Rhodium(III)-Catalyzed C-H Activation-Based First Total Synthesis of 6- O -Methyl Anciscochine, an Alkaloid Isolated from Ancistrocladus tectorius

Article abstract of DOI:10.1055/s-0039-1690701

The concise and efficient first total synthesis of 6- O -methyl anciscochine, employing a tandem C-C/C-N formation approach via a rhodium-catalyzed C-H activation/alkenylation/annulation strategy, is reported. This heterocycle was isolated from the liana Ancystrocladus tectorius and features a unique 3-hydroxymethylisoquinoline core that is found in a few other natural products and in some bioactive synthetic compounds. The synthesis, which was executed in four high-yielding steps and a global yield of 43percent, involved the oximation of commercial 2,4-dimethoxyacetophenone under CeCl ₃ ·7H ₂ O-promotion, followed by pivaloylation of the oxime. A one-pot pivaloxime-directed alkenyl-ation/annulation stage with methyl acrylate, furthered by a NaBH ₄ / CaCl _2- -mediated reduction of the resulting isoquinoline 3-carboxylate ester completed the sequence.

Full text of DOI:10.1055/s-0039-1690701

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
2
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X
©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
Synthesis
D. F. Vargas et al.
Paper
Rhodium(III)-Catalyzed C–H Activation-Based First Total Synthesis
of 6-O-Methyl Anciscochine, an Alkaloid Isolated from Ancistrocladus
tectorius
Didier F. Vargas*a,b
Brenda S. Romerob
Enrique L. Larghia,b
Teodoro S. Kaufman*a,b
0
0
0
0-
0
0
0
1-6
7
6
9-6
4
4
2
MeO
MeO
H
Oximation under
CeCl3-assistance
O
N
0
0
0
0-
0
0
0
2-9
7
9
1-4
8
31
• 4 Steps; yield: 43%
• No protective groups
OPiv
MeO
Me
MeO
Me
0
0
0
0-0
0
0
3-3
1
7
3-2
1
7
8
One-pot directed alkenylation/annulation
a
Instituto de Química Rosario (IQUIR, CONICET-UNR),
000 Santa Fe, Argentina
vargas@iquir-conicet.gov.ar
2
MeO
MeO
2
CO Me
OH
Reduction
kaufman@iquir-conicet.gov.ar
Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario, Suipacha 531,
N
N
b
Natural product from
Me Ancystrocladus tectorius
MeO
MeO
Me
(
2000) Rosario, Argentina
Received: 28.08.2019
Accepted after revision: 17.09.2019
Published online: 10.10.2019
its potential biogenetic precursor, the deoxygenated conge-
ner 2, which was prepared from 1 by formation of the
6b
DOI: 10.1055/s-0039-1690701; Art ID: ss-2019-m0489-op
mesylate, followed by its reductive deoxygenation with
6a
LiAlH in THF.
4
Abstract The concise and efficient first total synthesis of 6-O-methyl
anciscochine, employing a tandem C–C/C–N formation approach via a
rhodium-catalyzed C–H activation/alkenylation/annulation strategy, is
reported. This heterocycle was isolated from the liana Ancystrocladus
tectorius and features a unique 3-hydroxymethylisoquinoline core that
is found in a few other natural products and in some bioactive synthetic
compounds. The synthesis, which was executed in four high-yielding
steps and a global yield of 43%, involved the oximation of commercial
R
OMe
OH
5
4
1
6
3
R O
4a
Me
N2
N
N
7
8
a
MeO
OH
8
1
MeO
R = OH, R = Me
R = H, R1 = Me
Me
1
1
2
2
,4-dimethoxyacetophenone under CeCl ·7H O-promotion, followed
3 R = OH, R1 = Glc
3
2
N
OH
OMe
1
by pivaloylation of the oxime. A one-pot pivaloxime-directed alkenyl-
ation/annulation stage with methyl acrylate, furthered by a NaBH4/
4 R = OH, R = H
O
Me
1
HO
O
OMe
R O OMe
CaCl -mediated reduction of the resulting isoquinoline 3-carboxylate
Me
2
7
ester completed the sequence.
Me
5
R
R
OH
Me
RO
OH
Key words C–H activation, natural product, rhodium catalysis, 6-O-
methyl anciscochine, Ancystrocladus tectorius, one-pot alkenylation/
annulation
R1
N
N
HO
R1
OH
MeO
Me
MeO
OH
The Ancistrocladaceae distinguish themselves by the
1
9a R = OMe, R1 = H
9b R = H, R = OMe
6
6
a R = Me, R = H
N
production of unique acetogenic naphthylisoquinoline al-
1
1
b R = R = H
R
1
1
kaloids. Some of them exhibit interesting antiproliferative
6c R = R = Me
6d R = H, R = Me
MeO
Me
1
2
OH
and cytotoxic, as well as antiviral and antiparasitic activi-
8a R = H
8b R = OMe
Me
3
ties. Ancistrocladus tectorius (Lour.) Merr. (Ancistrocladace-
MeO
N
ae) is an evergreen woody climber, typical of a significant
region of the Southeast Asian rainforests. It is widely em-
ployed locally for roofing, making arrows and flavoring
food. This liana is also used in traditional medicine for
treating dysentery, malaria and kidney disease, as well as to
N
MeO
H
MeO
H
HO
OH
OH
1
0
11
Figure 1 Chemical structures of 6-O-methyl anciscochine (1), related
natural products 2–6, 10, and 11, and selected synthetic heterocycles
4
improve blood circulation.
7
–9
The constituents of A. tectorius have generated great in-
terest, and the plant has been phytochemically examined in
5
a number of studies. Fractionation of the extract of a bark
It has been noted that natural products carrying the 3-
hydroxymethylisoquinoline core are very scarce. This fea-
6a
sample gave 6-O-methylanciscochine (1), which features
an unusual 3-hydroxymethylene unit (Figure 1), along with
ture is present in glycoside 3 and its aglycon anciscochine
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
D. F. Vargas et al.
Paper
(
4), two natural products isolated from A. cochinchinensis,7a
as well as in penicisoquinoline (5), isolated from Penicillium
In line with our synthetic interests, and based on previ-
ous results, it was conjectured that the hydroxymethyl unit
could be obtained from a more oxidized moiety, through
functional group interconversion. On the other hand, the
heterocyclic ring was disconnected at the N–C3 level, after
assuming that it could be built from the resulting N-substi-
tuted 1-azatriene 12 by means of a thermally driven 6-
azaelectrocyclization reaction.
