Total Synthesis and Cytotoxic Activity of 6,8-Dimethoxy-1,3-dimethylisoquinoline Isolated from Ancistrocladus tectorius: A 6π-Azaelectrocyclization Approach

Article abstract of DOI:10.1055/s-0037-1610276

A facile and convenient approach toward the total synthesis of 1,3-dimethyl-6,8-dimethoxyisoquinoline from phloroacetophenone is reported. The sequence entailed the selective 2,4-di-O-methylation and further triflation of the resulting phenolic product. This was followed by a Stille-type allylation, an allyl-to-propenyl isomerization, and the methoximation of the carbonyl moiety. A final microwave-assisted 6π-azaelectrocyclization completed the sequence. Functionalized derivatives on C-1 were also prepared. The heterocycles exhibited cytotoxic activity.

Full text of DOI:10.1055/s-0037-1610276

SYNTHESIS
0
0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
I. Cortés et al.
Paper
Synthesis
Total Synthesis and Cytotoxic Activity of 6,8-Dimethoxy-1,3-
dimethylisoquinoline Isolated from Ancistrocladus tectorius:
A 6π-Azaelectrocyclization Approach
Iván Cortésa
Carla M. Borini Etichettib
Javier E. Girardinib
Teodoro S. Kaufman*a
Andrea B. J. Bracca*a
6p-aza-
electro-
cyclization
HO
OH
MeO
Me
Bu3Sn
H
O
N
OMe
OMe
0
0
0
0
0-
0
0
3
3-
1
7
3
2-
1
7
8
N
OH Me
MeO
Me
Me
6 steps
22% overall yield
H
MeO
MeO
Me
a Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531,
2000 Rosario, Argentina
N
N
kaufman@iquir-conicet.gov.ar
bracca@iquir-conicet.gov.ar
b Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR) and
Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de
Rosario, Esmeralda y Ocampo, 2000 Rosario, Argentina
MeO
R
MeO
Me
cytotoxic
isoquinolines
R = CHO, CH2OH
from Ancistrocladus tectorius
Received: 28.07.2018
Accepted after revision: 22.08.2018
Published online: 20.09.2018
muscle pain, dysentery, and malaria.5 Various naphthyliso-
quinoline alkaloids have been found in the roots, stem, and
leaves of the plant.6
DOI: 10.1055/s-0037-1610276; Art ID: ss-2018-m0508-op
The phytochemical examination of a sample of the bark
of this climber, collected in Malaysia, enabled the isolation
of minor amounts (0.002% w/w) of several compounds,
including 6,8-dimethoxy-1,3-dimethylisoquinoline (1),7 its
3-hydroxymethyl derivative (2), which is the heterocyclic
motif of other natural products8 and other alkaloids (Figure 1).
The structural motif 1 is the characteristic heterocyclic
nucleus found in several naphthylisoquinolines and their
related compounds, including 6-O-methylhamateine (3),9
dehydroancistrocladisine (4), a degradation product of an-
cistrocladine,10 ancisheynine (5),11 and others.8a,12 It is also
the core of synthetic 1-arylquinolinium derivatives like 6,
which is demonstrated to have antiproliferative, cytotoxic,
leishmanicidal,11a,13 anti-infective, and biofilm-inhibiting
activities.14 In addition, biphenyl derivative IQ-143 (7) pos-
sesses bactericidal action,14,15 whereas the heterocycle 8
was prepared as an analogue of the michellamine alkaloids
and proved to display relevant anticytopathic and antima-
larial activities.16
On the other hand, compound 2 is the core structure of
the very rare ancistrobenomines A–C (9–11) (Figure 1).8a,17
Compounds 10 and 11 exhibited growth inhibition of the
drug-sensitive acute lymphoblastic CCRF–CEM leukemia
cells and their multidrug-resistant subline CEM/ADR5000
(IC50 = 3.5–26.5 μM).18
Previous syntheses of 1 were performed from the very
scarce compound 27a and also through sequences, which
proceeded in low yield and/or included rather harsh condi-
tions.7a,19
Abstract A facile and convenient approach toward the total synthesis
of 1,3-dimethyl-6,8-dimethoxyisoquinoline from phloroacetophenone
is reported. The sequence entailed the selective 2,4-di-O-methylation
and further triflation of the resulting phenolic product. This was fol-
lowed by a Stille-type allylation, an allyl-to-propenyl isomerization, and
the methoximation of the carbonyl moiety. A final microwave-assisted
6π-azaelectrocyclization completed the sequence. Functionalized deriv-
atives on C-1 were also prepared. The heterocycles exhibited cytotoxic
activity.
