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Electroorganic Synthesis on the Solid Phase using Polymer Beads as Supports.

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Angewandte
Chemie
Solid-Phase Synthesis
Electroorganic Synthesis on the Solid Phase using
Polymer Beads as Supports**
Sukanya Nad and Rolf Breinbauer*
Dedicated to Professor M. T. Reetz
on the occasion of his 60th birthday
Solid-phase organic synthesis (SPOS) has become an invaluable tool in the quest for the synthesis of large compound
libraries. Since the pioneering work of Merrifield, organic
chemists have transferred almost all organic reactions known
in solution onto the solid phase.[1] However, a notable
exception are the electroorganic reactions, which are a
powerful tool for organic synthesis and even are applied in
large-scale industrial processes.[2] Although the parallelization of electrochemical reactions for solution-phase electroorganic synthesis has been addressed recently,[3] and electroorganic reactions have been carried out with substrates bound
to modified electrodes,[4] solid-phase electroorganic synthesis
using conventional polymeric beads has not been reported to
date. The latter would allow the integration of electrochemical reactions, with its advantages of complementary reactivity
and mild reaction conditions, into the pool of organic
reactions used for solid-phase library synthesis. Herein we
report the first examples of such electroorganic synthetic
reactions using conventional polymeric beads as a support.
For most resins used in SPOS, more than 95 % of the
substrate molecules are buried within the interior of the resin
bead,[1a] thus a direct electron transfer between the electrode
and the substrate molecules is not feasible. However, if a
redox catalyst (1 and 2) is used as a mediator, the electrontransfer step at the electrode and the redox reaction with the
substrate can be separated (Figure 1). This principle of
“indirect electrolysis” has already found widespread application in solution-phase electroorganic synthesis, where it offers
significant experimental advantages over a direct electrode
contact, such as, reduced overpotentials or higher selectivity.[5]
[*] S. Nad, Dr. R. Breinbauer
Department of Chemical Biology
Max-Planck-Institut f7r molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Universit;t Dortmund, Fachbereich 3, Organische Chemie
44227 Dortmund (Germany)
Fax: (+ 49) 231-133-2499
E-mail: rolf-peter.breinbauer@mpi-dortmund.mpg.de
[**] This work was supported by the Max-Planck-Society (pre-doctoral
fellowship for S.N.), the Fonds der Chemischen Industrie (Liebig
fellowship for R.B.), der Deutschen Forschungsgemeinschaft
(Br2324/1-1) and the District Nordrhein-Westfalen. R.B. thanks
Prof. H. Waldmann for ongoing support and encouragement.
Supporting information for this article (experimental details) is
available on the WWW under http://www.angewandte.org or from
the author.
Angew. Chem. Int. Ed. 2004, 43, 2297 –2299
Figure 1. Principle of redox-catalyst-mediated electroorganic synthesis
on the solid phase.
As a model reaction we chose the 2,5-dimethoxylation of
furans.[6] This electrolysis process is mediated by Br ions and
is performed widely in organic synthesis and on an industrial
scale.[7] The products formed are versatile starting materials
for further derivatization.[8] As the expected products are
known to be acid sensitive, we chose carboxy-terminated
linker 3 to enable cleavage of the reaction products from the
resin under basic conditions.[9] We attached 2-furan-propanol
(7 a) using common esterification methods (DIC) to tentagelresin 3 a (Scheme 1). Resin-bound substrate 4 a was subjected
Scheme 1. Reagents and conditions: a) 7 a (4 equiv), DIC (2.5 equiv),
DMAP (0.5 equiv), 0 8C!RT, 24 h; b) Tentagel 3 a: 0.2 m NH4Br,
MeOH, C-electrodes, undivided cell, galvanostatic electrolysis,
50 Fmol1, j = 15 mA cm2 ; PS-beads 3 b: 0.2 m Bu4NBr, MeOH/1,4dioxane (1/1), 0 8C, C-electrodes, 40 Fmol1, j = 15 mA cm2 ; c) LiOH
(5 equiv), 1,4-dioxane/H2O (20/1), RT, 2 days. DIC = diisopropylcarbodiimid, DMAP = N,N-dimethyl-4-aminopyridine.
to the standard electrolysis conditions used in solution
(Scheme 1). Cleavage of electrolysis product 5 a furnished
2,5-dimethoxydihydrofuran 6 a as a cis/trans mixture in
> 95 % purity (determined by 1H NMR spectroscopy and
GC/MS).
