COMMUNICATION
Nickel-catalyzed [2+2+1] cycloaddition of alkynes, acrylates and
isocyanatesw
Takuya Ozawa, Hiroaki Horie, Takuya Kurahashi* and Seijiro Matsubara*
Received 16th July 2010, Accepted 3rd September 2010
DOI: 10.1039/c0cc02613a
Intermolecular [2+2+1] cycloaddition which incorporates an
alkyne, an isocyanate, and an alkene into a c-butyrolactam
proceeds with nickel catalyst.
it was found that the ratio of 1a/2a/3a with 4 : 1 : 1 gave the
highest yield of 4aaa (entry 8). In other solvents, such
as THF, toluene, MeCN, or pyridine, yields were even lower
(entries 12–15).
We next investigated the scope of the reaction briefly
(Table 2). The reaction of 4-octyne (1b) with 2a and 3a
afforded correspondingly substituted g-butyrolactam 4baa in
66% isolated yield (entry 1). The cycloaddition is also
compatible with aryl-substituted alkyne 1c and provides
cycloadduct 4caa in 56% yield with a regioselectivity ratio of
2/1 (entry 2). The reaction with unsymmetrical alkynes such as
1d and 1e gave the products consisting of regioisomers in 1/1
and 2/1 ratio, respectively (entries 3 and 4), while bulky
isopropyl substituted alkyne 1f reacted with 2a and 3a to
afford g-butyrolactam 4faa in 72% yield with a regioselectivity
ratio of 7/1 (entry 5). Terminal alkynes, such as 1-octyne
and phenylacetylene, failed to participate in the reaction,
presumably due to rapid oligomerization of alkynes. The
scope of the [2+2+1] cycloaddition was also explored by
using various isocyanates. Either electron-donating or -with-
drawing substituents on phenyl isocyanate tolerated the
reaction conditions to afford correspondingly substituted
cycloadducts in moderate yield (entries 6–10). However, alkyl
isocyanates, such as cyclohexyl isocyanate and propyl
isocyanate, reacted with 1a and 2a to provide g-butyrolactam
in poor yields (entries 11 and 12). It should be noted that
isocyanates have no effects on the regioselectivity of the
reaction. The reaction of 1a and 3a with ethyl acrylate (2b)
or tert-butyl acrylate (2c) in place of methyl acrylate (2a)
afforded g-butyrolactam in lower yields but with better
regioselectivity (entries 13 and 14). Therefore, the steric
environment of the alkyne 1 and acrylate 2 dictated the
regioselectivity of the reaction.
Transition-metal-catalyzed cycloadditions are the most powerful
methodologies for the construction of structurally diverse hetero-
cyclic compounds from readily accessible starting materials.1
A formal [2+2+1] cycloaddition, in which an alkyne, an
imine and carbon monoxide are assembled, represents a facile
synthetic access to structurally diverse g-butyrolactams, and
has been a research subject of great interest (Scheme 1a).2,3
Herein, we wish to report an unprecedented type of [2+2+1]
cycloaddition, which incorporates an alkyne, an isocyanate,
and an alkene into a g-butyrolactam by using nickel catalyst
(Scheme 1b).
Our investigation began with an attempted [2+2+1]
cycloaddition between 2-octyne (1a), methyl acrylate (2a),
and phenyl isocyanate (3a). The results of optimization of
reaction conditions are summarized in Table 1. We first
examined ligands for the catalyst and found that a sterically
hindered N-heterocyclic carbene ligand is effective for the
cycloaddition to provide g-butyrolactam 4aaa. Phosphine
ligands, such as PPh3, PCy3, and PMe3, did not afford 4aaa
but gave 2-pyridone as a major product via [2+2+2] cyclo-
addition of two molecules of alkynes and an isocyanate
(entries 1–3).4,5 Among carbene ligands examined, IPr
(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) gave the
best yield of 4aaa.6,7 Thus, the reaction of 1a, 2a, and 3a in
the presence of 10 mol% of Ni(cod)2 and 10 mol% of IPr in
1,4-dioxane (100 1C) afforded g-butyrolactam 4aaa in 56%
yield consisting of regioisomers in 5/1 ratio along with trace
amount of 2-pyridone (ca. 5%) (entry 4). On screening of the
molecular ratio of 1a, 2a, and 3a to employ for the cycloaddition,
A plausible reaction pathway to account for the formation
of g-butyrolactam 4aaa based on the observed results is
outlined in Scheme 2. The catalytic cycle of the present
reaction may consist of oxidative cyclization of nickel(0) with
an alkyne 1 and an acrylate 2 to provide nickelacyclopentene
complex 5a, in which the steric repulsive interaction is minimal
between the bulkier RL and the IPr ligand on the nickel.6,8
The preferential formation of complex 5a may be attributed
to a steric repulsive interaction between the bulky IPr
ligand and alkyne 1, which prevents formation of nickel-
acyclobutadiene complex via coordination of two molecules
of alkyne 1 to a nickel metal center. Then, subsequent inser-
tion of isocyanate 3 takes place, to give nickel(II) intermediate
6. b-Hydride elimination would give 7, in which a C–C
double bond inserts into the hydride-nickel bond to provide 8.
Reductive elimination of 4 would regenerate the starting
nickel(0).
Scheme 1 [2+2+1] Cycloaddition to form g-butyrolactams.
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan.
E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp,
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp; Fax: +81 75 383 2461;
Tel: +81 75 383 2462
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c0cc02613a
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8055–8057 8055
Ozawa, Takuya
