A novel and efficient tributyltin azide-mediated synthesis of 1H-tetrazolylstilbenes from cyanostilbenes

Article abstract of DOI:10.1016/j.tetlet.2016.03.040

A novel and efficient route was established for the synthesis of a series of (Z)-5-(2-(heteroaryl-2-yl) and (Z)-5-(3-(heteroaryl-3-yl)-1-(phenyl)vinyl)-1H-tetrazoles (3a-g and 6a-f, respectively) from cyanostilbene analogs containing benzo[b]thiophene, be

Full text of DOI:10.1016/j.tetlet.2016.03.040

Tetrahedron Letters 57 (2016) 1807–1810
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and efficient tributyltin azide-mediated synthesis
of 1H-tetrazolylstilbenes from cyanostilbenes
⇑
Narsimha Reddy Penthala, Shobanbabu Bommagani, Jaishankar Yadlapalli, Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient route was established for the synthesis of a series of (Z)-5-(2-(heteroaryl-2-yl) and
Z)-5-(3-(heteroaryl-3-yl)-1-(phenyl)vinyl)-1H-tetrazoles (3a–g and 6a–f, respectively) from cyanostil-
bene analogs containing benzo[b]thiophene, benzo[b]furan, and indole moieties utilizing tributyltin azide
as a Lewis acid. This 1,3-dipolar [3+2]cycloaddition of azide to the cyano group of the cyanostilbene pre-
cursor molecule affords good yields of the corresponding tetrazolylstilbene analog and constitutes a sim-
ple and cost-effective procedure.
Received 13 February 2016
Revised 3 March 2016
Accepted 11 March 2016
Available online 12 March 2016
(
Keywords:
Ó 2016 Published by Elsevier Ltd.
5
-Substituted-1H-tetrazoles
Heteroaryl cyanostilbenes
Tributyltin azide
[
3+2]cycloaddition of azide
The chemistry of tetrazoles has acquired immense importance
1H-tetrazoles from acrylonitrile precursor molecules utilizing tri-
butyltin azide (Bu SnN ) as an azidation reagent.
Bu SnN is a covalently linked azide similar to TMSA and
diphenylphosphoryl azide (DPPA) that mediates azidation reac-
tions in fairly homopolar solvents. Although Bu SnN is toxic in
nature it is a popular reagent for the synthesis of many organic
1
in recent years, since the tetrazole moiety is a metabolically stable
structure and has similar acidic character (i.e. is bioisosteric) with
the carboxylic acid moiety2 but is more resistant to many of the
biological transformations that the carboxylic acid functionality
3
3
3
3
3
3
3
is susceptible to in the liver. The tetrazoles are ionized at physio-
2
7–31
8,32,33
logical pH (7.4) like their carboxylic acid counterparts, and the
anionic tetrazoles are nearly 10 times more lipophilic than their
corresponding carboxylates,4 which is an important factor with
regard to permeation of drug molecules through cell membranes.
The synthesis of 5-substituted-1H-tetrazoles by conventional
