Poly(ethylene glycol) supported liquid phase synthesis of biaryls

Article abstract of DOI:10.1055/s-1998-1630

The liquid phase synthesis of biaiyls via Suzuki cross-coupling reaction on polyethylene glycol) supports (PEGs) is described. The reaction is exemplified by parallel coupling of polymer bound aryl halides with boronic acids. Four different PEGs were employed as soluble polymer supports for parallel synthesis. The generated libraries include both sterically hindered aryl halides (2b, 2d) and boronic acids. The reactions were run in the homogeneous phase and the synthetic sequences performed in parallel fashion. Quantitative conversion in the Suzuki couplings was verified by ¹H-NMR analysis (3a-r). The polymer bound products were isolated in good to excellent (52% to 98%) yields by either simple precipitation of the soluble support or column filtration.

Full text of DOI:10.1055/s-1998-1630

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Poly(ethylene glycol) Supported Liquid Phase Synthesis of Biaryls
a,b
a
b
b *
Carsten G. Blettner , Wilfried A. König , Wolfgang Stenzel , Theo Schotten
a
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
Beiersdorf - Lilly GmbH, Wiesingerweg 25, D-20253 Hamburg, Germany
b
Received 16 December 1997
Abstract: The liquid phase synthesis of biaryls via Suzuki cross-
coupling reaction on poly(ethylene glycol) supports (PEGs) is
described. The reaction is exemplified by parallel coupling of polymer
bound aryl halides with boronic acids. Four different PEGs were
employed as soluble polymer supports for parallel synthesis. The
generated libraries include both sterically hindered aryl halides (2b, 2d)
and boronic acids. The reactions were run in the homogeneous phase
and the synthetic sequences performed in parallel fashion. Quantitative
1
conversion in the Suzuki couplings was verified by H-NMR analysis
(3a-r). The polymer bound products were isolated in good to excellent
(52% to 98%) yields by either simple precipitation of the soluble
support or column filtration.
The availability of general reaction protocols for organic molecule
libraries which lead to high yields of pure products is essential for the
success of combinatorial chemistry. Solid-phase synthesis can be
complicated by heterogeneous reaction conditions, the requirement for
large quantities of solid support and the difficulty in monitoring
1
reactions. The use of soluble supports offers a method to overcome
2
these difficulties while maintaining the ease of solid phase synthesis.
3
PEG is soluble in most common solvents and has a strong propensity to
crystallize. Inclusions due to gelatinous precipitation are avoided. The
recent interest in PEG-supported synthesis including liquid phase
4
5
hindered polymer bound aryl iodides (2b, 2d) and sterically hindered
boronic acids were chosen as reaction substrates for the reaction (Table
2).
6
7
combinatorial strategies prompted us to report our results.
PEG itself, the ester group and all functional groups remained stable
during the reaction process. The desired methyl esters 4a-r were
obtained in parallel fashion by transesterification with triethylamine
(TEA) in methanol. This mild cleavage procedure resulted in very
pure reaction products but gave variable yields (Table 2).
The biaryl subunit is an important pharmacophore in a variety of
8
biologically active compounds. We synthesized small libraries of
9
biaryls via the Suzuki cross-coupling reaction of aryl bromides or
12
iodides on four different PEGs. The aryl halides were activated for the
cross-coupling reaction by the electron withdrawing effect of the ester
9
linkage to the polymer. Commercially available monofunctional PEG
2000 monomethylether (MeO-PEG 2000), MeO-PEG 5000,
difunctional PEG 4000 and PEG 6000 were chosen as polymer supports.
Our target was to generate the libraries by using parallel synthesis and to
find the most suitable polymer in terms of loading capacity and ease of
workup.
5-Bromothiophene-2-carboxylic acid was esterified with MeO-PEG
The polymer bound products 3a-r were purified either by precipitation
of the polymer support into ice cold tert-butyl methyl ether (3a-g, 3o-
r) or by column filtration (3h-n).
10
2000 employing a variation of the DCC/DMAP method.
The
11
recovered yield of the product 2a was 73%. The conversion estimated
by NMR was >95%. No starting material was found by MALDI-TOF
MS. The iodo benzoic acids were esterified with the soluble polymers
To ensure crystalline precipitation and high recovery of the polymer
bound products in parallel fashion, the right choice of polymer was
essential. MeO-PEG 5000 provided crystalline precipitation products
under the conditions employed. The recovered yield of the polymer
bound biaryls was good to excellent (86-96%, 3c-g), but the polymer
suffered a loading capacity of only 0.2 mmol/g. MeO-PEG 2000 esters
3a and 3b provided a loading capacity of 0.47 mmol/g and a recovery of
88 and 97% respectively. The precipitation was strongly influenced by
impurities and the ester residue. Crystalline precipitates were only
obtained at carefully controlled temperatures below 0°C, thus making
the workup less suitable for parallel synthesis of larger libraries.
Disubstituted PEG 6000 offered the optimum conditions in terms of
loading capacity and workup via the precipitation method. The loading
capacity was 0.33 mmol/g and the precipitation property very similar to
MeO-PEG 5000. The PEG 6000 bound products 3o-r were isolated in
excellent yields (90-98%) and high purity (Table 3).
10
employing the same reaction conditions as above (Table 1).
9
The cross-coupling reaction was readily accomplished on the PEG
11
esters 2a-f utilizing a variation of standard Suzuki conditions.
Aqueous DMF was used as a solvent in combination with the weak base
Na CO . The aryl halides were converted quantitatively on the polymer
2
3
at 110°C overnight. Compared to non-polymer supported liquid phase
chemistry higher temperatures were necessary to assure quantitative
conversion of 2 a-f into the Suzuki reaction products. Both sterically

