Polyglycerol as a high-loading support for boronic acids with application in solution-phase Suzuki cross-couplings

Article abstract of DOI:10.1021/jo026076q

In this paper, we describe the usage of a soluble high-loading polyglycerol support for functionalized boronic acids without further linker design. The quantitatively formed polyglycerol boron esters were subsequently employed in homogeneous Suzuki cross-coupling reactions to give high yields (84-91%) of functional biaryls with minimal amounts of the Pd catalyst (0.2 mol %). In situ precipitation and ultrafiltration were used as simple and effective purification protocols. Furthermore, the reaction conditions were optimized by the choice of the solvent and the catalyst.

Full text of DOI:10.1021/jo026076q

catalyst.6 Alternatively, soluble linear and perfect den-
drimers were used to support aryl halides and thereby
avoid these problems.7 Another class of high-loading
supports for organic synthesis are dendritic polymers,
such as polyglycerol (PG) 1.8 This soluble polymer is
easily accessible via anionic ring-opening polymerization
of glycidol in kilogram quantities9 and recently became
commercially available.9e A major advantage of PG is its
high loading capacity of about 4.1 mmol g-1 of terminal
1,2-diol groups, which can be directly used as linkers for
various substrates, reagents, and ligands.2a,8
P olyglycer ol a s a High -Loa d in g Su p p or t for
Bor on ic Acid s w ith Ap p lica tion in
Solu tion -P h a se Su zu k i Cr oss-Cou p lin gs
Andre´ Hebel and Rainer Haag*
Freiburger Materialforschungszentrum und Institut fu¨r
Makromolekulare Chemie, Universita¨t Freiburg,
Stefan-Meier-Strasse 21, 79104 Freiburg, Germany
rainer.haag@fmf.uni-freiburg.de
Received J une 19, 2002
We here report on the synthesis of high-loading poly-
glycerol boronic esters which are subsequently used for
solution-phase Suzuki cross-coupling reactions and de-
scribe a simple workup protocol. The formation of the
boron esters 2a -2d occurs at room temperature within
4-18 h in dimethylformamide (DMF) by reacting a
boronic acid with the dendritic PG support (Scheme 1,
Table 1). This procedure is performed on the unfunction-
alized polymer and does not require an additional linker
design. Small amounts of molecular sieves were added
to drive the reactions to completion. Quantitative conver-
sions (>95%) were obtained for all substrates (Table 1),
and no further purification procedure was required as
Abstr a ct: In this paper, we describe the usage of a soluble
high-loading polyglycerol support for functionalized boronic
acids without further linker design. The quantitatively
formed polyglycerol boron esters were subsequently em-
ployed in homogeneous Suzuki cross-coupling reactions to
give high yields (84-91%) of functional biaryls with minimal
amounts of the Pd catalyst (0.2 mol %). In situ precipitation
and ultrafiltration were used as simple and effective puri-
fication protocols. Furthermore, the reaction conditions were
optimized by the choice of the solvent and the catalyst.
Boronic acids have grown into an important class of
organic compounds over the last few years due to their
broad application potential in organic synthesis. Espe-
cially in the palladium-catalyzed Suzuki cross-coupling
reaction1 boronic acids and esters are popular substrates
in the synthesis of organic building blocks as well as
druglike molecules. This C-C coupling reaction can be
achieved efficiently with arylic bromides and chlorides
(in some cases) and does not require expensive aryl
iodides. In addition, a broad tolerance toward functional
groups is observed. In recent years, Suzuki couplings
have also become very popular in combinatorial chem-
istry. Efforts were made to support one or two compo-
nents to simplify the workup protocol.2 Typically a solid
support, like the Wang or Merrifield resin, is chosen to
support the aryl halide,3 the boronic acid,4 or the cata-
lyst.5 However, these resins show some characteristic
disadvantages: they usually possess low loading capaci-
ties (typically <1.5 mmol g-1), and the resulting hetero-
geneous reaction conditions require large amounts of
1
demonstrated by H NMR analysis.
It appears that under the above-described conditions
the size of the polymeric support plays an important role.
For example, for the formation of 2d with a large PG
support (average molecular weight of 21000) only a poor
loading of 33% could be obtained. By far better loadings
were achieved by choosing a smaller PG support with an
average molecular weight (Mn) of 8000 (83%). In the case
of thiophene boronic acid 2d an additional slightly
increased temperature (50 °C) is necessary to obtain a
quantitative loading (>95%). The reason for the poor
loadings when using a high molecular weight PG can be
due to a back-folding of the polymer chains with a
resulting hindrance in the diffusion of the substrate.
Consequently, polyglycerol with an average molecular
weight of 8000 was used. As depicted in Table 1 all
products 2a -2d show excellent conversions and high
loadings of boronic acid (2.5-3.0 mmol g-1). The soluble
* To whom correspondence should be addressed. Fax: +49-761-203-
4709.
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Angew. Chem. 2002, 114, 4136-4173; Angew. Chem., Int. Ed. 2002,
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Chem. 2002, 67, 3-15.
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66, 3820-3827.
(6) Haag, R.; Hebel, A.; Stumbe´, J . F. In Handbook of Combinatorial
Chemistry: Drugs, Catalysts, Materials; Nicolaou, K. C., Hanko, R.;
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58.
(7) (a) Mizugaki, T.; Murata, M.; Ooe, M.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2002, 52-53. (b) Zhang, J . D.; Aszodi, J .; Chartier,
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(9) Polyglycerol (Mn ) 8000, Mn/ Mw ) 1.5) was prepared as
described previously, using bis(2,3-dihydroxypropyl)stearylamine as
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information see www.hyperpolymers.com.
10.1021/jo026076q CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/05/2002
9452
J . Org. Chem. 2002, 67, 9452-9455

