Expedient synthesis of novel coumarin-based sulfonamides

Article abstract of DOI:10.1007/s13738-014-0494-7

The synthesis of novel coumarin-based sulfonamides was accomplished in good yields via InCl₃-catalyzed three-component condensation of N-(2-formylphenyl)-N-methylbenzenesulfonamides, 4-hydroxycoumarin and cyclic secondary amines in toluene.

Full text of DOI:10.1007/s13738-014-0494-7

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0494-7
ORIgINAl PAPER
Expedient synthesis of novel coumarin‑based sulfonamides
Mehdi Ghandi · Elham Babazadeh
Received: 7 May 2014 / Accepted: 20 June 2014
© Iranian Chemical Society 2014
Abstract The synthesis of novel coumarin-based sulfona-
mides was accomplished in good yields via InCl3-catalyzed
three-component condensation of N-(2-formylphenyl)-
N-methylbenzenesulfonamides, 4-hydroxycoumarin and
cyclic secondary amines in toluene.
have been used for treatment of infections [18], Alzhei-
mer’s disease [19], HIV [20] and cancer [21].
The known properties of compounds containing the
sulfonamide moieties along with the documented multiple
biological activities of coumarins in treating various cancer,
cardiovascular, and rheumatic diseases [22–30] prompted
us to prepare novel coumarin-based sulfonamides since sig-
nificant enhancement in biological activity in the presence
of two different motifs in a single molecule was expected
[31].
Keywords Coumarin-based sulfonamides ·
Sulfonamides · Coumarins · Multicomponent
Introduction
The so-called multicomponent reactions (MCRs) are one-
pot processes in which at least three or more different sim-
ple substrates react for the preparation of target materials
[1–5]. These reactions which have gained much attention
during the past years are frequently occurring not through
a single-step procedure, but rather by several sequential
steps or multicomponent cascade or domino reactions
[6–10]. Simplicity, greater efficiency and atom economy
with generation of molecular complexity and diversity in
one-pot transformation are some of the advantages of these
reactions.
Sulfonamides, described as privileged structures [11],
have a rich chemical and biological history and are an
important class of compounds in drug discovery due to
their extensive chemical and biological activities [12, 13].
Sulfonamides have been used extensively as antibacterial
[14], anti-carbonic anhydrase [15], diuretic [16] and hypo-
glycemic reagents [17]. As pharmaceutical agents, they
Experimental
general information
All commercially available chemicals and reagents were
used without further purification. Melting points were
determined with an electrothermal mode 19100 appara-
tus and were uncorrected. IR spectra were recorded on a
Shimadzu 4300 spectrophotometer, in cm−1. H and 13C-
1
NMR Spectra: Bruker AVANCE 300 spectrometer at 300
(1H) and 75 MHz (13C) and Bruker Ultrashield 400 spec-
trometer at 400 (1H) and 100 MHz (13C) using CDCl3 as
solvent and with the residual solvent signal as internal ref-
erence (CDCl3, 7.24 ppm). Mass spectra of the products
were obtained with a HP (Agilent technologies) 5937 mass
selective detector. Elemental analyses were carried out by a
CHN-Rapid Heraeus elemental analyzer (Wellesley, MA).
General procedure for the preparation of 3c–e
M. ghandi (*) · E. Babazadeh
School of Chemistry, College of Science, University of Tehran,
P.O. Box 14155 6455, Tehran, Iran
To a stirred solution containing N-methylaminoben-
zaldehydes (10 mmol) and pyridine (15 mmol), dry
CH2Cl2 (15 ml) was added dropwise to a solution of
e-mail: ghandi@khayam.ut.ac.ir
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J IRAN CHEM SOC
p-toluenesulfonyl chloride (12 mmol). The mixture was
stirred at 25 ºC for 48 h. The organic solution was then
washed with water (30 ml) and saturated sodium sulfite
solution (30 ml), and dried over Na2SO4. After removal of
the solvent under reduced pressure, the crude residue was
purified by column chromatography on silica gel (230–400
mesh; Merck), using hexane–EtOAc (5:1, 3:1 and 1:1) as
eluent to give 3c–e.
was stirred for 3 h at room temperature. After evaporation
of the solvent at reduced pressure and addition of 10 ml
of n-hexane, the solid was separated by filtration. Recrys-
tallization of the solid from ethyl acetate finally afforded
coumarin-based sulfonamides 4a–n.
(E)‑N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(pyrroli‑
din‑1‑yl)methyl)phenyl)‑N‑methyl‑2‑phenylethenesulfon‑
amide (4a) White solid, mp: 179–181 ºC, yield: 0.366 g
(71 %). IR (KBr) (υmax, cm−1): 2,983, 1,636, 1,454, 1,343,
N‑(2‑Formyl‑4‑methoxyphenyl)‑N,4‑dimethylbenzene‑
sulfonamide (3c) Yellow solid, mp: 106–108 ºC; yield:
0.220 g (69 %). IR (KBr) (υmax, cm−1): 1,682, 1,332, 1,151;
1H NMR (500 MHz, CDCl3): δH = 2.45 (s, 3H, Me), 3.21
(s, 3H, NMe), 3.86 (s, 3H, OMe), 6.59 (d, J = 8.8 Hz, 1H,
Ar), 6.98 (dd, J = 8.8, 2.6 Hz, 1H, Ar), 7.29 (d, J = 8.0 Hz,
2H, Ar), 7.44–7.47 (m, 3H, Ar), 10.41 (s, 1H, CHO); 13C
NMR (125 MHz, CDCl3): δC = 21.6, 39.1, 55.7, 110.6,
121.5, 127.4, 128.2 (2C), 129.6 (2C), 132.9, 135.9, 136.6,
144.2, 159.1, 189.9 (CO); EI-MS: m/z (%): 319 (8, M
+), 164 (100), 155 (8), 136 (86), 91 (65); Anal. calcd for
C16H17NO4S (319.09): C 60.17, H 5.37, N 4.39 %. Found:
C 60.23, H 5.46, N 4.50 %.