A couple of further disconnections on the cinnamate 12,
at the C=N level and on the alkenyl side chain, unveiled
three distinguishable units as suitable starting materials.
These included the commercially available acetophenone
core 13, in addition to a suitable ammonia derivative (14,
hydrazine, oxime), which should have a dual role, acting as
efficient activating group for the directed alkenylation and
possess a leaving group ability to aid cyclization and, final-
ly, an acrylate ester (15) as the required three-carbon atom
alkenylation agent.
7b
sp. PSU-F40.
The motif is also found in the odd antiparasitic hetero-
cycles ancistrobenomine A (6a) and 6-O-demethylancistro-
benomine A (6b), isolated from A. benomensis, and in the
antileukemic agent ancistrobenomine B (6c), as well as in
ancistrobenomine C (6c), isolated from a specimen of A. tec-
2a
8
torius collected in China.
Some 3-hydroxymethylisoquinolines such as 7 have also
been used as intermediates for the synthesis of complex
natural products or have been synthesized as bioactive
compounds. Others have been prepared to test new meth-
odologies (8a,b) or for interest in their structural proper-
9
10
11
12
ties (9a,b).
In recent years, transition-metal-catalyzed ortho-direct-
ed alkenylation through C–H activation has evolved into a
feasible atom-economic strategic alternative to efficiently
build C–C bonds en route to heterocycles. However, de-
spite many key advances, its application to the synthesis of
natural products remains less intensively explored, and its
association with processes in which the directing group
also reacts with the incoming olefin to provide a dual func-
tionalization, resulting in a value-added molecule, still has
relatively scarce precedents.
Modern methods that allow direct access to 3-substitut-
ed isoquinolines are scarce. We have been engaged in the
total synthesis of unique natural products and their ana-
logues. Among others, we have synthesized several iso-
quinoline-derived natural products and their analogues,
carrying hydroxymethyl moieties, such as calycotomine
13
The projected synthesis began with the preparation of
potential substrates for the C–H activation reaction. Based
on our recent work on the synthesis of 3-methylisoquino-
lines by 6-electrocyclization of ortho-propenyl arylhydra-
zones,2 ketone 13 was submitted to hydrazonation (Table
1) with hydrazine and two N,N-disubstituted derivatives
(entries 1–3) in refluxing EtOH for 24 hours.
14
1a
15
Thus, the reaction with Me NNH was best performed
2
2
16
under AcOH promotion to afford 16b in 63% yield (72%
based on recovered starting material, entry 2), whereas a
slight excess of NaOAc was added in the case of the hydro-
17
chlorides, to free the corresponding bases. Under these con-
ditions, compounds 16a2
1b,c
and 16c were obtained in 74%
1
8a–c
(
(
10)
and the -adrenergic receptor inhibitor MY336-A
In addition, we have recently reported synthetic
and 98% yield, respectively (entries 1 and 3).
1
8d–f
11).
approaches toward the cytotoxic isoquinoline 2, one of
them relying on C–H activation.
Table 1 Synthesis of Potential Substrates for the C–H Activation Reac-
tion
19
Considering our interest in isoquinoline derivatives,20
here we report a directed alkenylation/cyclization-based
approach toward the first total synthesis of heterocycle 1,
which entails a tandem C–C/C–N formation process.
At the outset of this investigation, we performed a
retrosynthetic analysis of 1 (Scheme 1).
5
MeO
MeO
4
6
EtOH
O
N
Conditions
3
1
2
R
MeO
Me
MeO
Me
13
16
EntryReagent
Additive (equiv)
Temp Time Product Yield
Functional group
interconversion
MeO
C–H Activation/
Directed alkenylation
MeO
(%)a
(
°C)
(h)
(R)
CO2R1
XR
Carbonyl
derivatization
OH
1
2
3
4
5
H
2
NNH
2
·HCl
NaOAc (2.5)
reflux 24
reflux 24
reflux 24
16a
(NH )
2
74
N
N
(
2.0)
6
π-Azaelectrocyclization
63b
Me
2
NNH
2
(2.5) AcOH (1.5)
16b
(NMe )
2
MeO
Me
MeO
Me
1
12
Ph
2
NNH
2
·HCl
NaOAc (2.5)
NaOAc (1.5)
16c
(NPh
98
(
2.0)
2
)
MeO
H
XR
N
CO2R1
NH
(1.5)
2
OH·HCl
50
50
1.0 16d (OH) 98
+
+
O
3 2
CeCl ·7H O (0.05)
H
H
NH OMe·HCl
2
NaOAc (1.5)
0.5 16e
(OMe)
94
15
14 X = O, N
MeO
Me
(
1.5)
CeCl ·7H O (0.05)
3
2
1
3
a
Most of the compounds were obtained as mixtures of E and Z isomers.
The yield was 72%, based on recovered starting material.
Scheme 1 Retrosynthetic analysis of the target natural product 1
b
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

C
Synthesis
D. F. Vargas et al.
Paper
On the other hand, considering their excellent directing
(DCE), and 2 equivalents of silver salts (Ag CO , AgOAc) as
2
3
22a
ability for C–H bond activation, the oximes 16d
and
external oxidant, in the presence of 3 equivalents of pivalic
22b,c
24b,c
1
6e
were also prepared, by reaction of 13 with hydrox-
acid to facilitate C–H activation.
ylamine and methoxylamine hydrochlorides (Table 1, en-
tries 4 and 5), employing our recently developed protocol,
with stoichiometric amounts of NaOAc to free the corre-
sponding bases and 0.05 equivalents CeCl ·7H O as promot-
N-Substituted hydrazones are seldom utilized in C–H
bond activation reactions to construct nitrogen-containing
heterocycles;25 therefore, it was not surprising when the
initial trials, made with the hydrazones 16a–c, gave dis-
couraging results. None of the hydrazones gave any detect-
able product (Table 2, entry 2) and only decomposition of
the unstable starting materials was observed.
