One-Pot Reactions for Synthesis of 2,5-Substituted Tetrazoles from Aryldiazonium Salts and Amidines

Article abstract of DOI:10.1021/acs.orglett.5b03068

One-pot sequential reactions of aryldiazonium salts with amidines followed by the treatment of I₂/KI under basic conditions provide 2,5-disubstituted tetrazoles in moderate to excellent yields. This one-pot synthesis has several advantages such as mild reaction conditions, short reaction time, convenient workup, and high yields, making this methodology practical.

Full text of DOI:10.1021/acs.orglett.5b03068

Letter
pubs.acs.org/OrgLett
One-Pot Reactions for Synthesis of 2,5-Substituted Tetrazoles from
Aryldiazonium Salts and Amidines
Mani Ramanathan, Yu-Hao Wang, and Shiuh-Tzung Liu*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
S
* Supporting Information
ABSTRACT: One-pot sequential reactions of aryldiazonium salts with amidines followed by the treatment of I2/KI under basic
conditions provide 2,5-disubstituted tetrazoles in moderate to excellent yields. This one-pot synthesis has several advantages such
as mild reaction conditions, short reaction time, convenient workup, and high yields, making this methodology practical.
Scheme 1. Preparation of Tetrazoles from Diazonium Salts
mong various N-heterocycles, tetrazoles are one of the
Amost stable, nitrogen-rich heterocyclic compounds and
have been studied extensively owing to the biological,
pharmaceutical, and material uses.1−5 Both 1,5- and 2,5-
disubstituted tetrazoles are the most notable members of the
tetrazole family. In particular, 2,5-substituted tetrazoles are
often used as key pharmacophores3 and photosensitive
materials.4 In addition, some 2,5-disubstituted tetrazoles are
convenient precursors for the preparation of a variety of N-
heterocycles.5
1,3-Dipolar cycloaddition reactions of azides with nitrile
compounds,6 or sodium azide with imidoylbenzotriazoles,7 are
typical synthetic routes to yield 1,5-disubstituted tetrazoles. Pd-
catalyzed Suzuki−Miyaura coupling8 and Baylis−Hillman
reaction9 have also been reported to prepare this scaffold. For
the synthesis of 2,5-substituted derivatives, multistep proce-
dures based on various cyclization protocols have been
reported.10 Alternatively, approaches involving the metal-
catalyzed arylation of readily available 5-substitued 2H-
tetrazoles have been documented.11 However, some of these
synthetic potentials rely on C−N bond formation with a
regioselective arylation.
Aryldiazonium salts, a class of inexpensive and readily
available chemicals, are useful precursors in a variety of organic
transformations.12 In this context, the reaction of aryldiazonium
chloride with phenylsulfonylhydrazone to yield 2,5-substituted
tetrazoles was reported by Kakehi and co-workers.10b,c In this
reaction, formazan (I) is the initial product, which then
undergoes the cyclization with the elimination of benzene-
sulfinic acid to yield the product (Scheme 1a). However, this
protocol still suffers from some drawbacks such as limited
substrate scope, preparation of starting materials, and the
generation of waste molecules. Thus, further development is
needed to enable a new method for the preparation of 2,5-
substituted tetrazoles in terms of atom economy and
environmental impact. We herein report a facile method for
the synthesis of 2,5-disubstituted tetrazole from the reaction of
aryladiazonium salts with amidines, followed by oxidative ring
closure (Scheme 1b).
1-(Iminophenylmethyl)-3-phenyltriazene (2a), prepared by
the treatment of phenyldiazonium tetrafluoroborate (1a) with
phenylamidine under aqueous basic conditions, was used as a
model compound to screen the optimum conditions for the
ring closure (Scheme 2). With 1.5 equiv of iodosobenzene
diacetate (IBDA) at both ambient and refluxing temperatures
using acetonitrile as the solvent, no desired product was
observed; instead, the starting material was consumed to
Received: October 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03068
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Preparation of 2 and N−N Coupling Leading to 3
Scheme 3. Tetrazoles from Various Diazonium Salts
unidentified compounds (Table 1, entries 1, 2). Similar inferior
results were observed with variety of copper sources such as
Table 1. Optimization of the Oxidative Ring Closure of 2
a
c
entry compd
reagents
conditions
yield (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
1a
1b
1c
PhI(OAc)2
THF/Δ/12 h
THF/rt/12 h
dec.
