Synthesis of new functionally substituted 1-R-tetrazoles and their 5-amino derivatives

Article abstract of DOI:10.1007/s10593-005-0267-4

It has been shown that amino derivatives of sulfanilamide, and also some functionally substituted primary arylamines and cycloalkylamines, undergo heterocyclization with triethyl orthoformate and sodium azide with the formation of 1-monosubstituted tetraz

Full text of DOI:10.1007/s10593-005-0267-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
SYNTHESIS OF NEW FUNCTIONALLY
SUBSTITUTED 1-R-TETRAZOLES AND
THEIR 5-AMINO DERIVATIVES
S. V. Voitekhovich, A. N. Vorob'ev, P. N. Gaponik, and O. A. Ivashkevich
It has been shown that amino derivatives of sulfanilamide, and also some functionally substituted
primary arylamines and cycloalkylamines, undergo heterocyclization with triethyl orthoformate and
sodium azide with the formation of 1-monosubstituted tetrazoles. Primary amines of the azole series,
5-aminotetrazole, 5-amino-1-methyltetrazole, 4-amino-1,2,4-triazole, and also less basic arylamines
(4-fluoro-3-nitroaniline, 2,6-dibromo-4-nitroaniline) did not react. An efficient method of introducing an
amino group into position C(5) of the tetrazole ring of 1-aryltetrazoles is proposed, based on alkaline
decomposition of the tetrazole ring and heterocyclization of the resulting N-arylcyanamides on
interaction with ammonium azide generated in situ.
Keywords: 1-R-5-aminotetrazoles, N-arylcyanamides, 1-R-tetrazoles.
C- and N-tetrazolyl groups enter into the composition of a series of biologically active compounds,
many of which are used in medicinal practice [1, 2]. This is linked primarily with the unique structure of the
tetrazole ring which, depending on the location of substituents, may be a bioisostere of a carboxyl or an amide
grouping, possessing several advantages over them [2, 3]. One of the most preferred routes for making a
1-monosubstituted tetrazole ring is the heterocyclization of primary amines with triethyl orthoformate and
sodium azide [3]. This process is used for the synthesis of tetrazoles, starting from primary amines of various
nature, including aliphatic, aromatic, and heterocyclic [4-9]. It was shown that the reaction proceeds smoothly
with the participation of only the simplest alkyl and aryl amines. It was discovered that 2,4-dinitroaniline does
not react [7], and in the case of ortho-phenylenediamine the process stops at the stage of forming benzimidazole,
the condensation product of triethyl orthoformate with the initial amine [6]. Under analogous conditions
thiosemicarbazide forms a 2-aminothiadiazole [7]. Conversion products of several other compounds with a
primary amino group, including hydrazine, phenylhydrazine, melamine, and aminoguanidine, failed to be
identified [7]. The behavior of other functionally substituted primary amines has not been studied up to the
present time, in spite of the obvious effect of the nature of the substituent on the course of the heterocyclization
reaction.
In the development of these investigations and with the aim of broadening the preparative possibilities of
this reaction, the heterocyclization of some alkyl-, aryl-, and hetarylamines has been studied in this work. These
include substances of a series of widely known pharmaceutical preparations possessing antibacterial and antiviral
action, comprising sulfanilamide, sulfaethidole, sulfadimidine, rimantadine, etc. It was discovered that primary
amines 1 react with sodium azide and triethyl orthoformate in acetic acid at a molar ratio of reactants of 1:1.1:3,
forming the corresponding 1-monosubstituted tetrazoles 2.
__________________________________________________________________________________________
Research Institute for Physicochemical Problems, Belorussian State University, Minsk 220080; e-mail:
azole@bsu.by, azole@tut.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1174-1179,
August, 2005. Original article submitted February 20, 2003.
0009-3122/05/4108-0999©2005 Springer Science+Business Media, Inc.
999

