Synthesis of N-(oxiran-2-ylmethyl)-5-phenyltetrazole and its reactions with nitrogen nucleophiles

Article abstract of DOI:10.1134/S1070428016070216

The synthesis of N-(oxiran-2-ylmethyl)-5-phenyltetrazole was optimized, and its reactions with various nitrogen nucleophiles afforded bicyclic amino alcohols, including those containing an azole ring.

Full text of DOI:10.1134/S1070428016070216

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 7, pp. 1039–1042. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © T.V. Golobokova, L.I. Vereshchagin, G.V. Ratovskii, A.G. Proidakov, V.N. Kizhnyaev, 2016, published in Zhurnal Organicheskoi
Khimii, 2016, Vol. 52, No. 7, pp. 1044–1048.
Synthesis of N-(Oxiran-2-ylmethyl)-5-phenyltetrazole
and Its Reactions with Nitrogen Nucleophiles
T. V. Golobokova, L. I. Vereshchagin, G. V. Ratovskii, A. G. Proidakov, and V. N. Kizhnyaev*
Irkutsk State University, ul. Karla Marksa 1, Irkutsk, 664003 Russia
*e-mail: kizhnyaev@chem.isu.ru
Received April 19, 2016
Abstract—The synthesis of N-(oxiran-2-ylmethyl)-5-phenyltetrazole was optimized, and its reactions with
various nitrogen nucleophiles afforded bicyclic amino alcohols, including those containing an azole ring.
DOI: 10.1134/S1070428016070216
Oxirane compounds are widely used in various
branches of industry. High variability of epoxy com-
pounds makes it possible to obtain functional polymers
for heat- and chemically resistant compositions, op-
tically transparent lacquer-and-paint materials, and
adhesives. However, there are scarce published data on
mono- and polyepoxides containing azole (specifically
tetrazole) fragments. However, the importance of these
compounds is difficult to overestimate since the
presence of a reactive oxirane ring linked to a tetrazole
fragment makes them promising from the viewpoints
of both fundamental and applied chemistry.
involved difficulties mostly related to very poor yield
of the target products (Scheme 1).
In fact, the alkylation of 5-phenyltetrazole with
epichlorohydrin in the presence of NaOH or NEt3
(Scheme 1, method a) was inefficient because of the
low yield of 1. Variation of the alkylation conditions
showed that better results can be obtained by pro-
longed heating the reactants in a polar aprotic solvent
(DMF) in the absence of a base [5]. However,
a problem arose while attempting to scale up the
synthesis; in particular, it was difficult to remove DMF
after reaction completion, but even a small amount of
DMF hampered crystallization of the product, so that
the yield was reduced.
In keeping with published data, N-(oxiran-2-yl-
methyl)-substituted azoles are generally synthesized by
alkylation of the corresponding NH-heterocycle with
epichlorohydrin in the presence of a base (KOH,
NaOH, NEt3, NaOMe–MeOH) [1–4]. However, ap-
plication of known procedures to 5-phenyltetrazole
Variation of the solvent showed that the synthesis in
dioxane with addition of a small amount of DMF to
dissolve the initial 5-phenyltetrazole was more ef-
ficient and less laborious (method b). Dehydro-
Scheme 1.
Cl
Ph
NaOH, EtOH (a) or
DMF–dioxane (b)
N
OH
N
N
N
1
Ph
N
Cl
H
+
NaOH, acetone (d)
N
N
O
N
Ph
KOH, Na2SO4
(no solvent) (c)
O
N
N
N
N
2
1039

GOLOBOKOVA et al.
1040
Scheme 2.
NR1R2
Ph
Ph
N
R1R2NH
N
O
OH
N
N
N
N
N
N
2
3–9
3–7, R1 = H; 3, R2 = 1H-1,2,4-triazol-3-yl; 4, R2 = 1-methyl-1H-tetrazol-5-yl; 5, R2 = pyridin-2-yl; 6, R2 = Ph; 7, R2 = H2N(CH2)2;
8, R1R2N = morpholin-4-yl; 9, R1R2 = piperidin-1-yl.