3
2
22d
er.
These transformations were performed at 50 °C and
afforded the corresponding products in a short time (30–60
min) in 94–98% yield.
Interestingly, application of the cerium(III)-based proto-
col to the preparation of the hydrazones proved to be an
unsuitable alternative, since 16a–c were obtained in 20%,
24c
Furthermore, use of the more reactive acrolein as a
three-carbon atom synthon in place of methyl acrylate, also
met with failure and only starting material (50%) was re-
covered. Analogously, the reactions performed in the pres-
ence of 2 equivalents of Ag CO as source of silver and oxi-
15%, and 58% yield, respectively. On the other hand, NOE
experiments on the hydrazones revealed signal enhance-
ment between the protons of the methyl (16b) and o-phe-
nyl (16c) substituents and H-6, suggesting a Z-configura-
2
3
dant, under aerobic conditions, resulted in complete de-
composition of the unstable hydrazones and no trace of the
cyclized product could be detected (Table 2, entry 3).
Quite surprisingly, however, when the transformation
was executed with the oxime 16d in MeCN using Ag CO as
23
tion for their major stereoisomers. In contrast, the preva-
19b
lent isomer of 16e exhibited the E-configuration.
With the hydrazones and oximes in hand, the stage was
set to explore the direct alkenylation reaction. Despite a
2
3
silver source, 52% yield of the cyclized product 17 could be
obtained, after heating the reaction at 75 °C for 16 h (Table
2, entry 4),26 without observing any alkenylation product
19. Notably, less functionalized isoquinolines analogous to
17 were prepared through more circuitous ways or by em-
ploying less easily available starting materials.27
24a
hopeful literature precedent, it was confirmed that the
reaction of methoxime 16e with methyl acrylate (15a) un-
der [RuCl (p-cymene)] catalysis was unsuccessful (Table
2
2
2); no trace of 19 (Scheme 3) nor 17 could be detected and
only starting material (26%) along with 35% of ketone 13
were recovered (entry 1).
The source of silver proved to be important; when the
reaction was performed in the presence of AgOAc instead of
Ag CO , only 23% yield of 17 could be obtained (Table 2, en-
Therefore, the next transformations were executed un-
der promotion of 2.5 mol% (Cp*RhCl ) and a source of sil-
2
2
2
3
ver to activate the catalyst, in the presence of 3 equivalents
of 15a. The reactions were performed in 1,2-dichloroethane
try 5). It was also supposed that the type of oxime may have
an impact on the performance of the transformation.
Table 2 Optimization of the Directed Alkenylation/Cyclization Conditionsa
CO2Me
MeO
MeO
CO2Me
15a (3 equiv)
N
N
(
(
Cp*RhCl2)2
2.5 mol%)
Conditions
R
MeO
Me
MeO
Me
17
16a–d, 18
Entry
Starting Mat. (R)
[Ag] (equiv)
Additive/Oxidant (equiv)
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
16e (OMe)
16a–c (NR)d
16a-c (NR)d
16d (OH)
16d (OH)
18 (OPiv)
AgSbF
AgSbF
6
6
(0.2)
AcOH (2.5)/Cu(OAc)
2
(2)
DCE
100
100
75
20
20
16
16
16
20
20
–c
(0.15)
(2)
PivOH (3)/AgOAc (2)
DCE
–
Ag
Ag
2
CO
3
3
PivOH (2)/air (O
PivOH (2)
2
)
MeCN
MeCN
MeCN
DCE
–
2
CO
(2)
75
52
23
73
32e
AgOAc (2)
PivOH (2)
75
AgSbF
AgSbF
6
6
(0.15)
(0.15)
PivOH (3)/AgOAc (2)
PhCO H (0.5)/AgOAc (2)
90
7
18 (OPiv)
2
DCE
90
a
The experiments were carried out at a final concentration of 0.2 mmol of oxime in 1 mL of solvent.
Isolated yield after flash column chromatography.
The reaction was performed in the presence of [RuCl (p-cymene)] ; compounds 16e (26%) and 13 (35%) were recovered.
2 2
b
c
d
e
NR = NH
2 2 2
, NPh and NMe .
Compound 13 (11%) was also isolated.
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

D
Synthesis
D. F. Vargas et al.
Paper
Accordingly, 16d was exposed to pivalic anhydride in
MeO
2
CO Me
[Cp*RhCl2]2
CH Cl at room temperature for 16 h, affording the oxime
2
2
N
pivalate 18 in 83% yield (Scheme 2).
MeO
Me
2Cp*RhCl2
17
PivOH
5
MeO
MeO
4
6
1
MeO
2
2 Ag
Ag0
a
+
O
3
N
2
AgSbF6
N
OR
2
OPiv
MeO
CO2Me
MeO
Me
MeO
Me
PivO–
2 AgCl
MeO
Me
.
N+
13
16d R = H
H
18
b
1
8
R = Piv
c
MeO
Me
E
[Cp*RhIIIPiv]
Formation
of rhodacycle
MeO
PivO–
Cp*
MeO
MeO
CO2Me
Product
release
OH
PivOH
+
Rh
O
O
d
N
N
tBu
MeO
CO2Me
OPiv
N
MeO
Me
MeO
Me
MeO
CO2Me
Cp*
N
MeO
Me
A
1
17
N
+
Rh
MeO
Me
Scheme 2 Reagents and conditions: (a) HONH ·HCl, CeCl ·7H O (5
III
2
3
2
Alkene
insertion
MeO2C
5a
1
9
mol%), NaOAc, EtOH, 50 °C, 1 h (98%); (b) Piv O, CH Cl , r.t., 16 h (83%);
MeO
Me
2
2
2
O
O
1
(
c) (Cp*RhCl ) (2.5 mol%), AgSbF (15 mol%), PivOH (3 equiv), AgOAc
D
2
2
6
tBu
CO2Me
Cp*
(
2 equiv), DCE, 90 °C, 20 h (73%); (d) NaBH , CaCl , THF–EtOH (1:1, v/v),
4
2
MeO
0
°C to r.t., 16 h (72%).
