Nebivolol nanoparticles: A first catalytic use in Biginelli and Biginelli-like reactions

Article abstract of DOI:10.1139/cjc-2017-0621

Herein, we report the catalytic activity of nebivolol nanoparticles a novel organocatalyst for the synthesis of DHPMs and DHPM-5-carboxamides. The nanoparticles are confirmed by DSC, TEM, AFM, and IR spectroscopy. The catalyst can be readily recovered and

Full text of DOI:10.1139/cjc-2017-0621

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Nebivolol nanoparticles: A first catalytic use in Biginelli and Biginelli-like
reactions
Anamika Khaskel,*a Pranjit Barmana, Subir Kr Maitia and Utpal Janab
aDepartment of Chemistry, National Institute of Technology, Silchar 788010, Assam, India
bSchool of Pharmacy, Chouksey Engineering college, Lal Khadan, NHꢀ49, Bilaspur 495004
Abstract
Herein, we report the catalytic activity of nebivolol nanoparticles a novel organocatalyst for
the synthesis of DHPMs and DHPMꢀ5ꢀcarboxamides. The nanoparticles are confirmed by
DSC, TEM, AFM and IR spectroscopy. The catalyst can be readily recovered and reused for
the next four runs without any significant impact on the yields of the products. The products
1
are fully characterized by FTꢀIR, H NMR, 13C NMR and DEPT NMR. The methodology
adopted here offers several advantages such as solventꢀfree reaction, low loading of catalyst,
short reaction times and quantitative yields.
Graphical Abstract
Keywords
Organocatalyst, Nebivolol nanoparticles, DHPM and DHPMꢀ5ꢀcarboxamides
Introduction
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In recent times, the main objectives in multicomponent condensation reactions are to develop
a green methodology using an organoꢀbiogenic catalyst for better environmental
compatibility. Dihydropyrimidinones (DHPMs), the outcomes of Biginelli reaction are
considered as a major class of heterocycles that possesses a wide spectrum of diverse
biological and pharmacological properties.[1] Recently, G. Bifulco and his coꢀworkers
reported DHPM derivatives in order to identify more powerful and safer Hsp90 inhibitors.[2]
Nꢀ3 acylated DHPMs or DHPMꢀ5ꢀCarboxamides are known to be excellent selective αꢀ1aꢀ
adrenergic receptors[3] and show cochicineꢀlike property of destabilizing microtubes.[4] So
such derivatives have also been attracted by the medicinal chemists.
As DHPM derivatives are widely used many approaches can be found in literature.[5ꢀ17]
Nevertheless most of them have severe limitations, for example harsh reaction conditions,18
high costs,[19] low yields,[20] high catalyst loadings,[21] and longer reaction time.[22] Generally,
organocatalytic Biginelli reaction has been suffered from two main drawbacks a. longer
reaction time and b. use of costly solvent. There are very insignificant reports, to the best of
our knowledge on the synthesis of DHPMꢀ5ꢀcarboxamides for Biginelliꢀlike reaction in one
step.[23ꢀ24] So, there is certainly a scope for development of the synthesis of DHPMꢀ5ꢀ
carboxamides using green and clean methodology. Nebivolol is a β1 receptor blocker used in
the treatment of hypertension and also for the left ventricular failure.[25ꢀ26] Nebivolol has very
poor solubility but in its nanoparticulate form which leads to an enhanced dissolution rates
because of the increment in the surface area.[27] The enhancement of surface area may also
generate a new catalytic activity in nebivolol nanoparticles for organic reactions. This is the
first report that a well known drug nanoparticles can be used as an efficient catalyst in
organic reactions.
Results and Discussion
Biginelli and Biginelli like reactions that assemble aldehydes, enolizable carbonyls and urea
into DHPMs first screened by various catalysts (Table 1).
Scheme 1
Table 1
We consider a model reaction using benzaldehyde, urea and methylacetoacetate to investigate
the catalytic activity of nebivolol nanoparticles (2a, R = Ph, R1 = Me, DHPMs, Scheme 1).
2

