Copper(I)-catalyzed azide-alkyne cycloadditions in ionic liquids under amine-free conditions

Article abstract of DOI:10.1055/s-0029-1218760

Copper(I) iodide catalyzed cycloadditions of various combinations of structurally diverse organic azides and terminal alkynes were carried out in a commercially available, polyoxygenated ionic liquid (AMMOENG 100) without addition of free amine. Unlike th

Full text of DOI:10.1055/s-0029-1218760

PAPER
2043
Copper(I)-Catalyzed Azide–Alkyne Cycloadditions in Ionic Liquids under
Amine-Free Conditions
CuAAC in
Ionic
Ll
iquids essandra Vecchi,a Angela Chambery,b Cinzia Chiappe,c Alberto Marra,*a Alessandro Dondoni*a
a
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
Fax +39(0532)455167; E-mail: mra@unife.it; E-mail: adn@unife.it
b
c
Dipartimento di Scienze della Vita, II Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Received 2 February 2010; revised 17 March 2010
nally, the recovery of unaltered ILs from reaction mix-
tures and recycling compensate for their cost that,
however, is in general quite reasonable. Thus, we have re-
ported on a study of a model copper(I) iodide catalyzed
Abstract: Copper(I) iodide catalyzed cycloadditions of various
combinations of structurally diverse organic azides and terminal
alkynes were carried out in a commercially available, polyoxygen-
ated ionic liquid (AMMOENG 100™) without addition of free
amine. Unlike the previously tested ionic liquids, this solvent led cycloaddition of a sugar azide to a sugar acetylene in a
wide variety of ILs.7a Aiming at simplifying the reaction
exclusively to the 1,4-disubstituted triazole regioisomer.
conditions, we performed the reaction without addition of
free amine with the expectation that suitable ILs bearing
basic nitrogen atoms could play the role of a base that is
traditionally used in copper(I) iodide catalyzed azide–
alkyne cycloadditions.2b The most commonly used bases
are amines1 such as N,N-diisopropylethylamine, that are
thought to serve both as a base for the deprotonation of the
alkyne and as a ligand for the stabilization of copper(I)
ion.4,12 In contrast to our expectations, the model reaction
carried out in a range of basic ILs turned out to afford mix-
tures of 1,4- and 1,5-disubstituted triazoles in low overall
yield.7a We considered that the lack of regioselectivity
was due to the occurrence of the thermally induced, con-
certed Huisgen 1,3-dipolar cycloaddition instead of the
desired multistep copper(I)-catalyzed process.
Key words: alkynes, azides, carbohydrates, copper, cycloadditions
The copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC),1 discovered independently in the Meldal and
Sharpless laboratories,2 constitutes a substantial improve-
ment of the classical Huisgen-type thermal 1,3-dipolar cy-
cloaddition. While the latter takes place by a one-step
concerted mechanism and requires high temperature and
long reaction time to give mixtures of 1,4- and 1,5-disub-
stituted triazoles,3 catalytic copper(I) affects the kinetics
and mechanism4 of the reaction that, in fact, is a multistep
process that goes to completion in short time at room tem-
perature to give exclusively 1,4-disubstituted triazole de-
rivatives. For its remarkable efficiency and specificity, as
well as the stability of the triazole ring under a variety of
conditions, this reaction has become one of the most used
ligation tools in material, organic, and bioorganic sciences
over the last years.5 CuAAC can be carried out in a variety
of molecular solvents ranging from the apolar, aprotic
dichloromethane and toluene to the polar, aprotic acetoni-
trile and N,N-dimethylformamide. Quite interestingly for
bioorganic applications, the reaction can be performed
equally well in water as the solvent.6
In two recent papers from this laboratory,7 we have ex-
tended the scope of the CuAAC by using ionic liquids
(ILs) as solvents. ILs, with their vanishing low vapor pres-
sure, are safe and environmentally benign solvents.8 They
are convenient as media for metal-catalyzed reactions be-
cause of their capability to dissolve metal salts and stabi-
lize the formation of metal nanoparticles and nanorods.9
Moreover, ILs have proven to be good microwave
absorbers10 and therefore are well suited in reactions using
microwave dielectric heating11 by reducing substantially
the reaction time that is needed with thermal heating.7b Fi-
We now report on the copper(I) iodide catalyzed reactions
of structurally different azides and terminal alkynes in a
commercially available ionic liquid (IL), i.e. the densely
oxygenated nonbasic IL 8 (AMMOENG 100™), in the
absence of any added amine. All the CuAACs gave exclu-
sively the 1,4-disubstituted triazole derivatives13 in high
isolated yields.
We set out to investigate the copper(I) iodide catalyzed
cycloadditions of azides 1–4 to alkynes 5–7 in
AMMOENG 100™ (8) under basic ligand-free conditions
(Table 1). Each reaction was carried out at 80 °C for 2
hours by microwave dielectric heating14 using a single-
mode cavity dedicated reactor (Biotage Initiator); the tem-
perature was measured externally on the outside vessel
wall with an IR sensor. Initial experiments were conduct-
ed in the IL 8 using benzyl azide (1) and phenylacetylene
(5) on a 0.5 mmol scale in the presence of 0.50 equivalents
of copper(I) iodide as described in our earlier report.7a The
cycloaddition afforded the triazole 9 in 95% yield as pure
1,4-regioisomer. Then, the same cycloaddition was re-
peated using gradually reduced amounts of the copper cat-
alyst. We found that the very efficient reaction took place
even in the presence of 0.025 equivalents of copper(I) io-
dide, affording pure 9 in 92% isolated yield. This ap-
SYNTHESIS 2010, No. 12, pp 2043–2048
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Advanced online publication: 29.04.2010
DOI: 10.1055/s-0029-1218760; Art ID: T02710SS
© Georg Thieme Verlag Stuttgart · New York

2044
A. Vecchi et al.
PAPER
and total selectivity without addition of free amine
(Scheme 1).
