Cyclization-carbonylation-cyclization coupling reaction of γ-propynyl-1,3-diketones with palladium(ii)-bisoxazoline catalyst

Article abstract of DOI:10.1039/c2ob07016b

Cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of γ-propynyl-1,3-diketones catalyzed by (box)Pd^II complexes afforded symmetrical ketones bearing two oxabicyclic groups in moderate to excellent yields.

Full text of DOI:10.1039/c2ob07016b

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Organic &
Biomolecular
Chemistry
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Volume 10 | Number 16 | 28 April 2012 | Pages 3133–3344
ISSN 1477-0520
PAPER
K. Kato et al.
Cyclization–carbonylation–cyclization coupling reaction of
γ-propynyl-1,3-diketones with palladium(II)-bisoxazoline catalyst

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Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 3192
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PAPER
Cyclization–carbonylation–cyclization coupling reaction of γ-propynyl-1,3-
diketones with palladium(II)-bisoxazoline catalyst†
Taichi Kusakabe,a Yasuko Kawai,a Rong Shen,a Tomoyuki Mochidab and Keisuke Kato*a
Received 1st December 2011, Accepted 9th January 2012
DOI: 10.1039/c2ob07016b
Cyclization–carbonylation–cyclization coupling reaction (CCC-coupling reaction) of γ-propynyl-1,3-
diketones catalyzed by (box)PdII complexes afforded symmetrical ketones bearing two oxabicyclic groups
in moderate to excellent yields.
Furan rings are a common structure in a range of biologically
active natural products and important pharmaceuticals.1 Diaryl-
ketones are also frequently found in natural products and phar-
maceuticals2 [e.g., suprofen (a non-steroidal anti-inflammatory
drug), raloxifene (a selective estrogen receptor modulator – drug
for treatment of osteoporosis), benzbromarone (an antipodagric
drug), and amiodarone (an antiarrhythmic drug)]. Cascade reac-
tions are important tools for constructing a variety of hetero-
cycles in one step starting from simple compounds.3 Recently,
we reported a cyclization–carbonylation–cyclization coupling
reaction (CCC-coupling reaction) of propargylic acetates and
amides catalyzed by palladium(II)-bisoxazoline (box) complex-
es4a (Scheme 1). Symmetrical ketones bearing two oxazoles or
Scheme 1 Our concept of a cyclization–carbonylation–cyclization
cyclic orthoesters were obtained in a one-step reaction. In this
coupling reaction (CCC-coupling reaction) of propargylic compounds.
transformation, the triple bond of the substrate coordinates to
palladium(II) and undergoes nucleophilic attack by the intra-
molecular nucleophile X followed by CO insertion to produce
the acyl palladium intermediate A. Coordination of the triple
bond of a second molecule induces the second cyclization.
Reductive elimination then leads to formation of a ketone
bearing two heterocyclic groups. We believe that the box ligand
enhances the π-electrophilicity of palladium(II),4 and thus pro-
motes coordination of the second triple bond to the acyl palla-
dium intermediate A, leading to dimerization. Previously,
Scheme 2 Mascareñas et al.: Pd(II) catalyzed cyclization of 1 and 2.
Mascareñas et al. reported that the palladium(II) catalyzed cycli-
zation of cyclohexanediones 1 and cyclopentanediones 2
afforded oxabicyclic derivatives 3 and 4, which are important
Initially, we selected 1a as a standard substrate to search for
potential catalysts (Table 1). The reaction of 1a with
(CH3CN)2PdCl2 (5 mol%) in the presence of p-benzoquinone (2
equiv.) in methanol under carbon monoxide atmosphere
frameworks for the synthesis of prostaglandin derivatives5a
(Scheme 2). To extend our concept of the CCC-coupling reac-
tion, we planned to investigate the (box)PdII catalyzed carbony-
lation reaction of γ-propynyl-1,3-diketones 1, 2 and 5 (Table 1,
(balloon) generated the dimeric ketone 6a in 18% yield along
Schemes 3–5).
with a mixture of unidentified compounds (Table 1, entry 1).
(Ph3P)2PdCl2 and Pd(tfa)2 gave a complex mixture (Table 1,
aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama,
Funabashi, Chiba, 274-8510, Japan. E-mail: kkk@phar.toho-u.ac.jp;
Fax: +81 474 721 805; Tel: +81 474 721 805
entries 2–3). The use of (2,2′-bipyridine)dichloropalladium(II)
and (−)-sparteine (L1)/Pd(tfa)2, afforded product 6a in low
yields (Table 1, entries 4–5, Fig. 1). Next, an attempt was made
to use the box ligand according to our previous results.4a As
expected, the reaction occurred smoothly in the presence of the
box ligands L2 and L3, and the yields improved to 77–83%
