A versatile approach to 1-oxo-, 1-oxo-3,4-dihydro- and 1,3,4-trioxo isoquinoline alkaloids and first total synthesis of the dimeric 1-oxoisoquinoline alkaloids berbanine and berbidine

Article abstract of DOI:10.1016/j.tet.2020.131150

We have worked out a very short approach to 1-oxoisoquinoline alkaloids starting from readily available 2-bromobenzamides utilizing a 2-ethoxyvinylboronate as a C₂ building block for introduction of the C-3,C-4 unit of the isoquinoline core. TF

Full text of DOI:10.1016/j.tet.2020.131150

Tetrahedron 76 (2020) 131150
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A versatile approach to 1-oxo-, 1-oxo-3,4-dihydro- and 1,3,4-trioxo
isoquinoline alkaloids and first total synthesis of the dimeric
1-oxoisoquinoline alkaloids berbanine and berbidine
Ramona Schütz, Sandra Schmidt, Franz Bracher*
Department of Pharmacy e Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We have worked out a very short approach to 1-oxoisoquinoline alkaloids starting from readily available
2-bromobenzamides utilizing a 2-ethoxyvinylboronate as a C2 building block for introduction of the C-
3,C-4 unit of the isoquinoline core. TFA-mediated cyclization of crude ortho-ethoxyvinyl benzamides
gave 1-oxoisoquinolines in one single operation. Further modifications of these compounds opened an
access to the other chemotypes. In total, 14 alkaloids from four chemotypes (five 1-oxoisoquinolines, six
1-oxo-3,4-dihydroisoquinolines, one 1,3,4-trioxoisoquinoline, and two dimeric isoquinoline alkaloids)
were obtained in this investigation. With this approach we improved the total syntheses of the mono-
meric oxoisoquinolines, and worked out the first total syntheses of the dimeric alkaloids berbanine and
berbidine.
Received 6 October 2019
Received in revised form
18 March 2020
Accepted 20 March 2020
Available online 6 April 2020
Keywords:
Alkaloids
Total synthesis
Isoquinolines
Suzuki cross-coupling
Cyclization
© 2020 Elsevier Ltd. All rights reserved.
Hydrogenation
1. Introduction
3,4-dihydro analogues (e.g., 2a-f), and even
a
1,3,4-
trioxoisoquinoline (3) has been isolated from Menispermum daur-
icum [6] (Fig. 1).
1-Oxoisoquinoline alkaloids are a small class of natural products
from plants from different families (Berberidaceae, Ranunculaceae,
Menispermaceae, Papaveraceae), and most of these small mole-
cules are found together with larger isoquinoline-type alkaloids
such as benzylisoquinolines, bisbenzylisoquinolines, proto-
berberines and others [1], whereby very high similarities in the
substitution patterns of co-occurring alkaloids from the different
classes (typically methoxy and/or hydroxy or methylenedioxy
groups at the benzenoid ring) were observed. This raised the hy-
pothesis that the small 1-oxoisoquinolines arise from their larger
congeners by catabolic processes in the plant cells [2]. In vitro
degradation of bisbenzylisoquinoline alkaloids by photooxidation
[3,4] or chemical and enzymatic methods [5] has been shown to
provide products that are identical with some of the isolated 1-
oxoisoquinoline alkaloids. However, experimental verification of
this hypothesis on a cellular basis is still missing.
Further, two “dimeric” 1-oxoisoquinoline alkaloids, character-
ized by a diaryl ether connection have been identified from
different Berberis species. Berbidine (4) [2], is characterized by the
combination of a 1-oxo-3,4-dihydroisoquinoline moiety with a
1,2,3,4-tetrahydroisoquinoline unit, whereas berbanine (5) [7]
contains one fully aromatic isoquinoline unit. Most likely, also these
alkaloids arise from intracellular oxidative degradation of bisben-
zylisoquinoline alkaloids. As mentioned above, this hypothesis is
supported by the fact that bisbenzylisoquinolines bearing identical
substitution patterns were identified in the same plants [2,8].
Further other products of formal oxidative cleavage of bisbenzyli-
soquinoline alkaloids, albeit resulting from less extensive degra-
dation are known from nature, e.g., sindamine (6) [9] having the
same substitution pattern as berbidine (4) and the macrocyclic
bisbenzylisoquinoline alkaloid berbamine (7) [3] (Fig. 2).
The most frequently identified subclasses of this chemotype are
1-oxoisoquinolines like alkaloids 1b-f and their naturally occurring
Despite the reason for oxidative degradation of complex alka-
loids to the smaller 1-oxoisoquinolines (1e6) is obscure, these
compounds most likely are more than simply waste products of
plant cells. Some of these oxidized products show noteworthy
biological activities like vasorelaxant [10], cytotoxic [11] and hep-
atoprotective [12]. Further, diverse biological activities have been
* Corresponding author.
E-mail address: Franz.Bracher@cup.uni-muenchen.de (F. Bracher).
https://doi.org/10.1016/j.tet.2020.131150
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
R. Schütz et al. / Tetrahedron 76 (2020) 131150
Fig. 1. Three types of isoquinoline alkaloids: 1-oxoisoquinolines (1a-f), 1-oxo-3,4-dihydro analogues 2a-f, and even a 1,3,4-trioxoisoquinoline (3).
Fig. 2. “Dimeric” 1-oxoisoquinoline alkaloids berbidine (4) and berbanine (5), the
natural bisbenzylisoquinoline derivative sindamine (6), and putative natural precursor
berbamine (7).
Fig. 3. Published routes to 1-oxoisoquinoline alkaloids (see text).
Fully aromatic isoquinolines provide the corresponding 1-
oxoisoquinolines via N-methylation and oxidation with K3Fe(CN)6
[8]. Finally, a few publications report on the cyclization of benzoic
esters (or amides) bearing an acetaldehyde equivalent in ortho
position to give 1-oxoisoquinolines (Fig. 3, route D). The required
acetaldehyde equivalents were constructed either by oxidative
cleavage of a dimethylallyl residue [13], via TMS-acetylene residues
introduced by Sonogashira coupling [21] or via introduction of a 2-
ethoxyvinyl residue into an ortho-brominated N-tert-butylbenza-
mide using trans-2-ethoxyvinylboronic acid pinacol ester (9, see
Scheme 1) under Suzuki conditions [22]. Upon heating the obtained
Suzuki product with TFA under microwave irradiation, cyclization
and cleavage of the N-tert-butyl residue takes place giving N-
unsubstituted 1-oxoisoquinolines. Related procedures giving 1-
published for synthetic 1-oxoisoquinolines, as summarized in
Refs. [13,14]. But in many reported investigations, only a limited
number of compounds has been tested on the same target, most
likely due to limited availability of diverse substance libraries of 1-
oxoisoquinolines.
Hence, effective and flexible synthetic approaches for the
diverse subtypes of 1-oxoisoquinoline alkaloids are still strongly
demanded.
Previous approaches to the 1-oxoisoquinoline alkaloids of type
1e3 involved Bischler-Napieralski-type cyclization of phenylethyl-
amine derivatives like ethyl carbamates or isocyanates (Fig. 3,
routes A and B) with acidic reagents (polyphosphoric acid [15],
POCl3 [16,17], triflic anhydride/DMAP [18]) and cyclization of N-
formyl derivatives and subsequent N-methylation/oxidation of the
resulting 3,4-dihydroisoquinolines [8,19]. However, regioisomeric
products can be formed in these cyclizations. Alternatively, poorly
accessible ring-substituted homophthalic acids can be condensed
with amines to give 1,3-dioxoisoquinolines and further be con-
verted into 1-oxoisoquinolines by controlled reduction (Fig. 3, route
C) [14]. An alternative approach starting from homophthalic acids
includes Vilsmeier formylation and decarboxylation steps [20].
oxo-3,4-dihydroisoquinolines
through
ortho-ethenyl
in-
termediates (obtained by Heck olefination with gaseous ethylene
[23] or Rh-catalyzed direct vinylation using toxic ethenyl tributyl-
stannane [24]) require an additional Pd-catalyzed step for ring
closure.
