Development of chlorotriazine polymer dehydrocondensing reagents (Poly-Trzs)

Article abstract of DOI:10.1016/j.tet.2007.01.034

Polymer-type dehydrocondensing reagents comprising of a triazine dehydrocondensing reagent, itself in a polymerized form (Poly-Trz-MMs'), have been developed by exploiting the chemical properties of cyanuric chloride that readily binds to alcohol or amines. A chlorotriazine polymer bearing two alkoxy substituents at the 4- and 6- positions (Poly-O-Trz-Cl) was prepared by alternating copolymerization between cyanuric chloride and tetra(ethylene glycol). Similarly, polymers bearing both alkoxy and amino substituents (Poly-N-Trz-Cl) were synthesized from tetra(ethylene glycol) bis(4,6-dichlorotriazin-2-yl) ether 6 and tris(2-aminoethyl)amine 7 and/or ethylenediamine 8. All the polymers were shown to be good reagents for dehydrocondensation of carboxylic acids and amines in the presence of NMM, compared to the corresponding monomeric dehydrocondensing reagent (DMT-MM). The advantages of the polymeric reagents are as follows: (1) both the reaction and isolation procedure of dehydrocondensation can be greatly simplified, (2) the dehydrocondensation can be conducted in protic solvents as well as in common organic solvents, (3) the reagents can be efficiently prepared at a low cost, and (4) these reagents are considered eco-friendly, generating a lower amount of waste compared to conventionally related reagents because of high loading of the dehydrocondensing activity (ca. 3 mequiv/g).

Full text of DOI:10.1016/j.tet.2007.01.034

Tetrahedron 63 (2007) 2604–2612
Development of chlorotriazine polymer dehydrocondensing
reagents (Poly-Trzs)
a
a,b
Munetaka Kunishima,a,b,c, Kazuyoshi Yamamoto, Kazuhito Hioki,
*
Tomohito Kondo,a Masumi Hasegawaa and Shohei Tania,b
aFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
bLife Science Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
cPRESTO, JST, Nishi-ku, Kobe 651-2180, Japan
Received 11 December 2006; revised 16 January 2007; accepted 18 January 2007
Available online 20 January 2007
Abstract—Polymer-type dehydrocondensing reagents comprising of a triazine dehydrocondensing reagent, itself in a polymerized form
(Poly-Trz—MMs’), have been developed by exploiting the chemical properties of cyanuric chloride that readily binds to alcohol or amines.
A chlorotriazine polymer bearing two alkoxy substituents at the 4- and 6- positions (Poly-O-Trz–Cl) was prepared by alternating copolymer-
ization between cyanuric chloride and tetra(ethylene glycol). Similarly, polymers bearing both alkoxy and amino substituents (Poly-N-Trz–
Cl) were synthesized from tetra(ethylene glycol) bis(4,6-dichlorotriazin-2-yl) ether 6 and tris(2-aminoethyl)amine 7 and/or ethylenediamine
8. All the polymers were shown to be good reagents for dehydrocondensation of carboxylic acids and amines in the presence of NMM, com-
pared to the corresponding monomeric dehydrocondensing reagent (DMT–MM). The advantages of the polymeric reagents are as follows: (1)
both the reaction and isolation procedure of dehydrocondensation can be greatly simplified, (2) the dehydrocondensation can be conducted in
protic solvents as well as in common organic solvents, (3) the reagents can be efficiently prepared at a low cost, and (4) these reagents are
considered eco-friendly, generating a lower amount of waste compared to conventionally related reagents because of high loading of the
dehydrocondensing activity (ca. 3 mequiv/g).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
are many reports on polymer-supported acyl group-activat-
ing reagents consisting of a nitrophenol,2 1-hydroxybenzo-
triazole (HOBt),3 N-hydroxysuccinimide (HOSu),4
pyridine,5 and so on.6 For these polymer-supported reagents,
however, monomeric reagents for acylation or dehydro-
condensation, such as acid chlorides or 1,3-dicyclohexylcar-
bodiimide (DCC) is additionally required to introduce acyl
groups into the polymers.
In general, solid-supported reagents have advantages. For
example, the isolation and purification of desired products,
as well as the recovery of the reagents, can be simply per-
formed.1 The use of solid-phase reagents has advantages
over solid-phase synthesis, in that consumption of starting
materials and formation of desired products can be simply
monitored by chromatographic methods such as TLC. Fur-
thermore, when a reagent itself is toxic or has an irritating
odor, these properties can be buried by supporting it on
a polymer. In association with the progress in the field of
combinatorial chemistry, development and utilization of
solid-supported reagents were actively pursued for the pur-
pose of automating the synthetic process.
In contrast, solid-supported dehydrocondensing reagents are
very useful because they do not require the use of such addi-
tional coupling reagents. However, most reagents of this
type suffer disadvantages in practical use. For example, for
the preparation of reported polymer reagents carrying
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
DCC, 1-[bis(dimethylamino)methylene]-1H-benzotriazo-
lium tetrafluoroborate 3-oxide (TBTU), or 1,3-dimethyl-
2-imidazolidinone (DMC), chemical transformations of the
insoluble polymer under heterogeneous conditions were
required.7 In contrast, a polymer-supported carbodiimide
(P-EDC), in which 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide (EDC) is connected via its dimethylamino
group can be prepared with relative ease. However, the reac-
tion introducing EDC to a polymer requires an excess
amount of expensive EDC under forcing conditions.8 It
was reported that polymer-supported Mukaiyama reagents
Because of both the research and industrial importance of
amides and esters, development of useful dehydrocondens-
ing reagents has received much attention. In spite of many
reports on dehydrocondensing reagents, reports on develop-
ing solid-supported reagents of this type are limited. There
Keywords: Dehydrocondensing reagent; Triazine; Polymer; Immobilized
reagent.
* Corresponding author. Tel.: +81 78 974 1551; fax: +81 78 974 5689;
e-mail: kunisima@pharm.kobegakuin.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.034

M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
2605
could also be easily prepared by introducing 2-chloropyri-
dine to either Wang resin or Merrifield’s resin.9 On the
other hand, the weight proportion of the solid carrier rela-
tive to the amount of solid-supported reagent is generally
high, which inevitably generates a large amount of waste,
a serious problem common to solid-supported reagents.
For instance, the molecular weight per unit reactivity of
the aforementioned P-EDC and polymer-supported Mu-
kaiyama reagents reaches about 1250 and 800, respectively.
Therefore, practically useful solid-supported dehydrocon-
densing reagents that do not have these disadvantages
have been sought.
