Solid-phase organic synthesis of 1-(E)-phenylethenyl-4-substituted-1,2,3- triazoles from polystyrene-supported (2-azido-1-phenyl)ethyl selenide

Article abstract of DOI:10.3184/174751913X13720644355714

A facile method for solid-phase organic synthesis of 1-(E)-phenylethenyl-4- substituted-1,2,3-triazoles from polystyrene- supported (2-azido-1-phenyl)ethyl selenide and substituted ethynes has been developed. The advantages of this method include straightforward operation, high yield and purity of the products, as well as lack of odour and good stability of the polymeric reagent.

Full text of DOI:10.3184/174751913X13720644355714

422 RESEARCH PAPER
JULY, 422–424
JOURNAL OF CHEMICAL RESEARCH 2013
Solid-phase organic synthesis of 1-(E)-phenylethenyl-4-substituted-1,2,3-
triazoles from polystyrene-supported (2-azido-1-phenyl)ethyl selenide
Mei-Hong Weia, Dan Wua, Rui Suna and Shou-Ri Shenga,b*
aKey Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University, Nanchang, 330022, P. R. China
bCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, P. R. China
A facile method for solid-phase organic synthesis of 1-(E)-phenylethenyl-4-substituted-1,2,3-triazoles from polysty-
rene-supported (2-azido-1-phenyl)ethyl selenide and substituted ethynes has been developed. The advantages of
this method include straightforward operation, high yield and purity of the products, as well as lack of odour and
good stability of the polymeric reagent.
Keywords: Solid-phase organic synthesis, polystyrene-supported (2-azido-1-phenyl)ethyl selenide, 1-(E)-phenylethenyl-4-
substituted-1,2,3-triazoles, cycloaddition, oxidation-elimination
Solid-phase organic synthesis (SPOS) has gained widespread
acceptance in combinatorial chemistry for the high-speed
synthesis of structurally diverse compounds for use in drug
discovery programmes. Synthesis on a solid support shows
a number of advantages over solution chemistry. The most
salient one is the possibility of applying excesses of reagents
and removing them without involving time-consuming separa-
tion techniques.1 Organoselenium reagents have been increas-
ingly used as powerful tools for introducing new functional
groups into organic substrates under extremely mild condi-
tions.2 For example, the phenylseleno group is readily con-
verted into a leaving group giving access to a carbon–carbon
double bond by oxidation followed by β-elimination.3 More-
over, the polymeric selenium reagents4–7 have been now
developed for SPOS with the combined advantage of a decrease
in volatility and a simplification of product work-up.
new simple and efficient traceless solid-phase synthetic approach
to 1-(E)-phenylethenyl-4-substituted-1,2,3-triazoles based on a
novel polystyrene-supported (2-azido-1-phenyl)ethyl selenide
reagent (Scheme 1).
As showed in Scheme 1, polystyrene-supported selenenyl
4
bromide (1) (dark-red resin, Br: 1.25 mmol g–1) was chosen
as the starting material in our initial experiments. Polymeric
selenium resin 1 as prepared from polystyrene by lithiation
and quenching with MeSeSeMe, followed by treatment with
bromine. Reaction of a THF-swollen suspension of resin 1
with LiBH4, followed by treatment with (2-azido-1-iodoethyl)-
benzene20 to afford polymer-supported (2-azido-1-phenyl)ethyl
selenide (3) proceeded readily in excellent yield (>95%, deter-
mined by elemental analysis of the nitrogen: azide loading of
1.12 mmol g–1), which was amenable to FTIR monitoring for
the appearance of the characteristic azido band at 2092 cm–1. It
should be noted, that the non-supported 2-azido-1-phenyl-1-
(phenylseleno)ethane21 is relatively unstable and gradually
decomposes to give a fair amount of crystalline diphenyl disel-
enide after several days even when kept in a freezer under a
nitrogen atmosphere. However, this new reagent appeared to
be quite stable in air at ambient temperature and could be
stored at room temperature for several weeks without diminu-
tion of capacity or the liberation of disagreeable and toxic
odours.
