A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds

Article abstract of DOI:10.1515/hc-2019-0023

A green method has been developed for the synthesis of N-arylsulfonylhydrazones via a simple grindstone procedure. By grinding mixtures of benzensulfonyl hydrazides and a series of aryl aldehydes or ketones in the mortar using L-tyrosine as catalyst, 24 N

Full text of DOI:10.1515/hc-2019-0023

Heterocycl. Commun. 2019; 25: 152–156
Research Article
Open Access
Qian Yang*, Wangwang Hao, Yangqing He, Qian Zhang, Xiaojiao Yu and
YAaoGbinrgeHeuan* Synthesis and Antibacterial Activity
of N-Arylsulfonylhydrazone Compounds
https://doi.org/10.1515/hc-2019-0023
Received April 28, 2019; accepted September 15, 2019.
Aldol condensation [4], Dieckmann condensation [5],
Knevenagel condensation [6], Sonogashira reaction [7]
Abstract: A green method has been developed for the and other reactions [8,9] can be performed competently
synthesis of N-arylsulfonylhydrazones via a simple by the grindstone technique. Compared to a traditional
grindstone procedure. By grinding mixtures of benzen- organic reaction, the grindstone method often is more
sulfonyl hydrazides and a series of aryl aldehydes or efficient than solution-based methods and in some cases
ketones in the mortar using L-tyrosine as catalyst, 24 even more selective [10]. Furthermore, it also has many
N-arylsulfonylhydrazones were synthesized in a few advantages, such as mainly mild conditions, reduced
minutes with high yield. All compounds were screened pollution, short reaction time, low costs, effective repro-
for their antibacterial activities. Most of them exhibit ducibility and simplicity in process and handling [11-14].
some antibacterial activities especially for 3d, 3l and 3v Thus, the grindstone chemistry gained ever-widening
showing high activity against Staphylococcus aureus and attention in greener organic transformations during the
Escherichia coli.
past decades.
N-arylsulfonylhydrazones, a branch of acylhydrazo-
Keywords: Solvent-free; N-arylsulfonylhydrazone; L-Tyro- nes, serve a key role in medicinal chemistry. They display
sine; Grindstone method; Antibacterial activities
various biological activities, including anti-tumor [15],
antibacterial [16], antiviral [17], anti-inflammatory [18]
and as novel inhibitors of IMP-1[19] or carbonic anhyd-
rase [20]. In 2007, the N-arylsulfonylhydrazone derivative
(E)-N’-(1-(6-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)
Introduction
Grindstone chemistry can be regarded as the most effici- ethylidene)-N,2-dimethyl-5-nitrobenzenesulfonohydra-
ent and green chemistry technology, and its traditional zide was reported as a novel p110α inhibitor[21]. In 2014,
instrument—the mortar and pestle—was used in the Çevrimli et al. synthesized a new compound, 2-hydroxy-
stone age [1]. The first application of this technique was 1-naphthaldehydeethanesulfonylhydrazone, exhibiting
preparation of foods, then its application extended to excellent antibacterial activities [22]. The synthesis of
preparation of minerals, medicines and other types of N-arylsulfonylhydrazones is similar with that of N-acylhy-
materials. In 1893, Ling et al. first used the grindstone drazones. It is carried out by reacting arylsulfonylhydra-
method to synthesize the derivatives of quinhydrone zines with aryl/alkyl aldehydes or ketones under reflux,
[2]. Up to now, it has been demonstrated that more and in presence of Brønsted-Lowry acid catalysts and in protic
more types of synthesis such as Reformatsky reaction [3], polar solvents. The process takes from few minutes to
several hours. However, these conditions inevitably can
produce waste liquid pollution with poor stereoselectivity
because a mixture of E/Z diastereomers is often formed.
* Corresponding authors: Qian Yang and Yaobing Hua, School of
Herein, we report a new grindstone method to synthesize
Sciences, Xi`an University of Technology, Xi’an, 710054, e-mail:
N-arylsulfonylhydrazones using tyrosine as catalyst with
no environmental pollution and high stereoselectivity
(Scheme 1).
QianY@xaut.edu.cn
Wangwang Hao, Yangqing He, Qian Zhang and Xiaojiao Yu,
School of Sciences, Xi`an University of Technology, Xi’an, 710054
Open Access. © 2019 Qian Yang et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons

Q. Yang et al.: A Green Synthesis and antibacterial activity of N-Arylsulfonylhydrazone Compoundsꢁ
ꢁ153
O O
S
O O
S
O O
S
O
O
N
N
Ar
NH2
N
Tyrosine/r.t.
grinding
or
R1
N
N
or
2
H
H
Ar
H
H
R1
R
1
3
OCH Cl
,
R=H,
3
Scheme 1.ꢀSynthesis of N-arylsulfonylhydrazones by grindstone method.
Table 1ꢂOptimization of catalyst type and dosage.a
Results and discussion
Chemistry
O
O
O
O
O
catalyst
grinding
N
NH2
S
S
N
N
H
H
2a
3a
1a
Initially, according to Pinheiro [23], benzenesulfonyl hyd-
razine 1a (1mmol) and 2-cyclohexenone 2a (1mmol) were
ground together in the mortar using 50ul AcOH as catalyst.
After 12 minutes, the color of benzenesulfonyl hydrazide
gradually changed from light yellow to white, indicating
the completion of reaction. The arylsulfonylhydrazone
3a was isolated (52%) and characterized by NMR and
MS (Table 1, entry 1). In order to improve the yield, other
catalysts such as CeCl3·7H2O and K10 montmorillonite were
tested to get 3a in 41% and 58% (Table 1, entry 2 and 3).
Tyrosine as efficient, bifunctional, and ecofriendly cata-
lyst can catalyze the knoevenagel condensation in high
yield [24]. Inspired by this paper, tyrosine was used and
obtained 3a the highest yield ultimately (Table 1, entry 4).
Reduction in the amount of L-tyrosine to 10 mol% (Table
1, entry 5) did not show any decrease in the yield and res-
ponse time. However, the yield was reduced to 50% when
the amount of L-tyrosine was cut to 5 mol% and the reac-
tion time was up to 15 minutes, compared to 6 minutes at
10 mol% (Table 1, entry 6). Considering the atom economy
of reaction and the yield of 3a, 10 mol% L-tyrosine was
chosen as the appropriate catalyst for this reaction (Table
1, entry 5).
Entry
Catalyst
Catalyst
Time (min)
Yieldb(%)
load (mol%)
1
2
3
4
5
6
AcOH
CeCl3·7H2O
K10ꢀmont.
L-Tyrosine
L-Tyrosine
L-Tyrosine
50ul
15%
15%
15%
10%
5%
12
10
10
6
6
15
52
41
58
66
66
50
aA mixture of 1a (1mmol) and 2a (1mmol) ground in the mortar at
room temperature.
bIsolated yield.
Table 2ꢂSynthesis of N-arylsulfonylhydrazones 3a-3l.a
O O
S
O
O O
S
N
Tyrosine/r.t.
grinding
NH2
N
N
H
H
R
R
3
1
2
OCH Cl
,
3
R=H,
2a=2-cyclohexenone, 2b=2-cyclopentenone
2c=2-hydroxyacetophenone, 2d=acetophenone
Entry
R
1
2
3
Time
(min)
Yieldb
(%)
Having obtained the optimized reaction conditions,
we investigated the generality of these reaction conditions
by extending to a variety of phenyl ring substituted aryl-
sulfonyl hydrazine 1 and ketone or aldehyde derivatives 2.
Thus, grinding 1a with 2-cyclohexenone 2a or 2-cyclopen-
tenone 2b in the mortar at room temperature for 6 minutes,
gave yield of 66% of 3a and 62% of 3b respectively (Table
2, entry 1 and 2). Similarly, treatment of 2-hydroxyaceto-
phenone 2c and acetophenone 2d, gave a higher yield
of 3c 73% and 3d 78% in a shorter time (Table 2, entry 3
and 4). The similar result occurred from 3e to 3l (Table 2,
entry 5-12), reacting with the same arylsulfonyl hydrazine
1b or 1c, acetophenone 2d can produce the highest yield
1
H
H
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
3a
6
6
4
4
6
6
4
2
5
5
4
2
66
62
73
78
75
72
81
92
78
73
81
84
2
3b
3c
3d
3e
3f
3
H
4
H
5
OCH3
OCH3
OCH3
OCH3
Cl
6
7
3g
3h
3i
3j
3k
3l
8
9
10
11
12
Cl
Cl
Cl
aA mixture of 1 (1ꢀmmol) and 2a-2d (1ꢀmmol) ground in the mortar at
room temperature using 10% of L-tyrosine as catalyst.
(Table 2, entry 8 and 12), followed by 2c (Table 2, entry 7 bIsolated yield.

