A novel green synthesis of α/β-amino acid functionalized pyrimidinone peptidomimetics using triazole ligation through click-multi-component reactions

Article abstract of DOI:10.1016/j.tetlet.2013.11.002

An innovative synthetic pathway for the preparation of a new series of triazole-decorated dihydropyrimidinone peptidomimetics with skeletal α or β-amino acid residue is reported. The protocol involves two synthetic steps with an initial solvent-free and catalyst-free synthesis of propargylated dihydropyrimidinone precursors using Biginelli condensations. The subsequent cycloaddition reactions of pyrimidinone alkynes with small peptide like azides prepared from Ugi or alternate Mannich type multi-component reactions afforded the triazole decorated pyrimidinone peptide conjugates in excellent yield with high regio and stereospecificities. In total, a scaffold diversity contains 11 new pyrimidinone alkynes and 18 new pyrimidinone peptidomimetics were introduced into the chemical space.

Full text of DOI:10.1016/j.tetlet.2013.11.002

Accepted Manuscript
A novel green synthesis of α/β-amino acid functionalized pyrimidinone pepti-
domimetics using triazole ligation through click-multi-component reactions
Biny Balan, D. Bahulayan
PII:
S0040-4039(13)01938-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.002
TETL 43797
Reference:
Tetrahedron Letters
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Please cite this article as: Balan, B., Bahulayan, D., A novel green synthesis of α/β-amino acid functionalized
pyrimidinone peptidomimetics using triazole ligation through click-multi-component reactions, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.11.002
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Graphical Abstract
A novel green synthesis of α/β-amino acid
functionalized pyrimidinone peptidomimetics using
triazole ligation through
Leave this area blank for abstract info.
click- multi-component reactions
Biny Balan and D. Bahulayan *

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A novel green synthesis of α/β-amino acid functionalized pyrimidinone
peptidomimetics using triazole ligation through click-multi-component reactions
Biny Balan and D. Bahulayan 
Department of Chemistry, University of Calicut, Malappuram 673635, Kerala, India
ARTICLE INFO
ABSTRACT
An innovative synthetic pathway for the preparation of a new series of triazole-decorated
dihydropyrimidinone peptidomimetics with skeletal α or β-amino acid residue is reported. The
protocol involves two synthetic steps with an initial solvent-free and catalyst-free synthesis of
propargylated dihydropyrimidinones precursors using Biginelli condensations. The subsequent
cycloaddition reactions of pyrimidinone alkynes with small peptide like azides prepared from
Ugi or alternate Mannich type multi-component reactions afforded the triazole decorated
pyrimidinone peptide conjugates in excellent yield with high regio and stereospecificity. In total,
a scaffold diversity contains 11 new pyrimidinone alkynes and 18 new pyrimidinone
peptidomimetics were introduced to the chemical space.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Solvent free Synthesis
Multi-component Reactions
Dihydropyrimidinones
Click chemistry
2009 Elsevier Ltd. All rights reserved.
1,2,3-triazole
Development of structural scaffolds with skeletal diversity
suitable to populate the chemical space of drug leads has been
used in the algorithm of diversity oriented synthesis (DOS).1, 2
One of the important strategies to achieve DOS is the
hydroxyl aldehydes by base catalysed condensation reaction with
propargyl bromide and six such aldehydes with one or more
3
explorations in multicomponent reactions (MCRs) which are
useful tools for building large heterocyclic libraries in one-pot,
one step manner.4 These class of reactions are also amenable to
suitable design strategies for increasing the scaffold diversity in
manifold with desirable bio-profiles. Interesting examples in this
type of diversity intensification includes the union of MCRs4 or
Scheme 1. Synthesis of alkyne functionalized dihydropyrimidinones
by solvent free Biginelli reaction
5
‘clicking’ one of the MCR scaffolds with a different type of
privileged scaffold.6 Among the two, the latter one is more
versatile for the creation of stereo and / or regiospecific 1,4-
disubstituted 1,2,3-triazole derivatives. Many of such triazole
derivatives possess valuable clinical profiles like anti-HIV, anti-
allergic, anti-fungal or anti-viral properties.7-12
alkyne functionalities were prepared.. For performing Biginelli
reaction, methyl acetoacetate and ethyl cyanoacetate were taken
as the CH acidic oxo components and urea as the diamide
component.
Dihydropyrimidinone derivatives also displays a wide range
of biological activities and these have led to the development of a
number of therapeutics including calcium channel blockers,
antiviral, antitumor, antibacterial, anti-inflammatory and
antihypertensive agents.13-15 As part of our ongoing programmes
for developing green protocols for scaffold synthesis, we decided
to work on pyrimidinone chemistry and the subject matter of this
paper is the development of a solvent-free Biginelli condensation
route to functionalized pyrimidinones with cooperative
functionalities and subsequent structural diversifications based on
click chemistry to produce pyrimidinone-peptide conjugates. The
studies were started with the alkyne functionalization of various
———
Scheme 2. Synthesis of α-amino acid type azides by U-4CR
 Corresponding author. Tel.: +9995538062; fax: +91494-2400269; e-mail: bahulayan@yahoo.com