Because of limited solubility of 1,4-diphenyl-1H-
1,2,3-triazol-5-amine in ethanol, its reaction with 2
was carried out with addition of DMF to make the
reaction mixture homogeneous. We presumed that this
reaction would lead to the formation of a bicyclic
triazole-containing amino alcohol, as in reactions of 2
with 1H-1,2,4-triazole-3-amine and 1-methyl-1H-tetra-
zol-5-amine which are incapable of amine–imine
tautomerism [8] and behave as common aromatic
amines. However, no expected amino alcohol was
chlorination of chlorohydrin 1 thus obtained gave
target N-(oxiran-2-ylmethyl)tetrazole 2 (d). Method c
ensures introduction of an oxiranylmethyl substituent
into tetrazole ring in one step without additional dehy-
drochlorination of intermediate chlorohydrin. How-
ever, the yield of 2 did not exceed 11% in numerous
attempts to reproduce this procedure.
The structure of compounds 1 and 2 was confirmed
by IR and NMR spectra and elemental analyses. Com-
1
pound 1 showed in the H NMR spectrum signals at
1
isolated. The H NMR spectrum of the reaction
δ 4.77, 4.97, 3.61, 3.81, and 4.55 ppm due to non-
mixture contained weak multiplet signals assignable to
methylene group linked to the tetrazole ring (δ 5.22
and 4.74 ppm) and CH(OH) (δ 3.58 ppm) and CH2NH
groups (δ 2.82, 2.93 ppm); as followed from the signal
intensity, the fraction of the corresponding product did
not exceed 5%. Variation of the reaction conditions
(i.e., increase of temperature and reaction time) did not
improve the yield. This result may be accounted for by
steric shielding of the nucleophilic amino group in the
1,4-diphenyl-1H-1,2,3-triazol-5-amine molecule by
bulky phenyl groups.
equivalent protons in the CH2CH(OH)CH2Cl fragment.
The H NMR spectrum of 2 contained signals of the
1
oxirane ring at δ 2.26, 2.46 (CH2) and 3.55 ppm (CH)
and of the bridging methylene group at δ 4.55 and
4.31 ppm. In the IR spectrum of 1 we observed
characteristic absorption bands due to stretching vibra-
tions of the O–H (3380 cm–1) and C–Cl bonds
(783 cm–1). The oxirane ring in 2 gave rise to IR bands
at 1249 and 832 cm–1.
The regioisomers were identified, and their ratio
was determined, by the position and intensity of
1H NMR signals of the ortho-protons in the 5-phenyl
substituent. It is known that the signal of the N1-sub-
stituted isomer is located in a weaker field than the
corresponding signal of the N2-isomer [6, 7]. In the
1H NMR spectrum of 2, these signals were observed at
δ 8.09–8.16 and 7.68–7.76 ppm for the N1- and N2-
isomers, respectively, with an intensity ratio of 95:5.
In the reaction of 2 with ethane-1,2-diamine we
isolated monosubstitution product 7 instead of the
expected disubstituted compound despite large excess
of 2. The structure of 7 followed from the intensity
ratio of signals of the CH2 and CHOH protons (4:1).
Amino alcohols 3–9 are light yellow to rich brown
crystalline substances soluble in polar organic solvents
and aqueous mineral acids. Compound 2 failed to react
with NH-azoles (tetrazole, 5-phenyltetrazole, 4-nitro-
1,2,3-triazole, or 1,2,4-triazole) as nitrogen nucleo-
philes under the given (ethanol, 60°C) or more severe
conditions (DMF, 95°C); in all cases, the initial azoles
were recovered from the reaction mixtures.
The oxirane ring in 2 exhibits a behavior typical of
other epoxy compounds. In particular, compound 2
reacted with primary and secondary amines (1H-1,2,4-
triazole-3-amine, 1-methyl-1H-tetrazol-5-amine, pyri-
din-2-amine, aniline, ethane-1,2-diamine, morpholine,
and piperidine) to give the corresponding amino
alcohols 3–9 (Scheme 2). The reactions were carried
out in ethanol at 60–65°C (reaction time 2.5–3 h).
