Facile preparation of 3-aryl-4-iodoisoquinolines from N-(o-Arylethynyl)benzyl p-toluenesulfonamides with iodine and base

Article abstract of DOI:10.1016/j.tet.2021.131993

Treatment of N-(o-arylethynyl)benzyl p-toluenesulfonamides with molecular iodine in the presence of NaHCO₃ at 60 °C, followed by the reaction with ^tBuOK at room temperature gave 3-aryl-4-iodoisoquinolines in good yields. 4-Iodo-3-phenylisoquinoline, which is one of the obtained 3-aryl-4-iodoisoquinolines, was further transformed into isoquinoline derivatives smoothly. The present approach is a novel one-pot method for the preparation of 3-aryl-4-iodoisoquinolines from N-(o-arylethynyl)benzyl p-toluenesulfonamides under transition-metal-free conditions.

Full text of DOI:10.1016/j.tet.2021.131993

Tetrahedron 83 (2021) 131993
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Tetrahedron
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Facile preparation of 3-aryl-4-iodoisoquinolines from
N-(o-Arylethynyl)benzyl p-toluenesulfonamides with iodine and base
Hiroki Naruto, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba, 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of N-(o-arylethynyl)benzyl p-toluenesulfonamides with molecular iodine in the presence of
NaHCO3 at 60 ꢀC, followed by the reaction with tBuOK at room temperature gave 3-aryl-4-
iodoisoquinolines in good yields. 4-Iodo-3-phenylisoquinoline, which is one of the obtained 3-aryl-4-
iodoisoquinolines, was further transformed into isoquinoline derivatives smoothly. The present
approach is a novel one-pot method for the preparation of 3-aryl-4-iodoisoquinolines from N-(o-ary-
lethynyl)benzyl p-toluenesulfonamides under transition-metal-free conditions. © 2021 Elsevier Science.
All rights reserved.
Received 10 December 2020
Received in revised form
18 January 2021
Accepted 28 January 2021
Available online 6 February 2021
Keywords:
Isoquinoline
Iodine
© 2021 Elsevier Ltd. All rights reserved.
Iodocyclization
Alkyne
One pot
1. Introduction
disubstituted 1-ethoxyisoquinolines from O-ethyl benzimidates
and alkynes [3c]; the Ir(III)-catalyzed preparation of 1-substituted
Isoquinoline is one of the important nitrogen-containing het-
eroaromatics and is contained as a unit in many natural products,
i.e., isoquinoline alkaloids [1]. Some isoquinolines possess potent
biological activity. For example, Tamoxifen analogue shows anti-
estrogenic activity [1d], Decumbenine B exhibits antineuralgic ac-
tivity [1e], and Papaverine has antispasmodic activity [1e], as
shown in Fig. 1.
3,4-diphenylisoquinolines from aryl ketoximes and diphenylace-
tylene [3d]; and the Rh(III)-catalyzed preparation of 1,3,5-
trisubstituted isoquinolines from acetophenones, hydroxylamine-
O-sulfonic acid, and alkynes [3e]. The preparation of 3-
alkylisoquinolines from (
with trifluoroacetic acid [3f] and of 3-ethoxycarbonyl-1-(20,20,20-
trifluoroethyl)isoquinolines from -arylvinyl isocyanides with 2-
a-benzyl,a-alkyl)tosylmethyl isocyanides
b
Therefore, in addition to the conventional methods for the
preparation of the isoquinoline unit with the Pomeranz-Fritsch
iodo-1,1,1-trifluoroethane [3g] via cyclization of the isocyano
group, and the preparation of isoquinolines from o-bromo-
benzaldehyde acetal, ketones, and NH4Cl via a two-step operation
[3h] were also reported.
reaction using aromatic aldehydes and
and for the preparation of the 3,4-dihydroisoquinoline unit with
the Bischler-Napieralski reaction using N-acyl -arylethylamines
b-aminoacetals [2a,2b],
b
The Pd (0)-catalyzed preparation of 3,4-disubstituted iso-
quinolines from N-(tert-butyl) o-(1-alkynyl)benzaldimines with
aryl iodides (eq.1) [4] and the electrophile-mediated preparation of
3,4-disubstituted isoquinolines from N-(tert-butyl) o-(1-alkynyl)
benzaldimines with I2, ICl, or PhSeCl (eq. 2) [5], are attractive, as
shown in Scheme 1. In particular, the latter method does not
require any transition metals, and the introduced heteroatom
groups, such as iodine and phenylselenyl groups, at 4-position
could be further functionalized. However, the study for 4-
iodoisoquinoline synthesis in good yield with I2, which is much
less expensive than ICl and PhSeCl, is quite limited [5b]. The use of
molecular iodine in organic synthesis is very attractive and
important because it is a low-toxicity inorganic reagent and not a
and POCl3 [2c], extensive synthetic studies on the preparation of
the isoquinoline unit have been carried out [1b,1f]. Recent synthetic
studies for the preparation of isoquinolines with alkynes are as
follows:3 the Rh(I)-catalyzed preparation of 1-substituted 3,4-
diphenylisoquinolines from acetophenones, benzylamine, and
diphenylacetylene [3a]; the Ni(II)-catalyzed preparation of 3,4-
diarylisoquinolines from 2-iodobenzaldehydes, tert-butylamine,
and diarylacetylenes [3b]; the Ir(III)-catalyzed preparation of 3,4-
* Corresponding author.
E-mail address: togo@faculty.chiba-u.jp (H. Togo).
https://doi.org/10.1016/j.tet.2021.131993
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
Then, sulfonamide 1A (0.5 mmol) was treated with I2 (3.0 equiv.)
and NaHCO3 (1.1 equiv.) in acetonitrile at 60 ꢀC for 12 h (1st step).
Removal of the solvent followed by reaction with tBuOK (8.0 equiv.)
in THF at room temperature for 10 h (2nd step) gave 4-iodo-3-
phenylisoquinoline 3A in 65% yield in one pot, as shown in
Table 1 (entry 5). However, when K2CO3, Na2CO3, Cs2CO3, K3PO4,
and CH3CO2K were used as the base instead of NaHCO3 in the 1st
reaction step under the same procedure and conditions, isoquino-
line 3A was not obtained at all for the first four bases, and it was
obtained in only 13% yield when CH3CO2K was used as the base
(entries 6e10). In those reactions, sulfonamide 1A were recovered
mainly in the range of 50%e56% yields. Moreover, when the
amount of NaHCO3 was increased to 2.0 equiv. in the 1st reaction
step under the same procedure and conditions, the yield of iso-
quinoline 3A was decreased to 39% (entry 11). Increasing the
Fig. 1. Isoquinoline derivatives bearing biological activities.
Table 1
Optimization for one-pot preparation of 4-iodo-3-phenylisoquinoline 3A.
entry
X (equiv.)
base
Y (equiv.)
Yield (%)
1a
1.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
1.0
NaHCO3
NaHCO3
NaHCO3
e
e
(31)b
(49)b
(66)b
(63)b
65
0
0
0
0
2a
e
Scheme 1. Preparation of Isoquinoline Cores.
3a
e
4a
e
5
6
7
8
NaHCO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
10.0
10.0
10.0
15.0
10.0
10.0
10.0
e
transition metal. Recently, molecular iodine has been used for
functional group transformation and iodocyclization [6].
As part of our synthetic studies of nitrogen-containing hetero-
aromatics, such as quinolines, phenanthridines, and oxazoles, with
molecular iodine and related iodine reagents [7], we would like to
report herein a novel transformation of N-(o-arylethynyl)benzyl p-
toluenesulfonamides into 3-aryl-4-iodoisoquinolines through the
iodocyclization and the subsequent elimination of the tosyl group,
as shown in eq. 3 (Scheme 1).
9
10
11c
12d
13
14
15e
16f
17
18g
19h
20i
21a,j
22a,k
CH3CO2K
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
13
39
61
41 (42)b
85
19 (4)b
80
48
78
47
2. Results and discussion
First, iodocyclization of N-(o-phenylethynyl)benzyl p-toluene-
sulfonamide 1A (0.5 mmol) with I2 (1.0 equiv., 2.0 equiv., and 3.0
equiv.) in the presence of NaHCO3 (1.1 equiv.) in acetonitrile at 60 ꢀC
0
(46)b
(40)b
e
a
for 12
h
was studied to give 4-iodo-3-phenyl-2-tosyl-1,2-
Only 1st reaction step was carried out.
b
c
Yield of 4-iodo-3-phenyl-2-tosyl-1,2-dihydroisoquinoline (2A).
In 1st reaction step, NaHCO3 (2.0 equiv.) was added.
Reaction was carried out at 80 ꢀC in 1st reaction step.
dihydroisoquinoline 2A in 31%, 49%, and 66% yield, respectively
(entries 1e3). When the iodocyclization was carried out in the
absence of NaHCO3 under the same conditions as those of entry 3,
the yield of 1,2-dihydroisoquinoline 2A was slightly decreased to
63% (entry 4). Thus, the use of 3.0 equiv. of I2 with NaHCO3 (1.1
equiv.) was the best to form 1,2-dihydroisoquinoline 2A in good
yield (entry 3). Further treatment of 1,2-dihydroisoquinoline 2A
with tBuOK (8.0 equiv.) in THF at room temperature for 10 h gave 4-
iodo-3-phenylisoquinoline 3A quantitatively.
d
e
THF (5.0 mL) in 1st reaction step and CH3CN (10.0 mL) in 2nd step reaction were
used.
f
1st reaction step was carried out for 6 h.
g
h
i
Instead of N-Ts group in 1A, NeSO2C6H4Cl-p group was used.
Instead of N-Ts group in 1A, NeSO2C2H5 group was used.
Instead of I2, NIS (5.0 equiv.) was used.
NBS (1.0 equiv.) was added in 1st reaction step.
