Facile synthesis of 1,2,4-triazoles via a copper-catalyzed tandem addition-oxidative cyclization

Article abstract of DOI:10.1021/ja905056z

A simple one-step synthesis of 1,2,4-triazole derivatives is provided by a copper-catalyzed oxidative coupling reaction under an atmosphere of air. The process should consist of sequential N-C and N-N bond-forming copper-catalyzed oxidative coupling reactions. Starting materials and the copper catalyst are readily available and inexpensive. A wide range of functional groups are tolerated to achieve chemical diversity.

Full text of DOI:10.1021/ja905056z

Published on Web 10/02/2009
Facile Synthesis of 1,2,4-Triazoles via a Copper-Catalyzed Tandem
Addition-Oxidative Cyclization
Satoshi Ueda and Hideko Nagasawa*
Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical UniVersity, 5-6-1 Mitahora-higashi,
Gifu 502-8585, Japan
Received June 19, 2009; E-mail: hnagasawa-gifu-pu.ac.jp
The 1,2,4-triazole nucleus is an important structural motif present
in a large number of functionalized molecules with a wide variety
of uses, including applications in medicinal chemistry, materials
science, and organocatalysis. The importance of this heterocyclic
moiety has prompted the development of many practical synthetic
routes to 1,2,4-triazole derivatives.1 The majority of these routes
rely on intramolecular condensation reactions of N-acylamidora-
zones obtained from hydrazines and carboxylic acid derivatives.2
Although the existing synthetic methods have provided a wide
variety of 1,2,4-triazoles, these typically involve multistep reaction
sequences. Recently, Chen and co-workers3 reported one-pot
formation of copper(I) triazolates under stoichiometric solvothermal
conditions. Pertinent to the present research, there appears to be
no precedent for catalytic synthesis of 1,2,4-triazoles from readily
available starting materials. Herein, we report a single-step elabora-
tion of 1,2,4-triazole structure using a conceptually distinct copper-
catalyzed oxidative coupling approach.
such as toluene and dimethyl sulfoxide (DMSO), albeit in lower
yield (entries 5 and 6). Other copper sources, including CuBr2,
CuCl, and Cu(OAc)2, could be employed (entries 7-9). In the
absence of a copper source, no product formation was observed
(entry 10).
Table 2. Copper-Catalyzed Synthesis of Triazoloheterocycles
On the basis of the known ability of transition metals to activate
nitriles4 and the recently developed catalytic oxidative construction
of nitrogen heterocycles,5 we envisioned a direct synthesis of the
1,2,4-triazole nucleus by reaction of 2-aminopyridines and nitriles
involving transition-metal-catalyzed N-C bond formation and
oxidative N-N coupling. To explore this approach, we selected
2-aminopyridine (1a) and benzonitrile (2a) for reaction development
and screened several transition-metal catalysts in common solvents
for their catalytic activity. When 1a and 2a were reacted in the
presence of 5 mol % CuBr and 1,10-phenanthroline (1,10-Phen)6
in 1,2-dichlorobenzene (DCB) at 130 °C under an air atmosphere,
2-phenyl-1,2,4-triazolopyridine 3a was obtained in 39% yield (Table
1, entry 1). The addition of 10 mol % ZnI2 greatly improved the
reaction efficacy, and 3a was obtained in 81% yield (entry 2).7
Other zinc salts such as ZnCl2 and ZnBr2 were less effective than
ZnI2 (entries 3 and 4). The reaction also proceeded in other solvents
Table 1. Reaction Optimization
entry
catalyst
solvent
additive (10 mol %)
yield (%)
With the optimum reaction conditions in hand, we next investigated
the scope of the oxidative synthesis of triazoloheterocycles (Table 2).
Benzonitriles with electron-withdrawing halogen or trifluoromethyl
groups gave the corresponding triazolopyridines 3b-d, 3g, and 3h in
good yield. The reactions with methoxy-substituted benzonitriles were
slower than those with electron-deficient benzonitriles and gave
triazolopyridines 3f and 3i in moderate yields. Heterocyclic substituents
such as pyridine and thiophen could be incorporated (3k and 3l). The
reaction of a chloro-substituted 2-aminopyridine gave the corresponding
product 3n in moderate yield. The relatively lower yields probably
reflect the lower nucleophilicity of the aminopyridines. The reaction
1
2
3
4
5
6
7
8
9
CuBr
DCB
DCB
DCB
DCB
toluene
DMSO
DCB
DCB
DCB
DCB
-
39
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
