Synthesis of N-arylcarbamates with tetrazole fragment and some their derivatives

Article abstract of DOI:10.1134/S1070428014080193

Reactions of methyl(ethyl) N-(2-cyanophenyl)carbamates with sodium azide in dimethylformamide at 80-90°C in the presence of anhydrous CdCl₂ afforded the corresponding N-arylcarbamates with a 1,2,3,4-tetrazole fragment. The acylation of methyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]carbamate with acetic anhydride followed by the condensation of the obtained N-acyl derivative with thiophene-2-carbaldehyde in the KOH methanol solution led to the formation of methyl N-(2-{1-[3-(2-thienyl)-2-propenoyl]-1H-1,2,3,4-tetrazol-5-yl}phenyl)carbamate. The reaction of cyclohexyl N-(4-aminophenyl)carbamate with a triethyl orthoformate and sodium azide in glacial AcOH yielded cyclohexyl N-[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]carbamate.

Full text of DOI:10.1134/S1070428014080193

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 8, pp. 1184–1188. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.V. Velikorodov, N.N. Stepkina, V.A. Ionova, E.A. Melent’eva, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 8, pp. 1201–1205.
Synthesis of N-Arylcarbamates with Tetrazole Fragment
and Some Their Derivatives
A. V. Velikorodov, N. N. Stepkina, V. A. Ionova, and E. A. Melent’eva
Astrakhan State University,
pl. Shaumyana 1, Astrakhan, 414000 Russia
e-mail: avelikorodov@mail.ru
Received April 23, 2014
Abstract—Reactions of methyl(ethyl) N-(2-cyanophenyl)carbamates with sodium azide in dimethylformamide
at 80–90°С in the presence of anhydrous CdCl2 afforded the corresponding N-arylcarbamates with a 1,2,3,4-
tetrazole fragment. The acylation of methyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]carbamate with acetic
anhydride followed by the condensation of the obtained N-acyl derivative with thiophene-2-carbaldehyde in the
KOH methanol solution led to the formation of methyl N-(2-{1-[3-(2-thienyl)-2-propenoyl]-1Н-1,2,3,4-tetra-
zol-5-yl}phenyl)carbamate. The reaction of cyclohexyl N-(4-aminophenyl)carbamate with а triethyl orthofor-
mate and sodium azide in glacial AcOH yielded cyclohexyl N-[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]carbamate.
DOI: 10.1134/S1070428014080193
Specific properties of the tetrazole ring consisting
in its partial aromaticity and relatively high stability
regardless the presence of four heteroatoms attract the
interest to tetrazoles as objects of fundamental research
[1]. They serve as semiproducts in the synthesis of
versatile condensed, linearly connected, and spiro
fused heterocycles.
fuels, pyrotechnic, explosive, and gas-generating
compositions, they are exclusively important for
synthetic chemistry in the preparation of various
classes of compounds.
We studied the possibility of the synthesis of 1Н-
tetrazoles with phenylcarbamate fragment proceeding from
ethyl(methyl) (2-cyanophenyl)carbamates
I and II.
Carbamate I in its turn was obtained by acylation of 2-
aminobenzonitrile with methyl chloroformate in pyridine
solution and compound II was prepared by the cleavage
of О-acyl derivative of isatin oxime in the presence of
ethanol [21]. The synthesis of 1Н-tetrazole derivatives III
and IV was performed by heating a mixture of 1 equiv of
carbamates cyano derivatives I and II with 2 equiv of
sodium azide in DMF in the presence of anhydrous
cadmium chloride at 80–90°С for 8 h [22] (Scheme 1).
The tetrazole chemistry over the course of a century
of its development is encompassed in several general
reviews [2–8] and in a number of specialty surveys on
2-aryltetrazoles [9], tetrazolium salts [10], energetic
tetrazoles [11], synthesis and reactions of lithium
tetrazoles [12], acid-base properties [13], complex
formation [14, 15], phase transfer catalysis [16],
thermal transformations [17], analogy of thermal and
mass spectrometric fragmentation [18], medical
applications [19,20], and also on various kinds of
tautomerism, some synthetic problems, and other issues.
The structure of compounds III and IV was
1
confirmed by IR, Н NMR, and mass spectra, and of
tetrazole III, additionally by 13С NMR spectrum.
The growing world-wide interest in tetrazoles
originates above all from the considerable success in
manufacturing proceeding from 1-mono-, 1,5- and 2,5-
disubstituted tetrazoles of a number of highly efficient
drugs: antibiotics of cephalosporin series, cholesterol
reducing, antihypertensive and antiviral medications,
in particular, enzymes inhibitors of HIV/AIDS.
The formation of compounds III and IV occurs as a
result of the [3+2]-cycloaddition of the hydrogen azide
formed in the course of the reaction to the cyano group
of carbamates.
The acylation of tetrazole III with acetic anhydride
afforded the corresponding N-acyl derivative V whose
1
Tetrazoles are also promising as analytical reagents,
radioprotectors, herbicides, components of mixed
structure was confirmed by IR, Н NMR spectra and
by elemental analysis.
1184

