Application of differential reactivity towards synthesis of lamellarin and 8-oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines

Article abstract of DOI:10.1016/j.tet.2018.01.042

A unique differential reactivity between dihydroisoquinolines and 3-nitrocoumarins was observed and was exploited for the efficient construction of lamellarins and their isomeric benzofuran-8-oxoprotoberberine derivatives under acid-catalyzed or base-promoted conditions. Further, these prepared aryl-substituted benzofuran-8-oxoprotoberberine derivatives bearing electron-donating substituents on benzofuran moiety are found to be benchtop stable but light-sensitive, and can undergo oxidative ring-opening reaction to give the corresponding keto products when exposed to visible light under aerobic conditions.

Full text of DOI:10.1016/j.tet.2018.01.042

Tetrahedron xxx (2018) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of differential reactivity towards synthesis of lamellarin
and 8-oxoprotoberberine derivatives: Study of photochemical
properties of aryl-substituted benzofuran-8-oxoprotoberberines
Sameer Vyasamudri, Ding-Yah Yang*
Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung, 40704, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A unique differential reactivity between dihydroisoquinolines and 3-nitrocoumarins was observed and
was exploited for the efficient construction of lamellarins and their isomeric benzofuran-8-
oxoprotoberberine derivatives under acid-catalyzed or base-promoted conditions. Further, these pre-
pared aryl-substituted benzofuran-8-oxoprotoberberine derivatives bearing electron-donating sub-
stituents on benzofuran moiety are found to be benchtop stable but light-sensitive, and can undergo
oxidative ring-opening reaction to give the corresponding keto products when exposed to visible light
under aerobic conditions.
Received 23 December 2017
Received in revised form
20 January 2018
Accepted 22 January 2018
Available online xxx
Keywords:
Lamellarin
© 2018 Elsevier Ltd. All rights reserved.
Oxoprotoberberine
Grob coupling
Photooxidation
3-Nitrocoumarin
1. Introduction
action similar to that of anticancer drug camptothecin7 and ber-
berines.8 Camptothecin is a cytotoxic quinoline alkaloid that con-
Lamellarins1 are a diverse family of marine alkaloids. Ever since
their first discovery by Faulkner and co-workers2 in 1985, more
than 70 lamellarins and structurally-related pyrrole alkaloids have
been isolated from mollusks, ascidians, and sponges so far. Most of
tains a crucial pyridone moiety, whereas berberines represent a
large family of alkaloids that bear an isoquinoline ring-fused sys-
tem with various biological activities. By comparing the molecular
structures of lamellarin D, camptothecin, and berberine (Fig. 1), we
speculate that the replacement of the original lamellarin core with
its isomeric benzofuran-8-oxoprotoberberine skeleton might
potentially provide a new scaffold mimicking the critical in-
teractions of lamellarins with the topo I-DNA complex.
Protoberberines are alkaloids constituting many families of
natural products that share similar molecular skeletons such as
berberines, tetrahydroprotoberberines, and 8-oxoprotoberberines.
Most protoberberines exhibit a wide spectrum of biological
activities.9e12 Mainly due to their potential biological importance,
the synthesis of 8-oxoprotoberberines and their derivatives has
been well studied by synthetic and medicinal chemists in the
past.13 While previous efforts have been primarily focused on
synthesis, biological and therapeutic applications of 8-
oxoprotoberberines, their intrinsic photochemical properties,14
especially visible-light-sensitive properties, were much less
explored. Photosensitizer-free, visible-light-mediated organic re-
actions have recently received increasing attention owing to their
simplicity and sustainability.15 Thus, as a part of our ongoing
lamellarins share
a common pyrrolo[2,1-a]isoquinoline- and
coumarin-fused pentacyclic core structure but differ on their pe-
ripheral functional groups. These lamellarin alkaloids have been
found to exhibit a variety of biological activities such as antitumor
activity,3 reversal of multidrug resistance,4 and HIV-1 integrase
inhibition activity.5 Owing to their novel molecular structures and
intriguing biological properties, the synthesis of lamellarins and
their analogues has continued to attract considerable interest to
organic and medicinal chemists. Among these alkaloids, lamellarin
D3a has received the most attention of all, since it can not only
inhibit DNA topoisomerase I (topo I) activity at nanomolar con-
centration but also exhibit potent anticancer activity against
multidrug-resistant cell lines.6 Previous studies have demonstrated
that lamellarin D is capable of promoting DNA cleavage through
stabilization of topo IeDNA covalent complexes,6b-c a mode of
* Corresponding author.
E-mail address: yang@thu.edu.tw (D.-Y. Yang).
https://doi.org/10.1016/j.tet.2018.01.042
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Vyasamudri S, Yang D-Y, Application of differential reactivity towards synthesis of lamellarin and 8-
oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
https://doi.org/10.1016/j.tet.2018.01.042

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S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
research in pursuit of novel strategy for efficient construction of
lamellarin analogues so as to facilitate the process to the develop-
ment of lamellarin-derived anticancer drugs, here we describe a
concise synthesis of lamellarins and their isomeric benzofuran- and
pyridone-fused derivatives by acid-catalyzed or base-promoted
coupling of dihydroisoquinoline hydrochlorides and 3-
nitrocoumarins. The photochemical properties of the benzofuran-
8-oxoprotoberberines are then investigated. Some are found to be
light-insensitive, whereas others are light-sensitive and can un-
dergo oxidative ring-opening reaction when exposed to visible
light under aerobic conditions. A possible mechanism for this
photooxygenation is also proposed on the basis of experimental
data.
papaverine under sealed tube conditions. Success of this coupling
reaction serves as a good reference for the current investigation of
lamellarin type I synthesis. Scheme 1 outlines the optimized
preparation of lamellarin G trimethyl ether (1a) by SnCl2-catalyzed
direct coupling of 2a and 3a in toluene in sealed tube at 140 ꢀC for
8 h (Route I). To the best of our knowledge, this synthetic scheme
represents the shortest route for lamellarin G trimethyl ether (1a)
preparation ever reported in the literature18 (two steps only with
overall yield of 29.7% from commercial 2-hydroxy-4,5-
dimethoxybenzaldedyde). Alternatively, 1a can also be prepared
via a stepwise process (Route II) by coupling (2a) with 6,7-
dimethoxy-1-methyl-3,4-dihydroisoquinoline (3b) to afford the
pentacycle 4. Bromination of 4 with NBS generated the bromo-
substituted pentacycle 5. Finally, Suzuki coupling between 5 and
3,4-dimethoxyphenylboronic acid afforded 1a.19 While Route I is
shorter and gives higher overall yields, Route II has the advantage of
introducing different aryl groups onto the pentacyclic skeleton.
