Synthesis of tetrasubstituted furans by palladium-catalyzed decarboxylative [3+2] cyclization of propargyl β-keto esters

Article abstract of DOI:10.1002/chem.201103246

The decarboxylative [3+2] cyclization reaction of propargyl β-keto esters with a palladium catalyst is described. Tetrasubstituted furans with a variety of substituents were conveniently synthesized with high efficiency (see scheme). Copyright

Full text of DOI:10.1002/chem.201103246

DOI: 10.1002/chem.201103246
Synthesis of Tetrasubstituted Furans by Palladium-Catalyzed
Decarboxylative [3+2] Cyclization of Propargyl b-Keto Esters
AHCTUNGTRENNUNG
Masahiro Yoshida,* Shoko Ohno, and Kozo Shishido[a]
Palladium-catalyzed allylic substitutions with nucleophiles
have received considerable attention and have been exten-
sively studied due to their versatile and specific reactivi-
ties.[1] In these reactions, soft carbanions derived from b-di-
carbonyl compounds are suitable as nucleophiles, and exam-
ples of the reaction with nonstabilized carbanions, such as
monoketone enolates, are limited.[2] An elegant solution to
this problem is a decarboxylative allylation of allyl b-keto
esters, in which the nonstabilized monoketone enolate is ef-
fectively formed in situ to afford an allylated product
(Scheme 1).[3] Because the reaction can be carried out under
Scheme 2. Palladium-catalyzed decarboxylative [3+2] cyclization of prop-
argyl b-keto esters.
Table 1. Initial attempts at the synthesis of substituted furan 2a.
Entry
Solvent
T [8C]
Ligand
Yield of 2a [%]
1
2
3
4
5
6
DMSO
DMF
NMP
80
80
80
65
65
65
65
65
DPPF
DPPF
DPPF
DPPF
DPPF
DPPP
BINAP
DPPF
40
19
45
70
75
29
60
76
Scheme 1. Palladium-catalyzed decarboxylative allylation of allyl b-keto
esters.
THF
dioxane
dioxane
dioxane
dioxane
7
extremely mild conditions, a variety of applications, includ-
ing enantioselective reactions and utilization in the synthesis
of the natural products, have been reported.[2,4]
8[a]
[a] The reaction was carried out in the presence of [Pd
(2.5 mol%) and DPPF (10 mol%).
2ACHTUNGTRNEN(UNG dba)3·CHCl3]
We have recently published the palladium-catalyzed reac-
tions of propargylic compounds with bisnucleophiles, in
which various hetero- and carbocyclic molecules were syn-
thesized in a highly stereoselective manner.[5–7] In planning
the application of these reactions, we focused on the reactiv-
ity of propargyl b-keto esters. In contrast to the extensive
studies on the reaction of allyl b-keto esters, no examples
have been reported on the reactivity of propargyl b-keto
esters with palladium. Herein, we describe the palladium-
catalyzed reaction of propargyl b-keto esters 1, in which the
tetrasubstituted furans 2 have been constructed by a decar-
boxylative [3+2] cyclization pathway (Scheme 2).
When 1a was treated with 5 mol% of [Pd2ACTHUNTRGNE(UGN dba)3·CHCl3]
(dba=dibenzylideneacetone) and 20 mol% of 1,1’-bis(di-
phenylphosphino)ferrocene (DPPF) in DMSO at 808C, the
tetrahydrobenzofuran 2a was produced in 40% yield
(Table 1, entry 1). After experimenting with various ligands
and reaction temperatures (Table 1, entries 2–7), we found
that the yield of 2a could be improved to 75% when diox-
ane was used as the solvent at 658C (Table 1, entry 5). Fur-
thermore, the reactivity was maintained even in the pres-
ence of 2.5 mol% [Pd2ACHTNUTRGNE(NUG dba)3·CHCl3] and 10 mol% DPPF
The reactions were initially attempted by using 1-phenyl-
(76% yield, Table 1, entry 8).
2-propynyl 2-oxocyclohexanecarboxylate (1a, Table 1).[8]
Having identified a useful set of reaction conditions, we
next conducted the reactions of the propargyl b-keto esters
1b–1i with various substituents at the propargylic position
(Table 2). When the reactions of the substrates 1b and 1c
containing a naphthyl group were carried out, the tetrahy-
drobenzofurans 2b and 2c were obtained in moderate yields
(Table 2, entries 1 and 2). The propargyl b-keto esters 1d
and 1e with 4-fluorophenyl and 3,4-dimethoxyphenyl group
also reacted with the palladium catalyst to give the products
[a] Prof. Dr. M. Yoshida, S. Ohno, Prof. Dr. K. Shishido
Graduate School of Pharmaceutical Sciences
The University of Tokushima
1-78-1 Sho-machi, Tokushima 770-8505 (Japan)
Fax : (+81)88-633-7294
E-mail: yoshida@ph.tokushima-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103246.
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Chem. Eur. J. 2012, 18, 1604 – 1607

