A one-pot tandem ugi multicomponent reaction (MCR)/click reaction as an efficient protecting-group-free route to 1H-1,2,3-triazole-modified α-amino acid derivatives and peptidomimetics

Article abstract of DOI:10.1002/hlca.201100253

By a one-pot tandem Ugi multicomponent reaction (MCR)/click reaction sequence not requiring protecting groups, 1H-1,2,3-triazole-modified Ugi-reaction products 6a-6n (Scheme1 and Table2), 7a-7b (Table4), and 8 (Scheme2) were synthesized successfully. i.e., terminal, side-chain, or both side-chain and terminal triazole-modified Ugi-reaction products as potential amino acid units for peptide syntheses. Different catalyst systems for the click reaction were examined to find the optimal reaction conditions (Table1, Scheme1). Finally, an efficient Ugi MCR+Ugi MCR/click reaction strategy was elaborated in which two Ugi-reaction products were coupled by a click reaction, thus incorporating the triazole fragment into the center of peptidomimetics (Scheme3). Thus, the Ugi MCR/click reaction sequence is a convenient and simple approach to different 1H-1,2,3-triazole-modified amino acid derivatives and peptidomimetics. Copyright

Full text of DOI:10.1002/hlca.201100253

Helvetica Chimica Acta – Vol. 95 (2012)
87
A One-Pot Tandem Ugi Multicomponent Reaction (MCR)/Click Reaction as
an Efficient Protecting-Group-Free Route to 1H-1,2,3-Triazole-Modified
a-Amino Acid Derivatives and Peptidomimetics
by Teng-Fei Niu, Chun Cai*, and Lan Yi
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094,
P. R. China (phone: þ 86-25-84315514; fax: þ 86-25-84315030; e-mail: c.cai@mail.njust.edu.cn)
By a one-pot tandem Ugi multicomponent reaction (MCR)/click reaction sequence not requiring
protecting groups, 1H-1,2,3-triazole-modified Ugi-reaction products 6a – 6n (Scheme 1 and Table 2), 7a –
7b (Table 4), and 8 (Scheme 2) were synthesized successfully. i.e., terminal, side-chain, or both side-chain
and terminal triazole-modified Ugi-reaction products as potential amino acid units for peptide syntheses.
Different catalyst systems for the click reaction were examined to find the optimal reaction conditions
(Table 1, Scheme 1). Finally, an efficient Ugi MCR þ Ugi MCR/click reaction strategy was elaborated in
which two Ugi-reaction products were coupled by a click reaction, thus incorporating the triazole
fragment into the center of peptidomimetics (Scheme 3). Thus, the Ugi MCR/click reaction sequence is a
convenient and simple approach to different 1H-1,2,3-triazole-modified amino acid derivatives and
peptidomimetics.
Introduction. – Because of their wide-spread use in fields of pharmacy and synthetic
and materials chemistry, 1H-1,2,3-triazole derivatives have received much attention
[1 – 3]. The copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction between
acetylenes and azides is a very simple and effective route for the synthesis of 1,4-
disubstituted 1H-1,2,3-triazoles, which is generally recognized as the most typical
example of click chemistry [4][5]. Among the list of 1H-1,2,3-triazole derivatives, we
are particularly interested in 1H-1,2,3-triazole-modified peptidomimetics (Fig. 1) [6 –
8]. Due to their biological activities, triazole-modified peptidomimetics can act as
peptide surrogates [9]. They are used as blood components [10], anticancer
medications [11], and cysteine-protease [4] and HIV-1-protease inhibitors [12].
Moreover, triazole-modified peptidomimetics have been introduced as assembling
protein-like oligomers and nonpeptidic protein-mimetic foldamers [13][14]. Therefore,
triazole-modified peptidomimetics have gained considerable attention for the design of
biological effectors or foldamers [9][15][16].
Fig. 1. General structures of a) a peptide and b) a 1H-1,2,3-triazole-modified peptidomimetics
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Since the very beginning of preparing 1H-1,2,3-triazole-modified peptidomimetics
through solid-phase synthesis [4], many triazole(s) in terminal, center, or side-chain
positions of peptides linking to sugars or other peptides have been reported [17][18].
But most of the methods require protecting groups and complex procedures, while
multicomponent reactions (MCRs) have significant advantages over conventional
linear-type syntheses [19 – 21]. Owing to their atom economy, facile execution, and high
efficiency, a wide range of components can be subjected to one-pot reactions. However,
a multicomponent synthesis of 1H-1,2,3-triazole-modified peptidomimetics from
readily accessible starting materials still remains elusive, and only few successful
examples have been reported. Zanze and co-workers [22] described the coupling of one
MCR with the intramolecular alkyneꢀazide cycloaddition providing triazole ring
dipeptide systems in two steps. Nenajdenko and co-workers [23][24] developed chiral
scaffolds combining an isocyanide and azide group which enable the preparation of
hybrid peptide molecules. Melnyk and co-workers [25] described a three-component
reaction based on a CuII-triggered aminolysis of a peptide hydrazide resin and an
azideꢀalkyne cycloaddition sequence to generate neoglycopeptides. Kubik and co-
workers [26] prepared a 1,5-disubstituted 1H-1,2,3-triazole-modified pseudohexapep-
tide via a Ru-catalyzed alkyneꢀazide cycloaddition, but only 10% yield for the final
cycloaddition product was achieved.
To find a more convenient method, we are interested in developing a one-pot
synthesis of triazole-modified peptidomimetics with triazole(s) in terminal, center, and
side-chain position. Through screening of various multicomponent reactions, we
selected the Ugi reaction as an efficient method for the construction of peptide building
blocks and peptide-like molecules in one step. The Ugi reaction is one of the most
commonly used MCRs, in which a carboxylic acid, an amine, a carbonyl compound, and
an isocyanide are reacting to result in peptide derivatives [27 – 29]. In recent years, the
Ugi reaction has been well developed and widely used to generate natural products and
drugs in high yields and high diastereoselectivities [30 – 32]. We here report an efficient
tandem MCR/click reaction, in which two Ugi MCR products were coupled by a click
reaction to generate 1H-1,2,3-triazole-modified peptidomimetics.
Results and Discussion. – We first developed a one-pot Ugi MCR/click reaction
strategy to synthesize 1H-1,2,3-terminal triazole-modified Ugi-reaction products.
Starting from 4-aminobenzoic acid, the corresponding 4-azidobenzoic acid (3a; see
Fig. 2 for all starting materials) was prepared according to [33]. Based on classical
protocols for the Ugi reaction, we first treated 3a with aniline (1a), benzaldehyde (2b),
and cyclohexyl isocyanide (4a) in MeOH for 1 h (Scheme 1). Then, according to typical
thermal copper(I)-catalyzed azideꢀalkyne cycloadditions (CuAACs), we added
phenylacetylene and CuI to the mixture at room temperature, and to our delight,
after 8 h, the desired solid product 6a was formed in 43% yield and isolated by simple
filtration.
For a better performance, we then conducted an optimization with different catalyst
systems for the CuAAC step (Table 1). The most common catalysts for the CuAAC are
CuI complexes. A CuII salt in the presence of a reducing agent (often sodium ascorbate
or metallic copper) was also employed to generate the required CuI catalyst in situ.
Compared with the other tested catalyst systems, [Cu(OAc)2]/sodium ascorbate/Et3N

Helvetica Chimica Acta – Vol. 95 (2012)
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Fig. 2. Components involved in the described Ugi MCR/click reactions
Scheme 1. One-Pot Synthesis of a Terminal 1H-1,2,3-Triazole-Modified Ugi-Reaction Product
resulted in a slightly higher yield of 6a within a shorter reaction period, and it is also
cheaper, making [Cu(OAc)2]/sodium ascorbate/Et3N the most convenient catalyst for
practical reasons.
The scope of the one-pot Ugi MCR/click reaction sequence is illustrated by the
examples in Table 2. In most cases, the yields of the product 6 was good. For substituted
anilines R1-NH2, both electron-withdrawing and electron-donating groups gave similar
results (Table 2, Entries 1 – 3). However, the electronic properties of the substituted

