Diisopropylethylammonium acetate (DIPEAc): An efficient and recyclable catalyst for the rapid synthesis of 5-substituted-1H-tetrazoles

Article abstract of DOI:10.1080/00397911.2017.1281421

A simple and efficient protocol developed for the synthesis of 5-substituted 1H-tetrazole derivatives through [2+3] cycloaddition reaction between benzonitriles and sodium azide using diisopropylethylammonium acetate as a recyclable reaction medium is described. The reactions proceed well at 80 °C and provide the corresponding tetrazoles in good to excellent yields (up to 94% yield). Developed method has notable advantages, such as simple and mild conditions, easy workup, reusability with consistent catalytic activity, and safer alternative to hazardous, corrosive conventional Lewis acid catalysts.

Full text of DOI:10.1080/00397911.2017.1281421

Diisopropyl Ethylammonium Acetate (DIPEAc): An Efficient and Recyclable
Catalyst for the Rapid Synthesis of 5-Substituted-1H-Tetrazoles
Manisha R. Bhosle1, Dastgir S. Shaikh1, Lalit D. Khillare1, Amarsinh R. Deshmukh1,
Ramrao A. Mane1
1Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, Maharashtra, India
Corresponding to author: Ramrao A. Mane. E-mail: d.manisha11@gmail.com
Abstract
A simple and efficient protocol developed for the synthesis of 5-substituted 1H-tetrazole
derivatives via [2+3] cycloaddition reaction between benzonitriles and sodium azide
using diisopropyl ethylammonium acetate as a recyclable reaction medium is described.
The reactions proceed well at 80 ºC and provide the corresponding tetrazoles in good to
excellent yields (up to 94% yield). Developed method has notable advantages, such as
simple and mild conditions, easy workup, reusability with consistent catalytic activity
and safer alternative to hazardous, corrosive conventional lewis acid catalysts.
Graphical Abstact
KEYWORDS: 5-Substituted 1H-tetrazole, DIPEAc, Ionic liquid, Cycloaddition reation
1

INTRODUCTION
Tetrazoles and their derivatives are very important nitrogen containing
heterocycles which exhibit wide range of applications in the field of organic synthesis,
coordination chemistry, material science and medicinal chemistry.[1] The tetrazole ring,
particularly, 5-substituted-1H-tetrazole, known as tetrazolic acid is widely employed in
medicinal chemistry as a bioisostere for carboxylic acid group.[2] The compounds having
tetrazole building block in their molecular frame work, possess various biological and
pharmacological activities, such as antidiabetic,[3] antihypertensive,[4] antifungal,[5]
antimicrobial,[6] antibacterial,[7] anti-inflammatory,[8] hormonal,[9] anti HIV[10] and
diuretics.[11] Additionally Several biologically relevant scaffolds incorporating a tetrazole
moiety have been developed as pharmaceutical agents (Figure 1).[12] In view of such a
tremendous significance of tetrazoles, there is a great surge in the utility and applications
of tetrazoles.
The most direct and convenient route towards the synthesis of 5-substituted-(1H)-
tetrazoles is [2+3] cycloaddition between a nitrile and an azide.[13] Various synthetic
approaches have been developed for this transformation. Most of them rely on in situ
generation of highly toxic and explosive hydrazoic acid through activation of the azide by
expensive and toxic metals, strong Lewis acids or amine salts.[14] Apart from this number
of reports are available in the literature for this cycloaddition reaction which involves the
use of cyanuric chloride, CuFe2O4 nanoparticles, CAN supported HY-zeolite, etc.[15]
Sharpless et al. have reported an efficient and safe procedure for the synthesis of
tetrazoles using stoichiometric amounts of ZnBr2 in water.[16] However, reported methods
2

