A safe synthesis of 1,5-disubstituted 3-amino-1 H-1,2,4-triazoles from 1,3,4-oxadiazolium hexafluorophosphates

Article abstract of DOI:10.1055/s-0032-1316877

Hexafluorophosphoric acid promotes 1,3,4-oxadiazolium hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N- arylhydrazides under mild conditions. These 1,3,4-oxadiazolium hexafluorophosphates can be treated with cyanamid

Full text of DOI:10.1055/s-0032-1316877

PAPER
▌1083
paper
A Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles from
1,3,4-Oxadiazolium Hexafluorophosphates
Safety is Important for All Chemists
Brian Wong,a Andreas Stumpf,a Diane Carrera,a Chunang Gu,b Haiming Zhang*a
a
Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Fax +1(650)2256238; E-mail: zhang.haiming@gene.com
b
Small Molecule Analytical Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Received: 04.02.2013; Accepted after revision: 05.03.2013
ture.2,9–11
For
example,
the
reaction
of
Abstract: Hexafluorophosphoric acid promotes 1,3,4-oxadiazoli-
um hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhy-
drazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions.
These 1,3,4-oxadiazolium hexafluorophosphates can be treated
(benzotriazolyl)methanimines and substituted hydrazines
readily generates N,N-disubstituted 3-amino-1H-1,2,4-
triazoles;9,10 however, this chemistry is unable to produce
with cyanamide in propan-2-ol in the presence of triethylamine to N,N-unsubstituted triazole compounds (Scheme 1, A).
generate 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good
yields. This safe and scalable protocol displays a broad scope with
respect to N-substitutions and N′-acyl protecting groups.
Condensation of resin-bound S-methyl-N-acylisothio-
ureas with hydrazines led to the desired 1,5-disubstituted
3-aminotriazles after acid-promoted resin cleavage
(Scheme 1, B).11 This solid-phase synthesis provides a
Key words: heterocycles, substituent effects, rearrangement, hy-
drazide, aminotriazole
rapid entry to 1,5-disubstituted 3-amino-1H-1,2,4-tri-
azoles but has only been demonstrated on a very small
scale.11 Szilagyi has reported a synthesis of 1,5-disubsti-
The 3-amino-1H-1,2,4-triazole motif is found in a wide
variety of biologically active compounds with applica-
tions as herbicides1 and therapeutics with indications in
inflammatory diseases.2,3 In addition, 3-amino-1H-1,2,4-
triazole derivatives are also found to inhibit methionine
aminopeptidase-2 (MetAP2)4 and catalase and histidine
biosynthesis.5 Moreover, they have been described as
neuropeptide Y receptor ligands6 and potent antagonists
for the histamine H27 and corticotropin-releasing factor-1
(CRF1) receptors.8
tuted 3-amino-1H-1,2,4-triazoles through the reaction of
1,3,4-oxadiazolium perchlorates with cyanamide in
2-methoxyethanol (methyl cellosolve) at 120 °C (Scheme 1,
C).2 Unfortunately, the use of perchloric acid and perchlo-
rate salts raises serious safety concerns due to their explo-
sive nature and shock sensitivity,12 making them poorly
suited for large-scale synthesis. Moreover, while the focus
of Szilagyi’s work was on the structure–activity relation-
ship (SAR) of 1,5-disubstituted 3-amino-1H-1,2,4-tri-
azoles as potential anti-inflammatory agents, the
electronic and steric effects of the triazole substituents on
the reaction have yet to be established.
Only a few methods have been developed for the synthe-
sis of 1,5-disubsituted 3-amino-1H-triazoles in the litera-
A. Katritzky synthesis
R3
Bt
Bt
O
R4NHNH2
R3COCl
N
R1
R1
R4
N
N
R2
NH
N
R2
N
O
R3
R1
N
Et3N, THF
N
R2
B. Houghten synthesis
R1
N
R1
O
SMe O
R2NHNH2
TFA
N
N
N
R2
N
R2
O
N
N
H
R1
N
O
O
N
H
N
NH2
C. Szilagyi synthesis
Ar1
N
Ar1
Ar2
O
Ar1
Me
O
HClO4
Ac2O, 23 °C
H2NCN, Et3N
Ar2
N
N
N
MeOCH2CH2OH
120 °C
N
H
Me
Ar2
N
ClO4
NH2
Scheme 1 Literature syntheses of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles
SYNTHESIS 2013, 45, 1083–1093
Advanced online publication: 19.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316877; Art ID: SS-2013-M0104-OP
© Georg Thieme Verlag Stuttgart · New York

1084
B. Wong et al.
PAPER
R1
R1
Ar
O
O
R1
R2
O
HPF6
H2NCN, Et3N
N
N
N
N
Ar
N
N
H
R2
Ac2O, 23 °C
i-PrOH, 80 °C
Ar
N
PF6
NH2
Scheme 2 Improved synthesis of 3-amino-1H-1,2,4-triazoles
Our strategy focused on replacing the explosive perchlo-
ric acid reagent with a nonhazardous alternative to gener-
ate 1,3,4-oxadiazolium salts that could be handled safely
on process scale. Herein we wish to report a safe and scal-
able method for the preparation of 1,5-disubstituted 3-
amino-1H-1,2,4-triazoles from 1,3,4-oxadiazolium hexa-
fluorophosphates with a variety of electronically and ste-
rically diverse substituents (Scheme 2).
Table 1 Optimization of 1,3,4-Oxadiazolium Salt Formationa
O
O
HX
O
N
N
X
N
Ac2O, 23 °C
N
H
Our studies commenced with the investigation of 1,3,4-
oxadiazolium salt formation with N′-acetyl-4-methyl-N-
(p-tolyl)benzohydrazide (1a) in the presence of various
Brønsted acids (Table 1). As shown in Table 1, reactions
employing noncoordinating acids such as perchloric acid
(HClO4) and hexafluorophosphoric acid (HPF6) readily
reached quantitative conversion in two hours. The corre-
sponding 1,3,4-oxadiazolium salts were isolated in 97%
and 74% yield, respectively, by crystallization induced by
addition of the antisolvent tert-butyl methyl ether (Table
1, entries 1 and 2). Surprisingly, only moderate conver-
sion was observed when the reaction was performed using
the noncoordinating tetrafluoroboric acid (HBF4) (Table
1, entry 3; 61%). To our delight, trifluoromethanesulfonic
acid (TfOH) also successfully promoted the 1,3,4-oxadia-
zolium triflate formation in 100% conversion and 81%
isolated yield (Table 1, entry 4). Although reactions using
methanesulfonic acid (MsOH) and sulfuric acid (H2SO4)
afforded excellent conversions (Table 1, entries 5 and 6;
91% and 100%), the isolation of the 1,3,4-oxadiazolium
salts by crystallization was unsuccessful. Interestingly,
hydrochloric acid (HCl) did not produce any noticeable
1,3,4-oxadiazolium chloride, presumably because the nu-
cleophilic nature of chloride anion inhibits the formation
of the 1,3,4-oxadiazolium salt (Table 1, entry 7). The rel-
atively weaker acid trifluoroacetic acid (TFA) gave only
23% conversion (Table 1, entry 8), indicating that the pKa
of the acid plays an important role in salt formation. The
effect of pKa is clearly seen in Table 1 as full conversion
into the 1,3,4-oxadiazolium salt is observed in all cases
with acids having a pKa < –1.0. In contrast, when acids
with a pKa > –1.0 (in water), such as MsOH (–0.6, entry
5), HBF4 (–0.4, entry 3), and TFA (–0.25, entry 8) were
employed, the reactions typically generated incomplete
conversion. In general, as the pKa of the acid increases, the
conversion of the reaction decreases.
