Mechanistic investigation of the palladium-catalyzed decarboxylative cyclization of γ-methylidene-δ-valerolactones with isocyanates: Kinetic studies and origin of the site selectivity in the nucleophilic attack at a (π-allyl)palladium

Article abstract of DOI:10.1021/ja1023223

Mechanistic studies for the palladium-catalyzed decarboxylative cyclization reactions of γ-methylidene-δ-valerolactones 1 with isocyanates 2 are described. The reactions can be effectively catalyzed by palladium triarylphosphine complexes to give piperidones 3 and/or azaspiro[2.4]heptanones 4. Through kinetic studies using NMR spectroscopy, it has been determined that the oxidative addition of lactones 1 to palladium(0) is the turnover-limiting step of the catalytic cycle. By changes in the electronic properties of the triarylphosphine ligands, the product distribution between 3 and 4 can be easily controlled, and an explanation for the origin of this selectivity is provided. The selectivity between 3 and 4 is also influenced by the nature of the nitrogen substituent on isocyanates 2, and more electron-rich substituents tend to give higher selectivity toward azaspiro[2.4]heptanones 4. These studies represent the first systematic investigation into the selectivity between terminal attack and central attack at (π-allyl)palladium species by nitrogen-based nucleophiles.

Full text of DOI:10.1021/ja1023223

Published on Web 05/07/2010
Mechanistic Investigation of the Palladium-Catalyzed
Decarboxylative Cyclization of γ-Methylidene-δ-valerolactones
with Isocyanates: Kinetic Studies and Origin of the Site
Selectivity in the Nucleophilic Attack at a (π-Allyl)palladium
Ryo Shintani,* Takaoki Tsuji, Soyoung Park, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
Received March 24, 2010; E-mail: shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Abstract: Mechanistic studies for the palladium-catalyzed decarboxylative cyclization reactions of γ-meth-
ylidene-δ-valerolactones 1 with isocyanates 2 are described. The reactions can be effectively catalyzed by
palladium triarylphosphine complexes to give piperidones 3 and/or azaspiro[2.4]heptanones 4. Through
kinetic studies using NMR spectroscopy, it has been determined that the oxidative addition of lactones 1
to palladium(0) is the turnover-limiting step of the catalytic cycle. By changes in the electronic properties
of the triarylphosphine ligands, the product distribution between 3 and 4 can be easily controlled, and an
explanation for the origin of this selectivity is provided. The selectivity between 3 and 4 is also influenced
by the nature of the nitrogen substituent on isocyanates 2, and more electron-rich substituents tend to give
higher selectivity toward azaspiro[2.4]heptanones 4. These studies represent the first systematic investigation
into the selectivity between terminal attack and central attack at (π-allyl)palladium species by nitrogen-
based nucleophiles.
containing heterocycles,2,3 and 2-((trimethylsilyl)methyl)-2-prope-
nyl acetate and its derivatives are used as effective precursors for
Introduction
Intermolecular cycloadditions catalyzed by transition-metal
complexes are powerful methods for convergent synthesis of cyclic
compounds.1 The development of new and efficient intermolecular
cycloaddition reactions is therefore an important objective in
synthetic organic chemistry in order to expand the accessibility to
a wide variety of carbo- and heterocyclic materials. In this regard,
reactions of catalytically generated electrophilic (π-allyl)palladium
species bearing a pendant nucleophile with carbon-carbon or
carbon-heteroatom unsaturated bonds represent an efficient and
attractive approach. For example, vinyl epoxides and aziridines are
often utilized for the construction of oxygen- and nitrogen-
palladium trimethylenemethane species in the context of catalytic
[3 + n] cycloaddition reactions.4,5
To enhance the utility of palladium-catalyzed intermolecular
cycloaddition chemistry, we recently devised γ-methylidene-
δ-valerolactones (1 in Scheme 1) as new reagents for decar-
boxylative addition/cyclization reactions with several reaction
partners to produce various cyclic compounds under mild
palladium catalysis.6 These lactones 1 were originally designed
(4) (a) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101, 6429.
