Total synthesis of 8-oxypseudopalmatine and 8-oxypseudoberberine via ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2009.10.027

Concise synthesis of 8-oxypseudopalmatine and 8-oxypseudoberberine has been achieved using ruthenium-catalyzed ring-closing metathesis (RCM) as the key step, in which the RCM substrates, 3-arylisoquinolinones, were prepared by lithiated cycloaddition reac

Full text of DOI:10.1016/j.tet.2009.10.027

Tetrahedron 65 (2009) 10142–10148
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of 8-oxypseudopalmatine and 8-oxypseudoberberine via
ring-closing metathesis
,
Hue Thi My Van a, Su Hui Yang a, Daulat Bikram Khadka a, Yong-Chul Kim b, Won-Jea Cho a
*
a College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Yong-Bong dong, Buk-gu, Gwangju 500-757, Republic of Korea
b Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Concisesynthesis of8-oxypseudopalmatineand 8-oxypseudoberberinehasbeen achievedusing ruthenium-
catalyzed ring-closing metathesis (RCM) as the key step, inwhich the RCM substrates, 3-arylisoquinolinones,
were prepared by lithiated cycloaddition reaction with o-toluamides and benzonitriles.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 September 2009
Received in revised form
8 October 2009
Accepted 8 October 2009
Available online 13 October 2009
Keywords:
8-Oxypseudopalmatine
8-Oxypseudoberberine
3-Arylisoquinolinones
Ring-closing metathesis
MeO
MeO
O
O
1. Introduction
N
O
N
O
Protoberberines have been extensively investigated for their va-
riety of interesting biological activities such as antifungal,1 antitu-
mor,2 and antimicrobial3 properties, and the syntheses of these
alkaloids have been reported.4 Recently, we reported the efficient
synthesis of protoberberine and benzo[c]phenanthridine alkaloids
via 3-arylisoquinolines as key intermediates.5–7 To develop a novel
synthetic method for these alkaloids, we next applied Ring-Closing
Metathesis(RCM) tothe construction of the C ringofprotoberberines.
Amongprotoberberinealkaloids, wechose8-oxypseudopalmatine
and 8-oxypseudoberberine as target compounds. 8-Oxy-
pseudopalmatine is an alkaloid found in Stephama suberosa, Forman
(Menispermaceae).8 In vitro tests for cytostatic activity in MDA-MB-
231 mammary tumor cells showed that 8-oxypseudopalmatine in-
hibits cell proliferation more effectively than berberine or coralyne
chloride (Fig. 1).9
OMe
OMe
OMe
OMe
8-Oxypseudoberberine (2)
8-Oxypseudoplamatine (1)
Figure 1. Structure of 8-oxyprotoberberines.
2. Results and discussion
This strategy was based onpreparation of 3-arylisoquinolines that
retain olefins at the appropriate positions for the RCM reaction. For
this, a coupling reaction between N,N-diethyl-o-toluamide 3 and
benzonitrile4 wascarriedout toyield the 3-arylisoquinoline5, which
could be converted to the diene 6 via styrene preparation and N-
vinylation of 3-arylisoquinoline 5 as depicted in Scheme 1. The RCM
product 10 was then reduced by catalytic hydrogenation to afford the
desired 8-oxyprotoberines. Recently, we reported isoquinoline
alkaloid synthesis based on the coupling reaction of o-toluamides
with benzonitriles.5 Moreover, biological evaluations with molecular
modeling studies of various isoquinolines such as isoindolo[2,1-b]
isoquinolinones,12 benz[b]oxepines, 12-oxobenzo[c]phenan-
thridinones,13 and indeno[1,2-c]isoquinolines14 were also reported.
The advantages of our 3-arylisoquinoline synthesis methodology
are easy accessibility to the staring materials and a one-pot pro-
cedure for construction of all carbon atoms for the alkaloids.
RCM catalyzed by transition metal carbenes is a powerful tool for
the conversionofacyclicdienestocyclicrings.10 Whilea largenumber
of mono- and polycyclic compounds have been prepared by this
method, RCM has not been applied to the construction of C ring of
protoberberine alkaloids. Recent report showed the example of ap-
plication of RCM for A ring formation on protoberberine synthesis.11
* Corresponding author. Tel.: þ82 62 530 2933; fax: þ82 62 530 2911.
E-mail address: wjcho@jnu.ac.kr (W.-J. Cho).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.027

H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
10143
R2
R2
R2
RCM
A
C
R1
R1
R1
N
N
N
O
O
O
10
8-Oxyprotoberberines
9
R2
Me
NEt2
MOMO
NC
R2
R1
R1
NH
OMOM
O
O
o-Toluamides (3)
Benzonitriles (4)
3-Arylisoquinolines (5)
Scheme 1. Retrosynthetic pathway of 8-oxyprotoberberines.
As a model study, we first used simple starting materials. The
coupling reactions were performed with o-toluamides 3a–c and
PMB-protected benzonitrile 4a to afford 3-arylisoquinolines 5a–c
in moderate yield. To introduce the vinyl group on the amide
nitrogen, we applied the aryl vinyl ether preparation conditions.
Unsubstituted amide 5a was treated with tetravinyl tin in the
presence of Cu(OAc)2 in acetonitrile under an atmosphere of pure
O2 to generate compound 6a in 43% yield without an O-vinyl
product.15 This is the first example of the preparation of N-vinyl
compounds with the above-mentioned reaction. The substituted
amides 5b–e also gave the corresponding N-vinyl compounds in
36–48% yield in the same reaction. Deprotection of the PMB
group on 6a–c was accomplished by DDQ oxidation to provide the
hydroxymethyl compounds 7a–c. MOM of 6d was removed with
10% HCl to give 7d and the TBDMS group of 6e was deprotected
by tetrabutylammonium fluoride in THF to afford the desired
hydroxymethyl compound 7e in 74% yield. Hydroxymethyl group
of compound 6e was protected by TBDMS instead of MOM
because the corresponding MOM-protected hydroxymethyl com-
pound could not afford the desired products in various acidic
conditions. Instead, decomposed unknown products were
obtained. PDC oxidation of 7a–e gave the corresponding alde-
hydes 8a–e in 57–84% yields. Wittig reactions of the aldehydes
8a–e with Ph3PCH3Br and n-BuLi in THF provided the desired
olefins 9a–e in 53–85% yield, depending on the substituted
pattern on the aromatic rings. RCM reactions of 9a–e were
performed with second-generation Grubbs catalyst in CH2Cl2 gave
the desired cyclized compounds 10a–e in 24–91% yield.
Interestingly, dienes with more substituted benzene ring 9d–e
afforded much higher yield (91, 76%) in the above reaction.
Finally, the double bonds on 10a–e were selectively reduced by
catalytic hydrogenation with 5% Pd/C or 10% PtO2 under 70 psi
hydrogen pressure to give the desired 8-oxyprotoberberines 1,2,
11a–c in moderate yield. The above regioselective catalytic
hydrogen reaction could be explained by the fact that the di-
substituted double bond hydrogenation of 10a–e is preferred than
tri-substituted double bond because the rate of hydrogenation
decreases with an increase in the number of alkyl substituents of
double bond.16
studies of isoquinoline alkaloids that possess various biological
properties (Scheme 2).
