One-pot tandem copper-catalyzed library synthesis of 1-thiazolyl-1,2,3- triazoles as anticancer agents

Article abstract of DOI:10.1021/co1000234

One-pot multicomponent synthesis to assemble compounds has been an efficient method for constructing a compound library. We have developed one-pot tandem copper-catalyzed azidation and CuAAC reactions that afford 1-thiazolyl-1,2,3-triazoles with anticancer activity. By utilizing this one-pot synthetic strategy, we constructed a library of 1-thiazolyl-1,2,3-triazoles in search of the potent lead compound. Furthermore, 1-thiazolyl-1,2,3-triazoles were evaluated for anticancer activity against the multidrug-resistant cancer cells MES-SA/Dx5. Most of the 1-thiazolyl-1,2,3-triazoles revealed cytotoxic effect against cancer cells at micromolar to low micromolar range. Testing some of the most potent compounds (5{4,2-4} and 5{5,1-3}) against the normal cell line Vero showed no significant toxicity (except 5{4,2}) to normal cells. This result indicates that compounds 5{4,3-4} and 5{5,1-3} possessed good potency and selectivity to cancer cells over normal cells.

Full text of DOI:10.1021/co1000234

RESEARCH ARTICLE
pubs.acs.org/acscombsci
One-Pot Tandem Copper-Catalyzed Library Synthesis
of 1-Thiazolyl-1,2,3-triazoles as Anticancer Agents
Wen-Tai Li,† Wan-Hsun Wu,† Chien-Hsiang Tang,† Ready Tai,† and Shui-Tein Chen*,†,‡
†Institute of Biological Chemistry and Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan
‡Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
S Supporting Information
b
ABSTRACT: One-pot multicomponent synthesis to assemble compounds has been
an efficient method for constructing a compound library. We have developed one-pot
tandem copper-catalyzed azidation and CuAAC reactions that afford 1-thiazolyl-
1,2,3-triazoles with anticancer activity. By utilizing this one-pot synthetic strategy,
we constructed a library of 1-thiazolyl-1,2,3-triazoles in search of the potent lead
compound. Furthermore, 1-thiazolyl-1,2,3-triazoles were evaluated for anticancer
activity against the multidrug-resistant cancer cells MES-SA/Dx5. Most of the
1-thiazolyl-1,2,3-triazoles revealed cytotoxic effect against cancer cells at micromolar
to low micromolar range. Testing some of the most potent compounds (5{4,2-4}
and 5{5,1-3}) against the normal cell line Vero showed no significant toxicity
(except 5{4,2}) to normal cells. This result indicates that compounds 5{4,3-4}
and 5{5,1-3} possessed good potency and selectivity to cancer cells over normal
cells.
KEYWORDS: 1-thiazolyl-1,2,3-triazole, cytotoxic activity, CuAAC reaction, one-pot synthesis
Chart 1. Bioisosteric Replacement of 2-Aminothiazolyl
Imidazole
’ INTRODUCTION
One-pot multicomponent synthesis provides a highly valuable
synthetic tool to assemble compounds within a minimum number
of synthetic steps.1 The molecular complexity and diversity to be
created by the facile formation in a one-pot transformation is
quite suitable for combinatorial library synthesis.2
Cu(I)-promoted coupling reaction has been extensively used
for the preparation of numerous synthetic molecules and bio-
molecules.3 Cu(I)-promoted azidation reaction has been used as
a facile method for the transformation of an aryl halide into an aryl
azide.4 Synthetic applications of aryl azide have become highly
attractive alternatives to establish the nitrogen-linked aryl scaffolds.
Recently, the copper-catalyzed [3 þ 2] azide and alkyne
cycloaddition (CuAAC) reaction has drawn much attention.5
This high yield and regioselective reaction has found numerous
applications ranging from chemistry to biology. Furthermore,
this highly reliable reaction allows rapid synthesis of combinato-
rial libraries for biological screening at low cost and with high
efficiency. Copper-catalyzed azide-alkyne cycloaddition (CuAAC)
reaction is widely utilized in the synthesis of biologically active
compounds for the construction of 1,2,3-triazole. 1,2,3-Triazole
is an important class of heterocycle as a chemical scaffold with
interesting biological properties. Several therapeutically active
compounds containing 1,2,3-triazoles have been reported, such
as antimicrobials, anti-HIV agents, and kinase inhibitors.6
Tandem Cu(I)-catalyzed azidation and 1,3-dipolar [3 þ 2]
cycloaddition reactions between azides and terminal alkynes that
can be carried out in one-pot combinatorial synthesis seems to be
an attractive method. Recently, 2-aminothiazolyl imidazole has
been found to exhibit promising anticancer activity.7 In our con-
tinuous effort to search for new potent anticancer compounds with
rapid and efficient synthetic strategies, and on the basis of the
bioisosteric replacement of 2-aminothiazolyl imidazole, we have
designed a new drug scaffold, that is, 1-thiazolyl-1,2,3-triazole, which
could be efficiently prepared in one-pot combinatorially (Chart 1).
To the best of our knowledge, 1-thiazolyl-1,2,3-triazoles have
never been previously reported to possess anticancer activity.
Herein, we demonstrate an efficient combinatorial synthesis
of 1-thiazolyl-1,2,3-triazoles by performing one-pot tandem
Received: September 29, 2010
Published: November 10, 2010
r
2010 American Chemical Society
72
dx.doi.org/10.1021/co1000234 ACS Comb. Sci. 2011, 13, 72–78
|

ACS Combinatorial Science
RESEARCH ARTICLE
copper-catalyzed azidation and CuAAC reactions. Additionally,
we also evaluated the anticancer activity of these products, most
of which exhibited significant inhibition of cancer cell growth.
vided (2-furoyl)methylthiocyanate 2 in 64% yield in two steps.9
Cyclization of (2-furoyl)methylthiocyanate 2 was carried out by
treatment with hydrogen bromide in glacial acetic acid to obtain
2-bromo-4-(2-furyl)thiazole 3{1} in 83% yield.10 Using the same
strategy, 2-bromo-4-arylthiazoles 3{2-5} were also prepared
(Figure 1). Subsequently, we employed copper(I) iodide as catalyst
with terminal alkynes 4{1-5} in one pot through the azidation
and CuAAC reactions to produce a library of diverse 1-thiazolyl-
1,2,3-triazoles 5{3(1-5),4(1-5)}. Optimized reaction conditions
of the azidation and CuAAC reactions in one pot were conducted
by using 2-bromo-4-(2-furyl)thiazole 3{1}, sodium azide and
phenylacetylene 4{1} in the presence of copper(I) iodide and N,
N0-dimethylethylenediamine (DMEDA) in N,N-dimethyl form-
amide (DMF) at 60 °C for 6 h to afford 1-thiazolyl-1,2,3-triazole
5{1,1} in 71% yield.11 By following the same procedure, a library
of 1-thiazolyl-1,2,3-triazoles 5{3(1-5),4(1-5)} was generated in
one-pot tandem copper-catalyzed azidation and CuAAC reac-
tions (Table 1).
