Grindstone chemistry: A highly efficient and green method for synthesis of 3,4-dihydropyrimidin-2-(1H)-ones by l-tyrosine as an organocatalyst: A combined experimental and DFT study

Article abstract of DOI:10.1039/c4ra05244g

A single step, mild, environmentally friendly green method has been developed for the synthesis of physiologically active 3,4-dihydropyrimidin-2- (1H)-ones employing l-tyrosine as catalyst under solvent-free conditions at room temperature via grinding. Th

Full text of DOI:10.1039/c4ra05244g

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Grindstone chemistry: a highly efficient and green
method for synthesis of 3,4-dihydropyrimidin-2-
Cite this: RSC Adv., 2014, 4, 35559
(1H)-ones by L-tyrosine as an organocatalyst: a
combined experimental and DFT study†
a
a
a
b
Anamika Khaskel, Prasanta Gogoi, Pranjit Barman* and Biman Bandyopadhyay
A single step, mild, environmentally friendly green method has been developed for the synthesis of
physiologically active 3,4-dihydropyrimidin-2-(1H)-ones employing L-tyrosine as catalyst under solvent-
free conditions at room temperature via grinding. The procedure is efficient, time saving and gives high-
Received 11th June 2014
Accepted 6th August 2014
1
13
yields. The structures and purity of these compounds were confirmed by FT-IR, NMR ( H and C) and
HRMS spectral analysis. DFT calculations have been used to show the effectiveness of L-tyrosine as a
suitable catalyst for the above reaction.
DOI: 10.1039/c4ra05244g
www.rsc.org/advances
3
,4-Dihydropyrimidines are well-known for their wide range
Introduction
of bioactivities and their applications in the eld of drug
Development of less hazardous synthetic methodologies for research.
3–6
3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs) have
organic reactions is one of the most sought aer problems in high pharmacological value and they are used as calcium
7
8
contemporary research. For synthesis of complex molecules channel blockers, alpha-1a-antagonists, antihypertensive
9
employing environment friendly green methods, reactions agents and neuropeptide Y (NPY) antagonists. Their derivatives
1
a
conducted in aqueous media have received much attention.
But there have been associated drawbacks as well; primarily antifungal, antiviral, anticancer, and anti-inammatory
also exhibit a wide spectrum of biological effects including
10
owing to very poor ability of water in solubilizing organic effects.
reactants making the reaction mixture heterogeneous. This dihydropyrimidin-5-carboxylate core in their molecules. Bat-
Several bioactive marine alkaloids have the
1b
11
difficulty can be overcome using phase transfer catalysts but zelladine alkaloids A and B from the sponge of Batzella sp.
1
b
12
this will cause the process to be more expensive. Reactions in inhibit the binding of HIV gp-120 to human CD4 receptor.
dry media or under solvent free condition are especially Nitractin was rst reported in 1960s as an agent against the
13a
appealing, as they provide an opportunity to work in an open trachoma group of viruses. Monastrol, a thio derivative of
vessel, thus avoiding the risk of high internal pressure devel- DHPM has been identied as a compound that acts as a cell-
opment and with the possibility of up-scaling the reaction to the permeable molecule to block mitosis cell division by speci-
1
c
13b
larger scale. Recently, grindstone chemistry has been shown to cally inhibiting the motor activity of the mitotic kinesis Eg5.
be a highly viable green and rapid method for the synthesis of
Search for more suitable preparation of DHPMs continue
organic compounds without the complicacies associated with today. Recently many improved procedures have been reported
2
a
14
15
the use of different solvents, including water. The proposed using CuCl
–H
O, L-proline, praseodymium methanesulfo-
technique does not require external heating, leading to energy nate, phenyl pyruvic acid, chloroacetic acid, TMSCl, Lewis
, CdCl , heteropolyacids as catalyst in
3 2
and ecologically favorable procedure in chemistry. Toda and Biginelli reaction. In addition, methods employing micro-
2
2
16
17
18
19
20
21
22
23
24
efficient synthesis and may be regarded as more economical acids, InCl
3
,
InBr
2b
25
26
27
co-workers showed that many of the exothermic organic reac- waves, ultrasound, solid and uorous phase syntheses have
tions can be performed in good yield using mortar and pestle been reported.
