Synthesis of biologically active N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides

Article abstract of DOI:10.14233/ajchem.2014.16156

A new series of N-benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides (5a-f) was synthesized by using (3,4- methylenedioxyphenyl)methylamine (1). Compound 1 on reaction with arylsulfonyl chlorides (2a-f) in a weak basic aqueous medium gave N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides (3a-f), which were converted to target molecules 5a-f, by the reaction of 3a-f with electrophile, benzyl chloride (4) in the presence of LiH and N,N-dimethylformamide. All the synthesized molecules were characterized by IR, ¹H NMR and EIMS. Further, all the molecules were screened for the antibacterial activity and showed moderately good inhibition activity.

Full text of DOI:10.14233/ajchem.2014.16156

Asian Journal of Chemistry; Vol. 26, No. 15 (2014), 4651-4654
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16156
Synthesis of Biologically Active N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides
1
1,*
1
1
2
2
ASIA SIDDIQA , AZIZ-UR-REHMAN , M. ATHAR ABBASI , SHAHID RASOOL , IRSHAD AHMAD and SAIRA AFZAL
1Department of Chemistry, Government College University, Lahore-54000, Pakistan
2Department of Pharmacy; The Islamia University of Bahawalpur, Bahawalpur-63100, Pakistan
*Corresponding author: Tel: +92 42 111000010; Ext.450; E-mail: azizryk@yahoo.com; rehman@gcu.edu.pk
Received: 7 August 2013;
Accepted: 27 December 2013;
Published online: 16 July 2014;
AJC-15544
A new series of N-benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides (5a-f) was synthesized by using (3,4-
methylenedioxyphenyl)methylamine (1). Compound 1 on reaction with arylsulfonyl chlorides (2a-f) in a weak basic aqueous medium
gave N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides (3a-f), which were converted to target molecules 5a-f, by the reaction of
3a-f with electrophile, benzyl chloride (4) in the presence of LiH and N,N-dimethylformamide. All the synthesized molecules were
characterized by IR, 1H NMR and EIMS. Further, all the molecules were screened for the antibacterial activity and showed moderately
good inhibition activity.
Keywords: (3,4-Methylenedioxyphenyl)methylamine, Antibacterial activity, Arylsulfonyl chlorides.
solvent systems, followed by visualization under UV at 254
nm. Melting points of all compounds were recorded on a
Griffin-George melting point apparatus by open capillary tube
and were uncorrected. Infrared spectra were recorded in KBr
pellet method on a Jasco-320-A spectrophotometer. 1H NMR
spectra were recorded in CHCl3 (deuterated) on a Bruker
spectrometer at 400 MHz along with chemical shift in δ-values,
tetramethylsilane as reference standard and the coupling
constants (J) in Hz. Mass spectra (EIMS) were recorded on a
JMS-HX-110 spectrometer.
INTRODUCTION
All the sulfonamides bear sulfamoyl group in common
and have significance in medicinal chemistry due to their
biological activities. These are extensively employed as the
carbonic anhydrase inhibitors; anticancer, antiinflammatory,
antiviral agents; antimicrobial drugs and antitumor drugs,
plausibly because of reasonable cost, decremented toxicity and
incremented activities1-5. The sulfonamides have been evaluated
for a number of biological activities including antibacterial
activities6,7. The benzodioxol moiety has much significance
in the field of biological active compounds. The various natural
products like narciclasine, lycoricidine and pancratistatin bear
benzodioxole moiety and have been employed for anticancer
etc. Some other drugs like the antidepressant including paro-
xetine, escitalopram etc. also possess this moiety8,9.
In continuation of our previous work10-13, the synthesis
and biological screening of new N-benzyl-N-[(3,4-methylene-
dioxyphenyl)methyl]arylsulfonamides compounds with an
objective to detect the antimicrobial activity of the synthesized
compounds. This is crucial as the need of hour is to inaugurate
new potent molecules with great resistance against the existing
microbes. This encouraged us to develop new effective mole-
cules and the effort remained productive in this regard.
Synthesis of N-[(3,4-methylenedioxy-phenyl)methyl]-
arylsulfonamides (3a-f): (3,4-Methylene-dioxyphenyl)methyl-
amine (0.01 mol; 1) was suspended in 50 mL water using 200
mL round bottom flask. The pH of reaction mixture was
maintained 9-10 by using aqueous Na2CO3 solution. Different
arylsulfonyl chlorides (0.01 mol; 2a-f) were added into the
flask along with stirring. The reaction mass was kept on stirring
for 2-3 h and checked by TLC till the single spot. At the
completion of reaction, dil. HCl (2.0-3.0 mL) was added slowly
to make the pH slightly acidic. The reaction mixture was kept
undisturbed for 0-5 min and then shaken to get the precipitates.
