Enantiopure Fluorous Bis(oxazolines): Synthesis and Applications in Catalytic Asymmetric Reactions

Article abstract of DOI:10.1021/jo049853q

Various enantiopure fluorous bis(oxazolines) with fluorine content between 52.7 and 58.7% have been synthesized by a simple reaction sequence that involved the introduction of two fluorinated ponytails by alkylation of the corresponding nonfluorous bis(ox

Full text of DOI:10.1021/jo049853q

En a n tiop u r e F lu or ou s Bis(oxa zolin es): Syn th esis a n d Ap p lica tion s
in Ca ta lytic Asym m etr ic Rea ction s
J erome Bayardon and Denis Sinou*
Laboratoire de Synthe`se Asyme´trique, associe´ au CNRS, ESCPE Lyon, Universite´ Claude Bernard
Lyon 1, 43, boulevard du 11 novembre 1918, 69622 Villeurbanne Cedex, France
sinou@univ-lyon1.fr
Received J anuary 26, 2004
Various enantiopure fluorous bis(oxazolines) with fluorine content between 52.7 and 58.7% have
been synthesized by a simple reaction sequence that involved the introduction of two fluorinated
ponytails by alkylation of the corresponding nonfluorous bis(oxazolines). These new ligands have
been used in palladium-catalyzed alkylation of rac-(E)-1,3-diphenylpropenyl acetate with carbon
nucleophiles and in copper-catalyzed oxidation of cycloalkenes; these ligands exhibited enantio-
selectivities up to 98 and 77%, respectively, quite close to the values obtained using the analogous
nonfluorous bis(oxazolines). These ligands could be easily recovered by liquid-liquid extraction or
solid-liquid separation and reused with the same enantioselectivities.
In tr od u ction
Due to the broad range of applications of this class of
ligands and the very high enantioselectivities obtained,
much efforts have been devoted to its immobilization on
supports in order to recover and recycle the catalyst.
The C2-symmetric enantiopure bis(oxazolines) (box)
have emerged as one of the most efficient class of ligands
in the area of asymmetric organometallic catalysis.1 The
most frequently used bis(oxazolines) are those with one
carbon spacer between the two oxazoline rings. These
ligands have been successfully used in a variety of
catalytic asymmetric transformations over the past de-
cade, including palladium-catalyzed allylic alkylations,2
Diels-Alder3 and hetero-Diels-Alder reactions,4 copper-
catalyzed cyclopropanation5 and aziridination,5c,6 Mukaya-
ma-aldol7 and nitro-aldol (Henry) reactions,8 Michael
additions,9 carbonyl-ene reactions,4a,10 Friedel-Crafts
reactions,11 allylic oxidation,12 and reduction of ketones,13
giving generally very high enantioselectivities.
(4) (a) J ohannsen, M.; J ørgensen, K. A. J . Org. Chem. 1995, 60, 5757.
(b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J .; Krishnan, K. Tetra-
hedron: Asymmetry 1996, 7, 2165. (c) Yao, S.; J ohannsen, M.; Audrain,
H.; Hazell, R. G.; J ørgensen, K. A. J . Am. Chem. Soc. 1998, 120, 8599.
(d) Yao, S.; Roberson, M.; Reichel, F.; Hazell, R. G.; J ørgensen, K. A.
J . Org. Chem. 1999, 64, 6677. (e) Aggarwal, V. K.; J ones, D. E.; Martin-
Castro, A. M. Eur. J . Org. Chem. 2000, 2939. (f) Audrain, H.;
Thorhauge, J .; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem. 2000, 65,
4487. (g) Evans D. A.; J ohnson, J . S.; Olhava, E. J . J . Am. Chem. Soc.
2000, 122, 1635. (h) Bayer, A.; Gautun, O. R. Tetrahedron: Asymmetry
2001, 12, 2937.
(5) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005. (b) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett.
1991, 32, 7373. (c) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul,
M. M. J . Am. Chem. Soc. 1991, 113, 726. (d) Schumacher, R.; Dammast,
F.; Reissig, H.-U. Chem. Eur. J . 1997, 3, 614. (e) Alexander, K.; Cook,
S.; Gibson, C. L. Tetrahedron Lett. 2000, 41, 7135. (f) Charette, A. B.;
J anes, M. K.; Lebel, H. Tetrahedron: Asymmetry 2003, 14, 867. (g)
Østergaard, N.; J ensen, J . F.; Tanner, D. Tetrahedron 2001, 57, 6083.
(k) Schinnerl, M.; Bo¨hm, C.; Seitz, M.; Reiser, O. Tetrahedron:
Asymmetry 2003, 14, 765.
(1) For reviews partially or totally dedicated to C2-bis(oxazolines),
see: (a) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (b) Bommarius, A.
S.; Schwarm, M.; Stingl, K.; Kottenhahn, M.; Huthmacher, K.; Drauz,
K. Tetrahedron: Asymmetry 1995, 6, 2851. (c) Ghosh, A. K.; Mathi-
vanan, P.; Cappiello, J . Tetrahedron: Asymmetry 1998, 9, 1. (d) Doyle,
M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919. (e) J ørgensen,
K. A.; J ohannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J . Acc. Chem.
Res. 1999, 32, 605. (f) J ohnson, J . S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325. (g) Andrus, M. B.; Lashley, J . C. Tetrahedron 2002, 58,
845.
(2) (a) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.;
Pfaltz, A. Tetrahedron 1992, 48, 2143. (b) von Matt, P.; Lloyd J ones,
G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder,
M.; Ru¨egger, H.; Pregosin, P. S. Helv. Chim. Acta 1995, 78, 265. (c)
Hoarau, O.; A¨ıt-Haddou, H.; Daran, J .-C.; Cramaile`re, D.; Balavoine,
G. G. A. Organometallics 1999, 18, 4718. (d) Glorius, F.; Pfaltz, A. Org.
Lett. 1999, 1, 141. (e) Malkoch, M.; Hallman, K.; Lutsenko, S.; Hult,
A.; Malmstroem, E.; Moberg, C. J . Org. Chem. 2002, 67, 8197.
(3) (a) Corey, E. J .; Imai, N.; Zhang, H.-Y. J . Am. Chem. Soc. 1991,
113, 728. (b) Corey, E. J .; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807.
(c) Evans, D. A.; Miller, S. J .; Lectka, T.; von Matt, P. J . Am. Chem.
Soc. 1999, 121, 7559. (d) Evans, D. A.; Barnes, D. M.; J ohnson, J . S.;
Lectka, T.; von Matt, P.; Miller, S. J .; Murry, J . A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J . Am. Chem. Soc. 1999, 121, 7582.
(e) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron Lett. 1996,
37, 3815. (f) Ghosh, A. K.; Cho, H.; Cappiello, J . Tetrahedron:
Asymmetry 1998, 9, 3687. (g) Carbone, P.; Desimoni, G.; Faita, G.;
Filippone, S.; Righetti, P. Tetrahedron 1998, 54, 6099. (h) Crosignani,
S.; Desimoni, G.; Faita, G.; Righetti, P. Tetrahedron 1998, 54, 15721.
(6) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J . Am. Chem. Soc. 1993, 115, 5328.
(7) (a) Evans, D. A.; Kozlowski, M. C.; Murry, J . A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J . J . Am. Chem. Soc. 1999,
121, 669. (b) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S.
W. J . Am. Chem. Soc. 1999, 121, 686. (c) Evans, D. A.; Downey, C. W.;
Hubbs, J . L. J . Am. Chem. Soc. 2003, 125, 8706. (d) Matsunaga, H.;
Yamada, Y.; Ide, T.; Ishizuka, T.; Kunieda, T. Tetrahedron: Asymmetry
1999, 10, 3095. (e) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J .; Morken, J .
P. Org. Lett. 2001, 3, 1829.
(8) (a) Christensen, C.; J uhl, K.; J ørgensen, K. A. Chem. Commun.
2001, 2222. (b) Christensen, C.; J uhl, K.; Hazell, R. G.; J ørgensen, K.
