A tandem Ferrier and Click reaction: a facile synthesis of triazolyl-2,3-dideoxypyranosides

Article abstract of DOI:10.1016/j.tetlet.2008.02.052

Glycosyl azides, prepared in situ from glucal and trimethylsilyl azide via Ferrier rearrangement, undergo smooth coupling with alkynes under neutral conditions by means of 'Click reactions' to furnish 1,2,3-triazole-linked glycoconjugates in high yields a

Full text of DOI:10.1016/j.tetlet.2008.02.052

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2649–2652
A tandem Ferrier and Click reaction: a facile synthesis
of triazolyl-2,3-dideoxypyranosides
J. S. Yadav *, B. V. Subba Reddy, D. Narasimha Chary, Ch. Suresh Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 December 2007; revised 8 February 2008; accepted 11 February 2008
Available online 13 February 2008
Abstract
Glycosyl azides, prepared in situ from glucal and trimethylsilyl azide via Ferrier rearrangement, undergo smooth coupling with
alkynes under neutral conditions by means of ‘Click reactions’ to furnish 1,2,3-triazole-linked glycoconjugates in high yields and with
moderate stereoselectivity. The method provides a convenient route to prepare glycoconjugates from glucals, trimethylsilyl azide, and
alkynes via a three component reaction.
Ó 2008 Published by Elsevier Ltd.
Keywords: Glucal; Glycoconjugates; Alkynes; Click reaction; Triazoles
1,2,3-Triazoles are potential targets for drug discovery
as they exhibit a broad spectrum of biological properties
such as antiviral, antibacterial, antiepileptic, and antialler-
gic behavior.1,2 They have also found applications as opti-
cal brighteners, light stabilizers, fluorescent whiteners, and
corrosion-retarding agents.3 The classical method for the
preparation of 1,2,3-triazoles is the Huisgen reaction.4
However, this uncatalyzed cycloaddition results in prod-
ucts with poor regioselectivity and low yields. The Cu(I)-
catalyzed azide–alkyne cycloaddition (CuAAC),5 one of
the most reliable Click reactions,6 has enabled the practical
and efficient preparation of 1,4-disubstituted-1,2,3-tri-
azoles, from a wide range of substrates with excellent selec-
tivity, which cannot be attained with the traditional
Huisgen uncatalyzed thermal approaches.4 This powerful
and reliable Cu-catalyzed 1,3-dipolar cycloaddition has
found widespread applications in combinatorial chemistry
for drug discovery,7 material science,8 and bioconjuga-
tion.9,10 Since triazole-linked glycoconjugates have become
increasingly useful and important in glycobiology, the
development of a simple and efficient method for their syn-
thesis in a single-step operation is desirable.
In this Letter, we report a direct one-pot method for the
synthesis of triazole-linked glycoconjugates from readily
available D-glucals, TMS azide, and alkynes involving a
tandem Ferrier and Click reaction.11 In a preliminary
study, 3,4,6-tri-O-acetyl-D-glucal (1) was treated with tri-
methylsilyl azide and phenylacetylene (2) in the presence
of 5 mol % of Cu(OTf)2 and 10 mol % of metallic copper
in acetonitrile (Scheme 1).
The reaction proceeded smoothly at room temperature
and the product, 1,2,3-triazole-linked glycoside was
obtained in 85% yield as a mixture of a-3a and b-4a
N
N
N
Ph
O
AcO
AcO
3a
Cu(OTf)2/TMSN3
Cu, CH3CN, r.t.
O
AcO
AcO
Ph
N
+
+
N
N
Ph
O
AcO
AcO
OAc
1
2
*
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
4a
E-mail addresses: yadavpub@iict.res.in, yadav@iict.res.in (J. S.
Scheme 1. Reaction of glucal, TMSN3, and phenylacetylene.
Yadav).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.052

