Click synthesis of 5-substituted 1H-tetrazoles from aldehydes, hydroxylamine, and [bmim]N3 via one-pot, three-component reaction

Article abstract of DOI:10.1055/s-0032-1317671

An easy and efficient one-pot, three-component method for the synthesis of 5-substituted 1H-tetrazole derivatives, via the reaction of aldehydes, hydroxylamine, and [bmim]N₃, is reported. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317671

LETTER
▌2927
lCettlerick Synthesis of 5-Substituted 1H-Tetrazoles from Aldehydes, Hydroxyl-
amine, and [bmim]N via One-Pot, Three-Component Reaction
3
Click Synthesis of 5-Substituted 1H-Tetrazoles
a
a
a
a
b
Majid M. Heravi,* Azadeh Fazeli, Hossein A. Oskooie, Yahya S. Beheshtiha, Hassan Valizadeh
a
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran
Fax +98(21)88041344; E-mail: mmh1331@yahoo.com
b
Department of Chemistry, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran
Received: 13.10.2012; Accepted after revision: 29.10.2012
ic oximes with sodium azide in the presence of 25 mol%
of copper acetate in DMF.
Abstract: An easy and efficient one-pot, three-component method
for the synthesis of 5-substituted 1H-tetrazole derivatives, via the
1
9
reaction of aldehydes, hydroxylamine, and [bmim]N , is reported.
Due to various advantages proved for multicomponent re-
3
2
0
actions (MCR) and in continuation of our efforts to-
Key words: 5-substituted 1H-tetrazoles, three-component, click re-
action, cyclization, aldehydes, 1-butyl-3-methylimidazolium azide
2
1,22
wards the development of MCR,
we wish to report a
simple and efficient method for the synthesis of 5-substi-
tuted 1H-tetrazoles via a one-pot, three-component reac-
tion of aldehydes, hydroxylamine, and [bmim]N as an
azide source (Scheme 1).
Tetrazoles are a class of nitrogen-rich heterocycles, and
interest in the preparation of variously substituted tetra-
zoles over the past few years has been increased rapidly
3
1
H
due to their wide range of applications. Tetrazoles are
O
N
Cu(OAc)2
Ar
usually regarded as biologically equivalent to the carbox-
N
+
NH2OH + [bmim]N3
2
Ar
H
DMF, 120 °C
N N
ylic acid group. These heterocycles have found wide-
12 h
3
spread use as ligands in coordination chemistry or
4
information-recording systems in material sciences.
Scheme 1 Synthesis of 5-substituted 1H-tetrazoles from aldehydes
They can also be used as isosteric replacements in drug
design.5
,6
In this three-component reaction, we have employed ionic
liquid [bmim]N as a reagent instead of the classical
[
3+2] Cycloadditions between nitriles and an azide consti-
tute an efficient method for the synthesis of 5-substituted
H-tetrazoles. In 2001, Demko and Sharpless reported a
3
NaN . In the structure of this ionic liquid, azide is a coun-
3
terion and it could be used as nucleophile in the reactions
1
(Figure 1).
cycloaddition reaction between nitriles and sodium azide
in water in the presence of ZnBr as a catalyst to obtain 5-
2
7
substituted 1H-tetrazoles. Since then various methods
have been reported for the synthesis of 5-substituted 1H-
tetrazoles, including, the use of (1) nanopowder, DMF,
[
bmim]N3 =
+
N
N
n-Bu
Me
N3–
8
9
9
0–135 °C; (2) NaN , CoY, DMF, 120 °C; (3) NaN ,
3
3
Figure 1 Structure of 1-butyl-3-methylimidazolium azide
1
0
CuFe O , DMF, 120 °C; (4) NaN , zeolite and zirconia,
2
4
3
1
1
DMF and H O, reflux; (5) NaN , K-10-M (M = Fe, Zn,
2
3
1
2
Cu, Ni), DMF, reflux; (6) NaN , InCl , DMF, micro-
3
3
1
3
Table 1 Effect of Catalyst Loading for the Synthesis of 5-Phenyl
wave heating; (7) NaN , AcOH, NMP–H O, microwave
3
2
H-Tetrazolea
1
1
4
irradiation; (8) NaN , montmorillonite K-10, microwave
3
1
5
H
heating; (9) NaN , TMSCl–NMP, microwave irradia-
tion; (10) NaN , MBA–ZnO, DMSO, 120–130 °C; and
11) NaN , ionic liquids, AcOH, microwave heating sys-
3
O
N
Cu(OAc)2
1
6
17
Ph
N
3
+ NH2OH + [bmim]N3
1
8
Ph
H
DMF, 120 °C
(
N N
3
12 h
tems. In all of these methods, 5-substituted 1H-tetrazoles
have been synthesized from the reaction of various nitriles Entry
but some of them are fairly toxic and also expensive with
Catalyst (mol%)
Yield (%)b
1
5
10
15
20
25
32
44
62
96
96
sodium azide. Hence the use of less expensive and more
available starting materials is very important for the effi-
cient and facial synthesis of 5-substituted 1H-tetrazoles.
