Aryl and Heteroaryl N1-Tetrazoles through Ligand-Free Suzuki-Reaction under Aerobic, Aqueous Conditions

Article abstract of DOI:10.1002/ejoc.201700105

Substituted 1-biaryl-1H-tetrazoles are classically obtained from the corresponding 1-aminobiaryls, limiting the selection of substrates. The development and substrate scope of a green, ligand-free Suzuki protocol in aqueous media under ambient atmosphere, leading to 1-biaryl- and heteroaryl-substituted 1H-tetrazoles in very good to excellent yields is presented. The combination of PdCl₂/NEt₃/H₂O/EtOH was found to combine high yields and high purity for all substrates investigated. Comparative experiments investigating the reaction rate showed that the tetrazole does not act as a ligand for the palladium catalyst.

Full text of DOI:10.1002/ejoc.201700105

A Journal of
Accepted Article
Title: Aryl and heteroaryl N1- tetrazoles via ligand-free Suzuki-reaction
under aerobic, aqueous conditions
Authors: Marco Seifried, Christian Knoll, Gerald Giester, Jan M. Welch,
Danny Müller, and Peter Weinberger
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700105
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
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Aryl and heteroaryl N1- tetrazoles via ligand-free Suzuki-reaction
under aerobic, aqueous conditions
a
a
b
c
a
a
Marco Seifried, Christian Knoll, Gerald Giester, Jan M. Welch, Danny Müller * and Peter Weinberger
a.
Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9, A-1060 Vienna, Austria.
Faculty of Geosciences, Geography and Astronomy, University of Vienna, Althanstraße 14 (UZA 2), A-1090 Vienna, Austria.
Atominstitut, TU Wien, Stadionallee 2, 1020 Vienna, Austria
b.
c.
Abstract: Substituted 1-biaryl-1H-tetrazoles are classically obtained
from the corresponding 1-aminobiaryls, limiting the selection of
substrates. The development and substrate scope of a green,
ligand-free Suzuki protocol in aqueous media under ambient
atmosphere, leading to 1 biaryl- and heteroaryl- substituted 1H-
tetrazoles in very good to excellent yields is presented. The
isomers are obtained after alkylation of 1H-tetrazole and
subsequent chromatographic separation.[8]
In this context, a major obstacle regarding a simple
variation of substitution patterns or more sophisticated
target structures is the limited availability or often tedious
synthetic preparation of the necessary primary amines or
isonitriles.
2 3 2
combination of PdCl / N(Et) / H O-EtOH was found to combine high
yields and high purity for all substrates investigated. Comparative
experiments investigating the reaction rate showed, that the
tetrazole does not act as a ligand for the palladium catalyst.
Therefore, we focused on possible post-functionalization
procedures based on coupling protocols. Especially for
libraries of substituted aryltetrazoles, suitable for the
systematic investigations of substitution effects on the spin
crossover behaviour of the respective iron(II) spin crossover
compounds, a versatile coupling protocol would significantly
reduce the required synthetic effort. Based on the concept
of divergent synthesis and considering that tetrazole-
synthesis is often hampered by low yields, an additional
positive aspect of a tetrazole-compatible coupling protocol
would be its introduction in the first step. According to the
general aim for sustainable chemistry, special emphasize
was the establishment of an environmentally benign
coupling protocol.
Introduction
Substituted tetrazoles are known mainly for their
applicability as carboxylic acid bioisosteres in drug design[1]
and as ligands for spin crossover complexes.[2]
A
substitution pattern is commonly introduced by using an
appropriately substituted precursor for the ring formation,
rather than by a functionalization after tetrazole synthesis.
Whereas the N1 and N2-substituted derivatives are
commonly used for coordination chemistry (scheme 1), the
Suzuki-Miyaura coupling was originally reported as the
C5 substitution pattern displays a similar pK
a
to the
palladium catalyzed reaction of alkenylboranes with aryl
halides.[9] The reaction has since expanded in scope to the
corresponding carboxylic acid and is metabolized as non-
electrophilic glucuronide.[1b, 3]
current protocol coupling aryl boronic acids and aryl
halides[10] and offers
a
versatile method accessing
asymmetric biaryl motifs in a single synthetic step. With 4-
bromobenzyl-1H-tetrazole in hand, an investigation of its
performance in a Suzuki protocol would allow for easy
access to libraries of substituted biaryl-tetrazoles without
the necessity of the corresponding amine-precursor.
Scheme 1. Substitution patterns of tetrazole rings
References to C–C coupling protocols using tetrazoles are
very scarce. All examples of tetrazoles in coupling protocols
reported thus far describe substitution at the C5 position
directly, or remotely on an aryl group attached at the
tetrazole C5-position.[11] It is well known, that C5-
bisubsituted tetrazoles [12] differ notably not only in their
coordination behavior,[5-6] but also in their C5 or N1
reactivity, from exclusively N1-substituted tetrazoles and
are thus not directly chemically comparable. To the best of
our knowledge, we report the first coupling-protocol with
N1-substituted tetrazoles.
N1-substituted tetrazoles offer distinct advantages when
used as ligands for Fe(II) spin crossover materials.[2d, 4]
They feature a strict monodentate coordination via the exo
located N4,[2b, 5] whereas their C5-substituted equivalents
prefer in most cases a bridging coordination between metal-
ions.[6] Nearly all synthetic approaches to substituted
tetrazoles include a [2+3] cyclo-addition of an azide-source
and primary amines and isonitriles -yielding N1-isomers- or
nitriles, leading to the C5-isomers.[7] Commonly, N2-
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European Journal of Organic Chemistry
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Results and Discussion
protocol for the further optimization steps toluene and water
as solvents were selected.
The
reaction
of
4-bromobenzyl-1H-tetrazole
with
The combination of Pd(PPh3)4 and toluene has already
shown excellent performance for this reaction, but
nevertheless further catalysts, including Ni-species, were
compared regarding their performance (table 2). A special
emphasis was put on the identification of reaction
conditions for a ligand-free catalyst in water or at least
aqueous media.
phenylboronic acid (1.1 equivalents; scheme 2) was chosen
as model system for development and optimization of a
Suzuki protocol for the formation of N1-substituted
tetrazoles.
