First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction

Article abstract of DOI:10.1016/j.tet.2010.03.024

For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst in organic synthesis. A simple method of its preparation based on the reaction of aluminium triisopropoxide and tetrafluoroboric acid in isopropanol afforded

Full text of DOI:10.1016/j.tet.2010.03.024

Tetrahedron 66 (2010) 3463–3471
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Tetrahedron
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First application of hexaaquaaluminium(III) tetrafluoroborate as a mild,
recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and
efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones
by Biginelli reaction
a
,
a
a,
y
´
ˇ
ˇ
ˇ ´ a
´
*
Mladen Litvic , Ivana Vecenaj , Zrinka Mikuldas Ladisic , Marija Lovric
,
b
a,
*
´
´
Vladimir Vinkovic , Mirela Filipan-Litvic
a BELUPO Pharmaceuticals, Inc., R&D, Danica 5, 48 000 Koprivnica, Croatia
b
ˇ
ˇ
Institute RuCer Boskovi´c, Bijenicka c. 54, 10002 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst in
organic synthesis. A simple method of its preparation based on the reaction of aluminium triisoprop-
oxide and tetrafluoroboric acid in isopropanol afforded catalyst of high purity and activity. The three-
component Biginelli condensation of acetoacetate esters, urea and aldehydes catalyzed by 10 mol % of
[Al(H2O)6](BF4)3 in refluxing acetonitrile afforded 3,4-dihydropyrimidonones in good to high yields on
multigram scales. The tolerance to acid sensitive reactants such as thienyl and furyl carbaldehydes,
Received 12 November 2009
Received in revised form 18 February 2010
Accepted 8 March 2010
Available online 12 March 2010
Keywords:
3,4-Dihydropyrimidinone
Biginelli reaction
Heterocycles
Condensation
applicability to sterically hindered b-ketoesters and simple recyclability without losing catalytic activity
make this catalyst as good replacement to literature methods. The mechanism of the reaction includes
formation of the so called ‘ureido-crotonate’ rather than corresponding acylimino intermediate as found
with Brønsted type catalysts.
Ó 2010 Elsevier Ltd. All rights reserved.
Hexaaquaaluminium(III) tetrafluoroborate
1. Introduction
for the biosynthesis of cholesterol. Moreover, the 3,4-DHPM motif is
present in many products isolated from natural material such as
The Biginelli reaction1 is a well-known, simple and straightfor-
ward procedure for the synthesis of 3,4-dihydropyrimidinones (3,4-
DHPMs) by the three-component condensation of an aliphatic or
several species of sponges. The representatives such as batzella-
dines, ptilomycalines and crambescidines10 (Fig. 1) exhibit many
biological activities such as anticancer, antifungal, anti HIV etc.
During the last few years, numerous catalytic methods have
been developed in order to improve the reaction yield or the scope
of the Biginelli reaction. A recent review article shows the interest
of the synthetic chemists in order to find better and more selective
catalysts for Biginelli 3,4-DHPM synthesis.11 Most of the methods
are based on employing Brønsted or Lewis acid type catalysts.12–29
Probably the most effective methods involve the reagent(s), which
are stoichiometric dehydrating agents in the presence of protic or
Lewis acids: ethyl polyphosphate,30 TMSCl,31 TMSCl/NaI,32 FeCl3/
Si(OEt)4,33 etc. However these methods suffer from cumbersome
work-up of the reaction mixture and production of water waste and
thus are suitable for the synthesis only on a small scale. In the
recent years, catalysts, which are recyclable and capable of per-
forming the reaction under mild condition have gained particular
attention.11,22,34,35 Those characteristics of the catalyst are essential
in the case of the enantioselective version of Biginelli reaction.36
From that point there is still need to find catalyst, which are
capable to perform reaction under milder reaction conditions.
aromatic aldehyde, b-ketoester and a urea. The original reactionwas
first reported by Pietro Biginelli in 18932 and was catalysed by
mineral acids. This simple procedure has been successful in
a
number of Biginelli reactions involving substrates lacking
sterically-demanded groups. By the three-component Biginelli
condensation many 3,4-DHPMs have been synthesized to exhibit
variety of pharmacological activity such as calcium channel mod-
ulation,3 mitotic kinesin Eg5 inhibition (monastrol, Fig. 1),4 antivi-
ral,5 antibacterial and antifungal activity,6 anticancer7 (MAL3-101,
Fig. 1) etc.8 3,4-DHPMs are also used as starting material for the
synthesis of so called ‘superstatin’ rosuvastatin selective and com-
petitive inhibitor of HMG-CoA reductase,9 the enzyme responsible
* Corresponding authors. Tel.: þ385 48 65 24 57; fax: þ385 48 65 28 94; e-mail
´
addresses: mladen.litvic@belupo.hr (M. Litvic), mirela.filipan-litvic@belupo.hr
´
(M. Filipan-Litvic).
y
Present address: GlaxoSmithKline research center Zagreb d.o.o., Prilaz Baruna
´
Filipovica 29, 10000 Zagreb, Croatia.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.024

3464
M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
F
OH
OH OH
COO-
Ca2+
N
O
O
H
CO2Et
S
N
H3C
N
N
CH3
S
N
H
CH3
2
Monastrol
Rosuvastatin calcium
H
H
CO2
N+
N
H
N
H
O
O
CO2Bn
Ac
HN
H2N
O
CO2Me
O
N
N
N
H2N
O
O
O
N
H
MAL3-101
(–)-Ptilomycalin A
Figure 1.
Despite the plethora of different catalysts published so far and
proved to be an efficient in Biginelli reaction the synthetic chemists
may encounter the problem in finding the right one if reaction
should be performed on larger scale. Moreover, most of them are
exotic, expensive, complex, unavailable, harmful and sometimes
ineffective in reaction with more complex reactants. Therefore,
development of more selective and greener methods employing
recyclable catalysts in Biginelli 3,4-DHPM synthesis is still
demanded.
Biginelli reaction. That encouraged us to find appropriate alterna-
tive to mentioned aluminium salt equally efficient but more water
tolerant and recyclable.
One of the best alternative to aluminium halides is water tolerant
and recyclable aluminium triflate (Al(OTf)3), which has found its use
as a catalyst for acetal formation,41 ring opening of epoxides by
alcohols,42 synthesis of diethyl-1-aminophosphonates,43 etc.44 To the
best of our knowledge Al(OTf)3 has not been used as a catalyst in
Biginelli 3,4-DHPM synthesis although it is expected to be at least
equally active as other metallic triflates employed in the same
reaction.11,22,34,35 However, Al(OTf)3 is not easily available and thus
not appropriate as catalyst candidate for multigram scale synthesis of
3,4-DHPMs.45 A much less expensive alternative to Al(OTf)3 is the
corresponding tetrafluoroborate salt. Literature survey revealed that
aluminium tetrafluoroborate has been used as heterogenous cata-
lyst46 (impregnated to aluminosilicates or Al2O3) for isomerization of
tricyclic naphthenes into adamantanes,47 dealkylation of alkylphe-
nols48 or alkylaromatics49 and recentlyas an additive inproduction of
nonaqueous electrolyte batteries.50 To our surprise aluminium tet-
rafluoroborate has not been prepared in pure form without a solid
carrierandnotusedsofarinclassicalorganicsynthesis.Inordertotest
it in Biginelli reaction a few grams of catalyst was needed. The liter-
ature method of preparation was not convenient due to the difficult
evaporation of the aqueous solution obtained by the treatment of
Al(OH)3 and boric acid inwater with hydrofluoric acid.47,48a Therefore
we developed new simple and practical method for preparation of
pure [Al(H2O)6](BF4)3 according to Scheme 1.