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Reaction under solventꢀfree condition without any catalyst is not giving any positive result.
Initially, it was found that nebivolol has medium catalytic activity but it becomes very high
when encapsulated as polymeric nanoparticles. To ensure whether this enhancement in
catalytic efficiency is due to Polaxomer 188 additives or the encapsulation of nebivolol
nanoparticles a number of different experiments are carried out. When the reaction was
carried out with Polaxomer 188 in absence of any nebivolol catalyst, no observable product
formation happened. This observation ensured that the eudragit coating has no such catalytic
activity and the reaction is catalyzed by nebivolol nanoparticles only.
At the outset, we promote Biginelli reaction using nebivolol nanoparticles as catalyst and
using benzaldehyde, methyl acetoacetate and urea as the model reaction. We also envisaged
the reaction using 1.00: 1.00: 1.00 ratios between the reagents toward a more efficient and
green procedure.
A broad range of DHPMs (2aꢀ2w) for Biginelli reactions and DHPMꢀ5ꢀcarboxamides (2xꢀ
2aa) for Biginelliꢀlike reactions have been synthesized using nebivolol nanoparticles as
catalyst. We used acetoacetanilide in place of 1,3ꢀdiketones for the synthesis of DHPMꢀ5ꢀ
carboxamides (2xꢀ2aa). As shown in Table 2, a large range of substituted benzaldehydes,
heteroaromatic aldehydes could undergo the reaction in high yields. Nebivolol nanoparticles
also act as a very efficient catalyst in DHPMꢀ5ꢀcarboxamides synthesis .
Table 2
Eudragit is the coꢀpolymer of poly (ethylacrylate, methylꢀmethacrylate and chlorotrimethylꢀ
ammonioethyl methacrylate) and has high permeability and pH independent swelling
properties. Quaternary ammonium groups provide a surface positive charge.
The prepared nanoparticles are characterized by particle size analysis, TEM, FTꢀIR and AFM
studies. The mean particle size of nanoparticles as measured by the Photon correlation
spectroscopy are measured in size range ~500ꢀ580 nm (ES1, Figure 1). Formation of
nebivolol nanoparticles are confirmed by transmission electron microscope study (average
size ~ 50 nm) (ES1, Figure 2 and 3). The surface morphology of the nanoparticles is
confirmed by Atomic force microscopy (ES1, Figure 4 and 5). AFM investigations confirmed
disc like shape of the particles with slight aggregation. It was also proven that particles are
surrounded by a soft layer. FTꢀIR spectra are used to find out the drugꢀpolymer interaction in
the nanoparticles. Intensity of peak decreased than original nebivol at 1434 and 2928 cmꢀ1 due
3

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to hydrogen bonding interaction between nebivolol and Eudragit polymer in the nanoparticles
(ES1, Figure 6). This Hꢀbonding interaction gives the stability of nebivolol inside the
nanoparticles. Differential scanning calorimetry was used to detect the physioꢀchemical
interaction between the drug and polymer. The prominent and sharp peak at 192oC in
thermogram represents the melting point of nebivolol (ES1, Figure 7). The prepared
nanoparticles depicted no such peak of native nebivolol due to loss of crystallinity. In
Schemeꢀ2 the hydrogen bonding complex (2) formed by catalyst, urea and aldehyde will
enjoy greater stability and the reaction will follow iminium ion pathway.
Scheme 2
This intermolecular hydrogen bonding interaction makes the reaction facile with high yields.
Now, another question is why reaction rate and yield increase with the use of nebivolol
nanoparticles instead of simple nebivolol though simple nebivolol is free from polymeric
coating and it should react with aldehyde and urea more quickly. In nanoparticulate form
hydrogen bonding interaction between nebivolol and Eudragit polymeric coating has been
observed. So, nanoparticulate form is very stable and nebivolol is in much more oriented
manner to interact with the aldehyde and urea through the gap present in polymeric coating.
es
.
In nanoparticulate form surface area will be increased due to positively charge surface
reacting mixture will come into the surface easily with more organized manner. As the
reaction takes place in surface so rate of reaction will be very high.
Figure 1
Conclusion
In conclusion, we have synthesized and applied nebivolol nanoparticles as powerful catalyst
in Biginelli and Biginelli like reactions for the one pot synthesis of DHPMs and DHPMꢀ5ꢀ
carboxamides expecting advantages in nebivolol nanoparticles can easily disperse through the
flexible polymer coating, increment in surface area, simple work up procedure, very small
catalyst loading and simple green methodology. So, drug nanoparticles can play a good
catalytic role in organic synthesis.
Experimental
General
4

