Synthesis of unsymmetrical sulfides derived from tetrazole-5-thiols

Article abstract of DOI:10.1023/A:1015387108748

A series of unsymmetrical sulfides derived from I-substituted tetrazole-5-thiols was prepared by fusion of the corresponding 1-R-tetrazole-5-thiol sodium salt with 1-R′-5-halotetrazole. The structure was confirmed by ¹H NMR and ¹³C NMR spectra. The target compounds were prepared in 50-80% yields.

Full text of DOI:10.1023/A:1015387108748

Chemistry of Heterocyclic Compounds, Vol. 38, No. 2, 2002
SYNTHESIS OF UNSYMMETRICAL
SULFIDES DERIVED FROM
TETRAZOLE-5-THIOLS
A. Hrabálek, L. Pus, V. Baranek, J. Kunes, and K. Palat
A series of unsymmetrical sulfides derived from 1-substituted tetrazole-5-thiols was prepared by fusion
of the corresponding 1-R-tetrazole-5-thiol sodium salt with 1-R'-5-halotetrazole. The structure was
confirmed by 1H NMR and 13C NMR spectra. The target compounds were prepared in 50-80% yields.
Keywords: 1-substituted 5-halotetrazoles, 1-substituted tetrazole-5-thiols, unsymmetrical bis-5,5'-
tetrazolyl sulfides.
Both alkyl tetrazolyl sulfides and symmetrical ditetrazolyl sulfides are known, but unsymmetrical
sulfides of substituted tetrazoles (1) have not been described yet. Two synthetic approaches chosen by us for
their synthesis are presented below.
The first one was based on the reaction of 5-methylsulfonyl-1-phenyl tetrazole (2) with sodium salts of
1-substituted tetrazole-5-thiol (3) [1] under various conditions. The reaction started by the nucleophilic attack of
thiolate as a base towards the C(5) of the tetrazole skeleton where a negative partial charge is formed due to the
electronegativity of the sulfonyl group.
O
S
O
N
N
N
N
N
N
N N
N
N
N
+
δ
Me
NaS
S
N
+
N
R
N
N
R
N
3
1
2
1-R-Tetrazole-5-thiols were prepared from the corresponding aromatic or aliphatic amines (see
Experimental). First, tetrazolyl isothiocyanates were synthesized according to Hodgkins and Reewes [2]; these
intermediates gave 1-R-tetrazole-5-thiols according to Altland [3]. Methylation of 1-phenyltetrazole-5-thiol was
carried out under conditions of phase-transfer catalysis [4].
Condensation reactions of compounds 2 and 3 (R = Me, Ph, 2-MeOC6H4, 3-MeOC6H4, 4-FC6H4,
4-BrC6H4) were performed as follows: 1) in acetonitrile at room temperature [1]; 2) in boiling acetonitrile; 3) in
DMF at 100°C; 4) in acetonitrile under ultrasound (20 kHz, 50 W, 25°C, 60°C); 5) in DMF under ultrasound
(20 kHz, 50 W, 25°C, 100°C); 6) on fusion of the reaction mixture at the temperatures up to 110°C.
______
* Dedicated to Professor E. Lukevics on the occasion of his 65th birthday.
__________________________________________________________________________________________
Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;
e-mail: hrabalek@faf.cuni.cz. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 204-210,
February, 2002. Original article submitted July 29, 2001.
0009-3122/02/3802-0183$27.00©2002 Plenum Publishing Corporation
183