ꢁ
154ꢁ
Q. Yang et al.: A Green Synthesis and antibacterial activity of N-Arylsulfonylhydrazone Compounds
and 11), 2a (Table 2, entry 5 and 9) and 2b (Table 2, entry bearing EDG hydroxy are submitted to the grindstone che-
6 and 10). The results showed that electronic factors and mistry condensation, easily formatting a carbocation on
steric resistance play as major factors in these reactions. the carbonyl group, all reactions lead to a higher yield
The benzene ring of aryl ketones, equivalent to an elec- (Table 3, entry 2, 6 and 10). On the other hand, aldehydes
tron withdrawing group (EWG), can enhance the forma- bearing EWG chloro- have exhibited a lower yield (Table
tion of a carbocation on the carbonyl group, and further 3, entry 3, 7 and 11). The reactivity of furfural 2h is weaker
improve the yield of reaction. On the contrary, the elect- than benzaldehyde leading to the lower yield (Table 3,
ron donating effect of 2-cyclohexenone and 2-cyclopente- entry 4, 8 and 12). As described above, for aldehydes or
none obviously decrease the yield. The steric hindrance ketones, the ease of formation of the carbonyl carboca-
of 2-hydroxyacetophenone 2c may impede the approach tion depends upon the nature of the substituents present
of the NH2 group of the hydrazine to the carbocation on in the aromatic ring. Electron-donating groups favors its
the carbonyl group, which generates a lower yield than formation, whereas electron-withdrawing substituents
acetophenone 2d. However, the electronic donating group exert the opposite effect. Finally, an interesting pheno-
(EDG) at substituent R on the benzenesulfonyl hydrazine menon we observed was when furfural 2h, reacted with
cannot cause a significant difference to the yield of 3, p-methoxybenzenesulfonyl hydrazine 1b, the product 3t
compared to the substrates bearing an electronic with- was obtained as a mixture of E/Z diastereomers in a ratio
drawing group (EWG) at R (Table 2, entry 5-12). The main of 1:1. With benzenesulfonyl hydrazine 1a, the ratio is 2:1.
reason is the electronic factors of substituent R have no Meanwhile the E-isomer can be isolated from the tautomer
obvious influence on the nucleophilicity of the NH2 group by recrystallization. However, reacting with p-chloroben-
of the hydrazine.
zenesulfonyl hydrazine 1c, the product 3x was only the
As shown in Table 3, aryl aldehydes produce a much E-isomer was confirmed by 1H-NMR.
higher yield with benzosulfonyl hydrazine because of the
A plausible mechanism for the formation N-arylsul-
their increased reactivity compared to aryl ketones. Diffe- fonylhydrazones is depicted in Scheme 2 [24]. L-tyrosine,
rent substituents of EDG and EWG attached to the aroma- in its zwitterionic form (B), abstracts a proton from the
tic ring of aryl aldehydes can also lead to a similar result to NH2 group of the benzenesulfonyl hydrazine (1) forming
the one observed with aryl ketones. When benzaldehydes the negative ion of hydrazide (11) which then attacks the
protonated benzaldehyde (21) forming the corresponding
intermediate (22) that loses the water to form the end
product 3.
Table 3ꢂSynthesis of N-arylsulfonylhydrazones 3m-3x.a
O O
S
O O
S
NH2
O
N
Ar
Tyrosine/r.t.
grinding
N
N
H
H
H
Ar
R
R
Antibacterial activity
1
2
3
OCH Cl
,
R=H,
3
2e=benzalhyde, 2f=o-hydroxybenzaldehyde
2g=p-chlorobenzaldehyde, 2h=furaldehyde
All compounds were screened for their antibacterial acti-
vities in vitro by broth microdilution method [25] and the
minimum inhibitory concentration (MIC) values are pre-
sented in Table 4. The antimicrobial drug penicillin was
used as reference drug. The results in Table 4 revealed
that when the substituent R1 is OCH3, the antibacterial
activities of N-arysulfonylhydrazones were relatively weak
(compound 3e, 3f, 3g, 3q, 3r, 3s). Conversely, electron
withdrawing group chloro- can increase the antibacte-
rial activity (compound 3i, 3k, 3l, 3u, 3v, 3w, 3x). R2 has a
large influence on the antibacterial activities of N-arysul-
fonylhydrazones compounds. Furaldehyde and acetophe-
none can enhance the antibacterial activities. Especially
for acetophenone, where the MIC of the compounds was
found to be the same as that of penicillin against Staphylo-
coccus aureus (3d, 3h, 3l). For p-chlorobenzaldehyde, the
spatial stereo conformation of compounds was changed
which may reduce the antibacterial activity.
Entry
R
1
2
3
Time
(min)
Yieldb
(%)
1
H
H
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
2e
2f
2g
2h
2e
2f
2g
2h
2e
2f
2g
2h
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
4
2
5
6
4
2
4
6
4
2
4
6
82
87
78
67
91
96
85
78
88
94
83
66
2
3
H
4
H
5
OCH3
OCH3
OCH3
OCH3
Cl
6
7
8
9
10
11
12
Cl
Cl
Cl
aA mixture of 1 (1mmol) and 2e-2h (1mmol) ground in the mortar at
room temperature using 10% of L-tyrosine as catalyst.
bIsolated yield.

