Palladium cross-coupling reactions on solid support using a new silylated linker

Article abstract of DOI:10.1016/S0022-328X(01)01400-0

The synthesis and the use in palladium cross-coupling reactions of a new silylated stable resin were described. The products have been cleaved from the support using mild conditions and purified with a scavenger ionic resin. A small library of coupling pr

Full text of DOI:10.1016/S0022-328X(01)01400-0

Journal of Organometallic Chemistry 643–644 (2002) 512–515
www.elsevier.com/locate/jorganchem
Note
Palladium cross-coupling reactions on solid support using a new
silylated linker
Romain Duboc, Monique Savignac *, Jean-Pierre Geneˆt *
Laboratoire de Synthe`se Se´lecti6e et Produits Naturels, UMR 7573, Ecole Nationale Supe´rieure de Paris, 11, rue Pierre et Marie Curie, 75231
Paris Cedex, France
Received 18 July 2001; accepted 9 November 2001
Dedicated to Professor F. Mathey on the occasion of his 60th birthday
Abstract
The synthesis and the use in palladium cross-coupling reactions of a new silylated stable resin were described. The products
have been cleaved from the support using mild conditions and purified with a scavenger ionic resin. A small library of coupling
products was obtained. The polymer bond molecules were analyzed by magic angle spinning NMR spectroscopy. © 2002 Elsevier
Science B.V. All rights reserved.
Keywords: Silylated linker; Palladium; Cross-coupling; HR MAS NMR
1. Introduction
mediates with dialkyldichlorosilanes [4,5], has been
used for preparation of silyl chloride resins where the
silicon is directly attached to the polymer backbone.
The major drawback of these resins is that they are air
and moisture sensitive [5b,5c].
The transition metal-catalyzed cross-coupling reac-
tions, a powerful tool for the formation of carbon–car-
bon bond, have been widely applied in the synthesis of
natural products. Considerable attention has been given
to the transition metal-catalyzed cross-coupling reac-
tion mediated by palladium on solid support [6]. Sev-
eral different types of reactions such as Heck [7],
Suzuki [8], and Stille [9] reactions have been reported.
Modification of natural product scaffolds is an at-
tractive strategy for the discovery of new pharmaceuti-
cal agents. The combinatorial synthesis of molecular
libraries on polymeric supports is a powerful approach
for the rapid identification of new compounds that are
efficient tools for the study of biological phenomena
and new leads for the development of new drugs [1].
The choice of suitable supports and appropriate linkers
[2] are of great importance in synthetic sequences.
Silyl derivatives are widely used in synthetic organic
chemistry as protecting groups for alcohols, phenols,
carboxylic acids, amines, acetylenes and aromatic com-
pounds [3]. Silyl groups are inert to a wide range of
synthetic transformations but may be easily removed
under selective conditions. To complement existing so-
lution-phase silyl protecting groups, several resin-bound
silicon linkers have been developed to enable attach-
ment of alcohols to solid supports. Lithiation of
polystyrene, followed by trapping of aryllithium inter-
2. Results and discussion
In this paper, we describe the preparation of a new
stable silylated polystyrene, PsꢀSi(CH3)2ꢀCH2ꢀCl, and
its usefulness in the construction of a small library of
products obtained via palladium-mediated cross-cou-
pling using miniKan technology [10]. This silylated
polymer was similar to Merrifield resin but offered the
opportunity to be cleaved under mild conditions.
The reactors were filled up with the commercially
available resin (1% divinylbenzene–styrene copolymer),
* Corresponding authors. Tel.: +33-1-44-276743; fax: +33-1-44-
071062.
E-mail addresses: savignac@ext.jussieu.fr (M. Savignac),
genet@ext.jussieu.fr (J.-P. Geneˆt).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01400-0

R. Duboc et al. / Journal of Organometallic Chemistry 643–644 (2002) 512–515
513
scelled and washed with different solvents. Lithiation
[4,11] of the copolymer, followed by quenching with
chloro(chloromethyl)dimethylsilane in cyclohexane at
room temperature provided 2 (Scheme 1). The structure
was characterized by IR–FT and HR MAS NMR. The
resin 2, contrary to chlorodimethylsilane resin was sta-
ble and could be stored under argon.