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Table 1. Click-Reaction Step with Different Copper-Catalyst Systems in the One-Pot Ugi MCR/Click
Reaction Sequence (cf. Scheme 1)a)
CuI
CuI/Et3Nb)
[Cu(OAc)2]Cuc)
[Cu(OAc)2]sodium ascorbate/Et3Nd)
Time [h]e)
Yield [%]f)
8
43
8
45
12
27
4
48
a) Reaction conditions: 1a (1 mmol), 2b (1 mmol), 3a (1 mmol), 4a (1 mmol), and solvent (2 ml), 1 h at
r.t.; then phenylacetylene (1 mmol), and catalyst (0.1 mmol), r.t. b) CuI (0.1 mmol), and Et3N
(1 mmol). c) [Cu(OAc)2] (0.1 mmol), and Cu (0.1 mmol). d) [Cu(OAc)2] (0.1 mmol), sodium ascorbate
(0.2 mmol), and Et3N (1 mmol). e) Reaction progress was monitored by TLC. f) Yield of isolated
product 6a.
Table 2. Scope of the Ugi MCR/Click Reaction Sequence for the Synthesis of a Terminal 1H-1,2,3-
Triazole-Modified Ugi-Reaction Product 6 (Chx ¼ cyclhexyl)
Entry R1
R2
R3
R4
Product t1 [h]a), t2 [h]b) Yield [%]c)
1
2
3
4
5
6
7
8
9
10
11
12
13
4-ClC6H4
Ph
Ph
Ph
Ph
Chx Ph
Chx Ph
Chx Ph
Chx Ph
Chx Ph
Chx Ph
Chx Ph
Chx Ph
6b
6c
6d
6e
6f
6g
6h
6i
1, 4
3, 4
3, 4
6, 4
12, 4
4, 4
2, 4
3, 4
6, 4
12, 4
8, 4
6, 4
1, 4
49
47
45
53
38
65
51
45
64
35
44
73
62
4-NO2C6H4
4-MeC6H4
Bn
naphthalen-2-yl Ph
Chx
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
naphthalen-2-yl Chx Ph
PhCH¼CH
furan-2-yl
Ph
6j
6k
6l
Chx Ph
Chx Ph
tBu Ph
6m
Ph
Chx 4-MeC6H4 6n
a) Time of the Ugi-reaction step. b) Time of the click-reaction step. c) Overall yield of isolated product.
benzaldehydes R2-CHO had a significant influence on the yield of the reaction
(Table 2, Entries 6 – 8).
We found that the yield of the overall reaction sequence mainly depends on the Ugi-
reaction step (Table 3). For example, the electron-donating 4-methoxybenzaldehyde
(2c) led to the Ugi-reaction product isolated in 74% yield and the click-reaction
product in 88% yield (Table 3, Entry 1), while with 4-nitrobenzaldehyde (2e) only 52%
of the Ugi-reaction product (isolated) and 86% of the click-reaction product were
formed (Table 3, Entry 3). In all cases, the yields of the click reaction were similar. The

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Table 3. The Influence of Substituents of Benzaldehydes 2 on the Yields of the Ugi-Reaction and Click-
Reaction Step
Entry
2
R2
Ugi-reaction yield [%]
click-reaction yield [%]
1
2
3
2c
2d
2e
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
74
56
52
88
86
86
one-pot tandem reaction could be carried out without decrease of the yields compared
with those of the separate steps. Consequently, the above described procedure
represents an efficient one-pot Ugi MCR/click reaction strategy for the synthesis of
terminal 1H-1,2,3-triazole-modified Ugi products.
It is noteworthy that the Ugi reaction and the click reaction cannot be performed
directly in one step. When all reactants 1a, 2b, 3a, 4a, and 5a and the copper catalyst
were stirred in MeOH for 24 h (no Et3N was added), only 19% of Ugi-reaction product
was obtained, and no triazole-modified Ugi product 6a was formed. It is well known
that isocyanides are good ligands for transition metals [34]. Therefore, we think that
copper will be coordinated to the isocyanide C-atom of 4a, and this complex is not
effective as catalyst for the Huisgen 1,3-dipolar cycloaddition.
We then extended the protocol to prepare Ugi products with 1H-1,2,3-triazolyl-
substituted side-chains. Because of its simple synthesis [35], 4-azidobenzaldehyde (2a)
was selected as the key reactant for generating the triazole segment. The corresponding
triazole-modified Ugi products 7 were obtained in good yields (Table 4).
Table 4. One-Pot Synthesis of Side-Chain 1H-1,2,3-Triazole-Modified Ugi-Reaction Products 7 (Chx ¼
cyclohexyl, Boc ¼ tBuOC(¼O)
Entry
1
2
3
4
R1
R3
Ph
R4
Product t1 [h]a)/t2 [h]b) Yield [%]c)
1
2
3
4
5
6
1a 2a 3b 4a Ph
1b 2a 3b 4b 4-ClC6H4 Ph
1e 2a 3b 4b Bn
1g 2a 3b 4b Chx
1e 2a 3d 4b Bn
1e 2a 3e 4b Bn
Chx 7a
12, 4
10, 4
12, 4
24, 4
8, 4
54
48
62
58
51
55
tBu
tBu
tBu
7b
7c
7d
7e
7f
Ph
Ph
4-NO2C6H4 tBu
BocHNCH2 tBu
6, 4
a) The time of Ugi reaction step. b) The time of ꢂclick reactionꢃ time. c) Total yield.

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Encouraged by these results, we attempted to carry out the analogous reaction with
4-azidobenzoic acid (3a) and 4-azidobenzaldehyde (2a) in one-pot (Scheme 2);
benzylamine (1e) and tert-butyl isocyanide (4b) were used to form the amide of the
amino acid moiety of the triazole-modified Ugi-reaction product. Thus, a triazole-
modified Ugi-reaction product 8 containing two 1H-1,2,3-triazole units in both the
terminal and side-chain position was successfully synthesized.
Scheme 2. One-Pot Synthesis of a Both Side-Chain and Terminal 1H-1,2,3-Triazole-Modified Ugi-
Reaction Product
Finally, we paid attention to combinations based on two Ugi MCR and one click
reaction for the synthesis of triazolo-modified peptidomimetics which contain a central
triazole unit (Scheme 3). First, we chose benzylamine (1e), 4-azidobenzaldehyde (2a),
N-[(tert-butoxy)carbonyl]glycine (Boc-Gly; 3e) and butyl isocyanide (4b) to provide
the required intermediate Ugi product 9a which bears an azido function. Another
intermediate Ugi product 10a with an alkyne moiety was synthesized from 1h, 2i, 3c,
and 4b. Then, without further purification, the two intermediate Ugi products were
treated together with [Cu(OAc)2]/sodium ascorbate/Et3N in MeOH at room temper-
ature to result in the triazole-containing product 11a. A second conjugate was prepared
from 1e, 2h, 3a, and 4b to give the intermediate Ugi product 12a which was combined
with the Ugi product 10a to yield product 13a in the same way as mentioned above. It
should be noted that compound 11a, which contains a Boc-amino group, could be used
in other multicomponent reactions to yield new peptide molecules. Consequently, the
above described procedure represents an efficient Ugi MCR þ Ugi MCR/click strategy
reaction for the synthesis of modified peptidomimetics with a central 1H-1,2,3-triazole
group. No protecting groups and no separation of intermediate products were needed
in this protocol.
In conclusion, we have developed a mild and efficient one-pot Ugi MCR/click
reaction strategy for the synthesis of 1H-1,2,3-triazole-modified Ugi-reaction products
as potential precursors of triazole-modified peptidomimetics from an azido-aldehyde
or an azido-carboxylic acid component. Both types of Ugi-reaction products, with a
triazole unit at the potential peptide terminus and/or at its side chain were synthesized
in good yields. Finally, we developed an Ugi MCR þ Ugi MCR/click reactopm strategy,

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Scheme 3. Combination of Two Ugi-Reactions and One Click Reaction
not requiring protecting groups in which two Ugi-reaction products were combined by a
click reaction to generate a triazole-modified peptidomimetic with a central triazole
unit.
Experimental Part
General. All chemicals (AR grade) were commercially available and used without further
purification. TLC: precoated silica-gel (SiO2) glass plates impregnated with a fluorescent indicator
(254 nm); detection by UV light. Column chromatography (CC): silica gel 60 (SiO2; 100 – 200 mesh).
1
M.p.: Thiele tube; uncorrected. H- and 13C-NMR Spectra: Bruker-DRX500 spectrometer; at 500 (1H)
and 125 MHz (13C); d in ppm rel. to Me4Si as internal standard, J in Hz. ESI-MS: Finnigan-TSQ-
Quantum MS instrument; in m/z. Elemental analyses: Vario ELIII recorder.

