One-pot procedure for diazo transfer and azide-alkyne cycloaddition: Triazole linkages from amines

Article abstract of DOI:10.1021/ol0621506

(Chemical Equation Presented) A one-pot reaction for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (sometimes called click reaction) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields from a variety of readily available amines without the need for isolation of the azide intermediates. The reaction has a broad scope and is especially practical for the synthesis of multivalent structures because compounds substituted with multiple azides are potentially unstable.

Full text of DOI:10.1021/ol0621506

ORGANIC
LETTERS
2007
Vol. 9, No. 1
1-4
One-Pot Procedure for Diazo Transfer
and Azide Alkyne Cycloaddition:
−
Triazole Linkages from Amines
Henning S. G. Beckmann and Valentin Wittmann*
Fachbereich Chemie, UniVersita¨t Konstanz, D-78457 Konstanz, Germany
mail@Valentin-wittmann.de
Received August 30, 2006 (Revised Manuscript Received November 7, 2006)
ABSTRACT
A one-pot reaction for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide−alkyne 1,3-dipolar cycloaddition (sometimes called click reaction)
is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields from a variety of readily available amines without the need for
isolation of the azide intermediates. The reaction has a broad scope and is especially practical for the synthesis of multivalent structures
because compounds substituted with multiple azides are potentially unstable.
The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of
azides and alkynes1,2 has found widespread application,
e.g., in combinatorial drug research3 and material science.4
Due to its outstanding chemoselectivity and mild conditions,
the reaction has been especially used in bioconjugate
chemistry.5,6
interactions is an important principle used by nature to
increase weak interactions to biologically relevant levels.7
A common strategy to assemble multivalent ligands is the
covalent attachment of the epitope to a scaffold. Several
approaches using the azide-alkyne cycloaddition for this
purpose have been reported.8-10
In this field, the construction of multivalent structures is
often required because multivalency in ligand-receptor
Although organic azides are stable against most reaction
conditions, compounds of low molecular weight or those
containing several azides (like multivalent scaffolds) tend
to be explosive and are difficult to handle.11 Thus, some
procedures to generate the azide in situ followed by azide-
alkyne cycloaddition have been reported.10,12 In these cases,
(1) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-598. (b)
Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-
3064.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(3) (a) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless,
K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-9589. (b) Brik,
A.; Muldoon, J.; Lin, Y.-C.; Elder, J. H.; Goodsell, D. S.; Olson, A. J.;
Fokin, V. V.; Sharpless, K. B.; Wong, C.-H. ChemBioChem 2003, 4, 1246-
1248.
(4) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel,
A.; Voit, B.; Pyun, J.; Fre´chet, J. M. J.; Sharpless, K. B.; Fokin, V. V.
Angew. Chem., Int. Ed. 2004, 43, 3928-3932. (b) Helms, B.; Mynar, J. L.;
Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 2004, 126, 15020-
15021. (c) van Steenis, D. J. V. C.; David, O. R. P.; van Strijdonck, G. P.
F.; van Maarseveen, J. H.; Reek, J. N. H. Chem. Commun. 2005, 4333-
4335.
(5) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192-3193.
(6) (a) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc.
2003, 125, 4686-4687. (b) Link, A. J.; Tirell, D. A. J. Am. Chem. Soc.
2003, 125, 11164-11165. (c) Burley, G. A.; Gierlich, J.; Mofid, M. R.;
Nir, H.; Tal, S.; Eichen, Y.; Carell, T. J. Am. Chem. Soc. 2006, 128, 1398-
1399.
(7) (a) Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem.,
Int. Ed. 1998, 37, 2754-2794. (b) Kiessling, L. L.; Gestwicki, J. E.; Strong,
L. E. Angew. Chem., Int. Ed. 2006, 45, 2348-2368.
(8) (a) Pe´rez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.;
Herna´ndez-Mateo, F.; Calvo-Flores, F. G.; Calvo-As´ın, J. A.; Isac-Gac´ıa,
J.; Santojo-Gonza´lez, F. Org. Lett. 2003, 5, 1951-1954. (b) Tejler, J.;
Tullberg, E.; Frejd, T.; Leffler, H.; Nilsson, U. J. Carbohydr. Res. 2006,
341, 1353-1362.
(9) Joosten, J. A. F.; Tholen, N. T. H.; Maate, F. A. E.; Brouwer, A. J.;
van Esse, G. W.; Rijkers, D. T. S.; Liskamp, R. M. J.; Pieters, R. J. Eur.
J. Org. Chem 2005, 3182-3185.
(10) Chittaboina, S.; Fang, X.; Wang, Q. Tetrahedron Lett. 2005, 46,
2331-2336.
(11) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188-5240.
(12) (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6,
3897-3899. (b) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223-4225.
10.1021/ol0621506 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/14/2006

restricted to special amines, and a great variety of them is
commercially available. Hence, amines are adapted func-
tionalities for the generation of multivalent structures.
Table 1. Evaluation of the Reaction Conditions for a
Sequential One-Pot Procedure
Herein, we report convenient one-pot procedures for
generating triazole-linked (multivalent) structures starting
from amines and avoiding the isolation of the azide
intermediates. The essential element of these procedures is
to generate the Cu(I) species required for the azide-alkyne
cycloaddition by adding a reducing agent after complete or
during Cu(II)-catalyzed diazo transfer.
amine
TBTA
reaction yield
entry (equiv) conditionsa (mol %) T (°C)
time
(%)
1
2
3
4
5
6
1.5
1.5
1.5
1.5
1.0
1.0
A
B
A
A
A
B
5
5
rt
rt
80 MW
39 h
39 h
8 h
traces
traces
92b
The reaction conditions for a sequential one-pot procedure
were optimized using a simple test system starting from
benzylamine 1 (Table 1). First, the diazo transfer was
performed by analogy with literature-known conditions at
ambient temperature14,15 but with sodium bicarbonate as base.
After complete conversion to benzylazide, phenylacetylene
2 (1 equiv) and the reducing agent were added directly
without any workup procedure. Two different reagents were
tested: (A) sodium ascorbate2 and (B) Cu powder, which
was used together with 10 mol % CuSO4 to obtain the
Cu(I) species by comproportionation.5,16 Heating to 80 °C
by microwave irradiation was required in both cases to obtain
high yields within reasonable reaction times. Whereas in the
case of sodium ascorbate as reducing agent reaction times
of less than 1 h could be achieved only by addition of the
Cu(I)-stabilizing ligand tris(benzyltriazolylmethyl)amine
(TBTA)17 (cf. entries 3 and 4), the Cu/CuSO4 system gave
5
5
80 MW 30 min quant
80 MW 30 min 94
80 MW 20 min 89
a Conditions: (A) 2 mol % of CuSO4, then 10 mol % of Na ascorbate;
(B) 10 mol % of CuSO4, then 30 mol % of Cu powder. b After 4 h, an
additional 2 mol % of CuSO4 and 10 mol % of Na ascorbate were added.
the substitution of halides with sodium azide is used. While
circumventing the isolation of the azide intermediate, this
approach has the disadvantage that nucleophilic replacement
of halides only proceeds easily in the case of activated
halides, e.g., in benzylic or anomeric positions.
Another efficient and convenient method for generating
organic azides is the Cu(II)-catalyzed diazo transfer to amines
using trifluoromethanesulfonyl azide.13,14 The reaction is not
Table 2. One-Pot Synthesis of 1,2,3-Triazoles from Aminesa
a Amounts of reagent are given per amino group. b The reaction was performed at 120 °C. c 2 equiv of NaHCO3 was used. d 30 mol % of Na ascorbate
was used.
2
Org. Lett., Vol. 9, No. 1, 2007

Scheme 1. Synthesis of a Divalent Glycoconjugate Using the One-Pot Procedure
comparable reaction rates and yields without this additive
interferes with the diazo transfer nor a considerable reaction
of triflyl azide and alkyne takes place in the presence of 2
mol % of CuSO4, 10 mol % of sodium ascorbate, and 5 mol
% of TBTA. This is remarkable since copper-catalyzed
reactions between sulfonyl azides and alkynes have been
reported.20 Therefore, we added all components of our test
system simultaneously, and the desired triazole 3 was formed
in yields slightly lower than those of the sequential one-pot
procedure (Table 3). Both reducing agents could be applied;
however, in this case the Cu/Cu(II) system turned out to be
more reliable.
(entry 6). Using an excess of amine 1 (1.5 equiv relative to
2) gave slightly higher yields but was not essential (cf. entries
4 and 5).
While both variants proceeded well, we decided to use
sodium ascorbate as reducing agent for further studies
because the Cu/CuSO4 system seemed to be less reliable
regarding the formation of side products. To prove the
general adaptability, different amines 4-8 were applied in
the described one-pot procedure (Table 2). In all cases, the
triazole products 9-13 were isolated in very good yields.
The fact that Fmoc-protected lysine 6 could be converted
to 11 without problems illustrates the potential use of the
procedure for the functionalization of peptides. The use of
diamines 7 and 8 resulted in high yields of bis-triazoles 12
and 13, showing the capability for generating multivalent
structures.
It has been reported that ionic azides react with dichlo-
romethane to form explosive diazidomethane.21 Therefore,
an alternative procedure for the preparation of triflyl azide
and its use in diazo transfer reactions has been published
recently, in which dichloromethane is replaced with toluene.22
In order to test whether these conditions are also compatible
with our one-pot procedure, we reacted 1 and 2 in different
ternary solvent mixtures. With the system toluene/2-propanol/
water we found conditions that gave product 3 of our test
reaction in a yield of 77% (Scheme 2). Although this yield
Multivalency plays an important role in carbohydrate-
lectin interactions which are responsible for many biological
recognition and signal transduction processes.7,18 Therefore,
much attention has been paid to the synthesis of multivalent
neoglycoconjugates as ligands for lectins.8,10,19
To show the convenience of our approach for the synthesis
of multivalent glycoconjugates, we prepared divalent glu-
coconjugate 16 (Scheme 1). Starting from diamine 14 and
propargyl glucoside 15, the reaction proceeded cleanly,
obtaining 16 in a yield of 86%. A detailed study using this
approach for the synthesis of multivalent glycoconjugates
is ongoing and will be reported in due course.
We next investigated the possibility to perform diazo
transfer and cycloaddition as a one-step one-pot reaction. In
orienting experiments we could show that neither the alkyne
(13) (a) Cavender, C. J.; Shiner, V. J. J. Org. Chem. 1972, 37, 3567-
3569. (b) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV.
Chim. Acta 1991, 74, 2073-2077. (c) Alper, P. B.; Hung, S.-C.; Wong,
C.-H. Tetrahedon Lett. 1996, 37, 6029-6032.
(14) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J. Am.
Chem. Soc. 2002, 124, 10773-10778.
(15) Lundquist, J. T.; Pelletier, J. C. Org. Lett. 2001, 3, 781-783.
(16) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
(17) (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853-2855. (b) Lewis, W. G.; Magallon, F. G.; Fokin, V.
V.; Finn, M. G. J. Am. Chem. Soc. 2004, 126, 9152-9153.
(18) (a) Gabius, H.-J.; Siebert, H.-C.; Andre´, S.; Jime´nez-Barbero, J.;
Ru¨diger, H. ChemBioChem 2004, 5, 740-764. (b) Dam, T. K.; Brewer, C.
F. Chem. ReV. 2002, 102, 387-429.
(19) (a) Wittmann, V. In Highlights in Bioorganic Chemistry: Methods
and Applications; Schmuck, C., Wennemers, H., Eds.; Wiley-VCH:
Weinheim, 2004; pp 203-213. (b) Wittmann, V.; Seeberger, S. Angew.
Chem., Int. Ed. 2004, 43, 900-903. (c) Wittmann, V.; Seeberger, S. Angew.
Chem., Int. Ed. 2000, 39, 4348-4352. (d) Choi, S.-K. Synthetic MultiValent
Molecules. Concepts and Biomedical Applications; John Wiley & Sons:
Hoboken, NJ, 2004. (e) Lundquist, J. J.; Toone, E. J. Chem. ReV. 2002,
102, 555-578. (f) Lindhorst, T. K. Top. Curr. Chem. 2002, 218, 201-
235. (g) Roy, R.; Baek, M.-G. ReV. Mol. Biotechnol. 2002, 90, 291-309.
(20) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046-16057. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V.
Angew. Chem., Int. Ed. 2006, 45, 3154-3157. (c) Whiting, M.; Fokin, V.
V. Angew. Chem., Int. Ed. 2006, 45, 3157-3161.
(21) (a) Hassner, A.; Stern, M. Angew. Chem., Int. Ed. 1986, 25, 478-
479. (b) Hassner, A.; Stern, M.; Gottlieb, H. E. J. Org. Chem. 1990, 55,
2304-2306. (c) Dharanipragada, R.; VanHulle, K.; Bannister, A.; Bear,
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47, 2383-2385.
Table 3. One-Step, One-Pot Reaction
amine
CuSO4
TBTA
(mol %)
yield
(%)
entry (equiv) (mol %)
reducing agent
1
2
1.5
1.0
2
10 mol % of
Na ascorbate
30 mol % of
Cu powder
5
93
10
82
Org. Lett., Vol. 9, No. 1, 2007
3

the isolation of intermediate azides is prevented. While the
one-step procedure is convenient, the sequential variant,
however, has the advantage that it can be more easily
followed by TLC and gives higher reaction yields.
Scheme 2. Sequential One-Pot Procedure in Toluene,
Isopropyl Alcohol, and Water
Acknowledgment. We thank Prof. W. Pfleiderer, Uni-
versita¨t Konstanz, for valuable discussions regarding the
Cu/CuSO4 reducing system and Biotage AB for providing a
microwave synthesizer.
Supporting Information Available: Experimental pro-
cedures and full characterization of compounds 11-13 and
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
is lower compared to that given in Table 1, entry 5, this
procedure represents a safe alternative suitable for reactions
on a larger scale.23
In conclusion, efficient one-step and sequential one-pot
procedures for diazo transfer and azide-alkyne cycloaddition
have been developed giving access to triazoles commencing
with amines being commercially available in a great variety.
The one-pot reaction has a broad scope and is especially
practical for the synthesis of multivalent structures because
OL0621506
(23) It has to be noted that even if diazidomethane is formed, it would
be converted to stable triazole derivatives in the subsequent azide-alkyne
cycloadditions. However, we could never identify side products resulting
from such a reaction.
4
Org. Lett., Vol. 9, No. 1, 2007