(b) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105, 2315.
(c) Trost, B. M.; MacPherson, D. T. J. Am. Chem. Soc. 1987, 109,
3483. (d) Trost, B. M.; Seoane, P. R. J. Am. Chem. Soc. 1987, 109,
615. (e) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schwo¨rer, U.
J. Am. Chem. Soc. 2006, 128, 13328. (f) Trost, B. M.; Silverman,
S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129, 12398. (g)
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330. (h)
Shintani, R.; Park, S.; Duan, W.-L.; Hayashi, T. Angew. Chem., Int.
Ed. 2007, 46, 5901. See also: (i) Shimizu, I.; Ohashi, Y.; Tsuji, J.
Tetrahedron Lett. 1984, 25, 5183. (j) Inoue, Y.; Ajioka, M.; Toyofuku,
M.; Mori, A.; Fukui, T.; Kawashima, Y.; Miyano, S.; Hashimoto, H.
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(1) (a) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830.
(b) Varela, J. A.; Saa´, C. Synlett 2008, 2571. (c) Shibata, T. AdV.
Synth. Catal. 2006, 348, 2328. (d) Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127. (e) Wender, P. A.; Gamber, G. G.; Williams,
T. J. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A.,
Ed.; Wiley-VCH: Weinheim, Germany, 2005; p 263. (f) Mandai, T.
In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; p 925. (g) Kobayashi, S.,
Jørgensen, K. A., Eds. Cycloaddition Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2002.
(2) (a) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792.
(b) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1988, 110, 7933.
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Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; p 57. (a) Ogoshi, S. In Handbook of
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Wiley: Hoboken, NJ, 2002; p 1995.
(6) (a) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 12356. (b) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 14866. (c) Shintani, R.; Park, S.; Shirozu, F.; Murakami,
M.; Hayashi, T. J. Am. Chem. Soc. 2008, 130, 16174. (d) Shintani,
R.; Murakami, M.; Hayashi, T. Org. Lett. 2009, 11, 457. (e) Park, S.;
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9
7508 J. AM. CHEM. SOC. 2010, 132, 7508–7513
10.1021/ja1023223  2010 American Chemical Society

Pd-Catalyzed Decarboxylative Cyclization
A R T I C L E S
Scheme 1. Schematic Representation for the Palladium-Catalyzed
Decarboxylative Cyclization of γ-Methylidene-δ-valerolactones 1
with X)Y
Scheme 3. Proposed Catalytic Cycle for the Palladium-Catalyzed
Decarboxylative Cyclization of 1a and 2a
Scheme 2. Proposed Pathways for the Formation of Products A
and B
stoichiometric reactions with ester enolates.11a Since then,
several examples have been reported, including catalytic
reactions,12,13 but most of them rely on the use of carbon-based
nucleophiles such as ester enolates. In contrast, the use of
nitrogen-based nucleophiles is very rare for this type of
cyclopropanation.13
In this article, we employ isocyanates14 as the reaction partner
for the palladium-catalyzed decarboxylative cyclization of
γ-methylidene-δ-valerolactones6c and describe the results of our
mechanistic investigation, mainly focused on the kinetic studies
and the origin of the site selectivity in the nucleophilic attack
of nitrogen-based nucleophiles at (π-allyl)palladium species.
