Synthesis and cytotoxicity of novel N-sulfonyl-1,2,3,4- tetrahydroisoquinoline thiosemicarbazone derivatives

Article abstract of DOI:10.1007/s00044-012-0025-y

The modified Pictet-Spengler reaction of phenylethylbenzene sulfonamide with a commercially available glyoxal to construct 1-benzoyl- and 1-acetyl-1,2,3,4-tetrahydroisoquinolines 9a-n has been reported. The reaction could be accomplished, regardless of th

Full text of DOI:10.1007/s00044-012-0025-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:267–277
DOI 10.1007/s00044-012-0025-y
ORIGINAL RESEARCH
Synthesis and cytotoxicity of novel N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline thiosemicarbazone derivatives
•
Ratchanok Pingaew Supaluk Prachayasittikul
•
•
Somsak Ruchirawat Virapong Prachayasittikul
Received: 10 October 2011 / Accepted: 9 March 2012 / Published online: 27 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The modified Pictet–Spengler reaction of
phenylethylbenzene sulfonamide with a commercially avail-
able glyoxal to construct 1-benzoyl- and 1-acetyl-1,2,3,4-tet-
rahydroisoquinolines 9a–n has been reported. The reaction
could be accomplished, regardless of the oxygenation pattern
on the aromatic ring, leading to the N-sulfonyltetrahy-
droisoquinoline analogs which are versatile intermediates for
the synthesis of new thiosemicarbazone analogs of 1,2,3,4-
tetrahydroisoquinoline. Bioactivity test revealed that most
thiosemicarbazones displayed cytotoxic potency against
MOLT-3 cell lines with an IC50 less than 20 lg/mL. Signifi-
cantly, the thiosemicarbazone analog of 1-acetyltetrahy-
droisoquinoline 9j was the most potent cytotoxic compound
against HuCCA-1, HepG2, and MOLT-3 cells. This study
provides the novel lead molecules for further development.
Keywords Pictet–Spengler reaction ꢀ Isoquinoline ꢀ
Thiosemicarbazone ꢀ Sulfonamide ꢀ Cytotoxicity
Introduction
Many natural products containing the isoquinoline ring
system have been received much interest due to their potent
biological activities (Aune et al., 2002; Bentley, 1998; Scott
and Williams, 2002; Siengalewicz et al., 2008). Most nota-
ble, ecteinascidin-743, displayed the potent antitumor (Aune
et al., 2002). Besides natural alkaloid, synthetic analogs of
the isoquinoline exhibited a broad range of pharmacological
activities including cytotoxic, antimicrobial, antimalarial,
and anti-HIV properties (Cho et al., 2003; Cui et al., 2006;
´
Gonzalez et al., 2007; Iwasa et al., 2001; Saitoh et al., 2006).
The sulfonamide moiety is a common pharmacophore found
in diverse biologically active molecules (Scozzafava et al.,
2003). Aryl/heteroaryl sulfonamides belonging antitumor
agent have been documented (Hu et al., 2008). A series of
isoquinolines (1) and tetrahydroisoquinolines (2–3) based
sulfonamide have been revealed to act as the protein kinase
(Blaya et al., 1998; Collins et al., 2006) and the matrix
metalloproteinase (Ma et al., 2004; Matter and Schwab,
1999; Matter et al., 2002) inhibitors, respectively (Fig. 1).
Thiosemicarbazone is known to have anticancer activity
(Beraldo and Gambino, 2004). This results from its ability to
inhibit ribonucleotide reductase (RR) (Moore et al., 1970).
For example, 3-aminopyridine-2-carboxaldehyde thiosemi-
carbazone, triapine, has been tested for clinical trials as a
cancer chemotherapeutic agent (Jiang et al., 2006).
Recently, some cytotoxic thiosemicarbazone analogs of
1-benzoylisoquinolines (4) have been reported by our group
(Pingaew et al., 2010) (Fig. 2). Keeping in view of the
medicinal importance of such heterocyclic compounds, it
R. Pingaew (&) ꢀ S. Prachayasittikul
Department of Chemistry, Faculty of Science,
Srinakharinwirot University, Bangkok 10110, Thailand
e-mail: ratchanok@swu.ac.th
S. Prachayasittikul
Center for Innovation Development and Technology Transfer,
Faculty of Medical Technology, Mahidol University,
Bangkok 10700, Thailand
S. Ruchirawat
Chulabhorn Research Institute, Bangkok 10210, Thailand
S. Ruchirawat
Chulabhorn Graduate Institute, Bangkok 10210, Thailand
V. Prachayasittikul
Department of Clinical Microbiology and Applied Technology,
Faculty of Medical Technology, Mahidol University,
Bangkok 10700, Thailand
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Med Chem Res (2013) 22:267–277
H
N
was carried out using silica gel 60 (70–230 mesh ASTM).
Analytical thin-layer chromatography (TLC) was per-
BnO
OMe
O2S
N
R
H
1
N
O
formed with silica gel 60 F254 aluminium sheets. H- and
S
13C-NMR spectra were recorded on a Bruker Avance 300
NMR spectrometer (operating at 300 MHz for 1H and
75 MHz for 13C). Mass spectra were recorded on a Bru-
ker Daltonics (microTOF). Melting points were deter-
mined using a Griffin melting point apparatus and are
uncorrected.
O2
HO
N
N
H
1 : R = H, trans-CH=CH(4-Br-Ph), CH=C(Ph)2
2
Cl
O
OH
N
S
O2
3
Benzenesulfonamides (7a–f); general procedure
Fig. 1 Representative bioactive isoquinolines based sulfonamide 1–3
A solution of phenylethylamine 5 (10 mmol) in dichloro-
methane (50 mL) was added dropwise to a stirred mixture
of benzene sulfonyl chloride 6 (10 mmol) and sodium
carbonate (14 mmol) in dichloromethane (20 mL). The
reaction mixture was stirred at room temperature overnight,
and added distilled water (20 mL). The organic phase was
separated and the aqueous phase was extracted with
dichloromethane (2 9 30 mL). The organic extracts were
combined and washed with water (30 mL). The organic
layer was dried over anhydrous sodium sulfate, filtered and
evaporated to dryness under reduced pressure. The crude
product was further purified either by recrystallization or
column chromatography.
Fig. 2 Thiosemicarbazone
analogs 4
R
N
N
R
R
H
N
NH2
S
R
4a : R=H
4b : R=OMe
prompted us to structurally modify isoquinoline analogs that
giving rise to new molecules with sulfonamide and thio-
semicarbazone moieties. In this context, 1-benzoyl- and
1-acetyl-1,2,3,4-tetrahydroisoquinolines are the targets of
choice bearing the carbonyl moiety that is easily accessible
for further functionalizations.
4-Methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-benzenesulfon-
amide (7a) Yield: 76 %; mp 136–137 °C (135–136 °C
(Ito and Tanaka, 1977)). IR (UATR): 3274, 1516, 1325,
The modified Pictet–Spengler reaction, one of the most
important strategies for the construction of tetrahydroiso-
quinoline core, has been received much interest because it
could be applied for the synthesis of both activated and
unactivated isoquinolines (Cox and Cook, 1995; Larghi
et al., 2005). The reaction could be allowed for the syn-
thesis of the target compound, 1-benzoyl-N-sulfonylte-
trahydroisoquinoline using thioketone derivatives as
glyoxal equivalents (Huang et al., 2005; Silveira et al.,
2001). However, the method was tedious by an additional
step for preparation of the masked carbonyl entities.
In this article, we present a conveniently alternative
method to directly synthesize the 1-carbonyl-N-sulfonylte-
trahydroisoquinolines by the modified Pictet–Spengler
strategy using commercially available glyoxal deriva-
tives. Many new hybrids of the target 1,2,3,4-tetra-
hydroisoquinolines with the thiosemicarbazones are reported
as well as their in vitro cytotoxic activities were evaluated.
1261, 1156 cm-1 1H NMR (CDCl3): d = 2.41 (s, 3H,
.
ArCH3), 2.70 (t, J = 6.8 Hz, 2H, ArCH2), 3.17 (t,
J = 6.8 Hz, 2H, CH2NH), 3.80, 3.84 (2 s, 6H, 2 9 OCH3),
4.45 (br s, 1H, NH), 6.56 (s, 1H, ArH), 6.61 (d,
J = 7.9 Hz, 1H, ArH), 6.75 (d, J = 8.1 Hz, 1H, ArH),
7.26 (d, 2H, J = 7.8 Hz, ArH), 7.66 (d, J = 8.1 Hz, 2H,
ArH). 13C NMR (CDCl3): d = 21.5, 35.3, 44.3, 55.8, 55.9,
111.4, 111.8, 120.8, 127.1, 129.7, 130.1, 136.9, 143.4,
147.9, 149.1. HRMS-TOF: m/z [M ? H]? calcd for
C17H22NO4S: 336.1264; found: 336.1260.
