Three-component reaction of ketals, isonitriles, and trimethylsilyl azide

Article abstract of DOI:10.1007/s10593-017-2073-1

[Figure not available: see fulltext.] It was demonstrated that a ZnCl2-catalyzed three-component reaction of ketals, isonitriles, and trimethylsilyl azide led to 1,5-disubstituted tetrazoles in moderate to high yields.

Full text of DOI:10.1007/s10593-017-2073-1

DOI 10.1007/s10593-017-2073-1
Chemistry of Heterocyclic Compounds 2017, 53(4), 446–450
Three-component reaction of ketals, isonitriles,
and trimethylsilyl azide
Nikita E. Golantsov1, Hung M. Nguyen1, Aleksey V. Varlamov1,
Aleksander V. Aksenov2, Leonid G. Voskressensky1*
1 People's Friendship University of Russia,
6 Miklukho-Maklaya St., Moscow 117198, Russia; е-mail: lvoskressensky@sci.pfu.edu.ru
2 North Caucasus Federal University,
1 Pushkina St., Starvropol 355009, Russia; е-mail: alexaks05@rambler.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(4), 446–450
Submitted December 22, 2016
Accepted January 31, 2017
It was demonstrated that a ZnCl2-catalyzed three-component reaction of ketals, isonitriles, and trimethylsilyl azide led to 1,5-disub-
stituted tetrazoles in moderate to high yields.
Keywords: isonitrile, ketal, tetrazole, trimethylsilyl azide, Passerini reaction.
Tetrazole derivatives represent an important class of
heterocyclic compounds that are highly relevant to the
search for new biologically active compounds.1–4 Libraries
of such compounds, including tetrazoles, for the use in
biological activity screening programs are often created
through multicomponent reactions.5–7 One such reaction is
the well-studied interaction of iminium salts with isonitriles
and HN3 or azides – the Ugi-azide reaction, leading to 1,5-
disubstituted tetrazoles.7,8 Iminium salts can be generated
in situ from carbonyl compounds and amines (the four-
component variant) or can be isolated prior to the use in
reaction (the three-component variant). A direct reaction of
carbonyl compounds with isonitriles and HN3 (or azides) is
also known – it is a variant of the Passerini reaction.7,9 The
process proceeds through the formation of protonated
forms of carbonyl compounds, the oxocarbenium ions (or
their equivalents). In the case of aldehydes, the reaction
produced good yields of 1,5-disubstituted tetrazoles, while
the fraction of products arising from the two-component
interaction of azide with isonitrile increased for the less
reactive ketones, leading to tetrazoles that were
monosubstituted at position 1.9 Good product yields in the
three-component reaction with ketones were successfully
obtained by using aluminum azide.9 An effective procedure
was proposed very recently for performing the Passerini
reaction with trimethylsilyl azide under ultrasonication
conditions.10 Acetals and ketals were also reactive toward
isonitriles and produced various products.11,12 But the three-
component reaction of acetals with isonitriles and azide
was described with a very limited number of examples
featuring cyclic acetals of such specific class as
2-methoxyisochromanes.13 Analogous transformations of
ketals have not been studied.
While continuing our efforts toward the synthesis of
tetrazoles through multicomponent reactions involving
isonitriles,14–17 we decided to examine the interaction of
ketals with isonitriles and trimethylsilyl azide. The selected
model compounds were cyclohexanone dimethyl ketal (1a)
and benzyl isonitrile (2a) (Scheme 1). The main focus
during the screening of reaction conditions was toward the
use of Lewis acids in aprotic solvent, in order to minimize
the two-component interaction of ketal with isonitrile and
to prevent side reactions involving nucleophiles that are
different than azide. It was found that in the presence of
50 mol % of such readily available and cheap catalyst as
ZnCl2 the expected three-component reaction produced a
good yield of tetrazole 3a (Table 1). The other Lewis acids
that were tried in this reaction were not effective. The
structure of compound 3а was proved by using its spectral
data set and results of elemental analysis (Experimental).
The proposed mechanism of this transformation can be
described in the following way (Scheme 1). The initial
coordination of Lewis acid at the oxygen atom of the ketal
moiety is followed by the formation of the oxocarbenium
ion 4, which reacts with isonitrile and is converted to the
nitrilium ion 5, with subsequent cyclization with azide
forming a tetrazole ring.
