Water promoted one pot three-component synthesis of tetrazoles

Article abstract of DOI:10.1039/c2nj40733g

A one pot, three component synthesis of tetrazoles via thiourea has been accomplished in water. Water enhances the solubility of a higher number of components in the three component protocol thus promoting the reaction. The synthesis involves a chemoselective exocyclic reaction, regioselective electrocyclisation and a preferred conformational orientation of the tetrazole side chain which are rationalised based on the relative magnitude of Garbisch angle strain/allylic strains anticipated during the course of the reaction.

Full text of DOI:10.1039/c2nj40733g

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Water promoted one pot three-component synthesis
of tetrazoles†
Cite this: NewJ.Chem., 2013,
37, 488
Murugan Sathishkumar, Poovan Shanmugavelan, Sangaraiah Nagarajan,
Murugan Dinesh and Alagusundaram Ponnuswamy*
A one pot, three component synthesis of tetrazoles via thiourea has been accomplished in water. Water
enhances the solubility of a higher number of components in the three component protocol thus
promoting the reaction. The synthesis involves a chemoselective exocyclic reaction, regioselective
electrocyclisation and a preferred conformational orientation of the tetrazole side chain which are
rationalised based on the relative magnitude of Garbisch angle strain/allylic strains anticipated during
the course of the reaction.
Received (in Montpellier, France)
16th August 2012,
Accepted 12th November 2012
DOI: 10.1039/c2nj40733g
www.rsc.org/njc
azide anion (a) chlorine in a-chloroformamidines17 and (b) sulfur
Introduction
from thioureas in the presence of mercury 18 or lead salts.13a
Tetrazole and its derivatives rarely occur in nature1 and are well
known for their pharmacological activities2 (Fig. 1). They have
been shown to be potential P2X7-antagonists,3 TNF alpha
inhibitors,4 and inhibitors of anandamide cellular uptake.5
Moreover, 1,5-substituted tetrazoles serve as intermediates
opening synthetic routes to substituted dihydropyrimidinones,6
indolizidinones,7 and N-substituted heterocycles.8 Further,
their utility in biochemistry,9,10 coordination chemistry11 and
palladium-catalysed reactions12 is noteworthy. As a conse-
quence, the need for the development of efficient and elegant
protocols for their synthesis emerges.
Available methods for the synthesis of the tetrazole frame-
work include (i) addition of NaNO2 to aminoguanidine,13
(ii) addition of NaN3 to carbodiimides13c or cyanamides,14
(iii) reactions of amines with a leaving group in the tetrazole’s
5-position,15 (iv) reaction of primary amines with NaN3 and
triethyl orthoformate,16 and (v) nucleophilic substitution by an
Result and discussion
Recently the solvent-free protocol, multicomponent strategy
and reactions in water for heterocyclic synthesis are emerging
rapidly. These methods attain importance as they avoid the
toxicity due to the organic solvents and are eco-friendly.
It is pertinent to mention here that if not in all, in most of
the reports dealing with organic reactions in water, little or no
emphasis is given to explain why water is selected as the media.
In view of this, we were tempted to make an attempt to develop
an insight into the water promoted multicomponent reactions.
This would pave way for better understanding and planning of
water promoted protocols in organic syntheses. Thus, in a
Table 1 Screening of various bases in DMF
Entry
Base
Equivalents
Time (minutes)
Yielda
1
2
3
4
5
6
7
Et3N
Et3N
K2CO3
K2CO3
Pyridine
Na2CO3
DBU
1
2
1
2
2
2
2
40
30
20
15
30
20
15
60
64
69
79
41
65
70
Fig. 1 Some biologically important tetrazoles.
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Tamilnadu 625-021, India. E-mail: ramradkrish@yahoo.co.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2nj40733g
a
Isolated yield.
c
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of chalcones;19i to the best of our knowledge, we herein submit
the first report on an efficient water promoted synthesis of
tetrazoles from allylic thiourea. The synthesis is found to be
highly regio/chemoselective.
Table 2 Solvent screening in tetrazole synthesis
Perusal of prevailing protocols in the literature for the
tetrazole synthesis from thiourea in DMF (solvent of choice)
discloses that four components viz. thiourea, mercury(II) chloride,
sodium azide and an acid scavenger viz. triethylamine are used
in the synthesis. Herein, the reaction involves two organic
components viz. thiourea and triethylamine and two inorganic
components viz. sodium azide and mercury(II) chloride.
While the organic components are soluble in DMF, inorganic
reactants are not, thus making the reaction heterogeneous.