4. Experimental
4.1. General methods
Melting points were determined by the capillary method on
an Electrothermal IA9200 digital melting point apparatus and
were uncorrected. Nuclear magnetic resonance (NMR) data for 1H
NMR were taken on a Varian Unity 300 Plus spectrometer and
were reported in parts per million, downfield from the peak of
the internal standard, tetramethylsilane. The data are reported as
follows: chemical shift, number of protons, multiplicity (s: sin-
glet, d: doublet, t: triplet, q: quartet, m: multiplet, b: broadened).
IR spectra were recorded on JASCO-FT IR spectrometer using
CHCl3 and KBr pellets. Mass spectra were obtained on JEOL JNS-
DX 303 applying the electron-impact (EI) method. Column
chromatography was performed on Merck silica gel 60 (70–230
mesh). TLC was performed using plates coated with silica gel 60
F254 (Merck). Chemical reagents were purchased from Aldrich
Chemical Co. and used without further purification. Solvents
were distilled prior to use: THF and ether were distilled from
sodium/benzophenone.
4.1.1. N,N-Diethyl-2-methylbenzamide (3a)17. To a solution of thio-
nyl chloride (68 ml) in an ice-bath, o-toluic acid (13.6 g, 100 mmol)
was added portionwise. After removal from the ice-bath, the re-
action mixture was warmed to about 50 ꢀC for 45 min in order to
completely dissolve the o-toluic acid. The reaction mixture was
allowed to gradually cool to room temperature with stirring over-
night. The excess thionyl chloride was removed by vacuum distil-
lation. The residue was dissolved in CH2Cl2 (100 ml), and
diethylamine (78 ml, 760 mmol) was added at 0 ꢀC. After stirring
overnight, the reaction mixture was diluted with water, the organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2. The organic layers were washed with water and brine,
dried, and then concentrated. The residue was purified by column
chromatography with n-hexane–ethyl acetate (1:1) to obtain
compound 3a as a yellow oil (18.7 g, 98%). IR (cmꢁ1): 1631 (C]O).
3. Conclusion
1H NMR (300 MHz, CDCl3)
d: 7.23–7.13 (m, 4H), 3.80 (s, 1H), 3.40 (s,
1H), 3.09 (q, J¼6.9 Hz, 2H), 2.27 (s, 3H),1.24 (t, J¼6.9 Hz, 3H), 0.99 (t,
Herein, we successfully synthesized natural 8-oxy-
pseudopalmatine and 8-oxypseudoberberine with other sub-
stitutions using RCM as a key reaction. Our synthesis illustrates
a versatile method for synthesizing diversely substituted proto-
berberines and could be useful for structure–activity relationship
J¼7.2 Hz, 3H). EIMS: m/z 191 (Mþ, 100).
4.1.2. N,N-Diethyl-2,4-dimethylbenzamide (3b)13. The procedure
described for compound 3a was used with 2,4-dimethylbenzoic
acid (10 g, 66.7 mmol) and thionyl chloride (45 ml) to give amide

10144
H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
Scheme 2. Synthesis of 8-oxyprotoberberines.
3b as a yellow oil (12.5 g, 92%). IR (cmꢁ1): 1632 (C]O). 1H NMR
(300 MHz, CDCl3)
(s, 1H), 3.15–3.09 (m, 2H), 2.29–2.20 (d, 6H), 1.25 (t, J¼7.1 Hz, 3H),
1.02 (t, J¼7.1 Hz, 3H). EIMS: m/z 205 (Mþ, 100).
d
: 7.06–7.01 (m, 3H), 3.60 (s, 2H), 3.12 (q, J¼7.1 Hz,
2H), 2.31 (s, 3H), 2.24 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H), 1.02 (t, J¼7.1 Hz,
3H). EIMS: m/z 205 (Mþ, 100).
4.1.4. 4,5-Dimethoxy-2-methoxymethoxymethylbenzonitrile
(4b)12. To the mixture of alcohol (5.5 g, 28.5 mmol) in CH2Cl2
(20 ml) was added diisopropylethylamine (DIPEA) (7.35 g,
57 mmol) and chloromethylmethyl ether (4.59 g, 57 mmol) at 0 ꢀC.
After the reaction was over, CH2Cl2 was removed in vacuo and the
residue was purified by column chromatography with n-hexane–
ethyl acetate (3:1) to give benzonitrile 4b as a white solid (6.7 g,
4.1.3. N,N-Diethyl-2,5-dimethylbenzamide (3c)13. The procedure
described for compound 3a was used with 2,5-dimethylbenzoic
acid (7.5 g, 50 mmol) and thionyl chloride (50 ml) to afford com-
pound 3c as a yellow oil (9.6 g, 94%). IR (cmꢁ1): 1632 (C]O). 1H
NMR (300 MHz, CDCl3) d: 7.05 (s, 2H), 6.96 (s, 1H), 3.75 (s, 1H), 3.40

H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
10145
99%). Mp: 54.5–56.4 ꢀC. IR (cmꢁ1): 2222 (CN). 1H NMR (300 MHz,
155–157 ꢀC. IR (cmꢁ1): 3431 (NH), 1634 (C]O). 1H NMR (300 MHz,
CDCl3) : 10.18 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.94 (s,
1H), 6.52 (s,1H), 4.79 (s, 2H), 4.55 (s, 2H), 4.01 (m, 6H), 3.96 (m, 6H),
3.43 (s, 3H). Anal. Calcd for C22H25NO7: C, 63.60; H, 6.07; N, 3.37.
Found: C, 63.63; H, 6.05; N, 3.33. EIMS: m/z 415 (Mþ, 64).
CDCl3)
d
: 7.07–7.03 (d, 2H), 4.76 (s, 2H), 4.71 (s, 2H), 3.95 (s, 3H),
d
3.91 (s, 3H), 3.44 (s, 3H). EIMS: m/z 237 (Mþ, 100).
4.1.5. 6-(tButyldimethylsilanyloxymethyl)benzo[1,3]dioxole-5-carbo
nitrile (4c). To a stirred mixture of 6-hydroxymethylbenzo[1,3]di-
oxole-5-carbonitrile (3.9 g, 22 mmol) and butyl dimethyl silyl chlo-
t
4.1.10. 3-[6-(tButyldimethylsilanyloxymethyl)benzo[1,3]dioxol-5-yl]-
6,7-dimethoxy-2H-isoquinolin-1-one (5e). The procedure described
for compound 5a was used with N,N-diethyl-4,5-dimethoxy-2-
methylbenzamide 3d (5.0 g, 18.3 mmol), benzonitrile 4c (5.33 g,
18.3 mmol), and n-BuLi (17.6 ml of 2.5 M in hexane, 43.9 mmol) in
dry THF (10 ml) to afford compound 5e as a yellow oil (2.8 g, 32%).
ride (6.63 g, 44 mmol) in DMF (3 ml) was added triethylamine
(4.44 g, 44 mmol) at room temperature. After stirring overnight at
35 ꢀC, the mixture was diluted with water, extracted with ethyl
acetate, washed with brine, and dried over Na2SO4. The organic ex-
tracts were combined, concentrated in vacuo, and purified by column
chromatography on silica gel with n-hexane–ethyl acetate (4:1) to
give the protected alcohol 4c as a white solid (5.36 g, 84%). Mp:
IR (cmꢁ1): 3477 (NH), 1632 (C]O). 1H NMR (300 MHz, CDCl3)
d:
10.2 (s, 1H), 7.80 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 6.87 (s, 1H), 6.69 (s,
1H), 5.04 (s, 2H), 4.57 (s, 2H), 4.00 (s, 6H), 0.98 (s, 9H), 0.19 (s, 6H).