It is interesting to note that cyclohexanone itself under
the indicated conditions formed the 1,5-disubstituted
tetrazole 6 in merely 23% yield, while the main product
0009-3122/17/53(04)-0446©2017 Springer Science+Business Media New York
446

Chemistry of Heterocyclic Compounds 2017, 53(4), 446–450
Scheme 1
MeO
Scheme 2
N
N
OMe
N
TMSN3
MeO
Catalyst
N
+
Ph
0–20°C
CHCl3
CN
Ph
3a
1a
2a
ZnCl2
– TMSCl
component process – the respective tetrazoles 3a–e were
obtained in good to high yields (Table 2, entries 1–5). The
nature of isonitrile had a more significant effect – yields in
the range from good to high were observed for the
reactions of benzyl isonitrile (2a) and p-methoxyphenyl
isonitrile (2c) (entries 1, 2, 5 and 7, 9, 11, respectively),
while the yields were substantially lower for aromatic
isonitriles that did not contain electron-donating groups
(nitriles 2b and 2d) (entries 6, 8, 10, 12). Analogous results
were obtained in the reaction of isonitriles 2a,c,d and
trimethylsilyl azide with diethyl ketal 1f (entries 13–15).
Entirely different results were observed after reacting
the aromatic isonitrile 2e containing an ester group at the
ortho position with ketal 1e (Scheme 3). Instead of the
respective tetrazole, the isolated product turned out to be
amide 8, which was apparently formed as a result of
hydrolysis during the silica gel chromatography of
compound 9, the product of formal isonitrile insertion at
the ketal 1e C–O bond.11,12 The formation of the insertion
product in this case was probably facilitated by coordi-
nation between Zn(OMe)Cl and the oxygen atom of ester
group in nitrilium salt 10.
TMSN
N N
ZnCl2
OMe
Cl
O
Me
Ph
N
N
C
Ph
MeO
MeO
Cl
– Zn(OMe)Cl
4
5
+ Me3SiCl
Me3SiOMe + ZnCl2
Zn(OMe)Cl
Table 1. Optimization of synthesis conditions for tetrazole 3a
Catalyst (equiv)
TfOH (0.2)
ZnCl2 (0.2)
ZnCl2 (0.5)
ZnCl2 (1.0)
Yield, %
Catalyst (equiv)
AlCl3 (0.5)
Yield, %
0
15
0
26
76
61
BF3·Et2O (0.5)
SnCl4 (0.5)
14
8
SnCl4 (0.2)
was 1-benzyltetrazole (7) (46%) (Scheme 2). The spectral
characteristics of compounds 6 and 7 were in agreement
with previously published data.8,10
The approach that we developed was applied to the
reaction of 2-methoxytetrahydropyran (11), which can be
viewed as a cyclic acetal. Achieving acceptable yields in
this case required an increased amount of catalyst and
longer reaction time (Scheme 4). The obtained products 12
were of interest as analogs of nucleosides.
The developed methodology was extended to a series of
ketals (Table 2).
It was found that the ring size (5–7 atoms) and the
character of ketone group in dimethyl ketals 1a–e did not
have a strong effect on the effectiveness of this three-
Table 2. The conditions for reactions between ketals 1а–f, isonitriles 2–d, and TMSN3 and the yields of tetrazoles 3a–o
N
N
N
0.5 equiv ZnCl2
CHCl3, rt, 24 h
RO
OR
RO
R1 R2
R3CN
2a–d
+
N
+
TMSN3
R1 R2
R3
3a–o
1a–f
Entry
Ketal
Isonitrile
Tetrazole
R
R1
R2
R3
Yield, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Cyclohexyl
Cyclopentyl
Cycloheptyl
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
76
84
78
80
76
35
82
41
66
29
54
43
72
80
26
1a
1b
1c
1d
1e
1a
1a
1a
1b
1b
1e
1e
1f
2a
2a
2a
2a
2a
2b
2c
2d
2c
2d
2c
2d
2a
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
Bu
Ph
Et
Me
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclopentyl
Cyclopentyl
Ph
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
PhCH2
Ph
Ph
Me
Me
Cyclohexyl
Cyclohexyl
Cyclohexyl
Et
Et
4-MeOC6H4
4-ClC6H4
1f
1f
447

Chemistry of Heterocyclic Compounds 2017, 53(4), 446–450
Scheme 3
Scheme 4
H Ph); 7.27–7.35 (3H, m, H Ph). 13C NMR spectrum, δ, ppm:
21.2 (2С); 25.1; 33.8 (2C); 51.0; 51.7; 75.1; 127.8 (2C);
128.6; 128.9 (2C); 134.5; 157.5. Mass spectrum, m/z: 273
[M+H]+. Found, %: C 66.32; H 7.46; N 20.53. C15H20N4O.
Calculated, %: C 66.15; H 7.40; N 20.57.
1-Benzyl-5-(1-methoxycyclopentyl)-1H-tetrazole (3b).
Yield 260 mg (84%), yellowish crystals, mp 59–60°C
(EtOAc–hexane). IR spectrum, ν, cm–1: 3067, 3031, 2976,
2945, 2872, 2835, 1497, 1454, 1421, 1072, 965, 730, 693.
