Dialyzable carbosilane dendrimers as soluble supports for the functionalization of pyridine fragments via palladium-catalyzed coupling reactions

Article abstract of DOI:10.1021/ol0480776

(Chemical Equation Presented) The use of carbosilane (CS) dendrimers as soluble supports in liquid phase organic synthesis (LPOS) is described. Control of the three key steps is perfectly achieved by covalently binding a pyridine fragment to the soluble s

Full text of DOI:10.1021/ol0480776

ORGANIC
LETTERS
2
005
Vol. 7, No. 3
63-366
Dialyzable Carbosilane Dendrimers as
Soluble Supports for the
3
Functionalization of Pyridine Fragments
via Palladium-Catalyzed Coupling
Reactions
†
†
‡
‡
J e´ r oˆ me Le N oˆ tre, Judith J. Firet, Leo A. J. M. Sliedregt, Bart J. van Steen,
†
,†
Gerard van Koten, and Robertus J. M. Klein Gebbink*
Debye Institute, Department of Metal-Mediated Synthesis and Homogeneous Catalysis,
Utrecht UniVersity, Padualaan 8, 3584 CH Utrecht, The Netherlands, and
SolVay Pharmaceuticals B.V., Chemical Design and Synthesis Unit,
C.J. Van Houtenlaan 36, 1381 CP Weesp, The Netherlands
r.j.m.kleingebbink@chem.uu.nl
Received September 21, 2004
ABSTRACT
The use of carbosilane (CS) dendrimers as soluble supports in liquid phase organic synthesis (LPOS) is described. Control of the three key
steps is perfectly achieved by covalently binding a pyridine fragment to the soluble support, modifying it via coupling reactions, and releasing
it at the end. Nanofiltration (dialysis) allows facile purification of the supported molecules after each step.
Among the many applications of solid-phase chemistry, the
use of insoluble resins as supports for substrate modification
has become a powerful tool in organic syntheses, especially
within a pharmaceutical setting and using high throughput
by filtration and washings. Some limitations exist, however,
to the use of insoluble resins in solid-phase organic chemistry
(SPOS). Some supports can present total incompatibility with
certain reagents, such as polystyrene beads with strongly
1
2
experimentation. Advantages of this methodology include
basic reagents. Monitoring of reaction progress in these
the high conversions obtained by the use of large reagent
excesses and the easy purification of the supported products
heterogeneous systems using standard spectroscopic tech-
niques can furthermore be cumbersome.
As an alternative, soluble supports have recently been used
in so-called liquid-phase organic synthesis (LPOS). Linear
polymeric materials such as poly(ethylene glycol) (PEG)
†
Utrecht University.
Solvay Pharmaceuticals B.V.
3
‡
(
1) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154. (b)
Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555-600. Ellman,
J. A. Acc. Chem. Res. 1996, 29, 132-143. (c) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
(2) (a) Farrall, M. J.; Fr e´ chet, J. M. J. J. Org. Chem. 1976, 41, 3877-
3882. (b) Fyles, T. M.; Leznoff, C. C. Can. J. Chem. 1976, 54, 935-942.
(c) Yus, M.; Gomez, C.; Candela, P. Tetrahedron 2003, 59, 1909-1916.
(d) Gros, P.; Louerat, F.; Fort, Y. Org. Lett. 2002, 4, 1759-1761.
2
6
9, 123-131. (d) Krchnack, V.; Holladay, M. W. Chem. ReV. 2002, 102,
1-91.
1
0.1021/ol0480776 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/07/2005

