A divergent synthesis of new aliphatic poly(ester-amine) dendrimers bearing peripheral hydroxyl or acrylate groups

Article abstract of DOI:10.1016/S0040-4039(02)02329-8

A novel class of aliphatic poly(ester-amine) dendrimers, bearing hydroxyl or acrylate peripheral groups, was designed and synthesized via a divergent strategy using readily available piperazine, diethanolamine and acryloyl chloride as the monomeric building blocks.

Full text of DOI:10.1016/S0040-4039(02)02329-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9417–9419
A divergent synthesis of new aliphatic poly(ester-amine)
dendrimers bearing peripheral hydroxyl or acrylate groups
Yaowu Sha,* Liang Shen and Xiaoyin Hong
State Laboratory of Bioorganic Phosphorus Chemistry, Department of Chemistry, School of Life Science and Engineering,
Tsinghua University, Beijing 100084, PR China
Received 26 July 2002; revised 30 September 2002; accepted 11 October 2002
Abstract—A novel class of aliphatic poly(ester-amine) dendrimers, bearing hydroxyl or acrylate peripheral groups, was designed
and synthesized via a divergent strategy using readily available piperazine, diethanolamine and acryloyl chloride as the monomeric
building blocks. © 2002 Elsevier Science Ltd. All rights reserved.
Dendrimers are highly ordered, globular monodisperse
macromolecules composed of branched repeat units
emanating from a central core.1 As a result of their
structural precision, globular shape and high function-
ality, dendrimers are currently being synthesized and
investigated for applications in catalysis,2 molecular
encapsulation,3 light harvesting4 and drug delivery.5
However, the synthesis of dendrimers often involves
multiple steps of protection/deprotection and compli-
cated purification, that limits their widespread use. In
previous work, only methacrylate-terminated den-
drimers have been synthesized by modification of
amino functional poly(propyleneimine) dendrimers
through a Michael reaction.6 Here we report the devel-
opment of an efficient and convenient divergent
approach for the synthesis of aliphatic poly(ester-
The synthesis is shown in Scheme 1. Piperazine was
acylated using 2 equiv. of acryloyl chloride in the
presence of 2 equiv. of Et3N to produce GO-(acrylate)2,
1, which was purified by column chromatography (70%
yield). A Michael reaction between diethanolamine and
the acrylate end groups on GO-(acrylate)2 was readily
accomplished using only 1.05 equiv. of diethanolamine
in ethanol to produce G1-(OH)4, 2, in 85% yield after
purification by precipitation from acetone. Then, G1-
(OH)4 was acylated with 4.2 equiv. acryloyl chloride in
the presence of 4.2 equiv. of Et3N to produce G1-(acry-
late)4, 3, in 79% yield after column chromatography.
The G2-(OH)8, 4, dendrimer was prepared by reaction
of 4.4 equiv. of diethanolamine with G1-(acrylate)4 in
ethanol. The residual diethanolamine was removed by
precipitation of 4 from cold acetone (82% yield). Like-
wise, G2-(acrylate)8, 5, was obtained in 62% yield
through esterification of 4 and G3-(OH)16, 6, was
obtained in 80% yield by Michael addition of 5 with 9.2
equiv. of diethanolamine in THF. Reiteration of the
esterification with 6 produced G3-(acrylate)16 den-
drimer, 7 (48% yield). The structures were identified
through ESI-MS, NMR and IR spectroscopy.7
amine)
dendrimers
using
readily
available
diethanolamine and acryloyl chloride as monomeric
building blocks. The hydroxyl and acrylate peripheral
groups could be easily further derivatized for different
purposes. This divergent synthesis produced not only
water-soluble hydroxyl-terminated dendrimers but also
acrylate-terminated dendrimers for the first time. Using
this approach, a third generation G3-(OH)16 dendrimer
bearing 16 hydroxyl end groups and a third generation
G3-(acrylate)16 bearing 16 acrylate end groups were
obtained. In each step, only a small excess (515%) of
reagent was required to achieve quantitative growth.
A typical procedure is described as follows for the
preparation of compounds 5 and 6: A solution of
acryloyl chloride (2.7 g, 29.9 mmol) in 10 mL CH2Cl2
was added dropwise to solution of G2-(OH)8 (3.7 g, 3.6
mmol) and Et3N (3.2 g, 31.7 mmol) in 60 mL CH2Cl2 at
−5°C over 1 h. The reaction mixture was stirred
overnight at room temperature, then, Et3N·HCl was
filtered off. The filtrate was diluted with 100 mL
CH2Cl2 and extracted with 2×50 mL NaHCO3 (10%)
and 1×50 mL brine. The organic phase was dried over
MgSO4, filtered and distilled to give the crude product.
Keywords: synthesis; poly(ester-amine); dendrimer.
* Corresponding author. Tel.: 8610-62783878; fax: 8610-62771149;
e-mail: shayw@mail.tsinghua.edu.cn
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02329-8