1a
2a
Entry HX
pKa H2O (DMSO) Conv. (%)b Product Yield
2 h (4 h)
(%)c
2a1
2a2
1
2
3
4
5
6
7
8
HClO4 –10.013a
HPF6
< –3.013b
100
97
74
100
HBF4 –0.413c
61 (62)
100
–
–
d
TfOH –14.0 (0.3)13d
MsOH –0.6 (1.6)13a
H2SO4 –3.013e
81
2a3
d
91 (92)
100
–
–
–
–
–
d
–
HCl
–8.0 (1.8)13f
0
–
d
TFA
–0.25 (0.23)13g
23 (24)
–
a Reaction conditions: 1a (0.50 g, 1.77 mmol), HX (1.1 equiv), and
Ac2O (2.5 mL), 23 °C.
b Determined by 1H NMR analysis.
c Isolated yield. The salt was isolated by addition of MTBE (6.0 mL)
followed by filtration. All three isolated salts were stable for at least
two months on bench top at r.t.
d Isolation of the salt was not successful.
reported that 1,3,4-oxadiazolium perchlorates were con-
verted into the corresponding 3-amino-1H-1,2,4-triazoles
using the toxic solvent 2-methoxyethanol14 at 120 °C.2
This reaction temperature is alarmingly high, considering
that the perchlorates are potentially explosive at elevated
temperatures.12 To obviate the use of 2-methoxyethanol
and high reaction temperatures, the reaction was per-
formed using perchlorate 2a1 in propan-2-ol at the milder
temperature of 80 °C. The reaction proceeded smoothly to
afford the desired 3-amino-1H-1,2,4-triazole 3a in 74%
isolated yield after two hours (Table 2, entry 1). Gratify-
ingly, both reactions employing the hexafluorophosphate
2a2 and the trifluoromethanesulfonate 2a3 also successful-
ly generated the desired 3-amino-1H-1,2,4-triazole 3a in
77% and 88% yield, respectively (Table 2, entries 2 and
3).
With the 2,3-bis(p-tolyl)-1,3,4-oxadiazolium perchlorate
(2a1), hexafluorophosphate (2a2), and trifluoromethane-
sulfonate (2a3) salts in hand, their conversion into 3-ami-
no-1H-1,2,4-triazole through their reaction with
cyanamide were examined next. Szilagyi had previously
Synthesis 2013, 45, 1083–1093
© Georg Thieme Verlag Stuttgart · New York

PAPER
Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles
1085
Table 2 Aminotriazole 3a Formation from 2aa
Considering the safety hazard of the perchlorate salts and
the hydroscopic and corrosive nature of trifluoromethane-
sulfonic acid, a general synthesis of 3-amino-1H-1,2,4-tri-
azoles via their 1,3,4-oxadiazolium hexafluorophosphate
intermediates was pursued (Table 3). The formation of
O
H2NCN, Et3N
N
N
X
i-PrOH, 80 °C
2,3-bis(p-tolyl)-1,3,4-oxadiazolium
hexafluorophos-
2 h
N
N
phate (2a2) from N′-acetyl-4-methyl-N-(p-tolyl)benzohy-
drazide (1a) and its transformation to 1,5-bis(p-tolyl)-3-
amino-1H-1,2,4-triazole (3a) was performed on a ten-
gram scale and both reactions successfully generated the
desired compounds 2a2 and 3a in 71% and 89% yield, re-
spectively (Table 3, entry1). It is worth mentioning that on
this scale it was possible to isolate both compounds 2a2
and 3a by simple crystallization (Table 3, entry 1).
N
NH2
2a
3a
Entry
X
Salt
2a1
2a2
2a3
Product
Yield (%)b
1
2
3
ClO4
PF6
3a
3a
3a
74
77
88
CF3SO3
a Reaction conditions: 2a (1.0 mmol), cyanamide (3.0 equiv), and
Et3N (3.0 equiv) in i-PrOH (2.0 mL), 80 °C, 2 h.
b Isolated yield.
Table 3 Substrate Scope: Substitution at N- and N′-Positions
R1
R1
O
O
R1
R2
O
HPF6
H2NCN, Et3N
N
N
N
N
Ar
N
Ar
N
H
R2
Ac2O, 23 °C
2 h
i-PrOH, 80 °C
Ar
N
PF6
2 h
NH2
Entry Hydrazide
Salt
Yield
(%)a,b
Aminotriazole
Yield
(%)b,c
O
O
O
N
N
1
1a
74 (71)d
3a
77 (89)e
2a2
2b
2c
N
N
H
PF6
N
N
N
NH2
MeO
MeO
MeO
O
O
O
N
N
2
1b
1c
1d
69
71
61
3b
3c
3d
81
71
46
N
N
H
PF6
N
N
N
NH2
NC
NC
NC
O
O
O
N
N
3
PF6
N
N
H
N
N
N
NH2
O
O
O
N
N
4
2d
N
N
H
PF6
N
N
N
NH2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1083–1093

1086
B. Wong et al.
PAPER
Table 3 Substrate Scope: Substitution at N- and N′-Positions (continued)
R1
R1
O
O
R1
R2
O
HPF6
H2NCN, Et3N
N
N
N
N
Ar
N
Ar
N
H
R2
Ac2O, 23 °C
2 h
i-PrOH, 80 °C
Ar
N
PF6
2 h
NH2
Entry Hydrazide
Salt
Yield
(%)a,b
Aminotriazole
Yield
(%)b,c
O
O
O
N
N
N
N
N
H
5
1e
1f
2e
2f
65
58
3e
3f
70
N
PF6
N
NH2
O
O
O
N
N
N
6
62
78
N
N
H
PF6
N
N
NH2
O
O
O
N
N
7
1g
1h
2g
2h
78
3g
3h
N
N
H
PF6
N
MeO
N
N
MeO
NH2
MeO
O
O
O
N
N
8
60f
85
80
N
N
H
PF6
N
F3C
N
F3C
N
NH2
F3C
O
O
O
N
N
9
1i
2i
65
3i
N
N
H
PF6
N
N
N
NH2
O
CF3
O
O
N
N
10
11
1j
2j
54f
3a
3a
88
82
N
PF6
N
H
CF3
N
N
N
NH2
O
O
O
N
N
1k
2k
58
–
N
PF6
N
H
N
N
N
NH2
a Reaction conditions: 1 (0.50 g), HPF6 (1.1 equiv), and Ac2O (2.5 mL), 23 °C. The salt was isolated by adding MTBE (6.0 mL) and filtration.
b Isolated yield.
c Reaction conditions: 2 (1.0 mmol), cyanamide (3.0 equiv), Et3N (3.0 equiv), and i-PrOH (2.0 mL), 80 °C, 2 h.
d The yield in parentheses was obtained by performing the reaction with 1a at 10.0 g (35.4 mmol) scale.
e The yield in parentheses was obtained by performing the reaction with 2a2 at 10.0 g (24.4 mmol) scale. Product 3a was isolated by workup and crystallization.
f The reaction was performed at 23 °C for 2 h and then 50 °C for 20 h.
