Cu(OTf)2/Cu-catalyzed four-component reaction: a facile synthesis of α-alkoxytriazoles via click chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.08.027

Aldehyde, alcohol, azide, and alkyne undergo smooth coupling by means of acetal formation, azidation, and a subsequent 'click reaction' in the presence of copper(II) triflate and copper metal in acetonitrile to furnish α-alkoxy-1,2,3-triazoles in good yie

Full text of DOI:10.1016/j.tetlet.2009.08.027

Tetrahedron Letters 50 (2009) 6029–6031
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(OTf)2/Cu-catalyzed four-component reaction: a facile synthesis
of
a
-alkoxytriazoles via click chemistry
*
J. S. Yadav , B. V. Subba Reddy, G. Madhusudhan Reddy, S. Rehana Anjum
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Aldehyde, alcohol, azide, and alkyne undergo smooth coupling by means of acetal formation, azidation,
and a subsequent ‘click reaction’ in the presence of copper(II) triflate and copper metal in acetonitrile
Received 13 July 2009
Revised 13 August 2009
Accepted 15 August 2009
Available online 20 August 2009
to furnish
a wide range of triazoles in a one-pot operation via a four-component reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
a-alkoxy-1,2,3-triazoles in good yields. The method provides a convenient route to prepare
Keywords:
Click reactions
Hemi-acetal formation
Azidation
a-Alkoxytriazoles
The multi-component reactions are highly important because of
In this Letter, we report a multi-component, one-pot approach
for the synthesis of -alkoxytriazoles from aldehydes, alcohols,
their wide range of applications in pharmaceutical chemistry for
the production of the diversified structural scaffolds and combina-
torial libraries for drug discovery.1 MCRs are extremely convergent,
producing a remarkably high increase of molecular complexity in
just one step.2 Among MCRs, those based on the peculiar reactivity
of isocyanides, such as the Doemling and Ugi3 and the Passerini
reactions,4 have been the most widely used, also in an industrial
context.5 1,2,3-triazoles are potential targets for drug discovery be-
cause of their wide range of biological properties such as anti-bac-
terial, anti-viral, anti-epileptic, and anti-allergic behavior.6,7
Huisgen’s thermal 1,3-dipolar cycloaddition of an alkyne with an
azide, some times known as a ‘click reaction’, is one of the most
widely used methods for the synthesis of triazoles.8 However, this
uncatalyzed cycloaddition results in products with poor regiose-
lectivity and low yields. Subsequently, Cu(I)-catalyzed azide–al-
kyne cycloadditions (CuAACs), have been reported for the
preparation of 1,4-disubstituted-1,2,3-triazoles from a wide range
of substrates with excellent selectivity.9,10 This powerful and reli-
able Cu(I)-catalyzed 1,3-dipolar cycloaddition has found wide-
spread applications in combinatorial chemistry for drug
discovery,11 material science,12 and bioconjugation.13 Since 1,2,3-
triazoles have become increasingly useful and important in drugs
and pharmaceuticals,14 the development of a simple and conve-
nient method for their synthesis in a single step operation is
desirable.
a
azides, and alkynes via a four-component reaction, proceeding
via the formation of hemi-acetal followed by azidation and then
‘click reaction.’ In a preliminary study, n-hexanal (1) was treated
with benzyl alcohol, trimethylsilyl azide, and phenylacetylene (2)
in the presence of 5 mol % of Cu(OTf)2 and 1 equiv of metallic cop-
per in acetonitrile (Scheme 1).
The reaction proceeded smoothly at room temperature and the
product, 1-[1-(benzyloxy)hexyl]-4-phenyl-1H-1,2,3-triazole 5a
was obtained in 75% yield. This result provided the incentive for
further study with various other alkynes such as 1-octyne, 1-hep-
tyne, 3,3-dimethyl-1-butyne, and 4-ethynylbiphenyl. These
alkynes reacted readily with azides generated in situ from hemi-
acetals under similar conditions to produce
a-alkoxy-1,2,3-tria-
zoles in good yields (Table 1, entries b–l). Other aldehydes such
as propanaldehyde, 2-phenylacetaldehyde, 3-phenylpropanalde-
hyde, and n-butaraldehyde also underwent smooth coupling with
various alcohols, trimethylsilyl azide, and alkynes to produce a
range of a-alkoxy-1,2,3-triazoles in good yields.
A variety of alcohols such as benzylic, allylic, and primary and
cyclic secondary alcohols were reacted effectively in this reaction.
Cu(OTf)2
O
O
HO
Ph
2
4
Cu, CH3CN, rt
1
H
+
N
N
Ph
TMSN3
N
3
Ph
5a
* Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512.
E-mail addresses: yadav@iict.res.in, yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Preparation of
a-alkoxytriazole 5a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.027

