Cu(II) catalyzed imine C-H functionalization leading to synthesis of 2,5-substituted 1,3,4-oxadiazoles

Article abstract of DOI:10.1021/ol202409r

A direct access to symmetrical and unsymmetrical 2,5-disubstituted [1,3,4]-oxadiazoles has been accomplished through an imine C-H functionalization of N-arylidenearoylhydrazide using a catalytic quantity of Cu(OTf)₂. This is the first example of amidic oxygen functioning as a nucleophile in a Cu-catalyzed oxidative coupling of an imine C-H bond. These reactions can be performed in air atmosphere and moisture making it exceptionally practical for application in organic synthesis.

Full text of DOI:10.1021/ol202409r

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5976–5979
Cu(II) Catalyzed Imine CꢀH
Functionalization Leading to Synthesis of
2,5-Substituted 1,3,4-Oxadiazoles‡
Srimanta Guin, Tuhin Ghosh, Saroj Kumar Rout, Arghya Banerjee, and
Bhisma K. Patel*
Department of Chemistry, Indian Institution of Technology Guwahati,
Guwahati 781 039, India
patel@iitg.ernet.in
Received September 6, 2011
ABSTRACT
A direct access to symmetrical and unsymmetrical 2,5-disubstituted [1,3,4]-oxadiazoles has been accomplished through an imine CꢀH
functionalization of N-arylidenearoylhydrazide using a catalytic quantity of Cu(OTf)2. This is the first example of amidic oxygen functioning as a
nucleophile in a Cu-catalyzed oxidative coupling of an imine CꢀH bond. These reactions can be performed in air atmosphere and moisture making
it exceptionally practical for application in organic synthesis.
The π-conjugated heterocycles comprise an important
structure class as they find applications in the field of
material science and pharmaceutical chemistry. Among
them, the 2,5-disubstituted-1,3,4-oxadiazole motifs are of
considerable importance primarily due to their unique
optoelectronic properties that are being exploited in the
development of organic light emitting diodes (OLEDS)
and utilized in energy efficient, full-color, flat-panel
displays.1 Certain suitably conjugated oxadiazoles are also
‡ Dedicated to Professor Y. D. Vankar on the occasion of his 60th birthday.
€
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r
10.1021/ol202409r
Published on Web 10/18/2011
2011 American Chemical Society

known to perform as multiphoton absorbing systems.1b
Besides their electronic properties, these scaffolds encom-
pass a wide range of biological properties2ꢀ4 that make
them particularly attractive in the field of organic synthesis.
To date, the literature reports the following methods for
their preparation (Scheme 1): (a) oxidative cyclization of
N-acylhydrazones with various oxidizing agents such as
hypervalent iodines,5aꢀe chloramine T,5f ceric ammonium
nitrate,5g FeCl3,5h tetravalent lead reagents,5i,j Br2,5k
KMnO4 under microwave condition,5l or HgO/I2;5m (b)
cyclodehydration of 1,2-diacylhydrazines with reagents
such as thionyl chloride, PPA, phosphorus oxychloride,
or sulfuric acid;6 (c) direct reaction of carboxylic acids or
acyl chlorides with acid hydrazides or hydrazines;7 (d)
CꢀH activation/Cu mediated arylation of preformed
2-substituted 1,3,4-oxadiazole;8 and (e) electrophilic sub-
stitution of 2-substituted-5-trimethylsilyl-1,3,4-oxadiazole
toward various electrophiles.9
as being no longer inert and able to be viewed as dormant
synthetic equivalents of many reactive functional groups.
Development of various catalytic processes to activate the
ubiquitously available bond has emerged as the most
effective tool, due to operational simplicity and avoidance
of the arduous substrate preactivation steps, thereby im-
proving the overall efficiency of a targeted synthesis.10
In this context, however, the vast majority of the focus has
been directed toward the transition metal catalyzed fu-
nctionalization of the sp2 CꢀH bonds of arenes and
heteroarenes.10 In contrast, analogous addition across an
imineCꢀN throughfunctionalization of a C(sp2)ꢀH bond
is relatively rare. Some examples of imine C(sp2)ꢀH
functionalization are, a Pd catalyzed addition of 2-methyl
aza-arenes to imines,11a benzyl nitriles with sulfonyl-
imines,11b,c rhodium catalyzed oxidative coupling of aro-
matic imines with alkynes,11d and 2-pyridyl.11e Moreover,
compared to late transition metal catalysts, first row
transition metal catalysts, especially with Cu, have been
less explored toward CꢀH functionalization.12 Barring
one example of CꢀC bond formation involving C(sp2)ꢀH
of imine13 there is no report on CꢀO bond formation.
Mostly, substrates possessing imine functionality have
been observed to undergo skeletal rearrangement14aꢀc or
Scheme 1. Various Methods of Preparation of 2,5-Substituted
1,3,4-Oxadiazoles
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Yet, the disadvantages associated with these methodol-
ogies, owing to the use of expensive, hazardous materials
or cumbersome multistepped processes, bind them to a
limited synthetic scope. Although the Cu mediated direct
arylation/CꢀH activation path (route d)8 seems advanta-
geous, it uses preformed 2-substituted 1,3,4-oxadiazoles as
the precursors which are difficult to prepare.
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Org. Lett., Vol. 13, No. 22, 2011
5977

