An efficient (2-aminoarenethiolato)copper(I) complex for the copper-catalysed huisgen reaction (CuAAC)

Article abstract of DOI:10.1002/ejoc.200900779

A (2-aminoarenethiolato)copper(I) complex has been used as an efficient catalyst (1 mol-%) for the copper-catalysed Huisgen reaction (CuAAC) of azides and terminal alkynes in an organic solvent. The reaction was also extremely effective in CH₂C

Full text of DOI:10.1002/ejoc.200900779

FULL PAPER
DOI: 10.1002/ejoc.200900779
An Efficient (2-Aminoarenethiolato)copper(I) Complex for the
Copper-Catalysed Huisgen Reaction (CuAAC)
[a]
[a]
[a]
[b][‡]
Pierangelo Fabbrizzi,* Stefano Cicchi,* Alberto Brandi, Elena Sperotto,
Gerard van Koten[
and
b]
Keywords: Azides / Alkynes / Click chemistry / Cycloaddition / Dendrimers / N ligands
A (2-aminoarenethiolato)copper(I) complex has been used as
an efficient catalyst (1 mol-%) for the copper-catalysed
Huisgen reaction (CuAAC) of azides and terminal alkynes in
an organic solvent. The reaction was also extremely effective
in CH
scaffolds.
2 2
Cl allowing the complete decoration of dendrimeric
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
proves the rate and efficiency of more delicate reactions.
The limited solubility of cuprous salts in organic solvents
restricts the choice to soluble preformed coordination com-
The Huisgen reaction, the 1,3-dipolar cycloaddition of
azides to terminal alkynes, has probably become one of the
most frequently used reactions in organic chemistry, espe-
cially after the development by Sharpless and Fokin of a
copper-catalysed version (CuAAC).[ This reaction was the
first of a restricted group of reactions generally known by
the term “click chemistry”.[ The efficiency of this reaction
is demonstrated by the huge number of applications in sup-
I
plexes of Cu , for example, under these circumstances
[12]
[13]
I
[
Cu(PPh ) ]Br
and (EtO) PCuI
are the catalysts of
3
3
3
choice. The availability of new Cu complexes, which have
been shown to be active in other reactions, allows the effi-
ciency of these compounds to be tested in another useful
reaction.
1]
2]
In this work we report the results obtained by using the
ramolecular chemistry,[ peptidomimetics,
3]
[4]
dendrimer
synthesis, bioconjugation, polymer and materials synthe-
[14]
(
aminoarenethiolato)copper(I) complex 1 (Figure 1) as a
[
5]
catalyst in the 1,3-dipolar cycloaddition of azides to ter-
minal alkynes. In (aminoarenethiolato)copper(I) complexes,
the copper(I) cation is bonded to a monoanionic, poten-
tially S,N-bidentate-coordinating 2-aminoarenethiolate li-
gand. These complexes show excellent solubility in a range
of useful solvents. They exist, both in the solid state and in
sis[ and many other fields.
6,7]
[8]
Such a wide variety of applications requires the reaction
to be performed under many different conditions, for exam-
ple, organic and aqueous solvents, and heterogeneous con-
ditions. Despite this variety of reaction conditions a very
II
limited set of catalysts are available. The use of Cu salts
solution, as aggregate species, for example, as dimers, tri-
with a sacrificial reducing agent such as sodium ascorbate
is the most common procedure: sodium ascorbate provides
[15]
mers, tetramers or nonamers,
and exhibit good thermal
stability. In addition, electronic and physical properties can
easily be fine-tuned by introducing substituents onto the
arene ring or the amino functionality. These (aminoarene-
thiolato)copper(I) complexes have already been tested as
I
[1,9]
I
the Cu ions that are needed for the catalytic reaction.
However, even a copper wire can afford the required Cu
II
0
I
ions by comproportionation of Cu and Cu . Simple Cu
salts have also been used, but the thermodynamic instability
[16]
[17]
[18]
catalysts in allylic substitution, 1,4- and 1,6-addition
I
II
of Cu can lead to oxidation to catalytically inactive Cu .
The use of ligands such as tris(1-benzyltriazol-4-ylmethyl)-
[19]
reactions and aromatic N-arylation reactions
and have
shown good catalytic properties.
amine (TBTA) or sulfonated bathophenanthroline[11] im-
[
10]
[
a] Dipartimento di Chimica Organica “Ugo Schiff”, Università
degli Studi di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Fax: +39-055-4573531
E-mail: pfabbrizzi@gmail.com
[
[
b] Chemical Biology & Organic Chemistry, Utrecht University,
Padualaan 8, 3584 CH, Utrecht, The Netherlands
‡] Present address: Physikalische Chemie, Universität Siegen,
Adolf-Reichwein-Str. 2, 57076 Siegen, Germany
Figure 1. {[2-(Dimethylamino)methyl]thiophenolato}copper(I) (1).