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J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2649–2652
Table 1
Synthesis of triazole-linked glycosides via the Ferrier and Click reactions
Entry
Glucal
Alkyne
Productsa
Time (h)
4.5
Yieldb (%)
85
a:b
N
N
N
N
O
N
N
N
N
AcO
AcO
Ph
Ph
O
O
O
a
3:2
Ph
AcO
AcO
AcO
AcO
OAc
O
N
N
N
N
AcO
AcO
O
O
O
O
b
c
d
e
f
5.0
5.0
4.5
4.5
5.5
80
70
75
85
80
4:1
7:3
7:3
3:2
9:1
AcO
AcO
AcO
AcO
OAc
O
N
N
N
N
N
N
N
N
N
N
AcO
AcO
CH2OTHP
CH2OTHP
O
O
O
AcO
AcO
AcO
AcO
OTHP
OAc
O
N
N
N
N
AcO
AcO
AcO
AcO
AcO
AcO
Ph
Ph
Ph
Ph
Ph
OAc
O
N
N
N
N
BnO
BnO
Ph
BnO
BnO
BnO
BnO
OBn
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
BnO
BnO
O
O
O
O
O
O
O
O
O
O
BnO
BnO
BnO
BnO
OBn
O
N
N
N
N
BnO
BnO
g
h
i
6.0
5.5
4.5
5.0
6.0
6.5
6.5
80
70
80
75
70
65
65
4:1
3:2
3:2
4:1
7:3
4:1
7:3
BnO
BnO
BnO
BnO
OBn
O
N
N
N
N
BnO
BnO
BnO
BnO
BnO
BnO
Ph
Ph
Ph
Ph
Ph
OBn
O
N
N
N
N
MeO
MeO
Ph
MeO
MeO
MeO
MeO
OMe
O
N
N
N
N
MeO
MeO
j
MeO
MeO
MeO
MeO
OMe
O
N
N
N
N
N
N
TBSO
TBSO
Ph
Ph
O
O
k
l
Ph
TBSO
TBSO
TBSO
TBSO
OTBS
O
N
N
N
N
N
N
TBSO
TBSO
O
O
O
TBSO
TBSO
TBSO
TBSO
OTBS
O
N
N
N
N
N
N
O
Ph
Ph
O
m
Ph
O
O
O
O
O
O
a
All the products were characterized by NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
b

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2649–2652
2651
Cu(OTf)2
O
O
N3
O
N3
RO
RO
RO
RO
RO
TMSN3
+
+
CH3CN, r.t.
RO
OR
R'
N
Cu(0)
N
N
N
N
R'
R'
O
N
O
RO
RO
RO
+
RO
Scheme 2. Formation of 1,2,3-triazole-linked 2,3-dideoxy-pyranoside.
Table 2
The effect of various solvents on the preparation of 3a/4aa
stable triazole linkage between carbohydrates and other
functional groups and can be used as a new strategy for
the bioconjugation of carbohydrates.
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
a
CH3CN
CH2Cl2
CH3NO2
Toluene
THF
4.5
5.0
6.0
8.0
6.0
85
80
72
60
65
Acknowledgment
D.N.C. thanks UGC, New Delhi, for the award of
fellowship.
The ratio of 3a/4a was 3:2.
Isolated yield after chromatography.
b
References and notes
isomers in a 3:2 ratio favoring the a-isomer 3a. Stereo-
isomers 3a and 4a could be easily separated by column
chromatography. This result provided the incentive for
further study with various other alkynes such as 1-octyne,
1-hexyne, 4-phenyl-1-butyne, and a propargyl ether. These
alkynes readily reacted with glycosyl azides under identical
conditions to produce triazole-linked glycosides in high
yields (Table 1, entries b–m).
Other glucal derivatives such as 3,4,6-tri-O-methyl,
3,4,6-tri-O-benzyl, 3,4,6-tri-O-TBS, and 3,4,6-tri-O-allyl-
D-glucal also underwent smooth coupling with trimethyl-
silyl azide and alkynes to produce 1,2,3-triazole-linked
2,3-dideoxypyranosides in good yields. This method toler-
ates highly acid labile protecting groups such as THP and
TBDMS ethers. However, in the absence of either copper
triflate or copper(0), the reaction did not give the expected
triazole even after long reaction times (8–12 h). Both cop-
per triflate and copper metal are essential for the success
of the reaction. As solvent, acetonitrile gives the best
results. The scope and generality of this process is illus-
trated in Table 1.12 The reaction may proceed via Ferrier
rearrangement followed by [3+2] cycloaddition as depicted
in Scheme 2.
The effects of various solvents were studied for the prep-
aration of 3a and 4a and comparative results are presented
in Table 2. No significant change in the ratio of products
was observed in different solvents.
In conclusion, we have developed a direct one-pot glyco-
sylation method for the synthesis of 1,2,3-triazole-linked
glycoconjugates. By executing several reaction steps in a
single step and purifying only at the final stage, this proce-
dure avoids the isolation of the azide intermediate, which
significantly reduces the reaction time and improves the
overall yield. This method provides an easy access to a
1. (a) Wamhoff, H. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, p 669; (b)
Im, C.; Maiti, S. N.; Micetich, R. G.; Daneshtalab, M.; Atchison, K.;
Phillips, O. A. J. Antibiot. 1994, 47, 1030–1040; (c) Velazquez, S.;
Alvarez, R.; Perez, C.; Gago, F.; De, C.; Balzarini, J.; Camaraza, M.
J. Antivir. Chem. Chemother. 1998, 9, 481–489.
2. (a) Fan, W. Q.; Katritzky, A. R. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier Science: Oxford, 1996; Vol. 4, pp 1–126; (b) Genin, M. J.;
Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.;
Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko,
G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med.
Chem. 2000, 43, 953–970.
3. Gouault, N.; Cupif, J. F.; Sauleau, A.; David, M. Tetrahedron Lett.
2000, 41, 7293–7297.
4. (a) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565–598; (b) Huisgen,
R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; pp 1–176; (c) Padwa, A. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 4, pp
1069–1109.
5. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021; (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V.
V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599; (c)
Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064.
6. (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–
1137; (b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51–68.
7. (a) Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.; Moore, M.;
Neidle, S.; Moses, J. E. J. Am. Chem. Soc. 2006, 128, 15972–15973;
(b) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless,
K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588–9589.
8. (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V.
Angew. Chem., Int. Ed. 2004, 43, 3928–3932; (b) Wu, P.; Malkoch,
M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn, M. G.; Fokin, V.
V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun. 2005, 5775–5777;
(c) Rozkiewicz, D. I.; Janczewski, D.; Verboom, W.; Ravoo, B. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. 2006, 45, 5292–5296.

