Tetrazoles. 42. 2-4(Nitrophenyl)-5-functionally-substituted tetrazoles

Article abstract of DOI:10.1023/A:1014553125352

We have studied the reactions of 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole with N- and O-nucleophiles. For the first time we show that in 2-(4-nitrophenyl)-5-phenoxytetrazole, the tetrazole ring is substituted when treated with phenoxide ion, 4-nitrodiphenyl ether being formed.

Full text of DOI:10.1023/A:1014553125352

Chemistry of Heterocyclic Compounds, Vol. 37, No. 12, 2001
TETRAZOLES. 42.* 2-4(NITROPHENYL)-
5-FUNCTIONALLY-SUBSTITUTED
TETRAZOLES*2
R. V. Kharbash, L. V. Alam, A. P. Koreneva, and G. I. Koldobskii
We have studied the reactions of 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole with N- and O-nucleophiles.
For the first time we show that in 2-(4-nitrophenyl)-5-phenoxytetrazole, the tetrazole ring is substituted
when treated with phenoxide ion, 4-nitrodiphenyl ether being formed.
Keywords: 2,5-disubstituted tetrazoles, 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole, nucleophilic
substitution.
The choice of methods for obtaining 2,5-disubstituted tetrazoles is quite limited [2-4]. Nevertheless,
despite significant interest in these compounds, no new theoretical approaches have been proposed in recent
years indicating that a tetrazole ring might be formed with substituents in the 2 and 5 position of the
heterocycle. Obviously, one way to solve this problem may be to develop a simple method for functionalization
of 2-substituted tetrazoles as a result of reactions at a ring carbon atom. The effectiveness of such an approach
has been recently demonstrated for the example of 1-aryltetrazoles. It was shown that 1-aryl-5-functionally
substituted tetrazoles are formed in high yield upon reaction of 1-aryl-5-methylsulfonyltetrazoles with C-, N-,
and O-nucleophiles [5-7].
Continuing the study of derivatives of tetrazole-5-thiones as convenient synthons in the synthesis of
functionally substituted tetrazoles, we have studied the reactivity of 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole
relative to N- and O-nucleophiles. 5-Methylsulfonyl-2-(4-nitrophenyl)tetrazole was selected as the object of
investigation because of the following considerations. This substrate is an easily accessible reagent [8] and, very
importantly, may be used as a model in comparing the reactivity of 1-aryl- and 2-aryl-5-methylsulfonyltetrazoles
in nucleophilic substitution reactions.
We note that the problem of the reactivity of isomeric 1- and 2-substituted 5-R-tetrazoles in nucleophilic
substitution reactions has practically not been discussed previously. We know that substitution of bromine in
5-bromo-1-methyltetrazole when treated with hydroxide ion occurs significantly more easily than in the
isomeric 5-bromo-2-methyltetrazole [9].
Analogous data were obtained in studying the reaction kinetics of the same substrates with piperidine
[10]. These results agree well with a MNDO assessment of the electronic structure of tetrazoles [11]. Thus in
1-substituted tetrazoles, the carbon atom of the heterocycle is more electronegative than in 2-substituted
_______
* For Communication 41, see [1].
*2 Dedicated to Professor E. Lukevics on his 65th birthday.
__________________________________________________________________________________________
St. Petersburg State Technology Institute, St. Petersburg 198013, Russia; e-mail: koldobsk@tu.spb.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1646-1650, December, 2001. Original
article submitted May 7, 2001.
0009-3122/01/3712-1493$25.00©2001 Plenum Publishing Corporation
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tetrazoles. This to a significant degree determines the higher reactivity of 5-bromo-1-methyltetrazole compared
with the 2-methyl-substituted isomer in nucleophilic substitution reactions.
Thus we might expect that analogous behavior may be preserved on going from 5-methylsulfonyl-1-(4-
nitrophenyl)tetrazole to the isomeric 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole. In fact, when the indicated
substrates react with piperidine and benzimidazole, the corresponding derivatives 1a-d are formed (Tables 1
and 2). However, as hypothesized, substitution of the methylsulfonyl group in 5-methylsulfonyl-2-(4-
nitrophenyl)tetrazole occurs at a much slower rate.
