Liquid-phase traceless synthesis of 3,5-disubstituted 1,2,4-triazoles

Article abstract of DOI:10.1055/s-2005-917107

A liquid-phase traceless route to 3,5-disubstituted-1,2,4-triazoles has been developed, which allows for the incorporation of two elements of diversity. The heterocycle was constructed upon PEG6000 (soluble polymer) modified by 4-hydroxy-2-methoxy-benzaldehyde, from which a traceless cleavage could be realized with TFA-CH₂Cl₂. This method provided a library of 3,5-disubstituted-1,2,4-triazoles with high yields and purity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917107

LETTER
2595
Liquid-Phase Traceless Synthesis of 3,5-Disubstituted 1,2,4-Triazoles
S
ynthesis of 3,5-D
i
isubstit
-
uted-1,2
C
,4-Triazoles un Wang,*a Jun-Ke Wang,a,b Dong-Qing Wu,b Ying-Xiao Zongb
a
Gansu Key Laboratory of Polymer Materials, Northwest Normal University, College of Chemistry and Chemical Engineering,
Lanzhou 730070, P. R. of China
b
Key Laboratory of Resources and Environment, Chemistry of West China, Department of Chemistry, Hexi University, Zhangye 734000,
P. R. of China
Fax +86(936)8284286; E-mail: wangjk@hxu.edu.cn
Received 25 July 2005
would be of great value for drug discovery. The Yli-
Kauhaluoma8 group was the first to report the solid-phase
synthesis of 1,2,4-triazoles by the reaction of münchnones
with diethyl azodicarboxylate (DEAD) according to
Abstract: A liquid-phase traceless route to 3,5-disubstituted-1,2,4-
triazoles has been developed, which allows for the incorporation of
two elements of diversity. The heterocycle was constructed upon
PEG6000 (soluble polymer) modified by 4-hydroxy-2-methoxy-
benzaldehyde, from which a traceless cleavage could be realized Huisgen’s method.9 We have successfully translated
the solid-phase synthesis onto PEG support.3d
with TFA–CH2Cl2. This method provided a library of 3,5-disub-
Hitostuyanagi’s group10 has recently started from Boc-
stituted-1,2,4-triazoles with high yields and purity.
Key words: soluble polymer, 1,2,4-triazoles, Lawesson’s reagent,
cyclization reaction, traceless cleavage
thionotripeptides and performed cyclization only with
formic hydrazide to prepare 1,2,4-triazole derivatives.
According to this method, Fehrentz’s group reported
solid-supported synthesis of 3,4,5-trisubstituted 1,2,4-tri-
Solid-phase synthesis along with high-throughput screen- azoles with high purity.11
ing has emerged as a powerful tool for the discovery of
As part of our continuing effort to adapt heterocyclic
novel drug candidates.1 However, solid-phase synthesis
suffers from various problems, such as the heterogeneous
nature of the reaction condition, reduced rate of reactions,
and mass transport of reagents.
methods to a high-throughput synthesis format, we report
here our preliminary study in soluble polymer-supported
synthesis of 3,5-disubstituted-1,2,4-triazoles. The syn-
thetic route to the targeted molecule is outlined in
Recently, organic synthesis of small molecular com- Scheme 1. PEG-6000 was modified with the commer-
pounds on soluble polymers, i.e. liquid-phase chemistry, cially available methanesulfonyl chloride to afford the im-
has been a focus of intense research activity.2 In an effort mobilized 1 in quantitative yield.3d The PEG-bound 1
to develop a method for the rapid parallel synthesis of reacted with 4-hydroxy-2-methoxy-benzaldehyde (this
chemical libraries, we have been exploring liquid-phase linker may realize the cleavage of C–N bond8,12) in the
combinatorial synthesis (LPCS) by the use of soluble presence of potassium carbonate at 60 °C for ten hours to
polymer support poly(ethylene glycol) to generate librar- give immobilized PEG-bound aldehyde 2, which was
ies.3 Unlike an insoluble matrix, the soluble polymer converted to PEG-supported oxime 3 with hydroxylamine
support (PEG) couples the advantages of homogeneous hydrochloride in the presence of pyridine. The resultant
solution chemistry (high reactivity, lack of diffusion compound was reduced to PEG-supported benzylamine 4
phenomena and ease of analysis without the cleavage- with 1 M LiAlH4 in THF.13
and-check procedure) with those of solid-phase chemistry
(use of excessive regents and easy isolation and purifi-
cation of product). Among the various soluble polymers,
The first point of diversity of 4 is then incorporated by
several arylacyl chlorides in CH2Cl2 in the presence of tri-
ethylamine to give polymer-supported 5. The reaction
polyethylene glycol (PEG) has increasingly become an
proceeds well with various acyl chlorides without any un-
attractive support.4
expectedness. After reaction with Lawesson’s reagent,14
1,2,4-Triazole system has been known to be an important PEG-supported 5 was transformed to the corresponding
recognition element in biologically active molecules. This thioamide 6. This transformation is performed smoothly.