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Helvetica Chimica Acta – Vol. 95 (2012)
Compounds 6a – 6n: General Procedure. A soln. of the corresponding amine 1 (1 mmol) and
aldehyde 2 (1 mmol) in MeOH (2 ml) was stirred at r.t. for 30 min. Then, carboxylic acid 3a (1 mmol) and
isocyanide 4a or 4b (1 mmol) were added. The mixture was stirred for 1 – 12 h at r.t. Next, alkyne 5a or 5b
(1 mmol), [Cu(OAc)2] (0.1 mmol), sodium ascorbate (0.2 mmol), and Et3N (1 mmol) were added, and
the mixture was stirred for another 4 h at r.t. The products were isolated by filtration, and no further
purification was needed.
Compounds 7a – 7f: General Procedure. A soln. of aldehyde 2a (1 mmol) and amine 1 (1 mmol) in
MeOH (2 ml) was stirred at r.t. for 30 min. Then, carboxylic acid 3 (1 mmol) and isocyanide 4 (1 mmol)
were added. The mixture was stirred for 6 – 24 h at r.t. Next, alkyne 5a (1 mmol), [Cu(OAc)2]
(0.1 mmol), sodium ascorbate (0.2 mmol), and Et3N (1 mmol) were added, and the mixture was stirred
for another 4 h at r.t. The products were isolated by filtration and then recrystallized from EtOH.
Synthesis of 8. A soln. of aldehyde 2a (1 mmol) and amine 1e (1 mmol) in MeOH (2ml) was stirred
at r.t. for 30 min. Then, carboxylic acid 3a (1 mmol) and isocyanide 4b (1 mmol) were added. The mixture
was stirred for 12 h. Next, alkyne 5a (2 mmol), [Cu(OAc)2] (0.2 mmol), sodium ascorbate (0.4 mmol)
and Et3N (2 mmol) were added, and the mixture was stirred for another 6 h at r.t. The product 8 was
isolated by filtration and washed with hot EtOH.
Synthesis of 11a and 13a. A soln. of aldehyde 2a (1 mmol) and amine 1e in MeOH (2 ml) was stirred
at r.t. for 30 min. Then, carboxylic acid 3e (1 mmol) and isocyanide 4b (1 mmol) were added. The mixture
was stirred for 12 h to generated dipeptide 9a. In a parallel experiment, amine 1h, aldehyde 2i, carboxylic
acid 3d, and isocyanide 4b were treated by same method to generated Ugi-reaction product 10a. Then,
without isolation and further purification, 9a and 10a were combined, [Cu(OAc)2] (0.1 mmol), sodium
ascorbate (0.2 mmol), and Et3N (1 mmol) were added, and the mixture was stirred for another 6 h at r.t.
The solvent was evaporated and the residue purified by CC (AcOEt/hexane 1:4): pure 11a.
Product 13a was prepared by the same method.
N-[(Cyclohexylcarbamoyl)phenylmethyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzamide
(¼ N-Cyclohexyl-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benzeneacetamide; 6a):
1
Yield 0.27 g (48%). Yellow solid. M.p. > 2308. H-NMR ((D6)DMSO): 9.33 (s, 1 H); 8.13 (d, J ¼ 7.5,
1 H); 7.90 (d, J ¼ 8, 2 H); 7.78 (d, J ¼ 8.5, 2 H); 7.50 – 7.45 (m, 4 H); 7.39 – 7.36 (m, 1 H); 7.16 – 7.12 (m,
6 H); 6.97 – 6.90 (m, 4 H); 6.31 (s, 1 H); 3.68 – 3.66 (m, 1 H); 1.79 – 1.70 (m, 3 H); 1.64 – 1.54 (m, 2 H);
1.30 – 1.21 (m, 3 H); 1.11 – 1.02 (m, 2 H). 13C-NMR (CDCl3): 169.8; 168.3; 148.5; 140.9; 137.2; 136.5;
134.6; 130.4; 130.3; 130.2; 130.0; 128.9; 128.6; 128.61; 128.5; 127.5; 125.9; 119.3; 117.3; 66.8; 48.9; 32.9;
25.5; 24.8; 24.8. ESI-MS: 556 ([M þ 1]þ). Anal. calc. for C35H33N5O2 (555.26): C 75.65, H 5.99, N 12.60, O
5.76; found: C 75.61, H 5.95, N 12.63, O 5.72.
N-(4-Chlorophenyl)-N-[(cyclohexylcarbamoyl)phenylmethyl]-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-
benzamide (¼a-{(4-Chlorophenyl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}-N-cyclohexylben-
zeneacetamide; 6b): Yield 0.29 g (49%). Yellow solid. M.p. > 2308. 1H-NMR (CDCl3): 8.18 (s, 1 H); 7.88
(d, J ¼ 8, 2 H); 7.64 (d, J ¼ 8.5, 2 H); 7.51 (d, J ¼ 8.5, 2 H); 7.48 – 7.45 (m, 2 H); 7.39 – 7.36 (m, 1 H); 7.31 –
7.27 (m, 3 H); 7.26 – 7.24 (m, 2 H); 7.00 (s, 4 H); 6.28 (s, 1 H); 5.58 (d, J ¼ 8, 1 H); 3.91 (m, 1 H); 1.99 – 1.92
(m, 2 H); 1.71 – 1.60 (m, 3 H); 1.41 – 1.35 (m, 2 H); 1.18 – 1.09 (m, 3 H). 13C-NMR (CDCl3): 169.8; 168.3;
148.6, 139.1; 137.4; 136.2; 134.3; 133.4; 131.9; 130.0; 128.9; 128.8; 128.7; 128.5; 125.9; 119.5; 117.3; 65.9;
49.0; 32.9; 25.5; 24.9; 24.8. ESI-MS: 590 ([M þ 1]þ). Anal. calc. for C35H32ClN5O2 (589.22): C 71.24, H
5.47, N 11.87, O 5.42; found: C 71.21, H 5.44, N 11.82, O 5.39.
N-[(Cyclohexylcarbamoyl)phenylmethyl]-N-(4-nitrophenyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benz-
amide (¼ N-Cyclohexyl-a-{(4-nitrophenyl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benzene-
1
acetamide; 6c). Yield 0.28 g (47%). Yellow solid. M.p. > 2308. H-NMR (CDCl3): 9.26 (s, 1 H); 8.16
(d, J ¼ 7, 1 H); 7.90 (d, J ¼ 7.5, 2 H); 7.78 (d, J ¼ 8, 2 H); 7.50 – 7.46 (m, 4 H); 7.39 – 7.36 (m, 1 H); 7.25 (d,
J ¼ 8, 1 H); 7.18 – 7.17 (m, 3 H); 7.03 – 6.98 (m, 3 H); 6.28 (s, 1 H); 3.66 (m, 1 H); 1.78 – 1.72 (m, 3 H);
1.62 – 1.55 (m, 3 H); 1.30 – 1.20 (m, 3 H); 1.12 – 1.02 (m, 2 H). 13C-NMR ((D6)DMSO): 169.2; 168.5;
147.8; 140.4; 137.3; 137.0; 134.9; 132.8; 132.5; 131.5; 130.6; 130.1; 129.5; 128.8; 128.5; 128.4; 127.6; 125.8;
120.0; 119.4; 118.7; 64.1; 48.5; 32.7; 32.6; 25.7; 25.1; 24.9. ESI-MS: 601 ([M þ 1]þ). Anal. calc. for
C35H32N6O4 (600.25): C 69.98, H 5.37, N 13.99, O 10.65; found: C 69.93, H 5.35, N 13.95, O 10.67.
N-[(Cyclohexylcarbamoyl)phenylmethyl]-N-(4-methylphenyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-
benzamide (¼ N-Cyclohexyl-a-{(4-methylphenyl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}ben-

