Unusual synthesis of azines and their oxidative degradation to carboxylic acid using iodobenzene diacetate

Article abstract of DOI:10.1080/00397911.2017.1407791

Reaction of 3-hydrazonobutan-2-one oxime with aromatic aldehydes resulted in the formation of 1,2-bis(arylidene)hydrazine commonly referred as azine as an unexpected product, instead of expected product 3-(aryl)methylenehydrazonobutan-2-one oxime, which were subsequently oxidized to corresponding aromatic acids with an ecofriendly oxidizing agent iodobenzene diacetate. Azines and carboxylic acids were characterized by IR and NMR (¹H, ¹³C, HMBC, and HMQC) studies.

Full text of DOI:10.1080/00397911.2017.1407791

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Unusual synthesis of azines and their oxidative
degradation to carboxylic acid using iodobenzene
diacetate
Garima Sumran, Ranjana Aggarwal, Mona Hooda, Dionisia Sanz & Rosa M.
Claramunt
To cite this article: Garima Sumran, Ranjana Aggarwal, Mona Hooda, Dionisia Sanz & Rosa M.
Claramunt (2018): Unusual synthesis of azines and their oxidative degradation to carboxylic acid
using iodobenzene diacetate, Synthetic Communications, DOI: 10.1080/00397911.2017.1407791
To link to this article: https://doi.org/10.1080/00397911.2017.1407791
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https://doi.org/10.1080/00397911.2017.1407791
Unusual synthesis of azines and their oxidative degradation
to carboxylic acid using iodobenzene diacetate
a
b
b
c
Garima Sumran , Ranjana Aggarwal , Mona Hooda , Dionisia Sanz , and
c
Rosa M. Claramunt
a
b
Department of Chemistry, D.A.V. College (Lahore), Ambala City, Haryana, India; Department of Chemistry,
c
Kurukshetra University, Kurukshetra, Haryana, India; Departamento de Química y Bio-orgánica, Facultad de
Ciencias, UNED, Madrid, Spain
ABSTRACT
ARTICLE HISTORY
Reaction of 3-hydrazonobutan-2-one oxime with aromatic aldehydes
resulted in the formation of 1,2-bis(arylidene)hydrazine commonly
referred as azine as an unexpected product, instead of expected
product 3-(aryl)methylenehydrazonobutan-2-one oxime, which were
subsequently oxidized to corresponding aromatic acids with an
ecofriendly oxidizing agent iodobenzene diacetate. Azines and
Received 7 September 2017
KEYWORDS
3
-Hydrazonobutan-2-one
oxime; aromatic acid; azine;
iodobenzene diacetate;
oxidative degradation
1
13
carboxylic acids were characterized by IR and NMR ( H, C, HMBC,
and HMQC) studies.
GRAPHICAL ABSTRACT
Introduction
Azines also regarded as 2,3-diaza-1,3-butadiene derivatives contain two azomethine groups
(
C=N) which are linked by nitrogen–nitrogen bond. Azines as dipolarophiles are of
[
1,2]
fundamental importance as synthons in the synthesis of heterocyclic compounds
such
[
3]
[4]
as 1,3,4-thiadiazoles, 1,3,4-oxadiazoles. They undergo 1,3-cycloadditions to afford
[
5]
perhydro [1,2,4]triazolo[1,2-a][1,2,4] triazole-1,5-dithiones by crisscross cycloaddition.
Compounds possessing azine moiety are also of great significance as they exhibit diverse
pharmacological activities, such as antitumor,
[
6]
[7]
[8]
anticonvulsant,
antioxidant,
[
9]
antimicrobial, and allosteric modulators of metabotropic glutamate receptor subtype
CONTACT Garima Sumran
Ambala City 134 002, Haryana, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
garimasumran@gmail.com
Department of Chemistry, D.A.V. College (Lahore),
1
13
Supplemental data [full experimental detail, NMR ( H, C, HMBC, and HMQC) spectra] can be accessed on the
publisher’s website.
©
2018 Taylor & Francis

