Ionic liquid-assisted synthesis of 5-monoand 1,5-disubstituted tetrazoles

Article abstract of DOI:10.1016/j.mencom.2011.11.014

Interaction of aliphatic, aromatic and heteroaromatic nitriles with NaN₃ or activated nitriles with organic azides in ionic liquids affords the corresponding 5-mono- and 1,5-disubstituted tetrazoles, ionic liquids functioning both as a reaction medium and as a catalyst.

Full text of DOI:10.1016/j.mencom.2011.11.014

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 334–336
Ionic liquid-assisted synthesis of 5-mono-
and 1,5-disubstituted tetrazoles
Margarita A. Epishina,a Alexander S. Kulikov,a Nikolai V. Ignat’ev,b
Michael Schulteb and Nina N. Makhova*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
b Ionic Liquid Research Laboratory, Merck KGaA, 64293 Darmstadt, Germany. E-mail: nikolai.ignatiev@merck.de
DOI: 10.1016/j.mencom.2011.11.014
Interaction of aliphatic, aromatic and heteroaromatic nitriles with NaN3 or activated nitriles with organic azides in ionic liquids affords
the corresponding 5-mono- and 1,5-disubstituted tetrazoles, ionic liquids functioning both as a reaction medium and as a catalyst.
Tetrazole derivatives are of interest as important components of
This research was devoted to the development of a milder
and more general method for the synthesis of both 5-mono- (1)
and of 1,5-disubstituted (2) tetrazoles. Earlier we have found that
[3+2] cycloaddition reactions are truly accelerated in ILs.21,22 So
we hoped that this methodology could be developed in the tetrazole
synthesis through varying of ILs functioning as a reaction media
and as a catalyst. To prepare 5-substituted tetrazoles 1, aromatic,
heteroaromatic and aliphatic nitriles were introduced into the
reaction with NaN3 in readily available and stable to air and
moisture dialkylimidazolium ILs with different anions (Scheme 1,
Table 1).†
It was found that benzonitrile did not produce 5-phenyltetrazole
1a by heating with 1.2 equiv. NaN3 in [bmim][CF3SO3] and only
longtime heating of the reaction mixture (100 h) in [bmim][PF6]
or [bmim][BF4] at 100°C resulted in tetrazole 1a in 68% or 52%
yields, respectively (Table 1, entries 1–3). The best synthetic
conditions for 5-phenyltetrazole 1a proved to be heating of PhCN
with 1.2 equiv. of NaN3 at 100°C in acidic IL [emim][HSO4],
drugs, e.g., antibiotics, antiallergics or hormonal preparations.1 In
addition, these compounds have wide applications in agriculture (a
omponents of herbicides, pesticides, fungicides, plant growth regul-
ators, etc.)1,2 or as components of highly energetic formulations.3
s
c
Several methodologies were developed to produce different
tetrazole types. The simplest synthesis of tetrazoles is based on
the [3+2] cycloaddition reaction of nitriles with hydrazoic acid
or its derivatives. For example, the interaction of nitriles with
NaN3 or Me3SiN3 in the presence of acidic catalysts leads to
5-substituted tetrazoles, while the reaction of nitriles with alkyl
azides yields 1,5-disubstituted tetrazoles.The conditions required
for reactions with alkyl or aryl cyanides pose the key challenge.
A typical synthesis of 5-aryltetrazoles requires a prolonged
reactants heating (up to several days) in DMF, toluene or butanol
at 100–120°C in the presence of acidic promoters such as NH4Cl,
Et3N·HCl,4 Me2NH·HCl,5 BF3·Et2O,6 AcOH7 or ZnBr2.8 Pure
HN3 can also be used in the reaction, yet in this case the reaction
should be carried out in a sealed tube9 or in an autoclave.10
Me3SiN3 reacts with ArCN typically in the presence of dibutyltin
oxide11 or trimethylaluminum.12
Synthesis of 5-heteryltetrazoles is based on the interaction of
HN3 or NaN3 with nitriles of heterocyclic carboxylic acids.13–15
This process can be intensified by microwave irradiation in the
presence of NH4Cl. In this event, the reaction time can be reduced
to 10–25 min, however, a violent reaction temperature rise (up to
220°C within 10 min) results in the partial decomposition of the
starting compounds and products.16 Application of Me3SiN3/
Bu2SnO system under microwave irradiation allows the very
sophisticated nitriles to be converted into tetrazoles.17 Synthesis
of 5-alkyltetrazoles from alkyl cyanides and NaN3 proceeds even
under harsher conditions compared to 5-aryl- and 5-heteryltetr-
azoles, e.g., heating in benzene in a sealed tube at 150°C for
100–120 h is required to convert the alkyl cyanide and HN3 mix-
ture into 5-alkyltetrazole.8
†
New compounds exhibited satisfactory elemental analyses. IR spectra
were measured on a UR-20 spectrometer; 1H and 13C NMR spectra were
recorded on a Bruker AM300 (300 MHz for H and 75.5 MHz for 13C)
1
spectrometer (CDCl3 and DMSO-d6 were used as the internal standards).