NCS (1.0 equiv.) was added in 1st reaction step.
j
k
2

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
reaction temperature to 80 ꢀC in the 1st reaction step under the
same procedure and conditions gave isoquinoline 3A in 61% yield
(entry 12). On the other hand, treatment of sulfonamide 1A with I2
(5.0 equiv.) and NaHCO3 (1.1 equiv.) at 60 ꢀC for 12 h, followed by
the removal of the solvent and the reaction with tBuOK (8.0 equiv.
and 10.0 equiv.) at room temperature for 10 h gave isoquinoline 3A
in 41% yield together with 2A (42% yield, entry 13) and 3A in 85%
yield (entry 14), respectively. When the present one-pot reaction
was carried out in THF (5.0 mL) in the 1st reaction step and in
acetonitrile (10.0 mL) in the 2nd reaction step (inversed solvent
system) under same procedure and conditions, the yield of iso-
quinoline 3A was quite decreased to 19% together with 2A in 4%
(entry 15). When the reaction time was shortened to 6 h in the 1st
reaction step, the yield of isoquinoline 3A was slightly decreased to
80% (entry 16). Increasing the amount of tBuOK (15.0 equiv.)
reduced the yield of isoquinoline 3A (entry 17). When sulfonamides
1 bearing NeSO2C6H4Cl-p and NeSO2C2H5 groups instead of the N-
Ts group were used under the same procedure and conditions,
isoquinoline 3A was obtained in 78% and 47% yields, respectively
(entries 18, 19). On the other hand, when N-iodosuccinimide (NIS)
was used instead of I2, isoquinoline 3A was not formed at all (entry
20). Finally, the addition of N-bromosuccinimide (NBS) and N-
chlorosuccinimide (NCS) to promote the iodocyclization through
the interaction of I2 and NBS or NCS in 1st reaction step was not so
effective (entries 21, 22) [8]. Thus, treatment of sulfonamide 1A
(0.5 mmol) with I2 (5.0 equiv.) and NaHCO3 (1.1 equiv.) in aceto-
nitrile (5.0 mL) at 60 ꢀC for 12 h (1st step), followed by the removal
t
of the solvent and the reaction with BuOK (10.0 equiv.) in THF
(10.0 mL) at room temperature for 10 h (2nd step) gave isoquinoline
3A in the best yield (entry 14). As a gram-scale experiment, treat-
ment of N-(o-phenylethynyl)benzyl p-toluenesulfonamide 1A
(3.0 mmol) under the best reaction conditions gave 4-iodo-3-
phenylisoquinoline 3A in 83% yield, as shown in Scheme 2.
Then, to evaluate the generality of the present reaction, other N-
(o-arylethynyl)benzyl p-toluenesulfonamides 1 were studied, as
shown in Scheme 2. Treatment of N-(o-arylethynyl)benzyl p-tol-
uenesulfonamides 1 bearing.
O-methylphenyl (B), m-methylphenyl (C), p-methylphenyl (D),
p-ethylphenyl (E), p-tert-butylphenyl (F), 2,4-dimethylphenyl (G),
3,5-dimethylphenyl (H), o-methoxyphenyl (I), m-methoxyphenyl
(J), p-methoxyphenyl (K), p-ethoxyphenyl (L), p-fluorophenyl (M),
p-chlorophenyl (N), p-bromophenyl (O), naphthalen-1-yl (P), p-
biphenyl (Q), and 1,3-benzodioxol-5-yl (R) groups with I2 (5.0
equiv.) and NaHCO3 (1.1 equiv.) in acetonitrile (5.0 mL) at 60 ꢀC for
12 h (1st step), followed by the removal of the solvent and reaction
t
with BuOK (10.0 equiv.) in THF (10.0 mL) for 10 h at room tem-
perature (2nd step) generated 3-aryl-4-iodoisoquinolines 3B~3R in
good yields, respectively. N-[o-(Thiophen-3-yl)ethynyl]benzyl p-
toluenesulfonamide 1S and N-[o-(cyclohexen-1-yl)ethynyl]benzyl
p-toluenesulfonamide 1T also underwent the reaction under the
same procedure and conditions to give isoquinoline 3S in good
yield and isoquinoline 3T in moderate yield, respectively. Treat-
ment of N-(phenylethynyl)benzyl p-toluenesulfonamides 1U, 1V,
and 1W bearing substituents on the benzylic aromatic ring, such as
methyl, chloro, and 1,2-methylenedioxy groups, under the same
procedure and conditions generated 4-iodo-7-methyl-3-
phenylisoquinoline 3U, 7-chloro-4-iodo-3-phenylisoquinoline 3V,
and 4-iodo-6,7-methylenedioxy-3-phenylisoquinoline 3W in good
to moderate yields, respectively. As a related reagent to I2 that has
an electrophilic character, treatment of N-(o-phenylethynyl)benzyl
Scheme 2. One-pot Transformation of N-(o-Arylethynyl)benzyl p-Toluenesulfona-
mides 1 to 3-Aryl-4-iodoisoquinolines 3. a Compound 1A (3.0 mmol) was used. b In 1st
c
d
reaction, I2 (6.0 equiv.) was used. 1st reaction step was carried out at r. t. Only 1st
e
reaction step was carried out. Instead of I2, PhSeCl (5.0 equiv.) was used.
3

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
presence of CuI in isopropanol at 80 ꢀC gave 4-(p-methyl-
benzenesulfenyl)-3-phenylisoquinoline 5A in 75% yield. The Pd-
catalyzed CeC bond formation of 4-iodo-3-phenylisoquinoline 3A
with 4-ethynyltoluene and CuI in Et3N at 60 ꢀC, with 4-vinyltoluene
and K2CO3 in DMF at 130 ꢀC, and with 4-methylphenylboronic acid
and K2CO3 in a mixture of DMF and water at 60 ꢀC provided 4-(40-
methylphenyl)ethynyl-3-phenylisoquinoline 6A in 99% yield, 4-(40-
methylphenyl)ethenyl-3-phenylisoquinoline 7A in 90% yield, and
4-(40-methylphenyl)-3-phenylisoquinoline 8A in 94% yield,
respectively. Treatment of 4-iodo-3-phenylisoquinoline 3A with Zn
in ethanol under refluxing conditions, followed by the reaction
with benzoyl peroxide (BPO) and trifluoroacetic acid in a mixture of
cyclohexane and 1,2-dichloroethane at 100 ꢀC generated 1-
cyclohexyl-3-phenylisoquinoline 9A in 85% yield.
A possible reaction pathway for the present one-pot preparation
of 3-aryl-4-iodoisoquinolines 3 from N-(o-arylethynyl)benzyl p-
toluenesulfonamides 1 is shown in Scheme 4. I2 activates the
ethynyl group of N-(o-arylethynyl)benzyl p-toluenesulfonamides 1
to generate iodonium species I, and then the nitrogen atom of the
sulfonamide group attacks the activated carbon atom via 6-endo-
dig
mode
to
generate
3-aryl-4-iodo-2-tosyl-1,2-
t
dihydroisoquinoline 2 (1st step). BuOK abstracts a proton of 1-
position of 3-aryl-4-iodo-2-tosyl-1,2-dihydroisoquinoline 2 via E2
reaction to generate 3-aryl-4-iodoisoquinoline 3 together with
potassium p-toluenesulfinate, the latter of which was identified by
the reaction with iodomethane as methyl p-methylphenyl sulfone.
Scheme 3. Derivatization of 4-Iodo-3-phenylisoquinoline 3A.
3. Conclusion
3-Aryl-4-iodoisoquinolines could be efficiently obtained in good
yields by the reaction of N-(o-arylethynyl)benzyl p-toluenesulfo-
namides with I2 in the presence of NaHCO3, followed by the reac-
tion with tBuOK in one pot. The present method is a novel approach
for the preparation of 3-aryl-4-iodoisoquinolines from N-(o-aryle-
thynyl)benzyl p-toluenesulfonamides. We believe the present
method would be useful because of its easy operation and the use
of low-toxicity reagents under transition-metal-free conditions.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were obtained with JEOL-JNM-
ECX400 and JEOL-JNM-ECS400 spectrometers. Chemical shifts
were recorded as follows: chemical shift in ppm from internal
Scheme 4. Possible Reaction Pathway.
tetramethylsilane (TMS) on the
d
scale, multiplicity (s ¼ singlet;
p-toluenesulfonamide 1A with PhSeCl (5.0 equiv.) and NaHCO3 (1.1
equiv.) in acetonitrile (5.0 mL) at 60 ꢀC for 12 h (1st step) gave 3-
phenyl-4-phenylselenylisoquinoline 3X in good yield, without
d ¼ doublet; t ¼ triplet; q ¼ quartet; m ¼ multiplet; b ¼ broad),
coupling constant (Hz) and integration. High-resolution mass
spectra (HRMS) were recorded by a Thermo Fisher Scientific
Exactive Orbitrap mass spectrometer. IR spectra were measured
t
treatment with BuOK.
Overall,
the
formation
of
3-aryl-4-iodo-2-tosyl-1,2-
with
a JASCO FT/IR-4100 spectrometer. Melting points were
dihydroisoquinolines 2 from N-(o-arylethynyl)benzyl p-toluene-
sulfonamides 1 with I2 in the presence of NaHCO3 proceeded
smoothly. However, N-(o-alkylethynyl)benzyl p-toluenesulfona-
mides 1 bearing propyl, cyclohexyl, and cyclopropyl groups were
inert under the present reaction conditions (1st step). Therefore, 3-
alkyl-4-iodo-2-tosyl-1,2-dihydroisoquinolines were not formed
from N-(o-alkylethynyl)benzyl p-toluenesulfonamides.
determined with a Yamato Melting Point Apparatus Model MP-21.
Silica gel 60F254 (Merck) was used for TLC and Silica gel 60 N
(63e210 mesh, Kanto Kagaku Co.) was used for short column
chromatography.
4.2. Typical procedure for preparation of N-(o-arylethynyl)benzyl
Once 3-aryl-4-iodoisoquinolines 3 were formed, they could be
smoothly transformed into various 3-arylisoquinoline derivatives
because of their CeI bond. Specifically, 3-phenylisoquinoline 4A
was obtained in 99% yield by the treatment of 4-iodo-3-
phenylisoquinoline 3A with Zn in ethanol under refluxing condi-
tions, as shown in Scheme 3. Treatment of 4-iodo-3-
phenylisoquinoline 3A with p-toluenethiol and K2CO3 in the
p-toluenesuldonamide 1
To a solution of o-bromobenzaldehyde (10.0 mmol, 1.85 g),
PdCl2(PPh3)2 (0.2 mmol, 140.4 mg) and CuI (0.1 mmol, 19.0 mg) in
Et3N (0.3 M) was added ethynylbenzene (12.0 mmol, 1.32 mL). The
obtained mixture was stirred for 12 h at 50 C under argon atmo-
sphere. Sat. aq. NH4Cl solution (15.0 mL) was added to the mixture,
ꢀ
4

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
and the product was extracted with CHCl3 (15.0 mL ꢁ 3). The
organic layer was dried over Na2SO4 and filtered. After removal of
the solvent under reduced pressure, the residue was purified by
silica-gel column chromatography (eluent: n-hexane:EtOAc ¼ 19:1)
to give o-(phenylethynyl)benzaldehyde (1.96 g, 95%). To a solution
of o-(phenylethynyl)benzaldehyde in EtOH (1.0 M) was added hy-
droxylamine hydrochloride (1.2 equiv.). The mixture was stirred for
1 h at room temperature. To the obtained mixture were slowly
added Zn powder (2.5 equiv.) and hydrochloric acid (12.0 M, 4.0
equiv.) at 0 ꢀC. The obtained mixture was stirred for 0.5 h at room
temperature under argon atmosphere. A solution of ammonia
(28e30%) was slowly added until pH S 7, and the product was
extracted with CHCl3 (15.0 mL ꢁ 3). The organic layer was dried
over Na2SO4 and filtered. After removal of the solvent under
reduced pressure, p-toluenesulfonyl chloride (1.1 equiv.) and pyri-
dine (0.5 M) were added to the residue in dichloromethane (1.0 M)
at 0 ꢀC. The obtained mixture was stirred for 12 h at room tem-
perature under argon atmosphere. Aq. NH4Cl solution (15.0 mL)
was added to the mixture, and the product was extracted with
CHCl3 (15.0 mL ꢁ 3). Then, the organic layer was dried over Na2SO4
and filtered. After removal of the solvent under reduced pressure,
the residue was purified by silica-gel column chromatography
(eluent: n-hexane:EtOAc ¼ 3:1) to give N-(o-phenylethynyl)benzyl
p-toluenesulfonamide 1A (2.76 g, 76%). Other N-(o-arylethynyl)
benzyl p-toluenesulfonamides 1Be1W were obtained in 55%e78%
yields by the same procedure.