Initially, the influence of reaction solvent was investigated.
3 4
In THF using Pd(PPh ) and potassium carbonate led to 2a
in an isolated yield of 88 %. Variation of the solvents
increased the yield to 97 %. A complete overview of the
screening of various solvents is given in table 1.
Table 2. Suzuki reaction of 4-Bromobenzyl-1H-tetrazole and PhB(OH)
with different catalysts (1.1 eq. PhB(OH) , 0.03 eq. catalyst, 2 eq. K CO
20 °C, 18 h)
2
2
2
3
,
1
Scheme 2. Model reaction for protocol development
entry
catalyst
Solvent[a]
PhMe
yield [%][b]
conversion [%][c]
1
2
Pd(PPh
Pd(PPh
3
3
)
)
4
4
97
80
0
100
100
0
2
H O
3
Pd(PPh
Pd(PPh
3
3
)
)
2
2
Cl
2
2
PhMe
4
Cl
H
2
O
40
97*
27*
56
74
5
45
100
30
60
81
14
0
5
Pd/C
Pd/C
PhMe
6
2
H O
Table 1. Suzuki reaction of 4-Bromobenzyl-1H-tetrazole and PhB(OH)
2
in
7
PdCl2
PdCl
PhMe
various solvents (1.1 eq. PhB(OH) , 0.03 eq. Pd(PPh , 2 eq. K CO ,
2
3
)
4
2
3
8
2
2
H O
120 °C, 18 h)
9
Ni(dppp)Cl
Ni(dppp)Cl
Ni(OAc)
2
2
PhMe
entry
solvent[a]
THF
yield [%][b]
10
H
2
O
0
1
1
1
2
PhMe
0
0
1
2
3
4
5
6
7
8
9
88
95*
96*
50*, **
72**
95
Ni(OAc)
H
2
O
0
0
THF:H
THF:H
2
2
O (5:1)
O (1:1)
*
Impurities
[
a] 5 ml of solvent used. [b] Isolated yields. [c] Determined by 1H-NMR,
DMF
refers to unreacted starting material.
DMF:H
2
O (5:1)
1,4-dioxane
EtOH
The data in table 2 show that the presence of water affects
the activity and thus choice of the catalyst. The activity of
Pd(0) species is promoted by non-aqueous conditions,
whereas Pd(II)-catalysts achieve higher yields in an
aqueous solution.
62*
EtOH:H
EtOH:H
2
2
O (3:1)
O (1:1)
66
96
1
1
0
1
H
2
O
80
PhMe
97
The only one heterogeneous system investigated, Pd on
charcoal, featured high yields (97 % in PhMe), but resulted
*
Impurities
** Product contaminated with starting material.
[
a] 5 ml of solvent used. [b] Isolated yields.
2
in substantial by-product formation. The use of H O as
solvent dramatically decreases the activity of the
heterogeneous catalyst. In summary: toluene as organic
The highest isolated yields of 2a (97 %) were achieved with
toluene as solvent. To deduce whether the coupling was
sensitive to moisture, aqueous solvent mixtures were used.
Comparing the results for dry THF, EtOH and DMF with the
yields obtained for their aqueous mixtures it became
apparent, that high water contents improved the reaction
significantly: a 50 % water THF mixture yielded 96 % of 2a.
Increasing the water concentration up to 100 % water
resulted in 80 % isolated yield. The beneficial effect of
water may be attributed to the better solubility of polar
reactants.[13] Although the isolated yield from aqueous THF
mixtures seemed promising, a coloured and contaminated
product was isolated. This was not the case for toluene. To
develop an aqueous and therefore environmentally benign
3 4 2
solvent with Pd(PPh ) , and water with PdCl were identified
as the most promising catalyst candidates. Although, Pd/C
would offer the advantage of simple catalyst-separation,[14]
the formation of by-products diminishes this advantage. For
five comparable experiments using the conditions of the
catalyst-screening, the catalyst loading was decreased to
0.05 mol% while maintaining temperature and reaction
time. This resulted in a decreased conversion, whereas for
a control experiment without any added palladium catalyst
no product formation could be observed. Higher catalyst
loadings than 5 mol% did not lead to significantly shorten
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
reaction times. Therefore, a loading of 3 mol% proved as
the optimum concentration.
obtained using potassium carbonate or triethylamine as
base (see figure 1).
Among the Ni catalysts investigated, only with Ni(dppp)Cl
2
in PhMe could traces of 2a be identified.
The catalyst screening resulted in two candidates of choice:
Firstly, for protocol using an organic solvent, the
combination of toluene and Pd(PPh allowed for
a
3 4
)
quantitative conversion and high isolated yields. Second,
with the aim of a ligand-free coupling protocol under
2 2
aqueous conditions, PdCl in H O (74 % yield) was the
catalyst of choice for further investigations.
To further optimize the environmental efficiency of the
aqueous protocol, a selection of inorganic and organic
2 3
bases was compared to the K CO , aiming for improved
yields. In table 3 an overview of the performance of different
bases, using water as solvent is given.
Table 3. Suzuki reaction of 4-Bromobenzyl-1H-tetrazole and PhB(OH)
with different bases (1.1 eq. PhB(OH) , 0.03 eq. PdCl , 2 eq. base, 120 °C,
18 h)
2
Figure 1. Pure compound 2a (top) compared to the crude products
2
2
2 3 3
obtained using K CO (middle) or Et N (bottom) as base.
entry
base
yield [%][b]
conversion [%][b]
According to this observation for all subsequent
experiments N(Et) was used. In case the toxicity of
3
1
K
2
CO
3
74
66
52
100
84
triethylamine is of concern, the coupling scope was also
investigated with aqueous ammonia as base, leading to
comparable yields.
