Tin-Catalyzed Synthesis of 5-Substituted 1H-Tetrazoles from Nitriles: Homogeneous and Heterogeneous Procedures

Article abstract of DOI:10.1002/adsc.201801117

The preparation of 5-substituted 1H-tetrazoles was efficiently achieved by reaction of trimethylsilylazide with nitriles using a triorganotin alkoxide precatalyst. The reaction mechanism was first investigated using a homogeneous tributyltin derivative and was explored through experimental investigations and DFT calculations. A heterogeneous version was then developed using a polymer-supported organotin alkoxide and afforded an efficient method for the preparation of tetrazoles in high yields with an easy work-up and a residual tin concentration in the desired products compatible for pharmaceutical applications (less than 10 ppm). (Figure presented.).

Full text of DOI:10.1002/adsc.201801117

Title: Tin-Catalyzed Synthesis of 5-Substituted 1H-Tetrazoles from
Nitriles: Homogeneous and Heterogeneous procedures
Authors: Jean-Mathieu Chrétien, Gaëlle Kerric, Françoise Zammattio,
Nicolas Galland, Michael Paris, Jean-Paul Quintard, and
Erwan Le Grognec
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801117
Link to VoR: http://dx.doi.org/10.1002/adsc.201801117

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Tin-Catalyzed Synthesis of 5-Substituted 1H-Tetrazoles from
Nitriles: Homogeneous and Heterogeneous procedures
Jean-Mathieu Chrétien,a Gaelle Kerric,a Françoise Zammattio,a Nicolas Galland,a
Michael Paris,b Jean-Paul Quintard,a Erwan Le Grogneca *
a
Université de Nantes, CNRS, Chimie Et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR
CNRS 6230, Faculté des Sciences et des Techniques; 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France. Phone: (+33)-2.76.64.51.84; e-mail: erwan.legrognec@univ-nantes.fr
Université de Nantes, CNRS, Institut des Matériaux Jean Rouxel (IMN), 2 rue de la Houssinière BP 32229, 44322
b
Nantes cedex 3, France
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The preparation of 5-substituted 1H-tetrazoles was supported organotin alkoxide and afforded an efficient
efficiently achieved by reaction of trimethylsilylazide with method for the preparation of tetrazoles in high yields with
nitriles using a triorganotin alkoxide precatalyst. The reaction an easy work-up and a residual tin concentration in the
mechanism was first investigated using a homogeneous desired products compatible for pharmaceutical applications
tributyltin derivative and was explored through experimental (less than 10 ppm).
investigations and DFT calculations. A heterogeneous version
was then developed using a polymer-
Keywords: Azides; Stannanes; Tin; Cycloaddition; Solid-
phase synthesis
A literature survey reveals that one of the most
efficient syntheses of 5-substituted 1H-tetrazoles
involves an organotin azide generated in situ from
trimethylsilyl azide and dibutyltin oxide,[12] or
tributyltin chloride.[13] However, the use of organotin
reagents in synthetic chemistry is sometimes
detrimental for the targeted applications due to the
possible toxicity of organotin byproducts. To
circumvent this issue, numerous procedures and
methodologies have been developed to eliminate tin
byproducts from the products and have been
reviewed.[14] Most of these methodologies are based on
partition methods starting from usual triorganotin
reagents,[15] but some others involve highly polar
organotin reagents[16] or media[17] as well as
perfluorinated ones which highly improve the
elimination of organotin by-products.[18]
The use of a catalytic amount of organotin
reagents[19] or of monoorganotin reagents[20] have also
been exploited, but the most efficient approaches to
avoid contamination by organotin by-products remain
the grafting of the organotin reagent on an appropriate
substrate which can be a phosphonium salt,[21] an ionic
liquid,[22] an inorganic matrix,[23] or an organic
polymer.[14a-14d] While the above approaches have
demonstrated their efficiency in numerous reactions,
their use for the synthesis of 5-substituted 1H-
tetrazoles has been overlooked. It is, however, worth
Introduction
The tetrazole heterocycle has known an increasing
interest in the last decades. Its use concerns many areas
of chemistry such as medicinal chemistry,[1],[2] crop
protection,[3] explosives,[4] coordination chemistry[5] or
organocatalysis.[6] In medicinal chemistry, this interest
is focused on the 5-substituted 1H-tetrazole unit which
is considered as a carboxylic acid isostere for the
design of active pharmaceutical ingredients.[7] The
huge number of angiotensin II receptor blockers which
contain a biphenyltetrazole framework is illustrative of
this importance.[8] Therefore, the synthesis and
functionalization of 5-substituted 1H-tetrazoles have
been widely studied and numerous procedures have
been reported and reviewed.[9] Due to the hazards
encountered with the use of hydrazoic acid,[10] most of
them involve the [3+2] cycloaddition of an azide anion
to a nitrile in the presence of an acid. The
cycloaddition presents a high activation barrier which
prompted researchers to use additives or catalysts for
milder experimental conditions. For instance,
Brönsted or Lewis acids are efficient catalysts for this
reaction, as well as metal salts which have been found
to be efficient in stoichiometric or sub-stoichiometric
quantities.[11]
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
noting that procedures for the synthesis of 5-
high yields were obtained with DMF (entries 7 and 8),
while NMP afforded only moderate yields (entries 9
and 10). Finally, yields were significantly improved
using dibutylether (Bu2O) as solvent (entries 11 and
12). Through these runs, we also observed that the
presence of water, even in small quantities, had a
dramatic negative effect on the yield as previously
reported.[28] These results confirmed that trialkyltin
alkoxides can act as precatalysts for the synthesis of 5-
substituted 1H-tetrazoles. This screening also
highlights that compound 2a is more efficient than 2b.
