Microwave Synthesis of 5-Substituted 1 H-Tetrazoles Catalyzed by Bismuth Chloride in Water

Article abstract of DOI:10.1080/00397911.2014.989451

(Chemical Equation Presented). Bismuth chloride was used to catalyze the [2 + 3] cycloaddition between sodium azide with aryl nitriles, aliphatic nitriles, and vinyl nitriles. A number of 5-substituted 1H-tetrazoles were synthesized in water or isopropano

Full text of DOI:10.1080/00397911.2014.989451

This article was downloaded by: [Selcuk Universitesi]
On: 10 January 2015, At: 07:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Microwave Synthesis of 5-Substituted 1H-tetrazoles
Catalyzed by Bismuth Chloride in Water
Adiel Cocaa, Liana Feinna & Joshua Dudleya
a Chemistry Department, Southern Connecticut State University, New Haven, Connecticut
Accepted author version posted online: 06 Jan 2015.
Click for updates
To cite this article: Adiel Coca, Liana Feinn & Joshua Dudley (2015): Microwave Synthesis of 5-Substituted 1H-tetrazoles
Catalyzed by Bismuth Chloride in Water, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.989451
To link to this article: http://dx.doi.org/10.1080/00397911.2014.989451
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Microwave Synthesis of 5-Substituted 1H-Tetrazoles Catalyzed by Bismuth
Chloride in Water
Adiel Coca1, Liana Feinn1, Joshua Dudley1
1Chemistry Department, Southern Connecticut State University, New Haven, Connecticut
Corresponding author E-mail: cocaa2@southernct.edu
Abstract
Bismuth chloride was used to catalyze the [2 + 3] cycloaddition between sodium azide
with aryl nitriles, aliphatic nitriles, and vinyl nitriles. A number of 5-substituted 1H-
tetrazoles were synthesized in water or isopropanol/water mixtures using microwave
heating. High yields were obtained for these reactions when heated for one hour at 120-
160 oC in a 3:1 isopropanol/water mixture. A few of the less reactive nitriles required
longer reaction times for good yields.
KEYWORDS: [2 + 3] cycloaddition, bismuth chloride, 5-substituted 1H-tetrazoles,
microwave, water
INTRODUCTION
Tetrazoles are interesting heterocycles with numerous applications. For example,
tetrazoles are often used as bioisosteres for carboxylic acids due to similar acidity and
planarity. The pKa of tetrazole is approximately 4.90.[1] Tetrazoles offer the added
1

advantages that they are more metabolically stable, more lipophilic, and generally offer a
more favorable pharmacokinetic profile than carboxylic acids. Thus, tetrazoles have been
incorporated into several pharmaceuticals. For example, several approved angiotensin II
receptor antagonists including avapro and diovan contain a tetrazole ring.[2] In addition,
the tetrazole ring has also been incorporated into compounds that exhibited antiulcer,[3]
antibacterial,[4] anticancer,[5] antiviral,[6] anti-inflammatory,[7] and antifungal[8] properties.
Tetrazoles have also been employed in propellants, pyrotechnics and explosives. For
example, 5-aminotetrazole can be used as a perchlorate replacement in flares.[9]
Furthermore, tetrazoles have been incorporated in a proline-derived catalyst for
asymmetric synthesis[10] and as ligands in coordination chemistry[11] as it can participate
in at least seven coordination modes with metal ions. Tetrazoles have also been utilized
as precursors to other five-membered ring heterocycles such as thiadiazoles using the
Huisgen rearrangement.[12]
The synthesis of 5-substituted 1H-tetrazoles through a [2 + 3] cycloaddition of the azide
anion and a nitrile was first reported in 1901.[13] This cycloaddition works best with aryl
nitriles, especially when they are unhindered and contain an electron withdrawing
group.[14,15] Although sodium azide is utilized most often, many other azide sources have
been investigated including tin,[16] silicon,[17] and organoaluminum azides,[18]. Two
reviews that cover recent developments in the synthesis of tetrazoles have been
published.[19-20] Most examples in the literature to synthesize 5-substituted 1H-tetrazoles
utilized an aprotic polar solvent such as dimethylformamide. For example, Sivaguru et al.
used ceric ammonium nitrate supported on HY-zeolite to synthesize 5-substituted aryl
2

