A new water-soluble ligand for efficient copper-catalyzed Huisgen cycloaddition of aliphatic azides and alkynes

Article abstract of DOI:10.1016/j.tetlet.2015.09.110

Efficient procedures for the copper-catalyzed Huisgen cycloaddition reaction in aqueous media were developed using a novel water-soluble catalytic ligand, 2-{4-[(dimethylamino)methyl]-1,2,3-triazol-1-yl}cyclohexan-1-ol (AMTC). A series of aliphatic and ar

Full text of DOI:10.1016/j.tetlet.2015.09.110

Accepted Manuscript
A new water-soluble ligand for efficient copper-catalyzed Huisgen cycloaddi-
tion of aliphatic azides and alkynes
Przemysław W. Szafrański, Patryk Kasza, Marek T. Cegła
PII:
S0040-4039(15)30152-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.110
TETL 46782
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
22 May 2015
23 September 2015
24 September 2015
Please cite this article as: Szafrański, P.W., Kasza, P., Cegła, M.T., A new water-soluble ligand for efficient copper-
catalyzed Huisgen cycloaddition of aliphatic azides and alkynes, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.09.110
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A new water-soluble ligand for efficient
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Szafrański P.W.*, Kasza P., Cegła M.T.

1
Tetrahedron Letters
A new water-soluble ligand for efficient copper-catalyzed Huisgen cycloaddition of
aliphatic azides and alkynes
Przemysław W. Szafrańskia , Patryk Kaszaa,b and Marek T. Cegłaa
a Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland
b Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060, Kraków, Poland.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Efficient procedures for the copper-catalyzed Huisgen cycloaddition reaction in aqueous media
were developed using a novel water-soluble catalytic ligand, 2-{4-[(dimethylamino)methyl]-
1,2,3-triazol-1-yl}cyclohexan-1-ol (AMTC). A series of aliphatic and aromatic substrates were
tested and compared to the well-known tris(triazole)amine ligands (TBTA and THPTA). The
effect of solvent composition was also investigated.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Azides
Alkynes
Copper
Heterocycles
———
 Corresponding author. Tel.: +48-6205-467; fax: +48-12 62-05-619; e-mail: szafranski.p@wp.pl

