Metal-catalyzed release of supported boronic acids for C-C bond formation

Article abstract of DOI:10.1021/ol000338y

matrix presented The viability of solid-supported boronic acids as reagents for Suzuki couplings and nucleophilic additions to aldehydes and enones was successfully demonstrated. This metal-catalyzed cleavage strategy allows the synthesis of a series of functionalized biphenyl products, benzylic alcohols, and β-substituted ketones.

Full text of DOI:10.1021/ol000338y

ORGANIC
LETTERS
2
001
Vol. 3, No. 6
03-805
Metal-Catalyzed Release of Supported
Boronic Acids for C−C Bond Formation
8
†
Christelle Pourbaix, Fran c¸ ois Carreaux,* and Bertrand Carboni*
UniVersit e´ Rennes 1, Synth e` se et Electrosynth e` se organiques, UMR 6510 associ e´ e au
CNRS, Campus de Beaulieu, 35042 Rennes Cedex, France
francois.carreaux@uniV-rennes1.fr
Received November 7, 2000
ABSTRACT
The viability of solid-supported boronic acids as reagents for Suzuki couplings and nucleophilic additions to aldehydes and enones was
successfully demonstrated. This metal-catalyzed cleavage strategy allows the synthesis of a series of functionalized biphenyl products, benzylic
alcohols, and â-substituted ketones.
Solid-phase reactions play an important role in parallel
synthesis and combinatorial chemistry, particularly in the area
of medicinal chemistry, where their potential has emerged
However, this strategy suffers from the fact that there is a
limited number of commercially available aryl boronic acids.6
We recently reported the preparation of a macroporous
support (1) that can be employed to efficiently immobilize
1
as a result of the possibility of automation. A considerable
7,8
amount of attention has been focused on adapting and
exploiting the advantages of solid-phase synthesis (SPS) for
the production of libraries of nonoligomeric, small organic
and transform functionalized arylboronic acids. One of the
major advantages of this boronate linker system is its possible
9
use in a resin capture process. Since the biaryl subunit is
2
molecules for biological screening. In this context, transition-
an important pharmacophore, present in a variety of biologi-
metal-promoted reactions serve as efficient methods because
they proceed under mild conditions and are compatible with
many functional groups. For instance, solid-phase Suzuki
(
4) Original references of solid-phase Suzuki reactions: (a) Frenette, R.;
Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177-9180. (b) Backes, B. J.;
3
Ellman, J. A. J. Am. Chem. Soc. 1994, 116, 11171-11172.
(5) For a selection of recent examples of solid-phase Suzuki reactions,
coupling has been largely developed mainly by reacting a
see: (a) Huwe, C. M.; K u¨ nzer, H. Tetrahedron Lett. 1999, 40, 683-686.
(b) Blettner, C. G.; K o¨ nig, W. A.; Rh u¨ ter, G.; Stenzel, W.; Schotten, T.
Synlett 1999, 307-310. (c) Chamoin, S.; Houldsworth, S.; Kruse, C. G.;
Iwema Baker, W.; Snieckus, V. Tetrahedon Lett. 1998, 39, 4179-4182.
(d) Amparo Lago, M.; Nguyen, T. T.; Bhatnagar, P. Tetrahedron Lett. 1998,
39, 3885-3888. (e) Wendeborn, S.; Berteina, S.; Brill, W. K.-D., De
Mesmaeker, A. Synlett 1998, 671-675. (f) Lorsbach, B. A.; Bagdanoff, J.
T.; Bryan Miller, R.; Kurth, M. J. J. Org. Chem. 1998, 63, 2244-2250. (g)
Garigipati, R. S. Tetrahedron Lett. 1997, 38, 6807-6810. (h) Yoo, S.-E.;
Seo, J.-S.; Yi, K.-Y.; Gong, Y.-D. Tetrahedron Lett. 1997, 38, 1203-1206.
(i) Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62, 7076-7077.
