A novel synthesis of 1-aryl tetrazoles promoted by employing the synergy of the combined use of DMSO and an ionic liquid as the solvent system at ambient temperature

Article abstract of DOI:10.1016/j.tetlet.2009.08.063

The synergy of the combined use of DMSO and an ionic liquid viz. (bbim)⁺Br^- has brought about a mild, convenient, efficient, and rapid protocol for the synthesis of 1-substituted-1H-1,2,3,4-tetrazoles via the condensation of amines, triethyl orthoformate, and sodium azide at ambient temperature in excellent isolated yields (85-90%). The inherent Bronsted acidity of ionic liquid and high polarity of both IL and DMSO resulted in a significant enhancement in the reaction rate.

Full text of DOI:10.1016/j.tetlet.2009.08.063

Tetrahedron Letters 50 (2009) 6139–6142
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of 1-aryl tetrazoles promoted by employing the synergy
of the combined use of DMSO and an ionic liquid as the solvent system
at ambient temperature
Satish N. Dighe, Kishor S. Jain, Kumar V. Srinivasan *
Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Vadgaon (Bk), Pune 411 041, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
+
À
Article history:
The synergy of the combined use of DMSO and an ionic liquid viz. (bbim) Br has brought about a mild,
convenient, efficient, and rapid protocol for the synthesis of 1-substituted-1H-1,2,3,4-tetrazoles via the
condensation of amines, triethyl orthoformate, and sodium azide at ambient temperature in excellent
isolated yields (85–90%). The inherent Bronsted acidity of ionic liquid and high polarity of both IL and
DMSO resulted in a significant enhancement in the reaction rate.
Received 11 July 2009
Revised 17 August 2009
Accepted 21 August 2009
Available online 25 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1
-Substituted tetrazole
Amines
Triethyl orthoformate
Sodium azide
Ionic liquid
DMSO
7
1
. Introduction
The chemistry of heterocycles has acquired immense impor-
trimethyl azide, acetic acid or trifluoroacetic acid-catalyzed cycli-
zation between primary amines, or their salts, with an orthocarb-
oxylic acid ester and sodium azide, and PCl
9
5
and yttribium
tance in recent years. Tetrazoles represent an important class of
heterocycles which exhibit a wide range of applications in medic-
inal as well as synthetic chemistry. The tetrazole ring as an analog
and metabolically stable substitute of a carboxy group is exten-
sively used in molecular design and in the synthesis of modified
amino acids and peptidomimetics.2 Since the acidity of tetrazole
group corresponds closely with that of carboxylic acid, replace-
ment of C-terminal amino acid residue with a tetrazole analog of-
ten preserves or improves the biological activity of the parent
peptides. Alzheimer’s b-secretase (BACE1) inhibitor KMI-420 and
triflate-catalyzed cyclization from an amine, triethylorthoformate,
and sodium azide in volatile organic solvents.
1
0
1
Each of these methods has one or more of the following draw-
backs. For instance, the use of expensive and toxic metal catalysts,
harsh reaction conditions, refluxing for a prolonged period of time,
tedious work-ups, and the presence of hydrazoic acid, which is
highly toxic and explosive as well as volatile. The few methods that
seek to avoid hydrazoic acid liberation during the reaction by
avoiding acidic conditions require a very large excess of sodium
azide. In addition, all of the known methods made use of volatile
organic solvents, leading to complex isolation and recovery proce-
dures. Therefore, we sought to develop a more efficient and conve-
nient method that avoids these drawbacks and could be used on
both a laboratory and industrial scale.
its
a-isomer are potent drug molecules that possess tetrazole
3
4
sub-units. This nitrogen-rich ring system is used in propellants,
explosives, and pharmaceuticals. Furthermore, tetrazole moieties
are important synthons in synthetic organic chemistry.7
5
6
Although many synthetic protocols for 1-aryl tetrazoles have
been reported since the last mid-century, there is still a need for
the generation of more efficient processes for the synthesis of
The use of room temperature ionic liquids (ILs) as solvents for
chemical reactions offers several advantages from the environmen-
1
1,12
tal perspective.
In this context, in recent times, room temper-
1
-aryl tetrazoles. The routes to 1-substituted tetrazoles include
ature ionic liquids (RTILs), especially those based on the 1,3-di-
alkylimidazolium salts, have shown great promise as an attractive
alternative to conventional solvents. They possess the unique
advantages of high thermal stability, negligible vapor pressure,
immiscibility with a number of organic solvents, and recyclabil-
acid-catalyzed cycloaddition between hydrozoic acid and isocya-
nides, acid-catalyzed cycloaddition between isocyanides and
8
*
Corresponding author. Tel.: +91 20 25880349; fax: +91 20 25902629; mobile:
1
3
ity. In many cases, the products are weakly soluble in the ionic
phase so that the products can be easily separated by simple
+91 9823318406.
E-mail address: kumarv.srinivasan@gmail.com (K.V. Srinivasan).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.063