bDepartment of Chemistry, Faculty of Sciences, Kobe University,
Rokkodai, Nada, Kobe, 657-8501, Japan
†Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c2ob07016b
3192 | Org. Biomol. Chem., 2012, 10, 3192–3194
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Table 1 CCC-coupling reaction of γ-propynyl-1,3-cyclohexanediones 1a
Entry
R1
R2
Palladium source (5 mol%)
Ligand (7.5 mol%)
Time (h)
Yield of 6 (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
(CH3CN)2PdCl2
Pd(tfa)2
(Ph3P)2PdCl2
(2,2′-bipyridine)PdCl2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
—
—
—
1.5
14
3.0
14
6a: 18
Complex mixture
Complex mixture
6a: 9
6a: 16
6a: 77
6a: 83
6b: 94
6c: 80
6d: 86
6e: 99
6f: 83
6g: 71
6h: 90
6i: 99
6j: 81
L1
24
box (L2)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
box (L3)
2.0
3.0
2.5
2.0
2.0
53b
6.0
39c
12
9
Et
10
11f
12f
13f
14f
15f
16f
nHexyl
Cyclopropyl
Ph
4-MeOPh
4-CF3Ph
4-ClPh
Ph
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
11d
45e
Pd(tfa)2
f
a 6a was obtained as a diasteromeric mixture (ratio = 1.5 : 1–1 : 1). b −30 °C. c −20 °C. d −20 °C ∽0 °C. e −20 °C ∽−10 °C. Pd(tfa)2: 10 mol%, L3:
12 mol%
Fig. 1 Ligands for Table 1 (Scheme 3).
Scheme 3 This work: CCC-coupling reaction of γ-propynylcyclohex-
ane-1,3-diones 1 (for Table 1).
Fig. 2 Comparison of steric hindrance in acyl palladium intermediates
A1 and A2.
(Table 1, entries 12–16). A lower yield was obtained for 1g con-
taining an electron-rich aromatic group as R1 (Table 1, entry 13).
A chlorine atom on the aryl group was tolerated under the reac-
tion conditions (Table 1, entry 15). The reaction of 6j bearing
additional substituents on the cyclohexane ring also proceeded
well (Table 1, entry 16).
Scheme 4 CCC-coupling reaction of acyclic substrate 5.
The scope of the CCC-coupling reaction was then extended to
the acyclic substrate 5 and five-membered ring substrates 2
(Schemes 4 and 5). In the case of acyclic substrate 5, dimeric
ketone 7 was obtained in 60% yield along with monomeric ester
8 (23% yield). For five-membered ring substrates 2a and 2b with
small hydrocarbon substituents (R = Me or Et), the reactions pro-
ceeded well (94–96% yields).6 However, the reaction of 2c with
a large hydrocarbon substituent (R = nHexyl) afforded dimeric
ketone 9c in 57% yield along with monomeric ester 10c (14%
yield). Moreover, the substrate 2d bearing a phenyl group gave
the monomeric ester 10d exclusively. Although we do not have a
clear explanation for the different behavior observed with the
six-membered substrate 1f (R1 = Ph, R2 = H, Table 1, entry 12)
and five-membered substrate 2d (R = Ph, Scheme 5) at this
stage, we tentatively propose the following (Fig. 2): the acylpal-
ladium intermediates A1 and A2 could be produced by the 5-exo
cyclization of 1f and 6-endo cyclization of 2d, respectively. The
Scheme 5 CCC-coupling reaction of γ-propynylcyclopentane-1,3-
diones 2.
(Table 1, entries 6–7). Furthermore, CH2Cl2, CH3CN, DMF and
THF were not suitable as solvents.
Having optimized the reaction conditions, we examined the
reaction of various internal alkynes 1b–j with the box ligand L3.
For substrates 1b–e with hydrocarbon substituents (R1), the reac-
tion proceeded well (80–99% yields) (Table 1, entries 8–11).6
The aryl-substituted alkynes 1f–j (R1 = Ar) gave the correspond-
ing dimeric ketones 6f–j in moderate to excellent yields
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steric hindrance in A2 inhibited the coordination of the
additional substrate to palladium, and thus methanolysis of A2
proceeded slowly.
In conclusion, we have presented a cyclization–carbonylation–
cyclization coupling reaction (CCC-coupling reaction) of γ-pro-
pynyl-1,3-diketones 1, 2 and 5 catalyzed by (box)PdII com-
plexes. Symmetrical ketones possessing two oxabicyclic groups
were obtained in moderate to excellent yields. We believe that
the box ligand enhances the π-electrophilicity of palladium(II),4
and thus promotes coordination of the triple bond (second mol-
ecule) to the acyl palladium intermediate A, leading to the
dimerization reaction. We are currently investigating additional
cascade reactions based on the cyclization–carbonylation–cycli-
zation strategy presented here for the synthesis of other types of
ketones containing two heterocyclic groups.
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6 The structures of 5-exo cyclization product 6b and 6-endo cyclization
product 9a were confirmed by HMBC correlations. See the ESI†.
3194 | Org. Biomol. Chem., 2012, 10, 3192–3194
This journal is © The Royal Society of Chemistry 2012