HC(OEt)3, NaN3
AcOH
N
R
N
R
NH2
N
N
1a–n
2a–n
N
N
N
,
,
c X =
1, 2 a–e R = 4-C6H4SO2NHX; a X = H, b X =
S
S
Et
Me
OMe
N
N
N
,
,
d X =
e X =
N
,
f R =
Me
OMe
g R = 1-Ad, h R = 1-AdCH(Me), i R = cyclo-C3H5, j R = PhCH2CH2, k R = 4-F-3-ClC6H3,
l R = 4-I-2-MeC6H3, m R = 4-C6H4COOH, n R = 4-(4-O2NC6H4)C6H4
Their functional groups are not affected in this way. High yields of the desired tetrazoles were achieved
by heating the reaction mixture at 80-95°C for 4-5 h (Table 1).
It was established that 4-fluoro-3-nitroaniline and 2,6-dibromo-4-nitroaniline do not react under
analogous conditions. Probably the low basicity of these amines impedes their interaction with triethyl
orthoformate, the initial stage of heterocyclization [11]. It is also possible to explain in an analogous manner the
fact that the primary amines of the azole series, viz. 5-aminotetrazole, 5-amino-1-methyltetrazole, and 4-amino-
1,2,4-triazole also do not react under the studied conditions. In all cases the initial amines or their hydrochlorides
were isolated from the reaction medium.
The synthesized 1-R-tetrazoles are of interest not only as subjects for investigation of their biological
activity but also as synthons for obtaining other functional derivatives of tetrazole. It is known that certain
5-amino-1-aryltetrazoles possess anti-inflammatory, myorelaxant, antiulcer, analgesic, and other biological
activities [12]. However the possibilities of their practical application are substantially limited by a series of
synthetic complications, the unavailability of the initial raw material, low yields of products, and dangerously
explosive reactants [13-18].
As we have shown, compounds of this series, particularly tetrazoles 3a-e, may readily be obtained by the
recyclization of 1-aryltetrazoles 2, by alkaline decomposition of the tetrazole and subsequent azidification of the
intermediate N-arylcyanamides 4. We note the high yields of the desired products achieved at each stage of the
process (Table 1). In addition, the proposed route of introducing an amino group into position C(5) of
1-aryltetrazoles is significantly simpler experimentally compared with that described previously in [17].
It is extremely important that 5-amino-1-aryltetrazoles 3a-e are obtained as the sole products on
interacting the appropriate cyanamide with an excess of sodium azide, formed in situ from sodium azide and
ammonium chloride. N-(5-Tetrazolyl)anilines, which may be formed as by-products, were not detected. The
results of [13, 17] are thereby confirmed, indicating the regioselectivity of cyclization of guanidinium azides,
formed as intermediates in the course of the reaction by addition of azide ion to the nitrile group of the
cyanamide.
NH2
N
NaN3, NH4Cl
DMF
KOH, EtOH
DMSO
NC NH
R
2b,f,k,m,n
N
N
R
N
4a–e
3a–e
N
,
4 -C6H4SO2NH
3,4 a R =
b R =
,
S
c R = 4-F-3-ClC6H3, d R= 4-C6H4COOH, e R = 4-(4-O2NC6H4)C6H4
1000

TABLE 1. Physicochemical Characteristics of 1-Monosubstituted Tetrazoles
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
2a
2b
С7Н7N5O2S
37.48
37.33
3.59
3.13
30.86
31.09
205
(dec.)
57
96
С10Н8N6O2S2
38.60
38.95
2.49
2.62
27.10
27.26
235
(dec.)
2c
2d
2e
2f
С11Н11N7O2S2
С13Н13N7O2S
С13Н13N7O4S
С11Н8N4
39.98
39.16
47.28
47.12
43.19
42.97
67.41
67.34
64.77
64.68
67.34
67.21
43.88
43.63
61.85
62.05
42.22
42.34
33.70
33.59
50.60
50.53
58.30
58.43
3.44
3.29
3.87
3.95
3.90
3.61
4.29
4.11
8.01
7.89
8.75
8.68
5.60
5.49
5.62
5.79
1.99
2.03
2.80
2.47
3.11
3.18
3.30
3.39
28.68
29.06
29.40
29.59
27.07
26.98
28.68
28.55
27.58
27.43
24.39
24.12
50.90
50.88
32.11
32.16
28.50
28.22
20.40
19.58
29.62
29.46
26.68
26.31
193-195
215-217
195-197
95-96
66
98
58
73
84
85
74
71
89
73
91
91
74
2g
2h
2i
С11Н16N4
135-137*
133-135
42-44
С13Н20N4
С4Н6N4
2j
С9Н10N4
61-63
2k
2l
С7Н4N4ClF
С8Н7N4I
97-98
93-94
2m
2n
3a
С8Н6N4O2
С13Н9N5O2
С10Н9N7O2S2
255-256
257-259
37.39
37.14
2.90
2.81
30.11
30.32
225
(dec.)
3b
3c
3d
С11Н9N2
62.45
62.55
39.50
39.36
46.90
46.83
4.41
4.29
2.50
2.36
3.56
3.44
33.30
33.16
32.88
32.79
34.28
34.13
230-232
80
76
91
С7Н5ClFN5
С8Н7N5O2
188-189
290
(dec.)
3e
С13Н10N6O2
55.46
55.32
3.77
3.57
29.50
29.77
209-211
85
_______
* Mp 130-132, 140-141°C [10].
1
The compounds obtained were identified by data of IR, H and 13C NMR spectroscopy (Table 2). A
characteristic of 1-monosubstituted tetrazoles 2 is the singlet for the proton at C(5) of the tetrazole ring lying in
the 9.3-10.2 ppm region of the 1H NMR spectrum [4-9]. A strong absorption band was present in the IR spectra
of N-arylcyanamides 4 at 2210-2250 cm-1 belonging to the stretching vibration of the C≡N bond, and absorption
bands were present at 3100-3500 and 1580-1620 cm-1 characteristic of the stretching and deformation vibrations
of the N–H bond. In the IR spectra of 5-amino-1-aryltetrazoles 3 there were absorption bands for the stretching
(3100-3400 cm-1) and deformation (1580-1600 cm-1) vibrations of the N–H bonds of the primary amino group.
The signal for the tetrazole ring carbon atom in the 13C NMR spectrum of tetrazole 3a is displayed at 158.5 ppm,
which corresponds with that for 5-amino-1-R-tetrazoles in [17-19]. The structure of compound 3b was also
confirmed by us by data of X-ray structural analysis [20].
1001

