Boronate linker for 'traceless' solid-phase synthesis

Article abstract of DOI:10.1039/b003487h

The development of a new boron-based strategy for 'traceless' solid- phase synthesis of aromatic compounds is reported. A resin capture process can precede the cleavage step.

Full text of DOI:10.1039/b003487h

Boronate linker for ‘traceless’ solid-phase synthesis
Christelle Pourbaix,a François Carreaux,*a Bertrand Carboni,*a and Hervé Deleuzeb
a Synthèse et Electrosynthèse organiques, UMR 6510 CNRS, Université de Rennes 1, Campus de Beaulieu, 35042
Rennes Cedex, France. E-mail: francois.carreaux@univ-rennes1.fr
b Laboratoire de Chimie Organique et Organométallique, UMR 5802 CNRS, Université de Bordeaux 1, 351, Cours
de la libération, 33405 Talence, France
Received (in Liverpool, UK) 2nd May 2000, Accepted 2nd June 2000
Published on the Web 26th June 2000
The development of a new boron-based strategy for ‘trace-
less’ solid-phase synthesis of aromatic compounds is re-
ported. A resin capture process can precede the cleavage
step.
The solutions obtained after filtration of the resin were
evaporated to dryness, the residue was taken up in a mixture of
EtOAc and H2O, and, after separation of the layers, the organic
solvent was evaporated. In all cases, the remaining products
were > 85% pure as determined by GC or NMR.11
The combinatorial library approach is increasingly used for the
discovery and development of new drugs, catalysts and
materials.1 Most of the organic chemical libraries reported to
date have been constructed using solid-phase methods. A key
aspect of these strategies is the linkage element, which acts as a
tether to the polymeric support material. Typically, linkage to
the polymeric support is based on a protecting group. However,
after cleavage from the support, the presence of the functional
group previously used for the attachment may have a negative
effect on the biological or chemical properties of the target
compounds. To overcome this disadvantage, alternative ap-
proaches were developed where linkage through a functional
group can be excised efficiently, when desired, leaving behind
no trace or ‘memory’ of the solid-phase synthesis (formation of
a new C–H or C–C bond).
Of particular interest to combinatorial chemistry is the use of
resin 1 to immobilize functionalized boronic acid templates and
carry out different solid-phase transformations. As an example,
butan-1-ol was coupled to resin-bound p-carboxyphenylboronic
acid 2, to afford the corresponding ester 3 in 56% after cleavage.
Similarly, resin-bound m-aminophenylboronic acid 4 was
Only a few ‘traceless’ linkers have been reported so far for
the synthesis of aromatic compounds, none of which are
general.2 As part of a program to develop new solid-phase
synthetic methodologies, we became interested in exploring the
use of polymer-supported arylboronates. We have prepared
recently a macroporous support 1 which was found to be
efficient in immobilizing a wide variety of arylboronic acids
under mild and neutral conditions.3,4 Since protonolysis of
arylboranes is a well-documented reaction,5 we planned to use
the boronate functionality as a new traceless linker for the solid-
phase synthesis of aromatic compounds. Furthermore, since the
polymer 1 is extremely selective in its reactions with boronic
acids, the boronate linker can be used in another strategy where
the synthesis is initiated in solution and the material is
subsequently captured by solid support before performing
‘traceless’ cleavage. In each approach, the cleavage step is
associated with the regeneration of the resin 1 (Scheme 1).
In order to find an efficient procedure for the traceless
cleavage of supported arylboronates, preliminary experiments
have been performed on the resin-bound m-nitrophenylboronic
acid (Table 1). Protodeboronation of arylboranes usually occurs
under drastic hydrolytic conditions, catalysed by conc NaOH6
or conc HCl.7 Due to the incompatibility of these procedures
with various acid or base sensitive functional groups, transition
metal salts have attracted our attention as mild protonolysing
reagents.8 After some unsuccessful experiments, it was found
that nitrobenzene can be obtained using an aqueous solution of
Ag(NH3)2NO2 in EtOH at rt (entry 1)9 and that the use of THF
instead of EtOH significantly improved the yield (entry 2). The
optimized conditions required 10 equiv. of 0.5 M aq.
Ag(NH3)2NO3 in THF at 75–80 °C for 8 h (yield 75%, purity
> 95%)(entry 4). The use of a gel-type glycerol-PS resin10 led
to < 50% of deboronation under the same conditions, clearly
underlining the benefit of macroporous resin 1. This cleavage
was further examined with different aryl ring systems and the
liberated products were isolated in moderate to good yields
(entries 5–7).
Scheme 1
Table 1 Protodeboronation of resin-bound arylboronic acids using an
aqueous silver ammonium nitrate complexa
Yield Purity
Entry Ar
Conditions
(%)b (%)c
1
2
3
4
5
6
7
3-NO2-C6H4
Ag(NH3)2NO3 (2 equiv.),
EtOH–H2O (1 1), 48 h, rt
Ag(NH3)2NO3 (2 equiv.),
THF–H2O (1 1), 48 h, rt
Ag(NH3)2NO3 (10 equiv.),
THF–H2O (1 1), 48 h, rt
Ag(NH3)2NO3 (10 equiv.),
THF–H2O (1 1), reflux, 8 h
Ag(NH3)2NO3 (10 equiv.),
THF–H2O (1 1), reflux, 8 h
36
60
75
77
95
80
35
> 95
> 95
> 95
> 95
> 95
85
3-NO2-C6H4
3-NO2-C6H4
3-NO2-C6H4
1-Naphthyl
3,4-OCH2O-C6H4 Ag(NH3)2NO3 (10 equiv.),
THF–H2O (1 1), reflux, 8 h
4-MeO-C6H4
Ag(NH3)2NO3 (10 equiv.),
THF–H2O (1 1), reflux, 8 h
a Aqueous silver diamine nitrate (0.5 M) was prepared by titrating silver
nitrate solution with sufficient ammonia to dissolve all precipitate (pH 7–8).
b Yields of isolated product (based upon loading of resin 1, 1 mmol g21).
c GC purity of the crude reaction mixture.
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DOI: 10.1039/b003487h
Chem. Commun., 2000, 1275–1276
This journal is © The Royal Society of Chemistry 2000
1275

