A Ruthenium-Catalyzed C-H Activation Strategy as an Efficient Shortcut in the Total Synthesis of 6,8-Dimethoxy-1,3-dimethyl?-isoquinoline

Article abstract of DOI:10.1055/s-0037-1610720

A short and convenient total synthesis of 6,8-dimethoxy-1,3-dimethylisoquinoline, employing a C-H activation/alkenylation strategy, is reported. The approach involves the CeCl ₃ 7H ₂ O-promoted methoximation of 2,4-dimethoxyacetophenone and a methoxime-directed ruthenium-catalyzed allylation. This was followed by a one-pot, ruthenium-catalyzed allyl to propenyl isomerization and a microwave-assisted 6π-azaelectrocylization to complete the sequence. This approach, which entails a shortcut in the synthetic management of the three-carbon side chain, is an improved and more efficient route toward the natural product, which facilitated its access in just three steps and 27.3percent overall yield.

Full text of DOI:10.1055/s-0037-1610720

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
S. Fonzo et al.
Paper
Synthesis
A Ruthenium-Catalyzed C–H Activation Strategy as an Efficient
Shortcut in the Total Synthesis of 6,8-Dimethoxy-1,3-dimethyl-
isoquinoline
Santiago Fonzoa
Didier F. Vargas*a,b
Teodoro S. Kaufman*a,b
CeIII-Promoted
methoximation
MeO
H
MeO
H
0
0
0
0-
0
0
0
1-6
7
6
9-6
4
4
2
O
N
OMe
0
0
0
0-0
0
0
3-3
1
7
3-2
1
7
8
MeO
Me
MeO
Direct allylation by C-H Activation
Me
a Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Na-
cional de Rosario, Suipacha 531, Rosario 2000, Argentina
b Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531,
Rosario 2000, Argentina
vargas@iquir-conicet.gov.ar
kaufman@iquir-conicet.gov.ar
· 3 Steps; 27.3% yield
· Protective group free
One-pot isomerization-
6p-azaelectrocyclization
MeO
Me
MeO
N
N
OMe
Cytotoxic natural product
from Ancistrocladus tectorius
MeO
Me
MeO
Me
Dedicated to the memory of our treasured colleague and Master Prof.
Dr. Edmundo A. Rúveda (03/1934–12/2018) and our beloved friend
and co-worker Lic. María Virginia Méndez (02/1987–01/2019).
Received: 27.05.2019
Accepted after revision: 08.06.2019
Published online: 16.07.2019
The phytochemical analysis of its roots, stem and leaves
have afforded different naphthylisoquinoline alkaloids,5
and a bark sample of this liana, collected in Malaysia, yield-
ed 0.002% w/w of a mixture of alkaloids, including 6,8-di-
methoxy-1,3-dimethyl isoquinoline (1)6 and its 3-hy-
droxymethyl analogue 2, which is the key core of glycoside
2a7a and other relevant natural products,5a,7b,c as shown in
Figure 1.
The heterocyclic motif 1 is at the heart of a range of bio-
active compounds, such as the anticytopathic and antima-
larial agent 3, an analogue of the michellamine alkaloids.8
The core 1 is present in the cytotoxic and antiproliferative
1-aryl quinolinium derivative 4,9 and also exhibits leish-
manicidal,10a anti-infective and biofilm-inhibiting activi-
ties,10b and is present in IQ-143 (5), a bactericidal biphenyl
derivative.11
DOI: 10.1055/s-0037-1610720; Art ID: ss-2019-m0296-op
Abstract A short and convenient total synthesis of 6,8-dimethoxy-
1,3-dimethylisoquinoline, employing
a C–H activation/alkenylation
strategy, is reported. The approach involves the CeCl3·7H2O-promoted
methoximation of 2,4-dimethoxyacetophenone and a methoxime-di-
rected ruthenium-catalyzed allylation. This was followed by a one-pot,
ruthenium-catalyzed allyl to propenyl isomerization and a microwave-
assisted 6-azaelectrocylization to complete the sequence. This ap-
proach, which entails a shortcut in the synthetic management of the
three-carbon side chain, is an improved and more efficient route to-
ward the natural product, which facilitated its access in just three steps
and 27.3% overall yield.