As an example of an immobilized reagent of triazine deriv-
atives,15–17 Taddei and Masala reported on a reagent in
which cyanuric chloride is supported on the Wang resin,
bearing amino functional groups.16a An improved polymer
reagent, in which a cyanuric group is used as a spacer, has
also been reported.16b Since the carrier resin used in these
polymer-supported reagents contains 1.0 mequiv/g of amino
group, the mean molecular weight per unit of the condensing
reagent reached at least over 1000. Furthermore, a large ex-
cess (5 equiv) of cyanuric chloride had to be used to connect
the triazino group to polymer. On the other hand, poly(ethyl-
ene glycol)-2,4-dichloro-1,3,5-triazine (PEG–DCT) was
synthesized as a soluble nucleophilic scavenger by reacting
poly(ethylene glycol) methyl ether (MeO–PEG–OH) with
cyanuric chloride, but the generation of a large amount of
waste was inevitable because MeO–PEG–OH has a large
mean molecular weight, approximately 5000.17 Although
these polymers were synthesized utilizing the high reactivity
of cyanuric chloride, the idea did not go beyond the con-
ventional concept of supporting a reagent on an existing
polymer; therefore, the disadvantage of the increase in
molecular weight prevailed. We now show that a chloro-
triazino group can be immobilized without great increase
in molecular weight when cyanuric chloride 1 itself is con-
verted to a polymer by efficiently exploiting the reactivity
of all the chlorine atoms of 1.18
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
(DMT–MM), a triazine-type dehydrocondensing reagent de-
veloped at our and other laboratories, can be simply obtained
by mixing 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)
and N-methylmorpholine (NMM) (Scheme 1).10,11 We
have originally found that DMT–MM with an high water
solubility enables the efficient conduction of an amide-form-
ing reaction in a protic solvent such as alcohols or water
(Scheme 2).11,12 The coproduced 4,6-dimethoxy-1,3,5-tri-
azin-2(1H)-one was shown to be recyclable.13 Furthermore,
cyanuric chloride 1, used as a starting material for synthesiz-
ing DMT–MM, has the advantage of being inexpensive. In
addition to its cost effectiveness, the use of this starting
material allows chemical modifications to be made easily
by selective substitution of its chloro substituents. Taking
advantage of the chemical property of this triazine dehydro-
condensing reagent, we have succeeded in solving the afore-
mentioned problems associated with solid-supported
condensing agents. We report herein the development of
polymer dehydrocondensing reagents comprised of chloro-
triazines, which have excellent cost effectiveness as well
as good reactivity.14
2. Results and discussion
2.1. O,O-Type polymeric triazine reagent (Poly-O-Trz)
To retain the reactivity of DMT–MM, an O,O-type triazine
structure bearing two oxygen substituents corresponding to
4,6-dimethoxy groups was considered favorable; thus we
attempted to synthesize a straight-chain polymer by alter-
nating copolymerization of cyanuric chloride 1 and tetra-
(ethylene glycol) 2. First, we used sodium carbonate or
N,N-diisopropylethylamine as a base, but were unable to
obtain the desired polymer, perhaps, because the second
chlorine atom of 1 was less reactive for the substitution by
an alcoholic hydroxyl group.20 Based on this reasoning,
we replaced the base with sodium hydride to enhance the
nucleophilicity of the hydroxyl group by converting it to
the alkoxide; the reaction was performed in diglyme at
125 ꢀC, giving precipitates. The polymer thus obtained
was insoluble in any common solvents and could be simply
purified by filtration followed by washing with water and
THF. The theoretical structure of the polymer, based on
mechanistic considerations of the reaction, is shown in
Scheme 3 (Poly-O-Trz–Cl), and the yield of Poly-O-Trz–
Cl was calculated as 45%, based on this structure. The linear
chain of Poly-O-Trz–Cl might be partially branched because
the third chloro group can undergo substitution with alkoxy
group under these strong reaction conditions.21 Poly-O-Trz–
Cl was treated with an excess amount of NMM (3 equiv) to
generate its active form (Poly-O-Trz–MM) in 82%
yield.22,23 The condensing reactivity of Poly-O-Trz–MM
was determined by measuring the amount of free chloride
ions released by the substitution reaction. As a result, the
amount of chloride loaded on Poly-O-Trz–Cl was at least
3.07 mequiv/g, and the molecular weight per unit of the con-
densing activity was 326, indicating that our polymer was
Cl
MeO
N
NaHCO3
MeOH
N
N
N
Cl
N
Cl
MeO
N
Cl
1
(CDMT)
MeN
MeO
O
N
N Me
(NMM)
MeO
N
N
Cl
O
(DMT-MM)
Scheme 1.
OMe
N
DMT-MM
– NMM•HCl
O
O
N
N
R1
O
R1 OH
solvent
OMe
OMe
N
N
O
R2R3NH
O
+
R1 NR2R3
HN
OMe
Scheme 2.

2606
M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
Table 1. Attempts to produce 5a in various solvents by a combination of
Poly-O-Trz–Cl and NMM (in situ generation of Poly-O-Trz–MM)
high loading compared to conventional polymer-supported
dehydrocondensing reagents.
Run
Solvent
Poly-O-Trz–Cl
(equiv)
Time
(h)
Yielda
of 5a (%)
Cl
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
MeOH
H2O
AcOEt
CH3CN
MeOH
1.1
2.0
2.0
3.0
2.0
3.0
3.0
3.0
2.0
2.0
22
3
21
21
3
21
21
21
21
21
52
84
90
90
64
89
76
87
55
87
N
N
Cl
N
Cl
N
1
Cl
NaH
N
N
THF–diglyme
-78°C–125°C, 21 h
y. 45%
+
OCH2CH2
O
4
H
OCH2CH2 OH
n
4
(Poly-O-Trz-Cl)
2
O
a
Isolated yield.
Cl
N
N
Me
N
NMM
y. 82%
When an excess of Poly-O-Trz–Cl (2 equiv) was used in
CH2Cl2, the reaction proceeded and gave the desired product
in good yield (Runs 1 and 2). The reaction seemed to be al-
most complete at room temperature within 3 h; the yield of
the amide was not greatly improved by prolongation of the
reaction time (Runs 2 and 3). It is noteworthy that water or
methanol as well as commonly used neutral organic solvents
could be used. The swelling of the polymer was insufficient
in THF or acetonitrile, which may explain the decreased
yield of the amide in these solvents.
N
O
OCH2CH2
4
n
(Poly-O-Trz-MM)
Scheme 3. Synthesis of Poly-O-Trzs.
We examined dehydrocondensation between 3-phenyl-
propionic acid 3a and DL-1-phenylethylamine 4a, as model
reactants. The reaction with Poly-O-Trz–MM (1.9 equiv
based on the loading of chloride) in CH2Cl2 for 19 h gave
the amide 5a in 56% yield in pure form after filtration
followed by washing with water (Scheme 4). DMT–MM
is known to readily decompose in less-polar organic sol-
vents by dechloromethylation at the methylmorpholinio
group.10a,b Thus, the methylmorpholinio group in a hydro-
phobic pocket of Poly-O-Trz–MM might partially undergo
decomposition during isolation and on storage, which may
be responsible for the observed moderate yield of 5a. In
order to avoid such decomposition, we employed in situ gen-
eration of Poly-O-Trz–MM from Poly-O-Trz–Cl and NMM.