(j) Ruhland, B.; Bombrun, A.; Gallop, M. A. J. Org. Chem. 1997, 62, 7820-
7826. (k) Guiles, J. W.; Johnson, S. G.; Murray, W. V. J. Org. Chem. 1996,
61, 5169-5171. (l) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron
Lett. 1996, 37, 8219-8222.
(6) In comparison to more than 1500 commercially available carboxylic
acids, only 100-150 different boronic acids are offered by Aldrich and
Lancaster.
(7) Carboni, B.; Pourbaix, C.; Carreaux, F.; Deleuze, H.; Maillard, B.
Tetrahedron Lett. 1999, 40, 7979-7983.
(8) For other preparations of resin-bound boronic acids, see: Hall, D.
G.; Taylor, J.; Gravel, M. Angew. Chem., Int. Ed. 1999, 38, 3064-3067.
4-5
resin-bound aryl halide with a solution-phase boronic acid.
†
Current address: Facult e´ de Pharmacie, UMR CNRS/ULP 7081, 74
route du Rhin, 67401 Illkirch Cedex, France.
1) (a) Molecular DiVersity and Combinatorial Chemistry; Chaiken, I.
M., Janda, K. D., Eds; American Chemical Society: Washington, DC, 1996.
b) Combinatorial Chemistry; Wilson, S. R., Czarnik, A. W., Eds; Wiley-
Interscience: New York, 1997.
2) (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.; Gallop,
(
(
(
M. A. J. Med. Chem. 1994, 37, 1385-1401. (b) Thompson, L. A.; Ellman,
J. A. Chem. ReV. 1996, 96, 555-600. (c) Balkenhohl, F.; von dem Bussche-
H u¨ nnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996,
3
5, 2288-2337. (d) Obrecht, D.; Villalgordo, J. M. Solid Supported
Combinatorial and Parallel Synthesis of Small-Molecular-Weight Com-
pounds Libraries; Pergamon: New York, 1998. (e) Guillier, F.; Orain, D.;
Bradley, M. Chem. ReV. 2000, 100, 2091-2157.
(3) (a) Kingsbury, C. L.; Mehrman, S. J.; Takacs, J. M. Curr. Opin. Chem.
1
999, 3, 497-555. (b) Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99,
1
549-1581. (c) Wendeborn, S.; De Mesmaeker, A.; Brill, W. K.-D.;
Berteina, S. Acc. Chem. Res. 2000, 33, 215-224.
1
0.1021/ol000338y CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/22/2001

cally active compounds,10 we wished to determine whether
the synthesis of this structure could be carried out from
supported arylboronic acids.
product still being contaminated by 5% of the homocoupling
product (Scheme 2).
1
5
To the best of our knowledge, only one linear-solid-phase
strategy was so far reported based on immobilization of
boronic acids, which enables the concomitant formation of
a carbon-carbon bond and the functionalization within the
cleavage step.11,12 In this traceless approach, attachments of
boronic acids were indirectly achieved in a multistep
procedure and with the help of an auxiliary amide-containing
spacer.
Scheme 2
We describe herein the successful use of supported boronic
acids 2 as reagents not only in the Suzuki cross-coupling
reactions but also in addition reactions to aldehydes and
enones by metal-catalyzed cleavage procedures (Scheme 1).
This cleavage was further examined with different aryl
ring systems, and the liberated products were isolated in
moderate to good yields (Table 1). As significant demonstra-
Table 1. Suzuki Coupling-Release of Various Functionalized
Resins
Scheme 1
With the lack of an auxiliary spacer, our strategy offers the
additional advantage of attachment of boronic acids in a
single step by direct loading.
To find an efficient procedure for the Suzuki coupling of
supported arylboronic acids 2, preliminary experiments have
been performed on a model system. The resin-bound
phenylboronic acid was treated with 4-iodomethoxybenzene
13
under standard palladium coupling conditions. Analysis of
the resulting crude mixtures showed the presence of two
compounds: the desired product along with biphenyl derived
14
from homocoupling of the organoborane. Several combina-
tions of catalyst and base were tested to optimize the yield
and to lower the formation of the side product. The best result
a
was obtained with [Pd(dppf)Cl
2
] in association with K
3
PO
4
Yields of isolated products based on the loading of the resin 1 (1 mmol/
g). All compounds were purified by flash chromatography on silica gel.
