Synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles from ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate

Article abstract of DOI:10.1016/j.tet.2015.06.094

Abstract A general and efficient method for the synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles has been developed. The desired 3-amino-1H-1,2,4-triazoles (3) were prepared in good to excellent yields from ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)form

Full text of DOI:10.1016/j.tet.2015.06.094

Accepted Manuscript
Synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles from ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate
Jeff Shen, Haiming Zhang
PII:
S0040-4020(15)00991-6
10.1016/j.tet.2015.06.094
TET 26930
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 March 2015
Revised Date: 24 June 2015
Accepted Date: 25 June 2015
Please cite this article as: Shen J, Zhang H, Synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles from
ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.094.
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Graphical Abstract
Synthesis of 1-substituted 3-amino-1H-1,2,4-
triazoles from ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate
Leave this area blank for abstract info.
Jeff Shen and Haiming Zhang*
Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United
States

ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 1-substituted 3-amino-1H-1,2,4-
triazoles from ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate
Leave this area blank for abstract info.
Jeff Shen and Haiming Zhang*
Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United
States

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles from ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate
Jeff Shen1 and Haiming Zhang
Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general and efficient method for the synthesis of 1-subsituted 3-amino-1H-1,2,4-triazoles has
been developed. The desired 3-amino-1H-1,2,4-triazoles (3) were prepared in good to excellent
yields from ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate (1a) and anilines or amines (2)
via a one-pot process involving formimidamide formation followed by a thermal monocyclic
rearrangement. The benzoyl protecting group could be readily removed by sulfuric acid
promoted deprotection.
Available online
Keywords:
Aminotriazole
Formimidate
Aniline
©2012 Elsevier Ltd. All rights reserved
.
Amine
Rearrangement
1. Introduction
Other literature reported synthesis of 5-unsubstituted 3-amino-
1H-1,2,4-triazoles, despite providing complementary syntheses
for such compounds, either involved multi-step synthesis or were
low overall yielding and/or with limited scope, thus, the breadth
and applicability of these methods are lacking.13
3-Amino-1H-1,2,4-triazole and its derivatives have attracted
much attention in the literature, particularly in the areas of
medicinal and agrochemical research due to their biological
activities. For example, 3-amino-1H-1,2,4-triazoles are reported
to inhibit catalase2 and histidine3 biosynthesis, inhibit methionine
aminopeptidase-24 and neuropeptide Y receptor,5 and act as
histamine H2-receptor6 and CRF1 receptor7 antagonists. They
also have shown various therapeutic applications, such as anti-
inflammatory and anti-asthmatic activities,8 and have been
studied for the treatment of Alzheimer’s disease or Down
syndrome.9
We required a facile synthesis of 3-aminotriazole derivatives
unsubstituted at C-5 position to support our internal research
program. Our strategy was to focus on re-examining Ruccia’s
approach to understand the electronic and steric impact of the
anilines to the reaction and to develop an efficient and process
friendly protocol to synthesize 1-substituted 3-amino-1H-1,2,4-
triazoles. Herein we wish to report an improved and column
chromatography-free method for the preparation of 1-substituted
3-amino-1H-1,2,4-triazoles 3 from ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate (1a) and various anilines or amines
(2) (Eq 1).
A variety of synthetic methods have been developed for 1,5-
disubstituted 3-amino-1H-1,2,4-triazoles.10 However, the number
of syntheses for direct preparation of 3-amino-1H-1,2,4-triazoles
lacking any substitution at the 5-position is very limited. Among
the known methods, diazotization of 5-amino-substituted 3-
amino-1H-1,2,4-triazoles to remove the 5-amino group requires
an extra step and often raises safety concerns as the chemistry
involves diazonium salt.11 Ruccia previously reported the
conversion of N-(1,2,4-oxadiazol-3-yl)-N’-arylformamines into
3-acylamino-1-aryl-1H-1,2,4-triazoles
via
a
monocyclic
2. Results and discussion
rearrangement reaction.12 However, the reaction conditions, e.g.
neat and high temperature at 160‒170 °C were process unfriendly
and impractical, especially when both reactants were solids.
Moreover, only three aromatic anilines were examined and the
Our investigation commenced at the optimization of 3-
aminotriazole 3a formation using ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate (1a) and aniline (2a) in various
solvents at or near their respective refluxing temperature. As
yields for the transformation were moderate to good (60–70%).12
———
Corresponding author. Tel.: +1-650-467-8658; fax: +1-650-225-6238; e-mail: zhang.haiming@gene.com
1

2
Tetrahedron
ACCEPTED MANUSCRIPT
shown in Table 1 and Figure 1, the reactions using solvents
such as tetrahydrofuran (THF) at 65 ºC, 2-methyltetrahydrofuran
(MeTHF) at 80 ºC, 1,4-dioxane at 100 ºC, cyclopentylmethyl
ether (CPME) at 105 ºC, and toluene at 110 ºC all generated
relatively low conversions at 2h (33‒72%, Table 1, entries 1‒5).
Even at 6h, the reactions still did not reach completion. To our
delight, the reaction employing anisole as solvent at 145 ºC
produced nearly quantitative conversion in only 2h (Table 1,
entry 6). However, lower conversions at both 2h and 6h were
observed when the reactions were performed in anisole at lower
temperatures (Table 1, entries 7‒10 and Figure 2). As seen in
Table 1, Figures 1 and 2, very similar reaction profiles were
observed in different solvents at the same temperature. For
example, reactions carried out in PhMe and PhOMe at 110 °C
were essentially identical (compare Table 1, entries 5 and 7).
