Dioxygen-Triggered Oxo-Sulfonylation of Hydrazones

Article abstract of DOI:10.1021/acs.orglett.0c00759

A simple and highly efficient method for the oxo-sulfonylation of aldehyde-derived hydrazones has been developed using sulfinic acid as a source of sulfonyl group and oxygen as a green oxidant under metal-free conditions at room temperature. The present C

Full text of DOI:10.1021/acs.orglett.0c00759

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Dioxygen-Triggered Oxo-Sulfonylation of Hydrazones
Asim Kumar Ghosh, Susmita Mondal, and Alakananda Hajra*
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ABSTRACT: A simple and highly efficient method for the oxo-sulfonylation of aldehyde-derived hydrazones has been developed
using sulfinic acid as a source of sulfonyl group and oxygen as a green oxidant under metal-free conditions at room temperature. The
present C−O and N−S bond-forming difunctionalization strategy affords diversely functionalized N-acylsulfonamides in good yield.
Experimental results suggest a radical mechanistic pathway of the present reaction.
ifunctionalization is a powerful and straightforward
Dstrategy for the introduction of two functional groups
in a single reaction to synthesize highly functionalized organic
compounds.1 It has drawn the significant interest of the
synthetic organic community due to its wide synthetic utility in
chemical synthesis. Oxo-sulfonylation is an important approach
for the difunctionalization of various types of systems to
introduce oxo and sulfonyl groups.2 In this context, alkenes
and alkynes have been extensively studied for oxo-sulfonylation
to form C−O and C−S bonds.3 Although a number of
strategies for the oxo-sulfonylation of alkenes and alkynes have
been developed, the metal-free di-oxygen-triggered method is
the most practical and efficient technique because oxygen is a
readily available, nontoxic, and ecosustainable oxidant and
reagent. Recently Lei and coworkers reported convenient
dioxygen activation-mediated methods for the oxo-sulfonyla-
tion of alkenes and alkynes under transition-metal-free
conditions.4 Despite these significant achievements in the
direct construction of C−O and C−S bonds, C−O and N−S
bond-forming oxo-sulfonylation is rare and highly demanding.5
Figure 1. Some biologically active compounds containing the acyl
It is worth mentioning that molecules with C−O and N−S
sulfonamide moiety.
bonds show great importance in medicinal chemistry.6−9 We
envisioned that the CN group in hydrazone derivatives
group in their core structures. It is also present in many
might be explored for oxo-sulfonylation to construct a moiety
therapeutic agents,9a prostaglandin E receptor 3 (EP3)
having consecutive O−C, C−N, and N−S bonds. To the best
of our knowledge, there is no report on the oxo-sulfonylation
of hydrazones for the synthesis of N-acylsulfonamides.
Received: February 28, 2020
N-Acylsulfonamides are important carboxylic acid bioisos-
teres6 that are present in a variety of currently marketed drugs
and pharmacological tools, as shown in Figure 1.7 A number of
anti-hepatitis C drugs like beclabuvir,8a asunaprevir,8a
danoprevir,8b and paritaprevir8c contain an N-acylsulfonamide
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© XXXX American Chemical Society
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receptor antagonists,9b prostacyclin receptor agonists,9c and
HCV NS5B polymerase allosteric inhibitors.9d Therefore, the
development of novel and reliable synthetic methods for the
synthesis of N-acylsulfonamides derivatives has gained
significant interest of modern synthetic organic chemists.10
Hydrazones are attractive synthetic intermediates in organic
chemistry.11 As a part of our ongoing research on hydrazones12
and also considering the high importance of C−O and N−S
bond forming reactions, herein we report a simple and
straightforward method for the synthesis of N-acylsulfonamide
derivatives through the oxo-sulfonylation of aldehyde-derived
hydrazones using O2 as a green oxidant13 under metal-free
conditions at ambient temperature (Scheme 1).
reaction was performed under different conditions for the
further improvement of the reaction yield, and the results are
summarized in Table 1. During screening of different solvents
like 1,4-dioxane, CH3CN, THF, toluene, EtOH, DMF, and
DMSO for the present reaction (Table 1, entries 2−8),
CH3CN was found to be a better solvent for this trans-
formation, affording the desired product 3aa in 82% yield
(Table 1, entry 3). The desired product was obtained in 47%
yield under air (Table 1, entry 9). Next, the reaction was
performed using different oxidants (1 equiv) such as K2S2O8
and tert-butyl hydroperoxide (TBHP) under open air, but
lower yields were observed (Table 1, entries 10 and 11). No
significant increment of the reaction yield was found with
increasing the loading of 2a (2 equiv) and reaction
temperature (80 °C), but a decrease in yield was obtained in
the presence of 1 equiv of 2a (Table 1, entries 12 and 13).
