Synthesis of 4-Vinyl-1,2,3,4-tetrahydroisoquinoline from N-Tethered Benzyl-Alkenol Catalyzed by Indium(III) Chloride: Formal Synthesis of (±)-Isocyclocelabenzine

Article abstract of DOI:10.1055/s-0037-1610750

An intramolecular Friedel-Crafts cyclization reaction catalyzed by indium(III) chloride for the formation of 4-vinyl-1,2,3,4-tetrahydroisoquinoline from N-tethered benzyl-alkenol in good yields has been described. The reaction is highly regioselective and generates an exocyclic vinyl functionality in the piperidine ring. The reaction is compatible with a wide range of functional groups. The strategy is demonstrated for the formal synthesis of (±)-isocyclocelabenzine alkaloid.

Full text of DOI:10.1055/s-0037-1610750

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–J
paper
A
en
N. R. Devi et al.
Paper
Synthesis
Synthesis of 4-Vinyl-1,2,3,4-tetrahydroisoquinoline from
N-Tethered Benzyl-Alkenol Catalyzed by Indium(III) Chloride:
Formal Synthesis of (±)-Isocyclocelabenzine
Ngangbam Renubala Devi
Sudip Shit
Ts
O
N
InCl3 (10 mol%)
DCE, 80 °C
Bipin Kumar Behera
Anil K. Saikia*
NTs
R'
R'
N
HN
H
HO
R
N
Department of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781039, India
asaikia@iitg.ac.in
O
R
R = H, F,Cl, Br, CF3, Me
R' = H, Ph
14 examples
55–97% yield
(
)-Isocyclocelabenzine
Received: 20.12.2019
Accepted after revision: 20.01.2020
Published online: 12.02.2020
MeO
MeO
NMe
OMe
DOI: 10.1055/s-0037-1610750; Art ID: ss-2019-n0438-op
Abstract An intramolecular Friedel–Crafts cyclization reaction cata-
lyzed by indium(III) chloride for the formation of 4-vinyl-1,2,3,4-tetra-
hydroisoquinoline from N-tethered benzyl-alkenol in good yields has
been described. The reaction is highly regioselective and generates an
exocyclic vinyl functionality in the piperidine ring. The reaction is com-
patible with a wide range of functional groups. The strategy is demon-
strated for the formal synthesis of (±)-isocyclocelabenzine alkaloid.
NMe
MeO
Me
Nomifensine (1)
Homolaudanosine (2)
Figure 1 Structures containing isoquinoline alkaloids
lyzed [3+3] cycloadditions,12 alkylation of anodically pre-
pared -amino nitriles,13 intramolecular oxetane ring open-
ing,14 and others.15 Tietze and co-workers have developed a
methodology for the synthesis of THIQ by intramolecular
Heck reaction (Scheme 1a).16 Nevertheless, the reaction af-
fords a mixture of olefin isomers from either an unselective
-hydride elimination or olefin isomerization. Wu and You
group used palladium catalyst for cyclization of N-tethered
allylic alkylation of phenols (Scheme 1b).17 Notably, Bandini
and co-workers have recently reported the iron(III) chloride
catalyzed cyclization of challenging electron-deficient N-
tethered benzyl-alkenols to prepare tetrahydroisoquino-
lines (Scheme 1c).10 Recently, we have developed a few
methodologies for the synthesis of nitrogen heterocyclic
compounds via intramolecular C–C/C–O bond formation re-
actions from N-tethered alkanols/alkenols.18 Very recently,
we have synthesized 4-vinylpyrrolidine from N-tethered
Key words tetrahydroisoquinoline, (±)-isocyclocelabenzine, indi-
um(III) chloride, regioselectivity, N-tethered benzyl-alkenol, Friedel–
Crafts
Many N-containing heterocycles especially isoquino-
lines are found to be a major part in naturally occurring al-
kaloids. Tetrahydroisoquinoline (THIQ) is a substructure
found in a number of plant alkaloids as well as in various
synthetic compounds. They show an array of medicinal and
pharmacological properties such as antihyperglycemic ac-
tivity,1 analgesic and anticonvulsant effects,2 effective
against heart disease and liver damages,3 as calcium chan-
nel blocker,4 treatments against Parkinson’s disease,5 etc.
These biological properties of THIQs are attributed to the
substitution pattern on the isoquinoline scaffold. For exam-
ple, nomifensine (1), a C4-aryl-substituted THIQ derivative,
is used as an antidepressant drug (Figure 1).6 Another THIQ
alkaloid homolaudanosine (2), isolated from the plant Dys-
oxylum lenticellare shows cardioactive properties on rat
cardiac tissues (Figure 1).7 In addition to their biological
properties, THIQs also act as key intermediates in many re-
actions for the synthesis of several important substances.8
The most common approaches for the synthesis of THIQ
derivatives are Pictet–Spengler,9 Friedel–Crafts,10 rhodium
complex catalyzed [3+2] cycloaddition,11 Lewis acid cata-
19
alkyne-alkenols mediated by InCl3. The advantages of in-
dium(III) chloride as Lewis acid over other Lewis acids is
due to the fact that they have unique -acidity, alkyno-
philicity, relatively low toxicity, air, moisture compatibility,
and recyclability. Therefore, InCl3 has long been used for
various transformations in organic synthesis including con-
struction of heterocycles.20 We now report a new strategy
in which vinyl-substituted tetrahydroisoquinoline deriva-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. R. Devi et al.
Paper
Synthesis
tives can be prepared using intramolecular C–C bond for-
mation reaction from N-tethered benzyl-alkenols catalyzed
by InCl3 in high yields with good regioselectivity.
ids such as bismuth(III) triflate [Bi(OTf)3], p-toluenesulfonic
acid (p-TSA), and triflic acid (TfOH) (entries 9–15) were
found to be inappropriate reagents for this reaction.
We examined the substrate scope of the reaction as
shown in Table 2. Aromatic rings having both electron-
donating and electron-withdrawing groups gave the desired
tetrahydroisoquinoline products in high yields. However,
with the variation of electronic effect in the aromatic rings,
the yields of the reaction also varied. Electron-donating Me
group in the aromatic ring of N-tethered aryl-alkenol gave
62% yield (Table 2, entry 13). Whereas highly electron-
withdrawing NO2 and electron-donating OMe groups in the
aromatic ring gave decomposed products instead of desired
products (entries 5 and 14). This may be due to the interac-
tion of the Lewis acid with the oxygen of the NO2 and OMe
groups, respectively.21 Moreover the methoxy group is elec-
tron-withdrawing in this case since the cyclization has to
occur at the meta-position and the nitro group is meta-
directing. On the other hand, substrate having highly elec-
tron-withdrawing CF3 group in the benzene ring gave 82%
yield (entry 6).
Previous approach
NBoc
R
NBoc
R
Pd(0)
A, B or C
NBoc
R
a)
ref. 16
I
NBoc
R
NBoc
R
A = Pd(OAc)2, KOAc, TPAB, DMF
B = Pd(PPh3)4, NEt3, MeCN
C = Pd2(dba)3, PPh3, Ag3PO4, DMF
OCO2Me
OH
OH
OH
L2 (5.5 mol%)
Pd2(dba)3 (2.5 mol%)
b)
NBn
NBn
NBn
toluene
ref. 17
R
R
R
major
minor
O
O
HN
HN
Ph2P
Ph2P
L2
Ts
N
FeCl3 (10 mol%)
NTs
c)
Variation in the ortho- and para-substituents in the aro-
matic ring system also gave the tetrahydroisoquinoline
products in desirable yields (Table 2, entries 3, 4 and 7, 9,
12). Substrate 3h with meta-substituent in the aromatic
ring resulted in two isomeric products 4h and 4h′ because
of the availability of two sites for C-alkylation (entry 8).
