Palladium(0)-catalyzed ring expansion reactions of hydroxy methoxyallenylisoindolinones via inter- and intramolecular carbopalladation using aryl and vinyl halides

Article abstract of DOI:10.1055/s-2002-20471

Palladium(0)-catalyzed one-atom ring expansion of various hydroxy methoxyallenylisoindolinones 2 proceeded in the presence of aryl and vinyl halides to give the corresponding isoquinolinediones 3 in various yields. Tandem intramolecular carbo-palladation-

Full text of DOI:10.1055/s-2002-20471

480
LETTER
Palladium(0)-catalyzed Ring Expansion Reactions of Hydroxy
Methoxyallenylisoindolinones via Inter- and Intramolecular Carbopalladation
Using Aryl and Vinyl Halides
P
alladium(0)-catal
o
yzedRing
E
s
R
eactions imitsu Nagao,*a Satoru Tanaka,a Akiharu Ueki,a Ill-Yun Jeong,a Shigeki Sano,a Motoo Shirob
a
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi Tokushima 770-8505, Japan
Fax +81(88)6339503; E-mail: ynagao@ph2.tokushima-u.ac.jp
b
Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
Received 7 December 2001
alents of K2CO3, and 4 mol equivalents of aryl iodides or
an excess amount of vinyl bromide in THF for the indicat-
ed reaction times to give the corresponding N-alkyliso-
quinoline-1,4-diones 3 in 38–77% yields, respectively.5
Abstract: Palladium(0)-catalyzed one-atom ring expansion of var-
ious hydroxy methoxyallenylisoindolinones 2 proceeded in the
presence of aryl and vinyl halides to give the corresponding iso-
quinolinediones 3 in various yields. Tandem intramolecular carbo-
palladation-heterocyclic ring expansion reaction of compound 5 All experimental results are summarized in Scheme 1 and
was also achieved to give a tetracyclic compound 6.
the Table. The structures of 3 were determined by their
spectroscopic data [1H NMR (300 MHz, CDCl3) = 2.78–
Key words: allene, heterocycle, palladium, ring expansion, tandem
reaction
3.27 (s, 3 H, OMe), 5.43–5.60 (s, 1 H, olefin H), and 5.57–
6.02 (s, 1 H, olefin H); IR (neat): 1698–1715 (ketone),
1654–1660 (amide) cm–1; high resolution MS (M+)] and
elemental analyses. The new N-alkylisoquinoline-1,4-di-
ones, bearing a butadien-2-yl group, seem to be useful for
the Diels–Alder reactions toward the syntheses of azaste-
roidal compounds.
As the ring expansion reactions have proved to be effi-
cient tactics for the syntheses of various biologically ac-
tive products and drugs,1 recent efforts in our laboratory
have focused on the base-mediated or palladium(0)-medi-
ated ring expansion reactions using various hydroxy alle-
nyl cyclic compounds.2 In the previous ring expansion
reactions, we achieved a palladium(0)-catalyzed tandem
carbopalladation-heterocyclic one-atom ring expansion of
hydroxy methylallenylisoindolinones based on the Heck-
type reaction conditions giving the corresponding methyl
vinyl isoquinolinediones.2a,b,d However, the methyl group
of isoquinolinediones may restrict the flexibility of further
synthetic application of the product. Therefore, we at-
tempted the palladium(0)-catalyzed ring expansion reac-
tions of more useful hydroxy methoxyallenyl-
isoindolinones using aryl and vinyl halides, the results of
which are herein described.
MeO
O
HO
•
i)
N
R
N
R
1
2
O
O
R = Me 67%
= n-Bu
= i-Bu
= Bn
89%
89%
63%
ii)
XPd
MeO
O
OMe
H
O
R'
R
R'
N
R
38-77%
from 2
N
The starting hydroxy methoxyallenylisoindolinones 2
(63–89% yields) were prepared by treatment of the corre-
sponding N-alkylphthalimides 1 with 1.0 mol equivalent
of lithio methoxyallene3 in THF at –78 °C for 1 hour.4 The
structures of 2 were confirmed by their characteristic
3
O
O
X = I, Br
Scheme 1 Reagents and conditions: i) methoxyallene (1.2 mol
equiv), n-BuLi (1.0 mol equiv), THF, –78 °C. ii) Pd(PPh3)4 (10
mol%), R’-X (4 mol equiv), K2CO3 (3 mol equiv), THF, reflux.
spectroscopic data [1H NMR (300 MHz, CDCl3):
=
2.99–3.50 (s, 3 H, OMe), 3.09–3.35 (s, 1 H, OH), 5.68–
5.79 (d, 1 H, J = 8.5–8.6 Hz, allene H), and 5.74–5.84 (d,
1 H, J = 8.5–8.6 Hz, allene H); IR (KBr or neat): 3213–
3296 (OH), 1955–1966 (allenyl) cm–1; high resolution MS
(M+)] and elemental analyses. The ring expansion reac-