1H NMR spectrum, δ, ppm (J, Hz): 1.69–1.83 (4H, m,
H Cyp); 2.05–2.13 (2H, m, H Cyp); 2.13–2.21 (2H, m,
H Cyp); 2.85 (3H, s, OCH3); 5.69 (2H, s, NCH2); 7.26–
7.30 (2H, m, H Ph); 7.30–7.36 (3H, m, H Ph). 13C NMR
spectrum, δ, ppm: 23.6 (2С); 36.3 (2C); 51.6; 52.0; 83.5;
128.0 (2C); 128.7; 129.0 (2C); 134.3; 156.7. Mass
spectrum, m/z: 259 [M+H]+. Found, %: C 65.32; H 7.09;
N 21.53. C14H18N4O. Calculated, %: C 65.09; H 7.02; N 21.69.
1-Benzyl-5-(1-methoxycycloheptyl)-1H-tetrazole (3с).
Yield 268 mg (78%), colorless oil. IR spectrum, ν, cm–1:
3034, 2928, 2858, 2828, 1497, 1455, 1409, 1073, 722, 700.
1H NMR spectrum, δ, ppm (J, Hz): 1.45–1.69 (8H, m,
H cycloheptyl); 2.04–2.16 (4H, m, H cycloheptyl); 2.87
(3H, s, OCH3); 5.69 (2H, s, NCH2); 7.23–7.27 (2H, m,
H Ph); 7.27–7.34 (3H, m, H Ph). 13C NMR spectrum, δ, ppm:
21.8 (2C); 29.4 (2С); 37.3 (2C); 51.5; 51.8; 79.3; 128.0
(2C); 128.6; 129.0 (2C); 134.4; 158.3. Mass spectrum, m/z:
287 [M+H]+. Found, %: C 67.32; H 7.78; N 19.53.
C16H22N4O. Calculated, %: C 67.11; H 7.74; N 19.56.
1-Benzyl-5-(1-ethyl-1-methoxypentyl)-1H-tetrazole (3d).
Yield 276 mg (80%), colorless oil. IR spectrum, ν, cm–1:
3034, 2957, 2873, 2832, 1498, 1456, 1409, 1163, 1066,
Thus, we have demonstrated that ketals of aromatic and
aliphatic ketones participate in a three-component reaction
with isonitriles and trimethylsilyl azide in the presence of
the readily available and cheap ZnCl2 catalyst, leading to
the formation of 1,5-disubstituted tetrazoles.
Experimental
IR spectra were recorded on a Nicolet 6700 FT-IR
spectrometer in thin film (diamond ATR accessory, 4000–
400 cm-1 range). 1H and 13С NMR spectra were recorded on
a Bruker-400 instrument (400 and 100 MHz, respectively)
in CDCl3, with the residual solvent protons as internal
standard (7.26 and 77.2 ppm, respectively). The LC-MS
analysis was performed on a system consisting of an
Agilent 1100 Series liquid chromatograph, Agilent Techno-
logies LC/MSD VL mass spectrometer (electrospray
ionization), and a Sedex 75 ELSD detector. Elemental
analysis was performed on a EuroVector EA-3000
elemental analyzer. Melting points were determined in
capillaries on an SMP 10 apparatus. Sorbfil plates were
used for thin-layer chromatography (visualization with
iodine vapor), while silica gel from Macherey Nagel
GmbH & Co (0.04–0.06 mm / 230–400 mesh, 60 Å) was
used for column chromatography. The solvents were
purified according to standard procedures. Ketals 1a-f,18,19
isonitriles 2a-d,16,20 and 2-methoxypyran (11)21 were
synthesized according to published procedures.
Synthesis of tetrazoles 3a-o (General method). The
appropriate isonitrile 2 (1.6 mmol), trimethylsilyl azide
(184 mg, 0.211 ml, 1.6 mmol), and anhydrous ZnCl2 (80 mg,
0.6 mmol) were added to a solution of ketal 1 (1.2 mmol)
in anhydrous CHCl3 (1.8 ml). The reaction mixture was
stirred for 24 h at room temperature, diluted with CH2Cl2
(20 ml), washed with 5% aqueous NaOH solution (2×10 ml),
saturated NaCl solution (10 ml), and dried over anhydrous
Na2SO4. The solvent was removed at reduced pressure, and
the residue was separated by silica gel column
chromatography, eluting with a 5:1 mixture of hexane–
ethyl acetate.
1
721, 702. H NMR spectrum, δ, ppm (J, Hz): 0.57 (3H, t,
J = 7.5, CH3); 0.69 (3H, t, J = 7.3, CH3); 0.77–0.86 (2H,
m); 0.96–1.12 (2H, m); 1.74–1.82 (1H, m); 1.87–1.97 (2H,
m) and 1.99–2.08 (1H, m, 4CH2); 3.05 (3H, s, OCH3); 5.68–
5.76 (2H, m, NCH2); 7.17–7.22 (2H, m, Н Ph); 7.22–7.30
(3H, m, Н Ph). 13C NMR spectrum, δ, ppm: 13.9; 17.2;
22.5; 25.0; 27.8; 34.8; 49.5; 52.4; 80.5; 127.8 (2C); 128.4;
128.7 (2C); 135.1; 156.8. Mass spectrum, m/z: 289 [M+H]+.