Disubstituted aromatic rings on N-tethered benzyl-alkenol
also gave the desired products (entries 10, 11). The reaction
with trans-allylic alcohol (E)-3a also works well and gave
the desired product in 55% yield (entry 15). After consider-
ing cis- and trans-primary allylic alcohols, the reaction was
shifted to secondary allylic alcohol 3o and gave 4o in 78%
yield (entry 16). The side chain olefin configuration is found
HO
R = EWG
Present strategy
Ts
MeNO2, 80 °C
3–16 h
R
R
ref. 10
N
InCl3 (10 mol%)
NTs
DCE, 80 °C
4 h
HO
R
R
Scheme 1 Synthesis of tetrahydroisoquinolines
To start with N-tethered benzyl-alkenol (Z)-3a was
treated with 0.1 equivalent of indium(III) chloride at 0 °C to
room temperature in dichloromethane (DCM) for 12 hours,
but the starting material was recovered in 86% yield (Table
1, entry 1). When the reaction was performed at 40 °C, tet-
rahydroisoquinoline 4a was formed in 10% yield (entry 2).
In order to check the role of solvents, the same reaction was
conducted in dichloroethane (DCE) at 40 °C but resulted in
8% yield (entry 3). Having obtained the desired product in
both DCM and DCE, the reaction was then performed in di-
chloroethane at 60 °C and only 7% increment in yield was
observed (entry 4). When the reaction was performed at 80
°C, to our delight THIQ 4a was obtained in 97% yield (entry
5). On careful examination, the same reaction completed in
4 hours in 97% yield (entry 6). On the other hand, indi-
um(III) triflate [In(OTf)3] in DCM at 0 °C to room tempera-
ture failed to give the product but starting material was re-
covered in 82% yield (entry 7), whereas in DCE at 80 °C it
gave only 60% yield (entry 8). Other Lewis and Brønsted ac-
1
to be E-configured from the coupling constants of H NMR
spectrum. The reaction is highly regioselective, as deter-
mined by proton NMR analysis of crude products. Further,
the structure of the product is confirmed by X-ray crystal-
lographic analysis of compound 4b (see the Supporting In-
formation).22
Although the aforementioned cyclization can proceed
by either a stepwise or concerted process, we favor the for-
mer process as outlined in Scheme 2. The reaction is pre-
sumably initiated with the coordination of the Lewis acid to
the allylic alcohol to generate A, which can ionize to gener-
ate the allylic carbocation B. Intramolecular Friedel–Crafts
type addition of the aryl group will generate carbocation C,
which will undergo rapid rearomatization to afford 4. The
alternative process involving a concerted process is unlikely
given the process does not appear to be stereospecific. For
example, the cyclization of 3o to 4o affords the E- rather
than Z-geometrical isomer.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

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N. R. Devi et al.
Paper
Synthesis
Table 1 Optimization of the Reactiona
Ts
N
reagent
solvent
NTs
HO
4a
(Z)-3a
Entry
Reagent (equiv)
Solvent
Temp (°C)
Time (h)
Recovered SM (Z)-3a (%)b Yield (%)c of 4a
1
2
InCl3 (0.1)
DCM
DCM
DCE
DCE
DCE
DCE
DCM
DCE
DCM
DCE
DCM
DCM
DCM
DCM
DCE
0 to rt
40
12
12
12
12
12
4
86
78
80
57
0
0
10
8
InCl3 (0.1)
3
InCl3 (0.1)
40
60
80
80
4
InCl3 (0.1)
15
97
97
0
5
InCl3 (0.1)
6
InCl3 (0.1)
0
7
In(OTf)3 (0.1)
In(OTf)3 (0.1)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.1)
BF3·OEt2 (1.2)
TfOH (1.2)
p-TSA (1.2)
p-TSA (1.2)
p-TSA (1.2)
0 to rt
80
0 to rt
80
0 to rt
12
12
12
12
12
12
12
12
12
82
0
8
60
0
9
80
83
85
0
10
11
12
13
14
15
0
0
0 to rt
0 to rt
30d
0
80
78
0
40
80
15
66
a Reaction conditions: (Z)-3a (1.0 equiv), solvent (4 mL).
b Starting material (SM) recovered up to 86%.
c Isolated yield.
d Along with decomposed product.
To check the further applicability of the methodology, a
formal synthesis of (±)-isocyclocelabenzine was undertaken
(Scheme 3).23 Isocyclocelabenzine is a type of spermidine
alkaloid, first isolated from Maytenus mossmbicensis by
Wagner and co-workers.24 The alkaloid has a 13-membered
lactam ring linked to the benzoyl residue of spermidine
unit. We started with compound 4a, whereby its vinylic
functionality was oxidized by using hydroboration and oxi-
dation strategy25 to give the primary alcohol 5 in 75% yield.
The alcohol 5 was detosylated using Mg/MeOH26 to provide
the precursor 6 of (±)-isocyclocelabenzine in 67% yield.
In conclusion, we have developed a mild and efficient
method for the synthesis of vinyl-substituted tetra-
hydroisoquinoloine derivatives via intramolecular cycliza-
tion of N-tethered benzyl-alkenol in high yields. The meth-
odology is compatible with a wide range of functional
groups and catalytic in nature. The advantage of the reac-
tion is the generation of exocyclic vinyl functionality regio-
selectively at such a position, which can be used for the for-
mal synthesis of (±)-isocyclocelabenzine alkaloid.
Ts
Ts
Ts
Ts
N
N
N
N
stepwise
InCl3
HO
InCl3
HO
InCl3(OH)
R
R
R
R
B
A
Friedel–
Crafts
concerted
Ts
Ts
Ts
N
N
N
Friedel–Crafts
H
HO
InCl3
H
via C
H
4
R
R
R
InCl3 + H2O
InCl3(OH)
C
Scheme 2 Plausible mechanism of the reaction
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

D
N. R. Devi et al.
Paper
Synthesis
Table 2 Synthesis of Tetrahydroisoquinolinesa
Table 2 (continued)
Entry Substrate 3
Product 4
Yield (%)b
73
Ts
N
InCl3 (10 mol%)
DCE, 80 °C
NTs
R'
R'
Ts
Ts
N
N
HO
R
10
11
HO
HO
R
3j
4j
F
F
F
F
F
Entry Substrate 3
Product 4
Yield (%)b
Ts
N
Ts
N
Ts
N
Ts
N
77
81
Br
Br
1
97
70
4k
3k
HO
F
(Z)-3a
4a
Ts
N
Ts
N
Ts
N
Ts
N
12
13
14
HO
HO
HO
HO
2
3l
4l
F
F
3b
4b
Ts
N
Ts
N
Ts
N
Ts
N
62
3
4
87
76
Cl
Br
Cl
Br
3m
4m
HO
HO
Me
Me
4c
3c
3d
3e
Ts
N
Ts
N
Ts
N
Ts
N
0
3n
4d
4n
OMe
OMe
Ts
N
Ts
N
Ts
Ts
N
N
5
6
7
8
9
HO
HO
HO
0
15
16
55
78
HO
HO
4e
4a
(E)-3a
NO2
CF3
Br
NO2
Ts
N
Ts
N
Ts
N
Ts
N
Ph
Ph
80
87
77c
92
3o
3f
4o
4f
CF3
a Reaction conditions: 3 (1.0 equiv), InCl3 (10 mol%), DCE (4.0 mL), 80 °C.
b Isolated yield.