1
1,140; H-NMR (400 MHz, CDCl3): δH = 2.02–2.10 (m,
2H, CH2), 2.16–2.22 (m, 2H, CH2), 3.14–3.34 (m, 2H,
NCH2), 3.44 (s, 3H, NMe), 3.48–3.70 (m, 2H, NCH2),
6.11 (s, 1H, NCH), 7.00 (d, J = 15.5 Hz, 1H, CH), 7.20 (d,
J = 8.2 Hz, 1H, Ar), 7.24 (m, 1H, Ar), 7.28 (t, J = 2.0 Hz,
1H, Ar), 7.34–7.37 (m, 2H, Ar), 7.43–7.50 (m, 5H, Ar),
7.57–7.61 (m, 2H, Ar), 8.01 (dd, J = 7.8, 1.7 Hz, 1H, Ar),
8.25 (d, J = 9.7 Hz, 1H, Ar), 14.65 (bs, 1H, OH); 13C NMR
(125 MHz, CDCl3): δC = 23.9, 24.4, 41.2, 50.5, 55.1, 64.5,
95.5, 113.8, 115.9, 116.4, 121.4, 121.9, 122.9, 124.2, 124.4,
128.4 (2C), 128.5, 129.2 (2C), 131.2, 131.3, 132.6, 133.1,
141.2, 143.8, 154.0, 164.0; 174.8; EI-MS: m/z (%): 516 (3,
+
M ), 445 (56), 381 (54), 304 (82), 220 (100). Anal. calcd
N‑(2‑Formylphenyl)‑N,4‑dimethylbenzenesulfonamide
(3d) White solid, mp: 137–139 ºC; yield: 0.159 g (55 %).
IR (KBr) (υmax, cm−1): 1,682 (CO), 1,345, 1,151; 1H NMR
(500 MHz, CDCl3): δH = 2.44 (s, 3H, Me), 3.23 (s, 3H,
NMe), 6.69 (d, J = 7.8 Hz, 1H, Ar), 7.28 (d, J = 8.0 Hz,
2H, Ar), 7.41–7.48 (m, 4H, Ar), 8.00 (dd, J = 7.5, 2.4 Hz,
1H, Ar), 10.46 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3):
δC = 21.6, 38.8, 126.0, 128.2 (2C), 128.3, 128.3, 129.6 (2C),
132.6, 134.0, 134.9, 143.7, 144.3, 189.9 (CO); EI-MS: m/z
for C29H28N2O5S (516.17): C 67.42, H 5.46, N 5.42 %.
Found: C 67.12, H 5.57, N 5.66 %.
(E)‑N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(piperi‑
din‑1‑yl)methyl)phenyl)‑N‑methyl‑2‑phenylethene‑1‑sul‑
fonamide (4b) White solid, mp: 190–192 ºC, yield: 0.345 g
(65 %). IR (KBr) (υmax, cm−1): 3,065, 1,638, 1,452, 1,333,
1,135; 1H-NMR (400 MHz, CDCl3): δH = 1.60–1.68 (m, 2H,
CH2), 1.82–1.88 (m, 4H, 2CH2), 2.85-2.90 (m, 1H, NCH),
2.93–3.00 (m, 1H, NCH), 3.04-3.10 (m, 1H, NCH), 3.39 (s,
3H, NMe), 3.78-3.83 (m, 1H, NCH), 5.86 (s, 1H, CHN),
6.88 (d, J = 15.5 Hz, 1H, SO2CH), 7.05 (d, J = 8.0 Hz,
1H, Ar), 7.12–7.15 (m, 2H, Ar), 7.25 (t, J = 4.8 Hz, 1H,
Ar), 7.32 (t, J = 4.6 Hz, 1H, Ar), 7.37–7.40 (m, 5H, Ar),
7.48–7.52 (m, 2H, Ar), 7.93 (dd, J = 7.8, 1.5 Hz, 1H, Ar),
8.02 (d, J = 9.5 Hz, 1H, Ar), 14.2 (bs, 1H, OH); 13C NMR
(125 MHz, CDCl3): δC = 22.5, 24.8, 24.9, 41.1, 50.0, 54.2,
65.2, 95.2, 115.8, 116.5, 116.8, 120.8, 121.8, 122.9, 123.2,
124.3, 128.4 (2C), 128.6, 129.3 (2C), 130.6, 131.3, 132.5,
132.9, 137.2, 144.0, 154.0, 164.2, 174.8; EI-MS: m/z (%):
530 (4, M+), 445 (34), 429 (1), 262 (29), 91 (100). Anal.
calcd for C30H30N2O5S (530.19): C 67.90, H 5.70, N 5.28 %.
Found: C 68.30, H 5.92, N 5.29 %.
+
(%) : 289 (2, M ), 196 (5), 155 (10), 134 (100), 91 (85);
Anal. calcd for C15H15NO3S (289.08): C 62.27, H 5.23, N
4.84 %. Found: C 62.30, H 5.44, N 5.01 %.
