Iodine-catalysed oxidative cyclisation of acylhydrazones to 2,5-substituted 1,3,4-oxadiazoles

Article abstract of DOI:10.1039/c3ra44897e

An environmentally benign synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed starting from N-aroylhydrazones and N-acetylhydrazones at room or ambient temperature using a catalytic quantity of iodine in the presence of an aqueous hydrogen peroxide oxidant.

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ARTICLE TYPE
Iodine–catalysed oxidative cyclisation of acylhydrazones to 2,5-
substituted 1,3,4-oxadiazoles†
Ganesh Majji, Saroj Kumar Rout, Srimanta Guin, Anupal Gogoi and Bhisma K. Patel*
5
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An environmentally benign synthesis of 2,5ꢀdisubstituted 1,3,4ꢀoxadiazoles has been developed
starting from Nꢀaroylhydrazones and Nꢀacetylhydrazones at room or ambient temperature using
catalytic quantity of iodine in the presence of oxidant aqueous hydrogen peroxide.
10
.
Due to myriad of applications of 1,3,4ꢀoxadiazole motif several
Introduction
methodologies are described in the literature for their synthesis.
These scaffolds are synthesised by the electrophilic substitution
40 of 2ꢀsubstitutedꢀ5ꢀtrimethylsilylꢀ1,3,4ꢀoxadiazole toward various
electrophiles such as Cl2, Br2, acyl chlorides or isocyanates (path
I, Scheme 1).5 An alternative route to 2,5ꢀdisubstituted 1,3,4ꢀ
oxadiazoles is via the dehydrative cyclisation of 1,2ꢀ
diacylhydrazines. Typically, dehydrative cyclisation is carried out
45 using reagents such as phosphorus oxychloride, sulphuric acid,
thionyl chloride, PPA or [Et2NSF2]BF4 (path II, Scheme 1).6
Besides the traditional synthesis of 2,5ꢀdisubstituted 1,3,4ꢀ
oxadiazoles, involving acyl chlorides or carboxylic acids with
acid hydrazines or hydrazides,7 some elegant protocols have also
50 been developed. Oxidative cyclisation of Nꢀacylhydrazones is
another convenient method for the synthesis of 2,5ꢀdisubstituted
1,3,4ꢀoxadiazoles (path III, Scheme 1).
1,3,4ꢀOxadiazoles, a πꢀconjugated heterocycle are an interesting
class of compound since molecule possessing this skeleton has
been widely used in materials science, particularly in organic
15 light emitting diodes (OLEDs), as electron conducting and hole
blocking materials. Due to their electron deficient and electron
transporting abilities they are utilised in energy efficient, fullꢀ
colour, flat panel display.1 From medicinal chemistry point of
view, 1,3,4ꢀoxadiazoles display various biological activities such
20 as anticancer, benzodiazepine receptor agonists, antimicrobial,
analgesic, diuretic and tyrosinase inhibitors etc.2 Besides these,
2,5ꢀdisubstituted 1,3,4ꢀoxadiazoles are used as a bioisosteric
replacement of ester, amide and acid functionalities in
pharmaceutical chemistry3aꢀc as in Furamizole,3d Raltegravir,3e
25 Nesapidil3f and Zibotentan3g,h as shown in Fig. 1. Some other
significant molecules possessing 1,3,4ꢀoxadiazole as the core unit
include Butyl PBD or bꢀPBD which is used in the liquid
scintillator neutrino detector (LSND) (Fig. 1).4
30
Fig. 1 Representative examples of bioactive compounds possessing 1,3,4ꢀ
Scheme 1 Various routes to 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles.
oxadiazole motif
.