Opening of the oxirane ring in these reactions followed
the Krasuskii rule, i.e., nucleophilic attack was direct-
ed at the least substituted OCH2 carbon atom.
The structure of amino alcohols 3–9 was confirmed
by NMR and IR spectra and elemental analyses. In the
1H NMR spectra of 3–9, nonequivalent protons of the
CH2CH(OH)CH2 fragment resonated at δ 4.55–4.87,
4.18–4.30, and 3.16–4.37 ppm, respectively, and the
OH signal was located at δ 3.38–5.91 ppm. The IR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

SYNTHESIS OF N-(OXIRAN-2-YLMETHYL)-5-PHENYLTETRAZOLE
1041
spectra of 3–9 displayed OH stretching band in the
region 3160–3184 cm–1, and the spectra of 3–6 ad-
ditionally showed NH stretching band in the region
3320–3360 cm–1.
precipitate was filtered off, excess epichlorohydrin was
distilled off under reduced pressure, and the oily
residue was washed with petroleum ether (3×15 mL)
and recrystallized. Yield 0.2 g (14%), mp 46–48°C
(from EtOAc). IR spectrum, ν, cm–1: 875, 1250
1
EXPERIMENTAL
(oxirane). H NMR spectrum, δ, ppm: 2.26 d.d (1H,
3
2
3
2J = 6.3, J = 4.1 Hz) and 2.46 d.d (1H, J = 6.3, J =
3.4 Hz) (CH2O), 3.55 m (1H, OCH), 4.31 d.d (1H, 2J =
The IR spectra were recorded in KBr or mineral oil
1
3
2
3
on an Infralum FT-801 spectrometer. The H NMR
13.2, J = 6.6 Hz) and 4.55 d.d (1H, J = 13.2, J =
3.2 Hz) (CH2), 7.49 m (3H, m-H, p-H), 7.68 m (2H,
o-H, N2-isomer), 8.16 m (2H, o-H, N1-isomer). Found,
%: C 57.86; H 5.16; N 27.18. C10H10N4O. Calculated,
%: C 59.40; H 4.98; N 27.71.
spectra were measured on a Varian VXR-500s instru-
ment at 126 MHz using DMSO-d6 as solvent. The
elemental analyses were obtained on a Flash EA 1112
Series CHN analyzer. The progress of reactions was
monitored by TLC on Silufol plates using ethyl
acetate–hexane (2:3 by volume) as eluent.
d. A solution of 0.5 g (10 mmol) of sodium
hydroxide in 5 mL of water was added in portions to
a solution of 2 g (8 mmol) of compound 1 in 15 mL of
acetone, and the mixture was stirred for 1 h at 25°C.
The precipitate of sodium chloride was filtered off, and
the filtrate was diluted with 10 mL of water and
extracted with diethyl ether. The extract was dried over
CaCl2 and evaporated in air. Yield 1.4 g (88%), mp 46–
48°C (from EtOAc). The product showed no depres-
sion of the melting point on mixing with a sample
obtained as described in c.
1-Chloro-3-(5-phenyl-1H-tetrazol-1-yl)propan-2-
ol (1). a. A 50-mL volumetric flask was charged with
2 g (0.0137 mol) of 5-phenyltetrazole, a solution of
0.55 g (0.0137 mol) of sodium hydroxide in 2 mL of
water and 22.3 g (0.24 mol) of epichlorohydrin were
added, and the volume of the mixture was adjusted to
50 mL by adding ethanol. The mixture was kept for
6 days at room temperature until pH ~10 was attained,
20 mL of water was added, and the mixture was ex-
tracted with ethyl acetate. The combined extracts were
dried over CaCl2 and evaporated in air. Compound 1
was isolated in trace amount; mp 84–86°C. IR spec-
1-(5-Phenyl-1H-tetrazol-1-yl)-3-[(1H-1,2,4-tri-
azol-3-yl)amino]propan-2-ol (3). A solution of 0.5 g
(0.0025 mol) of 2 and 0.33 g (0.004 mol) of 1H-1,2,4-
triazol-3-amine in 15 mL of ethanol was stirred for
1.5–6 h at 60–65°C. The solvent was removed under
reduced pressure, and the residue was treated with
15 mL of water and extracted with diethyl ether
(4×15 mL). The combined extracts were dried over
CaCl2 and evaporated, and the residue was recrystal-
lized. Yield 0.2 g (29%), mp 212–215°C (from
1
trum, ν, cm–1: 3240 (OH), 780 (C–Cl). H NMR spec-
2
trum, δ, ppm: 3.54 br.s (1H, OH), 3.61 d.d (1H, J =
3
2
3
11.8, J = 2.8 Hz) and 3.81 d.d (1H, J = 11.8, J =
2
7.5 Hz) (CH2Cl), 4.55 m (1H, CH), 4.77 d.d (1H, J =
3
2
3
13.2, J = 7.0 Hz) and 4.97 d.d (1H, J = 13.2, J =
5.0 Hz) (CH2), 7.49 m (3H, m-H, p-H), 7.76 m (2H,
o-H, N2-isomer), 8.09 m (2H, o-H, N1 isomer). Found,
%: C 50.02; H 4.69; N 23.51. C10H11ClN4O. Calcu-
lated, %: C 50.32; H 4.65; N 23.47.