13C NMR spectra were recorded under proton decoupling conditions. Mass
spectra were measured on a Finnigan MAT INCOS-50 instrument. TLC
was carried out on Silufol UV-254 plates. Melting points were measured
on a Gallenkamp instrument (Sanyo).
†
General procedure for the synthesis of 5-monosubstituted tetrazoles
1a–f in 1-ethyl-3-methylimidazolium hydrogen sulfate [emim][HSO4].
A mixture of aromatic, heteroaromatic or aliphatic nitrile (5 mmol) and
NaN3 (6 mmol) (for PrCN, 15 mmol was used) in 2 ml of [emim][HSO4]
was stirred at 100°C in a round bottom flask with the condenser and
protection from moisture for the time specified in Table 1. The reaction
completion was generally judged by a full conversion of the starting
nitrile (TLC monitoring). Then the reaction mixture was cooled to 20°C
and extracted with a mixture of (1) 4 ml ethylacetate + 3 ml hexane (4 times)
or (2) 4 ml MeOBut + 3 ml CH2Cl2 (5 times). The solvents were evaporated
in vacuo and the final products were characterized by physicochemical
methods. The melting points and spectral characteristics of compounds 1a–f
were identical to those described in literature. The IL was reused in the
next synthesis after the evaporation of solvent residues.
A straightforward synthesis of 1,5-disubstituted tetrazoles from
nitriles and organic azides is still unstudied. This reaction is known
to run successfully with nitriles having electron-withdrawing
groups and proceeds at a rather high temperature (110–145°C)
in a sealed tube.18,19 Recently,20 the application of ionic liquids
(ILs) (dialkylimidazolium chlorides and bromides) for the micro-
wave-assisted synthesis of substituted tetrazoles in the presence
of acetic acid as a catalyst has been reported. However, microwave
irradiation results in a high reaction temperature (up to 170°C)
and decomposition of both ILs and initial or final compounds.
1a: Rf 0.17 (eluent, CHCl3), yield 0.62 g (85%), mp 215–216°C (lit.,8
215–216°C).
1b: Rf 0.23 (eluent, CHCl3–acetone, 10:1), yield 0.70 g (96%), mp
239–240°C (lit.,15 239–241°C).
1c: Rf 0.15 (eluent, CHCl3), yield 0.72 g (90%), mp 219–220°C (lit.,8
220°C).
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 334–336
R1
N
R2
R
N
N
IL
IL
R1CN
+
R2N3
RCN
+ NaN3
HN
N
N
100 °C
100 °C
N
N
2a–c
1a–f
a R1 = C(O)Ph, R2 = Bn
b R1 = C(O)Ph, R2 = Bu
c R1 = C(O)OEt, R2 = Bn
a R = Ph
b R = 3-Py
c R = 4-NO2C6H4
d R = Bn
e R = Pr
f R = 4-MeOC6H4
Scheme 1
Scheme 2
Table 1 Synthesis of compounds 1 and 2 in ionic liquids.a
Entry Nitrile Azide IL Product Time/h
NaN3 [bmim][CF3SO3] 1a
stituent 4-MeOC6H4CN (entry 9). In all the cases, the ILs were
r
egenerated and reused 3 times in the same reactions (e.g., entry 16).