Based on Toure’s approach [22] we present here an advanced
protocol for the synthesis of 1-oxo- and 1-oxo-3,4-
dihydroisoquinoline alkaloids using trans-2-ethoxyvinylboronic

R. Schütz et al. / Tetrahedron 76 (2020) 131150
3
Scheme 2. Synthesis of alkaloids berbanine (5) and berbidine (4).
substituted benzaldehyde 11 (Scheme 2). To access the isoquinoline
moiety in berbanine (5) a Pomeranz-Fritsch reaction should be
conducted with the intermediate 12. Subsequent N-methylation of
berbanine (5) and reduction of the resulting isoquinolinium should
provide berbidine (4).
Scheme 1. a) Synthesis of 1-oxoisoquinolines 1a-f and subsequent catalytic hydro-
genation to give 3,4-dihydro-1-oxoisoquinoline alkaloids 2a-f (for definition of the
residues R1-R4, see Fig. 1). b) Synthesis of 1,3,4-trioxoisoquinoline alkaloid 3.
2. Results and discussion
The required ortho-brominated primary and N-methyl-
benzamides, except commercially available 8f, were obtained in
yields mostly higher than 90% under standard conditions [38] from
commercially available ring-substituted bromobenzoic acids via
activation with thionyl chloride, followed by amidation with either
aqueous ammonia to give primary amides 8a/8c or methylamine to
give the corresponding N-methyl benzamides 8b/8d/8e. Construc-
tion of the fused pyridone ring was accomplished in a convenient
two-step procedure. First, Suzuki-type cross-coupling with 2-
ethoxyvinylboronate 9 under Pd catalysis [28] gave clean conver-
sion (TLC control) into the expected ethoxyvinyl derivatives 10a-f.
The crude reaction mixture was then treated with excess TFA to
achieve cyclization to 1-oxoisoquinoline 1a (most likely not a nat-
ural product) and the alkaloids 1b [1], N-demethyldoryphornine
(1c)[6], doryphornine (1d), thalactamine (1e), and the unnamed
alkaloid 1f [1] in overall yields ranging from 68 to 92%. Noteworthy,
this protocol is compatible with unprotected phenolic groups (see
1c and 1d). To the best of our knowledge, this represents the
hitherto shortest synthetic approach to N-substituted 1-
oxoisoquinoline alkaloids.
Next we intended to extend this methodology to the synthesis
of the corresponding 3,4-dihydro analogues 2a-f by subsequent
reduction of the C-3,C-4 double bonds of the 1-oxoisoquinolines
1a-f, preferably in a single operation along with the cyclization
step. For this purpose, reduction with triethylsilane-TFA appeared
most promising and straightforward, since TFA was already used as
an acid for the preceding cyclization reaction. We investigated the
feasibility of this approach with 1b, but unfortunately, this reduc-
tion could neither be achieved by treating crude intermediate enol
ether 10b with a TFA-triethylsilane mixture under various condi-
tions, nor could pure 1-oxoisoquinoline 1b be converted into its
3,4-dihydro derivative under triethylsilane-TFA treatment at
ambient or elevated temperatures. Consequently, an alternative
reduction protocol had to be applied in order to obtain the 1-oxo-
acid pinacol ester (9) as a versatile C2 building block for the intro-
duction of the C-3,C-4 unit of the target compounds. This building
block has meanwhile found considerable attention in the synthesis
of condensed heteroaromatic ring systems, e.g. indoles [25], pyrido
[3,4-d]pyrimidines [26] and naphthyridines [27], and has consid-
erable advantages over the alternative stannane-based building
block [28,29]. In contrast to the protocol of Toure et al. [22], which
provides in the first instance N-unsubstituted 1-oxoisoquinolines
after acid catalyzed cyclization, we intended to provide an easy
introduction of N-alkyl residues at an early stage of the synthesis,
since most of the 1-oxoisoquinoline alkaloids of interest bear an N-
methyl group. Subsequent N-methylation using iodomethane of
the unsubstituted 1-oxoisoquinolines following Toure’s protocol is
not an option for 1-oxoisoquinolines bearing a free phenol such as
our targeted compounds 1c and 1d. This should be accomplished by
starting from appropriate primary or secondary benzamide build-
ing blocks. Further, we intended to explore whether ring closure
and reduction of the C-3,C-4 double bond can be accomplished in
one single operation. Comparable alkylations of nitrogen-
containing functional groups (amides, carbamates, ureas, sulfina-
mides) using free or masked aldehydes (acetals, enol ethers) under
reductive conditions (typically organosilane-TFA combinations)
had been published before [30e33]. Very recently, our group re-
ported on convenient N-arylethylations of aromatic amines and N-
heterocycles with (2-methoxyvinyl)arenes using triethylsilane and
TFA [34,35]. A further extension of our approach was aimed at the
synthesis of 1,3,4-trioxoisoquinolines (see alkaloid 3 [6]) from in-
termediates of type 1 or 2, including a final oxidation step with
chromium reagents [36,37].
Next, with the 1-oxo-3,4-dihydroisoquinoline alkaloid thalifo-
line (2d) in hand we aimed to synthesize the “dimeric” alkaloids
berbanine (5) and berbidine (4). The diaryl ether bridge should be
built up by an Ullmann-type CeO coupling of 2d with the suitably

4
R. Schütz et al. / Tetrahedron 76 (2020) 131150
3,4-dihydroisoquinoline alkaloids. We investigated a number of
reduction protocols that had been applied successfully for related
substrates (triethylsilane-Pd on carbon [39], sodium borohydride-
Pd on carbon [40], sodium borohydride [41], zinc-acetic acid [42],
aluminium chloride-cyclohexane [43]), but did not achieve reduc-
tion with any of them. Finally, as a low-pressure catalytic hydro-
genation under palladium catalysis had been applied by Jangir et al.
[14] for the synthesis of the 1-oxo-3,4-dihydroisoquinoline alkaloid
oyxhydrastinine, we submitted the 1-oxoisoquinolines to catalytic
hydrogenation. However, attempts at low hydrogen pressure gave
only very poor conversions, but in accordance with a single
example published by Ajao and Bird [44] at 20e40 bar clean
reduction of the double bond was obtained giving the 3,4-dihydro-
1-oxoisoquinoline alkaloids corydaldine 2a [45], N-methylcor-
ydaldine 2b [46], northalifoline 2c [47], thalifoline 2d [48], N-
methylthalidaldine 2e [46] and noroxyhydrastine 2f [48] in high
yields (Scheme 1a). By using Pd/C as catalyst for the hydrogenation
we found a less cost-intensive method compared to Toure’s pro-
tocol, in which PtO2 is used.
By an extension of this approach, a new approach to 1,3,4-
trioxoisoquinoline alkaloid 3 was found. As shown for related 1-
oxoisoquinolines before [36,37], chromate oxidation allowed
direct conversion of 8b into the corresponding trione 3. The alka-
loid was obtained in 20% yield in one single operation (cross-
coupling/cyclization/oxidation) by simply adding pyridinium
chlorochromate to the solution of crude 1b in dichloromethane/TFA
(Scheme 1b). Due to its exceptional shortness, this approach com-
pares favorably with previously published total syntheses of alka-
loid 3, either by oxidation of different intermediates [49e51] or by
diverse cyclization reactions [52,53].
