A copper-catalyzed multicomponent reaction and 'click strategy' for the stereoselective synthesis of a new series of oxazolone peptidomimetics with α-acylamino amide and β-amido ketone structures

Article abstract of DOI:10.1002/hlca.201300057

A novel 'click ligation' strategy for the stereoselective synthesis of a medium-size library of structurally complex and functionally diverse oxazolone peptidomimetics, which contain α-acylamino carboxamide or β-amido ketone residues, is presented. Most of these molecules have lipophilicity constant values (log P) in the qualifying range for cell permeability, and that indicates the possibilities of these new molecules to be used in the search for potential inhibitors for a broad spectrum of enzymes. Copyright

Full text of DOI:10.1002/hlca.201300057

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A Copper-Catalyzed Multicomponent Reaction and ꢀClick Strategyꢁ for the
Stereoselective Synthesis of a New Series of Oxazolone Peptidomimetics with
a-Acylamino Amide and b-Amido Ketone Structures
by Biny Balan and Damodaran Bahulayan*
Department of Chemistry, University of Calicut, Malappuram-673635, Kerala, India
(phone: þ 91-9995538062; fax: þ 91-494-2400269; e-mail: bahulayan@yahoo.com)
A novel ꢀclick ligationꢁ strategy for the stereoselective synthesis of a medium-size library of
structurally complex and functionally diverse oxazolone peptidomimetics, which contain a-acylamino
carboxamide or b-amido ketone residues, is presented. Most of these molecules have lipophilicity
constant values (log P) in the qualifying range for cell permeability, and that indicates the possibilities of
these new molecules to be used in the search for potential inhibitors for a broad spectrum of enzymes.
Introduction. – The focus of modern drug discovery is the identification of
structurally complex and functionally diverse compounds that can target clinically
relevant pathways [1]. A recent method for the introduction of diversity and
complexity in a drug lead is the fragment-based assembly of diversity elements,
allowing the construction of small-molecule inhibitors with core and peripheral binding
sites [2]. The core functionality usually consists of a heterocyclic molecule, and the
peripheral functionality is made up of a peptidic or non-peptidic fragment. The
fragments are usually prepared in short reaction sequences, and are then assembled by
a mild reaction as ligation tool. An emerging trend in this concept is the use of
multicomponent reactions (MCRs) [3] for scaffold generation and the CuI-catalyzed
azideꢀalkyne [3 þ 2] cycloaddition (CuAAC) [4], leading to the formation of a 1,2,3-
triazole between two structural scaffolds. Several drug molecules developed by this
strategy are now commercially available, and many are in the final stages of clinical
trials [5]. In addition, due to the bioisosteric nature of amide bonds and 1,2,3-triazoles,
it is possible to convert a non-peptidic molecule to a peptidomimetic [6] with higher
stability and better bioavailability [7].
Oxazoles and its derivatives [8] represent an important heterocyclic class that shows
affinity to bind at the primary binding pockets of enzymes and are present in many
pharmacologically active molecules [9]. Among the oxazole derivatives, oxazolones
exhibit a wide spectrum of pharmacological features such as anticancer, antimicrobial,
antifungal, and sedative activities [10]. The functional groups at C(4) and C(2) of an
oxazolone are crucial for its enzyme-inhibitory activity. Many potential inhibitors of
enzymes such as tyrosinase [11], (11b)-hydrosteroid dehydrogenase type 1 (11b-HSD1)
[12], herpes protease [13], etc., are based on the structural modifications of oxazolones
at C(2) and C(4) with simple substituents such as Ph or naphthyl groups.
The a-acylamino amide group is a functional motif present in many commercially
available drug molecules such as telaprevir, used for the treatment of hepatitis C,
ꢂ 2013 Verlag Helvetica Chimica Acta AG, Zꢃrich

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bortezomib, a threonine protease inhibitor, and parziquantel used for the treatment of
schistosomiasis (Fig. 1) [14]. Similarly, b-amido ketones are important building blocks
for the synthesis of 1,3-amino alcohols and b-lactams. The former are structural parts of
peptidyl nucleoside antibiotics such as nikkomycins and polyoxins [15], and the latter
occur in b-lactamase inhibitors such as 6-b-bromopenicillinic acid [16].
Fig. 1. Commercial drug molecules with a-acylaminoamide core structure
We have recently developed a series of novel protocols for the synthesis of
peptidomimetics based on a-acylamino amides and b-amido ketones [17][18].
As part of our ongoing studies in MCRs and ꢀclick chemistryꢁ, we decided to search
for possibilities of functionalizing the oxazolone core structure with an a-acylamino
amide or a b-amido ketone group to generate a series of new peptidomimetic structures
A and B (cf. Fig. 2), which may be useful for development of new drug leads.
Results and Discussion. – We started our studies by functionalizing oxazolones with
a-acylaminoamide moieties. The oxazolones 1a – 1f (Scheme 1) were obtained in good-
Fig. 2. Oxazolone peptidomimetics

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to-excellent yields from the reactions of N-benzoylglycine with propargylated
benzaldehyde derivatives under ErlenmeyerꢀPerkin conditions [19]. All six oxazolone
derivatives, containing (alkynyloxy)phenyl and -napthyl substituents, were character-
ized by standard spectroscopic techniques [11].
Scheme 1. Oxazolones with [(Alkynyloxy)arenyl]methylidene Substituents Used in the Present Study
The a-(azidoacyl)amino amides 3a and 3b used in this study were prepared via an
Ugi four-component reaction between ClCH2COOH, chlorobenzaldehyde, a primary
amine, and tBuNC (Scheme 2). The reaction afforded the chloro derivatives 2a and 2b,
respectively, and subsequent replacement of the Cl-substituent by N3 by treating with
NaN3 in dimethylacetamide (DMA) afforded 3a and 3b, respectively, in excellent
yields. The assembly of the components 1 and 3 by a CuI-catalyzed [3 þ 2] azideꢀalkyne
cycloaddition was carried out in different solvents using different CuI sources. After
several attempts, an optimized condition was established based on the use of t-BuOH/
H2O/DMSO 4 :2 :1 in the presence of a catalytic amount of CuSO4 and sodium
ascorbate at room temperature (cf. Scheme 3).
The cycloaddition reactions took place with almost quantitative formation of the
1,2,3-triazole derivatives 4, and the precipitated products were collected and purified by
simple washing with solvent. The resulting products are collected in Fig. 3. The
cycloaddition reactions of 1d and 1e (both contain two alkynyloxy substituents) with 2
Scheme 2. a-Acylamino Acetamides Obtained from Ugi-4CR

