A liquid-phase approach to functionalized janus dendrimers: Novel soluble supports for organic synthesis

Article abstract of DOI:10.1021/ol0705393

A new kind of functionalized Janus dendrimer has been synthesized via a liquid-phase approach, which could easily be purified using a simple precipitation method without the need for chromatographic separation. Their use for liquid-phase organic synthesis has been achieved in the Pd-catalyzed Suzuki coupling reactions, giving biaryl products in excellent yields after cleavage.

Full text of DOI:10.1021/ol0705393

ORGANIC
LETTERS
2
007
Vol. 9, No. 12
261-2264
A Liquid-Phase Approach to
Functionalized Janus Dendrimers:
Novel Soluble Supports for Organic
Synthesis
2
Yu Feng,†,‡ Yan-Mei He, Li-Wen Zhao, Yi-Yong Huang, and Qing-Hua Fan*,†
†
†
†,‡
Beijing National Laboratory for Molecular Sciences, Center for Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China, and
Graduate School of the Chinese Academy of Sciences, Beijing 100080, China
fanqh@iccas.ac.cn
Received March 2, 2007
ABSTRACT
A new kind of functionalized Janus dendrimer has been synthesized via a liquid-phase approach, which could easily be purified using a
simple precipitation method without the need for chromatographic separation. Their use for liquid-phase organic synthesis has been achieved
in the Pd-catalyzed Suzuki coupling reactions, giving biaryl products in excellent yields after cleavage.
4
5
Dendrimers are well-defined, highly branched, three-
dimensional macromolecules with a large number of reactive
end groups. Dendrimers are therefore receiving great interest
delivery systems, and catalysts. Divergent and convergent
approaches are two general routes for the synthesis of
1
6
dendrimers. However, these two methods both involve
as new polymeric materials for applications in areas such as
molecular light harvesting, molecular encapsulation, drug-
multiple steps and time-consuming purifications, which often
2
3
(
4) For a review, see: Gillies, E. R.; Fr e´ chet, J. M. J. Drug. DiscoV.
Today 2005, 10, 35.
†
Institute of Chemistry, Chinese Academy of Sciences.
Graduate School of the Chinese Academy of Sciences.
(5) (a) Knapen, J. W. J.; van der Made, A. W.; de Wilde, J. C.; van
Leeuwen, P. W. N. M.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature
(London) 1994, 372, 659. For reviews, see: (b) Astruc, D.; Chardac, F.
Chem. ReV. 2001, 101, 2991. (c) van Heerbeek, R.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. ReV. 2002, 102, 3717. (d)
Helms, B.; Fr e´ chet, J. M. J. AdV. Synth. Catal. 2006, 348, 1125.
(6) (a) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, C.;
Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117. (b)
Newkome, G. R.; Yao, Z.;. Baker, G. R.; Gupta, V. K. J. Org. Chem. 1985,
50, 2003. (c) Hawker, C. J.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 1990, 112,
7638.
‡
(
1) (a) Newkome, G. R.; Moorefield, C. N.; V o¨ gtle, F. Dendrimers and
Dendrons, Concepts, Syntheses, Applications; Wiley-VCH: Weinheim,
001. (b) Fr e´ chet, J. M. J.; Tomalia, D. A. Dendrimers and Other Dendritic
Polymers; Wiley-VCH: Chichester, 2001.
2) For selected reviews, see: (a) Adronov, A.; Fr e´ chet, J. M. J. Chem.
Commun. 2000, 1701. (b) Lo, S.-C.; Burn, P. L. Chem. ReV. 2007, 107,
097.
3) For a review, see: Hecht, S.; Fr e´ chet, J. M. J. Angew. Chem., Int.
Ed. 2001, 40, 74.
2
(
1
(
1
0.1021/ol0705393 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/17/2007

result in low yields, thereby limiting their potential practical
applications. In this regard, the solid-phase synthesis of
dendrimers appears to be a promising alternative. Although
units, resulting in two-faced Janus dendritic molecules
(Figure 1). In addition, these Janus dendrimers and reaction
7
solid-phase synthesis techniques have been applied success-
8
fully in the synthesis of a number of dendrimers, the
heterogeneous reaction nature of this strategy might result
in some problems, such as relatively low reactivity, extended
reaction time, and difficulty in characterization of dendritic
hybrids.
