Aqueous, One-Pot, Three-Component Reaction for Efficient Synthesis of 2-[4-(Arylsulfonyl)piperazin-1-yl]-1,3-benzothiazole, -1 H -benzimidazole, or -1,3-benzoxazole Derivatives

Article abstract of DOI:10.1055/s-0036-1590972

A simple and efficient synthetic protocol has been developed involving a one-pot three-component reaction of a 2-chlorobenzazole, piperazine, and an arenesulfonyl chloride under aqueous conditions at room temperature in the absence of a catalyst, ligand, or base. By using this protocol, a variety of 2-[4-(arylsulfonyl)piperazin-1-yl]-1,3-benzothiazole, -1 H -benzimidazole, and -1,3-benzoxazole derivatives were synthesized in excellent yields.

Full text of DOI:10.1055/s-0036-1590972

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
K. Dileep, M. S. R. Murty
Letter
Synlett
Aqueous, One-Pot, Three-Component Reaction for Efficient
Synthesis of 2-[4-(Arylsulfonyl)piperazin-1-yl]-1,3-benzothiazole,
-1H-benzimidazole, or -1,3-benzoxazole Derivatives
Kommula Dileep*
M. S. R. Murty
0
0
0
0
0-
0
0
3
1-
1
9
5
6-
6
5
X
MCP Division, Discovery Building D-203, Indian Institute of
Chemical Technology, Uppal Road, Tarnaka, Hyderabad
500607, India
dilip.kommula@gmail.com
Received: 14.05.2017
Accepted after revision: 28.06.2017
Published online: 03.08.2017
increase in the number of reports on the successful use of
water as a solvent or a reaction medium for various chemi-
cal transformations.10
DOI: 10.1055/s-0036-1590972; Art ID: st-2017-d0360-l
Benzazole (benzoxazole, benzothiazole, or benzimidaz-
ole) motifs are important scaffolds in pharmaceutical re-
search, and their derivatives show diverse biological prop-
erties such as antibacterial, anticancer, HIV-1 reverse tran-
scriptase inhibition, and anti-Parkinsonian activities.11–14
Moreover, 2-aminobenzazole motifs with their substituted
cyclic amine/diamine analogues display properties such as
anti-HIV (I),15 11b-hydroxysteroid dehydrogenase inhibi-
tion (II),16 and anticancer (III) activities,17 and they have ap-
plications in the treatment of Alzheimer’s disease as well as
schizophrenia (IV) (Figure 1).18 Several protocols have been
reported for the synthesis of 2-aminoazoles through
Buchwald–Hartwig or Ullman coupling reactions of substi-
tuted amines with hetaryl halides in the presence of metal
catalysts such as Cu, Ag, Mn, Fe, Co, or Ni.19,20 Uday Kumar
et al. recently reported the metal-free amination of 2-chlo-
robenzazoles with various secondary amines in an aqueous
medium.21
Similarly, sulfonamides are a class of important scaffolds
in the pharmaceutical industry, and the sulfonamide func-
tionality is present in a range of sulfur–nitrogen heterocy-
cles such as sulfisoxazole, sulfafurazole and sulfamethoxaz-
ole.22,23 In addition, sulfonamide derivatives exhibit diverse
biological properties such as anticancer,24 antiinflammato-
ry,25 and antiviral activity.26 Among the various sulfon-
amides reported to date, piperazine sulfonamide and its de-
rivatives have received much recent attention because of
their widespread applications in medicinal chemistry as a
result of their antitumor,27 11β-hydroxysteroid dehydroge-
nase 1-inhibitory,17 antiplasmodial,28 anticonvulsant,29 fac-
tor Xa-inhibitory,30 and antimicrobial activities.31 Sulfon-
amides are usually obtained by the reaction of an amine
with a sulfonyl chloride in the presence of a base.32 We pre-
Abstract A simple and efficient synthetic protocol has been developed
involving a one-pot three-component reaction of a 2-chlorobenzazole,
piperazine, and an arenesulfonyl chloride under aqueous conditions at
room temperature in the absence of a catalyst, ligand, or base. By using
this protocol, a variety of 2-[4-(arylsulfonyl)piperazin-1-yl]-1,3-benzo-
thiazole, -1H-benzimidazole, and -1,3-benzoxazole derivatives were syn-
thesized in excellent yields.