2. Results and discussion
In continuation of our research on chemistry of 3,4-DHPMs we
required multigram scale samples as a starting material for the
study of their aromatization to the corresponding pyrimidines
(similarly to chemistry of Hantzsch 1,4-dihydropyridines37,38).
From our previous experience12,33 we have found Lewis acids
superior over Brønsted acids due to better selectivity and higher
yields of the products. Thus we were guided to choose one suitable
from the literature available on large scale, nonexpensive and
recyclable. Interestingly, not many of them fulfilled the above
35
34
requirements. Metallic triflates such as Cu(OTf)2 Zn(OTf)2 and
Yb(OTf)3
22
as very efficient easily recyclable catalysts are not
available in multigram quantities. Other, although readily available
as laboratory chemicals such as NiCl2$6H2O,13 FeCl3$6H2O,13
CuCl2$2H2O,14 CeCl3$7H2O,15 Mn(OAc)3$2H2O16 are not easily
recyclable and thus not appropriate for our study. From basic
organic synthesis it is known that aluminium halides such as AlCl3
and AlBr3 act as a strong Lewis acid catalyst in many organic
transformations such as Friedel–Crafts acylations39 and alkylations,
rearrangements etc. A literature survey revealed that AlCl3,40
1.
i
-PrOH, rt
[Al(H O) ](BF )
4 3
Al(Oi-Pr)3 + 3HBF4 (50% aq)
2
6
2. evaporation
40
21
AlBr3 and Al(HSO4)3 have already been used as a catalysts in
Scheme 1.

M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
3465
Table 1
By the treatment of commercial aluminium triisopropoxide
dissolved in isopropanol at room temperature with stoichiometric
amount of tetrafluoroboric acid (48% in water), evaporation of
solvent and drying under vacuum, pure [Al(H2O)6](BF4)3 was pre-
pared on 0.1 mol scale. The analysis of water content on dry catalyst
by the Karl–Fisher method revealed that corresponding hexahy-
drate is obtained ([Al(H2O)6](BF4)3). The catalyst is non-hygroscopic
and stable for a period of several months at room temperature.
According to X-ray diffraction data (XRD) the [Al(H2O)6](BF4)3 is
mainly amorphous substance characterized by the presence of
broad background signal as depicted from Figure 2.51 The re-
crystallization of [Al(H2O)6](BF4)3 (‘hexahydrate’) from water
Catalyst effect (10 mol %) in the model Biginelli reaction (Scheme 1) on the yield of
model 3,4-DHPM 3a (10 mmol scale). Comparative study with literature catalysts
Entry
Catalyst
Reaction timea
Yieldb (%)
Ref.
1
2
3
4
5
6
7
8
AlCl3$6H2O
Al2SO4$16H2O
AlCl3
[Al(H2O)6](BF4)3
NiCl2$6H2O
CeCl3$7H2O
ZnCl2
24
24
20
20
20
20
20
20
16
24
24
18
24
48
34
64
81
73
64
52
60
71
69
70
73
71
d
d
38
This article
13
15
19
55
14
14
16
d
ZnI2
9
CuCl2$2H2O
CuSO4$5H2O
Mn(OAc)3$2H2O
FeCl3
10
11
12
13
afforded
a literature new salt [Al(H2O)6](BF4)3$3H2O (‘non-
ahydrate’) with presumably similar structure as corresponding
hexaaquaaluminium(III) bromate trihydrate.52 The FT-IR spectra of
[Al(H2O)6](BF4)3 is characterized by the presence of strong water-
stretching region (3200–3600 cmꢀ1) and low intensive bands at
1060 and 530 cmꢀ1 characteristic for BFꢀ4 anion.53
FeCl3$6H2O
13
a
Determined by TLC analysis.
Isolated yield.
b
Next, we wanted to test the effect of the solvent on the reaction
in order to find the optimal reaction condition. As presented in
Table 2, acetonitrile emerged as the most convenient (entry 3)
although in toluene the yield of 3a (77%) is also high (entry 1). This
is probably due to much higher boiling point of toluene (111 ꢁC)
compared to acetonitrile (82 ꢁC).
Table 2
The influence of the solvent on the yield of model 3,4-DHPM 3a
Entry
Solvent
Time
Yieldc (%)
1
2
3
4
5
Toluenea
EtOHa
24
24
20
48
24
77
64
81
53
61
CH3CNa
THFa
b
–
a
Reflux temperature.
100 ꢁC, solventless media.
Isolated yield.
b
c
Figure 2. XRD pattern of [Al(H2O)6](BF4)3.
Interestingly, the reaction performed under solventless media at
100 ꢁC during 24 h (Table 2, entry 5) afforded product 3a in only
61% yield. It seems that coordination of solvent at coordination
sphere of cation determines the activity of catalyst, thereby
improving the yield of the product. Finally, the last parameter
needed to improve the reaction condition was the influence of the
amount of the catalyst on the yield of 3a, Table 3. The model
reaction without a catalyst during 48 h at reflux in acetonitrile gives
by TLC analysis only traces of the product (Table 3, entry 1). The
incremental amount of catalyst from 1 to 50 mol % increases
the conversion and yield of the product, (with shortening of the
reaction times) from 32 to almost quantitative (Table 3, entries
2–5). However, 10 mol % of catalyst has been choosen for further
studies because of satisfactory yield of the product (81%) in rea-
sonably short time (‘reflux overnight‘). Moreover, the isolation of
the product in case if reaction is carried out with 50 mol % of cat-
alyst is somehow difficult due to coprecipitation of the catalyst and
product.
The thus obtained catalyst has been tested in the three-com-
ponent condensation of benzaldehyde (1a), methyl-acetoacetate
(2a) and urea in acetonitrile at reflux temperature according to
Scheme 2.54
CO2Me
CH3
H
O
CO2Me
catalyst
O
N
+
+
H2N
NH2
MeCN / Δ / 20 h / 81%
O
N
H
CH3
CHO
3a
1a
2a
Scheme 2.
