A facile metal-free one-pot synthesis of 3-aminoisoquinolines by intramolecular transannulation of 1-sulfonyl-4-(2-aminomethylphenyl)-1,2,3-triazoles

Article abstract of DOI:10.1039/d0ra06563c

A metal-free one-pot intramolecular transannulation of 1-sulfonyl-4-(2-aminomethylphenyl)-1,2,3-triazoles has been developed, which enables the facile synthesis of the various 3-aminoisoquinolines as well as relevant scaffolds from readily available starting materials.

Full text of DOI:10.1039/d0ra06563c

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PAPER
A facile metal-free one-pot synthesis of 3-
aminoisoquinolines by intramolecular
transannulation of 1-sulfonyl-4-(2-
aminomethylphenyl)-1,2,3-triazoles†
Cite this: RSC Adv., 2020, 10, 39067
ab
a
a
Ling-Yu Li,a Yu Tian,
Hong-Mei Jiaa and Zhong-Mei Zou
*
Hai Shang,
Received 29th July 2020
Accepted 6th September 2020
A
metal-free one-pot intramolecular transannulation of 1-sulfonyl-4-(2-aminomethylphenyl)-1,2,3-
DOI: 10.1039/d0ra06563c
triazoles has been developed, which enables the facile synthesis of the various 3-aminoisoquinolines as
rsc.li/rsc-advances
well as relevant scaffolds from readily available starting materials.
secondary amines were converted slowly, and failed to proceed
to the formation of desired product with satisfying results in the
Introduction
most cases. In addition, some alternative procedures have also
been reported. These methods include the cyclization of aryl-
methylazapropenylium perchlorates,12 Cu(I)-catalyzed cyclo-
condensation of o-iodobenzylamine and acetonitriles13 and the
palladium catalyzed a-arylation reaction of tert-butyl cyanoace-
tate, followed by in situ trapping with an electrophile, and
aromatization with ammonium chloride.14 However, these
methods are revealed to suffer from difficult access to starting
material, the necessity of transition metal catalysts, the limited
scope of applicability or low yield. The synthetically practical
and operationally convenient method for preparing the 3-ami-
noisoquinoline is still necessary.
N-Sulfonyl ketenimine, which is readily in situ generated
from ring-opening of N-sulfonyl 1,2,3-triazole, has been evolved
into a useful synthetic intermediate in recent years for the
synthesis of numerous complex organic compounds, particu-
larly the biologically interesting heterocycles (Fig. 1b).15 As
a highly active intermediate, N-sulfonyl ketenimine can readily
undergo nucleophilic additions to give their corresponding
products.16 For example, Li's group developed a method for
synthesis of naphthalenes by intramolecular transannulation of
1-sulfonyl-4-(2-alkenylphenyl)-1,2,3-triazoles (Fig. 1c).17 Inspired
by this work, we envisaged the N-sulfonyl ketenimine could
pave the way of advancing to the aforementioned heterocycles.
As a result, we report herein a metal-free intramolecular trans-
Isoquinoline represents an important class of heterocyclic
skeleton, which is widely distributed in diverse natural prod-
ucts, and some are found to have promising biological perfor-
mance and medicinal importance.1–3 The unique structure of 3-
aminoisoquinolines is well-explored to be commonly used as
the unit for synthesizing biologically active representatives,
such as compounds 1–3 (Fig. 1a).4–6 In view of the wide appli-
cation of 3-aminoisoquinolines in medicinal chemistry, a large
array of synthetic methods had been developed for the
construction of 3-aminoisoquinolines and their structurally
similar analogues.
In general, synthetic approaches towards 3-aminoisoquino-
lines were historically reported, including the direct amination
of 3-haloisoquinoline with sodium amide, aqueous ammonia or
cyclic amine.7–9 In order to prove the acceptable reaction effi-
ciency of the above mentioned transformations, some harsh
reaction conditions are commonly required, such as high
reaction temperature or pressure. Otherwise, the cyclo-
condensation of 2-cyanomethyl benzoaldehydes or 2-acylphe-
nylacetonitriles with amines has been served as an accessible
option for obtaining the 3-aminoisoquinolines, which highly
depends on the intrinsic nature of nitrogen substrates used.10,11
For instance, ammonia or primary amines could smoothly
afford 3-aminoisoquinolines with good yields whereas the
annulation
of
1-sulfonyl-4-(2-aminomethylphenyl)-1,2,3-
aInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences,
Peking Union Medical College, Beijing 100193, P. R. China. E-mail: zmzou@implad.
