Unexpected PF 6 Anion Metathesis during the Bischler-Napieralski Reaction: Synthesis of 3,4-Dihydroisoquinoline Hexafluorophosphates and Their Tetrahydroisoquinoline Related Alkaloids

Article abstract of DOI:10.1055/s-0037-1610684

A series of N -phenethylcinnamamides were subjected to the Bischler-Napieralski reaction to furnish diverse 1-styryl-3,4-dihydroisoquinolines. We noticed that the desired products were unstable when the reaction was performed under conventional solvent co

Full text of DOI:10.1055/s-0037-1610684

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
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C. E. Puerto Galvis et al.
Paper
Synthesis
Unexpected PF6 Anion Metathesis during the Bischler–Napieralski
Reaction: Synthesis of 3,4-Dihydroisoquinoline Hexafluorophos-
phates and Their Tetrahydroisoquinoline Related Alkaloids
Carlos E. Puerto Galvisa
Mario A. Macíasb
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Vladimir V. Kouznetsov*a
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a Laboratorio de Química Orgánica y Biomolecular, CMN, Universidad
Industrial de Santander, Parque Tecnológico Guatiguará, Km 2 Vía
Refugio, Piedecuesta 681011, Colombia
kouznet@uis.edu.co
vkuznechnik@gmail.com
b Department of Chemistry, Universidad de los Andes, Carrera 1 No.
18A 10, Bogotá 111711, Colombia
Received: 22.10.2018
Accepted after revision: 20.12.2018
Published online: 18.02.2019
synthesis of functionalized isoquinoline compounds, in-
cluding numerous relevant alkaloids like protoberberines 1,
benzylisoquinolines 2, phenanthridones 3, pyrrolo[2,1-
a]isoquinolines 4, aporphines 5, and β-carbolines 6 (Figure
1).6,7
DOI: 10.1055/s-0037-1610684; Art ID: ss-2018-m0711-op
Abstract A series of N-phenethylcinnamamides were subjected to the
Bischler–Napieralski reaction to furnish diverse 1-styryl-3,4-dihydroiso-
quinolines. We noticed that the desired products were unstable when
the reaction was performed under conventional solvent conditions.
However, when [bmim]PF6 was used as the reaction media, the nature
of the Bischler–Napieralski reaction promoted an unusual in situ ionic
interchange between this ionic liquid and the dihydroisoquinoline core
that led to the stabilization of the desired 1-styryl-3,4-dihydroisoquino-
lines, allowing their isolation as hexafluorophosphate salts. Finally, the
one-pot reduction/reductive methylation process afforded the N-meth-
yl derivatives, establishing that our findings can be an efficient and use-
ful strategy for the concise synthesis of tetrahydroisoquinoline alka-
loids.
N
N
H
NH
O
1
2
3
N
N
N
N
H
4
5
6
Key words cinnamamide, Bischler–Napieralski reaction, dihydroiso-
quinoline hexafluorophosphate, Dysoxylum alkaloid, tetrahydroiso-
quinoline
Figure 1 Representative natural systems prepared through the BNR
Despite the recent advances in the BNR,8 the scope of
this reaction is generally limited by the need for electron-
donating groups, toxic and high-boiling-point solvents, and
elevated temperatures that result in extensive purification
processes. To date, the substrate scope of the BNR has been
extended to hundreds of amide compounds, and N-
phenethylcinnamamides are not an exception as they have
been used for the preparation of 1-styryl-3,4-dihydroiso-
quinolines. During the last six decades, scientific reports re-
garding the chemistry and biology of these derivatives have
been scarce. They were firstly prepared and used as a 1-aza-
dienes in a Diels–Alder reaction (1957),9 exhibited antibac-
terial activity (1970),10 uncoupled mitochondrial respira-
tion in rats (1996),11 and recently were obtained as
intermediates in the synthesis of hexahydrocyclopen-
Phosphoryl chloride (POCl3) has been traditionally used
as a dehydrating agent in the synthesis of nitriles from am-
ides,1 but when N-phenethylacylamides are employed as
the substrate, the formed nitrilium intermediate can easily
undergo an intramolecular cyclization to afford 3,4-dihy-
droisoquinolines in what is well known as a Bischler–
Napieralski reaction (BNR).2
Despite its harsh reaction conditions, the BNR is still
preferred over other methodologies, such as the intramo-
lecular cyclization of N-(2-acetylphenethyl)acetamides pro-
moted by HCl,3 the Pictet–Spengler,4 and Pomeranz–Fritsch
reaction,5 for the construction of the isoquinoline ring sys-
tem, since it is not a stereospecific reaction it does not re-
quire chiral catalysts, it is more versatile, and allows the
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C. E. Puerto Galvis et al.
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Synthesis
ta[ij]isoquinolines (2015), where their high instability
meant that they were reduced as soon as they were ob-
tained.12
used excess POCl3 and [bmim]PF6, the reactions were con-
ducted at high temperatures, and simple N-phenethylacet-
amides were used as starting materials, without having
evaluated the reactivity of α,β-unsaturated amides, more-
over, the corresponding 3,4-dihydroisoquinolines were ob-
tained as their free bases.15,16
Herein, we report the synthesis of new 1-styryl-3,4-di-
hydroisoquinolines through the BNR, examining the elec-
tronic demand on the aromatic ring of substituted N-
phenethylcinnamamides, describing mild reaction condi-
tions, and finding that an unexpected in situ ionic inter-
change with [bmim]PF6 allows the isolation of the desired
products as stable hexafluorophosphate salts, which were
then transformed into more complex heterocyclic compounds.
In preliminary experiments, we examined the reactivity
of N-phenethylcinnamamides 7a–f under the most com-
mon reaction conditions of the classical BNR (see Table SI1,
Supporting Information),13,14 nevertheless, none of these at-
tempts resulted in the formation of any product, the desired
3,4-dihydroisoquinolines 8, and the corresponding unreac-
tive cinnamamides were recovered after the reaction work-
up (Scheme 1).
Table 1 Optimization of Reaction Conditions for the BNR of N-(3,4-Di-
a
methoxyphenethyl)cinnamamide in [bmim]PF6
MeO
MeO
MeO
MeO
PF6
HN
O
NH
POCl3
[bmim]PF6
T, t
7g
8g
Entry
POCl3 (equiv) [bmim]PF6 (mL) Temp (°C) Time
Yield (%)b
1
2
3
4
5
6
7
8
1
25
100
50
3 d
1 h
90
81
96
95
95
98
64c
8
1
R3
R3
H
8
1
24 h
48 h
48 h
24 h
24 h
B
R2
R1
R2
R1
N
A
1.5
1.5
1.5
1
1
50
A
N
O
α
α
POCl3/P2O5/ZnCl2
0.8
0.5
0.5
50
7a = R1 = R2 = R3 = H
toluene/solvent-free
100 °C, 6 h
50
7b = R1 = Cl, R2 = R3 = H
7c = R1 = F, R2 = R3 = H
7d = R1 = OMe, R2 = R3 = H
7e = R2 = OMe, R1 = R3 = H
7f = R3 = OMe, R1 = R2 = H
50
B
8
a Reactions performed on a 1-mmol scale.
b Yield of the isolated product after precipitated from the reaction mixture
with crushed ice, filtering, and drying under vacuum.
c Incomplete conversion of 7g (TLC).
Scheme 1 Substituent scope at the A-ring of cinnamamides in the
classical reaction conditions for the BNR
In our study, we observed that after treatment cinnama-
mide 7g with POCl3 (8 equiv) in [bmim]PF6 (1 mL) for three
days at room temperature (Table 1, entry 1), the reaction
mixture turned yellow and during the aqueous workup
(crushed ice) a solid precipitated, which was then filtered,
washed with water, dried, and characterized. Due to the hy-
drolysis of POCl3, which releases high amounts of HCl,17 and
the basic nature of the nitrogen atom in the isoquinoline
core, our first thoughts were that the desired compound
was the hydrochloride salt, since it was insoluble in most
common organic solvents. However, further single crystal
X-ray crystallographic study confirmed that instead of the
chloride counterion, the anion that was really forming the
Those amides 7a–d,f with electron-withdrawing groups
(Cl, F) or with electron-donating groups (OMe) at the meta
or position to the α-carbon, where the intramolecular cy-
clization takes place, of the amide A-ring were completely
unreactive (Scheme 1). However, the presence of the OMe
group at the para position to this α-carbon promoted the
full conversion of the cinnamamide 7e into a new product
(TLC) after 3 hours at 100 °C using 8 equivalents of POCl3 in
toluene. Unfortunately, during the purification process of
this product, presumably the 3,4-dihydroisoquinoline as a
free base, by routine physical methods, we observed that
this compound rapidly decomposed and it could not be well
manipulated and stored.
–
salt was hexafluorophosphate [PF6 ]. This fact was also cor-
As we now knew the structural requirements in the A-
ring of cinnamamides to ensure their transformation in the
BNR and were also aware of the instability of the 3,4-dihy-
droisoquinoline derived from cinnamamide 7e, we focused
our efforts in a study of the BNR with the N-(3,4-dime-
thoxyphenethyl)cinnamamide (7g) using the ionic liquid
[bmim]PF6 as a solvent, seeking a more environmentally
friendly protocol that allowed the isolation of the desired
product (Table 1). Although this ionic liquid was reported
previously as a reaction media for the BNR, both studies
roborated by 31P NMR experiment where a septet (J = 714.4
Hz) was identified at δ = –69.15, while in the 19F NMR ex-
periment, the magnetic equivalence of the six fluorines in
the [PF6]– anion gave a doublet with a J = 714.4 Hz at δ =
–71.41 (see Figures SI26 and SI27, Supporting Information).