TABLE 2. 1H NMR Spectra of Compounds 2a-n and 3a-e
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
НСcycl
other signals
2a
2b
10.18
10.15
8.08-8.13 (4Н, m, C6H5); 7.55 (2Н, br. s, NH2)
8.04-8.10 (4Н, m, C6H5); 7.28 (1H, d, J = 4.6, HC=); 6.87 (1H, d,
J = 4.6, HC=)
2c
10.11
8.05-8.11 (4Н, m, C6H5); 2.83 (2H, q, J = 8.9, CH2); 1.22 (3H, t,
J = 8.9, CH3)
2d
2e
10.15
10.18
8.14-8.19 (4Н, m, C6H5); 6.72 (1H, s, HC=); 2.26 (6H, s, 2CH3)
8.15-8.20 (4Н, m, C6H5); 5.98 (1H, s, HC=); 3.80 (3H, s, CH3);
3.75 (3H, s, CH3)
2f
2g
2h
9.96
9.50
9.41
7.44-8.32 (7Н, m, C6H5)
2.19 (9H, s, Ad); 1.74 (6Н, s, Ad)
4.46 (1Н, q, J = 7.0, СН); 1.20-1.98 (15Н, m, Ad); 1.46 (3Н, d,
J = 7.0, CH3)
2i
2j
9.45
9.26
3.90-4.11 (1Н, m, СН); 1.12-1.21 (4H, m, 2CH2)
7.15-7.27 (5Н, m, C6H5); 4.73 (2Н, t, J = 7.2, CH2);
3.19 (2Н, t, J = 7.2, CH2)
2k
2l
10.08
9.80
7.64-8.31 (3Н, m, C6H5)
7.75-8.00 (2Н, m, C6H5); 7.28-7.33 (1Н, m, C6H5); 2.11 (3Н, s, CH3)
8.00-8.24 (4Н, m, C6H5)
7.94-8.40 (4Н, m, C6H5)
2m
2n
3a*
10.18
10.16
10.23 (2Н, br. s, NH2); 7.65-7.70 (4Н, m, C6H5); 7.20 (1Н, d,
J = 4.6, СН); 6.78 (1Н, d, J = 4.6, СН)
3b
3c
3d
3e
7.38-8.31 (7Н, m, C6H5); 5.32 (2Н, br. s, NH2)
7.57-7.91 (3Н, m, C6H5); 6.94 (2Н, br. s, NH2)
7.66-8.18 (4Н, m, C6H5); 6.99 (2Н, br. s, NH2)
7.50-8.30 (8Н, m, 2C6H5); 5.91 (2Н, br. s, NH2)
_______
*
13C NMR spectrum, δ, ppm: 112.3 (C, C(4)-thiazole); 127.9 (2C, C6H5);
128.4 (C, C6H5); 131.1 (2C, C6H5); 139.8 (C, C6H5); 146.5 (C, C(5)-thiazole);
158.5 (C, C(5)-tetrazole); 172.7 (C, C(2)-thiazole).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Tesla BS 567A spectrometer (100 and 25 MHz
respectively) in DMSO-d6, internal standard was HMDS (δ 0.05 ppm). The IR spectra were taken on a Shimadzu
FTIR-8601 spectrometer on thin films of pure substance placed in a diamond cuvette. The homogeneity of
compounds was checked by TLC on Merck Kieselgel 60/Kieselgur F254 plates.
1-Monosubstituted Tetrazoles 2a-n (General Procedure). Glacial acetic acid (40 ml) was added with
stirring to a suspension of primary amine or the corresponding hydrochloride (0.1 mol), and sodium azide (7.2 g,
0.11 mol) in triethyl orthoformate (44 ml, 0.3 mol), and the mixture was heated while being stirred on a boiling
water bath for 4-5 h. The reaction mixture was cooled, and conc. hydrochloric acid (0.2 mol) and water (50 ml)
were added. The precipitated solid was separated by filtration, washed with water, and dried. The obtained
tetrazoles were recrystallized from acetonitrile (2a-e), 2-propanol (2f-m), or a mixture of ethanol and DMF (2n).
N-Arylcyanamides 4a-e (General Procedure). DMSO (10 ml) was added dropwise with constant
stirring to a suspension of 1-aryltetrazole 2b,f,k,m,n (0.01 mol) in 10% aqueous KOH solution (6 ml) [for the
synthesis of cyanamides 4a,d 20% KOH solution (6 ml) was used]. Intense gas evolution was observed,
accompanied by self-heating of the reaction mixture. Stirring of the reaction mixture was continued for
1002

