Rapid, microwave-assisted synthesis of N1-substituted 3-amino-1,2,4-triazoles

Article abstract of DOI:10.1016/j.tetlet.2008.12.042

A robust, regioselective synthesis of 3-amino-1,2,4-triazoles is described. This reaction employs a key intermediate 2, which is coupled to carboxylic acids in good yields to afford intermediates 3a-d. These entities, in turn, react with a variety of hydr

Full text of DOI:10.1016/j.tetlet.2008.12.042

Tetrahedron Letters 50 (2009) 1667–1670
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Tetrahedron Letters
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Rapid, microwave-assisted synthesis of N1-substituted 3-amino-1,2,4-triazoles
*
Jerry Meng, Pei-Pei Kung
Pfizer Global Research and Development, La Jolla Laboratories, 10770, Science Center Dr., San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A robust, regioselective synthesis of 3-amino-1,2,4-triazoles is described. This reaction employs a key
intermediate 2, which is coupled to carboxylic acids in good yields to afford intermediates 3a–d.
These entities, in turn, react with a variety of hydrazines or hydrazine hydrochlorides to provide pro-
posed intermediates 4a–j, which under microwave conditions cyclize to the desired 3-amino-1,2,4-tri-
azoles (compounds 5a–j). This approach permits the rapid synthesis of regioselective N1-substituted
3-amino-1,2,4-triazoles, and is shown to afford a variety of such compounds in 34–70% isolated
yields.
Received 22 November 2008
Revised 8 December 2008
Accepted 9 December 2008
Available online 16 December 2008
Ó 2009 Elsevier Ltd. All rights reserved.
N1-substituted 3-amino-1,2,4-triazoles have shown numerous
beneficial pharmaceutical properties and have been utilized as
antiviral agents,1 CCK-A agonists,2 and urinary tract antibacterial
agents.3 As part of our efforts to develop novel anticancer drugs,
entry 1).9 The position of the 4-fluorobenzyl group present in
compound 5a was determined by 2D-NOESY-1H NMR (Fig. 1).
This substitution position is consistent with a proposed tria-
zole-forming reaction sequence in which the unsubstituted
hydrazine nitrogen displaces the thioether present in compound
3a to afford intermediate 4a. Excess hydrazine then cleaves the
carbamate group at the C3 amino moiety either before or after
the intramolecular cyclization/dehydration10 affords the observed
amino-triazole product (route A, Scheme 1). This sequence of
microwave-assisted chemical reactions is supported by the
observation of 5a in the crude reaction mixture by LC–MS with
no detection of the other possible cyclized product (6a, route
B, Scheme 1). Compounds 3a–d reacted with (4-fluorobenzyl)-
hydrazine to afford the corresponding amino-triazole products
(5a–d) in 50–70% isolated yields following preparative reverse
phase HPLC.
Six additional compounds containing a 2,4-dichloro-benzyl
substituent at the C5 position were then synthesized using the
method described above. The results of the yields for the last two
steps and the analytical data (1H NMR and microanalysis) for the
final compounds are summarized in Table 2. Based on these re-
sults, independent of the nature of the hydrazines, this micro-
wave-assisted cyclization reaction for the formation of N1-
substituted 1,2,4-triazoles gave 34–70% isolated yields following
preparative reverse phase HPLC.
we required
a rapid, divergent synthesis of such molecules
which could be performed in a parallel manner and which would
provide sufficient amounts of purified materials for multiple bio-
logical assessments (>100 mg). Unfortunately, none of the exist-
ing methods for 3-amino-1,2,4-triazole synthesis met our needs
since they were (1) limited in scope,4 (2) not regiospecific,5 or
(3) performed on solid phase which limited the scale of prepara-
tion.6,7 Accordingly, we sought to develop a new method for the
synthesis of the desired compounds which (1) would incorporate
at least two diverse functional points on the triazole core, (2)
would utilize commercially available starting materials, (3)
would allow the parallel generation of a large number of triazole
products in high yield, and (4) would provide the desired com-
pounds in larger quantities (>100 mg). The results of our efforts
are described below.
Commercially available carbonic acid benzyl ester 4-nitro-
phenyl ester (1) was reacted with S-methylisothiouronium sul-
fate to give the key intermediate 2 in 95% yield (Scheme 1).8
Compound 2 was coupled with four different carboxylic acids
using EDC/HOBt to give intermediates 3a–d. These intermediates
were purified by silica gel chromatography and were subse-
quently reacted with various hydrazines under microwave condi-
tions to afford the triazole products. For example, condensation
of 3a with (4-fluorobenzyl)-hydrazine in a microwave at 160 °C
for 30 min afforded a 70% isolated yield of compound 5a (Table 1,
In summary, we report a microwave-assisted synthesis of N1-
substituted 1,2,4-triazoles in reasonable yields. This three-step
methodology using commercially available carboxylic acids and
hydrazines can generate regioselective N1-substituted 1,2,4-tria-
zoles in an efficient way. In addition to these advantages, the tria-
zoles synthesized can serve as starting materials for further
acylation11–13 or alkylation14 to afford tri-substituted trizoles with
regioselective substitution patterns.
* Corresponding author.
E-mail address: peipei.kung@pfizer.com (P.-P. Kung).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.042

