A practical base mediated synthesis of 1,2,4-triazoles enabled by a deamination annulation strategy

Article abstract of DOI:10.1039/d0cc05828a

A rapid and efficient base mediated synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed using the annulation of nitriles with hydrazines, which can be expanded to a wide range of triazoles in good to excellent yields. Ammonia gas is liberated during the reaction, and halo and hetero functional groups as well as free hydroxyl and amino groups are tolerated in this transformation. A variety of alkyl and aryl-substituted nitriles can be functionalized with aromatic and aliphatic hydrazines employing this procedure. This finding provides a practical and useful strategy for the synthesis of various 15N-labeled 1,2,4-triazole derivatives, and two types of mGlu5 receptor pharmaceuticals can be easily assembled in a one-pot manner. This journal is

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Cite this: DOI: 10.1039/b000000
A practical base mediated synthesis of 1,2,4-triazoles
enabled by deamination annulation strategy
Received XXth XXX 202X,
Accepted XXth XXX 202X
Chunyan Zhang,*a Zuyu Liang,a Xiaofei Jia,a Maorong Wang,c Guoying Zhang*a
DOI: 10.1039/b000000
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and Mao-Lin Hu*b
Recently, several effectively annulation transformations catalyzed
45 by transition metal were discovered.6 However, these strategies
general suffers from lower regioselectivity or productivity. One
attractive approach to circumvent these problems is to use the
mild catalyst via cyclic transformation to access to 1,2,4-triazoles
directly from nitriles and hydrazines in absence of metal catalysts,
50 capricious ligands, or stoichiometric additives. To date, one
transformation dealing with stoichiometric AlCl3 mediated
annulation leading to several 1,2,4-triazole compounds under
high temperature reported by Kuberkar group.7 Thus, developing
a rapid, practical and convenient process for the assembled 1,2,4-
55 triazoles is still highly desirable.
A
rapid and efficient base mediated synthesis of 1,3,5-
trisubstituted 1,2,4-triazoles has been developed from annulation
of nitriles with hydrazines, which can be scaled up to a wide
range of triazoles in good to excellent yields. Ammonia gas is
liberated during the reaction, and halo, hetero functional groups
as well as free hydroxyl, amino are tolerated in this
transformation. A variety of alkyl, aryl-substituted nitriles can be
functionalized with aromatic and aliphatic hydrazines employing
10 this procedure. This finding provides a practical and useful
strategy for synthesis of various of 15N-labeled 1,2,4-triazole
derivatives and two type of mGlu5 receptor pharmaceuticals can
be easily assembled in a one-pot manner.
5
R = Ar
>15 h
Ar
previous work
K
R1
N
O-
N
H
R1CH2OH
NH2
R
Triazole, a class of significant N-heterocycles, are widely present
in various natural products and materials.1 In particular,
substituted 1,2,4-triazoles usually exhibit valuable physico-
30 chemical properties and biological activities and are emerging as
key pharmacophores for the treatment of Schizophrenia,
Huntington's disease, αvβ6 integrin antagonists, mGlu5 receptor
disease and anti-hypertensive drugs (Fig 1).2 Because of their
scientifically applications, the development of efficient methods
35 toward 1,2,4-triazoles is of great significance to medicinal
science and has attracted plenty of attention over the past
decades.3
N
C
Ar
R1
N
Ar
H
H
N
R = ArNH
TS-I
R
R3
N
R
H
R = ArNH
R2
C
N
this work
Cl
R2
H
N
O
H
N
K
R
C
Ar
N
N
N
10 min
N
N
N
N
N
Ar
TS-II
R
N
N
N
mGlu5
receptor
R2
N
C
Ar
Ar
Scheme 1 State of the art and the reaction described here.
Very recently, we have identified that t-BuOK could be served
as accelerator to promote alkylation of aromatic amines via the
60 intermediates TS-I. However, it is only compatible with aromatic
amine compounds, not applicable to hydrazines (Scheme 1, top).8
And Ren group’s reported a metal-free mediated synthesis of
1,3,5-trisubstituted 1,2,4-triazoles from hydrazones and aliphatic
amines under mild conditions.3m These results together with our
65 group on the use of base as the replacement of mild catalyst
prompted us to envision that t-BuOK could be mediated synthesis
of 1,2,4-triazoles via annulation of nitriles with hydrazines.
