Tetrazoles: XLIII. Polydentate tetrazole-containing ligands for biomimetic studies

Article abstract of DOI:10.1023/A:1021620300496

1(2)-Aryl-5-methylsulfonyltetrazoles react with ethylene glycol, di- and triethylene glycols, and tris(2-hydroxyethyl)amine in acetonitrile in the presence of sodium hydroxide to give tetrazole-containing ethers. The products can be used as polydentate li

Full text of DOI:10.1023/A:1021620300496

Russian Journal of Organic Chemistry, Vol. 38, No. 9, 2002, pp. 1356 1359. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 9, 2002,
pp. 1409 1412.
Original Russian Text Copyright
2002 by Kharbash, Gol’tsberg, Artamonova, Nordlander, Koldobskii.
Dedicated to Full Member of the Russian Academy of Sciences
V.A. Tartakovskii on the 70th Anniversary of His Birth
Tetrazoles: XLIII.* Polydentate Tetrazole-Containing
Ligands for Biomimetic Studies**
R. V. Kharbash1, M. A. Gol’tsberg1, T. V. Artamonova1,
E. Nordlander2, and G. I. Koldobskii1
1
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 198013 Russia
e-mail: koldobsk@tu.spb.ru
2
Inorganic Chemistry 1, University of Lund, Chemical Center, P.O. Box 124, Lund, S 22100 Sweden
e-mail: Ebbe.Nordlander@inorg.lu.se
Received December 12, 2001
Abstract 1(2)-Aryl-5-methylsulfonyltetrazoles react with ethylene glycol, di- and triethylene glycols, and
tris(2-hydroxyethyl)amine in acetonitrile in the presence of sodium hydroxide to give tetrazole-containing
ethers. The products can be used as polydentate ligands for biomimetic studies.
While continuing our search for optimal methods
of preparation of polydentate tetrazole-containing
ligands, as well as of tetrazole derivatives exhibiting
antituberculous activity, we have studied the reactivity
of 1(2)-aryl-5-methylsulfonyltetrazoles toward such
nucleophiles as ethylene glycol, di- and triethylene
glycols, and tris(2-hydroxyethyl)amine. We previously
showed that 1(2)-aryl-5-methylsulfonyltetrazoles react
with simple monobasic alcohols in the presence of
bases to give the corresponding 1(2)-aryl-5-alkoxy-
tetrazoles in high yields [1 3]. The rate of nucleo-
philic replacement of the methylsulfonyl group in
such substrates is strongly determined by the position
of the aryl substituent in the heteroring: It increases in
going from 2- to 1-substituted compounds, in keeping
with their electronic structure [4].
Reactions of 1(2)-aryl-5-methylsulfonyltetrazoles
with polyatomic functionally substituted alcohols as
nucleophiles were not discussed previously. We have
found that 5-methylsulfonyl-1-phenyltetrazole (Ia)
Scheme 1.
I, Ar = 1-phenyl (a), 2-(4-nitrophenyl) (b); II, Ar = 1-phenyl, n = 1 (a); Ar = 2-(4-nitrophenyl), n = 2 (b), 3 (c); III, Ar =
1-phenyl, n = 1 (a); Ar = 2-(4-nitrophenyl), n = 1 (b), 2 (c), 3 (d).
____________
*
For communication XLII, see [1].
**
This study was financially supported by the INTAS Founda-
tion (grant no. 97-1289).
1070-4280/02/3809-1356$27.00 2002 MAIK Nauka/Interperiodica

TETRAZOLES: XLIII.
1357
and 5-methylsulfonyl-2-(4-nitrophenyl)tetrazole (Ib)
react with ethylene, diethylene, and triethylene glycols
in the presence of sodium hydroxide to give the corre-
sponding tetrazole-containing ethers in good yields
(Scheme 1). The reactions occur at 20 C in aceto-
nitrile, and both mono- and disubstitution products
can be obtained, depending on the reactant ratio. The
replacement of methylsulfonyl group in tetrazole Ib
by the action of di- and triethylene glycols is charac-
terized by a higher rate, as compared to the reaction
with ethylene glycol. This may be due to catalytic
effect of di- and triethylene glycols, which is usually
observed in nucleophilic substitution processes [5].
which may be used for preparation of cooordination
compounds with iron and other transition metals. In
addition, the products obtained are expected to exhibit
antituberculous activity, as was found experimentally
for some other tetrazole-containing ethers [6]. Finally,
tetrazoles V, VIa, and VIb may be used in the syn-
thesis of dendrimers, following both convergent and
divergent schemes [7].