(dppf ) 1,1′-bis(diphenylphosphanyl)ferrocene). By using
this catalytic system and 5 equiv of 4-iodomethoxybenzene,
the yield of the desired biaryl product was 67%, the crude
tion of the potential of this cleavage strategy and the
usefulness of resin 1 to generate new aryl boronic acids, the
coupling reaction was realized with a functionalized resin-
bound boronic acid, which was obtained from an UGI four-
(
9) (a) McCarthy, P. A. Med. Res. ReV. 1993, 13, 139-159. (b) Pavia,
M. R.; Cohen, M. P.; Dilley, G. J.; Dubuc, G. R.; Durgin, T. L.; Forman,
F. W.; Hediger, M. E.; Milot, G.; Powers, T. S.; Sucholeiki, I.; Zhou, S.;
Hangauer, D. G. Bioorg. Med. Chem. 1996, 4, 659-666.
9 1
component condensation (entry 5). H NMR of the crude
(10) Pourbaix, C.; Carreaux, F.; Carboni, B.; Deleuze, H. Chem. Commun.
material isolated from the resin indicated the formation of
only the desired product 3f (no homocoupling) along with
the excess of the 4-iodomethoxybenzene.
2
000, 1275-1276.
(
11) Li, W.; Burgess, K. Tetrahedron Lett. 1999, 40, 6527-6530.
(12) Recently, a successful strategy for resin-to-resin Suzuki coupling
reactions via phase transfer of solid-supported arylboronic acids was
described: Gravel, M.; B e´ rub e´ , C. D.; Hall, D. G. J. Comb. Chem. 2000, 2,
2
28-231.
(15) The yield was measured by GC versus benzophenone internal
standard relative to the loading of resin 1 (1 mmol/g). The mixture was
passed through silica plugs to remove excess ligand/metal before analysis.
(
13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
14) Yamaguchi, S.; Ohno, S.; Tamao, K. Synlett 1997, 1199-1201.
(
804
Org. Lett., Vol. 3, No. 6, 2001

Recently, it was demonstrated that the transmetalation
between boron and rhodium provided another C-C bond-
forming reaction via the 1,2-addition of aryl or 1-alkenyl-
corresponding benzylic alcohols 4 in moderate to good yields
but with a good purity (>95%) in all cases (entries 2-5).
The supported boronic acids 2 were also useful reagents
for nucleophilic 1,4-additions to enones. Methyl vinyl ketone
(MVK) was chosen as representative substrate. By using
1.2 equiv of resin-bound phenylboronic acid in the presence
of Rh(acac)(CO) (3 mol %) and triphenylphoshine (6 mol
2
%), the â-functionalized ketone 5a was obtained in 50% yield
(Table 3, entry 1). The use of a large excess of MVK (5
1
6
boronic acids to aldehydes and the 1,4-addition to R,â-
unsaturated ketones.17 A catalytic asymmetric 1,4-addition
20
1
7b,c
to enones has been reported by Hayashi and co-workers.
The efficiency of the protocol was also demonstrated in
18
similar addition reactions of organotrifluoroborate salts. We
envisioned that supported boronic acids also could be good
reagents for the aforementioned Rh(I)-catalyzed reactions.
To the best of our knowledge, no examples of successful
application of these reactions on solid phase have been
described so far. Of particular interest is that, in contrast to
biphenyl, the structures obtained in these reactions are more
rarely found in pharmaceutical compounds, which makes this
process attractive for the preparation of original libraries.