have one or more drawbacks such as vigorous reaction conditions, tedious work-up
procedure, use of expensive reagents, longer reaction times, low yields, etc. Thus, there is
a need to develop convenient and rapid high-yielding synthetic method to fulfill timely
supply of library of 5-substituted-(1H)-tetrazoles.
Organic reactions using sustainable reaction media such as ionic liquids (ILs),
avoiding the use of volatile organic solvents, have attracted a great deal of attention of
synthetic organic chemist. ILs are not only easily available, environmentally safe, but
also excellent catalysts and medium having weakly coordinating ions, i.e. organic cation
and inorganic/organic anion.[17, 18] ILs having nonvolatility, nonflammability, and are
endowed with unique properties such as high thermal/chemical stability.[19] ILs act as
‘neoteric solvents’ for a broad range of chemical and industrial processes. Recently, ILs
have been found to be useful as green media for numerous organic transformations.[20]
The ability to dissolve many organic and inorganic substances makes ILs eco-friendly
reaction media/catalysts.[21]
Encouraged by the intense ongoing research activity in the field of ILs and in
pursuit of our continuous interest in the area of green chemistry[22] herein, we report a
simple, green, and efficient protocol for the synthesis of 5-substituted-(1H)-tetrazoles
employing diisopropylethylammonium acetate (DIPEAc) as IL (Scheme 1). Literature
survey reveals that there are no methods reported in the literature for the synthesis of 5-
substituted 1H-tetrazoles using DIPEAc as a catalyst and reaction medium.
3

RESULTS AND DISCUSSION
Synthesis
A series of 5-substituted-(1H)-tetrazoles (3a-p) were synthesized by the reaction
of substituted benzonitriles and sodium azide in diisopropylethylammonium acetate
(DIPEAc) at 80 ºC. The required starting precursors, substituted benzonitriles (2a-p)
were synthesized by reaction of aromatic carbaldehydes with iodine/ammonia in
MeOH:THF at room temperature.[23] Reaction of phenyl nitrile (2a) and sodium azide
was considered as a model reaction.
Initially, to develop better reaction conditions, different green and volatile organic
solvents such as toluene, acetonitrile and methanol along with various freshly prepared
ILs[24] were screened at 80 ºC for performing the model reaction (Table 1, entries 1-7)
and we found that DIPEAc showed excellent catalytic behavior and afford product in
92% yield within 30 min. (Table 1, entry 7). However, no product formation was
observed in toluene, acetonitrile and methanol within 30 min (Table 1, entries 1-3).
In order to optimize the suitable amount of DIPEAc, model reaction was
conducted using acetonitrile as solvent in the presence of 20, 40, 60, 80 mol% of DIPEAc
and neat. It was observed that neat DIPEAc yielded 92% of conversion at 80 ºC. It was
noted that, at 80 ºC in the absence of DIPEAc, condensation could not occur in
acetonitrile media (Table 1). This confirms DIPEAc plays a role of a medium and as a
catalyst in this cyclocondensation. Therefore, DIPEAc was chosen as the medium and
catalyst of choice for further optimization studies.
4

With the optimized conditions in hand, influence of other experimental
parameters such as temperature, amount and reusability of catalyst were also optimized.
The model reaction was performed using DIPEAc as a reaction medium at different
temperatures (35, 40, 60, 80, 100 ºC). Model reaction in DIPEAc at 80 ºC was found to
proceed with excellent yield (92%) in 30 min (Table 2). There was no reaction at room
temperature (35 ºC) within 30 min. As temperature increased from 35 to 100 ºC, the yield
of the product also increased 74%, 83%, 92%, 93% (Table 2). There was no significant
change in the product yield when model reaction was carried out above 80 ºC.
To generalize the scope of the DIPEAc promoted [2+3] cycloaddition reaction of
variety of structurally divergent benzonitriles were choosen to synthesize 5-substituted
1H-tetrazoles. All the results are presented in Table 3. Unsubstituted as well as
benzonitriles with electron donating substituents at both para and meta positions reacted
well and gave the corresponding products in good to excellent yields (Table 3). Further,
the reaction was extended to di and tri substituted benzonitriles such as 3,5-
dimethoxybenzonitrile and 3,4,5-trimethoxybenzonitrile respectively, to generate
tetrazoles in moderate to excellent yields (Table 3, entries 9, 11). Furthermore, the
reaction was equally effective with benzonitriles having substituted electron-withdrawing
groups and gave the expected tetrazoles in good yields.
Recycling Of Catalyst
5