Moreover, control experiments with dibutyltin oxide
afforded lower yields in similar experimental
conditions (entries 13 and 14). Similarly, when
Bu3SnCl was considered either with Me3SiN3 or with
NaN3, poor yields were obtained (entries 15 and 16).
The latter results are in good agreement with a
previous work reporting that a large excess (2.5 equiv)
of both tributyltin chloride and sodium azide is
required to obtain yields around 80%.[13b]
substituted
1H-tetrazoles
involving
higher
trialkylorganotin derivatives to facilitate the partition
between polar products and unpolar tin byproducts
have been reported.[24] In the same context, Curran et
al have proposed an efficient procedure for the
synthesis of 5-substituted 1H-tetrazoles using a
perfluorotin azide and a fluorous/organic liquid-liquid
extraction for the purification.[25]
Herein, we report the synthesis of 5-substituted 1H-
tetrazoles from nitriles through a [3+2] cycloaddition
catalyzed by tributyltin azide. This catalyst is
generated in situ with tributyltin alkoxide and
trimethylsilyl azide. The experimental and theoretical
investigations are reported and discussed. The results
related to the adaptation of this reaction to a
heterogeneous phase reaction involving a polymer-
supported catalyst,[26] allowing similar yields and
avoiding the drawbacks of the removal of organotin
residues are also described.
Table 1. Effect of solvent and catalyst on the formation of
tetrazole 3a from 1a.
Results and Discussion
Scope and limitations of the reaction catalyzed by
a tributyltin derivative. We set out to explore the
synthesis of 5-substituted 1H tetrazoles 3 resulting
from the addition of an organotin azide on a nitrile 1.
Our investigations started from contributions
involving trimethylsilyl azide (Me3SiN3) and
dibutyltin oxide considered in stoichiometric or in a
catalytic amount.[12] We focused on a dibutyltin oxide
surrogate readily graftable on the polymer. At this
stage, we assumed that trialkyltin alkoxides could be
valuable precursors of triorganotin azides and started
our investigations by this consideration. Tributyltin
methoxide 2a and tributyltin ethoxide 2b were
prepared according to the literature, starting from
bis(tributyltin) oxide and dimethyl or diethylcarbonate
(scheme 1).[27]
Entry Sn
precatalyst
Solvent
T(°C) Yield (%)
1
2
3
4
5
6
7
8
Bu3SnOMe
Bu3SnOEt
Bu3SnOMe
Bu3SnOEt
Bu3SnOMe
Bu3SnOEt
Bu3SnOMe
Bu3SnOEt
Bu3SnOMe
Bu3SnOEt
Bu3SnOMe
Bu3SnOEt
(Bu2SnO)n
(Bu2SnO)n
Bu3SnCl
toluene
toluene
DME
DME
1,4-dioxane 100
1,4-dioxane 100
DMF
DMF
NMP
NMP
Bu2O
Bu2O
DMF
Bu2O
Bu2O
Bu2O
110
110
85
15
14
24
11
44
42
93
57
53
47
99
85
45
73
26
18
85
150
150
150
150
140
140
150
140
140
140
9
10
11
12
13
14
15
16
[a]
Bu3SnCl
Scheme 1. Preparation of tributyltin alkoxides 2a and 2b.
[a] TMSN3 was replaced by NaN3 (1.5 equiv).
These tributyltin alkoxides were considered for the
synthesis of 5-phenyl 1H tetrazole 3a in different
solvents starting from benzonitrile. The results
obtained in this preliminary study using 10 mol% of
2a or 2b are reported in Table 1. When the reaction
was carried out in toluene (entries 1 and 2), 5-phenyl
1H-tetrazole 3a was obtained in low yields, regardless
the tin catalyst although this solvent was extensively
considered previously (entries 1 and 2).[12d] Similar
results were observed when 1,2-dimethoxyethane was
used (entries 3 and 4) and only moderate yields were
obtained with 1,4-dioxane (entries 5 and 6). By
considering polar solvents with high boiling points,
Then, precatalyst loading tests were performed with
2, 5 and 10 mol% of 2a in DMF or in Bu2O and it
appeared that 10 mol% of catalyst was necessary to
obtain yields over 90% after 4 h (Table 2). When
reducing the amount of 2a to 5 and 2 mol%, yields in
3a significantly decreased while control experiments
confirmed that no reaction occurred in the absence of
2a. Furthermore, when Me3SiN3 was replaced by
NaN3, the yield was found to be low (9%, entry 9).
At this stage, the scope of the reaction for
substituted benzonitriles was investigated using 2a as
precatalyst in DMF at 150 °C and in Bu2O at 140 °C.
The results reported in Table 3, revealed that a large
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
variety of substituents were found to be compatible
with the procedure. Both electron-donating and
electron-withdrawing groups on the aryl moiety
afforded efficiently tetrazole products 3a-3p.
a complete conversion of Bu3SnX to Bu3SnN3 after 18
h at room temperature. When NaN3 was replaced by
Me3SiN3, the reaction was found to proceed faster due
to the higher miscibility of Me3SiN3 with Bu3SnCl, and
conversion to Bu3SnN3 was observed at room
temperature in a few minutes. After distillation,
Bu3SnN3 was obtained in 95% yield and characterized
by FT-IR and 119Sn NMR. Interestingly, the 119Sn
chemical shift was found to be strongly solvent
dependent as reported in table 4. These differences in
chemical shifts can be explained by the modification
of the tin hybridization from sp3 to sp3d due to
intermolecular interactions between the tin atom and a
solvent heteroatom or a nitrogen atom of the second
molecule of Bu3SnN3.[30]
Table 2. Effect of precatalyst loading and solvent on the
conversion of benzonitrile into tetrazole 3a.
