Regioselective arylation of N-tributylstannylated 5-substituted tetrazoles by diaryliodonium salts in the presence of Cu(OAc)2

Article abstract of DOI:10.1016/S0040-4039(02)01326-6

The arylation of N-tributylstannylated 5-substituted tetrazoles with diaryliodonium salts at room temperature without base in CH₂Cl₂ in the presence of stoichiometric amounts of Cu(OAc)₂ proceeds regioselectively at the N-

Full text of DOI:10.1016/S0040-4039(02)01326-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6217–6219
Regioselective arylation of N-tributylstannylated 5-substituted
tetrazoles by diaryliodonium salts in the presence of Cu(OAc)2
Dmitri V. Davydov,a,* Irina P. Beletskaya,a Boris B. Semenovb and Yuri I. Smushkevichb
aChemical Department of Lomonosov Moscow State University, Leninsky Gory, Moscow 119899, B-234, Russia
bMendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, Moscow 125047, Russia
Received 29 April 2002; revised 18 June 2002; accepted 28 June 2002
Abstract—The arylation of N-tributylstannylated 5-substituted tetrazoles with diaryliodonium salts at room temperature without
base in CH2Cl2 in the presence of stoichiometric amounts of Cu(OAc)2 proceeds regioselectively at the N-2 position of the
tetrazole ring. © 2002 Elsevier Science Ltd. All rights reserved.
New catalytic methods of CꢀN bond formation have
attracted attention over recent years due to the huge
synthetic potential of these approaches1–3 and the mild
conditions required in comparison with the classical
Ullmann reaction4 particularly for labile substances
such as 2,5-disubstituted tetrazoles, which demonstrate
a broad spectrum of biological activity5 and which are
used as a convenient source of nitrylimines.6 The most
successful method of 2,5-disubstituted tetrazoles synthe-
sis is the direct regioselective introduction of the
required substituent at C(2) of readily available 5-sub-
stituted tetrazoles. Herein, we propose a mild and
convenient method of regioselective arylation of readily
available N-tributylstannylated 5-substituted tetra-
zoles7,8 with diaryliodonium salts in the presence of
Cu(OAc)2 under neutral conditions.
zole as substrate.7 The optimization data are summa-
rized in Table 1.
First of all we considered the possibility of thermal
reactions of the chosen substrate with the diphenyliodo-
nium salt used earlier for arylation of the Na-salt of
5-tolyltetrazole.9 It was shown that this process can be
realized only on heating in high boiling solvents, such
as o-xylene where fast decomposition of the product is
observed (Table 1, entry 1) resulting in low yields.
The first example of Pd-catalyzed CꢀN bond formation
by arylation of dialkylaminotrialkylstannanes with
PhBr was published by Migita in 1983.10 However, we
failed to realize arylation by this way using N-stannyl-
ated 5-phenyltetrazole under a broad variety of reaction
conditions (Table 1, entry 2) in good accordance with
later data of the Migita group during attempts to
arylate N-stanylated imines.11
Within the framework of reactions between stannylated
tetrazoles and arylation agents, it is possible to identify
different variations of 2,5-disubstituted tetrazole syn-
thesis. These include the thermal arylation of sub-
strates,9 the Pd-catalyzed arylation of N-stannylated
compounds,10,11 and the arylation of N-tributylstannyl-
ated 5-substituted tetrazoles by boron12 and bismuth13
organoelement compounds in the presence of
Cu(OAc)2. Optimization of the reaction conditions was
performed using N-tributylstannylated 5-phenyltetra-
Using p-tolylboronic acid,12,13 as the arylation agent,
arylation was also unsuccessful (Table 1, entry 3). It
14
was shown that Ph3Bi(OAc)2 has a low activity as an
arylation agent (Table 1, entry 4), moreover its large
molecular weight and the fact that only one Ph-group
can take part in the arylation process makes it an
Keywords: stannylated tetrazoles; arylation; regioselectivity; iodonium salts; Cu(OAc)2.
* Corresponding author. E-mail: dvdav@elorg.chem.msu.ru
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01326-6