N‑Ethyl‑N‑(2‑formylphenyl)‑4‑methylbenzenesulfonamide
(3e) White solid, mp: 105–107 ºC, yield: 0.152 g (50 %).
IR (KBr) (υmax, cm−1): 1,690 (CO), 1,346, 1,152; 1H NMR
(500 MHz, CDCl3): δH = 1.10 (t, J = 9.5 Hz, 3H, CH2CH3),
2.44 (s, 3H, Me), 3.33 (bs, 1H, NCH), 4.01 (bs, NCH), 6.71
(d, J = 7.8 Hz, 1H, Ar), 7.27 (d, J = 7.7 Hz, 2H, Ar), 7.42–
7.48 (m, 4H, Ar), 8.02 (dd, J = 7.6, 2.4 Hz, 1H, Ar), 10.44
(s, 1H, CHO); 13C NMR (125 MHz, CDCl3): δC = 13.8,
21.6, 46.3, 127.5, 127.9 (2C), 128.4, 128.5, 129.6 (2C),
134.1, 134.3, 136.4, 141.3, 144.0, 190.2 (CO); EI-MS: m/z
(%): 303 (1, M +), 210 (1), 155 (8), 148 (100), 91 (37). Anal.
calcd for C16H17NO3S (303.09): C 63.35, H 5.65, N 4.62 %.
Found: C 63.52, H 5.86, N 4.66 %.
tert‑Butyl
(E)‑4‑((4‑hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)
(2‑((N‑methyl‑2‑phenylvinyl)sulfonamido)phenyl)methyl)
piperazine‑1‑carboxylate (4c) White solid, mp: 216–
218 ºC, yield : 0.372 g (59 %). IR (KBr) (υmax, cm−1): 2,979,
Typical procedure for the preparation of 4a–n. To a
solution of an aldehyde (1 mmol), 4-hydroxycoumarin
(162 mg, 1 mmol) and secondary amine (1 mmol) in tolu-
ene (5 ml), InCl3 was added (10 mol %) and the mixture
1
1,683, 1,450, 1,334, 1,139; H-NMR (400 MHz, CDCl3):
δH = 1.49 (s, 9H, CMe3), 2.64 (s, 3H, NMe), 3.44–3.47
1 3

J IRAN CHEM SOC
(m, 4H, 2NCH2), 3.76–3.79 (m, 4H, 2 NCH2), 6.65 (s, 1H,
CHN), 6.83 (d, J = 15.5 Hz, 1H, SO2CH), 7.02 (dd, J = 7.8,
1.4 Hz, 1H, Ar), 7.17–7.20 (m, 2H, Ar), 7.29–7.32 (m, 2H,
Ar), 7.37 (d, J = 15.5 Hz, 1H, CH =), 7.40–7.46 (m, 5H,
Ar), 7.51 (m, 1H, Ar), 7.63 (d, J = 7.8 Hz, 1H, Ar), 7.98 (dd,
J = 7.9, 1.6 Hz, 1H, Ar), 8.17 (d, J = 8.1 Hz, 1H, Ar), 8.70
(bs, 1H, OH); 13C NMR (125 MHz, CDCl3): δC = 28.3 (3C),
35.0 (2C), 38.7, 44.4 (2C), 81.1, 100.7, 107.3, 115.8, 120.5,
123.3, 123.5, 125.0, 127.1, 127.1, 128.3 (2C), 128.8, 129.2
(2C), 130.5, 130.9, 131.2, 131.4, 132.4, 142.2, 143.7, 152.7,
166.9, 169.6, 172.0; EI-MS: m/z (%): 631 (5, M+), 430 (1),
351 (20), 206 (100), 77 (28); Anal. calcd for C34H37N3O7S
(631.24): C 64.64, H 5.90, N 6.65 %. Found: C 64.83, H
5.67, N 6.77 %.
128.5 (2C), 129.2 (2C), 131.2, 131.3,132.5, 133.7, 138.5,
143.8, 154.0, 159.8, 164.2, 174.9; EI-MS: m/z (%): 560 (2,
M+), 475 (100), 413 (3), 292 (33), 103 (32); Anal. calcd for
C31H32N2O6S (560.20): C 66.41, H 5.75, N 5.00 %. Found:
C 66.04, H 6.10, N 5.11 %.
tert‑Butyl
(5‑methoxy‑2‑((N‑methyl‑2‑phenylvinyl)sulfonamido)
phenyl)methyl)piperazine‑1‑carboxylate (4f) White
(E)‑4‑((4‑hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)
solid, mp: 219–221 ºC, yield: 0.370 g (56 %). IR (KBr)
1
(υmax, cm−1): 2,978, 1,683, 1,454, 1,337, 1,155; H-NMR
(400 MHz, CDCl3): δH = 1.41 (s, 9H, CMe3), 2.53 (s, 3H,
NMe), 3.39 (t, J = 5.2 Hz, 4H, 2NCH2), 3.64 (s, 3H, OMe),
3.74 (t, J = 5.1 Hz, 4H, 2NCH2), 6.49 (s, 1H, NCH) 6.58
(dd, J = 8.6, 3.0 Hz, 1H,Ar), 6.75 (d, J = 15.5, 1H, SO2CH),
6.84 (d, J = 8.8 Hz, 1H, Ar), 7.11 (t, J = 8.8 Hz, 1H, Ar),
7.19 (s, 1H, Ar), 7.28 (d, J = 15.5 Hz, 1H, CH =), 7.36–7.40
(m, 5H, Ar), 7.49 (t, J = 3.9 Hz, 1H, Ar), 7.91 (dd, J = 7.8,
1.6 Hz, 1H, Ar), 8.08 (dd, J = 7.9, 1.7 Hz, 1H, Ar), 8.57 (bs,
1H, OH); 13C NMR (125 MHz, CDCl3): δC = 28.3 (3C),
35.1 (2C), 38.7, 44.6 (2C), 55.2, 81.2, 100.7, 107.0, 111.9,
115.8, 115.9, 120.4, 123.3, 123.5, 125.0, 128.3, 128.4 (2C),
129.2 (2C), 130.9, 131.2, 131.4, 132.4, 141.0, 143.6, 154.0,
159.3, 163.6, 169.9, 172.0; EI-MS: m/z (%): 661 (2, M+),
475 (35), 411 (6), 380 (2), 334 (32), 57 (100); Anal. calcd
for C35H39N3O8S (661.25): C 63.52, H 5.94, N 6.35 %.