Helvetica Chimica Acta – Vol. 95 (2012)
95
1
zeneacetamide; 6d). Yield 0.26 g (45%). Yellow solid. M.p. > 2308. H-NMR (CDCl3): 8.14 (s, 1 H);
7.89 – 7.87 (m, 2 H); 7.61 (d, J ¼ 8.5, 2 H); 7.53 (d, J ¼ 9, 2 H); 7.47 (d, J ¼ 7.5, 2 H); 7.42 (d, J ¼ 6.5, 2 H);
7.38 – 7.36 (m, 1 H); 7.29 – 7.28 (m, 5 H); 6.92 (s, 2 H); 6.85 (d, J ¼ 8, 2 H); 6.18 (s, 1 H); 5.69 (d, J ¼ 8,
1 H); 3.92 (m, 1 H); 2.19 (s, 3 H); 1.99 – 1.72 (m, 2 H); 1.69 – 1.60 (m, 3 H); 1.41 – 1.35 (m, 2 H); 1.19 – 1.11
(m, 3 H). 13C-NMR (CDCl3): 169.9; 168.4; 148.5; 138.2; 137.4; 137.2; 136.7; 134.7; 130.3; 130.2; 130.0;
129.3; 128.9; 128.6; 128.5; 125.9; 119.3; 117.3; 66.8; 48.9; 32.9; 25.5; 24.8; 24.8; 21.0. ESI-MS: 570 ([M þ
1]þ). Anal. calc. for C36H35N5O2 (569.28): C 75.90, H 6.19, N 12.29, O 5.62; found: C 75.87, H 6.17, N 12.33,
O 5.67.
N-Benzyl-N-[(cyclohexylcarbamoyl)phenylmethyl]-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzamide
(¼ N-Cyclohexyl-a-{(phenylmethyl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benzeneacetamide;
1
6e). Yield 0.30 g (53%). White solid. M.p. 212 – 2148. H-NMR (CDCl3): 8.20 (s, 1 H); 7.91 (d, J ¼ 7.5,
2 H); 7.78 (s, 2 H); 7.68 (d, J ¼ 4.5, 2 H); 7.50 – 7.47 (t, J ¼ 7.5, 3 H); 7.41 – 7.35 (m, 4 H); 7.21 – 7.18 (m,
3 H); 7.10 (d, J ¼ 1.5, 2 H); 5.57 (s, 1 H); 4.76 (d, J ¼ 16.5, 1 H); 4.50 (s, 1 H); 1.95 – 1.88 (m, 2 H); 1.69 –
1.59 (m, 3 H); 1.40 – 1.33 (m, 2 H); 1.14 – 1.12 (m, 2 H). 13C-NMR (CDCl3): 171.9; 168.0; 148.7; 137.8;
136.6; 130.0; 129.8; 129.0; 129.0; 128.9; 128.6; 128.5; 128.4; 127.2; 126.9; 125.9; 120.2; 117.4; 48.8; 32.8;
30.9; 25.5; 24.8; 24.7. ESI-MS: 570 ([M þ 1]þ). Anal. calc. for C36H35N5O2 (569.28): C 75.90, H 6.19, N
12.29, O 5.62; found: C 75.88, H 6.15, N 12.26, O 5.59.
N-[(Cyclohexylcarbamoyl)phenylmethyl]-N-naphthalen-1-yl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benz-
amide (¼ N-Cyclohexyl-a-{(naphthalen-2-yl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benze-
1
neacetamide; 6f). Yield 0.23 g (38%). White solid. M.p. 209 – 2118. H-NMR (500 MHz, CDCl3): 8.53
(d, J ¼ 2.5, 1 H); 8.02 (d, J ¼ 3, 1 H); 7.82 (d, J ¼ 6.5, 2 H); 7.73 (d, J ¼ 9, 1 H); 7.64 (d, J ¼ 8, 1 H); 7.65 (m,
2 H); 7.58 – 7.56 (m, 3 H); 7.52 – 7.50 (m, 3 H); 7.44 – 7.43 (m, 2 H); 7.41 – 7.35 (m, 4 H); 7.31 – 7.28 (m,
1 H); 7.20 – 7.17 (m, 2 H); 5.82 (s, 1 H); 5.60 (d, J ¼ 7.5, 1 H); 3.97 – 3.96 (m, 1 H); 2.06 – 1.97 (m, 2 H);
1.70 – 1.60 (m, 3 H); 1.43 – 1.39 (m, 2 H); 1.16 – 1.14 (m, 3 H). 13C-NMR (CDCl3): 170.5; 168.2; 168.1;
148.4; 137.4; 137.3; 136.5; 134.5; 134.2; 131.0; 130.2; 130.0; 129.2; 129.1; 129.0; 128.9; 128.8; 128.7; 128.6;
128.5; 128.3; 127.3; 127.1; 126.4; 126.4; 125.8; 125.3; 125.0; 123.7; 123.4; 119.1; 117.2; 49.0; 48.8; 32.8; 30.9;
25.5; 24.9; 24.7. ESI-MS: 606 ([M þ 1]þ). Anal. calc. for C39H35N5O2 (605.28): C 77.33, H 5.82, N 11.56, O
5.28; found: C 77.31, H 5.78, N 11.58, O 5.24.
N-Cyclohexyl-N-[(cyclohexylcarbamoyl)(4-methoxyphenyl)methyl]-4-(4-phenyl-1H-1,2,3-triazol-1-
yl)benzamide (¼ N-Cyclohexyl-a-{cyclohexyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}-4-me-
thoxybenzeneacetamide; 6g). Yield 0.38 g (65%). Yellow solid. M.p. > 2308. 1H-NMR (CDCl3): 8.13
(s, 1 H); 7.87 (d, J ¼ 7.5, 2 H); 7.61 – 7.59 (m, 2 H); 7.53 – 7.51 (m, 2 H); 7.47 – 7.46 (m, 2 H); 7.39 – 7.36 (m,
1 H); 7.19 – 7.17 (m, 2 H); 7.07 (s, 5 H); 6.79 – 6.78 (m, 2 H); 6.18 (s, 1 H); 5.63 (d, J ¼ 8, 1 H); 3.79 (s,
3 H); 2.01 – 1.93 (s, 2 H); 1.73 – 1.60 (m, 3 H); 1.40 – 1.36 (m, 2 H); 1.18 – 1.10 (m, 3 H). 13C-NMR
(CDCl3): 169.7; 168.6; 159.7; 148.5; 140.8; 137.2; 136.6; 131.7; 130.5; 130.2; 130.0; 129.0; 128.6; 128.5;
127.5; 126.5; 125.9; 119.3; 117.3; 113.9; 66.0; 55.2; 48.9; 32.9; 25.5; 24.9; 24.8. ESI-MS: 585 ([M þ 1]þ).
Anal. calc. for C36H35N5O3 (585.27): C 73.82, H 6.02, N 11.96, O 8.20; found: C 73.78, H 6.00, N 11.93, O
8.18.
N-[(4-Chlorophenyl)(cyclohexylcarbamoyl)methyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-
benzamide (¼4-Chloro-N-cyclohexyl-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}ben-
1
zeneacetamide; 6h). Yield 0.30 g (51%). Yellow solid. M.p. > 2308. H-NMR (CDCl3): 8.15 (s, 1 H);
7.98 – 7.94 (m, 1 H); 7.67 (d, J ¼ 8.5, 2 H); 7.54 – 7.50 (m, 2 H); 7.48 – 7.44 (m, 3 H); 7.40 – 7.38 (m, 1 H);
7.23 – 7.28 (m, 3 H); 7.24 – 7.23 (m, 3 H); 6.39 (s, 1 H); 5.57 (d, J ¼ 7.5 1 H); 3.91 – 3.92 (m, 1 H); 2.06 – 1.97
(m, 2 H); 1.73 – 1.65 (m, 3 H); 1.42 – 1.38 (m, 2 H); 1.21 – 1.11 (m, 3 H). 13C-NMR (CDCl3): 169.6; 168.1;
148.7; 146.6; 146.2; 137.8; 135.6; 133.8; 131.7; 131.4; 130.3; 129.9; 129.2; 129.0; 129.0; 127.6; 126.0; 125.9;
123.7; 120.0; 117.2; 65.7; 49.2; 32.9; 25.4; 24.9; 24.8. ESI-MS: 590 ([M þ 1]þ). Anal. calc. for C35H32ClN5O2
(589.22): C 71.24, H 5.47, N 11.87, O 5.42; found: C 71.20, H 5.45, N 11.89, O 5.39.
N-[(Cyclohexylcarbamoyl)(4-nitrophenyl)methyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benz-
amide (¼ N-Cyclohexyl-4-nitro-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benzeneacet-
1
amide; 6i). Yield 0.27 g (45%). Yellow solid. M.p. > 2308. H-NMR ((D6)DMSO): 9.26 (s, 1 H); 8.16
(d, J ¼ 7.5, 1 H); 7.91 – 7.90 (m, 2 H); 7.79 – 7.77 (m, 2 H); 7.50 – 7.45 (m, 4 H); 7.39 – 7.36 (m, 1 H); 7.26 –
7.22 (m, 2 H); 7.18 – 7.13 (m, 4 H); 7.04 – 6.98 (m, 3 H); 6.28 (s, 1 H); 3.66 – 3.63 (m, 1 H); 1.76 – 1.69 (m,
3 H); 1.61 – 1.54 (m, 2 H); 1.30 – 1.19 (m, 3 H); 1.12 – 1.04 (m, 2 H). 13C-NMR ((D6)DMSO): 1169.2;