Q. Yang et al.: A Green Synthesis and antibacterial activity of N-Arylsulfonylhydrazone Compoundsꢁ
ꢁ155
O
H
2
O
OH
OH
NH2
HO
H
H
N
A
H
OH
H
H
O
N
S
N
N
H
S
21
O
O
O
O
O
OH
-H
2O
NH3
HO
22
3
C
O
HN
S
O
HN
11
O
NH3
HO
B
O O
S
H2N
HN
1
Scheme 2ꢂPlausible mechanism for the formation of N-arylsulfonylhydrazones.
Table 4ꢂIn vitro antibacterial activity of N-arysulfonylhydrazones
Conclusions
compounds.
O O
S
N
In summary, we have described the preparation of
N-arylsulfonylhydrazones by condensation reaction in
solvent free conditions under the grindstone method at
room temperature using L-tyrosine as an efficient cata-
lyst. Electronic factors and steric resistance of aryl alde-
hydes and ketones play key roles in these reactions, which
influence the formation of the carbonyl carbocation on
carbonyl group, then determine the ease of the reaction.
This strategy is useful and attractive for the preparation
of N-arylsulfonylhydrazones. Antimicrobial screening
studies were also performed. The results show that some
of the compounds exhibited a good antibacterial activity
especially for Staphylococcus aureus.
N
R2
H
R1
R
R
OCH Cl
,
1=H,
2=2-cyclohexenone, 2-cyclopentenone,
3
o-
2-hydroxyacetophenone, acetophenone,benzalhyde,
hydroxybenzaldehyde, -chlorobenzaldehyde, furaldehyde
p
Compounds
Minimum inhibitory concentration (ug/mL)a
Escherichia coli.
Staphylococcus aureus
Penicillin
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
15.6
62.5
125
125
62.5
125
125
125
125
62.5
125
62.5
62.5
62.5
125
125
62.5
125
125
>125
62.5
62.5
62.5
125
62.5
62.5
125
125
125
62.5
125
125
125
62.5
125
>125
125
62.5
125
62.5
125
125
>125
>125
125
125
125
62.5
62.5
125
Acknowledgements: This research was supported by
the National Natural Science Foundation of China (No:
21576220) and the Key Laboratory Project of Shaanxi edu-
cation department (No: 17JS085).
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