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5423
Eur. J. Org. Chem. 2009, 5423–5430

P. Fabbrizzi, S. Cicchi, A. Brandi, E. Sperotto, G. van Koten
FULL PAPER
Results and Discussion
As a preliminary test we studied the reaction of phenyl-
acetylene (3) with three different azides 2: an alkyl, a benzyl
and an aryl azide. The results are reported in Table 1.
Table 1. Cycloaddition reactions of phenylacetylene (3) and diverse
azides with two copper catalysts.
Scheme 1.
Yield[ [%]
a]
R
CuSO
4
(5)/Na ascorbate (10)[
b]
1 (1)[c]
[
d]
quantitative[e]
quantitative[e]
C
Bn
Ph
8
H
17
d]
[
76
88
91
81
Table 2. Cycloaddition reactions of benzyl azide (5) with several
dipolarophiles.
[
a] Yield after isolation (column chromatography). [b] Acetonitrile/
water (10:1), 1.1 equiv. azide, 18 h, room temp. [c] Dry acetonitrile,
1
determined by H NMR spectroscopy.
[20]
.1 equiv. azide, 18 h, room temp. [d] See ref. . [e] Conversion
1
As shown in Table 1, catalyst 1 is active at a low concen-
tration (1 mol-%) and requires no addition of a tertiary
amine. The purification of the crude reaction mixtures is
straightforward because the small amount of catalyst is re-
moved simply by filtration through a short pad of silica gel.
In comparison with the CuSO /Na ascorbate couple, the
4
results obtained with catalyst 1 are at least comparable or
better. For the CuSO /Na ascorbate couple we preferred
4
not to compare the yields with those reported in the litera-
ture, but rather with experimental results obtained in our
laboratory to make a more reliable comparison. Although
the catalyst 1 is somewhat sensitive to atmospheric oxygen,
it was not necessary to work under an inert atmosphere.
Thus, the reactions were performed in sealed vials with no
special precautions.
Two other reactions were examined, varying both the
azide and the alkyne (Scheme 1). Again the catalyst was
revealed to be extremely efficient, affording high yields of
the products, which were purified by filtration through a
short pad of silica gel (7) or by simple vacuum filtration
[
a] Isolated yield after column chromatography. [b] Dichlorometh-
ane, 1.1 equiv. benzyl azide, 1 equiv. alkyne, 1 mol-% catalyst 1. [c]
Isolated as the hydrochloride. [d] Dichloromethane, 2.2 equiv. ben-
zyl azide, 1 equiv. alkyne, 2 mol-% catalyst 1 (1 mol-% with respect
(10). The use of acetonitrile as the solvent was initially dic-
tated by the in situ formation of the starting aromatic to reaction sites).
azides, for example, the azide 8, which was obtained from
[
21]
4
-nitroaniline.
The choice of solvent is, however, important: for exam-
ple, whereas no reaction was observed in water, dichloro-
methane was found to be a good solvent, as demonstrated click chemistry is the possibility of functionalizing complex
by the results reported in Table 2. systems in a single, simple step. This challenge is provided
The new reactions performed in CH Cl were found to by the possibility of decorating dendrimers with a high
The real breakthrough offered by the introduction of
2
2
be efficient and afforded simple compounds in high yields. number of peripheral substituents. Therefore we tested the
The use of CH Cl or acetonitrile appears to be equivalent efficiency of catalyst 1 in the reactions of dendrons 13[
22,23]
2
2
for these simple reactions, but it is rather fundamental in and 14 with the commercial sugar derivative 15 (Schemes 2
the case of more complex substrates.
and 3).
5424
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5423–5430

Copper-Catalysed Huisgen Reaction
Scheme 2.
The reaction performed in CH CN was not efficient and the monodipersion of the compounds through a proper in-
3
only the use of 10 mol-% (per triple bond) of catalyst 1 tegration of signals (see Figure 3).
induced the disappearance of the starting materials. Al-
This result appears to be particularly significant com-
1
though in the reaction performed in CH CN, H NMR sig- pared with the outcome obtained from the use of the
3
nals at δ = 8.5 ppm suggested the presence of more than CuSO /Na ascorbate catalyst with the same reagents, which
4
one compound, the spectrum of the crude mixture derived in a CH CN/water mixture afforded no products.