To check reusability of the catalyst, the reaction was performed between
benzonitrile and sodium azide under the optimized reaction condition. DIPEAc was
separated from the reaction mixture by the following procedure. After completion of the
reaction, reaction mixture was cooled to room temperature and to it water and ethyl
acetate were added. The product (3a) was extracted with ethyl acetate. As the DIPEAc is
highly water soluble it goes in to the aqueous layer. Evaporation of aqueous layer under
reduced pressure provided the catalyst (DIPEAc). Catalysts purity was checked by 1H
NMR for subsequent reactions. Reusability of the DIPEAc was tested for four
consecutive cycles, but a decrease in the catalytic activity of DIPEAc was observed after
the third cycle (Figure 2).
Plausible Reaction Mechanism
On the basis of the experimental results and available literature,[25] possible mechanism
for the formation of 5-substituted-(1H)-tetrazoles using diisopropylethylammonium
acetate (DIPEAc) is presented in Scheme 2. Rate of acceleration for the formation of 5-
substituted-(1H)-tetrazoles has been found to be enhanced due to the dual nature of IL, as
a catalyst and reaction medium. IL might be helping to create a high initial concentration
of the reactants via solvation. Initially, coordination of nitrogen atom of phenyl nitrile
with DIPEA forms intermediate A which accelerates the cyclisation by increasing its
electrophilic character of nitrile carbon. This gets further attacked by the azide
component and [2+3] cycloaddition takes place readily to form the intermediate B. Then
acidic work up, afford the final product 5-substituted-(1H)-tetrazole.
6

CONCLUSION
To summarize, we have demonstrated an exceedingly simple and efficient protocol for
transforming variety of nitriles into corresponding 1H-tetrazoles using
diisopropylethylammonium acetate as a green catalyst as well as medium. The developed
protocol for [2+3] cycloaddition is associated with several advantages such as simple
procedure, mild reaction conditions, an alternative to hazardous, corrosive, and polluting
conventional Lewis acid catalysts and solvents. Reusability of DIPEAc with consistent
activity for at least four cycles is also established, indicating DIPEAc as a greener
reaction medium. DIPEAc can substitute metal salts and other heterogeneous catalysts,
and all these consign this method at an advantageous position compared to already
reported methods for these molecules of commercial value.
EXPERIMENTAL
General
All the solvents and reagents were purchased from commercial suppliers Spectrochem
Pvt. Ltd., Sigma Aldrich and Rankem India Ltd., and were used without further
purification. The progress of each reaction was monitored by ascending TLC using TLC
aluminum sheets, pre-coated silica gel F254 (Merck, Germany) and by locating the spots
using ultraviolet (UV) light as the visualizing agent or iodine vapors. Melting points were
taken in an open capillary method and are uncorrected. 1H NMR spectra were recorded
(DMSO) on a Bruker Avance 400 NMR spectrometer. 13C NMR spectra were recorded
(DMSO) on a Bruker Avance 100 NMR spectrometer. Chemical shifts (δ) are reported in
7

parts per million (ppm) using tetramethylsilane (TMS) as an internal standard. The
splitting pattern abbreviations are designed as singlet (s); doublet (d); double doublet
(dd); bs (broad singlet), triplet (t); quartet (q) and multiplet (m).
General Procedure For The Synthesis Of Diisopropylethylammonium Acetate (Dipeac)
A mixture of glacial acetic acid (0.02 mol) and N-ethyl-N-isopropylpropan-2-amine (0.02
mol) was stirred at 0-10 ºC for 30 min. to obtain diisopropylethylammonium acetate as a
viscous liquid [26].
General Procedure For The Synthesis Of 5-Substituted-(1H)-Tetrazoles (3a-P)
A mixture of benzonitriles (2a-p) (0.009 mol), sodium azide (0.009 mol) was dissolved in
DIPEAc (5 ml) and allowed to stirr for 30 min at 80 0C. After completion of the reaction
(monitored by thin-layer chromatography, TLC), the reaction mixture was cooled to
room temperature and poured on crushed ice. To it 5N HCl (10 mL) was added and
stirred vigorously. Otained solid products was filtered and crystallized from ethanol. The
synthesized compounds were confirmed by melting points, IR, 1H and 13C NMR and
which are in good agreement with those reported in the literature. [15, 16]
Spectral Data Of Representative Compounds
-1
5-Phenyl-1H-tetrazole (3a) White solid; mp 215-216°C; IR (KBr): υmax cm 3132, 2935,
1604, 1433, 1272, 748; 1H NMR (400 MHz, DMSO-d6) δ: 7.59-7.71 (m, 5H); 13C NMR
(100 MHz, DMSO-d6): δ 148.28, 133.06, 131.22, 125.66, 121.50.
8