to serve as precursors for 1,4-zwitterionic species through
oxidative addition to palladium(0) and successive decarboxyla-
tion,7,8 thereby introducing a four-carbon unit in a newly formed
cyclic framework (product A; Scheme 1). During the course of
our studies, however, we encountered some cases (particularly
with electron-deficient olefins6b or isocyanates6c as the reaction
partner) where they provide three carbons in a cyclic framework
with a spirocyclopropane moiety (product B). Both products A
and B are presumably formed through the common intermediate
C in Scheme 2, and the position of the subsequent nucleophilic
ring closure dictates the structure of the products. Namely, a
prototypical Tsuji-Trost-type intramolecular nucleophilic attack
at one of the two terminal carbons of the (π-allyl)palladium
moiety leads to A through D (path a),9 whereas an attack to the
central carbon gives palladacyclobutane E,10 reductive elimina-
tion of which leads to B (path b).10,11 Cyclopropane formation
through the latter mode of the reaction pathway was first
disclosed by Hegedus and co-workers in the context of
Results and Discussion
The reaction of γ-methylidene-δ-valerolactone 1a with
4-methoxyphenyl isocyanate (2a) was conducted in the presence
of 5 mol % of Pd(PPh3)4 as a catalyst in toluene at 30 °C (eq
1). The reaction was completed within 6 h, and the expected
piperidone 3aa was obtained along with the formation of
azaspiro[2.4]heptanone 4aa with a 3aa/4aa ratio of 91/9 (94%
combined yield). A proposed catalytic cycle of this process is
illustrated in Scheme 3. Thus, initial oxidative addition of the
allyl ester moiety of 1a to palladium(0) gives the allylpalladium
carboxylate I, decarboxylation of which leads to the 1,4-
(11) (a) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem.
1980, 45, 5193. (b) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew.
Chem., Int. Ed. Engl. 1992, 31, 234. (c) Wilde, A.; Otte, A. R.;
Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1993, 615. (d)
Otte, A. R.; Wilde, A.; Hoffmann, H. M. R. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1280.
(7) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199.
(b) Tsuda, T.; Chuji, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381. For reviews, see: (c) Tunge, J. A.; Burger,
E. C. Eur. J. Org. Chem. 2005, 1715. (d) You, S.-L.; Dai, L.-X. Angew.
Chem., Int. Ed. 2006, 45, 5246.
(12) (a) Formica, M.; Musco, A.; Pontellini, R.; Linn, K.; Mealli, C. J.
Organomet. Chem. 1993, 448, C6. (b) Satake, A.; Nakata, T. J. Am.
Chem. Soc. 1998, 120, 10391. (c) Satake, A.; Koshino, H.; Nakata,
T. Chem. Lett. 1999, 49. (d) Satake, A.; Kadohama, H.; Koshino, H.;
Nakata, T. Tetrahedron Lett. 1999, 40, 3597. (e) Liu, W.; Chen, D.;
Zhu, X.-Z.; Wan, X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131,
8734.
(8) For leading references, see: (a) Burger, E. C.; Tunge, J. A. Org. Lett.
2004, 6, 4113. (b) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem.
Soc. 2005, 127, 13510. (c) Waetzig, S. R.; Tunge, J. A. J. Am. Chem.
Soc. 2007, 129, 14860. (d) Trost, B. M.; Xu, J. J. Am. Chem. Soc.
2005, 127, 17180. (e) Mohr, J. T.; Behenna, D. C.; Harned, A. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44, 6924. (f) Patil, N. T.;
Huo, Z.; Yamamoto, Y. J. Org. Chem. 2006, 71, 6991.
(13) Grigg, R.; Kordes, M. Eur. J. Org. Chem. 2001, 707.
(14) For leading references on transition metal-catalyzed cycloadditions
using isocyanates, see: (a) Reference 2. (b) Baeg, J.-O.; Bensimon,
C.; Alper, H. J. Am. Chem. Soc. 1995, 117, 4700. (c) Duong, H. A.;
Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438. (d)
Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.;
Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (e) Tanaka,
K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737. (f) Tanaka, K.;
Hagiwara, Y.; Hirano, M. Angew. Chem., Int. Ed. 2006, 45, 2734. (g)
Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782. (h) Yu, R. T.;
Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (i) Yu, R. T.; Friedman,
R. K.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13250.
(9) For recent reviews on palladium-catalyzed allylic alkylation reactions,
see: (a) Trost, B. M.; Fandrick, D. R. Aldrichim. Acta 2007, 40, 59.
(b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (c)
Hayashi, T. J. Organomet. Chem. 1999, 576, 195. (d) Helmchen, G.
