A study of alkylation regioselectivity of 5-substituted tetrazoles with chloroacetamides

Article abstract of DOI:10.1134/S1070363210040262

Alkylation of 5-aryltetrazoles with N-arylchloroacetamides commonly proceeds regioselectively at 2 position of the tetrazole ring. The ratio of 1,5-and 2,5-regioisomers depends on the nature of a substituents in the benzene ring of the N-arylchloroacetami

Full text of DOI:10.1134/S1070363210040262

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 836–841. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.T. Pokhodylo, R.D. Savka, V.S. Matiichuk, N.D. Obushak, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4,
pp. 675–680.
A Study of Alkylation Regioselectivity
of 5-Substituted Tetrazoles with Сhloroacetamides
N. T. Pokhodylo, R. D. Savka, V. S. Matiichuk, and N. D. Obushak
Ivan Franko Lviv National University, ul. Kirilla i Mephodiya 6, Lviv, 79005 Ukraine
e-mail: obushak@in.lviv.ua
Received August 4, 2009
Abstract―Alkylation of 5-aryltetrazoles with N-arylchloroacetamides commonly proceeds regioselectively at
2 position of the tetrazole ring. The ratio of 1,5- and 2,5-regioisomers depends on the nature of a substituents in
the benzene ring of the N-arylchloroacetamide and position of a substituent in the aryltetrazole aryl group.
Features of 1H NMR spectra of the synthesized compounds are discussed.
DOI: 10.1134/S1070363210040262
Tetrazole derivatives are used as drugs [1], are
ethanol in the presence of KOH leading to the
applied in biochemistry [2–4] and agriculture [5, 6], as
formation of compounds III and IV.
well as in designing materials for the systems for the
registration of information [7]. Many compounds of
this class show biological activity of a wide range
[8–15]. Recently methods were developed for the
targeted synthesis of biologically active compounds
containing tetrazol-5-ylalkyl fragment [16].
2-Substituted and 2,5-disubstituted tetrazoles
remain poorly studied compounds because of the lack
of available methods for their synthesis [17–19]. These
compounds are prepared, in general, by alkylation of
tetrazole or 5-substituted tetrazoles. Note however, that
due to the prototropic tautomerism characteristic of
С-substituted tetrazoles these reactions can proceed by
two pathways leading to the formation of either 1,5- or
2,5-disubstituted regioisomers [12–15, 20–24]:
The reaction mixture was refluxed for 5 h, and the
1
crude products were analyzed by H NMR spec-
troscopy. In most cases only 2,5-regioisomers III were
formed. Their formation is associated probably with
the steric hindrances to the alkylation of tetrazole ring
at 1 position. This was confirmed, in particular, by the
absence of 1,5-regioisomers at the use of ortho-
methyl- and ortho-chloro-phenyltetrazoles Ib and Id,
although in these cases the yield of 2,5-regioisomers
was also reduced. Besides according to quantum-
chemical calculations and mass spectra, 2-H tautomer
of 5-substituted tetrazole is more stable than 1-H
tautomer, at least in the gas phase [25–28]. In the case
of chloroacetamides IIk, IIl, IIn, and IIo containing
an electron-withdrawing substituent in the aromatic
ring the regioselectivity decreased due to the increased
reactivity of these compounds. The minor product, 1,5-
regioisomer, was obtained with the highest yield at the
alkylation of tetrazole Ic with chloroacetamide IIo
containing two chlorine atoms in the ring. Tetrazoles
Ib and Id owing to the steric hindrances caused by the
substituent in the ortho-position to the tetrazole ring
formed at the alkylation only the 2,5-disubstituted
isomers regardless of the nature of R2 in compounds
IIb, IId, IIh–IIj, IIm, and IIp (Table 1).