Since the drug resistance limits the effectiveness of many anti-
cancer agents, development of a new class of anticancer agents
for patients with drug-resistant cancer is potentially valuable.
Thus, all the synthesized 1-thiazolyl-1,2,3-triazoles 5{3(1-5),4-
(1-5)} were evaluated for cytotoxicity in the multiple drug
resistant cancer cells MES-SA/Dx5. The cancer cell viability after
treatments with the test compounds was measured using a color-
imetric MTT assay system. The IC50 values of 1-thiazolyl-1,2,3-
triazoles 5{3(1-5),4(1-5)} against MES-SA/Dx5 cancer cells
were determined and summarized in Table 2. Most of the
1-thiazolyl-1,2,3-triazoles (except compound 5{1,1}) revealed
cytotoxic effect against MES-SA/Dx5 cancer cells at micro-
molar range, while some of them were potent at low micromolar
range.
’ RESULTS AND DISCUSSION
The synthetic strategy for the compound library is outlined in
Chart 2. 1-Thiazolyl-1,2,3-triazole was used as the structural
scaffold for the anticancer compound library synthesis, therefore
enabling the exploration of the lead compound. A variety of
2-bromo-4-arylthiazoles and terminal alkynes were used as the
building blocks to obtain a library of 1-thiazolyl-1,2,3-triazoles.
This library of 1-thiazolyl-1,2,3-triazoles was efficiently assembled
by employing the one-pot tandem copper-catalyzed reactions by
means of azidation and CuAAC reactions.
We first synthesized 2-bromo-4-arylthiazoles 3{1-5} for the
further combinatorial assembling with terminal alkynes 4{1-5}
to give the desired 1-thiazolyl-1,2,3-triazoles 5{3(1-5),4(1-5)}.
Synthesis of 2-bromo-4-(2-furyl)thiazole 3{1} is shown in Scheme 1.
2-Acetylfuran was used as a starting material for further reactions.
Bromination of 2-acetylfuran was conducted by using bromine in
diethyl ether-dioxane mixture.8 Subsequently, substitution reac-
tion of 2-bromoacetylfuran 1 with potassium thiocyanate pro-
Chart 2. Tandem Copper-Catalyzed Synthesis
We further examined the effect of R1 and R2 groups of 1-thiazolyl-
1,2,3-triazoles on the anticancer activity. The anticancer activity
of the phenyl group (5{3,1-5}) on the thiazole ring was superior
to that of thiophenyl (5{2,1-5}) and furanyl (5{1,1-5})
groups, and the order of activity of R1 group against MES-SA/
Dx5 can be described as phenyl > thiophenyl > furanyl for most
examples among these three substituents. Moreover, compounds
with 4-halophenyl substituent on thiazole ring (5{4,1-3} and
5{5,1-3}) were found to be more active than those with phenyl
(5{3,1-3}) and heteroaryl (5{1,1-3} and 5{2,1-3}) rings.
However, compared with fluoro substituents 5{5,1-5}, chloro
substituents 5{4,1-5} led to a slightly increased activity. Com-
pounds 5{4,1} and 5{4,2} with their phenyl group bearing chloro
Scheme 1
Figure 1. Building blocks for library synthesis.
73
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78

ACS Combinatorial Science
RESEARCH ARTICLE
Table 1. Synthesis of 1-Thiazolyl-1,2,3-triazoles 5
Table 2. Anticancer Activity of 1-Thiazolyl-1,2,3-triazoles
against Multiple Drug Resistant Cancer Cell Line
MES-SA/Dx5a
compound
IC50 (μM)
compound
IC50 (μM)
5{1,1}
5{1,2}
5{1,3}
5{1,4}
5{1,5}
5{2,1}
5{2,2}
5{2,3}
5{2,4}
5{2,5}
5{3,1}
5{3,2}
5{3,3}
>250
5{3,4}
5{3,5}
5{4,1}
5{4,2}
5{4,3}
5{4,4}
5{4,5}
5{5,1}
5{5,2}
5{5,3}
5{5,4}
5{5,5}
colchicine
82.8 ( 10.0
56.9 ( 4.1
1.1 ( 0.1
0.8 ( 0.1
4.4 ( 0.7
5.5 ( 0.3
26.4 ( 2.4
12.3 ( 2.3
5.1 ( 1.6
5.8 ( 1.1
16.9 ( 2.1
28.4 ( 2.7
0.06 ( 0.01
57.7 ( 3.7
128.4 ( 5.3
38.7 ( 7.2
48.2 ( 5.2
120.0 ( 27.5
60.0 ( 4.3
18.2 ( 1.6
15.2 ( 2.4
116.4 ( 10.6
81.2 ( 8.2
22.3 ( 2.5
9.2 ( 0.3
entry
R1
R2
yield (%)a
5{1,1}
5{1,2}
5{1,3}
5{1,4}
5{1,5}
5{2,1}
5{2,2}
5{2,3}
5{2,4}
5{2,5}
5{3,1}
5{3,2}
5{3,3}
5{3,4}
5{3,5}
5{4,1}
5{4,2}
5{4,3}
5{4,4}
5{4,5}
5{5,1}
5{5,2}
5{5,3}
5{5,4}
5{5,5}
2-furanyl
phenyl
71
69
62
66
58
67
61
59
60
58
52
60
58
48
52
61
55
57
58
64
62
67
55
51
63
2-furanyl
2-pyridinyl
3-pyridinyl
2-thiophenyl
2-furanyl
2-furanyl
2-furanyl
(E)-C6H5CHdCHCO2CH2
phenyl
2-thiophenyl
2-thiophenyl
2-thiophenyl
2-thiophenyl
2-thiophenyl
phenyl
2-pyridinyl
a Experiment was performed in triplicate for three repeats, and IC50
3-pyridinyl
values were expressed as mean ( SEM.
2-thiophenyl
(E)-C6H5CHdCHCO2CH2
phenyl
Table 3. Cytotoxicity of Selected 1-Thiazolyl-1,2,3-triazoles
against Vero Cell Linea
phenyl
2-pyridinyl
phenyl
3-pyridinyl
compound
IC50 (μM)
phenyl
2-thiophenyl
phenyl
(E)-C6H5CHdCHCO2CH2
phenyl
5{4,2}
5{4,3}
5{4,4}
5{5,1}
5{5,2}
5{5,3}
Colchicine
26.4 ( 1.4
>250
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-fluorophenyl
4-fluorophenyl
4-fluorophenyl
4-fluorophenyl
4-fluorophenyl
2-pyridinyl
>250
3-pyridinyl
>250
2-thiophenyl
>250
(E)-C6H5CHdCHCO2CH2
phenyl
>250
0.5 ( 0.1
a Experiment was performed in triplicate for three repeats and IC50
values were expressed as mean ( SEM.