1668
J. Meng, P.-P. Kung / Tetrahedron Letters 50 (2009) 1667–1670
NO2
O
O
S
O
O
S
b
a
Ph
O
O
Ph
O
N
3a-d
c
N
H
R1
Ph
O
N
NH2
1
2
R2
R2
NH
1
N
N
N
O
HN
O
R1
5
A
3
H2N
Ph
O
N
N
R1
5a-j
H
4a-j
B
R2
O
N
NH
O
N
H
R1
N
6a-j
Scheme 1. Reagents and conditions: (a) 2-methyl-2-thiopseudourea sulfate, DMF, 23 °C, 12 h, 95%; (b) carboxylic acid, 4-methylmorpholine, N-(3-dimethylaminopropyl)-N0-
ethylcarbodiimide hydrochloride, 1-hydroxy benzotriazole, DMF, 23 °C, 12 h, 40%; (c) substituted hydrazine, triethylamine, microwave, 160 °C, 30 min, 34–70%.
Table 1
F
N
N
R1
N
H2N
5a-d
Entry
R1
Isolated
yield (%)
1H NMR (DMSO-d6) ppm
CHN
Cl
5a
70
4.19 (s, 2H) 5.19 (s, 2H) 7.12–7.19 (m, 2H) 7.24–7.31 (m,
2H) 7.31 (s, 1H) 7.34–7.39 (m, 1H) 7.58 (d, J = 2.02 Hz,
1H)
C16H13Cl2FN4ꢀ0.4H2O: C, 53.62; H, 3.88; N, 15.63.
Observed: C, 53.58; H, 3.97; N, 15.63.
Cl
5b
5c
48
56
1.10 (d, J = 6.82 Hz, 6H) 3.02–3.14 (m, 1H) 5.09 (s, 2H)
5.15 (s, 2H) 7.09–7.20 (m, 2H) 7.20–7.30 (m, 2H)
C12H15FN4ꢀ0.33HOAc: C, 59.84; H, 6.47; N, 22.05.
Observed: C, 59.75; H, 6.52; N, 21.97.
1.50–1.75 (m, 6H) 1.78–1.91 (m, 2H) 3.19 (t, J = 7.83 Hz,
1H) 5.10 (s, 2H) 5.15 (s, 2H) 7.12–7.21 (m, 2H) 7.22–7.28
(m, 2H)
C14H17FN4ꢀ0.45H2O: C, 62.65; H, 6.72; N, 20.87.
Observed: C: 62.65, H: 6.53, N: 20.53.

J. Meng, P.-P. Kung / Tetrahedron Letters 50 (2009) 1667–1670
1669
Table 1 (continued)
Entry
R1
Isolated
yield (%)
1H NMR (DMSO-d6) ppm
CHN
N
5d
56
5.50 (s, 2H) 5.81 (s, 2H) 7.08–7.20 (m, 2H) 7.26–7.36 (m,
2H) 7.44–7.53 (m, 1H) 7.92–8.01 (m, 1H) 8.00–8.08 (m,
1H) 8.70
C14H12FN5ꢀ0.39H2O: C, 60.86; H, 4.66; N, 25.35.
Observed: C, 60.87; H, 4.78; N, 25.23.
(d, J = 4.04 Hz, 1H).
ADB-22726.005.000.ser.esp
F
21
10 11
4.0
12
6
9
19-13
6-13
8
7
Cl
18
23
4.5
5.0
5.5
6.0
6.5
7.0
7.5
17
19
14
N
N
16
2
1
15
3
5
8/12-6
H N
13
2
N
20
Cl
4
22
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
F2 Chemical Shift (ppm)
Figure 1. 2D-NOESY spectrum of 5a (DMSO, 400 MHz). Arrows indicate observed NOEs. The NOE between two benzylic protons (#6 and #13, red arrow) confirmed that the
benzylic substitution is at the N1 position, not at the N2 position. Other NOEs between benzylic protons (#6 and #13) and the phenyl protons (#8, #12, and #19, gray arrows)
were also observed.
Table 2
Cl
R2
N
N
Cl
N
H2N
5e-j
Entry
R2
Isolated
yield (%)
1HNMR (DMSO-d6) ppm
CHN
5e
38
1.23 (t, J = 7.20 Hz, 3H) 3.92 (q, J = 7.33 Hz, 2H) 4.04 (s,
2H) 5.12 (s, 2H) 7.27–7.36 (m, 1H) 7.36–7.44 (m, 1H)
7.60 (d, J = 2.02 Hz, 1H)
C11H12Cl2N4ꢀ0.19HOAc: C, 48.37; H, 4.55; N, 19.83.
Observed: C, 48.32; H, 4.46; N, 20.04.
(continued on next page)

