'Click' chemistry on sugar-derived alkynes: A tandem 'click-click' approach to bistriazoles

Article abstract of DOI:10.1055/s-0029-1217570

Development of a tandem 'click-click' approach to the formation of successive 1,4-disubstituted 1,2,3-triazole linkages and 'click chemistry' on sugar-derived alkynes are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217570

2162
LETTER
‘Click’ Chemistry on Sugar-Derived Alkynes: A Tandem ‘Click–Click’
Approach to Bistriazoles
‘
Click’ Chemistry
r
on Suga
i
r-Deriv
s
e
d
A
lkyne
h
s
na P. Kaliappan,* Palanichamy Kalanidhi, Subham Mahapatra
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received 15 April 2009
CuI, DIPEA
MeCN
1.
2.
Abstract: Development of a tandem ‘click–click’ approach to the
formation of successive 1,4-disubstituted 1,2,3-triazole linkages
and ‘click chemistry’ on sugar-derived alkynes are described.
R1OOC
N
N
N
N3
O
R2
N
N
O
Key words: C-glycoside, triazole, ‘click’ reaction, alkyne, azide,
azido-alkyne, bistriazole
N
sugar
O
sugar
OR1
R2N3
R1 = Me; R2 = benzyl, aryl
3.
The C-glycosides are an important class of glycosides
with a sizeable number of natural products belonging to
this category. They differ from the usual O-glycosides and
N-glycosides in having a C–C bond attached to the ano-
meric carbon.1 Due to this key change in the nature of this
bond, C-glycosides appear to show significant resistance
to hydrolytic and enzymatic cleavage and are generally
considered as potential drug candidates. In view of the in-
teresting behavior of C-glycosides, several synthetic ap-
proaches have been developed to synthesize a variety of
C-glycosides and to study their properties.2 Several C-gly-
cosides have been synthesized and their utility as probes
and inhibitors for biological processes have been stud-
ied.1,3 Furthermore, the intriguing biological profiles of
triazole-based molecules, such as their anti-HIV4 and anti-
microbial5 activity, have drawn interest from various
quarters in preparing a library of triazole-based C-glyco-
sides. In the field of bioconjugation chemistry,6 the bio-
compatible nature and the inertness of the triazole ring to
metabolic transformations7 has made it a good linker for
joining two biomolecules in a covalent manner. This ap-
proach uses Cu(I)-catalyzed Hüisgen 1,3-dipolar
cycloaddition8 (‘click’) reactions, discovered indepen-
dently by the groups of Sharpless and Meldal.9
Scheme 1 Tandem click approach to the synthesis of bistriazoles
ing iterative ‘click’ chemistry to generate triazole-linked
oligomers, albeit not on carbohydrates.14
Nevertheless, there has been a quest to develop a one-pot
approach to the successive linking of carbohydrates
through triazole rings. There are a few reports in the liter-
ature where multiple triazole rings are formed in one pot
by ‘click’ reactions between one component having one or
more alkyne moieties with a second component having
one or more azide moieties.11,15 While Hotha et al. report-
ed intramolecular ‘click’ reactions of azido-alkynes for
the synthesis of triazole-fused tetracyclic compounds,
Chandrasekhar et al. achieved the synthesis of furanotria-
zole macrocycles by inter and intramolecular ‘click’ reac-
tions of azido-alkynes.16
N3
O
O
N3
O
O
N3
O
O
O
O
Figure 1 Designed azido-alkynes
In light of its salient features, such as selectivity and func-
tional group tolerance, the emerging10 ‘click’ reaction has
found tremendous applications in the fields of drug dis-
covery and material science, etc., in addition to bioconju-
gation.6,11 For instance, in sugar chemistry, linking of a
carbohydrate with another unit or with a non-carbohy-
drate system has been accomplished through a 1,2,3-tria-
zole ring using the ‘click’ reaction of alkynes and azides.12
Later, Dondoni and co-workers reported an iterative
Cu(I)-catalyzed synthesis of triazole-linked oligoman-
noses from orthogonally protected mannose-derived
alkynes and azides.13 Also, there are a few reports on us-
However, there has been no report on the formation of
multiple triazole rings in one pot by intermolecular ‘click’
reaction between an azido-alkyne, an alkyne and an azide.
