Protecting-group-free total synthesis of isoquinoline alkaloids by nickel-catalyzed annulation of o-halobenzaldimine with an alkyne as the key step

Article abstract of DOI:10.1002/chem.200902275

An efficient short total synthesis of benzo[c]phenanthridine alkaloids including oxyavicine, oxynitidine, and oxysanguinarine is described. Thus, N-methyl-o-bromobenzaldimines 1 b-d undergo regioselective cyclization with 4-(benzo[d][1,3]dioxol-5-yl)but-3-yn-1-ol (2b) in the presence of [Ni(cod) ₂] (cod = 1,5-cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5b-d with benzo[d][1,3]dioxol-5-yl substitution at the C₃ atom and a (CH ₂)₂OH group at the C₄ atom. Later, oxidation of the alcohol group in 5b-d to the aldehyde moiety followed by acid-catalyzed cyclization and dehydration completes the total syntheses to give oxyavicine, oxynitidine, and oxysanguinarine in 67, 65, and 60% yields, respectively. The synthesis requires four steps from o-bromobenzaldehyde derivatives. Transformations of these alkaloids to the other alkaloids in this family are also discussed herein.

Full text of DOI:10.1002/chem.200902275

DOI: 10.1002/chem.200902275
Protecting-Group-Free Total Synthesis of Isoquinoline Alkaloids by Nickel-
Catalyzed Annulation of o-Halobenzaldimine with an Alkyne as the Key Step
Rajendra Prasad Korivi and Chien-Hong Cheng*[a]
Abstract: An efficient short total syn-
thesis of benzo[c]phenanthridine alka-
loids including oxyavicine, oxynitidine,
and oxysanguinarine is described. Thus,
N-methyl-o-bromobenzaldimines 1b–d
undergo regioselective cyclization with
salts gives isoquinolinone derivatives
5b–d with benzo[d][1,3]dioxol-5-yl sub-
stitution at the C3 atom and
(CH2)2OH group at the C4 atom. Later,
oxidation of the alcohol group in 5b–d
to the aldehyde moiety followed by
acid-catalyzed cyclization and dehydra-
tion completes the total syntheses to
give oxyavicine, oxynitidine, and oxy-
sanguinarine in 67, 65, and 60% yields,
respectively. The synthesis requires
four steps from o-bromobenzaldehyde
derivatives. Transformations of these
alkaloids to the other alkaloids in this
family are also discussed herein.
AHCTUNGTRENNUNG
a
4-(benzo[d]
ACHTUNGTRENNUNG
Keywords: alkaloids
·
isoquino-
ol (2b) in the presence of [NiAHCTNUGTRENNNUG
(cod=1,5-cyclooctadiene). In situ oxi-
dation of the resultant isoquinolinium
lines · nickel · ring-closing reac-
tions · total synthesis
Introduction
Efficient syntheses of natural products are important as
these products and their derivatives have been the basis for
new drug development.[1,2] Among the isoquinoline alka-
loids, over 80 types of benzo[c]phenanthridine alkaloids
have been characterized.[3] The structures of some of these
alkaloids are shown below. For example, oxyavicine isolated
from Zanthoxylum avicennae root bark,[4a] Broussonetia pap-
yrifera fruits,[4b] and Zanthoxylum nitidum root,[4c] can be
used to treat ophthalmic disorders.[4b] In addition, it exhibits
analgesic and anti-inflammatory effects.[4c] On the other
hand, oxynitidine, isolated from Zanthoxylum rhoifolium,[5a]
Zanthoxylum nitidum root,[5b] and Fagara macrophylla
bark,[5c] exhibited potent inhibitory activity toward the hepa-
titis B virus.[5d] Recently oxysangunarine was also isolated
from the Ranunculaceae (seeds of Coptis).[6a] One of the im-
portant crude drugs in both China and Japan were rhizomes
of Coptis spp.; oxysanguinarine was one of the constituents
in the drug.
