procedures for substrates.6 Pyridyl tag activation was realized
by pyridine coordination to the “heavy” fluorous copper-
(II)-carboxylate complex 1 (Scheme 1). Due to the high
The alcohol 2, obtained in 93% yield by reduction with
sodium borohydride, was subjected to Sonogashira coupling
conditions, affording the desired pyridyl-tagged benzyl
alcohol in 81% yield.
The efficiency of the hydrocarbon/perfluorocarbon phase-
switching of 3 was then evaluated accurately by UV-visible
spectroscopy. Aliquots of complex 1 (from 0.50 to 1.50 equiv
with respect to 3 in solution in perfluorodecalin) were added
successively to a chloroform solution of 3 (12.4 mM). Upon
stirring of the biphasic system, the extraction of 3 was
followed by the disappearance in the chloroform phase of
its characteristic 286 nm absorption band (ꢀ286 ) 49 300 M-1
cm-1). It was found that only 1.1 equiv of complex 1 was
necessary to quantitatively extract 3 into the fluorous phase.
Quantitative recovery of the tag into the chloroform was
achieved under stirring of the biphasic system, by adding
∼200 equiv of THF with respect to 3. This demonstrates
the high efficiency of the phase-switching procedure using
such a bis-monopyridyl tag.
Scheme 1
lability of monopyridyl ligands, porphyrin release was carried
out by simply adding THF in excess to the biphasic system,
a competitive pyridine ligand for copper. As previously
described, the use of THF as an unmasking agent allowed
recycling of the copper(II)-fluorous phase for subsequent
catch-and-release experiments with the same efficiency.5
On the basis of our previous results, we assumed that a
bis-monopyridyl benzyl alcohol Wang-type tag such as 3
could be used in association with a perfluorocarbon solution
of 1 for the separation and recovery of substrates/products
(Scheme 2). Acethylenic groups were introduced as rigid
The preparation of hydantoin 7 was chosen to evaluate
the efficiency of the fluorous phase-switching procedure for
synthetic application.6a,7 It also gave the opportunity to
compare the fluorous homogeneous approach to the previ-
ously reported nonfluorous homogeneous/heterogeneous
method.4 A limitation of the latter system is associated to
the release of the strongly coordinating bipyridine-linker-
product moiety from the support. This was achieved by
shaking the suspension of the beads for 8 h in the presence
of TMEDA ligand (N,N,N′,N′-tetramethylethylenediamine).
Moreover, the problem of the recovery of the copper-
carboxylate resin was not addressed. The hydantoin 7 was
prepared by the four-step procedure described in Scheme 3.
In the first step, the bis-monopyridyl Wang type tag 3 was
acylated in chloroform using a classic amide coupling
procedure. After removal of the poorly soluble dicyclohexyl-
urea (DCU) byproduct by filtration, compound 4 was
extracted quantitatively in a few minutes into the perfluo-
rodecalin phase containing 2.5 equiv of complex 1 with
respect to 3 under stirring of the biphasic system. After
decantation (∼30 min), removal of the organic layer, and
washing the fluorous phase (three times with chloroform),
compound 4 was released almost instantaneously into
chloroform by addition of THF (400 equiv with respect to
1). Both the uptake and release of 4 could be easily monitored
by thin-layer chromatography or UV-visible spectroscopy.
Evaporation of the chloroform/THF mixture afforded 4 in
Scheme 2. Synthesis of Bis-monopyridyl Benzyl Alcohol Tag
3
spacers between the pyridines to ensure minimum steric
hindrance upon coordination of 3 with two bulky copper(II)
complexes. The moderate reactivity of the acetylenic bonds
toward a rather wide range of reaction conditions and the
facile formation of ethylenic-aromatic carbon-carbon bonds
appeared as additional attractive features. The bis-mono-
pyridyl benzyl alcohol tag 3 was prepared by a two-step
procedure in 75% overall yield from commercially available
3,5-dibromobenzaldehyde and 3-ethynylpyridine (Scheme 2).
1
98% yield and >95% purity, as evidenced by its H NMR
spectrum (see Supporting Information). A significant broad-
ening of the ortho and para protons of the pyridine ring was
1
noticed on the H NMR spectrum of 4. This was attributed
to the leaching in the chloroform phase of traces of
paramagnetic copper(II) ions that should form highly labile
(7) Examples of hydantoin synthesis on solid-support: (a) Soza, A. C.
B.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 2002, 67, 4498-4500. (b)
Park, K.-H.; Kurt, M. J. Tetrahedron Lett. 2000, 41, 7409-7413. (c)
Matthews, J.; Rivero, A. J. Org. Chem. 1997, 62, 6090-6092. (d) Charton,
J.; Delarue, S.; Vendeville, S.; Debreu-Fontaine, M.-A.; Girault-Mizzi, S.;
Sergheraert, C. Tetrahedron Lett. 2001, 42, 7559-7561. (e) DeWitt, S. H.;
Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M.
R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6909-6913.
Chem. Soc. 2000, 122, 9391-9395. (l) Miura, T.; Hirose, Y.; Ohmae, M.;
Inazu, T. Org. Lett. 2001, 3, 3947-3950. (m) Miura, T.; Inazu, T.
Tetrahedron Lett. 2003, 44, 1819-1821. (n) Miura, T.; Goto, K.; Hosaka,
D.; Inazu, T. Angew. Chem., Int. Ed. 2003, 42, 2047-2051. (o) Mizuno,
M.; Goto, K.; Miura, T.; Hosaka, D.; Inazu, T. Chem. Commun. 2003, 972-
973.
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