Expedient synthesis of 1,2,3-triazole-fused tetracyclic compounds by intramolecular Huisgen ('click') reactions on carbohydrate-derived azido-alkynes

Article abstract of DOI:10.1016/j.tetlet.2005.05.012

An efficient, practical and convenient synthesis of 1,2,3-triazole-fused tetracyclic compounds was achieved by intramolecular 1,3-dipolar cycloaddition of carbohydrate-derived azido-alkynes.

Full text of DOI:10.1016/j.tetlet.2005.05.012

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4585–4588
Expedient synthesis of 1,2,3-triazole-fused tetracyclic
compounds by intramolecular Huisgen (‘click’) reactions
on carbohydrate-derived azido-alkynes
Srinivas Hotha,* Ramakrishna I. Anegundi and Arvind A. Natu
Combi Chem—Bio Resource Center, Division of Organic Chemistry: Synthesis, National Chemical Laboratory, Pune 411 008, India
Received 21 February 2005; revised 26 April 2005; accepted 4 May 2005
Abstract—An efficient, practical and convenient synthesis of 1,2,3-triazole-fused tetracyclic compounds was achieved by intra-
molecular 1,3-dipolar cycloaddition of carbohydrate-derived azido-alkynes.
Ó 2005 Elsevier Ltd. All rights reserved.
Several compounds of the 1,2,3-triazole class possess a
broad spectrum of biological properties including anti-
HIV,1a anti-allergic,1b anti-bacterial,1c herbicidal and
fungicidal activity.1d 1,2,3-Triazoles are synthesized by
1,3-dipolar cycloaddition of the corresponding azide
and alkyne, a procedure known as the Huisgen reac-
tion.2 Furthermore, 1,2,3-triazole formation is a highly
efficient reaction without any significant side products
and is currently referred to as a Ôclick reactionÕ.3 The sig-
nificant biological profiles of 1,2,3-triazoles coupled
with our interest in synthesizing chiral, oxygen-rich
chemical libraries prompted us to develop a synthetic
protocol that would enable the synthesis of a chiral,
fused, polycyclic 1,2,3-triazole class of compounds. To-
wards this end, we considered performing the 1,3-dipo-
lar cycloaddition reactions on carbohydrate-derived
azido-alkynes in an intramolecular fashion. In this let-
ter, we reveal an effective integration of click chemistry
onto carbohydrate substrates in order to synthesize
1,2,3-triazole-fused tetracyclic compounds in high
yields.
O
O
O
N3
N
HO
N
a,b,c
d
N
O
O
O
HO
O
O
O
O
O
3
1
2
Scheme 1. Reagents and conditions: (a) p-TsCl, py., 0 °C–rt, 10 h,
91%; (b) NaN3, DMF, 90 °C, 8 h, 95%; (c) NaH, propargyl bromide,
DMF, 0 °C–rt, 2 h, 93%; (d) toluene, 100 °C, 2 h, 95%.
p-TsCl in the presence of pyridine for 10 h at 0 °C fol-
lowed by treatment with sodium azide at 90 °C in
DMF to afford the required 5-deoxyazidoxylofurano-
side in 86% overall yield. The remaining hydroxyl group
was converted into a propargyl ether using sodium
hydride and propargyl bromide to afford the required
azido-alkyne 2.
1
In the H NMR spectrum of the azido-alkyne 2, reso-
nances corresponding to the alkyne CH were identified
at d 2.48 (t, J = 2.3 Hz) ppm and the C-5 methylene pro-
tons as a multiplet at d 3.51 ppm. The 1,3-dipolar cyclo-
addition reaction was carried out under reagent-free
conditions by heating a toluene solution of the azido-
alkyne 2 at 100 °C for 2 h.5 The resultant tetracyclic
1,2,3-triazole 3 precipitated as a white solid on cooling
to room temperature.
Carbohydrate-derived azido substrates for intramolecu-
lar click reactions were synthesized by an SN2 displace-
ment of the corresponding tosylates with NaN3 (Scheme
1). Accordingly, xylofuranosyl diol 14 was treated with
1
The H NMR spectrum of 3 revealed an olefinic proton
at d 7.49 ppm as a singlet and the anomeric proton at d
5.77 (d, J = 3.9 Hz) ppm; the high resolution NMR
spectrum proved that the 1,3-dipolar cycloaddition
had occurred in a regioselective manner. In the
Keywords: Click chemistry; Cycloaddition; Huisgen reaction; Carbo-
hydrates; Diversity oriented synthesis.
*
Corresponding author. Tel.: +91 20 25893400x2401; fax: +91 20
25893153; e-mail: shotha@ems.ncl.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.012