1,2,3-Triazoles are most useful heterocycles8 and have been
widely used in many research fields such as materials and
chemical and biological sciences.9 Because of their impor-
tance, the synthesis of 1,2,3-triazoles from various azides and
alkynes has been widely studied in the solution phase.10–12
Nevertheless, among them, little attention has been paid to the
preparation of 1-phenylethenyl-4-substituted-1,2,3-triazoles.13–15
To our knowledge, only a few papers have reported the solid-
phase synthesis of 1,2,3-triazoles using a selenium linker up to
now.16–18 Furthermore, there are no reported examples involv-
ing the SPOS of phenylethenyl-4-substituted-1,2,3-triazoles.
Therefore, the development of a versatile SPOS procedure for
the synthesis of functionalised 1,2,3-triazoles containing the
phenylethenyl moiety is timely. In continuation of our interest
in solid-phase organoselenium chemistry,19 we now describe a
With resin 3 in hand, [3 + 2] cycloaddition reaction of 3 with
various terminal alkynes, the key for the success of this proto-
col was then investigated. It has been reported that the copper-
catalysed alkyne–azide cycloaddition (CuAAC) is a reliable
means for the synthesis of 1,4-disubstituted-1,2,3-triazoles
exclusively.9–12 Based on these results, phenylacetylene was
Scheme 1
* Correspondent. E-mail: shengsr@jxnu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2013 423
chosen for the template reaction with 3. To optimise reaction
conditions, several solvents such as THF, MeCN, DMF,
DMSO, t-BuOH, CH2Cl2, and their co-solvents were tested in
the same standard reaction in the presence of catalyst (CuSO4/
sodium ascorbate or CuI). After a considerable number of
experiments, the 1,3-dipolar cycloaddition of 3 with phenyl-
acetylene was conducted smoothly in DMF/THF (1/2) in the
presence of triethylamine and 10 mol% of CuI at 65 °C for 6 h,
leading to the polymer-supported (1-phenyl-2-triazolyl)ethyl
selenide (4a). This transformation seemed to be quantitative,
since no characteristic azido absorption at 2092 cm–1 could be
detected in the FTIR spectrum of 4a after completing this
cycloaddition reaction. In the progress of this transformation,
it was found that the signal of the azido group (2092 cm–1) has
been distinctly shrunk after 5 h of reaction time, nearly 90%
conversion of the azido group depending on the transformation
of its IR absorption signal, and another 1h of reaction time led
to an almost complete disappearance of the characteristic azido
absorption.
Subsequently, treatment of resin 4a with 30% hydrogen
peroxide at room temperature afforded the corresponding
1-phenylethenyl-4-phenyl-1,2,3-triazole (5a).14,15 Without fur-
ther purification, the crude product 5a was obtained in high
purity (97%, indicated by HPLC analysis) after removal of
excess cleavage reagent and evaporation of residual solvent.
Then passing the crude product through a flash silica gel
column chromatography eluted with ethyl acetate/hexane
afforded the pure target molecule 5a in 90% yield based on
the loading of resin 3 (Table 1, entry 1). The residual resin,
polystyrene-supported phenylseleninic acid (6), whose IR data
were identical to those previously reported22 showed no resid-
ual triazolyl group. This was confirmed by nitrogen elemental
analysis of resin 6, indicating that the oxidation-elimination
was complete.
