Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4- tetrahydroisoquinoline analogs

Article abstract of DOI:10.1016/j.cclet.2013.06.019

An operationally simple and eco-friendly protocol has been developed for the synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinolines 3 using the modified Pictet-Spengler reaction of N-sulfonylphenylethylamines 1 and various aldehydes 2 in the presence of

Full text of DOI:10.1016/j.cclet.2013.06.019

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Chinese Chemical Letters xxx (2013) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs
b
c,d
Ratchanok Pingaew a, , Supaluk Prachayasittikul , Somsak Ruchirawat
,
*
Virapong Prachayasittikul e
a Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand
b Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
c Chulabhorn Research Institute, Bangkok 10210, Thailand
d Chulabhorn Graduate Institute and Center of Excellence on Environmental Health and Toxicology (EHT), Bangkok 10210, Thailand
e Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
A R T I C L E I N F O
A B S T R A C T
Article history:
An operationally simple and eco-friendly protocol has been developed for the synthesis of N-sulfonyl-
1,2,3,4-tetrahydroisoquinolines 3 using the modified Pictet–Spengler reaction of N-sulfonylphenylethy-
lamines 1 and various aldehydes 2 in the presence of tungstophosphoric acid hydrate.
ß 2013 Ratchanok Pingaew. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 28 March 2013
Received in revised form 1 June 2013
Accepted 8 June 2013
Available online xxx
Keywords:
Pictet–Spengler reaction
Isoquinoline
Heteropoly acid
Sulfonamide
1. Introduction
noted that the N-sulfonyl-1,2,3,4-tetrahydroisoquinolines could be
directly converted to both 1,2,3,4-tetrahydroisoquinolines and
The isoquinoline structural core is present in scores of natural
and synthetic products possessing many interesting pharmaco-
logical activities, including cytotoxic, antimicrobial, antimalarial
and anti-HIV properties [1–4]. The potent biological activities of
various isoquinoline alkaloids have drawn much attention from
various research groups in designing and synthesizing the
pharmacophore.
One of the most powerful methodologies to synthesize the
isoquinoline core is the acid-catalyzed Pictet–Spengler reaction
[5,6]. The protocol involves the cyclization of iminium ions derived
isoquinolines (Scheme 1). The 1,2,3,4-tetrahydroisoquinolines can
be readily achieved by reductive desulfonylation [14,17–19], and
isoquinolines can be practically derived through tandem
b-
elimination and aromatization as well [20,21]. However, many
of the Pictet–Spengler procedures suffer from disadvantages, such
as the use of corrosive, sensitive and expensive catalysts, and harsh
acidic conditions, in addition to the tedious preparation of catalysts
and protecting carbonyls. To avoid these limitations, a novel and
mild synthetic procedure has been developed for the synthesis of
the isoquinoline core.
from the condensation of
aldehydes (Scheme 1). Modifications of the original strategy by
increasing the electrophilicity of the iminium intermediates using
b
-arylethylamine derivatives with
Heteropolyacids (HPAs) have gained much attention as
versatile catalysts in organic synthesis owing to their environ-
mentally friendly property, high catalytic activities, commercial
availability, high stability toward humidity and air, and ease of
handling [22–25]. They have been applied to the synthesis of
many attractive products, particularly heterocyclic compounds.
In general, the most common Keggin-type HPAs were mainly
utilized as catalysts due to their availability and chemical stability
and are normally stronger than the conventional Lewis acids
(e.g., AlCl3) and mineral acids (e.g., H2SO4 and HCl). The acid
strength of a series of Keggin-type HPAs decreases as follow:
a sulfonyl or acyl group attached to the starting b-arylethylamines
have been developed [7–15]. The practice of using sulfonyl, as an
auxiliary group, showed superior reactivity to the use of an acyl
component [15], and has received much interest owing to its
promising properties, such as stability under a wide range of
reaction conditions and the ease of purification [16]. It should be
H3[PW12O40] > H4[SiW12O40] > H3[PMo12O40] > H4[SiMo12O40
]
* Corresponding author.
[24]. Herein, we wish to report the synthesis of N-sulfonyl-
E-mail address: ratchanok@swu.ac.th (R. Pingaew).