and benzylic 1H-tetrazoles in dimethylformamide with good yields after 2.5-9 h at 110
oC.[21] The post-transitional metal catalyst indium chloride has also been reported to
catalyze this transformation in dimethylformamide.[22-23] The methodologies in these
reports suffer from several disadvantages including long reaction times, high
temperatures, and water-intolerant or expensive reagents. Recently, a few groups have
used microwave heating to lower the reaction times.[24-25] Interestingly, Demko and
Sharpless converted nitriles to tetrazoles in water and an isopropanol/water mixture using
zinc salts as catalysts.[14] However, most substrates required 24 to 48 hours of heating at
100-170 oC and a large amount (0.5-1.0 equiv) of the zinc salt catalyst for good
conversion. It has been suggested that the cycloaddition of nitriles and sodium azide
occurs through either a two-step or concerted mechanism, where a Lewis acid catalyst
helps active the nitrile for azide addition by coordinating the nitrile, but neither
mechanism has been ruled out yet experimentally.[14,26] We recently reported the
cycloaddition of various nitriles with sodium azide in water by using the rare-earth metal
catalyst scandium triflate.[27] Here we report the preparation of 5-substituted 1H-
tetrazoles in water and isopropanol/water mixtures by using 0.2 equiv of the post-
transitional metal catalyst bismuth chloride (BiCl3). The cycloaddition of various nitriles
and sodium azide was accomplished in high yields with microwave irradiation for 30
minutes to 1 hour for most substrates.
RESULTS AND DISCUSSION
Preliminary experiments were performed using 4-nitrobenzonitrile (1a) in a multi-mode
microwave reactor. Given the highly acidic and crystalline nature of tetrazoles, a basic
3

extraction followed by acidification afforded highly pure tetrazole products. Heating 1a
in a sealed Pyrex microwave vessel at 120 oC for 1 h with 0.2 equiv of BiCl3 and with 2
equiv of NaN3 led to a low yield (22%) of the tetrazole product when the reaction was
done in water (Table 1). Performing the reaction in a 1:1 isopropanol/water mixture at
120 oC for 1 h increased the yield of the tetrazole to 44%. Using a 3:1 isopropanol/water
mixture as the solvent and heating the reaction at 120 oC for 0.5 h, increased the yield
further to 60%. Even better results were obtained when the 3:1 isopropanol/water mixture
was heated at 120 oC for 1 h as 4-nitrobenzotetrazole (2a) was obtained in a 71% yield.
At 120 oC, it was noticed that the nitrile was highly insoluble in water and even in the 1:1
isopropanol/water mixture. Increasing the reaction temperature to 140 oC (for 1 h) and
using a 3:1 isopropanol/water mixture led to an 80% yield of 2a. Switching the catalyst to
Bi(OTf)3 (0.2 equiv) and running the reaction in a 3:1 isoproponal/water mixture at 140
oC afforded only 61% of 2a after 1 h. For this reason, BiCl3 was used for the rest of this
study. Heating the 4-nitrobenzonitrile reaction to 160 oC for 1 h increased the yield of the
desired tetrazole further to 95% when the reaction was done in the 3:1 isopropanol/water
mixture. Interestingly, running the reaction at 160 oC for 1 h in either water or a 1:1
isopropanol/water mixture led to a similar yield (89%) for 2a. It appears that at the higher
temperature, the water insolubility of 4-nitrobenzonitrile is less of an issue. At lower
temperatures, a large amount of unreacted nitrile was seen especially when water or the
1:1 isopropanol/water mixture was used. Attempts with other nitriles such as 4-
acetylbenzonitrile (2b) and 4-chlorobenzonitrile (2c) also led to low to moderate yields at
lower temperatures. Similarly, low to modest yields were obtained for nitriles 2b and 2c
when using water or 1:1 isopropanol/water as the solvent at 160 oC. In the case of nitrile
4