To examine the scope of the methodology, a series of
1-phenylethenyl-4-substituted-1,2,3-triazoles (5a–i) were pre-
pared from different terminal alkynes with resin 3 under the
optimised conditions. As seen from Table 1, both aromatic and
aliphatic alkynes underwent the reaction smoothly to afford
the corresponding products 5a–i in good to high yields (83–
91%) with excellent purities (95–98%). Note that all target
compounds were formed with complete (E) stereoselectivities,
which were confirmed by the coupling constants of the olefinic
protons in their 1H NMR spectra. For instance, in the 1H NMR
spectrum of 1-(E)-phenylethenyl-4-(2-nitrophenoxymethyl)-
1,2,3-triazole (5e), the coupling constants (J = 14.8 Hz)
between the two olefinic protons at δ = 7.76 and 7.22 ppm
were observed, which indicated the exclusive production of
the E-isomer. In addition, the 1H NMR spectrum of 5e exhib-
ited a distinct singlet at δ = 8.05 ppm for the triazolyl C5–H
proton, and its IR spectrum displayed C=C olefin absorption at
1658 cm–1, and a characteristic band at 1521 cm–1, indicating
the presence of a nitro group.
In summary, a facile protocol for the solid-phase synthesis
of 1-(E)-phenylethenyl-4-substituted-1,2,3-triazoles has been
developed based on a traceless selenium linker. Simple work-
up, mild reaction conditions and good to high yields make this
methodology attractive and suitable for combinatorial library
production.
Experimental
1
Melting points are uncorrected. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance (400 MHz)
spectrometer, using CDCl3 as the solvent and tetramethylsilane (TMS)
as internal standard. FT-IR spectra were taken on a Perkin-Elmer SP
One FTIR spectrophotometer. Microanalyses were performed with
a Carlo Erba 1106 Elemental Analyzer. High performance liquid
chromatography (HPLC) analysis was performed on Agilent 1100
automated system having a photodiode array (PDA) detector (λmax
=
254 nm used for this study) using a gradient with CH3CN/H2O (1 mL
min−1) on a RP-18e column (150×4.6 mm), and chromatographic peak
areas were used to calculate the purities of crude products. Polysty-
rene (H 1000, 100–200 mesh, cross-linked with 1% divinylbenzene)
was purchased from Nankai University, and the other starting materi-
als were purchased from commercial suppliers and used without
further purification. THF was distilled from sodium-benzophenone
immediately prior to use.
Synthesis of polystyrene-supported (2-azido-1-phenyl)ethyl selenide
(3)
According to the reported procedure,4 polystyrene-supported sele-
nium bromide 1 (loading: 1.25 mmol Br g−1, analysed by elemental
analysis) was prepared from polystyrene by lithiation and quenching
with MeSeSeMe, followed by treatment with bromine. To 1 (1.0 g),
swelled in THF (10 mL) for 30 min, was added NaBH4 (3 mmol)
under nitrogen. After 1 h with stirring at room temperature, a solution
of 2-azido-1-phenyl-1-(phenylseleno)ethane (3 mmol) in THF (2 mL)
was added slowly and the mixture was stirred for 5 h. The resin was
collected on a filter and washed successively with H2O, CH3OH,
CH2Cl2 (2×10 mL of each), and then dried under reduced pressure
overnight to afford pale yellow polystyrene-supported (2-azido-1-
phenyl)ethyl selenide (3) (97.3% yield from selenium bromide resin)
with an azide loading value of 1.12 mmol g−1 (theoretical azide
loading of the resin 1.15 mmol g−1). IR (KBr): νN=N=N = 2092 cm–1.
Synthesis of 1-(E)-phenylethenyl-4-substituted-1,2,3-triazoles (5a–h);
general procedure
To a suspension of the resin 3 (893 mg, 1.0 mmol) pre-swollen in
DMF/THF (1:2, 15 mL) was added alkyne (3.0 mmol), CuI (191 mg,
10 mol%) and Et3N (0.5 mol) and the resulting reaction mixture was
heated to 65 °C and shaken for 6 h under an N2 atmosphere. The resin
4a–h was then collected by filtration and washed successively with
pyridine, CH2Cl2, THF and Et2O (2 × 10 mL of each). Subsequently,
the washed resin 4a–h was suspended in THF (10 mL) and 30%
hydrogen peroxide (0.5 mL, 5.8 mmol) was added; and the suspension
was shaken at room temperature for 30 min. The residual resin was
then collected by filtration and washed with CH2Cl2 (3 × 10 mL). The
filtrate was washed with saturated NaHCO3 (20 mL) and with water,
dried over magnesium sulfate and evaporated to give crude products
5a–h with over 95% purity determined by HPLC, which was further
purified by flash silica gel column chromatography eluted with
ethyl acetate/hexane to provide pure product 5a–h for their structural
analysis.
