Cobalt-promoted one-pot reaction of isothiocyanates toward the synthesis of aryl/alkylcyanamides and substituted tetrazoles

Article abstract of DOI:10.1007/s10593-018-2303-1

[Figure not available: see fulltext.] The synthesis of cyanamides and tetrazoles from isothiocyanates through tandem reaction using cobalt catalyst has been demonstrated. In the case of tetrazole preparation, the reaction involved addition/desulfurization/nucleophilic addition/electrocyclization, whereas aromatic cyanamides were constructed from isothiocyanates through addition/desulfurization. Cheap cobalt sulfate was used for the synthesis of various cyanamides and tetrazoles. In addition, cobalt catalyst was found to be desulfurization reagent that has not been previously reported. The final products have been obtained from starting precursors in good to high yield.

Full text of DOI:10.1007/s10593-018-2303-1

DOI 10.1007/s10593-018-2303-1
Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Cobalt-promoted one-pot reaction of isothiocyanatestoward
the synthesis of aryl/alkylcyanamides and substituted tetrazoles
1
1
2
Mohan Seelam , Prasada Rao Kammela *, Bajivali Shaikh ,
3
4
Ramana Tamminana , Sujatha Bogiri
1
Department of Chemistry, Bapatla Engineering College,
Bapatla, Andhra Pradesh 522101, India, e-mail: prasad17467@gmail.com, seelam.mohan123@gmail.com
2
3
Department of Chemistry, Gudlavalleru Engineering College,
Gudlavalleru, Andhra Pradesh 521356, India; e-mail: bajivali82@gmail.com
Department of Chemistry, GITAM University,
Bengaluru campus, NH-207, Doddaballapur Taluk, Bengaluru District, Karnataka 561203, India;
e-mail: rtamminana17@gmail.com
4
Department of Chemistry, Y. A. Govt Degree College for Women,
Chirala, Andhra Pradesh 523155, India; e-mail: sujathab1234@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
018, 54(5), 535–544
Submitted May 22, 2017
Accepted after revision January 9, 2018
2
The synthesis of cyanamides and tetrazoles from isothiocyanates through tandem reaction using cobalt catalyst has been demonstrated. In
the case of tetrazole preparation, the reaction involved addition/desulfurization/nucleophilic addition/electrocyclization, whereas
aromatic cyanamides were constructed from isothiocyanates through addition/desulfurization. Cheap cobalt sulfate was used for the
synthesis of various cyanamides and tetrazoles. In addition, cobalt catalyst was found to be desulfurization reagent that has not been
previously reported. The final products have been obtained from starting precursors in good to high yield.
Keywords: cobalt catalyst, cyanamides, tetrazoles, desulfurization, tandem reaction.
Cyanamides are very good intermediates in the synthesis
of heterocyclic compounds which have biological, medi-
deoxygenating or desulfurizing agent like sodium bis-
4,15
(trimethylsilyl)amide.1
Recently, Patel and coauthors
1
,2
cinal, and pharmaceutical importance. In recent decades,
reported the synthesis of cyanamides from thiocarbamate
1
16
cyanamides (RR N–CN) have been used in the synthesis of
salts using hypervalent iodine(III) reagent. However,
3
4
N-alkyl or N-aryl imides which are used as herbicides.
most of the reports have used highly caustic, harmful, and
costly reagents. Apart from the above-mentioned draw-
backs, some of the reactions required high temperature and
Cyanamides also have been used in organic synthesis as a
5
protected form of secondary amines. In addition, cyan-
6
+
amides inhibit the activity of tumor growth and they are
cyano cation (CN ), which is obtained from toxic cyanogen
2
9
synthetic intermediates. Apart from that, synthesis of
halides, while some other reactions could give low yields
many reagents has been developed from cyanamides.7
The preparation of cyanamides has been carried out by
the reaction of gaseous cyanogen chloride or cyanogen
and require cumbersome purification methods.
16
To
overcome the above-referred disadvantages, an efficient
method is needed. In this connection, herein we wish to
demonstrate synthesis of cyanamides from aryl/alkyl
isothiocyanates via addition/desulfurization using cheap,
readily available, and air-stable cobalt source as catalyst
under mild reaction conditions.
8
,9
bromide with amines or imide salts. In addition, the
cyanamides have been constructed from different starting
1
0
11
precursors such as ureas, thioureas,
amidoximes,
organic isocyanides and trimethylsilyl azide,12 and
1
3
N,N-disubstituted glycyclamide.
Wong and coauthors
In recent times, different organic transformations and
manufacturing of various heterocyclic compounds have
been developed by using cobalt catalysts,17 due to their
have developed a one-pot reaction for the manufacturing of
cyanamides from isocyanates and isothiocyanates using
0
009-3122/18/54(5)-0535©2018 Springer Science+Business Media, LLC
535

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Table 1. Solvent optimization for the synthesis
N
N
HN
of phenylcyanamide (2a)*
O
N
O
N
N
HN
MeO
H
O
O
N
OMe
N
H
N
N
Ph
CI-9222
7a
Anti-allergic activity27b
Anti-allergic activity
N
HN
N
N
N
H
N
N
N
Entry
Solvent
Yield, %
1
2
3
4
5
6
DMSO
DMF
75
95
Pr
MeCN
45
Endothelin-converting
H
2
O
No reaction
No reaction
No reaction
50
enzyme inhibitor24
THF
Figure 1. Some biologically important aminotetrazoles.
PhMe
7
8
9
DMF–H
DMF–H
2
O (1:1)
O (1:2)
availability, affordable cost, air stability, and nontoxic
nature. We recently have developed methodology for the
synthesis of aryl/alkyl isothiocyanates. In continuation of
our earlier work on cobalt catalysis and to address those
limitations that have been described in the literature, we
wish to demonstrate a procedure for the regioselective
synthesis of cyanamides using cobalt catalyst.
2
20
–
No reaction
1
8
*
(
(
Reaction conditions: phenyl isothiocyanate (1a) (1 mmol), solvent
2 ml), aqueous NH (2 ml), rt, 1 h, then CoSO ·H O (100 mol %), Et
1 equiv), rt, 2 h.
3
4
2
3
N
On the other hand, tetrazoles are an important hetero-
cyclic class which has drawn immense attention of
synthetic organic chemists due to their valuable biological
activity. Tetrazoles are of noticeable interest in medicinal
applications19 and they are also used as ligands in
use either toxic reagents or harsh reaction conditions, such
as high temperature, and lack of regioselectivity.40 To
overcome the above-mentioned drawbacks we wish to
describe methodology for the synthesis of substituted
tetrazoles from aryl/alkyl isothiocyanates using cobalt
catalyst via addition/desulfurization/addition/electrocycli-
zation.
2
0
coordination chemistry. These compounds also show
2
1
22
biological activities such as antibacterial, antiviral, anti-
inflammatory,2 and antineoplastic. Few examples of
2
23
Initially, optimization of the reaction for the synthesis of
aryl/alkylcyanamides was tested with phenyl isothio-
cyanate (1a) as model substrate. Various solvents were
screened for this reaction (Table 1). Among them, DMF
showed better efficiency (entry 2) than other solvents. The
24
aminotetrazoles having metalloprotease inhibiting,
antiviral,25 receptor modulating, and anti-allergic activi-
26
27
ties are shown in Figure 1.
Moreover, 5-substituted tetrazoles may serve as a non-
classical isostere for the carboxylic acid moiety in biolo-
solvents like H O, THF, and toluene did not give target
2
2
8
gically active compounds. Continuous and significant
efforts are being made in this area owing to synthetic and
medicinal importance of tetrazoles. Especially, substituted
product phenylcyanamide (2a) (Table 1, entries 4–6).
