N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal structure analysis to establish the tautomeric preferences

Article abstract of DOI:10.1016/j.tet.2018.05.024

The potentiality of the N-(acridin-9-yl)arenesulfonamide moiety as a hybrid pharmacophore due to the distinct pharmacological activities of acridines and aryl/heteroaryl sulfonamides prompts to synthesise N-(acridin-9-yl)arenesulfonamides and study their structural properties. Various N-(acridin-9-yl)arene/heteroarenesulfonamides were obtained through the development of a new methodology adopting the Pd₂(dba)₃-catalyzed C–N bond formation strategy for the reaction of 9-chloloroacridine with arene/heteroarenesulfonamides. The 1H and ¹³C NMR spectra suggest these N-(acridin-9-yl)arene/heteroarenesulfonamides to exist solely as the sulfonimide tautomer rather than anticipated sulfonamide form and was confirmed by the single crystal XRD analysis of one of the newly synthesized compounds. The quantum chemical studies rationalized this tautomeric preference revealing that the sulfonimide tautomers are more stable than the sulfonamide tautomers by ?0.67 to ?5.12 kcal/mol in the gas phase. In the solid state, the sulfonimide tautomer is stabilized by intermolecular hydrogen bond between N–H?O–S and π? π stacking between the acridine rings.

Full text of DOI:10.1016/j.tet.2018.05.024

Tetrahedron xxx (2018) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical
studies and crystal structure analysis to establish the tautomeric
preferences
,
**
Sumit S. Chourasiya a, Aabid A. Wani a, C.M. Nagaraja b, Asit K. Chakraborti a
,
,
*
Prasad V. Bharatam a
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062, Punjab, India
b Department of Chemistry, Indian Institute of Technology (IIT) Ropar, Roopnagar, 140 001, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The potentiality of the N-(acridin-9-yl)arenesulfonamide moiety as a hybrid pharmacophore due to the
distinct pharmacological activities of acridines and aryl/heteroaryl sulfonamides prompts to synthesise
N-(acridin-9-yl)arenesulfonamides and study their structural properties. Various N-(acridin-9-yl)arene/
heteroarenesulfonamides were obtained through the development of a new methodology adopting the
Pd2(dba)3-catalyzed CeN bond formation strategy for the reaction of 9-chloloroacridine with arene/
heteroarenesulfonamides. The 1H and 13C NMR spectra suggest these N-(acridin-9-yl)arene/hetero-
arenesulfonamides to exist solely as the sulfonimide tautomer rather than anticipated sulfonamide form
and was confirmed by the single crystal XRD analysis of one of the newly synthesized compounds. The
quantum chemical studies rationalized this tautomeric preference revealing that the sulfonimide tau-
tomers are more stable than the sulfonamide tautomers by ꢀ0.67 to ꢀ5.12 kcal/mol in the gas phase. In
the solid state, the sulfonimide tautomer is stabilized by intermolecular hydrogen bond between
Received 26 March 2018
Received in revised form
6 May 2018
Accepted 8 May 2018
Available online xxx
Keywords:
Ring-chain
Isomerism
DFT
Guanylhydrazone
NMR
NeH/OeS and
p
ꢀ
p stacking between the acridine rings.
© 2018 Published by Elsevier Ltd.
1. Introduction
(antibacterial),10 sulfadiazine (antibacterial),11 sulfathiazole (anti-
bacterial),12 sulfamethoxazole (antibacterial),13 sulfamethazine14
(Fig. 1B).
Many hybrid sulfonamides with different heterocycles have
gained attention for the development of drugs/leads. The recent
examples include (i) chloroquinoxaline sulfonamide (NSC-
339004)15,16 is a synthetic heterocyclic sulfonamide which has been
identified as investigational drug for the treatment of cancer, is in
the clinical trial stage.
The acridine moiety exerts its anticancer activity by intercalat-
ing between base pairs of double-stranded DNA through in-
p
-
p
teractions1,2 and represents the essential pharmacophoric feature
of drugs such as amsacrine (anticancer),3 mepacrine (antima-
larial),4 proflavin (topical antiseptic, antibacterial)5 (Fig. 1A). On the
other hand, sulfonamides have long been the subject of pharma-
ceutical interest due to their diverse biological activities6 and solid
state structural properties (originating from polymorphism and
tautomerism).7,8 The sulfonamide group contributes to the phar-
macophoric features in many drugs including the recently
Chloroquinoxaline was tested and found to be both
a
topoisomerase-IIa and topoisomerase-IIb poison; (ii) BMS-
a
19388417 which contain isoxazole sulfonamide moeity was iden-
tified as endothelin receptor antagonist, (iii) AM-046618 and PF-
05089777119 are clinical candidate with selective sodium channel
(Nav1.7) inhibitory activity for the management of pain; (iv) a
quinazoline sulfonamide derivative20 has been reported as anti-
cancer agent. (Fig. 2A). All these examples represent the hybrid
sulfonamides with different heterocycles. Considering the impor-
tance of these two moieties (acridine and sulfonamide) in medic-
inal chemistry, N-(acridine-9-yl)arenesulfonimide (NAAS) can also
approved
bosentan
(antihypertensive),9
sulfasalazine
* Corresponding author. Department of Medicinal Chemistry, National Institute
of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar, Punjab, 160 062,
India.
** Corresponding author.
E-mail addresses: akchakraborti@niper.ac.in (A.K. Chakraborti), pvbharatam@
niper.ac.in (P.V. Bharatam).
https://doi.org/10.1016/j.tet.2018.05.024
0040-4020/© 2018 Published by Elsevier Ltd.
Please cite this article in press as: Chourasiya SS, et al., N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal
structure analysis to establish the tautomeric preferences, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.024

2
S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
2. Results and discussion
2.1. Synthesis
Due to the lack of information on the synthesis of such class of
molecules,41 initially, we adopted SeN bond formation strategy for
the synthesis of N-(acridin-9-yl)benzenesulfonamide 3a′ from the
reaction of 9-aminoacridine (1) and benzenesulfonyl chloride (2)
using literature reports (Table 1).42e48 The treatment of 9-
aminoacridine (1) with benzenesulfonyl chloride (2) under
various conditions either did not form N-(acridin-9-yl)benzene-
sulfonamide 3a′ (Table 1, entry 1e8) or led to the formation of the
bissulfonylated product 4 in poor yield (Table 1, entry 9).
Next, we adopted the CeN bond formation strategy involving
the aromatic nucleophilic substitution reaction of 9-chloroacridine
(5) with arenesulfonamide (6) to from N-(acridin-9-yl)arenene-
sulfonamides (3a′, Table 2).