After carrying out the reaction during 20 h and work-up of re-
action mixture the product 3a was isolated in 81% yield on
a 10 mmol scale. For the comparison the same reaction has been
performed with 16 different catalysts and the obtained results are
outlined in Table 1. According to the obtained results
[Al(H2O)6](BF4)3 is not only superior over other aluminium salts
(Table 1, entries 1–3) but also to all other tested catalysts from the
literature such as CeCl3$7H2O, ZnCl2, CuCl2$2H2O, FeCl3$6H2O etc.
(Table 1, entries 5–13). The obtained results suggest that the non-
coordinating counter ion BFꢀ4 plays an important role in activity
of [Al(H2O)6](BF4)3 presumably by increasing acidity of
[Al(H2O)6]3þ cation.
Table 3
The influence of the amount of catalyst [Al(H2O)6](BF4)3 on the synthesis of model
3,4-DHPM 3a
a
Entry
[Al(H2O)6](BF4)3 (mol %)
Timea [h]
Yieldb (%)
1
2
3
4
5
No catalyst
1
5
10
50
48
48
24
20
19
Traces of the product
32
58
81
98
a
Determined by TLC analysis.
Isolated yield.
b

3466
M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
With optimized conditions in hand we decided to explore the
acetoacetate (2c), m-chlorobenzaldehyde (1k) and urea were con-
densed in Biginelli reaction to give 3k, Table 5. This feature provides
a significant benefit (environmental and cost) over traditional
Lewis and Brønsted acids.
In order to provide a reasonable explanation of obtained results
(tolerance to variety of substituted reactants) we performed a few
experiments regarding determination of possible mechanistic
pathways of the reaction.
scope and limitations of this method. Thus, series of Biginelli
3,4-DHPMs with significant steric, electron withdrawing and do-
nating substituents, were synthesized and the obtained results are
summarized in Table 4. While preliminary investigation (including
optimization) has been performed on 10 mmol scale all preparative
experiments were conducted on 200 mmol scale affording 40–50 g
of the products depending on the molecular weights.
Table 4
Three component synthesis of substituted 3,4-DHPMs 3a–q catalyzed by [Al(H2O)6](BF4)3 (10 mol %) in acetonitrile at reflux temperature
R
CO2R1
O
H
O
CO2R1
R2
R
10 mol% [Al(H O) ](BF )
4 3
2
6
N
+
+
H2N
NH2
H
O
MeCN / Δ
O
R2
N
H
1a-1n
3a-3q
2a-2g
Entry
3,4-DHPM
R
R1; R2
t (h)
Yield (%)a,b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
Ph
p-FC6H4
2,4-(CH3)2C6H4
o-OC2H5C6H4
2-Furyl
2-Thienyl
2-(5-Br-thienyl)
p-ClC6H4
2-Thienyl
o-ClC6H4
Me; Me
Me; Me
Me; Me
Me; Me
Me; Me
Me; Me
Me; Me
Me; i-Pr
Me; i-Pr
Et; Me
Et; Me
Et; Me
Et; Me
Et; n-Pr
Et; Ph
20
22
18
20
22
20
20
21
20
20
20
21
20
24
24
20
21
85
84
93
92
83 (92)c
80 (89)c
87
81
9
83 (90)c
88
10
11
12
13
14
15
16
17
m-ClC6H4
p-ClC6H4
p-NO2C6H4
Ph
95
81
85
81
80
83
82
Ph
p-OCH3C6H4
p-CH3C6H4
i-Pr; Me
CH2Ph; Me
a
Isolated yield.
b
c
All products were characterized by 1H NMR, 13C NMR, IR and MS spectra. Literature known compounds were compared with authentic samples.
Yield obtained with freshly distilled aldehyde.
The main characteristics of the reaction are good to excellent
yields (80–95%) of the products obtained after simple work-up,
ability to tolerate the variation in all the two components
Table 5
[Al(H2O)6](BF4)3 recycling experiments on Biginelli 3k synthesis
Runa
Yieldb (%)
(b-ketoesters and aldehydes), reuse of the catalyst without loosing
1
2
3
4
95
94
93
93
of activity and most of all possibility of scale-up of reaction in order
to prepare the products on multigram amounts. Both electronic
withdrawing (F, Cl, NO2) and donating substituents (CH3, OCH3) on
the aldehyde reactant are well tolerated in reaction without
significant impact on the yield of the product. Moreover, acid
sensitive aldehydes such as thienyl (1f), 5-bromothienyl (1g) and
furyl carbaldehydes (1e) furnished products in yields of 80%, 87%
and 83%, respectively. Interestingly, freshly distilled 1e and 1f used
in reaction have shown an improvement in yield of the products for
almost 10% (Table 4, entries 5, 6 and 9). However, this was not the
case for other usually stable aldehydes used in reaction. Most
importantly, the reaction with sterically hindered methyl iso-
butyrylacetate (entries 8 and 9), ethyl butyrylacetate (entry 14) and
ethyl benzoylacetate (entry 15) proceeded unexpectedly well and
the valuable literature unknown products usually prepared with
difficulty were isolated in excellent yield (>80%). As mentioned
above, the catalyst as well as the excess of urea are easily recycled
by extraction of residue obtained after evaporation of ethanolic
mother liquor (see Experimental Section) with hot water and
evaporation of thus formed catalyst solution. The recycled catalyst
was used over four times without loss of activity when ethyl-
a
The yield of isolated mixture of catalyst and unreacted urea is about 95% after
each run.
b
Isolated yield of 3k on 10 mmol scale.
According to the literature three possible mechanisms are pro-
posed but generally accepted Biginelli reaction mechanism in-
cludes the acid-catalysed formation of C]N bond from the
benzaldehyde (1a) and urea, followed by addition of b-ketoester 2a
to the arylidene–urea 4 and cyclodehydration of intermediates
yielding dihydropyrimidinone 3a (Scheme 3, pathway A).56–58
However, this mechanism is probably characteristic only for
protic acids but not for other types of acid catalysts including me-
tallic salts. This conclusion comes from our results obtained with
SbCl3-catalysed synthesis of 3,4-DHPMs where pathway
C
(Scheme 3) is dominant to yield the product12 while other two
(pathway A and B) surprisingly do not participate in reaction at all.
In order to clarify the role of [Al(H2O)6](BF4)3 three separated

M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
3467
[Al(H2O)6]3+
[Al(OH)(H2O)5]2+ + H+
Scheme 4.