DMSO solvent could give target product in 75% yield
(Table 1, entry 1) and MeCN gave target product in
moderate yield (Table 1, entry 3). We have also examined
the reaction in the presence of combination of solvents
(Table 1, entries 7–8). Unfortunately, no combination of
solvent could give target product in good yield.
tetrazoles have been prepared from the addition of NaNO
2
29
to aminoguanidine, addition of NaN
3
to carbodiimides or
cyanamides,30 reaction of amines with a leaving group in
3
1
position 5 of tetrazole, nucleophilic substitution of
–
32
chlorine by N
3
in α-chloroformamidines or sulfur in
Later, various bases were examined for this reaction
(Table 2). Both organic and inorganic bases showed similar
effect. The organic base pyridine could not give the target
product. The control experiment confirmed that no target
product could be observed in the absence of solvent (Table 1,
entry 9) and base (Table 2, entry 7) and the starting
material is recovered intact. Different cobalt sources were
tested. All cobalt sources showed similar effect (Table 3,
entries 1–3). Lower amounts of catalyst such as 50 mol %
and 25 mol % were tried, and they afforded the target
3
3
29c
thioureas in the presence of mercury or lead salts, or
iodine.34 5-Substituted 1H-tetrazoles have been prepared
also by the reaction between corresponding nitriles and
3
5
NaN via (3+2) cycloaddition using Zn(II) salts and ZnO
3
36
nanocrystals. Later, substituted tetrazoles have been
prepared by the reaction between substituted nitriles and
3
7
38
TMSN using TBAF and copper catalyst. Recently,
3
Ostrovskii and Myznikov have reviewed methodologies for
3
9
the synthesis of tetrazole derivatives. Often these methods
5
36

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Scheme 1
RNCS
Table 2. Base optimization for the synthesis
of phenylcyanamide (2a)*
3
1. NH , DMF, rt, 1 h
RNHCN
2a–n
2. CoSO4·H2O (25 mol %)
1a–n
NaOAc (1 equiv), rt, 2 h
Me
NHCN
NHCN
NHCN
NHCN
Me Me
2c (78%) 2d (94%)
2a (95%)
2b (70%)
NHCN
Me
NHCN
NHCN
NHCN
Entry
1
Base
Et
Yield, %
3
N
95
Me
OMe
2f (97%)
Cl
2g (82%)
F
2
3
4
5
6
7
Pyridine
NaOAc
No reaction
2e (85%)
2h (75%)
95
NaHCO
3
95
95
NO2
NHCN
NHCN
NHCN
2
Na HPO
4
NaOH
–
95
NC
MeOOC
No reaction
2i (40%)*
2j (72%)*
2k (42%)*
*
Reaction conditions: phenyl isothiocyanate (1a) (1 mmol), DMF (2 ml),
aqueous NH
rt, 2 h.
3 4 2
(2 ml), rt, 1 h, then CoSO ·H O (100 mol %), base (1 equiv),
NHCN
NHCN
l (88%)
Me
NHCN
2n (85%)
2
2m (83%)
product with complete conversion (Table 3, entries 4–5).
But unfortunately, the reaction produced target product in
moderate yield in the presence of 10 mol % catalyst
Table 3, entry 6). No reaction proceeded in the absence of
catalyst (Table 3, entry 7).
*
Temperature 70°C, K2CO3 as base.
(
Having established the optimal reaction conditions in
our hand, we explored the substrate scope (Scheme 1).
Since cobalt sulfate and NaOAc are cheaper than other
sources, they were used for the synthesis of cyanamides
Table 3. Catalyst optimization for the synthesis
of phenylcyanamide (2a)*
2
a–n. Substrates 1a–k having both electron-donating and
electron-withdrawing substituents on the aryl rings
produced respective target products in moderate to high
yield. The phenyl ring having electron-donating 4-methyl
and 4-methoxy groups, gave the respective aromatic
cyanamides 2d,f in 94–97% yield. The unsubstituted
phenyl isothiocyanate also gave target product 2a in
excellent yield.
The phenyl isothiocyanates having weak electron-
withdrawing groups, such as 4-chloro and 4-fluoro substi-
tuents, gave target products 2g,h in 82 and 75% yield,
respectively. Aryl isothiocyanates bearing strong electron-
withdrawing substituents, such as nitro, nitrile, and ester,
did not give target products 2i–k under optimized reaction
conditions. But it is interesting that the reactions could give
the target products in moderate yield upon at 70°C
Entry
Catalyst
CoCl ·6H
CoSO
Co(NO
Catalyst load, mol %
Yield, %
1
2
3
4
5
6
7
2
2
O
100
100
100
50
95
4
·H
2
O
95
temperature in the presence of strong base K
2
CO . Ortho-
3
3
)
2
·6H
2
O
95
or meta-methyl-substituted derivatives afforded respective
products 2b,c in 70 and 78% yield, respectively. Dimethyl-
substituted derivative gave product 2e in 80% yield.
Finally, we have also studied aliphatic isothiocyanates 1l–n.
The aliphatic substrates readily underwent the reaction to
produce target products 2l–n in 83–88% yields.
CoSO
CoSO
CoSO
4
4
4
·H
2
·H
2
·H
2
O
95
95
O
O
25
10
50
–
No reaction
After successful synthesis of cyanamides, we focused on
the construction of 1-aryl/alkyltetrazol-5-amines (Scheme 2).
*
Reaction conditions: phenyl isothiocyanate (1a) (1 mmol), DMF (2 ml),
aqueous NH (2 ml), rt, 1 h, then, catalyst, NaOAc (1 equiv), rt, 2 h.
3
5
37

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Scheme 2
Scheme 3
N N
N
1
. NH3, DMF, rt, 1 h
NHCN
Ph
N
N
N
N
N
PhN (1 equiv), CuI (5 mol %)
RNCS
R
3
2
. NaN3 (2 equiv), CoSO4·H2O (25 mol %)
NaOAc (1 equiv), rt, 2 h
Et3N (1 equiv), DMSO
1a–n
NH2
a–n
NH
3
rt, 3 h
R
R
2
a,e–i
5a–f
N
N N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
NH2
a (92%)
NH2
NH2
Me
NH
Me
N
NH
MeO
NH
3
3b (78%)
Me 3c (93%)
5
a (88%)
5c (80%)
Me
N
N
N
N
N
N
N
N
5
b (80%)
N
N
N
N
N
Ph
N
N
N
NH2
NH2
NH2
N
N
Ph
Ph
N
N
Me
Cl
Me
Me
MeO
N
N
3
d (93%)
3e (84%)
3f (95%)
N
NH
Cl
NH
5d (82%)
F
NH
5e (85%)
N
N
N
N
NO2
5f (70%)
N
N
N
NO2
N
N
N
N
N
NH2
NH2
NH2
F
place and starting materials were recovered intact. In order
to get the target product in this case, the reactions were
studied with various bases and at different temperatures.
Finally, it was found that products 3i–k could be synthe-
sized in lower yields at 70°C using strong base K
the other hand, phenyl ring having strong EWG like 4-CN,
-COOMe, and 2-NO gave also the corresponding isomeric
3
g (75%)
3h (78%)
3i (20%)*
N
N
N
N
N
N
N
N
2
CO
3
. On
NH2
NH2
NC
MeOOC
3
j (25%)*
3k (22%)*
4
2
products 4a–c in 34, 32, and 28% yields, respectively.
Alkyl isothiocyanates 1l–n readily underwent the reaction
to give respective target products 3l–n in 84–92% yields.
Expanding our research, we synthesized substituted
phenyltetrazolamines from aryl cyanamides and phenyl
azide through click reaction under reaction conditions
shown in Scheme 3. The click reaction of cyanamides
2a,e–i with phenyl azide gave the desired products 5a–f in
moderate to good yield.
N
N
N N
N
N
N
N
N
N
N
N
Me
NH2
NH2
3m (84%)
NH2
3
l (92%)
3n (88%)
N
N
N
N
N
N
N
N
N
HN
N
HN
N
HN
N
H
H
H
O2N
We proposed the mechanism of formation of aryl/alkyl-
cyanamides and tetrazoles from isothiocyanates (Scheme 4).
Isothiocyanate 1 reacts with ammonia in the presence of
solvent to give thiourea. Then cobalt coordinates to sulfur
4
a (28%)*
CN
b (34%)*
COOMe
4c (32%)*
41
4
in thiourea to give intermediate X. Desulfurization of inter-
42
*
Temperature 70°C, DMSO, K2CO3 as base.
mediate X afforded target product aryl/alkylcyanamide 2
via intermediate Y along with by-products CoS and
polysulfide (the extra sulfur might have converted into
sulfide)43 using base. Aryl/alkylcyanamide 2 undergoes
Phenyl isothiocyanate (1a) was chosen as model substrate
for the optimization of the synthesis. The best reaction
conditions were found to be as follows: aqueous ammonia,
nucleophilic addition of NaN
3
giving intermediate Q,
DMF as solvent, 25 mol % CoSO
4
·H
2
O, NaOAc (1 equiv),
which is in equilibrium with intermediate Z. Electron
density of the phenyl ring determines which intermediate
undergoes electrocyclization. While the phenyl ring contains
strong electron-withdrawing groups (4-CN, 4-COOMe, or
and NaN (2 equiv) at room temperature. Different isothio-
3
cyanates 1a–h,l–n have been explored under optimized
reaction conditions to give the final aryl/alkyltetrazol-
amines 3a–h,l–n in moderate to good yield.
2-NO ) it is possible to obtain target product 5-phenyl-
2
Aryl isothiocyanates 1d–f possessing electron-donating
groups on the phenyl ring (4-Me, 4-OMe, and 2,4-di-
methyl) were found to be more active than those having
electron-withdrawing functional groups (4-Cl, 4-F) on the
aryl ring. The reactions with compounds 1i–k having
aminotetrazole 4 via an intermediate Q, otherwise
phenyltetrazolamine 3 is formed via intermediate Z.