So, the solubility of the reactants may be one of the reasons
for the longer reaction time. Thus, it was envisaged that by
changing the solvent to water, most of the components could
be solubilised and hence the reaction may be promoted. On the
other hand, it was also presumed that if any water soluble
inorganic acid scavenger could efficiently replace the organic
scavenger viz. triethylamine, all the components except the
organic substrate will be soluble in water and hence facilitate
the progress of the reaction.
Entry
Solvent
Temperature
Time
Yielda
1
2
3
4
5
6
Ethanol
Acetonitrile
DMF
DMF
Acetonitrile/ethanol (1 : 1)
Water
Reflux
Reflux
80 1C
100 1C
Reflux
Reflux
2.5 h
1 h
20 min
15 min
2 h
45
57
70
78
53
76
30 min
a
Isolated yield.
continuation of our recent reports on the solvent-free synthesis
of amides,19a–c cyclic imides,19d thioamides,19e thiazolidones,19f
spirothiazolidones,19g triazoles19h and water promoted synthesis
Table 3 Synthesis of regioisomeric tetrazoles in water20
In view of the above, screening of the reaction (i) using
various acid scavengers and (ii) various water miscible solvents
and water was attempted, the details of which are presented
(vide infra).
At the outset, screening of the one pot reaction was
attempted with various bases in DMF (Table 1), the solvent
that is often used in the prevailing methodologies. The results
(entries 4 and 7) were more promising with regard to the
reaction time and yield i.e. when two equivalents of either
potassium carbonate (entry 4, Table 1) or DBU (entry 7,
Table 1) was used, the tetrazole was formed in good yield just
in 15 minutes. Of these scavengers, the low cost and water
Ratio of regioisomersa
Amines
Entry
Yieldb (%)
2a–n
4a–n
5a–n
1
2
H3C–NH2 (2a)
H3CH2C–NH2 (2b)
52
53
48
47
82
83
3
55
45
85
4
5
52
90
48
10
81
86
H3CH2CH2CH2C–NH2 (2e)
6
499
499
499
499
499
499
—
—
—
—
—
—
—
—
80
84
85
84
86
82
—
Table 4 Some successful tetrazole synthesis in water
Entry
Isothiocyanate
Amine
Tetrazole
Yielda
76
7
8
1
9
10
11
12
2
3
73
76
79
13
14
a
—
—
—
—
Trace
—
4
b
a
Identified by 1H NMR. Isolated yield.
Isolated yield.
c
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allylic A1,2 strain that could be envisaged during thiourea
formation.
Subsequently, the scope of the above discussed water pro-
moted protocol was also tested with thioureas (obtained from
phenylisothiocyanate and primary, secondary and aryl amines)
affording the following tetrazoles in good yield (Table 4).
However, tetrazole synthesis from cyclic thioureas (Fig. 2)
Fig. 2 Unsuccessful tetrazole synthesis in water–DMF via cyclic thiourea.
soluble/washable K2CO3 was taken as the base of choice. To the
best of our knowledge, this is the first report wherein an could not be achieved both in DMF and water. This may be due
inorganic scavenger is used in tetrazole synthesis. to the lack of carbodiimide formation, the intermediacy of
Further, having established K2CO3 as the base of choice, which is presumed to afford guanyl azide that undergoes
we investigated the efficacy of various water miscible solvents electrocyclisation to give the tetrazole.
and water as solvents in the synthesis of 1,5-substituted
The structures of the regioisomeric tetrazoles obtained in
tetrazole (Table 2). It was noted that DMF (entries 3 and 4, the present study were interpreted by spectral methods. As is
Table 2) and water suits the best with two equivalents of K2CO3. evident from Table 3, of the two regioisomers 4 and 5, the
Herein, the water insoluble substrate seems to be at the surface former is formed exclusively when the amines used are aryl
of water and hence the reaction proceeds via a ‘‘On-water’’ amines. This has been confirmed by 2D NMR i.e. homonuclear
protocol.
correlation spectroscopy (H, H COSY) of the product confirms it
Encouraged by these findings, the broad scope of the water to be 4 by the observation that the CHN proton shows correlation
promoted one pot protocol was established by synthesising a with the CNH proton (Fig. 3). Had it been the regioisomer 5, this
library of tetrazoles in good yield (Table 3).
correlation would be absent.