N N
NH
N N
NH
N
Ar
N
Ar
The dependence of the direction of the tetrazoles
alkylation on the nature of the reagents and the
environment was poorly described in the literature. In
this work we investigated the regioselectivity of
alkylation of 5-substituted tetrazoles with chloroacet-
amides. We studied a reaction of a series of
aryltetrazoles Ia–Ie containing substituents of different
nature in the ortho- and para-position of the aryl
fragment, with N-arylchloroacetamides (IIa–IIc) in
1
In the H NMR spectra of regioisomeric mixtures
(Table 2, Fig. 1) the signals of compounds IVe, IVn,
IVo, and IVx are shifted upfield as compared with the
836

A STUDY OF ALKYLATION REGIOSELECTIVITY OF 5-SUBSTITUTED TETRAZOLES
R2
837
R2
HN
R2
N NH
HN
N
O
N
N
N
N
N
N
O
R1
KOH
EtOH
+
+
NH
R1
Cl
N
N
O
N
R1
Iа−Ie
IIIа−IIIx
IIа−IIq
IVe, IVn, IVo, IVx
2,5-regioisomer
1,5-regioisomer
I, R1 = H (a), 2-Me (b), 4-Me (c), 2-Сl (d), 4-Сl (e); II, R2 = H (a), 2-Me (b), 3-Me (c), 4-Me (d), 2,6-Me2 (e), 3,4-Me2 (f), 2-
OMe (g), 3-OMe (h), 4-OMe (i), 2-Me-3-Сl (j), 2-Me-5-Сl (k), 2-Сl (l), 3-Сl (m), 4-Сl (n), 2,5-Сl2 (o), 3-Ac (p), 4-NHAc
(q); III, R1 = R2 = H (a); R1 = H, R2 = 3-Me (b) ; R1 = H, R2 = 3,4-Me2 (c); R1 = H, R2 = 2-OMe (d); R1 = H, R2 = 2-Me-5-Сl
(e); R1 = 2-Me, R2 = 4-Me (f); R1 = 2-Me, R2 = 3-OMe (g); R1 = 2-Me, R2 = 4-OMe (h); R1 = 2-Me, R2 = 2-Me-3-Сl (i); R1 =
2-Me, R2 = 3-Сl (j); R1 = 4-Me, R2 = H (k); R1 = 4-Me, R2 = 2-Me (l); R1 = 4-Me, R2 = 3-OMe (m); R1 = 4-Me, R2 = 4-Сl
(n); R1 = 4-Me, R2 = 2,5-Сl2 (o); R1 = 4-Me, R2 = 4-NHAc (p); R1 = 2-Сl, R2 = 2-Me (q); R1 = 2-Сl, R2 = 4-Me (r); R1 = 2-
Сl, R2 = 3-Al (s); R1 = 4-Сl, R2 = 2-Me (t); R1 = 4-Сl, R2 = 3-Me (u); R1 = 4-Сl, R2 = 4-Me (v); R1 = 4-Сl, R2 = 2,6-Me (w);
R1 = 4-Сl, R2 = 2-Сl (x). IV, R1 = H, R2 = 2-Me-5-Сl (e); R1 = 4-Me, R2 = 4-Сl (n); R1 = 4-Me, R2 = 2,5-Сl2 (o); R1 = 4-Сl,
R2 = 2-Сl (x).
Table 1. The products yield and ratio of regioisomers III and IV
Reagents
chloroacetanilide
Ratio of regioisomers in the productsa, %
R1
R2
Total yield III + IV, %
tetrazole
III
IV
H
H
H
H
H
2-Me
2-Me
2-Me
2-Me
2-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
2-Cl
2-Cl
2-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
3-Me
100
100
100
100
93
100
100
100
100
100
100
100
100
92
–
–
–
–
7
–
–
–
–
–
–
–
–
8
16
–
74
70
75
56
71
75
68
71
66
45
78
61
69
77
72
81
45
63
55
63
71
76
34
49
Ia
Ia
Ia
Ia
Ia
Ib
Ib
Ib
Ib
Ib
Ic
Ic
Ic
Ic
Ic
Ic
Id
Id
Id
Ie
Ie
Ie
Ie
Ie
IIa
IIc
IIf
IIg
IIk
IId
IIh
IIi
3,4-Me2
2-OMe
2-Me-5-Cl
4-Me
3-OMe
4-OMe
2-Me-3-Cl
3-Cl
IIj
IIi
H
2-Me
IIа
IIb
IIh
IIn
IIo
IIq
IIb
IId
IIp
IIb
IIc
IId
IIe
IIl
3-OMe
4-Cl
2,5-Cl2
4-NHAc
2-Me
4-Me
3-Ac
2-Me
3-Me
4-Me
2,6-Me2
2-Cl
84
100
100
100
100
100
100
100
100
93
–
–
–
–
7
a Ratio of isomers is determined from the 1H NMR spectra of crude mixture.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

838
POKHODYLO et al.
