Chemoselective preparation of unsymmetrical bis(1,2,3-triazole) derivatives and application in bis(1,2,3-triazole)-modified peptidomimetic synthesis

Article abstract of DOI:10.1002/ejoc.201201096

An efficient chemoselective methodology for the syntheses of unsymmetrical bis(1,2,3-triazole) derivatives has been developed. This protocol utilizes alkynyl-substituted amines as bifunctional linkers to conjoin a copper-free three-component cycloaddition with a copper(I)-catalyzed alkyne-azide cycloaddition in a one-pot procedure. In addition, we used this method for the construction of unsymmetrical bis(1,2,3-triazole)-modified peptidomimetics through a combination of multicomponent reactions taking place in a sequential process, which may be utilized in biological applications. A protocol for the syntheses of unsymmetrical bis(1,2,3-triazole) derivatives has been reported, which utilizes alkynyl-substituted amines as bifunctional linkers to conjoin a copper-free three-component cycloaddition with a copper(I)-catalyzed alkyne-azide cycloaddition in a one-pot procedure. This method was then used to construct unsymmetrical bis(1,2,3-triazole)-modified peptidomimetics. Copyright

Full text of DOI:10.1002/ejoc.201201096

FULL PAPER
DOI: 10.1002/ejoc.201201096
Chemoselective Preparation of Unsymmetrical Bis(1,2,3-triazole) Derivatives
and Application in Bis(1,2,3-triazole)-Modified Peptidomimetic Synthesis
Teng-fei Niu,[a] Lin Gu,[a] Liang Wang,[b] Wen-bin Yi,[a] and Chun Cai*[a]
Keywords: Nitrogen heterocycles / Multicomponent reactions / Cycloaddition / Click chemistry / Chemoselectivity / Pepti-
domimetics
An efficient chemoselective methodology for the syntheses
of unsymmetrical bis(1,2,3-triazole) derivatives has been de-
veloped. This protocol utilizes alkynyl-substituted amines as
bifunctional linkers to conjoin a copper-free three-compo-
nent cycloaddition with a copper(I)-catalyzed alkyne–azide
cycloaddition in a one-pot procedure. In addition, we used
this method for the construction of unsymmetrical bis(1,2,3-
triazole)-modified peptidomimetics through a combination of
multicomponent reactions taking place in a sequential pro-
cess, which may be utilized in biological applications.
and deprotection sequence, which increase the workload.
Recognizing the limitations associated with these processes,
Girard and co-workers synthesized a new kind of dialkyne
containing both activated and inactivated alkyne moieties
to generate simple unsymmetrical bis(triazoles) in a one-pot
process.[8] However, this method lacks regioselectivity, by
affording both 1,4- and 1,5-disubstituted triazoles. Beal et
al. employed a strain-promoted azide–alkyne cycloaddition
(SPAAC) and CuAAC reactions in sequential biomolecular
conjugations to achieve unsymmetrical bis(1,2,3-tri-
azoles).[9] More recently, Zhu et al. introduced unsymmetri-
cal bis(azide) compounds containing chelating and nonche-
lating azido groups that undergo chemoselective CuAAC
reactions with two different alkyne molecules.[10] However,
because they are potentially explosive, these bis(azide) com-
pounds are very dangerous. Although these approaches are
available for various degrees of chemoselective syntheses,
they suffer from the limitations mentioned above. More im-
portantly, these bifunctional molecules are not commer-
cially available and not so convenient to prepare in house.
Herein, we report an efficient procedure for the successive
copper-free and copper-mediated chemoselective formation
of two distinct triazole linkages using commercially avail-
able alkynyl-substituted amines as bifunctional linkers. In
addition, to verify its possible biological applications, we
utilized and took advantage of this chemoselective reaction
to access bis(1,2,3-triazole)-modified peptidomimetics by
tandem multicomponent reactions.
Introduction
Recently, new kinds of bis(triazole) derivatives have re-
ceived much attention in fields as diverse as biotechnology
and materials science. Various literature reports have men-
tioned that the bis(triazole) molecules could act as cross-
linkers in the conjugation of two different ligands such as
DNA,[1] RNA,[2] and peptidomimetics,[3] all of which usu-
ally have special bioactivities. In addition, metal-coordi-
nated bis(triazoles) have shown to be efficient catalysts and
form supramolecular structures.[4]
The typical approach for the construction of bis(triazole)
derivatives involves a copper(I)-catalyzed 1,3-dipolar cyclo-
addition reaction between an acetylene and an azide
(CuAAC), namely, “click chemistry”.[5] However, this
method is rather inefficient in its step-by-step reaction se-
quence, which requires many protecting groups. In most
cases, only symmetrically substituted bis(1,2,3-triazoles)
have been prepared. There are few reports for a flexible and
efficient chemoselective protocol for the syntheses of un-
symmetrical bis(1,2,3-triazole) molecules, until recently.
Aucagne and Leigh first reported a double-click method
by using TMS (trimethylsilyl)-protected dialkynes to give
the desired unsymmetrical bis(1,2,3-triazoles).[6] In a recent
discovery, other kinds of dialkynes were prepared to gener-
ate these molecules by using the double-click method.[7]
However, these double-click methods require a protection
[a] Chemical Engineering College, Nanjing University of Science
and Technology,
Nanjing, 210094, P. R. China
Fax: +86-25-84315030
Results and Discussion
E-mail: c.cai@mail.njust.edu.cn
Homepage: http://sce.njust.edu.cn
Taking into account recent reports of triazole syntheses,
it is known that azides easily and regioselectively react with
acetoacetic acids esters as well as amides to undergo a
three-component cycloaddition and form 5-methyl-1H-
[b] Jiangsu Province Key Laboratory of Fine Petrochemical Engi-
neering, Changzhou University,
Changzhou 213164, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201096.
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FULL PAPER
Scheme 1. Chemoselective synthesis of monotriazole by a three-component reaction.
1,2,3-triazole.[11] We wondered whether alkynyl-substituted Table 1. Optimization of conditions for the first cycloaddition.
amines could regioselectively be used for the formation of
a monotriazole, leaving the alkynyl group available for a
CuAAC reaction with another azide. In our initial experi-
ment (see Scheme 1), 2-propynylamine (3a) was chosen as
a bifunctional linker and was combined with 1 equiv. of az-
ide 1a and 1 equiv. of diketene 2a in MeCN under base-
catalyzed (1 equiv. of Et3N) conditions at reflux. To our
delight, the resulting monotriazole 4a was obtained in 37%
yield. However, a mixtures of the 1,4 and 1,5 isomers, bis-
(triazoles) 5a and 5b, also formed with as selectivity toward
4a [4a/(5a + 5b), 59:41].
To optimize the reaction, we screened a number of exper-
imental conditions to facilitate the cyclization. The results
of our optimization studies are summarized in Table 1.
Both organic and inorganic bases catalyzed the formation
of the monotriazole. Although strong bases such as NaOH
and tBuOK resulted in a short reaction time (see Table 1,
Entries 6 and 7), using DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene) afforded an excellent yield with a higher selectivity
(see Table 1, Entry 4). However, if no base was added, no
conversion was observed (see Table 1, Entry 8). The effect
of solvent was also examined, and from Table 1, Entries 9–
12, we can see that highly polar solvents such as MeOH
resulted in a higher yield and selectivity of the product
within a shorter reaction period. In addition, a long reac-
Entry
Conditions[a]
Solvent T [h] T [°C]
4a/(5a + 5b) % Yield 4a[b]
Catalyst
Et3N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
MeCN
8
8
8
8
8
80
80
80
80
80
80
80
80
100
70
70
100
70
70
50
70
59:41
61:39
65:35
85:15
73:27
81:19
85:15
–
37
35
47
60
53
22
19
trace
55
64
35
27
71
71
52
53
DIPEA[c] MeCN
DMAP[c] MeCN
DBU
MeCN
DABCO[c] MeCN
NaOH
tBuOK
–
DBU
DBU
MeCN
MeCN
MeCN
DMF[c]
MeOH
THF[c]
toluene
MeOH
MeOH
MeOH
–
4
4
24
12
8
12
12
8
83:17
90:10
65:35
51:49
Ͼ95
DBU
DBU
DBU[d]
DBU[e]
DBU[d]
DBU[d]
8
Ͼ95
90:10
83:17
24
6
[a] 1a (1 equiv.), 2a (1 equiv.), 3a (1 equiv.), and catalyst (1 equiv.).