2b, using a 3:1 isopropanol/water mixture as the solvent and heating the reaction at 160
oC increased the yield considerably (78%). However, for nitrile 2c there wasn’t a
significant increase in yield when using a 3:1 isopropanol/water mixture at 160 oC
compared to a 1:1 isopropanol/water mixture.
Using these optimized conditions, several other tetrazoles were prepared. For example, 4-
cyanobenzophenone (1d) and methyl 4-cyanobenzoate (1e) reacted to afford the
corresponding tetrazoles in high yield (75 and 79%). Other para-substituted nitriles such
as 4-bromobenzonitrile (1f) and the electron rich 4-methoxybenzonitrile (1g) afforded a
relatively low yield of the 5-substituted tetrazole after 1 h (50% and 20%, respectively).
Allowing these nitriles to react for 4 h at 160 oC led to an almost quantitative yield with
1f and a 61% yield with 1g. A 4 h reaction time is still a considerable improvement over
most current methods used to prepare 5-substituted 1H-tetrazoles. By using 0.4 equiv of
BiCl3 and 4 equiv of NaN3, 1,4-dicyanobenzene (1h) was also converted in high yield
(82%) after 1 h at 160 oC.
Two ortho-substituted aryl nitriles were also investigated in this reaction as shown in
Table 3. Among them, 2-nitrobenzonitrile (1i) did better as it was converted to the
tetrazole in 74% yield whereas 2-chlorobenzonitrile (1j) afforded 37% of the tetrazole
after 1h. The yield for the reaction with nitrile 1j was increased to 56% by increasing the
reaction time to 4 h. Previous reports have indicated that para-substituted nitriles are
generally more reactive than the ortho-substituted nitriles.[14,15] Several heteroaryl nitriles
were also investigated in the [2 + 3] cycloaddition with sodium azide. For example, 2-
5

furonitrile (1m) was converted to the tetrazole in almost quantitative yield at 150 oC.
Pyrazinecarbonitrile (1k) and 3-thiophenecarbonitrile (1l) also afforded a high yield of
the tetrazole whereas 1-isoquinolinecarbonitrile (1n) gave a moderate yield of the
tetrazole. 1,3-Dicyanobenzene (1o) was converted in high yield with 0.4 equiv of BiCl3
and 4 equiv of sodium azide.
Lastly, vinyl, benzylic, and aliphatic nitriles which are generally very unreactive
in this reaction were investigated and the results can be seen in Table 4.[28] Fumaronitrile
(1p) reacted well as it gave a very high yield when 4 equiv of sodium azide and 0.4 equiv
of BiCl3 were used. Cinnamonitrile (1q), on the other hand, performed poorly as only
38% of the tetrazole was obtained after 1 h. The yield for the reaction of nitrile 1q was
increased to 49% by increasing the reaction time to 4 h. Disappointedly, aliphatic nitriles
exemplified by heptyl cyanide (1r) were not very reactive using BiCl3 as a catalyst.
Similarly, the benzylic nitrile mandelonitrile (1s) was also very unreactive.
CONCLUSION
In summary, bismuth chloride was found to be an effective catalyst in the [2 + 3]
cycloaddition between nitriles and sodium azide in water and isopropanol/water mixtures.
Under the optimized conditions several 5-substituted 1H-tetrazoles were prepared in good
yields. With the use of microwave heating, the generally long reaction times for this
cycloaddition was reduced to 1 h. The yields for some of the less reactive nitriles were
improved by increasing the reaction time to 4 h. Even with the increased reaction time for
6

some nitriles, this methodology is still a significant improvement over alternative
methods to make tetrazoles given that most reports require 16-48 h reaction times.
EXPERIMENTAL
Typical Experimental Methodology
Synthesis of 5-(furan-2-yl)-1H-tetrazole (2m). 2-Furonitrile 1m (186 mg, 2 mmol), NaN3
(260 mg, 4 mmol), BiCl3 (126 mg, 0.4 mmol), and 8 mL of a 3:1 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. The reaction was
magnetically stirred and heated for 1 hour at 150 oC. 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 15 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 ⁰C and then under high vacuum. The tetrazole product was
recrystallized from ethyl acetate and hexane. All reagents mentioned above were used
unpurified.
NMR spectra were acquired on a spectrometer at 300 MHz for 1H and 75 MHz for 13C
acquisitions. All 1H NMR spectra were taken in DMSO-d6 using DMSO as a standard at
7