Table 2. Data of 1H NMR spectra of compounds III and IV
1H NMR chemical shifts, δ, ppm, J , Hz; solvent DMSO-d6
Aryl fragment in chloroacetamide Aryl fragment in tetrazole
Сomp.
R1
R2
NH
no.
СH3 (s) СH2 (s)
(br.s)
Н
Н
5.68 7.07 t (1Н, 4-Н, 3J 7.8), 7.30 t (2Н, 3,5-Н, 7.48–7.56 m (3Н, 3,4,5-Н), 8.12 10.56
IIIа
3J 7.8), 7.60 d (2Н, 2,6-Н, 3J 7.8)
d.d (2Н, 2,6-Н, 3J 7.8, 4J 2.0)
3
H
3-Me
2.33
5.66 6.88 d (1Н, 4-Н, J 7.8), 7.17 t (1Н, 5-Н, 7.48–7.56 m (3Н, 3,4,5-Н), 8.12 10.46
IIIb
3
3J 7.8), 7.41 d (1Н, 6-Н, J 7.8), 7.43 s d.d (2Н, 2,6-Н, 3J 7.8, 4J 2.0)
(1Н, 2-Н)
3
Н
Н
3,4-Me2
2-OMe
2.21,
2.23
3.92
5.64 7.03 d (1Н, 5-Н, J 7.8), 7.30 d (1Н, 6-Н, 7.46–7.56 m (3Н, 3,4,5-Н), 8.11 10.37
IIIc
IIId
3J 7.8), 7.36 s (1Н, 2-Н)
d (2Н, 2,6-Н, 3J 7.8)
3
5.81 6.88 t (1Н, 5-H, J 7.8), 7.02 d (1Н, 3-H, 7.46–7.56 m (3Н, 3,4,5-Н), 8.10 9.81
3J 7.8), 7.08 t (1Н, 4-H, J 7.8), 7.99 d d.d (2Н, 2,6-Н, 3J 7.8, 4J 2.0)
3
(1Н, 6-H, 3J 7.8)
3
H
2-Me-5-Cl 2.30/
2.15
5.78/ 7.07 d (1Н, 3-H, J 7.8), 7.20 d (1Н, 4-H, 7.48–7.56 m (3Н, 3,4,5-Н), 8.12 9.93/
IIIe/
IVe
5.55 3J 7.8), 7.64 d (1Н, 6-Н, J 1.6)/6.69 d d.d (2Н, 2,6-Н, J 7.8, J 2.0)/ 9.50
4
3
4
(1Н, 3-H, 3J 7.8), 7.13 d (1Н, 4-H, 3J 7.8), 7.48–7.56 m (3Н, 3,4,5-Н), 8.06
7.50 d (1Н, 6-Н, 4J 1.6)
d.d (2Н, 2,6-Н, 3J 7.8, 4J 2.0)
2-Me 4-Me
2.31,
2.63
2.62,
3.74
5.66 7.09 d (2Н, 3,5-H, 3J 7.8), 7.47 d (2Н, 2,6- 7.30–7.40 m (3Н, 3,4,5-Н), 7.98 10.43
H, 3J 7.8)
d (1H, 6-H)
IIIf
3
2-Me 3-OMe
5.68 6.61 d (1Н, 4-H, J 7.8), 7.09 d (1Н, 6-H, 7.31–7.40 m (3Н, 3,4,5-Н), 7.98 10.54
IIIg
3
3J 7.8), 7.18 t (1Н, 5-H, J 7.8), 7.29 s d (1H, 6-H)
(1Н, 2-H)
2-Me 4-OMe
2.62,
3.64
5.64 6.83 d (2Н, 3,5-H, 3J 7.8), 7.50 d (2Н, 2,6- 7.29–7.38 m (3Н, 3,4,5-Н), 7.96 10.42
IIIh
IIIi
IIIj
H, 3J 7.8)
d (1H, 6-H)
3