moiety was also found in potent agonist or antagonist re- The remaining step for completing the synthetic sequence
ceptor ligands.5 1,2,4-Triazole derivatives have been used involves a key cyclization of 7 with arylacyl hydrazide.
as mimics6 of the amide bond in attempts to increase bio- This cyclization reaction proceeds smoothly in the pres-
availability of the parent bioactive molecules. They have ence of mercury(II) acetate in acetonitrile after standing
also been incorporated into peptides to surrogate cis- 30 hours at room temperature. In general, the progress of
amide bonds.7 Therefore, a practical method for accelerat- the formation of 1,2,4-triazole was routinely determined
ing synthesis of diverse collection of 1,2,4-triazoles by IR spectroscopy (observing the disappearance of the
peak of –NH–). Compounds 1–7 were purified by precip-
itation and washing with diethyl ether. Whether the inter-
mediates formed was estimated directly by H NMR
without detaching the material from the PEG support.
SYNLETT 2005, No. 17, pp 2595–2598
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917107; Art ID: U23705ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5
1

2596
X.-C. Wang et al.
LETTER
OMe
CHO
K2CO3, DMF
OMe
CHO
HO
MeSO2Cl
PEG
OH
PEG
OMe
O
SO2Me
PEG
O
Pyridine, CH2Cl2, r.t.
1
2
OMe
NH2OH·HCl
1 M LiAlH4,
THF
PEG
PEG
O
O
PEG
O
pyridine
NH2
NOH
4
3
5
OMe
O
OMe
S
O
R1 CCl
Lawesson's reagent
THF
PEG
R1
O
R1
N
N
H
Et3N
H
6
OMe
R1
H
N
arylacyl hydrazides
Hg(OAc)2, r.t.
TFA/CH2Cl2
r.t.
R2
R1
PEG
O
N
N
N
N
N
7
8
R2
Scheme 1
terized by 200 MHz 1H NMR analysis in CDCl3: d = 3.08 (3 H, s,
CH3SO2), 3.52–3.74 (m, PEG–O–CH2CH2O). The polymer-sup-
ported 2 was characterized by IR analysis (1676 cm–1) and 200 MHz
1H NMR analysis in CDCl3: d = 3.66–3.87 (m, PEG), 4.20 (2 H, t,
PEG–OCH2CH2OC=O), 6.42 (1 H, s), 6.47 (1 H, d,) 7.38 (1 H, d),
8.59 (1 H, s).
Polymer-supported products 7 are subjected to a very ef-
ficient cleavage from the support with 30% TFA–CH2Cl2
at room temperature for about two hours to provide the de-
sired compounds 8 in 75–90% overall yield for eight steps
(Table 1). By employing the desired reaction sequence, a
validated library containing a diverse set of compounds is
synthesized. The structures, yields and purities obtained
for representative sets of compounds are summarized in
Table 1. As shown in Table 1, whether positions 3 and 5
of the target compounds are benzene rings or non-benzene
rings, the expected compounds were obtained in good
yield and good purity.
Preparation of PEG-Supported 3
PEG-supported 2 (1 mmol) was added into the mixture (30 mL) of
pyridine and EtOH (1:10, v/v). Hydroxylamine hydrochloride (5
mmol) was added into the mixture stirred for 15 h at 50 °C followed
by being cooled in an icebox. After 6 h, the system was filtred and
washed in Et2O to obtain PEG-supported 3, which was stored to be
used in the next step of the synthesis. IR indicates complete dis-
appearance of the carbonyl peak at 1676 cm–1.
Each crude product is then analyzed by HPLC, which
shows around 82–92% purity. Because compound librar-
ies are usually not purified before biological screening,
crude products of high purity obtained from our liquid-
phase protocol are especially valuable.