aDepartment of Chemistry, Indian Institute of Technology
Guwahati, 781 039, Assam, India. Email: patel@iitg.ernet.in
35 †Electronic supplementary information (ESI) available. See
DOI:10.1039/xxxxxxxxxxx
55 However the later methods use stoichiometric amount of
oxidising agents such as KMnO4,8a ceric ammonium nitrate,8b
Br2,8c chloramineT,8d FeCl3,8e HgO/I2,8f tetravalent lead
reagents,8g or hypervalent iodine reagents.8hꢀm Miura group9 has
developed a copper mediated C–H arylation of preformed 2ꢀ
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substituted 1,3,4ꢀoxadiazole with aryl halide (path IV, Scheme 1). 65 for the catalytic cycle.14 In the absence of any external oxidant
Recently we have achieved a direct access to the synthesis of
both symmetrical and unsymmetrical 2,5ꢀdisubstituted 1,3,4ꢀ
oxadiazoles via the imine C–H bond functionalisation of Nꢀ
arylidenearoylhydrazides or aroylhydrazone using catalytic
the desired product was obtained in a mere yield of 9% (entry 11,
Table 1), thereby suggesting the requirement of added oxidant for
the reoxidation of Iꢀ to I2. The transformation was completely
unproductive in the absence of either iodine or base; thus
5
quantity of Cu(OTf)2 (path V, Scheme 1).10 Although the above 70 suggesting the essential requirement of iodine, oxidant and base
method is superior to existing methods but the requirement of
expensive catalyst and performing the reaction at higher
temperature in DMF makes it unattractive from large scale
for this transformation.
Table 1. Screening of reaction conditions
10 synthesis. Further, the method is not successful with Nꢀ
acetylhydrazone in the preparation of alkylꢀsubstituted 1,3,4ꢀ
oxadiazoles.10
Usually iodine mediated reactions are preferred over metal
catalysed oxidation in pharmaceutical industries due to the
15 avoidance of removal of metal impurities, low cost,
environmental benignity and operational simplicity. In recent
years, several organic transformations have been achieved by our
group and several others using molecular iodine.11 The
combination of TBHP and I2 has been widely used in many
20 oxidative transformations to overcome the drawbacks of the
metal catalysed reactions.11a,11g,12 For any iodine catalysed
reactions the reduced iodide species needs to be reoxidised to
iodine with an external oxidant for maintaining the catalytic
cycle. If this process can be achieved at the expense of a cheap
25 and environmentally benign oxidant such as aqueous hydrogen
peroxide the method would be much more attractive. Although
the transformation of Nꢀacylhydrazones to 2,5ꢀsubstituted 1,3,4ꢀ
oxadiazoles has been reported using 20 mol% of iodine in the
absence of any base13 but the result could not be reproduced in
30 our hand. The failure to give any product using 20 mol% of the
iodine could possibly because I2 gets converted to I− during the
reaction and in the absence of any suitable oxidant the reduced I−
cannot be oxidised back to I2 to make the reaction catalytic.
Further from our subsequent finding it is clear that base is a must
35 for deprotonation of the starting material and neutralisation of HI
generated in the medium. Hence we aspired to report an iodine
catalysed oxidative cyclisation of acylhydrazones for the
synthesis of densely functionalised 2,5ꢀsubstituted 1,3,4ꢀ
oxadiazoles (path VI, Scheme 1).
75
Entry Catalyst
Oxidant
Solvent
Base
Yieldb (%)
1
2
3
10% I2 Aq. TBHP
10% I2 Aq. TBHP
10% I2
DMF
DMSO
DMSO
Toluene K2CO3
THF
CH3CN
CH3OH
DMSO
DMSO
DMSO
DMSO
Cs2CO3
Cs2CO3
K2CO3
77
86
88
Aq. H2O2
4
5
6
7
8
9
10
11
10% I2
10% I2
10% I2
10% I2
10% I2
10% I2
20% I2
10% I2
Aq. H2O2
Aq. H2O2
Aq. H2O2
Aq. H2O2
Aq. H2O2
Aq. H2O2
Aq. H2O2
nil
5
K2CO3
K2CO3
K2CO3
Et3N
DBU
K2CO3
K2CO3
10
10
15
0
20
90
09
aThe reactions were carried out in the same scale under identical reaction
conditions. bIsolated yields.
Having the above optimised conditions in hand various Nꢀ
benzoylhydrazones derived from benzoylhydrazide and various
80 aldehydes were subjected to the present reaction conditions and
the results are summarised in Scheme 2. This methodology gave
better yields of the products for substrates possessing electron
donating groups such as p–Me (2a), p–OMe (3a) and o–OH (8a)
when present in the aryl ring of the precursor aldehyde. However,
85 Nꢀbenzoylhydrazones derived from aldehydic moiety possessing
electronꢀwithdrawing groups such as p–F (4a), p–Cl (5a), p–CHO
(6a) and p–Ph (7a) gave lower yields of the products compared to
the substrates possessing electron donating groups as shown in
Scheme 2. This observation is quite contrary to our recent
90 observation during the Cu(II) catalysed synthesis of 2,5ꢀ
40
Results and discussion
Initially Nꢀbenzylidenebenzohydrazide (1 mmol) was treated
with iodine (10 mol %), aq. TBHP (4 equiv.) and Cs2CO3 (2
equiv.) in DMF solvent at room temperature which afforded the
45 product (1a) in 77% isolated yield (entry 1, Table 1).
