One-pot sequential synthesis of β-hydroxy-1,4-disubstituted-1,2,3- triazoles from in-situ generated β-azido alcohol by click chemistry

Article abstract of DOI:10.1080/00397910802026329

β-Hydroxy 1,2,3-triazoles from in situ generated 1,2-azidols were synthesized employing two sequential click reactions in very high yields with high regioselectivity using Cu(OAc)2·H2O as a catalyst in water at ambient temperature. Copyright Taylor & Fran

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One-Pot Sequential
Synthesis of β-Hydroxy-1,4-
disubstituted-1,2,3-triazoles
from in-situ Generated β-Azido
Alcohol by Click Chemistry
K. Rajender Reddy a , C. Uma Maheswari a , K.
Rajgopal a & M. Lakshmi Kantam a
a Inorganic and Physical Chemistry Division, Indian
Institute of Chemical Technology, Hyderabad, India
Version of record first published: 18 Aug 2008.
To cite this article: K. Rajender Reddy , C. Uma Maheswari , K. Rajgopal &
M. Lakshmi Kantam (2008): One-Pot Sequential Synthesis of β-Hydroxy-1,4-
disubstituted-1,2,3-triazoles from in-situ Generated β-Azido Alcohol by Click
Chemistry, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:13, 2158-2167
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Synthetic Communications1, 38: 2158–2167, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802026329
One-Pot Sequential Synthesis of
b-Hydroxy-1,4-disubstituted-1,2,3-triazoles
from in-situ Generated b-Azido Alcohol by
Click Chemistry
K. Rajender Reddy, C. Uma Maheswari, K. Rajgopal, and
M. Lakshmi Kantam
Inorganic and Physical Chemistry Division, Indian Institute of
Chemical Technology, Hyderabad, India
Abstract: b-Hydroxy 1,2,3-triazoles from in situ generated 1,2-azidols were
synthesized employing two sequential click reactions in very high yields with
high regioselectivity using Cu(OAc)2ꢀH2O as a catalyst in water at ambient
temperature
Keywords: 1,2-Azidol; Click reaction; Cycloaddition; Epoxide; Ring opening;
1,2,3-triazole.
INTRODUCTION
Drug discovery based on natural products is usually slow, costly, and
hampered by complex synthetic routes. Such targets are easily achieved
by a set of reliable reactions known as click reactions, originally proposed
by Kolb and coworkers.[1] These reactions generate diverse molecules
through readily available building blocks with a very high selectivity,
under simple reaction conditions, in the absence of solvent or solvent that
is benign (like water). Two types of click reactions that have influenced
drug discovery are the nucleophilic ring opening of strained ring
systems[2] and 1,3-dipolar cycloaddition between terminal alkyne and
Received in India August 19, 2007
Address correspondence to Dr. K. Rajender Reddy, Inorganic and Physical
Chemistry Division, Indian Institute of Chemical Technology, Hyderabad
500 007, India. E-mail: rajender@iict.res.in; rajenderkallu@yahoo.com
2158