In summary, we have developed methodology for the
synthesis of aryl/alkylcyanamides and substituted tetrazoles
from isothiocyanates using cheap, readily available, and air-
stable cobalt source as catalyst under mild reaction
conditions. In this paper, we have also described the
4
-CN, 4-COOMe, or 2-NO
2
groups were performed under
optimized conditions, but unfortunately no reaction took
5
38

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Scheme 4
isothiocyanates have been prepared by our reported
procedure.18
Synthesis of cyanamides 2a–h,l–n (General method).
Aryl/alkyl isothiocyanate 1a–h,l–n (2 mmol) was added
slowly to stirred DMF (4–5 ml), followed by addition of
aqueous NH (2 ml, 2 mmol) at room temperature. The
3
reaction mixture was stirred for 1 h at room temperature.
Thiourea formation was monitored by TLC on silica gel.
Then CoSO
4
·H O (121 mg, 0.5 mmol, 25 mol %) was
2
added slowly followed by addition of NaOAc (164 mg,
mmol), and the reaction mixture was stirred for 2 h at
room temperature. During this time, black precipitate
CoS) appeared and was removed by centrifugation. The
2
(
clear solution was concentrated using rotary evaporator,
and the crude mixture was purified by column
chromatography using 10% EtOAc in hexane as eluent to
obtain a corresponding cyanamide as a target product.
1
5
Phenylcyanamide (2a). Yield 224 mg (95%), gum.
–
1
R 0.8 (EtOAc–hexane, 1:19). IR spectrum, ν, cm : 3350,
f
1
3
064, 2222 (C≡N), 1693, 1489, 1250, 1070, 909. H NMR
spectrum, δ, ppm (J, Hz): 7.37–7.33 (2H, m, H Ar); 7.29–
.25 (3H, m, H Ar); 5.81 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 137.8; 130.6; 130.1; 128.9; 114.3.
Found, %: C 71.28; H 5.09; N 23.62. C . Calculated, %:
C 71.17; H 5.12; N 23.71.
-Methylphenylcyanamide (2b).16 Yield 185 mg (70%),
7
7
H
6
N
2
2
–1
gum. R 0.8 (EtOAc–hexane, 1:19). IR spectrum, ν, cm :
f
3
1
7
412, 3074, 2867, 2223 (C≡N), 1690, 1435, 1379, 1229,
1
125, 1036, 941, 875. H NMR spectrum, δ, ppm (J, Hz):
.26–7.21 (1H, m, H Ar); 7.17–7.12 (2H, m, H Ar); 6.99
(
1H, d, J = 8.8, H Ar); 6.09 (1H, br. s, NH); 2.14 (3H, s,
13
CH
3
). C NMR spectrum, δ, ppm: 147.0; 139.6; 137.8;
1
34.5; 130.9; 129.9; 117.0; 20.6. Found, %: C 72.80; H 6.02;
N 21.12. C
8
H
8
N
2
. Calculated, %: C 72.70; H 6.10; N 21.20.
16
3
-Methylphenylcyanamide (2c). Yield 206 mg (78%),
–1
gum. R 0.8 (EtOAc–hexane, 1:19). IR spectrum ν, cm : 3423,
f
3
048, 2899, 2217 (C≡N), 1656, 1588, 1490, 1409, 1288,
1
applications of cyanamides using click reaction. This
strategy is very simple, general, and efficient.
1261, 1123, 1078, 823. H NMR spectrum, δ, ppm (J, Hz):
7.39 (1H, s, H Ar); 7.22 (1H, d, J = 8.8, H Ar); 6.97–6.93
13
(
2H, m, H Ar); 2.31 (3H, s, CH ). C NMR spectrum,
3
Experimental
δ, ppm: 139.6; 131.6; 131.3; 130.4; 120.3; 120.0; 115.4; 24.1.
IR spectra were recorded on a PerkinElmer Spectrum
Found, %: C 72.80; H 6.02; N 21.12. C
C 72.70; H 6.10; N 21.20.
8
H
8
N . Calculated, %:
2
1
13
one FT-IR spectrometer in KBr pellets. H and C NMR
spectra were recorded on a Varian 400 spectrometer (400
4-Methylphenylcyanamide (2d).15 Yield 248 mg (94%),
–1
and 100 MHz, respectively) in CDCl
a–l,n, 4a–c, 5a–f and in DMSO-d
3
for compounds 2a–n,
for compound 3m,
gum. R 0.8 (EtOAc–hexane, 1:19). IR spectrum ν, cm : 3378,
f
3
6
3097, 2896, 2835, 2200 (C≡N), 1601, 1580, 1503, 1252,
1
TMS was used as internal standard. Elemental analyses
were performed on a Flash EA 1112 series CHNS analyzer.
Melting points were determined using glass capillary tubes
and Buchi M-565 melting point apparatus. TLC was
performed using custom-made glass plates (8 cm × 5 cm),
Preparative column chromatography was performed using
Merck silica gel (60–120 mesh). A VKSI Medico Centri-
fuge machine was used for our experimental procedure for
1179, 1028, 927. H NMR spectrum, δ, ppm (J, Hz): 7.24–
7.17 (2H, m, H Ar); 7.01 (2H, d, J = 9.6, H Ar); 5.23 (1H,
13
br. s, NH); 2.33 (3H, s, CH ). C NMR spectrum, δ, ppm:
3
142.3; 132.4; 128.5; 124.6; 120.0; 21.3. Found, %:
C 72.79; H 6.09; N 21.12. C
H 6.10; N 21.20.
8
H
8
N . Calculated, %: C 72.70;
2
2,4-Dimethylphenylcyanamide (2e).15 Yield 248 mg
(85%), gum. R 0.8 (EtOAc–hexane, 1:19). IR spectrum
f
–1
the synthesis of cyanamides and tetrazoles. CoCl
CoSO ·H O, Co(NO ·6H O, Et N, pyridine, NaHCO
and NH
2
·6H
2
O,
3
ν, cm : 3368, 3077, 2888, 2863, 2212 (C≡N), 1635, 1599,
1
4
2
3
)
2
2
3
,
1513, 1491, 1287, 1215, 1027, 823. H NMR spectrum,
3
were purchased from Aldrich and used without
further purification. The solvents were purchased and dried
according to standard procedure prior to use. Aryl/alkyl
δ, ppm (J, Hz): 7.03 (1H, s, H Ar); 6.85 (1H, d, J = 7.6,
H Ar); 6.56 (1H, d, J = 8.0, H Ar); 5.61 (1H, br. s, NH);
13
2.30 (3H, s, CH
3
); 2.26 (3H, s, CH ). C NMR spectrum,
3
5
39

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
δ, ppm: 139.6; 137.8; 134.5; 130.9; 129.9; 119.9; 113.9;
0.6; 18.2 (CH ). Found, %: C 74.02; H 6.88; N 19.09.
. Calculated, %: C 73.94; H 6.89; N 19.16.
NH (2 ml, 2 mmol) at room temperature. The reaction
3
2
C
3
mixture was stirred for 1 h at room temperature. Thiourea
formation was monitored by TLC on silica gel. Then
9
H
10
N
2
16
4
-Methoxyphenylcyanamide (2f). Yield 287 mg (97%),
CoSO
4
·H O (121 mg, 0.5 mmol, 25 mol %) was added
2
–
1
gum. R
f
0.8 (EtOAc–hexane, 1:19). IR spectrum ν, cm : 3357,
slowly followed by addition of K
2
CO (276 mg, 2 mmol),
3
3
9
076, 2899, 2236 (C≡N), 1587, 1253, 1212, 1104, 1055,
and the reaction mixture was stirred for 2 h at 70°C. During
this time, black precipitate (CoS) appeared and was
removed by centrifugation. The clear solution was concen-
trated using rotary evaporator, and the crude mixture was
purified by column chromatography using 10% EtOAc in
hexane as eluent to obtain a corresponding cyanamide as a
target product.
1
41, 808. H NMR spectrum, δ, ppm (J, Hz): 7.18 (2H, d,
J = 8.8, H Ar); 7.02 (2H, d, J = 9.6, H Ar); 5.81 (1H, br. s,
1
3
NH); 3.33 (3H, s, OCH ). C NMR spectrum, δ, ppm:
3
1
64.1; 138.6; 131.9; 127.8; 121.7; 55.4. Found, %:
C 64.99; H 5.42; N 18.85. C
C 64.85; H 5.44; N 18.91.
8
H
8
N O. Calculated, %:
2
15
44
4
-Chlorophenylcyanamide (2g). Yield 249 mg (82%),
2-Nitrophenylcyanamide (2i). Yield 130 mg (40%),
1
5
44
white solid, mp 111–112°C (mp 110–111°C ). R
f
0.6
colorless solid, mp 134–135°C (mp 134–135°C ). R
f
0.5
–
1
–1
(
EtOAc–hexane, 1:19). IR spectrum, ν, cm : 3399, 3076,
(EtOAc–hexane, 1:4). IR spectrum, ν, cm : 3375, 3065,
2215 (C≡N), 1656, 1564, 1490, 1379, 1229, 1125, 1036,
2
214, 1670, 1505, 1250, 1114 (C≡N), 1023, 959, 817.