Ts
N
Ts
N
c Ratio determined by 1H NMR spectroscopy.
Ts
N
InCl3 (10 mol%)
I2, NaBH4
NTs
NTs
OH
3g
4g
Br
H2O2, NaOH
75%
DCE, 80 °C
97 %
HO
5
Ts
N
Ts
Ts
N
N
4a
ref 25
3a
HO
HO
Mg/MeOH
4h
4h'
67%
Cl
Cl
3h
ultrasound
r. t.
Cl
ref 26
o:m = 1:1
O
Ts
N
Ts
N
ref. 23
NH
OH
N
HN
H
9 steps
N
O
6
3i
4i
Cl
Cl
(
)-Isocyclocelabenzine
Scheme 3 Formal synthesis of (±)-isocyclocelabenzine
Thieme. All rights reserved. Synthesis 2020, 52, A–J

E
N. R. Devi et al.
Paper
Synthesis
(Z)-3a
8
Br
OAc
Ts
TsHN
Ts
N
N
Mp 65–68 °C; Rf = 0.55 (hexane/EtOAc 3:2).
K2CO3
NaH
IR (KBr): 3406, 2921, 2864, 1598, 1495, 1340, 1158, 1091, 1028, 932,
816, 766, 701 cm–1
1H NMR (400 MHz, CDCl3):  = 1.60 (br s, 1 H), 2.41 (s, 3 H), 3.78 (d, J =
7.2 Hz, 2 H), 3.88 (d, J = 6.8 Hz, 2 H), 4.32 (s, 2 H), 5.21–5.24 (m, 1 H),
5.56–5.61 (m, 1 H), 7.27–7.30 (m, 5 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.74
(d, J = 8.4 Hz, 2 H).
HO
AcO
MeOH, 4 h
80%
DMF, 12 h
60%
.
(Z)-3a
7
9
1. MnO2 2. PhMgI
CH2Cl2
rt
Et2O
31%
Ts
N
OH
(Z)-N-(4-Hydroxybut-2-en-1-yl)-4-methyl-N-(naphthalen-2-yl-
Ph
methyl)benzenesulfonamide (3b)27b
3o
IR (KBr, neat): 3420, 2922, 2865, 1598, 1439, 1339, 1158, 1090, 1017,
917, 816, 750, 660, 572 cm–1
.
Scheme 4
White solid; yield: 300 mg (78%); mp 70–73 °C; Rf = 0.50 (hexane/
EtOAc 3:2).
1H NMR (400 MHz, CDCl3):  = 1.85 (br s, 1 H), 2.43 (s, 3 H), 3.80 (d, J =
7.2 Hz, 2 H), 3.83 (d, J = 4.8 Hz, 2 H), 4.46 (s, 2 H), 5.19–5.22 (m, 1 H),
5.53–5.60 (m, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.41 (dd, J = 1.2, 7.2 Hz, 1
H), 7.45 (dd, J = 7.2, 3.2 Hz, 2 H), 7.62 (s, 1 H), 7.72–7.81 (m, 5 H).
All the reagents were of reagent grade (AR grade) and used as pur-
chased without further purification. Silica gel (60–120 mesh size) was
used for column chromatography. Reactions were monitored by TLC
on silica gel GF254 (0.25 mm). Melting points were recorded in an open
capillary tube and are uncorrected. FT-IR spectra were recorded as
neat liquid or KBr pellets. NMR spectra were recorded in CDCl3 with
TMS as the internal standard for 1H (600 MHz, 400 MHz) or 13C (150
MHz, 100 MHz) NMR. Chemical shifts () are reported in ppm and
spin-spin coupling constants (J) are given in hertz (Hz). HRMS spectra
were recorded using Q-TOF mass spectrometer.
(Z)-N-(2-Chlorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3c)
Yellow gum; yield: 400 mg (89%); Rf = 0.50 (hexane/EtOAc 3:2).
IR (KBr, neat): 3441, 2923, 2867, 1638, 1444, 1340, 1158, 1091, 1036,
911, 755, 657, 550 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.87 (br s, 1 H), 2.44 (s, 3 H), 3.85 (d, J =
7.2 Hz, 2 H), 3.95 (d, J = 6.4 Hz, 2 H), 4.45 (s, 2 H), 5.23–5.28 (m, 1 H),
5.58–5.64 (m, 1 H), 7.27 (m, 5 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.74 (d, J =
8.4 Hz, 2 H).
Starting Materials (Z)-N-Benzyl-N-(4-hydroxybut-2-en-1-yl)-4-
methylbenzenesulfonamide [(Z)-3a]27a and (Z)-N-Benzyl-N-(4-hy-
droxy-4-phenylbut-2-en-1-yl)-4-methylbenzenesulfonamide (3o)
(Scheme 4); Typical Procedure
13C NMR (100 MHz, CDCl3):  = 21.7, 44.8, 48.5, 58.0, 126.0, 127.3,
In a round-bottomed flask, NaH (50 mg, 2.10 mmol, 1.1 equiv) was
taken under N2 atmosphere at 0 °C. To the NaH was added a solution
of compound 7 (500 mg, 1.91 mmol, 1 equiv) in DMF (15 mL) drop-
wise. The reaction mixture was stirred for 15 min and then a solution
of 4-bromobut-2-en-1-yl acetate (8; 405 mg, 2.10 mmol, 1.1 equiv) in
DMF (2 mL) was slowly added. The mixture was stirred for 6 h. After
the completion of the reaction (checked by TLC), the mixture was
quenched by sat. aq NH4Cl and extracted with EtOAc (2 × 30 mL). The
combined organic layers were washed with brine, dried (anhyd
Na2SO4), and the solvent was evaporated. The residue was purified by
column chromatography to give (Z)-4-(N-benzyl-4-methylphenylsul-
fonamido)but-2-en-1-yl acetate (9; 420 mg, 60%). Compound 9 was
then treated with K2CO3/MeOH at rt for 4 h. After completion of the
reaction, MeOH was evaporated and the compound was extracted
with EtOAc (2 × 30 mL). The combined organic extracts were washed
with brine, dried (anhyd Na2SO4), and evaporated. The residue was
purified by column chromatography to give (Z)-3a; yield: 300 mg,
0.90 mmol (80%). Compound (Z)-3a (200 mg, 0.60 mmol, 1 equiv) was
then oxidized with MnO2 (1.5 g, 30 equiv) in DCM at rt under N2 at-
mosphere for 12 h. The mixture was filtered and evaporated, purifica-
tion through column chromatography gave the required aldehyde.
The aldehyde was then reacted with PhMgI (prepared in situ) in Et2O
at 0 °C for 30 min. After completion of the reaction as determined by
TLC, the mixture was quenched with sat. aq NH4Cl, and extracted
with Et2O. The combined Et2O layers were washed with brine, dried
(anhyd Na2SO4), and evaporated. The residue was purified by column
chromatography to give the final compound (Z)-3o; yield: 46 mg (31%
over two steps); colorless oil; Rf = 0.60 (hexane/EtOAc 4:1) (see below
for spectral data).
127.4, 129.1, 129.6, 130.0, 130.2, 132.9, 133.3, 133.9, 136.8, 143.8.