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All chemicals were obtained from Aldrich and used without further purifications. IR spectra
1
were recorded as KBr pellets on a Perkin Elmer 782 spectrophotometer. The H NMR and
13C NMR spectra in DMSO were run on a Bruker AMꢀ300L instrument operating at 300
MHz and 75 MHz respectively.
Characterization of products
5-Aceto-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (2b): m.p. 232ꢀ234 ºC; white
1
colour, FTIR (KBr, cmꢀ1): 3259.4, 1705.5, 1680.4; H NMR (DMSO, 300MHz): δ 2.06 (s,
3H), 2.24(s, 3H), 5.22 (d, 1H), 7.20ꢀ7.31(m, 5H), 7.78(s, 1H), 9.13(s, 1H); 13C NMR
(DMSO, 75 MHz): δ 18.98, 30.38, 53.92, 109.69, 126.50, 127.42, 128.60, 144.32, 148.18,
152.21, 194.36 Anal. Calcld. for C13H14O2N2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.78;
H, 6.18; N, 12.13. HRMS: Calcld. for C13H14O2N2Na+ : 239.0796; found: 239.0795.
5-(Ethoxycarbonyl)-6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione
(2g): m.p. 152ꢀ153 ºC; yellow colour, FTꢀIR (KBr, cm ꢀ1 ): 3250, 1652, 1599, 1561; 1H NMR
(DMSO, 300 MHz): δ 1.07 (t, 3H, J = 7.2 Hz), 2.23 (s, 3H), 3.67 (s, 3H), 3.98 (q, 2H, J = 7.2
Hz), 5.06 (d, 1H), 6.86 (d, 2H, J = 8.7 Hz), 7.09 (d, 2H, J = 8.7 Hz), 9.53 (s, 1H), 10.22 (s,
1H); 13C NMR (DMSO, 75 MHz): δ 14.10, 17.20, 53.52, 55.17, 59.60, 101.06, 113.95,
127.67, 135.77, 144.78, 158.81,165.23, 174.12; Anal. Calcld. for C15H18N2O3S: C, 58.80; H,
5.92; N, 9.14. Found: C, 58.73; H, 5.96; N, 9.12. HRMS: Calcld. for C15H18N2O3SNa+ :
299.1008; found: 299.1007.
5-Aceto-6-methyl-4-(3, 4, 5-trimethoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (2h):
1
m.p. 200ꢀ201ºC; Yellow solid, H NMR (DMSO, 300 MHz): δ 2.08 (s, 3H), 2.26 (s, 3H),
3.59 (s, 3H ), 3.69 (s, 6H), 5.18 (s, 1H), 6.50 (s, 1H), 7.72 (s, 1H), 9.12 (s, 1H); 13C NMR: δ
18.86, 30.28, 53.97, 55.92, 60.04, 103.85, 109.12, 136.96, 139.79, 148.22, 152.15, 152.93,
194.55, Anal. Calcld for C16H20O5N2: C, 59.99; H, 6.29; N, 8.74. Found: C, 59.87; H, 6.38;
N, 8.64. HRMS: Calcld. for C16H20O5N2Na+ : 320.1372; found: 320.1370.
5-Aceto-6-methyl-4-(2-thienyl)-3,4-dihydropyrimidin-2(1H)-one (2j): m.p 200ꢀ202 ºC,
Yellow colour, 1H NMR (DMSO, 300 MHz): δ 2.14 (s, 3H), 2.21 (s, 3H), 5.47 (d,1H), 6.87ꢀ
6.91(m, 2H), 7.35(d, 2H, J = 4.5 Hz), 7.89 (s, 1H), 9.24 (s, 1H); 13C NMR: δ 18.85, 30.15,
49.32, 110.51, 123.94, 124.87, 126.73, 148.20, 148.68, 152.23, 193.80. Anal. Calcld for
C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86. Found: C, 55.87; H, 5.16; N, 11.90. HRMS:
Calcld. for C11H12N2O2SNa+ 259.0517; found: 259.0516.
º
5-Aceto-4-(3-thienyl)-3,4-dihydropyrimidin-2(1H)-one (2k): m.p. 202 C Yellow powder,
1H NMR (DMSO, 300 MHz): δ 2.11 (s, 3H), 2.22 (s, 3H), 5.25 (d, 1H), 6.97 (d, 2H, J = 5.1
5