Finally, we utilized 1-oxodihydroisoquinoline thalifoline (2d) as
building block for the first total syntheses of the “dimeric” 1-
oxoisoquinoline alkaloids berbidine (4) and berbanine (5).
Formally, an Ullmann-type coupling of phenolic compound 2d with
8-bromo-6,7-dimethoxyisoquinoline would lead to the desired
alkaloid 5. However, this approach was not promising, as Knabe and
coworkers [54] reported on unsuccessful attempts for achieving
Ullmann couplings of this compound with a 7-hydroxyisoquinoline
in their attempts to synthesize alkaloid phaeantharine. So we
decided to perform an Ullman coupling with 2-bromo-3,4-
dimethoxybenzaldehyde (11), and to construct the fully aromatic
isoquinoline unit of alkaloid berbanine (5) subsequently in a
Pomeranz-Fritsch reaction. Fortunately, Ullmann-type coupling of
this salt and those reported for isolated berbanine were almost
identical (for details, see Supporting Information).
Conversion of berbanine (5) into its N-methylated 1,2,3,4-
tetrahydro analogue berbidine (4) was achieved in two steps ac-
cording to a method of Chan et al. [59]. N-Methylation of the fully
aromatic isoquinoline moiety in 5 with iodomethane gave an iso-
quinolinium salt, which was reduced with sodium borohydride to
give alkaloid 4 in 88% yield over both steps (Scheme 2). Berbidine
(4) has previously been obtained only by photooxidative degrada-
tion of the bisbenzylisoquinoline alkaloids isotetrandrine [4] and
phlebicine [60].
3. Conclusion
In summary, we have worked out a very short approach to 1-
oxoisoquinoline alkaloids utilizing a 2-ethoxyvinylboronate 9 as a
C2 building block for introduction of the C-3,C-4 unit of the iso-
quinoline core. In total, 14 alkaloids from four chemotypes were
obtained in this investigation. This approach has a number of ad-
vantages: a) it uses easily accessible ortho-bromobenzamides as
precursors, b) the method allows the synthesis of both N-unsub-
stituted and N-methylated products, and thus is more flexible than
Toure’s protocol [22] which starts from N-tert-butylbenzamides,
and leads to N-unsubstituted products in the first instance, c) N-
methylated products are obtained without the need for using
hazardous methylation agents, d) in contrast to other approaches
(e.g., Ref. [18]), there is no need for protecting phenolic groups, e)
the formed alkaloids are not contaminated with isomeric by-
products, f) the obtained 1-oxoisoquinolines can easily be con-
verted into 1-oxo-3,4-dihydroisoquinoline alkaloids by catalytic
hydrogenation and into 1,3,4-trioxoisoquinolines by dichromate
oxidation.
Further, the first total syntheses of the “dimeric” 1-
oxoisoquinoline alkaloids berbidine (4) and berbanine (5) were
accomplished using alkaloid thalifoline (2d) as a building block. The
overall yield along the longest sequence amounts 18% for berbanine
(5) and 16% for berbidine (4).
4. Experimental section
4.1. General reagent and analytical information
All solvents were p.a. grade and/or purified following standard
procedures. Chemical reagents were purchased from Sigma Aldrich
(Schnelldorf, Germany), ABCR (Karlsruhe, Germany), Fluorochem
(Derbyshire, United Kingdom), Acros (Geel, Belgium), Thermo
Fisher Scientific GmbH (Dreieich, Germany) or Fluka Chemie AG
(Buchs, Switzerland). Melting points were determined by open
capillary method on a SMP10 device (Stuart Equipment, Stafford-
shire, United Kingdom). The values are reported in ꢀC and are un-
corrected. NMR spectra were recorded on an Avance III HD
400 MHz Bruker BioSpin spectrometer (Bruker, Billerica, USA).
NMR spectra were recorded in deuterated solvents and chemical
shifts are reported in parts per million (ppm) relative to tetrame-
phenolic
compound
2d
with
2-bromo-3,4-
dimethoxybenzaldehyde (11), readily available from 2-bromo-3-
hydroxy-4-methoxybenzaldehyde via O-methylation [55], gave
the diaryl ether 12 in 49% yield. For this conversion we applied a
coupling protocol that was recently optimized by us for related
Ullmann couplings in the course of the total syntheses of the bis-
benzylisoquinoline alkaloids tetrandrine/isotetrandrine [56], uti-
lizing copper(I) bromide-dimethyl sulfide complex as catalyst and
cesium carbonate as base [57]. Alkaloid berbanine (5) was obtained
from intermediate 12 in a Pomeranz-Fritsch reaction using ami-
noacetaldehyde dimethyl acetal and boron trifluoride/acetic acid
complex as Lewis acid according to a procedure of Patel [58] in 47%
yield. To our surprise, the NMR data of synthetic berbanine (5) were
thylsilane (TMS (
(CDCl3
¼ 7.26/77.16), DMSO‑d6
¼ 4.87/49.00)). J values are given in hertz (Hz). The spin multi-
d
¼ 0.00)) or relative to residual solvent peaks
(d
(d
¼ 2.50/39.52), methanol-d4
ꢀ
ꢀ
(d
not in accordance with the data published by Host’alkova et al. [7]
for the natural product isolated from Berberis vulgaris. The most
distinctive deviation in the 1H NMR is the signal of 1-H of the
isoquinoline moiety. In our spectrum it appears as a singlet at
plicity is expressed as: s (singlet), br s (broad singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) or combinations thereof. Signal
assignments were carried out based on 1H, 13C, HMBC, HSQC and
COSY spectra. HRMS were performed by electrospray ionization
(ESI) on a Thermo Finnigan LTQ instrument (Thermo Fisher Scien-
tific, Waltham, USA) and by electron impact ionization (EI) on a JMS
GCmate II instrument (Jeol, Beabody, USA). All reactions were
monitored by thin-layer chromatography (TLC) using polyester
ꢀ
ꢀ
9.16 ppm whereas Host’alkova et al. report a doublet at 9.23
ꢀ
ꢀ
(J ¼ 5.9 Hz). Finally we found that Host’alkova et al. most likely
reported the NMR data of protonated berbanine (5). We converted
synthetic berbanine into its hydrochloride salt, and the NMR data of

R. Schütz et al. / Tetrahedron 76 (2020) 131150
5
sheets POLYGRAM SIL G/UV 254, coated with 0.2 mm silica gel
(Macherey-Nagel, Düren, Germany). Mass spectrometry was per-
formed by atmospheric pressure solids analysis probe (ASAP) via
atmospheric-pressure chemical ionization (APCI) on an expressionL
CMS device (Advion, Ithaca, USA). Purification by flash column
chromatography (FCC) was performed using silicagel 60
(0.040e0.063 mm, 230e400 mesh ASTM) (Fa. Merck, Darmstadt,
Germany).
CDCl3):
(s, 1H, NH2), 3.90 (s, 3H, 5-OCH3), 3.90 (s, 3H, 4-OCH3). 13C NMR
(101 MHz, CDCl3):
¼ 168.5 (C]O), 151.4 (C-4), 148.6 (C-5), 127.6
d
¼ 7.36 (s, 1H, 6-H), 7.01 (s, 1H, 3-H), 6.50 (s, 1H, NH2), 6.13
d
(C-1), 116.1 (C-3), 113.6 (C-6), 110.4 (C-2), 56.5 (5-OCH3), 56.3 (4-
OCH3). HR-ESI-MS: m/z
259.99168, 261.98964, found: 259.99173, 261.98973.