Entry Solvent
x (mol%)
T(°C)
Yield
(%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
Bu2O
Bu2O
Bu2O
Bu2O
Bu2O
0
2
5
10
0
2
5
10
10
150
150
150
150
140
140
140
140
140
0
48
51
93
0
32
76
99
9[a]
Table 3. Synthesis of 5-substituted 1H-tetrazoles promoted
by Bu3SnOMe.
[a] Me3SiN3 was replaced by NaN3 (1.5 equiv)
Aromatic nitriles bearing electron-donating groups
like p-Me, p-OMe, p-NEt2 afforded good yields of
products 3b, 3c or 3d. Similarly, aromatic nitriles
bearing electron withdrawing groups (m-OMe, p-NO2,
m-Cl, p-Cl, m-CF3) afforded excellent yields in
products 3f, 3g, 3h, 3i or 3j. In addition, 4-
hydroxybenzonitrile gave the corresponding tetrazole
3k in good yield, while methyl 4-cyanobenzoate
afforded 4-(1H-tetrazol-5-yl)benzoic acid 3l due to the
hydrolysis of the ester function during the workup
procedure. On the other hand, moderate to low yields
were obtained with ortho substituted aromatic nitriles
(tetrazoles 3m, 3n, 3o), indicating that the reaction is
sensitive to the steric hindrance near the nitrile group.
However, 1-naphtonitrile where the effective
hindrance on the α-position is lower and the activation
of the nitrile higher when compared to ortho biphenyl
nitrile afforded high yield (3p). Finally, we
investigated the reactivity of aliphatic nitriles and
found that the procedure was also efficient for these
substrates. Phenylacetonitrile, valeronitrile, and
nonanenitrile furnished the desired tetrazoles 3q-s in
good to moderate yields in the same reaction
conditions, underlining the efficiency of the
methodology since these substrates are poorly reactive
in this type of reaction with other methods.[11e]
Experimental investigations of the reaction
mechanism. At this stage, further investigations were
conducted in order to collect insights on the reaction
mechanism. The reactive species supposed to be
formed in this reaction is tributyltin azide (Bu3SnN3).
Therefore, its synthesis was carried out using a
described procedure starting from tributyltin halide
and NaN3 (Table 4).[29] Due to the low solubility of
NaN3 in organic solvents, different experimental
conditions were considered for this reaction. A careful
monitoring of the reaction using 119Sn NMR revealed
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Table 4. Solvent dependence of 119Sn NMR chemical shift
for Bu3SnN3.
Entry Bu3SnX Solvent

119Sn
(ppm)[a]
(Bu3SnN3)
1
2
Bu3SnI
Bu3SnI
without
DMF-
d7
76
-51
3
4
5
6
Bu3SnI
Bu3SnCl without
Bu3SnCl
Bu3SnCl
THF-d8
66
63
103
111
C6D6
CDCl3
[a]
Me4Sn ( = 0 ppm) was used as internal standard for
chemical shift measurement.
When the reaction between Bu3SnOMe and
Me3SiN3 was carried out without any solvent at 25°C,
an NMR monitoring by 119Sn NMR and 29Si NMR
conducted at room temperature reveals the occurrence
of a partial exchange after 1 hour (Scheme 2, eq 1).
Indeed, two signals were observed on both spectra,
corresponding to Bu3SnOMe ( = 113 ppm) and
Bu3SnN3 ( = 63 ppm) on 119Sn NMR spectrum, and to
Me3SiN3 ( = 16.6 ppm) and Me3SiOMe ( = 19.5
ppm) on 29Si NMR spectrum. In addition, the FT-IR
spectrum clearly exhibits the characteristic band at
2065 cm-1 ascribed to the vibration asN3 in
Bu3SnN3.[31] Furthermore, the reaction between
benzonitrile and tributyltin azide does not occur at
room temperature and requires an appropriate heating
(4 h at 140 °C) to afford N-tributylstannyl 5-phenyl
1H-tetrazoles 3a-Sn (Scheme 2, eq 2).[12a],[32] After 4 h
at 140 °C, the solvent-free reaction afforded
quantitatively 3a-Sn, which was isolated and
characterized in spite of its sensitivity to hydrolysis.
Note that well-defined signals were observed in 13C
NMR spectrum, while broader signals were observed
Scheme 2. Tributyltin azide: its generation and its reactivity
with benzonitrile.
1
in H and 119Sn NMR spectra, a result which is in
agreement with the possible intermolecular
associations and metallotropy.[32] All attempts to
isolate the silylated tetrazole (intermediates 3a-Si)
obtained by reaction between 3a-Sn and Me3SiN3
were unsuccessful (Scheme 2, eq 3). However, when
the reaction was performed in a NMR tube under an
inert atmosphere, the 29Si NMR spectrum exhibits a
signal at 10.2 ppm, different from the chemical shifts
of Me3SiN3 (16.6 ppm) and Me3SiOMe (19.5 ppm)[33]
which could be assigned to intermediates 3a-Si.
Based on these results and taking into account the
previously proposed mechanism,[12d] we considered
the catalytic cycle described in scheme 3 as a plausible
one. First, the precatalyst 2a reacts with trimethylsilyl
azide to afford tributylstannyl azide which is the active
species of the reaction. This reaction proceeds at room
temperature and therefore cannot be the limiting step.
Scheme 3. Proposed mechanism for the synthesis of 5-
substituted 1H-tetrazoles promoted by Bu3SnOMe.