Page 6 of 13
Hz), 7.13 (s, 1H), 7.40ꢀ7.43 (m, 1H), 7.78 (s, 1H), 9.13 (s, 1H); 13C NMR (DMSO, 75 MHz):
δ 18.95, 30.24, 49.51, 110.06, 121.20, 126.57, 145.58, 148.12, 152.64, 194.20; Anal. Calcld.
For C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86. Found: C, 55.82; H, 5.17; N, 11.94. HRMS:
Calcld. for C11H12N2O2SNa+ 259.0517; found: 259.0517.
º
5-(Methoxycarbonyl)-4-(3-thienyl)-3,4-dihydropyrimidin-2(1H)-one (21): m.p. 223 C
1
Yellow powder, FTIR (KBr, cmꢀ1): 3349.6, 1694.3, 1641.5; H NMR (DMSO, 300 MHz): δ
2.18 (s, 3H), 3.54 (s, 3H), 5.17 (d, 1H), 6.95 (d, 1H, J = 7.2 Hz), 7.11 (s, 1H), 7.40ꢀ7.43(m,
1H), 7.73 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO, 75 MHz): δ 17.81, 49.42, 50.87, 99.28,
120.79, 126.21, 145.71, 148.77, 152.63, 165.82; Anal. Calcld for C11H12N2O3S: C, 52.37; H,
4.79; N, 11.10. Found: C, 52.40; H, 4.74; N, 11.20. HRMS: Calcld. for C11H12N2O3SNa+
275.0466; found: 275.0465.
º
5-(Ethoxycarbonyl)-4-(3-thienyl)-3,4-dihydropyrimidin-2(1H)-one (2m): m.p. 195 C,
Yellow powder, FTꢀIR (KBr, cm ꢀ1): 3239.6, 1711.8, 1648.1; 1H NMR (DMSO, 300 MHz): δ
1.13 (t, 3H, J = 7.2 Hz), 2.18 (s, 3H), 3.99 (q, 2H, J = 6.9 Hz), 5.18 (d, 1H), 6.96 (d, 2H, J =
5.1 Hz), 7.10 (d, 1H), 7.41 (m, 2H), 7.71 (s, 1H), 9.15 (s, 1H); 13C NMR (DMSO, 75 MHz): δ
14.24, 17.82, 49.52, 59.31, 99.55, 120.81, 126.20, 126.68, 145.85, 148.50, 152.67, 165.39.
Anal. Calcld. For C12H14O3N2S: C, 54.12; H, 5.30; N, 10.52. Found: C, 54.08; H, 5.35; N,
10.48. HRMS: Calcld. for C12H14O3N2SNa+:289.0623; found: 289.0623.
5-(Methoxycarbonyl)-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidn-2(1H)-one (2n):
m.p. 245ꢀ246oC, 1H NMR (DMSO, 300 MHz): δ2.27 (s, 3H), 3.53 (s, 3H), 5.26 (d, 1H), 7.58ꢀ
13
8.26 (m, 4H), 7.89 (s, 1H), 9.35 (s, 1H), C NMR (DMSO, 75 MHz): δ 17.98, 50.99, 53.44,
98.19, 120.97, 122.46, 130.31, 132.99, 146.81, 147.94, 149.73, 151.87, 165.68, Anal. Calcld
for C13H13O5N3: C, 53.61; H, 4.50; N, 14.43. Found: C, 53.45; H, 4.58; N, 14.50. HRMS:
Calcld. for C13H13O5N3Na+:300.0596; found: 300.0596.
5-(Methoxycarbonyl)-6-methyl-4-styryl-3,4-dihydropyrimidn-2(1H)-one (2r): m.p. 220ꢀ
222 oC, White solid, FTꢀIR (KBr, cm ꢀ1): 3243.6, 1715.9, 1651; 1H NMR (DMSO, 300 MHz):
δ 2.16 (s, 3H), 3. 59 (s, 3H ), 4.70 (s, 1H), 6.19 (dd, 1H, J = 5.7 Hz, 15.9 Hz), 6.35 (d, 1H, J =
15.9 Hz), 7.18ꢀ7.37 (m, 5H), 7.51 (s, 1H), 9.12 (s, 1H), 13C NMR: δ 17.89, 50.98, 51.76,
97.81, 126.45, 127.67, 128.08, 128.74, 130.11, 136.33, 148.80, 152.73, 165.81, Anal. Calcld
for C15H16O3N2: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.09; H, 5.82; N, 10.22. HRMS:
Calcld. for C15H16O3N2Na+ 295.1059 found: 295.1059.
1
5-Aceto-6-methyl-4-styryl-3,4-dihydropyrimidin-2(1H)-one (2s): m.p. 210ꢀ211 oC, H
NMR (DMSO, 300 MHz): δ 2.22 (s, 3H), 4.79 (s, 1H), 6.17 (dd, 1H, J = 6 Hz, 15.9 Hz), 6.37
6

