Decarbonylative cycloaddition of phthalimides with 1,3-dienes

Article abstract of DOI:10.1021/ol101842y

The decarbonylative cycloadditions of phthalimides with 1,3-dienes were performed by using nickel catalyst. The reactions afford 3- vinyldihydroisoquinolones regioselectively with respect to both 1,3-dienes and phthalimides.

Full text of DOI:10.1021/ol101842y

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4548-4551
Decarbonylative Cycloaddition of
Phthalimides with 1,3-Dienes
Kyohei Fujiwara, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto 615-8510, Japan
tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsub@orgrxn.mbox.media.kyoto-u.ac.jp
Received August 6, 2010
ABSTRACT
The decarbonylative cycloadditions of phthalimides with 1,3-dienes were performed by using nickel catalyst. The reactions afford
3-vinyldihydroisoquinolones regioselectively with respect to both 1,3-dienes and phthalimides.
The transition-metal-catalyzed reactions, which provide
structurally diverse heterocyclic compounds by replacing a
part of a readily available heterocyclic compound with
another molecule in a single step, are rare but represent a
straightforward and powerful synthetic methodology.1-5
Herein, we report our results of decarbonylative cycloaddi-
tions of phthalimides with 1,3-dienes, which provide 3-vi-
nyldihydroisoquinolones regioselectively.6 The reaction rep-
resents an unprecedented replacement reaction of a carbon
monoxide by a C-C double bond.
Initially, we examined the decarbonylative cycloaddition
of N-2-pyridylphthalimide (1a) with 1,2-dimethylenecyclo-
hexane (2a) using Ni(cod)2. After screening of various
ligands, PMe3 was found to give the highest yield (78%,
Table 1, entries 1-4). Trace amounts of 3aa were obtained
in the cases where N-heterocyclic carbene ligands such as
IPr or IMes was used in place of PMe3. In other solvents,
such as acetonitrile, tetrahydrofuran, and toluene, yields were
even lower (entries 5-7). While the reaction of N-phe-
nylphthalimide (1b) with 2a did not give any products (entry
8), electron-deficient N-arylphthalimides react with diene
efficiently. Indeed, the reaction of 2a with N-perfluorophe-
nylphthalimide (1c) successfully provided 3ca in 59% yield
(entry 9). The reactions of 2a with N-diazinephthalimides
1d and 1e afford the products in good yields (entries 10 and
11). The highest yield was obtained when N-pyrrolylphthal-
imide 1f was employed, and the corresponding cycloadduct
3fa was isolated in 99% yield (entry 12).
(1) For Pd-catalyzed cycloadditions via elimination of CO2, see: (a)
Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007, 129,
12356. (b) Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118. (c)
Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T. J. Am. Chem.
Soc. 2008, 130, 16174. (d) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem.
Soc. 2007, 129, 14866. (e) Shintani, R.; Tsuji, T.; Park, S.; Hayashi, T.
J. Am. Chem. Soc. 2010, 132, 7508. (f) Shintani, R.; Murakami, M.; Hayashi,
T. Org. Lett. 2009, 11, 457. (g) Shintani, R.; Hayashi, S.; Murakami, M.;
Takeda, M.; Hayashi, T. Org. Lett. 2009, 11, 3754
.
(2) For Ni-catalyzed cycloadditions via elimination of CO, see: (a) Kajita,
With the optimized conditions in hand, we next investi-
gated the use of other 1,3-dienes in this reaction (Scheme
Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2008, 130, 6058. (b)
Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2008, 130, 17226
.
(3) For Ni-catalyzed cycloadditions via elimination of N2, see: (a) Miura,
T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10, 3085. (b) Yamauchi,
M.; Morimoto, M.; Miura, T.; Murakami, M. J. Am. Chem. Soc. 2010, 132,
54. (c) Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem.,
Int. Ed. 2010, 49, 4955. (d) Miura, T.; Morimoto, M.; Yamauchi, M.;
(6) The isoquinolone skeleton is widely found in various natural products
and medicinal drugs that exhibit a broad range of biological properties.
For example, see: (a) Le, T. N.; Gang, S. G.; Cho, W.-J. J. Org. Chem.
2004, 69, 2768. (b) Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.;
Liu, L. F.; LaVoie, E. J. J. Med. Chem. 2005, 48, 792. (c) Asano, A.;
Kitamura, S.; Ohra, T.; Aso, K.; Igata, H.; Tamura, T.; Kawamoto, T.;
Tanaka, T.; Sogabe, S.; Matsumoto, S.; Yamaguchi, M.; Kimura, H.; Itoh,
F. Bioorg. Med. Chem. 2008, 16, 4715.
Murakami, M. J. Org. Chem. 2010, 75, 5359
(4) For Ni-catalyzed cycloadditions via elimination of CO2, see: Yoshino,
Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009, 131, 7494
(5) For Ni-catalyzed cycloadditions via elimination of isocyanate, see:
Yoshino, Y.; Kurahashi, T.; Matsubara, S. Chem. Lett. 2010, 39, 896
.
.
.
10.1021/ol101842y  2010 American Chemical Society
Published on Web 09/23/2010