Thus, this 3-aminotriazole formation is believed to be more
dependent on the reaction temperature than the solvent. Based on
these results, we therefore selected anisole as the reaction solvent
and performed the reaction at 145 ºC to further investigate the 3-
aminotriazole formation by employing ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate (1a) and a variety of anilines and
amines (2).
Figure 2. Formation of 3a in anisole at various temperatures
Under our optimal conditions, the reaction of formimidate 1a
and aniline (2a) successfully produced 3-amino-1H-1,2,4-triazole
3a in an excellent 97% yield in 2h (Table 1, entry 6 and Table 2,
entry 1). This reaction was readily scaled up to 10 gram of 1a and
afforded 3a in 95% yield (Table 2, entry 1). The electronic effect
of the anilines was then examined. As illustrated in Table 2,
electron-rich anilines such as p-toluidine (2b), p-anisidine (2c)
and 4-dimethyaminoaniline (2d) generated excellent yields of the
desired 3-aminotriazoles 3b−d in 89%, 91% and 95%,
respectively (Table 2, entries 2−4). Electron-deficient anilines,
for example, 4-trifluoromethyl, 4-cyano, 4-methoxycarbonyl, 4-
fluroro and 3,5-difluoro substituted anilines 2e−i also underwent
the 3-aminotriazole formation smoothly, affording the desired
products 3e−i in good to excellent yield (Table 2, entries 5−9).
The rate of 3-aminotriazole formation with anilines 2e, 2f and 2h
apparently is not impacted significantly by the electron-deficient
property of the anilines as the reactions reached completion in
only 2h (Table 2, entries 5, 6 and 8). However, the reactions
employing anilines 2g and 2i did suffer longer reaction time as
the conversions at 4h were 83% and 59% for 2g and 2i
respectively (Table 2, entries 7 and 9). Gratifyingly, the reaction
between formimidate 1a and 4-aminopyridine (2j) readily formed
the desired pyridine-substituted 3-aminotriazole 3j, albeit in a
longer reaction time 20h (83% conversion at 4h) and a relatively
lower 70% yield (Table 2, entry 10). Not surprisingly, this 3-
aminotriazole formation could easily be extended to alkyl and
benzyl substituted amines. For example, cyclohexylamine (2k)
and benzylamine (2l) reacted with formimidate 1a, generating the
desired 3-aminotriazoles 3k and 3l uneventfully in 90% and 75%
yield, respectively (Table 1, entries 11−12). Next, the steric
influence of the aniline to this aminotriazole formation chemistry
was probed using mesitylamine (2m). 3-Aminotriazole 3m was
isolated in 90% yield from the reaction after a slightly longer
reaction time (3h), which indicates that the reaction is not
particularly sensitive to the steric bulkiness of the aniline (Table
2, entry 13). Finally, methyl substituted formimidate 1b, when
subjected to the reaction with aniline 2a, produced the desired 3-
aminotriazole 3n in 85% yield in 2.5h (Eq 2).
Table 1
Optimization of 3-aminotriazole 3a formationa
Temp
(°C)
Time
(h)
Convb
(%)
Yieldc
(%)
Entry
Solvent
1
2
THF
MeTHF
1,4-Dioxane
CPME
65
80
2 (6)
2 (6)
2 (6)
2 (6)
2 (6)
2
33 (73)
56 (82)
59 (84)
64 (87)
72 (88)
99
-
-
3
100
105
110
145
110
80
-
4
-
5
PhMe
-
97d
-
6
PhOMe
PhOMe
PhOMe
PhOMe
7
2 (6)
2 (6)
2 (6)
70 (85)
52 (71)
47 (67)
8
-
10
65
-
a Reaction conditions: 1a (0.50 mmol), 2a (1.1 equiv) and solvent (0.50
mL).
b The conversion of the reaction was determined by HPLC analysis.
c Isolated yield.
d The reaction was performed with 2.5 mmol of 1a and 1.1 equiv of 2a in
PhOMe (2.5 mL).
Table 2
Formation of 3-aminotriazole 3 from formimidate 1a and
anilines or amines 2a
Time
(h)
Yieldb
(%)
Entry
1
Amine
Aminotriazole
Figure 1. Formation of 3a in solvents at refluxing temperatures
2
97(95)c
2a
3a

3
reaction mixture to room temperature, followed by addition of
ACCEPTED MANUSCRIPT
an anti-solvent heptane and then filtration. The only exception
was the pyridine-substituted 3-aminotriazole 3j which was
isolated by silica gel column chromatography due to the
contamination of small amount of insoluble 4-aminopyridine
(2j). The high yield of the reaction, along with the simple
procedure for isolation and purification, certainly makes this
chemistry a highly efficient and process friendly approach to
access a variety of 1-substituted 3-amino-1H-1,2,4-triazoles.