As an alternative, soluble supports have recently been used
9
in liquid-phase organic synthesis (LPOS). In this case, the
similar reaction conditions of classic orgainic chemistry are
reinstated, and yet product purification is still facilitated
through application of macromolecular properties. Over the
past decade, this methodology has achieved great success
in organic synthesis.10 To the best of our knowledge,
however, only two research groups reported the synthesis
of dendrimers or dendritic hybrids via LPOS by using linear
polymer or oligomer as supports. Fr e´ chet and co-workers
first reported the synthesis of dendritic linear hybrids using
linear poly(ethylene glycols) (PEGs) as the support via
LPOS.11 Most recently, Ahn et al. reported the synthesis of
12
alphatic ester dendrimers on linear polystyrene support. To
date, synthesis of codendrimers by using dendron support
via LPOS has not been reported in the literature.
Figure 1. Structure of the third-generation Janus dendrimer.
The concept of codendrimer was first established by
Hawker and Fr e´ chet in the synthesis of segmented and layed
intermediates were purified by simple solvent precipitation
without the need for column chromatography. Their potential
use as a novel soluble support for LPOS has been demon-
strated with the Pd-catalyzed Suzuki coupling reaction.
The Fr e´ chet-type poly(aryl ether) dendron was chosen as
support because of its high inertness toward organic reagents
and good accessibility. Synthesis and structure of the Janus
dendrimers are outlined in Scheme 1. The third-generation
Fr e´ chet’s dendron 1 was prepared according to the reported
13
codendrimers based on ester and ether monodendrons. Due
to their unique structures and properties, codendrimers have
14
been attracting great attention. So far, a number of diblock
codendrimers have been reported. However, almost all these
dendrimers were synthesized step by step via conventional
solution synthesis and therefore suffered from time-consum-
ing purifications and low yields. In relation to our interest
in applications of functionalized organometallic dendrimers
as homogeneous catalysts,15 we wish to report here a new
6
c
convergent approach. Commercially available dimethyl
-hydroxylisophthalate 2 was used as the growth unit for
5
kind of codendrimers via LPOS by using the third-generation
6c
16
the esterification with the hydroxy group of 1 under standard
Mitsunobu reaction conditions. The resulting dendritic ester
was then reduced by LiAlH to provide the G G -CH OH
4 3 1 2
Fr e´ chet-type poly(aryl ether) dendron as the support.
These dendrimers combine two functionally different surface,
nonpolar benzyl ether moieties and polar benzyl alcohol
(
7) (a) For a review, see: Dahan, A.; Portnoy, M. J. Polym. Sci., Part
A: Polym. Chem. 2004, 43, 235. (b) Tam, J. P. Proc. Natl. Acad. Sci. U.S.A.
988, 85, 5409. (b) Uhrich, K. E.; Boegeman, S.; Fr e´ chet, J. M. J.; Turner,
(14) Selected recent examples for codendrimers, see: (a) Yang, M.;
Wang, W.; Yuan, F.; Zhang, X.; Li, J.; Liang, F.; He, B.; Minch, B.; Wegner,
G. J. Am. Chem. Soc. 2005, 127, 15107. (b) Lee, C. C.; Gillies, E. R.; Fox,
M. E.; Guillaudeu, S. J.; Fr e´ chet, J. M. J.; Dy, E. E.; Szoka, F. C.; Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 16649. (c) Chen, Y. C.; Wu, T. F.; Jiang,
L.; Deng, J. G.; Liu, H.; Zhu, J.; Jiang, Y. Z. J. Org. Chem. 2005, 70,
1006. (d) Percec, V.; Imam, M. R.; Bera, T. K.; Balagurusamy, S. K. V.;
Peterca, M.; Heiney, P. A. Angew. Chem., Int. Ed. 2005, 44, 4739. (e) Lee,
J. W.; Kim, B. K.; Kim, J.-H.; Shin, W. S.; Jin, S.-H. J. Org. Chem. 2006,
71, 4988. (f) Bury, I.; Heinrich, B.; Bourgogne, C.; Guillon, D.; Donnio,
B. Chem.-Eur. J. 2006, 12, 8396. (g) Ropponen, J.; Nummelin, S.;
Rissanen, K. Org. Lett. 2004, 6, 2495. (h) Gillies, E. R.; Fr e´ chet, J. M. J.
