Fluorous phase-switching of pyridyl-tagged substrates/products

Article abstract of DOI:10.1021/ol048994b

A bis-monopyridyl Wang-type tag was prepared for application in the hydrocarbon/perfluorocarbon phase-switching of substrates/products. This "catch-and-release" strategy relies on the reversible coordination of the tag to a fluorous copper(II)-carboxylate

Full text of DOI:10.1021/ol048994b

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2765-2767
Fluorous Phase-Switching of
Pyridyl-Tagged Substrates/Products
Mounir El Bakkari and Jean-Marc Vincent*
Laboratoire de Chimie Organique et Organome´tallique (UMR-CNRS 5802),
UniVersite´ Bordeaux 1, 351 cours de la Libe´ration, 33405 Talence Cedex, France
jm.Vincent@lcoo.u-bordeaux1.fr
Received June 1, 2004
ABSTRACT
A bis-monopyridyl Wang-type tag was prepared for application in the hydrocarbon/perfluorocarbon phase-switching of substrates/products.
This “catch-and-release” strategy relies on the reversible coordination of the tag to a fluorous copper(II)−carboxylate complex. A hydantoin
was prepared in high yield and purity by a four-step protocol where the intermediates were purified by the straightforward liquid/liquid phase-
switching process.
The search for rapid and efficient protocols for the purifica-
tion of organic compounds is a major concern of modern
chemistry.1 Homogeneous “molecular approaches” have been
developed in which the phase separation is driven by a small
functional group called a phase tag.2 Among the various tags
developed to favor aqueous-phase extraction, the dimethyl-
(2-pyridyl)silyl tag developed by Yoshida and co-workers
is the prototypical example of a masked phase tag, which
allows products to be switched between organic solvents and
aqueous solution.2,3 Pyridine-containing ligands were also
used as masked phase tags for substrates.4 In that case, a
resin functionalized with iminodiacetic groups and loaded
with copper(II) ions was employed as a solid support to trap
substrates/products linked to a 4,4′-bis(hydroxymethyl)-2,2′-
bipyridine tag.
In a previous report we described an unprecedented
example of hydrocarbon/perfluorocarbon phase-switching of
pyridyl-tagged porphyrin and C60 fullerene.5 This “catch-
and-release” approach took advantage of both pyridyl and
fluorous tags, the latter being widely used in phase separation
(5) El Bakkari, M.; McClenaghan, N.; Vincent, J.-M. J. Am. Chem. Soc.
2002, 124, 12942-12943.
(6) Selected examples: (a) Zhang, W.; Lu, Y. Org. Lett. 2003, 5, 2555-
2558. (b) Manzoni, L. Chem. Commun. 2003, 2930-2931. (c) Chen, C.
H.-T.; Zhang, W. Org. Lett. 2003, 5, 1015-1017. (d) Zhang, W.; Luo, Z.;
Chen, C. H.-T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450.
(e) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004,
126, 36. (f) Luo, Z. Y.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science
2001, 291, 1766-1769. (g) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-
Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823-826. (h)
Curran, D. P.; Ferrito, R.; Hua, Y. Tetrahedron Lett. 1998, 39, 4937-4940.
(c) Ro¨ver, S.; Wipf, P. Tetrahedron Lett. 1999, 40, 5667-5670. (i) Wipf,
P.; Reeves, J. T. Tetrahedron Lett. 1999, 40, 5139-5142. (j) Wipf, P.;
Reeves, J. T. Tetrahedron Lett. 1999, 40, 4649-4652. (k) Wipf, P.; Reeves,
J. T.; Balachandran R.; Giuliano, K. A.; Hamel, E.; Day, B. W. J. Am.
(1) Reviews: (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174-
1196. (b) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel,
A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964-4000. (c) Curran, D.
P. Synlett 2001, 1488-1496. (d) Zhang, W. Chem. ReV. 2004, 104, 2531-
2556.
(2) Yoshida, J.-I.; Itami, K. Chem. ReV. 2002, 102, 3693-3716.
(3) Reviews: Yoshida, J.-I.; Itami, K. J. Synth. Org. Chem. Jpn. 2001,
59, 1086-1094. (b) Itami, K.; Mitsudo, K.; Nokami, T.; Kamei, T.; Koike,
T.; Yoshida, J.-I. J. Organomet. Chem. 2002, 653, 105-113.
(4) Ley, V. L.; Massi, A.; Rodriguez, F.; Horwell, D. C.; Lewthwaite,
R. A.; Pritchard, M. C.; Reid, A. M. Angew. Chem., Int. Ed. 2001, 40,
1053-1055.
10.1021/ol048994b CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/14/2004