2
3
4
2
2
2
89
91
95
2b
2c
3b
3c
N
NHBz
N
N
The mechanism of the aminotriazole formation, as illustrated
in Scheme 1 using formimidate 1a and aniline (2a), is believed to
involve the formation of formamidine 4 by extrusion of ethanol,
followed by a thermodynamic monocyclic rearrangement14 to
generate 3-aminotriazole 3a. In fact, Ruccia reported that
formamidine 4 could be isolated in 40−50% yield by reacting
formimidate 1a with aniline (2a) at room temperature for two
days. Heating formamidine 4 at 140 °C then produced
aminotriazole 3a in 70% yield.12
Me2N
2d
2e
2f
3d
5
6
7
8
2
2
78
82
85
93
3e
3f
20d
2g
2h
3g
3h
2
Scheme 1. Plausible mechanism of 3-aminotriazole formation
The benzoyl group on the 3-position amino group can be
readily removed in the presence of an acid. For example, 3-
aminotriazole 3a (5.0 g, 19 mmol) was treated with 5 equiv of 6
M aqueous sulfuric acid in MeTHF at 80 ºC, successfully
affording the deprotected 3-aminotriazole 5 in 86% yield (Eq 3).
Therefore, one can envision that a wide spectrum of 1-subsituted
3-amino-1H-1,2,4-triazoles with the amino group free of
substitution can be achieved in only two steps from formimidate
1a and anilines or amines 2.
9
20d
20d
85
70
2i
2j
3i
3j
10
11
12
13
2
2
3
90
75
90
2k
2l
3k
3l
To demonstrate the synthetic utility of 3-aminotriazole 5, we
converted compound 5 to various functionalized triazoles. For
example, Sandmeyer deamination and bromination15 generated 1-
phenyl-1,2,4-triazole (6) and 5-bromo-1-phenyl-1,2,4-triazole (7)
in 62% and 42% yields, respectively; Reductive amination16 of
benzaldehyde with 3-aminotriazole 5 produced benzylated 3-
aminotriazole 8 in 68% yield. Buchwald-Hartwig amination17 of
bromobenzene with 3-aminotriazole 5 in the presence of a
palladium catalyst afforded 3-phenyl-3-amino-1,2,4-triazole (9)
in 85% yield (Scheme 2).
2m
3m
a Reaction conditions: 1a (2.5 mmol), 2 (1.1 equiv), PhOMe (2.5 mL), 145
°C.
b Isolated yield.
c Yield in parenthesis was obtained by performing the reaction using 1a (10.0
g, 46.1 mmol) and 2a (1.10 equiv) in PhOMe (46.0 mL) at 145 °C.
d The conversions at 4 h for reactions with 2g, 2i and 2j were 83%, 59% and
83%, respectively. The reactions were left overnight (20 h).
N
N
N
N
a
b
c
NHBn
N
N
N
N
6
8
NH2
N
d
N
N
5
N
N
Br
NHPh
N
N
7
9
OEt
NH2
N
Scheme 2. Conditions: (a) 5 (1.0 mmol), amyl nitrite (1.2 equiv), MeCN (5.0
mL), 65 °C, 1 h, 62%. (b) 5 (1.0 mmol), amyl nitrite (1.2 equiv), CuBr2 (1.2
equiv), MeCN (5.0 mL), 65 °C, 1 h, 42%. (c) 5 (1.0 mmol), PhCHO (1.1
equiv), NaBH(OAc)3 (1.5 equiv), CH2Cl2 (5.0 mL), 23 °C, 48 h, 68%. (d) 5
(1.0 mmol), PhBr (1.1 equiv), Pd2(dba)3 (5 mol%), JohnPhos (10 mol%),
NaO-t-Bu (1.4 equiv), PhMe (5.0 mL), 110 °C, 4 h, 85%.
PhOMe
145 °C, 2.5 h
85%
N
N
+
N
(2)
NHAc
N
N
Me
O
1b
2a
3n
It is highly worth noting that essentially all the 3-
aminotriazole products were isolated by simply cooling the
3

4
Tetrahedron
3. Conclusion
The cake was dried under vacuum at 40 °C overnight to afford
ACCEPTED MANUSCRIPT
the second crop of compound 1a as a white solid (1.7 g, 12%).
The combined yield is 91%; mp 98 °C (Lit.12 95−98 °C); FTIR
In conclusion, we have developed a general and efficient
(thin film, cm−1) 3071, 2983, 1630, 1565; H NMR (300 MHz,
1
method for the synthesis of 1-subsituted 3-amino-1H-1,2,4-
triazoles. The desired 3-amino-1,2,4-triazoles (3) were prepared
in good to excellent yields (70−97%) from ethyl N-(5-phenyl-
1,2,4-oxadiazol-3-yl)formimidate (1a) and anilines or amines 2
via a one-pot process involving formimidamide formation
followed by a thermal monocyclic rearrangement. The isolation
and purification of the desired aminotriazole can be readily
achieved by addition of an anti-solvent heptane to the reaction
mixture to facilitate crystallization, followed by filtration. This
protocol can easily be scaled up to ten gram scale as exemplified
by the preparation of 3-aminotriazole 3a. The benzoyl protecting
group on 3-aminotriazole 3a was readily removed by sulfuric
acid promoted deprotection to afford 3-aminotriazole 5 which
can be further functionalized to various triazoles 6‒9. We
anticipate that this practical method will provide rapid access to
useful quantities of versatile 1-substituted-3-amino-1H-1,2,4-
triazoles.
CDCl3) δ 8.61 (s, 1H), 8.13 (dd, J = 9.0, 3.0 Hz, 2H), 7.60–7.50
(m, 3H), 4.49 (qd, J = 7.1, 0.9 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 175.6, 171.1, 163.1, 132.8, 129.1,
127.9, 124.4, 64.1, 14.0; HRMS (ESI+) calculated for
C11H12N3O2 (M+H), 218.0924; found, 218.0915.