Found: C 63.44, H 6.13, N 6.23 %.
(E)‑N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(pyrroli‑
din‑1‑yl)methyl)‑4‑methoxyphenyl)‑N‑methyl‑2‑phenyle‑
thene‑1‑sulfonamide (4d) White solid, mp: 189–191 ºC,
yield: 0.377 g (69 %). IR (KBr) (υmax, cm−1): 2,989,
1
1,640, 1,464, 1,313, 1,132; H-NMR (400 MHz, CDCl3):
δH = 1.27–1.34 (m, 2H, CH2), 1.91–1.99 (m, 2H, CH2),
3.13–3.25 (m, 2H, NCH2), 3.32 (s, 3H, NMe), 3.53–3.60 (m,
2H, NCH2), 3.68 (s, 3H, OMe), 5.96 (s, 1H, NCH), 6.77 (dd,
J = 8.8, 3.0 Hz, 1H,Ar), 6.88 (d, J = 15.5, 1H, SO2CH), 7.09
(d, J = 8.8 Hz, 1H, Ar), 7.13 (t, J = 7.5 Hz, 1H, Ar), 7.20 (s,
1H, Ar), 7.35–7.41 (m, 5H, Ar), 7.48 (d, J = 15.5 Hz, 1H,
CH =), 7.50 (t, J = 2.6 Hz, 1H, Ar), 7.73 (d, J = 2.8 Hz, 1H,
Ar), 7.91 (dd, J = 7.9, 1.7 Hz, 1H, Ar), 14.42 (bs,1H, OH);
13C NMR (125 MHz, CDCl3): δC = 23.9, 24.4, 41.2, 50.5,
55.1, 55.6, 64.5, 95.5, 113.8, 115.9, 116.4, 121.4, 121.9,
122.9, 124.2, 128.4, 128.5, 129.2 (2C), 131.2 (2C), 131.3,
132.6, 133.1, 140.2, 143.8, 154.0, 159.9, 164.0, 174.8; EI-
MS: m/z (%): 546 (2, M+), 475 (16), 430 (1), 334 (16), 188
(19), 70 (100). Anal. calcd for C30H30N2O6S (546.18): C
65.92, H 5.53, N 5.12 %. Found: C 65.84, H 5.53, N 5.26 %.
N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(pyrroli‑
din‑1‑yl)methyl)phenyl)‑N,4‑dimethylbenzenesulfonamide
(4g) White solid, mp : 209–211 ºC, yield 0.398 g (79 %).
IR (KBr) (υmax, cm−1): 3,085, 1,673, 1,461, 1,335, 1,156;
1H-NMR (400 MHz, CDCl3): δH = 1.88–2.01 (m, 2H, CH2),
2.10–2.18 (m, 2H, CH2), 2.42 (s, 3H, Me), 3.06–3.28 (m,
2H, NCH2), 3.29 (s, 3H, NMe), 3.48–3.63 (m, 2H, NCH2),
6.07 (s, 1H, NCH), 6.42 (d, J = 8.0 Hz, 1H, Ar), 7.06 (m,
1H, Ar), 7.11 (d, J = 8.2 Hz, 1H, Ar), 7.15 (t, J = 7.4 Hz,
1H, Ar), 7.22 (t, J = 7.5 Hz, 1H, Ar), 7.29 (d, J = 8.1 Hz,
2H, Ar), 7.36 (m, 1H, Ar), 7.59 (d, J = 8.1 Hz, 2H, Ar),
7.91 (dd, J = 7.8,1.5 Hz, 1H, Ar), 8.13 (dd, J = 8.0, 1.3 Hz,
1H, Ar), 14.92 (bs, 1H, OH); 13C NMR (125 MHz, CDCl3):
δC = 21.7, 24.0, 24.4, 41.4, 50.2, 55.2, 64.4, 96.0, 116.4,
121.3, 122.9, 124.1, 127.0, 128.5 (2C), 129.4, 129.5, 129.6,
129.7 (2C), 131.2, 134.1, 139.2, 140.6, 144.1, 154.0, 163.3,
174.5; EI-MS: m/z (%): 504 (2, M +), 347 (70), 280 (100),
249 (58), 139 (4), 91 (80). Anal. calcd for C28H28N2O5S
(504.17): C 66.65, H 5.59, N 5.55 %. Found: C 66.65, H
5.47, N 5.71 %.
