Alumina-promoted synthesis of N-aryl-1,2,4-triazoles from substituted hydrazines and imides

Article abstract of DOI:10.1016/j.tetlet.2016.09.086

Herein we report the highly efficient, environmentally friendly alumina-promoted synthesis of N-aryl-1,2,4-triazoles with a wide variety of substitution patterns from commercially available hydrazines with symmetrical and unsymmetrical imides. Aromatic hydrazines with a variety of substitution patterns provided the corresponding 1,2,4-triazoles in very high yields. Unsymmetrical imides with a wide variety of functional groups also provide the respective triazoles with high yield and complete regioselectivities. The high productivity and mild conditions allow for the large-scale preparation of 1,2,4-triazoles.

Full text of DOI:10.1016/j.tetlet.2016.09.086

Accepted Manuscript
Alumina-Promoted Synthesis of N-Aryl-1,2,4-Triazoles from Substituted Hy-
drazines and Imides
William C. Neuhaus, Gustavo Moura-Letts
PII:
S0040-4039(16)31269-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.086
TETL 48156
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 August 2016
23 September 2016
26 September 2016
Please cite this article as: Neuhaus, W.C., Moura-Letts, G., Alumina-Promoted Synthesis of N-Aryl-1,2,4-Triazoles
from Substituted Hydrazines and Imides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.09.086
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Alumina-Promoted Synthesis of N-Aryl-1,2,4-Triazoles
from Substituted Hydrazines and Imides
William C. Neuhaus and Gustavo Moura-Letts*
R1
R1
O
O
22 Examples, 76-98%
No purification required
Complete regioselectivity
60 oC, DMF
Al2O3
+
N N
N
R2
N
H
R3
NH
R3
R2
NH2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Alumina-Promoted Synthesis of N-Aryl-1,2,4-Triazoles from Substituted
Hydrazines and Imides
William C. Neuhaus and Gustavo Moura-Letts*
Department of Chemistry and Biochemistry, Rowan University, 201 Mullica Hill Rd., Glassboro, NJ, 08028, USA
ABSTRACT
Article history:
Herein we report the highly efficient, environmentally friendly alumina-promoted synthesis of
N-aryl-1,2,4-triazoles with a wide variety of substitution patterns from commercially available
hydrazines with symmetrical and unsymmetrical imides. Aromatic hydrazines with a variety of
substitution patterns provided the corresponding 1,2,4-triazoles in very high yields.
Unsymmetrical imides with a wide variety of functional groups also provide the respective
triazoles with high yield and complete regioselectivities. The high productivity and mild
conditions allow for the large-scale preparation of 1,2,4-triazoles.
Received
Received in revised form
Accepted
Available online
Keywords:
1,2,4-Triazoles
Alumina-promoted reactions
Green Chemistry
Imides
2009 Elsevier Ltd. All rights reserved.
1,2,4-Triazoles are a distinctive class of nitrogen-
containing heterocycles with wide variety of
Thus, this approach would allow access to a wide variety of
1,2,4-triazoles with diverse substitution patterns.
Table 1. Triazole synthesis optimization
a
pharmacological properties.1 They are highly recurrent in
many natural products and commercial drugs.2 This scaffold
has been a key focus in multiple therapeutics, including
anticancer, antibacterial, antifungal, antimicrobial, antiviral,
antidepressant, anticonvulsant, anti-inflammatory, and
central nervous system modulators.3 Substituted 1,2,4-
triazoles have also been applied in pesticides, functional
materials, and as ligands in catalysis.4 Based on the high
importance of this scaffold, the development of methods for
its synthesis has been a focus in organic chemistry.5 Most of
the available methods entail approaches with low
efficiencies and harsh reaction conditions.6 Recently,
Nagasawa reported that nitriles and amidines undergo
oxidative cyclizations to provide the respective triazoles.7 A
more recent report has shown that nitriles and
hydroxylamine can also form 1,2,4-trilazoles.8 These
contributions are novel, but they still lack generality and
overall efficiency. Thus, the development of simplified,
more efficient, and cost effective methods for the synthesis
NO2
NO2
O
O
60oC, DMF
additive
+
N
N
NH
N
H
NH2
N
triazole 1
Additive Temperature Yieldb
Entry Stoichiometrya
Solvent
1
2
1:1
1:1
Ethyl Lactate
Toluene
TiO2
TiO2
90 o
90 o
C
26%
25%
C
3
4
1:1
1:1
DMF
DMF
TiO2
TiO2
40 oC
53%
33%
90 o
C
C
Tartaric Acid
/DMU
5
1:1
TiO2
90 o
66%
c
6
7
8
9
1:1
1:2
1:2
1:2
DMF
DMF
TiO2/Al2O3
40 oC
60 o
78%
88%
25%
41%
d
Al2O3
C
d
EtOAc
CHCl3
Al2O3
60 o
60 o
C
d
Al2O3
C
of 1,2,4-triazoles remains
community.
a goal in the chemistry
d
10
1:2
Acetonitrile
Al2O3
60 o
C
31%
a. Hydrazine:diacetamide. b.Isolated yields. c. Neutral alumina.
d. Basic alumina.
This laboratory is focused on developing efficient and green
methods for the synthesis of pharmacologically relevant
nitrogen-containing heterocycles.9 Herein we report the
direct reaction of substituted hydrazines and imides under
mild conditions for the efficient synthesis of the proposed
triazoles. Symmetrical and unsymmetrical imides are easily
accessible synthons through several synthetic methods.10
This study began by assessing classical conditions to initiate
condensation between hydrazines and carbonyl derivatives
(Table 1). However, most of these required extremely high heat
or high concentrations of strong acids or bases.11