(E)-Ethyl N-(5-methyl-1,2,4-oxadiazol-3-yl)formimidate (1b):
To a 20 mL vial was added 5-methyl-1,2,4-oxadiazol-3-amine19
(0.98 g, 9.9 mmol) and triethyl orthoformate (5.5 mL) and the
mixture was heated at refluxing at 145 °C for 15h. The mixture
was cooled to room temperature, added heptane (5.5 mL) and
concentrated to ca. 5 mL. Heptane (5 mL) was added and the
mixture was cooled to 0−5 °C and stirred for 20 min. The solid
was filtered, washed with heptane (2 mL) and dried under
vacuum at 40 °C for 2 h to afford compound 1b as a yellow solid
(1.23 g, 79%). mp 40 °C (Lit.12 38−40 °C); FTIR (thin film,
cm−1) 2993, 2944, 1632, 1590; H NMR (300 MHz, CDCl3)
δ
1
8.61 (s, 1H), 8.13 (dd, J = 8.3, 1.5 Hz, 2H), 7.55 (m, 3H), 4.49
(m, 2H), 1.42 (t, J = 7.1 Hz, 3H)
13C NMR (75 MHz, CDCl3) δ
175.6, 171.1 , 163.1, 132.8, 129.1, 127.9, 124.4, 64.1, 14.0
;
4. Experimental section
4.1. General
;
HRMS (ESI+) calculated for C6H10N3O2 (M+H), 156.0768;
found, 156.0758.
Unless stated otherwise, reactions were performed under an
ambient atmosphere of nitrogen in 20 mL vials sealed with
Teflon-lined caps. All solvents and commercially obtained
reagents were used as received, unless specified otherwise. Thin-
layer chromatography (TLC) was conducted with EMD silica gel
60 F254 pre-coated plates and visualized using UV light (254
nm). Flash column chromatography was performed with pre-
packed RediSep silica gel columns on a CombiFlash ISCO
system using MeOH in CH2Cl2 (0−5% gradient) as eluent.
Analytical HPLC analyses were performed with an Agilent 1290
Infinity Series HPLC instrument. 1H NMR spectra were recorded
on a Bruker 300 (at 300 MHz) and are reported relative to the
residual solvent peak (δ 7.26 for CDCl3, 2.50 for DMSO-d6).
4.3. Procedure for preparation of 3-aminotriazole 3
To a 20 mL vial was added (E)-ethyl N-(5-phenyl-1,2,4-
oxadiazol-3-yl)formimidate (1a, 1.08 g, 5.0 mmol), aniline or
amine (2, 1.1 equiv) and anisole (5.0 mL). The mixture was
heated to 145 °C and monitored by HPLC. Upon reaction
completion based on HPLC analysis, the mixture was cooled to
room temperature and heptane (5.0 mL) was added. The mixture
was stirred for 15 min and the solids were filtered, washed with
heptane (1.0 mL) and dried under vacuum at 40 °C to afford the
desired 3-aminotriazole.
N-(1-Phenyl-1H-1,2,4-triazol-3-yl)benzamide
(3a):
1
Data for H NMR spectra are reported as follows: chemical shift
Compound 3a was prepared from 1a (1.08 g, 5.0 mmol) and
aniline (2a, 0.51 g, 5.5 mmol) as a white solid (1.28 g, 97%); mp
161 °C (Lit.12 172 °C); FTIR (thin film, cm−1) 3183, 3103, 1686,
(δ ppm), multiplicity, coupling constant (Hz), and integration. 13C
NMR spectra were recorded on a Bruker 300 (at 75 MHz), and
are reported relative the residual solvent peak (δ 77.0 for CDCl3,
39.5 for DMSO-d6). Data for 13C NMR spectra are reported in
terms of chemical shift (δ ppm). IR spectra were recorded on a
Bruker Alpha Platinum-ATR spectrometer and are reported in
frequency of absorption (cm−1). HRMS data was obtained on a
LTQ Orbitrap Discovery (Thermo Fisher Scientific) at
Genentech, Inc.. Melting points were measured by differential
scanning calorimetry (DSC) and were reported as onset
temperature.
1
1503; H NMR (300 MHz, CDCl3) δ 9.31 (s, 1H), 8.29 (s, 1H),
7.97 (m, 2H), 7.68 (m, 2H), 7.50 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 165.3, 157.5, 139.8, 136.7, 134.4, 132.1, 129.6, 128.6,
128.1, 127.8, 119.9; HRMS (ESI+) calculated for C15H13N4O
(M+H), 265.1084; found, 265.1074.
N-(1-(p-Tolyl)-1H-1,2,4-triazol-3-yl)benzamide
(3b):
Compound 3b was prepared from 1a (1.08 g, 5.0 mmol) and p-
toluidine (2b, 0.59 g, 5.5 mmol) as a white solid (1.24 g, 89%);
mp 205 °C (Lit.12 212 °C); FTIR (thin film, cm−1) 3127, 2958,
1696, 1583; 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 8.30 (d,
J = 0.8 Hz, 1H), 7.95 (m, 2H), 7.54 (m, 5H), 7.29 (m, 1H), 2.41
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 157.2, 139.7, 138.2,
134.5, 134.1, 132.2, 130.2, 128.7, 127.6, 119.9, 21.0; HRMS
(ESI+) calculated for C16H15N4O (M+H), 279.1240; found,
279.1228.