The chloromethyl resin 2 was then esterified with
various iodobenzoic acids according to previously opti-
mized conditions [12]. The cesium carboxylate was first
prepared, added to 2 in DMF and the mixture was
shaken at 50° C during 24 h (Scheme 2) [13]. A
complete conversion in supported aromatic iodo esters
3, 4, 5 was observed by FT–IR: disappearance of the
C–Cl band (603 cm−1) and by solid-phase HR MAS
1H-NMR: shift of CH2 signal from 3.05 to 4.2 ppm. To
confirm this conversion, the resin was cleaved by TFA
in THF and iodo benzoic methyl ester was isolated in
80% yield after chromatography.
Heck reactions with ethyl acrylate were carried out in
DMF under argon using Pd(OAc)2/PPh3 catalyst and
an excess of olefin and base. The conversion was com-
plete in 16 h at 80 °C as shown by HR MAS H-NMR
and FT–IR spectral analyses (Scheme 3) [14].
In the same way, the supported aryliodides were
coupled with trimethylsilylacetylene in THF under ar-
gon in the presence of catalytic CuI (Sonogashira cou-
plings). After 16 h at reflux of THF, complete
conversion was observed [15].
1
In a third series of experiment, we tested these sup-
ported aryliodides in the Suzuki coupling using typical
solution phase Suzuki coupling: excess of boronic acid,
K2CO3 as base, at reflux of DMF. Under these condi-
tions, again we observed a completed conversion
(Scheme 3) [16]. All conversions were determined by
1
HR MAS H-NMR.
To probe the efficiency of couplings, esters, after
separation, were cleaved with TBAF in THF. However
due to small quantities of resins in miniKan, excess of
TBAF was difficult to eliminate. Therefore an Am-
We next examined the palladium-catalyzed cross-
coupling reaction with these supported aryliodides. The
Scheme 1.
Scheme 2.
Scheme 3.

514
R. Duboc et al. / Journal of Organometallic Chemistry 643–644 (2002) 512–515
Scheme 4.
(d) J.T. Randolph, S.J. Danishefsky, Angew. Chem. Int. Ed.
Engl. 33 (1994) 1470;
(e) C. Zheng, P.H. Seeberger, S.J. Danishefsky, J. Org. Chem. 63
(1998) 1126;
berlyst A-15 and its calcium salt were used to purify the
mixture [17] as presented in Scheme 4. By simple filtra-
tion and solvent evaporation, the methyl ester was
1
obtained in 70% yield and in high purity proved by H-
(f) P.H. Seeberger, X. Beebe, G.D. Sukenick, S. Pochapsky, S.J.
Danishefsky, Angew. Chem. Int. Ed. Engl. 36 (1997) 491.
[6] C.L. Kingsbury, S.J. Mehrman, J.M. Takacs, Curr. Org. Chem.
3 (1999) 497.
and 13C-NMR.
[7] (a) S. Berteina, S. Wendeborn, W.K.-D. Brill, A. De Mesmaeker,
Synlett (1998) 676;
3. Conclusion
(b) B. Ruhland, A. Bombrun, M.A. Gallop, J. Org. Chem. 62
(1997) 7820;
(c) M. Hiroshige, J.R. Hauske, P. Zhou, Tetrahedron Lett. 36
(1995) 4567.
In this paper, we have shown that a variety of
aryliodides immobilized on a new silylated resin can be
subjected to preparatively useful coupling reactions. A
mini library has been developed and automatization
could be envisaged with miniKan technology. This
technology is presently being used in our laboratories
to create libraries of diversely functionalized molecules
with biological properties.
[8] (a) S. Chamoin, S. Houldsworth, C.G. Kruse, W. Iwema
Bakker, V. Sniekus, Tetrahedron Lett. 39 (1998) 4179;
(b) B.A. Lorsbach, J.T. Bagdanoff, R.B. Miller, M.J. Kurth, J.
Org. Chem. 63 (1998) 2244;
(c) S.-E. Yoo, J.-S. Seo, K.-Y. Yi, Y.-D. Gong, Tetrahedron
Lett. 38 (1997) 1203;
(d) Y. Han, S.D. Walker, R.N. Young, Tetrahedron Lett. 37
(1996) 2703.
[9] (a) S. Chamoin, S. Houldsworth, V. Sniekus, Tetrahedron Lett.