[b] Isolated yield. [c] DIPEA = N,N-diisopropylethylamine, DMAP
= 4-(dimethylamino)pyridine, DABCO = 1,4-diazabicyclo[2.2.2]oc-
tane, DMF = N,N-dimethylformamide , THF = tetrahydrofuran.
[d] 1a (1 equiv.), 2a (1.1 equiv.), 3a (1.1 equiv.), and catalyst
(1.1 equiv.). [e] 1a (1 equiv.), 2a (1.2 equiv.), 3a (1.2 equiv.), and cat-
alyst (1.2 equiv.).
tion time was needed or a lower yield resulted when a lower yields of the reaction (see Table 2, Entries 2–4 and 11–13).
temperature (see Table 1, Entry 15) or solvent-free condi- However, the steric effects of the substituted azides had a
tion (see Table 1, Entry 16) was applied. Gratifyingly, the significant influence on the yields of the reaction (see
best result was obtained with 1.1 equiv. of diketene 2a, Table 2, Entries 5, 6, and 14). In addition, compounds 3a,
1.1 equiv. of 2-propynylamine 3a, 1.1 equiv. of DBU as the 3b, and 3c were commercially available, and 3d can also be
catalyst, and MeOH as the solvent (see Table 1, Entry 13).
prepared easily.[12]
Using these optimized conditions, the scope of the reac-
Benzyl azide and 3-azidocoumarin were then employed
tion is illustrated by the examples in Table 2. To our delight, in the second triazole synthesis. The addition of the second
both aromatic and aliphatic alkynyl-substituted amines (see azide (1.0 equiv.) with a catalytic amount of CuI (20 mol-
Figure 1) were used and gave satisfactory yields and selec- %) and Et3N (1.0 equiv.) to the solution of the purified
tivities. The type of the alkynyl-substituted amine was im- monotriazoles 4 (1.0 equiv.) in CH2Cl2/MeOH gave the ex-
portant, as meta-substituted ethynylaniline (3c) gave a sig- pected unsymmetrical bis(1,2,3-triazoles) 6 in good yields
nificantly higher yield than alkynylamines 3a, 3b, or 3d, pre- (see Table 2). It is noteworthy that the three-component cy-
sumably because of electronic effects. However, para-substi- cloaddition and subsequent CuAAC can be performed as a
tuted ethynylaniline was not tolerated, and the desired “one-pot” tandem reaction. The first 3CR (three-compo-
product was not formed. Moreover, it was previously shown nent reaction) for the cyclization step was performed in
that different azides have various reactivities. Both electron- MeOH. After the reaction was complete, without separat-
donating and electron-withdrawing groups on the aromatic ing the intermediate monotriazoles 4, the second azide
ring of the azide were tolerated, and the electronic proper- (1.0 equiv.) and CuI (20 mol-%) were added (for 6k, 6l, and
ties of the substituted azides had a slight influence on the 6m, additional CH2Cl2 was added). The reaction was stirred
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Unsymmetrical Bis(1,2,3-triazole) Derivatives
Table 2. Chemoselective formation of mono- and bis(triazoles).
Eur. J. Org. Chem. 2012, 6767–6776
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T.-f. Niu, L. Gu, L. Wang, W.-b. Yi, C. Cai
FULL PAPER
Table 3. One-pot combination of two MCRs (multicomponent re-
action) to generate unsymmetrical bis(1,2,3-triazole)-modified pep-
tidomimetics.
Figure 1. Alkynyl-substituted amines.
at 40 °C for an additional 6 h. The one-pot sequence pro-
cess did not decrease the yields (e.g., 6a was obtained in
60% yield). Consequently, we developed an efficient one-
pot strategy for the syntheses of unsymmetrical bis(1,2,3-
triazole) molecules without the use of protecting groups.
We subsequently investigated the possibility of the
CuAAC triazole synthesis as the first reaction. An alterna-
tive route to the unsymmetrical bis(1,2,3-triazole) molecules
is presented in Scheme 2. However, the typical catalytic sys-
tems such as CuI/Et3N and CuSO4/sodium ascorbate/Et3N
could not catalyze the first “click reaction” when using ali-
phatic alkynyl-substituted amines, and no desired product
was found. Although aromatic alkynyl-substituted amines
could undergo this process, lower yields were obtained
(32% yield for 6j). Apparently, the chosen 3CR for the cy-
cloaddition in the first reaction was the best choice for this
combination.
Entry R3
R4
R5
4
Product
% Yield
1
2
3
4
n-butyl
4-ClC6H4 c-hex
4a
4c
4b
4b
12a
12b
12c
12d
56
73
76
72
4-ClC6H4 furan-2-yl c-hex
Bn
n-butyl
iPr
c-hex
4-ClC6H4 c-hex
Recently, our group discovered a six-component reaction
to generate 1,2,3-triazole-modified peptidomimetics by con-
jugating two MCRs in one pot.[15] The chemoselective bis-
(triazole) syntheses provide an opportunity to introduce a
six-component reaction to generate complex bis(1,2,3-tri-
azole)-modified peptidomimetics by combining three
MCRs in a sequential process. First, the Ugi 4CR was per-
formed by using para-azidobenzoic acid as the “bridge mo-
lecule”. After the reaction was complete, for the second
MCR, a one-pot combination with 1.1 equiv. of 3a,
1.1 equiv. of diketene 2a, and 1.1 equiv. of DBU at reflux
led to the intermediate monotriazole-modified peptidomi-
metics 17. No symmetrical bis(triazoles) were observed.
Then, a subsequent CuAAC reaction with another Ugi
4CR product, which contained an azide group, gave unsym-
metrical bis(1,2,3-triazole)-modified peptidomimetics in
good yields (see Scheme 3). In addition, an α,β-unsaturated
functional group, such as furaldehyde, was tolerated in the
process. These tandem multicomponent reactions provide
an opportunity to generate unsymmetrical bis(1,2,3-tri-
azole)-modified peptidomimetics in a rapid and efficient
process, which fully lives up to the principle of “green chem-
istry” and atom economy.
Scheme 2. An alternative route for unsymmetrical bis(1,2,3-tri-
azoles).
To further expand the scope of this combination of reac-
tions, we decided to focus on bis(1,2,3-triazole)-modified
peptidomimetic syntheses.[13] It is noteworthy that there is
an amido bond in the bis(triazole) structure, which is suit-
able for bis(1,2,3-triazole)-modified peptidomimetic synthe-
ses. Monotriazoles 4 were effective for the conjugation of a
peptide fragment that contains an azide group. In our re-
cent study, we found that the Ugi reaction was an efficient
method for the construction of peptide building blocks and
peptoid molecules in one step.[14] Azido acid was chosen as
the “bridge molecule” to combine a Ugi 4CR (four-compo-
nent reaction) with the 3CR used in the monotriazole syn-
Conclusions
We have described an efficient approach to the chemose-
thesis. The Ugi reaction was preferred as the first step for lective syntheses of unsymmetrical bis(1,2,3-trazoles). This
the MCRs. On the basis of classic reports on the Ugi 4CR, strategy employed alkynyl-substituted amines as bifunc-
9 was treated with 7, 8, and 10 in MeOH at room tempera- tional linkers, which could generate 1,2,3-trazoles by under-
ture to form intermediate 11. Then, without isolation of the going a copper-free cycloaddition and CuAAC reactions,
intermediate, a one-pot combination with monotriazoles 4 respectively. The commercially available bifunctional linkers
led to the desired unsymmetrical bis(1,3-triazole)-modified suggest this chemoselective ligation strategy could have
peptidomimetics 12 (see Table 3).
wide potential. In particular, this methodology is suitable
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Unsymmetrical Bis(1,2,3-triazole) Derivatives
Scheme 3. Unsymmetrical bis(1,2,3-triazole)-modified peptidomimetic syntheses by combining three MCRs in a sequential process.
(2.2 mmol) were placed in a sealed tube with MeOH (4 mL), and
the resulting mixture was stirred and heated at reflux for 8 h. Then,
the solvent was removed in vacuo, and the residue was purified
by column chromatography (hexanes/ethyl acetate, 2:1) to afford
monotriazole 4.
for the syntheses of unsymmetrical bis(1,2,3-trazoles)-modi-
fied peptidomimetics by combining the multicomponent re-
actions in a sequential process. This strategy allows direct
access to complex structures from simple building blocks
and fully lives up to the principle of “green chemistry” and
atom economy. We anticipate that this method could be a
useful protocol for biochemistry.
