5-phenyl-2H-tetrazol-2-ylmethyl ketones in the synthesis of tetrazolylalkanols and tetrazolyl(hydroxy)alkylphosphonates

Article abstract of DOI:10.1134/S1070428014060219

The reduction of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone with sodium tetrahydridoborate gave 1-(5-phenyl-2H-tetrazol-2-yl)propan-1-ol and 1-phenyl-2-(5-phenyl-2H- tetrazol-2-yl)ethanol, respectively. Only 1-(5-phenyl-2H-tetrazol-2-yl)propan-2- one was reduced with baker's yeast with an appreciable yield. 1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol- 2-yl)ethanone reacted with diethyl phosphonate in the presence of potassium fluoride to produce the corresponding diethyl [hydroxy(5-phenyl-2H-tetrazol-2- yl)alkyl]phosphonates.

Full text of DOI:10.1134/S1070428014060219

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 6, pp. 892–894. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.S. Krylov, A.V. Dogadina, R.E. Trifonov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 6, pp. 907–909.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 80th anniversary
5-Phenyl-2H-tetrazol-2-ylmethyl Ketones in the Synthesis
of Tetrazolylalkanols and Tetrazolyl(hydroxy)alkylphosphonates
A. S. Krylova, A. V. Dogadinaa, and R. E. Trifonova, b
a St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: rost_trifonov@mail.ru
b St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
Received May 11, 2014
Abstract—The reduction of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-
2-yl)ethanone with sodium tetrahydridoborate gave 1-(5-phenyl-2H-tetrazol-2-yl)propan-1-ol and 1-phenyl-2-
(5-phenyl-2H-tetrazol-2-yl)ethanol, respectively. Only 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one was reduced
with baker’s yeast with an appreciable yield. 1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-
phenyl-2H-tetrazol-2-yl)ethanone reacted with diethyl phosphonate in the presence of potassium fluoride to
produce the corresponding diethyl [hydroxy(5-phenyl-2H-tetrazol-2-yl)alkyl]phosphonates.
DOI: 10.1134/S1070428014060219
Tetrazolyl fragment is a known pharmacophore. It
constitutes a structural unit of many medicinal agents
and drug candidates [1, 2]. In the past decades, the
number of publications on the synthesis and properties
of tetrazoles as potential medicinal agents has consid-
erably increased as compared to other azoles. This is
determined by some unique properties of tetrazole
derivatives, in particular by their high stability in meta-
bolic processes, low toxicity, ability to form strong
hydrogen bonds with proton donors, etc. [3–5].
alkylation of 5-phenyltetrazole with 2-chloro-1-
phenylethanone and 1-chloropropan-2-one, respec-
tively, in acetonitrile in the presence of triethylamine
(Scheme 1). Under the reaction conditions 5-phenyl-
tetrazole exists as tetrazolate anion [8]. In both cases,
tetrazolyl ketones I and II were isolated in good yields.
The reaction was regioselective, and the products were
exclusively 2-substituted isomers. This is reliably con-
firmed by the presence in their 13C NMR spectra of
a signal at δC 164–165 ppm, which belongs to C5 in the
tetrazole ring, as well as by the methylene proton
It is known that tetrazolyl derivatives of aliphatic
alcohols exhibit various kinds of biological activity,
including antimicrobial, antifungal, anticonvulsant,
and others [6]. Phosphoryl derivatives of such alcohols
may also be interesting as substrates for medicinal
chemistry [7]. A combination of tetrazole ring and
phosphonate functionality in a single molecule could
give rise to a strong synergistic effect. However, the
synthesis of tetrazolylalkanols and their derivatives
still remains fairly laborious, and the number of acces-
sible compounds of this series is fairly limited.
1
signal at δ 6–7 ppm in the H NMR spectra [2, 9].
Selective formation of 2-substituted isomer I was
noted previously [10]; by contrast, the alkylation of
5-phenyltetrazole with 4-chlorophenacyl bromide in
acetone was reported to give a mixture of N1- and
N2-substituted isomers [6].
Scheme 1.
O
HN
N
+
N
Cl
N
Ph
R
O
N
With the goal of synthesizing (5-phenyl-2H-tetra-
zol-2-yl)alkanols and diethyl [hydroxy(5-phenyl-2H-
tetrazol-2-yl)alkyl]phosphonates we used as starting
compounds the corresponding 5-phenyl-2H-tetrazol-
2-ylmethyl ketones I and II which were prepared by
N
Et3N, 60°C
R
N
–Et3N·HCl
Ph
N
I, II
I, R = Me; II, R = Ph.
892