(E)‑N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(piperi‑
din‑1‑yl)methyl)‑4‑methoxyphenyl)‑N‑methyl‑2‑phenyle‑
thene‑1‑sulfonamide (4e) White solid, mp: 198–200 ºC,
yield: 0.336 g (60 %). IR (KBr) (υmax, cm−1): 2,952,
1
1,670, 1,454, 1,333, 1,136; H-NMR (400 MHz, CDCl3):
δH = 1.72–1.80 (m, 2H, CH2), 1.93–1.98 (m, 4H, 2CH2),
2.94–3.02 (m, 1H, NCH), 3.09–3.16 (m, 1H, NCH),
3.24–3.28 (m, 1H, NCH), 3.45 (s, 3H, NMe), 3.75 (s, 3H,
OMe), 3.87–3.90 (m, 1H, NCH), 5.91 (s, 1H, NCH), 6.87
(dd, J = 8.6, 3.0 Hz, 1H, Ar), 6.96 (d, J = 15.4 Hz, 1H,
SO2CH), 7.19 (d, J = 8.9 Hz, 1H, Ar), 7.20 (t, J = 8.5 Hz,
1H, Ar), 7.28 (s, 1H, Ar), 7.36–7.50 (m, 5H, Ar), 7.58 (d,
J = 15.4 Hz, 1H, CH=), 7.57 (t, J = 7.6 Hz, 1H, Ar), 7.70
(d, J = 3.0 Hz, 1H, Ar), 8.02 (dd, J = 7.8, 1.4, 1.0 Hz, 1H,
Ar), 14.15 (bs, 1H, OH); 13C NMR (125 MHz, CDCl3):
δC = 22.5, 24.9, 24.9, 41.2, 50.0, 54.2, 55.6, 65.3, 95.0,
114.4, 116.1, 116.5, 120.8, 121.9, 122.9, 124.3, 128.4,
N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(piperi‑
din‑1‑yl)methyl)phenyl)‑N,4‑dimethylbenzenesulfonamide
(4h) White solid, mp: 238–240 ºC, yield: 0.383 g (74 %).
IR (KBr) (υmax, cm−1): 2,955, 1,687, 1,450, 1,338, 1,171;
1 3

J IRAN CHEM SOC
1H-NMR (400 MHz, CDCl3): δH = 1.66–1.72 (m, 2H, CH2),
1.87–1.93 (m, 4H, 2CH2), 2.44 (s, 3H, Me), 2.57 (s, 3H,
OMe), 3.45 (t, J = 4.9 Hz, 4H, NCH2), 6.22 (d, J = 7.7 Hz,
1H,Ar), 6.72 (s, 1H, NCH), 6.99 (t, J = 7.4 Hz, 1H,Ar), 7.16
(t, J = 7.6 Hz, 1H, Ar), 7.28 (d, J = 7.5 Hz, 2H, Ar), 7.41
(m, 1H, Ar), 7.49 (m, 3H, Ar), 7.52 (d, J = 8.0 Hz, 1H, Ar),
7.64 (d, J = 7.9 Hz, 1H, Ar), 8.15–8.18 (m, 2H, Ar, OH);
13C NMR (125 MHz, CDCl3): δC = 21.6, 22.5, 23.1 (2C),
38.7, 45.8 (2C), 66.3, 100.8, 115.8, 120.8, 123.1, 124.9,
126.4, 126.6, 128.4, 128.5 (2C), 129.4 (2C), 130.3, 130.6,
131.2, 133.4, 139.3, 143.9, 152.8, 166.7, 171.8; EI-MS: m/z
(%): 519 (2, M++1), 278 (7), 249 (14), 162 (89), 120 (100),
92 (100). Anal. calcd for C29H30N2O5S (518.19): C 67.16, H
5.83, N 5.40 %. Found: C 66.99, H 6.05, N 5.34 %.
C29H30N2O6S (534.18): C 65.15, H 5.66, N 5.24 %. Found:
C 65.12, H 5.62, N 5.18 %.
N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(piperidin‑1‑yl)
methyl)‑4‑methoxyphenyl)‑N,4‑dimethylbenzenesulfona‑
mide (4k) White solid, mp: 216–218 ºC, yield: 0.395 g
(72 %). IR (KBr) (υmax, cm−1): 2,959, 1,692, 1,456, 1,340,
1
1,154; H-NMR (400 MHz, CDCl3): δH = 1.70–1.82 (m,
2H, CH2), 1.93–2.01 (m, 4H, 2CH2), 2.50 (s, 3H, Me), 3.01–
3.08 (m, 1H, NCH), 3.30–3.31 (m, 1H, NCH), 3.37 (s, 3H,
NMe), 3.45–3.48 (m, 1H, NCH), 3.73 (s, 3H, OMe), 3.86–
3.92 (m, 1H, NCH), 5.97 (s, 1H, NCH), 6.46 (d, J = 8.9 Hz,
1H, Ar), 6.69 (dd, J = 8.9, 3.0 Hz, 1H, Ar), 7.23 (m, 1H,
Ar), 7.28 (s, 1H, Ar), 7.38 (d, J = 8.0 Hz, 2H, Ar); 7.44 (m,
1H, Ar); 7.68 (d, J = 3.0 Hz, 1H, Ar), 7.70 (d, J = 8.2 Hz,
2H, Ar), 8.02 (dd, J = 7.9, 1.6 Hz, 1H, Ar), 14.27 (bs, 1H,
OH); 13C NMR (125 MHz, CDCl3): δC = 21.6, 22.5, 24.9,
25.0, 41.5, 49.8, 54.1, 55.5, 65.3, 95.2, 114.2, 115.7, 116.4,
121.4, 122.8, 124.3, 128.1, 128.4 (2C), 129.6 (2C), 131.2,
133.4, 134.4, 138.6, 144.0, 154.0, 159.6, 164.2, 174.8; EI-
MS: m/z (%): 548 (8, M +), 310 (100), 279 (78), 236 (16),
188 (86). Anal. calcd for C30H32N2O6S (548.20): C 65.68, H
5.88, N 5.11 %. Found: C 65.34, H 6.01, N 4.71 %.
tert‑Butyl 4‑((2‑(N,4‑dimethylphenylsulfonamido)phenyl)
(2,4‑dioxochroman‑3‑yl)methyl)piperazine‑1‑carboxylate
(4i) White solid, mp: 252–254 ºC, yield: 0.427 g (69 %).