SYNTHESIS OF N-ARYLCARBAMATES WITH TETRAZOLE FRAGMENT
1185
Scheme 1.
NOAc
Et3N,
EtOH
O
N
H
NHCO2R
CN
NHCO2R
,
NaN3 CdCl2
N
N
DMF,
Δ
MeO(CO)Cl,
Py
NH2
CN
N
HN
I, II
III, IV
The obtained N-acyl derivative V we further
brought into the aldol-crotonic condensation with
thiophene-2-carbaldehyde catalyzed by a base. The
study of the product structure by IR, 1Н NMR
spectroscopy and mass spectrometry showed that the
reaction as expected led to the formation of methyl N-
(2-{1-[3-(2-thienyl)-2-propenoyl]-1Н-1,2,3,4-tetrazol-
5-yl}phenyl)carbamate (VI) in 89% yield (Scheme 2).
heterocyclization of cyclohexyl N-(4-aminophenyl)-
carbamate (VII) [25], ethyl orthoformate, and sodium
azide [26, 27]. The reaction was performed by
refluxing the reaction mixture at TLC monitoring.
1
The study of the product structure by IR, Н,13С
NMR spectroscopy showed that as expected the
reaction product was cyclohexyl N-[4-(1H-1,2,3,4-
tetrazol-1-yl)phenyl]carbamate (VIII) (Scheme 3).
IR spectrum of compound VI along with the other
absorption bands contains the band at 1285 cm–1
generated by the stretching vibrations of N–N=N–
bonds, and also absorption bands at 1108 and 1138 cm–1
belonging to the stretching vibrations of the tetrazole
ring that does not contradict the spectral data on the
other 5-phenyl-1Н-tetrazoles [23].
In the 1Н NMR spectrum of chalcone VI along with
the signals of the other protons a doublet is present of
Нβ from the fragment Ht–НβС=СНα–СО at 7.81 ppm
(J 15.5 Hz), and the signal of Нα is overlapped with the
signal of the thiophene ring proton that appears as a
multiplet in the region 6.95–6.97 ppm. The large value
of the spin-spin coupling constant indicates the Е-
configuration of the chalcone [24].
1
In the Н NMR spectrum of compound VIII the
proton of the tetrazole ring appears in the weak field at
8.30 ppm, and in the 13С NMR spectrum the atom С5
gives rise to the signal at δ 147.90 ppm in agreement
with the spectral parameters of the other 1-aryl-
substituted 1Н-1,2,3,4-tetrazoles [28, 29].
The formation of 1-aryl-substituted 1Н-1,2,3,4-
tetrazoles proceeds apparently along Scheme 4.
Hence in this study the application of cyano and
amino derivatives of N-arylcarbamates to the synthesis
of 1- and 5-aryl substituted 1Н-1,2,3,4-tetrazoles
possessing a considerable potential of biologic action
was demonstrated.
EXPERIMENTAL
One among the general methods of 1-substituted
tetrazoles synthesis is the reaction of amines with ethyl
orthoformate and sodium azide [6]. We tested the
possibility to synthesize 1-substituted tetrazole by the
1Н NMR spectra were registered on a spectrometer
Bruker DRX-500 (500.13 MHz). 13С NMR spectra were
Scheme 2.
H
S
NHCO2Me
O
NHCO2Me
NHCO2Me
Ac2O
N
N
N
N
N
KOH, MeOH
N
N
N
N
HN
N
N
O
O
Me
S
III
V
VI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014

