Facile synthesis of aryl ether dendrimer from unprotected AB2 building blocks using thionyl chloride as an activating agent

Article abstract of DOI:10.1021/ol0605880

A novel, rapid, inexpensive, and highly efficient convergent approach for the synthesis of a Frechet- type aryl ether dendrimer using thionyl chloride has been developed. In this method, the purification of each dendron and a dendrimer occurs by recrystallization, extraction, and precipitation. The MALDI-TOF MS spectrum supported the formation of the G2, G3, and G4 dendrons and the star-shaped G4 dendrimer.

Full text of DOI:10.1021/ol0605880

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2321-2324
Facile Synthesis of Aryl Ether
Dendrimer from Unprotected AB2
Building Blocks Using Thionyl Chloride
as an Activating Agent
Natsuko Yamazaki, Isao Washio, Yuji Shibasaki, and Mitsuru Ueda*
Department of Organic and Polymeric Materials, Graduate School of Science and
Engineering, Tokyo Institute of Technology, 2-12-1-H120 O-okayama, Meguro-ku,
Tokyo 152-8552, Japan
mueda@polymer.titech.ac.jp
Received March 10, 2006
ABSTRACT
A novel, rapid, inexpensive, and highly efficient convergent approach for the synthesis of a Fre´chet- type aryl ether dendrimer using thionyl
chloride has been developed. In this method, the purification of each dendron and a dendrimer occurs by recrystallization, extraction, and
precipitation. The MALDI-TOF MS spectrum supported the formation of the G2, G3, and G4 dendrons and the star-shaped G4 dendrimer.
Dendrimers are highly branched macromolecules consisting
of a multifunctional core from which successive branched
repeating units extend radially outward. A large number of
reactive end groups at the periphery of dendrimers easily
react with kinds of reagents giving dendrimers with various
functionalities at their periphery. Therefore, they have
received a great deal of attention as new polymeric materials
for applications in areas such as molecular light harvesting,1
catalysts,2 liquid crystals,3 molecular encapsulation,4 and drug
delivery systems.5 Contrary to these useful prospects, a high
level of synthetic control is required to prepare dendrimers.
The general formation of dendrimers via divergent6 or
convergent7 route involves reiterative growth strategies. In
the divergent method, the molecule is assembled from the
core to the periphery, while in the convergent method, the
dendrimer is synthesized beginning from the outside and
terminating at the core. In either method, it requires a
(2) Knapen, J. W. J.; Van der Made, A. W.; de Wilde, J. C.; Van
Leeuwen, A. W.; Wijkens, P.; Grove, D. M.; Van Koten, G. Nature
(London) 1994, 372, 659.
(1) Jiang, D.-L.; Aida, T. Nature 1997, 388, 1681.
10.1021/ol0605880 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/25/2006