5-Methyl-1-phenyl-N-(prop-2-ynyl)-1H-1,2,3-triazole-4-carbox-
amide (4a): White solid (0.34 g, 71%); m.p. 86–88 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 9.00–8.97 (t, J = 6 Hz, 1 H), 7.66–
7.61 (m, 5 H), 4.06–4.04 (m, 2 H), 3.08–3.07 (t, J = 2.5 Hz, 1 H),
2.53 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 160.1,
137.3, 136.4, 134.8, 129.5, 129.2, 124.9, 80.9, 71.9, 39.5, 39.4, 39.2,
39.0, 38.8, 38.7, 38.5, 27.3, 8.8 ppm. MS (ESI): m/z = 241 [M +
1]+. C13H12N4O (240.26): calcd. C 64.99, H 5.03, N 23.32; found
C 64.86, H 4.95, N 23.22.
Experimental Section
General Methods: All of the chemicals were commercially available
and used without further purification. Analytical thin layer
chromatography was performed with glass plates that were pre-
coated with silica gel, which was impregnated with a fluorescent
indicator (254 nm). The plates were visualized by exposure to ultra-
1-(4-Chlorophenyl)-5-methyl-N-(prop-2-ynyl)-1H-1,2,3-triazole-4-
1
carboxamide (4b): White solid (0.46 g, 85%); m.p. 156–158 °C. H
1
violet light. The H NMR spectroscopic data were recorded with
NMR (500 MHz, [D6]DMSO): δ = 9.02–8.99 (t, J = 6 Hz, 1 H),
7.73–7.68 (m, 4 H), 4.05–4.03 (m, 2 H), 3.08–3.07 (t, J = 2.5 Hz, 1
H), 2.54 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
160.0, 137.4, 136.6, 134.1, 133.6, 129.2, 126.7, 80.8, 71.8, 39.5, 39.4,
39.2, 39.0, 38.9, 38.7, 38.5, 27.3, 8.7 ppm. MS (ESI): m/z = 275 [M
+ 1]+. C13H11ClN4O (274.71): calcd. C 56.84, H 4.04, N 20.40;
found C 56.71, H 4.11, N 20.31.
a Bruker DRX500 (500 MHz) spectrometer, and the 13C NMR
spectroscopic data were recorded with
a Bruker DRX500
(125 MHz) spectrometer. Mass spectra were recorded with a Finni-
gan TSQ Quantum-MS instrument in the electrospray ionization
(ESI) mode. Elemental analyses were performed with a Yanagim-
oto MT3CHN recorder.
Preparation of Monotriazoles 4: The azide (2.0 mmol), diketene
(2.2 mmol), alkynyl-substituted amine (2.2 mmol), and DBU
5-Methyl-N-(prop-2-ynyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carbox-
amide (4c): White solid (0.29 g, 83%); m.p. 136–138 °C. H NMR
1
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(500 MHz, [D6]DMSO): δ = 8.99–8.96 (t, J = 6 Hz, 1 H), 7.50 (d,
1-(4-Chlorophenyl)-N-(3-ethynylphenyl)-5-methyl-1H-1,2,3-triazole-
J = 8.5 Hz, 2 H), 7.44 (d, J = 8 Hz, 2 H), 4.05–4.03 (m, 2 H), 3.08– 4-carboxamide (4j): White solid (0.59 g, 88%); m.p. 136–138 °C. 1H
3.07 (t, J = 2.5 Hz, 1 H), 2.51 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 160.1, 139.3, 137.2, 136.3, 132.3, 129.5, 7.90 (d, J = 8.5 Hz, 1 H), 7.75–7.71 (m, 4 H), 7.38–7.35 (t, J =
NMR (500 MHz, [D6]DMSO): δ = 10.67 (s, 1 H), 8.07 (s, 1 H),
124.7, 80.9, 71.8, 27.3, 20.2, 8.7 ppm. MS (ESI): m/z = 255 [M +
1]+. C14H14N4O (254.29): calcd. C 66.13, H 5.55, N 22.03; found
C 66.30, H 5.63, N 22.15.
8 Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 4.19 (s, 1 H), 2.59 (s, 3
H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 159.1, 138.3,
137.6, 134.3, 133.5, 129.3, 128.5, 126.8, 126.4, 122.8, 121.4, 120.6,
82.9, 80.0, 8.9 ppm. MS (ESI): m/z = 338 [M + 1]+. C18H13ClN4O
(336.78): calcd. C 64.19, H 3.89, N 16.64; found C 64.08, H 3.98,
N 16.55.
5-Methyl-1-(4-nitrophenyl)-N-(prop-2-ynyl)-1H-1,2,3-triazole-4-
1
carboxamide (4d): White solid (0.49 g, 86%); m.p. 112–114 °C. H
NMR (500 MHz, [D6]DMSO): δ = 9.07–9.05 (t, J = 6 Hz, 1 H),
8.49 (d, J = 9 Hz, 2 H), 8.00 (d, J = 9 Hz, 2 H), 4.05–4.04 (m, 2
H), 3.09–3.08 (t, J = 2 Hz, 1 H), 2.62 (s, 3 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 159.8, 147.3, 139.6, 137.7, 137.0,
125.9, 124.6, 80.8, 71.9, 27.3, 8.9 ppm. MS (ESI): m/z = 286 [M +
1]+. C13H11N5O3 (285.26): calcd. C 54.74, H 3.89, N 24.55; found
C 54.53, H 3.97, N 24.41.
N-(3-Ethynylphenyl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carb-
oxamide (4k): White solid (0.54 g, 85 %); m.p. 144–146 °C. 1H
NMR (500 MHz, [D6]DMSO): δ = 10.64 (s, 1 H), 8.06 (s, 1 H),
7.90–7.88 (m, 1 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8 Hz, 2
H), 7.38–7.22 (t, J = 8 Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 4.19 (s,
1 H), 2.56 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 159.2, 139.4, 138.4, 137.5, 137.3, 132.3, 129.6, 128.5,
126.4, 124.7, 122.7,121.4, 120.5, 82.9, 80.0, 20.2, 8.9 ppm. MS
(ESI): m/z = 317 [M + 1]+. C19H16N4O (316.36): calcd. C 72.13, H
5.10, N 17.71; found C 72.05, H 5.167, N 17.53.
1-(2-Chlorophenyl)-5-methyl-N-(prop-2-ynyl)-1H-1,2,3-triazole-4-
1
carboxamide (4e): White solid (0.40 g, 74%); m.p. 106–108 °C. H
NMR (500 MHz, [D6]DMSO): δ = 7.07 (s, 1 H), 7.57–7.56 (m, 1
H), 7.52–7.49 (m, 1 H), 7.45–7.42 (m, 1 H), 7.38–7.37 (m, 1 H),
4.23–4.23 (m, 2 H), 2.42 (s, 3 H), 2.24 (s, 1 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 159.9, 136.6, 132.0, 131.1, 130.7,
129.7, 128.1, 127.1, 79.6, 70.4, 27.6, 8.0 ppm. MS (ESI): m/z = 275
[M + 1]+. C13H11ClN4O (274.71): calcd. C 56.84, H 4.04, N 20.40;
found C 56.75, H 4.11, N 20.32.
N-(3-Ethynylphenyl)-5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-
1
carboxamide (4l): White solid (0.60 g, 87%); m.p. 116–118 °C. H
NMR (500 MHz, [D6]DMSO): δ = 10.72 (s, 1 H), 8.51–8.49 (s, 2
H), 8.07–8.06 (t, J = 2 Hz, 1 H), 8.03–8.02 (m, 2 H), 7.90–7.88 (m,
1 H), 7.39–7.36 (t, J = 8 Hz, 1 H), 7.24–7.22 (m, 1 H), 4.20 (s, 1
H), 2.67 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
159.0, 147.4, 139.5, 138.3, 137.9, 128.5, 126.5, 126.0, 124.6, 122.8,
121.4, 120.6, 82.9, 80.0, 9.1 ppm. MS (ESI): m/z = 348 [M + 1]+.
C18H13N5O3 (347.33): calcd. C 62.24, H 3.77, N 20.16; found C
62.45, H 3.86, N 20.05.