Found, %: C 66.77; H 8.43; N 19.38. C16H24N4O.
Calculated, %: C 66.64; H 8.39; N 19.43.
1-Benzyl-5-(1-methoxy-1-phenylethyl)-1H-tetrazole (3e).
Yield 268 mg (76%), white crystals, mp 67–68°C (EtOAc–
hexane). IR spectrum, ν, cm–1: 2992, 2937, 1495, 1456,
1448, 1371, 1133, 1104, 1072, 1040, 877, 768, 722, 698.
1H NMR spectrum, δ, ppm (J, Hz): 2.01 (3H, s, СCH3);
2.95 (3H, s, OCH3); 5.05 (1H, d, J = 14.9) and 5.28 (1H, d,
J = 14.9, CH2); 6.95–6.99 (2H, m, Н Ph); 7.16–7.23 (5H,
m, Н Ph); 7.23–7.30 (3H, m, Н Ph). 13C NMR spectrum,
δ, ppm: 25.9; 51.5; 51.6; 76.9; 124.9 (2C); 128.1; 128.3;
128.4 (2C); 128.5 (2C); 128.8 (2C); 133.6; 143.0; 156.6.
Mass spectrum, m/z: 295 [M+H]+. Found, %: C 69.48;
H 6.18; N 18.95. C17H18N4O. Calculated, %: C 69.37;
H 6.16; N 19.03.
1-Benzyl-5-(1-methoxycyclohexyl)-1H-tetrazole (3a).
Yield 248 mg (76%), yellowish crystals, mp 72–73°C
(EtOAc–hexane). IR spectrum, ν, cm–1: 2935, 2858, 2207,
1707, 1498, 1455, 1411, 1150, 1068, 934, 723, 694.
1H NMR spectrum, δ, ppm (J, Hz): 1.24–1.36 (1H, m,
H Cy); 1.51–1.65 (5H, m, H Cy); 1.84–1.94 (4H, m, H Cy);
2.87 (3H, s, OCH3); 5.73 (2H, s, NCH2); 7.21–7.25 (2H, m,
448

Chemistry of Heterocyclic Compounds 2017, 53(4), 446–450
5-(1-Methoxycyclohexyl)-1-phenyl-1H-tetrazole (3f).
1-(4-Methoxyphenyl)-5-(1-methoxy-1-phenylethyl)-
1H-tetrazole (3k). Yield 201 mg (54%), white crystals, mp
112–113°C (EtOAc–hexane). IR spectrum, ν, cm–1: 3052,
2997, 2963, 2935, 2834, 1610, 1593, 1516, 1467, 1446,
1369, 1308, 1256, 1183, 1127, 1106, 1073, 1044, 826, 703,
Yield 108 mg (35%), yellowish crystals, mp 56–58°C
(EtOAc–hexane). IR spectrum, ν, cm–1: 3061, 2936, 2858,
2831, 1595, 1501, 1455, 1417, 1153, 1072, 769, 691.
1H NMR spectrum, δ, ppm (J, Hz): 1.25–1.37 (1H, m, H Cy);
1.40–1.47 (2H, m, H Cy); 1.47–1.58 (3H, m, H Cy); 1.87–
2.03 (4H, m, H Cy); 3.03 (3H, s, OCH3); 7.42–7.46 (2H, m,
H Ph); 7.49–7.57 (3H, m, H Ph). 13C NMR spectrum,
δ, ppm: 21.6 (2С); 25.2; 33.6 (2C); 50.8; 74.8; 126.4 (2C);
129.4 (2C); 130.6; 135.6; 157.0. Mass spectrum, m/z: 259
[M+H]+. Found, %: C 65.32; H 7.09; N 21.53. C14H18N4O.
Calculated, %: C 65.09; H 7.02; N 21.69.
1
624. H NMR spectrum, δ, ppm (J, Hz): 2.05 (3H, s,
СCH3); 3.18 (3H, s, OCH3); 3.78 (3H, s, OCH3); 6.70 (2H,
d, J = 9.1, H Ar); 6.74 (2H, d, J = 9.1, H Ar); 7.05–7.09
(2H, m, Н Ph); 7.16–7.20 (3H, m, Н Ph). 13C NMR
spectrum, δ, ppm: 25.9; 51.4; 55.6; 76.8; 113.7 (2C); 125.0
(2C); 127.3 (3C); 127.7; 128.3 (2C); 143.2; 157.5; 160.6.
Mass spectrum, m/z: 311 [M+H]+. Found, %: C 65.68;
H 5.88; N 17.97. C17H18N4O2. Calculated, %: C 65.79;
H 5.85; N 18.05.
