Synthesis of 1,2,4-triazine derivatives via [4 + 2] domino annulation reactions in one pot

Article abstract of DOI:10.1039/c5ra26638f

Simple and efficient [4 + 2] domino annulation reactions have been developed for the synthesis of 1,2,4-triazine derivatives. The strategies exhibit high performance with moderate to high yields, using easily available materials including ketones, aldehyd

Full text of DOI:10.1039/c5ra26638f

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DOI: 10.1039/C5RA26638F
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ARTICLE
Synthesis of 1,2,4-Triazine Derivatives via [4+2] Domino
Annulations Reactions in Onepot
Dong Tang,a Jing Wang,a Ping Wu,a Xin Guo,a Ji-Hui Li,b Sen Yang,a and Bao-Hua Chena*
Received 00th January 20xx,
Accepted 00th January 20xx
The simple and efficient [4+2] domino annulation reactions have developed for the synthesis 1,2,4-triazine derivatives. The
strategies exhibit high performance with moderate to high yields by using easily available materials including ketones,
aldehydes, alkynes, secondary alcohols and alkenes, and represent a powerful tool for the formation of potentially
DOI: 10.1039/x0xx00000x
www.rsc.org/
biological
active
derivatives.
reactions for making 1,2,4-triazine derivatives without the
addition of transition metal catalyst, and the works
systematically study the reactions of ketones / alkynes and
amidrazones7 to synthesize 1,2,4-triazine derivatives. These
strategies may be an highly efficient alternative to the
synthesis of 1,2,4-triazine compounds in pharmaceutical
chemistry and other fields.
Introduction
The 1,2,4-triazine moiety represents an important class of
heterocycles, and the 1,2,4-triazine derivatives have been
reported to possess a broad spectrum of biological activities
including anti-convulsant,1a anti-cancer,1b anti-cytokine,1c anti-
tumor,1d anti-viral,1e anti-hypertensive1f and anti-malarial.1g In
addition, some important metal coordinating ligands contain
1,2,4-triazine skeleton.2 These classes of compounds are
significant and useful, however, the systemic, operable and
versatile strategies are shortage to construct 1,2,4-triazine
skeleton for meeting the demand of synthetic chemistry.
Among the known methods for 1,2,4-triazines, the reactions of
amidrazones and 1,2-diketone compounds are the most
available protocols to form 3,5-disubstituted or 3,5,6-
trisubstituted 1,2,4-trizaines.3 Otherwise, the multi-
Results and discussion
Initially, we examined the reaction of acetophenone 1a and
benzimidohydrazide 2a as a model reaction, as shown in Table
1. A mixture of 1a (0.2 mmol), 2a (0.2 mmol), CuO (0.24mmol)
and I2 (0.24mmol) were carried out in DMSO under air at 110
oC for 2 h, and the desired product (3aa) was isolated in 14%
component reactions (MCR) of hydrazides, dicarbonyl yield (Table 1, entry 1), the structure was identified by X-ray
(Figure 1). Encouraged by this result, we continued to explore
other iodine sources, but only inferior results were obtained
(Table 1, entries 2-4). Noteworthily, when the reaction was
completed, we found that the byproduct of 1,2,4-triazole was
formed by TLC, and this side reaction had been documented in
previous reports.8 In order to avoid the loss of 2a, we, then,
introduced 2a into the reaction system after the
acetophenone reacted for 2 hours in presence of I2. To our
delight, a 60% yield of 3aa was obtained (Table 1, entry 5).
Other oxidants, such as MnO2, CuO and SeO2, were also
evaluated, and the SeO2 showed a better catalytic activity
(Table 1, entries 6-8). When the reaction time was prolonged
to 4 hours before 2a added, the yield was improved to 80%
(Table 1, entry 9). In the screening of solvents including DMF,
toluene, dioxane and H2O, and no better results were obtained
(Table 1, entries 10-13).
compounds and ammonium acetate also
a pathway to
synthesize 3,5-disubstituted 1,2,4-trizaines.4 Nevertheless, it is
remained considerable scope for improvement, such as
availability of the starting materials, tedious process and poor
tolerance.
In past years, our group had reported to obtain imidazole
skeleton by employing amidines and ketone / nitroolefin.5 To
the best of our knowledge, the units of ketone, acetaldehyde,
alkyne and alkene are useful building blocks providing two
carbon atoms to construct five or six member rings.6 Based on
our previous works, we shifted our attention to develop six
member nitrogen heterocyclic with simple operation, high
utilization of atoms and good yields. Herein, we report the
SeO2 or iodine sources catalyzed [4+2] domino annulation
a.State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu
Lanzhou, 730000, China and Key Laboratory of Nonferrous Metal Chemistry and
Resources Utilization of Gansu Province, Lanzhou 730000, China Fax: +(86)-931-
891-2582; e-mail: chbh@lzu.edu.cn.