Replacement of DMF with DMSO gave an improved yield of
86% (entry 2, Table 1). Interestingly, when the same reaction was
carried out with aq. H2O2 (4 equiv.) and K2CO3 (2 equiv.) instead
of aq. TBHP (4 equiv.) and Cs2CO3 (2 equiv.) in DMSO solvent
50 the yield improved marginally (88%, entry 3, Table 1). Since the
latter combination was better both from cost and yield
considerations the reaction condition was preset but the pursuit to
improve the yield continued. In a quest to improve the yield other
solvents such as toluene, THF, CH3CN and CH3OH (entries 4ꢀ7,
55 Table 1) were screened but all were found to be less effective
compared to the use of DMSO solvent. The use of organic bases
such as Et3N, DBU (entries 8ꢀ9, Table 1) were found to be
inferior to inorganic carbonate bases. No substantial improvement
in the yield (90%) was observed upon increasing the amount of
60 iodine from 10 to 20 mol%. In principle one equivalent of aq.
H2O2 is sufficient to reoxidise Iꢀ to I2. Decrease in the quantity of
H2O2 below 4 equiv. lowered the yield of the product. This is
because iodine is also known to decompose H2O2 thereby
effectively making it less available for the reoxidation of Iꢀ to I2
disubstituted
1,3,4ꢀoxiadiazoles
via
an
imine
C–H
functionalisation.10 During the oxadiazole synthesis via the C–H
functionalisation, substrates possessing electron withdrawing
groups in arylaldehydes gave better yields. This differential
95 observation in the trends of yields is due to the difference in their
reaction mechanisms. During C–H functionalisation strategy10 the
acidity of the imine C–H proton is enhanced when electron
withdrawing substituents are present in the aryl ring thereby
facilitating the reactions and improving the yields.
100
Mono Nꢀbenzoylhydrazone derived from phthalaldehyde, gave
oxadiazole (6a) without affecting the CHO functionality under
the reaction conditions. Nꢀbenzoylhydrazone derived from
cyclohexane carboxaldehyde and butyraldehyde gave lower
yields of the products (9a) and (10a) respectively. It may be
105 mentioned here that the benzoylhydrazones obtained from
aliphatic aldehydes were found to be inert in the Cu(II) catalysed
synthesis of 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles10 suggesting the
superiority of this method.
110
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Scheme 2. Formation of 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles via
oxidative cyclisation of Nꢀbenzoylhydrazonesa
corresponding products (3a), (11a) and (12a) respectively as
20 shown in Scheme 3. Heteroaromatic aldehydes derived Nꢀ
aroylhydrazone underwent smooth transformations giving
products (13a), (14a) and (15a) in excellent yields. It may be
mentioned here that synthesis 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles
possessing heterocyclic units required longer reaction time,
25 giving lower yields of products by the C–H functionalisation
strategy,10 delineating the superiority of this iodine catalysed
reaction. Further, Nꢀaroylhydrazone derived from aroylhydrazide
possessing electron withdrawing group (pꢀCl) and various
aromatic aldehydes underwent oxidative cyclisation to furnish
30 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles (5a), (16a), (17a) and (18a) in
moderate to good yields. Unlike in Scheme 3, no correlation
between the yields of the products obtained and electronic effects
of the substituents present in the aryl rings of aldehydes and
aroylhydrazides could be derived. The present reaction conditions
35 when applied to various Nꢀacetylhydrazone failed to give good
yields of the products. Interestingly upon increasing the reaction
o
temperature to 50 C and the use of stronger base Cs2CO3 gave
satisfactory yields of various 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles
19a-26a as shown in Scheme 4 demonstrating the power of this
40 methodology.
Scheme 4. Formation of 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles from
oxidative cyclisation of Nꢀacetylhydrazonesa
aReactions were monitored by TLC. Confirmed by spectroscopic analysis.