Yield
(%)
To prepare 1,5-disubstituted tetrazoles 2, PhCN, 4-O2NC6H4CN,
3-cyanopyridine and activated nitriles PhC(O)CN and EtO2CCN
were heated with BnN3 or BuN3 in different ILs at 100°C. It was
found that PhCN, 4-O2NC6H4CN, 3-cyanopyridine did not react
with BnN3 or BuN3 in any ILs ([emim][HSO4], [bmim][BF4]
or [bmim][PF6]). Instead of tetrazoles, the corresponding benz-
amides, hydrolysis products of the starting nitriles, were obtained
in low yields (~20–25%). Only use of activated nitriles EtO2CCN
and PhC(O)CN in reaction with aliphatic azides in ILs [bmim][PF6]
and [bmim][BF4] comprised anions derived from corresponding
strong Lewis acid resulted in 1,5-disubstituted tetrazoles 2a–c
(Scheme 2, Table 1, entries 10–13).‡ The acidic IL [emim][HSO4]
also appeared efficient for preparing 1,5-disubstituted tetrazoles
2a,b from nitriles and aliphatic azides, however, for this purpose
rather longtime heating was necessary and small amounts of
phenylglyoxylic acid amide and polymeric compounds were
identified in the reaction products (entries 14, 15). The conditions
found were significantly milder than previously reported (heating
at 110–145°C in a sealed tube without solvent18,19).
1
2
3
4
5
6
7
8
PhCN
PhCN
PhCN
PhCN
50
100
100
10
9
0
NaN3 [bmim][PF6]
NaN3 [bmim][BF4]
NaN3 [emim][HSO4]
1a
1a
1a
1b
1c
1d
1e
68
52
85
96
90
79
80
3-cyanopyridine NaN3 [emim][HSO4]
4-NO2C6H4CN NaN3 [emim][HSO4]
3.5
5
80
BnCN
PrCN
NaN3 [emim][HSO4]
NaN3 [emim][HSO4]
(3 equiv.)
9
10
11
12
13
14
15
16
4-MeOC6H4CN NaN3 [emim][HSO4]
1f
83
85
49
44
18
102
70
3.5
78
50
72
28
74
36
56
95(1),b
94(2),b
100(3)b
PhC(O)CN
PhC(O)CN
EtOC(O)CN
EtOC(O)CN
PhC(O)CN
PhC(O)CN
BnN3 [bmim][PF6]
BuN3 [bmim][BF4]
BnN3 [bmim][PF6]
BnN3 [bmim][BF4]
BnN3 [emim][HSO4]
BuN3 [emim][HSO4]
2a
2b
2c
2c
2a
2b
1c
4-NO2C6H4CN NaN3 [emim][HSO4]
(regenerated)
The structures of the synthesized compounds were established
by elemental analysis and physicochemical methods. For the known
compounds, characteristics were close to the reported data.
To conclude, we have developed a general and simple pro-
cedure for the synthesis of both 5-mono- and 1,5-disubstituted
tetrazoles based on heating of aromatic, heteroaromatic or aliphatic
nitriles with NaN3 or activated nitriles with aliphatic azides in ILs
proved to be appropriate reaction medium and catalysts in these
reactions.
aAll reactions were performed at 100°C. b Three cycles of IL regeneration.
which played a part of both a reaction medium and an acidic catalyst
(entry 4). These conditions also were the best for the synthesis of
5-(pyridin-3-yl)tetrazole 1b (entry 5), 5-(4-nitrophenyl)tetrazole
1c (entry 6) and 5-benzyltetrazole 1d (entry 7). The interaction
of PrCN with NaN3 in acidic [emim][HSO4] resulted in 5-propyl-
tetrazole 1e in 80% yield (entry 8), though a NaN3 excess (3 equiv.)
and longer heating (80 h, 100°C) were necessary. Longtime heating
was also needed for benzonitrile with the electron-donor sub-
This work was supported by Merck KGaA, the Russian Founda-
tion for Basic Research (grant no. 09-03-01091) and Russian
Academy of Sciences.
1d: Rf 0.35 (eluent, CHCl3–acetone, 10:1), yield 0.63 g (79%), mp
125–126°C (lit.,23 121–123°C).
1e: Rf 0.17 (eluent, CHCl3), yield 0.44 g (80%), mp 63–64°C (lit.,24
56–58°C).
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‡
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Received: 15th June 2011; Com. 11/3741
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