96
Helvetica Chimica Acta – Vol. 95 (2012)
168.5; 147.8; 132.5; 131.5; 130.5; 130.1; 129.5; 128. 8; 128.5; 128.4; 125. 8; 120.0; 119.4; 48.5; 32.7; 32.6;
25.6; 25.1. ESI-MS: 601 ([M þ 1]þ). Anal. calc. for C35H32N6O4 (600.25): C 69.98, H 5.37, N 13.99, O 10.65;
found: C 69.95, H 5.39, N 13.93, O 10.63.
N-[(Cyclohexylcarbamoyl)(naphthalen-1-yl)methyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-
benzamide (¼ N-Cyclohexyl-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}naphthalene-2-
1
acetamide; 6j). Yield 0.39 g (64%). Yellow solid. M.p. 224 – 2268. H-NMR (CDCl3): 8.21 (d, J ¼ 8.5 ,
1 H); 8.11 (s, 1 H); 7.87 – 7.85 (m, 3 H); 7.75 – 7.73 (m, 1 H); 7.69 – 7.66 (m, 1 H); 7.59 – 7.55 (m, 3 H);
7.55 – 7.53 (m, 2 H); 7.46 – 7.43 (m, 2 H); 7.38 – 7.36 (m, 1 H); 7.35 (s, 1 H); 7.31 (s, 1 H); 7.28 – 7.27 (m,
1 H); 7.25 – 7.22 (m, 2 H); 6.89 – 6.82 (s, 2 H); 5.66 (d, J ¼ 7.5, 1 H); 4.00 (m, 1 H); 2.05 – 2.00 (m, 2 H);
1.71 (m, 3 H); 1.68 – 1.61 (m, 2 H); 1.41 – 1.39 (m, 3 H). 13C-NMR (CDCl3): 169.9; 168.1; 148.5; 139.6;
137.2; 136.6; 133.5; 132.2; 130.3; 130.4; 130.2; 130.0; 129.5; 129.2; 129.1; 128.9; 128.5; 128.0; 127.3; 126.2;
125.9; 124.9; 123.0; 119.3; 117.3; 60.9; 49.2; 32.9; 25.5; 24.9; 24.8. ESI-MS: 606 ([M þ 1]þ). Anal. calc. for
C39H35N5O2 (605.28): C 77.33, H 5.82, N 11.56, O 5.28; found: C 77.30, H 5.78, N 11.55, O 5.25.
N-[1-(Cyclohexylcarbamoyl)-3-phenylallyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzamide
(¼ N-{1-[(Cyclohexylamino)carbonyl]-3-phenylprop-2-en-1-yl}-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-
1
1-yl)benzeneamide; 6k). Yield 0.20 g (35%). Yellow solid. M.p. 216 – 2188. H-NMR (CDCl3): 8.15 (s,
1 H); 7.89 – 7.88 (m, 2 H); 7.62 (d, J ¼ 9, 2 H); 7.53 (d, J ¼ 8.5, 2 H); 7.48 (d, J ¼ 8.5, 2 H); 7.40 – 7.31 (m,
5 H); 7.28 – 7.21 (m, 4 H); 6.75 (d, J ¼ 16, 1 H); 6.56 – 6.51 (m, 1 H); 6.13 (d, J ¼ 7.5, 1 H); 5.41 (d, J ¼ 9,
1 H); 2.00 (m, 2 H); 1.75 – 1,72 (m, 2 H); 1.39 (m, 1 H); 1.24 – 1.23 (m, 2 H); 1.22 – 1.21 (m, 3 H).
13C-NMR (125 MHz, CDCl3): 169.3; 168.0; 148.5; 141.8; 137.4; 137.2; 136.1; 135.8; 130.3; 129.3; 128.9;
128.7; 128.6; 127.8; 126.9; 125.9; 122.5; 119.4; 117.3; 66.5; 48.8; 33.0; 25.5; 24.8. ESI-MS: 582 ([M þ 1]þ).
Anal. calc. for C37H35N5O2 (581.28): C 76.40, H 6.06, N 12.04, O 5.50; found: C 76.35, H 6.04, N 12.01, O
5.52
N-[(Cyclohexylcarbamoyl)(furan-2-yl)methyl]-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benza-
mide (¼ N-Cyclohexyl-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}furan-2-acetamide;
1
6l). Yield 0.24 g (44%). White solid. M.p. 214 – 2168. H-NMR (CDCl3): 8.14 (s, 1 H); 7.87 (d, J ¼ 7.5,
2 H); 7.62 (d, J ¼ 8.5, 2 H); 7.52 (d, J ¼ 8.5, 2 H); 7.46 (d, J ¼ 7.5, 2 H); 7.44 (m, 2 H); 7.38 (m, 3 H); 7.14 –
7.08 (m, 2 H); 6.44 (d, J ¼ 3, 1 H); 6.33 (s, 1 H); 6.33 – 6.30 (m, 2 H); 6.07 (d, J ¼ 8); 3.90 (m, 1 H); 2.01 –
1.96 (m, 2 H); 1.75 – 1.72 (m, 2 H); 1.64 – 1.62 (m, 1 H); 1.42 – 1.39 (m, 2 H); 1.24 – 1.19 (m, 3 H).
13C-NMR (CDCl3): 169.6; 166.2; 148.5; 147.9; 143.0; 140.8; 137.4; 136.0; 130.3; 130.0; 129.5; 128.9; 128.8;
128.6; 127.8; 125.9; 119.4; 117.3; 112.4; 110.9; 60.2; 48. 9; 32.8; 25.5; 24.8; 24.7. ESI-MS: 546 ([M þ 1]þ).
Anal. calc. for C33H31N5O3 (545.24): C 72.64, H 5.73, N 12.84, O 8.80; found: C 72.62, H 5.70, N 12.86, O
8.78.
N-{[(tert-Butyl)carbamoyl]phenylmethyl}-N-phenyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzamide
(¼ N-(1,1-Dimethylethyl)-a-{phenyl[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoyl]amino}benzeneacetamide;
1
6m). Yield 0.39 g (73%). White solid. M.p. 216 – 2188. H-NMR (CDCl3): 8.13 (s, 1 H); 7.89 – 7.87 (m,
2 H); 7.62 – 7.76 (m, 2 H); 7.54 – 7.52 (m, 2 H); 7.47 – 7.44 (t, J ¼ 7.5, 2 H); 7.39 – 7.36 (m, 1 H); 7.28 – 7.27
(m, 5 H); 7.05 (s, 5 H); 6.14 (s, 1 H); 5.66 (s, 1 H); 1.41 (s, 9 H). 13C-NMR (CDCl3): 169.7; 168.4; 148.5;
140.9; 137.2; 136.6; 134.7; 130.3; 130.2; 130.0; 128.9; 128.6; 128.6; 128.5; 127.5; 125.9; 119.3; 117.3; 67.2;
51.8; 28.7. ESI-MS: 530 ([M þ 1]þ). Anal. calc. for C33H31N5O2 (529.25): C 74.84, H 5.90, N 13.22, O 6.04;
found: C 74.81, H 5.88, N 13.25, O 6.02.
N-[(Cyclohexylcarbamoyl)phenylmethyl]-4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]-N-phenyl-
benzamide (¼ N-Cyclohexyl-a-{{4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]benzoyl}phenylamino}ben-
zeneacetamide; 6n). Yield 0.35 g (62%). Yellow solid. M.p. > 2308. 1H-NMR ((D6)DMSO): 9.20 (s, 1 H);
8.13 (d, J ¼ 8, 1 H); 7.80 – 7.77 (m, 4 H); 7.46 – 7.44 (m, 2 H); 7.30 – 7.28 (m, 2 H); 7.19 – 7.13 (m, 6 H);
6.99 – 6.93 (m, 3 H); 6.31 (s, 1 H); 3.67 – 3.66 (m, 1 H); 2.34 (s, 3 H); 1.79 – 1.73 (m, 3 H); 1.69 – 1.54 (m,
2 H); 1.30 – 1.20 (m, 3 H); 1.11 – 1.04 (m, 2 H). 13C-NMR ((D6)DMSO): 169.3; 168.9; 147.9; 140.6; 138.2;
137.4; 136.9; 135.8; 131.5; 130.6; 130.1; 130.0; 128.3; 128.3; 128.1; 127.8; 127.4; 125.7; 119.5; 119.3; 64.8;
48.5; 32.7; 36.6; 25.7; 25.1; 25.0; 21.3. ESI-MS: 570 ([M þ 1]þ). Anal. calc. for C36H35N5O2 (529.28): C
75.90, H 6.19, N 12.29, O 5.62; found: C 75.85, H 6.17, N 12.24, O 5.61.
N-{(Cyclohexylcarbamoyl)[4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}-N-phenylbenzamide
( ¼ a-(Benzoylphenylamino)-N-cyclohexyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzeneacetamide; 7a).
Yield 0.29 g (53%). Yellow solid. M.p. 220 – 2228. 1H-NMR (CDCl3): 8.18 (s, 1 H); 8.12 (d, J ¼ 8.5,

