Preparation of 5-substituted 1H-tetrazoles catalyzed by scandium triflate in water

Article abstract of DOI:10.1080/00397911.2014.957775

Several 5-substituted 1H-tetrazoles were prepared in water or isopropanol/water mixtures using microwave heating. Good yields were obtained for the [2 + 3] cycloaddition of sodium azide with aryl nitriles, aliphatic nitriles, and vinyl nitriles when catal

Full text of DOI:10.1080/00397911.2014.957775

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Preparation of 5-Substituted 1H-Tetrazoles Catalyzed
by Scandium Triflate in Water
a
a
a
Adiel Coca , Evan Turek & Liana Feinn
a
Chemistry Department, Southern Connecticut State University, New Haven, Connecticut,
USA
Accepted author version posted online: 25 Sep 2014.
To cite this article: Adiel Coca, Evan Turek & Liana Feinn (2014): Preparation of 5-Substituted 1H-Tetrazoles Catalyzed by
Scandium Triflate in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2014.957775
To link to this article: http://dx.doi.org/10.1080/00397911.2014.957775
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Preparation of 5-Substituted 1H-Tetrazoles Catalyzed by Scandium Triflate in
Water
1
1
1
Adiel Coca , Evan Turek , Liana Feinn
1
Chemistry Department, Southern Connecticut State University, New Haven,
Connecticut, USA
Corresponding author to Adiel Coca: E-mail: cocaa2@southernct.edu
Abstract
Several 5-substituted 1H-tetrazoles were prepared in water or isopropanol/water mixtures
using microwave heating. High yields were obtained for the [2 + 3] cycloaddition of
sodium azide with aryl nitriles, aliphatic nitriles, and vinyl nitriles when catalyzed by
o
scandium triflate. The reactions were typically heated for one hour at 160 C in a 3:1
isopropanol/water mixture to obtain the best yields.
KEYWORDS: [2 + 3] cycloaddition, scandium triflate, 5-substituted 1H-tetrazoles,
microwave, water
INTRODUCTION
Tetrazoles are a nitrogen rich heterocycle with a wide range of applications. Perhaps the
most important application of tetrazoles is as a bioisostere for carboxylic acids since
[
1]
tetrazoles have a similar planarity and acidity to carboxylic acids. Tetrazoles do offer
1

some advantages over carboxylic acids such as being more easily absorbed through
biological membranes and being more metabolically stable than carboxylic acids. For
these reasons, tetrazoles are incorporated in a number of pharmaceuticals including
several approved angiotensin II receptor antagonists that are used to treat hypertension.
Tetrazoles are also used in explosives, propellant projectiles, and airbags in the
[
2]
[
3]
automobile industry due to the high amount of energy stored within these rings. In
addition, tetrazoles are also an important precursor to other heterocyclic rings such as
[
4,5]
thiazoles, oxazolidones, and triazoles through the Huisgen rearrangement.
Moreover,
[
6]
tetrazoles have seen extensive use in coordination chemistry and as catalysts in
[
7]
asymmetric synthesis. Other applications of tetrazoles include being used as peptide
[
8]
[9]
[10]
chelating agents, as lipophilic spacers, as cis-peptide bond mimics, in information
[
11]
[12]
recording systems, as antifoggants in photography, and in high-density energy
[
13]
materials.
Typically 5-substituted 1H-tetrazoles are prepared through the [2 + 3] cycloaddition of an
azide and a nitrile. Sodium azide (NaN
3
) is usually used as the azide source, although
[
13]
[14]
[15]
silicon, tin, and organoaluminum azides have also been explored. Most nitriles
react well in this cycloaddition, although sterically unhindered and electron deficient aryl
[
16,17]
nitriles give the highest yields.
All of the currently available methods to synthesize
tetrazoles through a [2 + 3] cycloaddition suffer from more than one of the following
limitations: high temperatures, long reaction times, using toxic, expensive, or water
sensitive reagents, and generation of hydrazoic acid, which is highly volatile, toxic, and
explosive. In addition, most methods in the literature to make tetrazoles rely on using
2