4.2. Procedure for preparation of formimidate 1a and 1b
(E)-Ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate (1a):
To a 100 mL round bottom flask under nitrogen were added 5-
phenyl-1,2,4-oxadiazol-3-amine18 (10.0 g, 62.0 mmol) and
triethyl orthoformate (34.0 mL, 3.3 equiv) and the mixture was
heated at 145 °C for 16 h. Upon reaction completion based on 1H
NMR analysis, the mixture was cooled to room temperature and
added with heptane (34.0 mL) over 5 min to facilitate
precipitation. The mixture was stirred at room temperature for 30
min and filtered. The solid was washed with heptane (10.0 mL)
and dried under vacuum at 40 °C overnight to afford compound
1a as a white crystalline solid (10.6 g, 79%). The mother liquor
was concentrated to ca. 15 mL and was added with heptane (15
mL). The mixture was filtered and washed with heptane (3 mL).
N-(1-(4-Methoxyphenyl)-1H-1,2,4-triazol-3-yl)benzamide
(3c): Compound 3c was prepared from 1a (1.08 g, 5.0 mmol) and
p-anisidine (2b, 0.68 g, 5.5 mmol) as a white solid (1.34 g, 91%);
mp 179 °C; FTIR (thin film, cm−1) 3246, 3099, 1652, 1509; H
1
NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.23 (d, J = 0.6 Hz, 1H),
7.95 (dd, J = 8.1, 1.5 Hz, 2H), 7.55 (m, 5H), 6.99 (m, 2H), 3.86
(d, J = 0.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 159.4,
157.1, 139.8, 134.0, 132.2, 130.3, 128.7, 127.6, 121.8, 114.7,

5
55.6; HRMS (ESI+) calculated for C16H1 N4O2 (M+H),
295.1190; found, 295.1180.
aminopyridine (2j, 0.83 g, 5.5 mmol) and was isolated by silica
5
ACCEPTED MANUSCRIPT
gel chromatography using MeOH/CH2Cl2 (0−5% gradient) as a
white solid (0.93 g, 71%); mp 189 °C; FTIR (thin film, cm−1)
3114, 3004, 1698, 1597; 1H NMR (300 MHz, DMSO-d6) δ 11.12
(s, 1H), 9.48 (s, 1H), 8.74 (m, 2H), 8.01 (dd, J = 8.3, 1.4 Hz,
N-(1-(4-(Dimethylamino)phenyl)-1H-1,2,4-triazol-3-
yl)benzamide (3d): Compound 3d was prepared from 1a (1.08 g,
5.0 mmol) and 4-dimethylaminoaniline (2d, 0.75 g, 5.5 mmol) as
an off-white solid (1.46 g, 95%); mp 208 °C; FTIR (thin film,
2H), 7.89 (m, 2H), 7.56 (m, 3H);
13C NMR (75 MHz, DMSO-
d6) δ 165.2, 157.7, 151.4, 143.0, 142.7, 133.4, 132.1, 128.4,
127.9, 112.5; HRMS (ESI+) calculated for C14H12N5O (M+H),
266.1036; found, 266.1026.
1
cm−1) 3207, 2949, 1686, 1521; H NMR (300 MHz, CDCl3) δ
8.72 (s, 1H), 8.21 (s, 1H), 7.94 (m, 2H), 7.51 (m, 5H), 6.75 (d, J
= 9.1 Hz, 1H), 3.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.0,
156.9, 150.3, 139.5, 134.3, 132.0, 128.6, 127.7, 126.5, 121.7,
112.3, 40.5; HRMS (ESI+) calculated for C17H18N5O (M+H),
308.1506; found, 308.1493.
N-(1-Cyclohexyl-1H-1,2,4-triazol-3-yl)benzamide
(3k):
Compound 3k was prepared from 1a (1.08 g, 5.0 mmol) and
cyclohexylamine (2k, 0.55 g, 5.5 mmol) as a white solid (1.22 g,
90%); mp 165 °C; FTIR (thin film, cm−1) 2929, 2856, 1674,
N-(1-(4-(Trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-
1
1518; H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 7.91 (m,
yl)benzamide (3e): Compound 3e was prepared from 1a (1.08 g,
5.0 mmol) and 4-trifluoromethylaniline (2e, 0.89 g, 5.5 mmol) as
a white solid (1.29 g, 78%); mp 249 °C; FTIR (thin film, cm−1)
3256, 3096, 1652, 1514; 1H NMR (300 MHz, DMSO-d6) δ 11.08
(s, 1H), 9.40 (s, 1H), 8.02 (m, 6H), 7.56 (m, 3H); 13C NMR (75
MHz, DMSO-d6) δ 165.2, 157.5, 142.6, 139.5, 133.5, 132.0,
128.4, 127.9, 127.1, 127.0, 119.2; HRMS (ESI+) calculated for
C16H12F3N4O (M+H), 333.0958; found, 333.0947.
3H), 7.50 (m, 3H), 4.16 (s, 1H), 2.25 (m, 2H), 1.60 (m, 8H)
;
13C NMR 75 MHz, CDCl3) δ 165.1, 156.1, 139.4, 134.5,
131.9, 128.5, 127.7, 59.8, 32.9, 25.1, 25.0; HRMS (ESI+)
calculated for C15H19N4O (M+H), 271.1553; found, 271.1541.