CO2Me
O
C
O
CH3
H2N
NH2
CHO
CHO
1a
2a
1a
In order to determine whether the [Al(H2O)6](BF4)3 acts as
a Lewis or Brønsted acid catalyst (or both) a series of experiments
were carried out employing glacial acetic acid (Brønsted acid) and
anhydrous AlCl3 (Lewis acid) as a catalysts. The reactions were
performed under the same reaction condition as outlined in
Scheme 3. As expected, none of the catalysts was capable of
performing the reaction between benzaldehyde (1a) and methyl
acetoacetate (2a) to give 5 (pathway B). The condensation of urea
and methyl acetoacetate (2a) catalysed by 10 mol % of glacial acetic
acid did not undergo formation of 6, which is in accordance to
literature results for this type of reaction.58 Interestingly, the con-
densation of urea and benzaldehyde (1a) even after 48 h at reflux in
acetonitrile furnished only a traces of condensation product 4,
presumably as corresponding ‘bisureide’58 obtained by addition of
second molecule of urea to 4. As already mentioned
[Al(H2O)6](BF4)3 with similar pKa value as the acetic acid reached
almost 10% conversion in the same reaction. Therefore, along with
an activity as a Brønsted acid (proton donor) the coordination of the
reactants on a coordination sphere of aluminium (Lewis acid
activity) should not be neglected. The condensation of urea and
methyl acetoacetate (2a) catalysed by 10 mol % of anhydrous AlCl3
in acetonitrile at room temperature afforded 6 in 80% yield whereas
urea and benzaldehyde (1a) did not react under the same reaction
condition. If the latter reaction was carried out at reflux tempera-
ture roughly 15% conversion was reached, probably by the action of
HCl released by decomposition of the catalyst with water formed in
reaction. According to obtained results the pathway A (Scheme 3) is
characteristic for the Brønsted type of catalysts whereas Lewis acid
type of catalysts follow the pathway C (ureido-crotonate mecha-
nism). Although without a free orbital (main characteristic of
a Lewis acid) the aluminium in [Al(H2O)6](BF4)3 similarly to anhy-
drous AlCl3 efficiently catalyzed reaction of urea and methyl
acetoacetate (2a) to give 6 in high yield (Scheme 3, path C).
To explain this observation the substitution of water molecules in
coordination spheres of aluminium is required to allow satisfactory
activity of the catalyst. Recently, Katakura and co-workers have
published the one-step synthesis of aluminium(III) acetylacetonate
from mineral Boehmite ([AlO(OH)]n) and acetylacetone in water at
room temperature.61 They have shown how by simple mixing of
reactants substitution of ligands such as hydroxide ions and oxygen
bridges in mineral are replaced by organic bidentate ligand at mild
reaction condition. We believe that substitution of two water
i
i
Pathway A
Pathway B
CO2Me
CH3
N
C
O
NH2
O
2a
urea
H
CO2Me
CH3
5
4
N
O
N
H
3a
1a
CO2Me
CH3
NH2
C
N
O
H
6
Pathway C
i
CO2Me
CH3
O
C
H2N
NH2
O
2a
i: 10 mol% [Al(H2O)6](BF4)3 / MeCN / reflux
Scheme 3.
reactions were conducted (Scheme 3, pathways A–C) under the
optimized reaction condition (10 mol % of [Al(H2O)6](BF4)3 at reflux
temperature during 24 h).
The prolonged heating of benzaldehyde (1a) and methyl ace-
toacetate (2a) did not undergo the expected reaction (pathway C)
to yield a mixture (E/Z) of Knoevenagel products (5). The reaction
of benzaldehyde (1a) and urea furnished only a trace (conversion
<10%) of the arylidene–urea 4 (pathway A) whereas the conden-
sation of methyl acetoacetate (2a) and urea smoothly furnished
N-(1-ethoxycarbonyl-propen-2-yl)urea (6), which upon addition
of benzaldehyde (1a) was easily converted to dihydropyr-
imidinone 3a (Scheme 3, pathway C). The isolation of intermediate
6 is possible by the chromatographic method described in our
previous article.12 These findings clearly indicate that Biginelli
reaction catalysed by [Al(H2O)6](BF4)3 proceeds predominately
through ureido-crotonate intermediate 6 (pathway C), which
somewhat supports prediction that Biginelli reaction catalysed by
other types of acid catalysts such as metallic salts does not include
formation of arylidene–urea 4 as in Brønsted type catalysis.58
According to these results [Al(H2O)6](BF4)3 acts as a Lewis acid
in reaction. Furthermore, this is also supported by the fact that
ureido-crotonate intermediate 6 in Biginelli reaction catalysed by
Brønsted type catalysts is regarded as unlikely.58 Despite this ob-
servation, it is well-known from the literature that the
[Al(H2O)6]3þ cation in water solution acts as a weak proton donor
(pKa¼4.97),59 of comparable acidity to acetic acid (pKa¼4.76).60
The dissociation of [Al(H2O)6]3þ cation and possible action of
a catalyst as Brønsted acid is presented in Scheme 4.
molecules in [Al(H2O)6](BF4)3 by b-ketoester is even more facili-
tated at elevated temperature (reflux of acetonitrile).
As a result of a detailed experimental mechanistic investigation
plausible simplified mechanism of [Al(H2O)6](BF4)3-catalysed
Biginelli 3,4-DHPM synthesis is proposed to include activation of
reactants by the dual action of the catalyst (Lewis and Brønsted
acid) according to Scheme 5.
The presented mechanism on 3,4-DHPM 3j having sterically-
demanded groups is used to explain low sensitivity of reaction to
electronic and sterical nature of substituents (Table 4). The catalytic
cycle begins with a complexation of methyl isobutyrylacetate 2b
and urea on a catalyst to form 7 with elimination of three water
molecules and HBF4. The formation of more stable complex
between catalyst and methyl isobutyrylacetate 2b (bidentate
ligand) than with aldehyde 1j (monodentate ligand) allows intra-
molecular nucleophilic attack (Michael addition) of urea to acti-
vated C]C double bond followed by tautomerisation and
elimination of HBF4 to give a complexed hemiaminal 8. The intra-
molecular tautomerization and elimination of water produce so

3468
M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
vacuum degasser SCM 1000, quaternary gradient pump P 4000,
autosempler AS 3000, scanning UV/vis detector UV 3000 HR and
ChromQuest 251 software. Elemental analyses were done in Central
ˇ
´
Analytical Service (CAS) at RuCer Boskovic Institute. Karl–Fischer
analysis was performed on Karl–Fischer Titrator Mettler Toledo
DL31. HPLC MS analysis was performed on HPLC Waters Alliance
2795 with PDA detector Waters 996 (210–350 nm) and MS detector
Micromass ZMD 4000 (ESI 3.50 kV). Powder X-ray data (XRD) were
collected on Philips PW 3710 diffractometer, Cu Ka1 radiation, flat
plate sample on a zero background in Bragg-Brentano geometry,
tension 40 kV, current 40 mA. The literature known products were
characterized by a comparison with authentic samples (melting
point) and their NMR (1H, 13C), MS and IR spectra.22,34,62–71
4.2. Preparation of [Al(H2O)6](BF4)3
To a solution of aluminium triisopropoxide (20.4 g, 0.1 mol) in
i-PrOH (240 mL), a commercial water solution of HBF4 (39.2 mL,
0.3 mol, 48% in water) was added dropwise at room temperature
during 30 min. The resulting solution after stiring at room tem-
perature during 2 h was evaporated off to give gelatinous mass,
which was slowly dried at 50 ꢁC under vacuum during 24 h and
additionally at 80 ꢁC for 24 h to furnish [Al(H2O)6](BF4)3 as a white
powder in almost quantitative yield (39 g), mp 100 ꢁC (decomp.);
[Found: H, 3.1. AlB3F12H12O6 requires Al, 6.82; B, 8.20; F, 57.65; H,
3.06%]; nmax(KBr) 3431, 3249, 1637, 1477, 1305, 1300, 1194, 1083,
1069, 1063, 1040, 884, 771, 650, 534, 522.
