Nickel-catalyzed decarbonylative alkylidenation of phthalimides with trimethylsilyl-substituted alkynes

Article abstract of DOI:10.1021/ja4068172

We have developed a nickel-catalyzed transformation, in which phthalimides react with trimethylsilyl-substituted alkynes in the presence of Ni(0)/PMe ₃/MAD catalyst to provide isoindolinones. The reaction process displays an unusual mechanistic

Full text of DOI:10.1021/ja4068172

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Decarbonylative Alkylidenation of Phthalimides
with Trimethylsilyl-Substituted Alkynes
Takahiro Shiba,† Takuya Kurahashi,*,†,‡ and Seijiro Matsubara*,†
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
‡JST, ACT-C, Saitama, 332-0012, Japan
S
* Supporting Information
Table 1. Effects of Lewis Acid on the Nickel-Catalyzed
Decarbonylative Alkylidenation
a
ABSTRACT: We have developed a nickel-catalyzed
transformation, in which phthalimides react with trime-
thylsilyl-substituted alkynes in the presence of Ni(0)/
PMe3/MAD catalyst to provide isoindolinones. The
reaction process displays an unusual mechanistic fea-
turedecarbonylation and alkylidenation. The use of both
trimethylsilyl-substiuted alkynes and MAD was found to
be essential for the transformation with high selectivities.
he transition-metal-catalyzed reaction of alkynes, which
b
T
involves isomerizations of the π bond for constructing two
more thermodynamically stable σ bonds, is widely used to form
cyclic and acyclic molecular frameworks as precursors for
complex organic compounds. A representative example would
be transition-metal-catalyzed vicinal difunctionalization of
internal alkynes, wherein various chemical bonds are cleaved
and alkynes are inserted to provide tetrasubstituted alkenes in a
single step.1 The related alkylidenation, i.e., geminal difunction-
alization of alkynes, has also been a research topic of great
interest. Herein, we wish to report that the reaction of
phthalimides with trimethylsilyl-substituted alkynes in the
presence of a Ni(0) catalyst to provide isoindolinones through
decarbonylation and alkylidenation.2
yield (%)
entry
ligand (mol %)
Lewis acid
3aa
4aa
5aa
1
2
PMe3 (40)
PMe3 (40)
PMe3 (40)
PMe3 (40)
PMe3 (40)
PMe3 (40)
PMe2Ph (40)
PMePh2 (40)
−
<1
20
56
11
13
2
12
22
22
20
20
7
3
18
5
AlMe3
c
3
MAD
4
AlMe2Cl
Al(OPh)3
B(C6F5)3
24
21
22
7
5
6
c
7
MAD
38
3
40
24
44
c
8
MAD
<1
8
e
c
9
IPr (20)
MAD
<1
c
d
d
d
10
11
PMe3 (20)
PMe3 (10)
MAD
82
7
3
c
MAD
35
3
8
We previously demonstrated that the decarbonylative
addition of phthalimides to alkynes provided isoquinolones in
the presence of a Ni(0)/PMe3 catalyst (Scheme 1a).3 During
the course of our study, we found that on addition of a catalytic
amount of Lewis acid, the reaction afforded isoindolinones
selectively via decarbonylation and alkylidenation of phthali-
mides with alkynes (Scheme 1b). The effects of Lewis acid and
detailed reaction conditions were also examined.4 These effects
are summarized in Table 1. When phthalimide 1a and alkyne
a
Reactions were carried out using Ni(cod)2 (10 mol %), ligand, Lewis
acid (20 mol %), 1a (0.2 mmol), and 2a (0.3 mmol) in 2 mL of
toluene (110 °C) for 2 h. Determined by H NMR analysis using
CHBr3 as internal standard. MAD: methylaluminum bis(2,6-di-tert-
b
1
c
d
e
butyl-4-methylphenoxide). Isolated yields are given. IPr: 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene.