5-Methyl-N-(prop-2-ynyl)-1-o-tolyl-1H-1,2,3-triazole-4-carbox-
1
amide (4f): White solid (0.36 g, 70%); m.p. 108–110 °C. H NMR
(500 MHz, [D6]DMSO): δ = 9.01–9.00 (t, J = 6 Hz, 1 H), 7.58–
7.52 (m, 2 H), 7.47–7.42 (m, 2 H), 4.06–4.04 (m, 2 H), 3.08–3.07
(t, J = 2.5 Hz, 1 H), 2.34 (s, 3 H), 1.98 (s, 3 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 160.1, 137.1, 136.8, 134.5, 133.6,
130.8, 130.3, 126.8, 126.7, 80.9, 71.9, 27.2, 16.1, 8.2 ppm. MS
(ESI): m/z = 255 [M + 1]+. C14H14N4O (254.29): calcd. C 66.13, H
5.55, N 22.03; found C 66.21, H 5.66, N 21.89.
1-(2-Chlorophenyl)-N-(3-ethynylphenyl)-5-methyl-1H-1,2,3-triazole-
4-carboxamide (4m): White solid (0.53 g, 76%); m.p. 112–114 °C.
1H NMR (500 MHz, [D6]DMSO): δ = 7.70 (s, 1 H), 7.57–7.56 (m,
1 H), 7.52–7.49 (m, 1 H), 7.45–7.42 (m, 1 H), 7.38–7.37 (m, 1 H),
4.24–4.22 (m, 2 H), 2.43 (s, 3 H), 2.24 (s, 1 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 159.9, 147.4, 137.8, 138.3, 136.6,
132.0, 131.1, 130.7, 129.7, 128.1, 127.1, 78.6, 70.4, 27.6, 8.0 ppm.
MS (ESI): m/z = 348 [M + 1]+. C18H13N5O3 (347.33): calcd. C
62.24, H 3.77, N 20.16; found C 62.35, H 3.69, N 20.24.
1-(4-Chlorophenyl)-5-methyl-N-(2-methylbut-3-yn-2-yl)-1H-1,2,3-tri-
azole-4-carboxamide (4g): White solid (0.53 g, 88 %); m.p. 116–
1
118 °C. H NMR (500 MHz, [D6]DMSO): δ = 8.14 (s, 1 H), 7.73–
7.67 (m, 4 H), 3.16 (s, 1 H), 2.53 (s, 3 H), 1.64 (s, 6 H) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 159.5, 136.7, 134.1, 133.6,
129.2, 126.7, 130.3, 126.8, 126.7, 87.2, 70.6, 46.0, 28.6, 8.7 ppm.
MS (ESI): m/z = 303 [M + 1]+. C15H15ClN4O (302.76): calcd. C
59.51, H 4.99, N 18.51; found C 59.43, H 5.06, N 18.43.
Bis(triazoles) 6: To a solution of compound 4 (0.5 mmol) and the
azide (0.5 mmol) in CH2Cl2/MeOH (50:50, 3 mL) were added Et3N
(0.5 mmol) and CuI (0.1 mmol). The reaction mixture was stirred
at room temperature for 8 h. Then, the solvent was removed in
vacuo, and the residue was purified by column chromatography
(hexanes/ethyl acetate, 2:1) to afford bis(triazole) 6.
1-(4-Chlorophenyl)-5-methyl-N-[1-phenyl-3-(prop-2-ynyloxy)propan-
2-yl]-1H-1,2,3-triazole-4-carboxamide (4h): White solid (0.59 g,
73 %); m.p. 102–104 °C. 1H NMR (500 MHz, [D6]DMSO): δ =
7.58–7.55 (m, 3 H), 7.44–7.41 (m, 2 H), 7.34–7.30 (m, 4 H), 7.26–
7.23 (m, 1 H), 4.54 (d, J = 9 Hz, 1 H), 4.27–4.18 (m, 2 H), 3.63–
3.56 (m, 2 H), 3.03 (d, J = 7 Hz, 2 H), 2.64 (s, 3 H), 2.46–2.45 (t,
J = 2.5 Hz, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
159.7, 137.7, 136.8, 135.7, 135.1, 133.1, 129.0, 128.5, 127.5, 125.5,
78.4, 73.0, 68.6, 57.5, 49.0, 36.6, 8.7 ppm. MS (ESI): m/z = 409 [M
+ 1]+. C22H21ClN4O2 (408.89): calcd. C 64.62, H 5.18, N 13.70;
found C 64.75, H 5.27, N 13.59.
One-Pot Process for Bis(triazoles) 6: The azide (2.0 mmol), diketene
(2.2 mmol), alkynyl-substituted amine (2.2 mmol), and DBU
(2.2 mmol) were placed in a sealed tube with MeOH (4 mL), and
the resulting mixture was stirred and heated at reflux for 8 h. After
the reaction was complete, without separating the intermediate
monotriazole 4, the second azide (1.0 equiv.) and CuI (20 mol-%)
were added (for 6k, 6l, 6m additional CH2Cl2 was added). The
reaction mixture was then stirred at 40 °C for another 6 h.
N-(3-Ethynylphenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carbox-
1
amide (4i): White solid (0.46 g, 76%); m.p. 160–162 °C. H NMR
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-methyl-1-phenyl-1H-
1,2,3-triazole-4-carboxamide (6a): White solid (0.16 g, 88%); m.p.
(500 MHz, [D6]DMSO): δ = 10.65 (s, 1 H), 8.07 (s, 1 H), 7.90 (d,
J = 6 Hz, 1 H), 7.67 (m, 5 H), 7.39–7.36 (t, J = 7.5 Hz, 1 H), 7.22
1
122–124 °C. H NMR (500 MHz, [D6]DMSO): δ = 9.13–9.10 (t, J
(d, J = 5.5 Hz, 1 H), 4.19 (s, 1 H), 2.58 (s, 3 H) ppm. 13C NMR = 6 Hz, 1 H), 8.65 (s, 2 H), 7.92–7.90 (d, J = 8 Hz, 2 H), 7.67–7.60
(125 MHz, [D6]DMSO): δ = 138.4, 137.6, 137.4, 134.8, 129.6,
129.2, 128.5, 126.4, 125.0, 122.8, 121.4, 120.6, 82.9, 80.0, 8.9 ppm.
MS (ESI): m/z = 303 [M + 1]+. C18H14N4O (302.33): calcd. C 71.51,
H 4.67, N 18.53; found C 71.44, H 4.59, N 18.41.
(m, 5 H), 7.60–7.57 (t, J = 7.5 Hz, 2 H), 7.49–7.46 (t, J = 7.5 Hz,
1 H), 4.66–4.64 (d, J = 6 Hz, 2 H), 2.55–2.50 (m, 3 H) ppm 13C
NMR (125 MHz, [D6]DMSO): δ = 160.4, 145.8, 137.6, 136.2,
134.8, 129.4, 129.3, 129.2, 128.0, 124.8, 120.6, 119.5, 33.6, 8.8 ppm.
6772
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6767–6776

Unsymmetrical Bis(1,2,3-triazole) Derivatives
MS (ESI): m/z = 374 [M + 1]+. C20H19N7O (373.42): calcd. C 64.33,
(ESI): m/z = 797 [M + 23]+. C22H16N8O5 (472.42): calcd. C 55.93,
H 5.13, N 26.26; found C 64.25, H 5.18, N 26.18.
H 3.41, N 23.72; found C 55.80, H 3.33, N 23.84.
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-1-(4-chlorophenyl)-5-
methyl-1H-1,2,3-triazole-4-carboxamide (6b): White solid (0.18 g,
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-1-(4-chlorophen-
yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (6h): White solid
88 %); m.p. 112–114 °C. 1H NMR (500 MHz, [D6]DMSO): δ = (0.18 g, 87%); m.p. 108–110 °C. 1H NMR (500 MHz, [D6]DMSO):
9.11–9.08 (t, J = 6 Hz, 1 H), 8.00 (s, 1 H), 7.73–7.67 (m, 4 H),7.39–
7.31 (m, 5 H), 5.57 (s, 2 H), 4.53 (d, J = 6 Hz, 2 H), 2.53 (s, 3
δ = 7.72 (s, 1 H), 7.55 (d, J = 8 Hz, 2 H), 7.49 (s, 1 H), 7.40–7.36
(m, 5 H), 7.28 (d, J = 6 Hz, 1 H), 5.52 (s, 2 H), 2.56 (s, 3 H), 1.88
H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 160.3, 146.0, (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.5, 152.6,
137.6, 136.5, 135.0, 134.1, 133.6, 132.2, 129.3, 126.7, 121.1, 120.7,
55.5, 33.6, 30.2, 18.0, 8.8 ppm. MS (ESI): m/z = 408 [M + 1]+.