6
140
S. N. Dighe et al. / Tetrahedron Letters 50 (2009) 6139–6142
N
reaction was completed in just 15 min (paper communicated to
N
NaN3
Synth. Commun.).
N
R
NH
2
+
CH(OEt)3
R
N
In continuation of our research devoted to the combined use of
ionic liquid and DMSO in 0.1:1 proportion, we extended the inves-
tigation of this system toward the synthesis of 1-substituted tetra-
zoles by a one-pot condensation of sodium azide, substituted
amines, and triethyl orthoformate to afford 1-substituted-1H-
1,2,3,4-tetrazoles in excellent isolated yields in remarkably short
reaction times without any added catalyst (Scheme 1).
IL / DMSO
Substituted
aniline
triethylortho-
formate
(0.1:1) proportion
8
5-91%
1
-1.5h, 30 C
°
1
-substituted tetrazole
1
2
3
Scheme 1.
It was observed that under similar conditions, a wide range of
anilines containing electron-withdrawing as well as electron-
donating groups such as chloro, fluoro, methyl, methoxy, and ali-
phatic benzylamine easily underwent condensation with triethyl
orthoformate and sodium azide to give 1-aryl-1H-1,2,3,4-tetra-
zoles in 1–1.5 h with excellent isolated yields. The results are sum-
marized in Table 1. Whereas the unsubstituted aniline reaction
was completed in just 20 min, in the presence of electron-with-
drawing or electron-donating groups in reactant, the reaction
was completed within 1–1.5 h. It may be postulated that the inher-
ent Bronsted acidity of the ionic liquid plays an important role in
the breakdown of triethyl orthoformate, DMSO by virtue of its
inherent properties activates the azide anion as a ‘naked anion’
due to its non-solvation effects and also high polarity of combined
extraction. Srinivasan and co-workers14 have recently reported the
synthesis of 1-substituted tetrazoles in monobutylimidazolium io-
nic liquid.
Very recently we have investigated the synergy of the combined
use of ionic liquid and DMSO in the proportion 0.1:1 to synthesize
a variety of esters in remarkably short reaction times from acyl or
alky halides by their reaction with sodium carboxylates in the
above-mentioned mixed solvent medium in the absence of any
added catalyst under ambient conditions. In individual solvents,
there was no reaction of phenacyl bromide with sodium benzoate
under ambient conditions in DMSO, whereas that in the IL took
1
6 h for completion under similar conditions. Using the above
solvent mixture conditions DMSO/IL (1:0.1 proportion), the
Table 1
Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles
Entry
Substrate
Product
Compd No.
Time (min)
Yielda (%)
N
N
N
1
NH2
N
3a
20
86
N
N
N
2
3
4
5
Cl
Cl
NH2
N
3b
3c
3d
3e
80
75
75
80
88
90
85
88
Cl
Cl
N
N
N
N
NH
2
N
N
N
F
NH
2
N
F
N
N
N
H C
3
NH2
N
3
H C