A. J . Org. Chem. 2002, 67, 4875. (c) Evans, D. A.; Seidel, D.; Rueping,
M.; Lam, H. W.; Shawn J . T.; Downey, C. W. J . Am. Chem. Soc. 2003,
125, 12692. (d) Risgaard, T.; Gothelf, K. V.; J ørgensen, K. A. Org.
Biomol. Chem. 2003, 1, 153.
(9) (a) Evans, D. A.; Willis, M. C.; J ohnston, J . N. Org. Lett. 1999,
1, 865. (b) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.;
Tedrow, J . S. J . Am. Chem. Soc. 2000, 122, 9134. (c) Cardillo, G.;
Fabbroni, S.; Gentilucci, L.; Gianotti, M.; Percacciante, R.; Tolomelli,
A. Tetrahedron: Asymmetry 2002, 13, 1407. (e) Halland, N.; Velgaard,
T.; J ørgensen, K. A. J . Org. Chem. 2003, 68, 5067.
10.1021/jo049853q CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004
J . Org. Chem. 2004, 69, 3121-3128
3121

Bayardon and Sinou
Effectively, their practical application in asymmetric
synthesis is actually limited, due to the low ratio substrate/
ligand usually used and the high cost of these ligands.
This immobilization could improve the efficiency of
asymmetric catalysis by allowing simple catalyst separa-
tion and recycling.14 Different strategies have been
employed in the design of immobilized enantiopure bis-
(oxazoline). In a first type, the heterogenization of the
ligand is performed using noncovalent or covalent bond-
ing to solid inorganic15 as well as organic supports.16 In
a second approach, the bis(oxazoline) is covalently bound
to a soluble organic polymer,17 allowing the reaction to
occur under homogeneous conditions, the recovery and
recycling of the catalyst being performed by precipitation
of the polymer. These different approaches gave enanti-
oselectivities quite close to those obtained when the
reaction was performed under homogeneous conditions,
the recycling of the supported enantiopure organometallic
catalyst being generally possible.
The fluorous biphase catalysis is a quite new concept.18
This methodology used the markedly temperature-de-
pendent miscibilities of organic and fluorous solvents.
The solubilization of the organometallic catalyst in the
fluorous phase is obtained by the use of fluorinated
ligands. This approach has been extended more or less
successfully to some asymmetric organometallic catalysis
in a two-phase system organic solvent-fluorous solvent.19
We recently reported the preparation of fluorous enan-
tiopure bis(oxazolines) and some preliminary results
concerning their use as ligands in asymmetric allylic
alkylation.20 At the same time, Benaglia et al.21 described
the preparation of two enantiopure fluorous-substituted
bis(oxazolines) and their applications in the ene and
cyclopropanation reactions. Here we report a full account
concerning the synthesis of a family of fluorinated
enantiopure bis(oxazolines) possessing different fluorine
content and their use as enantiopure ligands in allylic
alkylation and allylic oxidation.
(10) (a) Evans D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.;
Tregay, S. W. J . Am. Chem. Soc. 1998, 120, 5824. (b) Qian, C.; Wang,
L. Tetrahedron: Asymmetry 2000, 11, 2347.
(11) (a) Gathergood, N.; Zhuang, W.; J ørgensen, K. A. J . Am. Chem.
Soc. 2000, 122, 12517. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 2001, 66, 1009.
Resu lts a n d Discu ssion
(12) (a) Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A. Tetrahedron Lett.
1995, 36, 1831. (b) Andrus, M. B.; Chen, X. Tetrahedron 1997, 53,
16229. (c) Andrus, M. B.; Asgari, D. Tetrahedron 2000, 56, 5775. (d)
Andrus, M. B.; Zhou, Z. J . Am. Chem. Soc. 2002, 124, 8806. (e) Clark,
J . S.; Tolhurst, K. F.; Taylor, M.; Swallow, S. J . Chem. Soc., Perkin
Trans. 1 1998, 1167. (f) Schulz, M.; Kluge, R.; Gelalcha, F. G.
Tetrahedron: Asymmetry 1998, 9, 4341.
(13) (a) Bandini, M.; Cozzi, P. G.; Negro, L.; Umani-Ronchi, A. Chem.
Commun. 1999, 39. (b) Bandini, M.; Cozzi, P. G.; De Angelis, M.;
Umani-Ronchi, A. Tetrahedron Lett. 2000, 41, 1601. (c) Bandini, M.;
Bernardi, F.; Bottoni, A.; Cozzi, P. G.; Miscione, G. P.; Umani-Ronchi,
A. Eur. J . Org. Chem. 2003, 2972.
It was crucial to find a very easy and eventually
inexpensive access to these enantiopure fluorous bis-
(oxazolines) from available starting materials; the design
of an easily flexible approach in order to modify the
oxazoline structure was also needed. Since enantiopure
bis(oxazolines) are commercially available or easy to
prepare, we expected to introduce two fluorous ponytails
on the methylene bridge of these ligands.
In a preliminary experiment, tert-butyl-substituted box
1 was treated with BuLi (2.2 molar equiv in THF, -78
°C, 1 h) and then alkylated with nonaflate 222 (2.3 molar
equiv in THF, 50 °C, 24 h) (Scheme 1). Only monoalky-
lated bis(oxazoline) 3 was obtained in 67% isolated yield.
All attempts to dialkylated box 1, for example in the
presence of BuLi (1.2 molar equiv in THF, -78 °C), then
nonaflate 2 (1.2 molar equiv at 50 °C in THF), followed
by addition of BuLi (1.2 molar equiv in THF, -78 °C) in
the presence of TMEDA (1.5 molar equiv) and i-Pr2NH
(1 molar equiv), followed by addition of nonaflate 2 (1.2
molar equiv in THF) at 50 °C afforded the monoalkylated
bis(oxazoline) 3 as the sole product. Sequential treatment
of bis(oxazoline) 3 first by BuLi (1.2 molar equiv in THF)
(14) De Vos, D. E.; Vankelecom, I. F. J .; J acobs, P. A.; Eds. Chiral
Catalyst Immobilization and Recycling; Wiley-VCH: Weinheim, 2000.
(15) (a) Burguete, M. I.; Fraile, J . M.; Garc´ıa, J . I.; Garc´ıa-Verdugo,
E.; Luis, S. V.; Mayoral, J . A. Org. Lett. 2000, 2, 3905. (b) Altava, B.;
Burguete, M. I.; Fraile, J . M.; Garc´ıa, J . I.; Luis, S. V.; Mayoral, J . A.;
Vicent, M. J . Angew. Chem., Int. Ed. Engl. 2000, 39, 1503. (c) Burguete,
M. I.; Fraile, J . M.; Garc´ıa, J . I.; Garc´ıa-Verdugo, E.; Herrer´ıas, C. I.;
Luis, S. V.; Mayoral, J . A. J . Org. Chem. 2001, 66, 8893. (d) Burguete,
M. I.; Diez-Barra, E.; Fraile, J . M.; Garc´ıa, J . I.; Garc´ıa-Verdugo, E.;
Gonzalez, R.; Herrer´ıas, C. I.; Luis, S. V.; Mayoral, J . A. Bioorg. Med.
Chem. Lett. 2002, 12, 1821. (e) Clarke, R. J .; Shannon, I. J . Chem.
Commun. 2001, 1936. (f) Hallman, K.; Moberg, C. Tetrahedron:
Asymmetry 2001, 12, 1475. (g) Orlandi, S.; Mandoli, A.; Pini, D.;
Salvadori, P. Angew. Chem., Int. Ed. 2001, 40, 2519. (h) Park, J . K.;
Kim, S.-W.; Hyeon, T.; Kim, B. M. Tetrahedron: Asymmetry 2001, 12,
2931. (i) Rechavi, D.; Lemaire, M. Org. Lett. 2001, 3, 2493. (j) Rechavi,
D.; Lemaire, M. J . Mol. Catal. A: Chem. 2002, 182-183, 239. (k)
Corma, A.; Garc´ıa, H.; Moussaif, A.; Sabater, M. J .; Zniber, R.;
Redouane, A. Chem. Commun. 2002, 1058.