COMMUNICATION
Table 2. Reactions with various propargyl b-keto esters 1b–1i.[a]
Table 3. Reactions with various propargyl b-keto esters 1j–1p.[a]
Entry Substrate 1
Product
Yield [%]
Entry
Substrate 1
Product 2
Yield [%]
1
62
1
70
2
3
60
68
2
3
74
70
4
5
63
79
4
62
76
57
21
5
6
7
73
61
6
7[b]
[a] The reactions were carried out in the presence of [Pd2ACTHUNTRGNE(UGN dba)3·CHCl3]
(2.5 mol%), DPPF (10 mol%) in dioxane at 658C for 20–60 min. [b] The
reaction was carried out at 1008C.
43
AHCTUNGTRENGN(UN 3i: 38)
8
out, the corresponding substituted tetrahydrobenzofurans
2n and 2o were obtained as the sole products, respectively
(Table 3, entries 5 and 6). The acyclic propargyl b-keto ester
1p also reacted with the palladium catalyst to produce the
substituted furan 2p, but the yield was decreased to 21%
(Table 3, entry 7).
A plausible mechanism for the production of the tetrasub-
stituted furans 2 is shown in Scheme 3. Upon reaction with
the palladium catalyst, the propargyl b-keto ester 1 under-
goes decarboxylation to form the p-propargylpalladium eno-
late 4. The complex is in equilibrium with the ion pair 5,
[a] The reactions were carried out in the presence of [Pd2ACTHUNTRGNE(UGN dba)3·CHCl3]
(2.5 mol%), DPPF (10 mol%) in dioxane at 658C for 20–60 min.
2d and 2e in 68 and 63% yield, respectively (Table 2, en-
tries 3 and 4). The reactions of the substrates 1 f, 1g, and 1h,
which have a 3-furyl, 3-thienyl, and 3-pyridyl group, respec-
tively, successfully afforded the corresponding tetrahydro-
benzofurans 2 f, 2g, and 2h in good yields (Table 2, en-
tries 5–7). When the substrate 1i containing a pentyl group
was subjected to the reaction, the tetrahydrobenzofuran 2i
was obtained in 43% yield together with the dienones 3i
(1:1 mixture of isomers) in 38% yield (Table 2, entry 8).
Table 3 shows our attempts to use propargyl b-keto esters
1j–p containing various ketone moieties. The reactions of
the substrates 1j and 1k with a cycloheptanone and a cyclo-
octanone ring successfully proceeded to give the cyclohep-
ta[b]furan 2j and cycloocta[b]furan 2k in 70 and 74% yield,
respectively (Table 3, entries 1 and 2). The substrates 1l and
1m, which have a 1-tetralone and a spiroACTHNUTRGNE[NUG 4.5]decan-6-one
moiety, were also converted to the corresponding products
2l and 2m in good yields (Table 3, entries 3 and 4). When
the reactions of 1n and 1o with a phenyl and a methyl
group at the 4-position of the cyclohexane ring were carried
Scheme 3. Proposed reaction mechanism.
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M. Yoshida et al.
which undergoes nucleophilic attack of the enolate on the
p-propargylpalladium leading to the p-allylpalladium inter-
mediate 6. The intermediate 6 is subjected to an intramolec-
ular attack by the enolate oxygen to produce the 4-methyl-
ene-4,5-dihydrofuran 7, which isomerizes to give the substi-
tuted furan 2. One reason for the formation of the dienones
3i in the reaction of alkyl-substituted substrate 1i (Table 2,
entry 8) may be that b-elimination of palladium from the p-
allylpalladium intermediate 6 would occur prior to the cycli-
zation. The results from the reactions of the substituted
propargyl b-keto esters 1n and 1o to produce only one