4-Nitro-N-(2-(3,4-dimethoxyphenyl)ethyl)-benzenesulfon-
amide (7b) Yield: 80 %; mp 118–119 °C (120 °C (Parai
et al., 2008)). IR (UATR): 3278, 1517, 1349, 1161 cm-1
.
1H NMR (CDCl3): d = 2.74 (t, J = 6.6 Hz, 2H, ArCH2),
3.27 (q, J = 6.6 Hz, 2H, CH2NH), 3.80, 3.83 (2 s, 6H,
2 9 OCH3), 4.65 (br t, 1H, NH), 6.56 (s, 1H, ArH), 6.59
(d, J = 8.1 Hz, 1H, ArH), 6.73 (d, J = 7.9 Hz, 1H, ArH),
7.93 (d, J = 8.5 Hz, 2H, ArH), 8.30 (d, J = 8.5 Hz, 2H,
ArH). 13C NMR (CDCl3): d = 35.5, 44.5, 55.9, 111.4,
111.8, 120.7, 124.3, 128.2, 129.5, 145.9, 148.1, 149.2,
150.0. HRMS-TOF: m/z [M ? H]? calcd for C16H19N2O6S
367.0958; found: 367.0960.
Materials and methods
Chemistry
All reagents were used as purchased from commercial sup-
pliers without further purification. Column chromatography
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Med Chem Res (2013) 22:267–277
269
4-Methoxy-N-(2-(3,4-dimethoxyphenyl)ethyl)-benzenesul-
fonamide (7c) Yield: 85 %; mp 102–103 °C. IR (UATR):
J = 8.7 Hz, 2H, ArH), 7.07 (d, J = 6.8 Hz, 2H, ArH),
7.15–7.30 (m, 3H, ArH), 7.74 (d, J = 8.7 Hz, 2H, ArH).
13C NMR (75 MHz, CDCl3): d = 35.8, 44.2, 55.6, 114.3,
126.7, 128.7, 129.2, 131.4, 137.8, 162.9. HRMS-TOF: m/
z [M ? H]? calcd for C15H18NO3S: 292.1002; found:
292.1008.
3275, 1595, 1516, 1324, 1258, 1149 cm-1 1H NMR
.
(CDCl3): d = 2.74 (t, J = 6.6 Hz, 2H, ArCH2), 3.21 (q,
J = 6.6 Hz, 2H, CH2NH), 3.84, 3.89, 3.90 (3 s, 9H,
3 9 OCH3), 4.33 (br t, 1H, NH), 6.60 (s, 1H, ArH), 6.65
(d, J = 8.1 Hz, 1H, ArH), 6.79 (d, J = 8.1 Hz, 1H, ArH),
6.97 (d, J = 7.4 Hz, 2H, ArH), 7.74 (d, J = 8.7 Hz, 2H,
ArH). 13C NMR (CDCl3): d = 35.3, 44.2, 55.6, 55.8, 55.9,
111.4, 111.7, 114.2, 120.7, 129.2, 130.1, 131.4, 147.9,
149.1, 162.8. HRMS-TOF: m/z [M ? H]? calcd for
C17H22NO5S: 352.1213; found: 352.1213.
3-Nitro-N-(2-phenylethyl)-benzenesulfonamide
(7h)
Yield: 83 %; mp 81–82 °C. IR (UATR): 3297, 1529, 1350,
1
1162 cm-1. H NMR (CDCl3): d = 2.83 (t, J = 6.7 Hz,
2H, ArCH2), 3.33 (q, J = 6.6 Hz, 2H, CH2NH), 4.65 (br t,
1H, NH), 7.09 (d, J = 6.5 Hz, 2H, ArH), 7.18–7.32 (m,
3H, ArH), 7.72 (t, J = 8.0 Hz, 1H, ArH), 8.11 (d,
J = 7.8 Hz, 1H, ArH), 8.42 (dd, J = 8.2, 1.0 Hz, 1H,
ArH), 8.61 (s, 1H, ArH). 13C NMR (CDCl3): d = 35.9,
44.4, 122.2, 127.0, 128.7, 128.9, 130.4, 132.5, 137.1,
142.3, 148.4. HRMS-TOF: m/z [M ? H]? calcd for
C14H15N2O4S: 307.0747; found: 307.0753.
4-Chloro-N-(2-(3,4-dimethoxyphenyl)ethyl)-benzenesul-
fonamide (7d) Yield: 81 %; mp 113–114 °C. IR (UATR):
3270, 1589, 1516, 1328, 1260, 1157 cm-1 1H NMR
.
(CDCl3): d = 2.74 (t, J = 6.7 Hz, 2H, ArCH2), 3.22 (br q,
2H, CH2NH), 3.84, 3.88 (2 s, 6H, 2 9 OCH3), 4.48 (br t,
1H, NH), 6.59 (s, 1H, ArH), 6.63 (d, J = 8.2 Hz, 1H,
ArH), 6.78 (d, J = 8.1 Hz, 1H, ArH), 7.47 (d, J = 8.5 Hz,
2H, ArH), 7.73 (d, J = 8.6 Hz, 2H, ArH). 13C NMR
(CDCl3): d = 35.3, 44.3, 55.8, 55.9, 111.4, 111.7, 120.7,
128.5, 129.4, 129.8, 138.4, 139.1, 148.0, 149.2. HRMS-
TOF: m/z [M ? H]? calcd for C16H19ClNO4S: 356.0718;
found: 356.0725.
1-Benzoyl- or 1-acetyl-N-benzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline (8a–n); general procedure
A mixture of sulfonamide 7 (3 mmol) and glyoxal
(3.3 mmol) in trifluoroacetic acid (30 mL) was stirred
under reflux for 2 h and then allowed to cool to room
temperature. The reaction mixture was added to 30 mL of
ice cool water and the product was extracted with CH2Cl2
(2 9 30 mL). Combined extracts were washed with satu-
rated aqueous NaHCO3, dried (Na2SO4) and evaporated to
dryness under reduced pressure. Purification by column
chromatography gave a title compound.
4-Methyl-N-(2-phenylethyl)-benzenesulfonamide
Yield: 89 %; mp 64–65 °C (63–64 °C (Ito and Tanaka,
1977)). IR (UATR): 3282, 1326, 1158 cm-1 1H NMR
(7e)
.
(CDCl3): d = 2.40 (s, 3H, ArCH3), 2.74 (t, J = 6.9 Hz,
2H, ArCH2), 3.19 (br t, 2H, CH2NH), 4.49 (br s, 1H, NH),
7.05 (d, J = 6.8 Hz, 2H, ArH), 7.16–7.29 (m, 5H, ArH),
7.67 (d, J = 8.1 Hz, 2H, ArH). 13C NMR (CDCl3):
d = 21.5, 35.8, 44.2, 126.8, 127.1, 128.7, 128.8, 129.7,
136.9, 137.7, 143.4. HRMS-TOF: m/z [M ? H]? calcd for
C15H18NO2S: 276.1053; found: 276.1077.
1-Benzoyl-6,7-dimethoxy-N-4-methylbenzenesulfonyl-1,2,
3,4-tetrahydroisoquinoline (8a) (Silveira et al., 2001) Yield:
80 %; mp 122–123 °C. IR (UATR): 1689, 1518, 1340,
1
1158 cm-1. H NMR (CDCl3): d = 2.39 (s, 3H, ArCH3),
2.65–2.94 (m, 2H, ArCH2), 3.45–3.55, 3.80–3.90 (m, 2H,
CH2N), 3.64, 3.82 (2 s, 6H, 2 9 OCH3), 6.15 (s, 1H,
CHCO), 6.43 (s, 1H, C8-ArH), 6.54 (s, 1H, C5-ArH), 7.21 (d,
J = 8.1 Hz, 2H, C300-ArH, C500-ArH), 7.50 (t, J = 7.2 Hz,
2H, C30-ArH, C50-ArH), 7.61 (t, J = 7.4 Hz, 1H, C40-ArH),
7.65 (d, J = 8.3 Hz, 2H, C200-ArH, C600-ArH), 8.07 (d,
J = 7.2 Hz, 2H, C20-ArH, C60-ArH). 13C NMR (CDCl3):
d = 21.5, 27.1, 41.7, 55.8, 60.4, 109.7, 111.7, 121.7, 126.2,
127.6, 128.7, 129.2, 129.5, 133.2, 135.3, 136.2, 143.7, 147.6,
148.5, 197.5. HRMS-TOF: m/z [M ? H]? calcd for
C25H26NO5S: 452.1526; found: 452.1521.