N-(1-Benzyl-1H-1,2,4-triazol-3-yl)benzamide (3l): Compound
3l was prepared from 1a (1.08 g, 5.0 mmol) and benzylamine (2l,
0.59 g, 5.5 mmol) as a white solid (1.10 g, 75%); mp 133 °C;
FTIR (thin film, cm−1) 3210, 3031, 1695, 1526; H NMR (300
1
N-(1-(4-Cyanophenyl)-1H-1,2,4-triazol-3-yl)benzamide (3f):
Compound 3f was prepared from 1a (1.08 g, 5.0 mmol) and 4-
cyanoaniline (2f, 0.65 g, 5.5 mmol) as a pale yellow solid (1.19
g, 83%); mp 268 °C; FTIR (thin film, cm−1) 2992, 2227, 1698,
MHz, CDCl3) δ 8.91 (s, 1H), 7.90 (dt, J = 8.1, 1.3 Hz, 2H),
7.70 (s, 1H), 7.42 (m, 8H), 5.33 (s, 2H);
13C NMR (75 MHz,
CDCl3) δ 165.2, 156.8, 141.8, 134.5, 133.8, 131.9, 129.1,
128.8, 128.6, 128.5, 127.7, 54.1; HRMS (ESI+) calculated for
C16H15N4O (M+H), 279.1240; found, 279.1230.
1
1543; H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.42 (s,
1H), 8.04 (m, 6H), 7.56 (m, 3H); 13C NMR (75 MHz, DMSO-d6)
δ 165.1, 157.6, 142.8, 139.7, 134.2, 133.4, 132.1, 128.4, 127.9,
119.2, 109.6; HRMS (ESI+) calculated for C16H12N5O (M+H),
290.1036; found, 290.1027.
N-(1-Mesityl-1H-1,2,4-triazol-3-yl)benzamide
(3m):
Compound 3m was prepared from 1a (1.08 g, 5.0 mmol) and
mesitylamine (2m, 0.74 g, 5.5 mmol) as a white solid (1.38 g,
91%); mp 141 °C; FTIR (thin film, cm−1) 3273, 3096, 1683,
N-(1-(4-Methoxycarbonylphenyl)-1H-1,2,4-triazol-3-
1
1520; H NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 7.93 (m,
yl)benzamide (3g): Compound 3g was prepared from 1a (1.08 g,
5.0 mmol) and methyl 4-aminobenzoate (2g, 0.83 g, 5.5 mmol)
as a white solid (1.36 g, 85%); mp 221 °C; FTIR (thin film, cm−1)
3099, 2946, 1714, 1514; 1H NMR (300 MHz, DMSO-d6) δ 11.07
(s, 1H), 9.39 (s, 1H), 8.12 (m, 2H), 8.01 (m, 4H), 7.57 (m,
3H), 7.52 (m, 3H), 6.96 (q, J = 0.8 Hz, 2H), 2.34 (s, 3H), 2.05
(s, 6H);
13C NMR (75 MHz, CDCl3) δ 164.8, 157.2, 143.7,
140.0, 135.8, 134.3, 133.0, 132.0, 129.0, 128.5, 127.7, 21.1,
17.5; HRMS (ESI+) calculated for C18H19N4O (M+H), 307.1553;
found, 307.1542.
3H), 3.89 (s, 3H);
13C NMR (75 MHz, DMSO-d6) δ 165.4,
165.1, 157.5, 142.5, 140.0, 133.5, 132.0, 130.9, 128.4, 128.1,
127.9, 118.6, 52.3; HRMS (ESI+) calculated for C17H15N4O3
(M+H), 323.1139; found, 323.1129.
N-(1-Phenyl-1H-1,2,4-triazol-3-yl)acetamide (3n): Compound
3n was prepared from 1b (0.78 g, 5.0 mmol) and aniline (2a,
0.51 g, 5.5 mmol) as a white solid (0.85 g, 85%); mp 155 °C;
1
FTIR (thin film, cm−1) 3227, 3026, 1717, 1530; H NMR (300
N-(1-(4-Fluorophenyl)-1H-1,2,4-triazol-3-yl)benzamide (3h):
Compound 3h was prepared from 1a (1.08 g, 5.0 mmol) and 4-
fluoroaniline (2h, 0.61 g, 5.5 mmol) as an off-white solid (1.31 g,
93%); mp 203 °C; FTIR (thin film, cm−1) 3244, 3098, 1646,
MHz, CDCl3) δ 8.38 (s, 1H), 8.09 (s, 1H), 7.65 (d, J = 7.9 Hz,
2H), 7.45 (m, 3H), 2.38 (s, 3H);
13C NMR (75 MHz, CDCl3) δ
139.9, 136.7, 129.7, 129.4, 128.1, 119.8, 113.9, 23.8; HRMS
(ESI+) calculated for C10H11N4O (M+H), 203.0927; found,
203.0919.
1
1510; H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.20 (s,
1H), 7.95 (m, 4H), 7.52 (m, 5H); 13C NMR (75 MHz, DMSO-d6)
δ 165.3, 157.1, 142.0, 133.5, 133.3, 132.0, 128.4, 127.9, 121.2,
121.1, 116.7, 116.4; HRMS (ESI+) calculated for C15H12N4O
(M+H), 283.0990; found, 283.0980.
4.4. Procedure for 10-gram scale up of aminotriazole 3a
To a 125 mL round bottom flask was added compound (E)-
ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate (1a, 10.0 g,
46.0 mmol), aniline (2a, 4.70 g, 1.1 equiv) and anisole (46.0
mL). The mixture was heated to 145 °C and monitored by HPLC.