J. Org. Chem. 2004, 69, 46. (i) Tomalia, D. A.; Pulgam, V. R.; Swanson,
D. R.; Huang, B. PCT Int. Appl. WO 06105043, 2006.
(15) (a) Fan, Q. H.; Chen, Y. M.; Chen, X. M.; Jiang, D. Z.; Xi F.;
Chan, A. S. C. Chem. Commun. 2000, 789. (b) Deng, G. J.; Fan, Q. H.;
Chen, X. M.; Liu, D. S.; Chan, A. S. C. Chem. Commun. 2002, 1570. (c)
Yi, B.; Fan, Q. H.; Deng, G. J.; Li, Y. M.; Qiu, L. Q.; Chan, A. S. C. Org.
Lett. 2004, 6, 1361. (d) Deng, G. J.; Yi, B.; Huang, Y. Y.; Tang, W. J.; He,
Y. M.; Fan, Q. H. AdV. Synth. Catal. 2004, 346, 1440. (e) Wu, L.; Li, B.;
Huang, Y.; Zhou, H.; He, Y.; Fan, Q. H. Org. Lett. 2006, 8, 3605. (f) Wang,
Z. J.; Deng, G. J.; Li, Y.; He, Y. M.; Tang, W. J.; Fan, Q. H. Org. Lett.
2007, 9, 1243.
1
S. R. Polym. Bull. 1991, 25, 551. (c) Swali, V.; Wells, N. J.; Langley, G.
J.; Bradley, M. J. Org. Chem. 1997, 62, 4902.
(
8) Selected recent examples, see: (a) Bourque, S. C.; Maltais, F.; Xiao,
W. J.; Tardif, O.; Alper, H.; Arya, P.; Manzer, L. E. J. Am. Chem. Soc.
999, 121, 3035. (b) Bourque, S. C.; Alper, H.; Manzer, L. E.; Arya, P. J.
1
Am. Chem. Soc. 2000, 122, 956. (c) Fromont, C.; Bradley, M. Chem.
Commun. 2000, 283. (d) Basso, A.; Evans, B.; Pegg, N.; Bradley, M. Chem.
Commun. 2001, 697. (e) Dahan, A.; Portnoy, M. Macromolecules 2003,
3
3
6, 1034. (f) Dahan, A.; Dimant, H.; Portnoy, M. J. Comb. Chem. 2004, 6,
05.
(9) For reviews, see: (a) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997,
9
7, 489. (b) Toy, P. H.; Janda, K. D. Acc. Chem. Res.2000, 33, 546. (c)
Miao, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897.
10) Selected recent examples, see: (a) Annunziata, R.; Benaglia, M.;
(
Cinquini, M.; Cozzi, F. Chem.-Eur. J. 2000, 6, 133. (b) Hebel, A.; Haag,
R. J. Org. Chem. 2002, 67, 9452. (c) Guo, H. C.; Wang, Z.; Ding, K. L.
Synthesis 2005, 1061.
(
11) Ihre, H.; Padilla De Jes u´ s, O. L.; Fr e´ chet, J. M. J. J. Am. Chem.
Soc. 2001, 123, 5908.
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0, 205.
13) Hawker, C. J.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 1992, 114, 8405.
(
4
(16) The poly(aryl ether) dendrons have been synthesized on solid
support, see ref. 8d and e.
(
2262
Org. Lett., Vol. 9, No. 12, 2007

Scheme 1. Synthesis of Janus Dendrimers
Figure 2. 1H NMR of G
G -COOMe: (a) reaction mixture after
3 2
removal of most of organic solvent and (b) after purification by
precipitation in ether and methanol.