2a were treated in the presence of Ni(cod)2 (10 mol %) and
PMe3 (40 mol %) in toluene at 110 °C for 2 h, isoquinolones
4aa and 5aa were obtained in 12% and 3% yields, respectively
(entry 1). Isoindolinone 3aa was obtained in 20% yield as a
minor product when the same reaction was performed after
adding trimethylaluminium (20 mol %) (entry 2). Methyl-
aluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) is a
sterically bulky and monomeric homogeneous Lewis acid in
organic solvent and consequently shows high Lewis acidity.
The use of MAD was found to be effective in affording 3aa in
56% yield (entry 3).5 The use of Lewis acids, such as AlMe2Cl,
Al(OPh)3 and B(C6F5)3, was found to be less effective in
Scheme 1. Nickel-Catalyzed Decarbonylative Addition of
Phthalimides to Alkynes
Received: July 4, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4068172 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
affording 3aa (entries 4−6). When ligands, such as PMe2Ph,
PMePh2 and 1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene
(IPr), were used in place of PMe3, only trace or lower amounts
of 3aa were obtained (entries 7−9). Among the reaction
solvents examined, toluene gave the best results in affording
3aa. When optimizing the molecular ratio of Ni(cod)2 and
PMe3 for the reaction, a ratio of 1:2 was found to provide 3aa
stereoselectively in 82% yield (entries 3, 10, 11).
Table 2. Scope of Nickel-Catalyzed Decarbonylative
Alkylidenation
a
After obtaining these optimized conditions, we next
investigated the reaction of phthalimides 1 with 1-trimethylsil-
yl-substituted alkynes 2 having different functional groups
(Table 2). Under the optimized reaction conditions,
phthalimide 1a also reacted with 2b to afford 3ab in 77%
isolated yield (entry 2). A range of substituents tolerated the
reaction conditions sufficiently to afford the correspondingly
substituted isoindolinone 3 in good yields stereoselectively
(entries 3−7). We also found that N-phenyl phthalimide (1b)
can participate in the reaction with 2a to afford 3ba in 44%
yield with prolonged reaction time (4 h) and increased amount
of MAD (60 mol %); almost the rest of 1b was recovered
unchanged. The reaction of 1c with 2a under the same reaction
conditions provided 3ca in 73% yield as a sole isomer.
However, N-aryl phthalimides, which had pyridine and diazine
moiety as the substituent on the phthalimide nitrogen, did not
afford any products.
We next investigated the effects of substituents on alkynes 2.
As summarized in Table 3, the alkyne 2a possessing the
trimethylsilyl group exhibited better results in terms of
providing isoindolinone 3aa than dimethylphenylsilyl- or tert-
butyldimethylsilyl-substituted alkynes 2h and 2i (entries 1−3).
The reaction of 1a with sterically hindered tert-butyl-substituted
alkyne 2j or 2-nonyne (2k) did not furnish isoindolinones
(entries 4 and 5). It was found that aryl-substituted
trimethylsilylacetylenes also participated in the decarbonylative
1,1-addition with phthalimide 1a to afford the corresponding
substituted isoindolinones (entries 6−8). The reaction of 1-
phenyl-2-trimethylsilylacetylene (2l) with 1a provided 3al as a
major product in 72% isolated yield and 3al′ as a minor product
in 7% yield (entry 6). Although 1-aryl-2-trimethylsilylacetylene
2m, which possesses the electron-withdrawing trifluoromethyl
substituent on the phenyl group, reacted with 1a to afford 3am
as a sole product (entry 7), electron-donating methoxy-
substituted 1-aryl-2-trimethylsilylacetylene 2n reacted with 1a
to afford 3an and its isomer 3an′ in 53% and 21% yields,
respectively. The molecular structures of the major product 3an
and minor product 3an′ were determined using X-ray crystal
structure analysis (for details, see Supporting Information), and
the configurations of all other examples were assigned
analogously. The reaction of 1a with other carbon−carbon
unsaturated compounds, such as alkenes, 1,3-dienes, and
allenes, in place of alkynes did not afford any 1,1-addition
type products.