J. Organomet. Chem. 1999, 576, 203. (e) Negishi, E., Ed. Handbook
of Organopalladium Chemistry for Organic Synthesis; Wiley: Hobo-
ken, NJ, 2002; Vol. 2.
(10) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams,
D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 100.
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A R T I C L E S
Shintani et al.
Figure 1. Plot of the initial rate (mM/sec) vs concentration of isocyanate
2a (mM) ([Pd]0 ) 4 mM, [1a]0 ) 160 mM, [2a]0 ) 67-240 mM).
Figure 2. Plot of the initial rate (mM/sec) vs concentration of lactone 1a
(mM) ([Pd]0 ) 4 mM, [1a]0 ) 60-133 mM, [2a]0 ) 100 mM).
zwitterionic species II. The anionic carbon of II then attacks
the electrophilic carbon of 2a to give intermediate III. From
this intermediate, 3aa is obtained by a ring closure through a
nucleophilic attack of the nitrogen atom at the terminal carbon
of the (π-allyl)palladium moiety (path a), whereas 4aa is
generated through a nucleophilic attack at the central carbon
followed by reductive elimination (path b).
Figure 3. Plot of the initial rate (mM/sec) vs concentration of palladium
catalyst (mM) ([Pd]0 ) 4-11 mM, [1a]0 ) 80 mM, [2a]0 ) 100 mM).
Table 1. Palladium-Catalyzed Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactone 1a with 4-Methoxyphenyl
Isocyanate (2a): Effect of Ligands
Kinetic Studies on the Decarboxylative Cyclization of 1a
with 2a. A series of NMR experiments were carried out for the
kinetic studies of the reaction of lactone 1a with isocyanate 2a
in toluene-d8 in the presence of Pd(PPh3)4 as a catalyst at 25
°C. As shown in Figure 1, the initial concentration of isocyanate
2a has no influence on the initial rate of the production of 3aa,
indicating that the reaction is zero order in [2a]. In contrast,
the reaction rate shows first-order dependency both on the initial
concentration of lactone 1a and on that of palladium catalyst,
as illustrated in Figures 2 and 3. These results indicate that the
oxidative addition of 1a to palladium(0) (Pd(0) f I step in
Scheme 3) is the turnover-limiting step and successive decar-
boxylation and reaction with 2a occur much more quickly.
Effect of the Electronic Nature of Ligands for Palladium.
Interesting trends were observed by conducting a reaction of
lactone 1a with isocyanate 2a in the presence of a palladium
catalyst possessing several electronically different triarylphos-
phine ligands. The use of tris(4-methoxyphenyl)phosphine as
the ligand smoothly and selectively provided 3aa in 87% yield
with no formation of 4aa (Table 1, entry 1). By changing the
ligand to more electron-deficient triarylphosphines, the reactivity
became gradually lower and the selectivity toward 4aa gradually
became higher, reaching 3aa/4aa ) 5/95 with tris(4-(trifluo-
romethyl)phenyl)phosphine (entry 4).
entry
Ar
yield (%)a
3aa/4aab
1
2
3
4
4-MeOC6H4
Ph
4-FC6H4
4-CF3C6H4
87
85
71
73c
>99/1
88/12
31/69
5/95
b
a Combined isolated yield of 3aa and 4aa. Determined by H NMR.
1
c The reaction was conducted at 50 °C with a 0.67 M concentration of
2a.