2
a
only. Grindstone chemistry has been shown to be a very useful
Hitherto, all these methodologies have come up with draw-
backs such as prolonged reaction time, tedious catalyst prepa-
ration and work up, formation of inevitable sticky products and
exhaustive usage of solvents. Development of organocatalytic
processes in which the reactions are catalyzed by organic
2a
method for desktop as well as kilogram scale synthesis.
a
Department of Chemistry, National Institute of Technology, Silchar 788010, Assam,
India. E-mail: barmanpranjit@yahoo.co.in; Fax: +91-3842-224797
28a
b
Department of Basic Science & Humanities, Institute of Engineering and Management, molecules is an important area for the green synthesis.
Salt Lake Electronics Complex, Sector-5, Kolkata 700091, India
28b
Recently, Yadav and co-workers reported the application of L-
proline as catalyst in Biginelli reaction for the synthesis of
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c4ra05244g
1
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Results and discussions
Traditional condition for Biginelli reactions commonly require
a large excess of one of the reagents, large amounts of catalyst,
high temperatures, several hours reactions and occasionally the
29
presence of co-catalyst.
Our initial efforts were focused on the search of a catalyst,
which would be useful in grindstone methodology to carry out
the synthesis of DHPMs at room temperature. For our purpose,
L-tyrosine was chosen as the preferred catalyst. We rst started
to investigate the Biginelli reaction (Scheme 1) with 4-methoxy
benzaldehyde (1 mmol), urea (1 mmol) and methyl acetoacetate
Scheme 1 Synthesis of 3,4-dihydropyrimidin-2-(1H)-ones.
dihydropyrimidin-2-(1H)-ones (thiones). A natural bi-functional
organocatalyst phytic acid has also been reported by Guo and
(1 mmol) in presence of L-tyrosine (10 mol%) as catalyst under
2
8c
co-workers
in Biginelli 3,4-dihydrppyrimidin-2-(1H)-one
solvent free grinding condition using mortar and pestle. This
model reaction afforded compound 4a (Table 3) in 87% yield.
The yield of the reaction is optimum under grinding method
using L-tyrosine (10 mol%) at room temperature. Increment in
the amount of the catalyst to 20 mol% (Table 1, entry 6) did not
show any improvement in the yield, whereas the yield was found
to be lesser when the amount of the catalyst was reduced to 5
mol% (Table 1, entry 5). Another signicant observation is that
the reaction is more successful considering time and yield at
room temperature than microwave condition (Table 1, entry 7).
In Table 1 we also compare the catalytic activity of L-tyrosine
with others amino acid catalysts such as glycine, L-proline and L-
serine under grinding methodology for the synthesis of
compound 4a. L-Proline and glycine both are effective catalysts
for various organic reactions such as Biginelli reaction, but
28d
synthesis. Sinha and co-workers
reported glycine nitrate
catalyzed DHPM synthesis under microwave condition. Our aim
is to develop a fully green synthesis of various 3,4-DHPMs at
room temperature and we have selected L-tyrosine as the cata-
lyst for this purpose. The choice of L-tyrosine is based on the fact
that it is an efficient, bi-functional, zwitterionic and eco-friendly
organocatalyst capable of playing multiple catalytic roles as an
acid and base. Though L-tyrosine used in psychiatric disorder,
28e
schizophrenia, its catalytic activity in various organic trans-
formations is till unnoticed. The one report of the catalytic
ability of L-tyrosine is reected in its application in Knoevenagel
28f
condensation reaction under grindstone condition.
