PEG-supported synthesis of 3,5-disubstituted 1,2,4-triazoles

Article abstract of DOI:10.1055/s-2005-865209

1,3-Dipolar cycloadditions between diethyl azodicarboxylate and the polymer-bound munchnones generated from the corresponding carboxylic acids provided a library of 3,5-disubstituted 1,2,4-triazoles in excellent yield and high purity.

Full text of DOI:10.1055/s-2005-865209

LETTER
1135
PEG-Supported Synthesis of 3,5-Disubstituted 1,2,4-Triazoles
P
E
G
-Supp
u
orted Synthe
n
sis of 3,5-Di
-
substitut
K
ed 1,2,4-Triazolese Wang,* Ying-Xiao Zong, Guo-Ren Yue
Key Laboratory of Resources and Environment Chemistry of West China, Department of Chemistry, Hexi University,
Zhangye 734000, P. R. China
Fax +86(936)8282045; E-mail: wangjk@hxu.edu.cn
Received 18 February 2005
medicinal chemistry. Solution method for their synthesis
by the reaction of munchnones with diethyl azodicarbox-
ylate (DEAD) was firstly reported by the Huisgen group.4
In connection with our research on the PEG-supported liq-
uid-phase synthesis,5 we wish to report herein the parallel
synthesis of 3,5-disubstituted-1,2,4-triazoles through a
cycloaddition between diethyl azodicarboxylate and
munchnones on PEG support.
Abstract: 1,3-Dipolar cycloadditions between diethyl azodicar-
boxylate and the polymer-bound munchnones generated from the
corresponding carboxylic acids provided a library of 3,5-disubsti-
tuted 1,2,4-triazoles in excellent yield and high purity.
Key words: PEG-bound munchnones, diethyl azodicarboxylate,
cycloadditions, 1,2,4–triazoles, parallel synthesis
As described in Scheme 1, the commercially available
methanesulfonyl chloride was attached to the PEG6000
support by esterification of PEG with methanesulfonyl
chloride in anhydrous CH2Cl2 at room temperature for 8
hours. The conversion of the terminal hydroxyl groups on
Recently, organic synthesis of small molecular com-
pounds on soluble polymers, i.e. liquid-phase chemistry,
has been the focus of intense research activity.1 It couples
the advantages of homogeneous solution chemistry (high
reactivity, lack of diffusion phenomena, and ease of anal-
ysis without the cleavage-and-check procedure) with
those of solid-phase chemistry (use of an excess amount
of reagents, easy isolation, and purification of product).
Among the various soluble polymers, polyethylene glycol
(PEG) has increasingly become attractive as a solid
support.2
1
PEG was determined by H NMR analysis to be quan-
titative. The PEG-bound 1 reacted with 4-hydroxy-2-
methoxybenzaldehyde in the presence of potassium car-
bonate at 60 °C for 10 hours to give immobilized PEG-
bound aldehyde 2 in high yield. In general, the progress of
both formation of sulfonic acid ester and the etherification
was routinely determined by 1H NMR spectroscopy.6
Substituted 1,2,4-triazoles offer a high degree of structur-
al diversity and possess a broad spectrum of biological ac-
tivity,3 therefore, they have become very important in
After treatment with (R)-(–)-2-phenylglycine methyl ester
in the presence of sodium triacetoxyborohydride, the
Scheme 1
SYNLETT 2005, No. 7, pp 1135–1136
0
2.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865209; Art ID: U04505ST
© Georg Thieme Verlag Stuttgart · New York

1136
J.-K Wang et al.
LETTER
aldehyde 2 was converted into corresponding PEG-bound In conclusion, we have demonstrated a soluble polymer-
amino acid ester 3. Amino acid ester 3 was acylated with supported methodology for the efficient parallel synthesis
a variety of carboxylic acid chlorides and subjected to of 3,5-disubstituted 1,2,4-triazoles. Due to the homogene-
hydrolysis with 10% NaOH to yield the polymer-bound ity of the reactions on PEG support, products were ob-
carboxylic acids 5, which are precursors to the corre- tained in good yields under mild conditions. All the
sponding munchnones (Figure 1).
reactions furnished the desired compound in high yield.
Crude products are usually obtained in high purity and
high yield just by simple precipitation and washing,
allowing their direct use in primary biological assays
without further purification.
OMe
O–
+
N
O
O
R
Acknowledgment
Figure 1
The authors thank the Natural Science Foundation of Gansu
Province (ZS021-A25-006-Z) for financial support of this work.
Table 1 Liquid-Phase Synthesis of 3,5-Disubstituted 1,2,4-Tri-
azoles on PEG Support
References
Compd.
7a
R
Yield (%)a
Purity (%)b
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C6H5
93
92
94
87
88
94
90
89
92
88
95
92
96
93
97
92
98
96
96
92
95
95
7b
7c
2-CH3C6H4
3-CH3C6H4
3-NO2C6H4
4-NO2C6H4
4-CH3OC6H4
4-EtC6H4
4-ClC6H4
4-FC6H4
7d
7e
7f
7g
7h
7i
7j
4-IC6H4
7k
2-Naphthyl
a The yield is based on the PEG-6000.
b Purity is based on analysis by 1H NMR and HPLC (UV detector at
280 nm) of crude products.
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PEG-bound munchnones are key intermediates, which re-
acted with diethyl azodicarboxylate in CH2Cl2 to afford
PEG-bound 3,5-disubstituted 1,2,4-triazoles 6. Com-
pounds 1–6 were purified by precipitation and washing
with diethyl ether. The whole course of the reactions was
monitored directly by 1H NMR without detaching materi-
al from the PEG support. PEG-bound 6 was efficiently
cleaved from the support by 25% TFA/H2O at room
temperature within one hour to provide the desired
compounds 7.7
(6) The polymer-bound 1 was characterized by 200 MHz 1H
NMR analysis in CDCl3: d = 3.08 (3 H, s, CH3SO2), 3.52–
3.74 (PEGO-CH2CH2O, m). The polymer-bound 2 was
characterized by 200 MHz 1H NMR analysis in CDCl3: d =
3.66–3.87 (PEG, m), 4.20 (t, 2 H, -PEGOCH2CH2OC=O),
6.42 (1 H, d), 6.47 (1 H, d,) 7.38 (1 H, d), 8.59 (1 H, s).
(7) All the compounds were characterized and their structures
were confirmed by spectrometric methods (1H NMR, 13
C
NMR, MS) and elemental analysis. Compound 7f is as
follow: 1H NMR (400MHz, CD3OD): d = 3.84 (3 H, s),
7.03–7.06 (2 H, dt, J = 2.4, 9 Hz), 7.47–7.50 (3 H, m), 7.96–
7.99 (2 H, dt, J = 2.4, 9 Hz), 8.04–8.07 (2 H, m); 13C NMR
(CD3OD): d = 56.1, 115.5, 115.6, 127.8, 129.4, 129.4, 130.3,
130.6, 131.2, 131.4, 162.9; MS (EI): m/z = 251 (M+); Anal.
Calcd for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found: C,
71.52; H, 5.29; N, 16.64.
A variety of 3,5-disubstituted 1,2,4-triazoles were synthe-
sized using this procedure. As shown in Table 1, the
yields are good to excellent (87–94%) and the purity is
satisfactory (≥92%).
In order to extend the scope of the method, our research
group is utilizing various amino acids to examine the
synthesis of triazoles.
Synlett 2005, No. 7, 1135–1136 © Thieme Stuttgart · New York