The reaction of 9-chloroacridine with arenesulfonamide in the
absence of transition metal catalyst gave poor yield of desired
product (entry 1e3, Table 2). We observed that the aromatic
nucleophilic substitution reaction of heteroarylhalides with are-
nesulfonamide has been reported under the influence of Cu(I)49,50
and Pd(II)51,52 derived catalysts in the presence of suitable ligand
and stoichiometric amounts of base but till date there is no report
on the reaction of 5 with 6 to form 3′. Thus, we used the reaction
conditions of these literature reports49e52 for the model reaction of
5 with benzenesulfonamide 6a so as to find the best operative re-
action condition to form 3a′ under the influence of either CuI or
Pd2(dba)3 as the transition metal derived catalysts (TM-Cat) as well
as different variation of the reaction conditions such as the use of
different ligand, base, and solvent at 80e100 ꢁC (oil bath) for 12 h
(Table 2).
Fig. 1. A) Representative drugs containing the acridine moeity; B) Drugs containing N-
heterocyclic sulfonamide moieties.
The Cu(I)-catalyzed reactions led to either no product formation
or produced 3a in poor yields (GC-MS; ESI) (Table 2, entries 4e10).
Amongst the various trials for the Pd2(dba)3 catalyzed reaction
(Table 2, entries 11e16), the best result was obtained in performing
the reaction in tBuOH (Table 2, entry 14) affording 3a in 56% yield.
With this optimized condition in hand, we performed the reaction
of 5 with different arenesulfonamides 6 to obtain the N-(acridin-9-
yl)arenesulfonamides (3a-3o) in 55e60% yields (Table 3).
Fig. 2. A) Clinical sulfonamide candidates with different heterocycles; B) NAAS
considered in present study representing a hybrid pharmacophore of sulfonamide and
acridine moeity. The equilibrium represents the possible sulfonamide-sulfonimide
tautomers of NAAS.
Table 1
Synthesis of N-(acridin-9-yl)benzenesulfonamide by conventional methods.
be considered as novel hybrid pharmacophore (Fig. 2B).
It is surprising to note that hybrid of sulfonamide and acridine
heterocycle as a pharmacophore was not explored till now, the
reason could be the non availability of method of its synthesis or
difficulty in synthesis of this class of compound. Thus, herein, we
report, the synthesis of NAAS through the development of palla-
dium catalyzed method. The quantum chemical studies were car-
ried out to rationalize the formation of sulfonimide tautomer as the
sole product, and finally the crystal structure analysis was carried
out to confirm the tautomeric preferences.
Tautomerism in drugs is a topic of contemporary interest due to
its importance in medicinal chemistry,21e24 computer-aided drug
design,25e28 drug delivery,29 drug discovery,30 understanding the
interactions of the drug molecules with the biological targets31,32
chemical reactivity,33 structural property34 and polymorphism.35
Our lab has been extensively working on the importance of phar-
macophoric feature vs tautomer of medicinally important com-
pounds.23,36e40 Continuing the effort, it was realized that NAAS can
represent a pharmacophore and can exhibit tautomeric preference
towards sulfonimide tautomer, the results are presented below.
Entry Reaction conditions
Yield (%)
Literature reports
3aa
4
1
2
3
4
5
6
7
8
9
MeCN, Pyridine, rt, 12 h
Pyridine, 100 ꢁC, 12 h
trace
trace
0
0
Ref.42
Ref.43
H2O, Na2CO3, 80 ꢁC, 12 h
Silica gel, rt, 12 h
0
trace Ref.44,4544,4544,45
0
0
Ref.46
Ref.47
Ref.48
Current work
Current work
Current work
EtOH/AcOH, reflux, 12 h
Water, Na2CO3, pH ¼ 8, rt, 12 h
MeCN, Na2CO3, reflux, 12 h
MeCN, reflux, 12 h
0
0
0
0
0
0
<5
0
0
15
MeCN, K2CO3, reflux, 12 h
a
3a is the energetically stable sulfonimide tautomer of 3a′ and found to present
under experimental condition (vide infra).
Please cite this article in press as: Chourasiya SS, et al., N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal
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S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
3
Table 2
Table 3
Reaction of 5 with 6a Under Different Conditions to form 3a′.
The Pd2(dba)3-Catalyzed Reaction of 5 with Various arylsulfonamides (6) to Form
the N-(acridin-9-yl)arenesulfonamide (3a-3o).a
Entry
1
Compd
Ar
Time (h)
12
Yield (%)b
56
3a
2
3b
16
57
3
4
3c
3
3c
60
Entry
Catalyst
Ligand
Base
Solvent
Yield (%)d
1a
2b
3b
4c
5
6
7
8
9
10
11c
12
13
14
15
16
Conc. HCl
–
e
e
e
NMP
DMF
EtOH
MeCN
tBuOH
DMF
0
10
0
<5
0
15
<5
25
27
<5
15
25
28
56
42
38
3d
15
K2CO3
Et3N
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
DMEDA
Glycine
Glycine
DMEDA
DMEDA
DMEDA
DMEDA
Xantphos
Xantphos
Xantphos
Xantphos
dppf
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
5
6
7
3e
3f
16
16
17
55
59
50
dioxane
PhMe
DMF
tBuOH
dioxane
PhMe
DMF
3g
tBuOH
tBuOH
MeCN
8
9
3h
3i
12
12
55
54
Xantphos
a
5 (80 mg, 0.37 mmol) was treated with 6a in the presence of NMP as solvent
(2 mL) with catalytic HCl at rt for 12 h.
b
5 (80 mg, 0.37 mmol) was treated with 6a (1.2 equiv) in the presence of base (3
equiv) in the solvent (2 mL) at 80e100 ꢁC (oil bath) for 12 h.
c
5 (80 mg, 0.37 mmol) was treated with 6a (1.2 equiv) in the presence of the TM-
cat [CuI (5 mol %); Pd2(dba)3 (1 mol %)], ligand [DMEDA 0.5, Glycine 0.15, Xantphos/
dppf 0.03 equiv], and the base (3 equiv) in the solvent (2 mL) at 80e100 ꢁC (oil bath)
for 12 h.
10
11
3j
12
16
55
55
d
The isolated yield of 3a′.
3k
2.2. Establishment of tautomeric preferences through NMR
spectroscopy
The N-(acridin-9-yl)arenesulfonamides can exist either in sul-
fonamide tautomer and/or sulfonimide tautomer (Scheme 1). The
sulfonamide tautomer (3′) is characterized by the presence of eNH
group exocyclic to the acridine ring whereas sulfonimide tautomer
(3) is characterized by the exocyclic imine with proton is attached
to the endocyclic nitrogen of acridone ring.
