An efficient and high yielding protocol for the synthesis of substituted dihydropyrimidin-2(1H)-ones and spiro-fused heterocycles by involving tandem reactions

Article abstract of DOI:10.1002/jhet.5570440133

(Chemical Equation Presented) A simple and efficient method has been developed for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by a one-pot three component cyclocondensation reaction of alkyl acetoacetates, aldehyde, and urea in the presence of a cat

Full text of DOI:10.1002/jhet.5570440133

Jan-Feb 2007
211
An Efficient and High Yielding Protocol for the Synthesis of
Substituted Dihydropyrimidin-2(1H)-ones and Spiro-fused
Heterocycles by Involving Tandem Reactions
D Subhas Bose* and Mohd. Idrees
Organic Chemistry Division III, Fine Chemicals Laboratory
Indian Institute of Chemical Technology, Hyderabad 500 007, India.
E-mail: dsb@iict.res.in; bose_iict@yahoo.co.in; Fax: +91(040)-27160387
Received February 11, 2006
R
R
H
O
R2O2C
R1
H
X
R2O2C
R1
Zn(ClO4)2.6H2O
N
NH2
X
+
80°C, 20-60 min
80-95%
N
H
H2N
O
X = O, S
A simple and efficient method has been developed for the synthesis of 3,4-dihydropyrimidin-
2(1H)-ones by a one-pot three component cyclocondensation reaction of alkyl acetoacetates,
aldehyde, and urea in the presence of a catalytic amount of the reusable catalyst zinc per
chlorate hexahydrate, Zn(ClO4)2.6H2O (10 mol %) the scope of this protocol is utilized for the
synthesis of mitotic Kinesin EG5 inhibitor monastrol and new class of fused heterobicyclic
compounds in high yields.
J. Heterocyclic Chem., 44, 211 (2007).
The synthesis of complex natural products is
has been established that the activity of (±)-4g consists of
the specific and reversible inhibition of the motility of the
mitotic kinesin Eg5, a motor protein required for spindle
bipolarity.
traditionally carried out by a sequence of separate steps,
each of which requires its own conditions, catalyst,
reagents and solvent. After completion of each step, the
solvent and the waste products are removed and
discarded, and the intermediate product is separated and
purified. Economic and environmental considerations are
now forcing the chemical community to search for more
efficient ways of performing chemical transformations
[1]. These issues can be addressed by the development of
new synthetic methods that, by bringing together simple
components, can generate complex structures in one pot,
in much the same way as occurs in nature [2]. In this
context, the tandem transformations are of considerable
interest [3].
OH
O
O
NH
N
H
S
Monastrol
Figure 1
Dihydropyrimidines (DHPMs) have attracted consid-
erable attention in organic and medicinal chemistry as the
dihydropyrimidine scaffold displays a fascinating array of
pharmacological and therapeutic properties [4]. They have
emerged as integral backbones of several calcium channel
blockers, antihypersentive agents, ꢀ-1a-antagonists,
neuropeptide Y (NPY) antagonists [5] and HIV gp-120-
CD4 inhibitors activity in some marine natural products,
containing the DHPM skeleton, such as batzelladine
alkaloids [6]. The scope of this pharmacophore has been
further increased by the identification of the 4-(3-
hydroxyphenyl)-2-thione derivative (±)-4g called
monastrol [7], as a novel cell-permeable lead molecule for
the development of new anticancer drugs (Figure 1).
Monastrol (±)-4g has been identified as a compound that
specifically affects cell-division (mitosis) by a new
mechanism, which does not involve tubulin targeting. It
At present several general methods for the preparation
of DHPMs exist. The most well known approach is the
Biginelli reaction [8], in which aromatic aldehydes 1,
ureas 2 and alkyl acetoacetates 3 are condensed to
DHPMs. The classical Biginelli reaction proceeds under
relatively harsh conditions (EtOH, HCl, ꢁ) that are
detrimental to sensitive functional groups present in the
components used. Further, the use of aliphatic and o-
substituted aromatic aldehydes or thioureas as starting
materials affords the desired DHPMs in only moderate
yields (20-60%), particularly for substituted aromatic and
aliphatic aldehydes [9]. However, several improved
protocols have been reported involving combinations of
Lewis acids and transition metal salts, e.g. BF3.OEt2,
polyphosphate esters, and reagents like InCl3,
trimethylsilyltriflate, LaCl3.7H2O, CeCl3.7H2O, Yb(OTf)3,

212
D S. Bose and M. Idrees
Vol 44
clays, heterogeneous catalysts including various solid
phase modifications suitable for combinatorial chemistry
applications [10]. Unfortunately, these methods involve
expensive reagents, stoichiometric amount of catalysts,
long reaction times, strongly acidic conditions,
unsatisfactory yields, and incompatibility with other
functional groups. Therefore, the development of a neutral
alternative would extend the scope of the Biginelli
reaction.