Finally, the optimized reaction condition was achieved using
1.5 equiv of 2a in CH3CN at ambient temperature under an O2
atmosphere for 10 h (Table 1, entry 3). Moreover, other
sulfonylating agents like p-toluenesulfonyl chloride, sodium p-
toluenesulfinate, and p-toluenesulfonic acid were not effective
for this transformation under an O2 atmosphere.
Scheme 1. Synthesis of N-Acylsulfonamide from Hydrazone
After getting the optimized reaction conditions, we explored
the substrate scope of the present reaction by varying the
substituents of the hydrazone derivatives, and the results are
summarized in Scheme 2. Benzaldehyde-derived 4-morpholinyl
hydrazone containing electron-donating substituents like −Me
and −OMe at the C-4 position of the phenyl ring successively
reacted with 4-methylbenzenesulfinic acid (2a) to provide the
desired products in good yield (3ba and 3ca). Moreover, the
structure of 4-methyl-N-morpholino-N-tosylbenzamide (3ba)
was confirmed by the single-crystal X-ray analysis. Halogen-
substituted (−F, −Cl, and −Br) hydrazone derivatives gave
satisfactory yields of the products (3da−fa). The reaction
showed good tolerance toward a variety of electron-with-
drawing substituents like −CN and −NO2 (3ga and 3ha).
Hydrazone derivatives of 4-hydroxybenzaldehyde and benzo-
[d][1,3]dioxole-5-carbaldehyde (1i and 1j) also participated in
the present reaction to furnish the desired products in good
yield (3ia and 3ja). N-Morpholino-1-(naphthalen-2-yl)-
methanimine (1k) also reacted very well (3ka). 1-Piperidinyl
hydrazones of different substituted benzaldehydes gave the
desired products in good yield under the optimized reaction
conditions (3la−oa). However, benzylidenehydrazine (1p),
N,1-diphenylmethanimine (1q), and 1-cyclohexyl-N-morpho-
linomethanimine (1r) failed to produce the desired products
under the present reaction conditions. Hydrazones of 1-
methyl-1-phenylhydrazine produced benzamides under the
optimized reaction conditions (4a−d). In that case, the desired
N-acylsulfonamides were not formed. This may be due to the
steric crowding between the sulfonyl group and the methyl/
phenyl group of hydrazone. However, we were unable to cleave
the morpholino or piperidine group of the desired products.
To show the practical applicability of this present protocol, the
gram-scale reaction was also performed in the usual laboratory
setup by taking (E)-N-morpholino-1-phenylmethanimine (1a)
on a 5 mmol scale. The reaction afforded the corresponding N-
morpholino-N-tosylbenzamide (3aa) in 77% yield.
We examined the reaction taking (E)-N-morpholino-1-
phenylmethanimine (1a) as a model substrate and 4-
methylbenzenesulfinic acid (2a) as a sulfonylating agent.
Initially the reaction was carried out in the presence of 1.5
equiv of 2a under an O2 atmosphere in 1,2-DCE at room
temperature. Delightfully, N-morpholino-N-tosylbenzamide
(3aa) was obtained in 65% yield after 10 h (Table 1, entry
1). In addition, a very low amount (12%) of benzaldehyde was
formed in the reaction medium due to the hydrolysis of
hydrazone. No further improvement of the reaction yield was
found, even after 16 h. Encouraged by this initial result, the
a
Table 1. Optimization of the Reaction Conditions
entry
oxidant
solvent (2 mL)
yield (%)
1
2
3
4
5
6
7
8
O2
O2
O2
O2
O2
O2
O2
O2
air
1,2-DCE
1,4-dioxane
CH3CN
THF
toluene
EtOH
65
nr
82
58
37
nr
DMF
10
nr
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
47
58
52
10
11
12
13
K2S2O8 (1 equiv)
TBHP (1 equiv)
O2
O2
b
c
61 , 79
d
57
Subsequently, we explored the present reaction by
investigating the different substituents of arylsulfinic acid (2).