4586
S. Hotha et al. / Tetrahedron Letters 46 (2005) 4585–4588
HO
O
O
N
N
N
a, b
O
O
O
O
O
O
3
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, rt, 2.5 h;
(b) NaN3, DMF, 90 °C, 6 h, N2.
13C NMR spectrum, resonances characteristic of two
olefinic carbons were present at d 134.8 and 132.1 ppm
with the rest of the spectrum in complete agreement with
the assigned structure. During our studies, the forma-
tion of compound 3 was reported by Tripathi et al. start-
ing from 1,2-O-isopropylidene 3-O-allyl glucofuranose
(Scheme 2).6
Figure 1. ORTEP diagram of compound 3.
Table 1.
S. No.
Substrate
Product
Time (h)
Yield (%)
95
O
O
N
N3
H
N
N
H
O
O
O
1
2
O
O
O
2
3
O
O
O
O
O
N
N3
H
O
N
N
H
H
2
3
3.5
92
90
O
O
O
11
10
O
O
N
N
N
N3
O
O
O
2
6
O
O
12
13
OTs
OTs
H
O
O
H
H
O
H
O
N N
N
N3
4
5
6
7
8
80
78
75
87
91
O
O
O
O
5
6
TBDMSO
H
TBDMSO
H
N
H
O
O
N3
N
N
5
H
O
O
O
O
O
O
O
O
9
8
TBDMSO
TBDMSO
H
O
N3
H
O
N
N
N
H
O
5
H
O
O
O
O
14
15
OTs
H
OTs
H
O
N3
H
H
N N
N
O
O
6.5
O
O
O
O
17
16
O
OMe
OBn
N3
N
N
O
OMe
N
O
6
OBn
O
OBn
OBn
19
18

S. Hotha et al. / Tetrahedron Letters 46 (2005) 4585–4588
4587
N3
TsO
OTs
HO
HO
O
O
N
O
O
a,b
c,d
N
H
e
O
N
H
O
O
O
O
O
O
AcO
4
5
6
f
TBDMSO
HO
TBDMSO
H
TBDMSO
H
O
O
O
c,b,d
e
N
O
O
O
N3
N
N
H
O
H
O
O
O
O
AcO
7
8
9
Scheme 3. Reagents and conditions: (a) p-TsCl, py., 0 °C–rt, 15 h, 86%; (b) NaN3, DMF, 120 °C, 8 h, 92%; (c) p-TsCl, py., 100 °C, 6 h, 75%; (d) (i)
NaOMe, MeOH, rt, 0.5 h, 96%; (ii) NaH, propargyl Br, DMF, 0 °C–rt, 2 h, 87%; (e) C6H5CH3, 100 °C, 6 h; (f) TBDMSCl, im., DMF, 1 h, 84%.
This interesting observation was rationalized by assum-
ing that the initial triazoline possibly had the trans ring
fusion and was therefore oxidized by atmospheric oxy-
gen. However, the spectral data of triazole 3 derived
from propargyl ether 2 did not correlate with Tripathi
et al. data.6
formation of 1,2,3-triazole-fused tetracyclic compounds
was found to be high yielding and in most of the sub-
strates the resulting product precipitated from the reac-
tion mixture.9 Products were isolated either by filtration
from the reaction mixture for solids (3, 6, 11, 13, 17 and
19) or by conventional silica gel column chromatogra-
phy for gummy products (9 and 15).5,9
Compound 3 was crystallized by slow evaporation from
light petroleum (60–80 °C) and dichloromethane, and
was subjected to X-ray structure determination. Gratify-
ingly, the crystallographic analysis proved the structural
authenticity of the tetracyclic triazole 3 beyond any
doubt (Fig. 1).6,7 The bond lengths between C7,C8
In conclusion, we have investigated ÔclickÕ chemistry
using carbohydrates in an intramolecular fashion under
reagent-free conditions. Our further efforts will be dedi-
cated towards understanding biological profiles and
developing a diversity oriented synthetic pathway. The
results from these endeavours will be disclosed in the
future.
˚
and N17,N18 were found to be 1.363 and 1.324 A,
respectively, confirming the presence of double bonds
in the fused 1,2,3-triazole moiety.7 It is interesting to
note that the same set of reactions carried out on ara-
bino- and ribo-derived azido-alkynes 10 and 12 also
resulted in the formation of 1,2,3-triazole-fused tetra-
cyclic compounds 11 and 13. In addition, the versatility
of the current protocol was demonstrated using a range
of substrates comprising gluco-, allo-, xylo-,
ribo- and arabino- derived azido-alkynes as depicted in
Table 1.
Acknowledgements
S.H. thanks The Director, NCL and DST, New Delhi
for the financial support. We are grateful for the encour-
agement of Dr. K. N. Ganesh. We thank Dr. V. R. Ped-
diredi for helping in the crystal structure determination
and analysis. R.I.A. acknowledges the CSIR, New Del-
hi, for SRF.
We next synthesized 1,2,3-triazoles fused to hexofurano-
syl-derived seven- and eight-membered rings (Scheme 3).
Accordingly, the 3-O-acetyl derivative 4 was converted
into the azido-alkyne 5 in four steps. The primary alco-
hol of compound 48 was converted into the correspond-
ing toluene p-sulfonate using p-TsCl, reacted with NaN3
at 120 °C for 8 h and treated with p-TsCl to obtain an
azido-tosylate that was subsequently converted to the
required azido-alkyne 5. The ÔclickÕ reaction was effected
by heating a toluene solution of azido-alkyne 5 to
100 °C in toluene for 6 h to yield the triazole-fused tetra-
cyclic compound 6.7,9 In another set of reactions, the
primary hydroxyl group was protected as its tert-butyl-
dimethylsilyl ether and the secondary hydroxyl group
was converted to the azido-alkyne 8 using the aforemen-
tioned reagents and the click reaction was carried out to
provide the triazole 9.9,10
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.05.012.
References and notes
1. (a) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.;
De Clercq, E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185–4194; (b)
Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A.
J. Med. Chem. 1986, 29, 2269–2277; (c) 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.; Stper, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953–
970; (d) Wamhoff, H. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 5, pp 669–732.
These reactions were performed on the allo-series 14 and
16 to obtain triazoles 15 and 17. The glucopyranosylaz-
ido-alkyne 18 was also converted into the corresponding
tricyclic compound 19 successfully.9 In all cases, the

4588
S. Hotha et al. / Tetrahedron Letters 46 (2005) 4585–4588
2. Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984.
3. (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.
C, 52.17%; H, 5.97%; N, 16.59%. Found: C, 51.97%; H,
5.46%; N, 16.67%.
Compound 6: H NMR [CDCl3, 300 MHz]: d 1.29, 1.48
1
(2s, 6H), 2.47 (s, 3H), 4.00 (m, 1H), 4.18 (m, 1H), 4.26 (dd,
1H, J = 2.9, 8.2 Hz), 4.54 (d, 1H, J = 14.7 Hz), 4.62 (d, 1H,
J = 3.6 Hz), 4.67 (dd, 1H, J = 3.2, 12.4 Hz), 4.86 (d, 1H,
J = 14.7 Hz), 5.11 (d, 1H, J = 3.0 Hz), 5.91 (d, 1H,
J = 3.8 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.53 (s, 1H), 7.82
(d, 2H, J = 8.0 Hz); 13C NMR [CDCl3, 50 MHz]: 21.7,
26.1, 26.5, 48.2, 61.7, 69.8, 78.9, 81.3, 82.8, 104.9, 112.8,
127.8, 130.1, 133.1, 145.6; IR (cmÀ1): 1726, 1597, 1454,
1377; mp 149 °C. CHNS Anal. Calcd for C19H23N3O7S as
C, 52.16%; H, 5.30%; N, 9.61%; S, 7.33%. Found: C,
51.20%; H, 4.97%; N, 9.65%; S, 7.06%.
4. Hasegawa, A.; Kisho, M. Carbohydr. Res. 1980, 79, 265–
270.
5. General experimental protocol: A solution of azido-alkyne
2 (250 mg, 0.9 mmol) in 2 mL of toluene was heated to
100 °C for the appropriate time and cooled to room
temperature. The separated solid was filtered off and
crystallized by slow evaporation using petroleum ether
(60–80 °C) and CH2Cl2. In the cases of products 9 and 15
which did not result in a solid, the reaction mixture was
concentrated in vacuo to give a crude residue, which was
purified by passing through a pad of silica gel.
6. Tripathi, S.; Singha, K.; Achari, B.; Mandal, S. B.
Tetrahedron 2004, 60, 4959–4965.
1
Compound 9: H NMR [CDCl3, 200 MHz]: d 0.08, 0.13
(2s, 6H), 0.91 (s, 9H), 1.29, 1.48 (2s, 6H), 4.31 (d, 1H,
J = 2.1 Hz), 4.39–4.65 (m, 4H), 4.70–4.95 (m, 3H), 5.72 (d,
1H, J = 3.6 Hz), 7.61 (s, 1 H); 13C NMR [CDCl3, 75 MHz]:
d 5.4, 5.6, 18.2, 20.6, 25.6, 25.8, 26.0, 26.6, 59.2, 60.0, 72.6,
83.7, 85.0, 104.3, 111.8, 131.9, 135.1; IR (cmÀ1): 1722,
1462, 1375. CHNS Anal. Calcd for C18H31N3O5Si as C,
54.38%; H, 7.86%; N, 10.57%. Found: C, 54.16%; H,
7.48%; N, 10.33%.
7. Crystal data: C11H15N3O4, M = 253.26, orthorhombic,
space group P212121, a = 5.495(1), b = 10.054(2),
3
V = 1178.4(4) A ,
˚
˚
c = 21.330(4) A,
Z = 4,Dcalcd =