EIMS: m/z 69 (Mþ, 78). HRMS-EI (calcd for C25H31NO6Si): 469.1921,
found 469.1927.
48–49 ꢀC. IR (cmꢁ1): 2219 (CN). 1H NMR (300 MHz, CDCl3)
d: 7.07
(s, 1H), 6.95 (s, 1H), 6.04 (s, 2H), 4.79 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H).
EIMS: m/z 291 (Mþ, 100).
4.1.6. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-2H-isoquinolin-1-
4.1.11. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-2-vinyl-2H-iso-
quinolin-1-one (6a). Anhydrous Cu(OAc)2 (1.527 g, 8.4 mmol) was
added to a stirred solution of compound 8a (2.6 g, 7 mmol) in
CH3CN (30 ml) under dry O2 at room temperature. Tetravinyl tin
(1.907 g, 8.4 mmol) was added to the turquoise mixture. After
stirring the mixture for 6 h, the dark green reaction mixture was
poured into aqueous 25% NH4OAc (25 ml). After 10 min of stirring,
the blue aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated to give the residue, which was then
purified by column chromatography with n-hexane–EtOAc (1:2) to
afford compound 6a as a yellow oil (1.2 g, 43%). IR (cmꢁ1): 1658
one (5a). To
a solution of N-methyl-o-toluamide 3a (5.03 g,
33.7 mmol) in dry THF under nitrogen was added 2.5 M n-BuLi
(22.8 ml, 57 mmol in n-hexane) at ꢁ20 ꢀC, and the reaction tem-
perature was maintained so as not to exceed 0 ꢀC. After the addition
was complete, the red orange solution was stirred for 1 h at the
same temperature. To this solution was slowly added a solution of
2-(p-methoxybenzyloxymethyl)benzonitrile 4a18 (26.9 mmol,
6.82 g) in dry THF; the reaction mixture was then cooled to ꢁ50 ꢀC
and stirred for 20 min at the same temperature. The reaction was
carefully quenched with water, stirred vigorously for 10 min, and
extracted with ethyl acetate. The organic layers were washed with
water and brine and dried over sodium sulfate. After removing the
solvent, the residue was separated by column chromatography
with hexane–ethyl acetate (3:1) on silica gel to afford compound 5a
as a yellow oil (2.74 g, 44%). IR (cmꢁ1): 3400 (NH), 1657 (C]O). 1H
(C]O). 1H NMR (300 MHz, CDCl3)
d: 8.46 (m, 1H), 7.60–7.25 (m,
7H), 7.07 (m, 2H), 6.69–6.66 (m, 2H), 6.60–6.51 (m, 1H), 6.37 (s, 1H),
5.27(d, J¼15.9 Hz, 1H), 5.00 (d, J¼9.0 Hz, 1H), 4.46–4.28 (m, 4H),
3.67 (s, 3H). EIMS: m/z 397 (Mþ, 100). HRMS-EI (calcd for
C26H23NO3): 397.1678, found 397.1669.
NMR (300 MHz, CDCl3) d: 10.25 (s, 1H), 8.44 (m, 1H), 7.65 (m, 1H),
7.57–7.25 (m, 8H), 6.90 (m, 2H), 6.58 (s, 1H), 4.64 (s, 2H), 4.46 (s,
2H), 3.77 (s, 3H). EIMS: m/z 371 (Mþ, 65). HRMS-EI (calcd for
C24H21NO3): 371.1521, found 371.1529.
4.1.12. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-6-methyl-2-vinyl-
2H-isoquinolin-1-one (6b). The procedure described for compound
6a was used with compound 5b (3 g, 7.78 mmol), tetravinyl tin
(2.13 g, 9.4 mmol), and anhydrous Cu(OAc)2 (1.7 g, 9.4 mmol) to
afford compound 6b as a yellow oil (1.7 g, 53%). IR (cmꢁ1): 1654
4.1.7. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-6-methyl-2H-iso-
quinolin-1-one (5b). The procedure described for compound 5a
was used with toluamide 3b (1 g, 6.1 mmol) and 2-(p-methoxy
benzyloxymethyl)benzonitrile 4a (7.7 mmol,1.95 g) in the presence
of 1.6 M n-BuLi in hexane (8.8 ml, 14.0 mmol) to give compound 5b
as a yellow oil (892 mg, 38%). IR (cmꢁ1): 3400 (NH), 1657 (C]O). 1H
(C]O). 1H NMR (300 MHz, CDCl3)
d
: 8.35 (d, J¼8.2 Hz, 1H), 7.54 (m,
1H), 7.43–7.22 (m, 5H), 7.12–7.10 (m, 2H), 6.74–6.72 (m, 2H), 6.59–
6.51 (dd, J1¼9.0 Hz, J2¼15.9 Hz, 1H), 6.35 (s, 1H), 5.23 (d, J¼15.8 Hz,
1H), 5.02 (d, J¼9.0 Hz, 1H), 4.46–4.31 (m, 4H), 3.74 (s, 3H), 2.49 (s,
3H). EIMS: m/z 411 (Mþ, 88). HRMS-EI (calcd for C27H25NO3):
411.1834, found 411.1840.
NMR (300 MHz, CDCl3) d: 10.12 (s, 1H), 8.33 (d, 1H), 7.55–6.86 (m,
10H), 6.53 (s, 1H), 4.64 (s, 2H), 4.46 (s, 2H), 3.79 (s, 3H), 2.50 (s, 3H).
EIMS: m/z 385 (Mþ, 100). HRMS-EI (calcd for C25H23NO3): 375.1678,
found 385.1672.