Upon reaction completion based on HPLC analysis, the mixture
was cooled to room temperature and heptane (60.0 mL) was
added. The mixture was stirred for 15 min and the solids were
filtered, washed with heptane (15.0 mL) and dried under vacuum
at 40 °C to afford compound 3a as a white solid (11.6 g, 95%).
N-(1-(3,5-Difluorophenyl)-1H-1,2,4-triazol-3-yl)benzamide
(3i): Compound 3i was prepared from 1a (1.08 g, 5.0 mmol) and
3,5-difluoroaniline (2i, 0.71 g, 5.5 mmol) as a white solid (1.28 g,
85%); mp 189 °C; FTIR (thin film, cm−1) 3215, 3096, 1655,
1
1514; H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.40 (s,
1H), 7.95 (m, 2H), 7.55 (m, 3H), 7.32 (dd, J = 7.6, 2.3 Hz,
2H), 6.84 (m, 1H)
164.4 (d, J = 15.0 Hz), 161.2 (d, J = 15.0 Hz), 157.4, 142.7,
138.6, 128.4, 127.9, 102.8, 102.5 (d, J = 22.5 Hz), 102.4
;
13C NMR (75 MHz, DMSO-d6) δ 165.2,
4.5. Procedure for preparation of aminotriazole 5
;
HRMS (ESI+) calculated for C15H11F2N4O (M+H), 301.0895;
found, 301.0888.
To a 100 mL round bottom flask was added aminotriazole (3a,
5.00 g, 18.9 mmol), MeTHF (19 mL) and 6 M aqueous H2SO4
(15 mL, 4.8 equiv). The mixture was heated at 80 °C for 16 h and
cooled to room temperature. The reaction mixture was
N-(1-(Pyridine-4-yl)-1H-1,2,4-triazol-3-yl)benzamide
(3j):
Compound 3j was prepared from 1a (1.08 g, 5.0 mmol) and 4-
5

6
Tetrahedron
neutralized by addition of 20 wt% aqueous K3PO4 until pH 7,
1H); 13C NMR (75 MHz, CDCl3) δ 142.1, 141.3, 136.4, 129.9,
A
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added brine (10 mL) and the organic layer was separated and
dried over anhydrous Na2SO4. The mixture was filtered and
concentrated in vacuum to dryness to afford compound 5 as a
white solid (2.57 g, 86%); mp 146 °C; FTIR (thin film, cm−1)
3441, 3303, 1618, 1556; 1H NMR (300 MHz, CDCl3) δ 8.20 (s,
128.8, 119.9; HRMS (ESI+) calculated for C8H7BrN3 (M+H),
223.9818; found, 223.9808.
N-Benzyl-1-phenyl-3-amino-1H-1,2,4-triazole (8): To a 20 mL
vial was added aminotriazole 5 (0.16 g, 1.0 mmol), CH2Cl2 (5.0
mL), benzaldehyde (0.12 g, 1.1 equiv) and NaBH(OAc)3 (0.32 g,
1.4 equiv). The mixture was stirred at room temperature and
monitored by HPLC. Upon reaction completion in 48 h, the
mixture was quenched with 1N NaOH (1 mL), washed with brine
(4 mL), concentrated in vacuum and purified by silica gel column
chromatography using MeOH/CH2Cl2 (0−5% gradient) to afford
compound 8 as a white solid (0.17 g, 68%); mp 72 °C; FTIR
1H), 7.58 (m, 2H), 7.46 (m, 2H), 7.33 (m, 1H), 4.24 (s, 2H)
;
13C NMR(75 MHz, CDCl3) δ 164.0, 139.9, 137.1, 129.6,
127.2, 119.0; HRMS (ESI+) calculated for C8H9N4 (M+H),
161.0822; found, 161.0812.
4.6. Procedure for functionalization of aminotriazole 5
(thin film, cm−1) 3219, 3071, 2846, 1556; H NMR (300 MHz,
1
1-Phenyl-1H-1,2,4-triazole (6): To a 20 mL vial was added
aminotriazole 5 (0.16 g, 1.0 mmol), acetonitrile (5.0 mL) and
amylnitrite (0.15 g, 1.2 equiv). The mixture was heated at 65 °C
and monitored by HPLC. Upon reaction completion in 1 h, the
mixture was cooled to room temperature, concentrated in vacuum
and purified by silica gel column chromatography using
MeOH/CH2Cl2 (0−5% gradient) to afford compound 6 as a
yellow oil (90 mg, 62%). FTIR (thin film, cm−1) 3120, 2956,
1599, 1510; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.10 (s,
1H), 7.68 (m, 2H), 7.50 (m, 2H), 7.44 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 152.5, 140.8, 137.0, 129.8, 128.2, 120.0; HRMS
(ESI+) calculated for C8H8N3 (M+H), 146.0713; found,
146.0704.
CDCl3) δ 8.23 (s, 1H), 7.65 – 7.58 (m, 2H), 7.51 – 7.29 (m, 7H),
4.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.2, 139.8, 139.4,
137.3, 129.6, 128.5, 127.6, 127.2, 126.9, 118.9, 47.8; HRMS
(ESI+) calculated for C15H15N4 (M+H), 251.1291; found,
251.1275.