Scheme 2 GC or NMR purities are given in brackets. Reagents and
conditions: i, SOCl2 (15 equiv.), toluene, 70 °C, 12 h, then filtration and
washing, then BuOH (10 equiv.), pyridine (15 equiv.), toluene, 25 °C, 24 h;
ii, Ag(NH3)2NO3 (0.5 M in water, 10 equiv.), THF, reflux, 8h; iii,
4-MePhSO2Cl (5 equiv.), EtN(Pri)2 (10 equiv.), CH2Cl2, 25 °C, 12 h.
transformed into sulfonamide 5 upon treatment with p-
methylphenylsulfonyl chloride (Scheme 2).
The exact mechanism of the silver ion catalyzed proto-
deboronation has not been clearly demonstrated, but the
hypothesis of an arylmetal intermediate is strongly favoured.8
Note that, after washing (water, THF and Et2O), the filtered
slightly green resin can be reused for another attachment
without requiring a regeneration step and with no apparent loss
of activity.
The resin capture strategy is very promising for library
generation since it combines the flexibility of solution synthesis
with the purity of solid-phase products. In this regard, resin 1
could be very useful in capturing only organoboron products
from complex reaction mixtures and, subsequently, to perform
‘traceless’ cleavage. For example, some transformations in the
solution-phase of functionalized boronic acids have been
realized using an excess of various reagents. m-Aminophe-
nylboronic acid 6 was transformed into anilide by treatment
with benzoyl chloride and p-formylphenylboronic acid 9 was
subjected to a reductive amination with benzylamine. The crude
products of these reactions were combined with resin 1 at reflux
in THF to afford 7 and 10. The desired products 8 and 11 were
obtained in excellent purities and yields after cleavage. As
another significant demonstration of the interest of such an
approach, an UGI four-component condensation12 was carried
out with 12, benzylamine, benzylisonitrile and isobutyr-
aldehyde in MeOH at 60 °C for 12 h. After evaporation of the
solvent, the crude product was treated with 1 to selectively
afford 13. After cleavage, the a-(acylamino) amide 14 was
obtained in 57% yield and with a high purity ( > 90%), as shown
in Scheme 3. To the best of our knowledge, this constitutes the
first example of resin capture which releases product with
formation of a carbon–hydrogen bond in place of the resin
attachment.
In conclusion, we have developed a new ‘traceless’ linker
technology for solid-phase chemistry. The conditions of
cleavage are compatible with the presence of functional groups
such as amines, amides, esters, ethers and sulfonamides.13 The
boronate linker system is distinct from the existing alternatives
by its ability to regenerate the polymer, and its use in a resin
capture process. Other reactions of polymer-supported bor-