1001-8417/$ – see front matter ß 2013 Ratchanok Pingaew. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.06.019
Please cite this article in press as: R. Pingaew, et al., Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.019

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R
NH
O
R"
R
R
1,2,3,4-tetrahydroisoquinolines
H
R"
R
HN
R'
N+
R'
N
R'
S
S
S
O
O
2
2
O
2
R"
iminium ions
"
R
-arylethylamines
R
N-sulfonyl-1,2,3,4-
tetrahydroisoquinolines
N
R"
isoquinolines
Scheme 1. 1,2,3,4-Tetrahydroisoquinolines and isoquinolines from N-sulfonyl-1,2,3,4-tetrahydroisoquinolines.
1,2,3,4-tetrahydroisoquinolines by the eco-friendly Pictet–Spen-
gler strategy using commercially available tungstophosphoric
acid (H3[PW12O40]) as a catalyst.
J = 9.3, 4.3 Hz, C1), 6.30, 6.48 (2s, 2H, C5-ArH, C8-ArH), 7.08 (d, 2H,
J = 8.1 Hz, C30-ArH2), 7.55 (d,2H, J = 8.1 Hz, C20-ArH2). 13C NMR
(75 MHz, CDCl3): d 13.8, 19.8, 21.4, 25.7, 38.5, 39.7, 55.8, 56.0, 56.2,
109.7, 111.4, 124.6, 127.0, 129.1, 129.3, 138.1, 142.9, 147.4, 147.7.
IR (UATR, cmꢂ1): 1612, 1518, 1322, 1158, 1120. TOF-MS: m/z
390.1726; Calcd. for C21H28NO4S: 390.1734.
2. Experimental
Melting points were determined using a Griffin melting point
apparatus and were uncorrected. Column chromatography was
carried out using silica gel 60 (70–230 mesh ASTM). Analytical
thin-layer chromatography (TLC) was performed with silica gel 60
2.3. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[(4-
methylphenyl)sulfonyl]-1-cyclohexylisoquinoline (3e)
F
254 aluminum sheets. 1H NMR and 13C NMR spectra were recorded
Yield: 68%. Mp: 122–124 8C. 1H NMR (300 MHz, CDCl3):
d 1.00–
on a Bruker AVANCE 300 NMR spectrometer (operating at 300 MHz
for 1H NMR and 75 MHz for 13C NMR). FTIR were obtained using a
universal attenuated total reflectance attached on a PerkinElmer
Spectrum One spectrometer. Mass spectra were recorded on a
Bruker Daltonics (microTOF).
2.02 (m, 11H, CyH), 2.25 (s, 3H, ArCH3), 2.26–2.57 (m, 2H, C4),
3.44–3.70 (m, 2H, C3), 3.73, 3.82 (2s, 6H, 2ꢁ OCH3), 4.49 (d, 1H,
J = 8.8 Hz, C1), 6.27, 6.45 (2s, 2H, C5-ArH, C8-ArH), 7.00 (d, 2H,
J = 8.0 Hz, C30-ArH2), 7.44 (d, 2H, J = 8.0 Hz, C20-ArH2). 13C NMR
(75 MHz, CDCl3): d 21.3, 25.3, 26.2, 26.3, 30.4, 30.7, 55.8, 56.1, 61.8,
111.4, 111.5, 125.2, 127.1, 127.5, 129.1, 137.4, 142.7, 146.5, 147.9.
IR (UATR, cmꢂ1): 1611, 1514, 1336, 1158, 1114. TOF-MS: m/z
452.1865; Calcd. for C24H31NNaO4S: 452.1866.
2.1. General procedure for the synthesis of N-sulfonyl-1,2,3,4-tetrahydro-
isoquinolines (3)
A mixture of N-sulfonylphenylethylamine 1 (0.5 mmol), alde-
hyde 2 (0.6 mmol), and H3[PW12O40]ꢀaq (144 mg, 0.05 mmol) in
acetonitrile (2 mL) was stirred under refluxing for 0.5–48 h. The
reaction mixture was concentrated in vacuum and purified by
silica gel column chromatography to obtain N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline 3.