Synthesis 2013, 45, 1083–1093
© Georg Thieme Verlag Stuttgart · New York

PAPER
Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles
1087
The electronic and steric effects of the N-acyl substituent ation of intermediate 4 to generate intermediate 5 are fast
on hydrazides for 1,3,4-oxadiazolium salt and triazole for- and reversible. In fact, only hydrazide 1a and salt 2a were
mation were examined first. As shown in Table 3, both observed by 1H NMR analysis before the reaction reached
electron-rich 4-methoxy- and electron-deficient 4-cyano- completion. Intermediate 5 produces 1,3,4-oxadiazolium
substituted hydrazides 1b and 1c afforded the desired salt 2a by irreversibly losing a molecule of water which is
1,3,4-oxadiazolium hexafluorophosphates 2b,c and 3- subsequently consumed by readily reacting with acetic
amino-1H-1,2,4-triazoles 3b,c in satisfactory yields (Ta- anhydride. If the N3 position is substituted with an
ble 3, entries 2, 3; 69–81%). When steric hindrance on the electron-deficient aryl group, such as 4-trifluoromethyl-
N-aroyl substituent was introduced by employing a 2,4,6- phenyl, the ability of the N3 lone-pair electrons participat-
mesityl-substituted hydrazide 1d, the yields for both the ing in the dehydration process is thus reduced, therefore,
hexafluorophosphate salt 2d and the aminotriazole 3d the reaction requires higher temperature and longer time
were noticeably lower, in 61% and 46%, respectively, to reach completion (Table 3, entry 8). Salt 2a then reacts
which indicates that steric hindrance on the N-aroyl group with the cyanamide nucleophile to afford intermediate 6,
adversely impacts both reactions (Table 3, entry 4). As ex- which undergoes ring opening to form intermediate 7. Re-
pected, N-acetyl- and N-isobutyryl-substituted hydrazides arrangement of 7 gives the cyclized intermediate 8, which
1e and 1f also successfully produced the desired salts 2e then possibly reacts with another equivalent of cyanamide
and 2f and aminotriazoles 3e and 3f, in moderate yields to produce the fully aromatized 3-amino-1H-1,2,4-tri-
ranging from 58% to 70% (Table 3, entries 5, 6).
azole product 3a (Scheme 3). The reactive intermediates
6–8 were believed to have a short lifetime as we were un-
able to observe any of them by 1H NMR spectroscopy or
HPLC. Interestingly, when the aminotriazole formation
reaction was performed using salt 2a2 and only one equiv-
alent of cyanamide under otherwise identical conditions,
a mixture of starting salt 2a2, a relatively stable intermedi-
ate with mass corresponding to 8, and product 3a was ob-
served in a 15:20:65 ratio based on 1H NMR, HPLC, and
LCMS analyses, which clearly supports the proposed ami-
notriazole formation mechanism.
The electronic and steric effects of the N-aryl group on
hydrazides 1g–i were investigated next. Electron-rich
4-methoxyphenyl-substituted hydrazide 1g uneventfully
led to the formation of the hexafluorophosphate salt 2g
and the aminotriazole 3g, both in 78% yield (Table 3, en-
try 7). However, the electron-deficient 4-trifluoromethyl-
phenyl-substituted hydrazide 1h not only took longer at a
higher temperature (50 °C) to reach good conversion, but
also the isolated yield for salt 2h was lower (Table 3, entry
8; 60%). Interestingly, the formation of aminotriazole 3h
from salt 2h was not impeded significantly as the reaction In conclusion, we have developed a safe and potentially
generated 85% yield of 3h in two hours (Table 3, entry 8). scalable method for the preparation of 1,5-disubstituted 3-
The sterically hindered 2,4,6-mesityl-substituted hydra- amino-1H-1,2,4-triazoles from 1,3,4-oxadiazolium hexa-
zides 1i also afforded a moderate yield of salt 2i in 65% fluorophosphates. While both electronic and steric effects
(Table 2, entry 9). To our surprise, the transformation of have impact on the efficiency of the 1,3,4-oxadiazolium
2i to aminotriazole 3i was as efficient (80% in 2 h) as the hexafluorophosphate formation, they are less profound
reaction with the sterically unhindered hydrazide 1a for the formation of 3-amino-1H-1,2,4-triazoles. We an-
(compare entries 1 and 9 in Table 3). These results indi- ticipate that this practical method will provide rapid ac-
cate that the electronic and steric effects of the aryl group cess to useful quantities of versatile 1,5-disubstituted 3-
on the hydrazine generally impact the salt formation more amino-1H-1,2,4-triazoles.
remarkably than the aminotriazole formation.
Finally, the electronic and steric effects of the N′-acyl
group on the terminal nitrogen of the hydrazide were
probed. The electron-deficient trifluoroacetyl-substituted
hydrazide 1j and sterically bulky pivaloyl-substituted hy-
drazide 1k produced relatively low yields of the hexafluo-
rophosphate salts 2j and 2k (Table 3, entries 10 and 11;
54% and 58%). Again, the aminotriazole formation from
salts 2j and 2k went smoothly, giving the desired product
3a in 88% and 82% yield, respectively. As seen from
these two experiments, the electronic and steric effects of
the N′-acyl group noticeably affect the efficiency of salt
formation but have less impact on the efficiency of ami-
notriazole formation.
Unless stated otherwise, reactions were performed under an ambi-
ent atmosphere of N2 in 20 mL vials sealed with Teflon-lined caps.
All solvents and commercially obtained reagents were used as re-
ceived, unless specified otherwise. N′-Acyl-N-arylhydrazide start-
ing materials were prepared from N-arylhydrazine and Ac2O
according to a modified literature procedure.15 TLC was conducted
with EMD silica gel 60 F254 precoated plates and visualized using
UV light (254 nm). Flash column chromatography was performed
with prepacked RediSep silica gel columns on a CombiFlash ISCO
system using MeOH in CH2Cl2 (0–5% gradient) as eluent. Analyti-
cal 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, 2.05 for acetone-d6).
Data for 1H NMR spectra are reported as follows: chemical shift (δ
ppm), multiplicity, coupling constant (Hz), and integration. 13C
NMR spectra were recorded on a Bruker 300 spectrometer (at 75
MHz), and are reported relative to the residual solvent peak (δ =
Our proposed mechanism for the 1,3,4-oxadiazolium salt
formation and its subsequent conversion into 3-amino-
1H-1,2,4-triazole as exemplified by N′-acetyl-4-methyl- 77.0 for CDCl3, 39.5 for DMSO-d6, 29.9 for acetone-d6). Data for
13C NMR spectra are reported in terms of chemical shift (δ ppm). IR
N-(p-tolyl)benzohydrazide (1a) is given in Scheme 3. We
believe that both the cyclization of hydrazide 1a to form
intermediate 4 in the presence of an acid and the proton-
spectra were recorded on a Bruker Alpha Platinum-ATR spectrom-
eter and are reported in frequency of absorption (cm–1). HRMS data
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1083–1093

1088
B. Wong et al.
PAPER
OH2
HO
O
O
1
HX
AcOH
Ac2O
N
N
N
N
X
3
4
H2O
HX
4
5
O
O
O
N
N
X
N
N
H
1a
2a
1,3,4-oxadiazolium salt formation
H2NCN
3-amino-1H-1,2,4-triazole formation
HX
CN
O
HN
N
N
N
N
N
NH2
3a
6
N
O
H2NCN
N
NHCN
N
NH
O
N
N
N
NH
O
8
7
Scheme 3 Proposed mechanism for the formation of 3-amino-1H-1,2,4-triazole
were obtained on a LTQ Orbitrap Discovery (Thermo Fisher Scien-
tific) at Genentech, Inc. Melting points were measured by differen-
tial scanning calorimetry (DSC) and reported as onset temperature.
N′-Acetyl-4-methoxy-N-(p-tolyl)benzohydrazide (1b)
Prepared from N′-acetyl-p-tolylhydrazine (2.00 g, 12.2 mmol) and
p-anisoyl chloride (2.10 g, 1.0 equiv); white solid (2.16 g, 60%); mp
151 °C.
Hydrazides 1; General Procedure
FTIR (thin film): 3279, 3007, 1676, 1511, 1252 cm–1.