Key words chlorobenzazoles, piperazine, arenesulfonyl chlorides,
benzothiazoles, benzoxazoles, benzimidazoles
Multicomponent reactions (MCRs) are an important
field of research in relation to the construction of libraries
of highly functionalized drug-like molecules with diverse
biological properties.1 MCRs offer the possibility of forming
multiple bonds from three or more reactants in a single
synthetic operation,2 without isolating intermediates or al-
tering the reaction conditions. In addition, MCRs obey the
principles of green chemistry and, consequently, this kind
of approach has become a powerful strategy3 for the syn-
thesis of new chemical entities.4 Furthermore, MCRs can
provide cost-effective methods because they do not involve
protection/deprotection steps and because they minimize
the number of purification processes.5
Synthetic chemists are focusing upon the use of water
rather than volatile organic solvents as a reaction medium.6
Compared with standard organic solvents, water has sever-
al interesting properties, such as hydrophobic association,
high internal solvent pressure, high cohesive-energy densi-
ty, high solvent polarity, and hydrogen bonding, all of
which can positively promote the reactivity and selectivity
of chemical reactions.7–9 Consequently, there has been an
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
K. Dileep, M. S. R. Murty
Letter
Synlett
In our continued search for the development of novel
environmentally benign protocols for the construction of
heterocyclic frameworks34, we report a simple, one-pot,
three-component protocol for the synthesis of 2-[4-(substitut-
ed arenesulfonyl)piperazin-1-yl]-1,3-benzothiazole, -1H-im-
idazole, and -1,3-oxazole scaffolds (Scheme 1).
O
O
S
N
N
N
OH
N
I
H3C
O
O
X
N
N
S
N
HN OH
O
H
N
O
X
N
X
N
Cl
S
H2O
II
N
N
S
R
Cl
O
O
X = O, S, NH, NMe
rt, 2–4 h
O
O
S
X
N
N
H
R
R1
21 examples
Yield 70–89 %
N
N
O
R2
•
Metal free
Base free
III
X = O, S, NH
X = O, S, NH, NMe
1 = H. OMe, NO2, COOH, CO(NHOH)
R2 = H, Me, t-Bu, OMe, COOH,CO(NHOH)
•
•
•
R = Ph, 4-Tol, 4-BrC6H4, 4-MeOC6H4,
2-thienyl, 1-naphthyl, 2-naphthyl
R
One-pot reaction
O
S
Atom-economic reaction
O
N
O
N
NH
Scheme 1 Synthesis of 2-[4-(substituted arylsulfonyl)piperazin-1-yl]-
1,3-benzothiazoles, -1H-imidazoles, and -1,3-oxazoles
IV
Figure 1 Biologically active derivatives of piperazine-containing benz-
azole derivatives
We began our investigation by optimizing the reaction
conditions for the synthesis of 2-(4-tosylpiperazin-1-yl)-
1,3-benzoxazole (Table 1). Initially, the reaction of tosyl
chloride (1.0 mmol), piperazine (1.0 mmol), and 2-chloro-
1,3-benzoxazole (1.0 mmol) was carried out in H2O (3 mL)
as solvent in the presence of two equivalents of base under
viously reported a base-free synthesis of various piperazine
sulfonamides by using zinc in THF under neutral condi-
tions.33
Table 1 Optimization Studies: Screening of Various Bases and Solventsa
SO2Cl
H
N
O
O
N
O
Solvent
Cl
N
N
S
Me
Temp, Time
N
N
H
O
Me
1a
2a
3a
4a
Entry
Base
K2CO3
Solvent
Yieldb (%)
1
2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CHCl3
THF
60
72
76
88
80
44
72
91
82
78
80
65
69
Na2CO3
3
KOH
4
–
5
NaOH
6c
7d
8e
9
–
–
–
–
–
–
–
–
10
11
12
13
EtOH
DMSO
DMF
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), 3a (1.0 mmol), solvent (3 mL), r.t., 2 h.
b Isolated yield.
c 2a (1.2 mmol).
d 2a (1.5 mmol).
e 2a (2.5 mmol).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
K. Dileep, M. S. R. Murty
Letter
Synlett
various reaction conditions. Among the various bases ex-
amined, K2CO3 and Na2CO3 afforded the expected products
in good yields (Table 1, entries 1 and 2), whereas KOH and
NaOH provided improved yields (entries 3 and 5). While
studying different parameters of the process, we observed
that the reaction proceeded even in the absence of base to
give a 44% yield of the product (entry 6). We also observed
that, when 1.5 equivalents of piperazine were employed,
the reaction proceeded in improved yield (entry 7), and in-
creasing the amount of piperazine to 2.0 equivalents pro-
vided the highest yield (entry 4). A further increase in the
amount of piperazine did not lead to a significant improve-
ment in the yield (entry 8).
