New 1,3-dipolar cycloaddition/dehydrogenation of azomethines ylides and azodicarboxylates: Direct and effective construction of unsaturated 1,2,4-triazolines

Article abstract of DOI:10.1016/j.tetlet.2012.03.083

The first K₂CO₃-catalyzed 1,3-dipolar cycloaddition/dehydrogenation of azodicarboxylates with azomethines was developed and a wide range of unsaturated 1,2,4-triazolines have been successfully prepared in good yields (up to 93%).

Full text of DOI:10.1016/j.tetlet.2012.03.083

Tetrahedron Letters 53 (2012) 2985–2988
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New 1,3-dipolar cycloaddition/dehydrogenation of azomethines ylides
and azodicarboxylates: direct and effective construction of unsaturated
1,2,4-triazolines
Qi-Lin Wang a,b, Ji-Ya Fu a,b, Lin Peng a, Qing-Chuan Yang a,b, Li-Na Jia a,b, Xi-Ya Luo a,b, Yong-Yuan Gui a,b
,
a,
Fang Tian a, Wen Wang a, Xiao-Ying Xu a, , Li-Xin Wang
⇑
⇑
a Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate University of Chinese Academy of Sciences, Beijing 10039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first K2CO3-catalyzed 1,3-dipolar cycloaddition/dehydrogenation of azodicarboxylates with azometh-
ines was developed and a wide range of unsaturated 1,2,4-triazolines have been successfully prepared in
good yields (up to 93%).
Received 1 December 2011
Revised 15 March 2012
Accepted 22 March 2012
Available online 29 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Azomethine ylides
Azodicarboxylates
Nitrogen-containing compounds are basic moieties in many
medicines and natural products.1 In particular, 1,2,4-triazolines
are important scaffolds in organic synthesis and are frequently
found in biological active compounds which exhibit potential anti-
cancer, antiviral, and anticonvulsant properties.2 For the signifi-
cance of those molecules, development of new strategies for their
synthesis has drawn great attention. As a result, numerous meth-
construction of 3,4-unsaturated 1,2,4-triazolines has not been ad-
dressed, even if azomethines are extensively utilized in 1,3-dipolar
cycloaddition.11 For the correlation between the molecular struc-
tural diversities and the potential biological activities, it is still
highly desirable to develop a new protocol to afford a new family
of 3,4-unsaturated 1,2,4-triazolines.
Recently, our group is endeavoring to develop new methods for
the formation of carbon–hetero bond,12 especially for the forma-
tion of carbon–nitrogen bond, typically by asymmetric aminations
of aldehydes with azodicarboxylates,13 [3+2] cycloaddition reac-
tion of azomethines with maleimide,14 and hydroxyamination of
3-substituted oxindoles.15 Based on these achievements and
our continuing interests on construction of nitrogen-containing
compounds, herein, we wish to report the first example of 1,3-
dipolar cycloaddition/dehydrogenation of azodicarboxylates with
odologies were documented, including oxidation of
a-amino acid
under Mitsunobu conditions,3 transformations involving oxazoles,
thiazoles or oxazolones,4 and the reactions of azodicarboxylates
with imidazopyridine,5 N-[(trimethylsilyl)methyl] iminium,6 or
a
-isocyano ester.7 Among them, azodicarboxylates are promising
reagents and are widely used in electrophilic amination reactions
and pericyclic reactions, which may attribute to: (i) exhibit high
reactivities; (ii) easily functionalized; (iii) easily obtained and
commercially available. In 2010, Tepe’s group reported the reac-
tion of oxazolones with azodicarboxylates to construct 1,2,4-triaz-
olines in excellent yields (up to 100%).8 Continually, Jørgensen’s
group demonstrated a convenient synthesis of 1,2,4-triazolines
R3O2C
R3O2C
R3O2C
CO2R3
CO2R3
CO2R3
N
N
N
3
N
3
N
N
R1
5
from
a
-isocyano esters/amides and azodicarboxylates via the
R1
CO2H
3
5
5
R2
N
N
R1
CO2R2
COXR2
H
hydrazination/cyclization cascade reaction9 (Fig. 1). To the best
of our knowledge, there is only one report about the reaction of
N
R1= aryl, alkyl
R2= aryl, alkyl
R3= alkyl
R1= aryl, alkyl
X= O, N
R1= aryl
R2= Me, Et
R3= alkyl
a
-substituted azomethines with azodicarboxylates and affords
R3= alkyl
the saturated 1,2,4-triazolines,10 whereas the version for the
orgensen,
J s method
using isocyanides
Tepe,s method
using oxazolones
our method
using azomethines
⇑
Corresponding authors.
E-mail address: xuxy@cioc.ac.cn (X.-Y. Xu).
Figure 1. Methods to construct 1,2,4-triazolines.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.083