To a solution of N′-acyl-N-arylhydrazide (1.0 equiv) in toluene (30
vol, vol = mL/g) in a round-bottomed flask was added aroyl chlo-
ride (1.0 equiv) and the mixture was heated to 80 °C for 5 h. The
mixture was cooled to r.t., diluted with EtOAc (10 vol), washed
with H2O (5 vol) and brine (5 vol). The organic layer was concen-
trated and purified by silica gel column chromatography (MeOH–
CH2Cl2 gradient, 0–5% or EtOAc–CH2Cl2 gradient, 0–100%).
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.44 (dd, J = 8.7, 1.7
Hz, 2 H), 7.17–7.07 (m, 2 H), 7.07–6.98 (m, 2 H), 6.72 (dd, J = 8.7,
1.7 Hz, 2 H), 3.77 (s, 3 H), 2.29 (s, 3 H), 2.05 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 169.5, 161.5, 140.9, 137.0,
131.2, 129.6, 126.1, 125.9, 113.2, 55.3, 21.03, 21.00.
HRMS (ESI): m/z calcd for C17H19N2O3 ([M + H]+): 299.1390;
N′-Acetyl-4-methyl-N-(p-tolyl)benzohydrazide (1a)
Prepared from N′-acetyl-p-tolylhydrazine (5.65 g, 34.4 mmol) and
p-toluoyl chloride (5.43 g, 1.0 equiv); white solid (5.83 g, 60%); mp
143 °C.
FTIR (thin film): 3441, 3220, 2922, 1669, 1357 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.44 (s, 1 H), 7.35 (d, J = 8.0 Hz,
2 H), 7.11–7.01 (m, 6 H), 2.29 (s, 3 H), 2.28 (s, 3 H), 2.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.1, 169.6, 141.0, 140.6, 137.0,
131.2, 129.6, 128.9, 128.6, 126.1, 21.4, 21.0, 20.9.
HRMS (ESI): m/z calcd for C17H19N2O2 ([M + H]+): 283.1441;
found: 299.1383.
N′-Acetyl-4-cyano-N-(p-tolyl)benzohydrazide (1c)
Prepared from N′-acetyl-p-tolylhydrazine (6.00 g, 36.6 mmol) and
4-cyanobenzoyl chloride (6.18 g, 1.0 equiv); white solid (8.14 g,
76%); mp 167 °C.
FTIR (thin film): 3345, 3278, 2229, 1685, 1510, 1342 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.91 (s, 1 H), 7.88 (br s, 2 H),
7.64 (br s, 2 H), 7.40–7.10 (br m, 4 H), 2.28 (br s, 3 H), 1.71 (br s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 168.3, 140.0, 138.8 (br), 136.1
(br), 132.0, 129.2, 128.0 (br), 123.8 (br), 118.2, 112.5, 20.5, 20.2.
found: 283.1435.
Synthesis 2013, 45, 1083–1093
© Georg Thieme Verlag Stuttgart · New York

PAPER
Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles
1089
HRMS (ESI): m/z calcd for C17H16N3O2 ([M + H]+): 294.1237;
found: 294.1233.
N′-Acetyl-4-methyl-N-[4-(trifluoromethyl)phenyl]benzohydra-
zide (1h)
Prepared from N′-(4-trifluoromethylphenyl)acetohydrazide (1.00 g,
4.58 mmol) and p-toluoyl chloride (0.72 g, 1.0 equiv); white solid
(1.33 g, 86%); mp 183 °C.
FTIR (thin film): 3330, 1686, 1324, 1115 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1 H), 7.49 (d, J = 8.8 Hz,
2 H), 7.36 (d, J = 8.8 Hz, 2 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.08 (d,
J = 8.8 Hz, 2 H), 2.33 (s, 3 H), 2.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.0, 169.9, 145.8, 141.9, 130.5,
129.0, 128.8, 126.0 (q, J = 4.0 Hz), 125.3, 122.4, 21.5, 20.9.
N′-Acetyl-2,4,6-trimethyl-N-(p-tolyl)benzohydrazide (1d)
Prepared from N′-acetyl-p-tolylhydrazine (2.00 g, 12.2 mmol) and
2,4,6-trimethylbenzoyl chloride (2.27 g, 1.0 equiv); white solid
(1.91 g, 51%); mp 220 °C (dec.).
FTIR (thin film): 3223, 3004, 1644, 1510, 1340 cm–1.
1H NMR (400 MHz, CDCl3): δ (two rotamers in 85:15 ratio, major
rotamer) = 8.58 (s, 1 H), 7.05 (d, J = 8.0 Hz, 2 H), 6.92 (d, J = 8.0
Hz, 2 H), 6.68 (s, 2 H), 2.27 (s, 6 H), 2.22 (s, 3 H), 2.18 (s, 3 H),
2.12 (s, 3 H); δ (minor rotamer) = 7.78 (s, 1 H), 7.44 (d, J = 8.0 Hz,
2 H), 7.20 (d, J = 8.0 Hz, 2 H), 6.83 (s, 2 H), 2.36 (s, 6 H), 2.27 (s,
3 H) (two methyl peaks are missing due to overlap).
HRMS (ESI): m/z calcd for C17H16F3N2O2 ([M + H]+): 337.1158;
found: 337.1153.
13C NMR (100 MHz, CDCl3): δ = 172.6, 170.3, 169.9, 168.6, 138.9,
138.7, 137.3, 134.3, 132.2, 129.6, 129.1, 128.2, 128.1, 125.4, 125.1,
31.9, 29.0, 22.7, 21.1, 21.0, 19.5, 19.1, 14.1.
HRMS (ESI): m/z calcd for C19H23N2O2 ([M + H]+): 311.1754;
found: 311.1749.
N′-Acetyl-N-mesityl-4-methylbenzohydrazide (1i)
Prepared from N′-(2,4,6-trimethylphenyl)acetohydrazide (1.18 g,
6.15 mmol) and p-toluoyl chloride (0.97 g, 1.0 equiv); white solid
(1.54 g, 81%); mp 83 °C.
FTIR (thin film): 3466, 3184, 2996, 1640, 1344 cm–1.
1H NMR (400 MHz, CDCl3): δ (two rotamers in 85:15 ratio, major
rotamer): 7.95 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8 Hz,
2 H), 6.79 (s, 2 H), 2.27 (s, 3 H), 2.24 (s, 6 H), 2.22 (s, 3 H), 2.08 (s,
3 H); δ (minor rotamer) = 7.74 (s, 1 H), 7.56 (d, J = 8.8 Hz, 2 H),
7.20 (d, J = 8.8 Hz, 2 H), 6.93 (s, 2 H), 2.40 (s, 6 H), 2.39 (s, 3 H)
(two methyl peaks are missing due to overlap).
13C NMR (100 MHz, CDCl3): δ = 168.9, 168.8, 141.4, 138.3, 137.3,
135.7, 130.6, 129.8, 129.6, 128.9, 128.5, 128.4, 127.0, 21.5, 21.2,
20.9, 18.7.
N′-Acetyl-N-(p-tolyl)acetohydrazide (1e)
Prepared from N′-acetyl-p-tolylhydrazine (1.72 g, 10.5 mmol) and
acetyl chloride (0.82 g, 1.0 equiv); yellow solid (0.86 g, 40%); mp
94 °C.
FTIR (thin film): 3184, 3010, 1695, 1658, 1506 cm–1.
1H NMR (300 MHz, CDCl3): δ (two rotamers in 80:20 ratio) = 8.95
(br s, 0.2 H), 8.41 (br s, 0.8 H), 7.30–6.80 (br m, 4 H), 2.30 (br s, 3
H), 2.10 (br s, 1 H), 1.92 (br s, 5 H).
13C NMR (75 MHz, CDCl3): δ = 170.0, 169.4, 139.6, 138.9, 130.1,
129.5, 127.4, 125.0, 22.0, 21.1, 20.8.
HRMS (ESI): m/z calcd for C11H15N2O2 ([M + H]+): 207.1128;
found: 207.1120.