Wang-linkers. As shown in Scheme 2, standard Mitsunobu
condensation of G
zoate gave the dendritic ester in 97% yield. Reduction of
the ester groups with LiAlH afforded G G′ -CH OH in 98%
yield. This dendrimer was well characterized by H and C
NMR and TOF mass spectrometry as reported in Supporting
Information.
3 3 2
G -CH OH with methyl p-hydroxylben-
in quantitative yield. Repetitive Mitsunobu coupling and ester
reduction sequence led to the formation of higher generation
4
3
3
2
dendrimers, G
quantitative yields. Unlike solid-phase synthesis,
3
G
2
-CH
2
OH and G
3
G
3
-CH
2
OH, in almost
1
13
8
d,8e
the
reaction progress could be easily monitored by thin layer
chromatography (TLC). The purity and structure of all these
1
13
Janus dendrimers were confirmed by using H and C NMR
and TOF mass spectrometry (see Supporting Information).
In contrast to the classical solution-phase synthesis, during
the growth and reduction steps, there was no need for
purification by column chromatography. Usually, there is
difficulty during the product purification in Mitsunobu
Scheme 2. Synthesis of Janus Dendrimer with Wang-Linkers
1
7
reactions, in which separation of the reagent-derived
byproducts often need careful chromatography. In our case,
the resulting dendrimer was purified by a simple solvent
precipitation at the end of reaction, utilizing the difference
in solubility between the insoluble dendrimer and highly
soluble byproducts and excess growth units. Obviously, high
efficiency of this approach was exemplified in the product
3 2
purification of the synthesis of G G -COOMe. According
1
to the H NMR shown in Figure 2, precipitation of the crude
product in ether and methanol removed all the byproducts
[
triphenylphosphine oxide (TPPO) and diisopropoxycar-
bonylhydrazine (DICH)] and excess reagents [2, diisopropyl
azodicarboxylate (DIAD) and triphenylphosphine (TPP)].
To prove the versatility of these new Janus dendrimers,
the peripheral functional groups were further modified by
With these Janus dendrimers in hand, we investigated their
potential use for LPOS by choosing the Pd- catalyzed
1
8
(17) Dandapani, S.; Curran, D. P. Chem.-Eur. J. 2004, 10, 3130.
Org. Lett., Vol. 9, No. 12, 2007
2263

Suzuki coupling as a standard reaction. This choice was
based on the following facts:19, 20 (a) this reaction provides
a powerful tool for the synthesis of biaryls, which are found
in many natural and synthetic products; (b) the coupling
reactions are generally carried out at high temperature and
in the presence of a base, which can be used to demonstrate
the chemical stability of these dendritic supports; and (c)
separation of the homogeneous Pd-catalyst after the reaction
is often problematic.
Table 1. Janus Dendrimers as Soluble Supports for the
Pd-Catalyzed Suzuki Coupling Reactionsa
entry
dendrimer
Ar (sub.)
4 (%)b
5 (%)b
1
2
3
4
5
6
7
8
G3G1-CH2OH
G3G2-CH2OH
G3G2-CH2OH
G3G3-CH2OH
G3G′3-CH2OH
G3G3-CH2OH
G G -CH OH
Ph
Ph
Ph
Ph
97 (4aa)
98 (4ba)
96 (4ba)
98 (4ca)
98 (4da)
96 (4cb)
98 (4cd)
97 (4ce)
98 (99)c
97 (98)c
96 (97)c
98 (98)c
97 (97)c
96 (98)
98 (98)c
98 (97)c
d
Ph
The Pd-catalyzed Suzuki coupling of dendrimer-supported
p-iodo benzoate 3a∼3d with aromatic boronic acids was then
studied (Scheme 3).
c
p-MePh
p-AcPh
p-FPh
3
3
2
G3G3-CH2OH
a
Arylboronic acid/aryl iodide ) 1.15 (mol/mol), K3PO4‚7H2O/aryl iodide
2.0 (mol/mol), 1.0 mol % Pd[(P(p-C6H4CH3)3]3, dioxane, reflux, 22∼36
)
b
c
h. Isolated yield. Data in brackets are recovered yields of dendrimer
d
Scheme 3. Janus Dendrimers as Soluble Supports for the
supports. Recovered G3G2-CH2OH was used.