Table 1 The reaction conditions optimization of
acetophenone and benzimidohydrazide a
b.College of Materials and Chemical Engineering, Hainan University, Haikou,
570228, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
Ph
6
7
8
9
10
11
12
13
14
2-Me-C6H4, 1g
3,4-MeO-C6H4, 1h
4-F-C6H4, 1i
4-Cl-C6H4, 1j
3,4-Cl-C6H4, 1k
4-NH2-C6H4, 1l
1-Nap, 1m
4- C6H5-C6H4, 1n
2-furan, 1o
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
73
75
76
72
69
0
75
76
78
0
NH
O
N
Oxidant
Solvent
NH2
Ph
N
+
N
Ph
H
Ph
N
1a
2a
3aa
Entry
1
2
3
4
5
6
7
8
Oxidant
CuO /I2
I2
Solvent
Yield b
14
27
24
12
60
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
I2/TBHP c
TBAI/TBHP c
15
Propyl, 1p
Reaction conditions:
a
d
1 (0.2 mmol), 2a (0.2 mmol), SeO2 (0.24
I2
MnO2
d
mmol), DMSO (2 mL), 110 °C , 2a was added after reaction
initiated for 4 hours. b Isolated yield based on
CuO d
SeO2
0
1.
d
71
80
trace
12
0
e
9
SeO2
SeO2
SeO2
SeO2
e
To further investigate the reaction scope, various
(
10
11
12
13
e
amidrazones
acetophenone
2b
(
-
h
)
1a), as shown in Table 3. Those
were employed to react with
Tolene
Dioxane
H2O
e
e
transformations displayed good functional groups tolerance
including methyl, methoxyl, fluoro, chloro and bromo, and the
amidrazones with electron-donating or electron-withdrawing
groups had no remarkable difference on yields and gave the
corresponding 1,2,4-triazines in good yields (Table 3, entries 1–
7). Notably, picolinimidohydrazide (2h) was also proceeded
smoothly and produced yield in 58% (Table 3, entry 7).
SeO2
0
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), oxidant
(1.2 equiv.), solvent (2 mL), 110 °C, under air. b Isolated yield
c
d
Iodine source (0.1 equiv.), TBHP (6 equiv.). 2a
based on 1a.
was added after reaction initiated for 2 hours. 2a was added
after reaction initiated for 4 hours.
e
With the optimized conditions in hand, the scope of this Table 3 The scope investigation of amidrazones with 1a a
domino annulation reaction was expanded. A variety of
Ph
different substituted ketones
1 were examined under optimal
O
NH
conditions, and the results were summarized in Table 2. The
reaction tolerated well with both electron-withdrawing and
electron-donating groups on the aromatic ring, and the
expected products were obtained in moderate to high yields.
Generally, the substrates with electron rich groups provided
better yields than the ones with electron deficient groups
(Table 2, entries 1-10). Furthermore, the steric effect had no
remarkable influence on the yields (Table 2, entries 1-6), and
the substrates with steric bulk groups on the ketones, such as
SeO2
N
NH2
+
DMSO, 110oC
N
Ph
R2
N
R2
N
H
1a
3
2
Entry
R2
Product
3ba
3bb
3bc
3bd
3be
3bf
Yield b
1
2
3
4
5
6
4-Me- C6H4, 2b
3-Me- C6H4, 2c
85
79
88
75
74
82
58
4-MeO- C6H4, 2d
4-F- C6H4, 2e
4-Cl- C6H4, 2f
4-Br- C6H4, 2g
2-Py, 2h
1-(naphthalen-1-yl)ethanone
(1m) and 1-([1,1'-biphenyl]-4-
yl)ethanone (1n), and with heterocycle, such as 1-(furan-2-
yl)ethanone (1o), were well tolerated, affording good yields in
75-78% (Table 2, entries 12-14). Somewhat disappointingly,
when the aliphatic ketones and the substrates with amino
were performed in the catalyst system, the desired products
were not found (Table 2, entries 11 and 15).
7
3bg
a
Reaction conditions: 1a (0.2 mmol),
was added after reaction
initiated for 4 hours. b Isolated yield based on 1a
2 (0.2 mmol), SeO2 (0.24
mmol), DMSO (2 mL), 110 °C,
2
.
Inspired by the above results, we shifted our attention to
explore the reaction feasibility of alkynes and amidrazones.