In a number of experiments the condensation reaction was performed under different conditions but the
yields of the desired compounds were very low (0-20%). These unsatisfactory results were obtained in all
variants of the reaction performed in acetonitrile. Only reactions of the sodium salt of 1-methyltetrazole-5-thiol
exceptionally yielded about 20% of the desired sulfides. Stable yields ~15% were obtained by fusion of the
reaction mixture for 2-3 h, but only for several products.
So, the preparation of unsymmetrical sulfides of tetrazoles this way proved impossible. The reason may
be steric hindrance at the reaction center on the electron-deficient carbon of the tetrazole skeleton together with
the low basicity of the sulfide anion.
The second and much more successful variant of the synthesis was based on the reaction of 1-aryl-5-
halotetrazole 4 with the sodium salt of 1-R-tetrazole-5-thiol:
N N
N N
N N
+
N
S
N
N
X
3
N
N
R
N
R1
R1
5
4
1-Phenyltetrazole was prepared according to Gaponik et al. [5]. The classical approach according to
Stolle [6] was used first, but we were unable to reproduce these results in the preparation of 5-iodo-1-
phenyltetrazole. Yields of intermediates and the final compound were considerably lower. The substitution with
iodine was selected because of the presumed high reactivity of the iodine derivative, but the latter decomposed
during the reaction with sodium tetrazole-5-thiolate and the reaction mixture became brown. Yields of
unsymmetrical sulfides 1 in reactions performed by this method were very low (2-5%) and did not depend on
the temperature of the reaction mixture. Even the reaction according to Musliner [7] performed analogously
with chloro and iodo derivatives did not give products at all or gave only a minimal yield although the authors
described yields over 90%.
TABLE 1. Unsymmetrical Sulfides 5 Prepared from 1-Aryl-5-halotetrazoles
4 and Sodium Tetrazole-5-thiolates 3
Com-
pound
Method of
R1
R
mp, °C
Yield, %
purification
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
F
4-Bromophenyl
Phenyl
P-TLC*
P-TLC
178-182
128-131
130-133
168-170
137-140
156-159
128-130
112-114
127-129
118-120
98-100
79
68
80
66
72
59
65
69
75
43
78
77
50
63
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
4-Fluorophenyl
4-Ethylphenyl
2,4,6-Trimethylphenyl
4-Methylphenyl
2-Methoxyphenyl
Phenyl
Methyl
Cyclohexyl
Phenyl
P-TLC
P-LC*2
P-LC
P-LC
P-TLC
P-LC
P-LC
P-LC
Cryst. EtOH/H2O
Cryst. EtOH/H2O
Cryst. EtOH/H2O
Cryst. EtOH/H2O
F
F
F
4-Fluorophenyl
3-Methoxyphenyl
4-Bromophenyl
117-120
109-112
138-141
_______
* Preparative TLC (mobile phase – chloroform).
*2 Preparative LC (mobile phase – chloroform).
184

1
TABLE 2. Elemental Analysis, H and 13C NMR Spectra of the Prepared Sulfides 5
Found, %
——————
Calculated, %
Com-
Empirical
formula
NMR spectra, δ, ppm (J, Hz)
pound
C
3
H
4
N
5
S
6
1H
7
13C
8
1
2
C14H8BrClN8S
38.39
38.59
1.97
1.85
25.42
25.72
7.15
7.36
7.86-7.79 (m, AA', BB', 2H, H2', H6');
7.71-7.67 (m, 4H, H2, H3, H5, H6);
7.65-7.58 (m AA', BB', 2H, H3', H5')
124.7, 127.3, 127.4, 130.1, 131.7, 132.1,
133.0, 136.1, 148.8, 148.9
5a
C14H9ClN8S
46.95
47.13
2.31
2.54
31.35
31.41
8.71
8.99
7.73-7.67 (m, 4H, H2, H6, H2', H6');
125.3, 127.3, 130.1, 130.2, 131.3,
131.7, 132.9, 136.1, 148.8, 148.9
5b
5c
7.67-7.60 (m, 5H, H3, H5, H3', H4', H5')
C14H8ClFN8S
44.98
1.93
30.11
8.29
7.77-7.67 (m, 6H, H2, H3, H5, H6, H2', H6');
116.9 and 117.2 (J = 23.5), 127.3, 128.1
and 128.2 (J = 9.4), 129.2 and 129.2
(J = 2.9), 130.1, 131.7, 136.1, 148.9,
149.0, 161.6 and 164.9 (J = 249.4)
44.87
2.15
29.90
8.56
7.53-7.42 (m, 2H, H3', H5')
C16H13ClN8S
C17H15ClN8S
49.68
49.93
3.18
3.40
28.89
29.12
8.45
8.33
7.72-7.65 (m, 4H, H2, H3, H5,H6);
7.56-7.49 (m AA', BB', 2H, H2', H6');
7.47-7.41 (m AA', BB', 2H, H3', H5');
2.71 (q, J = 7.42, 2H, CH2);
15.5, 28.1, 125.2, 127.2, 129.3, 130.1,
5d
5e
130.5, 131.7, 136.0, 147.4, 148.9, 148.9
1.22 (t, J = 7.42, 3H, CH3)
51.31
51.19
3.55
3.79
28.16
28.09
8.11
8.04
7.76-7.69 (m AA', BB', 2H, H2, H6);
7.68-7.62 (m AA', BB', 2H, H3, H5);
7.11 (s, 2H, H3', H5'), 2.32 (s, 3H, CH3);
1.69 (s, 6H, CH3)
16.6, 20.9, 127.2, 127.5, 129.9, 130.1,
131.5, 135.1, 136.2, 142.1, 147.3, 150.8
21.0, 125.1, 127.2, 130.1, 130.4, 130.4,
131.7, 136.0, 141.4, 148.8, 148.9
C15H11ClN8S
48.32
48.58
2.78
2.99
30.36
30.22
8.41
8.65
2.41 (s, 3H, CH3); 7.44-7.35 (m, AA', BB',
2H, H3', H5'); 7.55-7.45 (m AA', BB', 2H, H2', H6');
7.74-7.62 (m, 4H, H2, H3, H5, H6)
5f
C15H11ClN8OS
46.41
46.57
2.82
2.87
28.88
28.97
8.21
8.29
3.74 (s, 3H, OCH3); 7.17 (dt, 1H, J = 7.83,
56.4, 113.3, 120.6, 121.4, 125.3, 127.7,
130.0, 131.3, 132.9, 133.6, 147.9, 150.7,
153.0
5g
J = 1.1, H5); 7.35-7.30 (m, 1H, H3);
7.44 (dd, 1H, J = 7.83, J = 1.37, H6);
7.69-7.59 (m, 6H, H4, H2', H3', H4', H5', H6')