J ¼ 7.4 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5 (2C), 46.3, 85.9,
94.6, 119.4, 122.4, 127.1, 127.8, 128.5, 128.8, 129.2, 129.5, 131.4, 132.2,
136.8, 137.6, 138.9, 143.2; HRMS (ESI): Calcd for C23H22O2NS
[MþH]þ ¼ 376.1366, Found ¼ 376.1362.
4.2.5. N-[o-(p-ethylphenyl)ethynyl]benzyl p-toluenesulfonamide
(1E)
White solid; mp: 152e153 ꢀC; IR (neat): 2331, 2212, 1321,
1157 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 1.27 (t, 3H, J ¼ 7.6 Hz)
2.38 (s, 3H), 2.69 (q, 2H, J ¼ 7.6 Hz), 4.36 (d, 2H, J ¼ 6.5 Hz), 4.96 (t,
1H, J ¼ 6.3 Hz), 7.17e7.20 (m, 4H), 7.22e7.25 (m, 3H), 7.33 (d, 2H,
J ¼ 8.1 Hz), 7.43e7.45 (m, 1H), 7.70 (d, 2H, J ¼ 8.3 Hz); 13C NMR
(100 MHz, CDCl3):
d
¼ 15.3, 21.4, 28.8, 46.2, 85.8, 94.6, 119.6, 122.4,
127.1, 127.7, 127.9, 128.5, 128.7, 129.5, 131.5, 132.1, 136.8, 137.6, 143.2,
145.2; HRMS (ESI): Calcd for C24H24O2NS [MþH]þ ¼ 390.1522,
Found ¼ 390.1519.
4.2.6. N-[o-(p-tert-butylphenyl)ethynyl]benzyl) p-
toluenesulfonamide (1F)
White solid; mp: 111e112 ꢀC; IR (neat): 2334, 2220, 1324,
1157 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 1.35 (s, 9H), 2.73 (s, 3H),
4.36 (d, 2H, J ¼ 6.3 Hz), 4.96 (t,1H, J ¼ 5.8 Hz), 7.17 (d, 2H, J ¼ 8.1 Hz),
7.21e7.26 (m, 3H), 7.33e7.39 (m, 4H), 7.43e7.45 (m, 1H), 7.70 (d, 2H,
J ¼ 8.1 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 31.1, 34.8, 46.3,
85.9, 94.6, 119.4, 122.4, 125.4, 127.1, 127.8, 128.5, 128.8, 129.5, 131.3,
132.2, 136.8, 137.6, 143.2, 152.1; HRMS (ESI): Calcd for C26H28O2NS
[MþH]þ ¼ 418.1835, Found ¼ 418.1832.
4.2.1. N-(o-phenylethynyl)benzyl p-toluenesulfonamide (1A)
White solid; mp: 165 ꢀC; IR (neat): 2337, 2212, 1322, 1152 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H), 4.37 (d, 2H, J ¼ 6.5 Hz),
4.2.7. N-[o-(20,40-dimethylphenyl)ethynyl]benzyl p-
toluenesulfonamide (1G)
4.94 (t, 1H, J ¼ 6.5 Hz), 7.18 (d, 2H, J ¼ 8.1 Hz), 7.23e7.29 (m, 3H),
7.34e7.42 (m, 5H), 7.45e7.89 (m, 1H), 7.71 (d, 2H, J ¼ 8.3 Hz); 13C
White solid; mp: 123e124 ꢀC; IR (neat): 2359, 2202, 1325,
NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.2, 86.4, 94.4, 122.2, 122.5, 127.1,
1157 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.35 (s, 3H), 2.36 (s, 3H),
127.8, 128.4, 128.7 (2C), 128.8, 129.5, 131.5, 132.2, 136.8, 137.7, 143.2;
22H20O2NS [MþH]þ
¼
362.1209,
2.73 (s, 3H), 4.37 (d, 2H, J ¼ 6.5 Hz), 4.96 (t, 1H, J ¼ 6.3 Hz), 6.99 (d,
1H, J ¼ 7.9 Hz), 7.05 (s,1H), 7.16 (d, 2H, J ¼ 7.9 Hz), 7.22e7.31 (m, 4H),
7.44e7.47 (m, 1H), 7.68 (d, 2H, J ¼ 8.3 Hz); 13C NMR (100 MHz,
HRMS (ESI): Calcd for
Found ¼ 362.1207.
C
CDCl3):
d
¼ 20.6, 21.4 (2C), 46.1, 89.6, 93.6, 119.3, 122.5, 126.4, 127.0,
4.2.2. N-[o-(o-methylphenyl)ethynyl]benzyl p-toluenesulfonamide
(1B)
127.7, 128.4 (2C), 129.5, 130.3, 131.8, 132.1, 136.8, 137.5, 138.9, 139.7,
143.2; HRMS (ESI): Calcd for C24H24O2NS [MþH]þ ¼ 390.1522,
Found ¼ 390.1519.
White solid; mp: 108 ꢀC; IR (neat): 2334, 2209, 1323, 1153 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 2.37 (s, 3H), 2.39 (s, 3H), 4.38 (d, 2H,
J ¼ 6.5 Hz), 4.93 (t, 1H, J ¼ 6.4 Hz), 7.16e7.20 (m, 3H), 7.22e7.30 (m,
5H), 7.37 (d, 1H, J ¼ 7.4 Hz), 7.45e7.49 (m, 1H), 7.69 (d, 2H,
4.2.8. N-[o-(30,50-dimethylphenyl)ethynyl]benzyl p-
toluenesulfonamide (1H)
J ¼ 8.5 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 20.8, 21.5, 46.2, 90.3,
93.4, 122.3, 122.4 (2C), 125.7, 127.1, 127.8, 128.6 (2C), 128.7, 129.6,
131.9, 132.3, 136.8, 137.5, 139.9, 143.3; HRMS (ESI): Calcd for
White solid; mp: 142e143 ꢀC; IR (neat): 2359, 2212, 1325,
1157 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.34 (s, 6H), 2.36 (s, 3H),
C
23H22O2NS [MþH]þ ¼ 376.1366, Found ¼ 376.1365.
4.37 (d, 2H, J ¼ 6.5 Hz), 5.01 (t, 1H, J ¼ 6.3 Hz), 7.02 (s, 1H), 7.08 (s,
2H), 7.17 (d, 2H, J ¼ 8.1 Hz), 7.22e7.24 (m, 3H), 7.42e7.44 (m, 1H),
4.2.3. N-[o-(m-methylphenyl)ethynyl]benzyl p-toluenesulfonamide
(1C)
7.69 (d, 2H, J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.1, 21.5,
46.3, 85.8, 94.9, 122.1, 122.3, 127.1, 127.8, 128.5, 128.7, 129.2, 129.5,
130.7, 132.3, 137.0, 137.7, 138.0, 143.2; HRMS (ESI): Calcd for
White solid; mp: 122 ꢀC; IR (neat): 2337, 2209, 1322, 1153 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 2.37 (s, 3H), 2.38 (s, 3H), 4.37 (d, 2H,
C
24H24O2NS [MþH]þ ¼ 390.1522, Found ¼ 390.1521.
J ¼ 6.5 Hz), 4.98 (t, 1H, J ¼ 6.5 Hz), 7.16e7.20 (m, 3H), 7.22e7.27 (m,
6H), 7.43e7.46 (m, 1H), 7.70 (d, 2H, J ¼ 8.5 Hz); 13C NMR (100 MHz,
CDCl3):
d
¼ 21.2, 21.4, 46.2, 86.1, 94.6,122.2,122.3,127.1, 127.7,128.3,
4.2.9. N-[o-(o-methoxyphenyl)ethynyl]benzyl p-
toluenesulfonamide (1I)
128.6 (2C), 128.7, 129.5, 129.6, 132.0, 132.2, 136.8, 137.7, 138.1, 143.2;
HRMS (ESI): Calcd for
Found ¼ 376.1361.
C
23H22O2NS [MþH]þ
¼
376.1366,
White solid; mp: 115e116 ꢀC; IR (neat): 2362, 2093, 1323, 1154,
1048 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.37 (s, 3H), 3.84 (s, 3H),
4.36 (d, 2H, J ¼ 6.5 Hz), 4.94 (t, 1H, J ¼ 6.5 Hz), 6.93 (d, 1H,
J ¼ 8.3 Hz), 6.98e7.01 (m, 2H), 7.19 (d, 2H, J ¼ 8.1 Hz), 7.23e7.29 (m,
4H), 7.45e7.47 (m, 1H), 7.71 (d, 2H, J ¼ 8.3 Hz); 13C NMR (100 MHz,
4.2.4. N-[o-(p-methylphenyl)ethynyl]benzyl p-toluenesulfonamide
(1D)
White solid; mp: 155 ꢀC; IR (neat): 2334, 2220, 1320, 1155 cmꢂ1
;
CDCl3):
d
¼ 21.4, 46.1, 55.3, 86.2, 94.3,115.1, 116.4, 122.1, 123.5, 124.0,
1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H), 2.40 (s, 3H), 4.36 (d, 2H,
127.0, 127.7 (2C), 128.7, 129.4, 129.5, 132.2, 136.7, 137.7, 143.3, 159.3;
HRMS (ESI): Calcd for
Found ¼ 392.1313.