Internal
Rh oxidation
N–O bond
cleavage
+
Rh
O
N
CO2Me
O
O
MeO
Rewardingly, when 18 was dissolved in DCE and sub-
mitted to reaction in the presence of pivalic acid, 15 mol%
I
MeO Me
tBu
Rh Cp*
N+
B
O
tBu
AgSbF as source of silver and AgOAc as oxidant, the expect-
6
MeO
Me
C–N bond formation
ed isoquinoline ester 17 was afforded in 73% yield after
heating for 20 h at 90 °C (Table 2, entry 6).
C
Scheme 3 Proposed mechanism for the rhodium-catalyzed tandem
The superior performance of the oxime pivalate 18 with
regards to its precursor, the oxime 16d, could presumably
be due to a series of improvements in the reaction condi-
tions, including the use of the more powerful AgSbF6 to
generate the actual catalyst, the better leaving group ability
of the pivalate and the possibility, offered by the lone pair of
the carbonyl oxygen of the ester, to engage in a stabilizing
C–H activation/alkenylation/annulation process
mediate and that coordination saturation of the rhodacycle
also serves to inhibit protonolysis of the Rh–Calkyl bond.
29
Although different alternatives can be considered, one
plausible scenario is that the metallacycle may subsequent-
ly rearrange, undergoing C–N bond formation and leading
to a coordinated Rh(I) species (C) able to undergo internal
oxidation with the oxime pivalate moiety as built-in oxi-
dant to afford the Rh(III)-coordinated dihydroisoquinoline
intermediate D.26
28
interaction with the rhodium catalyst.
Notably, the addition of pivalic acid also seemed critical
for attaining good yields of product, since performing the
reaction with benzoic acid gave only 32% yield of 17 (Table
2, entry 7).
The fine details of the mechanism of the reaction are
unknown; however, a mechanistic picture can be drawn
Scheme 3), on the basis of the literature and observations
Decomposition of D may yield a catalytically active
Rh(III) species and release the 3,4-dihydroisoquinoline in-
termediate E, thus accomplishing a full catalytic cycle. It has
been suggested that the presence of the acid additive facili-
tates the rhodium oxidation process.2 The latter interme-
(
made during the present work. The first steps involve acti-
vation of the rhodium reagent by reaction with the silver
source and stabilization by coordination with PivOH.2 The
resulting complex may further undergo ligand exchange
5d
2c
diate may then undergo oxidation under the assistance of
the silver(I) additive,2
4c–e
resulting in the isoquinoline 17.
29
with the oxime pivalate 18, and the oxime may suffer or-
tho-activation, leading to a directed C–H bond cleavage and
cyclorhodation, to afford the five-membered rhodacycle in-
termediate A. The latter can then coordinate with the acry-
late ester 15a and force a regioselective migratory insertion
of the activated alkene into the Rh–Caryl bond to give the
seven-membered rhodacyclic iminium cation B. It has been
suggested that the pivalate moiety may stabilize this inter-
Interestingly, some mechanistic proposals suggest that the
external oxidant may alternatively be involved in regenera-
tion of the rhodium(III) catalytic species.30
In this proposal, no intermediate cinnamate (19) is
formed, ruling out the possibility of a 6-electrocycliza-
tion/pivalate elimination toward the cyclized product 17.
This pathway has been proposed to take place in similar
transformations;3
1a–c
however, here it requires the dearo-
matization of the isocyclic ring, which could significantly
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

E
Synthesis
D. F. Vargas et al.
Paper
raise the kinetic barrier to electrocyclization, making it un-
likely that such a reaction could take place under the rather
mild conditions employed in this process.31d
ferred via cannula to dry Young ampoules and stored over molecular
sieves. All other commercial reagents were used as received, without
further purification.
Finally, the ester 17 was reduced with the NaBH /CaCl
The reactions were monitored by TLC, run on Kieselgel 60 GF254
4
2
32
plates, using hexane–EtOAc solvent mixtures of different polarities.
system in an EtOH–H O medium to afford isoquinoline 1
2
The chromatographic spots were detected by irradiation of the plates
with short wavelength UV light (254 nm), followed by exposure to io-
dine vapor or by spraying with ethanolic p-anisaldehyde/sulfuric acid
or Dragendorff reagents. Careful heating of the sprayed plates was
employed to improve the selectivity. All new compounds gave single
spots in different solvent systems. The flash column chromatography
systems were developed with slurry-packed silica gel 60 H (particle
size 63–200 m). The elution was performed under positive pressure,
using gradient of solvent (hexane–EtOAc mixtures) polarity tech-
niques.
in 72% yield. The NMR spectral data of the synthetic materi-
al was in full agreement with those recorded for the natural
product. However, additional experiments enabled an un-
6a
equivocal assignment of the signals. Irradiation at  =
6
=
.57 ppm caused NOE enhancement of the resonances at 
7.24 ppm and at  = 3.89 ppm, confirming their attribu-
tion to H-4, H-5, and OMe-6, respectively. In turn, the
HMBC experiment exhibited a cross-peak between 6-OCH3
and the signal at  = 161.4 ppm, which was attributed to C-
C
The structures of the products were determined by means of a combi-
nation of spectroscopic methods, which included NMR (HSQC and
6
. The cross-peak between the signals at  = 3.91 ppm (8-
H
OCH ) and  = 159.6 ppm (C-8) confirmed this assignment.
3
C
HMBC), IR, and HRMS. The NMR spectra were acquired in CDCl with
3
In conclusion, we have reported an expedient first total
synthesis of 6-O-methylanciscochine, an alkaloid isolated
from the South Asian rainforest liana Ancistrocladus tectori-
us, which includes a 3-hydroxymethylisoquinoline motif
that is found in a handful of natural products and various
synthetic bioactive compounds. The synthetic sequence in-
volved only four steps from the economic and easily avail-
able 2,4-dimethoxy acetophenone, and took place in 43%
overall yield.