Specifically, we postulated that the cyclometallated potassium
species TS-II might be generated from nitrile with hydrazine
70 under t-BuOK. Subsequently, TS-II further nucleophilic
condensation with another nitrile to afford the 1,2,4-triazole
product, which further transformed into various complex drug
molecules (Scheme 1, bottom). To date, however, there is no
practical catalytic systems dealing with annulation of two
75 molecule nitriles with hydrazines in the presence of base has been
disclosed. Herein, we describe a rapid and efficient protocol for
successful implementation of the base promoted annulation
condensation of nitriles with hydrazines, affording a broad range
of multi-substituted 1,2,4-triazoles under mild conditions.
F
N
N
N
N
N
mGlu5 receptor
Cl
N
N
N
N
N
PED10
N
N
Et
N
N
Et
N
O
N
HN
Et
F
N
HOOC
N
N
N
Bu
N
N
N
H
Bu
N
N
N
N
N
Forasartan
avb6 integrin antagonists
Fig. 1 Examples of triazole bio-active molecules.
40
Early studies on the synthesis of 1,2,4-triazoles mainly relied
on the use of large excess amounts of substrates and strong
oxidants,4 which not only requiring harsh reaction conditions, but
resulted in limited functional groups tolerance or poor yields.5
a Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education; Shan-dong
Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical Chem-istry for
Life Science in Universities of Shandong; Key Laboratory of Optic-electric Sensing and
Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular
Engineering. Qingdao University of Science and Technology, Qingdao 266042, P.R.
China. E-mail: zhanggy@qust.edu.cn
80
We commenced our studies by attempting the proposed cycled
of benzonitrile with phenyl hydrazine to synthesis of 1,3,5-
triphenyl-1H-1,2,4-triazole (3a) under base promoted. 3a could
be obtained in 42% yield with xylene as solvent in the presence
of an equivalent of t-BuOK.9 Further investigation of other
b College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035,
P.R. China. maolin_hu@yahoo.com
State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, 308 Ningxia
Road, Qingdao, 266071, PR China
† Electronic supplementary information (ESI) available. CCDC 1971369. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/0000000
c
85 solvents, such as THF, diglyme, menthol and 1,4-dioxane, the
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best result was achieved with 1,4-dioxane as the solvent.
Having demonstrated that the annulation process is compatible
Variation of the organic bases, type of t-BuOM or MHMDS (M = 35 with a wide range of nitriles, investigation of the scope regarding
Li, Na, K), indicated that potassium ion base demonstrated the
best promote efficiency for delivering 3a in excellent yield. In
addition, KH and KNH2 were used as promoter, giving the
desired products in good yields, respectively. It was noteworthy
the hydrazines was undertaken (Table 2, top). For most of the
hydrazines, the cyclization proceeded smoothly to give the
corresponding desired products in good to excellent yields.
Although lot of them is in the form of hydrochloride, the triazoles
5
that the reaction still worked well even in the presence of 20 40 could be obtained in better yield than free hydrazine in the
mol% base, whereas no appreciable increase in yield was
obtained with low loading base. The best result of 3a were
10 obtained after final optimization of the reaction parameters (base,
base amount, solvent, substrate ratio, reaction temperature and
time) with t-BuOK as the best active accelerator.9
presence of 1.2 equivalents of t-BuOK under the prolong reaction
time. The orientation of substituted had an obvious impact on the
efficacy of the transformation, affording the corresponding
products (4b, 4d, 4f, 4i) in moderate yields. In addition, halide
45 groups survived well in the standard procedure, leading to desired
adducts 4e-4k in good yields, which can be used for further
transformations. The 2-hydrazinylpyridine reacted smoothly
rendering the target 1,2,4-triazole 4n in high yield. Different
substituents of benzyl moieties, could be successfully
50 incorporated in the triazoles (4o-4q). Significantly, aliphatic
substituted hydrazines had no significant influence on the yield of
formed the desired triazoles (4r-4t). More importantly, the
product 4u containing the free hydroxyl could be attained in
excellent yield with 2-hydrazinylethanol as a reaction partner
55 under the standard reactions. Next, we turned our attention to
more challenging aliphatic nitriles with alkyl hydrazines (Table 2,
bottom). Cyclopropanecarbonitrile was initially surveyed and the
reaction proceeded smoothly to give the desired product 5a in
96% yield. Furthermore, similar results were obtained in the
60 transformations of aliphatic hydrazine with large steric or free
hydroxyl group to deliver the annulation adducts efficiently in
excellent yields (5b-5e). Notably, the hydrazine hydrochloride
can be applied to this process, giving the desired product 5f in
high yield.