Preparation of PEG-Supported 4
To a solution of PEG-supported oxime 3 (1 mmol) in THF (20 mL)
was added 1 M LiAlH4 in THF. The mixture was refluxed for 10 h,
before the reaction mixture was cooled to 0 °C. Then, EtOH was
added to quench the excess LiAlH4, and then filtration was conduct-
ed. The resultant filtrate was condensed followed by the addition of
Et2O to give PEG-supported benzylamine 4.
In conclusion, we have successfully developed an expedi-
ent synthesis sequence for effective preparation of the 3,5-
disubstituted 1,2,4-triazoles using PEG-6000 as support.
In each step of the reaction sequence, the immobilized
intermediates were purified by simple precipitation and
washing after the reactions were completed. Crude prod-
ucts are usually obtained in high purity and high yields
just by simple work up. Furthermore, the desired com-
pounds contain –NH, so if the diversity of molecule will
be increased, some electrophilic reagent, such as haloge-
nated hydrocarbon and acyl chloride, reacted with them to
obtain 3,4,5-trisubstituted 1,2,4-triazoles. Synthesis and
screening of combinatorial libraries based on pharma-
cophoric scaffolds may lead to the discovery of interesting
biological activities.
Preparation of PEG-Supported 6
Lawesson’s reagent (3 mmol) was added to the PEG-supported 5 (1
mmol) in THF (20 mL) and place under stirring at 60 °C for 2 h. The
solvent was removed under vacuum, and Et2O (20 mL) was added
to precipitate the solid that was the desired compound.
Preparation of PEG-Supported 7
A mixture of PEG-supported 6 (1 mmol) and arylacyl hydrazide (4
mmol) in MeCN (30 mL) was treated with (4 mmol) of Hg(OAc)2
for 30 h at r.t., and then it was filtered. The obtained filtrate was con-
centrated under vacuum and Et2O was added to the solution to pre-
cipitate the PEG-supported triazoles 7.
Preparation of the Desired Compounds 8
The PEG-supported 1,2,4-triazoles 7 was cleaved with 30% TFA–
CH2Cl2 at r.t. for 2 h. Then, CH2Cl2 was removed, and H2O was
added into the residue to give the desired compounds, which were
purified by chromatography on silica gel to obtain the analytical
samples.
The Typical Procedure – Preparation of PEG-Supported 1 and
2
According to the literature 3d, 1 and 2 were synthesized successful-
ly without any unexpectedness. The polymer-bound 1 was charac-
Synlett 2005, No. 17, 2595–2598 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5-Disubstituted-1,2,4-Triazoles
2597
Table 1 Synthesis of 3,5-Disubstituted-1,2,4-triazoles 8 on the PEG
Entry
1
Compd
8a
R1
R2
Yield (%)a
82
Purity (%)b
C6H5
4-CH3C6H4
4-ClC6H4
C6H5
90
90
88
92
87
89
88
92
90
86
89
90
90
86
91
96
94
2
8b
8c
C6H5
87
3
C6H5
85
4
8d
8e
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
CH3
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
C6H5
79
5
90
6
8f
80
7
8g
88
8
8h
8i
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
C6H5
75
9
78
10
11
12
13
14
15
16
17
8j
80
8k
8l
79
4-NO2C6H4
4-CH3C6H4
4-ClC6H4
4-NO2C6H4
CH3
80
8m
8n
8o
90
84
86
8p
8q
80
Benzyl
H
86
a Determined on weight of crude sample.
b Purity determined by HPLC analysis of crude products which show satisfactory IR, 1H NMR and mass data.15
(5) (a) Chen, C.; Dagnino, R.; Huang, C. Q.; McCarthy, J. R.;
Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2001, 11, 3165.
(b) Jenkins, S. M.; Wadsworth, H. J.; Bromidge, S.; Orlek,
B. S.; Wyman, P. A.; Riley, G. J.; Hawkins, J. J. Med. Chem.
1992, 35, 2392.
Acknowledgment
We thank the department of science and technology of Hexi Uni-
versity for the financial support.
(6) (a) Burrell, G.; Evans, J. M.; Hadley, M. S.; Hicks, F.;
Stemp, G. Bioorg. Med. Chem. Lett. 1994, 4, 1285.
(b) Tully, W. R.; Gardner, C. R.; Gillepsie, R. J.; Westwood,
R. J. Med. Chem. 1991, 34, 2060.
(7) Duncia, J. V.; Santela, J. B. III; Higley, A.; VanAtten, M. K.;
Weber, P. C.; Alexander, R. S.; Kettner, C. A.; Pruitt, J. R.;
Liauw, A. Y.; Quan, M. L.; Knabb, R. M.; Wexler, R. R.