¼
calcd. for C9H11BrNO3 [MþH]þ:
4.3.2. 2-Bromo-4,5-dimethoxy-N-methylbenzamide (8b)
Synthesized following general procedure A, using 2-bromo-4,5-
dimethoxybenzoic acid (1.04 g, 4.00 mmol), thionyl chloride (1 M in
CH2Cl2, 8 mL, 8 mmol, 2 eq) and methylamine (30% in water, 21 mL,
44 eq), yielding 8b (0.988 g, 3.60 mmol, 90%) as a white solid. mp:
4.2. General procedures
4.2.1. General procedure A: syntheses of the 2-bromobenzamides
(8a-e)
145 ꢀC (ref. [62]: 119e121 ꢀC). 1H NMR (400 MHz, CDCl3):
d
¼ 7.21
To the respective 2-bromobenzoic acid (2-bromo-4,5-
dimethoxybenzoic acid, 2-bromo-5-hydroxy-4-methoxybenzoic
acid or 2-bromo-3,4,5-trimethoxybenzoic acid) (1 eq) was added
thionyl chloride (1 M in CH2Cl2, 2 mL per mmol carboxylic acid) and
the reaction mixture was stirred at 76 ꢀC for 7 h. After cooling to
room temperature, the volatiles were removed in vacuo and the
amine (44 eq of conc. aqueous NH3 solution or methyl amine,
respectively) was added at 0 ꢀC. The reaction mixture was stirred at
(s, 1H, 6-H), 6.98 (s, 1H, 3-H), 6.28 (s, 1H, NH), 3.89 (s, 3H, 9-OCH3),
3.88 (s, 3H, 4-OCH3), 3.01 (d, J ¼ 4.9 Hz, 3H, NCH3). 13C NMR
(101 MHz, CDCl3):
d
¼ 167.6 (C]O), 150.9 (C-4), 148.6 (C-5), 129.2
(C-1), 115.9 (C-3), 113.1 (C-6), 109.8 (C-2), 56.4 (5-OCH3), 56.3 (4–
OCH3), 26.9 (NCH3). HR-ESI-MS: m/z ¼ calcd. for C10H13BrNO3
[MþH]þ: 274.00733, 276.00529, found: 274.00759, 276.00559.
4.3.3. 2-Bromo-5-hydroxy-4-methoxy-benzamide (8c)
0
ꢀC for 1 h and allowed to warm up to room temperature while
Synthesized following general procedure A, using 2-bromo-5-
hydroxy-4-methoxybenzoic acid (0.494 g, 2.00 mmol), thionyl
chloride (1 M in CH2Cl2, 4 mL, 4 mmol, 2 eq) and with conc. aqueous
NH3 solution (25%, 10 mL, 44 eq), yielding 8c (0.382 g, 1.55 mmol,
78%) as a white solid. mp: 218 ꢀC. 1H NMR (400 MHz, DMSO‑d6):
stirring overnight. The mixture was acidified with conc. HCl and
extracted with EtOAc (3 ꢁ 20 mL). The combined organic layers
were washed with water (20 mL) and brine (20 mL), dried over
Na2SO4 and the solvents were removed in vacuo.
d
¼ 9.49 (s, 1H, OH), 7.63 (s, 1H, NH2), 7.35 (s, 1H, NH2), 7.09 (s, 1H, 3-
H), 6.84 (s, 1H, 6-H), 3.79 (s, 3H, 4-OCH3). 13C NMR (101 MHz,
DMSO‑d6):
116.4 (C-3), 115.8 (C-6), 107.4 (C-2), 56.3 (4-OCH3). HR-ESI-MS: m/
z ¼ calcd. for C8H9BrNO3 [MþH]þ: 245.97658, 247.97453, found:
245.97609, 247.97407.
4.2.2. General procedure B: One pot Suzuki cross-coupling and ring
closure leading to 1a-f
d
¼ 169.0 (C]O), 149.1 (C-4), 145.8 (C-5), 131.4 (C-1),
The respective 2-bromobenzamide 8a-f (1 eq, typically
1e2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.05 eq)
and trans-2-ethoxyvinylboronic acid pinacol ester (1.5 eq) were
dissolved in degassed 1,4-dioxane (6 mL/mmol amide) (3 ꢁ vac-
uum/3 ꢁ nitrogen) under nitrogen atmosphere and stirred at room
temperature for 10 min. A solution of cesium carbonate (3 eq) in
degassed water (2 mL/mmol amide) (3 ꢁ vacuum/3 ꢁ nitrogen)
under nitrogen atmosphere was added and the reaction mixture
was stirred at 75 ꢀC for 19 h. After cooling to room temperature, TFA
(2 mL) was added at 0 ꢀC and the reaction mixture was stirred for
3 h at room temperature. Then, satd. aqueous NH4Cl solution
(15 mL) was added and the mixture was extracted with EtOAc
(3 ꢁ 20 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4 and the solvent was removed in vacuo.
The crude product was purified by flash column chromatography,
using the appropriate eluent.
4.3.4. 2-Bromo-5-hydroxy-4-methoxy-N-methylbenzamide (8d)
Synthesized following general procedure A, using 2-bromo-5-
hydroxy-4-methoxybenzoic acid (0.988 g, 4.00 mmol), thionyl
chloride (1 M, 8 mL, 8 mmol, 2 eq) and methylamine (30% in water,
20 mL, 44 eq), yielding 8d (0.997 g, 3.88 mmol, 97%) as a white
solid. mp: 196 ꢀC. 1H NMR (400 MHz, DMSO‑d6):
d
¼ 9.50 (s, 1H,
OH), 8.10 (q, J ¼ 4.3 Hz, 1H, NH2), 7.09 (s, 1H, 6-H), 6.79 (s, 1H, 3-H),
3.79 (s, 3H, 4-OCH3), 2.70 (d, J ¼ 4.6 Hz, 3H, NCH3). 13C NMR
(101 MHz, DMSO‑d6):
d
¼ 167.4 (C]O), 148.9 (C-4), 145.7 (C-5),
131.2 (C-1), 116.1 (C-6), 115.6 (C-3), 107.3 (C-2), 56.0 (4-OCH3), 26.0
(C-5). HR-ESI-MS: m/z ¼ calcd. for C9H11BrNO3 [MþH]þ: 259.99223,
261.99018, found: 259.99183, 261.98991.
4.2.3. General procedure C: catalytic hydrogenation of the 1-
oxoisoquinolines to give 2a-f
4.3.5. 2-Bromo-3,4,5-trimethoxy-N-methylbenzamide (8e)
Synthesized following general procedure A, using 2-bromo-
3,4,5-trimethoxybenzoic acid (9) (0.150 g, 0.515 mmol), thionyl
chloride (1 M in CH2Cl2, 1 mL, 1 mmol, 2 eq) and methylamine (30%
in water, 2.7 mL, 44 eq), yielding 8e (0.111 g, 0.365 mmol, 71%) as a
The 1-oxoisoquinoline 1a-f (1 eq) was dissolved in ethanol
(15 mL/mmol) and a catalytic amount of 10% palladium on activated
charcoal (10e40 mol %) and glacial acetic acid (2.5 mL/mmol) were
added. The reaction mixture was hydrogenated at 20e40 bar and
35 ꢀC for 3e12 d. After complete conversion, the mixture was
filtered over celite, the celite washed with methanol and the sol-
vent was removed in vacuo. The crude product was purified by flash
column chromatography, using the appropriate eluent.
white solid. mp: 115 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼ 6.97 (s, 1H,
6-H), 3.89 (s, 3H, 5-OCH3), 3.88 (s, 3H, 3-OCH3), 3.86 (s, 3H, 4-OCH3),
3.01 (d, J ¼ 4.9 Hz, 3H, NCH3). 13C NMR (101 MHz, CDCl3):
¼ 168.0
d
(C]O), 153.1 (C-5), 151.1 (C-3), 144.7 (C-4), 108.9 (C-6), 106.4 (C-2),
61.3 (5-OCH3), 61.2 (3-OCH3), 56.4 (4-OCH3), 26.9 (NCH3). HR-ESI-
MS: m/z ¼ calcd. for C11H15BrNO4 [MþH]þ: 304.01790, 306.01585,
found: 304.01797, 306.01611.