1
1
H NMR spectrum, δ, ppm (J, Hz): 7.22 (2H, d, J = 8.8,
941, 832. H NMR spectrum, δ, ppm (J, Hz): 8.40 (2H, d,
H Ar); 6.97–6.93 (2H, m, H Ar); 5.51 (1H, br. s, NH).
J = 9.2, H Ar); 7.65 (2H, d, J = 8.8, H Ar); 6.23 (1H, br. s,
1
3
13
C NMR spectrum, δ, ppm: 139.1; 132.5; 130.6; 129.1;
NH). C NMR spectrum, δ, ppm: 149.6; 141.6; 136.7;
1
17.1. Found, %: C 55.25; H 3.28; N 18.30. C
Calculated, %: C 55.10; H 3.30; N 18.36.
-Fluorophenylcyanamide (2h). Yield 204 mg (75%),
7
H
5
ClN
2
.
134.0; 132.1; 120.9; 115.1. Found, %: C 51.68; H 3.07;
7 5
N 25.70. C H N
N 25.76.
3
O . Calculated, %: C 51.54; H 3.09;
2
4
4
4
white solid, mp 124–126°C (mp 125–126°C ). R
f
0.6
EtOAc–hexane, 1:5). IR spectrum, ν, cm : 3359, 3056,
217 (C≡N), 1654, 1554, 1394, 1279, 1140, 939, 822.
4-Cyanophenylcyanamide (2j). Yield 206 mg (72%),
–
1
(
white solid, mp 141–142°C (mp 140–141°C). R 0.5
f
–1
2
(EtOAc–hexane, 1:5). IR spectrum, ν, cm : 3355, 3100,
1
H NMR spectrum, δ, ppm (J, Hz): 7.32–7.29 (2H, m, H Ar);
2256 (CN), 2217 (NHCN), 1667, 1526, 1348, 1277, 1078,
1
3
1
7
.22 (2H, d, J = 8.8, H Ar); 6.39 (1H, br. s, NH). C NMR
spectrum, δ, ppm: 154.7; 136.5; 126.2; 120.3; 114.9.
Found, %: C 61.92; H 3.67; N 20.52. C FN . Calculated, %:
C 61.76; H 3.70; N 20.58.
973, 892. H NMR spectrum, δ, ppm: 7.40–7.37 (2H, m,
H Ar); 7.34–7.31 (2H, m, H Ar); 5.29 (1H, br. s, NH).
13
7
H
5
2
C NMR spectrum, δ, ppm: 140.4; 132.7; 128.1; 120.0;
115.6; 115.0. Found, %: C 67.20; H 3.50; N 29.29.
. Calculated, %: C 67.12; H 3.52; N 29.35.
1
5
Benzylcyanamide (2l). Yield 232 mg (88%), gum.
C
8
H
5
N
3
–
1
15
R
f
0.8 (EtOAc–hexane, 1:19). IR spectrum, ν, cm : 3412,
Methyl 4-(cyanamido)benzoate (2k). Yield 148 mg
15
3
1
066, 2898, 2196 (C≡N), 1632, 1583, 1491, 1287, 1146,
(42%), white solid, mp 157–158°C (mp 156–157°C ).
–1
1
027, 826. H NMR spectrum, δ, ppm: 7.37–7.33 (2H, m,
R 0.5 (EtOAc–hexane, 1:4). IR spectrum, ν, cm : 3415,
f
H Ar); 7.30–7.27 (3H, m, H Ar); 5.61 (1H, br. s, NH); 4.40
3082, 2896, 2234 (C≡N), 1749, 1675, 1607, 1524, 1459,
13
1
(
2H, s, CH
2
). C NMR spectrum, δ, ppm: 139.6; 137.9;
1345, 1261, 1145, 1099, 870. H NMR spectrum, δ, ppm
1
30.3; 128.6; 118.0; 45.0. Found, %: C 72.78; H 6.08;
(J, Hz): 8.11 (2H, d, J = 9.6, H Ar); 7.38–7.33 (2H, m,
13
N 21.14. C
8
H
8
N
2
. Calculated, %: C 72.70; H 6.10; N 21.20.
H Ar); 5.91 (1H, br. s, NH); 3.80 (3H, s, CH ). C NMR
3
1
5
Cyclohexylcyanamide (2m). Yield 206 mg (83%),
spectrum, δ, ppm: 166.8; 142.8; 134.4; 130.5; 130.0; 121.7;
–1
gum. R
3
1
f
0.8 (EtOAc–hexane, 1:19). IR spectrum, ν, cm :
54.8. Found, %: C 61.50; H 4.56; N 15.84. C
Calculated, %: C 61.36; H 4.58; N 15.90.
9
H
8
N
2
2
O .
363, 3086, 2912, 2873, 2207 (C≡N), 1532, 1491, 1287,
1
146, 1027, 828. H NMR spectrum, δ, ppm: 5.24 (1H, br. s,
NH); 4.13–4.10 (1H, m, CH); 2.16–2.02 (2H, m, CH );
.94–1.75 (5H, m, CH ); 1.46–1.25 (3H, m, CH ).
C NMR spectrum, δ, ppm: 117.5; 48.5; 30.8; 25.2; 19.2.
Found, %: C 67.80; H 9.71; N 22.49. C . Calculated, %:
C 67.70; H 9.74; N 22.56.
Butylcyanamide (2n). Yield 167 mg (85%), gummy.
Synthesis of phenyltetrazolamines 3a–h,l–n (General
method). Aryl/alkyl isothiocyanate 1a–h,l–n (2 mmol) was
added slowly to stirred DMF (4–5 ml), followed by
2
1
2
2
1
3
addition of aqueous NH (2 ml, 2 mmol) at room tempe-
3
H N
7 12 2
rature. The reaction mixture was stirred for 1 h at room
temperature. Thiourea formation was monitored by TLC.
1
5
Then CoSO
4
·H O (121 mg, 0.5 mmol, 25 mol %) and
2
–
1
R
f
0.8 (EtOAc–hexane, 1:19). IR spectrum, ν, cm : 3423,
NaOAc (164 mg, 2 mmol) were added slowly over 5 min,
and the reaction mixture was stirred for 1 h. During this
period, a black-colored precipitate (CoS) was obtained. To
3
8
097, 2911, 2883, 2205 (C≡N), 1567, 1491, 1287, 1027,
1
08. H NMR spectrum, δ, ppm (J, Hz): 5.64 (1H, br. s,
NH); 3.92 (2H, t, J = 5.6, CH
2
); 1.73–1.60 (2H, m, CH
2
);
).
this solution, NaN (130 mg, 4 mmol) was added, and the
3
1
.35–1.21 (2H, m, CH
2
); 0.94 (3H, t, J = 7.2, CH
3
reaction mixture was stirred for 2 h. The progress of the
reaction was monitored by TLC (30% EtOAc in hexane).
After completion of the reaction, black-colored solid was
removed by centrifugation for 10 min. The resulted clear
solution was washed with EtOAc (3×10 ml) and water
(3×7 ml). Organic layer was concentrated using rotary
evaporator, and the crude mixture was purified by column
1
3
C NMR spectrum, δ, ppm: 115.4; 40.9; 30.8; 19.1; 14.2.
Found, %: C 61.30; H 10.24; N 28.46. C
lated, %: C 61.19; H 10.27; N 28.54.
5
H
10
2
N . Calcu-
Synthesis of cyanamides 2i–k (General method). Aryl/-
alkyl isothiocyanate 1i–k (2 mmol) was added slowly to
stirred DMF (4–5 ml), followed by addition of aqueous
5
40

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
3
4
chromatography using 30% EtOAc in hexane as eluent to
obtain a phenyltetrazolamine as a target product.
1-(4-Chlorophenyl)-1H-tetrazol-5-amine (3g). Yield
34
292 mg (75%), white solid, mp 178–179°C (mp 177–179°C ).
3
4
–1
1
-Phenyl-1H-tetrazol-5-amine (3a). Yield 296 mg
R
f
0.5 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3407,
3
4
(
92%), white solid, mp 167–168°C (mp 162–163°C ).
f
3399, 3076, 1670, 1505, 1250, 1114, 1046, 929, 802.
–
1
1
R
0.6 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3987,
H NMR spectrum, δ, ppm (J, Hz): 7.73 (2H, br. s, NH );
2
3
350, 3064, 1693, 1587, 1250, 1148, 1070, 909, 764.
7.39 (2H, d, J = 8.4, H Ar); 7.39 (2H, d, J = 8.8, H Ar).