The reaction conditions were also investigated (For details see
supporting information), and it was found that the reactions of
4a (0.4 mmol) and 2a (0.2 mmol) in presence of N-
iodosuccinimide (NIS) (0.24 mmol) and p-toluenesulfonic acid
( TsOH, 0.02 mmol) in DMSO (2 mL) furnished desired product
yield in 62% at 110 °C. Then, the substrate scopes were
investigated in details. Aryl-alkynes with different functional
groups, such as methoxyl, methyl, fluoro, chloro, bromo and
phenyl, all could provide the corresponding products in good
yields ranging from 51 to 82% (Table 4, entries 1-9). Notably,
the substrates with electron-donating groups tended to obtain
better yields, and the steric effect was not critical for those
transformations (Table 4, entries 7 and 9).
Table 2 The scope investigation of arylketones with 2a a
R1
NH
O
SeO2
N
NH2
Ph
N
+
R1
N
DMSO, 110oC
Ph
N
H
1a
2a
3aa
Entry
R1
Product
3ab
3ac
3ad
3ae
Yield b
1
2
3
4
5
4-MeO-C6H4, 1b
3-MeO-C6H4, 1c
2-MeO-C6H4, 1d
4-Me-C6H4, 1e
3-Me-C6H4, 1f
80
77
89
77
3af
85
2 | J. Name., 2012, 00, 1-3
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Table 4 The scope investigation of arylalkynes with 2a a
presence of iodine (1 equiv.) and DMSO (2ml) at 110 oC, and
the desired product 3aa was isolated in 38% (Scheme 1a).
R3
Moreover, 1-phenylethanol (6a) and 1,2-diphenylethyne (7a
)
NH
were reacted with 2a in presence of iodine (1 equiv.), 2-
iodoxybenzoic acid (IBX) (0.75 equiv.) and DMSO (2 ml) at 110
oC, and we were pleased to obtain the corresponding products
3aa and 8aa in 74% and 51% yields, respectively. To our
surprise, 2-phenylacetaldehyde (8a) was also compatible to
the reaction to the desired product 3aa in 53%. These
reactions are attractive, making a range of interesting 1,2,4-
NIS (1.1 equiv.)
N
NH2
R3
Ph
N
+
N
H
Ph
N
DMSO,
TsOH(0.1equiv.),110oC
4
2a
3
Entry
R3
Product
3ab
3ac
3ae
3af
Yield b
82
1
2
3
4
5
6
7
8
9
4-MeO-C6H4, 4b
3-MeO-C6H4, 4c
4-Me-C6H4, 4e
3-Me-C6H4, 4f
4-F-C6H4, 4i
77
59
67
66
triazine scaffolds through the useful, efficient, simple
procedure by using easily available starting materials.
a) The reaction property of styrene.
Ph
3ai
4-Br-C6H4, 4r
4-Cl-C6H4, 4j
3-F-C6H4, 4s
3ar
3aj
3as
3at
57
60
51
58
NH
I2 (1.0 equiv.)
DMSO, 110 o
N
NH2
N
Ph
Ph
N
Ph
N
+
H
C
yield=38%
3aa
5a
2a
2-Cl-C6H4, 4t
4-C6H5-C6H4, 4n
Reaction conditions: 4 (0.4 mmol), 2a (0.2 mmol), NIS (0.24
10
3an
79
a
b) The reaction property of 1-phenylethanol.
Ph
N
mmol), TsOH (0.02 mmol), DMSO (2 mL), 110 °C, 2a was added
after reaction initiated for 4 hours. Isolated yield based on
b
NH
I2 (1.0 equiv.)
OH
2a.
NH2
+
N
Ph
N
IBX (0.75 equiv.)
DMSO, 110 oC
Ph
Ph
N
H
3aa yield=74%
2a
With regards to the scope and generality of amidrazones,
different amidrazones were employed to react with
6a
ethynylbenzene (4a). As expected, the reactions of amidrazone
and 4a proceeded smoothly to give the
3bg in moderate to
substrates 2a
-
h
c) The reaction property of 1,2-diphenylethyne.
corresponding coupling products 3ba
−
Ph
Ph
N
good yields (Table 5, entries 1-7, 65−79%). Regardless of the
electronic nature, the functional groups had no remarkable
impact on the yields. It was noteworthy that the
picolinimidohydrazide (2h) was also afforded the desired
products in 64 % (Table 5, entry 7).
NH
I2 (1.0 equiv.)
NH2
Ph
Ph
+
N
Ph
N
IBX(0.75 equiv.)
DMSO, 110 oC
Ph
N
H
2a
8aa yield=51%
7a
Table 5 The scope investigation of amidrazones with 4a a
d) The reaction property of phenylacetaldehyde.
Ph
N
Ph
NH
I2 (1.0 equiv.)
NH
NIS (1.1 equiv.)