S. N. Dighe et al. / Tetrahedron Letters 50 (2009) 6139–6142
6141
Table 1 (continued)
Entry
Substrate
Product
Compd No.
Time (min)
Yielda (%)
3
H C
H
3
C
N
N
6
7
8
9
N
3f
3g
3h
3i
80
89
85
90
86
85
N
NH2
N
N
N
H CO
3
NH2
N
90
85
90
80
H
3
CO
Cl
Cl
N
N
N
N
F
NH
2
F
NH
2
N
N
N
N
N
N
1
0
NH
2
N
3j
N
N
N
a
Isolated yields; TLC single spot.
solvents serves to solubilize sodium azide and facilitates the [3+2]
cycloaddition.
The synergy of combined use of IL and DMSO is evident from
the observation that the reaction did not proceed at all either in
+
À
The methods reported so far for the synthesis of 1-substituted
tetrazoles, either in acidic conditions using acids such as hydro-
chloric, acetic, trifluoroacetic, and sulfuric or solvents such as 2-
methoxyethanol, DMF, and methanol required very harsh reaction
conditions such as refluxing for 6–24 h. Compared to the reported
methods, our method is convenient, safe, and can be performed
under ambient conditions with easy isolation procedures by
drowning the reaction mixture into ice water.
DMSO or in [bbim] Br individually under similar conditions. The
IL could be recovered from the aqueous filtrate by subjecting it
to dehydration and removal of DMSO. The IR of this recovered IL
À
was identical to the synthetic (bbim)Br used in the process.
In conclusion, we have developed a mild, convenient, and effi-
cient protocol for the synthesis of 1-substituted-1H-1,2,3,4-tetra-
zoles via the condensation of amines, triethyl orthoformate, and
sodium azide using an IL and DMSO (0.1:1 proportions) as a sol-
vent as well as a promoter. The process gave rise to excellent iso-
lated yields of 1-substituted-1H-1,2,3,4-tetrazoles in 1–1.5 h under
ambient reaction conditions in shorter reaction times than hitherto
reported under ambient conditions.
The [3+2] cycloaddition between hydrazoic acid and cyanide
derivatives is well known and is one of the most efficient routes.
Unfortunately, hydrazoic acid is highly explosive. Practically, the
use of sodium azide would be convenient even though the [3+2]
cycloaddition energy barrier is significantly lower when used with
hydrazoic acid than with azide. To overcome this energy limitation,
synthesis has been designed either to control the hydrazoic acid
2
. Typical procedure for 1-phenyl-1H-1,2,3,4-tetrazole in
IL+DMSO (0.1:1)
1
5
formation or to use a large excess of azide ions as sodium azide
16
+
À
in the presence of metal catalysts or strong lewis acids. However,
the present methodology needs only 1 equiv of NaN , since the IL
The IL [bbim] Br is synthesized as per the procedure reported
1
7
3
by us.
A
promotes this reaction by virtue of its inherent Bronsted acidity
and both IL and DMSO provide high polarity in addition to their
function as a reaction medium, thus obviating the necessity of
using any additional catalyst.
mixture of aniline (5.3 mmol), triethyl orthoformate
+
(
6.4 mmol), and sodium azide (5.3 mmol) in [bbim] Br and DMSO
in 0.1:1 (0.5 g:5 g) proportions was stirred at ambient reaction
conditions. The progress of the reaction was monitored by TLC