2-Me 2-Me-3-Cl 2.32,
2.63
2-Me 3-Cl
5.74 7.16 t (1Н, 5-H, J 7.8), 7.24 d (1Н, 4-H, 7.30–7.38 m (3Н, 3,4,5-Н), 7.98 10.10
3J 7.8), 7.41 d (1Н, 6-H, 3J 7.8)
d (1H, 6-H)
3
2.62
5.71 7.07 d (1Н, 4-Н, J 7.8), 7.30 t (1Н, 5-Н, 7.32–7.40 m (3Н, 3,4,5-Н), 7.96 10.79
3
3J 7.8), 7.47 d (1Н, 6-Н, J 7.8), 7.77 s d (1H, 6-H)
(1Н, 2-Н)
3
4-Me H
2.43
5.65 7.06 t (1Н, 4-Н, 3J 7.8), 7.31 t (2Н, 3,5-Н, 7.60 d (2Н, 3,5-Н, J 7.8), 7.99 10.52
IIIk
IIIl
3J 7.8), 7.29 d (2Н, 2,6-Н, 3J 7.8)
d (2Н, 2,6-Н, 3J 7.8)
3
4-Me 2-Me
2.30,
2.42c
5.69 7.07 t (1Н, 4-Н, 3J 7.8), 7.13 t (1Н, 5-Н, 3J 7.32 d (2Н, 3,5-Н, J 7.8), 7.99 9.83
7.8), 7.19 d (1Н, 3-Н, 3J 7.8), 7.48 d (1Н, d (2Н, 2,6-Н, 3J 7.8)
6-Н, 3J 7.8)
3
4
3
4-Ме 3-ОМе
2.41,
3.74
5.64 6.61 d.d (1Н, 4-Н, J 7.8, J 2.0), 7.08 d 7.32 d (2Н, 3,5-Н, J 7.8), 7.97 10.56
IIIm
(1Н, 6-Н, 3J 7.8), 7.18 t (1Н, 5-Н, J 7.8), d (2Н, 2,6-Н, 3J 7.8)
3
7.28 s (1Н, 2-Н)
3
4-Me 4-Cl
2.41/
2.37
5.67/ 7.29 d (2Н, 3J 7.8),7.32 d (2Н, 3J 7.8)/7.25 7.62 d (2Н, 3,5-Н, J 7.8), 7.97 10.81/
IIIn/
IVn
5.05 d (2Н, 3J 7.8), 7.30 d (2Н, 3J 7.8)
d (2Н, 2,6-Н, 3J 7.8)/7.62 d (2Н, 10.44
3,5-Н, J 7.8), 7.91 d (2Н, 2,6-
3
Н, 3J 7.8)
3
4
3
4-Me 2,5-Cl2
2.42/
2.35
5.80/ 7.18 d.d (1Н, 4-Н, J 7.8, J 2.0), 7.46 d 7.32 d (2Н, 3,5-Н, J 7.8), 7.98 10.35
IIIo/
IVo
3
4.90 (1Н, 3-Н, J 7.8), 7.99 s (1Н, 6-Н)/7.13 d (2Н, 2,6-Н, 3J 7.8)/7.28 d (2Н,
d.d (1Н, 4-Н, 3J 7.8, 4J 2.0), 7.46 d (1Н, 3- 3,5-Н, J 7.8), 7.94 d (2Н, 2,6-
3
Н, 3J 7.8), 7.99 s (1Н, 6-Н)
Н, 3J 7.8)
3
4-Ме 4-NHAc
2.02,
2.42
5.61 7.47 d (2Н, 3J 7.8), 7.52 d (2Н, 3J 7.8)
7.32 d (2Н, 3,5-Н, J 7.8), 7.98 10.44,
IIIp
d (2Н, 2,6-Н, 3J 7.8)
9.75 s
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A STUDY OF ALKYLATION REGIOSELECTIVITY OF 5-SUBSTITUTED TETRAZOLES
Table 2. (Contd.)