Helvetica Chimica Acta – Vol. 95 (2012)
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1 H); 7.98 – 7.95 (m, 1 H); 7.91 (d, J ¼ 7, 2 H); 7.71 (d, J ¼ 7.5, 2 H); 7.52 – 7.47 (m, 4 H); 7.41 – 7.40 (m,
1 H); 7.35 – 7.34 (m, 2 H); 7.27 – 7.23 (m, 1 H); 7.18 – 715 (m, 2 H); 7.08 – 7.05 (m, 4 H); 6.28 (s, 1 H); 6.11
(d, J ¼ 7.5, 1 H); 2.05 – 1.95 (m, 2 H); 1.76 – 1.62 (m, 3 H); 1.73 – 1.69 (m, 3 H); 1.43 – 1.38 (m, 2 H); 1.25 –
1.15 (m, 3 H). 13C-NMR (CDCl3): 171.4; 168.1; 158.4; 151.5; 148.5; 141.1; 136.8; 135.7; 135.6; 131.6; 130.2;
130.1; 130.1; 129.8; 129.3; 129.0; 128.7; 128.6; 128.6; 127.7; 127.5; 126.5; 125.9; 125.9; 120.9; 120.4; 120.1;
117.4; 65.9; 48.9; 32.9; 25.5; 24.8; 24.7. ESI-MS: 556 ([M þ 1]þ). Anal. calc. for C35H33N5O2 (555.26): C
75.65, H 5.99, N 12.60, O 5.76; found: C 75.63, H 5.97, N 12.56, O 5.73.
N-{[(tert-Butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}-N-(4-chlorophenyl)-
benzamide (¼a-[Benzoyl(4-chlorophenyl)amino]-N-(1,1-dimethylethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-
yl)benzeneacetamide; 7b). Yield 0.27 g (48%). Yellow solid. M.p. 180 – 1828. 1H-NMR (500 MHz,
CDCl3): 8.18 (s, 3 H); 7.92 (d, J ¼ 8.5, 2 H); 7.63 (s, 2 H); 7.63 (s, 4 H); 7.22 – 7.20 (m, 2 H); 7.43 – 7.40 (m,
1 H); 7.16 – 7.15 (m, 3 H); 6.93 (s, 2 H); 5.75 (s, 1 H); 5.61 (s, 1 H); 4.73 – 4.70 (d, J ¼ 15, 1 H); 4.52 (d, J ¼
16.5, 1 H); 1.389 (s, 9 H). 13C-NMR (CDCl3): 171.2; 167.5; 148.7; 148.4; 142.2; 137.2; 131.4; 129.9; 129.0;
128.7; 128.6; 127.7; 127.4; 126.7; 125.9; 123.8; 120.7; 117.3; 52.1; 28.6. ESI-MS: 565 ([M þ 1]þ). Anal. calc.
for C33H30ClN5O2 (563.21): C 70.27, H 5.36, N 12.42, O 5.67; found: C 70.25, H 5.33, N 12.39, O 5.62.
N-Benzyl-N-{[(tert-butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}benzamide
(¼a-[Benzoyl(phenylmethyl)amino]-N-(1,1-dimethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzeneacet-
1
amide; 7c). Yield 0.34 g (62%). Yellow solid. M.p. 180 – 1828. H-NMR (CDCl3): 8.17 (s, 1 H); 7.93 (d,
J ¼ 7.5, 2 H); 7.72 (d, J ¼ 8, 2 H); 7.54 – 7.48 (m, 6 H); 7.22 – 7.20 (m, 5 H); 7.19 – 7.08 (m, 3 H); 7.08 (s,
2 H); 7.35 – 7.34 (m, 2 H); 5.53 (s, 1 H); 4.84 – 4.80 (m, 1 H); 4.57 (d, J ¼ 15, 1 H); 1.36 (s, 9 H). 13C-NMR
(CDCl3): 173.3; 167.9; 148.6; 136.8; 135.9; 131.0; 130.1; 129.7; 129.0; 128.7; 128.6; 128.5; 128.1; 127.3;
126.7; 125.9; 120.5; 120.3; 117.4; 51.8; 30.9; 28.6. ESI-MS: 545 ([M þ 1]þ). Anal. calc. for C34H33N5O2
(543.26): C 75.11, H 6.12, N 12.88, O 5.89; found: C 75.08, H 6.10, N 12.85, O 5.85.
N-{[(tert-Butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}-N-cyclohexylbenz-
amide (¼a-[Benzoylcyclohexylamino)-N-(1,1-dimethylethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benze-
1
neacetamide; 7d). Yield 0.31 g (58%). Yellow solid. M.p. 190 – 1928. H-NMR (CDCl3): 8.20 (s, 1 H);
7.94 – 7.92 (m, 3 H); 7.82 – 7.80 (m, 2 H); 7.62 (d, J ¼ 8, 2 H); 7.50 – 7.46 (m, 3 H); 7.41 – 7.8 (m, 4 H); 5.01
(s, 1 H); 3.75 – 3.71 (m, 1 H); 1.91 – 1.86 (m, 2 H); 1.81 – 1.78 (m, 3 H); 1.65 – 1.55 (m, 2 H); 1.55 (s, 9 H);
1.11 (s, 3 H). 13C-NMR (CDCl3): 172.5; 169.8; 157.0; 148.6; 148.4; 138.2; 137.9; 137.0; 136.5; 136.2; 130.2;
130.1; 130.1; 129.4; 128.9; 128.7; 128.5; 128.4; 126.1; 125.9; 125.9; 120.6; 120.3; 117.5; 117.4; 70.0; 64.7;
60.7; 58.5; 51.4; 34.3; 31.7; 28.6; 25.7; 25.6; 25.5; 24.9; 24.7; 18.4. ESI-MS: 535 ([M þ 1]þ). Anal. calc. for
C33H37N5O2 (535.29): C 73.99, H 6.96, N 13.07, O 5.97; found: C 73.97, H 6.95, N 13.03, O 5.93.
N-Benzyl-N-{[(tert-butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}-4-nitrobenz-
amide (¼ N-(1,1-Dimethylethyl)-a-(4-nitrobenzoyl)(phenylmethyl)amino]-4-(4-phenyl-1H-1,2,3-triazol-
1
1-yl)benzeneacetamide; 7e). Yield 0.29 g (51%). Yellow solid. M.p. > 2308. H-NMR (CDCl3): 8.19 (s,
1 H); 7.91 (d, J ¼ 7.5, 2 H); 7.73 (d, J ¼ 7.5, 2 H); 7.50 – 7.47 (m, 4 H); 7.40 (t, J ¼ 7.5, 1 H); 7.32 (d, J ¼ 7,
2 H); 7.26 – 7.25 (m, 1 H); 7.21 – 7.18 (m, 2 H); 7.04 – 7.02 (m, 4 H); 6.25 (s, 1 H); 5.88 (s, 1 H); 1.43 (s,
9 H). 13C-NMR (CDCl3): 171.2; 168.1; 148.6; 139.3; 136.9; 135.4; 135.3; 133.3; 131.6; 130.0; 129.9; 129.0;
128.8; 128.6; 128.5; 127.9; 125.9; 120.3; 117.3; 65.4; 52.0; 30.9; 28.7. ESI-MS: 576 ([M þ 1]þ). Anal. calc.
for C33H30N6O4 (574.23): C 68.98, H 5.26, N 14.63, O 11.14; found: C 68.95, H 5.22, N 14.61, O 11.12.
N-{{Benzyl{[(tert-Butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}carbamoyl)-
methyl}carbamic Acid tert-Butyl Ester ( ¼ N-{2-{{2-[(1,1-Dimethylethyl)amino]-2-oxo-1-[4-(4-phenyl-
1H-1,2,3-triazol-1-yl)phenyl]ethyl}phenylmethyl)amino}-2-oxoethyl}carbamic Acid 1,1-Dimethylethyl
1
Ester; 7f). Yield 0.32 g (55%). Yellow solid. M.p. 198 – 2008. H-NMR (CDCl3): 8.15 (s, 1 H); 7.91 (d,
J ¼ 7.5, 2 H); 7.69 (d, J ¼ 7.5, 2 H); 7.54 – 7.47 (m, 4 H); 7.41 – 7.38 (t, J ¼ 7.5, 1 H); 7.22 – 7.15 (m, 3 H);
7.03 – 7.01 (d, J ¼ 7, 2 H); 5.89 (s, 1 H); 5.75 (s, 1 H); 5.43 (s, 1 H); 4.76 (d, J ¼ 17.5, 1 H); 4.61 (d, J ¼ 17.5,
1 H); 4.06 (d, J ¼ 19, 1 H); 3.94 – 3.90 (m, 1 H); 1.45 (s, 1 H); 1.38 (s, 1 H). 13C-NMR (CDCl3): 170.9;
167.8; 155.7; 148.6; 137.0; 136.2; 135.4; 131.2; 130.0; 129.0; 128.7; 128.6; 127.5; 126.2; 125.9; 120.5; 117.3;
79.8; 63.1; 52.0; 49.6; 43.1; 28.6; 28.4. ESI-MS: 584 ([M þ 1]þ). Anal. calc. for C33H38N6O4 (582.30): C
68.02, H 6.57, N 14.42, O 10.98; found: C 68.00, H 6.56, N 14.39, O 11.01.
N-Benzyl-N-{[(tert-butyl)carbamoyl][4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]methyl}-4-(4-phe-
nyl-1H-1,2,3-triazol-1-yl)benzamide (¼ N-(1,1-Dimethylethyl)-a-{(phenylmethyl)[4-(4-phenyl-1H-1,2,3-
triazol-1-yl)benzoyl]amino}-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzeneacetamide; 8). Yield 0.29 g

