Efficient Metallo-Ene Reactions in Organoaqueous Phase

Article abstract of DOI:10.1021/ol016023f

(matrixpresented)The easily prepared catalyst systems PdCl₂, RhCl₂ (COD) ₂, NiCl₂·6H₂O, or Ni (COD) ₂/TPPTS have been found to form a C-C bond in organoaqueous medium. Intramolecular metall

Full text of DOI:10.1021/ol016023f

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2065-2067
Efficient Metallo−Ene Reactions in
Organoaqueous Phase
Ve´ronique Michelet, Jean-Christophe Galland, Lise Charruault,
Monique Savignac, and Jean-Pierre Geneˆt*
Laboratoire de Synthe`se Organique, E.N.S.C.P., UMR7573, 11 rue P. et M. Curie,
F-75231 Paris Cedex 05, France
genet@ext.jussieu.fr
Received April 24, 2001
ABSTRACT
The easily prepared catalyst systems PdCl2, RhCl2(COD)2, NiCl2‚6H O, or Ni(COD)2/TPPTS have been found to form a C−C bond in organoaqueous
2
medium. Intramolecular metallo−ene reactions have been efficiently realized. Metal selectivity has been discovered.
Organic synthesis in water has recently received much
attention, not only because unique reactivity and selectivity
are often exhibited in water but also because it is an
economical and environmentally friendly solvent.1 Water-
soluble complex catalysts such as Rh, Ru, and Pd catalysts
have been intensively investigated for C-H and C-C bond
formations.1,2 The industrial applications in the fields of
hydrogenation and hydroformylation have already indicated
the wide scope of this type of catalyst. In our continuing
search for water-soluble complex catalysts,3 we have focused
on investigating new C-C bond formation reactions in
organoaqueous medium. The development of routes for the
synthesis of five-membered rings continues to attract atten-
tion due to the wide variety of natural products containing
this structural unit.4 We turned our attention to intramolecular
metallo-ene reactions, which have been widely described
by Oppolzer5 and proceed with a high level of atom
economy.6,7 The ene reactions involve the addition of a group
possessing a π-bond to a group possessing an allylic leaving
group and are regio- and stereoselective as well as entropi-
cally favored.8 In the presence of Pd(0) or Rh(I) catalysts,
anhydrous conditions usually need the use of acetic acid at
70-120 °C.9 A few catalytic examples of nickel catalysts10
have been reported, but they are limited to the use of
diphenylphosphinobutane. To our knowledge, metallo-ene
reactions have never been described in organoaqueous media.
In this report, we wish to disclose our preliminary results in
(5) (a) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1941. (b) Oppolzer,
W. Angew. Chem., Int. Ed. Engl. 1989, 28, 38. (c) Oppolzer, W. In
Organometallic Reagents in Organic Synthesis; Bateson, J. H., Mitchell,
M. B., Eds.; Academic Press: London, 1994; p 161.
(6) Trost, B. M. Science 1991, 1471.
(7) For recent cyclizations in organoaqueous and anhydrous media, see:
Galland, J.-C.; Savignac, M.; Geneˆt, J. P. Tetrahedron Lett. 1997, 38, 8695.
Mendez, M.; Munoz, M. P.; Echavarren, A. M. J. Am. Chem. Soc. 2000,
122, 11549.
(8) Gomez-Bengoa, E.; Cuerva, J. M.; Echavarren, A. M.; Martorell, G.
Angew. Chem., Int. Ed. Engl. 1997, 36, 767.
(9) (a) Hiroi, K.; Hirasawa, K. Chem Pharm. Bull. 1994, 42, 786. (b)
Oppolzer, W.; Swenson, R. E. Gaudin, J. M. Tetrahedron Lett. 1988, 29,
5529. (c) Oppolzer, W.; Gaudin, J. M.; Bedoya-Zurita, M.; Hueso-
Rodriguez, J.; Raynham, T. M.; Robyr, C. Tetrahedron Lett. 1988, 29, 4709.
(d) Oppolzer, W. Pure Appl. Chem. 1988, 60, 39.
(10) (a) Oppolzer, W.; Bedoya-Zurita, M.; Switzer, C. Y. Tetrahedron
Lett. 1988, 29, 6433. (b) Oppolzer, W.; Keller, T. H.; Bedoya-Zurita, M.;
Stone, C. Tetrahedron Lett. 1989, 30, 5883.
(1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blacky Academic
and Professional: London, 1998. (b) Organic Reactions in Aqueous Media;
Li, C.-J., Chan, T.-H., Eds.; Wiley & Sons: New York, 1997.
(2) Aqueous-Phase Organometallic Catalysis; Cornils, B., Herrmann, W.
A., Eds.; Wiley-VCH: New York, 1998.
(3) (a) Geneˆt, J. P.; Savignac, M. J. Organomet. Chem. 1999, 305. (b)
Geneˆt, J. P.; Savignac, M.; Lemaire-Audoire, S. In Chemistry for the 21st
Century. Transition Metal Catalysed Reactions, IUPAC Monographs;
Murahashi, S.-I., Davies, S. G., Eds.; Blackwell Science: London, 1999; p
55.
(4) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b) Paquette, L. A.
Top. Current Chem. 1984, 119, 1.
10.1021/ol016023f CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/31/2001