1
13
H NMR spectrum, δ, ppm: 7.97 (2H, br. s, NH
.57 (2H, m, H Ar); 7.40–7.28 (2H, m, H Ar); 7.21–7.17
1H, m, H Ar). 13C NMR spectrum, δ, ppm: 137.8; 130.9;
30.6; 130.1; 128.9. Found, %: C 52.30; H 4.34; N 43.36.
. Calculated, %: C 52.17; H 4.38; N 43.45.
2
); 7.61–
C NMR spectrum, δ, ppm: 139.1; 137.2; 130.8; 129.9;
7
124.1. Found, %: C 43.14; H 3.07; N 35.74. C
Calculated, %: C 42.98; H 3.09; N 35.80.
7
H
6
ClN .
5
(
1
1-(4-Fluorophenyl)-1H-tetrazol-5-amine (3h). Yield
C
7
H
7
N
5
279 mg (78%), white solid, mp 181–182°C. R 0.7 (EtOAc–
f
39
–1
1
-(2-Methylphenyl)-1H-tetrazol-5-amine (3b). Yield
73 mg (78%), white solid, mp 177–178°C. R 0.7 (EtOAc–
hexane, 3:7). IR spectrum, ν, cm : 3375, 3352, 3065,
920, 1656, 1490, 1379, 1229, 1125, 1036, 941, 901.
hexane, 3:7). IR spectrum, ν, cm : 3397, 3359, 3056,
1
2
f
1654, 1554, 1459, 1352, 1235, 1140, 909, 822. H NMR
–
1
spectrum, δ, ppm (J, Hz): 7.37–7.33 (2H, m, H Ar); 6.81
13
2
(2H, d, J = 8.4, H Ar); 6.08 (2H, br. s, NH ). C NMR
2
1
H NMR spectrum, δ, ppm (J, Hz): 7.73 (2H, br. s, NH
2
);
spectrum, δ, ppm: 148.3; 136.5; 126.2; 120.3; 114.9.
Found, %: C 47.10; H 3.36; N 39.02. C FN . Calculated, %:
C 46.93; H 3.38; N 39.09.
1-Benzyl-1H-tetrazol-5-amine (3l). Yield 322 mg (92%),
7
.45 (2H, d, J = 8.0, H Ar); 7.23–7.10 (2H, m, H Ar); 2.34
7
H
6
5
13
(
3H, s, CH ). C NMR spectrum, δ, ppm: 147.0; 139.6; 137.8;
3
1
34.5; 130.9; 129.9; 126.0; 20.6. Found, %: C 54.96; H 5.16;
N 39.89. C
8
H
9
N
5
. Calculated, %: C 54.85; H 5.18; N 39.98.
white solid, mp 171–172°C. R 0.7 (EtOAc–hexane, 3:7).
f
–1
1
-(3-Methylphenyl)-1H-tetrazol-5-amine (3c). Yield
IR spectrum, ν, cm : 3390, 3368, 3077, 2888, 1632, 1599,
1
3
25 mg (93%), white solid, mp 178–179°C. R
f
0.7 (EtOAc–
hexane, 3:7). IR spectrum, cm : 3412, 3385, 3035, 2920,
867, 1690, 1435, 1379, 1229, 1125, 1036, 941, 901.
1513, 1491, 1287, 1215, 1027, 823. H NMR spectrum,
–
1
δ, ppm: 7.79 (2H, br. s, NH ); 7.42–7.31 (5H, m, H Ar);
2
2
4.72 (2H, s). 13C NMR spectrum, δ, ppm: 139.6; 137.9;
1
H NMR spectrum, δ, ppm: 7.73 (2H, br. s, NH
2
); 7.40–
130.3; 128.6; 121.0; 45.0. Found, %: C 54.95; H 5.16;
7
.37 (2H, m, H Ar); 7.33–7.31 (2H, m, H Ar); 2.32 (3H, s,
N 39.90. C
8
H
9
N . Calculated, %: C 54.85; H 5.18; N 39.98.
5
13
29c
CH
3
). C NMR spectrum, δ, ppm: 139.6; 131.6; 131.3;
1-Cyclohexyl-1H-tetrazol-5-amine (3m). Yield 280 mg
1
30.4; 120.3; 120.1; 115.4; 24.1. Found, %: C 54.95; H 5.15;
(84%), white solid, mp 161–162°C. R 0.7 (EtOAc–hexane,
f
–1
N 39.91. C
8
H
9
N
5
. Calculated, %: C 54.85; H 5.18; N 39.98.
3:7). IR spectrum, ν, cm : 3412, 3387, 3052, 2898, 2833,
34
1
1
-(4-Methylphenyl)-1H-tetrazol-5-amine (3d). Yield
1602, 1583, 1491, 1287, 1146, 1027, 826. H NMR
3
4
3
R
3
1
9
25 mg (93%), white solid, mp 179–180°C (mp 188°C ).
spectrum, δ, ppm: 6.95 (2H, br. s, NH
2
); 3.54–3.50 (1H, m,
);
). C NMR spectrum, δ, ppm: 140.0;
48.5; 30.8; 25.2; 19.2. Found, %: C 50.36; H 7.83; N 41.81.
. Calculated, %: C 50.28; H 7.84; N 41.88.
1-Butyl-1H-tetrazol-5-amine (3n). Yield 248 mg (88%),
–
1
f
0.6 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3387,
CH); 1.64–1.56 (4H, m, CH
2
); 1.43–1.34 (4H, m, CH
2
13
318, 3097, 2896, 2835, 1661, 1601, 1580, 1503, 1292,
0.96–0.92 (2H, m, CH
2
1
252, 1179, 1028, 927. H NMR spectrum δ, ppm (J, Hz):
.33 (2H, br. s, NH
2
); 7.50 (2H, d, J = 8.0, H Ar); 7.29 (2H,
C
7
H
13
N
5
1
3
d, J = 8.8, H Ar); 2.26 (3H, s, CH ). C NMR spectrum,
3
δ, ppm: 142.3; 132.4; 128.5; 124.6; 120.0; 21.3. Found, %:
white solid, mp 157–158°C. R 0.7 (EtOAc–hexane, 3:7).
f
–1
C 54.96; H 5.15; N 39.90. C
H 5.18; N 39.98.
8
H
9
N
5
. Calculated, %: C 54.85;
IR spectrum, ν, cm : 3357, 3323, 3046, 2893, 2854, 1621,
1
1491, 1287, 1146, 1027, 828. H NMR spectrum, δ, ppm:
39
1
-(2,4-Dimethylphenyl)-1H-tetrazol-5-amine (3e). Yield
6.96 (2H, br. s, NH
(2H, m, CH
2
); 3.75–3.70 (2H, m, CH
2
); 1.60–1.56
); 0.96–0.92 (3H, m,
3
17 mg (84%), white solid, mp 182–183°C. R
f
0.7 (EtOAc–
2
); 1.43–1.34 (2H, m, CH
2
–
1
13
hexane, 3:7). IR spectrum, ν, cm : 3423, 3392, 3048,
CH ). C NMR spectrum, δ, ppm: 148.0; 41.0; 30.8; 19.1;
3
2
1
900, 2842, 1656, 1578, 1490, 1409, 1288, 1261, 1078,
14.2. Found, %: C 42.62; H 7.83; N 49.56. C
Calculated, %: C 42.54; H 7.85; N 49.61.
5
H
11
5
N .
1
023, 823. H NMR spectrum, δ, ppm (J, Hz): 7.60 (2H,
br. s, NH
2
); 7.33 (1H, s, H Ar); 7.07 (1H, d, J = 8.0, H Ar);
Synthesis of aryltetrazolamines 3i–k and arylamino-
tetrazoles 4a–c (General method). Respective aryl isothio-
cyanate 1i–k (2 mmol) was added slowly to stirred DMSO
6
.96 (1H, d, J = 7.6, H Ar); 2.31 (3H, s, CH
3
3
); 2.30 (3H, s,
13
CH
). C NMR spectrum, δ, ppm: 141.6; 133.6; 133.3;
1
28.1; 120.3; 120.1; 116.3; 21.1; 16.1. Found, %: C 57.22;
(4–5 ml), followed by addition of aqueous NH (2 ml,
3
H 5.85; N 36.93. C
N 37.01.
9
H
11
N
5
Calculated, %: C 57.13; H 5.86;
2 mmol) at room temperature. The reaction mixture was
stirred for 1 h at room temperature. Thiourea formation was
39
1
-(4-Methoxyphenyl)-1H-tetrazol-5-amine (3f). Yield
monitored by TLC. Then CoSO
4
·H
2
O (121 mg, 0.5 mmol,
(276 mg, 2 mmol) were added
3
9
3
R
63 mg (95%), white solid, mp 185–187°C (mp 190–191°C ).
25 mol %) and K CO
2
3
–
1
f
0.6 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3402,
slowly over 5 min, and the reaction mixture was stirred for
1 h at 70°C. During this period, a black-colored precipitate
3
322, 3087, 2899, 1587, 1496, 1265, 1212, 1125, 941, 808.
