Highly diastereoselective synthesis of tetrahydrobenzofuranones by palladium-catalyzed reaction of propargylic carbonates with 2-substituted cyclohexane-1,3-diones

Article abstract of DOI:10.1016/j.tetlet.2007.12.123

The reaction of propargylic carbonates with 2-substituted cyclohexane-1,3-diones in the presence of palladium catalyst is described. Substituted tetrahydrobenzofuranones having a quaternary carbon stereocenter were synthesized in a highly diastereoselecti

Full text of DOI:10.1016/j.tetlet.2007.12.123

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Tetrahedron Letters 49 (2008) 1678–1681
Highly diastereoselective synthesis of tetrahydrobenzofuranones
by palladium-catalyzed reaction of propargylic carbonates with
2-substituted cyclohexane-1,3-diones
Masahiro Yoshida *, Mariko Higuchi, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Received 3 December 2007; revised 21 December 2007; accepted 27 December 2007
Available online 8 January 2008
Abstract
The reaction of propargylic carbonates with 2-substituted cyclohexane-1,3-diones in the presence of palladium catalyst is described.
Substituted tetrahydrobenzofuranones having a quaternary carbon stereocenter were synthesized in a highly diastereoselective manner.
Ó 2008 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed reactions of propargylic
Pd+
R1
O
OCO2Me
R1
O
O
cat. Pd(0)
compounds have received considerable attention and have
been extensively studied due to their versatile and specific
reactivity.1 The palladium-catalyzed reaction of propar-
gylic compounds with soft nucleophiles is one of the most
successful chemical processes developed to date.2,3 For
example, Tsuji et al. reported the reaction of propargylic
carbonates with b-keto esters to produce substituted
dihydrofurans (Eq. 1),2b in which propargylic carbonates
react with b-keto esters via palladium catalysis to generate
the p-allylpalladium complexes. These complexes further
react with the resulting enolate intramolecularly to afford
the cyclized dihydrofurans. In our studies on the reaction
of propargylic compounds in the presence of palladium
catalysts,4 we focused on the nucleophilic activity of
2-substituted cyclohexane-1,3-diones. By introducing a
substituent on the nucleophilic carbon, we thought that a
quaternary carbon stereocenter could be constructed in
the product. Herein, we describe the palladium-catalyzed
reaction of propargylic carbonates with 2-substituted
cyclohexane-1,3-diones producing tetrahydrobenzofura-
nones having a quaternary carbon stereocenter with high
diastereoselectivity (Eq. 2).
+
MeO
OMe
O
ð1Þ
ð2Þ
O
MeO
R1
O
O
Pd+
R1
O
R2
OCO2Me
R2
O
cat. Pd(0)
+
R1
O
O
R2
*
R1
*
O
The initial reactions were attempted using methyl
1-phenylprop-2-ynyl carbonate (1a) and 2-methylcyclohex-
ane-1,3-dione (2a).5 When 1a and 2a were subjected to the
reaction in the presence of 10 mol % Pd(PPh3)4 in dioxane
at 100 °C for 5 min, tetrahydrobenzofuranone 3aa was
obtained in 37% yield as a single diastereomer, along with
the propargylic and allenic substitution compounds 4aa
and 5aa (Table 1, entry 1). After experimenting with vari-
ous reaction temperatures and solvents (entries 2–9), we
found that the yield of 3aa was improved to 66% when
the reaction was carried out in DMSO at 120 °C (entry 8).
*
Corresponding author. Tel./fax: +81 88 633 7294.
E-mail address: yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.123