stepwise process: attaching one generation to the last,
purifying, and then changing functional groups for the next
stage reaction. Several methods such as double-stage,8
double-exponential growth,9 hypermonomers,10 and orthogo-
nal coupling strategies11 have been reported to shorten the
time for these tedious syntheses by diminishing the number
of steps.12 These approaches, however, still require multiple
steps to obtain high generation dendrimers. Recently, a one-
pot, multiple-addition convergent synthesis of polycarbonate
dendrimers was reported, in which the second-generation
dendrimer was obtained by sequential activation of an alcohol
with 1,1-carbonyldiimidazole and an AB2 triol.13 Quite
recently, we have demonstrated a rapid synthesis of a
perfectly branched third-generation polyamide dendrimer by
a convergent method without repetitive protection-depro-
tection procedures.14 This method consists of the direct
condensation of a carboxylic acid and an unprotected AB2
building block using the condensing agent, diphenyl(2,3-
dihydro-2-thioxo-3-benzoxazolyl)phosphonate (DBOP),15 and
later using the more versatile activating reagent thionyl
chloride.16
Thionyl chloride is the most attractive reagent for the
chlorination of benzyl alcohols due to the short reaction time,
low reaction temperature, and low price.19 Percec et al. have
reported utilization of thionyl chloride as a chlorination agent
of benzyl alcohols and demonstrated that benzyl chloride is
sufficient for the synthesis of aryl ether dendrimers.20
However, they have used 3,5-dihydroxymethylbenzoate as
a protected building block instead of 3,5-dihydroxybenzyl
alcohol, which is conventionally used for preparation of aryl
ether dendrimers. Therefore, the methyl benzoate group
needed two-step reactions, reduction and chlorination, to
prepare the benzyl chloride of each generation dendron.
Here, we present a successful rapid synthesis of a perfectly
branched fourth generation (G4) Fre´chet-type dendrimer (7)
from unprotected AB2 building block 3,5-dihydroxylbenzyl
alcohol (1) by a convergent method using thionyl chloride
as an activating agent. In our method, each generation
dendron and dendrimer can be prepared in one pot: no
isolation of intermediate chlorinated dendrons is required.
Furthermore, the purification of every dendritic molecule
requires only precipitation, recrystallization, and solvent
extraction.
The Fre´chet-type aryl ether dendrimer7 is one of the most
accepted macromolecules in various fields such as biology,
although its synthesis is still difficult.12b Several methods
have been reported to avoid the most difficult step of the
bromination in the Fre´chet process. Utilization of the
Mitsunobu reaction and of the solid support system was
developed.17,18 They are, however, still tedious to prepare
the high-quality dendrimer in a practical scale.
First-generation (G1) dendron 2 was initially prepared by
the condensation of benzyl chloride with 1 in the presence
of K2CO3 in 1-methyl-2-pyrrolidinone (NMP) at 70 °C for
18 h under nitrogen atmosphere. The products, however,
contained only a few percent of 3,5-bis(benzyloxy)benzyl-
benzyl carbonate 3, which was isolated by column chroma-
1
tography and characterized by FT-IR, H NMR, and MS
spectroscopy (Scheme 1). We found that carbonate 3 was
(3) (a) Percec, V.; Cho, C. G.; Pugh, C.; Tomazos, D. Macromolecules
1992, 25, 1164. (b) Percec, V.; Kawasumi, M. Macromolecules 1992, 25,
3843. (c) Percec, V.; Johansson, G.; Heck, J.; Ungar, G.; Batty, S. J. Chem.
Soc., Perkin Trans. 1 1993, 1411. (d) Percec, V.; Chu, P.; Kawasumi, M.
Macromolecules 1994, 27, 4441. (e) Ponomarenko, S. A.; Eebrov, E. A.;
Bobrovsky, A. Yu; Boiko, N. I.; Muzafarov, A. M.; Shibaev, V. P. Liq.
Cryst. 1996, 21, 1. (f) Busson, P.; Ihre, H.; Hult, A. J. Am. Chem. Soc.
1998, 120, 9070.
Scheme 1. Synthesis of G1 Dendron 2
(4) (a) Jansen, J. F. G. A.; de Brabander-Van den Berg, E. M. M.; Meijer,
E. W. Science 1994, 266, 1226. (b) Hawker, C. J.; Fre´chet, J. M. J. J. Chem.
Soc., Perkin Trans. 1 1992, 2459.
(5) (a) Haensler, J.; Szoka, F. C. Bioconjugate Chem. 1993, 4, 372. (b)
Redemann, C. T.; Szoka, F. C. Bioconjugate Chem. 1996, 7, 703. (c) Meijer,
E. W.; Paulus, W.; Duncan, R. J. Controlled Release 2000, 65, 133.
(6) (a) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117. (b)
Tomalia, D. A.; Naylor, A. N.; Goddard, W. A. Angew. Chem., Int. Ed.
Engl. 1990, 29, 138.
(7) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(8) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc.
1991, 113, 4252.
(9) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; More, J. S. J. Am.
Chem. Soc. 1995, 117, 2159.
(10) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. Angew. Chem., Int.
Ed. Engl. 1994, 33, 82.
(11) Spindler, R.; Fre´chet, J. M. J., J. Chem. Soc., Perkin Trans. 1 1993,
913.
easily converted to the G1 dendron 2 and benzyl alcohol in
the presence of K2CO3 in NMP at 140 °C for 3 h.
Thus, the preparation of G1 dendron 2 was carried out
with an excess amount of K2CO3 in NMP at 120 °C for 1.5
h and then 140 °C for 8 h under nitrogen atmosphere
(12) For reviews, see, for example: (a) Newcome, G. R.; Moorefield,
C. N.; Vo¨gtle, F. In Dendrimers and Dendrons, Concepts, Syntheses,
Applications; VCH: Weinheim, Germany, 2001. (b) Fre´chet, J. M. J.;
Tomalia, D. A. In Dendrimer and Other Dendritic Polymers; VCH:
Weinheim, Germany, 2002. Grayson, M. S., Fre´chet, J. M. J. Chem. ReV.
2001, 101, 3819.
(13) Rannard, S. P.; Davis, N. J. J. Am. Chem. Soc. 2000, 122, 11729.
(14) Okazaki, M.; Washio, I.; Shibasaki, Y.; Ueda, M. J. Am. Chem.
Soc. 2003, 125, 8120.
(17) Forier, B.; Dehaen, W. Tetrahedron 1999, 55, 9829.
(18) Basso, A.; Evans, B.; Pegg, N.; Bradley, M. Chem. Commun. 2001,
697.
(19) Whitmore, F. C.; Karnatz, F. A.; Popkin, A. H. J. Am. Chem. Soc.
1938, 60, 2540.
(20) (a) Balagurusamy, V. S. K.; Ungar, G.; Percec, V.; Johansson, G.
J. Am. Chem. Soc. 1997, 119, 1539. (b) Percec, V.; Cho, W.-D.; Mosier, P.
E.; Ungar, G.; Yeardley, D. J. P. J. Am. Chem. Soc. 1998, 120, 11061. (c)
Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P. J. Am. Chem. Soc.
2001, 123, 1302. (d) Percec, V.; Mitchell, C. M.; Cho, W.-D.; Uchida, S.;
Glodde, M.; Ungar, G.; Zeng, X.; Liu, Y.; Balagurusamy, V. S. K.; Heiney,
P. A. J. Am. Chem. Soc. 2004, 126, 6078.
(15) Ueda, M.; Kameyama, A.; Hashimoto, K. Macromolecules 1988,
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(16) Washio, I.; Shibasaki, Y.; Ueda, M. Org. Lett. 2003, 5, 4159.
2322
Org. Lett., Vol. 8, No. 11, 2006