2
G. SUMRAN ET AL.
5
(mGluR5).[10] Recently azines have been reported as promising candidate for the
development of the potential quorum sensing inhibitors which could be used in
[
11]
conjugation of known antibiotics to curb the pathogenesis of Pseudomonas aeruginosa.
[
12]
In addition, they are also developed for use as fluorescence chemosensor,
optical
[
13]
[14]
sensors,
and conducting materials.
Azines are usually prepared by reacting two equiv. of a carbonyl compound with
equiv. of hydrazine hydrate or hydrazine salt in ethanol under reflux using conventional
1
[
15]
[16]
heating,
however, ultrasound irradiation using BiCl as catalyst,
grinding at room
3
[
17]
temperature,
microwave irradiation under solvent free conditions in the presence of
[
18]
CH COONa/CaCl have also been reported.
Transformation of semicarbazones/
3
2
thiosemicarbazones into azines under microwave irradiation has recently been described
[
19,20]
in literature.
A perusal of the literature revealed that products of diversified nature may be achieved
by the oxidation of azines depending upon the potential of oxidizing agent used (Scheme 1).
For instance, oxidation of azines with 30% hydrogen peroxide in the presence of
[
21]
poly(bis-1,2-phenylene) diselenide as catalyst resulted into arene carboxylic acids,
whereas m-chloroperbenzoic acid in alkaline medium afforded mononitrones.[22] When
cerium(IV) ammonium nitrate (CAN) was used as oxidizing agent cleavage of aromatic
[
23,24]
azines occurred leading into corresponding aldehydes.
Tribromoisocyanuric acid
(
TBCA) in the presence of wet SiO also led to the regeneration of carbonyl compounds
2
[
25]
from azines.
Oxidative cyclization of azines to 2,5-disubstituted 1,3,4-oxadiazoles has
[
26]
been reported with lead tetraacetate. Unfortunately, most of these methods involve toxic
or expensive reagents, harsh reaction conditions, longer reaction times, high/below zero
reaction temperatures and difficult workup procedures.
Scheme 1. Reported methods for oxidation of azines.
In view of above observations and in continuation of our interest in the greener
[
27–29]
synthesis of a wide variety of heterocyclic scaffolds,
we herein report an unusual
synthesis of azines from 3-hydrazonobutan-2-one oxime, followed by their oxidative
cleavage to corresponding aromatic acids utilizing iodobenzene diacetate (IBD) as an
oxidizing agent.

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3
Results and discussion
The reaction of diacetyl monoxime 1 with hydrazine hydrate 2 in ethanol afforded an
exclusive formation of 3-hydrazonobutan-2-one oxime 3 under refluxing condition.
We envisaged that reaction of 3-hydrazonobutan-2-one oxime 3 with aromatic aldehydes
(
4a–f) in methanol at room temperature might afford the required 3-(aryl)methylenehy-
drazonobutan-2-one oxime derivatives 5 (Scheme 2). However, stirring a mixture of 3
and aromatic aldehydes 4a–f in methanol at room temperature resulted in an unexpected
crystalline product in moderate yield together with a small amount of diacetyl monoxime 1
(
(
Scheme 2). The unexpected product was unambiguously characterized as (1E,2E)-1,2-bis
4-chlorobenzylidene)hydrazine 6a by combined application of various spectroscopic
1
13
techniques like IR, NMR ( H, C, HMBC, and HMQC studies) (see Supporting
[
17,30]
information).
of respective azines 6a–f were improved.
Typically, when two moles of aldehydes were treated with 3 the yields
IR spectrum of azine 6a, as a representative example, displayed a strong absorption band
at 1620 cm− due to C=N function. H NMR spectrum of 6a revealed, in addition to
1
1
expected aromatic signals, a characteristic singlet signal at δ 8.63 ppm corresponding to
two protons of the azomethine (CH=N). In addition, the 13C NMR spectrum of 6a
displayed a characteristic peak for two imine carbons at about δ 161.8 ppm. The signals
at δ 130.0, 130.9, and 161.8 ppm were attributed to C-3/C-5, C-2/C-6, and CH=N, respect-
1
13
ively, by performing a HMQC experiment. The long-range connectivities in the H– C
HMBC display correlation of C-1 and C-2/C-6 with the singlet at δ 8.63 ppm, which is
H
assigned as the azomethine proton. Other correlations are seen from H-2/H-6 to imine
carbon, C-4, C-2/C-6 and H-3/H-5 to C-1, C-3/C-5.
Scheme 2. Conversion of 3-hydrazonobutan-2-one oxime into azine and subsequent oxidative
degradation into carboxylic acid.