4
have first been developed. Due to the low loading capacity
They, furthermore, represent a model substrate for the study
of selective activation of C-H bonds in the presence of
halogen-carbon bonds via lithiation chemistry. This regio-
and chemoselective lithiation step constitutes the key step
of these polymers, hyperbranched polymers and dendrimers
appear to be more suitable supports.5
In relation to our interest in applications of functionalized
dendrimers as homogeneous catalysts, we recently showed
6
12
of substrate attachment to the dendritic support. As a test
that soluble carbosilane (CS) dendrimers are suitable supports
to allow classical organic reactions at their periphery.
substrate, a substituted pyridine, such as 3-bromopyridine
1, was chosen in which the presence of the 3-Br-C bond
allowed the introduction of an organic fragment on the
supported pyridine; see Scheme 1.
7
Among the variety of dendritic backbones, CS dendrimers
present several advantages such as high thermal stability,
high inertness toward organic reagents, good accessibility,
good solubility in classical organic solvents, and a size that
8
Scheme 1a
makes these supports separable via nanofiltration.
To further explore the scope and the multipurpose aspects
of this type of support, we present here the multistep
modification of pyridine derivatives via palladium-catalyzed
coupling reactions at the periphery of a soluble carbosilane
dendritic support. We have used a simple process based on
1
a
three key steps, including (1) attachment of the organic
fragment to the support, without linker, via a covalent bond;
(
(
2) modification of this fragment by coupling reactions; and
3) release of the target molecule from the support by a
simple and clean procedure. To complete the overall
methodology, the effective nanosize of the dendritic scaf-
folding allows the facile purification of the synthesized,
supported intermediates by means of dialysis.
Pyridine structures have been selected because these are
known to belong to numerous natural product skeletons and
9
pharmacophores, such as (-)-nicotine derivatives. Substi-
tuted pyridines are also used as ligands in organometallic
a
(a) LDA/THF/-100 °C; (b) TMSCl; (c) Pd(PPh ) (1 mol %),
3
4
and coordination chemistry,10 and for the study of cross-
6 4 2 2 3
p-MeC H B(OH) , Na CO (2 M), toluene/EtOH (5/1), 100 °C, 16
h; (d) Pd(OAc) (2.5 mol %), PPh (5 mol %), ethyl acrylate, Et N,
DMF, 130 °C, 16 h; (e) PdCl
1
1
coupling reactions in classical solution-phase chemistry.
2
3
3
2
(PPh
)
3 2
(5 mol %), PPh
3
(10 mol
%
), CuI (10 mol %), phenylacetylene, Et
3
N, THF, 70 °C, 16 h; (f)
(
3) Wentworth, P., Jr.; Vandersteen, A. M.; Janda, K. D. Chem. Commun.
997, 759-760.
4) (a) Geckeler, K.; Pillai, V. N. R.; Mutter, M. AdV. Polym. Sci. 1981,
9, 65-94. (b) van de Kuil, L. A.; Grove, D. M.; Zwikker, J. W.;
n-Bu NF, THF, rt, 16 h.
4
1
(
3
Jenneskens, W.; Drenth, W.; van Koten, G. Chem. Mater. 1994, 6, 1676-
683. (c) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-509.
5) (a) Tomalia, D. A. Aldrichimica Acta 2004, 37 (2), 39-57. (b)
As a simplified model system, a trimethylsilyl (TMS)
group was used as a mimic of the dendritic support. Selective
additions of electrophiles via lithiation of bromopyridines
are well-known, and controlled ortho- and para-lithiation of
1
(
Dendrimers and Other Dendritic Polymers; Tomalia, D. A., Fr e´ chet, J. M.
J., Eds.; J. Wiley & sons Ltd.: West Sussex, 2001. (c) Fr e´ chet, J. M. J.
Science 1994, 263, 1710-1714. (d) Kim, R. M.; Manna, M.; Hutchins, S.
M.; Griffin, P. R.; Yates, N. A.; Bernick, A. M.; Chapman, K. T. Proc.
Natl. Acad. Sci. U.S.A. 1996, 93, 10012-10017. (e) Klein Gebbink, R. J.
M.; Kruithof, C. A.; van Klink, G. P. M.; van Koten, G. ReV. Mol.
Biotechnol. 2002, 90, 183-193.
12b,12c
3-bromopyridine has been reported.
Para-lithiation using
LDA at low temperature (-100 °C) in tetrahydrofuran and
subsequent quenching with TMSCl afforded the correspond-
ing 3-bromo-4-trimethylsilylpyridine 2 in 53% yield, based
on the pyridine starting material. Because the TMS group is
used as a mimic of the dendritic support it should in
consequence be considered as the determining factor of the
reaction. Thus, an excess of the lithiated pyridine (2 equiv)
was employed which improved the yield to 91%, based on
the starting TMSCl.
(6) (a) Hovestad, N. J.; Eggeling, E. B.; Heidb u¨ chel, H. J.; Jastrzebski,
J. T. B. H.; Kragl, U.; Kleim, W.; Vogt, D.; van Koten, G. Angew. Chem.,
Int. Ed. 1999, 38, 1655-1658. (b) Knapen, J. W. J.; van der Made, A. W.;
de Wilde, J. C.; van Leeuwen, P. W. N. W.; Wijkens, P.; Grove, D. M.;
van Koten, G. Nature 1994, 372, 659-663. (c) Kleij, A. W.; Gossage, R.
A.; Klein Gebbink, R. J. M.; Brinkmann, N.; Reijerse, E. J.; Kragl, U.;
Lutz, M.; Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 2000, 122, 12112-
1
2124.
7) (a) Wijkens, P.; Jastrzebski, J. T. B. H.; van der Schaaf, P. A.; Kolly,
(
R.; Hafner, A.; van Koten, G. Org. Lett. 2000, 2, 1621-1624. (b) Hovestad,
N. J.; Ford, A.; Jastrzebski, J. T. B. H.; van Koten, G. J. Org. Chem. 2000,
6
5, 6338-6344. (c) Hovestad, N. J.; Jastrzebski, J. T. B. H.; van Koten, G.
Polym. Mater. Sci. Eng. 1999, 80, 53-54.
8) (a) Mulder, M. Basic Principles of Membrane Technology; Kluwer:
(10) (a) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.;
von Zelewsky, A. Coord. Chem. ReV. 1988, 84, 85-277. (b) Kaes, C.;
Katz, M.; Hosseini, M. W. Chem. ReV. 2000, 100, 3553-3590.
(11) (a) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208. (b) Unrau, C. M.; Campbell, M. G.; Snieckus, V. Tetrahedron Lett.
1992, 33, 2773-2276. (c) Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy,
P. R.; Rault, S. Tetrahedron 2002, 58, 2885-2890.
(12) (a) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137-4140. (b) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35,
151-169. (c) Comins, D. L.; Myoung, Y. C. J. Org. Chem. 1990, 55, 292-
298. (d) Choppin, S.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2001, 603-
606. (e) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 3375-3383.
(
Dordrecht, The Netherlands, 1996. (b) Dijkstra, H. P.; van Klink, G. P.
M.; van Koten, G. Acc. Chem. Res. 2002, 35, 798-810. (c) Haag, R. Chem.
Eur. J. 2001, 7, 327-335. (d) Vankelecom, I. F. J. Chem. ReV. 2002, 102,
3
779-3810.
(9) (a) Swango, J. H.; Quershi, M. M.; Crooks, P. A. Pharm. Res. 1997,
1
4, 695-699. (b) Baxendale, I. R.; Brusoti, G.; Matsuoka, M.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 2002, 143-154. (c) Felpin, F.; Girard, S.;
Vo-Thang, G.; Robins, R. J.; Villieras, J.; Lebreton, J. J. Org. Chem. 2001,
6
6, 6305-6312.
364
Org. Lett., Vol. 7, No. 3, 2005