ac.cn; Tel: +86-10-5783-3290
triazoles, a reaction enabling the efficient synthesis of 3-ami-
noisoquinolines (Fig. 1d).
bState Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union
Medical College, Beijing 100050, P. R. China
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of isolated compounds. CCDC 2026878. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra06563c
Results and discussion
Using 1a as a model substrate, we commenced our investigation
ꢀ
by treating it in 1,2-DCE at 80 C in a sealed tube (Scheme 1).
Aer 36 h, two main products were obtained, which were
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(Table 1). First of all, we discovered that the better reactivity
could be secured by gradually increasing the reaction temper-
ꢀ
ature from 80 to 140 C (entries 2–4). A good yield (73%) of 3a
ꢀ
was obtained with raising the reaction temperature to 140 C.
Gratifyingly, simply replacing the reaction solvent with non-
polar toluene can provide the best result (81%) instead of the
rest (THF, CHCl3, CH3CN and EtOAc). In sharp contrast, the
lower reaction temperature actually led to inferior results that
advance to the desired product 3a with only moderate yield
(entries 5 and 6). In addition, the Rh catalyst were also exam-
ined, but negative impact on the reaction outcome was
observed.
Having the optimal conditions in hands, we then turned to
evaluate the substrate scope generality of the above reaction
(Table 2). First of all, the substituent variants on the phenyl ring
were examined. It was shown that all of them could undergo the
desired reactions to provide the corresponding products 3b–k in
moderate to excellent yields. 5-Br, 5-Cl and 4-Cl substituted
phenyl triazoles delivered 1b–d with satisfactory yield (78–85%),
as well as 3e and 3f gave the acceptable results (65% and 63%)
when 4-F and 5-F substituted phenyl triazoles were used.
The arene substitution pattern indicates that the bromo and
chloro substituents are superior to uoro substituent. The 5-
and 4-functionalized substrates result in comparable reactivity,
afford their corresponding products with moderate to good
yield. For substrate 1g with triuoromethyl group, the reaction
gave the desired product 3g in moderate yield. The reaction
could also be applied to substrates with electron-donating
groups (1h–k). As shown, mono-substituted phenyl triazoles
with electron-donating groups (1h, 1i) could proceed smoothly
to furnish the desired products 3h and 3i in 72% and 74%
Fig. 1 Background and our work.
further identied as the 1,2-dihydroisoquinolin-3(4H)-imine 2a-
1, and its regioisomer 1,2-dihydroisoquinoline 2a-2 generated
from the enamine-iminium isomerization. The overall isolated
yield of 2a-1 and 2a-2 was 63% and the molar ratio 2a-1 : 2a-2 ¼
11 : 1. Of note, the two isomers were observed as an inseparable
mixture that each of them was unable to be respectively ob-
tained by simply using the silica gel column chromatography.
In order to unambiguously characterize the presumed struc-
tures of the two isomers, the mixture was subject to the treat-
ment of NaOH/DMSO solution that prompting the formation of
3-aminoisoquinoline 3a (80%) as an aromatized product.18 The
structure of 3a was unambiguously conrmed by the X-ray
crystallographic study.19 Furthermore, we found that the
tandem annulation and aromatization could be smoothly ach-
ieved in an operationally simple one-pot manner, which allowed
for the access of 3a directly from 1a with comparable efficiency.
To improve the efficiency of the above mentioned trans-
formation, we performed an extensive condition screening
Table 1 Condition optimization of intramolecular annulation of 1-
sulfonyl-4-(2-aminomethylphenyl)-1,2,3-triazolesa
Entry
Cat.
Solvent
T [ꢀC]
Yieldb
1
2
3
4
5
6
7
8
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
PhMe
PhMe
PhMe
THF
CHCl3
CH3CN
EtOAc
PhMe
80
48%
56%
65%
73%
59%
71%
81%
77%
62%
73%
77%
45%
39%
100
120
140
100
120
140
140
140
140
140
140
140
9
10
11
12
13
Rh2(Oct)4
Rh2(esp)2
PhMe
a
Reaction conditions: 1a (0.1 mmol), catalyst (2.0 mmol), and solvent
(1.0 mL) in a sealed tube, then NaOH (1.0 mmol) and DMSO (1.0 mL).
b
Refers to isolated yield. 1,2-DCE ¼ dichloroethane, Oct ¼ octanoate,
esp ¼ a,a,a0,a0-tetramethyl-1,3-benzenedipropionic acid.
