Solid phase synthesis of 4,5-disubstituted 1,2,4-triazol-3-one derivatives from resin-bound acylhydrazines

Article abstract of DOI:10.3184/030823408X314725

A new strategy for solid-phase synthesis of 4,5-disubstituted 2,4-dihydro-3H-1,2,4-triazol-3-ones has been developed. The 4-substituted 5-(4-hydroxyphenyl)-1,2,4-triazol-3-one derivatives were synthesised from resin-bound acylhydrazines in several steps, in good overall yields and purity.

Full text of DOI:10.3184/030823408X314725

216 RESEARCH PAPER
APRIL, 216–217
JOURNAL OF CHEMICAL RESEARCH 2008
Solid phase synthesis of 4,5-disubstituted 1,2,4-triazol-3-one derivatives
from resin-bound acylhydrazines
Zhanxiang Liu*, Yuanyuan Mu and Zhaosheng Song
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P.R. China
A new strategy for solid-phase synthesis of 4,5-disubstituted 2,4-dihydro-3H-1,2,4-triazol-3-ones has been
developed. The 4-substituted 5-(4-hydroxyphenyl)-1,2,4-triazol-3-one derivatives were synthesised from resin-bound
acylhydrazines in several steps, in good overall yields and purity.
Keywords: solid phase synthesis, 1, 2, 4-triazol-3-ones, resin-bound acylhydrazine
With the availability of automated techniques, the solid phase
synthesis of small organic molecules is becoming an important
method for the rapid and easy preparation of libraries of organic
compounds in order to accelerate drug discovery processes.1-3
This approach leads to the rapid synthesis of a large number
of compounds within a short time-frame and facilitates their
use in high throughput screening. Moreover, transferring
traditional solution chemistry to the solid-phase and exploring
new synthetic routes on solid support offers an opportunity for
the development of novel methodologies for the construction
of libraries of small heterocyclic compounds.4-6
1,2,4-Triazol-3-ones are a particularly attractive class
of five-membered heterocyclic ring analogues for their
potential anticonvulsant,7 anti-fungal,8 anti-inflammatory,9
anti-tumor,10 in vitro cyclooxygenase inhibition, and 5-
lipoxygenase activities.11 Recently a series of new triazolones
have been synthesised as cloned mammalian Ca2+-activated
potassium (maxi-K) channel openers,12 PPARs agonist13 and
NK1 antagonist14 agents.
O
a
CH -O
2
C
NH NH
2
1
O
O
CH -O
2
C
C
NHR
NH
NH NH
3
N
b
CH -O
2
O
N
R
4
Substituted 1,2,4-triazol-3-ones have been successfully
prepared by traditional synthesis via acylhydrazines.15-17
All intermediates and products were obtained in required
state of purity by chromatography or recrystallisation. N-
Acylhydrazines are a versatile class of nitrogen substituted
molecules with high degree of chemical reactivity, used as
precursors and intermediates for many important organic
molecules such as heterocycles, pharmaceuticals, polymers,
dyestuffs, and photographic products.18 In continuation of our
ongoing interest in solid-phase synthesis, we have recently
reported an easy method for preparation of polymer-supported
acylhydrazines on Merrifield resin. We have also reported the
synthesis of 1,3,4-oxadiazoline-5-thiones from resin-bound
acylhydrazines.13 To the best of our knowledge, the solid-
phase synthesis of 1,2,4-triazol-3-ones has not been reported
until now. Therefore, we were interested in the development
of benzyl ether-linked acylhydrazine resin in which the linker
group serves not only as a cleavage site of attachment for the
molecule to a solid support, but also as a phenol hydroxyl-
protecting group. Here we describe the solid-phase synthesis
of 5-(4-hydroxyphenyl)-2,4-dihydro-1,2,4-triazol-3-ones from
resin-bound acylhydrazines (Scheme 1).
N
NH
c
HO
O
N
R
5
Scheme 1 Synthesis of triazolones 5 Reactants/conditions:
a, R-N=C=O (2), EtOH, refl; b, 1M Aq. NaOH, EtOH, reflux;
c, TFA/CH2Cl2 (1:4).
to be quite general, both aromatic and aliphatic functionality
being tolerated (Table 1).