Despite the numerous reports on benzo[c]phenanthridine
alkaloids, to date, highly efficient synthesis remains a chal-
lenge. A Robinson–Bailey synthesis[7a] and enamide photo-
cyclization[7b] methods as key steps for the total synthesis
were reported by Bailey et al. and Ninomiya et al., respec-
tively. Diels–Alder cycloaddition reactions[7c] with arynes by
using pyrrolinediones and a-pyrones as aza diene equiva-
lents are known. Condensation of the homophthalic ester[6b]
with Schiff base and a 3,4-(methylenedioxy)homophthalic
anhydride[7d] reaction with Schiff base in benzene solution
[a] Dr. R. P. Korivi, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax : (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902275.
282
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Chem. Eur. J. 2010, 16, 282 – 287

FULL PAPER
followed by diazo ketone cyclization were devised for the
total synthesis of benzophenanthridines. Most of these syn-
theses require complex starting materials: an eight-step se-
quence to the homophthalic ester and seven-step sequence
to the 3,4-(methylenedioxy)homophthalic anhydride were
reported.[7e] Clark described the synthesis of oxynitidine by
a cycloaddition reaction of lithiated toluamide with imine.[8a]
Recently Cho et al. reported syntheses[8b,c] of oxyavicine,
oxynitidine, and oxysanguinarine from benzonitriles derived
from o-bromobenzaldehydes. Both of these syntheses re-
quired multistep procedures with a large number of reagents
and needed protection and deprotection techniques.
Our recent method of nickel-catalyzed regioselective cyc-
lization of o-halobenzaldimine with an alkyne has provided
an efficient access to isoquinolinium salts and isoquinoli-
nones with multiple substitutions.[9a] For aryl alkyl alkynes 2
used in the reaction, the reaction always yields the corre-
sponding isoquinolinium salts 3 with the aryl substitution on
the alkynes at the C3 position (Scheme 1). The observed re-
Scheme 2. Retrosynthetic analysis for isoquinolinone 7a.
be obtained from the corresponding isoquinolinium deriva-
tive 3a by a nucleophilic addition of a OHÀ group to the C1
carbon atom of 3a and oxidation of the resultant derivative.
Isoquinolinium salt 3a could be ultimately synthesized from
an intermolecular Ni-catalyzed[9e–g] cyclization reaction be-
tween imine 1a and alkyne 2b (Scheme 2). Imine 1a could
be readily obtained from o-bromobenzaldehyde and methyl-
amine,[9e–j] whereas internal alkyne 2b could be easily pre-
pared by a Sonogashira reaction from 5-bromobenzo[d]-
Scheme 1. Nickel-catalyzed synthesis of isoquinolinium and isoquinoli-
none derivatives. a) Ni0; b) K3[Fe(CN)6], CsOH.
AHCTUNGTREG[NNUN 1,3]dioxole and but-1-yn-4-ol. An attractive feature of this
sequence is that all the carbon atoms of the complex natural
product could be all obtained in the nickel-catalyzed annula-
tion step.
giochemical preference[9b] of the alkyne moiety in product 3
and the facile conversion of the isoquinolinium salt to the
corresponding amide prompted us to explore the application
of the present method to the total syntheses[9c,d] of isoquino-
linone alkaloids. Herein, we provide a full report of our ap-
proach to the total syntheses of three isoquinolinone (be-
longing to benzo[c]phenanthridine) alkaloids including oxy-
avicine, oxynitidine, oxysanguinarine, and 9-demethoxy-10-
methoxy oxynitidine by using this new regioselective strat-
egy to construct the key isoquinolinone intermediates. The
syntheses of the three natural products were completed in
much higher yields and with shorter steps than the previous-
ly reported procedures.
Alternatively, isoquinolinone 7a might also be obtained
from isoquinolinone 4a or 4b. Similar strategies have been
employed to construct the C ring of isoquinolinones.[8b–d,10]
With suitable terminal alkynes, amides 4a and 4b can be
synthesized from our nickel-catalyzed reaction described
above. However, since multiple steps are required for the
preparation of these terminal alkyne substrates, we eliminat-
ed these two strategies from our synthetic plan.