4-Nitro-N-(2-phenylethyl)-benzenesulfonamide
Yield: 79 %; mp 95–96 °C (95 °C (Ito and Tanaka, 1977)).
IR (UATR): 3293, 1529, 1350, 1164 cm-1 1H NMR
(7f)
.
(CDCl3): d = 2.79 (t, J = 6.7 Hz, 2H, ArCH2), 3.30 (q,
J = 6.5 Hz, 2H, CH2NH), 4.60 (br t, 1H, NH), 7.07 (d,
J = 7.0 Hz, 2H, ArH), 7.24 (br t, 3H, ArH), 7.94 (d,
J = 8.5 Hz, 2H, ArH), 8.30 (d, J = 8.6 Hz, 2H, ArH). 13
C
NMR (CDCl3): d = 35.9, 44.4, 124.4, 127.1, 128.2, 128.7,
128.9, 137.1, 145.8, 150.0. HRMS-TOF: m/z [M ? Na]?
calcd for C14H14N2NaO4S: 329.0566; found: 329.0582.
4-Methoxy-N-(2-phenylethyl)-benzenesulfonamide
Yield: 84 %. IR (UATR): 3279, 1596, 1497, 1323, 1259,
1150 cm-1 1H NMR (300 MHz, CDCl3): d = 2.75 (t,
J = 7.1 Hz, 2H, ArCH2), 3.17 (q, J = 7.1 Hz, 2H,
CH2NH), 3.84 (s, 3H, OCH3), 4.80 (br s, 1H, NH), 6.93 (d,
(7g)
1-Benzoyl-6,7-dimethoxy-N-4-nitrobenzenesulfonyl-1,2,3,
4-tetrahydroisoquinoline
(8b) Yield:
82 %;
mp
.
88–89 °C. IR (UATR): 1689, 1608, 1520, 1464, 1348,
1162 cm-1. 1H NMR (CDCl3): d = 2.70–2.90 (m, 2H,
ArCH2), 3.64–3.90 (m, 2H, CH2N), 3.54, 3.78 (2 s, 6H,
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Med Chem Res (2013) 22:267–277
2 9 OCH3), 6.34 (s, 1H, CHCO), 6.36 (s, 1H, C8-ArH),
6.53 (s, 1H, C5-ArH), 7.50 (t, J = 7.5 Hz, 2H, C30-ArH,
C50-ArH), 7.62 (t, J = 7.2 Hz, 1H, C40-ArH), 7.88 (d,
J = 8.6 Hz, 2H, C200-ArH, C600-ArH), 7.98 (d, J = 7.5 Hz,
2H, C20-ArH, C60-ArH), 8.20 (d, J = 8.6 Hz, 2H, C300-
ArH, C500-ArH). 13C NMR (CDCl3): d = 27.4, 41.8, 55.8,
55.9, 59.4, 109.8, 111.7, 121.1, 124.1, 126.1, 128.6, 129.0,
133.7, 136.3, 144.7, 147.7, 148.8, 150.0, 197.3. HRMS-
TOF: m/z [M ? Na]? calcd for C24H22N2NaO7S:
505.1040; found: 505.1050.
136.1, 143.7, 197.5. HRMS-TOF: m/z [M ? H]? calcd for
C23H22NO3S: 392.1315; found: 392.1307.
1-Benzoyl-N-4-nitrobenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline (8f) Yield: 80 %; mp 134–135 °C. IR (UATR):
1687, 1596, 1528, 1448, 1348, 1163 cm-1. 1H NMR
(CDCl3): d = 2.78–3.04 (m, 2H, ArCH2), 3.71–3.98 (m,
2H, CH2N), 6.51 (s, 1H, CHCO), 6.93–7.20 (m, 4H, C5-
ArH, C6-ArH, C7-ArH, C8-ArH), 7.52 (t, J = 7.4 Hz, 2H,
C30-ArH, C50-ArH), 7.65 (t, J = 7.4 Hz, 1H, C40-ArH),
7.87 (d, J = 8.8 Hz, 2H, C200-ArH, C600-ArH), 8.02 (d,
J = 7.4 Hz, 2H, C20-ArH, C60-ArH), 8.19 (d, J = 8.8 Hz,
2H, C300-ArH, C500-ArH). 13C NMR (CDCl3): d = 27.9,
41.9, 59.1, 124.1, 126.8, 127.2, 128.1, 128.6, 129.0, 129.1,
129.4, 129.8, 133.9, 134.0, 136.0, 144.7, 150.0, 197.1.
HRMS-TOF: m/z [M ? Na]? calcd for C22H18N2NaO5S:
445.0829; found: 445.0816.
1-Benzoyl-6,7-dimethoxy-N-4-methoxybenzenesulfonyl-1,2,
3,4-tetrahydroisoquinoline (8c) Yield: 82 %; mp
75–76 °C. IR (UATR): 1688, 1595, 1518, 1339, 1258,
1153 cm-1. 1H NMR (CDCl3): d = 2.60–2.90 (m, 2H,
ArCH2), 3.41–3.50, 3.70–3.90 (m, 2H, CH2N), 3.61, 3.76,
3.78 (3 s, 9H, 3 9 OCH3), 6.10 (s, 1H, CHCO), 6.40 (s,
1H, C8-ArH), 6.50 (s, 1H, C5-ArH), 6.84 (d, J = 8.8 Hz,
2H, C300-ArH, C500-ArH), 7.46 (t, J = 7.3 Hz, 2H, C30-
ArH, C50-ArH), 7.57 (t, J = 7.3 Hz, 1H, C40-ArH), 7.65
(d, J = 8.8 Hz, 2H, C200-ArH, C600-ArH), 8.05 (d,
J = 7.4 Hz, 2H, C20-ArH, C60-ArH). 13C NMR (CDCl3):
d = 27.1, 41.6, 55.6, 55.8, 60.5, 109.7, 111.7, 114.1, 121.8,
126.2, 128.7, 129.3, 129.8, 133.2, 136.2, 147.6, 148.5,
163.1, 197.6. HRMS-TOF: m/z [M ? H]? calcd for
C25H26NO6S: 468.1475; found: 468.1488.
1-Benzoyl-N-4-methoxybenzenesulfonyl-1,2,3,4-tetrahy-
droisoquinoline (8g) Yield: 84 %; mp 113–114 °C. IR
1
(UATR): 1688, 1595, 1497, 1337, 1260, 1155 cm-1. H
NMR (CDCl3): d = 2.70–3.02 (m, 2H, ArCH2), 3.46–3.92
(m, 2H, CH2N), 3.79 (s, 3H, OCH3), 6.30 (s, 1H, CHCO),
6.82 (d, J = 8.8 Hz, 2H, C300-ArH, C500-ArH), 6.93–7.18
(m, 4H, C5-ArH, C6-ArH, C7-ArH, C8-ArH), 7.47 (t,
J = 7.5 Hz, 2H, C30-ArH, C50-ArH), 7.58 (t, J = 7.4 Hz,
1H, C40-ArH), 7.65 (d, J = 8.8 Hz, 2H, C200-ArH, C600-
ArH), 8.06 (d, J = 7.4 Hz, 2H, C20-ArH, C60-ArH). 13C
NMR (CDCl3): d = 27.7, 41.6, 55.6, 59.9, 114.1, 126.5,
127.1, 127.7, 128.7, 129.3, 129.7, 130.1, 130.3, 133.3,
134.2, 136.0, 163.0, 197.5. HRMS-TOF: m/z [M ? H]?
calcd for C23H22NO4S: 408.1264; found: 408.1276.
1-Benzoyl-6,7-dimethoxy-N-4-chlorobenzenesulfonyl-1,2,3,
4-tetrahydroisoquinoline (8d) Yield: 75 %; mp 110–
111 °C. IR (UATR): 1688, 1584, 1518, 1448, 1345,
1161 cm-1 1H NMR (CDCl3): d = 2.66–2.90 (m, 2H,
.
