COMMUNICATION
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Development of novel polymer-type dehydrocondensing reagents
comprised of chlorotriazines{
abc
a
a
Munetaka Kunishima,* Kazuyoshi Yamamoto, Yasunobu Watanabe, Kazuhito Hioki and Shohei Tani
ab
ab
Received (in Cambridge, UK) 8th February 2005, Accepted 21st March 2005
First published as an Advance Article on the web 7th April 2005
DOI: 10.1039/b501917f
A novel immobilized dehydrocondensing reagent comprised of
a triazine-type dehydrocondensing reagent itself in a poly-
merized form was synthesized by copolymerization between
tetra(ethylene glycol) bis(dichlorotriazinyl) ether and tris(2-
aminoethyl)amine.
of cyanuric chloride toward nucleophilic substitution, the idea did
not go beyond the conventional concept of supporting a reagent
on an existing polymer, therefore, the disadvantage of the
increase in molecular weight has not been improved, which
remains a problem to be solved for practical use. Changing our
way of thinking, we speculated that the immobilization of a
chlorotriazino group could be achieved without great increase in
molecular weight, when a cyanuric chloride derivative itself
could be converted to a polymer by direct polymerization by
efficiently exploiting the reactivity of all chlorine atoms of the
Because of both the research and industrial importance of amides
and esters, development of useful dehydrocondensing reagents has
received much attention. In spite of many studies on dehydro-
condensing reagents, reports of developing a solid-supported
1
10,11
reagent of this type that is practically useful are limited. For
cyanuric acid.
example, for the preparation of reported polymer-supported
reagents carrying EEDQ, DCC, TBTU, or DMC, inefficient
chemical transformations on the insoluble polymer under hetero-
On the basis of the reactivity of cyanuric chloride, in which the
three chlorine atoms show different reactivity toward nucleophilic
12
substitution, we designed polymer A as illustrated in Scheme 1.
At first, tetra(ethylene glycol) was allowed to react with cyanuric
chloride (2 equiv) in THF at 0 uC for 27 h, giving a O,O9-
bis(dichlorotriazino) compound 1 in a yield of 83%. A copolymeri-
zation was conducted by reacting 1 with the cross-linking reagent,
tris(2-aminoethyl)amine 2 bearing three primary amino groups, at
2,3
geneous conditions were required. On the contrary, a polymer-
supported EDC (P-EDC), in which EDC is connected via its
dimethylamino group can be prepared relatively easily. However,
the reaction introducing EDC to a polymer requires an excess
4,5
amount of expensive EDC under drastic conditions. On the
other hand, the weight proportion of the solid carrier relative to
the amount of solid-supported reagent is generally high, which is
inevitably linked to the generation of a large amount of waste, this
being a serious problem common to solid-supported reagents. For
instance, the molecular weight per unit reactivity of the P-EDC
reaches about 1250, which is greatly increased compared to that of
EDC hydrochloride, of which the original molecular weight is 192.
Therefore, the development of practically useful solid-supported
dehydrocondensing reagents without these disadvantages has been
desired.
2
40 uC to room temperature for 4 h, giving polymer A in a yield
13
of 68%. The polymer thus obtained was insoluble in any
common solvents, and could be simply purified by filtration,
followed by washing with water and organic solvents. The
condensing reactivity of polymer A was determined by measuring
the amount of free chloride ions released from the polymer by the
substitution reaction with NMM to form its active form (polymer
14
A ). As a result, the amount of chloride loaded on polymer A
ac
21
was 2.91 meq g , and the molecular weight per a unit of the
condensing activity was 344, indicating that polymer A was high
loading compared to conventional polymer-supported dehydro-
2,4
In the course of our research on the triazine-type dehydrocon-
6
densing reagent, we have succeeded in the first development of a
condensing reagents.
quite novel polymer type of dehydrocondensing reagent comprised
of chlorotriazines, which can solve the aforementioned problems.
Thus, the polymer reagent is eco-friendly, and has excellent cost
efficiency as well as good reactivity.
We examined dehydrocondensation of various carboxylic acids
3
with amines 4 using 2–3 equiv of polymer A in the presence of
NMM in CH Cl (Table 1). The active species for the
2
2
dehydrocondensation are considered to be polymer Aac, which
6,15
As examples of an immobilized reagent of triazine derivatives,
reagents in which cyanuric chloride is supported on the Wang resin
will be formed in situ during the reaction.
Treatment of a
mixture of 3-phenylpropionic acid 3a, DL-1-phenylethylamine 4a,
7–9
or MeO-PEG-OH have been reported.
The mean molecular
and NMM (2 equiv) in CH Cl with polymer A (2 equiv) at room
2
2
weight per a unit reactivity of these reagents reached up to 5000.
Furthermore, a large excess (5 equiv) of cyanuric chloride is
sometimes required to connect the triazino group into insoluble
polymers because of the inefficiency of heterogeneous conditions.
Although these reagents were prepared utilizing the high reactivity
temperature for 18 h afforded 5a in 70% (Run 1). The yield of 5a
was increased to 82% when 3 equiv of polymer A and NMM were
used (Run 2). The polymer chain was found to be stable under the
reaction conditions, with no decomposed compounds derived from
the polymer reagent being detected. Thus, the desired amide 5
could be simply obtained in pure form by filtering the reaction
mixture, followed by washing the filtrate with water. When the
reaction mixture was treated with an anion-exchange resin for
30 minutes, the amide 5 could be more simply obtained at a good
{ Electronic supplementary information (ESI) available: details of
preparation of polymer A. See http://www.rsc.org/suppdata/cc/b5/
b501917f/
*kunisima@pharm.kobegakuin.ac.jp
2
698 | Chem. Commun., 2005, 2698–2700
This journal is ß The Royal Society of Chemistry 2005