12
13
3l
12
14
56
55
3m
To establish the tautomeric preferences, NMR spectroscopic
studies on a series of NAAS (3a-3o) was carried out. A broad signal
14
15
3n
3o
17
13
57
57
at
compounds 3a-3o that appeared to be much downfield in com-
d
12.7e13.2 was observed in the 1H NMR of the synthesized
parison to that of the NH proton
phenylbenzenesulfonamides.
(
d
6.84)53 in N-
This suggested that 3a-3o exist exclusively in the sulfonimide
tautomeric state (II, Fig. 2B) as the NH chemical shift values (
12.7e13.2 ppm) of 3a-3o are comparable to that of 10-(H)-acridone
in which the endocyclic eNH proton appears at
11.8 ppm54,55
Fig. 3 shows a presence of broad singlet at 12.88 due to the
a
5 (80 mg, 0.37 mmol) was treated with 6 (1.2 equiv) in the presence of Pd2(dba)3
(1 mol %), Xantphos (0.03 equiv), and Cs2CO3 (3 equiv) in tBuOH (2 mL) at 80 ꢁC (oil
bath) for the indicated time period.
d
d
b
The isolated yield.
d
presence of endocyclic eNH proton in compound 3a and hence
suggest the existence of sulfonimide tautomer.
with the corresponding experimental values (Table 4). Thus, the
It was realized that apart from the NH proton chemical shift, the
C9 carbon chemical shift values of the sulfonamide and sulfonimide
tautomeric forms would be more convincing probe (diagnostic
feature) to establish the tautomeric structure of 3a-3o. In the
absence of standard reference, we calculated (GIAO method)56 the
13C chemical shift values of the C9 carbon of both of the tautomers
in each of 3a-3o and observed that the calculated 13C chemical shift
values of the C9 carbon in the sulfonimide form compared well
compounds 3a-3o exist in the sulfonimide tautomeric state.
2.3. Quantum chemical studies to rationalize the stability of
sulfonimide tautomer
We next planned to rationalize the preference of 3a-3o for the
sulfonimide tautomer by calculating the tautomeric energy differ-
ences (DGT) between the sulfonimide and sulfonamide tautomers
Please cite this article in press as: Chourasiya SS, et al., N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal
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4
S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
Scheme 1. Two Possible Tautomeric forms (sulfonamide and sulfonimide) of N-(acri-
din-9-yl)arenesulfonamides.
Fig. 4. Quantum chemically [B3LYP/6-311 þ G(d,p) level] optimized 3D structures of
the sulfonamide and sulfonimide tautomers of 3a in their monomeric state.
with the C11eC9eN15eS torsional angle of 102.8ꢁ whereas, in the
sulfonimide tautomer the SO2 group is almost coplanar with the
acridine ring with the C11eC9eN15eS torsional angle of 170.3ꢁ
(Fig. 4).
The sulfonimide tautomer 3a shows conjugation of electron
density, unlike sulfonamide tautomer which is one of the reasons
for the greater stability of sulfonimide tautomer over sulfonamide
tautomer. This is clearly evident from the second order delocal-
ization energies of sulfonimide tautomer of 3a (Table 5). For
example, NBO analysis shows that the nN10 / p*C12eC5 second-
order delocalization is very strong (~44.27 kcal/mol) in sulfonimide
tautomer compared to the sulfonamide tautomer (2.11 kcal/mol).
Apart from this interaction, the other second order delocalizations
are also important for the stability of sulfonimide tautomer over
sulfonamide tautomer which is mentioned in Table 5. This second
order delocalization increases the aromaticity of both the benzene
rings (A and B, Table 5) of sulfonimide tautomer as compare to the
benzene rings of sulfonamide tautomer as it is evident from the
nucleus-independent chemical shifts (NICS), a measure of the
aromaticity58e60 which is found to be 8.4 ppm for ring A and ring B
in sulfonimide tautomer while it is 8.0 ppm for ring A and 7.1 ppm
for ring B of sulfonamide tautomer.
Fig. 3. 1H NMR spectrum of 3a (N-(acridin-9(10H)-ylidene) benzene sulfonamide) in
DMSO‑d6 indicating the presence of sulfonimide tautomer in solution state.
Table 4
Comparison of Experimental and Theoretical
fonamide and the Sulfonimide Tautomers of 3a-3o and the
d
13C Values (ppm) of C9 for the Sul-
DGT (kcal/mol) values.
a
S. No.
compd
d
13C, C9 (Exp.)
d
13C, C9 (Calc.)
DGT
Sulfonimide
Sulfonamide
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
159.7
160.0
160.8
159.8
159.8
160.3
160.2
160.4
160.3
160.4
160.5
160.4
159.8
160.0
163.7
162.9
162.8
162.5
164.8
162.9
162.9
163.2
163.1
163.1
163.7
164.2
163.3
164.6
163.2
163.6
142.4
142.4
142.6
142.6
142.8
143.8
141.5
141.7
141.4
140.5
141.0
141.2
142.8
142.2
144.4
ꢀ2.86
ꢀ2.19
ꢀ2.21
ꢀ3.74
ꢀ2.07
ꢀ0.81
ꢀ3.84
ꢀ3.38
ꢀ3.96
ꢀ5.12
ꢀ4.32
ꢀ4.24
ꢀ0.67
ꢀ3.27
ꢀ5.14
The quantum chemical study suggested that the tautomeric
equilibrium is strongly influenced by the polarity of the solvents.
For example, the
phase favoring the sulfonimide tautomer. This
D
GT value for 3a (Ar ¼ Ph) is ꢀ2.86 kcal/mol, in gas
D
GT increases in the
order ꢀ4.24, ꢀ5.68, ꢀ5.74, and ꢀ5.78 kcal/mol in Et2O (ε 4.3),
MeOH (ε 32.6), DMSO (ε 48.9), and H2O (ε 78.5), respectively
(Table 6)61,62 suggesting the preference for sulfonimide tautomer
increases as the polarity of solvent increases. This is in accordance
with the better polar character of the sulfonimide tautomer in
comparison to that of the corresponding sulfonamide form
(Table S1). These results are in good agreement with our previous
9
10
11
12
13
14
15
a
Sulfonamide ! Sulfonimide tautomeric energy difference,
D
GT in kcal/mol,
where T represent tautomer, calculated at [B3LYP/6-311
negative values indicate that sulfonimide tautomer is more stable.
þ
G(d,p) level]. The
Table 5
NBO Analyses of the Lower Energy Sulfonimide Tautomers of 3a at B3LYP level using
6-311 þ G (d, p) basis set.
Second order delocalization energy E2 (kcal/mol)
of 3a-3o (Table 2, col 6) using the density functional B3LYP/6-
311 þ G(d,p).57 method to obtain the energy differences (
DGT) be-
Sulfonamide tautomer
Sulfonimide tautomer
tween the sulfonimide and sulfonamide tautomers (Table 3, col 6).