TABLE 2 (continued)
1
2
3
4
5
6
7
8
C14H10N8S
C9H8N8S
C14H16N8S
51.93
52.16
3.01
3.13
34.92
34.76
10.12
9.95
7.70-7.53 (m, 10H, H2, H3, H4, H5, H6, H2',
H3', H4', H5', H6')
125.3, 130.1, 131.4, 132.8, 148.9
34.9, 125.5, 130.2, 131.4, 133.0, 147.8, 149.5
5h
5i
41.49
3.15
43.35
12.15
4.04 (s, 3H, CH3); 7.72-7.67 (m, 3H, H3, H4, H5);
41.53
3.10
43.05
12.32
7.80-7.73 (m, 2H, H2, H6)
51.03
51.20
4.76
4.91
34.28
34.12
9.89
9.76
1.46-1.14 (m, 3H, CH2); 1.89-1.58 (m, 5H, CH2);
2.07-1.92 (m, 2H, CH2); 4.66-4.50 (m, 1H, CH);
7.75-7.67 (m, 3H, H3, H4, H5);
24.6, 24.7, 32.3, 58.4, 125.4, 130.3, 131.4,
133.0, 146.6, 149.8
5j
7.84-7.76 (m, 2H, H2, H6)
C14H9FN8S
49.30
49.41
2.49
2.67
32.86
32.92
9.22
9.42
7.53-7.44 (m, 2H, H3', H5');
117.0 and 117.3 (J = 23.5), 125.3, 128.1 and
128.2 (J = 9.4), 129.2 and 129.2 (J = 3.2),
130.1, 131.3, 131.4, 132.9, 148.9, 149.0,
161.6 and 164.9 (J = 249.1)
117.0 and 117.3 (J = 23.5), 128.1 and 128.2
(J = 9.4), 129.2 and 129.2 (J = 2.9), 149.0,
161.3 and 164.9 (J = 249.1)
5k
5l
7.67-7.62 (m, 5H, H2, H3, H4, H5, H6);
7.77-7.68 (m, 2H, H2', H6')
C14H8F2N8S
46.68
46.93
2.11
2.25
31.35
31.27
8.87
8.95
7.53-7.43 (m, 4H, H3, H5, H3', H5');
7.78-7.67 (m, 4H, H2, H6, H2', H6')
C15H11FN8OS
48.41
48.64
3.12
2.99
30.08
30.25
8.52
8.66
3.79 (s, 3H, CH3); 7.27-7.11 (m, 3H, H2', H4', H5'); 55.9, 111.0, 111.1, 117.0 and
5m
7.57-7.42 (m, 3H, H3, H5, H6');
7.76-7.66 (m, 2H, H2, H6)
117.3 (J = 23.8), 117.0, 117.3, 128.0 and
128.1 (J = 9.5), 129.2 and 129.2 (J = 2.9),
131.0, 133.7, 148.9, 149.0, 160.0, 161.6 and
164.9 (J = 249.1)
C14H8BrFN8S
39.89
40.11
1.61
1.92
26.49
26.73
7.46
7.65
7.51-7.42 (m, 2H, H3', H5');
116.9 and 117.2 (J = 23.8), 124.7, 127.5,
128.1 and 128.2 (J = 9.4), 129.2 and
129.2 (J = 2.9), 132.1, 133.1, 148.8,
149.0, 161.6 and 164.9 (J = 249.4)
5n
7.66-7.58 (m AA', BB', 2H, H3, H5);
7.76-7.67 (m, 2H, H2', H6');
7.87-7.79 (m AA', BB', 2H, H2, H6)

