From Phenylhydrazone to 1H-1,2,4-Triazoles via Nitrification, Reduction and Cyclization

Article abstract of DOI:10.1002/adsc.201901563

Herein we report an annulation of phenylhydrazone via a tandem nitrification, reduction, cyclization protocol employing cobalt nitrate and 1,2-dichloroethane to produce substituted 1H-1,2,4-triazoles. Notably, 1,2-dichloroethane serves both the solvent and a hydrogen source for transfer hydrogenation. This methodology works under mild conditions, providing a direct approach for the synthesis of 1H-1,2,4-triazoles. (Figure presented.).

Full text of DOI:10.1002/adsc.201901563

Title: From Phenylhydrazone to 1H-1,2,4-Triazoles via Nitrification,
Reduction and Cyclization
Authors: Liqiang Hao, Guodong Wang, Jian Sun, Jun Xu, Hong-
Shuang Li, Gui-Yun Duan, Chengcai Xia, and Pengfei Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901563
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10.1002/adsc.201901563
Advanced Synthesis & Catalysis
Communications
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
From Phenylhydrazone to 1H-1,2,4-Triazoles via Nitrification,
Reduction and Cyclization
Liqiang Hao, a Guodong Wang, a Jian Sun, a Jun Xu, b Hongshuang Li, a Guiyun Duan,
a Chengcai Xia*, a and Pengfei Zhang b
a
Institute of Pharmacology, School of Pharmaceutical Sciences, Shandong First Medical University & Shandong
Academy of Medical Sciences, 619 Changcheng Road, Taian 271016, People’s Republic of China, E-mail:
xiachc@163.com
b
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036 China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
To the best of our knowledge, this represents a novel method to
synthesize these important scaffolds.
Abstract. Herein we report an annulation of
phenylhydrazone via a tandem nitrification, reduction,
cyclization protocol employing cobalt nitrate and 1,2-
dichloroethane to produce substituted 1H-1,2,4-triazoles.
Notably, 1,2-dichloroethane serves both the solvent and a
hydrogen source for transfer hydrogenation. This
methodology works under mild conditions, providing a
direct approach for the synthesis of 1H-1,2,4-triazoles.
Keywords: Tandem; Co(NO3)2•6H2O; Phenylhydrazone;
1H-1,2,4-Triazoles
1H-1,2,4-triazoles are highly valuable compounds, and have
shown
a
wide range of biological activities including
antihypertensive,[1] antitumor,[2] antiproliferative,[3] antibacterial,[4]
antidiabetic,[5] antipsychotic,[6] and anticonvulsant.[7] They are
also potent inhibitors of JAK1,[8] JAK2,[9] Pi3K,[10] PDE10,[11]
and they can be used as herbicides[12] or plant growth
regulators.[13] In addition, the 1H-1,2,4-triazole framework is
widely found in organic functional materials.[14] Therefore, the
development of methodology towards their synthesis have gained
much attention in the several past decades. These strategies often
rely on the use of hydrazides and amines or imines to build this
multi-nitrogen heterocycle. For example, formyl hydrazide is
used to react with an imine with leaving group or organic cyanide
or thioisocyanate to construct 1H-1,2,4-triazole rings (Scheme
1a).[15] Hydrazides have also been shown to react with an imine
or imine derived functionalities, such as triazine, amidines,
isocyanate
and
N,N-Dimethyl-N'-
(dimethylaminomethylene)formamidinium chloride to produce
1H-1,2,4-triazole (Scheme 1b).[16] Similarly, primary amines react
with N,N-dimethyl formamide azine (DMFA) or 1,3,4-oxadiazole
successfully to obtain the product (Scheme 1c).[17] In addition,
amidine,[18] and thiosemicarbazone[19] can also be used to prepare
1H-1,2,4-triazole rings (Scheme 1d). Based on our previous work
describing the synthesis of diverse heterocycles via a sequential
nitration-cyclization procedure,[20] we report an annulation of
phenylhydrazone to produce diverse 1H-1,2,4-triazole based
Scheme 1. Strategies for the preparation of 1H-1,2,4-triazole
We started our investigation by examining the reaction of (E)-1-
benzylidene-2-phenylhydrazine 1a with sodium nitrite in 1,2-
dichloroethane and the corresponding 1,2,4-triazole (2a) was
obtained in 19% yield (Table 1, entry 1).[21] Encouraged by this
promising result, we investigated how the reaction changed upon
changing the nitrate used (Table 1, entries 2–7). We observed that
the best reproducible yield was obtained when Co(NO3)2•6H2O
was used (Table 1, entry 6). We used wanted to examine if
external nitrate sources, such as NaNO2 or NaNO3, could act in
the same fashion in the presence of an alternative cobalt catalyst.