In all cases, the sulfonimide tautomer was found to be more stable
than the corresponding sulfonamide form by ~0.67e5.14 kcal/mol.
Fig. 4 provides a comparison of the optimized 3D structures of the
sulfonamide and sulfonimide tautomers of 3a. In case of the sul-
fonamide tautomer, the acridine ring is planar with the
C8eC11eC9eC13 torsional angle of 178.8ꢁ whereas, in case of the
sulfonimide tautomer, the acridine ring adopts a butterfly shape
with the C8eC11eC9eC13 torsional angle of 169.8ꢁ. The C9eN15
bond lengths were found to be 1.42 Å and 1.30 Å in the sulfonamide
and sulfonimide tautomers, respectively. The SO2 group was found
to be out of plane of the acridine ring in the sulfonamide tautomer
Interactions
nN10
nN15
nN15
nN15
/
/
/
/
p
p
p
p
*
*
*
*
2.11
5.99
3.18
5.17
44.27
8.40
11.98
1.23
C12-C5
C13-C9
C9-C11
C11-C8
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S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
5
Table 6
Influence of Substituents and Polarity of the Solvents on sulphonamide ! sulfonimide Tautomeric Energy Difference,
at B3LYP/6-311þþG(d,p) level.
D
GT in kcal/mol, where T represent tautomer, Calculated
Compd
Substituent (Ar)
DGT (kcal/mol)
Gas phase (ε ¼ 1)
Diethyl ether (ε ¼ 4.3)
Methanol (ε ¼ 32.7)
DMSO (ε ¼ 46.7)
Water (ε ¼ 80.1)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
Ph
ꢀ2.86
ꢀ2.19
ꢀ2.21
ꢀ3.74
ꢀ2.07
ꢀ0.82
ꢀ3.84
ꢀ3.38
ꢀ3.96
ꢀ5.12
ꢀ4.32
ꢀ4.24
ꢀ0.67
ꢀ3.27
ꢀ5.14
ꢀ4.24
ꢀ4.81
ꢀ4.48
ꢀ6.03
ꢀ4.52
ꢀ2.29
ꢀ5.60
ꢀ5.96
ꢀ5.73
ꢀ6.72
ꢀ6.69
ꢀ5.81
ꢀ3.29
ꢀ5.07
ꢀ7.71
ꢀ5.68
ꢀ5.87
ꢀ5.19
ꢀ6.96
ꢀ5.56
ꢀ2.50
ꢀ6.61
ꢀ5.20
ꢀ7.72
ꢀ7.35
ꢀ7.27
ꢀ7.03
ꢀ4.69
ꢀ5.82
ꢀ8.49
ꢀ5.74
ꢀ7.89
ꢀ5.34
ꢀ6.98
ꢀ5.64
ꢀ2.51
ꢀ6.66
ꢀ6.73
ꢀ6.76
ꢀ7.44
ꢀ6.67
ꢀ7.05
ꢀ4.74
ꢀ5.84
ꢀ9.11
ꢀ5.78
ꢀ7.83
ꢀ5.47
ꢀ6.98
ꢀ5.63
ꢀ2.55
ꢀ6.61
ꢀ6.78
ꢀ6.77
ꢀ7.47
7.12
4-CH3-Ph
n-Propyl-Ph
Mesityl
4-Ome-Ph
3,4-(Ome)2-Ph
4-Cl-Ph
4-F-Ph
3,4-dichloro-Ph
4-NO2-Ph
3-NO2-Ph
4-CF3-Ph
1-naphthyl
2-naphthyl
8-quinolinyl
ꢀ6.77
ꢀ4.79
ꢀ5.79
ꢀ9.09
studies.40 However, apart from the polarity (ε) the other physico-
formation of the compound in its preferred sulfonimide tautomeric
state (Fig. 5).
Quantum chemical analysis was carried out to rationalize the
stability of sulfonimide tautomer in its dimeric state. The geometry
optimization of sulfonamide dimer and sulfonimide dimer was
chemical parameters of the solvent could also contribute in
changing the
D
GT value with the change in the solvent.63,64
The substituents on the aromatic ring were also found to play an
important role in dictating the tautomeric equilibrium. In case of 3a
with unsubstituted benzene ring, the
is ꢀ2.86 kcal/mol (Table 6). The electron withdrawing substituents
such as Cl, F, NO2, CF3 (3g-3l) tend to increase the GT and thus
D
GT in the gas phase
carried out using B3LYP/
u
B97X-D/6-311 þ G(d,p) method. The
computationally obtained geometrical parameters of the dimer of
the sulfonimide tautomer are found to be seamlessly matching
with those of the crystal structure (Table 7). The energy difference
D
increase the preference towards the sulfonimide tautomer. On the
other hand, the electron donating substituents such as Me, nPr, and
(DGT) between the dimer of sulfonamide and sulfonimide tautomer
OMe groups (3b-3f) decrease the
which the two ortho Me groups exert steric influence).
D
GT (except for compound 3d in
was calculated and the results indicate that the sulfonimide dimer
is more stable than the sulfonamide dimer by ~16 kcal/mol, also the
energy gain due to the dimer formation from the monomer of the
sulfonimide tautomer in 3n is 24.86 kcal/mol in the gas phase
2.4. Crystal structure analysis of 3n
(
u
B97X-D/6-311 þ G(d,p)). Hence it can be concluded that in ag-
gregates these NAAS exist as sulfonimide dimer. The dimerization
provides extra stability to the sulfonimide tautomeric state of
The final proof of concept can be obtained through the crystal
structure of some specific examples. We observed that in the only
reported crystal structure; 3a exists in the sulfonimide form.65
However, in the absence of detailed crystal structure parameters
of this literature report, we planned to obtain the single crystal XRD
of the hitherto unknown compound 3n. The single crystal of
compound 3n was obtained from acetonitrile solution by a slow
evaporation method. The single crystal was obtained after 15 days
and suitable crystals were taken for single crystal XRD analysis.66
The X-ray structure of 3n unambiguously confirmed the
Table 7
Important Geometrical Parameters of 3n Obtained from XRD Analysis. Comparison
Between the XRD Data and DFT (B3LYP/
u
B97X-D/6-311 þ G(d,p)) Data is listed.
Distances are in Å and angle is in degree (ꢁ).
Parameters
Sulfonimide dimer (3n)a
Single crystal XRD
DFT
B3LYP
u
B97X-Db
Bond lengths
C9eN15
N10eC14
1.329
1.360
1.321
1.368
1.315
1.360
Intermolecular hydrogen bond
N(10)-H$$$$$OeS
Dihedral angle
2.115
1.88
1.80
C8eC11eC9eC13
167.80
166.80
167.67
a
For the ease of calculation and to reduce computational time, the naphthalene
ring in compound 3n was replaced with methyl group.
b
Fig. 5. The ORTEP diagram of 3n with 50% thermal probability ellipsoids in the dimeric
state representing sulfonimide tautomer. (pink dotted lines represent the intermo-
lecular hydrogen bonds).