Key words C–H activation, one-pot transformation, total synthesis,
natural product, ruthenium catalysis, 6,8-dimethoxy-1,3-dimethyliso-
quinoline
In addition, and not surprisingly, the same scaffold is
also found in natural products, including 6-O-methylha-
mateine (6),12 the methyl ether of antimalarial cassiarin A
(7), dehydro-ancistrocladisine (8),13 and ancisheynine (9),14
among others.7c,15
The heterocycle 1 has been targeted several times for
synthesis. Its first total synthesis involved the deoxygen-
ation of the very scarce compound 2,6a whereas other se-
quences suffered from low yields and/or transformations
under rather harsh conditions.6a,16
We have recently disclosed an alternative synthetic ap-
proach toward 1, which used phloroacetophenone as start-
ing material and relied on a Stille allylation for the introduc-
tion of the remaining three carbon atoms.17 We have also
demonstrated that compound 1, as well as its related deriv-
atives 10 and 11, displayed interesting cytotoxic activity in
the micromolar range.
The genus Ancistrocladus (Ancistrocladaceae) includes
flowering plants that are native to a vast tropical region
that spans from South East Asia to Central and West Africa.
They are characterized by producing naphthylisoquinoline
alkaloids,1 many of which have been shown to be active
against the etiological agents of various parasitic tropical
diseases, including leishmaniasis, African trypanosomiasis
(sleeping sickness), and malaria.2 Some of these heterocy-
cles also proved to have antiviral properties or to exhibit in-
teresting cytotoxic profiles.3
Ancistrocladus tectorius (Lour.) Merr. is a tropical woody
climber, typical of the rainforests of Southeast Asia. It is
widely employed in folk medicine as an analgesic, antima-
larial, antipyretic, antiphlogistic and diuretic agent, as well
as a spasmolytic and for treating dysentery.4
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Fonzo et al.
Paper
Synthesis
tention and the association between C–H activation and the
atom-economic 6-azaelectrocyclization has been rather
scarcely explored.21
5
4
R2O
3
R1
MeO
Me
6
4a
8a
N+
N
7
2
8
1
MeO
Me
Therefore, in pursuit of our research on the total synthe-
sis of bioactive and unique natural products and their ana-
logues,22 herein we wish to report a short and more effi-
cient total synthesis of 1, performed along the guidelines of
the retrosynthetic analysis outlined in Scheme 1. The ap-
proach features a ruthenium-catalyzed C–H activation reac-
tion as key transformation, and involves a one-pot allyl
isomerization/6-electrocyclization stage.
R
MeO
1 R = R1 = R2 = Me
2 R = R2 = Me, R1 = CH2OH
R
4
OMe
2a R = Me, R1 = CH2OH, R2 = Glc
10 R = CHO, R1 = R2 = Me
11 R = CH2OH, R1 = R2 = Me
OMe
HO
MeO
HO
Me
N+
Me
OH
Me
Me
Me
N
N
C–H activation
6π-azaelectrocyclization
MeO Me
Me
Me
MeO
OH
Me
HO
N
OMe
N
OH
OR
3
oximation
Me
MeO
Me
MeO
Me
Me
N+
Me
MeO
OMe
1
12
Me
OMe
N
O
MeO
Me
MeO
OR
N
+
+
Me
LG
O
OMe
H
H
5
MeO
N
MeO
14
Me
15
LG = leaving group
7
13
MeO
Me
Me
6
Scheme 1 Retrosynthetic analysis of the target natural isoquinoline 1
MeO
Me
Me
N+
MeO
OMe
OMe
Next, working on the conjecture that an oxime deriva-
tive could be a suitable activation and directing moiety for
the installation of the three-carbon side chain that is re-
quired by the heterocyclic ring, the disconnection of 12 was
performed to release the side chain. In addition, the oxime
moiety was retrosynthetically excised, generating the ideal
precursors for the synthesis; namely, a hydroxylamine de-
rivative (13), 2,4-dimethoxy acetophenone (14), and an al-
lyl moiety fitted with a suitable leaving group (15), as a po-
tential three-carbon-atom source.