C20H18ClN7O (407.86): calcd. C 58.90, H 4.45, N 24.04; found C
58.77, H 4.52, N 23.93.
138.0, 135.5, 135.1, 133.9, 133.1, 128.9, 128.1, 127.6, 127.0, 125.5,
119.4, 53.1, 50.5, 27.3, 8.7 ppm. MS (ESI): m/z = 436 [M + 1]+.
C22H22ClN7O (435.92): calcd. C 60.62, H 5.09, N 22.49; found C
60.49, H 5.17, N 22.37.
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-methyl-1-(p-tolyl)-1H-
1,2,3-triazole-4-carboxamide (6c): White solid (0.17 g, 87%); m.p.
126–130 °C. H NMR (500 MHz, [D6]DMSO): δ = 9.09–9.07 (t, J
N-{1-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-3-phenylpropan-2-
yl}-1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide
(6i): White solid (0.23 g, 85 %); m.p. 106–108 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 7.58–7.50 (m, 3 H), 9.28 (s, 1 H), 7.43–
1
= 6 Hz, 1 H), 8.02 (s, 1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.44–7.42 (d,
J = 8 Hz, 2 H), 7.38–7.32 (m, 5 H), 5.58 (s, 2 H), 4.55 (d, J = 7.42 (t, J = 2 Hz, 1 H), 7.41–7.40 (t, J = 3 Hz, 5 H), 7.39 (s, 2 H),
5.5 Hz, 2 H), 2.50 (s, 3 H), 2.41 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 160.3, 145.1, 139.3, 137.4, 136.2, 135.6, 132.4,
130.0, 128.2, 127.6, 127.5, 124.6, 122.5, 52.2, 33.6, 20.2, 8.7 ppm.
MS (ESI): m/z = 388 [M + 1]+. C21H21N7O (387.44): calcd. C 65.10,
H 5.46, N 25.31; found C 65.02, H 5.38, N 25.40.
7.38–7.36 (t, J = 4 Hz, 8 H), 7.31–7.22 (m, 4 H), 5.55 (s, 2 H),
4.68–4.50 (t, J = 2.5 Hz, 2 H), 4.50–4.49 (m, 1 H), 3.56–3.55 (d, J
= 4 Hz, 2 H), 3.01–2.98 (t, J = 7.5 Hz, 2 H), 2.62 (s, 3 H) ppm. 13
C
NMR (125 MHz, [D6]DMSO): δ = 159.6, 144.4, 137.7, 136.8,
135.7, 135.2, 133.7, 133.1, 129.0, 128.4, 128.1, 127.7, 127.5, 127.1,
125.5, 121.5, 69.2, 63.8, 53.2, 49.0, 36.6, 8.7 ppm. MS (ESI): m/z =
543 [M + 1]+. C29H28ClN7O2 (542.04): calcd. C 64.26, H 5.21, N
18.09; found C 64.12, H 5.33, N 18.17.
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-methyl-1-(4-nitrophen-
yl)-1H-1,2,3-triazole-4-carboxamide (6d): White solid (0.17 g, 84%);
1
m.p. 142–146 °C. H NMR (500 MHz, [D6]DMSO): δ = 9.15–9.13
(t, J = 5 Hz, 1 H), 8.48 (d, J = 5 Hz, 2 H), 8.01–7.97 (t, J = 10 Hz, N-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl]-5-methyl-1-phenyl-1H-
3 H), 7.38–7.32 (m, 5 H), 5.58 (s, 2 H), 4.54 (d, J = 5 Hz, 2 H), 1,2,3-triazole-4-carboxamide (6j): White solid (0.18 g, 85%); m.p.
1
2.61 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 160.0, 182–186 °C. H NMR (500 MHz, [D6]DMSO): δ = 10.63 (s, 1 H),
147.3, 139.6, 137.9, 136.8, 135.6, 128.2, 127.6, 127.5, 125.8, 124.6,
122.5, 52.2, 33.7, 8.9 ppm. MS (ESI): m/z = 419 [M + 1]+.
C20H18N8O3 (418.41): calcd. C 57.41, H 4.34, N 26.78; found C
57.18, H 4.46, N 26.65.
9.28 (s, 1 H), 8.59 (s, 1 H), 8.00 (d, J = 8 Hz, 2 H), 7.82 (d, J = 8 Hz,
1 H), 7.68–7.63 (m, 8 H), 7.54–7.47 (m, 2 H), 2.61 (s, 3 H) ppm. 13
C
NMR (125 MHz, [D6]DMSO): δ = 159.1, 147.0, 138.7, 137.7,
137.2, 136.2, 134.8, 130.2, 129.6, 129.4, 129.2, 128.7, 128.2, 125.0,
120.5, 119.9, 119.6, 119.2, 117.0, 9.0 ppm. MS (ESI): m/z = 436 [M
+ 1]+. C25H21N7O (435.49): calcd. C 68.95, H 4.86, N 22.51; found
C 69.08, H 4.98, N 22.39.
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-1-(2-chlorophenyl)-5-
methyl-1H-1,2,3-triazole-4-carboxamide (6e): White solid (0.18 g,
88%); m.p. 134–136 °C. 1H NMR (500 MHz, [D6]DMSO): δ = 8.53
(s, 1 H), 8.00 (s, 1 H), 7.39–7.36 (t, J = 6.5 Hz, 3 H), 7.34–7.30 (m,
3 H), 5.58 (s, 2 H), 4.31 (d, J = 5.5 Hz, 2 H), 3.32 (s, 2 H), 2.11 (s,
3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 202.4, 165.5,
144.4, 135.6, 128.2, 127.6, 127.4, 122.5, 52.5, 50.6, 33.8, 29.4 ppm.
MS (ESI): m/z = 408 [M + 1]+. C20H18ClN7O (407.86): calcd. C
58.90, H 4.45, N 24.04; found C 58.84, H 4.53, N 23.97.
N-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl]-1-(4-chlorophenyl)-5-
methyl-1H-1,2,3-triazole-4-carboxamide (6k): White solid (0.19 g,
82%); m.p. 152–156 °C. 1H NMR (500 MHz, CDCl3): δ = 10.65 (s,
1 H), 8.61 (s, 1 H), 8.46 (s, 1 H), 7.87–7.75 (m, 1 H), 7.75–7.73 (m,
3 H), 7.69–7.67 (m, 1 H), 7.59 (d, J = 8 Hz, 1 H), 7.43–7.35 (m, 6
H), 5.67 (s, 2 H), 2.43 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]
DMSO): δ = 159.0, 146.1, 138.6, 137.8, 137.5, 135.5, 134.2, 133.6,
130.5, 129.3, 128.6, 128.3, 127.7, 127.4, 126.8, 121.1, 120.2, 119.5,
116.7, 52.5, 8.9 ppm. MS (ESI): m/z = 470 [M + 1]+. C25H20ClN7O
(469.93): calcd. C 63.90, H 4.29, N 20.86; found C 63.83, H 4.35,
N 20.75.
N-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-5-methyl-1-(o-tolyl)-1H-
1,2,3-triazole-4-carboxamide (6f): White solid (0.17 g, 86%); m.p.
1
146–148 °C. H NMR (500 MHz, [D6]DMSO): δ = 9.10–9.08 (t, J
= 6 Hz, 1 H), 8.03 (s, 1 H), 7.58–7.52 (m, 2 H), 7.47–7.41 (m, 2
H), 7.39–7.36 (m, 2 H), 7.34–7.31 (m, 3 H), 5.58 (s, 2 H), 4.69 (d,
J = 5.5 Hz, 2 H), 2.64 (s, 3 H) ppm. 13C NMR (125 MHz, [D6] N-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl]-5-methyl-1-p-tolyl-1H-
DMSO): δ = 160.2, 160.0, 153.1, 147.3, 143.4, 139.6, 137.9, 136.9,
132.9, 125.8, 125.0, 124.6, 124.4, 124.3, 116.7, 113.9, 109.8, 33.5,
8.9 ppm. MS (ESI): m/z = 388 [M + 1]+. C21H21N7O (387.44):
calcd. C 65.10, H 5.46, N 25.31; found C 64.96, H 5.55, N 25.24.
1,2,3-triazole-4-carboxamide (6l): White solid (0.18 g, 83%); m.p.
