Synthesis of 6-chlorotetrazolo[1,5-a]quinazoline and 6-chloro-4,5-dihydrotetrazolo[1,5-a]quinazoline

Article abstract of DOI:10.1134/S1070363217040375

Reaction of 5-aminotetrazole triethylammonium salt and 2-fluoro-6-chlorobenzaldehyde resulted in the formation of 6-chlorotetrazolo[1,5-a]quinazoline instead of the expected azomethine. Hydrogenation of the obtained quinazoline afforded 6-chloro-4,5-dihydrotetrazolo[1,5-a]quinazoline.

Full text of DOI:10.1134/S1070363217040375

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 4, pp. 885–886. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Skryl’nikova, A.V. Khramchikhin, M.N. Krivchun, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 4, pp. 689–
690.
LETTERS
TO THE EDITOR
Synthesis of 6-Chlorotetrazolo[1,5-a]quinazoline
and 6-Chloro-4,5-dihydrotetrazolo[1,5-a]quinazoline
M. A. Skryl’nikova, A. V. Khramchikhin*, and M. N. Krivchun
St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
*e-mail: xram62@mail.ru
Received March 2, 2017
Abstract—Reaction of 5-aminotetrazole triethylammonium salt and 2-fluoro-6-chlorobenzaldehyde resulted in
the formation of 6-chlorotetrazolo[1,5-a]quinazoline instead of the expected azomethine. Hydrogenation of the
obtained quinazoline afforded 6-chloro-4,5-dihydrotetrazolo[1,5-a]quinazoline.
Keywords: 5-aminotetrazole, 5-benzylaminotetrazoles, tetrazolo[1,5-a]quinazolines, 4,5-dihydrotetrazolo[1,5-
a]quinazolines
DOI: 10.1134/S1070363217040375
Tetrazolo[1,5-a]quinazolines and 4,5-dihydrotetra-
zolo[1,5-a]quinazolines exhibit various types of
biological activity [1–4].
heterocycle led to the reduction of the C=N double
bond of quinazoline moiety to form 6-chloro-4,5-
dihydrotetrazolo[1,5-a]quinazoline 5. To confirm this
assumption, we stopped the process at the cyclization
stage and isolated the intermediate 6-chlorotetrazolo
[1,5-a]quinazoline 4 (pathway b). The structure of the
latter was unambiguously confirmed by 1H NMR
spectroscopy and mass spectrometry (Scheme 1).
Condensation of 5-aminotetrazole with various
benzaldehydes followed by hydrogenation of the
azomethines formed is a convenient method for the
synthesis of biologically active 5-benzylamino-
tetrazoles [5]. Thus, the reactions of 5-aminotetrazole
with 2-chloro-, 2-fluoro, and 2,6-dichlorobenzalde-
hydes in the presence of triethylamine in DMF fol-
lowed by reducing the formed intermediate azo-
methines with sodium borohydride furnished the
corresponding N-benzyl-1H-terazole-5-amines 1–3 in
yields of 61–81% (pathway a). However, in the case of
6-fluoro-2-chlorobenzaldehyde we found that the
reaction product containing no fluorine atom (by mass
Synthesis of compounds 1–3, 5. To a solution of
10 mmol of anhydrous 5-aminotetrazole and 10 mmol
of the corresponding benzaldehyde in 20 mL of DMF
was added 20 mmol of triethylamine. The mixture was
gradually brought to the boiling point for 10 min, and
then boiled for another 10 min so that 15–20% of the
solvent was evaporated. After the completion of the
reaction, the mixture was cooled and 40 mL of
methanol was added. Next, sodium borohydride
(30 mmol) was added by portions to the solution. The
reaction mixture was refluxed for 10 min, and then
diluted with 100 mL of cold water. The cooled
solution was acidified with concentrated hydrochloric
acid to pH 2. The precipitate was filtered off and
recrystallized from aqueous ethanol.
1
spectrometry data) was obtained. In the H NMR
spectrum of this compound there were no signals
characteristic of the protons of the benzylated amino
group (7.2–7.6 ppm) and tetrazole ring (14.3–
14.6 ppm). Additionally, the methylene group singlet
was shifted upfield (~1 ppm) in comparison with the
corresponding signals of 5-benzylaminotetrazoles.
Furthermore, the spectrum contained a singlet signal at
10.99 ppm corresponding to the resonance of one
proton. These data allowed us to assume that after the
formation of azomethine the intramolecular cyclization
unexpectedly took place due to the replacement of the
fluorine atom in the benzene ring by the tetrazole
nitrogen atom. Further hydrogenation of the resulting
N-(2-Chlorobenzyl)-1H-tetrazole-5-amine
(1).
1
Yield 74%, colorless solid, mp 215–216°C. Н NMR
spectrum, d, ppm: 14.5 s (1H), 7.52 s (1H), 7.45–7.22
m (4H), 4.48 s (1H), 4.46 s (1H). Mass spectrum
(HRMS-ESI), m/z: 232.0354 [M + Na]+ (calculated for
C8H8ClN5: 232.0360).
885

886
SKRYL’NIKOVA et al.
Scheme 1.
(C2H5)3N+H
N
N
N
N
O
NH
N
N
N
(11))NNaaBBHH44
2)HCl
1
2
N
N
R
R
(2) HCl
NH
N
(C2H5)3N
+
N
+
NH2
NH
a
A
1
2
1
2
R
R
R
R
1-3
1–3
R1 = Cl,
R1=Cl, R2=F
b
B
R2 = F
N
N
N
NH
N
N
1)NaBH4
(2) HCl
2)HCl
(1) NaBH4
N
N
Cl
N
N
Cl
4
5
1
2
1
2
1
2
5
4
R = Cl, R = H (1); R = Cl, R = Cl (2); R = F, R = H (3).
1
N-(2,6-Dichlorobenzyl)-1H-tetrazole-5-amine (2).
Yield 81%, colorless solid, mp 239–240°C. Н NMR
spectrum, d, ppm: 14.34 s (1H), 7.48–7.31 m (4H),
7.21 s (1H), 4.61 s (1H), 4.60 s (1H). Mass spectrum
(HRMS-ESI), m/z: 265.9965 [M + Na]+ (calculated for
C8H7Cl2N5: 265.9971).
203°C. Н NMR spectrum, d, ppm: 9.77 s (1H), 8.72–
7.87 m (3H). Mass spectrum (HRMS-ESI), m/z:
228.0055 [M + Na]+ (calculated for C8H4ClN5: 228.0047).
1
1Н NMR spectra (DMSO-d6) were obtained on a
Bruker AVANCE III 400 spectrometer operating at
400.13 MHz. High-resolution mass spectra (ESI) were
registered on a Bruker micrOTOF spectrometer.
N-(2-Fluorobenzyl)-1H-tetrazole-5-amine (3).
1
Yield 61%, colorless solid, mp 209–210°C. Н NMR
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C8H8FN5: 216.0656).
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6-Chloro-4,5-dihydrotetrazolo[1,5-a]quinazoline
(5). Yield 69%, colorless amorphous precipitate,
1
mp 293–294°C. Н NMR spectrum, d, ppm: 10.99 s
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of DMF was added 20 mmol of triethylamine. The
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aqueous ethanol. Yield 73%, pale yellow solid, mp 202
–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017