1-(4-Chlorophenyl)-5-(1-methoxy-1-phenylethyl)-1H-
tetrazole (3l). Yield 162 mg (43%), white crystals, mp 120–
121°C (EtOAc–hexane). IR spectrum, ν, cm–1: 3068, 2997,
2970, 2933, 2836, 1496, 1449, 1367, 1248, 1196, 1123,
1095, 1075, 1035, 1012, 830, 776, 752, 704, 600. 1H NMR
spectrum, δ, ppm (J, Hz): 2.08 (3H, s, СCH3); 3.20 (3H, s,
OCH3); 6.82 (2H, d, J = 8.8, H Ar); 7.05–7.10 (2H, m,
H Ar); 7.18–7.22 (5H, m, H Ar). 13C NMR spectrum, δ, ppm:
25.9; 51.5; 76.9; 125.0 (2C); 127.4 (2C); 128.0; 128.5
(2C); 128.9 (2C); 133.2; 136.4; 143.0; 157.5. Mass
spectrum, m/z: 315 [M+H]+. Found, %: C 59.89; H 4.81;
N 17.78. C16H15ClN4O. Calculated, %: C 61.05; H 4.80;
N 17.80.
5-(1-Methoxycyclohexyl)-1-(4-methoxyphenyl)-1H-
tetrazole (3g). Yield 283 mg (82%), yellowish oil. IR
spectrum, ν, cm–1: 3078, 2939, 2857, 1609, 1590, 1516, 1461,
1
1254, 1172, 1156, 1071, 1026, 837, 623. H NMR spectrum,
δ, ppm (J, Hz): 1.26–1.37 (1H, m, H Cy); 1.41–1.48 (2H,
m, H Cy); 1.48–1.60 (3H, m, H Cy); 1.90–2.02 (4H, m, H Cy);
3.04 (3H, s, OCH3); 3.87 (3H, s, OCH3); 7.00 (2H, d, J = 8.9,
H Ar); 7.35 (2H, d, J = 8.9, H Ar). 13C NMR spectrum, δ, ppm:
21.5 (2С); 25.0; 33.3 (2C); 50.6; 55.6; 74.6; 114.3 (2C);
127.5 (2C); 128.0; 156.9; 160.9. Mass spectrum, m/z: 289
[M+H]+. Found, %: C 62.70; H 7.01; N 19.36. C15H20N4O2.
Calculated, %: C 62.48; H 6.99; N 19.43.
1-(4-Chlorophenyl)-5-(1-methoxycyclohexyl)-1H-tetrazole
(3h). Yield 144 mg (41%), amber colored crystals, mp 80–
81°C (EtOAc–hexane). IR spectrum, ν, cm–1: 2944, 2864,
2854, 1495, 1458, 1411, 1242, 1157, 1084, 1012, 926, 830,
561. 1H NMR spectrum, δ, ppm (J, Hz): 1.29–1.38 (1H, m,
H Cy); 1.44–1.52 (2H, m, H Cy); 1.52–1.63 (3H, m, H Cy);
1.90–1.98 (2H, m, H Cy); 1.98–2.05 (2H, m, H Cy); 3.04
(3H, s, OCH3); 7.44 (2H, d, J = 8.8, H Ar); 7.52 (2H, d, J = 8.8,
H Ar). 13C NMR spectrum, δ, ppm: 21.6 (2С); 25.1; 33.6
(2C); 50.8; 74.8; 127.6 (2C); 129.7 (2C); 134.1; 136.8;
157.2. Mass spectrum, m/z: 293 [M+H]+. Found, %:
C 57.42; H 5.91; N 19.03. C14H17ClN4O. Calculated, %:
C 57.44; H 5.85; N 19.14.
1-Benzyl-5-(1-ethoxycyclohexyl)-1H-tetrazole (3m).
Yield 247 mg (72%), white crystals, mp 61–63°C (EtOAc–
hexane). IR spectrum, ν, cm–1: 3036, 2983, 2941, 2880,
2863, 1607, 1497, 1445, 1422, 1314, 1150, 1061, 980, 904,
1
774, 736, 691. H NMR spectrum, δ, ppm (J, Hz): 1.11
(3H, t, J = 7.0, CH2CH3); 1.26–1.37 (1H, m, H Cy); 1.51–
1.68 (5H, m, H Cy); 1.88–1.96 (2H, m, H Cy); 2.01–2.10
(2H, m, H Cy); 3.12 (2H, q, J = 7.0, CH2CH3); 5.79 (2H, s,
NCH2); 7.16–7.21 (2H, m, H Ph); 7.29–7.37 (3H, m, H Ph).
13C NMR spectrum, δ, ppm: 15.4; 21.4 (2С); 25.2; 34.3
(2C); 51.5; 58.6; 74.5; 127.3 (2C); 128.0 (2C); 128.5;
134.6; 157.9. Mass spectrum, m/z: 287 [M+H]+. Found, %:
C 67.30; H 7.78; N 19.49. C16H22N4O. Calculated, %:
C 67.11; H 7.74; N 19.56.