Scheme 5.
called ‘ureido-crotonate’ 9 in a complex with catalyst. The increased
nucleophilicity of the carbon from the enamine group facilitates the
addition to protonated thienyl carbaldehyde 1j to form in-
termediate 10, which with subsequent cyclodehydration yields
product 3j. The rate determining step of reaction is addition of urea
to 2b accelerated by chelation with aluminium cation, Scheme 5.
The reaction with aldehyde 1j is facilitated by the precomplex-
ation to 9 and/or protonation of carbonyl group by the action of
HBF4 released during the catalytical cycle. Therefore the reaction
with aldehydes having both electron donating and withdrawing
4.3. General procedure for synthesis of 3,4-DHPMs
To a solution of corresponding aldehyde 1a–n (0.2 mol, 1 equiv)
in the acetonitrile (250 mL) urea (18.02 g, 0.3 mol, 1.5 equiv),
substituents gives similar results in reaction. As
a result
b-ketoesters 2a–g (0.2 mol, 1 equiv) and catalyst [Al(H2O)6](BF4)3
[Al(H2O)6](BF4)3 primarly acts as a Lewis acid catalyst in reaction
but its Brønsted acid behaviour is particularly important during the
activation of aldehyde component by protonation during catalytical
cycle.
(10 mol %, 7.91 g) were added at once. The reaction mixture was
stirred at reflux temperature for the time indicated in Table 4. After
that acetonitrile was evaporated and the solid residue was recrys-
tallized from hot 96% ethanol. The thus obtained product was
filtered and dried in vacuum to constant weight to afford products
3a–q of purities >99% (HPLC). Analytical results (IR, 1H, 13C NMR)
of known products were identical to those reported in litera-
ture.22,34,62–71
3. Conclusion
In conclusion, [Al(H2O)6](BF4)3 in an amount of 10 mol % has
shown to be an excellent acid catalyst for one pot synthesis of
3,4-dihydropyrimidinones on multigram scales in good to high
yields. The tolerance to acid sensitive reactants such as thienyl and
4.3.1. 5-Methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one 3a. White needles (41.9 g, 85%); mp 208.0–210.0 ꢁC (lit.
Mp 208–210 ꢁC62); [Found: C, 63.3; H, 5.7; N, 11.3. C13H14N2O3
requires C, 63.40; H, 5.73; N, 11.38%]; Rf (10% MeOH/CH2Cl2) 0.46;
furyl carbaldehydes, applicability to sterically hindered b-ketoest-
ers and simple recyclability without losing catalytic activity making
a catalyst as valuable addition to existing methods. The mechanism
of the reaction includes formation of the so called ‘ureido-croto-
nate’ rather than corresponding acylimino intermediate as typical
for Brønsted type catalysts. Further work is in progress to explore
the catalytical activity of [Al(H2O)6](BF4)3 to other organic trans-
formations such as Friedel–Crafts acylations, synthesis of other
heterocyclic systems, rearrangements, etc.
nmax(KBr) 3246, 1732, 1664 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.19
(s, 3H, CH3), 3.87 (s, 3H, –COOCH3), 5.02 (d, 1H, J¼2.07 –CH), 7.25
(m, 5H, arom.), 7.64 (s, 1H, NH), 9.15 (s, 1H, NH); m/z 247 (MHþ).
4.3.2. 5-Methoxycarbonyl-6-methyl-4-(4-fluorophenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3b. White needles (44.4 g, 84%); mp
191.0–193.0 ꢁC (lit. Mp 192–194 ꢁC;22 193–194 ꢁC63); [Found: C,
59.2; H, 4.8; F, 7.1; N, 10.7. C13H13FN2O3 requires C, 59.09; H, 4.96; F,
7.19; N, 10.60%]; Rf (10% MeOH/CH2Cl2) 0.48; nmax (KBr) 3328, 3230,
3109, 2953, 1668, 1509, 1437, 1414, 1343, 1300, 1276, 1240, 1190,
4. Experimental
4.1. General
1159, 1120, 1095, 1039, 1016 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.26
(3H, s, CH3), 3.53 (3H, s, OCH3), 5.17 (1H, d, J¼2.8, CH), 7.14 (2H, t,
J¼8.7, arom.), 7.25–7.30 (2H, m, arom.), 7.81 (1H, br s, NH), 9.32 (1H,
s, NH); m/z 265 (MHþ).
All IR spectra were recorded on a Perkin-Elmer Spectrum One
spectrophotometer. 1H and 13C NMR spectra were recorded on a AV
Bruker (600 MHz) spectrometer, and shifts are given in ppm
downfield from TMS as an internal standard. TLC analyses were
performed on Merck’s (Darmstadt, Germany) DC-alufolien with
Kieselgel 60F254. Melting points were determined using a Bu¨chi
B-540 instrument. HPLC analyses were performed with a Thermo
Separation Products (San Jose, USA) instrument equipped with
4.3.3. 5-Methoxycarbonyl-6-methyl-4-(2,4-dimethylphenyl)-3,4-di-
hydropyrimidin-2(1H)-one 3c. Pale yellow needles (51.1 g, 93%); mp
245.0–247.0 ꢁC; [Found: C, 65.8; H, 6.4; N, 10.1. C15H18N2O3 requires
C, 65.68; H, 6.61; N, 10.21%] Rf (10% MeOH/CH2Cl2) 0.44; nmax (KBr)
3370, 3220, 3102, 2947, 1701, 1646, 1500, 1456, 1432, 1367, 1321,

M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
3469
1300, 1223, 1187, 1165, 1118, 1095 cmꢀ1
;
dH (600 MHz, DMSO-d6)
165.7, 157.1, 152.2, 143.5, 131.9, 128.5, 128.1, 97.6, 53.1, 51.0, 27.1, 19.2,
2.22 (3H, s, CH3), 2.29 (3H, s, CH3), 2.37 (3H, s, CH3), 3.45 (3H, s,
OCH3), 5.37 (1H, s, CH), 6.93–6.97 (2H, m, arom.), 7.07 (1H, d, J¼7.7,
arom.), 7.63 (1H, s, NH), 9.22 (1H, s, NH); dC (600 MHz, DMSO-d6)
165.83, 151.83, 148.39, 140.34, 136.26, 134.53, 130.86, 127.13, 126.55,
99.27, 50.75, 50.17, 20.61, 18.62, 17.78; m/z 275 (MHþ), 200, 183.