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.
2766
Org. Lett., Vol. 6, No. 16, 2004

yield and >95% purity (Figure 5). As noticed for 4, a
significant broadening of the proton resonances of the
pyridines was observed. The urea derivative 6 was then
treated with triethylamine in dichloromethane to produce an
equimolar mixture of the bis-monopyridyl tag 3 and the
expected hydantoin 7. Removal of the tag was achieved by
addition of the perfluorodecalin solution of 1 recovered from
the previous step. After phase separation and solvent
evaporation followed by washings of the solid residue with
pentane, the hydantoin 7 was isolated in 86% yield and purity
higher than 95%. The overall yield for the four-step reaction
sequence was 81%.
Scheme 3. Synthesis of Hydantoin 7
From the results presented above, a set of attractive
features emerged that should favor the development of the
fluorous phase-switching approach to other synthetic ap-
plications: (1) Only two pyridyl groups separated by a rigid
spacer was sufficient to ensure a very efficient extraction of
rather large and polar molecules into the fluorous phase. (2)
By the use of a masked phase tag, reactions were carried
out in usual organic solvents. There was no requirement for
mixed organic/fluorinated solvent mixture for a reaction to
proceed,6m-o not for limitation, as could be the case when
using solid-supports, to solvents that will favor the swelling
of the beads (such as DMF).4 (3) The advancement of
reactions and the phase-switching procedures may be moni-
tored by thin-layer chromatography and/or UV-visible
spectroscopy. (4) Both the extraction and release process
were shown to occur effectively and rapidly using a small
excess of complex 1 with respect to the tag compounds. (5)
The purified product was recovered in an organic solvent,
not in a perfluorocarbon as it could be the case when
employing fluorous tags; moreover, it has been demonstrated
that the perfluorocarbon-complex 1 couple can be recovered
almost quantitatively in an active form making this approach
“fluorous low consuming”.
coordination bonds with the monodentate pyridyl groups.
Notice that the leaching represents a very small amount of
copper, as titration of 1 in the fluorous phase monitored by
UV-visible spectroscopy after release of 4 revealed no
detectable loss. The fluorous phase was reactivated by
washing with chloroform to remove the excess THF solu-
bilized in the perfluorodecalin and was then reused in the
next steps with the same efficiency. This clearly demonstrates
the high recovery of complex 1 in an active form for further
pyridyl tag activation. The tris-TFA salt of 5 was obtained
quantitatively by treatment of 4 with TFA in dichloromethane
and removal of the excess reagent and solvent under reduced
pressure. Addition of 4-isopropylphenyl isocyanate (1.1
equiv) to a THF solution of 5 and Et3N (3 equiv) led to the
rapid formation of 6. After evaporation of the THF and
redissolution of the residue in chloroform, the urea derivative
6 was extracted using the copper-fluorous phase recovered
from the first step. After washing the fluorous phase, addition
of THF (400 equiv), 6 was released into chloroform in 96%
Acknowledgment. Financial support from the CNRS, la
Re´gion Aquitaine, and the French Ministry of Research (ACI
Jeunes Chercheurs) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds and 1H
NMR spectra for compounds 4, 6, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048994B
Org. Lett., Vol. 6, No. 16, 2004
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