5-(1-Methoxycyclopentyl)-1-(4-methoxyphenyl)-1H-
tetrazole (3i). Yield 217 mg (66%), yellowish crystals, mp
74–76°C (EtOAc–hexane). IR spectrum, ν, cm–1: 3088,
3012, 2947, 2876, 2842, 2828, 1609, 1590, 1516, 1464,
1
1253, 1177, 1095, 1067, 837, 625. H NMR spectrum,
5-(1-Ethoxycyclohexyl)-1-(4-methoxyphenyl)-1H-
tetrazole (3n). Yield 290 mg (80%), yellowish crystals, mp
78–79°C (EtOAc–hexane). IR spectrum, ν, cm–1: 2986,
2937, 2901, 2858, 1610, 1515, 1453, 1306, 1254, 1173, 1153,
δ, ppm (J, Hz): 1.63–1.76 (4H, m, H Cyp); 1.99–2.07 (2H,
m, H Cyp); 2.08–2.16 (2H, m, H Cyp); 3.02 (3H, s, OCH3);
3.86 (3H, s, OCH3); 7.00 (2H, d, J = 8.8, H Ar); 7.40 (2H,
d, J = 8.8, H Ar). 13C NMR spectrum, δ, ppm: 23.2 (2С);
35.9 (2C); 51.5; 55.7; 82.6; 114.4 (2C); 127.4 (2C); 127.7;
156.6; 161.1. Mass spectrum, m/z: 275 [M+H]+. Found, %:
C 61.19; H 6.64; N 20.37. C14H18N4O2. Calculated, %:
C 61.30; H 6.61; N 20.42.
1
1063, 1029, 903, 835, 622. H NMR spectrum, δ, ppm
(J, Hz): 1.02 (3H, t, J = 7.0, CH2CH3); 1.29–1.39 (1H, m,
H Cy); 1.40–1.65 (5H, m, H Cy); 1.95–2.05 (4H, m, H Cy);
3.22 (2H, q, J = 7.0, CH2CH3); 3.89 (3H, s, OCH3); 7.01
(2H, d, J = 8.9, H Ar); 7.39 (2H, d, J = 8.9, H Ar). 13C NMR
spectrum, δ, ppm: 15.3; 21.8 (2С); 25.3; 34.1 (2C); 55.8;
58.1; 74.3; 114.5 (2C); 127.7 (2C); 128.4; 157.2; 161.0. Mass
spectrum, m/z: 303 [M+H]+. Found, %: C 63.61; H 7.35;
N 18.49. C16H22N4O2. Calculated, %: C 63.55; H 7.33; N 18.53.
1-(4-Chlorophenyl)-5-(1-ethoxycyclohexyl)-1H-tetrazo-
le (3o). Yield 95 mg (26%), yellowish crystals, mp 90–91°C
(EtOAc–hexane). IR spectrum, ν, cm–1: 3074, 2972, 2963,
2934, 1497, 1451, 1271, 1153, 1093, 1064, 1006, 978, 903,
1-(4-Chlorophenyl)-5-(1-methoxycyclopentyl)-1H-
tetrazole (3j). Yield 97 mg (29%), yellowish oil. IR spectrum,
ν, cm–1: 3098, 2949, 2873, 2826, 1497, 1407, 1197, 1091,
1
1068, 1013, 955, 832, 528. H NMR spectrum, δ, ppm
(J, Hz): 1.67–1.80 (4H, m, H Cyp); 2.02–2.10 (2H, m,
H Cyp); 2.12–2.19 (2H, m, H Cyp); 3.04 (3H, s, OCH3);
7.49–7.53 (4H, m, H Ar). 13C NMR spectrum, δ, ppm: 23.3
(2С); 36.1 (2C); 51.6; 82.7; 127.4 (2C); 129.7 (2C); 133.6;
136.8; 156.7. Mass spectrum, m/z: 279 [M+H]+. Found, %:
C 55.94; H 5.46; N 20.03. C13H15ClN4O. Calculated, %:
C 56.02; H 5.42; N 20.10.
1
836, 746. H NMR spectrum, δ, ppm (J, Hz): 1.00 (3H, t,
J = 7.0, CH2CH3); 1.31–1.40 (1H, m, H Cy); 1.42–1.50
(2H, m, H Cy); 1.50–1.64 (3H, m, H Cy); 1.94–2.07 (4H,
449

Chemistry of Heterocyclic Compounds 2017, 53(4), 446–450
m, H Cy); 3.21 (2H, q, J = 7.0, CH2CH3); 7.48 (2H, d,
C 63.99; H 6.64; N 22.89. C13H16N4O. Calculated, %:
J = 8.7, H Ar); 7.52 (2H, d, J = 8.7, H Ar). 13C NMR
spectrum, δ, ppm: 15.2; 21.7 (2С); 25.2; 34.1 (2C); 58.2;
74.3; 127.6 (2C); 129.6 (2C); 134.1; 136.7; 157.0. Mass
spectrum, m/z: 307 [M+H]+. Found, %: C 58.71; H 6.29; N 18.28.