The successful formation of resin 3 was confirmed by
a comparative FT-IR study. In the IR spectrum of resin 3
several characteristic signals were present which revealed
the attachment of the moiety to the resin. There were strong
bands at 1685 and 1640 cm-1, typical for the C=O of an
aroylsemicarbazide. When the resin 3 was converted into the
resin 4 the IR peak shifted to 1677 cm-1 corresponding to the
signal for the C=O of a 1,2,4-triazol-3-one. When the resin 4
was cloven by TFA/DCM, the product 5 was obtained in good
yields and high purity.
Results and discussion
We prepared the polymer-supported hydrazide 1 from
Merrifield resin according to our previously reported method.19
The resin-bound acylhydrazine 1 was reacted with excess of
isocyanate 2 at reflux to afford the aroylsemicarbazide resin
3. Further the intramolecular cyclisation of the resin 3 was
carried out in the presence of 1M aqueous NaOH, providing
the 1,2,4-triazol-3-one resin 4 after acidification by HCl (3M).
Release of the final 4,5-disubstituted 1,2,4-triazol-3-one 5 was
effected by cleavage with TFA/CH2Cl2. The reactions appears
In summary, we have developed an novel solid phase
synthetic route toward 1, 2, 4-triazol-3-ones from resin-bound
acylhydrazines. Without column purification, 4, 5-substituted
1, 2, 4-triazol-3-ones can be obtained in good yield and high
purity. We have shown that various alkyl, aryl groups can be
tolerated with this method. Its simple and efficient production
and the mild conditions make it invaluable for application
to the automated synthesis of diverse drug-like molecules.
Further work on the solid phase synthesis of heterocyclic
compounds via the resin-bound acylhydrazines is under way.
* Correspondent. E-mail: liuzhanx@zju.edu.cn
PAPER: 08/5100

JOURNAL OF CHEMICAL RESEARCH 2008 217
4-(3-Chlorophenyl)-5-(4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5e): M.p. 276–278°C. IR: vmax 3204, 1673, 1610, 1598,
1513, 1492, 1432, 1167 cm-1. NMR: δH 6.80 (2H, d, J = 8.4 Hz),
7.04 (1H, m), 7.43 (2H, d, J = 8.4 Hz), 7.71 (2H, m), 10.02 (1H,
s), 12.03 (1H, s).; δC 115.9, 119.8, 121.3, 123.5, 125.1, 128.1, 130.6,
Table 1 Solid-phase synthesis of 1,2,4-triazol-3-ones 5a–h
Entry
Product
R
Yield/%a
Purity/%b
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
Ph
91
87
89
94
84
86
80
86
92
91
93
92
90
92
89
94
2-CH3C6H4
4-CH3OC6H4
4-CH3C6H4
3-ClC6H4
3-CH3C6H4
2,4-F2C6H3
isopropyl
134.2, 138.1, 152.2, 154.9, 159.9. MS (EI, 70 eV): m/z 289 (M+
+
2, 3), 287 (M+, 9), 153 (70), 127 (53), 121 (100). Anal. Calcd. for
C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61. Found C, 58.67; H, 3.63;
N, 14.43%.
5-(4-Hydroxyphenyl)-4-(3-methylphenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5f): M.p. 265–267°C. IR: vmax 3204, 1679, 1610, 1597,
1514, 1490, 1432, 1271, 1228, 1167 cm-1. NMR: δH 2.30 (3H, s), 6.68
(2H, d, J = 8.4 Hz), 6.98 (1H, m), 7.10 (2H, d, J = 8.4 Hz), 7.23 (2H,
m), 9.89 (1H, s), 11.99 (1H, s); δC 21.0, 115.5, 118.0, 125.1, 128.4,
129.3, 129.4, 134.1, 139.1, 145.8, 154.9, 159.0. MS (EI, 70 eV): m/z
267 (M+, 5), 253 (100), 210 (10), 196 (35), 134 (50), 119 (60), 107
(30), 91(42).77(95). Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90;
N, 15.72. Found C, 67.58; H, 4.83; N, 15.48%.