15-20 min after the end of visual observation of nitrogen evolution. The mixture was then diluted to 80 ml with
water, acidified with hydrochloric acid to pH 3-4 and stored at 5-10°C until precipitation of solid. The obtained
product was filtered off, washed with water, and dried in vacuum.
N-(2-Thiazolyl)-4-cyanoaminobenzenesulfonamide (4a). Yield 91%; mp 215-217°C (acetonitrile).
IR spectrum, ν, cm-1: 2234 (C≡N), 3190, 1600 (N–H), 1326 (S=O). Found, %: C 43.05; H 2.60; N 20.39.
C10H8N4O2S2. Calculated, %: C 42.85; H 2.88; N 19.99.
1-Naphthylcyanamide (4b). Yield 96%; mp 133-134°C (2-propanol) (135°C [21]). IR spectrum,
ν, cm-1: 2233 (C≡N), 3182, 1585 (N–H).
3-Chloro-4-fluorophenylcyanamide (4c). Yield 87%; mp 100-101°C (2-propanol). IR spectrum,
ν, cm-1: 2241 (C≡N), 3171, 1612 (N–H). Found, %: C 48.85; H 2.39; N 15.65. C7H4ClFN2. Calculated, %:
C 49.29; H 2.36; N 16.42.
4-(Cyanoamino)benzoic Acid (4d). Yield 74%; mp >350°C (reprecipitated through the sodium salt). IR
spectrum, ν, cm-1: 2237 (C≡N), 3344, 1612 (N–H). Found, %: C 59.19; H 3.58; N 17.18. C8H6N2O2. Calculated,
%: C 59.26; H 3.73; N 17.28.
4-(4-Nitrophenyl)phenylcyanamide (4e). Yield 95%; mp 252-254°C (ethanol–DMF). IR spectrum,
ν, cm-1: 2245 (C≡N), 3197, 1593 (N–H). Found, %: C 65.09; H 3.98; N 17.77. C13H9N3O2. Calculated, %:
C 65.27; H 3.79; N 17.56.
5-Amino-1-aryltetrazoles 3a-e (General Procedure). A suspension of cyanamide 4a-e (0.01 mol),
sodium azide (0.015 mol), and ammonium chloride (0.02 mol) in DMF (25 ml) was stirred at 70-80°C for 3-4 h,
after which water (100 ml) was added to the reaction mixture. The precipitated solid was filtered off, washed
with water, and recrystallized from acetonitrile (3a), 2-propanol (3b,c), reprecipitated from DMF–water (3e), or
purified through the sodium salt (3d).
The work was carried out within the framework of the "Bioorgsintez" State Program for Fundamental
Investigations, and also of Project KhO1-273, supported by the Belarus Republic Fund for Fundamental
Investigations.
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