Scheme 1 Initial result of intramolecular annulation of 1-sulfonyl-4-
(2-aminomethylphenyl)-1,2,3-triazoles.
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Table 2 Scope of intramolecular annulation of 1-sulfonyl-4-(2-ami-
nomethylphenyl)-1,2,3-triazolesa,b
Scheme 2 Proposed mechanism of intramolecular annulation of 1-
sulfonyl-4-(2-aminomethylphenyl)-1,2,3-triazoles.
ketenimine intermediate B. Through the intramolecular
nucleophilic addition, zwitterionic intermediate C and its res-
onanced intermediates C0 were generated, which could convert
to 2a-1 and 2a-2 via intramolecular proton transfer. Finally,
base-mediated elimination/aromatization of sulnate results in
3-aminoisoquinoline 3a.
Conclusions
a
Reaction conditions: 1 (0.1 mmol), toluene (1.0 mL) in a sealed tube,
b
In summary, we have developed an efficient method for the
construction of 3-aminoisoquinolines through a metal-free one-pot
intramolecular transannulation of 1-sulfonyl-4-(2-aminomethyl
phenyl)-1,2,3-triazoles. This method would provide an alternative
to the current toolbox for the synthesis of 3-aminoisoquinolines,
and further applications of the method to the syntheses of bioactive
molecules are in progress.
then NaOH (1.0 mmol), DMSO (1.0 mL). Refers to isolated yield.
yields. Comparably, substrates with double electron-donating
groups led to relatively lower yields (3j, 3k), most likely due to
the stronger electronic effect causing the decomposition of
partial substrate under the current reaction conditions.
In addition to the substituent on the phenyl ring, substitu-
tion effect on the benzylic position has also been evaluated. 2l
bearing Ph group (R2) at the benzylic position underwent the
reactions smoothly to afford the desired product 3l in 81% yield.
For the alkyl substituted substrates 1m and 1n, the corre-
sponding annulation products were obtained in 79 and 87%
total yields, respectively. However, it failed to undergo aroma-
tization to give the corresponding 3-aminoisoquinolines under
NaOH condition, presumably due to electron-donating effect of
alkyl group. Finally, it was found that the benzene ring unit of
the substrates could be replaced by some other aromatic rings,
such as naphthalene and thiophene, as shown by the cases of 3o
and 3p.
Experimental
General information
NMR spectra were recorded on Bruker AV III 600 NMR spec-
trometer and Bruker AV 400 instrument. Solvent signal was
used as reference for 1H NMR (CDCl3, 7.26 ppm; DMSO-d6, 2.50
ppm) and 13C NMR (CDCl3, 77.16 ppm; DMSO-d6, 39.52 ppm).
The following abbreviations were used to explain the
multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
td ¼ triple doublet, m ¼ multiplet. Infrared (IR) spectra were
recorded on a FTIR-8400S spectrometer. High-resolution mass
spectra (HRMS) were recorded on a Waters SYNAPT G2 HDMS.
Reactions were monitored by Thin Layer Chromatography
on plates (GF254) supplied by Yantai Chemicals (China). If not
specially mentioned, ash column chromatography uses silica
gel (200–300 mesh) supplied by Tsingtao Haiyang Chemicals
(China). Solvent purication was conducted according to Puri-
cation of Laboratory Chemicals (D. D. Peerrin, W. L. Armarego
and D. R. Perrins, Pergamon Press, Oxford, 1980).
Based on the above results and the previously reported
literature, the presumable mechanistic hypothesis of the
transannulation using substrate 1a as a model is rationally
illustrated in Scheme 2. Substrate 1a undergoes a ring-opening
denitrogenative process upon heating to afford carbene inter-
mediate A, which was followed by a 1,2-H migration to give
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General procedure for the preparation of 3-aminoisoquinolines
N-(7-Fluoroisoquinolin-3-yl)-4-methylbenzenesulfonamide
(3e). Yield: 65%; H NMR (600 MHz, DMSO-d6) d 11.02 (s, 1H),
1
A 10 mL pressure tube, tted with a rubber septum, was charged
with triazole (0.1 mmol, 1.0 eq.). The reaction vessel was added
freshly distilled toluene (1.0 mL) and then was sealed with
a Teon screwcap and placed in an oil bath preheated to 140 ꢀC.