4.3. Compounds
4.3.1. 2-Bromo-4,5-dimethoxybenzamide (8a)
4.3.6. 6,7-Dimethoxyisoquinolin-1(2H)-one (1a)
Synthesized following general procedure A, using 2-bromo-4,5-
dimethoxybenzoic acid (0.522 g, 2.00 mmol), thionyl chloride (1 M
in CH2Cl2, 4 mL, 4 mmol, 2 eq) and with conc. aqueous NH3 solution
(25%, 10 mL, 44 eq), yielding 8a (0.496 g, 1.91 mmol, 96%) as a light
brown solid. mp: 182 ꢀC (ref. [61]: 178 ꢀC). 1H NMR (400 MHz,
Synthesized following general procedure B, using 2-bromo-4,5-
dimethoxybenzamide (8a) (0.322 g, 1.24 mmol), tetrakis(-
triphenylphosphine)palladium(0) (0.068 g, 0.059 mmol, 0.047 eq)
and trans-2-ethoxyvinylboronic acid pinacol ester (0.37 mL,
1.8 mmol, 1.4 eq) in 10 mL 1,4-dioxane, adding cesium carbonate

6
R. Schütz et al. / Tetrahedron 76 (2020) 131150
(1.15 g, 3.52 mmol, 2.85 eq) in 2.5 mL water and TFA (2 mL). Work
up and purification by flash column chromatography (50:1 CH2Cl2/
MeOH) yielded 1a (0.221 g, 1.08 mmol, 87%) as a light brown solid.
mp: 239 ꢀC (ref. [63]: 227e230 ꢀC). 1H NMR (400 MHz, CDCl3):
4.3.10. 5,6,7-Trimethoxy-2-methylisoquinolin-1(2H)-one
(thalactamine) (1e)
Synthesized following general procedure B, using 2-bromo-
3,4,5-trimethoxy-N-methylbenzamide (8e) (0.465 g, 1.53 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol,
0.050 eq) and trans-2-ethoxyvinylboronic acid pinacol ester
(0.49 mL, 2.3 mmol, 1.5 eq) in 15 mL 1,4-dioxane, adding cesium
carbonate (1.49 g, 4.59 mmol, 3.00 eq) in 3 mL water and TFA
(2 mL). Work up and purification by flash column chromatography
(100:1 CH2Cl2/MeOH) yielded 1e (0.261 g,1.05 mmol, 69%) as a light
brown solid. mp: 120 ꢀC (ref. [1]: 111e112 ꢀC). 1H NMR (400 MHz,
d
¼ 11.52 (s, 1H, NH), 7.77 (s, 1H, 8-H), 7.12 (d, J ¼ 7.0 Hz, 1H, 3-H),
6.92 (s, 1H, 5-H), 6.51 (d, J ¼ 7.1 Hz, 1H, 4-H), 4.02 (s, 3H, 7-OCH3),
4.00 (s, 3H, 6-OCH3). 13C NMR (101 MHz, CDCl3):
d
¼ 163.6 (C-1),
154.0 (C-6), 149.5 (C-7), 134.0 (C-4a), 126.4 (C-3), 119.9 (C-8a), 107.1
(C-8), 106.7 (C-4), 106.3 (C-5), 56.4 (7-OCH3), 56.3 (6-OCH3). HR-EI-
MS: m/z ¼ calcd. for C11H11NO3 [M]∙þ: 205.0733, found: 205.0724.
CDCl3):
d
¼ 7.65 (s, 1H, 8-H), 6.98 (d, J ¼ 7.4 Hz, 1H, 3-H), 6.70 (d,
4.3.7. 6,7-Dimethoxy-2-methylisoquinolin-1(2H)-one (1b)
J ¼ 7.8 Hz, 1H, 4-H), 3.98 (s, 3H, 5-OCH3), 3.97 (s, 3H, 7-OCH3), 3.96
Synthesized following general procedure B, using 2-bromo-4,5-
dimethoxy-N-methylbenzamide (8b) (0.453 g, 1.65 mmol), tetra-
kis(triphenylphosphine)palladium(0) (0.096 mg, 0.083 mmol,
0.050 eq) and trans-2-ethoxyvinylboronic acid pinacol ester
(0.53 mL, 2.5 mmol, 1.5 eq) in 15 mL 1,4-dioxane, adding cesium
carbonate (1.62 g, 4.96 mmol, 3.00 eq) in 3 mL water and TFA
(2 mL). Work up and purification by flash column chromatography
(50:1 CH2Cl2/MeOH) yielded 1b (0.306 mg, 1.40 mmol, 85%) as a
light orange solid. mp: 109 ꢀC (ref. [64]: 112 ꢀC). 1H NMR (400 MHz,
(s, 3H, 6-OCH3), 3.60 (s, 3H, NCH3). 13C NMR (101 MHz, CDCl3):
d
¼ 162.0 (C-1), 153.3 (C-7), 147.5 (C-5), 145.7 (C-6), 130.7 (C-3),
127.1 (C-8a), 122.4 (C-4a), 104.1 (C-8), 100.5 (C-4), 61.7 (5-OCH3),
61.2 (6-OCH3), 56.3 (7-OCH3), 37.3 (NCH3). HR-ESI-MS: m/z ¼ calcd.
for C13H16NO4 [MþH]þ: 250.10738, found: 250.10755.
4.3.11. [1,3]Dioxolo[4,5-g]isoquinolin-5(6H)-one (1f)
Synthesized following general procedure B, using 6-
bromobenzo[d][1,3]dioxole-5-carboxamide
1.64 mmol), tetrakis(triphenylphosphine)palladium(0) (0.095 g,
0.082 mmol, 0.050 eq) and trans-2-ethoxyvinylboronic acid pinacol
ester (0.52 mL, 2.5 mmol, 1.5 eq) in 15 mL 1,4-dioxane, adding ce-
sium carbonate (1.60 g, 4.92 mmol, 3.00 eq) in 3 mL water and TFA
(2 mL). Work up and washing the crude product with CH2Cl2
yielded 1f (0.210 g, 1.11 mmol, 68%) as a light brown solid. mp:
266 ꢀC (ref. [1]: 268e270 ꢀC). 1H NMR (400 MHz, DMSO‑d6):
(8f)
(0.400
g,
CDCl3):
d
¼ 7.80 (s, 1H, 8-H), 7.00 (d, J ¼ 7.3 Hz, 1H, 3-H), 6.85 (s, 1H,
5-H), 6.40 (d, J ¼ 7.2 Hz,1H, 4-H), 4.00 (s, 3H, 7-OCH3), 3.97 (s, 3H, 6-
OCH3), 3.60 (s, 3H, NCH3). 13C NMR (101 MHz, CDCl3): 162.1 (C-1),
153.4 (C-6), 149.4 (C-7), 132.7 (C-3), 131.2 (C-4a), 120.3 (C-8a), 107.7
(C-8), 106.1 (C-5), 105.6 (C-4), 56.3 (7-OCH3), 56.2 (6-OCH3), 37.3
(NCH3). HR-EI-MS: m/z ¼ calcd. for C12H13NO3 [M]∙þ: 219.0890,
found: 219.0888.