2-pyridinyl
3-pyridinyl
2-thiophenyl
In conclusion, we have developed one-pot tandem copper-
catalyzed azidation and CuAAC reactions for constructing a
novel anticancer drug scaffold of 1-thiazolyl-1,2,3-triazole. Using
this one-pot synthesis, a library of 1-thiazolyl-1,2,3-triazoles has
been rapidly and efficiently synthesized. The synthesized com-
pounds were evaluated for anticancer activity, and some of them
demonstrated significant antiproliferative activity against drug-
resistant cancer cells (MES-SA/Dx5) without obvious toxicity to
normal cells (Vero). Further studies on the cellular and molecular
mechanism of action of 1-thiazolyl-1,2,3-triazoles are in progress
in our laboratory and will be reported in due course.
(E)-C6H5CHdCHCO2CH2
a Isolated yields.
substituent at the para position enhanced the potency against the
MES-SA/Dx5 cancer cell line dramatically. This indicates that an
electron withdrawing group, especially chloro substituent, at the
para position of the phenyl ring was important for the cytotoxic
activity of 1-thiazolyl-1,2,3-triazoles.
We next turned our attention to the R2 group on 1-thiazolyl-
1,2,3-triazoles. As seen in Table 2, good activity was found among
the phenyl, thiophenyl, and pyridinyl analogues. The aromatic
ring seems to be an important requirement for the compound's
cytotoxicity against MES-SA/Dx5 cells, especially 2- and 3-pyridinyl.
Switching R2 from aromatic ring to cinnamate ester (compounds
5{1-5,5}) resulted in partial loss of activity.
To test the selectivity of compounds, some of the potent
compounds (5{4,2-4} and 5{5,1-3}) were further examined
for their cytotoxicity against normal Vero cells (Table 3). Among
them, except 5{4,2}, all compounds exhibited no significant
toxicity to Vero cells up to the concentration of 250 μM, while
the majority of these selected compounds demonstrated potent
activity in MES-SA/Dx5 cancer cells. This suggested that these
1-thiazolyl-1,2,3-triazoles demonstrated the potency and selec-
tivity to multidrug resistant cancer cells over normal cells.
’ EXPERIMENTAL SECTION
Chemistry. All reactions were conducted in dried glassware
under an oven at 120 °C overnight and cooled in a desiccator
over anhydrous CaSO4. All reagents were used as received from
commercial suppliers unless otherwise stated. DMF was dried
over calcium hydride for 72 h prior to vacuum distillation.
Tetrahydrofuran (THF) was distilled from sodium/benzophenone
ketyl under a nitrogen atmosphere. Other solvents, including
acetone, dichloromethane, and ethanol, were distilled over CaH2
under nitrogen. The proton NMR spectra were obtained on a
Bruker Avance 400 (400 MHz) spectrometer. Chloroform-d of
spectrograde was used as solvent. All NMR chemical shifts were
74
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78

ACS Combinatorial Science
RESEARCH ARTICLE
reported as δ values in parts per million (ppm), and cou-
pling constants (J) were given in hertz (Hz). The splitting pattern
abbreviations are as follows: s, singlet; d, doublet; t, triplet; q,
quartet; br, broad; m, unresolved multiplet due to the field
strength of the instrument; dd, doublet of doublet; dt, doublet of
triplet; and ddd, doublet of doublet of doublet. High resolution
mass spectra were carried out on a Bruker (Bio-TOF) mass spec-
trometer. Melting points were measured with a B€uchi 510 melt-
ing point apparatus. Attenuated Total Reflectance (ATR) Fourier
transform infrared spectra were collected with a Bruker Optics
Tensor 27 spectrometer. Purification was performed by using
preparative separations in flash column chromatography (Merck
silica gel 60, particle size of 230-400 mesh). Analytical TLC was
carried out on precoated plates (Merck silica gel 60, F254).
Compounds analyzed on the TLC plates were visualized by using
UV light, I2 vapor, or 2.5% phosphomolybdic acid in ethanol with
heating.
δ 8.62 (s, 1H), 7.55 (dd, J = 3.6, 1.1 Hz, 1H), 7.51 (dd, J = 1.8,
0.6 Hz, 1H), 7.40 (dd, J=5.0, 1.1 Hz, 1H), 7.36 (s, 1H), 7.16 (dd,
J=5.0, 3.6 Hz, 1H), 6.87 (d, J=3.4 Hz, 1H), 6.55 (dd, J=3.4, 1.8 Hz,
1H). 13C NMR (CDCl3): δ 157.0, 149.2, 144.6, 143.7, 142.8,
131.5, 127.8, 126.0, 125.3, 116.3, 111.7, 110.0, 107.9. HRMS
calcd for C13H8N4OS2H (MþH)þ 301.0212, found 301.0228.
(E)-(1-(4-(Furan-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)methyl
cinnamate 5{1,5}. Yield: 58%. White solid. Mp=137-140 °C.
IR νmax (ATR): 2923, 1713, 1523, 1452, 1167 cm-1. 1H NMR
(CDCl3): δ 8.61 (s, 1H), 7.76 (d, J = 16.0 Hz, 1H), 7.54-7.52
(m, 2H), 7.49 (s, 1H), 7.42-7.38 (m, 3H), 7.32 (s, 1H), 6.84 (d,
J = 2.9 Hz, 1H), 6.52-6.46 (m, 2H), 5.47 (s, 2H). 13C NMR
(CDCl3): δ 166.5, 156.8, 149.0, 145.8, 144.5, 143.9, 142.7, 134.0,
130.4, 128.8, 128.1, 121.5, 117.1, 111.6, 109.9, 107.9, 57.2. HRMS
calcd for C19H14N4O3SH (MþH)þ 379.0859, found 379.0842.
C19H14N4O3SNa (MþNa)þ 401.0679, found 401.0665.
4-Phenyl-1-(4-(thiophen-2-yl)thiazol-2-yl)-1H-1,2,3-triazole
5{2,1}. Yield: 67%. White solid. Mp = 139-141 °C. IR νmax
(ATR): 3089, 2924, 1523, 1435, 1224 cm-1. 1H NMR (CDCl3):
δ 8.69 (s, 1H), 7.94 (d, J=8.6 Hz, 2H), 7.51-7.46 (m, 3H), 7.41
(d, J = 7.4 Hz, 1H), 7.34 (dd, J = 5.0, 0.9 Hz, 1H), 7.25 (s, 1H),
7.10 (dd, J=5.0, 3.7 Hz, 1H). 13C NMR (CDCl3): δ 156.6, 148.4,
147.6, 137.0, 129.3, 128.9, 128.8, 127.8, 126.0, 125.9, 124.8, 116.9,
109.4. HRMS calcd for C15H10N4S2H (MþH)þ 311.0420,
found 311.0405.