IR (KBr) (υmax, cm−1): 2,977, 1,682, 1,453, 1,339, 1,153;
1H-NMR (400 MHz, CDCl3): δH = 1.48 (s, 9H, CMe3),
2.45 (s, 3H, Me), 2.56 (s, 3H, NMe), 3.46 (t, J = 5.3 Hz,
4H, 2NCH2), 3.74 (t, J = 5.3 Hz, 4H, 2NCH2), 6.23 (d,
J = 7.6 Hz, 1H, Ar), 6.72 (s, 1H, NCH), 7.01 (t, J = 7.4 Hz,
1H, Ar), 7.17 (t, J = 7.5 Hz, 1H, Ar), 7.29 (d, J = 6.9 Hz,
2H, Ar), 7.43 (t, J = 7.8 Hz, 1H, Ar), 7.47-7.51 (m, 3H, Ar),
7.62 (d, J = 7.8 Hz, 1H, Ar), 7.97 (dd, J = 7.9, 1.6 Hz, 1H,
Ar), 8.17 (d, J = 7.6 Hz, 1H, Ar), 8.76 (bs, 1H, OH); 13C
NMR (125 MHz, CDCl3): δC = 21.6, 28.3 (3C), 35.0 (2C),
38.7, 44.4 (2C), 81.0, 100.7, 107.5, 115.8, 120.6, 123.3,
125.0, 126.5, 126.7, 128.4, 128.6, 129.5, 130.2, 130.8,
131.3, 133.2, 142.2, 144.0, 152.8, 166.8, 169.3, 172.2; EI-
MS: m/z (%): 619 (4, M+), 241 (2), 197 (100), 90 (41),57
(50); Anal. calcd for C33H37N3O7S (619.24): C 63.46, H
5.82, N 6.94 %. Found: C 63.75, H 5.96, N 7.04 %.
tert‑butyl 4‑((2‑(N,4‑dimethylphenylsulfonamido)‑5‑meth‑
oxyphenyl)(4‑hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)methyl)pip‑
erazine‑1‑carboxylate (4l) White solid, mp: 230–232 ºC,
yield: 0.442 g (68 %). IR (KBr) (υmax, cm−1): 3,135, 1,683,
O
R1
R1
(a)
R1
a
b,c
N
NH
R2
N
R2
1a-b
2a-c
N‑(2‑((4‑Hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)(pyrrolidin‑1‑yl)
methyl)‑4‑methoxyphenyl)‑N,4‑dimethylbenzenesulfona‑
mide (4j) Yield 427 mg (80 %). White solid, mp: 204–
206 ºC. IR (KBr) (υmax, cm−1): 3,110, 1,671, 1,460, 1,338,
O
O
(b)
R1
R1
d
O
O
S
N
NH
Me
1
Me
3a-b
1,155; H-NMR (400 MHz, CDCl3): δH = 1.98–2.07 (m,
2a-b
R1 : H , OMe
2H, CH2), 2.12–2.27 (m, 2H, CH2), 2.48 (s, 3H, Me), 3.17–
3.28 (m, 2H, NCH2), 3.33 (s, 3H, NMe), 3.57–3.68 (m, 2H,
NCH2), 3.72 (s, 3H, OMe), 6.10 (s, 1H, NCH), 6.38 (d,
J = 8.9 Hz, 1H, Ar), 6.65 (dd, J = 8.9, 2.9 Hz,1H, Ar), 7.19
(t, J = 7.2 Hz, 1H, Ar), 7.23 (s, 1H, Ar), 7.35 (d, J = 8.0 Hz,
2H, Ar), 7.43 (t, J = 7.7 Hz, 1H, Ar), 7.66 (d, J = 8.1 Hz,
2H, Ar), 7.77 (d, J = 2.6 Hz, 1H, Ar), 7.98 (d, J = 7.8 Hz,
1H, Ar); 14.8 (bs, 1H, OH); 13C NMR (125 MHz, CDCl3):
δC = 21.6, 24.0, 24.4, 41.5, 50.2, 55.1, 55.5, 64.5, 95.7,
113.5, 115.4, 116.4, 121.4, 122.8, 124.2, 127.9, 128.4(2C),
129.6 (2C), 131.2, 133.3, 134.2, 140.4, 143.9, 154.0, 159.7,
163.7, 174.6; EI-MS: m/z (%): 534 (6, M +), 414 (2),
377 (12), 347 (14), 310 (94), 279 (100); Anal. calcd for
O
O
(c)
R1
R1
e
O
O
S
N
NH
R2
R2
3c-e
Me
2a-c
R1 : H , OMe , R2 : Me , Et
Scheme 1 a Synthesis of 2-(alkylamino)benzaldehyde 2a–c; b, c
synthesis of sulfonamide–aldehydes 3a–e. Reagents and conditions:
a MeI or EtI, 1,4-dioxane, reflux,1 h; b KOH, H2O/CH2Cl2 (1:1); c
H2O2 (35 %), 48 h; d pyridine, dry CH2Cl2, styrene sulfonyl chloride,
48 h; e pyridine, dry CH2Cl2, 4-toluenesulfonyl chloride, 48 h
1 3

J IRAN CHEM SOC
Scheme 2 Synthesis of coumarin-based sulfonamides 4a–n
1,453, 1,333, 1,150; 1H-NMR (400 MHz, CDCl3): δH = 1.40
(s, 9H, CMe3), 2.36 (s, 3H, Me), 2.44 (s, 3H, NMe), 3.39
(t, J = 5.2 Hz, 4H, 2NCH2), 3.62 (s, 3H, OMe), 3.70 (t,