2
Tetrahedron
acetyl benzamides would react in high regioselectivity for the
predicted triazole (Table 3).
The initial concept for this reaction estimated that strong polar
media and a highly oxophilic additive would efficiently promote
the desired transformation. Moreover, similar studies have shown
that rutile (TiO2) can act as a mild and efficient promoter for
some organic transformations.12 The proposed reaction in ethyl
lactate and TiO2 unfortunately was only able to provide the
desired triazoles in 26% yield (Entry 1). Other solvents at
different temperatures were found to provide the expected
triazole in moderate yields (Entries 2-4). Moreover, Brønsted
acid media (tartaric acid/DMU mixture) allowed for the isolated
yield to rise to 66% with almost complete conversion (Entry 5).
The attention turned to other metal oxides as potential promoters
for this reaction, unfortunately without improving the formation
of the desired triazoles.13 On the other hand, neutral alumina in
combination with TiO2 at 40 oC provided triazole 1 in 78% yield
(Entry 6). Moreover, basic alumina in DMF at 60 oC with
hydrazine in excess provided triazole 1 in considerably higher
yield (88%, entry 7). The results with EtOAc, CHCl3, and
acetonitrile provided significantly lower yields (Entries 8-10).
The optimization efforts for the synthesis of triazole 1 showed
Table 2 Reaction scope for hydrazines
N
O
O
DMF
60-75oC, Al2O3
N
+
NH2
NH2
Hydrazine
N
R
N
H
R
Entrya
Triazole
Yieldb,c
N
N
1
86%c
N
NHNH2
NHNH2
Br
Br
N
N
2
3
78%c
82%c
N
F3C
CF3
N
N
NHNH2
NHNH2
N
N
Cl
N
N
4
5
99%
78%
N
N
o
that in DMF at 60 C followed by filtration through Al2O3 yields
Cl
are very high and required no purification.
Having identified the optimized conditions, we then focused on
studying the scope of this reaction for aromatic hydrazines. This
laboratory is dedicated to developing efficient methods for the
synthesis of nitrogen-containing heterocycles. Thus, this
approach would allow access to a wide variety of 1,2,4-triazoles
with diverse substitution patterns (Table 2).
N
N
F
NHNH2
F
Cl
N
N
N
N
Cl
6
7
8
90%
77%
90%
N
N
N
NHNH2
NHNH2
N
N
F
F
The scope study initially focused on assessing the effect of
monosubstituted phenylhydrazines. The results showed that o-
bromo-phenyl hydrazine provided the respective triazole in very
high yield (Entry 1). Similarly, o-trifluoromethyl and o-methyl
were successful at producing the expected triazoles (Entries 2 and
3). Moreover, o-chloro and m-fluoro phenyl hydrazine provided
the proposed triazoles in equally high yields (Entries 4 and 5).
Phenylhydrazines with halogens in the para position were also
suitable substrates for this reaction. Thus, p-chloro and p-fluoro
phenylhydrazines displayed great conversions and yields for this
reaction (Entries 6 and 7). There was a concern that para
activated phenylhydrazines would trigger side reactions and
eventually require difficult purifications. Successful efforts found
that p-isopropyl, 2,6-dimethyl, 2,4-dimethyl, and o-ethyl
provided the respective triazoles in excellent yields without
traces of side products (Entries 8-11). The focus then turned
towards highly deactivated phenylhydrazines. It was found that
3,4-dichloro, 3,5-dichloro phenylhydrazines were successful at
providing the respective triazoles without any purification step
(Entries 12 and 13). Moreover, m-nitro, p-fluoro, and p-cyano
phenylhydrazines were also successful at providing the expected
product in high yields without evidence of side reactions (Entries
14-16).
NHNH2
NHNH2
N
97%
99%
9
N
N
N
10
N
NHNH2
Et
N
N
11
12
96%
99%
N
N
NHNH2
Et
Cl
Cl
Cl
Cl
N
Cl
N
NHNH2
Cl
Cl
N
13
91%c
88%
N
N
NHNH2
NHNH2
Cl
N
N
14
15
16
N
O2N
O2N
NO2
The large hydrazine scope for this reaction encouraged us to look
into exploring the efficiency against unsymmetrical imides.
Several reports have described the synthesis of these molecules.
However, it was found that only by reacting aromatic nitriles
with alkyl anhydrides in the presence of PTSA at 80 oC the imide
was formed. These efforts were able to produce a large array of
unsymmetrical imides in significant yields.10c The interest mostly
lay in unsymmetrical imides with significantly different
electronic and steric properties. Thus, we anticipated that N-
N
N
NO2
86%c
92%c
N
NHNH2
NHNH2
N
NC
N
CN
N
a. Reaction conditions: Hydrazine (0.2 mmol), diacetamide (0.1 mmol)
in DMF at 60 oC for 12h, then filtered through Al2O3 (1 g).
b. Isolated without silica gel column chromatography purification.
c. Reactions were ran in 500 mg of scale.