J ¼ 6.5 Hz), 4.96 (t, 1H, J ¼ 6.4 Hz), 7.15e7.19 (m, 4H), 7.22e7.25 (m,
C
23H22O3NS [MþH]þ
¼
392.1315,
3H), 7.30 (d, 2H, J ¼ 8.1 Hz), 7.42e7.45 (m, 1H), 7.70 (d, 2H,
5

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
4.2.10. N-[o-(m-methoxyphenyl)ethynyl]benzyl p-
toluenesulfonamide (1J)
HRMS (ESI): Calcd for
Found 440.0315,
Found ¼ 442.0295.
C
22H19O2N79BrS [MþH]þ
¼
440.0314,
442.0294,
¼
C
22H19O2N81BrS [MþH]þ
¼
White solid; mp: 110 ꢀC; IR (neat): 2331, 2210, 1322, 1153,
1047 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.26 (s, 3H), 4.08 (s, 3H),
4.40 (d, 2H, J ¼ 7.2 Hz), 6.71 (t, 1H, J ¼ 6.7 Hz), 6.93e7.00 (m, 4H),
4.2.16. N-[o-(Naphthalen-1-yl)ethynyl]benzyl p-
7.08e7.11 (m, 3H), 7.21e7.24 (m, 1H), 7.36e7.40 (m, 1H), 7.43e7.46
toluenesulfonamide (1P)
(m, 3H); 13C NMR (100 MHz, CDCl3):
d
¼ 21.3, 47.1, 55.9, 91.1, 91.5,
White solid; mp: 158e159 ꢀC; IR (neat): 2331, 2192, 1321,
110.6, 111.6, 120.7, 122.4, 126.6, 127.4, 128.0, 128.8, 129.5, 130.3,
131.6, 132.6, 138.0, 138.1, 142.2, 160.2; HRMS (ESI): Calcd for
1156 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.27 (s, 3H), 4.46 (d, 2H,
J ¼ 6.5 Hz), 4.93 (t, 1H, J ¼ 6.9 Hz), 7.05 (d, 2H, J ¼ 8.1 Hz), 7.29e7.37
(m, 3H), 7.47 (t, 1H, J ¼ 8.3 Hz), 7.54e7.60 (m, 3H), 7.63e7.68 (m,
3H), 7.88e7.91 (m, 2H), 8.35e8.28 (m, 1H); 13C NMR (100 MHz,
C
23H22O3NS [MþH]þ ¼ 392.1315, Found ¼ 392.1312.
4.2.11. N-[o-(p-methoxyphenyl)ethynyl]benzyl p-
toluenesulfonamide (1K)
CDCl3):
d
¼ 21.4, 46.3, 91.2, 92.5, 120.2, 122.4, 125.2, 125.9, 126.6,
127.0 (2C), 127.9, 128.4, 128.8, 128.9, 129.2, 129.5, 130.6, 132.5, 133.0,
133.2, 136.7, 137.7, 143.2; HRMS (ESI): Calcd for C26H22O2NS
[MþH]þ ¼ 412.1366, Found ¼ 412.1363.
White solid; mp: 159e161 ꢀC; IR (neat): 2359, 2212, 1318, 1154,
1048 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H), 3.86 (s, 3H),
4.35 (d, 2H, J ¼ 6.5 Hz), 4.97 (t, 1H, J ¼ 6.3 Hz), 6.88 (d, 2H,
J ¼ 8.8 Hz), 7.18e7.24 (m, 5H), 7.35 (d, 2H, J ¼ 8.5 Hz), 7.42e7.44 (m,
4.2.17. N-[o-(p-biphenyl)ethynyl]benzyl p-toluenesulfonamide (1Q)
1H), 7.70 (d, 2H, J ¼ 8.1 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5,
Yellow solid; mp: 176e177 ꢀC; IR (neat): 2212, 1596, 1520 cmꢂ1
;
46.3, 55.3, 85.3, 94.5, 114.0, 114.5, 122.6, 127.1, 127.8, 128.3, 128.8,
129.6, 132.1, 133.0, 136.9, 137.5, 143.2, 159.9; HRMS (ESI): Calcd for
1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H), 4.39 (d, 2H, J ¼ 6.5 Hz),
4.96 (t, 1H, J ¼ 6.3 Hz), 7.20 (d, 2H, J ¼ 8.1 Hz), 7.24e7.29 (m, 3H),
C
23H22O3NS [MþH]þ ¼ 392.1315, Found ¼ 392.1314.
7.37e7.42 (m,1H), 7.46e7.50 (m, 5H), 7.59e7.64 (m, 4H), 7.72 (d, 2H,
J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.3, 87.1, 94.3,
4.2.12. N-[o-(p-ethoxyphenyl)ethynyl]benzyl p-toluenesulfonamide
(1L)
121.3, 122.3, 127.0, 127.1 (2C), 127.8, 127.9, 128.8 (2C), 128.9, 129.6,
132.0, 132.3, 136.8, 137.7, 140.1, 141.4, 143.3; HRMS (ESI): Calcd for
White solid; mp: 172 ꢀC; IR (neat): 2209, 1319, 1175, 1052 cmꢂ1
;
C
28H24O2NS [MþH]þ ¼ 438.1522, Found ¼ 438.1517.
1H NMR (400 MHz, CDCl3):
d
¼ 1.45 (t, 3H, J ¼ 7.0 Hz), 2.38 (s, 3H),
4.08 (q, 2H, J ¼ 7.0 Hz), 4.35 (d, 2H, J ¼ 6.5 Hz), 4.96 (t, 1H,
J ¼ 6.5 Hz), 6.87 (d, 2H, J ¼ 9.0 Hz), 7.18e7.25 (m, 5H), 7.33 (d, 2H,
J ¼ 8.8 Hz), 7.41e7.44 (m, 1H), 7.70 (d, 2H, J ¼ 8.3 Hz); 13C NMR
4.2.18. N-[o-(1,3-benzodioxol-5-yl)ethynyl]benzyl p-
toluenesulfonamide (1R)
Yellow solid; mp: 150e151 ꢀC; IR (neat): 2362, 2205, 1323, 1154,
(100 MHz, CDCl3):
d
¼ 14.7, 21.5, 46.3, 63.6, 85.2, 94.6, 114.3, 114.5,
1033 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.40 (s, 3H), 4.34 (d, 2H,
122.6,127.1,127.8,128.3,128.8,129.5,132.1,133.0,136.9,137.4,143.2,
159.3; HRMS (ESI): Calcd for C24H24O3NS [MþH]þ ¼ 406.1471,
Found ¼ 406.1470.
J ¼ 6.5 Hz), 4.90 (t, 1H, J ¼ 6.3 Hz), 6.02 (s, 2H), 6.79 (d, 1H,
J ¼ 8.1 Hz), 6.81 (s, 1H), 6.94 (dd, 1H, J ¼ 8.1, 1.6 Hz), 7.21e7.25 (m,
5H), 7.41e7.44 (m, 1H), 7.72 (d, 2H, J ¼ 8.2 Hz); 13C NMR (100 MHz,
CDCl3):
d
¼ 21.5, 46.3, 84.9, 94.4, 101.4, 108.5, 111.4, 115.7, 122.4,
4.2.13. N-[o-(p-fluorophenyl)ethynyl]benzyl p-toluenesulfonamide
(1M)
126.3,127.1, 127.8, 128.5, 128.8, 129.6,132.1, 136.8,137.5, 143.4,147.5,
148.2; HRMS (ESI): Calcd for C23H20O4NS [MþH]þ ¼ 406.1108,
Found ¼ 406.1107.
Gray solid; mp: 164e166 ꢀC; IR (neat): 2362, 2216, 1318,
1153 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s, 3H), 4.36 (d, 2H,
J ¼ 6.3 Hz), 4.88 (t,1H, J ¼ 6.7 Hz), 7.06 (t, 2H, J ¼ 8.8 Hz), 7.21 (d, 2H,
4.2.19. N-[o-(Thiophen-3-yl)ethynyl]benzyl p-toluenesulfonamide
(1S)
J ¼ 8.1 Hz), 7.24e7.25 (m, 3H), 7.39e7.46 (m, 3H), 7.71 (d, 2H,
J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.2, 86.2, 93.3,
Brown solid; mp: 163e164 ꢀC; IR (neat): 2359, 2205, 1322,
115.7 (d, JC-F ¼ 22.6 Hz), 118.6, 122.1, 127.1, 127.9, 128.7, 128.8, 129.6,
132.2, 133.5 (d, JC-F ¼ 8.5 Hz), 136.8, 137.7, 143.3, 162.7 (d, JC-
1154 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s, 3H), 4.34 (d, 2H,
J ¼ 6.5 Hz), 4.92 (t, 1H, J ¼ 6.7 Hz), 7.11 (dd, 1H, J ¼ 4.9, 1.1 Hz),
¼
250.9 Hz); HRMS (ESI): Calcd for C22H19O2NFS
7.19e7.25 (m, 4H), 7.32e7.34 (m, 2H), 7.43e7.45 (m, 2H), 7.71 (d, 2H,
F
[MþH]þ ¼ 380.1115, Found ¼ 380.1114.
J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.2, 86.0, 89.6,
121.5,122.3,125.6,127.1,127.9,128.6,128.8,129.1,129.6,129.7,132.2,
4.2.14. N-[o-(p-chlorophenyl)ethynyl]benzyl p-toluenesulfonamide
(1N)
136.8, 137.6, 143.3; HRMS (ESI): Calcd for
C20H18O2NS2
[MþH]þ ¼ 368.0773, Found ¼ 368.0771.
Gray solid; mp: 109e110 ꢀC; IR (neat): 2337, 2045, 1318,
1153 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s, 3H), 4.36 (d, 2H,
4.2.20. N-[o-(Cyclohexen-1-yl)ethynyl]benzyl p-
J ¼ 6.3 Hz), 4.86 (t, 1H, J ¼ 6.3 Hz), 7.21 (d, 2H, J ¼ 8.1 Hz), 7.23e7.27
toluenesulfonamide (1T)
(m, 3H), 7.34e7.34 (m, 4H), 7.44e7.47 (m, 1H), 7.71 (d, 2H,
White solid; mp: 119 ꢀC; IR (neat): 2363, 2205, 1323, 1155 cmꢂ1
;
J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.1, 87.4, 93.2,
1H NMR (400 MHz, CDCl3):
d
¼ 1.67e1.71 (m, 4H), 2.10e2.17 (m,
121.0,122.2,127.1,127.9,128.7,128.8,128.9,129.6,132.3,132.7,134.7,
4H), 2.40 (s, 3H), 4.28 (d, 2H, J ¼ 6.5 Hz), 5.01 (t, 1H, J ¼ 6.7 Hz),
6.11e6.13 (m, 1H), 7.14e7.19 (m, 3H), 7.22 (d, 2H, J ¼ 8.5 Hz),
7.30e7.33 (m, 1H), 7.69 (d, 2H, J ¼ 8.3 Hz); 13C NMR (100 MHz,
136.8, 137.7, 143.4; HRMS (ESI): Calcd for
C
22H19O2N35ClS
[MþH]þ ¼ 396.0820, Found ¼ 396.0818.