2
Tetrahedron Letters
1. Introduction
after 2 h at room temperature. A simple extraction of the product
with dichloromethane from a strongly alkaline solution gave
AMTC of high purity in 90% yield.
Since being independently reported by Sharpless1,2 and
Meldal,3,4 the copper-catalyzed azide-alkyne cycloaddition
reaction (CuAAC) has received considerable attention and found
numerous applications in organic chemistry,5,6 biotechnology,7,8
pharmacy,8,9 materials engineering and polymer science.6,10,11
The ligand-assisted CuAAC, allows synthesis of 1,4-
disubstituted 1,2,3-triazoles that are inaccessible using the
ligand-free variant of this reaction.5,6 In 2002, Sharpless
demonstrated that the copper-catalyzed Huisgen cycloaddition
could be accelerated by N-donor ligands. Initially these included
ethylenediamine or trimethylamine, however a later study
revealed tris(1-benzyl-1H-1,2,3-triazol-4-yl)amine (TBTA) as an
efficient catalyst for the cycloaddition of aromatic azides and
alkynes.12 Further studies resulted in the synthesis of more
catalytic ligands, most of them effective for aromatic
substrates.13–18 Notable for the scope of substrates tested,
Scheme 1. Synthesis of AMTC
To develop efficient synthetic procedures using AMTC as a
catalytic ligand, we initially examined the effect of the Cu(II) –
ascorbate catalytic system loading and various solvents. The best
solvent was found to be a mixture of water and ethanol, which
furnished the desired product in high yield and high purity.
Although the reactions conducted in dichloromethane were
efficient, with short reaction times and typical yields over 90%,
they unfortunately resulted in the formation of significant
amounts of by-products that were difficult to remove. Reactions
conducted in THF proceeded slowly, in poor yields and produced
a complex mixture of compounds.
Ozçubukçu
and
co-workers16,17
introduced
the
tris(triazolyl)methanol ligands whilst Fukuzawa described
pyridine-triazole ligands.18 Fukuzawa also proposed in-situ
formation of catalytic ligand, using an alkyne additive.
However, three important limitations of previous studies can
be noted. Firstly, many studies use a limited number of substrates
and often only examine the reaction of benzyl azide with
phenylacetylene. Secondly, most ligands are non-polar and are
mainly only soluble in organic media (e.g. TBTA, Log P > 4).
These non-polar ligands remain as impurities after extraction-
based workup and their removal typically requires
chromatography. Finally, there is the lack of clear guidelines for
selecting an efficient ligand for a given set of substrates. Some of
these limitations can be overcome by the use of a water-soluble
ligand such as THPTA,12,19 which was developed by Sharpless
and co-workers as a catalytic ligand for bioconjugation. In this
work we describe the synthesis and application of 2-{4-
[(dimethylamino)methyl]-1,2,3-triazol-1-yl}cyclohexan-1-ol
(AMTC) as a novel water-soluble ligand (Log P = 0.6620) that is
easier to synthesize than THPTA (Scheme 1).
The optimized conditions for ten substrate sets are presented
in Table 1. Two substrate set types were selected: aromatic-
aliphatic and aliphatic-aliphatic. The aliphatic-aliphatic group
contained compounds selected for their reported biological
activity21,22 (entries 2-5) and highly polar substrates such as
propargyl alcohol (entries 5-6). The reactions for the aliphatic-
aliphatic systems, were performed at room temperature using 1-5
mol% Cu and 1-10 mol% AMTC, whereas for the aliphatic-
aromatic systems, they were conducted at 30°C using 1 mol% Cu
and 1 mol% AMTC. The most important improvement was in the
product purity and complete removal of the catalytic ligand upon
workup.
It is important to note that all the aliphatic-aliphatic 1,2,3-
triazoles obtained are able to form stable chelates with copper, of
which traces may prevail in the product after workup. For
complete copper removal, the product could be diluted with ethyl
acetate and filtered through a pad of silica gel or washed with an
aqueous solution of EDTA instead of water during workup.
2. Results
AMTC was synthesized by the Huisgen cycloaddition reaction
of N,N-dimethylpropargylamine with trans-2-azidocyclohexanol
in water, in the presence of CuSO4 (1 mol%) and sodium
ascorbate (1 mol%). After a short induction period, the reaction
proceeded rapidly in an autocatalytic manner and was complete
Table 1 Synthesis of 1,2,3-triazoles under optimized conditions
Water/
EtOH
Isolated
yield (%) purity (%)
HPLC
Entry
azide
alkyne
Catalyst
Time (h)
24
2 mol% AMTC,
1 mol% Cu
0
2:1
2:1
2:1
2:1
51
82
77
89
93.5
96.5
97.8
96.7
10 mol% AMTC,
5 mol% Cu
1
2
3
2.5
24
1
2 mol% AMTC,
1 mol% Cu
6 mol% AMTC,
3 mol% Cu
6 mol% AMTC,
3 mol% Cu
4
1
2:1
82
94.9

3
3 mol% AMTC,
3 mol% Cu
5
6
7
8
9
18
1.5
24
24
24
1:2
2:1
2:1
2:1
2:1
75
99
69
82
95
100.0
97.3
6 mol% AMTC,
3 mol% Cu
1 mol% AMTC,
1 mol% Cu
95.7
1 mol% AMTC,
1 mol% Cu
100.0
95.1
1 mol% AMTC,
1 mol% Cu
1 mol% AMTC,
1 mol% Cu
10
24
2:1
91
96.4
To examine the substrate selectivity of AMTC and compare
its efficiency to that of TBTA and THPTA, 11 substrate sets,
including the entries from Table 1 and the benzyl azide –
phenylacetylene system which is commonly used as a benchmark
reaction for ligand-assisted cycloadditions,12,14,15 were selected.
For each set, five reactions were performed; no ligand, 1 mol%
and 2 mol% of AMTC, and 1 mol% of TBTA and THPTA, using
the CuSO4 – sodium ascorbate catalytic system, and a 2:1
water : ethanol mixture as solvent. The isolated crude products
were analyzed with HPLC-MS. The reactions for each substrate
set were performed under standardized, constant-temperature
conditions to ensure comparability and the results which show
the percentage yield increases over the ligand-free reaction are
plotted in Figure 1. Detailed results including procedures, yields,
HPLC purities and calculation details are given in the ESI.
For the substrate sets tested, use of AMTC resulted in an
increase in the synthetic yields and purity of the products. These
increases were most significant for the aliphatic-aliphatic sets,
especially those containing α-azidobutyrolactone (entries 3,4).
The second group where it performed well were the aliphatic-
aromatic sets, where both, high yields and product purities were
obtained, with the largest increase in yield for entry 7. TBTA
outperformed AMTC for only three substrate sets: the reaction of
phenylacetylene with benzyl azide (Fig. 1, entry 0) and the
reactions using propargyl alcohols (entries 5 and 6). THPTA also
gave better results in three cases (entries 1, 5 and 7). The results
of THPTA and AMTC were similar for the reaction of
3-methylpropargyl alcohol with azidocyclohexane (entry 6).
Notably, THPTA was efficient only for small or polar substrates,
whereas AMTC retained its activity even for non-polar systems
(entries 2, 9, and 10). With regard to ligand removal, AMTC and
THPTA could be easily removed while TBTA remained in the
isolated products.
Finally, we selected four aliphatic-aliphatic substrate sets
(entries 1, 2, 5 and 6, Table 1) and performed the CuAAC
reactions in various ethanol : water mixtures. The reactions were
performed with 2 mol% AMTC for entries 1 and 2, 1 mol%
AMTC for entries 5 and 6 (based on Figure 1), using the same
standardized protocol: CuSO4/sodium ascorbate (1 mol%), 30 °C,
24 h. The yields showed a significant dependence on solvent
composition (Figure 2), especially for substrate sets 5 and 6. For
entry 5, high yields (54% and 76%) were obtained in ethanol-rich
mixtures (1:9 and 1:2) which contrasted with very poor yields (7-
10%) in water-rich mixtures (2:1 and water). For entry 6, a
similar trend was observed, with smaller differences in yield
between the water-rich and ethanol-rich solvents. The opposite
was observed for entries 1 and 2, where better yields and purities
were observed for water-rich solvent mixtures. This was thought
to point towards the efficiency of reaction in aqueous suspension
(on-water procedure).23,24 However, when water was used as
solvent, a decrease in product purity was observed. In these
cases, the maximum HPLC yields were obtained using the 1:2
water:ethanol system.
Figure 1. Yield increase in comparison to ligand-free copper(I), using
AMTC, THPTA or TBTA as ligands. Entry 0 is the benchmark reaction for
TBTA