To study the generality of this process, several
examples were studied and are summarized in Table 1.
Many of the pharmacologically relevant substitution
patterns on the aromatic ring could be introduced with
high efficiency. A variety of substituted aromatic,
aliphatic, and heterocyclic aldehydes carrying either
electron donating or – withdrawing substituents afforded
high yields of products in high purity. Acid sensitive
aldehydes such as furfural worked well without the
formation of any side products. Thiourea has been used
with similar success to provide the corresponding
dihydropyrimidine-(2H)-thiones, which are also of much
interest with regard to biological activity (eg., monastrol
4g, 90%) [8]. By using traditional conditions ethanol/HCl
turned out to be not compatible with the thiourea obtained
4g in much lower yield (17%) [12]. Thus, variations in all
three components have been accommodated very
comfortably. However, under the present reaction
conditions ꢀ-ketoaldehydes do not produce the
corresponding dihydropyrimidinones; instead they lead to
multiple products whose identities are yet to be
established. Furthermore, we investigated the reaction in
the case of cyclic ꢀ-diketones, p-methyl benzaldehyde and
urea under the experimental conditions (80°C/ethylene
glycol/90 min), and found interestingly that the formation
of spiro-fused heterobicyclic 5b system exclusively (75
%) instead of expected fused heterobicyclic 5a system
(Scheme 2).
Recently, Zn(ClO4)2.6H2O [11] has emerged as a
powerful catalyst in various chemical transformations
such as acylation of alcohols with anhydrides, and in the
conversion of ꢀ-keto esters into ꢀ-enamino esters. Since
Zn(ClO4)2.6H2O is inexpensive, stable to air and moisture,
it could represent a very attractive choice for other Lewis
acid-promoted transformations. Therefore we decided to
investigate its catalytic activity in a challenging Biginelli
condensation (Scheme 1). This method not only preserved
the simplicity of Biginelli’s one-pot condensation but also
remarkably improved the yields (>90%) of dihydro-
pyrimidinones in shorter reaction times (20-60 min) as
against the longer reaction times required for other
catalysts after the addition of a low catalyst concentration.
The procedure gives the products in good yields and
avoids problems associated with solvent use (cost,
handling, safety and pollution). Decreased reaction times
are also realized because of the increased reactivity of the
reactant in the solid state and the fact that the other
reaction product, water, evaporates at the reaction
temperature of 80°C. In order to improve the yields, we
performed reactions using different quantities of reagents.
The best results were obtained with a 0.1:1:1:1.5 ratio of
Zn(ClO4)2.6H2O, aldehyde, 1,3-dicarbonyl compound and
urea or thiourea. Higher amounts of Zn(ClO4)2.6H2O did
not improve the result to a greater extent. After
completion of the reaction, as indicated by TLC, the
reaction mixture was poured onto crushed ice from which
the dihydropyrimidinones were isolated by filtration and
recrystallized. The crude products obtained are of high
Scheme 2
CH3
O
O
O
H3C
CH3
NH
HN
NH
N
O
O
H
5a
5b
1
purity (>95% by H NMR). When the filtered solution
containing the zinc perchlorate catalyst was reused, only a
slight decrease in the yield from 95 to 87% as observed
after the third run (entry 2, Table 1). Another important
aspect of this procedure is the survival of a variety of
functional groups such as NO2, OH, OCH3, and a
conjugated C=C double bond under the reaction
conditions.
It is interesting to note that when ethyl trifluoroaceto-
acetate is used as the 1,3-dicarbonyl compound in this
synthesis, the hexahydropyrimidine (Scheme 3),
considered to be an intermediate in the Biginelli reaction,
was isolated in good yields (65-70%). This confirms the
1
earlier report by Kappe et al. [13] that in the H NMR
spectrum of 6b the doublets at ꢁ 3.12 and 4.81 with a
coupling constant of 11.0 Hz are assignable to the 4-H
and 5-H protons, which are trans to each other. The
isolation and characterization of this intermediate (6b)
assumes significance in terms of confirming the
mechanism of the reaction. It may be presumed that the
OH group at C-6 may be cis to 5-H, thereby the
elimination of water requires drastic conditions.