tions were performed as follows. Namely, the compounds
2 were refluxed with 10 mol% of Pd(PPh3)4, 3 mol equiv-
Subsequently, an intramolecular carbopalladation-hetero-
cyclic ring expansion of hydroxy methoxyallenylisoin-
dolinone 5 was attempted. Compound 5, obtained by
treatment of N-o-iodobenzylphthalimide 4 with 1.2 mol
equivalents of lithio methoxyallene in THF at –78 °C for
1 hour, was allowed to react with 10 mol% of Pd(PPh3)4
and 3 mol equivalents of K2CO3 in THF under reflux for
19 hours to afford the desired tetracyclic crystalline prod-
uct 6 [mp 134–135 °C (from n-hexane–Et2O–CH2Cl2)] in
37% yield (Scheme 2). The structure of 6 was explicitly
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0480,0482,ftx,en;Y23901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Palladium(0)-catalyzed Ring Expansion Reactions
481
Table Conversion of Hydroxy Methoxyallenylisoindolinones 2 to N-Alkylisoquinoline-1,4-diones 3a
R
R
X
I
Time (h)
45
Yield (%)b
R
R
X
I
Time (h)
60
Yield (%)b
Me
Ph
61
77
75
67
62
46
44
67
i-Bu
i-Bu
i-Bu
i-Bu
Bn
Ph
73
62
38
73
74
69
51
65
Me
p-MePh
p-MeOPh
vinyl
I
48
p-MePh
p-MeOPh
vinyl
I
44
Me
I
20
I
24
Me
Br
I
21
Br
I
22
n-Bu
n-Bu
n-Bu
n-Bu
Ph
96
Ph
60
p-MePh
p-MeOPh
vinyl
I
48
Bn
p-MePh
p-MeOPh
vinyl
I
60
I
33
Bn
I
21
Br
41
Bn
Br
20
a 4 Mol eq. of aryl iodide (R -X) or an excess amount of vinyl bromide was employed.
b Isolated yields after purification by silica gel column chromatography.
MeO
manner similar to those for the previously reported ring
expansion reactions.2a
O
HO
•
i)
N
I
N
I
In conclusion, we have demonstrated palladium(0)-cata-
lyzed syntheses of various new N-alkylisoquinoline-1,4-
diones bearing 3-methoxy and 3-vinyl [or 3-butadien-2-
yl] groups. Intramolecular tandem carbopalladation-het-
erocyclic ring expansion reaction proved to be convenient
for the expeditious synthesis of a tetracyclic quinolitidine
derivative.
74%
O
O
4
5
ii)
Me
O
IPd
MeO
O
H
O
Acknowledgement
N
37% from 5
N
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas (A)(2)(No. 13029085) from the Ministry of Edu-
cation, Culture, Science, Sports, and Technology, Japan.
O
6
O
Scheme 2 Reagents and conditions: i) methoxyallene (1.2 mol
equiv), n-BuLi (1.2 mol equiv), THF, –78 °C, 1 h. ii) Pd(PPh3)4 (10
mol%), K2CO3 (3 mol equiv), THF, reflux, 19 h.
References
(1) Hesse, M. Ring Enlargement in Organic Chemistry; VCH
Publishers, Inc.: New York, 1991.
(2) (a) Jeong, I.-Y.; Nagao, Y. Tetrahedron Lett. 1998, 39,
8677. (b) Jeong, I.-Y.; Lee, W. S.; Goto, S.; Sano, S.; Shiro,
M.; Nagao, Y. Tetrahedron 1998, 54, 14437. (c) Jeong, I.-
Y.; Nagao, Y. Synlett 1999, 576. (d) Jeong, I.-Y.; Shiro, M.;
Nagao, Y. Heterocycles 2000, 52, 85. (e) Nemoto, H.;
Yoshida, M.; Fukumoto, K. J. Org. Chem. 1997, 62, 6450.
(3) (a) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1985, 50, 5308.
(b) Zimmer, R. Synthesis 1993, 165.
determined by X-ray crystallographic analysis, as shown
in the Figure.6
A possible reaction mechanism for the palladium(0)-cata-
lyzed inter- and intramolecular carbopalladation-hetero-
cyclic ring expansion reactions of hydroxy
methoxyallenylisoindolinones can be rationalized in a
(4) Typical Experimental Procedure for Synthesis of a
Hydroxy Methoxyallenylisoindolinone 2 (R = Me): A
solution of methoxyallene (1.14 g, 16.27 mmol) in anhyd
THF (17 mL) was treated with 1.61 M n-butyllithium in
n-hexane (8.44 mL, 13.59 mmol) under N2 atmosphere at
–30 °C and stirred for 10 min. Then the solution was added
to a THF (20 mL) solution of N-methylphthalimide 1
(R = Me) (2.19 g, 13.59 mmol) at –78 °C. After being stirred
at –78 °C for 10 min, the reaction mixture was quenched
with water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and filtered. The
filtrate was evaporated in vacuo to afford the crude product,
which was purified by column chromatography on silica gel
to give compound 2 (R = Me) (2.09 g, 67%) as yellow
powder.
Figure Computer-generated drawing from the X-ray coordinates of
6
Synlett 2002, No. 3, 480–482 ISSN 0936-5214 © Thieme Stuttgart · New York