Similarly, under the catalysis of a palladium complex
coordinated with tris(4-methoxyphenyl)phosphine, several
R-aryl-γ-methylidene-δ-valerolactones 1 smoothly reacted
with isocyanate 2a to provide almost exclusively piperidones
3 in high yield (76-86% yield, 3/4 g 97/3; Table 2, entries
1, 3, 5, and 7). The use of tris(4-(trifluoromethyl)phe-
nyl)phosphine as the ligand, on the other hand, led to the
9
7510 J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010

Pd-Catalyzed Decarboxylative Cyclization
A R T I C L E S
Table 2. Palladium-Catalyzed Decarboxylative Cyclization of 1
with 2a
the nucleophilic attack to (π-allyl)metal complexes can be
altered by subtle changes of the reaction parameters, due to the
possible closeness in energy level of the two empty orbitals
derived from the allyl moiety (n and π* orbitals).16,18 It has
also been proposed that higher nucleophilicity (higher HOMO)
of the incoming nucleophile provides a better overlap of its filled
orbital with the π*-derived empty orbital of the (π-allyl)metal
species without significant repulsive interaction, leading to the
formation of a metallacyclobutane.18 Furthermore, in the event
of a nucleophilic attack to a cationic (π-allyl)palladium(II)
complex, the rate is known to become faster with electron-
deficient triarylphosphine ligands such as tris(4-(trifluorometh-
yl)phenyl)phosphine than with electron-rich counterparts such
as tris(4-methoxyphenyl)phosphine.19
On the basis of these precedents, the dependence of selectivity
between 3aa and 4aa on the electronic nature of ligands could
be explained as follows. Thus, by having electron-deficient
phosphine ligands on palladium, the reaction pathway is more
kinetically controlled and the electron-withdrawing nature of the
ligands would facilitate lowering the energy level of the π*-derived
empty orbital. As a consequence, this empty orbital mixes well
with the HOMO of the incoming nucleophile, resulting in the
preferential formation of a palladacyclobutane, reductive elimina-
tion of which gives compound 4aa. On the other hand, the use of
electron-rich phosphine ligands, which slows down the step of
nucleophilic attack, leads to a thermodynamically more favorable
product (3aa) through the usual orbital overlap between the HOMO
of the incoming nucleophile and the n-derived empty orbital
(LUMO) of the (π-allyl)palladium species.
entry
1 (Ar)
ligand
product
yield (%)a
1b
2c
3b
4c
5b
6c
7b
8c
1b (4-MeOC6H4) P(4-MeOC6H4)3 3ba/4ba (>99/1)
80
64
86
73
85
62
76
71
1b
P(4-CF3C6H4)3
P(4-MeOC6H4)3 3ca/4ca (>99/1)
P(4-CF3C6H4)3 3ca/4ca (5/95)
P(4-MeOC6H4)3 3da/4da (>99/1)
P(4-CF3C6H4)3 3da/4da (5/95)
P(4-MeOC6H4)3 3ea/4ea (97/3)
P(4-CF3C6H4)3 3ea/4ea (6/94)
3ba/4ba (4/96)
1c (4-MeC6H4)
1c
1d (3-MeC6H4)
1d
1e (ferrocenyl)
1e
a Combined isolated yield of 3 and 4. b The reaction was conducted
at 30 °C with a 0.20 M concentration of 2a. c The reaction was
conducted at 50 °C with a 0.67 M concentration of 2a.
Effect of r-Substituent of Lactones 1. Under the reaction
conditions in eq 1, the use of the R-alkyl lactone 1f resulted in
much lower yield of piperidone 3fa (29% yield after 24 h) with
recovery of a significant amount of starting lactone 1f (1.0 equiv
recovery; eq 2). The reactivity difference between the R-phenyl
species 1a and R-benzyl 1f is further highlighted by the competition
experiment in eq 3. Thus, an equimolar mixture of 1a and 1f was
treated with isocyanate 2a in the presence of Pd(PPh3)4 catalyst at
30 °C. Under these conditions, only the products derived from
lactone 1a (3aa/4aa) were obtained in 75% yield with no formation
of the 1f-derived products 3fa/4fa.
Figure 4. Plot of conversion of 1a vs time for the reaction of 1a ([1a]0 )
0.080 M) with 2a ([2a]0 ) 0.100 M) in toluene-d8 (0.60 mL) in the presence
of PdCp(η3-C3H5)/2PAr3 ([Pd]0 ) 0.004 M). Reaction conditions: (a) Ar
) 4-MeOC6H4 at 30 °C; (b) Ar ) Ph at 30 °C; (c) Ar ) 4-FC6H4 at 50 °C;
(d) Ar ) CF3C6H4 at 80 °C.
formation of azaspiro[2.4]heptanones 4 with high selectivity
(62-73% yield, 3/4 e 6/94; entries 2, 4, 6, and 8).