To the best of our knowledge, the Biginelli reaction under
28g
grinding condition was rst reported by Bose and co-workers
using p-TSA as catalyst. In this report they used only aromatic
aldehydes, ethyl acetoacetate and urea for the synthesis of 3,4-
DHPMs. Very recently, Safari and co-workers reported diary-
3 4
lpyrimidones synthesis by Fe O –CNT nanocomposites via Table 2 Comparison of L-tyrosine with other Brønsted acid catalysts
28h
for the synthesis of 4a
grinding using aldehydes, urea and ketone. As a part of the
continuous efforts for employing grinding methodology, herein
we report the synthesis of 3,4-DHPMs (Scheme 1) using various
types of aldehydes (such as alkyl, aromatic and heterocyclic),
a
Catalyst load
(mol%)
Time
(min)
Yield
(%)
Entry
Catalyst
1
,3-diketones (acetyl acetone, methyl acetoacetate and ethyl
1
2
L-Tyrosine
Camphorsulphonic
acid
10
10
15
60
87
50
acetoacetate) and urea (or thiourea) using L-tyrosine as catalyst
under solvent-free condition at room temperature. Another
major aspect of our work is that the appreciably higher catalytic
activity of L-tyrosine compared to that of glycine has been
corroborated by means of DFT calculation.
3
4
Oxalic acid
10
10
120
60
45
57
HClO
4
a
Isolated yield.
Table 1 Optimization of the synthesis of 3,4-dihydropyrimidin-2-(1H)-one (4a)
a
Entry
Catalyst
Catalyst load (mol%)
Solvent
Time (min)
Yield (%)
ꢀ
1
2
3
4
5
6
7
8
9
Glycine
Glycine
10
10
10
10
5
20
10
10
10
Ethanol (reux at 80 C)
50
60
45
15
30
15
20
30
50
50
30
60
87
59
87
41
73
35
Solvent free (grinding method, rt)
ꢀ
L-Tyrosine
L-Tyrosine
L-Tyrosine
L-Tyrosine
L-Tyrosine
L-Serine
Ethanol (reux at 80 C)
Solvent free (grinding method, rt)
Solvent free (grinding method, rt)
Solvent free (grinding method, rt)
Microwave
Solvent free (grinding method, rt)
Solvent free (grinding method, rt)
L-Proline
a
Isolated yield.
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a
Table 3 One-pot, L-tyrosine catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and thiones
b
Entry
Aldehydes
1,3-Diketone
Urea/thiourea
Time (min)
Yield (%)
1
15
87 (4a)
2
10
91 (4b)
3
4
10
10
82 (4c)
89 (4d)
5
6
15
10
85 (4e)
81 (4f)
7
8
5
89 (4g)
83 (4h)
15
9
20
91 (4i)
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Table 3 (Contd.)
b
Entry
Aldehydes
1,3-Diketone
Urea/thiourea
Time (min)
Yield (%)
1
0
1
20
83 (4j)
1
10
85 (4k)
1
2
3
15
15
88 (4l)
1
87 (4m)
1
4
5
20
15
82 (4n)
90 (4o)
1
1
6
15
84 (4p)
a
Reaction conditions: aldehyde (1 mmol), urea (1 mmol), 1,3-dicarbonyl compounds (1 mmol) and L-tyrosine (10 mol%) ground at room
b
temperature. Isolated yield (aer recrystallization). All compounds have been characterized by IR, NMR and HRMS data.
under room temperature grinding condition L-tyrosine is protocol to produce the corresponding DHPMs (Table 3). Many
signicantly more effective. L-Serine was also found to be a of the pharmacologically signicant substitution patterns have
better catalyst compared to both glycine and L-proline for the been introduced efficiently. Aromatic aldehydes were found to
synthesis of compound 4a (yield 73%) in grinding condition at produce the corresponding DHPMs in high yield irrespective of
room temperature, but not as effective as L-tyrosine.
their electronic effects. Aldehydes with heterocyclic ring affor-
For the model reaction (4a) we have also compared the ded higher yields (Table 3, 4f and 4g). Thiourea was also used in
catalytic activity of other Brønsted acids with L-tyrosine under similar success (Table 3, 4c, 4i and 4m) which are of much
13
grinding condition and the details are given in Table 2.
broad range of structurally diverse 1,3-dicarbonyl
compounds, aldehydes and urea were subjected under this reaction (i.e. without catalyst) was carried out for entry 2 and no
interest with regard to the biological activity.