Fig. 2 lists the structures and yields for the prepared lamellarin
derivatives 1aꢁf via Route I. Since substituted 3-nitrocoumarins
and 3,4-dihydropapaverines are readily available, this Grob-type
coupling reaction provides an easy and rapid access to the biolog-
ically important lamellarin type I derivatives.
2. Results and discussion
Recently, we have reported16 the synthesis of lamellarin type II
derivatives by Grob-type coupling17 of 3-nitrocoumarins and
Similarly, Scheme 2 shows the two synthetic routes for the
preparation of benzofuran-8-oxoprotoberberine 6a. In Route I, 6a
was synthesized by Cs2CO3-mediated coupling reaction between
6,7-dimethoxy-3-nitrocoumarin (2a, prepared from condensation
of 2-hydroxy-4,5-dimethoxybenzaldedyde with ethyl nitroacetate)
and 3,4-dihydropapaverine hydrochloride (3a) in sealed tube in
18% yield (27% of 3a was recovered). Alternatively, compound 6a
can also be prepared via a stepwise process (Route II, Scheme 2) by
first coupling of 2a with 6,7-dimethoxy-1-methyl-3,4-
dihydroisoquinoline hydrochloride (3b) in sealed tube to afford
the pentacycle 7. The subsequent bromination of 7 with NBS
generated the bromo-substituted pentacycle 8. Final Suzuki
coupling of 8 with 3,4-dimethoxyphenylboronic acid afforded the
target 6a.13 While Route I is shorter and gives a higher overall yield,
Route II is capable of incorporating different aryl groups onto the
pentacyclic skeleton.
In order to prove that the formation of this oxoprotoberberine
scaffold is not a random process but follows a pattern that can be
applied to a large substrate scope, we have prepared a series of 3-
nitrocomarin and 3,4-dihydropapaverine derivatives with
electron-donating (N(Et)2, OMe) and electron-withdrawing (Cl,
NO2) substituents as the substrates. Fig. 3 lists the structures and
Fig. 1. Structures of lamellarin D, camptothecin, berberine, and benzofuran-8-
oxoprotoberberine.
Scheme 1. Synthesis of lamellarin 1a.
Fig. 2. Structures of the prepared lamellarins 1aꢁf.
Please cite this article in press as: Vyasamudri S, Yang D-Y, Application of differential reactivity towards synthesis of lamellarin and 8-
oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
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S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
3
Scheme 2. Synthesis of benzofuran-8-oxoprotoberberine 6a.
Fig. 4. ORTEP crystal structures of 1e (top) and 6h (bottom).
Fig. 3. Structures of the prepared 6aꢁj.
yields for the synthesized benzofuran-8-oxoprotoberberine de-
rivatives 6aꢁj via direct coupling of 3-nitrocoumarins and 3,4-
dihydropapaverines. The electronic nature of the substituents on
both substrates seems to have little effect on the yield of the
coupling reaction. Some of the molecular structures such as 1e and
6h were further confirmed by X-ray crystal analysis as shown in
Fig. 4.
Schemes 3 and 4 depict the proposed mechanism for the for-
mation of 1a and 6a, respectively. We envisioned that the mecha-
nism for the coupling of 2a and 3a under acidic conditions (Scheme
3) presumably involves SnCl2-catalyzed formation of Michael
adduct 9 which further undergoes isomerization to generate the
enamine 10. The intramolecular cyclization of 10 via nucleophilic
addition of the amine nitrogen to the iminium carbon generates the
cyclized dihydroxyamine 11. Final elimination of water and hypo-
nitrous acid from 11 gives the aromatized phenyl-substituted
pentacyclic lamellarin 1a.20
While Michael addition (1,4-addition) between 2a and 3a is the
major process when the coupling reaction is carried out under
acidic conditions, we found that the nucleophilic acyl substitution
to open up the coumarin lactone ring becomes the dominant re-
action when the coupling was performed under basic conditions.
Scheme 3. The proposed mechanism for the formation of 1a.
We speculate that the formation of 6a presumably begins with the
nucleophilic enamine nitrogen of 3a attacks coumarin carbonyl
carbon of 2a to give the enamide 12. The subsequent enamine-
mediated intramolecular conjugate addition of 12 affords the
cyclized 13. The second intramolecular cyclization of 13 via
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oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
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S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
Scheme 4. The proposed mechanism for the formation of 6a.
nucleophilic addition of the phenolic oxygen to the iminium carbon
generates the cyclized dihydroxyamine 14. Final elimination of
water and hyponitrous acid21 from 14 gives the aromatized aryl-
substituted benzofuran-8-oxoprotoberberine 6a. The differential
reactivity between dihydroisoquinolines and 3-nitrocoumarins
under different conditions is likely due to the intrinsic property
of 3-nitrocoumarins, that is, prone to undergo ring-opening of the
coumarin lactone in the presence of nitrogen nucleophiles under
basic conditions.22
Fig. 5. Structures and yields of the photogenerated products 13aꢁf.
With compounds 6aꢁi in hand, their photochemical properties
were then evaluated. Some of the prepared benzofuran-8-
oxoprotoberberine derivatives were found to be benchtop stable
but light-sensitive. After exposed to visible light (a 23 W fluores-
cence light bulb or blue LED) in the absence of any external sen-
sitizers under aerobic conditions in methylene chloride overnight,
compounds 6aꢁf were converted to the oxidized ring-opened
products, quantitatively, except 6e. The nitro-substituted 6d gave
relatively lower yield (32%) of the oxidized product 13e, suggesting
that the presence of an electron-withdrawing group on the 14-aryl
moiety of 6e hampers its photochemical reaction. Figs. 5 and 6
show the structures of the photogenerated products 13aꢁf and
the X-ray crystal structure of 13f, respectively. Only the compounds
bearing electron-donating group on benzofuran moiety (6aꢁe)
were found to be sensitive to light and undergo oxidative ring-
opening reaction upon visible light irradiation. Compounds with
no substituents (6gꢁi) or bearing electron-withdrawing groups
such as chloro (6j) are light-insensitive, and no oxidized products
were observed even after prolonged visible light irradiation.
Scheme 5 depicts the proposed mechanism for this visible-light-
mediated reaction. We envision that, upon visible light irradiation,
the oxygen molecule in solvent was trapped by double bond at C-14
and C-14a of benzofuran-8-oxoprotoberberine 6a (see Scheme 5 for
atom-numbering) to give the dioxetane 14 which further un-
dergoes ring-opening to afford the corresponding oxidized product
13a.