2652
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2649–2652
20
9. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192–3193.
112–114 °C. ½aꢁD ꢂ29.6 (c 0.8, chloroform). IR (KBr): mmax 3465,
3136, 2927, 2855, 1743, 1655, 1455, 1371, 1234, 1097, 1037, 975,
.
764 cmꢂ1 1H NMR (300 MHz, CDCl3): d 7.93 (s, 1H), 7.78–7.87
(m, 2H), 7.22–7.47 (m, 3H), 6.20–6.38 (m, 3H), 5.38–5.46 (m, 1H),
3.89–4.28 (m, 3H), 2.12 (s, 3H), 2.06 (s, 3H).
Compound 3f: (2R,5S,6R)-5-(benzyloxy)-6-[(benzyloxy)methyl]-5,6-
10. (a) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc.
2003, 125, 4686–4687; (b) Speers, A. E.; Cravatt, B. F. Chem. Biol.
2004, 11, 535–546; (c) Burley, G. A.; Gierlich, J.; Mofid, M. R.; Nir,
H.; Tal, S.; Eichen, Y.; Carell, T. J. Am. Chem. Soc. 2006, 128, 1398–
1399.
27
dihydro-2H-2-pyranyl-4-butyl-1H-1,2,3-triazole: Liquid, ½aꢁD 169 (c
11. (a) Ferrier, R. J.; Prasad, N. J. J. Chem. Soc. C 1969, 570–572; (b)
Ferrier, R. J. Adv. Carbohydr. Chem. Biochem. 1969, 24, 199–266; (c)
Fraser-Reid, B. Acc. Chem. Res. 1985, 18, 347–354; (d) Yadav, J. S.;
Reddy, B. V. S.; Chand, P. K. Tetrahedron Lett. 2001, 42, 4057–4059.
12. Experimental procedure: A mixture of glucal triacetate (0.5 mmol),
TMSN3 (0.6 mmol), and Cu(OTf)2 (5 mol %) in acetonitrile (2 mL)
was stirred at room temperature for 2 h. Then phenyl acetylene
(0.55 mmol) and Cu powder (10 mol %) were added and the resulting
mixture was stirred at room temperature for 2.5 h. After the
completion of the reaction, as monitored by TLC, the product was
extracted with ethyl acetate (3 ꢀ 10 mL) and dried over anhydrous
Na2SO4. Removal of the solvent in vacuo, followed by purification on
silica gel using hexane–ethyl acetate (4:1) afforded the pure 1,2,3-
triazole. Spectral data for selected products:
0.75, chloroform); IR (KBr): mmax 3064, 3031, 2924, 2856, 1725, 1652,
1454, 1364, 1256, 1114, 1046, 744, 699 cmꢂ1 1H NMR (300 MHz,
.
CDCl3): d 6.96–7.39 (m, 10H), 6.67 (d, J = 6.0 Hz, 1H), 5.47 (t,
J = 5.2 Hz, 1H), 4.82–4.94 (m, 1H), 4.44–4.67 (m, 3H), 3.97–4.14 (m,
2H), 3.70 (d, J = 3.0 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 1.60–1.73 (m,