approaches has been reported to proceed via [3+2]cycloaddition
compounds,
including tetrazoles,
owing to its solubility
in organic solvents, which can safely provide high azide concentra-
tions in solution. Convenient in situ generation, thermal stability,
and ease of hydrolysis are also additional merits of using Bu
In addition, conventional tetrazole-yielding reactions are generally
slow because of the biphasic reaction system involving NaN and
affords excellent yields of tetrazoles, and is a
3 3
SnN .
3
5
8
of azide with nitriles. Many protocols are available for the prepa-
3 3
nitriles. Bu SnN
particularly effective reagent for the conversion of sterically hin-
3
3
ration of 5-substituted tetrazoles from aromatic nitriles by utiliz-
6
–8
ing different azides such as silicon or tin azide,
Trimethylsilyl
dered nitriles to tetrazoles in comparison to the other reagents
9
8
azide (TMSA) and sodium azide in combination with different
3 4
such as TMSA, alkyl azides, or NaN /NH Cl.
1
0–12
Lewis acid catalysts.
Several homogeneous catalysts, i.e. Zn
Recently, we have reported on the synthesis and anti-cancer
activity of a series of novel triazole analogs of heteroaromatic
cyanostilbenes where the triazole unit has been incorporated as
1
1
3
7
14
15
11
16
(
(
OTf)
OTf)
3
,
,
AlCl
3
,
Pd(PPh
3
)
4
BF
3
.OEt
2
,
Pd(OAc)
2
/ZnBr
2
,
Yb
3
and various heterogeneous catalytic systems, such as
1
8
19
20
21
22
FeCl
3
/SiO
2
,
c
-Fe
2
O
3
,
ZnS, CdCl
2
,
Zn/AlHT, natural natrolite
a bridge between the two aromatic ring systems in the molecule
2
3
24
25,26
34–37
zeolite,
Zn hydroxyapatite,
and Cu
2
O
have also been
by chemical transformation of the cyanostilbene moiety.
We
reported for the synthesis of tetrazoles. However, there have been
no reports on the conversion of the acrylonitrile moiety to 5-sub-
stituted 1H-tetrazoles.
have now developed a convenient and viable process for the prepa-
ration of novel tetrazolylstilbene derivatives via chemical modifi-
cation of the cyano moiety of
a series of heteroaromatic
In this Letter, we describe the synthesis of a series of (Z)-5-(2-
heteroaryl-2-yl) and (Z)-5-(3-(heteroaryl-3-yl)-1-(phe-nyl)vinyl)-
cyanostilbenes that have previously been reported as potent anti-
cancer agents that target tubulin polymerization.
3
8,39
(
We focused on the formation of 1H-tetrazolyl analogs because
these tetrazole-tethered stilbene analogs are predicted to have
improved drug-likeness in comparison to the previously reported34
⇑
Corresponding author. Tel.: +1 501 686 6495; fax: +1 501 686 6057.
E-mail address: PACrooks@uams.edu (P.A. Crooks).
http://dx.doi.org/10.1016/j.tetlet.2016.03.040
040-4039/Ó 2016 Published by Elsevier Ltd.
0