Results and Discussion
First, we set about the synthesis of compound 7a
(Scheme 2), which aimed at developing an efficient route
flexible enough to provide access to various members of the
The requisite alkyne 2b was prepared by Sonogashira
coupling starting from commercially available 5-
benzo[c]phenanthridine alkaloids. From
a
retrosynthetic
bromobenzo[d]ACHTGUNTERNNU[G 1,3]dioxole (8) and 3-butyn-1-ol (9) in 83%
viewpoint, isoquinolinone 7a could be easily obtained from
isoquinolinone 5a (Scheme 2). The C ring could be con-
structed by oxidation of the (CH2)2OH group over the B
ring in 5a, followed by an acid-catalyzed cyclization and de-
hydration reaction. The isoquinolinone derivative 5a could
yield. N-Methyl-o-bromobenzaldimine (1a) was readily pre-
pared in essentially quantitative yield from commercially
available 2-bromobenzaldehyde by condensation with aque-
ous methylamine by using methanol as the solvent. Treat-
ment of 1a with alkyne 2b in the presence of [NiACHTUNGTRENNUNG(cod)2]
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283

C.-H. Cheng and R. Prasad Korivi
(5 mol%; cod=1,5-cyclooctadiene) and 10 mol% of PACHTUNTRGNEUNG(o-
Tol)3 in acetonitrile for 3.0 h at 808C, followed by the addi-
tion of K3[Fe(CN)6] and CsOH,[11a] in a mixture of H2O and
MeOH gave 5a in 71% yield. In this reaction, isoquinolini-
um salt 3a was first obtained from the nickel-catalyzed step
and was then transformed to 5a (Scheme 2). Pyridinium
chlorochromate (PCC) oxidation of the primary alcohol
group in 5a afforded the corresponding aldehyde derivative
6a in 91% yield. Under Swern oxidation conditions,[11b] by
using Et3N as the base, nearly the same yield of 6a was ob-
tained. As expected, 6a underwent subsequent acid-cata-
lyzed cyclization and dehydration smoothly to afford the
final product 7a in 96% yield.
The success of the synthesis of 7a prompted us to under-
take the total synthesis of oxyavicine (7b, Scheme 3)[4] by
using the nickel-catalyzed methodology. The required imine
Scheme 4. Total synthesis of isoquinolinone alkaloids. a) [Ni
Tol)3; b) CsOH, K3[Fe(CN)6].
ACHUTGTNNERNUG(cod)2], PACHTUNGTRENNUNG(o-
alyzed cyclization of imines 1c and 1d with alkyne 2b led to
the corresponding isoquinolinium salts; subsequent oxida-
tion procedures provided amides 5c and 5d in 78 and 69%
yields, respectively. Oxidation of the alcohol functionality in
5c and 5d yields the corresponding aldehyde derivatives 6c
and 6d in 89 and 93%, respectively. These were then cy-
clized under acidic conditions by using HCl (aq) and acetic
acid to complete the total synthesis[5,6] of oxynitidine (7c)[5]
and oxysanguinarine (7d).[6] The overall yields of 7c and 7d
were 65 and 60%, respectively.
Scheme 3. Total synthesis of oxyavicine (7b) from o-bromopiperonal.
a) [NiACHTUNGTRENNUNG(cod)2]/PACHTUNGTRENNUNG(o-Tol)3; b) CsOH, K3[Fe(CN)6]; c) (COCl)2, DMSO,
An alternative route to compound 5c was from N-methyl-
iodoveratraldehyde imine (1ei) and alkyne 2b via first the
isolation of isoquinolinium salt 3c and then the oxidation of
the salt (Scheme 5). The combined yield of the two steps
Et3N; d) HCl, AcOH.
1b was synthesized from commercially available 2-bromopi-
peronal and methylamine. Annulation of imine 1b with
alkyne 2b catalyzed by [NiACHTUNRTGENNUG(cod)2]/PACHUTNGTERNN(GUN o-Tol)3 and subsequent
nucleophilic addition and oxidation procedures gave amide
5b in 73% yield. We then converted this intermediate to
the corresponding aldehyde derivative 6b in 94% yield by
Swern oxidation. After a successful acid-catalyzed ring-clos-
ing and dehydration reaction, we obtained oxyavicine (7b)
in 98% yield. Thus, oxyavicine was synthesized in four steps
in 67% overall yield from the commercially available 2-bro-
mopipernal. Recent synthesis of this compound by cycload-
dition of lithiated toluamide with a benzonitrile derivative
required ten steps from 2-bromopiperonal (7% overall
yield).[8b–d]
The achievement of the synthesis of oxyavicine (7b) fur-
ther encouraged us to pursue the total syntheses of oxyniti-
dine[5] and oxysanguinarine as matter of course (Scheme 4).