(16) (a) Fraile, J . M.; Garc´ıa, J . I.; Mayoral, J . A.; Tarnai, T.
Tetrahedron: Asymmetry 1997, 8, 2089. (b) Fraile, J . M.; Garc´ıa, J . I.;
Mayoral, J . A.; Tarnai, T. Tetrahedron: Asymmetry 1998, 9, 3997. (c)
Fraile, J . M.; Garc´ıa, J . I.; Mayoral, J . A.; Tarnai, T.; Harmer, M. A.
J . Catal. 1999, 186, 214. (d) Fernandez, A. I.; Fraile, J . M.; Garc´ıa, J .
I.; Herrer´ıas, C. I.; Mayoral, J . A.; Salvatella, L. Catal. Commun. 2001,
2, 165. (e) Fraile, J . M.; Garc´ıa, J . I.; Harmer, M. A.; Herrer´ıas, C. I.;
Mayoral, J . A. J . Mol. Catal. A: Chem. 2001, 165, 211. (f) Langham,
C.; Piaggio, P.; Bethell, D.; Lee, D. F.; McMorn, P.; Page, P. C. B.;
Willock, D. J .; Sly, C.; Hancock, F. E.; King, F.; Hutchings, G. J . Chem.
Commun. 1998, 1601. (g) Langham, C.; Bethell, D.; Lee, D. F.; McMorn,
P.; Page, P. C. B.; Willock, D. J .; Sly, C.; Hancock, F. E.; King, F.;
Hutchings, G. J . Appl. Catal. A: General 1999, 182, 85. (h) Langham,
C.; Taylor, S.; Bethell, D.; McMorn, P.; Page, P. C. B.; Willock, D. J .;
Sly, C.; Hancock, F. E.; King, F.; Hutchings, G. J . J . Chem. Soc., Perkin
Trans. 2 1999, 1043. (i) Taylor, S.; Gullick, J .; McMorn, P.; Bethell,
D.; Page, P. C. B.; Hancock, F. E.; King, F.; Hutchings, G. J . J . Chem.
Soc., Perkin Trans. 2 2001, 1714 and 1724.
(18) (a) Horvath, I. T. Acc. Chem. Res. 1998, 31, 641. (b) Barthel-
Rosa, L. P.; Gladysz, J . A. Coord. Chem. Rev. 1999, 190-192, 587. (c)
de Wolf, E.; van Koten, G.; Deelman, B.-J . Chem. Soc. Rev. 1999, 28,
37. (d) Hope, E. G.; Stuart, A. M. J . Fluorine Chem. 1999, 100, 75. (e)
Cavazzini, M.; Montanari, F.; Pozzi, G.; Quici, S. J . Fluorine Chem.
1999, 94, 183. (f) Fish, R. H. Chem. Eur. J . 1999, 5, 1677. (g) Kitazume,
T. J . Fluorine Chem. 2000, 105, 265. (h) Curran, D. P. Synlett 2001,
1488.
(19) (a) Pozzi, G.; Cavazzini, M.; Quici, S.; Maillard, D.; Sinou, D.
J . Mol. Catal. A: Chem. 2002, 182-183, 455 and references therein.
(b) Cavazzini, M.; Quici, S.; Pozzi, G. Tetrahedron 2002, 58, 3943. (c)
Tian, Y.; Yang, Q. C.; Mak, T. C. W.; Chan, K. S. Tetrahedron 2002,
58, 3951. (d) Nakamura, Y.; Takeuchi, S.; Okumura, K.; Ohgo, Y.;
Curran, D. P. Tetrahedron 2002, 58, 3963. (e) Maillard, D.; Pozzi, G.;
Quici, S.; Sinou, D. Tetrahedron 2002, 58, 3971. (f) Nakamura, Y.;
Takeuchi, S.; Zhang, S.; Okumura, K.; Ohgo, Y. Tetrahedron Lett. 2002,
43, 3053. (g) Maillard, D.; Bayardon, J .; Kurichiparambil, J . D.;
Nguefack-Fournier, C.; Sinou, D. Tetrahedron: Asymmetry 2002, 13,
1449.
(17) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045. (b) Annunziata,
R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo, M. J . Org. Chem. 2001,
66, 3160. (c) Mandoli, A.; Orlandi, S.; Pini, D.; Salvadori, P. Chem.
Commun. 2003, 2466. (d) Diez-Barra, E.; Fraile, J . M.; Garc´ıa, J . I.;
Garc´ıa-Verdugo, E.; Herrer´ıas, C. I.; Luis, S. V.; Mayoral, J . A.;
Sanchez-Verdu, P.; Tolosa, J . Tetrahedron: Asymmetry 2003, 14, 773.
(20) Bayardon, J .; Sinou, D. Tetrahedron Lett. 2003, 44, 1449.
(21) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pozzi,
G. Eur. J . Org. Chem. 2003, 1191.
(22) Sinou, D.; Maillard, D.; Pozzi, G. Eur. J . Org. Chem. 2002, 269.
3122 J . Org. Chem., Vol. 69, No. 9, 2004

Enantiopure Fluorous Bis(oxazolines)
SCHEME 1. Syn th esis of Bis(oxa zolin e) 3a
TABLE 1. P a r tition Coefficien ts for th e F lu or ou s
Bis(oxa zolin es)a
FC72/CH2Cl2
Pb
FC72/CH3CN
bis
(oxazoline)
F content
(wt %)
%
%
Pb
6a
6b
7a
7b
13
52.66
55.75
55.93
58.73
56.94
11.8:88.2 0.14 19.5:80.5
52.3:47.7 1.09 89.9:11.1
29.7:70.3 0.42 85.6:14.4
75.7:24.3 3.11 94.2:5.8
24.4:75.6 0.32 59.4:40.6
0.24
8.01
5.94
16.33
1.46
a
b
a
In a 1:1 mixture of FC72/organic solvent at 25 °C. Partition
Conditions: n-BuLi, THF, -78 °C, then C7F15CH2OSO2C4F9
coefficient P ) cFC72/corganic solvent.
(2), 50 °C.
SCHEME 2. Syn th esis of Bis(oxa zolin es) 6-8a
lines) 4a and 4b were treated with NaH (3 molar equiv
in DMF, 25 °C, 1 h) and then alkylated with 1H,1H,2H,
2H,3H,3H-perfluoroundecyl iodide (5a ) (2.3 molar equiv,
DMF, 80 °C, 16 h) to afford fluorous bis(oxazolines) 6a
and 6b in 46% and 62% isolated yield, respectively
(Scheme 2). Sequential treatment of 4a and 4b, first with
NaH (3 molar equiv in DMF, 25 °C, 1 h) and then with
1H,1H,2H,2H,3H,3H-perfluorotridecyl iodide (5b), af-
forded the fluorous bis(oxazolines) 7a and 7b in 34% and
49% yield, respectively. The nonfluorous bis(oxazoline)
8, analogue of 6b, was obtained in 52% yield from 4b
according to the same procedure and using undecyl
bromide as the alkylating reagent.
Fluorous functionalized enantiopure bis(oxazoline) 13
was prepared following Scheme 3. Protection and reduc-
tion of (S)-serine methyl ester 9 according to the litera-
ture23 afforded the protected amino alcohol (R)-10, which
was readily converted to the silyl protected 2,2′methyl-
enebis[(4-hydroxymethyl)-4,5-dihydro-1,3-oxazole] 11 in
78% yield by condensation with malonimidate ethyl ester
dihydrochloride in CH2Cl2.24 Treatment of bis(oxazoline)
11 with NaH (3 molar equiv in DMF, 25 °C, 1 h) followed
by 1H,1H,2H,2H,3H,3H-perfluoroundecyl iodide (5a ) (2.3
molar equiv, DMF, 80 °C, 16 h) afforded the fluorous
O-silylated bis(oxazoline) 12 in 34% isolated yield. The
dihydroxy fluorous bis(oxazoline) 13 was obtained in 70%
yield by simple deprotection of compound 12 by NBu4F‚
3H2O in THF.
a
Conditions: (i) NaH, DMF, rt, then C8F17(CH2)3I (5a ) for 6,
C
10F21(CH2)3I (5b) for 7, 80 °C; (ii) NaH, DMF, rt, then C11H23Br,
80 °C.
at -78 °C and then with nonaflate 2 (1.2 molar equiv),
or even with MeI (1.2 molar equiv) at 50 °C in THF,
afforded only the unreacted substrate 3.