296
LETTERS
SYNLETT
Alternatively to the crystallization method, the Suzuki reaction mixtures
13
on PEG 4000 were purified by parallel flash column filtration. The
polymer was purified on a short silica gel column by successive elution
with tert-butyl methyl ether, i-propanol, toluene and ethyl acetate and
was finally eluted with warm ethanol. Due to the polydispersity of PEGs
distinct tailing was observed and the recovery of polymer 3h-n was only
modest. Although no fragmentation of the polymer was observed under
14
the employed conditions, PEGs are liable to degrade on silica gel.
For parallel synthesis of biaryls on PEGs the precipitation method
resulted in good to excellent recovery and high purity of the polymer
bound products and was therefore the method of choice. Disubstituted
PEG 6000 offered the optimum conditions in terms of loading capacity
and ease of workup.

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297
References and Notes
cold tert-butyl methyl ether. The crystalline polymer was filtered
off and washed with ice cold ethanol. The polymer was dissolved
1.
For excellent reviews see: a) Balkenhohl, F.; von dem Bussche-
in CH Cl and precipitated as above. This procedure was repeated
Hünnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., 1996, 108,
2436; Angew. Chem. Int. Ed. Engl., 1996, 35, 2288. b) Früchtel, J.
S.; Jung, G. Angew. Chem., 1996, 108, 19; Angew. Chem. Int. Ed.
Engl., 1996, 35, 17. c) Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Rees, D. C. Tetrahedron, 1997, 53, 5643.
2
2
once. TLC (CH Cl :EtOH, 98:2) only showed the polymer spot.
2
2
The product was dried overnight under vacuum. The high purity
1
of the compounds (>95%) was estimated by H-NMR. The
MALDI-TOF MS technique was used to follow the conversion of
the starting material quantitatively.
2.
3.
4.
a) Service, R. F.; Science, 1996, 272, 1266. b) Zalipsky, S.
Bioconjugate Chem., 1995, 6, 150.
11. The synthesis of PEG bound biphenyl 3g (entry 7, Table 2) is
representative for the parallel Suzuki reaction on the PEG-polymer
and the purification procedure via the precipitation method: 2b (1
g, approx. 0.19 mmol) was dissolved in 5 ml distilled DMF and 73
mg (0.38 mmol, 2 eq) 2,4-dichlorophenylboronic acid, 11.6 mg
(0.01 mmol, 0.05 eq) tetrakis-(triphenylphosphine)palladium(0)
and 0.25 ml (0.5 mmol, 2.5 eq) 2M sodium carbonate were added.
The mixture was stirred under argon at 110°C for 10 h in a screw-
cap culture tube. Toluene was added and insoluble material
removed by centrifugation. The volume of the solution was
reduced under vacuum and poured into ice cold tert-butyl methyl
ether for precipitation. The solution was filtered and washed with
Bayer, E.; Mutter, M.; Polster, J.; Uhmann, R. Pept. Proc. Eur.
th
Pept. Symp. 13 , 1974, 129.
a) Rajasekharan Pillai, V. N.; Mutter, M. Acc. Chem. Res., 1981,
14, 122. b) Harris, J. M. In Poly(Ethylene Glycol) Chemistry
Biotechnical and Biomedical Applications, Plenum Press, New
York, 1992, 2. c) The crystal structure of PEG is a 7 -helix:
2
Tadokoro, H.; Murahashi, S.; Yoshihara, T.; Tahara, S.;
Murahashi, S. Macromol. Chem., 1964, 73, 109.
5.
6.
Bayer, E.; Mutter, M. Angew. Chem., 1974, 2, 101.
Recent PEG-supported synthesis of a) small molecules:
Vandersteen, A. M.; Han, H.; Janda, K. D. Molecular Diversity,