6030
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 6029–6031
Table 1
Synthesis of a-alkoxytriazoles via the four-component reaction
Entry
Aldehyde
Alcohol
Alkyne
Producta
Time (h)
10
Yield (%)b
O
R
Ph
5a
5b
N
a
R=n-butyl
75
CHO
Ph
Ph OH
N
N
Ph
O
Ph
N
b
12
80
CHO
Ph OH
N
R=n-hexyl
N
R
O
Ph
N
OH
OH
c
14
13
75
80
5c
Ph CHO
N
N
R=n-pentyl
R
Ph
O
5d
CHO
N
d
Ph
Ph
N
N
Ph
O
Ph
Ph
OH
N
e
f
12
12
13
75
80
75
Ph CHO
5e
N
N
R=n-hexyl
R
O
OH
N
5f
CHO
Ph
N
Ph
N
Ph
OH
O
Ph
5g
g
N
Ph CHO
N
N
N
R=n-hexyl
R
Ph
O
N
h
15
75
CHO
Ph OH
5h
N
OBn
R=n-butyl
O
R
N
i
J
14
15
70
75
CHO
BnO
OH
Ph
N
5i
N
Ph
O
OH
N
N
N
CHO
5j
R
N
O
N
OH
OH
5k
R=n-pentyl
N
k
16
15
70
70
CHO
CHO
Ph
R
N
O
N
l
N
5l
R=n-pentyl
Ph
aThe products were characterized by IR, NMR, and mass spectroscopy.
bYield refers to pure products after chromatography.