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Scheme 3. CuI-Promoted [3 þ 2] Cycloaddition Reactions of Oxazolones 1 with a-Acylamino Acet-
amides 3
equiv. of azido derivatives 3a afforded the corresponding monocycloaddition products
4d and 4e, with one alkyne group remaining intact. On the other hand, when the same
alkynes were treated with 2 equiv. of azide 3b, the reaction afforded 4i and 4j, in which
both alkynyloxy groups participated in cycloaddition reactions.
The former reactions were repeated in different concentrations of the azido
derivative 3a, and no change in the nature of the product was observed. The presence of
a free prop-2-yn-1-yloxy group in 4d and 4e provides an additional binding handle and
is expected to increase the possibilities of these two compounds to be considered as
potent inhibitors of different enzyme classes.
To evalue the regio- and stereoselectivity in the triazole formation, we compared
1
the spectroscopic data of the peptidomimetics with literature values. The H-NMR
spectra showed a downfield shifted signal at ca. 8.8 ppm in all the ꢀclick productsꢁ, which
corresponds to the ethylenic H-atom of an anti-1,4-disubstituted 1,2,3-triazole isomer.
This value is in agreement with those in [20].
The success of this method prompted us to study the outcome of the functionaliza-
tion of oxazolones with b-amino acid derivatives, and we decided to prepare a series of
azido derivatives with b-amido ketone structures. A recent development in the
synthesis of N-substituted b-amino ketone derivatives is the emergence of a Mannich-

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Fig. 3. Peptidomimetics obtained from CuI-catalyzed [3 þ 2] cycloaddition reactions of oxazolones 1 with
a-aminoacyl amides
type MCR, which involves a one-pot condensation of a non-enolizable aldehyde, an
enolizable ketone, and MeCN in the presence of AcCl [21] (Scheme 4). Several new

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catalysts have been reported over the years, but many of them suffer from poor
stereoselectivity, and the scope of the nitrile component was limited to MeCN [22]. To
use a halogen-substituted nitrile instead of MeCN in this reaction to obtain a Br-
bearing amido group in the final product, we decided to investigate the reaction with 3-
bromopropionitrile in the presence of various catalysts. At room temperature, the
reaction in the presence of a catalytic amount of CuSO4 was suitable to introduce a
halogen-substituted moiety. The b-(bromo-amido) ketone derivatives 5a – 5e were then
quantitatively converted to the b-(azido-amido) ketones 6a – 6e in almost quantitative
yields by treatment with NaN3 in DMA (Scheme 4).
Scheme 4. b-Propanamido Ketone Scaffolds Used in the Present Study
Ligations of oxazolones 1 with b-amido ketones 6 were carried out by CuI-catalyzed
azideꢀalkyne [3 þ 2] cycloaddition reactions outlined in Scheme 5. The reactions of
1a – 1f with 6a – 6e afforded the (1-substituted 1,2,3-triazol-4-yl)methoxy-carrying
oxazolone peptidomimetics 7a – 10e in more than 90% yield (Fig. 4). The reactions did
not display any significant change in yields with respect to the nature of the substituents
in the b-amido ketone residue.
Compounds 4a – 4k and 7a – 10e represent oxazolone peptidomimetics with more
than one amide-bond isosteres. Groups such as 1,2,3-triazoles, esters, and alkenes have
the ability to participate in non-covalent interactions, and the extent of interaction is
comparable with that of amide bonds [23]. Peptide-bond isosteres can enable a detailed
evaluation of the structure and function of the peptidic molecules by amplifying or
attenuating biochemical properties. The oxazolone ring resembles a cyclic ester, and,
since the geometric parameters of an ester functionality is comparable to those of an
amide bond, the oxazolone ring can also be considered as a peptide-bond isostere [23].
In compounds 4a – 4k, the diversity elements such as oxazolone ring, 1,2,3-triazole,
and other isosteres are placed in alternate positions, and, therefore, these molecules can
be considered as conjugated acyclic oxazolone mimics with an a-acylamino amide-type
secondary binding group. Compounds 7a – 10e contain an additional b-oxo-alkyl group,
and there is a possibility for this keto group to form a tetrahedral adduct with
nucleophilic residues present in the target enzymes during the inhibition process.

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Scheme 5. CuI-Promoted [3 þ 2] Cycloaddition Reactions of Oxazolones 1 with b-Propanamido Ketones
6a – 6e
This possibility renders the second category of mimics 7a – 10e slightly more
promising than the first category of a-acylamino oxazolone derivatives 4a – 4k.
This assumption is further supported by the calculated lipophilicity constant (log P)
values of both categories of peptidomimetics. log P is a measure of cell permeability
and central nervous system-distribution capability of a molecule. It has been recognized
that lipophilic molecules have greater access to central nervous system than hydrophilic
molecules [24]. Drug-like molecules usually have log P values between ꢀ 0.4 and 5.6
[25]. As compiled in Fig. 4 , the log P values1) obtained for the b-amido ketone-
containing oxazolone mimics 7a – 10e are close to the upper limit of the qualifying
range of membrane-permeable drug classes [27].
Conclusions. – In conclusion, we have developed a medium-size library of
structurally complex and functionally diverse oxazolone peptide mimics based on the
ꢀclick ligationꢁ of oxazolone derivatives with a-acylamino amide or b-amido ketone
moieties. Preliminary calculations on biological activity providing descriptors such as
log P indicate the future perspectives for these new scaffolds as efficient cell-permeable
molecules.
1
)
Calculated by using Molinspiration calculation service [26].

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Fig. 4. Selected peptidomimetics obtained from CuI-catalyzed [3 þ 2] cycloaddition reactions of
oxazolones 1 with b-propanamido ketones 6a – 6e
Experimental Part
General. The chemicals were obtained from the SigmaꢀAldrich and Merck, and were used without
further purification. M.p.: Toshini Wall apparatus; uncorrected. IR Spectra (KBr): JASCO FT-IR 4100;

