A novel amino acid functionalized ionic liquid promoted one-pot solvent-free synthesis of 3,4-dihydropyrimidin-2-(1H)-thiones

Article abstract of DOI:10.1007/s11164-012-0689-4

An environmentally benign, cheap and reusable L-amino acid functionalized ionic liquid [L-AAIL]/AlCl₃ was found to be an effective catalyst for the synthesis of 3,4-dihydropyrimidine-2-(1H)-thione derivatives in good to excellent yield under so

Full text of DOI:10.1007/s11164-012-0689-4

Res Chem Intermed (2013) 39:1335–1342
DOI 10.1007/s11164-012-0689-4
A novel amino acid functionalized ionic liquid
promoted one-pot solvent-free synthesis
of 3,4-dihydropyrimidin-2-(1H)-thiones
•
Parasuraman Karthikeyan Sythana Suresh Kumar
•
•
•
Aswar Sachin Arunrao Muskawar Prashant Narayan
Pundlik Rambhau Bhagat
Received: 26 April 2012 / Accepted: 12 June 2012 / Published online: 11 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract An environmentally benign, cheap and reusable L-amino acid func-
tionalized ionic liquid [L-AAIL]/AlCl3 was found to be an effective catalyst for the
synthesis of 3,4-dihydropyrimidine-2-(1H)-thione derivatives in good to excellent
yield under solvent-free condition. Compared with the classical Biginelli reactions,
this method consistently enjoys the advantages of mild reaction conditions, easy
work-up, and short reaction time. These one-pot three-component Biginelli products
could be separated easily from the catalyst–water system, and the catalyst could be
reused at least five times without noticeably reducing catalytic activity.
Keywords Amino acid Á Ionic liquid Á Thiourea Á Reflux
Introduction
Due to the importance of dihydropyrimidinones (DHPMs) as valuable synthons,
pharmaceuticals, or precursors, a couple of methods to prepare these compounds
have been developed, with the Biginelli reaction gaining particular attention,
especially in the last few years [1]. Furthermore, these compounds have emerged as
the integral backbones of several calcium-channel blockers. Some marine alkaloids
containing the dihydropyrimidine core unit have interesting biological properties:
batzelladine alkaloids have been found to be potent HIV gp-120-CD4 inhibitors.
Recently, DHPMs have been considered as a new lead for the development of new
anticancer drugs.
In 1893, Italian chemist Pietro Biginelli [2] reported the simplest and the
most straightforward approach to preparation of DHPMs involves a one-pot
P. Karthikeyan Á S. S. Kumar Á A. S. Arunrao Á M. P. Narayan Á P. R. Bhagat (&)
Organic Chemistry Division, School of Advanced Sciences, VIT University,
Vellore 632 014, Tamilnadu, India
e-mail: drprbhagat111@gmail.com
123