NH2
N
Ph
CHO
+
Ph
N
NH2
N
DMSO, 100 oC
Ph
R2
N
H
+
Ph
N
N
R2
N
8a
H
DMSO,
TsOH(0.1equiv.),110oC
2a
3aa, yield=53%
2
4a
3
Entry
R2
Product
3ba
3bb
3bc
3bd
3be
3bf
Yield b
Scheme 1 The alternative transformations to construct 1,2,4-
triazine derivatives.
1
2
3
4
5
6
7
4-Me- C6H4, 2b
3-Me- C6H4, 2c
4-MeO-ph, 2d
4-F- C6H4, 2e
4-Cl- C6H4, 2f
4-Br- C6H4, 2g
2-Py, 2h
78
77
71
65
79
77
64
3bg
a Reaction conditions: 4a (0.4 mmol),
2
(0.2 mmol), NIS (0.24
mmol), TsOH (0.02 mmol), DMSO (2 mL), 110 °C, was added
after reaction initiated for 4 hours. b Isolated yield based on
2
2.
To get more insight into the diversity synthetic strategies for
1,2,4-triazine derivatives, the building blocks including styrene
Figure 1 The X-ray crystal structure of 3aa
.
(
5a), 1-phenylethanol (6a), 1,2-diphenylethyne (7a) and 2-
phenylacetaldehyde (8a) were introduced into this class of
reactions. The styrene (5a) and 2a were carried out in the
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For the probable mechanism of those kinds of reactions, and alkenes12 might follow a parallel procedure. Subsequently,
some works had reported that the starting materials, such as the diketones combined with amidrazones via [4+2] annulation
arylketones9 and arynes,10 converted into corresponding reaction to obtain the final 1,2,4-triazines products
3 (Scheme
diketones
B
. Similarly, the arylacetaldehydes, 1-Arylethanol11 2). 13
O
1
R2
SeO2
Se
R2
NH
I2, DMSO
DMSO
R3
NH2
R1
N
O
O
N
H
R2
I
O
R2
R2
N
R1
N
Annulation reaction
A
4
S
B
HI
+
S
3
Me
Me
Me
Me
Scheme 2 Plausible reaction pathway.
We are grateful to the project sponsored by the National
Science Foundation of P. R. China (Nos. J11003307 and
21372102).
Conclusions
In conclusion, we have reported effective and simple strategies
to synthesize 1,2,4-triazine derivatives through [4+2] domino
annulations in onepot. These transformations employ SeO2 or
iodine sources as oxidant without using transition metal
catalyst and show good tolerance with moderate to high yield.
Moreover, the reactions can access important 1,2,4-triazine
skeleton which can be potentially applied to afford a series of
biological activity derivatives.
Notes and references
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,
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Experimental
Typical procedure for the preparation of 1,2,4-triazine derivatives 3.
Bormotov and O. A. Serova, Pharm. Chem. J., 2012, 45
,
Procedure
sidearm flask (10 mL),
DMSO (2 mL) were added to the flask with a magnetic stirring
bar at 110 oC under air. After 4 h stirring at this temperature,
A
: The reaction was carried out in a round-bottom
655-659; (f) W. P. Heilman, R. D. Heilman, J. A. Scozzie, R.
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1
(0.2 mmol), SeO2 (0.24 mmol) and
2
(0.2 mmol) was introduced into the catalyst system. 2 hours
later, the flask was, then, took out and cooled to room
temperature. The mixture was washed with 20 ml water and
extracted with ethyl acetate (3 × 50mL). The oil layer was
combined and concentrated under reduced pressure to distill
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Procedure
sidearm flask (10 mL),
(0.02 mmol) and DMSO (2 mL) were added to the flask with a
magnetic stirring bar at 110 oC under air. After 4 h stirring at
this temperature, (0.2 mmol) was introduced into the
catalyst system. The following processing method was referred
to the procedure
B
: The reaction was carried out in a round-bottom
4
(0.4 mmol), NIS (0.24 mmol), TsOH
2
A
.
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DOI: 10.1039/C5RA26638F
O
SeO2, DMSO
NIS, DMSO
R2
R2
R2
N
3I2, DMSO
R
R2
R2
R3
NH
N
I2, IBX, DMSO
NH2
+
R1
N
N
R1
H
OH
I2, IBX, DMSO
I2, DMSO
R2
R2
CHO
The simple and efficient [4+2] domino annulation reactions have developed for the synthesis
1,2,4-triazine derivatives. The strategies exhibit high performance with moderate to high yields
by using easily available materials including ketones, aldehydes, alkynes, secondary alcohols and
alkenes, and represent a powerful tool for the formation of potentially biological active
derivatives.