N
N
N
MeSO2
HN
N
N
H
R
R
N
N
N
N
R
N
N
N
N
MeCN, NaOH
N
N
N
N
1a,b
1c,d
1 a, c R = 1-(4-nitrophenyl); b, d R = 2-(4-nitrophenyl)
The analogous dependence is preserved in reactions of 5-methylsulfonyl-1-(4-nitrophenyl)- and
5-methylsulfonyl-2-(4-nitrophenyl)tetrazoles with O-nucleophiles. In the first case, substitution occurs at 20°C
[7], while on going to the 2-substituted isomer, heating at higher temperature is required.
RO
MeSO2
N
N
NaOH
N
N
HOR
+
N
N
-4
C6H4NO2
N
-4
C6H4NO2
N
2a–d
2 a R = CH3, b R = C2H5, c R = Me2CH, d R = n-C4H9
TABLE 1. Characteristics of Tetrazoles 1-3
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С*
Yield, %
С
Н
N
С12Н14N6O2
С12Н14N6O2
С14Н9N7O2
С14Н9N7O2
С8Н7N5O3
С9Н9N5O3
С10Н11N5O3
С11Н13N5O3
С13Н9N5O3
52.59
52.54
5.29
5.15
30.65
30.64
91-92
65-166
227-229
210-211
158-159
142
78
63
51
45
92
82
95
51
33
1а
1b
1с
1d
2а
2b
2c
2d
3
52.32
5.15
30.71
52.54
5.15
30.64
54.71
54.72
3.00
2.93
31.69
31.92
54.75
2.98
31.86
54.72
2.93
31.92
43.43
43.44
3.41
3.17
31.60
31.67
45.84
3.76
29.87
45.96
3.83
29.79
48.08
48.19
4.30
4.42
28.29
28.11
112-113
86-87
50.96
5.27
26.88
50.12
4.92
26.61
55.32
55.12
3.41
3.18
24.66
24.73
138-139
_______
* Compounds 1a,b, 2a-d, and 3 were recrystallized from ethanol; compound
1c was recrystallized from a DMF–ethanol mixture, 1:1; 1d was
recrystallized from toluene.
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TABLE 2. IR Spectra and 1H NMR Spectra of Tetrazoles 1-3
Com-
IR spectrum, ν, cm-1
1H NMR spectrum, δ, ppm
pound
3000, 2960, 2940, 2870, 1620, 1600, 1560,
1535, 1505, 1475, 1455, 1450, 1420, 1380,
1350, 1340, 1305, 1300, 1290, 1265, 1215,
1160, 1115, 1085, 1055, 1040, 1025, 1015,
990, 965, 925
3130, 3105, 2955, 2935, 2865, 1585, 1525,
1500, 1470, 1450, 1385, 1340, 1320, 1300,
1270, 1225, 1205, 1170, 1135, 1110, 1020,
985, 930
1.65 (6H, s, 3CH2);
1a
3.14 [4H, s, N(CH2)];
8.00 (2H, d, C6H4); 8.48 (2H, d, C6H4)
1.65 (6H, s, 3CH2);
1b
1c
1d
3.55 [4H, s, N(CH2)];
8.20 (2H, d, C6H4); 8.40 (2H, d, C6H4)
3110, 3090, 1570, 1545, 1510, 1480, 1455,
1445, 1360, 1330, 1310, 1285, 1270, 1250,
1180, 1055, 1035, 1015, 1000, 975, 950, 905
7.33-7.38 (2Н, m, C6H4);
7.72-7.76 (2Н, m, C6H4);
7.86-8.48 (4Н, m, C6H4NO2);
8.63 (1Н, s, NCHN)
3140, 3100, 2940, 2870, 1620, 1580, 1540,
1510, 1460, 1440, 1410, 1370, 1350, 1301,
1203, 1107, 1102, 1001, 980, 860
7.39-7.55 (2Н, m, C6H4);
7.83 (1Н, d, C6H4); 8.29 (1Н, d, C6H4);
8.48-8.58 (4Н, m, C6H4NO2);
8.97 (1Н, s, NCHN)
3140, 3100, 3070, 3030, 2970, 2940, 2870,
1600, 1570, 1520-1500, 1460, 1425, 1390,
1380, 1360, 1320, 1210, 1180, 1120, 1060, 990
3100, 3020, 3000, 2940, 2860, 1600, 1575,
1540, 1500, 1440, 1400, 1350, 1315, 1210,
1180, 1110, 1060, 1030, 1015, 995, 910
3140, 3110, 3000, 2950, 2870, 1620, 1600,
1560, 1540, 1500, 1470, 1440, 1390, 1370,
1350, 1320, 1300, 1220, 1190, 1150, 1120,
1100, 1060, 1010, 990
4.20 (3H, s, CH3); 8.27 (2H, d, C6H4);
2a
2b
2c
8.47 (2H, d, C6H4)
1.50 (3H, t, CH3); 4.60 (2H, m, CH2);
8.25 (2H, d, C6H4); 8.45 (2H, d, C6H4)
