Hypervalent iodine (III)-mediated oxidation of aryl sulfonylhydrazones: A facile synthesis of N-aroyl-N′-acyl arylsulfonylhydrazides

Article abstract of DOI:10.1016/j.tetlet.2016.12.085

We have developed a novel and efficient method for the oxidation of aryl sulfonylhydrazones to N-aroyl-N′-acyl arylsulfonylhydrazides, using hypervalent iodine (III) reagent in good yields at room temperature.

Full text of DOI:10.1016/j.tetlet.2016.12.085

Accepted Manuscript
Hypervalent iodine (III)-mediated oxidation of aryl sulfonylhydrazones: A fac-
ile synthesis of N-aroyl-N'-acyl arylsulfonylhydrazides
E. Ramakrishna, Kapil Dev, Saransh Wales Maurya, Ibadur Rahman Siddiqui,
Rakesh Maurya
PII:
S0040-4039(16)31752-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.085
TETL 48497
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 December 2016
27 December 2016
29 December 2016
Please cite this article as: Ramakrishna, E., Dev, K., Wales Maurya, S., Rahman Siddiqui, I., Maurya, R., Hypervalent
iodine (III)-mediated oxidation of aryl sulfonylhydrazones: A facile synthesis of N-aroyl-N'-acyl
arylsulfonylhydrazides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.085
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Hypervalent iodine (III)-mediated oxidation
of arylsulfonylhydrazones: A facile synthesis
of N-aroyl-N'-acyl arylsulfonylhydrazides
Leave this area blank for abstract info.
E. Ramakrishnaa,#, Kapil Deva,#, Saransh Wales Mauryaa,b, Ibadur Rahman Siddiquib and Rakesh
Mauryaa,∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
Hypervalent iodine (III)-mediated oxidation of aryl sulfonylhydrazones: A facile
synthesis of N-aroyl-N'-acyl arylsulfonylhydrazides
E. Ramakrishnaa,#, Kapil Deva,#, Saransh Wales Mauryaa,b, Ibadur Rahman Siddiquib and Rakesh Mauryaa,∗
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
bDepartment of Chemistry, University of Allahabad, Allahabad-211001, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
We have developed a novel and efficient method for the oxidation of aryl sulfonylhydrazones to
N-aroyl-N'-acyl arylsulfonylhydrazides, using hypervalent iodine (III) reagent in good yields at
room temperature.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Hydrazide
Azapeptides
Hypervalent iodine
Phenyliodine diacetate
α-Sulfonylhydrazobenzyl acetate
1. Introduction
with hydrazine to yield hydrazides.5 These methods have
limitations such as harsh reaction conditions, use of hazardous
reagents, and generation of an excess amount of by-products.6
Hydrazide, which is the reversal of the oxalamide moiety, is a
very important chemical entity in the synthetic organic chemistry,
Scheme 1: Approaches for the synthesis of N-aroyl-N'-acyl
arylsulfonylhydrazides
peptide
chemistry,
polyamides,
pharmaceuticals
and
agrochemicals.1 Hydrazides are the building blocks for the
adducts of Diels-Alder cycloaddition and also form
supramolecular synthons.2 They are widely found in a diverse
range of medicinally important molecules like azapeptides and
drug candidates (Figure 1).3 The azapeptide containing molecules
possess a wide range of biological activities such as hepatitis C
virus inhibition, prevention of preterm birth and anti-cancer.4
A number of papers and reviews published in recent years on
hypervalent iodine, indicating its importance in many organic
reactions.7 The hypervalent iodine reagents have attracted the
interest of chemists due to their low toxicity, easy handling, and
mild reaction conditions.8 Hypervalent iodine reagents are
environment benign and their oxidizing ability is similar to toxic
mercury, metallic lead and thallium based reagents. Its mild
oxidizing properties have been used for the oxidation of
heteroatom-containing compounds.9 Hypervalent iodine mediated
oxidative cleavage of ketoximes,10 hydrazones11 and N',N'-
dialkylhydrazide12 to the parent ketone and acids/esters have been
studied. In 2010, Patel's group has successfully synthesized N-
acetoxy or N-hydroxy amides from aldoximes by using
Figure 1: Representative drug candidates with hydrazide
functionality.
To date, various methods have reported for the synthesis of
hydrazides. Conventionally, hydrazides synthesized by the
treatment of acyl anhydrides and acid chlorides both react rapidly
———
# Authors contributed equally
*Corresponding author. Tel +91-(522)-2772450; fax: +91-(522)-2771941; e-mail: mauryarakesh@rediffmail.com