The reaction between tributyltin azide and nitrile
exhibits a higher energetic barrier to lead to adducts
3a-Sn. The latter reacts with another molecule of
trimethylsilyl azide to give intermediates 3a-Si with
concomitant regeneration of Bu3SnN3 and finally, a
protonolysis of 3a-Si affords the 5-phenyl 1H-
tetrazole 3a.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Figure 1. Hammett plot for reactivity of substituted benzonitriles with in situ generated tributyltin azide.
At this stage, it remains to clarify the intimate
mechanism of the rate determining step of the reaction
in order to establish its synchronous or non-
synchronous character. For this purpose, we have
conducted additional experimental investigations. We
have carried out competitive experiments between
benzonitrile and meta- or para-substituted
benzonitriles in order to establish a Hammett
relationship based on the relative kinetics of these
reactions. These experiments have been carried out
according to the Doering-Henderson approximation
(reactant/substrate ratio = 1/5)[34] to ensure accurate
measurements in line with kinetics for Hammett
relationship.[35] As suggested from yields given in
Table 3, benzonitriles substituted by strong electron-
withdrawing groups exhibited a higher reactivity when
compared to those substituted by electron releasing
ones. As shown in Figure 1, a Hammett ρ.σ
relationship was obtained with a calculated ρ-value of
+0.58. This positive ρ-value is indicative of a slight
negative charge at the benzylic carbon in the transition
state, a result in agreement with a nucleophilic attack
of the azide on the carbon of the nitrile group probably
combined with an electrophilic assistance of tin on the
nitrogen atom of the nitrile.
DFT investigations of the reaction mechanism.
Further investigations have been performed by means
of quantum mechanical calculations at the BMK/cc-
pVDZ level of theory. The presented free energies are
corrected from solvent effects and are computed for
the 140 °C and 1 mol.L–1 standard state. At first, we
considered the mechanism of the reaction between
Me3SiN3 and benzonitrile in the absence of catalyst. In
agreement with the pioneering computational work of
Noodleman and Sharpless,[36] dealing with the
elucidation of the mechanisms of tetrazole formation
by addition of azide to nitriles, two different pathways
have been characterized which correspond to the
formation of either 1,5 or 3,5-regioisomers 3a-Si
(scheme 4). Both (A) and (B) reaction pathways
exhibit an energy barrier, corresponding to a concerted
[3+2] cycloaddition. The respective values, 46.1 kcal
mol–1 and 48.4 kcal mol–1 with respect to the reactants,
are calculated in good agreement with previous DFT
values obtained by Kappe et al.[37] for the
cycloaddition of Me3SiN3 with acetonitrile. These high
energy barriers are consistent with the absence of
reaction at 140 °C between Me3SiN3 and benzonitrile
although the reaction is predicted exergonic (GR < 0).
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Scheme 4. Evaluation of the activation energy for uncatalyzed cycloaddition of Me3SiN3 to benzonitrile (computed at the
BMK/cc-pVDZ level of theory).
Then, we studied the influence of the triorganotin
alkoxide on the reaction between Me3SiN3 and
benzonitrile. The catalytic cycle described in scheme
could explain the observed high yield for the reaction
between Me3SiN3 and benzonitrile when Bu3SnN3 was
in situ generated. Additional clues are provided
through the comparison between observed trends for
substituted benzonitriles and those predicted by DFT
calculations. We assumed that the first step of the (B)
pathway controls the reaction kinetic. Experimentally,
the reaction with the meta-chlorobenzonitrile proceeds
1.6 faster than the one with unsubstituted benzonitrile,
and the reaction with the para-hydroxybenzonitrile is
1.6 slower than the one with unsubstituted benzonitrile.
We have computed the energy barriers corresponding
to the activation of the nitrile in the meta-
chlorobenzonitrile (34.2 kcal mol–1) and in the para-
hydroxybenzonitrile (35.5 kcal mol–1). According to
the transition state theory and the resulting Eyring’s
equation,[38] these values lead to a rate constant for the
meta-chlorobenzonitrile 2.3 larger than for the
unsubstituted benzonitrile, and a rate constant for the
para-hydroxybenzonitrile 2.1 smaller than for the
unsubstituted benzonitrile. There is clearly a good
agreement with experiments, which supports the
proposed mechanism for the tin-catalyzed formation
of 5-substituted 1H-tetrazoles.
The reaction catalyzed by a polymer-supported tin
derivative. Considering our previous works related to
polymer-supported tin reagents,[39] we then embarked
in the adaptation of this reaction to the solid phase
using organotin reagents grafted on an insoluble
polystyrene matrix. Indeed these supported organotin
reagents bring important advantages concerning the
removal of tin byproducts from the reaction products
which can be achieved by a simple filtration allowing
less than 10 ppm as total tin in the desired products.
Due to the numerous applications of the tetrazole
moiety, such strategy presents a major interest to
obtain compounds of high purity. To the best of our
knowledge, there are only a few cases where the tin
mediated tetrazole synthesis has been developed with
the aim to limit the amount of residual tin in the
reaction product.