With the key alkyne 2b in hand, we next synthesized imines
1c and 1d from commercially available 6-bromoveratralde-
hyde and 5-bromo-1,3-benzodioxole-4-carboxaldehyde with
methylamine in quantitative yields. The standard nickel-cat-
Scheme 5. An alternative route to isoquinolinone 5c. a) [NiACTHNURGTENNUG(cod)2], PACHTUNGTRENNUNG(o-
Tol)3; b) CsOH, K3[Fe(CN)6].
was 84% yield. The spectral data of these final products are
in agreement with those reported previously.[8,10] Oxynitidine
is known to show significant activity of anti-HBV DNA rep-
lication.[5] Previously, oxynitidine was synthesized in seven
steps with an overall yield of 15% from 2-methyl-4,5-dime-
thoxybenzoic acid[8a] and in 10% overall yield from 2-bro-
mopiperonal.[8b–d] Oxysanguinarine was synthesized from pi-
peronal[6b] in less than 1% overall yield (16 steps) and in
11% overall yield from o-bromopiperonal.[8b–d]
284
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Chem. Eur. J. 2010, 16, 282 – 287

Protecting-Group-Free Total Synthesis of Isoquinoline Alkaloids
FULL PAPER
Recently, an alkaloid named as turraeanthin B was isolat-
ed from the stem bark of Turraeanthin africanus and its
structure was assigned as 9-demethoxy-10-methoxy oxyniti-
dine 7e.[12a] Based on the isoquinolinium salt approach, we
started the synthesis of this alkaloid. The required aldehyde
derivative was synthesized from bromination of the corre-
sponding aldehyde derivative according to a literature pro-
cedure.[12b] This was then converted to the corresponding
imine 1e. With the standard procedures described in
Scheme 4, 9-demethoxy-10-methoxy oxynitidine (7e) was
synthesized from 1e and 2b in 59% overall yield. The
nickel-catalyzed annulation of 1e with 2b followed by treat-
ment with CsOH and K3[Fe(CN)6] gave isoquinolinone 5e
in 65% yield. The acid-catalyzed cyclization reaction of al-
dehyde 6e, prepared in 94% yield from the oxidation of the
primary alcohol group in 5e (Scheme 4), in the presence of
aqueous HCl and acetic acid, produced 7e in 97% yield.
Unfortunately, we have found that the NMR spectroscop-
ic data of the synthesized compound 7e is different from the
compound isolated from the bark of Turraeanthus africanus.
The structure of intermediate compound 5e was thoroughly
verified by its NOE and X-ray crystallographic data. In ad-
dition, the chemical shift of the C11 proton of 7e is in agree-
ment with similar OMe-substituted compound 12 (entries 3
and 5, Table 1).[12c] The C11 proton of the OMe-substituted
compound 12 was shifted much more downfield relative to
the C11 proton of compound 11 (entries 4 and 5, Table 1).
This is likely due to the hydrogen-bonding interaction be-
tween the C11 proton and the OMe group at the C10 atom of
compound 12. The coupling constant[12c] for the C11 and C12
protons is at around 9.0 Hz for compound 12 and 8.0 Hz for
compound 11. Compound 7e shows a similar coupling con-
stant to that of compound 12 (Table 1). Also, the structure
of compound 7e was thoroughly verified by NOE experi-
ments. These results strongly indicate that the structure of
the isolated compound from the stem bark of Turraeanthin
africanus is different from molecule 7e and needs to be re-
vised.