CDCl3):
d
¼ 21.4, 21.5, 22.2, 25.7, 29.0, 46.3, 84.0, 96.5, 120.2, 122.6,
4.2.15. N-[o-(p-bromophenyl)ethynyl]benzyl p-toluenesulfonamide
(1O)
127.1, 127.6, 128.1, 128.6, 129.5, 132.0, 136.0, 137.0, 137.4, 1432.2;
HRMS (ESI): Calcd for
Found ¼ 366.1520.
C
22H24O2NS [MþH]þ
¼
366.1522,
Yellow solid; mp: 142e143 ꢀC; IR (neat): 2359, 2170, 1382,
1226 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s, 3H), 4.35 (d, 2H,
J ¼ 6.5 Hz), 4.84 (t, 1H, J ¼ 6.5 Hz), 7.21 (d, 2H, J ¼ 8.1 Hz), 7.24e7.28
4.2.21. N-(2-Phenylethynyl,5-methylbenzyl p-toluenesulfonamide
(1U)
(m, 5H), 7.44e7.53 (m, 3H), 7.71 (d, 2H, J ¼ 8.3 Hz); 13C NMR
(100 MHz, CDCl3):
128.0, 128.8, 129.0, 129.6, 131.7, 132.3, 132.9, 136.8, 137.7, 143.4;
d
¼ 21.5, 46.1, 87.6, 93.3, 121.5, 122.0, 123.0, 127.1,
White solid; mp: 180 ꢀC; IR (neat): 2358, 2212, 1323, 1156 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 2.28 (s, 3H), 2.37 (s, 3H), 4.33 (d, 2H,
6

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
J ¼ 6.3 Hz), 4.95 (t, 1H, J ¼ 6.3 Hz), 7.01e7.04 (m, 2H), 7.18 (d, 2H,
J ¼ 8.2 Hz), 7.32e7.41 (m, 6H), 7.70 (d, 2H, J ¼ 8.3 Hz); 13C NMR
(15.0 mL) was added to the mixture, and the product was extracted
with CHCl3 (15.0 mL ꢁ 3). The organic layer was dried over Na2SO4
and filtered. After removal of the solvent under reduced pressure,
the residue was purified by silica-gel column chromatography
(100 MHz, CDCl3):
d
¼ 21.3, 21.5, 46.2, 86.6, 93.7, 119.1, 122.7, 127.1,
128.4, 128.5, 128.6, 129.5, 129.6, 131.4, 132.1, 136.9, 137.5, 139.0,
143.2; HRMS (ESI): Calcd for C23H22O2NS [MþH]þ ¼ 376.1366,
Found ¼ 376.1364.
(eluent:
n-hexane:EtOAc
¼
4:1)
to
give
4-iodo-3-
phenylisoquinoline 3A (140.7 mg, 85%).
4.2.22. N-(2-Phenylethynyl,5-chloro)benzyl p-toluenesulfonamide
(1V)
4.4.1. 4-Iodo-3-phenylisoquinoline (3A)
Yield: 140.7 mg (85%); white solid; mp: 82e83 ꢀC; IR (neat):
White solid; mp: 142 ꢀC; IR (neat): 2362, 2216, 1323, 1154 cmꢂ1
;
2923, 1568, 1550 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.43e7.52
1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s, 3H), 4.34 (d, 2H, J ¼ 6.5 Hz),
(m, 3H), 7.63 (d, 2H, J ¼ 7.0 Hz), 7.69 (t, 1H, J ¼ 7.6 Hz), 7.84 (t, 1H,
4.99 (t, 1H, J ¼ 6.3 Hz), 7.13 (s, 1H), 7.17e7.21 (m, 3H), 7.34e7.40 (m,
J ¼ 7.4 Hz), 7.97 (d, 1H, J ¼ 8.1 Hz), 8.24 (d, 1H, J ¼ 8.5 Hz), 9.17 (s,
4H), 7.42e7.44 (m, 2H), 7.68 (d, 2H, J ¼ 8.3 Hz); 13C NMR (100 MHz,
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 98.0, 127.9 (2C), 128.0, 128.3,
CDCl3):
d
¼ 21.5, 45.8, 85.5, 95.5, 120.5, 122.2, 127.1, 128.0, 128.5,
129.8, 132.2 (2C), 132.3, 138.5, 143.7, 152.0, 157.1; HRMS (ESI): Calcd
for C15H11NI [MþH]þ ¼ 331.9931, Found ¼ 331.9927.
128.8, 129.0, 129.6, 131.5, 133.3, 134.5, 136.8, 139.5, 143.6; HRMS
(ESI): Calcd for
Found ¼ 396.0815.
C
22H19O2N35ClS [MþH]þ
¼
396.0820,
4.4.2. 4-Iodo-3-(20-methylphenyl)isoquinoline (3B)
Yield: 141.5 mg (82%); yellow oil; IR (neat): 2970, 1618,
1571 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.12 (s, 3H), 7.25 (d, 1H,
4.2.23. N-(2-Phenylethynyl,4,5-methylenedioxy)benzyl p-
toluenesulfonamide (1W)
J ¼ 7.4 Hz), 7.29e7.38 (m, 3H), 7.70 (t, 1H, J ¼ 7.6 Hz), 7.84 (t, 1H,
J ¼ 7.9 Hz), 7.98 (d, 1H, J ¼ 8.1 Hz), 8.20 (d, 1H, J ¼ 8.5 Hz), 9.19 (s,
White solid; mp: 188e189 ꢀC; IR (neat): 2205, 1320, 1155,
1038 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H), 4.27 (d, 2H,
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 19.6, 99.6, 125.6, 127.9 (3C),
J ¼ 6.3 Hz), 4.88 (t, 1H, J ¼ 6.7 Hz), 5.97 (s, 2H), 6.74 (s, 1H), 6.88 (s,
128.4, 128.9, 130.1, 131.8, 132.1, 135.5, 138.2, 143.8, 152.0, 157.9;
16H13NI [MþH]þ
¼
346.0087,
1H), 7.21 (d, 2H, J ¼ 8.6 Hz), 7.32e7.39 (m, 5H), 7.71 (d, 2H,
HRMS (ESI): Calcd for
C
J ¼ 8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 46.1, 86.5, 92.9,
Found ¼ 346.0082.
101.6, 109.5, 111.5, 115.4, 122.6, 127.1, 128.4, 128.5, 129.6, 131.4, 132.9,
136.9, 143.3, 147.1, 148.2; HRMS (ESI): Calcd for C23H20O4NS
[MþH]þ ¼ 406.1108, Found ¼ 406.1104.
4.4.3. 4-Iodo-3-(30-methylphenyl)isoquinoline (3C)
Yield: 150.2 mg (87%); yellow oil; IR (neat): 2989, 1615,
1568 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.45 (s, 3H), 7.26 (d, 1H,
4.3. Typical procedure for preparation of 4-iodo-3-phenyl-2-tosyl-
1,2-dihydroisoquinoline 2A
J ¼ 7.2 Hz), 7.38 (t, 1H, J ¼ 8.1 Hz), 7.42e7.44 (m, 2H), 7.68 (t, 1H,
J ¼ 7.3 Hz), 7.83 (t,1H, J ¼ 7.4 Hz), 7.96 (d, 1H, J ¼ 8.3 Hz), 8.24 (d, 1H,
J ¼ 8.5 Hz), 9.16 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 21.5, 98.0,
To a solution of N-(o-phenylethynyl)benzyl p-toluenesulfona-
mide 1A (0.5 mmol, 180.7 mg) and NaHCO3 (0.55 mmol, 46.2 mg) in
acetonitrile (5.0 mL) was added I2 (2.5 mmol, 634.5 mg) at room
temperature. The mixture was stirred for 12 h at 60 ꢀC under argon
atmosphere. Then, aq. Na2SO3 solution (15.0 mL) was added to the
mixture, and the obtained mixture was extracted with CHCl3
(15.0 mL ꢁ 3). Then, the organic layer was dried over Na2SO4 and
filtered. After removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography (eluent:
126.9, 127.7, 127.9 (2C), 128.0, 128.1, 130.2, 132.1, 132.3, 137.6, 138.5,
143.6, 151.9, 157.2; HRMS (ESI): Calcd for
C16H13NI
[MþH]þ ¼ 346.0087, Found ¼ 346.0082.
4.4.4. 4-Iodo-3-(40-methylphenyl)isoquinoline (3D)
Yield: 142.4 mg (83%); white solid; mp: 93 ꢀC; IR (neat): 2972,
1616, 1568 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.45 (s, 3H), 7.30
(d, 2H, J ¼ 7.9 Hz), 7.54 (d, 2H, J ¼ 8.1 Hz), 7.67 (t, 1H, J ¼ 7.4 Hz), 7.82
(t, 1H, J ¼ 7.9 Hz), 7.96 (d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.16
n-hexane:EtOAc
dihydroisoquinoline 2A (195.3 mg, 80%).
¼
4:1) to give 4-iodo-3-phenyl-2-tosyl-1,2-
(s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 21.4, 98.0, 127.8, 127.9 (2C),
128.6,129.7,132.1,132.3,138.1,138.5,140.8,151.9,157.1; HRMS (ESI):
Calcd for C16H13NI [MþH]þ ¼ 346.0087, Found ¼ 346.0084.