Fig. 1. HOMO orbital of phenyldichloroazomethine (cutoff = 0.11).
Only the last modification, viz. fusion of the reaction mixture, brought result. The low melting points of
1-R'-5-halotetrazoles 4, which are significantly below the temperature of decomposition, were favorable for the
reaction. The sodium salt of tetrazole-5-thiol in 10% excess was added to the melted starting compound and the
product was isolated after 2 to 3 h of heating. The yields were in the range between 50-80%.
5-Chloro-1-(4-fluorophenyl)tetrazole was prepared according to Kauer and Sheppard [8] by the reaction
of the corresponding dichloroazomethine with sodium azide. 5-Chloro-1-(4-chlorophenyl)tetrazole was prepared
by the reaction of phenylisothiocyanate (6) with chlorine. The expected addition of chlorine molecule at the
isothiocyanate group to form dichloroazomethine (7) proceeded, but the unexpected substitution in position 4 of
the aromatic ring to give compound 8 also took place during the reaction.
Cl
Cl
Cl
Cl
Cl
Cl
2
2
N
C
Cl
N C
N
C S
6
8
7
TABLE 3. Melting Points of 1-R-Tetrazole-5-thiols
R
mp (found), °C
mp, °C [lit.]
Phenyl
4-Bromophenyl
4-Fluorophenyl
147-148
178-180
155-156
144-146
153-155
155-156
139-140
148-148.5 [9]
178-181 [10]
155-156 [8]
New compound*
154-156 [9]
4-Ethylphenyl
4-Methylphenyl
2,4,6-Trimethylphenyl
2-Methoxyphenyl
3-Methoxyphenyl
156-157 [11]
139-140 [9]]
Not described
138-140
(decomp.)
sufficiently in the literature*2
124-125 [6]]
Methyl
Cyclohexyl
124-125
100-102
101-102 [12]
_______
* Found, %: C 52.35; H 4.57; N 27.01; S 15.48. C9H10N4S. Calculated, %:
1
C 52.41; H 4.89; N 27.16; S 15.55. H NMR (300 MHz, CDCl3), , ppm:
δ
1.30 (t, 3H, J = 7.42 Hz, CH3); 2.75 (q, 2H, J = 7.42 Hz, CH2); 7.43-7.37 (m
AA', BB', 2H, H3, H5); 7.84-7.77 (m AA', BB', 2H, H2, H6). 13C NMR
(75 MHz, CDCl3), , ppm: 15.3, 28.6, 123.9, 128.8, 131.4, 146.5, 163.3.
δ
*2 Found, %: C 45.96; H 3.96; N 26.63; S 15.19. C8H8N4OS. Calculated, %:
1
C 46.14; H 3.87; N 26.90; S 15.40. H NMR (300 MHz, CDCl3), , ppm:
δ
3.89 (s, 3H, OCH3), 7.12-7.02 (m, 1H, H4); 7.57-7.42 (m, 3H, H2, H5, H6).
13C NMR (75 MHz, CDCl3), , ppm: 55.7, 109.2, 115.8, 116.0, 130.2, 134.7,
δ
160.1.
187