1.428 g cmÀ1, T = 298(2) K, l = 0.110 mmÀ1, F(000) =
1
˚
536, k = Mo Ka = 0.7107 A, 5138 reflections measured,
Compound 11: H NMR [CDCl3, 300 MHz]: d 1.43, 1.60
1686 unique, observed with I > 2r(I), final R1 = 0.0283,
wR2 = 0.0306. Crystallographic data has been deposited
for compound 3 with the Cambridge Crystallographic
Data Centre, [CCDC 264130]. Copies of the data can be
obtained free of charge via ww.ccdc.cam.ac.uk/conts/
retrieving.html or CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: (+44) 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk).
(2s, 6H), 3.56 (ddd, 1H, J = 10.8, 9.0, 2.9 Hz), 3.95 (dd, 1H,
J = 9.0, 4.4 Hz), 4.36 (dd, 1H, J = 13.2, 10.8 Hz), 4.51 (d,
1H, J = 14.9 Hz), 4.73 (t, 1H, J = 4.7 Hz), 5.08 (d, 1H,
J = 14.9 Hz), 5.31 (dd, 1H, J = 13.4,2.9 Hz), 5.75 (d, 1H,
J = 4.9 Hz), 7.56 (s, 1H); 13C NMR [CDCl3, 50 MHz]: d
27.8, 28.1, 52.3, 62.8, 74.6, 85.5, 93.2, 103.6, 115.79, 133.5,
136.2; IR (cmÀ1): 1521, 1215; mp 214 °C. CHNS Anal.
Calcd for C11H15N3O4 as C, 52.17%; H, 5.97%; N, 16.59%.
Found: C, 52.00%; H, 5.99%; N, 16.61%.
8. Somanthan, R.; Helberg, L. H. Org. Prep. Proced. Int.
1984, 16, 388–391.
9. See Supplementary data.
1
Compound 13: H NMR [CDCl3, 200 MHz]: d 1.34, 1.52
(2s, 6H), 3.71 (dd, 1H, J = 8.59, 4.26 Hz), 4.00 (ddd, 1H,
J = 3.33, 8.78, 11.51 Hz), 4.23 (dd, 1H, J = 10.90,
13.32 Hz), 4.54 (d, 1H, J = 15.14 Hz), 4.80 (t, 1H,
J = 4.24 Hz), 5.14 (d, 1H, J = 15.10 Hz), 5.31 (dd, 1H,
J = 2.73, 13.02 Hz), 5.82 (d, 1H, J = 3.52 Hz), 7.59 (s, 1H);
13C NMR [CDCl3, 75 MHz]: d 26.0, 26.2, 51.6, 62.9, 72.1,
78.5, 87.7, 103.4, 114.0, 133.9, 135.48; IR (cmÀ1): 1465,
1377; mp 186 °C. CHNS Anal. Calcd for C11H15N3O4 as
C, 52.17%; H, 5.97%; N, 16.59%. Found: C, 52.44%; H,
5.90%; N, 16.34%.
10. Compound characterization data for:
1
Compound 3: H NMR [CDCl3, 200 MHz]: d 1.27, 1.46
(2s, 6H), 4.22 (d, 1H, J = 2.1 Hz), 4.39 (m, 1H), 4.49 (d, 1H,
J = 3.6 Hz), 4.58 (d, 1H, J = 14.7 Hz), 4.69 (dd, 1H, J =
15.2, 2.4 Hz), 4.92 (d, 1H, J = 14.7), 5.11 (dd, 1H, J =
5.6, 15.5 Hz), 5.77 (d, 1H, J = 3.6 Hz), 7.49 (s, 1 H); 13C
NMR [CDCl3, 50 MHz]: d 26.0, 26.6, 48.00, 60.6, 74.2,
83.8, 84.4, 104.7, 111.9, 132.1, 134.8; IR (cmÀ1): 1461,
1379; mp 200 °C. CHNS Anal. Calcd for C11H15N3O4 as