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13
(d, 1H, J = 15.9 Hz), 7.16ꢀ7.45 (m, 5H), 7.57 (s, 1H), 9.11 (s, 1H), C NMR: δ 18.99, 30.27,
51.91, 108.56, 126.42, 127.65, 128.20, 128.70, 128.95, 130.06, 136.30, 148.05, 152.76,
194.10, Anal. Calcld for C15H16O2N2: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.20, H, 5.80;
N, 10.32. HRMS: Calcld. for C15H16O2N2Na+ : 265.0953; found: 265.0952.
6-methyl-2-oxo-N-phenyl-4-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidin-5-
o
1
carboxamide (2x): m.p. 242ꢀ244 C, Pale orange, H NMR (DMSO, 300 MHz): 2.00 (s,
3H), 3.78 (s, 3H), 5.39 (d, 1H), 6.82ꢀ7.60 (m, 9H), 8.27 (1H, s), 8.66 (s, 1H), 9.47 (s, 1H) 13C
NMR (75 MHz): 17.10, 54.70, 55.01, 105.86, 115.13, 119.65, 123.07, 127.58, 128.52,
135.91, 138.00, 139.31, 152.59, 156.69, 165.44, Anal. Calcld for C19H19O3N3: C, 67.64; H,
5.68; N, 12.46. Found: C, 67.60; H, 5.62; N, 12.41. HRMS: Calcld. for C19H19O3N3Na+
:360.1324; found: 360.1325.
Acknowledgements
This work was supported by NIT Silchar.
Supporting Information
1
Full experimental detail and H NMR and 13C NMR spectra can be found via the
Supplementary Content section of the article’s webpage.
References
1.
2.
Singh, K.; Arora, D.; Singh, K.; Singh, S. Mini Rev. Med. Chem. 2009, 9, 95ꢀ106.
Strocchia M.; Terracciano S.; Chini, MG.; Vassallo A.; Vaccaro MC.; Piaz
A.; Riccio R.; Bruno, I.; Bifulco G. Chem. Commun. 2015, 51,
,
,
,
,
,
FD.; Leone
3850ꢀ3853.
,
,
,
3.
Barrow, J.C.; Nantermet, P.G.; Selnick, H.G.; Glass, K.L.; Rittle, K.E.; Gilbert,
K.F.; Steele, T.G.; Homnick, C.F.; Freidinger, R.M.; Ransom, R.W.; Kling, P.;
Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang, R. S.; Malley, S.S.O.;’ Olah, T.;
Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C.
J. Med. Chem. 2000, 43, 2703ꢀ2718.
4.
5.
Haggarty, S.J.; Mayer, T.U.; Miyamoto, D. T.; Fathi, R.; King, R.W.; Mitchison
T.J.; Schreiber, S.L. Chem. Biol. 2000, 7, 275.
Alvim, H.G.O.; de Lima, T. B.; de Oliveira, A.L.; de Oliveira, H.C. B.; Silva,
F.M.; Gozzo, F. C.; Souza, R.Y.; da Silva, W.A.; Neto, B.A.D. J. Org. Chem.
2014, 79, 3383ꢀ3397.
7