Scheme 1
R
R
H
X
R2O2C
R1
H
O
O
1
N
Zn(ClO4)2.6H2O
R2O2C
R1
NH2
+
80°C, 20-60 min
N
H
H2N
X
4a-o
2
3
X = O, S

Jan-Feb 2007
An Efficient and High Yielding Protocol for the
213
Synthesis of Substituted Dihydropyrimidin-2(1H)-ones
Table 1
Zn(ClO4)2.6H2O (10 mol%)-catalyzed synthesis of Dihydropyrimidinones under solvent-free conditions
Entry
R
R1
R2
Time
(min)
Product (4) [a]
Yield (%)[b]
X
CH3
Ph
CH3
CH3
O
O
30
20
45
60
20
20
4a
4b
4c
4d
4e
4e
90
1
C2H5
95, 90, 87[c]
4-(OCH3)-C6H4
4-N(CH3)2-C6H4
4-N(CH3)2-C6H4
2,4-(OCH3)2-C6H3
2,4-(OCH3)2-C6H3
3-(OCH3)-4-(OCH2-C CH)-C6H3
3-(OH)-C6H4
2
3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
O
S
88
4
5
CH3
86
CH3
O
O
S
95
6
CH3
90[d]
90
7
C2H5
C2H5
C(CH3)3
C2H5
50
25
35
30
4f
4g
4h
4i
8
S
90
9
3,4-(OCH3)2-C6H3
3,4-(OCH3)2-C6H3
C6H5-CH=CH
S
95
91
10
11
12
13
O
CH3
C2H5
45
O
4j
88
83
80
95
CH3CH2CH2
4k
4l
CH3
CH3
C2H5
C2H5
60
60
O
O
(CH3)2CH
3,4,5-(OCH3)3-C6H2
C(CH3)3
14
CH3
25
4m
O
15
16
CH3
CH3
C(CH3)3
C2H5
20
60
4n
4o
93
82
O
O
O
2-(NO2)-C6H4
[a]All products were characterized by 1H NMR, 13C NMR, IR and mass spectroscopy. [b]Isolated and unoptimized yields.
[c] catalyst was reused at least three times. [d]5 mol% catalyst was used.
filtration (water aspirator), washed with ice-cold water (10 mL)
and then recrystallized from hot ethanol to afford pure product
(0.58 g, 95%). The aqueous layer containing the catalyst could
be evaporated under reduced pressure to give a white solid. The
catalyst was recovered and reused in subsequent reactions, three
times without losing any significant activity (reaction yields
95%, 90% and 87%).
The known compounds have been identified by comparison of
spectral data and mp with those reported. The mp, spectral, and
analytical data of the new compounds have been presented
below in order of their entries.
In summary, we have developed a simple, convenient,
and one-pot atom economical synthesis of dihydro-
pyrimidine derivatives and
a
novel spiro-fused
heterocycle via the zinc perchlorate catalyzed three
component coupling of urea, alkylacetoacetate with
various aldehydes, involving tandem construction of C-N
and C-O bonds. Furthermore, the present procedure is
readily amenable to parallel synthesis and the generation
of combinatorial DHPMs libraries.