Although the mechanism of this reaction is not completely
elucidated, we proposed the following reaction mechanism
based on our observed results, to account for the
unprecedented decarbonylative alkylidenation and stereo-
chemical outcome of the reaction (Scheme 2). In view of the
reaction mechanism of the previously reported nickel-catalyzed
reaction of phthalimides with alkynes, the catalytic cycle of the
present reaction could be considered to consist of the oxidative
addition of an imide CO−N bond to a Ni(0) complex in
association with MAD.6 The subsequent decarbonylation and
coordination of alkyne 2 takes place to afford a five-membered
a
Reactions were carried out using Ni(cod)2 (10 mol %), PMe3 (20
mol %), MAD (20 mol %), 1 (0.2 mmol), and 2 (0.3 mmol) in 2 mL
of toluene 110 °C for 2 h. Isolated yields are given. MAD (60 mol
%) and reaction time was 4 h.
b
c
B
dx.doi.org/10.1021/ja4068172 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Effects of Substituents on Alkynes in
Decarbonylative Alkylidenation
Scheme 2. Plausible Reaction Mechanism
a
nickelacycle A. MAD, which is coordinated to carbonyl oxygen,
would then promote the formation of acyclic cationic nickel B;
electron-rich phosphine ligand PMe3 may also promote the
formation of B by stabilizing the cationic nature of the nickel
center. The nucleophilic addition of alkyne takes place to afford
cationic nickel vinylidene complex C via a [1,2]-shift of the silyl
group on alkyne 2.7−9 The insertion of vinylidene moiety to the
carbon−nickel bond affords a six-membered nickelacycle D,
which undergoes reductive elimination to furnish isoindolinone
3 and regenerates the starting Ni(0). The stereoselectivity of
the reaction can be attributed to the direction of insertion of
vinylidene moiety, in which the steric repulsive interaction is
minimal between the sterically bulkier trimethylsilyl group and
the phosphine ligand on the nickel to afford intermediate D in
preference to D′.10
In summary, we have developed an unprecedented reaction
pattern that provides isoindolinone with a nickel-catalyst and
MAD-cocatalyst from phthalimides and trimethylsilyl-substi-
tuted alkynes. This reaction represents the first example of
alkylidenation with alkynes involving decarbonylation. Efforts
to expand the scope of the reaction as well as detailed studies to
elucidate its underlying mechanism are underway.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectroscopic and analytical data for
new compounds, and crystallographic data (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
kurahashi.takuya.2c@kyoto-u.ac.jp
matsubara.seijiro.2e@kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
T.K. also acknowledges the Asahi Glass Foundation, The
Uehara Memorial Foundation, Tokuyama Science Foundation,
and Kurata Memorial Hitachi Science and Technology
Foundation.
a
Reactions were carried out using Ni(cod)2 (10 mol %), PMe3 (20
mol %), MAD (20 mol %), 1 (0.2 mmol), and 2 (0.3 mmol) in 2 mL
b
of toluene 110 °C for 2 h. Isolated yields are given.
C
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Journal of the American Chemical Society
Communication
REFERENCES
■
(1) For some selected reviews on vicinal difunctionalization of
internal alkynes, see: (a) Beletskaya, I.; Moberg, C. Chem. Rev. 1999,
99, 3435. (b) Suginome, M.; Ito, Y. Chem. Rev. 2000, 100, 3221.
(c) Oestreich, M.; Hartmann, E.; Mewald, M. Chem. Rev. 2013, 113,
402.
(2) The isoindolinone framework is widely found in various natural
product and medicinal drug that exhibits a broad range of biological
properties, e.g.: (a) Ren, J.; Esnouf, R. M.; Hopkins, A. L.; Stuart, D. I.;
Stammers, D. K. J. Med. Chem. 1999, 42, 3845. (b) Belliotti, T. R.;
Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise, L.