Table 1 Copper(I) Iodide Catalyzed Reactions of Azides 1–4 with
Alkynes 5–7 in the Absence of Amine Additive
CuI, 80 °C, 2 h
N N
R1
1–4
N3
R2
5–7
+
N
R2
N3
O
N3
N3
R1
R
N3
OH
m
–
N +
9–20
MeOSO3
Me
OH
O
n
CuI
+
R
R = -C12-C14 alkyl chain
IL 8, 80 °C, 2 h
m + n = 4–14
5–7
O
O
O
O
8
O
21
BnO
BnO
AZIDES R1
=
Bn
BnO
R
1
OMe
R
N
2
N
N
N
N
O
R
R
N
N
N
O
O
O
N
N
N
N
AcHN
O
O
O
O
3
4
ALKYNES R2
=
Ph
O
O
O
O
5
6
OBn
BnO
22 R = Ph
23 R =
O
BnO
BnO
22 81%
23 75%
24 74%
7
OBn
BnO
BnO
O
Entry
1
Azide
Alkyne
Triazole
9
Yielda (%)
24 R =
BnO
1
1
1
2
2
2
3
3
3
4
4
4
5
6
7
5
6
7
5
6
7
5
6
7
92
71
80
56
58
68
72
87
82
95
90
89
Scheme 1
2
10
All the cycloadducts, with the exception of 26, were re-
covered from the reaction mixtures by direct extraction
with diethyl ether or diethyl ether–ethyl acetate (1:1), i.e.
without dilution of the IL with water, and then purified by
column chromatography on silica gel. The latter operation
removed all the copper salts and the small amounts of IL
(5–8%) that were extracted by the molecular solvents.
3
11
4
12
5
13
6
14
7
15
The economical aspect was also examined by recycling
five times the IL 8 used in the reaction between benzyl
azide (1) and phenylacetylene (5) (Table 1, entry 1). The
observed yields of the isolated 1,4-disubstituted triazole 9
were 92% (first run) and 92%, 90%, 91%, 88%, and 84%
(subsequent runs). Hence, the IL appeared not to be dete-
riorated throughout six consecutive runs and very likely
could be reused as an effective solvent in further experi-
ments. Unfortunately, in the workup of the reaction mix-
ture in each cycle, the copper(I) iodide was extracted from
the IL together with the product and was lost in the chro-
matographic purification of the latter. Therefore, fresh
copper(I) iodide (0.025 equiv) was added before each re-
cycle. It is worth noting, however, that reuse of the IL was
simplified by the fact that the workup of the reaction mix-
ture usually did not require dilution with water and there-
fore the drying of IL 8 was easily performed at room
temperature under reduced pressure (0.1 mbar, 2 h).
8
16
9
17
10
11
12
18
19
20
a Yield of product isolated by column chromatography.
peared to be close to the lower limit of catalyst as
compound 9 was obtained in only 46% yield with 0.01
equivalents of copper(I) iodide. Therefore, all the other
azides and alkynes were allowed to react in AMMOENG
100™ (8) in the presence of a catalytic amount of cop-
per(I) iodide, such as 0.025 equivalents.
Even multiple reactions of three different terminal
alkynes on the same substrate, such as with the tetraazi-
docalixarene 21,13 appeared to occur with high efficiency
It is important to notice that although the standard condi-
tions under which the CuAAC is currently carried out in-
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PAPER
CuAAC in Ionic Liquids
2045
respectively; the source temperature was kept at 80 °C; N2 was used
as a drying gas at a flow rate of ca. 50 L/h. The time-of-flight ana-
lyzer was externally calibrated with NaI from m/z 300 to 2000 to
yield an accuracy near to 5 ppm. When necessary, an internal lock
mass was used to further increase the mass accuracy. Accurate mass
data were collected by directly infusing samples [10 pmol/mL in
MeCN–H2O (1:1) containing 10 mM ammonium formate] into the
system at a flow rate of 5 mL/min. The acquisition and data process-
ing were performed with MassLynx 4.1 software (Waters,
Manchester, UK). AMMOENG 100™ (8) was supplied by Solvent
Innovation. Commercial phenylacetylene (5) was distilled prior to
use. Commercially available 1-tetradecyne (6) and CuI (light grey
powder, Aldrich 215554) were used without further purification.
Benzyl azide (1) was prepared from benzyl bromide and NaN3 in
MeOH (r.t., 18 h); then, the reaction mixture was partially concen-
volve the use of a ligand (an amine or a densely
nitrogenated molecule) for the stabilization of copper(I)
ion and copper(I) complexes, all reactions reported in
Table 1 and Scheme 1 were performed without addition
of free amine. Therefore, we speculate that the densely
oxygenated IL 8 and/or the reagents/products bearing ox-
ygen atoms or phenyl rings served as ligands. In agree-
ment with this hypothesis, the reaction between two
aliphatic partners such as 1-adamantyl azide15 (25) and 1-
tetradecyne (6) in toluene did not produce any cycload-
duct whereas in the presence of N,N-diisopropylethyl-
amine afforded the expected triazole derivative 26 in 57%
yield. By contrast, the same reaction carried out in the IL
8 under amine-free conditions gave the product 26 in 62% trated, diluted with H2O, and extracted with Et2O; the organic phase
was dried (Na2SO4) and concentrated under a stream of N2 at r.t.
yield (Scheme 2).