Selected data, 4f: mp 165-167°C; ir (KBr): 3310, 3180, 2900-
1
2600, 2120, 1680, 1651, 1570 cm-1; H nmr (300 MHz, CDCl3,
Scheme 3
R
TMS): ꢀ 1.09 (t, J = 7.5 Hz, 3H), 2.38 (s, 3H), 2.45 (s, 1H), 3.85
(s, 3H), 4.16 (q, J = 7.5 Hz, 2H), 4.74 (s, 2H), 5.38 (s, 1H), 5.22
(d, J = 3.5 Hz, 1H), 6.82 (s, 1H), 6.88 (d, J = 4.5 Hz, 1H), 7.62
(br s, N1-H), 8.10 (br s, N3-H). 13C nmr (75 MHz, CDCl3) ꢀ =
174.3, 165.3, 149.8, 146.8, 142.7, 136.5, 118.8, 114.5, 111.0,
103.0, 96.1, 75.9, 60.4, 56.8, 55.9, 55.6, 18.2, 14.1. fabms: 361
(M++1). Anal. Calcd for C18H20N2 O4S: C, 59.98; H, 5.59; N,
7.77. Found: C, 59.95; H, 5.57; N, 7.73.
R
H
H
O
1
EtOOC
HO
EtO2C
F3C
NH2
NH
Zn(ClO4)2.6H2O (10 mol%)
80°C, 2 h
+
H2N
N
O
O
O
3
2
F3C
H
6a: R = C6H5
6b: R =4-(OCH3)-C6H4
Selected data, 4g: mp 185-187°C; IR (KBr): 3300, 3180,
1
2900-2600, 1680, 1651, 1570 cm-1; H nmr (300 MHz, DMSO-
d6, TMS): ꢀ 1.10 (t, J = 7.5 Hz, 3H), 2.36 (s, 3H), 4.08 (q, J =
7.5 Hz, 2H), 5.22 (d, J = 3.5 Hz, 1H), 6.64-6.78 (m, 3H), 7.02-
7.15 (m, 1H), 8.90 (s, 1H, OH), 9.18 (br s, N1-H), 9.82 (br s,
N3-H). 13C nmr (75 MHz, DMSO-d6) ꢀ = 174.1, 165.3, 157.1,
144.4, 144.0, 129.0, 117.4, 113.6, 101.4, 111.0, 59.5, 54.7, 17.4,
13.8. eims: m/z (%) 292 (M+, 80), 263 (45), 219 (41), 199 (100),
171(35). Anal. Calcd for C14H16N2 O3S: C, 57.52; H, 5.52; N,
9.58. Found: C, 57.43; H, 5.55; N, 9.42.
EXPERIMENTAL
General Procedure for the Preparation of 3,4-
Dihydropyrimidin-2(1H)-ones. To mixture of 4-
a
methoxybenzaldehyde (272 mg, 2.0 mmol), urea (120 mg, 2.0
mmol), ethyl acetoacetate (260 mg, 2.0 mmol) was added
Zn(ClO4)2.6H2O (37.2 mg, 0.01 mmol) at 80°C. After being
stirred for 20 min. at the same temperature (monitored by TLC)
the resulting mixture was poured onto crushed ice (10 g) and
stirred for 5-10 min. The resulting solid was collected by suction
Selected data, 6b: mp 98-100°C; ir (KBr): 3420, 3105, 3045,
1
1600, 1520 cm-1; H nmr: (300 MHz, DMSO-d6, TMS): ꢀ 0.90
(t, J = 7.5 Hz, 3H), 3.12 (d, 1H, J = 11.0 Hz), 3.82 (s, 3H), 3.92-

214
D S. Bose and M. Idrees
Vol 44
[5a] K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly J. Schwartz, J.
Org. Chem., 54, 5898 (1989); [b] J. Barluenga, M. Tomas, A.
Ballesteros L. A. Lopez, Tetrahedron Lett., 30, 4573 (1989).
[6a] B. B. Snider, J. Chen, A. D. Patil, A. Freyer, Tetrehedron
Lett., 37, 6977 (1996); [b] A. D. Patil, N. V. Kumar, W. C. Kokke, M. F.
Bean, A. J. Freyer, C. De Brosse, S. Mail, A. Trunch, D. J. Fulkner, B.
Carte, A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W. Westley, B. C.
M. Ports, J. Org. Chem., 60, 1182 (1995).
4.03 (m, 2H), 4.81(d, 1H, J = 11.0 Hz), 5.35 (br s, 1H, NH), 5.58
(s, 1H, OH), 5.90 (br s, 1H, NH), 6.82-6.93 (m, 2H), 7.21-7.36
(m, 2H). 13C nmr (75 MHz, DMSO-d6) ꢀ = 167.0, 159.1, 153.8,
129.8, 128.6, 113.2, 111.8, 102.7, 95.5, 60.0, 54.6, 52.8, 50.2,
23.4, 13.3. eims: m/z (%) 362 (M+). Anal. Calcd for C15H17 F3N2
O5: C, 49.71; H, 4.70; N, 7.74. Found: C, 49.85; H, 4.63; N,
7.76.
Preparation of Spiro-fused Heterocyclic Compound (5b).