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer in KBr; the IR spectrum of VIb was obtained
on a Perkin Elmer Spectrum BX-1000 instrument.
1
Tetrazole-containing alcohols IIa and IIb readily
undergo acylation with benzoyl chloride. Treatment
of compound IIb with thionyl chloride yields the
corresponding halogen derivative (Scheme 2).
The H NMR spectra were measured on a Bruker
AC-200 spectrometer. The purity of the products
was checked by TLC on Silufol UV-254 plates, using
chloroform as eluent.
5-Methylsulfonyl-1-phenyltetrazole (Ia), 5-methyl-
sulfonyl-1-(4-nitrophenyl)tetrazole, and 5-methylsul-
fonyl-2-(4-nitrophenyl)tetrazole (Ib) were synthesized
as described in [1 3]. The procedure for preparation
of 2-(1-phenyltetrazol-5-yloxy)ethanol (IIa) was
reported in [8].
Scheme 2.
2-[2-[2-(4-Nitrophenyl)-5-tetrazolyloxy]ethoxy]-
ethanol (IIb). Sodium hydroxide, 40 mmol, was
added to a solution of 0.74 mmol of tetrazole Ib and
40 mmol of diethylene glycol in 10 ml of acetonitrile.
The mixture was stirred for 6 h at 20 C and diluted
with 50 ml of water, and the precipitate was filtered
off. Yield 0.2 g (89%), mp 75 76 C (from ethanol).
IV, Ar = 1-phenyl, n = 1 (a); 2-(4-nitrophenyl), n = 2 (b).
1
IR spectrum, , cm : 920, 1000, 1040, 1060, 1070,
1120, 1150, 1220, 1250, 1320, 1350, 1380, 1450,
1
1470, 1505, 1540, 1570, 1600, 3100, 3550. H NMR
1-Aryl-5-methylsulfonyltetrazoles react with tris-
(2-hydroxyethyl)amine under the same conditions
as with the above polyatomic alcohols. As expected,
the reactivity of the nitrophenyl-substituted tetrazole
was higher (Scheme 3).
spectrum (CDCl3), , ppm: 3.7 m (4H, OCH2CH2OH),
4.0 t (2H, OCH2CH2OCH2), 4.7 t (2H, NCOCH2),
8.3 8.4 m (4H, Harom). Found, %: C 44.65; H 4.52;
N 23.78. C11H13N5O5. Calculated, %: C 44.75;
H 4.40; N 23.73.
Thus, we have developed a procedure for the syn-
thesis of tetrazole-containing polydentate ligands
2-[2-[2-[2-(4-Nitrophenyl)-5-tetrazolyloxy]-
ethoxy]ethoxy]ethanol (IIc) was synthesized in
Scheme 3.
VI, R = H (a), 4-NO2 (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1358
KHARBASH et al.
a similar way. Reaction time 5 h. Yield 90%, mp 62
63 C (from ethanol). IR spectrum, , cm : 900, 920,
1210, 1260, 1290, 1320, 1340, 1370, 1390, 1440,
1470, 1505, 1530, 1570, 1600, 1620, 2900, 2930,
3090, 3110, 3130. H NMR spectrum (DMSO-d6),
, ppm: 3.6 s (4H, OCH2CH2O), 3.9 t (4H, NCOCH2-
CH2), 4.6 t (4H, NCOCH2), 8.25 8.50 m (8H, Harom).
Found, %: C 45.51; H 3.97; N 26.48. C20H20N10O8.
Calculated, %: C 45.47; H 3.78; N 26.51.
1
1
940, 960, 1000, 1040, 1070, 1100, 1120, 1150, 1210,
1250, 1290, 1320, 1350, 1390, 1450, 1510, 1540,
1560, 1610, 1620, 2890, 2930, 3100, 3140, 3490.