Fig. 6. ORTEP X-ray crystal structure of 13f.
Scheme 5. Proposed photochemical mechanism of 6a to 13a.
reactions was illustrated by the preparation of six lamellarin de-
rivatives 1aꢁf and ten benzofuran-8-oxoprotoberberines 6aꢁj.
Although the yields of the reactions remain to be improved, this
synthetic approach not only demonstrates the feasibility of con-
struction of isomeric pentacyclic skeletons via differential coupling
reactions but also provides an easy and quick access to biologically
important lamellarins and 8-oxoprotoberberines. Moreover, the
3. Conclusions
In summary, we have established that the aryl-substituted
pentacyclic
oxoprotoberberine isomers can be prepared via SnCl2-catalyzed
or Cs2CO3-mediated coupling of dihydroisoquinoline hydrochlo-
rides and 3-nitrocoumarins in sealed tube. The scope of these two
lamellarins
and
their
benzofuran-8-
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oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
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S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
5
prepared aryl-substituted benzofuran-8-oxoprotoberberine de-
4.2.3. 14-(3,4-dimethoxyphenyl)-2,3,11,12-tetramethoxy-8,9-
dihydro-6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
(1a)
rivatives 6aꢁf bearing electron-donating substituents on benzo-
furan moiety were found to be light-sensitive and undergo aerobic
oxidative ring-opening to generate the products 13aꢁf when
exposed to visible light. The biological activities of the prepared
6aꢁj and their derivatives are currently under investigation and
will be reported in due course.
A sealed tube with Teflon screw-stopper (flame dried and cooled
under a stream of nitrogen) was charged with 5 (50 mg, 0.10 mmol),
3,4-dimethoxy phenylboronic acid (22.5 mg, 0.12 mmol, 1.2 equiv),
Pd(PPh3)4 (23 mg, 0.02 mmol, 0.2 equiv), and K2CO3 (21 mg,
0.15 mmol, 1.5 equiv) in THF (20 mL). The sealed mixture was
refluxed for 12 h. After cooled down to room temperature, the
green colored solution was evaporated in vacuo and the crude
product was subjected to column chromatography to give the
compound 1a (60%).
4. Experimental section
4.1. Instrumentation
Melting points were determined on a Mel-Temp melting point
apparatus in open capillaries and are uncorrected. Infrared (IR)
spectra were recorded using 1725XFT-IR spectrophotometer. High
resolution mass spectra (HRMS) were obtained on a Thermo Fisher
Scientific Finnigan MAT95XL spectrometer using magnetic sector
analyzer 1H NMR (400 MHz) and 13C NMR (100 or 150 MHz) spectra
were recorded on a Varian VXR300 or Bruker 400/600 spectrom-
eter. Chemical shifts were reported in parts per million on the
4.3. General procedure for synthesis of type-I lamellerins 1a-1f
(Route-I)
A flame-dried 50 mL sealed tube fitted with Teflon ring screw
cap was charged with 3-nitrocoumarin (0.15 mmol, 1 equiv),
dihydroisoquinoline hydrochlorides (0.18 mmol, 1.2 equiv), SnCl2
(0.03 mmol, 0.2 equiv) in toluene (10 mL) under argon atmosphere.
The resulting mixture was then heated to 140 ꢀC in the sealed tube
for 12 h. Once the reaction mixture was cooled down to room
temperature, the solvent was evaporated in vacuo. The crude
mixture was purified by column chromatography to get the pure
compound.
d
scale relative to an internal standard (tetramethylsilane, or
appropriate solvent peaks) with coupling constants given in hertz.
1H NMR multiplicity data are denoted by s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet). Analytical thin-layer chroma-
tography (TLC) was carried out on Merck silica gel 60G-254 plates
(25 mm) and developed with the solvents mentioned. Visualization
was accomplished by using portable UV light, ninhydrin spray, or
iodine chamber. Flash chromatography was performed in columns
of various diameters with Merck silica gel (230e400 mesh ASTM
9385 kieselgel 60H) by elution with the solvent systems. Solvents,
unless otherwise specified, were reagent grade and distilled once
prior to use. All new compounds exhibited satisfactory spectro-
scopic and analytical data.
4.3.1. 14-(3,4-dimethoxyphenyl)-2,3,11,12-tetramethoxy-8,9-
dihydro-6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
(1a)
Off-white solid. Rf ¼ 0.55 (40% EtOAc/hexanes); 28 mg; yield
35%; mp 236e238 ꢀC (Lit.24 235 ꢀC); 1H NMR (CDCl3, 400 MHz)
d
7.12 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.08 (d, J ¼ 8.0 Hz, 1H), 7.05 (d,
J ¼ 1.6 Hz, 1H), 6.91 (s, 1H), 6.76 (s, 1H), 6.72 (s, 1H), 6.67 (s, 1H),
4.83e4.75 (m, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86 (s,
3H), 3.46 (s, 3H), 3.37 (s, 3H), 3.12 (t, J ¼ 6.8 Hz, 2H).
4.2. Synthesis of 4, 5 and 1a (Route-II)
4.2.1. 2,3,11,12-Tetramethoxy-8,9-dihydro-6H-chromeno[40,3':4,5]
pyrrolo[2,1-a]isoquinolin-6-one (4)
4.3.2. Synthesis of 14-(3,4-dimethoxyphenyl)-3,11,12-trimethoxy-
8,9-dihydro-6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
(1b)
A flame-dried 50 mL sealed tube fitted with Teflon ring screw
cap was charged with 2a (100 mg, 0.39 mmol), 6,7-dimethoxy-1-
methyl-3,4-dihydroisoquinoline (98 mg, 0.47 mmol, 1.2 equiv),
SnCl2 (15 mg, 0.08 mmol, 0.2 equiv) in toluene (10 mL) under argon
atmosphere. The resulting mixture was then heated to 140 ꢀC in the
sealed tube for 12 h. Once the reaction mixture was cooled down to
room temperature, the solvent was evaporated in vacuo. The crude
mixture was purified by column chromatography to give an off-
white solid 4. Rf ¼ 0.50 (40% EtOAc/hexanes); 65 mg; yield 40%;
mp 250e252 ꢀC (Lit.23 249e252 ꢀC); 1H NMR (CDCl3, 400 MHz)
Off-white solid. Rf ¼ 0.58 (40% EtOAc/hexanes) 30 mg; yield
32%; mp 248e250 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.11 (d,
J ¼ 8.8 Hz, 1H), 7.06 (s, 2H), 6.99 (s, 1H), 6.90 (d, J ¼ 2.4 Hz, 1H), 6.75
(s, 1H), 6.65 (s, 1H), 6.61 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.81e4.76 (m, 2H),
3.98 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.36 (s, 3H), 3.11
(t, J ¼ 6.8 Hz, 2H); 13C NMR (CDCl3, 150 MHz)
d 159.2, 155.4, 152.6,
149.8,148.9,148.8,147.4,136.1,128.1,127.9,126.6,124.1,123.3,120.0,
115.1, 113.8, 113.3, 111.9, 111.5, 111.4, 110.9, 108.7, 101.5, 56.1, 55.9,
55.5, 55.2, 42.4, 28.7; IR nmax 2945, 1708, 1610, 1402, 1321, 1256,
1132, 1038, 951, 771, 693 cmꢁ1; HRMS (EI) m/z calcd for C30H27NO7
[Mþ] 513.1788, found 513.1790.
