Ammonium acetate mediated synthesis of 5-substituted 1H-tetrazoles

Article abstract of DOI:10.1007/s13738-012-0080-9

Synthesis of 5-substituted 1H-tetrazoles was achieved by [3+2] cycloaddition of nitriles and sodium azide in the presence of ammonium acetate. The reaction proceeds in situ formation of ammonium azide. Present protocol has advantage of good to excellent yields, short reaction times and simple isolation of products than reported methods. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-012-0080-9

J IRAN CHEM SOC (2012) 9:799–803
DOI 10.1007/s13738-012-0080-9
ORIGINAL PAPER
Ammonium acetate mediated synthesis of 5-substituted
1H-tetrazoles
Dipak R. Patil
Dipak S. Dalal
•
Mukesh B. Deshmukh
•
Received: 16 November 2011 / Accepted: 10 April 2012 / Published online: 24 April 2012
Ó Iranian Chemical Society 2012
Abstract Synthesis of 5-substituted 1H-tetrazoles was
achieved by [3?2] cycloaddition of nitriles and sodium
azide in the presence of ammonium acetate. The reaction
proceeds in situ formation of ammonium azide. Present
protocol has advantage of good to excellent yields, short
reaction times and simple isolation of products than
reported methods.
removal of zinc salts from acidic products. Earlier
reported methods for the synthesis of 5-substituted
1H-tetrazole suffer from drawback such as the use of strong
lewis acids or expensive and toxic metals. In order to
overcome these difficulties, several pathways have been
developed such as use of metal complexes [9, 10] as a cat-
alyst, use of TMSN –TBAF [11], micellar media and ionic
3
liquids [12, 13], FeCl –SiO [14], Zn/Al-hydrocalcite [15],
3
2
Keywords 5-Substituted 1H-tetrazole ꢀ Nitrile ꢀ NaN ꢀ
Fe O [16], Zn hydroxyapatite [17], Sb O [18], NaH-
2 3 2 3
3
Ammonium acetate ꢀ [3?2] Cycloaddition
SO ꢀSiO or I [19], CuFe O [20], mesoporous ZnS nano-
4
2
2
2 4
spheres [21], use of clay-montmorillonite K-10, kaoline [22],
use of various azide salts [23], microwave irradiation [24],
Introduction
Et NꢀHCl in nitrobenzene under microwave irradiation [25]
3
and use of various amine salts in aromatic solvents [26].
However, some methods still require long reaction times to
achieve reasonable yields and tedious purification of
products.
Tetrazoles are valuable heterocycles having wide range
of applications [1, 2] in the field of material science
including photography, information recording system and
explosives. They behave as metabolically stable surro-
gates for carboxylic acid groups [3], important precursors
for variety of nitrogen containing heterocycles and in
coordination chemistry as ligands [4, 5]. Several syn-
theses of 5-substituted 1H-tetrazoles have been reported
through [3?2] cycloaddition of nitriles and sodium
azide. Recently, Sharpless and co-workers [6–8] reported
a ‘‘click’’ chemistry approach for the synthesis of tetra-
An important objective of chemistry is to adopt clas-
sical process so that pollution effects are kept to a
minimum with both reduction in energy and consumption
of raw materials. Ammonium acetate is an example of
salts having orthorhombic crystals that melts at low
temperature. Quality like cheap and wide commercial
availability, safe and easy handling, fair solubility in
water and organic solvents, its nontoxic and ecofriendly
nature makes ammonium acetate a popular reagent and
effective alternative to gaseous ammonia [27]. In some
cases, ammonium acetate shows excellent catalytic
activities [28]. Ammonium acetate is an efficient reagent
in low and high boiling organic solvents at room tem-
perature as well as at refluxing condition. Its high effi-
ciency as reagent in water, ionic liquid, microwave
promoted solventless synthesis and supercritical water
gives it a unique position in present scenario of green
chemistry [27].