This stimulated us to develop a tandem ‘click’ approach
especially for the synthesis of triazole-linked sugar oligo-
mers. During the course of our investigation on this issue,
Leigh and Aucagne reported a one-pot ‘click–click’ pro-
cedure for the successive copper- and copper-and-silver-
mediated chemoselective formation of two distinct triaz-
ole linkages from amino acid derived alkynes and azides,
using the trimethylsilyl group as a temporary masking
group for one of the alkyne moieties.17 This prompted us
to disclose our initial results on developing a tandem
‘click’ approach to the formation triazole linkages succes-
SYNLETT 2009, No. 13, pp 2162–2166
x
x
.x
x
.2
0
0
9
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217570; Art ID: G13409ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
‘Click’ Chemistry on Sugar-Derived Alkynes
2163
sively in one pot (Scheme 1) using sugar-derived azido- Before realizing this tandem ‘click’ chemistry, our initial
alkynes (Figure 1).
task was to identify the best reaction conditions for this
approach. To this end, we carried out ‘click’ reactions be-
Table 1 ‘Click’ Chemistry between Sugar-Derived Alkynes and Azidesa
MeO
TBSO
O
O
O
O
O
O
O
O
O
OMe
Alkynes/azides
O
O
O
N
O
N
O
1
4
3
2
TBSO
N
N
O
R
MeO
R
N
N
N3
O
O
O
O
O
O
O
N
N
N
O
O
O
OMe
N
N
O
O
N
O
N
5
R = benzyl
R = benzyl
R
R = benzyl
R = benzyl
R
13 (82)
11 (86)
12 (85)
10 (80)
N
R
TBSO
MeO
N
N
R
N
N
N3
O
O
N
O
O
O
N
O
N
N
O
O
N
O
N
O
OMe
O
R
O
O
O
R
R = 4-MeC6H4
R = 4-MeC6H4
6
R = 4-MeC6H4
R = 4-MeC6H4
17 (82)
14 (81)
16 (84)
15 (83)
N
R
N
R
N
N
N
MeO
TBSO
N
N3
O
O
O
N
O
O
N
O
N
O
O
N
N
O
O
O
OMe
O
O
N
R
O
Cl
R
R = 4-ClC6H4
R = 4-ClC6H4
7
R = 4-ClC6H4
R = 4-ClC6H4
18 (82)
21 (87)
19 (86)
20 (88)
N
N
R
R
TBSO
N
MeO
N
N
N
O
O
N3
O
N
O
O
O
N
N
N
O
O
N
O
OMe
N
O
O
O
R
O
O
R
8
R = 1-naphthyl
R = 1-naphthyl
R = 1-naphthyl
R = 1-naphthyl
25 (83)
22 (75)
24 (86)
23 (85)
R
R
N
MeO
N
TBSO
O
N
N
N
N
N3
O
O
O
N
O
N
N
O
N
N
O
O
O
O
O
N
OMe
O
R
O
O
R
R = 9-anthracenyl
9
R = 9-anthracenyl
R = 9-anthracenyl
26 (83)
29 (86)
R = 9-anthracenyl
28 (98)
27 (84)
a Yield given in parentheses.
Synlett 2009, No. 13, 2162–2166 © Thieme Stuttgart · New York

2164
K. P. Kaliappan et al.
LETTER
for the reaction to go to completion. This observation led
us to follow another well-established ‘click’ protocol us-
ing copper(I) iodide, acetonitrile, and diisopropylethyl-
amine (DIPEA).9b As expected, the copper(I)-catalyzed
Hüisgen 1,3-dipolar cycloaddition reaction between
known alkynes18 and azides19 proceeded smoothly to af-
ford the corresponding 1,4-disubstituted 1,2,3-triazoles in
excellent yield. The reaction went to completion within
15–20 min (Table 1).20
N
N
N
R
O
O
CuI, DIPEA
MeCN
R
sugar
N3
sugar
+
R = benzyl, aryl
Scheme 2 ‘Click’ reaction between sugar-derived alkynes and azides
tween simple sugar-derived alkynes and azides
(Scheme 2). Although CuSO4/sodium ascorbate-based
‘click’ protocol has proven to be the most benign, for our
substrates, this method took a long time (more than 15 h)
Having succeeded in synthesizing 1,2,3-triazoles derived
from sugars, we turned to our main goal of devising a tan-
dem ‘click’ approach using the same reaction conditions.