Thus, a solution of both the reactants (3a and 4a) and NMM
was added to Poly-O-Trz–Cl, and the suspension was stirred
at room temperature. Results are summarized in Table 1.
The dehydrocondensation of various carboxylic acids with
amines was examined under the conditions using 2 equiv
of Poly-O-Trz–Cl with NMM in CH2Cl2 (Table 2). The re-
action was also found to proceed with a,b-unsaturated carb-
oxylic acid 3c or aromatic carboxylic acid 3d at room
temperature to give moderate to good yield within 3–4 h.
With regard to amines, the reaction proceeded not only
with primary amines, but also with bulky secondary amines
such as 4c (Run 5).
2.2. N,O-Type polymeric triazine reagent
(Poly-N-Trzs)14a
Although Poly-O-Trz–MM bearing two oxygen atoms in its
triazine rings showed good reactivity comparable to that of
DMT–MM, there were disadvantages in the reaction for
preparation of Poly-O-Trz–Cl; strong basic conditions and
a long heating time were required because the polymer
was not readily precipitated on polymerization. To solve
the problem, we planned to synthesize a cross-linked poly-
mer under milder conditions (at a lower temperature within
a shorter reaction period) by using an amino group with
higher nucleophilicity compared to that of a hydroxyl group.
Since the electron-donating property toward the triazine ring
is higher for nitrogen than for oxygen, it was anticipated
that dehydrocondensing reactivity might differ between an
Me
Poly-O-Trz-MM
COOH
3a (1 eq)
+
Ph
H2N Ph
CH2Cl2, rt, 19 h
y. 56%
4a (1 eq)
O
C
Me
Ph
N
H
Ph
5a
Scheme 4.
Table 2. Attempts to produce 5a in various solvents by a combination of Poly-O-Trz–Cl and NMM (in situ generation of Poly-O-Trz–MM)a
Run
Carboxylic acids
Amines
Amides
Yieldb (%)
1
2
3
4
5
3a
Ph(CH2)2NH2 (4b)
4b
4b
4b
Ph(CH2)2CONH(CH2)2Ph (5b)
p-MeO–C6H4CH2CONH(CH2)2Ph (5c)
PhCH]CHCONH(CH2)2Ph (5d)
PhCONH(CH2)2Ph (5e)
80
71
63
76
71
p-MeO–C6H4CH2COOH (3b)
PhCH]CHCOOH (3c)
PhCOOH (3d)
3a
PhCH2NHMe (4c)
Ph(CH2)2CONMeCH2Ph (5f)
a
The reaction was performed with Poly-O-Trz–Cl (2.1 equiv) and NMM (2.1 equiv) at rt for 3–4 h.
Isolated yield.
b

M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
2607
N,O-type cross-linked polymer and an O,O-type polymer.
Thus, in a preliminary experiment, we synthesized 2-chloro-
6-ethylamino-4-methoxy-1,3,5-triazine (AMT), an N,O-
type monomer bearing both methoxy and ethylamino
groups, as a model compound, and examined its reactivity.
The reactivity of AMT seemed somewhat lower than that
of CDMT; when a mixture of 3a and 4a was allowed to react
with AMT (1.2 equiv) in the presence of NMM (1.8 equiv) at
room temperature for 24 h, the desired amide 5a was
obtained in 62% yield in CH2Cl2. The reaction yield was
improved to 95% within 3 h by increasing the amount of
AMT (2 equiv) and NMM (3 equiv).
in 83% yield. A copolymerization was conducted by react-
ing 6 with the cross-linking reagent 7, bearing three primary
amino groups, at ꢁ40 ꢀC to room temperature, giving
Poly-N-Trz–Cl in 68% yield. The polymerization was com-
pleted within 4 h under milder conditions compared to the
polymerization for producing Poly-O-Trz–Cl. The amount
of reactive chlorotriazinyl group loaded on Poly-N-Trz–Cl
was 2.91 mequiv/g.25
The dehydrocondensation of 3a and 4a was performed using
Poly-N-Trz–MM generated in situ from Poly-N-Trz–Cl and
NMM in CH2Cl2, in a manner similar to that of Poly-O-
Trz–Cl (Table 3). Although the reaction was slower, than
that when AMT or Poly-O-Trz–Cl was used, 5a was
obtained in a good yield (82%) after being treated at room
temperature for 19 h (Run 1). The amides produced could
be simply obtained in an almost pure form by filtering the re-
action mixture, followed by washing the filtrate with water.
When the reaction mixture was treated with an anion-
exchange resin (Amberlite IRA-400) for 30 min, the desired
product could be more simply obtained in good purity by
concentrating the filtrate without washing with water
(Runs 3, 6–8). a,b-Unsaturated carboxylic acid 3c as well
as aliphatic carboxylic acids 3a and 3b were also found to
condense with primary amines 4a and 4b, or bulky second-
ary amine 4d, giving the corresponding amides in good
MeO
N
N
Cl
N
EtNH
(AMT)
On the basis of these findings an N,O-type polymer (Poly-N-
Trz), in which nitrogen and oxygen functionalities of differ-
ent reactivities are selectively introduced into the triazino
group was synthesized (Scheme 5). Initially, 1 (2 equiv)
was allowed to react with 2 (1 equiv) in THF at 0 ꢀC for
27 h, giving an O,O0-bis(dichlorotriazino) compound 614a
NH2
Cl
Cl
N
7
H2N
NH2
N
X
N
N
N
1 (2 equv)
+
i-Pr2NEt
THF, 0°C, 27 h
y. 83%
THF, -40°C to RT
N
N
N
2 (1 equv)
Cl
OCH2CH2
O
Cl
4 h
4
y. 68%
6
N
OCH2CH2
O
N
4
N
N
N
X
X
N
NH
X
N
X
X
N
NH
N
N
N
N
N
N
N
N
N
N
N
OCH2CH2
O
N
H
N
H
OCH2CH2
Me
O
N
H
N
H
4
4
n
Poly-N-Trz-Cl: X = Cl; Poly-N-Trz-MM: X =
Cl
O
N
Scheme 5. Synthesis of Poly-N-Trzs.