1H NMR spectrum (DMSO-d6), , ppm: 3.4 3.7 m
(8H, OCH2CH2OCH2CH OH), 3.9 t (2H, NCOCH2-
CH2O), 4.5 s (1H, OH), 24.7 t (2H, NCOCH2), 8.2
8.5 m (4H, Harom). Found, %: C 46.24; H 5.13;
N 20.78. C13H17N5O6. Calculated, %: C 46.02;
H 5.01; N 20.65.
2-(1-Phenyl-5-tetrazolyloxy)ethyl benzoate
(IVa). Benzoyl chloride, 1.4 mmol, was added to
a solution of 1.3 mmol of 2-(1-phenyl-5-tetrazolyl-
oxy)ethanol in 5 ml of pyridine. The mixture was
stirred for 5 h at 20 C, 30 ml of water was added,
and the precipitate was filtered off, washed with water
(2 20 ml), and dried in air. Yield 0.2 g (53%),
1,2-Bis(1-phenyl-5-tetrazolyloxy)ethane (IIIa).
Sodium hydroxide, 8.8 mmol, was added to a solution
of 8.8 mmol of tetrazole Ia and 4.2 mmol of ethylene
glycol in 15 ml of acetonitrile. The mixture was
stirred for 20 h at 20 C and diluted with 150 ml of
water, and the precipitate was filtered off. Yield
1.03 g (70%), mp 179 180 C (from DMF). IR spec-
1
mp 64 65 C (from ethanol). IR spectrum, , cm :
930, 980, 1030, 1060, 1080, 1130, 1180, 1280, 1310,
1400, 1450, 1500, 1570, 1608, 1730, 2860, 2930,
1
2960. H NMR spectrum (DMSO-d6), , ppm: 4.90 t
1
(2H, CH2OCO), 4.70 t (2H, CH2O), 7.50 8.0 m
(10H, Harom). Found, %: C 61.85; H 4.32; N 17.98.
C16H14N4O3. Calculated, %: C 61.93; H 4.52;
N 18.06.
trum, , cm : 910, 985, 1030, 1050, 1085, 1105,
1150, 1190, 1255, 1295, 1300, 1335, 1360, 1410,
1455, 1505, 1575, 1605, 1745, 2870, 2930, 3080.
1H NMR spectrum (DMSO-d6), , ppm: 4.92 s
(4H, CH2), 7.32 7.62 m (10H, Harom). Found, %:
C 55.11; H 3.92; N 31.81. C16H14N8O2. Calculated,
%: C 54.84; H 4.04; N 31.73.
2-[2-[2-(4-Nitrophenyl)-5-tetrazolyloxy]ethoxy]-
ethyl benzoate (IVb) was synthesized in a similar
way. Yield 63%, mp 73 74 C (from ethanol). IR
1
spectrum, , cm : 910, 940, 1000, 1030, 1040, 1130,
Tetrazoles IIIb IIId were synthesized by a similar
procedure.
1210, 1290, 1350, 1400, 1440, 1450, 1500, 1540,
1
1560, 1600, 1710, 2830, 2870, 3000. H NMR spec-
1,2-Bis[2-(4-nitrophenyl)-5-tetrazolyloxy]ethane
(IIIb). Reaction time 13 h. Yield 0.15 g (71%),
mp 180 181 C (from aqueous DMF). IR spectrum, ,
trum (DMSO-d6), , ppm: 3.8 3.9 m (4H, OCH2-
CH2O), 4.3 t (2H, CH2), 4.75 t (2H, CH2OCO), 7.40
7.60 m (5H, C6H5), 8.25 8.50 m (4H, C6H4). Found,
%: C 54.09; H 4.18; N 17.63. C18H17N5O6. Cal-
culated, %: C 54.14; H 4.26; N 17.54.