The reactivity difference, dependent on the electronic nature
of phosphine ligands, is visualized in Figure 4 by monitoring
the reactions in toluene-d8 using NMR spectroscopy. The trend
that more electron-rich triarylphosphines provide more reactive
catalysts is consistent with the conclusion of the kinetic studies
that the turnover-limiting step in the catalytic cycle is the step
of oxidative addition, which is known to become more facile
with electron-rich ligands on palladium.15
With regard to the site selectivity of the nucleophilic attack,
the central carbon of (π-allyl)metal complexes is known to be
more positively charged than the terminal carbons,16 and the
formation of a metallacyclobutane through a nucleophilic attack
at the central carbon atom is kinetically controlled.17 In addition,
a theoretical investigation indicates that the site selectivity of
To elucidate the behavior of 1f during the catalytic reaction,
the δ,δ-dideuterio lactone 1f-d2 was subjected to the reaction
with 2a and the recovered 1f-d2 was analyzed by NMR to show
(15) Amatore, C.; Carre´, E.; Jutand, A.; M’Barki, M. A. Organometallics
1995, 14, 1818.
(16) Curtis, M. D.; Eisenstein, O. Organometallics 1984, 3, 887.
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A R T I C L E S
Shintani et al.
Table 3. Palladium-Catalyzed Decarboxylative Cyclization of 1a
with Isocyanates 2: Effect of N-Substituents
that the deuterium content at the δ-position became 120% (out
of 200%) and the hydrogens on the exo-methylene carbon
showed 80% deuterium incorporation (eq 4). This result
indicates that oxidative addition of 1f does occur under these
conditions, but successive generation of 1,4-zwitterionic species
by decarboxylation becomes less favorable, presumably because
the resulting anionic charge on the R-carbon is not well
stabilized by the electron-donating alkyl substituent. This
hypothesis is further supported by a control experiment using
R-phenyl lactone 1a-d2 in the reaction with 2a (eq 5). Recovered
1a-d2 in this case kept its deuterium atoms at the δ-position
with essentially no migration to the exo-methylene carbon,
indicating that the rate-determining oxidative addition is rapidly
followed by decarboxylation, which is facilitated by the anion-
stabilization ability of the phenyl group at the R-position. On
the basis of these experiments, we prepared R-benzyl lactone
1f′ having a more electron-withdrawing phenyl ester, instead
of a methyl ester, to accelerate the decarboxylation step (I f
II in Scheme 3), and we were pleased to find that the reaction
of this lactone 1f′ with isocyanate 2a did smoothly proceed to
give the corresponding decarboxylative cyclization products in
high yield (81% yield; eq 6).
entry
2 (R)
product
yield (%)a
1b
2b
3c
4c
2a (4-MeOC6H4)
2b (4-ClC6H4)
2c (1-cyclohexenyl)
2d (CH2Ph)
3aa/4aa (91/9)
3ab/4ab (>99/1)
3ac/4ac (40/60)
3ad/4ad (4/96)
94
84
58
55
a Combined isolated yield of 3 and 4. b 1.4 equiv of 1a was used.
c 2.5 equiv of 1a was used.
(2a) provided piperidone 3aa as the major product under the
catalysis of Pd(PPh3)4 (3aa/4aa ) 91/9; Table 3, entry 1)
through a preferential nucleophilic ring closure at the terminal
carbon of the (π-allyl)palladium intermediate (path a in
Scheme 3). The use of electron-deficient aryl isocyanates such
as 4-chlorophenyl isocyanate (2b) led to further enhancement
of selectivity toward product 3 (3ab/4ab > 99/1; entry 2). In
contrast, the change of nitrogen substituent of the isocyanate
to a 1-cyclohexenyl group (2c) gave a 40/60 mixture of 3ac/
4ac (entry 3), and the predominant formation of azaspiro[2.4]-
heptanone 4ad was observed with an alkyl isocyanate such
as 2d (3ad/4ad ) 4/96; entry 4). The results observed here
indicate that more stabilized anionic amide nitrogens seem
to favor a terminal attack at a (π-allyl)palladium complex,
whereas less stabilized counterparts favor a central attack.