d
7.19 (s, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 6.80 (s, 2H), 4.72 (t, J ¼ 6.8 Hz,
2H), 4.0 (s, 3H), 3.99 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.11 (t,
J ¼ 6.8 Hz, 2H).
4.2.2. 14-Bromo-2,3,11,12-tetramethoxy-8,9-dihydro-6H-chromeno
[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (5)
4.3.3. Synthesis of 2,3,11,12-tetramethoxy-14-phenyl-8,9-dihydro-
6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (1c)
White solid. Rf ¼ 0.60 (40% EtOAc/hexanes); 29 mg; yield 38%;
To a solution of 4 (50 mg, 0.122 mmol) in THF (25 mL) was added
N-bromosuccinimide (NBS, 32.7 mg, 0.18 mmol, 1.5 equiv) at 0 ꢀC.
The resulting mixture was stirred at room temperature for 30 min.
The precipitate was then filtered-off, washed with hexanes
(3 ꢂ 5 mL), and dried in vacuo to yield the compound 5. Rf ¼ 0.55
(40% EtOAc/hexanes); pale-yellow solid; 55.5 mg; yield 93%; mp
mp 250e252 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.59e7.54 (m, 4H),
7.49e7.45 (m, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 6.56 (s, 1H),
4.80 (t, J ¼ 6.8 Hz, 2H), 3.88 (s, 6H), 3.39 (s, 3H), 3.29 (s, 3H), 3.12 (t,
J ¼ 6.8 Hz, 2H); 13C NMR (CDCl3, 150 MHz)
d 155.6, 148.9, 148.7,
147.5, 146.0, 145.5, 135.8, 135.8, 131.4, 129.3, 128.1, 128.0, 126.6,
120.0, 115.0, 113.9, 111.0, 110.3, 108.7, 104.4, 100.5, 56.0, 55.9, 55.3,
55.0, 42.4, 28.7; IR nmax 2998, 2832, 1702, 1517, 1414, 1341, 1214,
1165, 1043, 863 cmꢁ1; HRMS (EI) m/z calcd for C29H25NO6 [Mþ]
483.1682, found 483.1678.
225e228 ꢀC (Lit.23 227e230 ꢀC); 1H NMR (CDCl3, 400 MHz)
d 8.27
(s, 1H), 8.16 (s, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 4.78 (t, J ¼ 6.8 Hz, 2H),
4.00 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.07 (t, J ¼ 6.8 Hz,
2H).
Please cite this article in press as: Vyasamudri S, Yang D-Y, Application of differential reactivity towards synthesis of lamellarin and 8-
oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
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S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
4.3.4. Synthesis of 14-(3,4-dimethoxyphenyl)-11,12-dimethoxy-8,9-
dihydro-6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
(1d)
The precipitate was then filtered-off, washed with hexanes
(3 ꢂ 5 mL), and dried in vacuo to yield the compound 14. White
solid; Rf ¼ 0.53 (80% EtOAc/hexanes); 54.3 mg; yield 91%; mp
Off-white solid. Rf ¼ 0.63 (40% EtOAc/hexanes); 30 mg; yield
223e225 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.95 (s, 1H), 7.92 (s, 1H),
32%; mp 240e243 ꢀC (Lit.25 235e239 ꢀC); 1H NMR (CDCl3,
7.20 (s, 1H), 6.81 (s, 1H), 4.36 (bs, 2H) 2.89 (t, J ¼ 6.0 Hz, 2H); 13C
400 MHz)
d
7.38 (d, J ¼ 8.0 Hz, 1H), 7.30e7.22 (m, 2H), 7.10e7.07 (m,
NMR (CDCl3, 150 MHz) d 152.6, 152.5,151.8, 150.2,146.7, 146.6, 141.7,
2H), 7.03e6.99 (m, 2H), 6.76 (s, 1H), 6.65 (s, 1H), 4.85e4.80 (m, 2H),
3.99 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.36 (s, 3H), 3.12 (t, J ¼ 6.4 Hz,
2H).
136.5, 132.0, 129.7, 121.4, 115.5, 113.8, 109.9, 104.0, 95.5, 91.6, 56.5,
56.30, 56.25, 56.0, 41.8, 29.1; IR nmax 2928, 2852, 1652, 1512, 1463,
1332, 1262, 1210, 1110, 1029, 930 cmꢁ1; HRMS (EI) m/z calcd for
C
23H20BrNO6 [Mþ] 485.0474, found 485.0483.
4.3.5. Synthesis of 11,12-dimethoxy-14-phenyl-8,9-dihydro-6H-
chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (1e)
4.4.3. 14-(3,4-dimethoxyphenyl)-2,3,11,12-tetramethoxy-5,6-
dihydro-8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6a)
A sealed tube with Teflon screw-stopper (flame dried and cooled
under a stream of nitrogen) was charged with 8 (50 mg, 0.10 mmol),
3,4-dimethoxyphenylboronic acid (22 mg, 0.12 mmol, 1.2 equiv),
Pd(PPh3)4 (24 mg, 0.02 mmol, 0.2 equiv), and K2CO3 (21 mg,
0.15 mmol, 1.5 equiv) in THF (20 mL). The sealed mixture was
refluxed for 12 h. After cooled down to room temperature, the
green colored solution was evaporated in vacuo and the crude
product was subjected to column chromatography to give the
compound 6a; 31 mg; yield 55%.