200–204 °C. H NMR (500 MHz, [D6]DMSO): δ = 10.56 (s, 1 H),
1
8.61 (s, 1 H), 8.46 (s, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 7.58–7.54 (t,
J = 8 Hz, 3 H), 7.47 (d, J = 8 Hz, 2 H), 7.42–7.35 (m, 6 H), 5.66
(s, 2 H), 2.57 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]
DMSO): δ = 159.1, 146.1, 139.4, 138.6, 137.6, 137.2, 135.5, 132.3,
130.5, 129.6, 128.6, 128.3, 127.7, 127.4, 124.8, 121.1, 120.1, 119.4,
116.7, 52.5, 20.2, 8.9 ppm. MS (ESI): m/z = 450 [M + 1]+.
C26H23N7O (449.51): calcd. C 69.47, H 5.16, N 21.81; found C
69.34, H 5.23, N 21.63.
5-Methyl-1-(4-nitrophenyl)-N-{[1-(2-oxo-2H-chromen-4-yl)-1H-
1,2,3-triazol-4-yl]methyl}-1H-1,2,3-triazole-4-carboxamide (6g):
1
White solid (0.31 g, 81%); m.p. 116–118 °C. H NMR (500 MHz,
[D6]DMSO): δ = 9.6 (d, J = 6 Hz, 1 H), 8.68 (s, 1 H), 8.48 (d, J =
9 Hz, 2 H), 7.99 (d, J = 9 Hz, 2 H), 7.87 (d, J = 8 Hz, 1 H), 7.79–
7.76 (t, J = 7.5 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H), 7.47–44 (t, J =
7.5 Hz, 1 H), 6.93 (s, 1 H), 4.54–4.53 (d, J = 6 Hz, 2 H), 2.33 (s, 3
N-[3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl]-5-methyl-1-(4-nitro-
H), 1.97 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = phenyl)-1H-1,2,3-triazole-4-carboxamide (6m): White solid (0.19 g,
160.2, 144.9, 137.1, 136.9, 135.6, 134.5, 133.7, 130.8, 130.2, 128.2,
127.6, 127.5, 126.8, 126.6, 122.5, 52.2, 33.6, 16.2, 8.2 ppm. MS
80 %); m.p. 182–184 °C. 1H NMR (500 MHz, [D6]DMSO): δ =
10.66 (s, 1 H), 8.62 (s, 1 H), 8.52–8.48 (t, J = 10 Hz, 3 H), 8.04 (d,
Eur. J. Org. Chem. 2012, 6767–6776
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6773

T.-f. Niu, L. Gu, L. Wang, W.-b. Yi, C. Cai
FULL PAPER
J = 5 Hz, 2 H), 7.79 (d, J = 10 Hz, 1 H), 7.59 (d, J = 10 Hz, 1 H),
7.44–7.35 (m, 6 H), 5.67 (s, 2 H), 2.68 (s, 3 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 158.8, 147.4, 146.1, 139.6, 138.5,
138.1, 137.8, 135.5, 130.5, 128.7, 128.3, 127.7, 127.4, 126.0, 124.6,
124.2, 121.1, 120.3, 119.5, 116.7, 52.5, 9.1 ppm. MS (ESI): m/z =
481 [M + 1]+. C25H20N8O3 (480.48): calcd. C 62.49, H 4.20, N
23.32; found C 62.65, H 4.33, N 23.16.
solid (0.27 g, 76%); m.p. 100–104 °C. 1H NMR (500 MHz, CDCl3):
δ = 7.75–7.70 (m, 1 H), 7.62 (d, J = 6 Hz, 1 H), 7.56–7.55 (m, 3
H), 7.44–7.43 (m, 3 H), 7.42–7.39 (m, 3 H), 7.34–7.30 (m, 2 H),
7.28–7.26 (m, 2 H), 7.23–7.21 (m, 2 H), 6.75–6.59 (m, 1 H), 6.61
(d, J = 5.5 Hz, 3 H), 2.88 (d, J = 8 Hz, 1 H), 1.86–1.84 (m, 2 H),
1.71–1.68 (m, 2 H), 1.60–1.58 (m, 1 H), 1.39–1.30 (m, 2 H), 1.20–
1.14 (m, 3 H), 0.93–0.90 (m, 3 H), 0.75–0.69 (m, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 168.3, 168.0, 167.4, 166.9, 160.0,
143.2, 142.9, 137.5, 135.8, 135.1, 134.8, 133.1, 131.4, 131.2, 129.5,
129.3, 129.0, 128.7, 128.4, 128.1, 128.0, 127.9, 127.5, 127.3, 127.1,
127.0, 126.9, 125.7, 125.5, 125.1, 121.7, 121.6, 65.7, 64.6, 63.6, 48.1,
47.4, 47.1, 33.5, 32.0, 31.9, 31.6, 26.6, 26.2, 24.5, 23.8, 18.7, 18.5,
17.9, 8.7 ppm. MS (ESI): m/z = 744 [M + 23]+. C39H44ClN9O3
(722.29): calcd. C 64.85, H 6.14, N 17.45; found C 64.72, H 6.08,
N 17.36.
N-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl]-1-(2-chlorophenyl)-5-
methyl-1H-1,2,3-triazole-4-carboxamide (6n): White solid (0.20 g,
85 %); m.p. 158–162 °C. 1H NMR (500 MHz, [D6]DMSO): δ =
10.65 (s, 1 H), 8.61 (s, 1 H), 8.46 (s, 1 H), 7.87–7.78 (m, 1 H), 7.78–
7.73 (m, 3 H), 7.69–7.67 (m, 1 H), 7.59–7.57 (m, 1 H), 7.43–7.35
(m, 6 H), 5.67 (s, 2 H), 2.43 (s, 2 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 202.3, 164.7, 146.0, 138.9, 135.5, 130.6, 128.9,
128.3, 127.7, 127.4, 121.1, 120.0, 118.1, 115.2, 52.5, 51.8, 29.7 ppm.
MS (ESI): m/z = 470 [M + 1]+. C25H20ClN7O (469.93): calcd. C
63.90, H 4.29, N 20.86; found C 63.93, H 4.27, N 20.84.
N-{[1-(1-{Butyl[1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl]-
amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl]methyl}-1-
(4-chlorophenyl)-1H-1,2,3-triazole-4-carboxamide (12d): White solid
Unsymmetrical Bis(1,2,3-triazole)-Modified Peptidomimetics 12:
The amine (0.5 mmol) and aldehyde (0.5 mmol) were dissolved in
a sealed tube with MeOH (2 mL), and the resulting mixture was
stirred at room temperature for 30 min. Then, 2-azido-3-phenyl-
propanoic acid (0.5 mmol) and isocyanide (0.5 mmol) were added,
and the mixture was stirred for 24 h. Then, monotriazole 4
(0.5 mmol), Et3N (0.5 mmol), and CuI (0.1 mmol) were added to
the sealed tube, and the reaction mixture was stirred for another
8 h. The solvent was removed in vacuo, and the residue was puri-
fied by column chromatography (hexanes/ethyl acetate, 2:1).
1
(0.27 g, 72%); m.p. 98–100 °C. H NMR (500 MHz, CDCl3): δ =
7.77–7.73 (m, 1 H), 7.68 (d, J = 9.5 Hz, 1 H), 7.55–7.53 (m, 2 H),
7.48–7.46 (m, 2 H), 7.44–7.43 (m, 4 H), 7.41–7.39 (m, 2 H), 7.33
(s, 1 H), 7.27 (d, J = 8 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 6.82 (d,
J = 9.5 Hz, 1 H), 6.18 (d, J = 8 Hz, 0.5 H), 5.94 (s, 0.5 H), 5.91
(d, J = 8 Hz, 0.5 H), 5.54 (s, 0.5 H), 4.71–4.70 (m, 2 H), 3.79–3.77
(m, 1 H), 3.34–3.25 (m, 1 H), 2.58–2.57 (m, 3 H), 2.15 (s, 1 H),
1.87–1.83 (m, 2 H), 1.66–1.64 (m, 2 H), 1.59–1.56 (m, 2 H), 1.46–
1.43 (m, 1 H), 1.35–1.29 (m, 2 H), 1.16–1.03 (m, 5 H), 0.80–0.77
(m, 2 H), 0.68–0.65 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 166.7, 166.6, 166.4, 166.3, 160.0, 143.4, 137.5, 135.8, 135.1,
134.0, 133.4, 133.1, 132.7, 132.1, 131.9, 130.4, 129.0, 128.9, 128.7,
128.0, 127.7, 127.5, 127.3, 125.5, 122.1, 122.0, 63.8, 63.6, 62.9, 60.8,
47.7, 47.0, 45.1, 33.6, 31.7, 31.1, 30.6, 24.4, 23.7, 19.0, 18.9, 12.5,
12.3, 8.7 ppm. MS (ESI): m/z = 778 [M + 23]+. C39H43Cl2N9O3
(756.73): calcd. C 61.90, H 5.73, N 16.66; found C 61.84, H 5.67,
N 16.58.