2.52 ppm. All 13C NMR spectra were taken in DMSO-d6 using DMSO as a standard at
40.45 ppm. An IR spectrum was obtained using an FTIR spectrophotometer. A melting
point was also obtained for the solid products. 5-(furan-2-yl)-1H-tetrazole (2m) is a light
yellow solid. IR (KBr, thin film) vmax (cm-1): 3427 (br), 1645 (m); 1H NMR (DMSO-d6,
δ): 11.94 (s, br, 1H), 8.05 (dd, J = 1.77, 0.78 Hz, 1H), 7.29 (dd, J = 3.51, 0.78 Hz, 1H),
6.79 (dd, J = 3.51, 1.80 Hz, 1H); 13C NMR (DMSO-d6, δ): 149.3, 147.0, 141.0, 113.9,
113.4; mp 199−200 ⁰C.
All tetrazoles made in this report are known and characterization data matched closely
with literature values: 2a,14 2b,29 2c,30 2d,31 2e,32 2f,23 2g,14 2h,33 2i,28 2j,18 2k,14 2l,34
2m,18 2n,35 2o,33 2p,14 2q,14 2r,14 2s14.
ACKNOWLEDGEMENT
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, a Southern Connecticut State University
Undergraduate Research Grant, and an American Chemical Society New Haven section
Undergraduate Research award.
REFERENCES
1.
Hansen, L. D.; Baca, E. J.; Scheiner, P. Sagai. J. Heterocycl. Chem. 1970, 7,
991−995.
8

2.
3.
Patani, G. A.; La Voie, E. J. Chem. Rev. 1996, 96, 3147−3176.
Hayao, S.; Havera, H. J.; Strycker, W. G.; Leipzig, T. J.; Rodriguez, R. Sagai. J.
Med. Chem. 1967, 10, 400−402.
4. Smissman, E. E.; Terada, A.; El-antably, S. Sagai. J. Med. Chem. 1976, 19,
165−167.
5.
Itoh, F.; Yukishige, K.; Wajima, M.; Ootsu, K.; Akimoto, H. Sagai. Chem. Pharm.
Bull. 1995, 43 (2), 230−235.
6.
Song, W.-H.; Liu, M.-M.; Zhong, D.-W.; Zhu, Y.-L.; Bosscher, M.; Zhou, L.; Ye,
D.-Y.; Yuan, Z.-H. Sagai. Bioorg. Med. Chem. Lett. 2013, 23 (16), 4528−4531.
7.
K.; Bachar, S. C.; Sarker, S. D. Sagai. Med. Chem. 2012, 8 (5), 874−882.
8. Veeraswamy, B.; Santhosh, K. G.; Sambasiva Rao, P.; Kurumurthy, C.; Narsaiah,
B. Sagai. J. Heterocycl. Chem. 2014, 51 (4), 1073−1077.
Pal, R. K.; Yasmin, H.; Nahar, L.; Datta, B. K.; Chowdhury, A. K. A.; Kundu, J.
9.
Sabatini, J. J.; Moretti, J. D. Sagai. Chem.−Eur. J. 2013, 19 (38), 12839−12845.
Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Sagai. Chem. Commun. 2006,
10.
66−68.
11.
Wang, X. S.; Tang, Y. Z.; Huang, X. F.; Qu, Z. R.; Che, C. M.; Chan, P. W. H.;
Xiong, R. G. Sagai. Inorg. Chem. 2005, 44, 5278−5285.
12. Huisgen, R.; Sauer, J.; Sturm, H. J.; Markgraf, J. H. Sagai. Chem. Ber. 1960, 93,
2106−2124.
13.
14.
15.
Hantzsch, A.; Vagt, A. Sagai. Justus Liebigs Ann. Chem. 1901, 314, 339−369.
Demko, Z. P.; Sharpless, K. B. Sagai. J. Org. Chem. 2001, 66, 7945−7950.
Coca, A.; Turek, E. Sagai. Tetrahedron Lett. 2014, 55, 2718−2721.
9