Table 1. Nickel-Catalyzed Decarbonylative Cycloadditionsa
Scheme 2. Plausible Reaction Pathway for the Nickel-Catalyzed
Decarbonylative Cycloaddition of Phthalimides with 1,3-Dienes
entry
Ar
ligand
solvent
yield (%)b
1
2
3
4
5
6
7
8
2-pyridyl (1a)
2-pyridyl (1a)
2-pyridyl (1a)
2-pyridyl (1a)
2-pyridyl (1a)
2-pyridyl (1a)
2-pyridyl (1a)
Ph (1b)
PMe3
PMe2Ph
PPh3
dioxane
dioxane
dioxane
dioxane
MeCN
78
6
<1
<1
23
21
41
<1
59
69
82
99
PCy3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
THF
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
9
C6F5 (1c)
10
11
12
2-pyrimidinyl (1d)
2-pyrazinyl (1e)
N-pyrrolyl (1f)
catalyzed reaction, it is reasonable to consider that the
catalytic cycle of the present reaction should consist of the
oxidative addition of an amide CO-N bond to a Ni(0)
complex.2a,3,7,8 Subsequent decarbonylation and coordination
of bidentate diene 2 took place to give nickel(II) intermediate
6. The diene would then insert into the C-Ni bond to give
more stable acyclic π-allylnickel intermediate 7. Nucleophilic
addition of nitrogen atom onto π-allylnickel at the more
substituted carbon takes place to afford 3 and regenerate the
starting Ni(0) complex.9,10 Since electron-deficient N-
arylphthalimides, such as 1c, 1e, and 1f, react with dienes
efficiently, oxidative addition of 1 to Ni(0) is most likely
the rate-determining step. We thus presumed that the
regioselective cycloaddition of unsymmetrically substituted
phthalimides with dienes would be accomplished by pref-
erential oxidative addition of a more electrophilic carbonyl
moiety to Ni(0). Actually, the reaction of 4-fluorophthalimide
1g reacted with diene 2a to afford the correspondingly
substituted cycloadduct 3ga in 68% yield with a regioselec-
tivity ratio of 4/1, while the cycloaddition of 3-fluorophthal-
imide 1h with 2a gave 3ha in 99% yield with complete
regiocontrol (Table 2, entries 1 and 2). The electron-
withdrawing CF3 group also performed efficiently with
regiocontrol to give a sole cycloadduct 3ia in excellent yield
(entry 3). Furthermore, quinolimide 1j reacted with 2a to
provide 3ja regioselectively in 47% isolated yield (entry 4).
The effects of electron-donating substituents on phthalimides
were also examined. The reaction of 4-methylphthalimide
1k with 2a gave cycloadduct 3ka in 90% yield as a 1/1
mixture of regioisomers, while the reaction of 3-meth-
ylphthalimide 1l with 2a afforded 3la with complete regio-
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand (40
mol %), 1 (0.5 mmol), and 2 (0.55 mmol) in 20 mL of refluxing solvent
for 12 h . b Isolated yields.
1). The cycloaddition of 1f with 2,3-dimethyl-1,3-butadiene
(2b) gave product 3fb in 89% yield. The reactions of 1f with
unsymmetrical 1,3-dienes such as isoprene (2c) and 2-phenyl-
1,3-butadiene (2d) gave the products in 86 and 56% yields,
respectively. Myrcene (2e) also reacted with 1f as 1,3-diene
to afford cycloadduct 3fe selectively in 91% yield. However,
1,1-disubstituted 1,3-dienes 2f or nonconjugated olefins, such
as 1-octene, norbornene, and methyl acrylate, failed to
participate in the reaction.
Scheme 1
.
Scope of the Nickel-Catalyzed Decarbonylative
Cycloaddition of 1f with 1,3-Dienes
(7) For oxidative addition of the C-N bond to Ni, see: (a) Chan, Y. W.;
Renner, M. W.; Balch, A. L. Organometallics 1983, 2, 1888. (b) Lin, B. L.;
Clough, C. R.; Hillhouse, G. L. J. Am. Chem. Soc. 2002, 124, 2890. (c)
Ozerov, O. V.; Guo, C.; Fan, L.; Foxman, B. M. Organometallics 2004,
23, 5573
.
(8) (a) O’Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2003,
125, 10498. (b) Johnson, J. B.; Bercot, E. A.; Rowley, J. M.; Coates, G. W.;
Rovis, T. J. Am. Chem. Soc. 2007, 129, 2718
.
A plausible reaction pathway to account for the formation
of 3 based on the observed results is outlined in Scheme 2.
In view of the mechanism of the previously reported nickel-
(9) For an example which involves amination of π-allyl nickel inter-
mediate, see: Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 3669
.
Org. Lett., Vol. 12, No. 20, 2010
4549