3
was notably investigated. Computational
considerations prompted us to use Me3SnN3 as a model
compound in order to mimic Bu3SnN3. In principle,
Me3SnN3 can react with benzonitrile according to the
(A) and (B) mechanisms depicted for the direct
reaction with Me3SiN3. Indeed, a possible reaction
pathway involving a synchronous cycloaddition, as in
(A), and leading to a 1,5-disubstituted 3-Sn species
was evidenced (Figure 2). However, the predicted
energy barrier, 45.5 kcal mol–1 with respect to the
reactants, is close to that calculated for the uncatalyzed
reaction, which suggests that this process cannot occur
in our experimental conditions. In agreement with the
work of Kappe et al. on the tin-catalyzed addition of
Me3SiN3 to acetonitrile,[37] we found that the (B)
reaction pathway is markedly modified (Figure 2). A
stepwise mechanism emerges, beginning with the
approach of the benzonitrile nitrogen on the acidic tin
atom of Me3SnN3, while the nitrile carbon is activated
for the addition of the azide. This process leads to the
open-chain reaction intermediate RI B1, through the
transition state TS B1 computed 34.9 kcal.mol-1 above
the reactants., which is the rate-determining step of the
reaction. The next steps are part of the ring-closing
process. The latter involves two smaller energy
barriers (25.6 and 30.3 kcal mol–1 with respect to the
reactants), a further open-chain reaction intermediate
(RI B2), and results in the formation of a 1,5-
disubstituted 3-Sn species (with a reaction free energy
of -14.6 kcal mol–1). According to eq. 3 of scheme 2,
the latter would react with Me3SiN3 to afford the 3a-Si
species, while recovering the catalyst. Note that such
an efficient recovery process of the catalyst was
already
disclosed
for
organotin-catalyzed
cycloaddition between Me3SiN3 and acetonitrile.[37]
Thus, it exists a stepwise mechanism that (i) lowers
significantly the activation free energy, by 11.2 kcal
mol–1 with respect to the uncatalyzed reaction, and (ii)
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Figure 2. Free energy surface for the reaction between Me3SnN3 and benzonitrile (computed at the BMK/cc-pVDZ level of
theory, geometries and individual energies are provided in the Supporting Information). Atom color code: yellow for Sn,
blue for N, gray for C and white for H.
These processes concern the use of a trioctyltin reagent
to improve the partition between polar and nonpolar
compounds,[24] or the use of a perfluoroalkyltin azide
and a fluorous/organic liquid/liquid extraction.[25]
apparent quantitative conversion in every subsequent
steps of these heterogeneous reactions.
Precatalysts P6-P9 were then involved in the
synthesis of 5-substituted 1H-tetrazoles for
comparison with the results obtained with 2a and 2b.
We first evaluated the four polymer-grafted
alkoxystannanes for the synthesis of 3a (Table 5).
Otherwise,
a
crosslinked polystyrene-supported
azidostannane has been recently reported with its use
for the synthesis of aryl azides.[40]
According to our mechanistic studies, we required
a polymer which was not temperature sensitive like
Amberlite XE305,
a
commercially available
macroporous polystyrene reticulated with 10-12% of
divinylbenzene. This polymer is resistant to abrasive
effect induced by stirring and allow good loading (~1.5
mmol.g-1). In addition, a tetramethylene spacer was
required to minimize the steric hindrance both for
trimethylsilyl azide / triorganotin alkoxide exchange
and for the addition of the azide on the nitrile. We
prepared four different polymer-supported tin
precatalysts P6-P9 having different steric hindrance
around the tin atom. Briefly, the reaction sequence
involves the lithiation of Amberlite XE305 followed
by its reaction with 1-bromo-4-chlorobutane leading to
polymer P1 (Scheme 5). A subsequent stannylation
reaction with dialkylphenylstannyl lithium afforded
the stannylated polymers P2[41] and P3 whose
iododearylation with iodine in ethanol furnished
polymers P4 and P5. Finally, a reaction with sodium
hydroxide in methanol followed by reflux in dimethyl
or diethylcarbonate during 18 hours led to supported
organotin alkoxides P6-P9. The tin loading of P2 and
P3 were found to be 1.2 mmol.g-1 and 1.33 mmol.g-1
respectively from tin ICP analyses and 119Sn MAS
NMR analyses of polymers, P2-P9 pointed out an
Scheme 5. Preparation of polymer-supported
triorganotin alkoxides.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Table 6. Synthesis of 5-substituted 1H-tetrazoles promoted
In the typical procedure, benzonitrile was reacted with
Me3SiN3 in Bu2O in the presence of 10 mol% of
polymer-supported organotin precatalyst at 140 °C.
Initial attempts with a reaction time of 4 hours only
afforded moderate yields. Further studies reveal that
good yields could be obtained by carrying out the
reaction under reflux for 18 hours. This difference can
be explained by the heterogeneous nature of the
reaction involving catalysts P6-P9, which usually
lowers reaction kinetics.[39f] The reaction work-up used
for these reactions was similar to those applied for
homogeneous conditions but was preceded by a
filtration to remove the insoluble supported organotin
byproducts. By screening the four different catalysts,
we observed that the less bulky was the alkoxide group
of the precatalyst (P6 and P8), the higher was the
reaction yield. We also noted that the replacement of
two butyl groups linked to the tin atom by two methyl
groups (P6 and P7) influenced more significantly the
yield than the exchange of the ethoxy group by a
methoxy group, a result in good agreement with the
reaction mechanism which requires minimization of
the steric hindrance to facilitates both the Si-N3/Sn-OR
exchange affording the effective active species and the
addition reaction of the tin azide on the nitrile.
by polymer-supported organotin alkoxides.[a], [b]
Table 5. Screening of the polymer-supported organotin
alkoxides for the synthesis of 3a.
[a]
[b]
Isolated yields;
concentration in tin residues in the
reaction product measured as total tin by ICP-MS; nd = not
determined
Conclusion
Entry
1
Sn precatalyst
Yield (%)
82
P6
P7
P8
P9
Triorganotin alkoxides were found to be efficient
precatalysts for the synthesis of 5-substituted 1H-
tetrazoles starting from nitriles and Me3SiN3 through
the in situ generation of triorganotin azide. These
precatalysts were found to be more efficient than
dibutyltin oxide or tributyltin chloride often used for
this reaction. The reaction scope is quite large,
includes aryl and also alkyl nitriles and tolerates a wide
variety of functional groups. The reaction mechanism
is believed to proceed by a nucleophilic attack of the
azide on the nitrile with a concomitant assistance of
the tin on the nitrile nitrogen as suggested by Hammett
relationship and quantum mechanical calculations.