4.3.1. 4-Iodo-3-phenyl-2-tosyl-1,2-dihydroisoquinoline (2A)
Yield: 195.3 mg (80%); white solid; mp: 197 ꢀC; IR (neat): 2343,
4.4.5. 3-(40-Ethylphenyl)-4-iodoisoquinoline (3E)
1339, 1164 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.24 (s, 3H), 4.95
Yield: 131.1 mg (73%); yellow oil; IR (neat): 2989, 1614,
(s, 2H), 6.89 (d, 2H, J ¼ 7.7 Hz), 6.98e7.00 (m, 1H), 7.13e7.15 (m, 2H),
7.16e7.19 (m, 1H), 7.22 (d, 2H, J ¼ 8.3 Hz), 7.39e7.41 (m, 3H),
1570 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 1.30 (t, 3H, J ¼ 7.6 Hz),
7.60e7.62 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
¼ 21.4, 50.8, 94.4,
2.75 (q, 2H, J ¼ 7.6 Hz), 7.32 (d, 2H, J ¼ 8.5 Hz), 7.56 (d, 2H,
J ¼ 8.3 Hz), 7.67 (t, 1H, J ¼ 7.4 Hz), 7.82 (t, 1H, J ¼ 7.9 Hz), 7.95 (d, 1H,
J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.16 (s, 1H); 13C NMR (100 MHz,
124.6, 127.1, 127.5, 127.7, 128.6, 128.7, 129.1, 130.9, 131.2, 131.3, 134.7,
135.1, 139.1, 141.6, 143.3; HRMS (ESI): Calcd for C22H19O2NIS
[MþH]þ ¼ 488.0176, Found ¼ 488.0172.
CDCl3):
d
¼ 15.5, 28.7, 97.9, 127.4, 127.8 (2C), 127.9, 129.7, 132.1,
132.3, 138.5, 141.0, 144.4, 151.9, 157.1; HRMS (ESI): Calcd for
C
17H15NI [MþH]þ ¼ 360.0244, Found ¼ 360.0241.
4.4. Typical procedure for preparation of 3-aryl-4-
iodoisoquinolines 3
4.4.6. 3-(40-tert-Butylphenyl)-4-iodoisoquinoline (3F)
To a solution of N-(o-phenylethynyl)benzyl p-toluenesulfona-
mide 1A (0.5 mmol, 180.7 mg) and NaHCO3 (0.55 mmol, 46.2 mg) in
acetonitrile (5.0 mL) was added I2 (2.5 mmol, 634.5 mg) at room
temperature. The mixture was stirred for 12 h at 60 ꢀC under argon
atmosphere. After removal of the solvent under reduced pressure,
tBuOK (5.0 mmol, 561.0 mg) was added to the residue in THF
(10.0 mL) at 0 ꢀC. The mixture was stirred for 10 h at room tem-
perature under argon atmosphere. Then, aq. NH4Cl solution
Yield: 178.1 mg (92%); white solid; mp: 94e95 ꢀC; IR (neat):
2953, 1609, 1571 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 1.39 (s, 9H),
7.50 (d, 2H, J ¼ 8.5 Hz), 7.59 (d, 2H, J ¼ 8.5 Hz), 7.67 (t,1H, J ¼ 7.5 Hz),
7.82 (t, 1H, J ¼ 7.9 Hz), 7.95 (d, 1H, J ¼ 7.9 Hz), 8.24 (d, 1H, J ¼ 8.5 Hz),
9.16 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 31.3, 34.7, 97.8, 124.8,
127.8, 127.9 (2C), 129.5, 132.1, 132.3, 138.6, 140.7, 151.2, 151.9, 157.1;
HRMS (ESI): Calcd for
Found ¼ 388.0554.
C
19H19NI [MþH]þ
¼
388.0557,
7

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
4.4.7. 3-(20,40-Dimethylphenyl)-4-iodoisoquinoline (3G)
127.9 (2C), 128.0, 131.7 (d, JC-F ¼ 21.6 Hz), 132.2, 132.3, 138.4, 139.6
(d, JC-F ¼ 2.8 Hz), 152.0, 155.9, 162.6 (d, JC-F ¼ 247.1 Hz); HRMS (ESI):
Calcd for C15H10NFI [MþH]þ ¼ 349.9836, Found ¼ 349.9834.
Yield: 129.3 mg (72%); white solid; mp: 131e132 ꢀC; IR (neat):
2982, 1616, 1568 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.09 (s, 3H),
2.41 (s, 3H), 7.11e7.16 (m, 3H), 7.69 (t, 1H, J ¼ 7.6 Hz), 7.83 (t, 1H,
J ¼ 7.9 Hz), 7.97 (d, 1H, J ¼ 8.1 Hz), 8.19 (d, 1H, J ¼ 8.5 Hz), 9.18 (s,
4.4.14. 3-(40-Chlorophenyl)-4-iodoisoquinoline (3N)
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 19.5, 21.3, 99.9, 126.3, 127.9
Yield: 128.0 mg (70%); white solid; mp: 149 ꢀC; IR (neat): 2971,
(3C), 128.9, 130.8, 131.8, 132.1, 135.3, 138.0, 138.2, 141.0, 152.0, 158.1;
1592, 1574 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.47 (d, 2H,
HRMS (ESI): Calcd for
Found ¼ 360.0241.
C
17H15NI [MþH]þ
¼
360.0244,
J ¼ 8.8 Hz), 7.59 (d, 2H, J ¼ 8.5 Hz), 7.70 (t, 1H, J ¼ 7.5 Hz), 7.85 (t, 1H,
J ¼ 7.9 Hz), 7.97 (d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.16 (s,
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 98.0, 127.9, 128.1 (2C), 128.2
4.4.8. 3-(30,50-Dimethylphenyl)-4-iodoisoquinoline (3H)
Yield: 149.1 mg (83%); white solid; mp: 103 ꢀC; IR (neat): 2913,
1603, 1568 cmꢂ1; 1H NMR (400 MHz, CDCl3):
(2C), 131.3, 132.4, 134.3, 138.5, 142.0, 152.1, 155.8; HRMS (ESI): Calcd
for C15H10N35ClI [MþH]þ ¼ 365.9541, Found ¼ 365.9537.
d
¼ 2.40 (s, 6H), 7.08
(s,1H), 7.23 (s, 2H), 7.67 (t,1H, J ¼ 7.2 Hz), 7.82 (t,1H, J ¼ 7.7 Hz), 7.95
4.4.15. 3-(40-Bromophenyl)-4-iodoisoquinoline (3O)
(d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.15 (s, 1H); 13C NMR
Yield: 139.4 mg (68%); white solid; mp: 148e149 ꢀC; IR (neat):
(100 MHz, CDCl3):
d
¼ 21.4, 97.9, 127.5, 127.8, 127.9, 128.0, 129.9,
2973, 1596, 1573 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 7.53 (d, 2H,
132.1, 132.4, 137.4, 138.5, 143.6, 151.9, 157.5; HRMS (ESI): Calcd for
J ¼ 8.5 Hz), 7.61e7.65 (m, 2H), 7.71 (t, 1H, J ¼ 8.1 Hz), 7.85 (t, 1H,
J ¼ 7.2 Hz), 7.97 (d, 1H, J ¼ 8.3 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.16 (s,
C
17H15NI [MþH]þ ¼ 360.0244, Found ¼ 360.0241.
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 97.9, 122.6, 127.9, 128.0, 128.2,
4.4.9. 4-Iodo-3-(20-methoxyphenyl)isoquinoline (3I)
131.1, 131.6, 132.3 (2C), 138.5, 142.4, 152.1, 155.8; HRMS (ESI): Calcd
Yield: 133.6 mg (74%); yellow oil; IR (neat): 2987, 1579, 1568,
for
C
C
15H10N79BrI [MþH]þ
¼
409.9036, Found
¼
409.9034,
1549, 1065 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 3.88 (s, 3H), 7.00
15H10N81BrI [MþH]þ ¼ 411.9015, Found ¼ 411.9012.
(dd, 1H, J ¼ 8.3, 2.6 Hz), 7.15e7.16 (m, 1H), 7.20 (d, 1H, J ¼ 7.4 Hz),
7.41 (t, 1H, J ¼ 7.9 Hz), 7.69 (t, 1H, J ¼ 7.5 Hz), 7.84 (t, 1H, J ¼ 7.9 Hz),
7.97 (d, 1H, J ¼ 8.4 Hz), 8.24 (d, 1H, J ¼ 7.9 Hz), 9.17 (s, 1H); 13C NMR
4.4.16. 4-Iodo-3-(naphthalen-10-yl)isoquinoline (3P)
Yield: 183.0 mg (96%); white solid; mp: 108e109 ꢀC; IR (neat):
3044, 2985, 1569, 1551 cmꢂ1 1H NMR (400 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼ 55.3, 98.0, 114.3, 115.0, 122.2, 127.9, 128.0
;
(2C), 129.0,132.2,132.3,138.5,144.9,151.9,156.9,159.1; HRMS (ESI):
d
¼ 7.39e7.40 (m, 2H), 7.48e7.55 (m, 2H), 7.61 (t, 1H, J ¼ 8.1 Hz),
Calcd for C16H13ONI [MþH]þ ¼ 362.0036, Found ¼ 362.0035.
7.75 (td, 1H, J ¼ 7.5, 1.1 Hz) 7.88 (td, 1H, J ¼ 7.6, 1.4 Hz), 7.94e7.99 (m,
2H), 8.04 (d, 1H, J ¼ 8.1 Hz), 9.27 (s, 1H); 13C NMR (100 MHz, CDCl3):
4.4.10. 4-Iodo-3-(30-methoxyphenyl)isoquinoline (3J)
d
¼ 100.6, 125.2, 125.5, 125.9, 126.3, 127.3, 128.0, 128.1, 128.2, 128.3,
Yield: 162.5 mg (90%); white solid; mp: 108e109 ꢀC; IR (neat):
128.7, 131.2, 132.0, 132.3, 133.6, 138.3, 141.7, 152.1, 156.8; HRMS
2989, 1605, 1564 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 3.79 (s, 3H),
(ESI): Calcd for C19H13NI [MþH]þ ¼ 382.0087, Found ¼ 382.0085.
7.02e7.04 (m.1H), 7.10 (t,1H, J ¼ 7.4 Hz), 7.30 (dd,1H, J ¼ 7.5,1.6 Hz),
7.44 (t, 1H, J ¼ 7.4 Hz), 7.68 (t, 1H, J ¼ 7.0 Hz), 7.81 (t, 1H, J ¼ 7.0 Hz),
7.96 (d, 1H, J ¼ 8.1 Hz), 8.20 (d, 1H, J ¼ 8.5 Hz), 9.20 (s, 1H); 13C NMR
4.4.17. 3-(40-Biphenyl)-4-iodoisoquinoline (3Q)
Yield: 142.5 mg (70%); white solid; mp: 160e162 ꢀC; IR (neat):
(100 MHz, CDCl3):
d
¼ 55.5, 100.8, 111.1, 120.5, 127.9 (2C), 128.0,
3052, 3034, 1614, 1566 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.38
129.9, 130.5, 131.9, 132.0, 133.3, 138.3, 152.0, 155.6, 156.4; HRMS
(tt, 1H, J ¼ 7.4, 1.8 Hz), 7.48 (t, 2H, J ¼ 7.9 Hz), 7.68e7.72 (m, 3H),
7.73e7.74 (m, 4H), 7.85 (td, 1H, J ¼ 7.9, 1.4 Hz), 7.98 (d, 1H,
J ¼ 8.1 Hz), 8.26 (d, 1H, J ¼ 8.5 Hz), 9.19 (s, 1H); 13C NMR (100 MHz,
(ESI): Calcd for C16H13ONI [MþH]þ ¼ 362.0036, Found ¼ 362.0034.
