An efficient synthesis of argemonine, a pavine alkaloid

Article abstract of DOI:10.1016/S0040-4039(00)02233-4

A method for the synthesis of 1,2-dihydroisoquinoline derivatives is described and the conversion of the 1,2-dihydroisoquinoline intermediate to a pavine alkaloid via palladium-induced intramolecular hydroarylation reaction and radical cyclization is pres

Full text of DOI:10.1016/S0040-4039(00)02233-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1359–1361
An efficient synthesis of argemonine, a pavine alkaloid†
Somsak Ruchirawata,b,c,* and Anucha Namsa-aidb
aLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
bDepartment of Chemistry, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
cProgramme on Research and Development of Synthetic Drugs,
Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus, Thailand
Received 30 November 2000; accepted 5 December 2000
Abstract—A method for the synthesis of 1,2-dihydroisoquinoline derivatives is described and the conversion of the 1,2-dihydroiso-
quinoline intermediate to a pavine alkaloid via palladium-induced intramolecular hydroarylation reaction and radical cyclization
is presented. © 2001 Elsevier Science Ltd. All rights reserved.
Argemonine is a prototypical member of the pavine
alkaloids, a small group of tetracyclic natural products,
and contains the tetrahydroisoquinoline core embedded
in its skeleton.1 Recent findings of biological activities
of the pavine alkaloids include inhibition of herpes
simplex virus type 12 and inhibitory activity against
tumor necrosis factor-a (TNF-a) production.3
The key steps involve a palladium-induced intramolec-
ular hydroarylation5 and a radical cyclization6 of the
key halo derivatives of 1-benzyl-N-carboethoxy-1,2-di-
hydroisoquinolines. The intramolecular hydroarylation
involves the reduction of the organopalladium complex
formed during the carbonꢀcarbon bond formation in
the much exploited Heck reaction.7 We have also devel-
oped a new method for the synthesis of the key 1,2-di-
hydroisoquinoline derivatives. During our investigation
a method for the synthesis8 of this type of compound
was reported involving the addition of a benzylstan-
nane to an isoquinoline in the presence of methyl
chloroformate in dichloromethane. We found that 1-
benzyl-N-carboethoxy-1,2-dihydroisoquinolines could
be conveniently obtained by the reaction of 1-benzyliso-
quinoline derivatives with tributyltin hydride. For ex-
ample, treatment of papaverine 4a with tributyltin
hydride in dichloromethane at room temperature under
a nitrogen atmosphere, followed by addition of ethyl
chloroformate at −78°C and warming to room temper-
ature gave a white solid which, after recrystallization
from methanol–dichloromethane, provided compound
3a in 79% yield. Having found a method for the
synthesis of 1-benzyl-N-carboethoxy-1,2-dihydroiso-
quinolines, we then began the synthesis of our key
intermediate. The synthesis started with bromination of
commercially available papaverine 4a with a solution of
bromine in acetic acid at room temperature for 2 h to
give 2%-bromopapaverine9 4b in 75% yield.
There are a number of syntheses1,4 of pavine alkaloids
reported, but most involve an acid-catalyzed
intramolecular cyclization of the activated aromatic
ring with an iminium salt as in the Pictet–Spengler
reaction. The drawback of such a procedure is the
failure with nonactivated aromatic compounds and the
lack of chemoselectivity in the cyclization of unsymmet-
rical compounds.
We have developed a new synthesis of pavine alkaloids
based on the retrosynthetic analysis shown in Scheme 1.
Keywords: pavine alkaloid; intramolecular hydroarylation reaction;
radical cyclization reaction.
* Corresponding author. Fax: 66 2 574 0616 or 66 2 247 1222; e-mail:
somsak@tubtim.cri.or.th
Application of the tin hydride reduction gave the
required product which was recrystallized from
methanol–dichloromethane to give compound 3b as a
white solid in 85% yield. It is interesting to note the
†
This work has been taken in part from Namsa-aid, A., M.Sc.
Thesis, Mahidol University 1997, and was presented at the 8th
Belgian Organic Synthesis Symposium, July 10–14, 2000, Gent,
Belgium.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02233-4