We assumed that the lack of formation of the bisalky-
lated oxazoline was probably due to the less nucleophilic
character of the carbanion formed by abstraction of the
hydrogen of the substituted methylene bond of oxazoline
3, due to the presence of the fluorous chain bearing one
methylenic spacer only. To circumvent this problem, we
considered the use of an alkylating agent bearing three
methylene units as the spacer. Enantiopure bis(oxazo-
The calculated fluorine contents of some of the fluorous
bis(oxazolines) are summarized in Table 1, together with
the liquid-liquid partition coefficients P between FC72,
CH2Cl2, and CH3CN. Due to the low fluorine content of
ligands 3 and 12 (43.9 and 47.4% fluorine, respectively),
SCHEME 3. Syn th esis of Bis(oxa zolin es) 12 a n d 13a
a
Conditions: (i) ref 23; (ii) EtOC(NH)CH2C(NH)OEt‚2HCl, CH2Cl2; (iii) NaH, DMF, rt, then C8F17(CH2)3I (5a ), 80 °C; (iv) n-Bu4NF‚3H2O,
THF, rt.
J . Org. Chem, Vol. 69, No. 9, 2004 3123

Bayardon and Sinou
TABLE 2. En a n tioselective P a lla d iu m -Ca ta lyzed Allylic Alk yla tion of r a c-14 w ith Bis(oxa zolin es)a
entry
NuH
L
solvent
Pd (mol %)
base
NaH
t (h)
convnb (%)
ee (%) (config)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15a
15b
15c
3
3
THF
5
5
5
5
5
1
1
1
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
114
114
24
40
46
96
136
72
24
8
20
40
24
24
40
24
25
48
24
24
24
18
24
24
90
75
nr
89
93
31
53
45
81
100
98
100
47
100
100
98
99
97
66
100
99
1 (S)
CH2Cl2
CH2Cl2
BTF
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
NaH
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6be
6bf
6bg
7a
7a f
7b
7bf
8
94 (S)
92 (S)
90 (S)
95 (S)
91 (S)
87 (S)
88 (S)
94 (S)
90 (S)
78 (S)
93 (S)
94 (S)
90 (S)
94 (S)
94 (S)
98 (S)
94 (S)
93 (S)
96 (S)
96 (R)
89 (R)
90 (R)
93 (R)
THF
CH2Cl2
BTF
BTFd
BTFd
CH2Cl2
BTF
THF
NaH
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
96
97
100
93
83
12
13
6a
6a
a
b
Substrate (1 equiv), nucleophile (3 equiv), BSA (3 equiv), KOAc (0.1 equiv), or NaH (3 equiv), [Pd(C3H5)Cl]2/ligand L 1:1, 25 °C. The
conversion was determined by GC. c The ee values were determined by HPLC using a chiral column (Chiralpak AD, i-PrOH/n-hexane
d
4:6). The absolute configuration was determined by comparison of the HPLC retention time with literature data. Reaction performed at
50 °C. e [Pd(η3-C3H5)(6b)]PF6 was used as the catalyst. f Ligands separated by liquid-liquid extraction were used in these entries. g Ligand
separated by liquid-solid extraction was used in this entry.
their partition coefficients were not determined. This
table shows clearly for a compound with a given chain
length an increasing partition coefficient by the substitu-
tion of the phenyl group by a isopropyl one, whatever the
organic solvent used: 0.14 vs 1.09 or 0.24 vs 8.01 for
ligands 6a and 6b, respectively, using CH2Cl2 and CH3-
CN as the organic solvent, 0.42 vs 3.11 or 5.94 vs 16.33
for ligands 7a and 7b. More important, the two fluorous
bis(oxazolines) 6b and 7a revealed quite different parti-
tion coefficients (1.09 and 0.42, in the presence of CH2-
Cl2, 8.01 and 5.94 in the presence of CH3CN, respec-
tively), despite their similar fluorine contents; thus, the
presence of a phenyl group seemed to be detrimential for
the solubilization of the ligand in fluorous solvents, the
corresponding bis(oxazolines) showing a higher affinity
for organic solvents. Among the two organic solvents
tested, acetonitrile seemed the most appropriate for
performing organometallic catalysis in a two-phase sys-
tem.
the base (Table 2, entry 1) or no transformation at all in
the presence of BSA and KOAc (Table 2, entry 2). The
use of bis(oxazoline) 6a as the ligand and BSA/KOAc as
the base resulted in high enantioselectivities when the
reaction was performed in CH2Cl2 (94% ee), in BTF (or
benzotrifluoride) (92% ee), and in THF (90% ee) as the
solvent (Table 2, entries 3-5), although the conversion
was sluggish in the later one. Decreasing the amount of
palladium precursor from 5 to 1 mol % gave the alkylated
product 16a with the same enantioselectivities (95% and
91% ee, in CH2Cl2 and BTF, respectively), although the
conversions were lower (53 and 45%) (Table 2, entries
6-7). However, performing the reaction at 50 °C in BTF
in the presence of 1 mol % palladium increased the
conversion to 81%, the obtained enantioselectivity being
87% ee (Table 2, entry 8); it is to be noted that the use of
2 mol % palladium gave a complete conversion after 24
h with an enantioselectivity up to 88% (Table 2, entry
9). The use of NaH as the base gave the alkylated product
16a with enantioselectivities up to 94, 90, and 78% ee,
using CH2Cl2, BTF, and THF as the solvent, respectively
(Table 2, entries 10-12); the observed conversion in THF
was again lower. We also observed that the use of
fluorous ligands 6b, 7a , and 7b in this alkylation reaction
gave quantitatively the expected product 16a with enan-
tioselectivities up to 93, 94, and 94% ee, respectively
(Table 2, entries 13, 17, and 19). A quite similar enan-
These ligands were first assessed in palladium-
catalyzed allylic substitution of rac-(E)-1,3-diphenylpro-
penyl acetate 14 with dimethyl malonate 15a using [(η3-
C3H5)PdCl]2 as the palladium source (eq 1) (Table 2).
Bis(oxazoline) 3 gave very low conversion using NaH as
(23) Novachek, K. A.; Meyers, A. I. Tetrahedron Lett. 1996, 37, 1743.
(24) Hall, J .; Lehn, J . M.; De Cian, A.; Fischer, J . Helv. Chim. Acta
1991, 74, 1.