9418
Y. Sha et al. / Tetrahedron Letters 43 (2002) 9417–9419
Scheme 1. Divergent synthesis of poly(ester-amine) dendrimers. Reagents and conditions: (i) acryloyl chloride, CH2Cl2, Et3N,
−5°C, 1 h, room temperature, 12 h; (ii) diethanolamine, ethanol, room temperature, 20 h; (iii) diethanolamine, THF, 20 days.
After purification by silica gel column chromatography
(methanol:CH2Cl2=3:97–10:90), 3.2 g of dendrimer 5
was obtained in 62% yield as a pale-yellow oil. Dendrimer
5 (3.2 g, 2.2 mmol) and diethanolamine (2.1 g, 20.0 mmol)
were mixed in 50 mL THF at 0°C. The reaction mixture
was stirred at room temperature for 20 days. THF was
then removed by distillation under reduced pressure, the
crude product was washed with 3×10 mL cold acetone
to afford dendrimer 6 (4.2 g, 80% yield) as a yellow oil.
In conclusion, an efficient divergent procedure for
synthesizing novel aliphatic poly(ester-amine) den-
drimers bearing hydroxyl or acrylate peripheral
groups has been described, which may be easily
modified for various applications. This divergent syn-
thesis used readily available monomers and required
only small excesses of reagents to achieve quantitative
growth. The synthesis of high generation dendrimers
is in progress.

Y. Sha et al. / Tetrahedron Letters 43 (2002) 9417–9419
9419
References
7. Selected characterization data of the third generation den-
drimers. G3-(OH)16, 6: IR 3392, 2951, 2833, 1728(s), 1624(s)
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cm−1 1H NMR (500 MHz, CDCl3) l 4.13 (t, 24H,
;
-CO2CH2-, J=6.2 Hz), 3.78 (bs, 16H, -OH), 3.64–3.58 (m,
8H, -NCH2CH2N-, piperazine), 3.60 (t, 32H, -CH2OH,
J=5.5 Hz), 2.91–2.87 (m, 12H, OꢀCCH2CH2N-, J=
6.9 Hz), 2.84 (t, 16H, OꢀCCH2CH2N-, J=6.9 Hz), 2.78 (t,
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-NCH2CH2OH, J=5.5 Hz), 2.51 (t, 20H, OꢀCCH2-, J=6.9
Hz), 2.46 (t, 8H, OꢀCCH2-, J=6.9 Hz); 13C NMR (50 MHz,
CDCl3) l 173.06, 172.22, 62.70, 62.44, 60.49, 59.51, 59.10,
56.33, 55.82, 52.75, 50.83, 50.44, 49.81, 32.90, 32.77, 31.30;
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;
1H NMR (500 MHz, CDCl3) l 6.40 (q, 16H, ꢀCH, J=17.5
Hz, J%=1.0 Hz), 6.12 (q, 16H, OꢀCCHꢀ, J=17.5 Hz,
J%=10.5 Hz), 5.84 (q, 16H, ꢀCH, J=10.5 Hz, J%=1.0 Hz),
4.21 (t, 32H, CH2ꢀCHCOOCH2-, J=6.0 Hz), 4.10 (t, 24H,
-COOCH2-, J=6.0 Hz), 3.65–3.49 (q, 8H, -NCH2CH2N-,
piperazine), 2.91 (m, 28H, OꢀCCH2CH2N-, J=7.0 Hz), 2.85
(m, 32H, CH2ꢀCHCOOCH2CH2N-, J=6.0 Hz), 2.77 (t,
24H, -NCH2CH2OC=O, J=6.0 Hz), 2.47 (t, 28H,
OꢀCCH2-, J=7.0 Hz); 13C NMR (50 MHz, CDCl3) l
171.87, 165.77, 130.60 (-CHꢀCH2), 128.24 (-CHꢀCH2),
62.47, 62.28, 52.53, 50.28, 32.92, 31.15, 30.14; ESI-MS: calcd
for (M+H)+: 3180.5. Found: m/z (M+H)+: 3183.0.
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