Pd-catalyzed 5-endo-trig-type cyclization of β,γ-unsaturated carbonyl compounds: An efficient ring closing reaction to give γ-butenolides and 3-pyrrolin-2-ones

Article abstract of DOI:10.1039/c0cc02352c

The 5-endo-trig-type cyclization has been performed using a Pd-bis(isoxazoline) catalyst. The present cyclization of β,γ- unsaturated carbonyl compounds gave γ-butenolides and 3-pyrrolin-2-ones in good to excellent yields.

Full text of DOI:10.1039/c0cc02352c

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Pd-catalyzed 5-endo-trig-type cyclization of b,c-unsaturated carbonyl
compounds: an efficient ring closing reaction to give c-butenolides and
3-pyrrolin-2-onesw
Gan B. Bajracharya, Priti S. Koranne, Rashid N. Nadaf, Randa Kassem Mohamed Gabr,
Kazuhiro Takenaka, Shinobu Takizawa and Hiroaki Sasai*
Received 3rd July 2010, Accepted 6th October 2010
DOI: 10.1039/c0cc02352c
The 5-endo-trig-type cyclization has been performed using
a Pd–bis(isoxazoline) catalyst. The present cyclization of
b,c-unsaturated carbonyl compounds gave c-butenolides and
3-pyrrolin-2-ones in good to excellent yields.
Table 1 5-Endo-trig cyclization of (E)-3-hexenoic acid (1a)a
The preparation of complex target compounds via a simple
transformation of readily available starting materials is the
ultimate goal of organic synthesis. The intramolecular cycliza-
tion of an olefinic compound with a nucleophilic functionality
on its terminal end is a model of this type of transformation.
Recently, we developed isoxazoline-containing ligands and
found that a Pd–isoxazoline complex catalyzed the oxidative
cyclization of olefinic compounds.1 Because Pd–isoxazoline
complexes are effective in activating olefins, we began studying
the 5-endo-trig-type cyclization2–4 of (E)-3-hexenoic acid 1a
using a Pd–isoxazoline complex to produce g-butenolide 2a.
g-Butenolides are important structural units found in more
than 13 000 natural products and biologically active compounds.5
Until now, much attention has been devoted to developing
new methodologies for their preparation,6 including the
stepwise cyclizations of 3-alkenoic acids 1 via either halo-
lactonizations or seleno-lactonizations.7
Entry
Pd source
Ligand (mol%)
Yield of 2a (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OCOCF3)2
Pd(acac)2
3 (11)
None
cod (11)
Dppe (11)
(S,R)-BPPFAc (11)
tBu-Boxd (11)
(ꢀ)-Sparteine (11)
2,20-Bipyridine (11)
3 (11)
3 (11)
3 (11)
4 (11)
5 (22)
6 (22)
75
No reaction
Trace
31
No reaction
7
No reaction
No reaction
2
67
9
10
11
12
13
14
PdCl2(MeCN)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Trace
94
16
No reaction
a
Pd source and ligand were stirred at 30 1C for 2 h before the addition
of 1a and p-benzoquinone. Determined by 1H NMR. BPPFA =
b
c
N,N-Dimethyl-1-[10,2-bis(diphenylphosphino)ferrocenyl]ethylamine.
d
tBu-Box = 2,2-Bis[4-tert-butyl-2-oxazolin-2-yl]propane.
Kasahara et al. reported the 5-endo-trig cyclization of
b,g-unsaturated carbonyl compounds using a stoichiometric
amount of Pd(II) salts to give g-butenolides in up to 38%
yields.8 In our exploration of the catalytic system, we found
that a Pd complex with bis(isoxazoline) ligand 3 promoted the
reaction to afford product 2a in a 75% yield (Table 1, entry 1).
In contrast, product 2a was not efficiently formed in the
absence of a specific ligand or with other known ligands we
examined (entries 2–8). As the palladium source, Pd(OAc)2
gave the best results (entries 1, 9–11).9,10 SPRIX (spiro bis-
(isoxazoline)) 4 was more effective in producing 2a (entry 12).
We attributed these results to the relatively high Lewis acidity
of the Pd–bis(isoxazoline) complex, i.e., the weak coordinating
ability of isoxazoline-type ligands can activate the olefin more
easily than other ligands such as oxazoline.1 We observed
Pd-black formation when we employed monodentate isoxazoline
ligand 5 and/or hemilabile bidentate ligand 6 (entries 13 and 14).
An oxidant was essential to regenerate Pd(II) in the catalytic
cycle; therefore, p-benzoquinone was used. However, the amount
of p-benzoquinone could be reduced to 1 equiv. (2a, 88% yield).
Other benzoquinone derivatives, DDQ and 2,5-dihydoxybenzo-
quinone, failed to promote the reaction. Furthermore, other
reoxidation systems such as Cu(OAc)2/O2 (2a, 75% yield),
Cu(OAc)2/catechol/O2 (2a, 75% yield), NMO (2a, 16% yield),
and O2 (2a, 15% yield) were comparably less effective.
Under optimized conditions, substrates with shorter, longer,