4.1.13. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-7-methyl-2-vinyl-
2H-isoquinolin-1-one (6c). The procedure described for compound
6a was used with compound 8c (3.5 g, 9.08 mmol), tetravinyl tin
(2.47 g, 10.9 mmol), and anhydrous Cu(OAc)2 (1.98 g, 10.9 mmol) to
afford compound 6c as a yellow oil (1.4 g, 37%). IR (cmꢁ1): 1661
4.1.8. 3-[2-(4-Methoxybenzyloxymethyl)phenyl]-7-methyl-2H-iso-
quinolin-1-one (5c). The procedure described for compound 5a was
used with toluamide 3c (1.5 g, 9.2 mmol) and 2-(p-methoxy
benzyloxymethyl)benzonitrile 4a in the presence of n-BuLi (1.6 M
in hexane) to give compound 5c as a yellow oil (1.85 g, 52%). IR
(C]O). 1H NMR (300 MHz, CDCl3)
d
: 8.27 (s, 1H), 7.54 (d, J¼8.1 Hz,
1H), 7.46–7.23 (m, 5H), 7.11–7.06 (m, 2H), 6.71–6.66 (m, 2H), 6.61–
6.53 (dd, J1¼9.0 Hz, J2¼16 Hz, 1H), 6.36 (s, 1H), 5.24 (d, J¼16 Hz, 1H),
5.00 (d, J¼9 Hz, 1H), 4.46–4.30 (m, 4H), 3.68 (s, 3H), 2.48 (s, 3H).
EIMS: m/z 411 (Mþ, 82). HRMS-EI (calcd for C27H25NO3): 411.1834,
found 411.1836.
(cmꢁ1): 3400 (NH), 1657 (C]O). 1H NMR (300 MHz, CDCl3)
d: 10.2
(s,1H), 8.25 (s,1H), 7.54–7.41 (m, 8H), 6.90 (m, 2H), 6.56 (s,1H), 4.64
(s, 2H), 4.45 (s, 2H), 3.78 (s, 3H), 2.50 (s, 3H). EIMS: m/z 385 (Mþ,
100). HRMS-EI (calcd for C25H23NO3): 375.1678, found 385.1670.
4.1.9. 3-(4,5-Dimethoxy-2-methoxymethoxymethylphenyl)-6,7-di-
methoxy-2H-isoquinolin-1-one (5d). The procedure described for
compound 5a was used with N,N-diethyl-4,5-dimethoxy-2-methyl
benzamide (5.62 g, 22.4 mmol), benzonitrile 4b (6.7 g, 28 mmol),
and n-butyl lithium (21.5 ml of 2.5 M in hexane, 53.8 mmol) in THF
(50 ml) to afford compound 5d as a white solid (2.5 g, 27%). Mp:
4.1.14. 3-(4,5-Dimethoxy-2-methoxymethoxymethylphenyl)-6,7-di-
methoxy-2-vinyl-2H-isoquinolin-1-one (6d). The procedure de-
scribed for compound 6a was used with compound 5d (2.5 g,
6.02 mmol), tetravinyl tin (2.05 g, 9.03 mmol), and anhydrous
Cu(OAc)2 (1.63 g, 9.03 mmol) to afford compound 6d as a yellow
solid (1.3 g, 48%). Mp: 136–138 ꢀC. IR (cmꢁ1): 1650 (C]O). 1H NMR

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H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
(300 MHz, CDCl3)
d
: 7.83 (s, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 6.76 (s,
as a white solid (605 mg, 74%). Mp: 197–198 ꢀC. IR (cmꢁ1): 3524
(OH), 1651 (C]O). 1H NMR (300 MHz, CDCl3)
: 7.79 (s, 1H), 7.06 (s,
1H), 6.81 (s, 1H), 6.73 (s, 1H), 6.62–6.53 (m, 1H), 6.37 (s, 1H), 6.03 (s,
2H), 5.30 (m, 1H), 5.09 (m, 1H), 4.45 (s, 2H), 4.01 (s, 3H), 3.98 (s, 3H).
Anal. Calcd for C21H19NO6: C, 66.13; H, 5.02; N, 3.67. Found: C, 66.15;
H, 5.00; N, 3.69. EIMS: m/z 381 (Mþ, 87).
1H), 6.64–6.55 (m,1H), 6.39 (s,1H), 5.33 (d,1H), 5.08 (d,1H), 4.60 (s,
2H), 4.45–4.40 (m, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H), 3.87 (s,
3H), 3.27 (s, 3H). Anal. Calcd for C24H27NO7: C, 65.29; H, 6.16; N, 3.17.
Found: C, 65.27; H, 6.15; N, 3.14. EIMS: m/z 441 (Mþ, 56).
d
4.1.15. 3-[6-(tButyldimethylsilanyloxymethyl)benzo[1,3]dioxol-5-yl]-
6,7-dimethoxy-2-vinyl-2H-isoquinolin-1-one (6e). The procedure
described for compound 6a was used with the amide 5e (2.7 g,
5.73 mmol), anhydrous copper acetate (1570 mg, 8.6 mmol), and
tetravinyl tin (1960 mg, 8.6 mmol) in the presence of dry O2 for 36 h
to afford compound 6e as a yellow solid (1.02 g, 36%). Mp: 59–61 ꢀC.
4.1.20. 2-(1-Oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl)benzaldehyde
(8a). To a solution of alcohol 7a (450 mg, 1.6 mmol) in methylene
chloride (30 ml) was added PDC (1.28 g, 3.4 mmol) and the mixture
was stirred for 2 h. The reaction mixture was then filtered and
washed with CH2Cl2. The solvent was evaporated off and the residue
was purified by column chromatography on silica gel with n-hex-
ane–ethyl acetate to afford the aldehyde 8a as a yellow oil (300 mg,
IR (cmꢁ1): 1654 (C]O). 1H NMR (300 MHz, CDCl3)
d: 7.85 (s, 1H),
7.29 (s, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 6.72 (s, 1H), 6.61 (dd, J1¼9.0 Hz,
J2¼15.9 Hz, 1H), 6.37 (s, 1H), 6.05 (m, 2H), 5.36 (d, J¼16.0 Hz, 1H),
5.12 (d, J¼9.0 Hz, 1H), 4.47 (m, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 0.88 (s,
9H), 0.01 (s, 6H). Anal. Calcd for C27H33NO6Si: C, 65.43; H, 6.71; N,
2.83. Found: C, 65.46; H, 6.70; N, 2.86. EIMS: m/z 495 (Mþ, 78).
67%). IR (cmꢁ1): 1698, 1653 (C]O). 1H NMR (300 MHz, CDCl3)
d:
10.02 (s,1H), 8.46 (m, 1H), 7.96 (m,1H), 7.68–7.48 (m, 6H), 6.63–6.55
(m, 1H), 6.48 (s, 1H), 5.11–5.02 (m, 2H). EIMS: m/z 275 (Mþ, 100).
HRMS-EI (calcd for C18H13NO2): 275.0946, found 275.0939.