1H NMR spectra of 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-
methylphenyl)sulfonyl]-1-phenylisoquinoline(3a), 1,2,3,4-tetrahy-
dro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-isoquinoline (3b),
1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-
methylisoquinoline (3c), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-
methylphenyl)sulfonyl]-1-(4-bromophenyl)-isoquinoline (3f), 1,2,3,
4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-
nitrophenyl)-isoquinoline (3g), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-
[(4-methylphenyl)sulfonyl]-1-(4-hydroxyphenyl)-isoquinoline (3h),
1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-
2.4. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[(4-nitrophenyl)sulfonyl]-
isoquinoline (3p)
Yield: 88%. Mp: 141–142 8C. 1H NMR (300 MHz, CDCl3):
d 2.84
(t, 2H, J = 5.8 Hz, C4), 3.45 (t, 2H, J = 5.8 Hz, C3), 3.83 (s, 6H, 2ꢁ
OCH3), 4.28 (s, 2H, C-1), 6.52, 6.55 (2s, 2H, C5-ArH, C8-ArH), 8.02 (d,
2H, J = 8.9 Hz, C20-ArH2), 8.37 (d, 2H, J = 8.9 Hz, C30-ArH2). 13C NMR
(75 MHz, CDCl3):
d 28.2, 43.8, 47.1, 55.9, 56.0, 108.8, 111.4, 122.6,
124.3, 124.7, 128.7, 143.1, 147.9, 148.1, 150.1. IR (UATR, cmꢂ1):
1610, 1518, 1347, 1164, 1117. TOF-MS: m/z 401.0776; Calcd. for
C17H18N2NaO6S: 401.0778.
2.5. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[(4-nitrophenyl)sulfonyl]-
1-phenylisoquinoline (3q)
Yield: 68%. Mp 128–129 8C. 1H NMR (300 MHz, CDCl3):
d 2.50–
(4-methoxyphenyl)-isoquinoline
dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(2-hydroxyphenyl)-iso-
quinoline (3j), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphe-
nyl)sulfonyl]-1-(4-hydroxy-3-methoxyphenyl)-isoquinoline
(3i),
1,2,3,4-tetrahydro-6,7-
2.60 (m, 2H, C4), 3.20–3.34, 3.72–3.90 (m, 2H, C3), 3.73, 3.79 (2s,
6H, 2 ꢁ OCH3), 6.17 (s, 1H, C1), 6.40, 6.43 (2s, 2H, C5-ArH, C8-ArH),
7.12–7.28 (m, 5H, C20-ArH2, C30-ArH2, C40-ArH), 7.80 (d,2H,
J = 8.8 Hz, C200-ArH2), 8.12 (d,2H, J = 8.8 Hz, C300-ArH2). 13C NMR
(3k),
1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-
(3-hydroxy-4-methoxyphenyl)-isoquinoline (3l), and 1,2,3,4-tetrahy-
dro-2-[(4-methylphenyl)sulfonyl]-isoquinoline (3s) were consistent
with those reported in the literatures [26,27].
(75 MHz, CDCl3): d 26.5, 39.1, 55.9, 56.0, 59.3, 110.6, 111.1, 123.9,
125.1, 125.3, 128.1, 128.5, 128.8, 140.7, 146.8, 147.8, 148.5, 149.6.
IR (UATR, cmꢂ1): 1609, 1529, 1348, 1162, 1117. TOF-MS: m/z
477.1091; Calcd for C23H22N2NaO6S: 477.1091.