SCHEME 1. Im m obiliza tion of Va r iou s Bor on ic Acid s on to Den d r itic P olyglycer ol 1 w ith ou t F u r th er
Lin k er Design a
a
Cf. Table 1. The depicted polymer structures 1 and 2 show only one possible isomer and a small fragment of the polyglycerol (Mn
)
8000) scaffold.
TABLE 1. Im m obiliza tion of Va r iou s Bor on ic Acid s on to a Den d r itic P olyglycer ol Su p p or t
a
Determined by integration of the terminal C-atoms at 63 ppm and their corresponding chemical shift at 67-68 ppm in the 13C NMR,
relaxation agent Cr(acac)3.10
polymeric support allows for the easy determination of
the loading by integration of the terminal methylene
signal at 63 ppm in the 13C NMR spectrum (inverse
gated). In the case of a quantitative boron ester formation
the signal shifts completely to 67-68 ppm (see the
Supporting Information). By adding Cr(acac)3 as a re-
laxation agent, integration of these signals is possible to
determine the exact loading ((5%).10 Subsequently, the
polyglycerol boronic esters 2a -2d were tested in solution-
phase Suzuki couplings (Scheme 2). An excess of 2a -2d
(2 equiv) was treated with the particular aryl bromide
(1.0 equiv), 0.2 mol % of the respective catalyst (see
below), and potassium carbonate (2.5 equiv) in DMF at
120 °C for 18 h. Apart from DMF several other solvents,
such as THF, toluene, or dioxane, have been described
for this reaction.4,11 On account of their favorable proper-
ties (less toxic, lower boiling point), these solvents could
be preferential as compared to DMF. Therefore, the
synthesis of 4-methoxybiphenyl was performed in these
solvents to find the best for these homogeneous polymer-
supported Suzuki couplings using identical reaction
conditions (Figure 1). However, the usage of these
alternative solvents, THF, dioxane, chloroform, and
toluene, resulted in comparatively low conversions. One
possible explanation for this observation might be the
solution process of the polyglycerol boron ester in the
respective solvent. In all cases except DMF, a white
clouding of the solution was observed. This process is
known as the Tyndall effect and describes the formation
of large polymer aggregates. The poor conversions can
be due to the limited accessibility of either the boronic
acid or the catalyst in these aggregates. Therefore, for
all optimized reactions (Tables 2 and 3) we used DMF
as solvent. It is noteworthy that in contrast to solid-phase
(10) (a) Crisp, G. T.; Gebauer, M. G. J . Org. Chem. 1996, 61, 8425-
8431. (b) Gao, K.; Goroff, N. S. J . Am. Chem. Soc. 2000, 122, 9320-
9321. (c) Hany, R.; Rentsch, D.; Dhanapal, B.; Obrecht, D. J . Comb.
Chem. 2001, 3, 85-89. (d) Interrante, L. V.; Shen, Q.; Li, J . Macro-
molecules 2001, 34, 1545-1547. (e) Williamson, D. T.; Glass, T. E.;
Long, T. E. Macromolecules 2001, 34, 6144-6146.
(11) Hocek, M. J . Med. Chem. 2000, 43, 1817-1825.
J . Org. Chem, Vol. 67, No. 26, 2002 9453