4
G. SUMRAN ET AL.
Formation of azines 6 suggests a cross reaction between 3-hydrazonobutan-2-one oxime
and aromatic aldehydes 4. Further an experiment was accomplished with an objective to
3
ascertain the cross reaction by treating acetone hydrazone with 4-chlorobenzaldehyde 4a in
methanol under similar conditions which led to the formation of corresponding azine 6a.
The probable mechanism for the synthesis of azines 6 is shown in Scheme 3. Initially,
the nucleophilic addition of terminal nitrogen of 3-hydrazonobutan-2-one oxime 3 to
carbonyl carbon of aromatic aldehyde 4 and following the loss of water results in the
formation of intermediate, 3-(aryl)methylenehydrazonobutan-2-one oxime 5. In the next
step, nucleophilic attack of methanol to the imine moiety of 5 takes place which in turn
reacts with second equivalent of aldehyde to give the intermediate 9. This intermediate
can then undergo nucleophilic attack by methanol to afford intermediate, diacetyl mono-
xime dimethyl acetal 10 after elimination of (2-benzylidenehydrazinyl) (phenyl) methanol
1
1. Intermediate 11 undergoes dehydration to yield 6.
[
4]
Though Shang et al. has reported bis(trifluoroacetoxy)iodobenzene (BTI) mediated
oxidative cyclization of azines to 1,3,4-oxadiazoles, however, in the present study we
planned to study the behavior of IBD toward azines since the reactivity of I(III) reagents
is usually dependent on the nucleophilic ligands attached to the central iodine. Initially,
the reaction of azine 6a with 2.2 equiv. of IBD in different solvents, e.g., dichloromethane,
acetic acid, acetic acid–dichloromethane under stirring condition did not proceed even
after 12 h at room temperature. However, a change of solvent to THF in this reaction
resulted in oxidative degradation of 6 to corresponding carboxylic acids 8 (Scheme 2) con-
[
4]
trary to oxidative cyclization to oxadiazoles 7 by BTI. The structure of the compound 8a
1
13
was established from various spectroscopic studies like IR and NMR ( H, C, HMBC, and
HMQC).
HMQC spectrum of 8a shows signals for C-3/C-5 and C-2/C-6 at δ 129.6 and 132.3,
1
13
respectively. In the H– C HMBC, C-1, and C-3/C-5 give correlation with H-3/H-5
protons. Carbons of carboxyl group, C-4 and C-2/C-6 correlate with H-2/H-6.
To demonstrate the scope of this oxidative degradation, several different substituted
azines (6b–k) were treated with IBD at room temperature in THF and the respective arene
carboxylic acids (8b–k) were obtained in good yields (Table 1). The azines (6g–k) required
Scheme 3. Proposed mechanism for formation of azines 6 from 3-hydrazonobutan-2-one oxime 3 and
aromatic aldehydes 4.

SYNTHETIC COMMUNICATIONS®
5
Table 1. Substrate scope for oxidative degradation of azines (6a–k) into carboxylic acids (8a–k).
a
b
6
a
, 8
Ar
Yield (%)
90
Yield (%)
79
b
c
80
88
75
77
d
e
90
84
80
70
f
87
78
76
72
70
c
g
85
c
h
i
79
c
85
c
j
91
76
77
c
k
85
a
b
c
Isolated yield for product 6 obtained from 3-hydrazonobutan-2-one oxime except 6g–k.
Yield of the isolated product 8.
Isolated yield correspond to product 6g–k obtained from reaction of aldehyde and hydrazine hydrate.
for this purpose were prepared by the reaction of aromatic aldehydes 4 and hydrazine
[
15]
hydrate 2 using known procedure.
The identities of the known azines (6b–k) were
[
9,17,19]
established by comparison of their melting points with those reported earlier,
mixed
mp and co-TLC with authentic samples which were synthesized by reacting aldehydes with
hydrazine hydrate and the results are summarized in Table 1. The structure of carboxylic
acids 8b–k was confirmed on the basis of mixed mp and co-TLC with standard sample.
The versatility of the present protocol was further confirmed by the fact that oxidative
transformation of 6–8 was accomplished well on gram scale under the same conditions.

6
G. SUMRAN ET AL.
Scheme 4. Proposed mechanistic pathway for formation of arene carboxylic acids 8 through oxidative
degradation of azines 6.
Reactions of hypervalent iodine reagents are usually rationalized as ligand exchange,
oxidative addition, reductive elimination, and ligand coupling which resemble with the
chemistry of transition metal derivatives. A plausible mechanism for the oxidative degra-
dation of azine to carboxylic acid is outlined in Scheme 4. The electrophilic attack of IBD
on azines 6 would result in generation of nitrogen-iodine(III) species A which would
undergo reductive loss of iodobenzene along with elimination of acetic acid to afford
0
intermediate B. Tautomerization of intermediate B would afford N,N -diacylhydrazine C.
Subsequent nucleophilic attack of water on intermediate C would result in the formation
of desired product 8.
Conclusion
In summary, we have achieved an unusual synthesis of azines from 3-hydrazonobutan-2-
one oxime by cross reaction with aromatic aldehydes. The present protocol offers a novel
and efficient route for the preparation of a large number of arene carboxylic acids through
oxidative cleavage of crystalline azines using ecofriendly reagent IBD in a relatively short
period of time. Arene carboxylic acids have industrial significance and are otherwise
prepared by oxidation of carbonyl compounds.
Experimental
Melting points are taken in open glass capillaries in an electrical apparatus and are
uncorrected. IR spectra were recorded on Perkin-Elmer 1800 FTIR spectrophotometer
using neat technique. Analytical TLC was performed using Merck Kieselgel 60 F254 silica
1
13
gel plates. Visualization was performed by UV light (254 nm). H and C NMR spectra for
analytical purpose were recorded in THF-d operating at 400 and 101 MHz, respectively,
8
and chemical shifts were recorded in ppm (δ) downfield from internal standard