The synthesis comprised a Ce(III)-mediated catalytic ox-
imation of the starting ketone, followed by oxime activation
through pivaloylation. Next, a one-pot complex pivaloxime-
enabled key step installed the three-carbon chain and deliv-
ered the cyclized product. This process involved a rhodium-
catalyzed directed C–H activation/alkenylation stage, fol-
lowed by a C–N bond-forming reaction with concomitant in
situ Ag(I)-promoted aromatization. The resulting iso-
quinoline-3-carboxylate ester was finally reduced to its
Bruker Avance II 300 and Bruker Avance III HD 400 spectrometers.
Chemical shift data are reported in ppm downfield from TMS as inter-
13
nal standard (for CDCl
,
C  = 77.16 ppm). Signal characteristics and
3
splitting patterns are reported as: s (singlet), d (doublet), t (triplet)
and br (broad signal). Coupling constants (J) and w1/2 values are given
in Hertz. An asterisk is used to indicate exchangeable assignments.
The melting points were measured with an Ernst Leitz Wetzlar model
350 hot-stage microscope and are reported uncorrected. The IR spec-
tra were recorded with a Shimadzu Prestige 21 spectrophotometer, as
thin films held between NaCl disks or as solid dispersions in KBr. The
high-resolution mass spectra were obtained from UMyMFOR (Buenos
Aires, Argentina) with a Bruker MicroTOF-Q II equipment. Detection
of the ions was performed in the ESI+ (electrospray ionization, posi-
tive ion) mode.
1
-(2,4-Dimethoxyphenyl)ethan-1-one Hydrazone (16a)21b,21c
A mixture of 2,4-dimethoxyacetophenone (13; 100 mg, 0.55 mmol),
NaOAc (99 mg, 1.21 mmol), H NNH ·HCl (75 mg, 1.10 mmol) and acti-
2
2
vated powdered 3Å MS (30 mg) in absolute EtOH (1.5 mL) was heated
at reflux for 24 h. The solvent was then evaporated and the residue
was purified by column chromatography, to afford the hydrazone 16a
as an E/Z mixture of isomers.
3-hydroxymethyl congener.
In this approach, the olefination/annulation process em-
ployed a combination of external and internal oxidants,
with the oxime pivalate acting as a directing group and in-
ternal oxidant. The whole process, which was executed
without the assistance of protecting groups, paves the way
to the synthesis of more complex 3-hydroxymethylisoquin-
olines.
Yield: 79 mg (74%); yellow solid; mp 120–122 °C; obtained as an
16:84 (E/Z) mixture of isomers ( H NMR).
1
IR (KBr): 3660–3180, 3005, 2837, 1616, 1518, 1458, 1317, 1278,
–1
1117, 1030, 943, 818, 635 cm
.
1
H NMR (300 MHz, CDCl ):  (major isomer) = 7.51 (d, J = 8.4 Hz, 1 H,
3
H-6), 6.53 (d, J = 2.1 Hz, 1 H, H-3), 6.50 (dd, J = 2.1, 8.4 Hz, 1 H, H-5),
3.83 (s, 6 H, 2 × OMe), 2.20 (s, 3 H, Me).
13
C NMR (75 MHz, CDCl ):  = 161.5 (C=N), 158.9 (C-4), 158.4 (C-2),
3
All the reactions were carried out under an inert atmosphere of dry
argon, employing oven-dried glassware and freshly distilled anhy-
drous solvents. Anhydrous EtOH was prepared by treatment of the
analytical reagent with clean magnesium turnings and a crystal of io-
dine, followed by reflux until complete consumption of the metal was
achieved. The solvent was distilled from the so-formed magnesium
ethoxide. Anhydrous DCE and CH Cl were prepared by refluxing the
130.5 (C-6), 127.8 (C-1), 104.5 (C-5), 98.9 (C-3), 55.49 (OMe), 55.45
(OMe), 18.8 (Me).
1-(2,4-Dimethoxyphenyl)ethan-1-one N,N-Dimethylhydrazone
(16b)
A mixture of 2,4-dimethoxyacetophenone (13; 100 mg, 0.55 mmol),
AcOH (50 L, 0.82 mmol), Me NNH (100 L, 1.37 mmol) and activat-
2
2
2
2
corresponding PA solvent over P O for 4 h, followed by distillation.
2
5
ed powdered 3Å MS (30 mg) in absolute EtOH (1.5 mL) was heated at
reflux for 24 h. The solvent was then evaporated and the residue was
purified by column chromatography, to afford the hydrazone 16b as
an E/Z mixture of isomers.
Anhydrous MeCN was prepared by refluxing the solvent over CaH for
2
4
h, followed by distillation. All the anhydrous solvents were trans-
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

F
Synthesis
D. F. Vargas et al.
Paper
Yield: 77 mg (63%); yellow oil; obtained as an 14:86 (E/Z) mixture of
isomers ( H NMR).
(E)-1-(2,4-Dimethoxyphenyl)ethan-1-one O-Methyl Oxime (16e)22c
A mixture of 2,4-dimethoxyacetophenone (13; 300 mg, 1.66 mmol),
1
IR (film): 3680–3150, 2953, 2853, 1612, 1504, 1464, 1310, 1209,
NaOAc (203 mg, 2.47 mmol), CeCl
3 2
·7H O (32 mg, 0.086 mmol), and
–1
1159, 1034, 951, 833, 799 cm
.
MeONH ·HCl (209 mg, 2.50 mmol) in EtOH (13 mL) was heated at
2
1
50 °C for 30 min. The solvent was then evaporated and the residue
was purified by column chromatography to afford the oxime 16e as
an E/Z mixture of isomers.
H NMR (300 MHz, CDCl ):  (major isomer) = 7.27 (d, J = 8.1 Hz, 1 H,
3
H-6), 6.43–6.53 (m, 2 H, H-3 and H-5), 3.80 (s, 3 H, OMe), 3.79 (s, 3 H,
OMe), 2.57 (s, 6 H, NMe ), 2.28 (s, 3 H, Me).
2
1
3
Yield: 326 mg (94%); colorless oil; obtained as a 93:7 (E/Z) mixture of
isomers ( H NMR).
C NMR (75 MHz, CDCl ):  = 164.8 (C=N), 161.4 (C-4), 158.5 (C-2),
3
1
1
4
30.2 (C-6), 123.0 (C-1), 104.5 (C-5), 98.8 (C-3), 55.4 (2C, 2 × OMe),
7.1 (N(CH ) ), 47.0 (N(CH ) ), 18.8 (Me).