This finding shows that during the reaction and/or the
workup process, an anion metathesis take place between
the solvent and the N-heterocyclic product, affording the
respective 3,4-dihydroisoquinoline hexafluorophosphate
8g in 90% yield (Table 1, entry 1).
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The ionic liquid [bmim]PF6 is prepared by salt metathe-
sis from [bmim]Cl and aqueous HPF6 in high yields.18 Even
though this reaction is not reversible, an anion exchange
in the course of the BNR. This effect is obviously increased
when another OMe group is included in the A-ring, giving
better results for the series of compounds 8g–l (Scheme 3).
Traditionally, phenolic functions are protected before
being subjected to the BNR,22 and thus, such derivatives
were O-acetylated in order to prevent their possible phos-
phorylation. Interestingly, OAc groups were fully deacetyl-
ated during the aqueous workup, when the pH of the reac-
tion reaches values below 1, and compounds 8e, 8f, 8k, and
8l were obtained with the desired phenolic function. There-
by, the developed BNR exhibited a good tolerance to the
evaluated methoxy, methylenedioxy, and hydroxy groups at
both A- and B-rings (Scheme 3).
Finally, high quality crystals of compound 8i were ob-
tained and rigorous X-ray crystallography analysis (see the
Supporting Information), unambiguously confirmed the
proposed structure of derivatives 8a–l, indicated the pres-
ence of the PF6– anion as a counterion, and determined that
the styryl fragment was not altered during the course of the
BNR (Figure 2).23
(PF6 to Cl–) has been reported using a modified resin,19
–
while other studies have found that in binary mixtures of
[bmim]PF6–[bmim]Cl, the environment of the cation
[bmim]+ is altered and an exchange occurs, where chlorine
–
displaces the PF6 due to the stronger interaction between
this cation and the Cl– anion.20 This fact has been exploited
during the fine-tuning of the physiochemical properties in
ionic liquids.21
However, and to our delight, an anion metathesis be-
tween ionic liquids and N-heterocyclic compounds has not
been reported so far for the stabilization and isolation of
molecules obtained through organic synthesis. In order to
explain the formation of product 8g, we propose that
during the course of the BNR, and throughout the aqueous
workup, the high amounts of HCl(g) (pKa = –5.9) released
promotes the anion metathesis to form HPF6 (pKa = –10)
and the more stable ionic liquid [bmim]Cl.
Although the concentration of HCl will be higher than
the HPF6 in the reaction media, the dissociation of HPF6 will
X-ray analysis
be higher, increasing the concentration of H+ and PF6 ions
–
MeO
during the reaction workup. Thus, the reaction between
this strong Brønsted acid (HPF6) with the resulted dihy-
droisoquinoline (weak base) will afford the corresponding
hexafluorophosphate salt (Scheme 2).
PF6
NH
MeO
8i
MeO
OMe
N
HN
O
OMe
BNR
Figure 2 X-ray crystallographic structure of 8i, shown with anisotropic
displacement ellipsoids at the 50% probability level
Work-up
NH
PF6
POCl3
HCl
[bmim]PF6
+ HPF6
[bmim]Cl
With compounds 8a–l in hand, we focused our efforts in
obtaining the corresponding 3,4-dihydroisoquinolines as a
free base, but any attempt to neutralize the hexafluoro-
phosphate salts resulted in the rapid degradation/decom-
position of the desired derivatives during its isolation. Being
aware of the low stability of the dihydroisoquinoline core,
and with the knowledge of the reactivity of the 1-azadiene
system,9,24 we turned our attention in trapping the in situ
generated 1-styryl-3,4-dihydroisoquinoline (1-azadiene)
by maleimide 9 through a Diels–Alder cycloaddition under
basic conditions (Scheme 4a). Thus, after treatment com-
pound 8g with triethylamine in CH2Cl2 at room tempera-
ture the tetrahydropyrrolo[3′,4′:5,6]pyrido[2,1-a]isoquino-
line 10 was isolated as a single ortho-Diels–Alder cycload-
duct, but as a diastereomeric mixture.
Scheme 2 Release of HCl and anion exchange with [bmim]PF6 to af-
ford the hexafluorophosphate salts.
With the characterization of 8g, and the optimized con-
ditions in hand (Table 1, entry 6), we proceeded to evaluate
the substrate scope of this reaction (Scheme 3). Unfortu-
nately, unsubstituted or halogen-substituted cinnamamides
were unreactive, as well as amides with electron-donating
groups at R1 and R2 positions of the A-ring (see 7 in Scheme
1), while the presence of a OMe group at para-position to
the α-carbon was crucial to furnish the desired products
(Scheme 3).
In general, all the corresponding dihydroisoquinoline
hexafluorophosphates 8a–l were obtained in good to excel-
lent yields (61–98%), except for derivative 8a, which was
isolated in 61%. At first sight, this could be due to the pres-
ence of only one OMe group in ring A, but comparing the
series of derivatives 8a–f, the substitution at the B-ring
with electron-donating groups clearly has a positive effect
With the aim of increasing the diastereoselectivity and
enantioselectivity of this reaction, we employed a chiral
cationic oxazaborolidine as catalyst according to Corey’s
previous work where highly enantioselective Diels–Alder
reactions with maleimides were achieved.25 Unfortunately,
although compound 8g was treated with triethylamine and
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MeO
MeO
R1
A
PF6
HN
O
NH
α
R1
α
POCl3
[bmim]PF6
50 °C, 24 h
B
R2
R4
R2
R4
8a-l
(61–98%)
R3
R3
7
MeO
MeO
MeO
MeO
MeO
MeO
PF6
NH
PF6
PF6
NH
PF6
PF6
NH
PF6
NH
NH
OH
NH
8c
89%
8a
61%
8b
93%
8e
89%
8f
94%
8d
92%
MeO
OMe
OMe
OMe
OMe
O
OMe
OH
NH
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
PF6
PF6
PF6
PF6
PF6
PF6
NH
NH
NH
NH
NH
MeO
MeO
MeO
8k
88%
8l
91%
8g
98%
8h
79%
8i
86%
8j
90%
OMe
OMe
MeO
OMe
O
OH
OH
O
OMe
OMe
R1 = H, Cl, F, OMe
R2 = OMe
unreactive substrates
R1
O
N
H
R2
Scheme 3 Substrate scope for the BNR to afford hexafluorophosphate salts. Reagents and conditions: amide 7 (2 mmol), POCl3 (3 mmol, 1.5 equiv),
[bmim]PF6 (1 mL), 50 °C, 24 h. Yield of the isolated product after precipitated from the reaction mixture, filtering, and drying.
handled under an inert atmosphere before being intro-
duced into the reaction vial, the reaction did not afford the
desired product (Scheme 4b).
In pursuit to explore the synthetic utility of compounds
8a–l, our next attempt was to evaluate the Noyori reduction
of imines, also known as asymmetric transfer hydrogena-
tion (ATH), in order to examine the reactivity of the C=N
bond to furnish the corresponding 1,2,3,4-tetrahydroiso-
quinolines.26 Studies related with the reaction mechanism
have proposed that the imine substrate enter in the catalyt-
ic cycle as an iminium salt, which is the real intermediate
that interacts with the catalyst to promote the asymmetric
a) Et3N (1 equiv), CH2Cl2,
r.t, 16 h
MeO
MeO
MeO
MeO
O
O
64%
PF6
NH
N
*
Ph
H
N
N
Ph
+
NPh
Ph
*
Me
O
(20 mol%)
b)
Me
O
B
O
o-tol
Br3Al
8g
9
10
CH2Cl2, –78 °C, 6 h
No reaction
Scheme 4 Diels–Alder reaction of maleimide 9 and the in situ formed 1-styryl-3,4-dihydroisoquinoline as 1-azadiene
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C. E. Puerto Galvis et al.
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hydrogen transfer,27 even some bromine and chlorine imin-
ium salts have proven to undergo AHT reaction.28 Thus, we
expected that the respective hexafluorophosphates 8a–l
could be good substrates for the ATH reaction. However, by
using the hexafluorophosphate salt 8g as a model substrate,
the (S,S)-RuTsDPEN complex as a catalyst, different hydro-
gen sources, and solvents, the desired 1-styryl-1,2,3,4-tet-
rahydroisoquinoline could not be obtained (see Table SI5,
Supporting Information).29–31
MeO
R1
MeO
R1
PF6
NH
N
1. NaBH4, MeOH
5 h, r.t.
CH3
2. (CH2O)n, NaBH3CN
ZnCl2, MeOH, 0 °C,
6 h
R2
R4
R2
R4
( )-12a-l
(71–94 %)
8a-l
R3
R3
MeO
MeO
MeO
Thereby, in order to achieve the desired goal, sodium
borohydride (NaBH4) was employed as a reducing agent to
furnished the corresponding 1-styryl-1,2,3,4-tetrahy-
droisoquinoline 11 as a racemic mixture, to our delight, this
product was obtained in quantitative yield after 5 hours in
methanol as a solvent, at room temperature and with high
purity after a rapid extraction with CH2Cl2 (Scheme 5).
N
N
N
CH3
CH3
CH3
( )-12c
90 %
( )-12a
89 %
( )-12b
91 %
MeO
OMe
OMe
OMe
N
OMe
N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
NaBH4
CH3
CH3
CH3
PF6
NH
NH
*
MeOH, 5 h, r.t.