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P. Karthikeyan et al.
three-component acid-catalyzed condensation, which is still one of the most often
used multi-component reactions. But this Biginelli type reaction suffers from harsh
conditions, long duration with organic solvents, low yields, and low purity, and thus
this topic continues to attract the attention of researchers seeking a milder and more
efficient procedure and efficient catalysts for the synthesis of DHPMs.
In recent years, several synthetic procedures for the preparation of DHPMs have
been made to improve and modify this reaction. These include assistance FeCl3-
supported nanopore silica [3], ferric perchlorate [4], polyoxometalate [5], transition
metals containing halides [6–8], amino acids [9–12], and polymers [13–16] have
been used, and the search for new, readily available, and green catalysts is still being
actively pursued.
Currently, ionic liquids attract much interest as environmentally benign catalysts or
as excellent alternatives to organic solvents, because of their favorable properties, for
example, negligible volatility and high thermal stability. Moreover, the past few years,
a variety of catalytic reactions have been successfully conducted using ILs as solvents.
Task-specific ionic liquids (TSILs) have also been used as catalysts for the Biginelli
reaction [17]. Peng and Deng [18] synthesized DHPMs in BMImBF4, Shaabani and
Rahmati [19] used the room-temperature ionic liquid 1,1,3,3-tetra methyl guanidi-
nium trifluoroacetate as catalyst, Li et al. [20] reported an ionic liquid (BMImSac) as
catalyst, Zheng et al. [21] used CMImHSO4 as catalyst for a Biginelli-type reaction,
and Chen and Peng [22] found the Lewis acidic ionic liquid [bmim][FeCl4] to be an
efficient catalyst for synthesis of DHPMs. And, moreover, TSILs are those
incorporating functional groups designed to exhibit particular properties or reacti-
vates; in recent years, TSILs have attracted considerable attention [23]. Davis et al.
reported on TSILs in which the cations were both intrinsically Brønsted acidic and
nonvolatile. This was done by covalently tethering an alkane sulfonic acid group to the
IL cation [24]. Such sulfonic acid-based TSILs were used simultaneously as solvent
and catalyst for Fischer esterification [25], dehydrodimerization of alcohols [26],
pinacol–benzopinacol rearrangements [27], and electrophilic substitution of indoles
with aldehydes [28]. To the best of our knowledge of the open literature, Biginelli-type
reactions catalyzed by amino acid fictionalized ionic liquid [L-AAIL]/AlCl3 (Fig. 1)
have not been reported (Scheme 1).
Results and discussion
Initially, the condensation reaction was carried out in absence of any catalyst and
solvent. It was found that no product formed. This shows that the catalyst was
Br
HN
N
N
O
HO
O
Fig. 1 Molecular structure of 3-(3-(1-carboxy-2-methylpropylamino)-3-oxopropyl)-1-methyl-1H-
imidazol-3-ium bromide (L-AAIL)
123

A novel amino acid functionalized ionic liquid
1337
R3
R4
R2
R1
R2
R3
L-AAIL/AlCl3
S
O
O
O
O R5
R 1
N
H
S
R5
H2N
NH 2
O C2H5
C2 H5O
H3C
R4
N
H
R 1 = OCH3 ,H,Cl,OH
R 2 = H
R 3 = Cl,OCH3 ,H
R 4 = H
R 5 = OCH3 ,H
Scheme 1 Synthesis of 3,4-dihydropyrimidin-2(1-H)-thiones using L-AAIL/ALCl3
necessary for this reaction (Table 1, entry 1). The substrates in the given mole
proportion were condensed using L-AAIL/AlCl3 in the absence of solvent for
different times at room temperature. It was observed that the formation of the product
increases with time duration. This indicates that the catalyst was necessary for the
condensation reaction (Table 1, entries 2–6). Subsequently, the effect of temperature
on the rate of condensation was studied. The temperature of the reaction was gradually
increased from room temperature to 80 °C. The effect of temperature was clearly
distinct on the rate of condensation, enhancing it with temperature. The product
formation was most desirable at 80 °C in 6 h (Table 1, entries 7–11).
Finally, the effect of the duration of the reaction on the yield of the product was
studied at 80 °C by variation of time for the same condensation and also with
Table 1 Optimization reaction using L-AAIL/AlCl3
Sample no.
Catalyst
Solvent
Temperature (0 °C)
Time (h)
Yield (%)
1
NIL
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
RT
RT
RT
RT
RT
RT
40
24
6
7
30
35
43
45
51
70
74
77
80
94
88
87
86
89
95
2
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
L-AAIL/AlCl3
3
8
4
10
12
24
12
12
12
12
6
5
6
7
8
50
9
60
10
11
12
13
14
15
16
70
80
80
5
80
4
80
2
90
2
100
2
Reaction conditions: aldehyde (10.0 mmol), b-dicarbonyl compound (10.0 mmol), thiourea (12.0 mmol)
and L-AAIL/AlCl3 (0.05 mmol), 80 °C under solvent-free conditions
123

