Non-catalytic addition of 1,2,4-triazole to nucleophilic and electrophilic alkenes

Article abstract of DOI:10.1023/A:1020981816097

Non-catalytic addition of 1,2,4-triazole to vinyl ethers and esters occurs on heating (65-175°C, 4-20 h) to give Markovnikov adducts (yield 30-100%). Electron-deficient alkenes (acrylonitrile, acrylic acid, 4-phenyl-3-buten-2-one) react with 1,2,4-triazole (78-190°C, 4-20 h) to give anti-Markovnikov adducts in yields of 45-83%.

Full text of DOI:10.1023/A:1020981816097

Chemistry of Heterocyclic Compounds, Vol. 38, No. 8, 2002
NON-CATALYTIC ADDITION OF
1,2,4-TRIAZOLE TO NUCLEOPHILIC
AND ELECTROPHILIC ALKENES
B.V. Timokhin1, A. I. Golubin1, O. V. Vysotskaya2, V. A. Kron1, L. A. Oparina2,
N. K. Gusarova2, and B. A. Trofimov2
Non-catalytic addition of 1,2,4-triazole to vinyl ethers and esters occurs on heating (65-175°C, 4-20 h)
to give Markovnikov adducts (yield 30-100%). Electron-deficient alkenes (acrylonitrile, acrylic acid,
4-phenyl-3-buten-2-one) react with 1,2,4-triazole (78-190°C, 4-20 h) to give anti-Markovnikov adducts
in yields of 45-83%.
Keywords: acrylic acid, acrylonitrile, vinyl ethers, Markovnikov and anti-Markovnikov adducts,
1,2,4-triazole, 4-phenyl-3-buten-2-one, addition.
Triazoles and their derivatives are of constant interest to researchers as highly reactive structural units
and intermediates [1-3], among which substances with antibacterial, spasmolytic, analgesic, and
cardiostimulating activities [4-7], and other practically valuable properties [8, 9] were found so that the search
for new suitable routes to functionalized triazoles is a timely problem. One of the promising means for
introducing functional substituents into the triazole ring is the addition of triazoles to functionally substituted
alkenes.
In this work the rules of the addition of 1,2,4-triazoles to double bonds of various types have been
studied using vinyl ethers and esters, acrylic acid, acrylonitrile, and 4-phenyl-3-buten-2-one as examples.
Information on similar reactions is, so far as we know, limited to three papers [10-12] in which the addition of
symmetrical and vicinal triazoles to vinyl ethers, catalyzed by orthophosphoric acid [10], and to electron-
deficient alkenes (acrylic and crotonic acids and their derivatives, benzalacetophenone, etc) in the presence of
bases [11, 12] is briefly reported.
We have shown here for the first time that 1,2,4-triazole (1) can add to both nucleophilic and
electrophilic alkenes in the absence of catalysts, although for quantitative conversion of the starting materials
somewhat more vigorous temperature conditions are required in this case.
Thus triazole 1 reacts with alkyl and aryl vinyl ethers 2a-j and also with vinyl acetate 2k on heating
(65-175°C, 4-20 h) to give 1-[1-alkoxy(aroxy)ethyl]-1H-1,2,4-triazoles 3a-k, the yields of which depend on the
structure of the starting vinyl ethers 2a-k and on the reaction conditions (Table 1).
__________________________________________________________________________________________
1
2
Irkutsk State University, Irkutsk 664000, Russia; e-mail: tim@chem.isu.ru. A. E. Favorsky Irkutsk
Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk 664033, Russia; e-mail:
parshina@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1122-1126, August,
2002. Original article submitted May 31, 2002.
0009-3122/02/3808-0981$27.00©2002 Plenum Publishing Corporation
981