All of these alkaloids 7 can be conveniently transfor-
med[12c] into the corresponding dihydro derivatives, which
are also natural products, by reduction with LiAlH4
(Scheme 4). Dihydro derivatives 10 can be converted to iso-
quinolinium salts, avicine, nitidine,[7c,10c] and sanguinarine,[13a]
by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation, fol-
lowed by treatment with concentrated hydrochloric acid.[13]
The benzo[c]phenanthridine alkaloids containing the 12-me-
thoxy group can be obtained by conversion of the corre-
sponding alkaloids containing a hydrogen atom at C12. For
example, oxychelirubine was iodinated with N-iodosuccini-
mide to give the corresponding C12-iodo derivative, and oxy-
macarpine[13] was obtained by displacement of the iodine
atom with sodium methoxide. Most benzo[c]phenanthridine
alkaloids have multiple substituents on the A and D rings.[3a]
The present methodology constructs all carbon atoms of the
alkaloid in one step by the nickel-catalyzed cyclization of o-
halobenzaldimine and alkyne containing the necessary sub-
stitution over the A and D rings. Hence, a large number of
alkaloids can be prepared as these starting materials, with
desired substitutions on A and D rings, can be easily ob-
tained.
Conclusions
We have developed a distinctive strategy for the total syn-
thesis of benzo[c]phenanthridine alkaloids without using
protecting groups, which have recently attracted great atten-
tion from various researchers around the world.[14] The pres-
ent protocol is the shortest total synthesis procedure de-
scribed up to now and gives the highest yields of the natural
products synthesized including oxyavicine, oxynitidine,[5] and
oxysanguinarine with readily available starting materials for
benzo[c]phenanthridine alkaloids. This protocol may find
widespread use for other isoquinoline alkaloid syntheses as
well. Studies in this direction are underway.
Table 1. Selected 1H NMR spectroscopic data for turraeanthin B and
compounds 7e, 11, and 12.
Experimental Section
General information: Infrared (IR) spectra were recorded on a Horiba
1
FT-720 spectrophotometer using KBr as a matrix for the pellet. H NMR
spectra were measured on a Varian Mercury-400 (400 MHz), a Varian
Unity INOVA-500 (500 MHz) or a Bruker Avance-600 (600 MHz) in
CDCl3 or [D5]pyridine, while 13C NMR spectra were recorded on a Mer-
cury-400 (100 MHz) or a Varian Unity INOVA-500 (125 MHz) in CDCl3
using TMS as an internal standard. High-resolution mass (HR-MS) spec-
tra were obtained on a Finnigan MAT-95XL. Melting points are uncor-
rected and were measured with a Fargo MP-2D melting point apparatus.
Entry
Compound
d H11
d H12
JACHTNUGTREN(NUG H11–H12)
G
G
[Hz]
1
2
3
4
5
turraeanthin B ([D5]pyridine)[a]
7e ([D5]pyridine)[a]
7e (CDCl3)[a]
7.70
9.39
9.01
7.97
9.00
8.35
7.79
7.47
7.51
7.48
8.5
9.0
9.0
8.0
9.0
N-Methyl-o-bromoveratraldimine (1c): Aqueous methylamine solution
(100 mg, 35% in water, 1.13 mmol) was added to a solution of 6-bromo-
veratraldehyde (245 mg, 1 mmol) in methanol (2 mL), and the resultant
solution was stirred at room temperature for 12 h. After removal of sol-
11 (CDCl3)[a]
12 (CDCl3)[a]
[a] The solvent used to acquire the NMR spectra.
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285

C.-H. Cheng and R. Prasad Korivi
vents by a rotary evaporator, 1c solidified and was further dried under
1H NMR (400 MHz, CDCl3, 258C, TMS): d=3.30 (s, 3H), 3.47–3.51 (m,
2H), 3.93 (s, 3H), 4.00 (s, 3H), 6.05 (m, 2H), 6.70–6.71 (m, 2H), 6.76 (s,
1H), 6.91 (d, J=7.8 Hz, 1H), 7.88 (s, 1H), 9.56 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=34.3, 44.5, 56.0, 56.2, 101.6, 103.4,
106.0, 108.4, 109.0, 109.4, 119.5, 122.9, 128.4, 131.4, 141.7, 148.4, 148.5,
149.3, 153.6, 161.8, 199.6 ppm; HRMS (EI+): m/z: calcd for C21H19NO6:
381.1212; found: 381.1212.
vacuum for 12 h (nearly quantitative yield). The compound was pure as
1
shown by its H NMR spectrum and was used for further synthesis.