2.2. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-
2.6. 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[(4-nitrophenyl)sulfonyl]-
1-propylisoquinoline (3d)
1-(4-methoxyphenyl)-isoquinoline (3r)
Yield: 89%. 1H NMR (300 MHz, CDCl3):
d
0.90–1.85 (m, 7H,
Yield: 12%. Mp: 279–281 8C. 1H NMR (300 MHz, CDCl3):
d 2.45–
CH2CH2CH3), 2.30 (s, 3H, ArCH3), 2.32–2.40 (m, 2H, C4), 3.32–3.45,
3.75–3.90 (m, 2H, C3), 3.74, 3.84 (2s, 6H, 2ꢁ OCH3), 4.87 (dd, 1H,
2.65 (m, 2H, C4), 3.20–3.35, 3.70–3.90 (m, 2H, C3), 3.73, 3.76, 3.79
(3s, 9H, 3ꢁ OCH3), 6.13 (s, 1H, C1), 6.39, 6.41 (2s, H, C5-ArH, C8-
Please cite this article in press as: R. Pingaew, et al., Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.019

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3
ArH), 6.76 (d, 2H, J = 8.7 Hz, C30-ArH2), 7.07 (d, 2H, J = 8.7 Hz, C20-
ArH2), 7.79 (d, 2H, J = 8.9 Hz, C200-ArH2), 8.11 (d, 2H, J = 8.9 Hz, C300-
show any significant effect on the outcome of the reaction (Table 1,
entry 4 vs entry 5); however, the shorter reaction time was realized
by elevating the reaction temperature to furnish the anticipated
1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-
1-phenylisoquinoline 3a in 86% yield within 12 h (Table 1, entry 6).
The formation of the desired isoquinoline (3a) was confirmed
by 1H NMR spectra which showed the absence of the NH proton,
ArH2). 13C NMR (75 MHz, CDCl3):
d 26.5, 38.9, 55.3, 55.9, 56.0, 58.8,
110.6, 111.1, 113.7, 123.9, 125.2, 128.1, 130.0, 132.9, 147.0, 147.8,
148.5, 149.6, 159.4. IR (UATR, cmꢂ1): 1608, 1510, 1347, 1248, 1162.
TOF-MS m/z: 485.1382; Calcd. for C24H25N2O7S: 485.1377.
while the singlet of methine proton displayed at
d 6.19 indicated
3. Results and discussion
that the cyclized product 3a was formed. The structure was
consistent with that reported in the literature [26].
Initially, the Pictet–Spengler reaction of 4-methyl-N-(2-(3,4-
dimethoxyphenyl)ethyl)-benzenesulfonamide 1a [28] with benz-
aldehyde using H3[PW12O40]ꢀaq was optimized in various solvents
such as water, ethanol, dichloromethane and acetonitrile as
demonstrated in Table 1. The best result was obtained using
acetonitrile as solvent. Increasing the amount of catalyst did not
The success of forming 3a encouraged us to extend the reaction
of the activated benzene sulfonamide (1a) with other aldehydes 2,
as summarized in Table 2. The reactions were performed under
similar conditions to provide tetrahydroisoquinoline analogs 3 in
moderate to good yields. It was clear that the reaction could be
Table 1
Reaction of N-sulfonylphenylethylamine 1a with benzaldehyde using H3[PW12O40]ꢀaq as a catalyst in different reaction conditions.
MeO
Me
O
N
H
MeO
S
MeO
MeO
Me
O2
HN
.
S
H3[PW12O40] aq
O2
3a
1a
Entry
Solvent
H3[PW12O40]ꢀaq (mmol)
Time (h)
Yield (%)
1
2
H2O
0.05
0.05
0.05
0.05
0.10
0.05
48
48
48
48
48
12
0
EtOH
Trace
69
3
CH2Cl2
CH3CN
CH3CN
CH3CN
4
76
5
6a
78
86
Reaction of benzene sulfonamide 1a (0.5 mmol), benzaldehyde (0.6 mmol) and H3[PW12O40]ꢀaq in solvent (2 mL) at room temperature.
a
Reaction under reflux conditions.
Table 2
Tungstophosphoric acid hydrate catalyzed reaction of N-sulfonylphenylethylamines 1 with various aldehydes 2.
O
R1
R1
R2
R1
R1
R2
R3
H
2
N
HN
S
.