Key words total synthesis, bioactive natural product, Ancistrocladus
tectorius alkaloid, 6π-azaelectrocyclization, cytotoxic nitrogen hetero-
cycles
The high potency and diversity of the physiological ac-
tivities displayed by isoquinoline derivatives have turned
this nucleus into a privileged scaffold in medicinal chemis-
try;1 and convenient access to isoquinoline natural products
is also an important objective in modern organic synthesis.
Plants of the genus Ancistrocladus (Ancistrocladaceae)
are widely distributed along tropical West and Central Afri-
ca, as well as in South East Asia, and characterized by the
presence of naphthylisoquinoline alkaloids.2 Many of them
are cytotoxic3 or exhibit activity against pathogen parasites
causative of several tropical diseases, including malaria, Af-
rican trypanosomiasis (sleeping sickness), and leishmaniasis.4
Ancistrocladus tectorius (Lour.) Merr. is a widespread
tropical woody liana found in the rainforests of Southeast
Asia, which is indicated in folk medicine as a diuretic, anti-
phlogistic, spasmolytic, and antifebrile agent, as well as for
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
I. Cortés et al.
Paper
Synthesis
O-methylation
Me
O
5
4
MeO
OMe
6π-azaelectrocyclization
MeO Me
4a
8a
MeO
R
3
6
Stille cross-coupling
Me
N2
7
8
1
N
N
Me
OR
MeO
Me
O-methylation
MeO
Me
oximation
Me
1 R = Me
2 R = CH2OH
MeO
Me
O
Me
N
1
12
MeO
Me
Me
MeO
Me
N
3
HO
X
MeO
Me
OR
N
MeO
Me
+
+
Bu3Sn
O
N+
MeO
MeO
H
H
OH Me
MeO
Me
4
13
14
15
Me
R
6
X = Cl, Br, I, OH
R = alkyl, aryl
MeO
Me
RO
OMe
Scheme 1 Retrosynthetic analysis of the target compound 1
N+
OMe
MeO
Me
OMe
Me
R1O
OH
5
moiety would provide the required nitrogen atom. Finally,
despite some potentially useful 6-haloacetophenones are
known,25 the readily available phloroacetophenone (16)
was chosen as the starting material.
HO
MeO
OH
Me
Me
N
Me
HO
MeO
Me
N
N
9 R = H, R1 = Me
10 R = R1 = Me
11 R = Me, R1 = H
According to the retrosynthetic analysis, the selective
bis-O-methylation of 16 was first undertaken (Scheme 2).
However, the first attempts of a Williamson alkylation with
MeI/K2CO3 met with failure and only minor amounts of 17
could be obtained,26a contaminated with products resulting
from mono- and tri-O-methylation, as well as with C-meth-
ylation derivatives.26b However, the use of Me2SO4 as al-
kylating agent cleanly afforded 93% yield of 17, thanks to
the hydrogen bond formed between the oxygen of the car-
bonyl moiety and one of the ortho-OH groups.26c,d
Me
Me
OH
Me
HO
OMe
OH
8
MeO
Me
N+
Me
N+
Me
OMe
MeO
Me
7
OMe
Figure 1 Structures of 6,8-dimethoxy-1,3-dimethylisoquinoline (1),
related natural products 2–5, 9–11, and some of their analogues or
derivatives 6–8
HO
OH
MeO
OR
MeO
a
c
The 6π-electrocyclization of azatrienes is seldom used
in the total synthesis of natural products.20 We21 and oth-
ers22 have employed this transformation as an efficient and
atom-economic means toward natural products or their an-
alogues, containing the isoquinoline core.
O
O
O
OH Me
OMe Me
OMe Me
17 R = H
18 R = Tf
16
19
b
d
Therefore, in continuation of our research on the syn-
thesis of bioactive and unique natural products,21a,23 herein
we wish to report an alternative and convenient approach
toward the total synthesis of 1, employing a 6π-azaelectro-
cyclization-based strategy, according to the retrosynthetic
analysis outlined in Scheme 1. Additionally, the synthesis of
two derivatives of 1 and the cytotoxic activity of the three
heterocycles are also detailed.
The C–N disconnection shown on 1 suggested 12 as a
suitable key intermediate for the proposed 6π-azaelectro-
cyclization-based ring closure. In turn, 12 was disconnected
generating three building blocks, a 6-substituted 2,4-di-
hydroxyacetophenone 13, a hydroxylamine derivative 14,
and an olefinic trialkylstannane 15.24 This allowed to en-
visage that a Stille cross-coupling of 15 with a properly acti-
vated benzenoid would enable the installation of the three-
carbon atom side chain, whereas oximation of a carbonyl
MeO
f
Me
N
MeO
Me
e
O
OMe
OMe Me
OMe Me
20
21
H
N
MeO
Me
MeO
Me
N
– MeOH
OMe
OMe Me
OMe Me
22
1
Scheme 2 Reagents and conditions: a) Me2SO4, K2CO3, acetone, 50 °C,
24 h (93%); b) NaH, THF, PhNTf2, reflux, 24 h (81%); c) Bu3SnCH2CH=CH2,
LiCl, PPh3, Pd(PPh3)2Cl2 (cat.), diglyme, 90 °C, 4.5 h (19/20 = 2.1:1); d)
PdCl2(MeCN)2, CHCl3, reflux, overnight (72% overall); e) MeONH2·HCl,
NaOAc, CeCl3·7H2O (cat.), EtOH, 50–80 °C, 3 d (89%); f) DMA, MW
(160 °C), 3 h (45%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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I. Cortés et al.