zoles by [3?2] cycloaddition of nitriles and NaN using
3
stoichiometric amounts or 50 mol% of Zn(II) salts, but
still requires tedious time consuming steps such as
D. R. Patil ꢀ M. B. Deshmukh ꢀ D. S. Dalal (&)
Department of Organic Chemistry, North Maharashtra
University, Jalgaon 425 001, Maharashtra, India
e-mail: dsdalal2007@gmail.com
123

8
00
J IRAN CHEM SOC (2012) 9:799–803
Experimental
Table 1 Synthesis of 5-phenyl 1H-tetrazole under various reaction
conditions at 120 °C
a
Materials
Entry
NaN
mmol)
3
NH
(mmol)
4
OAc
Solvent
Time
(h)
Yield
(%)
(
All reagents were purchased from Merck and Spectrochem
and used without further purification. All yields refer to
isolated products after purification. Products were charac-
terized by comparing the physical data with those of
authentic samples and spectroscopic (IR and NMR) data.
The NMR spectra were recorded on a Bruker Avance-II
spectrophotometer operating at 200 and 500 MHz instru-
ment. The spectra were measured in DMSO relative to
TMS (0.00 ppm). IR spectra were recorded on an IR
affinity model-I spectrophotometer. Mass spectra were
recorded on an LC–MS (Q-TOFF), LC operating at an
ionization potential of 70 eV. Melting points were deter-
mined in open capillaries with a Lab Hosp melting point
apparatus. TLC was performed on silica-gel polygram
SILG/UV 254 plates.
1
2
3
4
5
6
7
8
9
10
13
15
15
15
15
15
15
15
15
15
10
13
15
–
DMF
DMF
DMF
DMF
3
75
78
85
–
2.5
2.25
24
12
6
15
15
15
15
15
15
15
H
2
O
–
DMSO
Acetic acid
THF
50
20
Trace
30
38
–
16
12
15
12
12
Ethanol
PEG-400
–
1
1
0
1
Reaction condition: benzonitrile (10 mmol)
a
Isolated yield
Table 2 Synthesis of 5-phenyl 1H-tetrazole by various reported
catalyst
General experimental procedure for synthesis
of 5-substituted 1H-tetrazoles
Entry
Catalyst
Time
h)
Yield
(%)
(
To a mixture of nitrile (10 mmol) and NaN (15 mmol) in
3
1
2
3
4
5
6
7
8
9
ZnBr
TMSN
FeCl –SiO
Zn/Al hydrocalcite [15]
Fe [16]
Zn hydroxyapatite [17]
Sb [18]
CuFe [20]
NH Cl [23]
(n-C NH
Cl [23]
NCl [23]
NH Cl [24]
2
(in H
–TBAFꢀ3H
[14]
2
O) [6]
24
76
DMF (20 mL), NH OAc (15 mmol) was added. The mix-
4
3
2
O[11]
18
86
ture was stirred at 120 °C for appropriate time until reac-
tion was completed (monitored by TLC). Then reaction
was allow to cool at room temperature, carefully acidified
by 5 M HCl with stirring, then ice cold water added, the
solid obtained was filter and washed with water, dried and
purified by simple recrystallization in ethanol or water–
ethanol. In case of entry 8, 9, 10 (Table 3), the reaction
mass on acidification was extracted with ethyl acetate,
washed with water thrice. Organic layer dried over anhy-
drous Na SO , on solvent evaporation affords product
3
2
12
79
12
84
2
O
3
36
81
12
78
2
O
3
08
86
2
O
4
12
82
4
07
59.6
51.6
73.8
40.4
10
11
12
4
9
H )
2
2
Cl [23]
07
C
6
H
5
NH
3
07
2
4
(CH
3
)
4
07
which further purified by simple recrystallization. All
13
a
96
1
compounds are characterized by FTIR, H NMR,
13
15 min
02
4
C
b
93
1
1
a
4
5
Et
Et
3
NꢀHCl [25]
NꢀHCl [26]
NMR, and mass spectroscopy, and found to be in good
agreement with the literature data. Spectroscopic data of
selected compounds:
c
96
3
08
Under N atmosphere and microwave irradiation (20 W)
2
b
c
5
-phenyl-1H-tetrazole (Table 3, entry 1): yield: 85 %;
1
Under microwave irradiation (75 W) in nitrobenzene
-
1
IR (KBr) cm = 2,459–3,213, 1,564, 1,608, 727;
H
Reactions were carried out in toluene
NMR (200 MHz, DMSO-d ): d = 7.62–7.65 (m, 3H, aro-
6
1
matic), 8.07–8.09 (m, 2H, aromatic); C NMR (500 MHz,
3
DMSO-d ): d = 124.05, 126.96, 129.45, 131.31, 155.62;
6
?