Bioorg. Med. Chem. Lett. 1998, 8, 775.
(8) Samanta, S. K.; Yli-Kauhaluoma, J. J. Comb. Chem. 2005,
7, 142.
(9) Brunn, E.; Funke, E.; Gotthardt, H.; Huisgen, R. Chem. Ber.
1971, 104, 1562.
(10) Hitostuyanagi, Y.; Motegi, S.; Fukaya, H.; Takeya, K. J.
Org. Chem. 2002, 67, 3266.
(11) Boeglin, D.; Cantel, S.; Heitz, A.; Martinez, J.; Fehrentz, J.-
A. Org. Lett. 2003, 5, 4465.
(12) Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-Kauhaluoma, J.
J. Comb. Chem. 2003, 5, 826.
(13) Pietta, P. G.; Cavallo, P. F.; Takahashi, K.; Marshall, G. R.
J. Org. Chem. 1974, 39, 44.
References
(1) (a) Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17. (b) Lorsbach, B. A.; Kurth, M. J. Chem. Rev.
1999, 99, 1549. (c) Dolle, R. E. J. Comb. Chem. 2003, 5,
693.
(2) (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489.
(b) Wentworth, P.; Janda, K. D. Chem. Commun. 1999,
1917. (c) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33,
546.
(3) (a) Li, Z.; Wang, J. K.; Wang, X. C. Synth. Commun. 2003,
33, 3567. (b) Wang, X. C.; Wang, J. K.; Li, Z. Chin. Chem.
Lett. 2004, 15, 635. (c) Wang, J. K.; Zong, Y. X.; An, H. G.;
Xue, G. Q.; Wu, D. Q.; Wang, Y. S. Tetrahedron Lett. 2005,
46, 3797. (d) Wang, J. K.; Zong, Y. X.; Yue, G. R. Synlett
2005, 1135. (e) Wang, J. K.; Zong, Y. X.; Yue, G. R.; An, H.
G.; Wang, X. C. J. Chem. Res., Synop. 2005, 335.
(4) (a) Zhao, X.; Metz, W. A.; Sieber, F.; Janda, K. D.
Tetrahedron Lett. 1998, 39, 8433. (b) Blettner, C. G.;
Konig, W. A.; Quhter, G.; Stenzel, W.; Schotten, T. Synlett
1999, 307. (c) Racker, R.; Doring, K.; Reiser, O. J. Org.
Chem. 2000, 65, 6932. (d) Luisa, G.; Giorgio, M.; Pietro, C.
J. Chem. Soc., Perkin Trans. 1 2002, 2504.
Synlett 2005, No. 17, 2595–2598 © Thieme Stuttgart · New York

2598
X.-C. Wang et al.
LETTER
1680, 2866, 3148 cm–1. MS (EI): m/z = 281 [M+]. Anal.
(14) (a) Clausen, K.; Thorsen, M.; Lawesson, S. O. Tetrahedron
1981, 37, 3635. (b) Majer, Z.; Zewdu, M.; Hollosi, M.;
Seprodi, J.; Vadasz, Z.; Teplan, I. Biochem. Biophys. Res.
Commun. 1988, 150, 1017. (c) Pons, J. F.; Mishir, Q.;
Nouvet, A.; Brookfield, F. Tetrahedron Lett. 2000, 41, 4965.
(15) All the compounds were characterized and their structures
were confirmed by spectrometric methods (1H NMR, IR and
MS) and elemental analysis.
Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found:
C, 68.39; H, 5.31; N, 14.90.
For compound 8i: 1H NMR (400 MHz, DMSO-d6): d = 3.86
(3 H, s), 7.03–7.08 (2 H, m), 7.44–7.52 (2 H, m), 7.57–7.79
(4 H, m). IR: 1570, 1694, 2891, 3133 cm–1. MS (EI): m/z =
285 [M+]. Anal. Calcd for C15H12ClN3O: C, 63.05; H, 4.23;
N, 14.71. Found: C, 63.17; H, 4.24; N, 14.68.
For compound 8e: 1H NMR (400 MHz, DMSO-d6): d = 3.86
(6 H, s), 7.04–7.06 (4 H, m), 7.93–7.96 (4 H, m). IR: 1575,
Synlett 2005, No. 17, 2595–2598 © Thieme Stuttgart · New York