Palladium-catalyzed arylation of α-methylene-γ-butyrolactone: 3-benzylfuran-2(5H)-ones vs (Z)-benzylidene-γ-butyrolactones and their reduction to 3-benzyl-γ-butyrolactones

Article abstract of DOI:10.1021/ol9912130

(formula presented) The palladium-catalyzed arylation of the α-methylene-γ-butyrolactone proceeds in good yields and may be directed toward the synthesis of 3-benzylfuran-2(5H)-ones when the starting aryl iodides contain strongly electron-withdrawing grou

Full text of DOI:10.1021/ol9912130

ORGANIC
LETTERS
2
000
Vol. 2, No. 1
9-72
Palladium-Catalyzed Arylation of
6
r-Methylene-γ-butyrolactone:
3-Benzylfuran-2(5H)-ones vs
(
Z)-Benzylidene-γ-butyrolactones and
Their Reduction to
-Benzyl-γ-butyrolactones
3
,†
†
†
‡
Antonio Arcadi,* Marco Chiarini, Fabio Marinelli, Zolt a´ n Berente, and
L a` szl o` Koll a` r
§
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Via Vetoio, 67010 Coppito
Due (AQ) Italy, Department of Biochemistry, UniVersity Medical School, H-7643 P e´ cs,
P.O. Box 99, Hungary, and Janus Pannonius UniVersity, Department of Inorganic
Chemistry and Research Group for Chemical Sensors of the Hungarian Academy of
Sciences, H-7624 P e´ cs, ifj u` s a` g u.6. Hungary
arcadi@aquila.infn.it
Received November 3, 1999
ABSTRACT
The palladium-catalyzed arylation of the r-methylene-γ-butyrolactone proceeds in good yields and may be directed toward the synthesis of
-benzylfuran-2(5H)-ones when the starting aryl iodides contain strongly electron-withdrawing groups. The combined palladium-catalyzed
arylation/hydrogenation of the r-methylene-γ-butyrolactone represents a new simple entry into functionalized r-benzyl-γ-butyrolactones.
3
Recently, a growing amount of attention has been paid to
eral methods for the synthesis of these latter derivatives it is
worth noting, owing to its simplicity, the synthesis of
1
the synthesis of 5H-furan-2-ones and R-benzylidene-γ-
2
butyrolactones. Some of these derivatives exhibit interesting
3
biological activities. Moreover, they are useful synthetic
(1) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J.
4
intermediates. In connection with our interest in developing
Org. Chem. 1999, 3305. Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G.
P. Tetrahedron Lett. 1999, 40, 989. Trost, B. M.; Toste, F. D. J. Am. Chem.
Soc. 1999, 121, 3543. Mabon, R.; Richecoeur, A. M. E.; Sweeney, J. B. J.
Org. Chem. 1999, 64, 328. Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387.
Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998,
new synthetic strategies for the construction of heterocycles
5
involving palladium catalysis, we report that R-methylene-
γ-butyrolactone 1 may represent a suitable building block
precursor for the synthesis of 5H-furan-2-ones 3 and stereo-
defined R-benzylidene-γ-butyrolactones 4. Among the sev-
3
9, 7599. Boukouvalas, J.; Lachanche, N.; Ouellet, M.; Trudeau, M.
Tetrahedron Lett. 1998, 30, 7665. Cacchi, S.; Ciattini, P. G.; Morera, E.;
Pace, P. Synlett 1996, 545. Matsushita, K.; Komori, T.; Oi, S.; Inoe, Y.
Tetrahedron Lett. 1994, 35, 5889. Knight, D. W. Contemp. Org. Synth.
1
994, 1, 287. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1993,
†
Ingegneria Chimica e Materiali.
University Medical School.
Janus Pannonius University.
65. Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.; Pietroni,
B. Tetrahedron Lett. 1989, 30, 3465. Arcadi, A.; Bernocchi, E.; Burini, A.;
Cacchi, S.; Marinelli, F.; Pietroni, B. Tetrahedron 1988, 44, 481.
‡
§
1
0.1021/ol9912130 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999