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Synthesis
Next, the phenol 17 was activated toward the Stille reac-
tion by formation of the triflate 18 in 81% yield by reaction
with N-phenyltriflimide in the presence of NaH.27a,b Tf2O
was disregarded as triflating agent due to previous failures
of the latter in analogous transformations.27c
Exposure of the triflate 18 to a Stille allylation with all-
yltributyltin in DMF, under Pd(PPh3)2Cl2 catalysis, gave a
2.1:1 mixture of the allyl 19 and propenyl 20 derivatives,
after 20 hours at 100 °C, as evidenced by the presence of di-
agnostic 1H NMR signals: δ = 3.33 (2 H, dt, J = 1.7, 6.4 Hz) for
the ArCH2 moiety of the allyl group and δ = 1.85 (3 H, d, J =
1.7, 6.7 Hz) for the methyl group of the propenyl moiety, re-
spectively.
This outcome was quite not unexpected; conversion of
allyl benzenoids into their respective 1-propenyl deriva-
tives has been occasionally observed as a secondary process
during Pd-catalyzed cross-couplings28 since the initial re-
ports of the reaction by Stille himself.29a,b This was especial-
ly observed when arenes carrying electron-withdrawing
substituents were employed as starting materials.29c
Therefore, in order to pursue with the synthesis, the
crude mixture of olefins was fully isomerized under Pd-
Cl2(MeCN)2 catalysis in refluxing CHCl321b,30a,b to afford 72%
overall yield of 20, mainly (>95:5) as the E-isomer, accord-
ing to the large scalar coupling between both olefinic pro-
tons (J = 17.2 Hz).
by spectroscopic means. The 1H NMR spectral data of the fi-
nal product were fully consistent with those previously re-
corded.7,19
Next, attempts were made to access the 3-hydroxyme-
thylisoquinoline 2, by oxidation of the 3-methyl group with
SeO2 in hot 1,2-dichlorobenzene.31 However, these trials
met with failure and the aldehyde 23 was obtained instead
as the sole product,32 in 70% yield (Scheme 3). In turn, the
latter was reduced to the alcohol 24 with NaBH4 in MeOH,
in 93% yield.
Considering that some naphthylisoquinolines have ex-
hibited cytotoxic activity, their core compound 1, and the
related heterocycles 23 and 24 were subjected to cytotoxic-
ity testing against three cell lines, namely H1299 (human
non-small cell lung carcinoma) MDA-MB-468 (human Tri-
ple Negative breast adenocarcinoma), and MCF7 (ER+, hu-
man breast adenocarcinoma).
After a 48-hour treatment with different concentrations
of each individual compound, the amount of remaining liv-
ing cells was quantified using the MTT bioreduction assay
and normalized relative to untreated cells. It was observed
that all the compounds exhibited dose-dependent effects,
The successful introduction of the three-carbon atom
side chain set the stage for the incorporation of the nitrogen
atom and final ring closure. Accordingly, 20 was exposed to
methoxime hydrochloride in EtOH to which NaOAc was
added to free the base, under CeCl3·7H2O catalysis.21a,30c
This provided 89% yield of 21 after 24 hours, consisting
mainly in a single isomer to which the E-configuration was
assigned based on the 13C NMR shielding of the methyl
group adjacent to the methoxime moiety (δC = 16.9), which
originally belonged to the methyl ketone.
Next, 21 was submitted to the key 6π-azaelectrocycliza-
tion reaction in DMA at 160 °C, providing 45% of the ex-
pected isoquinoline 1, presumably through the intermedia-
cy of 22. The results could not be improved by using other
solvents (1,2-Cl2C6H4) or reaction temperatures (180 °C). All
the intermediates and the final product were characterized
MeO
Me
MeO
Me
a
N
N
MeO
Me
MeO
b
CHO
23
1
MeO
Me
N
MeO
CH2OH
Figure 2 Cytotoxicity of the synthesized isoquinolines. Survival rate of
the target cells are normalized to the control treatment (DMSO) and ex-
pressed as mean and standard deviation values of triplicate determina-
tions.