4.1.16. 3-(2-Hydroxymethylphenyl)-2-vinyl-2H-isoquinolin-1-one
(7a). DDQ (1.048 g, 4.5 mmol) was added portionwise to a mixed
solution of compound 6a (1.2 g, 3.01 mmol) in CH2Cl2 (36 ml) and
water (2 ml) at room temperature. After the reaction mixture was
stirred overnight, satd aq NaHCO3 (20 ml) was added to the mix-
ture, which was then extracted with CH2Cl2. The organic phase was
washed with water and brine, dried over Na2SO4, and concentrated
to dryness. The residue was purified by column chromatography on
silica gel with n-hexane–EtOAc (2:1) to give compound 7a as
a yellow oil (500 mg, 60%). IR (cmꢁ1): 3398 (OH), 1648 (C]O). 1H
4.1.21. 2-(6-Methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl)ben-
zaldehyde (8b). The procedure described for compound 8a was used
with compound 7b (400 mg,1.37 mmol) and PDC (1.08 g, 2.88 mmol)
in CH2Cl2 (20 ml) to afford compound 8b as a white solid (294 mg,
74%). Mp: 143–144 ꢀC. IR (cmꢁ1): 1704, 1652 (C]O). 1H NMR
(300 MHz, CDCl3)
d: 10.02 (s, 1H), 8.36 (d, J¼8.4 Hz, 1H), 7.99 (dd,
J1¼1.5 Hz, J2¼7.8 Hz,1H), 7.68–7.65 (m,1H), 7.58 (m,1H), 7.46 (m,1H),
7.37–7.34 (m,1H), 7.28 (s,1H), 6.60 (dd, J1¼9 Hz, J2¼15.9 Hz, 1H), 6.41
(s,1H), 5.10–5.00 (m, 2H), 2.49 (s, 3H). EIMS: m/z 289 (Mþ, 63). HRMS-
EI (calcd for C19H15NO2): 289.1103, found 289.1110.
NMR (300 MHz, CDCl3)
d
: 8.34 (d, J¼7.8 Hz, 1H), 7.62–7.57 (m, 2H),
7.44–7.3 (m, 3H), 7.34–7.22 (m, 2H), 6.54–6.46 (m, 1H), 6.41 (s, 1H),
5.18 (d, J¼16.0 Hz, 1H), 4.96 (d, J¼8.9 Hz, 1H), 4.52 (m, 2H), 3.30 (s,
1H). EIMS: m/z 277 (Mþ, 100). HRMS-EI (calcd for C18H15NO2):
277.1103, found 277.1108.
4.1.22. 2-(7-Methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl)ben-
zaldehyde (8c). The procedure described for compound 8a was
used with the alcohol 7c (330 mg, 1.15 mmol) and PDC (902 mg,
2.4 mmol) in CH2Cl2 (20 ml) to afford the aldehyde 8c as a yellow oil
(260 mg, 79%). IR (cmꢁ1): 1698, 1654 (C]O). 1H NMR (300 MHz,
4.1.17. 3-(2-Hydroxymethylphenyl)-6-methyl-2-vinyl-2H-iso-
quinolin-1-one (7b). The procedure described for compound 7a
was used with compound 6b (1.6 g, 3.9 mmol) and DDQ (1.36 g,
5.85 mmol) to afford compound 7b as a yellow solid (460 mg, 40%).
Mp: 82–84 ꢀC. IR (cmꢁ1): 3436 (OH), 1655 (C]O). 1H NMR
CDCl3) d: 10.03 (s, 1H), 8.28 (s, 1H), 7.98 (m, 1H), 7.68–7.39 (m, 5H),
6.62 (dd, J1¼9.0 Hz, J2¼15.9 Hz, 1H), 6.45 (s, 1H), 5.11–5.00 (m, 2H),
2.52 (s, 3H). EIMS: m/z 289 (Mþ, 87). HRMS-EI (calcd for
C19H15NO2): 289.1103, found 289.1101.
(300 MHz, CDCl3)
d
: 8.31 (d, J¼8.3 Hz, 1H), 7.60–7.58 (m, 1H), 7.46
4.1.23. 2-(6,7-Dimethoxy-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-
yl)-4,5-dimethoxy benzaldehyde (8d). The procedure described for
compound 8a was used with compound 7d (300 mg, 0.75 mmol)
and PDC (496 mg, 1.3 mmol) in CH2Cl2 (20 ml) to afford compound
8d as a yellow solid (250 mg, 84%). Mp: 196–198 ꢀC. IR (cmꢁ1):
(m, 1H), 7.36–7.24 (m, 4H), 6.60–6.52 (m, 1H), 6.38 (s, 1H), 5.24 (d,
J¼16.0 Hz, 1H), 5.02 (d, J¼9.0 Hz, 1H), 4.60 (s, 2H), 2.47 (s, 3H), 1.73
(s, 1H). EIMS: m/z 291 (Mþ, 51). HRMS-EI (calcd for C19H17NO2):
291.1259, found 291.1261.
1665, 1597 (C]O). 1H NMR (300 MHz, CDCl3)
d: 9.92 (s, 1H), 7.84 (s,
4.1.18. 3-(2-Hydroxymethylphenyl)-7-methyl-2-vinyl-2H-iso-
quinolin-1-one (7c). The procedure described for compound 7a was
used with compound 6c (1.2 g, 2.9 mmol) and DDQ (987 mg,
4.35 mmol) to afford compound 7c as a yellow oil (367 mg, 44%). IR
1H), 7.49 (s, 1H), 6.8 (d, 2H), 6.62 (m, 1H), 6.43 (s, 1H), 5.10 (m, 2H),
4.04–3.97 (m, 12H). Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35; N,
3.54. Found: C, 66.87; H, 5.36; N, 3.51. EIMS: m/z 395 (Mþ, 100).
(cmꢁ1): 3402 (OH), 1652 (C]O). 1H NMR (300 MHz, CDCl3)
d: 8.19
4.1.24. 6-(6,7-Dimethoxy-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-
yl)benzo[1,3]dioxole-5-carbaldehyde (8e). The procedure described
for compound 8a was used with compound 7e (600 mg,1.58 mmol)
and PDC (1.25 g, 3.32 mmol) for 5 h to produce compound 8e as
a white solid (343 mg, 57%). Mp: 199–201 ꢀC. IR (cmꢁ1): 1678, 1644
(s, 1H), 7.59 (d, J¼7.6 Hz, 1H), 7.52–7.40 (m, 2H), 7.35–7.24 (m, 3H),
6.58–6.50 (m, 1H), 6.40 (s, 1H), 5.19 (d, J¼5.1 Hz, 1H), 4.98 (d,
J¼9.0 Hz, 1H), 4.55 (m, 2H), 2.46 (s, 3H). EIMS: m/z 291 (Mþ, 66).
HRMS-EI (calcd for C19H17NO2): 291.1259, found 291.1251.
(C]O). 1H NMR (300 MHz, CDCl3)
d: 9.86 (s,1H), 7.86 (s,1H), 7.43 (s,
4.1.19. 3-(6-Hydroxymethylbenzo[1,3]dioxol-5-yl)-6,7-dimethoxy-2-
vinyl-2H-isoquinolin-1-one (7e). To a solution of compound 6e
(1.05 g, 2.12 mmol) in dry THF (20 ml) was added tetrabutyl
ammonium fluoride (6.4 ml solution of 1.0 mol in THF, 6.4 mmol)
under N2 at 0 ꢀC. The resulting mixture was held at 0 ꢀC for 5 min
and then warmed to 25 ꢀC and stirred overnight. Water was added
to the reaction mixture, which was then extracted with ethyl ace-
tate, washed with water and brine, and dried over Na2SO4. After
removing solvent, the residue was purified by column chroma-
tography with n-hexane–ethyl acetate (1:2) to afford compound 7e
1H), 6.85–6.82 (m, 2H), 6.64 (m,1H), 6.40 (s,1H), 6.15 (m, 2H), 5.20–
5.12 (m, 2H), 4.04 (s, 3H), 3.99 (s, 3H). Anal. Calcd for C21H17NO6: C,
66.49; H, 4.52; N, 3.69. Found: C, 66.47; H, 4.55; N, 3.66. EIMS: m/z
379 (Mþ, 54).