Off-white solid. Rf ¼ 0.65 (40% EtOAc/hexanes); 25 mg; yield
38%; mp 274e276 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.57e7.50 (m,
5H), 7.37 (dd, J ¼ 8.4,1.2 Hz,1H), 7.26 (td, J ¼ 7.2,1.2 Hz,1H), 7.16 (dd,
J ¼ 8.0, 1.6 Hz, 1H), 6.96 (td, J ¼ 8.0, 1.2 Hz, 1H) 6.75 (s, 1H), 6.49 (s,
1H), 4.83 (t, J ¼ 6.8 Hz, 2H), 3.88 (s, 3H), 3.28 (s, 3H), 3.12 (t,
J ¼ 6.8 Hz, 2H); 13C NMR (CDCl3, 150 MHz)
d 155.3, 151.2, 148.9,
147.4, 136.0, 135.7, 131.1, 129.5, 128.1, 127.3, 127.2, 126.6, 123.7, 123.3,
119.9, 118.3, 117.1, 116.1, 114.6, 110.9, 108.7, 55.9, 55.0, 42.5, 28.7; IR
nmax 2934, 2837, 1667, 1494, 1446, 1245, 1139, 1019, 926, 815 cmꢁ1
;
HRMS (EI) m/z calcd for C27H21NO4 [Mþ] 423.1471, found 423.1474.
4.3.6. Synthesis of 14-(4-(benzyloxy)phenyl)-11,12-dimethoxy-8,9-
dihydro-6H-chromeno[40,3':4,5]pyrrolo[2,1-a]isoquinolin-6-one (1f)
Off-white solid. Rf ¼ 0.60 (40% EtOAc/hexanes); 26.5 mg; yield
4.5. General procedure for synthesis of benzofurane-8-
oxoprotoberberines (6a-6j, Route-I)
32%; mp 220e222 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.49 (d,
J ¼ 8.4 Hz, 2H), 7.44e7.36 (m, 6H), 7.27 (td, J ¼ 8.0, 1.2 Hz, 1H), 7.21
(dd, J ¼ 8.0, 1.2 Hz, 1H), 7.16 (d, J ¼ 8.0 Hz, 2H), 6.99 (td, J ¼ 8.0,
1.2 Hz, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 4.81 (t, J ¼ 6.4 Hz,
2H), 3.88 (s, 3H), 3.26 (s, 3H), 3.11 (t, J ¼ 6.4 Hz, 2H); 13C NMR
A flame-dried 50 mL sealed tube fitted with Teflon ring screw
cap was charged with appropriately substituted 3-nitrocoumarins,
(0.15 mmol), appropriately substituted dihydroisoquinoline hy-
drochlorides (0.18 mmol, 1.2 equiv), Cs2CO3 (0.30 mmol, 2.0 equiv)
in toluene (10 mL) under argon atmosphere. The resulting mixture
was then heated to 140 ꢀC in the sealed tube for 12 h. Once the
reaction mixture was cooled down to room temperature, the sol-
vent was evaporated in vacuo. The crude mixture was purified by
column chromatography.
(CDCl3, 150 MHz)
d 158.6, 155.3, 151.3, 148.9, 147.4, 136.8, 132.2,
128.7, 128.1, 127.8, 127.5, 127.34, 127.29, 126.6, 123.7, 123.3, 120.0,
118.4, 117.1, 115.9, 115.6, 114.5, 110.9, 108.7, 70.0, 55.9, 55.1, 42.5,
28.7; IR nmax 2933, 2858, 1695, 1610, 1454, 1402, 1220, 1168, 1044,
753 cmꢁ1; HRMS (EI) m/z calcd for C34H27NO5 [Mþ] 529.1889, found
529.1886.
4.5.1. 14-(3,4-dimethoxyphenyl)-2,3,11,12-tetramethoxy-5,6-
dihydro-8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6a)
Off-white solid. Rf ¼ 0.50 (80% EtOAc/hexanes); 15 mg; yield
4.4. General procedure for synthesis 7, 8 and 6a (Route-II)
4.4.1. 2,3,11,12-Tetramethoxy-5,6-dihydro-8H-benzofuro[30,2':4,5]
pyrido[2,1-a]isoquinolin-8-one (7)
18%; mp 254e256 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.14 (s, 1H), 7.01
(d, J ¼ 8.0 Hz, 1H), 6.99 (d, J ¼ 1.6 Hz, 1H), 6.95 (dd, J ¼ 8.0, 1.6 Hz,
1H), 6.75 (s, 1H), 6.72 (s, 1H), 6.22 (s, 1H), 4.60e4.54 (m, 1H), 4.57,
4.31 (dt, J ¼ 14.0, 5.6 Hz, 1H each), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s,
A flame-dried 50 mL sealed tube fitted with Teflon ring screw
cap was charged with 2a (100 mg, 0.39 mmol), 6,7-dimethoxy-1-
methyl-3,4-dihydroisoquinoline (98 mg, 0.47 mmol, 1.2 equiv),
Cs2CO3 (259 mg, 0.79 mmol, 2.0 equiv) in toluene (10 mL) under
argon atmosphere. The resulting mixture was then heated to 140 ꢀC
in the sealed tube for 12 h. Once the reaction mixture was cooled
down to room temperature, the solvent was evaporated in vacuo.
The crude mixture was purified by column chromatography to give
an off-white solid 7. Rf ¼ 0.50 (80% EtOAc/hexanes); 52 mg; yield
3H), 3.82 (s, 3H), 3.59 (s, 3H), 3.28 (s, 3H), 2.93 (t, J ¼ 5.6 Hz, 2H); 13
C
NMR (CDCl3,100 MHz) d 153.2,152.7,151.3,150.1,149.2,149.0,146.6,
146.5, 141.9, 135.5,131.1, 130.5, 129.8, 123.5, 122.2, 115.2, 114.2, 113.6,
112.9, 112.1, 109.9, 103.8, 95.6, 56.3, 56.1, 55.9, 55.4, 41.2, 28.9; IR
nmax 2922, 2851, 1668, 1599, 1455, 1270, 1134, 1001, 926, 770 cmꢁ1
;
HRMS (EI) m/z calcd for C31H29NO8 [Mþ] 543.1893, found 543.1884.