substituted R-benzylidene-γ-butyrolacones (E + Z steroiso-
mers) in excellent yields through the palladium-catalyzed
Assignment of the olefin geometry was unambiguosly
done by using T-ROESY NMR experiments. Surprisingly,
the reaction showed a very low selectivity in the â-elimina-
tion step and the 3-benzylfuran-2(5H)-one 4, derived from
endocyclic elimination of hydridopalladium species from the
addition intermediate 5, was isolated in 42% yield (Scheme
2). To our knowledge, this is the first example of butenolide
reaction of arenediazonium salts (Heck-type reaction) with
6
1.
On the basis of the stereochemical trend of the vinylic
substitution observed with a variety of reactions of unsatur-
ated halides/triflates with R-acetamido acrylic acid derivatives
7
and methyl R-methyl acrylic acid derivatives, we decided
to investigate the palladium-catalyzed arylation of 1 using
aryl iodides 2 as arylating agents with the aim of achieving
a stereoselective synthesis of substituted R-benzylidene-γ-
butyrolactones. Sterodefined R-benzylidene-γ-lactones are
useful intermediates for the synthesis of podophyllotoxin
and optically active R-spirocyclopropyllactones.9
Scheme 2
8
4-Iodoacetophenone was selected as the model aryl iodide,
and the preparation of the corresponding R-benzylidene-γ-
butyrolactone was attempted under a variety of conditions
to evaluate the influence of the catalytic system, bases, and
1/2 ratio on the reaction outcome (Scheme 1 and Table 1).
derivative formation starting from 1. Omitting the ligand
(Table 1, entry 2) produced only minor modifications of the
Scheme 1
reactivity and/or selectivity, at least from a synthetic point
of view. Switching to AcOK, in the presence of catalytic
amounts of Pd(OAc)
lectively 4 in 54% yield (Table 1, entry 3). The addition of
n-Bu NCl increased the reaction rate without modification
2
in DMF at 80 °C produced chemose-
4
1
0
in the selectivity (Table 1, entry 5). With N-methyl-2-
pyrrolidone and N,N-dimethylacetamide as solvents, a very
similar trend was observed; however, lower conversions of
the starting materials than in DMF took place (Table 1,
entries 6 and 7). The role of the base for directing the
â-palladium hydride elimination step is even demonstrated
by the lower selectivity obtained using a mixed system
With the use of Et
amounts of Pd(OAc)
corresponding R-benzylidene-γ-butyrolactone 3 was isolated
as single (Z) steroisomer after 8 h in 21% yield (Table 1,
entry 1).
3
N as base in the presence of catalytic
[Pd(o-tolyl) in DMF at 80 °C, the
2
3 2
]
3
AcOK/Et N (Table 1, entry 8). Finally, we used AcOTl in
place of AcOK, to make sure that the formation of 4 was
not a consequence of the migration of the double bond of
1
1
Table 1. Experimental Conditions for the Synthesis of 3 + 4a,b
from 1 and 4-Iodoacetophenone
the initially formed 3. Tl(I) salts are reported to eliminate
the isomerization of the double bond caused by â-palladium
hydride elimination/readdition/elimination sequence. The
isolation of 4 as the main product, also in the presence of
3
+ 4
entry
base
Et3N
solvent
catalyst
t (h) % yield (4:3)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
NMP
DMA
Pd(OAc)2/P(o-tol)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
20
9
63
60
54
53
54
45
32
66
2
1.3
24
5.6
25
(2) Iyer, S.; Ramesh, C. Tetrahedron Lett. 1999, 40, 4719. Ballini, R.;
Marcantoni, E.; Perella, S. J. Org. Chem. 1999, 64, 2954.
Et3N
(
3) Gebbink, E. A. K.; Stork, G. A.; Jansen, J. M.; de Groot, A.
AcOK
AcOKc
AcOKd
AcOK
AcOK
Tetrahedron 1999, 55, 11077-11094. Mulzer, J. In ComprehensiVe Organic
Synthesis; Flemming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol.
6, p 323. Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
48
4
2
4, 94.
(
21
23
9
28
30
11
4) Steuer S.; Podlech, J. Org. Lett. 1999, 1, 481. Rousset, S.; Abarbri,
M.; Thibonnet, J.; Duch eˆ ne, A.; Parrain, J.-L. Org. Lett. 1999, 1, 701. Rao,
Y. S. Chem. ReV. 1976, 76, 625.
(5) Arcadi, A.; Marinelli, F.; Rossi, E. Tetrahedron 1999, 55, 13233.
Skoda-F o¨ ldes, R.; V a´ ndor, K.; Koll a´ r, L.; Horv a´ t, J.; Tuba, Z. J. Org. Chem.
AcOK + DMF
Et3N
9
AcOK + DMF
K2CO3
Pd(OAc)2
5
-
1
999, 64, 5921.
(
6) Brunner, H.; Le Cousturier de Courcy, N.; Gen eˆ t, J.-P. Tetrahedron
1
1
0
1
AcOTl
AcOTl
DMF
DMF
Pd(OAc)2(PPh3)2
Pd(OAc)2
24
8
33
55
8.5
7.1
Lett. 1999, 40, 4815.
(7) Arcadi, A.; Cacchi, S.; Marinelli, F.; Morera, E.; Ortar, G. Tetrahe-
dron 1990, 46, 7151. Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1987, 28, 3039.
(8) Ishibashi, H.; Ito, K.; Hirano, T.; Tabuchi, M.; Ikeda, M. Tetrahedron
1993, 49, 4173.
(9) Otto, A.; Ziemer, B.; Liebscher, J. Synthesis 1999, 965.
(10) Jeffery, T. Tetrahedron Lett. 1999, 40, 1673.
(11) Crisp, T. J. Chem. Soc. ReV. 1998, 27, 427. Cabri, W.; Candiani, I.
Acc. Chem. Res. 1995, 28, 2.
a
Unless otherwise started, reactions were carried out at 80 °C under a
nitrogen atmosphere using the following molar ratios: 1:2:catalyst:base )
b
1
:1.5:0.05:3. Yields refer to single runs and are given for pure isolated
c
d
products. Temperature 40 °C. Reaction was carried out at 80 °C under
a nitrogen atmosphere using the following molar ratios: 1:2:catalyst:TBACl:
base ) 1:1.5:0.05:1:3.
70
Org. Lett., Vol. 2, No. 1, 2000