Pd-Catalyzed Suzuki Coupling Reactions
refluxing temperature. After concentration, the dendrimer
support was quantatitively recovered upon addition of diethyl
ether and filtration. This result indicates that these dendritic
supports are very stable under these relatively harsh reaction
conditions. Finally, the products were separated by ether
extraction in high yields after the filtrate was acidified (Table
1
). Unlike common dendrimer-supported organic synthesis,
separation of these dendrimer products did not require time-
consuming techniques, such as size exclusion chromatogra-
phy (SEC), dialysis, or even column chromatography.18 All
products in every step were purified by a simple solvent
precipitation and the product purity in each step is excellent
1
13
as confirmed by H NMR, C NMR, and MALDI-TOF (see
Supporting Information).
In conclusion, we have established for the first time a
liquid-phase approach for the synthesis of new kind of
functionalized Janus dendrimers. Dendrimers were grown
from the benzyl alcohol focal point of the Fr e´ chet’s dendron
and were purified using a simple precipitation method
without the need for chromatographic separation. The
potential application of these Janus dendrimers as well-
defined support for LPOS has been demonstrated in the Pd-
catalyzed Suzuki coupling reactions. Their uses as chiral
catalyst supports are in progress in the same laboratory.
Furthermore, this method may provide insight into design
of other codendrimers such as diblock codendrimers com-
The dendritic supports of G -CH
3
G
1
2 3 2 2
OH, G G -CH OH,
G
3
G
3
-CH OH, and G G′ -CH OH were loaded with p-
2
3
3
2
iodobenzoic acid under standard Mitsunobu reaction condi-
tions respectively, followed by Suzuki coupling with different
aromatic boronic acids. The reaction progress was monitored
by TLC. Both steps were demonstrated to give quantitative
conversions and excellent purity according to the H NMR
and TOF-MS spectra for every dendrimer support, giving
high isolated yields (Table 1). The Pd content in the product
ba was measured by ICP-MS and found to be 6.11 ppm
0.004%). It was noted that complete conversion could be
1
14e
posed of two extremely different dendrons without the
need for time and labor consuming purification steps.
4
(
achieved at prolonged time for higher generation dendrimers.
The dendrimer-supported coupling products 4 were cleaved
by using aqueous KOH in THF/methanol solvent system at
Acknowledgment. Financial support from the National
Natural Science Foundation of China, CAS, and the Major
State Basic Research Development Program of China (Grant
No. 2005CCA06600) is greatly acknowledged.
(
18) For dendritic supports in orgainic synthesis, see : (a) Haag, R.
Chem.- Eur. J. 2001, 7, 327. (b) Kim, R. M.; Manna, M.; Hutchins, S.
M.; Griffin, P. R.; Yates, N. A.; Bernick, A. M.; Chapman, K. T. Proc.
Natl. Acad. Sci. U.S.A. 1996, 93, 10012. (c) N oˆ tre, J. L.; Firet, J. J.; Sliedregt,
L. A. J. M.; van Steen, B. J.; van Koten, G.; Gebbink, R. J. M. K. Org.
Lett. 2005, 7, 363.
Supporting Information Available: General experimen-
tal methods, preparation and characterization data for Janus
1
13
dendrimers, and H and C NMR and TOF-MS spectral
data for the Janus dendrimers and dendritic intermediates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
19) For a review on Suzuki coupling reaction, see: Miyaura, N. In
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: New York, 2004; Chapter 2.
(20) For Suzuki coupling reaction on solid or soluble supports, see: (a)
Gravel, M.; B e´ rub e´ , C. D.; Hall, D. G. J. Comb. Chem. 2000, 2, 228. (b)
Hebel, A.; Haag, R. J. Org. Chem. 2002, 67, 9452.
OL0705393
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Org. Lett., Vol. 9, No. 12, 2007