2
Na
Cs
KH
NaOH
NH OH
DBU
DIPEA
Et
2
CO
3
3
2
CO
3
100
38
4
2
PO
4
35
0**
Variation of the solvent, base and catalyst led to the
5
0
conclusion, that although a ligand-free Suzuki coupling for
1
6
4
82
100
0
0**
would be possible in pure water, a mixture of an organic
solvent with water would possibly lead to higher yields. This
was confirmed by using a 1:1 mixture of water and ethanol,
resulting in excellent yields up to 97 % (see table 1).
7
8
78
87
79
9
3
N
100
*
Impurities
** Decomposition of 1.
a] Isolated yields. [b] Determined by 1H-NMR, refers to unreacted starting
All reactions described thus far were performed under
argon atmosphere. Initial experiments using aqueous
solvent mixtures and aerobic conditions led to yields and
purities comparable to the earlier achieved ones, the
influence of the oxygen concentration on the reaction was
investigated. A set of reactions using either pure THF or
[
material.
2 3 2 3 4 3
For K CO , Cs CO NH OH and N(Et) full conversion of
the starting material was observed. DBU was completely
inactive. NaOH led to decomposition of the 4-bromobenzyl-
2 2 3
THF/H O as solvent system and PdCl as catalyst with Et N
1
H-tetrazole
under
formation
of
N-(4-
bromobenzyl)cyanamide.[7a]
as base was performed comparing three different
atmospheres: Argon, air and oxygen.
Several attempts varying the amount of the base showed,
that two equivalents gave optimal results. To establish,
whether the presence of a base was necessary due to the
inherent basicity of the tetrazole conjugated base, a control
experiment without additional base was performed.
Absence of an auxiliary base led to complete recovery of
Table 4. Conversion of starting material determined by 1H-NMR (1.1 eq.
PhB(OH) , 0.03 eq. PdCl , 2 eq.N(Et)3, 120 °C, 18 h)
2 2
Solvent
THF
Atmosphere
Conversion [%]
the unreacted starting materials. Comparing N(Et)
3
and
Argon
Air
42
35
K
2
CO , apart from higher yields with N(Et) the workup was
3
3
also simplified since fewer side-products were formed and
upon extraction with an organic solvent these impurities
remain in the aqueous layer. This is demonstrated in the
direct comparison of the NMR-spectra of the crude product,
Oxygen
Argon
Air
35
THF / H
2
O (1:1)
100
100
100
Oxygen
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European Journal of Organic Chemistry
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Scheme 4. Reaction of 3 nitrophenylboronic acid and 4-bromotoluene in
From table 4 two relevant things on the coupling-reaction
can be deduced: First, water is absolutely necessary for
the presence of different amounts of additive
optimal conversion when using
a Pd(II)-catalyst and
second, the atmosphere has no significant impact on the
conversion, as the reaction works under an atmosphere of
pure oxygen. All further studies were performed in sealed
vessels under ambient atmosphere.
In figure 2 the conversion versus time is plotted for all five
series between 15 and 120 seconds.
In summary, optimum-conditions for this Suzuki-coupling of
N1-substituted tetrazoles were identified as a combination
of 3 mol% PdCl
2
as catalyst with 2 eq. N(Et)
3
as base in a
1
:1 mixture of aqueous ethanol at 120 °C. Following the
reaction of
1
by 1H-NMR showed full conversion after a
reaction time of 3 h.
To shed light on a possible coordination of the tetrazole
through its nitrogen-atoms and thus acting as ligand during
the coupling reaction, competitive experiments with benzyl
tetrazole and 4-bromobenzyl tetrazole were performed. In
case the tetrazole would coordinate the palladium during
the reaction, a change in the reaction rate would be
expectable, when a 10-fold excess of benzyl tetrazole, not
participating in the coupling and only coordinating to the
palladium, was added. Using the conditions described in
scheme 3, the reaction rates for one experiment without
benzyl tetrazole and one with a 10-fold molar excess
(based on the 4-bromobenzyl tetrazole) were compared.
Figure 2. Conversion of 3 nitrophenylboronic acid and 4-bromotoluene
with different amounts of additive
Scheme 3. Competitive reaction with 4-bromobenzyl tetrazole and
benzyl tetrazole
Comparing the reaction rate for the reaction without additive
and with 0.1 eq. or 1.0 eq. of added benzyl tetrazole it
becomes apparent, that there is no significant deviation in
the reaction rate. In contrast, once although a stoichiometric
3
amount (referring to the amount of Pd-catalyst) of PPh is
present in the reaction, the conversion is notably
decelerated. In the case of a large excess as present in the
series with 1.0 eq. of PPh
completely suppressed.
3
any product formation is
For both reactions a highly comparative conversion was
derived from the NMR-results. To further support the
hypothesis of the non-coordinative behaviour of the
tetrazole towards the palladium during the reaction another
reaction without a substituted tetrazole as reagent was
investigated.
Table 5. Scope of aryl-coupling protocol
Using the same conditions as for all the tetrazole-containing
coupling reactions, 3-nitrophenylboronic acid and 4-
bromotoluene were coupled to 4'-methyl-3-nitro-1,1'-
biphenyl (scheme 4). In five series, each repeated four
times, the reaction was investigated without any additive,
with 0.1 and 1.0 eq of benzyl tetrazole (BnTz), and 0.1 and
2
a
, 97 % (95 %)
2b, 91 % (90 %)
2c, 97 % (98 %)
3 3
1.0 eq of triphenylphosphine (PPh ) as additives. PPh was
chosen as additive which is known to act as ligand for Pd in
Suzuki-reactions.
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European Journal of Organic Chemistry
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FULL PAPER
2
d
, 86 % (91 %)
2e, 87 % (0 %)
2f, 87 % (96 %)
2i, 93 %* (98 %)
Only 2b and 2h required purification by flash-
chromatography demonstrating the flexibility and substrate
tolerance of the protocol. The comparably low yield for 2h
may be explained by the chromatographic work-up
combined with the electron withdrawing substituent, known
to reduce the performance of Suzuki reactions.