utilize the proximate effect of coordination to the metal
center which serves as a directing group toward sp2 and sp3
CꢀH bond activation.14dꢀf There are few examples of
amidic oxygen functioning as a nucleophile in catalytic
oxidative coupling reactions using Cu catalyst15 but no
precedence of it in catalytic oxidative coupling reactions of
imine CꢀH bonds.
To develop this idea, substrate N-benzylidenebenzohy-
drazide (1) was selected for the cyclization reaction. Varia-
tions in the nature of the base, solvents, and reaction
temperature were explored to arrive at the best possible
yield (Table 1). After a series of experimentation the
product (1a) could be obtained in 85% isolated yield when
performed in the presence of Cu(OTf)2 (10 mol %),
Cs2CO3 as the base, at 110 °C in DMF under an air
atmosphere (O2 as the terminal oxidant). Under all other
conditions substantial decomposition, multitudes of side
products, or poor yields were obtained. No product was
obtained in the absence of either catalyst or base which
suggests that a metal/base combination is required for the
reaction to occur.
Inspired by the recent development of CꢀH bond
functionalization particularly using Cu catalyzed direct
arylation of various heterocycles using aryl halides or aryl
iodonium(III) salts16 and intramolecular CꢀO bond for-
mation via a CꢀH bond cleavage,15 we anticipate that a
Cu-based strategy could be applied to construct 2,5-dis-
ubstitued 1,3,4-oxadiazole from N-aryl-N-arylidinehydra-
zines. Thus in anattempt toobliterate the limitations of the
earlier methods, herein, we report the development of
a straightforward and versatile protocol for the Cu(II)
catalyzed oxidative CꢀH bond functionalization/CꢀO
bondformation ofiminesfrom N-arylidenearoylhydrazide
derivatives to afford various 2,5-disubstituted-1,3,4-oxa-
diazoles. This method features the use of Cu(OTf)2 that
successfully performs the CꢀH functionalization followed
by an intramolecular CꢀO cross-coupling to afford cy-
clized products from readily available starting materials.
Scheme 2. One-Pot Synthesis of 2,5-Substituted [1,3,4]-Oxa-
diazolesa
Table 1. Screening of Reaction Conditions
catalyst
solvent
time/h
base
yield (%)a,b
10% Cu(OTf)2
10% Cu(OTf)2
10% Cu(OTf)2
10% Cu(OTf)2
10% Cu(OTf)2
10% Cu(OTf)2
10% CuSO4
10% Cu(OAc)2
10% CuI
DMSO
Toluene
Dioxane
CH3CN
DMF
36
36
36
36
16
16
16
16
16
16
16
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
20
12
30
10
63
85
55
40
8
a Reactions were monitored by TLC. Confirmed by spectroscopic
analysis. Yield of isolated pure product reported.
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
With these results in hand, we sought to examine the
scope and generality of the method. As the results shown in
Scheme 1 attest, this methodology is compatible with a
variety of electron-donating and -withdrawing groups. N-
Arylidenearoylhydrazides derived from arylaldehydes
possessing electron-donating groups such as ꢀMe, ꢀ
CMe3, ꢀOMe, ꢀOBu, di-OMe all gave substituted 1,3,4-oxa
ziazoles 2a, 3a, 4a, 5a, and 6a in good yields (Scheme 2).
Similarly substrates possessing electron-withdrawing groups
such as ꢀF, ꢀCl, ꢀBr, ꢀCO2Me underwent CꢀH func-
tionalization to give 1,3,4-oxaziazoles 7a, 8a, 9a, 10a, and
11a in excellent yields. As can be seen from Scheme 2,
compared to substrates bearing electron-donating groups,
electron-withdrawing substrates gave better yields. Benzo-
hydrazide substrates originating from heterocyclic alde-
hydes such as pyridine, furan, and thiophene gave poorer
yields of the products 12a, 13a, and 14a. Benzohydrazide
derived from aliphatic aldehydes are inert, and no CꢀH
10% CuBr
DMF
25
65
10% CuCl2
DMF
a Reactions were carried out in an air atmosphere. b Isolated yield.
(14) (a) Guru, M. M.; Ali, M, A.; Punniyamurthy, T. Org. Lett. 2011,
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ꢁ
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5978
Org. Lett., Vol. 13, No. 22, 2011