Synthesis of N-benzyl-N-[(3,4-methylenedioxyphenyl)-
methyl]arylsulfonamides (5a-f): Compounds 3a-f (0.01 mol)
was homogeneously dissolved in 10 mL N,N-dimethyl form-
amide in a 100 mL round bottom flask along with the addition
of lithium hydride (0.01 mol) at room temperature. The reaction
mixture were stirred for 30-45 min and then the electrophile;
benzyl chloride (0.01 mol; 4) was added to get the target mole-
EXPERIMENTAL
Purity of the synthesized molecules was analyzed by thin
layer chromatography (TLC) using EtOAc and n-hexane as

4652 Siddiqa et al.
Asian J. Chem.
cules 5a-f, after stirring for 3-4 h. After completion of reaction
as per single spot on TLC, the reaction mixture was quenched
with ice cold water (150 mL). The formed precipitates were
filtered, washed with distilled water and dried to yield the
corresponding products 5a-f.
Mass: 395 g mol-1; IR (KBr, νmax, cm-1): 3079 (Ar C-H), 1611
1
(Ar C=C), 1345 (S=O), 1234 (C-O); H NMR (CDCl3, 400
MHz, δ/ppm): 7.36-7.23 (m, 10H, H-2' to H-6' & H-2'' to
H-6''), 6.72 (d, J = 8.4 Hz, 1H, H-6), 6.69 (s, 1H, H-2), 6.66
(d, J = 8.0 Hz, 1H, H-5), 5.93 (s, 2H, H-8), 4.15 (s, 2H, H-7'),
4.10 (s, 2H, H-7), 3.96 (s, 2H, H-7''); EIMS (m/z): 395 [M]+,
155 [C7H7SO2]+, 150 [C8H8NO2]+, 135 [C8H7O2]+, 121
[C7H5O2]+, 91 [C7H7]+, 65 [C5H5]+.
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-
benzenesulfonamide (5a): Dark grey amorphous solid;Yield:
83 %; m.p.: 84-86 °C; m.f.: C21H19NO4S; Mol. Mass: 381 g
mol-1; IR (KBr, νmax, cm-1): 3067 (Ar C-H), 1608 (Ar C=C),
1346 (S=O), 1239 (C-O); 1H NMR (CDCl3, 400 MHz, δ/ppm):
7.82 (d, J = 8.0 Hz, 2H, H-2', H-6'), 7.52 (t, J = 8.0 Hz, 1H,
H-4'), 7.49 (t, J = 8.0 Hz, 2H, H-3', H-5'), 7.17-7.10 (m, 5H,
H-2'' to H-6''), 6.68 (d, J = 7.6 Hz, 1H, H-6), 6.65 (s, 1H,
H-2), 6.61 (d, J = 7.6 Hz, 1H, H-5), 5.90 (s, 2H, H-8), 4.07 (s,
2H, H-7), 3.85 (s, 2H, H-7''); EIMS (m/z): 381 [M]+, 150
[C8H8NO2]+, 141 [C6H5SO2]+, 135 [C8H7O2]+, 121 [C7H5O2]+,
91 [C7H7]+, 77 [C6H5]+, 65 [C5H5]+, 51 [C4H3]+.
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-1-
[(1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]-
methanesulfonamide (5f): Light grey amorphous solid;Yield:
79 %; m.p.: 114-116 °C; m.f.: C25H29NO5S; Mol. Mass: 455 g
mol-1; IR (KBr, νmax, cm-1): 3075 (Ar C-H), 1604 (Ar C=C),
1386 (S=O), 1232 (C-O); 1H NMR (CDCl3, 400 MHz, δ/ppm):
7.22-7.17 (m, 5H, H-2'' to H-6''), 6.71 (s, 1H, H-2), 6.67 (d,
J = 8.0 Hz, 1H, H-6), 6.63 (d, J = 8.0 Hz, 1H, H-5), 5.85 (s,
2H, H-8), 4.25 (s, 2H, H-7), 3.40 (s, 2H, H-7''), 3.13 (s, 2H,
H-10'), 2.35-2.30 (m, 2H, H-3'), 2.11-2.06 (m, 2H, H-6'), 1.99-
1.93 (m, 2H, H-4'), 1.49-1.45 (m, 1H, H-5'), 0.91 (s, 6H, CH3-
8', CH3-9'); EIMS (m/z): 455 [M]+, 215 [C10H15OSO2]+, 151
[C10H15O]+, 150 [C8H8NO2]+, 135 [C8H7O2]+, 121 [C7H5O2]+,
91 [C7H7]+, 65 [C5H5]+.
