Three component, regioselective, one-pot synthesis of β-hydroxytriazoles from epoxides via 'click reactions'

Article abstract of DOI:10.1016/j.tetlet.2007.09.160

2-Azidoalcohols derived in situ from epoxides and sodium azide undergo smooth coupling with alkynes under neutral conditions by means of 'click reactions' to furnish β-hydroxytriazoles in excellent yields and with high regioselectivity. This reaction proc

Full text of DOI:10.1016/j.tetlet.2007.09.160

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Tetrahedron Letters 48 (2007) 8773–8776
Three component, regioselective, one-pot synthesis of
b-hydroxytriazoles from epoxides via ‘click reactions’
J. S. Yadav,* B. V. Subba Reddy, G. Madhusudhan Reddy and D. Narasimha Chary
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 July 2007; revised 19 September 2007; accepted 26 September 2007
Available online 29 September 2007
Abstract—2-Azidoalcohols derived in situ from epoxides and sodium azide undergo smooth coupling with alkynes under neutral
conditions by means of ‘click reactions’ to furnish b-hydroxytriazoles in excellent yields and with high regioselectivity. This reaction
proceeds smoothly in water at room temperature without the need for acid catalysis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1,2,3-Triazoles are potential targets for drug discovery
because of their wide range of biological properties such
as antibacterial, antiviral, antiepileptic, and anti-allergic
behavior.1,2 They are also used as optical brighteners,
light stabilizers, fluorescent whiteners, and corrosion
retarding agents.3 Huisgen’s thermal 1,3-dipolar cyclo-
addition of an alkyne with an azide, sometimes known
as a ‘click reaction’, is one of the most widely used meth-
ods for the synthesis of triazoles.4 The Cu(I)-catalyzed
azide–alkyne cycloaddition (CuAAC),5 one of the most
reliable ‘click reactions’,6 has enabled practical and
efficient preparation of 1,4-disubstituted-1,2,3-triazoles,
from a wide range of substrates with excellent selectivity,
which cannot be prepared via traditional Huisgen uncat-
alyzed thermal approaches.4 This powerful and reliable
Cu-catalyzed 1,3-dipolar cycloaddition has found wide-
spread applications in combinatorial chemistry for drug
discovery,7 material science,8 and bioconjugation.9,10
Since b-hydroxytriazoles have become increasingly use-
ful and important in drugs and pharmaceuticals, the
development of a simple and efficient method for their
synthesis in a single-step operation is desirable.
hols from epoxides and sodium azide. In a preliminary
experiment, styrene oxide (1) was treated with sodium
azide and phenylacetylene (2) in the presence of
10 mol % of CuSO4Æ5H2O and 20 mol % of sodium
ascorbate in water. The reaction went to completion at
room temperature and the product, b-hydroxytriazole
3a was obtained in 92% yield (Scheme 1).
Various other alkynes such as 1-octyne, 1-hexyne,
3-phenyl-1-propyne, and trimethylsilylacetylene also
reacted readily with styrene oxide and sodium azide
under these reaction conditions to produce b-hydroxy-
triazoles in high yields (Table 1, entries b–e). In the case
of styrene oxide, product 3 was obtained as a result of the
cleavage of the epoxide with sodium azide in a regioselec-
tive manner with preferential attack at the benzylic
position. Encouraged by the results obtained with
styrene oxide, we turned our attention to various other
epoxides. Cyclohexene oxide also underwent smooth
coupling with sodium azide and phenylacetylene to
produce N-cyclohexyltriazole 4h in 84% yield (Scheme 2).
In the case of cyclohexene oxide, the stereochemistry of
the ring-opened products was found to be trans from the
coupling constants of the ring hydrogens as has been
observed in most epoxide ring-opening reactions.11
Next, we examined the reactivity of aliphatic epoxides;
propylene oxide, epichlorohydrin, hexene oxide, and
3-aryloxy-1,2-epoxy propane reacted smoothly with
sodium azide and alkynes under similar reaction condi-
tions to produce the corresponding b-hydroxytriazoles 5
and 6 in good to excellent yields (entries i–n, Table 1,
Scheme 3).
In this Letter, we report an efficient approach for the
one-pot synthesis of b-hydroxytriazoles from epoxides,
sodium azide, and alkynes by way of a three-component
reaction, proceeding via the formation of 2-azidoalco-
Keywords: Epoxides; 2-Azidoalcohols; Alkynes; Click reaction;
Triazoles.
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40
27160512; e-mail: yadav@iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.160