HRMS (ESI): m/z calcd for C18H21ClNO3S (M + H)+: 366.0931; found:
366.0937.
(Z)-N-(2-Bromobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3d)
White gum; yield: 366 mg (81%); Rf = 0.50 (hexane/EtOAc 3:2).
IR (KBr, neat): 3409, 2923, 2859,1596, 1441, 1340, 1158, 1092, 1024,
911, 813, 754, 659, 551 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.85 (br s, 1 H), 2.44 (s, 3 H), 3.85 (d, J =
7.2 Hz, 2 H), 3.94 (d, J = 6.4 Hz, 2 H), 4.43 (s, 2 H), 5.21–5.28 (m, 1 H),
5.59–5.62 (m, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.26–7.34 (m, 3 H), 7.50–
7.54 (m, 2 H), 7.74 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 44.9, 51.2, 58.1, 123.3, 125.9,
127.4, 127.9, 129.4, 130.1, 130.2, 132.9, 133.0, 135.5, 136.9, 143.9.
HRMS (ESI): m/z calcd for C18H21BrNO3S (M + H)+: 410.0426; found:
410.0438.
(Z)-N-(4-Hydroxybut-2-en-1-yl)-4-methyl-N-(4-nitrobenzyl)ben-
zenesulfonamide (3e)
Yellow gum; yield: 311 mg (73%); Rf = 0.40 (hexane/EtOAc 3:2).
IR (KBr, neat): 3405, 2925, 2862, 1654, 1522, 1346, 1158, 1091, 1017,
914, 771, 658 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.78 (br s, 1 H), 2.46 (s, 3 H), 3.85 (d, J =
7.2 Hz, 2 H), 3.97 (d, J = 6.4 Hz, 2 H), 4.40 (s, 2 H), 5.19–5.24 (m, 1 H),
5.62–5.68 (m, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H),
7.74 (d, J = 8.0 Hz, 2 H), 8.17 (d, J = 8.4 Hz, 2 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

F
N. R. Devi et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 21.8, 44.8, 50.7, 58.0, 124.0, 125.8,
127.4, 129.1, 130.2, 133.3, 136.7, 144.2, 144.3, 147.8.
HRMS (ESI): m/z calcd for C18H21N2O5S (M + H)+: 377.1171; found:
377.1216.
1H NMR (400 MHz, CDCl3):  = 2.15 (br s, 1 H), 2.44 (s, 3 H), 3.78 (d, J =
7.0 Hz, 2 H), 3.93 (d, J = 6.8 Hz, 2 H), 4.27 (s, 2 H), 5.11–5.18 (m, 1 H),
5.70–5.88 (m, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H),
7.32 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 44.0, 50.6, 57.9, 126.0, 127.3,
127.33, 128.8, 128.9, 129.8, 130.0, 132.9, 133.8, 134.8, 137.0, 143.8.
HRMS (ESI): m/z calcd for C18H20ClNO2S (M + H)+: 366.0926; found:
(Z)-N-(4-Hydroxybut-2-en-1-yl)-4-methyl-N-[4-(trifluorometh-
yl)benzyl]benzenesulfonamide (3f)
366.0928.
White solid; yield: 350 mg (77%); mp 85–87 °C, Rf = 0.48 (hexane/EtOAc
3:2).
(Z)-N-(3,5-Difluorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methyl-
benzenesulfonamide (3j)
IR (KBr, neat): 3422, 2925, 2865, 1619, 1420, 1326, 1159, 1122, 1066,
1018, 914, 816, 659, 548 cm–1
.
Colorless oil; yield: 327 mg (72%); Rf = 0.50 (hexane/EtOAc 3:2).
1H NMR (400 MHz, CDCl3):  = 1.71 (br s, 1 H), 2.45 (s, 3 H), 3.82 (d, J =
7.2 Hz, 2 H), 3.96 (d, J = 4.4 Hz, 2 H), 4.37 (s, 2 H), 5.21–5.24 (m, 1 H),
5.61–5.68 (m, 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H),
7.57 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 44.4, 50.9, 58.0, 122.9, 125.7,
125.76, 125.8, 125.84, 126.1, 127.4, 128.7, 130.1, 133.0, 137.0, 140.6,
144.0.
IR (KBr, neat): 3426, 2924, 2853, 1625, 1597, 1460, 1341, 1159, 1118,
992, 813, 660 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.06 (br s, 1 H), 2.36 (s, 3 H), 3.75 (d, J =
7.2 Hz, 2 H), 3.89 (d, J = 6.4 Hz, 2 H), 4.19 (s, 2 H), 5.11–5.14 (m, 1 H),
5.53–5.58 (m, 1 H), 6.59–6.64 (m, 1 H), 6.74 (d, J = 6.0 Hz, 2 H), 7.25
(d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z calcd for C19H21F3NO3S (M + H)+: 400.1194; found:
400.1213.
13C NMR (100 MHz, CDCl3):  = 21.7, 44.5, 50.5, 57.9, 103.4 (t, J = 25.0
Hz), 110.1 (d, J = 26 Hz) , 125.7, 127.3, 130.1, 133.2, 136.8, 140.8,
144.1, 163.2 (d, J = 248 Hz), 163.3 (d, J = 247 Hz).
HRMS (ESI): m/z calcd for C18H20F2NO3S (M + H)+: 368.1132; found:
(Z)-N-(4-Bromobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3g)
368.1134.
White solid; yield: 350 mg (78%); mp 80–83 °C; Rf = 0.55 (hexane/
EtOAc 3:2).
(Z)-N-(2-Bromo-5-fluorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-
methylbenzenesulfonamide (3k)
IR (KBr, neat): 3397, 2922, 2868, 1596, 1488, 1407, 1339, 1158, 1091,
1012, 910, 814, 767, 658 cm–1
.
Colorless gum; yield: 300 mg (66%); Rf = 0.50 (hexane/EtOAc 3:2).
1H NMR (400 MHz, CDCl3):  = 2.31 (br s, 1 H), 2.41 (s, 3 H), 3.75 (d, J =
6.2 Hz, 2 H), 3.90 (d, J = 6.0 Hz, 2 H), 4.22 (s, 2 H), 5.11–5.16 (m, 1 H),
5.56–5.60 (m, 1 H), 7.13 (d J = 6.0 Hz, 2 H), 7.30 (d, J = 6.0 Hz, 2 H),
7.39 (d, J = 6.0 Hz, 2 H), 7.69 (d, J = 6.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 44.1, 50.7, 58.0, 122.1, 126.2,
127.4, 130.1, 130.2, 131.9, 132.8, 135.4, 137.1, 143.9.
IR (KBr, neat): 3357, 2923, 2849, 1598, 1578, 1466, 1341, 1158, 1090,
1028, 813, 658, 556 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.02 (br s, 1 H), 2.45 (s, 3 H), 3.89 (d, J =
7.2 Hz, 2 H), 4.00 (d, J = 6.6 Hz, 2 H), 4.38 (s, 2 H), 5.25–5.30 (m, 1 H),
5.62–5.67 (m, 1 H), 6.88 (dt, J = 3.04, 5.24 Hz, 1 H), 7.25–7.29 (m, 1 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.43–7.47 (m, 1 H), 7.75 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z calcd for C18H21BrNO3S (M + H)+: 410.0426; found:
410.0433.
13C NMR (100 MHz, CDCl3):  = 21.8, 45.3, 51.1, 58.1, 116.6 (d, J = 22
Hz), 116.9, 117.1, 125.8, 127.4, 130.2, 133.4, 134.1, 134.2, 136.7,
138.2, 138.3, 144.1, 161.5 (d, J = 246.0 Hz).