F IGURE 1. Solvent screening: influence of different solvents on the conversion.
SCHEME 2. P olyglycer ol Bor on ic Ester s a s Solu ble Rea gen ts for Su zu k i Cr oss-Cou p lin g Rea ction sa
a
Cf. Tables 2 and 3.
TABLE 2. Ca ta lyst Scr een in g: Effect of th e Ca ta lyst on
th e Con ver sion for Tw o Differ en t Bip h en yls
entries 4-6). Three catalysts, Pd(dba)2, Pd(PPh3)2Cl2, and
Pd(PPh3)4, were screened for the maximum conversion
(Table 2). In the case of 4-methoxybiphenyl (entries 1-3),
the highest conversion was obtained with Pd(PPh3)4
(>95%). In comparison, with Pd(dba)2 only poor results
(19%) were possible. For the complementary system,
1-(2′-trifluoromethylbiphenyl)-4-ethanone (entries 4-6),
the best conversion was possible with Pd(dba)2 while both
other catalysts gave poor results. Thus, for the reactions
summarized in Table 3, the optimal catalyst for each
coupling system was chosen individually. This results in
high conversions (>95%) for most examples, which was
1
determined from the H NMR spectra by integration of
the methyl signal in each product vs the methyl signal
in the starting material. As described previously, easy
purification of all products can be achieved via ultrafil-
tration (UF)2,8 to give relatively pure products (>90%)
as determined by GC-MS and 1H NMR analysis. No
polymer-supported boronic acid could be detected in any
product.
a
Obtained from the 1H NMR spectrum.
Suzuki cross-couplings3,4 very low amounts of a Pd cata-
lyst (0.2 mol %) are necessary to drive the reactions to
completion (Scheme 2). That corresponds to a factor of
10-100 less as compared to solid-phase protocols and can
be explained by the homogeneous reaction conditions.3
To find the best catalyst for two complementary
examples, we chose two different systems consisting of
two electron-donating components (Table 2, entries 1-3)
and two electron-withdrawing components (Table 2,
We used a commercially available solvent-resistant
stirred pressure cell (6 bar, 47 mm) in combination with
solvent-resistant membranes. Typical separation times
were 2-3 h (including conditioning of the membrane) per
product. In some cases (e.g., Table 3, entries 5 and 6),
however, we observed that most of the polymer-supported
boronic compound precipitated during the reaction, and
therefore no further purification (UF) was required.
9454 J . Org. Chem., Vol. 67, No. 26, 2002

TABLE 3. Solu tion -P h a se Su zu k i Cou p lin gs Usin g 2a -2d u n d er Op tim ized Con d ition s
a
b
Obtained from the 1H NMR spectrum. Isolated yields after ultrafiltration. c This sample contains 13% of an unspecified side product.
13C with the solvent as the internal standard. For ultrafiltration
a commercially available solvent-resistant stirred pressure cell
(6 bar, 47 mm) in combination with solvent-resistant membranes
were used.
Nonetheless, with both methods a quantitative removal
of catalyst traces was not yet possible. This will be subject
to further investigations.
In summary, we have demonstrated that dendritic
polyglycerol 1 is well suited as a soluble polymeric
support for boronic acids. High loading values (2.5-3.0
mmol g-1) are possible without further linker design.
These polyglycerol boronic esters can be used in excess
(2.0 equiv) for solution-phase Suzuki cross-coupling reac-
tions and allow for the simple purification of the biaryl
products. Compared with normal homogeneous methods,
a much easier and faster purification protocol results,
which becomes significant when several reactions (typi-
cally 5-20) are performed simultaneously. In contrast
to common solid-phase techniques, the separation of the
soluble polymeric support is more time consuming (1-3
h), which makes this approach less suitable for high
throughput. However, the separation strategies used here
(precipitation and ultrafiltration) allow the efficient
workup on a preparative scale (1-5 mmol), which is not
easily achieved with solid-phase resins. Despite the
unique PG architecture (“built-in” diol groups), no further
linker design is necessary for the loading with boronic
acids. Furthermore, only very small amounts of a Pd
catalyst (0.2 mol %) were necessary to obtain high
conversions (87-99%).
Gen er a l Exp er im en ta l P r oced u r e for th e P olyglycer ol
Bor on Ester F or m a tion . To a solution of 1.0 g of polyglycerol
and 4.0 mmol of boronic acid in 10 mL of DMF was added 0.2 g
of 4 Å molecular sieves, and the resulting solution was stirred
for 4-18 h at 25-50 °C (cf. Table 1). After filtration, the solvent
was removed and the product dried in high vacuum. Despite
thorough drying of the products, they still contained some DMF.
For application in Suzuki coupling reactions the filtered DMF
solution can be used directly without further concentration.
Gen er a l Exp er im en ta l P r oced u r e for th e P G-Su p p or ted
Su zu k i cou p lin gs. To a suspension of 1.25 mmol of potassium
carbonate in 7.5 mL of DMF were added 1.0 mmol of polyglycerol
boronic ester 2a -d , 0.5 mmol of aryl halide 3a ,b, and 0.001
mmol of palladium catalyst (cf. Table 3), and the resulting
solution was stirred for 18 h at 120 °C. When the reaction was
completed, the solvent was substituted by toluene for ultrafil-
tration (cf. ref 8). In some cases (Table 3, entries 5 and 6), the
precipitation of the polymeric boron compound was quantitative
and no ultrafiltration was required.
Ack n ow led gm en t. We thank Prof. Rolf Mu¨lhaupt
for his support and Holger Kautz, Bernhard Siegel, and
Holger Tu¨rk for the preparation of the polyglycerol
supports. R.H. is indebted to the Bayer AG, the DFG,
the Fonds der chemischen Industrie, and Dr. Otto-Ro¨hm
Geda¨chtnisstiftung for financial support.
Su p p or tin g In for m a tion Ava ila ble: Analytical data and
NMR spectra of boronic esters 2a -2d and all biaryls. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were performed under
a nitrogen atmosphere with magnetic stirring. The employed
reagents and solvents were commercial grade. NMR spectra
were recorded in CDCl3 at 300 MHz for 1H and at 75 MHz for
J O026076Q
J . Org. Chem, Vol. 67, No. 26, 2002 9455