24
Scheme 3 Reagents and conditions: a) SeO2, 1,2-Cl2C6H4, 100 °C, 3 h
(70%); b) NaBH4, MeOH, r.t., 1 h (93%).
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Synthesis
and that at the 10 μM level, the three heterocycles had at
least a small effect against the three cell lines, with com-
pound 23 being the most potent (Figure 2).
sodium metal (benzophenone as indicator), followed by distillation.
Anhydrous DMF and DMA were prepared by heating the solvent for 3
h over dry BaO, followed by distillation under reduced pressure. An-
hydrous CHCl3 and 1,2-dichlorobezene (1,2-DCB) were prepared by
refluxing the solvents over P2O5 for 4 h, followed by distillation. Anhy-
drous MeOH was prepared by treatment of the PA reagent with clean
Mg turnings and a crystal of I2, followed by reflux until complete con-
sumption of the metal was achieved. The solvent was distilled from
the so formed Mg(OMe)2. Anhydrous acetone was obtained by distil-
lation of the PA product from KMnO4; the distillate was stored over
powdered pre-dried K2CO3. All the anhydrous solvents were trans-
ferred via cannula and stored in dry Young ampoules containing mo-
lecular sieves. All other commercial reagents were used as received,
without further purification.
In the 50 μM level experiments, it was observed that
around only half of the cells had survived, and that 23 and
24, the isoquinolines bearing oxygen substituents at C-1
proved to be slightly more active (survival rate ≅ 40%) than
the natural product 1. A further reduction in cell survival
rate was achieved by doubling the test concentration to 100
μM, with compound 23 displaying the best profile.
It has been shown that many naturally occurring iso-
quinoline alkaloids display anticancer activity.33a Further-
more, a recent structure–activity relationship study on a
small library of ancistrolikokines, 5,8′-coupled naphthyliso-
quinolines isolated from the twigs of the congolese liana
Ancistrocladus likoko, insinuated that within this group of
alkaloids, their pattern of the oxygen substituents on C-6
and C-8 of the isoquinoline portion play a crucial role for
the antileukemic activity.33b
Therefore, our results can be interpreted as a suggestion
that the isoquinoline core of the naphthylisoquinolines may
constitute the pharmacophore of these natural products,
the activity of which would be modulated by its oxygen
functionalities and the attached polysubstituted naphthyl
units.
In conclusion, we have reported a convenient total syn-
thesis of 1,3-dimethyl-6,8-dimethoxyisoquinoline, a natu-
rally occurring alkaloid and the heterocyclic motif featured
in various natural and synthetic bioactive products. The
synthesis, which took place in six steps and 22% overall
yield, employed the easily available phloroacetophenone as
starting material and proceeded without the use of protect-
ing groups.
The sequence took place through the selective 2,4-di-O-
methylation of phloroacetophenone and further 6-O-trifla-
tion of the product. This set the stage for a Stille cross-cou-
pling reaction with allyltributylstannane, which after an al-
lyl to propenyl isomerization completed the installation of
the required three carbon atoms chain. The introduction of
the required nitrogen atom was achieved by a Ce(III)-medi-
ated catalytic methoximation, whilst a final 6π-azaelectro-
cyclization under microwaves promotion completed the
synthesis.
The strategy involving the 6π-azaelectrocyclization ring
closure is an innovative and convenient approach to the to-
tal synthesis of 1. Functionalized derivatives (1-formyl and
1-hydroxymethyl) of the natural product were also pre-
pared. The isoquinolines were tested in vitro for their cyto-
toxic activity, being active in the micromolar range against
one lung cancer and two breast cancer cell lines.
The reactions were monitored by TLC, run on plates of Kieselgel 60
GF254, employing different hexane/EtOAc solvent systems. Chromato-
graphic spots were detected by irradiation of the plates with UV light
(254 nm), followed by exposure to I2 vapors or by spraying with etha-
nolic p-anisaldehyde/H2SO4 reagent and careful heating for improving
selectivity. All new compounds gave single spots. The flash column
chromatographies were run with slurry-packed silica gel 60 H (parti-
cle size 63–200 μm), eluting with hexane/EtOAc mixtures, under pos-
itive pressure and employing gradient of solvent polarity techniques.