39 (1998) 4175;
Acknowledgements
(b) M.J. Plunkett, J. Ellman, J. Am. Chem. Soc. 117 (1995) 3306;
(c) I. Sucholeiki, F.W. Forman, J. Org. Chem. 60 (1995) 523.
[10] (a) K.C. Nicolaou, X.Y. Xiao, Z. Parandoosh, A. Senyei, M.P.
Nova, Angew. Chem. Int. Ed. Engl. 34 (1995) 2289;
(b) K.C. Nicolaou, D. Vourloumis, T. Li, J. Pastor, N.
Winssinger, Y. He, S. Ninkovic, F. Sarabia, H. Vallberg, F.
Roschangar, N.P. King, M.R. Finlay, P. Giannakakou, P.
Verdier-Pinard, E. Hamel, Angew. Chem. Int. Ed. Engl. 36
(1997) 2097.
R.D. PhD fellow 1998–2000 thanks Aventis for
financial support.
References
[1] (a) N.K. Terrett, M. Gardner, D.W. Gordon, R.J. Kobylecki, J.
Steele, Tetrahedron 51 (1995) 8135;
[11] Polystyrene 1% divinylbenzene copolymer beads, 200–400 mesh
(2.5 g) was swollen in dry cyclohexane (5 ml). N,N,N%,N%-Te-
tramethylethylenediamine (3.8 ml, 10 equivalents, 25 mmol) was
added followed by a 2.5 M solution of n-butyllithium in hexane
(11 ml, 11 equivalents, 27 mmol). The suspension was gently
shaken at 68 °C during 5 h until the resin turned dark red. The
resin was allowed to settle and was washed three times with dry
cyclohexane (15 ml) under argon. The red resin was then swollen
in dry cyclohexane (10 ml) and chloro(chloromethyl)dimethyl-
silane (3.3 ml, 10 equivalents, 25 mmol) was added dropwise.
The resin turned white and was gently shaken for 30 min and
filtered off and washed with DMF (3×30 ml), DMF–water
(2×30 ml), THF (2×30 ml), THF–water (2×30 ml), THF
(3×30 ml) MeOH (30 ml) and alternatively three times with
CH2Cl2ꢀMeOH (30 ml). The resin (3 g) was dried in vacuo for 5
h. 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.35 (s, 6H) 3.05 (s,
(b) F. Balkenhohl, C. von dem Bussche-Hu¨nnefeld, A. Lansky,
C. Zechel, Angew. Chem. Int. Ed. Engl. 35 (1996) 2288;
(c) L.A. Thompson, J.A. Ellman, Chem. Rev. 96 (1996) 555;
(d) A.R. Brown, P.H.H. Hermkens, H.C.J. Ottenheijm, D.C.
Rees, Synlett (1998) 817;
(e) D. Obretch, J.M. Villargodo, Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries, Pergamon, New York, 1998.
[2] (a) I.W. James, Tetrahedron 55 (1999) 4855;
(b) F. Guillier, D. Orain, M. Bradley, Chem. Rev. 100 (2000)
2091.
[3] (a) T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic
Synthesis, Wiley, New York, 1991;
(b) P.J. Kocienski, Protecting Groups, Thieme, 1994.
[4] M.J. Farrall, M.J. Fre´chet, J. Org. Chem. 41 (1976) 3877.
[5] (a) T.H. Chan, W.Q. Huang, J. Chem. Soc. Chem. Commun.
(1985) 909;
2H). 13C-NMR (DMF D7, 100 MHz): −4,30. IR (KBr) cm−1
1411, 1249 wSiꢀCH , 838, 811 wSiꢀ(CH ) , 603 wCꢀCl
:
.
(b) S.J. Danishefsky, K.F. McClure, J.T. Randolph, R.B. Bug-
geri, Science 260 (1993) 1307;
(c) J.T. Randolph, K.F. McClure, S.J. Danishefsky, J. Am.
Chem. Soc. 117 (1995) 5712;
3
3
2
[12] S.S. Wang, B.F. Gisen, D.P. Winter, R. Makofske, I.D.
Kolesha, C. Tzougraki, J. Meinhoffer, J. Org. Chem. 42 (1977)
1286–1290.

