SHORT PAPER
1611
Development and Synthesis of an Arylboronic Acid-based Solid-Phase
Amidation Catalyst
Synthesis of
a
So
i
lid-Pha
c
se Amidati
honCatalyst Latta, Greg Springsteen, Binghe Wang*
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Fax +1(919)5153757; E-mail: binghe_wang@ncsu.edu
Received 8 March 2001; revised 2 May 2001
phase catalyst was studied following the procedure of
Yamamoto,3 and is summarized in Tables 1 and 2 for py-
ridine-3-boronic acid and the N-methyl derivative, respec-
tively. As can be seen from the results presented in these
two tables, both pyridineboronic acid and N-methylpy-
ridineboronic acid were efficient amidation catalysts.
Therefore, we proceeded to attach pyridineboronic acid to
a solid support.
Abstract: A polystyrene-bound pyridineboronic acid was synthe-
sized and shown to be an efficient, easily recoverable and reusable
amidation catalyst.
Key words: arylboronic acid, amidation, catalyst, solid-phase, re-
coverable
Amide bond formation is of great interest to synthetic and
pharmaceutical chemists, and several routes exist for the
formation of amides from carboxylic acids and amines in
solution phase.1 Although the reactions are high yielding,
stoichiometric byproducts from carboxyl activation need
to be removed from the reaction mixture and disposed of.
With the advent of combinatorial chemistry, there is a
great deal of interest in the development of solid-phase re-
agents for a variety of reactions that can be easily separat-
ed from the reaction mixture, and in some cases reused.
Herein we report the development of the first, to our
knowledge, solid-phase amidation catalyst.
Solution-phase catalysts
B(OH)2
B(OH)2
N
+
N
I-
1
2
Solid-phase catalyst
+
B(OH)2
PS
N
Cl-
Many boron-based compounds, such as ClB(OMe)2,
HB(i-Pr)2, and catecholborane,2 are known to activate car-
boxylic acids for amidation reactions via the formation of
mixed anhydrides. However, these reactions require a
minimum of one equivalent of boron reagent that will ul-
timately be transformed into an inactive species. Yama-
moto and coworkers3 have recently developed several
arylboronic acids that are efficient amidation catalysts in
solution-phase. Due to our long-standing interest in solid-
phase reactions4 and peptide chemistry5 we are interested
in exploring the possibility of developing boron-based
solid-phase amidation catalysts, which are easily removed
form the solution and reusable.
3
PS = polystyrene
Figure Structures of the solution-phase and solid-phase catalysts
prepared
Compound 3 (Figure) was designed and synthesized by
refluxing Merrifield’s resin (1.26 mmol Cl–/g of resin)
and pyridine-3-boronic acid propane-1,3-diol cyclic ester6
(2 equivalents) in CH2Cl2–DMF (1:1, 24–48 h). The re-
sulting resin was stirred in THF–water (4:1, 24 h, r.t.) to
To achieve a high yielding, efficient, amidation catalyst, a hydrolyze the boronate ester and provide polystyrene-
reagent had to be designed with a strongly Lewis acidic bound pyridine-3-boronic acid (92% loading). We chose
boronic acid. Pyridinium rings are known to be electron to use a polystyrene-based polymer as the solid support
deficient, and alkylation of the pyridine nitrogen allows because it is readily available and swells very well in or-
for its ready attachment to a solid-phase material. Howev- ganic solvents. Catalytic activity was examined by a mod-
er, neither pyridineboronic acid nor N-alkylated py- ified solution-phase procedure and in most cases the
ridineboronic acid has been tested as a catalyst for desired amide was isolated in excellent yield (Table 3)
amidation reactions. Therefore, we first performed the so- with the exception of entry 5. Improved yields and/or
lution-phase amidation reaction using pyridine-3-boronic shorter reaction times can be achieved, at no additional
acid6,7 (1) and N-methylpyridine-3-boronic acid (2)7 as the cost, by increasing the percentage of catalyst (Table 3, en-
catalysts (Figure). The catalytic activity of each solution-
tries 1 and 2). We also examined the potential of the cata-
lyst to be recycled and found that there was no loss of
activity over three runs (Table 4). Experience in the labo-
ratory has shown us that the resin can be reused many
more times, and is stable to open air. Preliminary studies
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1611,1613,ftx,en;M01201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881