HRMS (ESI): m/z calcd for C18H20BrFNO3S (M + H)+: 428.0331; found:
(Z)-N-(3-Chlorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3h)
428.0339.
Yellow oil; yield: 356 mg (77%); Rf = 0.50 (hexane/EtOAc 3:2).
(Z)-N-(4-Fluorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3l)
IR (KBr, neat): 3450, 2924, 2825, 1597, 1577, 1437, 1340, 1204, 1157,
1017, 921, 860, 814, 681, 657, 550 cm–1
.
Colorless oil; yield: 331 mg (72%); Rf = 0.50 (hexane/EtOAc 3:2).
1H NMR (400 MHz, CDCl3):  = 2.10 (br, 1 H), 2.44 (s, 3 H), 3.80 (d, J =
7.2 Hz, 2 H), 3.93 (d, J = 6.4 Hz, 2 H), 4.27 (s, 2 H), 5.16–5.22 (m, 1 H),
5.59–5.65 (m, 1 H), 7.15–7.17 (m, 1 H), 7.22 (m, 3 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 44.1, 51.0, 57.9, 125.8, 126.6,
127.3, 128.2, 128.4, 130.0, 133.0, 134.6, 136.9, 138.3, 143.9.
IR (KBr, neat): 3423,2924, 2855, 1603, 1509, 1339, 1226, 1158, 1091,
909, 816, 658, 548 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.10 (br s, 1 H), 2.44 (s, 3 H), 3.78 (d, J =
6.8 Hz, 2 H), 3.93 (d, J = 6.8 Hz, 2 H), 4.27 (s, 2 H), 5.16–5.22 (m, 2 H),
5.58–5.63 (m, 2 H), 6.96–7.01 (m, 2 H), 7.23–7.26 (m, 2 H), 7.33 (d, J =
8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 43.9, 50.6, 57.9, 115.6 (d, J = 21.0
Hz) 126.0, 127.3, 130.0, 130.1, 130.2, 131.8, 131.9, 132.7, 137.0, 143.8,
162.5 (d, J = 244.9 Hz).
HRMS (ESI): m/z calcd for C18H21ClNO3S (M + H)+: 366.0931; found:
366.0916.
(Z)-N-(4-Chlorobenzyl)-N-(4-hydroxybut-2-en-1-yl)-4-methylben-
zenesulfonamide (3i)
HRMS (ESI): m/z calcd for C18H21FNO3S (M + H)+: 350.1226; found:
350.1215.
Colorless oil; yield: 320 mg (85%); mp 80–82 °C; Rf = 0.50 (hexane/
EtOAc 3:2).
(Z)-N-(4-Hydroxybut-2-en-1-yl)-4-methyl-N-(4-methylben-
zyl)benzenesulfonamide (3m)
IR (KBr, neat): 3417, 2923, 2867, 1597, 1492, 1445, 1336, 1158, 1090,
1015, 911, 814, 657, 566 cm–1
.
Colorless oil; yield: 372 mg (81%); Rf = 0.45 (hexane/EtOAc 3:2).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

G
N. R. Devi et al.
Paper
Synthesis
IR (KBr, neat): 3444, 2923, 2864, 1597, 1513, 1438, 1340, 1157, 1090,
1019, 909, 814, 657, 577 cm–1
1H NMR (400 MHz, CDCl3):  = 2.09 (br s, 1 H), 2.31 (s, 3 H), 2.42 (s, 3
H), 3.76 (d, J = 7.2 Hz, 2 H), 3.89 (d, J = 6.8 Hz, 2 H), 4.26 (s, 2 H), 5.16–
5.23 (m, 1 H), 5.22–5.61 (m, 1 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.13( d, J =
8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H).
bined organic extarcts were dried (anhyd Na2SO4) and evaporation to
give the crude product, which was purified by column chromatogra-
phy using EtOAc and hexane as eluents (hexane/EtOAc 9:1); yellow
solid; yield: 137 mg (97%); mp 80–82 °C; Rf = 0.60 (hexane/EtOAc
9:1).
.
IR (KBr, neat): 2964, 2922, 2849, 1598, 1493, 1353, 1165, 1091, 956,
813, 743 cm–1
.
13C NMR (100 MHz, CDCl3):  = 21.2, 21.6, 43.6, 50.9, 57.9, 126.2,
127.3, 128.5, 129.4, 129.9, 132.5, 132.9, 137.2, 137.8, 143.6.
HRMS (ESI): m/z calcd for C19H24NO3S (M + H)+: 346.1477; found:
346.1470.
1H NMR (400 MHz, CDCl3):  = 2.35 (s, 3 H), 3.07 (dd, J = 4.8, 6.8 Hz, 1
H), 3.36 (dd, J = 6.8, 4.8 Hz, 1 H), 3.56 (dt, J = 5.6, 7.2 Hz, 1 H), 4.16 (dd,
J = 14.8, 13.2 Hz, 2 H), 5.11–5.16 (m, 2 H), 5.70–5.77 (m, 1 H), 6.95–
6.97 (m, 1 H), 7.08–7.09 (m, 3 H), 7.26(d, J = 8.4 Hz, 2 H), 7.65(d, J = 8.4
Hz, 2 H).
(Z)-N-(4-Hydroxybut-2-en-1-yl)-N-(4-methoxybenzyl)-4-methyl-
benzenesulfonamide (3n)
3-Tosyl-1-vinyl-1,2,3,4-tetrahydrobenzo[f]isoquinoline (4b)27b
Colorless oil; yield: 320 mg (71%); Rf = 0.40 (hexane/EtOAc 3:2).
Brown solid; yield: 100 mg (70%); mp 160–162 °C; Rf = 0.50 (hexane/
EtOAc 9:1).
IR (KBr, neat): 3451, 2924, 2855, 1612, 1511, 1458, 1336, 1249, 1156,
1093, 1031, 906, 814, 658, 548 cm–1
.
IR (KBr, neat): 2921, 2851, 1597, 1458, 1341, 1307, 1163, 1090, 810,
1H NMR (400 MHz, CDCl3):  = 1.74 (br s, 1 H), 2.45 (s, 3 H), 3.77 (d, J =
7.2 Hz, 2 H), 3.79 (s, 3 H), 3.93 (d, J = 6.4 Hz, 2 H), 4.32 (s, 2 H), 5.33–
5.38 (m, 1 H), 5.52–5.56 (m, 1 H), 7.2–7.33 (m, 7 H), 7.73 (d, J = 8.0 Hz,
2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 43.6, 50.8, 55.5, 58.0, 114.2,
126.6, 127.4, 127.9, 129.9, 130.0, 132.4, 137.3, 143.7, 159.6.
746, 661 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.42 (s, 3 H), 2.90 (dd, J = 3.5, 7.8 Hz, 1
H), 3.97 (d, J = 15.4 Hz, 1 H), 4.06–4.15 (m, 2 H), 4.77 (d, J = 15.2 Hz, 1
H), 4.99 (dt, J = 1.3, 17.2 Hz, 1 H), 5.19 (dt, J = 10.2, 1.2 Hz, 1 H), 6.10–
6.17 (m, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.42–
7.52 (m, 2 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.76–7.80 (m, 3 H), 7.93 (d, J =
8.4 Hz, 1 H).
HRMS (ESI): m/z calcd for C19H23NO4S (M + H)+: 362.1421; found:
362.1427.