aprotic organic solvents such as dimethylformamide (DMF). For example, recently 5-
[
18]
substituted 1H-tetrazoles were synthesized using microwave irradiation in DMF.
Demko and Sharpless demonstrated that the [2 + 3] cycloaddition of nitriles and sodium
azide could be achieved in water or an isopropanol/water mixture using zinc salts such as
[
16]
ZnBr
2
as catalysts. However, this methodology required 24 to 48 hours of heating at
o
1
00-170 C for most substrates reported. Furthermore, a large amount (0.5-1.0 equiv) of
the zinc salt catalyst was used. Here we report the synthesis of 5-substituted 1H-tetrazoles
in high yields from various nitriles and sodium azide using 0.2 equiv of the rare-earth
3
metal catalyst scandium triflate [Sc(OTf) ]. The preparation of these tetrazoles was
accomplished in water or an isopropanol/water mixture in 1 h using microwave
irradiation. Although using water as a solvent in an organic reaction often poses some
challenges, water (even as an isopropanol/water mixture) does provide practical and
environmental advantages over organic solvents including being nontoxic,
nonflammable, inexpensive, readily available, and easily disposed. Most organic chemists
have hesitated from using water as a solvent due to the general insolubility of many
organic compounds in water.
RESULTS AND DISCUSSION
Our studies were performed in a multi-mode microwave reactor in sealed Pyrex
o
microwave vessels. Initial attempts to convert 4-nitrobenzonitrile (1a) at 120 C in water
3 3
using 0.2 equiv of Sc(OTf) and with 2 equiv of NaN led to a low yield (41%) of the
tetrazole after 30 minutes of heating in the microwave reactor (Table 1). Increasing the
o
temperature to 140 C increased the yield to 60%. Given the insolubility of this nitrile in
3

water, an alcoholic co-solvent was tested. Running the same reaction with a 1:1
o
isopropanol/water mixture at 140 C increased the yield but not significantly (66%).
More satisfying was the fact that 4-nitrobenzonitrile in a 3:1 isopropanol/water mixture
gave a 98% yield.
Since a small amount of unreacted nitrile was seen in the initial attempts in water and
o
aqueous mixtures, the reaction temperature and reaction time were increased to 160 C
for 1 h. Using these conditions, the highly electron deficient 4-nitrobenzonitrile (1a) and
4
5
-(trifluoromethyl)benzonitrile (1b) were quantitatively converted to the corresponding
-substituted tetrazole (Table 2). Heating 4-chlorobenzonitrile (1c) with 2 equiv of NaN
3
o
and 0.2 equiv of Sc(OTf)
3
at 160 C for 1 h afforded the corresponding tetrazole in 89%
yield. Changing the catalyst from scandium triflate to ytterbium triflate hydrate decreased
the yield for the 4-chlorobenzonitrile (1c) reaction to 80% under the same conditions.
Thus, scandium triflate was used for the rest of the study.
Other para-substituted nitriles such as 4-methoxybenzonitrile (1d), 4-bromobenzonitrile
(
1e), 4-methylbenzonitrile (1f), and methyl 4-cyanobenzoate (1g) gave moderate to high
yields (50-80%). 1,4-Diacyanobenzene (1h) was also converted in high yield (85%) when
.4 equiv of Sc(OTf) and 4 equiv of sodium azide were used. The results with the para-
substituted aryl nitriles were very consistent with previous reports as the electron
0
3
[
16,17]
deficient nitriles were generally more reactive than the electron rich nitriles.
Other aryl nitriles were also investigated in the [2 + 3] cycloaddition with sodium azide
Table 3). Most substrates tested gave moderate to high yields of the tetrazole with the
(
exception of those that were sterically hindered. For example, ortho-substituted (2-
4

methoxyphenyl)acetonitrile (1k), 2-chlorobenzonitrile (1m), and 4'-methyl-2-
cyanobiphenyl (1n) all failed to reach yields higher than 39%. Among the ortho-
substituted aryl nitriles, 2-nitrobenzonitrile (1l) reacted well as it afforded a 76% yield of
the tetrazole. Heterocyclic aryl nitriles such as 3-thiophenecarbonitrile (1o) and
pyrazinecarbonitrile (1q) were converted in very high yields. Monosubstituted nitriles
such as benzonitrile (1i), benzoyl cyanide (1j), and 1-cyanonaphthalene (1p) gave
moderate yields of the tetrazole.
Vinyl and aliphatic nitriles were also reacted under the optimized conditions.
Cinnamonitrile (1r) afforded a very low yield (39%) of the tetrazole but fumaronitrile
(
1s) was converted to the tetrazole in near quantitative yield with 0.4 equiv of Sc(OTf)
3
and 4 equiv of sodium azide. The two aliphatic nitriles tested, heptyl cyanide (1t) and
cyclohexanecarbonitrile (1u), both gave identical yields (42%). Low yields for the
[
16,17]
aliphatic nitriles were expected based on previous reports.
CONCLUSION
In conclusion, scandium triflate was determined to be a suitable catalyst for the [2 + 3]
cycloaddition between nitriles and sodium azide in water and isopropanol/water mixtures
in a multi-mode microwave reactor. Although the cycloaddition could be achieved after
o
3
0 minutes at 120 C, the best results were obtained when the reaction was heated at 160
o
C for 1 h. Several 5-substituted tetrazoles were synthesized under these conditions using
. This methodology should provide a fast, reliable, and
only 0.2 equiv of Sc(OTf)
3
environmentally friendly route to other 5-substituted 1H-tetrazoles.
5