b-Hydroxy-1,4-disubstituted-1,2,3-triazoles
2159
an azide to generate substituted 1,2,3-triazoles.[3] The latter, which was
also known as ‘‘the cream of crop’’ of click reactions, has a wide range
of applications in agrochemicals, corrosion retardants, dyes, optical
brighteners, and pharmaceuticals.[4]
Nucleophilic ring openings, of strained rings such as epoxides, aziri-
dines, cyclic sulfates, sulfamidates, aziridinium ions, and episulfonium
ions are reliable, stereospecific, and regioselective and usually give quan-
titative yields, which make them known as ‘‘spring-loaded electrophiles.’’
This click reaction is frequently carried out using different nucleophiles
such as azides and amines, in alcohol=H2O mixture or in absence of any
solvent. The classical protocol for ring opening of oxirane with azide
to give 1,2-azido alcohol uses sodium azide as reagent and ammonium
chloride as coordinating salt in an alcohol=H2O mixture at 65–80ꢁC for
12–48 h. Fringuelli and coworkers reported this reaction in water at
different pH values and with varying metal salts. Without further addi-
tion of any coordinating salts and changing the pH of reactionꢁmedium,
trans-azidohydrin was obtained as sole product after 12 h at 30 C.[5]
The Huisgen 1,3-dipolar cycloaddition between an azide and alkyne
has rapidly gained importance for its ability to produce drug targets with
various biological importance.[6] This cycloaddition became very crucial
after the recent discovery of Cu(I)-catalyzed methodology reported
independently by Rostovtsev et al.[6c] and Tornøe et al.[7] with excellent
1,4-regioselectivity. Traditional noncatalyzed methods yield a mixture of
1,4- and 1,5-disubstituted triazoles. Cu(I)-catalyzed reactions tolerate vari-
ous functional groups, and a mechanism of the reaction was copper acet-
ylide intermediate generated by Cu(I) and terminal alkynes, which further
participates in cycloaddition process with coordinated alkyne.[8] Usually
the Cu(I) catalysts are introduced directly in the form of different Cu(I)
salts or generated in situ from Cu(II) salts with reducing agents such as
sodium ascorbate or the in situ oxidation of copper metal turnings.
RESULTS AND DISCUSSION
Organic azides are potentially explosive and difficult to handle, parti-
cularly the lower-molecular-weight ones.[9] Thus a methodology that
avoids isolation of organic azides is highly desirable. In this communi-
cation, we report a simple protocol for the synthesis of b-hydroxy
1,2,3-triazoles from in situ generated 1,2-azidol using Cu(OAc)2ꢀH2O in
water at ambient temperature (Scheme 1).
Initially the ring opening of styrene epoxide with sodium azide was
allowed to run for completion (nearly 12 h) as was monitored by thin-
layer chromatography (TLC) and gas chromatography (GC). The azidol

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K. R. Reddy et al.
Scheme 1. Protocol followed for the sythesis of b-hydroxy 1,2,3-triazoles.
thus produced was not isolated, and phenylacetylene and 10 mol% of
the CuI were added to the same reaction mixture, which resulted in the
separation of substituted triazoles as a solid within 1 h. Ring opening
of styrene epoxide usually yields a mixture of two isomers (Scheme 2),
1a being the major product. Under the present reaction condition, we
observed 1a as the sole product, as it was analyzed by GC.
We have screened different Cu(I) and Cu(II) salts for the cycloaddi-
tion of in situ generated 1,2-azidol with phenylacetylene (Scheme 3).
Among the different copper(II) salts, Cu(OAc)2ꢀH2O showed high
activity, which is comparable to that of CuI for the cycloaddition
reaction. Similar observations were found in our previous study with
the benzyl azide and terminal acetylenes.[10] As copper(II) salts are five
to six times less expensive than the corresponding copper(I) salts, further
reactions were carried out using Cu(OAc)2ꢀH2O as a catalyst.
The results for epoxide ring opening to produce 1,2-azidol and its
sequential cycloaddition with alkyne are summarized in Table 1. The azi-
dolysis step was in general carried out by reaction of epoxides (1.1 equiv)
with sodium azide (1 equiv) at room temperature for 12–14 h. The reac-
tion of phenyl acetylenes with 2-azido-2-phenyl-ethanol gave almost
quantitative yield of the corresponding triazole. Slightly lesser conversion
was observed with m- and p-methyl phenyl acetylenes ( 95 and 92%
respectively). In case of aliphatic alkynes, propargyl alcohol and homo-
propargyl alcohol gave good to moderate yield. A similar trend was also
observed for 2-phenyl-3-butyn-2-ol and 2-methyl-3-butyn-2-ol.
To investigate further diversity, ring opening of cyclohexene oxide
with azide was carried out followed by cycloaddition with various
alkynes. Here again the azidolysis step was analyzed by GC, which
Scheme 2. Possible isomers formed during ring opening of epoxide with azide.

