Validation of the copper(I)-catalyzed azide-alkyne coupling in ionic liquids. Synthesis of a triazole-linked C-disaccharide as a case study

Article abstract of DOI:10.1021/jo7026454

(Chemical Equation Presented) The first study of a copper(I)-catalyzed azide-alkyne click reaction in ionic liquids (ILs) is reported. The cycloaddition of a sugar azide with a sugar acetylene (CuI, i-Pr₂EtN, 80°C) was carried out in 10 ILs as

Full text of DOI:10.1021/jo7026454

been amply documented that this highly regioselective triazole
annulation served as a powerful ligation tool of the most
disparate molecular fragments, thus leading to the metaphoric
view of the triazole ring as a robust keystone in complex
molecular architectures.6 The wide scope of CuAAC is firmly
demonstrated by the use in different areas of life and material
sciences. DNA labeling7 and oligonucleotide synthesis,8 as-
sembly of glycoclusters9 and glycodendrimers,10 preparation of
stationary phases for HPLC column,11 development of micro-
contact printing,12 new polymer synthesis,13 conjugation of
molecular cargos to the headgroup of phospholipids,14 and
construction of bolaamphiphilic structures15 are just a few
examples. While a lot of efforts have been made on the search
of improved copper-based catalysts, the issue regarding the green
aspect of the method has not so far been addressed. While it is
well-known that the CuAAC can be carried out in water as a
green solvent, the lack of solubility of the reactants can create
a serious obstacle to the use of this reaction medium. The use
of ionic liquids (ILs)16 is another way to meet the principles of
green chemistry. In addition to this fundamental aspect which
is however occasionally questioned,17 recent studies have shown
substantial effects on reactions carried out in ILs18 while most
reactions proceed as in ordinary organic liquids. Innovations
on the use of chiral ILs in asymmetric synthesis have been
Validation of the Copper(I)-Catalyzed
Azide-Alkyne Coupling in Ionic Liquids.
Synthesis of a Triazole-Linked C-Disaccharide as
a Case Study
Alberto Marra,*,† Alessandra Vecchi,† Cinzia Chiappe,*,‡
Bernardo Melai,‡ and Alessandro Dondoni*,†
Dipartimento di Chimica, Laboratorio di Chimica Organica,
UniVersita` di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy,
and Dipartimento di Chimica Bioorganica e Biofarmacia,
UniVersita` di Pisa, Via Bonanno 33, 56126 Pisa, Italy
mra@unife.it; cinziac@farm.unipi.it; adn@unife.it
ReceiVed December 12, 2007
The first study of a copper(I)-catalyzed azide-alkyne click
reaction in ionic liquids (ILs) is reported. The cycloaddition
of a sugar azide with a sugar acetylene (CuI, i-Pr2EtN,
80 °C) was carried out in 10 ILs as well as in standard
molecular solvents (toluene and DMF) to give the 1,4-
disubstituted triazole-linked C-disaccharide. The highest
yields (84 and 95%) were registered in Ammoeng 110 and
[C8dabco][N(CN)2]. The latter solvent was recycled in four
subsequent reactions without loss of the reaction efficiency.
Reactions carried out in the absence of the Hu¨nig’s base
afforded mixtures of 1,4- and 1,5-disubstituted triazole
regioisomers.
(6) Dondoni, A. Chem. Asian J. 2007, 2, 700-708.
(7) Gierlich, J.; Burley, G. A.; Gramlich, P. M. E.; Hammond, D. M.;
Carell, T. Org. Lett. 2006, 8, 3639-3642.
(8) Nuzzi, A.; Massi, A.; Dondoni, A. QSAR Comb. Sci. 2007, 26, 1191-
1199.
(9) Dondoni, A.; Marra, A. J. Org. Chem. 2006, 71, 7546-7557 and
references therein.