N-Phenyl-1-phenyl-3-amino-1H-1,2,4-triazole (9): To a 20
mL vial was added aminotriazole 5 (0.16 g, 1.0 mmol), toluene
(5.0 mL), bromobenzene (0.17 g, 1.1 equiv), sodium t-butoxide
(0.15 g, 1.5 equiv), Pd2(dba)3 (47 mg, 5 mol%) and 2-(di-t-
butylphosphino)biphenyl (30 mg, 10 mol%). The mixture was
heated at 110 °C and monitored by HPLC. Upon reaction
completion in 4 h, the mixture was cooled to room temperature,
passed through a thin pad of celite, concentrated in vacuum and
purified by silica gel column chromatography using
MeOH/CH2Cl2 (0−5% gradient) to afford compound 9 as a
yellow solid (0.20 g, 85%); mp 178 °C; FTIR (thin film, cm−1)
3-Bromo-1-phenyl-1H-1,2,4-triazole (7): To a 20 mL vial was
added aminotriazole 5 (0.16 g, 1.0 mmol), CuBr2 (0.27 g, 1.2
equiv), acetonitrile (5.0 mL) and amylnitrite (0.15 g, 1.2 equiv).
The mixture was heated at 65 °C and monitored by HPLC. Upon
reaction completion in 1 h, the mixture was cooled to room
temperature, passed through a thin pad of celite, concentrated in
vacuum and purified by silica gel column chromatography using
MeOH/CH2Cl2 (0−5% gradient) to afford compound 7 as a white
solid (94 mg, 42%); mp 71 °C; FTIR (thin film, cm−1) 3133,
1
3272, 3049, 1600, 1560; H NMR (300 MHz, CDCl3) δ 8.34 (s,
1H), 7.72 (dd, J = 8.6, 1.2 Hz, 2H), 7.61 – 7.48 (m, 4H), 7.40 –
7.32 (m, 3H), 7.03 – 6.95 (m, 1H), 6.74 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 161.0, 140.5, 139.1, 137.2, 129.7, 129.1, 127.2,
120.9, 119.0, 116.5; HRMS (ESI+) calculated for C14H13N4
(M+H), 237.1135; found, 237.1123.
1
3075, 1594, 1504, 1464; H NMR (300 MHz, CDCl3) δ 8.41 (s,
1H), 7.65 – 7.59 (m, 2H), 7.54 – 7.45 (m, 2H), 7.44 – 7.37 (m,

7
10. (a) Temple, C., Jr. In Triazoles 1,2,4; Mongomery, J. A., Ed.;
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John Wiley and Sons: New York, 1981; p 130. (b) Polya, J. B. In
Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.;
Pergamon Press: Oxford, UK, 1984; Vol. 5, p 733. (c) Katritzky,
A. R.; Rogovoy, B. V.; Vvedensky, V. Y.; Kovalenko, K.; Steel,
P. J.; Markov, V. I.; Forood, B. Synthesis 2001, 6, 897–903 and
references cited therein. (d) Makara, G. M.; Ma, Y.; Margarida, L.
Org. Lett. 2002, 4, 1751–1754 and references cited therein.
11. Davies, R. J.; Arnost, M. J.; Bemis, G. W.; Forster, C. J.; Grey, R.,
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M.; Abdel-Malik, M. S. Indian J. Chem., Sect. B 1989, 28B, 6,
479–485. (f) Abdel-Rahman, R. M.; Ghareib, M. Indian J. Chem.,
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Acknowledgments
The authors wish to thank Dr. Christine Gu for collecting
HRMS data and Dr. Chong Han and Dr. Sushant Malhotra for
helpful discussion.
Supplementary Material
Supplementary data associated with this article including
copies of H and 13C NMR spectra can be found in the online
1
version, at http://dx.doi.org.
References and notes
1. Jeff Shen was a sophomore undergraduate student from the
California Institute of Technology at the time of this work, which
was part of his summer intern project at Genentech, Inc.
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5. Fauchere, J.-L.; Ortuno, J.-C.; Duhault, J.; Boutin, J. A.; Levens,
N. European Patent EP 1044970, 2000.
14. For reviews on monocyclic rearrangements, see: (a) Makhova, N.
N.; Ovchinnikov, I. V.; Kulikov, A. S.; Molotov, S. I.;
Baryshnikova, E. L. Pure Appl. Chem. 2004, 76, 1691−1703. (b)
L'abbe, G. J. Heterocycl. Chem. 1984, 21, 627−638.
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17. For recent reviews on Buchwald-Hartwig amination, see: (a)
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Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046–2067.
18. 5-Phenyl-1,2,4-oxadiazol-3-amine is commercially available. For
a literature procedure, see: Huffman, K. R.; Schaefer, F. C. J. Org.
Chem. 1963, 28, 1812−1816.
19. 5-Methyl-1,2,4-oxadiazol-3-amine is commercially available. For
a literature procedure, see: Anderson, G. W.; Faith, H. E.; Marson,
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64, 2902−2905.
9. Baumann, K.; Goetschi, E.; Jolidon, S.; Limberg, A.; Luebbers, T.
PCT Int. Appl. 2010052199, 2010.
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SUPPORTING INFORMATION
Synthesis of 1-substituted 3-amino-1H-1,2,4-triazoles from
ethyl N-(5-phenyl-1,2,4-oxadiazol-3-yl)formimidate
Jeff Shen and Haiming Zhang*
Zhang.haiming@gene.com
Small Molecule Process Chemistry, Genentech, Inc.,
1 DNA Way, South San Francisco, CA, 94080, United States
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