The mechanistic study underlines the importance of
the polarization of the tin azide bond and of the steric
hindrance both for trimethylsilyl azide / triorganotin
alkoxide exchange and for the addition of the azide on
the nitrile. Finally, a heterogeneous version of the
reaction has been developed and four polymer-
supported organotin alkoxides have been prepared and
evaluated as precatalysts for the reaction. The higher
yields were obtained with the less hindered organotin
alkoxide bearing a (CH2)4-SnMe2OMe appendage.
The 5-substituted 1H-tetrazoles were prepared in high
yields using this precatalyst and ICP-MS analyses
confirmed the high efficiency of this procedure to
2
3
4
75
70
68
We next extended the reaction study involving
precatalyst P6, and for this purpose, a selection of both
electron poor and electron-rich aromatic nitriles was
considered. The reaction procedure was similar to that
applied to benzonitrile. Remarkably, very good yields
were obtained indicating that these heterogeneous
conditions do not affect significantly the catalytic
system when the reaction time is prolonged from 4
hours to 18 hours (Table 6). In addition, after work-up
and isolation of the reaction product, several analysis
by ICP-MS were carried out and exhibited a low
residual tin concentration (under 10 ppm) to be
compared with a concentration of 1000 ppm obtained
with catalyst 2a or 2b. This result points out the
efficiency of this methodology which is compatible for
the synthesis of pharmaceutical substances.[42]
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Rev. 2011, 111, 7377-7436; d) T. M. Klapötke, T. G.
Witkowski, Propellants, Explosives, Pyrotechnics 2015,
40, 366-373.
avoid the presence of residual tin in the reaction
products.
[5]
[6]
G. Aromí, L. A. Barrios, O. Roubeau, P. Gamez, Coord.
Chem. Rev. 2011, 255, 485-546.
Experimental Section
a) A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B.
Gold, S. V. Ley, Org. Biomol. Chem. 2005, 3, 84-96; b)
D. A. Longbottom, V. Franckevicius, S. Kumarn, A. J.
Oelke, V. Wascholowski, S. V. Ley, Aldrichimica Acta
2008, 41, 3-11; c) B. Maji, H. Yamamoto, Angew. Chem.
Int. Ed. 2014, 53, 8714-8717.
a) R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379-3394;
b) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529-2591.
a) V. B. Vangala, R. M. Hindupur, H. N. Pati, Int. J.
Pharm. Research & Review 2014, 3, 46-56; b) R.
Vardanyan, V. J. Hruby, in Synthesis of Best Seller
Drugs, Elsevier, Amsterdam, 2016, pp. 329-356.
a) S. J. Wittenberger, Org. Prep. Proced. Int. 1994, 26,
499-531; b) G. I. Koldobskii, Russ. J. Org. Chem. 2006,
42, 469 - 486; c) L. Myznikov, A. Hrabalek, G. I.
Koldobskii, Chem. Hetereocycl. Compd. 2007, 43, 1-9;
d) U. Bhatt, in Modern Heterocyclic Chemistry, Wiley-
VCH Verlag GmbH & Co. KGaA, 2011, pp. 1401-1430;
e) J. Roh, K. Vávrová, A. Hrabálek, Eur. J. Org. Chem.
2012, 6101-6118.
General procedure for the synthesis of 5-substituted-1H-
tetrazoles 3 promoted by 2a. In a sealable tube, a solution of
nitrile (2.5 mmol), trimethylsilyl azide (432 mg, 497 µL,
3.75 mmol), precatalyst 2a (80.3 mg, 0.25 mmol) in dry
dibutyl ether (5 mL) was prepared and stirred for 4h at
140°C. The resulting mixture was cooled to 0°C and
quenched with 5 mL of NaOH (1N) and 15 mL of petroleum
ether. The aqueous phase of the filtrate solution is separated
from the organic one and acidified to pH = 1 at 0°C in order
to obtain the tetrazole as a solid. After filtration, the solid
was dried under vacuum. The procedure was similar when
catalyst 2b was used, or when DMF was the solvent
(reaction temperature = 150°C in this case).
[7]
[8]
[9]
General procedure for 5-substituted-1H-tetrazoles
synthesis 3 promoted by P6-P9. A sealable tube was
charged with polymer P6 or P7 (210 mg, tin loading = 1.2
mmol.g-1, 0.1 equiv), and purged by argon. Then, dibutyl
ether (5 mL), nitrile (2.5 mmol, 1 equiv.), trimethylsilyl
azide (432 mg, 497 µL, 3.75 mmol, 1.5 equiv) were
introduced. The reaction mixture was stirred under orbital
stirring and heated at 140°C under inert atmosphere during
18h. Then, petroleum ether (15 mL) and 1M NaOH solution
(5 mL) were added. The polymer was filtered and
successively washed with a 1M NaOH solution (5 mL),
THF (5 mL) and finally petroleum ether (5 mL). The
aqueous phase of the filtrate solution was separated from the
organic one and acidified to pH = 1 at 0°C in order to obtain
the tetrazole 3 as a solid. After filtration, the white solid was
dried under vacuum. A similar procedure was used for the
synthesis of 5-substituted-1H-tetrazoles catalyzed by P8 or
P9 (188 mg, tin loading = 1.33 mmol.g-1).
[10]
[11]
J.-P. Hagenbuch, Chimia 2003, 57, 773-776.
a) Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66,
7945-7950; b) T. Jin, S. Kamijo, Y. Yamamoto,
Tetrahedron Lett. 2004, 45, 9435-9438; c) T. Jin, F.