( )-12d
( )-12e
( )-12f
93 %
90 %
82 %
( )-11
> 99%
OMe
O
8g
O
N
OH
N
OH
N
Scheme 5 Reduction of the C=N bond present in the hexafluorophos-
phate salt 8g with NaBH4
MeO
MeO
MeO
MeO
CH3 MeO
CH3 MeO
CH3
Unfortunately, during the handle and storage of the tet-
rahydroisoquinoline 11 we noticed that this compound
rapidly decomposed under the laboratory standard condi-
tions. Thus, and exploiting the structural relationship be-
( )-12g
88 %
( )-12h
92 %
( )-12i
94 %
OMe
MeO
OMe
OMe
N
OMe
tween compounds 8a–l and the Dysoxylum alkaloids,32
a
MeO
MeO
MeO
MeO
NaBH4 reduction/reductive amination33 sequence was de-
veloped for the synthesis of functionalized 2-methyl-1-sty-
ryl-1,2,3,4-tetrahydroisoquinolines 12a–l in excellent
yields after two steps (Scheme 6).
N
N
MeO
CH3 MeO
CH3
CH3
( )-12k
( )-12l
( )-12j
In summary, we have demonstrated the substitution
pattern required in the structure of N-phenethylcinnama-
mides to be considered as good substrates for the Bischler–
Napieralski reaction under conditions that, besides employ-
ing significantly smaller quantities of POCl3 and lower tem-
peratures, use a benign solvent like [bmim]PF6. The desired
products are isolated as the hexafluorophosphate salts due
to an anionic interchange that stabilizes the 3,4-dihydroiso-
quinoline core, in high yields after an easy purification pro-
cess. Finally, the derivatives obtained in this study served as
versatile intermediates in the concise synthesis of tetrahy-
droisoquinoline alkaloids and could be use in the synthesis
of more complex related alkaloids.
71 %
82 %
90 %
OMe
O
OH
OH
O
Scheme 6 Concise synthesis of tetrahydroisoquinoline alkaloids 12a–l.
Reagents and conditions: 1. hexafluorophosphate salt 8a–l (1 mmol),
NaBH4 (2 mmol), MeOH (8 mL). 2. (±)-11a–l (1 mmol), (CH2O)n (3
mmol), NaBH3CN (1.1 mmol), ZnCl2 (0.5 mmol), MeOH (8 mL). Isolated
yield after two steps and after column chromatography.
vents (purchased from Aldrich and Merck) in air. TLC was performed
using Merck silica gel 60 F254 precoated plates (0.25 mm). Column
chromatography was performed using spherical silica gel 70 Å, 40–75
μm.
Infrared (FT-IR) spectra were recorded on a Lumex Infralum FT-02
spectrophotometer. 1H NMR spectra were recorded on a Bruker
Avance-400 (400 MHz) spectrometer with the solvent resonance as
the internal standard (CDCl3: δ = 7.26; DMSO-d6: δ = 2.50). 13C NMR
spectra were recorded on a Bruker Avance-400 (400 MHz) spectrom-
eter with complete proton decoupling from solvent resonance as the
internal standard (CDCl3: δ = 77.00; DMSO-d6: δ = 40.45). On DEPT-
135 spectra, the signals of CH3 and CH carbons are shown with posi-
Unless otherwise noted, all reactions have been carried out with dis-
tilled and dried solvents and under atmosphere pressure. All workup
and purification procedures were carried out with reagent grade sol-
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C. E. Puerto Galvis et al.
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tive phase (+), while CH2 carbons are shown with negative phase (–).
Quaternary carbons are not shown. HRMS were measured on a Ther-
mo Scientific LTQ Orbitrap XL apparatus. Melting points were mea-
sured on a Fisher Johns melting point apparatus and are uncorrected.
N-Phenethylcinnamamides were synthesized starting from commer-
cial phenethylamines and cinnamic acids according to reported pro-
cedure.34
6-Methoxy-1-(3,4,5-trimethoxystyryl)-3,4-dihydroisoquinoline
Hexafluorophosphate (8c)
Orange solid; yield: 0.88 g (1.78 mmol, 89%); Rf (CH2Cl2/MeOH 2:1) =
0.27; mp 186–188 °C.
IR (KBr disk): 2931 (OCH3), 2838 (NH+), 1650 (C=N), 1542 (C–N), 1226
(C–O), 817 cm–1 (P–F).
1H NMR (400 MHz, CDCl3): δ = 13.85 (br s, 1 H, NH+), 8.19 (d, J = 16.0
Hz, 1 H, =CHPh), 7.95 (d, J = 8.5 Hz, 1 H, 8-HAr), 7.45 (d, J = 16.0 Hz, 1 H,
=CH), 7.01–6.95 (m, 3 H, 5-HAr, 5′-HAr, 9′-HAr), 6.88 (m, 1 H, 7-HAr),
3.92 (s, 3 H, OCH3), 3.89 (s, 6 H, OCH3), 3.87 (s, 3 H, OCH3), 3.84–3.83
(m, 2 H, CH2N), 3.01–2.96 (m, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 166.9, 165.9, 153.5 (2 C), 150.2 (+),
141.3, 133.2 (+), 129.6, 118.4, 115.2 (+), 114.4 (+), 113.9 (+), 106.7 (2
C, +), 61.1 (+), 56.5 (2 C, +), 56.1 (+), 40.2 (–), 26.6 (–).
3,4-Dihydroisoquinoline Hexafluorophosphates 8a–l; General
Procedure
A 10-mL reactor vial equipped with a magnetic stirrer bar was
charged with the N-phenethylcinnamamide
7 (2 mmol) and
[bmim]PF6 (1 mL). The resulting solution was stirred at rt until com-
plete dissolution of the amide and POCl3 (3 mmol, 1.5 equiv) was add-
ed in one portion. Then, the system was heated at 50 °C for 24 h. After
cooling to rt, crushed ice was slowly added to the mixture until com-
plete precipitation of the respective hexafluorophosphate salt 8a–l,
the solid was filtered, washed with distilled water and dried under
vacuum.
HRMS (ESI): m/z [M – PF6] calcd for C21H24NO4: 354.1700; found:
354.1697.
6-Methoxy-1-[3,4-(methylenedioxy)styryl]-3,4-dihydroisoquino-
line Hexafluorophosphate (8d)
6-Methoxy-1-styryl-3,4-dihydroisoquinoline Hexafluorophos-
phate (8a)
Yellow solid; yield: 0.83 g (1.84 mmol, 92%); Rf (CH2Cl2/MeOH 2:1) =
0.31; mp 199–201 °C.
Orange solid; yield: 0.49 g (1.22 mmol, 61%); Rf (CH2Cl2/MeOH 2:1) =
0.35; mp 197–199 °C.
IR (KBr disk): 2977 (OCH3), 2838 (NH+), 1619 (C=N), 1558 (C–N), 1280
(C–O), 848 cm–1 (P–F).
1H NMR (400 MHz, CDCl3): δ = 10.05 (br s, 1 H, NH+), 7.95 (d, J = 16.1
Hz, 1 H, =CHPh), 7.91 (d, J = 8.8 Hz, 1 H, 8-HAr), 7.73 (dd, J = 7.9, 1.3 Hz,
2 H, 5′-HAr, 9′-HAr), 7.54–7.44 (m, 3 H, 6′-HAr, 7′-HAr, 8′-HAr), 7.27 (d, J =
16.2 Hz, 1 H, =CH), 7.02 (dd, J = 8.9, 2.5 Hz, 1 H, 7-HAr), 6.94 (d, J = 2.6
Hz, 1 H, 5-HAr), 3.98 (s, 3 H, OCH3), 4.01–3.96 (m, 2 H, CH2N), 3.16–
3.11 (m, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 167.2, 150.7 (+), 142.0, 136.6, 133.7
(+), 133.6, 132.8 (+), 129.7 (2 C, +), 129.6 (2 C, +), 117.9, 115.4 (+),
114.9 (+), 114.5 (+), 58.6 (–), 56.3 (+), 26.7 (–).
IR (KBr disk): 3101 (CHAr–CHAr), 3023 (OCH3), 2915 (NH+), 1589
(C=N), 1450 (C–N), 1249 (C–O), 833 cm–1 (P–F).
1H NMR (400 MHz, DMSO-d6): δ = 12.10 (br s, 1 H, NH+), 8.19 (d, J =
8.8 Hz, 1 H, 8-HAr), 7.77 (d, J = 15.9 Hz, 1 H, =CHPh), 7.66 (m, 1 H, 5-
HAr), 7.49 (d, J = 15.9 Hz, 1 H, =CHCO), 7.27 (dd, J = 8.2, 1.6 Hz, 1 H, 7-
HAr), 7.13–7.03 (m, 3 H, 5′-HAr, 6′-HAr, 9′-HAr), 6.14 (s, 2 H, OCH2O),
3.92 (s, 3 H, OCH3), 3.79 (t, J = 7.6 Hz, 2 H, CH2N), 3.09 (t, J = 7.5 Hz, 2
H, CH2Ph).
13C NMR (101 MHz, DMSO-d6): δ = 165.8, 150.7, 148.5 (+), 146.8,
141.8, 133.6 (+), 128.6 (+), 127.2, 118.3, 114.7 (+), 114.2 (+), 113.8 (+),
108.9 (+), 106.9 (+), 102.2 (–), 56.2 (+), 40.3 (–), 25.5 (–).
HRMS (ESI): m/z [M – PF6] calcd for C19H18NO3: 308.1281; found:
308.1286.
HRMS (ESI): m/z [M – PF6] calcd for C18H18NO: 264.1383; found:
264.1391.
