Efficient synthesis of 3,4-dihydropyrimidin-2-ones in low melting tartaric acid-urea mixtures

Article abstract of DOI:10.1039/c1gc00009h

A general, efficient and green method for the synthesis of dihydropyrimidinones is described under mild conditions employing low melting mixtures of L-(+)-tartaric acid and urea derivatives as a novel reaction medium. The melt plays a triple role: as solvent, as catalyst and as reactant, furnishing highly functionalized dihydropyrimidinones in good to excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c1gc00009h

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PAPER
Efficient synthesis of 3,4-dihydropyrimidin-2-ones in low melting tartaric
acid–urea mixtures†
Sangram Gore,a,b Sundarababu Baskaran*a and Burkhard Koenig*b
Received 3rd January 2011, Accepted 7th February 2011
DOI: 10.1039/c1gc00009h
A general, efficient and green method for the synthesis of dihydropyrimidinones is described
under mild conditions employing low melting mixtures of L-(+)-tartaric acid and urea derivatives
as a novel reaction medium. The melt plays a triple role: as solvent, as catalyst and as reactant,
furnishing highly functionalized dihydropyrimidinones in good to excellent yields.
One-pot multicomponent condensation reactions repre-
Introduction
sent an efficient tool to perform efficient synthesis, because
Dihydropyrimidinones (DHPMs) are important substructures
they allow the assembly of complex molecules with maxi-
present in a wide variety of biologically active natural products.1
mum simplicity and brevity.4 Pietro Biginelli reported more
In recent years, dihydropyrimidinones and their derivatives have
than one century ago a one-pot multicomponent approach
been used as calcium channel blockers and antihypertensive
agents.2a–d Numerous marine alkaloids containing the dihy-
for the synthesis of DHPMs by multicomponent reaction
of urea, aldehydes and b-ketoesters under strong acidic
dropyrimidinone skeleton have interesting biological properties,
conditions.5
such as batzelladine alkaloids that are potent HIV gp-120-
The unique biological significance of the DHPM skeleton
CD4 inhibitors.2a–d Monastrol, a thio derivative of DHPM, acts
stimulated several research groups to develop new synthetic
as a cell-permeable molecule to block mitosis by specifically
procedures based on the Biginelli reaction.6 Thus, various
inhibiting the motor activity of the mitotic kinesis Eg5 and
improved protocols for the synthesis of DHPMs based on the
is thus considered as a lead molecule for the development of
use of Lewis acids such as BF3·OEt2,7a strong protic acids
new anticancer drugs.3a In addition, (R)-SQ 32926 acts as a
like HCl7b and H2SO4,7c metal triflates,7d–f zeolites,7g as well
antihypertensive agent with potent oral activity,3b whereas Mon-
as microwave7h and ultrasonic assisted methods7i,j have been
97 shows promising anticancer activity (Fig. 1).3c
reported in the literature. However, many of these methods
are not environmentally friendly8,9 and suffer from several
drawbacks such as harsh or sensitive reaction conditions, low
yields, use of expensive or hazardous reagents and lack of
substrate scope. Moreover, most of these methods employ
organic solvents as reaction medium.
Recently, we have established low melting mixtures con-
sisting of urea, carbohydrates and inorganic salts as new
alternative renewable solvents for organic transformations.10
The stable melts of these mixtures are environmentally benign,
as they are easily biodegradable, and available from bulk
renewable resources without any further modification. The
reaction medium consists of only nontoxic materials and has
very low vapour pressure like ionic liquids. Moreover, the
polarity of these melts is very high.11 Our continued interest
in the exploration of low melting mixtures as novel and green
reaction media resulted in the development of several environ-
mentally benign organic transformations such as cycloaddition
reactions,10,11 coupling reactions11–13 and synthesis of glycosyl
ureas.14
Fig. 1 Pharmacologically active DHPMs.
aDepartment of Chemistry, Indian Institute of Technology Madras,
Chennai, 600036, India. E-mail: sbhaskar@iitm.ac.in;
Fax: 0091-44-22570545; Tel: 0091-44-22574218
bInstitut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040,
Regensburg, Germany.