CuCl
Cu(OAc)2
-
ZnI2
ZnCl2
ZnBr2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
81 (70)a
34
49
71
35
73
78
76
0
10
a Yield of gram-scale reaction in parentheses.
9
15080 J. AM. CHEM. SOC. 2009, 131, 15080–15081
10.1021/ja905056z CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
of 1-aminoisoquinoline with benzonitrile gave triazoloisoquinoline 3o,
which is known as a potent nonhormonal antifertility agent,8 in good
yield.
oxidative cyclization of the amidine provides triazolopyridine 3a
and reduced copper species.13 The second step (oxidative N-N
bond formation) was confirmed by conversion of amidine 8 to 3a
under the reaction conditions (eq 1):14
The efficiency of the expeditious copper-catalyzed oxidative
coupling process for triazoloheterocycles prompted us to examine
the synthesis of 1H-1,2,4-triazoles from amidines and nitriles. In
contrast to the synthesis of triazolopyridines, the use of ZnI2 in
DCB was not effective in the synthesis of 1,2,4-triazoles. The
addition of Cs2CO3 resulted in the successful production of the
corresponding 1H-1,2,4-triazoles from amidines 4 and nitriles 2
(Table 3). The reactions of benzamidine and benzonitriles afforded
triazoles 5a-c in good yields (entries 1-3). Acetonitrile could also
be employed instead of benzonitriles (entry 4). The reactions of
primary, secondary, and tertiary alkyl amidines provided the
corresponding 5-alkyl triazoles 5d-5k in moderate to good yield
(entries 5-12). Again, electron-deficient benzonitriles provided
better yields. 5-Amino-substituted 1,2,4-triazole 5l was successfully
prepared from a guanidine precursor (entry 13).
The cyclization was also achieved effectively by the use of a
stoichiometric amount of Cu(OAc)2 under an argon atmosphere.15
Reoxidation of the reduced copper by molecular oxygen completes
the catalytic cycle.
In summary, we have developed an efficient copper-catalyzed
oxidative synthesis of 1,2,4-triazole derivatives. The catalytic cycle
was achieved by use of molecular oxygen (air at 1 atm) as the
oxidant, which produces water as the sole theoretical byproduct.
The reaction allows the facile generation of diversity in the
construction of 1,2,4-triazoles, which are important privileged
structures. Therefore, the reaction described here should be an
attractive alternative for the preparation of potentially bioactive
compounds.
Table 3. Copper-Catalyzed Synthesis of Triazoles
Acknowledgment. We thank Dr. K. L. Kirk (NIDDK, NIH)
for helpful suggestions and Ms. Emi Inaba for her technical
assistance. This research was supported in part by a grant from
JST (Research for Promoting Technological Seeds).
Supporting Information Available: Experimental procedures,
spectral data, and copies of 1H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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a MeCN/DMSO (1:3) was used as the solvent.
Scheme 1. Proposed Mechanism for the Copper-Catalyzed
Oxidative Synthesis of Triazole Derivatives
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(12) Since 3- and 4-aminopyridine did not react with benzonitrile under the
reaction conditions, coordination of the pyridine nitrogen of 1a to the copper
center might assist the amidine formation process.
(13) The mechanism for forming the 1,2,4-triazoles (5) might resemble that
shown in Scheme 1.
In view of the reported intramolecular N-N bond-forming
process under oxidative conditions,9 the present reaction should
consist of initial amidine formation10,11 followed by intramolecular
oxidative N-N bond formation in the amidine intermediate
(Scheme 1). Thus, copper first promotes nucleophilic attack of
2-aminopyridine 1a on the nitrile, probably by forming coordinated
intermediate 6, to provide amidine 7.12 Subsequent copper-induced
(14) The cyclization reaction also proceeded smoothly without ZnI2, so the relatively
soft Lewis acid ZnI2 is likely to assist the initial amidine formation step.
(15) Copper(I) should be oxidized to copper(II) by the trace amount of water in
the solvent and dioxygen for catalyzing the cyclization, but addition of
water slightly lowered the reaction efficacy (see the Supporting Information).
Consequently, the speciation of copper cannot be specified at present.
JA905056Z
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J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15081