S
H3[PW12O40] aq (10 mol%)
O2
R3
O2
3
1
1a: R1 = OMe; R2 = Me; 1b: R1 = OMe; R2 = NO2; 1c: R1 = H; R2 = Me
Entry
Sulfonamide
Aldehyde
Isoquinoline
Time (h)
Yield (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
C6H5CHO
(CH2O)n
CH3CHO
3a
3b
3c
3d
3e
3f
12
0.5
1
86
95
90
89
68
79
80
66
55
11
62
67
3
4
CH3CH2CH2CHO
2
5
Cyclohexane carboxaldehyde
4-BrC6H4CHO
2
6
8
7
4-NO2C6H4CHO
3g
3h
3i
8
8
4-HOC6H4CHO
48
48
48
48
48
48
48
48
0.5
48
48
3
9
4-CH3OC6H4CHO
2-HOC6H4CHO
10
11
12
13
14
15
16
17
18
19
20
3j
4-HO,3-CH3OC6H3CHO
4-CH3O,3-HOC6H3CHO
3,4,5-(CH3O)3C6H2CHO
Pyridine-3-carboxaldehyde
Indole-3-carboxaldehyde
(CH2O)n
3k
3l
a
3m
3n
3o
3p
3q
3r
3s
3t
–
a
–
a
–
88
68
12
81
C6H5CHO
4-CH3OC6H4CHO
(CH2O)n
a
CH3CHO
48
–
Reaction of benzene sulfonamides 1 (0.5 mmol), aldehydes 2 (0.6 mmol) and H3[PW12O40]ꢀaq (0.05 mmol) in refluxing CH3CN (2 mL).
a
No reaction based on TLC analysis.
Please cite this article in press as: R. Pingaew, et al., Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.019

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applied to both aliphatic and aromatic aldehydes. The reaction
proceeded smoothly with aromatic aldehydes bearing both
electron-withdrawing (Br, NO2) and electron-donating groups
(OH, OCH3); however, the latter required longer reaction time to
consume 1a. The scope of the reaction was further studied using
salisaldehyde to determine the steric effect of ortho-substituted
aromatic aldehydes. The reaction gradually proceeded to afford the
cyclized product with low yield (Table 2; entry 10). The less
reactive 3,4,5-trimethoxy benzaldehyde (Table 2; entry 13) gave
no cyclized product along with the recovery of starting material.
Moreover, the reaction could not tolerate the use of heterocyclic
aldehydes, such as pyridine-3-carboxaldehyde and indole-3-
carboxaldehyde (Table 2; entries 14–15) even with prolonged
reaction times of up to 48 h. Both methyl and nitro substituted (R2)
benzene sulfonamides (1a and 1b) were determined as suitable
substrates for the Pictet–Spengler procedure under these reaction
conditions. It was found that the methyl analogs were more
reactive than the nitro counterparts (entry 1 vs entry 17 and entry
9 vs entry 18). When the benzene sulfonamide bearing no methoxy
activating group (1c) was used as the substrate, the cyclization
reaction was achieved only with paraformaldehyde (entry 19).
The synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinolines
promoted by silica-supported HPA catalysts has been shown;
however, the reaction scope was narrow [13,14]. The approach
could be applied only to N-sulfonyl-1,2,3,4-tetrahydroisoquino-
lines containing no substituent at position 1 using trioxane as the
carbonyl component. Mechanistically, HPA plays an essential role
in this Pictet–Spengler reaction by protonation of the carbonyl
oxygen of aldehyde, thus the formation of the iminium intermedi-
ate was accelerated [29].
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soquinolines have been reported as potent cytotoxic agents [26],
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4. Conclusion
We have presented a novel, simple and greener protocol for the
synthesis of N-substituted-1,2,3,4-tetrahydroisoquinolines via the
modified Pictet–Spengler reaction of N-(2-phenylethyl)-benzene-
sulfonamides with various aldehydes using tungstophosphoric
acid hydrate as an influential catalyst. Significantly, the method
offers several attractive advantages such as readily availability,
non-corrosive conditions, as well as
procedure.
a simple experimental
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Acknowledgments
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and QSAR study of N-tosyl-1,2,3,4-tetrahydroisoquinoline derivatives, Arch.
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lines and N-sulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepines. Conformational
analysis of N-[((30,40-dichlorophenyl) methyl)sulfonyl]-3-methyl-2,3,4,5-tetra-
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We gratefully acknowledge the research grant from Srinakhar-
inwirot University (B.E. 2555). This project is supported by Office of
the Higher Education Commission and Mahidol University under
the National Research Universities Initiative.
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Please cite this article in press as: R. Pingaew, et al., Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-
tetrahydroisoquinoline analogs, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.019