2-(1-(4-(Thiophen-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{2,2}. Yield: 61%. Yellow solid. Mp = 186-189 °C.
IR νmax (ATR): 2923, 2381, 1603, 1531, 1410 cm-1. 1H NMR
(CDCl3): δ 9.10 (s, 1H), 8.64 (d, J=4.7 Hz, 1H), 8.23 (d, J=7.9
Hz, 1H), 7.81 (dt, J=7.9, 1.7 Hz, 1H), 7.47 (dd, J=3.6, 0.9 Hz),
7.32 (dd, J=5.0, 0.9 Hz, 1H), 7.30-7.27 (m, 1H), 7.24 (s, 1H),
7.08 (dd, J=5.0, 3.6 Hz, 1H). 13C NMR (CDCl3): δ 156.4, 149.6,
149.2, 148.9, 147.8, 137.1, 137.1, 127.8, 126.0, 124.9, 123.7,
120.8, 119.7, 109.5. HRMS calcd for C14H9N5S2Na (MþNa)þ
334.0192, found 334.0197.
General Procedure for the Synthesis of 1-Thiazolyl-1,2,3-
triazoles 5
1-(4-(Furan-2-yl)thiazol-2-yl)-4-phenyl-1H-1,2,3-triazole
5{1,1}. To a solution of 2-bromo-4-(2-furyl)thiazole 3{1} (253
mg, 1.1 mmol), phenylacetylene 4{1} (111 mg, 1.1 mmol), CuI
(21 mg, 0.11 mmol), DMEDA (14.5 mg, 0.16 mmol), sodium azide
(215 mg, 3.3 mmol) were added in DMF (15 mL), and the reaction
wrapped in aluminum foil to prevent further exposure to light. The
resulting suspension was stirred under N2 at 60 °C for 6 h. The
mixture was cooled down to room temperature, and the catalyst was
filtered off. The solvent was removed in vacuum. EtOAc (10 mL)
and water (10 mL) were added. The separated aqueous layer was
extracted with EtOAc (10 mL). The combined organic layers were
washed with aqueous sat'd NH4Cl and brine, dried over MgSO4, and
concentrated. The residual was purified by silica gel column chro-
matography (EtOAc/hexanes = 1/2) to give a white solid 5{1,1}
(230 mg, 71%). Mp = 135-137 °C. IR νmax (ATR): 3146, 1531,
1445, 1228 cm-1. 1H NMR (CDCl3): δ 8.70 (s, 1H), 7.94 (d, J =
7.6 Hz, 2H), 7.50-7.47 (m, 3H), 7.42-7.39 (t, J=7.6 Hz, 1H), 7.34
(s, 1H), 6.85 (d, J=3.2 Hz, 1H), 6.54-6.52 (dd, J=3.2, 1.6 Hz, 1H).
13C NMR (CDCl3): δ 157.1, 149.1, 148.4, 144.5, 142.7, 129.3,
128.9, 128.8, 126.0, 116.9, 111.5, 109.0, 107.8. HRMS calcd for
C15H10N4OSH (MþH)þ 295.0648, found 295.0664.
3-(1-(4-(Thiophen-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{2,3}. Yield: 59%. Brown solid. Mp = 169-170 °C.
IR νmax (ATR): 2923, 1553, 1524, 1444, 1236 cm-1. 1H NMR
(CDCl3): δ 9.16 (s, 1H), 8.81 (s, 1H), 8.67 (d, J=3.7 Hz, 1H),
8.30 (d, J=7.8 Hz, 1H), 7.53-7.52 (m, 1H), 7.46-7.42 (m, 1H),
7.37 (d, J = 4.7 Hz, 1H), 7.29 (s, 1H), 7.13-7.11 (m, 1H). 13
C
2-(1-(4-(Furan-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)pyridine
5{1,2}. Yield: 69%. Yellow solid. Mp = 154-157 °C. IR νmax
NMR (CDCl3): δ 156.3, 149.8, 147.7, 147.2, 145.4, 136.8, 133.2,
127.8, 126.0, 125.6, 124.9, 123.7, 117.4, 109.6. HRMS calcd for
C14H9N5S2H (MþH)þ 312.0372, found 312.0383.
1
(ATR): 2924, 2853, 1599, 1531, 1420, 1259 cm-1. H NMR
(CDCl3): δ 9.14 (s, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.28 (d, J =
7.8 Hz, 1H), 7.87 (dt, J=7.8, 1.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H),
7.37 (s, 1H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 6.86 (d, J = 3.4 Hz,
1H), 6.55 (dd, J=3.4, 1.6 Hz, 1H). 13C NMR (CDCl3): δ 156.7,
149.6, 149.2, 149.1, 148.9, 144.6, 142.7, 136.8, 123.3, 120.6, 119.5,
111.6, 109.8, 107.9. HRMS calcd for C14H9N5SONa (MþNa)þ
318.0420, found 318.0410.
3-(1-(4-(Furan-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)pyridine
5{1,3}. Yield: 62%. Brown solid. Mp = 144-146 °C. IR νmax
(ATR): 3113, 1532, 1218 cm-1. 1H NMR (CDCl3): δ 9.15 (s,
1H), 8.71 (s, 1H), 8.27 (d, J = 3.7 Hz, 1H), 8.10 (d, J = 7.8 Hz,
1H), 7.63-7.41 (m, 1H), 7.38-7.22 (m, 1H), 7.32 (s, 1H), 7.30
(s, 1H), 7.21-7.10 (m, 1H). 13C NMR (CDCl3): δ 156.5, 149.7,
148.7, 148.2, 147.3, 138.9, 135.2, 133.8, 126.4, 125.3, 124.5,
123.3, 110.4, 108.6. HRMS calcd for C14H9N5OSH (MþH)þ
296.0601, found 296.0646.
4-(Thiophen-2-yl)-1-(4-(thiophen-2-yl)thiazol-2-yl)-1H-1,2,3-
triazole 5{2,4}. Yield: 60%. Brown solid. Mp=154-156 °C. IR
νmax (ATR): 3079, 2923, 1527 cm-1. 1H NMR (CDCl3): δ 8.61
(s, 1H), 7.55 (dd, J = 3.6, 1.1 Hz, 1H), 7.52 (dd, J = 3.7, 1.1 Hz,
1H), 7.40 (dd, J = 5.1, 1.1 Hz, 1H), 7.36 (dd, J = 5.1, 1.1 Hz,
1H), 7.27 (s, 1H), 7.15 (dd, J= 5.1, 3.6 Hz, 1H), 7.12 (dd, J=5.1,
3.7 Hz, 1H). 13C NMR (CDCl3): δ 156.3, 147.6, 143.6, 136.9,
131.4, 127.8, 127.7, 125.9, 125.9, 125.2, 124.8, 116.2, 109.5.
HRMS calcd for C13H8N4S3H (MþH)þ 316.9984, found
316.9966.