3124 J . Org. Chem., Vol. 69, No. 9, 2004

Enantiopure Fluorous Bis(oxazolines)
TABLE 3. En a n tioselective Cop p er -Ca ta lyzed Allylic Oxid a tion of Cycloa lk en es 17 w ith Bis(oxa zolin es)a
entry
alkene
metal salt-ligand
solvent
yieldb (%)
ee (%) (S)c
1
2
3
4
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17a
17c
17d
CuOTf‚0.5C6H6 + 6a
CuOTf‚0.5C6H6 + 6a
CuOTf‚0.5C6H6 + 6b
CuOTf‚0.5C6H6 + 6bd
CuOTf‚0.5C6H6 + 6bf
CuOTf‚0.5C6H6 + 6b
CuOTf‚0.5C6H6 + 8g
[Cu(CH3CN)4]PF6 + 6b
[Cu(CH3CN)4]PF6 + 6b
CuOTf‚0.5C6H6 + 7a
CuOTf‚0.5C6H6 + 7b
[Cu(CH3CN)4]PF6 + 7b
[Cu(CH3CN)4]PF6 + 7bd
[Cu(CH3CN)4]PF6 + 7b
CuOTf‚0.5C6H6 + 12
CuOTf‚0.5C6H6 + 13
CuOTf‚0.5C6H6 + 6a
CuOTf‚0.5C6H6 + 6a
CuOTf‚0.5C6H6 + 6a
CHCl3/CH3CN
FC72/CH3CN
CHCl3/CH3CN
CHCl3/CH3CN
CHCl3/CH3CN
FC72/CH3CN
CHCl3/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
CHCl3/CH3CN
CHCl3/CH3CN
FC72/CH3CN
FC72/CH3CN
FC72/CH3CN
51
61
48
51
53
66
64
67
<10
51
48
39
49
<10
37
9
73
69
62
57
37
60
61
61
nd
71
60
60
52
nd
71
nd
77
49
10
4bise
5
6
7
7bish
8
9
10
11
11bish
12
13
14
15
16
86
58
32
a
Alkene (1 equiv), tert-butyl perbenzoate (0.25 equiv), CuOTf‚0.5C6H6 or [Cu(CH3CN)4]PF6 (0.0125 equiv, 5 mol %), ligand (0.02 equiv,
8 mol %), 7 days, 25 °C. Isolated yield. c The ee values were determined by HPLC using a chiral column (Chirapald AD, i-PrOH/n-
b
hexane 1:150). The absolute configuration was determined by comparison of the HPLC retention time with literature data; nd: not
d
determined. Experiment performed at 50 °C for 2 days. e The precipitated catalyst from entry 4 was reused. f Experiment performed at
g
h
50 °C for 3 days. 9 days. Recycling experiment.
tioselectivity (ee 94%) was obtained when preformed [Pd-
(η3-C3H5)(6b)]PF6 was used instead of the catalyst pre-
pared in situ from [Pd(η3-C3H5)Cl]2 and ligand 6b (Table
2, entry14). The obtained values are quite similar to those
published in the literature using nonfluorous bis(oxa-
zolines). Moreover, we performed one experiment using
ligand 8, the nonfluorous analogue of 6b; an enantio-
selectivity of 96% was obtained in this alkylation reaction
in CH2Cl2 (Table 2, entry 21), quite close to the value
(93% ee) previously obtained using the fluorous ligand
6b. The functionalized fluorous ligands 12 and 13 gave
also quite high enantioselectivities using CH2Cl2 as the
solvent; the alkylation product 16a was formed with ee
up to 96 and 80%, respectively (Table 2, entries 22 and
23).
evaporation of the organic solvent by liquid-liquid
extraction using FC72 as the fluorous solvent. In a second
procedure, the ligand was recovered by solid-liquid-
phase extraction by using a short column of fluorous
reversed-phase silica gel. Ligands 6b, 7a , and 7b were
recovered in 76, 68, and 84% yield, respectively, using
the first procedure, while ligand 6b was recovered in 88%
yield using the second one; it is to be noted that the
conditions for this recovery have not been optimized. The
recovered ligands gave NMR spectra identical to those
of fresh samples and, more important, gave enantio-
selectivities very similar to those obtained with a fresh
sample of ligand when they were reused in this palladium
alkylation reaction. The recovered ligands 6b, 7a , and
7b obtained using the first procedure were reused with
a catalyst loading of 5 mol % and gave the alkylated
product 16a with enantioselectivities up to 90, 98, and
93% (Table 2, entries 14, 17, and 19), while the ligand
6b obtained using the second procedure gave ee up to
94% (Table 2, entry 15).
We then turned our attention to the enantioselective
allylic oxidation of cycloalkenes catalyzed by copper
complexes associated with the fluorous bis(oxazolines) (eq
2).12 The reaction was performed at room temperature
for 7 days by forming the copper(I) triflate- or copper-
(I)hexafluorophosphate-bis(oxazoline) complex (5 mol %)
and adding 80 equiv of cycloolefin followed by 20 equiv
of tert-butyl perbenzoate. The results are summarized in
Table 3.
This alkylation reaction was extended to other carbon
nucleophiles using bis(oxazoline) 6a as the chiral ligand
and CH2Cl2 as the solvent. Dimethyl methylmalonate
15b and dimethyl acetamidomalonate 15c gave the
expected alkylated products 16b and 16c in 90 and 93%
ee (Table 2, entries 24 and 25).
We try to recycle the catalyst obtained in situ from [(η3-
C3H5)PdCl]2 and ligands 6a , 7a , and 7b or the well-
characterized complex [Pd(η3-C3H5)(6b )]PF6, using the
two-phase system FC72/CH2Cl2. Unfortunatly all at-
tempts to recycle the fluorous-derivatized metal catalyst
failed, and this could be due to the low partition coef-
ficient of the formed palladium catalyst or eventually to
the desactivation of the catalyst, since formation of black
palladium occurred readily. So we studied the recovery
of the fluorous ligand and its subsequent reuse in
palladium-catalyzed alkylation. In a first procedure, the
ligand was recovered at the end of the reaction after
Oxidation reaction of cyclohexene 17b catalyzed by the
complex CuOTf-ligand 6a afforded (S)-cyclohex-2-enyl
benzoate 18b in 73 and 69% ee when the reaction was
performed using a monophasic system CHCl3/CH3CN or
J . Org. Chem, Vol. 69, No. 9, 2004 3125

Bayardon and Sinou
a biphasic system FC72/CH3CN, respectively (Table 3,
entries 1 and 2). It is to be noted that 59% ee was
obtained in the literature when the reaction was per-
formed in CH3CN in the presence of 2,2-bis[(4S)-4-
phenyl-1,3-oxazolin-2-yl]propane as the ligand.12b Oxi-
dation of 17b at room temperature catalyzed by copper
complex Cu(OTf)-6b gave 18b with ee up 62 and 60%
in CHCl3/CH3CN and FC72/CH3CN, respectively (Table
3, entries 3 and 5), while ee up to 57% was obtained when
the reaction was performed in CHCl3/CH3CN at 50 °C
for 2 days (Table 3, entry 4). The use of the nonfluorous
ligand 8, analogue of 6b, gave ee up to 61% using CHCl3/
CH3CN as the solvent, quite close to the value previously
obtained with the fluorous ligand 6b under the same
conditions (Table 3, entry 6). Changing the catalyst
precursor from CuOTf‚0.5C6H6 to Cu(CH3CN)4PF6 and
using the bis(oxazoline) 6b as the ligand gave almost the
same enantioselectivity (61% in the two-phase system
FC72/CH3CN) (Table 3, entry 7).
Con clu sion
An easy access to enantiopure fluorous bis(oxazolines)
with different fluorine content has been described. These
ligands have been used in two catalytic reactions: the
palladium-allylic substitution of unsaturated acetates
and the copper-catalyzed allylic oxidation of cyclic alk-
enes. The obtained enantioselectivities are as high as
those described in the literature or obtained using non
fluorous analogues: ee up to 98 and 77% for the allylic
substitution and oxidation, respectively. Although the
recycling of the catalyst was unsuccessful, recovery of the
fluorous bis(oxazolines) was possible by liquid-liquid
extraction using a fluorous solvent or by solid-liquid
extraction via a fluorous silica gel. The recovered ligands
could be recycled affording the product in quite similar
yield and enantioselectivity to those obtained in the first
cycle. The development of an efficient recyclable catalyst
for both allylic alkylation and oxidation required ligands
with higher fluorine content, and bis-hydroxy fluorous
bis(oxazoline) 13 seemed a good precursor for this
purpose.
Ligands 7a and 7b, associated with CuOTf or Cu(CH3-
CN)4PF6, in the two-phase system FC72/CH3CN gave
enantioselectivities up to 71 and 60% ee, respectively
(Table 3, entries 8-10). Higher conversion was obtained
when the reaction was performed at 40 °C (49% after 2
days), but a low decrease of the enantioselectivity was
observed (Table 3, entry 11). Finally, the functionalized
ligands 12 and 13 were also used. When the fluorous
silylated bis(oxazoline) 12 gave benzoate 18b in 37% yield
and 71% ee after 7 days, dihydroxy ligand 13 gave a very
low yield (9%) (Table 3, entries 12 and 13).