1
H NMR spectrum, δ, ppm: 7.67 (2H, br. s, NH
2
); 7.17–
appeared, and NaN (260 mg, 4 mmol) was added to the
3
7
.14 (2H, m, H Ar); 6.86–6.82 (2H, m, H Ar); 3.80 (3H, s,
reaction mixture followed by stirring for additional 2 h.
The progress of the reaction was monitored by TLC (40%
EtOAc in hexane). After completion of the reaction, black-
colored solid was removed by centrifugation for 10 min.
13
OCH
3
). C NMR spectrum, δ, ppm: 164.1; 138.6; 131.9;
1
C
27.8; 121.7; 55.4. Found, %: C 50.41; H 4.71; N 36.55.
8
H
9
N
5
O . Calculated, %: C 50.26; H 4.74; N 36.63.
6
5
41

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
The resulted clear solution was washed with EtOAc (3×10 ml)
2890, 1720, 1680, 1631, 1525, 1472, 1255, 1136, 1032,
1
and water (3×7 ml). The organic layer was concentrated
using rotary evaporator and the crude mixture was purified by
column chromatography using 40% EtOAc in hexane as
eluent to obtain the target product.
854. H NMR spectrum, δ, ppm (J, Hz): 8.09 (2H, d,
J = 9.6, H Ar); 7.71 (1H, br. s, NH tetrazole); 6.70–6.66
(2H, m, H Ar), 6.13 (1H, br. s, ArNH); 3.80 (3H, s, OCH ).
3
1
3
C NMR spectrum, δ, ppm: 165.7; 159.9; 147.3; 130.5;
130.0; 129.5; 54.8. Found, %: C 49.46; H 4.12; N 31.89.
. Calculated, %: C 49.31; H 4.14; N 31.95.
3
4
1
-(2-Nitrophenyl)-1H-tetrazol-5-amine (3i). Yield
34
8
2 mg (20%), white solid, mp 151–152°C (mp 161–162°C ).
C
9
H
9
N
5
O
2
–
1
R
f
0.5 (EtOAc–hexane, 4:6). IR spectrum, ν, cm : 3415,
Synthesis of diphenyl tetrazolamines 5a–f (General
3
1
(
382, 3082, 1721, 1675, 1617, 1571, 1504, 1345, 1261,
method). Aryl cyanamide 2a,e–i (1 mmol) was added
1
145, 1099, 870. H NMR spectrum, δ, ppm (J, Hz): 8.11
slowly to stirred DMSO (4 ml), followed by addition of
1H, d, J = 8.8, H Ar); 7.38–7.33 (1H, m, H Ar); 6.81 (1H,
phenyl azide (1 mmol) at room temperature. Then Et N
3
d, J = 8.4, H Ar); 6.72–6.68 (1H, m, H Ar); 6.07 (2H, br. s,
(121 mg, 1 mmol) and CuI (9.9 mg, 0.05 mol, 5 mol %)
were added. The whole reaction mixture was stirred for 3 h.
The resulting clear solution was washed with EtOAc
(3×10 ml) and water (3×7 ml), the organic layer was
concentrated using rotary evaporator, and the crude residue
was purified by column chromatography using 30% EtOAc in
hexane as eluent to obtain a diphenyltetrazolamine as a
target product.
13
NH ). C NMR spectrum, δ, ppm: 149.6; 141.6; 136.7;
2
1
34.0; 132.1; 126.1; 122.2. Found, %: C 40.93; H 2.91;
N 40.70. C
N 40.76.
7
H
6
N
6
O . Calculated, %: C 40.78; H 2.93;
2
4
-(5-Amino-1H-tetrazol-1-yl)benzonitrile (3j). Yield
0.5 (EtOAc–
hexane, 4:6). IR spectrum, ν, cm : 3389, 3355, 3074,
217, 1667, 1526, 1348, 1245, 1093, 973, 892, 850.
9
3 mg (25%), white solid, mp 157–158°C. R
f
–
1
2
N,1-Diphenyl-1H-tetrazol-5-amine (5a). Yield 208 mg
1
H NMR spectrum, δ, ppm: 7.79–7.75 (2H, m, H Ar); 7.63–
(88%), white solid, mp 198–199°C. R 0.7 (EtOAc–hexane,
f
1
3
–1
7
.61 (2H, m, H Ar); 6.57 (2H, br. s, NH
spectrum, δ, ppm: 140.4; 134.0; 132.7; 120.0; 115.6; 115.0.
Found, %: C 51.71; H 3.23; N 45.06. C . Calculated, %:
C 51.61; H 3.25; N 45.14.
Methyl 4-(5-amino-1H-tetrazol-1-yl)benzoate (3k). Yield
6 mg (22%), white solid, mp 156–157°C. R 0.5 (EtOAc–
hexane, 4:6). IR spectrum, ν, cm : 3415, 3392, 3082,
752, 1678, 1607, 1504, 1438, 1261, 1145, 1099, 872.
2
). C NMR
3:7). IR spectrum, ν, cm : 3426, 3097, 1645, 1631, 1567,
1
1512, 1491, 1287, 1250, 1146, 1027, 896. H NMR
8
H
6
N
6
spectrum, δ, ppm (J, Hz): 7.54–7.41 (7H, m, H Ar); 6.85
13
(3H, d, J = 8.8, H Ar); 6.02 (1H, br. s, NH). C NMR
spectrum, δ, ppm: 138.4; 132.8; 131.6; 129.2; 128.5; 128.1;
121.5; 120.9; 117.6. Found, %: C 65.90; H 4.65; N 29.45.
9
f
–
1
C
13
H
11
N
5
. Calculated, %: C 65.81; H 4.67; N 29.52.
N-(2,4-Dimethylphenyl)-1-phenyl-1H-tetrazol-5-amine
(5b). Yield 212 mg (80%), white solid, mp 192–193°C.
1
1
H NMR spectrum, δ, ppm (J, Hz): 8.11 (2H, d, J = 9.6,
H Ar); 7.38–7.33 (2H, m, H Ar); 6.77 (2H, br. s, NH );
). C NMR spectrum, δ, ppm: 166.8;
–
1
2
R 0.7 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3424,
f
1
3
3
1
.80 (3H, s, OCH
3
3054, 2896, 2855, 1651, 1602, 1580, 1503, 1358, 1252,
1
42.8; 134.4; 130.5; 130.0; 129.5; 54.8. Found, %: C 49.47;
1179, 1056, 1028, 898. H NMR spectrum, δ, ppm (J, Hz):
H 4.13; N 31.89. C
H 4.14; N 31.95.
9
H
9
N
5
O
2
. Calculated, %: C 49.31;
7.68–7.27 (5H, m, H Ar); 7.09 (1H, s, H Ar); 6.84 (2H, d,
J = 7.2, H Ar); 5.90 (1H, br. s, NH); 2.47 (3H, s, CH );
3
3
9
13
N-(2-Nitrophenyl)-1H-tetrazol-5-amine (4a). Yield
2.34 (3H, s, CH ). C NMR spectrum, δ, ppm: 143.4;
3
1
15 mg (28%), white solid, mp 147–148°C. R
f
0.7 (EtOAc–
hexane, 3:7). IR spectrum, ν, cm : 3399, 3297, 3101,
720, 1656, 1611, 1554, 1432, 1212, 1156, 1032, 832.
135.3; 134.8; 134.1; 133.2; 131.4; 130.0; 129.9; 127.1;
125.5; 121.4; 21.0; 20.9. Found, %: C 68.00; H 5.67; N 26.33.
–
1
1
C
15
H
15
N . Calculated, %: C 67.90; H 5.70; N 26.40.
5
1
H NMR spectrum, δ, ppm (J, Hz): 8.27 (1H, br. s, NH
tetrazole); 7.92 (1H, d, J = 8.0, H Ar); 6.70–6.66 (1H, m,
H Ar); 7.65–7.61 (1H, m, H Ar); 7.45–7.42 (1H, m, H Ar);
N-(4-Methoxyphenyl)-1-phenyl-1H-tetrazol-5-amine
(5c). Yield 213 mg (80%), white solid, mp 199–200°C.
–
1
R 0.7 (EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3426,
f
1
3
6
1
.20 (1H, br. s, ArNH). C NMR spectrum, δ, ppm: 161.5;
3082, 2900, 1657, 1612, 1586, 1514, 1448, 1325, 1216, 1145,
1
46.5; 137.7; 136.9; 125.6; 122.2; 116.8. Found, %:
1099, 829. H NMR spectrum, δ, ppm (J, Hz): 7.80 (2H, d,
C 40.93; H 2.91; N 40.69. C
C 40.78; H 2.93; N 40.76.
