Harnessing Autoxidation of Aldehydes: In Situ Iodoarene Catalyzed Synthesis of Substituted 1,3,4-Oxadiazole, in the Presence of Molecular Oxygen

Article abstract of DOI:10.1021/acs.orglett.9b02542

Isobutyraldehyde underwent auto-oxidation in the presence of molecular oxygen to generate an acyloxy radical under a "metal-free" environment. They were subsequently exploited in situ to afford hypervalent iodines with p-anisolyl iodide which generated substituted 1,3,4-oxadiazoles in moderate to excellent yields from N′-arylidene acetohydrazides. The reaction strategy tolerated diverse substitution on the hydrazide substrates. Control experiments and literature precedence supported the formation of an in situ iodosylarene complex that facilitates the formation of products.

Full text of DOI:10.1021/acs.orglett.9b02542

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Harnessing Autoxidation of Aldehydes: In Situ Iodoarene Catalyzed
Synthesis of Substituted 1,3,4-Oxadiazole, in the Presence of
Molecular Oxygen
Jyoti Chauhan,† Mahesh K Ravva,‡ and Subhabrata Sen*,†
†Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautambudh Nagar, Uttar Pradesh
201314, India
‡Department of Chemistry, SRM University-AP, Amaravati, Andhra Pradesh 522502, India
S
* Supporting Information
ABSTRACT: Isobutyraldehyde underwent auto-oxidation in
the presence of molecular oxygen to generate an acyloxy
radical under a “metal-free” environment. They were
subsequently exploited in situ to afford hypervalent iodines
with p-anisolyl iodide which generated substituted 1,3,4-
oxadiazoles in moderate to excellent yields from N′-arylidene
acetohydrazides. The reaction strategy tolerated diverse
substitution on the hydrazide substrates. Control experiments and literature precedence supported the formation of an in
situ iodosylarene complex that facilitates the formation of products.
eterocycles/heteroaromatics play an integral role in drug
discovery.1a−i They have been widely used as new
have gained immense popularity.10 However, there is always
scope for developing greener strategies for transformations
involving in situ generated hypervalent iodine.11 Oxygen is
envisioned as an appropriate alternative.12 Autoxidation of
H
chemical entities (NCE), active pharmaceutical ingredients
(API), and pharmaceutical building blocks.2a,b Each of these
molecules by virtue of their structural, electronic, and
functional attributes impose a unique modulation to the
biological systems. Among a myriad of such compounds,
oxadiazole is an interesting class of compounds implicated as
remedies in various physical ailments involving antibacterial,
antifungal, antiviral, antitumoral, and anti-inflammatory
activities.2c−e Typically oxadiazoles are synthesized by treating
arylketone acylhydrazones with a stoichiometric quantity of
(diacetoxy)iodobenzene (PIDA) and a few other hypervalent
reagents and bases.3 An interesting example, reported in 2013,
involved reaction of a carboxylic acid with thiosemicarbazide in
the presence of a coupling reagent to afford the desired
oxadiazole.4 In the recent past Fang et al. demonstrated a
palladium catalyzed synthesis of 2-aminooxadiazoles from
hydrazides and isocyanides.5 Gao et al. recently reported direct
annulation of hydrazides with methyl ketones in the presence
of iodine and potassium carbonate.6 In 2017, Tokumaru et al.
reported a convergent synthesis of 1,3,4-oxadiazoles from acyl
hydrazide under semiaqueous conditions.7
Hypervalent iodine has been ubiquitously utilized in diverse
organic reactions, including oxidation of alkenes, alkynes,
alcohols, and phenols; α-functionalization of carbonyl
compounds; and oxidative transformations to generate various
heterocycles.8 Its application in organic transformations began
as reagents and gradually evolved as catalysts.9
In the past decade, facile strategies for in situ generation of
hypervalent iodines in the presence of commercially available
oxidants such as m-CPBA (meta-chloroperbenzoic acid),
hydrogen peroxide, peracetic acid, sodium perborate, etc.
aldehydes in the presence of oxygen is a chemistry developed
12a
̈
in the 19th century by Wohler and Leibeg. Later in 1927
̈
Backstrom elucidated the radical chain mechanism associated
with the transformation.12b In recent decades various organic
transformations are facilitated through the radical chain
pathway of atutoxidation of aldehydes in the presence of
oxygen.12c−e In the recent past Miyamoto and Powers
harnessed the strategy to generate hypervalent iodine
species.12f−h Inspired by this century old chemistry, we
envisaged a metal devoid catalytic strategy for a facile synthesis
of substituted 1,3,4-oxadiazoles from N′-arylidene acetohy-
drazides (N-acetyl aldehyde hydrazone) by using p-iodoanisole
(as a source for generating in situ hypervalent iodine species)
in the presence of oxygen and an appropriate aldehyde.