HRMS (ESI): m/z calcd for C19H23N2O2 ([M + H]+): 311.1754;
found: 311.1747.
4-Methyl-N-(p-tolyl)-N′-(2,2,2-trifluoroacetyl)benzohydrazide
(1j)
Prepared from 2,2,2-trifluoro-N′-(p-tolyl)acetohydrazide (1.78 g,
8.15 mmol) and p-toluoyl chloride (1.29 g, 1.0 equiv); white solid
(2.38 g, 87%); mp 127 °C.
FTIR (thin film): 3203, 3018, 1744, 1643, 1137 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.86 (s, 1 H), 7.29 (d, J = 8.8 Hz,
2 H), 7.04–6.99 (m, 6 H), 2.28 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 156.4 (q, J = 38 Hz),
141.9, 139.2, 138.2, 130.0, 129.8, 129.1, 128.8, 126.5, 115.6 (q,
J = 27.8 Hz), 21.5, 21.0.
N′-Acetyl-N-(p-tolyl)isobutyrohydrazide (1f)
Prepared from N′-acetyl-p-tolylhydrazine (1.72 g, 10.5 mmol) and
isobutyryl chloride (1.23 g, 1.0 equiv); white solid (2.20 g, 90%);
mp 107 °C.
FTIR (thin film): 3205, 2973, 1700, 1649, 1503 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.53 (br s, 1 H), 7.33 (d, J = 9.0
Hz, 2 H), 7.20 (d, J = 9.0 Hz, 2 H), 2.63 (br s, 1 H), 2.38 (s, 3 H),
2.02 (s, 3 H), 1.10 (d, J = 8.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 177.2, 169.3, 139.3, 138.8, 130.0,
127.6, 31.0, 21.1, 20.9, 19.3.
HRMS (ESI): m/z calcd for C13H19N2O2 ([M + H]+): 235.1441;
HRMS (ESI): m/z calcd for C17H16F3N2O2 ([M + H]+): 337.1158;
found: 337.1153.
found: 235.1431.
4-Methyl-N′-pivaloyl-N-(p-tolyl)benzohydrazide (1k)
Prepared from 2,2-dimethyl-N′-(p-tolyl)propanehydrazide (2.20 g,
10.7 mmol) and p-toluoyl chloride (1.68 g, 1.0 equiv); white solid
(3.26 g, 94%); mp 189 °C.
N′-Acetyl-N-(4-methoxyphenyl)-4-methylbenzohydrazide (1g)
Prepared from N′-(4-methoxyphenyl)acetohydrazide (2.22 g, 12.3
mmol) and p-toluoyl chloride (1.94 g, 1.0 equiv); white solid (2.19
g, 60%); mp 149 °C.
FTIR (thin film): 3253, 2970, 1658, 1508, 1353 cm–1.
FTIR (thin film): 3254, 3008, 1644, 1506, 1362, 1244 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 7.36 (d, J = 8.8 Hz,
2 H), 7.09 (d, J = 8.8 Hz, 2 H), 7.03 (d, J = 8.8 Hz, 4 H), 2.29 (s, 3
H), 2.28 (s, 3 H), 1.22 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 177.7 (br), 140.9, 140.5, 136.7,
131.4, 129.5, 128.8, 128.5, 125.5, 38.4, 27.2, 21.5, 21.0 (one sp2
carbon missing due to peak broadening).
1H NMR (400 MHz, DMSO-d6): δ = 10.75 (s, 1 H), 7.35 (br s, 2 H),
7.21–7.15 (m, 4 H), 6.88 (d, J = 8.8 Hz, 2 H), 3.73 (s, 3 H), 2.30 (s,
3 H), 1.75 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.0, 157.6, 139.9, 132.3
(br), 128.3, 127.8 (br), 126.6 (br), 113.8, 55.3, 20.9, 20.3 (two sp2
carbons missing due to peak broadening).
HRMS (ESI): m/z calcd for C20H25N2O2 ([M + H]+): 325.1911;
found: 325.1902.
HRMS (ESI): m/z calcd for C17H19N2O3 ([M + H]+): 299.1390;
found: 299.1384.
Salts 2; General Procedure
To a 20 mL vial was added N′-acetyl-4-methyl-N-(p-tolyl)benzohy-
drazide (1a; 0.50 g, 1.77 mmol, 1.0 equiv), Ac2O (2.5 mL) and the
corresponding acid (1.1 equiv) while keeping the temperature be-
low 40 °C. The mixture was stirred at r.t. and the progress of the re-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1083–1093

1090
B. Wong et al.
PAPER
action was monitored by 1H NMR spectroscopy. Upon completion
of the reaction, MTBE (6.0 mL) was added to facilitate precipitation
and the mixture was stirred at r.t. for 18 h. The solid was filtered and
dried under vacuum at r.t. to afford the desired salt.
HRMS (ESI): m/z calcd for C17H17N2O2 ([M – PF6]+): 281.1285;
found: 281.1283.
2-(4-Cyanophenyl)-5-methyl-3-(p-tolyl)-1,3,4-oxadiazol-3-ium
Hexafluorophosphate (2c)
The compound was isolated as a white solid (0.52 g, 71%); mp
214 °C.
FTIR (thin film): 3277, 2229, 1685, 1510 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 8.17–8.04 (m, 4 H), 7.74–7.65
(m, 2 H), 7.65–7.60 (m, 2 H), 3.04 (s, 3 H), 2.52 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 167.7, 162.9, 145.0, 134.4,
132.3, 132.0, 130.1, 126.1, 122.4, 119.9, 117.7, 21.4, 11.2.
31P NMR (121 MHz, acetone-d6): δ = –144.4 (sept, J = 702 Hz).
19F NMR (282 MHz, acetone-d6): δ = 104.8 (d, J = 705 Hz).
HRMS (ESI): m/z calcd for C17H14N3O ([M – PF6]+): 276.1131;
5-Methyl-2,3-di-p-tolyl-1,3,4-oxadiazol-3-ium Perchlorate (2a1)
Prepared from N′-acetyl-4-methyl-N-(p-tolyl)benzohydrazide (1a;
0.50 g) and 70% aq HClO4 (0.28 g, 1.1 equiv); white solid (0.63 g,
97%); mp 156 °C.
FTIR (thin film): 3066, 2932, 1622, 1082 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.80–7.66 (m, 4 H), 7.65–7.56
(m, 2 H), 7.56–7.48 (m, 2 H), 2.95 (s, 3 H), 2.52 (s, 3 H), 2.48 (s, 3
H).
13C NMR (75 MHz, acetone-d6): δ = 166.4, 164.1, 149.0, 144.3,
132.4, 132.1, 131.32, 131.27, 131.1, 126.6, 115.8, 22.0, 21.4, 11.3.
HRMS (ESI): m/z calcd for C17H17N2O ([M – ClO4]+): 265.1335;
found: 265.1328.
found: 276.1129.
2-Mesityl-5-methyl-3-(p-tolyl)-1,3,4-oxadiazol-3-ium Hexafluo-
5-Methyl-2,3-di-p-tolyl-1,3,4-oxadiazol-3-ium Hexafluorophos-
phate (2a2)
Prepared from N′-acetyl-4-methyl-N-(p-tolyl)benzohydrazide (1a;
0.50 g) and 65% aq HPF6 (0.44 g, 1.1 equiv); white solid (0.54 g,
74%); mp 163 °C.
rophosphate (2d)
The compound was isolated as a white solid (0.43 g, 61%); mp
149 °C.
FTIR (thin film): 2954, 1613, 1289, 832 cm−1.
FTIR (thin film): 2927, 1621, 1514, 835 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.55–7.43 (m, 4 H), 7.22 (s, 2
1H NMR (300 MHz, acetone-d6): δ = 7.80–7.65 (m, 4 H), 7.64–7.56
(m, 2 H), 7.56–7.46 (m, 2 H), 2.95 (s, 3 H), 2.52 (s, 3 H), 2.48 (s, 3
H).