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P. Karthikeyan et al.
increases in temperature from 80 to 100 °C. It was found that there was not much
appreciable change in yield even when the reaction was carried for 2 h and at higher
temperature (Table 1, entries 12–16). With the optimized conditions, the derivatives
of the 3,4-dihydropyrimidine-2(1-H)-thione were synthesized using L-AAIL/AlCl3.
The formation of the product was confirmed by characterization of the represen-
tative compound.
In order to test the substrate generality of [L-AAIL]/AlCl3 catalyzed 3,4-
dihydropyrimidin-2(1-H)-thiones, the condensation of various aldehyde with ethyl
acetoacetate and thiourea were studied under the optimized conditions. The results
are summarized in Table 2. It can be noticed that a wide range of aldehyde can
efficiently contribute in the Biginelli reaction. However, the benzaldehyde-bearing
electron-withdrawing substituents furnished the Biginelli reaction with excellent
yields. On the other hand, longer reaction times were required for aldehyde
containing an electron-donating group to give comparatively inferior yields. This
can be explained by the electron-withdrawing groups improving the electrophilicity
of the carbonyl carbons aldehyde, which facilitates the reaction, while electron-
donating groups reduce the electrophilicity.
Reusability of the catalyst was next checked by the model reaction under
optimized condition. Indeed, the catalytic activity of L-AAIL/AlCl3 is comparable
to its parent salt FeCl3 in Biginelli condensation. It is worth noting, however, that
the L-AAIL/AlCl3 are much moe robust and water-tolerant in comparison with
ferric chloride, especially in the presence of hot water. After work-up procedure, the
catalyst L-AAIL/AlCl3 remaining in the filtrate can be recovered by removing the
water through heating and then drying under vacuum for 1 h. As shown in Table 3,
the catalytic ionic liquid could be reused at least five successive runs for the
synthesis of dihydrohydropyridimin-2(1-H)-thiones without significant loss of
activity. The yields remained around 86–75 % clearly illustrate the reusability of the
catalysts (Table 3).
The above experiments throw some light on the mechanism with the L-AAIL/
AlCl3 catalyst. Even though a detailed mechanistic scheme is not yet known, the
reaction is catalyzed most likely by L-AAIL/AlCl3 cation of the ionic liquid
complex. From that above mechanism, we can observe that addition of the
carbanion takes place in the form of a Michael addition. Here, we notice that
L-AAIL act as both the Brønsted acid and base (Scheme 2).
Conclusion
In conclusion, we have described an efficient protocol for the Biginelli reaction
catalyzed by the functionalized ionic liquid, L-AAIL/AlCl3. The methodology has
the advantages of short reaction time, lack of organic solvent, and easy work-up for
isolation of the products in good yield with high purity. The reusability of this novel
catalyst gave good yield even after being used five times. All these characteristics
make this protocol applicable for an industrial purpose.
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A novel amino acid functionalized ionic liquid
1339
Table 2 Derivative of Biginelli reaction in presence of L-AAIL/AlCl3
Sample no.
1
Reactant
Product
C2H5O
H3C
HN
Yield (%)
85
MP (°C)
208–212
O
CHO
NH
S
2
88
189–193
OCH3
O
OCH3
NH
CHO
C2H5O
H3C
N
H
S
3
95
226–228
OCH3
OCH3
CHO
O
H3CO
OCH3
OCH3
NH
O
C2H5O
H3C
N
S
H
4
95
182–188
CHO
OH
O
OH
NH
C2H5O
H3C
N
S
H
5
89
180–185
CHO
Cl
Cl
O
C2H5O
H3C
NH
N
S
H
123

1340
P. Karthikeyan et al.
Table 2 continued
Sample no.
6
Reactant
Product
Yield (%)
98
MP (°C)
150–156
OCH3
NH
OCH3
OHC
O
C2H5O
H3C
N
H
S
7
96
165–169
n-CH3CH2CH2CHO
O
C2H5O
H3C
NH
N
S
H
Reaction conditions: aldehyde (10.0 mmol), b-dicarbonyl compound (10.0 mmol), thiourea (12.0 mmol)
and L-AAIL/AlCl3 (0.05 mmol), 80 °C under solvent-free conditions
Table 3 Recycling of L-AAIL/AlCl3 system for the one-pot three-component synthesis of dihydrohy-
dropyridimin-2(1-H)-thiones
Entry
Cycle
Conversion (%)
Yield (%)
1
2
3
4
5
0
1
2
3
4
100
100
95
86
84
81
77
75
92
88
Reaction conditions: aldehyde (10.0 mmol), b-dicarbonyl compound (10.0 mmol), thiourea (12.0 mmol)
and L-AAIL/AlCl3 (0.05 mmol), 80 °C under solvent-free conditions
Materials and methods
Melting points were recorded on a Bu¨chi B-545 apparatus in open capillary tubes
and reported uncorrected. 1H NMR spectra were recorded on Bruker (500 MHz) and
mass spectra were recorded on JEOL GC MATE II HR-MS (EI) spectrometer.
FT-IR was recorded on AVATRA 330 Spectrometer with DTGS detector. All
solvents and chemicals were commercially available and used without further
purification unless otherwise stated.
Preparation of catalysts (L-AAIL)
A mixture of Boc-valine (11.0 mmol) and triethyl amine (22.0 mmol) in DMF was
cooled in an ice-bath. The 1-carboxy ethyl-3-methyl imidazolium bromide
123