b-Hydroxy-1,4-disubstituted-1,2,3-triazoles
2161
Scheme 3. Screening of various copper salts for the formation of b-hydroxy
1,2,3-triazoles.
provided trans azidol exclusively. Trans 2-azido-cyclohexanol with
various substituted phenyl acetylene derivatives gave excellent yields
(93–96%) of cycloaddition product. Aliphatic alkynes such as
2-phenyl-3-butyn-2-ol and 2-methyl-3-butyn-2-ol provided 88 and 76%
respectively of cycloaddition products.
Irrespective of the nature of alkynes and azidol, 1,4-regioselectivity was
observed in all reactions. We could observe a very low formation of the final
product, when we attempted to do a single-pot reaction by taking styrene
epoxide, sodium azide, phenyl acetylene, and copper acetate together.
This could be because of the formation of copper-azide complex.
Recently Wong and coworkers have shown that 1,2,3-triazole is an
effective replacement for a peptide group in HIV-1 protease inhibitors,
which has a b-hydroxy 1,2,3-triazole unit.[11]
GENERAL PROCEDURE FOR THE SYNTHESIS OF A–M
To a stirred solution of epoxide (1.1 mmol) in water (3 ml), sodium azide
(1 mmol) was added at room temperature and was allowed to run over-
night (12–14 h). The completion of the reaction was monitored by TLC
and GC, after which 1.0 mmol of alkyne was added followed by 10 mol%
copper catalyst. The completion of the reaction can be easily observed by
the separation of product as solid, which was extracted with ethyl acetate
(3 ꢂ 5 ml). Then the solvent was evaporatedunder reduced pressure, and

2162
K. R. Reddy et al.
Table 1. Synthesis of b-hydroxy 1,2,3-triazoles from in situ generated 1,2-azidol
with epoxide and terminal alkynesa
S. no.
1
Epoxide
Alkyne
Time (h)
0.5
Product
Yieldb (%)
98.8
2
3
1.0
1.0
92.0
95.0
4
1.0
92.0
5
6
3.0
1.0
80.0
99.0
7
8
2.0
1.0
96.0
93.0
9
1.5
96.0
(Continued)

b-Hydroxy-1,4-disubstituted-1,2,3-triazoles
2163
Table 1. Continued
S. no.
10
Epoxide
Alkyne
Time (h)
1.5
Product
Yieldb (%)
95.0
11
2.0
88.0
12
13
1.0
2.0
76.0
83.0
aReaction conditions: Epoxide (1.1 mmol) and sodium azide (1.0 mmol) were
stirred in 3 ml of H2O for 12–14 h and the mixture was respective alkynes and
10 mol% of Cu(OAc)2ꢀH2O were added, stirred at room temperature.
bNMR yields with respect to the corresponding azido-alcohol.
the residue was purified through recrystallization. The product thus
obtained was characterized by 1H NMR and confirmed by mass
spectral data.
2-Phenyl-2-(4-phenyl-[1,2,3]triazol-1-yl)-ethanol (a)
White crystals; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 4.05–4.2 (m, 1H),
4.3–4.5 (m, 1H), 4.95–5.1 (t, J ¼ 5.5Hz, 1H), 5.8 (dd, J ¼ 3.9, 7.8 Hz,
1H), 7.3–7.45 (m, 8H), 7.8 (d, J ¼ 8.6 Hz, 2H), 8.2 (s, 1H); expected mole-
cular weight ¼ 233; observed molecular weight by ESI-MS ¼ 234 (M þ 1).
2-Phenyl-2-(4-p-tolyl-[1,2,3]triazol-1-yl)-ethanol (b)
1
White solid; H NMR (CDCl3 þ DMSO-d6): d ¼ 1.3 (s, 1H), 2.4 (s, 3H),
4.1–4.3 (dd, J ¼ 3.5, 12.2 Hz, 1H), 4.65 (dd, J ¼ 8.9,12.2 Hz, 1H), 5.65
(dd, J ¼ 4.3 8.7 Hz, 1H), 7.1–7.4 (m, 7H), 7.6 (m, 3H); expected molecular
weight ¼ 233. Observed molecular weight by ESI-MS ¼ 234 (M þ 1).

2164
K. R. Reddy et al.
2-Phenyl-2-(4-m-tolyl-[1,2,3]triazol-1-yl)-ethanol (c)
White solid; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 4.1 (m, 1H), 4.35
(m, 1H), 5.1 (t, J ¼ 5.5 Hz, 1H); 5.75 (dd, J ¼ 4.4, 8.8 Hz, 1H),. 7.1
(d, J ¼ 7.3 Hz, 1H), 7.25–7.35 (m, 5H), 7.6 (m, 2H), 7.8 (s, 1H), 8.3
(s, 1H); expected molecular weight ¼ 233; observed molecular weight
by ESI-MS ¼ 234 (M þ 1).
2-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2-phenyl-ethanol (d)
1
Yellow solid; H NMR (CDCl3 þ DMSO-d6): d ¼ 4.1 (broad, 1H), 4.35
(b, 1H); 4.7 (s, 2H); 4.8 (b, 1H), 5.0 (t, J ¼ 5.5 Hz, 1H), 5.7 (dd,
J ¼ 4.7, 8.6 Hz, 1H), 7.3 (s, 5H), 7.8 (s, 1H); expected molecular
weight ¼ 219; observed molecular weight by ESI-MS ¼ 220 (M þ 1).
2-[4-(2-Hydroxy-ethyl)-[1,2,3]triazol-1-yl]-2-phenyl-ethanol (e)
1
White solid; H NMR (CDCl3 þ DMSO-d6): d ¼ 2.8–2.9 (t, J ¼ 6.8 Hz,
2H), 3.7–3.8 (m, 2H), 4.0–4.1 (m, 1H), 4.25–4.4 (broad, 2H), 5.0
(t, J ¼ 6.0 Hz, 1H), 5.7 (dd, J ¼ 5.3, 9.0 Hz, 1H), 7.3 (s, 5H), 7.8
(s, 1H); expected molecular weight ¼ 233. observed molecular weight
by ESI-MS ¼ 234 (M þ 1).
1-[1-(2-Hydroxy-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-1-phenyl-ethanol (f)
White crystals; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 2.5 (s, 1H), 3.1
(s, 3H), 4.7–5.0 (b, 1H), 5.3 (m, 1H), 5.7 (m, 1H), 6.8 (m, 1H), 8.4–8.6
(m, 10H), 8.7 (d, 1H, J ¼ 7.0 Hz); expected molecular weight ¼ 311;
observed molecular weight by ESI-MS ¼ 310.
2-[1-(2-Hydroxy-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-propan-2-ol (g)
Pale white solid; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 1.6 (s, 6H), 4.0 (m,
1H), 4.3–4.4 (m, 1H), 4.5 (broad, 1H), 4.9 (broad, 1H), 5.65 (dd, J ¼ 4.5,
8.3 Hz, 1H), 7.3 (s, 5H), 7.7 (s, 1H); expected molecular weight ¼ 247;
observed molecular weight by ESI-MS ¼ 248 (M þ 1).
2-(4-Phenyl-[1,2,3]triazol-1-yl)-cyclohexanol (h)
1
Yellow crystals; H NMR (CDCl3 þ DMSO-d6): d ¼ 1.8–2.1 (m, 5H);
3.8 (broad, 1H); 4.2 (broad, 1H), 4.7 (d, J ¼ 5.1 Hz, 1H), 7.85