MS: m/z = 147 (M?1) .
0
5
-(4 -chlorophenyl)-1H-tetrazole (Table 3, entry 3):
R
-
yield: 90 %; IR (KBr) cm = 2,684–3,124, 1,610, 829,
1
NH OAc
4
N
N
R CN + NaN3
1
NH
DMF, 120 °C
744; H NMR (200 MHz, DMSO-d ): d = 7.70 (d, 2H,
6
N
0
.83 -12 h
J = 8.6 Hz, aromatic), 8.08 (d, 2H, J = 8.6 Hz, aromatic);
1
3
C NMR (500 MHz, DMSO-d ): d = 123.16, 128.70,
6
7
4-91%
1
29.53, 135.94, 154.95; MS: m/z = 179 (M-1).
0
5
-(3 -methylphenyl)-1H-tetrazole (Table 3, entry 5):
Scheme 1 Ammonium acetate mediated synthesis of 5-substituted
H-tetrazole
-
yield: 87 %; IR (KBr) cm = 3,338, 1,660, 1,598, 1,562,
1
1
1
23

J IRAN CHEM SOC (2012) 9:799–803
801
a
Table 3 Synthesis of 5-substituted 1H-tetrazoles
b
Yield (%)
Entry
Substrate
Time (h)
2.25
M.p. (°C)
Found
Reported [Ref.]
217–218 [29]
1
2
85
89
218
140
CN
CN
0.83
138–139 [20]
Cl
3
4
5
1.5
2
90
84
87
254–256
267–268
152–153
250–252 [20]
268–269 [29]
–
CN
Cl
Br
CN
2.5
CN
CH3
6
7
3
91
84
250
251–252 [29]
219–220 [30]
CN
CN
H C
3
1.5
218–220
O N
2
8
9
8
87
82
121–123
163
123–124 [29]
–
CN
8.25
CN
H CO
3
1
0
1
4
82
74
162
160–162 [29]
165–166 [29]
CN
Cl
1
12
165–166
CN
1
1
2
3
1.5
78
83
209–210
257
208–210 [22]
254–258 [22]
N
CN
CN
1.25
N
a
Reaction was carried out with nitrile (10 mmol), NaN
Isolated yield
3
(15 mmol), ammonium acetate (15 mmol) in 20 mL of DMF at 120 °C
b
123

8
02
J IRAN CHEM SOC (2012) 9:799–803
1
7
7
98; H NMR (200 MHz, DMSO-d ): d = 2.42 (s, 3H),
temperature does not allows the sublimation of ammonium
azide even at longer reaction times, thereby increasing the
overall safety of the procedure. The advantage of this
method is a substantial decrease in reaction times com-
pared with literature methods and easy isolation of product
by acidification, making ammonium acetate as a better
catalyst for these reactions.
6
1
3
.43–7.89 (m, 4H, aromatic);
C NMR (500 MHz,
DMSO-d ): d = 20.90, 124.12, 127.39, 129.35, 131.93,
6
?
38.89, 155.32, 166.52; MS: m/z = 160 (M) .