N
N
ROCH=CH2
N
N
+
N
N
H
2a–k
ROCH–Me
1
3a–k
a R = n-Pr, b R = n-Bu, c R = n-C7H15, d R = Ph, e R = 3-MeC6H4, f R = 4-MeC6H4,
g R = 3-MeOC6H4, h R = 4-MeOC6H4, i R = 4-BrC6H4, j R = 3-ClC6H4, k R = AcO
The structures of the functionally substituted heterocycles 3a-k synthesized was demonstrated by
1H NMR spectroscopy and confirmed by mass spectrometry and elemental analysis (Table 2). The presence of a
doublet for the methyl group (1.5-1.9 ppm) and the quartet for the methyne proton (5.4-6.8 ppm) corresponds to
the Markovnikov structure of the adduct, while the presence of two signals for protons of the triazole ring in the
region of 7.8-8.2 ppm indicates the non-equivalence of atoms 3-H and 5-H in the ring, and shows that addition
of triazole 1 to the vinyl ethers and esters occurred with participation of atom N(1).
Conditions were found (120°C, 5 h) to obtain adducts 3a-c, on basis of alkyl vinyl ethers, in quantitative
yields (Table 1, exp 2,4,5). Addition of triazole 1 to aryl vinyl ethers 2d-j required more vigorous conditions
evidently due to the known [13] reduced nucleophilicity of the double bond in these compounds in comparison
with alkyl vinyl ethers. For example, vinyl phenyl ether 2d reacted with triazole 1 to give adduct 3d (Table 1,
exp. 6). Heating triazole 1 under these conditions with 3- and 4-methylphenyl vinyl ethers gave
1-[1-phenoxyethyl]-1H-1,2,4-triazoles 3e,f (Table 1, exp 7, 8). 3- and 4-Methoxyphenyl vinyl ethers are still less
reactive: the yields of the corresponding adducts 3g,h under more vigorous temperature conditions were 35 and
30% (Table 1, exp. 9 and 10). On the other hand, the presence of a halogen atom in the aromatic ring increased
the reactivity of the vinyloxy group: 1-[1-(4-bromo and 3-chloro)phenoxyethyl]-1H-1,2,4-triazoles (3i,j) were
obtained in yields of 74 and 71% respectively (Table 1, exp. 11, 12).
TABLE 1. Conditions for the Reactions of 1,2,4-Triazole with Alkenes 2
and 4 and the Yields of the Adducts 3 and 5
Experi-
ment
Yield
Alkene
Т, °С
Time, h
Adduct
of adduct, %*
1
65
120
93
20
5
7
5
5
18
18
18
12
12
12
18
15
20
4
48
97
77
97
96
42
35
50
35
30
74
71
42
83
73
50
2a
2a
2b
2b
2c
2d
2e
2f
3a
3a
3b
3b
3c
3d
3e
3f
2
3
4
5
6
7
8
120
120
155
150
150
175
175
175
170
120
78
9
2g
2h
2i
3g
3h
3i
10
11
12
13
14
15
16
2j
3j
2k
4a
4b
4c
3k
5a
5b
5c
120
190
20
_______
* Based on the amount of 1,2,4-triazole 1 used.
982

TABLE 2. Characteristics of Compounds 3a-j and 5a-c
1Н NMR spectrum (CDCl3), δ, ppm
Found, %
——————
Empirical
formula
bp, °С
Compound
Calculated, %
(mm Hg)
OCHN; R'CH2N*
Ме; RCH2*
3-Н, s
5-Н, s
C
H
N
C7H13N3O
53.86
54.18
8.58
8.44
27.20
27.06
40
5.52, q
5.42, q
5.50, q
6.25, q
6.21, q
6.26, q
6.13, q
6.28, q
6.25, q
6.27, q
6.80, q
4.38, t
1.65, d
1.54, d
1.65, d
1.83, d
1.86, d
1.85, d
1.91, d
1.88, d
1.91, d
1.86, d
1.80, d
2.91, t
2.81, t
7.89
7.84
7.89
7.89
7.92
7.93
7.94
7.93
7.94
7.93
7.88
7.91
8.21
8.13
8.21
8.16
8.15
8.19
8.12
8.18
8.19
8.21
8.22
8.14
3a
3b
3c
3d
3e
3f
(2)
C8H15N3O
C11H21N3O
C10H11N3O
C11H13N3O
C11H13N3O
C11H13N3O2
C11H13N3O2
C10H10BrN3O
C10H10ClN3O
C6H9N3O2
C5H6N4
56.55
8.76
24.77
60 (2)
56.78
8.93
24.82
73 (1) [9]
62.55
62.53
9.76
19.77
19.87
105
10.02
(2)
63.67
6.00
22.81
105
(3)
63.48
5.85
22.23
65.10
65.01
6.49
6.45
20.92
20.66
140
(1)
65.20
6.58
20.20
146
(2)
65.01
6.45
20.66
60.90
60.26
6.15
5.97
18.95
19.16
175
3g
3h
3i
(2)
60.20
6.31
19.50
140
(2)
60.26
5.97
19.16
44.92
44.80
3.70
3.76
15.18
15.66
175
(2)
54.15
4.55
18.53
154
(1)
3j
53.71
4.50
18.78
46.20
46.45
5.44
5.84
26.96
27.07
83
3k
5a
(3)
49.60
5.08
45.50
132
49.18
4.95
45.86
(1)
C5H7N3O2
C12H13N3O
42.80
42.56
5.16
4.99
30.02
29.76
178-179
4.38, t
7.93
7.87
8.40
8.09
5b
5c
66.80
5.95
19.17
163
(2)
5.90, m
66.96
6.08
19.51
_______
* Proton signals for compounds 5a-c.