2
Tetrahedron Letters
hypervalent iodine DIB or HTIB via intramolecular
rearrangement reaction.13
With the optimized reaction conditions (entry 6, Table 1), we
then investigated the substrate scope of PhI(OAc)2 mediated
reaction (Scheme 2). We first examine the substituents effect of
aldehydes used for hydrazone synthesis with p-toluene
sulfonylhydrazide.
Hydrozinolysis of the corresponding esters with hydrazine
monohydrate is the most commonly used process for the
synthesis of hydrazides. As our ongoing research interest in
hypervalent iodine mediated oxidative reactions14 we were
interested in the oxidation of arylsulfonylhydrazones into their
respective N-aroyl-N'-acyl arylsulfonylhydrazides, a hydrazide
analogue under metal-free reaction conditions. In 1965, Bhati has
synthesized such N-aroyl-N'-acyl arylsulfonylhydrazides by the
oxidation of their respective hydrazones by using toxic Pb(OAC)4
as an oxidant in acetic acid, later this was confirmed by Butler.
Buzykin et al. also synthesized N-aroyl-N'-acyl arylsulfonyl
hydrazides in two steps first bromination follwed by oxidation
using acetic acid (Scheme 1).15
Scheme 2: Synthesis of N-aroyl-N'-acyl arylsulfonylhydrazides
from arylsulfonylhydrazonesa,b
O
R
H
O
O
S
N
O
S
O
PhI(OCOR)2, Dry CH2Cl2
rt, 2-7h
N
N
N
H
O
R1
Me
R1
Me
O
4a-4v
3a-3t
O
O
O
O
O
O
O
N
O
S
N
N
N
H
S
N
N
S
H
H
O
O
O
Me
4a
Me
(
, 3.5h, 86%)
Me
Me
4b
, 4h, 79%)
(
4c
(
, 4h, 78%)
O
O
O
O
O
O
O
S
During the course, we have synthesized aryl
sulfonylhydrazones using different aromatic aldehydes and p-
toluene sulfonylhydrazide by the known procedure available in
the literature.16 The synthesized hydrazones were further treated
with hypervalent iodine (III) reagents to yield N-aroyl-N'-acyl
arylsulfonylhydrazides (Scheme 2). In order to achieve our
desired compound, we have carried out a series of experiments
for the optimization of reaction conditions. Initially, we screened
the reaction in methanol and acetone as solvent and aryl
sulfonylhydrazone (3a) with 1.0 eq. of PhI(OAc)2 as the oxidant,
afforded compound 517 in 70% and 76% respectively, instead of
our desired compound 4a (entry 1 & 2, Table 1). Later, we
screened acetonitrile as solvent and we were delighted to get our
desired compound 4a in 30% yield along with compound 5 in
25% yield (entry 3, Table 1) and approximately 20% of starting
material remained intact. The compound 4a was characterized
with help of 1D and 2D-NMR and mass spectrometric analysis.
N
O
S
O
S
O
N
Ph
O
N
N
N
N
H
O
H
H
O
MeO
Me
4d
(
, 5.5h, 74%)
Me
Me
(4f, 6h, 75%)
4e
(
, 7h, 71%)
OMe
O
O
O
O
O
O
O
S
O
S
O
S
N
N
N
N
N
H
OMe
N
H
H
O
O
O
Ph
O
Me
Me
Cl
Me
(4g, 5.5h, 78%)
4h
, 2h, 86%)
(
4i
(
, 3.5h, 81%)
O
O
O
O
Br
O
O
O
O
S
O
N
N
N
N
S
N
N
S
H
H
O
H
O
O
Br
Me
Me
(4k, 4.5h, 88%)
Me
(4j, 4.5h, 80%)
OMe 4l
(
, 6h, 44%)
O
O
O
Br
O
F
O
F
O
O
S
O
S
O
S
N
N
N
N
N
N
H
H
O
O
H
O
F
4o
Me
Me
4m
(
, 6h, 47%)
O
Me
4n
, 5.5h, 52%)
(
(
, 7h, 40%)
O
O
O
O
O
S
O
N
O
S
O
S
N
N
N
N
H
H
N
O
O
H
NC
O
O
S
Me
Me
4p
(
, 3.5h, 84%)
O
Me
4q
, 4h, 83%)
(
(4r, 4h, 78%)
Me
O
O
O
Table 1: Optimization of the reaction conditions.
O
S
O
O
O
N
O
N
S
N
O
N
H
N
O
S
Me
H
N
S
O
H
4s
, 5h, 51%)
(
N
Me
4t
(
, 6h, 43%)
Me
4u
(
, 4h, 82%)
O
CF3
O
O
N
Yield of Yield of
compound compound
N
H
S
O
(4v, 4h, 80%)
Me
Entry
Solvent
eq.
4a
(%)
5
(%)
aReaction conditions: PIDA (1.5 eq.), Dry DCM (10 mL), In case of 4u & 4v
we were used 1.5 eq. PhI(OCOtBu)2 and PhI(OCOCF3)2 instead of
PhI(OCOCH3)2, bIsolated yields
1
2
3
4
5
6
7
8
CH3OH
Acetone
CH3CN
Dry DCM
Dry DCM
Dry DCM
CHCl3
1.0
1.0
1.0
1.0
1.2
1.5
1.0
1.0
-
70
76
25
-
As shown in scheme 2, the effect of a variety of functional
groups such as hydrogen, electron-donating and halogens as well
as electron-withdrawing groups were investigated for this
oxidative transformation reaction. The substrate (E)-N'-
benzylidene-4-methylbenzenesulfonylhydrazone 3a reacted with
phenyliodine diacetate (PIDA) to give the oxidized product 4a in
86% yield. Similarly, other benzaldehyde derivatives containing
30
70
75
86
40
35
a
-
a
-
a
-
electron
donating
groups
reacted
with
p-toluene
a
sulfonylhydrazide to produce our starting material 3b-3g. These
starting substrates 3b-3g were further reacted with 1.5 eq. of
PIDA in DCM to give our desired compounds 4b-4g in good
yield. No significant change in the yield of the products was
observed in case of naphthyl/2-methoxy napthyl aldehydes 3h &
3i yielded corresponding products 4h & 4i. Irrespective of the
position of the electron donating as well as electron withdrawing
groups, all the substrates yielded their corresponding products
(4j-4o and 4p). p-Halobenzaldehydes like p-bromobenzaldehyde
and p-chlorobenzaldehydes gave products 4j & 4k in good yield,
however, in case of o-halobenzaldehydes lower yield of the
products (4l-4o) were observed. This might be due to the steric
hindrance of the group present at ortho position of benzaldehdes.
-
a
DCE
-
aCompound detected in trace amount.
To improve the yield of the product, we used dry DCM (10
mL) as a solvent and 1.0 eq. of PhI(OAc)2, afforded compound
4a in 70% yield, although about 15% of starting material 3a was
remained unreacted. Further increase in the amount of PhI(OAc)2
to 1.2 and 1.5 eq. in dry DCM, yield of the compound improved
to 75 and 86%, respectively (entry 5 & 6, Table 1). Further
screening of the solvents like chloroform and DCE were unable
to improve the yield f the product (entry 7 & 8, Table 1).