2H), 1.26–1.47 (m, 2H), 0.88–1.02 (m, 5H). 13C NMR (75 MHz,
CDCl3): d 147.6, 146.4, 132.9, 128.4, 128.4, 127.9, 127.8, 127.7, 120.5,
119.9, 95.5, 73.6, 73.2, 72.1, 71.8, 68.4, 52.2, 31.4, 25.3, 22.3, 13.7. LC–
MS: m/z: 456 (M+Na). HRMS calcd for C26H31N3O3Na (M+Na+):
456.2263; found, 456.2265.
Compound 3i: 1-[(2S,5S,6R)-5-methoxy-6-(methoxymethyl)-5,6-di-
hydro-2H-2-pyranyl]-4-phenyl-1H-1,2,3-triazole: Solid; mp 102–
27
104 °C. ½aꢁD 198 (c 0.5, chloroform); IR (KBr): mmax 3421, 2923,
2853, 1726, 1652, 1460, 1215, 1091, 1043, 761 cmꢂ1 1H NMR
.
Compound 3a: (2R,3S,6S)-2-[(acetyloxy)methyl]-6-(4-phenyl-1H-
1,2,3-triazol-1-yl)-3,6-dihydro-2H-3-pyranyl acetate: Solid; mp 104–
(300 MHz, CDCl3): d 7.79–7.86 (m, 3H), 7.24–7.43 (m, 3H), 6.55–6.59
(m, 1H), 5.27–5.32 (m, 2H), 4.80–4.84 (m, 1H), 3.63–3.99 (m, 3H),
3.42 (s, 3H), 3.15 (s, 3H). 13C NMR (75 MHz, CDCl3): d 148.0, 128.7,
127.9, 128.2, 125.8, 125.5, 119.4, 95.2, 74.1, 72.9, 70.6, 59.4, 57.9. LC–
MS: m/z: 324 (M+Na). HRMS calcd for C16H19N3O3Na (M+Na+):
324.1324; found, 324.1327.
27
106 °C, ½aꢁD 210 (c 0.7, chloroform); IR (KBr): mmax 3452, 3136, 2925,
2854, 1745, 1652, 1458, 1370, 1227, 1076, 1048, 892, 768 cmꢂ1 1H
.
NMR (300 MHz, CDCl3): d 7.76–7.90 (m, 3H), 7.19–7.51 (m, 3H),
6.80 (d, J = 6.0 Hz, 1H), 5.60 (t, J = 5.2 Hz, 1H), 5.23 (dd, J = 5.2,
6.5 Hz, 1H), 5.09 (t, J = 5.2 Hz, 1H), 4.09–4.35 (m, 3H), 2.05 (s, 3H),
2.04 (s, 3H). 13C NMR (75 MHz, CDCl3): d 170.3, 169.6, 148.2, 128.8,
128.2, 125.6, 119.5, 95.2, 70.2, 66.5, 61.7, 52.1, 29.6, 20.5. LC–MS:
m/z: 380 (M+Na). HRMS calcd for C18H19N3O5Na (M+Na+):
380.1222; found, 380.1215.
Compound 4i: [(2R,5S,6R)-5-methoxy-6-(methoxymethyl)-5,6-di-
hydro-2H-2-pyranyl]-4-phenyl-1H-1,2,3-triazole: Solid; mp 108–
20
110 °C. ½aꢁD ꢂ13.4 (c 0.5, chloroform); IR (KBr): mmax: 3447, 2923,
2852, 1650, 1460, 1243, 1112, 1046, 765 cmꢂ1 1H NMR (300 MHz,
.
CDCl3): d 7.93 (s, 1H), 7.75–7.86 (m, 2H), 7.19–7.45 (m, 3H), 6.70
(dd, J = 1.5, 5.2 Hz, 1H), 5.51–5.57 (m, 2H), 4.93–4.98 (m, 1H), 3.81–
4.05 (m, 3H), 3.52 (s, 3H), 3.41 (s, 3H).
Compound 4a: (2R,3S,6R)-2-[(acetyloxy)methyl]-6-(4-phenyl-1H-
1,2,3-triazol-1-yl)-3,6-dihydro-2H-3-pyranyl acetate: Solid; mp