(E)-(1-(4-(Thiophen-2-yl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
methyl Cinnamate 5{2,5}. Yield: 58%. White solid. Mp =
138-140 °C. IR νmax (ATR): 1700, 1625, 1525, 1158 cm-1
.
1H NMR (CDCl3): δ 8.63 (s, 1H), 7.78 (d, J=16.0 Hz, 1H), 7.56-
7.51 (m, 3H), 7.42-7.40 (m, 3H), 7.36 (dd, J=5.0, 1.1 Hz, 1H),
7.27 (s, 1H), 7.12 (dd, J=5.0, 3.6 Hz, 1H), 6.50 (d, J=16.0 Hz, 1H),
5.49 (s, 2H). 13C NMR (CDCl3): δ 166.6, 156.5, 147.8, 145.9,
144.0, 137.0, 134.2, 130.5, 128.9, 128.2, 127.9, 126.1, 125.0, 121.6,
1-(4-(Furan-2-yl)thiazol-2-yl)-4-(thiophen-2-yl)-1H-1,2,3-
triazole 5{1,4}. Yield: 66%. Brown solid. Mp=146-149 °C. IR
νmax (ATR): 3112, 1531, 1246, 1032 cm-1. 1H NMR (CDCl3):
75
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78

ACS Combinatorial Science
RESEARCH ARTICLE
117.2, 109.6, 57.3. HRMS calcd for C19H14N4O2S2Na (MþNa)þ
417.0450, found 417.0447.
3-(1-(4-(4-Chlorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{4,3}. Yield: 57%. Yellow solid. Mp = 185-188 °C.
IR νmax (ATR): 3096, 1602, 1529, 1473, 1421 cm-1. 1H NMR
(CDCl3): δ 9.16 (d, J=1.5 Hz, 1H), 8.82 (s, 1H), 8.67 (dd, J=4.7,
1.2 Hz, 1H), 8.31 (ddd, J = 7.9, 3.9, 1.8 Hz, 1H), 7.88 (d, J =
6.6 Hz, 2H), 7.48-7.44 (m, 4H). 13C NMR (CDCl3): δ 156.5,
151.9, 149.8, 147.2, 145.4, 134.7, 133.2, 131.6, 129.0, 127.4, 125.6,
123.8, 117.2, 111.3. HRMS calcd for C16H10ClN5SH (MþH)þ
340.0418, found 340.0423.
4-Phenyl-1-(4-phenylthiazol-2-yl)-1H-1,2,3-triazole 5-
{3,1}. Yield: 52%. White solid. Mp = 136-138 °C. IR νmax
(ATR): 1530, 1428, 1233 cm-1. 1H NMR (CDCl3): δ 8.65 (s, 1H),
8.00-7.93 (m, 4H), 7.52-7.44 (m, 4H), 7.44-7.38 (m, 3H).
13C NMR (CDCl3): δ 156.6, 153.0, 148.4, 133.3, 129.4, 128.9,
128.8, 128.7, 128.6, 126.1, 126.0, 116.8, 110.7. HRMS calcd for
C17H12N4SH (MþH)þ 305.0855, found 305.0884.
2-(1-(4-Phenylthiazol-2-yl)-1H-1,2,3-triazol-4-yl)pyridine
5{3,2}. Yield: 60%. Brown solid. Mp = 181-184 °C. IR νmax
(ATR): 3111, 1530, 1420, 1232 cm-1. 1H NMR (CDCl3): δ 9.10
(s, 1H), 8.66 (ddd, J=5.7, 1.7, 1.1 Hz, 1H), 8.24 (d, J=8.7, 0.9 Hz,
1H), 7.91 (dd, J=8.7, 1.1 Hz, 2H), 7.82 (dt, J=7.8, 1.7 Hz, 1H),
7.46 (dt, J = 8.7, 2.4 Hz, 2H), 7.42 (s, 1H), 7.41-7.37 (m, 1H),
7.31-7.28 (m, 1H). 13C NMR (CDCl3): δ 156.2, 153.0, 149.6,
149.2, 148.9, 136.8, 133.2, 128.8, 128.7, 126.0, 123.3, 120.6, 119.5,
110.8. HRMS calcd for C16H11N5SNa (MþNa)þ 328.0627, found
328.0616.
1-(4-(4-Chlorophenyl)thiazol-2-yl)-4-(thiophen-2-yl)-1H-
1,2,3-triazole 5{4,4}. Yield: 58%. Yellow solid. Mp = 165-
167 °C. IR νmax (ATR): 2924, 1527, 1472, 1243 cm-1. 1H NMR
(CDCl3): δ 8.63 (s, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.56 (dd, J=3.6,
0.8 Hz, 1H), 7.47-7.40 (m, 4H), 7.16 (dd, J=4.9, 3.6 Hz, 1H).
13C NMR (CDCl3): δ 156.6, 151.8, 143.6, 134.6, 131.7, 131.4,
129.0, 127.7, 127.4, 125.9, 125.2, 116.1, 111.1. HRMS calcd for
C15H9ClN4S2H (MþH)þ 345.0030, found 345.0042.
(E)-(1-(4-(4-chlorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
methyl cinnamate 5{4,5}. Yield: 64%. White solid. Mp=107-
109 °C. IR νmax (ATR): 2924, 1713, 1636, 1526, 1162 cm-1. 1H
NMR (CDCl3): δ 8.63 (s, 1H), 7.86 (dd, J = 6.6, 1.8 Hz, 2H),
7.77 (d, J = 16.0 Hz, 1H), 7.56-7.53 (m, 2H), 7.45 (dd, J = 6.6,
1.8 Hz, 2H), 7.44-7.40 (m, 4H), 6.50 (d, J=16.0 Hz, 1H), 5.49
(s, 2H). 13C NMR (CDCl3): δ 166.5, 156.5, 151.8, 145.8, 143.9,
134.6, 134.0, 131.6, 130.4, 129.0, 128.8, 128.1, 127.3, 121.5,
117.1, 111.2, 57.2. HRMS calcd for C21H15ClN4O2SH (MþH)þ
423.0677, found 423.0692.
3-(1-(4-Phenylthiazol-2-yl)-1H-1,2,3-triazol-4-yl)pyridine
5{3,3}. Yield: 58%. Yellow solid. Mp = 158-161 °C. IR νmax
1
(ATR): 1526, 1477, 1408, 1230 cm-1. H NMR (CDCl3): δ
9.14 (s, 1H), 8.81 (s, 1H), 8.65 (s, 1H), 8.29 (d, J=7.4 Hz, 1H),
7.92 (d, 2H, J = 7.4 Hz, 2H), 7.45-7.39 (m, 5H). 13C NMR
(CDCl3): δ 156.3, 153.1, 149.8, 147.2, 145.4, 133.2, 133.1, 128.8,
128.7, 126.1, 125.6, 123.7, 117.3, 111.0. HRMS calcd for C16H11-
N5SH (MþH)þ 306.0808, found 306.0788.