Accordingly, preliminary investigation with sterically bulky
isobutyraldehyde at 35 °C under O2 (1 atm) in acetone
afforded peracid A after 1 h, which could be generated from
the acyl peroxy radical A2 (Scheme 1). A2 in turn could lose an
oxygen to generate acyloxy radical A3 which subsequently
reacted with iodobenzene to generate a mixture of hypervalent
iodine compounds in 6 h as observed by the NMR kinetics
experiment.12i Similar reactions with acetaldehyde and
benzaldehyde were not as clean as it was with isobutyr-
aldehyde. After about 8 h, the reaction started to turn turbid at
which point, it was stopped and the turbid product was
Received: July 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02542
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
from p-anisolyl iodide, p-tolyl iodide, o-tolyl iodide, 2,4-
dimethyl iodobenzene, and p-nitro iodobenzene (Table 1,
entries 5−9). The yields of 2a with these new iodides ranged
from 33% to 96%. The best yield was obtained with p-anisolyl
iodide (Table 1, entry 5). The fact that p-nitro iodobenzene
provided 2a in the poorest yield (33%) proved that electron-
withdrawing moieties on the aryl iodides is not tolerated by
our system (Table 1, entry 9). The average reaction time were
∼6−8 h. In a bid to assess the catalytic ability of our protocol,
the next two experiments were conducted in the presence of
0.3 and 0.1 equiv of p-anisolyl iodide (Table 1, entries 10 and
11). To our utmost gratification both the reactions went
smoothly to afford 2a in 84% and 92% yield respectively
(Table 1, entries 10 and 11). To ascertain the role of oxygen in
the protocol, the reaction was conducted in the presence of an
inert atmosphere (argon) and as expected did not provide the
desired product (Table 1, entry 12). Reactions with
acetaldehyde and benzaldehyde under the same conditions
afforded 2a in a lower yield compared to isobutyraldehyde
(Table 1, entries 13 and 14). This further established our
initial hypothesis about usage of a bulky aldehyde like
isobutyraldehye to facilitate the transformation. It was
noteworthy that reactions with a lower loading of p-iodoanisole
(0.05 and 0.01 equiv) than 0.1 equiv (Table 1, entries 15 and
16) provided the desired products in a much lower yield.
Hence from this preliminary optimization study, 0.1 equiv of p-
anisolyl iodide to catalyze reaction was selected (Table 1, entry
11) as the most suitable protocol for conversion of N′-
arylidene acetohydrazides, 1a, to their corresponding sub-
stituted 1,3,4-oxadiazoles, 2a.
With the optimized conditions in hand we embarked on
assessing the generic nature of the protocol. The synthetic
sequence began by reacting 1 equiv of the appropriate aromatic
aldehyde (diverse aromatic and heteroaromatic) with 1 equiv
of acetyl, tolyl, or p-chlorobenzoyl hydrazide in ethanol at rt, to
afford the desired hydrazone 1a−r which precipitated from the
reaction mixture. Compounds 1a−r were pure enough to
subject it for further reaction. Under optimized conditions they
afforded the desired products 2a−r in 49−95% yield (Scheme
2). Various electron-withdrawing and electron-donating groups
at the aromatic moiety were tolerated by the reaction
conditions (Scheme 2). The desired compounds were isolated
by flash column chromatography with ethyl acetate and hexane
as eluents. The structures of the compounds were confirmed
by generating the single crystal X-ray structure of compound
1f. The protocol was well tolerant toward N′-heteroarylidene
acetohydrazide compounds 1g, k, and q to afford the desired
oxadiazoles in 49%−79% yield, respectively (Scheme 2).
Product 2p was formed in 71% yield. The drug isoniazid
(INH) or isonicotinyl hydrazide is a potent antimycobacterial
agent.13,13a Unfortunately in the recent past nearly 10% of TB
disease cases have been detected with nonmultidrug resistant
(MDR) INH.13b To circumvent this threat, serious endeavors
are in progress to modify the drug. Accordingly we utilized our
optimized strategy to convert INH to corresponding 1,3,4-
oxadizole which are also reported as potential antitubercular
agents.13c To our greatest satisfaction, two compounds 2s and
t were prepared from the corresponding hydrazone 1s and t,
containing the isoniazid moiety in excellent yield (84% and
91%, respectively).
Scheme 1. Mechanism of Autoxidation of Aldehydes and
Formation of Iodoarenes Complexes in Situ
isolated and characterized to be an hypervalent iodine
compound (refer to SI).