6
142
S. N. Dighe et al. / Tetrahedron Letters 50 (2009) 6139–6142
with an elluant mixture of n-hexane and ethyl acetate (4.5:0.5).
After completion, the reaction mixture was added to crushed ice.
The precipitated product was filtered, washed with water, and
dried. The product was pure enough (single spot on TLC) for all
practical purposes. However, for characterization purposes it was
11. Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-VCH: Weinheim,
003.
2
1
2. For recent IL reviews see: (a) Sheldon, R. Chem. Commun. 2001, 2399–2407; (b)
Gordon, C. M. Appl. Catal., A 2001, 101–116; (c) Zhao, D.; Wu, M.; Kou, Y.; Min,
E. Catal. Today 2002, 1–14; (d) Zhao, H.; Malhotra, S. V. Aldrichim. Acta 2002, 35,
7
5–83.
3. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2084; (b) Wilkes, J. S. Green Chem.
002, 4, 73–86; (c) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S.
1
18
further purified by column chromatography.
2
Tetrahedron 2005, 61, 1015–1060.
1
4. Potewar, T. M.; Siddiqui, S. A.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron Lett.
Acknowledgment
2007, 48, 1721–1724.
1
1
1
5. Sauer, J.; Huisgen, R.; Strum, H. Tetrahedron 1960, 11, 241–251.
6. Kumar, A.; Narayanan, R.; Shechter, H. J. Org. Chem. 1996, 61, 4462–4465.
7. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org.
Chem. 2003, 68, 9371–9378.
We are grateful to Professor M. N. Navale, Founder President,
Sinhgad Technical Education Society, for providing us with the nec-
essary financial support and infrastructure for carrying out this
work.
18. Selected data for compounds3a, 3b, 3g, 3i are given:1
0
Compound 3a: pale yellow solid; mp 64–65 °C (lit. 64–65 °C); IR (CHCl
1
3
):
1
598, 1506, 1465, 1401, 1215, 1091, 1075, 1042, 998; H NMR (200 MHz,
CDCl
CDCl
3
3
): d 7.51–7.75 (m, 5H, ArH), 9.02 (s, 1H, tetrazole H); 13C NMR (50 MHz,
): d 121.1, 129.9, 130.1, 133.7, 140.5; Anal. Calcd for C : C, 57.53; H,
7 6 4
H N
References and notes
4
.14; N, 38.34. Found: C, 57.23; H, 3.98; N, 38.12.1
0
3
Compound 3b: White solid; mp 154–156 °C (lit. 155–156 °C); IR (CHCl ):
1
2
3
.
.
.
Bulter, R. N.. In Comprehensive Heterocyclic Chemistry; Katrizky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 4.
(a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393; (b) Wittenberger, S. J.
Org. Prep. Proced. Int. 1994, 26, 499–531.
Kimura, T.; Shuto, D.; Hamada, Y.; Igawa, N.; Kasai, S.; Liu, P.; Hidaka, K.;
Hamada, T.; Hayashi, Y.; Kiso, Y. Bioorg. Med. Chem. Lett. 2005, 15, 211–215.
Koguro, K.; Toshikazu, O.; Sunao, M.; Ryozo, O. Synthesis 1998, 910–914.
Sauer, J.; Huisgen, R.; Strum, H. J. Tetrahedron 1960, 11, 241–251.
(a) Duncia, J. V.; Pierce, M. E.; Santella, J. B. J. Org. Chem. 1991, 56, 2395–2400;
653, 1505, 1460, 1425, 1215, 1088, 1034, 996; 1H NMR (200 MHz, CDCl
1
7
3
): d
C
13
.55–7.62(m, 2H, ArH), 7.66–7.73 (m, 2H, ArH), 9.02 (s, 1H, tetrazole H);
): d 122.4, 130.4, 136.0, 140.4; Anal. Calcd for C
6.55; H, 2.79; N, 31.02. Found: C, 46.28; H, 2.59; N, 30.91.
NMR (50 MHz, CDCl
4
3
7
5
H N
4
Cl: C,
):
10
Compound 3g. White needles; mp 117–118 °C (lit. 116–117 °C); IR (CHCl
2
3
954, 1611, 1594, 1521, 1465, 1215, 1182, 1092, 1043, 996; 1H NMR (200 MHz,
4.
5.
6.
CDCl ): d 3.89 (s, 3H, OCH ), 7.05–7.10 (dd, 2H, J = 7.06 and 2.10 Hz, 2H, ArH),
.58–7.63 (dd, J = 7.06 and 2.10 Hz, 2H, ArH), 8.93 (s, 1H, tetrazole H); C NMR
50 MHz, CDCl ): 55.6, 115.0, 122.8, 126.7, 140.6, 160.5; Anal. Calcd
3
3
13
7
(
3
d
(
b) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139–4141.
for C
8
8
H N
4
O: C, 54.54; H, 4.58; N, 31.80. Found: C, 54.19; H, 4.37; N,
7
8
.
.
Jin, T.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 9435–9437.
(a) Zimmerman, D. M.; Olofson, R. A. Tetrahedron Lett. 1969, 58, 5081–5084; (b)
Fallon, F. G.; Herbst, R. M. J. Org. Chem. 1957, 22, 933–936.
3
1.65.
10
Compound 3i. White solid; mp 59–60 °C (lit. 58–59 °C); IR (CHCl
3
): 2950,
): d 5.60 (s,
), 7.28–7.44 (m, 5H, ArH), 8.52 (s, 1H, tetrazole H); C NMR (50 MHz,
): d 52.0, 128.2, 129.2, 129.3, 132.8, 142.4; Anal. Calcd for C : C,
9.99; H, 5.03; N, 34.98. Found: C, 59.67; H, 4.89; N, 34.67.
1
2
2
845, 1530, 1476, 1436, 1244, 1163, 1104; H NMR (200 MHz, CDCl
3
13
9
.
(a) Satoh, Y.; Marcopulos, N. Tetrahedron Lett. 1995, 3, 1759–1762; (b) Gupta, A.
K.; Oh, C. H. Tetrahedron Lett. 2004, 45, 4113–4116.
H, CH
2
CDCl
5
3
8 8 4
H N
1
0. Su, W.; Hong, Z.; Shan, W.; Zhang, X. Eur. J. Org. Chem. 2000, 2723–2726.