1996, 2, 89. b) oligosaccharides: Rouhi, A. M. Science, 1996, 23,
62. and Douglas, S. P.; Whitfield, D. M.; Krepinsky, J. J. J. Am.
Chem. Soc., 1995, 117, 2116. c) oligonucleotides: Bonora, G. M.
Appl. Biochem. and Biotech., 1995, 54, 3. The organic synthesis
on soluble polymer supports has been reviewed during the
preparation of this work: Gravert, D.J.; Janda, K.D. Chem. Rev.,
1997, 97, 489.
ice cold ethanol. The polymer was taken up in CH Cl and the
2
2
procedure repeated twice. TLC (CH Cl :EtOH, 98:2) did only
2
2
1
show the polymer signal. H-NMR (500 MHz, CDCl ): 8.06 (1H,
3
d, J = 7.6 Hz); 7.59 (1H, t, J = 7.4 Hz); 7.49 (1H, t, J = 7.5 Hz);
7.44 (1H, s); 7.30 (1H, d, J = 8.2 Hz); 7.23 (1H, d, J = 7.8 Hz);
7.19 (1H, d, 8.2 Hz); 4.24 (2H, t, J = 4.8 Hz); 3.49-3.79 (m, PEG);
3.38 (3H, s).
12. The transesterification of 3g (entry 7, Table 2) in TEA/methanol is
representative for the cleavage procedure: 1g (approx. 0.19 mmol)
dry polymer bound biaryl was dissolved in 10 ml dry 20% TEA/
MeOH and stirred in a screw-cap culture tube under argon at 85°C
for 2d. The mixture was dried under vacuum, taken up in 4 ml
CH Cl , precipitated into ice cold tert-butyl methyl ether and
7.
8.
9.
a) Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D., Proc. Natl.
Sci. USA, 1995, 92, 6419. b) Erb, E.; Janda, K. D.; Brenner, S.
Proc. Natal. Acad. Sci. USA, 1994, 91, 11422.
Duncia, J. V.; Carini, J. D.; Chiu, A. T.; Johnson, A. L.; Price, W.
A.; Wong, P. C.; Wexler, R. R.; Timmermans, P. B. M. W. M.
Medical Research Reviews, 1992, 12, 149.
2
2
filtered. The polymer was washed with ice cold tert-butyl methyl
ether or EtOH, dissolved in CH Cl and precipitated again as
2
2
a) Miyaura, N.; Yanagi, Y.; Suzuki, A. Synth. Commun., 1981, 11,
513. b) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett, 1992, 207.
For reviews on the Suzuki reaction see: a) Martin, A. R.; Yang, Y.
Acta Chem. Scand. 1993, 47, 221. b) Suzuki, A. Pure & Appl.
Chem., 1994, 66, 213. c) Miyaura, N.; Suzuki, A. Chem. Rev.,
1995, 95, 2457.
11
above. The volume of the combined filtrates was reduced under
vacuum and the crude product purified via column filtration
(AcOEt : iso-Hexane; 4 : 1, Rf: 0.68) to give 4g as a colourless oil.
1
EIMS (70 eV), m/z 245, 230, 186, 152; H-NMR (500 MHz,
CDCl ): 8.06 (1H, d, J = 7.6 Hz); 7.59 (1H, t, J = 7.4 Hz); 7.49
3
(1H, t, J = 7.5 Hz); 7.44 (1H, s); 7.30 (1H, d, J = 8.2 Hz); 7.23
(1H, d, J = 7.8 Hz); 7.19 (1H, d, 8.2 Hz); 3.70 (3H, s); Anal.
10. Zalipsky, S.; Gilon, C.; Zilkha, A. J. Macromol. Sci. Chem. A21,
1984, 839. The procedure for esterification of PEG: DCC (4 eq)
Calcd. for C
H Cl O : C, 59.81; H, 3.59; Cl, 25.22. Found: C,
14 10 2 2
was taken up in CH Cl (2.5 mol/l) and added to a solution of
2
2
60.00; H, 3.53; Cl, 25.24.
PEG (1 eq OH), iodo benzoic acid or 5-bromothiophene-2-
carboxylic acid (4 eq) and DMAP (0.25 eq) in CH Cl or CH Cl /
13. Column filtration was performed on 63-200 µ silica gel in
disposable columns. 5g silica gel was used for one gram PEG
4000.
2
2
2
2
THF mixtures. The reaction mixture was stirred overnight at room
temperature. Dicyclohexylurea was filtered off, the volume of the
filtrate reduced under vacuum and poured into a tenfold volume of
14. Bayer, E., personal communication.