1H NMR (300 MHz, CDCl
):  (major isomer) = 7.22–7.25 (m, 1 H, H-
3
2
3 2
3
+
6), 6.44–6.48 (m, 2 H, H-3 and H-5), 3.95 (s, 3 H, NOMe), 3.81 (s, 3 H,
OMe-2), 3.80 (s, 3 H, OMe-4), 2.15 (s, 3 H, Me-2).
HRMS (ESI-TOF): m/z [M + H] calcd for C12H19N O : 223.1447; found:
2
2
223.1442.
13
C NMR (75 MHz, CDCl ):  = 161.7 (C-2), 158.7 (C-4), 156.5 (C-1),
3
1
30.3 (C-6), 120.1 (C-1), 104.4 (C-5), 99.0 (C-3), 61.7 (NOMe), 55.5
1
-(2,4-Dimethoxyphenyl)ethan-1-one N,N-Diphenylhydrazone
(OMe-2 and OMe-4), 16.1 (2-Me).
(16c)
A mixture of 2,4-dimethoxyacetophenone (13; 100 mg, 0.55 mmol),
(E)-1-(2,4-Dimethoxyphenyl)ethan-1-one O-Pivaloyl Oxime (18)
NaOAc (99 mg, 1.21 mmol), Ph NNH ·HCl (202 mg, 1.10 mmol) and
2
2
activated powdered 3Å MS (30 mg) in absolute EtOH (1.5 mL) was
heated at reflux for 24 h. The solvent was then removed under re-
duced pressure and the residue was purified by column chromatogra-
phy to afford the hydrazone 16c as an E/Z mixture of isomers.
Pivalic anhydride (110 L, 0.55 mmol) was added to a solution of aryl
ketone oxime 16d (100 mg, 0.5 mmol) in CH Cl (2 mL). The reaction
mixture was stirred for 16 h at r.t., then diluted with CH Cl (30 mL)
and washed with sat. NaHCO (10 mL). The organic layer was dried
2
2
2
2
3
over MgSO , filtered and concentrated under reduced pressure, and
the residue was purified by chromatography to afford 18.
4
Yield: 186 mg (98%); light-yellow solid; mp 79–81 °C; obtained as a
1
4:96 (E/Z) mixture of isomers ( H NMR).
Yield: 116 mg (83%); colorless oil.
IR (KBr): 3062, 2997, 2835, 1604, 1583, 1487, 1317, 1278, 1163, 1035,
–1
960, 819, 705 cm
.
IR (film): 2972, 2936, 1753, 1607, 1506, 1464, 1317, 1209, 1120,
–1
1
1030, 920, 872, 735 cm
1H NMR (300 MHz, CDCl
.
H NMR (300 MHz, CDCl ):  (major isomer) = 7.54 (d, J = 8.4 Hz, 1 H,
3
H-6), 7.30 (t, J = 7.2 Hz, 4 H, 2× H-3′ and 2 × H-5′), 7.15 (dd, J = 0.9,
3
):  = 7.38 (d, J = 8.6 Hz, 1 H, H-6), 6.47 (dd,
7
6
.2 Hz, 4 H, 2 × H-2′ and 2 × H-6′), 7.04 (t, J = 7.2 Hz, 2 H, 2 × H-4′),
.54 (dd, J = 2.4, 8.4 Hz, 1 H, H-5), 6.49 (dd, J = 2.4 Hz, 1 H, H-3), 3.84
J = 1.5, 8.6 Hz, 1 H, H-5), 6.46 (d, J = 1.5 Hz, 1 H, H-3), 3.82 (s, 3 H,
OMe), 3.81 (s, 3 H, OMe), 2.30 (s, 3 H, Me), 1.33 (s, 9 H, 3× Me).
(
1
s, 3 H, OMe), 3.82 (s, 3 H, OMe), 2.08 (s, 3 H, Me).
13
C NMR (75 MHz, CDCl ):  = 175.7 (CO ), 162.4 (C=N), 158.9 (C-4),
3
2
3
C NMR (75 MHz, CDCl ):  = 168.5 (C=N), 161.7 (C-4), 158.8 (C-2),
158.7 (C-2), 131.0 (C-6), 118.2 (C-1), 104.3 (C-5), 98.8 (C-3), 55.5 (2C,
2 × OMe), 38.8 (CMe ), 27.4 (3C, C(CH ), 17.4 (Me).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H21NNaO : 302.1363;
3
1
5
2
48.4 (2C, 2 × PhC-1′), 130.4 (C-6), 129.0 (4C, 2 × PhC-3′ and 2 × PhC-
′), 122.7 (2C, 2 × PhC-4′), 122.4 (C-1), 121.3 (4C, 2 × PhC-2′and
× PhC-6′), 104.6 (C-5), 98.9 (C-3), 55.53 (OMe), 55.48 (OMe), 21.2
3
)
3 3
4
found: 302.1363.
(Me).
+
Synthesis of (Cp*RhCl2)233
HRMS (ESI-TOF): m/z [M + H] calcd for C22H23N O : 347.1760; found:
2
2
347.1765.
A stirred mixture of RhCl ·3H O (146 mg, 0.55 mmol) and pentameth-
3
2
ylcyclopentadiene (91 L, 0.57 mmol) in anhydrous MeOH (4 mL)
were heated under reflux for 48 h under a strict atmosphere of argon.
After cooling to r.t., the precipitate was separated and the brown fil-
trate was concentrated to ca. 1 mL by passage of a dry argon flow, re-
sulting in the precipitation of a solid. The latter was separated, com-
(
E)-1-(2,4-Dimethoxyphenyl)ethan-1-one Oxime (16d)22a,b
A mixture of 2,4-dimethoxyacetophenone (13; 200 mg, 1.10 mmol),
NaOAc (135 mg, 1.65 mmol), CeCl ·7H O (20 mg, 0.055 mmol), and
HONH ·HCl (114 mg, 1.65 mmol) in absolute EtOH (11 mL) was heat-
3
2
2
ed at 50 °C for 1 h. The solvent was then removed under reduced pres-
sure and the residue was purified by column chromatography to af-
ford (E)-16d.
bined with the first crop and washed with anhydrous Et
the solid was dried in vacuo.