Patil and co-workers have reported a method for the syn-
thesis of 5-substituted 1H-tetrazoles by reaction of organ-
2
3
4
5
SYNLETT 2012, 23, 2927–2930
Advanced online publication: 23.11.2012
a
All reactions were performed on a 0.5 mmol scale in 2.5 mL of sol-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
vent.
DOI: 10.1055/s-0032-1317671; Art ID: ST-2012-B0881-L
Georg Thieme Verlag Stuttgart · New York
b
Yields are given for isolated products.
©

2928
M. M. Heravi et al.
LETTER
Table 2 Effect of Solvents and Temperature for the Synthesis of 5-
Phenyl 1H-Tetrazole
of product (Table 1, entry 3). A greater catalyst loading
was thus necessary. By using 20 mol% of the Cu(OAc)2,
the yield of product was reached to 96% (Table 1, entry 4).
Hence 20 mol% was selected as an optimum catalyst load-
ing.
a,b
H
O
N
Cu(OAc)2
Ph
N
+
NH2OH + [bmim]N3
Ph
H
solvent, 12 h
N
N
The effects of solvents and temperature for the synthesis
of 5-phenyl 1H-tetrazole were also investigated (Table 2).
We found for this reaction that DMF is the solvent of
choice at 120 °C. (Table 2, entry 4).
Entry
Solvent
MeCN
Temp (°C)
Yield (%)c
1
2
3
4
83
100
100
120
120
56
H O
trace
88
2
Various aldehydes were examined under the optimized re-
action conditions. All reactions proceeded to completion
within 12 hours, and tetrazoles were isolated in excellent
yields (Table 3).
DMF
DMF
96
5
solventless
trace
The better results were obtained with aldehydes contain-
ing an electron-donating substituent (Table 3, entries 2
and 3) in comparison with those containing an electron-
withdrawing substituent (Table 3, entries 4 and 5). Using
salicylaldehyde (Table 3, entry 6), with steric hindrance
a
All reactions were performed on a 0.5 mmol scale in 2.5 mL of sol-
vent.
b
c
2
0 mol% of Cu(OAc)2.
Yields are given for isolated products.
8
4% of product was obtained. This one-pot reaction for
Initially, in an effort to find the optimum reaction condi-
tions, the reaction of benzaldehyde with hydroxylamine
the synthesis of 5-substituted 1H-tetrazoles was not en-
couraging for aliphatic aldehydes such as acetaldehyde,
since no products were isolated under the same reaction
conditions probably due to undesired aldol condensation
and [bmim]N was chosen as a model reaction, and the ef-
3
fect of catalyst loading was screened for the preparation of
5-phenyl 1H-tetrazole (Table1). As shown in Table 1, us-
(
Table 3, entry 7).