1
cm : 860, 925, 980, 995, 1035, 1050, 1065, 1085,
1110, 1180, 1205, 1220, 1320, 1345, 1450, 1505,
1
1535, 1555, 1605, 2865, 2930, 3105, 3135. H NMR
2-[2-[2-(4-Nitrophenyl)-5-tetrazolyloxy]ethoxy]-
ethyl chloride (V). Thionyl chloride, 0.73 mmol,
was added at 0 2 C to a solution of 0.34 mmol of
compound IIb in 1 ml of pyridine. The mixture was
stirred for 15 min at 0 C and for 1 h at 20 C and
was poured into 30 ml of water. The precipitate was
filtered off, washed with water (2 20 ml), and dried
in air. Yield 0.1 g (85%), mp 63 65 C (from ethanol).
spectrum (DMSO-d6), , ppm: 4.90 s (4H, CH2),
8.25 8.50 m (8H, Harom). Found, %: C 43.66; H 2.79;
N 31.90. C16H12N10O6. Calculated, %: C 43.63;
H 2.73; N 31.82.
Bis[2-[2-(4-nitrophenyl)-5-tetrazolyloxy]ethyl]
ether (IIIc). Reaction time 10 h. Yield 78%, mp 188
189 C (from acetonitrile DMF, 1:1). IR spectrum,
1
1
, cm : 900, 930, 1000, 1050, 1060, 1100, 1120,
IR spectrum, , cm : 930, 960, 1000, 1030, 1060,
1220, 1270, 1320, 1340, 1350, 1450, 1480, 1500,
1550, 1580, 1600, 1620, 2940, 3100, 3140. H NMR
1120, 1200, 1270, 1320, 1360, 1450, 1480, 1510,
1550, 1570, 1600, 2950, 3100, 3140. H NMR spec-
1
1
spectrum (DMSO-d6), , ppm: 3.90 t (4H, CH2OCH2),
4.6 t (4H, NCOCH2), 8.20 8.40 m (8H, Harom).
Found, %: C 44.59; H 3.60; N 28.84. C18H16N10O7.
Calculated, %: C 44.65; H 3.31; N 28.93.
trum (DMSO-d6), , ppm: 3.75 4.10 m (6H, CH2),
4.50 t (2H, CH2), 8.25 8.50 m (4H, Harom). Found,
%: C 42.12; H 3.82; N 22.41. C11H12ClN5O4. Cal-
culated, %: C 42.11; H 3.83; N 22.33.
1,2-Bis[2-[2-(4-nitrophenyl)-5-tetrazolyloxy]-
Tris[2-(1-phenyl-5-tetrazolyloxy)ethyl]amine
(VIa). Sodium hydroxide, 3.8 mmol, was added to
a solution of 3.8 mmol of 5-methylsulfonyl-1-phenyl-
tetrazole (Ia) and 1.2 mmol of tris(2-hydroxyethyl)-
ethoxy]ethane (IIId). Reaction time 5 h. Yield 82%,
1
mp 169 C (from acetonitrile). IR spectrum, , cm :
900, 1000, 1040, 1050, 1060, 1110, 1120, 1130,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

TETRAZOLES: XLIII.
amine in 15 ml of acetonitrile. The mixture was
1359
REFERENCES
stirred for 26 h at 20 C, 150 ml of water was added,
and the precipitate was filtered off and dried in air.
Yield 0.49 g (70%), mp 111 112 C (from ethanol).
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1
IR spectrum, , cm : 870, 890, 920, 940, 980, 1010,
1030, 1050, 1080, 1100, 1140, 1190, 1295, 1305,
1320, 1360, 1365, 1400, 1460, 1505, 1570, 1600,
1
2860, 2900, 2940, 2980, 3080. H NMR spectrum
(DMSO-d6), , ppm: 3.10 s (6H, CH2), 4.58 s (6H,
CH2O), 7.32 7.67 m (15H, Harom). Found, %:
C 55.74; H 4.77; N 31.11. C27H27N13O3. Calculated,
%: C 55.77; H 4.64; N 31.32.
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1
ethanol, 1:1). IR spectrum, , cm : 892, 909, 953,
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1
1612, 2826, 3092, 3118, 3439. H NMR spectrum
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CH2O), 7.9 8.25 m (12H, Harom). Found, %: C 45.21;
H 3.52; N 31.31. C27H24N16O9. Calculated, %:
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002