1
808
N. R. Penthala et al. / Tetrahedron Letters 57 (2016) 1807–1810
a tetrazolyl moiety can exist as a water-soluble sodium tetrazolate
salt form. On the other hand, the triazolyl moiety is only weakly
acidic (pKa ꢀ8–10) with acidities comparable to b-ketoesters or
1
,3-diketo compounds. The pKa value more clearly shows the dif-
ferences in physical properties of the two scaffolds and the pre-
dicted usefulness of the more water-soluble tetrazole derivatives
as their sodium salts when compared to the triazole derivatives.
In this regard we have provided the comparative pKa values for
the tetrazole and triazole analogs in the supporting information
to justify our prediction of improved druglikeness of the tetrazole
analogs over the triazole analogs. In the present communication
three heteroaromatic cyano-stilbene scaffolds have been utilized,
i.e.
(Z)-3-(benzo[b]thio-phenyl)-2-phenylacrylonitrile,
(Z)-3-
(
benzo[b]-furan)-2-phenyl-acrylonitrile and (Z)-3-(indole)-2-phe-
Scheme 1. Synthesis of (Z)-5-(2-(heteroaryl-2-yl)-1-(phenyl)vinyl)-1H-tetrazoles
3a–g).
nyl-acrylonitrile ring systems. These heteroaromatic stilbenes sys-
tems have a cyano group at the sp2 carbon adjacent to the phenyl
substituent which can be chemically transformed into a tetrazole
moiety to afford novel tetrazolylstilbenes. We have developed a
two-step procedure for the synthesis of a variety of such stilbenes.
In the first step of the synthesis, heteroaromatic aldehydes have
been reacted with variously substituted phenyl acetonitriles in
(
5
% sodium methoxide/methanol solution at reflux temperatures
over 4–6 h to obtain the intermediate hetero aromatic cyanostil-
3
8,39
bene analogs via previously reported procedures.
these cyanostilbene intermediates have then been reacted with tri-
butyltin azide (Bu SnN ) formed in situ from the reaction of NaN
3
In step 2,
3
3
with tributyltin chloride, followed by hydrolysis of the resulting
tetrazolylstilbene-tributyltin complex in 5 N HCl at room temper-
ature to afford the corresponding (Z)-5-(heteroaryl)-1-(phenyl)-
vinyl)-1H-tetrazole analog (Schemes 1 and 2).
Initial optimization studies on the conversion of the cyano
group of the cyanostilbene moiety to a 5-substituted 1H-tetrazole
moiety were studied utilizing NaN
3 4
in the presence of NH Cl or
Bu SnCl as catalysts and a variety of solvents (o-xylene, DMF,
3
DMSO and water) at 100–130 °C. We utilized the synthesis of com-
pound 3a from 1a as a model reaction (Table 1). Refluxing (Z)-3-
(
(
benzo[b]thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)-acryl-onitrile
1a) with NaN in a mixture of DMF and water (4:1) for 36 h
Scheme 2. Synthesis (Z)-5-(2-(heteroaryl-3-yl)-1-(phenyl)vinyl)-1H-tetrazoles
6a–f).
3
(
afforded poor yields of the tetrazole product 3a (Table 1, entry
1
2
). Addition of NH
4
Cl led to a modest improvement in yield (entry
triazole analogs of this type. It is well known that tetrazolyl moi-
eties are unique because of their acidity (pKa ꢀ5). The tetrazolyl
moiety is bioisosteric with the carboxylic acid moiety, has a similar
pKa value as acetic acid and other aliphatic carboxylic acids, and is
often utilized in drug design to improve druglikeness and water
). Previous reports on the synthesis of tetrazoles clearly specify
4
2
22,42
10
33
that DMSO, DMF,
most suitable solvents for these reactions, presumably due to the
high boiling point and improved solubility of the reagents in these
water, or o-xylene and DMF are the
4
0,41
3
solvents. The use of Bu SnCl as a Lewis acid catalyst in these reac-
solubility.
Thus, because of their acidity, molecules containing
Table 1
Different reaction conditions and yields for the formation of 3a from (Z)-3-(benzo[b]thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)-acrylonitrile (1a)
Entry
Reagent (3 mol. equiv)
—
Solvent
NaN
3
(equiv)
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
DMF + H
DMF
DMF + H
DMF + H
DMSO
2
O (4:1)
2
2
3
2
1
1
1
2
3
3
3
3
120
120
120
120
120
100
130
100
100
100
130
100
36
24
24
24
24
24
24
24
24
15
24
36
10
25
34
40
55
30
25
80
90
81
85
80
NH
4
NH
4
NH
4
Cl
Cl
Cl
2
O (4:1)
O (4:1)
2
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
3
SnCl
SnCl
SnCl
SnCl
SnCl
SnCl
SnCl
SnCl
3
3
3
3
3
3
3
o-Xylene
o-Xylene
o-Xylene + DMF (3:1)
o-Xylene + DMF (3:1)
o-Xylene + DMF (3:1)
o-Xylene + DMF (3:1)
o-Xylene + DMF (3:1)
1
1
1
0
1
2