2
g, 94 % (37 %)
2h, 80 % (0 %)
2k, 89 % (98 %)
For chlorophenylboronic acids the reaction failed at 120 °C,
yielding an inseparable mixture of decomposition products
and product. Lowering the reaction temperature could
circumvent the decomposition of the product, allowing for
93 % (2i) and 90 % (2j) yield at room-temperature. It should
be mentioned, that after 18 h at room-temperature other
boronic acid substrates yielded only traces of the desired
product.
2j, 90 %* (80 %)
All these results confirm the hypothesis, that the tetrazole
does not coordinate towards the palladium during the
reaction and so the term ligand-free is appropriate for the
herein presented coupling protocol.
A further extension of the scope was possible using
heteroarylboronic acids (table 6).
Encouraged by the results achieved with phenylboronic
acid, scope and substrate tolerance of this protocol were
investigated using different phenylboronic acids (table 5).
Considering potential costs and technical relevance, all
Table 6. Scope of heteroaryl (Hy)-coupling protocol
experiments were performed in duplicate; once with N(Et)
and once with NH OH. The yields with NH OH as a base
are shown in parenthesis in table 5.
3
4
4
All products could be obtained in good to excellent yields,
ranging from 79-97 %, most of them in spectroscopic purity
without further purification (see experimental). This clearly
demonstrates the viability of the coupling protocol and its
broad scope.
3
a
, 82 % (0 %)
3b, 82 % (81 %)
3d, 89 % (0 %)
Aqueous ammonia could prove a practical alternative to
triethylamine due to its easy handling and work-up. For
larger scale application the handling of ammonia would be
attractive and enhance the ease of the protocol. As can be
3c, 92 % (92 %)
Compounds 3a-d were obtained in very good yields after
crystallization from ethyl acetate, whereas 3a and 3b
required further chromatographic purification. In the case of
heteroaryl-boronic acids substrate-dependent performance
4
seen from table 5, with NH OH as base a strong substrate-
dependency is observed. Whereas some examples work
slightly better, for 2e and 2h no product could be isolated.
Therefore, from an overall perspective, N(Et)
base of choice.
3
is still the
4
of NH OH is also found, since 3a and 3d did not react.
In many cases, directly after workup and recrystallization,
the products were obtained in crystalline form, suitable for
Conclusions
structural characterization. In figure
3 the molecular
structure of 2c is presented as an example.
Suzuki coupling of N1-substituted tetrazoles yielding
substituted tetrazolic biaryl-systems has been investigated
and optimized protocols have been developed. These
protocols expand upon the known procedures for C5- or C5
/
N1-bisubstituted tetrazoles, resulting in novel N1-tetrazolic
biaryl-systems with remarkably different reactivities. The
use of PdCl as ligand-free Pd-source in a 1:1 water-
2
ethanol mixture led to excellent yields under mild and
environmentally benign aerobic conditions. Optimal results
Z=4
P2
[°] 90
[°] 107.387(2)
[°] 90
wR 6.06
1
/n
a [Å] 10.0896(5)
b [Å] 10.1761(5)
c [Å] 13.1402(7)

were achieved using N(Et)
3
as base, since environmentally
OH
benign NH OH limits substrate scope, nevertheless NH
4
4

3
offers an interesting alternative especially when considering
technical scale syntheses and workup. In this case also the
V [Å ] 1287.5
2
Figure 3. Molecular structure of 2c (CCDC 1525257)
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
use of gaseous NH
3
could be considered. Whereas an
in toluene (featuring
cm−1 using a Perkin-Elmer Spectrum Two Fourier-transform
infrared spectrometer.
alternative protocol using Pd(PPh )
3 4
comparable yields) displays moisture- and oxygen
sensitivity, the ligand-free protocol requires large water
contents for complete conversion and high yields. In the
The melting points were determined via thermogravimetric
analysis performed on a Netzsch TG 209-C in a closed Al
crucibles with a heating rate of 10 K min−1 under nitrogen
atmosphere.
latter case, the O
reaction outcome.
2
-concentration had no effect on the
For high-resolution MS analysis methanolic solutions with a
10 µM sample concentration were used. The setup included
an HTC PAL system autosampler (CTC Analytics AG,
Zwingen, Switzerland), an Agilent 1100/1200 HPLC with
binary pumps, degasser and column thermostat (Agilent
Technologies, Waldbronn, Germany) and an Agilent 6230
AJS ESI-TOF mass spectrometer (Agilent Technologies,
Palo Alto, United States).
Competitive experiments of 4-bromobenzyl tetrazole and
benzyl tetrazole in the reaction leading to 1a showed no
significant deviation in the presence of an excess of benzyl
tetrazole. Additionally, using benzyl tetrazole as an additive
in the coupling reaction of 3-nitrophenylboronic acid with 4-
bromotoluene did not affect the reaction rate. In contrast,
even small amounts of PPh
3
notably decreased the
conversion rate. Based on these results it could be
confirmed, that the tetrazole is non-coordinative during the
coupling reaction and therefore does not act as a ligand
during the catalytic cycle.
Single crystals were attached to a glass fibre using
perfluorinated oil and mounted on a Bruker KAPPA APEX II
diffractometer equipped with a CCD detector. Data were
collected at 200 K (Cryostream 800, Oxford Cryosystems)
in a dry stream of nitrogen with Mo Kα radiation (Incoatec
Microfocus Source IµS: 30 W, multilayer mirror, λ=0.71073
Å). Redundant data sets were collected.
The method developed is further characterized by broad
substrate tolerance, including electron withdrawing groups
and heterocycles. The protocol allows for easy synthesis of
a library of tetrazoles with varying substitution patterns,
which offers a valuable tool for the investigation of a
substituent-effect driven structure-property relationships in
iron(II) spin crossover materials. In addition, this work may
act as stimulus for a further investigation of other coupling
reactions for substituted tetrazoles, offering ready access to
an even wider variety of tetrazole derivatives, many of
which are currently accessible by multi-step reactions.