Exp er im en ta l Section
1,1-Bis[(4S)-4-ter t-bu tyl-1,3-oxa zolin -2-yl]-(1H,2H,2H)-
p er flu or on on a n e (3). To a stirred solution of bis(oxazoline)
1 (300 mg, 1.13 mmol) in dry THF (5 mL) cooled to -78 °C
under nitrogen was added dropwise a 2.5 M solution of n-BuLi
in hexane (0.5 mL, 1.24 mmol). After being stirred for 1 h at
-78 °C, a solution of C7F15CH2OSO2C4F9 (2) (0.92 g, 1.35
mmol) in dry THF (5 mL) was added dropwise, and the
reaction mixture was stirred overnight at 50 °C. The reaction
was quenched by the addition of a saturated aqueous solution
of NH4Cl (10 mL), and the resulting mixture was extracted
with ether (3 × 10 mL). The combined organic phases were
washed with brine (10 mL), dried over Na2SO4, and concen-
trated under vacuum. The residue was purified by chroma-
tography on silica gel, using petroleum ether/ethyl acetate (1:
1, v/v) as the eluent to afford the fluorinated bis(oxazoline) 3
as a pale yellow solid (0.49 g, 67% yield): mp ) 66-68 °C; Rf
The reaction was extended to other cycloalkenes using
the enantiopur catalyst CuOTf‚0.5C6H6-6a . The ef-
ficiency of the oxidation of other cycloalkenes as well as
the enantioselectivity were in quite good agreement with
the results obtained previously under the same conditions
using various 2,2-bis[4-substituted-1,3-oxazolin-2-yl]pro-
panes.12 The highest enantioselectivity and yield were
obtained for cyclopentene 17a (77% ee and 86% yield),
when cycloheptene 17c and cyclooctene 17d gave lower
yields and enantioselectivities (49% ee and 58% yield for
17c, only 10% ee and 32% yield for 17d ) (Table 3, entries
14-16).
The recycling of the catalytic systems Cu(CH3CN)4PF6-
6b and Cu(CH3CN)4PF6-7b, having the highest fluorine
content, was studied using FC72/CH3CN as the two-
phase system. Although the fluorine contents of the
postulated catalytic species CuPF6-6b and CuPF6-7b
were 55.6 and 58.2%, respectively, the recycling of the
catalyst was very disappointing in these cases, less than
10% yield being observed after 7 days reaction (Table 3,
entries 7bis and 11bis). According to the blue color of the
organic solution, it seemed that most of the catalyst was
in the organic phase and not in the fluorous phase. So,
to try to recycle more efficiently the catalyst, cyclohexene
(17b) was oxidized at 50 °C for 2 days in a mixture
CHCl3/CH3CN using CuOTf‚0.5C6H6-6b as the catalyst;
at the end of the reaction, evaporation of the solvents
followed by addition of hexane allowed the precipitation
of the complex and the very easy separation of the allylic
benzoate in 51% yield and 57% ee (Table 3, entry 4). The
precipitaded complex was reused in another reaction
giving the allylic benzoate in 53% yield and 37% ee, after
3 days (Table 3, entry 4bis).
0.58 (petroleum ether/ethyl acetate 1:1); [R]25 +36.8 (c 0.2,
D
1
CHCl3); H NMR (CDCl3) δ 0.88 (s, 18H), 2.96-3.09 (m, 2H),
3.78 (dd, J ) 6.4, 8.6 Hz, 1H), 3.86-3.92 (m, 2H), 4.09-4.14
(m, 2H), 4.20-4.26 (m, 2H); 13C NMR (CDCl3) δ 25.8, 26.0,
27.2 (t, J ) 23.0 Hz), 34.6, 69.1, 70.5, 110.0-120.0, 166.1; 19
F
NMR (CDCl3) δ -126.6 (m, 2F), -124.0 (m, 2F), -123.2 (m,
2F), -122.6 (m, 2F), -122.1 (m, 2F), -114.8 (m, 2F), -81.3 (t,
J
) 10.3 Hz, 3F); HRMS calcd for C23H28F15N2O2 [MH]+
649.1911, found 649.1911.
Gen er a l P r oced u r e for th e Syn th esis of Bis(oxa zo-
lin es) 6-8. To a solution of 2,2′-methylenebis[(4S)-4-phenyl-
2-oxazoline] (4a ) or methylenebis[(4S)-4-isopropyl-2-oxazoline]
(4b) (2 mmol) in anhydrous DMF (20 mL) was added NaH (144
mg, 6 mmol). After the mixture was stirred for 1 h at rt, a
solution of Rf (CH2)3I (5a ,b) or CH3(CH2)10Br (4.6 mmol) in
anhydrous DMF (7 mL) was slowly added. After being stirred
at 80 °C for 16 h, half of the DMF was removed under reduced
pressure, water (20 mL) was added, and the resulting mixture
was extracted with ether (4 × 20 mL). The organic layers were
washed with brine and dried over Na2SO4. Concentration of
the organic solution under reduced pressure followed by
purification of the residue by chromatography on silica gel
afforded the corresponding bis(oxazolines) 6-8.
12,12-Bis[(4S)-4-p h en yl-1,3-oxa zolin -2-yl](9H,9H,10H,-
10H ,11H ,11H ,13H ,13H ,14H ,14H ,15H ,15H )p er flu or ot r i-
cosa n e (6a ): yield 46%; pale yellow solid; mp 68-70 °C; Rf
0.38 (petroleum ether/ethyl acetate 7:1); [R]25 -34.7 (c 0.3,
D
1
C6H5CF3); H NMR (CDCl3) δ 1.61-1.64 (m, 4H), 2.03-2.13
(m, 8H), 4.17 (dd, J ) 8.3, 8.3 Hz, 2H), 4.68 (dd, J ) 8.3, 9.6
3126 J . Org. Chem., Vol. 69, No. 9, 2004

Enantiopure Fluorous Bis(oxazolines)
Hz, 2H), 5.27 (dd, J ) 8.3, 9.6 Hz, 2H), 7.16-7.21 (m, 10H);
13C NMR (CDCl3) δ 15.9, 31.5 (t, J ) 22.3 Hz), 33.3, 46.5, 70.0,
75.6, 127.0, 128.1, 129.1, 142.4, 168.2; 19F NMR (CDCl3) δ
-126.9 (4F), -124.0 (4F), -123.4 (4F), -122.4 (12F), -114.7
2,2-Met h ylen eb is[(4R)-4-[[[ter t-b u t yl(d im et h yl)silyl]-
oxy]m eth yl]-1,3-oxa zolin e] (11). To the amino alcohol (R)-
1023 (0.87 g, 4.23 mmol) dissolved in CH2Cl2 (20 mL) was added
portionwise over 10 min diethyl malonimidate dihydrochloride
(0.49 g, 2.15 mmol). Afetr being stirred at rt for 48 h, the
solution was poured into water (20 mL), and the mixture was
extracted with CH2Cl2 (3 × 20 mL). The organic layers were
washed with brine (20 mL), dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
chromatography on silica gel, using CH2Cl2/CH3OH (9:1, v/v)
as the eluent to afford the bis(oxazoline) 11 as a pale yellow
(4F), -81. 7 (t, J ) 9.2 Hz, 6F). Anal. Calcd for C41H28
34N2O2: C, 40.13; H, 2.28. Found: C, 40.19; H, 2.38.