5-(4-Methylphenyl)-1H-Tetrazole (3b)
-1
White solid; mp 248-250°C; IR (KBr): υmax cm 3138, 3000-2400, 1612, 1571, 1504,
1458, 1401, 1165, 1085, 679. 1H NMR (400 MHz, DMSO-d6) δ: 2.67 (s, 3H, CH3), 7.75
(d, 2H, Ar-H), 8.13-8.34 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6): δ 146.86,
133.45, 126.03, 125.40, 124.54, 21.56.
SUPPORTING INFORMATION (SI)
Supplementary data associated with this article can be found in the online version on web
page.
ACKNOWLEDGMENTS
The authors are thankful to Professor D. B. Ingle for his invaluable discussions and
guidance. The authors are also thankful to Central Drug Research Institute (CDRI),
Lucknow for spectral analysis.
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13

Table 1: Screening of the solvents for the synthesis of 5-substituted-(1H)-tetrazole (3a)
Entry Solvent
Time
(min)
30
Yield (%)a
1
2
3
4
5
6
7
8
Toluene
b
Acetonitrile
30
b
Methanol
30
b
Piperidine ammonium acetate
Pyrrolidine ammonium acetate
Triethylethylammonium acetate
30
69
30
60
30
67
Diisopropylethylammonium acetate (DIPEA) 30
92
DIPEA(20, 40, 60, 80, 100 mol
30
65, 69, 81, 83, 92
%)/Acetonitrile
Reaction conditions: 2a (0.009 mol), sodium azide (0.009 mol), in solvent (5 ml), stirred
at 80 ºC
aIsolated yields b: No condensation
14

Table 2: Effect of catalyst DIPEAc at varying temperatures
Temp
35 ºC
40 ºC
85
60 ºC
87
80 ºC
92
100 ºC
93
Yield (%)
No condensation
Reaction conditions: 2a (0.009 mol), sodium azide (0.009 mol), in DIPEA (5 ml), stirred
for 30 min. aIsolated yields
15

Table 3: Physical data of 5-substituted-(1H)-tetrazoles (3a-p)
Entry Substrate
Productb
Yield (%)
H
N
1
3a
3b
3c
3d
3e
3f
92
CN
N
N
N
H
N
2
3
4
5
6
7
89
87
90
94
86
89
CN
N
N
N
H
N
CN
H3CO
N
N
H3CO
N
H
CN
N
Cl
N
N
Cl
N
H
CN
N
HO
N
HO
N
N
H
CN
N
O2N
N
O2N
N
N
H
3g
CN
N
N
N
N
Cl
Cl
H
N
8
9
3h
3i
81
79
CN
OH
N
N
N
OH
NO2
H
N
CN
NO2
N
N
N
16

H
N
10
3j
89
CN
H3CO
H3CO
N
N
H3CO
H3CO
N
H
N
11
12
3k
3l
90
85
CN
N
N
N
N
N
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H
N
N
N
CN
N
H
13
14
15
16
3m
3n
3o
81
75
79
71
CN
N
F
N
F
N
N
N
HN
CN
N
N
O
S
N
HN
HN
CN
CN
O
S
N
N
N
3p
N
N
Reaction conditions: benzonitriles (2a-p) (0.009 mol), sodium azide (0.009 mol), DIPEAc
(5 ml) stir at 80 ºC. aIsolated yields. b Melting points, 1H & 13C NMR are in good
agreement with those reported in the literature.[15, 16]
17

Scheme 1: Synthesis of 5-substituted-(1H)-tetrazoles (3a-p)
18

Scheme 2: Plausible mechanism for the synthesis of 5-substituted-(1H)-tetrazoles
19

Figure 1. Examples of relevant pharmacologically active substances
20

Figure 2: Reuse and recovery of DIPEAc and its effect on yield.
21