VELIKORODOV et al.
1186
1
Scheme 3.
1710 (C=O), 1610, 1585, 1565 (C=C, C=Carom). Н
NMR spectrum, δ, ppm: 3.71 s (3Н, NHCO2Me), 6.80
t (1Нarom, J 7.4 Hz),7.65 t (1Нarom, J 7.4 Hz), 7.93 d
(1Нarom, J 7.4 Hz), 8.03 d (1Нarom, J 7.4 Hz), 10.12 br.s
(1Н, NH). Found, %: С 61.25; Н 4.5; N 15. 85.
C9H8N2O2. Calculated, %: С 61.36; H 4.55; N 15.91.
O
O
NH
O
NaN3 HC(OEt)
,
HN
O
3
N
N
N
AcOH, Δ
Methyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]
carbamate (III). A mixture of 0.176 g (1 mmol) of
N
methyl N-(2-cyanophenyl)carbamate (I), 0.13
g
NH2
VII
(2 mmol) of sodium azide, and 0.018 g (0.1 mmol) of
anhydrous cadmium chloride in 5 mL of DMF was
heated at 80–90°С for 8 h, cooled, diluted with 10 mL
of water, and treated with ethyl acetate (2 × 15 mL).
The combined organic solutions were washed with 5 N
hydrochloric acid solution (20 mL), dried with
anhydrous magnesium sulfate, the solvent was
removed in a vacuum, the obtained crystals were
subjected to chromatography on a down-tending glass
column packed with activated Silicagel 100/400 µm,
eluent ethyl acetate–petroleum ether, 4 : 1 (v/v). Yield
0.19 g (86%), colorless crystals, mp 201–202°С. IR
spectrum, ν, cm–1: 3380, 3330 (NH), 1710, 1615, 1575,
1565 (С=С, C=Carom), 1285 (N–N=N–), 1108, 1138
(tetrazole ring). Н NMR spectrum, δ, ppm: 3.73 s (3H,
NHCO2Me), 6.48 s (1Htetrazole), 7.28 t (1Нarom, J 7 Hz),
7.59 d (1Нarom, J 7 Hz), 7.95 d (1Нarom, J 7 Hz), 8.24 d
(1Нarom, J 7 Hz), 10.42 br.s (1Н, NHCO2Me). 13С
NMR spectrum, δ, ppm: 52.24, 120.03, 121.11,
122.32, 123.15, 128.64, 133.29, 137.27, 153.64. Mass
spectrum, m/z (Irel, %): 220 (8) [M + 1]+, 219 (27) [M]+,
191 (7), 159 (16), 148 (31), 131 (29), 118 (100), 104
(20), 90 (12), 77 (17). Found, %: С 49.51; H 4.12; N
31.86. C9H9N5O2. Calculated, %: С 49.32; H 4.11; N
31.96. M 219.
VIII
recorded on a spectrometer Bruker WM-400 (100 MHz)
with a wide-band decoupling from protons, solvent
DMSO-d6. IR spectra were obtained on an IR Fourier
spectrophotometer Infra-LUM FT-02 in the range
4000–400 cm–1 from pellets with KBr. The purity of
compounds obtained was tested by TLC on Silufol
UV-254 plates, development in iodine vapor. Ethyl N-
(2-cyanophenyl)carbamate II was obtained by
procedure described in [2], mp 106–107°С (mp 107°С
[30]).
Methyl N-(2-cyanophenyl)carbamate (I). To a slurry
of 11.8 g (0.1 mol) of 2-aminobenzonitrile in 46 mL of
anhydrous pyridine was added dropwise at cooling to –1°С
under vigorous stirring within 1 h 7.8 mL (0.1 mol) of
methyl chloroformate. The reaction mixture was left
standing for 8 h at room temperature, poured in 150 mL
of water, and cautiously acidified with conc.
hydrochloric acid (against Congo red). The separated
precipitate was filtered off, thoroughly washed with
water on the filter, dried in air, and recrystallized from
hexane. Yield 17.3 g (98%), colorless crystals, mp 90–
92°С. IR spectrum, ν, cm–1: 3320 (NH), 2220 (С≡N),
Scheme 4.
NHAr
OEt
H+
OEt
ArNH2
_H+
H
EtO
H
HC(OEt)3
+
OEt
_EtOH
OEt
+
O
+
Et
H
+
NHAr
NHAr
+
NHAr
NHAr
+
OEt
NHAr
OEt
NaN3
H
N3
H
H
H
H
_EtOH
_EtOH
N3
N3
O
+
+
Et
H
H
Ar
N
N
N
D
N
Ar
N
_H+
N3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014