1-(E)-Phenylethenyl-4-phenyl-1,2,3-triazole (5a): Pale yellow
solid, m.p. 95–96 °C (lit.14 96–98 °C); H NMR: δ = 7.79–7.77 (m,
Table 1 Yields and purities of target molecules (5a–h)
1
2H), 7.72 (s, 1H), 7.42–7.32 (m, 8H), 5.80 (s, 1H), 5.48 (s, 1H); 13C
NMR: δ = 146.6, 142.0, 133.7, 129.2, 128.9, 128.0, 127.8, 127.4,
126.4, 124.8, 118.8, 108.4; IR (film): ν = 3061, 1644, 1021, 898, 763
cm–1. Anal. Calcd for C16H13N3: C, 77.71; H, 5.30; N, 17.00. Found: C,
77.56 H, 5.42; N, 17.11%.
Entry
R
Product Yield/%a Purity/%b
1
2
3
4
5
6
7
8
C6H5
5a
5b
5c
5d
5e
5f
90
91
87
86
85
86
84
83
97
98
97
95
97
96
97
95
4-CH3CH2C6H4
2-CH3C6H4OCH2
2-ClC6H4OCH2
2-NO2C6H4OCH2
4-NO2C6H4OCH2
2-Naphthoxymethyl
n-C4H9
1-(E)-Phenylethenyl-4-(4-ethylphenyl)-1,2,3-triazole (5b): Pale
1
yellow viscous oil; H NMR: δ = 7.90 (s, 1H), 7.71–7.68 (m, 2H),
7.41–7.29 (m, 5H), 7.19–7.12 (m, 2H), 5.78 (s, 1H), 5.47 (s, 1H), 2.60
(q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR: δ = 147.7,
144.6, 143.1, 134.7, 129.9, 128.9, 128.4, 127.7, 127.4, 125.8, 119.5,
109.3, 28.7, 15.5; IR (KBr): ν = 3028, 2964, 1642, 1017, 896, 839,
772 cm–1. Anal. Calcd for C18H17N3: C, 78.52; H, 6.22; N, 15.26.
Found: C, 78.41; H, 6.36; N, 15.38%.
5g
5h
a Overall isolated yields based on polystyrene-supported (2-
azido-1-phenyl)ethyl selenide 3 (azide loading: 1.12 mmol g–1).
b Determined by HPLC of crude cleavage product (λ = 254 nm).

424 JOURNAL OF CHEMICAL RESEARCH 2013
1-(E)-Phenylethenyl-4-(2-methylphenoxymethyl)-1,2,3-triazole
(5c): Pale yellow solid, m.p. 129–130 °C; 1H NMR: δ = 7.90 (s, 1H),
7.77 (d, J = 14.4 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.41–7.32 (m,
3H), 7.19–7.13 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 14.4 Hz,
1H), 5.28 (s, 2H), 2.04 (s, 3H); 13C NMR: δ = 156.4, 145.2, 133.5,
130.8, 129.0, 128.9, 127.0, 126.9, 126.8, 123.0, 122.1, 121.1, 120.0,
111.5, 62.2, 16.3; IR (KBr): ν = 3096, 2927, 1655, 1383, 1021, 950,
752 cm–1. Anal. Calcd for C18H17ON3: C, 74.20; H, 5.88; N, 14.42.
Found: C, 74.35; H, 5.98; N, 14.30%.
135.9, 133.9, 128.7, 128.1, 126.9, 125.7, 118.8, 32.3, 26.0, 22.6, 14.1;
IR (KBr): ν = 3050, 2923, 1655, 1040, 950, 835, 750, 695 cm–1. Anal.