Page 8 of 13
6.
Alvim, H.G.O.; de Lima, T.B.; de Oliveira, H.C.B.; Gozzo, F. C.; de Macedo,
J.L.; Abdelnur, P.V.; Silva, W.A.; Neto, B.A.D. ACS. Catal. 2013, 3, 1420ꢀ1430.
Gore, S.; Baskaran, S.; Koenig, B. Green. Chem. 2011, 13, 1009ꢀ1013.
Ramos, L.M.; Guido, B.C.; Nobrega, C.C.; Correa, J.R.; Silva, R.G.; de Oliveira,
H.C.B.; Gomes, A.F.; Gozzo, F.C.; Neto, B. A.D. Chem. Eur. J. 2013, 19, 4156ꢀ
4168.
7.
8.
9.
Ramos, L.M.; Tobio, A.Y.; dos Santos, M.R.; de Oliveira, H.C.B.; Gomes, A.F.;
Gozzo, F.C.; de Oliveira, A.L.; Neto, B.A.D. J. Org. Chem. 2012, 77, 10184ꢀ
10193.
10. Lima, C.G.S.; Silva, S.; Goncalves, R.H.; Leite, E.R.; Schwab, R.S.; Correa,
A.G.; Paixao, M.W. Chemcatchem 2014, 12, 3455ꢀ3463.
11. Oliverio, M.; Costanzo, P.; Nardi, M.; Rivalta, I.; Procopio, A. ACS Sustain.
Chem. Eng. 2014, 2, 1228ꢀ1233.
12. Puripat, M.; Ramozzi, R.; Hatanaka, M.; Parasuk,W.; Parasuk,V.; Morokuma, K.
J. Org. Chem. 2015, 80, 6959ꢀ6967.
13. Safari, J.; Jarneqar, Z. New. J. Chem. 2014, 38, 358ꢀ365.
14. Ma, J.; Xhong, L.; Peng, X.; Sun, R. Green Chem. 2016, 18, 1738ꢀ1750.
15. Khademinia, S.; Behzad, M.; Alemi, A.; Dolatyari, M.; Saiiadi, S.M. RSC Adv.
2015, 5, 71109ꢀ71114.
16. Safari, J.; GandomiꢀRavandi, S.; Ashiri, S. New J. Chem. 2016, 40, 512ꢀ520.
17. Vessally E, Hassanpour A, Khanmiri RH, Babazadeh M, Abolhasani J 2016,
Monatsh Chem doi:10.1007/s00706ꢀ016ꢀ1762ꢀ2
18. (a) Folkers, K.; Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784 –3791; (b)
Romanelli, G. P.; Sathicq, A. G.; Autino, J. C.; Baronetti, G.; Thomas, H. J.
Synth. Commun., 2007, 37, 3907; (c) Narsaiah, A.V.; Basak, A.K.; Nagaiah, K.
Synthesis, 2004, 8, 1253ꢀ1256.
19. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864ꢀ3868.
20. Liu, C. J.; Wang, J. D. Molecules, 2009, 14, 763ꢀ770.
21. Slimi,H.; Moussaoui, Y.; Salem, R.B. J. Société Chimique Tunisie. 2012, 14, 1ꢀ5
22. Debache, A.; Boumoud, B.; Amimour, M.; Belfaital, A.; Rhouati, S.; Carboni, B.
Tetrahedron Lett. 2006, 47, 5697
23. Kumar, B.R.P.; Sankar, G.; Baig, R.B.N.; Chandrashekaran, S. Eur. J. Med.
Chem. 2009, 44, 4192ꢀ4198.
24. Couto, I.; Tellitu, I.; Dominguez, E. ARKIVOC. 2011, ii, 115ꢀ126.
8

Page 9 of 13
25. Sjostrom B, Bergenstahl B, Kronberg B J. Pharm. Sci. 1993, 82, 584ꢀ589.
26. Boer R.A.D.; Voors A.A.; van Veldhuisen D.J. Expert Opinion on
Phermacotherapy, 2007, 8, 1539.
,
,
,
27. Jana, U.; Mohanty, A.K.; Manna, P.K.; Mohanta, G.P. Colloids and Surfaces B:
Biointerfaces 2014, 113, 269ꢀ275.
28. Sharma, N.; Sharma, U.K.; Kumar, R.; Richa, Sinha, A.K. RSC Adv. 2012, 2,
10648ꢀ10651.
29. Sharma, S.D.; Gogoi, P.; Konwar, D. Green. Chem. 2007, 9, 153ꢀ157.
30. Ma,Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864ꢀ3868.
31. Zhang, Q.; Wang, X.; Zhenjiang, L; Wenzhuo, W.; Jingjing, L.; Hao, W.; Saide
,C.; Kai, G. RSC Adv. 2014, 4, 19710ꢀ19715.
32. Nandurkar, N.S.; Bhanushali, M.J.; Bhor, M.D.; Bhanage, B.M. J. Mol. Catal. A
Chem. 2007, 271,14ꢀ17.
R
O
O
R
R1OOC
NH
PhHNOC
H2N
NH2
RCHO +
H2N
NH2
RCHO +
NH
Nebivolol NPs
N
H
O
CH3COCH2COOR1
N
H
O
CH3COCH2CONHPh
2a-2w
2x-2aa
DHPMs
DHPM-5-carboxamides
Reactants
Number
1A
CHO
OMe
1B
CHO
OMe
MeO
1C
1D
OMe
CHO
S
CHO
9

Page 10 of 13
S
1E
1F
CHO
CHO
NO2
OH
CHO
1G
1H
1I
CHO
CHO
OH
CHO
1J
NO2
1K
CHO
O
O
O
O
1a
1b
1c
1d
OMe
Me
Me
O
O
Me
Me
OEt
O
O
PhHN
Me
Scheme 1 Nebivolol nanoparticles catalyzed Biginelli reaction
Table 1 Screening of various catalysts on the synthesis of 2a solventꢀfree conditiona
Catalyst
(g)
loading
Yieldb
(%)
Traces
50
Entry Catalyst
Time(min)
1
PTS
0.01
0.01
0.01
0.01
120
120
120
120
Glycine
Lꢀproline
Lꢀserine
2
3
52
4
60
10

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5
6
Lꢀtyrosine
0.01
0.01
120
120
70
Polaxomerꢀ188
Traces
7
Nebivolol
0.01
0.02
0.05
0.01
50
10
10
25
72
89
89
78
8
Nebivolol NPs
Nebivolol NPs
Nebivolol NPs
9
10
b
aReaction temperature:70oC; molar ratio of benzaldehyde:urea:methylacetoacetate 1:1:1; Isolated
yields
Table 2 DHPMs synthesized using nebivolol nanoparticles as catalyst under solventꢀfree
conditiona
Entry
Aldehydes
1,3ꢀ
dicarbonyl
1a
1b
1c
1c
1b
1a
1c
1b
1c
1b
1b
1a
1c
1a
1c
1c
1a
1a
1b
1c
1a
1b
1b
1d
1d
1d
1d
X
Time (min)
Yield
1.
2.
3.
4.
5.
6.
7.
8.
1A
1A
1A
1B
1B
1B
1B
1C
1D
1D
1E
1E
1E
1F
1F
1G
1G
1H
1H
1I
O
O
O
O
O
O
S
10
10
15
10
10
15
15
20
10
10
5
15
10
10
15
15
10
15
10
15
15
10
10
15
10
10
10
89 (2a)28
90 (2b)29
92 (2c)28
91(2d)29
97 (2e)30
94 (2f)31
93 (2g)29
89 (2h)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
9.
93 (2i)22
90 (2j)
92 (2k)
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21
22.
23.
24.
25
26.
27.
95 (2l)
90 (2m)
92 (2n)
90 (2o)8
91 (2p)8, 28
93(2q)
92 (2r)
95 (2s)
96 (2t)28
91 (2u)27
94 (2v)32
93 (2w)8
92 (2x)
1I
1J
1F
1B
1A
1D
1K
95 (2y)24
91 (2z)24
94 (2aa)24
aReactions were performed with 1 mmol of each reagent at 70 ºC temperature
11

Page 12 of 13
O
X
O
X
+
HN
H O
H2N
NH2
R
H
O
HN
H O
H
O
X
H
X
(1)
H
H
O
O
N
H
O
R
(2)
NH2
H
+N
H2N
H
O
R
(3)
H+
O
H
H
R
ꢀH2O
H2N
N
H2N
N
R
HO
Oꢀ
O
(4)
O
O
H
H
HO
OH
H
N
X
X
R
O
R
O
H
ꢀH2O
H
HN
+N
+
ꢀO
O
N
NH2
O
H
(5)
Scheme 2 Plausible mechanism for the synthesis of DHPMs using nebivolol nanoparticles
(Nebivolol interacts with aldehyde and urea through the gap present in the polymeric coating)
12

Page 13 of 13
Figure 1 Structure of simple nebivolol
13