32%; mp 264e266 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.32 (s, 1H), 7.30
(s, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.77 (s, 1H), 4.43 (t, J ¼ 6.4 Hz, 2H),
4.5.2. 14-(3,4-dimethoxyphenyl)-2,3,11-trimethoxy-5,6-dihydro-
8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6b)
Off-white solid. Rf ¼ 0.50 (80% EtOAc/hexanes); 14.5 mg; yield
4.03 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 2.96 (t, J ¼ 6.4 Hz,
2H); 13C NMR (CDCl3, 100 MHz)
d 153.5, 152.5, 151.5, 150.5, 148.6,
147.2, 142.5, 138.8, 129.3, 128.5, 122.5, 114.7, 110.5, 108.1, 102.0, 95.8,
94.6, 56.6, 56.5, 56.3, 56.2, 39.7, 28.0; IR nmax 2923, 2848,1659, 1514,
1476, 1334, 1209, 1116, 1017, 928 cmꢁ1; HRMS (EI) m/z calcd for
19%; mp 254e256 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.13 (d, J ¼ 1.6 Hz,
1H), 7.00 (d, J ¼ 8.4 Hz, 1H), 6.95 (d, J ¼ 1.6 Hz, 1H), 6.92 (dd, J ¼ 8.0,
1.6 Hz, 1H), 6.75e6.72 (m, 2H), 6.71 (s, 1H), 6.70 (s, 1H), 4.57, 4.31
(dt, J ¼ 14.0, 5.6 Hz, 1H each), 3.97 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H),
3.79 (s, 3H), 3.27 (s, 3H), 2.93 (t, J ¼ 5.6 Hz, 2H); 13C NMR (CDCl3,
C
23H21NO6 [Mþ] 407.1369, found 407.1371.
4.4.2. 14-Bromo-2,3,11,12-tetramethoxy-5,6-dihydro-8H-benzofuro
[30,2':4,5] pyrido[2,1-a]isoquinolin-8-one (8)
150 MHz) d 160.9,158.6,153.1, 149.9, 149.0,148.9,146.5,141.9, 135.6,
130.9, 130.3, 129.6, 123.6, 123.2, 122.0, 116.6, 113.9, 113.4, 112.9,
To a solution of 7 (50 mg, 0.26 mmol) in THF (25 mL) was added
N-bromosuccinimide (NBS, 61 mg, 0.34 mmol, 1.3 equiv) at 0 ꢀC.
The resulting mixture was stirred at room temperature for 30 min.
112.6, 112.0, 109.7, 96.3, 56.2, 56.1, 55.8, 55.7, 55.2, 41.2, 28.8; IR nmax
2934, 2837, 2251, 1662, 1586, 1494, 1227, 1139, 1013, 815, 728 cmꢁ1
;
HRMS (EI) m/z calcd for C30H27NO7 [Mþ] 513.1788, found 513.1796.
Please cite this article in press as: Vyasamudri S, Yang D-Y, Application of differential reactivity towards synthesis of lamellarin and 8-
oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
https://doi.org/10.1016/j.tet.2018.01.042

S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
7
4.5.3. 14-(4-(benzyloxy)phenyl)-2,3,11,12-tetramethoxy-5,6-
dihydro-8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6c)
Off-white solid, Rf ¼ 0.50 (80% EtOAc/hexanes); 14 mg; yield
55.4, 41.5, 28.9; IR nmax 2944, 2836, 1658, 1506, 1251, 1142, 1024,
876, 746 cmꢁ1; HRMS (EI) m/z calcd for C29H25NO6 [Mþ] 483.1682,
found 483.1690.
19%; mp 234e236 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.46e7.36 (m,
4H), 7.35e7.32 (m, 3H), 7.13e7.11 (m, 3H), 6.71 (s, 1H), 6.66 (s, 1H),
6.18 (s, 1H), 5.15 (s, 2H), 4.43 (dt, J ¼ 6.0 Hz, 2H), 3.94 (s, 3H), 3.89 (s,
3H), 3.53 (s, 3H), 3.21 (s, 3H), 2.92 (t, J ¼ 6.0 Hz, 2H); 13C NMR
4.5.8. 2,3-Dimethoxy-14-phenyl-5,6-dihydro-8H-benzofuro
[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6h)
Off-white solid. Rf ¼ 0.65 (80% EtOAc/hexanes); 14 mg; yield
(CDCl3, 150 MHz)
d
158.4, 153.0, 152.5, 151.0, 148.9, 146.3, 146.2,
22%; mp 288e290 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.67 (d,
141.8, 136.6, 135.3, 132.3, 130.9, 130.2, 129.7, 128.7, 128.2, 127.2,
122.0, 115.6, 115.0, 113.6, 112.7, 109.6, 103.6, 95.4, 70.0, 56.2, 55.8,
55.2, 41.1, 28.8; IR nmax 2922, 2851, 1668, 1599, 1455, 1270, 1134,
1001, 926, 770 cmꢁ1; HRMS (EI) m/z calcd for C36H31NO7 [Mþ]
589.2101, found 589.2104.
J ¼ 8.0 Hz, 1H), 7.53e7.48 (m, 3H), 7.47e7.42 (m, 3H), 7.08 (t,
J ¼ 8.0 Hz, 1H), 6.76 (d, J ¼ 8.0 Hz, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 4.47
(t, J ¼ 6.0 Hz, 2H), 3.89 (s, 3H), 3.18 (s, 3H), 2.94 (t, J ¼ 6.0 Hz, 2H);
13C NMR (CDCl3, 150 MHz)
d 157.0, 153.5, 149.0, 146.4, 142.3, 137.8,
135.4, 131.0, 130.9, 129.5, 128.8, 128.4, 128.1, 123.5, 123.2, 123.1,
121.8, 113.7, 113.5, 112.7, 109.7, 55.8, 55.2, 41.3, 28.8; IR nmax 2947,
2834, 1667, 1506, 1275, 1209, 1107, 1037, 877, 723 cmꢁ1; HRMS (EI)
m/z calcd for C27H21NO4 [Mþ] 423.1479, found 423.1479.
4.5.4. 2,3,11,12-Tetramethoxy-14-phenyl-5,6-dihydro-8H-benzofuro
[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6d)
White solid, Rf ¼ 0.60 (80% EtOAc/hexanes); 16 mg; yield 21%;
mp 264e266 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.55e7.45 (m, 5H),
4.5.9. 14-(4-(benzyloxy)phenyl)-2,3-dimethoxy-5,6-dihydro-8H-
benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6i)
7.13 (s, 1H), 6.72 (s, 1H), 6.65 (s, 1H), 6.06 (s, 1H), 4.46 (t, J ¼ 6.0 Hz,
2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.53 (s, 1H), 3.18 (s, 3H), 2.94 (t,
Off white solid. Rf ¼ 0.65 (80% EtOAc/hexanes); 15.2 mg; yield
J ¼ 6.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d
153.2, 152.7, 151.2,
19%; mp 218e220 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.67 (d,
149.2, 146.6, 146.5, 142.0, 138.2, 135.2, 131.3, 131.1, 129.6, 129.5,
128.1, 122.0, 115.1, 113.9, 113.2, 109.9, 103.6, 95.5, 56.3, 56.0, 55.9,
55.3, 41.2, 29.0; IR nmax 2943, 2836, 1660, 1471, 1261, 1212, 1110,
1011, 927, 826, 726 cmꢁ1; HRMS (EI) m/z calcd for C29H25NO6 [Mþ]
483.1682, found 483.1684.
