Organic Letters
Letter
Scheme 1. General Approach for the Synthesis of N-
Table 1. Optimization of the Reaction Conditions
(Isoquinolin-1-yl)sulfonamides
a
b
entry
catalyst
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
Ag(OTf)
Ag(OTf)
Ag(OTf)
AgNO3
AgCl
Ag(CF3CO2)
Ag2O
Ag2O
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
toluene
THF
25
30
50
50
50
50
50
50
50
50
50
50
50
50
40
44
66
45
c
NR
73
91
60
56
66
64
37
48
55
9
Ag2O
Ag2O
Ag2O
10
11
12
13
14
MeCN
MeOH
DCE
DCE
Ag2O
d
Ag2O
e
Ag2O
alcohols as an efficient path for the synthesis of 2-(isoquinolin-
1-yl) prop-2-en-1-ones via a novel tandem reaction.6g After
careful examination of all these reports, we envisioned that o-
alkynylbenzaldoximes could be the key to solve the puzzle of
synthesizing N-(isoquinolin-1-yl)sulfonamides.
a
Reaction Conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10
mol %), solvent (1.5 mL), under N2 atmosphere, temp °C, 5 h.
b
c
d
e
Isolated yield. No reaction observed. Catalyst (5 mol %). Catalyst
(20 mol %).
Aware that cycloaddition reactions of ketenimine species as
a reactive heterocumulene with compatible 1,3-dipoles7 and 2-
or 4-atom synthons8 have been addressed on the synthesis of
myriad heterocyclic compounds,9 we have anticipated that
ketenimine may be a suitable reaction partner for ortho-
alkynylbenzaldoximes. Herein, we disclose the development of
a novel method for the synthesis of valuable N-(isoquinolin-1-
yl)sulfonamide derivatives through a tandem reaction of ortho-
alkynylbenzaldoximes and pyridine-stabilized ketenimine salts
in the presence of silver oxide as a catalyst.
product detected in the presence of AgCl (Table 1, entries 4
and 5). Further exploration revealed that (Z)-4-methyl-N-(3-
phenylisoquinolin-1(2H)-ylidene)benzenesulfonamide 3a
could be formed in 73% and 91% yields when Ag(CF3CO2)
and Ag2O are employed as the reaction catalyst, respectively
(Table 1, entries 6 and 7). We also inspected a series of
solvents (Table 1, entries 8−12), but no better results were
obtained, and dichloroethane was found to be the most
favorable in terms of yields. Also, performing of reaction under
ambient air condition was only accompanied by an increase in
byproducts, showing that an inert atmosphere is necessary for
the best results. Lower yields came about when the reaction
was carried out with the lesser and higher amounts of catalyst
(Table 1, entries 13 and 14), which might respectively be
related to the turnover number of Ag2O and the likely increase
of side reactions.
Following these optimization studies, a wide range of
substituted ortho-alkynylbenzaldoximes was tested to establish
the scope and generality of this Ag2O-catalyzed tandem
sequence (Scheme 2). In the majority of cases, the anticipated
reaction proceeded smoothly, leading to corresponding N-
(isoquinolin-1-yl)sulfonamides 3 in moderate to good yields.
ortho-Alkynylbenzaldoxime derivatives that bear electron-
donating groups (R = C6H5, Me, OMe, OCH2O) on phenyl
ring at both R1 and R2 positions were quite compatible,
furnishing the targeted products (3b−3d, 3f−3h) in 70−83%
yields. In contrast, chloro-substituted ortho-alkynylbenzaldox-
ime at R1 position could give the desired product 3e in only
51% yield, and no desired product was detected in case of
using a stronger electron-withdrawing group (3l, 3m). This
finding may be linked to the descending HOMO energy level
of isoquinoline N-oxide and eventuated stability in the
existence of electron-withdrawing groups. It appears that the
nature of substituents R2 attached to the triple bond could
have a large impact on the reaction efficiency since aryl groups
(3a−3i) have demonstrated better results than alkyls (3j, 3k,
To test the feasibility of our hypothesis, we first tried to
investigate the reaction of 2-(phenylethynyl)benzaldehyde
oxime 1a as the isoquinoline N-oxide precursor with
phenylacetylene and tosyl azide as a common in situ generated
ketenimine10 in the presence of a base and catalytic amount of
copper(I) bromide and silver triflate (see the Supporting
Information for more details). This targeted strategy was
inspired by Wu’s work for the synthesis of 2-amino-H-
pyrazolo[5,1-a]isoquinolines.11 This proposed route could not
fulfill our purpose since 3-phenylisoquinoline was obtained as
the product in 55% yield. Thus, we shifted our focus on newly
discovered pyridine-stabilized ketenimines,12 and zwitterionic
salt 2a was selected as a model substrate to react with 2-
(phenylethynyl)benzaldehyde oxime 1a. At the outset, when
the reaction was carried out in the presence of 10 mol % silver
triflate in dichloroethane at room temperature under a N2
atmosphere, unexpected (Z)-4-methyl-N-(3-phenylisoquino-
lin-1(2H)-ylidene)benzenesulfonamide 3a was obtained in
40% yield (Table 1, entry 1). X-ray structure shows that, due
to intramolecular hydrogen bonding, the iminoisoquinoline
tautomeric form of N-(isoquinolin-1-yl)sulfonamides is more
stable (Table 1). Encouraged by this result, we attempted to
optimize the reaction by raising the temperature (Table 1,
entries 1−3). Gratifyingly, the yield considerably increased to
66% at 50 °C (Table 1, entry 3). We then screened a variety of
several silver catalysts. Switching the catalyst to AgNO3,
compound 3a could be generated in only 45% yield, and no
3525
Org. Lett. 2021, 23, 3524−3529