4.4.11. 4-Iodo-3-(40-methoxyphenyl)isoquinoline (3K)
CDCl3):
d
¼ 97.9, 126.7, 127.2, 127.4, 128.0 (3C), 128.8, 130.3, 132.2,
Yield: 155.3 mg (86%); white solid; mp: 113e114 ꢀC; IR (neat):
132.4, 138.6, 140.7, 141.0, 142.5, 152.1, 156.7; HRMS (ESI): Calcd for
2971, 1608, 1567, 1026 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 3.89 (s,
C
21H15NI [MþH]þ ¼ 408.0244, Found ¼ 408.0241.
3H), 7.02 (d, 2H, J ¼ 8.5 Hz), 7.61 (d, 2H, J ¼ 8.3 Hz), 7.66 (t, 1H,
J ¼ 7.0 Hz), 7.82 (t, 1H, J ¼ 7.4 Hz), 7.95 (d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H,
4.4.18. 3-(10,30-Benzodioxol-50-yl)-4-iodoisoquinoline (3R)
J ¼ 8.5 Hz), 9.15 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 55.3, 98.0,
Yield: 176.3 mg (94%); white solid; mp: 81e83 ꢀC; IR (neat):
113.2, 127.7 (2C), 127.8, 131.2, 132.1, 132.3, 136.1, 138.6, 151.9, 156.7,
159.5; HRMS (ESI): Calcd for C16H13ONI [MþH]þ ¼ 362.0036,
Found ¼ 362.0034.
3045, 1603, 1547, 1108 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 6.05 (s,
2H), 6.93 (d,1H, J ¼ 8.5 Hz), 7.12e7.14 (m, 2H), 7.68 (t,1H, J ¼ 8.1 Hz),
7.83 (t,1H, J ¼ 7.9 Hz), 7.95 (d, 1H, J ¼ 7.9 Hz), 8.22 (d, 1H, J ¼ 8.5 Hz),
9.14 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 98.1, 101.2, 107.8, 110.5,
4.4.12. 3-(40-Ethoxyphenyl)-4-iodoisoquinoline (3L)
124.0, 127.9 (3C), 132.2, 132.4, 137.6, 138.6, 147.1, 147.5, 151.9, 156.5;
Yield: 168.8 mg (90%); white solid; mp: 153e155 ꢀC; IR (neat):
HRMS (ESI): Calcd for
Found ¼ 375.9826.
C
16H11O2NI [MþH]þ
¼
375.9829,
2971, 1605, 1509, 1043 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 1.46 (t,
3H, J ¼ 7.0 Hz), 4.12 (q, 2H, J ¼ 7.0 Hz), 7.01 (d, 2H, J ¼ 8.8 Hz), 7.60 (d,
2H, J ¼ 8.8 Hz), 7.67 (t, 1H, J ¼ 7.0 Hz), 7.82 (t, 1H, J ¼ 7.9 Hz), 7.95 (d,
1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 8.5 Hz), 9.15 (s, 1H); 13C NMR
4.4.19. 4-Iodo-3-(thiophen-30-yl)isoquinoline (3S)
Yield: 148.3 mg (88%); white solid; mp: 79e82 ꢀC; IR (neat):
3110, 2340, 1560, 1307, 1150 cmꢂ1 1H NMR (400 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼ 14.8, 63.4, 97.9, 113.7, 127.7, 127.8 (2C), 131.2,
;
132.1, 132.3 (2C), 135.9, 151.9, 156.7, 158.9; HRMS (ESI): Calcd for
d
¼ 7.42 (dd, 1H, J ¼ 4.9, 2.9 Hz), 7.54 (dd, 1H, J ¼ 4.9, 1.4 Hz), 7.67 (t,
C
17H15ONI [MþH]þ ¼ 376.0193, Found ¼ 376.0192.
1H, J ¼ 7.0 Hz), 7.77 (dd, 1H, J ¼ 2.9, 1.4 Hz), 7.82 (t, 1H, J ¼ 7.6 Hz),
7.94 (d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 9.4 Hz), 9.14 (s, 1H); 13C NMR
4.4.13. 3-(40-Fluorophenyl)-4-iodoisoquinoline (3M)
(100 MHz, CDCl3):
d
¼ 97.8, 124.7, 126.5, 127.9, 128.0, 129.4, 132.2,
Yield: 141.4 mg (81%); white solid; mp: 98e99 ꢀC; IR (neat):
132.5,138.6,143.9,152.0 (2C),152.5; HRMS (ESI): Calcd for C13H9NIS
2996, 1599, 1569 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 7.18 (t, 2H,
[MþH]þ ¼ 337.9495, Found ¼ 337.9492.
J ¼ 8.8 Hz), 7.61e7.64 (m, 2H), 7.70 (t, 1H, J ¼ 7.5 Hz), 7.84 (t, 1H,
J ¼ 7.7 Hz), 7.97 (d, 1H, J ¼ 8.1 Hz), 8.23 (d, 1H, J ¼ 7.6 Hz), 9.16 (s,
4.4.20. 3-(Cyclohexen-10-yl)-4-iodoisoquinoline (3T)
1H); 13C NMR (100 MHz, CDCl3):
d
¼ 98.1, 114.8 (d, JC-F ¼ 21.6 Hz),
Yield: 63.7 mg 38%); colorless oil; IR (neat): 2997, 1616,
8

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
1568 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 1.74e1.80 (m, 2H),
4.6. Preparation of 4-(40-methylbenzenesulfenyl-3-phenyl-
isoquinoline 5A
1.85e1.91 (m, 2H), 2.24e2.30 (m, 2H), 2.41e2.44 (m, 2H), 5.86
(quint, 1H, J ¼ 1.9 Hz), 7.62 (t, 1H, J ¼ 7.9 Hz), 7.77 (t, 1H, J ¼ 7.7 Hz),
7.90 (d, 1H, J ¼ 8.5 Hz), 8.15 (d, 1H, J ¼ 8.5 Hz), 9.08 (s, 1H); 13C NMR
To a mixture of 4-iodo-3-phenylisoquinoline (3A) (0.5 mmol,
165.7 mg), CuI (0.1 mmol, 19.0 mg), K2CO3 (1.0 mmol, 138.2 mg),
and p-Tol-SH (0.6 mmol, 74.5 mg) in i-PrOH (6.0 mL) was added
(100 MHz, CDCl3):
d
¼ 21.9, 22.8.25.1, 28.3, 97.5, 127.4, 127.8, 127.9,
129.4, 131.8, 132.0, 138.4, 141.7, 152.0, 159.5; HRMS (ESI): Calcd for
C
15H15IN [MþH]þ ¼ 336.0250, Found ¼ 336.0252.
ethylene glycol (1.0 mmol, 56 mL) under argon atmosphere. The
obtained mixture was stirred for 48 h at 80 ꢀC. H2O (5.0 mL) was
added to the reaction mixture, and the obtained mixture was
extracted with CHCl3 (15.0 mL ꢁ 3). The organic layer was dried
over Na2SO4 and filtered. After removal of the solvent under
reduced pressure, the residue was purified by silica-gel column
chromatography (eluent: n-hexane/EtOAc ¼ 4:1) to give 3-(40-
methylbenzenesulfenyl)-4-phenylisoquinoline (5A) (122.8 mg,
75%).
4.4.21. 4-Iodo-7-methyl-3-phenylisoquinoline (3U)
Yield: 155.3 mg (90%); yellow solid; mp: 94e95 ꢀC; IR (neat):
2930, 1614, 1570 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.61 (s, 3H),
7.43e7.50 (m, 3H), 7.61e7.67 (m, 3H), 7.73 (s, 1H), 8.12 (d, 1H,
J ¼ 8.8 Hz), 9.08 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼ 21.4, 97.8,
126.6 (2C), 127.9, 128.1, 129.8, 132.1, 134.4, 136.8, 138.1, 143.7, 151.3,
156.2; HRMS (ESI): Calcd for C16H13NI [MþH]þ ¼ 346.0087,
Found ¼ 346.0084.
4.6.1. 4-(40-Methylbenzenesulfenyl)-3-phenylisoquinoline (5A)
Yield: 122.8 mg (75%); yellow solid; mp: 107e109 ꢀC; IR (neat):
4.4.22. 7-Chloro-4-iodo-3-phenylisoquinoline (3V)
Yield: 122.5 mg (67%); yellow solid; mp: 89e90 ꢀC; IR (neat):
2921, 1615, 1549 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.23 (s, 3H),
2979, 1581, 1561 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.45e7.52
6.83 (d, 2H, J ¼ 8.3 Hz), 6.93 (d, 2H, J ¼ 8.3 Hz), 7.39e7.42 (m, 3H),
7.61e7.65 (m, 3H), 7.72 (t, 1H, J ¼ 7.6 Hz), 8.05 (d, 1H, J ¼ 8.1 Hz),
8.42 (d, 1H, J ¼ 8.5 Hz), 9.37 (s, 1H); 13C NMR (100 MHz, CDCl3):
(m, 3H), 7.61e7.63 (m, 2H), 7.75 (d, 1H, J ¼ 9.1 Hz), 7.97 (s, 1H), 8.21
(d, 1H, J ¼ 9.0 Hz), 9.10 (s, 1H); 13C NMR (100 MHz, CDCl3):
¼ 97.4,
d
126.3, 128.0, 128.2, 128.5, 129.7, 132.9, 133.9, 134.3, 137.0, 143.3,
d
¼ 20.9, 122.2, 126.2, 126.9, 127.5, 127.7, 128.1 (2C), 128.2, 129.7,
150.9,
157.5;
HRMS
(ESI):
Calcd
for
C
15H10N35ClI
129.8, 131.7, 134.4, 135.1, 138.3, 140.8, 153.2, 158.2; HRMS (ESI):
[MþH]þ ¼ 365.9541, Found ¼ 365.9539.
Calcd for C22H18NS [MþH]þ ¼ 328.1154, Found ¼ 328.1152.