Calcd for C14H17N3: C, 73.98; H, 7.54; N, 18.49. Found: C, 73.85; H,
7.61; N, 18.59%.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 21062007) and the
Research Programme of the Jiangxi Province Department of
Education (No. GJJ10385, GJJ10733 and GJJ11380).
1-(E)-Phenylethenyl-4-(2-chlorophenoxymethyl)-1,2,3-triazole
(5d): Pale yellow solid, m.p. 106–108 °C; 1H NMR: δ = 7.98 (s, 1H),
7.76 (d, J = 15.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.41–7.32 (m, 4H),
7.26–7.19 (m, 2H), 7.15 (d, J = 15.2 Hz, 1H), 6.92–6.89 (m, 1H), 5.34
(s, 2H); 13C NMR: δ = 153.7, 144.4, 133.5, 130.4, 129.0, 128.9, 127.9,
126.8, 123.2, 122.9, 122.2, 120.3, 116.2, 114.3, 63.4; IR (KBr): ν =
3086, 1654, 1242, 1018, 969, 750 cm–1. Anal. Calcd for C17H14ClON3:
C, 65.49; H, 4.53; N, 13.48. Found: C, 65.60; H, 4.63; N, 13.57%.
1-(E)-Phenylethenyl-4-(2-nitrophenoxymethyl)-1,2,3-triazole (5e):
Pale yellow solid, m.p. 134–135 °C; 1H NMR: δ = 8.04 (s, 1H), 7.87
(dd, J = 8.0, 1.2Hz, 1H), 7.76 (d, J = 14.8 Hz, 1H), 7.58–7.54 (m, 1H),
7.48 (d, J = 7.2 Hz, 2H), 7.41–7.30 (m, 4H), 7.22 (d, J = 14.8 Hz, 1H),
7.10–7.06 (m, 1H), 5.42 (s, 2H); 13C NMR: δ = 151.4, 143.6, 140.2,
134.3, 133.4, 129.0, 128.8, 126.8, 125.7, 122.8, 122.4, 121.2, 120.7,
115.4, 63.7; IR (KBr): ν = 3071, 2957, 1658, 1251, 1044, 957, 862,
775, 693 cm–1. Anal. Calcd for C17H14O3N4: C, 63.35; H, 4.38; N,
17.38. Found: C, 63.46; H, 4.49; N, 17.48%.
1-(E)-Phenylethenyl-4-(4-nitrophenoxymethyl)-1,2,3-triazole (5f):
Pale yellow solid, m.p. 149–150 °C; 1H NMR: δ = 8.22–8.19 (m, 2H),
7.99 (s, 1H), 7.77 (d, J = 14.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H),
7.42–7.33 (m, 3H), 7.22 (d, J = 14.8 Hz, 1H), 7.11–7.07 (m, 2H), 5.36
(s, 2H); 13C NMR: δ = 163.0, 143.1, 141.9, 133.3, 129.0, 128.8, 126.8,
126.0, 122.7, 122.6, 120.6, 114.9, 62.3; IR (KBr): ν = 3080, 2930,
1655, 1509, 1018, 951, 868, 751 cm–1. Anal. Calcd for C17H14O3N4: C,
63.35; H, 4.38; N, 17.38. Found: C, 63.23; H, 4.49; N, 17.49%.
1-(E)-Phenylethenyl-4-(2-naphthoxymethyl)-1,2,3-triazole (5g):
White solid, m.p. 158–160 °C; 1H NMR: δ = 7.97 (s, 1H), 7.97–7.74
(m, 4H), 7.48–7.44 (m, 3H), 7.40–7.34 (m, 5H), 7.23–7.20 (m, 1H),
7.19 (d, J = 14.8 Hz, 1H), 5.40 (s, 2H); 13C NMR: δ = 156.1, 144.6,
134.4, 133.5, 129.7, 129.2, 129.1, 128.9, 127.7, 126.9, 126.8, 126.6,
124.0, 122.9, 122.1, 120.1, 118.7, 107.3, 62.0; IR (KBr): ν = 3055,
2917, 1658, 1390, 1043, 951, 837, 749 cm–1. Anal. Calcd for
C21H17ON3: C, 77.04; H, 5.23; N, 12.84. Found: C, 76.91; H, 5.35; N,
12.94%.