b-Hydroxy-1,4-disubstituted-1,2,3-triazoles
2165
(d, 2H, J ¼ 7.5 Hz), 7.2–7.5 (m, 3H), 8.1 (s, 1H); expected molecular
weight ¼ 243; observed molecular weight by ESI-MS ¼ 244 (M þ 1).
2-(4-p-Tolyl-[1,2,3]triazol-1-yl)-cyclohexanol (i)
1H NMR (CDCl3 þ DMSO-d6): white crystals d ¼ 1.4–1.5 (s, 3H); 1.8–
2.3 (m, 8H); 3.8 (broad, 1H); 4.2 (broad, 1H); 4.7 (d, J ¼ 5.2 Hz, 1H);
7.15 (d, J ¼ 8.1 Hz, 2H); 7.65 (d, J ¼ 8.1 Hz, 2H); 7.9 (s, 1H); expected
molecular weight ¼ 257; observed molecular weight by ESI-MS ¼ 258
(M þ 1).
2-(4-m-Tolyl-[1,2,3]triazol-1-yl)-cyclohexanol (j)
White solid; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 1.2 (s, 3H); 1.8–2.4
(m, 8H); 2.6 (broad, 1H); 3.7–3.9 (broad, 1H), 4.1–4.3 (m, 1H), 4.8
(d, J ¼ 6.3 Hz, 1H), 7.1 (d, J ¼ 7.0, 1H), 7.3 (t, J ¼ 7.8 Hz, 1H), 7.65
(t, J ¼ 7.8 Hz , 3H); expected molecular weight ¼ 257; observed mole-
cular weight by ESI-MS ¼ 258 (M þ 1).
2-[4-(1-Hydroxy-1-phenyl-ethyl)-[1,2,3]triazol-1-yl]-cyclohexanol (k)
White solid; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 1.5 (s, 3H), 1.8–2.2
(m, 8H), 3.6 (broad, 1H), 4.1 (m, 1H), 4.7 (s, 1H), 5.4 (s, 1H), 7.1–7.3
(m, 3H), 7.5–7.6 (m, 3H); expected molecular weight ¼ 287; observed
molecular weight by ESI-MS ¼ 288 (M þ 1)
2-[4-(1-Hydroxy-1-methyl-ethyl)-[1,2,3]triazol-1-yl] cyclohexanol (l)
1
White crystals; H NMR (CDCl3 þ DMSO-d6): d ¼ 1.2 (s, 3H), 1.3–1.5
(broad, 4H), 1.75–2.0 (broad, 4H), 3.0 (s, 6H), 3.8 (broad, 1H), 4.1
(m, 1H), 4.45 (broad, 1H), 4.6 (s, 1H), 7.6 (s, 1H); expected molecular
weight ¼ 225; observed molecular weight by ESI-MS ¼ 226 (M þ 1).
3-Phenoxy-2-(4-phenyl-[1,2,3]triazol-1-yl)-propan-1-ol (m)
White crystals; 1H NMR (CDCl3 þ DMSO-d6): d ¼ 4.3–4.5 (b, 2H),
4.5 (dd, J ¼ 7.8, 13.9 Hz, 1H), 4.75 (dd, J ¼ 3.5, 13.9 Hz, 1H), 5.4–5.5
(d, J ¼ 4.4 Hz, 1H), 6.9–7.0 (m, 4H), 7.2–7.4 (m, 4H), 7.8 (d, J ¼ 7.8
Hz, 2H), 8.12 (s, 1H); expected molecular weight ¼ 295; observed
molecular weight by ESI-MS ¼ 296 (M þ 1).

2166
K. R. Reddy et al.
CONCLUSION
In conclusion, we have developed a simple protocol for the synthesis of
b-hydroxy 1,4-disubstituted 1,2,3-triazoles by applying two ‘‘clicks’’
sequentially in a single pot and in an environmentally benign solvent
water with copper(II) acetate as catalyst. The reaction was carried out
under ambient conditions to provide the products with high regio-
selectivity and in most cases with near quantitative yields.
ACKNOWLEDGMENT
We thank the Council for Scientific and Industrial Research (CSIR) for
financial support under the Task Force Project CMM-0006. C. U. M.
and K. R. thank the CSIR and University Grants Commission (UGC)
respectively for the awards of fellowships.
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