AcOTl (Table 1, entries 10 and 11) clearly rules out that
isomerization occurs. With regard to the effect of the acetate
anion on the reaction course, an explanation based on the
formation of a σ-alkylpalladium acetate intermediate 5 and
its decomposition through basic intramolecular attack of the
acetate moiety on the â-hydrogen1 could account for the
regioselective â-elimination observed in the presence of
favorable electronic effects (the presence of the electron-
withdrawing acyl group in the aromatic ring makes the â′-
hydridopalladium elimination more difficult) (Scheme 2).
Related mechanisms involving a seven-membered cyclic
Table 2. Experimental Condition for the Synthesis of (3 +
a,b
4)
and 6 Derivatives
3
+ 4
entry
2
% yield (4:3)
6 % yield
2a
1
4-CH3CO-C6H4-I
4-CH3OOC-C6H4-I
4-CH3OOC-C6H4-I
2-CH3OOC-C6H4-I
2-CH3OOC-C6H4-I
4-CH O-C H -I
4-CH3O-C6H4-I
4-CH3O-C6H4-I
4-CH3O-C6H4-I
4-CH3O-C6H4-I
1-iodonaphthalene
1-iodonaphthalene
3-CF3-C6H4-I
64 (8)
60 (20)
95c,d
95c
2
3
4
5
6
7
8
9
1
1
1
1
57e
81 (1.2)
96c
78e
96c
3
6
4
73 (0.6)
82 (0.6)f
63 (0.5)g
74 (0.6)h
1
2
transition state containing palladium have been reported.
According to that, when the system was extended to other
aryl iodides the chemoselective formation of the butenolide
derivatives has been accomplished only in the presence of
strongly electron-withdrawing substitutents in the aromatic
0
1
2
3
70e
95c
62 (0.7)
81 (0.7)
59e
1
3
ring.
96c
The stereochemistry of the R-benzylidene-γ-butyrolactones
was always found to be Z. It must be emphasized that
variable amounts of biaryl derivatives were observed in all
the reactions, and better results were usually obtained using
a 1.5 molar excess of the R-methylene-γ-butyrolactone over
the halide. Even if the selectivity of the â-hydropalladium
elimination is limited, the mixtures of 3 + 4 can be
hydrogenated to the corresponding R-benzyl-γ-butyrolactones
14
3-CF3-C6H4-I
78e
a
Unless otherwise stated, reactions were carried out at 80 °C in DMF
in the presence of an excess of AcOK under a nitrogen atmosphere using
b
the following molar ratios: 1:2:Pd(OAc)2:AcOK ) 1.5:1:0.05:3. Yields
refer to single runs, are given for pure isolated products, and are based on
c
2
3
.
Yields refer to reduced products derived from hydrogenation of isolated
and 4. d Yield refer to 3-(4′-ethybenzyl)furan-2(5H)-one. Yields refer
e
f
to isolated reduced products of the one-pot procedure. Reaction was carried
out at 80 °C in DMF in the presence of an excess of AcOK under a nitrogen
atmosphere using the following molar ratios: 1:2:Pd(OAc)2:ddpf:AcOK )
1
.5:1:0.05:0.05:3. g Reaction was carried out at 80 °C in DMF in the
6
in high yield. A one-pot arylation/hydrogenation reaction
presence of an excess of Et3N under a nitrogen atmosphere using the
to give 6 derivative has, also, been accomplished (Scheme
following molar ratios: 1:2:Pd(OAc) :Et N ) 1.5:1:0.05:4. h Reaction was
2
3
1
4
carried out at 80 °C in DMF in the presence of an excess of Et N under a
3
). The importance of these results is further stressed by
3
nitrogen atmosphere using the following molar ratios: 1:2:Pd(OAc)2:ddpf:
Et3N ) 1.5:1:0.05:0.05:4.
Scheme 3
Scheme 4
the observation that we failed to obtain the corresponding 6