1-(4-Hydroxystyryl)-6-methoxy-3,4-dihydroisoquinoline Hexaflu-
orophosphate (8e)
1-(3,4-Dimethoxystyryl)-6-methoxy-3,4-dihydroisoquinoline
Hexafluorophosphate (8b)
Orange solid; yield: 0.75 g (1.78 mmol, 89%); Rf (CH2Cl2/MeOH 2:1) =
0.34; mp 155–157 °C.
Orange solid; yield: 0.87 g (1.86 mmol, 93%); Rf (CH2Cl2/MeOH 2:1) =
0.28; mp 206–208 °C.
IR (KBr disk): 3332 (OH), 2993 (OCH3), 2946 (NH+), 1589 (C=N), 1450
(C–N), 1265 (C–O), 817 cm–1 (P–F).
IR (KBr disk): 2946 (OCH3), 2854 (NH+), 1604 (C=N), 1511 (C–N), 1265
(C–O), 817 cm–1 (P–F).
1H NMR (400 MHz, CDCl3): δ = 13.85 (br s, 1 H, NH+), 8.30 (d, J = 16.0
Hz, 1 H, =CHPh), 7.90 (d, J = 8.5 Hz, 1 H, 8-HAr), 7.39–7.34 (m, 2 H, =CH,
5-HAr), 7.27 (s, 1 H, 5′-HAr), 6.99 (d, J = 6.9 Hz, 1 H, 8′-HAr), 6.90–6.88
(m, 2 H, 7-HAr, 9′-HAr), 3.96 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 3.94 (s, 3
H, OCH3), 3.91–3.87 (m, 2 H, CH2N), 3.03 (t, J = 6.8 Hz, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 166.8, 165.7, 152.9, 150.7 (+), 149.5,
141.4, 132.9, 130.4, 127.3 (+), 125.0 (+), 118.7, 114.4 (+), 113.8 (+),
113.4 (+), 111.1 (+), 110.7 (+), 56.3 (+), 56.2 (+), 56.1 (+), 40.2 (–), 26.9
(–).
1H NMR (400 MHz, DMSO-d6): δ = 12.54 (br s, 1 H, NH+), 8.18 (d, J =
8.8 Hz, 1 H, 8-HAr), 8.01 (d, J = 16.0 Hz, 1 H, =CHPh), 7.90 (br s, 1 H,
OH), 7.73 (d, J = 8.6 Hz, 2 H, 6′-HAr, 8′-HAr), 7.41 (d, J = 16.0 Hz, 1 H,
=CH), 7.14–7.03 (m, 2 H, 5-HAr, 7-HAr), 6.92 (d, J = 8.6 Hz, 2 H, 5′-HAr,
9′-HAr), 3.91 (s, 3 H, OCH3), 3.76 (t, J = 7.0 Hz, 2 H, CH2N), 3.07 (t, J = 7.4
Hz, 2 H, CH2Ph).
13C NMR (101 MHz, DMSO-d6): δ = 167.0, 165.8, 161.9, 148.3 (+),
142.1, 133.8, 132.1 (2 C, +), 125.7 (+), 118.8, 116.7 (2 C, +), 114.5 (+),
114.1 (+), 113.0 (+), 56.5 (+), 40.4 (–), 39.1 (–).
HRMS (ESI): m/z [M – PF6] calcd for C18H18NO2: 280.1332; found:
280.1335.
HRMS (ESI): m/z [M – PF6] calcd for C20H22NO3: 324.1594; found:
324.1590.
1-(4-Hydroxy-3-methoxystyryl)-6-methoxy-3,4-dihydroisoquino-
line Hexafluorophosphate (8f)
Orange solid; yield: 0.85 g (1.88 mmol, 94%); Rf (CH2Cl2/MeOH 2:1) =
0.35; mp 168–170 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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C. E. Puerto Galvis et al.
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Synthesis
IR (KBr disk): 3378 (OH), 2946 (OCH3), 2885 (NH+), 1619 (C=N), 1573
(C–N), 1265 (C–O), 817 cm–1 (P–F).
IR (KBr disk): 2946 (OCH3), 2838 (NH+), 1604 (C=N), 1465 (C–N), 1280
(C–O), 833 cm–1 (P–F).
1H NMR (400 MHz, DMSO-d6): δ = 13.44 (br s, 1 H, NH+), 8.22 (d, J =
8.8 Hz, 1 H, 7-HAr), 8.07 (br s, 1 H, OH), 8.01 (d, J = 15.9 Hz, 1 H,
=CHPh), 7.50 (d, J = 1.9 Hz, 1 H, 5′-HAr), 7.47 (d, J = 15.9 Hz, 1 H, =CH),
7.26 (dd, J = 8.3, 1.9 Hz, 1 H, 9′-HAr), 7.12 (d, J = 2.5 Hz, 1 H, 5-HAr), 7.09
(dd, J = 8.8, 2.6 Hz, 1 H, 8-HAr), 6.93 (d, J = 8.2 Hz, 1 H, 8′-HAr), 3.92 (s, 3
H, OCH3), 3.86 (s, 3 H, OCH3), 3.79–3.76 (m, 2 H, CH2N), 3.08 (t, J = 7.5
Hz, 2 H, CH2Ph).
13C NMR (101 MHz, DMSO-d6): δ = 166.6, 165.4, 151.3, 148.3 (+),
148.2, 141.8, 133.4, 125.9 (+), 125.5 (+), 118.5, 115.9 (+), 114.1 (+),
113.8 (+), 112.8 (+), 111.7 (+), 56.2 (+), 56.0 (+), 40.1 (–), 38.8 (–).
1H NMR (400 MHz, CDCl3): δ = 9.92 (br s, 1 H, NH+), 7.86 (d, J = 16.3
Hz, 1 H, =CHPh), 7.30 (s, 1 H, 8-HAr), 7.16 (d, J = 16.0 Hz, 1 H, = CH),
7.00 (s, 2 H, 5′-HAr, 9′-HAr), 6.90 (s, 1 H, 5-HAr), 4.05 (s, 3 H, OCH3), 3.96
(s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 3.93 (s, 6 H, OCH3), 3.92–3.90 (m, 2
H, CH2N), 3.08 (t, J = 7.6 Hz, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 168.7, 161.8, 154.0 (+), 151.1 (2 C),
149.3 (2 C), 140.0, 135.0, 128.9, 115.0 (+), 114.5 (+), 113.5 (+), 107.7
(+, 2 C), 56.8 (+, 2 C), 56.7 (+, 2 C), 56.7 (+), 41.2 (–), 26.3 (–).
HRMS (ESI): m/z [M – PF6] calcd for C22H26NO5: 384.1805; found:
384.1808.
HRMS (ESI): m/z [M – PF6] calcd for C19H20NO3: 310.1438; found:
310.1442.
6,7-Dimethoxy-1-[3,4-(methylenedioxy)styryl]-3,4-dihydroiso-
quinoline Hexafluorophosphate (8j)
6,7-Dimethoxy-1-styryl-3,4-dihydroisoquinoline Hexafluoro-
phosphate (8g)
Orange solid; yield: 0.87 g (1.80 mmol, 90%); Rf (CH2Cl2/MeOH 2:1) =
0.29; mp 207–209 °C.
Orange solid; yield: 0.86 g (1.96 mmol, 98%); Rf (CH2Cl2/MeOH 2:1) =
0.30; mp 213–215 °C.
IR (KBr disk): 2931 (OCH3), 2823 (NH+), 1635 (C=N), 1493 (C–N), 1280
(C–O), 817 cm–1 (P–F).
IR (KBr disk): 2931 (OCH3), 2838 (NH+), 1604 (C=N), 1465 (C–N), 1280
(C–O), 833 cm–1 (P–F).
1H NMR (400 MHz, CDCl3): δ = 11.00 (br s, 1 H, NH+), 7.97 (d, J = 16.3
Hz, 1 H, =CHPh), 7.77–7.73 (m, 2 H, 8-HAr, 7′-HAr), 7.51–7.43 (m, 4 H,
5′-HAr, 6′-HAr, 8′-HAr, 9′-HAr), 7.30 (d, J = 16.3 Hz, 1 H, =CH), 6.89 (s, 1 H,
5-HAr), 4.05 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3), 3.95–3.91 (m, 2 H,
CH2N), 3.07 (t, J = 7.7 Hz, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 168.4, 156.8, 150.4 (+), 148.9, 134.8,
133.6, 132.6 (+), 129.6 (+, 2 C), 129.5 (+, 2 C), 117.5, 115.7 (+), 112.3
(+), 111.4 (+), 56.8 (+), 56.6 (+), 41.1 (–), 26.1 (–).
31P NMR (162 MHz, CDCl3): δ = –69.15 (hept, J = 714.4 Hz, PF6).
19F NMR (377 MHz, CDCl3): δ = –71.41 (d, J = 714.4 Hz, PF6).
1H NMR (400 MHz, DMSO-d6): δ = 12.64 (br s, 1 H, NH+), 8.04 (d, J =
15.9 Hz, 1 H, =CHPh), 7.68 (d, J = 1.6 Hz, 1 H, 5′-HAr), 7.57 (s, 1 H, 8-
HAr), 7.52 (d, J = 16.0 Hz, 1 H, =CH), 7.29 (dd, J = 8.1, 1.6 Hz, 1 H, 9′-
HAr), 7.17 (s, 1 H, 5-HAr), 7.05 (d, J = 8.0 Hz, 1 H, 8-HAr), 6.13 (s, 2 H,
OCH2O), 3.91 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 3.76 (t, J = 7.5 Hz, 2 H,
CH2N), 3.03 (t, J = 7.6 Hz, 2 H, CH2Ph).