4-(2,4-Difluorophenyl)-5-(4-hydroxyphenyl)-2,4-dihydro-3H-
1,2,4-triazol-3-one (5g): M.p. 282–284°C. IR: vmax 3214, 1676, 1610,
1597, 1514, 1490, 1432, 1167 cm-1. NMR: δH 6.71–6.73 (2H, d,
J = 8.0 Hz), 7.11–7.13 (2H, d, J = 8.0 Hz), 7.25–7.27 (1H, m), 7.61
(1H, m), 9.95 (1H, s), 12.11 (1H, s); δC 106.3, 115.5, 118.2, 122.4,
125.6, 126.5, 128.4, 129.9, 133.4, 139.1, 156.8, 159.4. MS (EI, 70
eV): m/z 287 (M+, 9), 153 (70), 134 (100), 119 (40). Anal. Calcd. for
C14H9F2N3O2: C, 58.14; H, 3.14; N, 14.53. Found C, 57.86; H, 3.42;
N, 14.46%.
5g
5h
aYield of crude product based on the loading of acylhydrazine
resin.
bDetermined by HPLC analysis.
Experimental
1H NMR spectra were recorded on a Bruker Avance (400 MHz)
spectrometer, using DMSO-d6 as solvent and TMS internal standard.
IR spectra were recorded on a Bruker Vector 22 spectrometer in
KBr. Mass spectra were obtained on a HP 5989B MS spectrometer.
Microanalyses were conducted using a Carlo Erba 1106 elemental
analyser. HPLC was performed on an Agilent 1100 (column, ODS
5 μm 250 ¥ 4 mm; mobile phase, MeOH/H2O) 75/25 (v/v); flow
rate, 0.8 ml/min; detector, UV 254 nm). Samples were purified by
recrystallisation for 13C NMR and microanalysis.
5-(4-Hydroxyphenyl)-4-(1-methylethyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5h): M.p. 224–226°C. IR: vmax 3291, 2971, 1661, 1586,
1415, 1311, 1285, 1241 cm-1. NMR: δH 1.36 (6H, d, J = 7.2 Hz), 3.74
(1H, m). 6.89–6.91 (2H, d, J = 8.0 Hz), 7.30–7.32 (2H, d, J = 8.0 Hz),
9.87 (1H, s), 11.66 (1H, s); δC 20.1, 46.6, 118.3, 123.6, 130.6, 147.3,
155.2, 159.4. MS (EI, 70 eV): m/z 219 (M+, 20), 176 (75), 134 (100),
119 (32), 107 (46), 91(35). Anal. Calcd. for C11H13N3O2: C, 60.26;
H, 5.98; N, 19.17; Found C, 60.43; H, 6.22; N, 19.04%.
Synthesis of compound 5a: typical procedure
Resin119 (0.50g,loading1.59mmol/g)andphenylisocyanate(0.286g,
2.4 mmol) in dry EtOH (5 ml) were heated to reflux for 4 h. After
cooling, the resin was filtered off, washed with EtOH and CH2Cl2 to
remove contaminating species, and then dried to provide the resin 3.
To a suspension of resin 3 in EtOH, aqueous NaOH (1M, 5 ml) was
added. Then the mixture was heated to reflux for 10 h. After cooling,
the resin was filtered off and aqueous HCl (3M, 5 ml) was added. The
resin was then washed with DMF (5 ml × 3), H2O (5 ml × 3), EtOH
(5 ml × 3) and CH2Cl2 (5 ml × 3) to remove contaminating species,
and then dried to give the resin 4.
This work was supported by the Foundation of Education
Department of Zhejiang Province grant no. 20 070 015.
Resin 4 was well swollen in CH2Cl2 (4 ml), and TFA (1 ml)
was added. The mixture was stirred at room temperature for 1 h.