19.0; m/z 309 (MHþ), 266, 234.
4.3.9. 5-Methoxycarbonyl-6-isopropyl-4-(2-thienyl)-3,4-dihydropyr-
imidin-2(1H)-one 3i. Pale yellow needles (46.5 g, 83%); mp 235.0–
237.0 ꢁC; [Found: C, 55.8; H, 5.6; N, 9.8; S, 11.2. C13H16N2O3S
requires C, 55.70; H, 5.75; N, 9.99; S, 11.44%]; Rf (10% MeOH/CH2Cl2)
0.56; nmax (KBr) 3467, 3280, 3112, 2961, 1683, 1626, 1526, 1448,
1434, 1409, 1370,1344, 1312, 1278, 1233,1221, 1192, 1174,1138, 1122,
4.3.4. 5-Methoxycarbonyl-6-methyl-4-(2-ethoxyphenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3d. White powder (53.4 g, 92%); mp
237.0–239.0 ꢁC (lit. Mp not reported64); [Found: C, 62.2; H, 6.2; N,
9.7. C15H18N2O4 requires C, 62.06; H, 6.25; N, 9.65%]; Rf (10% MeOH/
CH2Cl2) 0.54; nmax (KBr) 3371, 3237, 3106, 2974, 2949, 1699, 1643,
1598, 1586, 1494, 1473, 1432, 1395, 1377, 1349, 1324, 1306, 1268,
1098, 1031 cmꢀ1
;
dH (600 MHz, DMSO-d6) 1.10 (3H, d, J¼2.3, CH3),
1.13 (3H, d, J¼2.4, CH3), 3.59 (3H, s, OCH3), 4.08–4.17 (1H, m,
CH(CH3)2), 5.41 (1H, d, J¼3.7, CH), 6.73–6.97 (2H, m, arom.), 7.35
(1H, dd, J1¼1.2, J2¼5.0, arom.), 7.89 (1H, d, J¼1.7, NH), 9.02 (1H, s,
NH); dC (600 MHz, DMSO-d6) 165.44, 157.11, 152.74, 148.69, 126.79,
124.71, 123.75, 98.56, 51.05, 49.17, 26.97, 18.98, 18.85; m/z 281
(MHþ), 206, 163.
1232, 1187, 1154, 1123, 1141, 1099, 1043 cmꢀ1
; dH (600 MHz,
DMSO-d6) 1.37 (3H, t, J¼6.8, OCH2CH3), 2.28 (3H, s, CH3), 3.47 (3H, s,
OCH3), 4.02–4.06 (2H, m, OCH2CH3), 5.46 (1H, s, CH), 6.85 (1H, t,
J¼7.4, arom.), 6.97 (1H, d, J¼8.2, arom.), 7.06 (1H, d, J¼7.5, arom.),
7.18–7.24 (2H, m, NHþarom.), 9.18 (1H, s, NH); dC (600 MHz,
DMSO-d6) 165.8, 156.1, 152.2, 148.9, 131.4, 128.7, 127.6, 119.9, 111.9,
97.0, 63.3, 50.6, 50.1, 17.8, 14.5; m/z 291 (MHþ).
4.3.10. 5-Ethoxycarbonyl-6-methyl-4-(2-chlorophenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3j. Bright yellow needles (51.9 g, 88%); mp
212.5–214.5 ꢁC (lit. Mp 214–216 ꢁC34); [Found: C, 57.1; H, 5.2; Cl,
12.2; N, 9.6. C14H15ClN2O3 requires C, 57.05; H, 5.13; Cl, 12.03; N,
9.50%]; Rf (10% MeOH/CH2Cl2) 0.43; nmax (KBr) 3479, 3325, 3252,
3125, 2962, 1718, 1703, 1652, 1606, 1583, 1557, 1463, 1377, 1349,
4.3.5. 5-Methoxycarbonyl-6-methyl-4-(2-furyl)-3,4-dihydropyr-
imidin-2(1H)-one 3e. Grey needles (39.2 g, 83%); mp 229.5–
231.5 ꢁC (lit. Mp 231–232 ꢁC34); [Found: C, 55.8; H, 5.3; N, 11.8.
C11H12N2O4 requires C, 55.93; H, 5.12; N, 11.86%]; Rf (10% MeOH/
CH2Cl2) 0.60; nmax (KBr) 3317, 3119, 2955, 1708, 1673, 1638, 1505,
1433, 1381, 1340, 1315, 1277, 1238, 1221, 1189, 1152, 1088,
1319, 1287, 1223, 1173, 1142, 1089, 1014 cmꢀ1
; dH (600 MHz,
DMSO-d6) 0.74 (3H, t, J¼6.0, CH2CH3), 2.31 (3H, s, CH3), 3.69–3.80
(2H, m, CH2CH3), 5.29 (1H, d, J¼3.3, CH), 7.52 (1H, d, J¼8.7, arom.),
7.58–7.61 (1H, m, arom.), 7.90 (1H, br s, NH), 8.21–8.24 (2H, m,
arom.), 9.38 (1H, s, NH); m/z 295 (MHþ).
1013 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.23 (3H, s, CH3), 3.57 (3H, s,
OCH3), 5.20 (1H, d, J¼3.4, CH), 6.10 (1H, d, J¼3.1, arom.), 6.34–6.36
(1H, m, arom.), 7.55 (1H, d, J¼0.9, arom.), 7.78 (1H, br s, NH), 9.27
(1H, s, NH); m/z 237 (MHþ).
4.3.11. 5-Ethoxycarbonyl-6-methyl-4-(3-chloro-phenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3k. White needles; mp 216.0–218.0 ꢁC (lit.
Mp 217–219 ꢁC66); (56.0 g, 95%); [Found: C, 57.0; H, 5.3; Cl, 12.0; N,
9.6. C14H15ClN2O3 requires C, 57.05; H, 5.13; Cl, 12.03; N, 9.50%];
Rf (10% MeOH/CH2Cl2)¼0.53; nmax (KBr) 3368, 3228, 3118, 2982,
2927, 1706,1651, 1594, 1574,1476,1431, 1390, 1379, 1365,1331,1286,
4.3.6. 5-Methoxycarbonyl-6-methyl-4-(2-thienyl)-3,4-dihydropyr-
imidin-2(1H)-one 3f. White needles (40.4 g, 80%); mp 225.5–
227.0 ꢁC (lit. Mp not reported65); [Found: C, 52.3; H, 4.7; N, 11.3; S,
12.6. C11H12N2O3S requires C, 52.37; H, 4.79; N, 11.10; S, 12.71%];
Rf (10% MeOH/CH2Cl2) 0.50; nmax (KBr) 3351, 3218, 3111, 2947, 2813,
1692, 1642, 1526, 1499, 1454, 1428, 1380, 1316, 1302, 1231, 1202,
1268, 1227, 1187, 1149, 1122, 1112, 1091, 1023 cmꢀ1
; dH (600 MHz,
DMSO-d6) 1.10 (3H, t, J¼7.1, OCH2CH3), 2.28 (3H, s, CH3), 3.93–4.08
(2H, m, OCH2CH3), 5.18 (1H, d, J¼3.2, CH), 7.21–7.27 (2H, m, arom.),
7.30–7.40 (2H, m, arom.), 7.81 (1H, d, J¼2.2, NH), 9.23 (1H, s, NH);
m/z 295 (MHþ).