5-PHENYL-2H-TETRAZOL-2-YLMETHYL KETONES IN THE SYNTHESIS
893
By reduction of tetrazolylmethyl ketones I and II
with sodium tetrahydridoborate we obtained racemic
tetrazolylmethyl carbinols III and IV (Scheme 2). The
spectral parameters of III and IV were similar to those
given in [10, 11]. With a view to isolate pure enantio-
mers of III and IV we tried to reduce ketones I and II
with baker’s yeast. However, by column chromatog-
raphy we succeeded in isolating in a poor yield only
compound III whose spectral properties were identical
to those of a sample obtained by reduction with
sodium tetrahydridoborate.
of triethylamine in 30 mL of acetonitrile, and the mix-
ture was stirred for 6.5 h at 58°C. The precipitate of
triethylamine hydrochloride was filtered off, the fil-
trate was evaporated, and the residue was washed with
a saturated solution of sodium carbonate and recrystal-
lized from water–anhydrous ethanol (1:4). Yield 3 g
(44%), colorless crystals, mp 124–125°C. IR spectrum,
ν, cm–1: 2981, 2943, 1724, 1531, 1361, 1176, 1049,
1
802, 729, 686, 570. H NMR spectrum, δ, ppm: 2.31 s
(3H, CH3), 6.00 s (2H, CH2), 7.53–7.60 m (3H, Ph),
8.07–8.09 m (2H, Ph). 13C NMR spectrum, δC, ppm:
27.63, 61.62, 126.80, 127.27, 129.76, 131.08, 164.67.
Found, %: C 59.45; H 4.96; N 27.73. C10H10N4O. Cal-
culated, %: C 59.40; H 4.98; N 27.71.
Scheme 2.
HO
N
N
[H]
I, II
1-Phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethan-1-
one (II). ω-Chloroacetophenone, 4.9 g (34 mmol), was
added to a solution of 5 g (34 mmol) of 5-phenyl-
tetrazole and 4.6 mL of triethylamine in 30 mL of
acetonitrile, and the mixture was stirred for 9 h at
60°C. The precipitate of triethylamine hydrochloride
was filtered off, the filtrate was evaporated, and the
residue was washed with a saturated solution of
sodium carbonate and recrystallized from water–anhy-
drous ethanol (1:4). Yield 5.79 g (53%), colorless
crystals, mp 119–120°C. IR spectrum, ν, cm–1: 3386,
3074, 2989, 2954, 2923, 1701, 1450, 1342, 1226,
R
N
Ph
N
III, IV
III, R = Me; IV, R = Ph.
Tetrazolylmethyl ketones I and II reacted with di-
ethyl phosphonate in the presence of anhydrous potas-
sium fluoride to produce the corresponding diethyl
[hydroxy(5-phenyl-2H-tetrazol-2-yl)alkyl]phospho-
nates V and VI in high yield (Scheme 3).
Scheme 3.
1
OH
1041, 999, 759, 736, 698, 686, 640. H NMR spec-
N
N
(EtO)2P(O)H, KF
trum, δ, ppm: 6.75 s (2H, CH2), 7.57–8.12 m (10H,
C6H5). 13C NMR spectrum, δC, ppm: 59.50, 126.84,
127.28, 128.88, 129.51, 129.80, 131.13, 134.24, 135.04,
164.83, 191.78. Found, %: C 68.12; H 4.55; N 24.24.
C15H12N4O. Calculated, %: C 68.17; H 4.58; N 24.20.
P(O)(OEt)2
I, II
N
Ph
R
N
V, VI
V, R = Me; VI, R = Ph.
1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-ol (III).
Baker’s yeast, 2.5 g, was dispersed in a solution of 4 g
of sugar in 15 mL of water at 30°C, the suspension was
stirred for 15 min at 30°C, 0.5 g of 1-(5-phenyl-2H-
tetrazol-2-yl)propan-2-one (I) was added, and the mix-
ture was stirred for 4 days at 30°C. The mixture was
filtered under reduced pressure, the filtrate was treated
with chloroform (3×100 mL), and the combined ex-
tracts were evaporated. The residue was subjected to
chromatography on silica gel using first chloroform
and then chloroform–methanol (9:1) as eluent. Yield
0.07 g (14%). The spectral parameters of the product
were identical to those given in [10].
To conclude, 5-phenyl-2H-tetrazol-2-ylmethyl
ketones are convenient starting compounds for the syn-
thesis of tetrazolylmethyl carbinols and their deriva-
tives containing an asymmetric carbon atom.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker DPX-400 spectrometer at 400 and 100 MHz,
respectively, from solutions in DMSO-d6 using tetra-
methylsilane as internal reference. The IR spectra were
measured in KBr on a Shimadzu FTIR-8400 spectrom-
eter. The purity of the isolated compounds was
checked by TLC on Kieselgel 60F254 plates (Merck)
using hexane–ethyl acetate (7:3) as eluent; spots were
visualized under UV light.
1-Phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethan-1-ol
(IV). 1-Phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethan-1-
one (II), 0.5 g (1.9 mmol), was dissolved in 40 mL of
anhydrous propan-2-ol, 0.1 g (2.5 mmol) of sodium
hydroxide and 1.5 g (39 mmol) of finely powdered
sodium tetrahydridoborate were added, and the mix-
1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one (I).
Chloroacetone, 2.9 g (31 mmol), was added to a solu-
tion of 5 g (34 mmol) of 5-phenyltetrazole and 4.6 mL
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