Synthesis of 4-(benzo[d]
tomed flask (100 mL) equipped with a condenser was charged with [Pd-
ACHTUNGTRENNUNG(PPh3)4] (347 mg, 0.3 mmol) and CuI (114 mg, 0.6 mmol). Degassed dis-
ACHTUNGTRENNUNG[1,3]dioxol-5-yl)but-3-yn-1-ol (2b): A round-bot-
tilled water (60 mL), but-1-yn-4-ol (1.05 g, 15 mmol), and pyrrolidine
Synthesis of oxynitidine (7a): Isoquinoline derivative 6c (95 mg,
0.25 mmol) was placed in a 25 mL round-bottomed flask. Acetic acid
(1 mL) was added slowly to the flask followed by aqueous HCl (30%,
0.1 mL). The flask was kept over a water bath at room temperature and
was stirred for 20 min. Then KOH in water was added slowly to neutral-
ize the solution and the mixture was extracted with dichloromethane.
The solvent was removed under vacuum to give the crude product (the
NMR spectra of the crude product showed they were pure). Further pu-
rification on a short silica-gel column (10 cm) by using hexane and ethyl
acetate (30:70) as the eluent gave 85.0 mg of the desired product 7c in
94% yield. White solid; m.p. 278*C; Rf =0.59 (70% ethyl acetate in hex-
(45 mmol) were added to the flask under nitrogen. 5-Bromobenzo[d]-
ACHTUNGTRENNUNG[1,3]dioxole (2.81 g, 14 mmol) was added by a syringe and the stirring
was continued at room temperature for 30 min and at 608C for 3.0 h. The
mixture was extracted with ether and the solvents were removed by
vacuum. The residue was separated on a silica-gel column by using a mix-
ture of hexanes and ethyl acetate (30:70) as the eluent to afford the de-
sired pure product 2b in 83% yield.
Synthesis of 3-(benzo[d]ACTHNUTRGENUG[N 1,3]dioxol-5-yl)-4-(2-hydroxyethyl)-6,7-dime-
thoxy-2-methylisoquinolin-1(2H)one (5c): A screw-cap seal tube contain-
ing N-methyl-6-bromoveratraldimine 1c (129 mg, 0.5 mmol) was charged
with [NiACHTUNGTRENNUNG(cod)2] (7 mg, 0.025 mmol) and PHCATUNGTRNEN(GUN o-Tol)3 (16 mg, 0.05 mmol)
anes); IR (KBr): n˜ =1038, 1263, 1476, 1643, 2923 cmÀ1
;
1H NMR
inside a glove box and was then fitted with a septum. Alkyne 2b
(114 mg, 0.6 mmol) and freshly distilled MeCN (4 mL) were added to the
seal tube under a nitrogen atmosphere. The reaction mixture was stirred
at 808C for 3 h. Then, water (5 mL), MeOH (5 mL), K3[Fe(CN)6]
(1.65 g), and CsOH (aq) (0.9 mL, 50% w/w in H2O) were added and the
mixture was stirred vigorously at 708C for 12 h. The solvents were re-
moved by vacuum and the resultant residue was extracted with dichloro-
methane. Separation on a short column of silica gel by using hexane/
EtOAc as the eluent gave pure isoquinolinone derivative 5c in 78%
yield. White solid; m.p. 238*C; Rf =0.18 (75% ethyl acetate in hexanes);
(500 MHz, CDCl3, 258C, TMS): d=3.95 (s, 3H), 4.03 (s, 3H), 4.07 (s,
3H), 6.07 (s, 2H), 7.14 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.55 (s, 1H), 7.60
(s, 1H), 7.89 (s, 1H), 7.95 ppm (d, J=8.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3, 258C, TMS): d=41.2, 56.1, 56.2, 101.5, 102.6, 102.8, 104.7, 108.6,
116.6, 118.3, 119.1, 121.0, 123.2, 128.9, 131.8, 135.9, 147.0, 147.4, 149.7,
153.5, 164.3 ppm; HRMS (EI+): m/z: calcd for C21H17NO5: 363.1107;
found: 363.1104.