Zn(ClO4)2.6H2O (74.4 mg, 0.01 mmol) was added to a stirred
mixture of p-methylbenzaldehyde (480 mg, 2.0 mmol), urea
(240 mg, 2.0 mmol), 1,3-cyclohexanedione (448 mg, 2.0 mmol)
in ethyleneglycol (3mL) at 80°C. After being stirred for 60 min.
at the same temperature (monitored by TLC) the resulting
mixture was poured onto crushed ice (10 g) and stirred for 5-10
min. The resulting solid was collected under suction filtration
(water aspirator), washed with ice-cold water (10 mL) and then
recrystallized from ethanol/H2O to afford pure product (1.13 g,
75%). mp 188-190°C; ir (KBr): 3425, 2930, 1685, 1650, 1520,
[7a] D. R. Spring, Chem. Soc. Rev., 34, 472 (2005); [b] T. U.
Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, T. J.
Mitchison, Science, 286, 971 (1999).
[8] P. Biginelli, Gazz. Chim. Ital. 23, 360 (1893).
[9a] K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly, J. Schwartz, J.
Org. Chem., 54, 5898 (1989); [b] J. Barluenga, M. Tomas, A.
Ballesteros, L. A. Lopez, Tetrahedron Lett., 30, 4573 (1989).
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(1997); [c] E. H. Hu, D. R. Sidler U.-H. Dolling, J. Org. Chem., 63,
3454 (1998); [d] C. O. Kappe S. F. Falsone, Synlett, 718 (1998); [e] K.
Singh, J. Singh, P. K. Deb, H. Singh, Tetrahedron, 55, 12873 (1999); [f]
F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G. Sartori, Tetrahedron Lett.,
40, 3465 (1999); [g] J. Lu, H. R. Ma, Synlett, 63 (2000); [h] A. Dondoni,
A. Massi, Tetrahedron Lett., 42, 7975 (2001); [i] Y. N. Fu, Yuan, Z.
Cao, S. Wang, J. Wang, C. Peppe, Tetrahedron 58, 4801 (2002); [j] D.
S. Bose, L. Fatima, M. Hari Babu, J. Org. Chem., 68, 587 (2003); [k] J.
Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett., 41, 9075
(2000); [l] A. Dondoni, A. Massi, Tetrahedron Lett., 42, 7975 (2001);
[m] A. Dondoni, A. Massi, S. Sabbatini, Tetrahedron Lett., 43, 5913
(2002); [n] P. Salehi, M. Dabiri, M. A. Zolfogol, M. A. Bodaghi Fard,
Tetrahedron Lett., 44, 2880 (2003); [o] A. Shaabani, A. Bazgir, F.
Teimouri, Tetrahedron Lett., 44, 857 (2003); [p] A. K. Mitra, K.
Banerjee, Synlett, 1509 (2003); [q] D. S. Bose, M. Venu Chary, H. B.
Mereyala, Heterocycles, 68, 1217 (2006); [r] Gerard Jenner,
Tetrahedron Lett., 45, 6195 (2004); [s] D. S. Bose, R. K. Kumar, L.
Fatima, Synlett 279 (2004); [t] R. Zheng, X. Wang, H. Xu, J. Du,
Synth.Commun. 36, 1503 (2006) and references cited therein.
1
1200 cm-1; H nmr: (300 MHz, DMSO-d6, TMS): ꢀ 0.55 (t, J =
6.0 Hz, 2H), 1.55 (t, J = 6.2 Hz, 2H), 1.85 (t, J = 6.2 Hz, 2H),
2.22 (s, 6H), 5.10 (s, 2H), 6.85 (d, J = 7.5Hz, 4H), 7.15 (d, J =
7.5Hz, 4H). 13C nmr (75 MHz, DMSO-d6) ꢀ = 211.0, 206.5,
155.5, 139.0, 133.5, 131.0, 130.0, 128.6, 125.8, 67.2, 62.4, 43.7,
42.0, 22.5, 14.6. hrms Calcd for C23H24N2O3: 377.1860 [M+H]+;
found: 377.1858. Anal. Calcd for C23H24N2O3: C, 73.38; H,
6.43; N, 7.44. Found: C, 73.45; H, 6.39; N, 7.38.
Acknowledgment. One of the authors (M. I) thanks CSIR,
New Delhi for financial support.
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