organoaqueous conditions using TPPTS as a water-soluble
ligand.11 We first prepared various dienyl acetates such as
cyclic compound 1 which was obtained from regioselective
Pd(0) alkylation of cis-chloroacetoxycyclohexene (Scheme
1).12 Dienyl acetates 2a, 2b, 3a, and 3b derived respectively
Table 1. Metal-Catalyzed Ene Reaction in Organoaqueous
Media
Scheme 1
entry
2-3, X )
conditions (catalyst, T, t)
yield (%)
1
2
3
4
5
6
7
2a , C(CO2Me)2 Rh(TPPTS)3Cl, 60 °C, 6 h
3a , C(CO2Me)2 Rh(TPPTS)3Cl, 60 °C, 24 h
57
50
62
3b, NBn
2a , C(CO2Me)2 Ni(TPPTS)3, rt, 12 h
3b, NBn Ni(TPPTS)3, rt, 12 h
2b, C(SO2Ph)2 Ni(TPPTS)3, rt-60 °C, 12 h
2c, C(CN)2 Ni(TPPTS)3, rt-60 °C, 12 h
Rh(TPPTS)3Cl, 60 °C, 3 h
99
<5
0%
0%
from dimethyl malonate, bis(phenylsulfonyl)methane, and
protected allylamine were prepared in a two-step synthesis
according to a literature procedure.13 The diene 2c was
synthesized by two sequential alkylations, one by phase
transfer14 and one catalyzed by 5 mol % of palladium(0).
The ene reaction was then investigated and optimized by
mixing 10 mol % of PdCl2 and 30 mol % of TPPTS ligand
in a mixture of dioxane and water. The cyclized products
were formed at a temperature of 60 °C (Scheme 2). Lower
substituted compound 3a did not react, probably because of
the free doublet of the nitrogen atom that may chelate to
palladium intermediates8 and inhibit the catalytic cycle.
Indeed, the tosyl-protected aminodiene 3b could be cyclized
in a moderate yield of 50%.
As palladium-ene catalysis seemed to be limited to
dimethyl malonate and bis(phenylsulfonyl)methane deriva-
tives and needed a high temperature, we then turned our
attention to other transition metals such as rhodium and
nickel. The known hydrosoluble complexes15 Rh(TPPTS)3-
Cl and Ni(TPPTS)3 have been prepared using respectively
[Rh(COD)Cl]2/TPPTS and NaCl as the depolymerization
agents in a water/THF mixture and NiCl2‚6H2O/TPPTS and
NaBH4 as the reductive agents16 in a water/ethanol mixture.
As exemplified in Table 1, the Rh(I)-catalyzed reaction was
successful at 60 °C with the dienyl acetate 2a in 57% yield
(entry 1). In contrast to the previous palladium-catalyzed
reaction, cyclization of the benzyl-protected amino compound
3a could be performed after 24 h at 60 °C in 50% yield
(entry 2). The reaction of 3b led to 5e in the same manner
as the Pd(0)/TPPTS catalyst (entry 3). We were pleased to
see that the cyclization conducted in the presence of Ni(0)
catalyst occurred at room temperature. Five-membered ring
5a was cleanly isolated in 99% yield (entry 4). Unfortunately,
the sulfonated derivative 3b could not be transformed to 5d
(entry 5). No reactions were observed with 2b and 2c, even
at higher temperatures (entries 6 and 7). We tried Ni(OAc)2‚
4H2O as another Ni(II) precursor and enhanced the ligand
ratio to stabilize the catalyst without success.
Scheme 2
temperatures or the use of other cosolvents such as CH3CN
or THF led to poor yields. Cyclization of 1 gave a 1:1
mixture of diastereomers 4 in a 57% yield. More efficiently,
the formation of five-membered ring alkenes 5a and 5b
respectively occurred with 88% and 80% yield. The nitrile-
containing substrate 2c was inert to the reaction conditions.
Prolonged heating led to many degradation products. Nitrogen-
The low reproducibility due to the oxygen sensitivity of
the Ni(0) catalyst and undesirable presence of boron residues
prompted us to find another method. We prepared the catalyst
system without reductive agent by heating a mixture of Ni-
(COD)2 and TPPTS (Ni/L 1/5) at 80 °C in neat water. As
documented in Table 2, the Ni(0)-catalyzed reaction was first
tested with 3 mol % of the catalyst at room temperature in
(11) TPPTS: trisodium salt of 3,3′,3′′-phosphanetriylbenzenesulfonic acid.
(12) Ba¨ckvall, J. E.; Nystro¨m, J. E.; Nordberg, R. E. J. Am. Chem. Soc.
1985, 107, 3676.
(13) (a) Oppolzer, W.; Kuo, D. L.; Hutzinger, M. W.; Leger, R.; Durand,
J. O.; Leslie, C. Tetrahedron Lett. 1997, 38, 6213. (b) Oppolzer, W.; Ruiz-
Montes, J. HelV. Chim. Acta 1993, 76, 1266.
(14) Diez-Barra, E.; de la Hoz, A.; Moreno, A.; Sanchez-Verdu, P. J.
Chem. Soc., Perkin Trans. 1 1991, 2589.
(15) (a) Herrmann, W. A.; Kellner, J.; Riepl, H. J. Organomet. Chem.
1990, 389, 103. (b) Larpent, C.; Patin, H. Appl. Organomet. Chem. 1987,
529.
(16) Zinc was also employed for Suzuki cross-coupling: Galland, J. C.;
Savignac, M.; Geneˆt, J. P. Tetrahedron Lett. 1999, 40, 2323.
2066
Org. Lett., Vol. 3, No. 13, 2001