1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-1,2,3-triazole
5{3,4}. Yield: 48%. Yellow solid. Mp = 154-156 °C. IR νmax
(ATR): 1517, 1423, 1218 cm-1. 1H NMR (CDCl3): δ 8.63 (s,
1H), 7.93 (d, J=8.7 Hz, 2H), 7.54 (dd, J=3.6, 0.9 Hz, 1H), 7.47
(t, J=8.7 Hz, 2H), 7.42-7.38 (m, 3H), 7.14 (dd, J=5.0, 3.6 Hz,
1H). 13C NMR (CDCl3): δ 156.4, 153.0, 143.5, 133.2, 131.5,
128.8, 128.7, 127.7, 126.1, 125.9, 125.1, 116.2, 110.8. HRMS
calcd for C15H10N4S2H (MþH)þ 311.0420, found 311.0402.
(E)-(1-(4-Phenylthiazol-2-yl)-1H-1,2,3-triazol-4-yl)methyl
cinnamate 5{3,5}. Yield: 52%. White solid. Mp=133-136 °C.
1-(4-(4-Fluorophenyl)thiazol-2-yl)-4-phenyl-1H-1,2,3-triazole
5{5,1}. Yield: 62%. Brown solid. Mp > 220 °C. IR νmax (ATR):
1
1603, 1528, 1482, 1232 cm-1. H NMR (CDCl3): δ 8.73 (s,
1H), 7.97 (d, J=7.4 Hz, 2H), 7.93 (dd, J=8.6, 5.4 Hz, 2H), 7.51
(t, J=7.4 Hz, 2H), 7.45 (t, J=7.4 Hz, 1H), 7.36 (s, 1H), 7.18 (t, J=
8.6 Hz, 2H). 13C NMR (CDCl3): δ 162.9 (d, JC-F =247.3 Hz),
156.8, 152.0, 148.4, 129.6, 129.4, 128.9, 128.8, 127.9 (d, JC-F
=
6.8 Hz), 126.0, 116.8, 115.7 (d, JC-F = 21.6 Hz), 110.3. HRMS
calcd for C17H11FN4SH (MþH)þ 323.0761, found 323.0773.
2-(1-(4-(4-Fluorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{5,2}. Yield: 67%. Yellow solid. Mp = 156-158 °C.
IR νmax (ATR): 2924, 2853, 1709, 1636, 1531, 1443, 1165 cm-1
.
1H NMR (CDCl3): δ 8.65 (s, 1H), 7.93 (d, J=7.2 Hz, 2H), 7.78
(d, J= 16.0 Hz, 1H), 7.56-7.54 (m, 2H), 7.49 (dd, J=8.5, 7.2 Hz,
2H), 7.43-7.40 (m, 5H), 6.50 (d, J=16.0 Hz, 1H), 5.49 (s, 2H).
13C NMR (CDCl3): δ 166.6, 156.5, 153.2, 145.9, 144.0, 134.3,
134.2, 133.3, 130.5, 128.9, 128.8, 128.2, 126.2, 121.6, 117.6,
111.0, 57.4. HRMS calcd for C21H16N4O2SNa (MþNa)þ
411.0886, found 411.0874.
IR νmax (ATR): 2923, 2854, 1601, 1530, 1481, 1421, 1216 cm-1
.
1H NMR (CDCl3): δ 9.10 (s, 1H), 8.67 (d, J=4.4 Hz, 1H), 8.25
(d, J=7.8 Hz, 1H), 7.90 (dd, J=8.6, 5.4 Hz, 2H), 7.84 (dt, J=7.8,
1.6 Hz, 1H), 7.36 (s, 1H), 7.33-7.29 (m, 1H), 7.16 (t, J=8.6 Hz,
2H). 13C NMR (CDCl3): δ 163.0 (d, JC-F = 247.1 Hz), 156.5,
152.1, 149.7, 149.2, 149.0, 136.4, 129.6, (d, JC-F=2.7 Hz), 127.9
(d, JC-F=8.1 Hz), 123.4, 120.7, 119.5, 115.8 (d, JC-F=21.6 Hz),
110.4. HRMS calcd for C16H10FN5SH (MþH)þ 324.0714,
found 324.0698.
1-(4-(4-Chlorophenyl)thiazol-2-yl)-4-phenyl-1H-1,2,3-triazole
5{4,1}. Yield: 61%. White solid. Mp = 142-144 °C. IR νmax
1
(ATR): 1613, 1531, 1466, 1212 cm-1. H NMR (CDCl3): δ
3-(1-(4-(4-Fluorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{5,3}. Yield: 55%. Yellow solid. Mp > 220 °C. IR
νmax (ATR): 3095, 1529, 1441, 1231 cm-1. 1H NMR (CDCl3):
δ 9.17 (s, 1H), 8.83 (s, 1H), 8.68 (d, J=4.7 Hz, 1H), 8.33 (d, J=
7.8 Hz, 1H), 7.94 (dd, J=7.4, 5.7 Hz, 2H), 7.48-7.44 (m, 1H),
7.29 (s, 1H), 7.19 (t, J=8.3, 7.8 Hz, 2H). 13C NMR (CDCl3): δ
163.0 (d, JC-F = 247.1 Hz), 156.5, 152.1, 149.9, 147.2, 145.4,
133.2, 129.5, 127.9 (d, JC-F =8.0 Hz), 125.6, 123.7, 117.2, 115.8
(d, JC-F = 21.6 Hz), 110.6. HRMS calcd for C16H10FN5SH
(MþH)þ 324.0714, found 324.0720.
8.73 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.88 (dd, J = 6.7, 1.8 Hz,
2H), 7.53-7.43 (m, 5H), 7.42 (s, 1H). 13C NMR (CDCl3): δ
156.8, 151.8, 148.5, 134.6, 131.8, 129.3, 129.0, 128.9, 128.8, 127.4,
126.0, 116.8, 111.0. HRMS calcd for C17H11ClN4SH (MþH)þ
339.0471, found 339.0459.
2-(1-(4-(4-Chlorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
pyridine 5{4,2}. Yield: 55%. White solid. Mp=186-188 °C. IR
νmax (ATR): 1602, 1529, 1473, 1421 cm-1. 1H NMR (CDCl3):
δ 9.13 (s, 1H), 8.69 (br, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.90-7.84
(m, 3H), 7.46 (d, J=9.1 Hz, 2H), 7.43 (s, 1H), 7.33 (dd, J=7.9,
5.3 Hz, 1H). 13C NMR (CDCl3): δ 156.5, 151.9, 149.3, 148.9,
148.6, 137.2, 134.6, 131.7, 128.9, 127.3, 123.4, 120.7, 119.6, 111.1.
HRMS calcd for C16H10ClN5SH (MþH)þ 340.0418, found
340.0427.