SYNTHETIC COMMUNICATIONS®
13
7
1
1
13
tetramethylsilane (δ 0.00 ppm). 2D-Correlation spectra, ( H– C) gs-HMQC, ( H– C)
1
15
gs-HMBC, and ( H– N) gs-HMBC, of compounds were acquired in a spectrometer oper-
1
13
15
ating at 9.4 Tesla, 400.13 MHz for H, 100.62 MHz for C, and 40.56 for N with a 5-mm
inverse-detection H–X probe equipped with a z-gradient coil, at 300 K and processed using
standard NMR software and in nonphase-sensitive mode. Diacetyl monoxime 1, hydrazine
hydrate 2, aromatic aldehydes 4, IBD, methanol, ethanol, and THF were commercially
available.
Unusual synthesis of 1,2-bis(4-chlorobenzylidene)hydrazine 6a
3
-Hydrazonobutan-2-one oxime 3 (460 mg, 4 mmol) was dissolved in 25 mL of methanol
and 2 equiv. of 4-chlorobenzaldehyde 4a (8 mmol) was added to it. The reaction mixture
was allowed to stir for 3 h. Progress of reaction was monitored by TLC. A solid appeared
during stirring. Solid thus obtained on completion of reaction was filtered, washed with
ethanol and recrystallized from ethanol to afford 1,2-bis(4-chlorobenzylidene)hydrazine.
The mother liquor containing diacetyl monoxime and azine was slightly concentrated
and the products were separated by fractional crystallization.
[
17,19]
−1
6
a: Yellow crystals; mp 208–209 °C (lit
mp 209–211 °C); yield: 90%; IR (cm ):
1
1
620 (CH=N stretching); H NMR (400 MHz, THF-d , δ): 7.48 (d, 4H, J ¼ 8.1 Hz,
8
13
Ph-3,5-H), 7.87 (d, 4H, J ¼ 8.7 Hz, Ph-2,6H), 8.63 (s, 2H, CH=N); C NMR (101 MHz,
THF-d , δ): 130.0 (�4, C-3, C-5), 130.9 (�4, C-2, C-6), 134.4 (�2, C-1), 137.9 (�2,
8
C-4), 161.8 (� 2, CH=N). Anal. calc. for C H Cl N : C, 60.67; H, 3.64; N, 10.11; found:
1
4
10
2 2
C, 60.31; H, 3.27; N, 10.36.
General procedure for synthesis of azines 6g–k
To a solution of aromatic aldehyde 4 (1 mmol) in ethanol (10 mL) containing conc. HCl
1–2 drops) was added hydrazine hydrate 2 (0.5 mmol) dropwise. The reaction mixture
(
was stirred and then refluxed for 1 h. Upon completion of reaction (TLC analysis) the
solvent was reduced. The precipitate was filtered, washed with cold water and recrystallized
from ethanol to afford azines.
Procedure for oxidative degradation of 1,2-bis(4-chlorobenzylidene)hydrazine
into 4-chlorobenzoic acid 8a
To a stirred suspension (or) solution of 1,2-bis(4-chlorobenzylidene)hydrazine (6a)
(
1 mmol) in THF (15 mL) was added IBD (2.2 mmol) in small portions over a period of
5
min at room temperature. The reaction mixture was allowed to stir for about 4 h. Some
fine crystals appeared on stirring. Crystals were filtered and mother liquor was concen-
trated to get more crystals.
31]
1
8
a: White crystals; mp 240–242 °C (lit[
mp 242–243 °C); yield: 79%; H NMR
(
400 MHz, THF-d , δ): 7.45 (m, 2H, Ph-3,5-H), 7.99 (m, 2H, Ph-2,6-H), 11.52 (sbr, 1H,
OH); C NMR (101 MHz, THF-d , δ): 129.6 (C-3,5), 130.8 (C-1), 132.3 (C-2,6), 139.7
8
1
3
8
(
C-4), 166.9 (COOH).
Funding
We are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, India for
providing Junior Research Fellowship (Grant 09/105(0236/2016-EMR-1).

8
G. SUMRAN ET AL.
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