8774
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 8773–8776
OH
O
N
CuSO4.5H2O/NaN3
N
N
Ph
+
Ph
Sodium ascorbate/H2O
1
2
3a
Scheme 1.
Table 1. One-pot synthesis of b-hydroxytriazoles from various epoxides, sodium azide and alkynes
Entry
Epoxide
Alkyne
Producta
Time (h)
4.0
Yieldb (%)
OH
N
O
a
3a
92
Ph
N
N
Ph
Ph
Ph
Ph
OH
O
N
b
3b
5.0
90
N
N
N
Ph
Me
R
R
R = n-hexyl
OH
O
N
c
d
e
f
3c
3d
3e
3f
5.5
4.5
5.0
3.5
4.5
85
93
83
91
82
N
Ph
Ph
Me
R = n-butyl
OH
O
N
Ph
N
N
N
Ph
Ph
Ph
Ph
OH
N
O
Me3Si
N
Ph
SiMe3
OH
O
N
N
Ph
N
Me
Ph
Me
OH
N
g
4g
O
N
N
Me
Ph
R = n-butyl
R
OH
N
h
4h
5i
5j
4.0
4.0
4.5
84
O
N
N
Ph
N
N
N
Me
Cl
O
N
i
92 (9:1)
75 (8:2)
Ph
Me
Cl
OH
Ph
N
N
O
j
OH
R
R = n-hexyl
Me

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 8773–8776
8775
Table 1 (continued)
Entry
Epoxide
Alkyne
Producta
Time (h)
4.0
Yieldb (%)
N
N
N
O
Cl
k
5k
5l
77 (8:2)
87 (9:1)
85 (7:3)
Ph
Cl
OH
Ph
N
N
N
O
Me
l
6.0
5.0
Ph
Me
OH
Ph
N
O
BnO
MeO
O
N
N
m
5m
BnO
OH
R R =
n
-hexyl
Me
Ph
O
O
N
n
5n
4.5
80 (7:3)
N
N
MeO
OH
Ph
a All products were characterized by 1H NMR, IR and mass spectrometry.
b Yield refer to pure products after chromatography.
OH
CuSO4.5H2O/NaN3
O
Ph
+
N
N
N
Sodium ascorbate/H2O
Ph
4h
Scheme 2.
OH
N
N
CuSO4.5H2O/NaN3
Sodium ascorbate/H2O
Me
N
N
O
+
N
N
Ph
Me
+
Me
OH
Ph
Major (5i)
Ph
Minor (6i)
Scheme 3.
The product triazoles from aliphatic epoxides were
obtained from the terminal attack of the azide nucleo-
phile. Except for the reactions of aliphatic epoxides,
which produce a minor amount of the other regioisomer,
the reactions of other epoxides were found to be highly
regioselective affording a single product in good to excel-
lent yields. The direction of ring opening is that charac-
teristically observed for terminal epoxides under SN2
conditions, and is probably dictated by steric and elec-
tronic factors. However, in the absence of either copper
sulfate or sodium ascorbate, the reaction did not give
the expected triazole even after long reaction times
(8–12 h). Both copper sulfate and sodium ascorbate
were essential for the success of the reaction. As a
solvent, water gave the best results. The reactions were
also conducted in organic solvents such as methanol
and acetonitrile, but surprisingly, they took longer time
(10–22 h in methanol) and the products were obtained in
low yields (55–67%). This is probably due to the high
solubility of sodium azide and sodium ascorbate in
water. Furthermore, the reactions were clean in water
compared to those in organic solvents. For example,
treatment of styrene oxide with sodium azide and
phenylacetylene in water for 4.0 h gave the correspond-
ing 2-hydroxytriazole in 93% yield. However, the same
reaction in refluxing methanol, after 12 h, gave the
2-hydroxytriazole in only 67% yield. The scope and
generality of this process are illustrated with respect to
various epoxides and acetylenes and the results are pre-
sented in Table 1.12
In summary, we have described a direct and efficient
protocol for the preparation of b-hydroxytriazoles via
a three component reaction of an epoxide, sodium azide
and an alkyne. In addition to its simplicity and mild
reaction conditions, this method provides a wide range
of b-hydroxytriazoles in excellent yields with high regio-
selectivity in a single step operation.
Acknowledgment
G.M.R. and D.N.C. thank CSIR, New Delhi, for the
award of fellowships.