H), 3.03 (s, 3 H), 2.44 (s, 3 H), 2.41 (s, 3 H), 2.26 (s, 6 H).
13C NMR (75 MHz, acetone-d6): δ = 169.6, 164.6, 147.2, 144.4,
140.8, 131.9, 131.8, 131.1, 124.2, 114.7, 21.5, 21.3, 19.8, 11.8.
13C NMR (75 MHz, acetone-d6): δ = 166.4, 164.1, 149.5, 144.5,
132.3, 132.2, 131.5, 131.1, 126.4, 115.6, 22.0, 21.4, 11.1.
19F NMR (282 MHz, acetone-d6): δ = 104.7 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.4 (sept, J = 702 Hz).
19F NMR (282 MHz, acetone-d6): δ = 104.8 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 702 Hz).
HRMS (ESI): m/z calcd for C19H21N2O ([M – PF6]+): 293.1648;
found: 293.1644.
HRMS (ESI): m/z calcd for C17H17N2O ([M – PF6]+): 265.1335;
found: 265.1327.
2,5-Dimethyl-3-(p-tolyl)-1,3,4-oxadiazol-3-ium Hexafluoro-
phosphate (2e)
The compound was isolated as a white solid (0.53 g, 65%); mp
140 °C.
FTIR (thin film): 3004, 2951, 1635, 1509, 1300 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.71 (d, J = 8.0 Hz, 2 H), 7.60
(d, J = 8.0 Hz, 2 H), 3.21 (s, 3 H), 2.90 (s, 3 H), 2.51 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 168.3, 167.0, 144.1, 131.8,
5-Methyl-2,3-di-p-tolyl-1,3,4-oxadiazol-3-ium Trifluorometh-
anesulfonate (2a3)
Prepared from N′-acetyl-4-methyl-N-(p-tolyl)benzohydrazide (1a;
0.50 g) and CF3SO3H (0.30 g, 1.1 equiv); white solid (0.60 g, 81%);
mp 165 °C.
FTIR (thin film): 2930, 1624, 1258, 1031 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.76 (d, J = 9.0 Hz, 2 H), 7.73
(d, J = 9.0 Hz, 2 H), 7.60 (d, J = 9.0 Hz, 2 H), 7.50 (d, J = 9.0 Hz, 2
H), 2.92 (s, 3 H), 2.51 (s, 3 H), 2.47 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 166.4, 164.1, 149.0, 144.3,
132.4, 132.0, 131.3, 131.2, 126.6, 115.6, 21.9, 21.4, 11.3.
131.0, 125.5, 21.3, 12.5, 11.0.
19F NMR (282 MHz, acetone-d6): δ = 104.6 (d, J = 708 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.4 (sept, J = 702 Hz).
HRMS (ESI): m/z calcd for C11H13N2O ([M – PF6]+): 189.1022;
found: 189.1013.
19F NMR (282 MHz, acetone-d6): δ = 98.7.
HRMS (ESI): m/z calcd for C17H17N2O ([M – CF3SO3]+): 265.1335;
found: 265.1327.
2-Isopropyl-5-methyl-3-(p-tolyl)-1,3,4-oxadiazol-3-ium Hexa-
fluorophosphate (2f)
The compound was isolated as a white solid (0.45 g, 58%); mp
118 °C.
2-(4-Methoxyphenyl)-5-methyl-3-(p-tolyl)-1,3,4-oxadiazol-3-
ium Hexafluorophosphate (2b)
The compound was isolated as a white solid (0.50 g, 69%); mp
211 °C.
FTIR (thin film): 2987, 1625, 1509, 1289 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.71 (d, J = 9.0 Hz, 2 H), 7.60
(d, J = 9.0 Hz, 2 H), 3.84 (sept, J = 6.0 Hz, 1 H), 2.89 (s, 3 H), 2.51
(s, 3 H), 1.53 (d, J = 6.0 Hz, 6 H).
13C NMR (75 MHz, acetone-d6): δ = 173.1, 167.1, 144.4, 131.9,
131.0, 126.0, 27.5, 21.3, 19.2, 11.1.
19F NMR (282 MHz, acetone-d6): δ = 104.6 (d, J = 708 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.4 (sept, J = 702 Hz).
FTIR (thin film): 3016, 1576, 1502, 1273, 1183 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.86–7.77 (m, 2 H), 7.74–7.66
(m, 2 H), 7.66–7.57 (m, 2 H), 7.26–7.15 (m, 2 H), 3.97 (s, 3 H), 2.91
(s, 3 H), 2.53 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 167.2, 165.7, 163.6, 144.4,
133.6, 132.5, 132.3, 126.5, 116.6, 110.0, 56.7, 21.4, 11.1.
HRMS (ESI): m/z calcd for C13H17N2O ([M – PF6]+): 217.1335;
found: 217.1328.
19F NMR (282 MHz, acetone-d6): δ = 104.7 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 714 Hz).
Synthesis 2013, 45, 1083–1093
© Georg Thieme Verlag Stuttgart · New York

PAPER
Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles
1091
3-(4-Methoxyphenyl)-5-methyl-2-(p-tolyl)-1,3,4-oxadiazol-3-
ium Hexafluorophosphate (2g)
The compound was isolated as a white solid (0.57 g, 78%); mp
217 °C.
FTIR (thin film): 2978, 1582, 1514, 1257, 829 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.83–7.65 (m, 4 H), 7.59–7.44
HRMS (ESI): m/z calcd for C17H16F3N2O2 ([M + H2O – PF6]+):
337.1158; found: 337.1161.
5-(tert-Butyl)-2,3-di-p-tolyl-1,3,4-oxadiazol-3-ium Hexafluoro-
phosphate (2k)
The compound was isolated as a white solid (0.40 g, 58%); mp
252 °C.
(m, 2 H), 7.37–7.17 (m, 2 H), 3.97 (s, 3 H), 2.94 (s, 3 H), 2.48 (s, 3
H).
13C NMR (75 MHz, acetone-d6): δ = 166.2, 164.0, 163.6, 149.4,
FTIR (thin film): 2980, 1606, 1578, 1136, 832 cm−1.
1H NMR (300 MHz, acetone-d6): δ = 7.80 (d, J = 8.5 Hz, 2 H), 7.70
(d, J = 8.5 Hz, 2 H), 7.63–7.57 (m, 2 H), 7.54–7.48 (m, 2 H), 2.52
(s, 3 H), 2.48 (s, 3 H), 1.63 (s, 9 H).
13C NMR (75 MHz, acetone-d6): δ = 174.4, 164.1, 149.4, 144.5,
132.5, 132.2, 131.4, 131.2, 126.4, 115.9, 34.0, 27.6, 22.0, 21.4.
131.5, 131.1, 128.2, 127.1, 116.8, 115.7, 56.4, 22.0, 11.1.
19F NMR (282 MHz, acetone-d6): δ = 104.8 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 702 Hz).
HRMS (ESI): m/z calcd for C17H17N2O2 ([M – PF6]+): 281.1285;
found: 281.1277.
19F NMR (282 MHz, acetone-d6): δ = 104.8 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 702 Hz).
5-Methyl-2-(p-tolyl)-3-[4-(trifluoromethyl)phenyl]-1,3,4-oxadi-
azol-3-ium Hexafluorophosphate (2h)
The compound was isolated as a white solid (0.41 g, 60%); mp
187 °C.
HRMS (ESI): m/z calcd for C20H23N2O ([M – PF6]+): 307.1805;
found: 307.1800.
Aminotriazoles 3; General Procedure
To a 20 mL vial was added the salt (1.0 mmol), i-PrOH (2.0 mL),
solid cyanamide (127 mg, 3.0 mmol, 3.0 equiv), and Et3N (0.42 mL,
3.0 equiv). The mixture was heated at 80 °C for 2 h. Upon comple-
tion of the reaction based on HPLC analysis, the mixture was dilut-
ed with CH2Cl2 (20 mL), washed with H2O (3 × 10 mL) and the
organic layer was concentrated and purified by column chromatog-
raphy (MeOH–CH2Cl2 gradient, 0–5%).
FTIR (thin film): 3279, 1655, 1612, 1323, 1114 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 8.19 (d, J = 9.0 Hz, 2 H), 8.10
(d, J = 9.0 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2 H), 7.56 (d, J = 9.0 Hz, 2
H), 3.01 (s, 3 H), 2.50 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 166.9, 164.9, 150.0, 137.9,
134.8, 131.7, 131.4, 129.1 (q, J = 5.0 Hz), 127.8, 122.5, 115.2, 22.0,
11.1.
19F NMR (282 MHz, acetone-d6): δ = 114.3, 104.8 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 702 Hz).
HRMS (ESI): m/z calcd for C17H14F3N2O ([M – PF6]+): 319.1053;
1,5-Di-p-tolyl-1H-1,2,4-triazol-3-amine (3a)
The compound was isolated as a white solid (0.20 g, 77%); mp
147 °C.
FTIR (thin film): 3376, 3312, 3216, 1634, 1548, 1514 cm–1.
found: 319.1050.
1H NMR (300 MHz, acetone-d6): δ = 7.37–7.31 (m, 2 H), 7.27–7.11
(m, 6 H), 4.94 (br s, 2 H), 2.38 (s, 3 H), 2.34 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 164.4, 153.3, 140.3, 138.7,
137.6, 130.4, 129.8, 129.4, 127.0, 126.1, 21.3, 21.1.
HRMS (ESI): m/z calcd for C16H17N4 ([M + H]+): 265.1448; found:
3-Mesityl-5-methyl-2-(p-tolyl)-1,3,4-oxadiazol-3-ium Hexafluo-
rophosphate (2i)
The compound was isolated as a white solid (0.46 g, 65%); mp
186 °C.
FTIR (thin film): 2968, 1621, 1561, 830 cm–1.
265.1437.
1H NMR (300 MHz, acetone-d6): δ = 7.75 (d, J = 9.0 Hz, 2 H), 7.56
(J = 9.0 Hz, 2 H), 7.31 (s, 2 H), 3.00 (s, 3 H), 2.49 (s, 3 H), 2.45 (s,
3 H), 2.17 (s, 6 H).
5-(4-Methoxyphenyl)-1-(p-tolyl)-1H-1,2,4-triazol-3-amine (3b)
The compound was isolated as a white solid (0.23 g, 81%); mp
163 °C.
13C NMR (75 MHz, acetone-d6): δ = 168.0, 164.2, 150.8, 144.6,
136.0, 132.1, 131.6, 130.4, 115.1, 22.1, 21.3, 17.4, 11.7 (one sp2
carbon missing due to overlap).
19F NMR (282 MHz, acetone-d6): δ = 104.8 (d, J = 705 Hz).
31P NMR (121 MHz, acetone-d6): δ = –144.3 (sept, J = 702 Hz).
FTIR (thin film): 3405, 3302, 3203, 1610, 1543, 1439 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.45–7.30 (m, 2 H), 7.28–7.15
(m, 4 H), 6.94–6.80 (m, 2 H), 4.91 (br s, 2 H), 3.80 (s, 3 H), 2.36 (s,
3 H).
13C NMR (75 MHz, acetone-d6): δ = 164.3, 161.5, 153.1, 138.6,
HRMS (ESI): m/z calcd for C19H21N2O ([M – PF6]+): 293.1648;
found: 293.1644.
137.6, 130.9, 130.5, 126.1, 122.1, 114.6, 55.7, 21.1.
HRMS (ESI): m/z calcd for C16H17N4O ([M + H]+): 281.1397;
found: 281.1396.
2,3-Di-p-tolyl-5-(trifluoromethyl)-1,3,4-oxadiazol-3-ium Hexa-
fluorophosphate (2j)
The compound was isolated as an off-white solid (0.38 g, 54%).
Compound 2j is not stable in deuterated solvents such as acetone-d6
and CDCl3 with significant decomposition being observed in 1–2 h;
mp 137 °C.
FTIR (thin film): 1551, 1195, 1134, 825 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61–7.45 (m, 4 H), 7.36–7.24 (m,
4 H), 2.46 (s, 3 H), 2.40 (s, 3 H).
13C NMR: The spectrum could not be obtained due to the instability
of compound 2j.
19F NMR (282 MHz, CDCl3): δ = –65.4, –74.2 (d, J = 705 Hz).
31P NMR (121 MHz, CDCl3): δ = –145.1 (sept, J = 714 Hz).
5-(4-Cyanophenyl)-1-(p-tolyl)-1H-1,2,4-triazol-3-amine (3c)
The compound was isolated as a white solid (0.20 g, 71%); mp
193 °C.
FTIR (thin film): 3402, 3315, 3181, 2233, 1642, 1546 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.79–7.75 (m, 2 H), 7.72–7.59
(m, 2 H), 7.31–7.23 (m, 4 H), 5.07 (br s, 2 H), 2.40 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 164.8, 151.4, 139.5, 137.0,
133.9, 133.0, 130.7, 130.2, 126.2, 118.9, 113.7, 21.1.
HRMS (ESI): m/z calcd for C16H14N5 ([M + H]+): 276.1244; found:
276.1241.
5-Mesityl-1-(p-tolyl)-1H-1,2,4-triazol-3-amine (3d)
The compound was isolated as a white solid (0.13 g, 46%); mp
165 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1083–1093

1092
B. Wong et al.
PAPER
FTIR (thin film): 3481, 3296, 3205, 1615, 1544, 1371 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.07 (s, 4 H), 6.92 (s, 2 H),
4.97 (br s, 2 H), 2.28 (s, 3 H), 2.26 (s, 3 H), 1.98 (s, 6 H).
13C NMR (75 MHz, acetone-d6): δ = 164.6, 152.4, 140.2, 138.2,
137.3, 137.0, 130.2, 129.1, 128.1, 122.4, 21.2, 20.8, 19.8.
HRMS (ESI): m/z calcd for C18H21N4 ([M + H]+): 293.1761; found:
293.1757.
1H NMR (300 MHz, acetone-d6): δ = 7.33 (d, J = 9.0 Hz, 2 H),
7.13–7.05 (m, 2 H), 7.03–6.98 (m, 2 H), 4.92 (br s, 2 H), 2.32 (s, 3
H), 2.28 (s, 3 H), 1.93 (s, 6 H).
13C NMR (75 MHz, acetone-d6): δ = 164.9, 153.7, 140.4, 140.1,
136.6, 136.2, 130.0, 129.9, 127.8, 126.7, 21.2, 21.1, 17.6.
HRMS (ESI): m/z calcd for C18H21N4 ([M + H]+): 293.1761; found:
293.1752.
5-Methyl-1-(p-tolyl)-1H-1,2,4-triazol-3-amine (3e)
The compound was isolated as a white solid (0.13 g, 70%); mp
187 °C.
FTIR (thin film): 3320, 3185, 1646, 1555, 1509 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.15 (m, 4 H), 3.92 (br s, 2
H), 2.41 (s, 3 H), 2.40 (s, 3 H).
Acknowledgment
We thank Dr. Alan Deese for help with NMR analysis, Dr. Jeff
Stults and Ms. Keena Green for assistance with DSC analysis, Dr.