3
The scope for unsymmetrical imides began by reacting N-
acetylbenzamide with m-nitro phenylhydrazine under the
optimized conditions and the results showed that the triazole
scaffold was successfully isolated as a single isomer (Entry 1).
Then, it was found that N-acetylthiophene-2-carboxamide and N-
acetylcinnamide reacted with high efficiencies to provide the
expected triazoles (Entries 2 and 3).
found with N-butyryl benzamides (Entries 6 and 7). Complete
selectivity for the 1,5-regioisomer was observed and the high
regioselectivity was rationalized due to the hydrazine preference
for the electrophilic acetyl group on the imide substrate. These
results were confirmed by NOESY experiments on the resulting
triazoles (SI).
This study was also concerned with obtaining a better
understanding of the reaction mechanism for this
transformation (Scheme 1). Initial assessment of the effect
Table 3 Reaction Scope for Imides
R2
N
o
O
O
of Al2O3 found that heating the substrates in DMF at 60 C
DMF
60oC, Al2O3
N
+
R1
N
H
R2
in the absence of alumina provided N-acetyl amidrazone as
O2N
NH
N
R1
the only organic product.14 Thus, it was hypothesized that
upon initial condensation between the hydrazine and the
imide, the corresponding amidrazone undergoes alumina-
promoted intramolecular cyclization to ultimately provide
the observed triazole. Metal oxides have been reported to
promote condensation pathways for the synthesis of
heterocyclic scaffolds.15 This effect can be rationalized due
to the aluminium oxide (32-63 microns) strong surface
NH2
NO2
Yieldc
Entrya
Imide
O
Triazoleb
O2N
O
1
83%
81%
N
H
N
Ph
N
N
O2N
O
O
lattice interactions with the
N-acetyl amidrazone
2
3
S
N
H
intermediate; thus promoting the triazole-forming step.
N
N
S
N
O
O
60-75oC, DMF
O
O
+
N
N
NH
N
H
Basic
Al2O3
NH
Ph
N
94%
O2N
N
NH2
N
N
heat
Ph
Al2O3
NO2
H
N
N
O
O2N
O
O
N
N
N
N
+H
-H
N
4
47%
N
H
N
H
N
N
N
H
O
NO2
N
H
Al2O3
Al2O3
Scheme 1 Proposed 1,2,4-triazole synthesis mechanism
O
NO2
O
O
O
O
O
5
95%
N
H
Lastly, the attention shifted towards determining the green
properties of this method. We were interested in assessing
the recyclability and scalability of this reaction (Scheme 2).
The recyclability for the reaction was assessed through five
consecutive 20 mmol reactions using the same Al2O3 batch,
which was recovered after each filtration.
N
N
N
NO2
O
O
N
87%
93%
6
N
N
H
N
Ph
O2N
NO2
NO2
O
O
O
O
O
60oC, DMF
Al2O3
O
O
+
N
H
N N
7
O
N
NH
N
H
N
NH2
N
N
triazole 1
a. Reaction conditions: Hydrazine (0.2 mmol), imide (0.1 mmol)
in DMF at 60 oC for 12h, then filtered through Al2O3 (1 g).
b. Regioselectivity was determined by NOESY.
Cycle 1a Cycle 2 Cycle 3 Cycle 4 Cycle 5
84% 82% 86% 89% 85%
Yield of 1b
c. Isolated without silica gel column chromatography purification.
a. Hydrazine (40 mmol), diacetamide (20 mmol) in DMF(10 mL) at
60 oC for 12h, then filtered through Al2O3 (10 g) and then washed
with EtOAc (40 mL). b. Isolated yield after solvent evaporation.
There was also interest in assessing the effect of substituents on
the benzamide group. The results showed that deactivated N-acyl
o-nitrobenzamide reacted with slightly lower yield (Entry 4).
Despite the lower yield, no other triazole scaffold was isolated.
On the other hand, activated N-acylpiperonylamide provided the
triazole in very good yield (Entry 5). Similar high yields were
Scheme 2. Reaction promoter recyclability study
The results displayed high yields for the formation of triazole 1
after each cycle without erosion in conversion or purity. The