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J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 8773–8776
G. A.; Gierlich, J.; Mofid, M. R.; Nir, H.; Tal, S.; Eichen,
References and notes
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12. Experimental procedure: To a suspension of styrene oxide
(120 mg, 0.11 mL, 1.0 mmol) and sodium azide (78 mg,
1.2 mmol) in water (3.0 mL) were added CuSO4Æ5H2O
(16.0 mg, 0.1 mmol) and sodium ascorbate (39.6 mg,
0.2 mmol). The resulting solution was stirred for 2 h at
room temperature. After complete consumption of styrene
oxide as indicated by TLC, phenylacetylene (102 mg,
0.11 mL, 1 mmol) was added to the reaction mixture and it
was stirred for another 2 h. The reaction mixture was
extracted with ethyl acetate (3 · 10 mL). The combined
organic layers were dried over anhydrous Na2SO4, and
concentrated in vacuo. The resulting residue was purified
by column chromatography (hexane/EtOAc, 3:1) to give
the 1,2,3-triazole 3a as a pale yellow solid, mp 130–132 ꢁC.
Spectral data for selected products:
Compound 3b: 2-(4-hexyl-1H-1,2,3-triazol-1-yl)-2-phenyl-
ethanol: Solid, mp 64–66 ꢁC, IR (KBr): m(max) 3384, 2925,
2856, 1631, 1455, 1377, 1219, 1067, 770, 699, 533 cmÀ1. 1H
NMR (300 MHz, CDCl3): d 7.29– 7.39 (m, 3H), 7.11–7.21
(m, 3H), 5.51 (dd, J = 8.3, 3.7 Hz, 1H), 4.50–4.60 (m, 1H),
4.04–4.16 (m, 1H), 3.35–3.44 (m, 1H), 2.66 (t, J = 7.5 Hz,
2H), 1.58–1.68 (m, 2H), 1.24–1.38 (m, 6H), 0.87 (t,
J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 148.5,
136.3, 129.0, 128.7, 127.0, 121.4, 66.8, 65.1, 35.4, 29.2,
28.8, 25.6, 22.4, 13.9. LC-MS: m/z: 274 (M+1). HRMS
calcd for C16H23N3ONa: 296.1738; found, 296.1750.
Compound
3d:
2-(4-benzyl-1H-1,2,3-triazol-1-yl)-2-
phenylethanol: Solid, mp 110–112 ꢁC; IR (KBr): m(max)
3382, 3062, 3030, 2924, 2854, 2361, 1603, 1547, 1494, 1453,
1358, 1221, 1053, 728, 699, 531 cmÀ1; 1H NMR (300 MHz,
CDCl3): d 7.11–7.34 (m, 11H), 5.49 (dd, J = 8.3, 3.0 Hz,
1H), 4.49 (dd, J = 12.0, 9.0 Hz, 1H), 3.92–4.08 (m, 4H).
13C NMR (75 MHz, CDCl3): d 156.0, 147.5, 130.2, 129.9,
128.8, 128.1, 125.6, 121.3, 114.4, 69.1, 68.9, 53.1, 20.4. LC-
MS: m/z: 280 (M+1). HRMS calcd for C17H17N3ONa:
302.1269; found, 302.1259.
6. (a) Kolb, H. C.; Sharpless, K. B. Drug Discov. 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.
Compound 4h: 2-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclo-
hexan-1-ol: Solid, mp 182–184 ꢁC; 1H NMR (200 MHz,
CDCl3): d 8.05 (s, 1H), 8.22–8.82 (m, 5H), 4.78 (d,
J = 5.8 Hz, 1H), 4.12–4.26 (m, 1H), 3.72–3.87 (m, 1H),
1.12–2.26 (m, 8H). 13C NMR (75 MHz, CDCl3): d 128.7,
127.9, 125.5, 119.6, 72.6, 67.1, 33.7, 31.5, 29.6,24.7. LC-
MS: m/z: 244 (M+1).
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.
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.
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,
Compound 5k: 3-Chloro-1-(4-phenyl-1H-1,2,3-triazol-1-
yl)propan-2-ol: Solid, mp 100–102 ꢁC; IR (KBr): m(max)
3446, 2922, 2852, 2364, 1741, 1632, 1461, 1379, 1217, 1020,
761 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.80 (s, 1H),
;
7.68–7.72 (m, 2H), 7.29–7.40 (m, 3H), 4.63–4.69 (m, 1H),
4.45–4.52 (m, 1H), 4.31–4.38 (m, 1H), 3.56–3.63 (m, 2H).
LC-MS: m/z: 238 (M+1). HRMS calcd for
C11H13N3OCl(35) (M+1): 238.0747; found, 238.0739.