2
In an initial reaction, the components were mixed in
equimolar quantities and heated to 80 oC in an oil bath. After 1h,
the viscous mass obtained was cooled to room temperature and
the solid mass was then stirred with water to obtain the
precipitate of the alkynyl pyrimidinone derivative 1 in pure form
(Scheme 1).16 Accordingly, pyrimidinones 1a-k were synthesized
in 71-86% yield without the aid of a catalyst or solvent. The
results are presented in Table 1.
1a and 2a were mixed with 0. 2 equivalant of CuSO4 and 0.4
equivalent of sodium ascorbate in a mixed solvent system
containing tert-butanol, water and DMSO (4:2:1) at room
temperature (Scheme 3). After 12 h, the reaction mixture was
diluted with cold water to afford the click product 3a (83% yield)
in solid form.19 The results of the studies with azides 2a-b and
alkynes 1a-c are presented in Table 2. The regioselectivity in
triazole formation was confirmed from 1H NMR spectra in which
the appearance of a singlet in between δ8-8.5ppm corresponds to
the hydrogen on the 5-position of the 1,4-disubstituted 1,2,3-
triazole regioisomer.7c,d
Table 1. Solvent-free synthesis of alkynyl pyrimidinone scaffolds
BB5k
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
200
250
300
350
400
Wavelength (nm)
Figure 1. Absorption spectrum of compound 5k (2.805x10-5M) in
DMSO. λabs.max. (nm): 260.0
BB5k
200
150
100
50
0
300
350
400
450
500
Wavelengthv(nm)
Figure 2. Emission spectrum of compound 5k (2.805x10-5M) in
DMSO. λem.max. (nm): 364.0 and 446.0
Table 2. List of 1, 4-disubstituted triazolyl DHPMs with skeletal α-
amino acid residues.
Scheme 3. Synthesis of 1,4-disubstituted triazolyl DHPMs with skeletal
α-amino acid residues via Cu (I) catalyzed Huisgen cycloaddition.
We then moved onto the demonstration of an amenable
chemistry for increasing the skeletal diversity of some of the
pyrimidinones listed in Table 1. For this, we decided to
functionalize pyrimidinones 1a-c with α-amino acid residues or
β-amido ketone residues through ‘click’ cycloaddition to form
highly diversified triazole derivatives of pyrimidinone
peptidomimetics.
The azide derivatives of the α-amino acid residues 2a-b were
synthesized form the post condensation modification of chloro
derivatives of the α-acylamino carboxamides obtained from Ugi
MCR
The skeletal diversity expansion studies were further
extended with β-amino acid type azides 4a-d. The azides 4a-d
were obtained from a two-step process as shown in Scheme 4.
17
as shown in Scheme 2.18 Cycloaddition reactions
between 1a and 2a was carried out at modified Sharpless
condition.7c In a representative reaction, an equimolar mixture of

