204
Chemistry Letters Vol.38, No.3 (2009)
Palladium-catalyzed Decarboxylative [4 þ 1] Cyclization
of ꢀ-Methylidene-ꢁ-valerolactones with Isocyanides
Soyoung Park, Ryo Shintani,ꢀ and Tamio Hayashiꢀ
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
(Received December 16, 2008; CL-081176; E-mail: shintani@kuchem.kyoto-u.ac.jp, thayashi@kuchem.kyoto-u.ac.jp)
A palladium-catalyzed decarboxylative cyclization of ꢀ-
Table 1. Palladium-catalyzed decarboxylative cyclization of
ꢀ-methylidene-ꢁ-valerolactones 1 with isocyanides 2
methylidene-ꢁ-valerolactones with isocyanides has been devel-
oped to afford conjugated cyclopentenimines under mild condi-
tions. Some preliminary results toward the development of an
asymmetric variant have also been described.
R
Pd(PPh3)4
(5 mol %)
N
O
O
R
N
C
CO2Me
Ar
+
Toluene
40 °C, 24 h
CO2Me
Ar
Me
1 (1.4 equiv)
2
3
Carbon monoxide has been widely utilized as a source of
one-carbon unit in various transition-metal-catalyzed cycloaddi-
tion reactions (e.g., the Pauson–Khand reaction1) to produce cy-
clic ketones with high efficiency.2 In contrast, isoelectronic iso-
cyanides are often used in cycloaddition reactions as a source of
N–C or C–N–C fragment in a cyclic framework for the synthesis
of nitrogen-containing heterocycles.3,4 In fact, only a few reports
have been made on the use of isocyanides as a surrogate of car-
bon monoxide to form cyclic ketimines under transition-metal
catalysis,5–7 and none of them have been applied to asymmetric
variants so far. In this context, here we describe the development
of a palladium-catalyzed decarboxylative cyclization of ꢀ-meth-
ylidene-ꢁ-valerolactones8 with isocyanides to obtain cyclopen-
tenimines under mild conditions, including our preliminary re-
sults in its application to asymmetric catalysis.9
We initiated our study by conducting a reaction of ꢀ-meth-
ylidene-ꢁ-valerolactone 1a with 2-acetoxyphenyl isocyanide10
(2a) in the presence of 5 mol % Pd(PPh3)4 as a catalyst in
CH2Cl2 at 40 ꢁC (eq 1). The decarboxylative [4 þ 1] cyclization
product was successfully obtained as conjugated cyclopenten-
imine 3aa in moderate yield (53% yield). We subsequently
found that higher yield of 3aa can be achieved by conducting
the reaction in THF (75% yield) or in toluene (94% yield). Under
the conditions using toluene as the solvent, several other ꢂ-
(hetero)aryl-ꢀ-methylidene-ꢁ-valerolactones 1 can also be used
for the synthesis of cyclopentenimines 3 with isocyanide 2a in
high yield (83–97% yield; Table 1, Entries 1–5).11 With respect
to the nitrogen-substituent on isocyanide, various bulky aryl
groups are well suited under the present conditions (75–94%
yield; Entries 6–9), and a different set of conditions is necessary
to effectively employ an aryl group with no substituents at the
ortho-positions (dppf as the ligand; Entry 10). In addition to aryl
isocyanides, alkyl groups are also tolerated, giving cyclization
products 3 in good yield (62% yield; Entry 11).12
Entry
1
Ar
R
Product Yield/%a
OMe
3ba
3ca
3da
87
83
97
(1b)
(2a)
AcO
Me
2
3
(1c)
(1d)
Me
4b
5
3ea
3fa
3ab
85
93
75
(1e)
(1f)
S
6
(1a)
(2b)
(2c)
Me
7
8
3ac
3ad
79
94
t-Bu
Me
(2d)
Me
9
3ae
81
CO2Me (2e)
10c
11
3af
72
OMe
(2f)
3ag
62d
(2g)
aIsolated yield after chromatography on silica gel. b2.0 equiv of
1e was used. PdCp(ꢄ3-C3H5)/dppf (5 mol %) was used as the
catalyst. Determined by H NMR against internal standard (p-
xylene) after chromatography on alumina.
c
d
1
1 to palladium(0), followed by decarboxylation,13,14 gives 1,4-
zwitterionic species A. The anionic carbon of A then attacks
the carbon atom of 2 to give intermediate B, which undergoes
a ring-closure through a nucleophilic attack of the same carbon
atom to the ꢃ-allylpalladium moiety, leading to the formation of
five-membered carbocycle C along with regeneration of palladi-
um(0). Initially formed C having an exo-methylene readily iso-
merizes to more stable conjugated cyclopentenimine 3.15
It is worth noting that the use of lactone 1g having a methyl
group at the ꢁ-position in the reaction with 2a selectively gives
R
Pd(PPh3)4
(5 mol %)
N
O
O
R
N
C
CO2Me
Ph
+
Solvent
40 °C, 24 h
CO2Me
Ph
ð1Þ
Me
1a (1.4 equiv)
2a
3aa
(R = 2-AcOC6H4)
CH2Cl2: 53% yield
THF: 75% yield
Toluene: 94% yield
A proposed catalytic cycle of this process is illustrated in
Figure 1. Thus, oxidative addition of the allyl ester moiety of
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