839
1H NMR chemical shifts, δ, ppm, J , Hz; solvent DMSO-d6
Сomp.
R1
R2
NH
no.
СH3 (s) СH2 (s)
Aryl fragment in chloroacetamide
Aryl fragment in tetrazole
(br.s)
9.85
3
3
7.08 t (1Н, 4-HNHAr, J 7.8), 7.15 t (1Н, 5-HNHAr, J 7.8), 7.19 d (1Н, 3-
H
2-Cl
2-Me
2.30
2.37
3.08
2.30
2.32
5.76
5.70
5.75
5.74
5.67
IIIq
IIIr
IIIs
IIIt
IIIu
3
NHAr, J 7.8), 7.45–7.55 m (3Н, 6-НNHAr + 4,5-HAr), 7.60 d (1Н, 3-HAr,
3J 7.8), 7.97 d.d (1Н, 6-НAr, 3J 7.8, 4J 2.0)
3
7.09 d (2Н, 3,5-H, J 7.8), 7.46 d (2Н,
2-Cl
2-Cl
4-Cl
4-Cl
4-Me
3-As
2-Me
3-Me
7.50–7.56 m (2Н, 4,5-Н), 7.60 d 10.48
(1Н, 3-H, 3J 7.8), 7.97 d.d (1Н,
6-Н, 3J 7.8, 4J 2.0)
2,6-H, 3J 7.8)
7.48–7.62 m (3Н, 4,5-НNHAr + 4-HAr), 7.85 d (1Н, 6-HNHAr, 3J 7.8), 8.17 s
10.82
9.89 s
10.50
3
3
(1Н, 2-HNHAr), 7.66 d (1Н, 3-HAr, J 7.8), 7.44 t (1Н, 5-HAr, J 7.8), 7.96
d.d (1Н, 6-НAr, 3J 7.8, 4J 2.0)
7.56 d (2Н, 3,5-Н, 3J 7.8), 8.11
7.08 t (1Н, 4-Н, 3J 7.8), 7.15 t (1Н, 5-Н, 3J
7.8), 7.20 d (1Н, 3-Н, J 7.8), 7.47 d d (2Н, 2,6-Н, 3J 7.8)
3
(1Н, 6-Н, 3J 7.8)
6.88 d (1Н, 4-Н, J 7.8), 7.17 t (1Н, 5- 7.56 d (2Н, 3,5-Н, 3J 7.8), 8.11
3
Н, J 7.8), 7.36 d (1Н, 6-Н, J 7.8), d (2Н, 2,6-Н, 3J 7.8)
3
3
7.42 s (1Н, 2-Н)
7.09 d (2Н, 3,5-Н, J 7.8), 7.47 d (2Н, 7.55 d (2Н, 3,5-Н, 3J 7.8), 8.10
3
4-Cl
4-Cl
4-Cl
4-Me
2.30
2.23
5.67
5.72
10.50
9.87
IIIv
2,6-Н, 3J 7.8)
7.02–7.10 m (3Н)
d (2Н, 2,6-Н, 3J 7.8)
2,6-Me2
2-Cl
7.56 d (2Н, 3,5-Н, 3J 7.8), 8.06
d (2Н, 2,6-Н, 3J 7.8)
IIIw
7.18 t (1Н, 4-Н, J 7.8), 7.30 t (1Н, 5- 7.57 d (2Н, 3,5-Н, 3J 7.8), 8.11
3
5.81/
5.00
10.15
IIIx/
IVx
Н, 3J 7.8), 7.46 d (1Н, 3-Н, 3J 7.8), 7.84 d (2Н, 2,6-Н, J 7.8) / 7.52 d
3
3
3
3
d (1Н, 6-Н, J 7.8) / 7.14 t (1Н, 4-Н, J (2Н, 3,5-Н, J 7.8), 8.06 d
7.8), 7.26 t (1Н, 5-Н, J 7.8), 7.41 d (2Н, 2,6-Н, 3J 7.8)
3
(1Н, 3-Н, 3J 7.8), 7.80 d (1Н, 6-Н, 3J 7.8)
Me
Cl
Cl
H
N
N
N
N
N
Cl
Cl
H
N
O
+
N
N
N
O
N
8.0
7.8
7.6
7.4
7.2
Me
III
IV
CH2III
CH2IV
10.0 9.5 9.0 8.5 8.0
7.5
7.0 6.5 6.0 5.5 5.0 4.5 4.0
3.5
3.0 2.5 2.0 δ, ppm
Fig. 1. 1H NMR spectrum of a mixture of regioisomers IIIo and IVo.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

840
POKHODYLO et al.