A novel amino acid functionalized ionic liquid
1341
OH
H
from L-AAIL
NH2
H2N
C
S
NH2
C
O
Ph
N
Ph
H
H
S
AlCl3-Br
HN
Br
N
N
O
H2O
HO
O
O
O
O
O
H
N
NH 2
S
O
Ph
O
AlCl3-Br
Br
HN
N
N
O
O
O
AlCl3-Br
Br
HN
N
N
O
HO
O
O
H
S
C2H5O
N
H3C
N
H
Scheme 2 Tentative mechanism for the L-AAIL/AlCl3 catalyzed 3,4-dihydropyrimidin-2(1-H)-thiones
[Cemim]Br (10.0 mmol) was added and agitation continued at ambient temperature
for 24 h. After completion of the reaction, the mixture was extracted with ether and
poured into water. The unreacted Boc-valine was removed by centrifugation. The
aqueous layer was concentrated using a rotary evaporator and the ionic liquid was
dried under vacuum at 70 °C for 6 h. The Boc-3-(3-(1-carboxy-2-methylpropyla-
mino)-3-oxopropyl)-1-methyl-1H-imidazol-3-ium bromide was deprotected using
50 % TFA in dichloromethane (5 mL) for 1 h at 25 °C. After evaporation of the
solvent from the mixture, TFA was removed by triturating the residue with 5 mL of
methanol (saturated with ammonia). The resulting mixture was concentrated using
rotary evaporator, and the ionic liquid 3-(3-(1-carboxy-2-methylpropylamino)-3-
oxopropyl)-1-methyl-1H-imidazol-3-ium bromide (L-AAIL) was dried under vac-
uum 80 °C 3 h. 1H NMR (500 MHz, DMSO-d6) d: 0.9 (d, 6H), 1.8 (m, 1H), 2.4 (d,
2H), 3.4 (s, 3H), 4.3 (s, 1H), 5.2 (s, 2H), 6.8 (d, 1H), 7.2 (d, 1H), 7.7 (s, 1H), 8.3 (s,
1H), 10.2 (s, 1H); 13C NMR (125 MHz, DMSO-d6) d: 20.97, 23.02, 36.56, 54.45,
65.96, 127.93, 128.30, 128.90, 140.65, 177.01, 184.35. Microanalytical data: Cal
(C: 43.13; N: 12.57; H: 6.03), found: (C: 43.09; N: 12.54; H: 5.99).
A typical experimental procedure for Biginelli type reaction
Aldehyde (10.0 mmol), b-dicarbonyl compound (10.0 mmol), thiourea (12.0 mmol),
and L-AAIL/AlCl3 (0.05 mmol) were successively charged into a 100-mL
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P. Karthikeyan et al.
round-bottomed flask with a magnetic stirring bar. Then, the reaction proceeded at
80–100 °C in oil bath for 2–6 h, while the product formation was monitored by TLC.
After the completion of the reaction, the resulting solid product was poured into ice-
cold water followed by addition of chloroform (3 9 5 mL). Then, the organic layer
was separated, dried over anhydrous Na2SO4, and the chloroform was removed under
reduced pressure to get the solid product. The resulting product was recrystallized to
get white pure crystals with little amount of ethanol.
Data for representative product
Ethyl 1,2,3,4-tetra hydro-4-(4-methoxy phenyl)-6-methyl-2-thioxo pyrimidine-5-carbox-
ylate: 1H NMR (500 MHz, DMSO-d6): d 7.047–7.069 (d, J = 8.8 MHz, 2H),
