et al.: Multicomponent Biginelli-type synthesis of pyrimidinone derivativesꢀ
ꢀ71
(7E)-7-(3-Nitrobenzylidene)-3,4,6,7-tetrahydro-4-(3-nitro-
phenyl)-1H-cyclopenta[d]pyrimidin-2(5H)-one (4c)ꢀBrown solid;
yield 84%; mp 233–235°C ; (lit mp 235–239°C [25]); reaction time 4.2 h.
solid; yield 79%; mp 199–202°C; (lit mp 203–207°C [25]); reaction
time 3.25 h.
7-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-thione (4l)ꢀLight yel-
low solid; yield 93%; mp 218–220°C; reaction time 0.75 h; IR: ν 3851,
(7E)-7-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4d)ꢀYellow-green
solid; yield 89%; mp 250–253°C; (lit mp 252–255°C [25]); reaction time
4.5 h.
1
3566, 1541, 1508, 1245, 1174, 1026 cm-1; H NMR: δ 9.98 (1H, s, NH),
8.90 (1H, s, HC=), 6.90–7.29 (8H, m, CH), 6.84 (1H, s, NH), 5.11 (1 H,
s, CH), 3.73–3.74 (6H, OMe), 2.77 (2H, s, CH2), 2.41–2.42 (1H, d, CH2),
2.03–2.07 (1H, d, CH2); 13C NMR: δ 173.9, 158.9, 157.7, 135.5, 134.5, 133.9,
130.3, 129.3, 127.9, 120.1, 117.2, 114.0, 57.3, 28.4, 27.8. Anal. Calcd for
C22H22N2O2S: C, 69.81; H, 5.86; N, 7.40. Found: C, 69.92; H, 5.70; N, 7.61.
(7E)-7-(4-Bromobenzylidene)-4-(4-bromophenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4e)ꢀYellow solid;
yield 96%; mp 219–222°C; (lit mp 221–222°C [41]); reaction time 3.5 h.
(7E)-7-(4-Methylbenzylidene)-4-(4-methylphenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4f)ꢀDark yellow
solid; yield 96%; mp 241–243°C; (lit mp 238–241°C [25]); reaction time
2.2 h.
4-(Naphthalen-2-yl)-7-(naphthalen-2-ylmethylene)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidin-2(5H)-thione (4m)ꢀRed solid;
yield 82%; mp 238–240°C; reaction time 0.5 h; IR: ν 3392, 3322, 1544,
1483, 1191, 820, 746 cm-1; 1H NMR: δ 10.22 (1H, s, NH), 9.13 (1H, s, HC=),
7.41–7.99 (14H, m, CH), 7.14 (1H, s, NH), 5.41 (1H, s, CH), 2.84–3.02 (2H,
m, CH2), 2.44–2.52 (1H, m, CH2), 2.05–2.12 (1H, m, CH2); 13C NMR: δ
174.4, 139.6, 138.6, 135.3, 134.2, 133.2, 132.8, 132.6, 131.5, 128.6, 127.9,
127.6, 127.4, 126.7, 126.5, 126.2, 124.8, 125.2, 121.3, 117.9, 58.2, 28.5, 28.1.
Anal. Calcd for C28H22N2S: C, 80.35; H, 5.30; N, 6.69. Found: C, 80.48;
H, 5.42; N, 6.79.
(7E)-7-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-3,4,6,7-
tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4g)ꢀYellow
solid; yield 95%; mp 254–257°C; (lit mp 250–252°C [25]); reaction time
2 h.
(7E)-7-Benzylidene-3,4,6,7-tetrahydro-4-phenyl-1H-cyclo-
penta[d]pyrimidine-2(5H)-thione (4h)ꢀPink solid; yield 96%; mp
218–221°C; (lit mp 219–223°C [25]); reaction time 1 h.
7-(4-Bromobenzylidine)-4-(4-bromophenyl)-3,4,6,7-tetrahydro-
1H-cyclopenta[d]pyrimidin2(5H)-thione (4n)ꢀYellow solid; yield
86%; mp 226–228°C; reaction time 1.5 h; IR: ν 3240, 2920, 1672, 1558,
1
1489, 1186, 1090, 872 cm-1; H NMR: δ 10.12 (1H, s, NH), 9.03 (1H, s,
(7E)-7-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-3,4,6,7-tetra-
hydro-1H-cyclopenta[d]pyrimidine-2(5H)-thione (4i)ꢀLight red
solid; yield 90%; mp 223–225°C; (lit mp 226–228°C [25]); reaction
time 2.3 h.
HC=), 7.07–7.59 (8H, m, CH), 6.90 (1H, s, NH), 5.23 (1H, s, CH), 2.72–
2.88 (2H, m, CH2), 2.39–2.53 (1H, m, CH2), 2.02–2.09 (1H, m, CH2); 13C
NMR: δ 174.4, 141.1, 138.7, 136.5, 134.0, 132.4, 130.5, 129.6, 128.8, 128.6,
121.3, 116.7, 69.8, 57.1, 28.3, 27.9. Anal. Calcd for C20H16Br2N2S: C, 50.44;
H, 3.39; N, 5.88. Found: C, 50.31; H, 3.47; N, 5.64.
(7E)-7-(3-Nitrobenzylidene)-3,4,6,7-tetrahydro-4-(3-nitro-
phenyl)-1H-cyclopenta[d]pyrimidine-2(5H)-thione
(4j)ꢀDark
brown solid; yield 92%; mp 309–312°C; (lit mp 313–317°C [25]); reac-
Acknowledgments: We thank the Department of Chemis-
try of Semnan University for supporting this work.
tion time 3 h.
(7E)-7-(4-Nitrobenzylidene)-3,4,6,7-tetrahydro-4-(4-nitro-
phenyl)-1H-cyclopenta[d]pyrimidine-2(5H)-thione (4k) Brown Received October 20, 2012; accepted December 8, 2012
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