4.1.25. 2-Vinyl-3-(2-vinylphenyl)-2H-isoquinolin-1-one
(9a). To
a
solution of methyltriphenylphosphonium bromide (1.96 g,
5.5 mmol) in dry THF (30 ml) was added n-butyl lithium (2.2 ml of
2.5 M in n-hexane, 5.5 mmol) at 0 ꢀC and the solution was stirred
at 0 ꢀC for 1 h. To this mixture was added the aldehyde 8a (300 mg,

H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
10147
1.1 mmol) in THF (10 ml) and the resulting mixture was stirred at
room temperature for 1 h. The reaction was then quenched with
water and extracted with ethyl acetate. The organic layers were
washed with water and brine and dried over sodium sulfate. After
removal of the solvent in vacuo, the residue was purified by col-
umn chromatography with n-hexane–ethyl acetate to afford the
styrene 9a as a yellow oil (255 mg, 85%). IR (cmꢁ1): 1655 (C]O). 1H
CH2Cl2. The solvent was evaporated off and the residue was purified
by column chromatography on silica gel to afford compound 10a as
a yellow solid (22 mg, 42%). Mp: 164–166 ꢀC. IR (cmꢁ1): 1684
(C]O). 1H NMR (300 MHz, CDCl3)
d: 8.64 (d, J¼8 Hz, 1H), 8.57 (m,
1H), 8.25 (m, 1H), 7.72–7.68 (m, 2H), 7.55–7.47 (m, 5H), 6.76 (d,
J¼8 Hz, 1H). EIMS: m/z 245 (Mþ, 48). HRMS-EI (calcd for C17H11NO):
245.0841, found 245.0844.
NMR (300 MHz, CDCl3) d: 8.47 (m, 1H), 7.65–7.60 (m, 2H), 7.52–
7.49 (m, 2H), 7.46–7.29 (m, 3H), 6.62–6.53 (m, 2H), 6.45 (s, 1H),
5.70 (dd, J1¼1.0 Hz, J2¼17.4 Hz, 1H), 5.25–5.21 (d, J¼10.0 Hz, 1H),
5.15–5.10 (d, J¼15.0 Hz, 1H), 5.04–5.01 (d, J¼8.4 Hz, 1H). EIMS: m/z
273 (Mþ, 100). HRMS-EI (calcd for C19H15NO): 273.1154, found
273.1161.
4.1.31. 11-Methylisoquino[3,2-a]isoquinolin-8-one (10b). The pro-
cedure described for compound 10a was used with compound 9b
(180 mg, 0.63 mmol) and second-generation Grubbs catalyst
(107 mg, 0.13 mmol) to afford compound 10b as a yellow solid
(60 mg, 38%). Mp: 183–184 ꢀC. IR (cmꢁ1): 1654 (C]O). 1H NMR
(300 MHz, CDCl3)
d
: 8.63 (d, J¼7.9 Hz, 1H), 8.45 (d, J¼8.3 Hz, 1H),
4.1.26. 6-Methyl-2-vinyl-3-(2-vinylphenyl)-2H-isoquinolin-1-one
(9b). The procedure described for compound 9a was used with
compound 8b (280 mg, 0.97 mmol), methyltriphenylphosphonium
bromide (1.73 g, 4.85 mmol), and n-BuLi (1.9 ml of 2.5 M in hexane,
4.85 mmol) in THF (20 ml) to afford compound 9b as a yellow oil
8.23 (m,1H), 7.52–7.46 (m, 5H), 7.34–7.31 (m,1H), 6.75–6.72 (d,1H),
2.53 (s, 3H). EIMS: m/z 259 (Mþ, 100). HRMS-EI (calcd for
C18H13NO): 259.0997, found 259.0990.
4.1.32. 10-Methylisoquino[3,2-a]isoquinolin-8-one (10c). The pro-
cedure described for compound 10a was used with compound 9c
(142 g, 0.5 mmol) and second-generation Grubbs catalyst (43 mg,
0.05 mmol) to afford compound 10c as a yellow solid (31 mg, 24%).
Mp: 200–202 ꢀC. IR (cmꢁ1): 1691 (C]O). 1H NMR (300 MHz, CDCl3)
(196 mg, 70%). IR (cmꢁ1): 1660 (C]O). 1H NMR (300 MHz, CDCl3)
d:
8.35 (d, J¼8.2 Hz,1H), 7.60 (m, 1H), 7.34–7.26 (m, 5H), 6.62–6.52 (m,
2H), 6.38 (s, 1H), 5.69 (dd, J1¼1 Hz, J2¼17.4 Hz, 1H), 5.22 (dd,
J1¼1 Hz, J2¼12 Hz, 1H), 5.12–5.07 (d, 1H), 5.03–5.00 (d, 1H), 2.48 (s,
3H). EIMS: m/z 287 (Mþ, 100). HRMS-EI (calcd for C20H17NO):
287.1310, found 287.1312.
d
: 8.65 (d, J¼8 Hz, 1H), 8.36 (s, 1H), 8.24 (m, 1H), 7.64–7.42 (m, 6H),
6.75 (d, J¼8 Hz, 1H), 2.53 (s, 3H). EIMS: m/z 259 (Mþ, 100). HRMS-EI
(calcd for C18H13NO): 259.0997, found 259.0993.
4.1.27. 7-Methyl-2-vinyl-3-(2-vinylphenyl)-2H-isoquinolin-1-one
(9c). The procedure described for compound 9a was used with
compound 8c (240 mg, 0.83 mmol), methyltriphenylphosphonium
bromide (1.48 g, 4.15 mmol), and n-BuLi (1.7 ml of 2.5 M in hexane,
4.15 mmol) in THF (20 ml) to afford compound 9c as a yellow oil
(162 mg, 68%). IR (cmꢁ1): 1653 (C]O). 1H NMR (300 MHz, CDCl3)
4.1.33. 2,3,10,11-Tetramethoxyisoquino[3,2-a]isoquinolin-8-one
(10d). The procedure described for compound 10a was used with
compound 9d (120 mg, 0.3 mmol) and second-generation Grubbs
catalyst (76 mg, 30 mol %) to afford compound 10d as a yellow solid
(100 mg, 91%). Mp: 246–248 ꢀC. IR (cmꢁ1): 1646 (C]O). 1H NMR
d
: 8.28 (s, 1H), 7.59 (m, 1H), 7.47–7.28 (m, 5H), 6.64–6.51 (m, 2H),
(300 MHz, CDCl3) d: 8.69 (d, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.28 (d,
6.40 (s, 1H), 5.71–5.65 (dd, J1¼1 Hz, J2¼17.5 Hz, 1H), 5.23–5.19 (m,
1H), 5.12–5.07 (m, 1H), 5.02–4.99 (m, 1H), 2.48 (s, 3H). EIMS: m/z
287 (Mþ, 100). HRMS-EI (calcd for C20H17NO): 287.1310, found
287.1314.