(10) (a) Joosten, J. A. F.; Tholen, N. T. H.; Ait El Maate, F.; 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. (b) Fernandez-Megia, E.; Correa,
J.; Rodr´ıguez-Meizoso, I.; Riguera, R. Macromolecules 2006, 39, 2113-
2120.
(11) Guo, Z.; Lei, A.; Liang, X.; Xu, Q. Chem. Commun. 2006, 4512-
4514.
(12) Rozkiewicz, D. I.; Janczewski, D.; Verboom, W.; Ravoo, B. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. 2006, 45, 5292-5296.
(13) Review: Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018-1025.
(14) (a) Musiol, H.-J.; Dong, S.; Kaiser, M.; Bausinger, R.; Zumbusch,
A.; Bertsch, U.; Moroder, L. ChemBioChem 2005, 6, 625-628. (b) Cavalli,
S.; Tipton, A. R.; Overhand, M.; Kros, A. Chem. Commun. 2006, 3193-
3195. (c) Hassane, F. S.; Frisch, B.; Schuber, F. Bioconjugate Chem. 2006,
17, 849-854.
Since Sharpless and co-workers’ seminal reports1 on the so-
called click chemistry concept, a huge number of papers have
been published2 on the use of the prototypical click reaction
constituted the copper(I)-catalyzed azide-alkyne cycloaddition
(CuAAC) to give under mild conditions 1,4-disubstituted 1,2,3-
triazoles in very high yields. This metal-catalyzed reaction
discovered independently in the Sharpless and Meldal labora-
tories3 constitutes a substantial improvement of the classical
Huisgen-type thermal 1,3-dipolar cycloaddition4,5 which instead
affords mixtures of 1,4- and 1,5-disubstituted triazoles. It has
(15) O’Neil, E. J.; DiVittorio, K. M.; Smith, B. D. Org. Lett. 2007, 9,
199-202.
(16) For recent reviews, see: (a) Chiappe, C.; Pieraccini, D. J. Phys.
Org. Chem. 2005, 18, 275-297. (b) Jain, N.; Kumar, A.; Chauhan, S.;
Chauhan, S. M. S. Tetrahedron 2005, 61, 1015-1060. (c) Murugesan, S.;
Linhardt, R. J. Curr. Org. Synth. 2005, 2, 437-451. (d) Chowdhury, S.;
Mohan, R. S.; Scott, J. L. Tetrahedron 2007, 63, 2363-2389. (e) Imperato,
G.; Ko¨nig, B.; Chiappe, C. Eur. J. Org. Chem. 2007, 1049-1058. (f) El
Seoud, O. A.; Koschella, A.; Fidale, L. C.; Dorn, S.; Heinze, T. Biomac-
romolecules 2007, 8, 2629-2647. (g) Parvulescu, V. I.; Hardacre, C. Chem.
ReV. 2007, 107, 2615-2665. (h) van Rantwijk, F.; Sheldon, R. A. Chem.
ReV. 2007, 107, 2757-2785. (i) Weinga¨rtner, H. Angew. Chem., Int. Ed.
2008, 47, 654-670.
† Universita` di Ferrara.
‡ Universita` di Pisa.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery
Today 2003, 8, 1128-1137.
(2) For an updated list, see: http://www.scripps.edu/chem/sharpless/
click.html.
(3) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3062.
(4) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-598. (b)
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633-645.
(5) For a recent review on 1,3-dipolar cycloadditions, see: Gothelf, K.
V.; Jorgenson, K. A. Chem. ReV. 1998, 98, 863-909.
(17) (a) Dupont, J.; Spencer, J. Angew. Chem., Int. Ed. 2004, 43, 5296-
5297. (b) Smiglak, M.; Reichert, W. M.; Holbrey, J. D.; Wilkes, J. S.; Sun,
L.; Thrasher, J. S.; Kirichenko, K.; Singh, S.; Katritzky, A. R.; Rogers, R.
D. Chem. Commun. 2006, 2554-2556. (c) Zhao, D.; Liao, Y.; Zhang, Z.
Clean 2007, 35, 42-48.