Based on our previous experience, which showed that a
6-azaelectrocyclization can bring about the desired ring
closure, compound 1 was submitted to a C–N disconnec-
tion. The results confirmed that the olefinic compound 12
could be an appropriate advanced intermediate.
N
MeO
Me
9
MeO
MeO
OMe Me
Me
8
Figure 1 Chemical structures of 6,8-dimethoxy-1,3-dimethylisoquino-
line (1), related natural products and synthetic heterocycles
On this basis, we suggested that the isoquinoline motif
of the naphthylisoquinolines may constitute the pharmaco-
phore of these family of natural products, and proposed
that their bioactivity may be modulated by the polysubsti-
tuted naphthyl units attached to the alkaloidal core and the
array of oxygen functionalities that decorate the hetero-
cycle.17
During the last decade, directed alkenylation through
C–H bond activation has become established as a useful al-
ternative to more traditional transformations, such as the
Heck reaction, and it is a powerful and atom-economic tool
to build heterocycles.18 Among the latter, the isoquinolines
have received special attention,19 and a wide array of proto-
cols to access 4- and 3,4-substituted isoquinolines through
the sequential C–H activation/annulation of aromatic oxim-
es, imines, azines and azides with alkynes have been re-
ported.
In view of the dual role assigned by the retrosynthetic
analysis to the oxime derivative, its choice was critical.
However, we were inclined toward installation of a methox-
ime moiety based on previous experience and on some lit-
erature precedents.23 Accordingly, the starting acetophe-
none 14 was subjected to our recently developed ceri-
um(III)-catalyzed methoximation24 with methoxylamine
hydrochloride and NaOAc in EtOH at 50 °C (Scheme 2).
This uneventfully afforded 94% yield of compound 16 af-
ter 30 minutes at 50 °C, as a chromatographically separable
(93:7) mixture of E/Z isomers, according to 1H NMR integra-
tion. Access to the pure (E)-16 isomer, which was easily
achieved in 87% yield from 14, set the stage for the pro-
posed direct allylation via C–H activation.25
Contrastingly, however, the application of such advanc-
es to the synthesis of natural products remains compara-
tively limited.20 Furthermore, analogous transformations
involving ‘unactivated’ alkenes have received much less at-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

C
S. Fonzo et al.
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Synthesis
Table 1 Preparation of Intermediate 17: Optimization of the Reaction
Conditions for the Direct Allylation of 16a
MeO
MeO
a
O
N
OMe
MeO
14
Me
MeO
Me
LG
MeO
MeO
15 (2.5 equiv)
16
N
N
OMe
OMe
[RuCl2(p-cymene)]2 (5 mol%)
AgSbF6 (20 mol%)
b
MeO
Me
MeO
Me
DCE, r.t., 16 h
16
17
MeO
e
N
Entry
Leaving group (LG)
Isolated yield (%)b
OMe
MeO
Me
1c
2
OAc
OAc
72
73
68
50
17
c
3
OCO2Me
OPO(OEt)2
4d
MeO
Me
MeO
d
Me
a The experiments were carried out at a final concentration of 0.15 mmol
of 16 in 1 mL of DCE.
N
N
OMe
b Isolated yield after flash column chromatography.
c 10 mol% of the catalyst was used.
MeO
Me
MeO
Me
d The starting ketone 14 (15%) and oxime 16 (13%) were isolated concomi-
tantly.