M. Yoshida et al. / Tetrahedron Letters 49 (2008) 1678–1681
1679
Table 1
Table 3
Initial attempts using propargylic carbonate 1a and 2-methyl-1,3-cyclo-
hexanedione (2a)
Reactions using various substrates 1a–e and 2a–e
5 mol %
O
O
R2
Pd2(dba)3·CHCl3
20 mol % ligand
O
R2
O
OCO2Me
R1
OCO2Me
10 mol % Pd(PPh)4
+
R1
+
DMSO, 120 ºC
5-30 min
dioxane, 100 ºC
O
Ph
1a
_
2
20 min
O
_
_
1a
e
2a
d
3
2a
Entry
1a
Substrates
R2
Product 3
Yield (%)
83
O
O
O
R1
+
+
Ph
O
O
·
O
O
Ph
4aa
Ph
1-Naphthyl (1b) Me (2a)
2-Naphthyl (1c) Me (2a)
5aa
3aa
Solvent
O3ba
Entry
Temp (°C)
Yields (%)
3aa
4aa
5aa
O
1
2
3
4
5
6
7
8
9
Dioxane
DMF
DMSO
NMP
Toluene
1,2-Dichloroethane
DMSO
100
100
100
100
100
100
80
37
40
51
51
4
5
6
4
10
3
4
1
7
6
3
3
4
2b
3c
4d
5a
81
55
43
75
O 3ca
2
37
32
8
6
5
O
6
O
3-Furanyl (1d)
Pentyl (1e)
Ph (1a)
Me (2a)
Me (2a)
Pr (2b)
39
66
55
O
DMSO
DMSO
120
140
3da
O
O3ea
The results of attempted reactions using various biden-
tate phosphine ligands6 are summarized in Table 2. All of
the reactions proceeded to afford tetrahydrobenzofuranone
3aa (entries 1–7), the best results of which were obtained
when dppf was used as the ligand (84% yield, entry 5).
Having identified a useful set of reaction conditions, we
then carried out a study of the substrate scope (Table 3).
The propargylic carbonates 1b and 1c with a 1- and 2-
naphthyl group at propargylic position successfully reacted
with 2a to produce tetrahydrobenzofuranones 3ba and 3ca
in high yields, respectively (entries 1 and 2). Likewise the 3-
furanyl- and pentyl-substituted substrates 1d and 1e also
gave the corresponding products 3da and 3ea in moderate
yields (entries 3 and 4). When 2-propylcyclohexane-1,
O
O3ab
O
6a
Ph (1a)
Ph (1a)
Bn (2c)
76
82
O3ac
CN
O
CN
7d
(2d)
O
3ad
a
Dppf was used as a ligand.
Dppp was used a ligand.
Dpppentane was used a as a ligand.
Dppb was used as a ligand.
Table 2
Effect of bidentate ligands
b
c
d
5 mol %
Pd2(dba)3·CHCl3
20 mol % ligand
O
O
OCO2Me
Ph
+
Ph
DMSO, 120 ºC
3-dione (2b) was reacted with 1a, the propyl-substituted
tetrahydrobenzofuranone 3ab was produced in 75% yield
(entry 5). The benzyl- and 2-cyanoethyl-substituted sub-
strates 2c and 2d uneventfully reacted with 1a to deliver
the corresponding products 3ac and 3ad in 76% and 82%
yields, respectively (entries 6 and 7). The structure of tetra-
hydrobenzofuranone 3ca, including the stereochemistry,
was confirmed by an X-ray crystallographic analysis
(Fig. 1),7 and the stereochemistries of the other products
were assigned by comparison of their NMR spectra with
O
O
1a
2a
3aa
Entry
Ligand
Time (min)
Yield of 3aa (%)
1
2
3
4
5
6
7
dppe
dppp
dppb
dpppentane
dppf
40
20
5
5
5
46
49
75
61
84
57
76
BINAP
Tol-BINAP
10
5

1680
M. Yoshida et al. / Tetrahedron Letters 49 (2008) 1678–1681
Fig. 1. ORTEP drawing of 3ca.
X
ladium-catalyzed reaction of 1g and 2a in the presence of
2 equiv of K3PO4 successfully proceeded to give the desired
product 3fa in 93% yield.
O
5 mol % Pd2(dba)3·CHCl3
20 mol % dppf
DMSO, 120 °C, 5 min
+
OMe
OMe
O
A plausible mechanism, which may account for the
highly diastereoselective nature of this process, is shown
in Scheme 2. On reacting with the palladium catalyst,
the propargylic carbonate 1 undergoes decarboxylation
to give the p-propargylpalladium complex 6,8 which
further reacts with cyclohexane-1,3-dione 2 to lead to the
p-allylpalladium intermediate 8. Complex 8 is subjected
to the intramolecular attack of the enolate to produce
tetrahydrobenzofuranone 3. The observed high diastereo-
selectivity is likely the result of steric factors, which influ-
ence the relative energies of the competing transition
states TS A and TS B. It is expected that the transition
state TS A, leading to product 3, would have lower
energy because of the absence of steric repulsion between
the R1 and R2 groups that is present in TS B, which
yields the diastereomer 30. The propargylic and allenic
substitution byproducts 4 and 5 are produced via direct
nucleophilic substitution from allenylpalladium 9 and
propargylpalladium 10,3m which are in equilibrium with
p-propargylpalladium 6.
In conclusion, the effort described above has led to the
development of the palladium-catalyzed reaction of prop-
argylic carbonates with 2-substituted cyclohexane-1,3-
diones. The process yields tetrahydrobenzofuranones in a
highly diastereoselective manner. Natural products having
similar tetrahydrobenzofuranone structures have been
reported,9 and our methodology would provide a new
and significant protocol for the synthesis of these high effi-
ciency compounds.
2a
1f X = OCO2Me
1g X = OAc
O
yield
additive
_
OMe
OMe
O
1f
1g
decomp
93%
2 eq. K3PO4
3fa
1f
_
OMe
CO2
OMe
OMe
Scheme 1.
that of 3ca. Since, in all cases, the resulting products 3aa–ea
and 3ab–ad had been obtained as a single diastereomer, it
was ascertained that this addition reaction had proceeded
in a highly diastereoselective manner.
We next evaluated the reactivity of propargylic carbon-
ate 1f, which contained a 3,4-dimethoxyphenyl group at the
propargylic position (Scheme 1). However, the reaction
resulted in the decomposition of the substrate, presumably
because of the instability of the carbonate moiety caused by
the electron-donating effect of the methoxy groups. To
overcome this problem, propargylic acetate 1g having a less
reactive leaving group was examined. As a result, the pal-