8-Chloro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4c)
(E)-N-(4-Hydroxybut-2-en-1-yl)-N-(4-methoxybenzyl)-4-methyl-
benzenesulfonamide [(E)-3a]28
Brown solid; yield: 125 mg (87%); mp 100–102 °C; Rf = 0.45 (hexane/
EtOAc 9:1).
Colorless oil; yield: 332 mg (70%); Rf = 0.40 (hexane/EtOAc 3:2).
IR (KBr, neat): 3070, 2976, 2921, 2849, 1597, 1443, 1352, 1164, 1093,
1058, 950, 814, 779, 662, 549 cm–1
.
IR (KBr, neat): 3131, 3013, 2859, 1598, 1401, 1339, 1157, 1092, 1013,
896, 730, 550 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.17 (dd, J = 6.4, 5.2 Hz, 1
H), 3.38 (dd, J = 7.2, 4.4 Hz, 1 H), 3.61–3.64 (m, 1 H), 4.18 (d, J = 16.0
Hz, 1 H), 4.24, (d, J = 16.0 Hz, 1 H), 5.20 (s, 1 H), 5.19–5.24 (m, 2 H),
7.08 (m, 1 H), 7.12 (t, J = 7.6 Hz, 1 H), 7.19–7.22 (m, 1 H), 7.35 (d, J =
8.4 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 2 H).
1H NMR (600 MHz, CDCl3):  = 2.44 (s, 3 H), 3.73 (d, J = 6.5 Hz, 2 H),
3.93 (d, J = 5.2 Hz, 2 H), 3.93 (d, J = 6.4 Hz, 2 H), 4.26 (s, 2 H), 5.17–5.24
(m, 1 H), 5.58–5.64 (m, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.8 Hz,
2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 43.7, 46.4, 48.1, 118.2, 127.6,
127.8, 127.9, 129.7, 130.0, 132.2, 133.1, 137.8, 138.2, 144.1.
HRMS (ESI): m/z calcd for C18H19ClNO2S (M + H)+: 348.0820; found:
348.0827.
(Z)-N-Benzyl-N-(4-hydroxy-4-phenylbut-2-en-1-yl)-4-methylben-
zenesulfonamide (3o)
IR (KBr, neat): 3426, 2843, 1610, 1448, 1323, 1253, 1150, 1045, 1012,
810, 650 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.44 (s, 3 H), 3.77 (dd, J = 6.8, 7.0 Hz, 2
H), 4.23 (d, J = 14.8 Hz, 1 H), 4.33 (d, J = 14.8 Hz, 1 H), 5.00 (d, J = 5.4
Hz, 1 H), 5.39–5.46 (m, 1 H), 5.55 (dd, J = 15.4, 6.2 Hz, 1 H), 7.19 (d, J =
7.2 Hz, 4 H), 7.25–7.34 (m, 8 H), 7.71 (d, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 49.0, 51.2, 74.4, 125.6, 126.3,
127.5, 128.0, 128.1, 127.6, 128.7, 128.8, 130.0, 136.4, 137.1, 137.4,
142.4, 143.6.
8-Bromo-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4d)
Brown solid; yield: 109 mg (76%); mp 104–106 °C; Rf = 0.45 (hexane/
EtOAc 9:1).
IR (KBr, neat): 3068, 2921, 2853, 1597, 1563, 1438, 1350, 1163, 1091,
958, 813, 661, 550 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.17 (dd, J = 6.8, 4.8 Hz, 1
H), 3.37 (dd, J = 7.2, 4.4 Hz, 1 H), 3.61–3.64 (m, 1 H), 4.12–4.17 (m, 2
H), 5.22 (d, J = 14.0 Hz, 1 H), 5.75–5.83 (m, 1 H), 7.5 (t, J = 7.0 Hz, 1 H),
7.12 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 1 H),
7.75 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 43.9, 48.2, 49.0, 118.2, 122.6,
127.9, 128.3, 128.4, 130.1, 131.0, 131.1, 131.2, 133.1, 138.1, 138.3,
144.2.
Anal. Calcd for C24H23NO2S: C, 70.73; H, 6.18; N, 3.44. Found: C, 70.84;
H, 6.25; N, 3.48.
2-Tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4a)27c; Typical Pro-
cedure
To a solution of (E)-3a (150 mg, 0.45 mmol, 1 equiv) in anhyd 1,2-di-
chloroethane (4 mL) was added InCl3 (10 mol%, 10 mg) at 80 °C. The
reaction mixture was refluxed for 4 h. After the completion of the re-
action, as determined by TLC, the mixture was washed with sat. aq
NaHCO3 and brine, and extracted with EtOAc (2 × 15 mL). The com-
HRMS (ESI): m/z calcd for C18H19BrNO2S (M + H)+: 392.0320; found:
392.0307.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

H
N. R. Devi et al.
Paper
Synthesis
2-Tosyl-6-(trifluoromethyl)-4-vinyl-1,2,3,4-tetrahydroisoquino-
line (4f)
13C NMR (100 MHz, CDCl3):  = 21.7, 40.4, 47.4, 48.4, 117.4, 125.3,
127.9, 128.0, 128.1, 128.3, 130.0, 133.2, 133.0, 133.9, 134.9, 137.1,
144.1.
Brown solid; yield: 114 mg (80%); mp 90–92 °C; Rf = 0.45 (hexane/
EtOAc 9:1).
HRMS (ESI): m/z calcd for C18H19ClNO2S (M + H)+: 348.0820; found:
348.0829.
IR (KBr, neat): 2927, 2849, 1598, 1458, 1423, 1336, 1166, 1123, 817,
661, 568 cm–1
.
6-Chloro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4i)
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.12 (dd, J = 7.0, 4.8 Hz, 1
H), 3.49 (dd, J = 4.6, 7.2 Hz, 1 H), 3.68 (dd, J = 7.0, 6.6 Hz, 1 H), 4.22 (d,
J = 15.6 Hz, 1 H), 4.33 (d, J = 15.6 Hz, 1 H), 5.24–5.29 (m, 2 H), 5.74–
5.84 (m, 1 H), 7.17 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.41–
7.43 (m, 2 H), 7.73 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 44.4, 50.9, 58.0, 125.8 (q, J = 14.6,
15.0 Hz), 126.1, 127.4, 128.7, 130.1, 132.9, 137.0, 140.6, 144.0.
White solid; yield: 125 mg (92%); mp 133–135 °C; Rf = 0.66 (hexane/
EtOAc 9:1).
IR (KBr, neat): 2925, 1843, 1639, 1597, 1486, 1457, 1345, 1162, 1093,
1050, 811, 772, 684, 658, 575 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.36 (s, 3 H), 2.99 (dd, J = 4.4, 7.2 Hz 1
H), 3.38 (dd, J = 6.8, 4.8 Hz 1 H), 3.53 (dt, J = 6.0, 7.2 Hz, 1 H), 4.05 (d,
J = 14.8 Hz, 1 H), 4.17 (d, J = 14.8 Hz, 1 H), 5.15–5.19 (m, 2 H), 5.65–
5.72 (m, 1 H), 6.9 (d, J = 8.8 Hz, 1 H), 7.06–7.08 (m, 2 H), 7.27 (d, J = 8.4
Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H).
HRMS (ESI): m/z calcd for C19H19F3NO2S (M + H)+: 382.1084; found:
382.1106.