E-mail: burkhard.koenig@chemi.uniregensburg.de; Fax: +49 941
9431717; Tel: +49 941 9434576
† Electronic supplementary information (ESI) available: Synthetic pro-
cedures, characterization data and copies of NMR spectra. See DOI:
10.1039/c1gc00009h
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Table 1 Biginelli reaction of 4-nitrobenzaldehyde, ethylacetoacetate and DMU in various meltsa
Entry
Melt
Temp (◦ C)
Time (h)
Yield (%)b
1
2
3
4
5
Citric acid–DMU 40 : 60
65
70
71
67
75
17
12
33
19
30
90
96
42
80
54
L-(+)-Tartaric acid–DMU 30 : 70
D-(-)-Fructose–DMU 70 : 30
Sorbitol–DMU–NH4Cl 70 : 20 : 10
D-(+)-Mannose–DMU 30 : 70
a Reaction conditions: 4-nitrobenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol) in melt (1.5 g). b Isolated yield.
Herein, we report a facile and environmentally benign synthe-
sis of dihydropyrimidinones in low melting mixtures under mild
conditions.
thesis using thiourea as one of the melt components. However, all
our efforts towards the formation of a clear melt of L-(+)-tartaric
acid–thiourea were futile. Interestingly, L-(+)-tartaric acid–
choline chloride (50 : 50) formed a clear melt at 90 ◦C which was
used as a medium for the synthesis of thiopyrimidinones using
thiourea as one of the reactants. 3-Hydroxybenzaldehyde on
treatment with thiourea in L-(+)-tartaric acid–choline chloride
melt smoothly furnished the anticancer drug monastrol (18a) in
good yield (entry 11, Table 2).
The reaction works equally well with various 1,3 dicarbonyl
compounds such as benzoyl acetone (23a), allyl acetoacetate
(19a), ethyl benzoyl acetate (21a) and methyl acetoacetate (25a).
In all the cases the corresponding DHPMs were obtained in
good to excellent yields. Under the reaction conditions, the less
reactive simple ketone such as cyclohexanone also furnished the
corresponding DHPM in moderate yield (entry 5, Table 3).
For the first time, masked aldehydes are successfully used in
the Biginelli reaction. The masked aldehydes such as dihydropy-
ran and dihydrofuran reacted readily under the reaction condi-
tions to give corresponding functionalized dihydropyrimidinone
derivatives in excellent yields (Table 4).
Results and discussion
Since the Biginelli reaction works well under acidic conditions,
initially, we focused on the melt systems consisting of an
organic acid as one of the melt components. Thus, the citric
acid–dimethylurea (DMU) (40 : 60) melt (65 ◦C) was chosen
as a catalyst as well as reaction medium for the Biginelli
reaction. To test the feasibility of this melt system, initially
the Biginelli reaction of 4-nitrobenzaldehyde, ethylacetoacetate
and dimethylurea, which is one of the melt components, was
carried out at 65 ◦C. To our delight, the corresponding DHPM
derivative was obtained in good yield. In order to improve the
efficiency of this method, the Biginelli reaction was performed
in various low melting mixtures and the results are summarized
in Table 1.
The Biginelli reaction proceeds faster (12 h) in L-(+)-tartaric
acid–DMU melt and the corresponding DHPM is isolated in
excellent yield (96%) (entry 2, Table 1). Similarly, a Biginelli
reaction involving urea as one of the components in an L-(+)-
tartaric acid–urea melt at 90 ◦C gives the corresponding DHPMs
in good yield.15,16
Once the reaction conditions were established, the scope of
the multicomponent reaction was investigated with different
aldehydes and b-ketoesters yielding a variety of highly function-
alized DHPMs. The results are summarized in Tables 2, 3 and
4. The reaction proceeds smoothly with aromatic and aliphatic
aldehydes to provide a wide spectrum of DHPMs. Interestingly,
a,b-unsaturated aldehydes such as cinnamaldehyde gave the
corresponding DHPM in 72% yield without isomerization of the
double bond (entry 8, Table 2). Aromatic aldehydes having both
electron donating as well as electron withdrawing substituents
gave the corresponding dihydropyrimidinones in excellent yield.