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in cmꢀ1
.
1H- and 13C-NMR spectra: Bruker-DRX-500-Avance; at 500 (1H) and 125 MHz (13C) in
(D6)DMSO and CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. EI-MS (70 eV): Finnigan-
MAT-8430; in m/z.
Representative Procedure for the Synthesis of (4Z)-2-Phenyl-4-[2-(prop-2-yn-1-yloxy)benzylidene]-
1,3-oxazol-5(4H)-one (1a). A soln. of 2-(prop-2-yn-1-yloxy)benzaldehyde; 0.3 g, 2 mmol), hippuric acid
(0.354 g, 2 mmol), Ac2O (0.532 g, 6 mmol), and anh. AcONa (0.152 g, 2 mmol) was heated at reflux with
constant stirring for 3 h. Then, the mixture was cooled, 20 ml of EtOH was added slowly, and the mixture
was allowed to stand overnight. The crystallized crude product was filtered, washed with hot H2O, and
then with a small volume of an ice cold H2O/MeOH 1:1 mixture. The crude product obtained was dried
and recrystallized from abs. EtOH to yield 1a (0.465 g, 81%). M.p. 160 – 1628. IR (KBr): 3257, 2115, 1583,
1556. 1H-NMR: 3.66 (s, 1 H); 4.99 (s, 2 H); 7.17 – 8.81 (m, 9 H). 13C-NMR: 56.3; 78.7; 78.8; 113.1; 121.8;
123.2; 125.0; 127.9; 129.3. 132.1; 133.1; 133.7, 156.7; 163.0; 167.0. EI-MS: 304 (Mþ).
(4Z)-2-Phenyl-4-[4-(prop-2-yn-1-yloxy)benzylidene]-1,3-oxazol-5(4H)-one (1b). Yield: 0.465 g
1
(81%). M.p. 165 – 1668. IR (KBr): 3310, 1782, 1572, 1557. H-NMR: 3.63 (s, 1 H); 4.92 (s, 2 H); 7.14 –
9.88 (m, 9 H). 13C-NMR: 55.8; 78.5; 78. 8; 115.2; 115.4; 127.7; 129.3; 130.9; 131.0; 131.6; 133.4; 134.4;
159.7; 162.1; 167.0. EI-MS: 304 (Mþ).
(4Z)-4-[3-Methoxy-4-(prop-2-yn-1-yloxy)benzylidene]-2-phenyl-1,3-oxazol-5(4H)-one (1c). Yield:
0.397g (75%). M.p. 165 – 1678. IR (KBr): 3312, 1780, 1584, 1556. 1H-NMR: 2.56 (s, 1 H); 4.03 (s, 3 H);
4.86 (s, 2 H); 7.10 – 8.17 (m, 9 H). 13C-NMR: 46.7; 56.3; 78.7; 78.8; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9;
129.3; 132.1; 132.7; 133.1; 133.7; 156.7; 167.0. EI-MS: 334 (Mþ).
(4Z)-4-[2,4-Bis(prop-2-yn-1-yloxy)benzylidene]-2-phenyl-1,3-oxazol-5(4H)-one (1d). Yield: 0.458 g
(91%). M.p. 160 – 1628. IR: 3247, 2119, 1783, 1583, 1556, 946, 865, 696. 1H-NMR: 3.66 (s, 2 H); 4.94 – 5.00
(m, 4 H); 6.83 – 8.83 (m, 9 H). 13C-NMR: 56.6; 78.1; 78.4; 100.6; 108.4; 115.9; 123.6; 125.3; 127.8; 128.3;
130.5; 133.4; 133.6; 158.4; 162.0; 167.2. EI-MS: 358 (Mþ).
(4Z)-4-[3,4-Bis(prop-2-yn-1-yloxy)benzylidene]-2-phenyl-1,3-oxazol-5(4H)-one (1e). Yield: 0.396 g
(80%). M.p. 161 – 1638. IR: 3244, 3074, 2119, 1789, 1585. 1H-NMR: 2.57 (s, 4 H); 4.86 (s, 4 H); 7.17 – 9.88
(m, 9 H). 13C-NMR: 46.7; 56.3; 78.6; 78.7; 78.8; 78.9; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 132.1;
132.7; 133.1; 133.7; 156.7; 163.0; 167.0. EI-MS: 358 (Mþ).
(4Z)-2-Phenyl-4-{[2-(prop-2-yn-1-yloxy)naphthalen-1-yl]methylidene}-1,3-oxazol-5(4H)-one (1f).
Yield: 0.321 g (63%). M.p. 155 – 1598. IR: 3255, 3058, 2117, 1576. 1H-NMR: 2.58 (s, 1 H); 4.96 (s, 2 H);
7.26 – 10.90 (m, 12 H). 13C-NMR: 56.3; 78.7; 78.8; 113.1; 121.8; 123.2; 123.8; 125.0; 126.8; 127.9; 128.5;
129.3; 132.1; 132.7; 133.1; 133.7; 156.7; 163.0; 167.0. EI-MS: 353.2 (Mþ).
Representative Procedure for the Synthesis of N-Benzyl-N-{2-[tert-butyl)amino]-1-(2-chlorophenyl)-
2-oxoethyl}-2-chloroacetamide (2a). Equimolar amount of 2-chlorobenzaldehyde (1.41 g, 0. 01 mol) and
PhCH2NH2 (1.07 g, 0.01 mol) were dissolved in CH2Cl2 (8 ml) and stirred in r.t. for 20 min. Then, 1 equiv.
of t-BuNC (0.83 g, 0.01 mol) and ClCH2COOH (0.95 g, 0.01 mol) were added, and the mixture was
stirred at r.t. The reaction was monitored by TLC and was complete after 72 h. The solvent was
evaporated under vacuum, and the crude product was obtained after repeated washings with petroleum
ether (5 ꢁ 15 ml) to afford 2a (3.58 g, 88%). IR: 3334, 2963, 1690, 1658, 1540, 1485, 1455, 1382, 1363,
1256, 1232. 1014, 759, 629. 1H-NMR: 1.27 (s, 9 H); 4.36 (s, 2 H); 4.86 (s, 2 H); 5.75 (s, 1 H); 8.06 (s, 1 H);
7.04 – 7.42 (m, 9 H). 13C-NMR: 28.3; 43.1; 43.4; 50. 4; 63.9; 64.1; 115.4; 121.2; 121.5; 130.9; 131.6; 131.7;
132.1; 133.1; 137.5; 137.8; 165.2; 168.2. EI-MS: 407.1 (Mþ).
N-Butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-chloroacetamide (2b). Yield:
1
3.62 g (84%). M.p. 160 – 1628. IR: 3297, 3070, 1677, 1648, 750. H-NMR: 1.01 – 1.04 (t, J ¼ 14.5, 3 H);
1.05 – 1.09 (m, 2 H); 1.34 (s, 9 H); 1.38 – 1.46 (m, 2 H); 3.23 – 3.35 (m, 3 H); 4.22 (s, 2 H); 5.98 (s, 1 H);
7.27 – 7.60 (m, 4 H); 8.16 (s, 1 H). 13C-NMR: 28.3; 30.6; 30.8; 30.9; 43.1; 43.4; 50.4; 63.9; 63.9; 64.1; 129.9;
130.9; 131.6; 131.7; 137.5; 137.8; 165.2; 168.2. EI-MS: 373.3 ([M þ 1]þ).
Representative Procedure for the Synthesis of 2-Azido-N-benzyl-N-{2-[(tert-butyl)amino]-1-(2-
chlorophenyl)-2-oxoethyl}acetamide (3a). Compound 2a (1.02g, 0.0025 mol) and NaN3 (700 mg) were
dissolved in dimethylacetamide (DMA; 4 ml). Then, K2CO3 (1 g) was added, the mixture was stirred at
r.t. for 4 h, and was then diluted with H2O. The white precipitate obtained was filtered and washed
repeatedly with H2O to afford 3a (0.83 g, 81%). IR: 3304, 3072, 2100, 1649. 1H-NMR: 1.16 (s, 9 H); 2.50
(s, 2 H); 4.72 (s, 2 H); 5.60 (s, 1 H); 6.84 – 7.37 (m, 9 H); 8.09 (s, 1 H). 13C-NMR: 26.3; 30.6; 30.8; 31.9;