IVа
IIIа
Fig. 2. The steric structure of the regioisomers IIIa and IVa optimized by semiempirical PM3 method with WinMopac 7.2 program
package.
respective signals of 2,5-disubstituted tetrazoles IIIe,
IIIn, IIIo, and IIIx. The maximum difference in the
chemical shifts is observed for the protons of СH2
groups of the regioisomers (Δδ = 0.23–0.90 ppm).
Such a significant upfield shift of the signals of
methylene protons of 1,5-disubstituted tetrazoles IV
compared with the 2,5-regioisomers III can be
attributed to the features of their structures. We carried
out quantum-chemical optimization of geometry of the
molecules of 1,5- and 2,5-regioisomers by semi-
empirical PM3 method with WinMopac 7.2 program
package. The data obtained indicate that in the 1,5-
regioisomers the coplanar arrangement of the benzene
and tetrazole rings is hardly probable, as the sub-
stituent in 1 position creates steric hindrances and
promotes deviation of benzene ring from the plane of
the molecule (Fig. 2). In this case the protons of
methylene groups fall into the cone of anisotropy of
the benzene ring, that is, into the area of shielding. For
the 2,5-regioisomers such steric hindrances do not
exist, and therefore owing to the conjugation of
benzene and tetrazole rings they are in the same plane
(Fig. 2). A similar approach was applied in [29, 30] to
the analysis of the structure of regioisomeric N-
phenyltriazoles. Signals of protons of the substituent
R1С6H4 in 1,5-regioisomers IV also is shifted upfield
due to a decrease in the conjugation of the benzene
ring with the acceptor tetrazole ring.
preparative application to the molecular design of
tetrazole derivatives.
EXPERIMENTAL
1
The H NMR spectra of synthesized compounds
were recorded on a Varian Mercury 400 instrument at
the operating frequency 400 MHz, solvent DMSO-d6,
internal reference TMS. The data of elemental analysis
(С, H, N) of all synthesized compounds correspond to
the calculated values with the accuracy: С ±0.34,
H ±0.19, N ±0.20.
General procedure for the alkylation of tetra-
zoles I. To a solution of 0.56 g (0.01 mol) of KOH in
15 ml of ethanol was added at heating and stirring
0.01 mol of tetrazole I. To the resulting solution was
added 0.01 mol of chloroacetamide II, and the mixture
was heated under reflux for 5 h. Then the mixture was
diluted with water, the formed precipitate was filtered
off and recrystallized from ethanol. In the case of the
formation of two regioisomers, the pure 2,5-disub-
stituted tetrazole III was isolated after triple re-
crystallization (see Tables 1, 2).
REFERENCES
1. Myznikov, L.V., Grabalek, A., and Koldobskii, G.I.,
Khim. Geterotsikl. Soed., 2007, no. 1, p. 3.
Thus, it is shown that in most cases the alkylation
of 5-substituted tetrazoles with N-arylchloroacetamides
proceeds regioselectively at the position 2 of the
tetrazole ring and therefore such reaction can find a
2. Garegg, P.J., Stawinski, J., and Strömberg, R., J. Org.
Chem., 1987, vol. 52, no. 2, p. 284.
3. Karpyshev, N.N., Usp. Khim., 1988, vol. 57, no. 9,
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