13C NMR (101 MHz, DMSO-d6): δ = 166.9, 155.8, 150.8, 148.5 (+),
148.1, 147.3, 134.5, 128.9 (+), 127.4 (+), 117.9, 114.7 (+), 113.1, 111.8
(+), 109.0 (+), 107.2 (+), 102.2 (–), 56.5 (+), 56.5 (+), 40.3 (–), 38.4 (–).
HRMS (ESI): m/z [M – PF6] calcd for C20H20NO4: 338.1387; found:
338.1382.
1-(4-Hydroxystyryl)-6,7-dimethoxy-3,4-dihydroisoquinoline
Hexafluorophosphate (8k)
HRMS (ESI): m/z [M – PF6] calcd for C19H20NO2: 294.1489; found:
294.1489.
Orange solid; yield: 0.80 g (1.76 mmol, 88%); Rf (CH2Cl2/MeOH 2:1) =
0.20; mp 218–220 °C.
IR (KBr disk): 3378 (OH), 2946 (OCH3), 2854 (NH+), 1604 (C=N), 1465
(C–N), 1280 (C–O), 848 cm–1 (P–F).
1-(3,4-Dimethoxystyryl)-6,7-dimethoxy-3,4-dihydroisoquinoline
Hexafluorophosphate (8h)
Orange solid; yield: 0.74 g (1.58 mmol, 79%); Rf (CH2Cl2/MeOH 2:1) =
0.24; mp 212–214 °C.
IR (KBr disk): 2931 (OCH3), 2838 (NH+), 1604 (C=N), 1511 (C–N), 1265
(C–O), 802 cm–1 (P–F).
1H NMR (400 MHz, DMSO-d6): δ = 12.06 (br s, 1 H, NH+), 7.85 (d, J =
15.8 Hz, 1 H, =CHPh), 7.58–7.49 (m, 3 H, =CHCO, 5′-HAr, 8-HAr), 7.43
(dd, J = 8.4, 1.5 Hz, 1 H, 8′-HAr), 7.22 (m, 1 H, 5-HAr), 7.12 (d, J = 8.5 Hz,
1 H, 9′-HAr), 3.94 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
3.86 (s, 3 H, OCH3), 3.80 (t, J = 7.5 Hz, 2 H, CH2N), 3.07 (t, J = 7.5 Hz, 2
H, CH2Ph).
1H NMR (400 MHz, CDCl3): δ = 11.58 (br s, 1 H, NH+), 8.31 (br s, 1 H,
OH), 7.90 (d, J = 15.2 Hz, 1 H, =CHPh), 7.74 (d, J = 7.2 Hz, 2 H, 6′-HAr, 8′-
HAr), 7.27 (s, 2 H, 5-HAr, 8-HAr), 7.14 (d, J = 7.4 Hz, 2 H, 5′-HAr, 9′-HAr),
6.86 (d, J = 15.2 Hz, 1 H, =CHCO), 4.01 (s, 3 H, OCH3), 3.95 (s, 3 H,
OCH3), 3.84–3.80 (m, 2 H, CH2N), 3.02–2.98 (m, 2 H, CH2Ph).
13C NMR (101 MHz, CDCl3): δ = 169.0, 168.1, 157.0, 153.8, 149.1 (+),
134.8, 131.5, 130.8 (+, 2 C), 122.7 (+, 2 C), 117.7, 116.3 (+), 112.7 (+),
111.6 (+), 56.8 (+), 56.8 (+), 41.1 (–), 26.0 (–).
HRMS (ESI): m/z [M – PF6] calcd for C19H20NO3: 310.1438; found:
310.1434.7.
13C NMR (101 MHz, DMSO-d6): δ = 167.2, 155.7, 152.4, 149.2, 147.9,
147.5 (+), 134.5, 126.9 (+), 124.87, 117.6 (+), 114.6 (+), 113.2, 111.8
(+), 111.7 (+), 111.1 (+), 56.3 (+), 56.3 (+), 55.8 (+), 55.7 (+), 40.2 (–),
25.0 (–).
1-(4-Hydroxy-3-methoxystyryl)-6,7-dimethoxy-3,4-dihydroiso-
quinoline Hexafluorophosphate (8l)
Orange solid; yield: 0.88 g (1.82 mmol, 91%); Rf (CH2Cl2/MeOH 2:1) =
0.12; mp 223–225 °C.
HRMS (ESI): m/z [M – PF6] calcd for C21H24NO4: 354.1700; found:
354.1703.
IR (KBr disk): 3440 (OH), 2915 (OCH3), 2875 (NH+), 1604 (C=N), 1496
(C–N), 1280 (C–O), 817 cm–1 (P–F).
1H NMR (400 MHz, DMSO-d6): δ = 12.40 (br s, 1 H, NH+), 8.66 (br s, 1
H, OH), 7.88 (d, J = 15.9 Hz, 1 H, =CHPh), 7.42 (s, 1 H, 8-HAr), 7.34 (d, J =
15.9 Hz, 1 H, =CH), 7.33 (d, J = 1.9 Hz, 1 H, 5′-HAr), 7.15 (dd, J = 8.3, 1.9
6,7-Dimethoxy-1-(3,4,5-trimethoxystyryl)-3,4-dihydroisoquino-
line Hexafluorophosphate (8i)
Orange solid; yield: 0.91 g (1.76 mmol, 86%); Rf (CH2Cl2/MeOH 2:1) =
0.20; mp 191–193 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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C. E. Puerto Galvis et al.
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Synthesis
Hz, 1 H, 9′-HAr), 7.01 (s, 1 H, 5-HAr), 6.77 (d, J = 8.2 Hz, 1 H, 8′-HAr), 3.74
(s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3), 3.57 (t, J = 6.4
Hz, 2 H, CH2N), 2.86 (t, J = 7.6 Hz, 2 H, CH2Ph).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO: 280.1696; found:
280.1691.
13C NMR (101 MHz, DMSO-d6): δ = 166.8, 155.6, 151.4, 148.5, 148.3
(+), 148.0, 134.4 (+), 126.0 (+), 125.4, 118.0, 116.0 (+), 113.3 (+), 113.3
(+), 112.5 (+), 111.8 (+), 56.5 (+), 56.5 (+), 56.2 (+), 38.4 (–), 34.3 (–).
(±)-1-(3,4-Dimethoxystyryl)-6-methoxy-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (12b)
Intermediate 11b
HRMS (ESI): m/z [M – PF6] calcd for C20H22NO4: 340.1543; found:
340.1538.
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.6 Hz, 1 H, 8′-HAr), 6.97 (d,
J = 1.9 Hz, 1 H, 5-HAr), 6.92 (dd, J = 8.2, 1.9 Hz, 1 H, 7-HAr), 6.81 (d, J =
8.3 Hz, 1 H, 8-HAr), 6.71 (dd, J = 8.5, 2.7 Hz, 1 H, 9′-HAr), 6.66 (d, J = 2.6
Hz, 1 H, 5′-HAr), 6.52 (d, J = 15.7 Hz, 1 H, =CHPh), 6.19 (dd, J = 15.7, 8.0
Hz, 1 H, =CH), 4.61 (d, J = 8.2 Hz, 1 H, CH), 3.87 (s, 3 H, OCH3), 3.86 (s,
3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.30 (dt, J = 11.8, 5.2 Hz, 1 H, CHa-NH),
3.11–3.04 (m, 1 H, CHa-Ph), 2.99–2.90 (m, 1 H, CHb-NH), 2.84–2.74 (m,
1 H, CHb-Ph), 2.27 (br s, 1 H, NH).
N-Methyl-1-styryl-1,2,3,4-tetrahydroisoquinolines 12a–l; General
Procedure
Into a 25-mL round-bottom flask equipped with a magnetic stirrer
bar was added the hexafluorophosphate salt 8a–l (1 mmol) and
MeOH (8 mL) at rt. Then, NaBH4 (2 mmol, 2 equiv) was added in small
portions, until the solution became complete transparent. After stir-
ring for 5 h, the mixture was quenched with distilled water and was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated under reduced pressure to
afford the crude product in quantitative yield. The desired 1-styryl-
1,2,3,4-tetrahydroisoquinolines 11a–l was obtained sufficiently pure
to be used in the next step without any further purification. A solu-
tion of the 1,2,3,4-tetrahydroisoquinoline 11a–l (1 mmol), parafor-
maldehyde (3 mmol), and MeOH (4 mL), in a 25-mL round-bottom
flask, was added dropwise into a stirred solution of NaBH3CN (1.1
mmol, 1.1 equiv), ZnCl2 (0.5 mmol, 0.5 equiv), and MeOH (4 mL).
Then, the mixture was stirred for 6 h at 0 °C and the reaction was
quenched with 1 M NaHCO3, extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The crude material was purified by
column chromatography (silica gel, 15% MeOH/CH2Cl2) to furnish the
desired 2-methyl-1-styryl-1,2,3,4-tetrahydroisoquinolines 12a–l.
Compound 12b
White solid; yield: 0.31 g (0.91 mmol, 91%); Rf (CH2Cl2/MeOH 10:1) =
0.47; mp 100–102 °C.