The dichloroazomethine residue, as shown by quantum-chemical calculation, plays the role of an
activating substituent and strongly activates position 4 of the aromatic ring. The activation is so high that
electrophilic substitution of the ring can take place. For the explanation, an ab initio model of
phenyldichloroazomethine was calculated and its HOMO orbital was displayed. This orbital is responsible for
this type of reaction according to frontier orbital theory. The distribution of this orbital on the molecule (Fig. 1)
shows that SE of the aromatic ring must take place in position 4 of the ring. 4-Chlorophenyldichloroazomethine
then reacts with sodium azide and gives the corresponding 5-chlorotetrazole.
Sulfides 5a-n (Table 1) were prepared by the reaction of 1-aryl-5-chlorotetrazole with sodium tetrazole-
5-thiolates.
EXPERIMENTAL
TLC was carried out on Silufol UV 254 (Czech Republic) plates. Chloroform was used as the mobile
phase. Preparative TLC was carried out on Kieselgel 60 HF (MERCK) plates; chloroform was used as the
mobile phase. Preparative column chromatography was carried out on Kieselgel 60 (0.040-0.063 mm; MERCK).
Chloroform was used as the mobile phase.
Melting points were measured without correction using a Kofler apparatus.
Samples for elemental analysis were dried for 12 h in vacuum over phosphorus pentoxide at the
temperature 78°C. Elemental analysis were carried out on CHNS-OCE analyzer, type FISONS EA 1110.
NMR spectra were measured in deuterated dimethylsulfoxide on the spectrometer Varian Mercury-Vx
13
BB 300 working at 300 MHz for 1H and at 75 MHz for C. Chemical shifts were measured at values in ppm
δ
and relative to tetramethylsilane using the residual signals of the solvent (2.49 for 1H and 39.7 for 13C).
Quantum-chemical calculations were carried out by the following procedure. First the model of the
compound was calculated using the AM1 semiempirical method; the lowest energy conformer was searched
using the molecular dynamics (software HyperChem, version 6.03). This conformer was geometry optimized on
B3LYP/6-311+G(d,p) level (program Gaussian 94) and then the HOMO orbital was calculated.
Tetrazole-5-thiols (General Procedure).
Triethylammonium Salts of Dithiocarbamic Acids. Primary amine (0.01 mol) was dissolved in dry
diethyl ether (50 ml) and dry triethylamine (0.01 mol) was added. The solution was cooled to -10°C and dry
carbon disulfide (0.01 mol) was added through silicon septum during 5 min. The reaction mixture was stored
overnight at 2-5°C. Crystals of triethylammonium salt were filtered off and used for the next reaction without
further characterization. Yields were 75-95%.
Isothiocyanates. The triethylammonium salt of dithiocarbamic acid and an equimolar amount of
triethylamine was dissolved in 200 ml of dry chloroform and cooled to -50°C. An equimolar amount of ethyl
chloroformate was added rapidly such that the temperature did not rise above -10°C. Then the reaction mixture
was stirred, left to reach room temperature, extracted with 10% hydrochloric acid, and the water and organic
layer evaporated. The crude isothiocyanate was distilled in vacuo. Yields were 70-85%.
1-Substituted tetrazole-5-thiols. The isothiocyanate, water (250 ml), and an equimolar amount of
sodium azide were stirred under reflux for 3 h, cooled to room temperature, extracted by diethyl ether, and the
water phase acidified by conc. hydrochloric acid. The white crystals were filtered off, washed with water, and
recrystallized from aqueous ethanol.
1-Methyltetrazole-5-thiol was prepared according to Stolle [6]. All 1-substituted tetrazole-5-thiols
prepared are presented in Table 3.
N-Dichloromethylene-4-chloroaniline (8). Dry chlorine was loaded into the solution of phenyl
isothiocyanate (0.1 mol) in dry dichloromethane (250 ml) for 12 h. The excess of chlorine was then eliminated
by a flow of dry nitrogen; the reaction mixture was then evaporated in vacuo at a bath temperature of 25°C and
≤
the oily residue was immediately used in the following reaction.
188

5-Chloro-1-(4-chlorophenyl)tetrazole. Activated sodium azide [13] (0.1 mol) was added to crude
azomethine 8 dissolved in 250 ml of dry dimethoxyethane and this reaction mixture was stirred overnight. The
solution was then poured into ice water. The resulting solid was filtered off, washed with water, and dried. The
crude 5-chloro-4-chlorophenyltetrazole was recrystallized from benzene–petroleum ether mixture; mp 73-74°C
(74-75°C [14]).
Preparation of Sulfides 5 (General Procedure). 5-Halotetrazole (1 mmol) was melted on an oil bath at
95°C. Sodium tetrazole-5-thiolate 3 (1.1 mmol) was then added in portions. The reaction mixture was stirred
and the reaction process was monitored by TLC. The starting 5-halotetrazole 4 was used as a standard. The
reaction was finished after 3 h. The reaction mixture was suspended in dry chloroform and the unreacted
thiolate or sodium halogenide formed were filtered off. Filtrate was evaporated to dryness and recrystallized
from aqueous ethanol.
If the purity of the obtained product was not sufficient, column chromatography or preparative TLC was
performed.
The authors are much obliged to Mrs D. Karlickova for elemental analyses; they also acknowledge the
use of computers of the Prague Supercomputer Center of Charles University.
This work was carried out with the financial support of the research grant of the Ministry of Education,
Youth and Sports of the Czech Republic No. MSMT 111600001.
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