N. R. Penthala et al. / Tetrahedron Letters 57 (2016) 1807–1810
1809
Table 2
Z)-5-(2-(hetero-2-yl)-1-(phenyl)vinyl-1H-tetrazoles (3a–g), their reaction times and
yields
(
Compound
X
R1
R2
R3
Time (h)
Yield (%)
3
a
S
S
S
S
S
O
NH
OCH
OCH
OCH
H
3
3
3
OCH
H
3
OCH
OCH
H
3
24
30
30
36
36
36
30
90
88
82
80
77
70
78
3
b
3
3
3
3
3
3
c
d
e
f
OCH
OCH
OH
3
3
H
OCH
OCH
OCH
3
3
3
OCH
H
3
OCH
OCH
3
g
3
OCH
3
tions significantly improved product yields. A variety of reaction
conditions and solvents were investigated and it was found that
utilizing 2–3 molar equivalents of NaN in a mixture of o-xylene
3
and DMF afforded yields of 3a in the range 80–90% (Table 1). The
use of only o-xylene in the above reaction afforded low yields
because of the low solubility of the reactants in this solvent.
Refluxing 1a with NaN
3 mol. equiv) in o-xylene/DMF at 100 °C for 24 h followed by
hydrolysis of the resulting tetrazole-SnBu complex in 5 N HCl
3 3
(3 mol. equiv) in the presence of Bu SnCl
Scheme 3. Plausible mechanism for the formation of tetrazolyl -stilbenes 3 from
their cyanostilbene precursors 1.
(
3
afforded a 90% yield of product 3a (Table 1, entry 9).
Various (Z)-3-(heteroaryl-2-yl)-2-(phenyl)-acrylonitrile analogs
Increasing the number of electron-releasing methoxy sub-
stituents on the phenyl ring of the cyanostilbene precursor gener-
ally increased the rate of the reaction and the yield of the
corresponding tetrazolylstilbene products, which is consistent
with previous studies by Sisido et al., who reported that tri-
alkyltin azides react more readily with aromatic nitriles containing
electron-releasing substituents than with those containing elec-
tron-withdrawing groups.
3 3
(1a–g) and Bu SnN (prepared in situ from sodium azide and tribu-
tyltin chloride) were refluxed for 24–36 h in a mixture of o-xylene/
DMF at 100 °C to afford the corresponding (Z)-5-(heteroaryl-2-yl)-
3
2
1
-(phenyl)-vinyl)-1H-tetrazole-tributyltin azide intermediates 2a–
g, which were then hydrolyzed in the presence of 5 N HCl at room
temperature to yield the desired tetrazolyl stilbenes 3a–g
(Scheme 1) in 70–90% yields (Table 2). Similarly, the isomeric het-
eroaryl-3-yl cyanostilbenes 4a–f were converted into their corre-
sponding (Z)-heteroaryl-3-yl tetrazolylstilbenes 6a–f via azide
intermediates 5a–f (Scheme 2, Table 3) in 72–91% yield. The struc-
ture and purity of the products were verified by H- and C NMR
spectroscopy and by HPLC (1:1 water and ACN with 0.1% of formic
acid at 0.5 ml/min flow rate using C-18 column). The double bond
geometry was also confirmed as Z-isomer by single-crystal X-ray
analysis (Fig. 1).
A plausible mechanism for the formation of the above tetra-
zolylstilbenes from their precursor cyanostilbenes is shown in
Scheme 3. The initial attack of Bu
3 3
SnN on the cyano group of 1
1
13
occurs to form intermediate 7 as has been proposed by Aureggi
3
3
and Sedelmeier, which then undergoes cyclization by formation
of an N–N covalent bond between the nitrogen atom of azide moi-
ety and the nitrogen atom attached to tributyltin, resulting in the
formation of tetrazole-tributyltin intermediate 2. Hydrolysis of 2
in 5 N HCl then affords tetrazolylstilbene 3, with elimination of tri-
butyltin hydroxide.
Table 3
Various (Z)-5-(2-(heteroaryl-3-yl)-1-(phenyl)vinyl)-1H-tetrazoles (6a–f) and their
reaction times and yields
In conclusion, a novel and efficient route of synthesis has been
developed for the synthesis of a series of (Z)-5-(2-(heteroaryl-2-yl)
Entry
X
R1
R2
R3
Time (h)
Yield (%)
and
(Z)-5-(3-(heteroaryl-3-yl)-1-(phenyl)vinyl)-1H-tetrazoles
(
3a–g and 6a–f, respectively) that incorporate benzo[b]thio-phe-
6a
6b
6c
6d
6e
6f
S
S
S
S
O
NH
OCH
OCH
OCH
H
3
3
3
OCH
H
OCH
OCH
H
3
OCH
OCH
H
3
24
30
30
36
36
36
91
87
85
80
72
84
nyl, benzo[b]furanyl, and indolyl moieties. These products were
formed from cyanostilbene precursors via a tributyltin azide-
mediated [3+2]cycloaddition reaction. This method provides an
efficient, simple, and cost-effective procedure for the synthesis of
novel tetrazolylstilbenes in high yields.
3
3
3
H
OCH
OCH
3
OCH
OCH
3
3
H
3
Figure 1. Representative single crystal X-ray structures of (Z)-5-(2-(benzo[b]thiophen-2-yl)-1-(3,5-dimethoxyphenyl)vinyl-1H-tetrazole (3b) and (Z)-5-(2-(benzo[b]
thiophen-3-yl)-1-(3,4,5-trimethoxy-phenyl)vinyl)-1H-tetrazole (6a).

1
810
N. R. Penthala et al. / Tetrahedron Letters 57 (2016) 1807–1810
1
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5
1
We thank Dr. Guangrong Zheng for useful discussions. The
authors gratefully acknowledge the Arkansas Research Alliance
for financial support, the UAMS sub award to PNR and SA from
NIA Claude Pepper Center grant P30-AG028718 (J. Wei, P.I.) and
the NIH/National Institute of General Medical Sciences
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