1187, 1160, 1118, 1036 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.24 (3H, s,
CH3), 3.60 (3H, s, OCH3), 5.43 (1H, d, J¼3.4, CH), 6.91–6.95 (2H, m,
arom.), 7.35 (1H, dd, J1¼1.0, J2¼4.9, arom.), 7.93 (1H, br s, NH), 9.35
(1H, s, NH); dC (600 MHz, DMSO-d6) 165.55, 152.30, 148.96, 148.78,
126.79, 124.68, 123.62, 99.64, 50.92, 49.37, 17.77; m/z 253 (MHþ).
4.3.12. 5-Ethoxycarbonyl-6-methyl-4-(4-chloro-phenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3l. White needles; mp 230.0–232.0 ꢁC (lit.
Mp 231–232 ꢁC22); (47.7 g, 81%); [Found: C, 57.3; H, 5.0; Cl, 12.1; N,
9.4. C14H15ClN2O3 requires C, 57.05; H, 5.13; Cl, 12.03; N, 9.50%]; Rf
(10% MeOH/CH2Cl2)¼0.46; nmax (KBr) 3243, 3118, 2981, 1702, 1648,
1575, 1490, 1461, 1422, 1367, 1323, 1292, 1220, 1182, 1170, 1088,
4.3.7. 5-Methoxycarbonyl-6-methyl-4-(5-bromo-2-thienyl)-3,4-di-
hydropyrimidin-2(1H)-one 3g. Pale yellow needles (57.6 g, 87%);
mp 185.0–187.5 ꢁC; [Found: C, 39.8; H, 3.5; Br, 24.1; N, 8.6; S, 9.6.
C11H11BrN2O3S requires C, 39.89; H, 3.35; Br, 24.13; N, 8.46; S,
9.68%]; Rf (10% MeOH/CH2Cl2) 0.58; nmax (KBr) 3240, 3115, 2953,
1712, 1678, 1655, 1528, 1463, 1433, 1386, 1343, 1286, 1241, 1229,
1026, 1011 cmꢀ1
CH2CH3); 2.24 (3H, s, CH3); 3.95 (2H, q, J¼14.1, CH2CH3), 5.13 (1H, d,
J¼2.8, CH); 7.23 (2H, d, J¼8.5, arom.); 7.37 (2H, d, J¼8.5, arom.); 7.77
(1H, br s, NH); 9.24 (1H, br s, NH); m/z 295 (MHþ).
;
dH (600 MHz, DMSO-d6) 1.09 (3H, t, J¼7.0,
1189, 1154, 1094, 1049 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.23 (3H, s,
CH3), 3.62 (3H, s, OCH3), 5.34 (1H, d, J¼3.4, CH), 6.73 (1H, d, J¼3.7,
arom.), 7.05 (1H, d, J¼3.8, arom.), 7.96 (1H, br s, NH), 9.42 (1H, s,
NH); dC (600 MHz, DMSO-d6) 165.4, 152.2, 150.5, 149.6, 130.1, 124.4,
109.9, 99.9, 51.1, 49.6, 17.8; m/z 333 (MHþ), 290, 258.
4.3.13. 5-Ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3m. White needles; mp 216.0–217.5 ꢁC (lit.
Mp 208–210 ꢁC67); (51.9 g, 85%); [Found: C, 55.2; H, 5.0; N, 13.9.
C14H15N3O5 requires C, 55.08; H, 4.95; N, 13.76%]; Rf (10% MeOH/
CH2Cl2)¼0.60; nmax (KBr) 3353, 3228, 3113, 2979, 1697, 1639, 1572,
4.3.8. 5-Methoxycarbonyl-6-isopropyl-4-(4-chlorophenyl)-3,4-dihy-
dropyrimidin-2(1H)-one 3h. Pale yellow needles (50.0 g, 81%); mp
176.0–177.5 ꢁC; [Found: C, 58.2; H, 5.7; Cl, 11.6; N, 9.2. C15H17ClN2O3
requires C, 58.35; H, 5.55; Cl, 11.48; N, 9.07%]; Rf (10% MeOH/
CH2Cl2) 0.51; nmax (KBr) 3444, 3313, 3128, 2970, 1629, 1490, 1456,
1454, 1369, 1321, 1299, 1255, 1227, 1145, 1096, 1027 cmꢀ1
; dH
(600 MHz, DMSO-d6) 0.99 (3H, t, J¼7.1, CH2CH3), 2.31 (3H, s, CH3),
3.89 (2H, q, J¼14.1, CH2CH3), 5.64 (1H, d, J¼2.7, CH), 7.08–7.33 (3H,
m, arom.), 7.40 (1H, d, J¼7.6, arom.), 7.71 (1H, br s, NH), 9.28 (1H, s,
NH); m/z 306 (MHþ).
1435, 1343, 1314, 1277, 1227, 1191, 1144, 1100, 1014 cmꢀ1
; dH
(600 MHz, DMSO-d6) 1.13 (3H, d, J¼5.7, CH2(CH3)2), 1.15 (3H, d,
J¼5.9, CH2(CH3)2), 3.53 (3H, s, OCH3), 4.08–4.18 (1H, m, CH(CH3)2),
5.14 (1H, d, J¼3.5, CH), 7.23–7.26 (2H, m, arom.), 7.39–7.42 (2H, m,
arom.), 7.80 (1H, br s, NH), 8.95 (1H, s, NH); dC (600 MHz, DMSO-d6)
4.3.14. 5-Ethoxycarbonyl-6-n-propyl-4-(phenyl)-3,4-dihydropyr-
imidin-2(1H)-one 3n. Colourless needles; mp 138.0–140.0 ꢁC (lit.
Mp 162–165 ꢁC68); (46.7 g, 81%); [Found: C, 66.4; H, 6.8; N, 9.8.

3470
M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
C16H20N2O3 requires C, 66.65; H, 6.99; N, 9.72%]; Rf (7.5% MeOH/
CH2Cl2)¼0.51; nmax (KBr) 3443, 3347, 3248, 3116, 3037, 2983, 2961,
2930, 2903, 2870, 1703, 1649, 1598, 1464, 1425, 1362, 1347, 1324,
1311, 1289, 1269, 1229, 1214, 1181, 1172, 1155, 1144, 1129, 1097,
References and notes
1. Kappe, C. O. Tetrahedron 1993, 49, 6938–6963.
2. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
3. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052.