This trend is similar to that with carbon-based nucleophiles
(e.g., ester enolate vs malonate enolate) reported in the
literature11a,12b and is consistent with the conclusion of the
previous theoretical study.18
Reactions of 1a with Other Substrates. We previously
reported that lactones 1 could undergo decarboxylative cycliza-
tion with other reaction partners such as isatins6f and electron-
deficient olefins.6b To gain some insight into the reactivity
difference of these compounds, we conducted control experi-
ments as follows. The reaction of lactone 1a with an equimolar
mixture of isocyanate 2a and N-methylisatin (5) selectively
provided the spirooxindole 6a in 97% yield with no formation
of 3aa/4aa (eq 7). In contrast, the reaction of 1a with an
equimolar mixture of 2a and methyl acrylate (7) produced 3aa/
4aa in 17% combined yield and carbocycles 8a/9a derived from
7 in 63% combined yield (eq 8). In addition, a reaction of
lactone 1a with an equimolar mixture of N-methylisatin (5) and
methyl acrylate (7) selectively provided spirooxindole 6a with
no formation of 8a/9a. These results establish that the reactivity
toward 1a is in the order of isatin 5 > acrylate 7 > isocyanate
2a. Because the kinetic studies on the reaction of 1a with 2a
demonstrated that the oxidative addition of 1a is the turnover-
(17) (a) Tjaden, E. B.; Stryker, J. M. J. Am. Chem. Soc. 1990, 112, 6420.
(b) Wakefield, J. B.; Stryker, J. M. J. Am. Chem. Soc. 1991, 113,
7057.
(18) Carfagna, C.; Galarini, R.; Linn, K.; Lo´pez, J. A.; Mealli, C.; Musco,
A. Organometallics 1993, 12, 3019.
(19) Evans, L. A.; Fey, N.; Harvey, J. N.; Hose, D.; Lloyd-Jones, G. C.;
Murray, P.; Orpen, A. G.; Osborne, R.; Owen-Smith, G. J. J.; Purdie,
M. J. Am. Chem. Soc. 2008, 130, 14471.
Effect of N-Substituent of Isocyanates 2. As described in eq
1, a reaction of lactone 1a with 4-methoxyphenyl isocyanate
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Pd-Catalyzed Decarboxylative Cyclization
A R T I C L E S
limiting step, the same conclusions could be drawn for more
reactive substrates 5 and 7.
of γ-methylidene-δ-valerolactones 1 with isocyanates 2 to give
piperidones 3 and/or azaspiro[2.4]heptanones 4. Through kinetic
studies using NMR spectroscopy, we have determined that the
oxidative addition of lactones 1 to palladium(0) is the turnover-
limiting step of the catalytic cycle. By changing the electronic
property of the triarylphosphine ligands, we have demonstrated
that the product distribution between 3 and 4 can be easily
controlled. The selectivity between 3 and 4 is also influenced
by the nature of the nitrogen substituent on isocyanates 2, and
more electron-rich substituents tend to give higher selectivity
toward azaspiro[2.4]heptanones 4. These studies represent the
first systematic investigation on the selectivity between terminal
attack and central attack at (π-allyl)palladium species by
nitrogen-based nucleophiles under catalytic conditions. We have
also shown that other reaction partners such as isatins and
acrylates display the same turnover-limiting step in the reaction
with γ-methylidene-δ-valerolactones through competition ex-
periments with isocyanates.
Acknowledgment. Support has been provided in part by a
Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan (the Global COE
Program “Integrated Materials Science” on Kyoto University).
Supporting Information Available: Text and figures giving
experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Conclusions
We have described that palladium triarylphosphine complexes
can effectively catalyze decarboxylative cyclization reactions
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