2986
Q.-L. Wang et al. / Tetrahedron Letters 53 (2012) 2985–2988
1,2,4-triazoline 3a via a possible cascade reaction of 1,3-dipolar
cycloaddition and subsequent in situ dehydrogenation in 69% yield
and the structure was determined by X-ray (Fig. 2), while the nor-
mal [3+2] adducts were not separated (Scheme 1).16 Inspired by
this result, a series of bases were screened and the results were
shown in Table 1. The basicity has a significant impact on the reac-
tivity. The stronger bases gave the lower yields (Table 1, entries
1–7), and the weaker organic bases also gave relatively lower
yields (15–62%, Table 1, entries 10–14). Moderate basicity of
K2CO3 gave the best result and was chosen as the most suitable
base (69% yield, Table 1, entry 9).
To further optimize the reaction condition, the effects of a series
of solvents were then studied and the results were presented in
Table 2. Solvents have significant effects on the yields. Aprotic sol-
vents such as halogenated hydrocarbons, aromatic solvents, esters,
and hydrocarbon solvents afforded moderate to good yields (up to
79%, Table 2, entries 1–21). Among them, methyl tert butyl ether
(MTBE) gave the best yield (79%, Table 2, entry 15). By contrast,
alcohol solvents gave poor to moderate yields (3% and 44%, Table
2, entries 22 and 23). When the reaction was carried out in water,
only trace amount of product was monitored (Table 2, entry 24).
The screening of solvents demonstrated that MTBE was a suitable
solvent for further investigation. In general, reaction temperature
greatly affected yields. Lowering the reaction temperature to
0 °C, prolonged reaction time was required and the yield was de-
creased to 68% (Table 2, entry 25). Increasing the temperature to
40 °C, the reaction time was shortened and the yield was slightly
lowered (75% yield, Table 2, entry 26). Further increase of the tem-
perature led to no significant improvement in yield (Table 2, entry
Figure 2. X-ray crystal structure of 3a.
azomethines to construct 3,4-unsaturated 1,2,4-triazolines in good
yields under mild reaction conditions.
Preliminary experiments were conducted with 1a and 2 equiv
of 2a in the presence of 20 mol % base to optimize the reaction con-
dition. All the reactions occurred smoothly in toluene in the pres-
ence of 20 mol % K2CO3 and gave the unexpected 3,4-unsaturated
CO2R1
CO2R2
R2O2C
Ar
CO2R2
N
1, 3-dipolar
R2O2C
Ar
CO2R2
N
dehydrogenation
N
cycloaddition
N
N
+
N
N
CO2R1
R2O2C
CO2R1
N
H
Ar
N
Scheme 1. Cyclization/dehydrogenation reaction between azomethine ylide and azodicarboxylate.
Table 1
Base screeninga
i-PrO2C
CO2i-Pr
N
base (20 mol%)
N
+
CO2Me
DIAD
Ph
N
toluene (2 mL)
Ph
CO2Me
1a
2a
N
3a
30 °C
Entry
Base
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
n-BuLi
LDA
NaH
71
21.5
71
0.75
71
71
71
24
26
71
3
19
24
30
29
54
25
35
56
69
62
53
40
41
15
KOt-Bu
NaOH
LiOHÁH2O
Ba(OH)2ÁH2O
Cs2CO3
K2CO3
DABCO
DBU
DMAP
Imidazole
CH3COONa
71
72
71
a
Unless otherwise specified, all reactions were performed with 1 mmol of 1a, 2 mmol of 2a, and 0.2 mmol base at 30 °C in toluene.
Isolated yield.
b