12,12-Bis[(4S)-4-isop r op yl-1,3-oxa zolin -2-yl](9H ,9H ,-
-
F
10H,10H,11H,11H,13H,13H,14H,14H,15H,15H)p er flu or o-
tr icosa n e (6b): yield 62%; white solid; mp ) 34-36 °C; Rf
0.58 (petroleum ether/ethyl acetate 5:1); [R]25 -25.7 (c 0.18,
D
1
C6H5CF3); H NMR (CDCl3) δ 0.87 (d, J ) 6.6 Hz, 6H), 0.93
oil (0.74 g, 78% yield): Rf 0.78 (CH2Cl2/CH3OH 9:1); [R]25
D
(d, J ) 6.6 Hz, 6H), 1.56-1.60 (m, 4H), 1.75-1.79 (m, 2H),
1
-41.5 (c 0.34, CHCl3); H NMR (CDCl3) δ 0.00 (s, 12H), 0.83
2.01-2.07 (m, 8H), 3.97-4.00 (m, 4H), 4.18-4.26 (m, 2H); 13
C
(s, 18H), 3.27 (s, 2H), 3.49-3.54 (m, 2H), 3.74 (m, 2H), 4.19-
4.30 (m, 6H); 13C NMR (CDCl3) δ -5.0, 18.5, 26.2, 28.7, 64.9,
68.9, 70.9, 163.2. Anal. Calcd for C21H42N2O4Si2: C, 56.98; H,
9.57. Found: C, 56.42; H, 9.52.
NMR (CDCl3) δ 15.7, 18.1, 18.9, 31.5 (t, J ) 21.7 Hz), 32.8,
33.0, 46.1, 70.3, 72.2, 109.0-121.0, 166.6; 19F NMR (CDCl3) δ
-126.7 (m, 4F), -124.0 (m, 4F), -123.3 (m, 4F), -122.5 (m,
12F), -144.7 (m, 4F), -81.4 (t, J ) 9.3 Hz, 6F). Anal. Calcd
for C35H32F34N2O2: C, 36.27; H, 2.76. Found: C, 36.19; H, 2.86.
12,12-Bis[[(4R)-4-[ter t-bu tyl(dim eth yl)silyl]oxy]m eth yl-
1,3-oxa zolin -2-yl](9H,9H,10H,10H,11H,11H,13H,13H,14H,-
14H,15H,15H)p er flu or otr icosa n e (12). This bis(oxazoline)
was obtained from 11 by the general procedure previously
described in 34% yield: white solid; mp 33-35 °C; Rf 0.50
(petroleum ether/ethyl acetate 4:1); [R]25D -14.0 (c 0.2, CHCl3);
1H NMR (CDCl3) δ 0.00 (s, 12H), 0.83 (s, 18H), 1.49-1.53 (m,
4H), 1.98-2.03 (m, 8H), 3.48-3.50 (m, 2H), 3.75-3.78 (m, 2H),
4.17-4.23 (m, 6H); 13C NMR (CDCl3) δ -5.3, 15.5, 18.5, 26.0,
31.3 (t, J ) 21.7 Hz), 33.2, 46.1, 64.5, 68.0, 70.7, 168.1; 19F
NMR (CDCl3) δ -81.7 (t, J ) 10.3 Hz, 6F), -114.8 (m, 4F),
-122.6 (m, 12F), -123.5 (m, 4F), -124.2 (m, 4F), -126.9 (m,
4F). Anal. Calcd for C43H52F34N2O4Si2: C, 37.89; H, 3.82.
Found: C, 37.98; H, 3.89.
12,12-Bis[(4S)-4-(h yd r oxym et h yl)-1,3-oxa zolin -2-yl]-
(9H ,9H ,10H ,10H ,11H ,11H ,13H ,13H ,14H ,14H ,15H ,15H )-
p er flu or otr icosa n e (13). A solution of NBu4F‚3H2O (0.14 g,
0.52 mmol) in THF (3 mL) was added dropwise to a solution
of bis(oxazoline) 12 (0.18 g, 0.13 mmol) in THF (2 mL). The
mixture was stirred at rt for 2 h. After evaporation of the
solvent, the mixture was diluted with diethyl ether (10 mL),
and the solution was washed with water (3 × 10 mL) and dried
over Na2SO4. After evaporation of the solvent under reduced
pressure, the residue was purified by chromatography on silica
gel (CH2Cl2/CH3OH 12:1) to yield the fluorous bis(oxazoline)
14,14-Bis[(4S)-4-p h en yl-4,5;1,3-oxa zolin -2-yl](11H,11H,-
12H,12H,13H,13H,15H,15H,16H,16H,17H,17H)p er flu or o-
h ep ta cosa n e (7a ): yield 34%; white solid; mp 78-80 °C; Rf
0.48 (petroleum ether/ethyl acetate 4:1); [R]25 -25.1 (c 0.2,
D
1
C6H5CF3); H NMR (CDCl3) δ 1.61-1.64 (m, 4H), 2.08-2.14
(m, 8H), 4. 08 (dd, J ) 8.4, 8.4 Hz, 2H), 4.60 (dd, J ) 8. 4, 9.6
Hz, 2H), 5.18 (dd, J ) 8.4, 9.6 Hz, 2H), 7.16-7.27 (m, 10H);
13C NMR (CDCl3) δ 15.8, 31.5 (t, J ) 22.3 Hz), 33.1, 46.4, 70.0,
75.6, 127.0, 128.1, 129.2, 142.3, 168.2; 19F NMR (CDCl3) δ
-126.7 (m, 4F), -123.9 (m, 4F), -123.2 (m, 4F), -122.2 (m,
20F), -114.5 (m, 4F), -81.4 (t, J ) 10.3 Hz, 6F). Anal. Calcd
for C45H28F42N2O2: C, 37.87; H, 1.96. Found: C, 38.15; H, 1.92.
14,14-Bis[(4S)-4-isop r op yl-1,3-oxa zolin -2-yl](11H,11H,
12H,12H,13H,13H,15H,15H,16H,16H,17H,17H)p er flu or o-
h ep ta cosa n e (7b): yield 49%; white solid; mp 74-76 °C; Rf
0.50 (petroleum ether/ethyl acetate 4:1); [R]25 -23.4 (c 0.24,
D
1
C6H5CF3); H NMR (CDCl3) δ 0.86 (d, J ) 6.6 Hz, 6H), 0.93
(d, J ) 6.6 Hz, 6H), 1.55-1.59 (m, 4H), 1.76-1.80 (m, 2H),
2.04-2.07 (m, 8H), 3.97-3.99 (m, 4H), 4.18-4.22 (m, 2H); 13
C
NMR (CDCl3) δ 15.7, 18.1, 18.9, 31.5 (t, J ) 21.7 Hz), 32.8,
46.1, 70.3, 72.2, 110.1-119.0, 166.5; 19F NMR (CDCl3) δ -126.8
(m, 4F), -124.1 (m, 4F), -123.4 (m, 4F), -122.4 (m, 20F),
-114.8 (m, 4F), -81.5 (t, J ) 10.3 Hz, 6F). Anal. Calcd for
C
39H32 F42N2O2: C, 34.46; H, 2.37. Found: C, 34.68; H, 2.34.
13 as a solid (100 mg, 70% yield): white solid; mp 43-45 °C;
1
Rf 0.46 (CH2Cl2/CH3OH 12:1); [R]25 -30.2 (c 0.2, CHCl3); H
12,12-Bis[(4S)-4-isop r op yl-1,3-oxa zolin -2-yl]tr icosa n e
D
(8): yield 52%; colorless oil; Rf 0.58 (petroleum ether/ethyl
NMR (CDCl3) δ 1.64-1.69 (m, 4H), 2.00-2.16 (m, 8H), 3.52-
3.55 (m, 2H), 3.78-3.82 (m, 4H), 4.28-4.40 (m, 6H); 13C NMR
(CDCl3) δ 16.0, 31.3 (t, J ) 21.7 Hz), 33.7, 47.0, 61.1, 67.4,
70.2, 169.8; 19F NMR (CDCl3) δ -81.4 (t, J ) 10.3 Hz, 6F),
-114.6 (m, 4F), -122.4 (m, 12F), -123.2 (m, 4F), -124.0 (m,
4F), -126.7 (m, 4F). Anal. Calcd for C31H24F34N2O4: C, 32.80;
H, 2.12. Found: C, 33.16; H, 2.19.
acetate 1:1); [R]25 -53.8 (c 0.7, CHCl3); 1H NMR (CDCl3) δ
D
0.86 (d, J ) 6.6 Hz, 6H), 0.90 (m, 6H), 0.93 (d, J ) 6.6 Hz,
6H), 1.24-1.29 (m, 36H), 1.77-1.99 (m, 6H), 3.90-3;99 (m 4H),
4.12-4.20 (m, 2H); 13C NMR (CDCl3) δ 14.4, 18.0, 19.0, 23.0,
24.1, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 32.2, 32.6, 32.7, 46.2,
69.7, 72.0, 167.8. Anal. Calcd for C35H66N2O2: C, 76.85; H,
12.17. Found: C, 76.96; H, 12.45.
Deter m in a tion of P a r tition Coefficien ts. The partition
coefficients were determined by dissolving 20 mg of the bis-
(oxazoline) in a biphasic system consisting of FC72 (1 mL) and
the organic solvent (1 mL). The resulting mixture was stirred
at rt for 20 min. The two phases were separated, the solvents
evaporated to dryness, and the residues weighed.