1
18
Scheme 2 Reagents and conditions: (a) MeONH2·HCl, CeCl3·7H2O,
NaOAc, EtOH, 50 °C, 30 min (94%; E/Z 93:7; 87% of pure E-isomer); (b)
Allyl acetate (2 equiv), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%),
DCE, r.t., 16 h, (73%); (c) RuHCl(CO)(PPh3)3 (3 mol%), 90 °C, 24 h (PhMe,
95%; E/Z 90:10; PhCF3, 84%; E/Z 95:5); (d) AcOH, PhCF3, MW (160 °C), 3
h (40%); (e) 1. RuHCl(CO)(PPh3)3 (3 mol%), 90 °C, 24 h; 2. 150–160 °C,
22 h (PhMe, 43%; PhCF3, 20%).
Opposite to other metal-catalyzed direct allylations of
similar systems, which were found to provide mixtures of
allyl and propenyl derivatives,17 this ruthenium-catalyzed
reaction afforded 17 as the sole product. Various ruthenium
derivatives have been reported to promote the allyl to pro-
penyl isomerization,28 and allyl derivatives ortho to amide
groups have been isomerized in the presence of [RuCl2(p-
cymene)]2.28a Unfortunately, however, all attempts to obtain
compound 18 by adding anhydrous MeOH and/or increas-
ing the temperature of the reaction medium to reflux
proved fruitless and only the allyl derivative (ca. 65%) was
recovered in the latter case.
Therefore, the synthesis continued with the exposure of
the allyl benzenoid 17 to 3 mol% of the ruthenium catalyst
RuHCl(CO)(PPh3)3 in toluene,30a which effected a smooth
double-bond isomerization and cleanly provided the key
intermediate 18 in 95% yield, after heating at 90 °C for 24
hours. 1H NMR analysis of the product indicated that it con-
sisted of a 90:10 mixture of E/Z geometric isomers at the
olefin moiety.24
To optimize the reaction conditions, the transformation
was executed in the presence of 20 mol% of AgSbF6 as an
additive and under [RuCl2(p-cymene)]2 catalysis, in 1,2-di-
chloroethane (DCE) as solvent, at room temperature for 16
hours. The results are summarized in Table 1.
The initial trials were executed according to the proto-
col of Jeganmohan et al.,23a with freshly distilled allyl ace-
tate (2.5 equiv) as a convenient source of the necessary
three-carbon unit. The transformation proved to consis-
tently afford the desired product 17, which was isolated in
72% yield when 10 mol% of the catalyst was employed (Ta-
ble 1, entry 1), and was obtained in 73% yield with a cata-
lyst load of only 5 mol% (entry 2). These results demon-
strated the cost-effectiveness of the ruthenium reagent for
the direct allylation.18a,26
For comparison, the performance of other allyl esters
was tested. Interestingly, allyl methylcarbonate (prepared
by reaction of ClCO2Me and allyl alcohol in anhydrous CH2-
Cl2 and in the presence of Et3N as base)27a also proved to be
a suitable donor of the allyl moiety (Table 1, entry 3), al-
though its efficiency was slightly lower, furnishing 68%
yield of 17 when 5 mol% of the catalyst was employed.
In contrast, the diethylphosphate congener (synthesized
in a similar fashion from diethyl chlorophosphate)27b was
found to be less suitable, affording the product in only 50%
yield (Table 1, entry 4), accompanied by substantial
amounts of recovered starting material 16 (13%) and of re-
covered starting ketone 14 (15%).
Notably, although there are a few references concerning
the allyl to propenyl isomerizations of allyl moieties located
ortho to imine derivatives,29 to our knowledge, similar pro-
cedures employing methoxime derivatives of aromatic ke-
tones have not been disclosed before. Furthermore, in our
experience, the performance of the transformation com-
pared very favorably with analogous isomerizations per-
formed on ortho-allyl substituted benzaldehydes and ben-
zophenones.30a
Finally, the isomerized methoxime 18 was subjected to
a 6-azaelectrocyclization reaction30 in benzotrifluoride, as
an environmentally friendly solvent, to which a small
amount of AcOH was added as a promoter.31 After heating
for 3 hours at 160 °C in a synthesis microwave oven, the fi-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