R. Duboc et al. / Journal of Organometallic Chemistry 643–644 (2002) 512–515
515
[13] General procedure for the attachment of iodobenzoic acids to
chloromethyl silyl resin:
(CH2ꢀCH3), 57 (SiꢀCH2), 15 (CH3), −4.2 (SiꢀCH3). IR (KBr)
cm−1: 1718 wCꢁO, 1641 wCꢁC, 1415, 1249 wSiꢀCH
.
3
1
A solution of iodobenzoic acid (350 mg, four equivalents, 1.4
mmol, M=248.02) in methanol (7 ml) and water (0.7 ml) was
titrated to pH 7 with a 20% aqueous solution of cesium carbon-
ate (:3 ml). The mixture was evaporated to dryness and DMF
(2 ml) was added. After evaporation to dryness, a second portion
of DMF (2 ml) was added and evaporated. In the dry carboxylic
acid cesium salt the resin (350 mg, 0.35 mmol, ~=1) was added
followed by DMF (6 ml). The suspension was gently shaken at
50 °C during 24 h. The resin was filtered off and washed with
DMF (3×30 ml), DMF–water (2×30 ml), THF (2×30 ml),
THF–water (2×30 ml), THF (3×30 ml) MeOH (30 ml) and
alternatively three times with CH2Cl2 MeOH (30 ml). The resin
was dried in vacuo for 5 h.
8: H-NMR (DMF D7, 400 MHz): l (ppm) 0.35 (s, 6H), 1.27 (s,
CH3), 4.20 (s, CH2ꢀCH3), 4.23 (s, SiꢀCH2), 6.70 (s, CHꢁ), 7.70
(s, CHꢁ), 7.72, 7.95 (2s, 4Harom). IR (KBr) cm−1: 1717 wCꢁO
,
1639 wCꢁC, 1412, 1249 wSiꢀCH
.
3
[15] General procedure for the solid support Sonogashira couplings:
the iodate resin in miniKan (0.6 mmol, ~=1 mmol g−1) was
swollen in degassed THF (5 ml per miniKan). Trimethylsily-
lacetylene (850 ml, 10 equivalents), palladium acetate (5.4 mg,
0.024 mmol), triphenylphosphine (25.1 mg, 0.096 mmol), copper
iodide (4.5 mg, 0.024 mmol) and triethylamine (1.6 ml, 12 mmol)
were added. The suspension was shaken at reflux during 16 h.
The miniKan were filtered off and washed with DMF (3×50
ml), DMF–water (2×50 ml), THF (2×50 ml), THF–water
(2×50 ml), THF (3×50 ml), MeOH (50 ml and alternatively
CH2Cl2, MeOH (50 ml). The miniKans were dried in vacuo for
5 h.
Solid phase (dimethyl-phenyl-silanyl)-methyl-2-iodobenzoic ester
(3): according to general procedure for the attachment of
iodobenzoic acids to chloromethyl silyl resin (use of 2-iodoben-
zoic acid), 420 mg of resin were isolated (~=1 mmol g−1)).
1H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (s, 6H), 4.2 (s,
CH2), 7.12 (s, Harom), 7.38 (s, Harom), 7.66 (s, Harom), 7.98 (s,
9: 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.22 (s, Siꢀ(CH3)3),
0.32 (SiꢀCH3), 4.19 (SiꢀCH2), 7.30, 7.40, 7.45, 7.70 (4s, 4
Harom). IR (KBr) cm−1: 2159 wCꢂC, 1720 wCꢁO, 1250 wSiꢀCH
.
Harom). IR (KBr) cm−1: 1726 wCꢁO, 1411, 1248 wSiꢀCH
4: H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (s, 6H), 4.21 (s,
.
3
1
3
10: H-NMR (DMF D7, 400 MHz): l (ppm) 0.22 (s, Siꢀ(CH3)3),
0.32 (SiꢀCH3), 4.20 (SiꢀCH2), 7.50, 7.70, 8.03, 8.12 (4s,
1
CH2), 7.30 (s, 1Harom), 7.97 (s, 2Harom), 8.34 (s, 1Harom). IR
4Harom). IR (KBr) cm−1: 2158 wCꢂC, 1723 wCꢁO, 1250 wSiꢀCH
.
(KBr) cm−1: 1721 wCꢁO, 1411, 1248 wSiꢀCH
.