2
O. Finally,
Yield: 103 mg (60%); orange-red solid.
Yield: 210 mg (98%); white solid; mp 81–83 °C.
1
H NMR (300 MHz, CDCl ):  = 1.62 (s, 15 H, CpMe).
3
IR (KBr): 3600–2820, 2978, 2837, 1630, 1514, 1452, 1323, 1277,
13
C NMR (75 MHz, CDCl ):  = 94.2 (d, J
= 9.5 Hz, CpC), 9.5 (CpMe).
C–Rh
3
–1
1163, 1020, 925, 817, 783, 631 cm .
1
H NMR (300 MHz, CDCl ):  = 8.12 (br s, w1/2 = 80 Hz, 1 H, OH), 7.23
1-Methyl 6,8-Dimethoxy-1-methylisoquinoline-3-carboxylate (17)
3
(
d, J = 9.0 Hz, 1 H, H-6), 6.48 (d, J = 2.1 Hz, 1 H, H-3), 6.47 (dd, J = 2.1
Under an argon atmosphere, methyl acrylate (15a; 55 L, 0.60 mmol)
and PivOH (61 mg, 0.60 mmol) were added to a stirred suspension of
the oxime pivalate 18 (56 mg, 0.20 mmol) and AgOAc (66 mg, 0.40
mmol) in 1,2-dichloroethane (1 mL). The system was sequentially
treated with (Cp*RhCl ) (2.5 mol%) and AgSbF (15 mol%) and the re-
and 9.0 Hz, 1 H, H-5), 3.82 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 2.21 (s,
3
H, Me).
1
3
C NMR (75 MHz, CDCl ):  = 161.5 (C-4), 158.6 (C-2), 157.1 (C=N),
3
1
30.1 (C-6), 119.8 (C-1), 104.3 (C-5), 98.9 (C-3), 55.4 (2 × OMe), 15.2
2
2
6
(Me).
sulting mixture was stirred in an oil bath, at 90 °C for 20 h. The reac-
tion mixture was then cooled to r.t., diluted with EtOAc (50 mL) and
©
2019. Thieme. All rights reserved. Synthesis 2019, 51, A–H

G
Synthesis
D. F. Vargas et al.
Paper
washed with saturated NaHCO solution (25 mL). The organic phase
was dried over MgSO4 and concentrated under the reduce pressure.
The residue was submitted to column chromatography to afford 17.
quinoline Alkaloids, In The Alkaloids, Vol. 46; Cordell, G. A., Ed.;
Academic Press: New York, 1995, 127. (d) Bringmann, G.;
Günther, C.; Ochse, M.; Schupp, O.; Tasler, S. Biaryls in Nature, In
Progress in the Chemistry of Organic Natural Products, Vol. 82;
Herz, W.; Falk, H.; Kirby, G. W.; Moore, R. E., Ed.; Springer:
Vienna, 2001, 111.
3
Yield: 38 mg (73%); light-brown solid; mp 185–187 °C.
IR (KBr): 2945, 2849, 1717, 1616, 1570, 1452, 1396, 1237, 1145, 1042,
–1
9
84, 843, 797, 679 cm .
(
2) For recent reports, see: (a) Fayez, S.; Feineis, D.; Assi, L. A.; Seo,
E.-J.; Efferth, T.; Bringmann, G. RSC Adv. 2019, 9, 15738.
(b) Awale, S.; Dibwe, D. F.; Balachandran, C.; Fayez, S.; Feineis,
D.; Lombe, B. K.; Bringmann, G. J. Nat. Prod. 2018, 81, 2282.
(c) Tshitenge, D. T.; Feineis, D.; Mudogo, V.; Kaiser, M.; Brun, R.;
Seo, E.-J.; Efferth, T.; Bringmann, G. J. Nat. Prod. 2018, 81, 918.
1
H NMR (300 MHz, CDCl ):  = 8.24 (s, 1 H, H-4), 6.77 (d, J = 2.4 Hz,
3
1
H, C-5), 6.63 (d, J = 2.4 Hz, 1 H, C-7), 4.02 (s, 3 H, CO Me), 3.96 (s,
2
3
H, OMe-8), 3.94 (s, 3 H, OMe-6), 3.11 (s, 3 H, 1-Me).
13
C NMR (75 MHz, CDCl ):  = 166.6 (CO Me), 161.6 (C-6), 159.4 (C-8),
3
2
1
1
2
58.8 (C-1), 140.9 (C-3),* 140.0 (C-4a),* 121.9 (C-4), 117.9 (C-8a),
(
d) Kavatsurwa, S. M.; Lombe, B. K.; Feineis, D.; Dibwe, D. F.;
Maharaj, V.; Awale, S.; Bringmann, G. Fitoterapia 2018, 130, 6.
e) Seupel, R.; Hemberger, Y.; Feineis, D.; Xu, M.; Seo, E.-J.;
01.3 (C-7), 98.9 (C-5), 55.7 (OMe-8),* 55.6 (OMe-6),* 52.8 (CO Me),
2
8.8 (1-Me).
(
+
HRMS (ESI-TOF): m/z [M + H] calcd for C14H16NO : 262.1079; found:
4
Efferth, T.; Bringmann, G. Org. Biomol. Chem. 2018, 16, 1581.
3) For recent reports, see: (a) Mufusama, J.-P.; Feineis, D.; Mudogo,
V.; Kaiser, M.; Brun, R.; Bringmann, G. RSC Adv. 2019, 9, 12034.
262.1082.
(
6-O-Methyl Anciscochine (1)
(b) Fayez, S.; Feineis, D.; Assi, L. A.; Kaiser, M.; Brun, R.; Awale,
A suspension of anhydrous CaCl2 (39 mg, 0.35 mmol) in anhydrous
S.; Bringmann, G. Fitoterapia 2018, 131, 245. (c) Lombe, B. K.;
Feineis, D.; Mudogo, V.; Brun, R.; Awale, S.; Bringmann, G. RSC
Adv. 2018, 8, 5243. (d) Lombe, B. K.; Bruhn, T.; Feineis, D.;
Mudogo, V.; Brun, R.; Bringmann, G. Org. Lett. 2017, 19, 6740.