KRYLOV et al.
894
ture was stirred for 10 h at 82°C. The mixture was then
diluted with 100 mL of water and treated with ethyl
acetate (3×30 mL), and the combined extracts were
evaporated. Yield 0.446 g (89%), colorless crystals,
mp 86–87°C; published data [11]: mp 108–118°C.
IR spectrum, ν, cm–1: 3249, 1531, 1469, 1450, 1203,
1145, 1060, 1041, 1026, 925, 883, 790, 767, 729, 686,
617, 532. 1H NMR spectrum, δ, ppm: 4.86 d (2H, CH2,
J = 6.6 Hz), 5.24 m (1H, CH), 5.89 d (1H, OH, J =
4.9 Hz), 7.27–7.60 m (8H, Ph), 8.09 d.d (2H, Ph, J =
7.6, 1.4 Hz). 13C NMR spectrum, δC, ppm: 46.86,
126.65, 126.76, 127.17, 128.99, 129.72, 131.04, 134.45,
149.69, 164.39. Found, %: C 67.64; H 5.32; N 21.05.
C15H14N4O4. Calculated, %: C 67.65; H 5.30; N 21.04.
filtered off and washed with water. Yield 0.133 g
(74%), colorless crystals, mp 119–120°C. IR spectrum,
ν, cm–1: 3244, 1527, 1496, 1450, 1234, 1018, 941, 871,
798, 759, 736, 698, 605, 567.1H NMR spectrum
3
(CDCl3), δ, ppm: 1.13 t (3H, CH2CH3, JHH = 7.0 Hz),
3
1.21 t (3H, CH2CH3, JHH = 7.0 Hz), 3.76 m (1H,
OCH2, 3JHH = 7.3, 3JHP = 14.5 Hz), 3.96 m (1H, OCH2,
3JHH = 7.3, 3JHP = 14.5 Hz), 4.06 m (1H, OCH2, 3JHH
=
3
3
7.3, JHP = 14.5 Hz), 4.08 m (1H, OCH2, JHH = 7.3,
3JHP = 14.5 Hz), 5.57 br.s (1H, OH), 5.27 d.d (1H,
2
3
CH2N, JHH = JHP = 14.0 Hz), 5.45 d.d (1H, CH2N,
3
2JHH = 14.0, JHP = 2.7 Hz), 7.31–8.08 m (10H, Ph).
13C NMR spectrum (CDCl3), δC, ppm: 16.21 d (CH3,
3JCP = 5.4 Hz), 58.74 d (CH2N, 2JCP = 8.0 Hz), 63.53 d
(OCH2, 2JCP = 7.4 Hz), 64.41 d (OCH2, 2JCP = 7.4 Hz),
Diethyl 2-hydroxy-1-(5-phenyl-2H-tetrazol-2-yl)-
propan-2-ylphosphonate (V). A mixture of 0.2 g
(0.99 mmol) of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-
one (I), 0.3 g (2.2 mmol) of diethyl phosphonate, and
0.29 g (5 mmol) of anhydrous potassium fluoride was
stirred for 5 h. The resulting suspension was treated
with 2 mL of chloroform and extracted with a 1% so-
lution of potassium hydroxide (3 ×2 mL), and the
organic phase was evaporated. Yield 0.28 g (77%),
colorless crystals, mp 117–119°C. IR spectrum, ν,
cm–1: 3232, 1724, 1531, 1469, 1450, 1388, 1365, 1226,
1172, 1022, 948, 879, 798, 740, 702, 555, 509.
1H NMR spectrum (CDCl3), δ, ppm: 1.29 t (3H,
1
76.16 d (COH, JCP = 219.5 Hz); 126.20, 126.24,
126.90, 128.42, 128.47, 128.90, 130.54, 135.44 (Ph);
164.94 (C=N). 31P NMR spectrum (CDCl3):
δP 18.17 ppm. Found, %: C 56.74; H 5.75; N 13.95.
C19H23N4O4P. Calculated, %: C 56.71; H 5.76;
N 13.92.
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zol-2-yl)ethan-1-one (II), 0.3 g (2.2 mmol) of diethyl
phosphonate, and 0.25 g (4.3 mmol) of anhydrous
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014