product (Table 3, entries 5 and 6) indicate that the reaction
proceeds through the regioselective formation of the corre-
sponding enolates.[9] In the case of the acyclic substrate 1p
(Table 3, entry 7), a mixture of the E and Z enolates could
be generated in the intermediate 6, which presumably re-
sulted in the low yield.
Scheme 5. Crossover experiment.
ed furans with a variety of substituents by a decarboxylative
[3+2] cyclization pathway. Because many biologically active
natural products and industrially useful compounds with a
furan component have been reported,[13,14] our methodology
would provide a new protocol for the synthesis of these
compounds with high efficiency.
To examine the utility of propargyl b-keto esters as the
substrate, we compared the reactivity with the simple mono-
ketone as the intermolecular nucleophilic component
(Scheme 4). When the palladium-catalyzed reaction of cy-
Acknowledgements
This study was supported in part by a Grant-in-Aid for the Encourage-
ment of Young Scientists (B) from the Japan Society for the Promotion
of Science (JSPS), the Takeda Science Foundation, the Uehara Memorial
Foundation, and the Program for the Promotion of Basic and Applied
Research for Innovations in the Bio-oriented Industry (BRAIN).
Keywords: alkynes
· cyclization · domino reactions ·
heterocycles · palladium
Scheme 4. Attempts for the intermolecular reactions of propargyl carbon-
ate 9 with monoketone 8 or silyl enol ether 10.
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and 9 in the presence of CsF[10] or tetrabutylammonium di-
fluorotriphenylsilicate (TBAT)[11] also failed. These results
indicate that the propargyl b-keto esters are excellent sub-
strates for the effective formation of the nonstabilized mon-
oketone enolate in situ.
Crossover experiments were next conducted to confirm
that the dissociated ion pair 5 is actually generated in the re-
action (Scheme 5). Treatment of an equimolar mixture of
the propargyl b-keto esters 1 f and 1q with the palladium
catalyst leads to the formation of a mixture containing ap-
proximately equal amounts of the four products 2a, 2 f, 2j,
and 2q. This result demonstrates that the p-propargylpalla-
dium and the enolate ion completely dissociate during the
reaction.[12]
In conclusion, the experiments described above have led
to the development of a palladium-catalyzed reaction of
propargyl b-keto esters. This process produces tetrasubstitut-
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Chem. Eur. J. 2012, 18, 1604 – 1607

Synthesis of Tetrasubstituted Furans
COMMUNICATION
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Tong, H. N. C. Wong, Tetrahedron 1998, 54, 1955; b) S. F. Kirsch,
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Chem. Res. 2011, 44, 111.
[8] The propargyl b-keto esters 1 were easily prepared by the trans-
esterification of the methyl b-keto esters with propargyl alcohols
(see the Supporting Information).
[9] Similar regiospecificity has been observed in the decarboxylative al-
lylation, see: J. Tsuji, I. Minami, I. Shimizu, Tetrahedron Lett. 1983,
24, 1793.
Received: October 14, 2011
Published online: January 13, 2012
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