and branched alkyl chains (1b–f, R = Me, Pr, hexyl, Bn, and
iPr) at the 4-position of (E)-3-alkenoic acid and the a-substituted
substrate 1h produced the corresponding g-butenolides 2 in
good to excellent yields (Table 2, entries 1–5 and 7). An ether
substituent in 1g was also well tolerated but required higher
temperatures to obtain 2g in a good yield (entry 6). No reaction
took place with trisubstituted olefins 1-cyclohexenylacetic acid
and 4,8-dimethyl-3,7-nonadienoic acid and the (Z)-configuration
of olefin 1a even at an elevated temperature of 60 1C.
The Institute of Scientific and Industrial Research (ISIR),
Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
E-mail: sasai@sanken.osaka-u.ac.jp; Fax: +81 6 6879 8465;
Tel: +81 6 6879 8469
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/c0cc02352c
Having succeeded in inducing the ring closure for
g-butenolides, we next focused our attention on the other
type of 5-endo-trig cyclization to give 3-pyrrolin-2-ones.11
c
9064 Chem. Commun., 2010, 46, 9064–9066
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Table 2 Cyclization of (E)-alkenoic acids by Pd(II)–SPRIXa
Entry
Substrate
Product
Yield of 2d (%)
1b
2
1b: R = Me
1c: R = Pr
1d: R = hexyl
1e: R = Bn
1f: R = iPr
1g: R = OPn
1h
2b
2c
2d
2e
2f
71
84
94
99
70
71
3
4
5b
6c
2g
2h
53
7
a
Reaction conditions: Pd(OAc)2 (10 mol%), 4 (11 mol%), p-benzo-
b
c
d
quinone (2 equiv.), DCE, 30 1C, 24 h. DCM. 75 1C. Isolated
yield.
Scheme 1 Plausible mechanism.
b-Hydride elimination as shown in ‘‘path b’’ leads to the
formation of the isomeric product III, which ultimately iso-
merizes to the thermodynamically stable product with the
assistance of a Pd-hydride species. However, ‘‘path b’’ is
unlikely because we obtained 2a in 60% ee when we employed
optically pure 4. An interconversion between 2a and III would
not be included in the reaction because 2a was quantitatively
recovered without any loss of optical purity after the treatment
of 60% ee of 2a under the reaction conditions using an
optically pure Pd–iPr–SPRIX complex for 24 h.18 Moreover
a deuterium labeling experiment with 1a-d produced 2a-d in a
90% yield without deuterium scrambling (eqn (1)).
Table 3 Cyclization of b,g-unsaturated alkenamides 7 by Pd(II)–
SPRIX
Entry
Substrate
Product
Yield of 2a (%)
1
2
3
4
5
6
7a: R = Et
7b: R = Me
7c: R = Pr
7d: R = hexyl
7e: R = Bu
7f: R = Ph
7g
8a
8b
8c
8d
8e
8f
95
96
97
93
92
78b,c
8g
7
11d,e
a
b
Isolated yield. 20 mol% of catalyst was used. 96 h. Determined
c
d
ð1Þ
by 1H-NMR. 120 h.
e
In conclusion, we have demonstrated an efficient method for
the Pd-catalyzed 5-endo-trig type cyclization of b,g-unsaturated
carbonyl compounds to give g-butenolides and 3-pyrrolin-2-
ones in good to excellent yields. Detailed computational
insight into the mechanism of this cyclization and studies on
an enantioselective variant of this reaction are now in progress
in our laboratory.
We attempted the reaction of b,g-unsaturated alkenamides 7
bearing p-toluenesulfonyl as a protecting group,12 derived
from the corresponding alkenoic acid 1 with simple modification,13
using the Pd(II)–SPRIX complex under optimized conditions,
as shown in Table 3. Differentially alkyl substituted substrates
were well tolerated at the olefinic positions, producing
the corresponding 3-pyrrolin-2-ones 8 in excellent yields
(entries 1–5). In the case of phenyl substituted enamide 7f, higher
catalyst loading and a longer reaction time were effective to obtain
8f (entry 6). Enamide 7g produced small amounts of 8g with a
poor mass balance after a prolonged reaction time (entry 7).
Known catalytic systems such as Pd(OAc)2, (ꢀ)-(sparteine)-
Pd(OCOCF3)2,14 [(3,2,10-Z3-pinene)-PdOAc]2,15 Pd(OAc)2-(S,S)-
iPr-boxax,16 and Pd(OAc)2-(R,R)-Bn-box17 did not promote the
reaction of b,g-unsaturated alkenamides 7 at all.
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Scheme 1 depicts a plausible mechanism for the present
cyclization; it starts with anti-oxypalladation with the transi-
tion state I via an intramolecular nucleophilic attack of
the carboxylate ion on the activated CQC double bond to
afford the cyclic intermediate II. This reaction is followed by
b-hydride elimination via ‘‘path a’’ to give the desired product.
c
This journal is The Royal Society of Chemistry 2010
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c
9066 Chem. Commun., 2010, 46, 9064–9066
This journal is The Royal Society of Chemistry 2010