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43.1; 46.4; 49.4; 63.9; 63.9; 65.1; 129.9; 129.9; 131.6; 131.7; 136.5; 136.8.; 169.2; 169.8. EI-MS: 414.4 ([M þ
1]þ).
2-Azido-N-butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}acetamide (3b). Yield:
0.82 g (83%). IR: 3310, 3071, 2107, 1678, 1643. 1H-NMR: 0.64 – 0.67 (t, J ¼ 15, 3 H); 0.94 – 0.97 (m,
2 H); 1.35 (s, 9 H); 1.60 – 1.69 (m, 2 H); 3.10 (s, 2 H); 3.22 – 3.28 (m, 2 H); 6.08 (s, 1 H); 7.26 – 7.59 (m,
4 H); 7.60 (s, 1 H). 13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8; 50.1; 64.1; 64.3; 66.1; 129.8; 129.9; 131.6;
131.7; 136.5; 136.8; 169.9; 170. 2. EI-MS: 380.1 ([M þ 1]þ).
Representative Procedure for the CuI-Promoted 1,3-Dipolar Cycloaddition Reactions. Equimolar
amounts of 3a (60 mg, 2 mmol) and 1 (83 mg, 2 mmol) were dissolved in minimum amount of DMSO.
Then, 2 ml of t-BuOH, 1 ml of H2O, 70 mg of CuSO4 · 5 H2O, and 83 mg of sodium ascorbate were added,
and the mixture was stirred at r.t. After 24 h, the mixture was poured into cold H2O. The precipitated
ꢀclick productꢁ was filtered, washed with H2O, and dried under vacuum.
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({2-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4a). Yield: 128 mg
(91%). IR: 3258, 3060, 2965, 2926, 1780, 1583, 1556. 1H-NMR: 1.19 – 1.23 (m, 9 H); 4.82 (s, 2 H); 4.97 (s,
2 H); 5.88 (s, 2 H); 6.32 (s, 1 H); 6.86 – 8.35 (m, 20 H); 8.79 – 8.81 (d, J ¼ 7.6, 1 H). 13C-NMR: 26.3; 30.6;
30.8; 31.9; 43.1; 46.4; 49.4; 56.3; 63.9; 63.9; 65.1; 78.7; 78.8; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3;
129.8; 131.6; 131.7; 132.1, 132.7; 136.5; 136.8; 156.7; 163.0; 167.0; 169.2; 169. 8. EI-MS: 717 (Mþ).
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4b). Yield: 128 mg
(91%). IR: 3258, 3060, 2965, 2926, 1780, 1583, 1556. 1H-NMR: 1.19 (s, 9 H); 4.82 (s, 2 H); 4.97 (s, 2 H);
5.88 (s, 2 H); 6.32 (s, 1 H); 6.86 – 8.35 (m, 20 H); 8.81 (s, 1 H). 13C-NMR: 26.3; 30.6; 30.8; 31.9; 43.1; 46.4;
49.4; 55.4; 63.9; 63.9; 65.1; 78.5; 78.8; 115.2; 115.4; 127.7; 129.3; 129.8; 129.9; 130.9; 131.0; 131.5; 131.6;
131.7; 133.4; 136.5; 136.8; 159.7; 162.1; 167.0; 169.2; 169.8. EI-MS: 717 (Mþ).
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({2-methoxy-4-[(Z)-(5-
oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4c).
Yield: 106 mg (94%). IR: 3252, 3064, 2958, 2922, 1782, 1586, 1556. 1H-NMR: 1.19 (s, 9 H); 3.64 (s,
3 H); 3.89 (s, 2 H); 4.92 (s, 2 H); 5.27 (s, 2 H); 6.20 (s, 1 H); 7.15 – 8.15 (m, 19 H); 9.85 (s, 1 H). 13C-NMR:
26.0; 30.6; 30.8; 31.9; 43.1; 46.4; 46.7; 49.4; 56.3; 63.9; 65.1; 78.7; 78.8; 113.1; 121.8; 122.1; 122.2; 125.0;
129.9; 129.9; 129.9; 131.6; 131.7; 132.1; 132.7; 133.1; 133.7; 136.5; 136.8; 156.7; 163.0; 167.0, 169.2; 169. 8.
EI-MS: 747.1 (Mþ).
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]-3-(prop-2-yn-1-yloxy)phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acet-
1
amide (4d). Yield: 99 mg (89%). IR: 3289, 3065, 2965, 2928, 2120, 1783, 1583, 1556. H-NMR: 1.23 (s,
9 H); 3.67 (s, 1 H); 4.76 (s, 2 H); 4.90 (s, 2 H); 4.94 (s, 2 H); 5.86 (s, 2 H); 6.31 (s, 1 H); 6.84 – 8.28 (m,
19 H); 8.82 – 8.84 (m, 1 H). 13C-NMR: 26.0; 30.6; 30.8; 31.9; 43.1; 46.4; 49.4; 56.6; 63.9; 65.1; 78.1; 78.4;
100.6; 108.4; 115.9; 123.6; 125.3; 127.8; 128.3; 129.9; 12.9; 130.5; 131.6; 131.7; 133.4; 133.6; 136.5; 136.8;
158.4; 162.0; 167.2; 169.2; 169. 8. EI-MS: 771 (Mþ).
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({2-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]-6-(prop-2-yn-1-yloxy)phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acet-
amide (4e). Yield: 96 mg (89%). IR: 3079, 2965, 2925, 2117, 1789, 1597, 1557. 1H-NMR: 1.16 (s, 9 H); 3.62
(s, 1 H); 4.73 – 4.77 (s, 2 H); 4.89 – 4.91 (s, 2 H); 5.25 (s, 2 H); 6.27 (s, 1 H); 6.82 – 8.30 (m, 19 H); 9.80 (s,
1 H). 13C-NMR: 26.0; 30.6, 30. 8; 31.9; 43.1; 46.4; 46.7; 49.4; 56.3; 63.9; 65.1; 78.6; 78.7; 78.8; 78.9; 113.1;
121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 129.9; 129.9; 131.6; 131.7; 132.1; 132.7; 133.1; 133.7; 136.5; 136.8;
156.7; 163.0; 167.0; 169.2; 169.8. EI-MS: 771.0 (Mþ).
N-Butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({2-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4f). Yield: 64 mg
(94%). IR: 3258, 3074, 2962, 2932, 1790, 1596, 1557. 1H-NMR: 0.60 – 0.64 (m, 3 H); 0.91 – 1.02 (m,
2 H); 1.32 – 1.47 (m, 2 H); 1.25 (s, 9 H); 5.36 (s, 2 H); 5.66 (s, 2 H); 6.11 (s, 1 H); 7.16 – 8.31 (m, 15 H);
8.80 – 8.82 (m, 1 H).13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8; 50.1; 56.3; 64.1; 64.3; 66.1; 78.7; 78.8;
113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 129.8; 129.9; 131.6; 131.7; 132.1; 132.7; 133.1; 133.7; 136.5;
136.8; 156.7; 163.0; 166.9; 167.0; 170.2. EI-MS: 683.1 (Mþ).