Table 3. Condensation of carboxylic acids with amines in CH2Cl2 (in situ generation of Poly-N-Trz–MM)
Run
Carboxylic
acid
Amine
Poly-N-Trz–Cl
(equiv)
NMM
(equiv)
Time
(h)
Product
Yield
(%)
1
3a
3a
3a
3b
3c
3a
4a
4b
4b
4b
3.0
3.0
2.0
3.0
3.0
2.5
2.5
2.5
2.5
3.0
3.0
2.0
3.0
3.0
2.5
4.0
4.0
2.5
19
19
20
19
19
20
20
20
20
5a
5b
5b
5c
5d
82
97
85
Quant
97
83
2
3a
4
5
4b
6a
7a
8
Et2NH (4d)
H–Phe–OMe (4e)
4e
Ph(CH2)2CONEt2 (5g)
Z–Gly–Phe–OMe (5h)
Boc–Leu–Phe–OMe (5i)
Ph(CH2)2CONH(CH2)2OH (5j)
Z–Gly–OH (3e)
Boc–Leu–OH (3f)
3a
81
92b
87
9a
HO(CH2)2NH2 (4f)
a
The reaction mixture was treated with Amberlite IRA-400 OH and then filtered.
No detectable amount of the epimer was observed by HPLC.
b

2608
M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
Table 4. Yield and loading of lower degrees of cross-linked Poly-N-Trzs–Cl
unsuitable for practical use because it is very sticky. Thus,
the polymers with 50% (Poly-N-Trz50–Cl) and 25% (Poly-
N-Trz25–Cl) cross-linking were examined for dehydrocon-
densation to give 5b (Table 5). Both of them were found to
give amides in good yields in CH2Cl2, and a slight improve-
ment in reaction yield was observed compared with, Poly-N-
Trz–Cl with 100% cross-linking (Poly-N-Trz100–Cl). The
results may indicate that Poly-N-Trz100–Cl has a sufficient
space, which is attributable to the long chain of tetra(ethylene
glycol) connecting two triazinyl groups, allowing reactants
to approach to the triazinyl group inside the polymer net-
work. The dehydrocondensation of various compounds was
found to proceed in good yields by using Poly-N-Trz50–Cl
and Poly-N-Trz25–Cl (Table 6). Amides can be prepared in
MeOH in good yields and, in water, in moderate yields.
Cross-linking
(%)
Molar ratio
6:7:8
Yield
(%)
Loading
(mequiv/g)
MWav
50
25
10
5:2:2
9:2:6
21:2:18
63
70
64
3.76
3.30
2.85
266
303
351
yields under the same conditions. When polar compounds
are used for the reaction of non-immobilized monomeric re-
agents such as DMT–MM and EDC, the isolation procedures
may be troublesome. Condensation of amino acid deriva-
tives 3e, 3f, and 4e, or hydroxyethylamine 4f, could be read-
ily performed, and the desired products were isolated by the
simple procedures of filtration and concentration (Runs 7–
9). Notably, a selective reaction occurred at the nitrogen
atom, producing the corresponding amide in the case of
the reaction of 4f (Run 9).
3. Conclusion
The slow reaction using a combination of Poly-N-Trz–Cl/
NMM was due to not only electron-donating amino substit-
uents at the triazine ring (as observed in AMT), but also as
a consequence of the highly cross-linked structure of the
polymer in which access of the reactants to the reaction
center may be hindered. Thus, we attempted to prepare
polymers with low degrees of cross-linking, in which the
tris-primary amine 7 was partially substituted with ethylene-
diamine 8. Three types of Poly-N-Trz–Cl with different
degrees of cross-linking (50%, 25%, and 10%) were pre-
pared,14b and all of these were found to be high loading
(Table 4).26 The polymer with 10% cross-linking was found
In conclusion, by exploiting the reactivity of chlorotriazines,
we succeeded in developing new practical polymeric con-
densing reagents. The polymers developed here have an im-
portant, distinguishing characteristic, they are produced by
copolymerization of a monomeric condensing reagent. The
polymer can be synthesized in a homogeneous medium,
therefore, the polymerization proceeds with high efficiency
and only a stoichiometric amount of the chlorotriazine deriv-
atives is needed. Because no carrier is used, the amount of
waste can be greatly reduced. Furthermore, cyanuric chlo-
ride and ethylene glycols used as starting materials are
inexpensive, affording excellent cost effectiveness. Conden-
sation can be performed by a very simple procedure, mixing
a carboxylic acid and an amine together with the polymer. In
particular, there is a great advantage in Poly-Trzs, because
protic solvents such as eco-friendly water or alcohols can
be used. Unfortunately, however, an attempt in regenerating
the Poly-O-Trz–Cl, after it had been used for condensation,
according to our procedure for regeneration of CDMT using
POCl3/Et2NPh was unsuccessful.13 We are currently seeking
a suitable method for recycling the polymers. It is expected
that more highly functionalized polymeric dehydrocondens-
ing reagents can be synthesized by extending the concept
developed here, because it is possible to introduce various
types of hydroxyl or amino functionality in the side chain
of the triazinyl group.
Table 5. Effect of the degree of cross-linking on the synthesis of 5b
Cross-linking (%)
Time (h)
Yield of 5b (%)
100
100
50
25
25
10
20
20
10
20
71
81
88
73
88
Table 6. Condensation of carboxylic acids with amines by in situ generation
of Poly-N-Trz–MM with different degrees of cross-linkinga
Run Product
Solvent
Yield (%)
Cross-linking
50%
25%
1
Ph(CH2)2CONHCHMePh (5a)
Ph(CH2)2CONH(CH2)2Ph (5b)
5b
5b
p-MeO–C6H4CH2CONH(CH2)2Ph (5c) CH2Cl2 92
PhCH]CHCONH(CH2)2Ph (5d)
PhCONH(CH2)2Ph (5e)
CH2Cl2 85
CH2Cl2 88
MeOH 85
62
87
ncf
45
93
73
71
93
88
ncf
77
76
4. Experimental section
4.1. General methods
2
3b
4b
5
H2O
46
1H NMR spectra were recorded on a Bruker DPX 400 spec-
trometer. Chemical shifts are reported as d values relative to
tetramethylsilane as an internal standard. Infrared spectra
were recorded on a Nicolet FT-IR AVATER 360 spectro-
meter. Mass spectra were measured on a Micromass Zq2000
spectrometer (ESI-MS), and a JEOLThe MStation JMS-700
(EI-MS). Differential scanning calorimetric (DSC) study
was performed with Shimadzu DSC-50 with thermal ana-
lyzer (TA-50WS); a polymer (4–5 mg) was loaded into alu-
minum sample pan, sealed, and heated at a rate of 10 ꢀC/min
in the temperature range of ꢁ20 ꢀC to 150 ꢀC under a nitro-
gen flow of 20 mL/min.
6
7
CH2Cl2 79
CH2Cl2 80
CH2Cl2 91
CH2Cl2 87
CH2Cl2 85e
CH2Cl2 77
MeOH 83
8
Ph(CH2)2CONEt2 (5g)
9c,d Z–Gly–Phe–OMe (5h)
10d Boc–Leu–Phe–OMe (5i)
11c Ph(CH2)2CONH(CH2)2OH (5j)
12b 5j
a
Reactions were performed with 3 (1.0 equiv), 4 (1.5 equiv), Poly-N-Trz–
Cl (2.5 equiv), and NMM (2.5 equiv) at rt for 20 h.