7
H
6
N
6
O
2
. Calculated, %:
J = 7.6, H Ar); 7.54–7.47 (5H, m, H Ar); 6.85 (2H, d, J = 8.4,
1
3
H Ar); 6.02 (1H, br. s, NH); 3.77 (3H, s, OCH ). C NMR
3
4
-[(1H-Tetrazol-5-yl)amino]benzonitrile (4b). Yield
spectrum, δ, ppm: 154.7; 142.9; 133.7; 132.6; 129.7; 129.5;
1
26 mg (34%), white solid, mp 154–155°C. R
f
0.7 (EtOAc–
129.3; 126.1; 121.4; 55.0. Found, %: C 63.05; H 4.88; N 26.14.
–
1
hexane, 3:7). IR spectrum, ν, cm : 3046, 2221 (CN), 1692,
C
14
H
13
N O. Calculated, %: C 62.91; H 4.90; N 26.20.
5
1
1
621, 1567, 1481, 1277, 1136, 1027, 854. H NMR
N-(4-Chlorophenyl)-1-phenyl-1H-tetrazol-5-amine (5d).
spectrum, δ, ppm (J, Hz): 7.72 (1H, br. s, NH tetrazole);
Yield 222 mg (82%), white solid, mp 178–179°C. R 0.7
f
–1
7
6
1
.07 (2H, d, J = 8.4, H Ar); 6.97 (2H, d, J = 8.8, H Ar);
(EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3420, 3090,
1
3
.15 (1H, br. s, ArNH). C NMR spectrum, δ, ppm: 159.6;
1645, 1601, 1590, 1489, 1125, 1036, 941, 854, 788, 612.
1
41.6; 136.7; 134.0; 126.1; 116.2. Found, %: C 51.72;
H NMR spectrum, δ, ppm (J, Hz): 7.77–7.48 (4H, m,
H 3.22; N 45.06. C
N 45.14.
8
H
6
N
6
. Calculated, %: C 51.61; H 3.25;
H Ar); 7.25 (3H, d, J = 6.8, H Ar); 7.16 (2H, d, J = 8.8,
H Ar); 5.96 (1H, br. s, NH). 13C NMR spectrum, δ, ppm;
141.7; 137.0; 132.3; 128.3; 128.1; 127.8; 127.0; 124.7;
Methyl 4-[(1H-tetrazol-5-yl)amino]benzoate (4c). Yield
1
40 mg (32%), white solid, mp 152–153°C. R
f
0.7 (EtOAc–
118.1. Found, %: C 57.62; H 3.69; N 25.72. C13
H
10ClN .
5
–
1
hexane, 3:7). IR spectrum, ν, cm : 3387, 3362, 3096,
Calculated, %: C 57.47; H 3.71; N 25.78.
5
42

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
N-(4-Fluorophenyl)-1-phenyl-1H-tetrazol-5-amine (5e).
Yield 217 mg (85%), white solid, mp 181–182°C. R 0.7
Commun. 1986, 16, 1823. (c) Hu, N. X.; Aso, Y.; Otsubo, T.;
Ogura, F. Chem. Lett. 1985, 14, 603. (d) Sato, R.; Itoh, K.;
Nishina, H.; Goto, T.; Saito, M. Chem. Lett. 1984, 13, 1913.
f
–
1
(
EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3389, 3088,
1
1. Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V.
1
9
693, 1612, 1543, 1489, 1421, 1400, 1239, 1121, 1070,
Synthesis 2000, 1148.
1
27. H NMR spectrum, δ, ppm (J, Hz): 7.64–7.33 (7H, m,
1
2. Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
H Ar); 7.12 (2H, d, J = 8.0, H Ar); 5.98 (1H, br. s, NH).
2
002, 41, 1780.
Found, %: C 61.32; H 3.93; N 27.37. C13
Calculated, %: C 61.17; H 3.95; N 27.44.
H
10FN .
5
1
3. Chaudhari, K. H.; Mahajan, U. S.; Bhalerao, D. S.;
Akamanchi, K. G. Synlett 2007, 2815.
N-(2-Nitrophenyl)-1-phenyl-1H-tetrazol-5-amine (5f).
14. Wong, F. F.; Chen, C.-Y.; Yeh, M.-Y. Synlett 2006, 559.
1
1
1
5. Chen, C.-Y.; Wong, F. F.; Huang, J.-J.; Lin, S.-K.; Yeh, M.-Y.
Tetrahedron Lett. 2008, 49, 6505.
Yield 197 mg (70%), white solid, mp 174–175°C. R 0.7
f
–
1
(
EtOAc–hexane, 3:7). IR spectrum, ν, cm : 3417, 3087,
6. Ghosh, H.; Yella, R.; Ali, A. R.; Sahoo, S. K.; Patel, B. K.
Tetrahedron Lett. 2009, 50, 2407.
1
1
667, 1654, 1612, 1567, 1521, 1458, 1394, 1332, 1265,
1
104, 1080, 941. H NMR spectrum, δ, ppm (J, Hz): 8.92
7. (a) Saha, P.; Ali, M. A.; Ghosh, P.; Punniyamurthy, T. Org.
Biomol. Chem. 2010, 8, 5692. (b) Cahiez, G.; Moyeux, A.
Chem. Rev. 2010, 110, 1435. (c) Gosmini, C.; Bégouin, J.-M.;
Moncomble, A. Chem. Commun. 2008, 3221. (d) Amatore, M.;
Gosmini, C. Angew. Chem., Int. Ed. 2008, 47, 2089.
(e) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M.
J. Am. Chem. Soc. 2009, 131, 11949. (f) Bégouin, J.-M.;
Gosmini, C. J. Org. Chem. 2009, 74, 3221. (g) Cahiez, G.;
Chaboche, C.; Duplais, C.; Moyeux, A. Org. Lett. 2009, 11,
(
1H, br. s, NH); 8.09–8.06 (2H, m, H Ar); 7.78–7.75 (2H,
m, H Ar); 7.25 (2H, d, J = 8.0, H Ar); 7.07–7.01 (3H, m,
13
H Ar). C NMR spectrum, δ, ppm: 152.8; 146.3; 143.8;
1
41.8; 137.3; 129.6; 127.1; 125.6; 121.0; 120.7; 118.0.
Found, %: C 55.49; H 3.53; N 29.70. C13
H
10
N
6
O .
2
Calculated, %: C 55.32; H 3.57; N 29.77.
Supplementary information file containing 1H and
C NMR spectra of all synthesized compounds is available at
2
77. (h) Gomes, P.; Gosmini, C.; Périchon, J. Org. Lett. 2003,
1
3
5
, 1043. (i) Korn, T. J.; Schade, M. A.; Wirth, S.; Knochel, P.
the journal website at http://link.springer.com/journal/10593.
Org. Lett. 2006, 8, 725. (j) Punniyamurthy, T.; Velusamy, S.;
Iqbal, J. Chem. Rev. 2005, 105, 2329. (k) Wong, Y.-C.;
Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613.
References
1
. (a) Sandler, S. R.; Karo, W. Organic Functional Group
Preparations; Blomquist, A. T.; Wasserman, H., Eds.;
Academic Press: New York, 1972, Vol. 3, p. 1. (b) Sandler, S. R.;
Karo, W. Organic Functional Group Preparations;
Blomquist, A. T., Ed.; Academic Press: New York, 1971,
Vol. 2, p. 1. (c) Jia, Q.; Cai, T.; Haung, M.; Li, H.; Xian, M.;
Poulos, T. L.; Wang, P. G. J. Med. Chem. 2003, 46, 2271.
(
l) Teo, Y.-C.; Chua, G.-L. Chem.–Eur. J. 2009, 15, 3072.
1
1
2
8. Seelam, M.; Shaikh, B.; Kammela, P. R. Synth. Commun.
016, 46, 1759.
9. (a) Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499.
b) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
0. (a) Ek, F.; Wistrand, L.-G.; Frejd, T. Tetrahedron 2003, 59,
759. (b) Flippin, L. A. Tetrahedron Lett. 1991, 32, 6857.
c) Rhonnstad, P.; Wensbo, D. Tetrahedron Lett. 2002, 43,
2
(
6
(
d) Cai, T.; Xian, M.; Wang, P. G. Bioorg. Med. Chem. Lett.
(
3
2
002, 12, 1507. (e) Kumar, V.; Kaushik, M. P.; Mazumdar, A.
137.
Eur. J. Org. Chem. 2008, 1910.
2
1. Shin, K. J.; Koo, K. D.; Yoo, K. H.; Kim, D. C.; Kim, D. J.;
Park, S. W. Bioorg. Med. Chem. Lett. 2000, 10, 1421.
2
. (a) Nickon, A.; Fieser, L. F. J. Am. Chem. Soc. 1952, 74,
5
566. (b) McCall, J. M.; TenBrink, R. E.; Ursprung, J. J.