Simple benzenesulfinic acid, 4-methoxy, and 4-chloro
benzenesulfinic acid smoothly reacted with (E)-N-morpholi-
no-1-phenylmethanimine (1a) to produce the corresponding
a
Reaction conditions: 0.2 mmol of 1a, 1.5 equiv of 2a in the presence
b
of O2 in 2 mL of solvent at room temperature for 10 h. Reaction was
carried out using 1 equiv of 2a. Reaction was carried out using 2
equiv of 2a. Stirred at 80 °C.
c
d
B
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a
Scheme 2. Substrate Scope of the Present Method
Scheme 4. Control Experiments
a
zoquinone (BQ), and 1,1-diphenylethylene (DPE) (Scheme 4,
eq A), indicating the radical pathway of the reaction.
Moreover, the formation of sulfonyl trapping product 5 with
1,1-diphenylethylene strongly suggests the radical mechanism
(Scheme 4, eq B). The reaction did not take place under an
argon atmosphere, which implies that the molecular O2 might
be responsible for oxygenation (Scheme 4, eq C). However, we
were unable to perform the 18O2 experiment under our present
laboratory setup. Moreover, oxo-sulfonylation did not occur
using sulfonic acid (6) (Scheme 4, eq D). This result suggests
that the reaction did not proceed through the formation of
sulfonic acid from sulfinic acid via aerial oxidation. 4-
Methylstyrene (7) formed 1-((2-hydroperoxy-2-(p-tolyl)-
ethyl)sulfonyl)-4-methylbenzene (8) under the present re-
action conditions (Scheme 4, eq E). This result supports the
formation of intermediate C.
Reaction conditions: 0.2 mmol of 1, 1.5 equiv of 2a in the presence
b
of O2 in 2 mL of CH3CN at room temperature for 10 h. 5 mmol
scale.
sulfonylated products (3bb, 3bc, and 3ad) in moderate to
good yield (Scheme 3).
A few control experiments were carried out to propose the
plausible mechanistic pathway of the reaction (Scheme 4). The
present reaction did not proceed at all in the presence of
radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), 1,4-ben-
a
Scheme 3. Substrate Scope of Sulfinic Acids
On the basis of the control experimental results and
literature reports,4 a tentative mechanistic pathway is proposed
in Scheme 5. Initially, 4-methylbenzenesulfinic acid generates
an oxygen-centered sulfonyl radical I in the presence of
molecular O2, which resonates with sulfonyl radical II.4 Next,
the addition of sulfonyl radical (II) takes place at the iminium
nitrogen center of (E)-N-morpholino-1-phenylmethanimine
(1a) to form the intermediate A. Subsequently, intermediate A
reacts with dioxygen to form intermediate B, which is
subsequently converted to intermediate C via the hydrogen
radical abstraction from sulfinic acid (2a).4 Finally, the desired
product N-morpholino-N-tosylbenzamide (3aa) is formed
through the elimination of water from the intermediate C.
a
Reaction conditions: 0.2 mmol of 1, 1.5 equiv of 2 in the presence of
O2 in 2 mL of CH3CN at room temperature for 10 h.
C
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Notes
Scheme 5. Plausible Mechanistic Pathway
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.H. acknowledges the financial support from CSIR, New
Delhi (grant no. 02(0307)/17/EMR-II). A.K.G. thanks CSIR
for their fellowship.
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ASSOCIATED CONTENT
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CCDC 1985106 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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AUTHOR INFORMATION
Corresponding Author
■
Alakananda Hajra − Department of Chemistry, Visva-Bharati
(A Central University), Santiniketan 731235, India;
orcid.org/0000-0001-6141-0343;
Email: alakananda.hajra@visva-bharati.ac.in
Authors
́
̈
Asim Kumar Ghosh − Department of Chemistry, Visva-Bharati
(A Central University), Santiniketan 731235, India
Susmita Mondal − Department of Chemistry, Visva-Bharati (A
Central University), Santiniketan 731235, India; orcid.org/
0000-0002-8795-942X
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