(e) McMahon, J. B.; Currens, M. J.; Gulakowski, R. J.; Buckheit, R.
W. Jr.; Lackman-Smith, C.; Hallock, Y. F.; Boyd, M. R. Antimicrob.
Agents Chemother. 1994, 39, 484.
THF (0.5 mL) was cooled to 0 °C and treated with NaBH (27 mg, 0.71
4
mmol). After stirring the mixture for 30 min, a solution of the ester 17
(31 mg, 0.12 mmol) in anhydrous EtOH (0.5 mL) was added and the
mixture was further stirred at r.t. for 16 h. The reaction was quenched
by careful addition of a chilled solution of saturated NH Cl (0.5 mL)
4
and then the system was treated with saturated Na CO solution (5
2
3
mL). The organic products were extracted with EtOAc (3 × 25 mL) and
(4) (a) Jiang, C.; Li, Z.-L.; Gong, P.; Kang, S.-L.; Liu, M.-S.; Pei, Y.-H.;
Jing, Y.-K.; Hua, H.-M. Fitoterapia 2013, 91, 305.
(b) Ruangrungsi, H.; Wongpanchi, V.; Tantivatana, P.; Cowe, H.
J.; Cox, P. J.; Funayama, S.; Cordell, G. A. J. Nat. Prod. 1985, 48,
529. (c) Taylor, C. M.; Gereau, R. E.; Walters, G. M. Ann. Missouri
Bot. Gard. 2005, 92, 360. (d) Ong, H. C.; Faezah, A. W.; Milow, P.
Stud. Ethno Med. 2012, 6, 11.
the organic layers were combined, dried over MgSO and concentrat-
4
ed under reduced pressure. Column chromatography of the residue
1
13
gave 1. The H and C NMR data of the substance are in agreement
6a
with reported data.
Yield: 20 mg (72%); off-white solid; mp 162–163 °C.
IR (KBr): 3145, 2924, 2850, 1625, 1568, 1456, 1381, 1261, 1116, 1041,
(
5) For recent results, see: (a) Bringmann, G.; Seupel, R.; Feineis, D.;
Zhang, G.; Xu, M.; Wu, J.; Kaiser, M.; Brun, R.; Seo, E.-J.; Efferth,
T. Fitoterapia 2016, 115, 1. (b) Bringmann, G.; Xu, M.; Seupel, R.;
Feineis, D.; Wu, J. Nat. Prod. Commun. 2016, 11, 971.
(c) Bringmann, G.; Zhang, G.; Ölschläger, T.; Stich, A.; Wu, J.;
Chatterjee, M.; Brun, R. Phytochemistry 2013, 91, 220. (d) Xu,
M.; Bruhn, T.; Hertlein, B.; Brun, R.; Stich, A.; Wu, J.; Bringmann,
G. Chem. Eur. J. 2010, 16, 4206.
9
45, 821, 719, 636 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 7.24 (s, 1 H, H-4), 6.57 (d, J = 2.3 Hz,
3
1
H, H-5), 6.45 (d, J = 2.3 Hz, 1 H, H-7), 4.77 (br s, 2 H, 3-CH OH), 3.91
2
(s, 3 H, OMe-8), 3.89 (s, 3 H, OMe-6), 3.78 (br s, w1/2 = 99 Hz, 1 H, OH),
3.00 (s, 3 H, Me-1).
13
C NMR (100 MHz, CDCl ):  = 161.4 (C-6), 159.6 (C-8), 157.7 (C-1),
3
151.8 (C-3), 141.0 (C-4a), 115.9 (C-8a), 114.5 (C-4), 99.0 (C-7), 97.6
(
C-5), 64.4 (3-CH OH), 55.6 (OMe), 55.5 (OMe), 28.2 (1-Me).
(6) (a) Montagnac, A.; Hadi, A. H. A.; Remy, F.; Païs, M. Phytochemis-
try 1995, 39, 701. (b) Rizzacaza, M. A.; Sargent, M. V.; Skelton, B.
W.; White, A. H. Aust. J. Chem. 1990, 43, 79.
2
(
7) (a) Lien, L. Q.; Linh, T. M.; Giang, V. H.; Mai, N. C.; Nhiem, N. X.;
Tai, B. H.; Cuc, N. T.; Anh, H. L. T.; Ban, N. K.; Minh, C. V.; Kiem, P.
V. Bioorg. Med. Chem. Lett. 2016, 26, 3913. (b) Trisuwan, K.;
Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit, S.;
Preedanon, S.; Sakayaroj, J. Tetrahedron 2010, 66, 4484.
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). D.F.V. thanks CONICET for his
(
8) (a) Bringmann, G.; Seupel, R.; Feineis, D.; Xu, M.; Zhang, G.;
Kaiser, M.; Brun, R.; Seo, E.-J.; Efferth, T. Fitoterapia 2017, 121,
Doctoral fellowship.
F
o
n
d
o
p
ara la I
n
v
esti
g
a
c
i
ó
n
C
i
e
ntífi
c
a
y
T
e
c
n
o
l
ó
g
i
c
a
(P
I
C
T
2
0
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6)
76. (b) Salem, M. M.; Werbovetz, K. A. Curr. Med. Chem. 2006, 13,
Supporting Information
2571. (c) Bringmann, G.; Dreyer, M.; Rischer, H.; Wolf, K.; Hadi,
H. A.; Brun, R.; Meimberg, H.; Heubl, G. J. Nat. Prod. 2004, 67,
2058.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690701.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
(9) (a) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.;
Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C.
D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.;
Grünanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.; Stoltz, B.
M. Science 2019, 363, 270. (b) Clive, D. L. J.; Tao, Y.; Khodabocus,
A.; Wu, Y.-J.; Angoh, A. G.; Bennett, S. M.; Boddy, C. N.;
Bordeleau, L.; Kellner, D.; Kleiner, G.; Middleton, D. S.; Nichols,
References
(
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