Kitahara, S. Kamijo, Y. Yamamoto, Chem. Asian J.
2008, 3, 1575-1580; d) V. Aureggi, G. Sedelmeier,
Angew. Chem. Int. Ed. 2007, 46, 8440-8444; e) J.
Bonnamour, C. Bolm, Chem. Eur. J. 2009, 15, 4543 -
4545.
a) K. Sisido, K. Nabika, T. Isida, S. Kozima, J.
Organomet. Chem. 1971, 33, 337-346; b) J. V. Duncia,
M. E. Pierce, J. B. Santella, J. Org. Chem. 1991, 56,
2395-2400; c) F. A. J. Kerdesky, A. Haight, B. A.
Narayanan, C. W. Nordeen, D. Scarpetti, L. S. Seif, S.
Wittenberger, H. E. Morton, Synth. Commun. 1993, 23,
2027-2039; d) S. J. Wittenberger, B. G. Donner, J. Org.
Chem. 1993, 58, 4139-4141.
a) S. Aalla, G. Gilla, Y. Bojja, R. R. Anumula, P. R.
Vummenthala, P. R. Padi, Org. Proc Res. Dev. 2012, 16,
682-686; b) A. Sampath, V. Prabhakar Reddy, A. Kalyan
Chakravarthy, P. Pratap Reddy, Asian J. Chem. 2013, 25,
393-396.
a) E. Le Grognec, J.-M. Chrétien, F. Zammattio, J.-P.
Quintard, Chem. Rev. 2015, 115, 10207-10260; b) B.
Delmond, G. Dumartin, in Solid State Organometallic
Chemistry: Methods and Applications (Eds.: M. Gielen,
R. Willem, B. Wrackmeyer), John Wiley & Sons,
Chichester, 1999, pp. 445-471; c) J.-M. Chrétien, J. D.
Kilburn, F. Zammattio, E. Le Grognec, J.-P. Quintard, in
[12]
Acknowledgements
We gratefully acknowledge the Université de Nantes, the “Centre
National de la Recherche Scientifique” (CNRS), Réseau de
Recherche 2: “Aller vers une chimie éco-compatible”, the
“Agence Nationale de la Recherche” (ANR) (grant 07JCJC0144),
the Région Pays de la Loire (GREEN-SCO framework) for
financial support. We also gratefully acknowledge Julie Hemez
and Laurence Arzel for HRMS analyses and Isabelle Louvet for
HPLC analyses. G.K. acknowledges the « Ministère de la
Recherche et de l’Enseignement Supérieur » for a PhD grant.
[13]
[14]
References
[1]
[2]
[3]
V. A. Ostrovskii, R. E. Trifonov, E. A. Popova, Russ.
Chem. Rev. 2012, 61, 768-780.
M. Baumann, I. R. Baxendale, S. V. Ley, N. Nikbin,
Beilstein J. Org. Chem. 2011, 7, 442-495.
a) C. Beier, J. Benting, D. Bernier, P. Y. Coqueron, P.
Desbordes, C. Dubost, P. Genix, M. Ito, D. Portz, N.
Tin Chemistry
-
Fundamentals, Frontiers and
Applications (Eds.: A. G. Davies, M. Gielen, K. H.
Pannell, E. R. T. Tiekink), John Wiley & Sons, Ltd, 2008,
pp. 607-621; d) A. C. Albeniz, N. Carrera, Eur. J. Inorg.
Chem. 2011, 2347-2360; e) C. Cordovilla, C. Bartolomé,
J. M. Martínez-Ilarduya, P. Espinet, ACS Catalysis 2015,
5, 3040-3053.
a) J. E. Leibner, J. Jacobus, J. Org. Chem. 1979, 44, 449-
450; b) J. M. Berge, S. M. Roberts, Synthesis 1979, 471-
472.
E. Vedejs, S. M. Duncan, A. R. Haight, J. Org. Chem.
1993, 58, 3046-3050.
N. A. Bumagin, L. I. Sukhomlinova, S. O. Igushkina, A.
N. Vanchikov, T. P. Tolstaya, I. P. Beletskaya, Izv. Akad.
Sasaki,
U.
Wachendorff-Neumann,
(Bayer
CropScience), WO 2011134911 A2, 2011 ; b) F. Calo,
M. Kordes, H. Kraus, T. Seitz, T. W. Newton, K. Kreuz,
M. Pasternak, D. Massa, (BASF), WO 2015052173 A1,
2015 ; c) W. Krämer, U. Schrimer, P. Jeschke, M.
Witschel, Modern Crop Protection Compounds, 2nd ed.,
Wiley-VCH, Weinheim, 2012.
[15]
[16]
[17]
[4]
a) T. M. Klapötke, in High Energy Density Materials
(Ed.: T. M. Klapötke), Springer Berlin Heidelberg,
Berlin, Heidelberg, 2007, pp. 85-121; b) R. P. Singh, R.
D. Verma, D. T. Meshri, J. n. M. Shreeve, Chem. Rev.
2006, 45, 3584-3601; c) H. Gao, J. n. M. Shreeve, Chem.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
Nauk, Ser. Khim. 1992, 2683-2685; Bull. Acad. Sci.
[35]
[36]
C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91,
165-195.
a) F. Himo, Z. P. Demko, L. Noodleman, K. B.
Sharpless, J. Am. Chem. Soc. 2002, 124, 12210-12216;
b) F. Himo, Z. P. Demko, L. Noodleman, J. Org. Chem.
2003, 68, 9076-9080.