activation was observed. The substrate decomposed to
aldehyde along with several other inseparable products.
This is possibly because of the lesser acidic character of the
imine CꢀH bonds, consistent with the reactivity trend
observed for substituted aromatics.
It is interesting to mention here that both N0-(4-metho
xybenzylidene) benzylhydrazides (Scheme 2) and N0-ben-
zylidene-4-methoxybenzohydrazide (Scheme 3) gave 2-(4-
methoxyphenyl)-5-phenyl-1,3,5-oxadiazole (4). The yield
was superior by the latter approach. Similarly, product 9a
(Schemes 2 and 3) can be obtainedfrom eitherN0-4-chloro-
benzylidene)benzohydrazide (Scheme 2) or N0-benzyli-
dene-4-chlorobenzohydrazide (Scheme 3), but for this the
former approach is better.
Scheme 3. One-Pot Synthesis of 2,5-Substituted [1,3,4]-Oxa-
diazolesa
An insight into the mechanism through kinetic isotope
studies suggests that the hydrogen abstraction step is not
involved in the rate-limiting step (observed KH/KD = 1).
Thus a plausible mechanism of this reaction keeping in
view the above observations and related literature
reports10f,12l,13,16a suggests the possible occurrence of agos-
tic interaction (see Supporting Information (SI)) in which
the first step involves concurrent deprotonation/metala-
tion at the imine sp2 CꢀH bond followed by the reductive
elimination and CꢀO bond formation leading to the 2,
5-disubstituted 1,3,4-oxadiazoles. However, in view of the
earlier works17 where analogous substrates had undergone
heterocyclization, an alternative pathway cannot be ruled
out. The resultant Schiff base forms a five-coordinated
species with Cu(II) (see SI) which then undergoes oxidative
dehydrogenation to afford a CꢀO bond leading to corre-
sponding oxadiazoles. The catalytic cycle is retained by the
oxidation of Cu(I) to Cu(II) under atmospheric oxygen.
Further, a radical pathway cannot be overlooked for this
transformation.18
In summary, we have for the first time developed a
catalytic method for the synthesis of 2,5-disubstituted
[1,3,4]-oxadiazoles via imine CꢀH functionalization of
N-benzylidenebenzohydrazide. Low catalyst loading un-
der ligand-free conditions, an inexpensive metal catalyst,
performance under ordinary atmospheric conditions, and
compatibility with a wide range of substrates make this
method superior to all methods reported so far, which is of
potential industrial significance. A detailed mechanistic
study and further substrate scope are underway.
a Reactions were monitored by TLC. Confirmed by spectroscopic
analysis. Yield of isolated pure product reported.
Besides N-arylidenearoylhydrazides, other hydrazides
such as N0-arylidine-4-methoxybenzohydrazides reacted
equally efficiently giving substituted oxadiazoles 4a, 15a,
16a, and 17a in good to excellent yields (Scheme 3).
Similarly N0-arylidines-4-chlorobenzohydrazides under-
went reaction smoothly to afford the corresponding un-
symmetrical oxadiazoles 9a, 18a, 19a, and 20a (Scheme 3)
but in a slightly moderate yields compared to the methoxy
analogue. It may be worth mentioning here that a com-
parative study of the unsubstituted 4-OMe and 4-Cl sub-
strates on the aroylhydrazide part suggest the reaction to
be superior for the methoxy substrate (4a) (Scheme 3)
followed by unsubstituted (1a) (Scheme 2) and chloro (9a)
(Scheme 3) analogues in terms of yields and enhanced
reaction rates. Also it was observed that electron-with-
drawing substituents on the arylaldehydes improved the
yields as in the case of 7aꢀ11a (Scheme 2) probably
through an increment of the acidity of the imine proton
thereby facilitating the metalation step.
Acknowledgment. We are grateful to the DST (SR/S1/
OC-79/2009) and CSIR [01(2270)/08/EMR-II] for fund-
ing. S.M., T.G., S.K.R., and A.B. thank the CSIR for
fellowships. Thanks are also due to CIF, IIT Guwahati for
mass and NMR spectra.
Supporting Information Available. General informa-
tion, experimental procedures, spectral data, and copies
of 1H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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