zine (2.0 mmol), and 2-chloro-1,3-benzoxazole (1.0 mmol)
in water (3 mL) at room temperature (entry 4). The most
advantageous feature of this protocol is the purification
process, as the crude product can be purified without col-
umn chromatography by a simple wash with diethyl ether,
followed by crystallization from ethanol.
In an attempt to expand the scope of this protocol, ex-
periments were conducted with various substituted sulfo-
nyl chlorides, 2-chlorobenzazoles, and piperazine (Table 2).
This protocol was observed to be compatible with a broad
range of substituted arenesulfonyl chlorides bearing either
electron-withdrawing or electron-donating groups.
In summary, we have developed a simple and highly ef-
ficient approach to the synthesis of 2-[4-(substituted aryl-
sulfonyl)piperazin-1-yl]-1,3-benzothiazole, -1H-imidazole,
and -1,3-oxazole derivatives by a one-pot three-component
reaction, of a 2-chlorobenzazole, piperazine, and a substi-
tuted arylsulfonyl chloride in water without a catalyst.35
The salient features of this method are the scope of the sub-
strate, the absence of a catalyst, the use of water as a sol-
vent, and the ease of purification and good yields of the
product.
The effect of the solvent was also studied, and it was ob-
served that the reaction was effective in nonaqueous sol-
vent systems (Table 1, entries 9–13). Finally, the optimized
reaction conditions were chosen as TsCl (1.0 mmol), pipera-
Table 2 Synthesis of 2-[4-(Substituted arylsulfonyl)piperazin-1-yl]-1,3-
benzothiazoles, -1H-imidazoles, and -1,3-oxazolesa
H
N
O
S
Cl
S
X
N
H2O
X
N
Cl
N
N
R
O
OH
rt, 2–4 h
Funding Information
O
N
H
R
K.D. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for financial assistance through the 12th Five Year plan
projects “Affordable Cancer Therapeutics (ACT)’’ (CSC 0301) and
Entry
X
R
Yieldb (%)
1
2
O
Ph
Ph
Ph
85
79
77
88
82
85
82
76
70
76
78
74
84
80
80
86
78
79
86
89
89
“Small Molecules in Lead Exploration (SMiLE)” (CSC0111)
C
o
u
n
lc
i
of
Secnifit
a
n
d
n
I
d
uastril
Research
C(
S
C
0
3
0
1
C)
o
u
n
lc
i
of
Secnifit
a
n
d
n
I
d
uastrli
Reseacrh
C(
S
C
0
1
1
1)
S
3
NH
O
Supporting Information
4
4-Tol
Supporting information for this article is available online at
5
S
4-Tol
https://doi.org/10.1055/s-0036-1590972.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
6
NH
O
4-Tol
7
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-thienyl
2-thienyl
2-thienyl
1-naphthyl
1-naphthyl
1-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
References and Notes
8
S
9
NH
(1) (a) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev.
2014, 114, 8323. (b) Armstrong, R. W.; Combs, A. P.; Tempest, P.
A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(2) (a) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(b) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005.
(3) (a) Gu, Y. Green Chem. 2012, 14, 2091. (b) Ramachary, D. B.; Jain,
S. Org. Biomol. Chem. 2011, 9, 1277.
(4) (a) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003,
4101. (b) Bräse, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002,
10, 2415. (c) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168.
(5) (a) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259. (b) Wender,
P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London) 1997, 765.
(6) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (b) Herrmann, W.
A.; Kohlpaintner, C. W. Angew. Chem. Int. Ed. Engl. 1993, 32,
1524. (c) Li, C. J. Chem. Rev. 1993, 93, 2023. (d) Kobayashi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209. (e) Okuhara, T. Chem.
Rev. 2002, 102, 3641.
10
11
12
13
14
15
16
17
18
19
20
21
O
S
NH
O
S
NH
O
S
NH
O
S
NH
a Reaction conditions: arenesulfonyl chloride (1.0 mmol), piperazine (2.0
mmol), 2-chlorobenzazole (1.0 mmol), H2O (3 mL), r.t.
b Isolated yield.
(7) Head-Gordon, T.; Hura, G. Chem. Rev. 2002, 102, 2651.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
K. Dileep, M. S. R. Murty
Letter
Synlett
(8) (a) Lindström, U. M. Chem. Rev. 2002, 102, 2751. (b) Gawande,
M. B.; Bonifácio, V. D. B.; Luque, R.; Branco, P. S.; Varma, R. S.
Chem. Soc. Rev. 2013, 42, 5522.
(24) Bouissane, L.; El Kazzouli, S.; Léonce, S.; Pfeiffer, B.; Rakib, E. M.;
Khouili, M.; Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078.
(25) Weber, A.; Casini, A.; Heine, A.; Kuhn, D.; Supuran, C. T.;
Scozzafava, A.; Klebe, G. J. Med. Chem. 2004, 47, 550.
(26) Al-Ansary, G. H.; Ismail, M. A. H.; Abou El Ella, D. A.; Eid, S.;
Abouzid, K. A. M. Eur. J. Med. Chem. 2013, 68, 19.
(9) Hayashi, Y. Angew. Chem. Int. Ed. 2006, 45, 8103.
(10) (a) Tundo, P.; Anastas, P.; Black, D. StC.; Breen, J.; Collins, T.;
Memoli, S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl.
Chem. 2000, 72, 1207. (b) Manabe, K.; Iimura, S.; Sun, X. M.;
Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 11971. (c) Tsukinoki,
T.; Nagashima, S.; Mitoma, Y.; Tashiro, M. Green Chem. 2000, 2,
117. (d) Bigi, F.; Conforti, M. L.; Maggi, R.; Piccinno, A.; Sartori,
G. Green Chem. 2000, 2, 101.
(11) (a) Murty, M. S. R.; Ram, K. R.; Rao, R. V.; Yadav, J. S.; Murty, U. S.
N.; Kumar, K. P. Med. Chem. Res. 2011, 20, 626. (b) Kamal, A.;
Khan, M. N. A.; Reddy, K. S.; Rohini, K. Bioorg. Med. Chem. 2007,
15, 1004.
(12) (a) Murty, M. S. R.; Ram, K. R.; Rao, R. V.; Yadav, J. S.; Rao, J. V.;
Cheriyan, V. T.; Anto, R. J. Med. Chem. Res. 2011, 20, 576. (b) Kim,
J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem.
1996, 39, 992. (c) Zaharia, V.; Ignat, A.; Palibroda, N.; Ngameni,
B.; Kuete, V.; Fokunang, C. N.; Moungang, M. L.; Ngadjui, B. T.
Eur. J. Med. Chem. 2010, 45, 5080.
(27) Pingaew,
R.;
Prachayasittikul,
S.;
Ruchirawat,
S.;
Prachayasittikul, V. V. Med. Chem. Res. 2014, 23, 1768.
(28) Martyn, D. C.; Cortese, J. F.; Tyndall, E.; Dick, J.; Mazitschek, R.;
Munoz, B.; Clardy, J. Bioorg. Med. Chem. Lett. 2010, 20, 218.
(29) Harish, K. P.; Mohan, K. N.; Mallesha, L.; Prasanna kumar, B. N.
Eur. J. Med. Chem. 2013, 65, 276.
(30) Jia, Z. J.; Su, T.; Zucket, J. F.; Wu, Y.; Goldman, E. A.; Li, W.; Zhang,
P.; Clizbe, L. A.; Song, Y.; Bauer, S. M.; Huang, W.; Woolfrey, J.;
Sinha, U.; Arfsten, A. E.; Hutchaleelaha, A.; Hollenbach, S. J.;
Lambing, J. L.; Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem.
Lett. 2004, 14, 2073.
(31) Fan, H.; Xu, G.; Chen, Y.; Jiang, Z.; Zhang, S.; Yang, Y.; Ji, R. Eur. J.
Med. Chem. 2007, 42, 1137.
(32) Fieser, L. F.; Fieser, M. Fieser and Fieser’s Reagents for Organic
Synthesis;1Vo.
l
Wiley: New York, 1967, 1179.
(13) Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buckheit,
R. W. Jr.; Michejda, C. J. J. Med. Chem. 1997, 40, 4199.
(14) Azam, F.; El-gnidi, B. A.; Alkskas, I. A.; Ahmed, M. A. J. Enzyme
Inhib. Med. Chem. 2010, 25, 818.
(15) Massari, S.; Daelemans, D.; Barreca, M. L.; Knezevich, A.;
Sabatini, S.; Cecchetti, V.; Marcello, A.; Pannecouque, C.;
Tabarrini, O. J. Med. Chem. 2010, 53, 641.
(16) Hofer, S.; Kratschmar, D. V.; Schernthanner, B.; Vuorinen, A.;
Schuster, D.; Odermatt, A.; Easmon, J. Bioorg. Med. Chem. Lett.
2013, 23, 5397.
(17) Wang, L.; Kofler, M.; Brosch, G.; Melesina, J.; Sippl, W.;
Martinez, E. D.; Easmon, J. PLoS One 2015, 10, 1.
(33) Murty, M. S. R.; Rami Reddy, N.; Yadav, J. S. J. Sulfur Chem. 2006,
27, 589.
(34) (a) Kommula, D.; Madugula, S. R. M. J. Iran. Chem. Soc. 2017, 14,
1665. (b) Murty, M. S. R.; Katiki, M. R.; Rao, B. R.; Babu, N. J.;
Buddana, S. K.; Prakasham, R. S. Synth. Commun. 2014, 44, 2724.
(c) Murty, M. S. R.; Katiki, M. R.; Kommula, D. Can. Chem. Trans.
2016, 4, 47. (d) Murty, M. S. R.; Penthala, R.; Buddana, S. K.;
Prakasham, R. S.; Das, P.; Polepalli, S.; Jain, N.; Bojja, S. Med.
Chem. Res. 2014, 23, 4579.
(35) 2-[4-(Substituted arylsulfonyl)piperazin-1-yl]-1,3-benzothi-
azole, -1H-imidazole, and -1,3-oxazole Derivatives; General
Procedure
(18) Liu, K. G.; Lo, J. R.; Comery, T. A.; Zhang, G. M.; Zhang, J. Y.;
Kowal, D. M.; Smith, D. L.; Di, L.; Kerns, E. H.; Schechter, L. E.;
Robichaud, A. J. Bioorg. Med. Chem. Lett. 2009, 19, 1115.
(19) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11,
5178. (c) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am.
Chem. Soc. 2010, 132, 6900. (d) Cho, S. H.; Kim, J. Y.; Lee, S. Y.;
Chang, S. Angew. Chem. Int. Ed. 2009, 48, 9127. (e) Kim, J. Y.;
Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem. Int. Ed. 2010, 49,
9899. (f) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett.
2011, 13, 522. (g) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2011, 13, 2860.
The appropriate arenesulfonyl chloride (1.0 mmol), piperazine
(2.0 mmol), and 2-benzazole (1.0 mmol) were mixed in H2O (3
mL), and the mixture was stirred at r.t for 2–3 h until the start-
ing materials were completely consumed (TLC). The aqueous
layer was then extracted with EtOAc (3 × 10 mL), and the
organic layers were combined, washed with H2O (30 mL) and
sat. brine (30 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The resulting crude product was
washed with excess Et2O and crystallized from EtOH.
2-[4-(Phenylsulfonyl)piperazin-1-yl]-1,3-benzoxazole (Table2,
Entry 1)
1
White solid; yield: 0.29 g (85%); mp 244–246 °C; H NMR (500
(20) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068.
(21) Uday Kumar, R.; Reddy, K. H. V.; Anil Kumar, B. S. P.; Satish, G.;
Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett. 2016, 57, 637.
(22) Holland, H. L. Chem. Rev. 1988, 88, 473.
MHz, CDCl3): δ = 7.77 (dd, J = 5.3, 3.4 Hz, 2 H), 7.65 – 7.59 (m, 1
H), 7.54 (dd, J = 10.4, 4.7 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.23
(d, J = 8.0 Hz, 1 H), 7.16 (dd, J = 7.8, 1.1 Hz, 1 H), 7.03 (dd, J = 7.8,
1.1 Hz, 1 H), 3.81 (t, J = 5.1 Hz, 4 H), 3.16 (t, J = 5.1 Hz, 4 H). 13
C
NMR (126 MHz, CDCl3): δ = 168.0, 152.3, 135.4, 133.2, 130.8,
129.3, 127.7, 126.2, 121.9, 120.8, 119.4, 47.8, 45.4. ESI-MS:
m/z = 344 [M + H]+.
(23) Block, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D