Upon complete consumption of the substrate (monitored by
TLC), the solvent was removed and DMSO (1.0 mL) with an
aqueous solution of sodium hydroxide (30% w/w, 133 mg, 1.0
9.00 (s, 1H), 7.99 (dd, J ¼ 9.0 Hz, 5.3 Hz, 1H), 7.81 (d, J ¼ 8.2 Hz,
2H), 7.78 (d, J ¼ 9.0 Hz, 1H), 7.64–7.59 (m, 1H), 7.58 (s, 1H), 7.33
(d, J ¼ 8.2 Hz, 2H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 159.2 (d, J ¼ 244.8 Hz), 151.0 (d, J ¼ 5.0 Hz), 146.5 (d, J ¼ 1.8
Hz), 143.3, 137.3, 134.4, 129.6, 129.2 (d, J ¼ 8.2 Hz), 127.0, 125.8
(d, J ¼ 8.8 Hz), 121.6 (d, J ¼ 25.9 Hz), 110.4 (d, J ¼ 21.0 Hz),
106.0, 20.9; IR nmax (lm): 3057, 2849, 1596, 1521, 1354, 1341,
1209, 1154, 1091, 955 cmꢂ1; HRMS m/z calcd for C16H14FN2O2S
[M + H]+: 317.0760; found: 317.0762.
ꢀ
mmol) was added. The mixture was heated to around 125 C,
and then stirred at this temperature for 2 h. The reaction was
monitored by TLC. Aer the reaction was complete, the mixture
was allowed to cool to room temperature and diluted with water
(10 mL). The aqueous solution was then extracted with ethyl
acetate (3 ꢁ 15 mL) and the combined extracts were dried with
anhydrous Na2SO4. The solvent was evaporated in vacuo and the
residue was puried by a silica gel ash column chromatog-
raphy (eluent: petroleum ether/EtOAc) to give the correspond-
ing products.
N-(6-Fluoroisoquinolin-3-yl)-4-methylbenzenesulfonamide
1
(3f). Yield: 63%; H NMR (600 MHz, DMSO-d6) d 11.11 (s, 1H),
9.01 (s, 1H), 8.07 (dd, J ¼ 8.9 Hz, 5.8 Hz, 1H), 7.83 (d, J ¼ 8.3 Hz,
2H), 7.70 (dd, J ¼ 10.2 Hz, 2.2 Hz, 1H), 7.52 (s, 1H), 7.37 (td, J ¼
8.9 Hz, 2.2 Hz, 1H), 7.33 (d, J ¼ 8.3 Hz, 2H), 2.30 (s, 3H); 13C
NMR (150 MHz, DMSO-d6) d 163.1 (d, J ¼ 249.9 Hz), 151.6, 147.5,
143.4, 138.7 (d, J ¼ 11.4 Hz), 137.3, 131.3 (d, J ¼ 10.6 Hz), 129.6,
127.0, 122.8, 116.2 (d, J ¼ 26.1 Hz), 109.3 (d, J ¼ 21.6 Hz), 104.9
(d, J ¼ 5.3 Hz), 20.9; IR nmax (lm): 3356, 3260, 3066, 1635, 1436,
1345, 1161, 1092, 968 cmꢂ1; HRMS m/z calcd for C16H14FN2O2S
[M + H]+: 317.0760; found: 317.0756.
4-Methyl-N-(7-(triuoromethyl)isoquinolin-3-yl)benzenesulfon
amide (3g). Yield: 50%; 1H NMR (600 MHz, DMSO-d6) d 11.31 (s,
1H), 9.21 (s, 1H), 8.48 (s, 1H), 8.09 (d, J ¼ 8.8 Hz, 1H), 7.88 (d, J ¼
8.8 Hz, 1H), 7.85 (d, J ¼ 8.3 Hz, 2H), 7.59 (s, 1H), 7.35 (d, J ¼ 8.3 Hz,
2H), 2.31 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d 153.2, 148.7,
143.5, 138.7, 137.1, 129.6, 127.8, 127.1, 126.1 (q, J ¼ 4.6 Hz), 126.0
(q, J ¼ 4.4 Hz), 125.6 (q, J ¼ 32.1 Hz), 124.0 (q, J ¼ 272.2 Hz), 123.9,
104.7, 21.0; IR nmax (lm): 3063, 2865, 1641, 1605, 1485, 1309, 1178,
1123, 1064, 945 cmꢂ1; HRMS m/z calcd for C17H14F3N2O2S [M +
H]+: 367.0728; found: 367.0731.