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Helvetica Chimica Acta – Vol. 95 (2012)
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(43%). Yellow solid. M.p. > 2308. H-NMR ((D6)DMSO): 9.45 (s, 1 H); 9.26 (s, 1 H); 8.14 – 7.94 (m,
7 H); 7.80 – 7.73 (m, 4 H); 7.52 – 7.49 (m, 5 H); 7.41 – 7.38 (m, 3 H); 7.12 – 7.05 (m, 5 H); 5.55 (s, 1 H); 5.06
(s, 1 H); 4.39 (s, 1 H); 1.27 (s, 9 H). 13C-NMR ((D6)DMSO): 168.7; 148.0; 147.8; 137.2; 136.5; 131.2; 130.6;
130.6; 129.5; 128.8; 128.5; 128.1; 127.1; 125.9; 125.8; 120.2; 120.0; 51.0; 28.7. ESI-MS: 685 ([M ꢀ 1]ꢀ).
Anal. calc. for C42H38N8O2 (686.31): C 73.45, H 5.58, N 16.32, O 4.66; found: C 73.42, H 5.55, N 16.29, O
4.65.
N-{2-{Benzyl{2-[(tert-butyl)amino]-1-{4-{4-{{N-{1-[(tert-butyl)amino]-3-methyl-1-oxobutan-2-yl}-
4-chlorobenzamido}methyl}-1H-1,2,3-triazol-1-yl}phenyl}-2-oxoethyl}amino}-2-oxoethylcarbamic Acid
tert-Butyl Ester (¼ N-{2-{{1-{4-{{(4-Chlorobenzyl){1-{[(1,1-dimethylethyl)amino]carbonyl}-2-methylpro-
pyl}amino}methyl}-1H-1,2,3-triazol-1-yl}phenyl}-2-[(1,1-dimethylethyl)amino]-2-oxethyl}phenylmeth-
yl)amino}-2-oxoethyl}carbamic Acid 1,1-Dimethylethyl Ester; 11a). Yield 0.29 g (36%). White solid.
1
M.p. 134 – 1368. H-NMR (CDCl3): 8.11 – 7.82 (m, 1 H); 7.62 – 7.57 (m, 3 H); 7.49 – 7.47 (m, 2 H); 7.43 –
7.41 (m, 4 H); 7.21 – 7.16 (m, 3 H); 7.01 – 6.99 (m, 3 H); 5.85 (s, 1 H); 5.68 (s, 1 H); 5.42 (s, 1 H); 4.75 –
4.70 (m, 2 H); 4.65 – 4.56 (m, 2 H); 4.05 (d, J ¼ 17.5, 1 H); 3.91 (d, J ¼ 18, 1 H); 2.60 (m, 1 H); 1.50 (s,
1 H); 1.35 (s, 1 H); 1.27 – 1.23 (m, 1 H); 1.03 – 0.99 (q, J ¼ 5.5, 4 H); 0.90 – 0.83 (m, 2 H). 13C-NMR
(CDCl3): 173.0; 170.8; 169.26; 167.8; 155.7; 144.0; 136.8; 136.2; 135.5; 134.6; 131.1; 129.0; 128.8; 128.7;
127.5; 126.2; 121.2; 120.4; 79.7; 63.1; 52.0; 51.1; 49.6; 43.4; 43.1; 30.9; 29.7; 28.6; 28.5; 28.3; 26.9; 19.9; 19.1.
ESI-MS: 811 ([M ꢀ 1]ꢀ). Anal. calc. for C45H59ClN8O6 (812.41): C 64.08, H 7.05, N 13.29, O 11.38; found:
C 64.05, H 7.03, N 13.25, O 11.36.
N-Benzyl-N-{2-[(tert-butyl)amino]-1-(furan-2-yl)-2-oxoethyl}-4-{4-{{(N-{2-[(tert-butyl)amino]-3-
methylbutanoyl}-4-chlorobenzamido}methyl}-1H-1,2,3-triazol-1-yl}benzamide (¼a-{{4-{4-{{(4-Chloro-
benzoyl){2-[(1,1-dimethylethyl)amino]-3-methyl-1-oxobutyl}amino}methyl}-1H-1,2,3-triazol-1-yl}ben-
zoyl}(phenylmethyl)amino}-N-(1,1-dimethylethyl)furan-2-acetamide; 13a). Yield 0.26 g (33%). White
solid. M.p. 108 – 1108. 1H-NMR (CDCl3): 7.86 (s, 1 H); 7.61 – 7.56 (m, 6 H); 7.42 – 7.39 (m, 3 H); 7.32 – 7.32
(m, 1 H); 7.16 (s, 3 H); 6.92 (s, 2 H); 6.59 (s, 1 H); 6.31 – 6.30 (m, 1 H); 6.06 (s, 1 H); 5.84 (s, 1 H); 4.81 –
4.63 (m, 4 H); 4.12 (m, 1 H); 2.60 (s, 1 H); 1.36 (s, 11 H); 1.22 (s, 7 H); 1.03 – 1.00 (m, 4 H); 0.92 – 0.83 (m,
2 H). 13C-NMR (CDCl3): 173.1; 171.8; 169.2; 166.2; 148.3; 144.1; 143.2; 137.6; 136.4; 136.2; 134.6; 129.0;
128.8; 128.4; 128.3; 126.5; 121.3; 120.1; 112.1; 110.9; 62.3; 58.4; 51.9; 51.1; 43.3; 32.1; 29.9; 29.7; 28.6; 28.5;
26.8; 19.9; 19.8; 19.1; 18.4. ESI-MS: 802 ([M ꢀ 1]ꢀ). Anal. calc. for C43H50N7O5 (803.36): C 66.18, H 6.46,
N 12.56, O 10.25; found: C 66.15, H 6.45, N 12.53, O 10.23.
REFERENCES
[1] M. G. Finn, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1231.
[2] J.-F. Lutz, Angew. Chem., Int. Ed. 2007, 46, 1018.
[3] M. Aufort, J. Herscovici, P. Bouhours, N. Moreau, C. Girard, Bioorg. Med. Chem. Lett. 2008, 18,
1195.
[4] C. W. Tornøe, C. Christensen. M. Meldal, J. Org. Chem. 2002, 67, 3057.
[5] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem., Int. Ed. 2002, 41, 2596.
[6] D. S. Pedersen, A. Abell, Eur. J. Org. Chem. 2011, 2399.
[7] J. M. Holub, K. Kirshenbaum, Chem. Soc. Rev. 2010, 39, 1325.
[8] Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674.
[9] W. S. Horne, M. K. Yadav, C. D. Stout, M. R. Ghadiri, J. Am. Chem. Soc. 2004, 126, 15366.
[10] N. Miller, G. M. Williams, M. A. Brimble, Org. Lett. 2009, 11, 2409.
[11] Q. Wan, J. Chen, G. Chen, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8244.
[12] M. Whiting, J. C. Tripp, Y-C. Lin, W. Lindstrom, A. J. Olson, J. H. Elder, K. B. Sharpless, V. V. Fokin,
J. Med. Chem. 2006, 49, 7697.
[13] N. G. Angelo, P. S. Arora, J. Org. Chem. 2007, 72, 7963.
[14] N. G. Angelo, P. S. Arora, J. Am. Chem. Soc. 2005, 127, 17134.
[15] B. H. M. Kuijpers, S. Groothuys, A. R. Keereweer, P. J. L. M. Quaedflieg, R. H. Blaauw, F. L.
Van Delft, F. P. J. T. Rutjes, Org. Lett. 2004, 6, 3123.