D. Bioorg. Med. Chem. Lett. 1998, 8, 1499. (c) Kawanishi, N.;
Sugimoto, T.; Shibata, J.; Nakamura, K.; Masutani, K.; Ikuta, M.; Hirai,
H. Bioorg. Med. Chem. Lett. 2006, 16, 5122.
(3) (a) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2008, 130, 6058. (b) Miura, T.; Yamauchi, M.; Murakami, M. Org.
Lett. 2008, 10, 3085.
(4) (a) Ikeda, S.; Mori, N.; Sato, Y. J. Am. Chem. Soc. 1997, 119,
4779. (b) Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G. W. Angew.
Chem., Int. Ed. 2002, 41, 2781. (c) Kamijo, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 3230. (d) Getzler, Y. D. Y. L.; Mahadevan, V.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174.
(e) Fontaine, F.-G.; Zargarian, D. J. Am. Chem. Soc. 2004, 126, 8786.
(f) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc.
2005, 127, 12810. (g) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 5818. (h) Nakao, Y.; Yada, A.; Ebata, S.;
Hiyama, T. J. Am. Chem. Soc. 2007, 129, 2428. (i) Shen, Q.; Hartwig, J.
F. J. Am. Chem. Soc. 2007, 129, 7734. (j) Nakao, Y.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448. (k) Baxter, R. D.;
Montgomery, J. J. Am. Chem. Soc. 2008, 130, 9662. (l) Koester, D. C.;
Kobayashi, M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134,
6544. (m) Nakai, K.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2011, 133, 11066.
(5) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985,
107, 4573. (b) Maruoka, K.; Araki, Y.; Yamamoto, H. J. Am. Chem. Soc.
1988, 110, 2650.
(6) (a) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2008, 130, 17226. (b) Fujiwara, K.; Kurahashi, T.; Matsubara, S. Org.
Lett. 2010, 12, 4548. (c) Ochi, Y.; Kurahashi, T.; Matsubara, S. Org.
Lett. 2011, 13, 1374.
(7) (a) Yamazaki, S.; Katoh, S.; Yamabe, S. J. Org. Chem. 1992, 57, 4.
(b) Crabtree, R. H. New J. Chem. 2003, 27, 771. (c) Pezacki, J. P.;
Loncke, P. G.; Ross, J. P.; Warkentin, J.; Gadosy, T. A. Org. Lett. 2000,
2, 2733. (d) Barton, T. J.; Lin, J.; Ijadi-Maghsoodi, S.; Power, M. D.;
Zhang, X.; Ma, Z.; Shimizu, H.; Gordon, M. S. J. Am. Chem. Soc. 1995,
117, 11695.
(8) For some recent examples of the use of unique reactivity of silyl
substituted carbon−carbon unsaturated compounds in nickel-catalyzed
reaction, see: (a) Ho, C.-Y.; He, L. Chem, Commun. 2012, 48, 1481.
(b) Ogata, K.; Atsuumi, Y.; Fukuzawa, S. Org. Lett. 2011, 13, 122.
(c) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 5060.
(d) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410.
(9) For some examples of formation of vinylidene complexes from
internal alkynes, see: (a) Ikeda, Y.; Yamaguchi, T.; Kanao, K.; Kimura,
K.; Kamimura, S.; Mutoh, Y.; Tanabe, Y.; Ishii, Y. J. Am. Chem. Soc.
2008, 130, 16856. (b) Shaw, M. J.; Bryant, S. W.; Rath, N. Eur. J. Inorg.
Chem. 2007, 3943. (c) King, P. J.; Knox, S. A. R.; Legge, M. S.; Orpen,
A. G.; Wilkinson, J. N.; Hill, E. A. J. Chem. Soc., Dalton Trans. 2000,
1547.
(10) To gain insight into the reaction mechanism, partially 13C-
enriched alkynes were prepared and subjected to the reaction
conditions for the nickel-catalyzed decarbonylative 1,1-addition (for
details, see SI).
D
dx.doi.org/10.1021/ja4068172 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX