Efficiency and fidelity in a click-chemistry route to triazole dendrimers by the copper(I)-catalyzed ligation of azides and alkynes

Article abstract of DOI:10.1002/anie.200454078

Components that click: A large number of diverse dendrimers (see scheme) was prepared in almost quantitative yield by the click-chemistry transformation described in the title. In some cases filtration or solvent extraction was the only method required for purification in this highly efficient construction of the triazole units of the dendrimers.

Full text of DOI:10.1002/anie.200454078

Communications
Dendrimers
Efficiency and Fidelity in a Click-Chemistry
Route to Triazole Dendrimers by the Copper(i)-
Catalyzed Ligation of Azides and Alkynes**
Peng Wu, Alina K. Feldman, Anne K. Nugent,
Craig J. Hawker,* Arnulf Scheel, Brigitte Voit,
Jeffrey Pyun, Jean M. J. FrØchet, K. Barry Sharpless,*
and Valery V. Fokin*
Unique properties of dendrimers, which are a direct conse-
quence of their regular structure, have sparked significant
interest in recent years.[1] A large number of dendritic
structures varying in size, solubility, and function have been
prepared. However, most dendrimer syntheses, particularly at
later generations, require high monomer loading, rely on
tedious and lengthy chromatographic separations, and gen-
erate considerable waste.[2] For example, the synthesis of
polyether dendrimers,[3] based on a sequence of Williamson
etherifications and halogenations, suffers from its incompat-
ibility with various functional groups and complicated puri-
fications.[4]
Herein, we report on an efficient and preparatively simple
approach for the generation of diverse dendritic structures of
high purity and in excellent yield. The unique aspects of this
route arise from the near-perfect reliability of the CuI-
[*] A. K. Nugent, Dr. C. J. Hawker, A. Scheel, Dr. J. Pyun
IBM Almaden Research Center
650 Harry Road, San Jose, CA 95120 (USA)
Fax: (+1)408-927-3310
E-mail: hawker@almaden.ibm.com
P. Wu, A. K. Feldman, Prof. K. B. Sharpless, Prof. V. V. Fokin
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7562
E-mail: sharples@scripps.edu
fokin@scripps.edu
A. Scheel, Prof. B. Voit
Institut für Polymerforschung Dresden e.V.
Hohe Strasse 6, 01069 Dresden (Germany)
Dr. J. Pyun, J. M. J. FrØchet
University of California
Department of Chemistry andMaterials Sciences Division
Lawrence Berkeley National Laboratory
Berkeley, CA 94720 (USA)
[**] We thank the National Institute of General Medical Sciences, the
National Institutes of Health (GM 28284), the National Science
Foundation (CHE-9985553), the W. M. Keck Foundation, the Skaggs
Institute for Chemical Biology, the MRSEC Program of the National
Science Foundation (award no. DMR-0213618 for the Center for
Polymeric Interfaces andMacromolecular Assemblies), the NIRT
Program of the National Science Foundation (grant no. 0210247),
IBM Corporation, DOE-BES, andNSF International/DAAD for
financial support. We are also grateful to Prof. M. G. Finn for helpful
discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200454078
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catalyzed synthesis of 1,2,3-triazoles from azides and alkynes
(Scheme 1).[5] The reaction is experimentally simple—pro-
ceeding well in aqueous solutions without protection from
led to a variety of dendrimers with different chain-end groups
(R) and internal repeat units (X).
In exploiting CuI-catalyzed reaction for dendrimer con-
struction, we envisaged a variety of AB2 monomers based on
terminal alkynes and alkyl halide functionalities. Readily
available starting materials and simple synthetic strategies for
the introduction of alkynyl groups lead to significant struc-
tural diversity (Figure 1). However, one structural feature was
common to monomers 11–13, namely the presence of a single
chloromethyl group. This was specifically incorporated into
our synthetic strategy to allow facile activation of the focal-
point group during dendrimer construction by the conver-
gent-growth approach. We envisaged that reaction of den-
dritic fragments containing a single chloromethyl group with
sodium azide would lead to quantitative formation of the
desired azidomethyl group, which could then be coupled with
11, 12, or 13 to give the next-generation dendron (Scheme 2).
As with AB2 monomer units, a variety of the chain ends with
reactive functional groups ranging from carboxylic acid to
alcohol could be employed in the construction of diverse
triazole dendrimers (Figure 2).
Scheme 1. Copper(i)-catalyzedsynthesis of 1,4-disubstituted1,2,3-tria-
zoles.
oxygen, requiring only stoichiometric amounts of starting
materials, and generating virtually no by-products. Equally
important is the wide scope, high selectivity, and nearly
quantitative yields of this transformation. In our procedure
for the best click reaction to date,[6] the components and
catalyst are simply mixed and stirred, whereupon pure
products are isolated by filtration or simple extraction.
FrØchetꢀs convergent approach was utilized in our den-
drimer synthesis.[7] Thus, the individual branches or dendrons
were built sequentially, starting on the “outside” of the
molecule. They were then coupled to a multivalent center-
piece (“core”) in the last step, as outlined in Scheme 2, which
Copper(i)-catalyzed reactions of AB2 monomers and the
chain-end units were carried out in the presence of CuSO4 (2–
5 mol%) and sodium ascorbate (5–
10 mol%) in a 1:1 mixture of water
and tert-butyl alcohol at room tem-
perature to generate the desired
bistriazoles in near-quantitative
yields. Trace amounts of copper
salts in the products were easily
removed by washing with an am-
monium hydroxide/citrate aqueous
buffer. Owing to the high degree of
efficiency, the reaction could be
conducted with
a stoichiometric
amount (2.0 equiv) of the azides.
Purifications were greatly simpli-
fied due to the absence of side
products. This is in direct contrast
with the classical synthesis of poly-
ether dendrimers by the conver-
gent-growth approach, where an
excess
of
dendron
(2.05–
2.20 equiv) is typically used to
increase yields of the next-genera-
tion dendritic fragment. Further-
more, purification by flash chroma-
tography is usually required at each
step.[7]
In the next step, the primary
chlorides were converted into the
corresponding azides by reaction
with 1.5 equiv sodium azide in ace-
tone/water.[9] This transformation
was equally facile and typically
resulted in yields of more than
95% with NaCl as the only by-
product. The dendrons were then
“grown” by the reaction of the
Scheme 2. Convergent approach toward triazole dendrimers. a) CuSO4 (5 mol%), sodium ascorbate
(10 mol%), H2O/tBuOH (1:1); b) 1.5 equiv NaN3, CH3COCH3/H2O (4:1), 608C, 1–3 h.[8]
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Figure 1. Structures of the AB2 monomers 11–13 usedin the synthesis
of dendrimers based on click chemistry.
Figure 3. 1H NMR spectrum of the crude reaction mixture containing
dendron 3b.
azide. To overcome this difficulty, the copper-
catalyzed reaction was performed in THF with
an organosoluble CuI species, [(PPh3)3CuBr],
under microwave irradiation, leading to quan-
titative yields of the next-generation dendritic
fragment. Similar results for azide formation
were obtained when the displacement was
performed with sodium azide in dimethylfor-
mamide or dimethyl sulfoxide. Analysis of the
dendrons by MALDI-TOF mass spectrometry
as well as by gel-permeation chromatography
(GPC) provides no signs of products with
defects that would arise from incomplete
branches (Figure 4).
Figure 2. Azides 14–19 used in the synthesis of chain-end-functionalized dendrimers
basedon click chemistry.
resulting azides with the original monomers 11, 12, or 13. All
Works by Tomalia, FrØchet, and others
second-generation dendrons were isolated as pure white
solids by simple filtration or aqueous workup in yields
exceeding 90% for the isolated products. As seen in the
crude 1H NMR spectrum of dendron Bn-F-[G-2]-Cl 3b
(Figure 3), the integration ratio for protons f and c is 2:1
which, in comparison with the spectrum of the mixture
obtained from a purely thermal process, indicates 100%
regioselectivity in its construction.
demonstrate that the solubility properties of dendritic mol-
ecules are dominated by their periphery.[2] As expected, our
observations largely follow these trends. Aunique property of
Following the same procedure, dendrons based on amide
monomer 12 with tert-butyl azide 17 at the periphery as well
as the benzyl ether monomer 11 with azide 19 were
propagated to the fourth generation. Dendrons constructed
from monomer 12 with the azides 16 and 19 at the periphery
were propagated to the third generation. When the dendrim-
ers were not soluble in aqueous mixtures, slight modification
of the reaction conditions led to the same degree of efficiency
and near-quantitative yields. For example, benzyl-terminated
dendrons prepared from 14 and 11 were insoluble in 1:1 H2O/
THF solutions at the second generation and led to incomplete
conversions. Similarly, conversion of the chloromethyl group
to the azide group was unsuccessful with aqueous sodium
Figure 4. GPC traces for the crude reaction products MEE-B-[G-4]-N3
9d, MEE-B-[G-3]-N3 6d, andMEE-B-[G-2]-N 3 4d, obtained by dendritic
growth from the benzyl ether monomer 11 and the azido di(ethylene
glycol) derivative 19.
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these triazole-based dendrons is, as the molecules reach
higher generations, they become less soluble in ethyl acetate
and slightly more soluble in dichloromethane, chloroform,
alcohols and, surprisingly, aqueous mixtures.[10]
Finally, several third- and fourth-generation triazole
dendrimers were constructed by anchoring these dendrons
to a variety of polyacetylene cores (Figure 5). A representa-
tive example is shown in Scheme 3, where the third-gener-
ation dendron tBu-F-[G-3]-N3 6a was coupled directly with
2,4,6-tris(prop-2-ynyloxy)-1,3,5-triazine (23) in the presence
of the CuI catalyst generated in situ. It is noteworthy that even
at these low concentrations (0.06m in alkyne and azide), the
reaction proceeded rapidly enough at room temperature and
reached completion in less than 30 h as indicated by LC-MS
analysis. Dendrimer 7a, with 24 periphery units (Mw =
Figure 6. MALDI-TOF mass spectrum of 7a (M+Na+, resolution Æ 0.1%).
6322 Da), was isolated as a white solid in 92%
yield. All dendrimers were characterized by 1H
and 13C NMR spectroscopy, and the structure and
purity were confirmed further by GPC and
MALDI-TOF mass spectrometry (Figure 6).
High polarity, good solubility in alcohol/water
mixtures, and strong UV absorptions at l = 210
and 229 nm are unique features of this new class of
triazole dendrimers.
In summary, a highly efficient route to triazole-
based dendrimers is now available thanks to the
unprecedented reliability of the CuI-catalyzed
ligation of terminal alkynes and azides. This
chemistry is highly regioselective, resulting in
1,4-disubstituted triazoles. A variety of functional
groups are compatible with the process, and the
only major by-product formed in the reaction is
NaCl. All second-generation and some third-
generation dendrons were isolated directly as
pure solids (i.e. without chromatographic separa-
tions), meeting the requirements for large-scale
Figure 5. Polyacetylene cores used in the synthesis of chain-end-functionalized den-
drimers based on click chemistry.
applications.
The recently discovered ability of polyden-
tate 1,4-disubstituted 1,2,3-triazole ligands to
stabilize CuI species even under aqueous aerobic
conditions,[11] has already proven crucial in bio-
logical applications.[12] Exploration of the
copper-binding ability of this new class of
dendrimers and their ligand properties in homo-
geneous catalysis is underway.
Received: February 23, 2004 [Z54078]
Published Online: June 30, 2004
Keywords: alkynes · azides · click chemistry ·
.
copper · dendrimers
[1] For reviews, see: a) D. A. Tomalia, A. M. Naylor,
W. A. Goddard III, Angew. Chem. 1990, 102, 119 –
157; Angew. Chem. Int. Ed. Engl. 1990, 29, 138;
b) D. A. Tomalia, H. D. Durst in Topics in Current
Chemistry, Vol. 165 (Ed.: E. Weber), Springer,
Scheme 3. Synthesis of dendrimer 7a.
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Communications
Berlin, 1993, pp. 193 – 313; c) F. Zeng, S. C. Zimmerman, Chem.
Rev. 1997, 97, 1681 – 1712; d) C. J. Hawker in Advances in
Polymer Science, Vol. 147, Springer, Berlin, 1999, pp. 113 – 160;
e) M. Fischer, F. Vögtle, Angew. Chem. 1999, 111, 934 – 955;
Angew. Chem. Int. Ed. 1999, 38, 884 – 905; f) A. W. Bosman,
H. M. Janssen, E. W. Meijer, Chem. Rev. 1999, 99, 1665 – 1688;
g) J.-P. Majoral, A.-M. Caminade, Chem. Rev. 1999, 99, 845 – 880;
h) L. J. Twyman, A. S. H. King, I. K. Martin, Chem. Soc. Rev.
2002, 31, 69 – 82; i) J. M. J. FrØchet, Proc. Natl. Acad. Sci. USA
2002, 99, 4782 – 4787.
[2] a) S. M. Grayson, J. M. J. FrØchet, Chem. Rev. 2001, 101, 3919 –
3967; b) J. M. J. FrØchet, J. Polym. Sci. Part A 2003, 41, 3713 –
3725.
[3] a) S. C. Zimmerman, I. Zharov, M. S. Wendland, N. A. Rakow,
K. S. Suslick, J. Am. Chem. Soc. 2003, 125, 13504 – 13518; b) S.
Kimata, D. L. Jiang, T. Aida, J. Polym. Sci. Part A 2003, 41,
3524 – 3530; c) A. Dahan, M. Portnoy, Macromolecules 2003, 36,
1034 – 1038; d) E. M. Harth, S. Hecht, B. Helms, E. E. Malm-
strom, J. M. J. FrØchet, C. J. Hawker, J. Am. Chem. Soc. 2002,
124, 3926 – 3938; e) F. S. Precup-Blaga, G. C. Garcia-Martinez,
A. P. H. J. Schenning, E. W. Meier, J. Am. Chem. Soc. 2003, 125,
12953 – 12960.
[4] Protic functional groups at the periphery, such as OH, COOH,
and NH2, are not compatible with Williamson etherifications and
halogenations.
[5] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed.
2002, 41, 2596 – 2599; C. W. Tornøe, C. Christensen, M. Meldal, J.
Org. Chem. 2002, 67, 3057.
[6] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113,
2056 – 2075; Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021.
[7] C. J. Hawker, J. M. J. FrØchet, J. Am. Chem. Soc. 1990, 112,
7638 – 7647.
[8] The nomenclature used for the dendritic framework is as
follows: R-X-[G-n]-Y, where R describes the functional groups
at periphery, Bn for benzyl, Boc for tert-butyl carbamate, MEE
for (2-methoxyethoxy)ethane; X describes internal repeat units,
B for 3,5-dioxybenzyl, F for formamide, S for benzenesulfona-
mide; n is the number for generations; Y describes functional
group at the focal point, either chloride, Cl, or azide, N3.
[9] Monochloride dendrons generated from benzenesulfonamide 13
were converted into the corresponding azides in wet DMF.
[10] In general, dendrons generated from benzenesulfonamide 13 are
less soluble than dendrons made from acetamide 12 in all
solvents tested, while the incorporation of 19 as a chain end
increases the solubility substantially.
[11] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett., in
press.
[12] a) Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless,
M. G. Finn, J. Am. Chem. Soc. 2003, 125, 3192 – 3193; b) A. E.
Speers, G. C. Adam, B. F. Cravatt, J. Am. Chem. Soc. 2003, 125,
4686 – 4687; c) A. J. Link, D. A. Tirrell, J. Am. Chem. Soc. 2003,
125, 11164 – 11165; d) A. Deiters, T. A. Cropp, M. Mukherji,
J. W. Chin, J. C. Anderson, P. G. Schultz, J. Am. Chem. Soc. 2003,
125, 11782 – 11783.
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