Synthesis of the starting material
4-Bromobenzyl-1H-tetrazole
Bromobenzyl-1H-tetrazole was performed according to the
established Franke protocol[16]
mixture of 4-
(1)
Synthesis
of
4-
.
A
Bromobenzylamine (10 g, 53.75 mmol), sodium azide (3.84
g, 59.12 mmol) and triethyl orthoformate (9.16 g, 61.81
mmol) in 200 ml acetic acid was heated to 95 °C for 18 h.
After evaporation of all volatiles under reduced pressure,
200 ml of isopropyl alcohol were added and traces of
Experimental Section
remaining acetic acid were neutralized using sodium
bicarbonate. The precipitate was filtered off and the residual
solution was evaporated under reduced pressure. The
crude product was obtained as off-white solid after
recrystallization from MeOH. (11.2 g, 87 %)
Materials and methods
All organic solvents were dried and degassed in the
ultrasonic bath prior to use according to standard
methods.[15] Water was degassed prior to use. For all
experiments under aerobic conditions solvents and
reagents were used as supplied without further purification.
All reagents and boronic acids were commercially obtained
from Sigma Aldrich, TCI-Chemicals or Apollo Scientific and
used as supplied. Unless otherwise stated, all reactions
were performed in sealed vessels, closed under normal
aerobic conditions.
–1
1
Mp: 113.8-114.3 °C; νCH(Tz) cm : 3114; H NMR (400 MHz,
CD Cl , δ): 8.65 (s, 1H, TzCH), 7.61 – 7.46 (m, 2H, ArH),
2
2
7.25 – 7.15 (m, 2H, ArH), 5.57 (s, 2H, CH ); 13C{ H} NMR
1
2
(101 MHz, CD Cl , δ): 143.14 (TzCH), 132.89 (2ArCH,
2
2
ArC), 130.54 (2ArCH), 123.74 (ArC), 51.86 (CH ); HRMS
2
(ESI-TOF) m/z: [M + Na]+ Calc. for C H BrN Na 260.9752,
8
7
4
found 260.9754.
1H, 19F and C{ H} NMR spectra were recorded on a
Bruker 400 spectrometer with broad-band probe head. All
NMR chemical shifts are reported in ppm; H and 13C shifts
are referenced to the residual solvent resonance. A detailed
peak assignment was based on 2D NMR experiments
13
1
Coupling of arylboronic acids
General procedure To a stirred mixture of 4-Bromobenzyl-
1H-tetrazole (1) (1 eq) and boronic acid (1.1 eq) in
H O:EtOH (1:1), N(Et) (2 eq) and 0.03 eq. of an 0.01 M
1
2
3
aqueous solution of PdCl2 were rapidly added. The
dispersion was sealed, heated, if not stated otherwise, to
120 °C and kept at this temperature for 3 h. The reaction
mixture was allowed to cool to room-temperature and
extracted with EA. After filtration of the organic phase over
(
COSY, HSQC and HMBC) and is given in the supporting
information.
Mid-range IR spectra were recorded in attenuated total
reflection (ATR) technique within the range of 4000 – 450
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
–
1
–1
1
SiO
yield the crude product.
(4-Biphenylyl)methyl)-1H-tetrazole (2a) The crude product
2
the solvent was removed under reduced pressure to
Mp: 122.7-123.4 °C; νCH(Tz)cm : 3136, νC=O cm : 1685; H
NMR (400 MHz, CD Cl , δ): 8.68 (s, 1H, TzCH), 7.58 (ddd,
2
2
(
J = 7.6, 1.5, 0.6 Hz, 1H, ArH), 7.53 (td, J = 7.5, 1.5 Hz, 1H,
was recrystallized from DCM:PE (1:1) to afford 2a (white
solid, 95.9 mg, 97.2 % yield).
ArH), 7.44 (td, J = 7.5, 1.3 Hz, 1H, ArH), 7.39 – 7.33 (m,
); 13C{ H }
1
5H, ArH), 5.66 (s, 2H, CH
NMR (101 MHz, CD Cl
2
), 2.13 (s, 3H, CH
3
–
1
1
Mp: 178.9-179.6 °C; νCH(Tz) cm : 3113; H NMR (400 MHz,
CD Cl2, δ): 8.59 (s, 1H, Tz-CH), 7.65 (d, J = 8.6 Hz, 2H,
ArH), 7.60 (dd, J = 8.4, 1.4 Hz, 2H, ArH), 7.50 – 7.43 (m,
2
2
, δ): 203.82 (AcC), 143.22 (TzCH,
2
142.50 (ArC), 140.94 (ArC), 140.10 (ArC), 133.25 (ArC),
131.37 (ArCH), 131.02 (ArCH), 130.19 (2ArCH), 128.95
2
H, ArH), 7.42 – 7.36 (m, 3H, ArH), 5.63 (s, 2H CH
2
);
(2ArCH), 128.55 (ArCH), 128.29 (ArCH), 52.23 (CH
(CH ); HRMS (ESI-TOF) m/z: [M
Na]+ Calc. for
NaO: 301.1065, found 301.1067.
(4'-((1H-Tetrazolyl)methyl)-4-biphenylyl)ethan-1-one
2
), 30.66
1
3
1
C{ H } NMR (101 MHz, CD
2
Cl
2
, δ): 143.07 (TzCH), 142.70
3
+
(ArC), 140.56 (ArC), 132.67 (ArC), 129.46 (ArC), 129.38
2ArCH), 128.48 (2ArCH), 128.38 (ArCH), 127.61 (2ArCH),
16 14 4
C H N
(
(2f)
5
2.42 (CH
Na: 259.0960, found 259.0953.
(2'-Methyl-4-biphenylyl)methyl)-1H-tetrazole
2
); HRMS (ESI-TOF) m/z: [M + Na]+ Calc. for
The crude product was recrystallized with DCM:PE (1:1) to
afford 2f (white solid, 101.4 mg, 87.1 % yield).