4. (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974; (b) Kapoor, T. M.; Mayer, T. U.;
Coughlin, M. L.; Mitchison, T. J. J. Cell Biol. 2000, 150, 975–988.
5. Hurst, E. W.; Hull, R. J. Med. Pharm. Chem. 1961, 3, 215–229.
6. Ashok, M.; Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem. 2007, 42, 380–385.
7. Fewell, S. W.; Smith, C. M.; Lyon, M. A.; Dumitrescu, T. P.; Wipf, P.; Day, B. W.;
Brodsky, J. L. J. Biol. Chem. 2004, 279, 51131–51140.
1018 cmꢀ1
;
dH (600 MHz, DMSO-d6) 0.91 (3H, t, J¼7.3, CH2CH2CH3),
1.10 (3H, t, J¼7.1, CH2CH3), 1.50–1.62 (2H, m, CH2CH2CH3), 2.63
(2H, t, J¼7.5, CH2CH2CH3), 3.98 (2H, q, J¼14.1, CH2CH3), 5.15 (1H, d,
J¼3.3, CH), 7.22–7.25 (m, 2H, arom.), 7.30–7.34 (m, 3H, arom.), 7.27
(br s, NH), 9.17 (s, NH); m/z 289 (MHþ).
8. Magerramov, A. M.; Kurbanova, M. M.; Abdinbekova, R. T.; Rzaeva, I. A.;
Farzaliev, V. M.; Allakhverdiev, M. A. Russ. J. Appl. Chem. 2006, 79, 787–790.
9. Carswell, C. I.; Plosker, G. L.; Jarvis, B. Drugs 2002, 62, 2075–2085.
10. (a) Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. Rev. 2000, 29, 57–67; (b)
Bewley, C. A.; Ray, S.; Cohen, F.; Collins, S. K.; Overmann, L. E. J. Nat. Prod. 2004,
67, 1319–1324.
4.3.15. 5-Ethoxycarbonyl-6-phenyl-4-(phenyl)-3,4-dihydropyr-
imidin-2(1H)-one 3o. Colourless needles; mp 157.0–159.0 ꢁC (lit.
Mp 158 ꢁC69); (51.6 g, 80%); [Found: C, 70.9; H, 5.8; N, 8.8.
C19H18N2O3 requires C, 70.79; H, 5.63; N, 8.69%]; Rf (7.5% MeOH/
CH2Cl2)¼0.52; nmax (KBr) 3384, 3309, 3224, 3116, 3058, 3031,
3006, 2988, 2979, 2960, 2934, 2902, 1703, 1667, 1637, 1600, 1494,
1473, 1456, 1445, 1413, 1396, 1372, 1350, 1335, 1291, 1281, 1267,
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´
¨
12. Cepanec, I.; Litvic, M.; Filipan-Litvic, M.; Grungold, I. Tetrahedron 2007, 63,
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1247, 1187, 1159, 1130, 1099, 1030, 1014 cmꢀ1
; dH (600 MHz,
14. Gohain, M.; Prajapati, D.; Sandhu, J. S. Synlett 2004, 235–238.
15. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587–590.
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DMSO-d6) 0.71 (3H, t, J¼7.1, CH2CH3), 3.71 (2H, q, J¼14.2,
CH2CH3), 5.24 (1H, d, J¼3.4, CH), 7.27–7.31 (3H, m, arom.), 7.36–
7.43 (7H, m, arom.), 7.85 (1H, d, J¼2.2, NH), 9.28 (1H, s, NH);
m/z 323 (MHþ).
18. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270–6272.
19. Sun, Q.; Wang, Y.-q.; Ge, Z.-m.; Cheng, T.-m.; Li, R.-t Synthesis 2004, 1047–1051.
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3009–3016.
4.3.16. 5-Isopropyloxycarbonyl-6-methyl-4-(4-methoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-one 3p. Bright yellow powder; mp 223.0–
225.0 ꢁC (lit. Mp not reported70); (50.5 g, 83%); [Found: C, 63.0; H,
6.6; N, 9.1. C16H20N2O4 requires C, 63.14; H, 6.62; N, 9.20%]; Rf (10%
MeOH/CH2Cl2)¼0.46; nmax (KBr) 3243, 3115, 2983, 2834, 1723, 1702,
1650,1615,1584,1515,1461,1461,1440,1385,1348,1309,1277,1257,
1224, 1178, 1147, 1109, 1031 cmꢀ1
; dH (600 MHz, DMSO-d6) 1.00
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(3H, d, J¼6.2, CH3), 1.16 (3H, d, J¼6.2, CH3), 2.24 (3H, s, CH3), 3.72
(3H, s, OCH3), 4.77–4.87 (1H, m, CH(CH3)2), 5.08 (1H, d, J¼2.9, CH),
6.87 (2H, d, J¼8.6, arom.), 7.15 (2H, d, J¼8.6, arom.), 7.64 (1H, br s,
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Mp 170–171 ꢁC71); (55.2 g, 82%); [Found: C, 71.3; H, 6.1; N, 8.2.
C20H20N2O3 requires C, 71.41; H, 5.99; N, 8.33%]; Rf (10% MeOH/
CH2Cl2)¼0.50; nmax (KBr) 3389, 3222, 3090, 2934, 2819, 1692, 1638,
1511, 1497, 1452, 1429, 1374, 1321, 1293, 1265, 1223, 1183, 1139, 1094,
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33. Cepanec, I.; Litvic´, M.; Bartolincic,
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1024 cmꢀ1
; dH (600 MHz, DMSO-d6) 2.26 (3H, s, CH3), 2.27 (3H, s,
CH3), 5.00 (1H, d, J¼12.8, CH2Ph), 5.06 (1H, d, J¼12.8, CH2Ph), 5.16
(1H, d, J¼3.1, CH), 7.10–7.17 (6H, m, arom.), 7.27–7.30 (3H, m, arom.),
7.71 (1H, br s, NH), 9.24 (1H, s, NH); m/z 337 (MHþ).
ˇ ´
ˇ
´
´
38. (a) Litvic´, M.; Cepanec, I.; Filipan, M.; Kos, K.; Bartolincic, A.; Druskovic, V.;
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The ethanolic mother liquor obtained after crystallization of
products (Table 4) was evaporated to dryness and the residue was
triturated with three portions of hot distilled water (50 mL). The
combined water extracts if necessary were extracted with ethyl-
acetate to remove the traces of organic compounds and colouration
residues were evaporated to dryness to afford a mixture of excess of
urea (0.5 equiv) and regenerated catalyst (yield w95%). Thus
obtained catalyst was used in four successive reaction with
m-chlorobenzaldehyde (1k, 10 mmol), urea (10 mmol, 1 equiv) and
ethylacetoacetate (2c, 10 mmol) and the results are summarized in
Table 5.
Acknowledgements
The authors wish to express their gratitude to the Belupo
Pharmaceuticals, Inc. for financial support of this research.

M. Litvi´c et al. / Tetrahedron 66 (2010) 3463–3471
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