Both DMF and water promoted synthesis of ortho/meta
Having interpreted the structure of the tetrazole, it is perti-
methyl substituted and para nitro substituted tetrazoles nent to mention here that the reaction is highly chemoselective
(entries 12–14) were not fruitful. Apparently, the reason for this i.e. the substrate viz. allylic thiourea is susceptible to three
is attributed to the steric and electron withdrawing nature of reactions (i) azidomercuration of the cyclohexenyl double
the substituents which might have retarded the formation of the bond to afford the adduct (Scheme 1, route a), (ii) mercury
corresponding thioureas due to the increasing magnitude of induced cyclisation to afford the perhydro benzothiazole
Fig. 3 H,H COSY spectra of N-(2-phenylcyclohex-2-enyl)-l-p-tolyl-1H-tetrazol-5-amine.
c
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Scheme 1
(Scheme 1, route b) and (iii) electrocyclisation of guanyl azide
On the other hand, if the exocyclic reaction is considered,
formed via the desulphurization of thiourea (Scheme 1, route c) to it proceeds via guanyl azide wherein no prominent steric
afford the tetrazole. While the former two reactions initiated by hindrance is noted.
mercurinium ion intermediates are endocyclic reactions, the
Having rationalized the reason behind the chemoselectivity,
third reaction proceeding via the thiouranium salt is an exo- another noteworthy observation is the formation of the regio-
cyclic reaction. In this context it has to be mentioned that to the isomeric tetrazoles (4 and 5) which indicates that the reaction
best of our knowledge this is the first report focussing on the undergoes regioselective electrocyclisation. It is pertinent to
chemoselective synthesis of tetrazoles.
mention here that to the best of our knowledge, there is only a
Formation of the tetrazole indicates that the exocyclic reac- single report22 on the regioselective tetrazole synthesis wherein
tion is preferred over the endocyclic one. This chemoselectivity it is suggested that the regioselectivity is directed by the pKa of
is explicable based on the change in the relative magnitude of the amino components in the thiourea moiety.
the intramolecular interactions envisaged in the intermediate/s
In the present investigation, it is understood that not only
or the transition states compared to that in the substrate. the pKa but also the steric factor (allylic strain) plays a role in
This has been rationalised based on the Garbich angle strain directing the regioselectivity during the electrocyclisation i.e.
model21a which provides the details with regard to the changes regioselective electrocyclisation of guanyl azides 1 and 2 would
in the eclipsing strain during the course of addition reactions afford regioisomers 4 and 5 through TS1 and TS2 respectively.
in substituted cyclohexenyl systems. During the endocyclic While TS1 proceeds through the electrocyclisation involving
reaction, it can be seen that the eclipsing strain increases in less A1,2 strain, TS2 proceeds via the electrocyclisation involving
both the hypothetical mercurinium ion intermediates I and II a larger A1,2 strain, which is summarised in Fig. 5.
compared to the starting substrate (Fig. 4). This might have
disfavoured the endocyclic reaction.
This rationalization with regard to the regioselectivity based
on the steric factor is evident and prominent when ‘R’ happens
Fig. 4 Garbich angle strain model showing the eclipsing interaction in the intermediates.
c
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Fig. 5 Allylic strains in the transition states of regioisomeric tetrazoles 4 and 5.
Scheme 2
to be a very bulky group viz. n-butyl/aryl where the regioisomeric
Finally, with regard to the stereochemistry at the allylic carbon
ratio of 4 : 5 is around 90: 10/100: 0. Further, our recent study on in the tetrazoles, in accordance with that of the Garbisch
the synthesis of 2-iminothiazolidin-4-one from the allyl thiourea report,21b the half width value of the signal due to the methine
resulting in the exclusive formation of the regioisomer 7b and hydrogen is around 18 Hz indicating its pseudo axial orientation.
not 7a strongly supports that the steric factor is also directing the Thus, the amino tetrazole ring was assigned the pseudo equa-
regioselectivity. This is in contrast to the findings of an earlier torial preference (Fig. 6a). This has to be due to the fact that
report23 wherein other regioisomeric 2-iminothiazolidin-4-one pseudoaxial orientation of the tetrazole ring would lead to severe
6a was obtained exclusively which was explained based on the syn axial type of interaction with the axial hydrogen of C5 carbon
pKa of the amino component (Scheme 2).
(Fig. 6b), and hence not preferred. Thus, herein the conforma-
tional orientation of the tetrazole side chain in the synthesised
compounds is directed by the steric factor.
Conclusion
Water mediated chemoselective synthesis of regioisomeric
tetrazoles has been reported. Solubility of more number of
reactants in water promotes the reaction. The chemoselectivity
and regioselectivity of the reaction are rationalised based on
the change in the relative magnitude of intramolecular inter-
actions viz. eclipsing strain and A1,2 strain. The conformational
preference of the tetrazole side chain in the products is explic-
able based on the syn axial interactions.
Fig. 6 Conformational orientations of the heterocyclic side chain.
c
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