3
from the reaction in CH Cl showed a single sharp signal
for the 8 equiv. triazolic protons (Figure 2).
Unfortunately this efficient catalyst was not able to cata-
lyse the 1,3-dipolar cycloaddition reactions of benzyl azide
2
2
The use of 1 mol-% of catalyst 1 (with respect to the with internal alkynes either at room temperature or at 60 °C
[
24]
azide counterpart) in CH Cl afforded compounds 16 and or under MW irradiation.
2
2
17 in 84 and 82% yields, respectively. The reactions were
Finally, to complete this preliminary survey of the appli-
performed at room temp. in 18 h without the need of MW cation of this class of catalyst we performed a kinetic reso-
1
[25]
irradiation. In both cases the H NMR spectra confirmed lution of a racemic (1-azidoethyl)benzene by using a chi-
Eur. J. Org. Chem. 2009, 5423–5430
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5425

P. Fabbrizzi, S. Cicchi, A. Brandi, E. Sperotto, G. van Koten
FULL PAPER
Scheme 3.
ral and enantiopure analogue of compound 1, that is, com- ferent attempts. It is likely that the simple chiral environ-
pound 18 bearing a methyl group on the benzylic position ment of 18 is unable to differentiate the two reaction paths.
(Figure 4). Despite varying the solvent, reagent ratio and Other studies with more complex substrates are necessary
temperature, no significant ees were obtained in the dif- to explore the scope of this catalyst.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5423–5430

Copper-Catalysed Huisgen Reaction
Figure 4. Structure of the enantiopure compound 18.
Experimental Section
Figure 2. Signals of the triazolic protons of the crude reaction mix-
1
tures of 16 obtained in a) CH
3
CN ( H NMR in [D
).
6
]DMSO) and
General: 1H and C NMR spectra were recorded with a Varian
13
1
b) CH
2
Cl
2
( H NMR in CDCl
3
1
1
13
Mercury 400 ( H: 400 MHz) or Gemini 200 ( H: 200 MHz; C:
0 MHz) spectrometer with tetramethylsilane as the internal refer-
5
ence. The chemical shifts (δ) and coupling constants (J) are ex-
pressed in ppm and hertz, respectively. IR spectra were recorded
with a Perkin–Elmer 881 FT-IR spectrophotometer as KBr pellets.
Merck silica gel (0.040–0.063 mm) and MP EcoChrom silica gel
Conclusions
(
32–63, 60 Å) were used for flash chromatography. TLC was per-
Compound 1 has been shown to be an efficient and gene- formed on Merck silica gel 60 F254 plates. Elemental analyses were
performed with a Perkin–Elmer 240 C,H,N Analyzer. Mass spectra
were recorded with a Carlo Erba QMD 1000 spectrometer for EI–
ral catalyst for the copper-catalysed Huisgen reaction
(CuAAC) reaction, affording good yields of the cycload-
MS (70 eV), with a Thermo LTQ spectrometer for ESI–MS and
with a Bruker Ultraflex III TOF/TOF spectrometer for MALDI
MS. [α] values were measured with a Jasco DIP 370 instrument.
Gas chromatographic analysis of chiral mixtures were performed
with a Shimadzu-GC2014 instrument equipped with a Shimadzu
AOC-20i auto-sampler (isothermal 95 °C; Supelco β-DEX 120 chi-
dition products, and has also been found to be very useful
in more challenging cases, for example, in the complete dec-
oration of dendrimeric structures. Dichloromethane was the
solvent of choice for this reaction, although CH CN also
3
afforded good results. The long term stability and efficiency
of compound 1 make it a useful and practical alternative to ral column 30 mϫ0.25 mm i.d., d = 0.25 µ). All commercially
f
other commercially available copper(I) complexes.
available reagents and solvents were purchased from Sigma Aldrich
1
Figure 3. H NMR spectrum (400 MHz, CDCl
3
) of compound 16 (diagnostic signals and their assignments are shown).
Eur. J. Org. Chem. 2009, 5423–5430
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5427

P. Fabbrizzi, S. Cicchi, A. Brandi, E. Sperotto, G. van Koten
FULL PAPER
and used as received unless otherwise specified. Azide 15 was pur-
chased from Acros Organics. For the synthesis of catalyst 1 see
0.02 equiv., 1 % molar ratio to triple bonds) were dissolved in
dichloromethane (2 mL) and stirred for 18 h. The solvent was evap-
orated to dryness and the crude product purified by column
[
14]
[26]
ref. , for catalyst 18 see ref. for the synthesis of the ligand; the
copper complex was obtained by following the same procedure for
the synthesis of 1. Products whose characterizations are not re-
ported here have previously been synthesized and characterization
chromatography on silica starting elution with CH
creasing the polarity to CH Cl /MeOH (20:1) to afford a white
glass (0.120 g, 90%). H NMR (400 MHz, CDCl ): δ = 8.17 (s, 1
2 2
Cl then in-
2
2
1
3
[
27]
data has been reported in the literature.
For the synthesis and
H, central aromatic ring), 7.77 (d, J = 7.6 Hz, 2 H, central aromatic
ring), 7.72 (s, 2 H, triazole), 7.44–7.35 (m, 7 H, aromatic rings),
characterization of 13 see ref.[
22,23]
for the general procedures for
1
3
the synthesis of acetylenic dendrimers.
7.32–7.28 (m, 4 H, aromatic rings), 5.51 (s, 4 H, CH
NMR (50 MHz, CDCl ): δ = 147.4 (s, 2 C, triazole), 134.2 (s, 2 C),
30.7 (s, 2 C), 129.0 (d, 2 C, triazole), 128.8 (d, 1 C), 128.5 (d, 4
C), 127.8 (d, 4 C), 125.0 (d, 2 C), 122.4 (d, 2 C), 119.6 (d, 1 C),
4.0 (t, 2 C, CH ) ppm. IR (KBr): ν˜ = 3105 (m), 3083 (m), 3029
2
) ppm.
C
3
Safety Warning: Azides are potentially explosive. Maximum care
must be taken especially when manipulating large-scale reactions.
1
5
2
General Procedure for the Copper(I)-Catalysed Huisgen Reaction
(
(
m), 2943 (s), 1610 (m), 1588 (w), 1497 (s), 1454 (s), 1438 (m), 1411
m), 1411 (w), 1352 (w), 1342 (m), 1223 (m), 1212 (m), 1083 (m),
(Azide/Alkyne Cycloaddition: CuAAC)
Aminoarenethiolate Catalyst: The alkyne (1 equiv.) and azide
1072 (m), 1051 (s), 1029 (m), 1002 (m), 970 (w), 884 (w), 836 (w),
–
1
(1.1 equiv.) were dissolved in the solvent (acetonitrile or dichloro-
803 (s), 793 (s), 750 (m), 723 (s), 707 (s), 691 (s) 583 (w) cm . MS
+
methane, 2 mL per 100 mg of azide). The catalyst 1 (0.01 equiv.)
was added and the suspension was stirred for 18 h at room temp.
The solvent was evaporated to dryness and the crude product puri-
(EI, 70 eV): m/z (%) = 392.2 (14) [M] , 363.3 (12), 335.2 (13), 273.2
(52.3), 245.2 (21.3), 217. 2 (8), 154 (20.3), 127.1 (7.4), 91.1 (100),
65.1 (18). C24H20N (392.46): calcd. C 73.45, H 5.14, N 21.41;
6
fied by column chromatography on silica eluting with CH
CH Cl /CH OH, 20:1 (for more polar products).
2
Cl
2
or
found C 73.21, H 5.30, N 21.51.
2
2
3
Acet16-G4-COOCH
3
(14): Acet
equiv.), methyl 3,5-dihydroxybenzoate (0.0066 g, 0.0395 mmol,
.5 equiv.), K CO (0.065 g, 0.474 mmol, 6 equiv.) and 18-crown-6
-G3-Br[22,23] (0.1 g, 0.079 mmol
8
4
Na Ascorbate/CuSO : The alkyne (1 equiv.) and azide (1.1 equiv.)
1
0
were dissolved in acetonitrile (2 mL per 100 mg of azide) and
CuSO (1  solution in water, 0.05% equiv.) was added. Sodium
2
3
4
(
5 mg) were suspended in acetone (10 mL). The mixture was heated
ascorbate (0.1 equiv.) was dissolved in acetonitrile (0.2 mL) and
added to the solution. This mixture was stirred at room temp. for
at reflux under nitrogen for 48 h then evaporated to dryness and
partitioned between water and dichloromethane. The organic layer
was dried with Na SO , evaporated and purified by column
2 4
18 h, evaporated to dryness and purified by column chromatog-
raphy on silica.
chromatography on silica eluting with chloroform, then increasing
the polarity to chloroform/diethyl ether (20:1). A waxy solid
N,N-Dimethyl-4-[1-(4-nitrophenyl)-1H–1,2,3-triazol-4-yl]aniline
1
(
0.094 g, 94%) was obtained. H NMR (400 MHz,CDCl
3
): δ = 7.27
(
10): 1-Azido-4-nitrobenzene was generated in situ from 4-nitro-
[21]
(d, J = 4 Hz, 2 H, central aromatic ring), 6.77 (t, J = 4 Hz, 1 H,
central aromatic ring), 6.69–6.59 (m, 28 H), 6.58–6.49 (m, 14 H),
aniline following a procedure reported previously: 4-nitroaniline
(
(
0.73 mmol, 0.1 g, 1.1 equiv.) was dissolved in dry acetonitrile
5 mL) and cooled to 0 °C. tert-Butyl nitrite was added (0.99 mmol,
5
(
.02–4.92 (m, 28 H, CH
s, 3 H, CH ), 2.49 (t, J = 2.4 Hz, 16 H, alkynyl protons) ppm.
NMR (50 MHz, CDCl ): δ = 159.9 (s, C=O), 159.8 (s, 16 C), 159.2
s, 8 C), 158.7 (s, 6 C), 139.3 (s, 12 C), 139.1 (s, 2 C), 132 (s), 106.8
d, 2 C), 106.5 (d, 28 C), 101.8 (d, 15 C), 78.4 (s, 16 C, alkynyl
2 2
), 4.63 (d, J = 2.4 Hz, 32 H, CH ), 3.87
1
3
C
0
.102 g, 117 µL, 1.5 equiv.) followed by trimethylsilyl azide
3
(
0.79 mmol, 0.091 g, 104 µL, 1.2 equiv.) dropwise. This solution
3
(
(
was stirred at room temp. for 2 h. Then 4-ethynyl-N,N-dimethylani-
line (0.66 mmol, 0.096 g, 1 equiv.) dissolved in the minimum quan-
–
3
2
group), 75.9 (d, 16 C, alkynyl group), 69.8 (t, 14 C, CH ), 56.0 (t,
tity of acetonitrile was added, followed by catalyst 1 (6.6ϫ10
1
2 3
6 C, CH ), 51.2 (q, CH ) ppm. MS (ESI): m/z (%) = 2523.7 (88)
mmol, 1.5 mg, 0.01 equiv.). The reaction was stirred at room temp.
for 18 h. The resulting suspension was filtered and the insoluble
+
+
[
M + K] , 2507.8 (65) [M + Na] , 1217.8 (32), 861.4 (36), 773.5
50), 757.64 (94), 713.55 (100). C154 32 (2486.61): calcd. C
4.38, H 5.03; found C 74.22, H 5.01.
(
7
124
H O
solid was washed with CH
2 2
Cl (2 mL), petroleum ether (10 mL)
and diethyl ether (10 mL). A brown waxy solid (0.177 g, 86) was
1
obtained. H NMR (400 MHz, [D
azole), 8.46 (d, J = 9.2 Hz, 2 H, aromatic ring), 8.23 (d, J = 9.2 Hz,
H, aromatic ring), 7.5 (d, J = 8.8 Hz, 2 H, aromatic ring), 6.81
6
]DMSO): δ = 9.28 (s, 1 H, tri-
Glu
8 3
-G3-COOCH (16): 2,3,4,6-Tetra-O-acetyl-β--glucopyranosyl
azide (15; 0.1 g, 0.268 mmol, 8.8 equiv.), the dendritic core 13
2
–
4
1
3
(0.036 g, 0.03 mmol, 1 equiv.) and catalyst 1 (5.5 ϫ 10 g,
.0024 mmol, 0.08 equiv., 1 % molar ratio to triple bonds) were
added to dichloromethane (2 mL) and the mixture was stirred for
8 h. The mixture was evaporated and the crude product purified
(
d, J = 8.8 Hz, 2 H, aromatic ring), 2.94 (s, 6 H, NMe
2
) ppm.
C
0
NMR (100 MHz, [D
6
]DMSO): δ = 150.1 (s), 149.0 (s), 146.9 (s),
1
39.8 (s), 126.8 (d, triazole), 126.1 (d, 2 C), 120.6 (d, 2 C), 118.2
d, 2 C), 117.8 (s), 112.8 (d, 2 C), 41.3 (q, NMe ) ppm. IR (KBr):
ν˜ = 3105 (m), 3083 (m), 2964 (w), 2921 (w), 2857 (w), 2803 (w),
1
(
2
on a silica column eluting with dichloromethane/methanol (40:1)
to yield the product (0.126 g, 84%). The same reaction performed
in acetonitrile led to a mixture of products (see Results and Dis-
1
1
621 (m), 1594 (m), 1518 (s), 1502 (s), 1405 (m), 1341 (s), 1223 (m),
035 (m), 860 (m), 857 (m), 825 (m), 804 (m), 750 (m), 690
2
5
1
–1
+
cussion). [α]
(
2
D
=
–56.1 (c
): δ = 7.96 (s, 8 H, triazole), 7.27 (d, J = 2.0 Hz,
H, central aromatic ring), 6.78 (t, J = 2.0 Hz, 1 H, central aro-
=
0.25, chloroform).
H NMR
(
m) cm . MS (EI, 70 eV): m/z (%) = 309.1 (28.1) [M] , 281.2 (49.5),
68 (21.3), 237.1 (100), 235 (57.3), 161.1 (50.5), 159.1 (45.4), 158
39), 143.1 (16.7), 132.1(12.4), 125.8 (17.1), 117 (57.3), 113.1 (19.1),
12.1 (29.7), 103.5 (29.2), 99.1 (70.9), 98.1 (25.8), 91.1 (52.9), 57.1
44.3), 56.1 (61.8), 55.1 (81.3). C16 (309.32): calcd. C
400 MHz,CDCl
3
2
(
1
(
matic ring), 6.67 (d, J = 2.4 Hz, 8 H), 6.65 (d, J = 2.0 Hz, 4 H),
6
9
5
.60 (t, J = 2.4 Hz, 4 H), 6.52 (d, J = 2.0 Hz, 2 H), 5.92 (d, J =
.2 Hz, 8 H), 5.48 (t, J = 9.2 Hz, 8 H), 5.42 (t, J = 9.2 Hz, 8 H),
15 5 2
H N O
62.13, H 4.89, N 22.64; found C 62.22, H 4.93, N 22.70.
.26 (t, J = 9.2 Hz, 8 H), 5.17 (s, 16 H, CH
2 2
), 5.00 (s, 4 H, CH ),
1
,3-Bis(1-benzyl-1H-1,2,3-triazol-4-yl)benzene (12f): Benzyl azide
4.97 (s, 8 H, CH
2
), 4.28 (dd, J = 12.4, 4.8 Hz, 8 H, diastereotopic,
(
0
0.1 g, 0.75 mmol, 2.2 equiv.), 1,3 diethynylbenzene (0.043 g,
.34 mmol, 1.0 equiv.) and catalyst 1 (3.2 mg, 0.0068 mmol,
Glu-CH
Glu-CH
2
-OAc), 4.13 (dd, J = 12.4, 2.0 Hz, 8 H, diastereotopic,
-OAc), 4.02 (ddd, J = 9.2, 4.8, 2.0 Hz, 8 H), 3.88 (s, 3 H,
2
5428
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5423–5430

Copper-Catalysed Huisgen Reaction
CH
3
), 2.05 (s, 24 H, CH
3
), 2.03 (s, 24 H, CH
3
), 2.01 (s, 24 H, CH
3
),
1
1
1
7
3
.81 (s, 24 H, CH
3
) ppm. 13C NMR (100 MHz, CDCl
3
): δ = 170.5, [1] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
69.9, 169.4, 168.9, 166.7, 160, 159.7, 159.5, 144.6, 139.6, 139, 132,
21.5, 108.5, 107.1, 106.7, 106.5, 101.6, 101.2, 87.9, 85.7, 77.2, 75.1,
2.7, 70.3, 69.7, 67.7, 61.8, 61.5, 52.2 ppm. IR (KBr): ν˜ = 3183 (w),
107 (w), 2951 (m), 2909 (m), 2844 (w), 2121 (w), 1756 (s), 1597
Angew. Chem. Int. Ed. 2002, 41, 2596–2599; b) P. Fokin, V. V.
Wu, Aldrichimica Acta 2007, 40, 7–17.
2] H. C. Kolbe, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2001, 40, 2004–2021.
[
[
3] I. Aprahamina, O. S. Miljanic, W. R. Dichtel, K. Isoda, T. Ya-
suda, T. Kato, J. F. Stoddart, Bull. Chem. Soc. Jpn. 2007, 80,
(
(
s), 1456 (m), 1371 (s), 1253 (s), 1227 (s), 1151 (m), 1101 (m), 1029
–1
s), 921 (m), 815 (br), 683 (w), 596 (m) cm . MS (MALDI-TOF):
88 (4191.78): calcd.
C 53.29, H 5.10, N 8.02; found C 53.21, H 5.09, N 8.00.
1856–1869.
212 24
calcd. 4189.285; found 4189.263. C186H N O
[
[
[
4] Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674–1689.
5] G. Franc, A. Kakkar, Chem. Commun. 2008, 5267–5276.
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Chem. Soc. 2004, 126, 15020–15021.
Glu16-G4-COOCH
3
(17): The procedure used for the synthesis of
[
7] G. Ghini, L. Lascialfari, C. Vinattieri, S. Cicchi, A. Brandi, D.
Berti, F. Betti, P. Baglioni, M. Mannini, Soft Matter 2009, 5,
16 was followed using the following quantities: 2,3,4,6-tetra-O-ace-
tyl-β--glucopyranosyl azide (16; 0.1 g, 0.268 mmol, 18 equiv.),
acetylenic core 14 (0.037 g, 0.0149 mmol, 1 equiv.), catalyst 1
1863–1869.
[
8] a) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51–68; b) M. V. Gil, M. J. Arévalo, O. Lopez, Syn-
thesis 2007, 1589–1620; c) J. F. Lutz, Angew. Chem. Int. Ed.
(
5.5ϫ10–4 g, 0.00238 mmol, 0.16 equiv., 1% ratio to triple bonds)
and dichloromethane (2 mL). Column chromatography on silica
with dichloromethane/methanol (40:1) gave the product (0.103 g,
2007, 46, 1018–1025.
2%). [α]2
400 MHz,CDCl
aromatic ring), 6.79 (br. t, 1 H, central aromatic ring), 6.70–6.44
m, 42 H), 5.92 (d, J = 9.2 Hz, 16 H), 5.49 (t, J = 9.2 Hz, 16 H),
.41 (t, J = 9.2 Hz, 16 H), 5.26 (t, J = 9.2 Hz, 16 H), 5.14 (s, 32 H,
CH -O), 5.04–4.88 (m, 28 H, CH -O), 4.27 (dd, J = 12.8, 4.8 Hz,
6 H diastereotopic, Glu-CH -OAc), 4.12 (br. d, J = 12.8 Hz, 16
H, diastereotopic, Glu-CH -OAc), 4.07–3.98 (m, 16 H), 3.85 (s, 3
H, CH ), 2.05 (s, 48 H, CH ), 2.03 (s, 48 H, CH ), 2.01 (s, 48 H,
CH ), 1.81 (s, 48 H, CH ): δ =
) ppm. 13C NMR (100 MHz, CDCl
6
=
–36.6 (c
=
1, chloroform).
1
H
NMR
8
(
D
[9] B.-Y. Lee, S. R. Park, H. B. Jeon, K. S. Kim, Tetrahedron Lett.
2006, 47, 5105–5109.
3
): δ = 7.99 (s, 16 H, triazole), 7.25 (m, 2 H, central
[10] R. T. Chan, R. Hilgraf, K. B. Sharpless, V. F. Fokin, Org. Lett.
2004, 6, 2853–2855.
(
5
[
[
11] W. G. Lewis, F. G. Magallon, V. V. Fokin, M. G. Finn, J. Am.
Chem. Soc. 2004, 126, 9152–9158.
2
2
12] P. Wu, A. K. Feldman, A. K. Nugent, C. J. Hawker, A. Scheel,
B. Voit, J. Pyun, J. M. J. Frechet, K. B. Sharpless, V. V. Fokin,
Angew. Chem. Int. Ed. 2004, 43, 3928.
13] F. Perez-Balderas, M. Ortega-Munoz, J. Morales-Sanfruto, F.
Hernandez-Mateo, F. G. Calvo-Flores, J. A. Calvo-Asin, J.
Isac-Garcia, F. Santoyo-Gonzalez, Org. Lett. 2003, 5, 1951.
[14] E. Sperotto, G. P. M. van Klink, G. van Koten, Org. Synth.
2008, 85, 209–218, and references therein.
15] M. D. Janssen, D. M. Grove, G. van Koten, Prog. Inorg. Chem.
1
2
2
3
3
3
[
3
3
3
170.5, 169.9, 169.4, 168.8, 160.1, 159.9, 159.4, 144.6, 139.6, 121.7,
106.7, 106.5, 101.2, 85.6, 77.2, 75, 72.7, 70.3, 69.7, 67.7, 61.8, 61.5,
56, 20.6, 20.5, 20.48, 20 ppm. IR (KBr): ν˜ = 3184 (w), 3105 (w),
2954 (m), 2911 (m), 2846 (w), 2120 (w), 1755 (s), 1595 (s), 1459
[
1997, 46, 97–149.
(m), 1373 (s), 1255 (s), 1228 (br s), 1153 (m), 1099 (m), 1034 (br s),
–1
[16] G. J. Meuzelaar, A. S. E. Karlström, M. van Klaveren, E. S. M.
Persson, A. del Villar, G. van Koten, J. E. Bäckvall, Tetrahe-
dron 2000, 56, 2895–2903.