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-
2,4,6-trimethylbenzene sulfonamide (5b): White amorphous
solid;Yield: 87 %; m.p.: 108-110 °C; m.f.: C24H25NO4S; Mol.
Mass: 423 g mol-1; IR (KBr, νmax, cm-1): 3086 (Ar C-H), 1613
1
(Ar C=C), 1378 (S=O), 1251 (C-O); H NMR (CDCl3, 400
MHz, δ/ppm): 7.21-7.15 (m, 5H, H-2'' to H-6''), 6.89 (s, 2H,
H-3', H-5'), 6.70 (s, 1H, H-2), 6.66 (d, J = 7.6 Hz, 1H, H-6),
6.62 (d, J = 7.6 Hz, 1H, H-5), 5.90 (s, 2H, H-8), 4.15 (s, 2H,
H-7), 3.39 (s, 2H, H-7''), 2.59 (s, 6H, CH3-7', CH3-8'), 2.18 (s,
3H, CH3-9'); EIMS (m/z): 423 [M]+, 183 [C9H11SO2]+, 150
[C8H8NO2]+, 135 [C8H7O2]+, 121 [C7H5O2]+, 119 [C9H11]+, 91
[C7H7]+, 74 [C6H2]+, 65 [C5H5]+.
Antibacterial activity: Determination of the antibacterial
activity was based on the principle that microbial cell number
or microbial growth was directly related to the log phase of
growth with increase in absorbance of broth medium14,15. The
clinically isolated two Gram-positive (Bacillus subtilis and
Staphylococcus aureus) and three Gram-negative (Salmonella
typhi, Escherichia coli and Pseudomonas aeruginosa) bacteria
were stored on stock culture agar medium. 20 µg test samples
with dilution by suited solvents and 180 µL overnight main-
tained fresh bacterial culture with suited dilution with fresh
nutrient broth were mixed. The initial absorbance was crucially
between 0.12-0.19 at 540 nm. The incubation was processed
at 37 °C for 16-24 h with lid on the micro plate. The absorbance
was measured at 540 nm using micro plate reader before and
after incubation and the difference was noted as an index of
bacterial growth. The per cent inhibition was calculated using
the formula: Inhibition (%) = 100-(Abs of test sample/Abs of
control) × 100
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-2,4-
dinitrobenzenesulfonamide (5c): Light brown sticky solid;
Yield: 83 %; m.f.: C21H17N3O8S; Mol. Mass: 471 g mol-1; IR
(KBr, νmax, cm-1): 3083 (Ar C-H), 1601 (Ar C=C), 1356 (S=O),
1253 (C-O); 1H NMR (CDCl3, 400 MHz, δ/ppm): 8.49 (d, J =
2.0 Hz, 1H, H-3'), 8.37 (dd, J = 8.0, 2.4 Hz, 1H, H-5'), 8.21 (d,
J = 8.4 Hz, 1H, H-6'), 7.29-7.25 (m, 5H, H-2'' to H-6''), 6.73
(d, J = 8.4 Hz, 1H, H-6), 6.69 (s, 1H, H-2), 6.67 (d, J = 8.0 Hz,
1H, H-5), 5.86 (s, 2H, H-8), 4.31 (s, 2H, H-7), 3.39 (s, 2H,
H-7''); EIMS (m/z): 381 [M]+, 231 [C6H3N2O4SO2]+, 167
[C6H3N2O4]+, 150 [C8H8NO2]+, 135 [C8H7O2]+, 121 [C7H5O2]+,
91 [C7H7]+, 75 [C6H3]+, 65 [C5H5]+.
Results are mean of triplicate (n = 3, sem). Ciprofloxacin
was employed as standard. Minimum inhibitory concentration
(MIC) was measured with suitable dilutions (5-30 µg/well)
and results were calculated using EZ-Fit Perrella Scientific
Inc. Amherst USA software and data was expressed as MIC.
Statistical analysis: All the measurements were done in
triplicate and statistical analysis was performed by Microsoft
Excel 2010. Results are presented as mean sem.