4
Tetrahedron
efficiency, minimal use of organic solvents, recyclability, and
Am. Chem. Soc. 2009
,
131, 886. (c) Nepal, B.; Scheiner, S.
scalability of this method highlights its potential application in
large-scale 1,2,4-triazole manufacturing.
J. Phys. Chem. 2015
, 119, 13064.
5
Available methods for the synthesis of 1,2,4-triazoles: (a)
Chen, Z.; Li, H.; Dong, W.; Miao, M.; Ren, H. Org. Lett.
2016, 18, 1334. (b) Zhang, Q.; Keenan, S. M.; Peng, Y.; Nair,
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2006, 49, 4044. (c) Stocks, M. J.; Cheshire, D. R.; Reynolds,
R. Org. Lett. 2004, 6, 2969. (d) Li, Z. H.; Wong, M. S.;
Fukutani, H.; Tao, Y. Org. Lett. 2006, 8, 4271. (e) Buzykin,
B. I.; Bredikhina, Z. A. Synthesis 1993, 59. (f) Paulvannan,
K.; Hale, R.; Sedehi, D.; Chen, T. Tetrahedron 2001, 57,
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668. (h) Atkinson, M. R.; Poyla, J. B. J. Chem. Soc. 1952,
3418.
In summary, we have developed a highly efficient alumina-
promoted synthesis of substituted
N-aryl-1,2,4-triazoles
from hydrazines and easily accessible imides. The mild
reaction conditions allow for this method to tolerate a large
array of functional groups with diverse electronic and steric
properties. Additionally, all of the reaction products were
isolated without the need of complicated purifications. In the
case of unsymmetrical imides the reaction preceded with
complete regioselectivity. The proposed mechanism
logically validates the dramatic effect observed with
alumina. The reaction can be efficiently scaled-up and the
promoter can be reused without affecting the reaction yield.
Future efforts will focus on further understanding this
reaction for the construction of more structurally diverse
triazoles and other nitrogen-containing heterocycles.
6
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Acknowledgements
The donors of the American Chemical Society Petroleum
Research Fund financially supported these research efforts. We
are also thankful to Dr. John F. Eng at Princeton University for
his help with HRMS analysis.
7
8
Notes and references
§ Department of Chemistry and Biochemistry, Rowan University,
201 Mullica Hill Rd, Glassboro, New Jersey, USA. E-mail:
moura-letts@rowan.edu
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