D
S. Fonzo et al.
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Synthesis
nal product 1 was obtained with 40% yield. In this way, un-
like our previous syntheses of 1,17 the methoxime moiety
played a dual role, being a directing group in the C–H acti-
vation stage and the source of the nitrogen atom for the 6-
azaelectrocyclization. The spectroscopic data of the syn-
thetic isoquinoline were in full agreement with the report-
ed data for the natural product.6,17
To further improve the efficiency of our strategy, a one-
pot isomerization-cyclization process was attempted. To
this end, the allyl intermediate 17 was first isomerized to
18 by heating the compound in a closed vessel for 24 hours
at 90 °C in toluene, in the presence of RuHCl(CO)(PPh3)3;
then, the mixture was further heated in a silicone oil bath at
150–160 °C for 22 hours to carry out the final 6-azaelec-
trocyclization. To our delight, this resulted in the isolation
of compound 1 in 43% overall yield.
refluxing the corresponding AR (analytical reagent). PA = Pro analysis
grade solvent over P2O5 for 4 h, followed by distillation. Anhydrous
Et3N was prepared by refluxing the solvent over CaH2 for 4 h, followed
by distillation. All the anhydrous solvents were transferred via cannu-
la to dry Young ampoules and stored over molecular sieves. All other
commercial reagents were used as received, without further purifica-
tion.
The reactions were monitored by TLC, which were run on Kieselgel 60
GF254 plates, using hexane/EtOAc solvent mixtures of different polari-
ties. The chromatographic spots were detected by irradiation of the
plates with short wavelength UV light (254 nm), followed by expo-
sure to iodine vapor or by spraying with ethanolic p-anisalde-
hyde/sulfuric acid reagent. Careful heating of the sprayed plates was
employed to improve the selectivity. All new compounds gave single
spots in different solvent systems. Flash column chromatography col-
umns were developed with slurry-packed silica gel 60 H (particle size
63–200 m). The elution was performed under positive pressure, us-
ing gradient of solvent (hexane–EtOAc mixtures) polarity techniques.
It is worth noting that, although other one-pot isomeri-
zation/electrocyclization processes involving alkenes are
known, their first stages merely entail E/Z isomerizations,
rather than an allyl isomerization.32 On the other hand, it
has been reported that the palladium-assisted isoquinoline
synthesis devised by Tsutsui and Narasaka has been consid-
ered an amino-Heck reaction, which apparently does not
involve an allyl to propenyl double-bond isomerization
stage.33
In conclusion, we have reported a concise and improved
strategy toward the total synthesis of the naturally occur-
ring alkaloid 6,8-dimethoxy-1,3-dimethylisoquinoline,
which is a heterocyclic motif found in various natural prod-
ucts and synthetic bioactive compounds. The synthesis was
performed in only three steps and 27.3% overall yield, from
the economic and easily available 2,4-dimethoxy acetophe-
none. The approach does not require protecting groups and
features a ruthenium-catalyzed C–H activation stage as the
key transformation.
The synthetic sequence involved a Ce(III)-mediated cat-
alytic methoximation of the starting ketone and further in-
stallation of the required three-carbon side chain by a me-
thoxime-enabled ruthenium-catalyzed C–H activation
strategy. This was followed by a ruthenium-catalyzed allyl
to propenyl isomerization and a final microwave-promoted
6-azaelectrocyclization. The latter two steps were conve-
niently carried out as a one-pot process, thus increasing the
overall efficiency of the synthesis.
The structures of the products were determined based on a combina-
tion of spectroscopic methods, which included NMR (HSQC and
HMBC), IR and HRMS. The NMR spectra were acquired in CDCl3 with
Bruker Avance II 300 and Bruker Avance III HD 400 spectrometers.
Chemical shift data are reported in ppm downfield from TMS as inter-
nal standard (for CDCl3, 13C  = 77.16 ppm). Signal splitting patterns
are reported as follows: s (singlet), d (doublet), t (triplet), dd (doublet
of doublets), dt (doublet of triplets), dq (doublet of quartets), and m
(multiplet). Coupling constants (J) are reported in hertz.