C15H19ClN4O. Calculated, %: C 58.73; H 6.24; N 18.26.
Reaction of cyclohexanone with benzyl isonitrile (2a)
and trimethylsilyl azide. Benzyl isonitrile (2a) (152 mg,
1.3 mmol), trimethylsilyl azide (150 mg, 0.17 ml, 1.3 mmol),
and anhydrous ZnCl2 (68 mg, 0.5 mmol) were added to a
solution of cyclohexanone (98 mg, 1.0 mmol) in anhydrous
CHCl3 (1.5 ml). The reaction mixture was stirred at room
temperature for 24 h, diluted with CH2Cl2 (20 ml), washed
with 5% NaOH solution (2×10 ml), saturated NaCl solution
(10 ml), and dried over anhydrous Na2SO4. The solvent
was removed at reduced pressure, the residue was
separated by silica gel column chromatography, eluting
with 3:1 hexane–EtOAc mixture. The isolated products
were 1-(1-benzyl-1H-tetrazol-5-yl)cyclohexanol (6) (59 mg,
23%) and 1-benzyl-1H-tetrazole (7) (74 mg, 46%), with
spectral characteristics that matched the literature data.8,10
Methyl 2-[(2-methoxy-2-phenylpropane)amido]ben-
zoate (8). The compound was obtained according to the
general method for the synthesis of tetrazoles 3a–o, except
that TMSN3 did not participate in this reaction. Yield
124 mg (33%), yellowish oil. IR spectrum, ν, cm–1: 3265
(br.), 2986, 2952, 2832, 1694, 1585, 1516, 1449, 1266,
C 63.91; H 6.60; N 22.93.
1-(4-Methoxyphenyl)-5-(tetrahydro-2H-pyran-2-yl)-
1H-tetrazole (12b) was obtained analogously to compound
12a. Yield 166 mg (49%), yellowish oil. IR spectrum, ν, cm–1:
2939, 2844, 1609, 1508, 1443, 1250, 1172, 1083, 1043,
1
1023, 834, 637, 546. H NMR spectrum, δ, ppm (J, Hz):
1.47–1.59 (2H, m, Н pyran); 1.59–1.71 (1H, m, Н pyran);
1.80–1.89 (1H, m, Н pyran); 1.92–2.03 (1H, m, Н pyran);
2.08–2.22 (1H, m, Н pyran); 3.43–3.52 (1H, m, Н pyran);
3.85 (3H, s, OCH3); 3.93–4.00 (1H, m, Н pyran); 4.52 (1H,
dd, J = 2.6, J = 10.8, Н pyran); 7.01 (2H, d, J = 9.0, H Ar);
7.46 (2H, d, J = 9.0, H Ar). 13C NMR spectrum, δ, ppm:
22.5; 25.2; 28.8; 55.7; 68.6; 69.0; 114.7 (2C); 126.4 (2C);
126.8; 154.2; 161.0. Mass spectrum, m/z: 261 [M+H]+.
Found, %: C 60.32; H 6.28; N 21.45. C13H16N4O2.
Calculated, %: C 59.99; H 6.20; N 21.52.
This study received financial support from the Ministry
of Education and Science of the Russian Federation
(Contract No. 02.а03.21.0008) and the Russian Foundation for
Basic Research (grants 17-03-00605 а, 17-53-560020 Iran_а).
References
1. Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem.
Heterocycl. Compd. 2007, 43, 1. [Khim. Geterotsikl. Soedin.
2007, 3.]
2. Frija, L. M. T.; Ismael, A.; Cristiano, M. L. S. Molecules
2010, 15, 3757.
1
1137, 1086, 1049, 756, 699. H NMR spectrum, δ, ppm
(J, Hz): 1.89 (3H, s, CCH3); 3.39 (3H, s, OCH3); 3.96 (3H,
s, OCH3); 7.04–7.09 (1H, m, H Ar); 7.26–7.31 (1H, m,
H Ar); 7.33–7.38 (2H, m, H Ar); 7.46–7.52 (1H, m, H Ar);
7.56–7.60 (2H, m, H Ar); 8.03 (1H, dd, J = 1.7, J = 8.0,
H Ar); 8.72 (1H, dd, J = 1.7, J = 8.6, H Ar); 12.10 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 20.6; 51.8; 52.4; 82.7;
116.0; 120.4; 122.7; 126.3 (2C); 127.9; 128.5 (2C); 131.0;
134.5; 141.0; 141.1; 168.2; 172.9. Mass spectrum, m/z: 314
[M+H]+. Found, %: C 69.23; H 6.08; N 4.53. C18H19NO4.