The melting points were measured on an Ernst Leitz Wetzlar model
350 hot stage instrument. Product structures were determined em-
ploying a combination of spectroscopic methods, including IR, NMR
(DEPT, COSY, HSQC, and HMBC), and HRMS. The IR spectra were re-
corded with a Shimadzu Prestige 21 spectrophotometer, as thin films
held between NaCl cells, or as solid dispersions in KBr disks. The NMR
spectra were acquired in a Bruker Avance 300 MHz spectrometer in
CDCl3 (300 MHz for 1H and 75 MHz for 13C). Chemical shift data are
reported in ppm with TMS (1H, 0 ppm) and CDCl3 (13C, 76.9 ppm) as
internal standards. Standrad abbreviations are used for reporting sig-
nal splitting patterns. Coupling constants (J) are reported informed in
hertz (Hz). The signs asterisk (*) and hashtag (#) designate signals for
which the assignment may be exchanged. The low-resolution mass
spectra were acquired on a Shimadzu QP2010 Plus CG-MS instru-
ment. Fragments are described with regards to their m/z ratios, in
terms of the relative intensity (%) of their signals. The high-resolution
mass spectra were obtained from UMyMFOR (Buenos Aires, Argenti-
na) with a Bruker MicroTOF-Q II instrument. Detection of the ions
was performed in electrospray ionization, positive ion mode.
Cell Culture and Survival Assays
The in vitro antiproliferative activity of compounds 1, 23 and 24 was
studied on H1299, MCF-7 and MDA-MB-468 cells. The H1299 cells
were cultured in RPMI medium (Gibco) while MCF-7 and MDA-MB-
468 cells were cultured in Dulbecco’s modified Eagle’s medium
(DMEM, Gibco), using a 5% CO2 humidified incubator at 37 °C. Both
media were supplemented with 10% fetal bovine serum, penicillin G
(100 units/mL, Sigma) and streptomycin (100 μg/mL, Sigma). Cell via-
bility was analyzed using the MTT assay. Briefly, 24 h prior to treat-
ment, cells were seeded in 96-well plates at a density of 7 × 103
cells/well. The tested compounds were dissolved in DMSO (Merck) at
20 mM and then diluted in culture medium to achieve the final con-
centration for the different treatments. Negative controls were pre-
pared with cells incubated with DMSO at concentrations correspond-
ing to the different dilutions. After 48 h treatment, cells were stained
with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bro-
mide (MTT, 0.5 mg/mL, Sigma) for 4 h at 37 °C. After removal of the
All the reactions were executed under anhydrous argon atmospheres,
employing oven-dried glassware and freshly distilled anhydrous sol-
vents. Anhydrous THF was obtained by reflux of the AR solvent over
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I. Cortés et al.
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Synthesis
culture medium, the resulting formazan crystals were dissolved in
DMSO and their absorbances were measured at 540 nm, using a mi-
croplate reader.
was placed in a bath preheated at 100 °C for 24 h. After confirming the
completion of the reaction by TLC, the reaction was left to attain 45
°C, and the solvent was removed under reduced pressure. The residue
was diluted with EtOAc (20 mL) and the resulting suspension was fil-
tered through a short pad of Celite and Florisil. The filtrate was vigor-
ously stirred for 1 h with a saturated solution of KF (5 mL), when
brine (5 mL) was added, and the reaction products were extracted
with EtOAc (3 × 20 mL). The combined organic phases were dried
(Na2SO4) and then concentrated under reduced pressure. Chromatog-
raphy of the residue furnished a barely separable 2.1:1 mixture of ole-
fins 19 and 20 (30.2 mg, 90% mg) as a brownish oil.
1-(2-Hydroxy-4,6-dimethoxyphenyl)ethanone (17)
A solution of 2,4,6-trihydroxyacetophenone (16; 100 mg, 0.54 mmol)
and K2CO3 (238 mg, 1.7 mmol) in anhydrous acetone (1.5 mL) was
warmed at 50 °C and treated with a solution of Me2SO4 (156 mg, 1.24
mmol) in acetone (1 mL), delivered dropwise (1.0 mL/h) with a sy-
ringe pump. The system was further heated at 50 °C for 24 h, when
completion of the reaction was checked by TLC. Then the solvent was
evaporated, brine (10 mL) added, and the product was extracted with
EtOAc (3 × 20 mL). The combined extracts were concentrated under
reduced pressure and the residue was chromatographed to afford 17
as a light brown solid; yield: 109 mg (93%); mp 74–75 °C (Lit.22e mp
73–76 °C).
IR (film): 3995, 3102, 3007, 2982, 2968, 2943, 2849, 1616, 1597,
1570, 1458, 1441, 1423, 1389, 1368, 1323, 1273, 1223, 1206, 1188,
1157, 1111, 1082, 1045, 1028, 962, 941, 895, 835, 804 cm–1
.
1H NMR (300 MHz, CDCl3/TMS): δ = 6.34# (d, J = 2.1 Hz, 1 H, H-5′),
6.33# (d, J = 2.1 Hz, 1 H, H-3′), 5.87 (ddd, J = 6.4, 9.8, 17.2 Hz, 1 H, H-
2′′), 5.02 (dq, J = 1.7, 9.8 Hz, 1 H, H-3′′cis), 5.00 (dq, J = 1.7, 17.2 Hz, 1 H,
H-3′′trans), 3.80* (s, 3 H, OCH3-4′), 3.79* (s, 3 H, OCH3-2′), 3.33 (dt, J =
1.7, 6.4 Hz, 2 H, H-1′′), 2.46 (s, 3 H, CH3-2).