d
¼ 11.14 (s, 1H, NH), 7.49 (s, 1H, 8-H), 7.13 (s,1H, 5-H), 7.07e7.03 (m,
1H, 3-H), 6.44 (d, J ¼ 7.1 Hz, 1H, 4-H), 6.14 (s, 2H, OCH2O). 13C NMR
4.3.8. 7-Hydroxy-6-methoxyisoquinolin-1(2H)-one (N-
demethyldoryphornine) (1c)
(101 MHz, DMSO‑d6):
d
¼ 161.1 (C-1), 151.4 (C-6), 147.1 (C-7), 135.1
Synthesized following general procedure B, using 2-bromo-4-
methoxy-5-hydroxy-benzamide (8c) (0.322 mg, 1.31 mmol), tetra-
kis(triphenylphosphine)palladium(0) (0.072 g, 0.062 mmol, 0.047
eq) and trans-2-ethoxyvinylboronic acid pinacol ester (0.40 mL,
1.9 mmol, 1.4 eq) in 10 mL 1,4-dioxane, adding cesium carbonate
(1.21 g, 3.72 mmol, 2.84 eq) in 2.8 mL water and TFA (2 mL). Work
up and purification by flash column chromatography (40:1 CH2Cl2/
MeOH) yielded 1c (0.175 g, 0.915 mmol, 70%) as a light brown solid.
mp: 282 ꢀC (ref. [65]: 257e259 ꢀC). 1H NMR (400 MHz, methanol-
(C-4a), 127.5 (C-3), 121.3 (C-8a), 104.7 (C-5), 104.0 (C-4, C-8), 101.8
(OCH2O). HR-EI-MS: m/z ¼ calcd. for C10H7NO3 [M]∙þ: 189.0420,
found: 189.0420.
4.3.12. 6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-one
(corydaldine) (2a)
Synthesized following general procedure C, hydrogenating 6,7-
dimethoxyisoquinolin-1(2H)-one (1a) (0.230 g, 1.12 mmol) at
30 bar for 3 d, using palladium on activated charcoal (35 mol %,
0.42 g) in 15 mL EtOH and 5.6 mL AcOH. Purification by flash col-
umn chromatography (40:1 CH2Cl2/MeOH) yielded 2a (0.210 mg,
1.01 mmol, 90%) as a white solid. mp: 159 ꢀC (ref. [66]: 174e177 ꢀC).
d4):
d
¼ 7.63 (s, 1H, 8-H), 7.12 (s, 1H, 5-H), 7.04 (d, J ¼ 7.1 Hz, 1H, 3-
H), 6.63 (d, J ¼ 7.1 Hz, 1H, 4-H), 4.00 (s, 3H, 6-OCH3). 13C NMR
(101 MHz, methanol-d4):
d
¼ 164.4 (C-1), 154.7 (C-6), 148.3 (C-7),
1H NMR (400 MHz, CDCl3):
d
¼ 7.57 (s, 1H, 8-H), 6.67 (s, 1H, 5-H),
134.9 (C-4a), 126.5 (C-3), 121.2 (C-8a) 111.5 (C-8), 108.1 (C-5), 107.6
(C-4), 56.5 (6-OCH3). HR-EI-MS: m/z ¼ calcd. for C10H9NO3 [M]∙þ
:
6.21 (s, 1H, NH), 3.92 (s, 6H, 6-OCH3, 7-OCH3), 3.55 (td, J ¼ 6.7,
2.8 Hz, 2H, 3-H), 2.93 (t, J ¼ 6.7 Hz, 2H, 4-H). 13C NMR (101 MHz,
191.0577, found: 191.0579.
CDCl3):
d
¼ 166.6 (C-1), 152.3 (C-6), 148.2 (C-7), 132.8 (C-4a), 121.5
4.3.9. 7-Hydroxy-6-methoxy-2-methylisoquinolin-1(2H)-one
(doryphornine) (1d)
Synthesized following general procedure B, using 2-bromo-4-
methoxy-5-hydroxy-N-methylbenzamide (8d) (0.476 g,
(C-8a), 110.3 (C-8), 109.7 (C-5), 56.3 (7-OCH3), 56.2 (6-OCH3), 40.7
(C-3), 28.2 (C-4). HR-EI-MS: m/z ¼ calcd. for C11H13NO3 [M]∙þ
:
207.0890, found: 207.0889.
1.83 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g,
0.092 mmol, 0.050 eq) and trans-2-ethoxyvinylboronic acid pinacol
ester (0.58 mL, 2.8 mmol, 1.5 eq) in 10 mL 1,4-dioxane, adding ce-
sium carbonate (1.87 g, 5.73 mmol, 3.00 eq) in 4 mL water and TFA
(2 mL). Work up and purification by flash column chromatography
(30:1 CH2Cl2/MeOH) yielded 1d (0.344 g, 1.68 mmol, 92%) as a light
brown solid. mp: 217 ꢀC (ref. [1]: 215e217 ꢀC). 1H NMR (400 MHz,
4.3.13. 6,7-Dimethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one
(N-methylcorydaldine) (2b)
Synthesized following general procedure C, hydrogenating 6,7-
dimethoxy-2-methylisoquinolin-1(2H)-one (1b) (0.214 g,
0.976 mmol) at 40 bar for 5 d, using palladium on activated charcoal
(10 mol %, 0.10 g) in 15 mL EtOH and 5.6 mL AcOH. Purification by
flash column chromatography (50:1 CH2Cl2/MeOH) yielded 2b
(0.138 g, 0.624 mmol, 64%) as a white solid. mp: 125 ꢀC (ref. [67]:
CDCl3):
5-H), 6.69 (s, 1H, OH), 6.40 (d, J ¼ 7.2 Hz, 1H, 4-H), 3.99 (s, 3H, 6-
OCH3), 3.60 (s, 3H, NCH3). 13C NMR (101 MHz, CDCl3):
d
¼ 8.06 (s, 1H, 8-H), 6.96 (d, J ¼ 7.3 Hz, 1H, 3-H), 6.85 (s, 1H,
123e124 ꢀC). 1H NMR (400 MHz, CDCl3):
d
¼ 7.59 (s, 1H, 8-H), 6.62
d
¼ 162.1
(s, 1H, 5-H), 3.92 (s, 3H, 7-OCH3), 3.91 (s, 3H, 6-OCH3), 3.54 (t,
J ¼ 6.8 Hz, 2H, 3-H), 3.13 (s, 3H, NCH3), 2.93 (t, J ¼ 6.8 Hz, 2H, 4-H).
(C-1), 151.6 (C-6), 146.2 (C-7), 132.2 (C-3), 130.8 (C-4a), 120.9 (C-8a),
111.8 (C-8), 105.9 (C-5), 105.7 (C-4), 56.2 (C-10), 37.2 (C-9). HR-EI-
MS: m/z ¼ calcd. for C11H11NO3 [M]∙þ: 205.0733, found: 205.0727.
13C NMR (101 MHz, CDCl3):
131.7 (C-4a), 122.1 (C-8a), 110.6 (C-8), 109.4 (C-5), 56.2 (7-OCH3),
d
¼ 165.0 (C-1), 151.8 (C-6), 148.1 (C-7),

R. Schütz et al. / Tetrahedron 76 (2020) 131150
7
56.1 (6-OCH3), 48.5 (C-3), 35.3 (NCH3), 27.7 (C-4). HR-EI-MS: m/
z ¼ calcd. for C12H15NO3 [M]∙þ: 221.1046, found: 221.1044.