EXPERIMENTAL
Typical Experimental Methodology
Synthesis of 5-(4-chlorophenyl)-1H-tetrazole (2c). 4-chlorobenzonitrile 1c (274 mg, 2
mmol), NaN (260 mg, 4 mmol), Sc(OTf) (197 mg, 0.4 mmol), and 8 mL of a 3:1
3
3
isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel and capped.
The microwave vessel was then placed in a Milestone Start Synth microwave reactor.
o
The reaction was magnetically stirred and heated for 1 hour at 160 C. The reaction was
monitored by TLC using an ether/hexane mixture (typically 50/50) for development. The
reaction mixture was then diluted with saturated aqueous sodium bicarbonate (20 mL)
and washed with ethyl acetate (2 x 15 mL). The aqueous sodium bicarbonate layer was
cooled with ice and acidified to a pH of 2 or less with concentrated hydrochloric acid,
which was added drop-wise. The precipitate formed was extracted with ethyl acetate (3 x
1
5 mL). The combined organic layers were dried with anhydrous sodium sulfate and
decanted into a tared round bottom flask. The organic layer was concentrated under
reduced pressure by rotary evaporation at 40 ⁰ C and then under high vacuum. The
tetrazole product was recrystallized from ethyl acetate and hexane. All reagents
mentioned above were used unpurified.
1
13
NMR spectra were acquired on a spectrometer at 300 MHz for H and 75 MHz for C
1
acquisitions. All H NMR spectra were taken in DMSO-d
6
using DMSO as a standard at
using DMSO as a standard at
0.5 ppm. An IR spectrum was obtained using an FTIR spectrophotometer. A melting
1
3
2
4
.52 ppm. All C NMR spectra were taken in DMSO-d
6
point was also obtained for the solid products. 5-(4-chlorophenyl)-1H-tetrazole (2c) is a
6

-1
1
white solid. IR (KBr, thin film) vmax (cm ): 3385 (br), 1645 (m), 1634 (m); H NMR
13
(
DMSO-d
6
, δ): 11.60 (s, br, 1H), 8.07 (d, J = 8.28 Hz, 2H), 7.70 (d, J = 8.25 Hz, 2H); C
NMR (DMSO-d
6
, δ): 155.8 (br), 136.9, 130.6, 129.7, 124.1; mp 250−251 ⁰C.
All tetrazoles made in this report are known and characterization data matched
1
6
19
24
16
20
20
27
21
16
25
22
closely with literature values: 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k,
23
15
16
26
24
16
16
16
16
18
2
l, 2m, 2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u .
ACKNOWLEDGMENT
These results were obtained in large part thanks to a Connecticut State University-
American Association of University Professors Faculty Research grant, a Southern
Connecticut State University Faculty Creative Activity Research grant, a Minority
Recruitment and Retention Committee grant, and an American Chemical Society New
Haven section Undergraduate Research award.
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9

Table 1. Optimization attempts.
o
Solvent
Temperature ( C) % Yield
H
H
2
O
O
120
140
140
140
41
60
66
98
2
1
3
:1 isopropanol/H
:1 isopropanol/H
2
2
O
O
1
0

Table 2. Reactions of p-Substituted Aryl Nitriles.
Substrate
Yield (%)
1
00
9
9
9
1
8
6
5
4
0
5
1
1

8
8
0
5
a
.
8
3
2
mmol of NaN and 0.4 equiv of Sc(OTf) xH O were used with nitrile 1h.
3
1
2

Table 3. Reactions of non-para-Substituted Aryl Nitriles.
Substrate
Yield (%)
7
4
4
8
2
7
3
3
5
6
8
9
1
3

9
4
3
9
9
8
1
4

Table 4. Reactions of Vinyl and Aliphatic Nitriles.
Substrate
Yield (%)
3
9
9
8
4
2
4
2
a
.
8
3
2
mmol of NaN and 0.4 equiv of Sc(OTf) xH O were used with nitrile 1s.
3
1
5