3
Similarly, the heteroaromatic compounds like 2-furaldehyde
(3q) and thiophenecarboxaldehyde (3r) gave the products 4q &
4r in 83% and 78%, respectively. However, benzothiophene (3s),
and N-methyl indole (3t), yielded the corresponding products 4s
& 4t in 51% & 43% yield, respectively. Later, we investigated
the scope of the reaction with other hypervalent iodine reagents
like PhI(OCOtBu)2 and PhI(OCOCF3)2, therefore we obtained
their respective products 4u & 4v in 82% and 80% yields,
respectively (Scheme 2).
E. RK and KD is thankful to UGC and CSIR-New Delhi,
KD is thankful to CSIR-New Delhi and SWM is thankful to
Allahabad University for providing fellowship. We are also
thankful to SAIF division of CSIR-CDRI for providing spectral
data. RM is grateful to CSIR for providing emeritus scheme,
Reference No. 21(1019)/16/EMR-II. CSIR-CDRI communication
number for this manuscript is…..
Supplementary data
Supplementary data is associated with this manuscript. It contains
general experimental procedures, compound characterization
Scheme 3: Synthesis of N-aroyl-N'-acyl arylhydrazides from
arylhydrazonesa,b
1
data, and copies of H and 13C-NMR spectra of representative
compounds.
References
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aReaction conditions: Hypervalent iodine reagent (1.5 eq.), Dry DCM (10
mL), bIsolated yields
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Wan, L. J.; Shuai, Z. G. J. Org. Chem. 2007, 72, 4936.
For more generalization of the methodology (Scheme 3), we
tried our reaction with the hydrazone substrate 6 which was
readily synthesized from the reaction between benzaldehyde and
phenylhydrazine. The synthesized substrate 6 was further treated
with 1.5 eq. of PhI(OCOtBu)2, PhI(OCOCH3)2 and PhI(OCOCF3)
in DCM to obtain our desired oxidized product in 69%, 72% and
65% yields, respectively.
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Scheme 4: Proposed mechanism of the reaction
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The proposed mechanism for the product formation is shown
in the scheme 4. Initially, the phenyl hydrazone 3a got oxidized
to nitronium ion A by PhI(OAc)2, the resulting nitronium ion A
further reacts with acetate ion liberated from hypervalent iodine
reagent, to give another intermediate B, this intermediate B
eliminates iodobenzene and acetic acid to afford intermediate C.
The formed intermediate C yielded the desired compound 4a via
1,4-acyl migration.
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hydrazides by using hypervalent iodine reagents. This
methodology would have wide application in the synthesis of
peptidomemitic and biologically important molecules. The
introduction of the acyl group from hypervalent iodine reagents
allows us to synthesize of library of compounds. The final
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Acknowledgments

4
Tetrahedron Letters
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5
Highlights
• Developed a novel method for the synthesis of N-aroyl-N'-acyl arylsulfonylhydrazides.
• Hypervalent Iodine (III) mediated oxidation reaction.
• Wide range of functional group tolerability.
• Good yield of the products.
• No use of chromatographic techniques for purification.