hydrolyzed with KOH. G2 dendron 4 was purified simply
by reprecipitation to remove G1 dendron 2 and obtained in
80% yield as a white powder (Scheme 3). G3 dendron 5
and G4 dendron 6 were prepared by the same method in
82% and 73% yield,respectively (Scheme 3). The formation
of the G2 dendron 4, the G3 dendron 5, and G4 dendron 6
was confirmed by 1H NMR and MALDI-TOF MS spectros-
copy (see the Supporting Information).
Scheme 2. Improved Synthesis of G1 Dendron 2
A coupling reaction of 5 and bisphenol A was performed
to obtain a dumbbell-shaped G3 dendrimer 7 (Scheme 4).
(Scheme 2). The reaction mixture was poured into water,
and the precipitate was collected and dried. Recrystallization
from toluene/hexane gave the G1 dendron 2 in 85%.
One-pot synthesis of G2 dendron 4 was then prepared from
G1 dendron 2 and 1. G1 dendron 2 was activated with 1.10
equiv of SOCl2 in NMP at 0 °C for 10 min and then reacted
with 0.50 equiv of 1 to G1 dendron 2 at 140 °C for 3 h
under nitrogen atmosphere. The product was, however, only
3,5-bis(benzyloxy)benzyl chloride. The condensation of 3,5-
bis(benzyloxy)benzyl chloride with 1 was completely pro-
hibited with sulfurous acid generated from SO2 and water
because the isolated 3,5-bis(benzyloxy)benzyl chloride quan-
titatively reacted with 1 in the presence of K2CO3 in NMP.
To remove HCl and remaining SOCl2, an excess amount of
K2CO3 was added to the solution before the condensation
with 1 at 120 °C for 5 h. Desired G2 dendron 4 was produced
with a small amount of similar carbonate compound formed
in the synthesis of G1 dendron 2. This carbonate was easily
Scheme 4. Synthesis of Dumbbell-Shaped G3 Dendrimer 6
This reaction was performed using a two-step method similar
to the syntheses for the G2, G3, and G4 dendrons. Activation
of 5 was conducted using 1.10 equiv of SOCl2, and a
condensation reaction was carried out at 100 °C for 12 h.
The resulting solution was diluted with toluene and washed
with aqueous NaOH, aqueous HCl, and water. The organic
part was concentrated, dissolved in a small amount of ethyl
acetate, and poured into 2-methoxyethanol/ethyl acetate (10/1
Scheme 3. Synthesis of G2 (4), G3 (5), and G4 (6) Dendrons
Scheme 5. Synthesis of Star-Shaped G4 Dendrimer 8
Org. Lett., Vol. 8, No. 11, 2006
2323

volume ratio). Dendrimer 7 was obtained in 76% yield and
characterized by IR, NMR, and MALDI-TOF MS measure-
ments and elemental analysis (see the Supporting Informa-
tion).
(calcd mass 10127.7). A single signal was observed at m/z
([M + Na]+) ) 10149.4, indicating the formation of the star-
shaped G4 dendrimer.
In summary, a novel, very simple, inexpensive, and highly
efficient convergent approach for the synthesis of the Fre´chet-
type aryl ether dendrimer using thionyl chloride has been
developed. In this method, the purification of each dendron
and a dendrimer are only extraction, recrystallization and
precipitation. The MALDI-TOF MS spectrum supported the
formation of the each dendron, the dumbell-shaped G3
dendrimer, and the star-shaped G4 dendrimer. The simplicity
and experimental ease of this novel convergent route of the
Fre´chet-type dendrimer would make it extremely attractive
for preparation of dendrimers both for laboratory and
industrial scale.
Finally, a star-shaped G4 dendrimer 8, which is expected
to be a larger spherical shape, was prepared from 6 and 1,1,1-
tris(4′-hydroxyphenyl)ethane in the same manner as the
synthesis of G3 dendrimer 7 (Scheme 5). The resulting
solution was poured into 1 M hydrochloric acid/methanol
(1/1 in volume ratio). G4 dendrimer 8 was purified by
washing with 2-methoxyethanol using a Soxhlet extractor.
1
The yield of dendrimer 8 was 73%. IR, H NMR, and
MALDI-TOF MS measurements and elemental analysis were
performed for the characterization of the dendrimer 8. Figure
1 shows the MALDI-TOF MS spectrum of the dendrimer 8
Acknowledgment. This work was financially supported
by the New Energy and Industrial Technology Development
Organization (NEDO) for the project of nanostructure
polymers.
Supporting Information Available: Synthesis and char-
acterization of each dendron and the star-shaped G4 den-
drimer. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. MALDI-TOF MS spectrum of G4 dendrimer.
OL0605880
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Org. Lett., Vol. 8, No. 11, 2006