1
EtOAc). IR spectrum: ν 3176 cm–1 (OH). H NMR
spectrum, δ, ppm: 4.23 m and 4.34 m (1H each,
CH2NH), 4.28 m (1H, CH), 4.77 d.d (1H, 2J = 8.2, 3J =
4.0 Hz) and 4.87 d.d (1H, 2J = 8.2, 3J = 2.5 Hz) (CH2),
5.59 br.s (1H, OH), 7.55 m (3H, m-H, p-H), 8.07 m
(2H, o-H), 8.34 s (1H, 4′-H), 8.91 br.s (1H, CH2NH),
10.84 br.s (1H, 1′-H). Found, %: C 50.02; H 4.25;
N 38.81. C12H14N8O. Calculated, %: C 50.34; H 4.93;
N 39.14.
b. A solution of 2 g (0.014 mol) of 5-phenyltetra-
zole and 1.3 g (0.014 mol) of epichlorohydrin in
a mixture of 5 mL of DMF and 10 mL of dioxane was
stirred for 8 h at 80°C. The solvent was removed under
reduced pressure. Yield 1.5 g (45%), mp 84–86°C
(from EtOH). The product showed no depression of
the melting point on mixing with a sample obtained as
described in a.
Compounds 4–9 were synthesized in a similar way.
1-(Oxiran-2-ylmethyl)-5-phenyltetrazole (2).
c. Potassium hydroxide, 1.3 g (0.024 mol), and sodium
sulfate, 1.5 g (0.0108 mol), were added in portions to
a solution of 1 g (0.0068 mol) of 5-phenyltetrazole in
23 g (0.25 mol) of epichlorohydrin maintained at
30°C, and the mixture was stirred for 5 h at 30°C. The
1-[(1-Methyl-1H-tetrazol-5-yl)amino]-3-(5-phe-
nyl-1H-tetrazol-1-yl)propan-2-ol (4) was synthesized
from 0.5 g (2.5 mmol) of 2 and 0.25 g (2.5 mmol)
of 1-methyl-1H-tetrazol-5-amine. Yield 0.3 g (41%),
mp 205–208°C (from EtOAc). IR spectrum:
ν 3173 cm–1 (OH). 1H NMR spectrum, δ, ppm: 3.33 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

GOLOBOKOVA et al.
1042
2
3
(3H, CH3), 4.75 d.d (1H, J = 8.0, J = 4.0 Hz) and
4.84 d.d (1H, 2J = 8.0, 3J = 2.4 Hz) (CH2), 4.27 m and
4.37 m (1H each, CH2NH), 4.49 m (1H, CH), 5.70 br.s
(1H, OH), 6.08 s (1H, NH), 7.55 m and 7.88 m (3H,
m-H, p-H), 8.08 m (2H, o-H). Found, %: C 48.36;
H 4.69; N 41.03. C12H15N9O. Calculated, %: C 47.83;
H 5.02; N 41.84.