D. Cantillo, B. Gutmann, C. O. Kappe, J. Am. Chem.
Soc. 2011, 133, 4465-4475.
H. Eyring, J. Chem. Phys. 1935, 3, 107-115.
a) J.-M. Chrétien, F. Zammattio, E. Le Grognec, M.
Paris, B. Cahingt, G. Montavon, J.-P. Quintard, J. Org.
Chem. 2005, 70, 2870-2873; b) J.-M. Chrétien, F.
Zammattio, D. Gauthier, E. Le Grognec, M. Paris, J.-P.
Quintard, Chem. Eur. J. 2006, 12, 6816-6828; c) J.-M.
Chrétien, A. Mallinger, F. Zammattio, E. Le Grognec, M.
Paris, G. Montavon, J.-P. Quintard, Tetrahedron Lett.
2007, 48, 1781-1785; d) V. Fargeas, F. Zammattio, J.-M.
Chrétien, M.-J. Bertrand, M. Paris, J.-P. Quintard, Eur.
J. Org. Chem. 2008, 1681-1688; e) G. Fraboulet, V.
Fargeas, M. Paris, J.-P. Quintard, F. Zammattio,
Tetrahedron 2009, 65, 3953-3960; f) G. Kerric, E. Le
Grognec, F. Zammattio, M. Paris, J.-P. Quintard, J.
Organomet. Chem. 2010, 695, 103-110; g) G. Kerric, E.
Le Grognec, V. Fargeas, F. Zammattio, J.-P. Quintard,
M. Biesemans, R. Willem, J. Organomet. Chem. 2010,
695, 1414-1424.
USSR, Div. Chem. Sci. 1992, 2641, 2128-2129.
a) D. P. Curran, S. Hadida, S.-Y. Kim, Z. Luo, J. Am.
Chem. Soc. 1999, 121, 6607-6615; b) J. Otera, Acc.
Chem. Res. 2004, 37, 288-296.
J. Lipowitz, S. A. Bowman, J. Org. Chem. 1973, 38,
162-165.
a) E. Fouquet, M. Pereyre, A. Rodriguez, T. Roulet, Bull.
Soc. Chim. Fr. 1997, 134, 959-967; b) A. Hervé, A. L.
Rodriguez, E. Fouquet, J. Org. Chem. 2005, 70, 1953-
1956.
J.-C. Poupon, D. Marcoux, J.-M. Cloarec, A. B. Charette,
Org. Lett. 2007, 9, 3591-3594.
A. Faurie, J. Grolleau, F. Gohier, M. Allain, S. Legoupy,
P. Frère, Eur. J. Org. Chem. 2017, 2707-2714.
a) H. Schumann, B. Pachaly, Angew. Chem. Int. Ed.
1981, 20, 1043-1044; b) T. Toupance, L. Renard, B.
Jousseaume, C. Olivier, V. Pinoie, I. Verbruggen, R.
Willem, Dalton Trans. 2013, 42, 9764-9770.
T. Kato, Y. Shida, (Takeda Chemical Industries, Ltd.),
EP 578125 A1, 1996.
D. P. Curran, S. Hadida, S.-Y. Kim, Tetrahedron 1999,
55, 8997-9006.
E. Le Grognec, J.-P. Quintard, G. Kerric, J.-M. Chrétien,
F. Zammattio, (CNRS, Université de Nantes), WO
2013001235 A1, 2013.
[18]
[19]
[20]
[37]
[38]
[39]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
A. G. Davies, D. C. Kleinschmidt, P. R. Palan, S. C.
Vasishtha, J. Chem. Soc. (C) 1971, 3972-3976.
P. K. Kadaba, Synthesis 1973, 71-84.
J. G. A. Luijten, M. J. Janssen, G. J. M. van der Kerk,
Recl. Trav. Chim. Pays-Bas 1962, 81, 202-205.
P. J. Smith, A. P. Tupčiauskas, Annual Reports on NMR
Spectroscopy 1978, 8, 291-370.
J. Wiss, A. Zilian, Org. Proc Res. Dev. 2003, 7, 1059-
1066.
S. J. Blunden, M. F. Mahon, K. C. Molloy, P. C.
Waterfield, J. Chem. Soc. Dalton Trans. 1994, 2135-
2143.
[40]
[41]
L. Godoy Prieto, M. J. Lo Fiego, A. B. Chopa, M. T.
Lockhart, J. Organomet. Chem. 2017, 830, 26-32.
The SnMe2Ph grafting is slightly contaminated by an
SnPh2Me grafting, but after iododestannylation and
alkoxylation steps, we consider that the efficiency of the
obtained precatalyst will be only marginally modified
when compared to pure Polymer-(CH2)4SnMe2OR'.
M. M. Reddy, K. H. Reddy, M. U. Reddy, Pharmaceut.
Reg. Affairs 2016, 5, 168-175.
[28]
[29]
[30]
[31]
[32]
[42]
[33]
[34]
J. Sýkora, V. Blechta, L. Soukupová, J. Schraml, Magn.
Reson. Chem. 2008, 46, 1112-1118.
W. von E. Doering, W. A. Henderson, J. Am. Chem.
Soc. 1958, 80, 5274-5277.
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801117
Advanced Synthesis & Catalysis
FULL PAPER
Tin-Catalyzed Synthesis of 5-Substituted 1H-
Tetrazoles from Nitriles:Homogeneous and
Heterogeneous procedures
Adv. Synth. Catal. Year, Volume, Page – Page
Jean-Mathieu Chrétien,a Gaelle Kerric,a Françoise
Zammattio,a Nicolas Galland,a Michael Paris,b
Jean-Paul Quintard,a Erwan Le Grogneca *
11
This article is protected by copyright. All rights reserved.