2H), 7.04 (s, 1H), 6.91 (s, 1H), 6.76 (d, 1H), 4.09–4.01 (m, 12H). Anal.
Calcd for C21H19NO5: C, 69.03; H, 5.24; N, 3.83. Found: C, 69.02; H,
5.23; N, 3.80. EIMS: m/z 365 (Mþ, 58).
4.1.34. 10,11-Dimethoxy-[1,3]dioxolo[4,5-g]isoquino[3,2-a]iso-
quinolin-8-one (10e). The procedure described for compound 10a
was used with compound 9e (207 mg, 0.55 mmol) and second-
generation Grubbs catalyst (140 mg, 0.17 mol) to afford compound
10e as a yellow solid (146 mg, 76%). Mp: 297–299 ꢀC. IR (cmꢁ1):
4.1.28. 3-(4,5-Dimethoxy-2-vinylphenyl)-6,7-dimethoxy-2-vinyl-2H-
isoquinolin-1-one (9d). The procedure described for compound 9a
was used with compound 8d (250 mg, 0.63 mmol), methyl-
triphenylphosphonium bromide (1.12 g, 3.15 mmol) and n-butyl
lithium (1.3 ml of 2.5 M in hexane, 3.15 mmol) to afford compound
9d as a yellow oil (132 mg, 53%). IR (cmꢁ1): 1698 (C]O). 1H NMR
1648 (C]O). 1H NMR (300 MHz, CDCl3)
d: 8.62 (d, J¼8 Hz, 1H), 7.83
(s, 1H), 7.54 (s, 1H), 7.18 (s, 1H), 6.96 (s, 1H), 6.86 (s, 1H), 6.67 (d,
J¼8 Hz, 1H), 6.08 (s, 2H), 4.04 (d, 6H). Anal. Calcd for C20H15NO5: C,
68.76; H, 4.33; N, 4.01. Found: C, 68.74; H, 4.31; N, 4.00. EIMS: m/z
349 (Mþ, 100).
(300 MHz, CDCl3) d: 7.83 (s,1H), 7.10 (s,1H), 6.86 (s,1H), 6.76 (s,1H),
6.64–6.49 (m, 2H), 6.38 (s, 1H), 5.63–5.57 (d, 1H), 5.20 (d, 1H), 5.16
(d, 1H), 5.06 (d, 1H), 4.03 (s, 3H), 3.96 (d, 6H), 3.89 (s, 3H). EIMS: m/z
393 (Mþ, 88). HRMS-EI (calcd for C23H23NO5): 393.1576, found
393.1574.
4.1.35. 5,6-Dihydroisoquino[3,2-a]isoquinolin-8-one
(11a). The
mixture of compound 10a (22 mg, 0.09 mmol) and 5% Pd/C (20 mg)
in MeOH (10 ml) was treated with hydrogen gas at 70 psi for 24 h
using the Parr apparatus. The reaction mixture was filtered and the
filtrate was evaporated to give a residue that was purified by col-
umn chromatography to give protoberberine 11a as a yellow oil
4.1.29. 6,7-Dimethoxy-2-vinyl-3-(6-vinylbenzo[1,3]dioxol-5-yl)-2H-
isoquinolin-1-one (9e). The procedure described for compound 9a
was used with compound 8e (343 mg, 0.9 mmol), methyl-
triphenylphosphonium bromide (1.62 g, 4.5 mmol), and 2.5 M n-
BuLi in hexane (4.5 mmol, 1.81 ml) to give compound 9e as a white
solid (276 mg, 81%). Mp: 95–98 ꢀC. IR (cmꢁ1): 1652 (C]O). 1H NMR
(14 mg, 63%). IR (cmꢁ1): 1646 (C]O). 1H NMR (300 MHz, CDCl3)
d:
8.44 (m, 1H), 7.83 (m, 1H), 7.66–7.56 (m, 2H), 7.49–7.43 (m, 1H),
7.37–7.33 (m, 2H), 7.28–7.25 (m, 1H), 7.03 (s, 1H), 4.40–4.36 (m, 2H),
3.03–2.99 (m, 2H). EIMS: m/z 247 (Mþ, 100). HRMS-EI (calcd for
C17H13NO): 247.0997, found 247.0994.
(300 MHz, CDCl3) d: 7.83 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 6.75 (s,
1H), 6.63–6.43 (m, 2H), 6.35 (s, 1H), 6.04 (s, 2H), 5.56 (m, 1H), 5.20–
5.07 (m, 3H), 4.03 (s, 3H), 3.99 (s, 3H). Anal. Calcd for C22H19NO5: C,
70.02; H, 5.07; N, 3.71. Found: C, 70.04; H, 5.05; N, 3.74. EIMS: m/z
377 (Mþ, 100).
4.1.36. 11-Methyl-5,6-dihydroisoquino[3,2-a]isoquinolin-8-one
(11b). The procedure described for compound 11a was used with
compound 10b (70 mg, 0.27 mmol) and 5% Pd/C (40 mg) in MeOH
(10 ml) to afford compound 11b as a yellow solid (44 mg, 62%). Mp:
4.1.30. Isoquino[3,2-a]isoquinolin-8-one (10a). A reaction mixture
of compound 9a (60 mg, 0.22 mmol) and second-generation
Grubbs catalyst (38 mg, 20 mol %) in CH2Cl2 (30 ml) was refluxed
overnight. The reaction mixture was then filtered and washed with
115–116 ꢀC. IR (cmꢁ1): 1636 (C]O). 1H NMR (300 MHz, CDCl3)
d:
8.32 (d, J¼8.2 Hz, 1H), 7.81–7.78 (m, 1H), 7.36–7.19 (m, 5H), 6.94 (s,

10148
H.T.M. Van et al. / Tetrahedron 65 (2009) 10142–10148
1H), 4.35 (m, 1H), 2.98 (m, 2H), 2.47 (s, 3H). EIMS: m/z 261 (Mþ,
References and notes
100). HRMS-EI (calcd for C18H15NO): 261.1154, found 261.1158.
1. Vollekova, A.; Kost’alova, D.; Kettmann, V.; Toth, J. Phytother. Res. 2003, 17, 834.
2. Grycova, L.; Dostal, J.; Marek, R. Phytochemistry 2007, 68, 150.
4.1.37. 10-Methyl-5,6-dihydroisoquino[3,2-a]isoquinolin-8-one
(11c). The procedure described for compound 11a was used with
compound 10c (38 mg, 0.15 mmol) and 5% Pd/C (20 mg) in MeOH
(10 ml) to afford compound 11c as a yellow solid (15 mg, 38%). Mp:
3. Hwang, J. M.; Kuo, H. C.; Tseng, T. H.; Liu, J. Y.; Chu, C. Y. Arch. Toxicol. 2006, 80, 62.
4. Recent reports related to protoberberine synthesis, see: (a) Lee, C. H.; Yu, T. C.;
Luo, J. W.; Cheng, Y. Y.; Chuang, C. P. Tetrahedron Lett. 2009, 50, 4558; (b)
Tomasevich, L. L.; Kennedy, N. M.; Zitelli, S. M.; Hull, R. T.; Gillen, C. R.; Lam, S.