(2.4 mmol) of 2 and 0.2 g (2.4 mmol) of morpholine in
15 mL of ethanol. Yield 0.1 g (14%), mp 99–101°C
(from EtOAc). IR spectrum: ν 3180 cm–1 (OH).
1H NMR spectrum, δ, ppm: 2.42 m and 3.55 m (4H
each, NCH2CH2O), 3.50 m (CH2N), 4.64 d.d (1H, 2J =
8.0, J = 4.0 Hz) and 4.77 d.d (1H, J = 8.0, J =
2.4 Hz) (CH2), 4.24 m (1H, CH), 5.26 br.s (1H, OH),
7.50 m (3H, m-H, p-H), 8.06 m (2H, o-H). Found, %:
C 59.39; H 6.24; N 24.35. C14H19N5O2. Calculated, %:
C 58.12; H 6.62; N 24.21.
3
2
3
1-(5-Phenyl-1H-tetrazol-1-yl)-3-[(pyridin-2-yl)-
amino]propan-2-ol (5) was synthesized from 1 g
(5 mmol) of 2 and 0.47 g (5 mmol) of pyridin-2-amine.
Yield 0.8 g (54%), mp 68–72°C (from EtOAc). IR
3-(5-Phenyl-1H-tetrazol-1-yl)-1-(piperidin-1-yl)-
propan-2-ol (9) was synthesized from 0.5 g
(2.4 mmol) of 2 and 0.2 g (2.4 mmol) of piperidine.
Yield 0.55 g (84%), mp 64–68°C (from EtOAc). IR
spectrum: ν 3165 cm–1 (OH). H NMR spectrum, δ,
1
ppm: 3.47 m and 3.53 m (1H each, CH2NH), 4.18 m
2
3
(1H, CH), 4.55 d.d (1H, J = 8.0, J = 4.0 Hz) and
1
spectrum: ν 3186 cm–1 (OH). H NMR spectrum, δ,
2
3
4.86 d.d (1H, J = 8.0, J = 2.4 Hz) (CH2), 5.91 br.s
(1H, OH), 6.73 br.s (1H, NH), 6.86 m and 7.67 m (2H,
3′-H, 5′-H), 7.52 m (1H, 4′-H), 7.67 m (3H, m-H, p-H),
8.08 m (2H, o-H), 8.08 m (1H, 6′-H). Found, %:
C 61.25; H 5.94; N 28.51. C15H16N6O. Calculated, %:
C 60.80; H 5.44; N 28.36.
ppm: 1.52 m (6H, CH2, piperidine), 2.74 m (4H,
CH2N), 3.41 m (2H, CH2N), 4.22 m (1H, CH),
2
3
4.64 d.d (1H, J = 7.8, J = 4.0 Hz) and 4.77 d.d (1H,
3
2J = 7.8, J = 1.5 Hz) (CH2), 5.15 br.s (1H, OH),
7.54 m (3H, m-H, p-H), 8.06 m (2H, o-H). Found, %:
C 61.83; H 4.21; N 24.93. C15H21N5O. Calculated, %:
C 62.69; H 3.37; N 24.37.
1-Anilino-3-(5-phenyl-1H-tetrazol-1-yl)propan-
2-ol (6) was synthesized from 0.5 g (2.4 mmol) of 2
and 0.2 g (2.4 mmol) of aniline. Yield 0.55 g (79%),
mp 71–72°C (from EtOAc). IR spectrum: ν 3178 cm–1
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-33-60073_mol_a_dk).
1
(OH). H NMR spectrum, δ, ppm: 3.16 m and 3.24 m
(1H each, CH2NH), 4.29 m (1H, CH), 4.74 d.d (2J =
3
2
3
REFERENCES
7.8, J = 4.0 Hz) and 4.84 d.d (1H, J = 7.8, J =
1.5 Hz) (CH2), 5.46 br.s (1H, OH), 5.69 br.s (1H, NH),
6.56 m (1H, p′-H), 6.66 m (2H, o′-H), 7.54 m (3H,
m-H, p-H), 8.07 m (2H, o-H), 8.09 m (2H, m′-H).
Found, %: C 64.47; H 5.27; N 23.96. C16H17N5O.
Calculated, %: C 65.07; H 5.80; N 23.71.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016