N-(7-Methoxyisoquinolin-3-yl)-4-methylbenzenesulfonamide
(3h). Yield: 74%; 1H NMR (600 MHz, DMSO-d6) d 10.80 (s, 1H),
8.88 (s, 1H), 7.80 (d, J ¼ 9.1 Hz, 1H), 7.77 (d, J ¼ 8.3 Hz, 2H), 7.49
(s, 1H), 7.37 (d, J ¼ 2.5 Hz, 1H), 7.34 (dd, J ¼ 9.1 Hz, 2.5 Hz, 1H),
7.31 (d, J ¼ 8.3 Hz, 2H), 3.85 (s, 3H), 2.30 (s, 3H); 13C NMR (150
MHz, DMSO-d6) d 157.0, 149.9, 145.1, 143.1, 137.4, 132.7, 129.5,
127.7, 126.9, 126.7, 124.1, 106.8, 104.9, 55.4, 20.99; IR nmax
(lm): 3064, 2870, 1601, 1577, 1517, 1419, 1342, 1154, 1090,
981 cmꢂ1; HRMS m/z calcd for C17H17N2O3S [M + H]+: 329.0960;
found: 329.0954.
N-(Isoquinolin-3-yl)-4-methylbenzenesulfonamide
(3a).
Yield: 81%; 1H NMR (600 MHz, DMSO-d6) d 11.03 (s, 1H), 9.01 (s,
1H), 7.97 (d, J ¼ 8.2 Hz, 1H), 7.86 (d, J ¼ 8.3 Hz, 1H), 7.81 (d, J ¼
8.3 Hz, 2H), 7.67 (dd, J ¼ 8.4 Hz, 8.3 Hz, 1H), 7.51 (s, 1H), 7.49
(dd, J ¼ 8.4 Hz, 8.2 Hz, 1H), 7.33 (d, J ¼ 8.3 Hz, 2H), 2.30 (s, 3H);
13C NMR (150 MHz, DMSO-d6) d 152.2, 147.1, 143.8, 137.8,
137.5, 131.5, 130.0, 128.0, 127.4, 126.5, 126.3, 125.9, 106.1, 21.4;
IR nmax (lm): 3326, 2920, 1596, 1352, 1162, 1090, 986 cmꢂ1
;
HRMS m/z calcd for C16H15N2O2S [M + H]+: 299.0854; found:
299.0858.
N-(7-Bromoisoquinolin-3-yl)-4-methylbenzenesulfonamide
1
(3b). Yield: 82%; H NMR (600 MHz, DMSO-d6) d 11.13 (s, 1H),
8.99 (s, 1H), 8.26 (s, 1H), 7.86 (d, J ¼ 8.9 Hz, 1H), 7.82 (d, J ¼
8.3 Hz, 2H), 7.79–7.75 (m, 1H), 7.52 (s, 1H), 7.33 (d, J ¼ 8.3 Hz,
2H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d 150.9, 147.1,
143.4, 137.2, 135.7, 134.0, 129.6, 129.6, 128.4, 127.0, 126.3,
118.2, 105.4, 20.9; IR nmax (lm): 3056, 2847, 1585, 1560, 1513,
1341, 1155, 1091, 936 cmꢂ1; HRMS m/z calcd for C16H14BrN2O2S
[M + H]+: 376.9959; found: 376.9965.