A
To demonstrate the efficiency of the chosen catalyst, a blank
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suitable result has been observed. It is important to note that
A reaction mechanism for the Biginelli condensation via
this procedure is much simpler and faster than the protocols iminium intermediate has been proposed in Scheme 3. This
published till date. It requires neither tedious work up proce- intermediate is formed by reaction of aldehyde and urea in
dure nor column chromatographic purication. The grinding presence of the catalyst and is then stabilized by Zwitterionic
reaction mixture was quenched with water to remove the cata- form of L-tyrosine through H-bonding interaction. Subsequent
lyst and nally we got the precipitate of DHPMs. To probe the addition of 1,3-diketone to the acyl imine, followed by cycliza-
probable mechanism of L-tyrosine mediated Biginelli reaction tion and dehydration, produces the corresponding DHPMs. It is
three different routes (Scheme 2) were investigated: (a) carbe- worthwhile to mention here that the all the synthesized DHPMs
30a
30b
nium ion pathway, (b) bis-urea pathway and (c) iminium (Table 3; 4a–4p) were found to be racemic in nature. In fact, it
30c
ion pathway.
has been shown that L-proline and its corresponding hydro-
When 4-methoxy benzaldehyde (1 mmol), ethyl acetoacetate chloride catalyzed reaction, too, resulted in racemic
15,28b
(1 mmol) and L-tyrosine (10 mol%) were ground for 15 min, no DHPMs.
The chiral center in the DHPMs originates at the
product was obtained which rules out the possibility of the carbonyl carbon of the reactant aldehyde during the addition of
30a
carbenium ion pathway. Next to investigate the possibility of iminium ion intermediate and enolic form of 1,3-dicarbonyls.
bis-urea pathway, urea (3 mmol) was ground with 4-methoxy The fact that we obtained products with a chiral centre as a
benzaldehyde (1 mmol) for 15 min and no derivative was racemic mixture indicates that L-tyrosine does not participate in
30b
obtained, which rules out the idea of bis-urea pathway.
Finally, to investigate the iminium pathway, 4-methoxy- enantiomer over the other due to the catalyst's own chirality.
benzaldehyde (1 mmol) and urea (1 mmol) were ground for 15 From the results given in Table 1 it can be noted that under
this particular step as it would have facilitated formation of one
min in L-tyrosine (10 mol%), subsequently ethyl acetoacetate (1 room temperature grinding condition there is a signicant
mmol) was added and again ground for 5 min and we got the difference in product yield when two different amino acid
30c
desired product (Table 3, 4k, yield 85%). Neto and co-workers catalysts are used; for 4a glycine catalyzed reaction gave very
demonstrated that urea excess is the worst condition for the poor yield (30%) whereas for L-tyrosine the yield is considerably
Biginelli reaction when iminium-based mechanism is favour- higher (87%). So, it is clearly evident that L-tyrosine is a highly
30d
ed. So, we completely avoided using excess urea in any of the efficient catalyst for Biginelli reaction under room temperature
reaction reported here and always used it in equimolar amount grinding condition but the same is not true for glycine. This
with aldehyde and 1,3-diketone. Recently, it has been demon- large difference in catalytic activity between the two amino acid
strated that electrospray ionization mass spectrometry is an catalysts must be due to the marked difference in their molec-
excellent tool to study the Biginelli intermediates formed ular geometries and consequently, in chemical properties, too.
during the transformation. We observed two distinct peaks at The phenolic group present in L-tyrosine must be actively taking
m/z value of 178.03 and 198.08 in the mass spectra for 4g and 4h part in the catalytic process by reducing the transition energy
that corresponds to the two iminium intermediates (mass of and hence increasing reaction rate compared to that in glycine,
+
iminium intermediate + Na ), respectively. This fact reinforces which is reected in higher product yield.
our initial nding that the reaction follows the iminium ion
pathway (c) as shown in Scheme 2.
We propose here that it is the intermolecular hydrogen
bonding interaction between the catalyst and the reactant
species that makes the reaction facile under mild grinding
Scheme 2 Probable reaction mechanisms for Biginelli reaction.