Palladium-catalyzed coupling reactions were then tested
on the silylated bromopyridine 2 using standard procedures.
A Suzuki coupling reaction was first tested and after 16 h
in refluxing THF a complete conversion into the 3-p-tolyl-
unreacted Si-Cl groups were converted into unreactive Si-
OMe functions by a quench reaction with dry methanol and
dry triethylamine. Compound 12, obtained from a preliminary
experiment, showed approximately 80% of substitution, i.e.
10 of the 12 chlorosilane functions had reacted with lithio-
bromopyridine and two of them had not. Following experi-
ments presented higher levels of substitution (>95%) by
allowing the temperature to reach 0 °C before the addition
of methanol and triethylamine (see compound 13, Scheme
2).
The supported 3-bromopyridines were then used in the
different palladium-catalyzed cross-coupling reactions. Con-
0
cerning the G -dendrimer 11, complete conversions to the
coupling compounds were observed, and in the case of the
Suzuki coupling reaction, the corresponding modified den-
drimer 14 was isolated after chromatography in 91% yield
(Scheme 3).
4-trimethylsilylpyridine 3 was observed (isolated yield 85%);
see Scheme 1. This result shows that the mutual ortho-
positioning of the TMS and bromide groups on the pyridine
ring does not affect reaction at the C-Br bond and also that
desilylation, which would cause unwanted release of the
organic fragment from the dendritic support, does not take
place. In a similar way, a Heck coupling reaction was
successfully tested using ethyl acrylate. After an overnight
heating at 130 °C, the 3-(4-trimethylsilylpyridin-3-yl)acrylic
acid ethyl ester 4 was obtained in 85% yield. A Sonogashira
coupling reaction afforded the formation of 3-phenylethynyl-
4
-trimethyl-silylpyridine 5 in high yield without any desi-
lylation.
Classical desilylation conditions were then employed using
tetrabutylammonium fluoride to “release” the modified
pyridine fragment from the TMS group.13 Desilylated
compounds 6, 7, and 8 from the corresponding palladium-
catalyzed coupling reaction products were obtained in 94%,
a
Scheme 3
91%, and 93% yield, respectively, by purification using a
simple filtration through a plug of silica. Using a TMS group
as a mimic of the carbosilane dendrimer established the
synthetic principle of our methodology and showed that the
presence of the silicon substituent does not interfere with
the modification of the other positions at the pyridine ring.
a
(a) Pd(PPh
3
)
4
(4 × 1 mol %), p-MeC
6 4
H
B(OH)
2 2 3
, Na CO (2
M), toluene/EtOH (5/1), 100 °C, 16 h; (b) n-Bu
4
NF, THF, rt, 16 h.
Our strategy was then applied to the G
dendrimers 9 and 10 that carry, respectively, 4 and 12
peripheral chlorosilane groups. For the G -dendrimer 9 the
0 1
and G carbosilane
0
1
With the G -dendrimers, compound 12 presenting 10
linkage procedure using 2 equiv of lithiated pyridine per Si-
Cl moiety afforded a complete conversion into the fully
substituted dendrimer 11, which was readily purified by
column chromatography on silica using ethyl acetate as
eluent (61% yield), see Scheme 2.
bromopyridines moieties at its periphery was first employed
in a Suzuki coupling reaction using 1 mol % of palladium
catalyst per bromine atom. A complete conversion was
observed, which indicates that both the supported nature of
one of the cross-coupling partners as well as the presence
of Si-OMe moieties did not interfere with the catalytic
1
reaction. The G -dendrimer 13 bearing 12 3-bromopyridines
was then successfully used in different cross-coupling
reaction procedures (Scheme 4).
Scheme 2a
1
In all of the steps dealing with the G -dendrimer as
support, the crude reactions were purified using passive
8
dialysis over commercially available dialysis tubing (re-
cycled benzoylated cellulose) with a cutoff mass of 1200
g/mol (MW of 13, 3395.5 g/mol).
Passive dialysis purification of the crude mixture of the
linkage procedure afforded the compounds 12 and 13 in 74%
and 77% yield, respectively. Without any refreshment of the
solvent, compounds 12 and 13 were obtained in high purity
to allow subsequent cross-coupling reactions (see Supporting
Information for experimental details). The crude mixtures
of the cross-coupling reactions were again treated by passive
dialysis and the supported compounds 15, 16 and 17 were
isolated in 77%, 80%, and 70% yield, respectively.
a
(
a) LDA/THF/-100 °C; (b) dendrimer G
0
-Cl 9; (c) dendrimer
N/MeOH, rt.
G
1
-Cl 10, -100 to 0 °C; (d) Et
3
Similarly, using 2 equiv of lithiated bromopyridine 1, a
high level of substitution on the G -dendrimer was reached
according to H, C, and Si NMR analyses. The eventually
(13) (a) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61,
6
1
498-6499. (b) Fensterbank, L.; Malacria, M.; Sieburth, S. McN. Synthesis
1
997, 817-854. (c) Kumada, M.; Tamao, K.; Yoshida, J. J. Organomet.
1
13
29
Chem. 1982, 239, 115-132.
Org. Lett., Vol. 7, No. 3, 2005
365