IR (KBr disk): 2936 (CH2-Ar), 2900 (OCH3), 1604 (C=C), 1465 (N–C),
1234 (CH3), 1033 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 7.06 (d, J = 8.6 Hz, 1 H, 8′-HAr), 7.00 (d,
J = 2.0 Hz, 1 H, 5-HAr), 6.95 (dd, J = 8.2, 2.0 Hz, 1 H, 7-HAr), 6.83 (d, J =
8.3 Hz, 1 H, 8-HAr), 6.70 (dd, J = 8.7, 2.8 Hz, 1 H, 9′-HAr), 6.66 (d, J = 2.5
Hz, 1 H, 5′-HAr), 6.56 (d, J = 15.7 Hz, 1 H, =CHPh), 6.01 (dd, J = 15.7, 8.9
Hz, 1 H, =CH), 3.88 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.85 (d, J = 8.9
Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.15–3.05 (m, 2 H, CH2Ph), 2.85–2.77
(m, 1 H, CHa-N), 2.62 (ddd, J = 12.7, 10.5, 4.2 Hz, 1 H, CHb-N), 2.48 (s, 3
H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.2, 149.1, 148.9, 135.1, 133.6,
129.7 (+), 129.2 (+), 128.4 (+), 128.2, 119.8, 113.1 (+), 112.3 (+), 111.1
(+), 108.7 (+), 68.5 (+), 55.9 (+), 55.8 (+), 55.2 (+), 51.1 (–), 48.3 (+),
29.1 (–).
(±)-6-Methoxy-2-methyl-1-styryl-1,2,3,4-tetrahydroisoquinoline
(12a)
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO3: 340.1907; found:
340.1901.
Intermediate 11a
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 7.1 Hz, 2 H, 5′-HAr, 9′-HAr),
7.23 (t, J = 7.5 Hz, 1 H, 7′-HAr), 7.17 (d, J = 7.4 Hz, 2 H, 6′-HAr, 8′-HAr),
6.95 (d, J = 8.6 Hz, 1 H, 8-HAr), 6.63 (dd, J = 8.5, 2.7 Hz, 1 H, 7-HAr), 6.58
(d, J = 2.3 Hz, 1 H, 5-HAr), 6.50 (d, J = 15.8 Hz, 1 H, =CHPh), 6.25 (dd, J =
15.8, 8.0 Hz, 1 H, =CH), 4.55 (d, J = 8.1 Hz, 1 H, CH), 3.70 (s, 3 H, OCH3),
3.22 (dt, J = 11.7, 5.2 Hz, 1 H, CHa-NH), 3.04–2.96 (m, 1 H, CHa-Ph),
2.91–2.82 (m, 1 H, CHb-NH), 2.76–2.66 (m, 2 H, CHb-Ph, NH).
(±)-6-Methoxy-2-methyl-1-(3,4,5-trimethoxystyryl)-1,2,3,4-tetra-
hydroisoquinoline (12c)
Intermediate 11c
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.71 (dd,
J = 8.5, 2.7 Hz, 1 H, 7-HAr), 6.67 (d, J = 2.4 Hz, 1 H, 5-HAr), 6.63 (s, 2 H,
5′-HAr, 9′-HAr), 6.49 (d, J = 15.7 Hz, 1 H, =CHPh), 6.23 (dd, J = 15.6, 8.0
Hz, 1 H, =CH), 4.60 (d, J = 8.1 Hz, 1 H, CH), 3.85 (s, 6 H, OCH3), 3.84 (s,
3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.32–3.26 (m, 1 H, CHa-NH), 3.11–3.03
(m, 1 H, CHa-Ph), 2.97–2.89 (m, 1 H, CHb-NH), 2.77–2.64 (m, 1 H, CHb-
Ph), 1.83 (br s, 1 H, NH).
Compound 12a
White solid; yield: 0.24 g (0.89 mmol, 89%); Rf (CH2Cl2/MeOH 10:1) =
0.51; mp 101–103 °C.
IR (KBr disk): 2931 (CH2-Ar), 2838 (OCH3), 1604 (C=C), 1496 (N–C),
1234 (CH3), 1033 cm–1 (C–O).
Compound 12c
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 7.4 Hz, 2 H, 5′-HAr, 9′-HAr),
7.25 (t, J = 7.4 Hz, 1 H, 7′-HAr), 7.11 (d, J = 7.4 Hz, 2 H, 6′-HAr, 8′-HAr),
6.97 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.63–6.57 (m, 2 H, 5-HAr, 7-HAr), 6.54 (d,
J = 15.8 Hz, 1 H, =CHPh), 6.06 (dd, J = 15.8, 8.9 Hz, 1 H, =CH), 3.82 (d,
J = 8.9 Hz, 1 H, CH), 3.69 (s, 3 H, OCH3), 3.07–2.97 (m, 2 H, CH2Ph), 2.74
(dd, J = 17.7, 5.9 Hz, 1 H, CHa-N), 2.57–2.49 (m, 1 H, CHb-N), 2.39 (s, 3
H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.2, 136.6, 135.2, 133.9 (+), 130.5
(+), 129.2 (+), 128.7 (2 C, +), 128.2, 127.8 (+), 126.6 (2 C, +), 113.2 (+),
112.4 (+), 68.5 (+), 55.3 (+), 51.2 (–), 48.3 (+), 29.2 (–).
White solid; yield: 0.33 g (0.90 mmol, 90%); Rf (CH2Cl2/MeOH 10:1) =
0.44; mp 97–98 °C.
IR (KBr disk): 2931 (CH2-Ar), 2838 (OCH3), 1650 (C=C), 1465 (N–C),
1234 (CH3), 1126 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.95 (d,
J = 1.7 Hz, 1 H, 5’-HAr), 6.85 (dd, J = 8.1, 1.5 Hz, 1 H, 9’-HAr), 6.76 (d, J =
8.0 Hz, 1 H, 8’-HAr), 6.70-6.64 (m, 2 H, 5 and 7-HAr), 6.52 (d, J = 15.8
Hz, 1H, =CHPh), 5.98-5.89 (m, 1H, =CH), 5.93 (s, 2H, -OCH2O-), 3.80 (d,
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J = 8.6 Hz, 1 H, -CH), 3.77 (s, 3 H, OCH3), 3.13-3.03 (m, 2 H, -CH2Ph),
2.80-2.74 (m, 1 H, CHa-N), 2.61-2.52 (m, 1 H, CHb-N), 2.45 (s, 3 H,
NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.3, 153.4 (2 C), 138.0, 135.1, 134.0
(+), 132.2, 129.8 (+), 129.2 (+), 127.6, 113.2 (+), 112.5 (+), 103.6 (2 C,
+), 68.4 (+), 61.0 (+), 56.1 (2 C, +), 55.3 (+), 51.1 (–), 43.8 (+), 29.0 (–).
1H NMR (400 MHz, CDCl3): δ = 6.81 (d, J = 8.5 Hz, 2 H, 6′-HAr, 8′-HAr),
6.68 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.37 (d, J = 8.6 Hz, 2 H, 5′-HAr, 9′-HAr),
6.35–6.29 (m, 3 H, OH, 5-HAr, 7-HAr), 6.15 (d, J = 15.8 Hz, 1 H, =CHPh),
5.54 (dd, J = 15.8, 8.9 Hz, 1 H, =CH), 3.52 (d, J = 8.9 Hz, 1 H, CH), 3.41 (s,
3 H, OCH3), 2.84–2.75 (m, 2 H, CH2Ph), 2.49–2.39 (m, 1 H, CHa-N),
2.31–2.23 (m, 1 H, CHb-N), 2.14 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.2, 156.2, 135.2, 133.7, 129.3 (+),
128.9 (+), 128.0 (2 C, +), 121.2, 116.0 (2 C, +), 115.5 (+), 113.2 (+),
112.5 (+), 68.7 (+), 55.3 (+), 51.4 (–), 43.9 (+), 29.0 (–).
HRMS (ESI): m/z [M + H]+ calcd for C22H28NO4: 370.2013; found:
370.2018.
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
296.1640.
(±)-6-Methoxy-2-methyl-1-[3,4-(methylenedioxy)styryl]-1,2,3,4-
tetrahydroisoquinoline (12d)
(±)-1-(4-Hydroxy-3-methoxystyryl)-6-methoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (12f)
Intermediate 11d
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.94 (d,
J = 1.4 Hz, 1 H, 5′-HAr), 6.83 (dd, J = 8.0, 1.5 Hz, 1 H, 9′-HAr), 6.75 (d, J =
8.0 Hz, 1 H, 8′-HAr), 6.73–6.68 (m, 1 H, 7-HAr), 6.66 (d, J = 2.4 Hz, 1 H,
5-HAr), 6.49 (d, J = 15.7 Hz, 1 H, =CHPh), 6.13 (dd, J = 15.7, 8.1 Hz, 1 H,
=CH), 5.94 (s, 2 H, OCH2O), 4.56 (d, J = 8.0 Hz, 1 H, CH), 3.78 (s, 3 H,
OCH3), 3.31–3.23 (m, 1 H, CHa-NH), 3.09–3.00 (m, 1 H, CHa-Ph), 2.97–
2.87 (m, 1 H, CHb-NH), 2.81–2.71 (m, 1 H, CHb-Ph), 2.03 (br s, 1 H, NH).
Intermediate 11f
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.6 Hz, 1 H, 8′-HAr), 6.91 (s,
1 H, 5′-HAr), 6.87–6.79 (m, 2 H, 7-HAr, 8′-HAr), 6.71 (dd, J = 7.9, 2.6 Hz, 1
H, 9′-HAr), 6.67 (s, 1 H, 5-HAr), 6.49 (d, J = 15.6 Hz, 1 H, =CHPh), 6.13
(dd, J = 15.7, 8.3 Hz, 1 H, =CH), 5.63 (br s, 1 H, OH), 4.58 (d, J = 8.3 Hz, 1
H, CH), 3.83 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.32–3.27 (m, 2 H, CHa-
NH, NH), 3.11–3.03 (m, 1 H, CHa-Ph), 2.99–2.91 (m, 1 H, CHb-NH), 2.78
(dd, J = 12.0, 8.0 Hz, 1 H, CHb-Ph).