Helvetica Chimica Acta – Vol. 95 (2012)
99
[16] S. Cantel, A. L. C. Isaad, M. Scrima, J. J. Levy, R. D. DiMarchi, P. Rovero, J. A. Halperin, A. M.
DꢃUrsi, A. M. Papini, M. Chorev, J. Org. Chem. 2008, 73, 5663.
[17] S. Bera, G. G. Zhanel, F. Schweizer, Bioorg. Med. Chem. Lett. 2010, 20, 3031.
[18] V. D. Bock, D. Speijer, H. Hiemstra, J. H. Van Maarseveen, Org. Biomol. Chem. 2007, 5, 971.
[19] B. B. Toure, D. G. Hall, Chem. Rev. 2009, 109, 4439.
[20] R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, T. A. Keating, Acc. Chem. Res. 1996, 29,
123.
[21] L. F. Tietze, M. E. Lieb, Curr. Opin. Chem. Biol. 1998, 2, 363.
[22] I. Akritopoulou-Zanze, V. Gracias, S. W. Djuric, Tetrahedron Lett. 2004, 45, 8439.
[23] V. G. Nenajdenko, A. V. Gulevich, N. V. Sokolova, A. V. Mironov, E. S. Balenkova, Eur. J. Org.
Chem. 2010, 1445.
[24] N. V. Sokolova, G. V. Latyshev, N. V. Lukashev, V. G. Nenajdenko, Org. Biomol. Chem. 2011, 9, 4921.
[25] J.-P. Ebran, N. Dendane, O. Melnyk, Org. Lett. 2011, 13, 4336.
[26] M. R. Krause, R. Goddard, S. Kubik, J. Org. Chem. 2011, 76, 7084.
[27] A. Dçmling, I, Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168.
[28] A. Dçmling, Curr. Opin. Chem. Biol. 2002, 6, 306.
[29] L. A. Wessjohann, D. G. Rivera, O. E. Vercillo, Chem. Rev. 2009, 109, 796.
[30] A. Dçmling, Chem. Rev. 2006, 106, 17.
[31] S. Malaquin, M. Jida, J.-C. Gesquiere, R. Deprez-Poulain, B. Deprez, G. Laconde, Tetrahedron Lett.
2010, 51, 2983.
[32] H. Cao, H. Liu, A. Dçmling, Chem. – Eur. J. 2010, 16, 12296.
´
[33] C. C. Ciocoiu, N. Nikolic, H. H. Nguyen, G. H. Thoresen, A. J. Aasen, T. V. Hansen, Eur. J. Med.
Chem. 2010, 45, 3047.
[34] A. Perry, C. Neipert, B. Space, Chem. Rev. 2006, 106, 1234.
[35] R. Duval, S. Kolb, E. Braud, D. Genest, C. Garbay, J. Comb. Chem. 2009, 11, 947.
Received June 16, 2011