P r ep a r a tion of Com p lex [P d (η3-C3H5)(6b)]P F 6. A solu-
tion of [Pd(η3-C3H5)Cl]2 (60 mg, 165 µmol) and ligand 6b (401
mg, 347 µmol) in CH2Cl2 (9 mL) was stirred at rt under
nitrogen for 1 h and then treated with AgPF6 (90 mg, 360 µmol)
in THF (7 mL). After 15 min, the mixture was filtered through
a pad of Celite, and the filtrate was washed with a saturated
aqueous solution of NaCl and dried over Na2SO4. The solid
obtained after evaporation of the solvent under reduced
pressure was triturated with hexane to afford the complex [Pd-
(η3-C3H5(6b)]PF6 as a pale yellow solid (431 mg, 90% yield):
mp 76-78 °C; [R]25D +13.8 (c 0.24, CHCl3); 1H NMR (CDCl3) δ
0.79 (d, J ) 6.8 Hz, 6H), 0.97 (d, J ) 7.0 Hz, 6H), 1.53-1.56
(m, 4H), 2.07-2.17 (m, 10H), 3.13 (d, J ) 12.1 Hz, 1H), 3.34
(d, J ) 12.8 Hz, 1H), 4.01 (d, J ) 6.0, 1H), 4.07 (d, J ) 6.8 Hz,
1H), 4.35-4.55 (m, 6H), 5.76 (m, 1H); 13C NMR (CDCl3) δ 14.2,
16.6, 18.9, 29.9, 30.2 (t, J ) 23 Hz), 36.9, 49.7, 60.6, 63.1, 69.2,
74.2, 117.4, 170.0; 19F NMR (CDCl3) δ -72.3 (s, 3F), -74.8 (s,
3F), -81.2 (t, J ) 9.3 Hz, 6F), -114.4 (m, 4F), -122.3 (m, 12F),
-123.2 (m, 8F), -126.6 (m, 4F). Anal. Calcd for C38H3F40N2O2-
PPd: C, 31.45; H, 2.57. Found: C, 31.50; H, 2.77.
Gen er a l P r oced u r e for th e Ca ta lytic Allylic Alk yla -
tion . Ligand (31.2 µmol, 6.5 mol %) and [(η3-C3H5)PdCl]2 (4.6
mg, 12.5 µmol, 2.5 mol %) were dissolved in the solvent (1.5
mL) under nitrogen in a Schlenk tube. The reaction mixture
was stirred for 1 h at 50 °C, and 1,3-(E)-diphenyl-2-propenyl
acetate 14 (126 mg, 0.5 mmol) in the solvent (1.5 mL) was
transferred to this Schlenk tube. After 20 min, this solution
was transferred into another reaction vessel containing N,O-
bis(trimethylsilyl)acetamide (305 mg, 1.5 mmol), KOAc (4.9
mg, 0.05 mmol, 10 mol %), and the nucleophile (1.5 mmol) in
the corresponding solvent (2 mL). When NaH was used as the
base, the solution containing the acetate 14 and the catalyst
was transferred into another reaction vessel containing NaH
(36 mg, 1.5 mmol) and the nucleophile (1.5 mmol) in the
solvent (2 mL). The reaction mixture was stirred at the desired
J . Org. Chem, Vol. 69, No. 9, 2004 3127

Bayardon and Sinou
temperature for the appropriate time. The mixture was then
diluted with diethyl ether, and the organic layer was washed
with a saturated aqueous NH4Cl solution and then dried over
Na2SO4. Evaporation of the solvent under reduced pressure
gave a residue that was purified by chromatography on silica
gel to afford the alkylated product 15. The conversion was
determined by GC using a Quadrex OV1 column (30 m × 0.25
mm) and the enantioselectivity by HPLC with a Chiralpak AD
(25 cm × 0.46 cm) and eluting with hexane/i-PrOH (6:4).
Recyclin g. Meth od A: At the end of the reaction, the
solvent was removed under reduced pressure, and the residue
was extracted with FC72 (3 × 2 mL). The fluorous phase was
washed with CH3CN (2 × 2 mL), and the fluorous solvent was
removed under reduced pressure to afford the corresponding
fluorous bis(oxazoline). The alkylated product was purified by
chromatography on silica gel.
perbenzoate (61.3 mg, 0.32 mmol, 20 equiv). The resulting
solution was then stirred at rt for the time indicated in Table
3. The mixture was then diluted with ether (10 mL), and the
organic solution was washed with water (5 mL), HCl 2 N (5
mL), and water (5 mL). The solvent was removed in vacuo to
afford a residue that was purified by column chromatography
on silica gel to give the corresponding allylic benzoate 18. The
ee was determined by HPLC using a Chiralpak AD (25 cm ×
0.46 cm) and eluting with hexane/i-PrOH (150:1)
Recyclin g Usin g a Tw o-P h a se System . After reaction,
the organic phase was separated from the fluorous phase at 0
°C, and a new solution of alkene and tert-butyl perbenzoate
was added.
Recyclin g by P r ecip ita tion . After reaction, the solvent
was evaporated. Hexane (3 × 2 mL) was added and the
catalyst precipitated as a blue-green solid that was recovered
by simple decantation of the supernatant liquid. The catalyst
was reused in another catalytic oxidation without further
addition of copper or ligand. Evaporation of hexane afforded
a residue that was purified by chromatography on silica to give
the allylic benzoate.
Meth od B: At the end of the reaction, the solvent was
removed under reduced pressure, and diethyl ether (2 mL) was
added followed by (1H,1H,2H,2H)perfluorooctyldimethyl bound
silica gel (1 g). Evaporation of the solvent gave a powder that
was charged on
a column of chromatography containing
fluorous silica. Elution was performed successively with CH3-
CN and then FC72. Evaporation of the fluorous phase afforded
the fluorous bis(oxazoline), when evaporation of the organic
phase followed by column chromatography gave the alkylation
product.
Gen er a l P r oced u r e for th e Ca ta lytic Allylic Oxid a tion .
To a stirred solution of CuOTf‚0.5C6H6 (4 mg, 16 µmol, 5 mol
%) or Cu(CH3CN)4PF6 (5.9 mg, 16 µmol, 5 mol %) in the CHCl3
or FC72 (2 mL) was added the bis(oxazoline) (25 µmol, 8 mol
%). This solution was warmed at 50 °C for 1 h. The alkene 17
(1.28 mmol, 80 equiv) in 2 mL of CH3CN was added to the
solution cooled at rt, followed by dropwise addition of tert-butyl
Ack n ow led gm en t. J .B. thanks the French Minis-
tery of Education for a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Preparation of fluo-
1
rous iodide 5b and H, 13C, and 19F NMR spectra of compounds
3, 6a ,b, 7a ,b, 8, 12, 13, and [Pd(η3-C3H5)(6b)]PF6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O049853Q
3128 J . Org. Chem., Vol. 69, No. 9, 2004