1360
S. Ruchirawat, A. Namsa-aid / Tetrahedron Letters 42 (2001) 1359–1361
CH3O
CH3O
OCH3
OCH3
CH3O
CH3O
OCH3
N
N
OCH3
CO2CH2CH3
c
CH3
1
2
b
CH3O
CH3O
N
N
CH3O
CH3O
CH3O
CH3O
CO2CH2CH3
a
CH3O
X
CH3O
X
4
3
a) X = H, b) X = Br, c) X = I
Scheme 1. Reagents and conditions: (a) i. Bu3SnH/CH2Cl2, ii. EtOCOCl/CH2Cl2, −78°C“rt (3a, 79%; 3b, 85%; 3c, 85%); (b) See
Table 1; (c) LAH/THF, reflux 4 h (1, 87%).
chemoselective reduction of the iminium intermediate
with tributyltin hydride in the presence of the aryl
bromide group. Once the key compound 3b was
obtained, we applied the intramolecular hydroarylation
cyclization to effect pavine ring formation. The cycliza-
tion of 3b was accomplished using 10–20 mol% of a
reactive catalyst formed from Pd(PPh)4 in DMF at
80–90°C in the presence of sodium formate as a reduc-
ing agent. After purification by PLC, N-ethoxycar-
bonylpavine 210 was obtained in 44% yield together
with the corresponding reduction product 3a in 34%
yield as shown in entry 1 of Table 1. The yield of the
N-ethoxycarbonylpavine 2 was increased to 56% when
the starting iodo compound 3c was used instead of the
bromo compound 3b under similar conditions (entry 3,
Table 1). The 2%-iodopapaverine 4c could be conve-
niently obtained by the reaction of papaverine with
iodine and silver trifluoroacetate.11 The appearance of
four aromatic protons as singlets in the NMR spectrum
indicated that 2%-iodopapaverine was obtained.
3a was obtained from the reaction in 5% yield. Simi-
larly, the iodo compound 3b underwent cyclization with
tributyltin hydride to afford the pavine 2 in 42% yield
together with 10% of the reduction product 6. The
N-ethoxycarbonylpavine 2 was reduced by LAH to
form the N-methylpavine in 87% yield. The physical
and spectroscopic data of our synthetic compound are
in full agreement with those of argemonine 1.4b
In conclusion, we have devised a new method for the
synthesis of pavine alkaloids as illustrated in the syn-
thesis of natural ( )-argemonine. With appropriate
introduction of the iodo group, the approach could be
used to synthesize both symmetrical and unsymmetrical
pavine alkaloids. We found that the palladium-cata-
lyzed reductive intramolecular arylation reaction is very
useful and gives better yields than radical cyclization.
Acknowledgements
In addition, the radical cyclization using tributyltin
hydride and AIBN of compounds 3b and 3c was inves-
tigated. It was found that the yield of N-ethoxycar-
bonylpavine 2 was only 30% from the cyclization of the
bromo compound 3b under the tributyltin hydride/
AIBN conditions. The corresponding reduction product
We are grateful to the Thailand Research Fund (TRF)
for the generous financial support. We acknowledge the
facilities in the Department of Chemistry provided by
the PERCH programme.
Table 1. Intramolecular arylation of 3,4-dihydroisoquinoline derivatives 3a and 3b to pavine (2)
Entry
Starting material
Conditions
Yield%
Yield%
Comp. 2
Comp. 3a
1
2
3
4
Compound 3b
Compound 3b
Compound 3c
Compound 3c
Pd(PPh3)4/DMF/HCO2Na/reflux 24 h
Bu3SnH/AIBN, benzene, reflux 10 h
Pd(PPh3)4/DMF/HCO2Na/reflux 24 h
Bu3SnH/AIBN, benzene reflux 10 h
44
30
56
42
34
5
15
10

S. Ruchirawat, A. Namsa-aid / Tetrahedron Letters 42 (2001) 1359–1361
1361
References
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1708, 1633, 1227 cm−1 1H NMR (400 MHz, CDCl3) l
;
1.15 (t, 3H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz), 2.82–3.06
(m, 4H), 3.66 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.77 (s,
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J=8.4, 5.6 Hz), 5.55 (t, 1H, J=7.1 Hz), 5.79, 6.79 (AB q,
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1
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2H), 5.42 (d, 1H, J=5.6 Hz), 5.52 (d, 1H, J=5.6 Hz),
6.45 (s, 1H), 6.48 (s, 1H), 6.66 (s, 1H), 6.67 (s, 1H). 13C
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55.64, 55.89, 61.38, 108.97, 109.20, 111.47, 111.65, 123.95,
124.48, 128.78, 129.08, 147.45, 147.96, 148.05, 154.21.
EI-MS 413 (M+, 17.50), 412 (4.89), 340 (8.25), 278 (6.84),
262 (52.36), 28 (100.00). Anal. calcd for C26H22N2O3: C,
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.
.