IR (KBr): n˜ =1033, 1239, 1491, 1584, 1635, 2917 cmÀ1
;
1H NMR
(500 MHz, CDCl3, 258C, TMS): d=2.71–2.78 (m, 2H), 3.23 (s, 3H), 3.70
(t, J=7.5 Hz, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 6.03 (s, 2H), 6.70–6.71 (m,
2H), 6.90 (d, J=8.5 Hz, 1H), 7.10 (s, 1H), 7.87 ppm (s, 1H); 13C NMR
(125 MHz, CDCl3, 258C, TMS): d=32.0, 34.0, 56.1, 56.2, 62.5, 101.5,
103.9, 108.4, 108.8, 109.8, 111.0, 119.8, 123.1, 129.0, 131.7, 140.2, 148.1,
148.3, 149.2, 153.5, 161.8 ppm; HRMS (EI+): m/z: calcd for C21H21NO6:
383.1369; found: 383.1368.
Acknowledgements
We thank the National Science Council of Republic of China (NSC 96–
2113M-007–020-MY3) for support of this research.
Synthesis of 6,7-dimethoxy-3-(benzo[d]ACTHNUGRTNEUNG[1,3]dioxol-5-yl)-4-(2-hydroxyeth-
yl)-2-methyl-isoquinolinium iodide (3c): A screw-cap seal tube contain-
ing N-methyl-6-iodoveratraldimine (153 mg, 0.5 mmol) was evacuated
and purged with nitrogen gas three times. Later, the tube was charged
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with [NiACHTUNGTRENNUNG(cod)2] (7 mg, 0.025 mmol) and PHCATUNGTRNEN(GUN o-Tol)3 (16 mg, 0.05 mmol)
inside a glove box. Alkyne 2b (114 mg, 0.6 mmol) and freshly distilled
MeCN (3 mL) were added to the system. The reaction mixture was
stirred at 808C for 3.0 h. The reaction mixture was cooled to room tem-
perature and diluted with dichloromethane. The mixture was filtered
through a silica-gel pad (0.5 cm) and washed with a small amount of
methanol. The filtrate was concentrated in a rotary evaporator and the
residue was washed with ethyl acetate and hexane to afford the desired
pure product 3c in 88% yield. Yellow solid; m.p. 216*C; IR (KBr): n˜ =
1218, 1249, 1427, 1504, 3617 cmÀ1 1H NMR (400 MHz, CDCl3, 258C,
;
TMS): d=3.08–3.15 (m, 2H), 3.77 (m, 2H), 4.04 (s, 6H), 4.14 (s, 3H),
6.10 (s, 2H), 6.98 (m, 3H), 7.53 (s, 1H), 7.81 (s, 1H), 9.91 ppm (s, 1H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=32.7, 47.5, 57.1, 57.6, 61.2,
102.0, 104.0, 107.6, 109.3, 109.9, 124.0, 124.5, 133.5, 136.5, 143.0, 144.9,
148.7, 149.5, 152.7, 158.1, 176.7 ppm; HRMS (FAB+): m/z: calcd for
C21H22NO5+: 368.1498; found: 368.1494.
Synthesis of 2-(3-(benzo[d]ACTHNUTRGNEUG[N 1,3]dioxol-5-yl)-1,2-dihydro-6,7-dimethoxy-2-
methyl-1-oxoisoquinolin-4-yl)acetaldehyde (6c): DMSO (0.72 mmol) was
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and stirred for a further 15 min. The mixture was extracted with CH2Cl2
and the solvent was removed under vacuum to give the crude product.
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and ethyl acetate (30:70) as the eluent gave the desired pure product 6c
in 89% yield. Pale-yellow solid; m.p. 233*C; Rf =0.31 (50% ethyl ace-
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;
286
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Chem. Eur. J. 2010, 16, 282 – 287

Protecting-Group-Free Total Synthesis of Isoquinoline Alkaloids
FULL PAPER
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Received: August 17, 2009
Published online: November 10, 2009
Chem. Eur. J. 2010, 16, 282 – 287
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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