16.
Dunica, J. V.; Pierce, M. E.; Santella, J. B. Sagai. J. Org. Chem. 1991, 56,
2395−2400.
17.
18.
19.
20.
21.
Wittenberger, S. J.; Donner, B. G. Sagai. J. Org. Chem. 1993, 58, 4139−4141.
Aureggi, V.; Sedelmeier, G. Sagai. Angew. Chem., Int. Ed. 2007, 46, 8440−8444.
Yet, L. Sagai. Prog. Heterocycl. Chem. 2013, 25, 217−256.
Roh, J.; Vavrova, K.; Hrabalek, A. Sagai. Eur. J. Org. Chem. 2012, 6101−6118.
Sivaguru, P.; Bhuvaneswari, K.; Ramkumar, R.; Lalitha, A. Sagai. Tetrahedron
Lett. 2014, 55, 5683−5686.
22.
Sun, H.; Chen, W.; Sun, Y.; Qin, P.; Qi, X. Sagai. Adv. Mater. Res. 2012,
396−398, 2416−2419.
23.
Patil, V. S.; Nandre, K. P.; Borse, A. U.; Bhosale, S. V. Sagai. E-J. Chem. 2012, 9
(3), 1145−1152.
24.
25.
Yoneyama, H.; Usami, Y.; Komeda, S.; Harusawa, S. Synthesis 2013, 1051−1059.
Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. I.; Hrabalek, A. Sagai.
Synthesis 2009, 2175−2178.
26.
Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B. Sagai. J. Am. Chem.
Soc. 2003, 125, 9983−9987.
27.
Coca, A.; Turek, E.; Feinn, L. Sagai. Synth. Commun. 2014 (DOI:
10.1080/00397911.2014.957775).
28.
29.
30.
Bonnamour, J.; Bolm, C. Sagai. Chem. Eur. J. 2009, 15 (18), 4543−4545.
Aridoss, G.; Laali, K. Sagai. Eur. J. Org. Chem. 2011, 6343−6355.
Rama, V.; Kanagaraj, K.; Pitchumani, K. Sagai. J. Org. Chem. 2011, 76,
9090−9095.
10

31.
Sreedhar, B.; Kumar, A. S.; Yada, D. Sagai. Tetrahedron Lett. 2011, 52,
3565−3569.
32.
Tang, H.; Zhang, Z.; Cong, C.; Zhang, K. Sagai. Russ. J. Org. Chem. 2009, 45,
559−563.
33.
Papova, E. A.; Pavlyukova, Y. N.; Popov, E. V.; Ostrovskii, V. A.; Trifonov, R. E.
Sagai. Russ. J. Org. Chem. 2009, 45, 890−894.
34.
35.
Alterman, M.; Hallberg, A. Sagai. J. Org. Chem. 2000, 65, 7984−7989.
Lan, N. M.; Burgard, R.; Wentrup, C. Sagai. J. Org. Chem. 2004, 69, 2033−2036.
11

Table 1. Optimization Attempts.
Nitrile Solvent
Temperature (oC) % Yield
120
H2O
22
44
60a
71
80
89
89
95
19
58
40
57
78
14
40
17
60
61
1a
1a
1ª
1:1 isopropanol/H2O 120
3:1 isopropanol/H2O 120
3:1 isopropanol/H2O 120
3:1 isopropanol/H2O 140
1a
1a
1ª
H2O
160
1:1 isopropanol/H2O 160
3:1 isopropanol/H2O 160
3:1 isopropanol/H2O 120
3:1 isopropanol/H2O 140
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
H2O
160
1:1 isopropanol/H2O 160
3:1 isopropanol/H2O 160
3:1 isopropanol/H2O 120
3:1 isopropanol/H2O 140
H2O
160
1:1 isopropanol/H2O 160
3:1 isopropanol/H2O 160
12

a reaction time was 0.5 h.
13

Table 2. Reactions of p-Substituted Aryl Nitriles.
Substrate
% Yield
75
79
98
61
82
a reaction time with nitriles 1f and 1g was 4 h.
b 8 mmol of NaN3 and 0.4 equiv of BiCl3 were used with nitrile 1h.
14

Table 3. Reactions of non-para-Substituted Aryl Nitriles.
Substrate
% Yield
74
56
78
84
99
55
77
a reaction time with nitrile 1j was 4 h.
b reaction temperature with nitrile 1m was 150 oC.
c 8 mmol of NaN3 and 0.4 equiv of BiCl were used with nitrile 1o.
3
15

Table 4. Reactions of Vinyl, Benzylic, and Aliphatic Nitriles.
Substrate
% Yield
89
49
33
30
a 8 mmol of NaN3 and 0.4 equiv of BiCl were used with nitrile 1p and reaction time was
3
1 h.
16