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N-Butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4g). Yield: 103 mg
1
(91%). IR: 2962, 1767, 1650, 1556. H-NMR: 0.60 – 0.64 (m, 3 H); 0.91 – 1.02 (m, 2 H); 1.25 (s, 9 H);
1.32 – 1.47 (m, 2 H); 5.36 (s, 2 H); 5.66 (s, 2 H); 6.11 (s, 1 H); 7.16 – 8.31 (m, 15 H); 8.82 – 8.80 (m, 1 H).
13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8; 50.1; 55.8; 64.1; 64.3; 66.1; 78.5; 78.8; 115.2; 115.4; 127.7; 129.3;
129.8; 129.9; 130.9; 131.0; 131.5; 131.6; 131.7; 133.4; 133.4; 136.5; 136.8; 159.7; 162.1; 166.9; 167.0; 170. 2.
EI-MS: 683.1 (Mþ).
N-Butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-[4-({2-methoxy-4-[(Z)-(5-oxo-
2-phenyl-1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]acetamide (4h).
Yield: 59 mg (92%). IR: 3311, 3069, 2960, 2932, 1780, 1585, 1555. 1H-NMR: 0.58 – 0.68 (m, 3 H);
0.91 – 0.96 (m, 2 H); 1.24 (s, 9 H); 1.33 – 1.48 (m, 2 H); 3.82 – 3.85 (m, 2 H); 3.89 (s, 3 H); 4.92 (s, 2 H);
5.29 (s, 2 H); 6.10 (s, 1 H); 7.18 – 8.28 (m, 14 H); 9.86 (s, 1 H). 13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8;
46.7; 50.1; 56.3; 64.1; 66.1; 78.7; 78.8; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 129.8; 129.9; 131.6;
131.7; 132.1; 132.7; 133.1; 133.7; 136.5; 136.8; 156.7; 163.0; 166.9; 167.0; 170.2. EI-MS: 713.1 (Mþ).
2,2’-[{4-[(Z)-(5-Oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)methyl]benzene-1,3-diyl}bis(oxymethane-
diyl-1H-1,2,3-triazole-4,1-diyl)]bis(N-butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}acet-
amide) (4i). Yield: 89 mg (94%). IR: 3069, 2962, 2932, 1786, 1556. 1H-NMR: 0.56 – 0.69 (m, 6 H); 0.91 –
1.01 (m, 4 H); 1.28 (s, 18 H); 1.33 – 1.47 (m, 4 H); 4.94 (s, 4 H); 5.38 (s, 4 H); 6.12 (s, 2 H); 6.84 – 8.33 (m,
19 H); 8.82 – 8.85 (m, 2 H). 13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8; 52.4; 56.3; 64.1; 64.3; 66.1; 77.8;
78.8; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 129.7; 129.8; 131.6; 131.7; 132.1; 132.7; 133.1; 133.7;
136.5; 136.8; 156.7; 163.9; 167.0; 170.2. EI-MS: 1116.1 ([M þ 1]þ).
2,2’-[{4-[(Z)-(5-Oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)methyl]benzene-1,2-diyl}bis(oxymethane-
diyl-1H-1,2,3-triazole-4,1-diyl)]bis(N-butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}acet-
amide) (4j). Yield: 78 mg (86%). IR: 3281, 2929, 1655, 1542. 1H-NMR: 0.56 – 0.69 (m, 6 H); 0.91 – 1.01
(m, 4 H); 1.28 (s, 18 H); 1.33 – 1.47 (m, 4 H); 4.94 (s, 4 H); 5.38 (s, 4 H); 6.12 (s, 2 H); 6.84 – 8.33 (m,
19 H); 8.82 – 8.85 (m, 2 H). 13C-NMR: 26.3; 29.6; 30.1; 30.6; 43.1; 44.8; 50.1; 56.3; 64.1; 64.3; 66.1; 78.1;
78.8; 113.1; 121.8; 122.1; 123.2; 125.0; 127.9; 129.3; 129.7; 129.8; 129.9; 131.6; 131.7; 132.1; 132.7; 133.1;
133.7; 136.5; 136.8; 156.7; 163.0; 166.9; 167.0; 170.2. EI-MS: 1116.1 ([M þ 1]þ).
N-Butyl-N-{2-[(tert-butyl)amino]-1-(2-chlorophenyl)-2-oxoethyl}-2-{4-[({1-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetamide (4k).
1
Yield: 81 mg (93%). IR: 3080, 1667, 1590, 2929. H-NMR: 0.85 – 0.97 (m, 3 H); 1.15 – 1.18 (m, 2 H);
1.23 (s, 9 H); 1.52 – 1.53 (m, 2 H); 2.21 (s, 2 H); 3.18 – 3.19 (m, 2 H); 5.20 (s, 2 H); 6.30 (s, 1 H); 7.05 – 8.07
(m, 16 H); 8.23 (s, 1 H); 9.09 (s, 1 H). 13C-NMR: 26.5; 29.9; 31.4; 41.4; 48.3; 56.0; 62.4; 66.2; 77.8; 78.4;
115.5; 120.3; 127.2; 128.1; 128.4; 129.0; 129.1; 129.6; 129.7; 130.1; 130.5; 133.7; 134.5; 137.7; 156.2; 166.2;
166.4; 169.5. EI-MS: 732.3 (Mþ).
Representative Procedure for the Synthesis of 3-Azido-N-[1-(2-chlorophenyl)-3-(4-chlorophenyl)-3-
oxopropyl]propanamide (6a). A mixture of 4-chloroacetophenone (0.352 g, 2 mmol), 2-chlorobenzal-
dehyde ( 0.282 g, 2 mmol), and 3-bromopropanenitrile (0.268 g, 2 mmol) in MeCN (3 ml) was stirred in
the presence of 5 mol-% CuSO4 at r.t. for 8 h. After completion of the reaction (TLC), the mixture was
poured into ice-cold H2O and extracted with CH2Cl2 (15 ml). Evaporation of the solvent, followed by
purification on silica gel (SiO2; 100 – 200 mesh, AcOEt/hexane 3 :1) afforded pure functionalized bromo
b-acetamido ketone 5 (0.678 g, 79%). One mmol of 5 (0.428 g), 3 mmol of K2CO3, and 1 mmol of NaN3
were dissolved in DMA. The mixture was stirred for 6 – 8 h; after the completion of the reaction, it was
poured into ice-cold H2O, and the precipitate was filtered, washed, and dried in vacuum to afford 6a
(0.385 g, 86%). IR: 3282, 3070, 1685, 1654. 1H-NMR: 2.68 – 2.71 (m, 2 H); 2.81 – 2.83 (m, 1 H); 3.41 – 3.45
(m, 1 H); 3.74 – 3.78 (m, 2 H); 5.84 – 5.83 (m, 1 H); 7.13 – 7.97 (m, 8 H); 8.17 (s, 1 H). 13C-NMR: 39.6;
39.7; 41.4; 48.2; 76.8; 77.0; 127.1; 127.9; 128.3; 128.4; 128.9; 129.0; 130.0; 130.3; 132.4; 134.7; 137.6; 141.1;
169.1; 197.5.
3-Azido-N-[1-(2-bromophenyl)-3-(4-bromophenyl)-3-oxopropyl]propanamide (6b). Yield: 0.523 g
(98%). IR: 3296, 3066, 2107, 1682, 1645. 1H-NMR: 2.32 – 2.38 (m, 2 H); 3.34 (t, J ¼ 19.2, 2 H); 3.35 (d, J ¼
12.4, 1 H); 3.71 – 3.74 (m, 1 H); 5.61 – 5.66 (m, 1 H); 7.18 – 8.54 (m, 8 H); 8.57 (s, 1 H). 13C-NMR: 36.1;
39.2; 39.5; 39.7; 43.1; 47.3; 123.9; 125.1; 128.7; 129.4; 129.8; 133.6; 136.0; 140.4; 148.4; 150.6; 172.9; 196.6.
EI-MS: 480.8 ([M þ 1]þ).