J = 5.7 Hz, 4H, 2NCH2), 6.04 (d, J = 8.6 Hz, 1H, Ar), 6.40
(dd, J = 8.6, 3.0 Hz, 1H, Ar), 6.56 (s, 1H, CHN), 7.08 (m,
1H, Ar); 7.19 (s, 1H, Ar), 7.20 (d, J = 8.3 Hz, 2H, Ar), 7.34
(m, 1H, Ar), 7.42 (d, J = 8.2 Hz, 2H, Ar), 7.89 (dd, J = 8.0,
1.6 Hz, 1H, Ar), 8.08 (dd, J = 7.9, 1.6 Hz, 1H, Ar), 8.55 (bs,
1H, OH); 13C NMR (125 MHz, CDCl3): δC = 21.6, 28.3
(3C), 35.1 (2C), 38.8, 44.6 (2C), 55.2, 81.1, 100.8, 107.2,
111.5, 115.8, 115.9, 120.7, 123.3, 124.9, 127.2, 128.4 (2C),
129.5 (2C), 130.8, 131.3, 133.3, 143.7, 144.0, 154.0, 159.2,
166.9, 169.7, 172.0; EI-MS: m/z (%): 649 (7, M +), 463
(6), 308 (17), 279 (58), 236 (10), 188 (100). Anal. calcd for
C34H39N3O8S (649.25): C 62.85, H 6.05, N 6.47 %. Found:
C 63.13, H 5.98, N 6.68 %.
tert‑Butyl
4‑((2‑(N‑ethyl‑4‑methylphenylsulfonamido)
phenyl)(4‑hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)methyl)piper‑
azine‑1‑carboxylate (4n) White solid, mp: 223–225 ºC,
yield: 0.418 g (66 %). IR (KBr) (υmax, cm−1): 2,983, 1,692,
1,452, 1,343, 1,155; 1H-NMR (400 MHz, CDCl3): δH = 0.50
(t, J = 7.3 Hz, 3H, NCH2CH3), 1.40 (s, 9H, CMe3); 2.10 (s,
3H, Me), 2.94–3.15(m, 2H, NCH2), 3.39 (t, J = 5.1 Hz, 4H,
2NCH2), 3.70 (t, J = 5.3 Hz, 4H, 2NCH2), 6.30 (dd, J = 7.8,
1.4 Hz, 1H, Ar), 6.71 (s, 1H, NCH), 6.94 (m, 1H, Ar), 7.08
(m, 1H, Ar), 7.19 (d, J = 11.3 Hz, 2H, Ar), 7.33 (m, 1H,
Ar), 7.41 (m, 1H, Ar), 7.44 (d, J = 8.2 Hz, 2H, Ar), 7.65 (d,
J = 7.8 Hz, 1H, Ar), 7.87 (dd, J = 8.0, 1.7 Hz, 1H, Ar), 8.09
(dd, J = 8.1, 1.6 Hz, 1H, Ar), 8.67 (s, 1H, OH); 13C NMR
(125 MHz, CDCl3): δC = 12.5, 21.6, 28.3 (3C), 34.7, 44.5
(2C), 46.7 (2C), 81.1, 101.8, 107.1, 115.7, 120.0, 123.5,
125.0, 126.3, 128.0, 128.6, 128.6, 129.4, 130.8, 131.0,
131.3, 134.8, 142.8, 143.9, 152.7, 166.7, 170.5, 171.9; EI-
MS: m/z (%): 633 (3, M +), 604 (1), 587 (1), 91 (58), 57
(100); Anal. calcd for C34H39N3O7S (633.25): C 63.96, H
6.02, N 6.78 %. Found: C 64.13, H 6.25, N 6.82 %.
N‑Ethyl‑N‑(2‑((4‑hydroxy‑2‑oxo‑2H‑chromen‑3‑yl)
(piperidin‑1‑yl)methyl)phenyl)‑4‑methylbenzenesulfona‑
mide (4m) White solid, mp: 188–190 ºC, yield: 0.378 g
(71 %). IR (KBr) (υmax, cm−1): 3,034, 1,683, 1,454,
1
1,337, 1,155; H-NMR (400 MHz, CDCl3): δH = 0.84
(t, J = 7.1 Hz, 3H, NCH2CH3), 1.68–1.77 (m, 2H, CH2),
1.80–1.89 (m, 4H, 2CH2), 2.41 (s, 3H, Me), 2.95–3.04
(m, 2H, NCH2), 3.09–3.15 (m, 1H, NCH), 3.76–4.15 (m,
3H, NCH, NCH2), 5.82 (s, 1H, NCH), 6.75 (dd, J = 8.0,
1.3 Hz, 1H, Ar), 7.11 (d, J = 8.1 Hz, 1H, Ar), 7.14–7.19
(m, 2H, Ar), 7.26 (m, 1H, Ar), 7.30 (d, J = 8.1 Hz, 2H,
Ar), 7.37 (m, 1H, Ar), 7.71 (d, J = 8.2 Hz, 2H, Ar), 7.94
(dd, J = 7.9, 1.7 Hz, 1H, Ar), 8.13 (d, J = 7.9 Hz, 1H,
Ar), 13.96 (bs, 1H,OH); 13C NMR (125 MHz, CDCl3):
δC = 12.5, 21.6, 22.5, 24.9, 24.9, 47.5, 49.8, 53.9, 65.4,
94.5, 116.4, 122.9, 124.4, 127.9, 128.2, 129.3 (2C), 129.4,
129.8 (2C), 130.2, 131.0, 131.3, 136.7, 137.8, 138.6,
144.0, 154.0, 164.4, 175.3; EI-MS: m/z (%): 532 (4, M +),
198 (18), 169 (5), 75 (100), 63 (47), 50 (78); Anal. calcd
for C30H32N2O5S (532.20): C 67.65, H 6.06, N 5.26 %.