Table 1 Annulation of phenyl hydrazine with various nitrilesa
Ph
N
t-BuOK (20 mol%)
H
N
N
R
2
R
N
+
Ph
NH2
Ph
N
3
R
1
2a
Ph
Ph
N
N
N
N
N
N
N
N
N
3a
N
3b
N
3c
, 94%
, 95%
, 96%
Ph
Ph
Ph
Ph
N
N
N
N
Ph
OMe
N
N
N
Ph
MeO
3e
3f
N
, 93%
, 81%
3d
, 96%
Cl
Br
Ph
Ph
N
N
N
N
N
CF3
Cl
Br
N
N
N
F3C
b
b
3g
N
3h
3i
, 41%
, 63%
, 58%, (74%)
Ph
N
Ph
N
Ph
N
N
N
O
N
NH2
N
N
65 Table 2 Annulation of benzonitrile with various hydrazines a
O
H2N
3j
3k
3l
, 80%
, 90%
, 86%
R
H
N
t-BuOK (20 mol%)
N
N
Ph
Ph
2 R1CN
N
+
N
N
R
NH2
N
R1
R1
S
N
4
1
2
N
N
N
N
S
b
b
3m
3n
, 33%
, 65%, (83%)
N
Ph
Ph
R
N
N
N
N
N
Ph
Ph
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
N
Ph
, R = 3-Me, 93%
Ph
Ph
N
N
N
N
3p
b
b
3o
3q
N
, 94%
, 68%, (83%)
, 61%
b
4a
4b
4n
, 74%
4m
, 84%, (93%)
Ph
b
Ph
, R = 2-Et, 84%, (95%)
N
R
Ph
N
N
N
N
b
N
N
4c
4d
4e
, R = 4-OMe, 85%, (86%)
, R = 2-t-BuO, 70%
, R = 3-F, 87%
N
N
N
N
N
Ph
Ph
b
N
b
b
F
3r
, 78%, (91%)
3s
3t
, 78%, (93%)
, 66%, (84%)
Ph
Ph
N
b
4o
4p
, R = Ph, 79%, (87%)
, R = 4-MeOPh, 76%, (84%)
15 a Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), t-BuOK (0.2 mmol),
4q,
73%
b
4f
, R = 2-F, 63%
1,4-dioxane (2.0 mL), 120 oC, N2, 10 min. Isolated yield. b 15 h.
4g
4h
, R = 4-Cl, 91%
R
N
N
HO
b
We could apply a wide range of nitrile substrates using our
optimized conditions allowing the preparation of tri-substituted
1,2,4-triazoles (Table 1). The electronic properties of the phenyl
20 ring of nitriles had some effect on the reaction. Generally, the
aromatic nitriles possessing electron-donating groups gave
slightly higher yields than possessing electron-withdrawing ones
(3b-f vs 3g-i). Fortunately, free amine group survived well in the
standard procedure, leading to 3j in excellent yield. Meanwhile,
25 some hetero-cyclic moieties, including furan and pyridine, could
be smoothly incorporated in the 1,2,4-triazole molecules by using
corresponding nitriles (3m-3p). The structure of the product 3n
was confirmed by X-ray single-crystal diffraction analysis.10
Benzyl cyanide and pentanenitrile, importantly, can be well
30 transferred to the corresponding desired products 3q and 3r in
61% and 91% yields, respectively. In addition, cyclic alkyl
nitriles were also good annulation partners, providing 3s and 3t in
high yields, respectively.
, R = 3-Cl, 70%, (79%)
b
4i
4j
Ph
4r
, R = 2-Cl, 43%, (51%)
, R = 3,5-(Cl)2, 82%
Ph
N
N
N
b
, R = i-Pr, 87%, (96%)
Ph
Ph
Ph
b
b
N
4k
, R = 3-Br, 58%, (67%)
4s
, R = t-Bu, 85%, (93%)
4l
, R = 3-CF3, 73%
4t
4u
, 81%
, R = cyclohexyl, 87%
R
N
N
R
HN
N
N
N
Ph
N
N
N
b
b
b
5a
5b
5d
5e
5f
, 89%
, R = i-Pr, 88%, (96%)
, R = t-Bu, 81%, (92%)
5c, R = HOCH2CH2, 90%
, R = i-Pr, 80%, (91%)
, R = t-Bu, 85%, (94%)
b
b
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), t-BuOK (0.2 mmol),
1,4-dioxane (2.0 mL), 120 oC, N2, 10 min. Isolated yield. b RNHNH2·HCl,
t-BuOK (1.2 mmol), 15 h.
70
To further explore its potential application and understand the
mechanism of the reaction, we had done a series of experiments.