N-(7-Chloroisoquinolin-3-yl)-4-methylbenzenesulfonamide
1
(3c). Yield: 78%; H NMR (600 MHz, DMSO-d6) d 11.12 (s, 1H),
9.00 (s, 1H), 8.10 (d, J ¼ 2.0 Hz, 1H), 7.93 (d, J ¼ 8.9 Hz, 1H), 7.82
(d, J ¼ 8.3 Hz, 2H), 7.67 (dd, J ¼ 8.9 Hz, 2.0 Hz, 1H), 7.54 (s, 1H),
7.33 (d, J ¼ 8.3 Hz, 2H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO-
d6) d 151.0, 147.2, 143.4, 137.3, 135.6, 131.6, 129.8, 129.6, 128.4,
127.0, 126.2, 125.8, 105.4, 20.9; IR nmax (lm): 3056, 2870, 2848,
1625, 1515, 1341, 1155, 940, 811, cmꢂ1; HRMS m/z calcd for
4-Methyl-N-(6-methylisoquinolin-3-yl)benzenesulfonamide
1
(3i). Yield: 72%; H NMR (600 MHz, DMSO-d6) d 10.94 (s, 1H),
8.92 (s, 1H), 7.86 (d, J ¼ 8.4 Hz, 1H), 7.80 (d, J ¼ 8.3 Hz, 2H), 7.61
(s, 1H), 7.40 (s, 1H), 7.34–7.30 (m, 3H), 2.44 (s, 3H), 2.30 (s, 3H);
13C NMR (150 MHz, DMSO-d6) d 151.1, 146.8, 143.2, 141.2,
137.4, 129.5, 128.1, 127.4, 127.0, 124.7, 124.0, 105.1, 21.6, 20.9;
IR nmax (lm): 3058, 2849, 1634, 1595, 1520, 1343, 1155, 1092,
983 cmꢂ1; HRMS m/z calcd for C17H17N2O2S [M + H]+: 313.1011;
found: 313.1015.
C
16H14ClN2O2S [M + H]+: 333.0465; found: 333.0464.
N-(6-Chloroisoquinolin-3-yl)-4-methylbenzenesulfonamide
(3d). Yield: 85%; 1H NMR (600 MHz, DMSO-d6) d 11.14 (s, 1H),
9.03 (s, 1H), 8.05 (d, J ¼ 1.6 Hz, 1H), 8.01 (d, J ¼ 8.8 Hz, 1H),
7.83 (d, J ¼ 8.3 Hz, 2H), 7.50 (s, 1H), 7.48 (dd, J ¼ 8.8 Hz, 1.6 Hz,
1H), 7.33 (d, J ¼ 8.3 Hz, 2H), 2.30 (s, 3H); 13C NMR (150 MHz,
DMSO-d6) d 151.8, 147.6, 143.4, 138.0, 137.2, 136.0, 129.9,
129.6, 127.0, 126.4, 124.8, 123.7, 104.4, 20.9; IR nmax (lm):
3057, 2846, 2753, 1627, 1516, 1418, 1344, 1156, 1092,
946 cmꢂ1; HRMS m/z calcd for C16H14ClN2O2S [M + H]+:
333.0465; found: 333.0468.
N-([1,3]Dioxolo[4,5-g]isoquinolin-7-yl)-4-methylbenzenesulfon
1
amide (3j). Yield: 56%; H NMR (400 MHz, DMSO-d6) d 10.83 (s,
1H), 8.67 (s, 1H), 7.77 (d, J ¼ 8.0 Hz, 2H), 7.39 (s, 1H), 7.34–7.28 (m,
3H), 7.27 (s, 1H), 6.15 (s, 2H), 2.30 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) d 151.4, 148.7, 147.2, 146.1, 143.1, 137.5, 136.0, 129.5,
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127.0, 122.6, 106.5, 102.5, 101.9, 101.8, 21.0; IR nmax (lm): 3329,
2919, 2848, 1604, 1451, 1341, 1229, 1150, 1039 cmꢂ1; HRMS m/z
calcd for C17H15N2O4S [M + H]+: 343.0753; found: 343.0759.
N-(6,7-Dimethoxyisoquinolin-3-yl)-4-methylbenzenesulfon
amide (3k). Yield: 55%; 1H NMR (400 MHz, DMSO-d6) d 10.82 (s,
1H), 8.71 (s, 1H), 7.77 (d, J ¼ 8.3 Hz, 2H), 7.41 (s, 1H), 7.34–7.28 (m,
3H), 7.26 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 2.30 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 153.4, 149.1, 148.3, 145.6, 143.0, 137.7,
134.2, 129.5, 126.9, 121.5, 105.7, 105.3, 104.5, 55.8, 55.6, 21.0; IR
nmax (lm): 3060, 2848, 1597, 1507, 1423, 1337, 1244, 1161, 1091,
990 cmꢂ1; HRMS m/z calcd for C18H19N2O4S [M + H]+: 359.1066;
found: 359.1068.