Compound 12d
White solid; yield: 0.30 g (0.93 mmol, 93%); Rf (CH2Cl2/MeOH 10:1) =
0.55; mp 111–113 °C.
Compound 12f
IR (KBr disk): 2946 (CH2-Ar), 2900 (OCH3), 1604 (C=C), 1450 (N–C),
1249 (CH3), 1033 cm–1 (C–O).
Yellow solid; yield: 0.26 g (0.82 mmol, 82%); Rf (CH2Cl2/MeOH 10:1) =
0.36; mp 160–162 °C.
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 8.5 Hz, 1 H, 8-HAr), 6.95 (d,
J = 1.7 Hz, 1 H, 5′-HAr), 6.85 (dd, J = 8.1, 1.5 Hz, 1 H, 9′-HAr), 6.76 (d, J =
8.0 Hz, 1 H, 8′-HAr), 6.70–6.64 (m, 2 H, 5-HAr, 7-HAr), 6.52 (d, J = 15.8
Hz, 1 H, =CHPh), 5.98–5.89 (m, 1 H, =CH), 5.93 (s, 2 H, OCH2O), 3.80 (d,
J = 8.6 Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.13–3.03 (m, 2 H, CH2Ph),
2.80–2.74 (m, 1 H, CHa-N), 2.61–2.52 (m, 1 H, CHb-N), 2.45 (s, 3 H,
NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.1, 148.1, 147.3, 135.6, 132.9 (+),
131.4, 129.7 (+), 129.1 (+), 128.8, 121.1 (+), 113.2 (+), 112.2 (+), 108.3
(+), 105.9 (+), 101.1 (–), 68.6 (+), 55.3 (+), 51.4 (–), 44.2 (+), 29.6 (–).
IR (KBr disk): 3425 (OH), 2946 (CH2-Ar), 2864 (OCH3), 1604 (C=C),
1465 (N–C), 1265 (CH3), 1033 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 7.26 (br s, 1 H, OH), 7.06 (d, J = 8.5 Hz,
1 H, 8′-HAr), 6.96 (d, J = 1.7 Hz, 1 H, 5-HAr), 6.88 (dd, J = 8.1, 1.8 Hz, 1 H,
7-HAr), 6.84 (d, J = 8.1 Hz, 1 H, 8-HAr), 6.69 (dd, J = 8.5, 2.7 Hz, 1 H, 9′-
HAr), 6.66 (d, J = 2.6 Hz, 1 H, 7′-HAr), 6.53 (d, J = 15.8 Hz, 1 H, =CHPh),
5.98 (dd, J = 15.8, 8.9 Hz, 1 H, =CH), 3.85 (d, J = 9.1 Hz, 1 H, CH), 3.83 (s,
3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.16–3.04 (m, 2 H, CH2Ph), 2.82–2.74
(m, 1 H, CHa-N), 2.65–2.56 (m, 1 H, CHb-N), 2.48 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 158.1, 146.9, 145.8, 135.4, 133.4,
129.3 (+), 129.2 (+), 128.7 (+), 128.6, 120.6 (+), 114.6 (+), 113.1 (+),
112.2 (+), 108.1 (+), 68.6 (+), 55.8 (+), 55.3 (+), 51.4 (–), 44.1 (+), 29.4
(–).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO3: 326.1751; found:
326.1748.
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO3: 324.1594; found:
324.1599.
(±)-1-(4-Hydroxystyryl)-6-methoxy-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (12e)
Intermediate 11e
(±)-6,7-Dimethoxy-2-methyl-1-styryl-1,2,3,4-tetrahydroisoquino-
line (12g)
1H NMR (400 MHz, CDCl3): δ = 9.49 (br s, 1 H, OH), 7.23 (d, J = 8.6 Hz,
2 H, 6′-HAr, 8′-HAr), 6.96 (d, J = 8.4 Hz, 1 H, 8-HAr), 6.71 (d, J = 8.5 Hz, 2
H, 5′-HAr, 9′-HAr), 6.69 (s, 1 H, 5-HAr), 6.66 (dd, J = 9.7, 2.5 Hz, 1 H, 7-
HAr), 6.43 (d, J = 15.7 Hz, 1 H, =CHPh), 6.07 (dd, J = 15.8, 7.8 Hz, 1 H,
=CH), 4.42 (d, J = 7.7 Hz, 1 H, CH), 3.70 (s, 3 H, OCH3), 3.34 (br s, 1 H,
NH), 3.12–3.05 (m, 1 H, CHa-NH), 2.88–2.81 (m, 1 H, CHb-NH), 2.78–
2.70 (m, 1 H, CHa-Ph), 2.78–2.70 (m, 1 H, CHb-Ph).
Intermediate 11g
1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 7.3 Hz, 2 H, 5′-HAr, 9′-HAr),
7.31 (t, J = 7.3 Hz, 2 H, 6′-HAr, 8′-HAr), 7.26–7.22 (m, 1 H, 7′-HAr), 6.63–
6.56 (m, 3 H, =CHPh, 5-HAr, 8-HAr), 6.34 (dd, J = 15.7, 8.0 Hz, 1 H, =CH),
4.59 (d, J = 7.7 Hz, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3),
3.32–3.03 (m, 1 H, CHa-NH), 3.06 (ddd, J = 12.2, 7.5, 4.7 Hz, 1 H CHa-
Ph), 2.90–2.80 (m, 1 H, CHb-NH), 2.75–2.68 (m, 1 H, CHb-Ph), 2.09 (br
s, 1 H, NH).
Compound 12e
Yellow solid; yield: 0.26 g (0.90 mmol, 90%); Rf (CH2Cl2/MeOH 10:1) =
0.41; mp 188–189 °C.
IR (KBr disk): 3455 (OH), 2946 (CH2-Ar), 2792 (OCH3), 1604 (C=C),
1450 (N–C), 1265 (CH3), 1141 cm–1 (C–O).
Compound 12g
White solid; yield: 0.27 g (0.88 mmol, 88%); Rf (CH2Cl2/MeOH 10:1) =
0.42; mp 128–130 °C.
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IR (KBr disk): 2931 (CH2-Ar), 2838 (OCH3), 1604 (C=C), 1450 (N–C),
1249 (CH3), 1018 cm–1 (C–O).
Compound 12i
White solid; yield: 0.37 g (0.94 mmol, 94%); Rf (CH2Cl2/MeOH 10:1) =
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 7.4 Hz, 2 H, 5′-HAr, 9′-HAr),
7.25 (t, J = 7.5 Hz, 2 H, 6-HAr, 8′-HAr), 7.19–7.16 (m, 1 H, 7′-HAr), 6.55
(d, J = 15.6 Hz, 1 H, =CHPh), 6.54 (s, 2 H, 5-HAr, 8-HAr), 6.07 (dd, J =
15.8, 8.9 Hz, 1 H, =CH), 3.77 (s, 3 H, OCH3), 3.75 (d, J = 8.9 Hz, 1 H, CH),
3.66 (s, 3 H, OCH3), 3.04–2.90 (m, 2 H, CH2Ph), 2.67–2.61 (m, 1 H, CHa-
N), 2.54–2.46 (m, 1 H, CHb-N), 2.39 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 147.8, 147.2, 136.8, 133.4 (+), 131.5
(+), 128.7 (2 C, +), 128.2, 127.7 (+), 126.6 (2 C, +), 126.5, 111.3 (+),
110.9 (+), 68.6 (+), 56.0 (+), 55.9 (+), 51.4 (–), 44.2 (+), 28.9 (–).
0.28; mp 135–137 °C.
IR (KBr disk): 2946 (CH2-Ar), 2838 (OCH3), 1589 (C=C), 1465 (N–C),
1234 (CH3), 1002 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 6.65 (s, 2 H, 5′-HAr, 9′-HAr), 6.62 (s, 1 H,
8-HAr), 6.61 (s, 1 H, 5-HAr), 6.53 (d, J = 15.7 Hz, 1 H, =CHPh), 6.06 (dd,
J = 15.7, 8.8 Hz, 1 H, =CH), 3.85 (s, 9 H, 3 OCH3), 3.84 (s, 3 H, OCH3),
3.82 (d, J = 8.5 Hz, 1 H, CH),), 3.76 (s, 3 H, OCH3), 3.12–2.97 (m, 2 H,
CH2Ph), 2.73 (dt, J = 7.5, 3.5 Hz, 1 H, CHa-N), 2.62–2.56 (m, 1 H, CHb-
N), 2.47 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 153.4 (2 C), 147.9, 147.3, 137.9, 133.3
(+), 132.5, 130.9 (+), 128.0, 126.5, 111.3 (+), 111.0 (+), 103.6 (2 C, +),
68.4 (+), 61.0 (+), 56.1 (2 C, +), 56.1 (+), 55.9 (+), 51.3 (–), 44.2 (+), 28.8
(–).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO2: 310.1802; found:
310.1807.
(±)-1-(3,4-Dimethoxystyryl)-6,7-dimethoxy-2-methyl-1,2,3,4-tet-
rahydroisoquinoline (12h)
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO5: 400.2118; found:
400.21.