Table 2 Synthesis of Bistriazoles by a Tandem ‘Click–Click’ Approach Using Azido-alkyne 31, Methyl Propiolate 32 and Azides 5–9a
Azide
Product
By-product
MeOOC
N
MeOOC
N
N
N
N
N
N
N3
N
N
5
O
34 (33)
O
33 (23)
MeOOC
MeOOC
N
N
N
N
N
N
N
N
N
N3
O
6
O
36 (50)
35 (46)
Cl
MeOOC
N
MeOOC
N
N
Cl
N
N
N
N
N
N
N3
O
7
O
Cl
38 (36)
37 (38)
MeOOC
N
MeOOC
N
N
N
N
N
N
N
N
N3
O
O
8
40 (39)
39 (33)
MeOOC
MeOOC
N
N
N
N
N
N
N3
N
N
N
O
O
9
42 (48)
41 (45)
a Yield given in parentheses.
Synlett 2009, No. 13, 2162–2166 © Thieme Stuttgart · New York

LETTER
‘Click’ Chemistry on Sugar-Derived Alkynes
2165
As shown in Scheme 1, we presumed that successive ad-
dition of CuI, DIPEA and an azido-alkyne to a solution of
an alkyne in acetonitrile, would result in a ‘click’ reaction
to form the first triazole linkage. Subsequent addition of a
second azide to this reaction mixture would lead to the
formation of the second triazole. This process could per-
haps be repeated several times in order to access triazole
oligomers in one pot by sequential addition of the azido-
alkyne prior to the addition of the azide; the progress of
the reaction could be monitored by thin layer chromatog-
raphy from the consumption of the azido-alkyne at each
stage of the sequence. We chose azido-alkyne 31 as our
substrate for this sequence, which was easily prepared
from the known alkynol21 in two steps. Tosylation of pri-
mary alcohol 30 followed by an SN2 displacement with
sodium azide in N,N-dimethylformamide, afforded the
azido-alkyne 31 in good yield (Scheme 3). Then, as
shown in Scheme 1, copper(I) iodide and DIPEA were
added to a solution of methyl propiolate 32 in acetonitrile.
After stirring for a few minutes, the reaction mixture was
treated with azido-alkyne 31 and the mixture was stirred
for 15 minutes; the consumption of the azido-alkyne was
monitored by thin layer chromatography. Addition of ben-
zylazide 5 followed by stirring for another 15 minutes re-
sulted in the formation of bistriazole 33 (23% yield), but
along with the formation of the simple cycloadduct 34
(33%) as a by-product produced by a ‘click’ reaction be-
tween methyl propiolate and benzylazide. However, the
yield of the desired reaction was improved to 46% by in-
creasing the stirring time to one hour prior to the addition
of the azide. In this case, the azido-alkyne was purified
prior to use by rapid filtration through a short silica gel
column.
Acknowledgment
We thank CSIR, New Delhi and SAIF, IIT Bombay for financial
support and the use of spectral facilities, respectively. One of us
(P.K.) thanks CSIR, New Delhi for a fellowship.
References and Notes
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54, 9913. (g) Beau, J. M.; Gallagher, T. Top. Curr. Chem.
1997, 187, 1.
(3) For recent reviews on C-glycoside biology and biosynthesis,
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K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer,
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R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
(6) (a) Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018.
(b) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today
2003, 8, 1128. (c) Breinbauer, R.; Koehn, M.
N3
1.
2.
TsCl, pyridine
92%
HO
O
O
ChemBioChem 2003, 4, 1147.
NaN , dry DMF
O
O
3
(7) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.;
Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15,
269.
71%
31
30
(8) (a) Hüisgen, R.; Szeimies, G.; Moebius, L. Chem. Ber. 1967,
100, 2494. (b) Hüisgen, R. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984, 1–176.
(9) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornoe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
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(10) For an updated list, see: http://www.scripps.edu/chem/
sharpless/click.html
(11) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36,
1249.
Scheme 3 Synthesis of azido-alkyne 31
The azido-alkyne 31 was found to decompose, both on
storage and during the reaction, to give unidentified prod-
ucts. Consequently, the yield of the desired product be-
came poor, leaving the other two partners to react and give
the by-product 34. Under the above reaction conditions,
other bistriazoles 35, 37, 39 and 41 were also synthesized
as shown in Table 2.22
(12) For selected examples, see: (a) Giguere, D.; Patnam, R.;
Bellefleur, M.-A.; St-Pierre, C.; Sato, S.; Roy, R. Chem.
Commun. 2006, 2379. (b) Dorner, S.; Westermann, B.
Chem. Commun. 2005, 2852. (c) Dondoni, A.; Giovannini,
P. P.; Massi, A. Org. Lett. 2004, 6, 2929. (d) Perez-
Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.;
Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J.
A.; Isac-Garcia, J.; Santoyo-Gonzalez, F. Org. Lett. 2003, 5,
1951. (e) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.;
Wong, C.-H. J. Am. Chem. Soc. 2002, 124, 14397.
In summary, we have explored the ‘click’ chemistry of
sugar-derived alkynes and developed a tandem ‘click–
click’ approach to the synthesis of 1,4-disubstituted 1,2,3-
bistriazoles. Efforts are in progress to optimize the reac-
tion conditions and improve the yield with different cyclic
sugar-derived azido-alkynes (Figure 1) and also extend
this strategy for the synthesis of triazole-linked sugar oli-
gomers.
Synlett 2009, No. 13, 2162–2166 © Thieme Stuttgart · New York

2166
K. P. Kaliappan et al.
LETTER
(13) Cheshev, P.; Marra, A.; Dondoni, A. Org. Biomol. Chem.
2006, 4, 3225.
(14) (a) Montagnet, O. D.; Lessene, G.; Hughes, A. B.
Tetrahedron Lett. 2006, 47, 6971. (b) Angelo, N. G.; Arora,
P. S. J. Am. Chem. Soc. 2005, 127, 17134.
70.5, 64.6, 54.0, 26.1, 25.8, 24.8, 24.1; IR (KBr): 3019,
2923, 2395, 1966, 1651, 1374, 1259, 1215, 1069 cm–1;
HRMS (EI): m/z calcd for C20H26N3O3: 388.1872; found:
388.1892.
(21) (a) Kaliappan, K. P.; Ravikumar, V.; Pujari, S. A. J. Chem.
Sci. 2008, 120, 205. (b) Kaliappan, K. P.; Ravikumar, V.;
Pujari, S. A. Tetrahedron Lett. 2006, 47, 981. (c) Yadav,
J. S.; Chander, M. C.; Rao, C. S. Tetrahedron Lett. 1989, 30,
5455.
(15) (a) Marra, A.; Moni, L.; Pazzi, D.; Corallini, A.; Bridi, D.;
Dondoni, A. Org. Biomol. Chem. 2008, 6, 1396.
(b) Ornelas, C.; Aranzaes, J. R.; Salmon, L.; Astruc, D.
Chem. Eur. J. 2008, 14, 50. (c) Dondoni, A.; Marra, A.
J. Org. Chem. 2006, 71, 7546. (d) Fernandez-Megia, E.;
Correa, J.; Rodriguez-Meizoso, I.; Riguera, R.
(22) Typical procedure for the double ‘click’ reaction: To
methyl propiolate 32 (0.024 mL, 0.27 mmol) in MeCN
(1.5 mL) was added CuI (0.105 g, 0.552 mmol) and DIPEA
(0.147 mL, 0.82 mmol). The reaction mixture became a clear
solution. The azido-alkyne 31 (0.050 g, 0.27 mmol) was
added and the reaction was stirred for 1 h (reaction moni-
tored by TLC). Then, azide 6 (0.27 mmol) was added and the
reaction was stirred for 15 minutes. The reaction was
quenched by the addition of sat. aq NH4Cl (10 mL), the
organic layer was separated and the aqueous layer was
extracted with EtOAc (3 × 20 mL). After washing with brine
(20 mL), the organic layer was dried over Na2SO4 and
concentrated in vacuo to give the crude product, which was
purified by recrystallization from CH2Cl2–hexanes. The
mother liquor was purified by column chromatography
(hexanes–EtOAc, 1:1.5) to afford triazole 35 (0.050 g, 46%).