Reactions were performed with 3 (1.5 equiv) and 4 (1.0 equiv).
The reaction mixture was treated with Amberlite IRA-400 OH.
Four equivalents of NMM were used.
b
c
d
e
f
A trace amount of the epimer (0.2%) was detected by HPLC.
Reaction was not conducted.

M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
2609
1
All solvents and chemicals were obtained from commercial
sources and used as received unless otherwise noted. Prepar-
ative thin-layer chromatography (TLC) was performed on
Merck precoated silica gel plates.
IR (KBr): 3260, 1646, 1557 cmꢁ1; H NMR (CDCl3) d:
1.40 (d, J¼6.9 Hz, 3H), 2.46–2.50 (m, 2H), 2.97 (t,
J¼7.5 Hz, 2H), 5.10 (qd, J¼6.9, 7.2 Hz, 1H), 5.51 (br s,
1H), 7.16–7.32 (m, 10H); HRMS (EI) m/z calcd for
C17H19NO (M+) 253.1467, found 253.1457.
4.2. Preparation of Poly-O-Trz–Cl
4.4.2. N-Phenethyl-3-phenylpropanamide (5b).10b Color-
To a suspension of sodium hydride (5.47 g, 228 mmol) in
THF (40 mL) was added tetra(ethylene glycol) (2, 23.2 g,
119 mmol) at 0 ꢀC under nitrogen atmosphere and stirred
for 1 h at 0 ꢀC and for 1 h at room temperature. The reaction
mixture was cooled to ꢁ78 ꢀC, and cyanuric chloride (1,
20.0 g, 109 mmol) dissolved in THF (70 mL) was added
dropwise. The resulting mixture was stirred successively at
ꢁ78 ꢀC, ꢁ40 ꢀC, 0 ꢀC, and at room temperature in each
for 1 h. After addition of diglyme (35 mL), the mixture
was stirred at 50 ꢀC for 1 h and then heated to 125 ꢀC, during
which THF was distilled off. After heating for 16 h at
125 ꢀC, the resulting mixture was cooled to 0 ꢀC, and solid
material was collected by suction, followed by successive
washing with THF, water, and THF, and drying in vacuo to
give 14.8 g of (45% yield) Poly-O-Trz–Cl. IR (KBr):
less crystals; 94.5–95.5 ꢀC; IR (KBr): 3299, 1635,
1
1544 cmꢁ1; H NMR (CDCl3) d: 2.42 (t, J¼7.7 Hz, 2H),
2.74 (t, J¼6.9 Hz, 2H), 2.94 (t, J¼7.7 Hz, 2H), 3.48 (td,
J¼6.9, 6.0 Hz, 2H), 5.31 (br s, 1H), 7.07–7.10 (m, 5H);
HRMS (EI) m/z calcd for C17H19NO (M+) 253.1467, found
253.1476.
4.4.3. 2-(4-Methoxyphenyl)-N-phenethylacetamide
(5c).10b Colorless crystals; mp 98–98.5 ꢀC; IR (KBr):
1
3286, 1643, 1544, 1241, 1037 cmꢁ1; H NMR (CDCl3) d:
2.71 (t, J¼6.8 Hz, 2H), 3.45 (td, J¼6.8, 6.1 Hz, 2H), 3.46
(s, 2H), 5.39 (br s, 1H), 6.82–6.87 (m, 2H), 7.02–7.10 (m,
4H), 7.18–7.26 (m, 3H); HRMS (EI) m/z calcd for
C17H19NO2 (M+) 269.1416, found 269.1425.
1628, 1490, 1141, 1112, 1058, 858, 813, 1646, 1557 cmꢁ1
.
4.4.4. N-Phenethylcinnamamide (5d).10b Colorless nee-
dles; mp 126–127 ꢀC; IR (KBr): 3299, 1650, 1614,
1
4.3. Determination of the activity of Poly-O-Trz–Cl by
titration of chloride
1544 cmꢁ1; H NMR (CDCl3) d: 2.89 (t, J¼6.9 Hz, 2H),
3.66 (td, J¼6.9, 6.0 Hz, 2H), 5.73 (br s, 1H), 7.21–7.37 (m,
8H), 7.45–7.50 (m, 2H), 7.62 (d, J¼15.6 Hz, 1H); HRMS
(EI)m/zcalcdforC17H17NO(M+) 251.1310, found251.1319.
To a suspension of Poly-O-Trz–Cl (62.0 mg) in distilled wa-
ter (10 mL) was added NMM (0.61 mmol, 61.6 mg) at room
temperature. After being stirred for 1 h at room temperature,
sodium nitrate (1.01 mmol, 86.2 mg) was added, and stirred
for 2 h. The resulting suspension was diluted with distilled
water, and titrated with silver nitrate (0.01 mol/L). The
amount of chloride collected was 0.190 mmol, which indi-
cated the unit activity to be 3.07 mequiv/g (0.190 mmol/
62.0 mg).
4.4.5. N-Phenethylbenzamide (5e).10b Colorless crystals;
mp 113–114 ꢀC; IR (KBr): 3345, 1639, 1542 cmꢁ1 1H
;
NMR (CDCl3) d: 2.93 (t, J¼6.9 Hz, 2H), 3.71 (td, J¼6.9,
5.9 Hz, 2H), 6.24 (br s, 1H), 7.21–7.27 (m, 3H), 7.29–7.35
(m, 2H), 7.36–7.42 (m, 2H), 7.44–7.50 (m, 1H), 7.67–7.71
(m, 2H); HRMS (EI) m/z calcd for C15H15NO (M+)
225.1154, found 225.1161.
4.4. Preparation of Poly-O-Trz–MM
4.4.6. N-Benzyl-N-methyl-3-phenylpropanamide (5f).11
1
Colorless oil; IR (neat): 1645 cmꢁ1; H NMR (CDCl3) for
NMM (399 mg, 3.94 mmol) was added to a suspension of
Poly-O-Trz–Cl (402 mg, 1.23 mmol) in THF (10 mL) at
room temperature. After being stirred for 20 min, the reac-
tion mixture was filtered to collect solid material, which
was washed with THF, followed by Et2O, and then dried
in vacuo to give Poly-O-Trz–MM (432.5 mg). IR (KBr):
1302, 1333 cmꢁ1; the signals at 1058, 858, and 813 cmꢁ1
observed in Poly-O-Trz–Cl, which can be assigned for C–
Cl stretching of chlorotriazine, disappeared in the polymer
product.
a major conformational isomer d: 2.64–2.71 (m, 2H), 2.84
(s, 3H), 2.97–3.06 (m, 2H), 4.59 (s, 2H), 7.15–7.35 (m,
10H); for a minor conformational isomer d: 2.64–2.71 (m,
2H), 2.84 (s, 3H), 2.97–3.06 (m, 2H), 4.45 (s, 2H), 7.06–
7.10 (m, 2H), 7.15–7.35 (m, 8H); HRMS (EI) m/z calcd
for C17H19NO (M+) 253.1467, found 253.1461.