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Helvetica Chimica Acta – Vol. 96 (2013)
3-Azido-N-[1,3-bis(4-chlorophenyl)-3-oxopropyl]propanamide (6c). Yield: 0.455 g (98%). IR: 3296,
3066, 2107, 1682, 1645. 1H-NMR: 2.46 (t, J ¼ 20, 2 H); 2.67 (t, J ¼ 15, 2 H); 3.38 – 3.42 (m, 1 H); 5.54 (s,
1 H); 6.89 – 7.84 (m, 9 H). 13C-NMR: 35.9; 39.6; 40.1; 42.8; 47.3; 49.4; 76.7; 77.0; 77.2; 133.4; 134.7; 138.9;
139.0; 140.3; 169.0; 169.4; 197.0.
3-Azido-N-[3-(4-bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl]propanamide (6d). Yield: 0.455 g
(99%). IR: 3299, 3067, 2109, 1683, 1649. 1H-NMR: 2.46 – 2.48 (m, 2 H); 2.67 – 2.69 (m, 2 H); 3.37 – 3.42
(m, 1 H); 5.52 – 5.57 (m, 1 H); 6.83 – 7.77 (m, 9 H). 13C-NMR: 36.0; 39.6; 40.1; 42.7; 47.3; 49.4; 77.0; 127.8;
128.8; 128.9; 129.1; 129.6; 132.1; 135.1; 169.8; 197.3.
3-Azido-N-[3-(4-bromophenyl)-1-(2-chlorophenyl)-3-oxopropyl]propanamide (6e). Yield: 0.456 g
(99%). IR: 3296, 3066, 2107, 1682, 1645. 1H-NMR: 2.46 – 2.48 (m, 2 H); 2.67 – 2.69 (m, 2 H); 3.40 – 3.44
(m, 1 H); 5.80 – 5.85 (m, 1 H); 7.09 – 7.75 (m, 9 H). 13C-NMR: 35.9; 39.5; 47.3; 48.1; 76.7; 77.0; 127.1; 127.2;
128.2; 128.3; 128.9; 129.8; 131.4; 131.9; 132.4; 135.1; 137.6; 168.8; 197.7.
Representative Procedure for the CuI-Promoted 1,3-Dipolar Cycloaddition Reactions of 1a – 1c and 1f
with 6a – 6e. Synthesis of N-[1-(2-Chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-[(Z)-(5-oxo-
2-phenyl-1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (7a).
Equimolar amounts of 6a (78 mg, 2 mmol) and 1a (83 mg, 2 mmol) were dissolved in minimum amount
of DMSO. Then, 2 ml of t-BuOH, 1 ml of H2O, 70 mg of CuSO4 · 5 H2O, and 83 mg of sodium ascorbate
were added, and the mixture was stirred at r.t. After 24 h, the mixture was poured into ice-cold H2O. The
precipitated ꢀclick productꢁ 7a was filtered, washed with H2O, and dried under vacuum. Yield: 126 mg
(68%). IR: 3297, 3067, 1789, 1684, 1640, 1589, 1557. 1H-NMR: 2.68 – 2.70 (m, 2 H); 3.31 – 3.33 (m, 2 H);
4.74 (t, J ¼ 13.5, 2 H); 5.10 – 5.30 (s, 2 H); 5.81 (s, 1 H); 7.10 – 7.83 (m, 18 H); 8.14 – 8.16 (m, 1 H); 8.81 –
8.83 (m, 1 H). 13C-NMR: 39.6; 39.7; 41.4; 48.2; 56.3; 76.8; 77.0; 78.7; 78.8; 113.1; 121.8; 122.1; 123.2; 125.0;
127.1; 127.9; 128.1; 128.3; 128.4; 129.0; 129.3; 130.0; 130.3; 132.1; 132.4; 132.7; 133.1; 133.7; 134.7; 137.6;
141.1; 156.7; 163.0; 167.0; 169.1; 197.5. EI-MS: 694.2 (Mþ).
N-[1-(2-Bromophenyl)-3-(4-bromophenyl)-3-oxopropyl]-3-[4-({2-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (7b). Yield: 84 mg (65%).
IR: 3298, 3069, 1789, 1681, 1650, 1595, 1557. 1H-NMR: 2.67 – 2.70 (m, 2 H); 3.27 – 3.31 (m, 2 H); 4.71 (t,
J ¼ 11, 2 H); 5.20 (s, 2 H); 5.76 (s, 1 H); 7.06 – 7.75 (m, 18 H); 8.14 – 8.16 (m, 1 H); 8.82 – 8.83 (m, 1 H).
13C-NMR: 36.1; 39.2; 39.5; 39.7; 43.1; 47.3; 56.3; 78.7; 78.8; 113.1; 121.8; 122.1; 123.2; 123.9; 125.0, 125.1;
127.9; 128.7; 129.3; 129.4; 129.8; 132.1; 132.7; 133.1; 133.6; 133.7; 136.0; 140.4; 148.4; 150.6; 156.7; 163.0;
167.0; 172.9; 196.6. EI-MS: 782.3 (Mþ).
N-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)-
methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (7c). Yield: 89 mg (86%). M.p. 80 – 838. IR:
3284, 3068, 1580, 1557. 1H-NMR: 2.62 – 2.68 (m, 2 H); 3.26 – 3.41 (m, 2 H); 4.75 (t, J ¼ 12, 2 H); 5.20 (s,
2 H); 5.49 – 5.53 (m, 1 H), 6.84 – 7.83 (m, 17 H); 8.14 – 8.16 (m, 1 H); 8.83 – 8.84 (m, 1 H). 13C-NMR:
55.1; 76.6; 76.9; 77.1; 96.1; 115.3; 128.2; 128.8; 131.4; 133.0; 134.4; 159.9; 167.3. EI-MS: 694.2 ([M þ 1]þ).
N-[3-(4-Bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (7d). Yield: 86 mg (85%).
M.p. 79 – 828. IR: 3296, 3068, 1584, 1557. 1H-NMR: 2.67 – 2.68 (m, 2 H); 3.20 – 3.40 (m, 2 H); 4.60 – 4.80
(m, 2 H); 5.20 – 5.30 (br. s, 2 H); 5.40 – 5.60 (m, 1 H); 6.80 – 7.77 (m, 17 H); 8.14 – 8.16 (d, 1 H); 8.82 – 8.83
(m, 1 H). 13C-NMR: 55.7; 76.8; 77.1; 76.8; 96.0; 115.2; 125.8; 128.1; 128.8; 129.6; 131.3; 131.9; 132.9; 134.3;
159.8. EI-MS: 737.4 (Mþ).
N-[3-(4-Bromophenyl)-1-(2-chlorophenyl)-3-oxopropyl]-3-[4-({2-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (7e). Yield: 87 mg (85%).
1
M.p. 78 – 848. IR: 1649, 1585, 1557. H-NMR: 2.62 – 2.69 (m, 2 H); 3.32 – 3.34 (m, 2 H); 4.75 (t, J ¼ 11,
2 H); 5.21 – 5.26 (m, 1 H); 5.80 (s, 2 H); 7.18 – 7.74 (m, 18 H); 8.16 (s, 1 H); 8.83 (s, 1 H). 13C-NMR: 55.7;
76.6; 76.8; 77.1; 96.0; 115.2; 125.8; 128.1; 128.8; 129.6; 131.3; 131.9; 132.9; 134.3; 159.8. EI-MS: 737.4
(Mþ).
N-[1-(2-Chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl]-3-[4-({4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (8a). Yield: 113 mg (98%).
1
IR: 3308, 3067, 2916, 1788, 1685, 1652, 1588, 1555. H-NMR: 2.59 – 2.70 (m, 2 H); 2.71 – 2.91 (m, 1 H);
3.32 – 3.33 (m, 1 H); 4.69 – 4.78 (m, 2 H); 5.18 (s, 2 H); 5.79 – 5.78 (m, 1 H); 7.05 – 8.23 (m, 19 H); 9.89 (s,
1 H). 13C-NMR: 39.6; 39.7; 41.4; 48.2; 55.8; 76.8; 77.0; 78.5; 78.8; 115.2; 115.4; 127.1; 127.7; 127.9; 128.3;