Table 2. Ni(0)-Catalyzed Ene Reaction in Organoaqueous
Table 3. Metal Selectivity in Organoaqueous Ene Reaction
Media
diene, X )
Pd(TPPTS)2
RhCl(TPPTS)3
57%
Ni(TPPTS)3
5a , C(CO2Me)2
5c, C(CN)2
5d , NBn
88%
0%
<5%
56%
99%
51%
50%
62%
5e, NTs
65%
entry
2-3, X )
catalyst (mol %) yield (%) (conversion)
derivatives bearing nonchelating groups. The nitrogen-
substituted compounds were selectively cyclized in the
presence of rhodium. The use of nickel led to the best results
as all the dienyl acetates were cleanly cyclized at room
temperature.
1
2
3
4
5
2a , C(CO2Me)2
2a , C(CO2Me)2
2b, C(SO2Ph)2
2c, C(CN)2
3
10
10
30
10
nd (34)
92 (100)
65 (100)
51 (100)
45 (65)a
3b, NBn
a 35% of starting material was recovered.
In summary, water-soluble catalysts, easily prepared from
Pd(II), Rh(I), Ni(II), and Ni(0) precursors and TPPTS ligand,
have proven to be very efficient in intramolecular metallo-
ene reactions in organoaqueous media. The reactions were
conducted in the absence of acetic acid with palladium and
rhodium. A new water-soluble nickel catalyst was easily
prepared from Ni(COD)2 without reducing agent. This
inexpensive metal, combined with environmentally friendly
water and mild conditions, showed comparable and some-
times higher efficiency than metals in anhydrous conditions.
A major benefit consists of the facile separation of the
functionalized five-membered ring substrates from the
catalyst. Recycling tests and other catalytic applications are
currently under investigation and will be reported in due
course.
a 1/1 mixture of dioxane and water. Compound 2a was
cleanly cyclized but with only 34% conversion (entry 1).
The advantage of this protocol was the easy experimental
setup and workup. The formation of the cyclized product
was clean, and the catalyst was removed by simple filtration
over a neutral silica bed. The reaction was successfully
performed using 10 mol % of Ni(0) leading to the pentacyclic
diene 5a in 92% isolated yield (entry 2). Cyclization under
anhydrous conditions was only performed with palladium
catalyst in acid acetic at 80 °C, giving 5a in 77% yield.9d
Sulfonated derivative 5b was obtained in nonoptimized 65%
yield (entry 3). The dinitrile diene 2c could only be cyclized
in the presence of 30 mol % of Ni(0), which once again
may be due to a chelation between the nitrile group and the
catalyst (entry 4). The nitrogenated compound reacted very
cleanly under mild conditions leading to 65% conversion
and 45% yield (entry 5).
Acknowledgment. L.C. is grateful to the Ministe`re de
l’Education et de la Recherche for a grant (2000-2003).
Supporting Information Available: General experimen-
tal procedures for metallo-ene reactions. This information
is available free of charge via the Internet at http://pubs.acs.org.
Table 3 displays selected metallo-ene reactions in the
presence of palladium, rhodium, and nickel catalysts. The
palladium catalyst showed higher efficiency with malonic
OL016023F
Org. Lett., Vol. 3, No. 13, 2001
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