4.3.18. 6,7-Dimethoxy-2-methylisoquinoline-1,3,4(2H)-trione (3)
2-Bromo-4,5-dimethoxy-N-methylbenzamide 8b (0.296 g,
1.08 mmol), tetrakis(triphenylphosphine)palladium(0) (0.062 mg,
0.054 mmol, 0.050 eq) and trans-2-ethoxyvinylboronic acid pinacol
ester (9, 0.34 mL, 1.6 mmol, 1.5 eq) were dissolved in degassed 1,4-
dioxane (10 mL) under nitrogen atmosphere and stirred at room
temperature for 10 min. A solution of cesium carbonate (1.06 g,
3.24 mmol, 3.00 eq) in degassed water (2 mL) was added under
nitrogen atmosphere and the reaction mixture was stirred at 75 ꢀC
for 19 h. After cooling to room temperature, satd. aqueous NH4Cl
solution (15 mL) was added and the mixture was extracted with
EtOAc (3 ꢁ 20 mL). The combined organic layers were washed with
brine (20 mL), dried over MgSO4 and the solvent was removed in
vacuo. The residue was dissolved in CH2Cl2 (4 mL) and TFA (2 mL)
was added at 0 ꢀC. The reaction mixture was allowed to warm up to
room temperature and stirred for 3 h. Then pyridinium chlor-
ochromate (1.16 g, 5.40 mmol, 5.00 eq) was added and the mixture
was stirred at room temperature for 19 h. Water (20 mL) was added
and the mixture was extracted with CH2Cl2 (3 ꢁ 20 mL). The
combined organic layers were washed with satd. aqueous NaHCO3
solution (20 mL), brine (20 mL) and dried over MgSO4. The solvent
was removed in vacuo and the crude product was purified by flash
column chromatography (50:1 CH2Cl2/MeOH), yielding 3 (0.054 g,
0.22 mmol, 20%) as a greenish yellow solid. mp: 276 ꢀC (ref. [49]:
4.3.14. 7-Hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one
(northalifoline) (2c)
Synthesized following general procedure C, hydrogenating 7-
hydroxy-6-methoxyisoquinolin-1(2H)-one
(1c)
(0.100
g,
0.523 mmol) at 30 bar for 3 d, using palladium on activated char-
coal (20 mol %, 0.11 g) in 7.5 mL EtOH and 1.3 mL AcOH. Purification
by flash column chromatography (40:1 CH2Cl2/MeOH) yielded 2c
(0.074 g, 0.38 mmol, 73%) as a white solid. mp: 235 ꢀC (ref. [47]:
222e224 ꢀC). 1H NMR (400 MHz, methanol-d4):
d
¼ 7.36 (s, 1H, 8-
H), 6.84 (s, 1H, 5-H), 3.92 (s, 3H, 6-OCH3), 3.57e3.38 (m, 2H, 3-H),
2.90 (t, J ¼ 6.7 Hz, 2H, 4-H). 13C NMR: (101 MHz, methanol-d4):
d
¼ 196.8 (C-1), 181.0 (C-6), 174.7 (C-7), 161.8 (C-4a), 150.5 (C-8a),
143.1 (C-8), 139.2 (C-5), 84.6 (6-OCH3), 69.3 (C-3), 56.8 (C-4). HR-
ESI-MS: m/z ¼ calcd. for C10H12NO3 [MþH]þ: 194.08117, found:
194.08122.
4.3.15. 7-Hydroxy-6-methoxy-2-methyl-3,4-dihydroisoquinolin-
1(2H)-one (thalifoline) (2d)
Synthesized following general procedure C, hydrogenating 7-
hydroxy-6-methoxy-2-methylisoquinolin-1(2H)-one
(1d)
(0.254 g, 1.24 mmol) at 20 bar for 3 d, and using palladium on
activated charcoal (10 mol %, 0.13 g) in 15 mL EtOH and 3 mL AcOH.
Purification by flash column chromatography (30:1 CH2Cl2/MeOH)
yielded 2d (0.221 mg, 1.07 mmol, 86%) as a white solid. mp: 219 ꢀC
273 ꢀC). 1H NMR (400 MHz, CDCl3):
5-H), 4.08 (s, 3H,7-OCH3), 4.03 (s, 3H, 6-OCH3), 3.46 (s, 3H, NCH3).
13C NMR (101 MHz, CDCl3):
d
¼ 7.71 (s, 1H, 8-H), 7.58 (s, 1H,
d
¼ 173.5 (C-4), 162.5 (C-1), 157.9 (C-3),
(ref. [13]: 210e211 ꢀC). 1H NMR (400 MHz, CDCl3):
d
¼ 7.72 (s, 1H, 8-
155.8 (C-7), 154.1 (C-6), 125.4 (C-8a), 125.0 (C-4a), 110.7 (C-8), 108.5
(C-5), 57.0 (7-OCH3), 56.9 (6-OCH3), 27.6 (NCH3). HR-EI-MS: m/
z ¼ calcd. for C12H11NO5 [M]∙þ: 249.0632, found: 249.0629.
H), 6.60 (s, 1H, 5-H), 6.20 (s, 1H, OH), 3.91 (s, 3H, 6-OCH3), 3.52 (t,
J ¼ 6.7 Hz, 2H, 3-H), 3.12 (s, 3H, NCH3), 2.91 (t, J ¼ 6.7 Hz, 2H, 4-H).
13C NMR (101 MHz, CDCl3):
d
¼ 165.0 (C-1), 149.7 (C-6), 144.8 (C-7),
130.9 (C-4a), 122.7 (C-8a), 114.6 (C-8), 109.0 (C-5), 56.1 (6-OCH3),
48.6 (C-3), 35.3 (NCH3), 27.7 (C-4). HR-EI-MS: m/z ¼ calcd. for
4.3.19. 3,4-Dimethoxy-2-((6-methoxy-2-methyl-3,4-
dihydroisoquinolin-1(2H)-one-7-yl)oxy)benzaldehyde (12)
C
11H13NO3 [M]∙þ: 207.0890, found: 207.0895.
A
mixture of 2d (0.368 g, 1.77 mmol), 2-bromo-3,4-
dimethoxybenzaldehyde (11, 0.435 g, 1.77 mmol, 1.00 eq), cop-
per(I) bromide-dimethyl sulfide complex (0.365 g, 1.77 mmol, 1.00
eq) and cesium carbonate (1.735 g, 5.32 mmol, 3.00 eq) was sus-
pended in dry and degassed pyridine (7.5 mL) under nitrogen at-
mosphere in a pressure tube. The reaction mixture was heated in
the tightly closed tube at 110 ꢀC for 48 h. After cooling to room
temperature, the mixture was filtered over silica and the silica
washed with EtOAc. The solvent was removed in vacuo and the
crude product was purified by flash column chromatography
(40:60 EtOAc/H2Cl2), yielding the desired product (12) (0.323 g,
0.87 mmol, 49%) as a light yellow solid. mp: 129 ꢀC. 1H NMR
4.3.16. 5,6,7-Trimethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-
one (N-methylthalidaldine) (2e)
Synthesized following general procedure C, hydrogenating
5,6,7-trimethoxy-2-methylisoquinolin-1(2H)-one (1e) (0.100 mg,
0.401 mmol) at 40 bar for 12 d, using palladium on activated
charcoal (40 mol %, 0.16 g) in 9 mL EtOH and 3.3 mL AcOH. Purifi-
cation by flash column chromatography (50:1 CH2Cl2/MeOH) yiel-
ded 2e (0.042 g, 0.17 mmol, 42%) as a white solid. mp: 110 ꢀC (ref.