6.821–6.843 (d, J = 8.8 MHz, 2H), 10.229 (s, 1H), 9.539 (s, 1H), 3.656 (s, 3H), 5.038
(s, 1H), 3.907–3.960 (q, J = 21.2 MHz 2H), 1.020–1.056 (t, J = 14.4 MHz, 3H), 2.216
(s, 3H); 13C NMR (100 MHz, DMSO-d6) d: 173.66, 165.13, 158.70, 144.70, 135.66,
127.57, 113.85, 100.94, 59.51, 55.06, 53.40, 18.51, 17.09. HR-MS (ESI): 306.4066.
Acknowledgments We gratefully acknowledge the management of VIT University for providing the
required facilities and SAIF (IITM) for providing the spectral data.
References
1. C.O. Kappe, Tetrahedron 49, 6937 (1993)
2. P. Biginelli, Gazz. Chim. Ital. 23, 360 (1893)
3. B.J. Ahn, M.S. Gang, K. Chae, Y. Oh, J. Shin, W. Chang, J. Ind. Eng. Chem. 14, 401 (2008)
4. X.L. Zhang, Y.P. Li, C.J. Liu, J.D. Wang, J. Mol. Catal. A 253, 207 (2006)
5. J.T. Li, J.F. Han, J.H. Yang, T.S. Li, Ultrason. Sonochem. 10, 119 (2003)
6. M.M. Heravi, F.K. Behbahani, H.A. Oskooie, Chin. J. Chem. 26, 2203 (2008)
7. R. Fazaeli, S. Tangestaninejad, H. Aliyan, M. Moghadam, Appl. Catal. A 309, 44 (2006)
8. C. Liu, J. Wang, Y. Li, J. Mol. Catal. A 258, 367 (2006)
9. D.S. Bose, L. Fatima, H.B. Mereyala, J. Org. Chem. 68, 587 (2003)
10. H. Zhang, Z. Zhou, Z. Xiao, F. Xu, Q. Shen, Tetrahedron Lett. 50, 1622 (2009)
11. E. Rafiee, F. Shahbazi, J. Mol. Catal. A 250, 57 (2006)
12. M. Gohain, D. Prajapati, J.S. Sandhu, Synlett. 2, 235 (2004)
13. P. Salehi, M. Dabiri, M.A. Zolfigol, M.A.B. Fard, Tetrahedron Lett. 44, 2889 (2003)
14. Y.L. Zhu, S.L. Huang, J.P. Wan, L. Yan, Y.J. Pan, A. Wu, Org. Lett. 8, 2599 (2006)
15. D. Shobha, M.A. Chari, K.H. Ahn, Chin. Chem. Lett. 20, 1059 (2009)
16. B. Ahmed, R.A. Khan, K.M. Habibullah, Tetrahedron Lett. 50, 2889 (2009)
17. D. Fang, D.Z. Zhang, Z.L. Liu, Monatsh. Chem. 141, 419 (2010)
18. J.J. Peng, Y.Q. Deng, Tetrahedron Lett. 42, 5917 (2001)
19. A. Shaabani, A. Rahmati, Catal. Lett. 100, 177 (2005)
20. M. Li, W.S. Guo, L.R. Wen, Y.F. Li, H.Z. Yang, J. Mol. Catal. A 258, 133 (2006)
21. R.W. Zheng, X.X. Wang, H. Xu, J.X. Du, Synth. Commun. 36, 1503 (2006)
22. X. Chen, Y. Peng, Catal. Lett. 122, 310 (2008)
23. J.H. Davis, A. Wierzbicki, Proceedings of the Symposium on Advances in Solvent Selection and
Substitution for Extraction, New York, 2000
24. A.C. Cole, J.L. Jensen, I. Ntai, K.L.T. Tran, K.J. Weaver, D.C. Forbes, J.H. Davis, J. Am. Chem. Soc.
124, 5962 (2002)
25. J.H. Davis, Chem. Lett. 33, 1072 (2004)
26. D.C. Forbes, K.J. Weaver, J. Mol. Catal. A 214, 129 (2004)
27. H.P. Zhu, F. Yang, J. Tang, M.Y. He, Green Chem. 5, 38 (2003)
28. D.G. Gu, S.J. Ji, Z.Q. Jiang, M.F. Zhou, T.P. Lo, Synlett. 7, 959 (2005)
123