Helvetica Chimica Acta – Vol. 96 (2013)
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128.4; 128.9; 129.0; 129.3; 130.0; 130.3; 130.9; 131.0; 131.6; 132.4; 133.4; 134.4; 134.7; 137.6; 141.1; 159.7;
162.1; 167.0; 169.1; 197.5. EI-MS: 694.2 (Mþ).
N-[1-(2-Bromophenyl)-3-(4-bromophenyl)-3-oxopropyl]-3-[4-({4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (8b). Yield: 99 mg (76%).
1
IR: 1785, 1649, 1585, 1556. H-NMR: 2.55 – 2.62 (m, 2 H); 3.30 – 3.40 (m, 2 H); 4.77 – 4.78 (m, 2 H);
5.10 – 5.20 (br. s, 2 H); 5.70 – 5.80 (m, 1 H); 7.07 – 7.60 (m, 19 H); 8.17 – 8.22 (m, 1 H). 13C-NMR: 55.7;
76.1; 76.6; 76.9; 77.1; 77.8; 96.1; 115.3; 125.8; 127.3; 128.2; 128.8; 129.6; 131.3; 131.6; 132.0; 132.9; 134.4;
159.9; 167.6. EI-MS: 782.3 (Mþ).
N-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]-3-[4-({4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)-
methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (8c). Yield: 87 mg (86%). M.p. 142 – 1448.
IR: 3309, 3082, 2923, 1683, 1646, 1556. 1H-NMR: 2.59 – 2.70 (m, 2 H); 2.71 – 2.91 (m, 1 H); 3.32 – 3.33 (m,
1 H); 4.69 – 4.78 (m, 2 H); 5.18 (s, 2 H); 5.78 – 5.79 (m, 1 H); 7.05 – 8.23 (m, 19 H); 9.89 (s, 1 H).
13C-NMR: 55.1; 76.6; 76.9; 77.1; 96.1; 115.3; 128.2; 128.8; 131.4; 133.0; 134.4; 159.9; 167.3. EI-MS: 694.2
([M þ 1]þ).
N-[3-(4-Bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl]-3-[4-({4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (8d). Yield: 84 mg (83.5%).
M.p. 141 – 1448. IR: 2919, 1653, 1598, 1585. 1H-NMR: 2.58 – 2.68 (m, 2 H); 3.29 – 3.30 (m, 2 H); 4.69 – 4.79
(m, 2 H); 5.17 (s, 2 H); 5.46 – 5.55 (m, 1 H); 6.88 – 8.18 (m, 17 H); 8.21 – 8.23 (m, 1 H), 9.89 (s, 1 H).
13C-NMR: 55.7; 76.6; 76.8; 77.1; 96.0; 115.2; 125.8; 128.1; 128.8; 129.6; 131.3; 131.9; 132.9; 134.3; 159.8.
EI-MS: 737.4 (Mþ).
N-[3-(4-Bromophenyl)-1-(2-chlorophenyl)-3-oxopropyl]-3-[4-({4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (8e). Yield: 86 mg (84%).
1
M.p. 140 – 1428. IR: 3309, 2924, 1784, 1648, 1585, 1557. H-NMR: 2.59 – 2.68 (m, 2 H); 3.28 – 3.30 (m,
2 H); 4.69 – 4.78 (m, 2 H); 5.17 (s, 2 H); 5.46 – 5.55 (m, 1 H); 6.88 – 8.18 (m, 17 H); 8.21 – 8.23 (m, 1 H);
9.89 (s, 1 H). 13C-NMR: 55.7; 76.6; 76.8; 77.1; 96.0; 115.2; 125.8; 128.1; 128.8; 129.6; 131.3; 131.9; 132.9;
134.3; 159.8. EI-MS: 737.4 (Mþ).
N-[1-(2-Chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-methoxy-4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (9a). Yield:
1
104 mg (96%). IR: 3307, 2930, 1788, 1681, 1588. H-NMR: 2.67 – 2.69 (m, 2 H); 2.71 – 2.90 (m, 1 H);
3.30 (d, J ¼ 23, 1 H); 3.96 (s, 3 H); 4.85 – 4.86 (m, 2 H); 5.20 – 5.30 (br. s, 2 H); 5.70 – 5.80 (m, 1 H); 7.07 –
8.13 (m, 18 H); 9.80 (s, 1 H). 13C-NMR: 36.4; 39.7; 41.4; 56.0; 76.8; 77.1; 109.3; 112.5; 126.8; 127.2; 128.1;
128.4; 129.0; 129.1; 129.2; 129.6; 129.7; 130.1; 130.5; 130.7; 132.5; 134.7; 137.7; 140.4; 197.2. EI-MS: 723.2
(Mþ).
N-[1-(2-Bromophenyl)-3-(4-bromophenyl)-3-oxopropyl]-3-[4-({2-methoxy-4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (9b). Yield:
88 mg (81%). M.p. 85 – 898. IR: 3296, 2930, 1681, 1651, 1585. 1H-NMR: 2.69 – 2.91 (m, 2 H); 3.77 – 3.78
(m, 1 H); 4.66 (s, 3 H); 4.85 – 4.86 (t, 2 H); 5.25 (s, 2 H); 5.70 – 5.80 (m, 1 H); 7.07 – 8.14 (m, 18 H); 9.84 (s,
1 H). 13C-NMR: 36.4; 39.7; 40.1; 41.4; 50.2; 50.4; 56.0; 77.1; 77.4; 76.8; 112.5; 122.7; 127.8; 128.2; 129.1;
129.2; 129.3; 129.7; 129.8; 132.1; 133.2; 133.4; 135.1; 139.3; 197.5. EI-MS: 811.1 (Mþ).
N-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-methoxy-4-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-
4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (9c). Yield: 87 mg (89%).
1
M.p. 120 – 1248. IR: 2930, 1677, 1654, 1589. H-NMR: 2.66 – 2.69 (m, 2 H); 3.41 – 3.43 (m, 2 H); 3.87 (s,
3 H); 4.66 – 4.86 (m, 2 H); 5.24 (s, 2 H); 5.40 – 5.60 (m, 1 H); 6.91 – 8.15 (m, 18 H); 9.84 (s, 1 H).
13C-NMR: 36.4; 39.6; 40.1; 42.8; 42.9; 46.2; 49.4; 55.9; 76.7; 77.0; 77.3; 126.6; 127.8; 127.9; 128.1; 128.5;
128.8; 129.0; 129.1; 129.4; 129.5; 139.0; 190.9. EI-MS: 723.2 (Mþ).
N-[3-(4-Bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl]-3-[4-({2-methoxy-4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (9d). Yield:
1
82 mg (81%). M.p. 122 – 1258. IR: 3297, 3083, 2932, 1681, 1651, 1585. H-NMR: 2.66 – 2.69 (m, 2 H);
3.31 (dd, J ¼ 23, 21, 2 H); 4.03 (s, 3 H); 4.66 – 4.86 (m, 2 H); 5.23 (s, 2 H); 5.54 – 5.55 (m, 1 H); 6.86 – 8.17
(m, 18 H); 9.84 (s, 1 H). 13C-NMR: 36.6; 39.7; 40.2; 42.9; 43.0; 49.5; 55.9; 56.0; 56.6; 77.1; 76.8; 77.4; 113.2;
114.6; 125.8; 127.3; 127.6; 127.9; 128.2; 128.9; 129.1; 129.4; 129.6; 129.7; 130.1; 131.9; 132.2; 133.2; 133.5;
135.0; 139.1; 167.9; 191.0. EI-MS: 768.2 ([M þ 1]þ).