Yield of isolated pure product reported.
5
Scheme 3. Formation of 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles via
oxidative cyclisation of substituted Nꢀaroylhydrazonesa
45
aReactions were monitored by TLC. Confirmed by spectroscopic analysis.
Yield of isolated pure product reported.
50
As the results shown in Scheme 2, 3, and 4 demonstrate, this
protocol is compatible with a diversity of electron donating and
withdrawing groups. This method was however not successful for
acylhydrazones derived from aliphatic aldehydes and aliphatic
hydrazide as no desired products were observed. These substrates
55 decomposed to aldehyde along with numerous other inseparable
products. If both the counterpart is aliphatic for example aliphatic
aldehyde and aliphatic hydrazide the reaction do not work. If any
of the counterpart is aromatic for example aromatic aldehyde and
aliphatic hydrazide or aliphatic aldehyde and aromatic hydrazide
60 then the reaction is successful. Products (9a) and (10a) (Scheme
2) are derived from aliphatic aldehydes and aromatic hydrazide.
10
aReactions were monitored by TLC. Confirmed by spectroscopic analysis.
Yield of isolated pure product reported.
This methodology is equally successful with various other
15 Nꢀbenzoylhydrazones derived from substituted aroylhydrazide
possessing electron donating group (pꢀOMe) and
Some of the heterocyclics (3a) and (5a) can be prepared by
two alternative paths as shown in Scheme 5. For compound (3a)
pathꢀa gave better yield, while for (5a) pathꢀb was superior. No
aromaticaldehyde possessing electron neutral -H, electron
donating pꢀMe and electron withdrawing pꢀCl giving
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correlation between the substituent present in the aryl ring of
aldehyde or hydrazide could be found.
A mixture of Nꢀbenzylidenebenzohydrazide 1 (1 mmol, 224 mg),
30 K2CO3 (2 mmol, 276 mg) and I2 (10 mol %, 26 mg) in DMSO (2
mL) was stirred at room temperature. To this reaction mixture
H2O2 (30% solution in water, 0.45 mL, 4 mmol) was added in
nine equal lots over a period of 3 h. The progress of the reaction
was monitored by TLC. After completion of the reaction, the
35 reaction mixture was treated with a 5% hypo solution (5 mL).
The reaction mixture was then extracted with ethylacetate (2 x 15
mL) and the combined ethylacetate layer was washed with water
(1 x 3 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The product was purified over column of silica
40 gel and eluted with (15% EtOAc/hexane) to give 2,5ꢀdiphenylꢀ
1,3,4ꢀoxadiazole 1a (195 mg, 88% yield).
Acknowledgement
B. K. P acknowledges the support of this research by the
Department of Science and Technology (DST) (SR/S1/OCꢀ
45 79/2009), New Delhi, and the Council of Scientific and Industrial
Research (CSIR) (02(0096)/12/EMRꢀII). MG thanks UGC for
fellowship. Thanks are due to Central Instruments Facility (CIF)
IIT Guwahatifor NMR spectra and DSTꢀFIST for XRD facility.
5
Scheme 5. Dual routes to formation of 2,5ꢀsubstituted 1,3,4ꢀoxadiazoles
(3a) and (5a).
References and notes
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Scheme 6. Proposed mechanism for the formation of 2,5ꢀsubstituted
1,3,4ꢀoxadiazoles.
Conclusion
In summary, we have developed an oxidative cyclisation
20 method using I2/ H2O2 catalytic system for the synthesis of 2,5ꢀ
substituted 1,3,4ꢀoxadiazoles. An inexpensive, environmental
friendly catalyst, mild reaction conditions and compatibility with
a wide range of substrates make this method superior to all
methods documented in literature.
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General procedure for the preparation of 2,5-diphenyl-1,3,4-
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DOI: 10.1039/C3RA44897E
Iodine–catalysed oxidative cyclisation of acylhydrazones to 2,5-substituted 1,3,4-oxadiazoles
Ganesh Majji, Saroj Kumar Rout, Srimanta Guin, Anupal Gogoi and Bhisma K. Patel*
A room temperature iodine catalyzed synthesis of 2,5-substituted 1,3,4-oxadiazoles has been achieved from acylhydrazone.