4.4.7. N,N-Diethyl-3-phenylpropanamide (5g).11 Color-
less oil; IR (neat): 1641 cmꢁ1; 1H NMR (CDCl3) d: 1.10 (t,
J¼7.1 Hz, 3H), 1.11 (t, J¼7.1 Hz, 3H), 2.59 (t, J¼7.9 Hz,
2H), 2.99 (t, J¼7.9 Hz, 2H), 3.22 (q, J¼7.1 Hz, 2H), 3.38
(q, J¼7.1 Hz, 2H), 7.17–7.31 (m, 5H); HRMS (EI) m/z calcd
for C13H19NO (M+) 205.1467, found 205.1460.
4.4.1. Synthesis of N-(1-phenylethyl)-3-phenylpropan-
amide (5a) with Poly-O-Trz–MM.
A mixture of
3-phenylpropionic acid (3a, 0.150 mmol, 22.5 mg) and
DL-1-phenethylamine (4a, 0.150 mmol, 18.1 mg) was added
to Poly-O-Trz–MM (0.285 mmol) at room temperature, and
the mixture was stirred for 19 h at room temperature fol-
lowed by filtration. Solid material was washed successively
with CH2Cl2–acetone (1:1), and the organic phases were
combined and concentrated. The residue was dissolved in
Et2O, and the resulting solution was washed successively
with water, NaHCO3, water, HCl (1 mol/L), water, and brine.
The solution was dried over MgSO4 and concentrated to give
a 21.4 mg of 5a17 (56%). Colorless crystals; mp 50–51 ꢀC;
4.4.8. Z–Gly–Phe–OMe (5h).27 Colorless oil; IR (neat):
1731, 1673, 1531 cmꢁ1 1H NMR (DMSO-d6) d: 2.86–
;
3.01 (m, 2H), 3.56 (s, 3H), 3.51–3.64 (m, 2H), 4.42–4.48
(m, 1H), 4.99 (s, 2H), 7.16–7.38 (m, 11H), 8.28 (d,
J¼8.0 Hz, 1H); HRMS (FAB) m/z calcd for C20H23N2O5
[(M+1)+] 371.1607, found 371.1619.
4.4.9. Boc–Leu–Phe–OMe (5i).11 Colorless crystals; mp
83.5–84 ꢀC; IR (KBr): 3342, 3307, 1743, 1666,
1
1523 cmꢁ1; H NMR (CDCl3) d: 0.91 (d, J¼6.2 Hz, 3H),

2610
M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
0.92 (d, J¼6.4 Hz, 3H), 1.24–1.31 (m, 1H), 1.44 (s, 9H),
1.57–1.69 (m, 2H), 3.09 (dd, J¼5.9, 13.7 Hz, 1H), 3.14
(dd, J¼5.8, 13.7 Hz, 1H), 3.71 (s, 3H), 4.07 (br s, 1H),
4.77 (br s, 1H), 4.84 (td, J¼5.9, 7.8 Hz, 1H), 6.44 (br d,
J¼7.5 Hz, 1H), 7.08–7.13 (m, 2H), 7.21–7.31 (m, 3H);
MS (EI) m/z: 392 (M+).
diisopropylethylamine (11.9 g, 92.2 mmol) in THF (6 mL)
at 0 ꢀC under nitrogen atmosphere. After being stirred for
27 h at 0 ꢀC, the reaction mixture was filtered to remove in-
soluble material, and the filtrate was concentrated. The resi-
due was dissolved in AcOEt and washed with water. The
organic layer was dried, concentrated, and then purified by
silica gel column chromatography (hexane–AcOEt¼8:2) to
give 18.8 g of 6 (83%) as a colorless oil; IR (neat): 1541,
4.4.10. N-(2-Hydroxyethyl)-3-phenylpropanamide (5j).11
1
Colorless needles; mp 72.5–73.5 ꢀC (AcOEt/hexane); IR
1508, 1252, 1054, 804 cmꢁ1; H NMR (CDCl3) d: 3.64–
1
(KBr): 3293, 1646, 1556 cmꢁ1; H NMR (CDCl3) d: 2.36
3.70 (m, 8H), 3.86–3.88 (m, 4H), 4.65–4.67 (m, 4H); 13C
NMR (CDCl3) d: 68.8, 69.8, 71.0, 71.2, 171.4, 172.8. Anal.
Calcd for C14H16Cl4N6O5: C, 34.31; H, 3.29; N, 17.15; Cl,
28.93. Found: C, 34.12; H, 3.39; N, 16.96; Cl, 28.72.
(br s, 1H), 2.50 (t, J¼7.6 Hz, 2H), 2.98 (t, J¼7.6 Hz, 2H),
3.33–3.39 (m, 2H), 3.63 (d, J¼5.0 Hz, 2H), 5.58 (br s,
1H), 5.72 (dd, J¼17.6, 0.9 Hz, 1H), 7.18–7.24 (m, 3H),
7.27–7.32 (m, 2H). Anal. Calcd for C11H15NO2: C, 68.37;
H, 7.82. Found: C, 68.19; H, 7.82.
4.8. Preparation of Poly-N-Trz–Cl
To a solution of 6 (3.07 g, 6.26 mmol) in THF (4 mL) were
added dropwise a solution of tris(2-aminoethyl)amine (7,
0.61 g, 4.18 mmol) and N,N-diisopropylethylamine
(3.24 g, 25.1 mmol) in THF (2 mL) at ꢁ40 ꢀC, and stirred
for 1.5 h at the same temperature. The reaction mixture
was allowed to warm to 0 ꢀC and was stirred for 1.5 h, fol-
lowed by stirring at room temperature for 1.5 h. The result-
ing solid material was collected by suction, and washed
successively with dry THF, 2-PrOH, water, THF, and Et2O,
and dried in vacuo to give 2.18 g of Poly-N-Trz–Cl (68%);
4.5. General procedure for the synthesis of amides with
Poly-O-Trz–Cl
A mixture of 3a (0.194 mmol, 29.1 mg), 4a (0.194 mmol,
23.5 mg), and NMM (0.41 mmol, 41.7 mg) was added to
Poly-O-Trz–Cl (0.41 mmol) at room temperature, and the
mixture was stirred for 21 h at the same temperature. The
reaction mixture was filtered, and solid material was washed
with CH2Cl2–acetone (1:1) and MeOH. The filtrate was
combined with the organic phases, and concentrated. The
residue was dissolved in Et2O, and the resulting solution
was washed successively with water, NaHCO3, water, HCl
(1 mol/L), water, and brine. The solution was dried over
MgSO4 and concentrated to give a crude product, which
was purified on preparative TLC (hexane–AcOEt¼1:1) to
give 44.2 mg of 5a (90%).