Calculated, %: C 69.00; H 6.11; N 4.47.
3. Köhler, S. C.; Silbermann, K.; Wiese, M. Eur. J. Med. Chem.
2016, 124, 881.
4. Jawabrah Al-Hourani, B.; Al-Awaida, W.; Matalka, K. Z.;
El-Barghouthi, M. I.; Alsoubani, F.; Wuest, F. Bioorg. Med.
Chem. Lett. 2016, 26, 4757.
5. Chandgude, A. L.; Dömling, A. Eur. J. Org. Chem. 2016, 14,
2383.
6. Lygin, A. V.; De Meijere, A. Angew. Chem., Int. Ed. 2010, 49,
9094.
7. Maleki, A.; Sarvary, A. RSC Adv. 2015, 5, 60938.
8. Shmatova, O. I.; Nenajdenko, V. G. J. Org. Chem. 2013, 78, 9214.
9. Banfi, L.; Riva, R. In Organic Reactions; Wiley: New Jersey,
2005, Vol. 65, p. 1.
1-Benzyl-5-(tetrahydro-2H-pyran-2-yl)-1H-tetrazole
(12a). Benzyl isonitrile (2a) (200 mg, 1.7 mmol), tri-
methylsilyl azide (196 mg, 0.223 ml, 1.7 mmol), and an-
hydrous ZnCl2 (177 mg, 1.3 mmol) were added to a solu-
tion of 2-methoxytetrahydropyran (11) (150 mg, 1.3 mmol)
in anhydrous CHCl3 (1.8 ml). The reaction mixture was
stirred at room temperature for 96 h, diluted with CH2Cl2
(20 ml), washed with 5% NaOH solution (2×20 ml),
saturated NaCl solution (10 ml) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure,
and the residue was separated by silica gel column
chromatography, eluting with hexane–EtOAc mixture.
Yield 235 mg (74%), yellowish oil. IR spectrum, ν, cm–1:
2942, 2852, 1455, 1203, 1086, 1045, 911, 721, 695.
1H NMR spectrum, δ, ppm (J, Hz): 1.50–1.70 (3H, m,
Н pyran); 1.77–1.88 (1H, m, Н pyran); 1.89–1.99 (1H, m,
Н pyran); 1.99–2.09 (1H, m, Н pyran); 3.49–3.60 (1H, m,
Н pyran); 3.98–4.08 (1H, m, Н pyran); 4.57 (1H, dd,
J = 2.8, J = 10.7, Н pyran); 5.63 (1H, d, J = 15.0) and 5.73
(1H, d, J = 15.0, NCH2); 7.22–7.30 (2H, m, Н Ph); 7.31–
7.42 (3H, m, Н Ph). 13C NMR spectrum, δ, ppm: 22.4;
25.4; 29.3; 51.9; 68.6; 70.7; 128.2 (2C); 128.8; 129.0 (2C);
134.1; 154.2. Mass spectrum, m/z: 245 [M+H]+. Found, %:
10. Chandgude, A. L., Dömling, A. Green Chem. 2016, 18, 3718.
11. Tobisu, M.; Kitajima, A.; Yoshioka, S.; Hyodo, I.; Oshita, M.;
Chatani, N. J. Am. Chem. Soc. 2007, 129, 11431.
12. Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257.
13. Yanai, H.; Sakiyama, T.; Oguchi, T.; Taguchi, T. Tetrahedron
Lett. 2012, 53, 3161.
14. Borisov, R. S., Voskressensky, L. G., Polyakov, A. I.,
Borisova, T. N.; Varlamov, A. V. Synlett 2014, 955.
15. Voskressensky, L. G.; Borisov, R. S.; Kulikova, L. N.;
Kleimenov, A. V.; Borisova, T. N.; Varlamov, A. V. Chem.
Heterocycl. Compd. 2012, 48, 680. [Khim. Geterotsikl.
Soedin. 2012, 728.]
16. Borisov, R. S.; Polyakov, A. I.; Medvedeva, L. A.;
Guranova, N. I.; Voskressensky, L. G. Russ. Chem. Bull., Int.
Ed. 2012, 61, 1609. [Izv. Akad. Nauk, Ser. Khim. 2012, 1592.]
17. Borisov, R. S.; Polyakov, A. I.; Medvedeva, L. A.;
Khrustalev, V. N.; Guranova, N. I.; Voskressensky, L. G. Org.
Lett. 2010, 12, 3894.
18. Chopin, N.; Novitchi, G.; Médebielle, M.; Pilet, G. J. Fluorine
Chem. 2015, 179, 169.
19. Giersch, W.; Farris, I. Helv. Chim. Acta 2004, 87, 1601.
20. Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239.
21. Woods, G. F.; Kramer, D. N. J. Am. Chem. Soc. 1947, 69, 2246.
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