3
A CuSO4 catalyzed alternate Mannich type four-component
reaction20 of bromopropionitrile with enolizable and non-
enolizable oxo compounds in presence of an acid chloride
afforded the bromoamido ketones. 20, 21
We have also carried out some preliminary investigations on
the optical properties of compounds 3a-f and 5a-l by UV/Vis and
fluorescence spectroscopy. A typical absorption and emission
spectra of compound 5k is given as Figures 1&2. All of the
compounds have absorption wavelengths (λabs) in the UV region
(266–286.5 nm), and have their emission wavelengths (λem) in
the UV or visible region (332–446 nm).22 Slight deviation from
general behavior is observed in compounds with naphthyl
groups. Compounds with naphthyl groups for example 5k have
showed two emission maxima.
Scheme 5. Synthesis of 1,4-disubstituted triazolyl DHPMs with skeletal
β-amino acid residues via Cu (I) catalyzed Huisgen cycloaddition
Scheme 4. Synthesis of β-amido ketone azides by alternate Mannich
reaction.
In summary, we have introduced
a new class of
The bromoamido ketones were then converted to the azides
4a-d in moderate to good yield and purity and are used for the
azide-alkyne [3+2] click cycloaddition reactions with 1a-c
(Scheme 5). The reaction conditions applied was identical with
the same adopted for click chemistry with azides 2a-b. The
pyrimidinone scaffolds as well as pyrimidinone peptidomimetics
to the chemical space by sharing the principles of green
chemistry wherever possible. The procedure is simple with no
requirements of sophisticated experimental set-up. We hope that,
these new peptidomimetic molecules with a biological base can
find application in the search for new drug leads or flurophores.
resulting
1,4-disubstituted
1,2,3-triazolyl
pyrimidinone
peptidomimetics 5a-l were obtained in 70-80% yield (Table 3).
Table 3. List of 1,4-disubstituted triazolyl DHPMs with skeletal β-amino
acid residues.
References and notes
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Finn, M. G. Chem. Soc. Rev. 2010, 39, 1252–1261; (b)
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Tetrahedron Lett. 2004, 45, 8439-8441. (c) Gracias, V.; Darczak,
D.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett. 2005, 46,
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Tetrahedron Lett. 2006, 47, 3055-3058. (e) Chandrashekar, S.;
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7. (a) Huisgen, R. In: Padwa A Eds. Wiley, New York 1984, 1-117.
(b) Sha, C. –K.; Mohanakrishnan, A. K. In: Padwa A Eds.
Pearson WH Wiley New York 2003, 623-680. (c) Rostovtstev, V.
V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2002, 41, 2596-2599. (d) Kolb, H. C.; Finn, M. G.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.
Compounds 3a-f and 5a-l are promising in terms of their
structural features. The presence a 1,4-disubstituted 1,2,3-triazole
linker in between the pyrimidinone ring and the peptide residue
may impart better stability to the molecules. The liphophilicity
constant value (Log P) for both the sets of peptide conjugates 3a-
f and 5a-l was also calculated using an online calculation service
at www.molinspiration.com and the values are presented under
the corresponding structures in Tables 2 and 3.
8. Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med.
Chem. 1986, 29, 2262-2267.

4
9. Vicentini, C. B.; Brandolini, V.; Guarneri, M.; Giori, P.; II
Farmaco 1992, 47, 1021-1034.
10. Fung-Tomc, J. C.; Huczko, E.; Minassian, B.; Bonner, D. P.;
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11. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.;
Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega, K. C.;
Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford,
C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.;
Yagi, B. H. J. Med. Chem. 2000, 43, 953-970.
12. Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.;
Nishimura, H.; Sugiura, M.; Fukaya, C.; Kagittani, Y. J. Med.
Chem. 1996, 39, 3019-3029.
13. (a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38,
119-129 (b) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D.
M.; Moreland, S.; Hedbrg, A.; O’Reilly, B. C. J. Med. Chem.
1991, 34, 806-811. (c) Grover, G. J.; Dzwomczyk, S.; Mc Mullen,
D. M.; Normandin, D. E.; Parham, C. S.; Sleph, P. G.; Moreland,
S. J. Cardiovasc. Pharmacol. 1995, 26, 289-294.
14. (a) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron
1997, 53, 2803-2816. (b) Atwal, K. S.; Rovnyak, G. C.; Kimball,
S. D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.; Gougoutas, J.
Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med. Chem.
1990, 33, 2629-2635. (c) Atwal, K. S.; Rovnyak, G. C.; O’Reilly,
B. C.; Schwartz, J. J. Org. Chem. 1989, 54, 5898-5970. (d) Mayer,
T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S.
L.; Mitchison, T. J. Science 1999, 286, 971-974.
completion of the reaction, the reaction mixture was poured into
ice cold water. The solid product was filtered and dried under
vacuum to afford 2-{[N-benzyl-(N-1-azidopropan-2-one)-N-tert-
butyl-2-(2- chlorophenyl)]} acetamide 2a (0.335g, 81%) as white
solid: IR (KBr) (νmax, cm-1): 3304, 2100, 1685, 1640, 1552. 1H-
NMR (CDCl3, 500MHz) δH (ppm): 1.25 (s, 9H), 1.62 (s, 2H), 4.58
(s, 2H), 6.38 (s, 1H, -CH), 6.95-7.26 (m, 9H), 7.53 (s, 1H). 13C-
NMR (DMSO- (d6), 125MHz) δC (ppm): 31.1, 42.7, 48.3, 51.7,
52.2, 126.8, 127.2, 128.4, 129.6, 129.7, 130.1, 132.5, 134.7, 137.7,
137.9, 167.0, 167.2. EI-MS: 414.4 (M+).
19. Typical procedure for the synthesis of 1, 4-disubstituted triazolyl
DHPMs with skeletal α-amino acid residue 3a: An equi-molar
amount of 2a (69 mg, 0.2 mmol) and 1a (50 mg, 0.2mmol) are
dissolved in minimum amount of DMSO. To this, 2 ml of tert-
BuOH, 1ml of water, CuSO4.5H2O (11 mg) and sodium ascorbate
(50 mg) are added and stirred in room temperature for 12 h. After
12h, the mixture was poured in to cold water. The precipitated
solid was collected and washed with water and dried. The dried
product was washed with diethyl ether (3x 5ml) to afford 3a
(0.138g, 83%) as white solid. IR (KBr) (νmax, cm-1): 3331, 3296,
3225, 1687, 1658, 1604, 1549, 1316, 1176; 1H-NMR (DMSO-(d6),
400MHz) δH (ppm): 1.29 (s, 9H), 2.24 (s, 3H), 3.52 (s, 3H), 4.46
(s, 2H), 4.69 (s, 2H), 5.12 (s, 2H), 5.48 (s, 1H), 6.29 (s, 1H), 6.86-
7.88 (m, 14H, ArH, -CH), 8.07 (s, 1H), 9.18 (s, 1H), 9.87 (s, 1H).
13C-NMR (DMSO-(d6), 100MHz) δC (ppm): 17.4, 31.8, 46.2, 48.1,
49.3, 52.0, 56.6, 72.3, 102.4, 113.2, 121.2, 127.2, 128.2, 128.4,
129.0, 129.1, 129.7, 129.8, 130.1, 132.0, 132.1, 132.2, 132.5,
133.2, 135.1, 137.7, 142.0, 148.2, 151.1, 158.8, 167.5, 168.6,
169.9. EI-MS: 714.0 (M+).
15. (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879-888. (b) Kappe,
C. O. Tetrahedron, 1993, 49, 6937-6963. (c) Kappe, C. O.; Eur.
J. Med. Chem. 2000, 35, 1043-1052.
20. (a) Shinu, V. S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D.
Tetrahedron Lett. 2009, 50, 4838-4842; (b) Shinu, V. S.;
Pramitha, P.; Bahulayan, D. Tetrahedron Lett. 2011, 52, 3110-
315.
16. Typical experimental procedure for the synthesis of alkynyl
pyrimidinone 1a: A mixture of propargylated aromatic aldehyde
(300 mg, 1mmol), methylacetoacetate (183 mg, 1 mmol) and urea
21. Typical procedure for the synthesis of β-amido ketone azide 4a: A
mixture of 4-chloroacetophenone (140 mg, 1 mmol), 2-chloro
benzaldehyde (154mg, 1mmol), and 3-bromopropionitrile (133mg,
1mmol) in acetonitrile (8 ml) was stirred in the presence of 5
mol% CuSO4 at room temperature for 8h. After completion of the
reaction as indicated by TLC, the reaction mixture was poured
into ice cold water and extracted with CH2Cl2 (15 ml).
Evaporation of the solvent followed by purification on silica gel
(100-200 mesh), ethyl acetate/hexane (3:1) afford 3-bromo-N-[1-
(2-chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl] propanamide.
The resulted bromide (426 mg, 1 mmol), K2CO3 (414 mg, 3
o
(142 mg, 1. 5 mmol) were stirred and refluxed at 80 C for 1h in
an oil bath. The completion of reaction was monitored by TLC.
After cooling, the reaction mixture was poured into crushed ice.
The separated solid was filtered and dried in vacuum to afford the
crude product. Recrystallization from hot ethanol provides the
analytically pure product 1a (0. 243g, 81%) as white solid. Mp.
120-122 oC. IR (KBr) (νmax, cm-1): 3277, 3247, 3115, 2115,
1716, 1651, 1608, 1304, 1175. 1H-NMR (DMSO-(d6) 400MHz) δH
(ppm): 2.24 (s, 3H), 3.34 (s, 1H), 3.53 (s, 3H), 4.75 (s, 2H), 5.09
(s, 1H), 6.91-6.93 (m, 2H), 7.14-7.16 (m, 2H), 7.68 (s, 1H), 9.18
(s, 1H). 13C-NMR (DMSO-(d6), 100MHz) δC (ppm): 17.8, 50.6,
53.1, 55.6, 78.1, 79.2, 101.7, 114.2, 114.6, 127.3, 127.9, 137.5,
145.4, 152.1, 167.4. EI-MS: 301.1 (M+).
mmol), NaN3 (65 mg,
1
mmol) were dissolved in
dimethylacetamide and stirred for 6-8h. After completion, the
reaction mixture was poured into ice cold water and the precipitate
was filtered, dried under vacuum to afford the azide 4a (.0.332g,
86%) as white solid. IR (KBr) (νmax, cm-1): 3296, 2107, 1685,
17. (a) Ugi, I.; Lohberger, S.; Karl, R.; In Comprehensive Organic
Synthesis. (b) Trost, B. M.; Flemming, I.; Heathcock, H. Eds.
Pergamon; New York 1991, 2, 1083-1109. (c) Ugi, I.; Angew.
Chem. Int. Ed. Engl. 1982, 21, 810-819. (d) Keating, T. A.;
Armstrong, R. W.; J. Org. Chem. 1998, 63, 867-871.
1
1645, 1588. H-NMR (CDCl3, 500MHz) δH (ppm): 1.73 (t, 2H),
2.45 (t, 2H), 2.67 (dd, 1H), 3.38 (dd, 1H), 5.53 (m, 1H), 6.89-7.43
(m, 8H, ArH), 7.83 (d, J=7.5Hz, 1H). 13C-NMR (CDCl3, 125MHz)
δC (ppm): 35.6, 46.4, 48.2, 77.3, 128.3, 128.4, 128.9, 129.0, 129.6,
129.9, 130.3, 132.4, 134.7, 137.6, 140.2, 141.1, 169.1, 197.5. EI-
MS: 391.0 (M+).
18. Typical procedure for the synthesis of α-amino acid type azide 2a:
An equimolar amount of 2-chlorobenzaldehyde (140 mg, 1mmol),
and benzyl amine (107 mg, 1mmol), are taken in dichloromethane
(8 ml), and stirred at room temperature for 20 min. to form the
Schiff-base. To this, one equiv. of tert- butyl isocyanide (94 mg, 1
mmol) and chloroacetic acid (83 mg, 1 mmol) were added and
stirring was continued at room temperature. The reaction was
monitored by TLC and found to complete after 72h. The solvent
was evaporated under vacuum and the residue was washed with
peteroleum ether (5x15ml) to afford the chloro derivative of the
Ugi product. In a subsequent step, the Ugi chloride (407 mg, 1
mmol), K2CO3 (414mg, 3 mmol) and NaN3 (65 mg, 1 mmol) are
stirred at room temperature for 4h in dimethyl acetamide. After
22. Cornec, A.-S.; Baudequin, C.; Fiol-Petit, C.; Plé, N.; Dupas, G.;
Ramondenc, Y. Eur. J. Org. Chem. 2013, 1908-1915.
Supplementary Material: Copies of NMR, FT-IR and Mass
spectrum of new compounds.

List of Figures
Scheme 1. Synthesis of alkyne functionalized dihydropyrimidinones by solvent free Biginelli reaction
Scheme 2. Synthesis of α-amino acid type azides by U-4CR
Scheme 3. Synthesis of 1,4-disubstituted triazolyl DHPMs with skeletal α-amino acid residues via Cu (I)catalyzed
Huisgen cycloaddition.
Scheme 4. Synthesis of β-amido ketone azides by alternate Mannich reaction.

Scheme 5. Synthesis of 1,4-disubstituted triazolyl DHPMs with skeletal β-amino acid residues via Cu (I) catalyzed
Huisgen cycloaddition
BB5k
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
200
250
300
350
400
Wavelength (nm)
Figure 1. Absorption spectrum of compound 5k (2.805x10-5M) in DMSO. λabs.max. (nm): 260.0
BB5k
200
150
100
50
0
300
350
400
450
500
Wavelengthv(nm)
Figure 2. Emission spectrum of compound 5k (2.805x10-5M) in DMSO. λem.max. (nm): 364.0 and 446.0

List of Tables
Table 1. Solvent-free synthesis of alkynyl pyrimidinone scaffolds
Table 2. List of 1, 4-disubstituted triazolyl DHPMs with skeletal α-amino acid residues.

Table 3. List of 1,4-disubstituted triazolyl DHPMs with skeletal β-amino acid residues