Compound 35: Rf = 0.54 (EtOAc); mp 218–220 °C; [a]20
–55.148 (c 0.38, CHCl3); 1H NMR (300 MHz, CDCl3): dD=
8.32 (s, 1 H), 7.97 (s, 1 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.33 (d,
J = 8.1 Hz, 2 H), 4.95–4.64 (m, 4 H), 3.96 (s, 3 H), 2.43 (s,
3 H), 1.51 (s, 3 H), 1.39 (s, 3 H); 13C NMR (75 MHz,
CDCl3): d = 145.8, 135.0, 130.2, 129.2, 129.1, 128.9, 128.2,
122.3, 109.3, 78.2, 72.1, 54.3, 52.2, 50.4, 26.7, 26.7, 21.1. IR
(KBr): 3135, 3019, 2953, 2400, 1714, 1545, 1450, 1436,
1372, 1357, 1334, 1239, 1216, 1174, 1123, 1110, 1073, 1047
cm–1; HRMS (EI): m/z calcd for C19H23N6O4: 399.5706;
found: 399.5701. Compound 36: Rf = 0.68 (EtOAc); mp
134–136 °C; 1H NMR (CDCl3, 400 MHz): d = 8.47 (s, 1 H),
7.63 (d, J = 8.5 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 3.99 (s,
3 H), 2.44 (s, 3 H); 13C NMR (75 MHz, CDCl3): d = 145.8,
135.0, 130.2, 121.5, 120.6, 109.3, 52.0, 21.1; IR (KBr):
3019, 2928, 2857, 1726, 1552, 1521, 1434, 1259, 1215,
1148, 1038 cm–1; HRMS (EI): m/z calcd for C11H12 N3O2:
218.0861; found: 218.0865.
Macromolecules 2006, 39, 2113.
(16) (a) Chandrasekhar, S.; Rao, C. L.; Nagesh, C.; Reddy, C. R.;
Sridhar, B. Tetrahedron Lett. 2007, 48, 5869. (b) Hotha, S.;
Anegundi, R. I.; Natu, A. A. Tetrahedron Lett. 2005, 46,
4585.
(17) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
(18) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9,
1121.
(19) (a) Lan, P.; Berta, D.; Porco, J. A.; South, M. S.; Parlow,
J. J. J. Org. Chem. 2003, 68, 9678. (b) Alvarez, S. G.;
Alvarez, M. T. Synthesis 1997, 413. (c) Smith, P. A. S.;
Brown, B. B. J. Am. Chem. Soc. 1951, 73, 2438.
(20) Typical procedure for the simple ‘click’ reaction: To a
solution of alkyne 3 (0.050 g, 0.19 mmol) and azide 5 (0.026
g, 0.19 mmol) in MeCN (1.9 mL) were added CuI (0.0746 g,
0.38 mmol) and DIPEA (0.1 mL, 0.57 mmol) successively at
r.t. After stirring for 30 min, the reaction was quenched by
adding sat. aq NH4Cl (10 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc
(3 × 20 mL). After washing with brine (20 mL), the organic
layer was dried over Na2SO4, filtered and concentrated in
vacuo to give the crude product, which was purified by
recrystallisation from CH2Cl2–hexanes. The mother liquor
was further purified by column chromatography (hexanes–
EtOAc, 1.5:1) to afford triazole 12 (0.065 g, 85%). Rf = 0.62
(EtOAc–hexanes, 1:1); mp 155–157 °C; [a]20D –83.880 (c
0.21, CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.53 (s, 1 H),
7.38–7.25 (m, 5 H), 5.59 (d, J = 11.6 Hz, 1 H), 5.57 (d,
J = 1.2 Hz, 1 H), 5.43 (d, J = 14.8 Hz, 1 H), 5.18 (d, J = 2
Hz, 1 H), 4.70 (dd, J = 8.0, 2.4 Hz, 1 H), 4.36 (dd, J = 4.8,
2.4 Hz, 1 H), 1.59 (s, 3 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.31
(s, 3 H); 13C NMR (100 MHz, CDCl3): d = 145.5, 134.5,
128.9, 128.5, 128.0, 123.0, 109.1, 108.9, 96.4, 72.5, 70.6,
Synlett 2009, No. 13, 2162–2166 © Thieme Stuttgart · New York

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