As shown, CoSO4•7H2O and CoCl2•6H2O provided the desired
compounds employing
a
nitrification-reduction-cyclization
strategy (Scheme 1e). Compared with previously published
methods, we employ cobalt nitrate as a readily available nitrogen
source, and use this to install one of the amines within the ring.
We also show that the reaction utilizes 1,2-dichloroethane as a
hydrogen source, which negates the use of more traditional
sources such as isopropanol, hydrazine hydrate and formic acid.
1
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10.1002/adsc.201901563
Advanced Synthesis & Catalysis
triazole in good yield, however Co(OAc)2•4H2O and
[(C6H5)3P]2CoCl2 showed reduced reactivity (Table 1, entries 8–
11). Due to this, we decided that Co(NO3)2•6H2O was the
optimum nitrate source and proceeded to optimize the reaction
further, varying reaction temperature, loading Co(NO3)2•6H2O,
and the reaction time, also shown in Table 1 (Table 1, entries
12−15). Impressively, control experiments revealed that an O2
atmosphere has no reaction (Table 1, entry 16). Considering the
influence of 1,2-dichloroethane addition, different equivalents of
1,2-dichloroethane have been added in CH3CN (2 mL) and we
did not observe product (Table 1, entry 17). After much
experimentation, we found that 1,2-dichloroethane can act as both
the solvent and hydrogen source, with 0.6 equivalents of
Co(NO3)2•6H2O at 110 oC providing the optimal reactivity.
Besides, replacement of the 1,2-dichloroethane with benzyl
chloride in this reaction, and we have obtained (E)-1-benzyl-2-
benzylidene-1-phenylhydrazine (4) when we added more than 5.0
equivalents of benzyl chloride in CH3CN (2 mL).
such as 2-CF3 (3a), 2-Cl (3b), 2-F (3c), 3-Cl (3d), 3-CH3 (3e), 4-
CH3 (3f) at para-, meta- or ortho- position of phenylhydrazine
afforded the corresponding products in 63−78%. Surprisingly,
strongly electron withdrawing hydraziness (3g, 3h) failed to
produce the requisite triazole. Furthermore, the alkyl
phenylhydrazine such as (E)-1-benzylidene-2-methylhydrazine
(3i) did not react under standard reaction conditions (Table 3).
Table 2. Scope of aromatic aldehydes 1a, b
Table 1 Optimization of reaction conditions a, b
Entry
1
2
3
4
5
6
7
8
Nitro source
NaNO2
Cu(NO3)2
Fe(NO3)3
Ce(NH4)2(NO3)6
Bi(NO3)3
Co(NO3)2•6H2O
(CH3)3CONO
NaNO2
NaNO2
NaNO2 (NaNO3 )
Cobalt source
T ℃
110
110
110
110
110
110
110
110
110
110
110
80
Yield(%)b
19
-
-
-
-
-
-
-
74
69
61
53
80
42
12
50.
a Reaction conditions: 1 (0.15 mmol), Co(NO3)2•6H2O (0.6 equiv.)
and 1,2-dichloroethane (2.0 mL), Air, sealed tube, 110 °C for 3 h, b
Isolated yields.
Co(OAc)2•4H2O
CoSO4•7H2O
CoCl2•6H2O
[(C6H5)3P]2CoCl2
9
c
74,75c
N.R.