4
Tetrahedron Letters
10.
11.
12.
13.
14.
15.
16.
17.
W.H. Binder; R. Sachsenhofer, Macromol. Rapid Commun. 2007,
28, 15–54.
W. Binder; R. Sachsenhofer, Macromol. Rapid Commun. 2008, 29,
952–981.
T.R. Chan; R. Hilgraf; K.B. Sharpless; V. V Fokin, Org. Lett. 2004,
6, 2853–5.
W.G. Lewis; F.G. Magallon; V. V Fokin; M.G. Finn, J. Am. Chem.
Soc. 2004, 126, 9152–3.
V.O. Rodionov; S.I. Presolski; S. Gardinier; Y.-H. Lim; M.G. Finn,
J. Am. Chem. Soc. 2007, 129, 12696–704.
S.I. Presolski; V. Hong; S.-H. Cho; M.G. Finn, J. Am. Chem. Soc.
2010, 132, 14570–6.
S. Ozçubukçu; E. Ozkal; C. Jimeno; M.A. Pericàs, Org. Lett. 2009,
11, 4680–3.
E. Ozkal; S. Özçubukçu; C. Jimeno; M.A. Pericàs, Catal. Sci.
Technol. 2012, 2, 195.
Figure 2. Cycloaddition reaction yields for the reaction of selected
substrate sets (entries 1, 2, 5 and 6) when performed in various water:ethanol
mixtures
18.
19.
H. Hiroki; K. Ogata; S. Fukuzawa, Synlett 2013, 24, 843–846.
V. Hong; S.I. Presolski; C. Ma; M.G. Finn, Angew. Chem. Int. Ed.
Engl. 2009, 48, 9879–83.
Such behavior may be explained by the solubility of the
copper-ligand-substrates complex. In the cases of entries 5 and 6,
the alkynes are more soluble in water, which was opposite to
cyclohexyl azide, which forms a poorly water soluble complex
with AMTC and copper. Therefore, the copper-azide-AMTC
species would remain inaccessible to the water-soluble alkynes,
resulting in poor yield. In the cases of entries 2 and 3, the copper-
azide-AMTC species is slightly more water-soluble, whereas the
alkyne is non-polar and insoluble in water. Thus, the copper-
ligand-substrate complex can form easily at the interface between
water and the undissolved substrate, promoting the reaction.
20.
21.
Log P values were calculated using Marvin 6.3.1, ChemAxon Ltd.,
2014.
P. W. Szafranski; K. Dyduch; T. Kosciolek; T. P. Wrobel; M.
Gomez-Canas; M. Gomez-Ruiz; J. Fernandez-Ruiz; J. Mlynarski,
Lett. Drug Des. Discov. 2013, 10, 169–172.
G. Brackman; M. Risseeuw; S. Celen; P. Cos; L. Maes; H.J. Nelis;
S. Van Calenbergh; T. Coenye, Bioorg. Med. Chem. 2012, 20,
4737–43.
S. Narayan; J. Muldoon; M.G. Finn; V. V Fokin; H.C. Kolb; K.B.
Sharpless, Angew. Chem. Int. Ed. Engl. 2005, 44, 3275–9.
A. Chanda; V. V Fokin, Chem. Rev. 2009, 109, 725–48.
N. V. Dubrovina; L. Domke; I.A. Shuklov; A. Spannenberg; R.
Franke; A. Villinger; A. Börner, Tetrahedron 2013, 69, 8809–8817.
22.
23.
24.
25.
However, if the copper-ligand-substrates complex is trapped
within the undissolved organic substance layer, the reaction may
be inhibited. Such situation can easily occur in aqueous
suspension and explain the lower product purity.
Supplementary material
Electronic Supporting Information (ESI) for this article,
containing detailed procedures and spectral/analytical data for
novel compounds (AMTC and Entry 6) is available.
3. Conclusions
The studies presented herein show the efficiency of AMTC as
a CuAAC ligand, particularly for aliphatic substrate sets. The use
of AMTC is particularly beneficial for the reaction between
a polar azide and a nonpolar alkyne. For the selected substrate
sets, the optimum procedures require significantly less copper
and proceed under milder conditions than the originally
published ligand-free syntheses (typically, 10 mol% Cu). 21,22,25
Acknowledgments
The authors thank Professor L. Strekowski, Department of
Chemistry, Georgia State University, Atlanta, Georgia 30302,
USA, for critical reading of the manuscript.
References and notes
1.
2.
3.
H.C. Kolb; M.G. Finn; K.B. Sharpless, Angew. Chem. Int. Ed. Engl.
2001, 40, 2004–2021.
V. V. Rostovtsev; L.G. Green; V. V. Fokin; K.B. Sharpless, Angew.
Chemie 2002, 114, 2708–2711.
C. Tornøe; M. Meldal, Peptides: The Wave of the Future.
Proceedings of the Second International and the Seventeenth
American Peptide Symposium, June 9–14 2001, San Diego,
California, U.S.A., 2001, pp. 263-264.
4.
5.
C.W. Tornøe; C. Christensen; M. Meldal, J. Org. Chem. 2002, 67,
3057–3064.
V.D. Bock; H. Hiemstra; J.H. van Maarseveen, European J. Org.
Chem. 2006, 51–68.
6.
7.
8.
L. Liang; D. Astruc, Coord. Chem. Rev. 2011, 255, 2933–2945.
J.E. Moses; A.D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249–62.
P. Thirumurugan; D. Matosiuk; K. Jozwiak, Chem. Rev. 2013, 113,
4905–79.
9.
G.C. Tron; T. Pirali; R.A. Billington; P.L. Canonico; G. Sorba;
A.A. Genazzani, Med. Res. Rev. 2008, 28, 278–308.