1670
J. Meng, P.-P. Kung / Tetrahedron Letters 50 (2009) 1667–1670
Table 2 (continued)
Entry R2
Isolated 1HNMR (DMSO-d6) ppm
yield (%)
CHN
OCH3
OCH3
5f
34
3.56–3.62 (m, 3H) 3.67 (s, 6H) 4.11 (s, 2H) 5.20 (s, 2H) C19H20Cl2N4O3ꢀ0.74H2O: C, 52.27; H, 4.96; N, 12.83.
5.74 (s, 2H) 6.46 (s, 2H) 7.22–7.28 (m, 1H) 7.31–7.37 (m, Observed: C, 52.27; H, 4.57; N, 12.49.
1H) 7.52–7.59(m, J = 2.27 Hz, 1H)
OCH3
OH
5g
5h
65
34
3.49–3.55 (m, 1H) 3.64 (q, J = 5.31 Hz, 2H) 3.94 (t,
J = 5.43 Hz, 2H) 4.05 (s, 2H) 5.13 (s, 2H) 7.27–7.35 (m,
1H) 7.36–7.41 (m, 1H) 7.51–7.63(m, 1H)
C11H12Cl2N4Oꢀ1.13HOAc: C, 44.86; H, 4.69; N, 15.78.
Observed: C, 45.22; H, 4.35; N, 15.78.
0.78–0.91 (m, 6H) 1.20–1.34 (m, 1H) 1.45–1.59 (m, 2H) C14H18Cl2N4ꢀ0.43HOAc: C, 52.64; H, 5.86; N, 16.52.
3.82–3.94 (m, J = 6.06, 6.06 Hz, 2H) 4.04 (s, 2H) 5.12 (s, Observed: C, 52.60; H, 5.93; N, 16.53.
2H) 7.28–7.35 (m, 1H) 7.35–7.43 (m, 1H) 7.60 (s, 1H)
5i
40
50
0.83 (d, J = 6.82 Hz, 6H) 1.92–2.16 (m, 1H) 3.15 (s, 2H)
3.70 (d, J = 7.33 Hz, 2H) 4.04 (s, 2H) 7.30–7.37 (m, 1H)
7.37–7.45 (m, 1H) 7.60 (d, J = 2.02 Hz, 1H)
C13H16Cl2N4ꢀ0.43HOAc: C, 51.22; H, 5.55; N, 17.24.
Observed: C, 51 21; H, 5 54; N, 17 12.
5ja
1.84–1.96 (m, 2H) 2.01–2.15 (m, 2H) 3.65–3.84 (m, 2H) C14H16Cl2N4Oꢀ0.39HOAc: C, 50.63; H, 5.05; N, 15.98.
4.06–4.19 (m, 2H) 4.23–4.30 (m, 1H) 4.38 (d,
J = 10.86 Hz, 2H) 7.33–7.40 (m, 2H) 7.55 (d, J = 2.02 Hz,
1H)
Observed: C, 50.65; H, 5.23; N, 16.02.
O
a
Racemic.
9. Synthesis of compound (5a) 5-(2,4-dichloro-benzyl)-1-(4-fluoro-benzyl)-1H-
[1,2,4]triazol-3-ylamine. A 3 mL microwave tube was charged with benzyl
[(1Z)-{[(2,4-dichlorophenyl)acetyl]amino}(methylthio)methylene]carbamate
(3a) (123 mg, 0.3 mmol). (4-Fluorobenzyl)hydrazine hydrochloride (318 mg,
1.8 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added sequentially. The
Acknowledgments
We thank the Pfizer La Jolla analytical group for the analytical
and spectral data. We also thank Dr. Martin Wythes for helpful
discussions.
resulting mixture was heated in
a microwave oven at 160 °C for 30 min
(Biotage InitiatorTM Sixty). Microwave reactions were performed in sealed
tubes. Irradiation was automatically adjusted by the microwave software to
maintain a constant 160 °C reaction temperature. The desired product was
purified by reverse phase HPLC (using 0.1% acetic acid in H2O and acetonitrile
as eluents) to afford compound 5a as a white solid (71 mg, 0.2 mmol, 70%
yield). 1H NMR (400 MHz, DMSO-d6) ppm 4.19 (s, 2 H) 5.19 (s, 2 H) 7.12–7.19
(m, 2 H) 7.24–7.31 (m, 2H) 7.31 (s, 1H) 7.34–7.39 (m, 1H) 7.58 (d, J = 2.0 Hz,
1H). Calcd for C16H13Cl2FN4ꢀ0.4H2O C: 53.62, H: 3.88, N: 15.63. Observed: C:
53.58, H: 3.97, N: 15.63.
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