1
0
5
-(4 -methylphenyl)-1H-tetrazole (Table 3, entry 6):
-
yield: 91 %; IR (KBr) cm = 2,476–3,082, 1,614, 820;
1
1
H NMR (200 MHz, DMSO-d ): d = 2.39 (s, 3H), 3.60
6
(
brs, 1H), 7.42 (d, 2H, J = 8 Hz, aromatic), 7.93 (d, 2H,
1
We examined a variety of structurally divergent ben-
zonitriles, possessing a wide range of functional groups to
understand the scope and generality of ammonium acetate
promoted [3?2] cycloaddition reaction using DMF as a
solvent affording tetrazoles by complete conversion within
0.83–12 h (checked by TLC) with good to excellent yields.
The effects of substituent on aromatic ring were found to
be less significant. The reaction time increases for benzyl
nitriles (entries 8–10, Table 3) due to the absence of
electronic effect of aromatic ring. The heteroaromatic
nitrile such as 2-pyridinecarbonitrile and 4-pyridinecarbo-
nitrile (entries 12, 13, Table 3) gives desire product with 78
and 83 %, respectively, with short reaction time.
3
J = 8 Hz, aromatic); C NMR (500 MHz, DMSO-d6):
d = 21.02, 121.15, 126.87, 129.96, 141.32, 155.17; MS: m/
z = 161 (M?1) .
?
0
5
-(4 -chlorobenzyl)-1H-tetrazole (Table 3, entry 10):
-
yield: 82 %; IR (KBr) cm = 2,480–3,116, 1,585; H
1
1
NMR (200 MHz, DMSO-d ): d = 4.31 (s, 2H), 7.32 (d,
2
6
1
3
H, aromatic), 7.41 (d, 2H, aromatic);
C NMR
(
500 MHz, DMSO-d ): d = 28.18, 128.66, 130.62, 131.78,
6
?
1
34.81, 155.12; MS: m/z = 195 (M?1) .
-benzhydryl-1H-tetrazole (Table 3, entry 11): yield:
5
-
1
4 %; IR (KBr) cm = 2,455–3,103, 1,566, 1,496, 725;
7
1
H NMR (200 MHz, DMSO-d ): d = 5.98 (s, 1H),
6
1
.20–7.40 (m, 10H, aromatic); C NMR (500 MHz,
3
7
DMSO-d ): d = 45.73, 127.27, 128.40, 128.75, 140.00,
6
?
58.10; MS: m/z = 236 (M ).
1
7
Conclusions
0
2
-(1H-tetrazol-5 -yl) pyridine (Table 3, entry 12): yield:
-
8 %; IR (KBr) cm = 2,466–3109, 1,639, 1,558; H
1
1
In conclusion, an efficient practical method has been
developed for synthesis of 5-substituted 1H-tetrazoles
which has combined advantages of short reaction time than
previously reported methods, good to excellent yields,
simple experimental setup and workup procedure and
purification of products without column chromatography.
Note that the procedure also be scaled up to 70 g of starting
nitrile without decreasing the yield.
NMR (200 MHz, DMSO-d ): d = 3.87 (s, 1H), 7.73–8.90
(
6
1
m, 4H, aromatic); C NMR (500 MHz, DMSO-d6):
3
d = 122.64, 126.17, 138.31, 143.70, 150.12, 154.84; MS:
m/z = 148 (M?1) .
?
Results and discussion
Acknowledgments The authors thank to DST and UGC, New Delhi
for financial assistance.
The aim of study was to find a protocol for synthesis of
tetrazoles that has advantages of previous procedures
including good yields in short reaction times, versatility
and easy isolation of product without column chromatog-
raphy. For optimization of reaction condition, we synthe-
sized 5-phenyl 1H-tetrazole under various reaction
conditions (see Scheme 1; Table 1) and the DMF found to
be the best solvent regarding to yield. The quantity of NaN3
and ammonium acetate used also has effect on yields sig-
nificantly (Table 1). In order to check the efficiency of this
method, we compare our results with some literature
methods in response with reaction time and yields (see
Table 2). The best reaction condition was found at entry 3
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