2 | Journal Name, [year], [vol], 00–00
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Initially, we scaled up the reaction to 100 mmol scale, the desired
3a could be formed in 94% (13.99 g) yield.9 With the newly
developed catalytic system, the desired two type of mGlu5
methoxyphenyl)hydrazine (2a-15N), almost complete 15N-labeled
nitrogen atom was incorporated into desired product 4c-15N
(Scheme 3, d). This result showed that the one benzonitrile
receptor pharmaceutical were isolated in 78% (6a) and 73% (6b) 35 provided a nitrogen atom and the others two nitrogen atoms
5
yields, respectively (Scheme 2).11
derived from the hydrazine. In addition, the ammonia gas can be
collected in good yield, strongly indicating that the one
benzonitrile provided a nitrogen and the other one deliver the
ammonia gas (Scheme 3, e). The adduct of 3a was undetected,
40 when 1,2-diphenylhydrazineas as the react partner. Significantly,
the annulation of the intermediate specie 7a generated in situ
from 1b and 2a with 4-methoxybenzonitrile to form the 1,3,5-
trisubstituted-1,2,4-triazole 8f in good yield (Scheme 3, f).
O
N
OMe
b.
PMP
N
N
N
N
S1
N COCH2Cl
a. standard
conditions
N
N
N
(1)
PMP
mGlu5 receptor
6a,
78%
N
N
F
c.
Cl
N
O
N
Table 3 Tandem annulation with various reaction conditions a
N
N
N COCH2Cl
N
N
N
a. standard
conditions
N
N
S2
N
Cl
R2
(2)
NH
R3
N
H
H
NaH
(I)
N
N
N
R1
C
N
R1
N
R2 NH2
+
N
R1
N
H
7
R2
mGlu5 receptor
6b,
F
t-BuOK
(II)
R3
N
8
73%
1
2
F
Scheme 2 Synthetic versatility of the present annulation system
Ar
R
N
N
N
N
Subsequently, we examined experiments with the new reaction
N
N
Ph
Ph
N
10 tube, pure base and pure substrates for this transformation, the
yields of 3a was not affect. Furthermore, the transition metals
species in the reaction mixture was undetectable (< 0.1 ppm) by
ICP-MS analysis, indicating this transformation should not be the
transition metal catalyzed procedure. Only trace amount of 3a
15 was detected in the presence of 18-crown-6, attributing to the
strong complexing ability of 18-crown-6 with the potassium ion
(Scheme 3, a).12 Two equivalents of tetramethylpiperidin-1-oxyl
or ethene-1,1-diyldibenzene was added into the annulation as a
radical scavenger, the high yields of 3a were obtained,
20 respectively, revealing this reaction might not be a free radical
process (Scheme 3, b). These results showed that the significant
role of the t-BuOK in promoting the reactions rather than the
transition metal catalysts or its impurities.
Ph
Ph
N
8a
8b
8c
8d
8e
, Ar = Ph, 86%
, R = 2-pyridyl, 63%
, Ar = 3-MePh, 81%
, Ar = 4-ClPh, 80%
, R = cyclohexyl, 62%
OMe
b
8f
, 75%, (72%, 2.46 g)
45
50
a Reaction conditions: (I) 1 (1.0 mmol), 2 (1.2 mmol), NaH (1.2 mmol),
DMSO (1.0 mL), N2, rt, 15 h; (II) 7 (0.5 mmol), 1 (0.5 mmol), t-BuOK
(0.2 mmol), 1,4-dioxane (2.0 mL), 120 C, N2, 10 min. Isolated yield.
o
b
Gram-scale.