of oxygen to the nickel center through oxidative addition
and/or stabilization of aza-nickelacycle intermediate 5. The
same regioselectivity was also observed when dimethy-
lamino-substituted phthalimide 1o reacted with 2a (entry 9).
Moreover, it was found that protons also play an important
role in the regiocontrol of the reaction. That is, keto-enol
tautomerism may prevent oxidative addition of the corre-
sponding carbonyl moiety to Ni(0), and thus 3-aminoph-
thalimide 1p reacted with 2a to provide 1pa in 92% yield
(Scheme 3).
Table 2. Effects of Substituents on Regioselectivitya
Scheme 3. Regioselective Cycloaddition of 1p with 2a
Furthermore, the regioselective cycloaddition of unsym-
metrically substituted phthalimides with unsymmetrical 1,3-
dienes was successfully demonstrated (Scheme 4). The
reaction of 3-trifluoromethylphthalimide 1i with isoprene (2c)
afforded cycloadduct 3ic in 58% yield regioselectively as a
sole product out of eight possible regioisomers. The cy-
cloaddition of 3-methoxyphthalimide 1n with 2c also pro-
vided the correspondingly substituted cycloadduct 3nc in
64% yield as a sole product.
Scheme 4. Regioselective Cycloaddition of 1 with 2c
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand (40
mol %), 1 (0.5 mmol), and 2 (0.55 mmol) in 20 mL of refluxing solvent
for 12 h . b Isolated yields. c Ratio of regioisomers. d Single regioisomer.
e Reaction time, 36 h. f Reaction time, 72 h.
control (entries 5 and 6). The cycloaddition of 4-methox-
yphthalimide 1m with 2a provided 3ma as a major product
(entry 7). It is noteworthy that 3-methoxyphthalimide 1n
reacted with 2a to afford 3na regioselectively in 99% yield
(entry 8). The selectivity is thought to arise from coordination
In summary, we have developed a decarbonylative
cycloaddition of phthalimides with 1,3-dienes. It was
found that the cycloaddition proceeded regioselectively
with respect to 1,3-dienes. Moreover, the regioselective
cycloadditions of an unsymmetrically functionalized ph-
thalimide with 1,3-dienes were also achieved. The present
cycloadditions displayed excellent regio- and chemose-
lectivity in the presence of functional groups, which may
(10) For an intensive study on reductive elimination of the C-N bond
from Ni(II), see: (a) Koo, K.; Hillhouse, G. L.; Rheingold, A. L.
Organometallics 1995, 14, 456. (b) Koo, K.; Hillhouse, G. L. Organome-
tallics 1995, 14, 4421.
4550
Org. Lett., Vol. 12, No. 20, 2010

open the way for a facile divergent synthesis of function-
alized isoquinolones.
Supporting Information Available: Experimental pro-
cedures including spectroscopic and analytical data of new
compounds (PDF), and X-ray data (CIF). This material
is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. This work was supported by Grants-
in-Aid from MEXT, Japan. T.K. also acknowledges the
Asahi Glass Foundation and Mizuho Foundation for the
Promotion of Sciences.
OL101842Y
Org. Lett., Vol. 12, No. 20, 2010
4551