IR spectra were recorded with a Shimadzu Prestige 21 spectropho-
tometer, as a solid dispersion in NaCl. High-resolution mass spectra
were obtained at UMyMFOR (Buenos Aires, Argentina) with Bruker
MicroTOF-Q II equipment. Detection of the ions was performed in the
ESI+ (electrospray ionization, positive ion) mode. The microwave-as-
sisted reactions were executed in a CEM-Discover microwave synthe-
sis oven.
(E)-1-(2,4-Dimethoxyphenyl)ethan-1-one O-Methyl Oxime (16)25
A mixture of 2,4-dimethoxyacetophenone (14; 300 mg, 1.66 mmol),
NaOAc (203 mg, 2.47 mmol), CeCl3·7H2O (32 mg, 0.086 mmol), and
MeONH2·HCl (209 mg, 2.50 mmol) in EtOH (13 mL) was heated at
50 °C for 30 minutes. The solvent was then evaporated and the resi-
due was purified by column chromatography to afford the desired
product (E)-16. Increasing the polarity of the solvent furnished (Z)-
16.
Compound (E)-16
Yield: 302 mg (87%); colorless oil.
1H NMR (300 MHz, CDCl3):  = 7.22–7.25 (m, 1 H, 6-H′), 6.44–6.48 (m,
2 H, 2-H′ and 5-H′), 3.95 (s, 3 H, NOCH3), 3.81 (s, 3 H, 2′-OCH3), 3.80 (s,
3 H, 4′-OCH3), 2.15 (s, 3 H, 2-CH3).
13C NMR (75 MHz, CDCl3):  = 161.7 (C-2′), 158.7 (C-4′), 156.5 (C-1),
130.3 (C-6′), 120.1 (C-1′), 104.4 (C-5′), 99.0 (C-3′), 61.7 (NOCH3), 55.5
(2′-OCH3 and 4′-OCH3), 16.1 (2-CH3).
All the reactions were carried out under inert atmospheres of anhy-
drous argon, employing oven-dried glassware and freshly distilled an-
hydrous solvents. Anhydrous toluene was obtained by reflux of the
AR (analytical reagent) solvent over sodium metal (benzophenone as
indicator), followed by distillation. Anhydrous EtOH and MeOH were
prepared by treatment of the AR reagent (AR = analytical reagent;
equivalent to Pro-analysis grade) with clean magnesium turnings and
a crystal of iodine, followed by reflux until complete consumption of
the metal was achieved. The solvent was distilled from the so-formed
magnesium alkoxide. Anhydrous DCE and CH2Cl2 were prepared by
Compound (Z)-16
Yield: 22 mg (7%); colorless oil.
1H NMR (300 MHz, CDCl3):  = 7.04–7.07 (m, 1 H, 6-H′), 6.47–6.52 (m,
2 H, 2-H′ and 5-H′), 3.95 (s, 3 H, NOCH3), 3.81 (s, 3 H, 2′-OCH3), 3.80 (s,
3 H, 4′-OCH3), 2.13 (s, 3 H, 2-CH3).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

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S. Fonzo et al.
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Synthesis
13C NMR (75 MHz, CDCl3):  = 161.2 (C-2′), 157.0 (C-4′), 153.7 (C-1),
129.3 (C-6′), 117.4 (C-1′), 104.5 (C-5′), 99.0 (C-3′), 61.6 (NOCH3), 55.7
(2′-OCH3), 55.5 (4′-OCH3), 21.6 (2-CH3).