482
Y. Nagao et al.
LETTER
(5) Typical Experimental Procedure for the intermolecular
Ring Expansion Reaction: A mixture of N-methyl-3-
hydroxy-3-(1-methoxypropadienyl)isoindolin-1-one(2)
(R = Me) (0.10 g, 0.43 mmol), Pd(PPh3)4 (0.05 g, 0.043
mmol), K2CO3 (0.18 g, 1.30 mmol), and 4-iodotoluene (0.38
g, 1.74 mmol) in anhyd THF (8.6 mL) was refluxed under N2
atmosphere for 48 h. The reaction mixture was quenched
with sat. NH4Cl and extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and
filtered. The filtrate was evaporated in vacuo to afford the
crude product, which was purified by column
chromatography on silica gel with hexane–EtOAc (8:1) to
give N-methyl-3-methoxy-3-[1-(p-methylphenyl)ether-2,3-
dihydroisoquinoline]-1,4-dione 3 (R = Me, R = p-MePh)
(0.104 g, 77%) as a pale yellow oil.
(6) X-ray data for 4: C19H15NO3, MW = 305.33, yellow
prismatic crystal, monoclinic, space group P21/c (#14),
a = 7.836(1) Å, b = 26.084(5) Å, c = 7.770(1) Å,
V = 1477.7(4) Å3, = 111.50(1)°, Z = 4, R = 0.067,
Rw = 0.130.
Synlett 2002, No. 3, 480–482 ISSN 0936-5214 © Thieme Stuttgart · New York