SYNTHESIS OF N-ARYLCARBAMATES WITH TETRAZOLE FRAGMENT
1187
Ethyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-car-
bamate (IV) was obtained similarly. Yield 0.19 g
(83%), colorless crystals, mp 145–147°С. IR spectrum,
ν, cm–1: 3380, 3330 (NH), 1710, 1610, 1575, 1565
(С=С, С=Сarom), 1285 (N–N=N–), 1108, 1138
(tetrazole ring). 1Н NMR spectrum, δ, ppm: 1.27 t (3Н,
СН3СН2О, J 7 Hz), 4.17 q (2Н, СН3СН2О, J 7 Hz),
6.47 s (1Нtetrazole), 7.27 t (1Наrоm, J 7 Hz), 7.58 t
(1Нarom, J 7 Hz), 7.95 d (1Нarom, J 7 Hz), 8.06 d
(1Нarom, J 7 Hz), 10.40 br.s (1Н, NHCO2Et). Mass
spectrum, m/z (Irel, %): 234 (6) [M + 1]+, 233 (38) [M]+,
189 (12), 161 (21), 133 (18), 118 (100), 104 (18), 91
(27), 77 (12). Found, %: С 51.44; Н 4.84; N 29.83.
C10H11N5O2. Calculated, %: С 51.50; Н 4.72; N 30.04.
M 233.
НС=СН), 7.19 d (1Нthienyl, J 5.0 Hz), 7.56 t (1Нarom, J
7.3 Hz), 7.81 d (1Н, НС=СН, J 15.5 Hz), 7.95 t
(1Нarom, J 7.3 Hz), 8.45 d (1Нarom, J 7.3 Hz), 8.79 d
(1Нarom, J 7.3 Hz), 9.58 br.s (1Н, NH). Found, %: С
54.15; Н 3.70; N 19.54. C16H13N5O3S. Calculated, %:
С 54.09; Н 3.66; N 19.72.
Cyclohexyl N-[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]
carbamate (VIII). To a slurry of 1.17 g (5 mmol) of
cyclohexyl N-(4-aminophenyl)carbamate (VII) and
0.33 g (5.04 mmol) of sodium azide in 2.5 mL (15 mmol)
of ethyl orthoformate was added 2.3 mL (40 mmol) of
glacial acetic acid. The reaction mixture was refluxed
for 4 h at stirring, then it was cooled, diluted with 10 mL
of water, the mixture was extracted with ethyl acetate
(2 × 15 mL), the organic solutions were washed with
water, dried with anhydrous sodium sulfate, and the
solvent was removed. The obtained crystals were
recrystallized from a mixture ethyl acetate–hexane, 1 : 3
(v/v). Yield 1.21 g (84%), colorless crystals, mp 130–
132°С. IR spectrum, ν, cm–1: 3320 (NH), 1710 (С=O),
Methyl 2-(1-acetyl-1Н-tetrazol-5-yl)phenylcar-
bamate (V). A mixture of 1.1 g (5 mmol) of tetrazole
III and 0.5mL (5.1 mmol) of acetic anhydride was
heated on a boiling water bath for 20 min, cooled, and
diluted with 10 mL of ice water. The separated
precipitate was filtered off, washed with water on the
filter (10 mL), dried in air, and recrystallized from
ethanol. Yield 1.27 g (97%), colorless crystals, mp
150–152°С. IR spectrum, ν, cm–1: 3310 (NH), 1710,
1695 (С=O), 1610, 1570, 1565 (С=С, С=Сarom), 1285
(N–N=N–), 1108, 1138 (tetrazole ring). 1Н NMR
spectrum, δ, ppm: 2.78 s (3Н, СОСН3), 3.71 s (3Н,
NHCO2Me), 7.60 t (1Нarom, J 7.3 Hz), 7.80 t (1Нarom, J
7.3 Hz), 8.28 d (1Нarom, J 7.3 Hz), 8.59 d (1Нarom, J
7.3 Hz), 9.58 br.s (1Н, NH). Found, %: С 50.60; Н
4.13; N 26.71. C11H11N5O3. Calculated, %: С 50.58; Н
4.22; N 26.82.
1
1665 (С=N), 1610, 1585, 1565 (С=С, С=Сarom). Н
NMR spectrum, δ, ppm: 1.17–1.47 m (6Нcyclohexyl),
2.18–2.21 m (2Нcyclohexyl), 2.39–2.42 m (2Нcyclohexyl),
4.90–4.93 m (1Н, ОСН), 7.72 d (2Нarom, J 8.7 Hz),
8.50 d (2Нarom, J 8.7 Hz), 8.30 s (1Htetrazole), 9.64 br.s
(1Н, NH). 13С NMR spectrum, δ, ppm: 23.36, 25.32,
31.75 (5С, СН2cyclohexyl), 69.30 (С, СНcyclohexyl), 121.26,
126.07, 127.89, 135.16 (СAr), 147.90 (C5tetrazole), 154.10
(С=О). Found, %: С 58.47; Н 5.90; N 24.28.
C14H17N5O2. Calculated, %: С 58.54; Н 5.92; N 24.39.
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