Compound (Z)-18
1H NMR (300 MHz, CDCl3):  = 6.44 (d, J = 2.3 Hz, 1 H, 5-H′), 6.37–6.43
(m, 1 H, ArCH=CH-CH3), 6.37 (d, J = 2.3 Hz, 1 H, 3-H′), 5.76 (dq, J = 7.0,
11.3 Hz, 1 H, ArCH=CH-CH3), 3.93 (s, 3 H, NOCH3), 3.80 (s, 3 H, 4′-
OCH3), 3.78 (s, 3 H, 2′-OCH3), 2.02 (s, 3 H, 2-CH3), 1.78 (dd, J = 1.8,
7.0 Hz, 3 H, ArCH=CH-CH3).
(E)-1-(2-Allyl-4,6-dimethoxyphenyl)ethan-1-one O-Methyl Oxime
(17)
The O-methyl oxime 16 (32 mg, 0.15 mmol), [RuCl2(p-cymene)]2 (5
mg, 5 mol%), AgSbF6 (10 mg, 20 mol%) and 1,2-DCE (1 mL) were se-
quentially added to a pressure tube fitted with a septum; then, the
mixture was stirred and purged with dry argon for 5 minutes. Allyl
acetate (35 L, 0.38 mmol) was then added by using a microsyringe,
and the reaction mixture was purged again with dry argon for 5 min-
utes. The reaction tube was sealed and the mixture was stirred at r.t.
overnight. The reaction mixture was then diluted with CH2Cl2 and fil-
tered through a Celite/silica gel pad. The pad was washed with CH2Cl2
and the combined filtrates were evaporated in vacuo. The residue was
purified by chromatography to give 17.
6,8-Dimethoxy-1,3-dimethylisoquinoline (1)6b
A stirred solution of azatriene 18 (30 mg, 0.12 mmol) and glacial
AcOH (10 L) in PhCF3 (1 mL), contained in a septum-capped micro-
wave tube, was purged with argon. The vessel was then sealed and ir-
radiated (160 °C, ca. 250 W) in a microwave reactor (three cycles, 1 h
each). The solvent was recovered by distillation, and the oily residue
was purified by chromatography to afford the 1,3-dimethylisoquino-
line derivative 1.
Yield: 10 mg (40%); brownish solid.
1H NMR (400 MHz, CDCl3):  = 7.14 (s, 1 H, 4-H), 6.53 (d, J = 2.3 Hz,
1 H, 5-H), 6.43 (d, J = 2.3 Hz, 1 H, 7-H), 3.92 (s, 3 H, 8-OCH3), 3.90 (s,
3 H, 6-OCH3), 3.01 (s, 3 H, 1-CH3), 2.56 (s, 3 H, 3-CH3).
13C NMR (100 MHz, CDCl3):  = 161.1 (C-8), 159.7 (C-6), 157.6 (C-1),
151.0 (C-3), 141.2 (C-4a), 116.6 (C-4), 114.9 (C-8a), 98.5 (C-5), 97.0
(C-7), 55.6 (6-OCH3), 55.5 (8-OCH3), 28.3 (1-CH3), 24.1 (3-CH3).
Yield: 27 mg (73%); colorless oil.
IR (NaCl): 3076, 3001, 2937, 2839, 1604, 1583, 1421, 1323, 1207,
1157, 1051, 912, 873, 763 cm–1
.
1H NMR (300 MHz, CDCl3):  = 6.36 (d, J = 2.3 Hz, 1 H, 3-H′), 6.33 (d, J =
2.3 Hz, 1 H, 5-H′), 5.83–5.96 (m, 1 H, ArCH2CH=CH2), 5.00–5.07 (m,
2 H, ArCH2CH=CH2), 3.94 (s, 3 H, NOCH3), 3.79 (s, 3 H, 4′-OCH3), 3.76
(s, 3 H, 6′-OCH3), 3.36 (dt, J = 1.2, 6.6 Hz, 2 H, ArCH2CH=CH2), 2.05 (s,
3 H, 2-CH3).
13C NMR (75 MHz, CDCl3):  = 160.7 (C-6′), 158.9 (C-4′), 155.0 (C-1),
140.6 (C-2′), 137.4 (ArCH2CH=CH2), 119.5 (C-1′), 116.0
(ArCH2CH=CH2), 105.8 (C-3′), 96.7 (C-5′), 61.7 (NOCH3), 55.7 (6′-
OCH3), 55.4 (4′-OCH3), 37.9 (ArCH2CH=CH2), 16.9 (2-CH3).