It is known that the DFT B3LYP functional cannot adequately account for the
dispersion interaction67,68 such as
DFT functional i.e.
p
ꢀ
p
stacking and hence the dispersion corrected
u
B97X-D69 was used.
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6
S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
NAAS.
bond orbitals (NBO) analysis73 was used. Using NBO analysis, the
Next, a comparison of the 3-D optimized structure of sulfon-
amide dimer and sulfonimide dimer was carried out (Fig. 6). The 3-
D optimized structure of sulfonimide dimer indicates that it is
second order delocalization energy was calculated. The 13C NMR
chemical shift were estimated using the GIAO method57 for both
the sulfonamide and the sulfonamide tautomers of NAAS 3a-3o.
NICS aromaticity indexes58e60 (in ppm) at the ring centers (A and B)
for sulfonimide and sulfonamide tautomers of NAAS was calculated
at the GIAO/B3LYP/6-311 þ G (d,p) level. Gibbs free energy differ-
stabilized by
p-p stacking between two acridine rings and two
hydrogen bond interactions between NH$$$$O¼S (Fig. 6A). How-
ever, such dimeric state is not possible in case of sulfonamide
tautomer. Many attempts were tried to obtained dimer of sulfon-
ence between the two tautomers (DGT) was considered in all the
amide tautomer with
p-
p
stacking between two acridine rings, but
observations discussed in this article.
all attempts lead to sulfonamide dimer with different geometry
which is characterized by one NeH$$$$N- hydrogen bond interac-
4.2. Chemistry
tion and the
acridine heterocycle (Fig. 6B). Hence, in the crystal structure, the
sulfonimide dimer is preferred due to extra stabilization from p-p
stacking between two acridine rings and one extra hydrogen bond
interaction.
p-p stacking between the only one phenyl ring of
The reagents and chemicals required for the study were pro-
cured from the commercial suppliers and were used as such
without further purification. The progress of the reaction was
monitored by Thin Layer Chromatography (TLC) performed on silica
gel aluminium plates. The visualization of TLC was done by UV light.
The 1H NMR and 13C NMR spectra were recorded at 400 MHz and
100 MHz spectrometer respectively, using TMS as an internal
standard. The 1H NMR and 13C NMR spectra were recorded for
DMSO‑d6 at 2.50 ppm and 39.51 ppm respectively. Chemical shift
3. Conclusions
The present work reveals for the first time the synthesis of N-
(acridin-9-yl)arenesulfonamide as a promising pharmacophore
using palladium catalysis and sulfonamide-sulfonimide tautom-
erism therein. The 1H and 13C NMR chemical shift values of the NH
proton(s) and the C9 carbon revealed that various substituted N-
(acridin-9-yl)arenesulfonamides, obtained through the develop-
ment of a new methodology of Pd(II)-catalyzed reaction of 9-
chloroacridine with various arenesulfonamides, predominantly
exist as the sulfonimide tautomer that receives confirmatory evi-
dence in the single crystal XRD. The origin of the preference to-
wards the sulfonimide tautomer in the solid state is the
intermolecular hydrogen bonds in the dimeric form in the unit cell
(d) are reported in part per million (ppm). Coupling constants (J)
were reported in hertz (Hz). The abbreviations used to characterize
the signals are as follows: s ¼ singlet, m ¼ multiplet, d ¼ doublet, br
s ¼ broad singlet, t ¼ triplet. High resolution mass spectra were
taken using ESI-TOF method. Mass spectra were recorded using ESI
mode. Melting points were determined by using melting point
apparatus.
4.3. General synthesis of N-(acridin-9-yl)-N-(phenylsulfonyl)
benzenesulfonamide (4) using conventional method
and the p-p stacking interaction involving the acridine rings and in
the solution state due to the more polar character.
9-Aminoacridine (100 mg, 0.5 mmol) was added in three por-
tions to the warmed solution of potassium carbonate (211 mg,
1.53 mmol) in 2 mL of MeCN, 108 mg (0.61 mmol) of benzene-
sulfonyl chloride was added to the solution in 5 portions over a
period of 20 min. The reaction mixture was warmed at 60e70 ꢁC for
additional 0.5 h, and raised to 80 ꢁC. The reaction mixture was
filtered and filtrate was acidified with dilute HCl. The precipitate
observed was collected by filtration and washed with water. The
crude product 4 was recrystallized with EtOH/Hex (10%) to afford
yellow crystal, yield 15.0%. Yellow solid (44 mg, 25%). mp:
220e222 ꢁC; IR (KBr, cmꢀ1): 2924, 1376, 1173, 1084; 1H NMR
4. Experimental section
4.1. Computational methods
The quantum chemical calculations were carried out using
GAUSSIAN0970 suite of programmes. Full geometry optimizations
were carried out using DFT57 calculations using B3LYP71 B97XD68
/u
method. The basis set used was 6-311 þ G(d,p). Frequency calcu-
lations were carried out on all the structures to verify stationary
point with zero negative frequency. Implicit solvent study was
(400 MHz, DMSO‑d6)
d
¼ 8.26 (d, J ¼ 8.5 Hz, 2H), 8.01e7.84 (m, 8H),
7.75e7.62 (m, 4H), 7.46e7.40 (m, 4H); 13C NMR (100 MHz, DMSO-
performed using B3LYP/6-311
þ
G(d,p) and IEFPCM solvent
model.72 To understand the delocalization of the electron density
from the occupied (donor) NBOs to properly unoccupied (acceptor)
NBOs within the sulfonamide and sulfonimide tautomer, natural
d6)
d
¼ 149.9, 137.9, 136.4, 136.0, 131.2, 130.2, 129.9, 129.5, 127.8,
126.0, 124.4; LC-MS (ESI) m/z: [MþNa]þ Calcd for C25H18N2NaO4S2
497.0606; Found 497.05.
4.4. General synthesis of 3a-3o using palladium catalysis
A dry round bottom flask was cooled to rt under nitrogen, and
was charged with Pd2(dba)3 (3.38 mg, 0.0037 mmol), cesium car-
bonate (361 mg, 1.11 mmol), and arenesulfonamide (69 mg,
0.44 mmol). Tertiary-butanol (2 mL) was added, followed by ligand,
xantphos (6.4 mg, 0.011 mmol) and 9-chloroacridine (80 mg,
0.37 mmol). The resulting suspension was stirred at rt for 5 min,
then heated to 80 ꢁC for 12e17 h. The reaction mixture was then
cooled to rt and filtered through suction filtration. The organic
fraction was evaporated, and the resulting residue was purified by
silica gel chromatography with a hexane/Et-OAc as eluent (60:40).