Sushant Malhotra, Dr. Chong Han, Dr. Francis Gosselin, Prof. Scott
Denmark, and Prof. Stephen Buchwald for helpful discussions.
13C NMR (75 MHz, CDCl3): δ = 162.1, 151.3, 138.2, 135.0, 129.8,
124.1, 21.1, 13.1.
HRMS (ESI): m/z calcd for C10H13N4 ([M + H]+): 189.1135; found:
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
189.1129.
References
5-Isopropyl-1-(p-tolyl)-1H-1,2,4-triazol-3-amine (3f)
The compound was isolated as a white solid (0.14 g, 62%); mp
126 °C.
FTIR (thin film): 3648, 3152, 2967, 1626, 1549 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.26 (s, 4 H), 4.18 (br s, 2 H), 3.02
(sept, J = 6.0 Hz, 1 H), 2.41 (s, 3 H), 1.27 (d, J = 6.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 162.2, 160.4, 138.6, 135.0, 129.9,
125.2, 25.7, 21.6, 21.1.
HRMS (ESI): m/z calcd for C12H17N4 ([M + H]+): 217.1448; found:
217.1437.
(1) Hartmann, M.; Bauer, H.-J.; Wermann, K. Angew.
Makromol. Chem. 1985, 135, 1.
(2) Bozo, E.; Szilagyi, G.; Janaky, J. Arch. Pharm. (Weinheim,
Ger.) 1989, 322, 583.
(3) Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.;
Nishimura, H.; Sugiura, M.; Fukaya, C.; Kagitani, Y. J. Med.
Chem. 1996, 39, 3019.
(4) Marino, J. P.; Fisher, P. W.; Hofmann, G. A.; Kirkpatrick, R.
B.; Janson, C. A.; Johnson, R. K.; Ma, C.; Mattern, M.;
Meek, T. D.; Ryan, M. D.; Schulz, C.; Smith, W. W.; Tew,
D. G.; Tomazek, T. A.; Veber, D. F.; Xiong, W. C.;
Yamamoto, Y.; Yamashita, K.; Yang, G.; Thompson, S. K.
J. Med. Chem. 2007, 50, 3777.
1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-1,2,4-triazol-3-amine (3g)
The compound was isolated as a white solid (0.22 g, 78%); mp
147 °C.
(5) (a) Khadir, A.; Verreault, J.; Averill, D. A. Arch. Biochem.
Biophys. 1999, 370, 163. (b) Ventura, L.; Perez-Gonzales, J.
A.; Ramon, D. FEMS Microbiol. Lett. 1997, 149, 207.
(6) Fauchere, J.-L.; Ortuno, J.-C.; Duhault, J.; Boutin, J. A.;
Levens, N. European Patent EP 1044970, 2000; Chem.
Abstr. 2000, 133, 309895.
(7) Clitherow, J. W. European Patent EP 367484, 1990; Chem.
Abstr. 1990, 113, 231380.
(8) Lowe, R. F.; Nelson, J.; Dang, T. N.; Crowe, P. D.; Pahuja,
A.; McCarthy, J. R.; Grigoriadis, D. E.; Conlon, P.;
Saunders, J.; Chen, C.; Szabo, T.; Chen, T. K.; Bozigian, H.
J. Med. Chem. 2005, 48, 1540.
(9) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V. Y.;
Kovalenko, K.; Steel, P. J.; Markov, V. I.; Forood, B.
Synthesis 2001, 897.
(10) Makara, G. M.; Ma, Y.; Margarida, L. Org. Lett. 2002, 4,
1751.
FTIR (thin film): 3483, 3383, 3302, 1625, 1512, 1246 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.35 (d, J = 9.0 Hz, 2 H), 7.25
(d, J = 9.0 Hz, 2 H), 7.15 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 9.0 Hz, 2
H), 4.93 (br s, 2 H), 3.85 (s, 3 H), 2.33 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 164.3, 160.3, 153.3, 140.2,
133.0, 129.8, 129.3, 127.8, 127.0, 115.1, 55.9, 21.3.
HRMS (ESI): m/z calcd for C16H17N4O ([M + H]+): 281.1397;
found: 281.1395.
5-(p-Tolyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-
amine (3h)
The compound was isolated as a white solid (0.27 g, 85%); mp
155 °C.
FTIR (thin film): 3482, 3293, 3159, 1548, 1323, 1110 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.75 (d, J = 8.4 Hz, 2 H), 7.54
(d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2
H), 5.12 (br s, 2 H), 2.36 (s, 3 H).
(11) Yu, Y.; Ostresh, J. M.; Houghten, R. A. Tetrahedron Lett.
2003, 44, 7841.
13C NMR (75 MHz, acetone-d6): δ = 164.9, 154.1, 142.8, 141.0,
130.1, 129.6, 129.0 (q, J = 21.8 Hz), 127.1 (q, J = 3.8 Hz), 126.8,
125.9, 123.2, 21.3.
HRMS (ESI): m/z calcd for C16H14F3N4 ([M + H]+): 319.1165;
found: 319.1164.
(12) (a) Churchill, D. G. J. Chem. Educ. 2006, 83, 1798.
(b) Schilt, A. A.; McBride, L. C. Perchloric Acid and
Perchlorates; G. F. Smith Chemical Co: Columbus (USA),
2003. (c) Medard, L. A. Accidental Explosions: Types of
Explosive Substances; Vol. 2; Ellis Horwood Limited:
Chichester, 1989.
(13) (a) Brownstein, S.; Stillman, A. E. J. Phys. Chem. 1959, 63,
2061. (b) The pKa value of HPF6 (< –3.0) was based on the
definition of superacids. For a review of superacids, see:
Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J.
Superacid Chemistry, 2nd ed; Wiley-Interscience, 2009.
(c) Friestad, G. K.; Branchaud, B. P. Tetrafluoroboric Acid,
In Encyclopedia of Reagents for Organic Synthesis;
1-Mesityl-5-(p-tolyl)-1H-1,2,4-triazol-3-amine (3i)
The compound was isolated as a while solid (0.23 g, 80%); mp
175 °C.
FTIR (thin film): 3437, 3274, 3150, 1619, 1536 cm–1.
Synthesis 2013, 45, 1083–1093
© Georg Thieme Verlag Stuttgart · New York

PAPER
Paquette, L. A., Ed.; Wiley: New York, 2001.
Safe Synthesis of 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles
1093
penia, macrocytic anemia, oligospermia, and azoospermia.
For references, see: (a) Timbrell, J. A.; Draper, R. P.;
Butterworth, M.; Creasy, D. M. Occup. Hyg. 1996, 2, 153.
(b) Ku, W. W.; Wine, R. N.; Chae, B. Y.; Ghanayem, B. I.;
Chapin, R. E. Tox. Appl. Pharm. 1995, 134, 100.
(c) Feuston, M. H.; Bodnar, K. R.; Kerstetter, S. L.; Grink,
C. P.; Belcak, M. J.; Singer, E. J. Tox. Appl. Pharm. 1989,
100, 145.
(d) Subramanian, L. R.; Martinez, A. G.; Hanack, M.;
Prakash, G. K. S.; Hu, J. Trifluoromethanesulfonic Acid, In
Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley, 2006. (e) Kolthoff, I. M. Treatise on
Analytical Chemistry; Interscience Encyclopedia Inc: New
York, 1959. (f) March, J. In Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 3rd ed.; Wiley: New
York, 1985. (g) Dippy, J. F. J.; Hughes, S. R. C.; Rozanski,
A. J. Chem. Soc. 1959, 2492.
(15) O’Toole, S. E.; Connon, S. J. Org. Biomol. Chem. 2009, 7,
3584.
(14) 2-Methoxyethanol is toxic to the bone marrow and testicles.
Workers exposed to high levels are at risk for granulocyto-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1083–1093