Intermediate 11h
1H NMR (400 MHz, CDCl3): δ = 6.97 (d, J = 1.7 Hz, 1 H, 5′-HAr), 6.93 (dd,
J = 8.2, 1.7 Hz, 1 H, 9′-HAr), 6.80 (d, J = 8.3 Hz, 1 H, 8′-HAr), 6.60 (s, 1 H,
8-HAr), 6.57 (s, 1 H, 5-HAr), 6.52 (d, J = 15.7 Hz, 1 H, =CHPh), 6.24 (dd,
J = 15.7, 7.9 Hz, 1 H, =CH), 4.64 (d, J = 7.8 Hz, 1 H, CH), 3.86 (s, 3 H,
OCH3), 3.86 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3),
3.34–3.25 (m, 1 H, CHa-NH), 3.17 (br s, 1 H, NH), 3.08 (ddd, J = 12.4,
7.8, 4.9 Hz, 1 H, CHa-Ph), 2.93–2.83 (m, 1 H, CHb-NH), 2.75 (dt, J = 16.2,
5.1 Hz, 1 H, CHb-Ph).
(±)-6,7-Dimethoxy-N-methyl-1-[3,4-(methylenedioxy)styryl]-
1,2,3,4-tetrahydroisoquinoline (12j)
Intermediate 11j
1H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 1.5 Hz, 1 H, 5′-HAr), 6.83 (dd,
J = 8.0, 1.6 Hz, 1 H, 9′-HAr), 6.76 (d, J = 8.0 Hz, 1 H, 8′-HAr), 6.61 (s, 1 H,
8-HAr), 6.58 (s, 1 H, 5-HAr), 6.50 (d, J = 15.7 Hz, 1 H, =CHPh), 6.16 (dd,
J = 15.7, 8.1 Hz, 1 H, =CH), 5.94 (s, 2 H, OCH2O), 4.55 (d, J = 8.1 Hz, 1 H,
CH), 3.86 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.31–3.24 (m, 1 H, CHa-
NH), 3.09–3.01 (m, 1 H, CHa-NH), 2.90–2.81 (m, 1 H, CHb-Ph), 2.71
(dd, J = 15.9, 4.8 Hz, 1 H, CHb-Ph), 2.02 (br s, 1 H, NH).
Compound 12h
White solid; yield: 0.33 g (0.92 mmol, 92%); Rf (CH2Cl2/MeOH 10:1) =
0.40; mp 95–97 °C.
IR (KBr disk): 2915 (CH2-Ar), 2838 (OCH3), 1604 (C=C), 1465 (N–C),
1265 (CH3), 1018 cm–1 (C–O).
Compound 12j
White solid; yield: 0.31 g (0.90 mmol, 90%); Rf (CH2Cl2/MeOH 10:1) =
1H NMR (400 MHz, CDCl3): δ = 6.99 (d, J = 1.9 Hz, 1 H, 5′-HAr), 6.95 (dd,
J = 8.3, 1.9 Hz, 1 H, 9′-HAr), 6.82 (d, J = 8.3 Hz, 1 H, 8′-HAr), 6.61 (s, 2 H,
5-HAr, 8-HAr), 6.56 (dd, J = 15.8 Hz, 1 H, =CHPh), 6.01 (dd, J = 15.7, 8.9
Hz, 1 H, =CH), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 3.83 (d, J = 8.9 Hz, 1 H, CH), 3.74 (s, 3 H, OCH3), 3.13–2.96 (m, 2
H, CH2NH), 2.74 (dt, J = 7.5, 3.6 Hz, 1 H, CHa-Ph), 2.62–2.54 (m, 1 H,
CHb-Ph), 2.47 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 149.1, 148.9, 147.7, 147.1, 133.4,
129.7, 128.8 (+), 128.1, 126.2 (+), 119.8 (+), 111.2 (+), 111.0 (+), 110.8
(+), 108.6 (+), 68.5 (+), 56.0 (+), 55.9 (+), 55.9 (+), 55.8 (+), 51.2 (–),
44.0 (+), 28.6 (–).
0.40; mp 95–97 °C.
IR (KBr disk): 2931 (CH2-Ar), 2900 (OCH2O), 2838 (OCH3), 1650 (C=C),
1450 (N–C), 1265 (CH3), 1033 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 6.96 (s, 1 H, 5′-HAr), 6.86 (d, J = 7.8 Hz,
1 H, 9′-HAr), 6.77 (d, J = 8.0 Hz, 1 H, 8′-HAr), 6.61 (s, 1 H, 8-HAr), 6.59 (s,
1 H, 5-HAr), 6.53 (d, J = 15.8 Hz, 1 H, =CHPh), 6.01–5.95 (m, 1 H, =CH),
5.94 (s, 2 H, OCH2O), 3.85 (s, 3 H, OCH3), 3.82 (d, J = 8.9 Hz, 1 H, CH),
3.75 (s, 3 H, OCH3), 3.11–2.96 (m, 2 H, CH2NH), 2.76–2.67 (m, 1 H,
CHa-Ph), 2.58 (dd, J = 13.3, 7.8 Hz, 1 H, CHb-Ph), 2.45 (s, 3 H, NCH3).
13C NMR (101 MHz, CDCl3): δ = 147.9, 147.5, 147.1, 146.9, 132.8 (+),
131.1, 129.5 (+), 128.1, 126.2, 120.9 (+), 111.0 (+), 110.6 (+), 108.1 (+),
105.6 (+), 100.9 (–), 68.4 (+), 55.8 (+), 55.7 (+), 51.2 (–), 44.0 (+), 28.6
(–).
HRMS (ESI): m/z [M + H]+ calcd for C22H28NO4: 370.2013; found:
370.2008.
HRMS (ESI): m/z [M + H]+ calcd for C21H24NO4: 354.1700; found:
354.1696.
(±)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxystyryl)-1,2,3,4-
tetrahydroisoquinoline (12i)
(±)-1-(4-Hydroxystyryl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (12k)
Intermediate 11i
1H NMR (400 MHz, CDCl3): δ = 6.63 (s, 2 H, 5′-HAr, 9′-HAr), 6.62 (s, 1 H,
8-HAr), 6.60 (s, 1 H, 5-HAr), 6.7 (d, J = 2.4 Hz, 1 H, 5-HAr), 6.48 (d, J =
15.7 Hz, 1 H, =CHPh), 6.26 (dd, J = 15.7, 7.9 Hz, 1 H, =CH), 4.58 (d, J =
8.0 Hz, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.85 (s, 6 H, OCH3), 3.84 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 3.31–3.23 (m, 1 H, CHa-NH), 3.10–3.02 (m,
1 H, CHa-Ph), 2.90–2.80 (m, 1 H, CHb-NH), 2.72 (dt, J = 15.9, 4.7 Hz, 1
H, CHb-Ph), 1.98 (br s, 1 H, NH).
Intermediate 11k
1H NMR (400 MHz, CDCl3): δ = 7.66 (br s, 1 H, OH), 7.19 (d, J = 8.9 Hz,
2 H, 6′-HAr, 8′-HAr), 6.73 (d, J = 8.5 Hz, 2 H, 5′-HAr, 9′-HAr), 6.62 (s, 2 H,
5-HAr, 8-HAr), 6.49 (d, J = 15.4 Hz, 1 H, =CHPh), 6.11 (dd, J = 14.7, 7.0
Hz, 1 H, =CH), 4.57 (d, J = 7.1 Hz, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.77 (s,
3 H, OCH3), 3.33–3.30 (m, 1 H, CHa-NH), 3.09–3.06 (m, 1 H, CHb-NH),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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Paper
Synthesis
2.88–2.85 (m, 1 H, CHa-Ph), 2.76–2.66 (m, 1 H, CHb-Ph), 2.48 (br s, 1 H,
NH).
Acknowledgment
We thank Mary Helena Torres Flórez, from the Laboratorio de Reso-
nancia Magnetica Nuclear UIS-PTG, for the acquisition of the 19F NMR
spectra. CEPG acknowledges the fellowship given by the doctoral pro-
gram COLCIENCIAS-Conv. 617.
Compound 12k
Yellow solid; yield: 0.23 g (0.71 mmol, 71%); Rf (CH2Cl2/MeOH 10:1) =
0.20; mp 73–75 °C.
IR (KBr disk): 3455 (OH), 2931 (CH2-Ar), 2838 (OCH3), 1604 (C=C),
1450 (N–C), 1249 (CH3), 1018 cm–1 (C–O).
Supporting Information
1H NMR (400 MHz, CDCl3): δ = 8.01 (br s, 1 H, OH), 7.14 (d, J = 8.6 Hz,
2 H, 5′-HAr, 9′-HAr), 6.69 (d, J = 8.6 Hz, 2 H, 6′-HAr, 8′-HAr), 6.61 (s, 1 H,
8-HAr), 6.59 (s, 1 H, 5-HAr), 6.51 (d, J = 5.8 Hz, 1 H, =CHPh), 5.89 (dd, J =
15.8, 8.9 Hz, 1 H, =CH), 3.87 (d, J = 8.9 Hz, 1 H, CH), 3.85 (s, 3 H, OCH3),
3.73 (s, 3 H, OCH3), 3.18–3.01 (m, 2 H, CH2Ph), 2.77–2.69 (m, 1 H, CHa-
N), 2.67–2.59 (m, 1 H, CHb-N), 2.50 (s, 3 H, NCH3).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610684.
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References
13C NMR (101 MHz, CDCl3): δ = 156.6, 147.9, 147.3, 133.9 (+), 128.5,
128.0 (2 C, +), 127.9, 127.8 (+), 126.1, 116.2 (2 C, +), 111.3 (+), 111.1
(+), 68.6 (+), 56.1 (+), 55.9 (+), 51.3 (–), 43.8 (+), 28.1 (–).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO3: 326.1751; found:
326.1751.
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Funding Information
We thank the Colombian Institute for Science and Research (COL-
CIENCIAS) under the project No. RC-0346-2013 for the financial sup-
port.
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