The mixture was filtered and the resin was washed with EtOH
(5 mL × 3), then CH2Cl2 (5 ml × 3). The washings were combined
with the filtrate, then concentrated to dryness to give the product 5a.
5-(4-Hydroxyphenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one
(5a): M.p. 263–265°C. IR: vmax 3052, 1678, 1609, 1591, 1451, 1284,
1172 cm-1. NMR: δH 6.68 (2H, d, J = 8.4 Hz), 7.07 (2H, m), 7.24
(2H, d, J = 8.4 Hz), 7.44 (3H, m), 9.89 (1H, s), 12.00 (1H, s); δC
115.5, 117.9, 128.0, 128.7, 129.5, 129.5, 131.8, 134.1, 145.9, 154.8,
157.0. MS (EI, 70 eV): m/z 253 (M+, 100), 210 (25), 196 (30), 134
(95), 119 (30), 107 (40), 77 (43). Anal. Calcd. for C14H11N3O2: C,
66.40; H, 4.38; N, 16.59 Found C, 66.53; H, 4.60.; N, 16.83%.
5-(4-Hydroxyphenyl)-4-(2-methylphenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5b): M.p. 260–262°C. IR: vmax 3203, 1677, 1610, 1597,
1451, 1432, 1271, 1168 cm-1. NMR: δH 2.05 (3H, s), 6.67 (2H, d,
J = 8.4 Hz), 6.83 (2H, m), 7.06 (2H, d, J = 8.4 Hz), 7.21–7.37 (2H,
m), 9.90 (1H, s), 12.01 (1H, s); δC 17.6, 115.8, 118.2, 127.5, 128.8,
129.6, 129.8, 131.4, 133.5, 136.4, 146.0, 154.8, 159.2. MS (EI, 70
eV): 267 (M+, 100), 250 (15), 210 (15), 135 (95), 119 (20), 107 (18),
91(35). Anal. Calcd. for C15H13N3O2: C, 67.40; H, 4.90; N, 15.72.
Found C, 67.56; H, 4.68; N, 15.67%.
5-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5c): M.p. 268–270°C. IR: vmax 3241, 1676, 1612,
1587, 1509, 1301, 1283, 1171 cm-1. NMR: δH 3.77 (3H, s), 6.67–6.69
(2H, d, J = 8.0 Hz), 6.98–7.00 (2H, d, J = 8.4 Hz), 7.09–7.11 (2H, d,
J = 8.0 Hz), 7.15–7.17 (2H, d, J = 8.0 Hz), 9.88 (1H, s), 11.94 (1H,
s); δC 55.7, 114.7, 115.6, 118.1, 126.8, 129.3, 129.4, 146.0, 155.1,
159.0, 159.2. MS (EI, 70 eV): m/z 283 (M+, 90), 226 (15), 134 (100),
119 (20), 107 (25), 91(16). Anal. Calcd. for C15H13N3O3: C, 63.60;
H, 4.63; N, 14.83; Found C, 63.86; H, 4.78; N, 14.62%.
Received 18 February 2008; accepted 19 April 2008
Paper 18/5100 doi: 10.3184/030823408X314725
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5-(4-Hydroxyphenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (5d): M.p. 276–278°C. IR: vmax 3245, 1672, 1605,
1592, 1415, 1311,1282, 1174 cm-1. NMR: δH 2.33 (3H, s), 6.67–6.69
(2H, d, J = 8.4 Hz), 6.81–6.83 (2H, d, J = 8.0 Hz), 7.24 (2H, d,
J = 8.4 Hz), 7.77–7.79 (2H, d, J = 8.0 Hz), 9.89 (1H, s), 11.97 (1H,
s); δC 21.0, 115.4, 118.1, 121.6, 127.8, 130.0, 131.8, 145.9, 154.9,
159.0, 161.9. MS (EI, 70 eV): m/z 267 (M+, 100), 210 (15), 134 (80),
119 (24), 107 (25), 91 (35). Anal. Calcd. for C15H13N3O2: C, 67.40;
H, 4.90; N, 15.72. Found C, 67.28; H, 5.03.; N, 15.64%.
PAPER: 08/5100