(18) (a) Ranu, B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049-3052. (b)
Law, M. C.; Wong, K.-Y.; Chan, T. H. Chem. Commun. 2006, 2457-
2459. (c) Kumar, A.; Pawar, S. S. J. Org. Chem. 2007, 72, 8111-8114.
(d) Cao, H.; Xiao, W.-J.; Alper, H. J. Org. Chem. 2007, 72, 8562-8564.
(e) Gu, Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175-178.
10.1021/jo7026454 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/20/2008
2458
J. Org. Chem. 2008, 73, 2458-2461

TABLE 1. Effect of the Solvent in the Cu-Promoted Cycloaddition
of 1 and 2 on a 0.1 mmol Scale to Give the C-Disaccharide 3 (see
Scheme 1)
SCHEME 1
reported.19 ILs can be excellent solvents for metal-catalyzed
reactions because they are able to dissolve metal salts and
stabilize the formation of metal nanoparticles, nanorods, and
so on.20 The economical aspect regarding the use of these
solvents is still a pending problem due to their high cost. This,
however, is partly compensated by their potential recycling. New
techniques based on IL-supported species21 may contribute to
relieve this serious drawback. Also in respect to this broader
outlook, it is quite surprising that studies have not so far been
reported on the CuAAC reaction carried out in ILs.22 Therefore,
we were spurred to address this issue and considered a model
CuAAC reaction in a field of our direct interest such as the
assembly of triazole-linked oligosaccharides23 and glycoconju-
gates.9,24 Toward this end, we have selected the hitherto
unreported coupling of perbenzylated ethynyl C-galactoside25
1 with methyl 6-azidoglucopyranoside26 2 to give the triazole-
linked disaccharide 3 (Scheme 1). Carbohydrates are densely
functionalized compounds and therefore are perfect test vehicles
to probe the fidelity of the click reaction in ILs. Moreover,
performing a click reaction in ILs appeared to us a non-trivial
task, the main inconvenience that might occur being the
sequestering of the copper catalyst by complexation with the
solvent. Three types of ILs were considered by cation variation
(i.e., the ammonium derivative 4, the bmim-based derivatives
5-9, and the N-alkyl dabco-cation-based derivatives 10-13).
Structural diversity was also introduced by the anion change.
Crucial to the use of the selected ILs was the ability to dissolve
CuI and a low viscosity, thus enabling an efficient stirring of
the reaction mixture.
The cycloaddition of 1 and 2 was first performed at room
temperature overnight on a 0.1 mmol scale in the presence of
a After extraction of the reaction mixture with AcOEt and column
chromatography on silica gel. b Washed twice with Et2O, then dried under
vacuum, before the cycloaddition reaction. c Reaction mixture extracted with
Et2O instead of AcOEt. d Contaminated by 5% of the 1,5-regioisomer 14.
e Isolated yield on a 1 mmol scale.
(19) (a) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun.
2006, 3687-3689. (b) Ni, B.; Zhang, Q.; Headley; A. D. J. Org. Chem.
2006, 71, 9857-9860. (c) Schulz, P. S.; Mu¨ller, N.; Bo¨smann, A.;
Wasserscheid, P. Angew. Chem., Int. Ed. 2007, 46, 1293-1295.
(20) (a) Machado, G.; Scholten, J.; de Vargas, T.; Teixera, S. R.; Ronchi,
L. H.; Dupont, J. Int. J. Nanotechnol. 2007, 4, 541-563. (b) Biswas, K.;
Rao, C. N. R. Chem.sEur. J. 2007, 13, 6123-6129. (c) Fei, Z.; Zhao, D.;
Pieraccini, D.; Ang, W. H.; Geldbach, T. J.; Scopelliti, R.; Chiappe, C.;
Dyson, J. P. Organometallics 2007, 26, 1588-1598.
(21) Miao, W.; Chan, T. H. Acc. Chem Res. 2006, 39, 897-908.
(22) A related study involved the Cu(I)-catalyzed three-component
reaction of halides, NaN3, and alkynes in a mixture of [bmim][BF4] and
H2O. See: Zhao, Y.-B.; Yan, Z.-Y.; Liang, Y.-M. Tetrahedron Lett. 2006,
47, 1545-1549.
(23) Cheshev, P.; Dondoni, A.; Marra, A. Org. Biomol. Chem. 2006, 4,
3225-3227.
(24) Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929-
2932.
(25) (a) Lowary, T.; Meldal, M.; Helmboldt, A.; Vasella, A.; Bock, K.
J. Org. Chem. 1998, 63, 9657-9668. (b) Dondoni, A.; Mariotti, G.; Marra,
A. J. Org. Chem. 2002, 67, 4475-4486.
(26) Kobayashi, Y.; Shiozaki, M.; Ando, O. J. Org. Chem. 1995, 60,
2570-2580.
CuI (0.5 equiv) and freshly distilled i-Pr2EtN (Hu¨nig’s base, 5
equiv) using the ionic liquids 4-6 as the solvents. Under these
conditions, the C-disaccharide 3 was obtained in only 25-30%
isolated yield, while the reaction mixtures were mainly formed
by unreacted alkyne 1 and azide 2. Raising the reaction
temperature to 80 °C, we found that the cycloadduct 3 was
recovered in much higher yields (50-84%, entries 3-5).
Reactions under these optimized conditions were carried out in
other ILs as well as in toluene and DMF as standard molecular
solvents (Table 1, entries 1, 2, and 6-12). In all cases, with
one exception only (entry 8), the reaction afforded exclusively
the cycloadduct 3 in fair to excellent isolated yields. A yield of
3 (91%) comparable to that in toluene (96%) was obtained in
the N-octyl dabco-cation-based dicyanamide ([C8dabco][N(CN)2],
J. Org. Chem, Vol. 73, No. 6, 2008 2459

TABLE 2. Cycloaddition in the Absence of Hu1nig’s Base (80 °C,
16 h)
SCHEME 2
entry
solvent
yield (%)a
3:14 ratiob
1
2
3
4
5
6
7
toluene
4
9
10
11
12
13
96c
60d
61
1:0
25:1
1.7:1
1:1.5
1:1.0
6.0:1
9.0:1
62
34e
71
41e
13, entry 12). The yields in this IL decreased by shortening the
reaction time (74% in 4 h and 81% in 8 h), which indicated the
convenient reaction time employed (16 h).
a After extraction of the reaction mixture with AcOEt and column
chromatography on silica gel. b From 1H NMR analysis. c The reaction
mixture was concentrated and applied directly to a column of silica gel.
d Reaction mixture extracted with Et2O instead of AcOEt. e The reaction
mixture was diluted with H2O and extracted with AcOEt.
The 1,4-disubstitution pattern of the triazole linker in 3 was
established by 13C NMR spectroscopy according to our recent
method.9 In fact, a large and positive ∆(δC4-δC5) value (22.0
ppm) was found in the 13C spectrum27 as observed in other
compounds prepared by click reaction, including triazole-linked
C-glycoside clusters,9 C-oligosaccharides,23 and C-glycosyl
amino acids.24 On the other hand, in agreement with earlier
findings,9,27 the 1,5-disubstituted triazole 14 prepared by thermal
coupling of 1 and 2 neat (Scheme 2) displayed a small and
negative ∆(δC4-δC5) value as small as -3.3 ppm.
run. Noteworthy, the registered yields of isolated 3 in four
subsequent runs were 91, 77, 80, and 80%. Hence, a single stock
of 13 enabled the coupling of 0.4 mmol (ca. 200 mg) of each
reaction partner 1 and 2 to give the disaccharide 3 with an
average yield of 82%. The preparative value of the CuAAC
under study was further demonstrated by a reaction carried out
on a 1 mmol scale of each reagent 1 and 2. In this case, the
yield of isolated 3 (0.98 g) was 95%.
It is worth noting that the empirical rule3b,28 establishing that
the H-5 proton in 1,4-disubstituted triazoles resonates always
downfield compared to the H-4 proton in the corresponding 1,5-
isomer is not always reliable, especially in the case of complex
molecules such as the disaccharides 3 and 14. Actually, the
triazole proton in 3 was at upper field (δH5 ) 7.57 ppm) than
that of the proton of the regioisomer 14 (δH4 ) 7.68 ppm).
Instead, the free hydroxy C-disaccharides 15 and 16, obtained
by catalytic hydrogenation of 3 and 14, respectively, displayed
in their NMR spectra chemical shift values in accord with both
rules [15: (δH5 ) 8.02 ppm; ∆(δC4-δC5) ) +21.6 ppm; 16:
(δH4 ) 7.79 ppm; ∆(δC4-δC5) ) -5.3 ppm)].
While all runs reported in Table 1 were carried out in the
presence of i-Pr2EtN, we planned on performing reactions in
ILs without this base since successful click azide-alkyne
reactions were reported in the absence of such an additive.31
Moreover, we observed that, contrary to literature precedent
which encourages use of excess Hu¨nig’s base,3b the reaction of
1 and 2 in toluene without added i-Pr2EtN afforded exclusively
the cycloadduct 3 with the same high yield (96%) as in the
presence of the base (Table 1, entry 1; Table 2, entry 1). Quite
disappointedly, applying the same conditions to the reaction
carried out in the non-basic IL 4, we found that the 1,4- and
1,5-regioisomers 3 and 14 were formed in low overall yield
although with a net predominance of the former (Table 2, entry
2). Hence, the presence of i-Pr2EtN appeared to be crucial for
the occurrence of the effective click cycloaddition in the IL 4.
Therefore, we hoped that click chemistry could take place again
in a basic IL such as the bmim-based 9 displaying a structural
motif around the basic nitrogen atom in the alkyl chain similar
to that in Hu¨nig’s base. In the event, the IL would serve as
promoter and reaction medium. Instead, a modest yield was
again registered, and the two regioisomers formed in nearly
equal amounts (Table 2, entry 3). Similar results were found in
other basic ILs such as the dabco-derived ILs 10-13. We
suggest that the event feared at the outset of the research about
copper sequestering by the IL32 and therefore impairing the
catalytic cycle33 did in fact occur. The presence of i-Pr2EtN
serving as a copper ligand32 prevents such a drawback by the
The workup of the reaction mixture was a non-trivial
operation for reactions carried out in ILs. Although ethyl acetate
appeared to be the solvent of choice29 for the efficient extraction
of the product 3, small amounts of the IL were extracted by
this solvent30 and then retained by the silica gel column used
for the chromatographic purification of 3. Consequently, the
method suffered from the partial loss of these costly IL solvents.
Nevertheless, the recycling of 13 was considered. To this end,
following the workup of the reaction mixture, to the recovered
IL still containing the copper catalyst was added the Hu¨nig’s
base, and the resulting mixture was employed in a subsequent
(31) (a) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H.
J. Am. Chem. Soc. 2002, 124, 14397-14402. (b) Lipshutz, B. H.; Taft, B.
R. Angew. Chem., Int. Ed. 2006, 45, 8235-8238.
(32) Both cations and anions of the ILs 9-13, as well as i-Pr2EtN, can
serve as ligand for copper(I) ions. See: (a) MacFarlane, D. R.; Pringle, J.
M.; Johansson, K. M.; Forsyth, S. A.; Forsyth, M Chem. Commun. 2006,
1905-1917. (b) Batten, S. R.; Harris, A. R.; Jensen, P.; Murray, K. S.;
Ziebell, A. J. Chem. Soc., Dalton. Trans. 2000, 3829-3836. (c) Ding, C.