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Scheme 3 Proposed mechanistic pathway of Biginelli reaction by L-tyrosine as catalyst. The rate determining step, for which DFT calculation has
31
been carried out, is shown in red [for iminium ion pathway, this particular step is the slowest step ].
condition. To support the above proposition, we have modeled
When compared against glycine, L-tyrosine through its Ph–
the potential energy surface of the rate determining step (RDS) OH group can provide extra H-bonding site that facilitates the
employing electronic structure calculation by density functional reaction by further stabilization of the activation complex. Here,
theoretical methods. In Biginelli reaction, formation of we have taken the smallest aldehyde (i.e. formaldehyde; R]H in
2
RCH(OH)NHCONH by addition of urea with aldehyde (shown Scheme 3). The reactant complex, transition state and product
31
in red in Scheme 3) is known to be the slowest step. The complex involving glycine are designated here as GRC, GTS and
following step is faster and involves release of water molecule GPC, respectively and similarly TRC, TTS and TPC imply same
leading to the iminium intermediate. In our study, too, the species when L-tyrosine acts as a catalyst. The optimized
mass spectra showed peaks corresponding to the iminium geometries of these species are shown in Fig. 1 along with the H-
intermediates only and no signature for its precursor could be bond lengths.
identied. The above facts conrm that the addition of urea and The hydrogen bonded complex formed by the catalyst, urea
aldehyde is the RDS of Biginelli reaction when it follows imi- and formaldehyde was found to be enjoying greater stabiliza-
nium ion pathway.
tion in TRC compared to that in GRC. In both cases, urea is
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Fig. 1 Molecular geometries of reactant, product and transition complexes involving glycine and L-tyrosine catalysts optimized at B3LYP/6-
11++G(d,p) level. Hydrogen-bond lengths are given in A˚ .
3
bound to the amide group of the amino acid catalyst by two H-
bonds, one between the amine hydrogen of urea and carboxy-
late oxygen of the amino acid and the other between the
carbonyl oxygen of the former and the ammonium hydrogen of
the latter. It is the aldehyde whose binding pattern was found to
differ signicantly when two different amino acids were taken
as catalyst. For both of them, the hydrogen atom of formalde-
hyde is bonded to the carbonyl oxygen of urea. But the carbonyl
oxygen of formaldehyde forms H-bond with the phenolic
hydrogen of L-tyrosine in TRC, but it is bonded to the hydrogen
of free amino group of urea in GRC. This difference in the
conformation of formaldehyde has twofold effects on the
potential energy surface of the RDS step. Firstly, binding ener-
gies of the complexes involving L-tyrosine and glycine are
different, the rst one being larger in magnitude. Secondly,
which is more important from our viewpoint, this results in a
considerable difference between the barriers of activation
involving the two catalysts, the one with glycine i.e. GTS (46.0
À1
Fig. 2 Relative energies (in kcal mol ) of reactant, product and
À1
À1
kcal mol ) requires ꢁ12 kcal mol higher energy than that
transition complexes involving glycine (in red) and L-tyrosine (in black)
À1
needed with L-tyrosine i.e. TTS (34.4 kcal mol ). This large catalysts calculated by single point energy calculation at M06-2X/6-
increment in the reaction barrier makes glycine to be much less 311++G(d,p) using the optimized geometries calculated at B3LYP/6-
311++G(d,p) level.
effective in catalyzing the reaction which we have found to be
done efficiently by L-tyrosine. The relative energies of all the
species studied here are shown schematically in Fig. 2. The
ꢀ
energies of all species were computed relative to the isolated undergoes a rotation of ꢁ90 along an axis perpendicular to
ꢀ
urea, formaldehyde and catalyst molecules.