For reasons of cost and loading efficiency cross-linked
polystyrene (PS) resins still are the most widely used support
in SPOS, therefore we sought to modify our electrolysis
conditions to be compatible with polystyrene beads. We
identified Bu4NBr in MeOH/1,4-dioxane (1/1) as an ideal
DOI: 10.1002/anie.200352674
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2297
Communications
electrolyte, it has a high conducting efficiency and supports
the swelling properties of the resins. Repeating the experiment depicted in Scheme 1 with PS-beads (3 b) and the
adapted reaction conditions furnished 6 a in 57 % yield (over
three steps, > 97 % purity, determined by 1H NMR spectroscopy) without the need for a purification step after splitting
from the resin.[10]
Having identified the optimal reaction conditions we
explored the scope of this reaction (Scheme 1) with substrates
7 a–h (Scheme 2, Table 1). Apparently uninfluenced by the
substitution pattern the dimethoxylated 2,5-dihydrofurans
were formed in high yields (50–63 % over three steps) and
excellent purities starting from mono-, di-, and trisubstituted
Scheme 2. Reagents and conditions: a) 3 b, 7 a–h (4 equiv), DIC
(2.5 equiv), DMAP (0.5 equiv), RT, 24 h; b) 0.2 m Bu4NBr, MeOH/1,4dioxane (1/1), 0 8C, C-electrodes, 40 Fmol1, j = 15 mA cm2 ; c) LiOH
(5 equiv), 1,4-dioxane/H2O (20/1), RT, 1–2 days.
Scheme 3. Reagents and conditions: a) 3 b, 8 (4 equiv), DIC
(2.5 equiv), DMAP (0.5 equiv), RT, 24 h; b) TBAF (5 equiv), THF, RT,
36 h; c) 0.2 m Bu4NBr, MeOH/1,4-dioxane (1/1), 0 8C, C-electrodes,
40 Fmol1, j = 15 mA cm2 ; d) 2 % H2SO4, 1,4-dioxane, RT, 2 days;
e) HC(OMe)3 (1.4 equiv), BF3 ·Et2O (0.1 equiv), CH2Cl2, RT, 1 h;
f) NaBH4 (3 equiv), THF/H2O (20/1), RT, 4 h; g) LiOH (5 equiv), 1,4dioxane/H2O (20/1), RT, 1 day.
2,5-dialkoxydihydrofuran rearranged upon
addition of aq. H2SO4 in 1,4-dioxane to the
Entry Substrate R
R
R
R
Yield [%]
Purity [%]
6-hydroxy-2,3-dihydro-6H-pyran-3-on 10.
1
7a
(CH2)3OH
H
H H
57
97
After BF3·Et2O mediated acetalization
H
H CH3
63
97
2
7b
CH2OH
with HC(OMe)3, 1,2-reduction with
H
H H
50
95
3
7c
CH(CH3)OH
NaBH4, and cleavage by saponification the
4
7d
CH2NHCO(CH2)5OH H
H H
53
95
desired product (12) was isolated in 33 %
CH(CH3)OH H CH3
63
95
5
7e
CH3
yield (over seven steps on solid phase).[10]
6
7f
CH(OH)(CH2)4OH
H
H H
53
97
The reaction sequence detailed above
H
H H
0
–
7
7g
CO(CH2)4OH
H
H CH2NMe2
0
–
8
7h
CH2OH
clearly demonstrates that in contrast to
previous attempts using modified electro[a] Yield of isolated 6 a–h over three steps.
des[4] our indirect approach is suitable for
multistep syntheses on the solid phase
which can lead to libraries of diversified
furans (Table 1, entries 1–3 and 5). The electrochemical solidcompounds or natural products.
phase transformation tolerates various functional groups
In conclusion, we have presented a practical method for
(alkyl, OH, ester, amide). No reaction took place with
electroorganic synthesis with polymeric supports, which is
electron-poor furans 7 g and 5-(dimethylaminomethyl)furfurapplicable for library synthesis. We believe that the indirect
ylalcohol 7 h (Table 1, entries 7,8), whose unreactive behavior
electroorganic approach can be applied quite generally in
was known from earlier work in solution.[11] Substituting
solid-phase synthesis.
MeOH for EtOH in the electrolyte for the electrolysis of
Received: August 18, 2003
substrate 7 a furnished the corresponding diethoxylated
Revised: December 12, 2003 [Z52674]
dihydrofuran in 53 % (> 98 % purity).
To demonstrate the utility of the electroorganic solidKeywords: combinatorial chemistry · electrochemistry ·
phase method and that it can be easily implemented in a
heterocyclics · heterogeneous catalysts · solid-phase synthesis
multistep solid-phase synthesis, more demanding examples
Table 1: Scope and limitations of the electroorganic 2,5-dimethoxylation of 7 a–h on a solid phase.
1
2
3
4
[a]
.
were investigated. The target chosen was the highly functionalized product 12, which can serve as a scaffold for further
derivatization (Scheme 3).[8g, h, 12] The monosilyl-protected diol
8 was attached to PS-beads 3 b using a standard esterification
method. After deprotection with TBAF a-hydroxyfuran 9
was electrolyzed as described above. The resulting a-hydroxy-
2298
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angew. Chem. Int. Ed. 2004, 43, 2297 –2299
Angewandte
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For experimental procedures and a description of the electrochemical setup, see the Supporting Information. Experiments
comparing the electrochemical with non-electrochemical oxidation methods (see ref. [12]) are described there. In our hands the
electrochemical oxidation method gave superior results for the
chosen linker and substrate system than non-electrochemical
oxidation methods.
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618.
Angew. Chem. Int. Ed. 2004, 43, 2297 –2299
www.angewandte.org
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2299
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