onates in the formation of a new carbon–carbon bond instead of
the initial boron–carbon bond are currently in progress in our
laboratory.
Scheme 3 In brackets are given the GC or NMR purities. Reagents and
conditions: i, EtCOCl (7 equiv.), pyridine (7 equiv.), CH2Cl2, rt, 20 h; ii,
resin 1 (1 equiv.), THF, reflux, 16 h; iii, Ag(NH3)2NO3 (0.5 M in water, 10
equiv.), THF, reflux, 8 h; iv, propanediol (1.2 equiv.), Et2O, rt, 30 min; v,
PhCH2NH2 (4 equiv.), NaBH(OAc)3 (4 equiv.), CH2Cl2–DMF (1 1), rt, 24
h; vi, PhCH2NH2 (1.2 equiv.), PriCHO (1.2 equiv.), PhCH2NC (1.2 equiv.),
MeOH, 60 °C, 12 h.
D. J. Schaefer, T. S. Power, H. W. Turner and W. H. Weinberg, Angew.
Chem., Int. Ed., 1999, 38, 2494.
2 For a recent review, see: B. Reitz, Curr. Opin. Drug Discovery Dev.,
1999, 2, 358.
3 B. Carboni, C. Pourbaix, F. Carreaux, H. Deleuze and B. Maillard,
Tetrahedron Lett., 1999, 40, 7979.
4 For other preparations of resin bound boronic acids, see: D. G. Hall, J.
Taylor and M. Gravel, Angew. Chem., Int. Ed., 1999, 38, 3064; W. Li
and K. Burgess, Tetrahedron Lett., 1999, 40, 6527.
5 M. Vaultier and B. Carboni, in Comprehensive Organometallic
Chemistry II, eds. G. Wilkinson, F. G. A. Stone and V. E. Abel,
Pergamon Press, Oxford, 1995, Vol. 11, p. 191.
6 A. D. Ainley and F. Challenger, J. Chem. Soc., 1930, 2171.
7 H. G. Kuivila and K. V. Nahabedian, J. Am. Chem. Soc., 1961, 83,
2159.
8 H. G. Kuivila, J. F. Reuwer Jr. and J. A. Mangravite, J. Am. Chem. Soc.,
1964, 86, 2666.
9 D. S. Kemp and D. C. Roberts, Tetrahedron Lett., 1975, 52, 4629.
10 The glycerol-PS resin (Purchased from Novabiochem. Inc.) was
coupled to m-nitrophenylboronic acid in THF, under the same
conditions as with resin 1.
11 A small amount of boronic acid can be detected in some cases, (5–10%).
This by-product results from the hydrolysis of the boronate linker and is
easily removed by treating the crude of the reaction after cleavage with
the diol resin 1 under the immobilization conditions of boronic acids.
The polymer 1 is then used as solid-supported scavenger of boronic
acids.
12 I. Ugi, S. Lohberger and R. Karl, in Comprehensive Organic Synthesis,
eds. B. M. Trost and I. Fleming, Pergamon, New York, 1991, Vol. 2, p.
1083.
We thank Dr B. Maillard (Université de Bordeaux 1) for
fruitful discussions.
Notes and references
1 For selected reviews, see: D. Obrecht and J. M. Villalgordo, Solid
Supported Combinatorial and Parallel Synthesis of Small-Molecular-
Weight Compounds Libraries, Pergamon, New York, 1998; L. A.
Thompson and J. A. Ellman, Chem. Rev., 1996, 96, 555; B. Jandeleit,
13 All new, nonpolymeric compounds were completely characterized (1H
NMR, 13C NMR, IR, MS, elemental analysis, or HRMS).
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Chem. Commun., 2000, 1275–1276