ArCH2), 3.50–3.90 (m, 2H, CH2N), 3.63, 3.83 (2 s, 6H,
2 9 OCH3), 6.24 (s, 1H, CHCO), 6.42 (s, 1H, C8-ArH),
6.55 (s, 1H, C5-ArH), 7.38 (d, J = 8.5 Hz, 2H, C300-ArH,
C500-ArH), 7.52 (t, J = 7.5 Hz, 2H, C30-ArH, C50-ArH),
7.63 (t, J = 7.2 Hz, 1H, C40-ArH), 7.68 (d, J = 8.6 Hz,
2H, C200-ArH, C600-ArH), 8.05 (d, J = 7.6 Hz, 2H, C20-
ArH, C60-ArH). 13C NMR (CDCl3): d = 27.1, 41.6, 55.8,
55.9, 59.9, 109.7, 111.7, 121.5, 126.2, 128.5, 128.8, 128.9,
129.2, 133.4, 136.2, 137.1, 139.4, 147.7, 148.7, 197.4.
HRMS-TOF: m/z [M ? H]? calcd for C24H23ClNO5S:
472.0980; found: 472.0996.
1-Acetyl-6,7-dimethoxy-N-4-methylbenzenesulfonyl-1,2,
3,4-tetrahydroisoquinoline (8h) Yield: 87 %. IR
(UATR): 1714, 1609, 1514, 1464, 1343, 1229, 1160 cm-1
.
1H NMR (CDCl3): d = 2.21 (s, 3H, CH3CO), 2.42 (s, 3H,
ArCH3), 2.65–2.88 (m, 2H, ArCH2), 3.00–3.12, 3.97–4.06
(m, 2H, CH2N), 3.80, 3.83 (2 s, 6H, 2 9 OCH3), 4.70 (s,
1H, CHCO), 6.57 (s, 1H, C8-ArH), 6.63 (s, 1H, C5-ArH),
7.33 (d, J = 8.0 Hz, 2H, C30-ArH, C50-ArH), 7.72 (d,
J = 8.2 Hz, 2H, C20-ArH, C60-ArH). 13C NMR (CDCl3):
d = 21.5, 24.8, 28.5, 43.0, 55.9, 56.0, 66.9, 109.7, 111.2,
120.3, 126.2, 127.9, 129.8, 132.9, 144.2, 148.0, 148.7,
205.8. HRMS-TOF: m/z [M ? H]? calcd for C20H24NO5S:
390.1370; found: 390.1382.
1-Benzoyl-N-4-methylbenzenesulfonyl-1,2,3,4-tetrahydro-
isoquinoline (8e) (Huang et al., 2005; Silveira et al.,
2001) Yield: 85 %; mp 119–120 °C. IR (UATR): 1687,
1596, 1448, 1337, 1158 cm-1
.
1H NMR (CDCl3):
d = 2.34 (s, 3H, ArCH3), 2.70–3.02 (m, 2H, ArCH2),
3.50–3.60, 3.82–3.95 (2 m, 2H, CH2N), 6.31 (s, 1H,
CHCO), 6.92–7.20 (m, 6H, ArH), 7.43–7.64 (m, 5H, ArH),
8.06 (d, J = 7.5 Hz, 2H, C20-ArH, C60-ArH). 13C NMR
(CDCl3): d = 21.5, 27.7, 41.6, 59.8, 126.5, 127.1, 127.5,
127.7, 128.8, 129.3, 129.5, 130.3, 133.4, 134.2, 135.5,
1-Acetyl-6,7-dimethoxy-N-4-nitrobenzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline (8i) Yield: 82 %; mp 75–76 °C.
IR (UATR): 1717, 1608, 1529, 1515, 1465, 1349,
1
1164 cm-1. H NMR (CDCl3): d = 2.20 (s, 3H, CH3CO),
2.60–3.05 (m, 2H, ArCH2), 3.00–3.12, 3.88–4.00 (m, 2H,
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271
CH2N), 3.80 (s, 6H, 2 9 OCH3), 4.88 (s, 1H, CHCO), 6.54
(s, 1H, C8-ArH), 6.63 (s, 1H, C5-ArH), 8.00 (d,
J = 8.7 Hz, 2H, C20-ArH, C60-ArH), 8.34 (d, J = 8.7 Hz,
2H, C30-ArH, C50-ArH). 13C NMR (CDCl3): d = 25.2,
28.1, 42.9, 55.9, 56.1, 66.6, 109.9, 111.3, 120.0, 124.4,
125.9, 128.9, 142.6, 148.2, 149.1, 150.4, 204.4. HRMS-
TOF: m/z [M ? H]? calcd for C19H21N2O7S: 421.1030;
found: 421.1058.
d = 2.23 (s, 3H, CH3CO), 2.73–2.97 (m, 2H, ArCH2),
3.03–3.17, 3.95–4.05 (m, 2H, CH2N), 3.86 (s, 3H, OCH3),
4.88 (s, 1H, CHCO), 6.98 (d, J = 8.9 Hz, 2H, C30-ArH,
C50-ArH), 7.08–7.23 (m, 4H, C5-ArH, C6-ArH, C7-ArH,
C8-ArH), 7.78 (d, J = 8.9 Hz, 2H, C20-ArH, C60-ArH).
13C NMR (CDCl3): d = 25.2, 28.8, 42.8, 55.6, 67.1, 114.4,
127.0, 127.5, 127.9, 128.9, 130.0, 134.0, 163.4, 205.3.
HRMS-TOF: m/z [M ? H]? calcd for C18H20NO4S:
346.1108; found: 346.1117.
1-Acetyl-6,7-dimethoxy-N-4-methoxybenzenesulfonyl-1,2,
3,4-tetrahydroisoquinoline (8j) Yield: 72 %. IR (UATR):
1714, 1595, 1514, 1464, 1343, 1258, 1155 cm-1. 1H NMR
(CDCl3): d = 2.21 (s, 3H, CH3CO), 2.65–2.88 (m, 2H,
ArCH2), 3.00–3.12, 3.95–4.05 (m, 2H, CH2N), 3.81, 3.84,
3.87 (3 s, 9H, 3 9 OCH3), 4.69 (s, 1H, CHCO), 6.57 (s,
1H, C8-ArH), 6.63 (s, 1H, C5-ArH), 7.00 (d, J = 7.0 Hz,
2H, C30-ArH, C50-ArH), 7.78 (d, J = 7.0 Hz, 2H, C20-
ArH, C60-ArH). 13C NMR (CDCl3): d = 24.8, 28.5, 43.0,
55.6, 55.9, 56.0, 67.0, 109.7, 111.2, 114.4, 120.3, 126.2,
127.4, 130.1, 148.0, 148.7, 163.4, 205.9. HRMS-TOF:
m/z [M ? H]? calcd for C20H24NO6S: 406.1319; found:
406.1328.
1-Acetyl-N-3-nitrobenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline (8n) Yield: 85 %; mp 129–130 °C. IR
1
(UATR): 1720, 1606, 1531, 1495, 1350, 1168 cm-1. H
NMR (CDCl3): d = 2.20 (s, 3H, CH3CO), 2.70–3.02 (m,
2H, ArCH2), 3.19–3.30, 3.85–3.99 (m, 2H, CH2N), 5.18 (s,
1H, CHCO), 7.00–7.38 (m, 4H, C5-ArH, C6-ArH, C7-ArH,
C8-ArH), 7.70 (t, J = 8.0 Hz, 1H, C50-ArH), 8.12 (d,
J = 7.8 Hz, 1H, C60-ArH), 8.40 (d, J = 8.1 Hz, 1H, C40-
ArH), 8.62 (s, 1H, C20-ArH). 13C NMR (CDCl3): d = 25.9,
28.1, 42.8, 66.8, 122.7, 127.2, 127.4, 127.8, 128.5, 128.9,
129.1, 130.5, 133.1, 133.9, 139.8, 148.3, 203.8. HRMS-
TOF: m/z [M ? H]? calcd for C17H17N2O5S: 361.0853;
found: 361.0867.
1-Acetyl-N-4-methylbenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline (8k) Yield: 85 %. IR (UATR): 1717, 1599,
.
1348, 1163 cm-1 1H NMR (CDCl3): d = 2.24 (s, 3H,
1-Benzoyl- or 1-Acetyl-N-benzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline thiosemicarbazone (9a–n); General
procedure
CH3CO), 2.41 (s, 3H, ArCH3), 2.73–2.99 (m, 2H, ArCH2),
3.02–3.18, 3.96–4.07 (m, 2H, CH2N), 4.91 (s, 1H, CHCO),
7.08–7.24 (m, 4H, C5-ArH, C6-ArH, C7-ArH, C8-ArH),
7.32 (d, J = 8.0 Hz, 2H, C30-ArH, C50-ArH), 7.72 (d,
J = 8.3 Hz, 2H, C20-ArH, C60-ArH). 13C NMR (CDCl3):
d = 21.4, 25.2, 28.8, 42.8, 66.8, 127.0, 127.5, 127.8,
128.0, 128.9, 129.8, 134.0, 144.2, 205.7. HRMS-TOF:
m/z [M ? H]? calcd for C18H20NO3S: 330.1158; found:
330.1146.
Conc. hydrochloric acid (3 drops) were added to a mixture
of isoquinoline (1 mmol) and thiosemicarbazide (1 mmol)
in absolute ethanol (15 mL) and the resulting mixture was
then heated under reflux for 2 h. The separated crystalline
solid was filtered off. The crude product was further puri-
fied either by recrystallization or column chromatography.
1-Acetyl-N-4-nitrobenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline (8l) Yield: 89 %; mp 50–51 °C. IR (UATR):
1-Benzoyl-6,7-dimethoxy-N-4-methylbenzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline thiosemicarbazone (9a) Yield:
76 %; mp 236–237 °C. IR (UATR): 3440, 3345, 1591, 1517,
1468, 1341, 1156 cm-1. 1H NMR (DMSO-d6): d = 2.38 (s,
3H, ArCH3), 2.20–2.50 (m, 2H, ArCH2), 2.94–3.08,
3.27–3.40 (m, 2H, CH2N), 3.64, 3.70 (2 s, 6H, 2 9 OCH3),
5.72 (s, 1H, CHN), 6.65 (s, 1H, C8-ArH), 6.80–6.90 (m, 3H,
C5-ArH, C30-ArH, C50-ArH), 7.36 (d, 2H, J = 8.1 Hz, C300-
ArH, C500-ArH), 7.40–7.52 (m, 3H, C20-ArH, C40-ArH, C60-
ArH), 7.65 (d, 2H, J = 8.3 Hz, C200-ArH, C600-ArH), 7.88,
8.44, 8.60 (3 s, 3H, NH). 13C NMR (DMSO-d6): d = 21.5,
27.1, 41.4, 55.8, 56.0, 61.0, 111.4, 112.0, 123.0, 126.9, 127.5,
128.3, 129.7, 130.2, 131.0, 136.4, 144.0, 147.7, 148.6, 152.0,
178.9. HRMS-TOF: m/z [M ? H]? calcd for C26H29
N4O4S2: 525.1625; found: 525.1628.
1720, 1606, 1528, 1495, 1348, 1164 cm-1 1H NMR
.
(CDCl3): d = 2.25 (s, 3H, CH3CO), 2.73–3.08 (m, 2H,
ArCH2), 3.14–3.27, 3.90–4.01 (m, 2H, CH2N), 5.16 (s, 1H,
CHCO), 7.09–7.27 (m, 4H, C5-ArH, C6-ArH, C7-ArH,
C8-ArH), 8.02 (d, J = 8.8 Hz, 2H, C20-ArH, C60-ArH),
8.36 (d, J = 8.8 Hz, 2H, C30-ArH, C50-ArH). 13C NMR
(CDCl3): d = 25.7, 28.3, 42.8, 66.8, 124.4, 127.2, 127.7,
128.5, 128.8, 128.9, 133.8, 143.1, 150.3, 203.9. HRMS-
TOF: m/z [M ? H]? calcd for C17H17N2O5S: 361.0853;
found: 361.0865.
1-Acetyl-N-4-methoxybenzenesulfonyl-1,2,3,4-tetrahydro-
isoquinoline (8m) Yield: 75 %. IR (UATR): 1717, 1595,
1497, 1345, 1258, 1155 cm-1
.
1H NMR (CDCl3):
123

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Med Chem Res (2013) 22:267–277
1-Benzoyl-6,7-dimethoxy-N-4-nitrobenzenesulfonyl-1,2,3,4-tet-
rahydroisoquinoline thiosemicarbazone (9b) Yield: 82 %;
mp 123–124 °C. IR (UATR): 3456, 3336, 1570, 1519,
ArCH3), 2.30–2.60 (m, 2H, ArCH2), 3.00–3.60 (m, 2H,
CH2N), 5.80 (s, 1H, CHN), 6.73–7.50 (m, 11H, C5-ArH,
C6-ArH, C7-ArH, C8-ArH, C20-ArH, C30-ArH, C40-ArH,
C50-ArH, C60-ArH, C300-ArH, C500-ArH), 7.66 (d,
J = 8.2 Hz, 2H, C200-ArH, C600-ArH), 7.83, 8.47, 8.61 (3 s,
3H, NH). 13C NMR (DMSO-d6): d = 21.5, 27.5, 41.5,
61.5, 126.8, 127.6, 128.1, 128.2, 129.2, 129.7, 130.3,
130.4, 130.9, 131.6, 134.7, 136.1, 144.1, 151.7, 178.9.
HRMS-TOF: m/z [M ? H]? calcd for C24H25N4O2S2:
465.1413; found: 465.1427.
1477, 1350, 1170 cm-1
.
1H NMR (DMSO-d6):
d = 2.35–2.60 (m, 2H, ArCH2), 3.14–3.70 (m, 2H, CH2N),
3.58, 3.68 (2 s, 6H, 2 9 OCH3), 5.81 (s, 1H, CHN), 6.65
(s, 1H, C8-ArH), 6.70 (s, 1H, C5-ArH), 6.92–7.00,
7.41–7.50 (m, 5H, C20-ArH, C30-ArH, C40-ArH, C50-ArH,
C60-ArH), 7.58 (s, 1H, NH), 8.01 (d, J = 8.6 Hz, 2H, C200-
ArH, C600-ArH), 8.31 (d, J = 8.6 Hz, 2H, C300-ArH, C500-
ArH), 8.55, 8.59 (2 s, 2H, NH2). 13C NMR (DMSO-d6):
d = 27.1, 41.6, 55.9, 61.0, 111.4, 112.1, 122.9, 125.0,
126.5, 128.3, 129.0, 129.8, 130.4, 131.1, 144.8, 147.5,
148.7, 150.2, 151.4, 179.0. HRMS-TOF: m/z [M ? H]?
calcd for C25H26N5O6S2: 556.1319; found: 556.1310.
1-Benzoyl-N-4-nitrobenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9f) Yield: 57 %; mp
226–228 °C. IR (UATR): 3428, 3270, 1600, 1528, 1473,
1348, 1153 cm-1 1H NMR (DMSO-d6): d = 2.42–2.70
.
(m, 2H, ArCH2), 3.20–3.60 (m, 2H, CH2N), 5.90 (s, 1H,
CHN), 6.85–7.50 (m, 9H, C5-ArH, C6-ArH, C7-ArH, C8-
ArH, C20-ArH, C30-ArH, C40-ArH, C50-ArH, C60-ArH),
7.58 (s, 1H, NH), 8.03 (d, J = 8.8 Hz, 2H, C200-ArH, C600-
ArH), 8.30 (d, J = 8.8 Hz, 2H, C300-ArH, C500-ArH), 8.59,
8.63 (2 s, 2H, NH). 13C NMR (DMSO-d6): d = 27.5, 41.7,
61.5, 125.0, 126.7, 128.3, 129.0, 129.3, 129.8, 130.5,
131.0, 131.5, 134.4, 144.5, 150.2, 151.2, 179.1. HRMS-
TOF: m/s [M ? H]? calcd for C23H22N5O4S2: 496.1108;
found: 496.1116.
1-Benzoyl-6,7-dimethoxy-N-4-methoxybenzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline
77 %; mp 222–225 °C. IR (UATR): 3472, 3348, 1579,
1467, 1339, 1155 cm-1 1H NMR (DMSO-d6):
thiosemicarbazone
(9c) Yield:
.
d = 2.20–2.50 (m, 2H, ArCH2), 2.92–3.08, 3.26–3.40 (m,
2H, CH2N), 3.64, 3.69, 3.82 (3 s, 9H, 3 9 OCH3), 5.70 (s,
1H, CHN), 6.64 (s, 1H, C8-ArH), 6.80–6.85 (m, 3H, C5-
ArH, C30-ArH, C50-ArH), 7.04 (d, J = 8.7 Hz, 2H, C300-
ArH, C500-ArH), 7.38–7.50 (m, 3H, C20-ArH, C40-ArH,
C60-ArH), 7.69 (d, J = 8.7 Hz, 2H, C200-ArH, C600-ArH),
7.87, 8.42, 8.59 (3 s, 3H, NH). 13C NMR (DMSO-d6):
d = 27.2, 41.4, 55.8, 56.0, 56.2, 61.0, 111.3, 112.0, 114.9,
123.0, 126.9, 128.3, 129.7, 129.8, 130.3, 130.8, 131.1,
147.7, 148.6, 152.0, 163.1, 178.9. HRMS-TOF: m/
z [M ? H]? calcd for C26H29N4O5S2: 541.1574; found:
541.1577.
1-Benzoyl-N-4-methoxybenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9g) Yield: 67 %; mp
163–164 °C. IR (UATR): 3420, 3346, 1594, 1471, 1334,
1259, 1153 cm-1 1H NMR (DMSO-d6): d = 2.30–2.60
.
(m, 2H, ArCH2), 2.99–3.40 (m, 2H, CH2N), 3.81 (s, 3H,
OCH3), 5.79 (s, 1H, CHN), 6.76 (br d, J = 6.6 Hz, 2H, C5-
ArH, C8-ArH), 7.00–7.50 (m, 9H, C6-ArH, C7-ArH, C20-
ArH, C30-ArH, C40-ArH, C50-ArH, C60-ArH, C300-ArH,
C500-ArH), 7.71 (d, J = 8.8 Hz, 2H, C200-ArH, C600-ArH),
7.83, 8.46, 8.61 (3 s, 3H, NH). 13C NMR (DMSO-d6):
d = 27.6, 41.4, 56.2, 61.5, 114.9, 126.8, 128.0, 128.2,
129.2, 129.7, 129.8, 130.4, 130.5, 131.0, 131.7, 134.8,
151.8, 163.1, 178.9. HRMS-TOF: m/z [M ? H]? calcd for
C24H25N4O3S2: 481.1363; found: 481.1380.
1-Benzoyl-6,7-dimethoxy-N-4-chlorobenzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline thiosemicarbazone (9d) Yield:
75 %; mp 218–220 °C. IR (UATR): 3453, 3342, 1581,
1518, 1465, 1355, 1227, 1166 cm-1. 1H NMR (DMSO-d6):
d = 2.25–2.50 (m, 2H, ArCH2), 3.00–3.45 (m, 2H, CH2N),
3.63, 3.70 (2 s, 6H, 2 9 OCH3), 5.75 (s, 1H, CHN), 6.65
(s, 1H, C8-ArH), 6.81 (s, 1H, C5-ArH), 6.85–6.94,
7.41–7.50 (m, 5H, C20-ArH, C30-ArH, C40-ArH, C50-ArH,
C60-ArH), 7.60 (d, J = 8.7 Hz, 2H, C200-ArH, C600-ArH),
7.76 (d, J = 8.6 Hz, 2H, C300-ArH, C500-ArH), 7.77, 8.54,
8.59 (3 s, 3H, NH). 13C NMR (DMSO-d6): d = 27.0, 41.4,
55.8, 56.0, 61.1, 111.4, 112.0, 122.9, 126.7, 128.3, 129.4,
129.7, 129.9, 130.4, 131.1, 138.2, 138.5, 147.6, 148.7,
151.7, 179.0. HRMS-TOF: m/z [M ? H]? calcd for
C25H26ClN4O4S2: 545.1078; found: 545.1086.
1-Acetyl-6,7-dimethoxy-N-4-methylbenzenesulfonyl-1,2,3,4-tet-
rahydroisoquinoline thiosemicarbazone (9h) Yield: 67 %;
mp 172–174 °C. IR (UATR): 3444, 3329, 1581, 1514,
1
1341, 1158 cm-1. H NMR (DMSO-d6): d = 1.78 (s, 3H,
CH3CN), 2.35 (s, 3H, ArCH3), 2.50–2.80 (m, 2H, ArCH2),
3.10–3.40 (m, 2H, CH2N), 3.63, 3.67 (2 s, 6H, 2 9 OCH3),
5.19 (s, 1H, CHN), 6.64 (s, 1H, C8-ArH), 6.76 (s, 1H, C5-
ArH), 7.35 (d, J = 8.0 Hz, 2H, C30-ArH, C50-ArH), 7.43
(s, 1H, NH), 7.65 (d, J = 8.0 Hz, 2H, C20-ArH, C60-ArH),
8.20, 10.20 (2 s, 2H, NH). 13C NMR (DMSO-d6):
d = 14.1, 21.4, 27.3, 42.4, 55.8, 56.0, 62.1, 111.5, 111.9,
123.7, 126.7, 127.7, 130.2, 135.4, 144.0, 147.5, 148.4,
1-Benzoyl-N-4-methylbenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9e) Yield: 64 %; mp
175–176 °C. IR (UATR): 3420, 3347, 1590, 1471, 1334,
1157 cm-1 1H NMR (DMSO-d6): d = 2.38 (m, 2H,
.
123

Med Chem Res (2013) 22:267–277
273
152.8, 179.5. HRMS-TOF: m/z [M ? H]? calcd for
C21H27N4O4S2: 463.1468; found: 463.1475.
CHN), 7.05–7.22 (m, 4H, C5-ArH, C6-ArH, C7-ArH, C8-
ArH), 7.28 (s, 1H, NH), 8.05 (d, J = 8.7 Hz, 2H, C20-ArH,
C60-ArH), 8.26 (s, 1H, NH), 8.32 (d, J = 8.7 Hz, 2H, C30-
ArH, C50-ArH), 10.22 (s, 1H, NH). 13C NMR (DMSO-d6):
d = 14.4, 27.7, 42.3, 62.4, 125.0, 126.7, 127.9, 128.0,
129.1, 129.2, 132.0, 134.2, 143.9, 150.2, 151.4, 179.7.
HRMS-TOF: m/z [M ? H]? calcd for C18H20N5O4S2:
434.0951; found: 434.0962.
1-Acetyl-6,7-dimethoxy-N-4-nitrobenzenesulfonyl-1,2,3,4-tet-
rahydroisoquinoline thiosemicarbazone (9i) Yield: 72 %;
mp 162–164 °C. IR (UATR): 3374, 3228, 1594, 1513,
1
1349, 1249, 1162 cm-1. H NMR (DMSO-d6): d = 1.77
(s, 3H, CH3CN), 2.50–2.80 (m, 2H, ArCH2), 3.30–3.60 (m,
2H, CH2N), 3.65, 3.66 (2 s, 6H, 2 9 OCH3), 5.34 (s, 1H,
CHN), 6.65 (s, 1H, C8-ArH), 6.76 (s, 1H, C5-ArH), 7.34 (s,
1H, NH), 8.02 (d, J = 8.7 Hz, 2H, C20-ArH, C60-ArH),
8.23 (s, 1H, NH), 8.33 (d, J = 8.7 Hz, 2H, C30-ArH, C50-
ArH), 10.20 (s, 1H, NH). 13C NMR (DMSO-d6): d = 14.3,
27.2, 42.3, 55.9, 56.1, 62.0, 111.5, 112.0, 123.5, 125.0,
126.4, 129.2, 144.1, 147.6, 148.6, 150.2, 151.7, 179.7.
HRMS-TOF: m/z [M ? H]? calcd for C20H24N5O6S2:
494.1162; found: 494.1146.
1-Acetyl-N-4-methoxybenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9m) Yield: 42 %; mp
156–158 °C. IR (UATR): 3400, 3264, 1594, 1496, 1332,
1
1259, 1153 cm-1. H NMR (DMSO-d6): d = 1.78 (s, 3H,
CH3CN), 2.60–2.90 (m, 2H, ArCH2), 3.20–3.70 (m, 2H,
CH2N), 3.80 (s, 3H, OCH3), 5.27 (s, 1H, CHN), 7.04 (d,
2H, J = 8.8 Hz, C30-ArH, C50-ArH), 7.05–7.21 (m, 4H,
C5-ArH, C6-ArH, C7-ArH, C8-ArH), 7.33 (s, 1H, NH),
7.72 (d, J = 8.8 Hz, 2H, C20-ArH, C60-ArH), 8.23, 10.22
(2 s, 2H, NH). 13C NMR (DMSO-d6): d = 14.2, 27.7, 42.2,
56.1, 62.4, 114.9, 126.6, 127.7, 128.1, 129.0, 129.7, 129.9,
132.3, 134.4, 152.4, 163.1, 179.6. HRMS-TOF:
m/z [M ? H]? calcd for C19H23N4O3S2: 419.1206; found:
419.1225.