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-2-
naphthalenesulfonamide (5d):White crystalline solid;Yield:
79 %; m.p.: 114-116 °C; m.f.: C25H21NO4S; Mol. Mass: 431 g
mol-1; IR (KBr, νmax, cm-1): 3029 (Ar C-H), 1616 (Ar C=C),
1343 (S=O), 1237 (C-O); 1H NMR (CDCl3, 400 MHz, δ/ppm):
8.38 (s, 1H, H-8'), 7.95 (d, J = 8.4 Hz, 1H, H-3'), 7.90 (d, J =
8.4 Hz, 1H, H-2'), 7.80 (dd, J = 8.4, 1.6 Hz, 1H, H-4'), 7.73
(dd, J = 8.4, 1.6 Hz, 1H, H-7'), 7.64 (t, J = 8.0 Hz, 1H, H-6'),
7.60 (t, J = 7.6 Hz, 1H, H-5'), 7.19-7.10 (m, 5H, H-2'' to
H-6''), 6.64 (d, J = 7.2 Hz, 1H, H-6), 6.62 (d, J = 3.2 Hz, 1H,
H-2), 6.58 (d, J = 7.2 Hz, 1H, H-5), 5.82 (s, 2H, H-8), 4.06 (s,
2H, H-7), 3.46 (s, 2H, H-7''); EIMS (m/z): 431 [M]+, 191
[C10H7SO2]+, 150 [C8H8NO2]+, 135 [C8H7O2]+, 127 [C10H7]+,
121 [C7H5O2]+, 102 [C8H6]+, 91 [C7H7]+, 65 [C5H5]+.
RESULTS AND DISCUSSION
A new series of N-benzyl-N-[(3,4-methylenedioxyphenyl)-
methyl]arylsulfonamides (5a-f) was synthesized according to
the protocol sketched in Scheme-I.
The parent molecules, N-[(3,4-methylenedioxyphenyl)-
methyl]arylsulfonamides (3a-f) were synthesized by reacting
(3,4-methylenedioxyphenyl)methylamine (1) with arylsulfonyl
chlorides (2a-f) under basic pH control in an aqueous medium.
The products were separated after acidification by dil. HCl.
N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]-1-
phenylmethanesulfonamide (5e): Cream white amorphous
solid; Yield: 89 %; m.p.: 88-90 °C; m.f.: C22H21NO4S; Mol.

Vol. 26, No. 15 (2014)
Synthesis of Biologically Active N-Benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides 4653
O
O
S
O
O
O
O
O
O
Na2CO3/H2O
NH2
R
N
H
S
R
Cl
Stir, pH = 9-10
3a-f
1
2a-f
LiH, DMF
stirring
BzCl
4
O
O
S
O
R
N
7
1
3
8
5
O
3''
1''
5''
5a-f
Compd.
R
Compd.
R
Compd.
R
NO
2
7'
CH2
6'
6'
6'
5a
5c
5e
2'
4'
2'
4'
2'
4'
O N
2
CH3
8'
H3C
9'
7'
CH
3
9'
1'
4'
7'
5'
6'
5b
5d
5f
3'
H2C
1'
5'
2'
4'
8'
CH
9'
H C
10'
O
3
3
Scheme-I: Synthesis of N-benzyl-N-[(3,4-methylenedioxyphenyl)methyl]arylsulfonamides
1
The parent molecules were further treated with the electrophile,
benzyl chloride (4) to synthesize the product, 5a-f in the presence
of NaH as weak base and in a polar aprotic solvent using DMF.