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¨
4-Methyl-N-(1-phenylisoquinolin-3-yl)benzenesulfonamide
(3l). Yield: 81%; 1H NMR (400 MHz, CDCl3) d 7.95 (d, J ¼ 8.5 Hz,
1H), 7.84–7.78 (m, 3H), 7.77 (s, 1H), 7.68 (s, 1H), 7.63 (ddd, J ¼
8.3 Hz, 6.8 Hz, 1.0 Hz, 1H), 7.54–7.49 (m, 2H), 7.48–7.42 (m, 3H),
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´
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2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.5, 144.6, 144.1,
12444.
´
139.0, 138.4, 136.5, 130.7, 129.9, 129.8, 129.0, 128.5, 127.6, 11 A. S. Canepa and R. D. Bravo, J. Heterocycl. Chem., 2006, 43,
127.5, 127.0, 126.1, 124.5, 105.9, 21.6; IR nmax (lm): 3061, 2921, 235–238.
1733, 1622, 1592, 1558, 1339, 1154, 1089, 952 cmꢂ1; HRMS m/z 12 G. V. Boyd, P. F. Lindley and G. A. Nicolaou, J. Chem. Soc.,
calcd for C22H19N2O2S [M + H]+: 375.1167; found: 375.1168.
Chem. Commun., 1984, 1105–1107.
N-(Benzo[f]isoquinolin-2-yl)-4-methylbenzenesulfonamide
(3o). Yield: 91%; H NMR (600 MHz, DMSO-d6) d 11.22 (s, 1H), 14 B. S. Pilgrim, A. E. Gatland, C. T. McTernan, P. A. Procopiou
13 H. Suzuki and H. Abe, Synthesis, 1995, 1995, 763–765.
1
8.97 (s, 1H), 8.59–8.54 (m, 1H), 8.24 (s, 1H), 8.03–7.99 (m, 1H),
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2H), 2.29 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d 150.5, 148.8,
143.3, 137.5, 136.2, 133.4, 129.6, 129.3, 128.8, 127.5, 127.4,
127.1, 126.5, 124.5, 123.2, 123.1, 102.5, 20.9; IR nmax (lm): 3071,
2838, 1595, 1499, 1345, 1156, 963 cmꢂ1; HRMS m/z calcd for
(b) M. Alajarin, M. Marin-Luna and A. Vidal, Eur. J. Org.
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C
20H17N2O2S [M + H]+: 349.1011; found: 349.1014.
4-Methyl-N-(thieno[2,3-c]pyridin-5-yl)benzenesulfonamide
1
(3p). Yield: 55%; H NMR (600 MHz, DMSO-d6) d 10.94 (s, 1H),
8.86 (s, 1H), 8.07 (d, J ¼ 5.3 Hz, 1H), 7.78 (d, J ¼ 8.3 Hz, 2H), 7.59
(d, J ¼ 0.8 Hz, 1H), 7.47 (d, J ¼ 5.3 Hz, 1H), 7.32 (d, J ¼ 8.3 Hz,
2H), 2.31 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d 147.1, 143.1,
137.5, 135.2, 131.3, 129.5, 126.9, 123.1, 105.5, 20.9; IR nmax
(lm): 2869, 2848, 1596, 1490, 1437, 1406, 1341, 1302, 1152,
1091, 977 cmꢂ1; HRMS m/z calcd for C14H13N2O2S2 [M + H]+:
305.0418; found: 305.0426.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
17 Z. F. Xu, X. Yu, D. Yang and C. Y. Li, Org. Biomol. Chem., 2017,
15, 3161–3164.
18 J. Dong, X. X. Shi, J. J. Yan, J. Xing, Q. Zhang and S. Xiao, Eur.
J. Org. Chem., 2010, 6987–6992.
19 CCDC 2026878 (3a) contains the ESI† crystallographic data
for this paper.
This research was funded by the Drug Innovation Major Project
(2018ZX09711-001-005-008); National Natural Science Founda-
tion of China (81502929) and CAMS Innovation Fund for
Medical Sciences (2016-I2M-3-015).
Notes and references
1 M. Iranshahy, R. J. Quinn and M. Iranshahi, RSC Adv., 2014,
4, 15900–15913.
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