1-Acetyl-6,7-dimethoxy-N-4-methoxybenzenesulfonyl-1,2,3,4-
tetrahydroisoquinoline thiosemicarbazone (9j) Yield:
46 %; mp 169–170 °C. IR (UATR): 3433, 3324, 1594,
1515, 1497, 1335, 1152 cm-1 1H NMR (DMSO-d6):
.
d = 1.77 (s, 3H, CH3CN), 2.50–2.80 (m, 2H, ArCH2),
3.10–3.50 (m, 2H, CH2N), 3.63, 3.67, 3.81 (3 s, 9H,
3 9 OCH3), 5.17 (s, 1H, CHN), 6.65 (s, 1H, C8-ArH), 6.74
(s, 1H, C5-ArH), 7.05 (d, J = 8.8 Hz, 2H, C30-ArH, C50-
ArH), 7.44 (s, 1H, NH), 7.69 (d, J = 8.8 Hz, 2H, C20-ArH,
C60-ArH), 8.19, 10.19 (2 s, 2H, NH). 13C NMR (DMSO-
d6): d = 14.0, 27.3, 42.3, 55.8, 56.1, 62.1, 111.5, 112.0,
114.9, 123.7, 126.7, 129.9, 147.6, 148.4, 152.9, 163.1,
179.5. HRMS-TOF: m/z [M ? H]? calcd for
C21H27N4O5S2: 479.1417; found: 479.1414.
1-Acetyl-N-3-nitrobenzenesulfonyl-1,2,3,4-tetrahydroisoquino-
line thiosemicarbazone (9n) Yield: 80 %; mp 170–172 °C.
IR (UATR): 3410, 3253, 1593, 1531, 1505, 1349,
1170 cm-1
.
1H NMR (DMSO-d6): d = 1.82 (s, 3H,
CH3CN), 2.60–2.90 (m, 2H, ArCH2), 3.40–3.76 (m, 2H,
CH2N), 5.44 (s, 1H, CHN), 7.01–7.22 (m, 5H, C5-ArH,
C6-ArH, C7-ArH, C8-ArH, NH), 7.82 (t, J = 8.0 Hz, 1H,
C50-ArH), 8.22 (d, J = 8.1 Hz, 1H, C60-ArH), 8.25 (s, 1H,
NH), 8.38–8.47 (m, 2H, C20-ArH, C40-ArH), 10.27 (s, 1H,
NH). 13C NMR (DMSO-d6): d = 14.4, 27.4, 42.3, 62.6,
122.5, 126.6, 127.8, 128.1, 129.0, 131.8, 132.0, 133.5,
134.1, 139.8, 148.2, 151.4, 179.7. HRMS-TOF:
m/z [M ? H]? calcd for C18H20N5O4S2: 434.0951; found:
434.0971.
1-Acetyl-N-4-methylbenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9k) Yield: 63 %; mp
170–172 °C. IR (UATR): 3401, 3278, 1590, 1488, 1323,
1156 cm-1
.
1H NMR (DMSO-d6): d = 1.80 (s, 3H,
CH3CN), 2.34 (s, 3H, ArCH3), 2.55–2.90 (m, 2H, ArCH2),
3.20–3.72 (m, 2H, CH2N), 5.30 (s, 1H, CHN), 7.04–7.21
(m, 4H, C5-ArH, C6-ArH, C7-ArH, C8-ArH), 7.31 (s, 1H,
NH), 7.34 (d, J = 8.4 Hz, 2H, C30-ArH, C50-ArH), 7.67 (d,
J = 8.3 Hz, 2H, C20-ArH, C60-ArH), 8.24, 9.92 (2 s, 2H,
NH). 13C NMR (DMSO-d6): d = 14.2, 21.5, 27.7, 42.3,
62.4, 126.6, 127.7, 128.1, 129.0, 130.2, 132.2, 134.4,
135.3, 144.0, 152.3, 179.6. HRMS-TOF: m/z [M ? H]?
calcd for C19H23N4O2S2: 403.1257; found: 403.1267.
Cytotoxic assay
The cytotoxic assay was performed as previously described
(Tengchaisri et al., 1998). In brief, cell lines suspended in
RPMI 1640 containing 10 % FBS were seeded at 1 9 104
cells (100 lL) per well in 96-well plate, and incubated in
humidified atmosphere, 95 % air, 5 % CO2 at 37 °C. After
24 h, additional medium (100 lL) containing the test
compound and vehicle was added to a final concentration
of 50 lg/mL, 0.2 % DMSO, and further incubated for
3 days. After that, the cells were fixed with EtOH–H2O
(95:5, v/v), stained with crystal violet solution, and lysed
with a solution of 0.1 N HCl in MeOH, after which
absorbance was measured at 550 nm. The number of
1-Acetyl-N-4-nitrobenzenesulfonyl-1,2,3,4-tetrahydroisoquino-
line thiosemicarbazone (9l) Yield: 80 %; mp 197–199 °C.
IR (UATR): 3467, 3348, 1587, 1532, 1354, 1166 cm-1. 1H
NMR (DMSO-d6): d = 1.78 (s, 3H, CH3CN), 2.63–2.92
(m, 2H, ArCH2), 3.40–3.76 (m, 2H, CH2N), 5.43 (s, 1H,
123

274
Med Chem Res (2013) 22:267–277
surviving cells was determined from the absorbance. Eto-
poside and doxorubicin were used as the reference drugs.
modification reveals the advantages not only the phenyl
glyoxal is more accessible than the marked thioketone but
also reaction time is shorter than those previously recorded
as shown in Table 1 (entries 1 and 5) (Huang et al., 2005;
Silveira et al., 2001). In addition, the Pictet–Spengler using
glyoxal applied for the synthesis of 1-substituted b-carbo-
lines has been described (Yang et al., 2006). Thiosemi-
carbazones (9) were successfully synthesized in moderate
to good yields (42–82 %) by mixing equimolar amounts of
the keto isoquinoline (8) with thiosemicarbazide in re-
fluxing ethanol (Pingaew et al., 2010). Their 13C NMR
spectra showed a characteristic signal for thiocarbonyl
(C=S) at d in a range of 178–180 ppm and for imine (C=N)
at d in a range of 151–153 ppm instead of the C=O signal.
Based on the literatures, these thiosemicarbazones (9) were
not reported.
Results and discussion
Chemistry
We have planned our synthetic routes by considering
the preparation of the 1-carbonyl-N-sulfonyltetrahy-
droisoquinolines (8) via the modified Pictet–Spengler
reaction as the key step (Scheme 1). In practice, a variety
of benzene sulfonamides (7) were readily accomplished
in good yield (76–89 %) by the condensation of the
corresponding amines (5) either homoveratrylamine
(R1 = OMe) or phenylethylamine (R1 = H) with various
sulfonyl chlorides (6) in methylene chloride catalyzed by
sodium carbonate. The Pictet–Spengler cyclization was
performed by refluxing the key sulfonamides (7) with the
commercially available phenylglyoxal or methylglyoxal
dimethylacetal in trifluoroacetic acid. The reactions of both
activated (R1 = OMe) and unactivated (R1 = H) benzene
sulfonamides (7) readily afforded N-sulfonyl-1,2,3,4-tetra-
hydroisoquinoline analogs (8) in good yields (72–89 %)
within 2 h (Table 1).