The molecule 5a showed the [M]+ peak at m/z 381 and the
prominent peaks were appeared at m/z 141 for phenylsulfonyl
cation, at m/z 77 for phenyl cation after the loss of SO2 and at
m/z 135 for the (3,4-methylenedioxyphenyl)-methyl cation,
in EI-MS spectrum. The IR spectrum showed absorption bands
at 3067, 1608 and 1346 cm-1 due to Ar-C-H (aromatic C-H
stretching),Ar-C=C (aromatic C=C stretching), -SO2 (stretching
of sulfonyl group), respectively. In the 1H NMR spectrum, the
signals resonating at δ 6.68 (d, J = 7.6 Hz, 1H, H-6), 6.65 (s,
1H, H-2), 6.61 (d, J = 7.6 Hz, 1H, H-5) and 5.90 (s, 2H, H-8)
confirmed the presence of tri-substituted aromatic ring. The
three signals resonating at δ 7.82 (d, J = 8.0 Hz, 2H, H-2', H-
6'), 7.52 (t, J = 8.0 Hz, 1H, H-4') and 7.49 (t, J = 8.0 Hz, 2H,
H-3', H-5'), confirmed the phenyl ring attached to the with-
drawing sulfonyl group. A multiplet of five protons was
appeared in the aromatic region at δ 7.17-7.10 (m, 5H, H-2''
to H-6'') which showed the presence of mono-substituted
aromatic ring. In the aliphatic region, three signals were
appeared at δ 5.90 (s, 2H), 4.07 (s, 2H,) and 3.85 (s, 2H,) which
corresponding to the H-8, H-7 and H-7'' methylene protons,
respectively. On the basis of above data, the structure of the
molecule is N-benzyl-N-[(3,4-methylenedioxy-phenyl)methyl]-
benzenesulfonamide. In the same way, the structures of other
synthesized compounds were corroborated by H NMR, IR
and mass spectral data as described in experimental section.
Antibacterial activity: The results of antibacterial study
of the synthesized compounds are listed in Tables 1 and 2 as
their percentage inhibition and MIC values respectively. The
series of synthesized molecules has been shown to be poten-
tially active against the five bacterial strains of Gram-bacteria.
Among the Gram-negative bacterial strains, the molecules 8f
showed the most potential activity (with MIC value 10.77
1.88 µM) relative to the reference standard, ciprofloxacin (with
MIC value of 9.42 1.09 µM) against Salmonella typhi.
Among the Gram-positive bacterial strains, the molecules 8f
showed the significant activity against Staphylococcus aureus.
Almost the whole series remained active against all the
bacterial strains, credibly, because of the heterocyclic moiety
attached to the sulfamoyl group.
Conclusion
The projected structures of the synthesized compounds
are well supported by spectroscopic data. The newly synthe-
sized compounds showed varying degree of antibacterial
activity.
ACKNOWLEDGEMENTS
The authors are thankful to the Higher Education
Commission (HEC) of Pakistan for financial support.

4654 Siddiqa et al.
Asian J. Chem.
TABLE-1
PERCENTAGE INHIBITION OF ANTIBACTERIAL ACTIVITY
Percentage inhibition
Compound
S. typhi (-)
68.33 1.22
52.28 4.61
63.88 0.47
59.78 2.22
47.67 1.89
72.22 3.33
91.19 2.10
E. coli (-)
P. aeroginosa (-)
58.26 5.00
47.17 3.43
63.04 3.88
54.87 1.83
56.96 3.39
57.83 5.00
92.00 2.76
B. subtilis (+)
51.95 5.00
49.14 1.50
56.50 3.50
39.59 5.00
40.45 1.82
49.50 5.00
89.98 2.07
S. aureus (+)
40.05 1.68
49.23 1.28
57.45 0.35
56.89 2.81
35.00 2.35
64.18 11.73
92.21 1.59
75.37 0.84
68.95 4.74
82.06 2.31
53.26 5.00
61.42 0.37
68.11 1.26
90.44 1.23
8a
8b
8c
8d
8e
8f
Ciprofloxacin
TABLE-2
MIC OF ANTIBACTERIAL ACTIVITY
MIC
Compound
S. typhi (-)
11.49 2.32
15.68 1.65
11.35 5.00
15.02 3.98
-
E. coli (-)
P. aeroginosa (-)
15.85 1.31
-
B. subtilis (+)
S. aureus (+)
12.82 2.16
13.19 3.33
10.20 1.94
16.82 2.23
16.81 1.43
12.69 2.56
8.02 2.17
19.17 4.69
-
8a
-
-
8b
13.17 2.58
18.32 1.55
18.75 3.23
15.62 1.14
8.11 1.32
15.92 3.17
15.45 1.50
15.00 3.21
-
8c
-
8d
-
8e
8f
10.77 1.88
9.42 1.09
-
14.55 2.09
9.23 1.87
Ciprofloxacin
8.88 2.00
Note: Minimum inhibitory concentration (MIC) was measured with suitable dilutions (5-30 µg/well) and results were calculated using EZ-Fit
Perrella Scientific Inc. Amherst USA software, and data was expressed as MIC
8. B. Bar-Oz, T. Einarson,A. Einarson, R. Boskovic, L. O'Brien, H. Malm,
A. Bérard and G. Koren, Clin. Ther., 29, 918 (2007).
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