6-Bromo-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4g)
13C NMR (100 MHz, CDCl3):  = 21.8, 43.6, 47.6, 48.5, 118.7, 127.3,
127.9, 128.0, 129.0, 130.0, 130.1, 133.0, 137.2, 137.8, 144.2.
HRMS (ESI): m/z calcd for C18H19ClNO2S (M + H)+: 348.0825; found:
White solid; yield: 135 mg (87%); mp 128–130 °C; Rf = 0.66 (hexane/
EtOAc 9:1).
348.0834.
IR (KBr, neat): 2972, 2923, 2847, 1479, 1456, 1343, 1162, 1089, 806,
709, 652 cm–1
.
5,7-Difluoro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4j)
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.06 (dd, J = 4.8, 6.8 Hz, 1
H), 3.44 (dd, J = 6.8, 5.2 Hz, 1 H), 3.58–3.62 (m, 1 H), 4.09 (d, J = 15.2
Hz, 1 H), 4.22 (d, J = 15.2 Hz, 1 H), 5.22–5.26 (m, 2 H), 5.71–5.80 (m, 1
H), 6.91 (d, J = 8.8 Hz, 1 H), 7.26–7.29 (m, 2 H), 7.34 (d, J = 8.4 Hz, 2 H),
7.71 (d, J = 8.4 Hz, 2 H).
Brown solid; yield 105 mg (73%); mp 128–130 °C; Rf = 0.45 (hexane/
EtOAc 9:1).
IR (KBr, neat): 3084, 2923, 2853, 1627, 1598, 1489, 1441, 1344, 1161,
1118, 994, 949, 850, 815, 765, 664, 554 cm–1
.
13C NMR (100 MHz, CDCl3):  = 21.7, 43.5, 47.6, 48.4, 77.6, 118.7,
120.8, 127.9, 128.2, 130.0, 130.1, 130.6, 132.0, 133.1, 137.6, 137.8,
144.1.
HRMS (ESI): m/z calcd for C18H19BrNO2S (M + H)+: 392.0320; found:
392.0311.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 2.80 (dd, J = 8.0, 4.0 Hz, 1
H), 3.68–3.71 (m, 1 H), 3.78 (d, J = 15.6 Hz, 1 H), 3.85 (d, J = 12.0 Hz, 1
H), 4.59 (d, J = 15.6 Hz, 1 H), 5.07 (dd, J = 16.4, 1.0 Hz, 1 H), 5.14 (d, J =
10.4 Hz, 1 H), 5.93–5.98 (m, 1 H), 6.60–6.68 (m, 2 H), 7.35 (d, J = 8.0
Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.7, 36.7, 47.4, 48.1, 102.6 (t, J = 25.0
Hz) , 108.8 (q, J = 18.2 Hz), 116.7, 119.2, 119.3, 127.9, 130.0, 133.0,
135.0, 135.1, 137.5, 144.2, 161.2 (dd, J = 248.5, 12.2 Hz), 161.7 (dd, J =
246.2, 12.8 Hz).
HRMS (ESI): m/z calcd for C18H18F2NO2S (M + H)+: 350.1026; found:
350.1037.
7-Chloro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4h)
Brown solid; yield: 50 mg (34%); mp 80–81 °C; Rf = 0.55 (hexane/
EtOAc 9:1).
IR (KBr, neat): 2976, 2922, 2856, 1597, 1458, 1352, 1164, 1091, 964,
814, 753, 670, 586 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.11 (dd, J = 7.2, 4.8 Hz, 1
H), 3.43 (dd, J = 4.8, 7.2 Hz, 1 H), 3.59 (dd, J = 6.8, 6.0 Hz, 1 H), 4.13 (d,
J = 15.2 Hz, 1 H), 4.23 (d, J = 15.2 Hz, 1 H) 5.21–5.23 (m, 2 H), 5.72–
5.81 (m, 1 H), 7.03 (s, 1 H), 7.06–7.14 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H),
7.72 (d, J = 8.0 Hz, 2 H).
8-Bromo-5-fluoro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline
(4k)
Yellow solid; yield: 110 mg (77%); mp 120–123 °C; Rf = 0.50 (hexane/
EtOAc 9:1).
13C NMR (100 MHz, CDCl3):  = 21.7, 43.2, 47.7, 48.2, 118.3, 126.4,
127.4, 128.0, 130.0, 130.6, 132.7, 133.3, 133.8, 138.2, 144.2.
IR (KBr, neat): 2923, 2853, 1597, 1456, 1354, 1339, 1254, 1165, 1091,
1028, 955, 814, 773, 658, 549 cm–1
.
1H NMR (600 MHz, CDCl3):  = 2.44 (s, 3 H), 2.73 (dd, J = 11.8, 3.5 Hz, 1
H), 3.62 (d, J = 14.8 Hz, 1 H), 3.75–3.78 (m, 1 H), 3.89 (d, J = 11.8 Hz, 1
H), 4.64 (d, J = 16.2 Hz, 1 H), 5.09 (d, J = 17.2 Hz, 1 H), 5.17 (d, J = 10.2
Hz, 1 H), 5.97–6.03 (m, 1 H), 6.83 (t, J = 8.8 Hz, 1 H), 7.35–7.40 (m, 3
H), 7.75 (d, J = 8.0 Hz, 2 H).
13C NMR (150 MHz, CDCl3):  = 21.8, 37.4, 47.6, 48.8, 115.4 (d, J = 23.0
Hz), 116.6, 116.64, 117.2, 126.0 (d, J = 18.5 Hz), 128.0, 130.1, 131.9 (d,
J = 8.5 Hz), 133.2 (d, J = 9.1 Hz), 137.2, 144.2, 160.1 (d, J = 246.4 Hz).
HRMS (ESI): m/z calcd for C18H19ClNO2S (M + H)+: 348.0820; found:
348.0819.
5-Chloro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4h′)
Brown solid; yield: 48 mg (33%); mp 108–110 °C; Rf = 0.50 (hexane/
EtOAc 9:1).
IR (KBr, neat): 2921, 2850, 1596, 1458, 1444, 1351, 1165, 1091, 956,
816, 777, 657, 549 cm–1
.
HRMS (ESI): m/z calcd for C18H18BrFNO2S (M + H)+: 410.0221; found:
410.0241.
1H NMR (400 MHz, CDCl3):  = 2.42 (s, 3 H), 2.74 (dd, J = 3.4, 8.2 Hz, 1
H), 3.76–3.84 (m, 2 H), 3.99 (d, J = 11.6 Hz, 1 H), 4.66 (d, J = 15.2 Hz, 1
H), 4.99 (d, J = 17.2 Hz, 1 H), 5.17 (d, J = 10.28 Hz, 1 H), 5.92–6.00 (m, 1
H), 6.98 (d, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.8 Hz, 1 H), 7.23 (d, J = 7.8 Hz, 1
H) 7.34 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

I
N. R. Devi et al.
Paper
Synthesis
6-Fluoro-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4l)
IR (KBr, neat): 3425, 2926, 2857, 1644, 1598, 1455, 1337, 1163, 1090,
1034, 949, 812, 669, 553 cm–1
.
Yellow solid; yield: 125 mg (81%); mp 92–94 °C; Rf = 0.6 (hexane/
1H NMR (400 MHz, CDCl3):  = 1.81 (s, 1 H), 1.87–1.95 (m, 1 H), 2.02–
2.10 (m, 1 H), 2.42 (s, 3 H), 2.78 (dd, J = 8.4, 3.6 Hz, 1 H), 3.06–3.12 (m,
1 H), 3.76–3.89 (m, 4 H), 4.61 (d, J = 14.8 Hz, 1 H), 7.01–7.03 (m, 1 H),
7.12–7.17 (m, 3 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H).