PhI(OAc)2
dec.
Cu(OAc)2/O2
Cu2O (cat)/O2
CuBr/ZnI2/Air
I2/KI/K2CO3
I2/KI/K2CO3
I2/KI/K2CO3
I2/KI/K2CO3
I2/KI/K2CO3
CH3CN/Δ/12 h
CH3CN/Δ/24 h
DMSO/130 °C/5 h
DMSO/100 °C/1 h
DMSO/rt/2 h
DMSO/rt/2 h
DMSO/rt/2 h
DMSO/rt/2 h
SM
dec.
dec.
3a (94)
d
3a (89)
3a (81)
b
b
3b (82)
3c (87)
b
10
a
b
2 (0.22 mmol). One-pot reaction; 1 (1.04 mmol), benzamidine-
(HCl) (1.04 mmol), and K2CO3 (5.21 mmol) in DMSO at rt for 1 h,
and then I2 (1.25 mmol) and KI (1.56 mmol) were added and stirred
c
d
at rt for another 1 h. Isolated yields dec = decomposition. NMR
yield.
Cu(OAc)2, Cu2O with O2 (Table 1, entries 3−4). Although a
mixture of CuBr/ZnI2 under aerobic conditions is known to be
an effective system for the tandem oxidative synthesis of 1,2,4-
triazoles,13 in our case it led to a complicated result (Table 1,
entry 5). To our delight, 2,5-disubstituted tetrazole was isolated
as the sole product in 94% yield under I2/KI/K2CO3 in DMSO
at 100 °C for 1 h (Table, 1 entry 6). Further investigation on
modification of reaction conditions allowed learning that the
cyclization proceeded smoothly at room temperature (Table 1,
entry 7). At this point of the investigation, we speculated the
oxidative N−N bond formation can be carried out in situ after
generation of 2a. In addition, the isolations of imino-triazene
2a−2c were difficult to obtain in high yields. These prompted
us to explore the feasibility of a sequential one-pot synthesis by
combining aryldiazonium salt, amidine, and then an I2/KI
mixture in the presence of a base. Indeed, 3a was isolated in
81% yield in a sequential one-pot reaction (Table 1, entry 8).
This one-pot approach was also applicable to the substrate 1b
and 1c (Table 1, entries 9−10). It is noteworthy that this
oxidative transformation is insensitive to moisture and air,
allowing the reaction to be carried out in an open flask.
With suitable reaction conditions in hand, we next explored
the generality of these reaction conditions for variously
substituted diazonium salts (Scheme 3). Aryldiazonium salts
with common substituents such as 4-tBu, 2,4,6-trimethyl, 3,4,5-
trimethoxy, 2-methylthio, 3,5-dimethyl, and 2-phenyl groups
(Scheme 3, entries 4a−4f) readily reacted with phenylamidine
followed by the oxidative ring closure to give the corresponding
tetrazoles as a single product in good isolated yields. It is noted
that 2,4,6-trimethylbenzenediazonium salt reacted with phenyl-
a
Reaction conditions: diazonium salt (1.04 mmol), benzamidine(HCl)
(1.04 mmol) and K2CO3 (5.21 mmol) in DMSO at rt for 1 h, then I2
(1.25 mmol) and KI (1.56 mmol) were added and stirred at rt for
another 1 h. Isolated yields given in parentheses.
amidine to yield 4b in 80% yield. However, 2,6-diisopropyl-
benzenediazonium salt did not undergo such a coupling with
amidine presumably due to the steric hindrance. This one-pot
synthesis is also applicable for the reaction of 1-naphthylene-
diazonium tetrafluoroborate with phenylamidine to produce 4g
in 77% yield. It is noted that the reaction also succeeded with
aryldiazonium salts bearing ortho substituents in decent yields
(Scheme 3, entries 4b−d, 4f, 4g). In addition, this protocol was
found to tolerate a wide range of functional groups such as halo,
cyano, carbomethoxy, carbonyl, and 2-acetamido functionalities
and furnished the corresponding tetrazoles in good yields
(Scheme 3, entries 4h−4m). Furthermore, tetrazoles with F−
and CF3− substituents could be accessed by this transformation
in good to excellent yields (Scheme 3, entries 4n−o). Finally,
to extend the applicability of this method in more complicated
molecules, we tested this methodology for a heteroaromatic
B
DOI: 10.1021/acs.orglett.5b03068
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
framework embedded with an aryldiazonium moiety. Thus, 4-
benzoylmorpholine substituted tetrazole 4p was efficiently
obtained in 74% yield, which is notoriously difficult to achieve
with the existing routes and suitable for further functionaliza-
tion.14 X-ray crystallographic determination confirms the
structure of 4p, and the ORTEP plot of 4p is shown in Figure
1. It is documented that iodination of an indole molecule can
Scheme 4. Tetrazoles from Various Amidines
Figure 1. ORTEP plot of 4p (30% probability ellipsoids).