F., Yu, Y.; Jensen, R. H.; Balfour, W. J.; Qian, C. X. W. Chem. Phys. Lett.
2000, 331, 163-169.
(33) (a) Rodionov, D. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int.
Ed. 2005, 44, 2210-2215. (b) Bock, V. D.; Hiemstra, H.; van Maarseveen,
J. H. Eur. J. Org. Chem. 2006, 51-68. (c) Nolte, C.; Mayer, P.; Straub, B.
F. Angew. Chem., Int. Ed. 2007, 46, 2101-2215. (d) Straub, B. F. Chem.
Commun. 2007, 3868-3870.
(27) Rodios, N. A. J. Heterocycl. Chem. 1984, 21, 1169-1173.
(28) (a) Alonso, G.; Garc´ıa-Lo´pez, M. T.; Garc´ıa-Mun˜oz, G.; Madron˜ero,
R.; Rico, M. J. Heterocycl. Chem. 1970, 7, 1269-1272. (b) Crandall, J.
K.; Crawley, L. C.; Komin, J. B. J. Org. Chem. 1975, 40, 2045-2047. (c)
Wang, Z.-X.; Qin, H.-L. Chem. Commun. 2003, 2450-2451.
(29) When using IL 4 as the solvent, the reaction mixture was extracted
with diethyl ether because this ionic liquid is quite soluble in AcOEt (ca.
70 mg/mL). The solubility of 4 in AcOEt did not vary significantly in the
presence of H2O.
(30) The solubility of pure IL 13 in AcOEt at rt was ca. 25 mg/mL.
2460 J. Org. Chem., Vol. 73, No. 6, 2008

then cooled to room temperature, diluted with toluene (ca. 0.5 mL),
and eluted from a column of silica gel with cyclohexane-AcOEt
(from 3:1 to 2:1) to give first a mixture of unreacted 1 and 2, then
the disaccharide 3 (15 mg, 14%), and finally the regioisomer 14
(28 mg, 27%).
IL. Considerations on some physicochemical properties of ILs
may clarify this point. The interactions between anions and
cations in ILs produce ionic organized networks in the solid,
liquid, and gas phase, with the charge ordering degree deter-
mined mainly by the nature of anion and cation, while the
presence of sufficiently long alkyl chains on cation determines
the existence of polar and unpolar domains.34 The ability of
the anion and cation to interact with dissolved species, including
catalysts, is therefore a property partially determined by the
anion-cation interaction inside the network. The addition of
uncharged species affects the three-dimensional structure of ILs
and changes their physicochemical properties. Hence, the
Hu¨nig’s base may affect both the ability of the medium to
sequester the copper catalyst and the aptitude of the effective
catalyst to approach the reagents.
In summary, of the various ILs examined, the most suitable
one for performing the model CuAAC reaction examined is the
[C8dabco][N(CN)2] using CuI as catalyst and i-Pr2EtN as
additive. The validation of a synthetically important CuAAC
such as that involving carbohydrates in ILs opens new perspec-
tives on the use of this prototypical click reaction in glyco-
chemistry.
Disaccharide 3: Mp 110-111 °C (AcOEt/cyclohexane); [R]D
1
) +25.9 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.57 (s,
1H, H-5 Tr.), 7.39-7.20 (m, 30H, Ar), 7.18-7.12 (m, 3H, Ar),
7.05-7.02 (m, 2H, Ar), 5.00 and 4.66 (2d, 2H, J ) 11.6 Hz,
PhCH2), 4.93 and 4.78 (2d, 2H, J ) 10.9 Hz, PhCH2), 4.87 and
4.76 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.78 and 4.73 (2d, 2H, J )
11.7 Hz, PhCH2), 4.66 and 4.26 (2d, 2H, J ) 10.6 Hz, PhCH2),
4.58 and 4.42 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.53 (dd, 1H, J5,6a
5.6 Hz, J6a,6b ) 14.3 Hz, H-6a), 4.52 (d, 1H, J1′,2′ ) 9.7 Hz, H-1′),
4.46 and 4.40 (2d, 2H, J ) 11.6 Hz, PhCH2), 4.44 (d, 1H, J1,2
)
)
3.6 Hz, H-1), 4.44 (dd, 1H, J5,6b ) 2.8 Hz, H-6b), 4.20 (dd, 1H,
J2′,3′ ) 9.5 Hz, H-2′), 4.06 (dd, 1H, J3′,4′ ) 3.0 Hz, J4′,5′ ) 0.8 Hz,
H-4′), 3.94 (dd, 1H, J2,3 ) 9.7 Hz, J3,4 ) 8.8 Hz, H-3), 3.91 (ddd,
1H, J4,5 ) 10.0 Hz, H-5), 3.73 (dd, 1H, H-3′), 3.72 (ddd, 1H, J5′,6′a
) 7.0 Hz, J5′,6′b ) 6.2 Hz, H-5′), 3.60 (dd, 1H, J6a′,6′b ) 9.0 Hz,
H-6′a), 3.57 (dd, 1H, H-6′b), 3.23 (dd, 1H, H-2), 3.12 (dd, 1H,
H-4), 3.11 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3) δ 146.2 (C-4
Tr.), 138.9, 138.5, 138.4, 138.1, 138.0, 137.89, and 137.82 (C Ar),
128.5-127.5 (CH Ar), 124.2 (C-5 Tr.), 98.0 (C-1), 84.3 (C-3′),
81.8 (C-3), 79.9 (C-2), 78.7 (C-2′), 77.7 (C-4), 77.4 (C-5′), 75.6
(PhCH2), 74.9 (2 PhCH2), 74.61 (C-1′), 74.59 (PhCH2), 74.0 (C-
4′), 73.5 (PhCH2), 73.3 (PhCH2), 72.5 (PhCH2), 68.9 (C-5), 68.7
(C-6′), 55.3 (CH3), 50.3 (C-6). MALDI-TOF MS (1038.23): 1038.9
(M+ + H), 1060.9 (M+ + Na), 1076.7 (M+ + K). Anal. Calcd for
C64H67N3O10: C, 74.04; H, 6.50; N, 4.05. Found: C, 73.88; H,
6.41; N, 3.90.
Experimental Section
Cycloaddition in Molecular Solvents. A mixture of sugar azide
2 (49 mg, 0.10 mmol), C-galactoside 1 (60 mg, 0.11 mmol), freshly
distilled N,N-diisopropylethylamine (87 µL, 0.50 mmol), CuI
(9.5 mg, 0.05 mmol), and anhydrous toluene (1 mL) was sonicated
in an ultrasound cleaning bath for ca. 1 min, then stirred in the
dark at 80 °C for 16 h, cooled to room temperature, and
concentrated. The residue was eluted from a column of silica gel
with 2:1 cyclohexane/AcOEt to give first unreacted azide 2 (2.5
mg, 5%). Eluted second was the disaccharide 3 (100 mg, 96%) as
a colorless foam. When the same cycloaddition was performed
without the Hu¨nig’s base, the unmodified alkyne 1 (9 mg, 15%)
and the disaccharide 3 (100 mg, 96%) were isolated by column
chromatography.
Cycloaddition in Ionic Liquids. A mixture of sugar azide 2
(49 mg, 0.10 mmol), C-galactoside 1 (60 mg, 0.11 mmol), and ionic
liquid (0.50 g; previously dried at 0.1 mbar/50 °C for 4 h) was
sonicated or magnetically stirred at room temperature for a few
minutes to obtain a solution, then CuI (9.5 mg, 0.05 mmol) was
added. The mixture was sonicated for ca. 1 min, then diluted with
freshly distilled N,N-diisopropylethylamine (87 µL, 0.50 mmol),
and stirred in the dark at 80 °C. After 16 h, the reaction mixture
was cooled to room temperature and extracted with AcOEt (4 × 6
mL), waiting each time 15 min for a clear phase separation (in
some cases, 1 mL of H2O was also added to improve the extraction
yield; see Table 2). The combined extracts were concentrated and
dried under high vacuum to give crude 3 together with variable
amounts of ionic liquid. The residue was eluted from a column of
silica gel with 2:1 cyclohexane/AcOEt to give pure disaccharide
3. An identical procedure was followed for reactions performed
without the Hu¨nig’s base.
Disaccharide 14: [R]D ) +28.3 (c 0.8, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.68 (s, 1H, H-4 Tr.), 7.42-7.20 (m, 33H, Ar),
7.00-6.96 (m, 2H, Ar), 4.96 and 4.78 (2d, 2H, J ) 11.0 Hz,
PhCH2), 4.92 and 4.62 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.90 and
4.70 (2d, 2H, J ) 10.9 Hz, PhCH2), 4.77 and 4.69 (2d, 2H, J )
11.6 Hz, PhCH2), 4.68 and 4.54 (2d, 2H, J ) 12.3 Hz, PhCH2),
4.68 and 4.15 (2d, 2H, J ) 10.6 Hz, PhCH2), 4.64 (dd, 1H, J5,6a
2.8 Hz, J6a,6b ) 14.3 Hz, H-6a), 4.46 (d, 1H, J1′,2′ ) 9.6 Hz, H-1′),
4.46 and 4.40 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.44 (dd, 1H, J5,6b
)
)
6.5 Hz, H-6b), 4.38 (d, 1H, J1,2 ) 3.5 Hz, H-1), 4.10 (dd, 1H, J2′,3′
) 9.4 Hz, H-2′), 4.04 (dd, 1H, J3′,4′ ) 2.8 Hz, J4′,5′ ) 0.5 Hz, H-4′),
3.94 (ddd, 1H, J4,5 ) 10.0 Hz, H-5), 3.93 (dd, 1H, J2,3 ) 9.5 Hz,
J3,4 ) 9.0 Hz, H-3), 3.63-3.54 (m, 4H, H-3′, H-5′, 2 H-6′), 3.46
(dd, 1H, H-4), 3.38 (dd, 1H, H-2), 3.00 (s, 3H, OMe); 13C NMR
(75 MHz, CDCl3) δ 138.6, 138.5, 138.2, 138.1, 137.9, 137.6, and
137.5 (C Ar), 136.0 (C-5 Tr.), 132.7 (C-4 Tr.), 129.9-127.4 (CH
Ar), 97.6 (C-1), 84.3 (C-3′), 82.0 (C-3), 79.7 (C-2), 78.7 (C-4),
78.1 (C-2′), 75.6, 75.2, 74.8, 74.7, and 73.5 (PhCH2), 73.4 (C-4′),
73.3 and 72.2 (PhCH2), 72.1 (C-1′), 69.1 (C-5), 68.4 (C-6′), 55.0
(CH3), 48.6 (C-6). MALDI-TOF MS (1038.23): 1038.7 (M+
+
H), 1060.7 (M+ + Na), 1076.7 (M+ + K). Anal. Calcd for
C64H67N3O10: C, 74.04; H, 6.50; N, 4.05. Found: C, 73.81; H,
6.39; N, 3.92.
Supporting Information Available: Experimental procedures
and physical data of ILs 9, 10, 13, and disaccharides 15 and 16.
Cycloaddition in the Absence of Solvent. A mixture of syrupy
azide 2 (49 mg, 0.10 mmol) and crystalline alkyne 1 (60 mg, 0.11
mmol) was stirred at 80 °C for 16 h under a nitrogen atmosphere
(after a few minutes, the mixture became a homogeneous solution),
1
Copies of the H and 13C NMR spectra of 3, 9, 10, and 13-16.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(34) Chiappe, C. Monatsh. Chem. 2007, 138, 1035-1044.
JO7026454
J. Org. Chem, Vol. 73, No. 6, 2008 2461