1.50 (6H, m, 2CH3); 5.10 (1H, m, CH);
8.30 (2H, d, C6H4); 8.45 (2H, d, C6H4)
3130, 3110, 2980, 2950, 2890, 1620, 1600,
1560, 1550, 1540, 1500, 1470, 1440, 1400,
1370, 1350, 1320, 1210, 1180, 1120, 1070,
1060, 1020, 1000, 970
3135, 3105, 3030, 2935, 2870, 1735, 1625,
1605, 1590, 1530, 1490, 1470, 1440, 1390,
1375, 1350, 1320, 1270, 1200, 1180, 1165,
1080, 1060, 1030, 1000, 910
1.00 (3H, t, CH3); 1.50 (2H, m, CH2);
1.82 (2H, m, CH2); 4.50 (2H, t, CH2);
8.30 (2H, d, C6H4); 8.50 (2H, d, C6H4)
2d
3
7.40 (5H, m, C6H5); 8.25 (2H, d, C6H4);
8.45 (2H, d, C6H4)
Quite unexpected results were obtained in studying substitution of the methylsulfonyl group in
5-methylsulfonyl-2-(4-nitrophenyl)tetrazole when treated with phenoxide ion. It was shown that when
5-methylsulfonyl-1-(4-nitrophenyl)tetrazole reacts with phenol in the presence of sodium hydroxide,
1-(4-nitrophenyl)-5-phenoxytetrazole is formed in 82% yield [7]. 2-(4-Nitrophenyl)-5-phenoxytetrazole (3) and
4-nitrodiphenyl ether are formed in ~1:1 ratio from 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole in an analogous
process. The reaction obviously occurs according to the following scheme:
C6H5O
MeSO2
NaOH
MeCN
N
N
N
N
+
C6H5OH
N
N
-4
C6H4NO2
-4
C6H4NO2
N
N
3
C6H5O
H
N
C6H5OH
4-O2NC6H4OC6H5
+
N
N
N
1495

The validity of such a hypothesis is confirmed by formation of 5-phenoxytetrazole and 4-nitrodiphenyl
ether from known prepared 2-(4-nitrophenyl)-5-phenoxytetrazole and phenol upon heating the latter in
acetonitrile in the presence of sodium hydroxide.
In conclusion, we note that nucleophilic substitution of the tetrazole ring in 2-aryl-5-R-tetrazoles has not
been previously known. Such conversions have been described only for 5-aryl-2-benzoyltetrazoles, which are
widely used as mild and effective acylating reagents in reactions with primary and secondary alcohols, phenols,
amines, and NH-heterocycles [12, 13].
Thus the nucleophilic substitution of the tetrazole ring to 2-(4-nitrophenyl)-5-phenoxytetrazole when
treated with phenoxide ion observed here for the first time may be considered as one more important piece of
evidence for the fundamental differences in reactivity of 1,5- and 2,5-diaza-substituted tetrazoles.
EXPERIMENTAL
1
The IR spectra were obtained on a UR-20 spectrometer in KBr pellets; the H NMR spectra were
recorded on a Bruker AC-200 spectrometer (working frequency 200 MHz) in DMSO-d6. The purity and
homogeneity of the compounds obtained were monitored by TLC on Silufol UV-254 plates. 5-Methylsulfonyl-
1-(4-nitrophenyl)- and 5-methylsulfonyl-2-(4-nitrophenyl)tetrazoles were obtained as described in [7, 8].
The characteristics of the tetrazoles 1-3 obtained are presented in Tables 1 and 2.
1-(4-Nitrophenyl)-5-(piperidino)tetrazole (1a). A mixture of 5-methylsulfonyl-1-(4-nitrophenyl)-
tetrazole (0.80 g, 3.0 mmol) and piperidine (15 ml) was stirred for 1.5 h at 100-105°C, cooled down to 5°C, and
then water (50 ml) was added. The precipitate was filtered off, washed with water (15 ml), and dried in air.
Obtained 0.58 g of tetrazole 1a.
2-(4-Nitrophenyl)-5-(piperidino)tetrazole (1b) was obtained similarly; reaction time 10 h.
5-(Benzimidazol-1-yl)-1-(4-nitrophenyl)tetrazole (1c). Sodium hydroxide (0.12 g, 2.9 mmol) was
added to a solution of 5-methylsulfonyl-1-(4-nitrophenyl)tetrazole (0.70 g, 2.6 mmol) and benzimidazole
(0.34 g, 2.2 mmol) in acetonitrile (20 ml); this was stirred for 5.5 h at 20°C and then water (100 ml) was added.
The aqueous solution was cooled down to 0-5°C. The precipitate was filtered off, washed with water
(2 × 15 ml), and dried in air. Obtained 0.41 g of compound 1c, which was recrystallized from a mixture of
DMF–ethanol, 1:1.
5-(Benzimidazol-1-yl)-2-(4-nitrophenyl)tetrazole (1d) was obtained similarly. Reaction time 10h;
temperature 80°C.
5-Methoxy-2-(4-nitrophenyl)tetrazole (2a). 5-Methylsulfonyl-2-(4-nitrophenyl)tetrazole (0.46 g,
1.7 mmol) was added to a solution of sodium hydroxide (0.085 g, 2.1 mmol) in methanol (15 ml). This was
stirred for 30 min at 50°C and water (45 ml) was added. The precipitate was filtered off, washed with water
(3 × 10 ml), and dried at 50°C. Obtained 0.35 g of compound 2a, which was recrystallized from ethanol.
Tetrazoles 2b-d were obtained similarly.
Reaction of 5-Methylsulfonyl-2-(4-nitrophenyl)tetrazole with Phenol. Sodium hydroxide (0.09 g,
2.2 mmol) was added to a solution of 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole (0.48 g, 1.8 mmol) and phenol
(0.21 g, 2.2 mmol) in acetonitrile (15 ml). The reaction mixture was stirred at 80°C for 10 h. This was cooled
down to 15°C and water (100 ml) was added. The precipitate was filtered off, washed with water (3 × 10 ml),
dried at 50°C and chromatographed on silica gel (chloroform as eluent). Obtained 0.17 g of 2-(4-nitrophenyl)-5-
phenoxytetrazole (3), which was recrystallized from ethanol, and 0.14 g (36%) of 4-nitrodiphenyl ether with
mp 54-56°C [14]. IR spectrum, , cm-1: 2940, 1620, 1610, 1515, 1490, 1460, 1350, 1300, 1255, 1200, 1160,
ν
1120, 1080, 1030, 930, 875, 850. Found, %: C 66.93; H 4.10; N 6.50. C12H9NO2. Calculated, %: C 66.97;
H 4.18; N 6.51.
Reaction of 2-(4-Nitrophenyl)-5-phenoxytetrazole (3) with Phenol. Sodium hydroxide (0.06 g,
1.54 mmol) was added to a solution of compound 3 (0.4 g, 1.4 mmol) and phenol (0.14 g, 1.54 mmol) in
1496

acetonitrile (15 ml). The reaction mixture was stirred at 80°C for 20 h. This was cooled down to 15°C and then
water (75 ml) was added. The precipitate was filtered off, washed with water (3 × 15 ml), dried at room
temperature, and chromatographed on silica gel (chloroform as eluent). Obtained 0.14 g (58%) 4-nitrodiphenyl
ether; mp 54-56°C, and 0.04 g of compound 3. The combined aqueous filtrate was acidified with concentrated
HCl to pH 1 and extracted with chloroform (3 × 20 ml), the extract was dried with magnesium sulfate and the
solvent was distilled off. Obtained 0.1 g (43%) of 5-phenoxytetrazole; mp 136-138°C [15]. IR spectrum, , cm-1:
ν
3075, 2930, 2865, 2750, 1625, 1575, 1490, 1460, 1440, 1420, 1350, 1290, 1270, 1250, 1220, 1195, 1165, 1130,
1060, 1030, 985, 930, 885, 860. Found, %: C 51.84; H 3.87; N 34.24. C7H6N4O. Calculated, %: C 51.85;
H 3.70; N 34.57.
This research was carried out with the financial support of INTAS (grant 97-1289).
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