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 6029–6031
6031
Chem., Int. Ed. 2002, 41, 2596–2599; (c) Tornøe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057–3064.
10. (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.
11. (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.
Cu(OTf)2
TMSN3
O
O
HO
Ph
+
Ph
OH
H
Cu(0)
R
O
O
Ph
Ph
N3
N
N
N
12. (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.
13. (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; (d) Wang, Q.; Chan, T. R.; Hilgraf, R.;
Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192–
3193.
14. (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 9, 3897–3899; (b)
Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Eycken, E. V. Org. Lett. 2004, 6, 4223–
4225; (c) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2004, 69, 2386–
2393; (d) Kacprzak, K. Synlett 2005, 943–946; (e) Yan, Z.-Y.; Zhao, Y.-B.; Fan,
M.-J.; Liu, W.-M.; Liang, Y.-M. Tetrahedron 2005, 61, 9331–9337; (f) Xie, F.;
Chittaboina, S.; Wang, Q. Tetrahedron Lett. 2005, 61, 2331–2336; (g) Zhao, Y.-B.;
Yan, Z.-Y.; Liang, Y.-M. Tetrahedron Lett. 2006, 47, 1545–1549; (h) Beckmann,
H. S. G.; Wittman, V. Org. Lett. 2007, 9, 1–4; (i) Aufort, M.; Herscovici, J.;
Bouhours, P.; Moreau, N.; Girard, C. Bioorg. Med. Chem. Lett. 2008, 18, 1195–
1198.
R
Scheme 2. A plausible reaction mechanism.
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 copper triflate and copper metal are essential
for the success of the reaction. The effect of various solvents such
as THF, 1,2-dimethoxyethane, and acetonitrile was studied in the
reaction of n-hexanal, benzyl alcohol, TMSN3, and phenylacetylene
under identical conditions. The corresponding product 5a was ob-
tained in 58%, 62%, and 75% yields, respectively. Thus, acetonitrile
was found to give the best results. However, this method failed to
produce the 1,2,3-triazoles from phenols and aromatic aldehydes.
The reaction was successful only with aliphatic aldehydes and
alcohols. The scope and generality of this process is illustrated in
Table 1.15 The reaction may proceed via acetal formation followed
by azidation and a subsequent [3+2] cycloaddition as depicted in
Scheme 2.
15. General procedure: To a mixture of n-hexanal (120 mg, 1.2 mmol), benzyl
alcohol (108 mg, 1 mmol), and copper(II) triflate (18 mg, 5 mol %) in
acetonitrile (5 mL) was added TMSN3 (0.26 mL, 2.0 mmol) at 0 °C under
nitrogen atmosphere and allowed to warm to room temperature. The reaction
mixture was stirred until the complete consumption of alcohol. Then
phenylacetylene (102 mg, 1 mmol) and Cu(0) powder (Aldrich-7440-50-8,
65 mg, 1 mmol) were added to the reaction mixture and stirred for the
specified time (Table 1). The reaction mixture was then filtered through Celite
and extracted with ethyl acetate (2 Â 10 mL). The combined organic layers
were dried over anhydrous Na2SO4. Removal of the solvent followed by
purification on silica gel (Merck, 100–200 mesh, ethyl acetate-hexane, 3:97)
gave the pure triazole, which was characterized by IR, NMR, and mass
spectroscopy. Spectral data for selected compounds. Compound 5a: 1-[1-
(Benzyloxy)hexyl]-4-phenyl-1H-1,2,3-triazole: Solid, mp 84–86 °C. IR (KBr):
mmax 3446, 2923, 2855, 1727, 1635, 1459, 1350, 1219, 1095, 1033, 762,
In summary, we have developed a novel approach for the prep-
aration of a-alkoxytriazoles via a four-component reaction of alde-
hyde, alcohol, azide, and alkyne. In addition to its simplicity and
mild reaction conditions, this method provides a wide range of
a
-alkoxytriazoles in good yields in a single-step operation.
Acknowledgment
G.M.R. thanks CSIR, New Delhi, for the award of a fellowship.
References and notes
695 cmÀ1 1H NMR (200 MHz, CDCl3): d 7.80–7.86 (m, 3H), 7.45–7.24 (m, 8H),
.
5.75 (t, J = 6.2 Hz, 1H), 4.41 (q, J = 19.5 Hz, 2H), 1.89–2.19 (m, 2H), 1.22–1.30
(m, 6H), 0.86 (t, J = 6.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 148.4, 136.2, 130.5,
128.8, 128.5, 128.2, 128.1, 125.7, 116.2, 89.1, 70.8, 35.9, 31.0, 24.2, 22.3, 13.9,
13.8. ESI-MS: m/z: 336 (M+H)+. HRMS calcd for C21H25N3ONa: 358.1895.
Found: 358.1913. Compound 5b: 1-(1-(Benzyloxy)propyl)4-hexyl-1H-1,2,3-
1. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123; (b) Terret, N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J.; Steel, J. Tetrahedron 1995, 51, 8135.
triazole: Liquid, IR (neat): mmax 3445, 2925, 2856, 1629, 1113 cmÀ1 1H NMR
.
2. Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley: Weinheim, 2005.
3. Doemling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169–3210.
4. Banfi, L.; Riva, R. Org. React. 2005, 65, 1–140.
5. Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–
3329.
(300 MHz, CDCl3): d 7.36 (s, 1H), 7.22–7.31 (m, 5H), 5.58–5.62 (m, 1H), 4.29–
4.39 (q, J = 18.1 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.85–2.14 (m, 4H), 1.27–1.67
(m, 6H), 0.89 (t, J = 7.5 Hz, 6H). 13C NMR (75 MHz, CDCl3): d 148.5, 141.2, 127.9,
127.2, 127.1, 114.5, 90.6, 72.7, 38.9, 36.1, 31.6, 31.4, 20.4, 19.0, 15.2, 14.2. ESI-
MS: m/z: 302 (M+H)+. HRMS calcd for C18H27N3ONa: 324.2052, Found:
324.2078. Compound 5c: 1-[1-(Allyloxy)-2-phenylethyl]-4-pentyl-1H-1,2,3-
6. (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.
7. (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.
8. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 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.
triazole: Liquid, IR (neat):
m
max 3446, 2930, 2858, 2362, 1717, 1646, 1500, 1457,
1372, 1246, 1218, 1035, 756, 700 cmÀ1
.
1H NMR (200 MHz, CDCl3): d 8.06 (s,
1H), 7.28–7.09 (m, 5H), 5.91–5.98 (m, 1H), 5.58–5.77 (m, 1H), 5.12–5.22 (m,
2H), 3.78–3.99 (m, 2H), 3.17–3.38 (m, 2H), 3.08 (t, J = 7.0 Hz, 2H), 1.68–1.88 (m,
2H), 1.23–1.45 (m, 4H), 1.03 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
148.0, 134.1, 132.1, 129.5, 128.5, 127.5, 123.0, 118.9, 89.9, 70.3, 42.4, 41.5, 30.9,
29.7, 17.4, 13.8. ESI-MS: m/z: 300 (M+H)+. HRMS calcd for C18H25N3ONa:
322.1895, Found: 322.1927. Compound 5k: 1-[1-(Adamantanyloxy)hexyl]-4-
(4-phenyl)-phenyl-1H-1,2,3-triazole: Semi-solid, IR (neat): mmax 3256, 2929,
2853, 1469, 1441, 1342, 1253, 1006, 944, 903, 760 cmÀ1 1H NMR (300 MHz,
.
CDCl3): d 7.87–8.07 (m, 5H), 7.37–7.51 (m, 5H), 5.65–5.70 (m, 1H), 4.00–4.09
(m, 1H), 1.04–1.69 (m, 22H), 0.77–0.83 (t, J = 6.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): d 157.4, 130.0, 129.5, 126.6, 125.7, 125.4, 90.4, 75.7, 69.3, 35.2, 32.4,
31.9, 31.4, 31.0, 30.9, 30.1, 29.7, 29.3, 24.5, 24.3, 24.2, 23.9, 23.8, 23.7, 23.6,
23.3, 23.2, 22.9, 22.8, 22.6, 21.0, 20.9, 14.2. ESI-MS: m/z: 456 (M+H)+. HRMS
calcd for C30H37N3ONa: 478.2834, Found: 478.2856.
9. (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.