4.4.1. N-(acridin-9(10H)-ylidene)benzenesulfonamide (3a)
Fig. 6. A) 3D structure of sulfonimide dimer; B) 3D structure of sulfonamide dimer of
Orange solid (69 mg, 60%). mp: 256e258 ꢁC; IR (KBr, cmꢀ1):
3n obtained from DFT study (
uB97X-D/6-311 þ G(d,p)). The red dotted lines indicate
the intermolecular hydrogen bonds.
2925,1668, 1088, 805; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.88 (br s,
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S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
7
1H), 8.71 (d, J ¼ 8.5 Hz, 2H), 8.10e7.95 (m, 2H), 7.87 (t, J ¼ 7.4 Hz,
2H), 7.73 (d, J ¼ 8.3 Hz, 2H), 7.60e7.64 (m, 3H), 7.41 (t, J ¼ 7.5 Hz,
(br s, H), 8.68 (d, J ¼ 8.5 Hz, 2H), 8.01 (d, J ¼ 8.5 Hz, 2H), 7.94e7.84
(m, 2H), 7.74 (d, J ¼ 8.5 Hz, 2H), 7.68 (d, J ¼ 8.5 Hz, 2H), 7.43 (t,
2H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 159.7, 146.0, 140.4, 134.8,
J ¼ 7.7 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 160.2, 144.9,
131.7, 129.3, 128.9, 125.8, 122.8, 118.6, 118.2. HRMS (ESI-TOF) m/z:
[MþNa]þ Calcd for C19H14N2O2SNa: 357.0668 [MþNa]þ; Found
357.0656.
140.4, 136.4, 135.0, 129.5, 128.9, 127.9, 123.0, 118.6, 118.3; HRMS
(ESI-TOF) m/z: [MþNa]þ Calcd for C19H13ClN2NaO2S: 391.0278
[MþNa]þ; Found 391.0277.
4.4.2. N-(acridin-9(10H)-ylidene)-4-methylbenzenesulfonamide
(3b)
4.4.8. N-(acridin-9(10H)-ylidene)-4-fluorobenzenesulfonamide
(3h)
Yellowish solid (46 mg, 57%). mp: 240e242 ꢁC; IR (KBr, cmꢀ1):
Yellowish solid (45 mg, 55%). mp: 220e222 ꢁC; IR (KBr, cmꢀ1):
2923, 1630, 1072, 794; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.84 (br s,
2925, 1631, 1081, 805: 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.98 (br s,
1 H), 8.70 (d, J ¼ 8.3 Hz, 2 H), 7.93e7.81 (m, 4 H), 7.71 (d, J ¼ 8.3 Hz,
1H), 8.69 (d, J ¼ 8.5 Hz, 2H), 8.07e8.04 (m, 2H), 7.87 (t, J ¼ 8.5 Hz,
2 H), 7.45e7.35 (m, 4 H), 2.42 (s, 3 H); 13C NMR (100 MHz, DMSO‑d6)
2H), 7.74 (d, J ¼ 8.3 Hz, 2H), 7.51e7.32 (m, 4H); 13C NMR (100 MHz,
d
¼ 160.0, 143.3, 141.7, 140.4, 134.8, 129.7, 129.0, 125.9, 122.7, 118.6,
DMSO‑d6)
d
¼ 163.3 (d, 1JC-F ¼ 248 Hz), 159.6, 142.0 (d, 4JC-
118.2, 21.4; HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for
F ¼ 3 Hz), 140.0, 134.4, 128.4, 128.2 (d, 3JC-F ¼ 9 Hz), 122.4, 118.1,
117.9, 115.8 (d, 2JC-F ¼ 23 Hz); HRMS (ESI-TOF) m/z: [MþNa]þ Calcd
for C19H13FN2O2SNa: 375.0573 [MþNa]þ; Found 375.0571.
C
20H16N2NaO2S: 371.0824 [MþNa]þ; Found 371.0793.
4.4.3. N-(acridin-9(10H)-ylidene)-4-propylbenzenesulfonamide
(3c)
4.4.9. N-(acridin-9(10H)-ylidene)-3,4-dichlorobenzenesulfonamide
(3i)
Yellow solid (30 mg, 35%). mp: 246e248 ꢁC; IR (KBr, cmꢀ1):
3278, 2924, 1712, 1075, 818. 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.86
Yellowish solid 51 mg, 54%). mp: 229e231 ꢁC; IR (KBr, cmꢀ1):
(br s, 1H), 8.71 (d, J ¼ 7.3 Hz, 2H), 7.97e7.81 (m, 4H), 7.78e7.66 (m,
2H), 7.35e7.47 (m, 4H), 2.67 (t., J ¼ 7.3 Hz, 2H), 1.65 (sep., J ¼ 7.3 Hz,
3280, 2923, 1630, 1097, 752: 1H NMR (400 MHz, DMSO‑d6)
d
¼ 13.14
(br s, 1 H), 8.65 (d, J ¼ 8.3 Hz, 2H), 8.13 (d, J ¼ 4 Hz, 1H), 8.01e7.84
2H), 0.92 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO‑d6)
¼ 160.8,
d
(m, 3H), 7.77 (d, J ¼ 8.5 Hz, 3H), 7.45 (t, J ¼ 7.5 Hz, 2H); 13C NMR
157.7, 140.7, 134.8, 129.8, 128.9, 125.9, 122.7, 118.6, 118.1, 32.5, 24.3,
14.1; HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for C22H20N2O2SNa:
399.1137 [MþNa]þ; Found 399.1138.
(100 MHz, DMSO‑d6)
d
¼ 160.4, 146.4, 140.4, 135.1, 134.6, 132.1,
131.9, 128.7, 127.6, 126.3, 123.2, 118.6, 118.4; HRMS (ESI-TOF) m/z:
[MþNa]þ Calcd for C19H12Cl2N2O2SNa: 424.9888 [MþNa]þ; Found
424.9889.
4.4.4. N-(acridin-9(10H)-ylidene)-2,4,6-
trimethylbenzenesulfonamide (3d)
4.4.10. N-(acridin-9(10H)-ylidene)-4-nitrobenzenesulfonamide (3j)
Yellowish solid (49 mg, 55%). mp: 252e254 ꢁC; IR (KBr, cmꢀ1):
Yellow solid (52 mg, 60%). mp: 255e257 ꢁC; IR (KBr, cmꢀ1):
2924, 1712, 1630, 1106, 807; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.75
2925, 1631, 1081, 805; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 13.15 (br s,
(br s, 1 H), 8.63 (d, J ¼ 8.3 Hz, 2H), 7.84 (t, J ¼ 6.4 Hz, 2H), 7.69 (d,
1H), 8.66 (d, J ¼ 8.0 Hz, 2H), 8.44 (d, J ¼ 8.5 Hz, 2H), 8.25 (d,
J ¼ 8.0 Hz, 2H), 7.35 (t, J ¼ 7.7 Hz, 2H), 7.03 (s, 2H), 2.29 (s, 3H), 2.56
J ¼ 8.3 Hz, 2H), 7.96e7.85 (m, 2H), 7.78 (d, J ¼ 8.3 Hz, 2H), 7.45 (t,
(s, 6 H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 140.4, 140.0, 137.1, 134.6,
J ¼ 7.7 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6)
¼ 160.4,151.4,149.2,
d
131.7, 129.1, 122.6, 118.7, 118.1, 109.6, 108.9, 22.7, 20.9; HRMS (ESI-
TOF) m/z: [MþNa]þ Calcd for C22H20N2O2SNa: 399.1137 [MþNa]þ;
Found 399.1138.
140.6, 135.1, 128.7, 127.4, 124.9, 123.2, 118.7, 118.6; HRMS (ESI-TOF)
m/z: [MþNa]þ Calcd for C19H13N3O4SNa: 402.0518 [MþNa]þ; Found
402.0518.
4.4.5. N-(acridin-9(10H)-ylidene)-4-methoxybenzenesulfonamide
(3e)
4.4.11. N-(acridin-9(10H)-ylidene)-3-nitrobenzenesulfonamide
(3k)
Yellowish solid (62 mg, 55%). mp: 211e213 ꢁC; IR (KBr, cmꢀ1):
Yellow solid (49 mg, 55%). mp: 250e252 ꢁC; IR (KBr, cmꢀ1);
2923, 1631, 1074, 828; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.81 (br s,
2935, 1641, 1061, 815; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 13.20 (br s,
1H), 8.71 (d, J ¼ 8.0 Hz, 2H), 7.93 (d, J ¼ 8.5 Hz, 2H), 7.86 (t, J ¼ 7.7 Hz,
2 H), 7.71 (d, J ¼ 8.3 Hz, 2H), 7.39 (t, J ¼ 7.7 Hz, 2H), 7.13 (d, J ¼ 8.8 Hz,
1H), 8.68e8.64 (m, 2H), 8.44 (d, J ¼ 8.0 Hz, 2H), 8.47 (d, J ¼ 6.5 Hz,
2 H), 7.98e7.87 (m, 2H), 7.79 (d, J ¼ 8.3 Hz, 2H), 7.45 (t, J ¼ 7.4 Hz,
2H), 3.86 (s, 3H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 161.7, 159.9,
2 H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 160.0, 148.1, 146.0, 141.2,
140.4, 138.2, 134.7, 129.0, 127.9, 122.7, 118.6, 118.1, 114.4, 56.0; HRMS
(ESI-TOF) m/z: [MþNa]þ Calcd for C20H16N2NaO3S: 387.0773
[MþNa]þ; Found 387.0772.
134.7, 132.1, 131.6, 128.6, 127.0, 126.2, 123.1, 121.0, 120.4, 119.3;
HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for C19H13N3O4SNa: 402.0518
[MþNa]þ; Found 402.0518.
4.4.6. N-(acridin-9(10H)-ylidene)-2,5-
4.4.12. N-(acridin-9(10H)-ylidene)-4-(trifluoromethyl)
benzenesulfonamide (3l)
dimethoxybenzenesulfonamide (3f)
Greenish solid (54 mg, 59%). mp: 223e225 ꢁC; IR (KBr, cmꢀ1):
3436, 2923, 1630, 1057, 752; 1H NMR (400 MHz, DMSO‑d6)
Yellowish solid (58 mg, 56%). mp: 230e232 ꢁC; IR (KBr, cmꢀ1):
2924, 1633, 1061, 824: 1H NMR (400 MHz, DMSO‑d6)
d
¼ 13.08 (br s,
d
¼ 12.80 (br s, 1H), 8.64 (d, J ¼ 8 Hz, 2H), 7.85 (t, J ¼ 8 Hz, 2H), 7.71
1H), 8.68 (d, J ¼ 8.5 Hz, 2H), 8.22 (d, J ¼ 8.0 Hz, 2H), 8.00 (d,
(d, J ¼ 8.3 Hz, 2H), 7.49 (s, 1H), 7.38 (t, J ¼ 7.4 Hz, 2H), 7.18e7.13 (m,
J ¼ 8.5 Hz, 2H), 7.95e7.84 (m, 2H), 7.76 (d, J ¼ 8.3 Hz, 2H), 7.44 (t,
2H), 3.78 (s, 3H), 3.66 (s, 3 H); 13C NMR (100 MHz, DMSO‑d6)
J ¼ 7.7 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 160.4, 149.7,
d
¼ 160.3, 152.5, 150.9, 140.4, 134.7, 133.9, 129.2, 122.5, 118.9, 118.4,
140.5, 135.0, 131.8, 131.4, 128.8, 126.6 (q, 3JC-F ¼ 3.7 Hz), 126.8,
118.0, 114.9, 113.3, 56.8, 56.2; HRMS (ESI-TOF) m/z: [MþNa]þ Calcd
123.1, 118.6, 118.4; HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for
for C21H18N2NaO4S: 417.0879 [MþNa]þ; Found 417.0872.
C
19H13N3O4SNa: 425.0542 [MþNa]þ; found 425.05386.
4.4.7. N-(acridin-9(10H)-ylidene)-4-chlorobenzenesulfonamide
(3g)
4.4.13. N-(acridin-9(10H)-ylidene)naphthalene-1-sulfonamide
(3m)
Dark yellow solid (43 mg, 50%). mp: 218e220 ꢁC; IR (KBr, cmꢀ1):
Yellow solid (49 mg, 55%). mp: 245e247 ꢁC; IR (KBr, cmꢀ1);
3420, 2919, 1628, 1100, 801. 1H NMR (400 MHz, DMSO‑d6) 1H NMR
3473, 2922,1632, 1076, 813; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 13.01
Please cite this article in press as: Chourasiya SS, et al., N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal
structure analysis to establish the tautomeric preferences, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.024

8
S.S. Chourasiya et al. / Tetrahedron xxx (2018) 1e8
19. Swain NA, Batchelor D, Beaudoin S, et al. J Med Chem. 2017;60:7029.
(400 MHz, DMSO‑d6)
d
¼ 12.98 (br s, 1H), 8.67 (d, J ¼ 8.3 Hz, 1H),
20. Sleebs BE, Czabotar PE, Fairbrother WJ, et al. J Med Chem. 2011;54:1914e1926.
21. Milletti F, Vulpetti A. J Chem Inf Model. 2010;50:1062e1074.
22. Topiol S, Weinstein H, Osman RJ. Med Chem. 1984;27:1531e1533.
23. Bharatam PV, Patel DS, Iqbal PJ. Med Chem. 2005;48:7615e7622.
24. Di Martino RMC, De Simone A, Andrisano V, et al. Med Chem. 2016;59:
531e544.