N-{[1-(1-{Butyl[1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl]-
amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl]methyl}-1-
phenyl-1H-1,2,3-triazole-4-carboxamide (12a): White solid (0.20 g,
1
56%); m.p. 94–96 °C. H NMR (500 MHz, CDCl3): δ = 7.72–7.70
(t, J = 5.5 Hz, 1 H), 7.69 (s, 1 H), 7.60–7.56 (m, 3 H), 7.46–7.44
(m, 7 H), 7.37 (s, 3 H), 7.28 (s, 1 H), 6.83 (s, 1 H), 5.92 (s, 1 H),
5.72 (d, J = 7 Hz, 1 H), 4.75 (d, J = 7 Hz, 1 H), 3.84–3.80 (m, 1
H), 3.32–3.19 (m, 1 H), 2.62 (s, 3 H), 1.94–1.88 (m, 2 H), 1.52 (s,
4 H), 1.71–1.53 (m, 4 H), 1.39–1.36 (m, 2 H), 1.16–1.06 (m, 3 H),
1.02–0.96 (m, 1 H), 0.71–0.68 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.7, 160.2, 143.4, 137.3, 135.8, 134.6,
134.1, 132.0, 131.8, 130.4, 129.0, 128.7, 128.1, 127.3, 124.3, 122.1,
63.8, 60.9, 47.7, 45.2, 33.6, 31.8, 31.1, 24.4, 23.7, 19.0, 12.3,
8.7 ppm. MS (ESI): m/z = 744 [M + 23]+. C39H44ClN9O3 (722.29):
calcd. C 64.85, H 6.14, N 17.45; found C 64.78, H 6.21, N 17.53.
Unsymmetrical Bis(1,2,3-triazole)-Modified Peptidomimetics 19:
The amine (0.5 mmol) and aldehyde (0.5 mmol) were dissolved in
MeOH (3 mL) and placed in a sealed tube. The resulting mixture
was stirred at room temperature for 30 min. Then, para-azidoben-
zoic acid (0.5 mmol) and isocyanide (0.5 mmol) were added, and
the mixture was stirred for 24 h. Then, the corresponding aniline
(0.55 mmol), diketene (0.55 mmol), and DBU (0.55 mmol) were
added to the seal tube, and the reaction temperature was raised to
80 °C for 24 h. The solvent was removed in vacuo, and the residue
was purified by column chromatography (hexanes/ethyl acetate,
3:1) to give intermediate 17. To a solution of compound 17
(0.5 mmol) and Ugi products 18 (0.5 mmol) in MeOH (2 mL) were
added Et3N (0.5 mmol) and CuI (0.1 mmol). The reaction mixture
was stirred at 40 °C for 8 h. The solvent was removed in vacuo,
and the residue was purified by column chromatography (hexanes/
ethyl acetate, 2:1).
N-{[1-(1-{(4-Chlorophenyl)[2-(cyclohexylamino)-1-(furan-2-yl)-2-
oxoethyl]amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-
yl]methyl}-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide (12b): White
solid (0.27 g, 73%); m.p. 102–104 °C. 1H NMR (500 MHz, CDCl3):
δ = 7.67–7.64 (m, 2 H), 7.39–7.34 (m, 5 H), 7.31 (d, J = 8.5 Hz, 2
H), 7.28 (d, J = 2 Hz, 2 H), 7.25–7.23 (m, 2 H), 7.21 (d, J = 7.5 Hz,
2 H), 7.05 (s, 1 H), 6.98 (s, 1 H), 6.91 (s, 1 H), 6.43 (s, 1 H), 6.20–
6.18 (m, 1 H), 5.71 (d, J = 8 Hz, 1 H), 4.74–4.73 (m, 2 H), 3.85–
3.82 (m, 1 H), 2.59 (s, 3 H), 2.47 (s, 3 H), 1.99 (d, J = 10.5 Hz, 1
H), 1.88 (d, J = 10.5 Hz, 1 H), 1.65–1.61 (m, 3 H), 1.41–1.34 (m,
2 H), 1.19–1.16 (m, 2 H), 1.12–1.05 (m, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.0, 164.8, 160.2, 145.4, 143.3, 142.5,
139.2, 137.2, 135.8, 134.9, 134.1, 132.1, 131.9, 131.4, 130.0, 129.2,
128.6, 128.3, 128.0, 127.6, 124.1, 121.8, 112.0, 109.8, 63.8, 57.7,
48.0, 33.5, 31.8, 24.4, 23.8, 23.7, 20.3, 8.7 ppm. MS (ESI): m/z =
768 [M + 23]+. C40H40ClN9O4 (746.27): calcd. C 64.38, H 5.40, N
16.89; found C 64.31, H 5.19, N 16.97.
1-(4-{(4-Chlorophenyl)-[(4-chlorophenyl)cyclohexylcarbamoylmeth-
yl]carbamoyl}phenyl)-N-(1-{1-[(cyclohexylcarbamoylphenylmethyl)-
phenylcarbamoyl]-2-phenylethyl}-1H-1,2,3-triazol-4-ylmethyl)-5-
methyl-1H-1,2,3-triazole-4-carboxamide (19a): White solid (0.27 g,
1
48%); m.p. 142–146 °C. H NMR (500 MHz, CDCl3): δ = 9.12 (s,
1 H), 8.08 (s, 1 H), 7.93 (s, 1 H), 7.73 (d, J = 9 Hz, 1 H), 7.64 (d,
J = 7.5 Hz, 1 H), 7.43–7.37 (m, 6 H), 7.32–7.25 (m, 7 H), 7.17–
7.13 (m, 3 H), 7.01 (d, J = 8 Hz, 3 H), 6.66 (d, J = 7.5 Hz, 1 H),
6.44 (s, 1 H), 6.15 (s, 1 H), 5.48 (d, J = 8.5 Hz, 1 H), 3.88–3.85 (m,
1 H), 2.68 (s, 3 H), 2.50 (s, 2 H), 2.15 (d, J = 7.5 Hz, 1 H), 1.84 (d,
J = 7.5 Hz, 1 H), 1.65 (d, J = 8.5 Hz, 1 H), 1.63–1.57 (m, 4 H),
N-{[1-(1-{Benzyl[1-(cyclohexylamino)-3-methyl-1-oxobutan-2-
yl]amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl]methyl}-
1-(4-chlorophenyl)-1H-1,2,3-triazole-4-carboxamide (12c): White
6774
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6767–6776

Unsymmetrical Bis(1,2,3-triazole) Derivatives
1.40–1.35 (m, 4 H), 1.27 (s, 2 H), 1.20–1.16 (m, 3 H), 1.06–1.03 (m,
C56H62ClN11O6 (1020.63): calcd. C 65.90, H 6.12, N 15.10; found
2 H), 0.92–0.87 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = C 65.83, H 6.05, N 15.22.
166.6, 165.1, 158.4, 146.2, 139.4, 137.1, 134.5, 132.0, 130.9, 129.3,
N-{[1-(1-{[1-(tert-Butylamino)-3-methyl-1-oxobutan-2-yl](4-chloro-
128.5, 128.4, 127.9, 127.6, 124.1, 120.8, 120.0, 118.4, 115.9, 63.9,
63.0, 48.1, 31.8, 28.7, 24.4, 23.7, 20.3, 8.8 ppm. MS (ESI): m/z =
1146 [M + 23]+. C63H63Cl2N11O5 (1125.17): calcd. C 67.25, H 5.64,
N 13.69; found C 67.08, H 5.56, N 13.60.