ing of 15 mol% of Cu(OAc) in DMF afforded 62% yield
2
Table 3 Synthesis of 5-Substituted 1H-Tetrazoles 4a,24
H
O
N
Cu(OAc)2
R
N
+
NH2OH
+
[bmim]N3
R
H
DMF, 120 °C
12 h
N N
4a–g
1
a–g
2
3
Entry
1
Aldehyde 1a–g
Product 4a–gb
Yield (%)c
Mp (°C)
213–215
Lit. mp (°C)
213–21410
H
N
N
CHO
96
N
N
1
1
a
4
4
a
H
N
N
N
CHO
2
3
4
5
96
98
89
90
249
251–25216
231–23310
258–26012
219–2219
N
b
b
H
N
N
N
MeO
CHO
MeO
228–231
256–257
219–222
N
1
c
4
c
H
N
N
Cl
CHO
Cl
N
N
1
d
4
d
H
N
N
O2N
CHO
O2N
N
N
1
e
4
e
Synlett 2012, 23, 2927–2930
© Georg Thieme Verlag Stuttgart · New York

LETTER
Click Synthesis of 5-Substituted 1H-Tetrazoles
2929
Table 3 Synthesis of 5-Substituted 1H-Tetrazoles 4a,24 (continued)
H
O
N
Cu(OAc)2
R
N
+
NH2OH
+
[bmim]N3
R
H
DMF, 120 °C
12 h
N N
4a–g
1
a–g
2
3
Entry
Aldehyde 1a–g
Product 4a–gb
Yield (%)c
Mp (°C)
219
Lit. mp (°C)
220–22223
H
N
N
N
CHO
OH
6
N
84
OH
1
1
f
4
4
f
H
N
O
N
N
7
H
trace
N
g
g
a
Reaction time: 12 h.
b
c
All products are known and their physical data were compared with those already reported.9,10,12,16,23
Yields of pure products.
In summary, we have described a new and efficient proce-
dure for the synthesis of 5-substituted 1H-tetrazole deriv-
atives by using a one-pot, three-component reaction
between aromatic aldehydes, hydroxylamine, and
(3) Huisgen, R.; Sauer, J.; Sturn, H. J.; Markgraf, J. H. Chem.
Ber. 1960, 93, 2106.
(
(
(
4) Koldobskii, G. L.; Ostrovskii, V. A. Usp. Khim. 1994, 63,
8
47.
5) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra,
R. K. Prog. Med. Chem. 1980, 17, 151.
6) Roh, J.; Vávrová, K.; Hrabálek, A. Eur. J. Org. Chem. 2012,
6101.
[
bmim]N in the presence of 20 mol% of Cu(OAc) as cat-
3
2
alyst. In this method, the reaction of aldehydes with hy-
droxylamine has produced aldoximes, and they have been
reacted without isolation with [bmim]N as a green source
(7) Demko, Z. P.; Sharpless, B. J. Org. Chem. 2001, 66, 7945.
3
(
(
8) Aridoss, G.; Laali, K. K. Eur. J. Org. Chem. 2011, 6343.
9) Rama, V.; Kanagaraj, K.; Pitchumani, K. J. Org. Chem.
of azide to produce 5-substituted 1H-tetrazoles. Further
purification with column chromatography was not neces-
sary. The advantages and merits of this method are the re-
placement of nitriles with aldehydes in the one-pot, three-
2
011, 76, 9090.
10) Sreedhar, B.; Suresh Kumar, A.; Yada, D. Tetrahedron. Lett.
011, 52, 3565.
(
2
component reaction and using of [bmim]N as an ionic
(11) Teimouri, A.; Najafi Chermahini, A. Polyhedron 2011, 30,
3
liquid as a green source of azide instead of highly toxic
NaN3.
2606.
(
12) Najafi Chermahini, A.; Teimouri, A.; Moaddeli, A.
Heteroat. Chem. 2011, 22, 168.
In addition to the aforementioned advantages, our one-
pot, three-component protocol has all qualities and supe-
riorities expected from a click chemistry, which was first
fully described by Sharpless et al. in 2001.26 It offers
chemistry tailored to generate substances quickly and re-
liably by joining readily available and nontoxic small
units such as aldehydes, hydroxylamine, and green source
of azides together in a one-pot reaction to afford the key
heterocycle, 5-substituted 1,2,3-tetrazole.
(
13) Patil, V. S.; Nandre, K. P.; Borse, A. U.; Bhosale, S. V. E. J.
Chem. 2012, 9, 1145.
(14) Gutmann, B.; Roduit, J. P.; Roberge, D.; Kappe, C. O.
Angew. Chem. Int. Ed. 2010, 49, 7101.
(
(
(
(
(
(
(
15) Marvi, O.; Alizadeh, A.; Zarrahi, S. Bull. Korean Chem. Soc.
011, 32, 4001.
16) Cantillo, D.; Gutmann, B.; Kappe, C. O. J. Am. Chem. Soc.
011, 133, 4465.