13C NMR (75 MHz, CDCl3): δ = 205.1 (C-1), 161.3 (C-4′), 158.3 (C-2′),
139.8 (C-6′), 136.8 (C-2′′), 123.5 (C-1′), 116.2 (C-3′′), 106.6 (C-5′), 96.4
(C-3′), 55.6* (OCH3-4′), 55.4* (OCH3-2′), 37.5 (C-1′′), 32.6 (CH3-2).
IR (KBr): 2943, 1614, 1593, 1568, 1456, 1440, 1423, 1367, 1271, 1220,
1205, 1157, 1113, 895 and 835 cm–1
.
1H NMR (300 MHz, CDCl3/TMS): δ = 14.02 (s, 1 H, OH), 6.04 (d, J = 2.4
Hz, 1 H, H-3′), 5.90 (d, J = 2.4 Hz, 1 H, H-5′), 3.84* (s, 3 H, OCH3-6′),
3.80* (s, 3 H, OCH3-4′), 2.59 (s, 3 H, CH3-2).
13C NMR (75 MHz, CDCl3): δ = 203.1 (C-1), 167.6 (C-4′), 166.1 (C-2′),
162.9 (C-6′), 106.0 (C-1′), 93.5 (C-3′), 90.7 (C-5′), 55.5 (2 C, OCH3-3′
and OCH3-5′), 32.9 (CH3-2).
HRMS (ESI-TOF): m/z calcd for C13H16O3Na [(M + Na)+]: 243.0992;
found: 243.0993.
EI-MS: m/z (%) = 196 (M+, 33), 181 [(M – 15)+, 100], 178 181 [(M –
18)+, 7], 166 (11), 138 (9), 95 (11).
(E)-1-[2,yy4-Dimethoxy-6-(prop-1-en-1-yl)phenyl]ethan-1-one (20)
Without further purification, a stirred solution of 19 and 20 (30.2 mg,
0.14 mmol) in anhydrous CHCl3 (1.5 mL), under a N2 atmosphere, was
exposed to PdCl2(MeCN)2 (2.4 mg, 0.009 mmol), and the system was
refluxed for 24 h. Then, the mixture was filtered through a short pad
of Celite and Florisil to afford 20 as a brownish oil; yield: 24 mg (80%).
2-Acetyl-3,5-dimethoxyphenyl Trifluoromethanesulfonate (18)
A solution of 17 (44 mg, 0.22 mmol) in anhydrous THF (2.25 mL) was
cooled to 0 °C, treated with 50% w/w NaH (13.46 mg, 0.28 mmol) and
the resulting system was kept under vigorous stirring for 10 min. Sub-
sequently, a solution of N-phenyltriflimide (200 mg, 0.56 mmol) in
THF (0.75 mL) was added and the system was heated to 65 °C for 24 h.
After confirming the completion of the reaction by TLC, sat. aq NH4Cl
(10 mL) was added and the reaction products were extracted with
EtOAc (3 × 15 mL). The combined organic phases were dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue afforded 18 as a yellow oil; yield: 60 mg (81%).
IR (film): 2918, 1688, 1597, 1574, 1456, 1418, 1348, 1248, 1202,
1157, 1086, 1040, 964 and 664 cm–1
.
1H NMR (300 MHz, CDCl3/TMS): δ = 6.58 (d, J = 2.1 Hz, 1 H, H-3′), 6.38
(dq, J = 1.7, 15.5 Hz, 1 H, H-1′′), 6.34 (d, J = 2.1 Hz, 1 H, H-5′), 6.16 (dq,
J = 6.6, 15.5 Hz, 1 H, H-2′′), 3.81 (s, 3 H, OCH3-2′), 3.78 (s, 3 H, OCH3-
4′), 2.46 (s, 3 H, CH3-2), 1.83 (dd, J = 1.7, 6.7 Hz, 3 H, CH3-3′′).
13C NMR (75 MHz, CDCl3): δ = 204.7 (C-1), 161.2 (C-4′), 158.0 (C-2′),
137.5 (C-6′), 129.0 (C-2′′), 128.0 (C-1′′), 123.2 (C-1′), 102.0 (C-3′), 97.1
(C-5′), 55.6* (OCH3-2′), 55.3* (OCH3-4′), 32.7 (CH3-2), 18.6 (CH3-3′′).
IR (film): 2949, 1614, 1574, 1470, 1418, 1325, 1246, 1215, 1144,
1090, 1061, 835, 815 cm–1
.