C]O. But TRC–TTS transformation requires only ꢁ15 rotation
When the reactant and product complexes along with the in similar manner which should be much easier to perform.
transition states are scrutinized from a closer quarter (Fig. 1), it More importantly, this rotational reorientation disrupts the H-
can be observed that the formaldehyde moiety undergoes a bond formed by carbonyl oxygen of formaldehyde in GRC but
signicant reorientation with respect to the urea molecule no such effect is seen during TRC–TTS conversion where the
during the process for glycine, whereas for L-tyrosine it hardly said oxygen is H-bonded with the phenolic OH of L-tyrosine in
needs to change its orientation. The dihedral angle between the both TRC and TTS. On the contrary, the said H-bond becomes
formaldehyde C]O and the urea C–N (closer to the formalde- even stronger in TTS than that in TRC, its length being 1.650 A˚
ꢀ
ꢀ
ꢀ
˚
hyde) are À130 , À114 and À110 for TRC, TTS and TPC, in the former and 1.998 A in the later. We conclude here that
ꢀ
ꢀ
ꢀ
respectively, whereas these values are À178 , À90 and À70 for these two reasons are primarily responsible for the large
GRC, GTS and GPC, respectively. So it is directly evident that difference in barrier heights for the reaction catalyzed by glycine
during the transformation of GRC to GTS, formaldehyde and L-tyrosine. We may add to the above facts that this
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difference will get even more widened for reactions involving Calculation
bulkier aldehydes as their reorientation will require much
larger energy compared to formaldehyde.
Another notable observation was that when the reaction (for
entry 4a) was carried out using two more amino acids, namely L-
proline and L-serine (Table 1), it was found that the former one
Molecular geometries of all the species involved in the RDS of
the reaction, their H-bonded complexes, and the corresponding
transition states have been optimized by density functional
theoretical (DFT) methods employing B3LYP functional and 6-
311++G(d,p) basis set. Single point energy calculations have
(entry 9) gave yield that was comparable to what was obtained
been carried out at the M06-2X/6-311++G(d,p) level using the
optimized geometries calculated at B3LYP/6-311++G(d,p) level.
Basis set superposition errors (BSSEs) for all the complexes and
the transition states were corrected employing the single point
with glycine. On the other hand, the latter one (entry 8) gave
appreciably high yield (albeit lower than that for L-tyrosine).
Here, too, the difference between these two catalysts is that
while L-serine has an extra hydrogen bonding site (hydroxyl
group) like L-tyrosine, L-proline lacks such a feature similar to
glycine. In order to provide further support to the computa-
tional results we carried out the reaction with formaldehyde,
ethyl acetoacetate and urea using both glycine and L-tyrosine as
catalysts. It was found that in this case, too, that latter proved to
be a more efficient catalyst (Table 3, 4o, yield 90%) than the
former (yield 52%), but the difference in yield is not as large as
was found for the aromatic aldehyde (Table 1, entry 2 and 4).
32
counterpoise method proposed by Boys and Bernardi. Normal
mode frequencies were calculated for all species to ascertain
that optimized geometries corresponded to minima in the
potential energy surfaces characterized by no imaginary
frequencies and transition complexes corresponded to rst
order saddle points characterized by a single imaginary
33
frequency. The Gaussian 09 program package was used to
perform all the calculations reported herein.
Acknowledgements
Conclusions
BB gratefully acknowledges Indian Association for the Cultiva-
tion of Science, Kolkata for the Gaussian 09 programme
package, Professor Tapas Chakraborty for providing the
computational resources and Mr Indranil Duttagupta for many
helpful discussions.
We have developed an eco-friendly novel method for the
synthesis of DHPMs catalyzed by L-tyrosine in high yield. The
remarkable features of this procedure are solvent free, grinding
methodology, high conversion rates and operational simplicity.
Compared to the previously reported methods, most of which
required elevated temperatures, this methodology proceeds
smoothly at room temperature and therefore is able to sustain a
large number of functional groups. Mild reaction conditions,
fully green and clean reaction prole, shorter reaction time and
wide range of substrate applicability are the key advantages of
this methodology.
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General procedure for the synthesis of 3,4-dihydropyrimidine-
2
-ones
A mixture of aldehyde (1 mmol), urea (1 mmol) and 1,3-diketone
1 mmol) was ground together in a mortar and pestle in pres-
(
ence of L-tyrosine (10 mol%) as catalyst at room temperature.
For the few minutes later formation of a syrupy solution was
observed. The reaction was monitored by TLC. Aer completion
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