K.; Baker, N. J.; Rohanna, J. C.; Conley, J. M.; Guerra, M. L.; Starr, M. L.; Sever, J. B.;
Carroll, P. J.; Leonard, M. S. Tetrahedron Lett. 2007, 48, 599; (c) Le, T. N.; Cho, W. J.
Bull. Korean Chem. Soc. 2007, 28, 763; (d) Majumdar, K. C.; Basu, P. K.; Chatto-
padhyay, S. K. Tetrahedron 2007, 63, 793; (e) Li, W. D.; Yang, H. Tetrahedron
2005, 61, 5037; (f) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341; (g) Huang, W. J.; Singh, O. V.; Chen, C. H.; Chiou, S. Y.; Lee, S. S. Helv. Chim.
Acta 2002, 85, 1069; (h) Suau, R.; Lopez-Romero, J. M.; Ruiz, A.; Rico, R. Tetra-
hedron 2000, 56, 993; (i) Orito, K.; Satoh, Y.; Nishizawa, H.; Harada, R.; Tokuda,
M. Org. Lett. 2000, 2, 2535.
140–142 ꢀC. IR (cmꢁ1): 1641 (C]O). 1H NMR (300 MHz, CDCl3)
d:
8.25 (m, 1H), 7.83–7.80 (m, 1H), 7.48–7.47 (m, 2H), 7.36–7.34 (m,
2H), 7.28–7.25 (m,1H), 7.01 (s,1H), 4.40–4.36 (m, 2H), 3.04–2.99 (m,
2H), 2.50 (s, 1H). EIMS: m/z 261 (Mþ, 100). HRMS-EI (calcd for
C18H15NO): 261.1154, found 261.1148.
4.1.38. 2,3,10,11-Tetramethoxy-5,6-dihydroisoquino[3,2-a]iso-
quinolin-8-one: 8-oxypseudopalmatine (1). The procedure de-
scribed for compound 11a was used with compound 10d (19 mg,
0.05 mmol) and 5% Pd/C (10 mg) in acetic acid (5 ml) to afford 8-
oxypseudopalmatine as a yellow solid (7 mg, 37%). Mp: 187–189 ꢀC
(lit.4a 197–199 ꢀC. lit.19 198–199 ꢀC). IR (cmꢁ1): 1640 (C]O). 1H
5. Le, T. N.; Cho, W. J. Chem. Pharm. Bull. 2008, 56, 1026.
6. Le, T. N.; Gang, S. G.; Cho, W. J. Tetrahedron Lett. 2004, 45, 2763.
7. Le, T. N.; Gang, S. G.; Cho, W. J. J. Org. Chem. 2004, 69, 2768.
8. Patra, A. M.; Montgomery, C. T.; Freyer, A. J.; Guinaudeau, H.; Shamma, M.;
Tantisewie, B.; Pharadai, K. Phytochemistry 1987, 26, 547.
9. Weimar, C. V. A.; Silvia, W.; Wolfgang, W. Arch. Pharmacol. 1991, 324, 509.
10. Recent reviews related to RCM, see: (a) Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490; (c) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (d) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. For selected recent references on the
construction of heterocycles by RCM, see: (e) Donohoe, T. J.; Kershaw, N. M.;
Orr, A. J.; Wheelhouse, K. M. P.; Fishlock, L. P.; Lacy, A. R.; Bingham, M.; Pro-
copiou, P. A. Tetrahedron 2008, 64, 809; (f) Donohoe, T. J.; Ironmonger, A.;
Kershaw, N. M. Angew. Chem., Int. Ed. 2008, 47, 7314; (g) Anderson, D. R.; Lav-
allo, V.; O’Leary, D. J.; Bertrand, G.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46,
NMR (300 MHz, CDCl3) d: 7.78 (s, 1H), 7.33 (s, 1H), 6.96 (s, 1H), 6.85
(s, 1H), 6.76 (s, 1H), 4.36 (t, J¼6.0 Hz, 2H), 4.01(s, 3H), 4.01 (s, 3H),
3.98 (s, 3H), 3.94 (s, 3H), 2.90 (t, J¼6.0 Hz, 2H). Anal. Calcd for
C21H21NO5: C, 68.65; H, 5.76; N, 3.81; O, 21.77. Found: C, 68.63; H,
5.75; N, 3.84. EIMS: m/z (%): 367 (Mþ, 100), 352 (60).
´
´
7262; (h) Bennasar, M. L.; Roca, T.; Monerris, M.; Garcıa-Dıaz, D. Tetrahedron
Lett. 2005, 46, 4035; (i) Declerck, V.; Ribie`re, P.; Martinez, J.; Lamaty, F. J. Org.
Chem. 2004, 69, 8372; (j) Chen, Y.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett.
2003, 44, 1379.
4.1.39. 10,11-Dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-
a]isoquinolin-8-one: 8-oxypseudoberberine (2)7. The procedure de-
scribed for compound 1 was used with compound 10e (17 mg,
0.05 mmol) and 10% PtO2 (6 mg) in AcOH (5 ml) to afford com-
pound 11c as yellow solid (8 mg, 46%). Mp: 266–268 ꢀC. 1H NMR
11. Chang, J. K.; Chang, N. C. Tetrahedron 2008, 64, 3483.
12. Van, H. T. M.; Cho, W. J. Bioorg. Med. Chem. Lett. 2009, 19, 2551.
13. Lee, S. H.; Van, H. T. M.; Yang, S. H.; Lee, K. T.; Kwon, Y.; Cho, W. J. Bioorg. Med.
Chem. Lett. 2009, 19, 2444.
14. (a) Van, H. T. M.; Le, Q. M.; Lee, K. Y.; Lee, E. S.; Kwon, Y.; Kim, T. S.; Le, T. N.; Lee,
S. H.; Cho, W. J. Bioorg. Med. Chem. Lett. 2007, 17, 5763; (b) Cho, W. J.; Le, M. Q.;
Van, H. T. M.; Lee, K. Y.; Kang, B. Y.; Lee, E. S.; Lee, S. K.; Kwon, Y. Bioorg. Med.
Chem. Lett. 2007, 17, 3531.
(300 MHz, CDCl3) d: 7.78 (s, 1H), 7.22 (s, 1H), 6.90 (s, 1H), 6.77 (s,
1H), 6.72 (s, 1H), 6.10 (s, 2H), 4.34 (t, J¼6 Hz, 2H), 4.05 (d, 6H), 2.90
(t, J¼6 Hz, 2H). Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99.
Found: C, 68.34; H, 4.89; N, 3.97. EIMS: m/z 351 (Mþ, 100).
15. Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043.
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Oxford, 1991; Vol. 8, pp 424–442.
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This work was supported by Korea Research Foundation grant
(KRF-2007-521-E00190).