1H NMR (300 MHz, CDCl3/TMS): δ = 6.47 (d, J = 2.1 Hz, 1 H, H-6), 6.40
(d, J = 2.1 Hz, 1 H, H-4), 3.87* (s, 3 H, OCH3-5′), 3.84* (s, 3 H, OCH3-3′),
2.52 (s, 3 H, CH3-2′).
13C NMR (75 MHz, CDCl3): δ = 197.6 (C-1′), 162.3 (C-5), 159.3 (C-3),
147.0 (C-1), 118.5 (q, JC,F = 320 Hz, CF3), 117.7 (C-2), 99.5 (C-6), 98.3
(C-4), 56.2 (OCH3-3′), 55.9 (OCH3-5′), 32.1 (CH3-2′).
EI-MS: m/z (%) = 220 (M+, 13), 205 [(M – 15)+, 100], 190 (11), 177 (17),
147 (6), 91 (9).
HRMS (ESI-TOF): m/z calcd for C13H16O3Na [(M + Na)+]: 243.0992;
found: 243.0993.
(E)-1-{2,4-Dimethoxy-6-[(E)-prop-1-en-1-yl]phenyl}ethan-1-one
O-Methyl Oxime (21)
19F NMR (282.38 MHz, CDCl3): δ = –73.5 (s, CF3SO3Ar).
EI-MS: m/z (%) = 328 (M+, 28), 313 [(M – 15)+, 84], 181 (100), 152 (23),
137 (18).
HRMS (ESI-TOF): m/z calcd for C11H12F3O6S [(M + H)+]: 329.0301;
found: 329.0298.
NaOAc (5.1 mg, 0.06 mmol), CeCl3·7H2O (0.77 mg, 0.002 mmol), and
MeONH2·HCl (5.2 mg, 0.062 mmol) were successively added to a solu-
tion of 20 (9.1 mg, 0.04 mmol) in EtOH (1 mL) and the system was
progressively heated from 50 to 80 °C over 3 d. Then, the solvent was
removed under reduced pressure, brine (5 mL) was added, and the
product was extracted with EtOAc (3 × 15 mL). The combined organic
extracts were dried (Na2SO4) and then concentrated under reduced
pressure. Chromatography of the residue gave 21 as a brownish oil;
yield: 9.2 mg (89%).
1-(2-Allyl-4,6-dimethoxyphenyl)ethan-1-one (19)
Anhydrous LiCl (51.7 mg, 1.22 mmol), PPh3 (20 mg, 0.08 mmol), and
Pd(PPh3)2Cl2 (10.5 mg, 0.015 mmol) were successively added under N2
to a stirred solution of 18 (50 mg, 0.15 mmol) in anhydrous DMF (3
mL). The stirring was continued for 10 min, and then
Bu3SnCH2CH=CH2 (0.061 mL, 0.18 mmol) was added and the system
IR (film): 2922, 2849, 1626, 1593, 1454, 1418, 1331, 1263, 1109, 989,
870, 727, 694 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
I. Cortés et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3/TMS): δ = 6.62 (d, J = 2.4 Hz, 1 H, H-5′), 6.44
(dq, J = 1.7, 15.7 Hz, 1 H, H-1′′), 6.33 (d, J = 2.4 Hz, 1 H, H-3′), 6.17 (dq,
J = 6.6, 15.7 Hz, 1 H, H-2′′), 3.97 (s, 3 H, NOCH3), 3.81* (s, 3 H, OCH3-4′),
3.75* (s, 3 H, OCH3-2′), 2.07 (s, 3 H, CH3-2), 1.86 (dd, J = 1.7, 6.7 Hz, 3
H, CH3-3′′).
13C NMR (75 MHz, CDCl3): δ = 160.5 (C-4′), 158.7 (C-2′), 154.6 (C-1),
138.3 (C-6′), 128.3 (C-2′′), 127.8 (C-1′′), 118.3 (C-1′), 101.1 (C-3′), 97.4
(C-5′), 61.6 (NOCH3), 55.7* (OCH3-2′), 55.4* (OCH3-4′), 18.7 (CH3-3′′),
16.9 (CH3-2).
(6,8-Dimethoxy-3-methylisoquinolin-1-yl)methanol (24)
A solution of 23 (16 mg, 0.07 mmol) in anhydrous MeOH (1 mL) was
treated with NaBH4 (11 mg, 0.29 mmol) and the mixture was stirred
for 1 h at r.t. Then, the reaction was quenched with 10% aq HCl and
concentrated under reduced pressure. The solution was then basified
with 5% aq K2CO3 and the crude product was extracted with EtOAc
(3 × 15 mL) and the combined organic extracts were washed with
brine (5 mL). The combined organic extracts were dried (MgSO4) and
then concentrated under reduced pressure. Chromatography of the
residue gave 24 as a yellowish glass; yield: 15.1 mg (93%).