2
2
17) Myznikov, L. V.; Efimova, Y. A.; Artamonova, T. V.;
Koldobskii, G. I. Russ. J. Org. Chem. 2011, 47, 728.
18) Schmidt, B.; Meid, D.; Kieser, D. Tetrahedron 2007, 63,
4
92.
Acknowledgment
19) Patil, U. B.; Kumthekar, K. R.; Nagarkar, J. M. Tetrahedron
Lett. 2012, 53, 3706.
M.M.H. is thankful to Iran National Science Foundation for partial
financial assistance.
20) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S.
D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
21) (a) Heravi, M. M.; Baghernejad, B.; Oskooie, H. A. Mol.
Diversity 2009, 13, 395. (b) Heravi, M. M.; Jani, B. A.;
Derikvan, F.; Bamoharram, F. F.; Oskoiee, H. A. Catal.
Commun. 2008, 10, 272.
References and Notes
(
1) Butler, R. N. In Comprehensive Heterocyclic Chemistry;
Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, 674.
(22) Heravi, M. M.; Moghimi, S. Tetrahedron Lett. 2012, 53,
3
92.
23) Aureggi, V.; Sedelmeier, G. Angew. Chem. Int. Ed. 2007, 46,
440.
(2) Xue, H.; Gau, Y.; Twamley, B.; Shreeve, J. M. Chem. Mater.
(
2
005, 17, 191.
8
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2927–2930

2930
M. M. Heravi et al.
LETTER
(
24) General Procedure for the Synthesis of 5-Substituted
H-Tetrazoles 4a–g
remaining MeCN was removed under high vacuum to yield
yellow transparent liquid that became more viscous upon
extensive drying. Isolated yield was 92%.
1
To a mixture of aldehyde (1 mmol) and hydroxylamine (1.2
mmol) in DMF (5 mL) at 120 °C was added [bmim]N (1.5
Analytical Data for [bmim]N3
3
–
1 1
mmol) and Cu(OAc) (20 mol%). The mixture was stirred
IR (KBr): ν = 2019, 1636, 1571, 1465, 1337, 1168 cm . H
NMR (400 MHz, CDCl ): δ = 1.15 (3 H, t, CH ), 1.48 (2 H,
2
for further 12 h. After completion of the reaction, as
3
3
indicated by TLC, the reaction mixture was treated with H O
m, CH ), 1.80 (2 H, m, CH ), 3.85 (3 H, s, NCH ), 4.01 (2 H,
2
2 2 3
(
10 mL) and extracted with EtOAc (2 × 15 mL). The
t, NCH ), 7.24 (1 H, d, ArH), 7.45 (1 H, d, ArH), 9.21 (1 H,
2
1
3
aqueous layer was treated with 3 M HCl and extracted with
EtOAc (2 × 15 mL). The organic layers were dried over
anhyd Na SO and concentrated to give the 5-substituted
br s, ArH). C NMR (100 MHz, CDCl ): δ = 12.30, 19.1,
3
24.4, 36.4, 38.7, 124.1, 127.0, 142.8. Anal. Calcd (%) for
C H N : C, 53.02; H, 8.34; N, 38.64. Found (%): C, 53.12;
2
4
8
15
5
1
H-tetrazoles (Table 3).
H, 8.36; N, 38.61.
General Procedure for the Synthesis of 1-Butyl-3-
methylimidazolium Azide
Analytical Data for 5-Phenyl-1H-tetrazole (4a)
2
5
1
Mp 213–215 °C. H NMR (500 MHz, CDCl ): δ = 7.50 (m,
3
Freshly prepared 1-butyl-3-methylimidazolium chloride (20
mmol) and NaN (20 mmol) were added into deionized H O
3 H), 8.10 (m, 2 H), 10 (br s, 1 H). IR (KBr): ν = 683, 725,
–
1
785, 1162, 1561, 1607, 1733, 2606, 2852, 2923, 3424 cm .
(25) Valizadeh, H.; Amiri, M.; Khalili, E. Mol. Diversity 2012,
16, 319.
3
2
(25 mL), and the mixture was stirred for 24 h at r.t. The
solvent was removed under reduced pressure at 50 °C to
obtain the crude product containing azide ionic liquid and
NaCl, which was washed with MeCN (3 × 10 mL). The
(26) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
Synlett 2012, 23, 2927–2930
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