Cytotoxic activity
Cytotoxicity of the synthesized ketone 8a and thiosemi-
carbazone analogs 9a–n were assayed against HuCCA-1,
HepG2, A549, and MOLT-3 human cancer cell lines as
summarized in Table 2. Most thiosemicarbazones 9 dis-
played inhibition activities against MOLT-3 cell lines,
whereas none of the tested compounds showed cytotoxicity
against A549 cell lines. Cytotoxicity of the analog 9a was
observed against HepG2 and MOLT-3 cell lines, whereas
the ketone 8a was inactive. It should be noted that an
introduction of the thiosemicarbazone moiety is significant
for cytotoxicity. Compounds 9b and 9h were inactive
toward all the tested cells. Apparently, 1-acetyl-6,7-dime-
thoxy-N-4-methoxybenzenesulfonyl-1,2,3,4-tetrahydroiso-
quinoline thiosemicarbazone (9j) was shown to be the most
potent compound against HuCCA-1, HepG2, and MOLT-3
The formation of the desired isoquinolines (8) were
1
confirmed by H NMR spectra which showed the absence
of the NH proton, while the singlet of methine proton at d
in a range of 4–7 ppm was displayed indicating that the
cyclized products were formed. The structures of 8 were
further supported by 13C NMR spectra. A characteristic
signal for carbonyl group (C=O) appeared at chemical shift
nearly 200 ppm, and the presence of methine group
showed at d in a range of 50–70 ppm. The present
R3
Scheme 1 Synthesis of
thiosemicarbazones (9a–n) via
N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs
(8). Reagents and conditions:
(a) Na2CO3, CH2Cl2;
(b) HCOCOPh or
CH(OMe)2COMe, TFA, reflux;
(c) NH2NHCSNH2, HCl, EtOH,
reflux
R3
R1
R1
R1
R2
O O
S
Cl
a
R2
+
NH2
HN
R1
S
O2
5
6
a : R2=Me; R3=H
a : R1=OMe
b : R1=H
7
b : R2=NO2; R3=H
c : R2=OMe; R3=H
d : R2=Cl; R3=H
a : R1=OMe; R2=Me; R3=H e : R1=R3=H; R2=Me
b : R1=OMe; R2=NO2; R3=H f : R1=R3=H; R2=NO2
c : R1= R2=OMe; R3=H
g : R1=R3=H; R2=OMe
h : R1=R2=H; R3=NO2
e : R2=H; R3=NO2
d : R1=OMe; R2=Cl; R3=H
R3
b
R1
R1
R2
R3
5
8
4
R1
R1
R2
6
7
3
N
S
c
N
O2
S
1
R4
N
O2
R4
O
NH2
HN
8 : R4=Ph, Me
S
9 : R4=Ph, Me
123

Med Chem Res (2013) 22:267–277
275
Table 1 Chemical yield of the N-sulfonyl-1,2,3,4-tetrahydroisoquinolines (8a–n)
Entries
Sulfonamide
Glyoxal
Tetrahydroisoquinoline
R1
Yield (%)
R2
R3
R4
1
7a
7b
7c
7d
7e
7f
HCOCOPh
8a
8b
8c
8d
8e
8f
OMe
OMe
OMe
OMe
H
Me
H
Ph
80 (73)a,b
2
HCOCOPh
NO2
OMe
Cl
H
Ph
82
82
75
3
HCOCOPh
H
Ph
4
HCOCOPh
H
Ph
5
HCOCOPh
Me
H
Ph
85 (82)a,c (73)d,e
6
HCOCOPh
H
NO2
OMe
Me
H
Ph
80
84
87
82
72
85
89
75
85
7
7g
7a
7b
7c
7e
7f
HCOCOPh
8g
8h
8i
H
H
Ph
8
CH(OMe)2COMe
CH(OMe)2COMe
CH(OMe)2COMe
CH(OMe)2COMe
CH(OMe)2COMe
CH(OMe)2COMe
CH(OMe)2COMe
OMe
OMe
OMe
H
H
Me
Me
Me
Me
Me
Me
Me
9
NO2
OMe
Me
H
10
11
12
13
14
a
8j
H
8k
8l
H
H
NO2
OMe
H
H
7g
7h
8m
8n
H
H
H
NO2
PhSCHClCOPh was used as glyoxal equivalent (Silveira et al., 2001)
b
c
d
e
Reaction condition: SnCl4, CH2Cl2, rt 5 h (Silveira et al., 2001)
Reaction condition: ZnBr2, ClCH2CH2Cl, reflux 8 h (Silveira et al., 2001)
PhSCH2COPh was used as glyoxal equivalent (Silveira et al., 2001)
Reaction condition: polymer-supported bis(trifluoroacetoxyiodo)benzene, ClCH2CH2Cl, reflux 4 h (Huang et al., 2005)
cells, with IC50 of 31.00, 10.50, and 2.13 lg/mL,
respectively.
Whereas the unactivated isoquinoline analog 9m (R1 = H)
exerted no significant cytotoxic activity. More importantly,
complete loss of the cytotoxicity (HepG2) was observed for
1-benzoyl analog 9c (R4 = Ph) as compared to compound
9j (R4 = Me). It could be concluded that the electronic and
steric effects on the 1,2,3,4-tetrahydroisoquinoline thio-
semicarbazones played an important role in cytotoxic
effect.
The results suggested that all substituents (R1, R2, R3,
and R4) on the title molecule governed their cytotoxicities.
The 1-benzoyltetrahydroisoquinoline thiosemicarbazones
bearing electron donating groups (R2 = Me, OMe) exhib-
ited higher cytotoxicity (MOLT-3) than the analogs con-
taining an electron withdrawing group (NO2) as seen for
9a, 9c vs 9b and 9e, 9g vs 9f. Comparable results were also
observed for 1-acetyl analogs, whereas p-methoxy com-
pound (R2 = OMe) showed the highest cytotoxic potency
(9j vs 9h, 9i and 9m vs 9k, 9l). Obviously, the 1-acetyl
derivative 9j had 5-fold higher cytotoxicity (MOLT-3) than
the benzoyl analog 9c. It was noted that compounds 9l and
9n with NO2 substituent provided cytotoxicity against
MOLT-3 cells with the same IC50 value, indicating that the
position of NO2 group can be either R2 or R3 of the ben-
zene ring. Cytotoxic potency against MOLT-3 cells was
improved by about 7-fold when two methoxy groups (R1)
were introduced to the isoquinoline ring (9j vs 9m).
Moreover, the analog 9j was the only compound that dis-
played cytotoxicity against the HuCCA-1 cells. It is note-
worthy that the 1-acetyl analog (9j) with activated groups
(R1, R2 = OMe) on the isoquinoline and sulfonamide parts
of the title molecule showed higher inhibitory potency
against the HepG2 cells than the control drug, etoposide.
In comparison with thiosemicarbazone of isoquinoline,
these N-sulfonyl-1,2,3,4-tetrahydroisoquinoline analogs
9e–g exhibited less cytotoxic potency than the corre-
sponding isoquinoline analog 4a (Pingaew et al., 2010). It
is likely to explain that the better cytotoxicity may require
the planarity of isoquinoline moiety. This implies that the
N-sulfonyl group of the analogs 9 is not suitable for the
better cytotoxic activity. Thus, it is reasonable to assume
that the free amine moiety of the isoquinoline is important
for cytotoxic activity (Bermejo et al., 2002). In addition,
the finding supports that thiosemicarbazone possessing a
conjugated N–N–S tridentate ligand system is essential for
anticancer activity (French and Blanz, 1966). The activity
of many anticancer agents has been resulted from interca-
lative interaction with DNA (Liu et al., 2010). Thus, it is
presumably that the thiosemicarbazones 9 exert cytotoxic
activity through metal ion coordination which is essential
for metabolic processes (Galal et al., 2010).
123

276
Med Chem Res (2013) 22:267–277
Table 2 Cytotoxic activity of compounds (8a and 9a–n) against four cancer cell linesa
Compounds
R1
R2
R3
R4
Cytotoxic activity (IC50, lg/mL)b
HuCCA-1
HepG2
A549
MOLT-3
8a
OMe
OMe
OMe
OMe
OMe
H
Me
H
Ph
[50
[50
[50
[50
9a
Me
H
Ph
[50
21.50 2.12
[50
[50
8.45 0.38
[50
9b
NO2
OMe
Cl
H
Ph
[50
[50
9c
H
Ph
[50
[50
[50
10.41 0.76
5.03 0.34
7.85 1.04
11.27 0.38
8.44 0.81
[50
9d
H
Ph
[50
[50
[50
9e
Me
H
Ph
[50
[50
[50
9f
H
NO2
OMe
Me
H
Ph
[50
[50
[50
9g
H
H
Ph
[50
[50
[50
9h
OMe
OMe
OMe
H
H
Me
Me
Me
Me
Me
Me
Me
[50
[50
[50
9i
NO2
OMe
Me
H
[50
[50
[50
42.29 4.62
2.13 0.31
18.99 2.31
18.25 1.13
15.58 1.31
18.09 1.79
0.72 0.03
0.024 0.004
ND
9j
H
31.00 4.24
[50
10.50 4.03
46.00 1.41
32.33 4.04
33.50 4.50
38.50 2.12
16.00 1.41
16.00 5.29
0.23 0.03
[50
9k
H
[50
9l
H
NO2
OMe
H
H
[50
[50
9m
H
H
[50
[50
9n
4ac
H
NO2
[50
[50
35.00 5.65
ND
30.00 7.07
ND
Etoposided
Doxorubicine
0.35 0.21
0.38 0.03
ND not determined
a
Cancer cell lines are: HuCCA-1 Human cholangiocarcinoma cancer cells; HepG2 Human hepatocellular liver carcinoma cell line; A549
Human lung carcinoma cell line; and MOLT-3 Human lymphoblastic leukemia cell line
b
The assays were performed in triplicate
c
Pingaew et al., 2010
d,e
Etoposide and doxorubicin were used as the reference drugs
gratefully acknowledge the support by the office of the Higher Edu-
cation Commission and Mahidol University under the National
Research Universities Initiative.
Conclusion
The synthesis of 1-benzoyl- or 1-acetyl-N-sulfonyl-
1,2,3,4-tetrahydroisoquinolines has been accomplished by
the modified Pictet–Spengler reaction of phenylethylben-
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