IR (KBr): 3284, 1517, 1336, 1289, 1125, 1057, 807 cmꢁ1
.
4.9. Determination of the activity of Poly-N-Trz–Cl by
titration of chloride
To a suspension of Poly-N-Trz–Cl (26.4 mg) in distilled wa-
ter (10 mL) was added sodium nitrate (0.50 mmol, 43.6 mg).
After being stirred for 10 min at room temperature, the mix-
ture was filtered, and the solid was washed three times with
distilled water 5 mL each. The resulting solid was treated
with NMM (0.31 mmol, 31.2 mg) to determine the dehydro-
condensing activity according to the method for Poly-O-Trz–
Cl. The amount of chloride collected was 0.0769 mmol,
which indicated the unit activity to be 2.91 mequiv/g
(0.0769 mmol/26.4 mg).
4.6. Synthesis of 2-chloro-6-ethylamino-4-methoxy-
1,3,5-triazine (AMT)
To a solution of 2-methoxy-4,6-dichloro-1,3,5-triazine
(5.00 g, 27.8 mmol) in dry THF (200 mL) was added drop-
wise N,N-diisopropylethylamine (10.8 g, 83.3 mmol), fol-
lowed by ethylamine hydrochloride (2.27 g, 27.8 mmol).
After being stirred for 48 h, the solvent was removed
in vacuo, and the resulting crude product was dissolved in
AcOEt, followed by washing with 0.1 M HCl and water.
The organic phase was dried over MgSO4, and concentrated
in vacuo. Silica gel column chromatography (hexane–
AcOEt¼7:3) yielded AMT (4.24 g, 81%): colorless crystals;
4.10. General procedure for the synthesis of amides with
Poly-N-Trz–Cl
A mixture of 3a (0.155 mmol, 23.3 mg), 4a (0.155 mmol,
18.8 mg), and NMM (0.47 mmol, 47.1 mg) was added to
Poly-N-Trz–Cl (0.47 mmol) at room temperature, and the
mixture was stirred for 19 h at room temperature followed
by filtering. The solid was washed with CH2Cl2–acetone
(1:1), and the organic phases were combined and concen-
trated. The residue was dissolved in Et2O, and the resulting
solution was washed successively with water, NaHCO3,
water, 1 mol/L HCl, water, and brine. The solution was dried
and concentrated to give 32.2 mg of 5a (82%). Alternatively,
for 5g–5i, the reaction mixture was poured into a suspension
of IRA-400 (OH type) in MeOH, and stirred for 30 min. The
resulting mixture was filtered and concentrated to give 5.
mp 89–91 ꢀC, IR (KBr): 3268, 1637, 1570, 1299, 802 cmꢁ1
;
1H NMR (CDCl3) [a mixture of conformational isomers (ca.
1:2)] d: 1.24 (t, J¼7.2 Hz, 3H), 3.45–3.54 (m, 2H), 3.94 (s,
OCH3 of the minor isomer), 4.00 (s, OCH3 of the major iso-
mer), 5.61 (br s, CONH of the minor isomer), 5.83 (br s,
CONH of the major isomer); 13C NMR (CDCl3) the major
conformational isomer: d: 14.9, 36.5, 55.6, 167.2, 170.5,
171.7; the minor conformational isomer: d: 15.1, 36.6,
55.5, 167.3, 171.0, 171.8. Anal. Calcd for C6H9ClN4O: C,
38.21; H, 4.81; Cl, 18.80; N, 29.70. Found: C, 38.11; H,
4.64; Cl, 18.76; N, 29.96.
4.7. Synthesis of 1,11-bis(4,6-dichloro-1,3,5-triazin-2-
yloxy)-3,6,9-trioxaundecane (6)14a
4.11. General procedure for preparing lower cross-
linked polymer (Poly-N-Trz50–Cl)
To a solution of 1 (17.0 g, 92.2 mmol) in dry THF (50 mL)
was added a solution of 2 (8.95 g, 46.1 mmol) and N,N-
A solution of 7 (0.48 g, 3.26 mmol), ethylenediamine (8,
0.20 g, 3.26 mmol), and N,N-diisopropylethylamine

M. Kunishima et al. / Tetrahedron 63 (2007) 2604–2612
2611
1999, 40, 239–242; (d) Golisade, A.; Calenbergh, S. V.; Link,
A. Tetrahedron 2000, 56, 3167–3172.
7. (a) Brown, J.; Williams, R. E. Can. J. Chem. 1971, 49, 3765–
3766; (b) Weinshenker, N. M.; Shen, C.-M. Tetrahedron Lett.
1972, 3285–3288; (c) Weinshenker, N. M.; Shen, C.-M.;
Wong, J. Y. Org. Synth. Coll. Vol. VI 1988, 951–954; (d)
(2.11 g, 16.3 mmol) in THF (10 mL) was added dropwise to
a solution of 6 (4.00 g, 8.16 mmol) in THF (4 mL) at
ꢁ40 ꢀC, and stirred for 1.0 h at the same temperature. The
reaction mixture was allowed to warm to 0 ꢀC and stirred
for 1.5 h, followed by stirring for 1.5 h at room temperature.
The resulting solid material was collected by suction, and
washed successively with dry THF, 2-PrOH, water, THF,
and Et2O, and dried in vacuo to give 2.56 g of Poly-N-
Trz50–Cl (68%); IR (KBr): 3280, 1568, 1336, 1058,
ꢀ
Chinchilla, R.; Dodsworth, D. J.; Najera, C.; Soriano, J. M.
Tetrahedron Lett. 2000, 41, 2463–2466; (e) Disadee, W.;
Watanabe, T.; Ishikawa, T. Synlett 2003, 115–117; (f) Valeur,
E.; Bradley, M. Chem. Commun. 2005, 1164–1166.
8. (a) Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993,
34, 7685–7688; (b) Sturino, C. F.; Labelle, M. Tetrahedron
Lett. 1998, 39, 5891–5894.
9. (a) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004,
6, 4579–4582; (b) Convers, E.; Tye, H.; Whittaker, M.
Tetrahedron Lett. 2004, 45, 3401–3404.
807 cmꢁ1
.
DSC phase transition temperature (onset temperature): Poly-
N-Trz50–Cl: 74.6 ꢀC (4.69 mg); Poly-N-Trz25–Cl: 71.6 ꢀC
(4.98 mg); scan rate 10 ꢀC/min.
10. (a) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Tetrahedron Lett. 1999, 40, 5327–5330; (b) Kunishima, M.;
Kawachi, C.; Morita, J.; Terao, K.; Tani, S. Tetrahedron
1999, 55, 13159–13170; (c) Kaminski, Z. J.; Paneth, P.;
Rudzinski, J. J. Org. Chem. 1998, 63, 4248–4255; (d) Falchi,
A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000,
275–277.