13C NMR (150 MHz, CDCl3):  = 21.7, 35.5, 38.1, 47.1, 47.8, 60.6, 126.6,
126.7, 127.0, 127.9, 129.1, 130.0, 131.4, 133.2, 137.7, 144.0.
EtOAc 9:1).
IR (KBr, neat): 2972, 2923, 2847, 1479, 1456, 1343, 1162, 1089, 806,
709, 652 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3 H), 3.05 (dd, J = 7.2, 4.4 Hz, 1
H), 3.59–3.61 (m, 1 H), 3.61 (dd, J = 7.2, 5.6 Hz, 1 H), 4.11 (d, J = 14.8
Hz, 1 H), 4.26 (d, J = 14.8 Hz, 1 H), 5.22–5.26 (m, 2 H), 5.74–5.79 (m, 1
H), 6.84–6.89 (m, 2 H), 6.99–7.02 (m, 1 H), 7.34 (d, J = 8.0 Hz, 2 H),
7.72 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z calcd for C18H22NO3S (M + H)+: 332.1320; found:
332.1330.
13C NMR (100 MHz, CDCl3):  = 21.7, 43.7, 47.6, 48.4, 114.3 (d, J = 21.7
Hz), 115.5 (d, J = 21.6 Hz), 118.6, 127.1, 127.2, 127.9, 128.0, 128.1,
129.9, 133.2, 137.5, 137.9, 144.1, 161.7 (d, J = 243.9 Hz);
HRMS (ESI): m/z calcd for C18H19FNO2S (M + H)+: 332.1121; found:
332.1115.
2-(1,2,3,4-Tetrahydroisoquinolin-4-yl)ethanol (6)
To a solution of 5 (180 mg, 0.48 mmol) in anhyd MeOH was added Mg
turnings (230 mg, 9.6 mmol) and the reaction mixture was stirred
under sonication for 5 h at rr.t. After the completion of the reaction,
the mixture was quenched with brine, and extracted with CHCl3. The
combined organic layers were dried (anhyd Na2SO4) and concentrated
in vacuo. The product was purified by column chromatography on sil-
ica gel (DCM/MeOH 9:1) to give 6 as a colorless oil; yield: 56 mg
(67%); Rf = 0.55 (DCM/MeOH 9:1).
6-Methyl-2-tosyl-4-vinyl-1,2,3,4-tetrahydroisoquinoline (4m)
White gum; yield: 100 mg (62%); Rf = 0.50 (hexane/EtOAc 9:1).
IR (KBr, neat): 2976, 2922, 2856, 1597, 1458, 1352, 1164, 1091, 964,
814, 753, 670, 586 cm–1
.
IR (KBr, neat): 3383, 2924, 2854, 1730, 1641, 1462, 1376, 1283, 909,
1H NMR (400 MHz, CDCl3):  = 2.27 (s, 3 H), 2.41 (s, 3 H), 3.12 (dd, J =
7.2, 4.4 Hz, 1 H), 3.41 (dd, J = 4.8, 6.8 Hz, 1 H), 3.58 (dd, J = 7.2, 5.6 Hz,
1 H), 4.10–4.24 (m, 2 H), 5.17–5.23 (m, 2 H), 5.76–5.86 (m, 1 H), 6.91–
6.96 (m, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.2, 21.7, 43.6, 47.8, 48.8, 117.6,
126.4, 127.8, 127.9, 128.5, 129.5, 129.9, 133.3, 135.1, 136.7, 138.8,
143.9.
761, 722 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.95–2.02 (m, 1 H), 2.07–2.013 (m, 1
H), 3.26–3.38 (m, 3 H), 3.49 (d, J = 11.8 Hz, 1 H), 3.62–3.67 (m, 1 H),
4.19 (d, J = 16.0 Hz, 1 H), 4.32 (d, J = 16.0 Hz, 1 H), 6.90 (br s, 2 H), 7.04
(d, J = 7.4 Hz, 1 H), 7.12–7.21 (m, 3 H)
13C NMR (150 MHz, CDCl3):  = 35.6, 39.5, 46.8, 47.9, 57.7, 126.7,
126.8, 127.3, 129.1, 133.2, 135.5.
HRMS (ESI): m/z calcd for C19H22NO2S (M + H)+: 328.1371; found:
328.1381.
HRMS (ESI): m/z calcd for C11H16NO (M + H)+: 178.1227; found:
178.1238.
(E)-4-Styryl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (4o)
White gum; yield 35 mg (78%); Rf = 0.55 (hexane/EtOAc 4:1).
IR (KBr, neat): 2925, 2916, 2867, 1357, 1124, 1056, 912, 845, 746, 660
Funding Information
cm–1
.
This work was supported by Council of Scientific & Industrial Re-
search (CSIR), New Delhi (grant no. 02(0364)/19/EMR-II).
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1H NMR (400 MHz, CDCl3):  = 2.41 (s, 3 H), 3.14 (dd, J = 11.8, 7.2 Hz, 1
H), 3.57 (dd, J = 11.8, 6.0 Hz, 1 H), 3.82 (dd, J = 12.8, 7.2 Hz, 1 H), 4.20
(d, J = 15.0 Hz, 1 H), 4.36 (d, J = 15.0 Hz, 1 H), 6.15 (dd, J = 15.8, 8.7 Hz,
1 H), 6.57 (d, J = 15.8 Hz, 1 H), 7.06–7.08 (m, 1 H), 7.16–7.26 (m, 4 H),
7.28–7.36 (m, 6 H), 7.73 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.8, 43.0, 48.0, 49.0, 126.6 (2 C),
127.1, 127.2, 127.8, 128.0, 128.8, 129.3, 130.0, 130.1, 131.6, 132.9,
133.3, 135.6, 137.0, 143.9.
Acknowledgment
N.R.D. gratefully acknowledges the Indian Institute of Technology Gu-
wahati for her fellowship. The authors are also thankful to the Central
Instrument Facility (CIF) of IIT Guwahati for NMR facilities and X-ray
crystallography.
Anal. Calcd for C24H23NO2S: C, 74.00; H, 5.95; N, 3.60. Found: C, 74.09;
H, 5.98; N, 3.53.
Supporting Information
2-(2-Tosyl-1,2,3,4-tetrahydroisoquinolin-4-yl)ethanol (5)
Supporting information for this article is available online at
To a septum-capped round-bottomed flask charged with anhyd THF
(15 mL) was added NaBH4 (185 mg, 4.75 mmol). I2 (360 mg, 2.85
mmol) in anhyd THF (10 mL) was then added under N2 atmosphere at
0 °C and the reaction mixture was stirred for 2 h. A THF solution of
compound 4a (600 mg, 1.9 mmol) was added and the mixture was
stirred for 12 h at 25 °C. The mixture was quenched with H2O (2 mL)
and THF (10 mL) and oxidized with 30% H2O2 [10 mL/aq NaOH (3 N,
10 mL)]. The organic layer was extracted with Et2O (2 × 30 mL) and
the combined organic layers were washed with brine, and dried (an-
hyd Na2SO4). Evaporation of solvent and purification by column chro-
matography gave the desired compound 5 as a white solid; yield: 470
mg (75%); mp 117–119 °C; Rf = 0.55 (hexane/EtOAc 3:2).
https://doi.org/10.1055/s-0037-1610750.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J