[68]: 104e106 ꢀC). 1H NMR (400 MHz, CDCl3):
d
¼ 7.45 (s, 1H, 8-H),
3.91 (s, 3H, 7-OCH3), 3.89 (s, 3H, 6-OCH3), 3.85 (s, 3H, 5-OCH3), 3.52
(t, J ¼ 6.8 Hz, 2H, 3-H), 3.13 (s, 3H,NCH3), 2.93 (t, J ¼ 6.8 Hz, 2H, 4-H).
(500 MHz, CDCl3):
d
¼ 10.10 (d, J ¼ 0.9 Hz, 1H, CHO), 7.70 (d,
13C NMR (101 MHz, CDCl3):
d
¼ 164.7 (C-1), 152.4 (C-7), 149.5 (C-5),
J ¼ 8.9 Hz, 1H, 60-H), 7.31 (s, 1H, 8-H), 6.87 (d, J ¼ 8.8 Hz, 1H, 50-H),
6.74 (s, 1H, 5-H), 3.98 (s, 3H, 6-OCH3), 3.94 (s, 3H, 40-OCH3), 3.69 (s,
3H, 30-OCH3), 3.51 (t, J ¼ 6.7 Hz, 2H, 3-H), 3.06 (s, 3H, NCH3), 2.95 (t,
145.2 (C-6), 124.9 (C-8a), 124.8 (C-4a), 107.1 (C-8), 61.1 (6-OCH3),
61.0 (5-OCH3), 56.3 7-OCH3), 48.3 (C-3), 35.4 (NCH3), 21.4 (C-4). HR-
EI-MS: m/z ¼ calcd. for C13H17NO4 [M]∙þ:251.1152, found: 251.1152.
J ¼ 6.7 Hz, 2H, 4-H). 13C NMR (101 MHz, CDCl3):
d
¼ 188.2 (CHO),
164.2 (C-1), 159.4 (C-40), 151.7 (C-6), 151.6 (C-20), 147.6 (C-7), 141.4
(C-30), 133.7 (C-4a), 124.4 (C-60), 123.4 (C-10), 122.2 (C-8a), 115.0 (C-
8), 110.3 (C-5), 109.0 (C-50), 60.9 (30-OCH3), 56.3, 56.2 (4-’OCH3, 6-
OCH3), 48.2 (C-3), 35.0 (NCH3), 27.7 (C-4). HR-ESI-MS: m/
z ¼ calcd. for C23H29N2O5 [MþH]þ: 372.14416, found: 372.14389.
4.3.17. 7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one
(noroxyhydrastine) (2f)
Synthesized following general procedure C, hydrogenating [1,3]
dioxolo[4,5-g]isoquinolin-5(6H)-one (1f) (0.100 g, 0.529 mmol) at
20 bar for 3 d, using palladium on activated charcoal (20 mol %,
0.11 g) in 7 mL EtOH and 1.3 mL AcOH. Purification by flash column
chromatography (40:1 CH2Cl2/MeOH) yielded 2f (0.023 g,
0.12 mmol, 23%) as a white solid. mp: 189 ꢀC (ref. [66]: 185e187 ꢀC).
4.3.20. Berbanine (5)
Diarylether 12 (0.150 g, 0.404 mmol) and aminoacetaldehyde
dimethyl acetal (48.4 mL, 0.444 mmol, 1.10 eq) were dissolved in
anhydrous toluene (5.0 mL) and a small amount of molecular sieves
4 Å was added. The mixture was heated at 100 ꢀC for 4 h under
nitrogen atmosphere. After cooling to room temperature, the
mixture was filtered to remove the molecular sieves and the sol-
vent was evaporated in vacuo. The oily residue was suspended in
1H NMR (400 MHz, CDCl3):
d
¼ 7.51 (s, 1H, 8-H), 6.65 (s, 1H, 5-H),
6.21 (s, 1H, NH), 5.99 (s, 2H, OCH2O), 3.52 (td, J ¼ 6.7, 2.8 Hz, 2H, 3-
H), 2.90 (t, J ¼ 6.7 Hz, 2H, 4-H). 13C NMR (101 MHz, CDCl3):
¼ 166.2
d
(C-1), 150.9 (C-6), 147.0 (C-7), 134.7 (C-4a), 123.0 (C-8a), 108.1 (C-8),
107.4 (C-5), 101.6 (OCH2O), 40.4 (C-3), 28.6 (C-4). HR-EI-MS: m/
z ¼ calcd. for C10H9NO3 [M]∙þ: 191.0577, found: 191.0575.

8
R. Schütz et al. / Tetrahedron 76 (2020) 131150
trifluoroacetic anhydride (TFAA, 5.0 mL) at 0 ꢀC and added drop-
wise to a mixture of boron trifluoride acetic acid complex (112 L,
(C-70), 143.5 (C-80), 139.4 (C-10), 137.1 (C-4a0), 135.1 (C-4a), 131.1 (C-
30), 122.7 (C-40), 122.3 (C-8a), 119.5 (C-8a0), 114.8 (C-8), 110.9 (C-5),
103.0 (C-50), 61.5 (70-OCH3), 57.2 (60-OCH3), 56.5 (6-OCH3), 48.2 (C-
3), 35.2 (NCH3), 27.8 (C-4).
m
0.808 mmol, 2.00 eq) in 2.0 mL TFAA at 0 ꢀC. The reaction mixture
was allowed to warm up to ambient temperature and stirred for
18 h. The mixture was poured into ice-water, basified with 25%
aqueous NH3 (pH 12e14) and extracted with CHCl3 (3 ꢁ 50 mL). The
combined organic phases were dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (5% MeOH and 2% NEt3 in EtOAc) to give
the title compound as a white solid (75.2 mg, 0.191 mmol, 47%). mp:
Declaration of competing interest
None.
Acknowledgements
126 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼ 9.16 (s, 1H, 10-H), 8.40 (d,
J ¼ 5.7 Hz, 1H, 30-H), 7.50 (d, J ¼ 5.7 Hz, 1H, 40-H), 7.20 (s, 1H, 8-H),
6.99 (s, 1H, 50-H), 6.78 (s, 1H, 5-H), 4.04 (s, 3H, 6-OCH3), 4.01 (s, 3H,
60-OCH3), 3.85 (s, 3H, 70-OCH3), 3.49 (t, J ¼ 6.9 Hz, 2H, 3-H), 3.01 (s,
3H, NCH3), 2.95 (t, J ¼ 6.7 Hz, 2H, 4-H). 13C NMR (101 MHz, CDCl3):
ꢀ
ꢁ
We thank Prof. Lucie Cahlíkova and Prof. Jiri Kunes from Charles
University (Czech Republic) for kindly providing copies of the
original NMR spectra of isolated berbanine.
d
¼ 164.3 (C-1), 156.9 (C-60), 151.8 (C-6), 147.5 (C-7), 146.7 (C-10),
Appendix A. Supplementary data
143.4 (C-30), 143.0 (C-80), 142.1 (C-70), 134.0 (C-4a0), 133.7 (C-4a),
122.3 (C-8a), 119.6 (C-8a0), 119.3 (C-40), 114.9 (C-8), 110.4 (C-5), 102.7
(C-50), 61.3 (70-OCH3), 56.5 (6-OCH3), 56.2 (60-OCH3), 48.3 (C-3),
35.1 (NCH3), 27.8 (C-4). HR-ESI-MS: m/z ¼ calcd. for C23H29N2O5
[MþH]þ: 395.16015, found: 395.15963.
Supplementary data associated with this article can be found in
the online version, at https://doi.org/10.1016/j.tet.2020.131150.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.3.21. Berbidine (4)
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d
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