Received 12 December 2013; accepted 4 May 2013
Paper 1201676 doi: 10.3184/174751913X13720644355714
Published online: 18 July 2013
References
1
W. Bannwarth, In Combinatorial chemistry: a practical approach;
W. Bannwarth and E. Felder, eds. Wiley-VCH, Weinheim, 2000.
C. Paulmier, Selenium reagents and intermediates in organic synthesis.
Pergamon Press, Oxford, 1986.
2
3
4
H.J. Reich, Acc. Chem. Res., 1979, 12, 22.
K.C. Nicolaou, J. Pastor, S. Barluenga and N. Winssinger, Chem. Commun.,
1998, 1947.
5
6
T. Ruhland, K. Andersen and H. Pedersen, J. Org. Chem., 1998, 63, 9204.
K.-I. Fujita, S. Hashimoto, A. Oishi and Y. Taguchi, Tetrahedron Lett.,
2003, 44, 3793.
7
8
E. Tang, B.Z. Chen, L.P. Zhang, W. Li and J. Lin, Synlett, 2011, 707.
W.Q. Fan and A.R. Katritzky, In Comprehensive heterocyclic chemistry II;
A.R. Katritzky, C.W. Rees and E.F.V. Scriven, eds. Elsevier, Oxford,
1996.
9
A. Krasiski, Z. Radi, R. Manetsch, J. Raushel, P. Taylor, K.B. Sharpless
and H.C. Kolb, J. Am. Chem. Soc., 2005, 127, 6686.
10 M. Meldal and C.W. Tornøe, Chem. Rev., 2008, 108, 2952.
11 F. Amblard, J.H. Cho and R.F. Schinazi, Chem. Rev., 2009, 109, 4207.
12 C.O. Kappe and E. Van der Eycken, Chem. Soc. Rev., 2010, 39, 1280.
13 H. Jiang, Z. Feng, A. Wang, X. Liu and Z. Chen, Eur. J. Org. Chem., 2010,
1227.
14 M. Kavitha, B. Mahipal, P.S. Mainkar and S. Chandrasekhar, Tetrahedron
Lett., 2011, 52, 1658.
15 C.-Z. Tao, X. Cui, J. Li, A.-X. Liu, L. Liu and Q.-X. Guo, Tetrahedron
Lett., 2007, 48, 3525.
16 W-M. Xu, X. Huang and E. Tang, J. Comb. Chem., 2005, 7, 726.
17 Y.-G. Wang, W-M. Xu and X. Huang, Synthesis, 2007, 28.
18 J. Cao and X. Huang, J. Comb. Chem., 2008, 10, 526.
19 X.-C. Mao, X.-L. Liu, Q. Deng and S.-R. Sheng, J. Chem. Res., 2012, 36,
100.
1-(E)-Phenylethenyl-4-(n-butyl)-1,2,3-triazole (5h): Colourless
solid, m.p. 90–91 °C (lit.14 m.p. 92–93 °C); 1H NMR: δ = 7.98 (s, 1H),
7.75 (d, J = 14.8 Hz, 1H), 7.42–7.38 (m, 2H), 7.34–7.27 (m, 3H), 7.15
(d, J = 14.8 Hz, 1H), 2.70 (t, J = 7.2 Hz, 2H), 1.68–1.60 (m, 2H),
1.41–1.39 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H); 13C NMR: δ = 147.2,
20 P.V. Chouthaiwale, P.U. Karabal, G. Suryavanshi and A. Sudalai, Synthesis,
2010, 3879.
21 M. Tingoli, M. Tiecco, D. Chianelli, R. Balducci and A. Temperini, J. Org.
Chem., 1991, 56, 6809.
22 G. Zundel, Angew. Chem., Int. Ed. Engl., 1969, 8, 499.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.