EI-MS: m/z (%) = 249 (M+, 6), [207 (M – MeCH=CH2)+, 100], 193 (10),
177 (11).
IR (KBr): 3458, 2918, 2849, 1620, 1462, 1393, 1209, 1163, 1121 cm–1
.
1H NMR (300 MHz, CDCl3/TMS): δ = 7.20 (s, 1 H, H-4), 6.59 (d, J = 2.2
Hz, 1 H, H-7), 6.44 (d, J = 2.2 Hz, 1 H, H-5), 5.16 (s, 2 H, CH2OH), 3.92
(s, 3 H, OCH3-8), 3.90 (s, 3 H, OCH3-6), 2.59 (s, 3 H, CH3-3).
HRMS (ESI-TOF): m/z calcd for C14H20NO3 [(M + H)+]: 250.1438;
found: 250.1433.
6,8-Dimethoxy-1,3-dimethylisoquinoline (1)
13C NMR (75 MHz, CDCl3): δ = 161.6 (C-8), 159.2 (C-6), 156.9 (C-1),
149.5 (C-3), 141.0 (C-4a), 117.3 (C-4), 112.7 (C-8a), 98.5 (C-5), 97.0
(C-7), 64.2 (CH2OH), 55.5 (2 C, OCH3-6, OCH3-6), 23.6 (CH3-3).
EI-MS: m/z (%) = 233 (M+, 19), 218 (15), 203 (56), 193 (22), 177 (100),
160 (20).
A solution of 21 (18 mg, 0.07 mmol) in anhydrous DMA (1 mL) was
heated at 160 °C in a microwave oven for 3 h. The solvent was re-
moved under reduced pressure, brine (5 mL) was added, and the
product was extracted with EtOAc (3 × 15 mL). The combined organic
extracts were dried (MgSO4) and then concentrated under reduced
pressure. Chromatography of the residue gave 1 as a brownish solid;
yield: 7.2 mg (45%); mp 88–90 °C (Lit.7b mp 85–90 °C).
HRMS (ESI-TOF): m/z calcd for C13H16NO3 [(M + H)+]: 234.1125;
found: 234.1134.
IR (KBr): 2928, 2849, 1622, 1568, 1454, 1396, 1209, 1163, 1117, 1040,
935, 826, 606, 438, 411 cm–1
.
Funding Information
1H NMR (300 MHz, CDCl3/TMS): δ = 7.13 (s, 1 H, H-4), 6.52 (d, J = 2.3
Hz, 1 H, H-7), 6.41 (d, J = 2.3 Hz, 1 H, H-5), 3.91 (s, 3 H, OCH3-8), 3.89
(s, 3 H, OCH3-6), 3.00 (s, 3 H, CH3-1), 2.55 (s, 3 H, CH3-3).
13C NMR (75 MHz, CDCl3): δ = 161.0 (C-8), 159.6 (C-6), 157.4 (C-1),
150.8 (C-3), 141.0 (C-4a), 116.6 (C-4), 114.8 (C-8a), 98.3 (C-5), 96.9
(C-7), 55.4 (2 C, OCH3-6, OCH3-8), 28.2 (CH3-1), 24.0 (CH3-3).
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET,
PUE IQUIR 2016), Agencia Nacional de Promoción Científica y Tec-
nológica (ANPCyT, PICT 2014-0445), and Instituto Nacional del Cáncer
(INC, Asistencia Financiera a Proyectos de Investigación III, 2015).
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EI-MS: m/z (%) = 217 (M+, 100), [202 (M – 15)+, 39], 197 (22), 175 (14),
159 (15), 144 (21), 131 (11).
Acknowledgment
The authors gratefully acknowledge the Agencia Santafesina de Cien-
cia, Tecnología e Innovación Productiva (ASaCTeI) for an institutional
grant to IQUIR, to acquire a 400 MHz NMR spectrometer. I.C. thanks
CONICET for his doctoral fellowship.
HRMS (ESI-TOF): m/z calcd for C13H16NO2 [(M + H)+]: 218.1176;
found: 218.1168.
6,8-Dimethoxy-3-methylisoquinoline-1-carbaldehyde (23)
A solution of 1 (33.1 mg, 0.15 mmol) in anhydrous 1,2-DCB (1 mL)
was heated in an oven at 100 °C for 3 h. The solvent was removed un-
der reduced pressure, brine (5 mL) was added, and the product was
extracted with EtOAc (3 × 15 mL). The combined organic extracts
were dried (MgSO4) and then concentrated under reduced pressure.
Chromatography of the residue gave 23 as a light orange solid; yield:
25 mg (70%); mp 112–114 °C.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610276.
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References
IR (KBr): 2922, 2851, 1697, 1622, 1568, 1454, 1402, 1396, 1260, 1211,
1163, 654, 606, 438, 411 cm–1
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