One-Pot Procedure for the Sequential Allyl Group Isomeriza-
tion/6-Azaelectrocyclization of 17
A stirred solution of 17 (25 mg, 0.1 mmol) and RuClH(CO)(PPh3)3 (3
mol%) in anhydrous toluene (1 mL) was purged with argon and heated
at 90 °C for 24 h. The temperature was then maintained at 150–
160 °C for a further period of 22 h, when the reaction mixture was
diluted with EtOH and filtered through a short pad of Celite/silica gel.
The pad was washed with EtOH and the combined filtrates were
evaporated in vacuo on a rotary evaporator. The crude residue was
purified by chromatography to give 1 (9.3 mg, 43%). The spectroscop-
ic data of the product were in full agreement with the reported data6
and with those of the isoquinoline compound obtained through the
stepwise approach.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H20NO3: 250.1438; found:
250.1445.
(E)-1-[2,4-Dimethoxy-6(prop-1-en-1-yl)phenyl]ethan-1-one O-
Methyl Oxime (18)17
A solution of the 2-allyl derivative 17 (36 mg, 0.14 mmol) and
RuClH(CO)(PPh3)3 (3 mol%) in anhydrous toluene (1 mL) was purged
with argon and then heated at 90 °C for 24 h. The completion of the
reaction was confirmed by 1H NMR spectroscopic analysis of a crude
sample. The crude reaction mixture was concentrated under reduced
pressure and the remaining oil was purified by column chromatogra-
phy, to afford the desired product 18.
Funding Information
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET,
PUE IQUIR-2016) and Agencia Nacional de Promoción Científica y
Tecnológica (ANPCyT, PICT 2017-0149) are thanked for funding this
Yield: 33 mg (95%); white solid of low melting point, consisting of an
inseparable mixture of isomers (E/Z 9:1) on the olefin motif.
study.
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o
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esti
g
a
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es
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i
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ntífi
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y
T
é
c
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i
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as(P
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EI
Q
U
I
R
2
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1
6)F
o
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o
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aralaI
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esti
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a
(P
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1
7-0
1
4
9)
Compound (E)-18
1H NMR (300 MHz, CDCl3):  = 6.62 (d, J = 2.3 Hz, 1 H, 5-H′), 6.45 (dq,
J = 1.6, 15.6 Hz, 1 H, ArCH=CH-CH3), 6.34 (d, J = 2.3 Hz, 1 H, 3-H′), 6.17
(dq, J = 6.6, 15.6 Hz, 1 H, ArCH=CH-CH3), 3.96 (s, 3 H, NOCH3), 3.81 (s,
3 H, 4′-OCH3), 3.76 (s, 3 H, 2′-OCH3), 2.07 (s, 3 H, 2-CH3), 1.86 (dd, J =
1.6, 6.6 Hz, 3 H, ArCH=CH-CH3).
13C NMR (75 MHz, CDCl3):  = 160.6 (C-6′), 158.8 (C-4′), 154.7 (C-1),
138.4 (C-2′), 128.4 (ArCH=CH-CH3), 127.9 (ArCH=CH-CH3), 118.4 (C-
1′), 101.2 (C-5′), 97.5 (C-3′), 61.7 (NOCH3), 55.8 (6′-OCH3), 55.5 (4′-
OCH3), 18.8 (ArCH=CH-CH3), 17.0 (2-CH3).
Acknowledgment
The Agencia Santafesina de Ciencia, Tecnología e Innovación (ASaCTeI)
is acknowledged for awarding the Institutional Grant AC 2015-0005
(400 MHz NMR spectrometer). DFV also thanks CONICET for his Doc-
toral fellowship.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610720.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

F
S. Fonzo et al.
Paper
Synthesis
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G