922 (m), 814 (b), 680 (w), 594 (m) cm . MS (MALDI-TOF): calcd.
8454.602; found 8453.243. C378 176 (8459.66): calcd. C
53.67, H 5.10, N 7.95; found C 53.51, H 5.08, N 7.92.
H
428 48
N O
[
17] A. M. Arink, T. W. Braam, R. Keeris, J. T. B. H. Jastrzebski, C.
Benhaim, S. Rosset, A. Alexakis, G. van Koten, Org. Lett.
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Krause, J. Org. Chem. 1993, 58, 5849–5852.
19] T. Jerphagnon, G. P. M. van Klink, J. G. de Vries, G.
Kinetic Resolution Studies: (1-Azidoethyl)benzene was synthesized
[28]
following the method reported in the literature starting from the
racemic alcohol; it was then treated[
25]
with phenylacetylene and
[
catalyst 18 (1 mol-%) in three different solvents (2 mL of solvent
per 100 mg azide). A thermostatted bath was used to achieve a
constant temperature (–12 °C). All the reactions gave quantitative
yields; the disappearance of phenylacetylene was determined by
NMR and TLC of the reaction mixtures. After the reaction, the
residual azide was isolated and recovered by column chromatog-
raphy on silica, eluting with hexane/ethyl acetate (10:1). A sample
was analysed by GC on a Supelco chiral column to determine the
enantiomeric excess.
van Koten, Org. Lett. 2005, 7, 5241–5244.
20] K. Kacprzak, Synlett 2006, 943–946.
[
[
21] K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett. 2007, 9,
1809–1811.
[
22] S. Cicchi, P. Fabbrizzi, G. Ghini, A. Brandi, P. Foggi, A. Mar-
celli, R. Righini, C. Botta, Chem. Eur. J. 2008, 15, 754–764.
[23] M. Malkoch, K. Schleicher, E. Drockenmuller, C. J. Hawker,
T. P. Russell, P. Wu, V. V. Fokin, Macromolecules 2005, 38,
3663–3678.
[
[
[
24] S. Diez-Gonzàlez, A. Correa, L. Cavallo, S. Nolan, Chem. Eur.
J. 2006, 12, 7558–7564.
25] J. Meng, V. V. Fokin, M. G. Finn, Tetrahedron Lett. 2005, 46,
4543–4546.
26] E. Rijnberg, N. J. Hovestad, A. W. Kleij, J. T. B. H. Jastrzebski,
J. Boersma, M. D. Janssen, A. L. Spek, G. van Koten, Organo-
metallics 1997, 16, 2847.
Acknowledgments
[
27] Product 7: L. Duran Pachon, J. H. van Maarseveen, G. Ro-
thenberg, Adv. Synth. Catal. 2005, 347, 811–815; product 12a:
T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
Funding from the Italian Ministero dell’Università e della
Ricerca – Fondo Investimenti per la Ricerca di Base (FIRB) (FIRB
2004, “Molecular compounds and hybrid nanostructured materials
2
004, 6, 2853–2856; product 12b: B. E. Blass, K. R. Coburn,
A. L. Faulkner, W. L. Seibel, A. Srivastava, Tetrahedron Lett.
003, 44, 2153–2156; product 12c: N. Candelon, D. Lastecou-
with resonant and non-resonant optical properties for photonic de-
vices”, contract no. RBNE033KMA) and from the European Com-
munity (contract no. RIII-CT-2003-506350) is acknowledged. Mrs.
Brunella Innocenti and Mr. Maurizio Passaponti are acknowledged
for technical assistance.
2
eres, A. K. Diallo, J. R. Aranzaes, D. Astruc, J. M. Vincent,
Chem. Commun. 2008, 3, 741–743; product 12d: B. H. Lip-
shutz, B. R. Taft, Angew. Chem. Int. Ed. 2006, 45, 8235–8238;
Eur. J. Org. Chem. 2009, 5423–5430
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5429

P. Fabbrizzi, S. Cicchi, A. Brandi, E. Sperotto, G. van Koten
FULL PAPER
product 12e: A. Maisonial, P. Serafin, M. Taikia, E. Debitoy,
V. Thery, D. J. Aitken, P. Lemoine, A. Gautier, Eur. J. Inorg.
Chem. 2008, 298–305; see also: S. Chassaing, M. Kumarraja,
A. S. Souna Sido, P. Pale, J. Sommer, Org. Lett. 2007, 9, 883–
[28] A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J.
Mathre, E. J. J. Grabowski, J. Org. Chem. 1993, 58, 5886.
Received: July 13, 2009
Published Online: September 21, 2009
886, and references cited therein.
5430
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5423–5430