Found: C 67.37, H 6.32, N 5.48 %.
Results and discussion
Initially,
N-methyl-2-aminobenzaldehydes
2a–c
(Scheme 1a) and sulphonamide–aldehydes 3a–b were pre-
pared on the basis of the previously reported method start-
ing from quinolines 1a–c (Scheme 1b) in three steps [32]
and (E)-2-phenylethenesulfonyl chloride, respectively [33].
Sulphonamide–aldehydes 3c–e were then prepared from
condensation of aldehydes 2a–c and p-Toluenesulfonyl
chloride (Scheme 1c) in the presence of pyridine in CH2Cl2
within 48 h in moderate to good yields. Sulfonamide–alde-
hydes 3c–e were novel and were completely characterized
using their analytical and spectral data. For example, the 1H
NMR spectrum of 3c exhibited characteristic singlets at δ
2.45, 3.21 and 3.86 for Me, NMe and OMe together with a
singlet at 10.41 due to CHO. The 13C NMR of 3c showed
1 3

J IRAN CHEM SOC
Table 1 Isolated yields obtained for 4a–n
Entry
Sulfonamide aldehyde
Cyclic amine
Product
Yield (%)
1
71
3a
4a
2
65
3a
4b
3
59
3a
4c
4
69
60
3b
4d
4e
5
3b
6
56
3b
4f
1 3

J IRAN CHEM SOC
Table 1 continued
Entry
Sulfonamide-aldehyde
Cyclic amine
Product
Yield (%)
7
8
79
3c
4g
74
4h
3c
9
69
3c
4i
10
80
72
3d
4j
11
3d
4k
12
68
3d
4l
1 3

J IRAN CHEM SOC
Table 1 continued
Entry
Sulfonamide-aldehyde
Cyclic amine
Product
Yield (%)
13
71
4m
3e
14
66
3e
4n
Scheme 3 A plausible reaction
mechanism for the formation
of 4g
14 distinct signals including one appearing at δ 189.9 for
CO.
CHSO2), 7.48 (d, 1H, J = 15.5 Hz, CH=CSO2) and 14.42
(bs, 1H, OH) in agreement with the molecular structure.
The 13C NMR of 4d showed 28 distinct signals including
7 peaks appearing at δ 23.9–95.5 due to sp3 carbons, 21
peaks displaying at δ95.5–174.8 for sp2 carbons consistent
with the proposed structure.
As illustrated in Table 1, cyclic secondary amines such
as pyrrolidine, piperidine and piperazine-N-Boc are toler-
ated in these one-pot three-component reactions. Notably,
whereas no pronounced reduction in yields is observed in
unsubstituted or substituted sulfonamide–aldehydes (com-
pare entries 1–3 with 4–6 and 7–9 with 10–12, Table 1), a
regular decrease of 5–8 % in product yields is observed by
replacement of pyrrolidine with piperidine or piperazine-
N-Boc (compare entries 1–3, 4–6, 7–9 and 10–12, Table 1).
Such effect seems to be due the bulkier effect of the latter
two six-membered secondary amines. On the other hand,
In a model experiment, reaction of sulfonamide–
aldehyde 3a with 4-hydroxycoumarin and pyrrolidine in
CH2Cl2 using the protocol reported recently [34] failed
to show any progress based on TlC results. gratifyingly,
condensation of 3a–e with 4-hydroxycoumarin and a num-
ber of secondary cyclic amines in the presence of 10 %
InCl3 in toluene using the Rao and co-workers’ method
[35] afforded 4a–n in moderate to good yields within 3 h
at ambient temperature (Scheme 2; Table 1). The structure
of compounds 4a–n was confirmed by their analytical and
spectral data. For example, the mass spectra of 4d dis-
played the molecular ion peak at 516 consistent with the
1
molecular structure. The H NMR spectrum of 4d exhib-
ited characteristic signals at δ 3.32 (s, 3H, MeN), 3.70 (s,
3H, MeO), 5.96 (s, 1H, CHN), 6.88 (d, 1H, J = 15.5 Hz,
1 3

J IRAN CHEM SOC
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2-phenylethenesulfonyl chloride or partial participation in
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and cyclic secondary amines in toluene. An important
aspect of our syntheses which deserves some considera-
tions is the one-pot procedure, easy separation of products
by filtration, low reaction time and doing reactions under
mild conditions. These new structures broaden the chrome-
none scaffolds and many of them may represent interesting
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Acknowledgments The authors acknowledge the University of
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1 3