M. Yoshida et al. / Tetrahedron Letters 49 (2008) 1678–1681
1681
O
O
R2
R2
OCO2Me
R1
R1
R1
O
O
Pd+
Pd+
R1
3
1
3'
OMe
OMe
·
Pd(0)
CO2
R1
10
9
Pd+
H
O
Pd+
2
Pd+
H
O
R2
OMe
R1
O
R2
O
O
R1
6
R1
O
R2
MeOH
TS A
TS B
2
O
O
R2
MeOH
Pd+
R1
O
O
O R2
·
O
R2
R2
Pd
R1
R1
R1
4
5
O
8
O
7
Scheme 2. Proposed reaction mechanism.
M. Org. Biomol. Chem. 2004, 3099; (f) Yoshida, M.; Ihara, M. Chem.
Eur. J. 2004, 2886; (g) Yoshida, M.; Morishita, Y.; Ihara, M.
Tetrahedron Lett. 2005, 46, 3669; (h) Yoshida, M.; Ueda, H.; Ihara,
M. Tetrahedron Lett. 2005, 46, 6705; (i) Yoshida, M.; Murao, T.;
Sugimoto, K.; Ihara, M. Synlett 2006, 1923; (j) Yoshida, M.; Hayashi,
M.; Shishido, K. Org. Lett. 2007, 9, 1643; (k) Yoshida, M.; Okada, T.;
Shishido, K. Tetrahedron 2007, 63, 6996.
Acknowledgments
This study was supported in part by a Grant-in-Aid for
the Encouragement of Young Scientists (B) from the Japan
Society for the Promotion of Science (JSPS), Takeda
Science Foundation, Uehara Memorial Foundation and
Astellas Foundation for Research on Medicinal Resources.
5. General procedure for palladium-catalyzed reactions: To a stirred
solution of 1a (30.0 mg, 158 lmol) in DMSO (2.0 mL) were added
2-methylcyclohexane-1,3-dione (2a) (26.3 mg, 189 lmol), Pd2(dba)3ꢀ
CHCl3 (8.2 mg, 7.9 lmol) and dppf (17.5 mg, 31.6 lmol) at rt under an
argon atmosphere. The reaction mixture was allowed to heat to 120 °C,
and stirred for 20 min. After filtration of the reaction mixture using a
small amount of silica gel, the mass was concentrated. The residue was
chromatographed on silica gel with AcOEt–hexane (9:1 v/v) as eluent
to give tetrahydrobenzofuranone 3aa (32.0 mg, 133 lmol, 84%) as
colorless needles; mp: 53.7–55.6 °C (from hexane); IR (neat): 1715,
References and notes
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1
1695 cmꢁ1; H NMR (400 MHz, CDCl3) d 1.53 (s, 3H), 2.33–2.42 (m,
2H), 2.48–2.56 (m, 1H), 2.61–2.68 (m, 1H), 4.71 (d, J = 2.4 Hz, 1H),
5.19–5.21 (m, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.73 (t, J = 2.4 Hz, 1H),
7.22–7.27 (m, 2H), 7.31–7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) d
19.5 (CH2), 25.4 (CH3), 37.7 (CH2), 53.2 (Cq), 83.6 (CH), 92.6 (CH),
110.3 (CH2), 127.3 (CH ꢂ 2), 128.4 (CH), 128. 5 (CH ꢂ 2), 140.1 (Cq),
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this Letter have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 665659.
Copies of the data can be obtained, free of charge, on application to
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