Q.-L. Wang et al. / Tetrahedron Letters 53 (2012) 2985–2988
2987
Table 2
Table 3
Solvent screeningsa
Scope of substratesa
CO2R2
i-PrO2C
CO2i-Pr
N
CO2R2
R2O2C
Ar
K2CO3 (20 mol%)
N
N
N
K2CO3 (20 mol%)
+
CO2Me
Ph
N
+
Ar
N
CO2R1
DIAD
N
N
R2O2C
solvent (2 mL)
Ph
CO2Me
N
COOR1
MTBE (2 mL), 40 °C
30 °C
1a
N
2a
2
3a
1
3
Entry
Solvent
Time (h)
Yieldb (%)
Entry Ar
R1
R2
Product Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25c
26d
27e
DCM
CHCl3
1,1-DCE
1,2-DCE
23
23
22
22
37
23
23
10.5
24
26
7.5
12
9
6
10
5
6
5
1
5
4
37
12
59
64
33
29
68
50
68
69
45
47
54
48
79
59
44
50
35
59
53
Trace
44
Trace
68
75
53
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Et
i-Pr
Et
t-Bu 3c
Bn
3a
3b
4
8
8
6
6
75
54
36
42
51
11
54
46
72
67
68
71
84
93
—
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
1,1,2-TCE
Mesitylene
o-Xylene
m-Xylene
Chlorobenzene
Toluene
Et2O
Dioxane
DME
THF
i-Pr
i-Pr i-Pr
8.6
3
p-Cl-phenyl
o-Cl-phenyl
2-Thienyl
m-CH3-phenyl
p-CH3-phenyl
p-CH3O-phenyl
3,4-CH3O-phenyl
6-OCH3-2-naphthyl Me
o-OH-phenyl
p-OH-phenyl
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
6.2
2.5
6.5
16.5
26
29
40
4
MTBE
Me
Me
n-Hexane
c-Hexane
CH3CO2Et
DMF
Acetone
CH3CN
CH3OH
i-PrOH
H2O
7
—
a
Unless otherwise specified, all reactions were performed in 2 mL MTBE with
1.0 mmol 1, 2.0 mmol 2, and 0.2 mmol K2CO3 at 40 °C.
b
Isolated yield.
2 min
5
11
70
4
the aromatic ring failed to give the desired products (Table 3, en-
tries 15 and 16), which may attribute to the stronger acidity of
the hydroxyl compared with the
MTBE
MTBE
MTBE
a-H acidity of ester group that
3
leads to the catalyst consumption.
a
In conclusion, we have developed an efficient, general,
operationally simple method for the preparation of unsaturated
1,2,4-triazolines from readily available imine esters and azodicarb-
oxylates in good yields (up to 93%). Mechanistic studies and devel-
opment of asymmetric version of this protocol are underway in our
laboratory.
Unless otherwise specified, all reactions were performed with 1 mmol of 1a,
2 mmol of 2a, and 0.2 mmol of K2CO3 at 30 °C.
b
Isolated yield.
Reaction temperature 0 °C.
Reaction temperature 40 °C.
Reaction temperature 55 °C.
c
d
e
Acknowledgments
27). Taking into consideration of the compromising reaction time,
temperature, and yield (Table 2, entries 15 vs 26), the optimal reac-
tion conditions of 1 equiv of 1a, 2 equiv of 2a, and 20 mol % K2CO3
in MTBE at 40 °C were recommended.
We are grateful for the partial financial support from National
Natural Science Foundation of China (Nos. 20802075 and
21042006).
Under the optimized reaction condition, the generality of the
substrate scope was demonstrated by evaluating a variety of azo-
methine ylides and azodicarboxylates as shown in Table 3. The
azodicarboxylates gave a wide range of yields from 36% to 75% (Ta-
ble 3, entries 1–4), and the ethyl and i-propyl imine ester ylides
gave lower yields after a prolonged reaction time (Table 3, entries
5 and 6), which showed that the steric hindrance of the ester group
may have some impact on the reactivity. The effect of the substit-
uents on the aromatic ring of the azomethine ylides was also
studied and moderate to good yields (46–93%, Table 3, entries
7–14) were obtained except hydroxyl group (Table 3, entries
15 and 16), which showed an observable electronic effect. The
electron-donating substituents gave higher yields than those of
electron-withdrawing (Table 3, entries 7–8 vs 10–14). Particularly,
6-OCH3-2-naphthyl ylide gave the best yield (93%, Table 3, entry
14). By contrast, the position of the substituents slightly affected
the yields (Table 3, entries 7 vs 8, 10 vs 11). The optimized protocol
was also broadened to heteroaromatic compound, and 2-thienyl
substituted azomethine ylide proceeded the same reaction well
in 72% yield (Table 3, entry 9). However, the hydroxyl groups on
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
083.
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16. Typical experimental procedure for the synthesis of 3,4-unsaturated 1,2,4-
triazoline 3a. To a solution of 1a (1.0 mmol) and 2a (2.0 mmol) in solvent
(2.0 mL) was added base (20% mmol). The reaction was stirred at 40 °C until
the reaction was completed which was monitored by TLC. The crude product
was purified by column chromatography on silica gel (petroleum ether/
EtOAc = 25:1) to afford the pure 1,2,4-triazoline 3a as colorless crystal. 1H NMR
(300 MHz, CDCl3) d 7.40–7.32 (m, 5H), 6.87 (m, 1H), 5.13–4.98 (m, 2H), 3.95 (s,
3H), 1.61–1.25 (m, 12H).13C NMR (75 MHz, CDCl3) d 158.8, 157.0, 152.4, 148.9,
136.3, 128.8, 128.7, 125.8, 86.9, 72.6, 71.8, 53.4, 21.8, 21.5. HRMS (ESI–TOF):
calcd for [C18H23N3O6Na]+ 400.1484; found: 400.1478.
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