1-(4-(4-Fluorophenyl)thiazol-2-yl)-4-(thiophen-2-yl)-1H-1,2,3-
triazole 5{5,4}. Yield: 51%. Gray solid. Mp = 210-212 °C. IR
νmax (ATR): 3081, 1530, 1229 cm-1. 1H NMR (CDCl3): δ 8.64
(s, 1H), 7.95-7.91 (m, 2H), 7.56 (dd, J=3.6, 0.9 Hz, 1H), 7.41
(dd, J = 5.1, 0.9 Hz, 1H), 7.37 (s, 1H), 7.20-7.15 (m, 3H). 13C
76
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78

ACS Combinatorial Science
RESEARCH ARTICLE
NMR (CDCl3): δ 163.0 (d, JC-F = 246.9 Hz), 156.5, 152.0,
143.6, 131.5, 129.5, 127.9 (d, JC-F=8.1 Hz), 127.7, 125.9, 125.2,
116.1, 115.8 (d, JC-F = 21.7 Hz), 110.4. HRMS calcd for
C15H9FN4S2H (MþH)þ 329.0325, found 329.0332.
(b) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. Novel
isocyanide-based three-component one-pot synthesis of cyanophenylamino-
acetamide derivatives. J. Comb. Chem. 2008, 10, 883–885. (c) Janvier, P.;
Sun, X.; Bienaymꢀe, H.; Zhu, J. Ammonium chloride-promoted four-
component synthesis of pyrrolo[3,4-b]pyridin-5-one. J. Am. Chem. Soc.
2002, 124, 2560–2567. (d) Volonterio, A.; Zanda, M. Multicomponent,
one-pot sequential synthesis of 1,3,5- and 1,3,5,5-substituted barbitu-
rates. J. Org. Chem. 2008, 73, 7486–7497. (e) Maiti, S.; Biswas, S.;
Jana, U. Iron(III)-catalyzed four-component coupling reaction of
1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes: a simple
and direct synthesis of functionalized pyrroles. J. Org. Chem. 2010, 75,
1674–1683.
(2) (a) Tu, S.-J.; Zhang, X.-H.; Han, Z.-G.; Cao, X.-D.; Wu, S.-S.;
Yan, S.; Hao, W.-J.; Zhang, G.; Ma, N. Synthesis of isoxazolo[5,4-
b]pyridines by microwave-assisted multi-component reactions in water.
J. Comb. Chem. 2009, 11, 428–432. (b) Yermolayev, S. A.; Gorobets,
N. Y.; Desenko, S. M. Rapid three-step one-pot microwave-assisted
synthesis of 2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarbonitrile library.
J. Comb. Chem. 2009, 11, 44–46. (c) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.;
Wischnat, R.; Baasov, T.; Wong, C.-H. Programmable one-pot oligo-
saccharide synthesis. J. Am. Chem. Soc. 1999, 121, 734–753. (d) Zhang,
W.; Luo, Z.; Chen, C. H.-T.; Curran, D. B. Solution-phase preparation of
a 560-compound library of individual pure mappicine analogues by
fluorous mixture synthesis. J. Am. Chem. Soc. 2002, 124, 10443–10450.
(e) Ghahremanzadeh, R.; Shakibaei, G. I.; Ahadi, S.; Bazgir, A. One-pot,
pseudo four-component synthesis of a spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,30-indoline]-trione library. J. Comb. Chem. 2010, 12, 191–
194.
(E)-(1-(4-(4-Fluorophenyl)thiazol-2-yl)-1H-1,2,3-triazol-4-yl)-
methyl cinnamate 5{5,5}. Yield: 63%. White solid. Mp=124-
126 °C. IR νmax (ATR): 2924, 1706, 1634, 1527, 1167 cm-1
.
1H NMR (CDCl3): δ 8.61 (s, 1H), 7.88 (dd, J=8.6, 5.2 Hz, 2H),
7.76 (d, J=16.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.41-7.37 (m, 3H),
7.33 (s, 1H), 7.14 (t, J = 8.6 Hz, 2H), 6.49 (d, J = 16.0 Hz, 1H),
5.48 (s, 2H). 13C NMR (CDCl3): δ 166.6, 163.0 (d, JC-F=247.1
Hz), 161.7, 156.4, 152.0, 145.8, 143.9, 134.0, 130.4, 129.4 (d,
JC-F = 2.8 Hz), 128.8, 128.1, 127.9 (d, JC-F = 8.1 Hz), 121.4,
117.1, 115.7 (d, JC-F=21.7 Hz), 110.5. HRMS calcd for C21H15-
FN4O2SH (MþH)þ 407.0973, found 407.0934. C21H15FN4-
O2SNa (MþNa)þ 429.0792, found 429.0771.
Cytotoxic Activity Assay. Human uterus sarcoma doxorubicin
resistant cancer cells (MES-SA/Dx5) and african green monkey
kidney epithelial cells (Vero) were seeded at 1 ꢀ 104 cells/100 μL/
well and 1 ꢀ 103 cells/100 μL/well, respectively, in 96-well plates
and incubated for 24 h at 37 °C in a 5% CO2 incubator. Test
compounds were dissolved in dimethylsulfoxide (DMSO)
and diluted for cell treatment in culture medium containing
DMSO at the final concentration of e0.5%. Cells were treated
with test compounds of various concentrations in triplicates per
concentration in the culture medium (200 μL/well) and
incubated at 37 °C in a 5% CO2 incubator for 72 h. A color-
imetric assay using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) system was used to determine the
cytotoxic activity of the testing compounds. Optical density (OD)
values at 570 nm on a microtiter plate reader (MRX II, DYNEX)
were measured. IC50, the concentration that inhibited 50% of
the cancer cell growth activity, was estimated. All experiments were
repeated three times.
(3) (a) Zhang, Q.; Wang, D.; Wang, X.; Ding, K. (2-Pyridyl)acetone-
promoted Cu-catalyzed O-arylation of phenols with aryl iodides, bro-
mides, and chlorides. J. Org. Chem. 2009, 74, 7187–7190. (b) Amblard,
F.; Cho, J. H.; Schinazi, R. F. Cu(I)-catalyzed Huisgen azide-alkyne 1,3-
dipolar cycloaddition reaction in nucleoside, nucleotide, and oligo-
nucleotide chemistry. Chem. Rev. 2009, 109, 4207–4220. (c) Meldal,
M.; Tornøe, C. W. Cu-catalyzed azide-alkyne cycloaddition. Chem. Rev.
2008, 108, 2952–3015. (d) Bae, I.; Han, H.; Chang, S. Highly efficient
one-pot synthesis of N-sulfonylamidines by Cu-catalyzed three-component
coupling of sulfonyl azide, alkyne, and amine. J. Am. Chem. Soc. 2005,
127, 2038–2039.