Acknowledgements
M.K. thanks the Research Foundation for Pharmaceutical
Science. This work was partially supported by MEXT ‘Aca-
demic Frontier’ Project (2006).
11. Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Iwasaki, F.;
Tani, S. Tetrahedron 2001, 57, 1551–1558.
References and notes
12. Of course, the dehydrocondensing reaction can be performed
efficiently in commonly used neutral aprotic organic solvents
(Ref. 10).
13. Kunishima, M.; Hioki, K.; Wada, A.; Kobayashi, H.; Tani, S.
Tetrahedron Lett. 2002, 43, 3323–3326.
14. For preliminary reports, see: (a) Kunishima, M.; Yamamoto,
K.; Watanabe, Y.; Hioki, K.; Tani, S. Chem. Commun. 2005,
2698–2700; (b) Hioki, K.; Yamamoto, K.; Tani, S.;
Kunishima, M. Pept. Sci. 2006, 485–486.
15. (a) Kaminski, Z. J. Biopolymers 2000, 55, 140–164; (b) Blotny,
G. Tetrahedron 2006, 62, 9507–9522.
16. (a) Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355–1357; (b)
Luo, G.; Xu, L.; Poindexter, G. S. Tetrahedron Lett. 2002,
43, 8909–8912.
17. Falchi, A.; Taddei, M. Org. Lett. 2000, 22, 3429–3431.
18. For polymer dehydrocondensing reagents, catalytic decarbonyl-
ation of highly toxic diisocyanatohexane was reported to give
hexamethylenecarbodiimide as a linear polymeric structure
(Ref. 19a). More recently, a high-loading polymer-gel carrying
fluoroformamidinium salt was prepared by ring opening
metathesis polymerization (ROMP) (Ref. 19b).
1. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. C.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815–4195; (b) Kirschning, A.; Monenschein, H.;
Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650–679; (c)
Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.;
Hebel, A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3694–
4000; (d) McNamara, C. A.; Dixon, M. J.; Bradley, M.
Chem. Rev. 2002, 102, 3275–3300.
2. (a) Fridkin, M.; Patchornik, A.; Katchalski, E. J. Am. Chem.
Soc. 1966, 88, 3164–3165; (b) Kalir, R.; Fridkin, M.;
Patchornik, A. Eur. J. Biochem. 1974, 42, 151–156; (c)
Huang, X.; Chan, C.-C.; Zhou, Q.-S. Synth. Commun. 1982,
12, 709–714; (d) Cohen, B. J.; Karoly-Hafeli, H.; Patchornik,
A. J. Org. Chem. 1984, 49, 922–924; (e) Kim, K.; Le, K.
Synlett 1999, 1957–1959.
ꢀ
3. (a) Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997,
62, 2594–2603; (b) Dendrinos, K.; Jeong, J.; Huang, W.;
Kalivretenos, A. G. Chem. Commun. 1998, 499–500; (c)
Dendrinos, K. G.; Kalivretenos, A. G. Tetrahedron Lett.
1998, 39, 1321–1324; (d) Adamczyk, M.; Fishpaugh, J. R.;
Mattingly, P. G. Tetrahedron Lett. 1999, 40, 463–466; (e)
19. (a) Wolman, Y.; Kivity, S.; Frankel, M. J. Chem. Soc., Chem.
Commun. 1967, 629–630; (b) Barrett, A. G. M.; Bibal, B.;
€
Hopkins, B. T.; Kobberling, J.; Love, A. C.; Tedeschi, L.
Tetrahedron 2005, 61, 12033–12041.
ꢀ
Chinchilla, R.; Dodsworth, D. J.; Najera, C.; Soriano, J. M.
Tetrahedron Lett. 2001, 42, 4487–4489.
20. de Hoog, P.; Gamez, P.; Driessen, W. L.; Reedijk, J.
Tetrahedron Lett. 2002, 43, 6783–6786.
21. Both the degree of polymerization and cross-linking are
unclear because Poly-O-Trz–Cl is insoluble in any common
solvents.
22. The yield was calculated based on the theoretical structure.
23. CDMT cannot react directly with carboxylic acid whereas
DMT–MM can react with carboxylic acid leading to the forma-
tion of amides or esters (Ref. 24). Therefore, the addition of
NMM to Poly-Trz–Cl to generate Poly-Trz–MM is essential
for dehydrocondensation.
4. (a) Andreev, S. M.; Tsiryapkin, V. A.; Samoilova, N. A.;
Mironova, N. V.; Davidovich, Y. A.; Rogozhin, S. V.
Synthesis 1977, 303–304; (b) Barrett, A. G. M.; Cramp,
S. M.; Roberts, R. S.; Zecri, F. J. Org. Lett. 2000, 2, 261–
ꢀ
264; (c) Arnauld, T.; Barrett, A. G. M.; Hopkins, B. T.; Zecri,
F. J. Tetrahedron Lett. 2001, 42, 8215–8217.
5. (a) Barrett, A. G. M.; Smith, M. L.; Zecri, F. J. Chem. Commun.
1998, 2317–2318; (b) Chen, J.; Dixon, B. R.; Dumas, J.;
Brittelli, D. Tetrahedron Lett. 1999, 40, 9195–9199.
6. (a) Akiyama, M.; Shimizu, K.; Aiba, S.; Katoh, H. Bull. Chem.
Soc. Jpn. 1985, 58, 1421–1425; (b) Svirskaya, P. I.; Leznoff,
C. C.; Steinman, M. J. Org. Chem. 1987, 52, 1362–1364; (c)
Weidner, J. J.; Parlow, J. I.; Flynn, D. L. Tetrahedron Lett.
24. Kunishima, M.; Yoshimura, K.; Morigaki, H.; Kawamata, R.;
Terao, K.; Tani, S. J. Am. Chem. Soc. 2001, 123, 10760–10761.

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25. With regard to the cross-linking Poly-N-Trz–Cl, the tertiary
amino group derived from cross-linker 7 contained a chloride
anion as a hydrochloride, to some extent because hydrogen
chloride was produced in the synthetic process of the polymer.
Therefore, first, the chloride anion was exchanged for a nitrate
anion by treatment with an excess amount of an aqueous
sodium nitrate, and then, the amount of chloride anion newly
released from the chlorotriazino group by treatment with
NMM to form Poly-N-Trz–MM was determined according to
the method mentioned above.
26. The degree of cross-linking was defined as molar percentage of
7 per total amount of amines (7+8) employed. Since Poly-N-
Trzs in Scheme 5 was defined as 100% cross-linking, it can
be abbreviated as Poly-N-Trzs100
27. Miyazawa, T.; Ensatsu, E.; Hiramatsu, M.; Yanagihara, R.;
.
Yamada, T. J. Chem. Soc., Perkin Trans. 1 2002, 396–401.