21
Table 3. Scope of abenzoquinones 1a, b
10
11
12
13
14
15
16
17
NaNO2
Co(NO3)2•6H2O
Co(NO3)2•6H2O
Co(NO3)2•6H2O
Co(NO3)2•6H2O
Co(NO3)2•6H2O
Co(NO3)2•6H2O
-
-
-
-
-
-
120
110
110
110
110
74
71d, 80e
37f, 79g
71h, 0i
0j
a
Reaction conditions:1a (0.15 mmol), nitrate (0.6 equiv.) and 1,2-
dichloroethane (2.0 mL), Air, sealed tube, 110 °C for 3 h. b Isolated
yields. NaNO3 (0.6 equiv.). Co(NO3)2•6H2O (0.5 equiv.).
c
d
e
Co(NO3)2•6H2O (1.0 equiv.). f 1 h. g 4 h. h N2. i O2. j 2.0 , 3.0, or 5.0
equivalents 1,2-dichloroethane in CH3CN (2 mL).
With the optimized conditions in hand, we investigated the
substrate scope of this reaction, beginning with varying the
substituents on the benzene ring of the aromatic aldehyde (Table
2). Substrates with para-substituents bearing either electron
donating (2b-2f), halogen substituents (2g-2h) or withdrawing
character (2i) were well tolerated. Furthermore ortho-substituents
such as 2-Me (2j), 2-F (2k), 2-Br (2l) afforded the corresponding
products in good yields. Meta-substituents with diverse
electronics also worked well, with electron-donating groups (2n),
halogens (2o) and electron-withdrawing groups (2p) all providing
the triazole in good yields. Similarly, many disubstituted
compounds such as 2q, 2r, 2s and 2t also afforded the
corresponding products in synthetically useful yields (63–74%).
In addition, thiophene-2-aldehyde (2u) gave a 60% yield.
Unfortunately, in our hands, the methodology failed to produce
any product bearing a 2-CF3 (2m) group.
a Reaction conditions: 1 (0.15 mmol), Co(NO3)2•6H2O (0.6 equiv.)
and 1,2-dichloroethane (2.0 mL), Air, sealed tube, 110 °C for 3 h, b
Isolated yields.
We next turned our attention back to the use of NaNO2 as a
nitrogen source (Table 1, entry 1). We began our investigation by
examining the reaction of (E)-1-benzylidene-2-phenylhydrazine
1a with NaNO2 in 1,2-dichloroethane (Supporting Information).
From systematic screenings of a wide range of NaNO2, oxidants,
and temperature, we found that the reaction can be performed in
DCE at 120 °C in the presence of NaNO2 (2.5 equiv.) and K2S2O8
(6.0 equiv.) which provides the 1H-1,2,4-triazoles 2a in 68%
yield. One drawback of this reaction is that it used a large excess
of external oxidant, hampering both isolation and purification of
Various phenylhydrazines were also employed to discover the
limits of the reaction. As shown, phenylhydrazines bearing
electron-donating, electron-withdrawing, or halogen substituents
2
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10.1002/adsc.201901563
Advanced Synthesis & Catalysis
the products. Nevertheless, we were encouraged by the results
obtained, and pushed forward, testing other functionalized
phenylhydrazone in the reaction (Table 4). The yields of
substrates from aromatic aldehydes with the para-substituent 4-
Me (2b), 4-OEt (2f), 4-Br (2h) and ortho-substituted groups 2-F
(2k), 2-Cl (2v) and meta-substituted groups 3-CF3 (2p), 3-CH3
(2w) varied from 46% to 58%. The yields observed were lower
than those obtained using the cobalt mediated reaction (Table 2),
but are still within the synthetically useful range.
present. Additionally, a small amount of oxygen in a sealed tube
is better for the oxidation of C(sp2)-H at start time and can be
exhausted, but excessive oxygen can lead to inhibition of the
reaction (Table 1, entries 6, 16).
a, b
Table 4. Synthesis of 1,2,4-triazoles used NaNO2
a Reaction conditions: 1 (0.2 mmol), NaNO2 (2.5 equiv.), Oxidant (6.0
equiv.) and 1,2-dichloroethane (2.0 mL), Air, sealed tube, 120 °C for
24 h. b Isolated yields.
To show the synthetic utility of the reaction, we performed a
gram-scale reaction under standard reaction conditions, which
provided 2a in 51% yield (Scheme 2a). Compound 2i could be
further converted to 5, a PPAR modulator for the treatment of
diabetes, [22] through a simple etherification reaction in 92% yield
(Scheme 2b).