be easily achieved via the treatment of iodine under basic
conditions.15 Indeed, the iodinated product 4q was obtained
under the conditions described above.
This protocol represents an easy-to-handle and versatile
method for a wide variety of tetrazoles, and hence we checked
the scalability. Phenyldiazonium tetrafluoroborate 1a on a 2 g
scale was treated with benzamidine hydrochloride under the
optimized conditions yielding the tetrazole 3a in 83% yield
(1.81 g), comparable to the small-scale experiment.
a
Reaction conditions: diazonium salt (1.04 mmol), amidine(HCl)
(1.04 mmol), and K2CO3 (5.21 mmol) in DMSO at rt for 1 h, and
then I2 (1.25 mmol) and KI (1.56 mmol) were added and stirred at rt
for another 1 h. Isolated yields given in parentheses.
We next examined various amidines against functionalized
aryldiazonium salts under the standard conditions. Aliphatic,
heteroaryl, and formamidines smoothly participated in the one-
pot transformation to afford the corresponding 2,5-disubsti-
tuted tetrazoles in moderate to good yields (Scheme 4). The
reaction was amenable with functional groups such as cyano
(5b), benzoyl (5c), and ester (5d) in the ortho- and para-
positions of the aryldiazonium salts, delivering the correspond-
ing tetrazoles in 66%−77% yields. Reaction of 1H-pyrazole-1-
carboximidamide with various diazonium salts yielded the
corresponding 2,5-functionalized tetrazoles in good isolated
yields (Scheme 4, entries 5e−5g). It is worth noting that
polynitrogenated tetrazoles with structural diversity of this kind
are previously unknown by any other method. Moreover,
formamidine is also a viable substrate, providing the desired
products. A variety of 2-aryl-2H-tetrazoles with various
functional groups were obtained in acceptable yields (Scheme
4, entries 5h−5j).
A possible mechanistic pathway is depicted in Scheme 5.
Initial reaction of amidine with diazonium salt results in the
formation of imino-triazene II. Further interaction with iodine
and deprotonation resulted in the formation of iodide III. An
intramolecular nucleophilic attack gives the quaternary
ammonium ion with a new N−N bond. Finally, subsequent
deprotonation and rearomatization furnishes the desired
product.
Scheme 5. A Possible Mechanism for N−N Bond Coupling
requirements of inert or anhydrous reaction conditions. Further
developments of aryldiazonium salt based novel synthesis of N-
heterocycles are currently in progress in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03068.
Experimental procedures and details of the character-
ization of all of the new compounds (PDF)
ORTEP plot of 4p, tables of atomic positional
parameters, bond distances and angles, and anisotropic
thermal parameters of 4p (PDF)
In summary, a diverse array of 2,5-difunctionalized tetrazoles
were prepared from the reactions of aryldiazonium salts with
amidines, followed by an oxidative N−N bond formation with
the use of inexpensive and easy-to-handle starting materials and
reagents. This convenient one-pot approach tolerates various
functional groups and represents a facile, atom-efficient, and
easy-to-handle synthesis of tetrazoles. The desired products
were obtained in high yields, even on gram scale, with no
Crystallographic data for 4p (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stliu@ntu.edu.tw.
C
DOI: 10.1021/acs.orglett.5b03068
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Council, Taiwan (Grant No.
MOST103-2113-M-002-002-MY3) for the financial support.
We also thank “National Taiwan University Mass Spectrom-
etry-based Proteomics Core Facility” for the measurement of
ESI mass data.
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