’ ASSOCIATED CONTENT
(4) (a) Ma, D.; Cai, Q. Copper/amino acid catalyzed cross-couplings
of aryl and vinyl halides with nucleophiles. Acc. Chem. Res. 2008, 41,
1450–1460. (b) Ramana, C. V.; Goriya, Y. The [Cu]-catalyzed SNAR
reactions: direct amination of electron deficient aryl halides with sodium
azide and the synthesis of arylthioethers under Cu(II)-ascorbate redox
system. Tetrahedron 2010, 66, 7642–7650.
Supporting Information. Spectral data (1
H, 13C NMR
S
b
and HRMS) of the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(5) (a) Amblard, F.; Cho, J. H.; Schinazi, R. F. Cu(I)-catalyzed
Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in nucleoside,
nucleotide, and oligonucleotide chemistry. Chem. Rev. 2009, 109, 4207–
4220. (b) Dirks, A. J.; Cornelissen, J. L. M.; Nolte, R. J. M. Monitoring
protein-polymer conjugation by a fluorogenic Cu(I)-catalyzed azide-
alkyne 1,3-dipolar cycloaddition. Bioconjugate Chem. 2009, 20, 1129–
1138. (c) Meldal, M.; Tornøe, W. T. Cu-catalyzed azide-alkyne
cycloaddition. Chem. Rev. 2008, 108, 2952–3015. (d) Cintas, P.; Barge,
A.; Tagliapietra, S.; Boffa, L.; Cravotto, G. Alkyne-azide click reaction
catalyzed by metallic copper under ultrasound. Nat. Protoc. 2010, 5,
607–616. (d) Orski, S. V.; Poloukhtine, A. A.; Arumugam, S.; Mao, L.;
Popik, V. V.; Locklin, J. High density orthogonal surface immobilization
via photoactivated copper-free click chemistry. J. Am. Chem. Soc. 2010,
132, 11024–11026. (e) Jakobsen, U.; Shelke, S. A.; Vogel, S.; Sigurdsson,
S. T. Site-directed spin-labeling of nucleic acids by click chemistry:
detection of abasic sites in duplex DNA by EPR spectroscopy. J. Am.
Chem. Soc. 2010, 132, 10424–10428.
Corresponding Author
*E-mail: bcchen@gate.sinica.edu.tw. Phone: 886-2-27886230.
Fax: 886-2-27883473.
’ ACKNOWLEDGMENT
We would like to thank Dr. Chiung-Tong Chen for providing
MES-SA/Dx5 cancer cell line.
’ ABBREVIATIONS
DMF, N,N-dimethyl formamide; EtOAc, ethyl acetate; MTT,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;
HRMS, high resolution mass spectrometry; CuAAC, copper-
(I)-catalyzed [3 þ 2] azide and alkyne cycloaddition; DMEDA,
N,N0-dimethylethylenediamine
(6) (a) Ferreira, S. B.; Sodero, A. C. R.; Cardoso, M. F. C.; Lima,
E. S.; Kaiser, C. R.; Silva, F. P.; Ferreira, V. F. Synthesis, biological
activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives
of carbohydrates as R-glucosidases inhibitors. J. Med. Chem. 2010, 53,
2364–2375. (b) Yuldasheva, K.; Dzhuraev, A. D.; Makhsumov, A. G.;
Amanov, N. Antimicrobial activity of bis(1,2,3-triazole) derivatives.
’ REFERENCES
(1) (a) Akritopoulou-Zanze, I. Isocyanide-based multicomponent
reactions in drug discovery. Curr. Opin. Chem. Biol. 2008, 12, 324–331.
77
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78

ACS Combinatorial Science
RESEARCH ARTICLE
Pharm. Chem. J. 1991, 25, 728–730. (c) Cho, J. H.; Bernard, D. L.;
Sidwell, R. W.; Kern, E. R.; Chu, C. K. Synthesis of cyclopentenyl
carbocyclic nucleosides as potential antiviral agents against orthopox-
viruses and SARS. J. Med. Chem. 2006, 49, 1140–1148. (d) Giffin, M. J.;
Heaslet, H.; Brik, A.; Lin, Y.-C.; Cauvi, G.; Wong, C.-H.; McRee, D. E.;
Elder, J. H.; Stout, C. D.; Torbett, B. E. A copper(I)-catalyzed 1,2,3-
triazole azide-alkyne click compound is a potent inhibitor of a multidrug-
resistant HIV-1 protease variant. J. Med. Chem. 2008, 51, 6263–6270.
(e) Reck, F.; Zhou, F.; Girardot, M.; Kern, G.; Eyermann, C. J.; Hales,
N. J.; Ramsay, R. R.; Gravestock, M. B. Identification of 4-substituted
1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced
activity against monoamine oxidase A. J. Med. Chem. 2005, 48, 499–506.
(7) (a) Li, W.-T.; Hwang, D.-R.; Song, J.-S.; Chen, C.-P.; Chuu, J.-J.;
Hu, C.-B.; Lin, C.-C.; Lin, H.-L.; Wang, H.-S.; Shen, C.-C.; Huang, C.-L.;
Tseng, H.-Y.; Huang, C.-Y.; Chen, T.-W.; Lin, C.-H.; Chang, C.-M.;
Chao, Y.-S.; Chen, C.-T. Synthesis and biological activities of 2-amino-
1-arylidenamino imidazoles as orally active anticancer agents. J. Med.
Chem. 2010, 53, 2409–2417. (b) Li, W.-T.; Hwang, D.-R.; Song, J.-S.;
Chen, C.-P.; Chen, T.-W.; Lin, C.-H.; Chuu, J.-J.; Lien, T.-W.; Hsu,
T.-A.; Huang, C.-L.; Tseng, H.-Y.; Lin, C.-C.; Lin, H.-L.; Chang, C.-M.;
Chao, Y.-S.; Chen, C.-T. Synthesis and biological evaluation of 2-amino-
1-thiazolyl imidazoles as orally active anticancer agents. Unpublished
results.
(8) Giovannini, R.; Petrini, M. Ruthenium tetroxide catalyzed oxida-
tions of 3-alkyl-4-(2-furyl)-4-oxobutanenitriles: Synthesis of methyl
2-alkyl-3-cyanopropanoates. Tetrahedron Lett. 1997, 38, 3781–3784.
(9) Dotsenko, V. V.; Krivokolysko, S. G.; Chernega, A. N.; Litvinovc,
V. P. A new stereoselective synthesis of 2-amino-4,5-dihydrothiophene-
3-carbonitrile derivatives. Russ. Chem. Bul. 2007, 56, 1431–1436.
(10) Delbecq, F.; Cordonnier, G.; Pommery, N.; Barbrya, D.;
He'nichart, J.-P. New heteroarylbenzenesulphonamides as matrix metallo-
proteinase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 1119–1121.
(11) There is a byproduct, 2-amino-4-(2-furyl)thiazole, generated in
this step. This byproduct was contributed from the reduction of 2-azido-
4-(2-furyl)thiazole.
78
dx.doi.org/10.1021/co1000234 |ACS Comb. Sci. 2011, 13, 72–78