derivative through the palladium-catalyzed conjugate addition
15
of R-methylene-γ-butyrolactone with 4-iodoacephenone (3
+
4 were isolated in 75% yield; 3:4 ratio ) 1).
The results obtained are summarized in Table 2.
Interestingly, one application of this synthetic methodology
(
Scheme 4), by using the androsten-3,5-dienyl-17-one 3-tri-
reaction, gives special prominence to the possibility of
stereocontrol in the formation of the new sterocenters.
The steroidal substituted γ-lactone 7 was isolated in high
de (80%). No attempts were made to determine the config-
flate as σ-donor in the palladium-catalyzed Heck-type
(12) (a) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerrini, S.;
Fedeli, W.; Ortar, G. Tetrahedron 1989, 45, 813. (b) B a¨ ckvall, J.-E.;
Bystr o¨ m, S. E.; Nordberg, R. E. J. Org. Chem. 1984, 49, 4619. Hutchins,
R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380. B a¨ ckvall, J.-E.; Nordberg,
R. E.; Bj o¨ rkam, E. E.; Moberg, C. J. Chem. Soc. Chem. Commun. 1980,
(14) General Procedure. A total of 2 mmol of aryl iodide, 3 mmol of
R-methylene-γ- butyrolactone, 6 mmol of AcOK, and 0.1 mmol of Pd-
(OAc)2 were dissoved in 3 mL of DMF, and the mixture was stirred under
nitrogen at 80 °C for 3 h. After it was cooled, the reaction mixture was
washed with a mixture of ethyl acetate and saturated aqueous NaHCO3.
The phases were separated, and the combined organic phases were dried
over Na2SO4. After removal of the solvent, the crude product was dissolved
in ethyl acetate and was hydrogenated in the presence of Pd/C (5%) at
atmospheric pressure. After the completion of the hydrogenation the catalyst
was filtered, the solvent was evaporated and the crude product purified by
chromatography (silica gel, CHCl3/petroleum ether).
9
43. Trost, B. M. Tetrahedron 1977, 33, 2615.
13) General Procedure. A total of 2 mmol of aryl iodide, 3 mmol of
R-methylene-γ- butyrolactone, 6 mmol of AcOK, and 0.1 mmol of Pd-
OAc)2 were dissoved in 3 mL of DMF, and the mixture was stirred under
(
(
nitrogen at 80 °C for 3 h. After it was cooled, the reaction mixture was
washed with a mixture ethyl acetate and saturated aqueous NaHCO3. The
phases were separated, and the combined organic phases were dried over
Na2SO4. After removal of the solvent, the crude was purified by flash
chromatography. All products were identified by 1H and C NMR and
mass spectroscopy.
13
(15) Cacchi, S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236.
Org. Lett., Vol. 2, No. 1, 2000
71

uration of the new chiral centers. Further work is in progress
to evaluate the scope and the limitations of this synthetic
methodology with triflates.
combined arylation/hydrogenation reaction of the R-meth-
ylene-γ-butyrolactone represent a new simple entry into
functionalized R-benzyl-γ-butyrolactones.
In conclusion, the palladium-catalyzed arylation of the
R-methylene-γ-butyrolactone may give 3- benzylfuran-
Acknowledgment. We thank the CNR and MURST, as
well as OTKA (T023525) for providing financial support.
2(5H)-ones when the starting aryl iodides contain strongly
electron-withdrawing groups in the aromatic rings while the
OL9912130
72
Org. Lett., Vol. 2, No. 1, 2000