phenyl)amino}-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-
yl]methyl}-1-(4-{[2-(cyclohexylamino)-1-(furan-2-yl)-2-oxoethyl]-
(phenyl)carbamoyl}phenyl)-5-methyl-1H-1,2,3-triazole-4-carbox-
amide (19e): White solid (0.22 g, 45%); m.p. 120–124 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.76–7.70 (m, 2 H), 7.55–
7.53 (m, 2 H), 7.45–7.42 (t, J = 8.5 Hz, 2 H), 7.28–7.24 (m, 8 H),
7.12–7.10 (m, 4 H), 7.05 (s, 5 H), 6.21 (s, 2 H), 5.68 (s, 1 H), 4.95
(d, J = 10.5 Hz, 1 H), 4.76 (d, J = 6 Hz, 2 H), 4.31 (d, J = 11 Hz,
1 H), 3.91–3.87 (m, 1 H), 2.56 (s, 3 H), 2.48–2.43 (m, 1 H), 2.00–
1.82 (m, 6 H), 1.71–1.59 (m, 3 H), 1.36 (s, 10 H), 1.17–1.09 (m, 3
H), 0.891 (d, J = 6.5 Hz, 6 H), 0.73 (d, J = 6 Hz, 3 H), 0.56 (d, J
= 6 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.7, 168.6,
167.9, 167.3, 160.1, 143.9, 139.6, 137.4, 137.0, 135.8, 135.3, 134.9,
134.1, 133.5, 130.7, 130.0, 129.4, 129.3, 128.9, 128.7, 128.6, 127.6,
126.6, 123.3, 119.9, 67.4, 65.7, 65.2, 50.5, 48.0, 33.6, 32.3, 31.8,
27.6, 25.7, 24.5, 23.8, 23.7, 19.1, 18.5, 17.9, 17.4, 8.7 ppm. MS
(ESI): m/z = 994 [M + 23]+. C52H62ClN11O6 (972.59): calcd. C
64.22, H 6.43, N 15.84; found C 64.16, H 6.52, N 15.75.
N-{[1-(1-{[1-(tert-Butylamino)-3-methyl-1-oxobutan-2-yl](4-chloro-
phenyl)amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-
yl]methyl}-1-(4-{[2-(cyclohexylamino)-2-oxo-1-phenylethyl](phenyl)-
carbamoyl}phenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (19b):
1
White solid (0.24 g, 46%); m.p. 136–140 °C. H NMR (500 MHz,
CDCl3): δ = 7.64–7.61 (m, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.45 (s,
2 H), 7.39–7.37 (t, J = 7 Hz, 1 H), 7.32–7.22 (m, 9 H), 7.11 (d, J
= 7.5 Hz, 3 H), 7.04 (s, 4 H), 6.92 (d, J = 7.5 Hz, 1 H), 6.46 (s, 1
H), 6.26 (s, 1 H), 6.21 (s, 1 H), 5.67 (d, J = 8 Hz, 1 H), 4.72–4.68
(m, 2 H), 4.35 (d, J = 11 Hz, 1 H), 3.92–3.86 (m, 1 H), 2.49 (s, 3
H), 1.99–1.84 (m, 4 H), 1.69–1.59 (m, 3 H), 1.36 (s, 9 H), 1.17–1.09
(m, 3 H), 0.91–0.90 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 168.6, 167.5, 167.2, 160.0, 143.1, 139.6, 137.4, 136.9,135.7, 135.1,
134.9, 134.2, 133.5, 131.4, 130.8, 129.9, 129.4, 129.3, 128.9, 128.3,
127.6, 127.4, 126.6, 123.3, 121.7, 67.9, 65.7, 63.8, 50.5, 48.0, 33.5,
31.8, 28.7, 27.6, 25.5, 24.5, 23.8, 23.7, 19.1, 18.4, 8.7 ppm. MS
(ESI): m/z = 1052 [M + 23]+. C58H64ClN11O5 (1030.67): calcd. C
67.59, H 6.26, N 14.95; found C 67.67, H 6.32, N 14.83.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
N-{[1-(1-{[2-(Cyclohexylamino)-1-(furan-2-yl)-2-oxoethyl](phenyl)-
amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl]methyl}-1-
(4-{[1-(cyclohexylamino)-3-methyl-1-oxobutan-2-yl](phenyl)-
carbamoyl}phenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (19c):
We thank Nanjing University of Science and Technology (NUST)
research funding (grant number 2011ZDJH07) and the Jiangsu
Province Key Laboratory of Fine Petrochemical Engineering
(KF1101) for their financial support. We also thank the Analysis
and Testing Center of Nanjing University of Science and Technol-
ogy for assistance with the NMR spectroscopic analysis.
1
White solid (0.23 g, 45%); m.p. 110–114 °C. H NMR (500 MHz,
CDCl3): δ = 7.65–7.63 (m, 2 H), 7.43–7.36 (m, 4 H), 7.32–7.28 (m,
5 H), 7.24–7.23 (m, 2 H), 7.21–7.20 (m, 5 H), 7.04 (d, J = 7.5 Hz,
1 H), 6.77 (d, J = 7.5 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 6.75 (s,
1 H), 6.43 (s, 1 H), 6.26 (s, 1 H), 6.18 (d, J = 1 Hz, 2 H), 5.68 (d,
J = 8 Hz, 1 H), 4.71 (d, J = 5.5 Hz, 2 H), 4.57 (d, J = 5.5 Hz, 1
H), 3.84–3.82 (m, 1 H), 2.57 (s, 3 H), 2.42–2.41 (m, 1 H), 1.97–1.89
(m, 4 H), 1.73–1.61 (m, 5 H), 1.41–1.36 (m, 4 H), 1.28–1.21 (m, 7
H), 1.05–1.01 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
169.4, 167.9, 165.9, 164.4, 159.9, 145.4, 143.2, 142.5, 138.5, 137.6,
136.6, 135.7, 135.4, 134.9, 134.1, 132.7, 131.9, 131.4, 129.9, 129.1,
128.7, 128.3, 128.0, 127.6, 123.7, 121.8, 120.0, 109.8, 76.3, 76.0,
75.8, 69.2, 63.8, 57.7, 48.0, 47.2, 33.5, 32.0, 31.8, 25.8, 24.5, 23.7,
18.9, 18.8, 8.7 ppm. MS (ESI): m/z = 1034 [M + 23]+. C58H65N11O6
(1012.22): calcd. C 68.82, H 6.47, N 15.22; found C 68.91, H 6.53,
N 15.10.
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N-{[1-(1-{[1-(tert-Butylamino)-3-methyl-1-oxobutan-2-yl](4-chloro-
phenyl)amino}-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-
yl]methyl}-1-(4-{[2-(cyclohexylamino)-1-(furan-2-yl)-2-oxoethyl]-
(phenyl)carbamoyl}phenyl)-5-methyl-1H-1,2,3-triazole-4-carbox-
amide (19d): White solid (0.22 g, 43%); m.p. 140–144 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.63–7.62 (m, 2 H), 7.53–7.46 (m, 2 H),
7.38–7.37 (m, 2 H), 7.33–7.28 (m, 8 H), 7.12–7.08 (m, 4 H), 7.03
(s, 2 H), 6.92 (d, J = 8 Hz, 1 H), 6.47 (s, 1 H), 6.39 (d, J = 3.5 Hz,
1 H), 6.35 (s, 1 H), 6.31–6.30 (m, 1 H), 6.25 (s, 1 H), 5.90 (d, J =
7.5 Hz, 1 H), 4.74–4.70 (m, 2 H), 4.35 (d, J = 11 Hz, 1 H), 3.89–
3.86 (m, 1 H), 2.54 (s, 3 H), 1.95–1.92 (m, 3 H), 1.72–1.62 (m, 9
H), 1.37 (s, 9 H), 1.20–1.17 (m, 3 H), 0.93–0.91 (m, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 168.3, 167.5, 167.2, 164.9, 160.0,
146.4, 143.0, 142.3, 137.9,137.5, 136.0, 135.7, 135.3, 135.0, 134.2,
132.8, 131.3, 130.8, 130.0, 128.9, 128.4, 128.0, 127.4, 123.5, 121.7,
111.8, 110.0, 63.8, 58.7, 50.5, 48.1, 33.5, 31.8, 27.6, 25.5, 24.5, 23.8,
19.1, 18.4, 8.7 ppm. MS (ESI): m/z = 1042 [M + 23]+
.
Eur. J. Org. Chem. 2012, 6767–6776
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6775

T.-f. Niu, L. Gu, L. Wang, W.-b. Yi, C. Cai
FULL PAPER
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Received: August 13, 2012
Published Online: October 22, 2012
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Eur. J. Org. Chem. 2012, 6767–6776