J ¼ 8.4 Hz, 1H), 7.49e7.41 (m, 5H), 7.38 (d, J ¼ 6.8 Hz, 1H), 7.32 (d,
J ¼ 8.8 Hz, 2H), 7.12 (d, J ¼ 8.8 Hz, 2H), 7.14e7.10 (m, 1H), 6.86 (d,
J ¼ 7.6 Hz, 1H), 6.71 (s, 1H), 6.61 (s, 1H), 5.17 (s, 2H), 4.45 (t,
J ¼ 6.0 Hz, 2H), 3.90 (s, 3H), 3.20 (s, 3H), 2.93 (t, J ¼ 6.0 Hz, 2H); 13
C
NMR (CDCl3, 150 MHz)
d 158.5, 157.0, 153.5, 149.0, 146.4, 142.3,
136.6,135.6,132.1,130.9,130.1,129.1,128.7,128.4,128.2,127.4,123.6,
123.3, 123.1, 121.9, 115.9, 113.6, 113.2, 112.7, 109.6, 70.1, 55.8, 55.2,
41.3, 28.8; IR nmax 3048, 2835, 1668, 1505, 1219, 1104, 1032, 837,
732 cmꢁ1; HRMS (EI) m/z calcd for C34H27NO5 [Mþ] 529.1889, found
529.1883.
4.5.5. 2,3,11,12-Tetramethoxy-14-(4-nitrophenyl)-5,6-dihydro-8H-
benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6e)
Yellow solid, Rf ¼ 0.45 (80% EtOAc/hexanes); 21 mg; yield 25%;
mp 308e310 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
8.40 (d, J ¼ 8.8 Hz, 2H),
7.68 (d, J ¼ 8.8 Hz, 2H), 7.15 (s, 1H), 6.75 (s, 1H), 6.34 (s, 1H), 6.14 (s,
1H), 4.41 (t, J ¼ 6.0 Hz, 2H) 3.95 (s, 3H), 3.90 (s, 3H), 3.57 (s, 3H), 3.18
4.5.10. 11-Chloro-14-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5,6-
dihydro-8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6j)
Pale-yellow solid. Rf ¼ 0.60 (80% EtOAc/hexanes); 18 mg; yield
(s, 3H), 2.95 (t, J ¼ 6.0 Hz, 2H); 13C NMR (CDCl3, 150 MHz)
d 152.8,
152.6,151.4,149.7,147.3,146.6,145.2,142.0,136.0,132.7,131.6,128.0,
124.1, 120.9, 114.0, 113.9, 110.6, 110.1, 103.0, 95.5, 56.2, 56.0, 55.9,
55.3, 41.0, 28.7; IR nmax 2930, 2852, 1666, 1590, 1488, 1344, 1212,
1171, 1036, 837, cmꢁ1; HRMS (EI) m/z calcd for C29H24N2O8 [Mþ]
528.1533, found 528.1539.
23%; mp 244e246 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.66 (d,
J ¼ 1.6 Hz, 1H), 7.09 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.00 (d, J ¼ 8.4 Hz, 1H),
6.93 (s, 1H), 6.92 (d, J ¼ 8.4 Hz, 1H), 6.77 (d, J ¼ 8.4 Hz, 1H), 6.72 (s,
1H), 6.70 (s, 1H), 4.56, 4.33 (dt, J ¼ 14.0, 5.6 Hz, 1H each), 3.97 (s,
3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.28 (s, 3H), 2.93 (t, J ¼ 5.6 Hz, 2H); 13
C
4.5.6. 11-(diethylamino)-2,3-dimethoxy-14-phenyl-5,6-dihydro-
8H-benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6f)
Brown solid. Rf ¼ 0.50 (80% EtOAc/hexanes); 13.3 mg; yield 18%;
NMR (CDCl3, 150 MHz) d 157.1, 153.2, 150.0, 149.2, 149.0, 146.5,
142.6,136.1,134.4,130.9,129.8,128.8,124.1,123.9,123.1,122.3,121.7,
113.7, 113.3, 113.1, 112.8, 112.1, 109.7, 56.2, 56.1, 55.9, 55.2, 41.4, 28.8;
IR nmax 2989, 2839, 1665, 1506, 1460, 1231, 1141, 1023, 805,
727 cmꢁ1; HRMS (EI) m/z calcd for C29H24ClNO6 [Mþ] 517.1292,
found 517.1293.
mp 264e266 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.51e7.44 (m, 3H),
7.42e7.40 (m, 2H), 6.82 (d, J ¼ 2.0 Hz, 1H), 6.70 (s, 1H), 6.57 (s, 1H),
6.53 (d, J ¼ 8.8 Hz, 1H), 6.46 (dd, J ¼ 8.8, 2.0 Hz, 1H), 4.44 (t,
J ¼ 6.0 Hz, 2H), 3.39 (q, J ¼ 7.2 Hz, 4H), 2.91 (t, J ¼ 6.0 Hz, 2H), 1.17 (t,
J ¼ 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz)
d
160.0, 152.9, 148.9,
4.6. General procedure for the photochemical reaction: synthesis of
compounds 13a-13f
148.8, 146.3, 140.8, 138.4, 135.1, 131.0, 130.9, 130.0, 129.3, 127.8,
123.4, 122.1, 113.7, 113.2, 111.7, 109.6, 109.2, 93.5, 55.9, 55.2, 44.9,
41.0, 28.9, 12.4; IR nmax 2974, 2834, 1626, 1505, 1342, 1254, 1105,
1027, 875, 797 cmꢁ1; HRMS (EI) m/z calcd for C31H30N2O4 [Mþ]
494.2206, found 494.2203.
Compound (6aej, 0.02 mmol) was dissolved in dichloro-
methane (5 mL) and was kept the solution for stirring near a visible
light source (10 cm away from a 23 W fluorescence light bulb or
blue LED). The reaction was stirred for 8e18 h, and the reaction was
monitored by TLC. Once completed, the solution was concentrated
and the crude product was purified by column chromatography to
give the pure compound.