2
2. Girijavallabhan, V. M.; Pinto, P. A.; Ganguly, A. K.;
Versace, R. W. Eur. Patent EP0274867; Chem. Abstr. 1989,
J. Org. Chem. 1975, 40, 3304.
3
. (a) Hu, L.-Y.; Guo, J.; Magar, S. S.; Fischer, J. B.; Burke-
Howie, K. J.; Durant, G. J. J. Med. Chem. 1997, 40, 4281.
110, 23890.
2
3. (a) Akimoto, H.; Ootsu, K.; Itoh, F. Eur. Patent EP0530537;
Chem. Abstr. 1993, 119, 226417. (b) Taveras, A. G.;
Mallams, A. K.; Afonso, A. WO Patent 9811093; Chem.
Abstr. 1998, 128, 230253.
(
1
b) Robinson, J. R.; Brown, W. H. Can. J. Chem. 1951, 29,
069.
4
. Stephens, R. W.; Domeier, L. A.; Todd, M. G.; Nelson, V. A.
Tetrahedron Lett. 1992, 33, 733.
2
4. Yamazaki, K.; Hasegawa, H.; Umekawa, K.; Ueki, Y.; Ohashi, N.;
Kanaoka, M. Bioorg. Med. Chem. Lett. 2002, 12, 1275.
5. Häbich, D. Synthesis 1992, 358.
5
. (a) Donetti, A.; Omodei-Sale', A.; Mantegani, A. Tetrahedron
Lett. 1969, 10, 3327. (b) Pala, G.; Mantegani, A.; Zugna, E.
Tetrahedron 1970, 26, 1275. (c) Currie, A. C.; Newbold, G. T.;
Spring, F. S. J. Chem. Soc. 1961, 4693.
2
2
6. Vieira, E.; Huwyler, S.; Jolidon, S.; Knoflach, F.; Mutel, J.;
Wichmann, J. Bioorg. Med. Chem. Lett. 2005, 15, 4628.
7. (a) Robichaud, L. J.; Stewart, S. F.; Adolphson, R. L. Int. J.
Immunopharmacol. 1987, 9, 41. (b) Ford, R. E.; Knowles, P.;
Lunt, E.; Marshall, S. M.; Penrose, A. J.; Ramsden, C. A.;
Summers, A. J. H.; Walker, J. L.; Wright, D. E. J. Med. Chem.
6
7
. (a) Gilman, A. G.; Goodman, L. S.; Rall, T. W.; Murad, F.;
Goodman and Gilman's The Pharmacological Basis of
Therapeutics; Pergamon Press: New York, 1990, 8th ed.
2
(
b) Saneyoshi, M.; Tokuzen, R.; Maeda, M.; Fukuoka, F.
Chem. Pharm. Bull. 1968, 16, 505.
1
986, 29, 538.
. (a) Wheland, R. C.; Martin, E. L. J. Org. Chem. 1975, 40,
2
8. (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier:
New York, 1996, Vol. 4, p. 621. (b) Burger, A. Prog. Drug
Res. 1991, 37, 287. (c) Voitekhovich, S. V.; Gaponik, P. N.;
Ivashkevich, O. A. Russ. Chem. Rev. 2002, 71, 721. [Usp.
Khim. 2002, 71, 819.] (d) Thornber, C. W. Chem. Soc. Rev. 1979,
3
101. (b) Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.;
Hamilton, G. S. Org. Lett. 2000, 2, 795. (c) Van Leusen, A. M.;
Jagt, J. C. Tetrahedron Lett. 1970, 11, 967. (d) Hughes, T. V.;
Hammond, S. D.; Cava, M. P. J. Org. Chem. 1998, 63, 401.
(
e) Davis, W. A.; Cava, M. P. J. Org. Chem. 1983, 48, 2774.
8
9
1
. Kaupp, G.; Schmeyers, J.; Boy, J. Chem.–Eur. J. 1998, 4, 2467.
8
, 563. (e) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.;
. Braun, J. V. Ber. Dtsch. Chem. Ges. 1900, 33, 1438.
0. (a) Saraie, T.; Ishiguro, T.; Kawashima, K.; Morita, K.
Tetrahedron Lett. 1973, 14, 2121. (b) Mai, K.; Patil, G. Synth.
Malhotra, R. K. Prog. Med. Chem. 1980, 17, 151. (f) Butler, R. N.
In Advances in Heterocyclic Chemistry; Katritzky, A. R.;
Boulton, A. J., Eds.; Academic Press, Inc.: Orlando, 1977,
5
43

Chemistry of Heterocyclic Compounds 2018, 54(5), 535–544
Vol. 21, p. 323. (g) Lipinski, C. A. Annu. Rep. Med. Chem. 2006, 36, 1809. (c) Lakshmi Kantam, M.; Shiva Kumar, K. B.;
1
986, 21, 283.
Phani Raja, K. J. Mol. Catal. A: Chem. 2006, 247, 186.
37. Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccoro, L.
J. Org. Chem. 2004, 69, 2896.
2
3
9. (a) Jensen, K. A.; Holm, A.; Rachlin, S. Acta Chem. Scand.
1
966, 20, 2795. (b) Percival, D. F.; Herbst, R. M. J. Org.
Chem. 1957, 22, 925. (c) Finnegan, W. G.; Henry, R. A.;
Lieber, E. J. Org. Chem. 1953, 18, 779.
38. Jin, T.; Kitahara, F.; Kamijo, S.; Yamamoto, Y. Tetrahedron
Lett. 2008, 49, 2824.
0. (a) Moderhack, D.; Goos, K.-H.; Preu, L. Chem. Ber. 1990,
39. (a) Ostrovskii, V. A.; Popova, E. A.; Trifonov, R. E. In
Advances in Heterocyclic Chemistry; Scriven, E. F. V.;
Ramsden, C. A., Eds.; Academic Press, Inc.: Orlando, 2017,
Vol. 123, p. 1. (b) Myznikov, L. V.; Vorona, S. V.;
Artamonova, T. V.; Zevatskii, Y. E. Chem. Heterocycl.
Compd. 2016, 52, 887. [Khim. Geterotsikl. Soedin. 2016, 52,
887.]
1
23, 1575. (b) Garbrecht, W. L.; Herbst, R. M. J. Org. Chem.
1
953, 18, 1014. (c) Herbst, R. M.; Roberts, C. W.; Harvill, E. J.
J. Org. Chem. 1951, 16, 139. (d) Marchalin, M.; Martvoň, A.
Collect. Czech. Chem. Commun. 1980, 45, 2329.
1. (a) Klich, M.; Teutsch, G. Tetrahedron 1986, 42, 2677.
3
(
b) Barlin, G. B. J. Chem. Soc. B 1967, 641.
3
3
2. Erle, H.–E. Liebigs Ann. Chem. 1982, 201.
40. Nasrollahzadeh, M.; Habibi, D.; Shahkarami, Z.; Bayat, Y.
Tetrahedron 2009, 65, 10715.
3. (a) Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237.
(
b) Yu, Y.; Ostresh, J. M.; Houghten, R. A. Tetrahedron Lett.
41. (a) Ali, A. R.; Ghosh, H.; Patel, B. K. Tetrahedron Lett. 2010,
51, 1019. (b) Guin, S.; Rout, S. K.; Gogoi, A.; Nandi, S.;
Ghara, K. K.; Patel, B. K. Adv. Synth. Catal. 2012, 354, 2757.
42. (a) Sahoo, S. K.; Jamir, L.; Guin, S.; Patel, B. K. Adv. Synth.
Catal. 2010, 352, 2538. (b) Jamir, L.; Sinha, U. P.; Nath, J.;
Patel, B. K. Synth. Commun. 2012, 42, 951. (c) Nath, J.;
Patel, B. K.; Jamir, L.; Sinha, U. B.; Satyanarayana, K. V. V. V.
Green Chem. 2009, 11, 1503.
2
004, 45, 7787.
3
3
4. Yella, R.; Khatun, N.; Rout, S. K.; Patel, B. K. Org. Biomol.
Chem. 2011, 9, 3235.
5. (a) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66,
7
945. (b) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4,
525. (c) Himo, F.; Demko, Z. P.; Noodleman, L.;
2
Sharpless, K. B. J. Am. Chem. Soc. 2002, 124, 12210.
(
d) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B.
43. (a) Pinapati, S.; Mandapati, U.; Rudraraju, R. R.
ChemistrySelect 2017, 2, 295. (b) Ramana, T.;
Punniyamurthy, T. Chem.–Eur. J. 2012, 18, 13279.
44. Skinner, W. A.; Gram, H. F.; Greene, M. O.; Greenberg, J.;
Baker, B. R. J. Med. Pharm. Chem. 1960, 2, 299.
J. Am. Chem. Soc. 2003, 125, 9983.
3
6. (a) Lakshmi Kantam, M.; Shiva Kumar, K. B.; Sridhar, C.
Adv. Synth. Catal. 2005, 347, 1212. (b) Lakshmi Kantam, M.;
Balasubrahmanyam, V.; Shiva Kumar, K. B. Synth. Commun.
5
44