Azide 3 was prepared by acetylation of commercial 1-amino-11-
azido-3,6,9-trioxaundecane.
alkyne 6, CuI
N3
N
Cycloadditions in the Ionic Liquid; General Procedure
IL 8, 80 °C, 2 h
N
25
A mixture of an azide 1 (1.5 equiv) or 2–4, 21, 25 (1 equiv), an
alkyne 5–7 (1.0–1.1 equiv), CuI (0.025 equiv), and AMMOENG
100™ (8; 0.50 g) was sonicated or magnetically stirred at r.t. for a
few min, then heated to 80 °C (external vessel wall temperature) for
2 h in a single-mode cavity dedicated Biotage Initiator microwave
reactor. The crude reaction mixture was extracted with Et2O (4 × 6
mL) or EtOAc–Et2O (1:1, in the case of products 17 and 22), or
(only in the case of product 26) first diluted with H2O (1 mL) and
then extracted with CH2Cl2 (4 × 6 mL). The combined organic
phases were concentrated to give the crude products containing 5–
N
26 62%
Scheme 2
From the above results it may be concluded that the click
CuAAC can be conveniently carried out in ILs,
AMMOENG 100™ being the solvent of choice. In this
solvent the reaction is a fast and high-yielding process.
Moreover, the process is operationally simplified because 8% of IL and most of the copper salts. The residue was eluted from
a column of silica gel to give the triazole derivatives in analytically
the reaction occurs without the addition of free amine and
pure form.
it requires 2.5 mol% of copper(I) iodide as the catalyst.
The same reaction efficiency and regioselectivity, i.e. ex-
Recycling of the Ionic Liquid
clusive formation of the 1,4-disubstituted triazole in high
A mixture of phenylacetylene (5; 51 mg, 0.50 mmol), crude benzyl
yield, can be reached by microwave dielectric heating or
simply by using an oil bath. It is noteworthy that the IL
azide (1; 100 mg, ca. 0.75 mmol), CuI (2.4 mg, 12.5 mmol), and
AMMOENG 100™ (8; 0.50 g) was sonicated at r.t. for 3 min, then
can be easily recovered from the reaction mixture and re- heated to 80 °C (external vessel wall temperature) in a microwave
reactor for 2 h. The crude reaction mixture was extracted with Et2O
(4 × 6 mL) to recover crude 9 that was isolated in a pure form by
flash chromatography (see below). The IL was dried under reduced
used several times in subsequent runs. This compensates
for the cost of the solvent, which, however, is quite rea-
sonable. Therefore, given the advantages provided by the
use of ILs as green solvents, the valuable click CuAAC
appears to be endowed with the additional value of being
a process that can be efficiently performed under the prin-
ciples of green chemistry.
pressure (0.1 mbar) at r.t. for 2 h, then alkyne 5 (51 mg, 0.50 mmol),
azide 1 (100 mg, ca. 0.75 mmol), and CuI (2.4 mg, 12.5 mmol) were
added. The mixture was treated as described above in five subse-
quent runs.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (9)
The reaction between phenylacetylene (5; 51 mg, 0.50 mmol) and
crude benzyl azide (1; 100 mg, ca. 0.75 mmol) gave, after column
chromatography on silica gel (CH2Cl2–acetone, 1:0 → 1:1),
known18 9 as a solid; yield: 108 mg (92%).
Anhydrous solvents were dried over standard drying agents16 and
freshly distilled prior to use. Reactions were monitored by TLC on
silica gel 60 F254 with detection by charring with sulfuric acid. Flash
column chromatography17 was performed on silica gel 60 (40–63
mm) using distilled solvents. Melting points were determined with a
capillary apparatus. Optical rotations were measured at 20 2 °C in
1-Benzyl-4-dodecyl-1H-1,2,3-triazole (10)
The reaction between 1-tetradecyne (6; 68 mg, 0.35 mmol) and ben-
zyl azide (1; 69.2 mg, 0.52 mmol) gave, after column chromatogra-
phy on silica gel (CH2Cl2–acetone, 1:0 → 1:1), 10 as a solid; yield:
81 mg (71%).
1
the stated solvent; [a]D values are given in deg·mL·g–1·dm–1. H
NMR (300 and 400 MHz) and 13C NMR (75 MHz) spectra were re-
corded for CDCl3 solutions at r.t. unless otherwise specified. Peak
assignments were aided by 1H–1H COSY and gradient-HMQC ex-
Mp 78–79 °C (Et2O).
1
periments. In the H NMR spectra, the n and m values quoted in
1H NMR (300 MHz): d = 7.43–7.35 (m, 3 H, Ar), 7.30–7.25 (m, 2
H, Ar), 7.19 (s, 1 H, H-5 Tr.), 5.52 (s, 2 H, PhCH2), 2.70 (t, J = 7.8
Hz, 2 H, CH2), 1.65 (tt, J = 7.7, 7.8 Hz, 2 H, CH2), 1.40–1.20 (m, 18
H), 0.90 (t, J = 6.5 Hz, 3 H, CH3).
13C NMR: d = 149.1 (C-4 Tr.), 134.8 (C), 129.2 (CH), 128.6 (CH),
128.0 (CH), 120.6 (C-5 Tr.), 54.1 (CH2), 31.9 (CH2), 29.6 (CH2),
geminal or vicinal proton–proton coupling constants Jn,m refer to the
numbers of the corresponding sugar protons. For accurate mass
measurements, the compounds were analyzed in positive ion mode
using an electrospray hybrid quadrupole orthogonal acceleration
time-of-flight mass spectrometer (Q-TOF) fitted with a Z-spray
electrospray ion source (Waters, Manchester, UK). The capillary
source voltage and the cone voltage were set at 3500 V and 35 V,
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2046
A. Vecchi et al.
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29.5 (CH2), 29.3 (CH2), 29.2 (CH2), 25.8 (CH2), 22.6 (CH2), 14.1
(CH3).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C21H34N3: 328.2753;
Hz, J3,4 = 8.9 Hz, 1 H, H-3), 3.95 (ddd, J4,5 = 10.0 Hz, 1 H, H-5),
3.42 (dd, 1 H, H-2), 3.18 (s, 3 H, OCH3), 3.15 (dd, 1 H, H-4), 2.73–
2.64 (m, 2 H, CH2), 1.67–1.58 (m, 2 H, CH2), 1.36–1.20 (m, 18 H,
9 CH2), 0.88 (t, J = 6.8 Hz, 3 H, CH3).
13C NMR: d = 150.4 (C-4 Tr.), 138.4 and 137.9 (C Ar), 129.8,
128.5, 128.2, 128.0, 127.9, 127.7, and 125.6 (CH Ar), 120.1 (C-5
Tr.), 98.0 (C-1), 81.9 (C-3), 79.9 (C-2), 78.0 (C-4), 75.8, 74.9, and
73.4 (PhCH2), 69.2 (C-5), 55.2 (OCH3), 50.5 (C-6), 31.9, 29.63,
29.57, 29.4, 29.2, 25.6, and 22.7 (CH2), 14.1 (CH3).
found: 328.2733.
1-Benzyl-4-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranosyl)-1H-
1,2,3-triazole (11)
The reaction between ethynyl C-galactoside 7 (99 mg, 0.18 mmol)
and benzyl azide (1; 36 mg, 0.27 mmol) gave, after column chroma-
tography on silica gel (cyclohexane–EtOAc, 4:1 then 3:1), 11 as a
solid; yield: 98 mg (80%).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C42H58N3O5:
684.4376; found: 684.4391.
Mp 109–111 °C (MeOH); [a]D –14.0 (c 0.6, CHCl3).
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-[4-(2,3,4,6-tetra-O-ben-
zyl-b-D-galactopyranosyl)-1H-1,2,3-triazol-1-yl]-a-D-glucopyr-
anoside (14)
The reaction between ethynyl C-galactoside 7 (60 mg, 0.11 mmol)
and methyl 6-azidoglucopyranoside 2 (49 mg, 0.10 mmol) gave, af-
ter column chromatography on silica gel (cyclohexane–EtOAc, 3:1
then 2:1), known7a 14 as a solid; yield: 70 mg (68%).
1H NMR (400 MHz): d = 7.38–7.15 (s, 24 H, Ar, H-5 Tr.), 6.99–
6.96 (m, 2 H, Ar), 5.49 and 5.43 (2 d, J = 14.8 Hz, 2 H, PhCH2Tr.),
4.96 and 4.64 (2 d, J = 11.7 Hz, 2 H, PhCH2), 4.77 and 4.72 (2 d,
J = 11.8 Hz, 2 H, PhCH2), 4.68 and 4.30 (2 d, J = 10.7 Hz, 2 H,
PhCH2), 4.49 (d, J1,2 = 9.7 Hz, 1 H, H-1), 4.44 and 4.38 (2 d,
J = 11.8 Hz, 2 H, PhCH2), 4.20 (dd, J2,3 = 9.6 Hz, 1 H, H-2), 4.03
(dd, J3,4 = 2.7 Hz, J4,5 = 0.5 Hz, 1 H, H-4), 3.70 (dd, 1 H, H-3), 3.69
(dt, J5,6 = 6.5 Hz, 1 H, H-5), 3.56 (d, 2 H, 2 H-6).
13C NMR: d = 146.5 (C-4 Tr.), 138.8, 138.4, 138.2, 137.9, and
134.6 (C Ar), 129.0, 128.7, 128.4, 128.1, 127.9, 127.8, 127.6, and
127.5 (CH Ar), 122.4 (C-5 Tr.), 84.4 (C-3), 78.3 (C-2), 77.4 (C-5),
74.9 (PhCH2), 74.6 (PhCH2, C-1), 73.9 (C-4), 73.5 (PhCH2), 72.4
(PhCH2), 68.7 (C-6), 54.1 (PhCH2Tr.).
1-(11-Acetamido-3,6,9-trioxaundecyl)-4-phenyl-1H-1,2,3-tria-
zole (15)
The reaction between phenylacetylene (5; 31 mg, 0.30 mmol) and
azide 3 (70 mg, 0.27 mmol) gave, after column chromatography on
silica gel (CH2Cl2–MeOH, 1:0 → 9:1), 15 as a syrup; yield: 70 mg
(72%).
1H NMR (300 MHz): d = 7.99 (s, 1 H, H-5 Tr.), 7.88–7.84 (m, 2 H,
Ar), 7.48–7.42 (m, 2 H, Ar), 7.39–7.33 (m, 1 H, Ar), 6.05 (br s, 1 H,
NH), 4.62 (t, J = 5.0 Hz, 2 H, CH2), 3.95 (t, J = 5.0 Hz, 2 H, CH2),
3.70–3.60 (m, 4 H), 3.59–3.54 (m, 4 H), 3.53–3.48 (m, 2 H), 3.44–
3.38 (m, 2 H), 1.97 (s, 3 H, CH3).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C43H44N3O5:
682.3281; found: 682.3254.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-(4-phenyl-1H-1,2,3-tria-
zol-1-yl)-a-D-glucopyranoside (12)
The reaction between phenylacetylene (5; 28.6 mg, 0.28 mmol) and
methyl 6-azidoglucopyranoside 2 (122.3 mg, 0.25 mmol) gave, af-
ter column chromatography on silica gel (cyclohexane–EtOAc, 4:1
→ 2:1), 12 as a solid; yield: 83 mg (56%).
13C NMR: d = 170.3 (CO), 147.5 (C-4 Tr.), 130.5 (C Ar), 128.7,
128.0, and 125.6 (CH Ar), 120.9 (C-5 Tr.), 70.4, 70.3, 70.2, 69.9,
69.7, 69.3, 50.2, and 39.1 (CH2), 23.0 (CH3).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C18H27N4O4:
363.2032; found: 363.2038.
Mp 126–127 °C (MeOH); [a]D +59.7 (c 0.6, CHCl3).
1H NMR (400 MHz): d = 7.84–7.81 (m, 2 H, Ar), 7.80 (s, 1 H, H-5
Tr.), 7.45–7.28 (m, 18 H, Ar), 4.98 and 4.82 (2 d, J = 10.8 Hz, 2 H,
PhCH2), 4.92 and 4.78 (2 d, J = 10.9 Hz, 2 H, PhCH2), 4.76 and 4.62
(2 d, J = 12.1 Hz, 2 H, PhCH2), 4.61 (dd, J5,6a = 5.7 Hz, J6a,6b = 14.0
Hz, 1 H, H-6a), 4.56 (d, J1,2 = 3.6 Hz, 1 H, H-1), 4.55 (dd, J5,6b = 3.1
Hz, 1 H, H-6b), 4.02 (dd, J2,3 = 9.7 Hz, J3,4 = 9.0 Hz, 1 H, H-3), 4.00
(ddd, J4,5 = 10.0 Hz, 1 H, H-5), 3.42 (dd, 1 H, H-2), 3.23 (s, 3 H,
CH3), 3.19 (dd, 1 H, H-4).
13C NMR: d = 147.6 (C-4 Tr.), 138.4, 137.95, 137.92, and 130.6 (C
Ar), 128.8, 128.5, 128.45, 128.42, 128.2, 128.05, 128.00, 127.94,
127.87, 127.68, and 125.64 (CH Ar), 121.1 (C-5 Tr.), 98.1 (C-1),
81.8 (C-3), 79.9 (C-2), 77.9 (C-4), 75.7, 75.0, and 73.5 (PhCH2),
69.1 (C-5), 55.3 (CH3), 50.6 (C-6).
1-(11-Acetamido-3,6,9-trioxaundecyl)-4-dodecyl-1H-1,2,3-tria-
zole (16)
The reaction between 1-tetradecyne (6; 58.3 mg, 0.30 mmol) and
azide 3 (70 mg, 0.27 mmol) gave, after column chromatography on
silica gel (CH2Cl2–MeOH, 1:0 → 9:1), 16 as an amorphous solid;
yield: 107 mg (87%).
1H NMR (300 MHz): d = 7.43 (s, 1 H, H-5 Tr.), 6.21 (br s, 1 H, NH),
4.51 (t, J = 5.3 Hz, 2 H, CH2), 3.89 (t, J = 5.3 Hz, 2 H, CH2), 3.65–
3.52 (m, 10 H, 5 CH2), 3.49–3.42 (m, 2 H, CH2), 2.71 (t, J = 7.8 Hz,
2 H, CH2), 2.00 (s, 3 H, CH3CO), 1.72–1.62 (m, 2 H, CH2), 1.38–
1.24 (m, 18 H, 9 CH2), 0.88 (t, J = 6.7 Hz, 3 H, CH3).
13C NMR: d = 170.1 (CO), 148.3 (C-4 Tr.), 121.6 (C-5 Tr.), 70.5,
70.4, 70.1, 69.8, 69.6, 50.0, 39.2, 31.9, 29.6, 29.5, 29.4, 29.3, and
25.7 (CH2), 23.2 (CH3CO), 22.6 (CH2), 14.1 (CH3).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C36H38N3O5:
592.2811; found: 592.2830.
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C24H47N4O4:
455.3591; found: 455.3597.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-(4-dodecyl-1H-1,2,3-tria-
zol-1-yl)-a-D-glucopyranoside (13)
The reaction between 1-tetradecyne (6; 43 mg, 0.22 mmol) and
methyl 6-azidoglucopyranoside 2 (98 mg, 0.20 mmol) gave, after
column chromatography on silica gel (cyclohexane–EtOAc, 4:1),
13 as a solid; yield: 79 mg (58%).
1-(11-Acetamido-3,6,9-trioxaundecyl)-4-(2,3,4,6-tetra-O-ben-
zyl-b-D-galactopyranosyl)-1H-1,2,3-triazole (17)
The reaction between ethynyl C-galactoside 7 (77 mg, 0.14 mmol)
and azide 3 (34 mg, 0.13 mmol) gave, after column chromatography
on silica gel (CH2Cl2–MeOH, 1:0 → 9:1), 17 as a syrup; yield: 86
mg (82%).
Mp 65–66 °C (MeOH); [a]D +24.2 (c 0.6, CHCl3).
1H NMR (400 MHz): d = 7.36–7.22 (m, 16 H, Ar, H-5 Tr.), 4.98 and
4.81 (2 d, J = 10.8 Hz, 2 H, PhCH2), 4.90 and 4.73 (2 d, J = 10.8 Hz,
2 H, PhCH2), 4.77 and 4.62 (2 d, J = 12.1 Hz, 2 H, PhCH2), 4.53 (d,
J1,2 = 3.7 Hz, 1 H, H-1), 4.50 (dd, J5,6a = 3.0 Hz, J6a,6b = 14.3 Hz, 1
H, H-6a), 4.45 (dd, J5,6b = 6.2 Hz, 1 H, H-6b), 4.00 (dd, J2,3 = 9.7
[a]D –6.7 (c 0.6, CHCl3).
1H NMR (400 MHz): d = 7.66 (s, 1 H, H-5 Tr.), 7.39–7.25 (m, 15
H, Ar), 7.21–7.18 (m, 3 H, Ar), 7.03–7.00 (m, 2 H, Ar), 4.98 and
Synthesis 2010, No. 12, 2043–2048 © Thieme Stuttgart · New York

PAPER
CuAAC in Ionic Liquids
2047
4.64 (2 d, J = 11.5 Hz, 2 H, PhCH2), 4.78 and 4.73 (2 d, J = 11.7 Hz,
2 H, PhCH2), 4.72 and 4.36 (2 d, J = 10.7 Hz, 2 H, PhCH2), 4.52 (d,
J1,2 = 9.6 Hz, 1 H, H-1), 4.48 (t, J = 5.1 Hz, 2 H, CH2), 4.46 and 4.40
(2 d, J = 11.9 Hz, 2 H, PhCH2), 4.24 (dd, J2,3 = 9.4 Hz, 1 H, H-2),
4.06 (dd, J3,4 = 2.7 Hz, J4,5 = 0.5 Hz, 1 H, H-4), 3.86–3.79 (m, 2 H,
CH2), 3.73 (dd, 1 H, H-3), 3.73 (dt, J5,6 = 6.5 Hz, 1 H, H-5), 3.58 (d,
2 H, 2 H-6), 3.54–3.44 (m, 10 H, 5 CH2), 3.38–3.34 (m, 2 H, CH2),
1.90 (s, 3 H, CH3).
13C NMR: d = 170.2 (CO), 145.9 (C-4 Tr.), 138.8, 138.3, and 137.8
(C Ar), 128.4, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, and 127.4
(CH Ar), 123.7 (C-5 Tr.), 84.4 (C-3), 78.4 (C-2), 77.4 (C-5), 74.9
(PhCH2), 74.7 (PhCH2, C-1), 74.0 (C-4), 73.5 and 72.5 (PhCH2),
70.5, 70.4, 70.3, 70.1, 69.7, and 69.4 (CH2), 68.7 (C-6), 50.2 and
39.2 (CH2), 23.1 (CH3).
H, H-5¢), 3.60 (dd, J6¢a,6¢b = 9.5 Hz, 1 H, H-6¢a), 3.58 (dd, 1 H, H-
6¢b), 1.48, 1.36, 1.27, and 1.23 (4 s, 12 H, 4 CH3).
13C NMR: d = 145.7 (C-4 Tr.), 138.9, 138.4, and 137.9 (C Ar),
128.4, 128.15, 128.07, 128.0, 127.7, 127.5, and 127.4 (CH Ar),
124.0 (C-5 Tr.), 109.7 and 109.0 (OCO), 96.2 (C-1), 84.5 (C-3¢),
78.6 (C-2¢), 77.4 (C-5¢), 75.0 (PhCH2), 74.5 (PhCH2, C-1¢), 74.0 (C-
4¢), 73.5 and 72.5 (PhCH2), 70.9 (C-4), 70.7 (C-3), 70.3 (C-2), 68.7
(C-6¢), 66.9 (C-5), 50.1 (C-6), 26.0, 25.9, 24.8, and 24.4 (CH3).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C48H56N3O10:
834.3966; found: 834.3970.
5,11,17,23-Tetrakis[3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl]-
25,26,27,28-tetrapropoxycalix[4]arene (22)
The reaction between phenylacetylene (5; 20.4 mg, 0.20 mmol) and
tetraazidocalixarene 21 (46 mg, 0.05 mmol) gave, after column
chromatography on silica gel (acetone), 22 as an amorphous solid;
yield: 54 mg (81%).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C46H57N4O9:
809.4126; found: 809.4166.
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-(4-phenyl-1H-1,2,3-tri-
azol-1-yl)-a-D-galactopyranose (18)
The reaction between phenylacetylene (5; 22.5 mg, 0.22 mmol) and
6-azidogalactopyranose 4 (57 mg, 0.20 mmol) gave, after column
chromatography on silica gel (cyclohexane–EtOAc, 4:1 → 2:1),
known19 18 as a solid; yield: 74 mg (95%).
1H NMR (300 MHz): d = 7.78–7.74 (m, 8 H, Ar), 7.75 (s, 4 H, 4 H-
5 Tr.), 7.39–7.27 (m, 12 H, Ar), 6.51 (s, 8 H, Ar), 4.42 and 3.09 (2
d, J = 13.1 Hz, 8 H, 4 ArCH2Ar), 4.18 (t, J = 7.1 Hz, 8 H, 4
ArCH2CH2CH2), 3.82 (t, J = 7.5 Hz, 8 H, 4 CH3CH2CH2O), 2.29 (t,
J = 7.2 Hz, 8 H, 4 ArCH2CH2CH2), 2.06–1.90 (m, 16 H, 4
ArCH2CH2CH2, 4 CH3CH2CH2O), 1.00 (t, J = 7.5 Hz, 12 H, 4
CH3CH2CH2O).
13C NMR: d = 154.8 (C Ar), 147.3 (C-4 Tr.), 134.8, 133.3, and
130.6 (C Ar), 128.8, 128.1, 128.0, and 125.5 (CH Ar), 120.0 (C-5
Tr.), 76.8 (CH3CH2CH2O), 49.4 (ArCH2CH2CH2), 31.9 and 31.7
(ArCH2CH2CH2, ArCH2CH2CH2), 30.8 (ArCH2Ar), 23.2
(CH3CH2CH2O), 10.3 (CH3CH2CH2O).
6-Deoxy-6-(4-dodecyl-1H-1,2,3-triazol-1-yl)-1,2:3,4-di-O-iso-
propylidene-a-D-galactopyranose (19)
The reaction between 1-tetradecyne (6; 43 mg, 0.22 mmol) and 6-
azidogalactopyranose 4 (57 mg, 0.20 mmol) gave, after column
chromatography on silica gel (cyclohexane–EtOAc, 2:1), 19 as an
amorphous solid; yield: 86 mg (90%).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C84H93N12O4:
1333.7443; found: 1333.7405.
[a]D –38.0 (c 0.6, CHCl3).
1H NMR (400 MHz): d = 7.46 (s, 1 H, H-5 Tr.), 5.52 (d, J1,2 = 4.9
Hz, 1 H, H-1), 4.63 (dd, J2,3 = 2.6 Hz, J3,4 = 7.9 Hz, 1 H, H-3), 4.60
(dd, J5,6a = 4.1 Hz, J6a,6b = 14.1 Hz, 1 H, H-6a), 4.40 (dd, J5,6b = 8.1
Hz, 1 H, H-6b), 4.32 (dd, 1 H, H-2), 4.20–4.14 (m, 2 H, H-4, H-5),
2.71 (t, J = 7.7 Hz, 2 H, CH2), 1.69–1.61 (m, 2 H, CH2), 1.50, 1.38,
1.36, and 1.29 (4 s, 12 H, 4 CH3), 1.34–1.22 (m, 18 H, 9 CH2), 0.87
(t, J = 6.7 Hz, 3 H, CH3).
13C NMR: d = 148.5 (C-4 Tr.), 122.3 (C-5 Tr.), 110.0 and 109.3
(OCO), 96.5 (C-1), 71.5 (C-4), 71.0 (C-3), 70.6 (C-2), 67.6 (C-5),
50.8 (C-6), 32.2, 29.9, 29.8, 29.7, 29.6, and 29.4 (CH2), 26.2 (CH3),
26.0 (CH2), 25.1 and 24.6 (CH3), 22.9 (CH2), 14.4 (CH3).
5,11,17,23-Tetrakis[3-(4-dodecyl-1H-1,2,3-triazol-1-yl)propyl]-
25,26,27,28-tetrapropoxycalix[4]arene (23)
The reaction between 1-tetradecyne (6; 39 mg, 0.20 mmol) and tet-
raazidocalixarene 21 (46 mg, 0.05 mmol) gave, after column chro-
matography on silica gel (EtOAc–cyclohexane, 1:1 → 1:0), 23 as
amorphous solid; yield: 64 mg (75%).
1H NMR (300 MHz): d = 7.29 (s, 4 H, 4 H-5 Tr.), 6.47 (s, 8 H, Ar),
4.41 and 3.08 (2 d, J = 13.1 Hz, 8 H, 4 ArCH2Ar), 4.18 (t, J = 7.2
Hz, 8 H, 4 ArCH2CH2CH2), 3.82 (t, J = 7.5 Hz, 8 H, 4
CH3CH2CH2O), 2.68 (t, J = 7.8 Hz, 8 H, 4 CH2), 2.30 (t, J = 7.2 Hz,
8 H, 4 ArCH2CH2CH2), 2.06–1.88 (m, 16 H, 4 ArCH2CH2CH2, 4
CH3CH2CH2O), 1.75–1.60 (m, 8 H, 4 CH2), 1.40–1.20 (m, 72 H),
1.00 (t, J = 7.3 Hz, 12 H, 4 CH3CH2CH2O), 0.90 (t, J = 6.6 Hz, 12
H, 4 CH3).
13C NMR: d = 154.9 (C Ar), 148.3 (C-4 Tr.), 134.8 and 133.3 (C
Ar), 128.0 (CH Ar), 120.7 (C-5 Tr.), 76.8 (CH3CH2CH2O), 49.3
(ArCH2CH2CH2), 31.9, 30.9, 29.7, 29.6, 29.4, 29.3, 25.8, 23.2, and
22.7 (CH2), 14.1 (CH3), 10.3 (CH3CH2CH2O).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C26H46N3O5:
480.3437; found: 480.3442.
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-[4-(2,3,4,6-tetra-O-ben-
zyl-b-D-galactopyranosyl)-1H-1,2,3-triazol-1-yl]-a-D-galactopy-
ranose (20)
The reaction between ethynyl C-galactoside 7 (60 mg, 0.11 mmol)
and 6-azidogalactopyranose 4 (29 mg, 0.10 mmol) gave, after col-
umn chromatography on silica gel (cyclohexane–EtOAc, 4:1 →
2:1), 20 as an amorphous solid; yield: 74 mg (89%).
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C108H173N12O4:
1702.3703; found: 1702.3801.
[a]D –26.7 (c 0.6, CHCl3).
1H NMR (400 MHz): d = 7.66 (s, 1 H, H-5 Tr.), 7.39–7.25 (m, 15
H, Ar), 7.22–7.18 (m, 3 H, Ar), 7.10–7.06 (m, 2 H, Ar), 5.44 (d,
J1,2 = 5.0 Hz, 1 H, H-1), 5.00 and 4.66 (2 d, J = 11.5 Hz, 2 H,
PhCH2), 4.77 and 4.72 (2 d, J = 11.7 Hz, 2 H, PhCH2), 4.70 and 4.39
(2 d, J = 10.8 Hz, 2 H, PhCH2), 4.54 (dd, J5,6a = 5.4 Hz, J6a,6b = 14.2
Hz, 1 H, H-6a), 4.53 (d, J1¢,2¢ = 9.7 Hz, 1 H, H-1¢), 4.52 (dd, J2,3 = 2.7
Hz, J3,4 = 7.8 Hz, 1 H, H-3), 4.45 and 4.39 (2 d, J = 12.0 Hz, 2 H,
PhCH2), 4.43 (dd, J5,6b = 7.8 Hz, 1 H, H-6b), 4.30 (dd, J2¢,3¢ = 9.8 Hz,
1 H, H-2¢), 4.28 (dd, 1 H, H-2), 4.22 (ddd, J4,5 = 1.8 Hz, 1 H, H-5),
4.06 (dd, J3¢,4¢ = 2.7 Hz, J4¢,5¢ = 0.6 Hz, 1 H, H-4¢), 4.02 (dd, 1 H, H-
4), 3.72 (dd, 1 H, H-3¢), 3.72 (ddd, J5¢,6¢a = 6.7 Hz, J5¢,6¢b = 6.3 Hz, 1
25,26,27,28-Tetrapropoxy-5,11,17,23-tetrakis{3-[4-(2,3,4,6-tet-
ra-O-benzyl-b-D-galactopyranosyl)-1H-1,2,3-triazol-1-yl]pro-
pyl}calix[4]arene (24)
The reaction between ethynyl C-galactoside 7 (72 mg, 0.13 mmol)
and tetraazidocalixarene 21 (30 mg, 0.03 mmol) gave, after column
chromatography on silica gel (cyclohexane–EtOAc, 3:1 → 2:1),
known7b 24 as a syrup; yield: 75 mg (74%).
1-(1-Adamantyl)-4-dodecyl-1H-1,2,3-triazole (26)
The reaction between 1-tetradecyne (6; 72 mg, 0.37 mmol) and 1-
adamantyl azide (25; 60 mg, 0.34 mmol) gave, after column chro-
Synthesis 2010, No. 12, 2043–2048 © Thieme Stuttgart · New York

2048
A. Vecchi et al.
PAPER
Biomacromolecules 2007, 8, 2629. (g) Parvulescu, V. I.;
Hardacre, C. Chem. Rev. 2007, 107, 2615.
(h) van Rantwijk, F.; Sheldon, R. A. Chem. Rev. 2007, 107,
2757. (i) Weingärtner, H. Angew. Chem. Int. Ed. 2008, 47,
654.
matography on silica gel (cyclohexane–EtOAc, 15:1 → 5:1), 26 as
a syrup in 57% (using toluene, containing DIPEA) and 62% (using
IL 8) yield.
1H NMR (300 MHz): d = 7.34 (s, 1 H, H-5 Tr.), 2.72 (t, J = 7.7 Hz,
2 H, CH2), 2.30–2.22 (m, 9 H), 1.86–1.76 (m, 6 H), 1.72–1.62 (m,
2 H, CH2), 1.40–1.24 (m, 18 H), 0.90 (t, J = 6.7 Hz, 3 H, CH3).
13C NMR: d = 147.5 (C-4 Tr.), 116.8 (C-5 Tr.), 59.1 (C), 43.0, 36.0,
31.9 (CH2), 29.64 and 29.56 (CH2), 29.46 (CH), 29.3, 25.9, and 22.7
(CH2), 14.1 (CH3).
(9) (a) Machado, G.; Scholten, J.; de Vargas, T.; Teixera, S. R.;
Ronchi, L. H.; Dupont, J. Int. J. Nanotechnol. 2007, 4, 541.
(b) Biswas, K.; Rao, C. N. W. H.; Geldbach, T. J.; Scopelliti,
R.; Chiappe, C.; Dyson, J. P. Organometallics 2007, 26,
1293.
(10) (a) Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002,
67, 3145. (b) Hoffmann, J.; Nüchter, M.; Ondruschka, B.;
Wasserscheid, P. Green Chem. 2003, 5, 296.
(c) Obermayer, D.; Kappe, C. O. Org. Biomol. Chem. 2010,
8, 114.
(11) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Hayes, B. L. Aldrichimica Acta 2004, 37, 66.
(c) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
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A., Ed.; Wiley-VCH: Weinheim, 2006. (e) Kappe, C. O.;
Dallinger, D.; Murphree, S. S. Practical Microwave
Synthesis for Organic Chemists: Strategies, Instruments,
and Protocols; Wiley-VCH: Weinheim, 2009. (f) Martinez-
Palou, R. Mol. Diversity 2010, 14, 3.
HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for C24H42N3: 372.3379;
found: 372.3370.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Synthesis 2010, No. 12, 2043–2048 © Thieme Stuttgart · New York