It was shown that vinyl acetate reacted with triazole 1 according to Markovnikov addition scheme to
give 1-(1H-1,2,4-triazol-1-yl)ethyl acetate (3k). However the reactivity of vinyl acetate is considerably lower
than that of alkyl vinyl ethers: under comparable conditions (120°C, 15 h) the yield of compound 3k was 42%
(Table 1, exp. 13, cf. exp. 2).
Electrophilic addition of triazole to vinyl ethers is probably catalyzed by the dissociative formation of a
proton from triazole 1 and can be presented as follows:
N
N
+
_
H
+
N
N
N
H
N
N
1
_
N
+
+
H
N
3a–k
2a–k
[ROCH–Me]
General acid catalysis by the undissociated triazole molecule is not excluded, since it is a relatively
strong acid (pKa 10) [14].
The electrophilic alkenes 4a-c reacted with 1,2,4-triazole 1 by nucleophilic addition on heating the
reagents to give the anti-Markovnikov adducts 5a-c (Table 1, exp. 14-16; Table 2).
R–CH2–CH–R'
1
N
R–CH=CH–R'
+
N
4a–c
N
5a–c
4, 5 a R = CN, R' = H, b R = COOH, R' = H, c R = Ac, R' = Ph
It should be noted that heating (95-140°C) of 1,2,4-triazole 1 with cyclohexene (a symmetrical alkene
with a weakly polarized double bond) or styrene (weakly electrophilic alkene) did not give the expected
products. Under these conditions starting triazole and cyclohexene underwent no noticeable change, whereas
styrene underwent polymerization. Polystyrene was the sole product formed on heating a mixture of styrene and
triazole (90-110°C) in the presence of a catalytic amount of acid (phosphoric or styrylphosphonic acid) or base
(10% triton B in methanol).
EXPERIMENTAL
1H NMR spectra of CDCl3 solutions with TMS as internal standard were recorded with a Bruker
WP-200 (SY) spectrometer (200 MHz). Mass spectra were obtained with a LKB 2091 GCMS apparatus
(ionizing voltage 70 eV, direct inlet). 1,2,4-Triazole 1, vinyl acetate, acrylonitrile, acrylic acid, and 4-phenyl-3-
buten-2-one were commercial products. Alkyl and aryl vinyl ethers were synthesized according to [15] and [13]
respectively.
Addition of 1,2,4-Triazole 1 to Alkenes 2 and 4 (General Method). A. (Table 1, experiments 1, 3,
6-14, 16). Mixture of triazole 1 (20 mmol) and alkene 2a-k, 4a,c (26 mmol) was heated in a sealed ampoule.
After cooling, the unreacted triazole 1 was filtered off, the filtrate was fractionated in vacuum, to recover the
unreacted alkene, and adducts 3a-k, 5a and 5c were obtained. Mass spectra, m/z: 155 [M+] (3a); 203 [M+] (3e,f);
268 [M+] (3i); 223 [M+] (3j).
B. (Table 1, experiments 2, 4, 5). Mixture of triazole 1 (20 mmol) and alkyl vinyl ether 2a-c was heated
in a 0.25 l steel rotating autoclave (120°C, 5 h). The homogeneous reaction mixture obtained was distilled in
vacuum to recover the excess alkene and to obtain adducts 3a-c.
984

1-(1H-1,2,4-Triazol-1-yl)propanoic acid (5b) (Table 1, experiment 15). Mixture of triazole 1 (1.38 g,
20 mmol) and acrylic acid (3.66 g, 26 mmol) was heated (120°C) with stirring for 4 h. The fused mixture
produced was dissolved in a small quantity of hot water. A white crystalline precipitate of adduct 5b deposited
on cooling. Mp 178-179°C (mp 175-178 °C [11]).
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