As the proposed design was partially realized by successfully
employing t-BuOK as mediator for the cyclization of nitriles with
hydrazines, we next wanted to further investigate whether base
could promote the tandem annulation with two difference
molecules of nitriles by hydrazine. To our delight, the
55 combination of NaH and t-BuOK was identified as an efficient
cooperative promotion system for mediating the desired
annulation reaction. By using the procedure in Table 3, the
cyclization synthesis of triazoles proceeded favorably to form the
desired 8a in good yield. Similar results were obtained in the
60 reactions of other nitriles with hydrazines to generate rise to a
variety of tri-substituted triazoles in good yields (8b-8f). The
gram-scale reaction was successfully realized employing with
tandem cyclization, thus affording 8f in 72% (2.46 g) yield.9
Ph
H
N
N
t-BuOK (20 mol%)
N
2 PhCN
+
(a)
Ph
NH2
1,4-dioxane
Ph
Ph
3a
N
1a
2a
ICP-MS
: new seal tube, pure substrates; , 94%
3a
18-crown-6 (0.2 equiv); , <5%
Ph
H
N
N
t-BuOK (20 mol%)
N
2 PhCN
+
(b)
Ph
NH2
1,4-dioxane
Ph
TEMPO (2 equiv); , 95%
Ph
3a
N
1a
2a
3a
Ph2C=CH2 (2 equiv); , 92%
15
N
R
+ t-BuO
R
NHNH2
- t-BuOH
Ph
Ph
H
N
t-BuOK (20 mol%)
15N
(c)
K
2 PhC
+
N
N
Ph
NH2
1,4-dioxane
Ph
1a-15
N
K
R1
C
NHNH
2a
3a-15
N
N
, 91%
NH3
PMP
N15
15N
N
t-BuOK (20 mol%)
PMP
H2
2 PhCN
+
+
N
(d)
(e)
1,4-dioxane
Ph
4c-15
Ph
H
N
N
N
K
NHNH2
1a
2a-15
N
, 85%
R
N
R1
H
R
H
N
t-BuOK (20 mol%)
N
2 PhCN
3a
+
NH3
78%
H
Ph
NH2
1,4-dioxane
1,3-H
shift
A
1a
96%
2a
KN
H2
H
Ph
NH
H
H
N
N
N
K
1f
, (0.5 mmol)
H
N
K
N
N
H
Ph
(f)
N
t-BuOK (20 mol%)
N
R1
H
N
R1
OMe
R
N
1,4-dioxane
N
7a
8f
, 83%
R
R1
B
C
H
25 Scheme 3 Mechanistic investigations
N
H
R1
D
N
K
N
To gain insight into the origin of the nitrogen atom in the
product, we carried out several labeling experiments. The
annulation of 2a was firstly conducted with 15N-labeled
benzonitrile (1a-15N), only one 15N-labeled nitrogen atom was
30 incorporated into product 3a-15N (Scheme 3, c). Moreover, when
the reaction was carried out in the presence of 15N-labeled (4-
N
N
C
R2
R1
R1
N
C
R
N
R1
N
C
65 Fig. 2 Proposed reaction pathway
On the basis of the results described above and previous
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reports, a tentative reaction mechanism for this deamination
annulation reaction is shown in Fig. 2. Initially, nucleophilic
addition of hydrazine with nitrile under the base promoted,
generating the five membered intermediate A. Subsequently, the
60
5
A species could undergo isomerization to generate the
intermediate B and C. Consequent annulation of C with the other
nitrile took place to form the desired product 1,2,4-triazole and
KNH2. Followed by protonation with hydrazine or t-BuOH
release the ammonia gas and regenerated the active species for
65
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10 the next catalytic cycle.
In summary, we have developed a practical and efficient
protocol for the base mediated deamination annulation of
nitriles with hydrazines. A wide range of tri-substituted 1,2,4-
triazoles are compatible with this operationally simple and
15 rapid method, which could thus be employed for the synthesis
70
75
80
of biologically active triazoles with
a broad array of
substitution and functionalization patterns. Forty-one of the
51 synthesized examples are novel compounds. The
transformation affords a practical and useful strategy for
20 synthesis of various of 15N-labeled 1,2,4-triazole derivatives
and 13.99 gram of triazole can be easily assembled. Moreover,
this reaction can be employed to one-pot synthesis of the two
type of significant protein antagonists and receptor mGlu5.
Further investigates aimed at getting a detailed mechanistic
25 understanding of this annulation and employed triazoles as a
pharmaceuticals are currently under in our group.
4
85
This research was supported by the National Natural
Science Foundation of China (Nos. 22002067 ， 21571143),
30 the Qingdao Science and Technology Foundation (18-2-2-
49-jch), the Shandong Provincial Natural Science
90
5
95
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Foundation
of
China
(Nos.
ZR2017MB029,
ZR2017BB060) for financial support.
Conflicts of interest
6
(a) O. Guerret, S. Solé, H. Gornitzka, M. Teichert, G. Trinquier and G.
Bertrand, J. Am. Chem. Soc., 1997, 119, 6668; (b) F. Amblard, J. H.
Cho and R. F. Schinazi, Chem. Rev., 2009, 109, 4207; (c) S. Ueda and
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Yan, Z. Liu, Y. Xu and Y. Zhang, Angew. Chem., Int. Ed., 2013, 52,
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10444.
35 There are no conflicts of interest to declare.
100
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See the Supporting Information for details.
50
9
10 CCDC 1971369 (3n)†.
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ChemComm
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DOI: 10.1039/D0CC05828A
A practical base mediated synthesis of 1,2,4-triazoles enabled by
deamination annulation strategy
The t-BuOK mediates the deamination annulation of nitriles with hydrazines for
synthesis of 1,2,4-triazole. This protocol provides a practical strategy to construct
15N-labeled 1,2,4-triazoles and protein antagonists and receptor mGlu5 in one-pot.