Since the reaction conditions are very mild, several acid sensitive
functional groups such as olefins, ether, ester and cyano groups
remain unaffected under the reaction conditions.
It is important to note that the DHPM synthesis in a
melt requires neither tedious work up procedure nor column
chromatographic purification. The DHPMs are obtained by
quenching of the reaction mixture with water and recrystalliza-
tion of the precipitated solid from ethanol to yield analytically
pure products.
Conclusion
In summary, we have developed an environmentally benign
method for the preparation of DHPMs under mild and additive
free conditions using low melting mixtures as a novel and green
reaction medium. For the first time, masked aldehydes have been
used as substrates in the Biginelli reaction to give functionalized
DHPM derivatives. The melt medium plays a triple role: as
solvent, as catalyst and as reactant. Moreover, the method does
not require any tedious work up procedure and the DHPMs are
isolated in excellent yields and high purity.
Since thiopyrimidinones are important pharmacophores, our
next objective was to develop an efficient procedure for their syn-
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Table 2 Synthesis of dihydropyrimidinones in low melting mixturesa
Entry
1
Aldehydes
Time (h)
Product
Yield (%)b
R = NO2: 1a
Cl: 1b
CN: 1c
Br: 1d
OMe: 1e
H: 1f
12
20
15
15
14
24
R = NO2: 2a
Cl: 2b
CN: 2c
Br: 2d
OMe: 2e
H: 2f
96
90
97
84
98
97
2
R = NO2: 1a
Cl: 1b
11
13
R = NO2: 3a
Cl: 3b
91c
83c
3
4
14
98
16
92
5
6
22
21
93
99
7
8
9
12
18
15
70c
72
95
10
11
8
85d
86d
13
a Reaction conditions: aldehyde (1 mmol), ethyl acetoacetate (1 mmol) in L-(+)- tartaric acid–DMU melt (1.5 g) at 70 ◦C. b Isolated yield. c At 90 ◦C
in L-(+)- tartaric acid–urea melt. d Thiourea (2 mmol) was used in L-(+)- tartaric acid–choline chloride melt at 90 ◦C.
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Table 3 Synthesis of DHPMs from various carbonyl compoundsa
Table 4 Masked aldehydes as novel substrates for the Biginelli
reactiona
Entry Aldehydes
1
Time (h)
13
Product
Yieldb(%)
97
Entry Carbonyl compound Time (h) Product
Yield (%)b
83
1
13
2
3
15
16
94
87c
2
3
10
10
94
95
a Reaction conditions: masked aldehyde (1 mmol), ethyl◦acetoacetate
(1 mmol) in L-(+)-tartaric acid–DMU melt (1.5 g) at 70 C. b Isolated
yield. c Reaction was carried out at 90 ◦C by using L-(+)-tartaric acid–
urea melt.
Acknowledgements
SG thanks Dr Petra Hilgers for her help in the INDIGO
exchange programme. We thank CSIR and DST (New Delhi) for
financial support and DST-FIST (New Delhi) for NMR facility.
SG (SRF) thanks IIT Madras, INDIGO (Indian-German
exchange programme of the German Academic Exchange
Service, DAAD) and BASF for research fellowships. We thank
University of Regensburg for providing infrastructure facility.
4
5
8
97
70
48
Notes and references
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15 During the course of this study, two new melts have been iden-
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70 ◦C, whereas L-(+)-tartaric acid–urea (40 : 60) forms a melt at
90 ◦C.
16 Though chiral tartaric acid has been used as a melt component, the
DHPMs are obtained as racemates.
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