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Helvetica Chimica Acta – Vol. 96 (2013)
N-[3-(4-Bromophenyl)-1-(2-chlorophenyl)-3-oxopropyl]-3-[4-({2-methoxy-4-[(Z)-(5-oxo-2-phenyl-
1,3-oxazol-4(5H)-ylidene)methyl]phenoxy}methyl)-1H-1,2,3-triazol-1-yl]propanamide (9e). Yield:
1
84 mg (82%). M.p. 78 – 808. IR: 3091, 3069, 2963, 1681, 1651, 1585. H-NMR: 2.68 – 2.71 (m, 2 H); 2.88
(d, J ¼ 21, 1 H); 3.36 (d, J ¼ 20, 1 H); 4.03 (s, 3 H); 4.65 – 4.86 (m, 2 H); 5.25 (s, 2 H); 5.76 – 5.84 (m, 1 H);
7.09 – 8.40 (m, 18 H); 9.84 (s, 1 H). 13C-NMR: 36.4; 39.7; 40.1; 41.4; 46.2; 48.1; 48.3; 56.0; 56.6; 76.6; 76.8;
77.1; 77.3; 77.4; 112.4; 113.2; 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; 168.6; 191.1; 197.3; 197.9. EI-MS: 768.2 ([M þ 1]þ).
N-[1-(2-Chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl]-3-{4-[({1-[(Z)-(5-oxo-2-phenyl-1,3-oxa-
zol-4(5H)-ylidene)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}propanamide (10a). Yield:
88 mg (83%). IR: 3297, 3247, 3063, 1775, 1671, 1589. 1H-NMR: 2.56 (t, J ¼ 12.5, 2 H); 3.20 – 3.30 (m, 2 H);
4.85 – 4.95 (m, 2 H); 5.20 (s, 2 H); 5.70 – 5.80 (m, 1 H); 7.26 – 8.07 (m, 20 H); 9.26 – 9.28 (m, 1 H); 10.89 (s,
1 H). 13C-NMR: 57.3; 76.6; 76.9; 77.1; 96.1; 113.9; 125.2; 125.2; 128.1; 129.8; 137.0; 159.7; 191.6. EI-MS:
743.2 (Mþ).
N-[1-(2-Bromophenyl)-3-(4-bromophenyl)-3-oxopropyl]-3-{4-[({1-[(Z)-(5-oxo-2-phenyl-1,3-oxa-
zol-4(5H)-ylidene)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}propanamide (10b). Yield:
1
80 mg (79%). M.p. 80 – 848. IR: 2916, 1665, 1587, 1567. H-NMR: 2.59 – 2.69 (m, 2 H); 2.71 – 2.92 (m,
2 H); 4.70 – 4.96 (m, 2 H); 5.74 (s, 2 H); 5.75 – 5.78 (m, 1 H); 7.05 – 8.09 (m, 20 H); 9.21 – 9.28 (m, 1 H);
10.90 (s, 1 H). 13C-NMR: 57.3; 70.1; 76.6; 76.9; 77.1; 96.1; 113.9; 125.2; 125.2; 128.1; 129.1; 129.8; 131.5;
137.0; 161.7; 191.6. EI-MS: 831.4 (Mþ).
N-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]-3-{4-[({1-[(Z)-(5-oxo-2-phenyl-1,3-oxazol-4(5H)-ylide-
ne)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}propanamide (10c). Yield: 84 mg (86%).
M.p. 105 – 1078. IR: 3255, 2892, 1656, 1590. 1H-NMR: 2.56 (t, J ¼ 13, 2 H); 3.20 – 3.34 (m, 2 H); 4.87 – 4.95
(m, 2 H); 5.20 (s, 2 H); 5.70 – 5.80 (m, 1 H); 7.26 – 8.07 (m, 20 H); 9.26 – 9.28 (m, 1 H); 10.89 (s, 1 H).
13C-NMR: 57.3; 70.1; 76.6; 76.9; 77.1; 96.1; 113.9; 125.2; 125.2; 128.1; 129.1; 129.8; 131.5; 137.0; 161.7;
191.6. EI-MS: 743.2 (Mþ).
N-[3-(4-Bromophenyl)-1-(4-chlorophenyl)-3-oxopropyl]-3-{4-[({1-[(Z)-(5-oxo-2-phenyl-1,3-oxa-
zol-4(5H)-ylidene)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}propanamide (10d). Yield:
79 mg (81%). M.p. 110 – 1138. IR: 3297, 3083, 1666, 1586. 1H-NMR: 2.56 (t, J ¼ 12, 2 H); 4.82 – 4.95 (m,
2 H); 5.30 (s, 2 H); 5.70 – 5.80 (m, 1 H); 7.26 – 8.07 (m, 20 H); 9.26 – 9.28 (m, 1 H); 10.89 (s, 1 H).
13C-NMR: 57.3; 70.1; 76.6; 76.9; 77.1; 96.1; 113.9; 125.2; 125.2; 128.1; 129.1; 129.8; 131.5; 137.0; 161.7;
191.6. EI-MS: 787.2 (Mþ).
N-[3-(4-Bromophenyl)-1-(2-chlorophenyl)-3-oxopropyl]-3-{4-[({1-[(Z)-(5-oxo-2-phenyl-1,3-oxa-
zol-4(5H)-ylidene)methyl]naphthalen-2-yl}oxy)methyl]-1H-1,2,3-triazol-1-yl}propanamide (10e). Yield:
80 mg (80%). M.p. 100 – 1038. IR: 3295, 3086, 1671, 1589. 1H-NMR: 2.56 (t, J ¼ 12, 2 H); 4.77 – 4.95 (m,
2 H); 5.30 (s, 2 H); 5.70 – 5.80 (m, 1 H); 7.26 – 8.07 (m, 20 H); 9.26 – 9.28 (m, 1 H); 10.89 (s, 1 H).
13C-NMR: 57.3; 70.1; 76.6; 77.1; 96.1; 113.9; 125.2; 125.2; 128.1; 129.1; 129.8; 131.5; 137.0; 161.7; 191.6. EI-
MS: 787.2 (Mþ).
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Received January 26, 2013