14 12 4
C H N
–
1
(
(2b)
The
Mp: 134.7-136.2 °C; νCH(Tz) cm : 3106 (νTz), νC=O: 1680
1
crude product was purified by column chromatography on
silica gel with ethyl acetate/petroleum ether (1:1) to afford
(C=O); H NMR (400 MHz, CD
2
Cl
2
, δ): 8.61 (s, 1H, TzCH),
8.08 – 8.00 (m, 2H, ArH), 7.70 (dd, J = 8.6, 2.0 Hz, 4H,
2
b (clear viscous liquid, 95.3 mg, 91.0 % yield).
ArH), 7.45 – 7.39 (m, 2H, ArH), 5.65 (s, 2H, CH
2
), 2.61 (s,
–
1
1
); 13C{ H } NMR (101 MHz, CD
1
ν
CH(Tz) cm : 3130; H NMR (400 MHz, CD
2
Cl2, δ): 8.63 (s,
3H, CH
3
2
Cl2, δ): 197.85
1
5
H, TzCH), 7.37 (s, 4H, ArH), 7.31 – 7.14 (m, 4H, ArH),
(C=O), 144.89 (ArC), 143.11 (TzCH), 141.40 (ArC), 136.98
(ArC), 133.67 (ArC), 129.48 (2ArCH), 129.44 (2ArCH),
); 13C{ H } NMR (101
1
.64 (s, 2H, CH
2
), 2.24 (s, 3H, CH
3
MHz, CD
2
Cl2, δ): 143.56, 143.13, 141.38, 135.85, 132.25,
128.67 (2ArCH), 127.75 (2ArCH), 52.32 (CH
HRMS (ESI-TOF) m/z: [M + H]+ Calc. for C16
2
), 27.08 (CH
3
);
130.95, 130.64, 130.12, 128.65, 128.17, 126.39, 52.45
15 4
H N
O:
+
(
CH
2
3
), 20.69 (CH ); HRMS (ESI-TOF) m/z: [M + H] Calc.
279.1246, found 279.1247.
for C15
H
15
N
4
: 251.1297, found 251.1299.
(3'-Methyl-4-biphenylyl)methyl)-1H-tetrazole (2c) The crude
product was recrystallized with DCM:PE (1:1) to afford 2c
white solid, 101.6 mg, 97.1 % yield).
(4'-((1H-Tetrazolyl)methyl)-4-biphenylyl)carboxylic acid (2g)
The crude product was recrystallized with EA to afford 2g
(white solid, 109,0 mg, 93.8 % yield).
(
Mp: 267 °C (decomp.); νCH(Tz) cm : 3118, νC=O: 1674; 1
H
–
1
(
–
1
1
Mp: 122.2-123.6 °C; νCH(Tz) cm : 3126; H NMR (400 MHz,
CD Cl2, δ): 8.60 (s, 1H, TzCH), 7.64 (d, J = 8.3 Hz, 2H,
ArH), 7.43 – 7.41 (m, 1H, ArH), 7.41 – 7.36 (m, 3H, ArH),
NMR (400 MHz, DMSO-d6, δ): 13.00 (s, 1H, COOH), 9.57
(s, 1H, TzCH), 8.01 (d, J = 8.6 Hz, 2H, ArCH), 7.78 (dd, J =
2
11.2, 8.5 Hz, 4H, ArCH), 7.47 (d, J = 8.4 Hz, 2H, ArCH),
); 13C{ H } NMR (101 MHz, DMSO-d
1
7.33 (t, J = 7.5 Hz, 1H, ArH), 7.20 (d, J = 1.0 Hz, 1H, ArH),
5.78 (s, 2H, CH
2
6
, δ):
); 13C{ H} NMR (101
1
167.05 (C=O), 144.09 (TzCH), 143.52 (ArC), 139.12 (ArC),
134.81 (ArC), 129.94 (2ArCH), 129.86 (ArC), 128.88
5
.63 (s, 2H, CH
Cl
ArC), 139.23 (ArC), 132.56 (ArC), 129.32 (3ArCH), 129.09
ArCH), 128.43 (2ArCH), 128.33 (ArCH), 124.66 (ArCH),
2.40 (CH ), 21.77 (CH
); HRMS (ESI-TOF) m/z: [M + H]+
Calc. for C15 : 251.1297, found 251.1297.
(4'-Methyl-4-biphenylyl)methyl)-1H-tetrazole
2
), 2.41 (s, 3H, CH
3
MHz, CD
2
2
, δ): 143.09 (TzCH), 142.80 (ArC), 140.45
(
(
2
(2ArCH), 127.45 (2ArCH), 126.83 (2ArCH), 50.41 (CH );
HRMS (ESI-TOF) m/z: [M + H]+ Calc. for C15
13 4 2
H N O :
5
2
3
281.1039, found 281.1037.
H
15
N
4
((3'-Nitro-4-biphenylyl)methyl)-1H-tetrazole (2h) The crude
product was purified by column chromatography on silica
gel with EA:PE (2:1) to afford 2h (slightly yellow solid, 97.9
mg, 79.7 % yield).
(
(2d)
The
crude product was recrystallized with DCM:PE (1:1) to
afford 2d (white solid, 90 mg, 86.1 % yield).