4.5.7. 14-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5,6-dihydro-8H-
benzofuro[30,2':4,5]pyrido[2,1-a]isoquinolin-8-one (6g)
White solid, Rf ¼ 0.55 (80% EtOAc/hexanes); 14.6 mg; yield 20%;
mp 308e310 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.67 (d, J ¼ 8.4 Hz, 1H),
7.46 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.11 (t, J ¼ 7.6 Hz, 1H), 7.01 (d, J ¼ 8.0 Hz,
1H), 6.97 (d, J ¼ 2.0 Hz, 1H), 6.94 (dd, J ¼ 8.0, 2.0 Hz, 1H), 6.88 (d,
J ¼ 7.6 Hz, 1H), 6.72 (s, 2H), 4.59, 4.32 (dt, 14.0, 6.0 Hz,1H each), 3.98
(s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.28 (s, 3H), 2.94 (t, J ¼ 6.0 Hz, 2H);
4.6.1. 2-(3-(3,4-dimethoxybenzoyl)-5,6-dimethoxybenzofuran-2-
carbonyl)-7,8-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (13a)
Yellow solid; Rf ¼ 0.55 (50% EtOAc/hexanes); 10.2 mg; yield 96%;
mp 196e198 ꢀC; 1H NMR (CDCl3, 400 MHz)
2.0 Hz, 1H), 7.57 (s, 1H), 7.52 (d, J ¼ 2.0 Hz, 1H), 7.20 (s, 1H), 7.04 (s,
1H), 6.85 (d, J ¼ 8.4 Hz, 1H), 6.70 (s, 1H), 3.96 (s, 3H), 3.96e3.94 (m,
2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 2.81 (t,
d
7.66 (dd, J ¼ 8.4,
13C NMR (CDCl3, 100 MHz)
d
157.1, 153.6, 150.0, 149.2, 149.1, 146.6,
142.3, 135.7, 131.0, 130.2, 129.2, 128.5, 123.7, 123.4, 123.3, 123.2,
123.1, 122.1, 114.0, 113.5, 113.4, 112.8, 112.2, 109.8, 56.3, 56.2, 56.0,
Please cite this article in press as: Vyasamudri S, Yang D-Y, Application of differential reactivity towards synthesis of lamellarin and 8-
oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines, Tetrahedron (2018),
https://doi.org/10.1016/j.tet.2018.01.042

8
S. Vyasamudri, D.-Y. Yang / Tetrahedron xxx (2018) 1e9
J ¼ 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d
189.3, 165.0, 162.9,
mp 205e208 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.95 (d, J ¼ 8.4 Hz,1H),
154.0,153.6,151.0,149.4,149.1,148.9,148.6,148.2,135.1,131.4,124.9,
122.7, 120.0, 119.2, 111.2, 111.0, 110.3, 109.6, 102.3, 95.1, 56.5, 56.4,
56.2, 56.2, 56.1, 44.2, 27.9; IR nmax 2925, 2852, 1668, 1599, 1512,
1339, 1267, 1133, 1020, 837, 770 cmꢁ1; HRMS (EI) m/z calcd for
7.55e7.51 (m, 2H), 7.46 (d, J ¼ 8.4 Hz, 1H), 7.40 (t, J ¼ 8.4 Hz, 2H),
6.74 (dd, J ¼ 8.4, 2.0 Hz, 1H) 6.70 (d, J ¼ 2.0 Hz, 1H), 6.67 (s, 1H), 3.96
(s, 3H), 3.92 (t, J ¼ 6.4 Hz, 2H), 3.87 (s, 3H), 3.40 (q, J ¼ 6.4 Hz, 1H),
2.90 (t, J ¼ 6.4 Hz, 2H), 1.18 (t, J ¼ 6.4 Hz, 6H); 13C NMR (CDCl3,
C
31H29NO10 [Mþ] 575.1791, found 575.1785.
150 MHz) d 190.9, 164.7, 163.1, 156.9, 153.6, 148.6, 148.3, 147.7, 138.3,
134.8, 132.9, 129.5, 128.4, 123.2, 122.6, 120.1, 115.8, 111.4, 110.9,
109.4, 93.0, 56.2, 56.1, 44.9, 44.1, 27.7, 12.5; IR nmax 2922, 2851, 1645,
1514,1360,1262,1164,1035, 889, 804 cmꢁ1; HRMS (EI) m/z calcd for
4.6.2. 2-(3-(3,4-dimethoxybenzoyl)-6-methoxybenzofuran-2-
carbonyl)-7,8-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (13b)
Light brown solid 13b. Rf ¼ 0.60 (50% EtOAc/hexanes); 9.8 mg;
C
31H30N2O6 [Mþ] 526.2104, found 526.2114.
yield 97%; mp 192e194 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.63 (dd,
J ¼ 8.8, 2.0 Hz, 1H), 7.62 (d, J ¼ 8.8 Hz, 1H), 7.54 (s, 1H), 7.51 (d,
J ¼ 2.0 Hz, 1H), 7.02 (d, J ¼ 2.0 Hz, 1H), 6.96 (dd, J ¼ 8.8, 2.0 Hz, 1H),
6.84 (d, J ¼ 8.8 Hz, 1H), 6.70 (s, 1H), 3.98e3.95 (m, 2H), 3.97 (s, 3H),
3.92 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.91 (t, J ¼ 6.0 Hz,
Acknowledgement
We thank the Ministry of Science and Technology of the Re-
public of China, Taiwan, for financially supporting this research
under Contract No. MOST 106-2113-M-029-002.
2H); 13C NMR (CDCl3, 150 MHz)
d 188.8, 164.8, 162.9, 160.3, 155.3,
153.9, 153.5, 149.03, 148.97, 148.4, 134.9, 131.2, 124.7, 122.8, 122.4,
120.1, 119.9, 114.4, 111.1, 110.9, 110.1, 109.5, 95.6, 56.2, 56.1, 56.0, 55.7,
44.0, 27.7; IR nmax 2921, 2851, 1667, 1514, 1338, 1264, 1116, 1021, 818,
768 cmꢁ1; HRMS (EI) m/z calcd for C30H27NO9 [Mþ] 545.1686, found
545.1689.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.01.042.
4.6.3. 2-(3-(4-(benzyloxy)benzoyl)-5,6-dimethoxybenzofuran-2-
carbonyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (13c)
Off white solid; 1 Rf ¼ 0.55 (50% EtOAc/hexanes); 10.2 mg; yield
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