4.4.23. 4-Iodo-6,7-methylenedioxy-3-phenylisoquinoline (3W)
Yield: 95.7 mg (51%); yellow solid; mp: 148e149 ꢀC; IR (neat):
4.7. Preparation of 4-(40-methylphenyl)ethynyl-3-
phenylisoquinoline 6A
2989, 1603, 1565, 1036 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 6.18 (s,
2H), 7.19 (s, 1H), 7.40e7.49 (m, 3H), 7.59 (dd, 2H, J ¼ 8.0,1.2 Hz), 7.63
(s, 1H), 8.90 (s, 1H); 13C NMR (100 MHz, CDCl3):
To a mixture of 4-iodo-3-phenylisoquinoline (3A) (0.5 mmol,
165.7 mg), CuI (0.01 mmol, 1.9 mg), and PdCl2(PPh3)2 (0.01 mmol,
7.0 mg) in Et3N (2.0 mL) was added 4-methyl-1-ethynylbenzene
d
¼ 96.9, 102.1,
103.0,109.3,125.1,127.9, 128.1,129.7,137.4, 143.9,148.9,149.6,152.7,
156.4; HRMS (ESI): Calcd for C16H11O2NI [MþH]þ ¼ 375.9829,
Found ¼ 375.9825.
(0.6 mmol, 76 mL) under argon atmosphere. The obtained mixture
was stirred for 4 h at 60 ꢀC. Aq. NH4Cl solution (15.0 mL) was added
to the mixture, and the obtained mixture was extracted with CHCl3
(15.0 mL ꢁ 3). The organic layer was dried over Na2SO4 and filtered.
After removal of the solvent under reduced pressure, the residue
was purified by silica-gel column chromatography (eluent: n-hex-
4.4.24. 3-Phenyl-4-(phenylselenyl)isoquinoline (3X)
Yield: 156.7 mg (87%); white solid; mp: 107e109 ꢀC; IR (neat):
2923, 1615, 1574 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.01e7.05
(m, 2H), 7.06e7.10 (m, 3H), 7.38e7.43 (m, 3H), 7.55e7.58 (m, 2H),
7.63 (t, 1H, J ¼ 7.5 Hz), 7.71 (t, 1H, J ¼ 7.9 Hz), 8.03 (d, 1H, J ¼ 8.1 Hz),
8.45 (d, 1H, J ¼ 8.1 Hz), 9.35 (s, 1H); 13C NMR (100 MHz, CDCl3):
ane/EtOAc
phenylisoquinoline (6A) (158.1 mg, 99%).
¼
4:1) to give 4-(40-methylphenyl)ethynyl-3-
d
¼ 121.3, 126.0, 127.4, 127.6, 128.0, 128.1, 128.5, 129.1, 129.5, 129.8,
4.7.1. 4-(40-Methylphenyl)ethynyl-3-phenylisoquinoline (6A)
Yield: 158.1 mg (99%); white solid; mp: 74e77 ꢀC; IR (neat):
131.6, 133.1 (2C), 138.5, 142.0, 153.2, 158.5; HRMS (ESI): Calcd for
C
21H16N80Se [MþH]þ ¼ 362.0442, Found ¼ 362.0438.
2920, 2205,1615,1550 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.39 (s,
3H), 7.18 (d, 2H, J ¼ 7.6 Hz), 7.41e7.48 (m, 3H), 7.53 (t, 2H, J ¼ 7.6 Hz),
7.67 (t, 1H, J ¼ 7.5 Hz), 7.83 (t, 1H, J ¼ 7.6 Hz), 8.03 (d, 1H, J ¼ 8.1 Hz),
8.13e8.16 (m, 2H), 8.50 (d 1H, J ¼ 7.4 Hz), 9.28 (s, 1H); 13C NMR
4.5. Preparation of 3-phenylisoquinoline 4A
To a solution of 4-iodo-3-phenylisoquinoline (3A) (0.5 mmol,
165.6 mg) in EtOH (7.5 mL) was added Zn powder (5.0 mmol,
363.3 mg) under argon atmosphere. The obtained mixture was
stirred for 12 h at refluxing temperature. The cooled mixture was
filtered through Celite, and then the filtrate was concentrated un-
der reduced pressure. The residue was purified by column chro-
matography on silica gel (eluent: n-hexane/AcOEt ¼ 4:1) to afford
3-phenylisoquinoline (4A) (101.6 mg, 99%).
(100 MHz, CDCl3):
d
¼ 21.6, 85.1, 99.5,112.7,120.1,125.7,126.6,127.5,
127.8, 127.9, 128.5, 129.2, 129.9, 131.2, 131.3, 136.6, 138.9, 140.0,
151.2, 154.2; HRMS (ESI): Calcd for C24H18N [MþH]þ ¼ 320.1434,
Found ¼ 320.1430.
4.8. Preparation of (E)-4-(40-methylphenyl)ethenyl-3-
phenylisoquinoline (7A)
4.5.1. 3-Phenylisoquinoline (4A)
To a mixture of 4-iodo-3-phenylisoquinoline (3A) (0.5 mmol,
165.7 mg), K2CO3 (1.0 mmol, 138.2 mg), and PdCl2(PPh3)2
(0.05 mmol, 35.0 mg) in DMF (5.0 mL) was added 4-methylstyrene
Yield: 101.6 mg (99%); white solid; mp: 100 ꢀC; IR (neat): 2923,
1623, 1573 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.43 (t, 1H,
J ¼ 7.2 Hz), 7.52 (t, 2H, J ¼ 7.9 Hz), 7.60 (t, 1H, J ¼ 7.5 Hz), 7.71 (t, 1H,
J ¼ 7.7 Hz), 7.89 (d, 1H, J ¼ 8.3 Hz), 8.00 (d, 1H, J ¼ 8.3 Hz), 8.08 (s,
1H), 8.12e8.14 (m, 2H), 9.35 (s, 1H); 13C NMR (100 MHz, CDCl3):
(1.0 mmol, 131 mL) under argon atmosphere. The obtained mixture
was stirred for 12 h at 130 ꢀC. Sat. aq. NaHCO3 solution (15.0 mL)
was added to the reaction mixture, and the obtained mixture was
extracted with CHCl3 (15.0 mL ꢁ 3). The organic layer was dried
over Na2SO4 and filtered. After removal of the solvent under
reduced pressure, the residue was purified by silica-gel column
d
¼ 116.5, 126.9, 127.0 (2C), 127.5, 127.7, 128.5, 128.8, 130.5, 136.6,
139.6, 151.3, 152.4; HRMS (ESI): Calcd for
C15H12N
[MþH]þ ¼ 206.0964, Found ¼ 206.0964.
9

H. Naruto and H. Togo
Tetrahedron 83 (2021) 131993
chromatography (eluent: n-hexane/EtOAc ¼ 4:1) to give (E)-4-(40-
methylphenyl)ethenyl-3-phenylisoquinoline (7A) (144.6 mg, 90%
yield).
4.10.1. 1-Cyclohexyl-3-phenylisoquinoline (9A)
Yield: 122.1 mg (85%); colorless oil; IR (neat): 2924, 1620,
1566 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
¼ 1.39e1.47 (m, 1H),
1.51e1.54 (m, 1H), 1.56e1.61 (m, 1H), 1.82e1.85 (m, 1H), 1.92e2.06
(m, 6H), 3.52e3.62 (m, 1H), 7.39 (tt, 1H, J ¼ 7.2, 0.9 Hz), 7.48e7.57
(m, 3H), 7.63 (t, 1H, J ¼ 7.3 Hz), 7.86 (d, 1H, J ¼ 7.9 Hz), 7.92 (s, 1H),
4.8.1. (E)-4-(40-methylphenyl)ethenyl-3-phenylisoquinoline (7A)
Yield: 144.6 mg (90%); white solid; mp: 104e105 ꢀC; IR (neat):
8.20e8.25 (m, 3H); 13C NMR (100 MHz, CDCl3):
41.8, 114.3, 124.7, 125.3, 126.5, 126.8, 128.0, 128.2, 128.6, 129.5, 137.2,
d
¼ 26.3, 26.9, 32.6,
2924, 1609, 1550 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼ 2.38 (s, 3H),
6.87 (d, 1H, J ¼ 16.4 Hz), 7.18e7.20 (m, 2H), 7.25e7.26 (m, 1H),
7.35e7.37 (m, 3H), 7.44 (t, 2H, J ¼ 7.9 Hz), 7.63 (t, 1H, J ¼ 7.4 Hz),
7.72e7.76 (m, 3H), 8.04 (d, 1H, J ¼ 8.5 Hz), 8.39 (d 1H, J ¼ 8.5 Hz),
140.0, 149.3, 165.2; HRMS (ESI): Calcd for
C21H22N
[MþH]þ ¼ 288.1747, Found ¼ 288.1747.
9.27 (s, 1H); 13C NMR (100 MHz, CDCl3):
126.6, 126.8, 127.7 (3C), 128.0 (2C), 129.4, 130.4, 130.5, 134.4, 136.5,
d
¼ 21.3, 123.4,125.0,126.4,
Declaration of competing interest
137.9, 140.9, 150.5, 151.0; HRMS (ESI): Calcd for
C24H20N
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[MþH]þ ¼ 322.1590, Found ¼ 322.1586.
4.9. Preparation of 4-(40-methylphenyl)-3-phenylisoquinoline (8A)
Acknowledgment
To a mixture of 4-iodo-3-phenylisoquinoline (3A) (0.5 mmol,
167.1 mg) and p-TolB(OH)2 (1.0 mmol, 136.0 mg) in DMF (10.0 mL)
was added PdCl2(PPh3)2 (0.025 mmol, 17.5 mg) under argon at-
mosphere. The obtained mixture was stirred for 30 min at room
temperature. Then, K2CO3 (1.0 mmol,138.2 mg) in H2O (2.0 mL) was
added to the mixture, and the obtained mixture was stirred for
2 h at 60 ꢀC. Aq. NH4Cl solution (15.0 mL) was added to the mixture,
and the obtained mixture was extracted with CHCl3 (15.0 mL ꢁ 3).
The organic layer was dried over Na2SO4 and filtered. After removal
of the solvent under reduced pressure, the residue was purified by
silica-gel column chromatography (eluent: n-hexane/EtOAc ¼ 4:1)
to give 4-(40-methylphenyl)-3-phenylisoquinoline (8A) (138.8 mg,
94%).
This work was supported by JSPS KAKENHI Grant Number
JP18K05118 in Japan.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.131993.
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2916, 1615, 1554 cmꢂ1; 1H NMR (400 MHz, CDCl3):
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363.3 mg) under argon atmosphere. The obtained mixture was
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sat. aq. NaHCO3 solution (15.0 mL). The product was extracted with
CHCl3 (15.0 mL ꢁ 3). The organic layer was dried over Na2SO4. After
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EtOAc ¼ 30:1) to give 1-cyclohexyl-3-phenylisoquinoline (9A)
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10