–
1
1
–1
1
Mp: 167.0-168.3 °C; νCH(Tz) cm : 3099; H NMR (400 MHz,
CD Cl2, δ): 8.59 (s, 1H, TzCH), 7.63 (d, J = 8.3 Hz, 2H,
ArH), 7.49 (d, J = 8.3 Hz, 2H, ArH), 7.37 (d, J = 8.4 Hz, 2H,
Mp: 146.4-147.5 °C; νCH(Tz) cm : 3125; H NMR (400 MHz,
CD Cl , δ): 8.63 (s, 1H), 8.44 (t, J = 2.0 Hz, 1H, TzCH),
2
2
2
8.21 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H, ArH), 7.93 (ddd, J = 7.8,
1.8, 1.0 Hz, 1H, ArH), 7.73 – 7.68 (m, 2H, ArH), 7.65 (t, J =
ArH), 7.27 (d, J = 7.9 Hz, 2H, ArH), 5.62 (s, 2H, CH
2
), 2.39
); 13C{ H } NMR (101 MHz, CD
1
Cl2, δ): 143.07
8.0 Hz, 1H, ArH), 7.49 – 7.41 (m, 2H), 5.66 (s, 2H, CH
);
(
(
(
s, 3H, CH
3
2
2
1
3
1
TzCH), 142.59 (ArC), 138.42 (ArC), 137.56 (ArC), 132.32
ArC), 130.15 (2ArCH), 129.35 (2ArCH), 128.20 (2ArCH),
C{ H } NMR (101 MHz, CD Cl , δ): 149.39 (ArC), 143.13
2 2
(TzCH), 142.26 (ArC), 140.23 (ArC), 134.07 (ArC), 133.65
(ArCH), 130.54 (ArCH), 129.64 (2ArCH), 128.65 (2ArCH),
1
27.38 (2ArCH), 52.42 (CH
TOF) m/z: [M + H]+ Calc. for C15
51.1295.
4'-((1H-Tetrazol-1-yl)methyl)-2-biphenylyl)ethan-1-one (2e)
2
), 21.37 (CH
3
); HRMS (ESI-
H
15
N
4
: 251.1297, found
123.04 (ArCH), 122.44 (ArCH), 52.24 (CH
2
); HRMS (ESI-
+
2
TOF) m/z: [M + H] Calc. for C14
282.0980.
12 5 2
H N O : 282.0991, Found
(
The crude product was recrystallized with DCM:PE (1:1) to
afford 2e (white solid, 101.3 mg, 87.0 % yield).
((3'-Chloro-4-biphenylyl)methyl)-1H-tetrazole
(2i)
3-
Chlorophenylboronic acid (72.0 mg, 460.1 μmol) and 1 (100
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
mg, 418.3 μmol) were reacted according to the general
procedure at room temperature. The crude product was
recrystallized with DCM:PE (1:1) to afford 2i (off-white solid,
– 7.41 (m, 2H, ArH), 7.36 (ddd, J = 7.9, 4.8, 1.0 Hz, 1H,
); 13C{ H } NMR (101 MHz, CD
1
Cl
pyrH), 5.68 (s, 2H, CH
2
2
2
,
δ): 149.39 (PyrCH), 148.62 (PyrCH), 143.30 (TzCH),
139.20 (PyrC), 135.88 (ArC), 134.64 (PyrCH), 133.67
(ArC), 129.50 (2ArCH), 128.34 (2ArCH), 124.06 (PyrCH),
1
04.2 mg, 92.8 % yield).
Mp: 137.0-138.2 °C; νCH(Tz) cm : 3122; H NMR (400 MHz,
CD Cl , δ) : 8.62 (s, 1H), 7.66 – 7.60 (m, 2H, ArH), 7.58 (t, J
–
1
1
52.12 (CH
13 12 5
C H N : 238.1093, found 238.1085.
2
); HRMS (ESI-TOF) m/z: [M + H]+ Calc. for
2
2
=
–
5
1
1
1.9 Hz, 1H, ArH), 7.49 (dt, J = 7.5, 1.6 Hz, 1H, ArH), 7.43
7.38 (m, 3H, ArH), 7.36 (dt, J = 7.9, 1.7 Hz, 1H, ArH),
4-(4-((1H-Tetrazol-1-yl)methyl)phenyl)pyridine (3b) The
crude product was purified by column chromatography on
silica gel with EA:MeOH (10:1) to afford 3b (white solid,
81.3 mg, 81.9 % yield).
.64 (s, 2H, CH
2
); 13C{ H } NMR (101 MHz, CD
1
2
Cl
2
, δ):
43.12 (TzCH), 142.45 (ArC), 141.17 (ArC), 135.21 (ArC),
33.39 (ArC), 130.78 (ArCH), 129.45 (2ArCH), 128.46
–
1
1
(
2ArCH), 128.29 (ArCH), 127.68 (ArCH), 125.91 (ArCH),
2.28 (CH
); HRMS (ESI-TOF) m/z: [M + H]+ Calc. for
: 271.0751, found 271.0748.
(4'-Chloro-4-biphenylyl)methyl)-1H-tetrazole
Mp: 134.7-135.6 °C; νCH(Tz) cm : 3111; H NMR (400 MHz,
MeOD δ): 9.29 (s, 1H, TzCH), 8.59 – 8.55 (m, 2H, PyrH),
5
2
,
C
14
H
12ClN
4
7.78 (d, J = 8.6 Hz, 2H, ArH), 7.71 – 7.67 (m, 2H, PyrH),
); 13C{ H }
1
(
(2j)
4-
7.51 (d, J = 8.7 Hz, 2H, ArH), 5.78 (s, 2H, CH
2
Chlorophenylboronic acid (72.0 mg, 460.1 μmol) and 1 (100
mg, 418.3 μmol) were reacted according to the general
procedure at room temperature. The crude product was
recrystallized with DCM:PE (1:1) to afford 2j (white solid,
NMR (101 MHz, MeOD, δ): 150.64 (2PyrCH), 149.73
(PyrC), 144.82 (TzCH), 139.36 (ArC), 136.91 (ArC), 130.24
2
(2ArCH), 128.83 (2PyrCH), 123.12 (2ArCH), 52.28 (CH );
HRMS (ESI-TOF) m/z: [M + H]+ Calc. for C13
12 5
H N :
1
01.9 mg, 90.1 % yield).
Mp: 103.7-104.9 °C; νCH(Tz) cm : 3113; H NMR (400 MHz,
CD Cl2, δ): 8.60 (s, 1H, TzCH), 7.64 – 7.60 (m, 2H, ArH),
238.1093, found 238.1089.