Encouraged by these results, 1a (synthesized by condensa-
tion of benzaldehyde and acetylhydrazide in ethanol at rt) was
reacted with 0.5 equiv of iodobenzene (PhI) in various
solvents such as acetone, 1,2-dichoroethane (DCE), acetoni-
trile (ACN), and ethanol at 35 to 90 °C in the presence of
isobutyraldehyde (Table 1, entries 1−4). The reaction with
acetone afforded the desired product 2a in the best yield of
80% (Table 1, entry 1). Furthermore, with acetone as solvent,
a variety of aryl iodides were screened as catalysts, starting
Table 1. Reaction Optimization for Aryl Iodide Mediated
Conversion of N′-Arylidene Acetohydrazides to Substituted
1,3,4-Oxadiazole
a
entry
ArI (equiv)
solvent
T (°C) yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PhI (0.5)
Acetone
DCE
EtOH
CH3CN
35
80
40
90
35
″
″
″
″
″
″
″
″
″
″
″
80%
78%
68%
72%
96%
81%
84%
80%
33%
84%
92%
0%
″
″
″
p-anisolyl iodide (0.5)
p-tolyl iodide (0.5)
o-tolyl iodide (0.5)
2,4-dimethyl iodobenzene (0.5)
p-nitroiodobenzene (0.5)
p-anisolyl iodide (0.3)
″ (0.1)
″
Acetone
″
″
″
″
″
″
″
″
″
″
″
b
c
″
″
63%
54%
74%
39%
d
″ (0.05)
″ (0.01)
a
b
The optimized reaction condition was robust enough to
tolerate the conversion of aliphatic hydrazone like 1p to the
desired
Isolated (After 10 h). Solvent degassed and under an argon
c
d
atmosphere. With acetaldehyde. With benzaldehyde. DCE: 1, 2-
dichloroethane. CH3CN: Acetonitrile. EtOH: Ethanol.
B
DOI: 10.1021/acs.orglett.9b02542
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
afford in situ the hypervalent iodosyl arene complex V (Scheme
3).12i V reacts with 1a to afford VI. It is worth mentioning that
there is a chance of formation of Va as an alternative
hypervalent iodine species, but we were unable to isolate it.
Eventually VI cyclizes to VII which aromatizes to afford 2a and
in the course regenerates p-anisolyl iodide which continues the
catalytic cycle.
Scheme 2. Synthesis of Aromatic Oxadiazole 2a−r
Next to assess the robustness of the protocol, a scale up
reaction was conducted, where a 5 g scale of N′-benzylidene
acetohydrazides, 1a, under optimized conditions generated the
desired compound 2a in 76% yield.
In conclusion we have successfully demonstrated O2 as a
primary and an acyloxy radical as the terminal oxidant for facile
synthesis of substituted 1,3,4-oxadiazole. We leveraged the
autoxidation of isobutyraldehyde in an O2 atmosphere. The
final transformation involved reaction of N′-arylidene acetohy-
drazides 1 substrates with isobutyraldehyde and catalytic p-
anisolyl iodide under 1 atm of O2 at 35 °C in acetone. An in
situ generated hypervalent iodine is the key player in this
transformation. This strategy is replicated in gram scale and
displayed exceptional functional group tolerance. Control
experiment and literature precedence provided a preliminary
insight into the mechanism of the reaction. Investigation to
expand the scope and further elucidate the mechanism through
DFT studies is in progress in our lab.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02542.
From the literature report, our hypothesis, and initial proof-
of-concept studies, the mechanism of transformation of 1a →
2a is postulated and is depicted in Scheme 3. The
transformation is envisioned to be segregated into two aspects.
The preliminary stage involved autoxidation of isobutyralde-
hyde, which is assumed to be a bimolecular reaction between
the aldehyde and oxygen to afford the peracid III via the acyl
and acyl peroxy radicals I and II, respectively (Scheme 3).
From literature precedence we believe that acyl peroxy radical
II generates acyloxy radical IV which probably enacts the role
of oxidant and in the next stage reacts with p-anisolyl iodide to
NMR spectra (PDF)
Accession Codes
CCDC 1889823 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 3. Putative Mechanism for the Formation of Substituted 1,3,4-Oxadiazole 2a−r
C
DOI: 10.1021/acs.orglett.9b02542
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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AUTHOR INFORMATION
Corresponding Author
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Sons: New York, 2014. (b) Yoshimura, A.; Zhdankin, V. V. Chem. Rev.
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*E-mail: subhabrata.sen@snu.edu.in; subhabrata.s@srmap.edu.
in.
ORCID
Mahesh K Ravva: 0000-0001-9619-0176
Subhabrata Sen: 0000-0002-4608-5498
Notes
The authors declare no competing financial interest.
̈
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