For initial studies, we opted to adapt the conditions
developed by Miyaura and co-workers for the arylation of
Table 3. Conjuguate Arylation and Alkenylation of MVK with
Supported Boronic Acids
16a
aldehydes. Reaction of resin-bound p-methylphenylboronic
acid with 1 equiv of benzaldehyde, Rh(acac)(CO) (3 mol
), and the ligand dppf (3 mol %) resulted in the formation
entry
R1
MVK (equiv) ketone yield (%)a purity (%)b
2
%
1
2
3
4
Ph
Ph
4-MeC H4
1.2
5
5
5a
5a
5b
5c
50
60
47
55
>95
>95
>95
>95
of the desired benzyl alcohol 4a. The unreacted aldehyde
was easily removed using the diol resin 1 as solid-support
6
19
scavenger of aldehydes. After cleavage, the crude product
was combined with polymer 1 at reflux in THF in the
presence of PTSA (cat.) to afford 4a in 62% yield and with
a high purity (>95%) (Table 2, entry 1). The increase of
1-hexenyl
5
a
Yields of isolated products based on the loading of the resin 1 (1 mmol/
g). All compounds were purified by flash chromatography on silica gel.
b
1
Determined by H NMR (apart from triphenylphosphine oxide).
equiv) noticeably improved the isolated yield to 60% (entry
). The supported 1-hexenylboronic acid also reacted with
2
Table 2. Arylation of Aldehydes with Supported Boronic
MVK using the same protocol, giving a comparable isolated
yield of the product 5c (entry 4). In each case, the material
liberated from the resin was relatively pure (>95%) con-
taminated only with triphenylphosphine oxide.
Acids
In conclusion, we successfully demonstrated the viability
of supported boronic acids as reagents for Suzuki couplings
and nucleophilic additions to aldehydes and enones. This
metal-catalyzed cleavage strategy allows the synthesis of a
series of funtionalized biphenyl compounds, benzylic alco-
hols, and â-substituted ketones. Added to the potential of
the resin 1 to generate libraries of several new aryl boronics
acids as reagents, this strategy is particularly promising
toward high-throughput combinatorial library synthesis. We
are currently looking to expand this approach to other types
entry
R1
R2
alcohol yield (%)a purity (%)b
1
2
3
4
5
4-MeC6H4 Ph
4a
4b
4c
4d
4e
62
43
63
81
56
>95
>95
>95
>95
>95
4-MeC6H4 4-ClC6H4
4-MeC6H4 4-F3CC6H4
4-MeC6H4 4-NCC6H4
Ph
4-NCC6H4
a
Yields of isolated products based on the loading of the resin 1 (1 mmol/
g). b GC purity of the crude reaction mixture. The mixture was passed
through silica plugs to remove excess ligand/metal before analysis.
2
1
of reactions involving boronic acids.
Acknowledgment. This research was supported by the
CNRS. We thank Dr. H. Deleuze (Universit e´ de Bordeaux
) for the preparation of the diol resin 1.
the amount of benzaldehyde to 2 equiv resulted in a
significant drop in the product yield to 44%. A variety of
aldehydes were functionalized in this manner to give the
1
Supporting Information Available: Experimental pro-
(16) (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998,
3
7, 3279-3281. (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450-
cedures and characterizations for compounds 3b-f, 4a-e,
and 5a-c. This material is available free of charge via the
Internet at http://pubs.acs.org.
4
452.
(17) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4
229-4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett.
1
998, 39, 8479-8482. (c) Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am.
OL000338Y
Chem. Soc. 1998, 120, 5579-5580.
(
18) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1, 1683-
686.
19) Immobilization of aldehydes using the diol resin of Leznoff was
1
(20) MVK was selected because of its low boiling point.
(
(21) For examples, see: (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-
P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933-2936. (b) Evans, D.
A.; Katz, J. L.; West, T. H. Tetrahedron Lett. 1998, 39, 2937-2940.
reported. Chamoin, S.; Houldsworth, S.; Kruse, C. G.; Iwema Baker, W.;
Snieckus, V. Tetrahedron Lett. 1998, 39, 4179-4182.
Org. Lett., Vol. 3, No. 6, 2001
805