–
1
1
1-(4-(Thiophen-3-yl)benzyl)-1H-tetrazole (3c) The crude
product was recrystallized with EA to afford 3c (off-white
solid, 93mg, 91.8 % yield).
2
7.56 – 7.52 (m, 2H, ArH), 7.47 – 7.42 (m, 2H, ArH), 7.41 –
); 13C{ H} NMR (101
1
Mp: 184.8-185.9 °C; νCH(Tz) cm : 3110; H NMR (400 MHz,
DMSO-d , δ): 9.54 (s, 1H, TzCH), 7.92 – 7.87 (m, 1H), 7.78
–1
1
7.37 (m, 2H, ArH), 5.63 (s, 2H, CH
2
MHz, CD
2
Cl2, δ): 143.08 (TzCH), 141.41 (ArC), 139.10
ArC), 134.39 (ArC), 133.05 (ArC), 129.57 (2ArCH), 129.46
2ArCH), 128.96 (2ArCH), 128.34 (2ArCH), 52.34 (CH );
6
(
– 7.71 (m, 2H), 7.64 (dd, J = 5.1, 2.8 Hz, 1H), 7.57 – 7.54
); 13C{ H }
1
(
2
(m, 1H), 7.43 – 7.33 (m, 2H), 5.73 (s, 2H, CH
NMR (101 MHz, DMSO-d
135.25, 133.44, 128.76, 127.18, 126.48, 126.11, 121.44,
50.48 (CH
); HRMS (ESI-TOF) m/z: [M + H]+ Calc. for
S: 243.0704, found 243.0699.
2
HRMS (ESI-TOF) m/z: [M + H]+ Calc. for C14
71.0751, found 271.0749.
(4'-Fluoro-4-biphenylyl)methyl)-1H-tetrazole (2k) The crude
product was recrystallized with DCM:PE (1:1) to afford 2k
white solid, 94.7 mg, 89.4 % yield).
H
12ClN
:
4
6
, δ): 143.98 (TzCH), 140.69,
2
(
2
12 11 4
C H N
(
1-(4-(Furan-3-yl)benzyl)-1H-tetrazole (3d) The crude
product was recrystallized with EA to afford 3d (off-white
solid, 83.9mg, 88.7 % yield).
–
1
–1
1
Mp: 118.5-120.4 °C; νCH(Tz) cm : 3105, (νC-F) cm : 1252; H
NMR (400 MHz, CD Cl2, δ): 8.59 (s, 1H, TzCH), 7.63 – 7.59
m, 2H, ArH), 7.59 – 7.55 (m, 2H, ArH), 7.41 – 7.37 (m, 2H,
2
–
1
1
(
Mp: 141.1-142.1 °C; νCH(Tz) cm : 3149; H NMR (400 MHz,
DMSO-d , δ): 9.52 (s, 1H), 8.19 (t, J = 1.2 Hz, 1H), 7.74 (t,
J = 1.7 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.40 – 7.34 (m,
2H), 6.96 (dd, J = 1.9, 0.9 Hz, 1H), 5.71 (s, 2H, CH );
, δ): 144.35, 143.95,
); 13C{ H }
1
ArH), 7.20 – 7.11 (m, 2H, ArH), 5.62 (s, 2H, CH
NMR (101 MHz, CD Cl2, δ): 163.32 (d, J = 246.2 Hz, ArC),
43.07 (TzCH) , 141.69 (ArC) , 136.80 (d, J = 3.2 Hz, ArC),
2
6
2
1
1
2
5
2
1
3
1
32.71 (ArC) , 129.42 (2ArCH) , 129.33 (d, J = 8.1 Hz,
ArCH)), 128.37 (2ArCH) , 116.28 (d, J = 21.6 Hz, 2ArCH)),
C{ H } NMR (101 MHz, DMSO-d
6
139.63, 133.22, 132.17, 128.74, 125.92, 108.62, 50.52,
); 19F NMR (376 MHz, CD
Cl2) δ -115.66; HRMS
Na: 277.0865,
39.52; HRMS (ESI-TOF) m/z: [M + H] Calc. for C12
227.0933, found 227.0926.
+
2.37 (CH
2
2
11 4
H N O:
+
(ESI-TOF) m/z: [M + Na] Calc. for C14
H
11FN
4
found 277.0871.
Coupling of heteroarylboronic acids
Acknowledgements
3
-(4-((1H-Tetrazol-1-yl)methyl)phenyl)pyridine (3a) The
We acknowledge financial support of the Austrian Science
Fund (FWF-Der Wissenschaftsfond) project P24955-N28.
We also thank Dr. Laszlo Czollner for HRMS-analysis. This
work was performed in the framework of the Corporation in
Science and Technology (COST) action CM1305 “Explicit
Control Over Spin-states in Technology and Biochemistry
(ECOSTBio).
crude product was purified by column chromatography on
silica gel with EA:MeOH (10:1) to afford 3a (white solid,
8
1.6 mg, 82.2 % yield).
Mp: 96.5-98.7 °C; νCH(Tz) cm : 3111; H NMR (400 MHz,
CD Cl , δ): 8.81 – 8.79 (m, 1H, pyrH), 8.78 (s, 1H, TzCH),
–
1
1
2
2
8
.57 (dd, J = 4.8, 1.7 Hz, 1H, pyrH), 7.86 (ddd, J = 7.9, 2.5,
.5 Hz, 1H, pyrH), 7.61 (dd, J = 8.4, 2.1 Hz, 2H, ArH), 7.46
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.201700105
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Development and substrate scope of
a green, ligand-free Suzuki protocol
in aqueous media under ambient
atmosphere, leading to 1- biaryl- and
heteroaryl- substituted 1H-tetrazoles
in very good to excellent yields is
presented.
Cross-coupling*
Marco Seifried, Christian Knoll, Gerald Giester,
Jan M. Welch, Danny Müller* and Peter
Weinberger
Page No. – Page No.
Aryl and heteroaryl N1- tetrazoles
via ligand-free Suzuki-reaction
under aerobic, aqueous conditions
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