3
1
3
11: H-NMR (DMF D7, 400 MHz): l (ppm) 0.22 (s, Siꢀ(CH3)3),
0.32 (SiꢀCH3), 4.19 (SiꢀCH2), 7.50, 8.00 (2s, 4Harom). IR (KBr)
1
5: H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (s, 6H), 4.19 (s,
CH2), 7.72 (1s, 2Harom), 7.82 (1s, 2Harom). IR (KBr) cm−1
1730 wCꢁO, 1411, 1248 wSiꢀCH
:
cm−1: 2160 wCꢂC, 1718 wCꢁO, 1250 wSiꢀCH
.
[16] General procedure for the solid support 3Suzuki couplings: the
iodate resin in miniKan (0.6 mmol, ~=1 mmol g−1) was
swollen in degassed DMF (5 ml per miniKan). Phenyl boronic
acid (220 mg, three equivalents), palladium acetate (5.4 mg,
0.024 mmol), triphenylphosphine (25.1 mg, 0.096 mmol) and
potassium carbonate (500 mg, 3.6 mmol) were added. The
suspension was shaken at 80 °C during 16 h. The miniKans were
filtered off and washed with DMF (3×50 ml), DMF–water
(2×50 ml), THF (2×50 ml), THF–water (2×50 ml), THF
(3×50 ml), MeOH (50 ml and alternatively CH2Cl2, MeOH (50
ml). The miniKans were dried in vacuo for 5 h.
.
3
[14] General procedure for the solid support Heck couplings: the
iodate resin in miniKan (0.6 mmol, ~=1 mmol g−1) was
swollen in degassed DMF (5 ml per miniKan). Ethyl acrylate
(650 ml, 10 equivalents), palladium acetate (5.4 mg, 0.024 mmol),
triphenylphosphine (25.1 mg, 0.096 mmol) and triethylamine (1.6
ml, 12 mmol) were added. The suspension was shaken at 80 °C
during 16 h. The miniKans were filtered off and washed with
DMF (3×50 ml), DMF–water (2×50 ml), THF (2×50 ml),
THF–water (2×50 ml), THF (3×50 ml), MeOH (50 ml and
alternatively with CH2Cl2–MeOH (50 ml). The miniKans were
dried in vacuo for 5 h.
12: 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (SiꢀCH3), 4.19
(SiꢀCH2), 7.40 (s, 2Harom), 7.4–7.55 (m, 4Harom), 7.65 (s,
6: 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (s, 6H), 1.5 (s,
CH3), 4.20 (s, SiꢀCH2), 4.50 (s, CH2ꢀCH3), 6.75 (s, CHꢁ), 7.55
(s, 1Harom), 7.65 (s, 1Harom), 7.90 (s, 1Harom), 8.05 (s,
1Harom). IR (KBr) cm−1: 1718 wCꢁO, 1249 wSiꢀCH
.
3
13: 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.37 (SiꢀCH3), 4.19
(SiꢀCH2), 7.40 (s, 2Harom), 7.50 (s, 1Harom), 7.65 (s, 1Harom),
7.85, 8.01 (2s, 2Harom), 8.30 (s, 1Harom). IR (KBr) cm−1: 1718
1Harom), 8.65 (s, CHꢁ). IR (KBr) cm−1: 1721 wCꢁO, 1640 wCꢁC
,
1415, 1248 wSiꢀCH
.
3
7: 1H-NMR (DMF D7, 400 MHz): l (ppm) 0.35 (s, 6 H), 1.25 (s,
CH3), 4.20 (s, CH2ꢀCH3), 4.23 (s, SiꢀCH2), 6.65 (s, CHꢁ), 7.20
(s, 1Harom), 7.75 (s, 1Harom), 7.94 (s, 1Harom), 7.97 (s,
1Harom), 8.32 (s, CHꢁ). 13C-NMR (DMF D7, 100 MHz): 165
(CO), 148 (CHꢁ), 143, 142, 138, 131, 130 (Carom), 58
wCꢁO, 1249 wSiꢀCH
.
14: 0.37 (SiꢀCH33), 4.19 (SiꢀCH2), 7.40, 7.65, 7.70, 8.10 (s,
Harom). IR (KBr) cm−1: 1717 wCꢁO, 1249 wSiꢀCH
.
[17] J.J. Parlow, D.L. Flynn, Tetrahedron 54 (1998) 43013.