6218
D. V. Da6ydo6 et al. / Tetrahedron Letters 43 (2002) 6217–6219
Table 1. Arylation of N-tributylstannylated 5-phenyltetrazole under various conditions
N
Arylation agent
Catalyst, equiv.
Solvent, T (°C)
Reaction time (h)
2,5-Diphenyltetrazole yield (%)a
−
1
2
3
4
5
6
7
Ph2I+BF4
–
o-Xylene, 144
Solvent,c 20
CH2Cl2, 20
CH2Cl2, 20
CH2Cl2 20
CH2Cl2, 20
CH2Cl2, 20
1
8
16
8
8
8
Tars (traces of product)
No product
No product
Low yield
No product
75
PhI (PhBr)
‘Pd’b, 0.05
p-TolB(OH)2
Ph3Bi(OAc)2
Cu(OAc)2, 1.1
Cu(OAc)2, 1.1
Cu2Hal2,d 1.1
Cu(OAc)2, 1.1
Cu(OAc)2, 1.1
−
Ph2I+BF4
−
Ph2I+BF4
Ph2I+Cl−
8
72
a Yields of the products were measured spectroscopically (UV–vis) after the separation of aliquots of the reaction mixture by TLC.
b Various complexes of Pd(O) and Pd(II) were used.
c EtOH, C6H5CH3, CH3CN, DMFA were applied as solvents.
−
d Cu(I) halides initiate slow decomposition of Ph2I+BF4
.
inefficient reagent for arylation. Cu(I) salts are not
active as promoters of the arylation reaction (Table 1,
entry 5).
The reaction conditions found were used for obtaining
some biologically active tetrazoles containing the indole
fragment in the 5-position of the tetrazole ring. N-Stan-
nylated 5-(3-indolyl)tetrazole reacted readily with Ph2I+
Cl− giving 2,5-disubstituted tetrazole in high yield
(Table 2, entry 4). The introduction of a methylene
bridge between the indole and tetrazole parts of the
substrate led to a decrease in the product yield (Table 2,
entry 5). With a benzhydryl substituent at the 5-posi-
tion of the tetrazole ring no arylation product was
observed (Table 2, entry 9). Probably the result of this
reaction also depends on the stability of the radical
which is formed on the first oxidative stage of the
process. This radical must be intercepted by Ph2I+Cl− in
order for the reaction to proceed.16 The ion-radical
mechanism can be demonstrated with a benzhydryl
substituent in the 5-position of the tetrazole ring (Table
2, entry 8), when addition of p-dinitrobenzene leads to
disappearance of the arylation product in the reaction
mixture. The details of reaction mechanism are under
investigation.
During the course of these studies we found that aryla-
tion of N-tributylstannylated 5-phenyltetrazole does
occur with Ph2I+BF4 in the presence of Cu(OAc)2 in
−
CH2Cl2 at room temperature producing 2,5-
diphenyltetrazole in high yield (Table 1, entry 6). We
also found that Ph2I+BF4 can be replaced by the less
−
expensive Ph2I+Cl− without a decrease in the product
yields (Table 1, entry 7). The results of arylation of
some N-stannylated tetrazoles under these conditions
are presented in Table 2.
The data included in Table 2 show that stanylated
5-aryltetrazoles containing alkyl substituents in the aro-
matic ring, for example a methyl group (Table 2, entry
2), or a halogen atom, such as Br (Table 2, entry 3),
react readily with Ph2I+Cl−. However, the presence of
an electron-withdrawing group in the aromatic ring, for
example an NO2 group, prevented the arylation process
(Table 2, entry 6). Similarly a negative result was
observed when a 4-pyridyl fragment was in the 5-posi-
tion of the tetrazole ring (Table 2, entry 7). Thus, the
success of the reaction probably depends on the Red–
ox potential of the stannylated tetrazole according to
classical mechanism of R4Sn oxidation by Cu(OAc)2.15
Thus, this method allows the direct regioselective aryla-
tion of N-stannylated tetrazoles under mild and neutral
conditions.
Synthetic procedure: To 0.001 mol of N-tributylstannyl-
ated 5-substituted tetrazole and 0.001 mol of Ph2I+Cl−
Table 2. Arylation of N-tributylstannylated tetrazoles with Ph2I+Cl− in the presence of Cu(OAc)2 in CH2Cl2 at 20°C
N
Substituent at the 5-position of the substratea
Reaction time (h)
Isolated yield of 2,5-disubstituted tetrazole (%)
1
2
3
4
5
6
7
8
9
Ph
8
8
8
8
8
16
16
16
16
70
65
73
68
p-CH3C6H4
p-BrC6H4
3-(1H-Indol-3-yl)
3-(1H-Indol-3-ylmethyl)
34
b
p-NO2C6H4
No product
No product
No product
No Product
4-Pyb
3-(1H-Indol-3-ylmethyl)c
3-[1H-Indol-3-yl(phenyl)methyl]
a All substrates were obtained by known methods and their spectral characteristics were in good agreement with literature data.
b We did not observe products of arylation even under reflux with an excess of Cu(OAc)2 over 16 h.
c In the presence of 1 equiv. of p-dinitrobenzene.

D. V. Da6ydo6 et al. / Tetrahedron Letters 43 (2002) 6217–6219
6219
in 10 ml dry CH2Cl2, 0.0012 mol of Cu(OAc)2 was
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