Scheme 3. Control experiments
On the basis of these preliminary studies and previous reports,[23,
24, 25, 26]
a plausible pathway for the cobalt mediated formation of
2a is proposed in Scheme 4. Firstly, a free radical NO2• was
generated from Co(NO3)2 under thermal conditions[22] which
reacts with 1 to produce intermediate (A). Secondly, intermediate
(A) reacts with 1,2-dichloroethane to afford intermediate (B).
Intermediate (C) is then produced via cobalt mediated reduction
of the nitro group, with concurrent (sp2)-H oxidation to the
carbonyl.[23, 24] Finally, the target product 2a was obtained via an
intramolecular condensation and dehydration process.
Scheme 2. Synthetic Applications
We then wanted to learn more about the mechanism of this
reaction, and conducted several control experiments to elucidate
some of the key steps. First, we found that the reaction was
inhibited when the radical scavenger such TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) was added to the reaction mixture
(Scheme 3a). Furthermore, employing 1-diphenylethylene as
starting material and reacting under the standard conditions
(Scheme 3b), we observed a clean transformation to the
nitroolefin, which again suggests a radical process occurring.
When (E)-1-phenyl-2-(1-phenylethylidene)hydrazine was reacted
with Co(NO3)2•6H2O under standard reaction conditions, the
desired 8a was not obtained (Scheme 3c) effectively ruling out
that alkylation is the first step in the reaction. Furthermore, we
did not obtain product 2a when using (E)-N'-benzylidene-2-
chloro-N-phenylacetohydrazide
9
as the starting material
(Scheme 3d). These results indicate that there must be an
available C(sp3)–H for the reaction to proceed. Additionally, we
only observed
a
trace amount of product when N'-
phenylbenzohydrazonamide 10 was reacted under standard
reactions conditions (Scheme 3e). Interestingly however, when
we employed CoCl2 as the cobalt salt, we obtained 2a in 23%
yield (Scheme 3f). These results reveal that the cobalt salt could
indeed promote a tandem N-alkylation, oxidation and cyclization
reaction from N'-phenylbenzohydrazonamide to synthesize 1H-
1,2,4-triazoles, as long as there was a nitrogen atom already
Scheme 5. Postulated reaction mechanism used NaNO2
3
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10.1002/adsc.201901563
Advanced Synthesis & Catalysis
Furthermore, a plausible pathway for the formation of 2a from [7] a) S.-B. Wang, G.-C. Piao, H.-J. Zhang, Z.-S. Quan, Molecules
NaNO2 is proposed in Scheme 5. Initially, a NO• free radical is
generated from the reaction between NaNO2 and K2S2O4 (or
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was obtained via facile oxidation of 2F.
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In summary, we have developed a facile synthesis of 1H-1,2,4-
triazoles via a sequential nitrification, reduction, cyclization
protocol employing with cobalt nitrate and 1,2-dichloroethane.
Notably, the 1,2-dichloroethane serves as the solvent as well as
the hydrogen source. This method can be anticipated to construct [10] a) G. Bergamini, K. Bell, S. Shimamura, T. Werner, A.
structurally diversified 1H-1,2,4-triazoles for the screening of the
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Experimental Section
A mixture of the phenylhydrazone (0.15 mmol), Co(NO3)2•6H2O
(0.6 equiv.) in CH2ClCH2Cl (2.0 mL) was stirred in sealed tube at
110 °C for 3 h. After completion of the reaction, the reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was purified by flash
chromatography on a short silica gel column to afford the product.
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The authors gratefully acknowledge financial support for this
research from Shandong Provincial Natural Science Foundation
(ZR2017LB006).
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10.1002/adsc.201901563
Advanced Synthesis & Catalysis
Communications
From Phenylhydrazone to 1H-1,2,4-Triazoles via
Nitrification, Reduction and Cyclization.
Adv. Synth. Catal. Year, Volume, Page – Page
Liqiang Hao, a Guodong Wang, a Jian Sun, a Jun
Xu, b Hongshuang Li, a Guiyun Duan, a Chengcai
Xia*, a and Pengfei Zhang b
6
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