Scheme 4a
Scheme 5
a
(
a) Pd(PPh
3
)
4
(12 × 1 mol %), p-MeC
6
H
4
B(OH)
2
, Na
(12 × 2.5
N, DMF, 130 °C,
(12 × 10 mol %),
N, THF, 70 °C, 16 h.
2 3
CO (2
(
G
1
) allow easy control of the efficiency of reactions on
M), toluene/EtOH (5/1), 100 °C, 16 h; (b) Pd(OAc)
2
supported fragments and, furthermore, allow the purification
of (modified) fragments via filtration techniques (dialysis).
mol %), PPh
6 h; (c) PdCl
CuI (12 × 10 mol %), phenylacetylene, Et
3
(12 × 5 mol %), ethyl acrylate, Et
3
1
2
(PPh
3
)
2
(12 × 5 mol %), PPh
3
3
Studies on the use of this type of soluble synthesis support
for other classical organic reactions and for the total synthesis
of natural products and analogues are currently under
investigation, as is the potential to recycle the support.
The release reaction of the modified pyridine fragments
was performed using tetrabutylammonium fluoride solution
at room temperature. From the supported Suzuki coupling
0
compound 11 on the G -dendrimer, an overnight reaction
afforded the desilylated substituted pyridine 6 in 87% yield
after filtration over a short plug of silica (Scheme 3). Similar
1
release reactions of cross-coupling compounds from G -
Acknowledgment. This work was sponsored by the
Council for Chemical Sciences of The Netherlands Organi-
zation for Scientific Research (CW-NWO) program on
Combinatorial Chemistry (J.L.N.) and by The Netherlands
Research School Combination-Catalysis (R.J.M.K.G.).
dendrimer support were performed with complete conversion.
The desilylated coupling compounds 6, 7, and 8 were
separated from the degraded dendritic fragments by means
of chromatography and were isolated in 90%, 85%, and 81%
yield, respectively (Scheme 5).
By controlling the three steps of our dendrimer-supported
pyridine model system, we have shown that carbosilane
dendrimers are suitable and robust supports for LPOS which
are compatible with organolithium and Grignard (ref 7a)
reagents. In addition, relatively small generation dendrimers
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0480776
366
Org. Lett., Vol. 7, No. 3, 2005