8.61 (d, J ¼ 8.3 Hz, 2H), 8.28 (d, J ¼ 7.8 Hz, 1H), 8.22 (d, J ¼ 8.3 Hz,
1H), 8.11 (d, J ¼ 8.3 Hz, 1H), 7.85 (t, J ¼ 6.8 Hz, 2H), 7.74 (d, J ¼ 8.5 Hz,
2H), 7.70e7.60 (m, 3 H), 7.32 (t, J ¼ 7.4 Hz, 2H); 13C NMR (100 MHz,
DMSO‑d6)
d
¼ 159.8, 140.8, 140.5, 134.8, 134.4, 133.2, 129.2, 128.9,
128.2, 127.6, 127.0, 126.2, 125.8, 125.0, 122.8, 118.7, 118.3. HRMS (ESI-
TOF) m/z: [MþNa]þ Calcd for C23H16N2NaO2S: 407.0824 [MþNa]þ;
found 407.0823.
25. Milletti F, Storchi L, Sforna G, Cross S, Cruciani GJ. Chem Inf Model. 2009;49:
68e75.
26. Guasch L, Peach ML, Nicklaus MC. J Org Chem. 2015;80:9900e9909.
27. Oellien F, Cramer J, Beyer C, Ihlenfeldt WD, Selzer PM. J Chem Inf Model.
2006;46:2342e2354.
4.4.14. N-(acridin-9(10H)-ylidene)naphthalene-2-sulfonamide (3n)
Yellowish solid (49 mg, 57%). mp: 240e242 ꢁC; IR (KBr, cmꢀ1):
3434, 2923, 1632, 1063, 745; 1H NMR (400 MHz, DMSO‑d6)
28. Pospisil P, Ballmer P, Scapozza L, Folkers GJ. Recept Signal Transduct. 2003;23:
361e371.
29. Wojnarowska Z, Paluch M. Disord. Pharm. Mater.. Wiley-VCH Verlag GmbH &
Co. KGaA; 2016:183e200.
30. Katritzky AR, Hall CD, El-Gendy BEDM, Draghici BJ. Comput Aided Mol Des.
2010;24:475e484.
d
¼ 12.92 (br s, 1H), 8.72 (d, J ¼ 8.5 Hz, 2H), 8.58 (s, 1H), 8.23e8.12
(m, 2H), 8.06 (dd, J ¼ 4.1, 7.9 Hz, 2H), 7.88 (t, J ¼ 7.7 Hz, 2H), 7.74 (d,
31. Derat E, Shaik S. J Am Chem Soc. 2006;128:8185e8198.
32. Li D, Fedeles BI, Singh V, et al. Proc Natl Acad Sci. 2014;111:E3252eE3259.
33. Sakashita R, Oka Y, Akimaru H, et al. Org Chem. 2017;82:8686e8696.
34. Glaser R, Murmann RK, Barnes CLJ. Org Chem. 1996;61:1047e1058.
35. Long S, Zhang M, Zhou P, Yu F, Parkin S, Li T. Cryst Growth Des. 2016;16:
2573e2580.
36. Chourasiya SS, Kathuria D, Nikam SS, et al. J Org Chem. 2016;81:7574e7583.
37. Ramakrishnan A, Chourasiya SS, Bharatam PV. RSC Adv. 2015;5:55938e55947.
38. Chourasiya SS, Kathuria D, Singh S, Sonwane VC, Chakraborti AK, Bharatam PV.
RSC Adv. 2015;5:80027e80038.
39. Lammertsma K, Prasad BV. J Am Chem Soc. 1994;116:642e650.
40. Chourasiya SS, Patel DR, Nagaraja CM, Chakraborti AK, Bharatam PV. New J
Chem. 2017;41:8118e8129.
41. The N-(acridin-9-yl)-benzenesulfonamide represents the only literature report
of this class (NAAS) of compounds Gurewitsch S. Zh Fiz Khim. 1962;36:
734e741.
42. Bahrami K, Khodaei MM, Soheilizad MJ. Org Chem. 2009;74:9287e9291.
43. Luci DK, Jameson JB, Yasgar A, et al. J Med Chem. 2014;57:495e506.
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46. Jafarpour M, Rezaeifard A, Aliabadi M. Appl Catal A. 2009;358:49e53.
47. Mohamed SF, Kotb ER, Abd El-Meguid EA, Awad HM. Res Chem Intermed.
2017;43:437e456.
J ¼ 8.3 Hz, 2H), 7.68 (t, J ¼ 7.8 Hz, 2H), 7.41 (t, J ¼ 7.8 Hz, 2H); 13C
NMR (100 MHz, DMSO‑d6)
d
¼ 160.0,143.1,140.5,134.8,134.2,132.3,
129.7, 129.5, 128.6, 128.2, 127.9, 127.8, 125.4, 123.0, 122.9, 118.7,
118.3. HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for C23H16N2NaO2S:
407.0824 [MþNa]þ; Found 407.0823.
4.4.15. N-(acridin-9(10H)-ylidene)quinoline-8-sulfonamide (3o)
Brown solid (49 mg, 55%). mp: 250e252 ꢁC; IR (KBr, cmꢀ1):
3408, 2960, 2921, 1662, 1096, 799; 1H NMR (400 MHz, DMSO‑d6)
d
¼ 12.76 (br s,1 H), 8.82 (d, J ¼ 1.7 Hz,1H), 8.53 (t, J ¼ 8 Hz, 4H), 8.27
(d, J ¼ 8 Hz, 1H), 7.79e7.84 (m, 3H), 7.70 (d, J ¼ 8 Hz, 2H), 7.60e7.63
(m, 1 H); 7.26 (d, J ¼ 8 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6)
d
¼ 158.0, 151.1, 140.4, 137.0, 134.6, 133.2, 129.2, 125.8, 122.3, 118.9,
117.9; HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for C22H15N3NaO2S:
408.0777 [MþNa]þ; Found 408.0775.
Acknowledgments
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49. Baffoe J, Hoe MY, Toure BB. Org Lett. 2010;12:1532e1535.
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Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.05.024.
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ꢂ
Please cite this article in press as: Chourasiya SS, et al., N-(acridin-9-yl)arenesulfonamides: Synthesis, quantum chemical studies and crystal
structure analysis to establish the tautomeric preferences, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.024